CN100471837C - Process for preparing certain pyrrolotriazine compounds - Google Patents

Abstract

The present invention provides compounds of formula (I), (I) and pharmaceutically acceptable salts thereof.The formula I compounds inhibit the tyrosine kinase activity of growth factor receptors such as VEGFR-2 and FGFR-1, thereby making them useful as anti-cancer agents. The formula (I) compounds are also useful for the treatment of other diseases associated with signal transduction pathways operating through growth factor receptors.

Description

The method for preparing some Pyrrolotriazine compounds

The application is that to be called " method for preparing some Pyrrolotriazine compounds ", the applying date be that July 21, application number in 2003 are dividing an application of 03816201.6 patent application to name.

Technical field

The present invention relates to a kind of method of some Pyrrolotriazine compounds of preparation of novel improvement, this compounds can suppress the activity of the Tyrosylprotein kinase of growth factors such as VEGF R-2 and FGFR-1, thereby they can be used as carcinostatic agent.Except that cancer, also can be used for the treatment of and the relevant disease of signal transduction path that works by somatomedin and angiogenesis inhibitor acceptor such as VEGFR-2 with the compound of the inventive method preparation.

Technical background

Normal vasculogenesis plays an important role in some moietys of fetal development, wound healing, obesity, female fertility function in various physiological activity processes.Vasculogenesis non-expectation or morbid state with comprise diabetic retinopathy, psoriasis, rheumatic arthritis, atheroma, Ka Boxi (family name) sarcoma and vascular tumor, asthma, cancer and metastatic disease are at relevant (the Fan et al of interior disease, 1995, Trend Pharmacol.Sci.16:57-66; Folkman, 1995, Nature Medicine1:27-31).It is believed that the variation of vascular permeability in normal and pathophysiological process, all play a significant role (Cullinan-Bove et al, 1993, Endocrinology 133:829-837; Senger et al, 1993 Cancer and MetastasisReviews, 12:303-324).

Receptor tyrosine kinase (RTKs) has important effect with the bio signal transmission in by the cytoplasmic membrane process.Especially, these change membrane molecule and have the outer ligand binding region of a kind of born of the same parents, and this zone is connected with Tyrosylprotein kinase zone in the born of the same parents by the segment in the plasma membrane.Part produces and the related tyrosine kinase activity of acceptor in conjunction with stimulating with acceptor, thereby the tyrosine residues on acceptor and other intracellular proteins is carried out phosphorylation, and then causes various cellular response.Up to the present, have 19 different RTK subfamilies at least, delimit, identified with amino acid sequence homology.This one of them subfamily comprises fms sample tyrosine kinase receptor, Flt or Flt1 (VEGFR-1) at present, contain kinases inserts regional acceptor, KDR (also referring to Flk-1 or VEGFR-2) and other fms sample tyrosine kinase receptors, Flt4 (VEGFR-3).Among RTKs, Flt that these are relevant and the KDR wherein two demonstrated can be with very high avidity in conjunction with vascular endothelial growth factor (VEGF) (De Vries et al, 1992, Science 255:989-991; Terman et al, 1992, Biochem.Biophys.Res.Comm.1992,187:1579-1586).VEGF combines with these acceptors of expressing in heterogenous cell, is relevant with the variation of cell protein tyrosine phosphorylation state and calcium current.Verified, VEGF is with acid and alkaline fiber archeocyte somatomedin (aFGF; BFGF) has a short endothelial cell growth activity external.It is worthy of note that aFGF and bFGF are attached on the receptor tyrosine kinase that is called FGFR-1 and activate it.According to the restricted expression of its acceptor, the growth factor activity of VEGF has high relatively specificity compared with the growth factor activity of FGFs to endotheliocyte.Present evidence shows that VEGF is for vasculogenesis (Jakeman et al, 1993, Endocrinology, 133:848-859 normal and morbid state; Kolch et al, 1995, Breast Cancer Researchand Treatment, 36:139-155) and vascular permeability (Connolly et al, 1989, J.Biol.Chem.264:20017-20024) all be important stimulation body.

In the adult, except when tissue upgrades, during as wound healing, female fertility cycle, steatogenesis, endotheliocyte has lower proliferation index.Yet when being in morbid state, as cancer, heredity vascular disease, endometriosis, psoriasis, sacroiliitis, retinopathy and arteriosclerosis, endothelial cell proliferation enlivens and is organized into blood vessel.In case be subjected to the vasculogenesis stimulation such as the somatomedin of VEGF and bFGF, endotheliocyte reenters the cell cycle, breeds, moves, is organized into tridimensional network.Generally believe that now the ability of tumour diffusion and migration depends on the cancellated formation of this blood vessel.

VEGF or bFGF and their corresponding receptors bind cause dimerization, the automatic phosphorylation of tyrosine residues, and produce enzymic activity.These phosphorylated tyrosine residues serve as " grappling " site of special downstream signaling molecule, and enzymic activity activates EC activity (embryonal carcinoma activity).The interruption of these approach will suppress the activation of endotheliocyte.The FGFR-1 approach interruption also will influence tumor cell proliferation because except in the proliferative endotheliocyte, this kinases also is activated in the tumprigenicity cell of many types.At last, present evidence shows that also the interruption of VEGF signal conduction has suppressed endothelial cell migration, and endothelial cell migration is critical step in the netted structure-forming process of blood vessel.

Show that in the relevant vascular system of tumour, the overexpression of VEGFR-2 and FGFR-1 and activation play a role in tumor-blood-vessel growth.Vasculogenesis and tumor growth subsequently are subjected to the antibody at VEGF part and vegf receptor, and brachymemma the inhibition of (lack change film sequence and kytoplasm kinases zone) solubility VEGR-2 acceptor.Be incorporated into VEGFR-2 or FGFR-1 and cause the dominant mutation of enzymic activity forfeiture can suppress tumor growth in vivo.The antisense material (antisense) of these acceptors of target or their cognate ligand also can suppress vasculogenesis and tumor growth.Present evidence part has been illustrated in tumor growth instantaneous demand to these acceptors.Clearly, the conduction of VEGF signal is vital for early stage tumor growth, and bFGF is even more important in the later stage relevant with the tumour diffusion.

The compound that obtains benefit according to the inventive method comprises those priority applications and the disclosed compound of WO00/71129, and they are all introduced herein as a reference with it.

Summary of the invention

The invention provides a kind of method for preparing some Pyrrolotriazine compounds.The inventive method provides a kind of useful, convenient, method of having improved, is used to prepare Pyrrolotriazine derivatives, includes a hydroxyl that is directly connected in the pyrrolotriazine ring.

In one embodiment, the inventive method comprises the following steps: that pyrrolotriazine and oxide compound anionic reactive that chlorine is replaced generate ether; Ester is converted into benzylalcohol, and oxidation is reset alcohol and is formed phenol.This oxy-compound is generated the phenoxy group substitution compound by the electrophilic reagent alkylation subsequently, and hydrolysis generates amide compound again.This amide compound is converted into final compound, and method is at first to form chloro imido-ester (chloroimidate), itself and alkylating agent such as hydroxyl fluoro indole is reacted in the presence of alkali obtain final compound, is reflected in the polar solvent and carries out.

In second embodiment, the invention provides a kind of method of using the fluoro indole part of prepared compound novel improvement, that can be suitable for scale operation, and high-quality fluoro indole derivative is provided.In addition, using the fluoro indole derivative of method preparation described here is stable solid, and separate easily also has the stability of long term, makes this product have higher quality compared with the fluoro indole derivative with other alternative method preparations.

Detailed Description Of The Invention

The invention provides a kind of certain class Pyrrolotriazine compounds shown in the following general formula for preparing

With their method of enantiomer, diastereomer and pharmacy acceptable salt, prodrug and solvate thereof, these materials can suppress the activity of the Tyrosylprotein kinase of growth factor receptors such as VEGFR-2.In general formula I and whole specification sheets, above-mentioned symbol definition is as follows:

X and Y are independently selected from O, OCO, S, SO, SO ₂, CO, CO ₂, NR ¹⁰, NR ¹¹CO, NR ¹²CONR ¹³, NR ¹⁴CO ₂, NR ¹⁵SO ₂, NR ¹⁶SO ₂NR ¹⁷, SO ₂NR ¹⁸, CONR ¹⁹, halogen, nitro, cyano group, perhaps X or Y vacancy;

R ¹Be hydrogen;

R ²And R ³Be independently selected from hydrogen, alkyl, substituted alkyl, the rare base of chain, replace the rare base of chain, alkynyl, substituted alkynyl, aromatic base, substituted aromatic base, heterocycle, substituted heterocycle, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, Heterocyclylalkyl (heterocycloalkyl) or substituted heterocycle alkyl; Subsidiary restrictive condition is as follows, when X is halogen, nitro or cyano group, and R ²Vacancy and, when Y is halogen, nitro, cyano group, R ³Vacancy;

R ⁶Be H;

R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷, R ¹⁸And R ¹⁹Be independently selected from hydrogen, alkyl, substituted alkyl, aromatic base, substituted aromatic base, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle;

R ⁴²For

At (R ⁴³) _nIn, wherein n equals 0,1 or 2, and each R ⁴³Be independently selected from hydrogen, fluorine, chlorine and methyl; With

R ⁴⁴Be methyl or hydrogen,

Further restrictive condition is:

If a. X is SO, SO ₂, NR ¹³CO ₂Or NR ¹⁴SO ₂, R ²Can not be hydrogen; With

If b. Y is SO, SO ₂, NR ¹³CO ₂Or NR ¹⁴SO ₂, R ³Can not be hydrogen.

In one embodiment, the inventive method comprises the following steps:

A) transform compound shown in the following formula

R wherein ^eBe low alkyl group or aromatic base, X ¹Be halogen, to following formula: compound 1

R wherein ^dBeing low alkyl group, aromatic base, substituted aromatic base, heteroaryl or substituted heteroaryl, is to transform by handling with phenates or alkoxide.

B) compound 1 is carried out alkylation and generate the compound 2 shown in the following formula

C) in the presence of Lewis acid, generate following formula: compound 3 with peroxide treatment compound 2

D) phenolic hydroxyl group in the compound 3 (phenol group) is carried out alkylation following formula: compound 4 is provided

Wherein, R ²Be benzyl or substituted benzyl,

E) hydrolysis compound 4 generates following formula: compound 5

Wherein, R ²For benzyl or substituted benzyl and

F) compound 5 is converted into following formula: compound 6

By earlier compound 5 being converted into the chloro imido-ester, again the chloro imido-ester is carried out alkylation and obtain compound 6, wherein R2 is a benzyl.In the presence of catalyzer, handle the provide protection of going that realizes phenol with hydrogen donor, obtain compound 6, wherein R ²Be hydrogen.

In second embodiment of the present invention, the initial compounds that following formula is represented

X wherein ₁Be halogen;

Obtain following formula: compound 8 with the nucleophilic reagent reaction

Under cold condition, handle compound 8 with alkylating agent, obtain following formula: compound 9

Then, compound 9 is obtained compound 10 with peroxide treatment in the presence of Lewis acid

In a further embodiment of the present invention, the fluoro indole segment can prepare with following method:

A) with the fluorine cpd of following formula

Generate following formula: compound 11 with the nucleophilic reagent reaction

B), generate following formula: compound 12 with compound 11 and alkoxyl group anionic reactive

Wherein R is a blocking group,

C) spend the protection agent treated, alkoxyl group is gone protection, obtain following formula: compound 13

With

D) under reductive condition, cyclisation compound 13 obtains following formula: compound 14

In a preferred embodiment, the step 1 in the diagram scheme 1 comprises compound is converted into ether, is to handle with nucleophilic reagent such as phenates or alkoxide anion to carry out.Preferably, alkoxide anion is methylate or ethanol anion.

Preferred alkylating agent comprises alkyl halide magnesium in the step 2 of diagram scheme 1, and just methyl-magnesium-bromide or methylmagnesium-chloride are from approximately-25 ℃ to about 25 ℃ cold condition.

The preferred processing with superoxide such as hydrogen peroxide or Sodium peroxoborate of compound 2 in the step 3 obtains compound 3, is in organic solvent such as methylene dichloride (DCM), under the condition of Lewis acid such as boron trifluoride existence.Compound 3 carries out alkylating with electrophilic reagent in the presence of alkali such as NaH, electrophilic reagent such as bromotoluene or benzyl chloride, about 0 ℃ to about 100 ℃ of operative temperature.

Compound 4 usefulness acid treatment hydrolysis obtain compound 5, preferably carry out under the temperature that moisture HCl has increased.Compound 5 finally is converted into compound 6, and by the chloro imido-ester, it is subsequently by alkylation, preferably use the hydroxyl fluoro indole, be reflected at alkali such as salt of wormwood or sodium hydride and exist down, in polar solvent such as dimethyl formamide (DMF) or toluene, carry out, wherein preferred DMF in carry out.By using hydrogen source such as ammonium formiate, in the presence of catalyzer such as palladium carbon, the benzyl of finishing dealing with goes provide protection.

The optimum condition of second embodiment comprises, in step 1, uses nucleophilic group such as fluoro indole, in the presence of alkali such as salt of wormwood or sodium hydride, handles compound 7 and obtains compound 8.This reaction is preferably carried out in polar solvent such as DMF.Step 2 comprises with alkylating agent such as alkyl halide magnesium, handles compound 8 as methyl-magnesium-bromide or methylmagnesium-chloride under-25 ℃ to 25 ℃ low temperature.In a preferred embodiment, step 3 comprises uses superoxide, as hydrogen peroxide or Sodium peroxoborate at Lewis acid, as boron trifluoride exist following, at processing compound 9 between-25 ℃ to about 25 ℃ approximately, obtain compound 10.

During preparation indoles side chain, initial fluorochemical (be trifluoronitrobenzene in the present example) can with nucleophilic group such as methyl aceto acetate or butyl-acetoacetate reaction, then at acid or alkali, under preferred aqueous acids exists ester group is carried out decarboxylation.In step 2, compound 11 and alkoxyl group negatively charged ion such as sodium methylate or methyl alcohol, reaction obtains compound 12 in the presence of the sodium salt of alkali such as salt of wormwood or phenylcarbinol.Then, alkoxyl group or benzyloxy group are spent protective material,, in acetate, go provide protection, obtain compound 13 as pyridinium chloride or hydrogen bromide.In the step in the end, under reductive condition, preferably use reductive agent such as sodium hyposulfate or palladium carbon, cyclisation compound 13 in the presence of hydrogen source obtains the benzazolyl compounds of demand.

The present invention also provides a kind of pharmaceutical composition that comprises general formula I or II compound and pharmaceutically acceptable carrier.

The present invention also provides a kind of pharmaceutical composition that comprises general formula I or II compound and pharmaceutically acceptable carrier and a kind of anticancer or cytotoxic agent.In a preferred embodiment, described anticancer or cytotoxic agent be selected from a tetrahydroxy phenol chlorin, beta 2 integrin alpha v β 3 depressant of functions, angiostatin, tetrahydroform, Tamoxifen, Toremifene Citrate, raloxifene (a kind of selective estrogen receptor modulators), droloxifene, IDALL's former times sweet smell (iodoxifene), Magace, Anastrozole, letrozole, borazole (borazole), Exemestane, its amine of fluorine, mud Rumi spy, than catarrh amine, cyproterone acetate, goserelin acetate, leuprorelin acetate; Finasteride (finasteride), inhibitors of metalloproteinase, urokinase plasminogen activator function of receptors inhibitor, growth factor antibodies, growth factor receptor antibody as

(bevacizumab) and

(cetuximab), tyrosine kinase inhibitor, serine/threonine kinase inhibitor, methotrexate, 5 FU 5 fluorouracil, purine, neplanocin, cytosine arabinoside, Zorubicin, daunomycin, pidorubicin, idarubicin, Mitomycin-C, actinomycin D, mithramycin, cis-platinum, carbon platinum, mustargen, melphalan, Chlorambucil, Myelosan, endoxan, ifosfamide, nitrosourea, triamine sulfuric acid, vincristine(VCR), (taxol),

(Docetaxel), esperamicin (epothilone) analogue, discodermolide analogue, eleutherobin analogue, etoposide, for Buddhist nun uncle glucoside, amsacrine, topotecan hydrochloride, flavopyridols, biological response modifiers and proteinase inhibitor, as

(bortezomib).

The present invention also provides a kind of method that suppresses the protein kinase activity of growth factor receptors, and this method comprises that the Mammals kind that delivers medicine to needs treatments is with the effective compound of Formula I of arrestin kinase activity dosage.

In addition, the present invention also discloses the method for the tyrosine kinase activity that suppresses at least a growth factor receptors, comprises the Mammals kind that delivers medicine to needs treatments general formula I or the general formula I I compound with effective dose.In a preferred embodiment, described growth factor receptors is selected from VEGFR-2 or FGFR-1.

At last, the invention discloses a kind of method for the treatment of proliferative disease, comprise the Mammals kind that delivers medicine to needs treatments Compound I with effective dose.In a preferred embodiment, proliferative disease is a cancer.

Be the definition of the term that may use in the specification sheets below, unless otherwise noted, apply in the whole specification sheets separately or as the part of other groups for the initial definition of certain group or term here.

Term " alkyl " refers to the unsubstituted alkyl with 1 to 20 carbon atom of straight or branched, preferred 1 to 7 carbon atom.Statement " low alkyl group " refers to have the unsubstituted alkyl of 1 to 4 carbon atom.

Term " substituted alkyl " refers to that alkyl is by 1 to 4 substituting group.As halogen; hydroxyl; alkoxyl group; oxo; alkyloyl; aryloxy; alkanoyloxy; amino; alkylamino; virtue is amino; arylalkylamino (aralkylamino); (wherein two amino substituting groups are selected from alkyl to replace amine; aromatic base or aralkyl); alkyl amido (alkanoylamino); aromatic acylamino (aroylamino); aralkyl amido (aralkanoylamino); replace alkyl amido (alkanoylamino); it is amino to replace virtue; replace aralkyl amido (aralkanoylamino); sulfenyl; alkylthio; arylthio; aromatic alkylthio (aralkylthio); alkane thiocarbonyl group (alkylthiono); virtue thiocarbonyl group (arylthiono); aralkyl thiocarbonyl group (aralkylthiono); alkane alkylsulfonyl (alkylsulfonyl); arylsulfonyl (arylsulfonyl); sweet-smelling alkane sulfonyl (aralkylsulfonyl); sulfonamido is as SO ₂NH ₂, replace sulfonamido, nitro, cyano group, carbonyl, carbamyl, as CONH ₂, the substituted-amino formyl, as CONH-alkyl (CONHalkyl), CONH-aryl (CONHaryl), CONH-aralkyl (CONHaralkyl), or two substituting groups are arranged on nitrogen, these substituting groups are selected from alkyl, aromatic base or aralkyl; Alkoxy carbonyl, aromatic base, substituted aromatic base, guanidine radicals and heterocyclic substituent are as indyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and analogue thereof.Aforesaid, further be substituted as substituting group, will be alkyl, alkoxyl group, aromatic base or aralkyl.

Term " halogen " or " halogen " refer to fluorine, chlorine and iodine.

Term " aromatic base " refers to have the monocycle or the Bicyclic hydrocarbyl group of 1 to 6 carbon atom on ring, such as phenyl, naphthyl, biphenyl and phenylbenzene, each can both be substituted.

Term " aralkyl " refers to that an aromatic base is directly in conjunction with a last alkyl, as benzyl (phenmethyl).

Term " substituted aromatic base " refers to that an aromatic group is replaced by 1 to 4 substituting group, as alkyl; substituted alkyl; halogen; trifluoromethoxy; trifluoromethyl; hydroxyl; alkoxyl group; alkyloyl; alkanoyloxy; amino; alkylamino; virtue is amino; dialkylamino; alkyl amido; sulfenyl; alkylthio; urea groups; nitro; cyano group; carbonyl; sulfenyl; carbamyl; alkoxy carbonyl; alkane thiocarbonyl group (alkylthiono); virtue thiocarbonyl group (arylthiono); aralkyl sulfonamido (arylsulfonylamine); sulfonic acid; alkane alkylsulfonyl (alkylsulfonyl); sulfonamido; aryloxy and analogue.Substituting group further can be replaced by hydroxyl, alkyl, alkoxyl group, aromatic base, substituted aromatic base, substituted alkyl or aralkyl.

Term " heteroaryl " refers to any substituted aromatic base, as the monocycle of 4-7 unit, and the dicyclo of 7-11 unit, or three ring systems of 10-15 unit, it has the ring of at least one heteroatoms and at least one carbon atoms, as pyrimidine, tetrazolium, indazole, indoles.

Term " alkenyl " refers to have the straight or branched alkyl of 2 to 20 carbon atoms, preferred 2 to 15 carbon atoms, and most preferably 28 carbon atoms have 1 to 4 two key simultaneously.

Term " substituted alkenyl base " refers to that kiki alkenyl group is replaced by 1 to 2 substituting group, as halogen, hydroxyl, alkoxyl group, alkyloyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkyl amido, sulfenyl, alkylthio, alkane thiocarbonyl group (alkylthiono), alkane alkylsulfonyl (alkylsulfonyl), sulfonamido, nitro, cyano group, carbonyl, carbamyl, substituted-amino formyl, guanidine radicals, indyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and analogue thereof.

Term " alkynyl " refers to have the straight or branched alkyl of 2 to 20 carbon atoms, preferred 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms have 1 to 4 triple bond simultaneously.

Term " substituted alkynyl " refers to that alkynyl group is replaced by 1 to 4 substituting group, as halogen, hydroxyl, alkoxyl group, alkyloyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkyl amido, sulfenyl, alkylthio, alkane thiocarbonyl group (alkylthiono), alkane alkylsulfonyl (alkylsulfonyl), sulfonamido, nitro, cyano group, carbonyl, carbamyl, substituted-amino formyl, guanidine radicals and heterogeneous ring compound, for example imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and analogue.

Term " cycloalkyl " refers to the stable hydrocarbon ring system that replaces arbitrarily preferably comprise 1 to 3 ring, and each ring has 3 to 7 carbon atoms, and it can be further and undersaturated C ₃-C ₇Carbocyclic fused.Group for example comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group (cycloctyl), ring decyl cyclodecyl), cyclo-dodecyl (cyclododecyl) and diamantane.The substituting group of enumerating comprises the alkyl of one or more foregoing descriptions, or the alkyl substituent of one or more foregoing description.

Term " heterocycle ", " heterocyclic " and " heterocyclo " refers to that one is substituted arbitrarily, fully saturated or undersaturated, cyclic group fragrance or non-fragrance, as it is 4 to 7 yuan monocycle, three ring systems of the dicyclo of 7-11 unit or 10-15 unit, it comprises at least one heteroatoms in the ring of at least one carbon atoms.Each ring that contains a heteroatomic heterocyclic group can have 1,2 or 3 heteroatoms, and these heteroatomss are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, and wherein, nitrogen and sulfur heteroatom can be at random oxidized, and nitrogen heteroatom also can be arbitrarily by quaternized.Heterocyclic group can be incorporated on any heteroatoms or the carbon atom.

Monocyclic heterocyclic group for example comprises pyrrolidyl, pyrryl, pyrazolyl, oxygen Dan base (oxetanyl), pyrazolinyl, imidazolyl, imidazolinyl (imidazolinyl), imidazolidyl (imidazolidinyl) oxazolyl, oxazolidinyl (oxazolidinyl) isoxazoline-3-yl (isoxazolinyl) isoxazolyl, thiazolyl, thiadiazolyl group, thiazolinyl (thiazolidinyl), isothiazole (isothiazolyl), isothiazoline base (isothiazolidinyl), furyl, tetrahydrofuran base, thienyl oxadiazine base, piperidyl, piperazinyl, 2-oxo piperazinyl (2-oxopiperazinyl), 2-oxo-piperidine base (2-oxopiperidinyl), 2-oxo pyrrolinyl (2-oxopyrrolidinyl), 2-oxo azepine base (2-oxazepinyl), the azepine base, 4-piperidino-(1-position only) (4-piperidonyl), pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, THP trtrahydropyranyl, morpholinyl, thio-morpholinyl (thiamorpholinyl), thiomorpholine sulfoxide (thiamorpholinyl sulfoxide), thiomorpholine sulfone (thiamorpholinylsulfone), 1,3-dioxolane and tetrahydrochysene-1,1-dioxo thienyl diox, isothiazoline base (isothiazolidinyl), thietanyl, thiirane, triazinyl and triazolyl and analogue thereof

The heterocyclic group of dicyclo for example comprises 2,3-dihydro-2-oxo--1H-indyl, benzothiazolyl benzoxazolyl, benzothienyl, quinuclidinyl, quinolyl, quinolyl-N-oxide compound, tetrahydroisoquinoline (tetrahydroisoquinolinyl), isoquinolyl (isoquinolinyl), benzimidazolyl-(benzimidazolyl), benzopyranyl, the indolizine base, benzopyranyl, the chromone base, the tonka bean camphor base, the cinnolines base, quinoxalinyl, indazolyl, pyrrolopyridinyl, furans pyridyl (furopyridinyl) is (as furans [2,3-c] pyridyl, furans [3,1-b] pyridyl or furans [2,3-b] pyridyl), dihydro-iso indolyl, thiazoline quinoline base is as 3,4-dihydro-4-oxo-thiazolinyl), the benzisothiazole base, benzisoxazolyl, the benzodiazine base, benzimidazolyl-(benzimidazolyl), benzofuryl, benzimidazole thiophanate is for pyranyl, the benzotriazole base, benzpyrazolyl, the dihydrobenzopyrans base, the dihydrobenzo thienyl, dihydrobenzo sulfo-pyrans (dihydrobenzothiopyranyl), dihydrobenzo sulfo-pyrans sulfone (dihydrobenzothiopyranyl sulfone), dihydrobenzopyrans base (dihydrobenzopyranyl), indolinyl, indyl, isochroman base (isochromanyl), iso-dihydro-indole-group, 1, the 5-phthalazinyl, 2, the 3-phthalazinyl, 3,4-(methylenedioxy) benzyl, purine radicals, pyridopyridine, thiazolinyl, tetrahydric quinoline group, the thienofuran base, the thienopyridine base, thienothiophene base and analogue thereof.

Substituting group for example comprises the alkyl or the aralkyl of one or more foregoing descriptions, or the alkyl substituent of one or more foregoing descriptions.Also comprise less heterocycle, as epoxide and ethylene imine.

Term " heteroatoms " comprises oxygen, sulphur and nitrogen.

The compound of general formula I also can form salt, and it is also at the present invention's row.Preferably pharmaceutically acceptable (as, nontoxic, physiologically acceptable) salt, although other salt are separating, also are being useful during the purifying The compounds of this invention.

The compound of general formula I also can with basic metal, as sodium, potassium, lithium,,,,, form salt as arginine, Methionin and analogue as dicyclo hexylamine, Tributylamine, pyrimidine and amino acid with organic bases as calcium, magnesium with alkaline-earth metal.These salt can make with methods known in the art.

The compound of general formula I also can form salt with various organic and mineral acids.These salt comprise the salt (as nitrate, phosphoric acid salt, borate, tartrate, Citrate trianion, succinate, toluene hydrochlorate, ascorbate salt, salicylate and analogue) that forms with hydrogenchloride, hydrogen bromide, methylsulfonic acid, sulfuric acid, acetate, trifluoroacetic acid, oxalic acid, toxilic acid, Phenylsulfonic acid, toluenesulphonic acids and other various acid.These salt can make with method known to those skilled in the art.

In addition, also can form zwitter-ion (" inner salt ").

The steric isomer of all The compounds of this invention is all paid attention to, or with the form of mixture or with the form of pure compound or basic pure compound.Among the present invention, the definition of compound is comprised all possible steric isomer and their mixture.The compound and the optically active isomer that particularly comprise racemic form with specific activity.Can pass through physical method, obtain racemic modification as fractional crystallization, separation or crystallization diastereomer derivative or the isolating method of chiral column chromatography.

Each optically active isomer carries out crystallization by conventional method again as forming salt with an optically active acid, obtains each optically active isomer from racemic modification.

Compound of Formula I also can have the prodrug form.It is any that will to transform and provide the compound of biologically active agent (as compound of Formula I) in vivo be the prodrug that comprises within the scope of the invention and the novelty.

Various forms of prodrugs are well-known in the art.The example of these prodrug derivatives, ask for an interview:

A) " design of prodrug " (Design of Prodruss), H.Bundgaard compiles (Elsevier, 1985) and Enzymology method (Methods inEnzymolooy), Vol.42, p.309-396, K.Widder, et al. (Acamedic Press, 1985);

B) " medicinal design and exploitation textbook " (A Textbook of Drug Design andDevelopment) Krosgaard-Larsen and H.Bundgaard compile, the 5th chapter, the design of ＂ prodrug and application (Design and Applicaition of Prodrugs) ＂ H.Bundgaard compile p.113-191 (1991);

C) H.Bundgaard, up-to-date useful for drug delivery summary (Advanced Drugs DeliveryReviews), 8,1-38 (1992).

What further should know is that the solvate (as hydrate) of compound of Formula I also is the row in the present invention.The method of solvation is well-known in the art.

Therefore the further content according to the present invention the invention provides know clearly compound of Formula I or its pharmacy acceptable salt and is used for producing the application that angiogenesis inhibitor and/or vascular permeability reduce the medicine of effect in preparation in Mammals such as human body.

The further characteristics according to the present invention, the invention provides a kind of in needs treatments Mammals such as human body in produce the method that angiogenesis inhibitor and/or vascular permeability reduce effect, this method comprises compound of Formula I defined in this or its pharmacy acceptable salt that described animal is given effective dose.

Compound described here also can suppress other receptor tyrosine kinases, comprises HER1 and HER2, therefore can be used for treating proliferative disorders, as ox-hide moss and cancer.Show that the HER1 receptor kinase comprises in lung cancer in non-cellule type, intestinal cancer and the breast cancer and expressed and activate in many solid tumors.Similarly, shown the HER2 receptor kinase in the chest cancer, in ovarian cancer, lung cancer and the cancer of the stomach by overexpression.Can reduce HER2 acceptor abundance or suppress and before clinical He in the clinical study, demonstrate antitumor efficacy by the monoclonal antibody of HER1 signal conduction.Therefore, can predict that the kinase whose inhibitor of HER1 and HER2 relies on the tumour of these two kinds of acceptors or the signal of one of them conduction with powerful to treatment.The ability that these compounds suppress HER1 has further increased its application as angiogenesis inhibitor reagent.Document and the bibliography quoted of face as follows.Cobleigh，M.A.，Vogel，C.L.，Tripathy，D.，Robert，N.J.，Scholl，S.，Fehrenbacher，L.，Wolter，J.M.，Paton，V.，Shak，S.，Lieberman，G.，and?Slamon，D.J.，“Multinational?study?of?the?efficacy?andsafety?of?humanized?anti-HER2?monoclonal?antibody?in?women?who?haveHER2-overexpressing?metastatic?breast?cancer?that?has?progressed?afterchemotherapy?for?metastatic?disease”，J.of?Clin.Oncol.17(9)，p.2639-2648(1999)；Baselga，J.，Pfister，D.，Cooper，M.R.，Cohen，R.，Burtness，B.，Bos，M.，D′Andrea，G.，Seidman，A.，Norton，L.，Gunnett，K.，Falcey，J.，Anderson，V.，Waksal，H.，and?Mendelsohn，J.，“Phase?Istudies?of?anti-epidermal?growth?facter?receptor?chimeric?antibody?C225alone?and?in?combination?with?cisplatin”，J.Clin.Oncol.18(4)，p.904-914(2000)。

The penetrating reduction effect of the anti proliferative of Miao Shuing, angiogenesis inhibitor and/or blood vessel methods of treatment can be used as single methods of treatment use before this, except The compounds of this invention, also can comprise one or more other materials and/or methods of treatment.This combination therapy can realize by the method for while, priority and separate administration.The compounds of this invention also can comprise that radiotherapy uses with known anticancer and cytotoxic agent and methods of treatment.If make up a prescription with fixed dosage, this combined prod can be equipped with the The compounds of this invention in the dosage range that describes below and other forms of pharmacologically active agents of the dosage range ratified.When being not suitable for using combination formula, the compound of general formula I can use known anticancer and cytotoxic agent and methods of treatment comprise radiotherapy after use.

In the medical science oncology, it is normal thing that the various methods of treatment of integrated use is treated each cancer patients.In the medical science oncology, except previously described anti proliferative and angiogenesis inhibitor and/or the penetrating reduction effect of blood vessel methods of treatment, the additive method of this kind comprehensive treatment can be operation, radiotherapy or chemotherapy.This kind chemotherapy can comprise the therapeutical agent that three classes are main.

(i) anti-angiogenic agent, as a tetrahydroxy phenol chlorin, beta 2 integrin alpha v β 3 depressant of functions, angiostatin, tetrahydroform, it is with the different machining function of definition above.

(ii) cytostatic agent, as antiestrogen (as Tamoxifen, Toremifene Citrate, raloxifene (a kind of selective estrogen receptor modulators), droloxifene, IDALL's former times sweet smell (iodoxifene)), progestogen (as Magace), aromatase inhibitor is (as Anastrozole, letrozole, borazole (borazole), Exemestane), antihormone, antiprogestin, the antiandrogen material is (as its amine of fluorine, mud Rumi spy, than catarrh amine, cyproterone acetate), luteinising hormone-releasing hormo (LHRH) agonist and antagonist are (as goserelin acetate, leuprorelin acetate), testosterone 5 α-dihydro reductase inhibitor (as finasteride), farnesyl tranfering enzyme inhibitor, (these somatomedins comprise as EGF for anti-invasion agent (as inhibitors of metalloproteinase such as Marimastat and urokinase plasminogen activator function of receptors inhibitor) and somatomedin depressant of functions, FGF, platelet derived growth factor and pHGF, and inhibitor comprises growth factor antibodies, growth factor receptor antibody as

(bevacizumab) and

(cetuximab), tyrosine kinase inhibitor and serine/threonine kinase inhibitor); With

(iii) anti proliferative antitumor drug and composition thereof are used for the medical science oncology, as antimetabolite (as antifol such as methotrexate, fluorine pyrimidine such as 5 FU 5 fluorouracil, purine and neplanocin, cytosine arabinoside); Embedded antitumor antibiotics (as anthracycline antibiotics such as Zorubicin, daunomycin, pidorubicin, idarubicin, Mitomycin-C, actinomycin D, mithramycin); Platinum derivatives (as cis-platinum, carbon platinum); Alkylating agent is (as mustargen, melphalan, Chlorambucil, Myelosan, endoxan, ifosfamide, nitrosourea, triamine sulfuric acid; Antimitotic agent (as vinca alkaloids such as vincristine(VCR) and Japanese yew class medicine (taxoids) as

(taxol),

(Docetaxel) and new microtubule agent newer microbtubuleagents such as esperamicin (epothilone) analogue, discodermolide analogue and eleutherobin analogue); Topoisomerase enzyme inhibitor (as epipodophyllotoxins such as etoposide with for Buddhist nun uncle glucoside, amsacrine, topotecan hydrochloride); Cell cycle inhibitor (as eflavopyridols); Biological respinse adjust agent and proteasome inhibitor as

(bortezomib).

As mentioned above, formula I compound of the present invention is significant because of its anti-angiogenesis inhibitor and/or the penetrating reduction effect of blood vessel.Compound of the present invention is expected to be applied to the various diseases situation, comprise cancer, diabetes, ox-hide moss, sacroiliitis rheumatic arthritis, Kaposi sarcoma, vascular tumor, obesity, acute and chronic nephropathy, atheroma, arterial restenosis disease, autoimmune disease, acute inflammation and with relevant disease of eye such as the diabetic retinopathy of retina propagation.

More in particular, formula I compound can be used for the treatment of various cancers, includes, but is not limited to:

-cancer, bladder cancer, breast cancer, intestinal cancer, kidney, liver cancer, lung cancer comprises small cell lung cancer, esophagus cancer, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, uterus carcinoma, thyroid carcinoma, prostate cancer and skin carcinoma comprise squamous cell carcinoma;

-lymphatic system hematopoiesis tumour comprises leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B cell lymphoma, t cell lymphoma, hodgkin's lymphoma, non Hodgkin lymphoma, hair cell lymphoma and Burkitt lymphoma;

-myeloid lineage hematopoiesis tumour comprises acute and chronic lymphocytic leukemia, myelodysplastic syndrome and promyelocytic leukemia;

-mesenchymal cell tumour comprises fibrosarcoma and rhabdosarcoma;

-maincenter and peripheral nervous system tumour comprise astrocytoma, neuroblastoma, neurospongioma and schwannoma; With

-other tumours comprise melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum pigment cancer, keratoctanthoma, thyroid follcular carcinoma and Kaposi sarcoma.

Because kinases has key effect at large in regulating cell propagation, inhibitor can be as the reversibility cytostatic agent, it can be used for the treatment of any is the disease of feature with cellular abnormality propagation, as the restenosis after benign prostatic hyperplasia, familial adenomatous polyp, neurofibroma, arteriosclerosis, pulmonary fibrosis, sacroiliitis, ox-hide moss, glomerulonephritis, angiopoiesis or the vascular surgery, hypertrophic cicatrization, inflammatory bowel, transplant rejection, endotoxin shock and fungi infestation.

Formula I compound can cause or suppress apoptosis (apoptosis).This apoptosis response is unusual in various human diseasess.Formula I compound, as apoptotic conditioning agent, can be used for the treatment of cancer (including, but are not limited to type mentioned above), virus infection (includes, but are not limited to simplexvirus, poxvirus, epstein-Barr virus, sindbis alphavirus and adenovirus), sick the sending out of acquired immune deficiency syndrome (AIDS) of prevention HIV infected individuals, autoimmune disorders (includes, but are not limited to systemic lupus erythematous, the glomerulonephritis that autoimmunity is regulated, rheumatic arthritis, the ox-hide moss, diseases associated with inflammation, with the autoimmune diabetes, the neurodegeneration obstacle (includes, but are not limited to Alzheimer (family name) disease, the dementia relevant with acquired immune deficiency syndrome (AIDS), Parkinson's disease, amyotrophic lateral sclerosis (spinal cord) lateral sclerosis, retinitis pigmentosa, Duchenne-Arandisease and cerebellum degeneration disease), myelodysplastic syndrome, aplastic anemia, the ischemia injury that myocardial infarction is followed, apoplexy and reperfusion injury, arrhythmia, arteriosclerosis, the hepatic diseases that toxin brings out or alcohol is relevant, hemopathy (including, but are not limited to chronic anaemia and aplastic anemia), musculoskeletal system degeneration disease (including, but are not limited to osteoporosis and sacroiliitis), the Asprin allergic rhinitis, cystic fibrosis, multiple sclerosis, ephrosis and pain caused by cancer.

Formula I compound can be used for the treatment of the tumour of the tyrosine kinase activity with high incidence especially, as colon, lung and pancreatic neoplasm.By the composition (or uniting use) in order to The compounds of this invention, mammalian hosts tumour morbidity has reduced.

Formula I compound also can be used for treating the disease except that cancer, and these diseases and somatomedin are relevant with the signal transduction path of FGFR-1 effect as VEGFR-2.

The compounds of this invention also can be mixed with medicament with pharmaceutical carrier or thinner, with oral, intravenous injection, hypodermic mode administration.Pharmaceutical composition can be according to demand administering mode formulated according to ordinary method with solid-state or liquid vehicle, thinner and additive.Oral, compound can be with tablet, capsule, particulate, powder and similar form administration.The mode administration that this compound also can use the carrier of suitable this administering mode to make suspension.The dosage of this compound can about 0.05-300mg/kg/ days, preferably are less than 200mg/kg/ days, once take or divide and take for 2-4 time.

The preparation method

Certain compounds of formula I can be according to following proposal and those skilled in the art's knowledge preparation.

Unless otherwise noted, all temperature all refer to degree centigrade (℃).Preparation type anti-phase (RP) HPLC purifying carries out in C18 anti-phase (RP) post YMC S5 ODS post, uses to contain 90% aqueous methanol wash-out of 1% TFA damping fluid, and monitors under the 220nm wavelength.For analytical HPLC, use 0.2% phosphoric acid to substitute TFA.All synthetic compounds use proton magnetic resonance (PMR) (NMR) and liquid chromatograph mass spectrography (LC/MS) method to identify at least.Unless otherwise noted, progressively set up in the process, with organic extract sal epsom (MgSO in reaction ₄) drying.

Following abbreviation is used for the often reagent of use.Et ₂O: diethyl ether; Na ₂SO ₄: sodium sulfate; HCl: hydrochloric acid; NaOH sodium hydroxide; NaCl: sodium-chlor; Pd/C: palladium charcoal; K ₂HPO ₄: dipotassium hydrogen phosphate; K ₂CO ₃: salt of wormwood; NaHCO ₃: sodium bicarbonate; LiOH: lithium hydroxide; RT: room temperature; TFA: trifluoroacetic acid; H: hour.

Step 1

The compound of PCT publication number WO 0071129 is converted into ether (etherificate) in 4 sites, as handling with phenates or methylate or ethanol anion.

Step 2

Use alkylating agent then, handle compound 1 at low temperatures, obtain compound 2 as methyl-magnesium-bromide or methylmagnesium-chloride.

Step 3

Use superoxide, under Lewis acid such as boron trifluoride, handle compound 2, obtain phenolic compound 3, handle and under cold condition, carry out as hydrogen peroxide or Sodium peroxoborate.

Step 4

With electrophilic reagent such as bromotoluene, in the presence of alkali such as NaH, in 0-80 ℃ of temperature range, the phenolic group group in the compound 3 is carried out alkanisation, obtain compound 4.

Step 5

Use a kind of acid, the compound 4 as NaH hydrolysis this programme under the temperature that has increased obtains compound 5.

Step 6

The compound 5 of this programme is converted into compound 6; at first be converted into chloro imido-ester as described above; chloro imido-ester to obtaining again; use the hydroxyl fluoro indole; in the presence of alkali such as salt of wormwood; in polar solvent such as dimethyl formamide, carry out alkylating and obtain protected compound 6.

Scheme 2

Step 1

The compound of PCT publication number WO 0071129, wherein X ₁Be halogen such as chlorine, can and nucleophilic group, react in the presence of alkali such as salt of wormwood as fluoro indole and to obtain compound 8, be reflected at polar solvent, as carrying out in the dimethyl formamide.

Step 2

Use alkylating agent such as methyl-magnesium-bromide or methylmagnesium-chloride under cold condition, to handle compound 8 then, obtain compound 9.

Step 3

Compound 9 in the presence of Lewis acid such as boron trifluoride, is used superoxide then, obtains phenolic compound 10 as hydrogen peroxide or Sodium peroxoborate processing.

Scheme 3

Step 1

With fluorochemical,,, in the presence of acid or alkali, ester group is carried out decarboxylation again and generate compound 11 as the methyl aceto acetate reaction as trifluoronitrobenzene and nucleophilic reagent.

Step 2

Compound 11 can obtain compound 12 with the sodium salt reaction of alkoxyl group negatively charged ion such as sodium methylate or phenylcarbinol.

Step 3

In acetate, use reagent such as pyridinium chloride or hydrogen bromide to handle the compound 12 of this programme, and finish the provide protection of going, obtain compound 13 compound 12 alkoxyl groups.

Step 4

Compound 13 then can be under reductive condition, and as V-Brite B palladium carbon, cyclisation ` compound 13 in the presence of hydrogen obtains the indole derivatives of formula 14.

Can in the presence of hydrogen source such as ammonium formiate, handle compound 12 and directly obtain compound 14 with palladium carbon.

Embodiment 1

4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen connection)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-6-alcohol also

A.4-chloro-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester also

To place the 4-hydroxy-5-methyl base pyrrolo-[2 of toluene (800mL), 1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester (60.0g, 271.2mmol the preparation method sees WO 0071129), phosphoryl chloride (30.3mL, 325.4mmol) and di-isopropyl hexylamine (37.7mL, 217mmol) mixture reflux 18h, cool to room temperature then in argon.Enriched mixture in rotary evaporator (rotovap), residue dilutes with methylene dichloride (1000mL) and sodium bicarbonate solution (300mL).The mixture that obtains at room temperature stirs 10min.Organic layer with the cool brine washing is separated to concentrates in drying, the vacuum.Thick material silica-gel plate chromatography purification with the methylene dichloride wash-out, obtains the yellow solid mixture (64.8g, 99%) of demand.

B.4-oxyethyl group-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester also

(under 0 ℃ of condition, (115.2mmol), the dropping time surpasses 20min for 21%w/w, 43mL to drip the ethanol that contains sodium ethylate in argon for 23g, tetrahydrofuran (THF) 96mmol) (0.6L) solution to present embodiment mixture A.Be reflected at 0 ℃ and stir 1h down, with the ethyl acetate dilution, with ammonium chloride solution and salt water washing.Dry, concentrated organic layer, residue silica-gel plate chromatography purification with methylene dichloride and the hexane wash-out that contains 50% ethyl acetate, obtains the white solid mixture ((23.5g, 98%) of demand.LC/MS；(M+H) ⁺＝250.17

C.2-(4-oxyethyl group-5-methylpyrrole is [2,1-f] [1,2,4] triazine-6-yl also)-propan-2-ol

To THF (2.5L) solution of the compd B of present embodiment, under 0 ℃, (3M is in Et slowly to add methyl-magnesium-bromide with funnel ₂Among the O, 360mL, 1.08mol).Temperature can be brought up to room temperature, continue to stir 4h.Use the ammonium chloride solution termination reaction, use the ethyl acetate extracting.Organic layer washs with sodium chloride solution, and drying obtains the yellow solid compound (78g, 100%) of demand.LC/MS；(M+H) ⁺＝236.1

D.4-oxyethyl group-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-alcohol also

With hydrogen peroxide (30%, 10.3mL, 178.5mmol) and boron trifluoride diethyl etherate (271.4mL, mixture 2.14mol) stirs down 30min at 0 ℃.Be cooled to-20 ℃ then, (temperature of reaction mixture reaches-3 ℃ for 30g, methylene dichloride 129.5mmol) (1.45L) solution, and then is cooled to-40 ℃ to add the present embodiment Compound C down at-15 ℃.In this mixture, stir and add saturated sodium bisulfite solution.The ethyl acetate extracting of the mixture of gained, drying concentrates in the vacuum, obtains Compound D (26g, 76%).LC/MS；(M+H) ⁺＝194.2

E.6-benzyloxy-4-oxyethyl group-5-methylpyrrole [2,1-f] [1,2,4] triazine also

To contain the present embodiment Compound D (1g, 5.2mmol), bromotoluene (0.62mL, 5.2mmol) and salt of wormwood (2.1g, 15.5mmol) dimethyl formamide of mixture (10mL) at room temperature stirs 12h.Reactant dilutes with ethyl acetate, water, 10% lithium chloride solution and salt water washing.With organic layer Na ₂SO ₄Drying concentrates in the vacuum, obtains yellow solid compd E (lg), and it need not to be further purified and just is used for next step.

F.6-benzyloxy-5-methylpyrrole [2,1-f] [1,2,4] triazine-4-alcohol also

The compd E (90g, thick) of present embodiment is put into 1N HCl (600mL) and ethanol (800mL), reflux 4h.Solid precipitation filters and collects, and with mixed solvent (water/ethanol/methyl alcohol=4/4/2) washing, drying obtains shallow white solid, obtains white solid compound F 17-hydroxy-corticosterone (65g) with washed with dichloromethane again.LC/MS；(M+H) ⁺＝256.2

G.6-benzyloxy-4-chloro-5-methylpyrrole [2,1-f] [1,2,4] triazine also

To contain the present embodiment compound F 17-hydroxy-corticosterone (10g, 39.2mmol), phosphoryl chloride (4.4mL, 47.1mmol) and the di-isopropyl hexylamine (5.5mL, toluene 31.4mmol) (150mL) stirs down 2h at 85 ℃, add again then phosphoryl chloride (1.1mL, 11.8mmol).Behind the 2h, add once more phosphoryl chloride (1.1mL, 11.8mmol).Reaction mixture continues to stir 1h down at 85 ℃, concentrates then.Residue melts in methylene dichloride, and with cold sodium hydrogen carbonate solution washing, drying concentrates in the vacuum.Thick material silica-gel plate chromatography purification with the methylene dichloride wash-out, obtains yellow solid compound G (9.9g, 93%).

H.6-benzyloxy-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen connection)-5-methylpyrrole [2,1f] [1,2,4] triazine also

(6.47g, dimethyl formamide 39.2mmol) (100mL) solution outgases with argon, is cooled to-20 ℃ then with 4-fluoro-2-Methyl-1H-indole-5-hydroxyl of embodiment 2.Add a sodium hydride (60%, in oil, 1.57g, 39.2mmol).Stir above permission of 30min reaction mixture is brought up to 0 ℃, and then be cooled to-20 ℃, add dimethyl formamide (100mL) solution of a present embodiment compound G.Temperature of reaction is raised to room temperature.Behind the 30min, mixture is with 1N HCl (200mL) acidifying, and with ethyl acetate (1.8L) dilution, (pH=2 is 200mL) with NaCI solution (0.4L) washing for the lithium chloride solution with 10% (0.4L x 2), 1N NaOH solution (0.3L x 2), damping fluid.Dry organic layer concentrates in the vacuum, obtains brown solid chemical compound H (15g, 95%).LC/MS；(M+H) ⁺＝403.1

I.4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen connection)-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-alcohol also

At room temperature, will contain the present embodiment compound H (15g, 37.3mmol), ammonium formiate (12g, 190mmol) and Pd/C (10%, 1.5g) dimethyl formamide of mixture (100mL) stirs 2h.With (diatomite) filtering mixt, filtrate is diluted with ethyl acetate, uses 10% lithium chloride solution (2X), 5% sodium hydrogen carbonate solution (2X) and salt water washing successively.Organic layer Na ₂SO ₄Drying concentrates in the vacuum, obtains the light brown solid, uses washed with dichloromethane, obtains albescent title compound (7.8g, 64%).MS：[M+H] ⁺＝313.2。 ¹HNMR(CDCl ₃)：δ?2.44(s，3H)，2.51(s，3H)，6.31(s，1H)，6.95(dd，1H)，7.07(d，1H，J＝8.8Hz)，7.38(s，1H)，7.78(s，1H)。

Embodiment 1 also can prepare with the replacement program of following description.

A-1.4-chloro-5-methyl-pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester

Add in the reactor of 10L 4-hydroxy-5-methyl base-pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester (155.1g, 0.7mol) and toluene (2.7L).Add then phosphoryl chloride (128.8g, 78mL, 0.84mol), add again the di-isopropyl hexylamine (94.2g, 127mL, 0.7mol).At room temperature stirred reaction mixture 5min, reflux 20h then.HPLC analyzes and shows the initial substance completely dissolve.Reaction mixture is cooled to 0 ℃ then, adds cold K with certain speed ₂HPO ₄Solution (527g K ₂HPO ₄Be dissolved in 2.4L water), adding speed should be with the temperature maintenance in the reaction mixture below 5 ℃.The final pH value of mixture is 8.Mixture stirs 20min earlier between 0-5 ℃ then, at room temperature stirs 1h again.Separate organic layer, use K ₂HPO ₄Solution (85g is in 405mL water) and water (345mL) washing are filtered then, concentrate in the vacuum, begin precipitation until yellow solid.Add dimethyl formamide (1L), remove remaining toluene (bath temperature=38 ℃, pressure=9Torr) in a vacuum.After concentrating, can see about 4% toluene by the HPLC analysis.

J.4-(4-fluoro-2-methyl-IH-indoles-5-base oxygen connection)-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester also

The residue of preceding step A-1 is transferred in the reactor of a 10L, added dimethyl formamide (1.1L), add K again ₂CO ₃(276g, 2.1mol) and 4-fluoro-2-Methyl-1H-indole-5-hydroxyl (109.5g, 0.7mol).Stirred reaction mixture 16h is cooled to 0 ℃ then at ambient temperature.Add entry (2.0L) and ethyl acetate (2L) with certain speed, adding speed should be with the temperature maintenance in the reaction mixture below 20 ℃.Phase-splitting then, water ethyl acetate (2L) extracting.Mix organic extract water (2L), 10% moisture LiCl (2L) and water (2L) washing.Add toluene (1L) then, concentrate organic extract in the vacuum.Add toluene (500mL) again, mixture concentrates in the vacuum once more.LC/MS；(M+H) ⁺＝369.4. ¹HNMR(CDCl3)：δ1.41(t，3H，J＝7.15Hz)，2.45(s，3H)，2.87(s，3H)，4.39(q，2H，J＝7.15Hz)，6.34(s，1H)，6.98(dd，1H)，7.08(d，1H，J＝8.25Hz)，7.90(s，1H)，8.15(s，1H)。

K.2-[4-(4-fluoro-2-methyl-IH-indoles-5-base oxygen connection)-5-methyl-pyrrolo-[2,1-f] [1,2,4] triazine-6-yl]-propan-2-ol

The residue of preceding step (step J) is transferred in the reactor of a 10L, and the toluene that adds capacity makes total reaction volume reach 1.1L.Add THF (1.1L) then, add LiCl (140g) again, reaction mixture is cooled to 0 ℃.Add methyl-magnesium-bromide [1.4M is in toluene, THF (75:25), among the 2.1L, 2.8mol] with certain speed, adding speed should be with the temperature maintenance in the reaction mixture below 5 ℃, total about 2h of joining day.Reaction mixture stirs 2h down at 0 ℃ again, above in the time of 3h temperature is being brought up to 15 ℃ then, and at this moment HPLC analyzes and still can see 5% initial substance.Reaction mixture is cooled to 5 ℃ once more, adds the methyl-magnesium-bromide of 100mL again, with mixture restir 1.5h.Add ethyl acetate (1.5L and 15% NH internal temperature is maintained speed below 5 ℃ then ₄Cl (3.2L) solution and).Carry out layering then, water ethyl acetate (2L) extracting.Mix organic layer with 15% NH ₄Cl (2x 2L) and water (2L) washing, the concentrated unformed yellow solid product that obtains demand in the vacuum.Thick substance dissolves utilizes water-bath (T=37 ℃) to help dissolving in methylene dichloride (5L).Make solution pass through the silicagel pad (400g) of a weak point then, wash with the ethyl acetate/dichloromethane (1.2L) of methylene dichloride (7L) and 5%.The evaporation filtrate obtains shallow white solid, adds ethyl acetate (1.2L).The soup compound that obtains is transferred in the reactor of 10L, after stirring 2h under 50 ℃, obtained limpid solution.Solution is cooled to envrionment temperature, produces white precipitate.Add heptane (2.6L) then, mixture at room temperature stirs 20h.The solid that filtration obtains, with heptane (1L) washing, under 50 ℃, drying under reduced pressure 24h.Obtain also [2,1-f] [1,2,4] triazine-6-yl of white solid 2-[4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen connection)-5-methylpyrrole]-propan-2-ol (186g, 75%, surpassed for 3 steps).LC/MS；(M+H) ⁺＝355.4

I-1.4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen connection)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-6-alcohol also

Under 0 ℃, to BF ₃OEt ₂(120mL adds H in methylene dichloride 0.948mol) (200mL) solution ₂O ₂(50% aqueous solution, 4.6mL, 0.079mol).Reaction mixture stirs 30min down at 0 ℃, is cooled to-20 ℃ then.In separating flask, preceding step is obtained also [2,1-f] [1 of 2-[4-(4-fluoro-2-methyl-IH-indoles-5-base oxygen connection)-5-methylpyrrole, 2,4] triazine-6-yl]-(20g 0.0564mol) is dissolved in the methylene dichloride (400mL) propane-2-alcohol, utilizes indirect heating to reach dissolving fully.By a sleeve pipe solution is joined rapidly in the peroxide solutions (joining day=20min).Add fashionable temperature of reaction between-15--25 ℃, after adding finishes, temperature of reaction is risen to-15 ℃, and keep this temperature 40min again.Add Na ₂SO ₃(two kinds of reagent are all to add the speed of temperature maintenance under 0 ℃ for 33% the aqueous solution, 300mL) termination reaction mixture for (200mL, 20% aqueous solution) and thanomin.Remove cryostat, reaction mixture stirs 2h, injects separating funnel then.Carry out layering, water usefulness, ethyl acetate (100mL) extracting mixes organic layer with 5% aqueous citric acid (100mL), 10% moisture NaHCO ₃(100mL), the washing of water (2 x 100mL) and salt solution (100mL), drying is filtered, and concentrates in the vacuum, obtains orange foam.Thick material is filled in one

On the post, as weighting agent, post is with 30% ethyl acetate/heptane wash-out with tetrahydrofuran (THF).Collection contains product that part of of demand, concentrates in the vacuum, then recrystallization from ethyl acetate/heptane. and collect solid, use heptane wash, obtain the shallow white solid product (9.1g, 52%) of demand.Filtration product concentrates in a vacuum, purifying on the silica gel, and the ethyl acetate/heptane with 40% obtains other 2.5g (14%) requirement product as eluant.4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen the connection)-5-methylpyrrole also ultimate production of [2,1-f] [1,2,4] triazine-6-alcohol is 11.6g, 66%.

Reversed-phase HPLC: 3.75min (YMC S5 ODS post 4.6 x 50mm, 10-90% aqueous methanol surpass 4min and contain 0.2% phosphoric acid, and flow velocity 4mL/min detects at 220nm).LC/MS；(M+H) ⁺＝313.2。

Embodiment 2

4-fluoro-2-Methyl-1H-indole-5-alcohol

A.1-(2,3-two fluoro-6-oil of mirbane)-third-2-ketone

With tert.-butoxy potassium (570.6g, 5.082mol) and tetrahydrofuran (THF) (2L) join in the reactor of 10L.Start unsettled stirring, the suspension that obtains be cooled to 11 ℃, add then methyl aceto acetate (668mL, 5.082mol).The joining day of methyl aceto acetate needs 1h, can observe exothermic phenomenon.Control adding speed is so that the temperature in the reactor is no more than 25 ℃.The mixture that obtains becomes evenly, and color is light yellow.After interpolation was finished, reaction mixture was cooled to 10-25 ℃, and 1,2, (2.259mol) form with tetrahydrofuran (THF) (1L) solution is added drop-wise in the reaction mixture 3-trifluoronitrobenzene for 260mL, 600g, and this needs 35min, can observe exothermic phenomenon.The control rate of addition is so that the temperature in the reactor is no more than 21 ℃.After being added dropwise to complete, the brown reaction mixture that obtains is heated to room temperature, and stirs 2.5h, in this temperature, LC analyzes and has shown 100% transformation efficiency, 1,2 of noresidue, 3-trifluoronitrobenzene.Reaction mixture is cooled to 15 ℃ again, is surpassing the 1N HCL that slowly adds 3L in the time of 15min, and brown solution finally becomes limpid yellow solution.The pH of water is about pH4.With ethyl acetate (2 x 1L) extracting mixture, mix organic phase with salt water washing (1L), concentrate in the vacuum, get orange oil.

The oil that obtains is encased in the reactor of 10L, is dissolved in glacial acetic acid (1L).(vitriol oil (conc.) 1L), can also be observed the intensive phenomenon of deflation except exothermic phenomenon to add sulfuric acid then.Begin to carry out mechanical stirring, mixture heats 3h down at 70 ℃ then, and LC analyzes and shows 100% transformation efficiency behind the 3h.Reaction mixture is cooled between 15 ℃-20 ℃, adds ethyl acetate (3L), adds entry (6L) again, does not have visible interface and can be observed.Be separated to the water of 7L, with ethyl acetate (2 x 2L) extracting.At this moment, can observe a visible interface.Mixing organic extract washs with 1N NaOH (6 x 1L) (the pH value of water is 6.6) and salt solution (3 x 1L).(35 ℃ of bath temperatures 36torr) concentrate the about 10h of brown organic extract, obtain the thick brown oil of 569g demand, 82% AP (HPLC) under reduced pressure.Remaining ethyl acetate is 3% (GC).KF:0.25%. ¹H and ¹³C NMR wave spectrum coupling report data.Main impurity is pararegioisomer (contraposition regional isomer).

Methyl alcohol (1L) the reflux 3h that B. will contain 1-(2,3-two fluoro-6-oil of mirbane)-propane-2-ketone (183g) and salt of wormwood (100g) mixture.Reaction mixture, vacuum concentration is to remove most methyl alcohol.Resistates filters with ethyl acetate (1L) dilution, washing.The water layer that is separated to is with 2N HCl neutralization, with ethyl acetate (2 x 500mL) extracting.Mix organic layer salt water washing, drying (is used Na ₂SO ₄), vacuum concentration obtains brown solid.This solid is developed with diethyl ether, filters to obtain yellow solid 1-(2-fluoro-3-methoxyl group-6-oil of mirbane)-third-2-ketone (121g, 71%).C/MS；(M+H) ⁺＝228.2.

C. under 180 ℃, stir 1-(2-fluoro-3-methoxyl group-6-oil of mirbane)-third-2-ketone of obtaining by preceding step (454mg, 21mmol) and pyridinium chloride (0.9g, mixture 75min 7.8mmol).The reaction cool to room temperature, and with 1N HCL (3mL) and ethyl acetate (10mL) dilution, filter.Filtrate is washed with salt solution (2x), and drying concentrates in the vacuum, obtains gray solid 1-(2-fluoro-3-hydroxyl-6-oil of mirbane)-third-2-ketone (410mg, 96%), and it need not be further purified and be directly used in next step.LC/MS；(M+H) ⁺＝214. ¹HNMR(CDCl ₃)：82.37(s，3H)，4.22(s，2H)，6.95(dd，1H)，7.95(d，1H，J＝9.35Hz)。

D. (50g 0.234mol) joins in the round bottom flask of 2L 1-(2-fluoro-3-hydroxyl-6-oil of mirbane)-third-2-ketone that will be obtained by previous step, adds 1L water, at room temperature stirs this yellow suspension.Disposable adding sodium hyposulfate (225g, 5.5eq), stirred reaction mixture, temperature maintenance is analyzed demonstration no initial substance residual (being less than 1h usually) until HPLC under 30 ℃.In case after finishing, reaction mixture is cooled to 0 ℃, the brown solid is collected in vacuum filtration.Below 50 ℃ in vacuum the dry wet product, obtain brown crystalline powder 4-fluoro-2-Methyl-1H-indole-5-alcohol (31.4g, 81% productive rate).The HPLC purity of this material〉99.8. ¹HNMR(CDCl3，400MHz)δ7.8(s，1H)，6.9-6.7(m，2H)，6.2(s，1H)，4.7(s，1H)，2.4(s，3H).3C?NMR(CDCl3，100MHz)δ?145.7,143.4,137.5,136.7,134.4,120.1，112.7，106.8，95.4，13.3。

And 1-(2,3-two fluoro-6-oil of mirbane)-third-2-ketone can change into title compound by following replacement program.

E.1-(3-benzyloxy-2-fluoro-6-nitro-phenyl)-third-2-ketone

(2.5g, the HPLC purity assay is 82%, 9.54mmol) middle benzyl alcohol (2.5mL) and the LiOHH of adding to 1-(2,3-two fluoro-6-oil of mirbane)-third-2-ketone ₂O (1.07g, 25.58mmol).Then will reaction mixture heating up to 100 ℃-110 ℃, stir 4h, analyze until HPLC and show that reaction finishes.After the cool to room temperature, reaction mixture is with methylene dichloride (18mL) dilution, and the 1N HCI pH6-7 that neutralizes.Carry out layering, with salt water washing organic phase and collect it.Stir on the limit, and the limit adds heptane (30-25mL) in organic solution, thereby start the crystallization effect.The soup compound that obtains is cooled to 0-5 ℃, restir 1h.Filter soup compound, use the heptane wash filter cake.Dry yellowish-brown solid 12-15h under 50 ℃ obtains wanting compound (1.6g) in the vacuum, and HPLC analyzes and shows that purity is 95%.The HPLC method; Post: YMC Pack Cyano (3um4.6 x 50mm); Solvent orange 2 A: 0.05%TFA is in MeOH: in the water (20:80); Solvent B:0.05%TFA is in MeOH: in the water (20:80); Wavelength: 254nm; Flow velocity: 3mL/min; The gradient elution time: 3min; Final %B:100; Initial retention time (Initial Hold): 0.5min; Initial %B:0; Typical case residence time: SM, 1.2min; Product 2.2-2.3min.

F.4-fluoro-2-Methyl-1H-indole-5-alcohol

Forward the compd E that obtains of step (20.00g, methanol solution 66.03.30mmol), in nitrogen atmosphere (300mL), at room temperature, under the lucifuge condition, add 10%Pd/C (2.0g) and ammonium formiate (60.0g, 0.95mol).Reaction mixture stirs 3.5h, uses ethyl acetate (200mL) dilution then, by one

(diatomite)/silica-gel plate filters.Residue is with one of following method purifying:

After concentrating in the vacuum, the residue chromatography purification of acquisition with 30% ethyl acetate/hexane wash-out, grinds the white solid mixture (7.32g, 67%) of the demand that obtains afterwards with dichloromethane/hexane.

Vacuum concentration, residue is dissolved in methylene dichloride, by a silica-gel plate, and uses the methylene dichloride wash-out.The vacuum concentration filtrate obtains white solid title compound (6.66g, 61%).

The compd E of present embodiment also can be converted into 1-(2-fluoro-3-hydroxyl-6-oil of mirbane)-third-2-ketone by following two kinds of alternative methods.

1-(2-fluoro-3-hydroxyl-6-oil of mirbane)-third-2-ketone

Method G-1: at room temperature, to the 1-that is dissolved in diacetyl oxide (5mL) and acetate (5mL) (3-benzyloxy-2-fluoro-6-oil of mirbane)-third-2-ketone (3.03g, 10mmol) solution, add Hydrogen bromide (48% the aqueous solution, 3mL).After adding finishes, be reflected at 100 ℃ of heating 30min, be cooled to room temperature then.Stir on the limit, and the limit adds the hexane of 10mL to this mixture.Decantation and concentrated solution, residue is with ethyl acetate (50mL) dilution, with salt water washing (3 x 20mL).Dry organic layer concentrates in the vacuum, obtains brown solid 1-(2-fluoro-3-hydroxyl-6-oil of mirbane)-third-2-ketone (1.7g, 80%), and it need not to be further purified and is directly used in next step.LC/MS；(M+H) ⁺＝213.2

Method G-2:1-(3-benzyloxy-2-fluoro-6-oil of mirbane)-third-2-ketone (65.0g, 0.214mol) and pyridinium chloride (60.74g, mixture 0.526mol) stirs 1h, reaction mixture cool to room temperature down at 180 ℃, with 3N HCl (100mL) and ethyl acetate (500mL) dilution, filter.Water mixes organic layer salt water washing, MgSO with ethyl acetate (2X) extracting ₄Drying is filtered by a silica-gel plate, concentrates in the vacuum.Residue decolours in methyl alcohol with charcoal, filters and concentrates in a vacuum, obtains brown solid 1-(2-fluoro-3-hydroxyl-6-oil of mirbane)-third-2-ketone (37g, 81%).LC/MS；(M+H) ⁺＝213.2。

Alternately, 1-(3-benzyloxy-2-fluoro-6-oil of mirbane)-third-2-ketone can be cyclized into 5-benzyloxy-4-fluoro-2-Methyl-1H-indole by the method for following description, can carry out debenzylation according to above-described method then.

H. (9.09g, 30mmol) methyl alcohol (100mL) with blue Buddhist nun (family name) nickel (about 5g) is heated to 40 ℃ will to contain 1-(3-benzyloxy-2-fluoro-6-oil of mirbane)-third-2-ketone.Under the vigorous stirring, be added dropwise to methyl alcohol (15mL) solution of hydrazine, the dropping time surpasses 30min.After the backflow 1h, the reaction mixture cool to room temperature filters by silica-gel plate, uses the methylene dichloride wash-out, concentrates in the vacuum, obtains xanchromatic oil 5-benzyloxy-4-fluoro-2-Methyl-1H-indole (6.1g, 80%).LC/MS；(M+H) ⁺＝256.3 ⁺。

Claims (4)

1. a method is used to prepare following formula: compound

Described method comprises the following steps:

A) with the fluorine cpd of following formula

With the nucleophilic reagent reaction, generate following formula: compound 11

B), generate following formula: compound 12 with compound 11 and alkoxyl group anionic reactive

Wherein R is a blocking group,

C) spend protection reagent alkoxyl group is gone protection, obtain following formula: compound 13

With

D) cyclisation compound 13 under reductive condition obtains following formula: compound 14

2. the described method of claim 1, wherein step (d) is used the V-Brite B of water-soluble or water and organic solvent mixed solution.

3. the described method of claim 2, described organic solvent is THF.

4. the described method of claim 1, wherein step (c) is used pyridinium chloride or iodate pyridine or hydrogen bromide.