CN101563345A - Pharmaceutical compounds - Google Patents

Abstract

Compounds of the formula (I), and salts, solvates, tautomers and N-oxide thereof; wherein TG is selected from groups (1) and (2): wherein the asterisk (*) represents the point of attachment of the group E to the group X; R<la >is an optionally substituted aryl or heteroaryl group; R<lb> is hydrogen or a group Rla; X is an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 are heteroatoms selected from O, N and S; and A, E, R<2>, R<3>, R<4>, Q<1> and Q<2> are as defined in the claims; provided that when E is aryl or heteroaryl, then Q<2> is other than a bond; and further provided that the moiety (a) is other than a group (BG1) or (BG2); wherein (BGl) and (BG2) are each optionally substituted; T is N or CR<Z>; J<1>-J<2> is selected from N=C(R<Z>),(R<Z>)C=N, (R<Z>)N-C(O), (R<Z>)2C-C(O), N=N and (R<Z>)C=C(R<6>); J<4>-J<3> is a group N=C(R<Z>) or a group (R<Z>)N-CO; and R<Z> is hydrogen or a substituent. The compounds of the formula (I) have PKA and PKB kinase inhibiting activity and are useful in the treatment of cancers.

Description

Medical compounds

The present invention relates to suppress or regulate the active aryl of protein kinase B (PKB) and protein kinase A (PKA)-and heteroaryl-alkyl ammonium compounds, described compound is used for the treatment of or prevents by PKB and the disease of PKA mediation or the purposes of illness, and has PKB and PKA inhibition or regulate active new compound.The present invention also provides the pharmaceutical composition that comprises described compound and new chemical intermediate.

Background of invention

Protein kinase form a big nation undertake the structurally associated enzyme of multiple signal transduction process control in the cell (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA).Substrate (for example albumen-tyrosine, albumen-serine/threonine, lipid etc.) by their phosphorylations can be divided into kinases many families.Determined that the sequence die body generally is equivalent to these kinase whose each families (for example, Hanks, S.K., Hunter, T., FASEB J., 9:576-596 (1995); People such as Knighton, Science, 253:407-414 (1991); People such as Hiles, Cell, 70:419-429 (1992); People such as Kunz, Cell, 73:585-596 (1993); People such as Garcia-Bustos, EMBO J., 13:2352-2361 (1994)).

Protein kinase can show its feature by its regulation mechanism.These mechanism comprise for example autophosphorylation effect, are interacted by other kinases transphosphorylations, protein-protein interaction, albumen-fat interaction and albumen-polynucleotide.Single protein kinase can be by regulating more than a kind of mechanism.

By phosphate radical is added to target protein, kinases can be regulated a lot of different cell processes, includes but not limited to propagation, differentiation, apoptosis, motility, transcribes, translates and other signal conductive processes.These phosphorylation events serve as the molecule switch on and off that can regulate or adjust the target protein biological function.The phosphorylation of target protein responds generations such as multiple extracellular signal (hormone, neurotransmitter, growth and differentiation factor etc.), cell cycle events, environment or nutrition anxiety.The protein kinase that is fit to for example works in the signal transduction path of metabolic enzyme, adjusting albumen, acceptor, cytoskeletal protein, ionic channel or pump or transcription factor in activation or passivation (directly or indirectly).The no control signal conduction that is caused by protein phosphorylation control defective relates to multiple disease, comprises for example inflammation, cancer, allergy/asthma, disease of immune system and illness, central nervous system disease and illness and vasculogenesis.

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 important, its allows non-downright bad control to destroy, remove and recover cellular constituent.Remove cell also very important aspect the keeping of the karyomit(e) of grown cell colony and genomic integrity by apoptosis.Several known check points are arranged in the cell growth cycle of meticulous monitoring dna damage and genomic integrity.Detecting unusual reaction in these check points is the growth that stops this type of cell, and causes repair process.If damage or can not repair unusually, the then wrong and error in order to prevent to breed is by damaged cell trigger cell apoptosis.Cancer cells comprises a large amount of sudden changes, mistake or rearrangement in its chromosomal DNA.There's a widespread conviction that, and part takes place because most of tumours have defective in undertaking the one or more processes that cause apoptotic process in this.Normal controlling mechanism can not kill cancer cell, and karyomit(e) or dna encoding mistake still continue to propagate.Therefore, recover these short apoptotic signals or to suppress non-adjusting survival signal be the attractive method of treatment cancer.

People understand already, and the signal transduction pathway mediation that especially comprises enzyme phosphatidyl-inositol 3-kinase (PI3K), PDK1 and PKB increases the anti-apoptotic or the survival reaction of a lot of cells.Have considerable data to show, this approach is that a lot of somatomedins suppress the important survival approach that apoptosis uses.Enzyme PI3K activates by the growth of certain limit and survival factors (for example EGF, PDGF) and by producing many phosphatidylinositols, and causes and activate downstream signal conduction incident, comprises the activity of kinases PDK1 and protein kinase B (PKB) (being also referred to as Akt).In host tissue (for example vascular endothelial cell) and tumorigenesis also is like this.PKB regulates the albumen ser/thr kinases that the territory is formed by the kinases territory with N-end PH territory and C-end.Enzyme PKB self is by PDK1 phosphorylation on Thr 308, and by a kind of Unidentified so far kinases phosphorylation on Ser 473.Activation need be two position phosphorylations fully, and for enzyme being fixed to the tenuigenin face that substrate is provided the adipose membrane of optimal path, then need associate between PIP3 and PH territory.

Activatory PKB makes the certain limit substrate phosphorylation that helps the overall survival reaction again.Though can not determine, we have understood all factors of undertaking mediation PKB dependency survival reaction, but believe that some important activities are phosphorylation and inactivations of short antiapoptotic factors BAD and Caspase 9, the phosphorylation of Forkhead transcription factor (for example FKHR causes it to get rid of) and owing to activate the NfkappaB approach from nuclear in the kinase whose phosphorylation of cascade middle and upper reaches.

Except the anti-apoptosis and short survival effect of PKB approach, enzyme also plays an important role in promoting cell proliferation.This effect may think that at present some are arranged is p21 by multiple effect mediation equally ^Cip1/WAF1Phosphorylation and the inactivation of the phosphorylation of cell cycle protein dependent kinase inhibitor and inactivation and mTOR (a kind of control cell grow the kinases of several aspects).

The Phosphoric acid esterase PTEN that makes many phosphatidylinositols dephosphorylation and inactivation is a kind of crucial tumor suppressor protein that PI3K/PKB survival approach is regulated in normal effect.The importance of PI3K/PKB approach can be judged by a kind of like this observation in tumour takes place, PTEN is one of the most common target of human tumor sudden change, sudden change in this Phosphoric acid esterase is～50% or more melanoma (people such as Guldberg, 1997, Cancer Research 57,3660-3663) and advanced prostate cancer (people such as Cairns, 1997, Cancer Research 57,4997) finds in.These observations and other observations show that all the tumor type of wide region relies on active raising of PKB of growth and survival, and the PKB inhibitor that response is fit in treatment.

3 kinds of closely-related PKB isotypes are arranged, be called α type, β type and γ type, these genetic researches show to have difference but the eclipsed function.There is proof to show that they can play use independently in cancer.For example, found PKB β overexpression or activation in the ovarian cancer of 10-40% and carcinoma of the pancreas (people such as Bellacosa, 1995, Int.J.Cancer 64,280-285; People such as Cheng, 1996, PNAS 93,3636-3641; People such as Yuan, 2000, Oncogene 19,2324-2330), PKB α in people's cancer of the stomach, prostate cancer and mammary cancer, increase (Staal, 1987, PNAS 84,5034-5037; People such as Sun, 2001, Am.J.Pathol.159,431-437), and the increase of PKB gamma activity in mammary gland that does not rely on steroid and prostate cell line, observe (people such as Nakatani, 1999, J.Biol.Chem.274,21528-21532).

The PKB approach also works in the growth of healthy tissues and survival, and can regulate in normal physiological, with control cell and function of organization.Therefore, relevant with survival with the propagation that do not cater to the need of normal cell and tissue disorder also can have benefited from the PKB inhibitor for treating in treatment.This type of disorderly example is to cause prolonging or go up to regulating immunoreactively prolonging expansion and the relevant immunocyte disorder of surviving with cell colony.For example, T and bone-marrow-derived lymphocyte react (for example interleukin-2 activation PI3K/PKB approach) to isogeneic or somatomedin, and undertake the survival of keeping the antigen-specific lymphocyte clone during immune response.Lymphocyte and other immunocytes cause prolonging under the activatory condition to unsuitable autoantigen or exotic antigen reaction or other unusually therein; the PKB approach is supplied with important survival signal, and sort signal prevents to stop immunoreactive normal mechanism by the apoptosis of activating cells colony.Have quite a lot of evidence to show, lymphocyte population expansion be under the immune condition to the reaction of autoantigen, for example multiple sclerosis and sacroiliitis.Lymphocyte population expansion to the inappropriate reaction of exotic antigen is the feature of another set condition, for example anaphylaxis and asthma.In a word, PKB suppresses to can be Immunological diseases provides useful treatment.

Wherein PKB can the inappropriate expansion of active normal cell, other examples of growth, propagation, hyperplasia and survival include but not limited to arteriosclerosis, myocardosis and glomerulonephritis.

Except the effect in cell growth and survival, the PKB approach also works in Regular Insulin control glucose metabolism.The evidence that obtains from the mouse that lacks α and β isotype PKB shows that this effect is mediated by the β isotype.Therefore, the PKB active regulator also can be used for wherein having the disease of glucose metabolism and energy storage dysfunction, as diabetes, metabolic trouble and obesity.

The protein kinase (PKA) that relies on cAMP is a kind of serine/threonine protein kitase, this protein kinase makes the substrate phosphorylation of wide region, and a lot of cell processes are relevant with regulating, and comprise cell growth, cytodifferentiation, ionic channel conductivity, genetic transcription and neurotransmitter associated release.In its nonactive attitude, the PKA holoenzyme is a kind of two tetramers of regulating subunit and two catalytic subunits that comprise.

Contact between the cell processes that PKA regulates as the protein mediated signal transduction incident of G-and their.Hormone part (as hyperglycemic-glycogenolytic factor) is attached to transmembrane receptor activated receptor coupling G-albumen (GTP combination and protolysate).When activating, the proteic α subunit dissociation of G is attached to and activated adenyl cyclase, and this makes ATP change into ring AMP (cAMP) again.So the cAMP that produces is attached to the adjusting subunit of the dissociated PKA of catalytic subunit that causes associating then.Be that the catalytic subunit of inactive PKA becomes activity when dissociating with regulating when subunit associates, and participating in other and regulate proteic phosphorylation.

For example, the catalytic subunit of PKA makes the phosphorylase kinase phosphorylation, and this phosphorylase kinase relates to the phosphorylation of Starch phosphorylase, and described enzyme is responsible for glycogenolysis and is discharged glucose.PKA is also with relevant with inactivation adjusting glucose level by the Glycogensynthase phosphorylation.Therefore, the disease that PKA active regulator (this conditioning agent can increase or reduce the PKA activity) can be used for treating or regulating glucose metabolism and energy storage dysfunction is as diabetes, metabolic trouble and obesity.

PKA also is confirmed as the sharp inhibitor of t cell activation.People such as Anndahl have studied I type PKA possible effect in the disorder of HIV-inductive T cell function, the basis of this effect is the cAMP that the T cell from the HIV-infected patient has the increase level than normal T cell, and the cAMP analogue is suppressed more responsive.They infer that from research the activation of I type PKA improves the progressive T cell function disorder that can increase in the HIV infection, so I type PKA can be the latent target of immune modulating treatment.-Aandahl，E.M.，Aukrust，P.，

B.S.，Müller，F.， S.S.，Hansson，V.，Taskén，K.Protein?kinase?A?type?I?antagonist?restores?immune?responses?of?T?cellsfrom?HIV-infected?patients.FASEB?J.12，855-862(1998)。

Have realized that also the sudden change that PKA regulates in the subunit can produce superactivation in endocrine tissue.

Because as courier's diversity and importance, the abnormal response of cAMP can cause multiple human diseases to PKA in cell is regulated, for example irregular cell growth and propagation (Stratakis, C.A.; Cho-Chung, Y.S.; Protein Kinase A and human diseases, TrendsEndrocri.Metab.2002,13,50-52).The overexpression of PKA is observed in people's multiple cancer cells, comprises the cell from ovarian cancer, mammary gland and colon patient.Therefore, the PKA inhibition is a kind of method (Li, the Q. of treatment cancer; Zhu, G-D.; Current Topics inMedicinal Chemistry, 2002,2,939-971).

About the review that PKA acts in the human disease, referring to for example Protein Kinase A andHuman Disease, Constantine A.Stratakis edits, Annals of the New YorkAcademy of Sciences, Volume 968,2002, ISBN 1-57331-412-9.

hERG

Late 1990s, some medicines of US FDA approval have to withdraw from from American market, find that at that time the not normal death that causes of they and heart function is relevant.Find again that subsequently these Side effects of pharmaceutical drugs are the arrhythmias that caused by hERG carrier frequency channel break in the core cell.The hERG passage is a family of potassium-channel, its first member discerned in sudden change fruit bat (Drosiphila melanogaster) (referring to Jan in late 1980s, L.Y. and Jan, Y.N. (1990), A Superfamily ofIon Channels, Nature, 345 (6277): 672).The bio-physical property of hERG potassium-channel is described in Sanguinetti, M.C., Jiang, C., Curran, M.E., and Keating, M.T. (1995), A Mechanistic Link Betweenan Inherited and an Acquired Cardiac Arrhythmia:HERG encodes the Ikrpotassium channel.Cell, 81:299-307, and Trudeau, M.C., Warmke, J.W., Ganetzky, B., and Robertson, G.A. (1995) .HERG, a Human InwardRectifier in the Voltage-Gated Potassium Channel Family.Science, 269:92-95.

Prior art

Openly count compounds now and have PKA and PKB inhibition activity.

For example, in WO 01/91754 (Yissum), disclose and have PKB and suppress active Isoquinolinium base-sulfonamido-diamines.

WO 2005/061463 (Astex) discloses has PKB and PKA suppresses active pyrazole compound.

Summary of the invention

The invention provides have protein kinase B (PKB) and protein kinase A (PKA) and suppress or regulate active compound, described compound can be used for preventing or treats disease or illness by PKB or PKA mediation.

First aspect the invention provides the compound of formula (I):

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

Wherein TG is selected from:

(1) group

With

(2) group

Wherein the tie point of group E and radicals X represented in asterisk (*);

A is that the stable hydrocarbon that comprises 1 to 7 carbon atom connects base, and described connection base has at R ^1aAnd NR ²R ³Between the maximum chain length of 5 atoms extending, and have at E and NR ²R ³Between the maximum chain length of 4 atoms extending, wherein connect one of carbon atom in the base and can choose wantonly by oxygen or nitrogen-atoms and replace; And the carbon atom that wherein connects basic A can be chosen wantonly and carry one or more substituting groups that are selected from oxo, fluorine and hydroxyl, and its condition is that hydroxyl is not positioned at and NR when existing ²R ³On the alpha-carbon atom that group is correlated with, and its condition is that oxo group is positioned at when existing and NR ²R ³On the alpha-carbon atom that group is correlated with;

E is monocycle or bicyclic carbocyclic or heterocyclic group;

Radicals X is the bicyclic heterocyclic group with 8 to 12 ring memberses, and maximum 5 ring memberses are the heteroatoms that is selected from O, N and S;

R ^1aBe aryl or heteroaryl;

R ^1bBe hydrogen or radicals R ^1a

R ²And R ³Independently be selected from hydrogen, C _1-4Alkyl and C _1-4Acyl group, wherein alkyl and acyl moiety are optional is replaced by one or more substituting groups that are selected from fluorine, hydroxyl, amino, methylamino, dimethylamino and methoxyl group;

Perhaps R ²And R ³Form cyclic group with their bonded nitrogen-atoms, described cyclic group is selected from imidazole group and has 4 to 7 ring memberses and the optional saturated monocycle heterocyclic group that comprises the second heteroatomic ring member who is selected from O and N;

Perhaps R ²And R ³One of have 4 to 7 ring memberses and the optional saturated monocycle heterocyclic group that comprises the second heteroatomic ring member who is selected from O and N with their bonded nitrogen-atoms with forming from the one or more atoms that are connected basic A;

Perhaps NR ²R ³The carbon atom that is connected basic A with its bonded forms cyano group together;

N is 0 to 4;

Each R ⁴Independently be selected from oxo, halogen, optional by halogen, hydroxyl or C _1-2The C that alkoxyl group replaces _1-6Alkyl, cyano group, optional by halogen, hydroxyl or C _1-2The C that alkoxyl group replaces _1-6Alkyl oxygen base, CONH ₂, CONHR ⁹, CF ₃, NH ₂, NHCOR ⁹, NHCONHR ⁹And NHR ⁹

R ⁹Be radicals R ^9aOr (CH ₂) R ^9a, R wherein ^9aFor can be carbocyclic ring or heterocyclic monocycle or bicyclic radicals;

Carbon ring group or heterocyclic group R ^9aOptional be selected from following substituting group and replace by one or more: halogen, hydroxyl, trifluoromethyl, cyano group, nitro, carboxyl, amino, list-or two-C _1-4Alkyl 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 ₂And R ^bBe selected from hydrogen, have the heterocyclic group and the C of 3 to 12 ring memberses _1-8Alkyl, described C _1-8Alkyl is optional by one or more hydroxyl, oxo, halogen, cyano group, nitro, carboxyl, amino, list-or two-C that are selected from _1-4The substituting group of alkyl amino, the carbocyclic ring with 3 to 12 ring memberses and heterocyclic group replaces, and C wherein _1-8One or more carbon atoms of alkyl can be chosen wantonly by O, S, SO, SO ₂, NR ^c, X ¹C (X ²), C (X ²) X ¹Or X ¹C (X ²) X ¹Replace;

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

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

Q ¹For key or the stable hydrocarbon that comprises 1 to 3 carbon atom connect base, wherein connect one of carbon atom in the base and can choose wantonly by oxygen or nitrogen-atoms and replace, perhaps adjacent carbon atom is to can be by CONR ^qOr NR ^qCO replaces, wherein R ^qBe hydrogen, C _1-4Alkyl or cyclopropyl, perhaps R ^qFor being connected to R ^1bOr Q ¹Another carbon atom to form the C of circular part _1-4Alkylidene chain, and wherein connect basic Q ¹Carbon atom can choose wantonly and carry one or more substituting groups that are selected from fluorine and hydroxyl;

Q ²For key or the stable hydrocarbon that comprises 1 to 3 carbon atom connect base, wherein connect one of carbon atom in the base and can choose wantonly by oxygen or nitrogen-atoms and replace; And the carbon atom that wherein connects base can be chosen wantonly and carry one or more substituting groups that are selected from fluorine and hydroxyl, and its condition is that hydroxyl is not positioned at and NR when existing ²R ³On the relevant alpha-carbon atom of group, and its condition is for when E is aryl or heteroaryl, Q ²Be different from key;

And its further condition is a part

Be different from group (BG1) or (BG2);

Wherein (BG1) and (BG2) optional respectively being substituted;

The tie point of asterisk (*) expression group E;

T is N or group CR ^z

J ¹-J ²Expression is selected from N=C (R ^z), (R ^z) C=N, (R ^z) N-C (O), (R ^z) ₂C-C (O), N=N and (R ^z) C=C (R ⁶) group;

J ⁴-J ³Be group N=C (R ^z) or group (R ^z) N-CO; And

R ^zBe hydrogen or substituting group.

The compound that comprises group B G1 and BG2 is disclosed in our previous International Patent Application PCT/GB2005/004115, PCT/GB2005/004119 and PCT/GB2005/004323 (its content is attached to herein by reference), and this compounds is clearly got rid of from the scope of the application's formula (I).

The present invention further provides:

The formula (I) that this paper limits, (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII) and (IX) or the compound of its any subgroup, described compound is used to prevent or treat disease or the illness that is mediated by protein kinase B.

The compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that this paper limits is used to prepare the purposes of medicine, and described medicine is used to prevent or treat disease or the illness that is mediated by protein kinase B.

A kind of prevention or treatment are by the disease of protein kinase B mediation or the method for illness, and described method comprises the compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup of the experimenter this paper qualification that needs.

The formula (I) that this paper limits, (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII) and (IX) or the compound of its any subgroup, described compound are used for the treatment of and comprise in the Mammals abnormal cell growth or block necrocytosis unusually or by its disease that causes or illness.

The compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that this paper limits is used to prepare the purposes of medicine, and described medicine is used for the treatment of and comprises in the Mammals abnormal cell growth or block necrocytosis unusually or by its disease that causes or illness.

A kind of treatment comprises abnormal cell growth in the Mammals or blocks necrocytosis unusually or by the method for its disease that causes or illness, and described method comprises the compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that this paper of giving the active amount of the effective arrestin kinase b of Mammals limits.

Be used for formula (I) that this paper of arrestin kinase b limits, (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII) and (IX) or the compound of its any subgroup.

A kind of method of arrestin kinase b, described method comprise that the kinase inhibiting compound of the formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that make kinases and this paper qualification contacts.

The formula (I) that this paper limits, (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII) and (IX) or the compound of its any subgroup, described compound is used for the activity adjusting cell processes (for example cell fission) by the arrestin kinase b.

The method that a kind of activity of the compound arrestin kinase b by the formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that limit with this paper is regulated cell processes (for example cell fission).

The compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that this paper limits or concrete kind, described compound are used to prevent or treat disease or the illness that is mediated by protein kinase A.

The compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that this paper limits or concrete kind is used to prepare the purposes of medicine, and described medicine is used to prevent or treat disease or the illness that is mediated by protein kinase A.

A kind of prevention or treatment are by the disease of protein kinase A mediation or the method for illness, and described method comprises formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup of the experimenter this paper qualification that needs or the compound of concrete kind.

A kind of treatment comprises abnormal cell growth in the Mammals or blocks necrocytosis unusually or by the method for its disease that causes or illness, and described method comprises formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that this paper of giving the active amount of Mammals effective arrestin kinases A limits or the compound of concrete kind.

The method of a kind of arrestin kinases A, described method comprise contacts formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that kinases and this paper limits or the kinase inhibiting compound of concrete kind.

The method that the activity of a kind of compound arrestin kinases A by the formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that limit with this paper or concrete kind is regulated cell processes (for example cell fission).

A kind of treatment comprises abnormal cell growth in the Mammals or by the method for its disease that causes or illness, and described method comprises and gives the compound that Mammals effectively suppresses abnormal cell growth or blocks formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that this paper of the amount of necrocytosis limits unusually.

The compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that this paper limits or concrete kind, described compound are used for reducing or reduce and comprise the Mammals abnormal cell growth or block necrocytosis unusually or by the sickness rate of its disease that causes or illness.

A kind of reduce or reduce comprise abnormal cell growth in the Mammals or block necrocytosis unusually or that described method comprises the compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that this paper of giving the amount that Mammals effectively suppresses abnormal cell growth limits by the method for the sickness rate of its disease that causes or illness.

A kind of pharmaceutical composition, described pharmaceutical composition comprise the new compound and the pharmaceutically acceptable carrier of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup of this paper qualification.

The compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that a kind of this paper that is used for medicine limits.

The compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that this paper limits is used to prepare the purposes of medicine, and described medicine is used for prevention or treats any disease disclosed herein or illness.

A kind of method for the treatment of or preventing any disease disclosed herein or illness, described method comprises the compound (for example treating significant quantity) of the formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that give patient (for example, the patient of Xu Yaoing) this paper qualification.

A kind of method that reduces or reduce the sickness rate of disease disclosed herein or illness, described method comprises the compound (for example treating significant quantity) of the formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that give patient (for example, the patient of Xu Yaoing) this paper qualification.

The compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that this paper limits or concrete kind, described compound is used for the treatment of or prevents disease of patient or illness, described patient is through examination and determine to suffer to having the disease or the illness of the active compounds for treating sensitivity of anti-protein kinase B, or emits and suffer from described disease or the danger of illness.

A kind of diagnosis and treatment are by the disease of protein kinase B mediation or the method for illness, described method comprises (i) examination patient, to determine whether disease or illness that the patient is just suffering from or may just suffer from are disease or the illnesss that has the active compounds for treating sensitivity of anti-protein kinase B to using; (ii) when therefore showing that disease of patient or illness are responsive, give the compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup of patient this paper qualification subsequently.

The compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that this paper limits is used to prepare the purposes of medicine, described medicine is used for the treatment of or prevents disease of patient or illness, described patient is through examination and determine to suffer to having the disease or the illness of the active compounds for treating sensitivity of anti-protein kinase B, or emits and suffer from described disease or the danger of illness.

A kind of diagnosis and treatment are by the disease of protein kinase A mediation or the method for illness, described method comprises (i) examination patient, to determine whether disease or illness that the patient is just suffering from or may just suffer from are disease or the illnesss that has the active compounds for treating sensitivity of anti-protein kinase A to using; (ii) when therefore showing that disease of patient or illness are responsive, give the compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup or the concrete kind of patient this paper qualification subsequently.

The compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that this paper limits or concrete kind is used to prepare the purposes of medicine, described medicine is used for the treatment of or prevents disease of patient or illness, described patient is through examination and determine to suffer to having the disease or the illness of the active compounds for treating sensitivity of anti-protein kinase A, or emits and suffer from described disease or the danger of illness.

The compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) or its any subgroup that this paper limits or concrete kind, described compound is used for the treatment of or prevents disease of patient or illness, described patient is through examination and determine to suffer to having the disease or the illness of the active compounds for treating sensitivity of anti-protein kinase A, or emits and suffer from described disease or the danger of illness.

General preferred and definition

Unless otherwise indicated herein, below general preferred and definition should be applicable to part A, E, Q ¹, Q ²And R ^1aTo R ⁹And each of inferior definition, subgroup or concrete kind.

This paper quotes formula (I) any should think finger formula (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX) and any other compound subgroup in (I), unless this paper needs in addition.

In this application, for convenience can be with part:

Be called " bicyclic radicals X " or " bicyclic radicals ".

Unless otherwise indicated herein, " carbocyclic ring " used herein and " heterocycle " group should comprise aromatics and non-aromatics loop systems the two.General this type of group can be monocycle or dicyclo, and can comprise for example 3 to 12 ring memberses, more generally 5 to 10 ring memberses.The example of monocyclic groups is the group that comprises 3,4,5,6,7 and 8 ring memberses, more generally 3 to 7, and preferred 5 or 6 ring memberses.The example of bicyclic radicals is the group that comprises 8,9,10,11 and 12 ring memberses, more generally 9 or 10 ring memberses.

Carbocyclic ring or heterocyclic group can be for having the aryl or the heteroaryl of 5 to 12 ring memberses, more generally 5 to 10 ring memberses.Term used herein " aryl " is meant the carbon ring group with aromatic character, the heterocyclic group that term used herein " heteroaryl " expression has aromatic character.Term " aryl " and " heteroaryl " comprise that wherein one or more rings are many rings of non-aromatics (for example dicyclo) loop systems, and its condition is aromatics at least one ring.In this multi-loop system, group can connect by aromatic ring or by non-aromatic ring.Aryl or heteroaryl can be monocycle or bicyclic radicals, and can be for not replacing or replacing with one or more substituting groups, and for example the one or more radicals R 10 that limit with this paper replace.

The non-aromatic group of term comprises unsaturated loop systems, fractional saturation and complete saturated carbocyclic ring and the heterocyclic ring system that does not have aromatic character.Term " unsaturated " and " fractional saturation " are meant that wherein ring structure comprises the ring of sharing more than the atom of a valence link, that is, described ring comprises at least one Multiple Bonds, for example C=C, C ≡ C or N=C key.Term " saturated fully " is meant the ring that does not wherein have Multiple Bonds between annular atoms.Saturated carbon ring group comprises the cycloalkyl of following qualification.The carbon ring group of fractional saturation comprises the cycloalkenyl group of following qualification, for example cyclopentenyl, cycloheptenyl and cyclooctene base.

The example of heteroaryl is monocycle and the bicyclic radicals that comprises 5 to 12 ring memberses, more generally 5 to 10 ring memberses.Heteroaryl can be for for example five yuan or single six-membered rings or by five yuan of condensed and six-ring or two twin nucleis that the condensed six-ring forms.Each ring can comprise about 4 heteroatomss at most, generally is selected from nitrogen, sulphur and oxygen.General heteroaryl ring comprises maximum 3 heteroatomss, more generally maximum 2, for example single heteroatoms.In one embodiment, heteroaryl ring comprises at least 1 theheterocyclic nitrogen atom.The heteroaryl ring nitrogen can be alkalescence, under the situation of imidazoles or pyridine, is non-alkalescence substantially perhaps, for example under the situation of indoles or pyrroles's nitrogen for example.The number of the general basic nitrogen atom (any amino substituting group that comprises ring) that exists in heteroaryl is less than 5.

The example of quinary heteroaryl comprises but should not be limited to pyrroles, furans, thiophene, imidazoles, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazoles, triazole and tetrazyl.

The example of six membered heteroaryl includes but not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.

Bicyclic heteroaryl can be for for example being selected from following group:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Comprise the example that 6 yuan of rings are fused to the bicyclic heteroaryl of 5 yuan of rings and include but not limited to cumarone, thionaphthene, benzoglyoxaline, benzoxazole, benzoisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indoles, isoindole, indolizine, indoline, isoindoline, purine (for example, VITAMIN B4, guanine), indazole, benzodioxole and Pyrazolopyridine base.

The example that comprises the bicyclic heteroaryl of 6 yuan of rings of two condensed includes but not limited to quinoline, isoquinoline 99.9, chroman, thiochroman, chromene, different chromene, chroman, isochroman, benzo dioxane, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnolines, phthalazines, naphthyridines and pteridyl.

Comprise the polyaromatic of aromatic ring and non-aromatic ring and the example of heteroaryl and comprise naphthane, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzo thiophene (dihydrobenzthiene), Dihydrobenzofuranes, 2,3-dihydro-benzo [1,4] dioxine, 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 heterocyclic group is the group with 3 to 12 ring memberses, more generally 5 to 10 ring memberses.This type of group can be for example monocycle or dicyclo, and generally has 1 to 5 heteroatomic ring member (more generally 1,2,3 or 4 heteroatomic ring member), is selected from nitrogen, oxygen or sulphur usually.

Heterocyclic group can comprise for example cyclic ethers part (for example in tetrahydrofuran (THF) and dioxane), epithio ether moiety (for example in tetramethylene sulfide and dithiane), cyclammonium part (for example in tetramethyleneimine), ring sulfone (for example at tetramethylene sulfone and cyclobufene sultone), ring sulfoxide, cyclic sulfonamides and combination (for example parathiazan) thereof.Other examples of non-aromatic heterocyclic group comprise cyclic amide part (for example in pyrrolidone) and cyclic ester part (for example in butyrolactone).

The example of monocycle non-aromatic heterocyclic group comprises 5-, 6-and 7-unit monocyclic heterocycles group.Specific examples comprises morpholine, parathiazan and S-oxide compound and S, S-dioxide (especially parathiazan), piperidines (for example, piperidino, the 2-piperidyl, 3-piperidyl and 4-piperidyl), N-Alkylpiperidine (as the N-methyl piperidine), piperidone, tetramethyleneimine (for example, 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, dioxane, tetrahydropyrans (for example, 4-THP trtrahydropyranyl), tetrahydroglyoxaline, imidazolidone oxazoline, thiazoline, the 2-pyrazoline, pyrazolidine, piperazine ketone, piperazine and N-alkylpiperazine (N methyl piperazine for example, N-ethyl piperazidine and N-sec.-propyl piperazine).

A subgroup of monocycle non-aromatic heterocyclic group comprises morpholine, piperidines (for example, piperidino, the 2-piperidyl, 3-piperidyl and 4-piperidyl), piperidone, tetramethyleneimine (for example, the 1-pyrrolidyl, 2-pyrrolidyl and 3-pyrrolidyl), pyrrolidone, pyrans (2H-pyrans or 4H-pyrans), dihydro-thiophene, dihydropyrane, dihydrofuran, thiazoline, tetrahydrofuran (THF), tetramethylene sulfide, dioxane, tetrahydropyrans (for example, 4-THP trtrahydropyranyl), tetrahydroglyoxaline, imidazolidone oxazoline, thiazoline, the 2-pyrazoline, pyrazolidine, piperazine ketone, piperazine and N-alkylpiperazine (for example N methyl piperazine).Usually preferred non-aromatic heterocyclic group comprises piperidines, tetramethyleneimine, azetidine, morpholine, piperazine and N-alkylpiperazine.The further specific examples of non-aromatic heterocyclic group that also forms above group part of preferred non-aromatic heterocyclic group is an azetidine.

The example of non-aromatics carbon ring group comprises cycloalkyl (as cyclohexyl and cyclopentyl), cycloalkenyl group (as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctene base) and cyclohexadienyl, cyclooctatetraene, naphthane methyne and naphthalane base.

When quoting carbocyclic ring and heterocyclic group in this article, unless otherwise indicated herein, carbocyclic ring or heterocycle can not replace, or by one or more substituent R ¹⁰Replace R ¹⁰Group is selected from halogen, hydroxyl, trifluoromethyl, cyano group, nitro, carboxyl, amino, list-or two-C _1-4Alkyl amino, have the carbocyclic ring and the heterocyclic group of 3 to 12 ring memberses; 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 ₂And R ^bBe selected from hydrogen, have carbocyclic ring and the heterocyclic group and the C of 3 to 12 ring memberses _1-8Alkyl, described C _1-8Alkyl is optional by one or more hydroxyl, oxo, halogen, cyano group, nitro, carboxyl, amino, list-or two-C that are selected from _1-4The substituting group of alkyl amino, the carbocyclic ring with 3 to 12 ring memberses and heterocyclic group replaces, and C wherein _1-8One or more carbon atoms of alkyl can be chosen wantonly by O, S, SO, SO ₂, NR ^c, X ¹C (X ²), C (X ²) X ¹Or X ¹C (X ²) X ¹Replace;

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

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

In substituent R ¹⁰When comprising or comprising carbocyclic ring or heterocyclic group, described carbocyclic ring or heterocyclic group not can be and to replace, but or self is with one or more other substituent R ¹⁰Replace.In a subgroup of formula (I) compound, this other substituent R ¹⁰Can comprise general carbocyclic ring or the heterocyclic group that self does not replace in addition.In another subgroup of formula (I) compound, described other substituting group does not comprise carbocyclic ring or heterocyclic group, but is selected from above at R in addition ¹⁰Listed group in the definition.

The optional substituent R of selecting ¹⁰, make them contain no more than 20 non-hydrogen atoms, for example no more than 15 non-hydrogen atoms, for example no more than 12 or 10 or 9 or 8 or 7 or 6 or 5 non-hydrogen atoms.

When carbocyclic ring and heterocyclic radical on adjacent annular atoms, have substituting group to the time, two substituting groups can connect into cyclic group.For example, the adjacent substituting group on the adjacent carbons of ring to can by one or more heteroatomss and the optional alkylidene group that replaces connect into the condensed oxa--, two oxa-s-, azepine-, diaza-or oxa--azepine-cycloalkyl.The substituent example of this type of connection comprises:

The example of halogenic substituent comprises fluorine, chlorine, bromine and iodine.Fluorine and chlorine are especially preferred.

After above and this paper in the definition of used formula (I) compound, unless otherwise indicated, term " alkyl " is the general terms that comprises aliphatic series with all carbon skeletons, alicyclic and aromatic group.In some cases, limit as this paper, one or more carbon atoms of forming carbon skeleton can be replaced by regulation atom or atomic group.The example of alkyl comprises alkyl, cycloalkyl, cycloalkenyl group, isocyclic aryl, thiazolinyl, alkynyl, cycloalkylalkyl, cycloalkenyl alkyl and carbocyclic ring aralkyl, arylalkenyl and sweet-smelling alkynyl.This type of group not can be and replaces, and perhaps when explanation, can be replaced by the substituting group that one or more this paper limit.Unless otherwise indicated herein, the following example of Biao Daing and preferably be applicable to each hydrocarbyl substituent that in the substituting group different definition of formula (I) compound, relates to or contain the alkyl substituting group.

Generally as an example, alkyl can have maximum 8 carbon atoms, unless this paper needs in addition.In the subgroup of the alkyl with 1 to 8 carbon atom, special example is C _1-6Alkyl, for example C _1-4Alkyl (C for example _1-3Alkyl or C _1-2Alkyl), specific examples is for being selected from C ₁, C ₂, C ₃, C ₄, C ₅, C ₆, C ₇And C ₈The single value of alkyl or the combination of a plurality of values.

Term " alkyl " promptly comprises straight chained alkyl, also comprises branched-chain alkyl.The example 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 the subgroup of the alkyl with 1 to 8 carbon atom, special example is C _1-6Alkyl, for example C _1-4Alkyl (C for example _1-3Alkyl or C _1-2Alkyl).

The example of cycloalkyl is those groups derived from cyclopropane, tetramethylene, pentamethylene, hexanaphthene and suberane.In the subgroup of cycloalkyl, cycloalkyl has 3 to 8 carbon atoms, and special example is C _3-6Cycloalkyl.

The example of thiazolinyl includes but not limited to vinyl, 1-propenyl, 2-propenyl (allyl group), pseudoallyl, butenyl, fourth-1,4-dialkylene, pentenyl and hexenyl.In the subgroup of thiazolinyl, thiazolinyl has 2 to 8 carbon atoms, and special example is C _2-6Thiazolinyl is as C _2-4Thiazolinyl.

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

The example of alkynyl includes but not limited to ethynyl and 2-propynyl (propargyl).In the subgroup of the alkynyl with 2 to 8 carbon atoms, special example 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.

Term C used herein _1-10Alkyl and C _1-8Alkyl comprises alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, phenyl, benzyl and styroyl, and wherein preferred the and example of each aforementioned group is defined as above.In this definition, special alkyl is alkyl, cycloalkyl, phenyl, benzyl and styroyl (for example 1-phenylethyl or 2-phenylethyl), and a subgroup of alkyl is made up of alkyl and cycloalkyl, particularly C _1-4Alkyl and cycloalkyl are as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, cyclopropyl and cyclobutyl.

Term C used herein _1-4Alkyl comprises alkyl, thiazolinyl, alkynyl, cycloalkyl and cycloalkenyl group, and wherein preferred the and example of aforementioned group is defined as above.In this definition, special C _1-4Alkyl is alkyl and cycloalkyl, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, cyclopropyl and cyclobutyl.

Exist and during explanation, alkyl can be chosen wantonly 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 to 12 (common 3 to 10, more generally 5 to 10) monocycles of ring members or the substituting group of bicyclic carbocyclic and heterocyclic group replaces.Preferred substituted comprises halogen, as fluorine.Therefore, for example the alkyl of Qu Daiing can be partially fluorinated or fully-fluorinated group, as difluoromethyl or trifluoromethyl.In one embodiment, preferred substituted comprises monocycle carbocyclic ring and the heterocyclic group with 3 to 7 ring memberses.

When explanation, one or more carbon atoms of alkyl can be chosen wantonly 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 subgroup) replaces, wherein X ¹And X ²As preceding qualification, its condition is for keeping at least one carbon atom of alkyl.For example, 1,2,3 or 4 carbon atom of alkyl can be replaced by one of listed atom or group, and displaced atom or group can be identical or different.Usually, the number of displaced straight chain or backbone c atoms be equivalent to replace the number of straight chain in their group or backbone atoms.Wherein one or more carbon atoms of alkyl comprise ether and thioether (C is replaced by O or S), acid amides, ester, thioamides and thioesters by above replacement atom that limits or the displaced examples of groups of group (C-C are by X ¹C (X ²) or C (X ²) X ¹Replacement), (C is by SO or SO for sulfone and sulfoxide ₂Replacement), (C is by NR for amine ^cReplace).Other examples comprise urea, carbonic ether and carbamate, and (C-C-C is by X ¹C (X ²) X ¹Replace).

When amino had two hydrocarbyl substituents, the nitrogen-atoms that they can connect with their and optional and another heteroatoms (as nitrogen, sulphur or oxygen) connected into the ring structure of 4 to 7 ring memberses.

Definition " R used herein ^a-R ^b", relevant with the substituting group that exists on carbocyclic ring or the heterocyclic moiety, or relevant with other substituting groups of existing of other positions on formula (I) compound, especially comprise more such compounds, wherein R ^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 ₂, R wherein ^cAs preceding qualification.

Part R ^bCan be hydrogen, the C that perhaps can have 3 to 12 ring memberses for the being selected from carbocyclic ring of (common 3 to 10, more generally 5 to 10) and heterocyclic group and optional as preceding qualification replaces _1-8The group of alkyl.The example of alkyl, carbocyclic ring and heterocyclic group as mentioned above.

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

Alkyl oxygen base can be replaced by the different substituents that this paper limits.For example, alkoxyl group can be by halogen (for example in difluoro-methoxy and trifluoromethoxy), hydroxyl (for example in hydroxyl-oxethyl), C _1-2Alkoxyl group (for example in methoxy ethoxy), hydroxyl-C _1-2Alkyl (for example in the '-hydroxyethoxy base oxethyl) or cyclic group (for example, the cycloalkyl or the non-aromatic heterocycle of this paper qualification) replace.Carrying non-aromatic heterocycle is the alkoxyl group of saturated cyclic amines as the example of substituent alkoxyl group for heterocyclic radical wherein, cyclammonium such as morpholine, piperidines, tetramethyleneimine, piperazine, C _1-4-alkyl-piperazine, C _3-7-cycloalkyl-piperazine, tetrahydropyrans or tetrahydrofuran (THF), alkoxyl group are C _1-4-alkoxyl group, more general C _1-3-alkoxyl group is as methoxyl group, oxyethyl group or positive propoxy.

Alkoxyl group can be replaced by for example monocyclic groups, as tetramethyleneimine, piperidines, morpholine and piperazine and N-substitutive derivative thereof, as N-benzyl, N-C _1-4Acyl group and N-C _1-4Alkoxy carbonyl.Special example comprises tetramethyleneimine-1-base oxethyl, piperidino-(1-position only) oxyethyl group and piperazine-1-base oxethyl.

Work as R ^aBe key, and R ^bBe C _1-8During alkyl, alkyl R ^a-R ^bExample such as preceding qualification.Alkyl can be saturated group, and as cycloalkyl and alkyl, the specific examples of this type of group comprises methyl, ethyl and cyclopropyl.Alkyl (for example alkyl) can be replaced by different groups and the atom that this paper limits.The example of the alkyl that replaces 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 are as trifluoromethyl), hydroxyl (for example hydroxymethyl and hydroxyethyl), C _1-8Acyloxy (for example acetoxy-methyl and benzyl oxygen ylmethyl), amino and single-and two-alkylamino (for example amino-ethyl, methylamino ethyl, dimethylaminomethyl, dimethyl aminoethyl and tertiary butyl amino methyl), alkoxyl group (C for example _1-2Alkoxyl group, for example methoxyl group-as in methoxy ethyl) and cyclic group (as cycloalkyl, aryl, heteroaryl and the non-aromatic heterocyclic group of preceding qualification).

The special example of the alkyl that is replaced by cyclic group is these compounds, and wherein cyclic group is saturated cyclammonium, as morpholine, piperidines, tetramethyleneimine, piperazine, C _1-4-alkyl-piperazine, C _3-7-cycloalkyl-piperazine, tetrahydropyrans or tetrahydrofuran (THF), and alkyl is C _1-4-alkyl, more general C _1-3-alkyl is as methyl, ethyl or n-propyl.The specific examples of the alkyl that is replaced by cyclic group comprises the N-replacement form 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.

The special example of the alkyl that is replaced by aryl and heteroaryl 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 or carbocyclic ring or heterocyclic group.R wherein ^aBe SO ₂NR ^cR ^a-R ^bExample comprise amino-sulfonyl, C _1-4Alkyl amino sulfonyl and two-C _1-4Alkyl amino sulfonyl and the sulphonamide that forms by ring amino, the amino piperazine (as N methyl piperazine) that replaces as piperidines, morpholine, tetramethyleneimine or optional N-of ring.

R wherein ^aBe SO ₂Radicals R ^a-R ^bExample comprise alkyl sulphonyl, heteroarylsulfonyl and aryl sulfonyl, particularly monocyclic aryl and heteroarylsulfonyl.Special example 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 or carbocyclic ring or heterocyclic group.R wherein ^aBe NR ^cR ^a-R ^bExample comprise amino, C _1-4Alkylamino (for example, methylamino, ethylamino, propyl group amino, sec.-propyl amino and tertiary butyl amino), two-C _1-4Alkylamino (for example, dimethylamino and diethylamino) and cycloalkyl amino (for example, cyclopropyl amino, cyclopentyl amino and cyclohexyl amino).

A, E, T, Q ¹, Q ², J ¹, J ²And R ¹To R ¹⁰Specific examples and preferred

Group " A "

TG is therein

(1) group:

The compound of formula (I) in,

A is that the stable hydrocarbon that comprises 1 to 7 carbon atom connects base, and described connection base has at R ^1aAnd NR ²R ³Between the maximum chain length of 5 atoms extending, and have at E and NR ²R ³Between the maximum chain length of 4 atoms extending.In these restricted conditions, part E and R ^1aCan be connected to any position on the group A.

Term used herein " maximum chain length " is meant the number that is located immediately at the atom between described two parts, and does not consider any hydrogen atom that any branch in the chain maybe may exist.For example, in structure shown below (A):

At R ^1aAnd NR ²R ³Between chain length be 3 atoms, and at E and NR ²R ³Between chain length be 2 atoms.

Usually, preferred at present connection base has the maximum chain length (for example 1 or 2 atom) of 3 atoms.

In one embodiment, connecting base has at R ^1aAnd NR ²R ³Between the chain length of 1 atom extending.

In another embodiment, connecting base has at R ^1aAnd NR ²R ³Between the chain length of 2 atoms extending.

In another embodiment, connecting base has at R ¹And NR ²R ³Between the chain length of 3 atoms extending.

The preferred base that connects has at E and NR ²R ³Between the maximum chain length of 3 atoms extending.

In a special preferred group of compound, connect base and have at R ^1aAnd NR ²R ³Between the chain length of 2 or 3 atoms extending, and have at E and NR ²R ³Between the chain length of 2 or 3 atoms extending.

One of carbon atom in the connection base can be chosen wantonly by oxygen or nitrogen-atoms and replace.

When existing, nitrogen-atoms can be directly connected to group E.

In one embodiment, R ^1aThe carbon atom that connects is replaced by Sauerstoffatom.

In another embodiment, R ^1aBe connected on the same carbon atom that is connected base with E, and at E and NR ²R ³Between carbon atom in the chain that extends replace by Sauerstoffatom.

When having nitrogen or Sauerstoffatom, preferred nitrogen or Sauerstoffatom and NR ²R ³Group is spaced apart by at least two carbon atoms between two parties.

In the particular group of the compound in formula (I), the connection atom that is directly connected to group E is a carbon atom, and connects basic A and have full carbon skeleton.

The carbon atom that connects basic A can be chosen wantonly and carry one or more substituting groups that are selected from oxo, fluorine and hydroxyl, and its condition is that hydroxyl is not positioned at and NR ²R ³On the alpha-carbon atom that group is correlated with, and another condition is that oxo group is positioned at and NR ²R ³On the alpha-carbon atom that group is correlated with.If exist, general hydroxyl is positioned at and NR ²R ³On the β position that group is correlated with.Usually there is no more than 1 hydroxyl.When fluorine existed, fluorine can be used as single fluoro substituents and exists, and perhaps can for example exist in difluoro methylene or trifluoromethyl.In one embodiment, fluorine atom is positioned at and NR ²R ³On the β position that group is correlated with.

Should be appreciated that, with NR ²R ³When having oxo group on the adjacent carbon atom of group, the compound of formula (I) is an acid amides.

In one embodiment of the invention, on the basic A of connection, there is not fluorine atom.

In another embodiment of the invention, on the basic A of connection, there is not hydroxyl.

In another embodiment, on the basic A of connection, there is not oxo group.

In a group of formula (I) compound, hydroxyl all is not present in fluorine atom and is connected among the basic A, for example connects basic A and is not substituted.

When preferably the carbon atom in connecting basic A was replaced by nitrogen-atoms, group A carried a no more than hydroxyl substituent, does not more preferably carry hydroxyl substituent.

At E and NR ²R ³Between when the chain length of 4 atoms is arranged, preferably connect the nonnitrogenous atom of basic A, more preferably have full carbon skeleton.

Connect basic A and can be connected to NR ²R ³The carbon atom place of group has branched structure.For example, be connected to NR ²R ³The carbon atom of group can be connected to a pair of together with-dimethyl.

In a special group of formula (I) compound, the part R of compound ^1a-A-NR ²R ³By formula R ^1a-(G) _k-(CH ₂) _m-W-O _b-(CH ₂) _n-(CR ⁶R ⁷) _p-NR ²R ³Expression, wherein G is NH, NMe or O; W is connected to group E, and is selected from (CH ₂) _j-CR ²⁰, (CH ₂) _j-N and (NH) _j-CH; B is 0 or 1, and 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; B and k sum are 0 or 1; J, k, m, n and p sum are no more than 4; R ⁶And R ⁷Identical or different, and be selected from methyl and ethyl, perhaps CR ⁶R ⁷Form cyclopropyl; And R ²⁰Be selected from hydrogen, methyl, hydroxyl and fluorine;

In another subgroup of formula (I) compound, the part R of compound ^1a-A-NR ²R ³By formula R ^1a-(G) _k-(CH ₂) _m-X ^x-(CH ₂) _n-(CR ⁶R ⁷) _p-NR ²R ³Expression, wherein G is NH, NMe or O; X ^xBe connected to group E, and be selected from (CH ₂) _j-CH, (CH ₂) _j-N 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 j, k, m, n and p sum are no more than 4; R ⁶And R ⁷Identical or different, and be selected from methyl and ethyl, perhaps CR ⁶R ⁷Form cyclopropyl.

A special groups CR ⁶R ⁷Be C (CH ₃) ₂

Preferred X ^xBe (CH ₂) _j-CH.

The part R of compound wherein ^1a-A-NR ²R ³By formula R ¹-(G) _k-(CH ₂) _m-X ^x-(CH ₂) _n-(CR ⁶R ⁷) _p-NR ²R ³The ad hoc structure of expression is these structures, 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 ^xBe (CH ₂) _j-CH, k are 1, and m is 0, and n is 0,1,2 or 3, and p is 0.

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

X ^xBe (CH ₂) _j-CH, G are O, and k is 1, and m is 0, and n is 0,1,2 or 3, and p is 0.

The part R of compound wherein ^1a-A-NR ²R ³By formula R ¹-(G) _k-(CH ₂) _m-W-O _b-(CH ₂) _n-(CR ⁶R ⁷) _p-NR ²R ³The ad hoc structure of expression is these structures, wherein:

K is 0, and m is 0, and W is (CH ₂) _j-CR ²⁰, j is 0, R ²⁰Be hydrogen, b is 1, and n is 2, and p is 0.

K is 0, and m is 0, and W is (CH ₂) _j-CR ²⁰, j is 0, R ²⁰Be hydroxyl, b is 0, and n is 1, and p is 0.

K is 0, and m is 0, and W is (CH ₂) _j-CR ²⁰, j is 0, R ²⁰Be methyl, b is 0, and n is 1, and p is 0.

K is 0, and m is 0, and W is (CH ₂) _j-CR ²⁰, j is 0, R ²⁰Be fluorine, b is 0, and n is 1, and p is 0.

In a preferred construction, the part R of compound ^1a-A-NR ²R ³By formula R ^1a-X ^x-(CH ₂) _n-NR ²R ³Expression, wherein X ^xBe connected to group E, and be group CH, and n is 2.

Connect basic A and and radicals R thereof ^1a, E and NR ²R ³The particular instance of tie point be shown in the following table 1.

Table 1:

Current preferred group comprises A1, A2, A3, A6, A10, A11, A22 and A23.

A special group of group comprises A1, A2, A3, A10 and A11.

The special group of another of group comprises A2 and A11.

The special group of another of group comprises A6, A22 and A23.

Another group of group comprises A1, A2 and A3.

In group A2, chiral centre represented in asterisk.A preferred subgroup that has the compounds represented The compounds of this invention of R configuration at this chiral centre.

Q ¹And Q ²

TG is therein

(2) group:

The compound of formula (I) in,

Q ¹For key or the stable hydrocarbon that comprises 1 to 3 carbon atom connect base, wherein connect one of carbon atom in the base and can choose wantonly by oxygen or nitrogen-atoms and replace, perhaps adjacent carbon atom is to can be by CONR ^qOr NR ^qCO replaces, wherein R ^qBe hydrogen, C _1-4Alkyl or cyclopropyl, perhaps R ^qFor being connected to R ^1bOr Q ¹Another carbon atom to form the C of circular part _1-4Alkylidene chain, and wherein connect basic Q ¹Carbon atom can choose wantonly and carry one or more substituting groups that are selected from fluorine and hydroxyl.

Q ²For key or the stable hydrocarbon that comprises 1 to 3 carbon atom connect base, wherein connect one of carbon atom in the base and can choose wantonly by oxygen or nitrogen-atoms and replace; And the carbon atom that wherein connects base can be chosen wantonly and carry one or more substituting groups that are selected from fluorine and hydroxyl, and its condition is that hydroxyl is not positioned at when existing on the alpha-carbon atom relevant with the G group.

In one embodiment, Q ¹And Q ²Identical or different, and the stable hydrocarbon that is respectively key or comprises 1 to 3 carbon atom connects base, wherein connect one of carbon atom in the base and can choose wantonly by oxygen or nitrogen-atoms and replace; And wherein saidly respectively connect basic Q ¹And Q ²Carbon atom or respectively connect basic Q ¹And Q ²Can choose wantonly and carry one or more substituting groups that are selected from fluorine and hydroxyl, its condition is that hydroxyl is not positioned at and NR when existing ²R ³On the alpha-carbon atom that group is correlated with.

In a group of The compounds of this invention, Q ¹And Q ²At least one the expression key.In this compound group, subgroup is by Q wherein ¹And Q ²The two all represents the compound composition of key.In another subgroup, Q ¹And Q ²One of the expression key, and another expression comprises the stable hydrocarbon of 1 to 3 carbon atom and connects base, wherein connects one of carbon atom in the base and can choose wantonly by oxygen or nitrogen-atoms and replace.

Work as Q ¹And/or Q ²During for saturated alkyl, alkyl is generally alkylidene group, as (CH ₂) _n, wherein n is that 1,2 or 3, one specific examples is CH ₂Alkylidene group Q ¹In one of carbon atom can choose wantonly by for example Sauerstoffatom and replace, an example of this group is CH ₂-O-CH ₂

Connect basic Q ¹And Q ²Carbon atom can choose wantonly and carry one or more substituting groups that are selected from oxo, fluorine and hydroxyl, its condition is that hydroxyl is not positioned at and NR ²R ³On the alpha-carbon atom that group is correlated with, and another condition is that oxo group is positioned at and NR ²R ³On the alpha-carbon atom that group is correlated with.If exist, general hydroxyl is positioned at and NR ²R ³On the β position that group is correlated with.Usually there is no more than 1 hydroxyl.When fluorine atom existed, they for example can be present in difluoro methylene or the trifluoromethyl.

In a subgroup of compound, Q ¹For the stable hydrocarbon that comprises 1 to 3 carbon atom connects base, wherein adjacent carbon atom is to by CONR ^qOr NR ^qCO replaces, wherein R ^qBe hydrogen, C _1-4Alkyl or cyclopropyl, perhaps R ^qFor being connected to R ^1bOr Q ¹Another carbon atom to form the C of circular part _1-4Alkylidene chain.In a preferred embodiment, R ^qBe hydrogen.In another embodiment, R ^qBe C _1-4Alkyl or cyclopropyl are preferably methyl.In another embodiment, R ^qFor being connected to R ^1bOr Q ¹Another carbon atom to form the C of circular part _1-4Alkylidene chain.

Comprise CONR ^qOr NR ^qThe connection base Q of CO ¹Example be group CH ₂NHCO and CH ₂N (Me) CO, wherein carbonyl is connected to E.

R wherein ^qFor being connected to Q ¹Another carbon atom to form the C of circular part _1-4Alkylidene chain comprise CONR ^qOr NR ^qThe connection base Q of CO ¹Example be the group that is expressed from the next:

Wherein * represents to be connected to the point of part E, q " is 0,1 or 2, and is connected to R ^1bPoint by the letter " c " expression.

R wherein ^qFor being connected to R ^1bTo form the C of circular part _1-4Alkylidene chain comprise CONR ^qOr NR ^qThe connection base Q of CO ¹Example be the group that is expressed from the next:

Wherein q such as this paper limit, and R ^1bBe aryl or heteroaryl.The part R of this type ^1b-Q ¹Specific examples comprise 1,2,3,4-tetrahydroisoquinoline-2-base carbonyl.

Should be appreciated that, with NR ²R ³When having oxo group on the adjacent carbon atom of group, the compound of formula (I) is an acid amides.

In one embodiment of the invention, connecting basic Q ¹And/or Q ²On do not have fluorine atom.

In another embodiment of the invention, connecting basic Q ¹And/or Q ²On do not have hydroxyl.

In another embodiment, connecting basic Q ¹And/or Q ²On do not have oxo group.

In a group of formula (I) compound, hydroxyl all is not present in fluorine atom and is connected basic Q ¹And/or Q ²In, for example connect basic Q ¹And/or Q ²Be not substituted.

In another group of The compounds of this invention, connect basic Q ²NR can be connected to ²R ³The carbon atom place of group has branched structure (when existing).For example, be connected to NR ²R ³The carbon atom of group can be connected to a pair of together with-dimethyl.

Q ¹And Q ²Can be connected to the same atom of group E or homoatomic not.In one embodiment, Q ¹And Q ²Be connected to the same atom (being carbon atom) of group E.

R ^1a

Radicals R ^1aBe aryl or heteroaryl, and optional leisure is general preferred and the inventory of described this type of group of title division of definition.

R ^1aCan be monocycle or dicyclo, be monocycle in a preferred embodiment.The special example of monocyclic aryl and heteroaryl is to comprise maximum 2 azo-cycle members' hexa-atomic aryl and heteroaryl and comprise maximum 3 quinary heteroaryls that are selected from the heteroatomic ring member of O, S and N.

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

Radicals R ^1aNot can be replacement, or replaced by maximum 5 substituting groups, substituent example is above in radicals R ¹⁰In those listed groups.

Special substituting group comprises hydroxyl, C _1-4Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano group, CONH ₂, nitro, optional by C respectively _1-2The C that alkoxyl group, carboxyl or hydroxyl replace _1-4Alkyl oxygen base and C _1-4Alkyl, C _1-4Acyl amino, benzamido, tetramethyleneimine-1-base carbonyl, piperidines-1-base carbonyl, morpholino carbonyl, piperazine-1-base carbonyl, contain 1 or 2 heteroatomic five yuan and six membered heteroaryl that is selected from N, O and S and heteroaryl oxygen base, phenyl, phenyl-C _1-4Alkyl, phenyl-C _1-4Alkoxyl group, heteroaryl-C _1-4Alkyl, heteroaryl-C _1-4Alkoxyl group and phenoxy group, wherein heteroaryl, heteroaryl oxygen base, phenyl, phenyl-C _1-4Alkyl, phenyl-C _1-4Alkoxyl group, heteroaryl-C _1-4Alkyl, heteroaryl-C _1-4Alkoxyl group and phenoxy group are optional respectively to be selected from C with 1,2 or 3 _1-2Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano group, CONH ₂The optional respectively C that replaces by methoxyl group or hydroxyl _1-2Alkyl oxygen base and C _1-2The substituting group of alkyl replaces.

Preferred substituted comprises hydroxyl, C _1-4Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, cyano group, optional by C respectively _1-2The C that alkoxyl group or hydroxyl replace _1-4Alkyl oxygen base and C _1-4Alkyl, C _1-4Acyl amino, benzamido, tetramethyleneimine-1-base carbonyl, piperidines-1-base carbonyl, morpholino carbonyl, piperazine-1-base carbonyl, (heteroaryl is optional by one or more C to contain 1 or 2 heteroatomic five yuan and six membered heteroaryl that is selected from N, O and S _1-4Alkyl substituent replaces), phenyl, pyridyl and phenoxy group, wherein phenyl, pyridyl and phenoxy group are optional respectively is selected from C with 1,2 or 3 _1-2Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano group and the optional respectively C that replaces by methoxyl group or hydroxyl _1-2Alkyl oxygen base and C _1-2The substituting group of alkyl replaces.

In one embodiment, radicals R ^1aDo not replace, or replaced by maximum 5 substituting groups, substituting group is selected from hydroxyl, C _1-4Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, phenyl, thienyl, furyl, phenoxy group, benzyl oxygen base, cyano group, optional by C respectively _1-2The C that alkoxyl group or hydroxyl replace _3-4Cycloalkyl and C _1-4Alkoxyl group and C _1-4Alkyl.

Though can there be maximum 5 substituting groups, more general have 0,1,2,3 or 4 substituting group, preferred 0,1,2 or 3, more preferably 0,1 or 2.

In a special subgroup of compound, radicals R ^1a(R wherein for example ^1aBe the phenyl that replaces) can have one or two substituting group that is selected from fluorine, chlorine, cyano group, methyl, ethyl, sec.-propyl, cyclopropyl, the tertiary butyl, trifluoromethyl, methoxyl group, trifluoromethoxy, difluoro-methoxy, phenyl, phenoxy group and benzyl oxygen base.

At R ^1aDuring for phenyl, the special example of substituting group combination comprises mono chloro benzene base, dichlorophenyl, hydroxy phenyl, fluorochlorobenzene base, cyano-phenyl, p-methoxy-phenyl, methoxyl group-chloro-phenyl-, fluorophenyl and difluorophenyl.

At R ^1aDuring for hexa-atomic aryl (for example phenyl) or heteroaryl, substituting group can favourablely be present in the contraposition on the six-ring.When substituting group was present in contraposition, preferred substituents was in size greater than fluorine atom.

In a subgroup of compound, radicals R ^1aBe phenyl, phenyl has the substituting group that is selected from fluorine, chlorine, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, benzyl oxygen base, methyl, methoxyl group and the tertiary butyl in contraposition.

In another subgroup of compound, radicals R ^1aBe phenyl, phenyl has the substituting group that is selected from fluorine, chlorine, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, methyl and methoxyl group at the ortho position, and chooses wantonly in a position or contraposition has second substituting group that is selected from fluorine, chlorine, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, methyl and methoxyl group.

Radicals R ^1aSpecific examples be shown in the following table 2, be connected to A or Q ¹(or E, at Q ¹During for key) point represent by asterisk.

Table 2

One group of preferred group comprises group B 2, B4, B5, B10, B11, B13, B14, B15, B16, B17, B18, B19 and B19.

A kind of particularly preferred group is B2.

R ^1b

Radicals R ^1bBe hydrogen or radicals R ^1a, wherein as above limit with its elsewhere of this paper.

In a subgroup of compound, R ^1bBe hydrogen.

In another subgroup of compound, R ^1bBe aryl or heteroaryl R ^1a

R ²And R ³

In a group of formula (I) compound, R ²And R ³Can independently be selected from hydrogen, C _1-4Alkyl and C _1-4Acyl group, wherein alkyl and acyl group are optional is replaced by one or more substituting groups that are selected from fluorine, hydroxyl, cyano group, amino, methylamino, dimethylamino, methoxyl group and monocycle or bicyclic aryl or heteroaryl.

In this compound group, these compounds are arranged, wherein R ²And R ³Independently be selected from hydrogen, C _1-4Alkyl and C _1-4Acyl group, wherein alkyl and acyl group are optional respectively by monocycle or bicyclic aryl or heteroaryl replacement.

In this compound group, also have these subgroup compound, wherein R of the present invention ²And R ³Independently be selected from hydrogen, C _1-4Alkyl and C _1-4Acyl group.

In another subgroup of compound, R ²And R ³Independently be selected from hydrogen, C _1-4Alkyl and C _1-4Acyl group, wherein alkyl and acyl moiety are optional is replaced by one or more substituting groups that are selected from fluorine, hydroxyl, amino, methylamino, dimethylamino and methoxyl group.

In each aforementioned group of compound and subgroup, no matter replace still and replace, form NR ²R ³The alkyl of part be generally alkyl, C more generally ₁, C ₂Or C ₃Alkyl, for example methyl.

When hydrocarbyl portion is replaced by hydroxyl, amino, methylamino, dimethylamino or methoxyl group, generally at substituting group and group NR ²R ³Nitrogen-atoms between at least two carbon atoms are arranged.The special example of the alkyl that replaces is hydroxyethyl and hydroxypropyl.

In another group of The compounds of this invention, R ²And R ³Independently be selected from hydrogen, C _1-4Alkyl and C _1-4Acyl group.

In a special subgroup of compound, 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 particular, NR ²R ³Be methylamino.

In a embodiment for choosing, C _1-4Alkyl can be cyclopropyl, cyclopropyl methyl or cyclobutyl.

In another group of compound, R ²And R ³Form cyclic group with their bonded nitrogen-atoms, cyclic group is selected from imidazole group and has 4 to 7 ring memberses and the optional saturated monocycle heterocyclic group that comprises the second heteroatomic ring member who is selected from O and N.

In another group of compound, R ²And R ³Form with their bonded nitrogen-atoms and to have 4 to 7 ring memberses and the optional saturated monocycle heterocyclic group that comprises the second heteroatomic ring member who is selected from O and N.

Saturated monocyclic heterocycles group not can be and replaces, or by the above one or more substituent R that limit at the application's general preferred and definitional part ¹⁰Replace.Yet general any substituting group on heterocyclic group should be relatively than small-substituent, as C _1-4Alkyl (for example methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, normal-butyl, sec-butyl and the tertiary butyl), fluorine, chlorine, hydroxyl, amino, methylamino, ethylamino and dimethylamino.Concrete substituting group is a methyl.

Saturated monocycle can be azacycloalkyl, and as azetidine, tetramethyleneimine, piperidines or azepan ring, and this type of ring does not generally replace.Perhaps, saturated monocycle can comprise the other heteroatoms that is selected from O and N, and this type of examples of groups comprises morpholine and piperazine.Have the other N atomic time in ring, the N atom can form NH group or N-C _1-4The part of alkyl is as N-methyl, N-ethyl, N-propyl group or N-sec.-propyl.

At NR ²R ³When forming imidazole group, imidazole group not can be and replaces, or is for example replaced by one or more less relatively substituting groups, as C _1-4Alkyl (for example methyl, ethyl, propyl group, cyclopropyl and butyl), fluorine, chlorine, hydroxyl, amino, methylamino, ethylamino and dimethylamino.Concrete substituting group is a methyl.

In formula (I), when TG is group (1), R ²And R ³One of have 4 to 7 ring memberses and the optional saturated monocycle heterocyclic group that comprises the second heteroatomic ring member who is selected from O and N with their bonded nitrogen-atoms with forming from the one or more atoms that are connected basic A.

This type of examples for compounds comprises wherein NR ²R ³Compound with A formation unit of following formula:

Wherein t and u are respectively 0,1,2 or 3, and its condition is that t and u sum drop in 2 to 4 the scope.

Other examples of this compounds comprise wherein NR ²R ³Form the compound of the cyclic group of following formula with A:

Wherein v and w are respectively 0,1,2 or 3, and its condition is that v and w sum drop in 2 to 5 the scope.The special example of ring compound is for wherein v and w are those compounds of 2.

Other examples of this compounds comprise wherein NR ²R ³Form the compound of the cyclic group of following formula with A:

Wherein x and w are respectively 0,1,2 or 3, and its condition is that x and w sum drop in 2 to 4 the scope.The special example of ring compound for x wherein be 2 and w be those compounds of 1.

TG is in another embodiment of formula (I) of group (2) therein, NR ²R ³Be connected basic Q with its bonded ²Carbon atom form cyano group.

TG is in another embodiment of formula (I) of group (2) therein, NR ²R ³As preceding qualification, difference is NR ²R ³Be connected basic Q with its bonded ²Carbon atom can not form cyano group.

TG is in another embodiment of formula (I) of group (2) therein, R ²And R ³One of with their bonded nitrogen-atoms with from being connected basic Q ²One or more atoms form together and have 4 to 7 ring memberses and the optional saturated monocycle heterocyclic group that comprises the second heteroatomic ring member who is selected from O and N.

Group " E "

In formula (I), E is monocycle or bicyclic carbocyclic or heterocyclic group, and can be selected from above at the described group of title division general preferred and definition.

Carbocyclic ring or heterocyclic group E can be aromatics or non-aromatics.

In one embodiment, carbocyclic ring or heterocyclic group E are non-aromatics.

In another embodiment, carbocyclic ring or heterocyclic group E are aromatics.

When E is aromatic group, i.e. aryl or heteroaryl groups, described group can be selected from above in general preferred and described this type of examples of groups of definitional part.

TG is in the formula (I) of group (2) therein

Preferred group E is monocycle and bicyclic aryl and heteroaryl, especially for containing the group of five yuan or hexa-atomic aromatics or heteroaromatic rings, for example phenyl, pyridine, pyrazoles, pyrazine, pyridazine or pyrimidine ring, more in particular be phenyl, pyridine, pyrazoles, pyrazine or pyrimidine ring, be preferably pyridine, pyrazoles or benzyl ring, most preferably be benzyl ring.

The example of bicyclic radicals comprises benzo-fused and pyrido condensed group, and wherein group A and cyclic group X all are attached to benzo-or pyrido-part.

In one embodiment, E is a monocyclic groups.

Monocycle carbocyclic ring or heterocyclic group generally comprise 5 or 6 ring memberses, and heterocyclic group generally comprises maximum 3 heteroatomss that are selected from O, N and S.

The special example of monocyclic groups comprises monocyclic aryl and heteroaryl, and for example phenyl, thiophene, furans, pyrazoles, pyrimidine, pyrazine and pyridine are preferred at this phenyl.

A subgroup of monocyclic aryl and heteroaryl comprises phenyl, pyrazoles, thiophene, furans, pyrimidine and pyridine.

The non-aromatic monocyclic examples of groups is preferred with described in the definitional part as above.

The special example of described group comprises naphthenic hydrocarbon (as hexanaphthene and pentamethylene) and contains azo-cycle (as piperidines, tetramethyleneimine, piperidines, piperazine and piperazine ketone).

A kind of special non-aromatic monocyclic group is a piperidyl, is more particularly the piperidyl that the nitrogen-atoms of piperidine ring wherein is attached to bicyclic radicals.

Another kind of special group is that wherein a nitrogen-atoms of piperidine ring is attached to bicyclic radicals, and another nitrogen-atoms of piperidine ring is attached to the piperazinyl of group A.

TG is that preferred group A and cyclic group X are not joined to the adjacent ring member of group E in formula (I) compound of group (1) therein.For example, cyclic group X can between the position or the contraposition relative positioning be connected to group E.The example of this type of group E comprises 1,4-phenylene, 1,3-phenylene, 2,5-pyridylidene and 2,4-pyridylidene, 1,4-piperazinyl and 1,4-piperazine ketone group (piperazonyl).Other example comprises 1, the dibasic five-ring of 3-.

Group E not can be and replaces, and perhaps can have maximum 4 optional preceding freely radicals R that limit ¹⁰Substituent R ⁸Yet, more general substituent R ⁸Be selected from hydroxyl, oxo (when E is non-aromatics), halogen (for example chlorine and bromine), trifluoromethyl, cyano group, optional by C _1-2The C that alkoxyl group or hydroxyl replace _1-4Alkyl oxygen base, optional by C _1-2The C that alkoxyl group or hydroxyl replace _1-4Alkyl and the optional phenyl that replaces by halogen (for example chlorine and bromine), trifluoromethyl, cyano group, methyl or methoxy.

Preferably have 0-3 substituting group, more preferably 0-2 substituting group, for example 0 or 1 substituting group.In one embodiment, group E is not substituted.

E can be different from:

The pyriconyl of-replacement;

The thiazolyl of-replacement;

-replace or unsubstituted pyrazoles or pyrazoline ketone group;

-replace or unsubstituted bicyclic condensed pyrazolyl;

-with thiphene ring condensed benzyl ring or with the hexa-atomic nitrogenous heteroaryl ring of thiphene ring condensed;

-replace or unsubstituted piperazinyl.

Part TG is in formula (I) compound of group (1) therein, and group E can be for having five yuan or hexa-atomic and comprise maximum three heteroatomic aryl or heteroaryls that are selected from O, N and S, and group E is expressed from the next:

Wherein * represents to be connected to the point of cyclic group X, the connection of " a " expression group A;

R is 0,1 or 2;

U is selected from N and CR ^12aAnd

V is selected from N and CR ^12bR wherein ^12aAnd R ^12bIdentical or different, and be respectively hydrogen or comprise the substituting group of maximum 10 atoms that are selected from C, N, O, F, Cl and S, its condition is at R ^12aAnd R ^12bThe sum of the middle non-hydrogen atom that exists is no more than 10;

Perhaps R ^12aAnd R ^12bForm with their bonded carbon atoms and to comprise maximum two heteroatomic not substituted five-membered or the hexa-atomic saturated or unsaturated rings that are selected from O and N; And

R ¹⁰As preceding qualification.

In a preferred group of compound, E is a group:

Wherein * represents to be connected to the point of cyclic group X, the connection of " a " expression group A;

P, Q and T are identical or different, and are selected from N, CH and NCR ¹⁰, its condition is attached to carbon atom for group A; And U, V and R ¹⁰As preceding qualification.

In another preferred group of compound, E is a group:

R wherein ¹⁶Radicals R for hydrogen or this paper qualification ¹⁰, R ^12aOr R ^12b

R ^12aAnd R ^12bExample comprise hydrogen and as the substituent R with no more than 10 non-hydrogen atoms of preceding qualification ¹⁰R ^12aAnd R ^12bSpecific examples comprise methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 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.

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

In formula (I), when TG is group (1), group E and with group A ( ^a) and ring X ( ^*) the particular instance of tie point be shown in the following table 3.

Table 3:

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

Below optional an eliminating applicable to formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII) and the definition of E (IX) and in any subgroup that limits of this paper or inferior the definition:

E can be different from and has the phenyl that is connected to the sulphur atom of the relevant contraposition of radicals X.

E can be different from and replace or unsubstituted benzoglyoxaline, benzoxazole or benzothiazolyl.

Part TG is in the formula (I) of group (2) therein, part Q ¹And Q ²Can be connected on the same carbon atom among the group E, perhaps can be connected on the different atoms.Should be appreciated that, when E is aromatics, Q ¹And Q ²Can not be connected on the same carbon atom among the group E, but can for example be connected on the adjacent carbon atom.

In one embodiment, E is non-aromatics, and Q ¹And Q ²Be connected on the same carbon atom among the group E.

In another embodiment, Q ¹And Q ²Be connected on the not homoatomic among the group E.

Preferred group Q ²Be connected to group E, i.e. Q with bicyclic radicals with a position or contraposition relative positioning ²Be free of attachment to adjacent group E ring members with bicyclic radicals.The 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, 1,4-piperazinyl and 1,4-piperazine ketone group.

Group E not can be and replaces, and perhaps can have maximum 4 optional preceding freely radicals R that limit ¹⁰Substituent R ¹¹Yet, more general substituent R ¹¹Be selected from hydroxyl, oxo (when E is non-aromatics), halogen (for example chlorine and bromine), trifluoromethyl, cyano group, optional by C _1-2The C that alkoxyl group or hydroxyl replace _1-4Alkyl oxygen base and optional by C _1-2The C that alkoxyl group or hydroxyl replace _1-4Alkyl.

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

In a particular group of The compounds of this invention, E is a group:

G wherein ³Be selected from C, CH, CH ₂, N and NH; And G ⁴Be selected from N and CH.

Group E and with group Q ¹And Q ²(a) and the particular instance of the tie point of bicyclic radicals (*) be shown in the following table 4.

Table 4:

A kind of preferred group E is group D9.

Radicals X

Cyclic group X is the bicyclic heterocyclic group with 8 to 12 ring memberses, and maximum 5 ring memberses are the heteroatoms that is selected from O, N and S.

The example of bicyclic heterocyclic group is preferred with described in the definitional part as above.

General cyclic group X has 8 to 10 ring memberses, for example 9 to 10 ring memberses.

In one embodiment, cyclic group X is the optional bicyclic heteroaryl that replaces.

The example of bicyclic heteroaryl comprises pyridine or the pyrimidine ring that is fused to 5-or 6-unit's carbocyclic ring or heterocyclic aromatic ring.A special example of this group is thieno-[3, a 2-d] pyrimidine group.

In one embodiment, cyclic group X can take

Form,

G wherein ⁵Be hydrogen bond receptor atom or group.

Term " hydrogen bond receptor " is a term of continuing to use for a long time, is meant the group that can form hydrogen bond with the hydrogen atom in identical or the adjacent molecule; Referring to for example " Advanced OrganicChemistry " by Jerry March, the 4th edition, 75-79 page or leaf and middle document thereof.In this article, hydrogen bond receptor comprises the group of nitrogen, oxygen and sulphur atom and nitrogenous, oxygen and sulphur atom.

The special example of hydrogen bond receptor is a group listed in the following table 5.The point of group E represented to be connected in asterisk.

Table 5

Cyclic group X can comprise a hydrogen bond receptor or more than (for example two or three a) hydrogen bond receptor part.

Cyclic group X can comprise and group G ⁵Adjacent hydrogen-bond donor group, so cyclic group X can take:

Form,

G wherein ⁵Be hydrogen bond receptor atom or group, D is the hydrogen-bond donor group.

The hydrogen-bond donor group can be for example NH, C-NH ₂, C-NH, C-OH, C-SH or C-H.

n&R ⁴

Do not consider to form hydrogen acceptor G ⁵Any atom or the group (when existing) of part, cyclic group X can be unsubstituted loop systems (n=0) or the loop systems (n=1,2,3 or 4) that replaces.

In formula (I), R ⁴Independently be selected from oxo, halogen, optional by halogen, hydroxyl or C _1-2The C that alkoxyl group replaces _1-6Alkyl, cyano group, optional by halogen, hydroxyl or C _1-2The C that alkoxyl group replaces _1-6Alkyl oxygen base, CONH ₂, CONHR ⁹, CF ₃, NH ₂, NHCOR ⁹, NHCONHR ⁹And NHR ⁹

More general R ⁴Be selected from oxo, amino, NHCOR ⁹, NHR ⁹, halogen, C _1-5Saturated alkyl, cyano group and CF ₃R ⁴Preferred value comprise oxo and methyl.

Preferred n is 0,1 or 2.

In one embodiment, n is 0.

In another embodiment, n is 1 or 2.

At R ⁴Be CONHR ⁹, NHCOR ⁹, NHCONHR ⁹Or NHR ⁹The time, R ⁹Be radicals R ^9aOr (CH2) R ^9a, R wherein ^9aCarbocyclic ring or heterocyclic group for monocycle or dicyclo.

The example of carbocyclic ring and heterocyclic group is preferred with described in the definitional part as above.

General carbocyclic ring and heterocyclic group are monocycle.

Preferred carbocyclic ring and heterocyclic group are aromatics.

Radicals R ⁹Be generally unsubstituted phenyl or benzyl, or the phenyl or the benzyl that replace by 1,2 or 3 substituting group, substituting group is selected from halogen, hydroxyl, trifluoromethyl, cyano group, carboxyl, C _1-4Alkoxy carbonyl, C _1-4Acyloxy, amino, list-or two-C _1-4Alkylamino, optional by halogen, hydroxyl or C _1-2The C that alkoxyl group replaces _1-4Alkyl, optional by halogen, hydroxyl or C _1-2The C that alkoxyl group replaces _1-4Alkoxyl group, phenyl, comprise maximum 3 and be selected from heteroatomic five yuan and the six membered heteroaryl of O, N and S and comprise maximum 2 heteroatomic saturated carbon ring and heterocyclic groups that are selected from O, S and N.

Part:

Example list in the table 6.The point of group E represented to be connected in asterisk.

Table 6

Preferred group comprises F1, F19 and F20.

Particularly preferred group is F1.

The subgroup of concrete and preferred formula (I)

A subgroup of formula (I) compound has general formula (II):

And salt, solvate, tautomer and N-oxide compound,

Wherein group A be connected to phenyl ring between the position or contraposition, q is 0-4; R ¹, R ², R ³, R ⁴And R ⁵As this paper about formula (I) and subgroup thereof, example and preferred the qualification; And R ⁸Be substituting group as preceding qualification.In formula (II), q is preferably 0,1 or 2, and more preferably 0 or 1, most preferably be 0.Preferred group A is connected to the contraposition of phenyl ring.

For example a subgroup of formula (II) compound can be by formula (IIa):

And salt, solvate, tautomer and N-oxide compound represent,

Wherein X, R ^1a, R ², R ³, R ⁴Limit with n such as this paper, x is 0 or 1, and y is 0,1 or 2.In one embodiment, x and y are 1.In another embodiment, x is 0, and y is 1.

Another subgroup of compound in formula (II) can be by formula (IIb):

And salt, solvate, tautomer and N-oxide compound represent,

Wherein X, R ^1a, R ², R ³, R ⁴, x and y such as preceding qualification, z is 0,1 or 2, its condition is that y and z sum are no more than 4.In a particular, y is 2, and z is 1.

Another subgroup of formula (I) compound has general formula (IIc):

And salt, solvate, tautomer and N-oxide compound,

Wherein group A is connected to the 3-position or the 4-position of piperidine ring, and q is 0-4; And X, n, A, R ^1a, R ², R ³And R ⁴As this paper about formula (I) and subgroup thereof, example and preferred the qualification; And R ¹⁰Be substituting group as preceding qualification.In formula (IIc), q is preferably 0,1 or 2, and more preferably 0 or 1, most preferably be 0, and/or n is preferably 0.

Another subgroup of formula (I) compound has general formula (III):

And salt, solvate, tautomer and N-oxide compound,

Wherein X, R ^1b, R ⁴, Q ¹, Q ²And NR ²R ³As this paper about formula (I) and subgroup thereof, example and preferred the qualification.In formula (III), special compound is Q wherein ¹Be key or C _1-2Alkylidene group and Q ²Compound for key or methylene radical.Preferred R ^1bBe aryl or heteroaryl R ^1a

In formula (III), preferred NR ²R ³Be NH ₂Or NHMe.

Another group of preferred compound of the present invention can be by formula (IV):

And salt, solvate, tautomer and N-oxide compound represent,

T wherein ¹Be S, O or NR ¹⁸R ¹⁷Be hydrogen or radicals R ⁴R ¹⁸Be hydrogen or C _1-4Alkyl; And A, E, T, R ^1aTo R ⁴And R ¹⁶Limit as this paper.

In the subgroup of compound, T is N, and T in (IV) formula ¹Be selected from S, O and NH.In a preferred group of compound, T ¹Be S.

In formula (II), (IIa), (IIb), (IIc), (III) with (IV) and in the embodiment, radicals R ^1aAnd R ^1bBe preferably optional aryl or the heteroaryl that replaces respectively, and be generally the monocyclic aryl or the heteroaryl of 5 or 6 ring memberses.Concrete aryl and heteroaryl are phenyl, pyridyl, furyl and thienyl, and each group is optional to be substituted.The optional phenyl that replaces is particularly preferred.

Perhaps, radicals R ^1aAnd R ^1bCan be for example optional naphthyl that replaces, for example optional 1-naphthyl that replaces.A special example of this group is unsubstituted 1-naphthyl.

Aryl or heteroaryl (for example phenyl, pyridyl, furyl or thienyl) not can be and replace, or are replaced by maximum 5 substituting groups.

The specific subgroup of formula (II), (IIa), (IIb), (IIc) or compound (III) is made up of these compounds, wherein R ^1aAnd R ^1bBe respectively unsubstituted phenyl, or more preferably carry 1 to 3 (more preferably 1 or 2) substituent phenyl, substituting group is selected from hydroxyl, C _1-4Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano group, C _1-4Alkyl oxygen base and C _1-4Alkyl (C wherein _1-4Alkyl oxygen base and C _1-4Alkyl is optional respectively by one or more C _1-2Alkoxyl group, halogen, hydroxyl or the optional phenyl that replaces or pyridyl replace), C _1-4Acyl amino, benzamido, tetramethyleneimine-1-base carbonyl, piperidines-1-base carbonyl, morpholino carbonyl, piperazine-1-base carbonyl, (heteroaryl is optional by one or more C to contain 1 or 2 heteroatomic five yuan and six membered heteroaryl that is selected from N, O and S _1-4Alkyl substituent replaces), the optional phenyl that replaces, the optional pyridyl that replaces and the optional phenoxy group that replaces, wherein the optional substituting group of phenyl, pyridyl and phenoxy group is respectively 1,2 or 3 and is selected from C _1-2Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano group and C _1-2Alkyl oxygen base and C _1-2Alkyl (C wherein _1-2Alkyl oxygen base and C _1-2Alkyl is optional respectively to be replaced by methoxyl group or hydroxyl) substituting group.

Though can there be maximum 5 substituting groups, more general have 0,1,2,3 or 4 substituting group, preferred 0,1,2 or 3, more preferably 0,1 or 2.

In each formula (II), (IIa), (IIb), (IIc), (III) with in the embodiment (IV), R ^1aAnd R ^1bThe phenyl that is selected from unsubstituted phenyl respectively or is replaced by 1 or 2 substituting group, substituting group independently is selected from hydroxyl, C _1-4Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, benzyl oxygen base, cyano group, optional by C respectively _1-2The C that alkoxyl group or hydroxyl replace _1-4Alkyl oxygen base and C _1-4Alkyl.

More preferably R ^1aAnd R ^1bBe selected from the phenyl that carries 1 or 2 substituent replacement respectively, substituting group independently is selected from fluorine, chlorine, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, cyano group, methoxyl group, oxyethyl group, isopropoxy, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl and benzyl oxygen base.

In each formula (II), (IIa), (IIb), (IIc), (III) with in the specific subgroup of the compound (IV), radicals R ^1aAnd R ^1bBe respectively the monosubstituted phenyl that has chlorine substituent in contraposition.

R ¹⁷Be preferably hydrogen.

Another subgroup of compound in the formula (III) has logical formula V:

And salt, solvate, tautomer and N-oxide compound,

Wherein X, R ², R ³And R ⁴As this paper about formula (I) and subgroup thereof, example and preferred the qualification.

Another subgroup of compound in the formula (III) has general formula (VI):

And salt, solvate, tautomer and N-oxide compound,

Wherein m is 0,1 or 2; M ' is 0 or 1, and its condition is that m and m ' sum are 0-2; N is 0 or 1; P is 0,1,2 or 3; R ^xAnd R ^yIdentical or different, and be selected from hydrogen, methyl and fluorine respectively; R ¹²Be CN or NR ²R ³, and each R ¹³Independently be selected from R ¹⁰, wherein X, R ², R ³, R ⁴And R ¹⁰Limit as this paper.

In formula (VI), m is preferably 0 or 1.When m ' was 0, more preferably m was 1.When m ' was 1, preferred m was 0.

In a group of compound, n is 0.In another group of compound, n is 1.

Preferred p is 0,1 or 2, and R ¹³Be selected from hydroxyl, C _1-4Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, benzyl oxygen base, cyano group, optional by C respectively _1-2The C that alkoxyl group or hydroxyl replace _1-4Alkyl oxygen base and C _1-4Alkyl.

More preferably R ¹³Be selected from fluorine, chlorine, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, cyano group, methoxyl group, oxyethyl group, isopropoxy, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl and benzyl oxygen base.

For example, phenyl can have the substituent R that is selected from fluorine, chlorine, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, benzyl oxygen base, methyl, the tertiary butyl and methoxyl group in contraposition ¹³, and choose wantonly at the ortho position or a position has second substituting group that is selected from fluorine, chlorine or methyl.In this subgroup, phenyl can be single replacement.Perhaps, phenyl can be two replacements.

In another subgroup of compound, p is 1, and substituent R ¹³Be chlorine substituent in contraposition.

In another subgroup of compound, p is 2, and phenyl is dichlorophenyl, and its specific examples is a 2,4 dichloro benzene base, 2,5-dichlorophenyl, 3,4-dichlorophenyl and 2,3-dichlorophenyl.

In the subgroup of the compound in formula (VI), R ¹²Be NR ²R ³, more preferably R ¹²Be selected from NH ₂, NHMe and NMe ₂, and NH ₂Be especially preferred.

A specific subgroup of the compound in formula (VI) can be by formula (VII):

And salt, solvate, tautomer and N-oxide compound represent,

R wherein ^x, R ^yAnd R ^wRespectively independent is hydrogen or methyl, and X, n, p, R ⁴And R ¹³Limit as this paper.

In one embodiment, R ^wBe hydrogen.In another embodiment, R ^wBe methyl.Preferred p is 0,1 or 2.Preferred R ^xAnd R ^yThe two is hydrogen.

Perhaps, R ^xAnd R ^yBut the two is methyl, but perhaps the two is fluorine, but perhaps R ^xAnd R ^yOne of be hydrogen, and another can be methyl or fluorine.

Another subgroup of compound in formula (III) can be by formula (VIII):

And salt, solvate, tautomer and N-oxide compound represent,

R wherein ²⁵Be hydrogen or methyl, and X, R ¹³, R ⁴And R ^wLimit as this paper.

Preferred p is 0,1 or 2.

In a subgroup of compound, R ²⁵Be hydrogen.In another subgroup of compound, R ²⁵Be methyl.

In one embodiment, R ^wBe hydrogen.In another embodiment, R ^wBe methyl.

In formula (VII) and the specilization compound (VIII) be those compounds of 0 for n wherein.

In each formula (VII) with (VIII), preferred substituents R ¹³A group form by chlorine, fluorine, methyl, ethyl, sec.-propyl, methoxyl group, difluoro-methoxy, trifluoromethoxy, trifluoromethyl, the tertiary butyl, cyano group and benzyl oxygen base.

In formula (VII) with (VIII), p is preferably 1 or 2.

In one embodiment, p is 1.

In another embodiment, p is 2.

At p is 1 o'clock, and benzyl ring can replace or 3-replacement or 4-replacement for 2-.

Wherein p is that the special example of 1 group is group B 2, B3, B5, B6, B8, B9, B10, B11, B12, B15, B18 and the B19 in the above table 2.Preferred group is group B 2, B5, B10, B11, B15, B18 and the B19 in the table 2.

At p is 2 o'clock, and benzyl ring can be for example 2, and 3-two replaces, 2, and 4-two replaces or 2, and 5-two replaces.

Wherein p is that the special example of 2 group is group B 4, B7, B13, B14, B16, B17 and the B20 in the above table 2.

Another subgroup of compound of the present invention can be by formula (IX):

And salt, solvate, tautomer and N-oxide compound represent,

Wherein Ar has maximum 2 to be selected from the heteroatomic ring member of O, N and S and to choose five yuan or single six-membered rings aryl or the heteroaryl that is selected from the substituting group replacement of fluorine, chlorine, methyl and methoxyl group by or two wantonly; R ^13aFor being selected from the substituting group of fluorine, chlorine, methyl, trifluoromethyl, trifluoromethoxy and methoxyl group; R is 0,1 or 2 (more general 0 or 1); X, Q ¹, Q ², NR ²R ³And R ⁴Limit as this paper.

In formula (IX), special five yuan or single six-membered rings aryl or heteroaryl Ar can be selected from phenyl, pyridyl, furyl and thienyl, and each group is optional to limit replacement as this paper.A kind of special monocyclic aryl is the optional phenyl that replaces, and unsubstituted phenyl is a special example.

In formula (IX), preferred compound is these compounds, wherein NR ²R ³Be selected from NH ₂, NHMe and NMe ₂(and NH ₂Be especially preferred); And/or R ⁴Be hydrogen or methyl (hydrogen more preferably); And/or Q ¹Be selected from CH ₂And CH ₂NHCO (wherein carbonyl is connected to piperidine ring); And/or Q ²Be selected from CH ₂And key (key more preferably).

For fear of query, should be appreciated that R ^1aAnd R ^1bEach general and concrete preferred, embodiment and example can with radicals X and/or Q ¹And/or Q ²And/or R ²And/or R ³And/or R ⁴And/or R ⁵And/or R ⁹Each general and concrete preferred, embodiment and example combination, and all these are combined as the application and comprise.

The different functional groups of composition formula (I) compound and substituting group are generally through selecting, so that the molecular weight of formula (I) compound is no more than 1000.More generally the molecular weight of compound is 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, and for example 500 or littler.

Particular compound of the present invention is as shown in following examples.

Salt, solvate, tautomer, isomer, N-oxide compound, ester, prodrug and isotropic substance

The same with the application's every other part, in this part, unless otherwise indicated herein, to quoting of formula (I) comprise to formula (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII) and (IX) and the every other subgroup that limits of this paper, preferably with the quoting of example.

Unless regulation also comprises ion for example discussed below, salt, solvate and protection form thereof to quoting of specific compound in addition.

A lot of compounds of formula (I) can salt form exist, acid salt for example perhaps in some cases, exists with the form of the salt of organic and mineral alkali, for example carboxylate salt, sulfonate and phosphoric acid salt.All these salt all within the scope of the invention, and to the salt form that also comprises described compound of quoting of formula (I) compound.The same with the application's aforementioned part, should think same finger formula (II) and subgroup thereof to all references of formula (I), unless otherwise indicated herein.

Selecting and prepare salt form can be according to Pharmaceutical Salts:Properties, Selection, and Use, P.Heinrich Stahl (Editor), Camille G.Wermuth (Editor), ISBN:3-90639-026-8, Hardcover, the 388th page, August 2002 described methods.For example, can be by in organic solvent, dissolving free alkali, the wherein insoluble or bad dissolving of the salt form of being given adds required acid in the solvent that is fit to then, prepares acid salt so that be settled out salt from solution.

Acid salt can form with multiple acid, comprise mineral acid and organic acid the two.The example of acid salt comprises the salt that forms with acid; acid is selected from acetate; 2; the 2-dichloro acetic acid; hexanodioic acid; alginic acid; xitix (for example 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; cyclohexane sulfamic acid; dodecyl sulphate; ethane-1; the 2-disulfonic acid; ethyl sulfonic acid; the 2-ethylenehydrinsulfonic acid; formic acid; fumaric acid; tetrahydroxyadipic acid; 2; the 5-resorcylic acid; glucoheptonic acid; the D-glyconic acid; glucuronic acid (for example D-glucuronic acid); L-glutamic acid (for example L-L-glutamic acid); alpha-oxo--pentanedioic acid; oxyacetic acid; urobenzoic acid; Hydrogen bromide; spirit of salt; hydroiodic acid HI; isethionic acid; lactic acid (for example (+)-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 (for example 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; pamoic acid; phosphoric acid; propionic acid; the L-Pyrrolidonecarboxylic acid; Whitfield's ointment; the 4-aminosallcylic acid; sebacic acid; stearic acid; succsinic acid; sulfuric acid; tannic acid; (+)-L-tartrate; thiocyanic acid; toluenesulphonic acids (for example tosic acid); the amino acid of undecylenic acid and valeric acid and acidylate and Zeo-karb.

A special group of acid salt comprises the salt that forms with hydrochloric acid, hydroiodic acid HI, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succsinic acid, toxilic acid, oxysuccinic acid, hydroxyethylsulfonic acid, fumaric acid, Phenylsulfonic acid, toluenesulphonic acids, methylsulfonic acid, ethyl sulfonic acid, naphthene sulfonic acid, valeric acid, acetate, propionic acid, butyric acid, propanedioic acid, glucuronic acid and lactobionic acid.

Another group of acid salt comprises the salt that forms with acetate, hexanodioic acid, xitix, aspartic acid, citric acid, DL-lactic acid, fumaric acid, glyconic acid, glucuronic acid, urobenzoic acid, spirit of salt, L-glutamic acid, DL-oxysuccinic acid, methylsulfonic acid, sebacic acid, stearic acid, succsinic acid and tartrate.

According to the pKa in order to the salifiable acid of shape, compound of the present invention can be used as single salt or disalt exists.

If compound is an anionic property, or have possibility be anionic functional group (for example ,-COOH may be-COO ^-), then available suitable salt forming cation.The example of the inorganic cation that is fit to includes but not limited to alkali metal cation (Na ⁺And K ⁺), alkaline earth cation is (as Ca ²⁺And Mg ²⁺) and other positively charged ions (Al ³⁺).The organic cations example that is fit to includes but not limited to that ammonium ion (is NH ₄ ⁺) and the ammonium ion that replaces (NH for example ₃R ⁺, NH ₂R ²⁺, NHR ₃ ⁺And NR ₄ ⁺).The example of the ammonium ion of the replacement that some are fit to is the ammonium ion from following compound deriving: ethylamine, diethylamide, dicyclohexylamine, triethyl ammonium, butyl ammonium, quadrol, thanomin, diethanolamine, piperazine, benzyl amine, phenylbenzyl amine, choline, meglumin and Tutofusin tris and amino acid (as Methionin and arginine).The example of general quaternary ammonium ion is N (CH ₃) ₄ ⁺

When the compound of formula (I) comprised amine official energy, these compounds can form quaternary ammonium salt, for example according to method well known to those skilled in the art and alkylating agent reaction.This type of quaternary ammonium compound is in the scope of formula (I).

Comprise the functional formula of amine (I) compound and also can form the N-oxide compound.This paper also comprises the N-oxide compound to comprising quoting of the functional formula of amine (I) compound.

Compound comprise several amine official can the time, also can or be oxidized to the N-oxide compound with one more than a nitrogen-atoms.The special example of N-oxide compound is the N-oxide compound of tertiary amine or nitrogenous heterocyclic nitrogen-atoms.

By with the corresponding amine of oxidizer treatment, as hydrogen peroxide or peracid (for example peroxycarboxylic acid), can form the N-oxide compound, for example referring to Advanced Organic Chemistry, by JerryMarch, 4 ^ThEdition, Wiley Interscience, pages.More particularly, can pass through L.W.Deady (Syn.Comm.1977,7, method 509-514) prepares the N-oxide compound, wherein amine compound and metachloroperbenzoic acid (MCPBA) react in for example inert solvent (as methylene dichloride).

The compound of formula (I) can multiple different rotamerism and tautomeric form exist, and quoting of formula (I) compound comprised all these forms.For fear of query, can exist and only clearly describe or show that when a kind of, every other form is also comprised by formula (I) with one of multiple rotamerism or tautomeric form at compound.

Compound in formula (I) comprises one or more chiral centres, and when form that can two or more optical isomers exists, quoting of formula (I) compound comprised all optical siomerism forms (for example enantiomer and diastereomer), can be used as independent optical isomer, also can be used as the mixture of two or more optical isomers, unless this paper needs in addition.

For example, group A can comprise one or more chiral centres.Thereby at E and R ¹When being connected to the same carbon atom that connects on the basic A simultaneously, described carbon atom is generally chirality, so the compound of formula (I) exists as a pair of enantiomer when existing more than a chiral centre in compound (or, more than a pair of enantiomer).

Optical isomer can by its opticity (be conduct+and-isomer) characterize and identify, perhaps utilize " R and S " nomenclature of Cahn, Ingold and Prelog research, according to the absolute stereo chemical characterization, referring to Advanced Organic Chemistry by Jerry March, 4 ^ThEdition, John Wiley ﹠amp; Sons, New York, 1992, pages 109-114 also can be referring to Cahn, Ingold ﹠amp; Prelog, Angew.Chern.Int.Ed.Engl, 1966,5,385-415.

Optical isomer can be by comprising chirality chromatography (chromatography on chiral support) some technical points from, these technology are familiar with by those skilled in the art.

The choosing method that supplies as the chirality chromatography, the separating optical isomeric body can form diastereo-isomerism salt with chiral acid, separate diastereomer by the preferential crystallization method, salt is dissociated, to obtain the independent enantiomer of free alkali, chiral acid is as (+)-tartrate, (-)-Pyrrolidonecarboxylic acid, (-)-two-toluyl (toluloyl)-L-tartrate, (+)-amygdalic acid, (-)-oxysuccinic acid and (-)-camphorsulfonic acid.

When the compound of formula (I) existed as two or more optical siomerism forms, a kind of enantiomer of enantiomer centering can show the advantage that for example surpasses another kind of enantiomer aspect biological activity.Therefore, in some cases,, or only may cater to the need as therapeutical agent with a kind of of multiple diastereomer only with right a kind of of enantiomer.Therefore, the invention provides and comprise formula (I) compound compositions with one or more chiral centres, wherein at least 55% formula (I) compound of (for example at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) shows as single optical isomer (for example enantiomer or diastereomer).In a general embodiment, 99% or more (for example whole in fact) of formula (I) total amount of compound show as single optical isomer (for example enantiomer or diastereomer).

Formula (I) also comprises the ester of formula (I) compound that carries hydroxy-acid group or hydroxyl, as carboxylicesters and acyloxyate.In one embodiment of the invention, formula (I) comprises the ester of formula (I) compound that carries hydroxy-acid group or hydroxyl in its scope.In another embodiment of the invention, formula (I) does not comprise the ester of formula (I) compound that carries hydroxy-acid group or hydroxyl in its scope.(=O) the compound of OR, wherein R is the ester substituting group to the example of ester, for example C in order to comprise group-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 polymorphic, the solvate (for example hydrate) of compound, the complex compound of compound (for example, with the clathrate complex or the inclusion compound of compound (for example cyclodextrin), or with the complex compound of metal) and the prodrug of compound." prodrug " is meant for example interior any compound that transforms the bioactive compounds of an accepted way of doing sth (I) of body.

For example, some prodrugs are the ester (for example, the unstable ester of physiologically acceptable metabolism) of active compound.Between metabilic stage, ester group (C (=O) OR) cracking obtains active medicine.This type of ester can generate by the esterification of any hydroxy-acid group in the parent compound (C (=O) OH), in the time of suitably, protects any other reactive group that exists in the parent compound in advance, goes protection (if desired) subsequently.

The example of the unstable ester of this type of metabolism comprise formula-C (=O) compound of OR, wherein R is:

C _1-7Alkyl (for example ,-Me ,-Et ,-nPr ,-iPr ,-nBu ,-sbu ,-iBu ,-tBu);

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

Acyloxy-C _1-7Alkyl (acyloxy methyl for example, the acyloxy ethyl, oxy acid methyl neopentyl, acetoxy-methyl, 1-acetoxyl group ethyl, 1-(1-methoxyl group-1-methyl) ethyl-ketonic oxygen base ethyl, 1-(benzoyloxy) 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 and 1-(4-THP trtrahydropyranyl) ketonic oxygen base ethyl).

Some prodrugs also enzymatic activate into active compound, perhaps enzymatic activates the compound (for example, treating in (LIDEPT) at the enzyme prodrug treatment (ADEPT) of antigen orientation, the enzyme prodrug treatment (GDEPT) of gene orientation and ligand directed enzyme prodrug) that produces active compound when further chemical reaction.For example, prodrug can perhaps can be amino acid ester derivative for sugar derivatives or other glucosides title complexs.

The method of preparation formula (I) compound

The same with the application's every other part, in this part, unless otherwise indicated herein, to quoting of formula (I) comprise to formula (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII) and (IX) and the every other subgroup that limits of this paper, preferably with the quoting of example.

Wherein TG is

(1) group

Formula (I) but the compound of compound through type (X) and compound or its N-protected derivatives reaction of formula (XI) prepare:

Wherein X, XG, A, E, n and R ^1aTo R ⁴As preceding qualification, one of radicals X G and Y are chlorine, bromine or iodine or trifluoromethayl sulfonic acid (trifluoromethanesulfonic acid) base, and another of radicals X G and Y is the organic boronic residue, for example organic boric acid ester or organic boronic residue.

Exist down at palladium catalyst (closing palladium) and alkali (for example carbonate, as salt of wormwood), can under general Suzuki coupling condition, react as two (three-tertiary butyl phosphines).Reaction can be carried out in aqueous solvent system, and for example aqueous ethanol generally makes reaction mixture through heating, for example is heated to surpass 100 ℃ temperature.

A kind of example synthetic route that comprises the Suzuki coupling step is shown in the scheme 1.The raw material of synthetic route shown in the scheme 1 is the aryl that replaces of halogen-or heteroaryl methyl nitrile (XII), and wherein X is chlorine, bromine or iodine atom or trifluoromethanesulfonic acid base.Nitrile (XII) and aldehyde R ¹CHO condensation in aqueous solvent system (as aqueous ethanol) in the presence of alkali (as sodium hydroxide or potassium hydroxide).Reaction can be carried out in room temperature.

Handle the acrylonitrile derivative (XIII) that gained replaces with reductive agent then, reductive agent is answered the two keys of selective reduction alkene, and does not reduce itrile group.For this reason, available hydroborate (as the sodium borohydride) acetonitrile derivative (XIV) that obtains replacing.Reduction reaction is generally carried out in solvent (as ethanol), utilizes heating usually, for example is heated to the highest about 65 ℃ temperature.

Under above-mentioned Suzuki coupling condition, make reductive nitrile (XIV) and organic boric acid ester (XV) coupling, then to obtain the compound of formula (I), wherein A-NR ²R ³Be the acetonitrile-base that replaces.

Scheme 1

Then, can the cyanide compound (XVI) that replace be reduced into corresponding amine (XVII) by handling with the reductive agent (as Raney nickel and the ammonia in the ethanol) that is fit to.

The aminocompound of synthetic route production shown in the scheme 1 (I), wherein aryl or heteroaryl E are connected to the β-position with respect to the group A of amino.In order to obtain wherein R ¹Be connected to aminocompound, can make in the condensation step functional group on two kinds of raw materials opposite, so that wherein XG is compound and the formula R of the formula XG-E-CHO of bromine, chlorine, iodine or trifluoromethanesulfonic acid base with respect to the formula (I) of the β-position of amino ^1a-CH ₂The compound condensation of-CN with the acrylonitrile derivative that obtains replacing, subsequently, before becoming amino with organic boric acid ester (XV) coupling and with cyano reduction, is reduced into corresponding acetonitrile derivative with the acrylonitrile derivative that replaces.

Can prepare wherein R by the reaction sequence shown in the scheme 2 ^1aBe connected to compound with respect to the formula (I) of the alpha-position of amino.

In scheme 2, raw material is the aryl that replaces of halogen-or heteroaryl methyl Grignard reagent (XVIII, X=bromine or chlorine), this Grignard reagent and nitrile R ^1a-CN reacts in anhydrous ether (as ether), obtains intermediate imines (not shown), with reductive agent (as lithium aluminum hydride) reduction, obtains amine (XIX).Can under above-mentioned Suzuki coupling condition, make amine (XIX) and organic boric acid ester (XV) be reacted into amine (XX).

Scheme 2

The also compound of the nitrile compound of available replacement (XXI) preparation formula (I).

Can make nitrile (XXI) and the formula R that wherein is 0 or 1 for r ^1a-(CH ₂) _rThe aldehyde condensation of-CHO is being similar under the above scheme 1 described condition subsequently, and the vinyl cyanide of the replacement that obtains is reduced into corresponding replacement nitrile.Can remove protecting group PG by the method that is fit to then.Available subsequently above-mentioned suitable reductive agent is reduced into corresponding amine with nitrile compound.

Also can under standard Grignard reaction conditions, make nitrile compound (XXI) and formula R ^1a-(CH ₂) _rThe Grignard reagent react of-MgBr, deprotection base subsequently, the aminocompound of the present invention of the structure shown in (XXII) that obtains having formula.

In above generalized preparation process, in the presence of palladium catalyst and alkali, with organic boric acid ester or organic boronic reaction group E and cyclic group X are coupled at by halogenated aryl or heteroaryl compound.The a lot of organic boric acid esters that are applicable to the preparation The compounds of this invention can be buied, for example available from Boron Molecular Limited of Noble Park, and Australia, perhaps available from Combi-Blocks Inc, of San Diego, USA.When organic boric acid ester can not be buied, can prepare by methods known in the art, for example be described in N.Miyaura and A.Suzuki, Chem.Rev.1995 is in 95,2457 the review article.Therefore, the preparation organic boric acid ester can make corresponding bromine-containing compound and lithium alkylide reaction, and for example butyllithium reacts with boric acid ester then.If desired, can make the organic boronic ester derivative hydrolysis of gained obtain corresponding organic boronic.

Wherein group A comprise formula (I) compound of the nitrogen-atoms that is connected to group E can be with the compound of formula (XXIII) or its protection form by the synthetic method preparation of knowing.Compound of through type (XV) (referring to scheme 1) and formula Br-E-NH ₂The Suzuki linked reaction of compound (for example 4-bromaniline), can obtain the compound of formula (XXIII).

Can shown in scheme 3, prepare wherein R ^1aBe connected to the compound of the formula (I) of same carbon atom with E.

Scheme 3

In scheme 3, wherein XG is the aldehyde cpd (XXIV) and ethyl cyanacetate condensation in the presence of alkali of bromine, chlorine, iodine or trifluoromethanesulfonic acid base, obtains cyanoacrylate intermediate (XXV).Condensation generally by carrying out in the presence of alkali in the heating of Dean Stark condition, is preferably non-hydroxide, as piperidines.

Then, make cyanoacrylate intermediate (XXV) and be fit to by the Michael addition radicals R ^1aIntroduce the Grignard reagent R of the carbon-to-carbon double bond of acrylate part ^1aThe MgBr reaction.The Grignard reaction can be carried out in low temperature (for example about 0 ℃) polar aprotic solvent (as tetrahydrofuran (THF)).The product of Grignard reaction is cyanopropionic acid ester (XXVI), makes this product through hydrolysis and decarboxylation, obtains propanoic derivatives (XXVII).Hydrolysis and decarboxylation step can be by carrying out in acidic medium (for example mixture of sulfuric acid and acetate) heating.

By with amine HNR ²R ³React under the condition that is applicable to the formation amido linkage, propanoic derivatives (XXVII) changes into acid amides (XXVIII).Propanoic derivatives (XXVII) and amine HNR ²R ³Between linked reaction preferably in the presence of the reagent that generally is used to form peptide bond, carry out.Examples of such agents comprises 1,3-dicyclohexylcarbodiimide (DCC) (people such as Sheehan, J.Amer.ChemSoc.1955,77,1067), 1-ethyl-3-(3 '-dimethylaminopropyl)-carbodiimide (this paper is called EDC or EDAC) (people such as Sheehan, J.Org.Chem., 1961,26,2525), the urea groups coupling agent is (as phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea (HATU)) and phosphorus base coupling agent (as phosphofluoric acid 1-benzotriazole base oxygen base three (tetramethyleneimine-1-yl) phosphorus (PyBOP) (people such as Castro, Tetrahedron Letters, 1990,31,205).Favourable and 1-hydroxyl-7-azepine benzotriazole (HOAt) (L.A.Carpino, J.Amer.Chem.Soc, 1993 of carbodiimide coupling agent, 115,4397) or I-hydroxybenzotriazole (HOBt) (people such as Konig, Chem.Ber., 103,708,2024-2034) be used in combination.Preferred coupling agent comprises the combination of EDC (EDAC) and DCC and HOAt or HOBt.

Linked reaction is generally carried out in non-water, aprotic solvent, as acetonitrile, dioxane, methyl-sulphoxide, methylene dichloride, dimethyl formamide or N-crassitude, perhaps carries out in the water-containing solvent of optional and one or more miscibility cosolvent.Reaction can be carried out in room temperature, perhaps, (is for example carrying under the situation of electron-deficient aniline of electron-withdrawing group (as sulfamyl)) for than small reactivity the time at reagent, carries out at suitable high temperature.Reaction can be carried out in the presence of non-interference alkali, tertiary amine for example, and as triethylamine or N, the N-diisopropyl ethyl amine.

At amine HNR ²R ³During for ammonia, can be before adding ammonia with 1,1 '-carbonyl dimidazoles (CDI) carries out the acid amides linked reaction, with the activating carboxy acid.

Perhaps can use the response derivative of carboxylic acid, for example acid anhydride or acyl chlorides.Utilize the reaction of response derivative (as acid anhydride) in room temperature and in the presence of alkali (as pyridine), stir amine and acid anhydride carries out.

By under above-mentioned Suzuki coupling condition with organic boric acid ester (XV) reaction, (being equivalent to wherein, A has next-door neighbour NR can to make acid amides (XXVIII) transform the compound of an accepted way of doing sth (XXX) ²R ³The compound of the substituent formula of the oxo of group (I)).Subsequently, utilize hydride reducer (as lithium aluminum hydride) in the presence of aluminum chloride with acid amides (XXX) reduction, (being equivalent to wherein, A is CH-CH with the amine that obtains formula (XXXI) ₂-CH ₂-the compound of formula (I)).Reduction reaction is generally carried out in ether solvents (for example ether), and is heated to the reflux temperature of solvent.

Can not make acid amides (XXVIII) and organic boric acid ester (XV) reaction, but for example using lithium aluminum hydride/aluminum chloride with reduction of amide in the ether solvents in envrionment temperature, to obtain amine (XXIX), under above-mentioned Suzuki coupling condition, react then, to obtain amine (XXX) with organic boric acid ester (XV).

Homologue for the amine (XXIX) that obtains comprising more several methylene radical, can make carboxylic acid (XXVII) change into trinitride by standard method, and in the presence of alcohol (as benzylalcohol), reset, to obtain carbamate (referring to Advanced Organic Chemistry, 4 through Curtius ^ThEdition, by Jerry March, John Wiley ﹠amp; Sons, 1992, pages 1091-1092).During Suzuki coupling step subsequently, benzyl carbamate can be used as the protecting group of amine, then can be behind coupling step removes benzyl oxygen base carbonyl moiety in the carbamate groups by standard method.Perhaps, handle the benzyl carbamate base with hydride reducer (as lithium aluminum hydride), to obtain wherein NR ²R ³Be methylamino rather than amino compound.

Can for example in the presence of sodium cyanoborohydride, in alcoholic solvent (as methyl alcohol or ethanol), use formula HNR in standard reductive amination condition ²R ³Amine make the aldehyde cpd of formula (XXXII)

Reductive amination, preparing wherein, part X is that chlorine, bromine or iodine atom and A are group CH-CH ₂-the midbody compound of formula (X).

By with the corresponding alcohol of Dess-Martin periodinane oxidation for example (XXXIII), can obtain aldehyde cpd (XXXII) (referring to, Dess, D.B.; Martin, J.C.J.Org.Soc., 1983,48,4155 and Organic Syntheses, Vol.77,141).

The cyclic intermediate of the organic boronic ester cpds of through type (XV) and formula (XXXIV) or the Suzuki coupling of its N-protected derivative can generate wherein A, N and R ²Form the compound of the formula (I) of cyclic group together.

Generate wherein R ¹For the cyclic intermediate of the formula (XXXIV) of aryl (as the optional phenyl that replaces) can pass through aryl compound R ¹The Friedel Crafts alkylated reaction of-H and formula (XXXV) compound:

Alkylated reaction generally carries out at low temperature (for example less than 5 ℃) in the presence of Lewis acid (as aluminum chloride).

Find that Friedel Crafts reaction generally is applicable to the intermediate of a series of formula of preparation (X).Therefore, in the general method of preparation formula (X) compound, make the compound of formula (LXX):

With formula R ^1aThe compound of-H under Friedel Crafts alkylation conditions for example at aluminum halide (AlCl for example ₃) exist down and react.

Preparing wherein part NR ²R ³Be connected to the CH of part A ₂In the another kind of method of formula (I) compound of base, can make the aldehyde and the formula HNR of formula (XXXVI) ²R ³Amine coupling under above-mentioned reductive amination condition.In formula (XXXVI) with (XXXVII), A ' is the residue of group A, that is, and and part A ' and CH ₂Form group A together.By pure accordingly, can generate aldehyde (XXXVII) with for example Dess-Martin periodinane oxidation.

Also available above Friedel Crafts alkylation to the described type of synthesis type (XXXIV) intermediate prepares wherein, and XG is the intermediate of the formula (X) of bromine.The example of this method is shown in the scheme 4.

Scheme 4

The raw material that synthetic route is used shown in the scheme 4 is epoxide (XXXVIII), and described epoxide can be buied, perhaps can be by method preparation well-known to those having ordinary skill in the art, for example aldehyde Br-E-CHO and iodate trimethylammonium reaction of Salmon-Saxl.Epoxide (XXXVIII) and amine HNR ²R ³Carry out reacting under the condition of ring-opening reaction with epoxide being fit to, to obtain the compound of formula (XXXIX).Ring-opening reaction can be carried out in room temperature polar solvent (as ethanol), the perhaps optional mild heat of utilizing, the high excessive amine of general using.

Make amine (XXXIX) then and can participate in the alkylating aryl compound R of Friedel Crafts ^1aH reaction, be generally phenyl compound (referring to, Advanced OrganicChemistry for example, by Jerry March, pages 534-542).Therefore, generally in the presence of aluminum chloride catalyst in room temperature or make the amine and the aryl compound R of formula (XXXIX) near room temperature ^1aThe H reaction.At aryl compound R ^1aWhen H was liquid, for example under the situation of anisole (for example methyl-phenoxide) or halogeno-benzene (for example chlorobenzene), aryl compound can be used as solvent.In addition, can use less reactive solvent, as oil of mirbane.Compound R ¹The compound of the FriedelCrafts alkylated reaction giving construction (XL) of H and amine (XXXIX) is that bromine and A are CHCH corresponding to XG wherein ₂The compound of formula (X).

Also the hydroxy intermediate (XXXIX) in the available solutions 4 preparation wherein with radicals R ^1aAdjacent hydrocarbon connects the compound of the carbon atom of basic A by the displaced formula of Sauerstoffatom (X).Therefore, can make the compound of formula (XXXIX) or its N-protected derivative (R wherein ²Or R ³Be hydrogen) and formula R ^1aThe phenolic compound of-OH is in the reaction of Mitsunobu alkylation conditions, for example in the presence of diethyl azodiformate and triphenyl phosphine.Reaction is generally carried out in neutral temperature (for example envrionment temperature) polar aprotic solvent (as tetrahydrofuran (THF)).

Further using hydroxy intermediate (XXXIX) is in order to prepare corresponding fluorochemicals.Therefore, by with pyridine: hydrogen fluoride complex (Olah reagent) reaction, can be by fluoro for hydroxyl.Can make fluorinated intermediates through the Suzuki linked reaction, to obtain having the compound of the formula (I) of fluoridizing alkyl A.Perhaps; by hydroxy intermediate (XXXIX) or its protection form and heteroaryl organic boronic or organic boric acid ester are reacted under the Suzuki condition; use pyridine then: hydrogen fluoride complex with fluoro for the hydroxyl in gained formula (I) compound, but the fluorinated compound of preparation formula (I).

Can prepare wherein part by the reaction sequence shown in the scheme 5

Be group:

The compound of formula (I), wherein A " is the hydrocarbon residue of group A.

Scheme 5

Shown in scheme 5, make aldehyde (XXIV) and Grignard reagent R ^1aMgBr reacts under standard Grignard condition, to obtain secondary alcohol (XLI).Can make the compound reaction of secondary alcohol and formula (XLII) then, wherein R ²' and R ³' expression radicals R ²And R ³Or amine protecting group group, A " be the residue of group A, and XG ' expression hydroxyl or leavings group.

Amine protecting group group can be for example phthaloyl, NR in the case ²' R ³' be phthaloyl imino.

When XG ' is hydroxyl, compound (XLI) and (XLII) between reaction can take the form of the catalytic condensation reaction of toluenesulphonic acids.Perhaps, when XG ' is leavings group, as halogen, can at first use highly basic (for example sodium hydride) to handle alcohol (XLI), to generate alcoholate, alcoholate reacts with compound (XLII) then.

Under the general Suzuki coupling condition of the above-mentioned type, utilize organic boric acid ester reagent (XV) to make the compound of gained formula (XLIII) then through the Suzuki linked reaction, to obtain the compound of formula (XLIV).Then can be from protected amido NR ²' R ³' remove protecting group, to obtain the compound of formula (I).

Can prepare wherein part by the reaction sequence shown in the scheme 6

Be group:

The compound of formula (I), wherein A " is the hydrocarbon residue of group A.

Scheme 6

Raw material in the scheme 6 is chlorine acyl compounds (XLV), and this compound can be by literature method (for example, J.Med.Chem., 2004,47, the method described in the 3924-3926) or the preparation of its similar approach.By in polar solvent (as water/tetrahydrofuran (THF)), reducing, make compound (XLV) change into secondary alcohol (XLVI) with hydride reducer (as sodium borohydride).

Then, can make secondary alcohol (XLVI) and formula R as mentioned above ^1aThe phenolic compound of-OH is in for example reaction in the presence of diethyl azodiformate and triphenyl phosphine of Mitsunobu alkylation conditions, to obtain aryl ethers compound (XLVII).

Then by with amine HNR ²R ³Chlorine atom in the reaction displacement aryl ethers compound (XLVII) is to obtain the compound of formula (XLVIII).Nucleophilic displacement reaction can be undertaken by heating amine and aryl ethers in elevated temperature (for example about 100 ℃) polar solvent (as alcohol).Can utilize the microwave heater heating.Can utilize the organic boric acid ester of formula (XV) then as mentioned above, make the amine (XLVIII) that obtains through the Suzuki coupling step, to obtain compound (XLIX).

In the variation of reaction sequence shown in the scheme 6, becoming the ether reaction to introduce radicals R by Mitsunobu ¹Before, can utilize amine HNR ²R ³Make secondary alcohol (XLVI) through nucleophilic displacement reaction.

Wherein E and R ^1aAnother synthetic route that is connected to formula (I) compound of same carbon atom among the group A is shown in the scheme 7.

Scheme 7

In scheme 7, organic boronic compound (L) reacts with cyano compound XG-E-CN under the Suzuki coupling condition, and wherein XG is generally halogen, as bromine or chlorine.Available EP 1382603 described methods of organic boronic (L) or the preparation of its similar approach.

Then, can make the nitrile (LI) and Grignard reagent R that obtains ^1a-MgBr reaction is to introduce radicals R ^1aAnd generation ketone (LII).In the presence of highly basic, as lithium alkylide, butyllithium especially, ketone (LII) is by changing into enamine (LIV) with two phenenyl phosphinyl methylamine (LIII) reaction.

Make then enamine (LIV) on palladium-Pd/carbon catalyst through over hydrogenation, with the reduction enamine two keys and remove the 1-styroyl, thereby the compound of the formula of obtaining (LV).

Perhaps, under the described condition of Tetrahedron:Asymmetry 14 (2003) 1309-1316, reduce enamine (LIV) with hydride reducer, and through chiral separation.Then, remove the photolytic activity form that 2-styroyl protecting group obtains formula (LV) compound.

Wherein A and R ²The intermediate that connects into the formula (X) of the ring that comprises Sauerstoffatom can be prepared by the general method shown in the scheme 8.

Scheme 8

In scheme 8, ketone (LVI) becomes epoxide (LVII) with iodate trimethylammonium reaction of Salmon-Saxl.Reaction is generally being carried out in polar solvent (as methyl-sulphoxide) in the presence of the hydride base (as sodium hydride).

Epoxide (LVII) and thanomin in the middle ring-opening reaction of passing through of polar solvent (as alcohol, for example Virahol), utilize mild heat (for example the highest about 50 ℃) usually under non-interference alkali (as triethylamine).Then, by in solvent (as containing the alcoholic acid methylene dichloride), making the secondary alcohol that obtains be cyclized into the morpholine ring with vitriol oil processing.

Under the Suzuki coupling condition, make morpholine intermediate (LIX) and organic boric acid ester (XV) reaction then, to obtain the compound of formula (LX), this compound is equivalent to wherein A-NR ²R ³Form the compound of the formula (I) of morpholinyl.

Can not make epoxide (LVII) and thanomin reaction, but react, thereby the synthetic route that comprises with the compound of lower section is provided with list or dialkylamine:

Can pass through epoxide (LVII) and potassium phthalimide prepared in reaction R wherein in polar solvent (as DMSO) ²And R ³Be the compound of hydrogen.During the Suzuki coupling step, phthalimide-based can pass through partial hydrolysis, and to obtain corresponding phthalamic acid, phthalamic acid can be used the hydrazine cracking, to obtain amino N H ₂Perhaps, the available standards acid amides generates agent makes phthalamic acid be cyclized into phthalic imidine again, removes phthaloyl with hydrazine then, to obtain amine.

Wherein A and NR ²R ³Another synthetic route that is combined into formula (I) compound of cyclic group is shown in the scheme 9.

Scheme 9

In scheme 9, raw material (LXI) is generally two-aryl/hetaryl methane, and wherein aryl/hetaryl one or both of can be stablized or promote at E and R ^1aBetween methylene radical on form negatively charged ion.For example, R ^1aCan favourablely be pyridyl.In the presence of non-interference highly basic (as hexamethyl two silica-based sodium amides); raw material (LXI) reacts in low temperature (for example about 0 ℃) polar solvent (as tetrahydrofuran (THF)) with the two-2-chloroethyl amine (LXII) of N-protected, obtains the cyclic intermediate (LXIII) of N-protected.Protecting group can be for any standard amine protecting group, as the Boc group.After cyclisation, under the Suzuki coupling condition, make intermediate (LXIII) be coupled to the organic boric acid ester of formula (XV), go protection then, obtain the compound of formula (I).

Can generate wherein part by the synthetic route shown in the scheme 10

Be group:

The compound of formula (I), wherein " Alk " is little alkyl, as methyl or ethyl.

Scheme 10

In scheme 10, the carboxylic acid of formula (LXIV) is handled esterification with methyl alcohol in the presence of acid catalyst (example hydrochloric acid).Ester (LXV) then and highly basic (as lithium diisopropylamine (LDA)) and alkyl iodide (as methyl-iodide) react at low temperature (for example between 0 ℃ and-78 ℃).The ester of branching (LXVI) is hydrolyzed into acid (LXVII) then, and with amine HNR ²R ³Coupling under the standard amide formation condition of the above-mentioned type.With lithium aluminum hydride acid amides (LXVIII) is reduced into amine (LXIX) then, then under the Suzuki coupling condition, makes amine (LXIX) and heteroaryl organic boric acid ester or organic boronic reaction, obtain the compound of formula (I).

The another kind of method of preparation formula (I) compound comprises that the bromine atoms with in heterocyclic ring precursor group displaced type (LXX) intermediate of certain limit will encircle precursor group then and change into heterocycle.

Specifically, when group E is aryl or heteroaryl (as phenyl), can make the bromine atoms in formula (LXX) compound be transformed into for example CONH by the synthetic method of knowing ₂, NH ₂, COOH, CHO or C (O) CH ₃Group, these groups can be respectively applied for and constitute different heterocyclic ring systems.

Illustrate, by bromine-containing compound and lithium alkylide reaction, for example butyllithium makes the lithiumation intermediate formylation that obtains with dimethyl formamide then, can make the bromine-containing compound of formula (LXX) change into aldehyde (LXXI).In low temperature (for example less than-50 ℃) anhydrous polar aprotic solvent (as THF), carry out as the lithiumation step 1.

The available then chemical process that those skilled in the art are afamiliar with makes aldehyde radical in the compound (LXXI) change into the heterocyclic radical of certain limit.For example, by the reaction of aldehyde and tolylsulfonyl methyl isocyanide (tosmic), can make aldehyde Zhuanization Wei oxazole ring.

Wherein TG is

(2) group

And E be aryl or heteroaryl formula (I) but the compound of the compound of compound through type (CX) and formula (XI) react and prepare, wherein (CX) and (XI) can be fit to protected, and Q wherein ¹, Q ², E and R ^1bTo R ⁴As preceding qualification, one of radicals X G and Y are chlorine, bromine or iodine or trifluoromethayl sulfonic acid (trifluoromethanesulfonic acid) base, and another of radicals X and Y be the organic boronic residue, for example organic boric acid ester or organic boronic residue.

Reaction can be carried out under above-mentioned general Suzuki coupling condition.

A kind of example synthetic route that comprises the Suzuki coupling step is shown in the scheme 11.In scheme 11, by with lithium alkylide (for example butyllithium) and boric acid ester (iPrO) ₃B reaction, can make E wherein is that the bromine-containing compound (CXII) of aryl or heteroaryl changes into organic boronic (CXIII).Reaction is generally carried out in low temperature (for example-78 ℃) anhydrous polar solvent (as tetrahydrofuran (THF)).

Then, make the gained organic boronic (CXIII) and the chlorine-containing compound (XIV) of N-protected close reaction under these conditions in the presence of the palladium, obtain the compound of formula (CXV) at two (triphenylphosphines).

In scheme 1, NR ²R ³In nitrogen-atoms general with being fit to the protecting group protection, list below the example.Can be used in the amino a kind of special protecting group of protection at Suzuki coupling environment is tert-butoxycarbonyl, and this protecting group can be introduced by amino the reaction with the dimethyl dicarbonate butyl ester in the presence of alkali (as triethylamine).Generally can remove protecting group from the compound of formula (CXV) by method well known to those skilled in the art.

Scheme 11

In above generalized preparation process, in the presence of palladium catalyst and alkali, the bicyclic radicals X that replaces by halogen reacts with organic boric acid ester or organic boronic and makes aryl or heteroaryl E be coupled to bicyclic radicals.Be applicable to the preparation The compounds of this invention organic boric acid ester as mentioned above.

The compound of the compound of through type (CXIV) and formula (CXVII) or its protected derivatives reaction; can preparing wherein, TG is that (2) and E are non-aromatics cyclic group and formula (I) compound that is connected to bicyclic radicals by nitrogen-atoms; wherein encircle X and be constituted as permission nucleophilic displacement chlorine atom, wherein R ^1b, Q ¹, Q ²And NR ²R ³As preceding qualification, and ring E represents to contain the cyclic group E of nucleophilic NH group as ring members.

Reaction is generally carried out in high temperature (for example 90 ℃ to 160 ℃ temperature) polar solvent (as alcohol, for example ethanol, propyl alcohol or propyl carbinol), chooses wantonly in the presence of non-interference amine (as triethylamine).Reaction can be carried out in the pipe of sealing, especially when needing temperature of reaction to surpass the boiling point of solvent.When T was N, reaction is generally carried out in about 100 ℃ to 130 ℃ temperature, when T is CH, may need higher temperature, and was for example the highest about 160 ℃, therefore can use more high boiling solvent, as dimethyl formamide.Usually use excessive nucleophilic amine, and/or in reaction mixture, comprise other non-reaction base, as triethylamine.The reacting by heating mixture can or use microwave heater to finish by general device.

Can be by the midbody compound of the reaction sequence preparation formula (CXVII) shown in the scheme 12, wherein E is a piperidyl, Q ¹For saturated hydrocarbon connects base, and Q ¹And Q ²All be connected to the 4-position of piperidyl.

Scheme 12

In scheme 12, at first for example in the presence of non-interference alkali, react with the dimethyl dicarbonate butyl ester, protect (PG=protecting group) 4-methoxycarbonyl piperidines by tertiary butyl oxygen base carbonyl (boc) group with standard manner, to obtain protected compound (CXX).Then, by with highly basic (as lithium diisopropylamine (LDA)) and formula R ^1bQ ¹The reaction of the compound of-Hal makes shielded piperidines carboxyl ester (CXX) in the alpha-position alkylation with respect to the carbonyl of ester, and wherein Hal is a halogen, is preferably bromine, Q ¹Be saturated alkyl.Use alkali metal hydroxide then,, make ester (CXXI) be hydrolyzed into corresponding carboxylic acid (CXXII) as sodium hydroxide.The different amine intermediate of available carboxylic acid (CXXII) preparation certain limit makes the amine intermediate transform the compound of an accepted way of doing sth (I) again.For example, can make carboxylic acid change into acyl chlorides (for example,, perhaps handling the salt of acid), then with reaction of sodium azide, to generate the acid azide (not shown) with oxalyl chloride with the DMF processing of oxalyl chloride and optional catalytic amount.Can heat acid azide then, with in Curtius reaction, reset (referring to AdvancedOrganic Chemistry, the 4th edition, Jerry March, John Wiley ﹠amp; Sons, 1992, the 1091-1092 pages or leaves), obtain the wherein amino compound (CXXIII) that is directly connected to piperidine ring.Make amine (CXXIII) go protection (for example, under the situation of Boc protecting group, using hydrochloric acid) according to standard method subsequently, and with the reaction of the compound of formula (CXIV), obtain the compound of formula (I).

In another kind of reaction sequence, ester (CXXI) can be reduced into corresponding alcohol, after the piperidine ring nitrogen-atoms went protection, alcohol can obtain a kind of alcohol with the compound reaction of formula (CXXI), available Dess-Martin periodinane (referring to, Dess, D.B.; Martin, J.C.J.Org.Soc., 1983,48,4155 and Organic Syntheses, Vol.77,141) or cross ruthenic acid tetrapropyl ammonium (TPAP) this alcohol is oxidized to aldehyde.Utilize sodium cyanoborohydride and amine HNR ²R ³, the aldehyde that obtains can be used for multiple synthetic change, as reductive amination, obtain wherein Q ²Be CH ₂The compound of formula (CXVII).

By with amine HNR ²R ³React above-mentioned being applicable under the condition that forms amido linkage, also can make carboxylic acid (CXXII) change into acid amides.

Gained acid amides (not shown) is reduced in the presence of aluminum chloride with hydride reducer (as lithium aluminum hydride), obtain corresponding amine.

The compound of the sequence of steps preparation formula (CXVII) shown in the available solutions 13, wherein E is a piperidyl, Q ¹Be key, and R ^1bBe aryl or heteroaryl R ^1a

Scheme 13

As shown in figure 13, can make wherein R ^1aBe (PG=protecting group) two (2-chloroethyl) amine reaction of the nitrile (CXXV) of aryl or heteroaryl with alkali and N-protected; to obtain piperidines nitrile (CXXVI); available then Raney nickel is reduced into amine (CXXVII); (for example go subsequently protection; when protecting group is acid labile; use HCl), obtain amine (CXXVIII).Perhaps, the nitrile (CXXVI) and the compound of formula (CXVI) are reacted, obtain wherein Q ²And NR ²R ³Form the compound of the formula (I) of itrile group together.

The also compound of the reaction sequence preparation formula (I) shown in the available solutions 14, wherein E is a piperidine ring, Q ²Be key, and NR ²R ³Be amino.

Scheme 14

Shown in scheme 14, in the presence of titanium tetraethoxide, wherein PG is that protected 4-piperidone (CXXIX) and the tertiary butyl sulfinyl amine (sulphinimide) of protecting group (as Boc) reacts in anhydrous polar solvent (as THF), obtains sulfenimide (CXXX).The reaction general using heats, and for example is heated to the reflux temperature of solvent.Make sulfenimide (CXXX) then and be fit to introduce part R ^1a-Q ¹Organometallic reagent reaction, for example Grignard reagent as bromination aralkyl magnesium or bromination aryl magnesium, obtains sulfinyl amine (CXXXI).Can remove tertiary butyl sulfinyl by hydrolysis in hydrochloric acid/dioxane/carbinol mixture then, obtain amine (XXIV).Subsequently under these conditions, make amine (XXIV) and chloro-substituted heterocyclic ring (XVI) reaction, obtain product (CXXXI), promptly wherein E is a piperidines, Q ²Be key and NR ²R ³Formula (I) compound for amino.

By intermediate (CXXXI) and highly basic (for example metal hydride, as sodium hydride) reaction, add alkylogen (as methyl-iodide) subsequently, can prepare wherein Q from tertiary butyl sulfinyl midbody compound (CXXXI) ²Be key and NR ²R ³Respective compound for alkylamino (for example methylamino).Reaction is generally carried out in low temperature (for example 0-5 ℃) polar aprotic solvent (as dimethyl formamide).

By using the reaction of Suzuki coupling method and above intermediate (XI) (at X ^LDuring for bromine), perhaps use aforesaid method and condition and intermediate (CXIV) reaction (at X ^LBe hydrogen, and group E is when comprising the nucleophilic nitrogen-atoms), can be from formula (CXXXII) and intermediate preparation (CXXXIII) Q wherein ¹The compound that comprises the formula (I) of amido linkage.

In formula (CXXXII) with (CXXXIII), Q ^1aAnd Q ^1bBe respectively key or group Q ¹Residue, and X ^LBe hydrogen or halogen (as bromine).For example, Q ^1aCan be key, and Q ^1bCan be group CH ₂, vice versa.

React by the amine one that makes suitable carboxylic acid or its activated derivatives (for example acyl chlorides) with above-mentioned acid amides formation condition and be fit to, but preparation formula (CXXXII) and compound (CXXXIII).

Part Q wherein ¹The generation of formula (I) compound that comprises amide group is by the reaction sequence explanation shown in the scheme 15.

Scheme 15

In scheme 15, use above-mentioned acid amides formation condition to make the piperidines amino acid (CXXXIV) and arylamines or heteroaryl amine R of boc-protection ^1a-NH ₂Reaction.Therefore, can for example use HATU (on seeing) in the presence of alkali (as the N-ethyl diisopropyl amine), in polar solvent (as DMF), to carry out the acid amides formation reaction.Make acid amides (CXXXV) go protection then; In the case by remove the boc group with acid treatment; In high temperature (for example about 100 ℃) and dicyclo chlorine-containing compound (CXIV) reaction, obtain product (CXXXVII) then.Generally in the presence of non-interference alkali (as triethylamine), in polar solvent (as high-boiling point alcohol, for example propyl carbinol), carry out with the reaction of chlorine-containing compound.

Utilization is similar to above to Q ¹Comprise the described method of compound of amido linkage, can prepare wherein Q ¹Formula (I) compound that comprises ehter bond.Reaction sequence shown in the scheme 16 has illustrated the preparation of the compound that comprises ehter bond.

Scheme 16

In scheme 6, generally in polar aprotic solvent (as tetrahydrofuran (THF)), the piperidines amino acid (CXXXIV) of N-protected is reduced into corresponding alcohol (CXXXVIII) with reductive agent (as lithium aluminum hydride) near room temperature.Use highly basic (for example metal hydride, as sodium hydride) to handle alcohol (CXXXVIII) then, to generate alcoholate, then with alcoholate and arylmethyl bromine or heteroaryl monobromomethane R ^1a-CH ₂-Br reaction generates ether (CXXXIX).Become the ether reaction generally to carry out with aprotic polar solvent (as DMF) at low temperature (for example about 0 ℃).Make ether go protection by standard method then, and de-protected ether (CXL) and chlorine-containing compound (CXIV) are reacted under these conditions, obtain product (CXLI).

In case generate, the compound of a lot of formulas (I) be transformed into the compound of other formulas (I) with regard to available standards functional group change method.For example, can be with NR wherein ²R ³Formula (I) compound that forms the part of itrile group is reduced into corresponding amine.Can make wherein NR by reductive alkylation ²R ³Be NH ₂The compound of base changes into corresponding alkylamine, perhaps changes into cyclic group.By the Suzuki linked reaction, can utilize wherein R ^1aThe compound that comprises halogen atom (as chlorine or bromine) is introduced R with aryl or heteroaryl substituting group ^1aGroup.Other examples of the another kind of compound of a kind of compound change accepted way of doing sth (I) of formula (I) can be found in the following example.Carry out the functional group's change of this transformation and the other example of reagent and condition and can be found in for example Advanced Organic Chemistry, by JerryMarch, 4 ^ThEdition, 119, Wiley Interscience, New York, Fiesers ' Reagentsfor Organic Synthesis, Volumes 1-17, John Wiley, edited by MaryFieser (ISBN:0-471-58283-2) and Organic Syntheses, Volumes 1-8, JohnWiley, edited by Jeremiah P.Freeman (ISBN:0-471-31192-8).

In a lot of above-mentioned reactions, one or more groups that may need protection react to prevent the position that do not cater to the need on molecule.The example of protecting group and protective group and de-protected method can be found in Protective Groups in Organic Synthesis (T.Green and P.Wuts; 3rd Edition; John Wiley and Sons, 1999).

For example; can be that ether is (OR) or ester (OC (=O) R), for example as tertbutyl ether, benzylic ether, dibenzyl ether (diphenyl methyl ether) or trityl ether (trityl group ether), trimethyl silyl ether or t-butyldimethylsilyl ether or ethanoyl ester (OC (=O) CH with hydroxyl protection ₃,-OAc).For example, the aldehydes or ketones base can be protected respectively and be acetal (R-CH (OR) ₂) or ketal (R ₂C (OR) ₂), wherein carbonyl (＞C=O) by changing into diether (＞C (OR) with the reaction of primary alconol for example ₂).By in the presence of acid, using high excessive water hydrolysis, can be easy to make the regeneration of aldehydes or ketones base.For example, can with amido protection for acid amides (NRCO-R) or carbamate (NRCO-OR), for example as methyl nitrosourea (NHCO-CH ₃), benzyl oxygen base acid amides (NHCO-OCH ₂C ₆H ₅,-NH-Cbz), 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), (NH-Fmoc), (NH-Nvoc), 2-trimethyl silyl ethyl oxygen base acid amides (NH-Teoc), 2 for 6-nitro veratryl oxygen base acid amides for 9-fluorenyl methoxy acid amides; 2,2-three chloroethyl oxygen base acid amides (NH-Troc), allyl group oxygen base acid amides (NH-Alloc) or 2-(phenyl sulfonyl) ethyl oxygen base acid amides (NH-Psec).Other protecting groups of amine (as cyclammonium and heterocycle N-H group) comprise tosyl group (tolylsulfonyl) and methane sulfonyl (methylsulfonyl) and benzyl (as to methoxy-benzyl (PMB)).The hydroxy-acid group protection can be ester, for example C _1-7Alkyl ester (for example methyl esters, the tert-butyl ester), C _1-7Haloalkyl ester (C for example _1-7The tri haloalkyl ester), three C _1-7Alkyl silyl-C _1-7Alkyl ester or C _5-20Aryl-C _1-7Alkyl ester (for example benzyl ester, nitrobenzyl ester), perhaps protection is acid amides (for example methyl nitrosourea).The thiol group protection (SR), for example as the benzyl thioether, perhaps can be protected to be acetylamino methyl ether (S-CH for for example thioether ₂NHC (=O) CH ₃).

A lot of above-mentioned chemical intermediates are new, and this type of new intermediate forms another aspect of the present invention.

Pharmaceutical preparation

Though active compound can be individually dosed, but preferably be rendered as a kind of pharmaceutical composition (for example preparation), described pharmaceutical composition comprises at least a active compound of the present invention and one or more pharmaceutically acceptable carriers, assistant agent, vehicle, thinner, weighting agent, buffer reagent, stablizer, sanitas, lubricant or other materials well-known to those having ordinary skill in the art and optional other treatment agent or preventive.

Therefore, the present invention also provides the pharmaceutical composition of above qualification, and the method for pharmaceutical compositions, described method comprises mixing active compound and one or more pharmaceutically acceptable carriers, vehicle, buffer reagent, assistant agent, stablizer or other materials described herein of more than one qualifications at least.

Term used herein " pharmaceutically acceptable " is meant in the appropriate medical care determination range, is fit to contact with experimenter's (for example people) tissue and the compound, material, composition and/or the formulation that do not have undue toxicity, stimulation, anaphylaxis or other problems or complication, match with reasonable terrible ratio.On the meaning compatible with other compositions of preparation, each carrier, vehicle etc. also must be " acceptable ".

The pharmaceutical composition that comprises formula (I) compound can be prepared according to known technology, referring to for example Remington ' s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

Therefore, the present invention provides formula (I) compound and the subgroup thereof that this paper of pharmaceutical compositions limits on the other hand.

Pharmaceutical composition can for anyly be fit in oral, parenteral, part, the nose, the form of medicament for the eyes, ear, rectum, intravaginal or transdermal administration.When composition is intended for parenteral admin, can directly import Target organ or tissue is prepared them for intravenously, intramuscular, intraperitoneal, subcutaneous administration or by injection, infusion or other mode of movements.Loading can by inject, short-term infusion or longer-term infusion, and can pass through passive loading, perhaps utilize the infusion pump that is fit to carry out.

The pharmaceutical preparation that is applicable to parenteral admin comprises moisture and non-water aseptic parenteral solution, injection liquid can comprise antioxidant, buffer reagent, fungistat, solubility promoter, 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 gel polymer that is used to form polymer gel, freeze-drying protective agent and be used for especially making activeconstituents stable and give and expect that recipient's blood etc. oozes the combination of each agent of preparation with soluble form.The pharmaceutical preparation that is used for parenteral admin also can be taked the form of the aseptic suspensoid of moisture and non-water, suspensoid can comprise suspension agent and thickening material (R.G.Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21 (2) 2004, p 201-230).

Serve as reasons outside lipid bilayer and inner moisture nuclear of liposome is formed and have＜the closed spherical vesicles of 100 μ m overall diameters.According to the hydrophobicity level, seal or embed in the liposome if medicine becomes, then can make appropriate hydrophobic drug solubilising by liposome.If drug molecule becomes the intact part of lipid bilayer, also can make the hydrophobic drug solubilising by liposome, in the case, hydrophobic drug is dissolved in the fat part of lipid bilayer.

Described preparation can be presented in unitary dose or the multi-dose container, for example Mi Feng ampoule and bottle, and can be stored in lyophilize (freeze-drying) condition, only need just add before use sterile liquid carrier, for example water for injection.

Can be by compound or its subgroup useful in preparing drug formulations of freeze-drying formula (I).Freeze-drying is meant the step of freeze-dried composition.Therefore, lyophilize and freeze-drying are synonym in this article.

Interim injection liquid and suspensoid can be used sterilized powder, particle and sheet preparation.

The pharmaceutical composition of the present invention that is used for parenteral injection also can comprise pharmaceutically acceptable aseptic moisture or non-aqueous solution, dispersion, suspensoid or emulsion and the sterilized powder that is used for just reassembling into before use sterile injectable solution or dispersion.The example of moisture and nonaqueous carrier, thinner, solvent or the vehicle that is fit to comprises water, ethanol, polyvalent alcohol (as glycerine, propylene glycol, polyoxyethylene glycol etc.), carboxymethyl cellulose and suitable mixture, vegetables oil (as sweet oil) and injectable organic ester (as ethyl oleate) thereof.By for example using coating (as Yelkin TTS), keep required granular size (under the situation of dispersion) and using tensio-active agent, can keep the flowability that is fit to.

Composition of the present invention also can comprise assistant agent, as sanitas, wetting agent, emulsifying agent and dispersion agent.By comprising various antiseptic-germicides and anti-mycotic agent, for example parabens, trichloro-butyl alcohol, phenol Sorbic Acid etc. can guarantee to suppress microbial process.Comprise isotonic agent and also may cater to the need, as sugar, sodium-chlor etc.By comprising the medicament that postpones absorption, also can prolong the absorption of injectable drug formulation, as aluminum monostearate and gelatin.

In an embodiment preferred of the present invention, pharmaceutical composition is the formulation that is applicable to intravenously administrable, for example injection or infusion.For intravenous administration, but the medication of solution former state perhaps can be injected before administration in the infusion bag (comprising pharmaceutically acceptable vehicle, as 0.9% salt solution or 5% glucose).

In another preferred embodiment, pharmaceutical composition is for being applicable to the formulation of subcutaneous (s.c.) administration.

The pharmaceutical dosage form that is applicable to oral administration comprises tablet, capsule, Caplet, pill, dragee, syrup, solution, powder, particle, elixir and suspensoid, sublingual tablet, wafer or patch and mouth paster.

Therefore, tablet composition can comprise unit dose of active compound and inert diluent or carrier, as sugar or sugar alcohol, and for example lactose, sucrose, sorbyl alcohol or N.F,USP MANNITOL; And/or non-sugared deutero-thinner, as yellow soda ash, calcium phosphate, lime carbonate or Mierocrystalline cellulose or derivatives thereof, as methylcellulose gum, ethyl cellulose, Vltra tears and starch (as W-Gum).Tablet also can comprise these standard analysis, as tackiness agent and granulating agent (as polyvinylpyrrolidone), disintegrating agent (for example, the cross-linked polymer of swellable is as crosslinked carboxymethyl cellulose), lubricant (for example stearate), sanitas (for example p-Hydroxybenzoate), antioxidant (for example BHT), buffer reagent (for example phosphoric acid salt or citrate buffer agent) and effervescent (as Citrate trianion/bicarbonate mixture).This type of vehicle is familiar with by those skilled in the art, does not need to go through at this.

Capsule can be glutoid or soft gelatin kind, and can comprise the active ingredient of solid, semisolid or liquid form.Gelatine capsule can be formed by animal gelatin or synthetic gelatin or the suitable thing of its plant derivation.

Solid dosage (for example tablet, capsule etc.) but dressing or dressing not but generally have coating, for example protectiveness film coating (for example wax or paint) or controlled releasing coating.Can be with coating (Eudragit for example ^TMType polymer) is designed to desired location release active ingredient in gi tract.Therefore, can select to degrade under coating some pH condition in gi tract, thereby in stomach or ileum or duodenum, select to discharge compound.

Replace outside coating or the removing coating, medicine can present in solid substrate, and solid substrate comprises control-released agent, for example can be adapted at selecting to discharge under different acidity in the gi tract or the basicity condition release retardant of compound.Perhaps, substrate substance or hang-over n. coating can be taked the form of erodable polymkeric substance (for example maleic anhydride polymkeric substance), the erodable polymkeric substance formulation during by gi tract essence suffer erosion continuously.Select as another kind, can permeate the medicine releasing system form preparation active compound that the control compound discharges.Can discharge and other slowly-releasings or extended release preparation according to method preparation infiltration well known to those skilled in the art.

Pharmaceutical composition comprises about 1% to about 95% activeconstituents, and preferred about 20% to about 90%.Pharmaceutical composition of the present invention can be for example unit dosage, for example ampoule, bottle, suppository, coated tablet, tablet or Capsule form.

Mix with solid carrier by activeconstituents,, and if desired or necessary, after adding the vehicle that is fit to, mixture is processed into tablet, sugar-coat label or capsule, can obtain being used for pharmaceutical composition for oral administration if desired with the gained granulating mixture.Also they can be joined and allow in the plasticity carrier of activeconstituents with measured quantity diffusion or release.

Compound of the present invention also can be formulated as solid dispersion.Solid dispersion is the even superfine disperse phase of two or more solid.Sosoloid (molecular dispersion system), a kind of solid dispersion is known and is used for pharmaceutical technology (referring to (Chiou and Riegelman, J.Pharm.Sci., and be used to increase the dissolution rate and the bioavailability of poorly water soluble drugs 60,1281-1300 (1971)).

The present invention also provides the solid dosage that comprises above-mentioned sosoloid.Solid dosage comprises tablet, capsule and chews sheet.Can be with known vehicle and sosoloid blend, so that required formulation to be provided.For example, capsule can comprise and (a) disintegrating agent and lubricant, or (b) sosoloid of disintegrating agent, lubricant and tensio-active agent blend.Tablet can comprise the sosoloid with at least a disintegrating agent, lubricant, tensio-active agent or glidant blend.Chew sheet and can comprise sosoloid with swelling agent, lubricant and other sweeting agent (if desired) (as artificial sweetening agent) and the correctives blend that is fit to.

Pharmaceutical preparation can " patient's bag " be to the patient, and " patient's bag " comprises the whole course of treatment in single packing (normally Blister Package).The advantage that patient bag surpasses tradition prescription (the pharmacist from large quantities of during for medicine distribution patient medicine) is that the patient always contacts the packing inset that comprises that does not normally reach in patient's prescription in patient's bag.Shown that comprising the packing inset impels the patient to be obedient to doctor's doctor's advice.

The composition that is used for local application comprises ointment, creme, sprays, patch, gelifying agent, dropping liquid agent and slotting agent (for example intraocular is inserted agent).Can prepare this based composition according to currently known methods.

The examples of formulations that is used for rectum or intravaginal administration comprises vaginal suppository and suppository, this type of suppository can be by the shaping that for example comprises active compound moldable or waxy substance form.

The composition that is used for inhalation can take to suck the form of powder composition or liquid or powder spray agent, and available powder inhalation device or aerosol dispensing device are with the standard dosage forms administration.This type of device is familiar with by those skilled in the art.About inhalation, powderous preparations generally comprises active compound and inert solid powdery thinner (as lactose).

The compound of formula (I) generally presents with unit dosage, therefore, generally comprises enough compounds that required biologically active level is provided.For example, preparation can comprise 1 nanogram(ng) to 2 gram activeconstituents, for example 1 nanogram(ng) to 2 milligram activeconstituents.In this scope, the compound of specific inferior scope be 0.1 milligram to 2 gram activeconstituentss (more generally 10 milligrams to 1 gram, for example 50 milligrams to 500 milligrams), perhaps 1 microgram to 20 milligram (for example 1 microgram to 10 milligram, for example 0.1 milligram to 2 milligrams activeconstituents).

For composition for oral administration, unit dosage can comprise 1 milligram to 2 the gram active compounds, more general 10 milligrams to 1 the gram, for example 50 milligrams to 1 the gram, for example 100 milligrams to 1 the gram.

Can obtain patient (for example human or animal patient) active compound that the q.s of required result of treatment needs.

Protein kinase inhibiting activity

Test determination The compounds of this invention described in available following examples is as the activity of the inhibitor of protein kinase A and protein kinase B, and the activity level of specific compound performance can be used the IC50 value representation.

Preferred compound of the present invention is the IC that has less than the anti-protein kinase B of 20 μ M ₅₀The compound of value is more preferably less than 10 μ M.

Therepic use

Prevention or treatment propagation are sick

The compound of formula (I) is the inhibitor of protein kinase A and protein kinase B.With regard to this point, can expect provides the method that prevents the knurl growth or induce apoptosis of tumor with them.Therefore, but expecting compound is used for the treatment of or prevent propagation sick, as cancer.Particularly, having the tumour that disappearance or inactivation suddenly change or PTEN expresses or reset forfeiture in (T-cell lymphocyte) TCL-1 gene in PTEN may be especially to PKB inhibitor sensitivity.Have other unusual tumours that cause incremental adjustments PKB approach signal also may be especially to the inhibitor sensitivity of PKB.This type of unusual example includes but not limited to the overexpression of one or more PI3K subunits, the overexpression of one or more PKB isotypes, or the PI3K that causes described enzyme basis activity to increase, PDK1 or PKB sudden change, or the incremental adjustments of growth factor receptors or overexpression or sudden change activation, these growth factor receptorses are as being selected from Cuticle of cell growth factor receptors (EGFR), fibroblast growth factor acceptor (FGFR), platelet derived growth factor receptor (PDGFR), the growth factor receptors of type-1 insulin like growth factor acceptor (IGF-1R) and each family of vascular endothelial growth factor receptor (VEGFR).

Also can imagine compound of the present invention and be used for the treatment of other illnesss that cause by for example propagation or the disease (as virus infection) that causes of survival and neurodegenerative disease.PKB keeps playing an important role in the immunocyte survival during immune response, and therefore, the PKB inhibitor can usefully especially be used for Immunological diseases, comprises autoimmune disease.

Therefore, the PKB inhibitor can be used for treating wherein propagation, apoptosis or the disorderly disease of differentiation.

The PKB inhibitor also can be used for destroying the disease that causes, for example metabolic trouble and obesity by insulin resistant and insensitivity and glucose, energy and fat stores.

The example of quenchable cancer includes but not limited to cancer, bladder cancer for example, mammary cancer, colorectal carcinoma (colorectal carcinoma for example, as adenocarcinoma of colon and adenoma of colon), kidney, epidermal carcinoma, liver cancer, lung cancer (gland cancer for example, small cell lung cancer and nonsmall-cell lung cancer), the esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas (for example exocrine pancreas cancer), cancer of the stomach, cervical cancer, carcinoma of endometrium, thyroid carcinoma, prostate cancer or skin carcinoma (for example squamous cell carcinoma), hematopoietic system cancer (acute myelocytic leukemia for example, acute promyelocyte leukemia, acute lymphoblastic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia and other B-cell lympahadenisms), myelodysplastic syndrome, T-cell lympahadenism (comprises the disease that is derived from natural killer cell, non_hodgkin lymphoma (Non-Hodgkin ' s lymphoma) and Hodgkin's disease (Hodgkin ' s disease)), the multiple myeloma of Bortezomib susceptibility and refractory, no matter the disease of hematopoietic system of abnormal cell proliferation (is precancer or stable, for example myeloproliferative disease comprises polycythemia vera, primary thrombocytosis and PMF), hairy cell leukemia or uncle's basic lymphoma (Burkett ' s lymphoma), the hematopoietic system cancer of marrow system (acute and chronic myelomatosis for example, myelodysplastic syndrome or promyelocyte leukemia), thyroid follcular carcinoma, the tumour (for example fibrosarcoma or rhabdosarcoma) in mesenchyme source, the tumour of central nervous system or peripheral nervous system (astrocytoma for example, neuroblastoma, neurospongioma or Scs knurl (schwannoma), melanoma, spermocytoma, teratoma, osteosarcoma, xeroderma pitmentosum, keratoacanthoma, thyroid follcular carcinoma or Kaposi sarcoma (Kaposi ' s sarcoma).

Therefore be used for the treatment of in pharmaceutical composition, purposes or the method for the disease that comprises abnormal cell growth or illness in the present invention, comprise that in one embodiment the disease of abnormal cell growth or illness are cancer.

The special subgroup of cancer comprises mammary cancer, ovarian cancer, colorectal carcinoma, prostate cancer, esophagus cancer, squama cancer and nonsmall-cell lung cancer.

Another subgroup of cancer comprises mammary cancer, ovarian cancer, prostate cancer, carcinoma of endometrium and neurospongioma.

Some protein kinase B inhibitors also can be used in combination with other carcinostatic agents.For example, can be valuably with the inhibitor of cell death inducing and the another kind of medicament combination of doing by different mechanisms in order to the growth of adjusting cell, the cancer of therefore treating two kinds of features takes place.The example of this type of combination is as described below.

Immunological diseases

The Immunological diseases of PKA and the useful treatment of PKB inhibitor possibility include but not limited to autoimmune disease and chronic inflammatory disease (for example glomerulonephritis, rheumatoid arthritis, psoriatic, inflammatory bowel and the autoimmune diabetes of systemic lupus erythematous, autoimmunization mediation), eczema allergy, asthma, COPD, rhinitis and upper respiratory disease.

The other treatment purposes

PKB is at apoptosis, work in propagation and the differentiation, so the PKB inhibitor also can be used for treating cancer and relevant disease in addition with immunologic function disorder, viral infection (simplexvirus for example, poxvirus, Ai Ba (Epstein-Barr) virus, Xin Peisi (Sindbis) virus, adenovirus, HIV, HPV, HCV and HCMV), suppress the AIDS development of HIV infected patient, cardiovascular disorder (cardiac hypertrophy for example, restenosis, atherosclerosis), neurodegenerative disease (alzheimer's disease (Alzheimer ' s disease) for example, AIDS dependency dementia, Parkinson's disease (Parkinson ' s disease), amyotrophic lateral sclerosis (amyotrophic lateralsclerosis), retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration, glomerulonephritis, myelodysplastic syndrome, the myocardial infarction that ischemia injury is relevant, apoplexy and reperfusion injury, the degenerative disease of musculoskeletal system (for example osteoporosis and sacroiliitis), the Asprin allergic sinusitis, cystic fibrosis, multiple sclerosis, ephrosis.

Methods of treatment

Can imagine the compound prevention of the formula (I) that limits with this paper and subgroup thereof or treatment disease or illness by the certain limit of protein kinase A and/or protein kinase B mediation.The example of this type of disease and illness as mentioned above.

Compound generally needs the experimenter of this administration, for example human or animal patient, preferably administration of human.

Compound is generally with treatment or prevent useful and be generally atoxic amount administration.(for example under the situation of life-threatening disease) yet in some cases, the benefit of giving construction (I) compound may surpass the unfavorable of toxic action or side effect, in this case, can think to cater to the need to follow to a certain degree toxic amount to give compound.

In order to keep useful result of treatment, can give compound for a long time, perhaps can a short-term give.Perhaps give with pulse or continuous mode.

Dosage every day of general expression (I) compound can be 100 pico-gram to 100 mg/kg body weight, more general 5 nanogram(ng) to 25 mg/kg body weight, 10 nanogram(ng) to 15 mg/kg (10 nanogram(ng)s to 10 milligram for example more generally, more general 1 microgram/kilogram is to 20 mg/kg, 1 microgram to 10 mg/kg for example)/and kg body weight, although can give higher or lower dosage when needed.For example, formula (I) but compound administration every day, perhaps by per 2 or 3 or 4 or 5 or 6 or 7 or 10 or 14 or 21 or 28 days repeat administrations.

Compound of the present invention can be by the administration of certain limit oral dose, and for example 1 to 1500mg, and 2 to 800mg, or 5 to 500mg, and for example 2 to 200mg or 10 to 1000mg, and the special example of dosage comprises 10,20,50 and 80mg.Compound can be once a day or every day more than single administration.But compound successive administration (that is, take medicine every day treatment plan extended period, do not interrupt).Perhaps, intermittently administration of compound promptly during whole treatment plan, is taken medicine through the fixed time (as a week) continuously, interrupts through for some time (as a week) then, and then takes medicine continuously through another section period (as a week), and is like that.Comprise that intermittently the example of the treatment plan of administration comprises these treatment plans, wherein the administration cycle is that a week is continuous, and a week interrupts; Perhaps fortnight continuous, a week interrupts; Perhaps three weeks continuous, a week interrupts; Perhaps fortnight continuous, fortnight interrupts; Perhaps four weeks continuous, fortnight interrupts; Perhaps a week continuous, interrupt one or more cycles of administration like this, for example 2,3,4,5,6,7,8,9 or 10 or more a plurality of cycle three weeks.

In a specific scheme of taking medicine, give the compound of patient's infusion formula (I) through 1 hour every day of maximum 10 days (particularly maximum 5 days an of week), and treat and repeat at interval with required time, as two to four weeks, especially per timed interval in three weeks.

More particularly, can give the compound of patient's infusion formula (I) through 5 day 1 hour every day, and treatment repeated with per three week.

In another specific scheme of taking medicine, give patient's infusion 30 minutes to 1 hour, keep the infusion variable time subsequently, for example 1 to 5 hour, as 3 hours.

In another specific scheme of taking medicine, give patient's continuous infusion 12 hours to 5 days, especially continuous infusion is 24 hours to 72 hours.

Yet the type that finally gives the amount of compound and composition therefor should be suitable with disease character or the physiological situation that will treat, and judge according to the doctor and to decide.

The compound that this paper limits can be used as unique therapeutical agent administration, perhaps with one of more other compounds for the treatment of specified disease (for example tumor disease, cancer as described above) combined therapy administration.Can include but not limited to the other treatment agent of formula (I) compound administration (no matter simultaneously still with the different time interval) or the example of treatment:

The topoisomerase I inhibitor

Antimetabolite

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 therapy

Radiotherapy, and

Other treatment or preventive for example reduce or alleviate the medicament of some side effects relevant with chemotherapy.The specific examples of this type of agent comprises antiemetic, with stop or reduce that the relevant neutrophilic leukocyte of chemotherapy reduces the disease time length and the medicament of the complication that prevents to be caused by red corpuscle or the minimizing of white corpuscle amount, for example erythropoietin (EPO), rHuGM-CSF (GM-CSF) and granulocyte-colony stimulating factor (G-CSF).Comprise the medicament that suppresses bone resorption equally, as the diphosphonate agent, for example Zoledronic acid salt, pamldronate and ibandronate; The medicament that suppresses Inflammatory response is as dexamethasone, prednisone and prednisolone; And the medicament that reduces acromegaly blood samples of patients tethelin and IGF-I level, brain hormones somatostatin as synthesized form, comprise Sostatin LAR, this is a kind of long term octapeptide with pharmacological properties of simulating the natural hormone somatostatin.Also comprise for example medicament of formyl tetrahydrofolic acid, this medicament is as the toxinicide of the medicine that reduces folate level; Or formyl tetrahydrofolic acid itself and the medicament that can be used for treating the side effect that comprises oedema and thromboembolic events, as Magace.

Can and can be present in every kind of compound in the present invention's combination by the scheme of taking medicine of independent variation by different approaches.

When the compound of formula (I) and a kind of, two kinds, three kinds, four kinds or more kinds of other treatment agent (preferred a kind of or two kinds, more preferably a kind of) combined therapy administration, compound can be simultaneously or administration successively.When administration successively, they can tight spacings (for example through 5-10 minute) or longly (for example separate 1,2,3,4 or more hours, or separate when needed even the longer time) administration at interval, and accurate dosage regimen should match with the character of therapeutical agent.

The compound of the present invention administration that also can combine with for example radiotherapy, photodynamic therapy, gene therapy, surgical operation and the therapy for treating of keeping on a diet etc. non-chemically.

For with another kind of chemotherapeutic combined therapy, the compound of formula (I) and a kind of, two kinds, three kinds, four kinds or more kinds of other treatment agent can be for example preparation together in comprising the formulation of two kinds, three kinds, four kinds or more kinds of therapeutical agents.Perhaps, independent therapeutical agent can separately be prepared, and presents together with kit form, the optional working instructions of putting into.

Those skilled in the art will understand therapeutic regimen and use combined therapy by his or her general general knowledge.

Diagnostic method

Before the compound administration of formula (I), but the examination patient, to determine whether disease or illness that the patient is just suffering from or may just suffer from are disease or the illnesss that has anti-protein kinase A and/or the active compounds for treating sensitivity of protein kinase B to using.

For example, can analyze the biological sample of getting from the patient, to determine whether disease or illness (as cancer) that the patient is just suffering from or may just suffer from are the disease or the illness of gene unconventionality or paraprotein expression characteristic, gene unconventionality or paraprotein are expressed and are caused PKA and/or PKB incremental adjustments, perhaps cause the active approach sensitivity of normal PKA and/or PKB, the signal transduction composition incremental adjustments that perhaps causes PKA and/or PKB upstream is for example at PKB, P13K, GF acceptor and PDK 1﹠amp; Under 2 the situation.

Perhaps, can analyze the negative regulator or suppressor gene (as the PTEN) forfeiture of the PKB approach of the biological sample of getting from the patient.In this article, term " forfeiture " comprises the disappearance of the gene of compiling adjusting albumen or suppressor gene, the cut-out of the cut-out of gene (for example sudden change), gene transcription product, the perhaps inactivation of transcription product (for example by point mutation) or by another kind of gene product combination.

The term incremental adjustments comprises improving to be expressed or overexpression, comprises gene amplification (that is polygene copy) and increases expression and hyperaction and activation (comprising by the sudden change activation) by transcribing effect.Therefore, can carry out diagnostic test, to detect the flag sign of PKA and/or PKB incremental adjustments to the patient.The term diagnosis comprises examination.Sign comprises the gene sign, comprises that for example detecting DNA forms, with the sudden change of identification PKA and/or PKB.The term sign also comprises the sign with PKA and/or PKB incremental adjustments feature, comprises enzymic activity, enzyme level, enzyme attitude (for example phosphorylation or non-phosphorylating) and aforementioned proteic mRNA level.

Generally the biological sample that is selected from tumour biopsy sample, blood sample (separation of the tumour cell that comes off and enrichment), ight soil biopsy, phlegm, chromosome analysis, pleura fluid, peritonaeum fluid or urine is carried out above diagnostic test and examination.

Definite individuality carries PKA and/or PKB sudden change or TCL-1 resets or PTEN expression forfeiture may mean that the patient is particularly suitable for PKA and/or PKB inhibitor for treating.Can be before treatment the PKA of preferential examination tumour and/or the existence of PKB variant.Screening method generally comprises direct order-checking, oligonucleotide is analyzed or the mutant specific antibody for little gust.

The identification and the analytical procedure of protein mutation and incremental adjustments are familiar with by those skilled in the art.Screening method includes but not limited to standard method, as reversed transcriptive enzyme polymerase chain reaction (RT-PCR) or in situ hybridization.

By in the RT-PCR examination,, assess the level of mRNA in the tumour subsequently by pcr amplification cDNA by producing the cDNA copy of mRNA.The condition of the amplification method of PCR, selection of primers and amplification is familiar with by those skilled in the art.Nucleic acid operation and PCR are undertaken by standard method, as Ausubel, and F.M.et al., eds., Current Protocolsin Molecular Biology, 2004, John Wiley ﹠amp; Sons Inc., or Innis, M.A.et-al., eds., PCR Protocols:a guide to methods and applications, 1990, Academic Press, San Diego is described.The reaction and the operation that comprise the nucleic acid technology also are described in people such as Sambrook, 2001,3 ^RdEd, Molecular Cloning:A LaboratoryManual, Cold Spring Harbor Laboratory Press.Perhaps can use the commercial reagent box (for example Roche Molecular Biochemicals) of RT-PCR, perhaps can use 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 described methods, these patents are attached to herein by reference.

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

General in situ hybridization comprises following key step: (1) fixes tissue to be analyzed; (2) hybridization pre-treatment sample with the accessibility of increase target nucleic acid, and reduces non-specific combination; (3) mixture of nucleic acid is hybridized to nucleic acid in biological structure or the tissue; (4) post-hybridization washing is to remove not bonded nucleic acid fragment in hybridization; (5) detection is through the nucleic acid fragment of hybridization.The probe general use case such as radio isotope or the fluorescence reporter gene mark that in this uses, use.Preferred probes is a sufficiently long, and for example about 50,100 or 200 Nucleotide are to about 1000 or more a plurality of Nucleotide, so that can use the target nucleic acid specific hybridization under stringent condition.The standard method of carrying out FISH is described in Ausubel, F.M.et al., eds., Current Protocols in MolecularBiology, 2004, John Wiley ﹠amp; Sons Inc. and Fluorescence In SituHybridization:Technical Overview by John M.S.Bartlett in MolecularDiagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN:1-59259-760-2; March 2004, pps.077-088; Series:Methods inMolecular Medicine.

Perhaps, can assess by the following method from mRNA expressed proteins product: the immunohistochemistry of tumor sample, carry out solid-phase immunoassay, Western blotting, two-dimentional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and measuring the known additive method in differential protein field with microtiter plate.Measuring method comprises use site-specific antibody.Those skilled in the art will appreciate that and to use all these known technologies of measuring the PKB incremental adjustments or measuring the PKB variant in the present circumstance.

Therefore, also available all these technology identifications are particularly suitable for the tumour with PKA and/or PKB inhibitor for treating.

For example, as mentioned above, found PKB β in the ovarian cancer of 10-40% and carcinoma of the pancreas incremental adjustments (people 1995 such as Bellacosa, Int.J.Cancer 64,280-285; People such as Cheng 1996, PNAS 93,3636-3641; People such as Yuan 2000, Oncogene 19,2324-2330).Therefore, can imagine with PKB inhibitor (the particularly inhibitor of PKB β) treatment ovarian cancer and carcinoma of the pancreas.

PKB α increases in people's cancer of the stomach, prostate cancer and mammary cancer, and (Staal 1987, PNAS84,5034-5037; People such as Sun 2001, Am.J.Pathol.159,431-437).Therefore, can imagine cancer of the stomach, prostate cancer and the mammary cancer for the treatment of the people with PKB inhibitor (the particularly inhibitor of PKB α).

In mammary gland that does not rely on steroid and prostate cell line, observed increase the PKB gamma activity (Nakatani et al 1999, J.Biol.Chem.274,21528-21532).Therefore, can imagine mammary cancer and the prostate cancer that does not rely on steroid with PKB inhibitor (the particularly inhibitor of PKB γ) treatment.

Test

About the specific embodiments described in following steps and the embodiment the present invention is described now, but the invention is not restricted to these embodiments.

The raw material that each step of the following stated is used can be buied, unless stipulate in addition.

In an embodiment, the compound of preparation utilize following system and operational condition by liquid chromatography, mass spectrum and ¹The H nuclear magnetic resonance spectrum characterizes.

Unless otherwise indicated, at 27 ℃, Me-d ₃Write down on the BrukerAV400 instrument of-OD and 400.13MHz operation proton resonance ( ¹H NMR) spectrum, and following report: chemical shift δ/ppm (proton number, multiplicity, unimodal at this s=, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad peak).With remaining protonic solvent MeOH (δ _H=3.31ppm) as interior mark.

For mass spectrum, when having chlorine, the quality that compound is quoted is right ³⁵Cl.

In each embodiment, be free alkali or when generating in compound separation as free alkali, they can be changed into salt form, as acetate or hydrochloride.On the contrary, be salt or when generating in compound separation as salt, can salt be changed into corresponding free alkali by method well-known to those having ordinary skill in the art, optionally then change into another kind of salt.

Use in test some liquid chromatographic systems, below describe these systems.

LCT system 1

HPLC system: Waters Alliance 2795 separation modules

Mass detector: Waters/Micromass LCT

UV detector: Waters 2487Dual λ absorption photometric detector

The polarity analysis condition:

Elutriant A: methyl alcohol

The formic acid of elutriant B:0.1% 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

Ionization pattern :+ve/-ve electrospray ESI (Lockspray ^TM)

LCT system 2

HPLC system: Waters Alliance 2795 separation modules

Mass detector: Waters/Micromass LCT

UV detector: Waters 2487Dual λ absorption photometric detector

Analysis condition:

Elutriant A: methyl alcohol

The formic acid of elutriant B:0.1% 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 C18 5cm * 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 electrospray ESI (Lockspray ^TM)

In following examples, in order to following keyword identification LCMS condition

The LCT1 LCT 1-of system polarity analysis condition

The LCT2 LCT 2-of system polarity analysis condition

General step

Method 1

4-bromobenzaldehyde in toluene (3g, 16.21mmol) and ethyl cyanacetate (1.9ml, 17.84mmol, 1.1 equivalents) add piperidines (27 μ l), utilize Dean Rodney Stark (Dean-Stark) separator with reaction mixture refluxed 1 hour.Under reduced pressure remove and desolvate, resistates is ground with warm ethyl acetate, filter and obtain required product, be a kind of yellow solid.

Method 2

(1.5g, 5.36mmol) drips of solution in dry toluene (12ml) is added to 0 ℃ bromination 4-chloro-phenyl-magnesium (solution of 0.5M in tetrahydrofuran (THF), 6.96ml, 6.96mmol, 1.3 equivalents) with 3-(4-bromophenyl)-2-cyanacrylate.Reaction mixture was heated to 85 ℃ of experience 3 hours, is poured on ice,, and use ethyl acetate extraction with 1N HCl acidifying.Organic layer is separated dry (MgSO ₄), filtering and concentrate, crude product obtains required product by the quick silicon-dioxide chromatography purifying with petroleum ether-ethyl acetate/sherwood oil (5: 95) wash-out.

Method 3

With 3-(4-bromophenyl)-3-(4-chloro-phenyl-)-2-cyanopropionate (1.91,4.87mmol), the mixture of acetate (10ml), the vitriol oil (5ml) and water (5ml) refluxed 2 hours.Reaction mixture is poured in the frozen water, and used ethyl acetate extraction.Organic layer is separated dry (MgSO ₄), filtering and concentrate, crude product obtains required product by the quick silicon-dioxide chromatography purifying with ethyl acetate/petroleum ether (1: 1) wash-out.

Method 4

Adding the ammonia (solution of 2N in methyl alcohol, 0.74ml, 1.47mmol, 2.0 equivalent) and 1-(3-dimethylaminopropyl)-ethyl-carbodiimide hydrochloride (0.17g, 0.88mmol, 1.2 equivalents) before, with 3-(4-bromophenyl)-3-(4-chloro-phenyl-)-propionic acid (0.25g, 0.74mmol) and I-hydroxybenzotriazole (benatriazole) (0.12g, 0.88mmol) mixture in methylene dichloride (3ml) stirred 15 minutes.Reaction mixture was stirred 16 hours, under reduced pressure remove then and desolvate, resistates distributes between ethyl acetate and 1N HCl.Organic layer is separated, with saturated sodium bicarbonate, salt water washing, dry (MgSO ₄), filter and concentrate, obtain title compound, title compound is used for next step, need not to be further purified.

Method 5

Under nitrogen atmosphere, thick 3-(4-bromophenyl)-3-(4-chloro-phenyl-)-propionic acid amide is cooled to 0 ℃, add lithium aluminum hydride (0.075g, 1.97mmol) and ether (3ml).Under cooling, (0.23g 1.69mmol) is dissolved in ether (2ml) and adding with aluminum chloride.Reaction mixture was stirred 16 hours, add water quencher reaction, alkalization (2N NaOH), and use ethyl acetate extraction.Organic layer is separated dry (MgSO ₄), filtering also and concentrate, crude product obtains required product by with methyl alcohol and be used in the Phenomenex_Strata_SCX column chromatography purification of the 2N ammonia wash-out in the methyl alcohol subsequently.

Method 7

(4.02g, suspensoid 15.7mmol) are added drop-wise to aluminum chloride (7.32g, suspensoid 54.9mmol) in 0 ℃ of chlorobenzene (10ml) with 4-(4-bromophenyl) in the chlorobenzene (30ml)-piperidines-4-alcohol.Reaction mixture was stirred 2 hours at 0 ℃, and quencher reaction on the rocks adds methyl tertiary butyl ether then.Stir after 1 hour, filter collecting precipitation, water, methyl tertiary butyl ether and water washing obtain required compound.

Method 8

4-in methylene dichloride (150ml) (4-bromophenyl)-4-(4-chloro-phenyl-)-piperidines (10g, 25.8mmol) suspensoid add triethylamine (4.3ml, 31.0mmol) and tert-Butyl dicarbonate (6.2g, 28.4mmol).Stir after 72 hours, add entry, and remove organic layer.At dry (MgSO ₄) and concentrate in a vacuum to provide as white solid before the required compound, organic layer is washed with water, wash with saturated nacl aqueous solution then.

Method 9

Under nitrogen, with 4-(4-bromophenyl)-4-(4-chloro-phenyl-)-piperidines-1-t-butyl formate (5.0g, 11.1mmol), two valeryl two boron (bis (pinacolato) diboron) (2.8g, 11.1mmol), salt of wormwood (3.3g, 33.3mmol) and [1,1 '-two (diphenylphosphino)-ferrocene] dichloro closes palladium (II) (406mg, mixture heating up to 80 0.55mmol) ℃ experience 2.5 hours.Make the reaction cooling then,, under suction, filter subsequently with the ethyl acetate dilution.Solid is ground with ethyl acetate,, be a kind of beige solid so that required compound to be provided.

Method 10

Use≤50 watts of power, with 4-(4-chloro-phenyl-)-4-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-phenyl]-piperidines-1-t-butyl formate (200mg, 0.4mmol), two (three-tertiary butyl phosphines) close palladium (0) (6mg, 3mol%), 4-chloro-thieno-[3,2-d]-pyrimidine (0.5mmol), salt of wormwood (299mg, 1.4mmol), the mixture of ethanol (1.1ml), toluene (1.1ml), methyl alcohol (1.6ml) and water (1.5ml) is at CEM Explorer ^TMBe heated to 80 ℃ of experience in the microwave 30 minutes.Remove and desolvate, resistates is distributed between ethyl acetate and water.Use the ethyl acetate extraction water layer, the salt water washing of the organic layer of merging, dry (MgSO ₄), and under reduced pressure concentrate.Crude product mixture provides protected amine by the SCX ion-exchange column purification with ammonia-methylene chloride-methanol mixture wash-out.Concentrate from methyl alcohol and reconcentration (x3) before, removed protecting group in 30 minutes by stirring in room temperature methylene dichloride (1ml) and trifluoroacetic acid (1ml).Resistates is by the silicon-dioxide column chromatography purification with DMAW90 to DMAW60 gradient elution.

Method 11

(278mg 2.087mmol) joins 1-(4-bromophenyl) in the chlorobenzene (3ml)-2-methylamino-ethanol (160mg, stirred solution 0.696mmol), and stirring at room reaction mixture 17 hours in batches with aluminum chloride.Drip water (2ml), make reaction mixture then at methylene dichloride (100ml) and saturated NaHCO ₃Distribute (30ml).With organic layer drying (MgSO ₄), filter, and under reduced pressure concentrate.Then by with methyl alcohol and the Phenomenex Strata SCX column chromatography that is used in the 2N ammonia wash-out in the methyl alcohol subsequently make the crude product purifying, obtain required product.

Method 12

[2-(4-bromophenyl)-2-(4-chloro-phenyl-)-ethyl]-methyl-amine in the room temperature methylene dichloride (4.3g, solution 13.3mmol) (150ml) add triethylamine (2.22ml, 16mmol) and tert-Butyl dicarbonate (3.2g, 15mmol).Mixture was stirred 3 hours, add entry subsequently.Organic liquor is separated, concentrate in a vacuum then.Resistates by the silicon-dioxide column chromatography purification, obtains required compound with 2-15% ethyl acetate/gasoline gradient, is a kind of water white oil.

Method 13

Room temperature in 15 fens clockwise ethyl acetate (14ml)/water (10ml) 4-chlorine Bian Jiqing (1g, 6.60mmol) and sodium bromate (1.99g, solution 13.19mmol) drip sodium bisulfite in the water (21ml) (1.37g, 13.19mmol).Stir after 4 hours, reaction mixture is poured in the ether, and make and be separated.With water extracted with diethyl ether (x2), organic layer merges, with moisture saturated sodium thiosulfate washing, dry (MgSO ₄), remove in a vacuum and desolvate, obtain bromo-(4-chloro-phenyl-)-acetonitrile, the compound that obtains is used for next step.[Ref：JOC，1998，63，6023-6026]

4-piperazine-1-base-thieno-[3 in acetonitrile (1.4ml), 2-d] pyrimidine (83mg, 0.38mmol, 0.9 solution equivalent) adds bromo-(4-chloro-phenyl-)-acetonitrile (97mg, 0.42mmol, 1.0 equivalents), tetrabutylammonium iodide (8mg, 0.08mmol, 0.05 equivalent) and salt of wormwood (70mg, 0.50mmol, 1.2 equivalents).In the stirring at room mixture overnight.Under reduced pressure remove and desolvate, make to obtain thick material and between ethyl acetate and water, distribute.Layer is separated organic layer salt water washing, dry (MgSO ₄), and under reduced pressure concentrate.The thick material that obtains obtains some impure (4-chloro-phenyl-)-(4-thieno-[3,2-d] pyrimidine-4-base-piperazine-1-yl)-acetonitrile by the column chromatography purification with 50% ethyl acetate-gasoline wash-out.

Method 14

The solution of thick (4-chloro-phenyl-)-(4-thieno-[3,2-d] pyrimidine-4-base-piperazine-1-yl)-acetonitrile (from method 22) adds lithium aluminum hydride (159mg, 4.2mmol, 10.0 equivalents) in batches in toluene (42ml).Reaction mixture is heated to backflow 4 hours.Aqueous solution quencher reaction very lentamente with 2N sodium hydroxide adds ethyl acetate subsequently.Mixture is filtered, layer is separated, organic layer salt water washing, dry (MgSO ₄), and under reduced pressure concentrate.Use (gradient elution) 100%DCM to DMAW90 column chromatography, further use preparation HPLC subsequently, make the thick material purifying that obtains, to obtain required product.

Embodiment 1 to 4

The compound for preparing embodiment 1 to 4 according to the method described above.

Embodiment 5

5A.4-tert-butoxycarbonyl amino-4-(4-chloro-benzylamino formyl radical)-piperidines-1-t-butyl formate

Under nitrogen, dry DMF (1mL) is joined 4-tert-butoxycarbonyl amino-piperadine-1, the 4-diformate mono tert-butyl ester (151mg, 0.44mmol) and HATU (220mg, mixture 0.58mmol).(0.38mL 2.1mmol) joins in the solution, and reaction mixture was stirred 15 minutes with the N-ethyl diisopropyl amine.(70uL, 0.57mmol), stirred solution is 23 hours under room temperature and nitrogen to add 4-benzyl chloride base amine.Reaction mixture is distributed between methylene dichloride (10mL) and water (10mL).Water is further used dichloromethane extraction (20mL).With the organic layer drying (Mg that merges ₂SO ₄), filter and concentrate.With 4% methanol-eluted fractions in the methylene dichloride, rapid column chromatography on silicon-dioxide, obtain 4-tert-butoxycarbonyl amino-4-(4-chloro-benzylamino formyl radical)-piperidines-1-t-butyl formate (177mg, 0.38mmol, 86%).

LC-MS(LCT2)m/z?490[M+Na ⁺]，R _t?8.09min.

5B.4-amino-piperadine-4-formic acid 4-chloro-benzyl acid amides dihydrochloride

With the 4M solution (7.7ml of HCl in dioxane; 31mmol) be added drop-wise to 4-tert-butoxycarbonyl amino-4-(4-chloro-benzylamino formyl radical)-piperidines-1-t-butyl formate (96mg; 0.20mmol) solution in methyl alcohol (7.7mL), and stirring at room 17 hours.Solvent is concentrated, obtain 4-amino-piperadine-4-formic acid 4-chloro-benzyl acid amides dihydrochloride (71mg, 0.20mmol, 100%), this compound is used for next step, need not to be further purified.

¹H?NMR(500MHz，CD ₃OD)：2.18(2H，m)，2.64(2H，m)，3.44(4H，m)，4.47(2H，s)，7.36(4H，m).

5C.4-amino-1-thieno-[3,2-d] pyrimidine-4-base-piperidines-4-formic acid 4-chloro-benzyl acid amides

With 4-chloro-thieno-[3,2-d] pyrimidine (0.016g, 0.094mmol), 4-amino-piperadine-4-formic acid 4-chloro-benzyl acid amides (0.030g, 0.098mmol) and triethylamine (0.07mL, 0.50mmol) solution in propyl carbinol (0.5mL) by microwave irradiation be heated to 120 ℃ the experience 1 hour.Refrigerative solution is filtered by the SCX-II acidic resins, use methanol-eluted fractions earlier, use 1M ammonia-methanol-eluted fractions then.Basic moiety is merged.Preparation TLC with 5% methyl alcohol-methylene dichloride wash-out obtains 4-amino-1-thieno-[3,2-d] pyrimidine-4-base-piperidines-4-formic acid 4-chloro-benzyl acid amides, is a kind of pale solid (0.014g, 33%).

LC/MS：(LCT1)[M+J] ⁺402，R _t2.98min. ¹H(500MHz，MeOD)δ7.89(1H，s)，7.45(1H，d，J＝6Hz)，6.82(1H，d，J＝6Hz)，6.75-6.65(4H，m)，4.10-3.95(2H，m)，3.81(2H，s)，3.20-3.15(2H，m)，1.70-1.60(2H，m)，1.15-1.05(2H，m)

Embodiment 6

1-thieno-[3,2-d] pyrimidine-4-base-piperidin-4-yl-amine

(6A. 1-thieno-[3,2-d] pyrimidine-4-base-piperidin-4-yl)-t-butyl carbamate

Use the method for embodiment 5 to prepare title compound (AT11980), difference is to replace 4-amino-piperadine-4-formic acid 4-chloro-benzyl acid amides with piperidin-4-yl-t-butyl carbamate.

LC/MS：(LCT1)[M+H] ⁺334，R _t?4.62min

6B.1-thieno-[3,2-d] pyrimidine-4-base-piperidin-4-yl-amine

Stirring at room 2 hours, be evaporated to dried then the solution of product in 2M HCl (2ml) of embodiment 6A.Solid-Phase Extraction on the SCX-II acidic resins (is used the MeOH wash-out, is used in the 1M NH among the MeOH then ₃Wash-out), obtain de-protected product.LC/MS(LCT1)：[M+H] ⁺234，R _t0.85min. ¹H(250MHz，MeOD)δ8.45(1H，s)，8.04(1H，d，J＝5.5Hz)，7.38(1H，d，J＝5.5Hz)，4.95-4.81(2H，m)，3.34-3.29(2H，m)，3.08-2.98(1H，m)，2.06-2.00(2H，m)，1.52-1.36(2H，m).

Embodiment 7

4-(4-benzyl chloride base)-1-thieno-[3,2-d] pyrimidine-4-base-piperidin-4-yl-amine

(7A.4-4-benzyl chloride base)-piperidines-1,4-dioctyl phthalate 1-tert-butyl ester 4-methyl esters

To 0 ℃ of isopropylamine (3.71ml, 26.45mmol) solution in THF (110ml) add n-Butyl Lithium (solution of 10.1ml 2.5M in hexane, 25.25mmol).By sleeve pipe gained LDA solution is joined-78 ℃ of piperidines-1,4-dioctyl phthalate 1-tert-butyl ester 4-methyl esters (5.85g, the 24.04mmol) solution in THF (110ml) and HMPA (20ml), and continue to stir 1 hour.(6.4ml 50.49mmol), and was warming to room temperature 2 hours with solution to add 4-chlorobenzyl chloride among the THF (20ml).Stir after 18 hours, add saturated aqueous ammonium chloride (500ml), water extracted with diethyl ether (2 * 200ml).Organic phase is merged,, and be concentrated into dried through dried over mgso.Obtain ester by silicon-dioxide column chromatography (0.5% methyl alcohol among the DCM) purifying, be a kind of oil (3.03g, 34%).LC-MS(LCT1)m/z?390[M+Na ⁺]，R _t?8.02min.

(7B.4-4-benzyl chloride base) piperidines-1, the 4-diformate mono tert-butyl ester

4-in room temperature dioxane (20ml), methyl alcohol (10ml) and water (10ml) (4-benzyl chloride base) piperidines-1,4-dioctyl phthalate 1-tert-butyl ester 4-methyl esters (1.515g, solution 4.117mmol) add a hydronium(ion) oxidation lithium (3.455g, 82.341mmol).After 2 days, solution is acidified to pH 6 with 2M HCl 50 ℃ of stirrings, the white precipitate that obtains extracted with diethyl ether (2 * 100ml).Organic phase is merged, through dried over sodium sulfate, be concentrated into driedly, the acid that obtains is white solid (1.460g, 100%).LC-MS(LCT)m/z?376[M+Na ⁺]，R _t?7.62min.

(7C.4-4-benzyl chloride base) piperidin-4-yl amine

To-15 ℃ of acid (1.46g, 4.126mmol) and triethylamine (1.15ml, 8.252mmol) mixture in THF (41ml) add isobutyl chlorocarbonate (0.812ml, 6.189mmol).After 1 hour, add sodiumazide (0.536g, the 8.252mmol) solution in water (10ml), and solution is warming to ambient temperature overnight.Add entry (100ml), water extracted with diethyl ether (3 * 50ml).Organic phase is merged, with saturated sodium bicarbonate washing (50ml), through dried over sodium sulfate.Add toluene (100ml), make cumulative volume reduce to about 90ml.Gained solution is warmed to 90 ℃ of experience 2 hours, cooling then, and join in 10% hydrochloric acid (70ml).Biphase mixture is warming to 90 ℃ of experience 24 hours.Organic phase is separated, and be concentrated into driedly, obtain thick amine salt (1.109g).

Make thick amine salt be dissolved in 2M NaOH (20ml), and the adding tert-Butyl dicarbonate (1.61g, 7.391mmol).After 2 days, water extracted with diethyl ether (2 * 50ml).Organic phase is merged, with 1M HCl (20ml), saturated sodium bicarbonate (20ml) and salt solution (20ml) washing, then through dried over mgso and concentrated.Obtain the amine (0.685g) of two BOC-protections by column chromatography purification (50% in hexane ether), stir removal in 2 days by the 4M HCl in room temperature and dioxane (10ml) and methyl alcohol (10ml) subsequently and protect.Concentrate and obtain required amine, be dihydrochloride (0.492g, 40% from acid).

¹H?MR(MeOD)δ7.48-7.44(m，2H)，7.35-7.32(m，2H)，3.53-3.47(4H，m)，3.21(s，2H)，2.18-2.13(4H，m).

(7D.4-4-benzyl chloride base)-1-thieno-[3,2-d] pyrimidine-4-base-piperidin-4-yl-amine

According to the method for embodiment 5C, make product and the reaction of 4-chloro-thieno-[3,2-d] pyrimidine of embodiment 7D, obtain title compound.

LC/MS：(LCT2)[M+H] ⁺359，R _t2.73min. ¹H(500MHz，MeOD)δ7.51(1H，d，J＝2.0Hz)，7.10(1H，dd，J＝5.5，2.0Hz)，6.46-6.31(5H，m)，3.51-3.48(2H，m)，2.94-2.89(2H，m)，1.86(2H，s)，0.87-0.82(2H，m)，0.66-0.64(2H，m).

Embodiment 8

C-(4-chloro-phenyl-)-C-(1-thieno-[3,2-d] pyrimidine-4-base-piperidin-4-yl)-methylamine

(8A.4-4-chlorobenzene formacyl) piperidines-1-t-butyl formate

(4-chloro-phenyl-) piperidin-4-yl ketone hydrochloride in room temperature acetonitrile (15ml) (0.996g, 3.828mmol) and triethylamine (2.7ml, 19.142mmol) mixture add tert-Butyl dicarbonate (1.003g, 4.594mmol).In room temperature after 16 hours, mixture is evaporated to dried, between ethyl acetate (50ml) and 1M hydrochloric acid (20ml), distribute then.Through dried over mgso and be concentrated into do before, organic phase is separated, use saturated aqueous sodium bicarbonate (20ml), salt solution (20ml) washing in succession.Thick material is by silicon-dioxide column chromatography purification (60% in hexane ether), and the ketone that obtains is a kind of oil (1.116g, 90%).LC/MS：(LCT1)R _t?7.42[M+H] ⁺323.

8B.4-[amino-(4-chloro-phenyl-) methyl] piperidines-1-t-butyl formate

4-in room temperature methyl alcohol (34ml) (4-chlorobenzene formacyl) piperidines-1-t-butyl formate (1.116g, 3.446mmol) and ammonium acetate (3.188g, 41.358mmol) mixture add sodium cyanoborohydride (0.866g, 13.786mmol).After refluxing 20 hours, with the mixture cooling, concentrate, and stir with 1M sodium hydroxide (100ml).Water with extracted with diethyl ether (3 * 75ml), organic layer is merged, through dried over sodium sulfate and be concentrated into dried.Thick material is by silicon-dioxide column chromatography purification (15% in DCM methyl alcohol), and the amine that obtains is a kind of oil (0.913g, 82%).LC/MS(LCT1)：R _t5.56[M-Boc-NH ₂] ⁺208.

(8C.C-4-chloro-phenyl-)-C-piperidin-4-yl methylamine hydrochloride

4-[amino in room temperature methyl alcohol (6ml)-(4-chloro-phenyl-) methyl] (0.192g, solution 0.591mmol) adds 2M hydrochloric acid (6ml) to piperidines-1-t-butyl formate.After stirring 16 hours, to doing, the amine salt that obtains is a kind of white foam (0.174g, 99%) with solution evaporation.

¹HNMR(MeOD)δ1.40-1.82(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).

(8D.C-4-chloro-phenyl-)-C-(1-thieno-[3,2-d] pyrimidine-4-base-piperidin-4-yl)-methylamine

According to the method for embodiment 5C, make product and the reaction of 4-chloro-thieno-[3,2-d] pyrimidine of embodiment 8C, obtain title compound.LC/MS：(LCT2)[M+H] ⁺358，R _t?3.51min.

¹H(250MHz，MeOD)δ8.42(1H，s)，8.01(1H，d，J＝5.5Hz)，7.38-7.31(5H，m)，5.00-4.79(2H，m)，3.60(1H，d，J＝8.5Hz)，3.25-3.02(2H，m)，2.18-1.89(2H，m)，1.48-1.17(3H，m).

Embodiment 9

1-thieno-[2,3-d] pyrimidine-4-base-piperidin-4-yl-amine

(9A. 1-thieno-[2,3-d] pyrimidine-4-base-piperidin-4-yl)-t-butyl carbamate

In propyl carbinol (3.2ml) the 4-chlorothiophene also [2,3-d] pyrimidine (0.55g, 0.322mmol) and the piperidin-4-yl t-butyl carbamate (0.129g, 0.646mmol) mixture add triethylamine (0.225mL, 1.617mmol)., remove and desolvate after 48 hours 100 ℃ of heating, the solid that obtains obtains required product by silicon-dioxide column chromatography purification (5% methyl alcohol-methylene dichloride eluent), is a kind of pale solid (0.108g, 100%).LC/MS：(LCT1)[M+H] ⁺334，R _t6.54min

9B.1-thieno-[2,3-d] pyrimidine-4-base-piperidin-4-yl amine

(0.108g, 0.322mmol) solution in 1M HCl (in ether (3mL) and methyl alcohol (3mL)) is evaporated to dried stirring at room 24 hours then with (1-thieno-[2,3-d] pyrimidine-4-base-piperidin-4-yl)-t-butyl carbamate.Solid-Phase Extraction on the SCX-II acidic resins (use the MeOH wash-out, be used in the 1M ammonia wash-out in the methyl alcohol then) obtains de-protected amine, is a kind of white solid (0.076g, 100%).

LC/MS(LCT1)：[M+H] ⁺234，R _t?2.24min. ¹H(250MHz，MeOD)δ8.36(1H，s)，7.54(1H，d，J＝6.0Hz)，7.49(1H，d，J＝6.0Hz)，4.70-4.64(2H，m)，3.35-3.26(2H，m)，3.07-2.95(1H，m)，2.04-1.99(2H，m)，1.54-1.38(2H，m).

Embodiment 10

4-(4-amino-piperadine-1-yl)-1H-pyrrolo-[2,3-b] pyridine-2,3-diketone and 4-(4-amino-piperadine-1-yl)-1,3-dihydro-pyrrolo-[2,3-b] pyridin-2-ones

10A.1H-pyrrolo-[2,3-b] pyridine 7-oxide compound

(6.35g, 53mmol) solution in ethyl acetate (200mL) is cooled to 0-5 ℃ with 1H-pyrrolo-[2,3-b] pyridine in ice bath.Through 10 fens clockwise refrigerative solution add mCPBA (14g, 64mmol).Gained solution is warmed to room temperature, up to raw material completely consumed (2.5h).With the gained slurries filtration, collect the N-oxide compound as m-chlorobenzoic acid salt.Solid washs with other ethyl acetate, and drying provides 10.4g (36mmol).M-chlorobenzoic acid 7-hydroxyl-1H-pyrrolo-[2,3-b] pyridine (10.4g, the saturated aqueous K of suspensoid 36mmol) in water (100mL) ₂CO ₃Alkalize to pH 11.Mixture cooling (+4 ℃) is spent the night, obtain crystal, collect crystal, use hexane wash, with the ether washing, obtain 1H-pyrrolo-[2,3-b] pyridine 7-oxide compound (3.22g, 24mmol, 67%) subsequently.LC-MS(LCT1)m/z?135.1[M+H ⁺]，R _t?2.62min.

10B.4-chloro-1H-pyrrolo-[2,3-b] pyridine

(5mL 64mmol) is added drop-wise to 1H-pyrrolo-[2,3-b] pyridine 7-oxide compound among the DMF (16mL) (3.18g, solution 24mmol), and be heated to 50 ℃ with methylsulfonyl chloride.With the gained mixture 72 ℃ of heated overnight.Reaction mixture is cooled to 30 ℃, and water quencher reaction (50mL).Cooling mixture in ice bath adds enough 10M aqueous NaOH, so that pH is brought up to 7.The gained slurry is warmed to room temperature, stirred 15 minutes, filter then and collect product.Solid washes with water, and is dry in a vacuum, obtains 4-chloro-1H-pyrrolo-[2,3-b] pyridine (2.97g, 19.5mmol, 81%).LC-MS(LCT1)m/z?153.03[M+H ⁺]，R _t?5.77min.

10C.3,3-two bromo-4-chloro-1,3-dihydro-pyrrolo-[2,3-b] pyridin-2-ones

4-chloro-1H-pyrrolo-[2,3-b] pyridine in 7 fens clockwise 50mL trimethyl carbinols (1g, stirred solution 6.5mmol) divide short run add tribromide pyridine 90% (7.24g, 22.6mmol).Spend the night in the stirring at room reaction.Remove the trimethyl carbinol in a vacuum, the resistates that obtains is dissolved in ethyl acetate-water (200mL: 200mL).Organic layer is separated, and water layer is further used ethyl acetate extraction (2 * 100mL).With organic extract water, the salt water washing that merges, dry (MgSO ₄), concentrate in a vacuum, obtain 3,3-two bromo-4-chloro-1,3-dihydro-pyrrolo-[2,3-b] pyridin-2-ones (2.17g, 6.6mmol, 100%).LC-MS(LCT1)m/z?326.78[M+H ⁺]，R _t?5.75min.

10D.4-chloro-1,3-dihydro-pyrrolo-[2,3-b] pyridin-2-ones

With 3,3-two bromo-4-chloro-1,3-dihydro-pyrrolo-[2,3-b] pyridin-2-ones (1.05g, 3.15mmol), the suspensoid of ethanol (120mL) and 10%Pd/C (391mg) is room temperature and constant pressure hydrogenation 6 hours 15 minutes.Reaction mixture is filtered by the celite pad, and use methanol wash.With solvent evaporation, and thick material is distributed between methylene dichloride (50mL) and saturated aqueous sodium bicarbonate (50mL).Two be separated after, water layer is further used dichloromethane extraction (2 * 50mL).With the organic layer drying (MgSO that merges ₄), filter and evaporation, obtain 4-chloro-1,3-dihydro-pyrrolo-[2,3-b] pyridin-2-ones (328mg, 1.94mmol, 62%).LC-MS(LCT1：15min?run)m/z?169.02[M+H ⁺]，R _t?3.96min.

(10E.[1-2,3-dioxo-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl)-piperidin-4-yl]-t-butyl carbamate

Method A

With piperidin-4-yl-t-butyl carbamate (76mg, 0.6mmol), 4-chloro-1,3-dihydro-pyrrolo-[2,3-b] pyridin-2-ones (50mg, 0.3mmol), triethylamine (0.31mL, 2.1mmol) and the degassing mixture of propyl carbinol (3ml) stirred 3.5 hours at 100 ℃.With solvent evaporation, crude mixture is by with the quick silicon-dioxide column chromatography purification of 5% methyl alcohol-methylene dichloride wash-out, obtains that [1-(2,3-dioxo-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl)-piperidin-4-yl]-t-butyl carbamate (24.4mg, 0.07mmol, 24%).LC-MS(LCT2)m/z?347.22[M+H ⁺]，R _t?5.80min.

Method B

With 4-chloro-1,3-dihydro-pyrrolo-[2,3-b] pyridin-2-ones (25mg, 0.15mmol), the piperidin-4-yl t-butyl carbamate (38mg, 0.3mmol) and the mixture of N-methyl-pyrrolidone (0.2ml) in 155 ℃ of microwaves, shone 1 hour.Solution is diluted purifying on the SCX-II acidic resins (use methanol-eluted fractions earlier, use 2M ammonia-methanol-eluted fractions then) in methyl alcohol.Thick material is further by the quick silicon-dioxide column chromatography purification with 10% methyl alcohol-methylene dichloride wash-out, obtain that [1-(2,3-dioxo-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl)-piperidin-4-yl]-t-butyl carbamate and [1-(2-oxo-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl)-piperidin-4-yl]-mixture of t-butyl carbamate.These compounds separate (Discovery C18 Supelco HPLC post 15cm * 10mm, 5 μ L by preparation HPLC; Acetonitrile/water gradient solvent system).

[1-(2,3-dioxo-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl)-piperidin-4-yl]-t-butyl carbamate: 6.4mg, 0.018mmol, 12%, LC-MS (LCT2) m/z 347.22[M+H ⁺], R _t5.90min

[1-(2-oxo-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl)-piperidin-4-yl]-t-butyl carbamate: 1.6mg, 0.005mmol, 3%, LC-MS (LCT2) m/z 333.27[M+H ⁺], R _t3.43min

(10F.4-4-amino-piperadine-1-yl)-1H-pyrrolo-[2,3-b] pyridine-2, the 3-diketone

(0.5ml 6.7mmol) is added drop-wise to [1-(2,3-dioxo-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl)-piperidin-4-yl]-t-butyl carbamate (4.7mg, 0.014mmol) solution in methylene dichloride (1mL) with trifluoroacetic acid.Stirring at room solution 45 minutes.Solvent is concentrated, and crude mixture is gone up purifying at SCX-II acidic resins (use methanol-eluted fractions earlier, use 2M ammonia-methanol-eluted fractions then), obtains 4-(4-amino-piperadine-1-yl)-1H-pyrrolo-[2,3-b] pyridine-2,3-diketone (3.5mg, 0.014mmol, 100%).

LC-MS(LCT2)m/z247.19[M+H ⁺]，R _t?0.79min. ¹H(500MHz，MeOD)δ7.84(d，J＝5Hz，1H)，6.60(d，J＝5Hz，1H)，4.22-4.28(m，2H)，3.14-3.21(m，2H)，2.96-3.08(m，1H)，2.00-2.05(m，2H)，1.30-1.62(m，2H).

Embodiment 11

8-[4-amino-4-(4-chloro-benzyl)-piperidines-1-yl]-4H-pyrido [3,2-b] [1,4] oxazine-3-ketone

11A.5-oxygen base (Oxy)-4H-pyrido [3,2-b] [1,4] oxazine-3-ketone

(2.76g 16.0mmol) joins room temperature 4H-pyrido [3,2-b] [1,4] oxazine-3-ketone (2g, 13.3mmol) the stirring suspension body in the mixture of ethyl acetate (150mL) and acetone (100mL) in batches with metachloroperbenzoic acid.Stirring at room after 2 days, is carefully precipitated.Collect solid, use washing with acetone, dry in a vacuum, [1,4] oxazine-3-ketone (1.9g, 86%) is a kind of light grey powder to obtain 5-oxygen base-4H-pyrido [3,2-b].

LC-MS(LCT2)m/z?167.1[M+H ⁺]，R _t?1.69min. ¹H(500MHz，d ₆-DMSO)δ8.00(1H，dd，J＝6.3，1.4Hz)，7.10-6.95(2，m)，4.72(2H，s

11B.8-chloro-4H-pyrido [3,2-b] [1,4] oxazine-3-ketone

Methylsulfonyl chloride (1.2mL) is added drop-wise to 50 ℃ of 5-oxygen base-4H-pyrido [3,2-b] [1,4] oxazine-3-ketone (0.99g, solution 6.0mmol) in DMF (6mL).Solution is heated to 80 ℃, and stirred 16 hours.The dark-coloured solution that obtains is diluted with salt solution, and with ethyl acetate extraction (2 * 50mL).With the moisture NaHCO of organic layer that merges ₃(2 * 40mL), salt solution (2 * 40mL) washings, and dry (Na ₂SO ₄).Make solvent evaporation, obtain a kind of thick oil (0.36g).The silicon-dioxide column chromatography obtains 8-chloro-4H-pyrido [3,2-b] [1,4] oxazine-3-ketone (36mg, 3%), is a kind of yellow powder.

LC-MS(LCT2)m/z?185.0[M+H ⁺]，R _t?4.68min. ¹H(500MHz，d ₆-DMSO)δ11.40(1H，s)，7.82(1H，d，J＝6.5Hz)，7.12(1H，d，J＝6.5Hz)，4.75(2H，s).

11C.8-[4-amino-4-(4-chloro-benzyl)-piperidines-1-yl]-4H-pyrido [3,2-b] [1,4] oxazine-3-ketone

With 8-chloro-4H-pyrido [3,2-b] [1,4] oxazine-3-ketone (6mg, 0.03mmol), 4-(4-benzyl chloride base)-piperidin-4-yl amine hydrochlorate (embodiment 7C) (9.5mg, 0.03mmol), the mixture of triethylamine (0.024mL) in propyl carbinol (1mL) shine 2 hours (300W) in 200 ℃ of CEM microwaves.After the cooling, make solvent evaporation.Crude product is being used purifying on the SCX-II acidic resins of ammonia-methanol-eluted fractions, then by the silicon-dioxide column chromatography (ethyl acetate: purifying methyl alcohol 3: 1) obtains 8-[4-amino-4-(4-chloro-benzyl)-piperidines-1-yl]-4H-pyrido [3,2-b] [1,4] oxazine-3-ketone (1mg, 8%).

LC-MS(LCT2)m/z373.3[M+H ⁺]，R _t?3.60min. ¹H(500MHz，d ₄-MeOD)δ7.70(1H，d，J＝6.5Hz)，7.30(2H，d，J＝7.0Hz)，7.23(2H，d，J＝7.0Hz)，6.64(1H，d，J＝6.5Hz)，4.56(2H，s)，3.48(2H，m)，3.30(2H，m)，2.78(2H，s)，2.05(2H，m)，1.60(2H，m).

Biological activity

Embodiment 12

Measure PKA kinase inhibiting activity (IC ₅₀)

Use PKA catalyst structure domain (available from Upstate Biotechnology (#14-440)) and 9 residue PKA specific peptides (GRTGRRNSI) (also available from UpstateBiotechnology (#12-257)) as substrate, the PK that can test The compounds of this invention suppresses active.1nM enzyme ultimate density is used for buffer reagent, and buffer reagent comprises 20mM MOPS pH 7.2,40 μ M ATP/ γ ³³P-ATP and 5 μ M substrates.Compound is added in methyl-sulphoxide (DMSO) solution to final DMSO concentration 2.5%.Before adding excessive ortho-phosphoric acid quenching activity, reaction was carried out 20 minutes.Phosphorylated protein from the Millipore MAPH filter plate separates unconjugated γ then ³³P-ATP.With the plate washing, add scintillator, make plate process counting on PackardTopcount then.

Calculate the active % of PKA and suppress and mapping, to determine to suppress 50%PKB activity (IC ₅₀) concentration of required test compound.

Embodiment 1 and 4 compound have the IC less than 1 μ M ₅₀Value.

Embodiment 13

Measure PKB kinase inhibiting activity (IC ₅₀)

Compound arrestin kinase b (PKB) activity is basically as mensuration (Mol.Cell.Biol.19 as described in the people such as Andjelkovic, 5061-5072 (1999)), but use a kind of fusion rotein, this fusion rotein is described to PKB-PIF, and (NatureStructural Biology 9,940-944 (2002)) fully described by people such as Yang.This albumen is purified, and with the PDKl activation, as described in people such as Yang.With the peptide AKTide-2T (H-A-R-K-R-E-R-T-Y-S-F-G-H-H-A-OH) that obtains from Calbiochem (#123900) as substrate.0.6nM enzyme ultimate density is used for buffer reagent, and buffer reagent comprises 20mM MOPS pH 7.2,30 μ MATP/ γ ³³P-ATP and 25 μ M substrates.Compound is added in the DMSO solution to final DMSO concentration 2.5%.Before adding excessive ortho-phosphoric acid quenching activity, reaction was carried out 20 minutes.Reaction mixture is transferred to the phosphorylated cotton filter plate, and in this peptide combination, and the ATP of usefulness is not washed off.After the flushing, add scintillator, the bonded activity is measured by scintillation counting.

Calculate the active % of PKB and suppress and mapping, to determine to suppress 50%PKB activity (IC ₅₀) concentration of required test compound.

According to above-mentioned rules, find the IC of the compound of embodiment 1 to 5,7 and 8 ₅₀Value is less than 1 μ M, and the compound of embodiment 6 and 11 has the IC less than 5 μ M respectively ₅₀Value, and the compound of embodiment 9 and 10 has the IC less than 50 μ M ₅₀Value.

Embodiment 14

Antiproliferative activity

By detection compound cytostatic ability in some clones, can measure the antiproliferative activity of The compounds of this invention.Cell growth-inhibiting Alamar Blue assay method mensuration (Nociari, M.M, Shalev, A., Benias, P., Russo, C.Journal ofImmunological Methods 1998,213,157-167).This method is the ability that resazurin is reduced into its fluorescence-causing substance resorufin according to viable cell.For each proliferation test, the cell plating to 96 orifice plates, and adding inhibitor compound before other 72 hours, was made cellular-restoring 16 hours.Finish in the incubation period, add 10% (v/v) Alamar Blue, and before 535nM ex/590nM em measures fluorescence-causing substance, cultivated again 6 hours.Under the situation of non-proliferative cell test, adding inhibitor compound before other 72 hours, cell is kept merging 96 hours.As the preceding Alamar Blue test determination viable count that passes through.All cells system all derives from ECACC (European Collection of cell Cultures) or ATCC.

Embodiment 15

(i) tablet formulation

By mixing also tablet forming in a known way of 50mg compound and 197mg lactose (BP) (as thinner) and 3mg Magnesium Stearate (as lubricant), prepare the tablet composition that comprises formula (I) compound.

(ii) capsule formulation

By mixing compound and the 100mg lactose of 100mg formula (I), and the mixture that obtains is inserted the opaque hard gelatin capsule of standard, thereby prepare capsule formulation.

(iii) injectable formulation I

Be dissolved in the water that contains 10% propylene glycol by compound (for example salt form), with the parenteral composition that obtains the active compound of 1.5% weight concentration, can prepare being used for drug administration by injection with formula (I).With the solution filtration sterilization, insert ampoule and sealing then.

(iv) injectable formulation II

By with the compound (for example salt form) of formula (I) (2mg/ml) and N.F,USP MANNITOL (50mg/ml) water-soluble, with the solution sterilization filtration, and insert sealable 1ml bottle or ampoule, the parenteral composition that preparation is used to inject.

V) injectable formulation III

By the compound (for example salt form) of formula (I) is water-soluble with 20mg/ml, can prepare preparation by injection or infusion intravenously loading.Then with bottle sealing and autoclaving.

Vi) injectable formulation IV

Contain buffer reagent (for example, 0.2M acetate pH 4.6) water can prepare the preparation by injection or infusion intravenously loading by the compound (for example salt form) of formula (I) is dissolved in 20mg/ml.Then with bottle sealing and autoclaving.

(vii) subcutaneous injection preparation

Be mixed into 5mg/ml concentration by compound and pharmaceutical grade Semen Maydis oil with formula (I), preparation is used for the composition of subcutaneous administration.With the composition sterilization, and insert in the suitable container.

Viii) freeze-dried preparation

The aliquot of formula (I) compound of preparation is put into the 50ml bottle, and freeze-drying.During freeze-drying, go on foot freezing scheme at (45 ℃) frozen composition with one.Raise the temperature to-10 ℃ of annealing (annealing), be reduced to then-45 ℃ freezing, about 3400 minutes of+25 ℃ of elementary dryings, carry out secondary drying (if temperature reaches 50 ℃) with cumulative step subsequently subsequently.Pressure during elementary drying and secondary drying is set in 80 millitorrs.

Be equal to meaning

Previous embodiment is used to illustrate the present invention, these embodiment should be interpreted as force at any restriction of the scope of the invention.Obviously, can not break away under the principle of the present invention making many modifications and variations with the specific embodiments of the present invention of explanation described in the embodiment.All such modifications and variation are intended to be comprised by the application.

Claims (78)

1. the compound of a formula (I):

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

Wherein TG is selected from:

(1) group

With

(2) group

Wherein the tie point of group E and radicals X represented in asterisk (*);

A is that the stable hydrocarbon that comprises 1 to 7 carbon atom connects base, and described connection base has at R ^1aAnd NR ²R ³Between the maximum chain length of 5 atoms extending, and have at E and NR ²R ³Between the maximum chain length of 4 atoms extending, wherein connect one of carbon atom in the base and can choose wantonly by oxygen or nitrogen-atoms and replace; And the carbon atom that wherein connects basic A can be chosen wantonly and carry one or more substituting groups that are selected from oxo, fluorine and hydroxyl, and its condition is that hydroxyl is not positioned at and NR when existing ²R ³On the alpha-carbon atom that group is correlated with, and its condition is that oxo group is positioned at when existing and NR ²R ³On the alpha-carbon atom that group is correlated with;

E is monocycle or bicyclic carbocyclic or heterocyclic group;

Radicals X is the bicyclic heterocyclic group with 8 to 12 ring memberses, and maximum 5 ring memberses are the heteroatoms that is selected from O, N and S;

R ^1aBe aryl or heteroaryl;

R ^1bBe hydrogen or radicals R ^1a

R ²And R ³Independently be selected from hydrogen, C _1-4Alkyl and C _1-4Acyl group, wherein alkyl and acyl moiety are optional is replaced by one or more substituting groups that are selected from fluorine, hydroxyl, amino, methylamino, dimethylamino and methoxyl group;

Perhaps R ²And R ³Form cyclic group with their bonded nitrogen-atoms, described cyclic group is selected from imidazole group and has 4 to 7 ring memberses and the optional saturated monocycle heterocyclic group that comprises the second heteroatomic ring member who is selected from O and N;

Perhaps R ²And R ³One of have 4 to 7 ring memberses and the optional saturated monocycle heterocyclic group that comprises the second heteroatomic ring member who is selected from O and N with their bonded nitrogen-atoms with forming from the one or more atoms that are connected basic A;

Perhaps NR ²R ³The carbon atom that is connected basic A with its bonded forms cyano group together;

N is 0 to 4;

Each R ⁴Independently be selected from oxo, halogen, optional by halogen, hydroxyl or C _1-2The C that alkoxyl group replaces _1-6Alkyl, cyano group, optional by halogen, hydroxyl or C _1-2The C that alkoxyl group replaces _1-6Alkyl oxygen base, CONH ₂, CONHR ⁹, CF ₃, NH ₂, NHCOR ⁹, NHCONHR ⁹And NHR ⁹

R ⁹Be radicals R ^9aOr (CH ₂) R ^9a, R wherein ^9aFor can be carbocyclic ring or heterocyclic monocycle or bicyclic radicals;

Carbon ring group or heterocyclic group R ^9aOptional be selected from following substituting group and replace by one or more: halogen, hydroxyl, trifluoromethyl, cyano group, nitro, carboxyl, amino, list-or two-C _1-4Alkyl 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 ₂And R ^bBe selected from hydrogen, have the heterocyclic group and the C of 3 to 12 ring memberses _1-8Alkyl, described C _1-8Alkyl is optional by one or more hydroxyl, oxo, halogen, cyano group, nitro, carboxyl, amino, list-or two-C that are selected from _1-4The substituting group of alkyl amino, the carbocyclic ring with 3 to 12 ring memberses and heterocyclic group replaces, and C wherein _1-8One or more carbon atoms of alkyl can be chosen wantonly by O, S, SO, SO ₂, NR ^c, X ¹C (X ²), C (X ²) X ¹Or X ¹C (X ²) X ¹Replace;

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

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

Q ¹For key or the stable hydrocarbon that comprises 1 to 3 carbon atom connect base, wherein connect one of carbon atom in the base and can choose wantonly by oxygen or nitrogen-atoms and replace, perhaps adjacent carbon atom is to can be by CONR ^qOr NR ^qCO replaces, wherein R ^qBe hydrogen, C _1-4Alkyl or cyclopropyl, perhaps R ^qFor being connected to R ^1bOr Q ¹Another carbon atom to form the C of circular part _1-4Alkylidene chain, and wherein connect basic Q ¹Carbon atom can choose wantonly and carry one or more substituting groups that are selected from fluorine and hydroxyl;

Q ²For key or the stable hydrocarbon that comprises 1 to 3 carbon atom connect base, wherein connect one of carbon atom in the base and can choose wantonly by oxygen or nitrogen-atoms and replace; And the carbon atom that wherein connects base can be chosen wantonly and carry one or more substituting groups that are selected from fluorine and hydroxyl, and its condition is that hydroxyl is not positioned at and NR when existing ²R ³On the relevant alpha-carbon atom of group, and its condition is for when E is aryl or heteroaryl, Q ²Be different from key;

And further condition is a part

Be different from group (BG1) or (BG2);

Wherein (BG1) and (BG2) optional respectively being substituted;

The tie point of asterisk (*) expression group E;

T is N or group CR ^z

J ¹-J ²Expression is selected from N=C (R ^z), (R ^z) C=N, (R ^z) N-C (O), (R ^z) ₂C-C (O), N=N and (R ^z) C=C (R ⁶) group;

J ⁴-J ³Be group N=C (R ^z) or group (R ^z) N-CO; And

R ^zBe hydrogen or substituting group.

2. the compound of claim 1, wherein TG is

(1) group:

3. the compound of claim 2, wherein the part R of compound ^1a-A-NR ²R ³By formula R ^1a-(G) _k-(CH ₂) _m-W-O _b-(CH ₂) _n-(CR ⁶R ⁷) _p-NR ²R ³Expression, wherein G is NH, NMe or O; W is connected to group E, and is selected from (CH ₂) _j-CR ²⁰, (CH ₂) _j-N and (NH) _j-CH; B is 0 or 1, and 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; B and k sum are 0 or 1; J, k, m, n and p sum are no more than 4; R ⁶And R ⁷Identical or different, and be selected from methyl and ethyl, perhaps CR ⁶R ⁷Form cyclopropyl; And R ²⁰Be selected from hydrogen, methyl, hydroxyl and fluorine.

4. the compound of claim 2, wherein the part R of compound ^1a-A-NR ²R ³By formula R ^1a-(G) _k-(CH ₂) _m-X ^x-(CH ₂) _n-(CR ⁶R ⁷) _p-NR ²R ³Expression, wherein G is NH, NMe or O; X ^xBe connected to group E, and be selected from (CH ₂) _j-CH, (CH ₂) _j-N 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 j, k, m, n and p sum are no more than 4; R ⁶And R ⁷Identical or different, and be selected from methyl and ethyl, perhaps CR ⁶R ⁷Form cyclopropyl.

5. the compound of claim 4, wherein the part R of compound ^1a-A-NR ²R ³By formula R ¹-(G) _k-(CH ₂) _m-X ^x-(CH ₂) _n-(CR ⁶R ⁷) _p-NR ²R ³Expression, wherein:

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

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

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

X ^xBe (CH ₂) _j-CH, k are 1, and m is 0, and n is 0,1 or 2, and p is 1; Perhaps

X ^xBe (CH ₂) _j-CH, G are O, and k is 1, and m is 0, and n is 0,1,2 or 3, and p is 0.

6. each compound in the claim 2 to 5 is wherein defined in group A such as this paper table 1.

7. the compound of claim 1, wherein TG is

(2) group:

Q ¹For key or the stable hydrocarbon that comprises 1 to 3 carbon atom connect base, wherein connect one of carbon atom in the base and can choose wantonly by oxygen or nitrogen-atoms and replace, perhaps adjacent carbon atom is to can be by CONR ^qOr NR ^qCO replaces, wherein R ^qBe hydrogen, C _1-4Alkyl or cyclopropyl, perhaps R ^qFor being connected to R ^1bOr Q ¹Another carbon atom to form the C of circular part _1-4Alkylidene chain, and wherein connect basic Q ¹Carbon atom can choose wantonly and carry one or more substituting groups that are selected from fluorine and hydroxyl.

8. the compound of claim 7, wherein R ^1bBe hydrogen.

9. the compound of claim 7, wherein R ^1bBe radicals R ^1a

10. each compound, wherein R in the claim 2 to 6 and 9 ^1aBe selected from optional phenyl, naphthyl, thienyl, furyl, pyrimidyl and the pyridyl that replaces.

11. the compound of claim 10, wherein R ^1aBe the optional phenyl that replaces.

12. the compound of claim 10 or 11, wherein Ren Xuan substituting group is selected from hydroxyl, C _1-4Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano group, CONH ₂, nitro, optional by C respectively _1-2The C that alkoxyl group, carboxyl or hydroxyl replace _1-4Alkyl oxygen base and C _1-4Alkyl, C _1-4Acyl amino, benzamido, tetramethyleneimine-1-base carbonyl, piperidines-1-base carbonyl, morpholino carbonyl, piperazine-1-base carbonyl, contain 1 or 2 heteroatomic five yuan and six membered heteroaryl that is selected from N, O and S and heteroaryl oxygen base, phenyl, phenyl-C _1-4Alkyl, phenyl-C _1-4Alkoxyl group, heteroaryl-C _1-4Alkyl, heteroaryl-C _1-4Alkoxyl group and phenoxy group, wherein heteroaryl, heteroaryl oxygen base, phenyl, phenyl-C _1-4Alkyl, phenyl-C _1-4Alkoxyl group, heteroaryl-C _1-4Alkyl, heteroaryl-C _1-4Alkoxyl group and phenoxy group are optional respectively to be selected from C with 1,2 or 3 _1-2Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano group, CONH ₂The optional respectively C that replaces by methoxyl group or hydroxyl _1-2Alkyl oxygen base and C _1-2The substituting group of alkyl replaces.

13. the compound of claim 12, wherein R ^1aBe replacement, or be selected from hydroxyl, C by maximum 5 _1-4Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, phenyl, thienyl, furyl, phenoxy group, benzyl oxygen base, cyano group, optional by C respectively _1-2The C that alkoxyl group or hydroxyl replace _3-4Cycloalkyl and C _1-4Alkoxyl group and C _1-4The substituting group of alkyl replaces.

14. the compound of claim 13, wherein R ^1aHas the substituting group that one or two is selected from fluorine, chlorine, cyano group, methyl, ethyl, sec.-propyl, cyclopropyl, the tertiary butyl, trifluoromethyl, methoxyl group, trifluoromethoxy, difluoro-methoxy, phenyl, phenoxy group and benzyl oxygen base.

15. the compound of claim 14, wherein R ^1aFor being selected from for example phenyl of the replacement of 4-chloro-phenyl-, dichlorophenyl, hydroxy phenyl, fluorochlorobenzene base, cyano-phenyl, p-methoxy-phenyl, methoxychlor phenyl, fluorophenyl and difluorophenyl of mono chloro benzene base.

16. the compound of claim 13, wherein R ^1aBe the group shown in this paper table 2.

17. each compound, wherein R in the aforementioned claim ²And R ³Independently be selected from hydrogen, C _1-4Alkyl and C _1-4Acyl group, wherein alkyl and acyl group are optional is replaced by one or more substituting groups that are selected from fluorine, hydroxyl, cyano group, amino, methylamino, dimethylamino, methoxyl group and monocycle or bicyclic aryl or heteroaryl.

18. the compound of claim 17, wherein R ²And R ³Independently be selected from hydrogen and methyl, so NR ²R ³Be amino, methylamino or dimethylamino.

19. the compound of claim 18, wherein NR ²R ³Be amino.

20. the compound of claim 18, wherein NR ²R ³Be methylamino.

21. the compound of claim 2 and any dependent claims thereof, wherein R ²And R ³One of have 4 to 7 ring memberses and the optional saturated monocycle heterocyclic group that comprises the second heteroatomic ring member who is selected from O and N with their bonded nitrogen-atoms with forming from the one or more atoms that are connected basic A.

22. the compound of claim 21, wherein NR ²R ³Cyclic group with A formation following formula:

Wherein v and w are respectively 0,1,2 or 3, and its condition is that v and w sum drop in 2 to 5 the scope.

23. the compound of claim 22, wherein v and w are 2.

24. the compound of claim 22 or 23, wherein R ³Be hydrogen.

25. each compound in the aforementioned claim, wherein E is a monocyclic groups.

26. the compound of claim 25, wherein E is benzyl ring or piperazine ring or piperidine ring.

27. the compound of claim 26, wherein E is a benzyl ring.

28. the compound of claim 26, wherein E is a piperidine ring, and its nitrogen-atoms is connected to bicyclic radicals X.

29. each compound in the claim 1 to 24, wherein E is as group listed in this paper table 3 or the table 4.

30. each compound, wherein part in the claim 1 to 29

Be the optional bicyclic heteroaryl that replaces.

31. the compound of claim 30, wherein bicyclic heteroaryl is pyridine or the pyrimidine ring that is fused to 5-or 6-unit's carbocyclic ring or heterocyclic aromatic ring, and a specific examples of this group is thieno-[3, a 2-d] pyrimidine group.

32. the compound of claim 31, wherein bicyclic radicals X takes following form:

G wherein ⁵Be hydrogen bond receptor atom or group, for example listed hydrogen bond receptor in this paper table 5.

33. each compound in the claim 1 to 29, wherein bicyclic radicals X is selected from:

34. the compound of claim 33, wherein bicyclic radicals X is selected from F1, F19 and F20.

35. the compound of claim 1, described compound have general formula (II):

And salt, solvate, tautomer and N-oxide compound,

Wherein group A be connected to phenyl ring between the position or contraposition, q is 0-4; R ^1a, R ², R ³And R ⁴Each limits in the claim as described above; And R ⁸Be selected from hydroxyl, halogen for example chlorine and bromine, trifluoromethyl, cyano group, optional by C _1-2The C that alkoxyl group or hydroxyl replace _1-4Alkyl oxygen base, optional by C _1-2The C that alkoxyl group or hydroxyl replace _1-4Alkyl and optional by the halogen phenyl that replaces of chlorine and bromine, trifluoromethyl, cyano group, methyl or methoxy for example.

36. the compound of claim 35, wherein q is 0,1 or 2, more preferably 0 or 1, most preferably be 0.

37. the compound of claim 35 or 36, wherein group A is connected to the contraposition of phenyl ring.

38. the compound of claim 37, described compound have general formula (IIa):

And salt, solvate, tautomer and N-oxide compound,

Wherein X, R ^1a, R ², R ³, R ⁴Each limits in the claim as described above with n, and x is 0 or 1, and y is 0,1 or 2.

39. the compound of claim 37, described compound have formula (IIb):

And salt, solvate, tautomer and N-oxide compound,

Wherein X, R ^1a, R ², R ³, R ⁴, x and y such as claim 37 qualification, and z is 0,1 or 2, its condition is that y and z sum are no more than 4.

40. the compound of claim 1, described compound have general formula (IIc):

And salt, solvate, tautomer and N-oxide compound,

Wherein group A is connected to the 3-position or the 4-position of piperidine ring, and q is 0-4; X, n, A, R ^1a, R ², R ³And R ⁴Each limits in the claim as described above, and R ¹⁰For being selected from following substituting group: halogen, hydroxyl, trifluoromethyl, cyano group, nitro, carboxyl, amino, list-or two-C _1-4Alkyl amino, have the carbocyclic ring and the heterocyclic group of 3 to 12 ring memberses; 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 ₂And R ^bBe selected from hydrogen, have carbocyclic ring and the heterocyclic group and the C of 3 to 12 ring memberses _1-8Alkyl, described C _1-8Alkyl is optional by one or more hydroxyl, oxo, halogen, cyano group, nitro, carboxyl, amino, list-or two-C that are selected from _1-4The substituting group of alkyl amino, the carbocyclic ring with 3 to 12 ring memberses and heterocyclic group replaces, and C wherein _1-8One or more carbon atoms of alkyl can be chosen wantonly by O, S, SO, SO ₂, NR ^c, X ¹C (X ²), C (X ²) X ¹Or X ¹C (X ²) X ¹Replace;

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

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

41. the compound of claim 40, wherein q is 0,1 or 2, more preferably 0 or 1, most preferably be 0.

42. the compound of claim 41, wherein n is 0.

43. the compound of claim 1, described compound have general formula (III):

And salt, solvate, tautomer and N-oxide compound,

Wherein X, R ^1b, R ⁴, Q ¹, Q ²And NR ²R ³Each limits in the claim as described above.

44. the compound of claim 1, described compound have formula (IV):

And salt, solvate, tautomer and N-oxide compound,

Wherein T is CH or N, T ¹Be S, O or NR ¹⁸R ¹⁶Be hydrogen or radicals R ¹⁰, R ¹⁷Be hydrogen or radicals R ⁴R ¹⁸Be hydrogen or C _1-4Alkyl; And A, E, R ^1aTo R ⁴And R ¹⁰Each limits in the claim as described above.

45. the compound of claim 44, wherein T is N, and T ¹Be selected from S, O and NH.

46. the compound of claim 45, wherein T ¹Be S.

47. the compound of claim 1, described compound has logical formula V:

And salt, solvate, tautomer and N-oxide compound,

Wherein X, R ², R ³And R ⁴Each limits in the claim as described above.

48. the compound of claim 43, described compound have general formula (VI):

And salt, solvate, tautomer and N-oxide compound,

Wherein m is 0,1 or 2; M ' is 0 or 1, and its condition is that m and m ' sum are 0-2; N is 0 or 1; P is 0,1,2 or 3; R ^xAnd R ^yIdentical or different, and be selected from hydrogen, methyl and fluorine respectively; R ¹²Be CN or NR ²R ³, and each R ¹³Independently be selected from R ¹⁰, wherein X, R ², R ³, R ⁴And R ¹⁰Each limits in the claim as described above.

49. the compound of claim 48, wherein m is 0 or 1, is preferably 0.

50. the compound of claim 48 or 49, wherein p is 0,1 or 2, and R ¹³Be selected from hydroxyl, C _1-4Acyloxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, benzyl oxygen base, cyano group, optional by C respectively _1-2The C that alkoxyl group or hydroxyl replace _1-4Alkyl oxygen base and C _1-4Alkyl.

51. the compound of claim 48, described compound have formula (VII):

And salt, solvate, tautomer and N-oxide compound,

R wherein ^x, R ^yAnd R ^wRespectively independent is hydrogen or methyl, and X, n, p, R ⁴And R ¹³Such as claim 48 qualification.

52. the compound of claim 51, wherein R ^xAnd R ^yThe two is hydrogen.

53. the compound of claim 43, described compound have formula (VIII):

And salt, solvate, tautomer and N-oxide compound,

R wherein ²⁵Be hydrogen or methyl, and X, R ¹³, R ⁴And R ^wLimit as claim 43 or its any dependent claims.

54. the compound of claim 53, wherein n is 0.

55. the compound of claim 53 or 54, wherein R ²⁵Be hydrogen.

56. each compound, wherein R in the claim 53 to 55 ^wBe hydrogen.

57. each compound, wherein R in the claim 53 to 55 ^wBe methyl.

58. each compound in the aforementioned claim, described compound are salt, solvate such as hydrate, ester or N-oxide form.

59. each compound in the claim 1 to 58, described compound are used to prevent or treat disease or the illness that is mediated by protein kinase B.

60. each compound is used to prepare the purposes of medicine in the claim 1 to 58, described medicine is used to prevent or treat disease or the illness that is mediated by protein kinase B.

61. prevention or treatment be by the disease of protein kinase B mediation or the method for illness, described method comprises in the experimenter's claim 1 to 58 that needs each compound.

62. a treatment comprises abnormal cell growth in the Mammals or by the method for its disease that causes or illness, described method comprises in the claim 1 to 58 that gives the amount that Mammals effectively suppresses abnormal cell growth each compound.

63. a treatment comprises abnormal cell growth in the Mammals or by the method for its disease that causes or illness, described method comprises the compound that gives in the claim 1 to 58 that Mammals effectively suppresses the active amount of PKB each.

64. the method for an arrestin kinase b, described method comprise kinases is contacted with each kinase inhibiting compound in the claim 1 to 58.

65. method by regulating cell processes with the activity of each compound arrestin kinase b in the claim 1 to 58.

66. a method for the treatment of immunologic derangement in the Mammals, described method comprise the compound that gives in the claim 1 to 44 that Mammals effectively suppresses the active amount of PKB each.

67. each compound in the claim 1 to 58, described compound are used to prevent or treat disease or the illness that is mediated by protein kinase A.

68. each compound is used to prepare the purposes of medicine in the claim 1 to 58, described medicine is used to prevent or treat disease or the illness that is mediated by protein kinase A.

69. each formula (I) compound is used to prepare the purposes of medicine in the claim 1 to 58, described medicine is used to prevent or treat disease or the illness that is caused by abnormal cell growth.

70. each formula (I) compound is used to prepare the purposes of medicine in the claim 1 to 58, described medicine be used to prevent or treat propagation is wherein arranged, apoptosis or the disorderly disease of differentiation.

71. prevention or treatment be by the disease of protein kinase A mediation or the method for illness, described method comprises in the experimenter's claim 1 to 58 that needs each compound.

72. a treatment comprises abnormal cell growth in the Mammals or by the method for its disease that causes or illness, described method comprises in the claim 1 to 58 that gives the amount that Mammals effectively suppresses PKA each compound.

73. the method for an arrestin kinases A, described method comprise kinases is contacted with each kinase inhibiting compound in the claim 1 to 58.

74. method by regulating cell processes with the activity of each compound arrestin kinases A in the claim 1 to 58.

75. a method for the treatment of immunologic derangement in the Mammals, described method comprise the compound that gives in the claim 1 to 58 that Mammals effectively suppresses the active amount of PKA each.

76. the apoptotic method of inducing cancer cell, described method comprise cancer cells is contacted with each compound in the claim 1 to 58.

77. a pharmaceutical composition, described pharmaceutical composition comprise in the claim 1 to 58 each new compound and pharmaceutically acceptable carrier.

78. each compound in the claim 1 to 58, described compound is used for medicine.