CN101479263A

CN101479263A - Pharmaceutical compounds

Info

Publication number: CN101479263A
Application number: CNA2007800234642A
Authority: CN
Inventors: T·G·达维斯; M·D·加雷特; R·G·博伊尔; I·科林斯
Original assignee: Institute of Cancer Research; Cancer Research Technology Ltd; Astex Therapeutics Ltd
Current assignee: Institute of Cancer Research; Cancer Research Technology Ltd; Astex Therapeutics Ltd
Priority date: 2006-04-25
Filing date: 2007-04-25
Publication date: 2009-07-08
Also published as: GB0608175D0

Abstract

The invention provides a compound having the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR<5>; J<1>-J<2> is N=C(R<6>), (R<7>)C=N, (R<8>)N-C(O), (R<8>)2C-C(O), N=N or (R<7>)C=C(R<6>); A is an optionally substituted saturated C1-7 hydrocarbon linker group having a maximum chain length of 5 atoms extending between R<1> and NR<2>R<3> and a maximum chain length of 4 atoms extending between E and NR<2>R<3>, one of the carbon atoms in the linker group being optionally replaced by oxygen or nitrogen; E is a monocyclic or bicyclic carbocyclic or heterocyclic group or an acyclic group X-G wherein X is CH2, O, S or NH and G is a C1-4 alkylene chain wherein one of the carbon atoms is optionally replaced by O, S or NH; R<1> is hydrogen or an aryl or heteroaryl group; R<2> and R<3> are each hydrogen, optionally substituted C1-4 hydrocarbyl or optionally substituted C1-4 acyl; or NR<2>R<3> forms an imidazole group or a saturated monocyclic heterocyclic group having 4-7 ring members; or NR<2>R<3> and A together form a saturated monocyclic heterocyclic group having 4-7 ring members which is optionally substituted by C1-4 alkyl; or NR<2>R<3> and the adjacent carbon atom of linker group A together form a cyano group; or R<1>, A and NR<2>R<3> together form a cyano group; and R<4>, R<5>, R<6>, R<7> and R<8> are each independently selected from hydrogen and various substituents as defined in the claims, wherein the compound is for use in: (a) the treatment or prophylaxis of a disease or condition in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase p70S6K is indicated; and/or (b) the treatment of a subject or patient population in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase p70S6K is indicated.

Description

Medicinal compound

Technical field

The present invention relates to the following purposes of purine, purinone (purinone) and denitrification purine (deazapurine) and denitrification purinone (deazapurinone) compound: (a) treatment or prevention wherein need regulation and control (as suppressing) kinase whose disease of ROCK or illness; And/or (b) treatment wherein needs regulation and control (as suppress) kinase whose experimenter of ROCK or patient group; And/or (c) treatment or prevention wherein need disease or the illness of regulation and control (as suppress) protein kinase p70S6K; And/or (d) treatment wherein needs experimenter or the patient group of regulation and control (as suppress) protein kinase p70S6K.The invention still further relates to the described compound that is used for described purposes, relate to the various medicinal compositionss that comprise purine, purinone and denitrification purine and denitrification purinone compound.

Background of invention

Protein kinase

Protein kinase constitutes the extended familys (Hardie that is responsible for the structurally associated enzyme of multiple signal transduction process in the control cell, G. and Hanks, S. (1995) The Protein Kinases Facts Book.I and II, Academic Press, San Diego, CA).Substrate (as protein-tyrosine, albumen serine/threonine, lipid etc.) by their phosphorylations can be divided into kinases several families.Identified usually sequence die body corresponding to various these kinases families (as Hanks, S.K., Hunter, T., FASEB J., 9:576-596 (1995); Knighton etc., Science, 253:407-414 (1991); Hiles etc., Cell, 70:419-429 (1992); Kunz etc., Cell, 73:585-596 (1993); Garcia-Bustos etc., EMBO J., 13:2352-2361 (1994)).

Can it be characterized by the regulation mechanism of protein kinase.These mechanism for example comprise autophosphorylation, by other kinases change phosphorylation, protein-protein interaction, albumen-lipid interacts and albumen-polynucleotide interact.Each protein kinase can be regulated by more than one mechanism.

Kinases is regulated many different cell processes by phosphate is added in the target protein, include but not limited to propagation, differentiation, apoptosis, move, transcribe, translate and other signal process.These phosphorylation events serve as molecule ON/OFF adjustable or that regulate the target protein biological function.The target protein phosphorylation is stress wait the reaction of making to various kinds of cell external signal (hormone, neurotransmitter, growth and differentiation factor etc.), cell cycle events, environment or nutrition.Suitable protein kinase plays a role in signal pathway, and activation or deactivation (directly or indirectly) be metabolic enzyme, modulin, acceptor, cytoskeletal protein, ionic channel or pump or transcription factor for example.Relate to multiple disease by uncontrolled signal due to the protein phosphorylation control defective, comprised for example disease and the illness and the vasculogenesis of inflammation, cancer, transformation reactions/asthma, immune disease and illness, central nervous system.

Apoptosis or apoptosis are the important physiological processs of removing the cell that organism no longer needs.This process in early days embryo growth and grow in very important, allow the non-gangrenosum acne control of cellular component to decompose, remove and repair.The apoptosis scavenger cell is complete also very important for keeping grown cell group karyomit(e) and genome.Several known check points are arranged in cell growth cycle, carefully monitor dna damage and genomic integrity at this.To the unusual reaction in this type of check point discovery is the growth that stops this type of cell, starts repair process.If can not repair damage or unusual, then start apoptosis, to prevent the propagation of wrong and error by damaging cells.Cancer cells comprises mass mutation, mistake or rearrangement all the time in its chromosomal DNA.People generally believe that the partly cause of its generation is that most of tumours have defective in one or more processes of being responsible for the startup apoptotic process.Normal controlling mechanism can not kill cancer cell, karyomit(e) or dna encoding mistake continuation propagation.Therefore, recover these preceding apoptotic signals or suppress unadjusted survival signal be the treatment cancer attractive method.

The resistance that the signal transduction pathway of knowing enzymes such as comprising phosphatidyl-inositol 3-kinase (PI3K), PDK1 and PKB already can mediate apoptosis in many cells or survival reaction increases.There is mass data to show that this approach is the important survival approach that many somatomedins are used to suppress apoptosis in fact.The enzyme of PI3K family by producing phosphatidylinositols, starts the activation of (comprising kinases PDK1 and the activity that is also referred to as the protein kinase B (PKB) of akt) of downstream signal incident by multiple growth and survival factors such as EGF, PDGF activation.This also is like this in host tissue such as vascular endothelial cell and knurl.

Protein kinase p70S6K

70kDa ribosomal protein kinases p70S6K (being also referred to as SK6, p70/p85 S6 kinases, p70/p85 ribosome S 6 kinases and pp70s6k) is the member of protein kinase A GC subfamily.P70S6K is a serine-threonine kinase, is the component of phosphatidylinositols 3 kinases (PI3K)/AKT approach.P70S6K is the downstream of PI3K, responds multiple mitogen, hormone and somatomedin in a plurality of sites, activates by phosphorylation.This reaction can because rapamycin can suppress the p70S6K activity and blocks protein is synthetic, particularly be translated the result of downward modulation as these mRNA coding ribosomal proteins under the control of mTOR.P70S6K is also regulated by the target AKT in PI3K and downstream thereof.Wortmannin and rapamycin cause the p70S6K phosphorylation to reduce in the site that relies on the PI3K approach.The p70S6K of sudden change is suppressed by wortmannin but is not suppressed by rapamycin, and prompting PI3K approach can be independent of the active adjusting of mTOR, to p70S6K generation effect.

The p70S6K enzyme is synthetic by S6 ribosomal protein phosphorylation modulin.It is relevant that S6 phosphorylation and the mRNA translation of coding translating equipment component increase, and described component comprises ribosomal protein and translation elongation factor, its expression increase to the cell growth and propagation institute essential.These mRNA (are called 5 ' TOP) and comprise few pyrimidine track (tract), shown that the adjusting for their translation skills is essential at its 5 ' transcription initiation place.

Except relevant with translation, p70S6K activates and also relates to cell cycle control, neuronal cell differentiation, the adjusting of cell migration and the cell response very important to metastases, immune response and tissue repair.The antibody of anti-p70S6K is eliminated the rat fibroblast that mitogenic response drives and is entered the S phase, prompting p70S6K function be in the cell cycle G1 phase make progress to the S phase essential.And, determined rapamycin suppress cell cycle G1 to S during the phase cell cycle propagation be to suppress hyperphosphorylation, activate the result that the p70S6K of form produces.

The sub-LKB1 of tumor suppression activates AMPK, makes the TSC1/2 mixture phosphorylation in the mTOR/p70S6K approach, therefore enters p70S6K by PKB independence approach.The possibility that the LKB1 sudden change causes Peutz-Jeghers syndrome (PJS), PJS patient cancer to occur is 15 times of general population.In addition, 1/3 adenocarcinoma of lung is containing the LKB1 sudden change of passivation.

Participate in tumor tissue growth's factor acceptor signal transduction, overexpression and activation according to p70S6K, confirm that it is to tumor cell proliferation with prevent apoptotic effect.For example, Northern and Western analyze to disclose amplification PS6K gene and follow the corresponding increase of mRNA and protein expression (Cancer Res. (1999) 59:1408-11.Localization of PS6K toChromosomal Region 17q23 and Determination of Its Amplification inBreast Cancer (PS6K to the location of chromosomal region 17q23 and the mensuration that increases)) respectively in mammary cancer.

The breast tumor and 50% that contains the BRCA2 sudden change in 20% primary breast tumour, 87% at the most contains in the tumour and other cancer types such as carcinoma of the pancreas, bladder cancer and neuroblastoma of BRCA1 sudden change, karyomit(e) 17q23 amplification (is consulted M Barlund, O Monni, J Kononen, R Cornelison, J Torhorst, G Sauter, O-P Kallioniemi and Kallioniemi A, Cancer Res., 2000,60:5340-5346).Be presented in the mammary cancer 17q23 amplification and related to PAT1, RAD51C, PS6K and SIGMA1B gene (Cancer Res. (2000): 60,5371-5375 page or leaf).

Determined that the p70S6K gene is the target of this zone amplification and overexpression, has observed the significant correlation on the statistics between amplification and the prognosis mala.

The visible clinical inhibition of p70S6K activated in the patients with renal cell carcinoma of upstream kinases mTOR inhibitor C CI-779 (rapamycin esters) treatment.It is reported, have remarkable linear dependence between the active inhibition of progression of disease and p70S6K.

P70S6K relates to metabolic disease and disorder.It is reported that the shortage of p70S6 prevents the obesity that age and diet bring out, and improves insulin sensitivity simultaneously.These find to support p70S6K at metabolic disease and disorderly as the effect in obesity, diabetes, metabolism syndrome, insulin resistant, hyperglycemia, hyperaminoacidemia and the hyperlipidaemia.

The ROCK kinases

ROCK kinases family comprises two kinds of known member: ROCK1 and ROCK2:

ROCK1. synonym: Rho dependency protein kinase 1, p160 ROCK, P160 ROK, p160 ROCK-1, Rho dependency contain protein kinase 1, Rho kinases 1, the ROK β of coiled coil.

ROCK2. synonym: Rho dependency protein kinase 2, p164 ROCK, p164 ROK, p164 ROCK-2, Rho dependency contain protein kinase 2, Rho kinases 2, the ROK α of coiled coil.

Transfer process relates to cytoskeleton reconstruct and allows the cell-cell of cell detachment tumour body and cell-matrix to adhere to, and invades local organization, and finally diffuses to whole body everywhere.These pair cell morphology and adherent effect are regulated by the member of Rho GTPase family.

Activated RhoA can interact with several effect proteins that comprise ROCK kinases ROCK1 and ROCK2.ROCK1 and ROCK2 can associate by physics and be activated by the RhoA-GTP mixture.Activated ROCK makes multiple substrate phosphorylation, plays a significant role in the maincenter cell function.The substrate of ROCK comprises that the myosin of MLCP is in conjunction with subunit's (MBS is also referred to as MYPT1), adducin, moesin, myosin light chain (MLC), lim kinase and transcription factor FHL.The biologic activity of the phosphorylation regulation protein of these substrates provides the mode of cell to outside irritant reaction that change.

The raising that RhoA and RhoC and Rho effect protein ROCK1 and ROCK2 express is common in human cancer, comprises the tumour progression of the invasion and attack of testis germinoma progress, the little breast cancer with transfer ability, bladder cancer and transfer, ovarian cancer.

Tumor development is aggressive and transfer form, needs tumour cell that violent form takes place and changes, and this is the process of being regulated by Rho GTPases.It is the mechanism of cell to the motoricity of its environment generation that actomyosin shrinks.The downstream signal of little GTPase Rho increases shrinkability by the adjusting of myosin-II light chain (MLC2) phosphorylation of ROCK mediation.

The ROCK kinases is considered to participate in inducing focal adhesion and stress fiber, and the calcium sensitization of the phosphorylation mediation smooth muscle contraction of the adjusting light chain by strengthening myosin.

Research has shown that also ROCK suppresses to reduce the invasiveness of several tumor cell lines in the body.ROCK inhibitor such as Y-27632 or WF-536 have been used to confirm these characteristics in some researchs.

Proposed with the multiple disease of ROCK inhibitor for treating.These diseases comprise cardiovascular disorder such as hypertension, chronic heart failure, myocardial hypertrophy, restenosis, chronic renal failure and atherosclerosis.And because have flesh pine characteristic, inhibitor is also applicable to asthma, male erectile dysfunction, Female sexual dysfunction and I type bladder hyperactivity hyperkinesia syndrome.

Shown that the ROCK inhibitor has anti-inflammatory property.Therefore they can be used for treating neural inflammatory diseases such as apoplexy, multiple sclerosis, alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and inflammatory pain, and other inflammatory diseases such as rheumatoid arthritis, irritable bowel syndrome and inflammatory bowel.Induce the external effect of aixs cylinder based on them, the ROCK inhibitor can be the useful medicine of neuron regeneration, induces interior new axon growth of CNS and aixs cylinder to walk around injury region again.Therefore the ROCK inhibitor has the regenerative therapy that helps the CNS disease, described disease such as Spinal injury, acute neuronal damage (apoplexy, traumatic brain injury), Parkinson's disease, alzheimer's disease and other nerve degenerative diseases.Because the ROCK inhibitor reduces cell proliferation and cell migration, so they can be used for treating cancer and metastases.Finally, the cytoskeleton of pointing out the ROCK inhibitor to suppress due to the virus attack is on evidence reset, so they also have potential therapeutic value antiviral and that antibacterium is used.The ROCK inhibitor also helps to treat insulin resistant and diabetes.

ROCK inhibitor Y-27632

Tumour cell and host cell layer adhere to strides the maincenter step that cell migration is invasive cancer and transfer then.Little GTPase Rho is by the reorganization actin cytoskeleton and regulate the actomyosin shrinkability, control cell adhesion and migration.The rat MM1 liver cancer cell of cultivating moves in the mode of serum dependency, Rho mediation, by external mesothelial cell's individual layer.In several albumen that are separated into supposition Rho target molecule, the ROCK kinases is considered to participate in focal adhesion and the stress fiber in the inducing culture cell, and regulates the calcium sensitization of the phosphorylation mediation smooth muscle contraction of light chain by strengthening myosin.CDNA transfection MM1 cell with coding ROCK dominance active mutant provides the invasion and attack that do not rely on serum and Rho activity.On the contrary, the expression of the ROCK mutant of dominant, kinase deficiency obviously weakens the invasion and attack phenotype.

Concrete ROCK inhibitor (Y-27632) had both been blocked the actomyosin activation of Rho mediation, also blocked the invasion and attack activity of these cells.And, send this inhibitor continuously with osmotic pump and reduce the propagation of implanting the MM1 cell in the homology rat abdominal cavity largely.These results show that ROCK is the integral part of tumor cell invasion, confirm that it is as the potential that prevents the treatment target of invasive cancer and transfer.

VEGF induces the RhoA activation, and RhoA is raised to the cytolemma of people EC.The VEGF that the active this increase of RhoA is the F-actin cytoskeleton induces reorganization necessary, shown in the Adenovirus Transfection of dominant RhoA.This effect of the kinase mediated RhoA of Rho is shown in the purposes of concrete Rho kinase inhibitor Y-27632.The kinase whose inhibition of Rho prevents to respond the VEGF enhanced EC migration of mechanical trauma, but to the no effect of basic EC migration.And, in the external model of vasculogenesis, the inside growth of RhoA or Rho kinase whose inhibition weakening EC VEGF mediation in 3 dimension fibrin matrix.Conclusion: VEGF inductive cytoskeleton changes in EC needs RhoA and Rho kinases, the activation of RhoA/Rho kinase signal to relate to external EC migration of VEGF inductive and vasculogenesis.

But the Y-27632 relaxing smooth muscle increases vascular flow.Y-27632 is the small molecules that can enter cell, with 30mg/kg orally give rat nontoxicity after 10 days.The effective dose of using this compound is about 30, uM.Though it reduces the blood pressure of Hypertensive Rats, do not influence the blood pressure of normal rat.This has caused definite (Somlyo, the 1997 Nature 389:908s of Rho signal antagonist in hypertension therapeutic; Uehata etc., 1997 Nature 389:990).

Concrete ROCK inhibitor Y-27632 (Uehata etc., Nature, 389,990 994,1997, Davies etc., Biochemical Journal., 351,95-105,2000 and Ishizaki etc., Molecular Pharmacology., 57,976-983,2000) purposes, confirm this kind of enzyme in multiple tissue, not rely on Ca2+ and regulated the effect of contraction, described tissue comprises blood vessel (Uehata etc., Nature., 389,990-994,1997), air flue (IIikuka etc., EuropeanJournal of 30 Pharmacology., 406,273-279,2000) and reproductive tract (Chitaley etc., Nature Medicine., 7 (1), 119-122,2001) unstriated muscle.In addition, BritishJournal of Pharmacology. such as Jezior, 134,78-87,2001 have shown that Y-27632 weakens the contraction that bethanechol brings out in isolating rabbit uropoiesis 35 smooth muscle of bladder.

Rho kinase inhibitor Y-27632 has tested and has been used for following disease application:

Hypertension (Uehata etc., 1997 IBID; Chitaley etc., 2001a IBID; Chrissobolis and 15 Sobey, 2001 C.Circ.Res 88:774)

Asthma (Iizuka etc., 2000 Eur.J.Pharmacol 406:273; Eur.J.Pharmacol 389:103 such as Nakahara, 2000)

Lung vasoconstriction (Takamura etc., 2001 Hepatology 33:577)

Vascular disease (Miyata etc., 2000 Thromb Vase Biol 20:2351; Robertson etc., 2000 Br.J.Pharmacol 131:5)

Penile erectile function obstacle (Chitaley etc., 2001b Nature Medicine 7:119; Mills etc., 2001 J.Appl.Physiol.91:1269; Rees etc., Br.J.Pharmacol133:455 2001)

Glaucoma (Honjo etc., 2001 method Enzymol 42:137; Rao etc., 2001Invest.Opthalmol.Urs.Sci.42:1029)

Cell transformation (Sahai etc., 1999 Curr.Biol.9:136-5)

Prostate cancer shifts (Somlyo etc., 2000 BBRC 269:652)

Hepatocellular carcinoma and transfer (Imamura etc., 2000; Takamura etc., 2001)

Hepatic fibrosis (Tada etc., 2001 J.Hepatol 34:529; Wang etc., 2001 Am.J.Respir.Cell MoI Biol.25:628)

Renal fibrosis (Ohlci etc., J.Heart Lung Transplant 20:9562001)

Cardioprotective and allograft survival (Ohlci etc., 2001 IBID)

Cerebral vasospasm (Sato etc., 2000 Circ.Res 87:195).

ROCK kinases and cardiovascular disorder

More and more evidences show that ROCK (being close to the downstream targets of the little conjugated protein Rho of GTP (guanosine triphosphate)) can facilitate cardiovascular disorder.ROCK brings into play central role in various kinds of cell function such as smooth muscle contraction, stress fiber formation and cell migration and propagation.The overactivity of ROCK is found in cerebral ischemia, coronary vasospasm, hypertension, vascular inflammation, arteriosclerosis and atherosclerosis.Therefore, ROCK may be the important and relative therapeutic goal that utilizes not yet in the cardiovascular disorder.Recently experiment and the clinical study with ROCK inhibitor such as Y-27632 and fasudil discloses the keying action of ROCK in fetal development, inflammation and tumour generate.This summary will concentrate on the latent effect of ROCK in cell function, and the prospect of ROCK inhibitor as the cardiovascular disorder new therapy is discussed.

Unusual smooth muscle contraction may be the major cause of diseases, such as hypertension, and the smooth muscle relaxant of regulating and control this process will help treatment.Smooth muscle contraction is regulated by the Ca2+ susceptibility of cytosol Ca2+ concentration and myofilament: the former activates myosin light chain kinase, and latter's part is obtained by the inhibition of myosin Phosphoric acid esterase.

In the illness hypertension relevant with multiple vascular disease (comprising restenosis damage and atherosclerosis), the Rho signal pathway in the vascular smooth muscle cell is highly activated.

Hypertension is to reinvent the cardiovascular disorder that increases to feature with peripheral vascular resistance and/or blood vessel structure.Recently, from the evidence prompting of the quick growth of hypertension animal model, the sub-Rho-kinases of little GTPaseRho and downstream effect thereof plays a significant role in hypertension incidence mechanism.The activation of Rho/Rho-kinase pathways is that smooth muscle contraction is necessary in the hypertension.RhoA express to increase and the RhoA increased activity, sees the hypertension of the Aorta (as the heredity spontaneous hypertensive rat) of Hypertensive Rats and N (ω)-nitro-L-arginine methyl esters-bring out.

ROCK kinases and nervous system disease

The abnormal activation of Rho/ROCK approach sees the various illnesss of central nervous system.Damage to grow up vertebrates brain and spinal cord activates ROCK, thereby suppresses axon growth and budding.Suppress ROCK and can promote regeneration, the function reparation after the enhancing Mammals Spinal injury, also proof inhibition Rho/ROCK approach is effective to the animal model of apoplexy, inflammation and demyelination, alzheimer's disease and neuropathic pain.Therefore the ROCK inhibitor has and prevents nerve degenerative diseases and at the potential of various sacred disease moderate stimulation neurotization.

Neuronic growth needs series of steps, from by its birth migration and start external process and begin, finally causes breaking up and forms allowing itself and the connecting of suitable target communication.In the past few years, known that the Rho family of GTPase and associated molecule all play a significant role in all respects of neuronal development, comprised that aixs cylinder is external and differentiation, axon are sought the footpath and dendritic spine forms and keeps.

The common ground that external inhibition of aixs cylinder and aixs cylinder are repelled is that Actin muscle is reset in the growing tip.The center that actin cytoskeleton is regulated in neurone and non-neuronal cell is the Rho family of little GTPase.The Rho family member is circulated between the GDP of non-activity combining form and active GTP combining form.Several respects evidence all points out the adjustable growing tip of active condition of control Rho GTPase to decay and the external inhibition of aixs cylinder.

Recently, in the performance, the deactivation of Rho approach can be induced the quick reparation of action and the carrying out property recovery that forelimb-hind leg is coordinated.The evidence that these discoveries provide, Rho signal pathway are the potential targets that treatment is intervened after the Spinal injury.

WO 93/13072 (Italfarmaco) discloses the two-sulfonyl ammonia diamines of a class as kinases inhibitor.

Openly purine has multiple different biologic activity with purine analogue and derivative.

For example, WO03/057696 (Eisai) discloses indyl-denitrification purine that a class is used for the treatment of inflammatory or autoimmunization or proliferative disease.

WO 99/65909 (Pfizer) discloses pyrroles [2, the 3-d] pyrimidine compound of a class as protein tyrosine kinase such as Janus kinases 3 inhibitor.Describe this compound and have multiple therepic use.

Czech.Chem.Comm. such as Semonsky (1960), 25, the open 6-carboxyl alkylthio purine derivative of 1091-1099 as carcinostatic agent.

Noell etc., J.Org.Chem., (1958), 23, open 4-(amino of replacement) pyrazoles [3, the 4-d] pyrimidine of 1547-1550 as the potential antineoplastic agent.

Lettre etc., Naturwissenschaften (1958), 45,364 openly have the active several aminoalkyl group-amino purine derivatives of antitumor cell.

US 2003/0139427 (OSI) openly has Adenosine Receptors in conjunction with active tetramethyleneimine-and the purine and the purine analogue of piperidines-replacement.

WO 2004/043380 (Harvard College etc.) openly contains the technetium of disubstituted piperidine metal ion-chelant aglucon and the preparation of rhenium mark.

WO 97/38665 (Merck) openly has farnesyl transferase and suppresses active together with-disubstituted piperidine derivatives.

EP 1568699 (Eisai) openly has DPPIV and suppresses active 1,3-glyoxalidine fused ring compound.Described compound is described to have and comprises the multiple potential use for the treatment of cancer.

US 2003/0073708 and US 2003/045536 (be Castelhano etc. patent), WO 02/057267 (OSI Pharmaceuticals) and WO 99/62518 (CadusPharmaceutical Corporation) disclose the amino denitrification purine of a class 4-separately, and wherein 4-amino can form the part of cyclammonium such as azetidine, tetramethyleneimine and piperidines.Described compound is described to have the Adenosine Receptors antagonistic activity.

US 6162804 (Merck) discloses benzoglyoxaline and the imidazopyridine of a class as tyrosine kinase inhibitor.

The invention summary

The present invention's (to small part) has the multiple new medical usage of the compound of this paper limitation type (I) based on discovery.

Specifically, the inventor now discoverable type (I) compound have following purposes: (a) treatment or prevention wherein need disease or the illness of regulation and control (as suppress) ROCK kinases or protein kinase p70S6K; And/or (b) treatment wherein needs experimenter or the patient group of regulation and control (as suppress) ROCK kinases or protein kinase p70S6K.

Therefore, first aspect the invention provides formula (I) compound:

Or its salt, solvate, tautomer or N-oxide compound, wherein

T is N or group CR ⁵

J ¹-J ²Representative is selected from N=C (R ⁶), (R ⁷) C=N, (R ⁸) N-C (O), (R ⁸) ₂C-C (O), N=N and (R ⁷) C=C (R ⁶) group;

A is the stable hydrocarbon linking group that comprises 1-7 carbon atom, and described linking group is at R ¹With NR ²R ³Between have the maximum chain length of 5 atoms, at E and NR ²R ³Between have the maximum chain length of 4 atoms, wherein a carbon atom in the linking group can be by oxygen or the optional displacement of nitrogen-atoms; Wherein the carbon atom of linking group A can be chosen wantonly and carry one or more substituting groups that are selected from oxo, fluorine and hydroxyl, and prerequisite is when having hydroxyl, and hydroxyl is not positioned at respect to NR ²R ³On the alpha-carbon atom of group, and prerequisite is when having the oxo base, and the oxo base is positioned at respect to NR ²R ³On the alpha-carbon atom of group;

E is monocycle or bicyclic carbocyclic or heterocyclic radical or acyclic radicals X-G, and wherein X is selected from CH ₂, O, S and NH, G is C _1-4Alkylidene chain, one of them carbon atom is by O, S or the optional displacement of NH;

R ¹Be hydrogen or aryl or heteroaryl;

R ²And R ³Independently be selected from hydrogen, C _1-4Alkyl and C _1-4Acyl group, wherein alkyl and acyl group are by one or more optional replacements of substituting group that are selected from fluorine, hydroxyl, amino, methylamino-, dimethylamino, methoxyl group and monocycle or bicyclic aryl or heteroaryl;

Perhaps R ²And R ³The nitrogen-atoms that connects with them forms cyclic group, and described cyclic group is selected from imidazolyl and has 4-7 ring members and the optional saturated monocycle heterocyclic radical that comprises second the heteroatomic ring member who is selected from O and N;

Perhaps R ²And R ³The nitrogen-atoms that one of them connects with their and one or more atom from linking group A form saturated monocycle heterocyclic radical, described monocyclic heterocycles base has 4-7 ring members and optional comprises second the heteroatomic ring member who is selected from O and N, and the monocyclic heterocycles base is by one or more C _1-4Alkyl is optional to be replaced;

Perhaps NR ²R ³The carbon atom of the linking group A that connects with its forms cyano group; Perhaps

R ¹, A and NR ²R ³Form cyano group together; With

R ⁴, R ⁵, R ⁶, R ⁷And R ⁸Independently be selected from hydrogen separately; Halogen; By halogen, hydroxyl or C _1-2The optional C that replaces of alkoxyl group _1-6Alkyl; Cyano group; CONH ₂CONHR ⁹CF ₃NH ₂NHCOR ⁹And NHCONHR ⁹

R ⁹Be separately by one or more halogen, hydroxyl, trifluoromethyl, cyano group, nitro, carboxyl, amino, list-or two-C that are selected from _1-4Optional phenyl or the benzyl that replaces of the substituting group of alkyl amino; Radicals R ^a-R ^b, R wherein ^aBe key, O, CO, X ¹C (X ²), C (X ²) X ¹, X ¹C (X ²) X ¹, S, SO, SO ₂, NR ^c, SO ₂NR ^cOr NR ^cSO ₂R ^bBe selected from hydrogen, have the heterocyclic radical of 3-12 ring members and by one or more hydroxyl, oxo, halogen, cyano group, nitro, carboxyl, amino, list-or two-C that are selected from _1-4The optional C that replaces of the substituting group of alkyl amino, carbocyclic ring and heterocyclic radical with 3-12 ring members _1-8Alkyl, wherein C _1-8One or more carbon atoms of alkyl can be by O, S, SO, SO ₂, NR ^c, X ¹C (X ²), C (X ²) X ¹Or X ¹C (X ²) X ¹Optional displacement;

R ^cBe selected from hydrogen and C _1-4Alkyl; With

X ¹Be O, S or NR ^cAnd X ²Be=O ,=S or=NR ^c

Wherein said compound is used for: (a) treatment or prevention wherein need disease or the illness of regulation and control (as suppressing) ROCK kinases or protein kinase p70S6K; And/or (b) treatment wherein needs experimenter or the patient group of regulation and control (as suppress) ROCK kinases or protein kinase p70S6K.

On the other hand, the invention provides formula (Ia) compound:

Or its salt, solvate, tautomer or N-oxide compound, wherein

T is N or group CR ⁵

R ¹Be hydrogen or aryl or heteroaryl;

R ²And R ³Independently be selected from hydrogen, C _1-4Alkyl and C _1-4Acyl group;

Perhaps R ²And R ³The nitrogen-atoms that connects with their forms to have 4-7 ring members and chooses the saturated monocycle heterocyclic radical that comprises second the heteroatomic ring member who is selected from O and N wantonly, and described monocyclic heterocycles base is by one or more C _1-4Alkyl is optional to be replaced;

R ¹, A and NR ²R ³Form cyano group together; With

R ^cBe selected from hydrogen and C _1-4Alkyl; With

X ¹Be O, S or NR ^cAnd X ²Be=O ,=S or=NR ^c

Aspect another, the invention provides formula (Ib) compound:

Or its salt, solvate, tautomer or N-oxide compound, wherein

T is N or group CR ⁵

R ¹Be hydrogen or aryl or heteroaryl;

R ¹, A and NR ²R ³Form cyano group together; With

R ^cBe selected from hydrogen and C _1-4Alkyl; With

X ¹Be O, S or NR ^cAnd X ²Be=O ,=S or=NR ^c, prerequisite is:

(a-i) work as J ¹-J ²Be (R ⁷) C=C (R ⁶) and E when being the monocycle that is connected with the ring that contains T by nitrogen-atoms or bicyclic group, then A does not comprise the oxo substituting group;

(a-ii) E is not an indyl unsubstituted or that replace;

(a-iii) work as J ¹-J ²When being N=CH, E-A (R then ¹)-NR ²R ³Not group-S-(CH ₂) ₃-CONH ₂Or-S-(CH ₂) ₃-CN;

(a-iv) work as J ¹-J ²When being CH=N, E-A (R then ¹)-NR ²R ³It or not group

-NH-(CH ₂) _n-N (CH ₂CH ₃) ₂, wherein n is 2 or 3; With

(a-v) work as J ¹-J ²When being N=CH, E-A (R then ¹)-NR ²R ³Not group-NH-(CH ₂) ₂-NH ₂Or-NH-(CH ₂) ₂-N (CH ₃) ₂

On the other hand, the invention provides formula (Ic) compound:

Or its salt, solvate, tautomer or N-oxide compound, wherein

T is N or group CR ⁵

A is the stable hydrocarbon linking group that comprises 1-7 carbon atom, and described linking group is at R ¹With NR ²R ³Between have the maximum chain length of 5 atoms, at E and NR ²R ³Between have the maximum chain length of 4 atoms, wherein a carbon atom in the linking group can be by oxygen or the optional displacement of nitrogen-atoms; Wherein the carbon atom of linking group A can be chosen wantonly and carry one or more substituting groups that are selected from fluorine and hydroxyl, and prerequisite is when having hydroxyl, and hydroxyl is not positioned at respect to NR ²R ³On the alpha-carbon atom of group;

E is monocycle carbocyclic ring or heterocyclic radical;

R ¹Be aryl or heteroaryl;

Perhaps R ²And R ³The nitrogen-atoms that connects with their forms to have 4-7 ring members and chooses the saturated monocycle heterocyclic radical that comprises second the heteroatomic ring member who is selected from O and N wantonly;

R ¹, A and NR ²R ³Form cyano group together; With

R ^cBe selected from hydrogen and C _1-4Alkyl; With

X ¹Be O, S or NR ^cAnd X ²Be=O ,=S or=NR ^c

Another aspect the invention provides:

Formula (I) compound itself that this paper limits, wherein said compound is used for: (a) treatment or prevention wherein need disease or the illness of regulation and control (as suppressing) ROCK kinases or protein kinase p70S6K; And/or (b) treatment wherein needs experimenter or the patient group of regulation and control (as suppress) ROCK kinases or protein kinase p70S6K.

Formula (I) compound that this paper limits, wherein said compound is used for: (a) treatment or prevention wherein need disease or the illness of regulation and control (as suppressing) ROCK kinases or protein kinase p70S6K; And/or (b) treatment wherein needs experimenter or the patient group of regulation and control (as suppress) ROCK kinases or protein kinase p70S6K.

The purposes of formula (I) compound that this paper limits in the preparation medicine, described medicine is used for: (a) treatment or prevention wherein need disease or the illness of regulation and control (as suppressing) ROCK kinases or protein kinase p70S6K; And/or (b) treatment wherein needs experimenter or the patient group of regulation and control (as suppress) ROCK kinases or protein kinase p70S6K.

Prevention or treatment are by ROCK kinases or the disease of protein kinase p70S6K mediation or the method for illness, and described method comprises formula (I) compound that has the experimenter of needs this paper to limit.

Treatment comprises or is derived from abnormal cell growth in the Mammals or the disease of the necrocytosis that abends or the method for illness, and described method comprises and gives formula (I) compound that this paper that Mammals suppresses ROCK kinases or the active significant quantity of protein kinase p70S6K limits.

The method that suppresses ROCK kinases or protein kinase p70S6K, described method comprise makes kinases contact with formula (I) compound that suppresses kinase whose this paper qualification.

The method of regulating cell process (as cell fission), formula (I) compound that described method limits with this paper suppresses the activity of ROCK kinases or protein kinase p70S6K.

Formula (I) compound that this paper limits, described compound are used to prevent or treat disease or the illness that is mediated by ROCK kinases or protein kinase p70S6K.

The purposes of formula (I) compound that this paper limits in the preparation medicine, described medicine are used to prevent or treat disease or the illness that is mediated by ROCK kinases or protein kinase p70S6K.

The purposes of formula (I) compound that this paper limits in the preparation medicine, described medicine are used to prevent or treat disease or the illness that is derived from abnormal cell growth that is mediated by ROCK kinases or protein kinase p70S6K or the necrocytosis that abends.

Alleviate or reduce the method for disease or illness sickness rate, described disease or illness comprise or are derived from abnormal cell growth that is mediated by ROCK kinases or protein kinase p70S6K in the Mammals or the necrocytosis that abends that described method comprises formula (I) compound of this paper qualification that gives Mammals inhibition abnormal cell growth significant quantity.

The purposes of formula (I) compound that this paper limits in the preparation medicine, described medicine is used for prevention or treats any disease disclosed herein or illness.

Treatment or prevent the method for any disease disclosed herein or illness, described method comprise and give patient (patient if needed) (as the treatment significant quantity) formula (I) compound that this paper limits.

Alleviate or reduce the method for disease disclosed herein or illness sickness rate, described method comprises and gives patient (patient if needed) (as the treatment significant quantity) formula (I) compound that this paper limits.

Diagnosis and treatment are by ROCK kinases or the disease of protein kinase p70S6K mediation or the method for illness, described method comprises (i) screening patient, whether will have the treatment sensitivity of anti-ROCK kinases or the active compound of protein kinase p70S6K to using to determine disease or illness that this patient is suffered from maybe may be suffered from; Be responsive (ii), give formula (I) compound that patient this paper limits then when pointing out this disease of patient or illness.

The purposes of formula (I) compound that this paper limits in the preparation medicine, described medicine is used for the treatment of or prevents through screening and be confirmed as ill or the disease of patient or the illness of ill danger are arranged, and described disease or illness will be to having the treatment sensitivity of anti-ROCK kinases or the active compound of protein kinase p70S6K.

Generalized reference and definition

When being used for this paper, term " ROCK kinases " and " ROCK " are the synonym general names, comprise all members of ROCK kinases family, so ROCK1 and ROCK2 are included in this kind.Mention the ROCK kinase inhibitor especially, when ROCK kinase regulatory and ROCK kinase activity, also should make corresponding explanation.

Term " Rho albumen " is to be used to limit the technical term that the Actin muscle tissue is regulated the gtp binding protein extended familys that relate to, and comprises RhoA and RhoC.

When being used for this paper, term " Rho signal pathway " is defined as any cell signal approach that wherein relates to one or more members of Rho albumen.Special relevant with the present invention is that wherein ROCK kinases (as ROCK1 and/or ROCK2) is the Rho signal pathway of the proteic near-end effector of one or more Rho (proximate effector) (as binding partners), preferred this type of Rho signal pathway of the Rho signal pathway of mentioning especially in the embodiment that the present invention limits.

When being used for this paper, when term " regulation and control " is used for ROCK kinases described herein or protein kinase p70S6K, be intended to be defined as the change of kinases level of biological activity.Therefore, regulation and control comprise that the physiology that causes kinase activity to increase or descend changes.Under latter event, regulation and control can be described as " inhibition ".Regulation and control can directly or indirectly take place, can mediate in any physiology level by any mechanism, for example comprise at gene expression dose (for example comprise transcribe, translation and/or posttranslational modification), directly or indirectly act on the expression of gene level of the regulatory element of kinase activity level at coding, perhaps in the active level of enzyme (as ROCK or p70S6K) (as by allosterism, competitive inhibition, avtive spot deactivation, interference feedback inhibition approach etc.).Therefore, regulation and control can refer to the expression or the overexpression of kinases raising/inhibition or express not enough (comprising that the expression that gene amplification (being the polygene duplicate) and/or Transcription cause increases or decline), and cause kinases (comprising activation (deactivation)) hyperactivity (or low excessively) and activate (deactivation) by sudden change.Explain term " regulation and control " and " regulation and control " thus.

When being used for this paper, when term " mediation " uses (for example being applied to various physiological processes, disease, state, illness, therapy, treatment or intervention) in conjunction with kinases described herein (being ROCK and protein kinase p70S6K), be intended to restrictively use, so that described kinases is brought into play biological action in various processes, disease, state, illness, treatment and the intervention of using this term.Be used at this term under the situation of disease, state or illness, the effect of kinases performance can be direct or indirect, can be disease, state or condition symptoms performance (or its nosetiology or progress) institute must and/or enough.Therefore, kinase activity (particularly the kinase activity of abnormal level, as the kinases overexpression) immediate cause of disease, state or illness not necessarily; And disease, state or the illness of ROCK or protein kinase p70S6K mediation comprise that wherein only part relates to kinase whose disease, state or illness with Different types of etiopathogenises and complicated progress.Be used for the treatment of, prevent or intervene at this term under the situation of (as in the present invention's " treatment of ROCK mediation ", " prevention of ROCK mediation " " treatment of protein kinase p70S6K mediation " and " prevention of p70S6K mediation "), the effect of kinases performance can be direct or indirect, can be that therapeutic action, prevention or intervention result are essential and/or enough.Physiological processes, disease, state, illness, therapy, treatment or the intervention of the many ROCK mediations of the present invention relates to Rho signal pathway (limiting as this paper), therefore, can amplify is " Rho mediates " physiological processes, disease, state, illness, therapy, treatment or intervention.

It is the technical term relevant with disease, illness, experimenter or patient group used herein that term " needs ... treat or prevent ", represents the clinical needs or the necessity of the special intervention relevant with described disease, illness, experimenter or patient group.Therefore, this paper mentions disease, illness, experimenter or patient's group time of " wherein needing regulation and control (as suppressing) ROCK kinases or protein kinase p70S6K ", is intended to be defined as those diseases of maybe necessary regulation and control ROCK kinases of wherein clinical needs or protein kinase p70S6K etc.This may be this situation, for example, wherein regulate and control ROCK kinases or protein kinase p70S6K and will be appeasing property, preventative or (to small part) curative.

Term " intervention " is that this paper is used to be limited to the technical term that any level causes any processing of physiology change.Therefore, intervention can comprise and induces or check any physiological processes, incident, bio-chemical pathway or cell/biological chemistry incident.Intervention of the present invention influences (or facilitating) disease or treatment of conditions, processing or prevention usually.

When also not using, following any one or multinomial optional prerequisite can be applied to any or multiple of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (III) or any subclass or its embodiment that this paper limits in any combination way, are used for above any one or the many aspects of the present invention listed with other place of this paper.

(a-i) work as J ¹-J ²Be (R ⁷) C=C (R ⁶) and E when being the monocycle that is connected with the ring that contains T by nitrogen-atoms or bicyclic group, then A does not comprise the oxo substituting group.

(a-ii) E is not an indyl unsubstituted or that replace.

(a-iii) work as J ¹-J ²When being N=CH, E-A (R then ¹)-NR ²R ³Not group-S-(CH ₂) ₃-CONH ₂Or-S-(CH ₂) ₃-CN.

(a-iv) work as J ¹-J ²When being CH=N, E-A (R then ¹)-NR ²R ³Not group-NH-(CH ₂) _n-N (CH ₂CH ₃) ₂, wherein n is 2 or 3.

(b-i) E is not an indyl unsubstituted or that replace, and wherein A is connected with the phenyl ring of indyl.

(b-ii) when E be monocycle or the bicyclic group that is connected with the ring that contains T by nitrogen-atoms, and R ²And R ³When one of them nitrogen-atoms that connects with their and one or more atoms from A form the optional saturated monocycle heterocyclic radical that comprises second heteroatomic ring member, J then ¹-J ²Not (R ⁷) C=C (R ⁶).

(b-iii) part E-A (R ¹)-NR ²R ³Not aminoalkyl group amino or alkylamino alkylamino.

(b-iv) work as R ¹When being hydrogen, E is not non-cyclic group X-G.

(b-v) when E is piperidines or tetramethyleneimine, part A (R ¹)-NR ²R ³Not pyrrolidyl ethyl or pyrrolidyl methyl.

Unless context is indicated in addition, otherwise following generalized reference and definition should be applicable to each several part A, E, J ¹, J ², T and R ¹-R ⁹With any inferior definition, subclass or its embodiment.

Unless the other requirement of context, otherwise this paper also is used for any other subclass of formula (Ia), (Ib), (Ic), (II), (IIa), (IIb), (III) and formula (I) compound or its embodiment about any reference of formula (I).

In this manual, unless context indicate in addition, otherwise refer to group about group E tie point used " bicyclic group ":

Unless context is indicated in addition, otherwise " carbocyclic ring " mentioned in this article and " heterocycle " group should comprise aromatics and non-aromatics loop systems.Generally speaking, this type of group can be monocycle or dicyclo, can comprise for example 3-12 ring members, is more typically 5-10 ring members.The example of monocycle base is the group that comprises 3,4,5,6,7 and 8 ring memberses, more generally is the group of 3-7, preferred 5 or 6 ring memberses.The example of bicyclic group is the group that comprises 8,9,10,11 and 12 ring memberses, more generally is the group of 9 or 10 ring memberses.

Carbocyclic ring or heterocyclic radical can be have 5-12 ring members, be the aryl or the heteroaryl of 5-10 ring members more generally.Term " aryl " is used for the carbocylic radical that this paper refers to have aromatic character, and term " heteroaryl " is used for the heterocyclic radical that this paper refers to have aromatic character.Term " aryl " and " heteroaryl " comprise that wherein one or more rings are many rings (as dicyclo) loop systems of non-aromatic ring, and prerequisite is that at least one ring is an aromatic ring.In this type of multi-loop system, group can connect aromatic ring or non-aromatic ring.Aryl or heteroaryl can be monocycle or bicyclic group, the one or more radicals R that can not be substituted or limited by one or more substituting groups example this paper ¹⁰Replace.

The non-aromatic group of term comprises unsaturated loop systems, fractional saturation and the complete saturated carbocyclic ring and the heteroaryl ring system of no aromatic character.Term " undersaturated " and " fractional saturation " refer to that ring structure wherein comprises the ring of the atom of sharing an above valence link, and promptly this ring comprises at least one Multiple Bonds such as C=C, C ≡ C or N=C key.Term " fully saturated " refers to wherein not have between the annular atoms ring of Multiple Bonds.The saturated carbon cyclic group comprises the cycloalkyl of following qualification.The carbocylic radical of fractional saturation comprises the cycloalkenyl group of following qualification, as cyclopentenyl, cycloheptenyl and cyclooctene base.

The example of heteroaryl be comprise 5-12 ring members, be the monocycle and the bicyclic group of 5-10 ring members more generally.Heteroaryl can be for example 5 yuan or 6 yuan of monocycles or the twin nuclei that formed by condensed 5 and 6 yuan of rings or 6 yuan of rings of 2 condensed.Each ring can comprise about at the most 4 heteroatomss that are selected from nitrogen, sulphur and oxygen usually.Usually hetero-aromatic ring will comprise at the most 3 heteroatomss, 2 for example single heteroatomss at the most more generally.In one embodiment, hetero-aromatic ring comprises at least one theheterocyclic nitrogen atom.Nitrogen-atoms in the hetero-aromatic ring can be for alkalescence as under the situation of imidazoles or pyridine, and perhaps non-substantially alkalescence is as under the situation of indoles or pyrroles's nitrogen.The basic nitrogen atom number that is present in general in the heteroaryl (comprising any amino substituting group in the ring) will be less than 5.

The example of 5 yuan of heteroaryls includes but not limited to pyrroles, furans, thiophene, imidazoles, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazoles, triazole and tetrazol group.

The example of 6 yuan of heteroaryls includes but not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.Bicyclic heteroaryl can be for example to be selected from following group:

A) with 5-that comprises 1,2 or 3 ring hetero atom or 6-unit ring condensed phenyl ring;

B) with 5-that comprises 1,2 or 3 ring hetero atom or 6-unit ring condensed pyridine ring;

C) with 5-that comprises 1 or 2 ring hetero atom or 6-unit ring condensed pyrimidine ring;

D) with 5-that comprises 1,2 or 3 ring hetero atom or 6-unit ring condensed pyrrole ring;

E) with 5-that comprises 1 or 2 ring hetero atom or 6-unit ring condensed pyrazoles ring;

F) with 5-that comprises 1 or 2 ring hetero atom or 6-unit ring condensed pyrazine ring;

G) with 5-that comprises 1 or 2 ring hetero atom or 6-unit ring condensed imidazole ring;

H) condense De oxazole ring with 5-that comprises 1 or 2 ring hetero atom or 6-unit ring;

I) with 5-that comprises 1 or 2 ring hetero atom or 6-unit ring condensed isoxazole ring;

J) with 5-that comprises 1 or 2 ring hetero atom or 6-unit ring condensed thiazole ring;

K) with 5-that comprises 1 or 2 ring hetero atom or 6-unit ring condensed isothiazole ring;

L) with 5-that comprises 1,2 or 3 ring hetero atom or 6-unit ring condensed thiphene ring;

M) with 5-that comprises 1,2 or 3 ring hetero atom or 6-unit ring condensed furan nucleus;

N) with 5-that comprises 1,2 or 3 ring hetero atom or 6-unit ring condensed cyclohexyl ring; With

O) with 5-that comprises 1,2 or 3 ring hetero atom or 6-unit ring condensed cyclopentyl ring.

The specific examples of bicyclic heteroaryl comprises and 6 yuan of rings of 5 yuan of ring condensed, includes but not limited to cumarone, thionaphthene, benzoglyoxaline, benzoxazole, benzoisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indoles, isoindole, indolizine, indoline, isoindoline, purine (as VITAMIN B4, guanine), indazole, benzodioxole and Pyrazolopyridine base.

The specific examples of bicyclic heteroaryl comprises 6 yuan of rings of 2 condensed, includes but not limited to quinoline, isoquinoline 99.9, chroman, sulphur chroman (thiochroman), chromene, heterochromatic alkene, chroman, heterochromatic full, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnolines, phthalazines, naphthyridines and pteridyl.

The example of polyaromatic and heteroaryl comprises aromatic ring and non-aromatic ring, comprise naphthane, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzo thiophene, Dihydrobenzofuranes, 2,3-dihydro-benzo [1,4] dioxin, benzo [1,3] dioxole, 4,5,6,7-tetrahydrochysene benzfuran, indoline and indanyl.

The example of isocyclic aryl comprises phenyl, naphthyl, indenyl and tetralyl.

The example of non-aromatic heterocycle comprises and not being substituted or (by one or more radicals R ¹⁰) heterocyclic radical that replaces, have 3-12 ring members, common 4-12 ring members, more generally be 5-10 ring members.This type of group can be monocycle or dicyclo, for example has 1-5 the heteroatomic ring member (more generally being 1,2,3 or 4 heteroatomic ring member) who is selected from nitrogen, oxygen and sulphur usually usually.

When sulphur exists, under the situation of adjacent atom and group property permission, as-S-,-S (O)-or-S (O) ₂-exist.

Heterocyclic radical for example can comprise cyclic ethers part (as in tetrahydrofuran (THF) and diox), epithio ether moiety (as in tetramethylene sulfide and dithiane), cyclammonium part (as in tetramethyleneimine), cyclic amide part (as in pyrrolidone), ring urea part (as at imidazolidin-2-one), epithio urea part, epithio for acid amides, ring monothioester, cyclic ester part (as in butyrolactone), ring sulfone (as in tetramethylene sulfone and cyclobufene sultone), ring sulfoxide, cyclic sulfonamides and combination (as morpholine and thiomorpholine and S-oxide compound and S, S-dioxide) thereof.

The example of monocycle non-aromatic heterocycle comprises 5-, 6-and 7-unit monocyclic heterocycles base.Specific examples comprises morpholine, thiomorpholine and S-oxide compound and S, S-dioxide (particularly thiomorpholine), piperidines is (as piperidino, the 2-piperidyl, 3-piperidyl and 4-piperidyl), N-Alkylpiperidine such as N-methyl piperidine, piperidone, tetramethyleneimine is (as the 1-pyrrolidyl, 2-pyrrolidyl and 3-pyrrolidyl), pyrrolidone, azetidine, pyrans (2H-pyrans or 4H-pyrans), dihydro-thiophene, dihydropyrane, dihydrofuran, thiazoline, tetrahydrofuran (THF), tetramethylene sulfide diox, tetrahydropyrans (as the 4-THP trtrahydropyranyl), tetrahydroglyoxaline, imidazolidone oxazoline, thiazoline, the 2-pyrazoline, pyrazolidine, piperazine ketone, piperazine and N-alkylpiperazine such as N methyl piperazine, N-ethyl piperazidine and N-sec.-propyl piperazine.In general, preferred non-aromatic heterocycle comprises piperidines, tetramethyleneimine, azetidine, morpholine, piperazine and N-alkylpiperazine.

The example of non-aromatic carbocyclyl groups comprises loop chain alkyl (as cyclohexyl and cyclopentyl), cycloalkenyl group (as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctene base), and cyclohexadienyl, cyclooctatetraene base, naphthane methyne and decahydro naphthyl.

Preferred non-aromatic carbocyclyl groups is a monocycle, most preferably saturated monocycle.

Representative instance is 3,4,5 and 6 yuan of saturated carbon rings, as optional cyclopentyl and the cyclohexyl ring that replaces.

A kind of subclass of non-aromatic carbocyclyl groups comprises and not being substituted or (by one or more radicals R ¹⁰) the monocycle base, particularly saturated mono cyclic group that replace, as cycloalkyl.The example of this type of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl; More generally be cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, particularly cyclohexyl.

Other example of non-aromatics cyclic group comprises the bridged ring system, as dicyclo alkane and azabicyclo alkane, but more not preferred usually this type of bridged ring system.Refer to the wherein loop systems of 2 shared 2 above atoms of ring with " bridged ring system ", consult for example Advanced OrganicChemistry, Jerry March, the 4th edition, Wiley Interscience, 131-133 page or leaf, 1992.The example of bridged ring system comprises dicyclo [2.2.1] heptane, aza-bicyclo [2.2.1] heptane, dicyclo [2.2.2] octane, aza-bicyclo [2.2.2] octane, dicyclo [3.2.1] octane and aza-bicyclo [3.2.1] octane.

Unless context indicates in addition, otherwise when this paper mentions carbocyclic ring and heterocyclic radical, carbocyclic ring or heterocycle can not be substituted or by one or more substituent R ¹⁰Replace, substituting group is selected from halogen, hydroxyl, trifluoromethyl, cyano group, nitro, carboxyl, amino, list-or two-C _1-4Alkyl amino, carbocyclic ring and heterocyclic radical with 3-12 ring members; Radicals R ^a-R ^b, R wherein ^aBe key, O, CO, X ¹C (X ²), C (X ²) X ¹, X ¹C (X ²) X ¹, S, SO, SO ₂, NR ^c, SO ₂NR ^cOr NR ^cSO ₂, R ^bBe selected from hydrogen, have the carbocyclic ring of 3-12 ring members and heterocyclic radical and by one or more hydroxyl, oxo, halogen, cyano group, nitro, carboxyl, amino, list-or two-C that are selected from _1-4The optional C that replaces of the substituting group of alkyl amino, carbocyclic ring and heterocyclic radical with 3-12 ring members _1-8Alkyl, wherein C _1-8One or more carbon atoms of alkyl can be by O, S, SO, SO ₂, NR ^c, X ¹C (X ²), C (X ²) X ¹Or X ¹C (X ²) X ¹Optional displacement;

R ^cBe selected from hydrogen and C _1-4Alkyl; With

X ¹Be O, S or NR ^cAnd X ²Be=O ,=S or=NR ^c

Work as substituent R ¹⁰When containing or comprising carbocyclic ring or heterocyclic radical, described carbocyclic ring or heterocyclic radical can not be substituted or itself is by one or more other substituent R ¹⁰Replace.In a kind of subclass of formula (I) compound that this paper limits, this type of other substituent R ¹⁰Can comprise carbocyclic ring or heterocyclic radical, they are not further replaced usually itself.In the another kind of subclass of formula (I) compound that this paper limits, described other substituting group does not comprise carbocyclic ring or heterocyclic radical, but is selected from above R in addition ¹⁰The group of listing in the definition.

The optional substituent R of selecting ¹⁰Be no more than 20 non-hydrogen atoms so that they comprise, for example be no more than 15 non-hydrogen atoms, as be no more than 12 or 10 or 9 or 8 or 7 or 6 or 5 non-hydrogen atoms.

Substituent R ¹⁰A kind of subclass R ^10aExpression, form by being selected from following substituting group: halogen, hydroxyl, trifluoromethyl, cyano group, nitro, carboxyl, amino, list-or two-C _1-4Alkyl amino, carbocyclic ring and heterocyclic radical with 3-7 ring members; Radicals R ^a-R ^b, R wherein ^aBe key, O, CO, OC (O), NR ^cC (O), OC (NR ^C), C (O) O, C (O) NR ^c, OC (O) O, NR ^cC (O) O, OC (O) NR ^c, NR ^cC (O) NR ^c, S, SO, SO ₂, NR ^c, SO ₂NR ^cOr NR ^cSO ₂R ^bBe selected from hydrogen, have the carbocyclic ring of 3-7 ring members and heterocyclic radical and by one or more hydroxyl, oxo, halogen, cyano group, nitro, carboxyl, amino, list-or two-C that are selected from _1-4The optional C that replaces of the substituting group of alkyl amino, carbocyclic ring and heterocyclic radical with 3-7 ring members _1-8Alkyl, wherein C _1-8One or more carbon atoms of alkyl can be by O, S, SO, SO ₂, NR ^c, OC (O), NR ^cC (O), OC (NR ^c), C (O) O, C (O) NR ^c, OC (O) O, NR ^cC (O) O, OC (O) NR ^cOr NR ^cC (O) NR ^cOptional displacement; R ^cBe selected from hydrogen and C _1-4Alkyl.

Substituent R ¹⁰Another kind of subclass R ^10bExpression, form by being selected from following substituting group: halogen, hydroxyl, trifluoromethyl, cyano group, amino, list-or two-C _1-4Alkyl amino, cyclopropyl amino, carbocyclic ring and heterocyclic radical with 3-7 ring members; Radicals R ^a-R ^b, R wherein ^aBe key, O, CO, OC (O), NR ^cC (O), OC (NR ^c), C (O) O, C (O) NR ^c, S, SO, SO ₂, NR ^c, SO ₂NR ^cOr NR ^cSO ₂R ^bBe selected from hydrogen, have the carbocyclic ring of 3-7 ring members and heterocyclic radical and by one or more hydroxyl, oxo, halogen, cyano group, amino, list-or two-C that are selected from _1-4The optional C that replaces of the substituting group of alkyl amino, carbocyclic ring and heterocyclic radical with 3-7 ring members _1-8Alkyl, wherein C _1-8One or more carbon atoms of alkyl can be by O, S, SO, SO ₂Or NR ^cOptional displacement; Prerequisite is to work as R ^bR when being hydrogen ^aIt or not key; R ^cBe selected from hydrogen and C _1-4Alkyl.

Substituent R ¹⁰Another kind of subclass R ^10cExpression, form by being selected from following substituting group: halogen,

Hydroxyl,

Trifluoromethyl,

Cyano group,

Amino, single-or two-C _1-4Alkyl amino,

Cyclopropyl amino,

Monocycle carbocyclic ring and heterocyclic radical with 3-7 ring members, wherein 0,1 or 2 ring members is selected from O, N and S, all the other are carbon atoms, and wherein monocycle carbocyclic ring and heterocyclic radical are by one or more optional replacements of substituting group that are selected from halogen, hydroxyl, trifluoromethyl, cyano group and methoxyl group;

Radicals R ^a-R ^b

R ^aBe key, O, CO, OC (O), NR ^cC (O), OC (NR ^c), C (O) O, C (O) NR ^c, S, SO, SO ₂, NR ^c, SO ₂NR ^cOr NR ^cSO ₂

R ^bBe selected from hydrogen, have the monocycle carbocyclic ring and the heterocyclic radical of 3-7 ring members, wherein 0,1 or 2 ring members is selected from O, N and S, all the other are carbon atoms, and wherein monocycle carbocyclic ring and heterocyclic radical are by one or more optional replacements of substituting group that are selected from halogen, hydroxyl, trifluoromethyl, cyano group and methoxyl group;

R ^bFurther be selected from by one or more hydroxyl, oxo, halogen, cyano group, amino, list-or two-C that are selected from _1-4(wherein 0,1 or 2 ring members is selected from O, N and S for alkyl amino, the monocycle carbocyclic ring with 3-7 ring members and heterocyclic radical, all the other are carbon atoms, and wherein monocycle carbocyclic ring and heterocyclic radical are replaced by one or more substituting groups that are selected from halogen, hydroxyl, trifluoromethyl, cyano group and methoxyl group are optional) the optional C that replaces of substituting group _1-8Alkyl, wherein C _1-81 or 2 carbon atom of alkyl can be by O, S or NR ^cOptional displacement; Prerequisite is to work as R ^bR when being hydrogen ^aIt or not key; And

R ^cBe selected from hydrogen and C _1-4Alkyl.

When carbocyclic ring and heterocyclic radical had a pair of substituting group on the adjacent ring atom, two substituting groups can connect to form cyclic group.For example, a pair of adjacent substituting group on the adjacent carbons of ring can be connected by one or more heteroatomss and the optional alkylidene group that replaces, with the formation oxa--, two oxa-s-, azepine-, diaza-or oxa--azepine-cycloalkyl.This type of connects substituent example and comprises:

The halogenic substituent example comprises fluorine, chlorine, bromine and iodine.Preferred especially fluorine and chlorine.

In formula (I) the compound definition of above and hereinafter using, unless otherwise indicated, otherwise term " alkyl " be comprise have full carbon backbone chain and the aliphatic series of forming by carbon and hydrogen atom, the general name of alicyclic and aromatic group.

In some cases, limit as this paper, one or more carbon atoms of forming carbon backbone chain can be by the group displacement of specific atoms or atom.The alkyl example comprises alkyl, cycloalkyl, cycloalkenyl group, isocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenyl alkyl and carbocyclic ring aralkyl, arylalkenyl and sweet-smelling alkynyl.This type of group can not be substituted, and perhaps under situation about indicating, can be replaced by one or more substituting groups that this paper limits.Unless context indicates in addition, otherwise example hereinafter and preferably be applicable to the various hydrocarbyl substituents of in the various substituting groups definition of the compound of formula (I) compound that this paper limits and subclass thereof, mentioning or contain the alkyl substituting group.

For example, unless the other requirement of context, alkyl can have 8 carbon atoms at the most.In having the alkyl subclass of 1-8 carbon atom, specific examples is C _1-6Alkyl is as C _1-4Alkyl is (as C _1-3Alkyl or C _1-2Alkyl), specific examples is to be selected from C ₁, C ₂, C ₃, C ₄, C ₅, C ₆, C ₇And C ₈Any individuality or the combination of alkyl.

No matter term " saturated hydrocarbyl " uses (as " alkyl oxygen base ") separately or with suffix as " oxy ", all refer to not comprise the non-aromatic hydrocarbyl of Multiple Bonds such as C=C and C ≡ C.

Concrete alkyl is alkyl and the cycloalkyl that saturated hydrocarbyl such as this paper limit.

Term " alkyl " comprises straight chain and branched-chain alkyl.Examples of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, 2-methyl butyl, 3-methyl butyl and n-hexyl and isomer thereof.In having the alkyl subclass of 1-8 carbon atom, specific examples is C _1-6Alkyl is as C _1-4Alkyl is (as C _1-3Alkyl or C _1-2Alkyl).

The example of cycloalkyl is the cycloalkyl from cyclopropane, tetramethylene, pentamethylene, hexanaphthene and suberane.In the cycloalkyl subclass, cycloalkyl will have 3-8 carbon atom, and specific examples is C _3-6Cycloalkyl.

Non-limiting examples of alkenyls includes but not limited to vinyl (vinyl), 1-propenyl, 2-propenyl (allyl group), pseudoallyl, butenyl, fourth-1,4-dialkylene, pentenyl and hexenyl.In the alkenyl subclass, alkenyl will have 2-8 carbon atom, and specific examples is C _2-6Alkenyl is as C _2-4Alkenyl.

The example of cycloalkenyl group includes but not limited to cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclopentadienyl and cyclohexenyl.In the cycloalkenyl group subclass, cycloalkenyl group has 3-8 carbon atom, and specific examples is C _3-6Cycloalkenyl group.

The example of alkynyl includes but not limited to ethynyl and 2-propynyl (propargyl).In having the alkynyl subclass of 2-8 carbon atom, specific examples is C _2-6Alkynyl is as C _2-4Alkynyl.

The example of isocyclic aryl comprise replacement with unsubstituted phenyl, naphthyl, indane and indenyl.

The example of cycloalkylalkyl, cycloalkenyl alkyl, carbocyclic ring aralkyl, arylalkenyl and sweet-smelling alkynyl comprises styroyl, benzyl, styryl, phenylacetylene base, cyclohexyl methyl, cyclopentyl-methyl, cyclobutylmethyl, cyclopropyl methyl and cyclopentenyl methyl.

When existing and mentioning alkyl, described alkyl can be by one or more hydroxyl, oxo, alkoxyl group, carboxyl, halogen, cyano group, nitro, amino, list-or two-C that are selected from _1-4Alkyl is amino and have 3-12 (normally 3-10, the be 5-10 more generally) monocycle of individual ring members or the substituting group of bicyclic carbocyclic and heterocyclic radical is optional replaces.Preferred substituents comprises halogen such as fluorine.Therefore, the alkyl that for example replaces can be partially fluorinated or fluoridized group such as difluoromethyl or trifluoromethyl.In one embodiment, preferred substituents comprises monocycle carbocyclic ring and the heterocyclic radical with 3-7 ring members.

When mentioning one or more carbon atom of alkyl, described carbon atom can be by O, S, SO, SO ₂, NR ^c, X ¹C (X ²), C (X ²) X ¹Or X ¹C (X ²) X ¹(or its subunit) optional displacement, wherein X ¹And X ²Be defined as above, prerequisite is at least one carbon atom that keeps alkyl.For example, 1,2,3 or 4 carbon atom of alkyl can be by a listed atom or group displacement, and metathetical atom or group can be identical or different.In general, metathetical straight chain or backbone c atoms number will be corresponding to straight chain or the backbone atoms numbers in their group of displacement.Wherein the group example of the substitutional atom that has been defined as above of one or more carbon atoms of alkyl or group displacement comprises ether and thioether (C is by O or S displacement), acid amides, ester, thioamides and monothioester (C-C is by X ¹C (X ²) or C (X ²) X ¹Displacement), (C is by SO or SO for sulfone and sulfoxide ₂Displacement), (C is by NR for amine ^cDisplacement).Other example comprises urea, carbonic ether, carbamate, and (C-C-C is by X ¹C (X ²) X ¹Displacement).

When amino had 2 hydrocarbyl substituents, the nitrogen-atoms that they can connect with their and optional another heteroatoms such as nitrogen, sulphur or oxygen formed the ring structure of 4-7 ring members.

Term " azepine-cycloalkyl " is used for this paper and refers to that wherein 1 carbocyclic ring member is by nitrogen-atoms metathetical cycloalkyl.Therefore the example of azepine-cycloalkyl comprises piperidines and tetramethyleneimine.Term " oxa--cycloalkyl " is used for this paper and refers to that wherein 1 carbocyclic ring member is by Sauerstoffatom metathetical cycloalkyl.Therefore the example of oxa--cycloalkyl comprises tetrahydrofuran (THF) and tetrahydropyrans.Similarly, term " diaza-cycloalkyl ", " two oxa-s-cycloalkyl " and " azepine-oxa--cycloalkyl " refer to respectively that wherein 2 carbocyclic ring members are by 2 nitrogen-atoms, 2 Sauerstoffatoms or 1 nitrogen-atoms and 1 Sauerstoffatom metathetical cycloalkyl.

Definition " R ^a-R ^b" when being used for this paper, no matter be meant the substituting group that is present on carbocyclic ring or the heterocyclic moiety, perhaps refer to be present in other substituting group of other position on formula (I) compound that this paper limits, all particularly including R wherein ^aBe selected from key, O, CO, OC (O), SC (O), NR ^cC (O), OC (S), SC (S), NR ^cC (S), OC (NR ^c), SC (NR ^c), NR ^cC (NR ^c), C (O) O, C (O) S, C (O) NR ^c, C (S) O, C (S) S, C (S) NR ^c, C (NR ^c) O, C (NR ^c) S, C (NR ^c) NR ^c, OC (O) O, SC (O) O, NR ^cC (O) O, OC (S) O, SC (S) O, NR ^cC (S) O, OC (NR ^c) O, SC (NR ^c) O, NR ^cC (NR ^c) O, OC (O) S, SC (O) S, NR ^cC (O) S, OC (S) S, SC (S) S, NR ^cC (S) S, OC (NR ^c) S, SC (NR ^c) S, NR ^cC (NR ^c) S, OC (O) NR ^c, SC (O) NR ^c, NR ^cC (O) NR ^c, OC (S) NR ^c, SC (S) NR ^c, NR ^cC (S) NR ^c, OC (NR ^c) NR ^c, SC (NR ^c) NR ^c, NR ^cC (NR ^cNR ^c, S, SO, SO ₂, NR ^c, SO ₂NR ^cAnd NR ^cSO ₂Compound, R wherein ^cLimit as mentioned.

Part R ^bCan be hydrogen, perhaps can be to be selected from and to have 3-12 the carbocyclic ring and the heterocyclic radical of (normally 3-10 and more generally be 5-10) individual ring members and be defined as above the optional C that replaces _1-8Alkyl.The example of alkyl, carbocyclic ring and heterocyclic radical is enumerated as mentioned.

Work as R ^aBe O and R ^bBe C _1-8During alkyl, R ^aAnd R ^bForm-oxyl together.Preferred-oxyl comprises that saturated-oxyl such as alkoxyl group are (as C _1-6Alkoxyl group more generally is C _1-4Alkoxyl group such as oxyethyl group and methoxyl group, particularly methoxyl group), cycloalkyloxy is (as C _3-6Cycloalkyloxy is as ring propoxy-, cyclobutoxy group, cyclopentyloxy and cyclohexyloxy) and cycloalkyl alkoxy (as C _3-6Cycloalkyl-C _1-2Alkoxyl group such as cyclo propyl methoxy).

-oxyl can be replaced by the various substituting groups that this paper limits.For example, alkoxyl group can be by halogen (as in difluoro-methoxy and the trifluoromethoxy), hydroxyl (in hydroxyl-oxethyl), C _1-2Alkoxyl group (as in the methoxy ethoxy), hydroxyl-C _1-2Alkyl (in the '-hydroxyethoxy base oxethyl) or cyclic group (cycloalkyl of Xian Dinging or non-aromatic heterocycle as mentioned) replace.Carry non-aromatic heterocycle and be substituent alkoxyl group example and be wherein heterocyclic radical and be saturated cyclic amines such as morpholine, piperidines, tetramethyleneimine, piperazine, C _1-4-alkyl-piperazine, C _3-7-cycloalkyl-piperazine, tetrahydropyrans or tetrahydrofuran (THF) and alkoxyl group are C _1-4Alkoxyl group, be C more generally _1-3The group of alkoxyl group such as methoxyl group, oxyethyl group or positive propoxy.

Alkoxyl group can be by for example monocycle base such as tetramethyleneimine, piperidines, morpholine and piperazine and N-substitutive derivative thereof such as N-benzyl, N-C _1-4Acyl group and N-C _1-4Alkoxy carbonyl replaces.Specific examples comprises tetramethyleneimine-1-base oxethyl, piperidines-1-base oxethyl and piperazine-1-base oxethyl.

Work as R ^aBe key and R ^bBe C _1-8During alkyl, alkyl R ^a-R ^bExample be defined as above.Alkyl can be saturated group such as cycloalkyl and alkyl, and the specific examples of this type of group comprises methyl, ethyl and cyclopropyl.Alkyl (as alkyl) can be replaced by various groups and the atom that this paper limits.The example of substituted alkyl comprises the alkyl that is replaced by following group: (specific examples comprises bromotrifluoromethane, chloroethyl, difluoromethyl, 2 for one or more halogen atoms such as fluorine and chlorine, 2,2-trifluoroethyl and perfluoroalkyl such as trifluoromethyl), hydroxyl (as hydroxymethyl and hydroxyethyl), C _1-8Acyloxy (as acetoxy-methyl and benzyloxymethyl), amino and single-and dialkyl amido (as amino-ethyl, methylamino ethyl, dimethylamino methyl, dimethylaminoethyl and tertiary butyl amino methyl), alkoxyl group (as C _1-2Alkoxyl group such as methoxyl group-as in methoxy ethyl) and cyclic group (cycloalkyl of Xian Dinging, aryl, heteroaryl and non-aromatic heterocycle as mentioned).

The specific examples of the alkyl that is replaced by cyclic group is that wherein cyclic group is saturated cyclic amines such as morpholine, piperidines, tetramethyleneimine, piperazine, C _1-4-alkyl-piperazine, C _3-7-cycloalkyl-piperazine, tetrahydropyrans or tetrahydrofuran (THF) and alkyl are C _1-4Alkyl, be C more generally _1-3The group of alkyl such as methyl, ethyl or n-propyl.The specific examples of the alkyl that is replaced by cyclic group comprises that the N-that tetramethyleneimine-1-ylmethyl, tetramethyleneimine-1-base propyl group, morpholino methyl, morpholino ethyl, morpholino propyl group, piperidino methyl, piperazine-1-ylmethyl and this paper thereof limit replaces form.

Specific examples by the alkyl of aryl and heteroaryl replacement comprises benzyl, styroyl and pyridylmethyl.

Work as R ^aBe SO ₂NR ^cThe time, R ^bCan be for example hydrogen or the optional C that replaces _1-8Alkyl, perhaps carbocyclic ring or heterocyclic radical.R wherein ^aBe SO ₂NR ^cR ^a-R ^bExample comprise amino-sulfonyl, C _1-4Alkyl amino sulfonyl and two-C _1-4The sulphonamide that alkyl amino sulfonyl and the piperazine that replaces with cyclic amino such as piperidyl, morpholinyl, pyrrolidyl or optional N-such as N methyl piperazine form.

R wherein ^aBe SO ₂Radicals R ^a-R ^bExample comprise alkyl sulphonyl, heteroarylsulfonyl and aryl sulfonyl, particularly monocyclic aryl and heteroarylsulfonyl.Specific examples comprises methyl sulphonyl, phenyl sulfonyl and tosyl group.

Work as R ^aBe NR ^cThe time, R ^bCan be for example hydrogen or the optional C that replaces _1-8Alkyl, perhaps carbocyclic ring or heterocyclic radical.R wherein ^aBe NR ^cR ^a-R ^bExample comprise amino, C _1-4Alkylamino (as methylamino, ethylamino, propyl group amino, sec.-propyl amino, tertiary butyl amino), two-C _1-4Alkylamino (as dimethylamino and diethylamino) and cycloalkyl amino (as cyclopropyl amino, cyclopentyl amino and cyclohexyl amino).

A, E, T, J ¹ , J ² And R ¹ -R ¹⁰ Specific embodiments and preferred

In the formula (I) that this paper limits, T can be a nitrogen, perhaps group CR ⁵And J ¹-J ²Can represent and be selected from N=C (R ⁶), (R ⁷) C=N, (R ⁸) N-C (O), (R ⁸) ₂C-C (O) and (R ⁷) C=C (R ⁶) group.Therefore bicyclic group can adopt for example following form:

(T is N to purine, J ¹-J ²Be N=C (R ⁶));

(T is CR to 3H-imidazo [4,5-b] pyridine ⁵, J ¹-J ²Be N=C (R ⁶));

(T is N to 7H-pyrrolo-[2,3-d] pyrimidine, J ¹-J ²Be (R ⁷) C=C (R ⁶));

(T is CR to 1H-pyrrolo-[2,3-b] pyridine ⁵, J ¹-J ²Be (R ⁷) C=C (R ⁶));

5, pyrimidine-(T is N to 6-ketone to 7-dihydro-pyrrolo-[2,3-d], J ¹-J ²Be (R ⁸) ₂C-C (O));

3H-[1,2,3] (T is N to triazolo [4,5-d] pyrimidine, J ¹-J ²Be N=N);

3H-[1,2,3] (T is CR to triazolo [4,5-b] pyridine ⁵, J ¹-J ²Be N=N);

7, (T is N to 9-dihydro-purine-8-ketone, J ¹-J ²Be (R ⁸) N-C (O));

(T is N to 1H-pyrazolo [3,4-d] pyrimidine, J ¹-J ²Be (R ⁷) C=N); Perhaps

(T is CR to pyrazolo [3,4-b] pyridine ⁵, J ¹-J ²Be (R ⁷) C=N).

R ⁴Be selected from hydrogen; Halogen; By halogen, hydroxyl or C _1-2The optional C that replaces of alkoxyl group _1-6Alkyl; Cyano group; CONH ₂CONHR ⁹CF ₃NH ₂NHCOR ⁹And NHCONHR ⁹Common R ⁴Be selected from hydrogen, halogen, C _1-5Saturated hydrocarbyl, cyano group and CF ₃R ⁴More generally be selected from hydrogen, chlorine, fluorine and methyl, preferred R ⁴Be hydrogen.

R ⁵Be selected from hydrogen; Halogen; By halogen, hydroxyl or C _1-2The optional C that replaces of alkoxyl group _1-6Alkyl; Cyano group; CONH ₂CONHR ⁹CF ₃NH ₂NHCOR ⁹And NHCONHR ⁹Common R ⁵Be selected from hydrogen, halogen, C _1-5Saturated hydrocarbyl, cyano group and CF ₃Preferred R ⁵Be selected from hydrogen, chlorine, fluorine and methyl, more preferably R ⁵Be hydrogen.

R ⁶Be selected from hydrogen; Halogen; By halogen, hydroxyl or C _1-2The optional C that replaces of alkoxyl group _1-6Alkyl; Cyano group; CONH ₂CONHR ⁹CF ₃NH ₂NHCOR ⁹And NHCONHR ⁹Usually, R ⁶Be selected from hydrogen, halogen, C _1-5Saturated hydrocarbyl, cyano group and CF ₃More generally be R ⁶Be selected from hydrogen, chlorine, fluorine and methyl, preferred R ⁶Be hydrogen.

R ⁷Be selected from hydrogen; Halogen; By halogen, hydroxyl or C _1-2The optional C that replaces of alkoxyl group _1-6Alkyl; Cyano group; CONH ₂CONHR ⁹CF ₃NH ₂NHCOR ⁹And NHCONHR ⁹R ⁷More generally be selected from hydrogen, halogen, C _1-5Saturated hydrocarbyl, cyano group and CF ₃Preferred R ⁷Be selected from hydrogen, chlorine, fluorine and methyl, more preferably R ⁷Be hydrogen.

R ⁸Be selected from hydrogen, halogen, C _1-5Saturated hydrocarbyl, cyano group, CONH ₂CONHR ⁹CF ₃NH ₂NHCOR ⁹And NHCONHR ⁹Usually, R ⁸Be selected from hydrogen, halogen, C _1-5Saturated hydrocarbyl, cyano group and CF ₃R ⁸More generally be selected from hydrogen, chlorine, fluorine and methyl, preferred R ⁸Be hydrogen.

R ⁹Be defined as above optional phenyl or the benzyl that replaces separately.Concrete radicals R ⁹Be phenyl and the benzyl that is not substituted or is replaced as the amino, carboxylic acid group or the sulfonic alkyl that carry amino, replacement or alkoxyl group by solubilizing group.The specific examples of solubilizing group comprises amino-C _1-4-alkyl, list-C _1-2-alkylamino-C _1-4-alkyl, two-C _1-2-alkylamino-C _1-4-alkyl, amino-C _1-4-alkoxyl group, list-C _1-2-alkylamino-C _1-4-alkoxyl group, two-C _1-2-alkylamino-C _1-4-alkoxyl group, piperidyl-C _1-4-alkyl, piperazinyl-C _1-4-alkyl, morpholinyl-C _1-4-alkyl, piperidyl-C _1-4-alkoxyl group, piperazinyl-C _1-4-alkoxyl group and morpholinyl-C _1-4-alkoxyl group.

A is the stable hydrocarbon linking group that comprises 1-7 carbon atom, and described linking group is at R ¹With NR ²R ³Between have the maximum chain length of 5 atoms, at E and NR ²R ³Between have the maximum chain length of 4 atoms.In these limiting factors, part E and R ¹Can connect any position on group A.

Term " maximum chain length " is used for this paper and refers to be located immediately at atomicity between described two portions, does not consider any hydrogen atom that any branch of chain maybe may exist.For example, in the structure A of following demonstration:

R ¹With NR ²R ³Between chain length be 3 atoms, and E and NR ²R ³Between chain length be 2 atoms.

At present preferred in general linking group is at R ¹With NR ²R ³Between have the maximum chain length of 3 atoms (more preferably 1 or 2 atom, most preferably 2 atoms).

Preferred linking group is at E and NR ²R ³Between have 4 atoms, be the maximum chain length of 3 atoms more generally.

Particularly preferred classes of compounds is that linking group is at R ¹With NR ²R ³Between have the chain length of 1,2 or 3 atom, at E and NR ²R ³Between have the chain length of 1,2 or 3 atom.

A carbon atom in the linking group can be by oxygen or the optional displacement of nitrogen-atoms.When having oxygen or nitrogen-atoms, preferred directly linking group E.

When having oxygen or nitrogen-atoms, preferred nitrogen or Sauerstoffatom and NR ²R ³Group is opened by the carbon atoms separate of 2 insertions at least.

In a kind of particular type of formula (I) compound that this paper limits, directly the connection atom of linking group E is that carbon atom and linking group A have full carbon skeleton.

The carbon atom of linking group A can be chosen wantonly and carry one or more substituting groups that are selected from oxo, fluorine and hydroxyl, and prerequisite is a hydroxyl Be not positioned atWith respect to NR ²R ³On the alpha-carbon atom of group, and prerequisite is the oxo base Be positioned atWith respect to NR ²R ³On the alpha-carbon atom of group.Usually, if there is hydroxyl, then be positioned at respect to NR ²R ³The β position of group.In general, existence is no more than 1 hydroxyl.When having fluorine atom, they for example can be present in difluoro methylene or the trifluoromethyl.

Should understand when the oxo base and be present near NR ²R ³During the carbon atom of group, formula (I) compound will be an acid amides.

In one embodiment of the invention, there is not fluorine atom in the linking group A.

In another embodiment of the invention, there is not hydroxyl in the linking group A.

In another embodiment, there is not the oxo base in the linking group A.

At class formula (I) compound, both there be not hydroxyl not have fluorine atom in the linking group A yet, A is not substituted as linking group.

Preferably when the carbon atom among the linking group A was replaced by nitrogen-atoms, group A carried and is no more than 1 hydroxyl substituent, does not more preferably carry hydroxyl substituent.

Be used for another kind of compound of the present invention, linking group A is connecting NR ²R ³Can have branched configurations on the carbon atom of group.For example, connect NR ²R ³The carbon atom of group can be connected together with-dimethyl with a pair of.

In the concrete formula of a class (I) compound that this paper limits, the R of compound ¹-A-NR ²R ³Section is by formula R ¹-(G) _k-(CH ₂) _m-X-(CH ₂) _n-(CR ⁶R ⁷) _p-NR ²R ³Expression, wherein G is NH, NMe or O; X is connected with group E, is selected from (CH ₂) _j-CH, (CH ₂) _j-N, O-CH and (NH) _j-CH; J is 0 or 1, and k is 0 or 1, and m is 0 or 1, and n is 0,1,2 or 3, and p is 0 or 1, and the sum of j, k, m, n and p is no more than 4; R ⁶And R ⁷Identical or different, be selected from methyl and ethyl, perhaps CR ⁶R ⁷Form cyclopropyl.

One concrete CR ⁶R ⁷Be C (CH ₃) ₂

Preferred X is (CH ₂) _j-CH.

Concrete structure is wherein:

K is 0, and m is 0 or 1, and n is 0,1,2 or 3, and p is 0;

K is 0, and m is 0 or 1, and n is 0,1 or 2, and p is 1;

X is (CH ₂) _j-CH, k are 1, and m is 0, and n is 0,1,2 or 3, and p is 0; With

X is (CH ₂) _j-CH, k are 1, and m is 0, and n is 0,1 or 2, and p is 1.

In another embodiment, the R of compound ¹-A-NR ²R ³Section is by formula R ¹-(CH ₂) _x-X '-(CH ₂) _y-NR ²R ³Expression, wherein x is 0,1 or 2, and y is 0,1 or 2, and prerequisite is that the sum of x and y is no more than 4; X ' is connected with group E, is group C (R ^x), (i) R wherein ^xBe hydrogen or (ii) R ^xWith R ²Constitute the alkylidene group connection chain that length is at most 3 carbon atoms together, so that part X '-(CH ₂) _y-NR ²R ³Form 4-7 unit saturated heterocyclic.

In a compounds, R ²And R ³Independently be selected from hydrogen, C _1-4Alkyl and C _1-4Acyl group, wherein alkyl and acyl group are by one or more optional replacements of substituting group that are selected from fluorine, hydroxyl, amino, methylamino, dimethylamino, methoxyl group and monocycle or bicyclic aryl or heteroaryl.

In this compounds, R ²And R ³Can independently be selected from hydrogen, C _1-4Alkyl and C _1-4Acyl group.Usually alkyl is an alkyl, more generally is C ₁, C ₂Or C ₃Alkyl, for example methyl.In the compound of concrete subclass, R ²And R ³Independently be selected from hydrogen and methyl, so NR ²R ³Can be amino, methylamino or dimethylamino.In one embodiment, NR ²R ³Be amino.In another embodiment, NR ²R ³It is methylamino.

In another kind of compound, R ²And R ³The nitrogen-atoms that connects with their forms and is selected from imidazolyl and has 4-7 ring members and choose the cyclic group of the saturated monocycle heterocyclic radical that comprises second the heteroatomic ring member who is selected from O and N wantonly.

In this compounds, subclass is R wherein ²And R ³The nitrogen-atoms that connects with their forms to have 4-7 ring members and chooses the saturated monocycle heterocyclic radical that comprises second the heteroatomic ring member who is selected from O and N wantonly.

Work as NR ²R ³When forming the saturated mono cyclic group, can independently be selected from the radicals R that this paper limits ¹⁰One or more substituting groups replace.More specifically the monocyclic heterocycles base can be by one or more C _1-4Alkyl replaces.Perhaps, the monocyclic heterocycles base can not be substituted.

Saturated monocycle can be azacycloalkyl such as azetidine, tetramethyleneimine, piperidines or nitrogen heterocyclic ring in heptan, and this type of ring is not substituted usually.

Perhaps, saturated monocycle can comprise other heteroatoms that is selected from O and N, and this type of examples of groups comprises morpholine and piperazine.In ring, there is other N atomic time, can forms NH group or N-C _1-4The part of alkyl such as N-methyl, N-ethyl, N-propyl group or N-sec.-propyl.

In another compounds, R ²And R ³The nitrogen-atoms that one of them connects with their and one or more atoms of linking group A form to have 4-7 ring members and chooses the saturated monocycle heterocyclic radical that comprises second the heteroatomic ring member who is selected from O and N wantonly.

This type of examples for compounds comprises wherein NR ²R ³Form the unitary compound of following formula with A:

Wherein t and u each naturally 0,1,2 or 3, prerequisite is that the sum of t and u is in the 2-4 scope.

Other example of this compounds comprises wherein NR ²R ³Compound with A formation following formula group:

Wherein v and w each naturally 0,1,2 or 3, prerequisite is that the sum of v and w is in the 2-5 scope.The specific examples of this compounds is that wherein v and w are 2 compounds.

Linking group A and and radicals R thereof ¹, E and NR ²R ³Tie point specific examples such as following table 1 together shows.

Table 1

Preferred group comprises A1, A2, A3, A10 and A11 at present.Special preferred group comprises A1 and A11.

In formula (I), E is monocycle or bicyclic carbocyclic or heterocyclic radical or non-annularity radicals X-G, and wherein X is selected from CH ₂, O, S and NH, G is that one of them carbon atom is by O, S or the optional metathetical C of NH _1-4Alkylidene chain.

When E is monocycle or bicyclic carbocyclic or heterocyclic radical, can be selected from the above general preferred group of listing with the definition title division.

Concrete cyclic group E is monocycle and bicyclic aryl and heteroaryl, specifically, group comprises 6 yuan of aromatic rings or hetero-aromatic ring such as phenyl, pyridine, pyrazine, pyridazine or pyrimidine ring, more specifically is phenyl, pyridine, pyrazine or pyrimidine ring, more preferably pyridine ring or phenyl ring.

The example of bicyclic group comprises benzo-fused and pyridine condensed group, wherein group A and pyrazoles ring all with benzo-or pyrido-part be connected.

In one embodiment, E is the monocycle base.

The specific examples of monocycle base comprises monocyclic aryl and heteroaryl, as phenyl, thiophene, furans, pyrimidine, pyrazine and pyridine, and at present preferred phenyl.

The example of non-aromatic monocyclic base comprises loop chain alkane such as hexanaphthene and pentamethylene and contains azo-cycle such as piperidines, piperazine and piperazine ketone (piperazone).

A kind of concrete non-aromatic monocyclic base is a piperidyl, more especially the piperidyl that is connected with bicyclic group of the nitrogen-atoms of piperidine ring wherein.

In a kind of compound of concrete subclass, E is selected from phenyl and piperidyl.

Preferred group A is connected with group E with the relative direction of bicyclic group with a position or contraposition; Be that A is not connected with the adjacent ring member of group E with bicyclic group.The group example of this type of group E comprises 1,4-phenylene, 1,3-phenylene, 2,5-pyridylidene and 2,4-pyridylidene, 1,4-piperidyl, 1,4-piperidone base (piperindonyl), 1,4-piperazinyl and 1,4-piperazine ketone group (piperazonyl).

Group E can not be substituted or can have at the most 4 and can be selected from the radicals R that above limits ¹⁰Substituent R ¹¹But, substituent R ¹¹More generally be selected from hydroxyl; CH ₂CN, oxo (when E is non-aromatics); Halogen (as chlorine and bromine); Trifluoromethyl; Cyano group; By C _1-2The optional C that replaces of alkoxyl group or hydroxyl _1-4-oxyl; With by C _1-2The optional C that replaces of alkoxyl group or hydroxyl _1-4Alkyl.

Usually, 0-3 substituting group arranged, be more typically 0-2 substituting group, for example 0 or 1 substituting group.In one embodiment, group E is not substituted.

Group E has 5 or 6 members and comprises 3 heteroatomic aryl or heteroaryls that are selected from O, N and S at the most, and group E is expressed from the next:

Wherein * represents and the tie point of bicyclic group, and ＂ a ＂ represents the connection of group A;

R is 0,1 or 2;

U is selected from N and CR ^12aWith

V is selected from N and CR ^12bR wherein ^12aAnd R ^12bIdentical or different, each is hydrogen or comprise 10 substituting groups that are selected from the atom of C, N, O, F, Cl and S at the most naturally, and prerequisite is R ^12aAnd R ^12bThe sum of middle non-hydrogen atom is no more than 10; Perhaps R ^12aAnd R ^12bThe carbon atom that connects with their forms and comprises 2 heteroatomic unsubstituted 5 or 6 yuan of saturated or unsaturated rings that are selected from O and N at the most; With

R ¹⁰Limit as mentioned.

In a class particular compound, E is a group:

Wherein * represents and the tie point of pyrazolyl, and ＂ a ＂ represents the connection of group A;

P, Q and M are identical or different, are selected from N, CH and NCR ¹⁰, prerequisite is that group A is connected with carbon atom; U, V and R ¹⁰Limit as mentioned.

R ^12aAnd R ^12bExample comprises hydrogen and has the substituent R that is defined as above that is no more than 10 non-hydrogen atoms ¹⁰R ^12aAnd R ^12bSpecific examples comprise methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, cyclobutyl, cyclopentyl, fluorine, chlorine, methoxyl group, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, difluoro-methoxy, trifluoromethoxy, 2,2,2-trifluoroethyl, cyano group, amino, methylamino, dimethylamino, CONH ₂, CO ₂Et, CO ₂H, kharophen, azetidinyl, tetramethyleneimine-1-base, piperidines, piperazine-1-base, morpholino, methyl sulphonyl, amino-sulfonyl, methanesulfonamido and trifluoroacetamido.

When U is CR ^12aAnd/or V is CR ^12bThe time, directly connect the R of carboatomic ring member C ^12aAnd R ^12bIn atom or group be preferably selected from H, O (in methoxyl group), NH (in amino and methylamino) and CH ₂(in methyl and ethyl).

Be used for another kind of particular compound of the present invention, E is a group:

X wherein ²Be N or CH.

Group E also can be non-cyclic group X-G, and wherein X is selected from CH ₂, O, S and NH, G is C _1-4Alkylidene chain, one of them carbon atom is by O, S or the optional displacement of NH.

The example of non-annularity radicals X-G comprises NHCH ₂CH ₂, NHCH ₂CH ₂CH ₂, NHCH ₂CH ₂CH ₂CH ₂, OCH ₂CH ₂, OCH ₂CH ₂CH ₂, OCH ₂CH ₂CH ₂CH ₂, SCH ₂CH ₂, SCH ₂CH ₂CH ₂And SCH ₂CH ₂CH ₂CH ₂Concrete non-annularity radicals X-G is NHCH ₂CH ₂And NHCH ₂CH ₂CH ₂

Linking group E and with group A ( ^a) and bicyclic group ( ^*) specific examples of tie point shows in following table 2:

Table 2:

In table, substituent R ¹³Be selected from methyl, chlorine, fluorine and trifluoromethyl.

Radicals R ¹Be hydrogen or aryl or heteroaryl, wherein aryl or heteroaryl can be selected from above general preferred this type of group of listing with the definition title division.

In a kind of compound of subclass, R ¹Be hydrogen.

In the compound of another kind of subclass, R ¹Be aryl or heteroaryl.

Work as R ¹When being aryl or heteroaryl, can be monocycle or dicyclo, be monocycle in a specific embodiments.The specific examples of monocyclic aryl and heteroaryl is to comprise 6 yuan of aryl and heteroaryls of 2 azo-cycle members at the most and comprise 35 yuan of heteroaryls that are selected from the heteroatomic ring member of O, S and N at the most.

This type of examples of groups comprises phenyl, naphthyl, thienyl, furans, pyrimidine and pyridine, at present preferred phenyl.

Aryl or heteroaryl R ¹Can not be substituted or replaced by 5 substituting groups at the most, the substituting group example is in radicals R above ¹⁰(or R ^10a, R ^10bOr R ^10c) list.Preferred substituents comprises hydroxyl; C _1-4Acyloxy; Fluorine; Chlorine; Bromine; Trifluoromethyl; Cyano group; Separately by C _1-2The optional C that replaces of alkoxyl group or hydroxyl _1-4-oxyl and C _1-4Alkyl; C _1-4Acyl amino; Benzoyl-amido; Tetramethyleneimine-1-base carbonyl; Piperidines-1-base carbonyl; Morpholino carbonyl; Piperazine-1-base carbonyl; Comprise 1 or 2 heteroatomic 5 and 6 yuan of heteroaryl that are selected from N, O and S, heteroaryl is by one or more C _1-4Alkyl substituent is optional to be replaced; Phenyl; Pyridyl; And phenoxy group, wherein phenyl, pyridyl and phenoxy group are selected from C by 1,2 or 3 separately _1-2Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano group, separately by methoxyl group or the optional C that replaces of hydroxyl _1-2-oxyl and C _1-2The substituting group of alkyl is optional to be replaced.

Though can there be 5 substituting groups at the most, 0,1,2,3 or 4 substituting group is more generally arranged, preferred 0,1,2 or 3, more preferably 0,1 or 2 substituting group.

In one embodiment, radicals R ¹Be not substituted or by at the most 5 be selected from hydroxyl, C _1-4Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano group and separately by C _1-2The optional C that replaces of alkoxyl group or hydroxyl _1-4-oxyl and C _1-4The substituting group of alkyl replaces.

In another embodiment, radicals R ¹Can have 1 or 2 substituting group that is selected from fluorine, chlorine, trifluoromethyl, methyl and methoxyl group.Work as R ¹When being phenyl, the specific examples of substituting group combination comprises list-chloro-phenyl-and dichlorophenyl.

Work as R ¹When being 6 yuan of aryl or heteroaryl, substituting group can be preferably placed at the contraposition of 6 yuan of rings.When substituting group was positioned at contraposition, its size was preferably greater than fluorine atom.

In one embodiment, R ¹Be selected from 4-fluorophenyl, 4-chloro-phenyl-and phenyl.

In formula (I), R ⁴Be selected from hydrogen, halogen, C _1-5Saturated hydrocarbyl, cyano group and CF ₃R ⁴Preferred value comprise hydrogen and methyl.

In formula (I), R ⁵Be selected from hydrogen, halogen, C _1-5Saturated hydrocarbyl, cyano group, CONH ₂, CONHR ⁹, CF ₃, NH ₂, NHCOR ⁹And NHCONHR ⁹, R wherein ⁹Be optional phenyl or the benzyl that replaces.

More preferably R ⁵Be selected from hydrogen, halogen, C _1-5Saturated hydrocarbyl, cyano group, CF ₃, NH ₂, NHCOR ⁹And NHCONHR ⁹, R wherein ⁹Be optional phenyl or the benzyl that replaces.

Radicals R ⁹Normally unsubstituted phenyl or benzyl perhaps are selected from phenyl or the benzyl that following substituting group replaces by 1,2 or 3: halogen; Hydroxyl; Trifluoromethyl; Cyano group; Carboxyl; C _1-4Alkoxy carbonyl; C _1-4Acyloxy; Amino; Single-or two-C _1-4Alkylamino; By halogen, hydroxyl or C _1-2The optional C that replaces of alkoxyl group _1-4Alkyl; By halogen, hydroxyl or C _1-2The optional C that replaces of alkoxyl group _1-4Alkoxyl group; Phenyl; Comprise 3 heteroatomic 5 and 6 yuan of heteroaryls that are selected from O, N and S at the most; With comprise 2 heteroatomic saturated carbon ring and heterocyclic radicals that are selected from O, S and N at the most.

Part R ⁵Specific examples comprise hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyethyl, methoxymethyl, cyano group, CF ₃, NH ₂, NHCOR ^9aAnd NHCONHR ^9a, R wherein ^9aBy hydroxyl, C _1-4Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano group, by C _1-2The optional C that replaces of alkoxyl group or hydroxyl _1-4-oxyl (as alkoxyl group) and C _1-4Optional phenyl or the benzyl that replaces of alkyl (as alkyl).

Concrete and the preferred subclass of formula (I)

In an embodiment of the formula (I) that this paper limits, compound can be represented by general formula (II):

Wherein position or contraposition are connected between group A and phenyl ring, and q is 0-4; T, J ¹-J ², A, R ¹, R ², R ³And R ⁴As this paper about formula (I) and subclass thereof, example and preferred the qualification; R ¹¹It is the substituting group that is defined as above.In formula (II), q is preferred 0,1 or 2, and more preferably 0 or 1, most preferably 0.

In formula (II), the R of compound ¹-A-NR ²R ³Section can be by formula R ¹-(CH ₂) _x-X '-(CH ₂) _y-NR ²R ³Expression, wherein x is 0,1 or 2, and y is 0,1 or 2, and prerequisite is that the sum of x and y is no more than 4; X ' is connected with group E, is group C (R ^x), (i) R wherein ^xBe hydrogen or (ii) R ^xWith R ²Constitute the length alkylidene group connection chain of 3 carbon atoms at the most together, so that part X '-(CH ₂) _y-NR ²R ³Form 4-7 unit saturated heterocyclic.

For example, a kind of formula (II) compound subclass can be represented by formula (IIa):

In formula (IIa), x preferred 0 or 1, and y is 0,1 or 2.In one embodiment, x and y are 1.In another embodiment, x be 0 and y be 1.

Another kind of formula (II) compound subclass can be represented by formula (IIb):

R wherein ⁴, J ¹-J ², T, x and y limit as mentioned, z is 0,1 or 2, prerequisite is that the sum of y and z is no more than 4.In a specific embodiments, y be 2 and z be 1.

At various (II), (IIa) with (IIb) and in the embodiment, radicals R ¹Preferred optional aryl or the heteroaryl that replaces, normally 5 or 6 ring members monocyclic aryl or heteroaryl.Concrete aryl and heteroaryl are phenyl, pyridyl, furyl and thienyl, and respectively this paper qualification is optionally substituted freely.The phenyl that especially preferably is optionally substituted.

At various (II), (IIa) with (IIb) in the concrete subclass of compound, comprise this compounds, wherein R ¹Be unsubstituted phenyl, or carry more preferably that 1-3 (more preferably 1 or 2) is individual to be selected from following substituent phenyl: hydroxyl; C _1-4Acyloxy; Fluorine; Chlorine; Bromine; Trifluoromethyl; Cyano group; C _1-4-oxyl and C _1-4Alkyl, wherein C _1-4-oxyl and C _1-4Alkyl is separately by one or more C _1-2Alkoxyl group, halogen, hydroxyl or the optional phenyl that replaces or the optional replacement of pyridyl; C _1-4Acyl amino; Benzoyl-amido; Tetramethyleneimine-1-base carbonyl; Piperidines-1-base carbonyl; Morpholino carbonyl; Piperazine-1-base carbonyl; Comprise 1 or 2 heteroatomic 5 and 6 yuan of heteroaryl that are selected from N, O and S, heteroaryl is by one or more C _1-4Alkyl substituent is optional to be replaced; The optional phenyl that replaces; The optional pyridyl that replaces; With the optional phenoxy group that replaces; Wherein the optional substituting group of phenyl, pyridyl and phenoxy group is 1,2 or 3 and is selected from C _1-2Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano group and C _1-2-oxyl and C _1-2The substituting group of alkyl, wherein C _1-2-oxyl and C _1-2Alkyl is separately by methoxyl group or the optional replacement of hydroxyl.

Various (II), (IIa) and (IIb) compound comprise this compounds, wherein R more specifically in the subclass ¹Be unsubstituted phenyl, or carry more preferably that 1-3 (more preferably 1 or 2) is individual independently to be selected from following substituent phenyl: hydroxyl; C _1-4Acyloxy; Fluorine; Chlorine; Bromine; Trifluoromethyl; Cyano group; C _1-4Alkoxyl group and C _1-4Alkyl, wherein C _1-4Alkoxyl group and C _1-4Alkyl is separately by one or more fluorine atoms or by C _1-2Alkoxyl group, hydroxyl or the optional replacement of the optional phenyl that replaces; C _1-4Acyl amino; Benzoyl-amido; Tetramethyleneimine-1-base carbonyl; Piperidines-1-base carbonyl; Morpholino carbonyl; Piperazine-1-base carbonyl; The optional phenyl that replaces; The optional pyridyl that replaces; With the optional phenoxy group that replaces, wherein optional phenyl, pyridyl and the phenoxy group that replaces is selected from C by 1,2 or 3 separately _1-2Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano group, separately by methoxyl group or the optional C that replaces of hydroxyl _1-2-oxyl and C _1-2The substituting group of alkyl is optional to be replaced.

In various (II), (IIa) and an embodiment (IIb), R ¹Be unsubstituted phenyl or independently be selected from the phenyl that following substituting group replaces: hydroxyl, C by 1 or 2 _1-4Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, benzyloxy, cyano group, separately by C _1-2The optional C that replaces of alkoxyl group or hydroxyl _1-4-oxyl and C _1-4Alkyl.

More preferably radicals R ¹Be to carry 1 or 2 phenyl that independently is selected from the substituent replacement of fluorine, chlorine, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, cyano group, methoxyl group, oxyethyl group, isopropoxy, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl and benzyloxy.

In various (II), (IIa) and a kind of compound subclass (IIb), radicals R ¹It is phenyl, described phenyl has the substituting group that is selected from fluorine, chlorine, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, benzyloxy, methyl, the tertiary butyl and methoxyl group in contraposition, chooses wantonly at the ortho position or a position has second substituting group that is selected from fluorine, chlorine or methyl.In this subclass, but the phenyl coverlet replaces.Perhaps, phenyl can be replaced by two.

In various (II), (IIa) and an embodiment (IIb), R ¹Be selected from 4-fluorophenyl, 4-chloro-phenyl-and phenyl.

At various (II), (IIa) with (IIb) in a kind of concrete subclass of compound, radicals R ¹It is the mono-substituted phenyl that has chlorine substituent in contraposition.

At various (II), (IIa) with (IIb) and in above-mentioned embodiment, subclass and the example:

The preferred N of-T; And/or

-R ⁴Be hydrogen; And/or

-J ¹-J ²Representative is selected from the group of N=CH, HN-C (O), (Me) NC (O), (Et) NC (O) and HC=CH.

Another kind of formula (I) compound subclass has general formula (III):

Wherein group A is connected with the 3-position or the 4-position of piperidine ring, and q is 0-4; T, J ¹-J ², A, R ¹, R ², R ³And R ⁴As this paper about formula (I) and subclass thereof, example and preferred the qualification; R ¹¹It is the substituting group that is defined as above.In formula (III), q is preferred 0,1 or 2, and more preferably 0 or 1, most preferably 0.

In a kind of compound of subclass, R ¹Be hydrogen.

In the compound of another kind of subclass, R ¹Be aryl or heteroaryl.

Aryl or heteroaryl R ¹Can not be substituted, perhaps replaced by 5 substituting groups at the most, the substituting group example is in radicals R above ¹⁰(or R ^10aOr R ^10bOr R ^10c) list.Preferred substituents comprises hydroxyl; C _1-4Acyloxy; Fluorine; Chlorine; Bromine; Trifluoromethyl; Cyano group; Separately by C _1-2The optional C that replaces of alkoxyl group or hydroxyl _1-4-oxyl and C _1-4Alkyl; C _1-4Acyl amino; Benzoyl-amido; Tetramethyleneimine-1-base carbonyl; Piperidines-1-base carbonyl; Morpholino carbonyl; Piperazine-1-base carbonyl; Comprise 1 or 2 heteroatomic 5 and 6 yuan of heteroaryl that are selected from N, O and S, described heteroaryl is by one or more C _1-4Alkyl substituent is optional to be replaced; Phenyl; Pyridyl; And phenoxy group, wherein phenyl, pyridyl and phenoxy group are selected from C by 1,2 or 3 separately _1-2Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano group, separately by methoxyl group or the optional C that replaces of hydroxyl _1-2-oxyl and C _1-2The substituting group of alkyl is optional to be replaced.

In one embodiment, radicals R ¹Be not substituted or quilt 5 substituting groups replacements at the most, described substituting group is selected from hydroxyl; C _1-4Acyloxy; Fluorine; Chlorine; Bromine; Trifluoromethyl; Cyano group; Separately by C _1-2The optional C that replaces of alkoxyl group or hydroxyl _1-4-oxyl and C _1-4Alkyl.

Work as R ¹When being 6 yuan of aryl or heteroaryl, substituting group can be preferably placed at 6 yuan of contrapositions on the ring.When substituting group was positioned at contraposition, preferably its size was greater than fluorine atom.

Radicals R ⁹Normally unsubstituted phenyl or benzyl, perhaps by the phenyl or the benzyl of 1,2 or 3 substituting group replacement, described substituting group is selected from halogen; Hydroxyl; Trifluoromethyl; Cyano group; Carboxyl; C _1-4Alkoxy carbonyl; C _1-4Acyloxy; Amino; Single-or two-C _1-4Alkylamino; By halogen, hydroxyl or C _1-2The optional C that replaces of alkoxyl group _1-4Alkyl; By halogen, hydroxyl or C _1-2The optional C that replaces of alkoxyl group _1-4Alkoxyl group; Phenyl; Comprise 3 heteroatomic 5 and 6 yuan of heteroaryls that are selected from O, N and S at the most; With comprise 2 heteroatomic saturated carbon ring and heterocyclic radicals that are selected from O, S and N at the most.

Be used for the compound of another kind of subclass of the present invention, A is the stable hydrocarbon linking group that comprises 1-7 carbon atom, and described linking group is at R ¹With NR ²R ³Between have the maximum chain length of 5 atoms, at E and NR ²R ³Between have the maximum chain length of 4 atoms, wherein linking group carbon atom can be by oxygen or the optional displacement of nitrogen-atoms; Wherein the carbon atom of linking group A can be chosen wantonly and carry one or more substituting groups that are selected from fluorine and hydroxyl, and prerequisite is when having hydroxyl, and hydroxyl is not positioned at respect to NR ²R ³The alpha-carbon atom of group; And

R ⁵Be selected from hydrogen, C _1-5Saturated hydrocarbyl, cyano group, CONH ₂, CF ₃, NH ₂, NHCOR ⁹And NHCONHR ⁹

For avoiding feeling uncertain, should understand radicals R ¹Various general and concrete preferred, embodiment and example can with radicals R ²And/or R ³And/or R ⁴And/or R ⁵And/or R ⁹Various general and concrete preferred, embodiment and example combination, all these type of combinations all are included in the application.

Usually select the various functional groups and the substituting group of composition formula (I) compound like this, so that the molecular weight of formula (I) compound is no more than 1000.The molecular weight of compound more generally will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550.More preferably molecular weight is less than 525, for example below 500 or 500.

Be used for particular compound of the present invention and list, comprising in following examples:

N-methyl-N '-(9H-purine-6-yl)-propane-1, the 3-diamines;

6-(3-methylamino-propyl group amino)-7,9-dihydro-purine-8-ketone;

1-(4-fluorophenyl)-N ³-(9H-purine-6-yl) propane-1, the 3-diamines;

6-[3-amino-3-(4-fluorophenyl) propyl group amino]-7,9-dihydro purine-8-ketone;

1-(4-chloro-phenyl-)-N ³-(9H-purine-6-yl) propane-1, the 3-diamines;

Methyl-(4-(9H-purine-6-yl) benzyl) amine;

Methyl-(3-(9H-purine-6-yl) benzyl) amine;

(4-(9H-purine-6-yl) phenyl) acetonitrile;

2-(4-(9H-purine-6-yl) phenyl) ethamine;

2-(3-(9H-purine-6-yl) phenyl) ethamine;

1-(9H-purine-6-yl) piperidines-4-carboxylic acid amide;

C-[1-(9H-purine-6-yl) piperidin-4-yl] methylamine;

6-[4-(aminophenyl methyl) piperidines-1-yl]-7,9-dihydro purine-8-ketone;

6-[4-(amino (4-chloro-phenyl-) methyl) piperidines-1-yl]-7,9-dihydro purine-8-ketone;

6-(4-amino methyl piperidines-1-yl)-7,9-dihydro purine-8-ketone;

3-[3-(9H-purine-6-yl)-phenoxy group]-propylamine;

C-[1-(1H-pyrazolo [3,4-d] pyrimidine-4-yl)-piperidin-4-yl]-methylamine;

C-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-piperidin-4-yl]-methylamine;

C-phenyl-C-[4-(9H-purine-6-yl)-phenyl]-methylamine;

2-phenyl-1-[4-(9H-purine-6-yl)-phenyl]-ethamine;

6-[4-(1-amino-2-phenylethyl) piperidines-1-yl]-7,9-dihydro purine-8-ketone;

6-(4-[4-(4-chloro-phenyl-)-piperidin-4-yl)-phenyl)-the 9H-purine;

4-{4-[4-(4-chloro-phenyl)-piperidin-4-yl]-phenyl }-7H-pyrrolo-[2,3-d] pyrimidine;

C-phenyl-C-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-piperidin-4-yl]-methylamine;

C-4-chloro-phenyl--C-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-piperidin-4-yl]-methylamine;

C-(4-chloro-phenyl)-C-[1-(9H-purine-6-yl)-piperidin-4-yl]-methylamine;

4-{4-[4-(4-chloro-phenyl)-piperidin-4-yl]-phenyl }-1H-pyrrolo-[2,3-b] pyridine;

C-(4-chloro-phenyl)-C-[4-(9H-purine-6-yl)-phenyl]-methylamine;

C-(4-chloro-phenyl-)-C-[1-(1H-pyrrolo-[2,3-b] pyridin-4-yl) piperidin-4-yl] methylamine;

2-(4-chloro-phenyl)-2-[4-(1H-pyrrolo-[2,3-b] pyridin-4-yl)-phenyl]-ethyl }-methyl-amine;

C-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidines-3-yl] methylamine; With

And salt, solvate, tautomer or N-oxide compound.

Salt, solvate, tautomer, isomer, N-oxide compound, ester, prodrug and same The position is plain

Unless otherwise, otherwise mention particular compound and also comprise its ion, salt, solvate and protection form, following discussion.

Many formulas (I) compound can salt acid salt for example, or exist with organic and salt form mineral alkali in some cases, as carboxylate salt, sulfonate and phosphoric acid salt.All these type of salt are mentioned the salt form that formula (I) compound comprises compound all within the scope of the invention.As the description of the above-mentioned part of the application, unless context indicate in addition, also relate to formula (II) and (III) and subclass otherwise all of formula (I) are described.

The method that can select and prepare salt form is described in Pharmaceutical Salts:Properties, Selection, and Use, P.Heinrich Stahl (editor), Camille G.Wermuth (editor), ISBN:3-90639-026-8, Hardcover, 388 pages, August2002.

The available inorganic and various acid formation of organic acid acid salt.The example of acid salt comprises the salt that forms with acid; described acid is selected from acetate; 2; the 2-Mono Chloro Acetic Acid; hexanodioic acid; Lalgine; xitix (as the L-xitix); the L-aspartic acid; Phenylsulfonic acid; phenylformic acid; the 4-acetylamino benzoic acid; butyric acid; (+) dextrocamphoric acid; camphorsulfonic acid; (+)-(1S)-camphor-10-sulfonic acid; capric acid; caproic acid; sad; styracin; Citric Acid; cyclohexylsulfamic acid; dodecyl sulphate; second-1; the 2-disulfonic acid; ethyl sulfonic acid; the 2-ethylenehydrinsulfonic acid; formic acid; fumaric acid; tetrahydroxyadipic acid; gentisinic acid; glucoheptonic acid; maltonic acid; glucuronic acid (as the D-glucuronic acid); L-glutamic acid (as L-L-glutamic acid); α-Tong Wuersuan; oxyacetic acid; urobenzoic acid; Hydrogen bromide; hydrochloric acid; hydroiodic acid HI; isethionic acid; lactic acid (as (+)-L-lactic acid and (±)-DL-lactic acid); lactobionic acid; toxilic acid; oxysuccinic acid; (-)-L MALIC ACID; propanedioic acid; (±)-DL-amygdalic acid; methylsulfonic acid; naphthene sulfonic acid (as naphthalene-2-sulfonic acid); naphthalene-1; the 5-disulfonic acid; 1-hydroxyl-2-naphthoic acid; nicotinic acid; nitric acid; oleic acid; vitamin B13; oxalic acid; palmitinic acid; pounce on acid; phosphoric acid; propionic acid; the L-Pyrrolidonecarboxylic acid; Whitfield's ointment; 4-amino-Whitfield's ointment; sebacic acid; stearic acid; succsinic acid; sulfuric acid; tannic acid; (+)-L-tartrate; thiocyanic acid; toluenesulphonic acids (as tosic acid); undecylenic acid and positive valeric acid, and acylated amino and Zeo-karb.

For example, if compound is a negatively charged ion, perhaps have possibility and be anionic functional group (can be-COO as-COOH ^-), then can with suitable salt forming cation.Suitable inorganic cation example includes but not limited to alkalimetal ion such as Na ⁺And K ⁺, alkaline earth cation such as Ca ²⁺And Mg ²⁺, and other positively charged ion such as Al ³⁺Suitable organic cation example includes but not limited to that ammonium ion is (as NH ₄ ⁺) and the ammonium ion that replaces (as NH ₃R ⁺, NH ₂R ₂ ⁺, NHR ₃ ⁺, NR ₄ ⁺).Some suitable substituted ammonium ion examples are derived from ethamine, diethylamine, dicyclohexyl amine, triethylamine, butylamine, quadrol, thanomin, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and Tutofusin tris and amino acid such as Methionin and arginine.Quaternary ammonium ion example commonly used is N (CH ₃) ₄ ⁺

When formula (I) when compound comprises amine functional group, then these compounds can form quaternary ammonium salt, and for example the method for knowing with the technician is by forming quaternary ammonium salt with the alkylating agent reaction.This type of quaternary ammonium compound is in formula (I) scope that this paper limits.

The salt form that is used for compound of the present invention is pharmacy acceptable salt normally, about the case description of pharmacy acceptable salt in Berge etc., 1977, ＂ PharmaceuticallyAcceptable Salts (pharmacy acceptable salt), ＂ J.Pharm.Sci., 66 volumes, 1-19 page or leaf.But, also unacceptable salt pharmaceutically can be prepared into intermediate form, be translated into pharmacy acceptable salt then.This type of pharmaceutically unacceptable salt form can be used for for example purifying or separating compound, also is applicable to the present invention.

Formula (I) compound that comprises ammonia functional group also can form the N-oxide compound.When this paper mentions formula (I) compound that comprises ammonia functional group, also comprise the N-oxide compound.

When compound comprises several ammonia functional group, 1 or 1 the oxidable formation of above nitrogen-atoms N-oxide compound.The specific examples of N-oxide compound is the N-oxide compound of tertiary amine or nitrogen heterocyclic ring nitrogen-atoms.

Available oxidant such as hydrogen peroxide or peracid (as peroxycarboxylic acid) are handled corresponding amine and are formed the N-oxide compound, consult for example Advanced Organic Chemistry, Jerry March, the 4th edition, Wiley Interscience, pages.More specifically, can prepare by the method for L.W.Deady the N-oxide compound (Syn.Comm.1977,7,509-514), wherein amine compound and metachloroperbenzoic acid (MCPBA) for example react in inert solvent such as methylene dichloride.

Formula (I) compound can multiple different geometrical isomer and tautomeric forms exist, comprise all these type of forms when mentioning formula (I) compound.For avoiding confusion, when compound can be used as a kind of existence in several rotamerisms or the tautomeric form and only specifically describes or show when a kind of, all other isomeric form all are included in the formula (I) that this paper limits.

For example, work as J ¹-J ²Be N=CR ⁶The time, bicyclic group may be tautomeric form A and B.

Work as J ¹-J ²When being N=N, bicyclic group may be tautomeric form C and D.

Work as J ¹-J ²When being HN-CO, bicyclic group may be tautomeric form E, F and G.

All these type of tautomers all are included in the formula (I) of this paper qualification.

Other example of tautomeric form comprise ketone-, enol-and enolate anion-form, right as following tautomerism: ketone/enol (hereinafter showing), imines/enamine, acid amides/imidohydrine, amidine/amidine, nitroso-group/oxime, thioketones/alkene mercaptan and nitro/isonitro.

When formula (I) when compound comprises one or more chiral centre, can there be two or more optically active isomer forms, unless the other requirement of context, otherwise comprise its all rotational isomerism forms (as enantiomorph, table isomer and diastereomer) when mentioning formula (I) compound, as individual optically active isomer, the perhaps mixture of two or more optically active isomers (as racemic mixture).

Optically active isomer can characterize and identify by its optically active (be conduct+and-isomer, perhaps d and l isomer), perhaps use " R " and " S " nomenclature according to its absolute stereo chemical characterization, described nomenclature is by Cahn, Ingold and Prelog exploitation, consult Advanced OrganicChemistry, Jerry March, the 4th edition, John Wiley ﹠amp; Sons, New York, 1992, the 109-114 page or leaf is also consulted Cahn, Ingold ﹠amp; Prelog, Angew.Chem.Int.Ed.Eng1., 1966,5,385-415.

Available several different methods comprises chirality chromatography (chromatography on chiral support) separating optical isomers, and these class methods are known for those skilled in the art.

When formula (I) compound existed as two or more rotational isomerism forms, a kind of enantiomorph of enantiomorph centering can show the advantage that surpasses another kind of enantiomorph, and biological example is learned active advantage.Therefore, in some cases, may only need a kind of with in one or more diastereomers of enantiomorph centering as therapeutical agent.Therefore, the invention provides and comprise formula (I) compound compositions with one or more chiral centres, wherein at least 55% (as at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) formula (I) compound exists as single optically active isomer (as enantiomorph or diastereomer) of planting.In a general embodiment, 99% or more (as whole substantially) of formula (I) total amount of compound can be used as single optically active isomer (as enantiomorph or diastereomer) of planting and exist.

Be used for compound of the present invention and comprise having the compound that one or more isotropic substances replace, its scope comprises all isotropic substances of this element when mentioning concrete element.Its scope comprises when for example, mentioning hydrogen ¹H, ²H (D) and ³H (T).Its scope comprises respectively when similarly, mentioning carbon and oxygen ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O.

Isotropic substance can be radioactivity or on-radiation.In one embodiment of the invention, compound does not comprise radio isotope.This compounds is preferred for treatment.But in another embodiment, compound can comprise one or more radio isotope.Comprise radioisotopic compound and can be used for diagnosis.

Carrying the ester of formula (I) compound of carboxylic acid group or hydroxyl such as carboxylicesters and acyloxyate is also included within formula (I) scope that this paper limits.In one embodiment of the invention, the scope of formula (I) comprises the ester of formula (I) compound that carries carboxylic acid group or hydroxyl.In another embodiment of the invention, the scope of formula (I) does not comprise the ester of formula (I) compound that carries carboxylic acid group or hydroxyl.The example of ester is to comprise group-C (=O) compound of OR, wherein R is ester substituting group, for example C _1-7Alkyl, C _3-20Heterocyclic radical or C _5-20Aryl, preferred C _1-7Alkyl.The specific examples of ester group includes but not limited to-C (=O) OCH ₃,-C (=O) OCH ₂CH ₃,-C (=O) OC (CH ₃) ₃With-C (=O) OPh.The example of acyloxy (anti-ester) by-OC (=O) R represents, wherein R is acyloxy substituting group, for example C _1-7Alkyl, C _3-20Heterocyclic radical or C _5-20Aryl, preferred C _1-7Alkyl.The specific examples of acyloxy includes but not limited to-OC (=O) CH ₃(acetoxyl group) ,-OC (=O) CH ₂CH ₃,-OC (=O) C (CH ₃) ₃,-OC (=O) Ph and-OC (=O) CH ₂Ph.

Formula (I) also comprise any polymorph, the solvate (as hydrate) of compound, the complex compound of compound (as with the clathrate complex of compounds such as cyclodextrin or Runge-Kutta integration or with the complex compound of metal) and compound prodrug.Any compound that refers to for example to be converted in vivo biological activity formula (I) compound that this paper limits with " prodrug ".

For example, some prodrugs are esters (as acceptable easy metabolic ester on the physiology) of active compound.When metabolism, ester group (C (=O) OR) cracking obtains active medicine.This type of ester can form by any carboxylic acid group in the esterification parent compound for example (C (=O) OH), and wherein suitably protection in advance is present in any other reactive group in the parent compound, then deprotection as required.

The example of this type of easy metabolic ester comprise formula-C (=O) ester of OR, wherein R is:

C _1-7Alkyl

(as-Me ,-Et ,-nPr ,-iPr ,-nBu ,-sBu ,-iBu ,-tBu);

C _1-7Aminoalkyl group (as amino-ethyl, 2-(N, N-diethylamino) ethyl, 2-(4-morpholino) ethyl); With

Acyloxy-C _1-7Alkyl

(as the acyloxy methyl;

The acyloxy ethyl;

Pivaloyl oxygen ylmethyl;

Acetoxy-methyl;

1-acetoxyl group ethyl;

1-(1-methoxyl group-1-methyl) ethyl-ketonic oxygen base ethyl;

1-(benzoyl oxygen base) ethyl; Isopropoxy-ketonic oxygen ylmethyl;

1-isopropoxy-ketonic oxygen base ethyl; Cyclohexyl-ketonic oxygen ylmethyl;

1-cyclohexyl-ketonic oxygen base ethyl;

Cyclohexyl oxygen base-ketonic oxygen ylmethyl;

1-cyclohexyl oxygen base-ketonic oxygen base ethyl;

(4-THP trtrahydropyranyl oxygen base) ketonic oxygen ylmethyl;

1-(4-THP trtrahydropyranyl oxygen base) ketonic oxygen base ethyl;

(4-THP trtrahydropyranyl) ketonic oxygen ylmethyl; With

1-(4-THP trtrahydropyranyl) ketonic oxygen base ethyl).

In addition, some prodrugs are obtained active compound by enzyme activation, perhaps through the compound that obtains active compound behind the further chemical reaction (for example at Antibody-directed EnzymeProdrug Therapy (antibody targeted enzymolysis prodrug therapy) (ADEPT), Gene-directedEnzyme Prodrug Therapy (gene targeting enzymolysis prodrug therapy) (GDEPT), Polymer-directed Enzyme Prodrug Therapy (polymkeric substance guiding enzymolysis prodrug therapy) (PDEPT), Ligand-directed Enzyme Prodrug Therapy (part guiding enzymolysis prodrug therapy) (LIDEPT) etc.).For example, prodrug can be sugar derivatives or other glucosides conjugates, perhaps can be amino acid ester derivative.

The preparation method of formula (I) compound

In this part, unless the other requirement of context, otherwise comprise formula (II) that this paper limits and (III) and various subclass when mentioning formula (I) compound.

Aspect another, the invention provides the preparation method of formula (I) compound of this paper qualification.

By making the reaction of formula (X) compound and formula (XI) compound, can prepare wherein that E is formula (I) compound of aryl or heteroaryl, wherein (X) but and (XI) due care, wherein A, E and R ^1-R ⁵Limit as mentioned, one of them is chlorine, bromine or iodine or trifluoromethanesulfonic acid (trifluoromethanesulfonic acid) base for radicals X and Y, and another group is the boronate residue among radicals X and the Y, as boric acid ester or boric acid residue.

Reaction can be under conventional Suzuki coupling condition, (as is described in R.B.Bedford ﹠amp at palladium catalyst such as tetrakis triphenylphosphine palladium or palladacycle catalyzer; C.S.J.Cazin, Chem.Commun., 2001, the palladocycle catalyzer of 1540-1541) and the existence of alkali (as carbonate such as salt of wormwood) under carry out.Reaction can be at polar solvent such as water-containing solvent such as aqueous ethanol, or carries out in ether such as the glycol dimethyl ether Huo diox, with the reaction mixture heating, for example is heated to 80 ℃ or higher temperature usually, as surpassing 100 ℃ temperature.

The exemplary route of synthesis that comprises Suzuki coupling step is shown in flow process 1.In flow process 1, by with lithium alkylide such as butyllithium and boric acid ester (iPrO) ₃B reaction is that the bromo compound (XII) of aryl or heteroaryl is converted into boric acid (XIII) with E wherein.Reaction is carried out under the temperature (as-78 ℃) that reduces in anhydrous polar solvent such as tetrahydrofuran (THF) usually.

Then under these conditions, in the presence of tetrakis triphenylphosphine palladium, the gained boric acid (XIII) and the chlorinated compound (XIV) of N-protected are reacted.Then handle and remove blocking group PG (for example can be THP trtrahydropyranyl (THP)), obtain formula (I) compound that this paper limits with sour example hydrochloric acid.

In flow process 1, work as R ²And/or R ³When being hydrogen, usually with the appropriate protection radical protection amino N R that hereinafter lists ²R ³A kind of concrete blocking group that can use in the Suzuki coupling is a tert-butoxycarbonyl, can make amino the reaction with the dimethyl dicarbonate butyl ester introduce tert-butoxycarbonyl in the presence of alkali such as triethylamine.Usually on removing bicyclic group, remove this blocking group in the blocking group PG.

Flow process 1

As using substituting of boric acid (compounds X III) in the Suzuki coupling step, can use boric acid ester.Can phosphine such as tricyclohexyl phosphine and palladium (0) reagent as three (dibenzalacetone)-two palladiums (0) in the presence of, make formula (XII) compound and hypoboric acid ester as the reaction of connection boric acid pinacol ester, preparation boric acid ester (as tetramethyl ethylene ketone boric acid ester (pinacolatoboronate)).The formation of boric acid ester is carried out in anhydrous polar aprotic solvent such as diox usually, is heated to about at the most 100 ℃ temperature, as at about 80 ℃.

Also can show with aldehyde cpd (XVI) preparation formula (I) compound as flow process 2.Can be under above-mentioned Suzuki coupling condition, at palladium catalyst Pd (PPh ₃) ₄Existence under, dicyclo chlorinated compound (XIV) that makes N-protected and formula (HO) ₂The boric acid derivatives reaction of B-E-CHO, preparation aldehyde cpd (XVI).Multiple different formula (I) compound that available then aldehyde (XVI) preparation this paper limits.Therefore, for example, at room temperature, in the methylene dichloride, in the presence of suitable dewatering agent such as sal epsom and acid catalyst such as tosic acid pyridine, aldehyde and the reaction of tertiary butyl sulfinyl amine obtain intermediate tertiary butyl sulfenimide (not shown), then with Grignard reagent R ¹-MgBr reaction, wherein R ¹Be aryl or heteroaryl (as in tetrahydrofuran (THF), under the room temperature or reflux), obtain tertiary butyl sulfinyl aminoderivative (XVII), then with its in methyl alcohol with hydrochloric acid hydrolysis and deprotection, obtain amine (XVIII).

Usually under the temperature that reduces, in polar solvent such as ethanol or tetrahydrofuran (THF) (THF), use amine HNR ²R ³Make aldehyde (XVI) reductive amination with reductive agent such as hydroborate (as sodium borohydride) or hydroborate derivative (as sodium cyanoborohydride or sodium triacetoxy borohydride), obtain corresponding compound (XIX), wherein A is CH and R ¹Be hydrogen.

Flow process 2

Form wherein ANR ²R ³Be CHCH ₂CN or CHCH ₂CH ₂NR ²R ³Formula (I) compound, can be by (consulting Advanced OrganicChemistry, J.March, the 4th edition, John Wiley ﹠amp at standard K noevenagel condensation condition; Sons, 1992,945-947 page or leaf and reference wherein) under, in the presence of alkali such as sodium hydroxide or potassium hydroxide or amine such as diethylamine or triethylamine, make aldehyde (XVI) and propane dinitrile or ethyl cyanacetate reaction, obtain intermediate cyanacrylate derivant (not shown).Then cyanacrylate derivant can with Grignard reagent R ¹-MgBr reaction makes product hydrolysis and decarboxylation, obtains formula (XX) compound, wherein R ¹Be aryl or heteroaryl.Perhaps, available reductive agent is handled cyanacrylate derivant, and described reductive agent is with the two keys of the alkene of selective reduction alpha-cyanoacrylate ester group and the itrile group that do not reduce, the acetonitrile derivative that obtains replacing (XIV).Hydroborate such as sodium borohydride can be used for this purpose.Reduction reaction is carried out in solvent such as ethanol usually, for example is heated to about at the most 65 ℃ temperature usually.Make product hydrolysis and decarboxylation then, obtain wherein R ¹It is formula (XX) compound of hydrogen.

Can handle by in ethanol, using appropriate reductant such as Raney nickel and ammonia or hydrazine then, make the cyanide compound (XX) of replacement be reduced to corresponding amine (XXI).

Can make aldehyde (XVI) and Nitromethane 99Min. condensation in the presence of alkali, reduce gained nitroethylene intermediate (not shown) then, preparing wherein, A is CHCH ₂And R ¹It is formula (I) compound of hydrogen.

Can form formula (I) compound by the Method type that flow process 3 shows, wherein group A comprises the heteroatoms of direct connection E, and E is aryl or heteroaryl.

Flow process 3

In flow process 3, make wherein X ²The bromo aryl or the bromo heteroaryl derivative (XXII) that are O carry out Mitsunobu coupled reaction, wherein X with hydroxyalkyl compound (XXIII) ³Be OH, A ' is the residue of group A, and PG is blocking group such as tert-butoxycarbonyl.The Mitsunobu coupled reaction uses diisopropyl azo-2-carboxylic acid (DIAD) and triphenylphosphine to carry out in polar solvent such as THF as coupler usually.

X wherein ²The bromo compound that is the formula (XXIV) of S or NH also can be by making wherein X ²Be formula (XXII) compound of S and X wherein ³Formula (XXIII) the compound reaction that is halogen, particularly bromine or chlorine forms.By using wherein X ³Formula (XXIII) compound that is aldehyde radical makes wherein X ²Be formula (XXII) the compound reductive amination of NH, form wherein X ²It is formula (XXIV) compound of NH.

Gained bromo compound (XXIV) and hypoboric acid ester reagent (XXVII) are reacted in the presence of palladium catalyst; obtain boric ester derivative (XXV); then can under the Suzuki condition, make itself and chloro-dicyclic compound (XIV) coupling, with obtaining formula (XXVI) compound behind the sour deprotection.

In preparation process listed above, in the presence of palladium catalyst and alkali, make halo-purine (or its aza analogues) or halo-aryl or heteroaryl compound and boric acid ester or acid reaction, finish the coupling of aryl or heteroaryl E and bicyclic group.Be applicable to that preparation is used for the commercially available acquisition of many boric acid esters of compound of the present invention, for example available from Boron Molecular Limitedof Noble Park, Australia, or available from Combi-Blocks Inc, of San Diego, USA.When buying less than boric acid ester, available methods known in the art prepare, and for example are described in the summary of N.Miyaura and A.Suzuki, Chem.Rev.1995,95,2457.Therefore, can be by making the reaction of corresponding bromo compound and lithium alkylide such as butyllithium, react with boric acid ester then, the preparation boric acid ester.Can obtain corresponding boric acid as required with the hydrolysis of gained boric ester derivative.

Available formula (XXVIII) compound or its protection form prepare formula (I) compound that group A wherein comprises the nitrogen-atoms of linking group E by well-known synthetic method.But through type (XIV) compound (consulting flow process 1) and formula (HO) ₂B-E-NH ₂Compound or the Suzuki coupled reaction of its N-protected derivative, obtain the compound of formula (XXVIII).

But through type (XXIX) compound and amine compound H ₂It is non-aromatics cyclic group or non-cyclic group and formula (I) compound that is connected with bicyclic group by nitrogen-atoms that N-G or formula (XXX) compound or its protected derivatives reaction prepare E wherein; wherein G such as this paper limit, and ring E representative comprises the cyclic group E of nucleophilic NH group as ring members.

Reaction is carried out under the temperature of temperature as 90 ℃ of-160 ℃ of scopes that improves in as alcohol (as ethanol, propyl alcohol or propyl carbinol) at polar solvent usually.Reaction can be carried out in sealed tube, particularly when desired reaction temperature surpasses the boiling point of solvent.When T was N, reaction was carried out under the temperature of about 100 ℃ of-130 ℃ of scopes usually, but when T is CH, may need higher temperature, for example about at the most 160 ℃, therefore can use more high boiling solvent such as dimethyl formamide.In general, will use excessive nucleophilic amine and/or comprise other non-reactive alkali such as triethylamine in the reaction mixture.But by general tool or use microwave heater reacting by heating mixture.

Change above method, formula (XXIX) compound can with the reactive ketone of formula (XXXI, A ＂ are key or alkylidene group such as methylene radical), show as flow process 4.

Flow process 4

The reaction of ketone (XXXI) and chloro dicyclic compound (XXIX) usually in alcoholic solvent such as propyl carbinol, in the temperature that improves as in the temperature of 100 ℃ of scopes with in the presence of glitch-free alkali such as triethylamine, carry out.In polar solvent such as methyl alcohol, in the presence of reductive agent such as sodium cyanoborohydride, make gained ketone (XXXII) carry out reductive amination then with ammonium acetate.

Formula (XXIX) compound is commercially available, the perhaps method preparation known of available techniques personnel.For example, wherein T is N and J ¹-J ²Be CH=N formula (XXIX) compound can with corresponding oxy-compound by with chlorizating agent such as POCl ₃Prepared in reaction.J wherein ¹-J ²Be HN-C (O) formula (XXIX) but neighbour-diamino compounds and N,N'-carbonyldiimidazole prepared in reaction in the presence of glitch-free alkali such as triethylamine of compound through type (XXXIV).

Wherein T is CR ⁵And J ¹-J ²Be (R ⁷) H=CH (R ⁶) formula (XXIX) compound can be with the N-oxide compound and temperature such as the POCl of phosphorus oxychloride of corresponding formula (XXXV) in raising ₃Reflux temperature under prepared in reaction.

The method preparation that formula (X) and raw material available techniques personnel (XII) know.For example, when E be that aryl or heteroaryl, X are halogen such as bromine and radicals R ¹-A-NR ²R ³Be CH (CN) CH ₂R ¹The time, formula (I) compound can prepare with the method that flow process 5 shows.The raw material of route of synthesis shown in the flow process 5 is aryl-or the heteroaryl formonitrile HCN (XXXVI) of halogen-replacement, and wherein X is chlorine, bromine or iodine atom or trifluoromethanesulfonic acid base.Nitrile (XXXVI) and aldehyde R ¹CHO in the presence of alkali such as sodium hydroxide or potassium hydroxide, condensation in aqueous solvent system such as aqueous ethanol.Reaction can at room temperature be carried out.

Handle the acrylonitrile derivative (XXXVII) that gained replaces with reductive agent then, reductive agent is with the selective reduction olefinic double bonds and the itrile group that do not reduce.Hydroborate such as sodium borohydride can be used for this purpose, the acetonitrile derivative that obtains replacing (XXXVIII).Reduction reaction is carried out in solvent such as ethanol usually, is heated to for example about at the most 65 ℃ temperature usually.Under above-mentioned Suzuki coupling condition, after wherein Y is formula (XI) the boric acid ester compound reaction of boric acid ester or boric acid residue,, itrile group can be reduced to corresponding CH by in ethanol, using appropriate reductant such as Raney nickel and ammonia treatment ₂NH ₂Group.

Perhaps, can with the boric acid ester coupling before be reduced to itrile group amino and introduce amine protecting group group.

Flow process 5

The route of synthesis that flow process 5 shows obtains formula (X) and aminocompound (XII), and wherein aryl or heteroaryl groups E are connected with β-position with respect to the group A of amino.In order to obtain wherein R ¹Formula (X) that is connected with β-position with respect to amino or (XII) aminocompound, the functional group in the condensation step on two kinds of raw materials can reverse, so that wherein X is the formula X-E-CHO compound and the formula R of bromine, chlorine, iodine or trifluoromethanesulfonic acid base ¹-CH ₂-CN compound condensation, the acrylonitrile derivative that obtains replacing makes it be reduced to corresponding acetonitrile derivative then, and then with boric acid ester (XI, Y=boric acid ester residue) coupling, it is amino making cyano reduction.

The response procedures preparation formula (X) that can show by flow process 6 or (XII) compound, wherein R ¹Be connected with alpha-position with respect to amino.

In flow process 6, raw material is the aryl that replaces of halogen-or heteroaryl methyl Grignard reagent (XXXIX), X=bromine or chlorine), with nitrile R ¹-CN reacts in anhydrous ether such as ether, obtains intermediate imines (not shown), makes its reduction obtain amine (XXXX) with reductive agent such as lithium aluminum hydride.Amine (XXXX) can react under above-mentioned Suzuki coupling condition with boric acid ester or boric acid (XI), obtains formula (I) compound that this paper limits.

Flow process 6

Can show preparation formulas (X) and (XII) compound, wherein R according to flow process 7 ¹Be connected identical carbon atom with E.

Flow process 7

In flow process 7, wherein X is the aldehyde cpd (XXXXI) and ethyl cyanacetate condensation in the presence of alkali of bromine, chlorine, iodine or trifluoromethanesulfonic acid base, obtains cyanoacrylate intermediate (XXXXII).Condensation in the presence of alkali, preferred non-hydroxide such as piperidines, is undertaken by heating under Dean Stark condition usually.

Cyanoacrylate intermediate (XXXXII) and Grignard reagent R then ¹The MgBr reaction, described reagent is fit to by the Michael addition radicals R ¹Introduce the carbon-to-carbon double bond of acrylate part.Grignard reaction can be in polar aprotic solvent such as tetrahydrofuran (THF), low temperature according to appointment 0 ℃ carry out.The product of Grignard reaction is cyanopropionic acid ester (XXXXIII), with its hydrolysis and decarboxylation, obtains propanoic derivatives (XXXXIV).Hydrolysis and decarboxylation step can heat in acidic medium such as sulfuric acid and acetate mixture to be finished.

By making propanoic derivatives (XXXXIV) and amine HNR ²R ³Under the condition that is fit to the formation amido linkage, react, be converted into acid amides (XXXXV).Propanoic derivatives (XXXXIV) and amine HNR ²R ³Between coupled reaction preferably in the presence of the reagent that is generally used for forming peptide bond, carry out.This type of example agents comprises 1,3-dicyclohexylcarbodiimide (DCC) (Sheehan etc., J.Amer.Chem Soc.1955,77,1067), 1-ethyl-3-(3 '-dimethylamino-propyl)-carbodiimide (being called EDC or EDAC here) (Sheehan etc., J.Org.Chem., 1961,26,2525), coupler such as O-(7-azepine benzo triazol-1-yl)-N based on uronium, N, N ', the coupler of N '-tetramethyl-urea hexafluorophosphate (HATU) and Ji Yu Phosphonium such as 1-benzo-triazolyl oxygen base three-(tetramethyleneimine-1-base) Phosphonium hexafluorophosphate (PyBOP) (Castro etc., Tetrahedron Letters, 1990,31,205).Based on the coupler of carbodiimide preferably with 1-hydroxyl-7-azepine benzotriazole (HOAt) (L.A.Carpino, J.Amer.Chem.Soc, 1993,115,4397) or I-hydroxybenzotriazole (HOBt) (Konig etc., Chem.Ber., 103,708,2024-2034) be used in combination.Preferred coupler comprises EDC (EDAC) and the DCC with HOAt or HOBt combination.

Coupled reaction or in aqueous solvent, is optionally carried out with one or more compatibility cosolvent usually in non-aqueous, aprotic solvent such as acetonitrile, dioxane, dimethyl sulfoxide (DMSO), methylene dichloride, dimethyl formamide or N-crassitude.Reaction can at room temperature be carried out, and perhaps works as reactant activity and carries out under the temperature that suitably improves than hour (as under the situation of light current (electron-poor) aniline that carries electron-withdrawing group such as sulfoamido).Reaction can be carried out under the existence of N-diisopropylethylamine at glitch-free alkali such as tertiary amine such as triethylamine or N.

As amine HNR ²R ³When being ammonia, can be before adding ammonia with 1,1 '-N,N'-carbonyldiimidazole (CDI) activation carboxylic acid carries out the acid amides coupled reaction.

Perhaps, can use response derivative such as the acid anhydride or the chloride of acid of carboxylic acid.With the reaction of response derivative such as acid anhydride usually in the presence of alkali such as pyridine, at room temperature finish by stirring amine and acid anhydride.

Can make acid amides (XXXXV) and boric acid ester (XI) reaction under above-mentioned Suzuki coupling condition, be translated into formula (I) compound, wherein A has the oxo substituting group near NR ²R ³Group.Then in the presence of aluminum chloride,, obtain formula (I) compound, wherein NR with hydride reducer such as lithium aluminium hydride reduction gained formula (I) acid amides ²R ³Be NH ₂, wherein A is CH-CH ₂-CH ₂-.Reduction reaction is heated to solvent usually in ether solvents such as ether reflux temperature carries out.

Acid amides (XXXXV) does not react with boric acid ester or boric acid (XI), the substitute is, acid amides can be reduced with lithium aluminum hydride/aluminum chloride, as in ether solvents, reducing at ambient temperature, obtain corresponding amine (XXXXVI), itself and boric acid ester or boric acid (XI) are reacted under above-mentioned Suzuki coupling condition, obtain formula (I) compound that this paper limits.

Homologue for the amine that obtains to comprise less methylene radical, carboxylic acid (XXXXIV) can be converted into triazo-compound and carries out Curtius and reset and (to consult AdvancedOrganic Chemistry by standard method, the 4th edition, Jerry March, John Wiley ﹠amp; Sons, 1992, the 1091-1092 page or leaf).

By making the aldehyde cpd of formula (XXXXVII):

With formula HNR ²R ³Amine in standard reductive amination condition as in the presence of at sodium cyanoborohydride, reductive amination in alcoholic solvent such as methyl alcohol or ethanol, but the midbody compound of preparation formula (X), wherein part X is chlorine, bromine or iodine atom, A is group CH-CH ₂-.

Make corresponding alcohol (XXXXVIII) oxidation obtain aldehyde cpd (XXXXVII) with for example Dess-Martin periodinane and (consult Dess, D.B.; Martin, J.C.J.Org.Soc, 1983,48,4155 and Organic Syntheses, 77 volumes, 141).

But the spiral ring intermediate of the boric acid ester of through type (XI) or boronic acid compounds and formula (XXXXIX) or the Suzuki coupling of its N-protected derivative form wherein A, N and R ²Form formula (I) compound of spiral ring group together.

Can pass through aryl compound R ¹The Friedel Crafts alkanisation of-H and formula (L) compound forms the spiral ring intermediate of formula (L), wherein R ¹Be the phenyl of aryl as optional replacement:

Alkanisation is sour as carrying out as being lower than 5 ℃ in the temperature that reduces in the presence of the aluminum chloride at Lewis usually.

Preparing wherein part NR ²R ³CH with part A ₂In another method of formula (I) compound that group connects, can under above-mentioned reductive amination condition, make the aldehyde and the formula HNR of formula (LI) ²R ³The amine coupling.In formula (LI) with (LII), A ' is residue-be part A ' and CH of group A ₂Form group A together.The available for example Dess-Martin of aldehyde (LI) periodinane forms corresponding alcohol (LII) oxidation.

In case form, then available standards functional group exchanges and makes many formulas (I) compound be converted into other formula (I) compound.

For example, can be by using bromizating agent such as N-bromine succinimide (NBS) bromination J ¹-J ²In carbon atom, then with the hydrolysis of mineral acid example hydrochloric acid, wherein J ¹-J ²Formula (I) compound or its protected form that are CH=N are converted into wherein J ¹-J ²It is the corresponding compound of N-C (CO).

Other exchange example comprises makes wherein NR ²R ³Formula (I) compound that forms an itrile group part is reduced to corresponding amine.Can make wherein NR by the reductibility alkanisation ²R ³Be NH ₂The compound of group is converted into corresponding alkylamine, or is converted into cyclic group.

Carrying out the functional group's exchange of this type of conversion and the example of reagent and condition for example can consult, Advanced Organic Chemistry, Jerry March, the 4th edition, 119, WileyInterscience, New York, Fiesers ' Reagents for Organic Synthesis, 1-17 volume, John Wiley, Mary Fieser edits (ISBN:0-471-58283-2), and OrganicSyntheses, the 1-8 volume, John Wiley, Jeremiah P.Freeman edits (ISBN:O-471-31192-8).

In above-mentioned many reactions, one or more groups that may need protection are to prevent that unwanted position reacts on molecule.The method of blocking group example and protective group and deprotection can be consulted Protective Groups in Organic Synthesis (T.Green and P.Wuts; The 3rd edition; John Wiley and Sons, 1999).

Can with hydroxyl protection for for example ether (OR) or ester (OC (=O) R), for example, as uncle's butyl ether; Benzyl, diphenyl-methyl (diphenyl methyl) or trityl (trityl group) ether; Trimethyl silyl or t-butyldimethylsilyl ether; Perhaps ethanoyl ester (OC (=O) CH ₃,-OAc).The aldehydes or ketones base can be protected, for example, respectively as acetal (R-CH (OR) ₂) or ketal (R ₂C (OR) ₂), wherein by with the reaction of primary alconol for example, make carbonyl (〉 C=O) be converted into diether (〉 C (OR) ₂).By in the presence of acid, being easy to make the regeneration of aldehydes or ketones base with excessive water hydrolysis.Can be with amido protection for for example, as acid amides (NRCO-R) or urethane (NRCO-OR), for example conduct: methyl nitrosourea (NHCO-CH ₃); Benzyloxy acid amides (NHCO-OCH ₂C ₆H ₅,-NH-Cbz); As tert.-butoxy acid amides (NHCO-OC (CH ₃) ₃,-NH-Boc); 2-xenyl-2-propoxy-acid amides (NHCO-OC (CH ₃) ₂C ₆H ₄C ₆H ₅-NH-Bpoc); as 9-fluorenyl methoxy acid amides (NH-Fmoc); as 6-nitro veratryl oxygen base acid amides (NH-Nvoc), as 2-trimethyl silyl ethyl oxygen base acid amides (NH-Teoc), as 2; 2; 2-three chloroethoxy acid amides (NH-Troc), as the allyloxy acid amides (NH-Alloc), or as 2-(phenyl sulfonyl) oxyethyl group acid amides (NH-Psec).Other blocking group of amine such as cyclammonium and heterocycle N-H group comprises that tosyl group (tosyl group) and methane sulfonyl (methylsulfonyl) and benzyl are as to methoxy-benzyl (PMB).Can with carboxylic acid group protection for ester for example as C _1-7Alkane ester (as methyl esters, the tert-butyl ester); C _1-7The haloalkane ester is (as C _1-7The tri haloalkyl ester); Three C _1-7Alkyl silyl-C _1-7Alkyl ester; Perhaps C _5-20Aryl-C _1-7Alkane ester (as benzyl ester, nitrobenzyl ester); Or as acid amides, for example as methyl nitrosourea.The thiol group protection can be (SR), for example conduct: benzyl thioether, kharophen methyl ether (S-CH of for example thioether ₂NHC (=O) CH ₃).

The separation and the purifying that are used for compound of the present invention

Can be used for compound of the present invention according to standard method separation well known to those skilled in the art and purifying.A kind of concrete technology that is used for purifying compounds is a preparative liquid chromatography, results from the method for the purifying compounds of chromatography column as detection with mass spectroscopy.

Preparation LC-MS is standard and the effective ways that are used for the little organic molecule compound as described herein of purifying.The method that can change liquid chromatography (LC) (LC) and mass spectroscopy (MS) to be separating raw product better, with MS test sample better.Optimize preparation gradient LC method and will comprise change post, volatility eluent and properties-correcting agent, and gradient.Well known optimization prepares the method that the LC-MS method is used their purifying compounds then.These class methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC/MS; J CombChem.; 2004; 6 (2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquidchromato graphy/mass spectrometer platform for the preparativepurification and analytical analysis of compound libraries; J Comb Chem.; 2003; 5 (3); 322-9.

Medicinal preparations

Though being used for compound of the present invention can be individually dosed, but preferably exist as medicinal compositions (as preparation), described medicinal compositions comprises at least a active compound of the present invention that is used for, and one or more pharmaceutically acceptable carriers, assistant agent, vehicle, thinner, weighting agent, buffer reagent, stablizer, sanitas, lubricant or other material well known to those skilled in the art and optional other treatment or preventive.

Therefore, the present invention also provides the medicinal compositions that is defined as above, with the method for preparing medicinal compositions, described method comprises is mixed together at least a active compound that is defined as above and one or more pharmaceutically acceptable carriers described herein, vehicle, buffer reagent, assistant agent, stablizer or other material.

Term " pharmaceutically acceptable " is used for this paper and refers in the rational medicine determination range, be fit to contact compound, material, composition and/or the formulation of use with experimenter (as the people) tissue, do not produce excessive toxicity, pungency, anaphylaxis or other problem or complication, have rational benefit/risk-benefit risks.Various carriers, vehicle etc. must " can be accepted " to be meant can be compatible with other batching of preparation.

Can comprise the medicinal compositions of formula (I) compound according to the currently known methods preparation, described method is consulted for example Remington ' s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

Therefore, another aspect the invention provides formula (I) compound and subclass thereof that this paper of adopting the medicinal compositions form limits.

Medicinal compositions can adopt be fit in oral, parenteral, part, the nose, any form of eye, ear, rectum, intravaginal or percutaneous dosing.When composition is used for parenteral admin, its preparation can be used for by injection, infusion or other pass prescription formula intravenously, intramuscular, intraperitoneal, subcutaneous administration be used for directly being delivered to target organ or tissue in.Can pass medicine by fast infusion, short-term infusion or more long-term infusion, can pass medicine or by using suitable infusion pump to pass medicine by passive.

The medicinal preparations that is fit to parenteral admin comprises water and non-aqueous aseptic injectable solution, described solution can comprise antioxidant, buffer reagent, bacteriostatic agent, cosolvent, ORGANIC SOLVENT MIXTURES, cyclodextrin complexing agent, emulsifying agent (being used to form and the stable emulsion preparation) but, be used to form the liposome component of liposome, the gelatinate polymer that is used to form polymer gel, lyophilized vaccine and especially for making active batching be stabilized in solubilized form and making the combination of preparation and the isoosmotic material of expection receptor's blood.The medicinal preparations that is used for parenteral admin also can adopt water and non-aqueous sterile suspension form, can comprise suspension agent and thickening material (R.G.Strickly, SolubilizingExcipients in oral and injectable formulations (the solubilising vehicle in the oral and injection formulations), Pharmaceutical Research, 21 (2) volumes, 2004, the 201-230 page or leaf).

Liposome is closed spherical vesicles, is made of integral diameter＜100 μ m outside bilayer lipid membrane and inboard aqueous core.According to the hydrophobicity level, if dewatering medicament is wrapped or inserts in the liposome, medium hydrophobic medicine can be by the liposome solubilising.If drug molecule becomes the intact part of bilayer lipid membrane, dewatering medicament also can be by the liposome solubilising, and in this case, dewatering medicament is dissolved in the lipid part of double-layer of lipoid.

Preparation can adopt for example form of sealed ampoule and bottle of single dose or multi-dose container, can be stored under lyophilize (freeze-drying) condition, only needs add immediately before use for example water for injection of sterile liquid carrier.

Can prepare medicinal preparations by formula (I) compound or its subclass that freeze-drying this paper limits.Freeze-drying refers to the process of freeze-dried composition.Therefore lyophilize and freeze-drying are used as synonym at this paper.

Injection solution that available sterile powder, granula and tablet preparation are interim and suspension.

The medicinal compositions that the present invention is used for the parenteral injection also comprises pharmaceutically acceptable sterilized water or non-aqueous solution, dispersion liquid, suspension or emulsion, and the sterile powder that is mixed with aseptic injectable solution or dispersion liquid before facing use again.The example of suitable water and non-aqueous carrier, thinner, solvent or solvent comprises water, ethanol, polyvalent alcohol (as glycerine, propylene glycol, polyoxyethylene glycol etc.), carboxymethyl cellulose and suitable mixture, vegetables oil (as sweet oil) and injection organic ester such as ethyl oleate.For example can by with coating material such as Yelkin TTS, under the situation of dispersion liquid, keep required granular size and use tensio-active agent, to keep adequate liquidity.

Composition of the present invention also can comprise assistant agent such as sanitas, wetting agent, emulsifying agent and dispersion agent agent.Can guarantee to prevent action of microorganisms by adding various antibacterial agents and anti-mycotic agent such as metagin, butylene-chlorohydrin, phenol Sorbic Acid etc.Also preferably include isotonic agent as sugar, sodium-chlor etc.Medicine by adding delayed absorption such as aluminum monostearate and gelatin can prolong the absorption of injectable drug form.

In a preferred embodiment of the invention, medicinal compositions adopts the form of for example passing through injection or infusion intravenous administration.During intravenous administration, can or before administration, inject infusion bag (comprising pharmaceutically acceptable vehicle) with the direct administration of solution as 0.9% salt solution or 5% dextrose.

In a further preferred embodiment, medicinal compositions adopts the form that is fit to subcutaneous (s.c.) administration.

The pharmaceutical dosage form that is fit to oral administration comprises tablet, capsule, cachet, pill, lozenge, syrup, solution, powder, granula, elixir and suspensoid, sublingual lozenge, wafer or patch and buccal bioadhesive tablet.

Therefore, tablet composition can comprise unit dose of active compound, and inert diluent or carrier such as sugar or sugar alcohol, as lactose, sucrose, sorbyl alcohol or N.F,USP MANNITOL; And/or non-sugared deutero-thinner such as yellow soda ash, calcium phosphate, lime carbonate, perhaps Mierocrystalline cellulose or derivatives thereof such as methylcellulose gum, ethyl cellulose, Vltra tears and starch such as W-Gum.Tablet also can comprise standard batching as bonding and granulating agent such as polyvinylpyrrolidone, disintegrating agent (as deglutible cross-linked polymer such as cross-linked carboxymethyl cellulose), lubricant (as stearate), sanitas (as p-Hydroxybenzoate), antioxidant (as BHT), buffer reagent (as phosphoric acid salt or citrate buffer reagent) and effervescent such as citrate/bicarbonate mixture.This type of vehicle is well-known, does not need here to go through.

Capsule preparations can be hard capsule or soft capsule, can comprise the activeconstituents of solid, semisolid or liquid form.Gelatine capsule can form with animal gelatin or its equivalent synthetic or plant derivation.

Solid dosage (as tablet, capsule etc.) can dressing or dressing not, but has dressing usually, for example protectiveness film coating (as wax or paint film) or sustained release dressing.Can be with dressing (as Eudragit ^TMThe type polymkeric substance) is designed to desired location release of active ingredients in gi tract.Therefore, can so select dressing,, thereby compound selective is released in stomach or in ileum or duodenum so that in gi tract, degrade under a certain pH condition.

Replace dressing or except that dressing, medicine can be present in the solid skeletal that comprises sustained release agent, described sustained release agent is as being adapted at the releasing agent that delays of selectivity release compound under various acidity in the gi tract or the alkaline condition.Perhaps, framework material or delayed release coating can adopt the form of erodibility polymkeric substance (as the maleic anhydride polymkeric substance), and described polymkeric substance is corroded substantially continuously when formulation is passed gi tract.Alternative as another, active compound can be formulated in the delivery system that the release of compound is controlled on perviousness ground.Can delay to discharge or extended release preparation according to method preparation infiltration release well known to those skilled in the art and other.

Medicinal compositions comprises about 95%, preferred about 90% active batching of about 20%-of about 1%-.Medicinal compositions of the present invention can adopt for example unit dosage, as ampoule, bottle, suppository, coated tablet, tablet or capsule.

By merging active batching and solid carrier (if desired then granulation gained mixture), (if wish or must) after adding appropriate excipients, be processed into tablet, drageeing nuclear or capsule with mixture, can obtains to be used for the medicinal compositions of oral administration.They can also be added and allow in active batching diffusion or the plastic carrier with quantitative release.

Also can be mixed with solid dispersion with being used for compound of the present invention.Solid dispersion is two or more solid very fine disperse phase uniformly.Solid solution (molecular dispersion system), a kind of solid dispersion type is widely used in medical technical elements and (consults (Chiou and Riegelman, J.Pharm.Sci., 60,1281-1300 (1971)), can be used for increasing dissolution rate and increase the bioavailability of medicament that is insoluble in water.

The present invention also provides the solid dosage that comprises above-mentioned solid solution.Solid dosage comprises tablet, capsule and chewable tablet.Can be with known vehicle and solid solution fusion to obtain required formulation.For example, capsule can comprise and (a) disintegrating agent and lubricant or (b) solid solution of disintegrating agent, lubricant and surfactant blend.Tablet can comprise the solid solution with at least a disintegrating agent, lubricant, tensio-active agent and glidant fusion.Chewable tablet can comprise and swelling agent, lubricant, also has the solid solution of affixing sweetening agent (as artificial sweetner) and suitable seasonings fusion if desired.

Medicinal preparations can be offered the patient in the mode of " patient's packing ", this packing is included in whole therapeutic process in the individual packaging, normally Blister Package.Patient's packing has the advantage that is better than the tradition prescription, and (the tradition prescription is, the pharmacist is divided into patient's medicine supply by a large amount of supply medicines in bulk), this advantage is that the patient can obtain being included in the patient and pack interior package insert, and this is omitted in patient's prescription usually.Shown already that adding package insert can improve the compliance of patient to doctor's instruction.

The local composition that uses comprises ointment, creme, sprays, patch, gelifying agent, liquid drops and inset (as the intraocular inset).Can prepare this based composition according to currently known methods.

The formulation examples of rectum or intravaginal administration comprises vaginal suppository and can for example use the suppository that the shaping that comprises active compound is plastic or wax-like materials forms.

But the composition of inhalation can adopt the form of inhaling type dust composition or liquid or pulvis sprays, and available powder inhaler device or aerosol dispensing device are with the standard form administration.This device is known.During inhalation, powderous preparations comprises the active compound with inert solid powdery thinner such as lactose usually.

Usually formula (I) compound is provided with unit dosage, therefore will comprise enough compounds usually so that the biologic activity of desired level to be provided.For example, preparation can comprise 1 nanogram-2 gram activeconstituents, as 1 nanogram-2 milligram activeconstituents.In this scope, the concrete inferior scope of compound is 0.1 milligram-2 a gram activeconstituents (more generally being 10 milligrams-1 grams, as 50 milligrams-500 milligrams), perhaps 1 milligram-20 milligrams (as 1 milligram-10 milligrams, as 0.1 milligram of-2 milligrams of activeconstituents).

For oral compositions, unit dosage can comprise 1 milligram-2 gram, more generally is 10 milligrams-1 grams, as 50 milligrams-1 grams, as 100 milligrams-1 gram active compounds.

The patient (as human or animal patient) that the active compound that is enough to obtain the amount of required treatment effect can be had needs.

Therepic use

The activity of formula (I) compound regulation and control (as suppressing) ROCK kinases or protein kinase p70S6K.Therefore the purposes of compound is: (a) treatment or prevention wherein need disease or the illness of regulation and control (as suppressing) ROCK kinases or protein kinase p70S6K; And/or (b) treatment wherein needs experimenter or the patient group of regulation and control (as suppress) ROCK kinases or protein kinase p70S6K; And/or (c) treatment or prevention wherein need the disease or the illness of regulation and control (as suppress) Rho signal pathway; And/or (d) treatment wherein needs the experimenter or the patient group of regulation and control (as suppress) Rho signal pathway.

Suitable disease and the illness relevant with the ROCK kinase regulatory

Therefore the present invention is applicable to and is selected from following disease and illness: (a) metastases; (b) tumor invasion; (c) tumour progression; (d) tumour adheres to (as tumor cell adhesion); (e) actinomycin convergent force dependent tumors shifts, attacks or progress; (f) cell transformation; (g) metastases, invasion and attack, progress or the adhesion of ROCK mediation; (h) the actinomycin convergent force dependent tumors of ROCK mediation shifts, attacks or progress; (i) cell transformation of ROCK mediation.

Therefore the present invention also is applicable to cancer (as the ROCK cancers mediated), and particularly wherein cancer (as the ROCK cancers mediated) is selected from: (a) germinal cell tumor of testis; (b) has the little mammary cancer of transfer ability; (c) bladder cancer; (d) ovarian cancer; (e) prostate cancer; (f) hepatocellular carcinoma.

Other suitable disease and illness comprise invasion and attack, transfer and the tumour progression of any cancer that this paper limits.

The present invention also is applicable to cardiovascular disorder or illness, particularly is selected from: (a) hypertension; (b) cardiac insufficiency (as chronic heart failure); (c) myocardial hypertrophy; (d) restenosis; (e) renal insufficiency (as chronic renal failure); (f) atherosclerosis (arteriosclerosis); (g) myocardial preservation; (h) allogeneic survival; (i) cerebral ischemia; (j) coronary vasospasm; (k) vascular inflammation.

Other suitable disease and illness comprise muscle (as unstriated muscle) dysfunction, as are selected from: (a) asthma; (b) penile erectile function obstacle; (c) Female sexual dysfunction; (d) I type bladder excessive activities syndrome; (e) unusual unstriated muscle (as the unusual unstriated muscle relevant) with hypertension.

Other suitable disease and illness comprise inflammation, and wherein for example inflammation comprises or shows as following disease: (a) rheumatoid arthritis; (b) irritable bowel syndrome; (c) inflammatory bowel; (d) vascular inflammation and (e) neural inflammatory diseases or illness.

With neural inflammatory diseases or illness related embodiment in, can be selected from: (a) apoplexy; (b) multiple sclerosis; (c) alzheimer's disease; (d) Parkinson's disease; (e) amyotrophic lateral sclerosis; (f) inflammatory pain.

Other suitable disease and illness comprise CNS disease or illness, comprise being selected from: (a) Spinal injury or wound; (b) brain injury or wound; (c) acute neuronal damage (as apoplexy or traumatic brain injury); (d) Parkinson's disease; (e) alzheimer's disease; (f) nervus retrogression illness or disease; (g) apoplexy (as the apoplexy relevant) with hypertension; (h) cerebral vasospasm; (i) inhibition of axon growth and budding; (j) repressed axon regeneration; (k) functional rehabilitation defective after the wound; (1) demyelination or disorder; (m) inflammatory CNS disease or disorder; (n) neuropathic pain; (o) nerve degenerative diseases.

CNS disease that other is suitable for or illness comprise and are selected from following disease or illness: mongolism and amyloid-beta vascular disease, such as but not limited to brain amyloid blood vessel disease, hereditary cerebral hemorrhage; With the cognitive impairment diseases associated, such as but not limited to MCI (＂ mild cognitive defective ＂), alzheimer's disease, the loss of memory, the attention deficit symptom relevant with alzheimer's disease, with disease such as alzheimer's disease or dull-witted relevant nerve degenerative diseases, comprise the dementia that Combination blood vessel and sex change cause, presenile dementia, senile dementia and the dementia relevant with Parkinson's disease, stein-leventhal syndrome or corticobasal degeneration, Parkinson's disease, the dull-witted Parkinson's type of volume temporal lobe, GuamShi parkinsonism dementia simulator sickness, the HIV dementia, be entangled with the pathology diseases associated with neuroneme, dementia pugilistica, amyotrophic lateral sclerosis, the degeneration of cortex oblongata, mongolism, huntington's chorea, postencephalitic parkinsonism, stein-leventhal syndrome, pager's disease, niemann-Pick disease, apoplexy, head trauma and other chronic nerve degenerative diseases, the bipolarity obstacle, affective disorder, dysthymia disorders, anxiety disorder, schizophrenia, cognitive disorder, alopecia, use contraceptive bian, state before dull-witted, the age related memory impairment, the age related cognitive decline, no dementia form cognitive impairment, mild cognitive goes down, slight neuro-cognitive defective, old forgetful, memory impairment and cognitive impairment, vascular dementia, Lewy corpusculum dementia, volume temporal lobe dementia and androgenetic alopecia.

Also have other disease and illness of being suitable for to comprise: (a) insulin resistant; (b) graft protection (as cardiovascular or inflammatory graft protection); (c) diabetes; (d) asthma; (e) lung vasoconstriction; (f) glaucoma; (g) fibrosis (as hepatic fibrosis and renal fibrosis).

Other disease and illness that is suitable for comprises infectious diseases or illness, comprises metazoan, protozoon, fungi, Protein virus, virus or bacteria attack, disease or infection.

In this type of embodiment, infectious diseases or illness gram comprise the cytoskeleton of pathogenic agent mediation and reset.

Proliferative disease (comprising cancer): the present invention also is applicable to as the prevention knurl and becomes growth or induce knurl to become the instrument of apoptosis.Therefore the present invention will help treatment or prevention proliferative disease such as cancer.This type of unusual example includes but not limited to one or more Rho signal pathway members' overexpression, perhaps described member's sudden change, (can be for example relevant to adjusted or overexpression or sudden change activation with growth factor receptors for example is selected from EGF-R ELISA (EGFR) to cause the primary activity of ROCK kinases or Rho signal pathway to increase, fibroblast growth factor acceptor (FGFR), platelet derived growth factor receptor (PDGFR), the somatomedin of type-1 insulin like growth factor acceptor (IGF-1R) and vascular endothelial growth factor receptor (VEGFR) family).

The present invention will be used for the treatment of other illness that is caused by propagation or survival disease such as virus infection, can be used for treating for example nerve degenerative diseases.

Therefore the present invention is widely used in treating the disease that propagation, apoptosis or dysdifferentiation are wherein arranged.

Quenchable cancer example includes but not limited to cancer, as bladder cancer, mammary cancer, colorectal carcinoma (as colorectal carcinoma such as adenocarcinoma of colon and adenoma of colon), kidney, epidermal carcinoma, liver cancer, lung cancer such as gland cancer, small cell lung cancer and nonsmall-cell lung cancer, the esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas such as exocrine pancreas cancer, cancer of the stomach, cervical cancer, carcinoma of endometrium, thyroid carcinoma, prostate cancer, perhaps skin carcinoma such as Squamous Cell Carcinoma; Hematopoietic cell malignant tumour such as acute myelocytic leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic granulocytic leukemia, lymphocytic leukemia and other B cell lymphoproliferative disease, myelodysplastic syndrome, comprise T cell lymphoproliferative disease, non-Hodgkin lymphoma and Hodgkin's disease from natural killer cell; Bortezomib susceptibility and intractable multiple myeloma; No matter be the hematopoietic cell disease of preceding or stable abnormal cell proliferation of cancerating, for example myelosis's property disease comprises polycythemia vera, essential thrombocythemia and PMF; Hair cell lymphoma or Burkett ' s lymphoma; The medullary system hematopoietic tumor, for example acute and chronic lymphocytic leukemia, myelodysplastic syndrome, promyelocytic leukemia; Thyroid follcular carcinoma; The tumour of mesenchymal cell, for example fibrosarcoma and rhabdosarcoma; The tumour of maincenter or peripheral nervous system, for example astrocytoma, neuroblastoma, neurospongioma or schwannoma; Melanoma; Spermocytoma; Teratoma; Osteosarcoma; Xenoderoma pigmentosum; Keratoctanthoma; Thyroid follcular carcinoma; Or Kaposi's sarcoma.

The cancer of concrete subclass comprises mammary cancer, ovarian cancer, colorectal carcinoma, prostate cancer, the esophageal carcinoma, squama cancer and nonsmall-cell lung cancer.Another subclass cancer comprises mammary cancer, ovarian cancer, prostate cancer, carcinoma of endometrium and neurospongioma.

Immunologic derangement: the immunologic derangement that the present invention can bring into play beneficial effect includes but not limited to autoimmune disorder and chronic inflammatory disease, for example glomerulonephritis, rheumatoid arthritis, psoriatic, inflammatory bowel and autoimmune diabetes, eczema allergy, asthma, COPD, rhinitis and the upper respiratory disease of systemic lupus erythematous, autoimmunization mediation.

The physiological processes of other therepic use: ROCK mediation plays a role in apoptosis, propagation, differentiation, so the present invention also can be used for treating following disease except cancer, and these diseases are with following relevant: immune dysfunction; Virus infection is as simplexvirus, poxvirus, Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; Prevent that AIDS from appearring in the individuality that HIV infects; Cardiovascular disorder is as cardiac muscle plumpness, restenosis, atherosclerosis; Nerve degenerative diseases is as alzheimer's disease, AIDS-dependency dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; Glomerulonephritis; Myelodysplastic syndrome, ischemic injuries dependency myocardial infarction, apoplexy and reperfusion injury, the degenerative disease of musculoskeletal system, for example, osteoporosis and sacroiliitis, aspirin sensitive sinusitis paranasal sinusitis, cystic fibrosis, multiple sclerosis, kidney disease.

The present invention also can be used for the disease that insulin resistant and insensitive, breakdown of glucose, energy and depot fat cause, as metabolic disease and obesity.

With relevant suitable disease and the illness of protein kinase p70S6K regulation and control

Therefore the present invention is applicable to and is selected from following illness: (a) cancer (as the p70S6K cancers mediated); (b) metastases; (c) immune dysfunction; (d) tissue injury (tissue injury that causes as inflammation); (e) karyomit(e) 17q23 amplification (perhaps it causes or relevant illness); (f) Peutz-Jeghers syndrome (perhaps it causes or relevant illness); (g) LKB1 sudden change (perhaps it causes or relevant illness); (h) BRCA1 sudden change (perhaps it causes or relevant illness); (i) BRCA2 sudden change (perhaps it causes or relevant illness); (j) handicapped apoptosis program; (k) growth factor receptors signal transduction, overexpression and activation in the tumor tissues; (1) metabolic trouble or disorder; (m) with abnormal cell proliferation and/or metabolism diseases associated; (n) neuronal disease.

In this type of embodiment, cause or can be selected from by karyomit(e) 17q23 amplification: (a) primary breast tumour with its diseases associated or illness; (b) comprise the tumour (as breast tumor) that BRCA2 suddenlys change; (c) comprise the tumour (as breast tumor) that BRCA1 suddenlys change; (d) pancreatic neoplasm; (e) tumor of bladder; (f) neuroblastoma.

By LKB1 sudden change cause or with its diseases associated or illness can be the adenocarcinoma of lung that comprises LKB1 sudden change (as passivation LKB1 sudden change).

By BRCA1/2 sudden change cause or with its diseases associated or illness can be mammary cancer.

Metabolic trouble or disorder can be selected from: (a) obesity (obesity that obesity of bringing out as the age or diet bring out); (b) diabetes; (c) metabolism syndrome; (d) insulin resistant; (e) hyperglycemia; (f) hyperaminoacidemia; (g) hyperlipidaemia.

Proliferative disease (comprising cancer): the present invention also is suitable as the prevention knurl and becomes growth or induce knurl to become the instrument of apoptosis.Therefore the present invention will help treatment or prevention proliferative disease such as cancer.This type of unusual example includes but not limited to p70S6K overexpression (or other syndrome described herein).

The present invention will help to treat other illness that is caused by propagation or survival disease such as virus infection, can be used for treating for example nerve degenerative diseases.

Therefore the present invention will be widely used in treating the disease that propagation, apoptosis or dysdifferentiation are wherein arranged.

Quenchable cancer example includes but not limited to cancer, for example bladder cancer, mammary cancer, colorectal carcinoma (as colorectal carcinoma such as adenocarcinoma of colon and adenoma of colon), kidney, epidermal carcinoma, liver cancer, lung cancer such as gland cancer, small cell lung cancer and nonsmall-cell lung cancer, the esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas such as exocrine pancreas cancer, cancer of the stomach, cervical cancer, carcinoma of endometrium, thyroid carcinoma, prostate cancer, perhaps skin carcinoma such as Squamous Cell Carcinoma; Lymphatic system hematopoietic tumor such as leukemia, acute lymphoblastic leukemia, B cell lymphoma, t cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hair cell lymphoma or Burkett ' s lymphoma; The medullary system hematopoietic tumor, for example acute and chronic lymphocytic leukemia, myelodysplastic syndrome or promyelocytic leukemia; Thyroid follcular carcinoma; The tumour of mesenchymal cell, for example fibrosarcoma and rhabdosarcoma; The tumour of maincenter or peripheral nervous system, for example astrocytoma, neuroblastoma, neurospongioma or schwannoma; Melanoma; Spermocytoma; Teratoma; Osteosarcoma; Xenoderoma pigmentosum; Keratoctanthoma; Thyroid follcular carcinoma; Or Kaposi's sarcoma.

The physiological processes of other therepic use: p70S6K mediation plays a role in apoptosis, propagation, differentiation, so the present invention also can be used for treating following disease except cancer, and these diseases are with following relevant: immune dysfunction; Virus infection is as simplexvirus, poxvirus, Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; Prevent that AIDS from appearring in the individuality that HIV infects; Cardiovascular disorder is as cardiac muscle plumpness, restenosis, atherosclerosis; Nerve degenerative diseases is as alzheimer's disease, AIDS-dependency dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; Glomerulonephritis; Myelodysplastic syndrome, ischemic injuries dependency myocardial infarction, apoplexy and reperfusion injury, the degenerative disease of musculoskeletal system, for example, osteoporosis and sacroiliitis, aspirin sensitive sinusitis paranasal sinusitis, cystic fibrosis, multiple sclerosis, kidney disease.

The present invention also can be used for the disease that caused by insulin resistant and insensitive, breakdown of glucose, energy and depot fat, for example metabolic trouble and obesity.

Suitable intervention, treatment and the prevention method relevant with the ROCK kinase regulatory

The present invention relates to any intervention, treatment or the prevention type of ROCK mediation.Therefore, the treatment or the prevention that are suitable for of the present invention comprises: (a) regulation and control (as suppressing) ROCK kinases; Perhaps (b) is in the kinase whose activity level intervention of ROCK; Perhaps (c) intervenes in the level of Rho signal pathway (as RhoA and or the level of RhoC).

Other usability methods comprises the intervention that produces following effect: (a) muscle (as unstriated muscle) is lax; (b) vascular muscle lax (as increasing blood flow); (c) neurocyte regulation and control; (d) reduce cell proliferation; (e) reduce cell migration; (f) suppress the cytoskeleton rearrangement that pathogenic agent invasion and attack or infection cause; (g) quicken tissue regeneration; (h) functional rehabilitation after the enhancing wound.

In this type of embodiment, the neurocyte regulation and control can comprise: (a) neuron regeneration; (b) induce new axon growth; (c) make aixs cylinder once more by the injury region in the CNS; (d) spinous process is external; (e) spinous process differentiation; (f) aixs cylinder is sought the footpath; (g) dendritic spine forms; (h) dendritic spine maintenance; (i) regulation and control neurite outgrowth awl withers; (j) the external inhibition of regulation and control spinous process.

Other treatment that is suitable for comprises transplantation therapy (as comprising the graft protection).

Also have other method that is suitable for to comprise the method for diagnosis and treatment disease or illness, described method comprises: (i) the screening patient is to determine that whether disease that the patient is suffered from maybe may suffer from or illness are to using the treatment sensitivity of the compound with anti-ROCK kinase activity; (ii) when showing that disease of patient or illness are responsive, then give the patient compound of the present invention.

With relevant suitable intervention, treatment and the prevention method of p70S6K regulation and control

The present invention relates to any intervention, treatment or the prevention type of protein kinase p70S6K mediation.Therefore, the treatment or the prevention that are suitable for of the present invention comprises: (a) regulation and control (as suppressing) protein kinase p70S6K; (b) in the activity level intervention of protein kinase p70S6K; (b) progress of inhibition G1-S phase in cells in vivo cycle; (c) suppress cell cycle propagation in the G1-S phase of cell cycle; (d) use formula (I) compound as the rapamycin quid pro quo; (e) use formula (I) compound as the wortmannin quid pro quo; (f) rebuild suitable apoptosis program; (g) growth factor receptors signal transduction, overexpression and the activation in the inhibition tumor tissues; (h) regulation and control neuronal cell differentiation; (i) regulating cell vigor; (j) regulating cell reaction; (k) strengthen insulin sensitivity.

Treatment or prevention also can comprise the method for diagnosis and treatment disease or illness, and described method comprises

The screening patient is to determine whether disease or illness that the patient is suffered from maybe may suffer from have the treatment sensitivity of the active compound of anti-protein kinase p70S6K to using; (ii) when showing that disease of patient or illness are responsive, then give formula (I) compound that patient this paper limits.

The target subject of ROCK kinase regulatory or patient group

Experimenter or patient group can be selected from: (a) colony of ROCK kinase function obstacle (for example overactivity); (b) carried out the colony of ROCK dysfunction (as the ROCK overactivity) diagnostic test; (c) the handicapped colony of Rho signal pathway; (d) carried out the colony of Rho signal pathway dysfunction diagnostic test.

The target subject or the patient group of p70S6K regulation and control

Experimenter or patient group can be selected from: (a) colony of protein kinase p70S6K dysfunction (for example overactivity); (b) carried out the colony of p70S6K dysfunction (as the p70S6K overactivity) diagnostic test; (c) colony of karyomit(e) 17q23 amplification; (d) carried out the colony of the diagnostic test of karyomit(e) 17q23 amplification; (e) colony that exists BRCA1 to suddenly change; (f) carried out the colony of BRCA1 sudden change diagnostic test; (g) colony that exists BRCA2 to suddenly change; (h) carried out the colony of BRCA2 sudden change diagnostic test; (i) colony that exists LKB1 to suddenly change; (j) carried out the colony of LKB1 sudden change diagnostic test; (k) limit the colony of screening according to this paper.

Methods of treatment and posology

Formula (I) compound that this paper limits and subclass will be used to prevent or treat various diseases or the illness that is mediated by ROCK kinases or protein kinase p70S6K.The example of this type of disease and illness is listed at this paper.

Usually the experimenter who formula (I) compound is needed such administration, for example human or animal patient, preferably people.

Usually give the compound of effective treatment or prevention and common atoxic amount.But (as under the situation of life-threatening disease) in some cases, the advantage of giving construction (I) compound may surpass the shortcoming of any toxic action or side effect, and consideration need have the compound of the amount of certain toxic degree in this case.

Can give compound to keep beneficial therapeutic effect in the time period that prolongs, perhaps can be the short-term administration.Perhaps can be according to pulse or the administration of successive mode.

The representative per daily dose of formula (I) compound can be at per kilogram of body weight 100 piks-100 nanogram range, more generally be per kilogram of body weight 5 nanograms-25 milligram, more generally be that per kilogram of body weight 10 nanograms-15 milligram are (as 10 nanograms-10 milligram, more generally be 20 milligrams of per kilogram 1 micrograms-per kilogram, as per kilogram 1 microgram-10 milligram), but can give higher or lower dosage as required.Formula (I) compound can administration every day, and is perhaps for example per 2 in the multiple mode, or 3, or 4, or 5, or 6, or 7, or 10 or 14, or 21, or administration in 28 days.

Be used for dosage range that compound of the present invention can be taken orally and be for example 1-1500mg, 2-800mg or 5-500mg, as 2-200mg or 10-1000mg, the specific examples of dosage comprises 10,20,50 and 80mg.Compound can administration every day more than 1 time or 1 time.Compound can successive administration (i.e. administration every day incessantly duration of treatment plan).Perhaps, compound can intermittent administration, and promptly one specified period of successive administration is interrupted for some time as 1 week then as 1 week duration of whole treatment plan, and another section of successive administration period is as 1 week then, or the like.The treatment plan example that relates to intermittent administration comprises following scheme: wherein the administration cycle is to carry out for 1 week, stops for 1 week; Perhaps carried out for 2 weeks, stopped for 1 week; Perhaps carried out for 3 weeks, stopped for 1 week; Perhaps carried out for 2 weeks, stopped for 2 weeks; Perhaps carried out for 4 weeks, stopped for 2 weeks; Perhaps carry out stopping in 1 week 3 the week-continue one or more cycles, as 2,3,4,5,6,7,8,9 or 10 or more a plurality of cycle.

In a concrete dosage regimen, the patient is with infusion formula every day (I) compound 1 hour 10 days at the most, particularly 5 days at the most 1 week, with required interval such as 2-4 week, particularly per 3 all repetitive therapy.

More specifically, but patient's infusion every day formula (I) compound 1 hour totally 5 days, per 3 all repetitive therapy.

In another concrete dosage regimen, patient's infusion 30 minutes-1 hour then keeps different time length of infusion such as 1-5 hour, as 3 hours.

In another concrete dosage regimen, patient's continuous infusion 12 hours-5 days, particularly continuous infusion is 24 hours-72 hours.

But the dosage of compound and composition therefor type will match with disease character or physiology state to be treated, be judged by the doctor.

The compound that this paper limits can be used as single therapy agent administration, perhaps can with one or more other compound Combined Preparation, described other compound is used for the treatment of for example cancer that limits of neoplastic disease such as this paper of disease specific.Can include but not limited to formula (I) compound other therapeutical agent or the therapy example of (no matter be simultaneously or with the different timed intervals) administration together:

The topoisomerase I inhibitor

Metabolic antagonist

The agent of tubulin target

DNA wedding agent and topoisomerase II inhibitor

Alkylating agent

Monoclonal antibody

Hormone antagonist

Signal transduction inhibitor

Proteasome inhibitor

Dnmt rna

Cytokine and retinoid

The chromatin targeted therapies

Radiotherapy and

Other treatment or preventive; As alleviate or the medicine of some side effects that alleviation is relevant with chemotherapy.The specific examples of this type of medicine comprises antiemetic, with prevention or shortening chemotherapy dependency neutrophilic granulocytopenia time length and the medicine that prevents to reduce the complication that causes, as erythropoietin (EPO), rHuGM-CSF (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) by red corpuscle or leucocyte level.Also comprise the medicine such as diphosphonate medicine such as Zoledronic acid, pamidronic acid and the ibandronate that suppress bone resorption, the medicine such as dexamethasone, prednisone and the prednisolone that suppress Inflammatory response, reduce the medicine of acromegalic tethelin and IGF-I blood level such as the brain hormones Somatostatin of synthesized form with being used for, comprise the long-acting octapeptide acetate Sostatin of pharmacological property with simulation natural hormone Somatostatin.For example also comprise as the medicine of the folinic acid of the toxinicide of the medicine that reduces folate level or folinic acid itself and for example can be used for treating the medicine of the megestrol of the side effect that comprises oedema and thromboembolism.

All cpds in combination can be according to different separately dosages with by the different approaches administration.

When formula (I) compound and 1,2,3,4 or during the treatment of multiple other therapeutical agent (preferred 1 or 2 kind, more preferably a kind) Combined Preparation, can simultaneously or give compound in order.When sequential administration, the timed interval that they can be close (as 5-10 minute) or longer interval (as separate 1,2,3,4 or a plurality of hours, and perhaps separate as required even the longer time section) administration, the character of accurate dose scheme and therapeutical agent matches.

Be used for compound of the present invention and also can combine administration with non-chemotherapeutics such as radiotherapy, photodynamic therapy, gene therapy, perform the operation and keep on a diet etc.

In order to be used for the combination therapy with another kind of chemotherapeutics, can with formula (I) compound with 1,2,3,4 or multiple other therapeutical agent for example be formulated in comprise 2,3,4 or the formulation of multiple therapeutical agent in.Perhaps, can prepare each therapeutical agent separately, provide with kit form (optional) with its working instructions.

Those skilled in the art will be clear with the dosage regimen and the conjoint therapy that use by his or her general knowledge.

Diagnostic method

Before formula (I) compound that gives this paper qualification, can screen the patient to determine the patient is suffered from disease or the illness that maybe may suffer from whether will be to treating sensitivity.For example, can screen patient's ROCK active function obstacle (as the ROCK expression that improves or raise, the sudden change or the ROCK gene regulatory elements of ROCK gene) or Rho semiotic function obstacle (limiting) as this paper.

Term raises and comprises that expression improves or overexpression, comprises that the expression that gene amplification (being poly-gene duplication) and Transcription cause increases and overactivity and activation (comprising the activation that sudden change causes).The term diagnosis comprises screening.About marker, comprise gene marker, comprise that for example measuring DNA forms to identify sudden change.The terms tag thing also comprises and characterize to raise the marker that feature comprises enzymic activity, enzyme level, enzyme state (phosphorylation as whether) and mRNA level.

Above diagnostic test and screening are carried out on biological sample usually, and described sample is selected from tumor biopsy sample, blood sample (tumour cell that separation and enrichment come off), ight soil biopsy, sputum, chromosome analysis, hydrothorax, ascites and urine.

Determine that the individuality that carries sudden change can mean that this patient will be particularly suitable for treatment of the present invention.Can preferably before treatment, pass through to detect concrete sudden change/allelic existence, screening tumour.Screening process will generally include direct order-checking, oligonucleotide microarray analysis or mutant specific antibody.

The method that known evaluation of those skilled in the art and analysis sudden change and protein raise.Screening method can include but not limited to standard method such as reverse transcriptase-polymerase chain reaction (RT-PCR) or in situ hybridization.

When screening, by producing the cDNA copy of mRNA, then with the mRNA level in the pcr amplification cDNA assessment tumour with RT-PCR.The method of the known pcr amplification of those skilled in the art, selection primer and amplification condition.Carry out nucleic acid with standard method and handle and PCR, described method is as being described in Ausubel, F.M. etc., eds.Current Protocols in MolecularBiology, 2004, John Wiley ﹠amp; Sons Inc., perhaps Innis, M.A. etc., eds.PCRProtocols:a guide to methods and applications, 1990, Academic Press, San Diego.Relate to the reaction of nucleic acid technology and handle and also be described in Sambrook etc., 2001,3 ^RdEd, Molecular Cloning:A Laboratory Manual, Cold Spring HarborLaboratory Press.Perhaps can use the RT-PCR test kit (as RocheMolecular Biochemicals) of commercially available acquisition, described method is listed in United States Patent (USP) 4,666,828,4,683,202,4,801,531,5,192,659,5,272,057,5,882,864 and 6,218,529, be attached to herein by reference.

The example of the hybridization in situ technique that assessment mRNA expresses be fluorescence in situ hybridization (FISH) (consult Angerer, 1987 Meth.Enzymol., 152:649).

In general, in situ hybridization comprises following key step: (1) fixing organization is used for analyzing; (2) the sample prehybridization is handled to increase the target nucleic acid accessibility, reduced non-specific binding; (3) make nucleic acid mixture and biological structure or the tissue in nucleic acid hybridization; The nucleic acid fragment of hybridization was measured in unconjugated nucleic acid fragment and (5) when (4) post-hybridization washing was hybridized to remove.Usually mark is used for the probe of this type of purposes, for example with radio isotope or fluorescent indicators mark.Preferred probe sufficiently long, for example about 50,100 or 200 Nucleotide-Yue 1000 or more a plurality of Nucleotide allow under the condition of strictness and the target nucleic acid specific hybrid.The standard method of carrying out FISH is described in Ausubel, F.M. etc., eds.Current Protocols in Molecular Biology, 2004, John Wiley ﹠amp; Sons lnc and Fluorescence In Situ Hybridization:Technical Overview by John M.S.Bartlett in Molecular Diagnosis ofCancer, Methods and Protocols, the 2nd edition; ISBN:1-59259-760-2; March2004, the 077-088 page or leaf; Series:Methods in Molecular Medicine.

Perhaps, can carry out the additive method mensuration mRNA expressed protein product of solid-phase immunoassay, Western trace, 2-dimension SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and detection specified protein known in the art by the tumor sample immunohistochemical methods, with titer plate.Detection method comprises the use site-specific antibodie.The technician will understand the situation that all these type of well-known technology all can be used for this paper.

Concrete person about LKB1 considers

Dna sequencing is the effective ways (consulting the 36:365-368 as J Med Genet (1999)) that genetic test is carried out in sudden change to LKB1 in the diagnostic laboratory.This article is described the germ line mutation of LKB1 among one group of 12 Peutz-Jeghers patient of screening, reports this results of screening.This type of experimental design is applicable to the present invention.

The more details of suitable experimental design can be consulted as (2003) Cancer Res.63:1382-1388 such as (2004) Cancer Cell 6:91-99 such as Shaw (describe LKB1 tumor suppression and how to bear adjusting mTOR signal) and Jimenez.

Kinase whose amplification of ROCK and detection

Can detect ROCK at mRNA or protein level.

Measured that the concrete grammar example of Rho and ROCK level comprises in the clinical sample:

American Journal of Pathology.2002; 160:579-584. being described in formalin fixed tissue, this article carries out immunohistochemical methods to characterize the RhoC expression in people's mammary tissue.

Clinical Cancer Research 9 volumes, 2632-2641, July 2003.This article is described will be quantitative from pairing tumour and the Rho and the ROCK protein expression in the non-tumor operation sample of 107 successive Japan bladder cancer patients with the Westem trace.

·Pancreas.24(3)：251-257，April 2002。This article is described the expression of measuring ROCK-1 in the Human Pancreas by immunoblotting and immunohistochemical methods.

·WorldJ Gastroenterol 2003 September；9(9)：1950-1953。This article is described the mRNA expression level that detects RhoC gene in the hepatocellular carcinoma (HCC) by reverse transcriptase-polymerase chain reaction (RT-PCR).

The methods involving quantitatively relevant with Rho and/or ROCK activity or expression level that above-mentioned publication comprises openly is attached to herein by reference.

The amplification of protein kinase p70S6K and detection

Can detect p70S6K at mRNA or protein level.

Exemplary methods is described in for example J Naltl Cancer Inst (2000): 92,1252-9 page or leaf (describe by complementary DNA and the kinase whose activation of micro-array tissue analyzing and testing ribosomal protein S6, use genomic hybridization (CGH) relatively and cDNA and micro-array tissue analysis) to identify the gene of amplification and overexpression.

The detection of the p70S6K of overexpression is described in Int J Oncol (2004): 24 (4), and the 893-900 page or leaf.This article is described with immunohistochemical methods PI3K/PTEN-Akt-mTOR approach in common people's tumour is carried out medicine genome mensuration, and high p70S6K, AKT are expressed and the contrast of tumour susceptibility.

Experiment

Specific embodiments (but non-limiting) referring now to following method and embodiment description is explained the present invention.

Unless otherwise, otherwise the raw material of the whole bag of tricks described below is commercially available, and perhaps is easy to the material preparation with commercially available acquisition.

With proton resonance ( ¹H MR) spectrum be recorded on the Bruker AV400 instrument, under 27 ℃ with 400.13MHz at Me-d ₃Operate among-the OD, unless otherwise indicated, otherwise following report: chemical shift δ/ppm (wherein s=is unimodal for proton number, multiplicity, and d=is bimodal, t=three peaks, q=four peaks, m=multimodal, br=broad peak).With residual protonic solvent MeOH (δ _H=3.31ppm) as internal standard substance.

In an embodiment, characterize the compound of preparation by liquid chromatography (LC) and mass spectroscopy with system that hereinafter lists and operational condition.When having chlorine, the compound quality of listing is right ³⁵Cl.The following description of used operational condition.

The FractionLynx system

System: Waters FractionLynx (double analysis/preparation)

HPLC pump: Waters 2525

Syringe-automatic sampler: Waters 2767

Mass detector: Waters-Micromass ZQ

PDA detector: Waters 2996 PDA

Acid analysis condition:

Eluent A:H ₂O (0.1% formic acid)

Eluent B:CH ₃CN (0.1% formic acid)

Gradient: 5-95% eluent B was through 5 minutes

Flow velocity: 2.0ml/min

Post: Phenomenex Synergi 4 μ Max-RP 80A, 50 * 4.6mm

The MS condition:

Capillary voltage: 3.5kV

Awl voltage (cone voltage): 25V

Source temperature: 120 ℃

Sweep limit: 125-800amu

Ionization pattern: positive ion electrospray spraying or the spraying of positive and negative ion-conductance

Plateform system

HPLC system: Waters 2795

Mass detector: Micromass Platform LC

PDA detector: Waters 2996 PDA

The polarity analysis condition:

Eluent A:H ₂O (0.1% formic acid)

Eluent B:CH ₃CN (0.1% formic acid)

Gradient: 00-50% eluent B was through 3 minutes

Flow velocity: 1.5ml/min

Post: Phenomenex Synergi 4 μ Hydro 80A, 50 * 4.6mm

The MS condition:

Capillary voltage: 3.5kV

Awl voltage: 30V

Source temperature: 120 ℃

Sweep limit: 165-700amu

Ionization pattern: negative ion, positive ion or the spraying of positive and negative ion-conductance

Acid analysis condition:

Eluent A:H ₂O (0.1% formic acid)

Eluent B:CH ₃CN (0.1% formic acid)

Gradient: 5-95% eluent B was through 3.5 minutes

Flow velocity: 0.8ml/min

Post: Phenomenex Synergi 4 μ Max-RP 80A, 50 * 2.0mm

LCT system 1

HPLC system: Waters Alliance 2795 Separations Module

Mass detector: Waters/Micromass LCT

UV detector: Waters 2487 dual λ absorption photometric detectors

The polarity analysis condition:

Eluent A: methyl alcohol

Eluent B:0.1% formic acid is in water

Gradient:

Time (mins) A B

0 10 90

0.5 10 90

6.5 90 10

10 90 10

10.5 10 90

15 10 90

Flow velocity: 1.0ml/min

Post: Supelco DISCOVERY C ₁₈5cm * 4.6mm i.d., 5 μ m

The MS condition:

Capillary voltage: 3500v (+ve ESI), 3000v (ve ESI)

Awl voltage: 40v (+ve ESI), 50v (ve ESI)

Source temperature: 100 ℃

Sweep limit: 50-1000amu

Clastotype :+ve/-ve electron spray(ES) ESI (Lockspray ^TM)

LCT system 2

HPLC system: Waters Alliance 2795 Separations Module

Mass detector: Waters/Micromass LCT

UV detector: Waters 2487 dual λ absorption photometric detectors

Analysis condition:

Eluent A: methyl alcohol

Eluent B:0.1% formic acid is in water

Gradient:

Time (mins) A B

0 10 90

0.6 10 90

1.0 20 80

7.5 90 10

9 90 10

9.5 10 90

10 10 90

Flow velocity: 1ml/min

Post: Supelco DISCOVERY C ₁₈5cm * 4.6mm i.d., 5 μ m

The MS condition:

Capillary voltage: 3500v (+ve ESI), 3000v (ve ESI)

Awl voltage: 40v (+ve ESI), 50v (ve ESI)

Source temperature: 100 ℃

Sweep limit: 50-1000amu

Ionization pattern :+ve/-ve electron spray(ES) ESI (LocksprayT ^M)

The Agilent system

HPLC system: Agilent 1100 series

Mass detector: Agilent LC/MSD VL

Multiwavelength detector: Agilent 1100 serial MWD

Software: HP Chemstation

The chiral analysis condition:

Eluent: MeOH+0.1% NH4/AcOH at room temperature

Flow velocity: 1.0ml/min

Total time: 60.0min

Volume injected: 20uL

Sample concentration: 2mg/ml

Post: Astec, Chirobiotic V; 250 * 4.6mm

Chirality preparation condition 1:

Eluent: MeOH+0.1% NH4/TFA at room temperature

Flow velocity: 6.0ml/min

Total time: 50min

Volume injected: 50uL

Sample concentration: 20mg/ml

Post: Astec, Chirobiotic V; 250 * 10mm

In the following example, determine used LCMS condition in order to following keyword:

PS-P plateform system-polarity analysis condition

PS-A plateform system-acid analysis condition

FL-A FractionLynx system-acid analysis condition

The LCT1 LCT 1-of system polarity analysis condition

The LCT2 LCT 2-of system polarity analysis condition

AS-CA Agilent system-chiral analysis condition

Embodiment 1

N-methyl-N '-(the fast cry of certain animals of 9H--6-yl)-propane-1, the 3-diamines

In CEMA Discover microwave, (0.3g, 1.94mmol) with the N-methyl isophthalic acid, (0.61ml, 5.82mmol) solution in ethanol (5ml) was 120 ℃ (100W) heating 15 minutes for the 3-propylene diamine with 6-chloropurine in the sealing microwave tube while stirring.Removal of solvent under reduced pressure with quick silica gel column chromatography purifying, with ethanol/methylene (2:8) wash-out, obtains white solid title compound (0.197g, 49% yield) with residue.LC/MS：(FL-A)R _t 0.36[M+H] ⁺ 207.22. ¹HNMR(DMSO)□1.92-2.03(2H，m)，2.52(2H，t)，2.81(2H，t)，8.14(1H，s)，8.20(1H，s).

Embodiment 2

6-(3-methylamino-propyl group amino)-7,9-dihydro-purine-8-ketone

(2A.N-8-bromo-9H-purine-6-yl)-N '-methyl-propane-1, the 3-diamines

(0.86g 4.84mmol) adds N-methyl-N '-(9H-purine-6-yl)-propane-1, and (0.2g 0.97mmol) in the solution in acetonitrile, at room temperature stirred reaction mixture 64 hours the 3-diamines with N-bromine succinimide.Removal of solvent under reduced pressure with quick silica gel column chromatography purifying, with methylene chloride/acetic acid/water (90:18:3:2) wash-out, obtains title compound (0.044g, 16% yield) with residue.LC/MS：(PS-P)R _t 1.72[M+H] ⁺ 284.93，286.93。

2B. methyl-[3-(8-oxo-8,9-dihydro-7H-purine-6-base is amino)-propyl group]-carboxylamine The tert-butyl ester

With N-(8-bromo-9H-purine-6-yl)-N '-methyl-propane-1, (0.04g, 0.14mmo1) solution in concentrated hydrochloric acid (1ml) was 100 ℃ of heating 16 hours for the 3-diamines.Reaction mixture is transferred in the frozen water, with the neutralization of 2N sodium hydroxide, add dimethyl dicarbonate butyl ester in the tetrahydrofuran (THF) (1.5ml) (0.03g, 0.17mmol) and sodium hydroxide (0.01g, 0.14mmol).Reaction mixture was stirred 1 hour, use ethyl acetate extraction.With organic layer salt water washing, dry (MgSO ₄), removal of solvent under reduced pressure.With quick silica gel column chromatography purifying,, obtain white solid title compound (0.042g, 93% yield) with ethanol/methylene (5:95) wash-out.LC/MS：(PS-P)R _t2.56[M+H] ⁺ 323.08。

(2C.6-3-methylamino-propyl group amino)-7,9-dihydro-purine-8-ketone

With 4M HCl/ diox handle methyl-[3-(8-oxo-8,9-dihydro-7H-purine-6-base is amino)-propyl group]-t-butyl carbamate (0.042g, 0.13mmol).Reaction mixture was stirred 2 hours, and removal of solvent under reduced pressure obtains white solid title compound (0.01g, 35% yield).LC/MS：(PS-P)R _t 1.55[M+H] ⁺ 223.05. ¹H NMR(Me-d ₃-OD)□2.04-2.13(2H，m)，3.03(2H，t)，3.45(3H，s)，3.87(2H，t)，8.32(1H，s).

Prepare following compounds according to similar approach:

Embodiment 3

1-(4-fluorophenyl)-N ³ -(9H-purine-6-yl) propane-1, the 3-diamines

(3A.[1-4-fluorophenyl)-3-(9H-purine-6-base is amino) propyl group] t-butyl carbamate

With 2 times of excessive amine and 5 equivalent triethylamines, under the condition that embodiment 1A describes, make 6-chloropurine and [3-amino-1-(4-fluoro-phenyl)-propyl group]-t-butyl carbamate (Pharmacore, Inc, NC, USA) reaction obtains title compound: LC/MS:(LCT1) R _t5.87[M+H] ⁺387.

3B.1-(4-fluorophenyl-N ³ -(9H-purine-6-yl) propane-1, the 3-diamines

Remove the Boc blocking group with the method that embodiment 2C describes, obtain title compound: LC/MS:(LCT1) R _t2.52[M-NH ₂] ⁺270.

Embodiment 4

6-[3-amino-3-(4-fluorophenyl) propyl group amino]-7,9-dihydro purine-8-ketone

(4A.[3-the fast cry of certain animals of 8-bromo-9H--6-base is amino)-1-(4-fluorophenyl) propyl group] the carboxylamine uncle Butyl ester

According to the method for embodiment 2A, the product with N-bromine succinimide bromination embodiment 3A obtains title compound: LC/MS:(LCT1) R _t6.64[M+H] ⁺465.

4B.6-[3-amino-3-(4-fluorophenyl) propyl group amino]-7,9-dihydro purine-8-ketone

With the method for embodiment 2B, make bromo compound hydrolysis in hydrochloric acid of embodiment 4A, obtain title compound: LC/MS:(LCT1) R _t3.05[M-NH ₂] ⁺286.

Embodiment 5

1-(4-chloro-phenyl-)-N ³ -(9H-purine-6-yl) propane-1, the 3-diamines

(5A.[1-4-chloro-phenyl-)-3-(9H-purine-6-base is amino) propyl group] t-butyl carbamate

According to the method that embodiment 1 describes, (USA) reaction obtains title compound: LC/MS:(LCT1) R for Pharmacore Inc, NC with [3-amino-1-(4-chloro-phenyl)-propyl group]-t-butyl carbamate to make 6-chloropurine _t6.49[M+H] ⁺403.

(5B.1-4-chloro-phenyl-)-N3-(9H-purine-6-yl) propane-1, the 3-diamines

Make the product deprotection of embodiment 5A with the method for embodiment 2C, obtain title compound: LC/MS:(LCT1) R _t3.02[M-NH ₂] ⁺286.

Embodiment 6

Methyl-(4-(9H-purine-6-yl) benzyl) amine

(6A.4-9-(tetrahydropyrans-2-yl)-9H-purine-6-yl) phenyl aldehyde

Make 9-(tetrahydropyrans-2-yl)-6-chloropurine (J.Am.Chem.Soc.1961,2574) (0.13g, 0.55mmol), 4-formyl boric acid (0.11g, 0.75mmol), 2M K ₂CO ₃Aq. (0.70ml, 1.4mmol) and Pd (PPh ₃) ₄(0.03g, 5mol%) 1, argon cleaning is used in the mixture degassing of 2-glycol dimethyl ether (DME) in (5ml).Under argon gas yellow solution was stirred 24 hours at 85 ℃, cooling is then used

Filter, wash with EtOAc.Filtrate is concentrated, use quick purification by silica gel column chromatography,, obtain pale solid (0.354g, 64%) with 50% EtOAc-hexane wash-out.LC/MS：(LCT1)R _t 6.15[M+H-THP] ⁺ 225

6B. methyl-(4-(9-(tetrahydropyrans-2-yl)-9H-purine-6-yl) benzyl) amine

With the aldehyde of embodiment 6A (0.25g, 0.812mmol) and methylamine (33% in EtOH, and solution 25ml) at room temperature stirred 2 hours, then evaporating solvent and excess amine.White solid is dissolved among the MeOH (25ml), adds NaBH ₄(0.05g, 1.32mmol).With solution with water (200ml) dilution, use CH after 30 minutes ₂Cl ₂(100ml) extract.With extract drying (Na ₂SO ₄), filter and concentrate, obtain colourless gummy amine (0.231g, 88%).LC/MS(LCT1)：R _t 3.94[M+H] ⁺ 325。

6C. methyl-(4-(9H-purine-6-yl) benzyl) amine

At room temperature, be evaporated to dried then with the solution stirring of amine in EtOH (15ml) and 1M HCl (10ml) of embodiment 6B 16 hours.On the SCX-II acidic resins, carry out solid phase extractions, successively use MeOH and 1M NH ₃/ MeOH wash-out.Obtain the amine (0.142g, 83%) of cream-colored solid deprotection.LC/MS(LCT1)：R _t 2.43[M+H] ⁺ 240.

Embodiment 7

Methyl-(3-(the fast cry of certain animals of 9H--6-yl) benzyl) amine

Method according to embodiment 6 lists obtains title compound with 6-chloro-9-(tetrahydrochysene-pyrans-2-yl)-9H-purine and 3-formyl radical boric acid: LC/MS (LCT1): R _t2.77[M+H] ⁺240

Embodiment 8

(4-(the fast cry of certain animals of 9H--6-yl) phenyl) acetonitrile

(8A. 4-(9-(tetrahydropyrans-2-yl)-9H-purine-6-yl) phenyl) acetonitrile

With the chloropurine of N-protected (0.27g, 1.12mmol), 4-cyano methyl phenyl-boron dihydroxide (0.22g, 1.37mmol), 2M K ₂CO ₃Aq. (1.4ml, 2.8mmol) and Pd (PPh ₃) ₄(0.03g, 2.5mol%) solution in DME (4ml) in microwave reactor 150 ℃ the irradiation 25 minutes.Organic layer is absorbed on the silica gel, uses the rapid column chromatography purifying,, obtain yellow solid (0.25g, 70%) with 50% EtOAc-hexane wash-out.LC/MS(LCT1)：R _t 5.84[M+H-THP] ⁺236。

(8B. 4-(9H-purine-6-yl) phenyl) acetonitrile

With the protected purine product of embodiment 8A (0.026g, 0.081mmol) and the mixture of 1M HCl (1ml) in EtOH (1.5ml) stirred 6 hours at 80 ℃, be evaporated to dried then.Filter with the SCX-II acidic resins, successively use MeOH and 1M NH ₃/ MeOH wash-out obtains cream-colored solid title compound (0.015g, 79%).LC/MS(LCT1)：R _t 4.37[M+H] ⁺ 236。

Embodiment 9

2-(4-(9H-purine-6-yl) phenyl) ethamine

9A2-(4-(9-(tetrahydropyrans-2-yl)-9H-purine-6-yl) phenyl) ethamine

The suspension of Raney nickel in water (0.25ml) added (4-(9-(tetrahydropyrans-2-yl)-9H-purine-6-yl) phenyl), and (0.021g is (0.066mmol) 1, in the solution in the 4-diox (2ml) for acetonitrile.At 80 ℃ of vigorous stirring suspensions, add hydrazine hydrate (0.5ml) carefully.After 30 minutes, make the solution cooling, filter, successively use MeOH and 1M NH with the SCX-II acidic resins ₃/ MeOH wash-out obtains colorless oil title compound (0.021g, 98%).LC/MS(LCT1)：R _t 4.22[M+H-THP] ⁺ 240。

(9B.2-4-(the fast cry of certain animals of 9H--6-yl) phenyl) ethamine

With the protected purine of embodiment 9A (0.021g, 0.065mmol) and the solution of 1M HCl (2ml) and EtOH (2ml) at room temperature stirred 16 hours, be evaporated to dried then.Filter with the SCX-II acidic resins, successively use MeOH and 1MNH ₃/ MeOH wash-out obtains pale solid (0.011g, 71%).LC/MS(LCT1)：R _t 2.82[M+H] ⁺ 240。

Prepare following compounds according to similar approach:

Embodiment 10

2-(3-(9H-purine-6-yl) phenyl) ethamine

Method according to embodiment 8A makes 6-chloro-9-(tetrahydrochysene-pyrans-2-yl)-9H-purine and the reaction of 4-cyano methyl phenyl-boron dihydroxide, according to reduction and the deprotection steps that embodiment 9A and 9B list, and preparation title compound: LC/MS (LCT1): R _t3.02[M+H] ⁺240.

Embodiment 11

1-(9H-purine-6-yl) piperidines-4-carboxylic acid amide

With 6-chloropurine (0.500g, 3.24mmol), six hydrogen Isonicotinamides (isonipecotamide) (0.829g, 6.47mmol) and triethylamine (2.25ml, 16.2mmol) solution in propyl carbinol (32ml) stirred 40 minutes at 1000C.Concentrate suspension, residue and methyl alcohol (20ml) were stirred 1 hour.Insoluble white solid is collected, and vacuum-drying obtains product (0.775g, 96%) .LC/MS:(LCT1) R _t2.04[M+H] ⁺247.

Embodiment 12

C-[1-(9H-purine-6-yl) piperidin-4-yl] methylamine

(12A.[1-the fast cry of certain animals of 9H--6-yl) piperidin-4-yl methyl] t-butyl carbamate

LC/MS：(LCT1)R _t 5.42[M+H] ⁺ 332。

(12B.C-[1-the fast cry of certain animals of 9H--6-yl) piperidin-4-yl] methylamine

LC/MS(LCT1)：R _t 1.18[M+H] ⁺ 233。

Embodiment 13

6-[4-(aminophenyl methyl) piperidines-1-yl]-7,9-dihydro purine-8-ketone

13A.5,6-diamino-4-chloropyrimide

Vigorous stirring limit, limit is 4,6-chloro-5-aminopyrimidine (Aldrich Chemical Co.) (2.0g, 12.2mmol) and the mixture of strong aqua (20ml) sealed glass tube internal heating to 100 ℃ 18 hours.Reinstall strong aqua (8ml) in the refrigerative pipe, condensation product scatters, with mixture 100 ℃ of reheat 28 hours.It is dried that mixture is evaporated to, and with solid water (20ml) washing and dry, obtains yellow crystals product (1.71g, 97%).LC/MS(LCT1)：R _t 1.59[M+H] ⁺147，145。

13B.6-the fast cry of certain animals of chloro-79-dihydro-8-ketone

Make 5 of embodiment 13A under argon gas, (1.0g, 6.92mmol) and N, (2.13g, 13.2mmol) 1, the mixture in the 4-diox (20ml) refluxed 48 hours N '-N,N'-carbonyldiimidazole 6-diamino-4-chloropyrimide.Solution concentration is become brown oil, it is ground and washing with methylene dichloride, obtain pale solid (1.02g, 86%).LC/MS(LCT1)：R _t 2.45[M+H] ⁺ 173，171。

13C6-(4-benzoyl piperidines-1-yl)-7,9-dihydro purine-8-ketone

To the 6-of embodiment 13B chloro-7,9-dihydro purine-8-ketone (0.100g, 0.586mmol) and (0.265g, 1.172mmol) mixture in propyl carbinol (5.8ml) in the adding triethylamine (0.408ml, 2.930mmol)., remove and desolvate after 24 hours in the 1000C heating, grind the gained solid with methyl alcohol (10ml).Filtration obtains white solid title product (0.121g, 64%).LC/MS：(LCT1)R _t 5.70[M+H] ⁺ 324。

(13D.6-[4-aminophenyl methyl) piperidines-1-yl]-7,9-dihydro purine-8-ketone

To the purinone of embodiment 13C (0.060g, 0.186mmol) add in the solution in methyl alcohol (2ml) ammonium acetate (172mg, 2.227mmol) and sodium cyanoborohydride (47mg, 0.742mmol).Reflux after 2 days, cooling solution carries out the solid phase extractions purifying then on the SCX-II acidic resins, successively use MeOH and 1M NH ₃/ MeOH wash-out obtains the title amine (0.055g, 92%) of white solid.LC/MS(LCT1)：R _t 3.90[M+H] ⁺ 325

Embodiment 14

6-[4-(amino (4-chloro-phenyl-) methyl) piperidines-1-yl]-7,9-dihydro purine-8-ketone

14A6-(4-(4-chlorobenzene formacyl) piperidines-1-yl)-7,9-dihydro purine-8-ketone

Method by embodiment 13C makes 6-chloro-7, and the reaction of 9-dihydro purine-8-ketone and 4-(amino (4-chloro-phenyl-) methyl) piperidines obtains title compound: LC/MS:(LCT1) R _t6.42[M+H] ⁺358.

(14B.6-[4-amino (4-chloro-phenyl-) methyl) piperidines-1-yl]-7,9-dihydro purine-8-ketone

Make 6-(4-(4-chlorobenzene formacyl) piperidines-1-yl)-7,9-dihydro purine-8-ketone carries out the reductive amination method of embodiment 13D, obtains title compound: LC/MS (LCT1): R _t4.43[M+H] ⁺359.

Embodiment 15

6-(4-amino methyl piperidines-1-yl)-7,9-dihydro purine-8-ketone

(15A.[1-8-oxo-8,9-dihydro-7H-purine-6-yl) piperidin-4-yl methyl] carboxylamine The tert-butyl ester

According to the method for embodiment 13C, but obtain title compound as amine: LC/MS:(LCT1) R with the piperidin-4-yl methyl carbamic acid tert-butyl ester _t5.70[M+H] ⁺349.

(15B.6-4-amino methyl piperidines-1-yl)-7, the fast cry of certain animals of 9-dihydro-8-ketone

Make the product deprotection of embodiment 15A according to the method for embodiment 2C, obtain title compound: LC/MS (LCT1): R _t1.59[M+H] ⁺249.

Embodiment 16

3-[3-(9H-purine-6-yl)-phenoxy group]-propylamine

(16A.[3-3-bromo-phenoxy group)-propyl group]-t-butyl carbamate

To the 3-bromophenol (4.75g, 27.2mmol) add in the solution in THF (40ml) THF (30ml) and triphenylphosphine (10.9g, 41mmol) the 3-hydroxypropyl t-butyl carbamate in (5.75g, 32.8mmol).Cooling (ice bath) solution, and dropping diisopropyl azo-2-carboxylic acid (DIAD) (7ml, 35.5mmol).Solution was at room temperature stirred 48 hours, add hexane (100ml) then.(7 * 50ml) washings, dry then, concentrated, (silica gel, the 4:1 hexane: ethyl acetate) purifying obtains product (3.28g, 35%) with rapid column chromatography with 1M NaOH solution with solution. ¹H NMR (250MHz, d ₆-acetone) 1.42 (9H, s), 1.99 (2H, m), 3.28 (2H, q), 4.09 (2H, t), 6.10-6.20 (1H, br s), 6.95 (1H, m), 7.10-7.15 (2H, m), 7.25 (1H, t)

(16B.{3-[3-4455-tetramethyl--[132] dioxane pentaborane-2-yl)-phenoxy group]- Propyl group }-t-butyl carbamate

To three (dibenzalacetones), two palladiums (0) (Pd ₂Dba ₃) (100mg is 0.11mmol) with three hexamethylene phosphines (76mg, 0.27mmol) the interior diox (30ml) that adds.Make the solution degassing, at room temperature stirred 30 minutes.Add connection boric acid pinacol ester (1.44g, 5.67mmol), [3-(3-bromo-phenoxy group)-propyl group]-t-butyl carbamate (1.80g, 5.45mmol) and potassium acetate (0.86g 8.76mmol), heats solution 16 hours at 80 ℃.After being cooled to room temperature, solution is poured in the ethyl acetate (150ml) into water (50ml) and salt solution (50ml) washing.With organic layer drying, concentrated, (silica gel, the 4:1 hexane: ethyl acetate) purifying obtains product (0.844g, 43% yield) with rapid column chromatography.

1H NMR(250MHz，CDCl ₃)1.29(9H，s)，1.37(6H，s)，1.47(6H，s)，1.99(2H，ddt，J6.2，6.2，6.2Hz)，3.30-3.40(2H，m)，3.98-4.07(2H，m)，6.80-7.40(4H，m)

16C. (3-{3-[9-(tetrahydrochysene-pyrans-2-yl)-9H-purine-6-yl]-phenoxy group }-propyl group)-ammonia The base t-butyl formate

To { 3-[3-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-phenoxy group]-propyl group }-t-butyl carbamate (0.252mg, 0.68mmol) add salt of wormwood (1ml in the solution in DME (7ml), the 2M aqueous solution, 2mmo]), 6-chloro-9-(tetrahydrochysene-pyrans-2-yl)-9H-purine (157mg, 0.65mmol) and Pd (PPh ₃) ₄(90mg, 0.08mmol).Made the solution reflux 8 hours, and be cooled to room temperature then, pour in the ethyl acetate (75ml).With the saturated NaHCO of solution ₃(50ml), salt solution (50ml) washing, dry then, concentrate, with rapid column chromatography (SiO ₂, the 1:1 hexane: ethyl acetate) purifying obtains required product.

¹H NMR(250MHz，CDCl ₃)1.48(9H，s)，1.60-2.30(7H，m)，3.39(2H，m)，3.84(1H，dt，J2.8，11.0Hz)，4.16-4.30(3H，m)，5.00(1H，br s)，5.88(1H，dd，J2.9，9.8Hz)，7.10(1H，ddd，J1.0，2.6，8.2Hz)，7.48(1H，m)，8.30-8.40(2H，m)，8，45(1H，m)，9.03(1H，s)

(16D.3-[3-the fast cry of certain animals of 9H--6-yl)-phenoxy group]-propylamine

To (3-{3-[9-(tetrahydrochysene-pyrans-2-yl)-9H-purine-6-yl]-phenoxy group-propyl group)-t-butyl carbamate (77.5mg, 0.17mmol) add in the solution in ethanol (1ml) HCl (1ml, the 4M dioxane solution, 4mmol).With solution stirring 16 hours, vacuum concentration then.Residue is dissolved in the methyl alcohol, adds on the acidic resins SCX-2 post, with methyl alcohol (2 * 10ml) washings.Use 1M NH ₃/ methanol-eluted fractions obtains product (44mg, 96% yield).LC/MS(LCT1)R _t 3.37[M+H] ⁺ 270

Embodiment 17

C-[1-(1H-pyrazolo [3,4-d] pyrimidine-4-yl)-piperidin-4-yl]-methylamine

To 4-chloro-1H-pyrazolo [3,4-d] pyrimidine (J.Amer.Chem.Soc.1957,79,6407-6413) (51mg, 0.33mmol) add in the solution in ethanol (2ml) triethylamine (100 μ l, 0.72mmol) and 4-(N-Boc-amino methyl) piperidines (87mg, 0.41mmol).Solution 80 ℃ of heating 3 hours, is cooled to room temperature then.Solution evaporation to doing, is made residue recrystallization purifying (Virahol), obtain the product (33mg, 30% yield) of intermediate NH-BOC protection.

To the product of intermediate NH-BOC protection (32mg, add in 0.096mmol) HCl (1ml, the 4M dioxane solution, 4mmol).Suspension was at room temperature stirred 1 hour, use ether (4ml) dilution then.Discard the ether layer, solid is washed with another part ether (2ml).Discard the ether layer once more, with gained solid high vacuum dry.This material is dissolved in separates out free alkali in the methyl alcohol, add on the acidic resins SCX-2 post,, obtain title compound (21mg, quantitative) with ammonia/methyl alcohol wash-out from post.LC/MS R _t 0.86[M+H] ⁺ 233

Embodiment 18

C-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-piperidin-4-yl]-methylamine

18A.6-amino-5-(2,2-diethoxy-ethyl)-2-sulfydryl-pyrimidine-4-alcohol

In ethanol (200ml), add in batches sodium (2.05g, 89mmol).Stirred solution dissolves fully until the sodium metal.Add 2-cyano group-4 then, 4-diethoxy-ethyl butyrate (J.Chem.Soc, 1960,131-138) (9.292g, the 40.5mmol) solution in ethanol (50ml), then add thiocarbamide (3.08g, 40.4mmol).Solution 85 ℃ of heating 18 hours, is cooled to room temperature then.With solution concentration, add saturated aqueous ammonium chloride (150ml).Mixture was at room temperature stirred 18 hours, solid collected by filtration then, water (20ml) washing obtains product (3.376g, 36%).

18B.6-amino-5-(2,2-diethoxy-ethyl)-pyrimidine-4-alcohol

To 6-amino-5-(2,2-diethoxy-ethyl)-2-sulfydryl-pyrimidine-4-alcohol (1.19g, 4.6mmol) add in the suspension in water (50ml) Raney nickel (Aldrich Raney 2800 nickel, 4.8ml).Made the mixture reflux 1 hour, and then hot solution was used

Filter.The nickel residue with more water (100ml) washing, is used Celite filtration washing thing.Aqueous filtrate is evaporated to dried, obtains product (0.747g, 71%).

18C.7H-pyrrolo-[23-d] pyrimidine-4-alcohol

By being described in J.Chem.Soc, 1960, the method for 131-138 page or leaf is with 6-amino-5-(2,2-diethoxy-ethyl)-pyrimidine-4-alcohol preparation 7H-pyrrolo-[2,3-d] pyrimidine-4-alcohol.

18D.4-chloro-7H-pyrrolo-[2,3-d] pyrimidine

To 7H-pyrrolo-[2,3-d] pyrimidine-4-alcohol (0.425g, 3.14mmol) the interior phosphorus oxychloride (4ml) that adds.Make the mixture reflux 90 minutes, and be cooled to room temperature then.Solution is poured on the trash ice, with chloroform (3 * 50ml) and ethyl acetate (100ml) extraction.Then that extract is dry and concentrated, grind the gained residue with hot ethyl acetate (200ml), obtain required product (0.204g, 42%).

(18E.[1-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-piperidin-4-yl methyl]-the carboxylamine uncle Butyl ester

To 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine (67mg, 0.44mmol) add in the solution in ethanol (1ml) triethylamine (200 μ l, 1.43mmol) and 4-N-Boc-amino methyl-piperidines (103mg, 0.48mmol).Solution 80 ℃ of heating 4 hours, is cooled to room temperature then.Throw out is filtered collection, recrystallization from alcohol-water (1:3), vacuum-drying then obtains product (41mg, 28%).LC/MS(LCT1)R _t 4.68[M+H] ⁺ 332

(18F.C-[1-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-piperidin-4-yl]-methylamine

Make the product deprotection of embodiment 18E with the method for embodiment 17, obtain title compound.LC/MS(LCT1)R ₄ 0.85[M+H] ⁺ 232

Embodiment 19

C-phenyl-C-[4-(9H-purine-6-yl)-phenyl]-methylamine

19A.2-methyl-propane-2--sulfinic acid 4-[9-(tetrahydrochysene-pyrans-2-yl)-9H-purine-6-yl]- The benzylidene acid amides

To racemic tertiary butyl sulfinyl amine (105mg, 0.87mmol) add in the solution in anhydrous methylene chloride (3.4ml) the tosic acid pyridine (6mg, 0.025mmol) and anhydrous magnesium sulfate (140mg, 1.16mmol), then add embodiment 6A aldehyde (200mg, 0.67mmol).Under room temperature and nitrogen, mixture is stirred 48 hours (J.Am.Chem.Soa, 1997,119,9913).Then reaction mixture is used

Pad filters, and uses washed with dichloromethane, vacuum evaporating solvent.With the quick purification by silica gel column chromatography of crude product, obtain the required compound (124mg, 0.30mmol, 45%) of white solid with ethyl acetate/hexane (6:4) wash-out.LC/MS(LCT1)R _t 7.24[M+H] ⁺ 412。

19B.2-methyl-propane-2--sulfinic acid (phenyl-{ 4-[9-(tetrahydrochysene-pyrans-2-yl)-9H-purine -6-yl]-phenyl }-methyl)-acid amides

(37mg, (0.06ml, 0.18mmol), the while is-60 ℃ of stirrings 0.09mmol) to drip the 3M solution of phenyl-magnesium-bromide in ether in the solution in anhydrous methylene chloride (1ml) to sulfinyl amine.After 1 hour, make temperature slowly rise to 0 ℃-60 ℃ of stirrings.TLC analyzes and shows that raw material exhausts after 3 hours.Reaction mixture with saturated aqueous ammonium chloride (1ml) quencher, is used ethyl acetate extraction.With the organic layer drying (MgSO that merges ₄), vacuum concentration.With the quick purification by silica gel column chromatography of roughage, obtain required compound (17mg, 0.034mmol, 38%) with ethyl acetate/hexane (8:2) wash-out.LC/MS(LCT1)R _t 7.14[M+H] ⁺ 490。

19C.C-phenyl-C-[4-(9H-purine-6-yl)-phenyl]-methylamine

At room temperature with 2-methyl-propane-2--sulfinic acid (phenyl-{ 4-[9-(tetrahydrochysene-pyrans-2-yl)-9H-purine-6-yl]-phenyl }-methyl)-acid amides (16mg, 0.033mmol), the solution stirring of ethanol (1.3ml) and the 1M HCl aqueous solution (1ml) spends the night.Vacuum evaporating solvent makes roughage pass through basic resin NH ₂(2g 15ml), obtains required compound (5.3mg, 0.017mmol, 53%) with methanol-eluted fractions to post.LC/MS(LCT1)R _t 4.9[M+H] ⁺ 302。

Embodiment 20

2-phenyl-1-[4-(9H-purine-6-yl)-phenyl]-ethamine

20A.2-methyl-propane-2--sulfinic acid (2-phenyl-1-{4-[9-(tetrahydrochysene-pyrans-2-yl)-9H- Purine-6-yl]-phenyl }-ethyl)-acid amides

(38mg, (0.14ml 0.28mmol), at room temperature stirs 0.09mmol) to drip the 2M tetrahydrofuran solution of benzylmagnesium chloride in the solution in anhydrous tetrahydro furan (3ml) to the sulfinyl amine of embodiment 19A.Make solution refluxed under nitrogen 3 hours.With the reaction mixture cooling,, use ethyl acetate extraction with saturated aqueous ammonium chloride (1ml) quencher.With the organic layer drying (MgSO that merges ₄), vacuum concentration.With the quick purification by silica gel column chromatography of roughage, obtain required compound (13mg, 0.034mmol, 29%) with ethyl acetate/hexane (8:2) wash-out.LC/MS(LCT1)R _t 7.34[M+H] ⁺ 504。

20B.2-phenyl-1-[4-(the fast cry of certain animals of 9H--6-yl)-phenyl]-ethamine

At room temperature with the product of embodiment 20A (2-methyl-propane-2--sulfinic acid (2-phenyl-1-{4-[9-(tetrahydrochysene-pyrans-2-yl)-9H-purine-6-yl]-phenyl-ethyl)-acid amides (13mg, 0.026mmol), the solution stirring of methyl alcohol (0.5ml) and 4M HCl/ dioxane solution (0.04ml) spends the night.Vacuum evaporating solvent makes roughage pass through basic resin NH ₂(2g 15ml), obtains required compound (3.5mg, 0.011mmol, 43%) with methanol-eluted fractions to post.LC/MS(LCT1)R _t 4.37[M+H] ⁺ 316。

Embodiment 2]

6-[4-(1-amino-2-phenylethyl) piperidines-1-yl]-7,9-dihydro purine-8-ketone

21A4-(1-hydroxyl-2-phenylethyl) piperidines-1-carboxylic acid tert-butyl ester

0 ℃ to alcohol (0.503g, 2.336mmol), 4-methylmorpholine N-oxide compound (NMO) (356mg, 3.037mmol) and the mixture of molecular sieve (4.0g) in methylene dichloride (23ml) in add Tetrapropyl ammonium perruthenate (TPAP) (41mg, 0.117mmol).After at room temperature stirring 2 hours, mixture is filtered with silicagel pad,, concentrate, obtain thick aldehyde (not shown) with the ether washing.

0 ℃ in the solution of thick aldehyde in ether (20ml), add benzyl bromination magnesium solution (with bromotoluene (695ml, 5.840mmol) and magnesium (153mg 6.307mmol) prepares in ether (12ml)).After at room temperature stirring 15 hours, add saturated aqueous ammonium chloride (150ml), separate each phase, extract water with ether (50ml).Organic phase is merged, and drying (sal epsom) and concentrated with gained crude product silica gel column chromatography (60% ether/hexane) purifying, obtains the title alcohol (256mg, 36%) of transparent oily matter.LC/MS：(LCT1)R _t 7.11[M+Na] ⁺ 328。

21B.4-phenyl acetyl piperidines-1-carboxylic acid tert-butyl ester

0 ℃ of alcohol to embodiment 21A (0.241g, 0.789mmol), NMO (129mg, add 1.105mmol) and in the mixture of molecular sieve (1.5g) in methylene dichloride (8ml) TPAP (14mg, 0.039mmol).After at room temperature stirring 15 hours, mixture is filtered with silicagel pad,, concentrate with the ether washing.With roughage silica gel column chromatography (60% ether/hexane) purifying, obtain the title ketone (101mg, 42%) of transparent oily matter.LC/MS(LCT1)：R _t 6.93[M+Na] ⁺ 326。

(21C.6-4-phenyl acetyl piperidines-1-yl)-79-dihydro purine-8-ketone

To the ketone of embodiment 21B (101mg, 0.33mmol) add in the solution in ether (3ml) 1M HCl/ ether (3ml, 3mmol).After 3 hours, add methyl alcohol (2ml).Concentrate suspension after 2 days.On the SCX-II acidic resins, carry out solid phase extractions, successively use MeOH and 1MNH ₃/ MeOH wash-out, obtain deprotection piperidines (54mg, 0.266mmol).

To the deprotection piperidines (54mg, 0.266mmol) and 6-chloro-7,9-dihydro purine-8-ketone (45mg, 0.266mmol) the adding triethylamine solution in propyl carbinol (2.7ml) in (185ml, 1.328mmol).Reflux after 24 hours,, grind the gained solid, obtain the title ketone (18mg, 20%) of white solid with methyl alcohol (5ml) with solution cooling and concentrated.LC/MS(LCT1)：R _t5.84[M+H] ⁺ 338。

(21D.6-[4-1-amino-2-phenylethyl) piperidines-1-yl]-79-dihydro purine-8-ketone

To the purinone of embodiment 21C (0.015g, 0.0445mmol) add in the solution in methyl alcohol (1ml) ammonium acetate (41mg, 0.5335mmol) and sodium cyanoborohydride (11mg, 0.1778mmol).Reflux after 2 days, the cooling suspension carries out the solid phase extractions purifying then on the SCX-II acidic resins, successively use MeOH and 1M NH ₃/ MeOH wash-out obtains title amine, for the 9:1 mixture of raw material.Repeat above response procedures, obtain the title amine (15mg, 100%) of white solid.LC/MS(LCT1)：R _t 4.15[M+H] ⁺ 339。

Embodiment 22

6-(4-[4-(4-chloro-phenyl-)-piperidin-4-yl)-phenyl)-the 9H-purine

(22A.4-4-bromo-phenyl)-4-(4-chloro-phenyl)-piperidines

(4.02g, 15.7mmol) suspension in chlorobenzene (30ml) is added dropwise to aluminum chloride (7.32g is 54.9mmol) in the suspension in chlorobenzene (10ml) with 4-(4-bromo-phenyl)-piperidines-4-alcohol at 0 ℃.At 0 ℃ reaction mixture was stirred 2 hours, add the ice quencher, add methyl tert-butyl ether then.Stir after 1 hour, throw out is filtered collect, water, methyl tert-butyl ether and water washing obtain title compound (5.59g, 92% yield).LC/MS：(PS-B3)R _t 3.57[M+H] ⁺ 350.352。

(22B.4-4-bromophenyl)-4-(4-chloro-phenyl-)-piperidines-1-carboxylic acid tert-butyl ester

At room temperature with 4-(4-bromophenyl)-4-(4-chloro-phenyl-)-piperidine hydrochlorate (1.02g of embodiment 22A, 2.64mmol), triethylamine (2.8ml, 20mmol) and tert-Butyl dicarbonate (0.60g, 2.75mmol) solution stirring in methylene dichloride (50ml) is 24 hours.Solution is washed dry (Na with 1M Citric Acid (50ml) ₂SO ₄), filter and concentrate, obtain white solid (1.15g, 97%).

¹H NMR(250mHz，CDCl ₃)□1.47(9H，s)，2.31-2.35(4H，m)，3.46-3.52(4H，m)，7.10-7.20(4H，m)，7.28(2H，d，J＝6Hz)，7.44(2H，d，J＝6Hz).

(22C.4-4-(4-chloro-phenyl-)-piperidin-4-yl)-phenyl-boron dihydroxide

Under-78 ℃ and nitrogen, stir embodiment 22B 4-(4-bromophenyl)-4-(4-chloro-phenyl-)-piperidines-1-carboxylic acid tert-butyl ester (0.50g, 1.11mmol) and triisopropyl borate ester (0.31ml, 1.33mmol) solution in anhydrous THF (6ml).Drip positive fourth lithium solution (2M in pentane, 0.67ml, 1.33mmol).At-78 ℃ dark red solution was stirred 30 minutes, become light yellowly, be warmed to room temperature then, with (2ml) quencher of 1M HCl (aq).Mixture was stirred 5 minutes, use H then ₂O (25ml) dilution is extracted with EtOAc (25ml).With extract drying (Na ₂SO ₄), filter and concentrate, obtain yellow viscous foam shape thing.Obtain white solid (0.188g, 41%) with the acetonitrile crystallization.

(22D.6-4-(4-(4-chloro-phenyl-)-piperidin-4-yl)-phenyl)-9-(tetrahydropyrans-2-yl)-9H- Purine

Make embodiment 22C boric acid (0.083g, 0.2mmol), 6-chloro-9-(tetrahydropyrans-2-yl)-9H-purine (0.050g, 0.21mmol), 2M K ₂CO ₃(aq) (0.20ml, 0.40mmol) and Pd (PPh ₃) ₄(0.02g, 7mol%) 1, nitrogen wash is used in the solution degassing in the 2-glycol dimethyl ether (3ml).Solution was stirred 16 hours at 85 ℃.Make solution be distributed in EtOAc (15ml) and H ₂Between the O (15ml).With organic layer drying (Na ₂SO ₄), filter and concentrate.Preparation t.l.c with 50% EtOAc/50% hexane wash-out, obtains title product (0.030g, 26%).LC/MS：(LCT1)R _t 8.34[M+H-THP-tBu] ⁺ 434，436。

(22E.6-4-[4-(4-chloro-phenyl-)-piperidin-4-yl)-phenyl]-the 9H-purine

At room temperature with the protected purine of embodiment 22D EtOH (4ml) and 1M HCl (aq) solution stirring in (2ml) 24 hours.Add dense HCl (3), at room temperature mixture was stirred 24 hours, stirred 5 hours at 80 ℃ then.Make solution absorption on 5g SCX-II acidic resins post, successively use MeOH and 1M NH ₃/ MeOH wash-out.The concentrated alkaline elutriant.Obtain pale solid product (0.014g, 69%) with ether grinding and flushing.LC/MS：(LCT1)R _t 5.00[M+H] ⁺ 390，392。

Embodiment 23

4-{4-[4-(4-chloro-phenyl)-piperidin-4-yl]-phenyl }-7H-pyrrolo-[2,3-d] pyrimidine

By being similar to the method that embodiment 22 lists, the preparation title compound.LC/MS(LCT1)R _t 4.48(ESI)m/z 389[M+H] ⁺

Embodiment 24

C-phenyl-C-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-piperidin-4-yl]-methylamine

(24A.4-4-chlorobenzene formacyl) piperidines-1-benzyl carboxylate

0 ℃ to (4-chloro-phenyl-) piperidin-4-yl ketone hydrochloride (0.752g, 2.890mmol) and triethylamine (1.21ml, 8.670mmol) add in the mixture in DCM (20ml) chloroformic acid benzyl ester (0.495ml, 3.468mmol).After at room temperature 18 hours, mixture is successively used saturated sodium bicarbonate aqueous solution (25ml) and salt solution (25ml) washing, then with dried over sodium sulfate and concentrated.Roughage with silica gel column chromatography (ethyl acetate) purifying, is obtained buttery ketone (0.934g, 100%).LC/MS：(LCT1)R _t 7.47[M+H] ⁺ 357。

24B.4-[amino-(4-chloro-phenyl-) methyl] piperidines-1-benzyl carboxylate

At room temperature to 4-(4-chlorobenzene formacyl) piperidines-1-benzyl carboxylate (0.630g, 1.948mmol) and ammonium acetate (1.802g, 23.377mmol) add in the mixture in methyl alcohol (19.5ml) sodium cyanoborohydride (0.490g, 7.792mmol).Reflux after 20 hours,, stir with 1M sodium hydroxide (50ml) with mixture cooling, concentrated.(3 * 50ml) extract water with ether.Organic layer is merged,, obtain buttery amine (0.611g, 97%) with dried over sodium sulfate and concentrated.LC/MS(LCT1)：R _t 10.67[M+H] ⁺358。

24C.4-[tert-butoxycarbonyl amino (4-chloro-phenyl-) methyl] piperidines-1-benzyl carboxylate

At room temperature to 4-[amino-(4-chloro-phenyl-) methyl] piperidines-1-benzyl carboxylate (0.611g, 1.883mmol) and tert-Butyl dicarbonate (0.493g, 2.260mmol) add in the solution in acetonitrile (19ml) triethylamine (0.788ml, 5.650mmol).After 24 hours, mixture is concentrated, be dissolved in again in the ethyl acetate (50ml), successively use saturated sodium bicarbonate aqueous solution (50ml) and salt solution (50ml) washing organic phase.Organic phase with dried over mgso and concentrated, with silica gel column chromatography (60% ether/hexane) purifying, is obtained the protected amine of buttery (0.600g, 69%) with the gained crude product.LC/MS(LCT1)：R _t 7.79[M+H] ⁺ 458。

24D. Phenylpiperidine-4-ylmethyl t-butyl carbamate

Under room temperature and 1 atmospheric pressure hydrogen atmospheric pressure, with 4-[tert-butoxycarbonyl amino (4-chloro-phenyl-) methyl] piperidines-1-benzyl carboxylate (0.217g, 0.473mmol) go up at 5% palladium/carbon (40mg) and stirred 1 hour by the solution in ethanol (20ml).Reaction mixture is filtered with Celite pad, and concentrated filtrate obtains oily matter (0.136g, 100%).LC/MS(LCT1)：R _t 4.15[M+H] ⁺290。

24E.{ phenyl-[1-(7H-pyrrolo-[23-d] pyrimidine-4-yl) piperidin-4-yl] methyl } amino T-butyl formate

With Phenylpiperidine-4-ylmethyl t-butyl carbamate (0.070g, 0.216mmol), 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine (0.033g, 0.216mmol) and triethylamine (0.15ml, 1.078mmol) solution in propyl carbinol (2ml) 100 ℃ the heating 2 days.Crude mixture is concentrated, and (purifying of 10% methyl alcohol/DCM) obtains oily matter (52mg, 59%) with silica gel column chromatography.

¹H NMR(MeOD)□1.20-1.60(2H，m)，1.43(9H，s)，1.85-2.15(2H，m)，2.98-3.16(2H，m)，4.32-4.36(1H，m)，4.67-4.88(2H，m)，6.59-6.60(1H，m)，7.11-7.13(1H，m)，8.12(1H，s).

24F.C-phenyl-C-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidin-4-yl] methylamine

At room temperature (0.050g 0.123mmol) adds 2M hydrochloric acid (3ml) in the solution in methyl alcohol (3ml) to { phenyl-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidin-4-yl] methyl } t-butyl carbamate.Mixture is evaporated to dried after 13 hours.On the SCX-II acidic resins, carry out solid phase extractions, successively use MeOH and 1M NH ₃/ MeOH wash-out obtains the amine (0.035g, 92%) of the deprotection of white solid.LC/MS(LCT1)：R _t 2.70[M+H] ⁺307。

Embodiment 25

C-4-chloro-phenyl--C-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-piperidin-4-yl]-methylamine

(25A.4-4-chlorobenzene formacyl) piperidines-1-carboxylic acid tert-butyl ester

At room temperature to (4-chloro-phenyl-) piperidin-4-yl ketone hydrochloride (0.996g, 3.828mmol) and triethylamine (2.7ml, 19.142mmol) add in the mixture in acetonitrile (15ml) tert-Butyl dicarbonate (1.003g, 4.594mmol).After at room temperature 16 hours, mixture is evaporated to dried, is distributed in then between ethyl acetate (50ml) and the 1M hydrochloric acid (20ml).Separate organic phase, use the washing of saturated sodium bicarbonate aqueous solution (20ml) and salt solution (20ml) successively, use dried over mgso then, be concentrated into dried.Roughage with silica gel column chromatography (60% ether/hexane) purifying, is obtained buttery ketone (1.116g, 90%).LC/MS：(LCT1)R _t 7.42[M+H] ⁺ 323。

25B.4-[amino-(4-chloro-phenyl-) methyl] piperidines-1-carboxylic acid tert-butyl ester

At room temperature to 4-(4-chlorobenzene formacyl) piperidines-1-carboxylic acid tert-butyl ester (1.116g, 3.446mmol) and ammonium acetate (3.188g, 41.358mmol) add in the mixture in methyl alcohol (34ml) sodium cyanoborohydride (0.866g, 13.786mmol).Reflux after 20 hours,, stir with 1M sodium hydroxide (100ml) with mixture cooling, concentrated.(3 * 75ml) extract water, and organic layer is merged, and use dried over sodium sulfate, are concentrated into dried with ether.(purifying of 15% methyl alcohol/DCM) obtains buttery amine (0.913g, 82%) with silica gel column chromatography with roughage.LC/MS(LCT1)：R _t 5.56[M-Boc-NH ₂] ⁺208。

(25C.C-4-chloro-phenyl-)-C-piperidin-4-yl methylamine hydrochloride

At room temperature to 4-[amino-(4-chloro-phenyl-) methyl] (0.192g 0.591mmol) adds 2M hydrochloric acid (6ml) to piperidines-1-carboxylic acid tert-butyl ester in the solution in methyl alcohol (6ml).Stir after 16 hours, solution evaporation obtains white foam shape amine salt (0.174g, 99%) to doing.

¹H NMR(MeOD)□1.40-1.82(2H，m)，2.22-2.50(2H，m)，2.90-3.17(2H，m)，3.35-3.61(2H，m)，4.22(1H，d，9.5Hz)，7.53-7.61(4H，m).

(25D.C-4-chloro-phenyl-)-C-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidin-4-yl] first Amine

With C-(4-chloro-phenyl-)-C-piperidin-4-yl methylamine hydrochloride (0.050g, 0.168mmol), 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine (0.026g, 0.168mmol) and triethylamine (0.117ml, 0.840mmol) solution in propyl carbinol (1.7ml) 100 ℃ the heating 2 days.Crude mixture is concentrated, pass-NH ₂Separator column (2g) concentrates once more, and (purifying of 15% methyl alcohol/DCM) obtains pale solid (30mg, 52%) with silica gel column chromatography.LC/MS(LCT1)：R _t 3.35[M+H] ⁺341。

Embodiment 26

C-(4-chloro-phenyl)-C-[1-(9H-purine-6-yl)-piperidin-4-yl]-methylamine

With the method that is described in embodiment 25D, pass through C-(4-chloro-phenyl)-C-piperidin-4-yl-methylamine (embodiment 25C) and 6-chloropurine prepared in reaction title compound in propyl carbinol at 100 ℃.LC/MS：(LCT1)R _t 4.13[M+H] ⁺ 342。

Embodiment 27

4-{4-[4-(4-chloro-phenyl)-piperidin-4-yl]-phenyl }-1H-pyrrolo-[2,3-b] pyridine

By being similar to the method that embodiment 22 lists, the preparation title compound.LC/MS：(LCT1)R _t 4.34[M+H] ⁺388。

Embodiment 28

C-(4-chloro-phenyl)-C-[4-(the fast cry of certain animals of 9H--6-yl)-phenyl]-methylamine

(28A. 4-bromo-phenyl)-4-chloro-phenyl)-methyl alcohol

To the 4-bromobenzaldehyde (6.90g, 37mmol) drip in cooling (ice bath) solution in THF (20ml) 4-chloro-phenyl-magnesium bromide (40ml, the 1M diethyl ether solution, 40mmol).With solution stirring 50 minutes, add saturated ammonium chloride (200ml) then, then add ethyl acetate (250ml).Separate each layer, with organic flow point water (100ml) washing, dry then, concentrated, (the 6:1 hexane: ethyl acetate) purifying obtains required product (4.47g, 41% yield) with rapid column chromatography.1HNMR(250MHz，d6-dmso)3.50(1H，br s)，5.71(1H，s)，7.33(4H，d，J8.44Hz)，7.38(2H，s)，7.51(2H，d，J 8.46Hz)

28B.2-[(4-bromo-phenyl)-(4-chloro-phenyl)-methyl]-isoindole-1, the 3-diketone

To (4-bromo-phenyl)-(4-chloro-phenyl)-methyl alcohol (2.30g, 7.73mmol), triphenylphosphine (3.42g, 13.03mmol) and phthalic imidine (1.91g, 12.98mmol) drip in the solution in THF (60ml) diisopropyl azo-2-carboxylic acid (2.40ml, 12.19mmol).With solution stirring 18 hours, pour into then in the ether (250ml).With solution with saturated sodium bicarbonate (2 * 100ml) and salt solution (50ml) wash.With organic flow point drying, concentrated, (the 6:1 hexane: ethyl acetate) purifying obtains required product (0.698g, 21% yield) with rapid column chromatography then.LC/MS：(LCT1)R _t 8.21[M+H] ⁺ 426。

(28C.2-{ 4-chloro-phenyl)-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane -2-yl)-phenyl]-methyl }-isoindole-1, the 3-diketone

To Pd ₂Dba ₃(13mg, 0.014mmol) and tricyclohexyl phosphine (20mg adds diox (6ml) in 0.07mmol).Make the solution degassing, at room temperature stirred 30 minutes.Add connection boric acid pinacol ester (0.256g, 1mmol), 2-[(4-bromo-phenyl)-(4-chloro-phenyl)-methyl then]-isoindole-1, the 3-diketone (0.424g, 1mmol) and potassium acetate (0.164g 1.67mmol), heats solution 16 hours at 80 ℃.After being cooled to room temperature, solution is poured in the ethyl acetate (10ml) into water (50ml) and salt solution (50ml) washing.With organic layer drying, concentrated, with rapid column chromatography (SiO ₂, the 6:1 hexane: ethyl acetate) purifying obtains required product (0.142g, 30% yield).LC/MS：(LCT1)R _t 8.55[M+Na] ⁺ 497。

28D.2-((4-chloro-phenyl)-4-[9-(tetrahydrochysene-pyrans-2-yl)-9H-purine-6-yl]-benzene Base }-methyl)-isoindole-1, the 3-diketone

To 6-chloro-9-(tetrahydrochysene-pyrans-2-yl)-9H-purine (0.105g, 0.44mmol) and 2-{ (4-chloro-phenyl)-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-phenyl]-methyl }-isoindole-1, (0.211mg 0.44mmol) adds PdCl to the 3-diketone in the solution in DME (2ml) ₂(PPh ₃) ₂Add 1M K then ₂CO ₃(1ml), solution was heated 18 hours at 80 ℃.Mixture is poured in the chloroform/water (100ml/50ml), separated each layer.Product is extracted with chloroform (100ml), with the organic extraction drying (Na that merges ₂SO ₄), concentrate, (1:1 hexane: ethyl acetate → 1:3 hexane: ethyl acetate) purifying obtains required product (0.101g, 42% yield) to rapid column chromatography then.

1H NMR(250MHz，CDCl ₃)1.60-2.30(6H，m)，3.82(1H，dt，J2.76，10.99Hz)，4.15-4.26(1H，m)，5.85(1H，dd，J3.1，9.8Hz)，6.77(1H，s)，7.30-7.41(4H，m)，7.55(2H，d，J8.38Hz)，7.74(2H，dd，J3.04，5，37Hz)，7.86(2H，dd，J3.1，5.61Hz)，8.33(1H，s)，8，76(2H，d，J8.46Hz)，9.01(1H，s)

(28E.C-4-chloro-phenyl)-C-{4-[9-(tetrahydrochysene-pyrans-2-the yl)-fast cry of certain animals of 9H--6-yl]-benzene Base }-methylamine

To 2-((4-chloro-phenyl)-{ 4-[9-(tetrahydrochysene-pyrans-2-yl)-9H-purine-6-yl]-phenyl }-methyl)-isoindole-1, (0.099g 0.18mmol) adds hydrazine hydrate (1ml) to the 3-diketone in the solution in ethanol (6ml).With solution stirring 48 hours, remove by filter throw out then, concentrated filtrate.The gained residue is dissolved in the methyl alcohol, adds on the SCX-2 post (2g), (2M ammonia/methyl alcohol (3 * 5ml) wash-outs are used in 3 * 5ml) washings then with methyl alcohol.Not repurity of products therefrom continues to use.

(28F.C-4-chloro-phenyl)-C-[4-(the fast cry of certain animals of 9H--6-yl)-phenyl]-preparation of methylamine

To C-(4-chloro-phenyl)-C-{4-[9-(tetrahydrochysene-pyrans-2-yl)-9H-purine-6-yl]-phenyl }-add 4M HCl/ diox (2ml) in the solution of methylamine (from previous step) in methyl alcohol (2ml).Mixture was stirred 18 hours, concentrate then.Residue is dissolved in the methyl alcohol, adds on the SCX-2 post (2g), (3 * 5ml) washings are with product 2M ammonia/methyl alcohol (3 * 5ml) wash-outs with methyl alcohol.Concentrated solution obtains required product (0.044g, 2 steps, 73%).LC/MS：(LCT1)R _t 4.48[M+H] ⁺ 336。

Embodiment 29

C-(4-chloro-phenyl-)-C-[1-(1H-pyrrolo-[2,3-b] pyridin-4-yl) piperidin-4-yl] methylamine

Prepare title compound with the method that is described in embodiment 25.LC-MS(LCT1)m/z340[M+H ⁺]，R _t 2.88min。

Embodiment 30

2-(4-chloro-phenyl)-2-[4-(1H-pyrrolo-[2,3-b] pyridin-4-yl)-phenyl]-ethyl }- Methyl-amine

(30A.{2-4-chloro-phenyl)-2-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxane penta boron Alkane-2-yl)-phenyl]-ethyl }-methyl-t-butyl carbamate

At room temperature with potassium acetate (218mg, 2.2mmol) adding [2-(4-bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-t-butyl carbamate (550mg, 1.30mmol) and (338mg is 1.32mmol) in the de-gassed solution in no Shui diox (8ml) to join boric acid pinacol ester.This solution is outgased again, with nitrogen wash (2 circulations).(28mg, 0.098mmol) (17.6mg 0.019mmol) adds in the reaction mixture with three (dibenzalacetones), two palladiums (0) with tricyclohexyl phosphine.Suspension is outgased again, under 80 ℃ and nitrogen, stirred 19 hours.After being cooled to room temperature, reaction mixture is distributed between ethyl acetate (50ml) and the water (50ml).With the organic layer water (2 * 30ml), salt solution (50ml) washing, dry (Mg ₂SO ₄), filter and concentrate.Use the silica gel rapid column chromatography,, obtain { 2-(4-chloro-phenyl)-2-[4-(4,4 with 15% ethyl acetate/hexane wash-out, 5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-phenyl]-ethyl }-methyl-t-butyl carbamate (131mg, 0.28mmol, 21%).LC-MS(LCT2)m/z 494[M+Na ⁺]，R _t 9.59min。

(30B.{2-4-chloro-phenyl)-2-[4-(1H-pyrrolo-[2,3-b] pyridin-4-yl)-phenyl]-second Base } methyl-t-butyl carbamate

Under 100 ℃ and nitrogen, with { 2-(4-chloro-phenyl)-2-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-phenyl]-ethyl }-methyl-t-butyl carbamate (100mg, 0.21mmol), 4-chloro-1H-pyrrolo-[2,3-b] pyridine (45mg, 0.29mmol), 2M wet chemical (0.38ml, 0.74mmol), diox (4ml) and Bedford ' s palladacycle catalyzer (Bedford etc., Chem.Commun.2001,1540-1541) (13.5mg, degassing mixture heating up 0.016mmol) 17 hours.Make the solution cooling, be distributed between methylene dichloride (40ml) and the water (40ml).(40ml) extracts water layer again with methylene dichloride.With the organic layer drying (Na that merges ₂SO ₄), filter and concentrate.Quick purification by silica gel column chromatography, with 50% ethyl acetate/hexane wash-out, obtain 2-(4-chloro-phenyl)-2-[4-(1H-pyrrolo-[2,3-b] pyridin-4-yl)-phenyl]-ethyl }-methyl-t-butyl carbamate (49mg, 0.11mmol, 51%).LC-MS(LCT2)m/z 462[M+H ⁺]，R _t 8.65min。

(30C.{2-4-chloro-phenyl)-2-[4-(1H-pyrrolo-[2,3-b] pyridin-4-yl)-phenyl]-second Base }-methyl-amine

Trifluoroacetic acid (3.5ml) is dropped to { 2-(4-chloro-phenyl)-2-[4-(1H-pyrrolo-[2,3-b] pyridin-4-yl)-phenyl]-ethyl }-methyl-t-butyl carbamate (49mg, 0.11mmol) in the solution in methylene dichloride (3.5ml), cool off with ice bath.At room temperature reactant was stirred 90 minutes.Concentrated solvent then.Purifying on the SCX-II acid resin is successively used methyl alcohol and 2M ammonia/methanol-eluted fractions, obtain 2-(4-chloro-phenyl)-2-[4-(1H-pyrrolo-[2,3-b] pyridin-4-yl)-phenyl]-ethyl }-methyl-amine (33mg, 0.09mmol, 83%).LC-MS(LCT2)m/z 362[M+H ⁺]，R _t 4.19min。

Embodiment 31

C-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidines-3-yl] methylamine

The method of describing with embodiment 18 prepares title compound.LC-MS(LCT2)m/z 232[M+H ⁺]，R _t 0.72min。

Embodiment 32

Prepare title compound with Agilent chirality preparation condition listed above by the enantiomorph product that chirality HPLC separates embodiment 29.The retention time that obtains with Agilent chiral analysis condition AS-CA is 33.7.Then carry out LC/MS with the PS-A condition, obtaining retention time is 1.69, [M+H] ⁺Value is 341.

Biologic activity

Embodiment 33

Antiproliferative activity

Determine the antiproliferative activity of The compounds of this invention by the ability of measuring cell growth in the compound inhibition various kinds of cell system.Measure (Nociari, M.M, Shalev, A., Benias, P., Russo, C.Journal of Immunological Methods 1998,213,157-167) inhibition of mensuration cell growth with Alamar Blue.This method is reduced to resazurin based on viable cell the ability of its fluorescence-causing substance resorufin.Each proliferation assay all places cell on 96 orifice plates, allows to recover 16 hours, adds inhibitor compound then 72 hours.When incubation period finishes, add 10% (v/v) Alamar Blue, cultivated 6 hours, measure fluorescence-causing substance at 535nM ex/590nM em then.Under the situation that non-proliferative cell is measured, make cell keep merging 96 hours, added inhibitor compound then 72 hours.As above determine viable count with Alamar Blue assay method.All cells system derives from ECACC (European Collection of CellCultures) or ATCC.

Specifically, use PC3 clone (ATCC Reference:CRL-1435) to test The compounds of this invention from human prostate gland cancer.Preferred The compounds of this invention has the IC less than 30 μ M in this mensuration ₅₀Value.

Medicinal preparations

Embodiment 34

(i) tablet

By making the 50mg compound and mixing as the 197mg lactose (BP) of thinner with as the 3mg Magnesium Stearate of lubricant, to form tablet, preparation comprises the tablet composition of formula (I) compound with known method compression.

(ii) capsule

By 100mg formula (I) compound is mixed with the 100mg lactose, the gained mixture is inserted in the opaque hard gelatin capsule of standard the preparation capsule preparations.

(iii) injection formulations I

By formula (I) compound (as salt form) is dissolved in the water that comprises 10% propylene glycol, the concentration that makes active compound is 1.5% weight, can prepare the parenteral composition of drug administration by injection.Make the solution filtration sterilization then, insert in the ampoule and sealing.

(iv) injection formulations II

By make formula (I) compound (as salt form) (2mg/ml) and N.F,USP MANNITOL (50mg/ml) soluble in water, sterile filtration solution is inserted in sealable 1ml bottle or the ampoule, preparation injection parenteral composition.

V) injection formulations III

By making formula (I) compound (as salt form) soluble in water, can prepare the preparation that injection or infusion i.v. pass medicine with 20mg/ml.Then with bottle sealing, autoclaving sterilization.

Vi) injection formulations IV

By formula (I) compound (as salt form) is dissolved in the water that comprises damping fluid (as 0.2M acetate pH4.6) with 20mg/ml, can prepare the preparation that injection or infusion i.v. pass medicine.Then with bottle sealing, autoclaving sterilization.

(vii) subcutaneous injection preparation

By formula (I) compound is mixed with pharmaceutical grade Semen Maydis oil, obtain the concentration of 5mg/ml, the composition of preparation subcutaneous administration.With the composition sterilization, insert in the suitable vessel.

Viii) freeze-dried preparation

Insert in the 50ml bottle formula (I) compound of equal portions preparation and freeze-drying.When freeze-drying, go on foot freezing scheme frozen composition with one at (45 ℃).Make temperature rise to-10 ℃ of annealing, be reduced to then-45 ℃ freezing, then about 3400 minutes of+25 ℃ of preliminarily drieds, the step redrying to increase reached 50 ℃ then.Pressure during preliminarily dried and redrying is set at 80 millitorrs (millitor).

Embodiment 35:ROCK-II (h) mensuration scheme

With 25 μ l end reaction volumes, make ROCK-II (h) (5-10mU) with 50mM Tris pH7.5,0.1mM EGTA, 30 μ MKEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK, 10mM magnesium acetate (MgAcetate) and [γ- ³³P-ATP] (the about 500cpm/pmol of specific activity, desired concn) cultivate together.Add MgATP mix and start reaction.After at room temperature cultivating 40 minutes, add 5 μ l3% phosphoric acid solution termination reactions.Then 10 μ l are reacted object point on P30 filtermat, washing is 5 minutes 3 times in 75mM phosphoric acid, and washing is 1 time in methyl alcohol, then drying and scintillation counting.

Embodiment 36: anti--the ROCK-II activity

Anti--ROCK-II the activity of test implementation example 29 compounds (as above describe and measure):

Embodiment number	IC ₅₀(μM)
Embodiment number	IC ₅₀(μM)	29	<0.1

Therefore, the compound of test shows the inhibition activity of anti-ROCK-II.

Embodiment 37:P70s6 radioassay

General introduction

The P70S6 enzyme is used for measuring with 2nM available from Upstate.Used substrate S6 mixture (cocktail) is 25 μ M (not detecting Km) (AKRRRLSSLRA).In the phosphoryl shift reaction, with ATP's ³³P-γ phosphate (phosphate) is transferred to serine residue.Reaction mixture is transferred to the phosphorylated cotton filter plate, at this, peptide combination, the untapped ATP of flush away.After the washing, add scintillator, measure the bonded activity with scintillation counting.

Reagent

Active P70S6 kinases (T412E) is available from Upstate (#14-486)

S6 kinase substrate mixture is available from Upstate (#20-122)

Measure buffer reagent 10mM MOPS pH 7.0

0.1mg/ml BSA

0.001％ Brij-35

0.5% glycerine

0.2mM EDTA

10mM MgCl ₂

0.01% beta-mercaptoethanol

Be prepared as 10 * stoste, be stored in 20 ℃ with the 2ml equal portions

15μM ATP

ATP (10mM stoste) is by the fresh interpolation of concentrated stoste.

ATP will decompose in time, remain on as much as possible on ice, use little equal portions to guarantee that stoste is fresh.

γ ³³P-ATP APBiotech(BF1000)

12.5% ortho-phosphoric acid

0.5% ortho-phosphoric acid

Microscint 20(Packard)

Measure preparation

Enzyme mixture (every 1ml-100 measuring point):

743.75μl H ₂O

250 μ l 10 * mensuration damping fluid

3.75μl 10mM ATP

2.5 μ l enzyme

Substrate mixture (every 1ml-100 measuring point):

250 μ l S6 mixture substrates

750μl H ₂O

3.5 μ l ³³P-ATP (BF1000 is available from APBiotech)

Add ³³The amount of P-ATP is that supposition added on its indication date.Need regulate definite amount according to the time.

Compound-preparation is the dilution curve in DMSO in polypropylene 96 orifice plates, and 40 * eventually measure concentration (whole DMSO 2.5%).

1:8 is diluted in the water and (adds in the 35 μ l water 5 μ l compounds enough).

The mensuration scheme

In polypropylene 96 orifice plates, be sequentially added into:

5 μ l compounds

10 μ l substrate mixture

10 μ l enzyme mixtures.

Whole ATP concentration is near 15 μ M.The KM that calculates ATP is 47uM (radioactivity).Contrast is " no compound " (having only DMSO) and " no enzyme " (before adding enzyme with 10 μ l enzyme mixtures).Plastic cover (the appropriateness radiation intercepts) with plate envelope (plate seal) (TopSeal A-Packard) or filter plate covers.Slight concussion mixes.At room temperature cultivated 50 minutes.Add 20 μ l, 2% ortho-phosphoric acid termination reaction.

Filtration step

Make the hole pre-wetted of Millipore MAPH NOB plate with 50 μ l, 0.5% ortho-phosphoric acid lavation buffer solution.With Millipore vacuum filter filter liquide.The terminated reactant all is transferred in the hole.Filter.With 20.0 μ l, 0.5% ortho-phosphoric acid lavation buffer solution washing 2 times.Vacuum is done near.Remove the plate holder, allow filter further dry on paper handkerchief.Plate holder (snap) is gone in the Packard TopCount joint.Add 20 μ l Microscint, 20 scintillators,, counted 30 seconds with TopCount with a slice Topseal A sealing.

Equivalent

The purpose that proposes the foregoing description is to explain the present invention, should not be considered as any restriction to the scope of the invention.Be readily understood that under the situation that does not break away from principle of the present invention, can carry out multiple modification and change the specific embodiments of above describing and embodiment lists of the present invention.All these type of modifications and change all are intended to be included in the application.

Claims

1. a formula (I) compound:

Or its salt, solvate, tautomer or N-oxide compound, wherein

T is N or group CR ⁵

R ¹Be hydrogen or aryl or heteroaryl;

R ¹, A and NR ²R ³Form cyano group together; With

R ^cBe selected from hydrogen and C _1-4Alkyl; With

X ¹Be O, S or NR ^cAnd X ²Be=O ,=S or=NR ^c

2. a formula (Ia) compound:

Or its salt, solvate, tautomer or N-oxide compound, wherein

T is N or group CR ⁵

R ¹Be hydrogen or aryl or heteroaryl;

R ¹, A and NR ²R ³Form cyano group together; With

R ^cBe selected from hydrogen and C _1-4Alkyl; With

X ¹Be O, S or NR ^cAnd X ²Be=O ,=S or=NR ^c

3. a formula (Ib) compound:

Or its salt, solvate, tautomer or N-oxide compound, wherein

T is N or group CR ⁵

R ¹Be hydrogen or aryl or heteroaryl;

R ¹, A and NR ²R ³Form cyano group together; With

R ^cBe selected from hydrogen and C _1-4Alkyl; With

X ¹Be O, S or NR ^cAnd X ²Be=O ,=S or=NR ^c,

Prerequisite is:

(a-ii) E is not an indyl unsubstituted or that replace;

-NH-(CH ₂) _n-N (CH ₂CH ₃) ₂, wherein n is 2 or 3; With

4. each compound among the claim 1-3, wherein E is the monocycle base.

5. the compound of claim 4, described compound has formula (Ic):

Or its salt, solvate, tautomer or N-oxide compound, wherein

T is N or group CR ⁵

A is the stable hydrocarbon linking group that comprises 1-7 carbon atom, and described linking group is at R1 and NR ²R ³Between have the maximum chain length of 5 atoms, at E and NR ²R ³Between have the maximum chain length of 4 atoms, wherein a carbon atom in the linking group can be by oxygen or the optional displacement of nitrogen-atoms; Wherein the carbon atom of linking group A can be chosen wantonly and carry one or more substituting groups that are selected from fluorine and hydroxyl, and prerequisite is when having hydroxyl, and hydroxyl is not positioned at respect to NR ²R ³On the alpha-carbon atom of group;

E is monocycle carbocyclic ring or heterocyclic radical;

R ¹Be aryl or heteroaryl;

R ¹, A and NR ²R ³Form cyano group together; With

R ^cBe selected from hydrogen and C _1-4Alkyl; With

X ¹Be O, S or NR ^cAnd X ²Be=O ,=S or=NR ^c

6. the compound of claim 4 or claim 5, wherein the monocycle base is selected from aryl and heteroaryl such as phenyl, thiophene, furans, pyrimidine, pyrazine and pyridine, preferred phenyl.

7. the compound of claim 4 or claim 5, wherein the monocycle base is selected from loop chain alkane such as hexanaphthene and pentamethylene and contains azo-cycle such as piperidines, piperazine and piperazine.

8. the compound of claim 4 or claim 5, wherein E is selected from phenyl and piperidyl.

9. each compound among the claim 4-8, wherein E is not substituted or has 4 substituent R at the most ¹¹, described substituting group is selected from hydroxyl; CH ₂CN, oxo base (when E is non-aromatics); Halogen (as chlorine and bromine); Trifluoromethyl; Cyano group; By C _1-2The optional C that replaces of alkoxyl group or hydroxyl _1-4-oxyl; With by C _1-2The optional C that replaces of alkoxyl group or hydroxyl _1-4Alkyl.

10. the compound of claim 9, wherein E is not substituted.

Each compound during 11. aforesaid right requires, wherein E is selected from the group that this paper table 2 is listed.

Each compound, wherein R during 12. aforesaid right requires ⁴Be selected from hydrogen, chlorine, fluorine and methyl, preferred hydrogen.

Each compound during 13. aforesaid right requires, wherein T is N.

14. each compound among the claim 1-12, wherein T is CR ⁵

15. the compound of claim 14, wherein R ⁵Be selected from hydrogen, halogen, C _1-5Saturated hydrocarbyl, cyano group and CF ₃, preferred R ⁵Be selected from hydrogen, chlorine, fluorine and methyl, more preferably R ⁵Be hydrogen.

Each compound, wherein R during 16. aforesaid right requires ⁶Be selected from hydrogen, chlorine, fluorine and methyl, preferred R ⁶Be hydrogen.

Each compound, wherein R during 17. aforesaid right requires ⁷Be selected from hydrogen, halogen, C _1-5Saturated hydrocarbyl, cyano group and CF ₃, preferred R ⁷Be selected from hydrogen, chlorine, fluorine and methyl, more preferably R ⁷Be hydrogen.

Each compound, wherein R during 18. aforesaid right requires ⁸Be selected from hydrogen, chlorine, fluorine and methyl, preferred R ⁸Be hydrogen.

Each compound, wherein R during 19. aforesaid right requires ⁹Be selected from phenyl and benzyl, described phenyl and benzyl are not substituted, and are perhaps replaced as amino, carboxylic acid group or sulfonic alkyl or the alkoxyl group that carries amino, replacement by solubilizing group, and for example wherein solubilizing group is selected from amino-C _1-4-alkyl, list-C _1-2-alkylamino-C _1-4-alkyl, two-C _1-2-alkylamino-C _1-4-alkyl, amino-C _1-4-alkoxyl group, list-C _1-2-alkylamino-C _1-4-alkoxyl group, two-C _1-2-alkylamino-C _1-4-alkoxyl group, piperidyl-C _1-4-alkyl, piperazinyl-C _1-4-alkyl, morpholinyl-C _1-4-alkyl, piperidyl-C _1-4-alkoxyl group, piperazinyl-C _1-4-alkoxyl group and morpholinyl-C _1-4-alkoxyl group.

Each compound during 20. aforesaid right requires, wherein linking group A is at R ¹With NR ²R ³Between have the maximum chain length of 3 atoms (more preferably 1 or 2 atom, most preferably 2 atoms).

Each compound during 21. aforesaid right requires, wherein linking group A is at E and NR ²R ³Between have 4 atoms, be the maximum chain length of 3 atoms more generally.

Each compound during 22. aforesaid right requires, wherein linking group A is at R ¹With NR ²R ³Between have the chain length of 1,2 or 3 atom and at E and NR ²R ³Between have the chain length of 1,2 or 3 atom.

Each compound during 23. aforesaid right requires, wherein linking group A has full carbon skeleton.

Each compound during 24. aforesaid right requires, wherein linking group A is selected from the group that this paper table 1 is listed.

Each compound, wherein R during 25. aforesaid right requires ¹Be aryl or heteroaryl, as monocyclic aryl or heteroaryl.

26. each compound, wherein R among the claim 1-3 ¹Be selected from the phenyl, naphthyl, thienyl, furyl, pyrimidyl and the pyridyl that are not substituted or replace.

27. the compound of claim 26, wherein R ¹Be not substituted or quilt 5 substituting groups replacements at the most, described substituting group is selected from hydroxyl; C _1-4Acyloxy; Fluorine; Chlorine; Bromine; Trifluoromethyl; Cyano group; Separately by C _1-2The optional C that replaces of alkoxyl group or hydroxyl _1-4-oxyl and C _1-4Alkyl.

Each compound, wherein R during 28. aforesaid right requires ²And R ³Independently be selected from hydrogen, C _1-4Alkyl and C _1-4Acyl group, wherein alkyl and acyl group are by one or more optional replacements of substituting group that are selected from fluorine, hydroxyl, amino, methylamino-, dimethylamino, methoxyl group and monocycle or bicyclic aryl or heteroaryl.

29. the compound of claim 28, wherein R ²And R ³Independently be selected from hydrogen, unsubstituted C _1-4Alkyl and unsubstituted C _1-4Acyl group.

30. the compound of claim 29, wherein R ²And R ³Independently be selected from hydrogen and methyl, for example NR wherein ²R ³Be amino, methylamino-or dimethylamino.

31. the compound of claim 30, wherein NR ²R ³Be amino or methylamino-.

Each compound, wherein J during 32. aforesaid right requires ¹-J ²Be selected from N=CH, HC=N, HN-C (O) and CH=CH.

A 33. formula (II) compound:

Wherein position or contraposition are connected between group A and phenyl ring, and q is 0-4; T, J ¹-J ², A, R ¹, R ², R ³And R ⁴As each qualification in the above-mentioned claim, R ¹¹Be the substituting group that this paper limits, wherein compound is used for: (a) treatment or prevention wherein need disease or the illness of regulation and control (as suppressing) ROCK kinases or protein kinase p70S6K; And/or (b) treatment wherein needs experimenter or the patient group of regulation and control (as suppress) ROCK kinases or protein kinase p70S6K.

A 34. formula (III) compound:

Wherein group A is connected with the 3-position or the 4-position of piperidine ring, and q is 0-4; T, J ¹-J ², A, R ¹, R ², R ³And R ⁴As each qualification in the above-mentioned claim, R ¹¹Be the substituting group that this paper limits, wherein compound is used for: (a) treatment or prevention wherein need disease or the illness of regulation and control (as suppressing) ROCK kinases or protein kinase p70S6K; And/or (b) treatment wherein needs experimenter or the patient group of regulation and control (as suppress) ROCK kinases or protein kinase p70S6K.

The compound of each qualification during 35. aforesaid right requires, described compound is salt, solvate or N-oxide form.

36. each compound among the claim 1-35, wherein disease or illness are selected from: (a) metastases; (b) tumor invasion; (c) tumour progression; (d) tumour adheres to (as tumor cell adhesion); (e) actinomycin convergent force dependent tumors shifts, attacks or progress; (f) cell transformation; (g) metastases, invasion and attack, progress or the adhesion of ROCK mediation; (h) the actinomycin convergent force dependent tumors of ROCK mediation shifts, attacks or progress; (i) cell transformation of ROCK mediation.

37. each compound among the claim 1-35, wherein disease or illness are cancer (as the ROCK cancers mediated).

38. the compound of claim 37, wherein cancer (as the ROCK cancers mediated) is selected from: (a) testis germinoma; (b) has the little mammary cancer of transfer ability; (c) bladder cancer; (d) ovarian cancer; (e) prostate cancer; (f) hepatocellular carcinoma.

39. each compound among the claim 1-35, wherein disease or illness are invasion and attack, transfer and the tumour progressions that this paper limits any cancer of (limiting as claim 38).

40. each compound among the claim 1-35, wherein disease or illness are cardiovascular disorder or illness.

41. the compound of claim 40, wherein cardiovascular disorder or illness are selected from: (a) hypertension; (b) cardiac insufficiency (as chronic heart failure); (c) myocardial hypertrophy; (d) restenosis; (e) renal tubal dysfunction (as chronic renal failure); (f) atherosclerosis (arteriosclerosis); (g) myocardial preservation; (h) allogeneic survival; (i) cerebral ischemia; (j) coronary vasospasm; (k) vascular inflammation..

42. each compound among the claim 1-35, wherein disease or illness comprise muscle (as unstriated muscle) dysfunction.

43. the compound of claim 42 wherein comprises handicapped disease of muscle (as unstriated muscle) or illness and is selected from: (a) asthma; (b) penile erectile function obstacle; (c) Female sexual dysfunction; (d) I type bladder excessive activities syndrome; (e) unusual unstriated muscle (as following hypertension).

44. each compound among the claim 1-35, wherein disease or illness comprise inflammation.

45. the compound of claim 44, wherein inflammation comprises or shows as: (a) rheumatoid arthritis; (b) irritable bowel syndrome; (c) inflammatory bowel; (d) vascular inflammation and (e) neural inflammatory diseases or illness.

46. the compound of claim 45 (e), wherein neural inflammatory diseases or illness are selected from: (a) apoplexy; (b) multiple sclerosis; (c) alzheimer's disease; (d) Parkinson's disease; (e) amyotrophic lateral sclerosis; (f) inflammatory pain.

47. each compound among the claim 1-35, wherein disease or illness are CNS disease or illness.

48. the compound of claim 47, wherein CNS disease or illness are selected from: (a) Spinal injury or wound; (b) brain injury or wound; (c) acute neuronal damage (as apoplexy or traumatic brain injury); (d) Parkinson's disease; (e) alzheimer's disease; (f) nervus retrogression illness or disease; (g) apoplexy (as following hypertension); (h) cerebral vasospasm; (i) inhibition of axon growth and budding; J) repressed axon regeneration; (k) functional rehabilitation defective after the wound; (1) demyelination or disorder; (m) inflammatory CNS disease or disorder; (n) neuropathic pain; (o) nerve degenerative diseases.

49. each compound among the claim 1-35, wherein disease or illness are selected from: (a) insulin resistant; (b) graft protection (as cardiovascular or inflammatory graft protection); (c) diabetes; (d) asthma; (e) lung vasoconstriction; (f) glaucoma; (g) fibrosis (as hepatic fibrosis and renal fibrosis).

50. each compound among the claim 1-35, wherein disease or illness are infectious diseases or illness.

51. the compound of claim 50, wherein infectious diseases or illness are metazoan, protozoon, fungi, Protein virus, virus or bacterial disease, infection or invasion and attack.

52. the compound of claim 50 or claim 51, wherein infectious diseases or illness comprise the cytoskeleton rearrangement of pathogenic agent mediation.

Each compound during 53. aforesaid right requires, wherein treatment or prevention comprise: (a) regulation and control (as suppressing) ROCK kinases; Or (b) in the kinase whose activity level intervention of ROCK.

Each compound during 54. aforesaid right requires, wherein treatment or prevention comprise the intervention of finishing following effect: (a) muscle (as unstriated muscle) is lax; (b) vascular muscle lax (as increasing vascular flow); (c) transplantation therapy (as comprising the graft protection); (d) neurocyte regulation and control; (e) reduce cell proliferation; (f) reduce cell migration; (g) suppress the cytoskeleton rearrangement that pathogenic agent invasion and attack or infection cause; (g) promote tissue regeneration; (h) functional rehabilitation after the enhancing wound.

55. the compound of claim 54, wherein the regulation and control of (d) neurocyte comprise: (a) neuron regeneration; (b) induce new axon growth; (c) make aixs cylinder once more by the injury region in the CNS; (d) spinous process is external; (e) spinous process differentiation; (f) aixs cylinder is sought the footpath; (g) dendritic spine forms; (h) dendritic spine maintenance; (i) regulation and control neurite outgrowth awl withers; (j) the external inhibition of regulation and control spinous process.

Each compound during 56. aforesaid right requires, wherein treatment or prevention comprise the method for diagnosis and treatment disease or illness, and described method comprises: (i) the screening patient is to determine that whether disease that the patient is suffered from maybe may suffer from or illness are to using the treatment sensitivity of the compound with anti-ROCK kinase activity; (ii) when showing that disease of patient or illness are responsive, then give among patient's claim 1-35 each compound.

Each compound during 57. aforesaid right requires, wherein experimenter or patient's mass selection are certainly: (a) colony of ROCK kinase function obstacle (for example overactivity); (b) carried out the colony of ROCK dysfunction (as the ROCK overactivity) diagnostic test; (c) the handicapped colony of Rho signal pathway; (d) carried out the colony of Rho signal pathway dysfunction diagnostic test.

58. the purposes of the compound of each qualification in the preparation medicine among the claim 1-35, described medicine is used for: (a) disease or the illness of treatment or prevention this paper qualification; And/or (b) experimenter or the patient group that limit of treatment this paper.

59. a method, described method is used for: (a) disease or the illness of treatment or prevention this paper qualification; And/or (b) treat the experimenter or the patient group of this paper qualification, described method comprises the compound that each qualification among the experimenter of the needs claim 1-35 is arranged.

Each invention during 60. aforesaid right requires, wherein the ROCK kinases is ROCK1 and/or ROCK2.

61. the compound of each qualification among the claim 1-35, wherein disease or illness are selected from: (a) cancer (as the p70S6K cancers mediated); (b) metastases; (c) immune dysfunction; (d) tissue injury (tissue injury that causes as inflammation); (e) karyomit(e) 17q23 amplification (perhaps it causes or relevant illness); (f) Peutz-Jeghers syndrome (perhaps it causes or relevant illness); (g) LKB1 sudden change (perhaps it causes or relevant illness); (h) BRCA1 sudden change (perhaps it causes or relevant illness); (i) BRCA2 sudden change (perhaps it causes or relevant illness); (j) handicapped apoptosis program; (k) growth factor receptors signal transduction, overexpression and activation in the tumor tissues; (1) metabolic trouble or disorder; (m) with abnormal cell proliferation and/or metabolism diseases associated; (n) neuronal disease.

62. the compound of claim 61, wherein (e) caused by karyomit(e) 17q23 amplification or relative disease or illness are selected from: (a) primary breast tumour; (b) comprise the tumour (as breast tumor) that BRCA2 suddenlys change; (c) comprise the tumour (as breast tumor) that BRCA1 suddenlys change; (d) pancreatic neoplasm; (e) tumor of bladder; (f) neuroblastoma.

63. the compound of claim 61, wherein (g) caused by LKB1 sudden change or relative disease or illness are the adenocarcinomas of lung that comprises LKB1 sudden change (as the LKB1 sudden change of passivation).

64. the compound of claim 61, wherein (h) or (i) cause by BRCA1/2 sudden change or relative disease or illness are mammary cancer.

65. the compound of claim 61, wherein (1) metabolic trouble or disorder are selected from: (a) obesity (obesity that obesity of bringing out as the age or diet bring out); (b) diabetes; (c) metabolism syndrome; (d) insulin resistant; (e) hyperglycemia; (f) hyperaminoacidemia; (g) hyperlipidaemia.

66. each compound among claim 1-35 and the 61-65, wherein treatment or prevention comprise: (a) regulation and control (as suppressing) protein kinase p70S6K; (b) in the activity level intervention of protein kinase p70S6K; (b) progress of inhibition G1-S phase in cells in vivo cycle; (c) suppress cell cycle propagation in the cell cycle G1-S phase; (d) as the rapamycin quid pro quo; (e) as the wortmannin quid pro quo; (f) rebuild suitable apoptosis program; (g) growth factor receptors signal transduction, overexpression and the activation in the inhibition tumor tissues; (h) regulation and control neuronal cell differentiation; (i) regulating cell motility; (j) regulating cell reaction; (k) strengthen insulin sensitivity.

67. each compound among claim 1-35 and the 61-66, wherein treatment or prevention comprise the method for diagnosis and treatment disease or illness, and described method comprises: (i) the screening patient is to determine whether disease or illness that the patient is suffered from maybe may suffer from have the treatment sensitivity of the active compound of anti-protein kinase p70S6K to using; (ii) when showing that disease of patient or illness are responsive, then give among patient's claim 1-35 each compound.

68. each compound among claim 1-35 and the 61-67, wherein experimenter or patient's mass selection are certainly: (a) colony of protein kinase p70S6K dysfunction (for example overactivity); (b) carried out the colony of p70S6K dysfunction (as the p70S6K overactivity) diagnostic test; (c) colony of karyomit(e) 17q23 amplification; (d) carried out the colony of the diagnostic test of karyomit(e) 17q23 amplification; (e) colony that exists BRCA1 to suddenly change; (f) carried out the colony of BRCA1 sudden change diagnostic test; (g) colony that exists BRCA2 to suddenly change; (h) carried out the colony of BRCA2 sudden change diagnostic test; (i) colony that exists LKB1 to suddenly change; (j) carried out the colony of LKB1 sudden change diagnostic test; (k) according to the described colony of screening of claim 67 (i).