CN104130265A

CN104130265A - Spiral ring or bridged ring containing pyrimidine compound

Info

Publication number: CN104130265A
Application number: CN201410177979.XA
Authority: CN
Inventors: 周鼎; 崔大为; 蔡振伟
Original assignee: SUZHOU JINGHONG BIOTECHNOLOGY Co Ltd
Current assignee: Shanghai Hongbo Zhiyuan pharmaceutical Limited by Share Ltd
Priority date: 2014-04-29
Filing date: 2014-04-29
Publication date: 2014-11-05
Anticipated expiration: 2034-04-29
Also published as: CN104130265B

Abstract

The invention discloses a spiral ring or bridged ring containing pyrimidine compound. The compound has a structure shown as formula I, and also can be an enantiomer, a diastereomer, a pharmaceutically acceptable salt, a prodrug molecule, a solvate, a tautomer, a resonant body and an isotope marker of formula I. Through the way, the spiral ring or bridged ring containing pyrimidine compound can effectively inhibit the growth of various tumor cells, also generates an inhibiting effect on EGFR (epidermal growth factor receptor), and other proteases of Her family, can be used for preparing antitumor drugs, and also can overcome the drug resistance induced by gefitinib, erlotinib and other existing drugs. Compared with similar non-spiral ring or bridged ring pyrimidine compounds, the spiral ring or bridged ring containing pyrimidine compound I can better improve the biological metabolic stability.

Description

A kind of pyrimidines that contains volution or bridged ring

Technical field

The present invention relates to a kind of pyrimidines that contains volution or bridged ring, can be applied to compound for the treatment of nonsmall-cell lung cancer and preparation method thereof by mutation inhibiting type EGFR thereby relate to, also comprise the drug regimen that contains these compounds and the method for applying these compounds.

Background technology

In 30 years, lung cancer mortality has risen 465% in the past, and sickness rate increases by 26.9% every year, has replaced liver cancer to become the first Death Cause for Malignant Tumors of China.A kind of disease that this mortality ratio is the highest, the mankind's health in serious threat.Wherein nonsmall-cell lung cancer (non-small cell lung cancer, NSCLC) account for the more than 80% of all lung cancer, only there is 1/3rd NSCLC patient to have the chance of operative treatment, approximately 70% patient has belonged to local late period or has occurred distant metastasis when medical, has lost operative treatment chance.In this case, pharmacological agent seems and is even more important.

In traditional cancer treatment procedure, chemotherapy is main treatment means; Thereby chemotherapeutics is non-specifically blocked cell fission and is made necrocytosis, they in killing tumour cell, also large havoc human normal cell's growth, bring many untoward reactions.A lot of people make even abandoning cure of mood pessimism because of the serious side effects of worry chemotherapy, add the resistance of chemotherapeutics, the chemotherapy of NSCLC is allowed of no optimist, and the cycle of prolongation chemotherapy have only increased toxic side effect, do not increase curative effect.The cancer cells of nonsmall-cell lung cancer is insensitive to chemotherapy, conventional chemotherapy simultaneously, and total remission rate also only has 25% left and right; Due to the restriction of these reasons, Patients with Non-small-cell Lung five year survival rate is lower than 20%.

In patient NSCLC of 50%-80%, all overexpressions of their EGF-R ELISA (epidermal growth factor receptor, EGFR), thus cause canceration.Targeting EGFR medicine mainly contains two classes: a class is the small molecule tyrosine kinase inhibitors (TKI) that acts on acceptor intracellular region; Another kind of is the monoclonal antibody (MAb) that acts on acceptor extracellular region.Be applied to clinical first-generation EGFR inhibitor as Iressa, erlotinib, lapatinibditosylate etc., they have obtained very large success for the treatment of NSCLC lung cancer, and Patients with Non-small-cell Lung five year survival rate improves.Meanwhile, compared with chemotherapy, their advantage is can not produce bone marrow depression, feels sick and the side effect such as neurotoxicity; But their drug effects in the time treating are separately lower, and have the very significantly side effect such as fash and diarrhoea, and after using 1 year, patient occurs resistance to medicine.Research thinks that the sudden change in EGFR gene T790M site is the main inducing of this type of Drug-resistant, has clinical case data presentation, and patient's acquired resistance of nearly 50% all comes from due to the sudden change in T790M site.Further studies confirm that, due to EGFR gene T790M sudden change, the Threonine of coding changes first comb propylhomoserin into, thereby has caused the sterically hindered inhibitor that hindered to be combined with ATP-binding domain and finally to have caused inhibitor activity forfeiture.Also have at present and studies show that the sudden change in T790M site is not the affinity that directly affects inhibitor and EGFR, but sudden change causes the affinity of EGFR and ATP greatly to increase, make relative the greatly reducing of affinity (inhibitor and ATP are competitive bindings) of inhibitor and EGFR.S-generation inhibitor is if Ah method is for Buddhist nun, Dacomitinib, and they are better than the first-generation and are characterised in that the identity increase to EGFR, can distinguish tumour cell and normal cell, and side effect will reduce like this; But the poor selectivity of these molecules to EGFRT790M mutant, causes clinical drug tolerance dose lower, under its maximum tolerated dose (MTD), medicine cannot reach in vivo its effective concentration and make most resistance patients invalid.

In a word, current EGFR-TKI still can not solve the caused clinical pressure of drug resistance, and mostly existing medicine be the reversible or irreversible inhibitor of EGFR taking quinazoline or quinoline amine as basic parent nucleus, its toxic side effect that poor selectivity of wild-type cell is brought is also inevitable.Therefore, exigence novel type, the compound of especially novel skeleton solves the problem such as resistance, poor selectivity.

Summary of the invention

The technical problem that the present invention mainly solves is to provide a kind of pyrimidines that contains volution or bridged ring, and this compound can suppress kinds of tumor cells.

For solving the problems of the technologies described above, the technical scheme that the present invention adopts is: a kind of pyrimidines that contains volution or bridged ring is provided, it is characterized in that, the structure that described compound has is formula I: , wherein W is NH, R ₁for hydrogen, halogen or C ₁-C ₄substituted alkyl, R ₂for hydrogen, halogen, C ₁-C ₄alkoxyl group or C ₁-C ₄substituted alkyl, R ₃and R ₄for form volution or the bridged ring of replacement, R together with N atom ₅and R ₆for hydrogen, halogen or C ₁-C ₄substituted alkyl.

In a preferred embodiment of the present invention, the structure of described volution or bridged ring is: , wherein R ₇for the C replacing ₁-C ₄the C of carboxylic acid group, cycloalkanes carboxylic acid group, replacement ₁-C ₄alkylsulfonyl, cycloalkanes alkylsulfonyl, C ₁-C ₄the C of alkyl, replacement ₁-C ₄alkyl.

In a preferred embodiment of the present invention, described pyrimidines also comprises the enantiomorph, diastereomer of formula I, pharmaceutically receptible salt, prodrugs, solvate, tautomer, resonance body, isotopic label.

In a preferred embodiment of the present invention, in the medicine of described pyrimidines for the preparation for the treatment of tumour.

In a preferred embodiment of the present invention, described tumour is any in nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, skin carcinoma, cell carcinoma, gastrointestinal stromal tumors (GISTs), white leukemia, histocyte lymphatic cancer, nasopharyngeal carcinoma.

The invention has the beneficial effects as follows: the pyrimidines that contains volution or bridged ring of the present invention, can suppress kinds of tumor cells, especially can selectively acting in EGFR L858R/T790M and EGFR E745_A750/T790M lung carcinoma cell, contrast wild-type cancer cells, the IC50 of this compounds wants high 10 times of order of magnitude difference of 100 times even, this compounds be a class novelty the resistance that can overcome existing EGFR-TKI and there is optionally proteinase inhibitor.With respect to similar non-volution or bridged ring pyrimidines, the pyrimidines I that contains volution or bridged ring will improve its biological metabolism stability better.

The pyrimidines with formula I constitutional features or its pharmacy acceptable salt that the present invention relates to, can suppress the growth of kinds of tumor cells, and to EGFR, other protease-producing restraining effect of Her family, can be used for effectively preparing antitumor drug, and can overcome the resistance that existing medicine Gefitinib, Tarceva etc. bring out, can be used for the transition proliferative disease such as the preparation treatment mankind and other mammiferous tumours.

Embodiment

To the technical scheme in the embodiment of the present invention be clearly and completely described below, obviously, described embodiment is only a part of embodiment of the present invention, instead of whole embodiment.Based on the embodiment in the present invention, those of ordinary skill in the art, not making all other embodiment that obtain under creative work prerequisite, belong to the scope of protection of the invention.

Following is the definition of the term that uses in this specification sheets.Unless otherwise noted, the initial definition of group provided herein or term separately or be applied in this specification sheets as a part for other group.

Term " alkyl " refers to straight or branched alkyl, comprises 1-12 carbon atom, especially refers to 1-6 carbon atom.Typically " alkyl " comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, isopentyl, heptyl, 4,4 – dimethyl amyl groups, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl etc.Term " (C ₁-C ₄) alkyl " refer to straight or branched alkyl, comprise from 1-4 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-." substituted alkyl " refers to that the one or more positions in alkyl are substituted, and especially 1-4 substituting group can replace on any position.Typical replacement, includes but not limited to one or more following groups: as hydrogen, halogen (for example, single halogenic substituent or many halogenic substituents, the latter is as trifluoromethyl or comprise Cl ₃alkyl), itrile group, nitro, oxygen (as=O), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, aromatic ring, OR _a, SR _a, S (=O) R _e, S (=O) ₂r _e, P (=O) ₂r _e, S (=O) ₂oR _e, P (=O) ₂oR _e, NR _br _c, NR _bs (=O) ₂r _e, NR _bp (=O) ₂r _e, S (=O) ₂nR _br _c, P (=O) ₂nR _br _c, C (=O) OR _d, C (=O) R _a, C (=O) NR _br _c, OC (=O) R _a, OC (=O) NR _br _c, NR _bc (=O) OR _e, NR _dc (=O) NR _br _c, NR _ds (=O) ₂nR _br _c, NR _dp (=O) ₂nR _br _c, NR _bc (=O) R _a, or NR _bp (=O) ₂r _e, wherein at the R of this appearance _acan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring, R _b, R _cand R _dcan independently represent hydrogen, alkyl, cycloalkyl, heterocycle or aromatic ring, in other words R _band R _ccan form heterocycle together with N atom; R _ecan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring.Above-mentioned typical substituting group, as alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring can optionally replace.

Term " thiazolinyl " refers to that straight or branched alkyl contains 2-12 carbon atom, the substituting group of at least one carbon-carbon double bond.Typical group comprises vinyl or allyl group.Term " (C ₂-C ₆) thiazolinyl " refer to 2-6 the carbon atom that contain of straight or branched, have the group of a carbon-carbon double bond at least, as vinyl, propenyl, 2-propenyl, ( e)-crotyl, (Z)-crotyl, ( e)-2-methyl-2-butene base, ( z)-2-methyl-2-butene base, 2,3-dimethyl-crotyl, (Z)-pentenyl, ( e)-1-pentenyl, ( z)-1-hexenyl, ( e)-pentenyl, ( z)-2-hexenyl, ( e)-1-hexenyl, ( z)-1-hexenyl, ( e)-2-hexenyl, ( z)-3-hexenyl, ( e)-3-hexenyl and ( e)-1,3-hexadienyl." substituted alkenyl " refers to that the one or more positions in thiazolinyl are substituted, and especially 1-4 substituting group can replace on any position.Typical replacement, includes but not limited to one or more following groups: as hydrogen, halogen (for example, single halogenic substituent or many halogenic substituents, the latter is as trifluoromethyl or comprise Cl ₃alkyl), itrile group, nitro, oxygen (as=O), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, aromatic ring, OR _a, SR _a, S (=O) R _e, S (=O) ₂r _e, P (=O) ₂r _e, S (=O) ₂oR _e, P (=O) ₂oR _e, NR _br _c, NR _bs (=O) ₂r _e, NR _bp (=O) ₂r _e, S (=O) ₂nR _br _c, P (=O) ₂nR _br _c, C (=O) OR _d, C (=O) R _a, C (=O) NR _br _c, OC (=O) R _a, OC (=O) NR _br _c, NR _bc (=O) OR _e, NR _dc (=O) NR _br _c, NR _ds (=O) ₂nR _br _c, NR _dp (=O) ₂nR _br _c, NR _bc (=O) R _a, or NR _bp (=O) ₂r _e, wherein at the R of this appearance _acan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring, R _b, R _cand R _dcan independently represent hydrogen, alkyl, cycloalkyl, heterocycle or aromatic ring, in other words R _band R _ccan form heterocycle together with N atom; R _ecan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring.Above-mentioned typical substituting group, as alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring can optionally replace.

Term " alkynyl " refers to that straight or branched alkyl contains 2-12 carbon atom, the substituting group of at least one carbon carbon triple bond.Typical group comprises ethynyl.Term " (C ₂-C ₆) alkynyl " refer to 2-6 the carbon atom that contain of straight or branched; have the group of a carbon-carbon double bond at least, as ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 1-pentynyl, valerylene base, 1-hexin base, 2-hexin base, 3-hexin base." substituted alkynyl " refers to that the one or more positions in alkynyl are substituted, and especially 1-4 substituting group can replace on any position.Typical replacement, includes but not limited to one or more following groups: as hydrogen, halogen (for example, single halogenic substituent or many halogenic substituents, the latter is as trifluoromethyl or comprise Cl ₃alkyl), itrile group, nitro, oxygen (as=O), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, aromatic ring, OR _a, SR _a, S (=O) R _e, S (=O) ₂r _e, P (=O) ₂r _e, S (=O) ₂oR _e, P (=O) ₂oR _e, NR _br _c, NR _bs (=O) ₂r _e, NR _bp (=O) ₂r _e, S (=O) ₂nR _br _c, P (=O) ₂nR _br _c, C (=O) OR _d, C (=O) R _a, C (=O) NR _br _c, OC (=O) R _a, OC (=O) NR _br _c, NR _bc (=O) OR _e, NR _dc (=O) NR _br _c, NR _ds (=O) ₂nR _br _c, NR _dp (=O) ₂nR _br _c, NR _bc (=O) R _a, or NR _bp (=O) ₂r _e, wherein at the R of this appearance _acan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring, R _b, R _cand R _dcan independently represent hydrogen, alkyl, cycloalkyl, heterocycle or aromatic ring, in other words R _band R _ccan form heterocycle together with N atom; R _ecan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring.Typical substituting group can optionally replace.

Term " cycloalkyl " refers to saturated cyclic hydrocarbon compounds group completely, comprises 1-4 ring, contains 3-8 carbon atom in each ring." (C ₃-C ₇) cycloalkyl " refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl." substituted cycloalkyl " refers to that the one or more positions in cycloalkyl are substituted, and especially 1-4 substituting group can replace on any position.Typical replacement, includes but not limited to one or more following groups: as hydrogen, halogen (for example, single halogenic substituent or many halogenic substituents, the latter is as trifluoromethyl or comprise Cl ₃alkyl), itrile group, nitro, oxygen (as=O), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, aromatic ring, OR _a, SR _a, S (=O) R _e, S (=O) ₂r _e, P (=O) ₂r _e, S (=O) ₂oR _e, P (=O) ₂oR _e, NR _br _c, NR _bs (=O) ₂r _e, NR _bp (=O) ₂r _e, S (=O) ₂nR _br _c, P (=O) ₂nR _br _c, C (=O) OR _d, C (=O) R _a, C (=O) NR _br _c, OC (=O) R _a, OC (=O) NR _br _c, NR _bc (=O) OR _e, NR _dc (=O) NR _br _c, NR _ds (=O) ₂nR _br _c, NR _dp (=O) ₂nR _br _c, NR _bc (=O) R _a, or NR _bp (=O) ₂r _e, wherein at the R of this appearance _acan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring, R _b, R _cand R _dcan independently represent hydrogen, alkyl, cycloalkyl, heterocycle or aromatic ring, in other words R _band R _ccan form heterocycle together with N atom; R _ecan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring.Above-mentioned typical substituting group can optionally replace.Typical replacement also comprises volution or fused ring substituents, especially spiro cycloalkyl group, volution thiazolinyl, Spirocyclic heterocyclic (not comprising hetero-aromatic ring), condensed ring alkyl, condensed ring thiazolinyl, fused ring heterocycle base or condensed ring aromatic ring yl, above-mentioned cycloalkyl, cycloalkenyl group, heterocyclic radical and heterocyclic aryl can optionally replace.

Term " cycloalkenyl group " refers to the undersaturated cyclic hydrocarbon compounds of part group, comprises 1-4 ring, contains 3-8 carbon atom in each ring.Typical cycloalkenyl group is as cyclobutene base, cyclopentenyl, cyclohexenyl etc." substituted cycloalkenyl " refers to that the one or more positions in cycloalkyl are substituted, and especially 1-4 substituting group can replace on any position.Typical replacement, includes but not limited to one or more following groups: as hydrogen, halogen (for example, single halogenic substituent or many halogenic substituents, the latter is as trifluoromethyl or comprise Cl ₃alkyl), itrile group, nitro, oxygen (as=O), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, aromatic ring, OR _a, SR _a, S (=O) R _e, S (=O) ₂r _e, P (=O) ₂r _e, S (=O) ₂oR _e, P (=O) ₂oR _e, NR _br _c, NR _bs (=O) ₂r _e, NR _bp (=O) ₂r _e, S (=O) ₂nR _br _c, P (=O) ₂nR _br _c, C (=O) OR _d, C (=O) R _a, C (=O) NR _br _c, OC (=O) R _a, OC (=O) NR _br _c, NR _bc (=O) OR _e, NR _dc (=O) NR _br _c, NR _ds (=O) ₂nR _br _c, NR _dp (=O) ₂nR _br _c, NR _bc (=O) R _a, or NR _bp (=O) ₂r _e, wherein at the R of this appearance _acan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring, R _b, R _cand R _dcan independently represent hydrogen, alkyl, cycloalkyl, heterocycle or aromatic ring, in other words R _band R _ccan form heterocycle together with N atom; R _ecan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring.Above-mentioned typical substituting group can optionally replace.Typical replacement also comprises volution or fused ring substituents, especially spiro cycloalkyl group, volution thiazolinyl, Spirocyclic heterocyclic (not comprising hetero-aromatic ring), condensed ring alkyl, condensed ring thiazolinyl, fused ring heterocycle base or condensed ring aromatic ring yl, above-mentioned cycloalkyl, cycloalkenyl group, heterocyclic radical and heterocyclic aryl can optionally replace.

Term " aryl " refers to aromatic ring-shaped hydrocarbon compound group, has 1-5 ring, especially refers to monocycle and bicyclic radicals, as phenyl, xenyl or naphthyl.All two or more aromatic nucleus (dicyclo etc.) that contain, the aromatic nucleus of aromatic yl group can be connected by singly-bound (as biphenyl), or condenses (as naphthalene, anthracene etc.)." substituted aryl " refers to that the one or more positions in aryl are substituted, and especially 1-3 substituting group can replace on any position.Typical replacement, includes but not limited to one or more following groups: as hydrogen, halogen (for example, single halogenic substituent or many halogenic substituents, the latter is as trifluoromethyl or comprise Cl ₃alkyl), itrile group, nitro, oxygen (as=O), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, aromatic ring, OR _a, SR _a, S (=O) R _e, S (=O) ₂r _e, P (=O) ₂r _e, S (=O) ₂oR _e, P (=O) ₂oR _e, NR _br _c, NR _bs (=O) ₂r _e, NR _bp (=O) ₂r _e, S (=O) ₂nR _br _c, P (=O) ₂nR _br _c, C (=O) OR _d, C (=O) R _a, C (=O) NR _br _c, OC (=O) R _a, OC (=O) NR _br _c, NR _bc (=O) OR _e, NR _dc (=O) NR _br _c, NR _ds (=O) ₂nR _br _c, NR _dp (=O) ₂nR _br _c, NR _bc (=O) R _a, or NR _bp (=O) ₂r _e, wherein at the R of this appearance _acan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring, R _b, R _cand R _dcan independently represent hydrogen, alkyl, cycloalkyl, heterocycle or aromatic ring, in other words R _band R _ccan form heterocycle together with N atom; R _ecan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring.Above-mentioned typical substituting group can optionally replace.Typical replacement also comprises fused ring substituents, especially condensed ring alkyl, condensed ring thiazolinyl, fused ring heterocycle base or condensed ring aromatic ring yl, and above-mentioned cycloalkyl, cycloalkenyl group, heterocyclic radical and heterocyclic aryl can optionally replace.

Term " carbocyclic ring " refers to the saturated or undersaturated cyclic hydrocarbon compounds of part group completely, comprises 1-4 ring, contains 3-8 carbon atom in each ring.Or aromatic ring-shaped hydrocarbon compound group, has 1-5 ring, especially refers to monocycle and bicyclic radicals, as phenyl, xenyl or naphthyl.Term " carbocyclic ring " comprises cycloalkyl, cycloalkenyl group, cycloalkynyl radical and aryl defined above.Term " replacement carbocyclic ring " refers to that the one or more positions in carbocyclic ring or carbocyclic ring substituting group are substituted, and especially 1-4 substituting group can replace on any position.Typical replacement, includes but not limited to above-described group: as substituted cycloalkyl, substituted cycloalkenyl, substituted ring alkynyl and substituted aryl.The typical volution or the fused ring substituents that are included on optional position of replacing, especially spiro cycloalkyl group, volution thiazolinyl, Spirocyclic heterocyclic (not comprising hetero-aromatic ring), condensed ring alkyl, condensed ring thiazolinyl, fused ring heterocycle base or condensed ring aromatic ring yl, above-mentioned cycloalkyl, cycloalkenyl group, heterocyclic radical and heterocyclic aryl can optionally replace.

Term " heterocycle " and " heterocycle " refer to completely saturated part is undersaturated or the completely undersaturated cyclic group that comprises aromatic ring (as hetero-aromatic ring) (as 4-7 unit monocycle, 7-11 unit dicyclo, or 8-16 unit three-loop system), wherein have at least a heteroatoms to be present in the ring that has a carbon atom at least.Each contain heteroatomic heterocycle can be with 1,2,3 or 4 heteroatomss, these heteroatomss are selected from nitrogen-atoms, Sauerstoffatom/or sulphur atom, wherein nitrogen-atoms or sulphur atom can be oxidized, nitrogen-atoms also can be quaternized.(term " hetero-aromatic ring ion " refers to and contains hetero-aromatic ring group quaternary carbon, positively charged.) heterocyclic group can be connected to ring or any heteroatoms of ring system molecule or the residue of carbon atom on.Typical monocyclic heterocycles comprises azetidinyl, pyrrolidyl, pyrryl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidyl, oxazolyl, oxazolidinyl, isoxazole alkyl, isoxazolyl, thiazolyl, thiadiazolyl group, thiazolidyl, isothiazolyl, isothiazole alkyl, furyl, tetrahydrofuran base, thienyl, oxadiazolyl, piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo azepines base, azepines base, hexahydroazepine base, 4-piperidone base, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, three nitrogen piperazine bases, triazol radical, tetrazole base, THP trtrahydropyranyl, morpholine base, thio-morpholine group, sulfo-morpholine sulfoxide group, sulfo-morpholine sulfuryl, 1, 3-alkyl dioxin and tetrahydrochysene-1, 1-dioxy thiophene etc.Typical bicyclic heterocycle comprise indyl, pseudoindoyl, benzothiazolyl, benzoxazolyl, benzo oxygen di azoly, benzothienyl, benzo [ d] [1,3] two oxyalkyls, 2,3-dihydrobenzo [ b] [1,4] two oxyalkyls, quinine base, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl-, benzopyranyl, indolinyl, benzofuryl, coumaran base, chromanyl, tonka bean camphor base, cinnolines base, quinoxalinyl, indazolyl, pyrrolopyridinyl, furo pyridyl are (as furo [2,3- c] pyridyl, furo [3,2- b] pyridyl or furo [2,3- b] pyridine), dihydro-iso indolyl, dihydroquinazoline base (as 3,4-dihydro-4-oxo quinazolyl), three azepine azepines bases, tetrahydric quinoline group etc.Typical tricyclic heterocyclic comprises carbazyl, benzindole, phenanthroline base, acridyl, phenanthridinyl, xanthyl etc.Term " heterocycle " may comprise the heterocycle of replacement.

" substituted heterocycle " and " substituted heterocycle " (as replaced hetero-aromatic ring) refers to that the one or more positions in heterocycle or heterocyclic group are substituted, and especially 1-4 substituting group can replace on any position.Typical replacement, includes but not limited to one or more following groups: as hydrogen, halogen (for example, single halogenic substituent or many halogenic substituents, the latter is as trifluoromethyl or comprise Cl ₃alkyl), itrile group, nitro, oxygen (as=O), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, aromatic ring, OR _a, SR _a, S (=O) R _e, S (=O) ₂r _e, P (=O) ₂r _e, S (=O) ₂oR _e, P (=O) ₂oR _e, NR _br _c, NR _bs (=O) ₂r _e, NR _bp (=O) ₂r _e, S (=O) ₂nR _br _c, P (=O) ₂nR _br _c, C (=O) OR _d, C (=O) R _a, C (=O) NR _br _c, OC (=O) R _a, OC (=O) NR _br _c, NR _bc (=O) OR _e, NR _dc (=O) NR _br _c, NR _ds (=O) ₂nR _br _c, NR _dp (=O) ₂nR _br _c, NR _bc (=O) R _a, or NR _bp (=O) ₂r _e, wherein at the R of this appearance _acan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring, R _b, R _cand R _dcan independently represent hydrogen, alkyl, cycloalkyl, heterocycle or aromatic ring, in other words R _band R _ccan form heterocycle together with N atom; R _ecan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring.Above-mentioned typical substituting group can optionally replace.Typical replacement also comprises fused ring substituents, especially condensed ring alkyl, condensed ring thiazolinyl, fused ring heterocycle base or condensed ring aromatic ring yl, and above-mentioned cycloalkyl, cycloalkenyl group, heterocyclic radical and heterocyclic aryl can optionally replace.

Term " alkylamine " refer to structure-NHR ' group, wherein R ' refers to the cycloalkyl of alkyl, cycloalkyl or the replacement of halogen, alkyl or replacement, as hereinbefore defined.The example of alkylamine includes but not limited to one or more following groups: as methylamino, ethylamino-, Tri N-Propyl Amine base, isopropylamine base, cyclopropyl amino, n-butylamine-based, TERTIARY BUTYL AMINE base, neopentyl amine base, n-amylamine base, hexylamine base, cyclohexylamino etc.

Term " dialkylamine " refer to structure-NRR ' group, wherein R and R ' can independently represent the heterocycle of aryl, heterocycle or the replacement of cycloalkenyl group, aryl or the replacement of cycloalkyl, cycloalkenyl group or the replacement of alkyl, cycloalkyl or the replacement of alkyl or replacement, as hereinbefore defined.R and R' can be identical or different in dialkylamine fragment.The example of dialkylamine includes but not limited to one or more following groups: as dimethylin, methylethyl amido, diethylin, methyl-propyl amido, two (n-propyl) amido, two (sec.-propyl) amido, two (cyclopropyl) amido, two (normal-butyl) amido, two (tertiary butyl) amido, two (neo-pentyl) amido, two (n-pentyl) amido, two (hexyl) amido, two (cyclohexyl) amido etc.In some instances, R and R' connect together and form a ring texture.Consequent ring texture can be aromatic nucleus or non-aromatic ring.Cyclic dialkyl amine includes but not limited to following group, as nitrogen heterocyclic propyl group, pyrrolinyl, piperidyl, morpholinyl, pyrryl, imidazolyl, 1,3, and 4 – triazol radicals and tetrazole base.

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

Unless otherwise indicated, the heteroatoms of supposing any discontented valence state has enough hydrogen atoms to supplement its valence state.

The salt that compound in the present invention may form is also to belong to scope of the present invention.Except as otherwise noted, the compound in the present invention is understood to include its esters.Term " salt " as used herein, refers to the salt by inorganic or organic bronsted lowry acids and bases bronsted lowry formation acid or alkali formula.In addition, in the time that the compound in the present invention contains an alkaline fragment, it includes but not limited to pyridine or imidazoles, during containing an acidic moiety, includes but not limited to carboxylic acid, and the zwitter-ion (" inner salt ") that may form is included in the scope of term " salt ".Pharmaceutically acceptable (nontoxic, physiology is acceptable) salt is first-selected, although other salts are also useful, for example, can be used in the isolated or purified step in preparation process.Compound of the present invention may form salt, for example, Compound I and a certain amount ofly saltout out in medium as the acid of equivalent or alkali reaction, or in the aqueous solution, lyophilize gets.

The alkaline fragment that compound in the present invention contains, includes but not limited to amine or pyridine or imidazole ring, may form salt with organic or inorganic acid.Typical acid that can salify comprises acetate (as with acetic acid or three halogenated acetic acids, as trifluoroacetic acid), adipate, alginate, ascorbate salt, aspartate, benzoate, benzene sulfonate, hydrosulfate, borate, butyrates, Citrate trianion, camphor salt, camsilate, cyclopentane propionate, glycol ether hydrochlorate, dodecyl sulfate, ethane sulfonate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, isethionate (as, 2-isethionate), lactic acid salt, maleate, mesylate, naphthalenesulfonate (as, 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectate, persulphate, phenpropionate (as 3-phenpropionate), phosphoric acid salt, picrate, Pivalate, propionic salt, salicylate, succinate, vitriol (as formed with sulfuric acid), sulfonate, tartrate, thiocyanate-, mesylate is as tosilate, dodecanoate etc.

The acidic moiety that compound of the present invention contains, includes but not limited to carboxylic acid, may form salt with various organic or inorganic alkali.The salt that typical alkali forms comprises that ammonium salt, an alkali metal salt are as sodium, lithium, sylvite, and alkaline earth salt is as calcium, magnesium salts, and the salt (as organic amine) that forms of organic bases, as benzyl star, dicyclohexyl amine, sea bar amine (with n,Nthe salt that-bis-(dehydroabietyl) quadrol forms), n-methyl D-glycosamine, n-methyl D-glucamide, tert-butylamine, and and amino acid as arginine, Methionin etc. form salt.Alkalescence nitrogen-containing group can with halogenide quaternary ammonium salt, as small molecules alkyl halide (as the muriate of methyl, ethyl, propyl group and butyl, bromide and iodide), dialkyl sulfate (as, methyl-sulfate, diethyl ester, dibutylester and diamyl ester), long-chain halogenide (as the muriate of decyl, dodecyl, tetradecyl and tetradecyl, bromide and iodide), aralkyl halide (as benzyl and phenyl-bromide compound) etc.

In the present invention, the prodrug of compound and solvate are also within the scope containing.Term " prodrug " refers to a kind of compound herein, in treatment when relative disease, produces compound, salt or the solvate in the present invention through the chemical conversion of metabolism or chemical process.Compound of the present invention comprises solvate, as hydrate.

Compound, salt or solvate in the present invention, the tautomeric form that may exist (for example acid amides and imines ether).All these tautomers are all parts of the present invention.

The steric isomer (for example, those are due to the unsymmetrical carbon that may exist various replacements) of all compounds, comprises its enantiomeric form and diastereomeric form formula, all belongs to imagination scope of the present invention.Compound in the present invention independently steric isomer may (for example not exist with other isomer simultaneously, pure or be in fact that pure optical isomer has special activity as one), or may be also mixture, as raceme, or the mixture forming with every other steric isomer or a part wherein.Chiral centre of the present invention has S or two kinds of configurations of R, by International Union of Pure and Applied Chemistry (IUPAC) suggestion in 1974 definition.Racemic form can solve by physical method, for example fractional crystallization, or by deriving as diastereomeric separation crystallization, or separate by chiral column chromatography.Single optical isomer can be obtained by racemic modification by suitable method, includes but not limited to traditional method, for example with optical activity acid salify after recrystallize.

Compound in the present invention, its weight content of this compound obtaining by preparation, separation and purification is successively equal to or greater than 90%, for example, is equal to or greater than 95%, is equal to or greater than the compound of 99%(" very pure "), describe and list at text.This " very pure " compound of the present invention is also as a part of the present invention herein.

No matter all configurational isomer of compound of the present invention all within the scope containing, is mixture, pure or very pure form.The definition of the compounds of this invention comprise cis ( z) and return formula ( e) two kinds of olefin isomers, and the cis of carbocyclic ring and heterocycle and trans-isomer(ide).

In whole specification sheets, group and substituting group can be selected the fragment and the compound that provide stable.

Particular functional group and technical term of chemistry definition are all described in detail as follows.For purposes of the invention, chemical element and Periodic Table of the Elements, CAS version, handbook of Chemistry and Physics, 75 ^thed. in, definition is consistent.Particular functional group's definition is also described therein.In addition vitochemical fundamental principle and particular functional group and reactive at " Organic Chemistry ", Thomas Sorrell,, University Science Books, Sausalito:1999, also has explanation, and its full content is included the row of reference in.

Some compound of the present invention may be present in specific geometry or stereoisomer form.All compounds are contained in the present invention, comprise its cis and trans-isomer(ide), R and S enantiomer, diastereomer, (D) type isomer, (L) type isomer, racemic mixture and other mixture.Unsymmetrical carbon can represent substituting group in addition, as alkyl.All isomer and their mixture, all forgive in the present invention.

According to the present invention, the ratio that the mixture of isomers contains isomer can be various.For example, can there is following combination: 50:50 at the mixture that only has two isomer, 60:40,70:30,80:20,90:10,95:5,96:4,97:3,98:2,99:1, or 100:0, all ratios of isomer is all within the scope of the invention.Those skilled in the art hold intelligible similar ratio in this specialty, and are that the ratio of mixture of more complicated isomer is also within the scope of the invention.

The present invention also comprises isotope-labeled compound, is equal to original chemical open at this.But in fact one or more atoms is replaced and conventionally be there will be by the atom different from its nucleidic mass or quality ordinal number.Can classify the isotopic example of compound of the present invention as and comprise hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine isotope, respectively as ²h, ³h, ¹³c, ¹¹c, ¹⁴c, ¹⁵n, ¹⁸o, ¹⁷o, ³¹p, ³²p, ³⁵s, ¹⁸f and ³⁶cl.Compound in the present invention, or enantiomorph, diastereomer, isomer, or pharmacy acceptable salt or solvate, wherein contain the isotropic substance of above-claimed cpd or other other isotope atoms all within the scope of the present invention.Some compound isotopically labelled in the present invention, for example ³h and ¹⁴the radio isotope of C also therein, is useful in the tissue distribution experiment of medicine and substrate.Tritium, ³h and carbon-14, ¹⁴c, their preparation and determination methods ratio is easier to.It is the first-selection in isotropic substance.In addition, higher isotope replaces as deuterium, ²h, because its good metabolic stability has superiority in some therapy, for example, increases in vivo the transformation period or reduces consumption, therefore, can pay the utmost attention in some cases.Isotope-labeled compound can be by general method, and the isotope labeling reagent being easy to get by use replaces with non isotopic reagent, can prepare by the scheme in example.

If a specific enantiomorph of compound of the present invention of design is synthetic, it can asymmetric synthesis preparation, or with chirality assistant agent derivatize, by produced mixture of diastereomers separation, then removes chirality assistant agent and obtains pure enantiomorph.In addition, if contain a basic functionality in molecule, as amino acid, or acidic functionality, as carboxyl, can be with the diastereomeric salt of formation with it of suitable optically active acid or alkali, separate by conventional meanses such as fractional crystallization or chromatograms again, then just obtained pure enantiomorph.

As described herein, the compound in the present invention can be got with any quantity substituting group or functional group and expand it and forgive scope.Conventionally, term " replacement ", no matter occur at term " optional ", comprises substituent general formula at the present invention's formula above or below, refers to and uses specified structure substituting group, replaces hydroperoxyl radical.In the time that multiple in ad hoc structure are replaced by multiple specific substituting groups in position, each position of substituting group can be identical or different.Term used herein " replacement " comprises that all permission organic compound replace.In broad terms, that the substituting group of permission comprises is acyclic, ring-type, the non-side chain of side chain, carbocyclic ring with heterocycle, aromatic ring and organic compound non-aromatic ring.In the present invention, as can having the organic compound mentioned above of hydrogen substituting group or any permission, heteroatoms nitrogen supplements its valence state.In addition, the present invention is not intended to restriction by any way to allow substituted organic compound.It is considered herein that being combined in of substituting group and variable group is well with stable compound form in the treatment of disease, for example transmissible disease or proliferative disease.Term " is stablized " and is referred to have stable compound herein, detects the integrity that is enough to maintain compound structure within the sufficiently long time, preferably within the sufficiently long time all in effect, be used herein to above-mentioned purpose herein.

In one embodiment, the application provides excess proliferative disease or the symptom such as compound and pharmacologically acceptable salts treatment people or other mammal tumors that a kind of utilization has formula I.

In one embodiment, designed compound and the pharmacologically acceptable salts thereof of the application can be used for the treatment of or control the excessively appreciation disease such as nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, skin carcinoma, cell carcinoma, gastrointestinal stromal tumors (GISTs), leukemia, histocyte lymphatic cancer, nasopharyngeal carcinoma.

Drug metabolism and prodrug: the compound that the application is related and the meta-bolites of pharmacologically acceptable salts thereof, and can change in vivo the prodrug of the structure of the related compound of the application and pharmacologically acceptable salts thereof into, be also contained in the application's claim.

Drug combination: formula I compound can or improve the other drug coupling of similar symptom to known treatment.When Combined Preparation, originally the administering mode & dosage of medicine remains unchanged, and simultaneously or take subsequently the compound of formula I.In the time that formula I compound and other one or more medicines are taken simultaneously, preferably use contains the medicinal compositions of one or more known drugs and formula I compound simultaneously.Drug combination is also included within the overlapping time period and takes formula I compound and other one or more known drugs.In the time that formula I compound and other one or more medicines carry out drug combination, the dosage that the dosage of formula I compound or known drug may be than they independent medications is low.

Medicine or the activeconstituents that can carry out drug combination with I compound comprise but are not limited to:

Estrogenic agents, androgen receptor is adjusted, retina receptor modulators, cytotoxin/cytostatics, antiproliferative, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV kinases inhibitor, reverse transcriptase inhibitors, angiogenesis inhibitor, cell proliferation and survival signaling inhibitor, medicine and the cell death inducer at the interference cell cycle outpost of the tax office, cytotoxic drug, tyrosine protein inhibitor, EGFR inhibitor, VEGFR inhibitor, serine/threonine protein inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, mek inhibitor, MMP inhibitor, topoisomerase enzyme inhibitor, Histone deacetylase inhibitor, proteoplast enzyme inhibitors, CDK inhibitor, Bcl-2 family protein inhibitor, MDM2 family protein inhibitor, IAP family protein inhibitor, STAT family protein inhibitor, PI3K inhibitor, ATK inhibitor, integrin retarding agent, interferon-' alpha ', interleukin-I2, cox 2 inhibitor, P53, P53 activator, VEGF antibody, EGF antibody etc.

Medicine or the activeconstituents that in one embodiment, can carry out drug combination with I-III chemical combination comprise but are not limited to: rIL-2, clinic effect of alendronate, Interferon, rabbit, Ah Qu Nuoying, allopurinol, epidermal growth factor, Palonosetron hydrochloride, altretamine, amino glutethimide, peace phosphorus spit of fland, pacify the soft star that compares, SN-11841, anastrozole, dolasetron, aranesp, arglabin, white arsenic, Arnold is new, U-18496, azathioprine, bacille Calmette-Guerin vaccine, or tice bacille Calmette-Guerin vaccine, bestatin, betamethasone acetate, betamethasone sodium phosphate inhibitor, bexarotene, bleomycin sulfate, broxuridine, bortezomb, busulfan, thyrocalcitonin, A Laizuo monoclonal antibody injection, capecitabine, carboplatin, Kang Shi get, cefesone, celmoleukin, daunorubicin, Chlorambucil, cis-platinum, CldAdo, chlorine is bent phosphoric acid, endoxan, cytosine arabinoside, Dacarbazine, dactinomycin, daunorubicin liposome, dexamethasone, Wymesone, Estradiol Valerate, denileukin diftitox, Di Bomei, deslorelin, ground La Zuosheng, diethylstilbestrol, Fluconazole, docetaxel, doxifluridine, Zorubicin, dronabinol, admire-166-chitosan complexes, eligrand, rasburicase, epirubicin hydrochloride, aprepitant, pidorubicin, Epoetin Alfa, erythropoietin, eptalatin, Ergamisole, estradiol inhibitor, 17-β-estradiol, estramustine phosphate sodium, female alkynol, amifostine, hydroxyl phosphoric acid, Etopophos, etoposide, fadrozole, tamoxifen preparation, filgrastim, Tamsulosin, Fei Leisi replaces, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5 FU 5 fluorouracil, Fluoxymesterone, flutamide, formestane, 1-β-D arabinofuranosylcytosine-5 '-hard acyl phosphoric acid ester, fotemustine, fluorine Wei Siqiong, gamma-globulin, gemcitabine, WAY-CMA 676, imatinib mesylate, carmustine wafer capsule, Ge Shelinrui, hydrochloric acid glug Ni Xi Gansu Province, Supprelin, new with U.S., hydrocortisone, erythro-hydroxyl nonyl VITAMIN B4, hydroxyurea, for not monoclonal antibody of smooth different shellfish, idarubicin, ifosfamide, interferon alpha, interferon α-2 A, interferon α-2 B, interferon alfa-n1, Alferon N, interferon beta, interferon-gamma-la, interleukin II, intron A, Iressa, Rinotecan, Kytril, sulfuric acid lentinan, letrozole, formyl tetrahydrofolic acid, Leuprolide, leuprolide acetate, L-tetramisole, levo leucovorin calcium salt, levothyroxine sodium, levothyroxine sodium preparation, lomustine, lonidamine, dronabinol, mustargen, mecobalamin, medroxyprogesterone acetate, Magace, melphalan, esterified estriol, Ismipur, mesna, methotrexate, amino-laevulic acid methyl esters, replace good fortune new, Minomycin, ametycin, mitotane, rice holder green onion quinone, Win-24540, citric acid Evacet, S 254, Pegylation filgrastim, oprelvekin, neupogen, Nilutamide, tamoxifen, NSC-631570, recombination human interleukins-11-β, Sostatin, Ondansetron Hydrochloride, dehydrohydro-cortisone oral solution, oxaliplatin, taxol, Pediapred, pegaspargase, Pai Luoxin, pentostatin, Picibanil, hydrochloric acid pilocarpine, adjoin the soft star that compares, Plicamycin, porfimer sodium, prednimustine, prednisolone steaglate, prednisone, premarin, the third kappa navel, epoetin, thunder is carried Qu Sai, Libiee, etidronate rhenium-186, Mabthera, Redoxon-A, romurtide, Salagen, Sostatin, sargramostim, semustine, sizofiran, sobuzoxane, bluff sodium prednisolone, Paphos acid, stem-cell therapy, streptozocin, Metastron, levothyroxine sodium, tamoxifen, YM-617, Ta Suonaming, tastolactone, taxotere, Ro 23-6019, Temozolomide, teniposide, testosterone propionate, Tioguanine, thio-tepa, thyrotropic hormone, for Shandong phosphoric acid, topotecan, toremifene, tositumomab, Herceptin, Treosulfan, tretinoin, methylamine dish purine tablet, trimethylammonium melamine, trimetrexate, acetic acid triptorelin, triptorelin pamoate, excellent good fortune pyridine, uridine, valrubicin, vesnarinone, vinealeucoblastine(VLB), vincristine(VCR), vindesine, vinorelbine, virulizin, ADR-529, Zinostatin stimalamer, Zudan, the protein stabilized preparation of taxol, aco lbifene/ interferon-gamma-lb, affinitak, amino dish purine, arzoxifene, asoprisnil, Atamestane, BAY43-9006, Avastin, CCI-779, CDC-501, celecoxib, Cetuximab, that holder of carat, cyproterone acetate, Decitabine, DN-101/ Zorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, Exatecan, fenretinide, histamine dihydrochloric acid, Supprelin hydrogel implant, holmium-166DOTMP, ibandronic acid, interferon-gamma, intron-PEG, ixabepilone, keyhole shape hemocyanin, L-651582, lanretide, Lasofoxifene, libra, lonafamib, Miproxifene, minot is bent acid esters, MS-209, liposome MEP-PE, MX-6, nafarelin, Nemorubicin, Neovastat, Nola Qu Te, Ao Limosen, onco-TCS, osidem, taxol polyglutamic acid esters, pamidronate disodium injection, PN-401, OS-21, overstate the West, R-1549, raloxifene, ranpirnase, isotretinoin, Satraplatin, seocalcitol, T-138067, tarceva, docosahexenoic acid taxol, thymosin α1, loud, high-pitched sound azoles furan woods, tipifarnib, bright for pulling eye, TLK-286, toremifene, trans MID-lo7R, valspodar, vapreotide, vatalanob, Visudyne, Vinflunine, Z-100 and Zoledronate or their combination.

On the one hand, compound structure provided by the invention is as formula ishown in,

? I

Or its enantiomorph, diastereomer, resonance body, or pharmacy acceptable salt or solvate, wherein:

W can independently represent NH;

R ₁can independently represent hydrogen, halogen, (C ₁-C ₄) substituted alkyl;

R ₂can independently represent hydrogen, halogen, (C ₁-C ₄) substituted alkyl, (C ₁-C ₄) alkoxyl group;

R ₃and R ₄form volution or the bridged ring of replacement together with N atom, can be but be not limited to following group:

R ₇can independently be expressed as (the C of replacement ₁-C ₄) (the C of carboxylic acid group, cycloalkanes carboxylic acid group, replacement ₁-C ₄) alkylsulfonyl, cycloalkanes alkylsulfonyl, (C ₁-C ₄) (the C of alkyl, replacement ₁-C ₄) alkyl;

R ₅and R ₆can independently represent hydrogen, halogen, (C ₁-C ₄) substituted alkyl.

following table is shortenings:

The compound of containing in the present invention can be synthetic by known conventional art.These compounds can be from facilitating available starting raw material synthetic expediently.It is below the general synthetic schemes of the synthetic compound of the present invention.These schemes disclosed herein are descriptive, do not represent to limit those skilled in the art and use other possible method synthetic compound.The whole bag of tricks is all the routine techniques in this area.In addition, different synthesis steps can be applied in synthesising target compound in different schemes.Among all documents of quoting at this are all incorporated to herein in the mode of reference.

The compound with general formula I can the knowledge in this field synthesize by following scheme and experienced individual.Scheme 1 has been described the different methods of synthetic these intermediates, and these methods can be applied in the preparation of the compound in patent of the present invention with general formula I – IV structure.Those skilled in the art can complete the synthetic of described analogue compounds below author by the various modifications of these methods.

There is general formula icompound be prepared as follows shown in:

Step 1: taking DMSO as solvent, to fluoronitrobenzene iIat K ₂cO ₃existence is descended and amine reaction obtains p-Nitroaniline intermediate III.

Step 2: under atmosphere of hydrogen, intermediate III hydrogenating reduction in methyl alcohol obtains intermediate compound IV.

Step 3: intermediate compound IV obtains final Compound I with the pyrimidine reaction replacing under TFA effect.

drug regimen

The present invention also provides a kind of drug regimen, comprises at least one compound described herein or pharmaceutically acceptable salt, solvate or pharmaceutically acceptable carrier.

Here phrase used " pharmaceutically acceptable carrier " refers to material, composition or the medium that pharmacy is accepted, as liquid or solid filler, thinner, auxiliary material, solvent or packaged material, comprise from certain part of an organ or health and carry or transport main pharmaceutical agents to certain part of another organ or health.Each carrier must be " can accept ", can become and patient is not damaged by compatible other forms of medicine.Some can be used as the pharmaceutically example of acceptable carrier and comprise: sugar, as lactose, dextrose plus saccharose sugar; Starch, as wheat starch and yam starch starch; Mierocrystalline cellulose and derivative thereof, as CMC (Sodium Carboxymethyl Cellulose) BP/USP, ethyl cellulose, cellulose acetate, powdery tragakanta, Fructus Hordei Germinatus, gelatin, talcum powder; Auxiliary material, as cocoa butter and suppository wax; Oil, as peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil; Glycol, as butyleneglycol; Polyvalent alcohol, as glycerine, sorbyl alcohol, N.F,USP MANNITOL and polyoxyethylene glycol; Ester, as ethyl oleate and Laurate ethyl; Agar; Buffer reagent, as magnesium hydroxide and aluminium hydroxide; Lalgine; Apirogen water; Physiological saline; Ringer's solution; Ethanol; Phosphate buffered saline buffer, and other nontoxic be applied in pharmaceutical preparation can compatible material.

As described above, some example of this medicament can be presented as the pharmaceutically form of acceptable salt.In this respect, term in the present invention " salt that pharmacy is accepted ", refers to the salt that relatively nontoxic, organic and inorganic acid compound adds formation.These salts in the present invention can be on-the-spot generations when isolation and purification compound in the end, or in single reaction, form with suitable organic or inorganic acid and free alkali when purifying compounds in the present invention, thereby separate and formation salt.Typical salt comprises hydrobromate, hydrochloric acid, vitriol, hydrosulfate, phosphoric acid salt, nitrate, acetate, valerate, oleate, palmitate, stearate, lauroleate, benzoate, lactic acid salt, tosilate, Citrate trianion, maleate, fumarate, succinate, tartrate, naphtholate, mesylate, gluceptate, Lactobionate and dodecane sulfonate etc.(example is referring to Berge et al., (1977) " Pharmaceutical Salts ", j. Pharm. Sci.66:1-19.).

The main compound of pharmacy acceptable salt comprises salt or the quaternary ammonium salt of traditional non-toxic compound, as nontoxic organic or inorganic acid.This nontoxic salt comprises the derivative of mineral acid, example hydrochloric acid salt, hydrobromate, vitriol, sulfamate, phosphoric acid salt, nitrate etc.; The salt of preparing than organic acid, as acetate, butyrates, succinate, glycol hydrochlorate, stearate, lactic acid salt, malate, tartrate, Citrate trianion, ascorbate salt, palmitate, maleate, hydroxymaleic acid salt, phenylacetate, glutaminate, benzoate, salicylate, sulfanilate, Aspirin salt, fumarate, tosylate, methane sulfonates, ethane disulfonic acid hydrogen salt, oxalate, isethionate etc.

In other cases, compound of the present invention may comprise one or more acidic functionalities, therefore can form and pharmacy acceptable salt with pharmaceutically acceptable alkali.Term " salt that pharmacy is accepted " refers to the salt that the compounds of this invention forms with relative nontoxic inorganic and organic bases in this case.These salt in the present invention can be on-the-spot generation when isolation and purification compound in the end equally, or in single reaction, form with suitable organic or inorganic alkali and free acid when purifying compounds in the present invention, oxyhydroxide, carbonate or the supercarbonate of metallic cation of accepting as pharmacy, or ammoniacal liquor, pharmacy organic primary amine, secondary amine or the tertiary amine accepted.Typical an alkali metal salt or alkaline earth salt comprise lithium salts, sodium salt, sylvite, calcium salt, magnesium salts, aluminium salt etc.The organic amine that is typically used to form salt comprises ethamine, diethylamine, quadrol, thanomin, diethanolamine, piperazine etc.(example is referring to Berge et al., supra.).

Wetting agent, emulsifying agent and lubricant, as the multipolymer of sodium lauryl sulphate, Magnesium Stearate, polyethylene oxide and polybutene oxide compound, and among the composition that is also present in of tinting material, releasing agent, coating-forming agent, sweeting agent, spices and fumigating agent, sanitas and antioxidant.

Formula of the present invention comprises those suitable oral cavities, nasal cavity, external application (comprising oral cavity and hypogloeeis), rectum, vagina and vein treatment.This formula can become unit dosage form easily, and can be prepared by any known method pharmaceutically.The dosage of active ingredient can combine with a solid support material and produce single formulation, therapeutic modality that can factor receptor, the difference of specific mode of administration and difference.The dosage of effective ingredient can combine with solid support material and produce single formulation, generally will produce the dosage for the treatment of as this compound.In general, outside 100%, the active ingredient of this dosage is between about 1%-99%, and preferably from about 5%-70% left and right, optimum is about 10%-30% left and right.

The method of preparing these formulas or Chemical Composition in the present invention comprises that compound enters and in conjunction with the step of one or more carriers and assistant agent composition.In the ordinary course of things, formula is prepared into even energy, the carrier in the present invention is combined nearly, as liquid vehicle, solid smalls carrier or both have both at the same time.Then, fashion into if necessary product.

Applicable oral preparation of the present invention can have following form, as capsule, cachet, pill, tablet, lozenge (normally sucrose and Acacia or tragakanta, have certain taste), pulvis, granule, or as a solution or at the non-aqueous liquid being suspended in water, or as water-in-oil or oil-in-water emulsion liquid, or as elixir or syrup, or granular (use such as gelatin and glycerine, the inert base of sucrose and Acacia) and/or collutory and so on, the each predetermined dose of the compounds of this invention as active ingredient that comprise.The compounds of this invention also can be used as bolus, paste or stickup plaster.

At the oral solid formulation (capsule, tablet, pill, drageeing, powder, particle etc.) of invention, its effective ingredient is mixed with one or more pharmaceutically acceptable carriers, as Trisodium Citrate or secondary calcium phosphate, and/or any following content: filler or weighting agent, as starch, lactose, sucrose, glucose, N.F,USP MANNITOL; And/or silicic acid, for example tackiness agent, Xylo-Mucine, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or Sudan Gum-arabic, wetting Agent for Printing Inks, as glycerine; Disintegrating agent, as agar, calcium carbonate, potato or tapioca (flour), alginic acid, some silicate, sodium carbonate, ethanol and Starch Sodium; Separate retardant, as paraffin, absorption enhancer, as quarternary ammonium salt compound; Wetting agent, as hexadecanol, Zerol and polyethylene oxide, polyoxygenated multipolymer; Absorption agent, as kaolin clay, wilkinite, lubricant, as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and composition thereof; And tinting material.The in the situation that of capsule, tablet, pill, drug regimen may also comprise sustained release dosage.Similar solid type composition can use auxiliary material to become soft filling and hard filled capsules, as lactose or caramel, and the weighting material of ultrahigh molecular weight polyethylene(UHMWPE) ethylene glycol and so on.

Tablet can be selected one or more auxiliary composition compressions or moulding.Compressed tablets can be prepared with binding agent (as gelatin or HBMC), lubricating oil, inert diluent, preservation agent, disintegrating agent (as ethanol or Starch Sodium croscarmellose sodium), surfactivity or dispersion agent.Model tablet may be by the mixture of powdered compounds and inert liq diluent, injection molded on a suitable injection moulding machine.

Activeconstituents can be with above-mentioned auxiliary material micro encapsulation.The drug regimen of tablet and other solid preparations of the present invention, as drageeing, capsule, pill, granule, can selectively use coating and shell preparation or moulding, as enteric coating layer, and the coating of other known pharmacy forms.The preparation slow or active ingredient that control discharges also may be provided, and for example, HBMC provides required release profiles different in the situation that, other polymeric matrixs, liposome and/or dermatosome.They may be able to sterilize, and for example, filter bacterium and keep off strainer, or merge sterilization reagent and aseptic solid composition by one, and they dissolve in sterilized water, or in some sterile injectable medium.These compositions also may contain the composition of opacifying agent, or the composition of the active substance slowly discharging, or preferentially form a kind of mode of delay in GI some part.Embed the operable material of composition and comprise polymkeric substance and wax.Activeconstituents also can adopt one or more auxiliary materials to be prepared into microencapsulation form.

Compound oral liquid formulation of the present invention is comprised to pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.Except activeconstituents, the liquid of formulation may contain pharmaceutically conventional inert diluent, for example water or other solvents, solubilising reagent and emulsifying agent, as ethanol, isopropylcarbinol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, methyltrimethylene glycol, 1,3-butyleneglycol, oil (particularly Oleum Gossypii semen, peanut oil, Fructus Maydis oil, sweet oil, Viscotrol C, sesame oil), glycerine, tetrahydrofuran (THF) alcohol, polyoxyethylene glycol and fatty acid ester sorbyl alcohol and composition thereof.In addition, cyclodextrin, as hydroxyl butyl-beta-cyclodextrin, also can be used for the compound dissolving.

Except inert diluent, oral composition can also comprise as wetting agent, emulsification and suspension agent, sweeting agent, essence, pigment, preservation agent and sanitas.

Except active compound, suspension may contain suspension agent, for example Unimac 5680 ethyl ester, polyoxyethylene sorbitol and sorbitol ester, Microcrystalline Cellulose, aluminum metal oxyhydroxide, wilkinite, agar and tragakanta and composition thereof.

The present invention treats rectum or intravaginal drug composite formula can be suppository, it can be comprised and be prepared to sponsor by the compound of one or more inventions and one or more suitable nonirritant excipient or carrier, for example, theobroma oil, polyoxyethylene glycol, a suppository wax or Whitfield's ointment, and be at room temperature solid, but the liquid of body temperature, therefore, will be melted in the invention of rectum or vaginal canal and release active agents.

Formula of the present invention is to be suitable for treating vagina class disease, comprises and contains in pharmacy known carrier as pessary, cotton balls, paste, gel, paste, foam or spray agent.

Part or transdermal administration formulation for the compounds of this invention comprise pulvis, sprays, ointment, ointment, face cream, emulsion, gel, solution, plaster and inhalation.The carrier of accepting with pharmacy under active compound aseptic condition, and any sanitas, buffer reagent, maybe may need to mix.

Except the active ingredient beyond the region of objective existence in the present invention, ointment, ointment, in ointment and gel, may comprise as the auxiliary material of animal and plant fat, oil, wax, paraffin, starch, tragakanta, derivatived cellulose, polyoxyethylene glycol, organosilicon, organobentonite active compound, silicic acid, talcum powder, zinc oxide, or their mixture.

Except the active ingredient beyond the region of objective existence in the present invention, the auxiliary material that powder and spray can comprise is as lactose, talcum, silicic acid, aluminium hydroxide, calcium-silicate and Silon, or the mixture of these materials.Spray may add conventional, if fluorochlorohydrocarbon and volatility are without the hydrocarbon polymer replacing, as butane and butylene.

In the present invention, the patch of compound is distributed with extra benefit to medicine is controllable in health.This formulation can form by the medicament dissolving or be dispersed in buffer medium.Absorption enhancer also can be used for increasing the flux to the medicament in skin the present invention.The rate controlling membranes that this velocity of variation can provide by either party or be dispersed in polymeric matrix or gel compound is controlled.

Ophthalmic preparation, spongaion, powder, solution etc., within also belonging to scope of the present invention.

The drug regimen of the suitable one or more compounds of the present invention is treated and is comprised and one or more pharmaceutically acceptable sterile physiological aqueous solution or non-aqueous solution, dispersion agent, suspension agent or emulsion, or sterilized powder outside intestines.They may be reassembled as aseptic injection or the preferential dispersion agent using, and may contain antioxidant, snubber, and fungistat, can make preparation and expection receiver's the vadose solution such as blood or suspension agent or thickening material close.

In some cases, in order to extend drug effect, can delay the absorption of medicine from subcutaneous or intramuscular injection.This can complete by a suspension liquid with the bad water solubility of crystallization or amorphous substance.The specific absorption of medicine is depended on to its dissolution rate, depend on possibly grain-size and crystal formation simultaneously.In addition, the absorption that postpones the outer therapeutic dosage forms of intestines realizes by being dissolved or suspended in oily medium Chinese traditional medicine.Wherein storage type injection strategy comprises use polyethylene oxide-polybutene oxide compound, and the medium wherein using is mobile in room temperature, in the time of body temperature, solidifies.

Storage type injection type be by host compound at Biodegradable polymeric, make as formed microcapsule under poly-glue ester-polyglycolic acid glue ester.According to the ratio of medicine and polymkeric substance, and the character of special polymkeric substance, drug release rate can be controlled.The poly-example of other biological degradation polymer comprises POE and poly acid anhydrides.Storage type injection type can also be by being embedded in liposome by pharmaceutical pack or prepared by microemulsion, and this and tissue are compatible.

In the time that compound of the present invention is treated to human and animal as medicament, they can itself or as pharmaceutical composition and administration.For example, comprise preferably 0.5%-90% of 0.1%-99.5%() activeconstituents and pharmaceutically acceptable carrier.

Compound in the present invention and pharmaceutical composition can be applied to combination treatment, compound and pharmaceutical composition can be simultaneously before or after, the treatment of one or more required drug uses or medical procedure.This specific combination treatment (treatment or program) that is applied in combining rule is realized required treatment compatibility and/or program and desirable result for the treatment of by considering.The application of this therapy can realize needed effect (for example, compound of the present invention may work with another anti-HCV reagent simultaneously) to identical disease, or likely reaches different effects (as controlled any detrimentally affect).

Compound of the present invention can be by intravenous injection, intramuscular injection, and abdominal injection, subcutaneous injection, external application, oral, or other acceptable ways are treated disease.These compounds can be used for the condition Mammals (for example, the mankind, domestic animal and domestic animal) for the treatment of of arthritis, birds, lizard, and any can compatible these compound other biologicals.

The present invention also provides drug packaging or external member, comprises one or more packagings, wherein contains the drug regimen to one or more compositions in the present invention.Optional this type of form of packing to announce is produced by government organs' specification, uses or sell medicine or biological products with the open method of permitting in production regulation, uses or sell the treatment preparation to people.

similarly describe

Representational example is intended to help to set forth the present invention below, instead of the scope also should not be construed as limiting the invention intentionally.In fact, except those occur and described herein, the full content of file in the present invention, comprises the example according to scientific and technical literature cited herein and patent, and consequent various modification and many further variations are all clear clear to the interior those skilled in the art of this specialty.Be to be further appreciated that, quoting of these reference contributes to statement content herein.Example has below comprised important side information, example and guidance, can be adapted to various variations and analogue in the present invention.

Embodiment 1:N-(3-((2-((4-(6-ethanoyl-2,6-diaza spiroheptane-2-yl)-2-p-methoxy-phenyl) amine)-5-(trifluoromethyl) pyrimidine-4-yl) amine) phenyl) acrylamide

Step 1:(3-((the chloro-5-of 2-(trifluoromethyl) pyrimidine-4-yl) amino) phenyl) t-butyl carbamate

3-aminophenyl t-butyl formate (4.8 g, 23 mmol) is dissolved in propyl carbinol (45 mL), is then cooled to 0 ^oc.The chloro-5-of 2,4-bis-(trifluoromethyl) – pyrimidine (5.0 g, 23 mmol) and DIPEA are added drop-wise in above-mentioned solution successively.The mixture obtaining is at 0-5 ^oc stirs and within one hour, is then raised to room temperature instead until reaction finishes.Then PE for reaction solution (45 mL) making beating filters.Filter cake obtains white solid (3-((the chloro-5-of 2-(trifluoromethyl) pyrimidine-4-yl) amino) phenyl) t-butyl carbamate (4.434 g, productive rate: 49.6%) with collecting vacuum-drying after PE washing.LC-MS:?m/z?389?(M+H) ⁺.

Step 2:N-(3-((the chloro-5-of 2-(trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide

(3-((the chloro-5-of 2-(trifluoromethyl) pyrimidine-4-yl) amino) phenyl) t-butyl carbamate (4.434 g, 11.4 mmol) be dissolved in DCM (44.5 mL), be then cooled to 0 ^oc, slowly drips TFA (44.5 mL) subsequently.Reaction solution is 0 ^oc stir 0.5 hour then concentrating under reduced pressure obtain faint yellow oily N-(3-((the chloro-5-of 2-(trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide, be directly used in next step reaction.LC-MS:?m/z?289?(M+H) ⁺。

Step 3:6-(3-methoxyl group-4-nitrophenyl)-2,6-diaza spiroheptane-2-t-butyl carbamate

The fluoro-2-methoxy nitrobenzene of 4-(520 mg, 3.0 mmol) is dissolved in DMF(20 mL), add subsequently 2,6-diaza spiroheptane-2-t-butyl carbamate (300 mg, 1.7 mmol) and K ₂cO ₃(840 mg, 6.08 mmol).Reaction solution spends the night 70 ° of C reactions, then adds shrend to go out.The mixture obtaining is extracted with ethyl acetate.The concentrated thick product 6-(3-methoxyl group-4-nitrophenyl)-2,6-diaza spiroheptane-2-t-butyl carbamate (300 mg, productive rate: 56%), be directly used in next step reaction of obtaining after anhydrous sodium sulfate drying for organic phase.LC-MS:?m/z?350?(M+H) ⁺。

Step 4:2-(3-methoxyl group-4-nitrophenyl)-2,6-diaza spiroheptane

6-(3-methoxyl group-4-nitrophenyl)-2,6-diaza spiroheptane-2-t-butyl carbamate (300 mg, 2.58 mmol) be dissolved in TFA/DCM (1/4 (v/v), 5 mL), then stirring at room temperature two hours.Reaction solution vacuum concentration obtains thick product 2-(3-methoxyl group-4-nitrophenyl)-2,6-diaza spiroheptane (200 mg, productive rate: 90%), be directly used in next step reaction.LC-MS:?m/z?250?(M+H) ⁺。

Step 5: 1-(6-(3-methoxyl group-4-nitrophenyl)-2,6-diaza spiroheptane-2-yl) ethyl ketone

2-(3-methoxyl group-4-nitrophenyl)-2,6-diaza spiroheptane (200 mg, 0.8 mmol) be dissolved in DCM (10 mL), then be cooled to 0 ° of C, add subsequently TEA (303 mg, 3 mmol) and AcCl (203 mg, 2.6 mmol).Then reaction solution adds shrend to go out for two hours 0 ° of C reaction.Organic phase separates after washing, again with the concentrated thick product 1-(6-(3-methoxyl group-4-nitrophenyl)-2 that obtains of anhydrous sodium sulfate drying final vacuum, 6-diaza spiroheptane-2-yl) ethyl ketone (200 mg, productive rate: 85%), be directly used in next step reaction.LC-MS:?m/z?292?(M+H) ⁺。

Step 6: 1-(6-(3-methoxyl group-4-aminophenyl)-2,6-diaza spiroheptane-2-yl) ethyl ketone

1-(6-(3-methoxyl group-4-nitrophenyl)-2,6-diaza spiroheptane-2-yl) ethyl ketone (200 mg, 2.3 mmol) be dissolved in MeOH (20 mL), add Pd/C (10% wt, 20 mg) subsequently.Under reaction solution atmosphere of hydrogen, (50psi) at room temperature reacted after 12 hours, passed through diatomite filtration.Filtrate vacuum concentration obtains thick product 1-(6-(3-methoxyl group-4-aminophenyl)-2,6-diaza spiroheptane-2-yl) ethyl ketone (140 mg, productive rate: 78%), be directly used in next step reaction.LC-MS:?m/z?262?(M+H)+.

Step 7:N-(3-((2-((4-(6-ethanoyl-2,6-diaza spiroheptane-2-yl)-2-p-methoxy-phenyl) amine)-5-(trifluoromethyl) pyrimidine-4-yl) amine) phenyl) acrylamide

1-(6-(3-methoxyl group-4-aminophenyl)-2,6-diaza spiroheptane-2-yl) ethyl ketone (60 mg, 0.23 mmol) and N-(3-((the chloro-5-of 2-(trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide be dissolved in dioxane (5 mL), then add TFA (1).Mixture concentrates and obtains thick product at 18 hours final vacuums of 50 ° of C reactions.Thick product is separated and is obtained N-(3-((2-((4-(6-ethanoyl-2 by preparative liquid chromatography; 6-diaza spiroheptane-2-yl)-2-p-methoxy-phenyl) amine)-5-(trifluoromethyl) pyrimidine-4-yl) amine) phenyl) acrylamide (20 mg, yield:14%).

¹H?NMR?(400?MHz,?DMSO-d ₆)?δ?10.14?(s,?1H),?8.57?(s,?1H),?8.26?(s,?1H),?8.11?(s,?1H),?7.74?(s,?1H),?7.50?(d,? J?=?7.5?Hz,?1H),?7.37?(d,? J?=?8.5?Hz,?1H),?7.22?(d,? J?=?7.6?Hz,?2H),?6.45?(m,?1H),?6.27?(m,?1H),?6.05?(s,?1H),?5.77?(m,?2H),?4.28?(s,?2H),?4.00?(s,?2H),?3.88?(s,?4H),?3.73?(s,?3H),?1.76?(s,?3H).?LC-MS:?m/z?568?[M+H] ⁺。

Embodiment 2:N-(3-((2-((4-(3-ethanoyl-3,8-diazabicyclo [3.2.1] octane-8-yl)-2-p-methoxy-phenyl) amine)-5-(trifluoromethyl) pyrimidine-4-yl) amine) phenyl) acrylamide

Synthetic method is as embodiment 1

¹H?NMR?(400?MHz,?DMSO-d ₆)?δ?10.17?(s,?1H),?8.61?(s,?1H),?8.26?(s,?1H),?8.09?(s,?1H),?7.74?(s,?1H),?7.44?(m?2H),?7.22?(s,?2H),?6.44?(m,?2H),?6.29?–?6.00?(m,?2H),?5.75?(d,? J?=?9.8?Hz,?1H),?4.22?(s,?2H),?3.91?(d,? J?=?12.3?Hz,?1H),?3.74?(s,?3H),?2.82?(d,? J?=?12.9?Hz,?1H),?1.97-1.90?(m,?4H),?1.87?(s,?2H),?1.75?(d,? J?=?11.1?Hz,?1H),?1.54?(d,? J?=?10.2?Hz,?1H),?1.39-1.33?(m,?1H).?LC-MS:?m/z?582?[M+H] ⁺。

Embodiment 3:N-(3-((2-((4-(4-ethanoyl-4,7-diaza spiro [2.5] octane-7-yl)-2-p-methoxy-phenyl) amine)-5-(trifluoromethyl) pyrimidine-4-yl) amine) phenyl) acrylamide

Synthetic method is as embodiment 1

? ¹H?NMR?(400?MHz,?DMSO-d ₆)?δ?10.18?(s,?1H),?8.67?(s,?1H),?8.28?(s,?1H),?8.07?(s,?1H),?7.74?(s,?1H),?7.55?(d,? J?=?7.1?Hz,?1H),?7.48?(d,? J?=?8.7?Hz,?1H),?7.26?(t,? J?=?7.8?Hz,?1H),?7.14?(s,?1H),?6.54?(s,?1H),?6.47?–?6.35?(m,?1H),?6.26?(m,?1H),?6.13?(s,?1H),?5.76?(d,? J?=?10.0?Hz,?1H),?3.76?(s,?3H),?3.67?(d,? J?=?11.9?Hz,?2H),?3.08?(m,?2H),?2.93?(s,?2H),?2.08?(s,?3H),?1.1-0.68?(m,?4H).?LC-MS:?m/z?582?[M+H] ⁺。

Bioexperiment:

The kinases IC50 test of this compounds to EGFR wild-type and EGFR-T790M sudden change:

EGFR (WT) is wild-type egf acceptor, EGFR (T790M) is for being sported the EGF-R ELISA of methionine(Met) by Threonine with the 790th amino acids, RGFR (L858R) is for to sport arginic EGF-R ELISA with the 858th amino acids by leucine, and EGFR (L858R/T790M) is for sported arginine and the 790th amino acids and sported by Threonine the EGF-R ELISA of methionine(Met) simultaneously by leucine with the 858th amino acids.

Kinase activity detects: that this test is used is Kinase-Glo Plus luminescence kinase assay kit (Promega).After it swashs enzymatic reaction by quantitative analysis, residual ATP content detects kinase activity.Fluorescent signal in test is relevant to existing ATP content.

The reaction solution of configuration 50uL, comprises 40 mM Tris, pH 7.4,10 mM MgCl ₂, 0.1 mg/ml BSA, 1 mM DTT, 0.2 mg/ml Poly (Glu, Tyr) substrate, 10 μ M ATP and EGFR.Testing compound is made into 10%DMSO solution, gets 5uL and be diluted to and in the above-mentioned reaction solution of 50uL, obtain the reaction solution that final DMSO concentration is 1%.All enzymic catalytic reactions are all 30 ^ounder C, carry out 35 minutes.For pre-incubated reaction in 30 minutes, enzyme elder generation and inhibitor hatching 30 minutes, then added ATP and substrate to start reaction.After enzymic catalytic reaction finishes, in reaction solution, add 50uL Kinase-Glo Plus Luminescence kinase assay solution (Promega), continue room temperature hatching 5 minutes.When fluorescent signal by BioTek synergy 2microplate reader measures.

IC50 is with GraphPadPrism5.00(tetra-parameter logistic equations) calculate.

Be the bioassay data of example 1-3 below, record by above-described method.

?in the competition experiments that contains volution or bridged ring compounds and ATP, form irreversible Michael reaction owing to existing with protein cysteine site, so kinases is all embodied to higher inhibition activity.

The above embodiment has only expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but can not therefore be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.

Claims

1. a pyrimidines that contains volution or bridged ring, is characterized in that, the structure that described compound has is formula I: , wherein W is NH, R ₁for hydrogen, halogen or C ₁-C ₄substituted alkyl, R ₂for hydrogen, halogen, C ₁-C ₄alkoxyl group or C ₁-C ₄substituted alkyl, R ₃and R ₄for form volution or the bridged ring of replacement, R together with N atom ₅and R ₆for hydrogen, halogen or C ₁-C ₄substituted alkyl.

2. pyrimidines according to claim 1, is characterized in that, the structure of described volution or bridged ring is: , wherein R ₇for the C replacing ₁-C ₄the C of carboxylic acid group, cycloalkanes carboxylic acid group, replacement ₁-C ₄alkylsulfonyl, cycloalkanes alkylsulfonyl, C ₁-C ₄the C of alkyl, replacement ₁-C ₄alkyl.

3. pyrimidines according to claim 1, it is characterized in that, described pyrimidines also comprises the enantiomorph, diastereomer of formula I, pharmaceutically receptible salt, prodrugs, solvate, tautomer, resonance body, isotopic label.

4. pyrimidines according to claim 1, is characterized in that, in the medicine of described pyrimidines for the preparation for the treatment of tumour.

5. pyrimidines according to claim 4, it is characterized in that, described tumour is any in nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, skin carcinoma, cell carcinoma, gastrointestinal stromal tumors (GISTs), white leukemia, histocyte lymphatic cancer, nasopharyngeal carcinoma.