CN101454326A

CN101454326A - Triazolopyrazine compounds useful for the treatment of degenerative & inflammatory diseases

Info

Publication number: CN101454326A
Application number: CNA2007800191562A
Authority: CN
Inventors: M·J·I·安德鲁斯; P·爱德华兹; M·S·钱伯斯; W·施密特; J·A·克拉塞; G·巴尔; K·L·赫斯特; A·麦克劳德
Original assignee: Galapagos NV
Current assignee: Galapagos NV
Priority date: 2006-05-31
Filing date: 2007-05-30
Publication date: 2009-06-10

Abstract

Novel [1.2.4]triazolo[1,5-a]pyrazine compounds are disclosed that have a formula represented by the following (formula I). The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, arthritis, inflammation, and others.

Description

The triazolopyrazine compounds that is used for the treatment of sex change and inflammatory diseases

Invention field

The present invention relates to a class can be in conjunction with the triazolopyrazine compounds of serine/threonine kinase avtive spot, and this kinase whose expression relates to the approach that causes extracellular matrix (ECM) degraded, joint degeneration and relate to the disease of this type of degraded and/or inflammation.

The disease that relates to extracellular matrix degraded includes but not limited to psoriatic arthritis, childhood sacroiliitis, early stage sacroiliitis, reactive arthritis, osteoarthritis, ankylosing spondylitis, osteoporosis, musculoskeletal disease (for example tendinitis and periodontal disease), cancer metastasis, airway disorders (COPD, asthma), kidney and hepatic fibrosis, cardiovascular disorder (for example atherosclerosis and heart failure) and sacred disease (for example neuritis and multiple sclerosis).The disease that relates to the primary joint degeneration includes but not limited to psoriatic arthritis, childhood sacroiliitis, early stage sacroiliitis, reactive arthritis, osteoarthritis and ankylosing spondylitis.

Rheumatoid arthritis (RA) is chronic degenerative joint disease, it is characterized in that the inflammation and the destruction of articulation structure.When disease is undetected, owing to the forfeiture of function of joint and even premature dead cause substantial deformity and pain.Therefore, the target of RA treatment is not the disease that slows down, but obtains to alleviate, so that stop destruction of joint.Except disease result's seriousness, the high morbidity of RA (adult in the whole world about 0.8% is influenced) means high socioeconomic impact.(for the summary of RA, with reference to Smolen and Steiner (2003); Lee and Weinblatt (2001); Choy and Panayi (2001); O ' Dell (2004) and Firestein (2003)).

Although what accept extensively is that RA is an autoimmune disease, there is not consensus about the accurate mechanism that causes disease " initial period ".Be known that the cascade of start trigger agent mediation incident in susceptible host, this causes various kinds of cell type (B cell, T cell, scavenger cell, inoblast, endotheliocyte, dendritic cell and other cell) activation.The consequent is that the output of observing the various kinds of cell factor in joint and periarticular tissue increases (for example TNF-α, IL-6, IL-1, IL-15, IL-18 and other cytokine).When disease progression, cell activation and cytokine generate cascade and become self-perpetuating.At this commitment, the destruction of articulation structure is very obvious.30% patient diagnosis the time have the X roentgenogram x evidence of bone erosion and after 2 years this ratio rise to 60%.

The histologic analysis in RA patient joint has clearly proved the mechanism that relates to RA related degradation process.This analysis shows that to the RA associated joint it is pannus that degraded has the main effects device of response, and wherein synovia inoblast (by producing the multiple protein lytic enzyme) is the main driving of cartilage and bone erosion.The joint typically comprises the bone of two vicinities, and it is connected on the cartilage layers of being surrounded by synovia and joint capsule.Among the RA patient, the synovium of joint size increases to form pannus late, and this is because the infiltration of synovia fibroblasts proliferation and monocyte (for example T cell, B cell, monocyte, scavenger cell and neutrophilic granulocyte) causes.The degraded of the contiguous cartilage of pannus mediation causes the narrow of joint cavity, and has the bone of the vicinity of invading and the potentiality of cartilage.Because bone and cartilaginous tissue mainly are made up of collagen I type or II type respectively, destruction of pannus and invasion character are the secretion mediations by procollagen enzyme (mainly being matrix metalloproteinase (MMPs)).Be positioned at below the cartilage and the erosion of contiguous bone also is the part of RA process, and mainly cause by the existence of the osteoclast at bone and pannus interface.Osteoclast is a syncyte, and it adheres to osseous tissue, forms closed compartment, and the proteolytic enzyme of the degraded of osteoclast secretion therein osseous tissue (cathepsin K, MMP9).Osteoclast group in the joint is formed by osteoclast and unusual increasing, and osteoclast to be secretion inductive precursor cell by the receptor activator (RANKL) of the NF κ B part of SF and T cell activation form.

Multiple collagen-type has vital role in the stability of definition extracellular matrix (ECM).For example collagen I type and collagen I I type are respectively the main components of bone and cartilage.Collagen protein is formed the polygene structure usually, and it is called as collagen fibril.Natural collagen fibril has very strong resistibility to proteolytic cleavage.Reported that only the ECM protein degradation of a few types has the ability of degraded natural collagen: MMP and kethepsin.In kethepsin, the tool feature of cathepsin K (it mainly has activity in osteoclast).Known MMP1, MMP2, MMP8, MMP13 and MMP14 have the procollagen characteristic in MMP.The MMP1 that synovia inoblast (SF) is expressed increase and the process of arthritis disease between dependency clearly and be omen people such as (, 2001) Cunnane of joint erosion process.Therefore, in the context of RA, MMP1 represents the collagen degradation albumen of height correlation.External, the SF that cultivates with relevant cytokine (for example TNF-α and the IL1 β) treatment of RA pathology will increase MMP1 people such as (, 2003) Andreakos of these cell expressings.Therefore, the MMP1 that monitoring SF expresses is a relevant readings in the RA field, because its indication SF is to corroding the activation of phenotype, described erosion phenotype has response to cartilage degradation in vivo.For the treatment of RA, the MMP1 that suppresses the SF expression represents valuable methods of treatment.

The activity of ECM-degrade proteins can also be the reason of disease (for example other relates to the disease of joint degraded) of the multiple RA of being different from or associated.These diseases include but not limited to psoriatic arthritis, childhood sacroiliitis, early stage sacroiliitis, reactive arthritis, osteoarthritis and ankylosing spondylitis.Other disease that the compounds for treating that can determine with the present invention and application relate to the target that MMP described herein expresses is an osteoporosis, musculoskeletal disease (tendinitis and periodontal disease (people such as Gapski for example, 2004)), cancer metastasis (people such as Coussens, 2002), airway disorders (COPD, asthma) (people such as Suzuki, 2004), lung, renal fibrosis (people such as Schanstra, 2002), the hepatic fibrosis relevant (people such as Reiff with chronic hepatitis C, 2005), cardiovascular disorder (for example atherosclerosis and heart failure (people such as Creemers, 2001)) and sacred disease (for example neuritis and multiple sclerosis (people such as Rosenberg, 2002)).The patient who suffers from this type of disease can be benefited from stablize ECM (avoiding degraded by protecting it).

471 amino acid whose serine/threonine kinases (being accredited as mitogen-activated protein kinase activated protein kinase 5 (MAPKAPK5 or PRAK)) are being expressed in a series of tissues widely.This albumen comprises the catalytic domain of N-end and the nuclear localization signal (NLS) and the nuclear export signal (NES) of C-end.Endogenous MAPKAPK5 mainly is present in the tenuigenin, but cell stress or its transposition of cytokine activation mediation people such as (, 2003) New to nuclear.This incident depends on the phosphorylation of MAPKAPK5.Thr182 is the adjusting phosphorylation site of MAPKAPK5.Although the p38 alpha kinase can crossed phosphorylation MAPKAPK5 under the expression environment, do not support this hypothesis people such as (, 2003) Shi about the test of endogenous MAPKAPK5.Produced the MAPKAPK5 knock-out mice, it is survivable and is fertile.The phenotype of these mouse is different from phenotype people such as (, 2003) Shi of MAPKAPK2 (it is the MAPKAPK5 associated kinase of being regulated by p38 α) deficient mice fully.This shows that every kind of proteinic function is different and does not have a kind of kinases can compensate other kinase whose activity.In the lump, MAPKAPK5 and the different target that does not have unnecessary effect of MAPKAPK2 representative.Recently, MAPK6 (being also referred to as ERK3) is accredited as the physiology related substrates of MAPKAPK5, and it has defined new signal transduction pathway (people such as Seternes, 2004).

Background of invention

The quality of life that NSAIDS (NSAID (non-steroidal anti-inflammatory drug)) is used to alleviate the pain relevant with RA and improves the patient.But the not effect of destruction of joint that these medicines will be relevant to RA.

Find that glucocorticosteroid reduces the process of RA (detecting as the X roentgenogram x) and with low dose applications in treatment part RA patient (30 to 60%).But severe side effect relevant with the prolonged application glucocorticosteroid (thinning of skin, osteoporosis, cataract, hypertension, hyperlipidaemia).

Synthetic DMARD (antirheumatic that palliates a disease) (for example methotrexate, leflunomide, sulfasalazine) mainly handles the immunoinflammatory component of RA.As main drawback, these medicines only have limited effect (destruction of joint is only slowed down by DMARD and do not stop, so disease process continues for a long time).The shortage of effect is shown by such fact: average only 30% patient obtains the ACR40 branch with the methotrexate treatment after 24 months.This means that according to U.S. rheumatism institute (AmericanCollege of Rheumatology) only 30% patient obtains 50% doing well,improving (O ' people such as Dell, 1996).In addition, the accurate mechanism of DMARD effect is normally unclear.

Biology DMARD (infliximab, etanercept, adalimumab, Rituximab, CTLA4-Ig) is therapeutic protein (people such as Kremer, 2003 of the as killed cells factor (for example TNF-α) or cell (for example T cell or B cell) (it has vital role in the RA physiopathology); People such as Edwards, 2004).Although TNF-alpha blocker (infliximab, etanercept, adalimumab) and methotrexate combined therapy are the most effective at present applicable RA treatments, noticeable is this treatment acquisition 50% improve (ACR40) people such as (, 2004) St Clair in 50-60% disease of patient symptom only after the treatment in 12 months.Have some deleterious event alerts for anti-TNF-α medicine, this clearly shows the side effect relevant with this type of medicine.Increase (tuberculosis), hematology incident and the demyelination obstacle (also referring to people such as Gomez-Reino, 2003) of infection risk have been described for the TNF-alpha blocker.Except severe side effect, the TNF-alpha blocker also has the general shortcoming of biology kind treatment, and they are that offending route of administration (following the frequent injection of transfusion part reaction) and high production expend.Be in new drug target T cell co-stimulatory molecules and the B cell of nearest development stage.The effect expection of these medicines is similar with the TNF-alpha blocker.The fact of multiple targeted therapy has similar but limited effect, and this shows for RA and has a plurality of paathogenic factors.Also point out in the deficiency aspect the understanding of the pathogenic incident relevant with RA.

Because limited effect, the treatment for RA is unsafty (patient for 30% does not have enough treatments) at present.This just needs other strategy to obtain to alleviate.Alleviation needs, because residual disease has the risk of carrying out property joint injury, and therefore has the risk of progressive disability.The immunoinflammatory component (it represents the main target of medicine used in the present RA treatment) that suppresses the RA disease can not cause the blocking-up (item key of disease) of joint degraded.

US 2005/0009832 has described imidazo [1, the 2-a] pyrazine-8-base-amine as the replacement of protein kinase (comprising MAPKAPK5) conditioning agent.WO02/056888 has described as the MAPKAPK5 inhibitor that can regulate the TNF conditioning agent of some cytokine-expressing.These formerly technical literature be not disclosed in any compound in the scope of a compounds described below.

Summary of the invention

The present invention is based on following discovery: cause that MAPKAPK5 function and MAPKAPK5 activity inhibitor (for example The compounds of this invention) in the approach of expression of MMP1 are used for the treatment of the disease that relates to the active unusual high expression level of MMP.

The compounds of this invention can be described as 5 usually and be replaced by aryl and heteroaryl and [1,2,4] triazolo [1,5-a] pyrazine-8-base-amine that 8 are replaced by arylamino or heteroaryl amino.

More particularly, the present invention relates in mammalian cell, have formula (I) compound or pharmaceutically acceptable salt thereof, hydrate, solvate or the prodrug of matrix metalloproteinase rejection characteristic:

Wherein

A and B are CR2R independently ", NR ", oxygen or sulphur;

AA is CR2 or N;

D is C=O, CR2R " or NR ";

When k was 0, E was NH or CR " R6, and when k was 1, E was NH or CR " R6a;

F is sulphur, oxygen or NH;

T is oxygen or NR;

U, V, W and X are CR independently " R7 or NR ";

Y is CR " or N;

Z is hydrogen, amino, hydroxyl, lower alkoxy, formamyl, carboxyl, SO ₂Rz, SO ₂NRRz ,-NR (CO) (CH2) d-Rz ,-NRRz ,-(CO)-ORz ,-(CO)-NR (CH2) d-Rz or

R is hydrogen or low alkyl group independently;

R " be H or form two keys with adjacent atom;

R1 is H; R2; Or low alkyl group, low-grade cycloalkyl and low alkyl group-low-grade cycloalkyl, optional replaced by one or more R2;

R3 be H or with contiguous R " form two keys;

R2 is H, F, Cl, CN, COOR4, OR4, C (O) N (R4R5), S (O) 2N (R4R5), low alkyl group, O-low alkyl group, NH-low alkyl group, S-low alkyl group, COO-low alkyl group, OC (O)-low alkyl group, C (O) N (R4)-low alkyl group, S (O) ₂N (R4)-low alkyl group, S (O) N (R4)-low alkyl group, S (O) ₂-low alkyl group, S (O)-low alkyl group, N (R4) S (O) ₂-low alkyl group and N (R4) S (O)-low alkyl group, wherein each low alkyl group is optional is replaced by one or more F and Cl.

R4 and R5 are H independently; F, Cl; Or low alkyl group, low-grade cycloalkyl or low alkyl group-low-grade cycloalkyl, optional by one or more F and Cl replacement;

R6 is hydrogen, amino, hydroxyl, formamyl, carboxyl, SO ₂R, NRR ' ,-(CO)-OR or-(CO)-NRR ';

R6a is R6, Cl, F, lower alkoxy, cyano group, trifluoromethoxy; Or with contiguous being-(CHR ") _n-NR-(CHR ") _p-, and ring condensed 5 or 6 yuan of heterocycles of formation and its bonding;

R7 is hydrogen, halogen, low alkyl group or lower alkoxy independently;

Rz is a hydrogen, low alkyl group, low-grade alkane acidyl, phenyl, 1-low alkyl group tetramethyleneimine-3-base, pyrazoles-4-base, pyrazoles-2-base or low alkyl group, low-grade alkane acidyl, phenyl, 1-low alkyl group tetramethyleneimine-3-base, pyrazoles-4-base, pyrazoles-2-base or pyridin-3-yl replaced by one or more following groups: hydroxyl, amino, one or two elementary alkyl amido, kharophen, low-grade alkane acidyl, low alkyl group, 4-hydroxyl-phenyl, the 3-aminomethyl phenyl, the low alkyl group alkylsulfonyl, 4-two elementary alkyl amido phenyl, pyridin-3-yl, the 1H-indol-3-yl, morpholine-4-base;

R and Rz can be together-(CHR) _q-T-(CHR) r-and

form

5 or 6 yuan of heterocycles with the nitrogen of their bondings;

Rz and R7 can be together-(CHR ") _n-NR-(CHR ") _p-, and ring condensed 5 or 6 yuan of heterocycles of formation and its bonding;

B and d are 0 or 1 independently; Condition is that at least one is 1 among b or the d;

K is 0 or 1;

M is 0 or 1;

N and p are 0,1 or 2 independently;

Q and r are 1 or 2;

X is 0 or 1;

Condition is that at least one is not a hydrogen among R7 or the Rz;

Another aspect of the present invention be formula III compound or pharmaceutically acceptable salt thereof, solvate or prodrug with and steric isomer, isotopic variations and tautomer:

Wherein

R ¹Be H or replacement or unsubstituted alkyl; And each R ⁸And R ⁹Be independently selected from replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl.

In one embodiment, about formula III compound, R ⁸Be selected from replacement or unsubstituted cyclopentyl, cyclohexyl, replacement or unsubstituted phenyl, replacement or unsubstituted pyridine base, replacement or unsubstituted pyrimidine and replacement or unsubstituted pyrazine, replacement or unsubstituted pyrroles, replacement or unsubstituted pyrazoles and replacement or unsubstituted imidazoles.

In one embodiment, about formula III compound, R ¹Be H, Me, Et, i-Pr or CF ₃

In one embodiment, about formula III compound, R ¹Be H.

Another aspect of the present invention relate to formula IVa, IVb, IVc or IVd compound or pharmaceutically acceptable salt thereof, solvate or prodrug with and steric isomer, isotopic variations and tautomer:

And wherein L be key ,-CO-,-O (CH ₂) _M1-,-CON (H) (CH ₂) _M1-or-NHCO-; Subscript m 1 is selected from 1-4; Ring P is that replace or unsubstituted Heterocyclylalkyl; Subscript n is selected from 1-4; Each R ^8aBe independently selected from hydrogen, replacement or unsubstituted alkyl, alkoxyl group, cyano group, formamyl, CHO and halogen; And R ⁹Be independently selected from replacement or unsubstituted aryl and heteroaryl.

In one embodiment, about formula III-IVd compound, R ⁹Be that replace or unsubstituted aryl.In another embodiment, R ⁹Be that replace or unsubstituted phenyl.

In one embodiment, about formula III-IVd compound, R ⁹Be that replace or unsubstituted heteroaryl.In another embodiment, R ⁹Be replace or the unsubstituted pyridine base.

In one embodiment, about formula III-IVd compound, R ⁹Be selected from replacement or unsubstituted phenyl, indyl, pseudoindoyl, pyrryl, furyl, thienyl, pyrazolyl, oxazolyl and thiazolyl.

Further, the invention provides pharmaceutical composition, this pharmaceutical composition comprises triazolopyrazine compounds of the present invention and pharmaceutical carrier, vehicle or thinner.In this aspect of the invention, pharmaceutical composition can comprise one or more compounds described herein.In addition, the The compounds of this invention of using in pharmaceutical composition and the methods of treatment disclosed herein all is pharmaceutically useful as preparation with what use.

Another aspect of the present invention relates to The compounds of this invention at methods of treatment, pharmaceutical composition and prepare purposes in this based composition; its disease that is used for the treatment of comprises inflammation, collagen degradation and particularly has unusual matrix metalloproteinase (MMP1) and/or the disease of mitogen-activated protein kinase activated protein kinase 5 (MAPKAPK5) living features that wherein rheumatoid arthritis (RA) is the special example of this type of disease.The invention still further relates to the method for preparing The compounds of this invention.

By considering detailed subsequently description (it carries out with reference to following illustrative embodiments), other target and advantage will become apparent for those skilled in the art.

Summary of drawings

Fig. 1. this figure shows significant histology difference between healthy joint and the RA patient joint.

Fig. 2. this figure shows that the expression of MMP1 in the synovia inoblast that is triggered by the cytokine that relates to rheumatoid arthritis Neo-Confucianism increases.

Fig. 3. this figure shows the MMPI that is expressed by SF by known anti-inflammatory compound dosage dependence inhibition " based on TNF-α triggering agent " inductive.

Fig. 4. this glue shows the reduction that MAPKAPK5 expresses at protein level among the SF that causes by the Ad-siRNA virus infected cell with target MAPKAPK5.

Fig. 5. this figure shows the reduction of the MMP1 level that ' complex body triggers agent (complex trigger) ' inductive that the Ad-siRNA virus by target MAPKAPK5 causes is expressed by SF.

Detailed Description Of The Invention

Definition

When the description compound, when comprising the pharmaceutical composition of this compounds and using the method for this compounds and composition, unless otherwise indicated, otherwise following term has following implication. It is to be further understood that any group that defines in the context can be replaced by multiple substituting group, and definition separately is intended to be included in the substituted radical in its scope. In the mode of limiting examples, this type of substituting group for example can comprise halogen (for example fluorine, chlorine, bromine) ,-CN, CF₃、-OH、-OCF ₃、C ₂-C ₆Alkenyl, C₃-C ₆Alkynyl, C₁-C ₆Alkoxyl, aryl and two-C₁-C ₆Alkyl amino. Should be understood that further that term " group " and " base " are when can consider exchange when this paper uses.

" alkoxyl " refers to alkyl-O-. The example of alkoxyl comprise methoxyl group, ethyoxyl, just-propoxyl group, different-propoxyl group, just-butoxy and heptan the oxygen base. Preferred alkoxyl is lower alkoxy.

" alkyl " refers to has the 1 straight or branched aliphatic hydrocarbon to about 20 carbon atoms. Preferred alkyl has 1 to about 12 carbon atoms. Low alkyl group more preferably. Side chain refers to one or more low alkyl groups (for example methyl, ethyl or propyl group) and is connected on the linear alkyl chain.

" alkyl amino " refers to alkyl-NH-. Preferred alkyl amino is (C₁-C ₆)-alkyl amino. The example of alkyl amino comprises methylamino and ethylamino.

" amino low-grade alkane acidyl " refers to NH₂-R-CO-, wherein R is low-grade alkylidene. Preferred group comprises glycyl (ethanoyl) and glycyl (acetyl).

" carbamoyl low alkyl group " refers to group NH₂The CO-low alkyl group-. Preferred group comprises carbamoyl ethyl and carbamyl ylmethyl.

" carboxyl low-grade alkyl ester " refers to the lower alkyl esters of carboxyl (COO-group).

" the compounds of this invention " and the expression that is equal to refer to and comprise above-described formula (I, II or III) compound, and this expression comprises prodrug, officinal salt and solvate (for example hydrate), and wherein context is like this license. Similarly, with reference to intermediate, no matter himself whether be required, refer to the salt and the solvate that comprise them, wherein context is like this license.

" expression " refers to endogenous expression.

" halo " or " halogen " refers to fluorine, chlorine, bromine or iodine.

" hydrogen " in context, refer to exist in the compound position-H and comprise the substituting group of its isotope (deuterium).

" low-grade alkane acidyl is amino " refers to the amino with organic functional group R-CO-, and wherein R represents low alkyl group.

" low alkyl group " refer on the linear alkyl chain that can be straight or branched 1 to about 6 carbon atoms.

" lower alkoxy " on the linear alkyl chain that can be straight or branched 1 to about 6 carbon atoms, and it is by the oxygen atom bonding.

" low alkyl group sulfonamide " refers to formula-SO₂NR ^＊R ^＊The low alkyl group acid amides of sulfonamide, R wherein^＊Hydrogen or low alkyl group, and at least one R^＊It is low alkyl group.

" prevention " refers to the method for taking for prevent disease.

" solvate " refers to the physical union for compound of the present invention and one or more solvent molecules. This physical union comprises hydrogen bond. In some cases, solvate can separate, for example when one or more solvent molecules are impregnated in the lattice of crystalline solid. " solvate " comprises solution phase and separable solvate. The compounds of this invention can be for example with the crystalline form preparation and can be solvation or hydration. The solvate that is fit to comprises the acceptable solvent compound, hydrate for example, and further comprise stoichiometric solvate and non-stoichiometric solvate. Conventional solvent comprises water, ethanol, acetic acid etc., and therefore, representational solvate comprises hydrate, alcoholate and methylate.

" replacement " refers in the molecule atom or atomic radical is replaced by other atom or group.

" sulfonamide " refers to and comprises chemical group-SO₂NH ₂The compound group.

" treatment effective dose " refers to and can cause individual biology or the medicine of medicinal response (it is that medical science doctor or other clinician explore) or the amount of medicament. " treatment effective dose " can depend on compound, disease and the order of severity thereof and the age of the individuality for the treatment of, body weight etc. and different. Specifically, have the disease illness of extracellular matrix degraded feature about treatment, term " effectively matrix metalloproteinase amount of suppression " is intended to refer to and causes MMP1 produces in the individual affect tissue the significant reduction of biology so that the amount of the compounds of this invention that the free burial ground for the destitute reduction is had a mind in the extracellular matrix degraded. Compound or " matrix metalloproteinase Inhibitor " with matrix metalloproteinase rejection characteristic refer to the compounds of this invention that can cause the significant reduction of biology that MMP1 produces in this type of cell that effective dose is provided to cell.

" aryl " refers to the unit price aromatic hydrocarbon radical, and its single carbon atom from female aromatics ring system is removed a hydrogen atom and derived. Typical aryl includes but not limited to derived from following group: aceanthrylene, acenaphthene, the luxuriant and rich with fragrance alkene (acephenanthrylene) of vinegar, anthracene, Azulene, benzene,, guan, fluoranthene, fluorenes, hexacene, hexaphene, oneself takes alkene (hexalene), asymmetric-indacene (as-indacene), symmetry-indacene (s-indacene), 1,2-dihydroindene, indenes, naphthalene, and eight benzene (octacene), Xin Fen (octaphene), suffering take alkene (octalene), ovalene, penta-2,4-diene, pentacene, pentalene (pentalene), pentaphene, perylene, non-that alkene (phenalene), Fei, Pi, seven days of the week alkene (pleiadene), pyrene, pyranthrene, rubicene, benzo [9,10] phenanthrene, trinaphthylene (trinaphthalene) etc. Specifically, aryl comprises 6 to 14 carbon atoms.

" aryl of replacement " comprises those groups of describing in this paper " replacement " definition; and refer specifically to and can choose wantonly by one or more substituting groups, for example 1 to 5 substituting group, particularly 1 to 3 aryl that substituting group replaces, described substituting group be selected from the thio alkoxy, thioaryl oxygen base, sulfydryl, alkyl-S-(O) of cycloalkyl, halogen, hydroxyl, nitro, thio alkoxy, the replacement of amino, amino carbonyl, amino carbonyl amino, amino carbonyl oxygen base, aryl, aryloxy, azido, carboxyl, cyano group, cycloalkyl, the replacement of alkynyl, amino, the replacement of alkyl, alkynyl, the replacement of alkoxyl, alkoxy carbonyl, alkyl, the replacement of alkenyl, alkoxyl, the replacement of acyl group, acyl amino, acyloxy, alkenyl, replacement-, aryl-S-(O)-, alkyl-S-(O)₂-and aryl-S-(O)₂-。

" aryl bicyclic " refers to by a hydrogen atom on the single carbon atom of parent bicyclic aromatic ring system is removed the unit price aromatic hydrocarbon radical of deriving. Typical aryl bicyclic includes but not limited to derived from following group: 1,2-dihydroindene, indenes, naphthalene, tetrahydronaphthalene etc. Specifically, aryl comprises 8 to 11 carbon atoms.

" bicyclic heteroaryl " refers to by a hydrogen atom on the single atom of parent bicyclic heteroaromatic ring system being removed the unit price bicyclic heteroaromatic group of deriving. Typical bicyclic heteroaryl includes but not limited to derived from following group: benzofuran, benzimidazole, benzo indazole, benzodioxan, chromene, look alkane, cinnolines, phthalazines, indoles, indoline, indolizine, isobenzofuran, heterochromatic alkene, iso-indoles, isoindoline, isoquinolin, benzothiazole, benzoxazole, 1,5-benzodiazine, Ben Bing oxadiazole, pteridine, purine, chromene, benzopyrazines, Pyridopyrimidine, quinazoline, quinoline, quinolizine, quinoxaline, benzomorphans, tetrahydroisoquinoline, tetrahydroquinoline etc. Preferably, bicyclic heteroaryl is the bicyclic heteroaryl between the 9-11 unit, particularly preferably 5-10 unit heteroaryl. Special bicyclic heteroaryl is derived from benzothiophene, benzofuran, benzothiazole, indoles, quinoline, isoquinolin, benzimidazole, benzoxazole and benzodioxan.

" carbamoyl " refers to group-C (O) N (R⁴²) ₂, each R wherein⁴²Group is hydrogen, alkyl, cycloalkyl or the aryl that this paper defines independently, and it can choose being substituted as defined herein wantonly. In special embodiment, term " carbamoyl " refers to-C (O)-NH₂。

" cycloalkyl " refers to be had 3 to about 10 carbon atoms and has monocycle or the cyclic hydrocarbon radical of a plurality of condensed ring (comprise condense with bridged ring system), and it can be chosen wantonly by 1 to 3 alkyl and replace. This type of cycloalkyl comprises single ring architecture such as cyclopropyl, cyclobutyl, cyclopenta, ring octyl group, 1-methyl cyclopropyl, 2-methylcyclopentyl, 2-methyl ring octyl group etc. in the mode of example, and multiring structure such as adamantyl etc.

" cycloalkyl of replacement " comprises those groups of describing in this paper " replacement " definition; and refer specifically to have one or more substituting groups, for example 1 to 5 substituting group and particularly 1 to 3 substituent cycloalkyl, described substituting group be selected from the thio alkoxy, thioaryl oxygen base, sulfo-ketone group, sulfydryl, alkyl-S-(O) of cycloalkyl, halogen, hydroxyl, ketone group, nitro, thio alkoxy, the replacement of amino, amino carbonyl, amino carbonyl amino, amino carbonyl oxygen base, aryl, aryloxy, azido, carboxyl, cyano group, cycloalkyl, the replacement of alkoxyl, alkoxy carbonyl, alkoxycarbonyl amino, amino, the replacement of acyl group, acyl amino, acyloxy, alkoxyl, replacement-, aryl-S (O)-, alkyl-S (O)₂-and aryl-S (O)₂-。

" replacement " refers to the group that wherein one or more hydrogen atoms are replaced by identical or different substituting group independently of one another. Typical substituting group includes but not limited to-X ,-R⁴⁶、-O ^-、＝O、-OR ⁴⁶、 -SR ⁴⁶、-S-、＝S、-NR ⁴⁶R ⁴⁷、＝NR ⁴⁶、-CX ₃、-CF ₃、-CN、-OCN、-SCN、 -NO、-NO ₂、＝N ₂、-N ₃、-S(O) ₂O ^-、-S(O) ₂OH、-S(O) ₂R ⁴⁶、-OS(O ₂)O ^-、 -OS(O) ₂R ⁴⁶、-P(O)(O ^-) ₂、-P(O)(OR ⁴⁶)(O ^-)、-OP(O)(OR ⁴⁶)(OR ⁴⁷)、-C(O)R ⁴⁶、 -C(S)R ⁴⁶、-C(O)OR ⁴⁶、-C(O)NR ⁴⁶R ⁴⁷、-C(O)O ^-、-C(S)OR ⁴⁶、 -NR ⁴⁸C(O)NR ⁴⁶R ⁴⁷、-NR ⁴⁸C(S)NR ⁴⁶R ⁴⁷、-NR ⁴⁹C(NR ⁴⁸)NR ⁴⁶R ⁴⁷With-C (NR⁴⁸)NR ⁴⁶R ⁴⁷, wherein each X is halogen independently; Each R⁴⁶、R ⁴⁷、R ⁴⁸And R⁴⁹Be independently heteroaryl, heteroaryl alkyl, the replacement of assorted alkyl, heteroaryl, the replacement of alkyl, cycloalkyl, the alkyl of replacement, the assorted alkyl of ring of alkyl, aryl alkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement heteroaryl alkyl ,-NR⁵⁰R ⁵¹、-C(O)R ⁵⁰Or-S (O)₂R ⁵⁰Perhaps choose R wantonly⁵⁰And R⁵¹The atom that all connects with them forms the assorted alkyl ring of the ring that encircles assorted alkyl or replacement; And R⁵⁰And R⁵¹The heteroaryl alkyl of heteroaryl, heteroaryl alkyl or replacement of assorted alkyl, heteroaryl, the replacement of alkyl, cycloalkyl, the alkyl of replacement, the assorted alkyl of ring of alkyl, aryl alkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement independently.

The example of the aryl of representational replacement comprises following:

With

In these formulas, R⁵²And R⁵³One of can be hydrogen and R⁵²And R⁵³In at least one is selected from the assorted alkyl of alkyl, alkenyl, alkynyl, ring, alkanoyl, alkoxyl, aryloxy, heteroaryl oxygen base, alkyl amino, arylamino, heteroaryl amino, NR independently of one another⁵⁴COR ⁵⁵、NR ⁵⁴SOR ⁵⁵、 NR ⁵⁴SO ₂R ⁵⁷, COO alkyl, COO aryl, CONR⁵⁴R ⁵⁵、CONR ⁵⁴OR ⁵⁵、NR ⁵⁴R ⁵⁵、 SO ₂NR ⁵⁴R ⁵⁵, S-alkyl, S-alkyl, SO alkyl, SO₂Alkyl, S aryl, SO aryl, SO₂Aryl; Perhaps can be with R⁵²And R⁵³Be connected to form the ring (saturated or unsaturated) of 5 to 8 atoms, the optional hetero atom that comprises one or more N of being selected from, O or S. R⁵⁴、R ⁵⁵And R⁵⁶Be independently the assorted alkyl of hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, cycloalkyl, ring, aryl, replacement aryl, heteroaryl, replacement or assorted alkyl etc.

When the compound that exists on being used for the description compound or group, one or more carbon atoms that " mixing " refers in compound or the group are replaced by nitrogen, oxygen or sulfur heteroatom. Assorted can be used for any above-mentioned alkyl, alkyl assorted alkyl for example for example, cycloalkyl is for example encircled assorted alkyl, and aryl is heteroaryl for example, cycloalkenyl group, the ring thiazolinyl etc. of mixing, it has 1 to 5 and 1 to 3 hetero atom particularly.

" heteroaryl " refers to from the single atom of parent heteroaromatic ring system and removes a hydrogen atom and the unit price heteroaromatic group of deriving. Typical heteroaryl includes but not limited to derived from following group: acridine, arsindole, carbazole, B-carboline, look alkane, chromene, cinnolines, furans, imidazoles, indazole, indoles, indoline, indolizine, isobenzofuran, heterochromatic alkene, iso-indoles, isoindoline, isoquinolin, isothiazole, Yi oxane, 1,5-benzodiazine, oxadiazole, oxazole,

Pyridine, phenanthridines, phenanthroline, azophenlyene, phthalazines, pteridine, purine, pyrans, pyrazine, pyrazoles, pyridazine, pyridine, pyrimidine, pyrroles, pyrroles's piperazine (pyrrolizine), quinazoline, quinoline, quinolizine, quinoxaline, tetrazolium, thiadiazoles, thiazole, thiophene, triazole, xanthene etc. Preferably, heteroaryl is the heteroaryl between the 5-15 unit, particularly preferably 5-10 unit heteroaryl. Special heteroaryl is derived from thiophene, pyrroles, benzothiophene, benzofuran, indoles, pyridine, quinoline, imidazoles, oxazole and pyrazine.

The example of representational heteroaryl comprises following:

Wherein each Y is selected from carbonyl, N, NR⁵⁸, O and S; And R⁵⁸Hydrogen, alkyl, cycloalkyl, the assorted alkyl of ring, aryl, heteroaryl, assorted alkyl etc. independently.

Term used herein " the assorted alkyl of ring " refers to the heteroatomic stable non-aromatic ring of heterocycle and the condensed ring that comprise one or more N of being independently selected from, O and S. The heterocycle system that condenses can comprise carbocyclic ring and only need to comprise a heterocycle. The example of heterocycle includes but not limited to piperazinyl, homopiperazine base, piperidyl and morpholinyl, and shows in following illustrative example:

Wherein each X is selected from CR⁵⁸ ₂、NR ⁵⁸, O and S; And each Y is selected from NR⁵⁸, O and S; And R⁵⁸Hydrogen, alkyl, cycloalkyl, the assorted alkyl of ring, aryl, heteroaryl, assorted alkyl etc. independently. The assorted alkyl ring of these rings can be chosen wantonly by one or more and be selected from following group and replace: the thio alkoxy of the cycloalkyl of the amino of the alkoxyl of acyl group, acyl amino, acyloxy, alkoxyl, replacement, alkoxy carbonyl, alkoxycarbonyl amino, amino, replacement, amino carbonyl, amino carbonyl amino, amino carbonyl oxygen base, aryl, aryloxy, azido, carboxyl, cyano group, cycloalkyl, replacement, halogen, hydroxyl, ketone group, nitro, thio alkoxy, replacement, thioaryl oxygen base, sulfo-ketone group, sulfydryl, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O)₂-and aryl-S (O)₂-. Substituting group comprises carbonyl or thiocarbonyl, and it for example provides lactams and urea derivative.

The example of the assorted thiazolinyl of representational ring comprises following:

Wherein each X is selected from CR⁵⁸ ₂、NR ⁵⁸, O and S; And each Y is selected from carbonyl, N, NR⁵⁸, O and S; And R⁵⁸Hydrogen, alkyl, cycloalkyl, the assorted alkyl of ring, aryl, heteroaryl, assorted alkyl etc. independently.

Representational example with aryl of hetero atom (comprising replacement) comprises following:

With

Wherein each X is selected from CR⁵⁸ ₂、NR ⁵⁸, O and S; And each Y is selected from carbonyl, NR⁵⁸, O and S; And R⁵⁸Hydrogen, alkyl, cycloalkyl, the assorted alkyl of ring, aryl, heteroaryl, assorted alkyl etc. independently.

The personnel with ordinary skill in the organic synthesis field generally acknowledge: the heteroatomic maximum number in stable, chemically feasible heterocycle (no matter it is aromatics or non-aromatic) is to be decided by size, degree of unsaturation and the heteroatomic valence encircled. Usually, heterocycle can have one to four hetero atom, as long as heteroaromatic rings is chemically feasible and stable.

" pharmaceutically useful " refer to by the approval of federation or continent governability office or American Pharmacopeia or other pharmacopeia of generally admitting in list be used for animal and more particularly be used for the people.

" officinal salt " refers to nontoxic, inorganic and organic acid addition salt and the base addition salts of the compounds of this invention, and specifically, they are pharmaceutically useful and have the pharmacological activity of parent compound expection. The in the present invention last separation of used compound of these salt and the process situ preparation of purifying. This type of salt comprises: (1) acid-addition salts forms described inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc. with inorganic acid; Perhaps use the organic acid form, described organic acid is acetic acid, propionic acid, caproic acid, pentamethylene propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, butanedioic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxy benzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, 1 for example, and 2-ethionic acid, 2-ethylenehydrinsulfonic acid, benzene sulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalene sulfonic acids, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl bicyclic be [2.2.2]-oct-2-ene-1-formic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylace tonitric, butylacetic acid, dodecyl sulphate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid etc. also; Perhaps (2) salt of when the acid proton that exists in the parent compound is replaced by metal ion, forming, described metal ion is alkali metal ion, alkaline-earth metal ions or aluminium ion for example; Or with the coordination of organic base, described organic base such as monoethanolamine, diethanol amine, triethanolamine, N-METHYL-ALPHA-L-GLUCOSAMINE etc. Salt only further comprises sodium salt, sylvite, calcium salt, magnesium salts, ammonium salt, tetraalkylammonium salt etc. in the mode of example; And when compound comprises alkaline degree of functionality, the salt of nontoxic organic or inorganic acid, such as hydrochloride, hydrobromate, tartrate, mesylate, acetate, maleate, oxalates etc. Term " pharmaceutically acceptable cation " refers to cationic counter ion nontoxic, acceptable acidic functionality. This type of cationic example is sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cation etc.

" pharmaceutically suitable carrier " refers to diluent, adjuvant, excipient or the carrier of using with the compounds of this invention.

" prevention " refers to and reduce the risk (clinical symptom that promptly causes at least a disease does not develop, and this individuality may be exposed to or the easy infection disease, but does not also experience or show the symptom of disease) that obtains disease or obstacle in individuality.

" prodrug " refers to the compound that has the cleavable group and be converted into The compounds of this invention (it has pharmaceutical activity in vivo) by solvolysis or under physiological condition, comprises the derivative of The compounds of this invention.This type of example includes but not limited to cholinesterase derivative etc., N-alkyl morpholine ester etc.

" individuality " comprises the people.Term " people ", " patient " and " individuality " interchangeable in this article application.

" treatment " of any disease or obstacle refers in one embodiment and improves disease or obstacle (promptly stop or reduce advancing of disease or its a kind of clinical symptom at least).In another embodiment, " treatment " refers to and improves at least a body parameter, and it may not gone out by appersonification.In another embodiment, " treatment " refers to and regulates disease or obstacle, or (for example the stablizing recognizable symptom) of health, physiological (for example stablizing body parameter) or both.In another embodiment, " treatment " refer to the outbreak that postpones disease or obstacle.

Other derivative of The compounds of this invention they acid and sour derivative form in all have activity, but the advantage that solubleness, histocompatibility or slowly-releasing are provided in mammalian organism in acid-sensitive sense form usually is (referring to Bundgard, H., Design of Prodrugs (design of prodrug), the 7-9 page or leaf, the 21-24 page or leaf, Elsevier, Amsterdam 1985).Prodrug comprises the well-known acid derivative of practitioner in the art, for example, and for example by the ester of parent acid and the pure prepared in reaction that is fit to or by the acid amides of amine prepared in reaction parent acid compound and replacement or unsubstituted, perhaps acid anhydrides or mixed acid anhydride.Simple aliphatic series or aromatic ester, acid amides and acid anhydrides derived from the acidic-group on the The compounds of this invention are preferred prodrugs.In some cases, wish the prodrug of preparation dibasic acid esters type, for example (acyloxy) alkyl ester or ((alkoxy carbonyl) oxygen base) alkyl ester.The C of The compounds of this invention preferably ₁To C ₈Alkyl, C ₂-C ₈Alkenyl, aryl, C ₇-C ₁₂The aryl and the C that replace ₇-C ₁₂Alkyl aryl.

Term used herein " isotopic variations " refers to the isotopic compound that comprises the non-natural ratio on one or more atoms of forming this compounds.For example, " isotopic variations " of compound can comprise one or more non radioactive isotopes, for example deuterium ( ²H or D), carbon-13 ( ¹³C), nitrogen-15 ( ¹⁵N) etc.Should be understood that in the compound that the preparation isotropic substance replaces, following atom (when existing) can change, so that for example any hydrogen can be ²H/D, any carbon can be ¹³C or any nitrogen can be ¹⁵N, and the existence of this type of atom and layout are determined in art technology.Equally, the present invention can be included under the following situation and prepare isotopic variations with radio isotope: for example the compound of Chan Shenging can be used for medicine and/or the research of substrate tissue distribution.The radio isotope tritium (promptly ³H) and carbon-14 (promptly ¹⁴C) be used in particular for this purpose, detect because it is easy to introduce and is easy to.In addition, compound can be with the positron radiation isotropic substance (for example ¹¹C, ¹⁸F, ¹⁵O and ¹³N) replace and to prepare, and will be used for positron emission computerized tomography (PET) research and be used to check that the substrate acceptor occupies.

All isotopic variations of compound provided herein no matter whether it has radioactivity, all are intended to be included in the scope of the present invention.

It is to be further understood that but the character of the Cheng Jian that will have same molecular formula its atom or order or its atom arrange different compounds at spatial and be called " isomer ".Its atom is arranged different isomer at spatial be called " steric isomer ".

The steric isomer that is not mutual mirror image is called " diastereomer ", and will be mutually can not the eclipsed mirror image those steric isomers be called " enantiomer ".When compound have asymmetric center, during for example with four different group bondings, enantiomer is possible in pairs.Enantiomer is characterised in that the absolute configuration of its asymmetric center, and R-by Cahn and Prelog and S-sequence rule or describe, and called after dextrorotation or left-handed (promptly being respectively (+) or (-) isomer) by the method for molecule rotation polarizing plane.Chipal compounds can exist with its single enantiomer or its mixture.The mixture that will comprise the enantiomer of equal proportion is called " racemic mixture ".

" tautomer " refers to change form with specilization laminate structures and different compound in hydrogen atom and electron replacement.Therefore, two kinds of structures can moving but equilibrated by mobile πDian Zi and atom (normally H).For example, enol and ketone are tautomers, because by using acid or alkaline purification, their quick changes.The acid that tautomeric another example is a phenyl nitromethane-and nitro-form, they are the form by using acid or alkaline purification equally.

Tautomeric form is reactive relevant with biologic activity with the optimum chemical that reaches compound of interest.

The compounds of this invention can have one or more asymmetric centers; Therefore this compounds can be prepared into single (R)-or (S)-steric isomer or its mixture.Unless otherwise indicated, the description of the specilization compound in this specification sheets and the claim or name are intended to comprise single enantiomer and its mixture, racemic modification or other.Stereochemical isolating method definite and steric isomer is well-known in the art.

Compound

The compounds of this invention can be described to 5 usually and be replaced by aryl and heteroaryl and [1,2,4] triazolo [1,5-a] pyrazine-8-base-amine that 8 are replaced by arylamino or heteroaryl amino.

Wherein:

A and B are CR2R independently ", NR ", oxygen or sulphur;

AA is CR2 or N;

D is C=O, CR2R " or NR ";

When k was 0, E was NH or CR " R6, and when k was 1, E was NH or CR " R6a;

F is sulphur, oxygen or NH;

T is oxygen or NR;

U, V, W and X are CR independently " R7 or NR ";

Y is CR " or N;

R is hydrogen or low alkyl group independently;

R " be H or form two keys with adjacent atom;

R3 be H or with adjacent R " form two keys;

R2 is H, F, Cl, CN, COOR4, OR4, C (O) N (R4R5), S (O) ₂N (R4R5), low alkyl group, O-low alkyl group, NH-low alkyl group, S-low alkyl group, COO-low alkyl group, OC (O)-low alkyl group, C (O) N (R4)-low alkyl group, S (O) ₂N (R4)-low alkyl group, S (O) N (R4)-low alkyl group, S (O) ₂-low alkyl group, S (O)-low alkyl group, N (R4) S (O) ₂-low alkyl group and N (R4) S (O)-low alkyl group, wherein each low alkyl group is optional is replaced by one or more F and Cl.

R7 is hydrogen, halogen, low alkyl group or lower alkoxy independently;

R and Rz can be together-(CHR) _q-T-(CHR) _r-and

form

5 or 6 yuan of heterocycles with the nitrogen of their bondings;

K is 0 or 1;

M is 0 or 1;

N and p are 0,1 or 2 independently;

Q and r are 1 or 2;

X is 0 or 1;

Condition is that at least one is not a hydrogen among R7 or the Rz.

Preferred aspect of the present invention is formula II compound subclass or its pharmacologically acceptable salt, hydrate, solvate or prodrug,

Wherein

A and B are CR2R independently ", NR ", oxygen or sulphur;

AA is CR2 or N;

D is C=O, CR2R " or NR ";

When k was 0, E was NH or CR " R6, and when k was 1, E was NH or CR " R6a;

F is sulphur, oxygen or NH;

T is oxygen or NR;

R " be H or form two keys with adjacent atom;

R is hydrogen or low alkyl group independently;

R2 is H, F, CI, CN, COOR4, OR4, C (O) N (R4R5), S (O) ₂N (R4R5), low alkyl group, O-low alkyl group, NH-low alkyl group, S-low alkyl group, COO-low alkyl group, OC (O)-low alkyl group, C (O) N (R4)-low alkyl group, S (O) ₂N (R4)-low alkyl group, S (O) N (R4)-low alkyl group, S (O) ₂-low alkyl group, S (O)-low alkyl group, N (R4) S (O) ₂-low alkyl group and N (R4) S (O)-low alkyl group, wherein each low alkyl group is optional is replaced by one or more F and Cl.

R8 is a phenyl, its independently at the ortho position by R _a, in a position by R _bAnd in contraposition by R _cReplace; Pyridin-3-yl; At 5 by R _cThe pyridin-3-yl that replaces; Or cyclohexyl, its independently at 2 by R _aAnd at 4 by R _dReplace;

R _aBe hydrogen, halogen, low alkyl group, trifluoromethyl or lower alkoxy;

R _bBe hydrogen, trifluoromethyl, lower alkoxy, low alkyl group sulphonamide, carboxyl ,-NR _eR _f,-(CO)-OR or-(CO)-NR _eR _f

R _cBe hydrogen, amino, hydroxyl, lower alkoxy, formamyl, carboxyl, SO ₂R, SO ₂NR _eR _f, NR _eR _f,-(CO)-OR or-(CO)-NR _eR _fOr

R _bAnd R _cCan form indazole together or at 3 indoles that replaced by R ';

R _dBe hydroxyl, halogen, amino, lower alkoxy or NR _eR _f

R _eAnd R _fBe hydrogen, 1-low alkyl group tetramethyleneimine-3-base, 1-R-pyrazoles-4-base, low-grade alkane acidyl, phenyl or optional independently: 4-hydroxy phenyl, 3-aminomethyl phenyl, low alkyl group alkylsulfonyl, 4-two elementary alkyl amido phenyl, pyridin-3-yl, 1H-indol-3-yl, morpholine-4-base, hydroxyl, amino, one or two elementary alkyl amido or low-grade alkane acidyl by the low alkyl group of one or more following groups replacements; Perhaps R ' and R " be together-(CHR) _n-T-(CHR) _n-and form five or hexa-member heterocycle with the nitrogen of their bondings;

M is 0,1 or 2;

N is 1 or 2;

Condition is R _a, R _bAnd R _cIn at least one is not a hydrogen.

Particularly preferred embodiment of the present invention relate to formula III compound or pharmaceutically acceptable salt thereof, solvate or prodrug with and steric isomer, isotopic variations and tautomer:

R wherein ¹Be H or replacement or unsubstituted alkyl; And each R ⁸And R ⁹Be independently selected from replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl.

In one embodiment, about formula III compound, R ¹Be H, Me, Et, i-Pr or CF ₃

In one embodiment, about formula III compound, R ¹Be H.

In one embodiment, about formula III compound, R ⁸Be selected from replacement or unsubstituted cycloalkyl.

In another embodiment, about formula III compound, R ⁸Be selected from replacement or unsubstituted cyclohexyl or cyclopentyl.

In one embodiment, about formula III compound, R ⁸Be selected from replacement or unsubstituted Heterocyclylalkyl.

In another embodiment, about formula III compound, R ⁸Be selected from replacement or unsubstituted piperidyl, morpholinyl or pyrrolidyl.

In one embodiment, about formula III compound, R ⁸Be selected from replacement or unsubstituted phenyl, pyridyl or pyrimidine.

In one embodiment, about formula III compound, R ⁸Be selected from the phenyl of replacement, the pyridyl of replacement and the pyrimidine of replacement; And substituting group is-L-R ^8dAnd wherein

L be selected from key, alkylidene group, assorted alkylidene group ,-O-,-N (R ^8e)-,-CO-,-CO ₂-,-SO-,-SO ₂-,-CON (R ^8e)-,-SO ₂N (R ^8e)-,-N (R ^8e) CO-,-N (R ^8e) SO ₂-,-N (R ^8e) CON (R ^8e)-,-N (R ^8e) SO ₂N (R ^8e)-; And

R ^8dBe selected from replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted amino, replacement or unsubstituted aralkyl, replacement or unsubstituted heteroarylalkyl and replacement or unsubstituted aminoalkyl group; And

R ^8eBe selected from H, replacement or unsubstituted alkyl and replacement or unsubstituted cycloalkyl.

In one embodiment, about formula III compound, R ⁸Be

Wherein L and R ^8dAs describing in the leading portion; Subscript n is selected from 1-4; And each R ^8aBe independently selected from hydrogen, replacement or unsubstituted alkyl, alkoxyl group, cyano group and halogen.

In one embodiment, about formula III compound, R ⁸As above-mentioned and subscript n is 1, R ^8aBe Me, Et, Pr, different-Pr, Cl, F, CN, OMe or CF ₃In another embodiment, R ^8aIn 2-(neighbour of L) position.In another embodiment, R ^8aBe 2-Cl, 2-F, 2-Me or 2-CF ₃

In one embodiment, about formula III compound, R ⁸As above-mentioned and

L be key ,-O-,-CO-,-CON (R ^8e)-or-N (R ^8e) CO-;

R ^8dBe selected from replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl, replacement or unsubstituted heteroarylalkyl and replacement or unsubstituted aminoalkyl group; And

R ^8eBe selected from H, replacement or unsubstituted alkyl.

In one embodiment, about formula III compound, R ⁸As above-mentioned and

L be key ,-O-,-CO-,-CON (R ^8e)-or-N (R ^8e) CO-; And

R ^8dBe selected from H, alkylamino ethyl, dialkyl amido ethyl, cycloalkyl, Heterocyclylalkyl, arylalkyl and heteroarylalkyl.

In one embodiment, about formula III compound, R ⁸As above-mentioned and

L be key ,-O-,-CO-,-CON (R ^8e)-or-N (R ^8e) CO-; And

R ^8dBe selected from methylamino ethyl, ethylamino ethyl, dimethyl aminoethyl, diethylamino ethyl, replacement or unsubstituted pyrrolidyl, benzyl and pyridylmethyl.

In one embodiment, about formula III compound, R ⁸As above-mentioned and

L be key ,-CO-, SO ₂,-(CH ₂) _M1-,-O (CH ₂) _M1-,-NH (CH ₂) _M1-,-CON (H) (CH ₂) _M1-or-SO ₂NH (CH ₂) _M1-; Subscript m 1 is selected from 1-4; And R ^8dBe

And wherein encircling P is that replace or unsubstituted Heterocyclylalkyl.In another embodiment, L be key ,-CO-,-O (CH ₂) _M1-,-CON (H) (CH ₂) _M1-or-NHCO-;

In one embodiment, about formula III compound, R ⁸As above-mentioned; L is a key; And ring P is that replace or unsubstituted Heterocyclylalkyl.

In one embodiment, about formula III compound, R ⁸As above-mentioned; L is a key; And ring P be replace or unsubstituted piperidines, replacement or unsubstituted piperazine and replacement or unsubstituted piperidines, morpholine.

In one embodiment, about formula III compound, R ⁸As above-mentioned; L is CO; And ring P is that replace or unsubstituted Heterocyclylalkyl.

In one embodiment, about formula III compound, R ⁸As above-mentioned; L is CO; And ring P be replace or unsubstituted piperidines, replacement or unsubstituted piperazine and replacement or unsubstituted piperidines, morpholine.

In one embodiment, about formula III compound, R ⁸As above-mentioned; L is-(CH ₂) _M1-,-O (CH ₂) _M1-or-NH (CH ₂) _M1-; Subscript m 1 is selected from 1-4; And ring P is that replace or unsubstituted Heterocyclylalkyl.

In one embodiment, about formula III compound, R ⁸As above-mentioned; L is-(CH ₂) _M1-,-O (CH ₂) _M1-or-NH (CH ₂) _M1-; Subscript m 1 is 2 or 3; And ring P be replace or unsubstituted piperidines, replacement or unsubstituted piperazine and replacement or unsubstituted piperidines, morpholine.

In one embodiment, about formula III compound, R ⁸As above-mentioned; L is-CON (H) (CH ₂) _M1-or-NHCO (CH ₂) _M1-; Subscript m 1 is selected from 1-4; And ring P is that replace or unsubstituted Heterocyclylalkyl.

In one embodiment, about formula III compound, R ⁸As above-mentioned; L is-CON (H) (CH ₂) _M1-; Subscript m 1 is 2 or 3; And ring P be replace or unsubstituted piperidines, replacement or unsubstituted piperazine and replacement or unsubstituted piperidines, morpholine.

In one embodiment, about the formula III compound, compound be formula IVa, IVb, IVc or IVd or its pharmacologically acceptable salt, solvate or prodrug with and steric isomer, isotopic variations and tautomer:

And wherein L and the ring P such as above-mentioned; Subscript n is selected from 1-4; Each R ^8aBe independently selected from hydrogen, replacement or unsubstituted alkyl, alkoxyl group, cyano group and halogen; And R ⁹Be independently selected from replacement or unsubstituted aryl and heteroaryl.

In one embodiment, about formula IVa-IVd compound, L is a key.

In one embodiment, about formula IVa-IVd compound, L is methylene radical, ethylidene, propylidene and butylidene.

In one embodiment, about formula IVa-IVd compound, L is-CO-.

The compound of claim 9, wherein L is-CO-.

The compound of claim 9, wherein L be-NHCO-or-CONH-.

The compound of claim 9, wherein L is-CON (H)-CH ₂-CH ₂-or-N (H)-CO-CH ₂-CH ₂-.

The compound of claim 9, wherein L is-OCH ₂-CH ₂-or-NHCH ₂-CH ₂-.

In one embodiment, about formula IVa-IVd compound, L is-SO ₂-.

In one embodiment, about formula IVa-IVd compound, L is-CON (H)-CH ₂-CH ₂-or-SO ₂NH-CH ₂-CH ₂-.

In one embodiment, about formula IVa-IVd compound, L is-OCH ₂-CH ₂-or-NHCH ₂-CH ₂-.

In preferred embodiments, L is a key.

In one embodiment, about formula IVa-IVd compound, ring P be replace or unsubstituted piperidines, morpholine or piperazine.

In one embodiment, about formula IVa-IVd compound, L and ring P such as above-mentioned; Subscript n is 4 and each R ^8aBe H.

In one embodiment, about formula IVa-IVd compound, L and ring P such as above-mentioned; Subscript n is 1 and R ^8aBe Me, Et, Pr, different-Pr, Cl, F, CN, OMe or CF ₃In another embodiment, R ^8aIn 2-(neighbour of L) position.In another embodiment, R ^8aBe 2-Cl, 2-F, 2-Me or 2-CF ₃

In further embodiment, about formula III compound, R ⁸Be

And wherein encircling P is that replace or unsubstituted Heterocyclylalkyl; Subscript n is selected from 1-4 and each R ^8aBe independently selected from hydrogen, replacement or unsubstituted alkyl, alkoxyl group, cyano group and halogen.

In one embodiment, about formula III compound, R ⁸As above-mentioned and ring P be replace or unsubstituted piperidines, morpholine or piperazine.

In one embodiment, about formula III compound, R ⁸As above-mentioned and subscript n is 4 and each R ^8aBe H.

In one embodiment, about formula III compound, R ⁸As above-mentioned and subscript n is 1 and R ^8aBe Me, Et, Pr, different-Pr, Cl, F, CN, OMe or CF ₃In another embodiment, R ^8aIn 2-(neighbour of N-ring P) position.In another embodiment, R ^8aBe 2-Cl, 2-F, 2-Me or 2-CF ₃

In further embodiment, about formula III compound, R ⁸Be

And wherein subscript n is selected from 1-4; Each R ^8aBe independently selected from hydrogen, replacement or unsubstituted alkyl, alkoxyl group, cyano group and halogen; R ^8bBe hydrogen, replacement or unsubstituted alkyl or replacement or unsubstituted cycloalkyl; R ^8cBe hydrogen, replacement or unsubstituted alkyl and subscript x be selected from 1-8.

In further embodiment, about formula III compound, R ⁸Be

And wherein subscript n is selected from 1-4; Each R ^8aBe independently selected from hydrogen, replacement or unsubstituted alkyl, alkoxyl group, cyano group and halogen; R ^8bBe hydrogen, replacement or unsubstituted alkyl or replacement or unsubstituted cycloalkyl; R ^8cBe hydrogen or Me.

In further embodiment, about formula III compound, R ⁸Be

And wherein subscript n is selected from 1-4; Each R ^8aBe independently selected from hydrogen, replacement or unsubstituted alkyl, alkoxyl group, cyano group and halogen.

In further embodiment, about formula III compound, R ⁸Be

And wherein subscript n is selected from 1-4; Each R ^8aBe independently selected from hydrogen, replacement or unsubstituted alkyl, alkoxyl group, cyano group and halogen; And R ^8bBe hydrogen, replacement or unsubstituted alkyl or replacement or unsubstituted cycloalkyl.

In one embodiment, about formula III compound, R ⁸As above-mentioned and R ^8bBe H.

In one embodiment, about formula III compound, R ⁸As above-mentioned and R ^8bBe replace or unsubstituted alkyl.

In one embodiment, about formula III compound, R ⁸As above-mentioned and R ^8bBe that replace or unsubstituted cycloalkyl.

In one embodiment, about formula III compound, R ⁸As above-mentioned and R ^8bBe Me, Et, Pr, i-Pr, t-Bu, i-Bu, CH ₂CF ₃, CF ₃, CH ₂CONH ₂, cyclopropyl or cyclopropyl methyl.

In a special embodiment, about formula III compound, R ⁸As above-mentioned and R ^8bBe i-Pr.

In further embodiment, about formula IVa-IVd compound, R ^8aBe independently selected from hydrogen, replacement or unsubstituted alkyl, alkoxyl group, cyano group, formamyl, CHO and halogen.In one embodiment, R ^8aBe H, Me, F or Cl.In preferred embodiments, R ^8aBe H.

In one embodiment, about formula IVa-IVd compound, compound is formula Va, Vb, Vc, Vd, Ve or Vf:

And R wherein ⁹As describe in the formula III and R ^8bBe hydrogen, replacement or unsubstituted alkyl or replacement or unsubstituted cycloalkyl.

In one embodiment, about formula Va-Vf compound, R ^8bBe H.

In one embodiment, about formula Va-Vf compound, R ^8bBe replace or unsubstituted alkyl.

In one embodiment, about formula Va-Vf compound, R ^8bBe that replace or unsubstituted cycloalkyl.

In one embodiment, about formula Va-Vf compound, R ^8bBe Me, Et, Pr, i-Pr, t-Bu, i-Bu, CH ₂CF ₃, CF ₃, CH ₂CONH ₂, cyclopropyl or cyclopropyl methyl.

In one embodiment, about formula Va-Vf compound, R ^8bBe i-Pr.

In one embodiment, about formula III-Vf compound, R ⁹Be that replace or unsubstituted aryl.In another embodiment, R ⁹Be that replace or unsubstituted phenyl.

In one embodiment, about formula III-Vf compound, R ⁹Be that replace or unsubstituted heteroaryl.In another embodiment, R ⁹Be replace or the unsubstituted pyridine base.

In one embodiment, about formula III-Vf compound, R ⁹Be selected from replacement or unsubstituted phenyl, indyl, pseudoindoyl, pyrryl, furyl, thienyl, pyrazolyl, oxazolyl and thiazolyl.

In one embodiment, about formula III-Vf compound, R ⁹Be

Or

And each A ¹, A ²And A ³Be independently selected from S, O, N, NR ^9aAnd CR ^9aEach R ^9aBe independently H or replacement or unsubstituted alkyl; And R ^9bBe CONH ₂, CONHMe or CN.

In further embodiment, about formula III-Vf compound, R ⁹Be

Or

In further embodiment, about formula III-Vf compound, R ⁹Be

Or

In further embodiment, about formula III-Vf compound, R ⁹Be

And wherein subscript m is selected from 1-4 and each R ^9dBe independently H, replacement or unsubstituted alkyl or halogen.

In further embodiment, about formula III-Vf compound, R ⁹Be

In further embodiment, about formula III-Vf compound, R ⁹Be

Or

And wherein subscript m is selected from 1-3 and each R ^9dBe independently H, replacement or unsubstituted alkyl or halogen.

In further embodiment, about formula III-Vf compound, R ⁹As above-mentioned; And each R ^9dBe H.

In further embodiment, about formula III-Vf compound, R ⁹As above-mentioned; M is 1 or 2 and each R ^9dBe Me, Cl or F independently.

In one embodiment, about the formula III compound, compound is formula VIa, VIb, VIc, VId, VIe or VIf:

And R ^8bBe hydrogen, replacement or unsubstituted alkyl or replacement or unsubstituted cycloalkyl.

In further embodiment, about formula VIa-VIf compound, R ^8bBe H.

In further embodiment, about formula VIa-VIf compound, R ^8bIt is cycloalkyl.

In further embodiment, about formula VIa-VIf compound, R ^8bIt is cyclopropyl.

In further embodiment, about formula VIa-VIf compound, R ^8bBe replace or unsubstituted alkyl.

In further embodiment, about formula VIa-VIf compound, R ^8bBe Me, Et, Pr, i-Pr, t-Bu, i-Bu, CF ₃, CH ₂CF ₃, CH ₂CONH ₂Or cyclopropyl methyl.

In one embodiment, about the formula III compound, compound is formula VIIa, VIIb, VIIc, VIId, VIIe or VIIf:

In further embodiment, about formula VIIa-VIId compound, R ^8bBe H.

In further embodiment, about formula VIIa-VIIf compound, R ^8bIt is cycloalkyl.

In further embodiment, about formula VIIa-VIIf compound, R ^8bIt is cyclopropyl.

In further embodiment, about formula VIIa-VIIf compound, R ^8bBe replace or unsubstituted alkyl.

In further embodiment, about formula VIIa-VIIf compound, R ^8bBe Me, Et, Pr, i-Pr, t-Bu, i-Bu, CF ₃, CH ₂CF ₃, CH ₂CONH ₂Or cyclopropyl methyl.

In one embodiment, about the formula III compound, compound is formula VIIIa, VIIIb, VIIIc, VIIId, VIIIe or VIIIf:

In further embodiment, about formula VIIIa-VIIIf compound, R ^8bBe H.

In further embodiment, about formula VIIIa-VIIIf compound, R ^8bIt is cycloalkyl.

In further embodiment, about formula VIIIa-VIIIf compound, R ^8bIt is cyclopropyl.

In further embodiment, about formula VIIIa-VIIIf compound, R ^8bBe replace or unsubstituted alkyl.

In further embodiment, about formula VIIIa-VIIIf compound, R ^8bBe Me, Et, Pr, i-Pr, t-Bu, i-Bu, CF ₃, CH ₂CF ₃, CH ₂CONH ₂Or cyclopropyl methyl.

In one embodiment, about the formula III compound, compound is formula IXa, IXb, IXc, IXd, IXe or IXf:

In further embodiment, about formula IXa-IXf compound, R ^8bBe H.

In further embodiment, about formula IXa-IXf compound, R ^8bIt is cycloalkyl.

In further embodiment, about formula IXa-IXf compound, R ^8bIt is cyclopropyl.

In further embodiment, about formula IXa-IXf compound, R ^8bBe replace or unsubstituted alkyl.

In further embodiment, about formula IXa-IXf compound, R ^8bBe Me, Et, Pr, i-Pr, t-Bu, i-Bu, CF ₃, CH ₂CF ₃, CH ₂CONH ₂Or cyclopropyl methyl.

In one embodiment, about the formula III compound, compound is formula Xa, Xb, Xc, Xd, Xe or Xf:

In further embodiment, about formula Xa-Xf compound, R ^8bBe H.

In further embodiment, about formula Xa-Xf compound, R ^8bIt is cycloalkyl.

In further embodiment, about formula Xa-Xf compound, R ^8bIt is cyclopropyl.

In further embodiment, about formula Xa-Xf compound, R ^8bBe replace or unsubstituted alkyl.

In further embodiment, about formula Xa-Xf compound, R ^8bBe Me, Et, Pr, i-Pr, t-Bu, i-Bu, CF ₃, CH ₂CF ₃, CH ₂CONH ₂Or cyclopropyl methyl.

In one embodiment, about the formula III compound, compound is formula XIa, XIb, XIc, XId, XIe or XIf:

And R ^8bBe hydrogen, replacement or unsubstituted alkyl or replacement or unsubstituted cycloalkyl; And R ^9eBe hydrogen, Me or CN.

In one embodiment, about formula XIa-XIf compound, R ^9eBe H.

In one embodiment, about formula XIa-XIf compound, R ^9eBe Me.

In one embodiment, about formula XIa-XIf compound, R ^9eBe CN.

In further embodiment, about formula XIa-XIf compound, R ^8bBe H.

In further embodiment, about formula XIa-XIf compound, R ^8bIt is cycloalkyl.

In further embodiment, about formula XIa-XIf compound, R ^8bIt is cyclopropyl.

In further embodiment, about formula XIa-XIf compound, R ^8bBe replace or unsubstituted alkyl.

In further embodiment, about formula XIa-XIf compound, R ^8bBe Me, Et, Pr, i-Pr, t-Bu, i-Bu, CF ₃, CH ₂CF ₃, CH ₂CONH ₂Or cyclopropyl methyl.

In one embodiment, about the formula III compound, compound is formula XIIa, XIIb, XIIc or XIId:

In one embodiment, about the formula III compound, compound is formula XIIIa, XIIIb, XIIIc or XIIId:

In one embodiment, about the formula III compound, compound is formula XIVa, XIVb, XIVc or XIVd:

In one embodiment, about the formula III compound, compound is formula XVa, XVb or XVc:

And L be key or-O-CH ₂-CH ₂-; Ring P is

Or

And R ^8bBe H, Me, i-Pr, t-Bu, CH ₂CONH ₂, cyclopropyl methyl or CH ₂CF ₃

In a special embodiment, about formula XVa-XVc compound, L is a key.In another special embodiment, L is-O-CH ₂-CH ₂-.

In a special embodiment, about formula XVa-XVc compound, ring P is

In a more specific embodiment, about formula XVa-XVc compound, ring P is

In another embodiment, about the formula III compound, compound is selected from table 1.

In another embodiment, about the formula III compound, compound is selected from table 2.

In some aspects, the invention provides the prodrug and the derivative of following formula compound.Prodrug is the derivative of The compounds of this invention, and it has metabolism cleavable group and is converted into The compounds of this invention by solvolysis or under physiological condition, and it has pharmacological activity in vivo.Prodrug can be non-activity when being applied to individuality, but is converted into active compound of the present invention in vivo." pharmaceutically acceptable prodrug " used herein refers to the prodrug that is used for compound of the present invention, contact in its undue toxicity that in the scope that health examination is judged, is suitable for matching, stimulation, the anaphylactoid patient tissue, and be effective for the desired use of The compounds of this invention with rational interests/risk ratio.Term " prodrug " refers to and transforms in vivo to obtain to be used for the compound of active compound of the present invention or its pharmacologically acceptable salt, hydrate or solvate.Conversion can take place by number of mechanisms, for example by hydrolysis in blood.The compound that contains metabolism cleavable group has following advantage: compare with parent compound, because the existence of metabolism cleavable group, as the result who improves solubleness and/or uptake rate, it can show the bioavailability of improvement, so this compounds is as prodrug.Discussing completely by following document provides: Design of Prodrugs (design of prodrug), and H.Bundgaard compiles, Elsevier (1985); Methods in Enzymology (method in the zymetology); People such as K.Widder compile, Academic Press, 42,309-396 (1985); A Textbook of Drug Design andDevelopment (medicinal design and exploitation textbook), Krogsgaard-Larsen and H.Bandaged compile, the 5th chapter; " Design and Applications of Prodrugs (design of prodrug and application) " 113-191 (1991); Advanced Drug Delivery Reviews (high drug release summary), H.Bundgard, 8,1-38, (1992); J.Pharm.Sci., 77,285 (1988); Chem.Pharm.Bull., people such as N.Nakeya, 32,692 (1984); Pro-drugs as Novel DeliverySystems (as the prodrug of new release system), T.Higuchi and V.Stella, 14 A.C.S.Symposium Series and Bioreversible Carriers in Drug Design (bioreversible carrier in the medicinal design), E.B.Roche compiles, American Pharmaceutical Associationand Pergamon Press, 1987, incorporate it into this paper as a reference.This type of example includes but not limited to cholinesterase derivative etc., N-alkyl morpholine ester etc.

Other derivative of The compounds of this invention they acid and the acid derivative form in all have activity, but the advantage that solubleness, histocompatibility or slowly-releasing are provided in mammalian organism in acid-sensitive sense form usually is (referring to Bundgard, H., Design of Prodrugs (design of prodrug), the 7-9 page or leaf, the 21-24 page or leaf, Elsevier, Amsterdam 1985).Prodrug comprises the well-known acid derivative of practitioner in the art, for example, and for example by the ester of parent acid and the pure prepared in reaction that is fit to or by the acid amides of amine prepared in reaction parent acid compound and replacement or unsubstituted, perhaps acid anhydrides or mixed acid anhydride.Simple aliphatic series or aromatic ester, acid amides and acid anhydrides derived from the acidic-group on the The compounds of this invention are preferred prodrugs.In some cases, wish the prodrug of preparation dibasic acid esters type, for example (acyloxy) alkyl ester or ((alkoxy carbonyl) oxygen base) alkyl ester.The C of The compounds of this invention preferably ₁To C ₈Alkyl, C ₂-C ₈Alkenyl, aryl, C ₇-C ₁₂The aryl and the C that replace ₇-C ₁₂Alkyl aryl.

Pharmaceutical composition

When as medicine, The compounds of this invention is used with the form of pharmaceutical composition usually.This based composition can and comprise at least a active compound with the well-known method preparation of pharmacy field.

Usually, The compounds of this invention is used with medicinal significant quantity.The actual amount of using of compound will be determined that usually described situation comprises the severity of the illness of being treated, selected route of administration, the pragmatize compound of using, single patient's age, body weight and response, patient's symptom etc. by the doctor according to relevant situation.

Pharmaceutical composition of the present invention can be used by number of ways, and that described approach comprises is oral, in rectum, transdermal, subcutaneous, intravenously, intramuscular and the nose.Depend on the expection delivery pathways, The compounds of this invention preferably is formulated as injectable or oral compositions or ointment, lotion or patch and is used for transdermal administration.

Be used for the form that Orally administered composition can adopt (bulk) in bulk liquor agent or suspensoid or powder in bulk.But more generally composition exists with unit dosage so that accurately administration.Term " unit dosage " refers to and is suitable as the physically complete isolating unit that is used for individual human and other mammiferous unitary dose, and each unit comprises the active substance of the predetermined amount that calculates generation expection therapeutic action and suitable pharmaceutical excipient.Typical unit dosage comprises the ampoule pre-filling, premeasuring of liquid composition or syringe or the pill in the situation of solids composition, tablet, capsule etc.In this based composition, the furans sulfoacid compound normally than small component (about 0.1 to about 50% weight or preferably from about 1 to about 40% weight), remainder is multiple medium or carrier and the processing material that helps to form the expection formulation.

Be suitable for Orally administered liquid form and can comprise suitable moisture or water-free medium and buffer reagent, suspensoid and dispersion agent, tinting material, correctives etc.Solid form can comprise the compound of for example any following composition or similarity: tackiness agent, for example Microcrystalline Cellulose, tragacanth gum or gelatin; Vehicle, for example starch or lactose; Disintegrating agent, for example Lalgine, Primogel or W-Gum; Lubricant, for example Magnesium Stearate; Glidant, for example colloid silica; Sweeting agent, for example sucrose or asccharin; Or correctives, for example peppermint, wintergreen oil or orange flavor seasonings.

Injectable composition is normally based on injectable Sterile Saline or phosphate buffered saline (PBS) or other injectable carrier known in the art.As above-mentioned, the active compound in this based composition is generally about 0.05 to 10% weight normally than small component, and remainder is an injectable carrier etc.

Transdermal composition is usually formulated as topical ointments or ointment, its common packet content be about 0.01 to about 20% weight, preferred about 0.1 to about 20% weight, preferred about 0.1 to about 10% weight and 0.5 activeconstituents more preferably from about to about 15% weight.When being formulated as ointment, activeconstituents common and paraffin or water-mixable ointment base combination.Alternatively, activeconstituents can be formulated as ointment with for example oil-in-water ointment base.This type of preparation capable of permeating skin is well-known in the art and generally includes other composition to strengthen the activeconstituents or the stability of formulation of skin penetration.All these type of known preparation capable of permeating skin and composition are included in the scope of the present invention.

The compounds of this invention can also be used by transdermal device.Therefore, transdermal administration can application container or porous membranous type or the patch of solid substrate kind finish.

Be used for orally using, injectable or the local said components that can use only be representative.Other material and treatment technology etc. exist Remington ' s Pharmaceutical Sciences, the 17th edition, 1985, Mack Publishing Company, Easton, the 8th part of Pennsylvania proposes, and incorporates it into this paper as a reference.

The compounds of this invention can also be used with the slowly-releasing form or from slow-release medicament release system.The description of representational sustained-release materials can Remington ' s Pharmaceutical SciencesIn search.

Following formulation examples illustrates representational pharmaceutical composition of the present invention.But the present invention is not limited to following pharmaceutical composition.

Preparation 1-tablet

The compounds of this invention is mixed with about 1:2 weight ratio with the exsiccant gelatin adhesive as dried powder.Add a small amount of Magnesium Stearate as lubricant.Mixture is made 240-270mg tablet (every active amide compound that contains 80-90mg) in tabletting machine.

Preparation 2-capsule

The compounds of this invention is mixed with about 1:1 weight ratio with the starch thinner as dried powder.Mixture is filled into (each capsule contains the active amide compound of 125mg) in the 250mg capsule.

Preparation 3-liquid

The compounds of this invention (125mg), sucrose (1.75g) and xanthan gum (4mg) are mixed, by No.10 order U.S. sieve, then with previously prepared Microcrystalline Cellulose and Xylo-Mucine (11:89, aqueous solution 50mg).With Sodium Benzoate (10mg), correctives and tinting material dilute with water and adding under agitation.Add enough water then to make the cumulative volume of 5mL.

Preparation 4-tablet

The compounds of this invention is mixed with about 1:2 weight ratio with the exsiccant gelatin adhesive as dried powder.Add a small amount of Magnesium Stearate as lubricant.Mixture is made 450-900mg tablet (the active amide compound of 150-300mg) in tabletting machine.

Preparation 5-injection

The compounds of this invention is dissolved in or is suspended in the buffered Sterile Saline aqueous injectable medium, make concentration be about 5mg/mL.

Preparation 6-part

With stearyl alcohol (250g) and white vaseline (250g) in about 75 ℃ of following fusions, the mixture that adds The compounds of this invention (50g), methyl p-hydroxybenzoate (0.25g), propylparaben (0.15g), sodium lauryl sulphate (10g) and the propylene glycol (120g) of water-soluble (about 370g) solidifies the mixture stirring that produces until it.

Methods of treatment

The compounds of this invention is used for the treatment of the Mammals illness as therapeutical agent, and this illness comes from or be attributable to the abnormal activity of MMP1 and/or MAPKAPK5.Therefore, The compounds of this invention and pharmaceutical composition are used to prevent and/or treat the Mammals inflammatory diseases of (comprising the people) as medicine.

Aspect methods of treatment, the invention provides the treatment susceptible or suffer from and extracellular matrix (ECM) degrade relevant illness, the particularly sacroiliitis and the mammiferous method of rheumatoid arthritis more particularly, this method comprises one or more The compounds of this invention or the aforementioned pharmaceutical compositions of using significant quantity.

Aspect another methods of treatment, the invention provides the treatment susceptible or suffer from the mammiferous method of expressing relevant illness with the MMP1 abnormal cells, this method comprises The compounds of this invention or its pharmaceutical composition of administering therapeutic significant quantity.

Aspect another methods of treatment; the invention provides the method that treatment or prevention have the illness of unusual matrix metal proteinase activity feature, this method comprises one or more The compounds of this invention or its pharmaceutical composition of the effective matrix metalloproteinase amount of suppression of administering therapeutic.

Aspect another methods of treatment, the invention provides the treatment susceptible or suffer from disease and the mammiferous method of obstacle, described disease and obstacle be by inflammation mediated or cause inflammation, for example rheumatoid arthritis and osteoarthritis, myocardial infarction, various autoimmune disease and obstacle, uveitis and atherosclerosis; Itch/itch for example, psoriatic for example; And nephropathy, this method comprises one or more aforementioned pharmaceutical compositions of using effective treatment for diseases or illness preventive dose.

The invention still further relates to The compounds of this invention is used for the treatment of or prevents the illness preventing, improve or eliminate by the inhibitor of using mitogen-activated protein kinase activated protein kinase 5 in preparation, or has an illness of unusual collagenase activities, or the illness relevant with ECM degraded or be selected from the illness of the disease that relates to inflammation, most preferably be used for the treatment of the purposes in the medicine of rheumatoid arthritis.

As further aspect of the present invention, provide especially at the The compounds of this invention for the treatment of or prevent to be used as in above-mentioned illness and the disease medicine.This paper also provides The compounds of this invention to be used for the treatment of or to prevent purposes in the medicine of one of above-mentioned illness and disease in preparation.

The preferred version of the inventive method comprises to the individuality of suffering from the disease illness with inflammatory feature uses the abnormal level of the enough time of The compounds of this invention of effective matrix metalloproteinase amount of suppression with the degraded of reduction patient extracellular matrix, and the preferred self-perpetuating process that stops described degraded response.The special embodiment of this method comprise to suffer from or enough time of The compounds of this invention that the individual patient of susceptible generation rheumatoid arthritis is used effective matrix metalloproteinase amount of suppression reducing respectively or to prevent collagen and bone degraded in the described patient joint, and the preferred self-perpetuating process that stops described degraded response.

The injected dose horizontal extent is about 0.1mg/kg/ hour to 10mg/kg/ hour at least, and total time about 1 was to about 120 hours and particularly 24 to 96 hours.About 0.1mg/kg is to about 10mg/kg or more be pre-loaded into bolus and also can use to obtain enough steady-state level.For 40 to 80kg human patientses, maximum total dose was not wished above about 2g/ days.

For preventing and/or treating long-term illness, for example inflammatory and autoimmune disorder, treatment plan prolong usually to be gone through several months or several years, and therefore preferred oral administration for patient's convenience and tolerance.For oral administration, 1 to 5 of every day and particularly 2 to 4 and typically 3 oral dosages are representational schemes.Use these mode of administration, each dosage provides about The compounds of this invention of 0.01 to about 20mg/kg, and preferred dose is that each provides about 0.1 to about 10mg/kg and particularly about 1 to about 5mg/kg.

Transdermal dosage compositions is usually selected provide with use the blood that injected dose obtains in level compare level in the similar or lower blood.

When being used for the outbreak of prevention of inflammatory conditions, The compounds of this invention is applied to the patient who has generation illness risk usually under the doctor informs and monitors with above-mentioned dosage level.Exist the patient that special illness risk takes place to generally include those patients, or be accredited as those patients that are easy to take place illness especially by genetic test or examination with illness family history.

The compounds of this invention can be used as that independent promoting agent is used or they can with the other medicines combined administration, described other medicines comprise that proof has identical or similar therapeutic activity and is determined for this type of combined administration is safety and effective other compound.

Conventional synthetic method

Triazolo of the present invention [1,5-a] pyridinyl compounds can be used following ordinary method and be operated and prepare by the raw material that is easy to obtain.Should be understood that the typical or preferable methods condition (being the mol ratio, solvent, pressure etc. of temperature of reaction, time, reactant) that provided; Unless otherwise indicated, also can use other method condition.Optimum reaction conditions can depend on used special reactant or solvent and difference, but this type of condition can be definite by the optimization routine operation by those skilled in the art.

In addition, it will be apparent to one skilled in the art that the GPF (General Protection False base is essential to prevent that some functional group from participating in undesirable reaction.Be used for special functional group the protecting group that is fit to selection and to be suitable for protecting the condition with deprotection be well-known in the art.For example, kinds of protect base and their introducing and remove at T.W.Greene and P.G.M.Wuts ProtectingGroups in Organic Synthesis (protecting group in the organic synthesis); second edition; Wiley, NewYork, 1991 and the document quoted in describe.

Following method has at length presented the representational bicyclic heteroaryl listed above of preparation.The compounds of this invention can be prepared by the technician in the organic synthesis field by known or commercially available raw material and reagent.

Conventional synthetic route

General

Unless otherwise indicated, all reagent are commercial grade and as the application of receiving and need not to be further purified.Commercially available anhydrous solvent is used for the reaction under inert atmosphere, carried out.Unless otherwise indicated, the SILVER REAGENT solvent is used for all other situations.Column chromatography is carried out on silica gel 60 (35-70 μ m).Tlc is that the silica gel F-254 plate (thickness 0.25mm) of using precoated layer carries out. ¹H NMR spectrum is gone up record at Bruker DPX 400 NMR spectrographs (400MHz). ¹H NMR spectrographic chemical shift (δ) is with respect to tetramethylsilane (δ 0.00) or suitable residual solvent peak, i.e. CHCl ₃(δ 7.27) as in be marked with 1,000,000/(ppm) report.Multiplicity provides with unimodal (s), bimodal (d), triplet (t), quartet (q), multiplet (m) and broad peak (br).Coupling constant (J) provides with Hz.Electrospray ionization mass spectrum obtains on Micromass platform LC/MS spectrograph.The post that all lcms analysis are used: Waters Acquity UPLC BEH C18 1.7 μ m, 2.1mm internal diameter * 50mm long (Part No.186002350)).Preparation HPLC:Waters XBridge Prep C185 μ m ODB 19mm internal diameter * 100mm long (Part No.186002978).All methods are used MeCN/H ₂The O gradient.H ₂O comprises 0.1%TFA or 0.1%NH ₃

The representativeness of The compounds of this invention is synthetic

Compound 1:(4-morpholine-4-base phenyl)-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl] amine

Step 1:N '-(3,6-two bromo-pyrazine-2-yl)-N, N-dimethyl carbonamidine

To be suspended in 3 in the ethanol (150mL), (15.37g, 60.80mmol) and N, (10.1mL, mixture 76.00mmol) refluxed 2 hours the dinethylformamide dimethylacetal 6-two bromo-pyrazine-2-base amine.With reaction mixture vacuum-evaporation, obtain title compound (18.6g). ¹H-NMR(400MHz，CDCl ₃)δ(ppm)3.20(s，3H)，3.21(s，3H)，7.93(s，1H)，8.48(s，1H)。LCMS:Rt 3.81 minutes (99.1%), m/z (APCI) 307 (M+H) ⁺

Step 2:N-(3,6-two bromo-pyrazine-2-yl)-N '-hydroxy formamidine

At N '-(3,6-two bromo-pyrazine-2-yl)-N, N-dimethyl carbonamidine (18.6g, and disposable adding oxammonium hydrochloride in methyl alcohol 60.80mmol) (200mL) solution (5.91g, 85.12mmol).To react and at room temperature stir 16 hours.Collect with cooling (ice-cooled) water treatment and by filtering with solvent evaporation and with solid residue.To precipitate twice of water and petroleum ether and vacuum-drying, obtain title compound (17.45g), be white solid.

¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)7.82(1H，br s)，8.21(1H，s)，8.34(1H，m)，11.17(1H，br s)。LCMS:Rt 3.17 minutes (98.7%), m/z (APCI) 295 (M+H) ⁺

Step 3:5,8-two bromo-[1,2,4] triazolos [1,5-a] pyrazine

(17.4mg 58.80mmol) handled 1 hour down at 50 ℃ with Tripyrophosphoric acid (150g), handled 1.75 hours down at 70 ℃ then with N-(3,6-two bromo-pyrazine-2-yl)-N '-hydroxy formamidine.After being cooled to room temperature, in reaction mixture, add entry.With the suspension that produces by carefully adding solid NaHCO with small portion ₃Transfer to pH 8.The precipitation that forms is collected by filtering, with 1N NaOH washing once, wash with water three times and vacuum-drying.Residue is distributed between ethyl acetate and 1N NaOH, and organic phase washed once with 1N NaOH and once again with the salt water washing.With organic phase through MgSO ₄Drying is filtered and evaporation, obtains title compound (10.15g), is white solid. ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)8.43(s，1H)，8.92(s，1H)。LCMS:Rt 2.73 minutes (94.2%), m/z (APCI) 277 (M+H) ⁺

Step 4:(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-(4-morpholine-4-base phenyl) amine

With 5,8-two bromo-[1,2,4] triazolo [1,5-a] pyrazine (123mg, 443 μ mol), 4-(4-morpholino) aniline (118mg, 0.664mmol) and N-ethyl diisopropyl amine (116mL, mixture 0.664mmol) reflux 4.5 hours in 2-propyl alcohol (3mL).Reaction mixture is evaporated to drying and residue is distributed between methylene dichloride and citric acid (10%).With organic phase water and salt water washing once, through MgSO ₄Drying is filtered and evaporation, obtains title compound (156mg, 94%), is yellow solid. ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)3.11(m，4H)，3.78(m，4H)，6.97(d，2H)，7.82(d，2H)，7.87(s，1H)，8.71(s，1H)，9.93(br s，1H)。LCMS:Rt 3.32 minutes (96.8%), m/z (APCI) 375 (M+H) ⁺

Step 5:(4-morpholine-4-base phenyl)-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl] amine

With (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-(4-morpholine-4-base phenyl) amine (220mg, 0.586mmol), 4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane (dioxaborolan)-2-yls)-and the 1H-pyrazoles (171mg, 0.879mmol), Pd (PPh ₃) ₄(225mg, 4mL DMF/ water (3:1) suspension 2.34mmol) outgased in sealed tube 5 minutes for (68mg, 59 μ mol) and NaOtBu.With reaction mixture the sealing test tube in, 90 ℃ of following heated overnight.After solvent evaporation, residue is collected water (3 *) and ether (2 *) washing and vacuum-drying by filtering.Crude product by column chromatography (silica gel, 96:4 DCM/MeOH) purifying, is obtained title compound (76mg, 36%), be yellow solid. ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)3.11(4H，m)，3.79(4H，m)，6.98(2H，d)，7.90(2H，d)，8.17(1H，s)，8.35(1H，br s)，8.64(1H，br s)，8.75(1H，s)，9.73(1H，br s)。LCMS:Rt 2.68 minutes (97.7%), m/z (APCI) 363 (M+H) ⁺

Compound 4:4-(8-(4-(4-methylpiperazine-1-yl) phenyl amino)-[1,2,4] triazolo [1,5a] pyrazine-5-yl] pyridine-2 (1H)-ketone

Step 1:[5-(2-methoxyl group-pyridin-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-[4-(4-methyl-piperazine-1-yl)-phenyl]-amine

This compound can be used the method for describing in compound 6 steps 4, be applied in (the 5-bromo-[1 in the 2:1 DMF/ diox (2.2mL), 2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(4-methyl-piperazine-1-yl)-phenyl]-amine (80mg, 0.206mmol), 2-methoxypyridine-4-boric acid (63mg, 0.412mmol), Pd (PPh ₃) ₄(0.052mmol) with 1.5N Na ₂CO ₃(1.1mL, 1.65mmol) preparation.Crude product by the silica gel column chromatography purifying, is used 96:4 DCM:NH ₃(7M is in MeOH) and will comprise and expect that the fraction of product merges and evaporation, obtains title compound (40mg, 47%).HPLC (254nm): Rt 2.26 minutes (65%).

Step 2:4-(8-(4-(4-methylpiperazine-1-yl) phenyl amino)-[1,2,4] triazolo [1,5a] pyrazine-5-yl] pyridine-2 (1H)-ketone

With [5-(2-methoxyl group-pyridin-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-[4-(4-methyl-piperazine-1-yl)-phenyl]-amine (40mg, 0.096mmol) and pyridine hydrochloride (55mg, water 0.48mmol) (1mL) solution at room temperature stirred 1 hour.The solvent vacuum removed and with residue by the silica gel column chromatography purifying, use 96:4 DCM:NH ₃(7M is in MeOH) wash-out.Title compound is separated (23mg, 60%).

The free alkali compound of 11mg (0.0273mmol) is dissolved among the MeOH/DCM of minimum (being back to dissolving) and be added in 0.1M methylsulfonic acid (0.273mL) among the MeOH.Behind the evaporating solvent mixture of residue with 1:1 ethyl acetate-ether and DCM-ether ground for several times, filter and vacuum-drying, obtain title compound, be mesylate (13mg, 99%). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)2.21(3H，s)，2.91(3H，s，MsOH)，3.00(2H，t)，3.18-3.26(2H，m)，3.58(2H，d)，3.90(2H，d)，6.83(1H，s)，7.07(2H，d)，7.25(1H，s)，7.53(1H，d)，7.93(2H，d)，8.14(1H，s)，8.76(1H，s)，9.69(1H，br s)，10.21(1H，s)，13.3(1H，br s)。LCMS:Rt 1.71 minutes (97.5%), m/z (APCI) 403 (M+H) ⁺

Compound 6:4-{8-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives

Step 1:(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(4-methyl-piperazine-1-yl)-phenyl]-amine

With 5,8-two bromo-[1,2,4] triazolo [1,5-a] pyrazine (2g, 7.20mmol), 4-(4-methyl-piperazine-1-yl)-phenyl amine (1.65g, 8.64mmol) and the N-ethyl diisopropyl amine (1.5mL, mixture 8.64mmol) under 80 ℃, in 2-propyl alcohol (50mL) heating 8 hours.Reaction mixture is evaporated to drying and residue is distributed between methylene dichloride and water.With twice of dichloromethane extraction of water.With organic layer salt water washing, through MgSO ₄Drying is filtered and evaporation, obtains title compound (1.41g), is gray solid. ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)2.27(3H，s)，2.54(4H，m)，3.14(4H，m)，6.97(2H，d)，7.80(2H，d)，7.87(1H，s)，8.72(1H，s)，9.92(1H，br s)。LCMS:Rt 2.07 minutes (77.4%), m/z (APCI) 388 (M+H) ⁺

Step 2:4-bromo-thiophene-2-carboxamide derivatives

With 4-bromo-thiophene-2-carboxylic acid (2.0g, 9.66mmol), 1-ethyl-3-(3 '-dimethylaminopropyl) carbodiimide hydrochloride (2.04g, 10.63mmol) and the I-hydroxybenzotriazole hydrate (1.44g, DMF 10.63mmol) (20mL) solution at room temperature stirred 2 hours.Then reaction mixture is cooled to 0 ℃ and adding NH ₃The aqueous solution (1mL, 17.3mmol).With mixture restir 5 hours at room temperature, in reaction mixture, add entry then and the precipitation that will produce is collected and with 1M NaOH, H by filtering ₂O and petroleum ether.Title compound is separated, be white solid (1.56g, 78%).

Step 3:4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-thiophene-2-carboxamide derivatives

With 4-bromo-thiophene-2-carboxamide derivatives (1.3g, 6.34mmol), two (tetramethyl ethylene ketone (pinacolato)) two boron (3.22g, 12.7mmol), PdCl ₂Dppf (0.26g, 0.318mol) and KOAc (1.87g 19.10mmol) is suspended in the diox (20mL), blasts nitrogen 5 minutes, then 90 ℃ of following heated overnight.The solvent vacuum is removed and residue is distributed between ethyl acetate and water.With water layer usefulness ethyl acetate extraction 3 times and with the organic phase salt water washing that merges, through MgSO ₄Filter and evaporation.With title product crystallization from the EtOAc-sherwood oil (2.135g detects purity 77% through LCMS).

Step 4:4-{8-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives

With 5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(4-methyl-piperazine-1-yl)-phenyl]-amine (100mg, 258mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and thiophene-2-carboxamide derivatives (130mg, 516mmol) and Pd (PPh ₃) ₄(74mg is 64.5mmol) at Na ₂CO ₃The aqueous solution (1.37mL, 1.5M, 2.06mmol) and DMF/ diox 2/1 (2.75mL) in suspension in reaction tubes, outgased 5 minutes.With test tube sealing and with reaction mixture 90 ℃ of following heated overnight.After being cooled to room temperature reaction mixture is distributed between ethyl acetate and water.To precipitate by filtering and collect and water (1 *) and ether (2 *) washing and vacuum-drying.Crude product is passed through column chromatography purifying (silica gel, DCM/MeOH/NH ₃96:4), obtain title compound (43mg), be yellow solid. ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)2.26(3H，s)，2.50(4H，m)，3.15(4H，m)，6.99(2H，d)，7.60(1H，br s)，7.88(2H，d)，8.10(2H，m)，8.48(1H，s)，8.66(1H，s)，8.79(1H，s)，9.97(1H，br s)。LCMS:Rt 1.99 minutes (97.6%), m/z (APCI) 435 (M+H) ⁺

Compound 9:5-{8-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives

Step 1:5-bromo-thiophene-2-carboxamide derivatives

With 5-bromo-thiophene-2-carboxylic acid (4.51g, 21.78mmol), 3-hydroxy benzotriazole hydrate (3.24g, 23.96mmol), (4.6g, DMF 23.9mmol) (70mL) solution at room temperature stirred 2 hours 1-ethyl-3-(3 '-dimethylaminopropyl) carbodiimide.Then reaction mixture is cooled to 0 ℃ and adding 35%NH ₃The aqueous solution (2.2mL).Mixture at room temperature stirred spend the night.The solvent vacuum is removed and residue is dissolved among the EtOAc, use 1N NaHCO ₃And salt water washing.Organic layer is merged, through MgSO ₄Drying is filtered and is concentrated, and obtains title compound (3.78g, 84%).HPLC (254nm): Rt 2.46 minutes (96.5%).

Step 2:5-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-thiophene-2-carboxamide derivatives

With 5-bromo-thiophene-2-carboxamide derivatives (0.5g, 2.426mmol), two (tetramethyl ethylene ketone) two boron (678mg, 2.669mmol), PdCl ₂Dppf (59mg, 0.072mmol) and KOAc (0.714g 7.28mmol) is suspended in the diox (5mL), blasts nitrogen 5 minutes, then 85 ℃ of following heated overnight.The solvent vacuum is removed and residue is distributed between ethyl acetate and water.With water layer again with ethyl acetate extraction and with the organic phase that merges with the salt water washing, through MgSO ₄Filter and vacuum-evaporation, obtain title compound (417mg, 68%).

Step 3:5-{8-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃The aqueous solution (1.37mL, 2.06mmol) is with the 5-bromo-in the diox (2.75mL) [1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(4-methyl-piperazine-1-yl)-phenyl]-amine (100mg, 0.258mmol), 5-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and thiophene-2-carboxamide derivatives (130mg, 0.516mmol) and Pd (PPh ₃) ₄(74mg, 0.0645mmol) preparation.Behind the evaporating solvent, residue by the silica gel column chromatography purifying, is used 96:6 DCM:NH ₃(7M is in MeOH) wash-out obtains title compound (23mg, 21%).LCMS:Rt 1.94 minutes (97.9%). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)2.26(3H，s)，2.49(4H，m)，3.14(4H，m)，6.98(2H，d)，7.51(1H，br s)，7.85-7.89(2H，m)，8.03(2H，d)，8.10(1H，br s)，8.38(1H，s)，8.82(1H，s)，10.10(1H，s)。LCMS:Rt 1.94 minutes, (97.9%), m/z (APCI) 435 (M+H) ⁺

Compound 12:5-(5-methyl isophthalic acid H-pyrazoles-4-yl)-N-(4-morpholino phenyl)-[1,2,4] triazolo [1,5-a] pyrazine-8-amine

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(aqueous solution) (2.84mL, 4.26mmol) is with (5-bromo-[1,2, the 4] triazolo [1 in the diox (8.5mL), 5-a] pyrazine-8-yl)-(4-morpholine-4-base-phenyl)-amine (0.2g, 0.53mmol), 5-methyl-4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and the 1H-pyrazoles (222mg, 1.06mmol) and Pd (PPh ₃) ₄(0.154mg, 0.134mmol) preparation.Reaction mixture by the silica gel column chromatography purifying, is used 98:2 and 97:3 DCM:NH ₃(7M is in MeOH) obtains title compound (15mg, 7.5%).The 0.1M methylsulfonic acid that is applied among the MeOH (0.398mL) is translated into mesylate, obtains title compound (15mg), is the light green solid. ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)2.41(3H，s，MsOH)，2.46(3H，s)，3.20(4H，m)，3.71(4H，m)，7.11(2H，d)，7.74(1H，s)，7.97(2H，d)，8.15(1H，s)，8.69(1H，s)，9.88(1H，s)。LCMS:Rt 2.41 minutes (98.3%), m/z (APCI) 377 (M+H) ⁺

Compound 15:4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiophene-2-carboxamide derivatives

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(aqueous solution) (2.84mL, 4.26mmol) is with (5-bromo-[1,2, the 4] triazolo [1 in the diox (10mL), 5-a] pyrazine-8-yl)-(4-morpholine-4-base-phenyl)-amine (0.2g, 0.53mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and thiophene-2-carboxamide derivatives (0.27mg, 1.06mmol) and Pd (PPh ₃) ₄(0.15mg, 0.133mmol) preparation.Reaction mixture is distributed between water and ethyl acetate.Form precipitation,, obtain title compound (84.1mg, 37.4%) by filtering collection and, using 95:5 DCM:MeOH by the silica gel column chromatography purifying. ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)3.13(4H，m)，3.79(4H，m)，7.01(2H，d)，7.60(1H，br s)，7.91(2H，d)，8.10(2H，s)，8.48(1H，s)，8.66(1H，s)，8.79(1H，s)，9.96(1H，s)。LCMS:Rt 2.61 minutes (97.1%), m/z (APCI) 422 (M+H) ⁺

Compound 16:5-(5-methyl isophthalic acid H-pyrazoles-4-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-[1,2,4] triazolo [1,5-a] pyrazine-8-amine

Step 1:5-methyl-4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-1H-pyrazoles

This compound can be used in compound 86 steps 2 method of describing, be applied in 4-bromo-5-methyl isophthalic acid H-pyrazoles in the methyl-sulphoxide (30mL) (3g, 18.6mmol), two (tetramethyl ethylene ketone) two boron (8.52g, 33.5mmol), PdCl ₂Dppf (913mg, 1.118mmol) and KOAc (5.49mg, 55.9mmol) preparation.By the silica gel column chromatography purifying, use the 1:1 sherwood oil subsequently with 7:3: eluent ethyl acetate obtains 5-methyl-4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-1H-pyrazoles (3.87g, 100%) with reaction mixture.

Step 2:5-(5-methyl isophthalic acid H-pyrazoles-4-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-[1,2,4] triazolo [1,5-a] pyrazine-8-amine

This compound can be used the method for describing in compound 6 steps 4, be applied in (5-bromo-[1,2, the 4] triazolo [1 in the diox (5.4mL), 5-a] pyrazine-8-yl)-[4-(4-methyl-piperazine-1-yl)-phenyl]-amine (132mg, 0.340mmol), 5-methyl-4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and the 1H-pyrazoles (141mg, 0.68mmol) and Pd (PPh ₃) ₄(98mg is 0.085mmol) with 1.5N Na ₂CO ₃(1.81mL, 2.72mmol) preparation.Crude product by the silica gel column chromatography purifying, is used 95:5 DCM:NH ₃(7M is in MeOH) wash-out grinds with ether and sherwood oil subsequently, obtains title compound (9mg, 7%), is the light green solid. ¹H-NMR (400MHz, d ₆-DMSO) δ (ppm) 2.27 (3H, s), 2.38-2.49 (7H, m), 3.14 (4H, m), 6.97 (2H, d), 7.70 (1H, s), 7.88 (2H, d), 7.99 and 8.43 (1H, br s), 8.68 (1H, s), 9.71 (1H, s), 12.92 and 12.98 (1H, br s).

Use 0.1M methylsulfonic acid (0.231mL) and be translated into mesylate, obtain target compound (11mg).LCMS:Rt 1.78 minutes (86%), m/z (APCI) 390 (M+H) ⁺

Compound 17:N-(3-fluoro-4-morpholino phenyl)-5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-amine

Step 1:(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-(3-fluoro-4-morpholine-4-base-phenyl)-amine

This compound can be used the method for describing in compound 6 steps 1, be applied in 5 in the 2-propyl alcohol (6mL), 8-two bromo-[1,2,4] triazolo [1,5-a] pyrazine (0.5g, 1.799mmol), 3-fluoro-4-morpholine-4-base-phenyl amine (0.53g, 2.70mmol) and DIPEA (0.470mL, 2.70mmol) preparation.Reaction mixture is distributed between 10% aqueous citric acid solution and DCM.With organic phase separation and water and salt water washing, through MgSO ₄Drying is filtered and vacuum concentration, obtains title compound (697mg, 98%), is applied to next step and need not to be further purified.LCMS:Rt 3.52 minutes (98.2%).

Step 2:N-(3-fluoro-4-morpholino phenyl)-5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-amine

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(1.36mL, 2.03mmol) is with (5-bromo-[1,2, the 4] triazolo [1 in the diox (4mL), 5-a] pyrazine-8-yl)-(3-fluoro-4-morpholine-4-base-phenyl)-amine (100mg, 0.254mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and the 1H-pyrazoles (99mg, 0.51mmol) and Pd (PPh ₃) ₄(73mg, 0.063mmol) preparation.Thick material by the silica gel column chromatography purifying, is used 98:2 DCM:NH ₃(7M is in MeOH) wash-out and grind with ether and sherwood oil obtains target compound (43mg, 44%). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)3.01(4H，m)，3.79(4H，m)，7.08(1H，t)，7.79(1H，d)，8.06(1H，d)，8.26(1H，s)，8.38(1H，s)，8.67(1H，s)，8.79(1H，s)，10.03(1H，s)，13.3(1H，br s)。LCMS:Rt 2.83 minutes (99%), m/z (APCI) 381 (M+H) ⁺

Compound 19:5-(5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-2-Morpholinobenzamide

Step 1:5-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-2-morpholine-4-base-benzamide

This compound can be used the method for describing in compound 6 steps 1, be applied in 5 in the 2-propyl alcohol (7mL), 8-two bromo-[1,2,4] triazolo [1,5-a] pyrazine (250mg, 0.90mmol), 5-amino-2-morpholine-4-base-benzamide (299mg, 1.35mmol) and N, N-diisopropyl ethyl amine (0.24mL, 1.35mmol) preparation.With iPrOH and Et ₂O grinds, and obtains title compound (273mg, 73%).

Step 2:5-(5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-2-Morpholinobenzamide

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MK ₂CO ₃(aqueous solution) is (1.93mL) with 5-(the 5-bromo-[1 in the diox (3.44mL), 2,4] triazolo [1,5-a] pyrazine-8-base is amino)-2-morpholine-4-base-benzamide (140mg, 0.33mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and the 1H-pyrazoles (130mg, 0.67mmol) and Pd (PPh ₃) ₄(96mg, 0.083mmol) preparation.Thick material by the silica gel column chromatography purifying, is used 99:1,97:3,95:5 DCM:NH then then subsequently with DCM ₃(7M is in MeOH) wash-out obtains title compound, is white solid (40.5mg, 30%). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)2.96(4H，m)，3.79(4H，m)，7.28(2H，d)，7.45(1H，m)，7.54(1H，br s)，8.01-8.09(1H，dd)，8.25(1H，s)，8.50(1H，d)，8.69(1H，br s)，8.78(1H，s)，9.98(1H，s)，13.3(1H，br s)。LCMS:Rt 2.23 minutes (96.9%), m/z (APCI) 406 (M+H) ⁺

Compound 21:4-(8-(4-(2-morpholino oxyethyl group) phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) thiophene-2-carboxamide derivatives

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(1.44mL, 2.16mmol) is with (5-bromo-[1,2, the 4] triazolo [1 in the diox (4.3mL), 5-a] pyrazine-8-yl)-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-amine (113mg, 0.27mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and thiophene-2-carboxamide derivatives (136mg, 0.537mmol) and Pd (PPh ₃) ₄(78mg, 0.067mmol) preparation.Reaction mixture by the silica gel column chromatography purifying, is used 97:3 DCM:NH ₃(7M is in MeOH) wash-out obtains title compound (65mg, 52%).LCMS:Rt 1.98 minutes (98.9%).The 0.1M methylsulfonic acid that is applied among the MeOH (1.1385mL) is translated into mesylate, obtains title compound (50mg, 95%). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)2.37(3H，s，MsOH)，3.21-3.64(6H，m)，3.76(2H，t)，4.05(2H，d)，4.40(2H，m)，7.09(2H，d)，7.61(1H，br s)，8.02(2H，d)，8.11(2H，s)，8.48(1H，s)，8.67(1H，s)，8.82(1H，s)，9.91(1H，br s)，10.09(1H，s)。LCMS:Rt 1.98 minutes (97.7%), m/z (APCI) 466 (M+H) ⁺

Compound 22:5-(8-(4-(2-morpholino oxyethyl group) phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) thiophene-2-carboxamide derivatives

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(1.5mL, 2.24mmol) is with (5-bromo-[1,2, the 4] triazolo [1 in the diox (4.5mL), 5-a] pyrazine-8-yl)-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-amine (118mg, 0.28mmol), 5-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and thiophene-2-carboxamide derivatives (142mg, 0.56mmol) and Pd (PPh ₃) ₄(81mg, 0.07mmol) preparation.Reaction mixture through the silica gel column chromatography purifying, is used 97:3 DCM:NH ₃(7M is in MeOH) wash-out obtains title compound (33mg, 25%).LCMS:Rt 2.66 minutes (99%).The 0.1M methylsulfonic acid that is applied among the MeOH (0.569mL) is translated into mesylate, obtains title compound (24mg, 86%). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)2.37(3H，s，MsOH)，3.25(2H，m)，3.50-3.64(4H，m)，3.76(2H，t)，4.05(2H，d)，4.40(2H，m)，7.09(2H，d)，7.51(1H，br s)，7.87(1H，d)，7.99-8.05(3H，m)，8.11(1H，br s)，8.37(1H，s)，8.84(1H，s)，9.92(1H，br s)，10.21(1H，s)。LCMS:Rt 1.95 minutes (98.8%), m/z (APCI) 466 (M+H) ⁺

Compound 23:(4-morpholine-4-base-phenyl)-[5-(2H-pyrazole-3-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine

Step 1:1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles

The TFA of catalytic amount (0.1mL, under existence 1.3mmol), with the 1H-pyrazoles (14.3g 0.21mol) is dissolved in 3,4-dihydro-2H-pyrans (26.74g, 0.32mol) in.Reaction mixture was stirred 5 hours down at 95 ℃, and NaH (0.2g, 5mmol) quencher are used in cooling then.Solvent is removed, obtained title compound, be brown oil (33.3g, 99%), be applied to next step and need not to be further purified.

Step 2:1H-pyrazoles-2-boric acid

At 1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles (7.6g, (33mL, 2.5M are in hexane, 82.5mmol) with triisopropyl borine (12.7mL 52mmol) to drip nBuLi in the cooling solution (78 ℃) of THF (50mL), 55mmol), with temperature maintenance at-70 ℃.Reaction mixture was stirred 1 hour down at-70 ℃, go through making it reach room temperature in 4 hours then.With after the 2M HCl quencher reaction, the solvent vacuum is removed and pH is transferred to pH 6 with 1M NaOH.Form precipitation, collect and with toluene and petroleum ether by filtering.Grind with ethyl acetate, obtain target compound, be white solid (2.7g, 48%), be applied to next step and need not to be further purified.

Step 3:(4-morpholine-4-base-phenyl)-[5-(2H-pyrazole-3-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine

This compound can be used the method for describing in compound 6 steps 4, be applied in (the 5-bromo-[1 among the DMF (2mL), 2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(morpholine-4-yl)-phenyl]-amine (100mg, 0.267mmol), 1H-pyrazoles-2-boric acid (60mg, 0.535mmol), Pd (PPh ₃) ₄(93mg, 0.08mmol) and Na ₂CO ₃(88mg, 0.80mmol) preparation.Reaction mixture is put into test tube (stem-tube) and descended stirring 18 hours at 100 ℃.After the cooling, with mixture NaHCO ₃Solution dilution and extract with EtOAc (4 *).Organic layer is washed with water, through MgSO ₄Drying is filtered and evaporation, obtains crude product, and it is by the silica gel column chromatography purifying, with DCM, 96:4DCM:NH subsequently ₃(7M is in MeOH) wash-out.With after the ether grinding title compound being separated (12.4mg, 13%).(0.342mL 0.0342mmol) is translated into mesylate, obtains target compound (10mg, 81%) to use the 0.1M methylsulfonic acid. ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)2.34(3H，s，MsOH)，3.14(4H，m)，3.81(4H，m)，7.04(2H，d)，7.27(1H，m)，7.92(3H，m)，8.24(1H，s)，8.76(1H，s)，9.92(1H，s)。LCMS:Rt 2.45 minutes (97.6%), m/z (APCI) 363 (M+H) ⁺

Compound 28:4-(8-(4-(4-sec.-propyl piperazine-1-yl) phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) thiophene-2-carboxamide derivatives

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(1.28mL, 1.92mmol) is with the 5-bromo-N-in the diox (3.84mL) (6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-amine (100mg, 0.24mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and thiophene-2-carboxamide derivatives (121mg, 0.48mmol) and Pd (PPh ₃) ₄(69mg, 0.059mmol) preparation.Crude product by the silica gel column chromatography purifying, is used DCM and 97:3 DCM:NH ₃(7M is in MeOH) wash-out obtains title compound (68mg, 61%), is the light green solid.(1.47mL, 0.147mmol) the 0.1M methylsulfonic acid in is translated into mesylate, grinds with DCM and ether subsequently, obtains title compound (67mg, 98.5%) to be applied in MeOH. ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)1.35(6H，d)，2.34(3H，s，MsOH)，3.00(2H，t)，3.22-3.25(2H，m)，3.56-3.61(3H，m)，3.89(2H，d)，7.09(2H，d)，7.60(1H，br s)，7.97(2H，d)，8.10(2H，s)，8.48(1H，s)，8.67(1H，s)，8.81(1H，s)，9.23(1H，br s)，10.03(1H，s)。LCMS:Rt2.13 minute (98.4%), m/z (APCI) 463 (M+H) ⁺

Compound 29:5-(8-(4-morpholino phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) furans-3-methane amide

Step 1:[5-(4-formamyl-furans-2-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-(4-morpholine-4-base-phenyl)-t-butyl carbamate

This compound can be used the method for describing in compound 35 steps 3, be applied in (4-morpholine-4-base-phenyl)-(the 5-tributyl tin alkyl-[1 among the DMF (1mL), 2,4] triazolo [1,5-a] pyrazine-8-yl)-t-butyl carbamate (137mg, 0.199mmol), 5-bromo-furans-3-methane amide (76mg, 0.4mmol) and Pd (PPh ₃) ₄(23mg, 0.020mmol) preparation.The purification reaction mixture is with 98:2DCM:MeOH and 96:4 DCM:NH ₃(7M is in MeOH) wash-out obtains title compound (33mg, 33%).

Step 2:5-(8-(4-morpholino phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) furans-3-methane amide

With [5-(4-formamyl-furans-2-yl)-[1; 2; 4] triazolo [1,5-a] pyrazine-8-yl]-(33mg, 0.065mmol) solution in 1:1 DCM:TFA (2mL) (2 drip) mixture at room temperature stirred 2 hours (4-morpholine-4-base-phenyl)-t-butyl carbamate.Add saturated Na ₂CO ₃After, form precipitation, by filtering collection and water, ether and petroleum ether.After the vacuum-drying, title compound is separated (20mg, 76%).The 0.1M methylsulfonic acid that is applied among the MeOH (0.444mL) is translated into mesylate, obtains target compound (19mg, 100%).

¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)2.36(3H，s，MsOH)，3.22(4H，m)，3.82-3.89(4H，m)，7.13(2H，d)，7.36(1H，br s)，7.86(1H，s)，7.95(3H，m)，8.17(1H，s)，8.40(1H，s)，8.84(1H，s)，10.17(1H，s)。LCMS:Rt 2.60 minutes (96.9%), m/z (APCI) 406 (M+H) ⁺

Compound 33:5-(8-(4-morpholino phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) isoindoline-1-ketone

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(14.3mL) with (the 5-bromo-[1 in the diox (40mL), 2,4] triazolo [1,5-a] pyrazine-8-yl)-(4-morpholine-4-base-phenyl)-amine (1.0g, 2.67mmol), 5-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-2, and 3-dihydro-isoindole-1-ketone (referring to the description in the compound 79) (1.03g, 4.01mmol) and Pd (PPh ₃) ₄(0.77g, 0.67mmol) preparation.By the silica gel column chromatography purifying, with DCM, 96:4 DCM:NH subsequently ₃(7M is in MeOH) wash-out obtains title compound (0.895g, 79%). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)3.12(4H，m)，3.79(4H，m)，4.51(2H，s)，7.01(2H，d)，7.84(1H，d)，7.92(2H，d)，8.01(1H，s)，8.09(1H，d)，8.23(1H，s)，8.72(1H，s)，8.73(1H，s)，10.02(1H，s)。LCMS:Rt 2.51 minutes (97.8%), m/z (APCI) 428 (M+H) ⁺

Compound 34:4-(8-(4-morpholino phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) furans-2-methane amide

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(aqueous solution) (1.1mL, 1.68mmol) is with (5-bromo-[1,2, the 4] triazolo [1 in the diox (3mL), 5-a] pyrazine-8-yl)-(4-morpholine-4-base-phenyl)-amine (78mg, 0.16mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and furans-2-methane amide (100mg, 0.34mmol) and Pd (PPh ₃) ₄(60mg, 0.052mmol) preparation.Reaction mixture is distributed between water and ethyl acetate, collect with the title compound precipitation and by filtering.By the silica gel column chromatography purifying, with DCM and 95:5 DCM:NH ₃(7M is in MeOH) wash-out obtains title compound (42mg, 65%).Use 0.1M methylsulfonic acid (0.82mL) and be translated into mesylate, obtain solid, it is ground with ether, obtain title compound (30.5mg). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)2.19(3H，s，MsOH)，3.03-3.07(4H，m)，3.67(4H，m)，6.99(2H，br s)，7.43(1H，d)，7.74-7.82(4H，m)，8.06(1H，br s)，8.59(1H，br s)，8.64(1H，s)，9.91(1H，br s)。LCMS:Rt 2.64 minutes (98.1%), m/z (APCI) 406 (M+H) ⁺

Compound 35:6-(8-(4-morpholino phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl)-3,4-dihydro-isoquinoline-1 (2H)-ketone

Step 1:(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-(4-morpholine-4-base-phenyl)-t-butyl carbamate

With (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(morpholine-4-yl)-phenyl]-amine (300mg, 0.800mmol), dimethyl aminopyridine (10mg, 0.08mmol) and tert-Butyl dicarbonate (523mg, methylene dichloride 2.4mmol) (5mL) solution stir down at 50 ℃ and spend the night.Reaction mixture distributed between DCM and water and with organic layer with 1N NaOH and salt water washing.With organic layer through MgSO ₄Drying is filtered and vacuum concentration, obtains crude compound, and it is passed through the silica gel column chromatography purifying.With 98:2 DCM:MeOH wash-out, obtain title compound (352mg, 93%).LCMS:Rt 3.45 minutes (97.8%).

Step 2:(4-morpholine-4-base-phenyl)-(5-tributyl tin alkyl-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-t-butyl carbamate

At (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-(4-morpholine-4-base-phenyl)-t-butyl carbamate (370mg, 0.78mmol) THF (12mL) cooling (78 ℃) solution in be added in THF (0.78mL, 1.56mmol) the 2M isopropylmagnesium chloride in, and after stirring 5 minutes, the adding tributyltin chloride (0.42,1.56mmol).Reaction mixture was stirred 15 minutes down and restir 15 minutes at room temperature at-78 ℃.Remove desolvate after, residue by the silica gel column chromatography purifying, is used the 5:1 sherwood oil: ethyl acetate, 1:1 sherwood oil subsequently: eluent ethyl acetate.Title compound is separated (105mg, 20%).

Step 3:(4-morpholine-4-base-phenyl)-[5-(1-oxo-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-t-butyl carbamate

(4-morpholine-4-base-phenyl)-(5-tributyl tin alkyl-[1 in the degassing, 2,4] triazolo [1,5-a] pyrazine-8-yl)-t-butyl carbamate (100mg, 0.15mmol) and 6-bromo-3, (17mg 0.015mmol) and with reaction mixture stirring under 90 ℃ spends the night to add four (triphenyl phosphine) palladium (O) in DMF (1mL) solution of 4-dihydro-2H-isoquinoline 99.9-1-ketone.After the solvent removed in vacuo, residue is passed through the silica gel column chromatography purifying.Use the 1:1 sherwood oil: ethyl acetate and eluent ethyl acetate, obtain target compound, be yellow solid (30mg, 37%).

Step 4:6-(8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl)-3,4-dihydro-2H-isoquinoline 99.9-1-ketone

With (4-morpholine-4-base-phenyl)-[5-(1-oxo-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-(30mg, 0.055mmol) solution in the 1:1 mixture of TFA:DCM (1 drips) at room temperature stirred 2 hours t-butyl carbamate.The solvent vacuum removed and with residue at ethyl acetate and saturated NaHCO ₃Distribute between (aqueous solution).With water layer ethyl acetate extraction (2 *).Organic layer is merged and evaporation, obtain residue, it by the silica gel column chromatography purifying, is used eluent ethyl acetate.The 0.1M methylsulfonic acid (0.317mL) that title compound is separated (18mg, 75%) and be applied among the MeOH is translated into mesylate (16.6mg, 97%).

¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)2.36(3H，s MsOH)，3.04(2H，t)，3.21(4H，m)，3.47(2H，t)，3.83(4H，m)，7.11(2H，d)，7.95-8.02(6H，m)，8.05(1H，s)，8.74(1H，s)，10.09(1H，br s)。LCMS:Rt 2.81 minutes (97.9%), m/z (APCI) 442 (M+H) ⁺

Compound 36:5-(8-(4-(4-sec.-propyl piperazine-1-yl) phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) isoindoline-1-ketone

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(7.7mL) with the 5-bromo-N-in the diox (23mL) (6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-amine (0.6g, 1.44mmol), 5-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-2, and 3-dihydro-isoindole-1-ketone (0.56g, 2.16mmol) and Pd (PPh ₃) ₄(0.416g, 0.36mmol) preparation.By the silica gel column chromatography purifying, with DCM, 98:2 DCM:NH subsequently ₃(7M is in MeOH) wash-out obtains title compound (0.36g, 53%), and the 1M methylsulfonic acid that is applied among the MeOH (0.77mL) is translated into mesylate.After ether and DCM grinding, title compound is separated, be solid (0.410g). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)1.35(6H，d)，2.35(3H，s，MsOH)，3.04(2H，t)，3.20-3.27(2H，m)，3.56-3.63(3H，m)，3.89(2H，d)，4.52(2H，s)，7.09(2H，d)，7.85(1H，d)，7.95-8.01(3H，m)，8.10(1H，d)，8.24(1H，s)，8.72(1H，s)，8.74(1H，s)，9.27(1H，br s)，10.07(1H，s)。LCMS:Rt 2.93 minutes (97.9%), m/z (ES ⁺) 469 (M+H) ⁺

Compound 37:{5-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-2-morpholino phenyl } methyl alcohol

Step 1:(2-morpholine-4-base-5-nitro-phenyl)-methyl alcohol

(0.8g adds NaBH in the cooling of MeOH 3.39mmol) (5mL) (0 ℃) solution at 2-morpholine-4-base-5-nitro-phenyl aldehyde ₄(0.125g 3.39mmol) and with reaction mixture at room temperature stirred 3 hours.After the water quencher reaction, the solvent vacuum removed and be dissolved in residue in the ethyl acetate and use the salt water washing.With organic layer through MgSO ₄Drying is filtered and is concentrated, and obtains title compound (870mg), is applied to next step and need not to be further purified.

Step 2:(5-amino-2-morpholine-4-base-phenyl)-methyl alcohol

In ethanol (40mL) solution of (2-morpholine-4-base-5-nitro-phenyl)-methyl alcohol (870mg), add palladium hydroxide (87mg) and with mixture in the Parr-device, stirred 4 hours down at hydrogen pressure (10 crust).Reaction mixture is filtered through diatomite 521,, obtain title compound (640mg, 83%) with washing with alcohol and vacuum concentration.

Step 3:3-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-4-morpholine-4-base-phenyl amine

With (5-amino-2-morpholine-4-base-phenyl)-methyl alcohol (640mg, 3.07mmol), tert-butyldimethylsilyl chloride thing (509mg, 3.38mmol) and imidazoles (250mg, dimethyl formamide 3.68mmol) (20mL) solution at room temperature stirs and spends the night.The solvent vacuum is removed and residue is distributed between water and ethyl acetate.With organic layer salt water washing, through MgSO ₄Drying is filtered and is concentrated, and obtains crude product.Use the silica gel column chromatography purifying,, obtain title compound, be incarnadine solid (390mg, 27%) with DCM, 95:5DCM:MeOH mixture wash-out subsequently.

Step 4:(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[3-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-4-morpholine-4-base-phenyl]-amine

With 5,8-two bromo-[1,2,4] triazolo [1,5-a] pyrazine (0.391g, 1.41mmol), 3-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-4-morpholine-4-base-phenyl amine (0.5g, 1.55mmol) and N-ethyl di-isopropyl-amine (0.27mL, mixture 1.55mmol) was heating under 90 ℃, in 2-propyl alcohol (10mL) 8 hours.Reaction mixture is evaporated to drying and residue is distributed between methylene dichloride and water.With twice of dichloromethane extraction of water.Organic layer is merged, use the salt water washing, through MgSO ₄Drying is filtered and vacuum concentration, obtains title compound (335mg, 46%).

Step 5:[5-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-2-morpholine-4-base-phenyl]-methyl alcohol

Will be at (the 5-bromo-[1 in the 1M tetrabutyl ammonium fluoride solution, 2,4] triazolo [1,5-a] pyrazine-8-yl)-(285mg, THF 0.549mmol) (0.63mL) solution at room temperature stirred 1 hour [3-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-4-morpholine-4-base-phenyl]-amine.Reaction mixture is distributed between ethyl acetate and water.With organic layer with 10% citric acid solution and salt water washing, through MgSO ₄Drying is filtered and is concentrated, and obtains title compound, is paste solid (100mg, 45%).

Step 6:{5-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-2-morpholino phenyl } methyl alcohol

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(1.12mL) with [5-(the 5-bromo-[1 in the diox (2.0mL), 2,4] triazolo [1,5-a] pyrazine-8-base is amino)-2-morpholine-4-base-phenyl]-methyl alcohol (85mg, 0.21mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and the 1H-pyrazoles (81mg, 0.42mmol) and Pd (PPh ₃) ₄(60mg, 0.052mmol) preparation.Reaction mixture by the silica gel column chromatography purifying, is used 95:3 DCM:NH ₃(7M is in MeOH) wash-out is subsequently with anti-phase preparation HPLC purifying.Obtain title compound, be light brown solid (10mg, 12%). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)2.87(4H，m)，3.77(4H，m)，4.63(2H，d)，5.12(1H，t)，7.11(1H，d)，7.84(1H，d)，8.12(1H，s)，8.21(1H，s)，8.39(1H，s)，8.69(1H，s)，8.77(1H，s)，9.78(1H，s)，13.29(1H，br s)。LCMS:Rt 2.45 minutes (96.3%), m/z (APCI) 393 (M+H) ⁺

Compound 41:(6-[morpholine-4-yl] pyridin-3-yl)-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl] amine

This compound can be used the method for describing in the compound 120, uses the preparation of (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-(6-morpholine-4-base-pyridin-3-yl) amine in step 4.LCMS:Rt=0.80 minute (95%), m/z (ESI) 364 (M+H) ⁺

Compound 42:[6-(4-[cyclopropyl methyl] piperazine-1-yl) pyridin-3-yl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl] amine

This compound can be used the method for describing in the compound 120, in step 4, use (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[6-(4-[cyclopropyl methyl] piperazine-1-yl) pyridin-3-yl] the amine preparation.LCMS:Rt=0.80 minute (95%), m/z (ESI) 417 (M+H) ⁺

Compound 43:[6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl] amine

This compound can be used the method for describing in the compound 120, uses the preparation of (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl] amine in step 4.LCMS:Rt=0.77 minute (95%), m/z (ESI) 405 (M+H) ⁺

Compound 44:[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-6-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] and pyridin-3-yl } amine

This compound can be used the method for describing in the compound 120, in step 4, use (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-6-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl]-pyridin-3-yl } the amine preparation.LCMS:Rt=0.95 minute (95%), m/z (ESI) 445 (M+H) ⁺

Compound 46:{4-[4-(cyclopropyl methyl) piperazine-1-yl] phenyl }-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl] amine

This compound can be used the method for describing in compound 120 steps 4, use (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-4-[4-cyclopropyl methyl) and piperazine-1-yl] phenyl } the amine preparation.LCMS：Rt＝1.02(95％)，m/z(ESI)＝444(M+H) ⁺。

Compound 47:4-[8-(6-[morpholine-4-yl] pyridin-3-yl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl] thiophene-2-carboxamide derivatives

This compound can be used the method for describing in the compound 167, uses the preparation of (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-(6-morpholine-4-base-pyridin-3-yl) amine in step 4.LCMS:Rt=0.85 minute (95%), m/z (ESI) 423 (M+H) ⁺

Compound 48:(5-benzo [b] thiene-3-yl--[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-(4-morpholine-4-base phenyl) amine

This compound can be used the method for describing in the compound 120, uses (5-bromo-[1,2,4] triazolo [1 in step 4,5-a] pyrazine-8-yl)-(4-morpholine-4-base phenyl) amine and 4,4,5,5-tetramethyl--2-benzo [b] thiene-3-yl--[1,3,2] two oxa-boron heterocycle pentanes preparation.LCMS:Rt 0.84 minute (95%), m/z (ESI) 402 (M+H) ⁺

Compound 50:(4-morpholine-4-base phenyl)-(5-thiene-3-yl--[1,2,4] triazolo [1,5-a] pyrazine-8-yl) amine

This compound can be used the method for describing in the compound 120, uses (5-bromo-[1,2,4] triazolo [1 in step 4,5-a] pyrazine-8-yl)-(4-morpholine-4-base phenyl) amine and 4,4,5,5-tetramethyl--2-thiene-3-yl--[1,3,2] two oxa-boron heterocycle pentanes preparation.LCMS:Rt 1.19 minutes (95%), m/z (ESI) 379 (M+H) ⁺

Compound 51:[4-(4-sec.-propyl piperazine-1-yl) phenyl]-(5-thiene-3-yl--[1,2,4] triazolo [1,5-a] pyrazine-8-yl) amine

This compound can be used the method for describing in the compound 50, uses the preparation of (5-bromine [1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(4-sec.-propyl piperazine-1-yl)-phenyl] amine in the step in the end.LCMS:rt=1.11 minute (95%), m/z (ESI) 420 (M+H) ⁺

Compound 52:5-(5-ethyl-1H-pyrazoles-4-yl)-N-(4-morpholino phenyl)-[1,2,4] triazolo [1,5-a] pyrazine-8-amine

Step 1:3-ethyl-1H-pyrazoles

(0.5g, 3.25mmol) (0.56g adds saturated Na in ethanol 4.33mmol) (15mL) solution with hydrazine vitriol at the 1-TMS-penta-1-alkynes-3-ketone that stirs ₂CO ₃(0.52g 4.87mmol) and with mixture refluxed 5 hours down at 90 ℃.With the dilution of reaction mixture water and salt solution and with extracted with diethyl ether (3x).Organic layer is merged, through MgSO ₄Drying is filtered and is concentrated, and obtains crude product, by the silica gel column chromatography purifying.Use the 90:10 sherwood oil: eluent ethyl acetate obtains title compound (0.1196g, 36%).

Step 2:4-bromo-5-ethyl-1H-pyrazoles

(0.114g, (0.061mL 1.186mmol) and with mixture at room temperature stirred 2 hours to add bromine in acetate 1.186mmol) (2mL) solution at the 3-ethyl-1H-pyrazoles that stirs.With reaction mixture with saturated NaHCO ₃Alkalization, and with ethyl acetate extraction (3 *).Organic layer is merged, through MgSO ₄Drying is filtered and is concentrated, and obtains title compound (0.180g, 87%).Compound is applied to next step and need not to be further purified.

Step 3:4-bromo-5-ethyl-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles and 4-bromo-3-ethyl-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles

The TFA of catalytic amount (0.001mL, under existence 0.00103mmol), with 4-bromo-5-ethyl-1H-pyrazoles (0.179g 1.032mmol) is dissolved in 3,4-dihydro-2H-pyrans (0.28mL, 3.098mmol).Reaction mixture was stirred 3 hours down at 90 ℃, and NaH (1.5mg, 0.0061mmol) quencher are used in cooling then.Except that after desolvating, residue by the silica gel column chromatography purifying, is used 90:10 petroleum ether-ethyl acetate mixture wash-out.The fraction that will contain expecting compound is collected and vacuum concentration, obtains title compound (175mg, 66%).

Step 4:5-ethyl-1-(tetrahydrochysene-pyrans-2-yl)-4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-1H-pyrazoles and 3-ethyl-1-(tetrahydrochysene-pyrans-2-yl)-4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-the 1H-pyrazoles

This compound can be used the method for describing in compound 86 steps 2, be applied in 4-bromo-5-ethyl-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles and 4-bromo-3-ethyl-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles (168mg in the methyl-sulphoxide (2mL), 0.65mmol), two (tetramethyl ethylene ketone) two boron (331mg, 1.3mmol), PdCl ₂Dppf (53mg, 65 μ mol) and KOAc (190mg, 1.95mmol) preparation.By the silica gel column chromatography purifying, use the 90:10 sherwood oil: eluent ethyl acetate obtains title compound (61.1mg, 31%) with reaction mixture.

Step 5:{5-[5-ethyl-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles-4-yl]-[1,2,4] triazolo [1,5-a] pyrazine-8-yl-(4-morpholine-4-base-phenyl)-amine and 5-[3-ethyl-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles-4-yl]-[1,2,4] triazolo [1,5-a] pyrazine-8-yl }-(4-morpholine-4-base-phenyl)-amine

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(aqueous solution) (0.45mL, 0.6mmol) is with (the 5-bromo-[1 in the diox (2.0mL), 2,4] triazolo [1,5-a] pyrazine-8-yl)-(4-morpholine-4-base-phenyl)-amine (0.032g, 0.085mmol), 5-ethyl-1-(tetrahydrochysene-pyrans-2-yl)-4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-IH-pyrazoles and 3-ethyl-1-(tetrahydrochysene-pyrans-2-yl)-4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and the 1H-pyrazoles (0.52mg, 0.17mmol) and Pd (PPh ₃) ₄(0.025mg, 0.021mmol) preparation.Reaction mixture by the silica gel column chromatography purifying, is used the 1:1 sherwood oil: ethyl acetate, use the 1:4 sherwood oil subsequently: eluent ethyl acetate obtains title compound (45mg).

Step 6:5-(5-ethyl-1H-pyrazoles-4-yl)-N-(4-morpholino phenyl)-[1,2,4] triazolo [1,5-a] pyrazine-8-amine

Will 5-[5-ethyl-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles-4-yl]-[1,2,4] triazolo [1,5-a] pyrazine-8-yl-(4-morpholine-4-base-phenyl)-amine and 5-[3-ethyl-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles-4-yl]-[1,2,4] triazolo [1,5-a] pyrazine-8-yl }-(40mg, 0.077mmol) methyl alcohol (10mL) solution with dense HCl (0.3mL) at room temperature stirred 5 hours (4-morpholine-4-base-phenyl)-amine.Remove desolvate after, with solid residue at ethyl acetate and saturated NaHCO ₃Between distribute.Undissolved solid by filtration is collected, and water, ether and petroleum ether and drying obtain title compound (5mg, 17%).Use 0.1M methylsulfonic acid (0.128mL) and be translated into mesylate, obtain title compound (5.6mg, 89%), be solid.

¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)1.13(3H，m)，2.29(3H，s，MsOH)，2.74(2H，m)，3.29(4H，m)，3.77(4H，m)，7.06(2H，m)，7.62(1H，s)，7.89(2H，d)，8.00(1H，s)，8.61(1H，s)，9.83(1H，s)。LCMS:Rt 2.69 minutes (98.4%), m/z (APCI) 391 (M+H) ⁺

Compound 53:6-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-1,1-dioxo-1,2-dihydro-1 λ ⁶-benzo [d] isothiazole-3-ketone

Step 1:1,1-dioxo-6-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-1,2-dihydro-1 λ ⁶-benzo [d] isothiazole-3-ketone

This compound can be used the method for describing in compound 86 steps 2, is applied in the 6-bromo-1 in the diox (10mL), 1-dioxo-1,2-dihydro-1 λ ⁶-benzo [d] isothiazole-3-ketone (0.5,1.9mmol), two (tetramethyl ethylene ketone) two boron (0.53g, 2.1mmol), PdCl ₂Dppf (0.047g, 0.058mmol) and KOAc (0.56g, 5.7mmol) preparation.The solvent vacuum is removed and residue is distributed between DCM and water.With organic layer with saturated NaHCO ₃With 2M HCl washing, through MgSO ₄Drying is filtered and evaporation, obtains title compound (990mg, 169%), is applied to next step and need not to be further purified.

Step 2:(4-morpholine-4-base-phenyl)-[5-(1,1,3-trioxy--2,3-dihydro-1H-1 λ ⁶-benzo [d] isothiazole-6-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-t-butyl carbamate

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(2mL is 3mmol) with (the 5-bromo-[1,2 in the diox (6mL), 4] triazolo [1,5-a] pyrazine-8-yl)-(4-morpholine-4-base-phenyl)-t-butyl carbamate (170mg, 0.36mmol), 1,1-dioxo-6-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-1,2-dihydro-1 λ ⁶-benzo [d] isothiazole-3-ketone (374mg, 0.72mmol) and Pd (PPh ₃) ₄(100mg, 0.082mmol) preparation.Reaction mixture is by the silica gel column chromatography purifying, and use the 1:1 sherwood oil: ethyl acetate obtains still impure compound.Second silica gel column chromatography used the 10:1DCM:MeOH wash-out, obtains title compound (91mg, 44%).

Step 3:6-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-1,1-dioxo-1,2-dihydro-1 λ ⁶-benzo [d] isothiazole-3-ketone

(4-morpholine-4-base-phenyl) that will be in 4M HCl (2.5mL)-[5-(1,1,3-trioxy--2,3-dihydro-1H-1 λ ⁶-benzo [d] isothiazole-6-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-(100mg, 0.173mmol) De diox suspension at room temperature stirred 2 hours t-butyl carbamate.The solvent vacuum is removed and residue is ground with DCM, ether and sherwood oil, obtain title compound (84mg, 100%). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)3.25(4H，m)，3.85(4H，m)，7.20(2H，d)，7.88(2H，d)，8.16(1H，d)，8.24(1H，s)，8.58(1H，d)，8.82(2H，s)，8.96(1H，s)，10.31(1H，s)。LCMS:Rt 2.31 minutes (95.7%), m/z (APCI) 478 (M+H) ⁺

Compound 54:4-{8-[6-(4-[cyclopropyl methyl] piperazine-1-yl)-pyridin-3-yl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl } thiophene-2-carboxamide derivatives

This compound can be used the method for describing in the compound 120, in step 4, use (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[6-(4-[cyclopropyl methyl] piperazine-1-yl) pyridin-3-yl] the amine preparation.LCMS:Rt=0.85 minute (95%), m/z (ESI) 476 (M+H) ⁺

Compound 55:4-{8-[6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl } thiophene-2-carboxamide derivatives

This compound can be used the method for describing in the compound 167, uses the preparation of (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl] amine in step 4.LCMS:Rt=0.82 minute (95%), m/z (ESI) 464 (M+H) ⁺

Compound 56:4-(8-{6-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl]-pyridin-3-yl amino }-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) thiophene-2-carboxamide derivatives

This compound can be used the method for describing in the compound 167, in step 4, use (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-6-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl]-pyridin-3-yl } the amine preparation.LCMS:Rt=0.99 minute (95%), m/z (ESI) 504 (M+H) ⁺

Compound 57:4-(8-{4-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl]-phenyl amino }-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) thiophene-2-carboxamide derivatives

This compound can be used the method for describing in the compound 58, use (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-4-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] and phenyl } the amine preparation.LCMS:Rt=1.07 minute (95%), m/z (ESI) 503 (M+H) ⁺

Compound 58:4-{8-[4-(4-(cyclopropyl methyl) piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl } thiophene-2-carboxamide derivatives

This compound can be used the method for describing in the compound 46, uses 2-(aminocarboxyl) thiophene-4-boric acid preparation.LCMS：Rt＝0.93(95％)，m/z(ESI)475(M+H) ⁺。

Compound 59:[4-(4-cyclopropyl piperazine-1-yl) phenyl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl] amine

This compound can be used the method for describing in the compound 46, uses the preparation of (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(4-cyclopropyl piperazine-1-yl)-phenyl] amine.LCMS：Rt＝0.84(95％)，m/z(ESI)402(M+H) ⁺。

Compound 60:[6-(4-cyclopropyl piperazine-1-yl) pyridin-3-yl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl] amine

This compound can be used the method for describing in the compound 120, uses the preparation of (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[6-(4-cyclopropyl piperazine-1-yl) pyridin-3-yl] amine in step 4.LCMS:Rt=0.76 minute (95%), m/z (ESI) 403 (M+H) ⁺

Compound 61:4-[8-(4-morpholine-4-base phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl] thiazole-2-methane amide

This compound can be used the method for describing in the compound 73, uses ammonia (7M is in MeOH) preparation in step 3.LCMS:Rt=1.00 minute (95%), m/z (ESI) 423 (M+H) ⁺

Compound 62:4-{8-[4-(4-sec.-propyl piperazine-1-yl) phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl } thiazole-2-methane amide

This compound can be used the method for describing in the compound 61, uses the preparation of (5-bromine [1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(4-sec.-propyl piperazine-1-yl)-phenyl] amine in the step in the end.LCMS:rt=0.96 minute (95%), m/z (ESI) 464 (M+H) ⁺

Compound 63:4-(8-{4-[1-(2,2, the 2-trifluoroethyl) piperidin-4-yl] phenyl amino }-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) thiophene-2-carboxamide derivatives

Step 1:1-trifluoroacetyl group-4-(4-nitrophenyl) piperidines

With triethylamine (1.0mL, 7.3mmol) and 4-(4-nitrophenyl) piperidines (1.0g, 4.8mmol) in DCM (25mL), at 0 ℃, N ₂Following stirring and adding trifluoroacetic anhydride (0.81mL, 5.8mmol).Mixture was stirred 3 days, with the temperature temperature to room temperature.Then with solution with DCM (50mL) dilution and water (2 * 15mL), NaHCO ₃(50% saturated aqueous solution, 2 * 15mL) and salt solution (15mL) washing.With solvent through MgSO ₄Dry and evaporation, obtain expecting compound (1.46g, 4.66mmol).

Step 2:1-(2,2, the 2-trifluoroethyl)-4-(4-nitrophenyl) piperidines

(1.42g, THF 4.7mmol) (15mL) solution stirs in the 25mL2-neck flask of condenser and constant voltage feed hopper is housed with 1-trifluoroacetyl group-4-(4-nitrophenyl) piperidines.With the N of system ₂Flushing adds NaBH ₄(210mg 5.6mmol) and with flask is cooled to 0 ℃.Go through then and dripped iodine in 20 minutes (600mg, THF 2.3mmol) (5mL) solution are removed the application of sample funnel and afterwards with mixture heated overnight under refluxing.The faint yellow suspension that produces is cooled to room temperature and carefully adds MeOH (1.5mL), cause that gas acutely discharges.Evaporating solvent obtains title compound, and its application be need not to be further purified.

Step 3:4-[1-(2,2, the 2-trifluoroethyl) piperidin-4-yl] phenyl amine

With ammonium formiate (1.38g, 22mmol) and 10%Pd/C (230mg, (1.26g is in EtOH 4.4mmol) (10mL) and EtOAc (10mL) solution 0.2mmol) to join 1-(2,2, the 2-trifluoroethyl)-4-(4-nitrophenyl) piperidines.Suspension was heated 24 hours under refluxing, further add part ammonium formate (2g) after 4 hours and 8 hours.Mixture by diatomite filtration and evaporation, is obtained orange solids.It is distributed between DCM (40mL) and water (20mL) and each layer separated.With water with DCM (2 * 20mL) extractions and with the organic layer that merges through MgSO ₄Drying and reduction vaporization obtain N-{4-[1-(2,2, the 2-trifluoroethyl) piperidin-4-yl] phenyl } methane amide, be greenish orange look solid (980mg).

MeOH (20mL) solution of methane amide at room temperature stirred and add HCl (dense, 1mL).Deep purple solution was heated 1 hour under refluxing, cool off and MeOH is evaporated.Residue water (20mL) is stirred and adding NaHCO ₃(the saturated aqueous solution) stops up to bubbling.With mixture with DCM (20mL, 2 * 10mL) extractions and with the extract that merges through MgSO ₄Drying and reduction vaporization obtain title compound, are orange solids (870mg).

Application class is similar to method used in the compound 89, with this material be used to prepare 4-(8-{4-[1-(2,2, the 2-trifluoroethyl) piperidin-4-yl] phenyl amino }-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) thiophene-2-carboxamide derivatives.

LCMS:Rt=2.11 minute (100%), m/z (ESI) 502 (M+H) ⁺

Compound 65:5-(8-(4-(2-morpholino oxyethyl group) phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) isoindoline-1-ketone

Step 1:(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-amine

According to the method for describing in compound 6 steps 1, will be in 2-propyl alcohol (6mL) 5,8-two bromo-[1,2,4] triazolo [1,5-a] pyrazine (0.5g, 1.799mmol), 4-(2-morpholine-4-base-oxyethyl group)-phenyl amine (0.6g, 4.5mmol) and N, the N-diisopropyl ethyl amine (0.47mL, 2.7mmol) spend the night under 95 ℃ by stirring.Behind the evaporating solvent, be dissolved in residue among the DCM and water (2 *) and salt water washing.With organic layer through MgSO ₄Drying is filtered and vacuum concentration, obtains oily matter, and it is passed through the silica gel column chromatography purifying.With 97:3 DCM:MeOH mixture wash-out, obtain title compound (650mg, 86%), be faint yellow solid.LCMS:Rt 2.06 minutes (97.7%).

Step 2:5-(8-(4-(2-morpholino oxyethyl group) phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) isoindoline-1-ketone

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(1.02mL is 1.53mmol) with (the 5-bromo-[1,2 in the diox (3mL), 4] triazolo [1,5-a] pyrazine-8-yl)-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-amine (80mg, 0.19mmol), 5-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-2,3-dihydro-isoindole-1-ketone (74mg, 0.29mmol) and Pd (PPh ₃) ₄(55mg, 0.047mmol) preparation.Reaction mixture by the silica gel column chromatography purifying, is used DCM and 97:3 DCM:NH ₃(7M is in MeOH) mixture wash-out.After using the ether grinding, title compound is separated, be solid (61.9mg, 69%).The 1M methylsulfonic acid (0.134mL) that is applied among the MeOH is converted into mesylate with material, obtains title compound (57.1mg). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)2.40(3H，s，MsOH)，3.25-3.38(2H，m)，3.60-3.78(4H，m)，3.84(2H，t)，4.09(2H，d)，4.45(2H，m)，4.56(2H，s)，7.14(2H，d)，7.90(1H，d)，8.05-8.19(4H，m)，8.28(1H，s)，8.76(1H，br s)，8.79(1H，s)，10.00(1H，br s)，10.16(1H，s)。LCMS:Rt1.98 minute (99.1%), m/z (APCI) 472 (M+H) ⁺

Compound 67:N-(2-fluoro-4-morpholino phenyl)-5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-amine

Step 1:(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-(2-fluoro-4-morpholine-4-base-phenyl)-amine

This compound can be used the method for describing in compound 6 steps 1, be applied in 5 in the 2-propyl alcohol (2mL), 8-two bromo-[1,2,4] triazolo [1,5-a] pyrazine (0.105g, 0.89mmol), 2-fluoro-4-morpholine-4-base-phenyl amine (93mg, 0.474mmol), DIPEA (0.123mL, 0.706mmol) and 1, also [2.2.2] octane (53mg, 0.472mmol) preparation of 4-diazabicylo.Reaction mixture is distributed between DCM and 10% aqueous citric acid solution, with the organic layer separation and with 10% citric acid solution, water and salt water washing, through MgSO ₄Drying is filtered and vacuum concentration.Title compound is separated, for incarnadine solid (77mg, 42%) and be applied to next step and need not to be further purified.LCMS:Rt 3.48 minutes (89%).

Step 2:N-(2-fluoro-4-morpholino phenyl)-5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-amine

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5NNa ₂CO ₃(1.09mL, 1.62mmol) is with (5-bromo-[1,2, the 4] triazolo [1 in the diox (3.25mL), 5-a] pyrazine-8-yl)-(2-fluoro-4-morpholine-4-base-phenyl)-amine (80mg, 0.203mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and the 1H-pyrazoles (79mg, 0.406mmol) and Pd (PPh ₃) ₄(59mg, 0.051mmol) preparation.Reaction mixture by the silica gel column chromatography purifying, is used 97:3 DCM:NH ₃(7M is in MeOH) wash-out.The fraction that will contain product merges and vacuum-evaporation, obtains solid, and it is ground with ether and sherwood oil, obtains title compound (29mg, 38%).LCMS:Rt 2.90 minutes (96%).

(0.762mL, 0.076mmol) solution is translated into mesylate to the MeOH of application 0.1M methylsulfonic acid, obtains title compound (35mg). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)2.36(3H，s，MsOH)，3.19(4H，m)，3.79(4H，m)，6.84-6.94(2H，m)，7.54(1H，t)，8.08(1H，s)，8.48(2H，s)，8.76(1H，s)，9.31(1H，s)。LCMS:Rt 2.91 minutes (95.4%), m/z (APCI) 381 (M+H) ⁺

Compound 70:(4-(8-(4-morpholino phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl)-1H-pyrazoles-5-yl) methyl alcohol

Step 1:4-bromo-5-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-1H-pyrazoles

With (4-bromo-2H-pyrazole-3-yl)-methyl alcohol (0.64mg, 3.63mmol), tert-butyldimethylsilyl chloride thing (0.82g, 5.45mmol) and imidazoles (dinethylformamide (20mL) solution at room temperature stirs and spends the night for 0.42g, N 6.18mmol).With reaction mixture 50:50 ether: ethyl acetate mixture dilution and water (3 *) washing.With organic layer through MgSO ₄Drying is filtered and is concentrated.By the silica gel column chromatography purifying, use the 80:20 sherwood oil: eluent ethyl acetate obtains title compound (1.035g, 98%) with residue.

Step 2:4-bromo-3-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles and 4-bromo-5-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles

The TFA of catalytic amount (0.0026mL, under existence 0.035mmol), with 4-bromo-5-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-1H-pyrazoles (1g 3.45mmol) is dissolved in 3,4-dihydro-2H-pyrans (0.944mL, 10.34mmol) in.Reaction mixture was stirred 18 hours down at 90 ℃, and NaH (4.69mg, 0.206mmol) quencher are used in cooling then.Remove desolvate after, with residue by the silica gel column chromatography purifying, with the 95:5 petroleum ether-ethyl acetate, use 90:10 petroleum ether-ethyl acetate mixture wash-out subsequently.The fraction that will contain expecting compound is collected and vacuum concentration, obtain 4-bromo-3-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles and 4-bromo-5-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles (724mg, 56%).

Step 3:{5-[5-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles-4-yl]-[1,2,4] triazolo [1,5-a] pyrazine-8-yl-(4-morpholine-4-base-phenyl)-t-butyl carbamate and 5-[3-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles-4-yl]-[1,2,4] triazolo [1,5-a] pyrazine-8-yl }-(4-morpholine-4-base-phenyl)-t-butyl carbamate

This compound can be used the method for describing in compound 35 steps 3, be applied in (4-morpholine-4-base-phenyl)-(the 5-tributyl tin alkyl-[1 among the DMF (4mL), 2,4] triazolo [1,5-a] pyrazine-8-yl)-t-butyl carbamate (210mg, 0.30mmol), 4-bromo-3-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles and 4-bromo-5-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles (170mg, 0.45mmol) and four (triphenyl phosphine) palladium (0) (35mg, 0.030mmol) preparation.By the silica gel column chromatography purifying, use the 3:7 sherwood oil then with 7:3: eluent ethyl acetate obtains title compound (62.5mg) with crude compound.

Step 4:(4-(8-(4-morpholino phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl)-1H-pyrazoles-5-yl) methyl alcohol

Will 5-[3-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-1-(tetrahydrochysene-pyrans-3-yl)-1H-pyrazoles-4-yl]-[1,2,4] triazolo [1,5-a] pyrazine-8-yl-(4-morpholine-4-base-phenyl)-amine and 5-[5-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-1-(tetrahydrochysene-pyrans-3-yl)-1H-pyrazoles-4-yl]-[1,2,4] triazolo [1,5-a] pyrazine-8-yl }-(53.6mg, 0.077mmol) MeOH (5mL) solution with dense HCl (0.27mL) at room temperature stirred 2 hours (4-morpholine-4-base-phenyl)-amine.Except that after desolvating, residue is distributed between ethyl acetate and water.With water layer with ethyl acetate (3 *) washing and with the organic layer that merges through MgSO ₄Drying is filtered and is concentrated.Residue is dissolved among the 4MHCI in the Zai diox, and vacuum concentration is then at ethyl acetate and saturated NaHCO ₃Between distribute.With organic layer through MgSO ₄Drying is filtered and vacuum concentration, obtains crude compound, and it is passed through the silica gel column chromatography purifying.With EtOAc and 95:5 DCM:MeOH mixture wash-out, title compound is separated (5.4mg, 18%).

¹H-NMR (400MHz, d ₆-DMSO) δ (ppm) 3.11 (4H, m), 3.79 (4H, m), 4.65 (2H, d), 5.25 and 5.53 (1H, br s), 6.99 (2H, m), 7.84 and 8.51 (1H, br s), 7.92 (2H, d), 8.12 (1H, d), 8.70 (1H, s), 9.74 (1H, s), 13.12 and 13.23 (1H, br s).LCMS:Rt 2.26 minutes (96.2%), m/z (APCI) 393 (M+H) ⁺

Compound 73:4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiazole-2-methylformamide

Step 1:2,4-two bromo thiazoles

With thiazolidone (3.43g, 29.32mmol) and POBr ₃(25g, 87.96mmol, 3 equivalents) mix as solid under nitrogen.Under agitation reaction mixture is heated to 110 ℃ then and reaches 3 hours, cause that dark slurries form.Then reaction mixture is cooled to room temperature and adds entry/ice (200mL) mixture very carefully, with grey suspension ether (3 * 50mL) extractions that produce, organic layer is merged, filter and evaporation by silica filler, obtain title compound, be orange (4g, 57%), be applied to next step and need not to be further purified.

Step 2:4-bromo thiazole-2-ethyl formate

Under 0 ℃, at two bromo thiazoles (1g, THF (2M, 2.3mL, 4.57mmol, the 1.10 equivalents) solution of dropping iPrMgCl in THF 4.15mmol) (15mL) solution.To be reflected at 0 ℃ stirred 0.25 hour down.In the orange solution that produces, be added in the diethyl carbonate (3mL) among the THF (5mL) by sleeve pipe.The green solution that produces was at room temperature further stirred 0.5 hour, reaction is passed through to add saturated NH ₄The Cl quencher.Title compound by the LC purifying, as elutriant, is obtained 514.2mg (52%) title compound with 6/4 hexanaphthene/DCM, be pale yellow powder shape solid.

Step 3:4-bromo thiazole-2-methylformamide

(500mg 2.13mmol) is dissolved in the methyl alcohol (1mL) and is added in methylamine in the methyl alcohol (10mL) with 4-bromo thiazole-2-ethyl formate.Mixture at room temperature stirred spend the night.The vapourisation under reduced pressure solvent obtains title compound, is yellow solid.0.92 minute (100%) m/z (ESI) of LCMS:Rt, 219/221 (M+H) ⁺

Step 4:4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiazole-2-methylformamide

To be similar to the method for describing in compound 6 steps 3,4-bromo thiazole-2-methylformamide is converted into boride (boronate).Use the method for describing in compound 120 steps 4 then and prepare title compound.LCMS:Rt=1.06 minute (95%), m/z (ESI) 437 (M+H) ⁺

Compound 79:5-(8-(6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) isoindoline-1-ketone

Step 1:4-bromo-2-brooethyl-methyl benzoate

(4.6g 21.39mmol) is dissolved among the 2 M HCl in MeOH and refluxed 3 hours with 4-bromo-2-methyl-phenylformic acid.With solvent evaporation, obtain 4-bromo-2-methyl-methyl benzoate (4.24g, 86%) this intermediate (18.51mmol) is dissolved in the tetracol phenixin (100mL) and add N-bromine succinimide (NBS) (5.57g, 24.06mmol).Add AIBN (122mg, 740 μ mol) then and mixture is used nitrogen purging 5 minutes.Then with reaction mixture refluxed 4 hours.After being cooled to room temperature, evaporate with the reaction mixture filtration and with filtrate.Residue by purified by flash chromatography (silica gel, 2:1 petrol ether/ethyl acetate), is obtained title compound (3.42g, 60%).

Step 2:5-bromo-2,3-dihydro-isoindole-1-ketone

(0.5g is 16.2mmol) with methanol ammonia (10mL, the 7N NH in MeOH with 4-bromo-2-brooethyl-methyl benzoate ₃) handled 5 minutes down at 90 ℃.Form precipitation after being cooled to room temperature, collect and wash, obtain title compound, be colorless solid (224mg, 65%) with small amount of methanol by filtering. ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)4.41(2H，s)，7.64(1H，d)，7.70(1H，d)，7.87(1H，s)，8.67(1H，br s)。LCMS:Rt 2.49 minutes (99.6%), m/z (APCI) 212 (M+H) ⁺

Step 3:5-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-2,3-dihydro-isoindole-1-ketone

With 5-bromo-2,3-dihydro-isoindole-1-ketone (230mg, 1.08mmol), two (tetramethyl ethylene ketone) two boron (300mg, 1.18mmol), PdCl ₂(320mg 3.26mmol) is suspended in the diox (4mL), uses nitrogen purging 5 minutes, then 85 ℃ of following heated overnight for dppf (25mg, 31 μ mol) and KOAc.The solvent vacuum is removed and residue is distributed between ethyl acetate and water.Water layer is used the salt water washing once with ethyl acetate (3 *) extraction and with the organic phase that merges, pass through MgSO ₄Filter and evaporation.Solid residue is ground and vacuum-drying with hexane, obtain title compound (185mg, 66%), be gray solid. ¹H-NMR(400MHz，CDCl ₃)δ(ppm)1.37(12H，s)，4.45(2H，s)，6.38(1H，br s)，7.87(1H，d)，7.93(2H，m)。

Step 4:1-sec.-propyl-4-(5-nitro-pyridine-2-yl)-piperazine

2-chloro-5-nitropyridine (2.5g, add in THF 15.7mmol) (25mL) solution 1-sec.-propyl piperazine (2.01g, 15.7mmol) and K ₂CO ₃(3.25g, 23.6mmol).Reaction mixture was stirred 4 hours down at 50 ℃, stir down at 70 ℃ then and spend the night.The solvent vacuum is removed and the orange solids that produces is ground with the 10:1 petroleum ether-ethyl acetate.Isolated compound (3.7g, 94%) is used for next step and need not to be further purified.

Step 5:6-(4-sec.-propyl-piperazine-1-yl)-pyridin-3-yl-amine

With 1-sec.-propyl-4-(5-nitro-pyridine-2-yl)-piperazine (0.9g, 3.6mmol) be dissolved among the MeOH (20mL) and add tindichloride (II) dihydrate (4g, 18mmol).The application water-bath is with the mixture cooling and add dense HCl (4mL).To react at room temperature to stir and spend the night.After removing methyl alcohol, the yellow solution that produces is alkalized with dense NaOH (pH 11) and the formation white depositions.Solid by filtration is collected and extract with ether (5 *).Organic layer is merged, through MgSO ₄Drying is filtered, and vacuum concentration obtains orange, and it places post crystallization, obtains orange solids (0.68g, 86%).

Step 6:5-bromo-8-(6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-amine

This compound can be used the method for describing in compound 6 steps 1, be applied in 5 in the 2-propyl alcohol (2mL), 8-two bromo-[1,2,4] triazolo [1,5-a] pyrazine (0.188g, 0.68mmol), 6-(4-sec.-propyl-piperazine-1-yl)-pyridin-3-yl amine (0.180g, 0.816mmol) and N-ethyl di-isopropyl-amine (0.20mL, 1.02mmol) preparation.Thick material by the silica gel column chromatography purifying, with DCM, use 95:5 DCM:MeOH subsequently, is obtained title compound, be light brown solid (260mg, 92%).

Step 5:5-(8-(6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) isoindoline-1-ketone

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(0.64mL) with the 5-bromo-N-in the diox (2mL) (6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-amine (50mg, 0.12mmol), 5-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-2, and 3-dihydro-isoindole-1-ketone (56mg, 0.216mmol) and Pd (PPh ₃) ₄(35mg, 0.03mmol) preparation.With crude product by the silica gel column chromatography purifying, with 95:5 DCM:MeOH, use 90:10 DCM:MeOH wash-out subsequently.Use the 10:1 normal hexane: the DCM mixture grinds the back and obtains title compound (19mg, 34%).Use 0.1M methylsulfonic acid (0.35mL) and be translated into mesylate, obtain title compound, be yellow solid (20mg, 69%).

¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)1.34(6H，d)，2.36(6H，s，2×MsOH)，3.16-3.21(5H，m)，3.57(2H，m)，4.45(2H，d)，4.52(2H，s)，7.11(1H，d)，7.86(1H，d)，8.01(1H，s)，8.10(1H，d)，8.24-8.29(2H，m)，8.72(1H，s)，8.76(1H，s)，8.82(1H，d)，9.39(1H，br s)，10.21(1H，s)。LCMS:Rt 1.92 minutes (98.5%), m/z (APCI) 470 (M+H) ⁺

Compound 80:3-[8-(4-morpholine-4-base phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-benzo [b] thiophene-7-methane amide

Step 1:1-bromo-2-(2-vinyl ethyl ether base sulfane base) benzene

Under nitrogen, (10.50g adds salt of wormwood (9.2mL, 61.46mmol, 1.10 equivalents) carefully in exsiccant DMF (50mL) solution 55.87mmol) at the 2-bromo thiophenol.In case bubbling reduces, in mixture, add 2-bromo-1,1-diethoxyethane (8.46g, 61.46mmol, 1.10 equivalents) and at room temperature stirring 2 hours.The suspension that produces is poured into (3 * 50mL) extract in the frozen water of 200mL and with ether.With organic layer salt water washing, through MgSO ₄Drying obtains title compound after solvent is removed, and is the heavy-gravity orange, and its application be need not to be further purified.

Step 2:7-bromobenzene is [b] thiophene also

1-bromo-2-(2-vinyl ethyl ether base sulfane base) benzene is dissolved in the chlorobenzene (50mL) and with solution and is heated to 70 ℃.Add PPA (10.5mL) then carefully and with two-phase mixture 150 ℃ of following heated overnight.Remove with transfer pipet with the dark slurries cooling of generation and with the upper strata solvent.In residue, add chlorobenzene (15mL) and be heated to 150 ℃ and reach 30 minutes.Solvent is removed once more and residue is clarified up to washings with a small amount of washed with dichloromethane.With organic fraction merging and through diatomite filtration, obtain clear yellow solution.Vacuum concentration carries out LC subsequently, is elutriant with cyclohexane give, produces title compound, is heavy-gravity colorless oil (1.21g, 35%).

Step 3: benzo [b] thiophene-7-ethyl formate

Under nitrogen, with the 7-bromobenzene also [b] thiophene (500mg 2.36mmol) is dissolved among the exsiccant THF (5.0mL).Add magnesium chips (530mg, 2.83mmol, 1.20 equivalents) and the mixture heating under refluxing that produces is occurred up to the magnesium dissolving.The muddy yellow solution that produces is cooled to room temperature and adding diethyl carbonate (2mL, excessive) and continuation stirred 1 hour, add ammonium chloride (10% aqueous solution).The mixture that produces is distributed between DCM and water and water layer is extracted with DCM.Organic fraction is merged, use the salt water washing, through Na ₂SO ₄Dry and be adsorbed onto on the silicon-dioxide.By the LC purifying, as elutriant, obtain title compound with 8/2 hexanaphthene/methylene dichloride, be greenish orange look oily matter (346.2mg, 71%).

Step 4: benzo [b] thiophene-7-formic acid

(1.0g adds sodium hydroxide (5g, excessive) in methyl alcohol 48mmol) (10mL) and water (10mL) solution at benzo [b] thiophene-7-ethyl formate.Solution was at room temperature stirred 30 minutes, and used ester is consumed.Reaction mixture is adjusted to pH 1 by adding 6M HCl solution, and extracts with DCM.The organic layer that merges is filtered by silica filler, obtain title compound, be yellow solid (505.2mg, 59%).

Step 5: benzo [b] thiophene-7-methane amide

(505mg, methylene dichloride 2.84mmol) (10mL) solution at room temperature stir and add thionyl chloride (669mg, 5.68mmol, 2.0 equivalents), add DMF (0.06mL) subsequently, cause that gas emits with benzo [b] thiophene-7-formic acid.The solution that produces was at room temperature stirred 1 hour.In mixture, add ammoniacal liquor (10mL) then carefully, cause that violent gas emits.Then with mixture water (50mL) dilution that produces, and by adding saturated NaHCO ₃(aqueous solution) is extremely neutral with pH regulator.Water layer is extracted with DCM, and with the organic layer merging and through Na ₂SO ₄Dry.The vapourisation under reduced pressure solvent obtains title compound (purity 81%), for yellow solid (500mg, 98%), its application be need not to be further purified.

Step 6:3-bromobenzene is [b] thiophene-7-methane amide also

(500mg, methylene dichloride 2.82mmol) (5mL) solution at room temperature stirs and adds acetate (5mL), adds NBS (750mg, 4.23mmol, 1.5 equivalents) subsequently with benzo [b] thiophene-7-methane amide.To react and at room temperature stir 1 hour, LC-MS analyzes and shows that raw material all is converted into expecting compound (79%) and dibromide (21%).To react water (50mL) dilution, with moisture Potassium hydrogen sulfite, neutralize with sodium bicarbonate subsequently.Then water layer is merged with dichloromethane extraction and with the organic layer that produces, use the salt water washing, through Na ₂SO ₄Drying and evaporation.Thick material by the LC purifying, as elutriant, is obtained title compound with DCM, be white solid (300mg, 41%).

Step 7:3-(4,4,5,5-tetramethyl-[1,3,2] two oxa-boron heterocycle pentane-2-yls) benzo [b] thiophene-7-methane amide

With the 3-bromobenzene also [b] thiophene-7-methane amide (300mg, 1.18mmol) De diox (5mL) solution stirs under nitrogen.Add Pd (dppf) Cl ₂(29mg 3mol%), potassium acetate (230mg, 2.35mmol, 2.0 equivalents) and two tetramethyl ethylene ketone two boron (450mg, 1.77mmol, 1.5 equivalents), and is heated to 80 ℃ and stir and spend the night with reaction.The orange suspension that produces is diluted with DCM,, obtain oily matter, be applied to next step and need not to be further purified through diatomite filtration and vacuum concentration.

Step 8:3-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-benzo [b] thiophene-7-methane amide

This compound can be used the method preparation of describing in compound 120 steps 4. ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)3.19(4H，br s)，3.76(4H，br s)，5.70(1H，d)，7.12(2H，m)，7.43(1H，t)，7.63(1H，br s)，7.76-7.80(2H，m)，7.92(1H，d)，8.03(1H，d)，8.21(1H，s)，8.28(1H，s)，8.6(1H，s)，10.09(1H，s)。LCMS:Rt=1.01 minute (95%), m/z (ESI) 472 (M+H) ⁺

Compound 81:3-{8-[4-(4-sec.-propyl piperazine-1-yl) phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl } benzo [b] thiophene-7-methane amide

This compound can be used the method for describing in the compound 80, uses the preparation of (5-bromine [1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(4-sec.-propyl piperazine-1-yl)-phenyl] amine in the step in the end.LCMS:rt=0.94 minute (95%), m/z (ESI) 513 (M+H) ⁺

Compound 83:(4-{8-[4-(4-sec.-propyl piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl } pyridine-2-yl) methyl alcohol

Step 1:4-bromo-2-picoline-1-oxide compound

(5g, DCM 29mmol) (20mL) solution are cooled to 0 ℃ and go through and dripped m-CPBA (7.55g, 43.87mmol, 1.5 equivalents) in 30 minutes with 4-bromo-2-picoline.Remove ice bath then and mixture was at room temperature stirred 3 hours.The solution that produces is extracted with sodium bicarbonate (the saturated aqueous solution) dilution and with DCM.Organic layer is merged, with sodium bicarbonate (the saturated aqueous solution) washing, through Na ₂SO ₄Drying and vacuum concentration obtain title compound, are greenish orange look oily matter, and it need not to be further purified.

Step 2: acetate 4-bromopyridine-2-base methyl esters

(4.00g adds diacetyl oxide (6mL) in DCM 21.40mmol) (20mL) solution at 4-bromo-2-picoline-1-oxide compound.Mixture was at room temperature stirred 1 hour, then heated overnight under refluxing.The solvent vacuum is removed and crude product is filtered by silica filler, use the DCM wash-out, obtain title compound, be orange (815mg).

Step 3: acetate 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls) pyridine-2-base methyl esters

With acetate 4-bromopyridine-(800mg, 3.49mmol) De diox (5mL) solution stirs under nitrogen 2-base methyl esters.Add Pd (dppf) Cl ₂(85mg 3mol%), potassium acetate (1.03g, 10.5mmol, 3.0 equivalents) and two tetramethyl ethylene ketone two boron (1.33g, 5.24mmol, 1.5 equivalents), and will be reflected at 80 ℃ of following heated overnight.The orange suspension that produces is diluted with DCM,, obtain oily matter, be applied to next step and need not to be further purified through diatomite filtration and vacuum concentration.

Step 4: acetate 4-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-pyridine-2-base methyl esters

With (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(4-sec.-propyl-piperazine-1-yl) phenyl] amine (300mg, 0.723mmol) and Pd (dppf) Cl ₂(59mg, 4/1 diox 10mol%)/water (5mL) suspension at room temperature stirs and adds salt of wormwood (200mg, 1.45mmol, 2.0 equivalents) and acetate 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls) pyridine-2-base methyl esters (300mg, 1.08mmol, 1.5 equivalents).With the mixture that produces 85 ℃ of following heated overnight.The solution that produces is distributed between methylene dichloride and water, and be concentrated to organic layer on the silica gel and, obtain title compound, be yellow solid by column chromatography purifying (98/2 DCM/MeOH).LCMS:Rt=0.78 minute (100%), m/z 445 (M+H) ⁺

Step 5:(4-{8-[4-(4-sec.-propyl piperazine-1-yl) phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl } pyridine-2-yl) methyl alcohol

With acetate 4-{8-[4-(4-sec.-propyl piperazine-1-yl) phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl pyridine-2-base methyl esters at room temperature, in the methanol solution of the 1.5M of 10mL salt of wormwood, stir and spend the night.By adding 10% aqueous citric acid solution pH regulator is extracted with DCM to neutrality and with mixture then.By the LC purifying, be used in 98/2 DCM/2M NH among the MeOH ₃As elutriant, obtain title compound, be yellow powder (40.3mg, 12.5% went through for two steps). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)1.02(6H，m)，2.33(1H，m)，2.60(4H，br m)，3.10(4H，br m)，4.65(2H，d)，5.51(1H，t)，6.96(2H，d)，7.84-7.89(3H，m)，8.11(1H，s)，8.17(1H，m)，8.61(1H，d)，8.73(1H，m)，10.08(1H，s)。LCMS:Rt=0.78 minute (100%), m/z (ESI) 445 (M+H) ⁺

Compound 84:[4-(1-sec.-propyl piperidin-4-yl) phenyl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl] amine

This compound can be used the method for describing in the compound 92, uses pyrazoles-4-boric acid preparation in step 4.0.89 minute (100%) m/z (ESI) of LCMS:Rt, 403 (M+H) ⁺

Compound 86:4-(8-(6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) furans-2-methane amide

Step 1:4-bromo-furans-2-methane amide

4,5-two bromo-furans-2-formic acid (7.79g, NH 28.85mmol) ₄Branch small portion adding zinc powder in OH (100mL) solution (2.29g, 34.62mmol).Reaction mixture was at room temperature stirred 7 minutes, then through diatomite filtration and water and 2 M HCI washing.Using dense HCl is acidified to pH1 with filtrate and extracts with ethyl acetate (3 *).With organic phase salt water washing, through MgSO ₄Drying is filtered and vacuum concentration, obtains oily matter (4.96g), and it places after fixing, obtains white solid, and its application be need not to be further purified.

(4.93g 25.81mmol) is dissolved in the thionyl chloride (44.2mL) and refluxed 1 hour with solid.After the solvent removed in vacuo residue is dissolved in methylene dichloride (75mL) and adds 0.5 M NH ₃De diox (52mL) solution.Reaction mixture was at room temperature stirred 1 hour, add 33% ammoniacal liquor (5mL) then, and will react restir 2 hours.The solvent vacuum is removed and residue is dissolved in saturated NaHCO ₃In the solution.With alkaline solution with ethyl acetate (3 *) extraction, with the organic layer that merges through MgSO ₄Drying and vacuum concentration.By the silica gel column chromatography purifying, use (50:49:1) ethyl acetate: sherwood oil: the mixture wash-out of acetate obtains title compound (1.2g, 22%).

Step 2:4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-furans-2-methane amide

With 4-bromo-furans-2-methane amide (1.2g, 6.32mmol), two (tetramethyl ethylene ketone) two boron (1.76g, 6.94mmol), PdCl ₂Dppf (0.154g, 189mol) and KOAc (1.85g 18.94mmol) is suspended in the diox (20mL), with nitrogen purging 5 minutes, then 90 ℃ of following heated overnight.The solvent vacuum is removed and residue is distributed between ethyl acetate and water.With water layer usefulness ethyl acetate extraction three times and with the organic phase salt water washing that merges, through MgSO ₄Filter and evaporation.Solid residue is ground and vacuum-drying with hexane, obtain title compound, be solid (0.984g, 66%).

Step 3:4-(8-(6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) furans-2-methane amide

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(0.8mL, 1.15mmol) is with the 5-bromo-8-in the diox (2mL) (6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-amine (60mg, 0.144mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and furans-2-methane amide (59mg, 0.26mmol) and Pd (PPh ₃) ₄(42mg, 0.036mmol) preparation.Behind the evaporating solvent, with thick material by the silica gel column chromatography purifying, with DCM, use 97.5:2.5 and 95:5 DCM:NH subsequently ₃(7M is in MeOH).Obtain title compound, be yellow solid (30mg, 47%). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)1.05(6H，d)，2.54-2.59(4H，m)，2.70-2.74(1H，m)，3.47(4H，m)，6.90(1H，d)，7.60(1H，br s)，7.91(1H，s)，7.99(1H，br s)，8.12(1H，dd)，8.19(1H，s)，8.68(1H，s)，8.75(1H，s)，8.81(1H，s)，10.03(1H，s)。LCMS:Rt 2.64 minutes (98.1%), m/z (APCI) 406 (M+H) ⁺LCMS:Rt 2.74 minutes (93%), m/z (ES ⁺) 448 (M+H) ⁺

Compound 88:4-(8-(4-(4-sec.-propyl piperazine-1-yl) phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) furans-2-methane amide

Step 1:1-sec.-propyl-4-(4-nitro-phenyl)-piperazine

The 4-fluoronitrobenzene (5g, add in THF 35.4mmol) (50mL) solution 1-sec.-propyl piperazine (4.54g, 35.4mmol) and K ₂CO ₃(7.35g, 53.2mmol).Reaction mixture at room temperature stirred spend the night.The solvent vacuum is removed and residue is distributed between EtOAc and water.With organic layer salt water washing, through MgSO ₄Drying is filtered and is concentrated.Crude compound by the silica gel column chromatography purifying, is used 99:1 and 98:2 DCM:NH ₃(7M is in MeOH) obtains title compound (8.2g, 94%).

Step 2:4-(4-sec.-propyl-piperazine-1-yl)-phenyl amine

With 1-sec.-propyl-4-(4-nitro-phenyl)-piperazine (8.3g, 33.2mmol) be dissolved among the MeOH (120mL) and add tindichloride (II) dihydrate (37.4g, 0.165mol).With mixture with water-bath cooling and add dense HCl (36mL).To react at room temperature to stir and spend the night.After removing methyl alcohol, the solution that produces is alkalized with dense NaOH (pH 11).Water is merged with extracted with diethyl ether (3 *) and with organic layer, through MgSO ₄Drying is filtered, and vacuum concentration obtains title compound (6.4g, 88%).

Step 3:(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl]-amine

This compound can be used the method for describing in compound 6 steps 1, be applied in 5 of 2-propyl alcohol (30mL), 8-two bromo-[1,2,4] triazolo [1,5-a] pyrazine (2g, 7.20mmol), 4-(4-sec.-propyl-piperazine-1-yl)-phenyl amine (1.89g, 8.62mmol) and N, (1.88mL 10.8mmol) stirs the preparation of spending the night down at 95 ℃ to the N-diisopropyl ethyl amine.After grinding with ether and sherwood oil title compound is separated, be gray solid (2.59g, 87%).

Step 4:4-(8-(4-(4-sec.-propyl piperazine-1-yl) phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) furans-2-methane amide

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(aqueous solution) (1.143mL, 1.71mmol) is with the 5-bromo-N-in the diox (4mL) (6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-amine (80mg, 0.21mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and furans-2-methane amide (101mg, 0.42mmol) and Pd (PPh ₃) ₄(62mg, 0.053mmol) preparation.Crude product by the silica gel column chromatography purifying, is used DCM and 97:3 DCM:NH ₃(7M is in MeOH) wash-out.With after the ether grinding title compound being separated (35.4mg, 42%).The 1M methylsulfonic acid that is applied among the MeOH (0.0793mL) is translated into mesylate, obtains title compound, is solid (35mg).

H-NMR(400MHz，d ₆-DMSO)δ(ppm)1.35(6H，d)，2.35(3H，s，MsOH)，3.01(2H，t)，3.22-3.35(2H，m)，3.58(3H，m)，3.88(2H，d)，7.09(2H，d)，7.61(1H，br s)，7.94(2H，m)，8.00(1H，br s)，8.22(1H，s)，8.76(1H，s)，8.82(1H，s)，9.27(1H，br s)，10.02(1H，s)。LCMS:Rt 2.02 minutes (98.9%), m/z (APCI) 447 (M+H) ⁺

Compound 89:4-{8-[4-(1-sec.-propyl piperidin-4-yl) phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives

This compound can be used the method for describing in the compound 92, uses 2-(aminocarboxyl) thiophene-4-boric acid preparation in step 4.0.94 minute (100%) m/z (ESI) of LCMS:Rt, 462 (M+H) ⁺

Compound 90:(4-{8-[6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl } pyridine-2-yl) methyl alcohol

This compound can be used the method for describing in the compound 83, uses the preparation of (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[6-(4-sec.-propyl piperazine-1-yl) pyridin-3-yl] amine in step 4.LCMS:Rt=0.71 minute (95%), m/z (ESI) 446 (M+H) ⁺

Compound 92:5-{8-[4-(1-sec.-propyl piperidin-4-yl) phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-xylylenimine-1-ketone

Step 1:1-sec.-propyl-4-(4-nitrophenyl) piperidines

With 4-(4-nitrophenyl) piperidines (250mg, 1.21mmol), K ₂CO ₃(170mg, 1.21mmol) and 2-iodopropane (240 μ L 2.4mmol) in acetonitrile (3mL), in the test tube of sealing, stirred 45 minutes down at 120 ℃.Under reduced pressure remove with the mixture cooling and with solvent.Residue is distributed between DCM (20mL) and water (5mL), each layer separated and water (5mL) and salt solution (5mL) washing DCM, and through MgSO ₄Dry.With solvent evaporation, obtain title compound (300mg), its application be need not to be further purified.

Step 2:4-(1-sec.-propyl piperidin-4-yl) phenyl amine

(35% weight is in water with hydrazine, 0.67mL, 7.2mmol) and 10%Pd/C (38mg, (180mg is in EtOH 0.72mmol) (10mL) solution and with mixture heating 3 hours under refluxing 0.03mmol) to join 1-sec.-propyl-4-(4-nitrophenyl) piperidines.After the cooling, with mixture by diatomite filtration and with solvent evaporation.Residue is dissolved among the DCM (25mL), through MgSO again ₄Dry and with solvent evaporation, obtain expecting compound, (113mg 0.52mmol), need not its application to be further purified for faint yellow solid.

Step 3:(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(1-sec.-propyl piperidin-4-yl) phenyl] amine

With N, N-diisopropyl ethyl amine (200 μ L, 1.2mmol) join 4-(1-sec.-propyl piperidin-4-yl) phenyl amine (220mg, 1.0mmol) and 5,8-two bromo-[1,2,4] triazolo [1,5-a] (280mg 1.0mmol) heated 48 hours in the mixture in iPrOH (5mL) and under refluxing pyrazine.With the mixture cooling and with the solvent vapourisation under reduced pressure, obtain orange-brown solid.It is distributed between DCM (50mL) and water (20mL) and each layer separated.(10% aqueous solution, 3 * 25mL) wash with citric acid with organic phase.The washings that merges is extracted with DCM (25mL), then by adding NaHCO ₃(solid) is with its alkalization.With mixture with DCM (3 * 25mL) extractions, with the extraction liquid that merges through MgSO ₄Drying and evaporation.Crude product by the silica gel chromatography purifying, is used in the 5%-10%MeOH wash-out among the DCM, obtains expecting compound, be mixed with raw material aniline.It from the MeOH recrystallization, is obtained pure title compound (110mg).

To be similar to the method for describing in compound 79 steps 4, this material can be used to prepare 5-{8-[4-(1-sec.-propyl piperidin-4-yl) phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-xylylenimine-1-ketone.

0.91 minute (100%) m/z (ESI) of LCMS:Rt, 468 (M+H) ⁺

Compound 100:1-(4-(5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino) phenyl) piperazine-2-ketone

Step 1:4-(4-amino-phenyl)-3-oxo-piperazine-1-t-butyl formate

With right-iodo-aniline (918mg, 4.8mmol), 3-oxo-piperazine-1-t-butyl formate (960mg, 4.2mmol), (1R, 2R)-hexanaphthene-1, the 2-diamines (0.05mL, 0.42mmol), cupric iodide (I) (14.9mg, 0.0042mmol) and K ₂CO ₃(1.19g, 2.04mmol) De diox (4mL) suspension is used nitrogen purging 5 minutes in reaction tubes.Heated 15 hours down at 119 ℃ with the test tube sealing and with reaction mixture.After being cooled to room temperature, reaction mixture is filtered through silicagel column, with ethyl acetate (40mL) washing.With the filtrate vacuum concentration, obtain title compound, be brown liquid (1.06g, 87%).LCMS:Rt 0.88 minute (91%).

Step 2:1-[4-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-phenyl]-piperazine-2-ketone

This compound can be used the method for describing in compound 6 steps 1, be applied in 5 in the 2-propyl alcohol (1mL), 8-two bromo-[1,2,4] triazolo [1,5-a] pyrazine (0.283g, 1.00mmol), 4-(4-amino-phenyl)-3-oxo-piperazine-1-t-butyl formate (0.300g, 1.00mmol) and N-ethyl di-isopropyl-amine (0.20mL, 1.02mmol) preparation.Thick material by the silica gel column chromatography purifying, with DCM, use 98:2 DCM:MeOH wash-out subsequently, is obtained 4-[4-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-phenyl]-3-oxo-piperazine-1-t-butyl formate, be white solid (0.252g, 51%).

With 4-[4-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-phenyl]-(0.252mg, 2:1 DCM:TFA (4.8mL) solution 0.6mmol) at room temperature stirred 1 hour 3-oxo-piperazine-1-t-butyl formate.Then with mixture with DCM dilution and with saturated NaHCO ₃Alkalization.Water layer is merged with DCM (3 *) extraction and with organic layer, through MgSO ₄Drying is filtered and is concentrated, and obtains title compound, is solid (180mg, 78%).

Step 3:1-(4-(5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino) phenyl) piperazine-2-ketone

This compound can be used the method for describing in compound 1 step 5, be applied in 1-[4-(5-bromo-[1,2, the 4] triazolo [1 in the 3:1DMF/ water of 2mL, 5-a] pyrazine-8-base amino)-phenyl]-piperazine-2-ketone (70mg, 0.18mmol), 4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-and the 1H-pyrazoles (64mg, 0.33mmol), Pd (PPh ₃) ₄(21mg, 18 μ mol) and NaOtBu (70mg, 0.72mmol) preparation.Reaction mixture concentrated under vacuum and with residue by the silica gel column chromatography purifying, with gradient 99:1 to 90:10 DCM:NH ₃(7M is in MeOH) wash-out.Title compound is separated, be light green solid (13mg, 19%). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)3.05(2H，m)，3.42(2H，s)，3.62(2H，m)，7.32(2H，d)，8.07(2H，d)，8.26(1H，s)，8.39(1H，br s)，8.67(1H，br s)，8.81(1H，s)，10.05(1H，s)，13.32(1H，br s)。LCMS:Rt 6.98 minutes (92.4%), m/z (APCI) 376 (M+H) ⁺

Compound 102:5-{8-[4-(the 4-tertiary butyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone

The step 1:1-tertiary butyl-4-(4-nitro-phenyl)-piperazine

(314mg, 2.23mmol) (1g 3.34mmol) adds K in De diox (15mL) solution with the 4-tertiary butyl-piperazine at 1-fluoro-4-nitro-benzene ₂CO ₃(1.65mg, 11.9mmol) and will be reflected at 130 ℃ and stir down and spend the night.Distribute between ethyl acetate and water with solvent vacuum-evaporation and with residue.With organic layer salt water washing, through MgSO ₄Drying is filtered and is concentrated, and obtains crude compound.By the silica gel column chromatography purifying, with DCM, use 99:1 DCM:NH subsequently ₃(7M is in MeOH) wash-out obtains title compound (348mg, 55.4%).LCMS:Rt 3.87 minutes (99%).

Step 2:4-(the 4-tertiary butyl-piperazine-1-yl)-phenyl amine

With the 1-tertiary butyl-4-(4-nitro-phenyl)-piperazine (348mg, 1.32mmol) be dissolved among the MeOH (10mL) and add tindichloride (II) dihydrate (1.08g, 4.79mmol).The application water-bath is with the mixture cooling and add dense HCI (3mL).Stir under will being reflected at 40 ℃ and spend the night.After removing methyl alcohol, the solution that produces is alkalized with dense NaOH (pH 11).Water is merged with ether (3 *) extraction and with organic layer, through MgSO ₄Drying is filtered, and vacuum concentration obtains title compound (308mg, 99%), is applied to next step and need not to be further purified.LCMS:Rt 2.16 minutes (87%).

Step 3:(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(the 4-tertiary butyl-piperazine-1-yl)-phenyl]-amine

This compound can be used the method for describing in compound 6 steps 1, be applied in 5 in the 2-propyl alcohol (5mL), 8-two bromo-[1,2,4] triazolo [1,5-a] pyrazine (0.308g, 1.107mmol), 4-(the 4-tertiary butyl-piperazine-1-yl)-phenyl amine (0.310g, 1.33mmol) and N-ethyl di-isopropyl-amine (0.289mL, 1.66mmol) preparation.Reaction mixture is distributed between DCM and 1N NaOH, with organic layer separation and water and salt water washing, through MgSO ₄Drying is filtered and vacuum concentration.Grind residue with ether and sherwood oil, obtain title compound (440mg, 92%), be the paste solid.LCMS:Rt 2.25 minutes (96%).

Step 4:5-{8-[4-(the 4-tertiary butyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(aqueous solution) is (1.24mL) with (the 5-bromo-[1 in the diox (3.7mL), 2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(the 4-tertiary butyl-piperazine-1-yl)-phenyl]-amine (100mg, 0.232mmol), 5-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-2, and 3-dihydro-isoindole-1-ketone (90mg, 0.32mmol) and Pd (PPh ₃) ₄(67mg, 0.058mmol) preparation.Reaction mixture is distributed between ethyl acetate and salt solution, organic layer is separated, through MgSO ₄Drying is filtered and vacuum-evaporation.Residue by the silica gel column chromatography purifying, is used 98:2 DCM:NH ₃(7M is in MeOH), use 95:5 DCM:NH subsequently ₃(7M is in MeOH) wash-out obtains solid, and it is ground with ether and sherwood oil, obtains title compound (71mg, 63%). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)1.43(9H，s)，2.36(3H，s，MsOH)，3.02(2H，m)，3.19-3.26(2H，m)，3.67(2H，d)，3.90(2H，d)，4.52(2H，s)，7.10(2H，d)，7.86(1H，d)，7.96-8.01(3H，m)，8.10(1H，d)，8.24(1H，s)，8.72(1H，s)，8.75(1H，s)，9.09(1H，br s)，10.09(1H，s)。LCMS:Rt 2.07 minutes (99%), m/z (APCI) 483 (M+H) ⁺

Compound 105:5-{8-[4-(2-oxo-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone

Step 1:3-oxo-4-{4-[5-(1-oxo-2,3-dihydro-1H-isoindole-5-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-piperazine-1-t-butyl formate

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(aqueous solution) (1.3mL is 1.92mmol) with 4-[4-(the 5-bromo-[1,2 in the diox (2.5mL), 4] triazolo [1,5-a] pyrazine-8-base is amino)-phenyl]-3-oxo-piperazine-1-t-butyl formate (115mg, 0.24mmol), 5-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-2,3-dihydro-isoindole-1-ketone (92mg, 0.35mmol) and Pd (PPh ₃) ₄(83mg, 0.072mmol) preparation.Reaction mixture is diluted with salt solution, add toluene and formation precipitation then and pass through to filter collection.The solid that produces is dissolved among the DCM and through silicagel column filters, obtain title compound, be yellow solid (60mg, 47%).

Step 2:5-{8-[4-(2-oxo-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone

With 3-oxo-4-{4-[5-(1-oxo-2,3-dihydro-1H-isoindole-5-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base amino]-phenyl }-(59mg, 3:1DCM:TFA 0.1mmol) (1.2mL) solution at room temperature stirred 1 hour piperazine-1-t-butyl formate.With reaction mixture with DCM dilution and with saturated NaHCO ₃Alkalization.Water layer is merged with DCM (3 *) extraction and with organic layer, through MgSO ₄Drying is filtered and vacuum concentration, obtains title compound, is yellow solid (38mg, 86%). ¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)3.07(2H，m)，3.44(2H，s)，3.64(2H，m)，4.50(2H，s)，7.32(2H，d)，7.83(1H，d)，8.04-8.10(4H，m)，8.22(1H，s)，8.70(1H，br s)，8.74(1H，s)，10.25(1H，s)。LCMS:Rt 7.17 minutes (93.7%), m/z (APCI) 441 (M+H) ⁺

Compound 108:7-fluoro-5-{8-[4-(4-sec.-propyl piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-xylylenimine-1-ketone

Step 1:4-bromo-2,6-difluoro-benzoic acid methyl esters

At 4-bromo-2, (5g adds thionyl chloride (15mL) and DMF (0.5mL) to 6-two fluoro-phenylformic acid in DCM 21mmol) (10mL) suspension.Mixture was at room temperature stirred 2.5 hours.Then it is cooled to 0 ℃ and add MeOH (20mL) carefully, causes that violent HCl emits.Behind the restir 0.5 hour, clear soln is distributed between DCM (50mL) and water (50mL).With organic layer with saturated NaHCO ₃, the salt water washing, through MgSO ₄Dry and the solvent vacuum removed, obtain title compound, be faint yellow oily thing, its application be need not to be further purified.

Step 2:4-bromo-2-fluoro-6-(nitro methyl) methyl benzoate

At room temperature, Nitromethane 99Min. (10mL, 169mmol, 8 equivalents) is joined sodium hydride (4.05g, 169mmol, 8 equivalents) and MgSO carefully ₄Stirred 0.25 hour in DMSO (40g) (100mL) suspension and with the slurries that produce.Add 4-bromo-2 in the yellow slurry that produces, (5.3g 21mmol) and with mixture at room temperature stirred 3 days 6-difluoro-benzoic acid methyl esters, and all raw materials are consumed.Add entry (200mL) and 6 M HCl (50mL), add DCM (200mL) subsequently.Add more water (500mL) to produce clarifying two-phase system.(3 * 100mL) extract, then that DCM is also laminated, with saturated NaHCO with DCM with water layer ₃With the salt water washing and through MgSO ₄Dry.Evaporating solvent obtains orange solids, and it contains 64% expection material, and its application be need not to be further purified.LCMS:Rt=1.27 minute (64%).

Step 3:5-bromo-7-fluoro-2,3-dihydro-isoindole-1-ketone

Thick 4-bromo-2-fluoro-6-(nitro methyl) methyl benzoate of previous step preparation is dissolved among the MeOH (100mL).Add zinc powder (3.35g, 51.3mmol, 3 equivalents) in this settled solution, add ammonium formiate (3.23g, 51.3mmol, 3 equivalents) subsequently, it causes thermopositive reaction.0.3 after hour, be added in the 7M NH among the MeOH (50mL) ₃And mixture at room temperature stirred spend the night.Through diatomite filtration, and be adsorbed onto yellow filtrate on the silicon-dioxide and the mixture that produces by the rough purifying of LC, with 94/6D CM/MeOH 7M NH ₃Remove and desolvate, obtain the brown solid, it is dissolved among the DCM again,, and under reduced pressure concentrate, obtain white solid, it is further ground with a small amount of DCM, obtain title compound with the 10%NaOH washing.0.96 minute (100%) m/z 230/232 (M+H) of LCMS:Rt ⁺

Step 4:7-fluoro-5-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-2,3-xylylenimine-1-ketone

With 5-bromo-7-fluoro-2, (531mg, 2.31mmol) De diox (5mL) solution stirs under nitrogen 3-xylylenimine-1-ketone.Add Pd (dppf) Cl ₂(94mg 5mol%), potassium acetate (453mg, 4.62mmol, 2.0 equivalents) and two tetramethyl ethylene ketone two boron (1.17g, 4.62mmol, 2 equivalents), and will be reflected at 80 ℃ of heating 3 hours down.The orange suspension that produces is diluted with DCM,, obtain oily matter, it is dissolved among a small amount of DCM again through diatomite filtration and vacuum concentration.Slowly add ether, obtain title compound, be the brown solid.1.18 minutes (100%) m/z277/279 (M+H) of LCMS:Rt ⁺

Step 5:7-fluoro-5-{8-[4-(4-sec.-propyl piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-xylylenimine-1-ketone

This compound can be used the method for describing in the compound 91, uses above-mentioned boride preparation.LCMS:Rt=0.90 minute (95%), m/z 487 (M+H) ⁺

Compound 112:5-(8-(4-(4-sec.-propyl-2-oxo piperazine-1-yl) phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) isoindoline-1-ketone

Step 1:1-[4-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-phenyl]-4-sec.-propyl-piperazine-2-ketone

At 1-[4-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base amino)-phenyl]-(embodiment 31 for piperazine-2-ketone, step 2) (180mg, add in MeOH 0.47mmol) (4mL) solution acetate (0.03mL, 0.47mmol), NaOAc (38mg, 0.47mmol) and acetone (0.2mL, 1.18mmol).Reaction mixture was at room temperature stirred 1 hour, add NaCNBH then ₃(60mg 0.94mmol) and with mixture stirring under 40 ℃ spends the night.After being cooled to room temperature, with reaction mixture with dense HCl (pH1) acidifying and vacuum concentration.Residue is distributed between 6N NaOH and DCM.With water layer with DCM (3 *) extraction and with the organic layer that merges through MgSO ₄Drying and vacuum concentration obtain crude compound, and it is passed through the silica gel column chromatography purifying.With DCM and 98:2 DCM:MeOH wash-out, obtain title compound, be yellow solid (45mg, 25%).

Step 2:5-(8-(4-(4-sec.-propyl-2-oxo piperazine-1-yl) phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl) isoindoline-1-ketone

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MNa ₂CO ₃(aqueous solution) (0.5mL, 0.75mmol) 1-[4-(5-bromo-[1,2 in the diox (1.2mL), 4] triazolo [1,5-a] pyrazine-8-base is amino)-phenyl]-4-sec.-propyl-piperazine-2-ketone (40mg, 0.09mmol), 5-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-2,3-dihydro-isoindole-1-ketone (37mg, 0.14mmol) and Pd (PPh ₃) ₄(31mg, 0.027mmol) preparation.Reaction mixture is diluted with salt solution, add toluene and formation precipitation then and pass through to filter collection.Filtrate with ether, sherwood oil and MeOH washing, is passed through the silica gel column chromatography purifying then.Use 99:1DCM:NH ₃(7M is in MeOH), use 98:2 and 95:5 DCM:NH subsequently ₃(7M is in MeOH) wash-out obtains title compound, is yellow solid (24mg, 55%).

¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)1.08(6H，d)，2.73-2.87(3H，m)，3.27(2H，s)，3.62-3.68(2H，m)，4.52(2H，s)，7.36(2H，d)，7.84(1H，d)，8.07-8.10(4H，m)，8.25(1H，s)，8.70(1H，br s)，8.77(1H，s)，10.28(1H，s)。LCMS:Rt 1.94 minutes (95.2%), m/z (APCI) 483 (M+H) ⁺

Compound 114:5-{8-[4-(4-sec.-propyl piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-3,3-dimethyl-2,3-xylylenimine-1-ketone

Step 1:5-bromo-2-(4-methoxy-benzyl)-3,3-dimethyl-2,3-xylylenimine-1-ketone

With sodium hydride (130mg, 60% is scattered in the mineral oil, 3.2mmol) and tetrabutylammonium iodide (243mg, 0.68mmol) THF (20mL) suspension at room temperature stir and add 5-bromo-2,3-xylylenimine-1-ketone (675mg, THF 3.2mmol) (20mL) and DMF (4mL) solution.Add after 75 minutes 4-methoxy-benzyl bromine (460 μ L, 3.2mmol) and continue to stir 4 hours.Add then sodium hydride (635mg, 60% is scattered in the mineral oil, 15.9mmol) and continue to stir 30 minutes, (1.19mL 19mmol) and with mixture heating up to 70 ℃ reaches 30 minutes to add methyl iodide then.The cooling back adds NH ₄Cl (the saturated aqueous solution) and with mixture with ethyl acetate (120mL) dilution.Each layer separated, with organic phase through MgSO ₄Dry and solvent under reduced pressure removed.Residue by the silica gel chromatography purifying, is used in 5% in the sherwood oil to 10% eluent ethyl acetate, obtains title compound, for yellow oil (640mg, 1.78mmol).

Step 2:5-bromo-3,3-dimethyl-2,3-xylylenimine-1-ketone

With 5-bromo-2-(4-methoxy-benzyl)-3,3-dimethyl-2, (640mg, 1.78mmol) (2.91g, acetonitrile 5.33mmol) (11mL) and water (5mL) solution stirred 45 minutes down at 0 ℃ 3-xylylenimine-1-ketone with the high cerium of ammonium nitrate.Solution is washed with ethyl acetate (100mL) dilution and with salt solution (40mL).With organic solvent through MgSO ₄Drying and vapourisation under reduced pressure.Residue by the silica gel chromatography purifying, is used in 10% in the sherwood oil to 50% eluent ethyl acetate, obtain title compound (367mg, 1.53mmol).

Step 3:5-{8-[4-(4-sec.-propyl piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-3,3-dimethyl-2,3-xylylenimine-1-ketone

To be similar to the method in compound 6 steps 3, with 5-bromo-3,3-dimethyl-2,3-xylylenimine-1-ketone is converted into corresponding boride.Use it for the preparation title compound then, it is to use the method for describing in compound 120 steps 4, is obtained by (5-bromine [1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(4-sec.-propyl piperazine-1-yl)-phenyl] amine.LCMS：Rt＝0.92(100％)，m/z＝497(M+H) ⁺。

Compound 118: 4-(5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-N-(pyridin-3-yl methyl) benzamide

Step 1:4-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-methyl benzoate

This compound can be used the method for describing in compound 6 steps 1, be applied in 5 in the 2-propyl alcohol (2.5mL), 8-two bromo-[1,2,4] triazolo [1,5-a] pyrazine (250mg, 0.90mmol), 4-Methyl anthranilate (163mg, 1.08mmol) and N-ethyl di-isopropyl-amine (0.19mL, 1.08mmol) preparation.Grind the back with the 2-propyl alcohol and obtain title compound, be brown solid (148mg, 47%).

Step 2:4-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-phenylformic acid

(460mg 1.32mmol) is suspended among the THF (11mL) and adding lithium hydroxide monohydrate (554mg, water 13.2mmol) (11mL) solution with 4-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-methyl benzoate.Reaction mixture was at room temperature stirred 4 hours, add methyl alcohol (11mL) then and mixture is descended stirring 24 hours at 50 ℃.Mixture is distributed between water and DCM, water is used 2M HCl (pH 2) acidifying and formed yellow mercury oxide.To precipitate by filtering and collect, water and ether washing and dry obtain title compound (215mg, 49%).

Step 3:4-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-N-pyridin-3-yl methyl-benzamide

With 4-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base amino)-phenylformic acid (0.230g, 0.69mmol), 3-hydroxybenzotriazole (0.103g, 0.76mmol), (0.146g, (0.077mL, 0.76mmol) solution at room temperature stirred 21 hours 1-ethyl-3-(3 '-dimethylaminopropyl) carbodiimide hydrate for DMF 0.76mmol) (5mL) and 3-picolyl amine.The solvent vacuum is removed and residue is ground with ether, ethyl acetate and methylene dichloride.Obtain faint yellow solid, wash with water and drying, obtain title compound (241mg, 82%).

Step 4:4-(5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-N-(pyridin-3-yl methyl) benzamide

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MK ₂CO ₃(aqueous solution) is (1.4mL) with 4-(the 5-bromo-[1 in the diox (2.5mL), 2,4] triazolo [1,5-a] pyrazine-8-base is amino)-N-pyridin-3-yl methyl-benzamide (100mg, 0.24mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and the 1H-pyrazoles (93mg, 0.48mmol) and Pd (PPh ₃) ₄(70mg, 0.06mmol) preparation.With thick material by the silica gel column chromatography purifying, with DCM, use 98:2,96:4,90:10 DCM:NH then then subsequently ₃(7M is in MeOH) wash-out obtains title compound, is white solid (19.6mg, 20%).

¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)4.52(2H，d)，7.40(1H，m)，7.78(1H，d)，7.93(2H，d)，8.18(2H，d)，8.32(1H，s)，8.48-8.62(4H，m)，8.82(1H，s)，9.01(1H，t)，10.21(1H，br s)，13.3(1H，br s)。LCMS:Rt 1.86 minutes (93%), m/z (ES ⁺) 412 (M+H) ⁺

Compound 119:4-(5-(2-oxo-1,2-dihydropyridine-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-N-(pyridin-3-yl methyl) benzamide

Step 1:4-[5-(2-methoxyl group-pyridin-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-N-pyridin-3-yl methyl-benzamide

This compound can be used the method for describing in compound 6 steps 4, is applied in 1.5MK ₂CO ₃(aqueous solution) is (1.6mL) with 4-(the 5-bromo-[1 in the diox (2.9mL), 2,4] triazolo [1,5-a] pyrazine-8-base is amino)-N-pyridin-3-yl methyl-benzamide (120mg, 0.28m mol), 2-methoxypyridine-4-boric acid (87mg, 0.57mmol) and Pd (PPh ₃) ₄(81mg, 0.07mmol) preparation.With thick material by the silica gel column chromatography purifying, with DCM, use 99:1,97:3,95:5 DCM:NH then then subsequently ₃(7M is in MeOH) wash-out obtains title compound, is white solid (92.6mg, 73%).

Step 2:4-(5-(2-oxo-1,2-dihydropyridine-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-N-(pyridin-3-yl methyl) benzamide

With 4-[5-(2-methoxyl group-pyridin-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base amino]-N-pyridin-3-yl methyl-benzamide (71.5mg, 0.16mmol) and pyridine hydrochloride (91mg, 0.79mmol) mixture in water (0.5mL) is in the test tube of sealing, 150 ℃ of down heating 25 minutes.Then the solvent vacuum is removed.Residue is carried out silica gel chromatography, with DCM, use 98:2 and 90:10 DCM:NH subsequently ₃(7M is in MeOH) wash-out will comprise and expect that the fraction of product merges and evaporation.Title compound is separated, be yellow solid (34.5mg, 49%).

¹H-NMR(400MHz，d ₆-DMSO)δ(ppm)4.52(2H，d)，6.82(1H，m)，7.22(1H，s)，7.38(1H，m)，7.51(1H，d)，7.78(2H，d)，8.18-8.23(3H，m)，8.51(1H，d)，8.62(1H，s)，8.82(1H，s)，9.01(1H，t)，10.58(1H，br s)，11.8(1H，br s)。LCMS:Rt 1.72 minutes (97%), m/z (ES ⁺) 439 (M+H) ⁺

Compound 120:2-methoxyl group-N-(6-picoline-3-yl) methyl-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide

Step 1:2-methoxyl group-N-(6-picoline-3-yl) methyl-4-nitrobenzamide

With 2-methoxyl group-4-nitrobenzoic acid (293mg, 1.49mmol) be dissolved in DMF (2mL) and 4-methylmorpholine (220 μ L, 3.0mmol) in and add TBTU (1.79g, 1.7mmol).Mixture at room temperature stirred 30 minutes and add C-(6-picoline-3-yl) methylamine (400mg, 3.27mmol).At room temperature continue to stir 12 hours.Add DCM (10mL) and with organic phase Na ₂CO ₃(5% aqueous solution), HCl (3% aqueous solution) and water washing are then through Na ₂SO ₄Dry.Behind the evaporating solvent, residue is ground with ether-hexane, obtain title compound, be white solid.

Step 2:4-amino-2-methoxyl group-N-[(6-picoline-3-yl) methyl] benzamide

With 2-methoxyl group-N-(6-picoline-3-yl) methyl-4-nitrobenzamide (448mg, EtOH 1.49mmol) and EtOAc (every kind of 8mL) solution stirring and add ammonium formiate (375mg, 6mmol) and 10%Pd/C (100mg).Mixture was heated 20 minutes under refluxing, and cooling through diatomite filtration, with the EtOH washing and with the solvent evaporation that merges, obtains title compound with solid.

Step 3:4-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-2-hydroxy-n-[(6-methyl-pyridin-3-yl) methyl] benzamide

With 5,8-two bromo-[1,2,4] triazolo [1,5-a] pyrazine (285mg is 1.03mmol) with 4-amino-2-methoxyl group-N-[(6-picoline-3-yl) methyl] benzamide (280mg, 1.03mmol) in iPrOH (5mL), stir and adding HBr (48% aqueous solution, 380 μ L).Mixture was heated 24 hours under refluxing.Refrigerative suspension is poured into NaHCO ₃(the saturated aqueous solution is 25mL) and in the water (25mL) and use CHCl ₃(4 * 30mL) extractions.With extract through MgSO ₄Drying and evaporation.Residue by the column chromatography purifying, is used 10%CH ₂Cl ₂/ MeOH wash-out.To contain the fraction evaporation of product and residue will be ground with MeOH, obtain title compound, be brown solid.

Step 4:2-methoxyl group-N-(6-picoline-3-yl) methyl-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide

With pyrazoles-4-boric acid (19mg, 0.17mmol), 4-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base amino)-2-hydroxy-n-[(6-methyl-pyridin-3-yl) methyl] benzamide (40mg, 0.085mmol), K ₂CO ₃(24mg, 0.17mmol) and Pd (dppf) Cl ₂CH ₂Cl ₂(4mg 0.005mmol) weighs and pours in the sealable test tube.With test tube with nitrogen wash and add diox-water (4:1,4mL).With test tube sealing, transferred in the ultra sonic bath 30 seconds in nitrogen gas stream, put into 85 ℃ oil bath then.To react and stir 28 hours, after 2 hours and 18 hours, add the boric acid (10mg) and the catalyzer (2mg) of part in addition.Crude mixture is adsorbed onto SiO ₂Go up and, use the 1%-10%MeOH/DCM wash-out by the column chromatography purifying.With the product that obtains be dissolved in again MeOH/DCM (4:1,10mL) in and add 0.1M MsOH/MeOH (2 equivalent), with solvent evaporation and soluble in water and freeze-drying, obtain title compound with residue, be dimethanesulfonate (38mg).0.92 minute (93.9%) m/z (ESI) of LCMS:Rt, 455 (M+H) ⁺

Compound 122:N-benzyl-2-methoxyl group-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide

This compound can be used the method for describing in the compound 120, uses the preparation of benzyl amine in step 1.1.62 minutes (100%) m/z (ESI) of LCMS:Rt, 440 (M+H) ⁺

Compound 124:N-pyridine-2-ylmethyl 3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino] benzamide

This compound can be used the method for describing in the compound 129, uses the preparation of 2-pyridylmethyl amine in step 5.LCMS:Rt=0.84 minute (100%), m/z (ESI) 412 (M+H) ⁺

Compound 127:(4-sec.-propyl piperazine-1-yl)-3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino] phenyl } ketone

This compound can be used the method for describing in the compound 129, uses the preparation of 4-sec.-propyl piperazine in step 5.LCMS:Rt=0.84 minute (100%), m/z (ESI) 432 (M+H) ⁺

Compound 129:N-ethyl 3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino] benzamide

Step 1:3-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino) ethyl benzoate

With 5,8-two bromo-[1,2,4] triazolos [1,5-a] pyrazine (1.39g, 5.00mmol) and the 3-subcutin (0.93g, 5.60mmol) among iPrOH (10mL), stir and adding HBr (48% aqueous solution, 1.14mL, 10mmol).Mixture was heated 4 hours down at 85 ℃, be cooled to room temperature then and use NaHCO ₃(saturated aqueous solution, 25mL) quencher.The suspension that produces is cooled to 0 ℃ and white solid collected by suction filtration and water (10mL) washing.Be dissolved in crude product among the EtOH and with solvent evaporation, obtain title compound, (1.79g 4.9mmol), need not its application to be further purified for the off-white color solid.

Step 2:3-[(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-and tert-butoxycarbonyl-amino] ethyl benzoate

(1.79g, DCM 4.93mmol) (20mL) solution is at N for ethyl benzoate with 3-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino) ₂Down, stirring at room temperature and adding BOC ₂O (1.34g, 6.16mmol) and DMAP (0.30g, 2.46mmol).Continue to stir 2 hours, transform fully up to LCMS indication raw material.Mixture filtered and (pH 6,5mL) and salt solution (5mL) washs and through Na with rare citric acid with filtrate ₂SO ₄Dry.Evaporating solvent obtains title compound, and (1.87g 4.0mmol), need not its application to be further purified for yellow oil.

Step 3:3-{ tert-butoxycarbonyl-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine } ethyl benzoate

Nitrogen is blasted 3-[(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-tert-butoxycarbonyl-amino] ethyl benzoate (0.58g, 1.25mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and the 1H-pyrazoles (0.49g, 2.50mmol), K ₂CO ₃(0.35g, 2.50mmol) and Pd (dppf) Cl ₂(102mg is 0.125mmol) in the mixture in Zai diox (37.5mL) and the water (9.6mL) for DCM.Condenser is installed on the flask, system is vacuumized and uses N ₂(gas) purges, and heats 25 minutes down at 115 ℃ then.Heating bath removed and add CO ₂(solid) is with cooling and buffer system.Solvent under reduced pressure removed and with residue by the silica gel chromatography purifying, be used in 10% among the DCM to 50% eluent ethyl acetate, obtain title compound, be orange (0.61g,〉100%), its application be need not to be further purified.

Step 4:3-{ tert-butoxycarbonyl-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amino } phenylformic acid

With impure 3-{ tert-butoxycarbonyl-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amino } ethyl benzoate (0.61g, 1.25mmol) be dissolved among the THF (2.5mL) and adding KOH (the 2M aqueous solution, 2.5mL, 5mmol) and with mixture 60 ℃ of following heated overnight.With the solution cooling and through diatomite filtration, the water flushing.With filtrate pour into citric acid (the 2M aqueous solution, 2.5mL) in and stir down at 0 ℃.The solid that produces is collected by suction filtration, washed with water and, obtain brown jelly (280mg) by being suspended in drying and vapourisation under reduced pressure among the EtOH.

Further product is by obtaining the title compound of the total amount 352mg that obtains merging with DCM extraction filtrate.Its application be need not to be further purified.

Step 5:N-ethyl 3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino] benzamide

With 3-{ tert-butoxycarbonyl-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amino } phenylformic acid (42mg, 0.10mmol), ethylamine (the 12M aqueous solution, 42 μ L, 0.50mmol) and triethylamine (28 μ L, 0.20mmol) in DMF (0.30mL), stir and add PyBOP (57mg, 0.11mmol).Continue to stir and spend the night.With reaction mixture at EtOAc (7mL) and NaHCO ₃(the saturated aqueous solution distributes between 7mL) and each layer is separated.With the organic layer that merges with salt solution (2 * 5mL) washings and through Na ₂SO ₄Dry.Evaporating solvent obtains oily matter, it is dissolved in contains HCl (the 12M aqueous solution is among MeOH 0.15mL) (0.3mL) and stir and to spend the night.Add triethylamine (0.25mL) and EtOH (0.3mL) and solvent is under reduced pressure removed.Residue by preparation HPLC purifying, is obtained title compound, be white solid (7mg). ¹H NMR (DMSO-d6,400MHz): δ=13.29ppm (s, 0.8H); 10.01 (s, 0.9H); 8.77 (s, 1.0H); 8.65 (s, 1.0H); 8.52 (s, 1.1H); 8.41-8.37 (m, 2.1H); 8.25 (s, 1.0H); 8.08 (d, 1.0H); 7.47 (d, 1.0H); 7.41 (t, 1.1H); 7.04-7.03 (m, 0.5H); (3.32 s, 29.2H (water)); 1.14 (t, 3.5H).LCMS:Rt=0.95 minute (100%), m/z (ESI) 349 (M+H) ⁺

Compound 131:N-(4-hydroxybenzyl) 3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino] benzamide

This compound can be used the method for describing in the compound 129, uses the preparation of 4-hydroxybenzyl amine in step 5.LCMS:Rt=0.98 minute (100%), m/z (ESI) 427 (M+H) ⁺

Compound 134:N-benzyl-N-methyl 3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino] benzamide

This compound can be used the method for describing in the compound 129, uses the preparation of N-methyl-benzyl amine in step 5.LCMS:Rt=1.15 minute (100%), m/z (ESI) 425 (M+H) ⁺

Compound 167:4-[8-(6-phenyl acetyl amino-pyridine-3-base is amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiophene-2-carboxamide derivatives

Step 1:N-(5-nitropyridine-2-yl)-2-phenyl-acetamides

(4.17g, pyridine 30mmol) (30mL) solution at room temperature stir and drip phenyl Acetyl Chloride 98Min. (4.64g, THF 30mmol) (30mL) solution with 2-amino-5-nitropyridine.Mixture was stirred 24 hours, pour into then in ice-water (250mL), obtain brown solid, its application be need not to be further purified.

To be similar to the step 2 and 3 of the method for describing in the compound 120, this material is used to prepare N-[5-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-pyridine-2-yl]-the 2-phenyl-acetamides.

Step 4:4-[8-(6-phenyl acetyl amino-pyridine-3-base is amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiophene-2-carboxamide derivatives

This compound can be used the method for describing in compound 120 steps 4, uses N-[5-(5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino)-pyridine-2-yl]-2-phenyl-acetamides and 2-(aminocarboxyl) thiophene-4-boric acid preparation.1.06 minutes (100%) m/z (ESI) of LCMS:Rt, 471 (M+H) ⁺

Compound 169:2-(4-{4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino] phenyl }-piperidines-1-yl) ethanamide

This compound can be used the method for describing in the compound 84, uses the preparation of 2-bromoacetamide in step 1.LCMS:Rt=0.81 minute (100%), m/z (ESI) 418 (M+H) ⁺

Compound 170:5-{8-[4-(4-sec.-propyl piperazine-1-yl)-3-trifluoromethyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-xylylenimine-1-ketone

This compound can be used the method for describing among the compound GB15, uses 5-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-2,3-xylylenimine-1-ketone preparation.LCMS:Rt=0.99 minute (95%), m/z (ESI) 537 (M+H) ⁺

Compound 171:[4-(4-sec.-propyl piperazine-1-yl)-3-trifluoromethyl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl] amine

This compound can be used the method for describing in the compound 46, uses the preparation of (5-bromo-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(4-sec.-propyl piperazine-1-yl)-3-trifluoromethyl] amine.LCMS：Rt＝0.99(95％)，m/z(ESI)472(M+H) ⁺。

Other example of The compounds of this invention by the preparation of above method is described hereinbefore.

Purification condition and sign

Usually, all compounds after synthesizing can be used the reversed-phase HPLC purifying, use Gilson and prepare HPLC system (322 pumps, 155 ultraviolets/visible detection device, 215 liquid treatment machines).Gilson215 is as automatic sampler and fraction collector.Compound can also pass through flash chromatography on silica gel method purifying.

Compound characterizes by mass spectroscopy, uses the single-phase quadrupole instrument of being furnished with electrospray ionization source.

The validity of biological test explanation compound

Embodiment 1:MAPKAP-K5 analyzes

MAPKAP-K5 is reflected to dodge in the plate form carries out, use 0.1 or 0.2 μ Ci ³³P-ATP; 0.6 μ M ATP; 1mU MAPKAP-K5; 3 μ M MAPKAP-K5 peptide substrates were at room temperature cultivated 30 minutes.

The test of sudden strain of a muscle plate:

The MAPKAP-K5 kinase reaction is carried out in 384 hole polypropylene boards (Matrix Technologies), transfer to 384 holes of Streptavidin bag quilt then and dodge in the plate (Perkin-Elmer).

In the hole of containing 2 μ L test compounds or standard inhibitor, use Hydra (RobbinsScientific) and add 13 μ L enzyme mixture or thinners.

By use Multidrop (Thermo-Labsystems) add 10 μ L[2.5 *] substrate mixture starts reaction, obtain in test following material final concentration to be:

1mU MAPKAP-K5

3 μ M MAPKAP-K5 peptide substrates

0.6μM ATP

0.004μCi[ ³³P]-γ-ATP/μL

1 * reaction buffer

Plate was at room temperature cultivated 30 minutes.

In every hole, add 25 μ L EDTA (50mM) by application Micro-fill (Biotek) and come termination reaction.

Using the Zymark robot system transfers to reaction in the sudden strain of a muscle plate of Streptavidin bag quilt.Plate was at room temperature cultivated 60 minutes.

Use Tecan and wash the plate machine the porose usefulness 100 μ L phosphate buffered saline (PBS)s washing of institute 3 times.

Radioactivity is dodged plate (emptying aperture) by scintillation counting on Packard TopCount and is measured.

Enzyme mixture:

Enzyme

50mM Tris HCl(pH 7.5)

0.1mM EGTA

2mM DTT

1mg/mL BSA

Reaction buffer:

50mM Tris HCl(pH 7.5)

0.1mM EGTA

The 10mM magnesium acetate

2mM DTT

Prepared maybe according to above-mentioned synthetic method and can prepare following compound.For following table 1 and table 2, can Application Example the activity of each compound of measuring of the 1 MAPKAPK5 analytical procedure of describing be expressed as follows:

++ ++ the MAPKAPK5 IC of compound exhibits ₅₀1-100nM

++ the MAPKAPK5 IC of+compound exhibits ₅₀101-500nM

++ the MAPKAPK5 IC of compound exhibits ₅₀501-1000nM

The MAPKAPK5 IC of+compound exhibits ₅₀1000nM

Table 1: the structure of instantiation compound and activity

Table 2: the structure of example benzamide compounds and activity

Embodiment 2. is used for the MMP1 conditioning agent of being expressed by former synovia inoblast of activatory The exploitation of the test of identifying

In order to identify the compound of the ECM degrading activity that reduces cell, the ECM degrading activity of cell can be induced so that should activity be fit to detect and obtain clearer reading.In contextual RA, the cell of selection is that to induce the triggering agent of ECM degrading activity be the relevant cytokine in sacroiliitis field for Mammals synovia inoblast and can being used for: for example TNF-α, IL1 β, IL6, OSM, IL17 and MIF1-α.This tabulation is not whole, because the potential too much cytokine (Smolen and Steiner, 2003) that relates in the RA pathogenesis.In order to set up test method external, approaching as far as possible pathological complicacy, used triggering agent should be that the cell by generation cytokine relevant in the sacroiliitis field contacts with the triggering agent and the mixture of the factor that produces, for example monocyte, scavenger cell, T cell and B cell.The cell that produces cytokine passes through to produce the complex body of the factor with no inclined to one side mixture and to contact response.If in pannus, also find the cell of used generation cytokine, and find to be used to produce the cytokine of this triggering agent in the synovial membrane liquid of patient with rheumatoid arthritis, the so final factor mixture that produces will comprise the part factor that exists in the arthritic joint.

The principle of " MMP test "

Matrix metalloproteinase (MMP) has multiple physiological role, for example the degraded of the maturation of other proteolytic enzyme, somatomedin and extracellular matrix composition.MMP1 is one of member of MMP family, its natural collagen of can degrading (main component of bone and cartilage).The MMP1 that is expressed by synovia inoblast (SF) increases and is used for diagnosing the process of arthritis disease and is the joint omen that corrodes process people such as (, 2001) Cunnane.The MMP1 that SF expresses can be by strengthening with the relevant triggering agent activation SF of rheumatoid arthritis, and cytokine is TNF-α or IL1 β people such as (, 2003) Andreakos for example.In sum, the level of measuring the MMP1 that is produced by activatory SF is the reading that has height correlation in context RA, because this incident has reflected that SF is to corroding the activation levels of phenotype (seen in pannus).If the expression of reduction drug candidate target in activatory SF causes the reduction by the MMP1 of these cell expressings, drug targets is proved the adjusting that relates to the MMP1 expression and therefore is considered relevant with the exploitation of the therapeutic strategy that is used for the treatment of RA so.

In following examples, the MMP1 (embodiment 2.1) that the exploitation of test (further being called ' MMP test ') monitoring is produced multiple activation triggers agent response by synovia inoblast (SF).Then, the purposes of this test is described for the conclusive evidence of gene product, and this gene product is considered to develop the drug targets (embodiment 2.2) of RA treatment.The conclusive evidence of target is used recombinant adenovirus and is carried out, described adenovirus further is called as and knocks out virus or Ad-siRNA, its mediation shRNA expression in cell, thereby by reducing target gene expression level (referring to WO 03/020931) based on RNAi (RNA interference) mechanism.Then, the evaluation of regulating the active compound of drug targets of conclusive evidence has been described in the table 3.' MMP test ' purposes in the active compound of the drug targets that the test adjusting is identified is further described below.

Experimental example

Used contrast virus:

Listed the contrast virus of in these research, using below.The dE1/dE2A adenovirus be by helper plasmid pWEAd5AflII-rITR.dE2A in the PER.E2A packing cell cotransfection and connect plasmids by these and produce, as describing among the WO99/64582.

Negative control virus:

Ad5-eGFP_KD: target sequence: GCTGACCCTGAAGTTCATC (SEQ IDNO:1).Use the Sap1 site and be cloned in the carrier and generation virus, as describing among the WO03/020931.

Ad5-Luc_v13_KD: target sequence GGTTACCTAAGGGTGTGGC (SEQ IDNO:2).Use the Sap1 site and be cloned in the carrier and generation virus, as describing among the WO03/020931.

Ad5-M6PR_v1_KD: target sequence CTCTGAGTGCAGTGAAATC (SEQ IDNO:3).Use the Sap1 site and be cloned in the carrier and generation virus, as describing among the WO03/020931.

Positive control virus:

Ad5-MMP1_v10_KD: target sequence ACAAGAGCAAGATGTGGAC (SEQID NO:4).Use the Sap1 site and be cloned in the carrier and generation virus, as describing among the WO03/020931.

The virus that is used for the target conclusive evidence:

Ad5-MAPKAPK5_v13_KD: target sequence CGGCACTTTACAGAGAAGC (SEQ ID NO:5).Use the Sap1 site and be cloned in the carrier and generation virus, as describing among the WO03/020931.

Ad5-MAPKAPK5_v12_KD: target sequence ATGATGTGTGCCACACACC (SEQ ID NO:6).Use the Sap1 site and be cloned in the carrier and generation virus, as describing among the WO03/020931.

The exploitation of embodiment 2.1:MMP test

Exploitation is used to measure the ELISA of 384 well format of MMP1.Test multiple one anti-and multiple ELISA test method.Develop following test method and conclusive evidence and measure the MMP1 level of SF supernatant liquor in 384 orifice plates: white Lumitrac 600 384 orifice plates (Greiner) are wrapped quilt with 2 μ g/mL anti-MMP1 antibody MAB1346 (Chemicon).With antibody at damping fluid 40 (the 1.21g Tris alkali (Sigma) in 1L milliQ water, 0.58g NaCl (Calbiochem) and 5mL10%NaN ₃(Sigma) and be adjusted to pH 8.5) in dilution.After 4 ℃ of following overnight incubation, with plate PBS (the 80g NaCl in 10L milliQ, 2g KCl (Sigma), 11.5gNa ₂HPO ₄7H ₂O and 2g KH ₂PO ₄PH 7.4) washing and seal with the casein damping fluid (2% casein in PBS (VWR International)) in 100 μ L/ holes.Second day, the casein damping fluid removed from elisa plate and with EC damping fluid (the 4g casein in 1L milliQ, the 2.13g Na in 50 μ L/ holes ₂HPO ₄(Sigma), 2g bovine serum albumin (Sigma), 0.69g NaH ₂PO ₄H ₂O (Sigma), 0.5g CHAPS (Roche), 23.3g NaCl, 4mL 0.5MEDTA pH 8 (Invitrogen), 5mL 10%NaN ₃And be adjusted to pH 7.0) replace.In the sample panel of melting, add 0.25mM DTT (Sigma).After removing the EC damping fluid, with the sample transfer of 20 μ L in elisa plate.After 4 ℃ of following overnight incubation, with plate with the PBS washed twice and with PBST (PBS that contains 0.05%Tween-20 (Sigma)) washing once and with the biotinylated anti-MMP1 antibody-solutions (R﹠amp in 35 μ L/ holes; D) cultivate together.With this two anti-with concentration 5 μ g/mL at damping fluid C (the 0.82g NaH in 2L milliQ ₂PO ₄H ₂O, 4.82g Na ₂HPO ₄, 46.6gNaCl, 20g bovine serum albumin and 4mL0.5M EDTA pH 8 and be adjusted to pH 7.0) in dilution.After at room temperature cultivating 2 hours, cultivate with plate such as above-mentioned washing and with the Streptavidin-HRP conjugate (Biosource) in 50 μ L/ holes.Streptavidin-HRP conjugate is diluted in damping fluid C with concentration 0.25 μ g/mL.After 45 minutes, cultivate with plate such as above-mentioned washing and with the BM Chem ELISA substrate (Roche) in 50 μ L/ holes.Go up reading at Luminoscan AscentLuminometer (Labsystems), be 200 milliseconds or with Envision reader (Perkin Elmer) integral time.

Shown that with white rod the MMP1 of the SF expression of using cytokine (TNF-α, IL1 β and OSM) relevant in the RA field or their combined treatment increases among Fig. 2.For this test, SF is seeded in 96 orifice plates 3,000 cells/well.After 24 hours, substratum is changed to the M199 substratum that adds 1%FBS.After substratum is changed one day, add cytokine or their combination in substratum, the final concentration of added every kind of cytokine is 25ng/mL.Add cytokine after 72 hours, supernatant liquor is collected and as more than describe in the test method that provides carry out MMP1ELISA.Parallel with this test, use identical test method, the supernatant liquor with the THP1 cell (2 times of dilutions in M199+1%FBS) of the combined treatment of identical cytokine or cytokine in M199 substratum+1%FBS triggers SF.Shown MMP1 level with the grey rod among Fig. 2 for these samples.The inducing action of the MMP1 that the SF that the supernatant liquor of the THP1 cell of handling with TNF-α triggers expresses is better than (〉 4.5 times of inducing actions) inducing action (3 times of inducing actions) of the MMP1 that expresses of the SF that triggers with reorganization TNF-α separately, and the inducing action that obtains of the mixture of 5 times of cytokines to 3 kinds of purifying (TNF-α, IL1 β b, OSM) no better than.This result shows that the supernatant liquor of TNF-α-inductive THP1 cell also comprises the proinflammatory factor of other activation about the SF of MMP1 expression except comprising TNF-α.Because the effect of TNF-α in the RA pathogenesis obtains the representative that conclusive evidence (TNF-alpha block agent (for example infliximab and etanercept) demonstrates some effect in treatment among the RA patient) and THP-1 cell are the monocyte/macrophages that exist in the RA patient joint, will comprise the factor that exists in the RA patient joint and relevant with RA subsequently by THP-1 cell and TNF-α being contacted the triggering agent composition for preparing based on TNF-α.Should trigger the main component that agent (further being called ' complex body triggering agent ') will further be used as " MMP test " based on the complex body of TNF-α.

Use dexamethasone (effectively antiphlogiston can also reduce collagen-induced sacroiliitis greatly in rodents) and show that " complex body triggering agent " suppresses people such as (, 2004) Yang (Fig. 3) to the SF activatory.Dexamethasone has shown that dose-dependently ground reduces the amount that is triggered the MMP1 of agent activatory SF generation by complex body.SF is seeded in 96 orifice plates with 3000 cells/well of density.Inoculate after 24 hours, the dexamethasone that increases concentration is joined in the cell.After the overnight incubation, the substratum in every hole is updated to the supernatant liquor of the THP-1 cell of handling with TNF-α (in 50% dilution among the M199+0.5%FBS) and as the day before yesterday, adds the dexamethasone of same concentrations.Handle after 48 hours, supernatant liquor is collected and carried out above-mentioned MMP1 ELISA.The adding of dexamethasone has reduced the MMP1 that SF expresses, IC significantly ₅₀Be worth about 1nM (referring to Fig. 3).The MMP1 that these data presentation are expressed by activatory SF can reduce by the inhibitor that adding physiology is correlated with and represent the principle of " MMP test " to prove.

Embodiment 2.2:MAPKAPK5 regulates SF " complex body triggering agent "-inductive MMP1 and expresses

(A) Ad-siRNA virus is to knocking out the function that MAPKAPK5 expresses

The method of describing according to WO03/020931 produces the recombinant adenovirus of the siRNA expression of mediated targeted MAPKAPK5 and eGFP.The target sequence of using in recombinant adenovirus is: CGGCACTTTACAGAGAAGC (SEQ ID NO:5) and ATGATGTGTGCCACACACC (SEQ ID NO:6).Target sequence in recombinant adenovirus in the used eGFP mRNA is: GCTGACCCTGAAGTTCATC (SEQ ID NO:1).Use the Sap1 site with these sequence clones to connecting in the plasmid.The dE1/dE2A adenovirus is to connect plasmid by the cotransfection of helper plasmid pWEAd5AflII-rITR.dE2A in the PER.E2A packing cell by these to produce, and describes as WO99/64582.

The functional trial of the adenovirus of target MAPKAPK5 is as follows.These adenovirus are used for infecting the former generation people SF that cultivates at culture dish as follows.First day, by 500,000 SF inoculations of each culture dish.After one day, be 4000 (based on the virus titer of determining by Q-rt-PCR (every mL virion number)) cells infected with MOI with Ad5-MAPKAPK5-v13_KD (1.6E9VP/mL) or Ad5-eGFP-v5_KD (1.3E10 VP/mL).The 7th day, use trypsinase EDTA solution according to standard method cell is separated from culture dish.Add the DMEM growth medium of 10%FBS with the trypsinase deactivation by adding then.Pass through centrifugation step (1000rpm, 5 minutes) then with cell harvesting.With throw out cracking in the new system RIPA damping fluid (50mM TrispH7.5,150mM NaCl, 1% deoxycholate salt, 1%Triton X100,0.1%SDS) of 100 μ L.Then with sample ultrasonic 10 seconds.The application BCA test kit of describing as supplier (Pierce, Cat N ° 23227) is used the protein concentration of BSA as the standard test sample then.Be diluted at 30 μ g and add 3.5 μ L reductive agents in the cell lysate in the 19.5 μ L RIPA damping fluids (NuPage reductive agent N ° 10, Invitrogen NP0004) and 7.5 μ L sample buffers (NuPage LDS sample buffer, Invitrogen NP0007).Then 30 μ L samples were boiled 5 minutes and last sample to 10% polyacrylamide gel (Invitrogen NP0301).For the level of estimating that protein knocks out, the lysate of 5 μ g, 7.5 μ g and 3.75 μ g Ad5-eGFP-v5_KD cells infecteds is also gone up sample to gel.Then gel is moved 2 hours with 100V in 1 * MOPS/SDS NuPage running buffer (Invitrogen NP001).10 μ L Seablue Plus are dyed standard (Invitrogen LC5925) in advance be used to estimate proteic size on the gel.By the wet method trace protein transduction on the glue is moved on on the pvdf membrane (Invitrogen LC2002) then, it uses the transfering buffering liquid by 100mL Nupage transfering buffering liquid 20* (NP0006-1), 400mL methyl alcohol and 1500mL Milli Q water are mixed with.Before transfer, film at first is immersed in methyl alcohol and the transfering buffering liquid.Transfer was carried out under 100V 90 minutes.Be formulated in PBST and (added in the sealing damping fluid (2% sealing powder (Amersham, RPN 2109)) among the 0.1%Tween 20 (Sigma, PBS P1379)) 30 minutes and seal by film is immersed in then.After the sealing, be applied in the mouse monoclonal antibody (BD Biosciences, the Cat N that dilute 250 times anti-MAPKAPK5 in the sealing damping fluid ^o612080) carry out immunodetection.After this anti-overnight incubation, film is washed 3 times and is used in two anti-((polyclone sheep anti mouse Ig, HRP link coupled (DAKO the P0447)) cultivations 1 hour of diluting 50000 times in the sealing damping fluid with PBST.Then trace is washed in PBST 3 times and (RPN2109 Amersham) detects with ECLadvance according to manufacturers instruction on Kodakimager.Western blotting shows and compares with the cell of Ad5-eGFP-v5_KD negative control virus infection that the expression level of MAPKAPK5 is lower in the cell that Ad5-MAPKAPK5-v13_KD infects.The sample that infects with the Ad5-eGFP-v5_KD that dilutes relatively is used for estimating to express reducing by 2 times.Remove MAPKAPK5 antibody by ' strip operation ' (film was boiled 5 minutes) in PBST after, 30 μ g samples of sample on the equivalent immunodetection by beta-actin is illustrated.The immunodetection of beta-actin is that the method for describing in detecting according to MAPKAPK5 is carried out, but uses sheep polyclonal antibody (Santa Cruz, the Cat N of anti-beta-actin ^oSC-1615) (it is anti-as one with 1000 times of dilutions) and the anti-goat-anti body of rabbit (it is anti-as two with 50000 times of dilutions).Fig. 4 has provided the result of this test.In sum, this evidence the Ad-siRNA that produces in order to reduce MAPKAPK5 expression level among the former generation people SF functional.

(B) MAPKAPK5 knocks out Ad-siRNA and reduces SF-inductive MMP1 expression

The efficacy test of Ad5-MAPKAPK5-v13_KD virus in ' MMP test ' is as follows.First day, SF (going down to posterity 9 to 10) is seeded in 96 orifice plates with complete synovia growth medium (Cell Applications) with the density of 3000 cells in every hole.After one day, cell is used the following virus infection of incremental change (3,6,9,12 or 15 μ L): Ad5-eGFP-v5_KD, Ad5-MAPKAPK5-v12_KD, Ad5-MAPKAPK5-v13_KD, Ad5-MMP1-v10_KD.Virus load is that neutral virus of A d5-Luc-v13_KD proofreaies and correct so that final viral volume is every hole 15 μ L in the cell by adding.This correction guarantees that viewed effect is not from the virus load that is applied to cell.Then before activation step with cell cultures 5 days.This step comprises that every Kong Zhongyong adds the 75 μ L M199 substratum replacement growth medium of 25 μ L ' complex body triggering agent '.Behind the activation step 48 hours, supernatant liquor collected and as among the embodiment 1 description carry out MMP1 ELISA.Test-results shows in Fig. 5.The quality of test confirms by the effect of the Ad-siRNA virus of target MMP1 self.This positive control virus greatly reduces the MMP1 that SF expresses, and negative control virus (for the expression of target luciferase designs) does not influence the MMP1 expression level.Be used to verify that two kinds of viruses (Ad5-MAPKAPK5-v12_KD and Ad5-MAPKAPK5-v13) of MAPKAPK5 target also cause the MMP1 of the former generation people of complex body triggering agent inductive SF expression significantly to reduce.Can be drawn to draw a conclusion by this test: MAPKAPK5 represents the valuable drug target, and it has shown that MMP1 expresses among the adjusting SF.Similarly be to wish that suppressing the MAPKAPK5 enzymic activity by micromolecular compound reduces ' complex body cytokine ' inductive MMP1 expression in ' MMP test '.Also wish to suppress the degraded that the MAPKAPK5 enzymic activity reduces the joint relevant with RA by micromolecular compound.

(C) External ' MMP test ' test suppresses the compound of MAPKAPK5

In ' MMP test ', test the active compound of (promptly acellular, the enzyme of application of purified) inhibition MAPKAPK5 in biochemical test according to following test method.

The former storing solution of compound (all in 100%DMSO, concentration is 10mM) is diluted in the water (distilled water, GIBCO, no DNA enzyme and RNA enzyme) to obtain active redundancy liquid in the middle of the 1mM in 10%DMSO with 10 times.This centre active redundancy liquid further is diluted among the 10%DMSO to obtain the middle active redundancy liquid of the 333 μ M (or 100 μ M) in 10%DMSO respectively with 3 times (or 10 times).Then active redundancy liquid in the middle of 1mM and the 333 μ M (or 100 μ M) further is diluted among the 1.1%DMSO to obtain 100 μ M in 2%DMSO and 10 * active redundancy liquid of 33.3 μ M (or 10 μ M) concentration with 10 times.Then 10 * active redundancy liquid is diluted in the M199 substratum that adds 1%FBS to obtain final ' 1 * compound formulation ' with 10 times, it comprises compound and the 0.2%DMSO of 10 μ M and 3.33 μ M (or 1 μ M).These are final conditions of test compound on cell.Parallel therewith, 10 * active redundancy liquid is diluted in ' complex body triggering agent ' (i.e. supernatant liquor of the THP1 that handles as the TNF-α that describe to produce among the embodiment 1) with 10 times, it is diluted among the M199 that adds 1%FBS to produce ' triggering 1 * compound formulation in the agent at 50% complex body ' with 2 times.

The 1st day, with RASF with the density of 3000 cells/well be seeded in 96 orifice plates with complete synovia growth medium (Cell Applications) (flat, tissue culture medium (TCM) is handled, Greiner) in.The 5th day, compound is joined in the cultured cells as follows.Substratum removed from cell fully and replace with ' 1 * compound formulation ' of 75 μ L, described ' 1 * compound formulation ' is included in that concentration is the compound of 10 μ M or 3.33 μ M (or 1 μ M) in the M199 substratum that adds 1%FBS and 0.2%DMSO.Cultivate after 2 hours (make the compound balance and enter in the cell), 25 μ L ' 1 * compound formulation in 50% complex body triggering agent ' joined in the hole, it comprises the respective compound of respective concentration in these holes on ' 1 * compound formulation '.In the method, 8 diluted complex bodys being triggered agent finally is applied in the cell.Cultivated then 48 hours, and, obtained raw data (RLU: relative flat light emission) then with cell conditioned medium liquid such as the above-mentioned MMP1 ELISA that carries out of 20 μ L.Below contrast comprises in test.The highest signal contrast, wherein cell triggers the agent activation by complex body, but only adds 0.2%DMSO medium (and therefore not having compound).Be somebody's turn to do highest level to the MMP1 that can obtain in test as directed.Minimum signal contrast is also included within these tests.Wherein cell is not triggered.Be changed to the M199 substratum that 100 μ L add 1%FBS at the 5th day substratum then with cell.This contrast returns to the basic MMP1 level that is produced by RASF.The MMP1 that obtains by compound of the RLU data computation of returning based on the ELISA inhibition percentage ratio of expressing then, use following formula:

[[(the highest MMP1 level-minimum MMP1 level)-(the MMP1 level-minimum MMP1 level of compounds X under concentration Y)]/(the highest MMP1 level-minimum MMP1 level)] * 100.

The toxicity assessment of compound is as follows.The 1st day, SF is seeded in white with the complete synovia growth medium of 100 μ L, 96 orifice plates that tissue culture medium (TCM) is handled with the density of 3000 cells in every hole.In the present embodiment as above-mentionedly further carry out compound treatment, join in the cell compound and active cells, be used to measure the MMPI level.Cultivate after 48 hours, substratum is removed from the hole, and add the new system M199 substratum replacement of 1%FBS with 50 μ L.Substrate (Promega Celltiter Glow cell viability test kit) with 50 μ L joins in the hole then.Cultivate after 10 minutes, measure luminous signal.Compare the luminous signal reduction with the highest control wells and be considered to reflect significant toxicity above 50%.The compound of test is not observed toxicity in ' MMP test '.

Should be understood that multiple factor (for example different Premeabilisation of cells abilities of different compounds) can cause the difference of compound activity between external biological chemistry and the cell MMP test.

For following table 3 and table 4, can use the MMP1 EC of each definite compound of test method described herein ₅₀Be expressed as follows:

The MMP1 EC of * * * compound exhibits ₅₀1-100nM

The MMP1 EC of * * compound exhibits ₅₀101-500nM

The MMP1 EC of * compound exhibits ₅₀501-1000nM

* the MMP1 EC of compound exhibits ₅₀1000nM

Table 3

Compound #	MMP1 EC ₅₀(nM)
Compound #	MMP1 EC ₅₀(nM)	1	＊
2	＊	1	＊
2	＊	3	＊＊＊
4	＊	3	＊＊＊
4	＊	5	＊＊＊
6	＊＊＊	5	＊＊＊
6	＊＊＊	7	＊
8	＊＊	7	＊
8	＊＊	9	＊＊
10	＊＊	9	＊＊
10	＊＊	11	＊＊＊
12	＊＊	11	＊＊＊
12	＊＊	13	＊＊＊
14	＊	13	＊＊＊
14	＊	15	＊＊＊
16	＊	15	＊＊＊
16	＊	17	＊
18	＊＊	17	＊

Compound #	MMP1 EC ₅₀(nM)
Compound #	MMP1 EC ₅₀(nM)	19	＊
20	＊	19	＊
20	＊	21	＊＊＊
22	＊	21	＊＊＊
22	＊	23	＊
24	＊＊＊	23	＊
24	＊＊＊	25	＊
26	＊	25	＊
26	＊	27	＊＊
28	＊＊	27	＊＊
28	＊＊	29	＊
30	＊	29	＊
30	＊	31	＊
32	＊＊	31	＊
32	＊＊	33	＊＊＊
34	＊＊＊＊	33	＊＊＊
34	＊＊＊＊	35	＊＊＊
36	＊＊＊	35	＊＊＊
36	＊＊＊	37	＊＊
38	＊	37	＊＊
38	＊	39	＊
40	＊	39	＊
40	＊	41	＊
42	＊	41	＊
42	＊	43	＊
44	＊	43	＊

Compound #	MMP1 EC ₅₀(nM)
Compound #	MMP1 EC ₅₀(nM)	45	＊
46	＊	45	＊
46	＊	47	＊＊
48	＊＊＊	47	＊＊
48	＊＊＊	49	＊
50	＊＊＊	49	＊
50	＊＊＊	51	＊＊
52	＊	51	＊＊
52	＊	53	＊＊
54	＊＊＊	53	＊＊
54	＊＊＊	55	＊＊＊
56	＊＊	55	＊＊＊
56	＊＊	57	＊＊＊
58	＊＊＊	57	＊＊＊
58	＊＊＊	59	＊
60	＊	59	＊
60	＊	61	＊＊
62	＊	61	＊＊
62	＊	63	＊＊＊
64	＊	63	＊＊＊
64	＊	65	＊＊＊
66	＊＊	65	＊＊＊
66	＊＊	67	＊
68	＊	67	＊
68	＊	69	＊
70	＊	69	＊

Compound #	MMP1 EC ₅₀(nM)
Compound #	MMP1 EC ₅₀(nM)	71	＊
72	＊	71	＊
72	＊	73	＊
74	＊	73	＊
74	＊	75	＊
76	＊＊	75	＊
76	＊＊	77	＊
78	＊	77	＊
78	＊	79	＊＊
80	＊＊＊	79	＊＊
80	＊＊＊	81	＊
82	＊	81	＊
82	＊	83	＊
84	＊	83	＊
84	＊	85	＊
86	＊	85	＊
86	＊	87	＊＊＊
88	＊＊	87	＊＊＊
88	＊＊	89	＊＊
90	＊	89	＊＊
90	＊	91	＊
92	＊＊＊	91	＊
92	＊＊＊	93	＊
94	＊	93	＊
94	＊	95	＊
96	＊	95	＊
96	＊	97	＊

Compound #	MMP1 EC ₅₀(nM)
Compound #	MMP1 EC ₅₀(nM)	98	＊
99	＊	98	＊
99	＊	100	＊
101	＊	100	＊
101	＊	102	＊
103	＊＊	102	＊
103	＊＊	104	＊
105	＊	104	＊
105	＊	106
107		106
107		108	＊
109	＊	108	＊
109	＊	110	＊
111	＊	110	＊
111	＊	112	＊
113	＊＊＊	112	＊
113	＊＊＊	114	＊
115	＊	114	＊
115	＊	116	＊
117	＊＊＊	116	＊
117	＊＊＊	168	＊
169	＊	168	＊
169	＊	170	＊
171	＊	170	＊
171	＊	172	＊
173	＊	172	＊

Compound #	MMP1 EC ₅₀(nM)
Compound #	MMP1 EC ₅₀(nM)	174	＊
175	＊	174	＊
175	＊	176	＊＊
177	＊	176	＊＊
177	＊	178	＊
179	＊	178	＊
179	＊	180	＊
181	＊	180	＊
181	＊	182	＊
183	＊	182	＊
183	＊	184	＊
185	＊	184	＊

Table 4

Compound #	MMP1 EC ₅₀(nM)
Compound #	MMP1 EC ₅₀(nM)	118	＊
119	＊	118	＊
119	＊	120	＊
121	＊	120	＊
121	＊	122	＊
123	＊	122	＊
123	＊	124	＊
125	＊	124	＊
125	＊	126	＊
127	＊	126	＊
127	＊	128	＊
129	＊	128	＊
129	＊	130	＊
131	＊＊	130	＊

Compound #	MMP1 EC ₅₀(nM)
Compound #	MMP1 EC ₅₀(nM)	132	＊
133	＊	132	＊
133	＊	134	＊＊
135		134	＊＊
135		136	＊
137	＊	136	＊
137	＊	138	＊
139	＊	138	＊
139	＊	140	＊
141	＊	140	＊
141	＊	142	＊
143	＊	142	＊
143	＊	144
145	＊	144
145	＊	146	＊
147	＊	146	＊
147	＊	148	＊
149	＊	148	＊
149	＊	150	＊
151	＊	150	＊
151	＊	152	＊
153	＊	152	＊
153	＊	154	＊
155	＊	154	＊
155	＊	156	＊
157	＊	156	＊
157	＊	158	＊
159	＊	158	＊
159	＊	160	＊
161	＊	160	＊
161	＊	162	＊

Compound #	MMP1EC ₅₀(nM)
Compound #	MMP1EC ₅₀(nM)	163	＊
164	＊	163	＊
164	＊	165	＊
166	＊	165	＊
166	＊	167	＊
191	＊	167	＊
191	＊	192	＊＊＊
193	＊	192	＊＊＊
193	＊	194	＊＊
195	＊	194	＊＊
195	＊	196	＊
197	＊	196	＊
197	＊	198	＊

Embodiment 3: be used for the test of assessing compound to the effect of cytokines of human PBMC's release

Human peripheral blood mononuclear cell (PBMC) is isolating by healthy volunteer's blood preparation " buffy coat ", separates basis basically

(1984) method.In brief, buffy coat is placed at 20mL Lymphoprep in the 50mL Falcon test tube with 1 * PBS (Gibco) carefully with 1:1 dilution and with 30mL ^TMAbove (Lucron Bioproducts).After centrifugal (35 minutes, 400g, 18 ℃), with monocyte from collect between white boundary and by resuspension and centrifugal (10 minutes, 200g) wash three times with 1 * PBS.With isolating PBMC be resuspended at last the RPMI 1640 that adds 10% heat-inactivated FBS (Hyclone) (Cat.No.21875, Gibco) in.

For this test, PBMC is seeded in 96 orifice plates (Nunc) with 160 μ L with 2.5E6 cell/mL.The test compound of stepwise dilution is at first prepared in DMSO (Sigma), in containing the M199 substratum (Gibco) of 1% heat-inactivated FBS, dilute 50 times then.Is 0.2% with compound further 1/10 dilution in test board to obtain final DMSO concentration.With cell and compound at 37 ℃, 5%CO ₂Pre-down the cultivation 1 hour.Then, (Sigma) (being added to final concentration with volume 20 μ L is 1 μ g/mL) stimulates and cell further cultivated 24 hours for e. coli serotype 026:B6, Cat.No.L2654 with LPS with cell.Plate is centrifugal and supernatant liquor collected and-80 ℃ of suitable dilution of storing down in analyzing ELISA.

The following 384 hole chemoluminescence ELISA test methods of exploitation are to measure the TNF alpha levels in the supernatant liquor: with white Lumitrac 600 384 orifice plates (Greiner) (40 μ L/ hole) anti-TNF alpha capture antibody (Cat.No.551220, BD Pharmingen) bag quilt, this antibody is diluted to 1 μ g/mL in 1 * PBS (Gibco).After 4 ℃ of following overnight incubation, with plate with 1 * PBS (80gNaCl in 10L milliQ, 2g KCl (Sigma), 11.5g Na ₂HPO ₄7H ₂O and 2g KH ₂PO ₄PH 7.4) washing and (comprise 1%BSA (Sigma), 5% sucrose (Sigma) and 0.05%NaN with 100 μ L/ hole buffer B ₃(Sigma) 1 * PBS) sealing.After at room temperature cultivating 4 hours, will seal that damping fluid is removed and (1 * PBS) washing that contains 0.05%Tween-20 (Sigma) once with PBST with plate.Then, 40 μ L sample transfer are cultivated down at 4 ℃ in elisa plate and with plate.Second day, plate is washed 3 times (washing once with the PBST washed twice and with PBS) and adds the biotinylated anti-TNF alpha antibodies (Cat.No.554511 in 35 μ L/ holes, BD Pharmingen), this antibody at first damping fluid D (contain 1%BSA 1 * PBS) in weaker concn be 250ng/mL.After at room temperature cultivating 2 hours, with plate such as above-mentioned washing and add 1/2000 dilution in damping fluid D in 35 μ L/ holes Streptavidin-HRP conjugate (Cat.No.SNN2004, Biosource).After 45 minutes, cultivated 5 minutes with plate such as above-mentioned washing and with 50 μ L/ hole BM chemoluminescence ELISA substrate POD (Roche).Reading carries out on Luminoscan Ascent Luminometer (Labsystems), and be 100 milliseconds integral time, provides raw data (RLU: relative flat light emission).Below contrast comprises in test, the highest signal contrast, and wherein cell is activated by LPS, but only adds 0.2%DMSO medium (and therefore not having compound).Be somebody's turn to do highest level to the TNF α that can obtain in test as directed.Minimum signal contrast is also included within these tests.Wherein cell is not triggered.This contrast returns to the basic TNF alpha levels that is produced by PBMC.The RLU data computation of returning based on ELISA suppresses percentage ratio (PIN) by the TNF α release that compound obtains then, uses following formula: the TNF alpha levels-minimum TNF alpha levels of 100-[((compounds X under concentration Y)/(the highest TNF alpha levels-minimum TNF alpha levels)) * 100].Wherein compound is at 8 concentration (1/3 stepwise dilution) test down, EC ₅₀The fitting of a curve of the mean value of the PIN data that value can be obtained under each experimental concentration by compound is calculated.

For test compound is cultivated the influence that the IL1 that causes and IL6 discharge to the PBMC that is stimulated by LPS, suitably the supernatant liquor of dilution can be used above-mentioned identical ELISA test method and measures.With IL1 and IL6 ELISA (all available from R﹠amp; D Systems) paired antibody can be used as follows: anti-IL1 capture antibody (Cat.No.MAB601) is used with 0.5 μ g/mL, and biotinylated anti-IL1 detects antibody (Cat.No.BAF201) and uses with 50ng/mL; Anti-IL6 capture antibody (Cat.No.MAB206) is used with 1 μ g/mL, and biotinylated anti-IL6 detects antibody (Cat.No.BAF206) and uses with 50ng/mL.

For following table 5, can use the PBMC EC of each definite compound of test method described herein ₅₀Be expressed as follows:

The PBMC EC of #### compound exhibits ₅₀1-100nM

The PBMC EC of ### compound exhibits ₅₀101-500nM

The PBMC EC of ## compound exhibits ₅₀501-1000nM

The PBMC EC of # compound exhibits ₅₀1000nM

Table 5

Compound #	PBMC EC ₅₀(nM)
Compound #	PBMC EC ₅₀(nM)	1	#
2	#	1	#
2	#	3	#
4	#	3	#
4	#	5	#
6	#	5	#
6	#	7	#
8	#	7	#
8	#	9	###
10	#	9	###
10	#	11	#
12	#	11	#
12	#	13	#
14	#	13	#
14	#	15	##
16	#	15	##
16	#	17	#
18	#	17	#

Compound #	PBMC EC ₅₀(nM)
Compound #	PBMC EC ₅₀(nM)	19	#
20	#	19	#
20	#	21	#
22	#	21	#
22	#	23	#
24	#	23	#
24	#	25	#
26	##	25	#
26	##	27	#
28	#	27	#
28	#	29	#
30	#	29	#
30	#	31	#
32	##	31	#
32	##	33	#
34	#	33	#
34	#	34	#
35	#	34	#
35	#	36	#
36	#	36	#
36	#	36	#
36	#	36	#
36	#	36	#
36	#	36	#
36	#	37	#
38	#	37	#
38	#	39	#
40	##	39	#
40	##	41	#
42	#	41	#
42	#	43	###

Compound #	PBMC EC ₅₀(nM)
Compound #	PBMC EC ₅₀(nM)	43	##
43	#	43	##
43	#	43	#
43	#	43	#
43	#	44	#
45	#	44	#
45	#	46	#
47	#	46	#
47	#	48	#
49	#	48	#
49	#	50	#
51	#	50	#
51	#	52	#
53	#	52	#
53	#	54	##
54	#	54	##
54	#	56	#
57	#	56	#
57	#	58	#
59	#	58	#
59	#	60	#
61	#	60	#
61	#	62	##
62	##	62	##
62	##	63	#
64	#	63	#
64	#	65	#
66	#	65	#
66	#	67	#
68	#	67	#
68	#	69	#

Compound #	PBMC EC ₅₀(nM)
Compound #	PBMC EC ₅₀(nM)	70	#
71	#	70	#
71	#	72	#
73	#	72	#
73	#	74	#
75	#	74	#
75	#	76	#
77	#	76	#
77	#	78	##
79	#	78	##
79	#	81	#
84	#	81	#
84	#	85	#
86	#	85	#
86	#	87	#
88	####	87	#
88	####	88	#
89	#	88	#
89	#	90	#
91	#	90	#
91	#	92	#
94	#	92	#
94	#	99	##
101	#	99	##
101	#	102	#
103	###	102	#
103	###	104	#
105	#	104	#
105	#	108	#
110	#	108	#
110	#	113	#

Compound #	PBMC EC ₅₀(nM)
Compound #	PBMC EC ₅₀(nM)	115	#
116	#	115	#
116	#	117	#
169	#	117	#
169	#	170	#
171	##	170	#
171	##	172	#
174	#	172	#
174	#	176	#
179	#	176	#
179	#	180	#
181	#	180	#

The invention still further relates to the method for treatment or prevention inflammatory diseases, this method comprises the individual administering therapeutic effective inhibitors to needs, and this inhibitor is the formula I compound that mitogen-activated protein kinase activated protein kinase 5 presses down dosage.

Another aspect of present method invention relates to the method for the treatment of or preventing to have the illness of unusual matrix metal proteinase activity feature, and this method comprises the formula I compound of the inhibition matrix metalloproteinase of administering therapeutic significant quantity.

The further aspect of present method invention is the method that treatment or prevention are selected from the illness of the disease that relates to the extracellular matrix degraded, and this method comprises the formula I compound of the effective matrix metalloproteinase amount of suppression of administering therapeutic.

The further aspect of present method invention is the method that treatment or prevention are selected from the illness of the disease that relates to the expression of MMP1 abnormal cells, and this method comprises the formula I compound of the effective matrix metalloproteinase amount of suppression of administering therapeutic.

The special embodiment of present method invention is the method for treatment or prevention rheumatoid arthritis, and this method comprises the formula I compound to the individual administering therapeutic significant quantity of needs.

The invention still further relates to The compounds of this invention and be used for the treatment of or prevent, most preferably be used for the treatment of the purposes in the medicine of rheumatoid arthritis by using the illness that mitogen-activated protein kinase activated protein kinase 5 inhibitor prevent, improve or eliminate or having the illness of unusual collagenase activities feature or be selected from the illness of the disease that relates to inflammation in preparation.

Use The compounds of this invention to individual patient and comprise that the oneself uses and uses by another person.The patient may need to treat the disease or the medical conditions of existence, may wish that maybe prophylactic treatment is to prevent or to reduce the disease that caused by bone metabolism disturbance and the risk of medical conditions.The compounds of this invention can be by oral, transdermal, in suction, injection, nose, rectum or be passed to individual patient by sustained release preparation.

The preferred version of present method comprises to the individuality of suffering from the disease illness with inflammatory feature uses the abnormal level of the enough time of The compounds of this invention of effective matrix metalloproteinase amount of suppression with the degraded of reduction patient extracellular matrix, and the preferred self-perpetuating process that stops described degraded response.The special embodiment of this method comprise to suffer from or enough time of The compounds of this invention that the individual patient of susceptible generation rheumatoid arthritis development is used effective matrix metalloproteinase amount of suppression reducing respectively or to prevent collagen and bone degraded in the described patient joint, and the preferred self-perpetuating process that stops described degraded response.

The toxicity of this compounds and therapeutic efficiency can be measured in cell cultures or experimental animal by the pharmaceutical methods of standard, for example for measuring LD50 (lethal dose of 50% colony) and ED50 (the treatment effective dose of 50% colony).Toxicity and the dosage ratio of treatment between the effect are that therapeutic index and it can be expressed as LD50/ED50.Preferably show the compound of high therapeutic index.In the time can using the compound that demonstrates toxic side effect, should careful design release system, this system with this type of targeting compounds to affected tissue site so that will drop to minimum to the latent lesion of non-infected cells, thereby reduce side effect.

The data that obtained by cell culture test and zooscopy can be used to prepare the dosage range that is used for the people.The dosage of this compounds is preferably placed in the scope of circulation composition, and it comprises having very little or avirulent ED50.Dosage can depend in this scope that used formulation is with applied route of administration and different.For any compound used in the inventive method, the treatment effective dose can be estimated by cell culture test at first.Can prepare dosage obtaining the circulating plasma concentration range in animal model, it comprises the IC50 that measures in the cell cultures (promptly obtaining maximum half the concentration of test compound of symptom that suppresses).This type of information can be used for measuring more accurately people's useful dosage.Level in the blood plasma can for example be measured by high performance liquid chromatography.

The preferred therapeutic significant quantity that is applied to the The compounds of this invention of individual patient is extremely about 10mg/kg of about 0.1mg/kg, uses every day once to three times.For example, the effective scheme of present method can be used about 5mg to the described The compounds of this invention of about 1000mg, once a day to three times.But should be understood that, will depend on that multiple factor comprises the severity of age, body weight, general health, sex, diet, application times, route of administration, discharge rate, drug regimen and special inflammatory conditions and different for the special dosage level of any special individual patient.The consideration of these factors is in the scope of common skilled clinician, is used to measure prevention, eliminates or stops the required treatment of illness process effectively or the purpose of prevention effective dose.

The compounds of this invention can be participated in the pharmaceutical composition that is suitable for using.This based composition typically comprises at least a The compounds of this invention and at least a pharmaceutically acceptable carrier.Language used herein " pharmaceutically acceptable carrier " is intended to comprise the solid carrier compatible with medicament administration, for example lactose, Magnesium Stearate, terra alba, sucrose, talcum powder, stearic acid, gelatin, agar, pectin, gum arabic etc.; And liquid, for example vegetables oil, peanut oil and sterilized water etc., any and all solvents, dispersion medium, Drug coating, antiseptic-germicide and anti-mycotic agent, etc. blend to absorb and prolong agent etc.The tabulation of pharmaceutically acceptable carrier is not interpreted as restriction.This type of medium and reagent are well-known in the art as the purposes of active medicinal matter.Except with inconsistent any conventional media of active compound or reagent, its purposes in composition will think over.The active compound that replenishes can also be incorporated in the composition.

Pharmaceutical composition of the present invention is formulated as compatible with its expection route of administration.The example of route of administration comprises non-enteron aisle, for example intravenously, intracutaneous, subcutaneous, oral (for example sucking), transdermal (part), saturating mucous membrane and rectal administration.The solution or the suspensoid that are used for non-enteron aisle, intracutaneous or subcutaneous application can comprise following component: sterile diluent, for example water for injection, normal saline solution, fixed oil, polyoxyethylene glycol, glycerine, propylene glycol or other synthetic; Antiseptic-germicide, for example benzyl alcohol or methyl p-hydroxybenzoate; Antioxidant, for example xitix or sodium bisulfite; Sequestrant, for example ethylenediamine tetraacetic acid (EDTA); Buffer reagent, for example reagent of acetate, Citrate trianion or phosphoric acid salt and adjustment of tonicity, for example sodium-chlor or dextrose.PH can regulate with acid or alkali, for example hydrochloric acid or sodium hydroxide.Parenteral formulation can be sealed in ampoule, disposable syringe or the multi-dose vials made with glass or plastics in.

The pharmaceutical composition that is applicable to injection comprises aseptic aqueous solution (water-soluble) or dispersion agent and the sterilized powder that is used for temporarily preparing sterile injectable solution agent or dispersion agent.Use for intravenously, the carrier that is fit to comprise physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS) (PBS).In all situations, composition must be aseptic and should be the liquid that is easy to inject to a certain extent.It must be stable under the condition of preparation and storage and must be able to prevent the contamination of microorganism (for example bacterium and fungi).Carrier can be solvent or dispersion medium, for example comprises water, ethanol, polyvalent alcohol (for example glycerine, propylene glycol and liquid macrogol etc.) and their suitable mixtures.Suitable flowability can be for example by use dressing (for example Yelkin TTS), under the dispersive situation by keeping required granular size and keeping by the application surface promoting agent.Prevent that microbial process from can realize by multiple antiseptic-germicide and anti-mycotic agent, for example parabens, trichloro-butyl alcohol, phenol, xitix, Thiomersalate etc.In a lot of situations, preferably include isotonic agent in the composition, for example sugar, polyvalent alcohol (for example N.F,USP MANNITOL, sorbyl alcohol), sodium-chlor.Prolong the Injectable composition that absorbs and can prolong the reagent that absorbs by comprising in composition, for example aluminum monostearate and gelatin are realized.

The sterile injectable solution agent can be incorporated in the suitable solvent with above-named combination (if desired) a kind of or composition by the active compound (for example compound of embodiment of the present invention) with aequum, prepares by filtration sterilization subsequently.Usually, dispersion agent is to prepare by active compound being incorporated in the sterile media that comprises basic dispersion medium and required other above-named composition.Preparing with sterilized powder in the situation of sterile injectable solution agent, preferred manufacturing procedure is vacuum-drying and freeze-drying, and its powder that produces activeconstituents adds any other expection composition (from previous sterile filtration solution).

Oral compositions generally includes inert diluent or edible carrier.They can be sealed in the capsule or be pressed into tablet.Use for oral administration, active compound can be used with mixed with excipients and with tablet, lozenge or Capsule form.The liquid vehicle that oral compositions can also be used as mouth wash shua prepares, wherein with the compound oral application in the liquid vehicle and swish and spue or swallow.

Pharmaceutically useful tackiness agent and/or adjuvant can comprise the part as composition.Tablet, pill, capsule, lozenge etc. can comprise the compound of any following ingredients or similarity: tackiness agent, for example Microcrystalline Cellulose, tragacanth gum or gelatin; Vehicle, for example starch or lactose; Disintegrating agent, for example Lalgine, Primogel or W-Gum; Lubricant, for example Magnesium Stearate or Sterotes; Glidant, for example colloid silica; Sweeting agent, for example sucrose or asccharin; Or correctives, for example peppermint, wintergreen oil or orange class correctives.

Use for suction, compound discharges with aerosol form, and it is by the pressurized vessel that comprises suitable propellent (for example gas, for example carbonic acid gas) or divider or spraying gun ejection.

Systemic administration can also be mucous membrane or transdermal means.For saturating mucous membrane or transdermal administration, use the permeate agent that is fit to penetration barriers in the preparation.This type of permeate agent is normally known in the art and for example comprise washing agent, cholate and fusidic acid derivatives for saturating mucosal administration.Saturating mucosal administration can be finished by using nasal spray or suppository.For transdermal administration, active compound is mixed with ointment, ointment, gelifying agent or the ointment that is known in the art usually.

Compound can also be used for rectum and discharge with the form preparation of suppository (for example with conventional suppository bases, for example theobroma oil and other glyceryl ester are together) or retention enema.

In one embodiment, with preventing that the carrier that compound is eliminated in the body fast from preparing, for example controlled release preparation comprises implant and micro-capsule release system with active compound.Can degradable, the biocompatible polymkeric substance of applying biological, for example ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, poe class and poly(lactic acid).The method for preparing this type of preparation is conspicuous for those skilled in the art.Material can also be for example from Alza Corporation and Nova Pharmaceuticals, and Inc. is commercially available.Liposome suspensoid (comprising that target has the liposome at the cells infected of the monoclonal antibody of virus antigen) can also be used as pharmaceutically acceptable carrier.These can prepare according to method known to those skilled in the art.

Particularly advantageously be oral or non-enteron aisle composition is mixed with is easy to use and the dosage unit form of dosage homogeneous.Dosage unit form used herein refers to physically separated unit, and it is suitable as the individually dosed individuality of being treated of being used for; Each unit comprises the active compound of predetermined amount of calculating with the therapeutic action that produces expection and required pharmaceutical carrier.The specification sheets of dosage unit form of the present invention is used for the treatment of the inherent limitations description in this type of individual active compound and directly depends on them with the special therapeutic action that is obtained and in preparation by the unique property of active compound.

Pharmaceutical composition can be included in container, packing or the divider with using specification sheets.

The compound of embodiment of the present invention can be with salt, and preferably the pharmacologically acceptable salt with formula I compound provides.The example of the pharmacologically acceptable salt of these compounds comprises those salt derived from acid, and described organic acid is acetate, oxysuccinic acid, tartrate, citric acid, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, toluylic acid, amygdalic acid, methylsulfonic acid, Phenylsulfonic acid and right-toluenesulphonic acids for example; Mineral acid, for example salt solution and sulfuric acid etc. obtain mesylate, benzene methanesulfonic acid salt, right-tosylate, hydrochloride and vitriol etc. separately, perhaps derived from those salt of alkali, for example organic and mineral alkali of described alkali.The example of the mineral alkali that is fit to that is used to form the salt of The compounds of this invention comprises oxyhydroxide, carbonate and the supercarbonate of ammonium, lithium, sodium, calcium, potassium, aluminium, iron, magnesium, zinc etc.Salt can also form with the organic bases that is fit to.This type of alkali that is suitable for forming pharmaceutically acceptable base addition salt with The compounds of this invention comprises nontoxic and intensity is enough to the salifiable organic bases of shape.This type of organic bases has been well-known in the art and can have comprised amino acid, for example arginine and Methionin, one, two or trihydroxy-alkylamine (for example, two and trolamine), choline,, two and trialkylamine (for example methylamine, dimethylamine and Trimethylamine 99), guanidine; The N-methylglucosamine; N methyl piperazine; Morpholine; Quadrol; The N-benzyl-1-phenylethylamine; Three (hydroxymethyl) aminomethane etc.

The salt of the compound of embodiment of the present invention can be used the methods known in the art preparation in a usual manner.The acid salt of described basic cpd can by will according to of the present invention first or the free alkali compound of second aspect be dissolved in the water that comprises required acid or aqueous alcohol solutions or other the suitable solvent and prepare.When The compounds of this invention comprised acid functional, the alkali salt of described compound can be by preparing described compound and the alkali reaction that is fit to.Acid or alkali salt can directly separate maybe can pass through concentrated solution, for example obtains by evaporating.The compounds of this invention can also exist with solvation or hydrated form.

One skilled in the art will appreciate that above description is exemplary with illustrative in essence, and be intended to illustrate the present invention and its embodiment preferred.By routine test, the technician will recognize conspicuous modification and variation and not break away from spirit of the present invention.Therefore, the present invention is intended to not be by above description definition, but is defined by following claim and their coordinator.

Reference

Choy EH，Panayi GS.(2001).N Engl J Med.344：907-16.

Firestein GS.(2003).Nature.423：356-61.

Smolen JS，Steiner G.(2003).Nat Rev Drug Discov.2：473-88.

Lee DM，Weinblatt ME(2001).Lancet.358：903-11.

Kremer J.M.，Westhovens R.，Leon M.，Di Giorgio E.，Alten R.，Steinfeld S.，Russell A.，Dougados M.，Emery P.，Nuamah I.F.，Williams G.R.，Becker J.-C.，Hagerty D.T.，Moreland L.W.(2003)N Engl J Med.349：1907-1915.

Edwards J.C.W.，Szczepanski L.，Szechinski J.，Filipowicz-SosnowskaA.，Emery P.，Close D.R.，Stevens R.M.，Shaw T.(2004)N Engl J Med.350：2572-2581.

O’Dell JR，Leff R，Paulsen G，Haire C，Mallek J，Eckhoff PJ，Fernandez A，Blakely K，Wees S，Stoner J，Hadley S，Felt J，Palmer W，Waytz P，Churchill M，Klassen L，Moore G.(2002)Arthritis Rheum.46：1164-70.

St Clair EW, van der Heij de DM, Smolen JS, Maini RN, Bathon JM, Emery P, Keystone E, Schiff M, Kalden JR, Wang B, Dewoody K, Weiss R, Baker D; (2004) Combination of infliximab and methotrexate therapy forearly rheumatoid arthritis:a randomized, controlled trial (infliximab and the early stage rheumatoid arthritis of methotrexate combined therapy: at random, controlled trial) .Arthritis Rheum.50:3432-43.

People (2003) .Arthritis Rheum.48:2122-7. such as Gomez-Reino JJ

O ' Dell JR. (2004) Therapeutic strategies for rheumatoid arthritis (therapeutic strategy of rheumatoid arthritis) .N Engl J Med.350 (25): 2591-602.

New L, Jiang Y, Han J. (2003) Regulation of PRAK subcellularlocation by p38 MAP kinases (the p38MAP kinases is to the adjusting of PRAK Subcellular Localization) .Mol Biol Cell.14 (6): 2603-16.

Shi Y, Kotlyarov A, Laabeta K, Gruber AD, Butt E, Marcus K, MeyerHE, Friedrich A, Volk HD, Gaestel M. (2003) Elimination of protein kinaseMK5/PRAK activity by targeted homologous recombination (the target homologous recombination is to the active elimination of protein kinase MK5/PRAK) .Mol Cell Biol.23:7732-41.

Seternes OM, Mikalsen T, Johansen B, Michaelsen E, ArmstrongCG, Morrice NA, Turgeon B, Meloche S, Moens U, Keyse SM. (2004) Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines anovel signal transduction pathway (atypia map kinase ERK3 has defined new signal transduction pathway to the activation of MK5/PRAK).

EMBO J.23：4780-91.

People (2003) .Arthritis Rheum.48:1901-12. such as Andreakos E

People (2001) .Arthritis Rheum 44:2263-74. such as Cunnane G

People (2002) .Science 295:2387-92. such as Coussens LM

People (2001) .Circ Res.2001 89:201-10 such as Creemers EE

People (2004) .J Periodontol.75:441-52. such as Gapski R

Reif S，Somech R，Brazovski E，Reich R，Belson A，Konikoff FM，Kessler A.(2005)Digestion.71：124-130.

Rosenberg GA.(2002).Glia.39：279-91.

People (2002) .J Clin Invest.110:371-9. such as Schanstra JP

People (2004) .Treat Respir Med.3:17-27. such as Suzuki R

As seen from the above description, multiple modification in the present composition and the method and change are finished for those skilled in the art.All these type of modifications in the appended claims scope are intended to be included in wherein.

Should be understood that multiple factor (for example different Premeabilisation of cells abilities of different compounds) can cause the difference of compound activity between external biological chemistry and the test cell line.

Incorporate all publications (including but not limited to patent and patent application) of quoting in this manual into this paper as a reference, illustrate especially and individually that just as the publication that each is independent incorporating this paper into is equal to as a reference and will all incorporates this paper into as a reference.

The chemical name of the The compounds of this invention that provides in the application's book be produce by MDL ' s ISIS DrawAutonom Software tool and be unconfirmed.In the incident of discordance, the structure that advantageous applications is described.

<110>Galapagos N.V.

Andrews，Martin J I

Edwards，Paul

Chambers，Mark S

Schmidt，Wolfgang

Clase，Juha A

Bar，Gregory

Hirst，Kim L

Angus，MacLeod

＜120〉be used for the treatment of the triazolopyrazine compounds of sex change and inflammatory diseases

<130>GAL-033-WO-PCT

<150>US 60/803,552

<151>2006-05-31

<150>US 60/

<151>2007-05-25

<150>US 60/

<151>2007-05-25

<150>US 60/

<151>2007-05-25

<150>US 60/

<151>2007-05-29

<160>6

＜170〉PatentIn version 3 .4

<210>1

<211>19

<212>DNA

＜213〉artificial

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<210>2

<211>19

<212>DNA

＜213〉artificial

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<400>2

<210>3

<211>19

<212>DNA

＜213〉artificial

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<211>19

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<400>4

<210>5

<211>19

<212>DNA

＜213〉artificial

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<400>5

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<400>6

Claims

Formula III compound or pharmaceutically acceptable salt thereof, solvate or prodrug with and steric isomer, isotopic variations and tautomer:

Wherein

R ¹Be H or replacement or unsubstituted alkyl; And each R ⁸And R ⁹Be independently selected from replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl.
2. the compound of claim 1, wherein R ⁸Be selected from replacement or unsubstituted cyclopentyl, cyclohexyl, replacement or unsubstituted phenyl, replacement or unsubstituted pyridine base, replacement or unsubstituted pyrimidine and replacement or unsubstituted pyrazine, replacement or unsubstituted pyrroles, replacement or unsubstituted pyrazoles and replacement or unsubstituted imidazoles.
3. the compound of claim 1, wherein R ⁸Be selected from the phenyl of replacement, the pyridyl of replacement and the pyrimidine of replacement; And substituting group is

-L-R ^8dAnd wherein

L be selected from key, alkylidene group, assorted alkylidene group ,-O-,-N (R ^8e)-,-CO-,-CO ₂-,-SO-,-SO ₂-,-CON (R ^8e)-,-SO ₂N (R ^8e)-,-N (R ^8e) CO-,-N (R ^8e) SO ₂-,-N (R ^8e) CON (R ^8e)-,-N (R ^8e) SO ₂N (R ^8e)-; And

R ^8dBe selected from replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted amino, replacement or unsubstituted aralkyl, replacement or unsubstituted heteroarylalkyl and replacement or unsubstituted aminoalkyl group; And

R ^8eBe selected from H, replacement or unsubstituted alkyl and replacement or unsubstituted cycloalkyl.
4. the compound of claim 1, wherein R ⁸Be

Wherein L and R ^8dAs describing in the claim 3; Subscript n is selected from 1-4; And each R ^8aBe independently selected from hydrogen, replacement or unsubstituted alkyl, alkoxyl group, cyano group and halogen.
5. the compound of claim 4, wherein L be key ,-O-,-CO-,-CON (R ^8e)-or-N (R ^8e) CO-;

R ^8dBe selected from replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl, replacement or unsubstituted heteroarylalkyl and replacement or unsubstituted aminoalkyl group; And

R ^8eBe selected from H, replacement or unsubstituted alkyl.
6. the compound of claim 4, wherein L be key ,-O-,-CO-,-CON (R ^8e)-or-N (R ^8e) CO-; And

R ^8dBe selected from H, alkylamino ethyl, dialkyl amido ethyl, cycloalkyl, Heterocyclylalkyl, arylalkyl and heteroarylalkyl.
7. the compound of claim 4, wherein L be key ,-O-,-CO-,-CON (R ^8e)-or-N (R ^8e) CO-; And

R ^8dBe selected from H, methylamino ethyl, ethylamino ethyl, dimethyl aminoethyl, diethylamino ethyl, replacement or unsubstituted pyrrolidyl, benzyl and pyridylmethyl.
8. the compound of claim 4, wherein L be key ,-CO-,-O (CH ₂) _M1-,-CON (H) (CH ₂) _M1-or-NHCO-; Subscript m 1 is selected from 1-4; And R ^8dBe

And wherein encircling P is that replace or unsubstituted Heterocyclylalkyl.
Formula IVa, IVb, IVc or IVd compound or pharmaceutically acceptable salt thereof, solvate or prodrug with and steric isomer, isotopic variations and tautomer:

And wherein L and ring P are as describing in the claim 8; Subscript n is selected from 1-4; Each R ^8aBe independently selected from hydrogen, replacement or unsubstituted alkyl, alkoxyl group, cyano group and halogen; And R ⁹Be independently selected from replacement or unsubstituted aryl and heteroaryl.
10. the compound of claim 9, wherein L is a key.
11. the compound of claim 9, wherein L is-CO-.
12. the compound of claim 9, wherein L be-NHCO-or-CONH-.
13. the compound of claim 9, wherein L is-CON (H)-CH ₂-CH ₂-or-N (H)-CO-CH ₂-CH ₂-.
14. the compound of claim 9, wherein L is-OCH ₂-CH ₂-or-NHCH ₂-CH ₂-.
15. any one compound among the claim 9-14, wherein encircle P and be replace or unsubstituted piperidines, morpholine or piperazine.
16. the compound of claim 9, wherein each R ^8aBe H.
17. the compound of claim 9, wherein subscript n is 1 and R ^8aBe Me, Et, Pr, different-Pr, Cl, F, CN, OMe or CF ₃
18. the compound of claim 1, wherein compound is formula Va, Vb, Vc, Vd, Ve or Vf:

R wherein ⁹As describe in the claim 1 and R ^8bBe hydrogen, replacement or unsubstituted alkyl or replacement or unsubstituted cycloalkyl.
19. the compound of claim 18, wherein R ^8bBe H.
20. the compound of claim 18, wherein R ^8bBe that replace or unsubstituted alkyl or replacement or unsubstituted cycloalkyl.
21. the compound of claim 18, wherein R ^8bBe Me, Et, Pr, i-Pr, t-Bu, i-Bu, CH ₂CONH ₂, cyclopropyl or cyclopropyl methyl.
22. the compound of claim 1, wherein R ⁹Be selected from replacement or unsubstituted aryl.
23. the compound of claim 1, wherein R ⁹Be selected from replacement or unsubstituted phenyl.
24. the compound of claim 1, wherein R ⁹Be selected from replacement or unsubstituted heteroaryl.
25. the compound of claim 1, wherein R ⁹Be selected from replacement or unsubstituted phenyl, pyridyl, indyl, pseudoindoyl, pyrryl, furyl, thienyl, pyrazolyl, oxazolyl and thiazolyl.
26. any one compound among the claim 1-25, wherein R ⁹Be

Or

And each A ¹, A ²And A ³Be independently selected from S, O, N, NR ^9aAnd CR ^9aEach R ^9aBe independently H or replacement or unsubstituted alkyl; And R ^9bBe CONH ₂, CONHMe or CN.
27. any one compound among the claim 1-25, wherein R ⁹Be

Or
28. any one compound among the claim 1-25, wherein R ⁹Be

Or
29. any one compound among the claim 1-25, wherein R ⁹Be

And wherein subscript m is selected from 1-4 and each R ^9dBe independently H, replacement or unsubstituted alkyl or halogen.
30. any one compound among the claim 1-25, wherein R ⁹Be

And wherein subscript m is selected from 1-4 and each R ^9dBe independently H, replacement or unsubstituted alkyl or halogen.
31. any one compound among the claim 1-25, wherein R ⁹Be

Or

And wherein subscript m is selected from 1-3 and each R ^9dBe independently H, replacement or unsubstituted alkyl or halogen.
32. any one compound among the claim 29-31, wherein each R ^9dBe H.
33. any one compound among the claim 29-31, wherein m is 1 or 2 and each R ^9dBe Me, Cl or F.
34. the compound of claim 1, wherein compound is formula VIa, VIb, VIc, VId, VIe or VIf:

And R ^8bBe hydrogen, replacement or unsubstituted alkyl or replacement or unsubstituted cycloalkyl.
35. the compound of claim 1, wherein compound is formula VIIa, VIIb, VIIc, VIId, VIIe or VIIf:

And R ^8bBe hydrogen, replacement or unsubstituted alkyl or replacement or unsubstituted cycloalkyl.
36. the compound of claim 1, wherein compound is formula VIIIa, VIIIb, VIIIc, VIIId, VIIIe or VIIIf:

And R ^8bBe hydrogen, replacement or unsubstituted alkyl or replacement or unsubstituted cycloalkyl.
37. the compound of claim 1, wherein compound is IXa, IXb, IXc, IXd, IXe or IXf:

And R ^8bBe hydrogen, replacement or unsubstituted alkyl or replacement or unsubstituted cycloalkyl.
38. the compound of claim 1, wherein compound is formula Xa, Xb, Xc, Xd, Xe or Xf:

And R ^8bBe hydrogen, replacement or unsubstituted alkyl or replacement or unsubstituted cycloalkyl.
39. the compound of claim 1, wherein compound is formula XIa, XIb, XIc, XId, XIe or XIf:

And R ^8bBe hydrogen, replacement or unsubstituted alkyl or replacement or unsubstituted cycloalkyl; And R ^9eBe H, Me or CN.
40. any one compound among the claim 34-39, wherein R ^8bBe H.
41. any one compound among the claim 34-39, wherein R ^8bIt is cycloalkyl.
42. any one compound among the claim 34-39, wherein R ^8bIt is cyclopropyl.
43. any one compound among the claim 34-39, wherein R ^8bBe replace or unsubstituted alkyl.
44. any one compound among the claim 34-39, wherein R ^8bBe Me, Et, Pr, i-Pr, t-Bu, i-Bu, CF ₃, CH ₂CF ₃, CH ₂CONH ₂Or cyclopropyl methyl.
45. the compound of claim 1, wherein compound is formula XIIa, XIIb, XIIc or XIId:
46. the compound of claim 1, wherein compound is formula XIIIa, XIIIb, XIIIc or XIIId:
47. the compound of claim 1, wherein compound is formula XIVa, XIVb, XIVc or XIVd:
48. the compound of claim 1, wherein compound is formula XVa, XVb or XVc:

And L be key ,-CO-or-O-CH ₂-CH ₂-; Ring P is

And R ^8bBe H, Me, i-Pr, t-Bu, CH ₂CONH ₂, cyclopropyl methyl or CH ₂CF ₃
49. the compound of claim 48, wherein L is that key and ring P are
50. the compound of claim 1, wherein compound is selected from

(4-morpholine-4-base-phenyl)-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

[4-(4-methyl-piperazine-1-yl)-phenyl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

4-{8-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-benzamide;

4-{8-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-the 1H-pyridin-2-ones;

4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-benzamide;

4-{8-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

2-fluoro-4-{8-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-benzamide;

3-fluoro-4-{8-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-benzamide;

5-{8-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

3-fluoro-4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-benzamide;

2-fluoro-4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-benzamide;

[5-(5-methyl isophthalic acid H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-(4-morpholine-4-base-phenyl)-amine;

[5-(5-methyl isophthalic acid H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-(4-morpholine-4-base-phenyl)-amine;

5-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiophene-2-carboxamide derivatives;

2,6-two fluoro-4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolos [1,5-a] pyrazine-5-yl]-benzamide;

4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiophene-2-carboxamide derivatives;

[4-(4-methyl-piperazine-1-yl)-phenyl]-[5-(5-methyl isophthalic acid H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

(3-fluoro-4-morpholine-4-base-phenyl)-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

(3-chloro-4-morpholine-4-base-phenyl)-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

4-{8-[4-(2-morpholine-4-base-oxyethyl group)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

5-{8-[4-(2-morpholine-4-base-oxyethyl group)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

(4-morpholine-4-base-phenyl)-[5-(2H-pyrazole-3-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

4-{8-[4-((2R, 6S)-2,6-dimethyl-morpholine-4-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

(4-morpholine-4-base-3-trifluoromethyl-phenyl)-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

2,6-two fluoro-4-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-benzamide;

4-[8-(4-piperazine-1-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiophene-2-carboxamide derivatives;

4-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

5-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-furans-3-methane amide;

5-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-furans-3-methane amide;

[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-[4-((2S, 5R)-2,4,5-trimethylammonium-piperazine-1-yl)-phenyl]-amine;

4-{8-[4-((2S, 5R)-2,4,5-trimethylammonium-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

5-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-2,3-dihydro-isoindole-1-ketone;

4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-furans-2-methane amide;

6-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-3,4-dihydro-2H-isoquinoline 99.9-1-ketone;

5-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

2-morpholine-4-base-5-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-methyl alcohol;

[4-(4-sec.-propyl-piperazine-1-yl)-phenyl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

6-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-3,4-dihydro-1H-quinoline-2-one-;

(4-piperazine-1-base-phenyl)-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

(6-morpholine-4-base-pyridin-3-yl)-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

[6-(4-cyclopropyl methyl-piperazine-1-yl)-pyridin-3-yl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

[6-(4-sec.-propyl-piperazine-1-yl)-pyridin-3-yl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-6-[4-(2,2,2-three fluoro-ethyls)-piperazine-1-yl]-pyridin-3-yl }-amine;

[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-4-[4-(2,2,2-three fluoro-ethyls)-piperazine-1-yl]-phenyl }-amine;

[4-(4-cyclopropyl methyl-piperazine-1-yl)-phenyl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

4-[8-(6-morpholine-4-base-pyridin-3-yl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiophene-2-carboxamide derivatives;

(the 5-benzo [#b! ] thiene-3-yl--[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-(4-morpholine-4-base-phenyl)-amine;

(the 5-benzo [#b! ] thiene-3-yl--[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl]-amine;

(4-morpholine-4-base-phenyl)-(5-thiene-3-yl--[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-amine;

[4-(4-sec.-propyl-piperazine-1-yl)-phenyl]-(5-thiene-3-yl--[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-amine;

[5-(5-ethyl-1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-(4-morpholine-4-base-phenyl)-amine;

6-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-1,1-dioxo-1,2-dihydro-1$l%6﹠amp;-benzo [#d! ] isothiazole-3-ketone;

4-{8-[6-(4-cyclopropyl methyl-piperazine-1-yl)-pyridin-3-yl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

4-{8-[6-(4-sec.-propyl-pyrazine-1-yl)-pyridin-3-yl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

4-(8-{6-[4-(2,2,2-three fluoro-ethyls)-piperazine-1-yl]-pyridin-3-yl amino }-[1,2,4] triazolo [1,5-a] pyrazine-5-yl)-thiophene-2-carboxamide derivatives;

4-(8-{4-[4-(2,2,2-three fluoro-ethyls)-piperazine-1-yl]-phenyl amino }-[1,2,4] triazolo [1,5-a] pyrazine-5-yl)-thiophene-2-carboxamide derivatives;

4-{8-[4-(4-cyclopropyl methyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

[4-(4-cyclopropyl-piperazine-1-yl)-phenyl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

[6-(4-cyclopropyl-piperazine-1-yl)-pyridin-3-yl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiazole-2-methane amide;

4-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiazole-2-methane amide;

4-(8-{4-[1-(2,2,2-three fluoro-ethyls)-piperidin-4-yl]-phenyl amino }-[1,2,4] triazolo [1,5-a] pyrazine-5-yl)-thiophene-2-carboxamide derivatives;

[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-4-[1-(2,2,2-three fluoro-ethyls)-piperidin-4-yl]-phenyl }-amine;

5-{8-[4-(2-morpholine-4-base-oxyethyl group)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

(5-benzothiazole-6-base-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-(4-morpholine-4-base-phenyl)-amine;

(2-fluoro-4-morpholine-4-base-phenyl)-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

(2-chloro-4-morpholine-4-base-phenyl)-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

1-{5-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiophene-2-yl }-ethyl ketone;

4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-the 2H-pyrazole-3-yl }-methyl alcohol;

6-{4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-phenyl }-4,5-dihydro-2H-pyridazin-3-one;

(the 5-benzo [1,2,5] oxadiazole-5-bases-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-(4-morpholine-4-base-phenyl)-amine;

4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiazole-2-methylformamide;

4-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiazole-2-methylformamide;

5-[8-(2-fluoro-4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-2,3-dihydro-isoindole-1-ketone;

5-[8-(2-chloro-4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-2,3-dihydro-isoindole-1-ketone;

5-{8-[2-chloro-4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

[5-(2-amino-pyrimidine-5-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-(4-morpholine-4-base-phenyl)-amine;

5-{8-[6-(4-sec.-propyl-piperazine-1-yl)-pyridin-3-yl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

3-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-benzo [#b! ] thiophene-7-methane amide;

3-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl-benzo [#b! ] thiophene-7-methane amide;

4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-pyridine-2-yl }-methyl alcohol;

(4-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-pyridine-2-yl)-methyl alcohol;

[4-(1-sec.-propyl-piperidin-4-yl)-phenyl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

5-[4-(2-amino-thiazolyl--4-yl)-phenyl]-[1,2,4] triazolo [1,5-a] pyrazine-8-yl }-(4-morpholine-4-base-phenyl)-amine;

4-{8-[6-(4-sec.-propyl-piperazine-1-yl)-pyridin-3-yl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-furans-2-methane amide;

5-[8-(6-morpholine-4-base-pyridin-3-yl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-2,3-dihydro-isoindole-1-ketone;

4-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-furans-2-methane amide;

4-{8-[4-(1-sec.-propyl-piperidin-4-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

(4-{8-[6-(4-sec.-propyl-piperazine-1-yl)-pyridin-3-yl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-pyridine-2-yl)-methyl alcohol;

[5-(2-methyl fluoride-pyridin-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl]-amine;

5-{8-[4-(1-sec.-propyl-piperidin-4-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

[5-(1H-indazole-6-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-(4-morpholine-4-base-phenyl)-amine;

4-[8-(6-morpholine-4-base-pyridin-3-yl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-furans-2-methane amide;

4-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-5-methyl-thiophene-2-carboxamide derivatives;

4-{8-[6-(4-sec.-propyl-piperazine-1-yl)-pyridin-3-yl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-5-methyl-thiophene-2-carboxamide derivatives;

4-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

4-{8-[6-(4-sec.-propyl-piperazine-1-yl)-pyridin-3-yl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

5-[8-(2-morpholine-4-base-pyrimidine-5-base is amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-2,3-dihydro-isoindole-1-ketone;

1-{4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-piperazine-2-ketone;

5-{8-[2-(4-sec.-propyl-piperazine-1-yl)-pyrimidine-5-base is amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

5-{8-[4-(uncle 4-#!-butyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

[4-(uncle 4-#!-butyl-piperazine-1-yl)-phenyl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

[5-(1H-indazole-5-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-(4-morpholine-4-base-phenyl)-amine;

5-{8-[4-(2-oxo-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

[5-(1H-indazole-6-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl]-amine;

[6-(4-sec.-propyl-piperazine-1-yl)-pyridin-3-yl]-(5-{ (E)-1-[4-methylene radical-2,4-dihydro-pyrazoles-(3E)-ylidenylmethyl]-propenyl }-[1,2,4] triazolo [1,5-a] pyrazine-8-yl)-amine;

7-fluoro-5-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

6-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

(3-methylamino methyl-4-morpholine-4-base-phenyl)-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine;

2-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-5, the 6-dihydro-furan also [2,3-#c! ] pyrroles-4-ketone;

5-{8-[4-(4-sec.-propyl-2-oxo-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

2-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-4,5-dihydro-thieno-[2,3-#c! ] pyrroles-6-ketone;

5-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-3,3-dimethyl-2,3-dihydro-isoindole-1-ketone;

5-(8-cyclohexyl amino-[1,2,4] triazolo [1,5-a] pyrazine-5-yl)-2,3-dihydro-isoindole-1-ketone;

5-[8-(tetrahydrochysene-pyrans-4-base is amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-2,3-dihydro-isoindole-1-ketone; With

5-[8-(4-fluoro-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-2,3-dihydro-isoindole-1-ketone.
51. the compound of claim 1, wherein compound is selected from:

4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-N-pyridin-3-yl methyl-benzamide;

4-[5-(2-oxo-1,2-dihydro-pyridin-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-N-pyridin-3-yl methyl-benzamide;

2-methoxyl group-N-(6-methyl-pyridin-3-yl methyl)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

4-(8-{3-methoxyl group-4-[(6-methyl-pyridin-3-yl methyl)-formamyl]-phenyl amino }-[1,2,4] triazolo [1,5-a] pyrazine-5-yl)-thiophene-2-carboxamide derivatives;

N-benzyl-2-methoxyl group-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

N-benzyl-3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-N-pyridine-2-ylmethyl-benzamide;

N, N-diethyl-3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [i, 5-a] pyrazine-8-base is amino]-benzamide;

3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-tetramethyleneimine-1-base-ketone;

(4-sec.-propyl-piperazine-1-yl)-3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-ketone;

3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

N-ethyl-3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

N-cyclohexyl methyl-3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

N-(4-hydroxyl-benzyl)-3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

4-[8-(4-benzylamino formyl radical-3-methoxyl group-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiophene-2-carboxamide derivatives;

4-[8-(6-benzoyl-amido-pyridin-3-yl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiophene-2-carboxamide derivatives;

N-benzyl-N-methyl-3-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

N-{5-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-pyridine-2-yl }-benzamide;

1-{4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzoyl }-piperidines-4-methylformamide;

4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-N-(2-pyridin-4-yl-ethyl)-benzamide;

(4-ethyl-piperazine-1-yl)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-ketone;

N-(1-ethyl-tetramethyleneimine-2-ylmethyl)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

(2,5-dihydro-pyrroles-1-yl)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-ketone;

[4-(2-oxyethyl group-ethyl)-piperazine-1-yl]-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-ketone;

N-cyclopropyl methyl-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

N-methyl-N-(1-{4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzoyl }-tetramethyleneimine-3-yl)-ethanamide;

[4-(4-fluoro-benzyl)-piperazine-1-yl]-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-ketone;

(4-phenyl-Piperazine-1-yl)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-ketone;

((S)-2-methoxymethyl-tetramethyleneimine-1-yl)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-ketone;

N-((R)-1-benzyl-tetramethyleneimine-3-yl)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-(4-pyridine-2-base-piperazine-1-yl)-ketone;

N-(1-methoxymethyl-propyl group)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

[4-(2-methoxyl group-ethyl)-piperazine-1-yl]-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-ketone;

N-[2-(4-hydroxyl-phenyl)-ethyl]-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

(4-# second month in a season!-butyl-piperazine-1-yl)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-ketone;

N-[4-(4-methyl-piperazine-1-yl)-phenyl]-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

(benzyl-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzoyl }-amino)-ethyl acetate;

N-sec.-propyl-2-(4-{4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzoyl }-piperazine-1-yl)-ethanamide;

N-(2-methoxyl group-ethyl)-N-methyl-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

N-ethyl-N-(2-methoxyl group-ethyl)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-N-(tetrahydrochysene-furans-2-ylmethyl)-benzamide;

(3,6-dihydro-2H-pyridine-1-yl)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-ketone;

N-(2-methyl sulfane base-ethyl)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

N-(2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

N-(2-diisopropylaminoethyl-ethyl)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

N-((S)-1-ethyl-tetramethyleneimine-2-ylmethyl)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

N-isobutyl--4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide;

[1,4 '] dipiperidino-1 '-Ji-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-phenyl }-ketone;

N-(2-hydroxyl-ethyl)-4-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-base is amino]-benzamide; With

4-[8-(6-phenyl acetyl amino-pyridine-3-base is amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiophene-2-carboxamide derivatives.
52. the compound of claim 1, wherein compound is selected from:

4-{8-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

5-{8-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

[5-(5-methyl isophthalic acid H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-(4-morpholine-4-base-phenyl)-amine;

4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiophene-2-carboxamide derivatives;

4-{8-[4-(2-morpholine-4-base-oxyethyl group)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

4-{8-[4-((2R, 6S)-2,6-dimethyl-morpholine-4-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

4-[8-(4-piperazine-1-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiophene-2-carboxamide derivatives;

4-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

4-{8-[4-((2S, 5R)-2,4,5-trimethylammonium-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

5-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-2,3-dihydro-isoindole-1-ketone;

4-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-furans-2-methane amide;

5-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

4-[8-(6-morpholine-4-base-pyridin-3-yl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-thiophene-2-carboxamide derivatives;

4-{8-[6-(4-cyclopropyl methyl-piperazine-1-yl)-pyridin-3-yl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

4-{8-[6-(4-sec.-propyl-piperazine-1-yl)-pyridin-3-yl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

4-(8-{6-[4-(2,2,2-three fluoro-ethyls)-piperazine-1-yl]-pyridin-3-yl amino }-[1,2,4] triazolo [1,5-a] pyrazine-5-yl)-thiophene-2-carboxamide derivatives;

4-(8-{4-[4-(2,2,2-three fluoro-ethyls)-piperazine-1-yl]-phenyl amino }-[1,2,4] triazolo [1,5-a] pyrazine-5-yl)-thiophene-2-carboxamide derivatives;

4-{8-[4-(4-cyclopropyl methyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

5-{8-[4-(2-morpholine-4-base-oxyethyl group)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

5-{8-[6-(4-sec.-propyl-piperazine-1-yl)-pyridin-3-yl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

5-[8-(6-morpholine-4-base-pyridin-3-yl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-2,3-dihydro-isoindole-1-ketone;

4-{8-[4-(4-sec.-propyl-piperazine-1-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-furans-2-methane amide;

4-{8-[4-(1-sec.-propyl-piperidin-4-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-thiophene-2-carboxamide derivatives;

5-{8-[4-(1-sec.-propyl-piperidin-4-yl)-phenyl amino]-[1,2,4] triazolo [1,5-a] pyrazine-5-yl }-2,3-dihydro-isoindole-1-ketone;

5-[8-(2-morpholine-4-base-pyrimidine-5-base is amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-2,3-dihydro-isoindole-1-ketone;

[4-(the 4-tertiary butyl-piperazine-1-yl)-phenyl]-[5-(1H-pyrazoles-4-yl)-[1,2,4] triazolo [1,5-a] pyrazine-8-yl]-amine; With

2-[8-(4-morpholine-4-base-phenyl amino)-[1,2,4] triazolo [1,5-a] pyrazine-5-yl]-4,5-dihydro-thieno-[2,3-c] pyrroles-6-ketone.
53. pharmaceutical composition, this pharmaceutical composition comprise in the claim 1 to 52 of pharmaceutically acceptable carrier and medicinal significant quantity the compound of any one.
54. the pharmaceutical composition of claim 53, wherein carrier is non-enteron aisle carrier.
55. the pharmaceutical composition of claim 53, wherein carrier is an oral carrier.
56. the pharmaceutical composition of claim 53, wherein carrier is a topical vehicle.
57. any one compound is used for the treatment of or prevents to have purposes in the medicine of illness of ECM degraded feature in preparation in the claim 1 to 52.
58. any one compound is used for the treatment of or prevents to be selected from purposes in the medicine of illness of the disease that relates to inflammation in preparation in the claim 1 to 52.
59. the purposes of claim 58 compound, wherein said disease is a rheumatoid arthritis.
60. any one compound is used for the treatment of or prevents by the purposes in the medicine of using the illness that mitogen-activated protein kinase activated protein kinase 5 inhibitor prevent, improve or eliminate in preparation in the claim 1 to 52.
61. treatment has the method for the illness of unusual matrix metal proteinase activity feature, this method comprises that matrix metalloproteinase any in the claim 1 to 52 of administering therapeutic significant quantity suppresses compound.
62. treatment is selected from the method for the illness of the disease that relates to extracellular matrix degraded, this method comprises any one compound in the claim 1 to 52 of the effective matrix metalloproteinase amount of suppression of administering therapeutic.
63. treatment is selected from the method for the illness that relates to the disease that the MMP1 abnormal cells expresses, this method comprises any one compound in the claim 1 to 52 of the effective matrix metalloproteinase amount of suppression of administering therapeutic.
64. the method for treatment or prevention inflammatory diseases, this method comprises to any one compound in the claim 1 to 52 of the individual administering therapeutic significant quantity of needs.
65. the method for treatment or prevention rheumatoid arthritis, this method comprises to any one compound in the claim 1 to 52 of the individual administering therapeutic significant quantity of needs.