CN1894260A - Pyrido- and pyrimidopyrimidine derivatives as anti-proliferative agents - Google Patents
Pyrido- and pyrimidopyrimidine derivatives as anti-proliferative agents Download PDFInfo
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- CN1894260A CN1894260A CN200480037451.7A CN200480037451A CN1894260A CN 1894260 A CN1894260 A CN 1894260A CN 200480037451 A CN200480037451 A CN 200480037451A CN 1894260 A CN1894260 A CN 1894260A
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Abstract
The present invention concerns the compounds of formula (I) the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein a<1>-a<2>=a<3>-a<4> represents a divalent radical selected from N-CH=CH-CH, N-CH N-CH or CH-CH=N-CH; Z represents NH; Y represents -C3-9alkyl-, -Cl-5alkyl-NR<13>-Cl-5alkyl-,-C1-6alkyl-NH-CO- or -CO-NH -C1-6alkyl- ; X<1 >represents -O- or -NR<11>-; X<2> represents -C1-2alkyl-, -O-C1-2alkyl, -O- or -O-CH2-;R<1 >represents hydrogen or halo; R<2 >represents hydrogen, cyano, halo, hydroxycarbonyl-Cl-4 alkyloxycarbonyl-, Het<16>-carbonyl- or Ar<5>; R<3 >represents hydrogen; R<4> represents hydroxy, C1-4alkyloxy-, Ar<4>-C1-4alkyloxy or R<4> represents Cl-4alkyloxy substituted with one or where possible two or more substituents selected from C1-4alkyloxy- or Het<2>-; R<11 >represents hydrogen; R<12 >represents hydrogen, Cl-4alkyl- or Cl-4alkyl-oxy-carbonyl-; R<13 >represents Het<14>-Cl-4alkyl, in particular morpholinyl-Cl-4alkyl; Het<2> represents a heterocycle selected from morpholinyl or piperidinyl optionally substituted with C1-4alkyl-, preferably methyl; Het<14> represents morpholinyl; Het<16> represents a heterocycle selected from morpholinyl or pyrrolidinyl; Ar<4> represents phenyl; Ar<5> represents phenyl optionally substituted with cyano.
Description
The present invention relates to the big ring of Mi Dingbing pyrimidine derivates, find that it has antiproliferative activity, for example anticancer disease activity, therefore and be used for the treatment of the method for the mankind or animal body, for example preparation is used for for example medicament of atherosclerosis, restenosis and cancer of hyper-proliferative illness.The invention still further relates to the described Mi Dingbing pyrimidine derivatives of preparation method, contain they pharmaceutical composition and they be used for producing the purposes of the product of anti-proliferative effect in preparation.
Especially, find that compound of the present invention can suppress Tyrosylprotein kinase.Tyrosylprotein kinase is a class of enzyme, and the terminal phosphate of its catalysis adenosine triphosphate is to the transfer of the phenolic hydroxyl group that is present in the tyrosine residues in the target protein.More knownly relate to the oncogene coding Tyrosylprotein kinase that cell transformation is a malignant cell, Tyrosylprotein kinase comprises some growth factor receptors for example EGF, FGF, IGF-1R, IR, PDGF and VEGF.The EGF family of the family of receptor tyrosine kinase and especially receptor tyrosine kinase, usually be present in the common human cancer, mammary cancer for example, nonsmall-cell lung cancer comprises the gland cancer and the squamous cell carcinoma of lung, bladder cancer, esophagus cancer, gastrointestinal cancer be colorectal carcinoma, the rectum cancer or cancer of the stomach for example, prostate cancer, leukemia and ovarian cancer, bronchogenic carcinoma or carcinoma of the pancreas, these are examples of the related illness of cell proliferation.
Therefore the selectivity that has realized that Tyrosylprotein kinase suppresses and will have value in the illness that treatment cell proliferation relates to.By first example Herceptin based on the cancer medicine of target
(Trastuzumab) and Gleevec
TMThe development of (imatinib mesylate) has formed the support for this viewpoint.Herceptin
(Trastuzumab) at be Her2/neu, Her2/neu is a kind of receptor tyrosine kinase, it has among the patient of invasive mammary cancer about 30% and amplifies up to 100 times.In clinical trial, prove Herceptin
(Trastuzumab) antitumour activity that has at mammary cancer (is summarized: people such as L.K Shawer, " Smart Drugs:Tyrosine kinase inhibitors in cancer therapy ", 2002, Cancer Cell Vol.1,117), and correspondingly provide is the evidence of the treatment principle of target with the receptor tyrosine kinase.Second example, Gleevec
TM(imatinib mesylate) is target with abelson Tyrosylprotein kinase (BcR-Abl), this Tyrosylprotein kinase is the structure-activity cytoplasmic tyrosine kinase, and the patient and 15% to 30% who almost is present in all chronic lymphocytic leukemias (CML) has in the adult patients of acute lymphoblastic leukemia.In clinical trial, Gleevec
TM(imatinib mesylate) shown surprising effect, and it has minimum side effect, just obtained approval submitting within 3 months.The speed that this medicament is evaluated by clinical trial and supervision has become case study (the Drucker B.J.﹠amp in the quick medicine development; Lydon N., " Lessons learned from the developmentof an Abl tyrosine kinase inhibitor for chronic myelogenousleukaemia. ", 2000, J.Clin.Invest.105,3).
By but EGF receptor tyrosine kinase inhibitors specificity reduce being transplanted for example human breast cancer or the human squamous cell carcinoma proof of in nude mouse, growing of cancer, obtained further support (summary: T.R Burke Jr., Drugs of the Future, 1992,17,119).Therefore, can treat with the EGFR acceptor in development is in the medicine of various cancers of target, has sizable interest.For example, the extracellular domain bonded antibody of some and EGFR is carrying out clinical trial, comprises Erbitux
TM(being also referred to as C225, Cetuximab), it is developed by Imclone Systems, and is in the III clinical trial phase of certain cancers treatment.Equally, as the EGFR Tyrosylprotein kinase effectively and some Orally active medicines likely of relative specificity inhibitor, in clinical trial, make progress fine now.AstraZeneca compound ZD1839, it is called as IRESSA now
And prove that it can treat nonsmall-cell lung cancer and OSI/Genentech/Roche compound OSI-774 in late period, it is called as Tarceva now
TM(erlotinib), two kinds of compounds have all shown obvious effects (Morin M.J. to certain cancers in the human clinical trial, " From oncogene to drug:development of small molecule tyrosine kinase inhibitors as anti-tumour and anti-angiogenic agents ", 2000, Oncogene 19,6574).
Except that above-mentioned, for example relevant (people Science such as elder, 1989,243 of psoriatic of EGF receptor tyrosine kinase and non-malignant proliferation illness have been proved; 811).Therefore wish that the inhibitor of EGF receptor Tyrosylprotein kinase can be used for treating nonmalignant disease such as psoriatic, benign prostatauxe, atherosclerosis and the restenosis of excessive cell proliferation.
At International Patent Application WO 96/07657 ﹠amp; The Mi Dingbing pyrimidine is disclosed among the WO 97/32880 as Tyrosylprotein kinase and the especially inhibitor of EGF receptor Tyrosylprotein kinase.Beyond thought is to it is found that the Mi Dingbing pyrimidine derivatives of the different formula of structure (I) has shown to have the tyrosine-kinase enzyme inhibition activity.
Correspondingly, target of the present invention provides further tyrosine kinase inhibitor, and it can prepare and be used for the treatment of the medicament that related disorders is arranged with cell proliferation.
The present invention relates to the compound of formula (I)
Its N-oxide form, pharmacy acceptable addition salt and stereochemistry heterogeneous forms, wherein
a
1-a
2=a
3-a
4Expression is selected from following divalent radical: N-CH=CH-CH, N-CH=N-CH or CH-CH=N-CH;
Z represents O, NH or S;
Y represents-C
3-9Alkyl-,-C
3-9Thiazolinyl-,-C
1-5Alkyl-oxygen base-C
1-5Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-,-C
1-5Alkyl-NR
14-CO-C
1-5Alkyl-,-C
1-5Alkyl-CO-NR
15-C
1-5Alkyl-,-C
1-6Alkyl-CO-NH-,-C
1-6Alkyl-NH-CO-,-CO-NH-C
1-6Alkyl-,-NH-CO-C
1-6Alkyl-,-CO-C
1-7Alkyl-, C
1-7Alkyl-CO-, C
1-6Alkyl-CO-C
1-6Alkyl;
X
1Represent direct key, O ,-O-C
1-2Alkyl-, CO ,-CO-C
1-2Alkyl-, NR
11,-NR
11-C
1-2Alkyl ,-NR
16-CO-, NR
16-CO-C
1-2Alkyl-,-O-N=CH-or C
1-2Alkyl;
X
2Represent direct key, O ,-O-C
1-2Alkyl-, CO ,-CO-C
1-2Alkyl-, NR
12, NR
12-C
1-2Alkyl-, NR
17-CO-, NR
17-CO-C
1-2Alkyl-, Het
20-C
1-2Alkyl-,-O-N=CH-or C
1-2Alkyl;
R
1Expression hydrogen, cyano group, halogen, hydroxyl, formyl radical, C
1-6Alkyl oxy-, C
1-6Alkyl-, the C that is replaced by halogen
1-6Alkyl oxy-, by one or may the time two or more substituting groups that are selected from hydroxyl or halogen C of replacing
1-4Alkyl;
R
2Expression hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-, Het
16-carbonyl-, C
1-4The alkyl oxy carbonyl-, C
1-4Alkyl-carbonyl-, aminocarboxyl-, single or two (C
1-4Alkyl) aminocarboxyl-, Het
1, formyl radical, C
1-4Alkyl-, C
2-6Alkynyl-, C
3-6Cycloalkyl-, C
3-6Cycloalkyl oxy-, C
1-6Alkyl oxy-, Ar
5, Ar
1-oxygen base-, boronic acid, the C that is replaced by halogen
1-6Alkyl oxy-, by one or may the time two or more are selected from halogen, hydroxyl or NR
5R
6The C that replaces of substituting group
1-4Alkyl,
C
1-4Alkyl-carbonyl-, wherein said C
1-4Alkyl chooses wantonly by one or two or more are selected from hydroxyl or C when possible
1-4Alkyl-oxygen base-substituting group replace;
R
3Expression hydrogen, C
1-4Alkyl, cyano group or be selected from the C that following substituting group replaces by one or more
1-4Alkyl: halogen, C
1-4Alkyl oxy-, amino-, single or two (C
1-4Alkyl) amino-, C
1-4Alkyl-alkylsulfonyl-or phenyl;
R
4Expression hydrogen, hydroxyl, Ar
3-oxygen base, Ar
4-C
1-4Alkyl oxy-, C
1-4Alkyl oxy-, optional by Het
12The C that replaces
2-4Thiazolinyl oxygen base, or R
4Expression is by one or two or more are selected from the C that following substituting group replaces when possible
1-4Alkyl oxy: C
1-4Alkyl oxy-, hydroxyl, halogen, Het
2-,-NR
7R
8,-carbonyl-NR
9R
10Or Het
3-carbonyl-;
R
5And R
6Be selected from hydrogen or C independently of one another
1-4Alkyl;
R
7And R
8Each is independently selected from hydrogen, C
1-4Alkyl, Het
8, amino-sulfonyl-, single or two (C
1-4Alkyl)-and amino-sulfonyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-, hydroxycarbonyl group-C
1-4Alkyl-, C
3-6Cycloalkyl, Het
9-carbonyl-C
1-4Alkyl-, Het
10-carbonyl-, poly-hydroxy-C
1-4Alkyl-, Het
11-C
1-4Alkyl-or Ar
2-C
1-4Alkyl-;
R
9And R
10Each is independently selected from hydrogen, C
1-4Alkyl, C
3-6Cycloalkyl, Het
4, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl-or poly-hydroxy-C
1-4Alkyl-;
R
11Expression hydrogen, C
1-4Alkyl, Het
5, Het
6-C
1-4Alkyl-, optional by Het
7-C
1-4The C of alkyl amino-carbonyl-replacement
2-4Alkenyl carbonyl-, C
2-4The thiazolinyl alkylsulfonyl-, C
1-4Alkyl oxy C
1-4Alkyl-optional by one or may the time two or more are selected from hydrogen, hydroxyl, amino or C
1-4The phenyl of alkyl oxy-replacement;
R
12Expression hydrogen, C
1-4Alkyl, C
1-4Alkyl-oxygen base-carbonyl-, Het
17, Het
18-C
1-4Alkyl-, optional by Het
19-C
1-4The C of alkyl amino-carbonyl-replacement
2-4Alkenyl carbonyl-, C
2-4The thiazolinyl alkylsulfonyl-, C
1-4Alkyl oxy C
1-4Alkyl-optional by one or may the time two or more are selected from hydrogen, hydroxyl, amino or C
1-4Alkyl oxy-the phenyl that replaces of substituting group;
R
13Expression hydrogen, C
1-4Alkyl, Het
13, Het
14-C
1-4Alkyl-optional by one or may the time two or more are selected from hydrogen, hydroxyl, amino or C
1-4Alkyl oxy-the phenyl that replaces of substituting group;
R
14And R
15Each is independently selected from hydrogen, C
1-4Alkyl, Het
15-C
1-4Alkyl-or C
1-4Alkyl oxy C
1-4Alkyl-;
R
16And R
17Each is independently selected from hydrogen, C
1-4Alkyl, Het
21-C
1-4Alkyl-or C
1-4Alkyl oxy C
1-4Alkyl-;
Het
1Expression is selected from following heterocycle: piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolanyl, thiazolyl, azoles base, imidazolyl, different azoles base, di azoly, pyridyl or pyrrolidyl, wherein said Het
1Optional by one or may the time two or more are selected from following substituting group and replace: amino, C
1-4Alkyl, hydroxyl-C
1-4Alkyl-, phenyl, phenyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-, single or two (C
1-4Alkyl) amino-or amino-carbonyl-;
Het
2Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl, pyrrolidyl, thio-morpholinyl or dithian base, wherein said Het
2Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, halogen, amino, C
1-4Alkyl-, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-, hydroxyl-C
1-4Alkyl-oxygen base-C
1-4Alkyl-, single or two (C
1-4Alkyl) amino-, single or two (C
1-4Alkyl) amino-C
1-4Alkyl-, amino C
1-4Alkyl-, single or two (C
1-4Alkyl) amino-sulfonyl-, amino-sulfonyl-;
Het
3, Het
4And Het
8Each represents to be selected from following heterocycle independently: morpholinyl, piperazinyl, piperidyl, furyl, pyrazolyl, dioxolanyl, thiazolyl, azoles base, imidazolyl, different azoles base, di azoly, pyridyl or pyrrolidyl, wherein said Het
3, Het
4Or Het
8Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl-, amino-, C
1-4Alkyl-, C
3-6Cycloalkyl-C
1-4Alkyl-, amino-sulfonyl-, single or two (C
1-4Alkyl) amino-sulfonyl or amino-C
1-4Alkyl-;
Het
5Expression is selected from the heterocycle of pyrrolidyl or piperidyl, and wherein said heterocycle chooses wantonly by one or two or more are selected from following substituting group replacement: C when possible
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
6And Het
7Each represents to be selected from following heterocycle independently: morpholinyl, pyrrolidyl, piperazinyl or piperidyl, wherein said Het
6Or Het
7Optional by one or may the time two or more are selected from following substituting group and replace: C
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
9And Het
10Each represents to be selected from following heterocycle independently: furyl, piperidyl, morpholinyl, piperazinyl, pyrazolyl, dioxolanyl, thiazolyl, azoles base, imidazolyl, different azoles base, di azoly, pyridyl or pyrrolidyl, wherein said Het
9Or Het
10Optional by following replacement: C
1-4Alkyl, C
3-6Cycloalkyl-C
1-4Alkyl-or amino-C
1-4Alkyl-;
Het
11Expression is selected from the heterocycle of indyl or following formula;
Het
12Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl, pyrrolidyl, thio-morpholinyl or dithian base, wherein said Het
12Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, halogen, amino, C
1-4Alkyl-, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-, hydroxyl-C
1-4Alkyl-oxygen base-C
1-4Alkyl-, single or two (C
1-4Alkyl) amino-or single or two (C
1-4Alkyl) amino-C
1-4Alkyl-;
Het
13Expression is selected from the heterocycle of pyrrolidyl or piperidyl, and wherein said heterocycle chooses wantonly by one or two or more are selected from following substituting group replacement: C when possible
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
14Expression is selected from following heterocycle: morpholinyl, pyrrolidyl, piperazinyl or piperidyl, wherein said heterocycle choose wantonly by one or two or more are selected from following substituting group replacement: C when possible
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
15And Het
21Each represents to be selected from following heterocycle independently: morpholinyl, pyrrolidyl, piperazinyl or piperidyl, wherein said Het
15Or Het
21Optional by one or may the time two or more are selected from following substituting group and replace: C
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
16Expression is selected from following heterocycle: morpholinyl, and pyrrolidyl, piperazinyl, 1,3,2-two oxa-boron heterocycle pentane or piperidyls, wherein said heterocycle is optional by one or more C that are selected from
1-4The substituting group of alkyl replaces;
Het
17Expression is selected from the heterocycle of pyrrolidyl or piperidyl, and wherein said heterocycle chooses wantonly by one or two or more are selected from following substituting group replacement: C when possible
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
18And Het
19Each represents to be selected from following heterocycle independently: morpholinyl, pyrrolidyl, piperazinyl or piperidyl, wherein said Het
18And Het
19Optional by one or may the time two or more are selected from following substituting group and replace: C
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
20Expression is selected from following heterocycle: pyrrolidyl, 2-pyrrolidyl, piperidyl, piperazinyl or pyrazolidyl, wherein said heterocycle choose wantonly by one or two or more are selected from following substituting group replacement: C when possible
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-; With
Ar
1, Ar
2, Ar
3, Ar
4And Ar
5Each represents optional by the phenyl of following replacement independently: cyano group, C
1-4Alkyl sulphonyl-, C
1-4Alkyl sulfonyl-amino-, amino-sulfonyl amino-, hydroxyl-C
1-4Alkyl, amino-sulfonyl-, hydroxyl-, C
1-4Alkyl oxy-or C
1-4Alkyl.
For in above-mentioned definition with hereinafter use,
-halogen generally is fluorine, chlorine, bromine and iodine;
-C
1-2Alkyl is defined as methyl or ethyl;
-C
1-3Alkyl is defined as straight chain and the branched saturated hydrocarbon group with 1 to 3 carbon atom, for example methyl, ethyl, propyl group or the like;
-C
1-4Alkyl is defined as straight chain and the branched saturated hydrocarbon group with 1 to 4 carbon atom, for example methyl, ethyl, propyl group, butyl, 1-methylethyl, 2-methyl-propyl, 2,2-dimethyl ethyl or the like;
-C
1-5Alkyl is defined as straight chain and the branched saturated hydrocarbon group with 1 to 5 carbon atom, for example methyl, ethyl, propyl group, butyl, amyl group, 1-methyl butyl, 2,2-dimethylpropyl, 2,2-dimethyl ethyl or the like;
-C
1-6Alkyl comprises C
1-5Alkyl and have its higher homologues of 6 carbon atoms, hexyl, 1 for example, 2-dimethylbutyl, 2-methyl amyl or the like;
-C
1-7Alkyl comprises C
1-6Alkyl and have its higher homologues of 7 carbon atoms, for example 1,2,3-dimethylbutyl, 1,2-methyl amyl or the like;
-C
3-9Alkyl is defined as straight chain and the branched saturated hydrocarbon group with 3 to 9 carbon atoms, for example propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl or the like;
-C
2-4Thiazolinyl is defined as straight chain and the branched hydrocarbyl that has 2 to 4 carbon atoms, contains two keys, for example vinyl, 2-propenyl, 3-butenyl, crotyl or the like;
-C
3-9Thiazolinyl is defined as straight chain and the branched hydrocarbyl that has 3 to 9 carbon atoms, contains two keys, for example 2-propenyl, 3-butenyl, crotyl, pentenyl, 3-pentenyl, 3-methyl-2-butene base, 3-hexenyl or the like;
-C
2-6Alkynyl is defined as to have 2 to 6 carbon atoms, contains a triple-linked straight chain and branched hydrocarbyl, for example 2-propynyl, 3-butynyl, 2-butyne base, valerylene base, 3-pentynyl, 3-methyl-2-butyne base, 3-hexin base or the like;
-C
3-6Cycloalkyl generally is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
-C
1-4Alkyl oxy is defined as the straight or branched saturated hydrocarbyl, for example methoxyl group, oxyethyl group, propoxy-, butoxy, 1-methyl ethoxy, 2-methyl propoxy-or the like;
-C
1-6Alkyl oxy comprises C
1-4Alkyl oxy and higher homologue, for example methoxyl group, oxyethyl group, propoxy-, butoxy, 1-methyl ethoxy, 2-methyl propoxy-or the like;
-poly-hydroxy-C
1-4Alkyl generally be have two, three or may the time more a plurality of hydroxyl substituents C defined above
1-4Alkyl, for example trifluoromethyl.
For in above-mentioned definition and the term formyl radical that hereinafter uses be meant formula-CH (=O) group.Work as X
1Or X
2During expression divalent radical-O-N=CH-, described group respectively with the R that has of formula (I) compound
3, R
4Circular part, have R
1, R
2The carbon atom of phenyl moiety be connected.
For at above-mentioned definition and the heterocycle hereinafter mentioned, comprise the possible isomeric form that they are all, for example pyrryl also comprises the 2H-pyrryl; Triazolyl comprises 1,2,4-triazolyl and 1,3,4-triazolyl; The di azoly comprises 1,2,3- di azoly, 1,2,4- di azoly, 1,2,5- di azoly and 1,3,4- di azoly; Thiadiazolyl group comprises 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group and 1,3,4-thiadiazolyl group; Pyranyl comprises 2H-pyranyl and 4H-pyranyl.
Further, for being connected with the remainder of formula (I) molecule by arbitrary ring carbon or heteroatoms as one sees fit with the heterocycle of hereinafter mentioning in above-mentioned definition.Thus, for example when heterocycle was imidazolyl, it can be the 1-imidazolyl, 2-imidazolyl, 3-imidazolyl, 4-imidazolyl and 5-imidazolyl; When it was thiazolyl, it can be the 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; When it was triazolyl, it can be 1,2,4-triazol-1-yl, 1,2,4-triazole-3-base, 1,2,4-triazole-5-base, 1,3,4-triazol-1-yl and 1,3,4-triazole-2-base; When it was benzothiazolyl, it can be the 2-[4-morpholinodithio base, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl and 7-benzothiazolyl.
For pharmacy acceptable addition salt mentioned above, comprise formula (I) compound non-toxic acid additive salt that can form, that have therapeutic activity form.The latter can be by obtaining with suitable acid treatment alkali form easily.Suitable acid comprises, mineral acid for example, for example for example hydrochloric acid or Hydrogen bromide of haloid acid; Sulfuric acid; Nitric acid; Phosphoric acid or the like; Or organic acid for example, acetate, propionic acid, oxyacetic acid, lactic acid, pyruvic acid, oxalic acid, propanedioic acid, succsinic acid (being Succinic Acid), toxilic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, right-toluenesulphonic acids, cyclohexane sulfamic acid, Whitfield's ointment, right-aminosallcylic acid, pamoic acid or the like acid.
For pharmacy acceptable addition salt mentioned above, comprise formula (I) compound nontoxic base addition salt form that can form, that have therapeutic activity.The example of this base addition salt form for example is, sodium, potassium, calcium salt, and with the acceptable amine of pharmacy for example ammonia, alkylamine, N, N '-dibenzyl-ethylenediamin, N-methyl D-glycosamine, breathe out for example salt that becomes with Methionin of arginine of amine (hydrabamine), amino acid.
Otherwise described salt form can be by being converted into free acid or alkali form with suitable alkali or acid treatment.
For the term additive salt that above uses, also comprise formula (I) compound with and the salt solvate that can form.This solvate is for example hydrate, alcoholate or the like.
Term stereochemistry heterogeneous forms for above using is defined as possible different isomerization form and conformation form that formula (I) compound can have.Unless otherwise mentioned or indicate, the chemical symbol of compound is represented the mixture of all possible stereochemistry and conformational isomerism form, and described mixture contains all diastereomers, enantiomorph and/or the conformer of base molecule structure.All stereochemistry heterogeneous forms of formula (I) compound of pure form or mutual form of mixtures are included in the scope of the present invention.
The compound of some formulas (I) also can exist with their tautomeric form.Although clearly do not indicate this form in above-mentioned formula, it is included in the scope of the present invention.
The N-oxide form of formula (I) compound comprises that one of them or several nitrogen-atoms are oxidized to those formulas (I) compound of so-called N-oxide compound.
One group of preferred compound is by wherein using one or more following formula that limits (I) compound to constitute:
Z represents NH;
Y represents-C
3-9Alkyl-,-C
2-9Thiazolinyl-,-C
1-5Alkyl-oxygen base-C
1-5Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-,-C
1-6Alkyl-NH-CO-,-CO-C
1-7Alkyl-,-C
1-7Alkyl-CO-or C
1-6Alkyl-CO-C
1-6Alkyl;
X
1Expression O ,-O-C
1-2Alkyl-,-O-N=CH-, NR
11Or-NR
11-C
1-2Alkyl-; In one specific embodiment, X
1Expression-NR
11-,-O-or-O-CH
2-;
X
2Represent direct key, O ,-O-C
1-2Alkyl-,-O-N=CH-, C
1-2Alkyl, NR
12Or NR
12-C
1-2Alkyl-; In one specific embodiment, X
2Represent direct key ,-O-N=CH-, C
1-2Alkyl-,-O-C
1-2Alkyl ,-O-or-O-CH
2-;
R
1Expression hydrogen, cyano group, halogen or hydroxyl, preferred halogen;
R
2Expression hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-, C
1-4The alkyl oxy carbonyl-, Het
16-carbonyl-, C
1-4Alkyl-, C
2-6Alkynyl-, Ar
5Or Het
1In further embodiment, R
2Expression hydrogen, cyano group, halogen, hydroxyl, or Ar
5
R
3Expression hydrogen;
R
4Expression hydrogen, hydroxyl, C
1-4Alkyl oxy-, Ar
4-C
1-4Alkyl oxy or R
4Expression is by one or two or more are selected from C when possible
1-4Alkyl oxy-or Het
2-the C that replaces of substituting group
1-4Alkyl oxy;
R
11Expression hydrogen, C
1-4Alkyl-or C
1-4Alkyl-oxygen base-carbonyl-;
R
12Expression hydrogen, C
1-4Alkyl-or C
1-4Alkyl-oxygen base-carbonyl-;
R
13Expression Het
14-C
1-4Alkyl, especially morpholinyl-C
1-4Alkyl;
Het
1The optional thiazolyl that is replaced by following substituting group of expression: amino, C
1-4Alkyl, hydroxyl-C
1-4Alkyl-, phenyl, phenyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-, single or two (C
1-4Alkyl) amino-or amino-carbonyl-;
Het
2Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl or pyrrolidyl, wherein said Het
2Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, amino or C
1-4Alkyl-; In further embodiment, Het
2Expression is selected from optional by C
1-4The morpholinyl that alkyl-preferable methyl replaces or the heterocycle of piperidyl;
Het
14Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl or pyrrolidyl, wherein said Het
14Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, amino or C
1-4Alkyl-;
Het
16Expression is selected from following heterocycle: piperidyl, morpholinyl or pyrrolidyl;
Ar
4Expression optional by cyano group, hydroxyl-, C
1-4Alkyl oxy or C
1-4The phenyl that alkyl replaces;
Ar
5Expression optional by cyano group, hydroxyl-, C
1-4Alkyl oxy or C
1-4The phenyl that alkyl replaces.
One group of further compound is by wherein using one or more following formula that limits (I) compound to constitute:
Z represents NH;
Y represents-C
3-9Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-,-C
1-6Alkyl-NH-CO-or-CO-NH-C
1-6Alkyl-;
X
1Expression-O-or-NR
11-;
X
2Represent direct key ,-C
1-2Alkyl-,-O-C
1-2Alkyl ,-O-or-O-CH
2-;
R
1The expression hydrogen or halogen;
R
2Expression hydrogen, cyano group, halogen, hydroxycarbonyl group-, C
1-4The alkyl oxy carbonyl-, Het
16-carbonyl-or Ar
5
R
3Expression hydrogen;
R
4Expression hydrogen, hydroxyl, C
1-4Alkyl oxy-, Ar
4-C
1-4Alkyl oxy; Or R
4Expression is by one or two or more are selected from C when possible
1-4Alkyl oxy-or Het
2-the C that replaces of substituting group
1-4Alkyl oxy;
R
11Expression hydrogen;
R
12Expression hydrogen, C
1-4Alkyl-or C
1-4Alkyl-oxygen base-carbonyl-;
R
13Expression Het
14-C
1-4Alkyl, especially morpholinyl-C
1-4Alkyl;
Het
2Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl or pyrrolidyl, wherein said Het
2Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, amino or C
1-4Alkyl-; In further embodiment, Het
2Expression is selected from optional by C
1-4The morpholinyl that alkyl-preferable methyl replaces or the heterocycle of piperidyl;
Het
14The expression morpholinyl;
Het
16Expression is selected from following heterocycle: morpholinyl or pyrrolidyl;
Ar
4The expression phenyl;
Ar
5The optional phenyl that is replaced by cyano group of expression.
Another group compound is by wherein using one or more following formula that limits (I) compound to constitute:
Z represents NH;
Y represents-C
3-9Alkyl-,-C
2-9Thiazolinyl-,-C
1-5Alkyl-oxygen base-C
1-5Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-,-C
1-5Alkyl-NR
14-CO-C
1-5Alkyl-,-C
1-6Alkyl-NH-CO-,-CO-C
1-7Alkyl-,-C
1-7Alkyl-CO-or C
1-6Alkyl-CO-C
1-6Alkyl;
X
1Expression O ,-O-C
1-2Alkyl-,-O-N=CH-, NR
11Or-NR
11-C
1-2Alkyl-; In a specific embodiment, X
1Represent direct key, C
1-2Alkyl-,-O-C
1-2Alkyl-, NR
11-,-O-or-O-CH
2-;
X
2Represent direct key, O-,-O-C
1-2Alkyl-,-O-N=CH-, NR
17-CO-, NR
17-CO-C
1-2Alkyl-, C
1-2Alkyl, Het
20-C
1-2Alkyl-, NR
12Or NR
12-C
1-2Alkyl-; In a specific embodiment, X
2Represent direct key, C
1-2Alkyl-,-O-C
1-2Alkyl, NR
17-CO-, NR
17-CO-C
1-2Alkyl-, Het
20-C
1-2Alkyl-,-O-or-O-CH
2-;
R
1Expression hydrogen, cyano group, halogen or hydroxyl, preferred halogen;
R
2Expression hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-, C
1-4The alkyl oxy carbonyl-, Het
16-carbonyl-, C
1-4Alkyl-, C
2-6Alkynyl-, Ar
5Or Het
1In further embodiment, R
2Expression hydrogen, cyano group, halogen, hydroxyl, or Ar
5In a more particular embodiment, R
2The expression hydrogen or halogen;
R
3Expression hydrogen;
R
4Expression hydrogen, hydroxyl, C
1-4Alkyl oxy-, Ar
4-C
1-4Alkyl oxy; Or R
4Expression is by one or two or more are selected from C when possible
1-4Alkyl oxy-or Het
2-the C that replaces of substituting group
1-4Alkyl oxy;
R
11Expression hydrogen, C
1-4Alkyl-or C
1-4Alkyl-oxygen base-carbonyl-;
R
12Expression hydrogen, C
1-4Alkyl-or C
1-4Alkyl-oxygen base-carbonyl-;
R
13Expression hydrogen or Het
14-C
1-4Alkyl, especially morpholinyl-C
1-4Alkyl;
R
14Expression hydrogen or C
1-4Alkyl;
R
17Expression hydrogen, C
1-4Alkyl-, Het
21-C
1-4Alkyl or C
1-4Alkyl-oxygen base-C
1-4Alkyl; Especially R
17Expression hydrogen or C
1-4Alkyl;
Het
1The optional thiazolyl that is replaced by following substituting group of expression: amino, C
1-4Alkyl, hydroxyl-C
1-4Alkyl-, phenyl, phenyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-, single or two (C
1-4Alkyl) amino-or amino-carbonyl-;
Het
2Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl or pyrrolidyl, wherein said Het
2Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, amino or C
1-4Alkyl-; In further embodiment, Het
2Expression is selected from optional by C
1-4The morpholinyl that alkyl-preferable methyl replaces or the heterocycle of piperidyl;
Het
14Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl or pyrrolidyl, wherein said Het
14Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, amino or C
1-4Alkyl-;
Het
16Expression is selected from following heterocycle: piperidyl, morpholinyl or pyrrolidyl;
Het
20Expression is selected from following heterocycle: pyrrolidyl, 2-pyrrolidyl or piperidyl;
Het
21Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl or pyrrolidyl, wherein said Het
2Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, amino or C
1-4Alkyl-;
Ar
4Expression optional by cyano group, hydroxyl-, C
1-4Alkyl oxy or C
1-4The phenyl that alkyl replaces;
Ar
5Expression optional by cyano group, hydroxyl-, C
1-4Alkyl oxy or C
1-4The phenyl that alkyl replaces.
One group of further compound is by wherein using one or more following formula that limits (I) compound to constitute:
Z represents NH;
Y represents-C
3-9Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-,-C
1-5Alkyl-NR
14-CO-C
1-5Alkyl-,-C
1-6Alkyl-NH-CO-or-CO-NH-C
1-6Alkyl-;
X
1Represent direct key ,-C
1-2Alkyl-,-O-C
1-2Alkyl ,-O-,-O-CH
2-or-NR
11-;
X
2Expression-O-,-O-C
1-2Alkyl ,-NR
12-, NR
12-C
1-2Alkyl ,-NR
17-CO-, NR
17-CO-C
1-2Alkyl or Het
20-C
1-2Alkyl-;
R
1The expression hydrogen or halogen;
R
2Expression hydrogen, cyano group, halogen, hydroxycarbonyl group-, C
1-4The alkyl oxy carbonyl-, Het
16-carbonyl-or Ar
5Especially R
2The expression hydrogen or halogen;
R
3Expression hydrogen;
R
4Expression hydrogen, hydroxyl, C
1-4Alkyl oxy-, Ar
4-C
1-4Alkyl oxy; Or R
4Expression is by one or two or more are selected from C when possible
1-4Alkyl oxy-or Het
2-the C that replaces of substituting group
1-4Alkyl oxy;
R
11Expression hydrogen;
R
12Expression hydrogen, C
1-4Alkyl-or C
1-4Alkyl-oxygen base-carbonyl-;
R
13Expression hydrogen or Het
14-C
1-4Alkyl, especially hydrogen or morpholinyl-C
1-4Alkyl;
R
14Expression hydrogen;
R
17Expression hydrogen;
Het
2Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl or pyrrolidyl, wherein said Het
2Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, amino or C
1-4Alkyl-; In further embodiment, Het
2Expression is selected from optional by C
1-4The morpholinyl that alkyl-preferable methyl replaces or the heterocycle of piperidyl;
Het
14The expression morpholinyl;
Het
16Expression is selected from following heterocycle: morpholinyl or pyrrolidyl;
Het
20Expression pyrrolidyl or piperidyl;
Ar
4The expression phenyl;
Ar
5The optional phenyl that is replaced by cyano group of expression.
Other one group of special compound is:
-a wherein
1-a
2=a
3-a
4The compound of the formula (I) of expression N-CH=CH-CH;
-a wherein
1-a
2=a
3-a
4The compound of the formula (I) of expression N-CH=N-CH;
-a wherein
1-a
2=a
3-a
4The compound of the formula (I) of expression CH-CH=N-CH;
-wherein-X
1The compound of the formula of-expression-O-(I);
-wherein-X
1-expression-NR
11-, especially-compound of the formula (I) of NH-;
-wherein-X
2-expression-NR
17-CO-C
1-2Alkyl-, especially-NH-CO-C
1-2Alkyl-the compound of formula (I);
-wherein-X
2-expression-NR
12-C
1-2Alkyl, especially-NH-C
1-2Alkyl-the compound of formula (I);
-wherein-Y-represents-C
1-5Alkyl-NR
14-CO-C
1-5Alkyl-, especially-C
1-5Alkyl-NH-CO-C
1-5Alkyl-the compound of formula (I);
-R wherein
1It is the compound of the formula (I) of fluorine, chlorine or bromine;
-R wherein
2It is the compound of the formula (I) of fluorine, chlorine or bromine;
-R wherein
1And R
2The compound of the formula (I) of expression halogen, especially wherein R
1Expression fluorine and R
2The compound of the formula (I) of expression chlorine;
-R wherein
2Be Het
1, especially optional by the compound of the formula of methyl substituted thiazolyl (I);
-R wherein
2Be C
2-6Alkynyl-, the compound of the formula of ethynyl (I) especially;
-R wherein
2Be Ar
5, the especially optional phenyl that is replaced by cyano group the compound of formula (I);
-R wherein
3It is the compound of the formula (I) of cyano group;
-R wherein
4Expression methoxyl group and wherein said methoxyl group are at 7 formula (I) compound of formula (I) structure.
-R wherein
4Expression is selected from C by one
1-4Alkyl oxy-or Het
2-the C that replaces of substituting group
1-4Formula (I) compound of alkyl oxy, the propoxy-that especially replaced by morpholinyl;
-R wherein
12Be hydrogen or C
1-4Alkyl-, especially methyl or R wherein
12Be C
1-4Alkyl-oxygen base-carbonyl-, especially the tertiary butyl-oxygen base-carbonyl-formula (I) compound;
-Het wherein
2Expression is optional by C
1-4Formula (I) compound that the morpholinyl that alkyl replaces, preferred morpholinyl are connected with the remainder of formula (I) compound by nitrogen-atoms;
-Het wherein
3Expression is optional by C
1-4Formula (I) compound that the morpholinyl that alkyl replaces, preferred morpholinyl are connected with the remainder of formula (I) compound by nitrogen-atoms;
-Het wherein
12Expression is optional by C
1-4Formula (I) compound that the morpholinyl that alkyl replaces, preferred morpholinyl are connected with the remainder of formula (I) compound by nitrogen-atoms.
In further embodiment of the present invention, the R in formula (I) structure
1Substituting group is at 4 ' position, R
2Substituting group is at 5 ' position, R
3Substituting group is at 2, R
4Substituting group is at 6.According to one group of concrete compound of the present invention be wherein the aniline fragment 5 ' position is by R
2Substituting group, 4 ' position is by R
1The compound of the formula (I) that substituting group replaces, wherein said R
1Substituting group is represented halogen, especially fluorine, wherein said R
2Substituting group is selected from halogen, C
1-4The alkyl oxy carbonyl-, Het
16-carbonyl-, hydroxycarbonyl group-, cyano group or Ar
5Especially described R
2Be selected from chlorine, bromine, methoxycarbonyl, pyrrolidyl carbonyl, morpholino-carbonyl, hydroxycarbonyl group, cyano group or phenyl.
Compound of the present invention can be by any prepares in some standard synthetic methods, and organic chemistry filed technician uses these synthetic methods usually, and has made description in the reference below; " Heterocyclic Compounds "-Vol.24 (part 4) p 261-304Fused pyrimidines, Wiley-Interscience; Chem.Pharm.Bull., Vol 41 (2) 362-368 (1993); J.Chem.Soc., Perkin Trans.1,2001,130-137.
In a word, for wherein-X
1The compound of the formula of-expression-NH-(I), described compound usually use known reaction conditions, for example use alkali for example triethylamine, N-ethyl-N-(1-methylethyl)-2-propylamine (DIPEA) and analogue, or mineral alkali Na for example
2CO
3, K
2CO
3And analogue, at suitable polar solvent for example in propane-2-alcohol, 1-butanols, acetonitrile and the analogue, under high temperature (60-90 ℃ or reflux temperature), by 4 of 4-chloro-6-fluoro-Pyridopyrimidine or formula (II), 6-two chloro-Pyridopyrimidines and the reaction of suitable aniline (III) prepare.Thus obtained aniline Pyridopyrimidine (IV) is further replaced by the amine of suitable formula (VII), obtains the intermediate of formula VIII.This substitution reaction for the second time is following carrying out under the known reaction conditions: for example randomly suitable solvent for example among propane-2-alcohol, 1-butanols or the DMSO, alkali for example triethylamine, N-ethyl-N-(1-methylethyl)-2-propylamine (DIPEA) and analogue in the presence of, in high temperature (70-100 ℃) time reaction stirred.Use condition known in the art to carry out obtaining compound of the present invention at last after deprotection and the closed loop.Closed loop is typically at coupling reagent for example 1,3-dicyclohexylcarbodiimide (DCC), N, N '-N,N'-carbonyldiimidazole (CDI), POCl
3, TiCl
4, chlorofluorination sulphur (SO
2ClF) or under the existence of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDCI), under the condition that has or do not exist hydroxybenzotriazole, carry out.
Reaction scheme 0
P
1And P
2Each represents optional protected functional group independently, for example uncle or secondary amine, hydroxyl, hydroxycarbonyl group or halogen (Cl, Br or I), the Y that it connects respectively according to reaction product and they
1And Y
2Substituting group and deciding, divalence Y base are as mentioned for the definition of formula (I) compound.X
1, X
2, R
1, R
2, R
3And R
4According to the above definition of formula (I) compound.
As further illustrating in the experimental part of specification sheets, wherein-X
1One group of formula (I) compound of-expression-O-hereinafter to be referred as the compound of formula (I '), uses following building-up reactions route to prepare usually.Compound of the present invention can provide midbody compound (IV) by aniline (III) coupling with suitable replacement of known 4-chloro-6-chloropyrimide and pyrimidine (II) is prepared, and wherein can prepare according to reaction scheme 3-7 when preparation (III).Under the known technology condition, use for example phenylcarbinol salt of suitable alkoxide, methylate, 2-trimethyl silyl ethanol carries out the replacement of 6-cl radical, carries out deprotection then, is respectively catalytic hydrogenation, TMSCl, Na
2S, TFA should obtain the Mitsunobu precursor of needed formula (VI).And then, under the Mitsunobu condition, carry out closed loop, obtain target compound (I ').
Reaction scheme 1
V=hydrogen or protecting group be methyl carbonyl, the tertiary butyl, methyl, ethyl, benzyl or trialkylsilkl for example; R represents benzyl or methyl; a
1-a
2=a
3-a
4, Y, X
2, R
1, R
2, R
3And R
4As definition for formula (I) compound
X wherein
2Expression-O-and a
1-a
2=a
3-a
4The compound of the formula (I ') of expression N-C=N-C is to prepare by the 2-aminophenol derivates with fungicidal property coupling of known 8-chloro-2 (methylthio group)-Mi Dingbing [5,4-d] pyrimidines (XXVII) with formula (XXVIII), wherein production (XXIX) midbody compound.Next, after phenol protection and methylthio group oxidation, use suitable alkoxide the Mi Dingbing pyrimidine of formula (VIII) to be changed into the intermediate of formula (IX).Deprotection then carries out closed loop under the Mitsunobu condition subsequently, obtains target compound (I ").
Reaction scheme 2
V=hydrogen or protecting group be methyl carbonyl, the tertiary butyl, methyl, ethyl, benzyl or trialkylsilkl for example; And Y, X
2, R
1, R
2, R
3And R
4As definition for formula (I) compound
Perhaps, X wherein
2Expression-O-and a
1-a
2=a
3-a
4The compound of the formula (I ') of expression C-C=C-N, described compound have wherein produced the midbody compound of formula (VII) by known 4-chloro-6-fluorine Pyridopyrimidine (II) and formula (XXVIII) 2-aminophenol derivates with fungicidal property coupling preparation.Next, after the phenol protection, use suitable alkoxide the Pyridopyrimidine of formula (VIII) to be changed into the intermediate of formula (IX).Deprotection then carries out closed loop under the Mitsunobu condition subsequently, obtains target compound (I ").
Reaction scheme 3
V=hydrogen or protecting group be methyl carbonyl, the tertiary butyl, methyl, ethyl, benzyl or trialkylsilkl for example; And Y, R
1, R
2, R
3And R
4As definition for formula (I) compound
For those X wherein
2The compound of expression-O-, formula (III
a) the aniline of suitable replacement normally under the alkali condition, in reaction-inert solvent, for instance, use N,N-DIMETHYLACETAMIDE (DMA) at K
2CO
3Existence under, by can commercial nitro-phenol (X) and the α that buys, the halohydrin of ω-protection (XI) prepares.Subsequently nitro-the phenyl derivatives (XII) that obtains is reduced according to standard conditions, for instance, use iron/acetate, acquisition formula (III
a) the aniline (reaction scheme 4) of replacement.
Reaction scheme 4
X for example represents halogen, Cl, Br and I
V represents for example methyl carbonyl of protecting group
For those X wherein
2Expression-NR
12-or-NR
12-C
1-2Alkyl-compound, formula (III
b) suitable replacement aniline usually by can commercial 2-nitro-phenyl aldehyde (XIII) of buying and the alcohol (XIV) that replaces of amine prepare by reduction amination under standard conditions, for example use NaBH
4And titanium (IV) isopropoxide obtains the nitro-benzylamine of formula (XV) as reductive agent, under the condition of ethanol as solvent in the first step.
Be right after and use methods known in the art that free primary alconol is protected, for example, use and the esterification of diacetyl oxide in the presence of pyridine.Intermediate with thus obtained formula (XVI) reduces according to standard conditions subsequently, for example, uses iron/acetate, acquisition formula (III
b) the aniline (reaction scheme 5) of replacement.
Reaction scheme 5
V represents for example methyl carbonyl of protecting group
M=0 or 1 and n=1 or 2
For those X wherein
2The compound of expression-O-N=CH-, formula (III
c) the aniline of suitable replacement normally according to reaction scheme 5 preparation.
In the first step, use for example known in the art and condensation reaction azanol, change known 2-nitro-phenyl aldehyde (XIII) into corresponding oxime (XVII).
And then the oxime that makes described formula XVII for example under the alkali condition, for example uses the K in DMSO
2CO
3With haloalkyl acetic ester reaction, or react as under the reaction conditions, then for example make nitroreduction, formula (III is provided with iron/acetate with stronger silyl protecting group such as TBDMS or TBDPS, NaH in THF
c) the aniline of suitable replacement.
Reaction scheme 6
X represents halogen for example Cl, Br or I
For those X wherein
2Represent that a direct key and Y represent C
1-6The compound of alkyl-NH-CO-, formula (III
d) the aniline of suitable replacement normally according to reaction scheme 7 preparation.
In the first step, under condition known in the art, with the intermediate of known 2-nitro-phenylformic acid (XX) amidation becoming formula (XXII), for example, the hydroxylated amine of use formula (XXI), its dropwise joined under the two 1H-imidazoles of 1,1 ' carbonyl exist at CH
2Cl
2In the mixture of (XX) in.
Be right after and use methods known in the art that free primary alconol is protected, for example, use and the esterification of diacetyl oxide in the presence of pyridine.
Intermediate with thus obtained formula (XXIII) reduces according to standard conditions subsequently, for example, uses iron/acetate, acquisition formula (III
d) the aniline of replacement.
Reaction scheme 7
V represents for example methyl carbonyl of protecting group
For those X wherein
2The compound of a direct key of expression, formula (III
e) the aniline of suitable replacement normally according to reaction scheme 7 preparation.
In the first step, under condition known in the art, for example use the Wittig reaction with the phosphorus salt of suitable formula (XXIV), be the intermediate of formula (XXV) with known 2-nitro-phenyl aldehyde (XIII) alkylene.
With after free carboxy acid's esterification, for example, use ethanol esterification under acidic conditions under standard conditions, the intermediate reduction with formula (XXVI) obtains needed formula (III
e) substituted aniline.
Reaction scheme 8
Y
1Expression C
1-7Alkyl
Further illustrating of book experimental section as an illustration, wherein-X
1-expression-NR
11-and a
1-a
2=a
3-a
4One group of formula (I) compound of expression N-CH=N-CH, (compound of I ") uses following building-up reactions route to prepare (reaction scheme 9) usually hereinafter to be referred as formula.Described compound is the 2-aminophenol derivates with fungicidal property coupling preparation by known 8-chloro-2 (methylthio group)-Mi Dingbing [5,4-d] pyrimidine and formula (XXVIII), wherein production (XXIX) midbody compound.
And then, use aminating alcohol (XXX) Mi Dingbing [5,4-d] pyrimidine amination with formula (XXIX) under condition known in the art, closed loop under the Mitsunobu condition then obtains the target compound of formula (I ).
Reaction scheme 9
Perhaps, for those wherein-X
1-expression-NR
11-and a
1-a
2=a
3-a
4The compound of formula (I) of expression N-CH=CH-CH is by known 4, the 2-aminophenol derivates with fungicidal property coupling preparation of 6-two chloro-(XXVII ') and formula (XXVIII), the midbody compound of production (XXIX ') wherein.
And then, use aminating alcohol (XXX) pyrido [3,2-d] pyrimidine amination with formula (XXIX ') under condition known in the art, then closed loop under the Mitsunobo condition obtains formula (I " ") target compound (reaction scheme 10).
Reaction scheme 10
Where necessary or as required, can carry out an any step or multistep of following further step with any order:
(i) remove any residual protecting group;
(ii) make the compound of formula (I) or the form of its protection be converted into the compound of further formula (I) or the form of its protection:
(iii) the form of the compound of formula (I) or its protection is converted into N-oxide compound, salt, quaternary ammonium or the solvate of formula (I) compound or its protection form;
(iv) N-oxide compound, salt, quaternary ammonium or the solvate with formula (I) compound or its protection form is converted into the compound of formula (I) or the form of its protection;
(v) N-oxide compound, salt, quaternary ammonium or the solvate of formula (I) compound or its protection form is converted into another kind of N-oxide compound, pharmacy acceptable addition salt, quaternary ammonium or the solvate of the form of the compound of formula (I) or its protection;
(be under the situation that with (R) and (S) form of mixture of enantiomers obtains vi), split this mixture, obtain needed enantiomorph at the compound of formula (I).
Can use the compound of methods known in the art with formula (I), its N-oxide compound, additive salt, quaternary ammonium and stereochemistry heterogeneous forms change into according to further compound of the present invention.
The functional group that it will be appreciated by those skilled in the art that midbody compound in aforesaid method may need to seal by protecting group.
The functional group that wishes protection comprises hydroxyl, amino and carboxylic acid.Comprise trialkylsilkl (for example t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl silyl), benzyl and THP trtrahydropyranyl for the suitable protecting group of hydroxyl.Comprise tertbutyloxycarbonyl or carbobenzoxy-(Cbz) for the suitable protecting group of amino.The protecting group suitable for carboxylic acid comprises C
(1-6)Alkyl or benzyl ester.
The protection of functional group and deprotection may carry out before or after reactions steps.
In addition, can be with the N-atom in formula (I) compound by methods known in the art, use CH
3-I for example methylates in acetone, tetrahydrofuran (THF) or the dimethyl formamide at suitable solvent.
The compound of formula (I) can also be according to functional group known in the art method for transformation phase co-conversion, and the some of them example is discussed hereinafter.
Can also trivalent nitrogen be converted into the method for its N-oxide form according to known in the art, change the compound of formula (I) into corresponding N-oxide form.Described N-oxidizing reaction usually can through type (I) raw material and 3-phenyl-2-(benzenesulfonyl) oxa-ethylenimine (oxaziridine) reaction or carry out with suitable organic or inorganic peroxide reactions.Suitable inorganic peroxide comprises, for example, and hydrogen peroxide, basic metal or alkaline earth metal peroxide, sodium peroxide for example, Potassium peroxide; Suitable organo-peroxide can comprise peroxy acid such as, for example, the peroxybenzoic acid that peroxybenzoic acid or halogen replace, 3-chloro peroxybenzoic acid for example, peroxidation alkanoic acid, Peracetic Acid for example, alkyl peroxide, for example tertbutyl peroxide.Suitable solvent is, for example, and water, low-grade alkane alcohol, ethanol or the like for example, hydrocarbon, toluene for example, ketone, 2-butanone for example, halohydrocarbon, for example mixture of methylene dichloride and these solvents.
Can obtain the pure stereochemistry heterogeneous forms of formula (I) compound by using methods known in the art.Diastereomer can be by physical method for example selective freezing and chromatographic technique, counter-current distribution method for example, and liquid chromatography or the like is separated.
The compound of some formulas (I) and some intermediates may contain unsymmetrical carbon in the present invention.Can obtain the pure stereochemistry heterogeneous forms of described compound and described intermediate by using methods known in the art.For example, diastereomer can be by physical method for example selective freezing or chromatographic technique, counter-current distribution method for example, and liquid chromatography or the like method is separated.Enantiomorph can obtain from racemic mixture, by at first with suitable resolving agent for example chiral acid described racemic mixture is converted into the mixture of diastereomeric salt or compound; Mixture with described diastereomeric salt or compound passes through for example selective freezing or chromatographic technique, for example liquid chromatography or the like method physical sepn then; And at last described isolating diastereomeric salt or compound are converted into corresponding enantiomorph.Pure stereochemistry heterogeneous forms can also be obtained by the pure stereochemistry heterogeneous forms of suitable intermediate and starting raw material, and condition is that stereospecific intervention reaction takes place.
The alternative method of the compound of separate type (I) and the enantiomeric form of intermediate comprises liquid chromatography, particularly uses the liquid chromatography of chiral stationary phase.
Some intermediates that use in reaction scheme mentioned above and starting raw material are compound known and are commercially to buy, or can prepare according to methods known in the art.Yet, in the compound of formula (I) synthetic, the present invention further provides the intermediate of formula (III):
Its pharmacy acceptable addition salt and stereochemistry heterogeneous forms, wherein
V represents hydrogen or is preferably selected from the protecting group of methyl carbonyl, the tertiary butyl, methyl, ethyl, benzyl or trialkylsilkl;
Y represents-C
3-9Alkyl-,-C
3-9Thiazolinyl-,-C
1-5Alkyl oxy-C
1-5Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-,-C
1-5Alkyl-NR
14-CO-C
1-5Alkyl-,-C
1-5Alkyl-CO-NR
15-C
1-5Alkyl-,-C
1-6Alkyl-CO-NH-,-C
1-6Alkyl-NH-CO-,-C
1-7Alkyl-CO-, C
1-6 alkyl-CO-C
1-6Alkyl;
X
2Represent direct key, O ,-O-C
1-2Alkyl-, CO ,-CO-C
1-2Alkyl-, NR
12,-NR
12-C
1-2Alkyl-,-CH
2-,-O-N=CH-or C
1-2Alkyl;
R
1Expression hydrogen, cyano group, halogen, hydroxyl, formyl radical, C
1-6Alkyl oxy-, C
1-6Alkyl-, the C that is replaced by halogen
1-6Alkyl oxy-, by one or may the time two or more substituting groups that are selected from hydroxyl or halogen C of replacing
1-4Alkyl; With
R
2Expression hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-, Het
16-carbonyl-, C
1-4The alkyl oxy carbonyl-, C
1-4Alkyl-carbonyl-, aminocarboxyl-, single or two (C
1-4Alkyl) aminocarboxyl-, Het
1, formyl radical, C
1-4Alkyl-, C
2-6Alkynyl, C
3-6Cycloalkyl-, C
3-6Cycloalkyl oxy-, C
1-6Alkyl oxy-, Ar
5, Ar
1-oxygen base-, boronic acid, the C that is replaced by halogen
1-6Alkyl oxy-, by one or may the time two or more are selected from halogen, hydroxyl or NR
5R
6The C that replaces of substituting group
1-4Alkyl,
C
1-4Alkyl-carbonyl-, wherein said C
1-4Alkyl chooses wantonly by one or two or more are selected from hydroxyl or C when possible
1-4Alkyl-oxygen base-substituting group replace;
R
5And R
6Be selected from hydrogen or C independently of one another
1-4Alkyl;
R
12Expression hydrogen, C
1-4Alkyl, C
1-4Alkyl-oxygen base-carbonyl-, Het
17, Het
18-C
1-4Alkyl-, optional by Het
19-C
1-4The C of alkyl amino-carbonyl-replacement
2-4Alkenyl carbonyl-, C
2-4The thiazolinyl alkylsulfonyl-, C
1-4Alkyl oxy C
1-4Alkyl-optional by one or may the time two or more are selected from hydrogen, hydroxyl, amino or C
1-4Alkyl oxy-the phenyl that replaces of substituting group;
R
13Expression hydrogen, C
1-4Alkyl, Het
13, Het
14-C
1-4Alkyl-optional by one or may the time two or more are selected from hydrogen, hydroxyl, amino or C
1-4Alkyl oxy-the phenyl that replaces of substituting group;
R
14And R
15Each is independently selected from hydrogen, C
1-4Alkyl, Het
15-C
1-4Alkyl-or C
1-4Alkyl oxy C
1-4Alkyl-;
Het
1Expression is selected from following heterocycle: piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolanyl, thiazolyl, azoles base, imidazolyl, different azoles base, di azoly, pyridyl or pyrrolidyl, wherein said Het
1Optional by amino, C
1-4Alkyl, hydroxyl-C
1-4Alkyl-, phenyl, phenyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-, single or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
Het
13Expression is selected from the heterocycle of pyrrolidyl or piperidyl, and wherein said heterocycle chooses wantonly by one or two or more are selected from following substituting group replacement: C when possible
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
14Expression is selected from following heterocycle: morpholinyl, pyrrolidyl, piperazinyl or piperidyl, wherein said heterocycle choose wantonly by one or two or more are selected from following substituting group replacement: C when possible
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
15Expression is selected from following heterocycle: morpholinyl, pyrrolidyl, piperazinyl or piperidyl, wherein said heterocycle choose wantonly by one or two or more are selected from following substituting group replacement: C when possible
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
16Expression is selected from following heterocycle: morpholinyl, and pyrrolidyl, piperazinyl, 1,3,2-two oxa-boron heterocycle pentane or piperidyls, wherein said heterocycle is optional by one or more C that are selected from
1-4The substituting group of alkyl replaces; With
Het
17Expression is selected from the heterocycle of pyrrolidyl or piperidyl, and wherein said heterocycle chooses wantonly by one or two or more are selected from following substituting group replacement: C when possible
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
18And Het
19Each represents to be selected from following heterocycle independently: morpholinyl, pyrrolidyl, piperazinyl or piperidyl, wherein said Het
18And Het
19Optional by one or may the time two or more are selected from following substituting group and replace: C
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Ar
1, Ar
2, Ar
3, Ar
4And Ar
5Each represents optional by the phenyl of following replacement independently: cyano group, C
1-4Alkyl sulphonyl-, C
1-4Alkyl sulfonyl-amino-, amino-sulfonyl amino-, hydroxyl-C
1-4Alkyl, amino-sulfonyl-, hydroxyl-, C
1-4Alkyl oxy-or C
1-4Alkyl.
The intermediate of formula (III) particularly, wherein use one or more following qualifications:
I) Y represents-C
3-9Alkyl-,-C
1-5Alkyl-oxygen base-C
1-5Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-,-C
1-6Alkyl-NH-CO-;
Ii) X
2Represent direct key, O ,-O-C
1-2Alkyl-, NR
12,-NR
12-C
1-2Alkyl-,-CH
2-,-O-N=CH-or C
1-2Alkyl;
Iii) W represents hydrogen, cyano group, halogen or hydroxyl, preferred halogen;
Iv) R
2Expression hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-, C
1-4The alkyl oxy carbonyl-, Het
16-carbonyl-, C
1-4Alkyl-, C
2-6Alkynyl-, Ar
5Or Het
1
In further embodiment, R
2Expression hydrogen, cyano group, halogen, hydroxyl, C
2-6Alkynyl-or Het
1R particularly
2Expression hydrogen, cyano group, halogen, hydroxyl, or Ar
5
V) R
12Expression hydrogen, C
1-4Alkyl, or C
1-4The alkyl oxy carbonyl;
Vi) R
13Expression Het
14-C
1-4Alkyl, particularly morpholinyl-C
1-4Alkyl,
Vii) Het
1The optional thiazolyl that is replaced by following substituting group of expression: amino, C
1-4Alkyl, hydroxyl-C
1-4Alkyl-, phenyl, phenyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-, single or two (C
1-4Alkyl) amino-or amino-carbonyl-;
Viii) Het
16Expression is selected from the heterocycle of piperidyl or pyrrolidyl.
The intermediate that a further object of the invention provides formula (III) is in the Macrocyclic kinase inhibitors purposes in compound synthetic of formula (I) for example.
The intermediate of the compound of formula of the present invention (I) and formula (XXXI) is useful, because they have pharmacological property.Therefore they can be used as medicine.
Correspondingly, at the intermediate that relates to formula (XXXI) aspect further of the present invention.
Its N-oxide form, pharmacy acceptable addition salt and stereochemistry heterogeneous forms, wherein:
a
1-a
2=a
3-a
4Expression is selected from the divalent radical of N-CH=CH-CH or N-CH=N-CH;
Y represents-C
3-9Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-,-C
1-6Alkyl-NH-CO-or-CO-NH-C
1-6Alkyl-;
R
1The expression hydrogen or halogen;
R
2Expression hydrogen, cyano group, halogen, hydroxycarbonyl group-, C
1-4The alkyl oxy carbonyl-, Het
16-carbonyl-or Ar
5
R
4The expression hydroxyl, C
1-4Alkyl oxy-, Ar
4-C
1-4Alkyl oxy; Or R
4Expression is by one or two or more are selected from C when possible
1-4Alkyl oxy-or Het
2-the C that replaces of substituting group
1-4Alkyl oxy;
R
11Expression hydrogen;
R
13Expression Het
14-C
1-4Alkyl, especially morpholinyl-C
1-4Alkyl;
Het
2Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl or pyrrolidyl, wherein said Het
2Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, amino or C
1-4Alkyl-; In further embodiment, Het
2Expression is selected from optional by C
1-4The morpholinyl that alkyl-preferable methyl replaces or the heterocycle of piperidyl;
Het
14The expression morpholinyl;
Het
16Expression is selected from following heterocycle: morpholinyl or pyrrolidyl;
Ar
4The expression phenyl;
Ar
5The optional phenyl that is replaced by cyano group of expression; And the intermediate of formula (XXXI) is in the synthetic Macrocyclic kinase inhibitors purposes in the compound of formula (I) for example.
As described in experimental section hereinafter, the growth inhibitory effect of this compound and some intermediates and anti-tumor activity have obtained explanation in external enzymatic test about receptor tyrosine kinase EGFR.In another experiment, use cell toxicity test known in the art for example LIVE/DEAD (molecular probe) or MTT, in ovarian cancer cell line SKOV3, tested the growth inhibitory effect of this compound.
Correspondingly, the invention provides formula (I) compound and formula (XXXI) intermediate and their the acceptable N-oxide compound of pharmacy, additive salt, quaternary ammonium and the stereochemistry heterogeneous forms that is used for the treatment of.More particularly, be used for the treatment of or prevent the disease of cell proliferation mediation.The intermediate of the compound of formula (I), formula (XXXI) and their the acceptable N-oxide compound of pharmacy, additive salt, quaternary ammonium and stereochemistry heterogeneous forms are called as compound of the present invention hereinafter.
The illness that The compounds of this invention is used for treatment is atherosclerosis, restenosis, cancer and diabetic complication retinopathy for example especially.Practicality in view of The compounds of this invention, a kind of treatment cell proliferation illness for example atherosclerosis, restenosis and method for cancer are provided, and this method comprises the animal that suffers from the cell proliferation illness The compounds of this invention of Mammals (comprising the mankind) treatment significant quantity for example that needs this treatment.
Described method comprises the The compounds of this invention of system or topical administration animal (comprising the mankind) significant quantity.The treatment significant quantity that those of skill in the art will recognize that EGFR inhibitor of the present invention is to be enough to cause the amount of growth inhibitory effect and this amount especially to change according to the situation of compound concentrations and patient in tumor type and size, the therapeutical agent.Usually, as the treatment cell proliferation illness amount of the EGFR inhibitor that given of atherosclerosis, restenosis and treatment for cancer agent for example, will decide as the case may be by the attending doctor.
Usually, proper dosage is the dosage of the EGFR inhibitor concentration in the treatment site produces 0.5nM to 200 μ M scope, and is more typically 5nM to 10 μ M.In order to obtain this treatment concentration, may need the treatment patient 0.01mg/kg body weight to the 300mg/kg body weight, particularly from the 10mg/kg body weight to the 100mg/kg body weight.As mentioned above, above-mentioned amount can change for the basis as the case may be.In these methods of treatment, preferably The compounds of this invention was prepared before administration.Described in below herein, suitable pharmaceutical formulations is to use composition well-known and that obtain easily, prepares by known method.
Because they are as the high selectivity of EGFR inhibitor, the intermediate of the compound of formula as defined above (I) and formula (XXXI) is used to also indicate or differentiate that receptor tyrosine kinase is subjected to intravital kinases territory.For this purpose, can mark compound of the present invention, particularly come partially or completely to substitute one or more atoms in the molecule by their radio isotope.The example of interested tagged compound is those compounds with at least one halogen, and this halogen is the radio isotope of iodine, bromine or fluorine; Or has at least one
11Those compounds of C-atom or tritium atom.
Concrete group is by R wherein
1Those formulas (I) compound and formula (XXXI) intermediate that are radioactive halogen atom constitute.In principle, the of the present invention any compound that contains halogen atom is to be easy to usually to substitute halogen atom by suitable coordination carry out radiolabeled.For the suitable halogen radio isotope of this purpose, it is a radioiodide, for example
122I,
123I,
125I,
131I; The radiobromination thing, for example
75Br,
76Br,
77Br and
82Br and Radiofluorinated thing are for example
18F.The introducing of radioactive halogen atom can be undertaken by suitable replacement(metathesis)reaction, or is undertaken by any method described in the halogen derivative that uses preparation formula (I) above.
The interested form of radiolabeled another kind be by
11The C-atom comes alternate c atoms, or replaces hydrogen atom by the tritium atom.
Therefore, described radiolabeled The compounds of this invention can be used for the special method of indicating the receptor site in biomaterial.Described method comprises the following steps: (a) radio-labeling compound of the present invention, (b) gives the radiation that this radiolabeled compound of biomaterial and (c) detection subsequently come from radio-labeled compound.
The term biomaterial comprises the material of any kind of with biogenetic derivation.More particularly, this term is meant tissue sample, blood plasma or body fluid, also refers to animal, particularly warm blooded animal, or the part of animal organ for example.
When in testing in vivo, using, in suitable composition, give animal, and for example single photon emission computerized tomography (SPECT) or positron emission tomography (PET) or the like detect described radiolabeled compound to use imaging technique with radiolabeled compound.In such a way, can detect the distribution of the concrete receptor site of whole health, and can manifest the organ that contains described acceptor site by imaging technique mentioned above.By giving radiolabeled formula (I) compound with the organ imaging with detect the radiating method come from radioactive compound, also constituted a part of the present invention.
Aspect further, the invention provides The compounds of this invention and be used for the treatment of in above-mentioned cell proliferation illness or the indication purposes in each the medicament in preparation.
Requirement can reach the amount of the The compounds of this invention (also being equivalent to active ingredient at this paper) of result of treatment, certainly changes with age of particular compound, route of administration, recipient and situation and the concrete illness or the disease of being treated.Suitable per daily dose be from the 0.01mg/kg body weight to the 300mg/kg body weight, especially from the 10mg/kg body weight to the 100mg/kg body weight.Methods of treatment can comprise that also the scheme with every day one and four absorptions gives active ingredient.
Simultaneously can give active ingredient separately, preferably the form with pharmaceutical composition provides.Correspondingly, the present invention further provides a kind of pharmaceutical composition, it comprises The compounds of this invention and pharmaceutically acceptable carrier or thinner.Carrier or thinner must be " acceptable ", its in a sense with another component compatibility of composition, and harmless to its recipient.
Pharmaceutical composition of the present invention can prepare by the well-known arbitrary method of pharmaceutical field, for example use (18th ed. at people such as Gennaro Remington ' s Pharmaceutical Sciences, Mack Publishing Company, 1990, especially see Part 8:Pharmaceutical preparations and their Manufacture) middle those methods of describing.With the particular compound as the treatment significant quantity of active ingredient of alkali form or additive salt form, mix closely with pharmaceutically acceptable carrier, according to the desired dosage form that gives, described carrier can adopt various ways.Preferred these pharmaceutical compositions are to be suitable for and single formulation that vote gives, and are for example oral, through skin or administered parenterally; Or topical administration is for example by suction, nasal spray, eye drops or by creme, gel, shampoo or the like.For example, in the composition process of preparation oral dosage form, any pharmaceutical media commonly used be can adopt, for example for example water, glycol, oils, alcohol or the like adopted under suspension, syrup, elixir and the solution situation at oral liquid; Or under the situation of powder, pill, capsule and tablet, adopt solid carrier for example starch, sugar, kaolin, lubricant, binding agent, disintegrating agent or the like.Because tablet and capsule are easy to give, they represent the oral dosage unit form of most convenient, obviously adopt the solid pharmaceutical carriers under these circumstances.For parenteral composition, although can comprise other component, carrier generally includes sterilized water for example to help dissolving, comprises sterilized water at least most ofly.Can be prepared into injectable solution, for example, wherein carrier comprises the mixture of salts solution, glucose solution or salts solution and glucose solution.Also injectable suspension can be prepared into, under these circumstances, suitable liquid vehicle, suspending agent or the like can be adopted.In being suitable for the composition of transdermal administration, carrier randomly comprises penetration enhancers and/or suitable wetting agent, optional appropriate addn combination with than any character of small proportion, and this additive can not produce significant harmful effect to skin.Described additive can be so that give skin and/or can help to prepare needed composition.These compositions can give in many ways, for example the form of transdermal diaphragm, drops or paste.
Aforementioned pharmaceutical compositions is mixed with to be convenient to the dosage unit form that gives with uniform dose especially favourable.The dosage unit form that uses in the specification sheets of this paper and claim is meant the physics discrete units that is suitable as single dose, that each unit contains is predetermined amount, that estimate to produce required result of treatment, with required pharmaceutical carriers bonded active ingredient.The example of this dosage unit form is tablet (comprising indentation or coated tablet), capsule, pill, pockets of powder, sequin, injectable solution or suspension, tspn agent, a soupspoon capacity agent or the like and its isolating multiple doses unit.
Experimental section
Hereinafter, term " ADDP " is meant 1,1 '-(azo dicarbapentaborane) two piperidines, " DMF " is meant N, dinethylformamide, " THF " is meant tetrahydrofuran (THF), " DMSO " is meant methyl-sulphoxide.
A. the preparation of intermediate
Embodiment A 1
A) preparation phenol, 4-chloro-2-[(6-chloropyridine is [3,2-d] pyrimidine-4-yl also) amino]-(intermediate 1)
With 4,6-two chloro-pyridos [3,2-d] pyrimidines (0.00255 mole) and the mixture of 4-chloro-2-amino-phenol (0.00446 mole) in Virahol (30 milliliters) stirred 2 hours 30 minutes at 50 ℃, made it to room temperature and evaporate to dryness then.Resistates is received in the ether, filters and drying, obtain 1g (100%) intermediate 1.
B) preparation phenol, 4-chloro-2-[[6-[(6-hydroxyl hexyl) amino] pyrido [3,2-d] pyrimidine-4-yl] amino]-(intermediate 2)
The mixture of intermediate 1 (0.00255 mole) and 6-amino-1-hexanol (0.0255 mole) was stirred 3 hours at 100 ℃, make it then to room temperature.With resistates silica gel chromatography (elutriant: DCM/MeOH/NH
4OH 97/3/0.1; 70-200 μ m) purifying obtains 0.71g (72%) intermediate 2,260 ℃ of fusing points.
Embodiment A 2
Preparation phenol, 4-chloro-2-[[6-[(4-hydroxybutyl) amino] pyrido [3,2-d] pyrimidine-4-yl] amino]-(intermediate 3)
The mixture of intermediate 1 (0.0013 mole) and 4-amino-1-butanols (0.026 mole) was stirred 4 hours at 100 ℃, make it to room temperature then, and use the saturated nacl aqueous solution hydrolysis.Mixture is extracted with DCM, and decant is used MgSO
4Drying is filtered, and with solvent evaporation, up to exsiccation.With resistates (0.5g) silica gel column chromatography (elutriant: DCM/MeOH/NH
4OH 95/5/0.1; 70-200 μ m) purifying.With resistates (81mg, 17%) acetonitrile and ether crystallization.Leach precipitation and dry, obtain 69mg (15%) intermediate 3,227 ℃ of fusing points.
Embodiment A 3
Preparation phenol, 4-chloro-2-[[6-[(5-hydroxyl amyl group) amino] pyrido [3,2-d] pyrimidine-4-yl] amino]-(intermediate 4)
The mixture of intermediate 1 (0.0013 mole) and 5-amino-1-amylalcohol (0.0195 mole) was stirred 4 hours at 100 ℃, make it to room temperature then, and use the saturated sodium-chloride hydrolysis.Mixture is extracted with DCM, and decant is used MgSO
4Drying is filtered, and with solvent evaporation, up to exsiccation.With resistates (0.45g) silica gel column chromatography (elutriant: DCM/MeOH/NH
4OH 95/5/0.1; 70-200 μ m) purifying.With resistates (66mg, 14%) acetonitrile and ether crystallization.Leach precipitation and dry, obtain 59mg (12%) intermediate 4,240 ℃ of fusing points.
Embodiment A 4
A) preparation phenol, 4-chloro-2-[[6-(methylthio group) Mi Dingbing [5,4-d] pyrimidine-4-yl] amino]-(intermediate 5)
With 8-chloro-2-(methylthio group)-Mi Dingbing [5,4-d] pyrimidine (0.0047 mole) and the mixture of 2-amino-4-chlorophenol (0.0094 mole) in two alkane (5 milliliters) stirred 1 hour at 80 ℃, be cooled to room temperature then, leach precipitation, water washs with ether then, vacuum-drying obtains 1.2g (80%) intermediate 5.
B) preparation phenol, 4-chloro-2-[[6-[(6-hydroxyl hexyl) amino] Mi Dingbing [5,4-d] pyrimidine-4-yl] amino]-(intermediate 6)
With the mixture of intermediate 1 (0.00172 mole) in 6-amino-n-hexyl alcohol (0.0022 mole) after 100 ℃ melt 8 hours.With resistates silica gel column chromatography (elutriant: CH
2Cl
2/ CH
3OH/NH
4OH 97/3/0.1; 35-70 μ m) purifying obtains the 0.170g solid.Add ether, leach solid and vacuum-drying, obtain 135mg (20%) intermediate (6).
Embodiment A 5
A) preparation pyrido [3,2-d] pyrimidine, 4,6-two chloro-(intermediate 7)
DMF (3) is joined in the mixture of 6-chloro-pyrido [3,2-d] pyrimidines-4 (1H)-ketone [171178-33-9] (0.00275 mole) and thionyl chloride (0.179 mole).Stirred reaction mixture and backflow (at 80 ℃) 90 minutes.Evaporating solvent, and add methylene dichloride, evaporating solvent is dissolved in resistates in the methylene dichloride.With the saturated K of organic solution
2CO
3Solution washing, dry then (MgSO
4), filter and evaporating solvent, obtain 0.49g (89%) intermediate (7).(HPLC：85％P)。
B) preparation 4-[2-(6-chloro-pyrido [3,2-d] pyrimidine-4-base is amino)-phenoxy group]-ethyl butyrate (intermediate 8)
Intermediate (7) (0.00245 mole) is dissolved in the Virahol (20ml) (is difficult for molten).Add 4-(2-amino-benzene oxygen) ethyl butyrate (0.00416 mole), then add N, N-diethyl ethamine (0.00490 mole).Reaction mixture stirring and backflow are spent the night.Then, reaction mixture is cooled to room temperature and evaporating solvent.Resistates is received in the ether.Leach precipitation and dry (pump), (jade-green solid detects by HPLC-MS: 92%P to obtain 1.48g fraction (1); There are some raw material B).With this fraction (1) according to purifying as described below.
Repeat this reaction.
Intermediate (7) (0.0055 mole) is dissolved in the Virahol (40ml) (is difficult for molten).Add 4-(2-amino-benzene oxygen) ethyl butyrate (0.00935 mole), then add N, N-diethyl ethamine (0.0110 mole).Reaction mixture stirring and backflow are spent the night.Then, reaction mixture is cooled to room temperature and evaporating solvent.Resistates and fraction (1) are merged, and carry out purifying with silica gel flash column chromatography (elutriant: normal hexane/EtOAc 3/1).Collect the product fraction, evaporating solvent obtains 3.04g intermediate (8) (quantitatively obtain jade-green solid, just need not be further purified and can use) in the subsequent reactions step.
C) preparation 4-{2-[6-(3-t-butoxycarbonyl amino-third amino)-pyrido [3,2-d] pyrimidine-4-base is amino]-phenoxy group }-ethyl butyrate (intermediate 9)
With intermediate (8) (0.00026 mole) and (3-aminopropyl) carboxylamine 1,1-dimethyl ethyl ester (0.00288 mole) mixed 3 hours at 100 ℃ in closed reactor, obtained fraction (1) (57%P utilizes the acid amides of HPLC+35%).
With this fraction (1) according to purifying as described below.
Repeat this reaction.
100 ℃ with intermediate (8) (0.00026 mole) and (3-aminopropyl) carboxylamine 1,1-dimethyl ethyl ester (0.00288 mole) mixes 2.5 hours (not in aforesaid closed reactor) in open reaction flask.This mixture and fraction (1) are merged.(elutriant: normal hexane/EtOAc 3/1) carries out purifying with the silica gel flash column chromatography.Collect the product fraction, evaporating solvent obtains intermediate (9) (HPLC:92%P).D) preparation 4-{2-[6-(3-amino-third amino)-pyrido [3,2-d] pyrimidine-4-base is amino]-phenoxy group }-ethyl butyrate (intermediate 10)
Intermediate (9) (0.00019 mole) is dissolved in the methylene dichloride (4.00 milliliters).Add trifluoroacetic acid (0.05192 mole), and at room temperature stirred this reaction mixture 2 hours.Evaporating solvent and residual acid in rotatory evaporator.Resistates (oil) dry (high-vacuum pump) with obtaining obtains intermediate (10) (HPLC:93%P; Quantitatively obtain; Just need not be further purified and in the subsequent reactions step, to use).
E) preparation 4-{2-[6-(3-amino-third amino)-pyrido [3,2-d] pyrimidine-4-base is amino]-phenoxy group }-butyric acid (intermediate 11)
With (0.00019 mole in intermediate (10); 1 equivalent) is dissolved in the tetrahydrofuran (THF) (8.00 milliliters).Add entry (1.00 milliliters).Add lithium hydroxide monohydrate (0.0019 mole) solid.Add more lithium hydroxide monohydrate, until reaching the alkaline pH value (theretofore, because CF
3The COOH resistates, it is acid).Reaction mixture was stirred 2 days at 65 ℃.Evaporating solvent in rotatory evaporator obtains intermediate (11).(HPLC:78%P; Quantitatively obtain; Just need not be further purified and in the subsequent reactions step, to use).
Embodiment A 6
A) preparation 4-chloro-6-fluoro-pyrido [3,4-d] pyrimidine, (intermediate 12)
DMF (5) is joined in the mixture of 6-fluoro-3H-pyrido [3,4-d] pyrimidin-4-one (0.00605 mole) and thionyl chloride (0.39 mole).Reaction mixture stirred and reflux (at 80 ℃) 7 hours.Evaporating solvent obtains 1.254g intermediate (12) and (quantitatively obtains impurity; Just need not be further purified and in the subsequent reactions step, to use).
B) preparation 4-[2-(6-fluoro-pyrido [3,4-d] pyrimidine-4-base is amino)-phenoxy group]-ethyl butyrate (intermediate 13)
Intermediate (12) (0.00605 mole) is dissolved in the Virahol (40 milliliters).Add 4-(2-amino-benzene oxygen)-ethyl butyrate [112290-16-1] hydrochloride (0.01028 mole), then add N, N-diethyl ethamine (0.01210 mole).Reaction mixture stirring and backflow are spent the night.Then, reaction mixture is cooled to room temperature and evaporating solvent.With resistates silica gel flash column chromatography (elutriant: normal hexane/EtOAc 3/1) purifying.Collect the product fraction, evaporating solvent obtains 0.922g intermediate (13) (41%, two step of productive rate; Light yellow solid; 97%P utilizes HPLC).
C) preparation 4-{2-[6-(3-t-butoxycarbonyl amino-third amino)-pyrido [3,4-d] pyrimidine-4-base is amino]-phenoxy group }-ethyl butyrate (intermediate 14)
In reactor, intermediate (13) (0.00027 mole) is dissolved among the DMSO (in right amount).Add (3-aminopropyl) carboxylamine 1,1-dimethyl ethyl ester [75178-96-0] (0.07 milliliter) and N-ethyl-N-(1-methylethyl)-2-propylamine [7087-68-5] (0.10 milliliter).Reactor is airtight, and at 80 ℃ of heating this mixtures 7 days.Reaction mixture is toppled in the entry, and with dichloromethane extraction product three times.With the organic layer drying (MgSO that merges
4), filter and evaporating solvent, obtain the fraction 1 of intermediate (14).
Two other fractions of intermediate 14 are prepared as follows:
In (airtight) reactor, with intermediate (13) (0.00027 mole) and (3-aminopropyl) carboxylamine 1,1-dimethyl ethyl ester [75178-96-0] (0.00299 mole) mixes, and 100 ℃ of heating 3 hours, obtains the fraction 2 of intermediate (14).
In (airtight) reactor, with intermediate (13) (0.00008 mole) and (3-aminopropyl) carboxylamine 1,1-dimethyl ethyl ester [75178-96-0] (0.0009 mole) mixes, and 80 ℃ of heating 3 days, obtains the fraction 3 of intermediate (14).
The fraction 1,2 of intermediate 14 and 3 is merged, and with silica gel flash column chromatography purifying.
Intermediate 14 also can be prepared as follows:
Intermediate (13) (0.00027 mole) is dissolved among the DMF (3 milliliters).Add (3-aminopropyl) carboxylamine 1,1-dimethyl ethyl ester [75178-96-0] (0.00040 mole) and cesium carbonate (0.00135 mole), and 100 ℃ of stirred reaction mixtures 4 hours, spend the night at 115 ℃ then.Remove by filter excessive cesium carbonate.Evaporated filtrate obtains intermediate (14).
D) preparation 4-{2-[6-(3-amino-third amino)-pyrido [3,4-d] pyrimidine-4-base is amino]-phenoxy group }-ethyl butyrate (intermediate 15)
Intermediate (14) (0.00055 mole) is dissolved in the methylene dichloride (11.00 milliliters).Add trifluoroacetic acid (0.143 mole), and at room temperature stirred this reaction mixture 2 hours.Evaporating solvent and residual acid in rotatory evaporator.Resistates (oil) dry (high-vacuum pump) with obtaining obtains intermediate (15) (HPLC:91%P; Quantitatively obtain; Just need not be further purified and in the subsequent reactions step, to use).
E) preparation 4-{2-[6-(3-amino-third amino)-pyrido [3,4-d] pyrimidine-4-base is amino]-phenoxy group }-butyric acid (intermediate 16)
Intermediate (15) (0.00055 mole) is dissolved in the tetrahydrofuran (THF) (16.00 milliliters).Add entry (2.00 milliliters).Add lithium hydroxide monohydrate (0.0055 mole) solid.Add more lithium hydroxide monohydrate, until reaching the alkaline pH value (theretofore, because CF
3The COOH resistates, it is acid).Reaction mixture stirring under 65 ℃ is spent the night.Evaporating solvent in rotatory evaporator obtains intermediate (16) (HPLC:88%P; Quantitatively obtain; Just need not be further purified and in the subsequent reactions step, to use).
Embodiment A 7
A) preparation allyl group-(4-chloro-5-fluoro-2-nitro-benzyl)-methyl-amine (intermediate 17)
N-methyl-2-propylene-1-amine (1.1 equivalent) is joined 1 of 4-chloro-5-fluoro-2-nitro-phenyl aldehyde (1 equivalent), in 2-ethylene dichloride (207 milliliters) solution, add MgSO then
4(2 spoons), and at room temperature with the solution stirring that obtains 2 hours.Divide 5 parts to add NaBH (OAc)
3(3 equivalent) (per hour part), and with reaction mixture K
2CO
3Washing.Use CH
2Cl
2After the extraction, separate each layer.With organic layer MgSO
4Drying is filtered and evaporation, obtains intermediate (17).
B) preparation 2-[(allyl group-methyl-amino)-methyl]-5-chloro-4-fluoro-aniline (intermediate 18)
At room temperature, with water (120ml) solution and the NH of nitro-derivative intermediate (17)
4Cl (5 equivalent) is dissolved in the toluene (120ml), adds iron powder (5 equivalent) then at leisure, and reaction mixture is stirred and refluxes at 105 ℃.By the crude product that purified by flash chromatography obtained.Collect needed product fraction, evaporating solvent obtains 4.8 intermediates (18) that restrain.
C) preparation 2-[(allyl group-methyl-amino)-methyl]-5-chloro-4-fluoro-phenyl }-(6-chloro-pyrido [3,2-d] pyrimidine-4-yl)-amine (intermediate 19)
Triethylamine (3 equivalent) is joined 4, and the acetonitrile of 6-two chloro-pyridos [3,2-d] pyrimidines (1 equivalent) (is used Al
2CO
3Drying) in (9 milliliters) solution.Separate out HCl, and with reaction mixture N
2Purged 10 to 15 minutes.Add intermediate (18) (1.7 equivalent), then reaction mixture is stirred and refluxed 5 hours.After being cooled to room temperature, from mixture, being settled out and coughing up yellowish solid.Collect product, and high vacuum dry, needed product obtained.EtOAc is joined in the mother liquor layer, be settled out white solid then.After the filtration, filtrate is concentrated, and with enriched material flash chromatography on silica gel method (elutriant: the hexane/EtOAc 9/1) purifying that is obtained.Collect needed fraction, and evaporating solvent, needed product obtained.Collect two fractions of needed product, obtain 0.750 gram intermediate (19).
D) preparation N
6-allyl group-N
4-2-[(allyl group-methyl-amino)-methyl]-5-chloro-4-fluoro-phenyl }-pyrido [3,2-d] pyrimidine-4,6-diamines (intermediate 20)
At 100 ℃, with 2-propenyl amine (9.8 equivalent) solution heated overnight in sealed tube of intermediate (19) (1 equivalent),, obtain the semisolid of 0.487 gram (115%) then with the solution concentration and the high vacuum dry that obtain, it is dissolved in CH again
2Cl
2In.Then solution is filtered, concentrated filtrate obtains 0.412g (100%) intermediate (20) once more.
E) preparation 4,6-ethanetetrayl Mi Dingbing [4,5-b] [1,4,6,11] benzo tetraazacyclododecane 14 carbynes, 16-chloro-15-fluoro-7,8,11,12,13,18-six hydrogen-12-methyl-, (9E)-(intermediate 21)
With intermediate (20) and the Grubbs ' s catalyzer s-generation (0.2 equivalent) at CH
2Cl
2Mixture in (7 milliliters) stirs and refluxed 6 hours, then at room temperature stirred reaction mixture 72 hours and backflow once more.The B (20%) that adds additional quantity stirs reaction mixture also then and refluxed once more 6 hours.The B (20%) that adds additional quantity once more refluxes mixture once more then and spends the night.After concentrating, with the resistates that obtains flash chromatography on silica gel method (elutriant: purifying acetic ester/hexane 1/1).Collect needed fraction, evaporating solvent obtains 0.025 gram (38%) pure intermediate (21).
B. the preparation of compound
Embodiment B 1
Preparation 7H, 19H-4,6-ethanetetrayl Mi Dingbing [4,5-b] [13,1,4,6] benzo oxa-three nitrogen heterocyclics 15 carbynes, 17-chloro-8,9,10,11,12,13-six hydrogen-(compound 1)
At 0 ℃, in nitrogen atmosphere, in two isolating dropping funnels, THF (20 milliliters) solution of tributylphosphine (0.00268 mole) and THF (20 milliliters) solution of ADDP (0.00155 mole) are joined among the THF (20 milliliters) and DMF (2m) cooling solution of intermediate 2 (0.00103 mole) at leisure simultaneously.Reaction mixture was at room temperature stirred 4 hours, pour in the 1N aqueous hydrochloric acid, after 1 hour, this mixture is diluted with DCM.Leach precipitation, organic phase is distributed with 10% wet chemical, dry (MgSO
4) and vacuum concentration.With solid residue supersound process in hot Virahol, leach, with anhydrous ether washing and vacuum-drying, obtain the compound (1) of 0.16g (44%).
Embodiment B 2
Preparation 6,4-(nitrilo time methylene (metheno)) Mi Dingbing [4,5-b] [13,1,4,6] benzo oxa-three nitrogen heterocyclics 15 carbynes, 17-chloro-7,8,9,10,11,12,13,19-octahydro-(compound 2)
In two isolating dropping funnels, THF (2 milliliters) solution of ADDP (0.00102 mole) and THF (2 milliliters) solution of tributylphosphine (0.00177 mole) are joined among the THF (10 milliliters) and DMF (1.4 milliliters) solution of intermediate 6 (0.000681 mole) at leisure simultaneously, and at room temperature stirred 18 hours.Then, at room temperature with THF (0.7 milliliter) solution of the THF that added ADDP (0.000340 mole) in 2 hours simultaneously (0.7 milliliter) solution and tributylphosphine (0.000592 mole).With this mixture hydrolysis and leach precipitation, with Virahol and ether washing, vacuum-drying obtains 0.124g (49%) compound (2) to water then, fusing point＞260 ℃.
Embodiment B 3
Preparation 7H, 21H-4,6-ethanetetrayl Mi Dingbing [4,5-b] [15,1,4,6,10] benzo oxa-tetraazacyclododecane 17 carbynes-12 (13H)-ketone, 8,9,10,11,14,15-six hydrogen-(compound 3)
With 1-[two (dimethylamino) methylene radical]-3-oxide compound-1H-benzotriazole , hexafluorophosphate (1-) [94790-37-1] (0.00057 mole) is dissolved in DMF (20 milliliters), and at room temperature stirs.Intermediate (11) (0.00019 mole) is dissolved among the DMF (10 milliliters), and adds N-ethyl-N-(1-methylethyl)-2-propylamine (0.00114 mole).This solution was joined in first solution at leisure with 2 hour time.Pale green solution at room temperature stirred spend the night.Solvent (DMF) is evaporated.With resistates flash column chromatography purifying, obtain compound (3).
| Compound according to Embodiment B 3 preparations | |
| 4,6-ethanetetrayl Mi Dingbing [4,5-b] [1,4,6,10,13] benzo five-nitrogen heterocyclic hexadecine-12 (7H)-ketone, 18-chloro-17-fluoro-8,9,10,11,13,14,15, the 20-octahydro- | Compound 6 |
| -4,6-ethanetetrayl Mi Dingbing [4,5-b] pyrrolo-[2,1-1] [1,4,6,10,13] benzo five-nitrogen heterocyclic hexadecine-12 (7H)-ketone, 20-chloro-19-fluoro-8,9,10,11,12a, 13,14,15,17, the 22-decahydro- | Compound 7 |
| -4,6-ethanetetrayl Mi Dingbing [4,5-b] [1,4,6,10,13] benzo five-nitrogen heterocyclic hexadecine-12 (7H)-ketone, 18-chloro-17-fluoro-8,9,10,11,13,14,15,20-octahydro-14-methyl- | Compound 8 |
| 4,6-ethanetetrayl-11H-Mi Dingbing [4,5-b] [1,4,6,9,12] benzo five-nitrogen heterocyclic 15 carbynes-11-ketone, 17-chloro-16-fluoro-7,8,9,10,12,13,14,19-octahydro-13-methyl- | Compound 9 |
| 4,6-ethanetetrayl Mi Dingbing [4,5-b] [1,4,6,10,13] benzo five-nitrogen heterocyclic hexadecines-12 (7H)-ketone, 18-chloro-17-fluoro-8,9,10,11,13,14,15,20-octahydro-13-(2- | Compound 10 |
| 4,6-ethanetetrayl Mi Dingbing [4,5-b] [1,4,6,10,13] benzo five-nitrogen heterocyclic octadecynes-15 (16H)-ketone, 20-bromo-7,8,9,10,11,12,13,14,17, the 22-decahydro- | Compound 11 |
| 4,6-ethanetetrayl Mi Dingbing [4,5-b] [1,4,6,10,14] benzo five-nitrogen heterocyclic octadecynes-16 (7H)-ketone, 20-chloro-8,9,10,11,12,13,14,15,17, the 22-decahydro- | Compound 12 |
| 4,6-ethanetetrayl-7H-Mi Dingbing [4,5-b] [1,4,6,10,14] benzo five-nitrogen heterocyclic 19 carbynes-16 (17H)-ketone, 21-chloro-8,9,10,11,12,13,14,15,18, the 23-decahydro- | Compound 13 |
| 4,6-ethanetetrayl Mi Dingbing [4,5-b] [1,4,6,10,13] benzo five-nitrogen heterocyclic octadecynes-15 (16H)-ketone, 20-chloro-7,8,9,10,11,12,13,14,17, the 22-decahydro- | Compound 14 |
Embodiment B 4
Preparation 7H, 21H-6,4-(nitrilo time methylene) Mi Dingbing [5,4-m] [1,6,10,15] benzo oxa-three nitrogen heterocyclic 17 carbynes-12 (13H)-ketone, 8,9,10,11,14,15-six hydrogen-(compound 4)
With 1-[two (dimethylamino) methylene radical]-3-oxide compound-1H-benzotriazole , hexafluorophosphate (1-) (0.00165 mole) is dissolved among the DMF (40 milliliters), and at room temperature stirs.Intermediate (16) (0.00055 mole) is dissolved among the DMF (20 milliliters), and adds N-ethyl-N-(1-methylethyl)-2-propylamine (0.0033 mole).This solution was joined in first solution at leisure with 2 hour time.Pale green solution at room temperature stirred spend the night.With solvent (DMF) evaporation, obtain compound (4).
| Compound according to Embodiment B 4 preparations | |
| 6,4-(nitrilo time methylene) Mi Dingbing [4,5-b] [1,6,10,13] benzo tetraazacyclododecane hexadecines-12 (7H)-ketone, 18-chloro-17-fluoro-8,9,10,11,13,14,15, the 20-octahydro- | Compound 15 |
| -6,4-(nitrilo time methylene) Mi Dingbing [4,5-b] pyrrolo-[2,1-1] [1,6,10,13] benzo tetraazacyclododecane hexadecine-12 (7H)-ketone, 20-chloro-19-fluoro-8,9,10,11,12a, 13,14,15,17, the 22-decahydro- | Compound 16 |
| -6,4-(nitrilo time methylene) Mi Dingbing [4,5-b] [1,6,10,13] benzo tetraazacyclododecane hexadecine-12 (7H)-ketone, 18-chloro-17-fluoro-8,9,10,11,13,14,15,20-octahydro-14-methyl- | Compound 17 |
| 6,4-(nitrilo time methylene)-11H-Mi Dingbing [4,5-b] [1,6,9,12] benzo tetraazacyclododecane 15 carbynes-11-ketone, 17-chloro-16-fluoro-7,8,9,10,12,13,14,19-octahydro-13-methyl- | Compound 18 |
| 6,4-(nitrilo time methylene) Mi Dingbing [4,5-b] [1,6,10,13] benzo tetraazacyclododecane hexadecine-12 (7H)-ketone, 18-chloro-17-fluoro-8,9,10,11,13,14,15,20-octahydro-13-(2-methyl-propyl)- | Compound 19 |
| 6,4-(nitrilo time methylene) Mi Dingbing [4,5-b] [1,6,10,13] benzo tetraazacyclododecane octadecynes-15 (16H)-ketone, 20-bromo-7,8,9,10,11,12,13,14,17, the 22-decahydro- | Compound 20 |
| 6,4-(nitrilo time methylene) Mi Dingbing [4,5-b] [1,6,10,14] benzo tetraazacyclododecane octadecynes-16 (7H)-ketone, 20-chloro-8,9,10,11,12,13,14,15,17, the 22-decahydro- | Compound 21 |
| 6,4-(nitrilo time methylene)-7H-Mi Dingbing [4,5-b] [1,6,10,14] benzo tetraazacyclododecane 19 carbynes-16 (17H)-ketone, 21-chloro-8,9,10,11,12,13,14,15,18, the 23-decahydro- | Compound 22 |
| 6,4-(nitrilo time methylene) Mi Dingbing [4,5-b] [1,6,10,13] benzo tetraazacyclododecane octadecynes-15 (16H)-ketone, 20-chloro-7,8,9,10,11,12,13,14,17, the 22-decahydro- | Compound 23 |
All other compounds can notice that Y is C according to these method preparations
1-5Alkyl and X
2/ X
1The compound of NH be to use s-generation Grubbs diene catalyzer under the closed loop permutizer condition by (Embodiment B 5 that vide infra) of cyclisation.
Embodiment B 5
Preparation 4,6-ethanetetrayl Mi Dingbing [4,5-b] [1,4,6,11] benzo tetraazacyclododecane 14 carbynes, 16-chloro-15-fluoro-7,8,9,10,11,12,13,18-octahydro-12-methyl-(compound 5)
Intermediate (21) (1 equivalent) is dissolved in methyl alcohol/two alkylating mixtures (4/1), adds catalyst Pt/C (0.3 equivalent) then, and with this reaction mixture at H
2Stirred 4 hours in the atmosphere.The mixture that obtains is filtered with short diatomite liner, and filtrate is concentrated into dried.With the resistates drying under high vacuum that obtains, obtain the pure compound (5) of 0.029g (60%).
Compound identification
Utilize LC/MS, use gradient elution system, authenticating compound on reversed-phase HPLC.Relative retention time and its protonated molion MH by compound
+Peak value comes authenticating compound.Provide HPLC gradient by Waters Alliance HT 2790 systems with the post well heater that is set in 40 ℃.Effusive liquid stream is branched to Waters 996 photodiode arrays (PDA) detector and is had in the Waters-Micromass ZQ mass spectrograph in the electrospray ionization source of moving in the negative ions mode from post.At flow velocity is that (3.5 μ m carry out reversed-phase HPLC on 4.6 * 100mm) for the Xterra MS C18 post of 1.6ml/min.Adopt three moving phases (mobile phase A: 95%25mM ammonium acetate+5% acetonitrile; Mobile phase B: acetonitrile; Moving phase C: methyl alcohol), the operation gradient condition: 100% A to 50% B and 50% C:6.5 minute, to 100% B:1 minute, 100% B:1 minute, and with 100% A reequilibrate 1.5 minutes.Use the injection volume of 10 μ L.
Use 0.1 second the residence time, obtained mass spectrum in 1 second by from 100 to 1000 scannings.Capillary cartridge voltage is 3kV, and the source temperature maintains 140 ℃.Use nitrogen as atomizing gas.Cone voltage for the positively ionized mode is 10V, is 20V for the cone voltage of negative ionization mode.Carry out data gathering with Waters-Micromass MassLynx-Openlynx data system.
Table: retention time (RT, minute) and with MH
+The molecular weight of expression
| Compound number | Rt | MH+ |
| 9 | 6.57 | 416 |
| 6 | 8.78 | 387 |
| 7 | 6.87 | 458 |
| 11 | 5.44 | 470 |
| 14 | 5.42 | 426 |
| Intermediate 20 | 8.62 | 413 |
| Intermediate 21 | 8.06 | 387 |
| 3 | 6.08 | 379 |
| 4 | 5.77 | 379 |
C. pharmacological examples
Embodiment C .1: vitro inhibition EGFR
Use Flash Plate technology or glass-fabric filter technology to estimate the vitro inhibition of EGFR, as passing through Davies, people such as S.P. are in Biochem J. (2000), 351; Described in the 95-105 page or leaf.Flash Plate technology usually by people such as B.A.Brown in HighThroughput Screening (1997), the 317-328 page or leaf, Editor (s): Devlin, JohnP.Publisher:Dekker, New York describes among the N.Y.
In Flash Plate EGFR kinase reaction test, the kinase substrate that will constitute by biotinylated poly-(L-L-glutamic acid-L-tyrosine) (poly-(GT) vitamin H) (
33P) radiolabeled ATP exists down with above-mentioned protein cultivation.Use subsequently streptavidin-coating Flash Plate (PerkinElmer Life Sciences), by the combination of biotin labeling and radiolabeled substrate is caught and quantitatively, with the emission luminous energy mode measure substrate (
33P) phosphorylation.
Describe in detail
In 96-hole microtitration FlashPlate (PerkinElmer Life Sciences), carry out 60 minutes EGFR kinase reactions at 30 ℃.For every kind of test compound, carry out full dose response 1.10
-6M to 1.10
-10M.IRESSA
And Tarceva
TM(erlotinib) as reference compound.Contain 54.5mM TrisHCl in the 100 μ l reaction volumes, pH value 8.0,10mM MgCl
2, 100 μ M Na
3VO
4, the unlabelled ATP of 5.0 μ M, 1mM DTT, 0.009% BSA, 0.8 μ Ci AT
33P, poly-(GT) vitamin H and the 0.5 μ gEGFR-kinases territory/hole in 0.35 μ g/ hole.
Also wash/stop damping fluid (PBS+100mMEDTA) washing plate 3x by the sucking-off reaction mixture and come stopped reaction with 200 μ l.After the last washing step, 200 μ l are washed/stop damping fluid joining in each hole, and in the microtiter plate scintillometer by count (30-second/hole) measure phosphorylation (
33P) amount of poly-(GT) vitamin H.
In the test of the EGFR kinase reaction of glass-fabric filter technology, the kinase substrate that will constitute by poly-(L-L-glutamic acid-L-tyrosine) (poly-(GT)) (
33P) radiolabeled ATP exists down with above-mentioned protein cultivation.Subsequently with the radioactive form on glass fibre-strainer of being combined in measure substratum (
33P) phosphorylation.
Describe in detail
In the microtiter plate of 96-hole, carry out 10 minutes EGFR kinase reactions at 25 ℃.For every kind of test compound, carry out full dose response 1.10
-6M to 1.10
-10M.IRESSA
And Tarceva
TM(erlotinib) as reference compound.Contain 60mMTrisHCl in the 25 μ l reaction volumes, pH value 7.5,3mM MgCl
2, 3mM MnCl
2, 3 μ M Na
3VO
4, 50 μ g/mlPEG20000, the unlabelled ATP of 5.0 μ M, 1mM DTT, 0.1uCi AT
33P, (GT) and 0.5 μ g EGR-kinases territory/hole are gathered in the 62.5ng/ hole.
Come stopped reaction by 3% phosphoric acid solution that adds 5 μ l.Then with the reaction mixture point sample of 10 μ l to Filtermat A strainer (Wallac), in 75mM phosphoric acid, washed 3 times 5 minutes and in methyl alcohol, washed 1 time 5 minutes, afterwards, carry out drying and use the LEphosphorage storage screen, go up quantitative analysis at Typhoon (Amersham).
Embodiment C .2: the clear proliferation test of ischemic on ovarian cancer SKOV3 cell
Ovarian cancer cell line (SKOV3) is used for the test of Urogastron stimulated cell proliferation, with the inhibition effect of assessing compound for the EGF in whole cells.
In the first step, the SKOV3 cell was cultivated 24 hours in the presence of 10% FCS serum.Second the step, with this cell at serum-free condition (37 ℃ and 5% (v/v) CO
2) in cultivate with test compound, be the EGF stimulation 72 hours of 100ng/ml subsequently with ultimate density.Come of the effect of last assessing compound with the test of standard MTT cell survival for the EGF stimulation.
Following table provides the pIC50 value according to The compounds of this invention, and this value is to use above-mentioned kinase assay to obtain.
| Compound number | Body examination: I tests C outward and swashs (5 enzyme C 0,1 n lives): M | S (I K:C C O 25 V) 00 3:, cell μ M |
| 2 | 8.5 | ＜5.0 |
| The intermediate numbering | Body examination I tests C outward and swashs (5 enzyme C 0 live 1, property): nM | S I K (C O3 C 5 V 20 are thin), born of the same parents: μ M |
| 2 | 8.2 | 5.5 |
| 3 | 8.4 | 6.1 |
| Compound number | Body examination I tests C outward and swashs (50 enzyme C1, activity): nM | S (I K C C O 2 50 V), 3 cells: μ M |
| 1 | 8.3 | 6.23 |
| The intermediate numbering | Body examination I tests C outward and swashs (C1 50 enzymes), activity: nM | S (I K C C O 2 50 V3), cell: μ M |
| 4 | 8.3 | 5.8 |
| 6 | 8.4 | 6.0 |
D. composition embodiment
According to the present invention, following series preparation has illustrated and has been suitable for the typical pharmaceutical composition that system gives animal and human's class patient.
Run through these embodiment employed " active ingredient " and (A.I.) relate to the compound of formula (I), (XXXI) or its pharmacy acceptable addition salt.
Embodiment is D.1: film coating tablet
Preparation tablet core
The mixture of A.I. (100g), lactose (570g) and starch (200g) is carried out thorough mixing, then use about 200ml aqueous solution of sodium lauryl sulphate (5g) and polyvinylpyrrolidone (10g) to make it moistening.Should sieve by moistening powdered mixture, drying is also sieved once more.Add Microcrystalline Cellulose (100g) and hydrogenated vegetable oil (15g) then.With whole thorough mixing and be compressed into tablet, obtain 10.000, each comprises the active ingredient of 10mg.
Dressing
The CH that in Denatured alcohol (75ml) solution of methylcellulose gum (10g), adds ethyl cellulose (5g)
2Cl
2(150ml) solution.Add CH then
2Cl
2(75 milliliters) and 1,2,3-glycerol (2.5 milliliters).Polyoxyethylene glycol (10 gram) is melted and be dissolved in the methylene dichloride (75 milliliters).Back one solution is joined among the former, add Dolomol (2.5 gram), polyethylene-pyrrolidone (5g) and concentrated pigment suspension (30ml) then, and will all carry out homogenate.In coating device, with thus obtained mixture with on the tablet core pericardium.
Claims (18)
1. the compound that has following formula
Its N-oxide form, pharmacy acceptable addition salt and stereochemistry heterogeneous forms, wherein:
a
1-a
2=a
3-a
4Expression is selected from following divalent radical: N-CH=CH-CH, N-CH=N-CH or CH-CH=N-CH;
Z represents O, NH or S;
Y represents-C
3-9Alkyl-,-C
3-9Thiazolinyl-,-C
1-5Alkyl-oxygen base-C
1-5Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-,-C
1-5Alkyl-NR
14-CO-C
1-5Alkyl-,-C
1-5Alkyl-CO-NR
15-C
1-5Alkyl-,-C
1-6Alkyl-CO-NH-,-C
1-6Alkyl-NH-CO-,-CO-NH-C
1-6Alkyl-,-NH-CO-C
1-6Alkyl-,-CO-C
1-7Alkyl-,-C
1-7Alkyl-CO-, C
1-6Alkyl-CO-C
1-6Alkyl;
X
1Represent direct key, O ,-O-C
1-2Alkyl-, CO ,-CO-C
1-2Alkyl-, NR
11,-NR
11-C
1-2Alkyl-, NR
16-CO-, NR
16-CO-C
1-2Alkyl-,-O-N=CH-or C
1-2Alkyl;
X
2Represent direct key, O ,-O-C
1-2Alkyl-, CO ,-CO-C
1-2Alkyl-, NR
12, NR
12-C
1-2Alkyl-, NR
17-CO-, NR
17-CO-C
1-2Alkyl-, Het
20-C
1-2Alkyl-,-O-N=CH-or C
1-2Alkyl;
R
1Expression hydrogen, cyano group, halogen, hydroxyl, formyl radical, C
1-6Alkyl oxy-, C
1-6Alkyl-, the C that is replaced by halogen
1-6Alkyl oxy-, by one or may the time two or more substituting groups that are selected from hydroxyl or halogen C of replacing
1-4Alkyl;
R
2Expression hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-, Het
16-carbonyl-, C
1-4The alkyl oxy carbonyl-, C
1-4Alkyl-carbonyl-, aminocarboxyl-, single or two (C
1-4Alkyl) aminocarboxyl-, Het
1, formyl radical, C
1-4Alkyl-, C
2-6Alkynyl-, C
3-6Cycloalkyl-, C
3-6Cycloalkyl oxy-, C
1-6Alkyl oxy-, Ar
5, Ar
1-oxygen base-, boronic acid, the C that is replaced by halogen
1-6Alkyl oxy-,
By one or may the time two or more are selected from halogen, hydroxyl or NR
5R
6The C that replaces of substituting group
1-4Alkyl,
C
1-4Alkyl-carbonyl-, wherein said C
1-4Alkyl chooses wantonly by one or two or more are selected from hydroxyl or C when possible
1-4Alkyl-oxygen base-substituting group replace;
R
3Expression hydrogen, C
1-4Alkyl, cyano group or be selected from the C that following substituting group replaces by one or more
1-4Alkyl: halogen, C
1-4Alkyl oxy-, amino-, single or two (C
1-4Alkyl) amino-, C
1-4Alkyl-alkylsulfonyl-or phenyl;
R
4Expression hydrogen, hydroxyl, Ar
3-oxygen base, Ar
4-C
1-4Alkyl oxy-, C
1-4Alkyl oxy-, optional by Het
12The C that replaces
2-4Thiazolinyl oxygen base; Or R
4Expression is by one or two or more are selected from the C that following substituting group replaces when possible
1-4Alkyl oxy: C
1-4Alkyl oxy-, hydroxyl, halogen, Het
2-,-NR
7R
8,-carbonyl-NR
9R
10Or Het
3-carbonyl-;
R
5And R
6Be selected from hydrogen or C independently of one another
1-4Alkyl;
R
7And R
8Each is independently selected from hydrogen, C
1-4Alkyl, Het
8, amino-sulfonyl-, single or two (C
1-4Alkyl)-and amino-sulfonyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-, hydroxycarbonyl group-C
1-4Alkyl-, C
3-6Cycloalkyl, Het
9-carbonyl-C
1-4Alkyl-, Het
10-carbonyl-, poly-hydroxy-C
1-4Alkyl-, Het
11-C
1-4Alkyl-or Ar
2-C
1-4Alkyl-;
R
9And R
10Each is independently selected from hydrogen, C
1-4Alkyl, C
3-6Cycloalkyl, Het
4, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl-or poly-hydroxy-C
1-4Alkyl-;
R
11Expression hydrogen, C
1-4Alkyl, Het
5, Het
6-C
1-4Alkyl-, optional by Het
7-C
1-4The C of alkyl amino-carbonyl-replacement
2-4Alkenyl carbonyl-, C
2-4The thiazolinyl alkylsulfonyl-, C
1-4Alkyl oxy C
1-4Alkyl-optional by one or may the time two or more are selected from hydrogen, hydroxyl, amino or C
1-4The phenyl of alkyl oxy-replacement;
R
12Expression hydrogen, C
1-4Alkyl, C
1-4Alkyl-oxygen base-carbonyl-, Het
17, Het
18-C
1-4Alkyl-, optional by Het
19-C
1-4The C of alkyl amino-carbonyl-replacement
2-4Alkenyl carbonyl-, C
2-4The thiazolinyl alkylsulfonyl-, C
1-4Alkyl oxy C
1-4Alkyl-optional by one or may the time two or more are selected from hydrogen, hydroxyl, amino or C
1-4Alkyl oxy-the phenyl that replaces of substituting group;
R
13Expression hydrogen, C
1-4Alkyl, Het
13, Het
14-C
1-4Alkyl-optional by one or may the time two or more are selected from hydrogen, hydroxyl, amino or C
1-4Alkyl oxy-the phenyl that replaces of substituting group;
R
14And R
15Each is independently selected from hydrogen, C
1-4Alkyl, Het
15-C
1-4Alkyl-or C
1-4Alkyl oxy C
1-4Alkyl-;
R
16And R
17Each is independently selected from hydrogen, C
1-4Alkyl, Het
21-C
1-4Alkyl-or C
1-4Alkyl oxy C
1-4Alkyl-;
Het
1Expression is selected from following heterocycle: piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolanyl, thiazolyl, azoles base, imidazolyl, different azoles base, di azoly, pyridyl or pyrrolidyl, wherein said Het
1Optional by one or may the time two or more are selected from following substituting group and replace: amino, C
1-4Alkyl, hydroxyl-C
1-4Alkyl-, phenyl, phenyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-, single or two (C
1-4Alkyl) amino-or amino-carbonyl-;
Het
2Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl, pyrrolidyl, thio-morpholinyl or dithian base, wherein said Het
2Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, halogen, amino, C
1-4Alkyl-, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-, hydroxyl-C
1-4Alkyl-oxygen base-C
1-4Alkyl-, single or two (C
1-4Alkyl) amino-, single or two (C
1-4Alkyl) amino-C
1-4Alkyl-, amino C
1-4Alkyl-, single or two (C
1-4Alkyl) amino-sulfonyl-, amino-sulfonyl-;
Het
3, Het
4And Het
8Each represents to be selected from following heterocycle independently: morpholinyl, piperazinyl, piperidyl, furyl, pyrazolyl, dioxolanyl, thiazolyl, azoles base, imidazolyl, different azoles base, di azoly, pyridyl or pyrrolidyl, wherein said Het
3, Het
4Or Het
8Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl-, amino-, C
1-4Alkyl-, C
3-6Cycloalkyl-C
1-4Alkyl-, amino-sulfonyl-, single or two (C
1-4Alkyl) amino-sulfonyl or amino-C
1-4Alkyl-;
Het
5Expression is selected from the heterocycle of pyrrolidyl or piperidyl, and wherein said heterocycle chooses wantonly by one or two or more are selected from following substituting group replacement: C when possible
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
6And Het
7Each represents to be selected from following heterocycle independently: morpholinyl, pyrrolidyl, piperazinyl or piperidyl, wherein said Het
6And Het
7Optional by one or may the time two or more are selected from following substituting group and replace: C
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
9And Het
10Each represents to be selected from following heterocycle independently: furyl, piperidyl, morpholinyl, piperazinyl, pyrazolyl, dioxolanyl, thiazolyl, azoles base, imidazolyl, different azoles base, di azoly, pyridyl or pyrrolidyl, wherein said Het
9Or Het
10Optional by following replacement: C
1-4Alkyl, C
3-6Cycloalkyl-C
1-4Alkyl-or amino-C
1-4Alkyl-;
Het
11Expression is selected from the heterocycle of indyl or following formula;
Het
12Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl, pyrrolidyl, thio-morpholinyl or dithian base, wherein said Het
12Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, halogen, amino, C
1-4Alkyl-, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-, hydroxyl-C
1-4Alkyl-oxygen base-C
1-4Alkyl-, single or two (C
1-4Alkyl) amino-or single or two (C
1-4Alkyl) amino-C
1-4Alkyl-;
Het
13Expression is selected from the heterocycle of pyrrolidyl or piperidyl, and wherein said heterocycle chooses wantonly by one or two or more are selected from following substituting group replacement: C when possible
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
14Expression is selected from following heterocycle: morpholinyl, pyrrolidyl, piperazinyl or piperidyl, wherein said heterocycle choose wantonly by one or two or more are selected from following substituting group replacement: C when possible
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
15And Het
21Each represents to be selected from following heterocycle independently: morpholinyl, pyrrolidyl, piperazinyl or piperidyl, wherein said Het
15Or Het
21Optional by one or may the time two or more are selected from following substituting group and replace: C
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
16Expression is selected from following heterocycle: morpholinyl, and pyrrolidyl, piperazinyl, 1,3,2-two oxa-boron heterocycle pentane or piperidyls, wherein said heterocycle is optional by one or more C that are selected from
1-4The substituting group of alkyl replaces;
Het
17Expression is selected from the heterocycle of pyrrolidyl or piperidyl, and wherein said heterocycle chooses wantonly by one or two or more are selected from following substituting group replacement: C when possible
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
18And Het
19Each represents to be selected from following heterocycle independently: morpholinyl, pyrrolidyl, piperazinyl or piperidyl, wherein said Het
18And Het
19Optional by one or may the time two or more are selected from following substituting group and replace: C
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-;
Het
20Expression is selected from following heterocycle: pyrrolidyl, 2-pyrrolidyl, piperidyl, piperazinyl or pyrazolidyl, wherein said heterocycle choose wantonly by one or two or more are selected from following substituting group replacement: C when possible
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkyl oxy C
1-4Alkyl or poly-hydroxy-C
1-4Alkyl-; With
Ar
1, Ar
2, Ar
3, Ar
4And Ar
5Each represents optional by the phenyl of following replacement independently: cyano group, C
1-4Alkyl sulphonyl-, C
1-4Alkyl sulfonyl-amino-, amino-sulfonyl amino-, hydroxyl-C
1-4Alkyl, amino-sulfonyl-, hydroxyl-, C
1-4Alkyl oxy-or C
1-4Alkyl.
2. the compound of claim 1, wherein:
Z represents NH;
Y represents-C
3-9Alkyl-,-C
2-9Thiazolinyl-,-C
1-5Alkyl-oxygen base-C
1-5Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-,-C
1-5Alkyl-NR
14-CO-C
1-5Alkyl-,-C
1-6Alkyl-NH-CO-,-CO-C
1-7Alkyl-,-C
1-7Alkyl-CO-or C
1-6Alkyl-CO-C
1-6Alkyl;
X
1Expression O ,-O-C
1-2Alkyl-,-O-N=CH-, NR
11Or-NR
11-C
1-2Alkyl-; In one specific embodiment, X
1Represent direct key, C
1-2Alkyl-,-O-C
1-2Alkyl-,-NR
11-,-O-or-O-CH
2-;
X
2Represent direct key, O ,-O-C
1-2Alkyl-,-O-N=CH-, NR
17-CO-, NR
17-CO-C
1-2Alkyl-, C
1-2Alkyl, Het
20-C
1-2Alkyl-, NR
12Or NR
12-C
1-2Alkyl-; In one specific embodiment, X
2Represent direct key, C
1-2Alkyl-,-O-C
1-2Alkyl, NR
17-CO-, NR
17-CO-C
1-2Alkyl-, Het
20-C
1-2Alkyl-,-O-or-O-CH
2-;
R
1Expression hydrogen, cyano group, halogen or hydroxyl, preferred halogen;
R
2Expression hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-, C
1-4The alkyl oxy carbonyl-, Het
16-carbonyl-, C
1-4Alkyl-, C
2-6Alkynyl-, Ar
5Or Het
1In further embodiment, R
2Expression hydrogen, cyano group, halogen, hydroxyl, or Ar
5In a more particular embodiment, R
2The expression hydrogen or halogen;
R
3Expression hydrogen;
R
4Expression hydrogen, hydroxyl, C
1-4Alkyl oxy-, Ar
4-C
1-4Alkyl oxy; Or R
4Expression is by one or two or more are selected from C when possible
1-4Alkyl oxy-or Het
2-the C that replaces of substituting group
1-4Alkyl oxy;
R
11Expression hydrogen, C
1-4Alkyl-or C
1-4Alkyl-oxygen base-carbonyl-;
R
12Expression hydrogen, C
1-4Alkyl-or C
1-4Alkyl-oxygen base-carbonyl-;
R
13Expression hydrogen or Het
14-C
1-4Alkyl, especially morpholinyl-C
1-4Alkyl;
R
14Expression hydrogen or C
1-4Alkyl;
R
17Expression hydrogen, C
1-4Alkyl-, Het
21-C
1-4Alkyl or C
1-4Alkyl-oxygen base-C
1-4Alkyl; Especially R
17Expression hydrogen or C
1-4Alkyl;
Het
1The optional thiazolyl that is selected from following substituting group replacement of expression: amino, C
1-4Alkyl, hydroxyl-C
1-4Alkyl-, phenyl, phenyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-, single or two (C
1-4Alkyl) amino-or amino-carbonyl-;
Het
2Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl or pyrrolidyl, wherein said Het
2Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, amino or C
1-4Alkyl-; In further embodiment, Het
2Expression is selected from optional by C
1-4The morpholinyl that alkyl-preferable methyl replaces or the heterocycle of piperidyl;
Het
14Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl or pyrrolidyl, wherein said Het
14Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, amino or C
1-4Alkyl-;
Het
16Expression is selected from following heterocycle: piperidyl, morpholinyl or pyrrolidyl;
Het
20Expression is selected from following heterocycle: pyrrolidyl, 2-pyrrolidyl or piperidyl;
Het
21Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl or pyrrolidyl, wherein said Het
21Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, amino or C
1-4Alkyl-;
Ar
4Expression optional by cyano group, hydroxyl-, C
1-4Alkyl oxy or C
1-4The phenyl that alkyl replaces;
Ar
5Expression is optional by cyano group, hydroxyl, C
1-4Alkyl oxy or C
1-4The phenyl that alkyl replaces.
3. the compound of claim 1, wherein:
Z represents NH;
Y represents-C
3-9Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-,-C
1-5Alkyl-NR
14-CO-C
1-5Alkyl-,-C
1-6Alkyl-NH-CO-or-CO-NH-C
1-6Alkyl-;
X
1Expression-O-,-NR
11-,-NR
16-CO-, or-NR
16-CO-C
1-2Alkyl-;
X
2Represent direct key ,-C
1-2Alkyl-,-O-C
1-2Alkyl ,-O-,-O-CH
2-or Het
20-C
1-2Alkyl-;
R
1The expression hydrogen or halogen;
R
2Expression hydrogen, cyano group, halogen, hydroxycarbonyl group-, C
1-4The alkyl oxy carbonyl-, Het
16-carbonyl-or Ar
5Especially R
2The expression hydrogen or halogen;
R
3Expression hydrogen;
R
4Expression hydrogen, hydroxyl, C
1-4Alkyl oxy-, Ar
4-C
1-4Alkyl oxy; Or R
4Expression is by one or two or more are selected from C when possible
1-4Alkyl oxy-or Het
2-the C that replaces of substituting group
1-4Alkyl oxy;
R
11Expression hydrogen;
R
12Expression hydrogen, C
1-4Alkyl-or C
1-4Alkyl-oxygen base-carbonyl-;
R
13Expression hydrogen or Het
14-C
1-4Alkyl, especially hydrogen or morpholinyl-C
1-4Alkyl;
Het
2Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl or pyrrolidyl, wherein said Het
2Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, amino or C
1-4Alkyl-; In further embodiment, Het
2Expression is selected from optional by C
1-4The morpholinyl that alkyl-preferable methyl replaces or the heterocycle of piperidyl;
Het
14The expression morpholinyl;
Het
16Expression is selected from following heterocycle: morpholinyl or pyrrolidyl;
Het
20Expression pyrrolidyl or piperidyl;
Ar
4The expression phenyl;
Ar
5The optional phenyl that is replaced by cyano group of expression.
4. claim 1 or 2 compound, the R in its Chinese style (I) structure
1Substituting group is at 4 ' position, R
2Substituting group is at 5 ' position, R
3Substituting group is at 3, R
4Substituting group is at 7.
5. each compound, wherein a in the claim 1 to 4
1-a
2=a
3-a
4Expression N-CH=CH-CH.
6. each compound, wherein a in the claim 1 to 4
1-a
2=a
3-a
4Expression N-CH=N-CH.
7. each compound, wherein a in the claim 1 to 4
1-a
2=a
3-a
4Expression CH-CH=N-CH.
8. the intermediate of following formula
Its N-oxide form, pharmacy acceptable addition salt and stereochemistry heterogeneous forms, wherein
a
1-a
2=a
3-a
4Expression is selected from the divalent radical of N-CH=CH-CH or N-CH=N-CH;
Y represents-C
3-9Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-,-C
1-6Alkyl-NH-CO-or-CO-NH-C
1-6Alkyl-;
R
1The expression hydrogen or halogen;
R
2Expression hydrogen, cyano group, halogen, hydroxycarbonyl group-, C
1-4The alkyl oxy carbonyl-, Het
16-carbonyl-or Ar
5
R
4The expression hydroxyl, C
1-4Alkyl oxy-, Ar
4-C
1-4Alkyl oxy; Or R
4Expression is by one or two or more are selected from C when possible
1-4Alkyl oxy-or Het
2-the C that replaces of substituting group
1-4Alkyl oxy;
R
11Expression hydrogen;
R
13Expression Het
14-C
1-4Alkyl;
Het
2Expression is selected from following heterocycle: morpholinyl, piperazinyl, piperidyl or pyrrolidyl, wherein said Het
2Optional by one or may the time two or more are selected from following substituting group and replace: hydroxyl, amino or C
1-4Alkyl-;
Het
14The expression morpholinyl;
Het
16Expression is selected from following heterocycle: morpholinyl or pyrrolidyl;
Ar
4The expression phenyl;
Ar
5The optional phenyl that is replaced by cyano group of expression.
9. the kinase inhibitor of formula (I) or formula (XXXI).
10. each described compound in the claim 1 to 7, it is as medicine.
11. each described compound is used for the treatment of for example purposes in the medicine of atherosclerosis, restenosis and cancer of cell proliferation illness in preparation in the claim 1 to 7.
12. pharmaceutical composition, comprise pharmaceutically acceptable carrier and as active ingredient, effective each described compound in the claim 1 to 7 of kinase inhibition amount.
13. the described intermediate of claim 8, it is as medicine.
14. the described intermediate of claim 8 is used for the treatment of for example purposes in the medicine of atherosclerosis, restenosis and cancer of cell proliferation illness in preparation.
15. pharmaceutical composition, comprise pharmaceutically acceptable carrier and as active ingredient, the effective described intermediate of claim 6 of kinase inhibition amount.
16. prepare the method for the described compound of claim 1 to 7, comprising:
A) with also aniline (III) coupling of [5,4-d] pyrimidine derivatives (II) and suitable replacement of 2-acetoxyl group-8-chloropyrimide, so that the intermediate of formula (IV) to be provided, and with the intermediate deprotection of formula (IV), closed loop under optimum conditions then,
B), obtain the midbody compound of formula (XXII) with the 2-aminophenol derivates with fungicidal property coupling of known 8-chloro-2 (methylthio group)-Mi Dingbing [5,4-d] pyrimidine and formula (XXI).And then, use aminating alcohol (XXIII) pyrido [3,2-d] pyrimidine amination with formula (XXII) under condition known in the art, closed loop under the Mitsunobu condition then, obtain formula (target compound of I "),
17. the method for treatment cell proliferation illness, this method comprises each described compound in the claim 1 to 7 that needs the treatment of animals of this treatment significant quantity.
18. the method for treatment cell proliferation illness, this method comprises needs the described intermediate of the claim 8 of the treatment of animals of this treatment significant quantity.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP0351062 | 2003-12-18 | ||
| EPPCT/EP03/51058 | 2003-12-18 | ||
| EPPCT/EP03/51062 | 2003-12-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1894260A true CN1894260A (en) | 2007-01-10 |
| CN100506823C CN100506823C (en) | 2009-07-01 |
Family
ID=34957033
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800374517A Active CN100506823C (en) | 2003-12-18 | 2004-12-15 | Pyrido- and pyrimidopyrimidine derivatives as anti-proliferative agents |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN100506823C (en) |
| AT (1) | ATE391129T1 (en) |
| ZA (1) | ZA200604972B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102127087A (en) * | 2011-01-21 | 2011-07-20 | 江苏先声药物研究有限公司 | Quinazoline derivatives |
| WO2019201282A1 (en) * | 2018-04-18 | 2019-10-24 | 成都先导药物开发股份有限公司 | Macrocyclic kinase inhibitor |
-
2004
- 2004-12-15 AT AT04804852T patent/ATE391129T1/en not_active IP Right Cessation
- 2004-12-15 CN CNB2004800374517A patent/CN100506823C/en active Active
-
2006
- 2006-06-15 ZA ZA200604972A patent/ZA200604972B/en unknown
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102127087A (en) * | 2011-01-21 | 2011-07-20 | 江苏先声药物研究有限公司 | Quinazoline derivatives |
| CN102127087B (en) * | 2011-01-21 | 2012-07-04 | 江苏先声药物研究有限公司 | Quinazoline derivatives |
| WO2019201282A1 (en) * | 2018-04-18 | 2019-10-24 | 成都先导药物开发股份有限公司 | Macrocyclic kinase inhibitor |
| CN110386945A (en) * | 2018-04-18 | 2019-10-29 | 成都先导药物开发股份有限公司 | A kind of big ring class kinase inhibitor |
| CN110386945B (en) * | 2018-04-18 | 2021-09-28 | 广州白云山医药集团股份有限公司白云山制药总厂 | Macrocyclic kinase inhibitor |
| US11584759B2 (en) | 2018-04-18 | 2023-02-21 | Hitgen Inc. | Macrocyclic kinase inhibitor |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200604972B (en) | 2008-12-31 |
| CN100506823C (en) | 2009-07-01 |
| ATE391129T1 (en) | 2008-04-15 |
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