CN104130265B

CN104130265B - Spiral ring or bridged ring containing pyrimidine compound

Info

Publication number: CN104130265B
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: 2017-01-25
Anticipated expiration: 2034-04-29
Also published as: CN104130265A

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 containing volution or bridged ring

Technical field

The present invention relates to a kind of pyrimidines containing volution or bridged ring, it is related to energy mutation inhibiting type egfr thus answering For treating compound of nonsmall-cell lung cancer and preparation method thereof, also include the drug regimen containing these compounds and application The method of these compounds.

Background technology

In Past 30 Years, lung cancer mortality rises 465%, and sickness rate increases by 26.9% every year, has replaced hepatocarcinoma to become China's first place Death Cause for Malignant Tumors.A kind of disease of this mortality rate highest, seriously threatens the health of the mankind.Wherein non- Small cell lung cancer (non-small cell lung cancer, nsclc) accounts for more than the 80% of all pulmonary carcinoma, only three/ There is the chance of operative treatment in one nsclc patient, about 70% patient has belonged to Locally Advanced when medical or occurred turning at a distance Move, lose operative treatment chance.In this case, Drug therapy seems and is even more important.

In traditional cancer treatment procedure, chemotherapy is main treatment meanss；Chemotherapeutics non-specifically block carefully Born of the same parents divide so that cell death, and they also destroy the growth of human normal cell while killing tumor cell significantly, Bring many untoward reaction.A lot of people make the pessimistic even abandoning cure of mood because of the serious side effects of worry chemotherapy, then plus The drug resistance of upper chemotherapeutics, makes the chemotherapy of nsclc allow of no optimist, and the cycle extending chemotherapy merely add toxic and side effects, and Do not increase curative effect.The cancerous cell of nonsmall-cell lung cancer is insensitive to chemotherapy, conventional chemotherapy simultaneously, and Overall response rate also only has 25% Left and right；Restriction for these reasons, Patients with Non-small-cell Lung five year survival rate is less than 20%.

In patient nsclc of 50%-80%, their EGF-R ELISA (epidermal growth factor Receptor, egfr) all overexpressions, thus causing canceration.Targeting egfr medicine mainly has two classes: a class is to act on receptor The small molecule tyrosine kinase inhibitors (tki) of intracellular region；The another kind of monoclonal antibody being to act on receptor extracellular region (mab).Be applied to clinic first generation egfr inhibitor such as IRESSA, erlotinib, Lapatinib etc., they for The treatment of nsclc pulmonary carcinoma achieves very big success, and Patients with Non-small-cell Lung five year survival rate improves.Meanwhile, with chemotherapy phase Their advantage is to produce bone marrow depression, the side effect such as nausea and neurotoxicity to ratio；But their medicines in monotherapy Effect is relatively low, and has the obviously side effect such as erythra and diarrhoea, and after using 1 year, patient drug resistance to medicine Property.Research thinks that the mutation in egfr gene t790m site is the main inducing of such Drug-resistant, has clinical case data to show Show, caused by about 50% patient's acquired drug-resistance all originates from the mutation in t790m site.Research confirms further, due to egfr Gene t790m be mutated, that is, the threonine encoding be changed into first comb propylhomoserin, thus cause sterically hindered hinder inhibitor with Atp land combines and has ultimately resulted in inhibitor activity forfeiture.The mutation having research display t790m site at present is not direct yet The affinity of impact inhibitor and egfr, but mutation lead to the affinity of egfr and atp to greatly increase so that inhibitor with What the affinity of egfr was relative greatly reduces (inhibitor and atp are competitive bindings).Second filial generation inhibitor such as Afatinib, Dacomitinib, they are characterised by the identity of egfr is increased better than the first generation, can distinguish tumor cell and normal Cell, such side effect will reduce；But the poor selectivity to egfrt790m mutant for these molecules, causes clinical drug resistance to Relatively low by dosage, under its maximum tolerated dose (mtd), medicine cannot reach its valid density in vivo and make resistance to majority Medicine patient is invalid.

In a word, current egfr-tki still can not solve the clinical pressure caused by drug resistance, and existing medicine Mostly thing is that it is to wild-type cell so that quinazoline or egfr that quinoline amine is basic parent nucleus be reversible or irreversible inhibitor The toxic and side effects that poor selectivity is brought are also inevitable.Therefore, exigence new type, especially novel skeleton Compound is solving the problems such as drug resistance, poor selectivity.

Content of the invention

The invention mainly solves the technical problem of providing a kind of pyrimidines containing volution or bridged ring, this chemical combination Thing can suppress kinds of tumor cells.

For solving above-mentioned technical problem, one aspect of the present invention is: provides one kind to contain volution or bridged ring Pyrimidines it is characterised in that the structure that has of described compound is formula i:, Wherein w is nh, r₁For hydrogen, halogen or c₁-c₄Replace alkyl, r₂For hydrogen, halogen, c₁-c₄Alkoxyl or c₁-c₄Replace alkyl, r₃ And r₄It is to form substituted volution or bridged ring, r together with n atom₅And r₆For hydrogen, halogen or c₁-c₄Replace alkyl.

In a preferred embodiment of the present invention, the structure of described volution or bridged ring is:, wherein r₇ For the c replacing₁-c₄Carboxylic acid group, cycloalkane-carboxylic acid's base, the c replacing₁-c₄Sulfonyl, cycloalkanes sulfonyl, c₁-c₄Alkyl, the c replacing₁- c₄Alkyl.

In a preferred embodiment of the present invention, described pyrimidines also include the enantiomer of formula i, diastereomer, Pharmaceutically receptible salt, prodrugs, solvate, tautomer, resonating body, isotopic label.

In a preferred embodiment of the present invention, described pyrimidines are used in the medicine of preparation treatment tumor.

In a preferred embodiment of the present invention, described tumor is nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung Scale cancer, cancer of pancreas, breast carcinoma, carcinoma of prostate, hepatocarcinoma, skin carcinoma, cell carcinoma, gastrointestinal stromal tumors (GISTs), white leukemia, histiocyte Any one in property lymphatic cancer, nasopharyngeal carcinoma.

The invention has the beneficial effects as follows: the pyrimidines containing volution or bridged ring of the present invention, can suppress multiple Tumor cell, especially can selectively acting thin in egfr l858r/t790m and egfr e745_a750/t790m pulmonary carcinoma Born of the same parents, contrast wild type cancerous cell, and the ic50 of such compound wants high 10 times even 100 times of order of magnitude difference, such compound It is novel can the overcoming the drug resistance of existing egfr-tki and there is selective protease inhibitor of a class.With respect to similar Non- volution or bridged ring pyrimidines, the pyrimidines i containing volution or bridged ring will preferably improve its biological generation Thank to stability.

The pyrimidines with formula i architectural feature according to the present invention or its pharmaceutically acceptable salt, can press down The growth of kinds of tumor cells processed, and inhibitory action is produced to other protease of egfr, her family, can be used for effectively suppressing to make Standby antitumor drug, it is possible to overcome the drug resistance of the inductions such as existing medicine gefitinib, Erlotinib, can be used for preparation treatment people The transition proliferative disease such as tumor of class and other mammals.

Specific embodiment

The enforcement it is clear that described will be clearly and completely described to the technical scheme in the embodiment of the present invention below Example is only a part of embodiment of the present invention, rather than whole embodiments.Based on the embodiment in the present invention, this area is common All other embodiment that technical staff is obtained under the premise of not making creative work, broadly falls into the model of present invention protection Enclose.

Following be term used in this specification definition.Unless otherwise noted, group provided herein or term Initially definition is applied in this specification individually or as a part for other groups.

Term " alkyl " refers to straight or branched alkyl, comprises 1-12 carbon atom, especially 1-6 carbon atom.Allusion quotation " alkyl " of type include methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, amyl group, isopentyl, heptyl, 4, 4 dimethyl amyl groups, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl etc..Term " (c₁- c₄) alkyl " refer to straight or branched alkyl, including from 1-4 carbon atom, such as methyl, ethyl, propyl group, isopropyl, positive fourth Base, the tert-butyl group, isobutyl group." replacement alkyl " refers to that one or more of alkyl position is substituted, especially 1-4 replacement Base, can replace on any position.The typical including but not limited to one or more following groups that replace: such as hydrogen, halogen (example As, single halogenic substituent or many halogenic substituents, the latter's such as trifluoromethyl or comprise cl₃Alkyl), 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, the r that wherein here occurs_aPermissible Independent expression 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, r in other words_bAnd r_cHeterocycle can be formed together with n atom；r_eCan independently represent Hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring.Above-mentioned typical substituent group, such as alkyl, cycloalkyl, alkene Base, cycloalkenyl group, alkynyl, heterocycle or aromatic ring can be optionally substituted.

Term " thiazolinyl " refers to that straight or branched alkyl contains 2-12 carbon atom, the replacement of at least one carbon-carbon double bond Base.Typical group includes vinyl or pi-allyl.Term " (c₂-c₆) thiazolinyl " refer to the former containing 2-6 carbon of straight or branched Son, at least group of a carbon-carbon double bond, such as vinyl, acrylic, 2- acrylic, (e)- crotyl, (z) -2-butylene Base, (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- hexene Base, (e) -2- hexenyl, (z) -3- hexenyl, (e) -3- hexenyl and (e) -1,3- hexadienyl." substituted alkenyl " refers to One or more of thiazolinyl position is substituted, and especially 1-4 substituent group can replace on any position.Typical replacement Including but not limited to one or more following groups: such as hydrogen, halogen (for example, single halogenic substituent or many halogenic substituents, the latter Such as trifluoromethyl or comprise cl₃Alkyl), itrile group, nitro, oxygen (as=o), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkene Base, 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, the r that wherein here occurs_aHydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynes can independently be represented Base, heterocycle or aromatic ring, r_b、r_cAnd r_dHydrogen, alkyl, cycloalkyl, heterocycle or aromatic ring, r in other words can independently be represented_bAnd r_c Heterocycle can be formed together with n atom；r_eCan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or Aromatic ring.Above-mentioned typical substituent group, such as alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring can be optionally substituted.

Term " alkynyl " refers to that straight or branched alkyl contains 2-12 carbon atom, the replacement of at least one triple carbon-carbon bonds Base.Typical group includes acetenyl.Term " (c₂-c₆) alkynyl " and refer to straight or branched containing 2-6 carbon atom, at least There is the group of a carbon-carbon double bond, such as acetenyl, 1- propinyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 1- pentynyl, 2- Pentynyl, 1- hexin base, 2- hexin base, 3- hexin base." substituted alkynyl " refers to that one or more of alkynyl position is substituted, Especially 1-4 substituent group, can replace on any position.Typical replacement includes but is not limited to one or more following bases Group: as hydrogen, halogen (for example, single halogenic substituent or many halogenic substituents, the latter's such as trifluoromethyl or comprise cl₃Alkyl), 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 here The r occurring_aHydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring, r can independently be represented_b、r_cAnd r_dPermissible Independent expression hydrogen, alkyl, cycloalkyl, heterocycle or aromatic ring, r in other words_bAnd r_cHeterocycle can be formed together with n atom；r_eCan Represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring with independent.Typical substituent group can optionally take Generation.

Term " cycloalkyl " refers to fully saturated ring-type hydro carbons compound group, including 1-4 ring, contains in each ring 3-8 carbon atom.“(c₃-c₇) cycloalkyl " it is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl." replace cycloalkanes Base " refers to that one or more of cycloalkyl position is substituted, and especially 1-4 substituent group can replace on any position.Allusion quotation The replacement of type includes but is not limited to one or more following groups: such as hydrogen, (for example, single halogenic substituent or many halogens take halogen Dai Ji, the latter's such as trifluoromethyl or comprise cl₃Alkyl), itrile group, nitro, oxygen (as=o), trifluoromethyl, trifluoromethoxy, ring Alkyl, 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, the r that wherein here occurs_aHydrogen, alkyl, cycloalkyl, alkene can independently be represented Base, cycloalkenyl group, alkynyl, heterocycle or aromatic ring, r_b、r_cAnd r_dHydrogen, alkyl, cycloalkyl, heterocycle or aromatic ring can independently be represented, or Person says r_bAnd r_cHeterocycle can be formed together with n atom；r_eHydrogen, alkyl, cycloalkyl, thiazolinyl, cyclenes can independently be represented Base, alkynyl, heterocycle or aromatic ring.Above-mentioned typical substituent group can be optionally substituted.Typical replacement also includes volution or condensed ring takes Dai Ji, especially spiro cycloalkyl group, volution thiazolinyl, Spirocyclic heterocyclic (not including hetero-aromatic ring), cycloalkyl, condensed ring thiazolinyl, condensed ring are miscellaneous Ring group or condensed ring aromatic ring yl, above-mentioned cycloalkyl, cycloalkenyl group, heterocyclic radical and heterocyclic aryl can be optionally substituted.

Term " cycloalkenyl group " refers to partly undersaturated ring-type hydro carbons compound group, including 1-4 ring, contains in each ring There is 3-8 carbon atom.Typical cycloalkenyl group such as cyclobutane base, cyclopentenyl, cyclohexenyl group etc.." substituted cycloalkenyl " refers to One or more of cycloalkyl position is substituted, and especially 1-4 substituent group can replace on any position.Typically take Generation including but not limited to one or more following group: such as hydrogen, halogen (for example, single halogenic substituent or many halogenic substituents, after Person's such as trifluoromethyl or comprise cl₃Alkyl), itrile group, nitro, oxygen (as=o), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkene Base, 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, the r that wherein here occurs_aHydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynes can independently be represented Base, heterocycle or aromatic ring, r_b、r_cAnd r_dHydrogen, alkyl, cycloalkyl, heterocycle or aromatic ring, r in other words can independently be represented_bAnd r_c Heterocycle can be formed together with n atom；r_eCan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or Aromatic ring.Above-mentioned typical substituent group can be optionally substituted.Typical replacement also includes volution or fused ring substituents, especially volution Alkyl, volution thiazolinyl, Spirocyclic heterocyclic (not including hetero-aromatic ring), cycloalkyl, condensed ring thiazolinyl, fused ring heterocycle base or condensed ring aromatic ring Base, above-mentioned cycloalkyl, cycloalkenyl group, heterocyclic radical and heterocyclic aryl can be optionally substituted.

Term " aryl " refers to aromatic ring-shaped hydrocarbon compound group, has 1-5 ring, especially monocyclic and bicyclic group Group, such as phenyl, xenyl or naphthyl.All containing two or more aromatic rings (bicyclic etc.), the aromatic rings of aromatic yl group can (as biphenyl) is coupled by singly-bound, or condenses (as naphthalene, anthracene etc.)." substituted aryl " refers to one or more of aryl position Substituted, especially 1-3 substituent group, can replace on any position.Typical replacement is including but not limited to one or more Following group: as hydrogen, halogen (for example, single halogenic substituent or many halogenic substituents, the latter's such as trifluoromethyl or comprise cl₃'s Alkyl), itrile group, nitro, oxygen (as=o), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, virtue 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, The r that wherein here occurs_aHydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring, r can independently be represented_b、r_c And r_dHydrogen, alkyl, cycloalkyl, heterocycle or aromatic ring, r in other words can independently be represented_bAnd r_cCan be formed together with n atom Heterocycle；r_eHydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring can independently be represented.Above-mentioned typical replacement Base can be optionally substituted.Typical replacement also includes fused ring substituents, especially cycloalkyl, condensed ring thiazolinyl, fused ring heterocycle base Or condensed ring aromatic ring yl, above-mentioned cycloalkyl, cycloalkenyl group, heterocyclic radical and heterocyclic aryl can be optionally substituted.

Term " carbocyclic ring " refers to fully saturated or partly undersaturated ring-type hydro carbons compound group, including 1-4 ring, often 3-8 carbon atom is contained in individual ring.Or aromatic ring-shaped hydrocarbon compound group, has 1-5 ring, especially monocyclic and bicyclic Group, such as phenyl, xenyl or naphthyl.Term " carbocyclic ring " includes cycloalkyl, cycloalkenyl group, cycloalkynyl radical and aryl defined above. Term " replacement carbocyclic ring " refers to that one or more of carbocyclic ring or carbocyclic ring substituent group position is substituted, especially 1-4 replacement Base, can replace on any position.Typical replacement includes but is not limited to above-described group: such as substituted cycloalkyl, replacement Cycloalkenyl group, replacement cycloalkynyl radical and substituted aryl.Typical replacement includes volution or the fused ring substituents gone up at an arbitrary position, especially It is spiro cycloalkyl group, volution thiazolinyl, Spirocyclic heterocyclic (not including hetero-aromatic ring), cycloalkyl, condensed ring thiazolinyl, fused ring heterocycle base or condensed ring Aromatic ring yl, above-mentioned cycloalkyl, cycloalkenyl group, heterocyclic radical and heterocyclic aryl can be optionally substituted.

Term " heterocycle " and " heterocycle " refer to fully saturated or partly undersaturated or completely undersaturated inclusion The cyclic group (such as 4-7 unit monocycle, 7-11 membered bicyclic, or 8-16 membered tricyclic system) of aromatic ring (as hetero-aromatic ring), wherein at least has One hetero atom is present at least in the ring of a carbon atom.Each contains heteroatomic heterocycle and can carry 1,2,3 or 4 Hetero atom, these hetero atoms are selected from nitrogen-atoms, oxygen atom/or sulphur atom, and wherein nitrogen-atoms or sulphur atom can be oxidized, and nitrogen is former Son can also be quaternized.(term " hetero-aromatic ring ion " refers to containing quaternary carbon, positively charged heteroaromatic group.) heterocyclic radical Group may be coupled on ring or any hetero atom of ring system molecule or the residue of carbon atom.Typical monocyclic heterocycles include azacyclo- Butane group, pyrrolidinyl, pyrrole radicals, pyrazolyl, oxetanyl, pyrazolinyl, imidazole radicals, imidazolinyl, imidazolidinyl, Oxazolyl, oxazolidinyl, isoxazole alkyl, isoxazolyl, thiazolyl, thiadiazolyl group, thiazolidinyl, isothiazolyl, isothiazole Alkyl, furyl, tetrahydrofuran base, thienyl, di azoly, piperidyl, piperazinyl, 2- oxopiperazinyl, 2- oxo-piperidine Base, 2- oxo-pyrrolidine base, 2- oxo azepines base, azepines base, hexahydroazepine base, 4- piperidone base, pyridine radicals, pyrrole Piperazine base, pyrimidine radicals, pyridazinyl, three nitrogen piperazine bases, triazol radical, tetrazole base, THP trtrahydropyranyl, morpholine base, thio morpholine Base, thio morpholine sulfoxide group, thio morpholine sulfuryl, 1,3- dialkyl group and tetrahydrochysene -1,1- dioxy thiophene etc..Typical case Bicyclic heterocycle include indyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzo oxygen di azoly, benzothienyl, Benzo [d] [1,3] two oxyalkyls, 2,3-dihydrobenzo [b] [1,4] two oxyalkyls, quinine base, quinolyl, tetrahydrochysene be different Quinolyl, isoquinolyl, benzimidazolyl, benzopyranyl, indolinyl, benzofuranyl, coumaran base, color Man Ji, coumarin base, cinnolines base, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridyl are (as furo [2,3-c] pyridine radicals, furo [3,2-b] pyridine radicals or furo [2,3-b] pyridine), dihydro-iso indolyl, dihydroquinazoline base (such as 3,4- dihydro -4- oxoquinazolin base), three azepine azepines bases, tetrahydric quinoline group etc..Typical tricyclic heterocyclic includes carbazole Base, benzindole, phenanthroline, acridinyl, phenanthridinyl, xanthyl etc..Term " heterocycle " potentially includes substituted heterocycle.

" substituted heterocycle " and " substituted heterocycle " (as replace hetero-aromatic ring) refer to one of heterocycle or heterocyclic group or Multiple positions are substituted, and especially 1-4 substituent group can replace on any position.Typical replacement including but not limited to one Individual or multiple following groups: such as hydrogen, halogen (for example, single halogenic substituent or many halogenic substituents, the latter such as trifluoromethyl or bag Containing cl₃Alkyl), 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, the r that wherein here occurs_aHydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or virtue can independently be represented Ring, r_b、r_cAnd r_dHydrogen, alkyl, cycloalkyl, heterocycle or aromatic ring, r in other words can independently be represented_bAnd r_cTogether with n atom Heterocycle can be formed；r_eHydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring can independently be represented.Above-mentioned allusion quotation The substituent group of type can be optionally substituted.Typical replacement also includes fused ring substituents, especially cycloalkyl, condensed ring thiazolinyl, thick Ring heterocyclic radical or condensed ring aromatic ring yl, above-mentioned cycloalkyl, cycloalkenyl group, heterocyclic radical and heterocyclic aryl can be optionally substituted.

Term " alkylamine " refers to carry structured-nhr ' group, wherein r ' refer to halogen, alkyl or substituted alkyl, Cycloalkyl or substituted cycloalkyl, as hereinbefore defined.The example of alkylamine including but not limited to one or more following groups: As methylamino, ethylamino-, n-propylamine base, isopropylamine base, cyclopropyl amino, n-butylamine-based, tert-butylamine base, neopentyl amine base, n-amylamine Base, hexylamine base, cyclohexylamino etc..

Term " dialkylamine " refers to carry structured-nrr ' group, the representative alkyl that wherein r and r ' can be independent or take The alkyl in generation, cycloalkyl or substituted cycloalkyl, cycloalkenyl group or substituted cycloalkenyl group, aryl or substituted aryl, heterocycle or take The heterocycle in generation, as hereinbefore defined.R and r' can be identical or different in dialkylamine fragment.The example of dialkylamine includes But be not limited to one or more following groups: as dimethylamino, Methylethyl amido, diethylin, methyl-propyl amido, two (n-pro-pyl) amido, two (isopropyl) amido, two (cyclopropyl) amido, two (normal-butyl) amido, two (tert-butyl group) amido, two (neopentyl) amido, two (n-pentyl) amido, two (hexyl) amido, two (cyclohexyl) amido etc..In some instances, r and R' connects together and forms a circulus.Consequent circulus can be aromatic rings or non-aromatic ring.Ring-type dioxane Base amine includes but is not limited to following group, such as aziridinyl, pyrrolinyl, piperidyl, morpholinyl, pyrrole radicals, imidazole radicals, 1, 3,4 triazol radicals and tetrazole base.

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

Unless otherwise indicated it is assumed that the hetero atom of any discontented valence state has enough hydrogen atoms to supplement its valence state.

The salt that compound in the present invention is likely to form also is belonging to the scope of the present invention.Unless otherwise stated, the present invention In compound be understood to include its esters.Term " salt " as used herein, refers to form acid with inorganic or organic bronsted lowry acids and bases bronsted lowry Or the salt of alkali formula.Additionally, when the compound in the present invention contains a basic moiety, it includes but is not limited to pyridine or imidazoles, During containing an acidic moiety, including but not limited to carboxylic acid, it is possible to create amphion (" inner salt ") be included in term " salt " In the range of.Pharmaceutically acceptable (i.e. nontoxic, physiologically acceptable) salt be first-selected although other salts are also useful, for example may be used With the isolated or purified step in preparation process.The compound of the present invention is likely to form salt, for example, compound i with certain The acid of amount such as equivalent or alkali reaction, saltout out in media as well, or lyophilization get in aqueous.

The basic moiety that compound in the present invention contains, including but not limited to amine or pyridine or imidazole ring, may be with Organic or inorganic acid forming salt.Can become salt typically acid include acetate (as with acetic acid or three halogenated acetic acids, such as trifluoro second Acid), adipate, alginate, Ascorbate, aspartate, benzoate, benzene sulfonate, disulfate, boric acid Salt, butyrate, citrate, Camphora salt, camsilate, cyclopentane propionate, diethylene glycol hydrochlorate, lauryl sulfate, Ethane sulfonate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, caproate, hydrochlorate, hydrogen Bromate, hydriodate, isethionate (e.g., 2- isethionate), lactate, maleate, mesylate, naphthalene sulphur Hydrochlorate (e.g., 2- naphthalene sulfonate), nicotinate, nitrate, oxalates, pectate, persulfate, phenpropionate are (as 3- phenylpropyl alcohol Hydrochlorate), phosphate, picrate, Pivalate, propionate, salicylate, succinate, sulfate are (as formed with sulphuric acid ), sulfonate, tartrate, rhodanate, mesylate such as tosilate, dodecanoate etc..

The acidic moiety that the compound of the present invention contains, including but not limited to carboxylic acid, may be with various organic or inorganics Alkali forming salt.The salt that typical alkali is formed includes ammonium salt, alkali metal salt such as sodium, lithium, potassium salt, alkali salt such as calcium, magnesium salt, and The salt (as organic amine) that organic base is formed, such as benzyl star, dicyclohexyl amine, extra large bar amine (withn ,n- two (dehydroabietyl) ethylenediamine The salt being formed),n- methyl-d- glycosamine,n- methyl-d- glucamide, tert-butylamine, and and aminoacid such as arginine, The salt that lysine etc. is formed.Basic nitrogen-containing groups can with halogenide quaternary ammonium salt, such as lower alkyl halogenide (as methyl, The chloride of ethyl, propyl group and butyl, bromide and iodide), and dialkyl sulfate (e.g., dimethyl sulfate, diethylester, two Butyl ester and diamyl ester), long chain halide (as the chloride of decyl, dodecyl, myristyl and myristyl, bromide and Iodide), aralkyl halide (as benzyl and pheriyl bromide) etc..

In the present invention, the prodrug of compound and solvate are also within the scope of covering.Term " prodrug " refers to one herein Kind of compound, in therapy-related disease, produce through the chemical conversion of metabolism or chemical process compound in the present invention, Salt or solvate.The compound of the present invention includes solvate, such as hydrate.

Compound in the present invention, salt or solvate, it is understood that there may be tautomeric form (such as amide and imines Ether).All these tautomers are all the parts of the present invention.

(for example, those are due to former to various replacement asymmetric carbon that may be present for the stereoisomer of all compounds Son), including its enantiomeric form and diastereomeric forms, broadly fall into the imagination scope of the present invention.Compound in the present invention is independent Stereoisomer may not exist with other isomers (for example, as a pure or substantially pure optics simultaneously Isomer has special activity), or be also likely to be mixture, such as raceme, or with every other stereoisomer or its In a part formed mixture.The chiral centre of the present invention has two kinds of configurations of s or r, by theoretical connection international with applied chemistry Credit union (iupac) suggestion in 1974 definition.Racemic form can be solved by physical method, for example fractional crystallization, or by spreading out Life is diastereomeric separation crystallization, or is separated by chiral column chromatography.Single optical isomer can be by suitable Method is obtained by racemic modification, including but not limited to traditional method, for example, become recrystallization after salt with optically active acid.

Compound in the present invention, pass sequentially through preparation, isolate and purify acquisition its weight content of this compound be equal to or More than 90%, for example, equal to or more than 95%, equal to or more than the compound of 99%(" very pure "), list in text description. The compound of this herein " very pure " present invention also serves as the part of the present invention.

The all of configurational isomer of compound of the present invention all within the scope of covering, either 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 carbocyclic ring Cis and trans isomer with heterocycle.

Throughout the specification, group and substituent group can be selected to provide stable fragment and compound.

Particular functional group and technical terms of chemistry definition are all described in detail as follows.For purposes of the invention, chemical element with periodic table of the elements, cas version,handbook of chemistry and physics, 75^thEd. consistent defined in.The definition of particular functional group also describes wherein.Additionally, it is vitochemical basic Principle and particular functional group and reactivity are in " organic chemistry ", thomas sorrell, university Science books, sausalito:1999, are also described, and entire contents include the row of list of references.

Some compounds of the present invention are likely to be present in specific geometry or stereoisomer form.The present invention covers all Compound, different including its cis and trans isomer, r and s enantiomer, diastereomer, the isomer of (d) type, (l) type Structure body, racemic mixture and other mixture.In addition asymmetric carbon atom can represent substituent group, such as alkyl.All isomers And their mixture, all forgive in the present invention.

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

Present invention additionally comprises isotope-labeled compound, it is equal to original chemical and is disclosed.But actually right One or more atoms is replaced by the atom different from its atomic weight or quality ordinal number and generally occurs.The present invention can be classified as The isotopic example of compound include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotope, respectively such as²h、³h、¹³c、¹¹c、¹⁴c 、¹⁵n、¹⁸o、¹⁷o、³¹p、³²p、³⁵s、¹⁸F and³⁶cl.Compound in the present invention, or enantiomer, diastereomer, isomer, or medicine Acceptable salt or solvate on, the wherein isotope containing above-claimed cpd or other other isotope atoms are all at this Within the scope of invention.Some compound isotopically labelleds in the present invention, for example³H and¹⁴The radiosiotope of c also wherein, The tissue distribution experiment of medicine and substrate is useful.Tritium, that is,³H and carbon-14, that is,¹⁴C, their preparation and detection are compared Easily.It is the first-selection in isotope.Additionally, higher isotope replaces such as deuterium, that is,²H, because its good metabolic stability is at certain Advantageous in a little therapies, for example increase the half-life in vivo or reduce consumption, therefore, can pay the utmost attention in some cases. Isotope-labeled compound can be replaced with non isotopic with general method by the isotope labeling reagent with being easy to get Reagent, can be prepared with the scheme in example.

If the synthesis of the specific enantiomer of compound designing a present invention, it can be prepared with asymmetric synthesis, Or use chiral auxiliaries derivatization, produced mixture of diastereomers is separated, then removes chiral auxiliaries and obtain pure enantiomer. In addition, if containing a basic functionality, such as aminoacid, or acidic functionality, such as carboxyl in molecule, suitable light can be used Learn the acid of activity or the formation diastereomeric salt therewith of alkali, then separated by the conventional meanses such as fractional crystallization or chromatograph, so Just obtain pure enantiomer afterwards.

As described herein, the compound in the present invention can take and expand it and forgive model with any quantity substituent group or functional group Enclose.Generally, term " replacement ", no matter occurring in term " optional " above or below, includes the logical of substituent group in inventive formulation Formula, refers to use specified structure substituent group, replaces hydroperoxyl radical.As multiple in ad hoc structure in position by multiple specific replacements When base replaces, each position of substituent group can be identical or different.Term " replacement " used herein includes all fair Permitted organic compound to replace.In broad terms it is allowed to substituent group include acyclic, ring-type, side chain non-branched, carbon Ring and heterocycle, aromatic ring and non-aromatic ring organic compound.In the present invention, as hetero atom nitrogen can have hydrogen substituent group or The organic compound mentioned above of any permission is supplementing its valence state.Additionally, the present invention be not intended to be in any way limiting fair Permitted substituted organic compound.It is considered herein that the group of substituent group and variable groups is combined in stable compound form controlling in disease It is good in treatment, such as infectious disease or proliferative disease.Term " stablizing " refers to there is stable compound, enough herein In the long time, detection, enough to maintain the integrity of compound structure, all in effect preferably within the sufficiently long time, exists herein This is for the above purpose.

In one embodiment, this application provides a kind of using the compound with formula i and its pharmaceutically acceptable The excess proliferative disease such as salts for treating people or other mammal tumors or symptom.

In one embodiment, the compound designed by the application and its pharmaceutically acceptable salt can be used for treatment or Control nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast carcinoma, carcinoma of prostate, hepatocarcinoma, skin carcinoma, The hyperproliferative diseases such as cell carcinoma, gastrointestinal stromal tumors (GISTs), leukemia, histiocytic lymphatic cancer, nasopharyngeal carcinoma.

Drug metabolism and prodrug: the compound involved by the application and its metabolite of pharmaceutically acceptable salt, and The prodrug of the structure of compound involved by the application and its pharmaceutically acceptable salt can be changed in vivo, be also contained in this In the claim of application.

Drug combination: formula i compound can be to known treatment or the other drugs combination improving similar condition of illness.Combine to During medicine, the administering mode ＆ dosage of originally medicine keeps constant, and subsequently or simultaneously takes the compound of formula i.When formula i compound When taking with one or more medicines other simultaneously, preferably use and contain one or more known drugs and formula i compound simultaneously Pharmaceutical composition.The time period that drug combination is also included within overlap takes formula i compound and other medicines known to one or more Thing.When formula i compound carries out drug combination with one or more medicines other, the dosage of formula i compound or known drug can Can be lower than the dosage that their independent medications are.

The medicine of drug combination can be carried out with i compound or active component includes but is not limited to:

Estrogenic agents, androgen receptor adjustment, retina receptor modulators, cytotoxin/cytostatics, Antiproliferative, protein transferase inhibitor, hmg-coa reductase inhibitor, hiv kinases inhibitor, reverse transcriptase suppression Agent, angiogenesis inhibitor, cell proliferation and survival signaling inhibitor, the medicine of interference cell cycle check and apoptosis lure Lead agent, cytotoxic drug, tyrosine protein inhibitor, egfr inhibitor, vegfr inhibitor, serine/threonine protein suppression Preparation, bcr-abl inhibitor, c-kit inhibitor, met inhibitor, raf inhibitor, mek inhibitor, mmp inhibitor, topology are different Structure enzyme inhibitor, Histone deacetylase inhibitor, protesome inhibitors, cdk inhibitor, the suppression of bcl-2 family protein Agent, mdm2 family protein inhibitor, iap family protein inhibitor, stat family protein inhibitor, pi3k inhibitor, atk suppression Agent, integrin blocker, interferon-' alpha ', interleukin-i2, cox-2 inhibitor, p53, p53 activator, vegf antibody, egf resist Body etc..

In one embodiment, the medicine of drug combination can be carried out with i-iii chemical combination or active component include but not Be limited as: aldesleukin, alendronic Acid, interferon, Ah Qu Nuoying, allopurinol, allopurinol sodium, palonosetron hydrochlorate, Altretamine, amino glutethimide, peace phosphorus spit of fland, peace soft than star, SN-11841, arimidex, dolasetron, aranesp, Arglabin, arsenic trioxide, Aromasin, U-18496, azathioprine, bacillus calmette-guerin vaccine or tice bacillus calmette-guerin vaccine, bestatin, acetic acid Betamethasone, betamethasone sodium phosphate inhibitor, bexarotene, Bleomycin Sulphate, broxuridine, bortezomb, busulfan, Calcitonin, A Laizuo monoclonal antibody injection, Capecitabine, carboplatin, CASODEX, cefesone, celmoleukin, daunorubicin, benzene Butanoic acid chlormethine, cisplatin, cladribine, chlorine bend phosphoric acid, cyclophosphamide, cytosine arabinoside, dacarbazine, D actinomycin D d, daunorubicin Liposome, dexamethasone, dexamethasone phosphate, estradiol valerate, denileukin diftitox, Di Bomei, deslorelin, dilazep assistant be raw, Diethylstilbestrol, Fluconazole, docetaxel, Doxifluridine, amycin, dronabinol, admire -166- chitosan complexes, Eligrand, rasburicase, Epirubicin Hydrochloride, aprepitant, epirubicin, Epoetin Alfa, erythropoietin, according to Platinum, Ergamisole, estradiol inhibitor, 17-β-estradiol, estramustine phosphate sodium, female alkynol, amifostine, hydroxyl phosphoric acid, all Bi Fu, etoposide, fadrozole, tamoxifen preparation, filgrastim, Tamsulosin, Fei Leisi replace, floxuridine, fluconazol, fluorine Reach and draw shore, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, fluoxymesterone, flutamide, formestane, 1- β-d Ah Sugared furanose born of the same parents' thialdine -5 '-hard acyl phosphate ester, fotemustine, fluorine Wei Siqiong, gamma globulin, gemcitabine, lucky appropriate list Anti-, imatinib mesylate, carmustine wafer capsule, Ge Shelinrui, hydrochloric acid glug Ni Xi Gansu Province, Supprelin, Hycamtin, hydrogen Change cortisone, erythro-hydroxynonyl adenine, hydroxyurea, replace smooth different shellfish not monoclonal antibody, idarubicin, ifosfamide, interferon α, Intederon Alpha-2a, Interferon Alpha-2b, interferon alfa-n1, Alferon N, interferon beta, interferon gamma-la, interleukin- 2, intron a, IRESSA, Irinotecan, Kytril, sulphuric acid lentinan, letrozole, formyl tetrahydrofolic acid, leuprorelin, bright Third nafarelin acetate salt, L-tetramisole, levo leucovorin calcium salt, levothyroxine sodium, levothyroxine sodium preparation, Luo Mosi Spit of fland, lonidamine, dronabinol, chlormethine, Mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterification is female to swash Element, Ismipur, mesna, methotrexate, amino-laevulic acid methyl ester, come for good fortune is new, minocycline, mitomycin c, rice Tuo Tan, rice support Herba Alii fistulosi quinone, trilostane, citric acid Evacet, nedaplatin, Pegfilgrastim, Puri difficult to understand are white Interleukin, neupogen, nilutamide, tamoxifen, nsc-631570, recombination human interleukins-11-β, octreotide, hydrochloric acid are difficult to understand Red Shillong, dehydrohydro-cortisone oral solution, oxaliplatin, paclitaxel, Pediapred, pegaspargase, group Luo Xin, pentostatin, Picibanil, hydrochloric acid pilocarpine, adjoin soft than star, plicamycin, porfimer sodium, prednimustine, Prednisolone steaglate, prednisone, premarin, the third kappa umbilicuss, epoetin, thunder carry Qu Sai, Rebif, according to for phosphorus Sour rhenium -186, Mabthera, Redoxon-a, romurtide, Salagen, octreotide, sargramostim, semustine, Sizofiran, sobuzoxane, bluff sodium Solu-Medrol, Paphos acid, stem-cell therapy, streptozocin, Metastron, levothyrocine Sodium, tamoxifen, YM-617, Ta Suonaming, tastolactone, taxotere, teceleukin, temozolomide, teniposide, Testosterone Propionate, thioguanine, thio-tepa, thyrotropin, for Shandong phosphoric acid, topotecan, toremifene, tositumomab, Herceptin, treosulfan, Retinoic acid, methylamine dish purine tablet, trimethyl melamine, trimetrexate, acetic acid triptorelin, double hydroxyl Naphthoic acid triptorelin, excellent good fortune pyridine, uridnine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, The protein stabilized preparation of virulizin, ADR-529, Zinostatin stimalamer, Zofran, paclitaxel, aco lbifene/ interferon γ-lb, affinitak, amino dish purine, arzoxifene, asoprisnil, atamestane, bay43-9006, Avastin, That support of cci-779, cdc-501, celecoxib, Cetuximab, carat, cyproterone acetate, decitabine, dn-101/ Ah Mycin-mtc, dslim, dutasteride, edotecarin, eflornithine, Exatecan, fragrant dimension a amine, histamine dihydrochloric acid, Supprelin hydrogel implant, holmium -166dotmp, ibandronic acid, interferon gamma, intron-peg, ixabepilone, spoon Hole shape hemocyanin, l-651582, lanreotide, lasofoxifene, libra, lonafamib, Miproxifene, minot bend acid esters, ms- 209th, liposome mep-pe, mx-6, nafarelin, Nemorubicin, Neovastat, Nola Qu Te, Ao Limosen, onco- Tcs, osidem, paclitaxel polyglutamic acid esters, pamidronate disodium injection, pn-401, os-21, overstate the West, r-1549, raloxifene, the leopard frog Enzyme, 13- along Retinoic acid, Satraplatin, seocalcitol, t-138067, tarceva, docosahexenoic acid paclitaxel, thymosin α1, Loud, high-pitched sound azoles furan woods, tipifarnib, for pulling eye is bright, tlk-286, toremifene, trans mid-lo7r, valspodar, vapreotide, Vatalanob, Verteporfin, vinflunine, z-100 and Zoledronate or their combination.

On the one hand, the present invention provide compound structure as shown in formula i,

i

Or its enantiomer, diastereomer, resonating body, or pharmaceutically acceptable salt or solvate, wherein:

W can independently represent nh；

r₁Hydrogen, halogen, (c can independently be represented₁-c₄) replace alkyl；

r₂Hydrogen, halogen, (c can independently be represented₁-c₄) replace alkyl, (c₁-c₄) alkoxyl；

r₃And r₄Form substituted volution or bridged ring together with n atom, can be, but not limited to, following group:

r₇(the c replacing can be independently expressed as₁-c₄) carboxylic acid group, cycloalkane-carboxylic acid's base, replace (c₁-c₄) sulfonyl, cycloalkanes Sulfonyl, (c₁-c₄) alkyl, replace (c₁-c₄) alkyl；

r₅And r₆Hydrogen, halogen, (c can independently be represented₁-c₄) replace alkyl.

Following table is abbreviation:

The compound covered in the present invention can be synthesized by known conventional art.These compounds can from convenient can Initiation material advantageously synthesizes.The following is the general synthetic schemes of compound of present invention synthesis.These sides disclosed herein Case is descriptive, is not offered as limiting those skilled in the art using other possible method synthesis compounds.Various sides Method is all the routine techniquess in this area.In addition, different synthesis steps can apply synthesis targeted in different schemes Compound.Among all documents cited herein are all expressly incorporated herein by way of reference.

The compound with formula i can be closed by below scheme and experienced personal knowledge in this field Become.Scheme 1 describes to synthesize the distinct methods of these intermediate, these methods can apply have in patent of the present invention logical In the preparation of compound of formula i iv structure.Those skilled in the art can complete to make by the various modifications of these methods The synthesis of person's analogue compounds disclosed below.

Have formula i compound prepare as follows:

Step 1: with dmso as solvent, to fluoronitrobenzene ii in k₂co₃In the presence of and amine reaction obtain in the middle of paranitroanilinum Body iii.

Step 2: under an atmosphere of hydrogen, hydrogenating reduction obtains intermediate iv to intermediate iii in methyl alcohol.

Step 3: intermediate 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 is pharmaceutically subjected to Salt, solvate or pharmaceutically acceptable carrier.

Refer to pharmaceutically acceptable material, composition or medium used herein of phrase " pharmaceutically acceptable carrier ", such as liquid Body or solid packing, diluent, adjuvant, solvent or encapsulating material, including certain part from an organ or body to another Certain part of organ or body carries or transports main pharmaceutical reagent.Each carrier must be " can accept ", can compatible other The medicine of form becomes and patient is not damaged.Some can include as the example of pharmaceutically acceptable carrier: sugar, such as Lactose, dextrose and saccharose sugar；Starch, such as wheaten starch and potato starch starch；Cellulose and its derivates, such as sodium carboxylic first Base cellulose, ethyl cellulose, cellulose acetate, powdered gum tragacanth, Fructus Hordei Germinatus, gelatin, Pulvis Talci；Adjuvant, such as cocoa butter And suppository wax；Oil, such as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum sesami, olive oil, Semen Maydis oil and Oleum Glycines；Glycol, such as butanediol； Polyhydric alcohol, such as glycerol, Sorbitol, Mannitol and Polyethylene Glycol；Ester, such as ethyl oleate and ethyl laurate；Agar；Buffer agent, As magnesium hydroxide and aluminium hydroxide；Alginic acid；Apirogen water；Normal saline；Ringer's solution；Ethanol；Phosphate buffer, and What other were nontoxic applies the compatible material in pharmaceutical preparation.

As described above, some examples of this medicament can be presented as the form of pharmaceutically acceptable salt.In this side Face, the term " pharmaceutically acceptable salt " in the present invention, refer to relative nontoxic, organic and inorganic acid compound adds and formed Salt.These salts in the present invention can be that scene produces when being finally separating with purifying compound, or in list in the present invention With suitable organic or inorganic acid and free alkali formation during purifying compound in individual reaction, thus separating and forming salt.Allusion quotation The salt of type includes hydrobromate, hydrochloric acid, sulfate, disulfate, phosphate, nitrate, acetate, valerate, oleate, palm fibre Palmitic acid hydrochlorate, stearate, laruate, benzoate, lactate, tosilate, citrate, maleate, rich horse Hydrochlorate, succinate, tartrate, naphtholate, mesylate, gluceptate, Lactobionate and dodecane sulfonate etc. Deng.(example is referring to bergeet al., (1977) “pharmaceutical salts”,j. pharm. sci.66:1- 19.).

The main compound of pharmaceutically acceptable salt includes salt or the quaternary ammonium salt of traditional non-toxic compound, as nontoxic Organic or inorganic acid.This nontoxic salt includes the derivant of mineral acid, example hydrochloric acid salt, hydrobromate, sulfate, amino sulphur Hydrochlorate, phosphate, nitrate etc.；The salt of ratio organic acid preparation, such as acetate, butyrate, succinate, glycol hydrochlorate, hard Fat acid salt, lactate, malate, tartrate, citrate, Ascorbate, palmitate, maleate, hydroxyl horse Come hydrochlorate, phenylacetate, glutamate, Glu, benzoate, salicylate, sulfanilate, Aspirin salt, Fumarate, toluene fulfonate, methane sulfonates, ethane disulfonic acid hydrogen salt, oxalates, isethionate etc..

In other cases, the compound of the present invention may comprise one or more acidic functionalities, therefore can be with medicine On, acceptable alkali is formed and pharmaceutically acceptable salt.Term " pharmaceutically acceptable salt " refers to this in this case The salt that the inorganic and organic base of bright compound and relative nontoxic is formed.These salt in the present invention can be finally separating Produce with scene during purifying compound, or in the present invention in single reaction during purifying compound with suitably organic or no Machine alkali is formed with free acid, such as the pharmaceutically acceptable hydroxide of metal cation, carbonate or bicarbonate, or ammonia, Pharmaceutically acceptable organic primary amine, secondary amine or tertiary amine.Typical alkali metal salt or alkaline earth salt include lithium salts, sodium salt, potassium salt, calcium Salt, magnesium salt, aluminium salt etc..The organic amine being typically used for forming salt includes ethamine, diethylamine, ethylenediamine, ethanolamine, diethanol Amine, piperazine etc..(example is referring to bergeet al., supra.).

Wetting agent, emulsifying agent and lubricant, such as sodium lauryl sulphate, magnesium stearate, polyethylene oxide and polybutene The copolymer of oxide, and coloring agent, releasing agent, coating agent, sweeting agent, spice and fumigating agent, preservative and antioxidant Among the composition existing in.

The formula of the present invention include those suitable oral cavities, nasal cavity, external (include oral cavity and Sublingual), rectum, vagina and Vein treatment.This formula easily can become unit dosage form, and can be by pharmaceutically any of method preparation.Active ingredient Dosage can combine with a carrier material and produce single dosage form, can the therapeutic modality of factor receptor, specific mode of administration Difference and different.The dosage of active ingredient can be combined with carrier material and produce single dosage form, typically will be used as this chemical combination Thing produces the dosage for the treatment of.In general, outside 100%, the active ingredient of this dose between about 1%-99%, It is well from about 5%-70%, optimum is about 10%-30%.

The method preparing these formula or chemical analysis in the present invention includes compound and enters and combine one or more loads Body and the step of adjuvant composition.In general, formula preparation uniformly can, can nearly be tied with the carrier in the present invention Close, such as liquid-carrier, solid smalls carrier or both have both at the same time.Then, fashion into product if necessary.

The preparation being suitable for being administered orally of the present invention can have following form, such as capsule, cachet, pill, tablet, buccal tablet (typically sucrose and Acacia farnesiana Willd. or tragakanta, have certain taste), powder, granule, or as a solution or outstanding Float over the non-aqueous liquid in water, or as Water-In-Oil or oil-in-water emulsion liquid or as elixir or syrup or granular (using such as gelatin and glycerol, the inert base of sucrose and Acacia farnesiana Willd.) and/or collutory etc, each comprises of the present inventionization Compound is as a predetermined close of active ingredient.The compounds of this invention also can be used as boluss, unguentum or plaster.

Invention oral solid formulation (capsule, tablet, pill, dragee, powder, granule etc.), its active ingredient with One or more pharmaceutically acceptable carrier mixing, such as sodium citrate or calcium hydrogen phosphate, and/or any herein below: filler Or filler, such as starch, Lactose, sucrose, glucose, Mannitol；And/or silicic acid, for example binding agent, sodium carboxymethyl cellulose, Alginate, gelatin, Polyvinylpyrrolidone, sucrose and/or Radix Acaciae senegalis, wetting agent, such as glycerol；Disintegrating agent, such as agar, carbon Sour calcium, Rhizoma Solani tuber osi or tapioca, alginic acid, some silicate, sodium carbonate, ethanol and Starch Sodium；Solution retarder, such as paraffin, Absorption enhancer, such as quarternary ammonium salt compound；Wetting agent, such as hexadecanol, glyceryl monostearate and poly(ethylene oxide), polyoxygenated is common Polymers；Absorbent, such as kaolin clay, bentonite, lubricant, such as Pulvis Talci, calcium stearate, magnesium stearate, the poly- second of solid two Alcohol, sodium lauryl sulphate and its mixture；And coloring agent.In the case of capsule, tablet, pill, drug regimen may be also Including slow releasing agent.Similar solids versions composition can become soft filling using adjuvant and firmly fill capsule, such as Lactose or milk sugar, And the implant of ultra-high molecular weight polyethylene ethylene glycol etc.

Tablet can select one or more auxiliary ingredients compressions or molding.Compressed tablets can be prepared with binding agent (as bright Glue or HBMC), lubricating oil, inert diluent, antistaling agent, disintegrating agent is (as ethanol or Starch Sodium crosslinking carboxylic Sodium carboxymethylcellulose pyce), surface activity or dispersant.Model tablet may be by powdered compounds and inert fluid diluent Mixture, being molded on a suitable injection machine.

Active component can be with above-mentioned adjuvant micro encapsulation.The medicine group of other solid preparations of tablet and the present invention Close, such as dragee, capsule, pill, granule, can selectively use coating and shell to prepare or moulding, such as enteric coating layer, with And the coating of known other pharmaceutical form.It is likely to provide the preparation of the active ingredient of slow or control release, for example, hydroxyl Butyl methyl cellulose provides required release profiles in different situations, other polymers substrate, liposome and/or micro- Cellulose.They may be able to sterilize, and for example, keep off filter by filter bacteria, or merges anti-microbial agents and aseptic Solid content, they dissolve in sterilized water, or in some sterile injectable medium.These compositions are likely to containing opacifiers Composition, or the composition of the active substance of slow release, or preferentially form a kind of mode of delay in some parts of gastrointestinal. The material that embedded composition can use includes polymer and wax.Active component can also be prepared into micro- using one or more adjuvants Capsule form.

The compound oral liquid formulation of the present invention is included with pharmaceutically acceptable emulsion, microemulsion, solution, suspension, Syrup and elixir.Except active component, the liquid of dosage form may contain the inert diluent pharmaceutically commonly used, for example water or other Solvent, solubilising reagent and emulsifying agent, such as ethanol, isobutanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene Ethylene glycol, 1,3 butylene glycol, oily (particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Fructus Maydis oil, olive oil, Oleum Ricini, Oleum sesami), sweet Oil, oxolane alcohol, Polyethylene Glycol and fatty acid ester Sorbitol and its mixture.Additionally, cyclodextrin, such as hydroxyl butyl- Beta- cyclodextrin it can also be used to dissolving compound.

Except inert diluent, oral composition can also include such as wetting agent, emulsifying and suspending agent, sweeting agent, essence, color Element, antistaling agent and preservative.

Except reactive compound, suspension may contain suspending agent, such as isostearic acid ethyl ester, polyoxyethylene sorbitol and Sorbitol ester, Microcrystalline Cellulose, aluminum metal hydroxide, bentonite, agar and tragakanta and its mixture.

Present invention treatment rectum or intravaginal drug composite formula can be suppository, and it can be by one or more inventions Compound mixing includes preparation with one or more suitable nonirritant excipients or carrier and sponsors, for example, cocoa butter, poly- second Glycol, a suppository wax or salicylic acid, and be solid at room temperature, but the liquid of body temperature, therefore, rectum or vaginal canal will be melted in Invention with release active agents.

The formula of the present invention is adapted for treating vagina class disease, including containing the such as pessary of known carrier in pharmacy, cotton balls, Unguentum, gel, paste, foam or spray agent.

Local for the compounds of this invention or transdermal administration include powder, spray, ointment, ointment, facial cream, breast Liquid, gel, solution, plaster and inhalant.With pharmaceutically acceptable carrier under reactive compound aseptic condition and any anti-corrosion Agent, buffer agent, or may need to mix.

Except the active ingredient beyond the region of objective existence in the present invention, ointment, ointment, may comprise as animal and plant in ointment and gel The adjuvant of fat, oil, wax, paraffin, starch, tragakanta, cellulose derivative, Polyethylene Glycol, organosilicon, organobentonite is lived Property compound, silicic acid, Pulvis Talci, zinc oxide, or their mixture.

Except the active ingredient beyond the region of objective existence in the present invention, the adjuvant such as Lactose that powder and spray can comprise, Talcum, silicic acid, Aluminium hydroxide, calcium-silicate and Silon, or the mixture of these materials.Spray may add conventional, such as fluorochlorohydrocarbon and The unsubstituted Hydrocarbon of volatility, such as butane and butylene.

In the present invention, the patch of compound is controllable in the body to medicine is distributed with extra benefit.This dosage form can Formed by the medicament being dissolved or dispersed in buffer medium.Absorption enhancer can also be used for increasing in the skin present invention The flux of medicament.This rate of change by the rate controlling membranes of either party offer or can be dispersed in polymeric matrix or gel Compound is controlled.

Ophthalmic preparation, spongaion, powder, solution etc., fall within the scope of the present invention.

The drug regimen of the suitably one or more compound of the present invention includes and one or more medicines in parenteral treatment Acceptable sterile physiological aqueous solution or non-aqueous solution, dispersant, suspending agent or emulsion on, or sterilized powder.They may Be reassembled as aseptic injection or the preferential dispersant using, antioxidant, buffer, antibacterial may be contained, can make preparation with pre- The blood of phase acceptor or suspending agent or thickening agent are isotonic fused.

In some cases, in order to extend drug effect, medicine can be delayed from the absorption subcutaneously or intramuscularly injected.This can lead to The suspension crossing a bad water solubility with crystallization or amorphous substance is completing.The absorbance of medicine is then depended on In its rate of dissolution, crystallite dimension and crystal formation may be depended on simultaneously.In addition, the absorption postponing parenteral therapeutic dosage forms is By being dissolved or suspended in what medicine in oil medium was realized.Wherein storage type injection strategy include using polyethylene oxide- Polybutylene oxide thing, used in it, medium is flowing in room temperature, solidifies in body temperature.

Storage type injection type is in Biodegradable polymeric by host compound, such as poly- glue ester-polyglycolic acid glue Form microcapsule under ester and make.According to the ratio of medicine and polymer, and the property of special polymer, drug release rate Can control.The example that other biological degradation polymer gathers includes POE and many condensing model.Storage type injection Type can also be prepared by medicine is embedded in liposome or microemulsion, and this is compatible with tissue.

When the compound of the present invention is treated to human and animal as medicament, they can be in itself or as medicine Compositionss and be administered.For example, comprise 0.1%-99.5%(and be preferably 0.5%-90%) active component and pharmaceutically acceptable Carrier.

Compound in the present invention and pharmaceutical composition can apply to combination treatment, and that is, compound and pharmaceutical composition can Simultaneously front or rear, treatment or medical procedure that one or more required medicines use.This apply in rule of combination specific Combination treatment (treatment or program) will allow for realizing required treatment compatibility and/or program and preferable therapeutic effect. The application of this therapy can achieve required effect to identical disease, and (for example, the compound of the present invention may be anti-with another Hcv reagent works simultaneously), or be possible to reach different effects (such as controlling any harmful effect).

The compound of the present invention can pass through intravenous injection, intramuscular injection, lumbar injection, subcutaneous injection, external, is administered orally, or Other acceptable methods are treating disease.These compounds can be used for condition mammal (for example, the people for the treatment of of arthritis Class, domestic animal and domestic animal), birds, Eremiatis argi, and any can these compound other biologicals compatible.

Present invention also offers drug packaging or external member, including one or more packagings, wherein contain in the present invention The drug regimen of one or more compositions.Optionally such packaging is produced by government organs' specification, to produce in the form of announcing In regulation the open method of license using or sell medicine or biological product, using or the treatment preparation to people for the sale.

Similar description

Representational example is intended to help illustrate the present invention below, rather than has a mind to also should not be construed as limited to this The scope of invention.It is true that except those occur and described herein in addition to, the full content of file in the present invention, including according to According to the example of scientific and technical literature cited herein and patent, and consequent various modification is further change in originally special with many Those skilled in the art clearly understand in the industry.It should also be appreciated that quoting of these lists of references contributes in statement herein Hold.The examples below contains important side information, example and guidance, is adaptable to various change and similar feelings in the present invention Condition.

Embodiment 1:n- (3- ((2- ((4- (6- acetyl group -2,6- diaza spiroheptane -2- base) -2- methoxyl group Phenyl) amine) -5- (trifluoromethyl) pyrimidine-4-yl) amine) phenyl) acrylamide

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

3- aminophenyl t-butyl formate (4.8 g, 23 mmol) is dissolved in n-butyl alcohol (45 ml), is then cooled to 0^oc.2,4- bis- chloro- 5- (trifluoromethyl) pyrimidine (5.0 g, 23 mmol) and dipea are added drop-wise to above-mentioned solution successively In.The mixture obtaining is in 0-5^oC stirs one hour and then is raised to room temperature instead until reaction terminates.Reactant liquor pe (45 Ml) making beating and then filtration.Filter cake is collected vacuum drying after being washed with pe and is obtained white solid (3- ((2- chloro- 5- (fluoroform Base) pyrimidine-4-yl) amino) phenyl) t-butyl carbamate (4.434 g, yield: 49.6%). lc-ms: m/z 389 (m+h)⁺.

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

(3- ((2- chloro- 5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) t-butyl carbamate (4.434 g, 11.4 mmol) it is dissolved in dcm (44.5 ml), then it is cooled to 0^oC, is subsequently slowly added dropwise tfa (44.5 ml).Reactant liquor 0^oC stirs 0.5 hour and then is concentrated under reduced pressure to give faint yellow oily n- (3- ((2- chloro- 5- (trifluoromethyl) pyrimidine-4-yl) Amino) phenyl) acrylamide, it is directly used in next step reaction. lc-ms: m/z 289 (m+h)⁺.

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

4- fluoro- 2- methoxy nitrobenzene (520 mg, 3.0 mmol) is dissolved in dmf(20 ml), it is subsequently added 2,6- phenodiazine Miscellaneous spiral shell [3.3] heptane -2- t-butyl carbamate (300 mg, 1.7 mmol) and k₂co₃(840 mg, 6.08 mmol). Reactant liquor reacts overnight in 70 ° of c, is subsequently adding water quenching and goes out.The mixture obtaining is extracted with ethyl acetate.Organic faciess are with anhydrous Sodium sulfate is concentrated to give crude product 6- (3- methoxyl group -4- nitrobenzophenone) -2,6- diaza spiroheptane -2- ammonia after being dried Base t-butyl formate (300 mg, yield: 56%), be directly used in next step reaction.lc-ms: m/z 350 (m+h)⁺.

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

6- (3- methoxyl group -4- nitrobenzophenone) -2,6- diaza spiroheptane -2- t-butyl carbamate (300 Mg, 2.58 mmol) it is dissolved in tfa/dcm (1/4 (v/v), 5 ml), then it is stirred at room temperature two hours.Reactant liquor vacuum is dense Contracting obtain crude product 2- (3- methoxyl group -4- nitrobenzophenone) -2,6- diaza spiroheptane (200 mg, yield: 90%), It is directly used in next step reaction.lc-ms: m/z 250 (m+h)⁺.

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

2- (3- methoxyl group -4- nitrobenzophenone) -2,6- diaza spiroheptane (200 mg, 0.8 mmol) is dissolved in Dcm (10 ml), is then cooled to 0 ° of c, be subsequently added tea (303 mg, 3 mmol) and accl (203 mg, 2.6 mmol).Reactant liquor is subsequently adding water quenching in two hours in 0 ° of c reaction and goes out.Organic be separated after wash, then with anhydrous sodium sulfate do Concentrated in vacuo crude product 1- (6- (3- methoxyl group -4- nitrobenzophenone) -2,6- diaza spiroheptane -2- base) is obtained after dry Ethyl ketone (200 mg, yield: 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- base) ethyl ketone

1- (6- (3- methoxyl group -4- nitrobenzophenone) -2,6- diaza spiroheptane -2- base) ethyl ketone (200 mg, 2.3 mmol) it is dissolved in meoh (20 ml), add subsequent pd/c (10% wt, 20 mg).Under reactant liquor atmosphere of hydrogen (50psi) After reacting 12 hours at room temperature, filtered by kieselguhr.Filter vacuum is concentrated to give crude product 1- (6- (3- methoxyl group -4- ammonia Base phenyl) -2,6- diaza spiroheptane -2- base) ethyl ketone (140 mg, yield: 78%), be directly used in next step reaction. lc-ms: m/z 262 (m+h)+.

Step 7:n- (3- ((2- ((4- (6- acetyl group -2,6- diaza spiroheptane -2- base) -2- methoxybenzene Base) amine) -5- (trifluoromethyl) pyrimidine-4-yl) amine) phenyl) acrylamide

1- (6- (3- methoxyl group -4- aminophenyl) -2,6- diaza spiroheptane -2- base) ethyl ketone (60 mg, 0.23 mmol) and n- (3- ((2- chloro- 5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide be dissolved in dioxane (5 ml), is subsequently adding tfa (1).Mixture is concentrated in vacuo after 50 ° of c react 18 hours to obtain crude product.Crude product is led to Cross preparative liquid chromatography and separate and obtain n- (3- ((2- ((4- (6- acetyl group -2,6- diaza spiroheptane -2- base) -2- first Phenyl) amine) -5- (trifluoromethyl) pyrimidine-4-yl) amine) phenyl) acrylamide (20 mg, yield:14%).

¹h nmr (400 mhz, dmso-d₆) 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- acetyl group -3,8- diazabicyclo [3.2.1] octane -8- base) -2- first Phenyl) amine) -5- (trifluoromethyl) pyrimidine-4-yl) amine) phenyl) acrylamide

Synthetic method such as embodiment 1

¹h nmr (400 mhz, dmso-d₆) 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- acetyl group -4,7- diaza spiro [2.5] octane -7- base) -2- methoxyl group Phenyl) amine) -5- (trifluoromethyl) pyrimidine-4-yl) amine) phenyl) acrylamide

Synthetic method such as embodiment 1

¹h nmr (400 mhz, dmso-d₆) 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]⁺.

Biotic experiment:

The kinases ic50 test to egfr wild type and egfr-t790m mutation for such compound:

Egfr (wt) is wild-type egf receptor, and egfr (t790m) is by ammonia of reviving with the 790th amino acids Acid mutation is the EGF-R ELISA of methionine, and rgfr (l858r) is to be mutated by leucine with the 858th amino acids For arginic EGF-R ELISA, egfr (l858r/t790m) is to be dashed forward by leucine simultaneous with the 858th amino acids It is changed into arginine and the 790th amino acids are sported the EGF-R ELISA of methionine by threonine.

Kinase activity detects: this test uses kinase-glo plus luminescence kinase assay kit (promega).Its residual atp content after quantitative analyses swash enzymatic reaction detects kinase activity.Test In fluorescence signal related to existing atp content.

The reactant liquor of configuration 50ul, including 40 mm tris, ph 7.4,10 mm mgcl₂, 0.1 mg/ml bsa, 1 mm dtt, 0.2 mg/ml poly (glu, tyr) substrate, 10 μm atp and egfr.By test compounds Thing is made into 10%dmso solution, takes 5ul to be diluted in the above-mentioned reactant liquor of 50ul and obtains the reactant liquor that final dmso concentration is 1%.Institute There is enzymic catalytic reaction all 30^oCarry out under c 35 minutes.For pre-incubated reaction in 30 minutes, enzyme was first and inhibitor hatches 30 points Clock, is subsequently adding atp and substrate starts to react.After enzymic catalytic reaction terminates, in reactant liquor, add 50ul kinase-glo Plus luminescence kinase assay solution (promega), continues in incubation at room temperature 5 minutes.Fluorescence is believed Number when by bioteksynergy 2Microplate reader measures.

Ic50 is with graphpadprism5.00(tetra- parameter logistic equation) it is calculated.

The biological test data of example 1-3 is presented herein below, records with the method outlined supra.

Containing in the volution or bridge cyclics competition experiments with atp, due to existing and protein cysteine site shape Become irreversible Michael addition reaction, so higher inhibitory activity is all embodied to kinases.

Embodiment described above only have expressed the several embodiments of the present invention, and its description is more concrete and detailed, but simultaneously Therefore the restriction to the scope of the claims of the present invention can not be interpreted as.It should be pointed out that for those of ordinary skill in the art For, without departing from the inventive concept of the premise, some deformation can also be made and improve, these broadly fall into the guarantor of the present invention Shield scope.Therefore, the protection domain of patent of the present invention should be defined by claims.

Claims

1. a kind of pyrimidines containing volution or bridged ring are it is characterised in that the structure that described compound has is formula i:

,

Wherein w is nh, r₁For-cf₃, r₂For-och₃, r₃And r₄For、Or, r₅For h, r₆For h.

2. the pyrimidines containing volution or bridged ring according to claim 1 answering in preparation tumor With.

3. the application containing volution or the pyrimidines of bridged ring according to claim 2 is it is characterised in that described swell Tumor be nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast carcinoma, carcinoma of prostate, hepatocarcinoma, skin carcinoma, Any one in gastrointestinal stromal tumors (GISTs), white leukemia, histiocytic lymphatic cancer, nasopharyngeal carcinoma.