CN1794996A - Macrocyclic quinazoline derivatives as antiproliferative agents - Google Patents
Macrocyclic quinazoline derivatives as antiproliferative agents Download PDFInfo
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- CN1794996A CN1794996A CN200480014512.8A CN200480014512A CN1794996A CN 1794996 A CN1794996 A CN 1794996A CN 200480014512 A CN200480014512 A CN 200480014512A CN 1794996 A CN1794996 A CN 1794996A
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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 Z represents O, CH2, NH or S; in particular Z represents NH; Y represents -C3-9alkyl-, -C3-9alkenyl-, -C3-9alkynyl-, -C3-7alkyl-CO-NH- optionally substituted with amino, mono- or di(C1-4alkyl)amino or C1-4 alkyloxycarbonylamino-, -C3-7alkenyl-CO-NH- optionally substituted with amino, mono- or di(C1-4alkyl)amino- or C1-4alkyloxycarbonylamino-, C1-5alkyl-oxy-C1-5alkyl-, -C1-5alkyl NR<13>-, -C1-5alkyl-, -C1-5alkyl-NR<14>-CO-C1-5alkyl-, -C1-5alkyl-CO NR<15>-C1-5alkyl-, -C1-6alkyl-CO-NH-, -C1-6alkyl-NH-CO-, -C1-3alkyl-NH-CS-Het<20>-, -C1-3alkyl-NH-CO-Het<20>-, -C1-2alkyl-CO-Het<21>-CO-, -Het<22>-CH2-CO-NH-C1-3alkyl-, -CO-NH-C1-6alkyl-, -NH-CO-C1-6alkyl-, -CO-C1-7alkyl-, -C1-7alkyl-CO-, -C1-6alkyl-CO-C1-6alkyl-, -C1-2alkyl-NH-CO-CR<16>R<17>-NH-, -C1-2alkyl-CO-NH-CR<18>R<19>-CO-, -C1-2alkyl-CO-NR<20>-C1-3alkyl-CO-, C1-2alkyl-NR<21>-CH2-CO-NH-C1-3alkyl-, or -NR<22>-CO-C1-3alkyl-NH-; X<1> represents a direct bond, O or -O-C1-2alkyl-, CO, -CO-C1-2alkyl-, NR<11>, -NR<11>-C1-2alkyl-, CH2-, -O-N=CH- or -C1-2alkyl-; X<2> represents a direct bond, O, -O-C1-2alkyl-, CO, -CO-C1-2alkyl-, NR<12>, -NR<12>-C1-2alkyl-, -CH2-, -O-N=CH- or -C1-2alkyl-. The growth inhibitory effect anti-tumour activity of the present compounds has been demonstrated in vitro, in enzymatic assays on the receptor tyrosine kinase EGFR.
Description
The present invention relates to the deutero-macrocycle molecule of quinazoline, have been found that it has antiproliferative activity, as: active anticancer, and therefore be used to treat in the method for the mankind or animal body, for example: be used to make the pharmaceuticals that are used for hyperproliferation disease, as: arteriosclerosis, restenosis and cancer.The invention still further relates to the method for making this quinazoline derivant, the Pharmaceutical composition that comprises them and in the manufacturing purposes of the medicine that is used to produce anti-proliferative effect.
Especially, chemical compound of the present invention is found and suppresses Tyrosine kinases enzyme, is also referred to as the Tyrosine kinases.The Tyrosine kinases is a class of enzymes, and the phenolic hydroxyl group of the Tyrosine residue of the terminal phosphoric acid of its catalysis adenylic acid triphosphoric acid in being present in target protein shifts.Knownly relate to several carcinogenophores that cell transfer converts malignant cell to, coding Tyrosine kinases comprises some growth factor receptors, as EGF, FGF, IGF-1R, IR, PDGF and VEGF.The receptor Tyrosine kinases of this family and the kinase whose EGF of special receptor Tyrosine family, usually be present in the general human cancer, as breast carcinoma, nonsmall-cell lung cancer, the squamous cell carcinoma, bladder cancer, esophageal carcinoma, the intestines and stomach cancer that comprise adenocarcinoma and pulmonary, as colon, rectum or gastric cancer, carcinoma of prostate, leukemia and ovary, bronchus or pancreatic cancer, these are the example of cell breeding disease.
Therefore, have recognized that it is valuable to the treatment disease relevant with cell proliferation that selectivity suppresses the Tyrosine kinases.The support of this viewpoint is provided by Herceptin_ (Trastuzumab) and Gleevec_ (the methanesulfonic acid wheat is for Buddhist nun's cloth (imatinib) ester) exploitation, and it is first example based on the cancer drug of target.Herceptin_ (Trastuzumab) is the receptor Tyrosine kinases of targeting at Her2/neu, and being found in 30% has in the sufferer of invasive breast carcinoma and be amplified to 100 times.In clinical trial, Herceptin_ (Trastuzumab) is proved to be anti-tumor activity with anti-breast carcinoma (people's summary such as L.K.Shawer, " Smart Drugs:Tyrosine kinaseinhibitors in cancer therpy ", 2002, Cancer Cell Vol.1,117)), and therefore providing with receptor Tyrosine kinases is that the principle of target therapy proves.Second example: Gleevec_ (the methanesulfonic acid wheat is for Buddhist nun's cloth ester) target antagonism abelson Tyrosine kinases (BcR-Abl), the Cytoplasm Tyrosine kinases of a constitutive activity, in fact be present among the patient of all chronic lymphocytic leukemias (CML), and in 15% to 30% the adult patient that acute lymphoblastic leukemia is arranged.In clinical trial, Gleevec_ (methanesulfonic acid wheat for Buddhist nun's cloth ester) demonstrates surprising effectiveness, minimum side effect, and it causes being checked and approved submitting in 3 months.This agent has become a case (DruckerB.J.﹠amp of quick medicament exploitation by the speed of clinical trial and rules examination; Lydon N, " Lessons learned from the development of an Ab1tryrosine kinase inhibitor for chronic myelogenous leukaemia) ", J.Clin.Invest.105 in 2000,3).
Further support it is specifically to slow down the proof of transplanting the cancer growth in athymism (athymic) nude mice by EGF receptor Tyrosine inhibitors of kinases to be given, this cancer such as the mankind's breast carcinoma or human squamous cell carcinoma are (by T.R.Burke Jr., Drugs of the Future, 1992,17,119 summaries).The result is, sizable interest be to develop treatment different be the cancer drug of target position with the EGFR receptor.For example, the regional bonded antibody of several cell portions with EGFR comprises Erbitus carrying out clinical trial
TM(be also referred to as C225, Cetuximab), develop, and be used for the treatment of several cancers at the III clinical trial phase by ImcloneSystems.Also have several Orally active medicines likely for effectively with relative specific EGFR Tyrosine inhibitors of kinases, carrying out clinical trial at present well.The chemical compound ZD1893 of AstraZeneca, it is called as IRESSA_ now and is used for the treatment of the nonsmall-cell lung cancer of advancing by being checked and approved, and OSI/Genetech/Roche chemical compound OSI-774 of science, and it is called as Tarceva now
TM(erlotinib), in clinical trial, several cancers are shown obvious effect (Morin M.J. " from oncogene to the medicine: development is as the micromolecule Tyrosine inhibitors of kinases (From oncogene to drug:development of small molecule tyrosine kinase inhibitors as anti-tumourand anti-angiogenic agents) of antitumor and angiogenesis inhibitor (angiogenic) reagent ", 2000 Oncogene 19,6574).
Except above-mentioned, EGF receptor Tyrosine kinases has shown and has related to non-malignant proliferation disease, as psoriasis (people such as Elder, Science, 1989,243; 811).Therefore expection: the kinase whose inhibitor of EGF receptoroid Tyrosine is used in the nonmalignant disease of the excessive cell proliferation of treatment, as psoriasis, benign prostatauxe, arteriosclerosis and restenosis.
As at international patent application book WO96/33980 and J.Med.Chem.2002, disclosed in 45,3865, the quinazoline derivant that some 4 phenylamino replaces can be used as the Tyrosine kinases, particularly the kinase whose inhibitor of EGF receptoroid Tyrosine.Beyond thoughtly be, find the quinazoline derivant of formulas different on the structure of the present invention (I), show to have kinase whose the inhibitions activity of Tyrosine.
Therefore, one object of the present invention is used to make the medicine that is used for the treatment of the relevant disease of cell proliferation for other Tyrosine inhibitors of kinases is provided.
The present invention relates to formula (I) chemical compound and N-oxide, pharmaceutically acceptable addition salt and stereoisomeric forms in any ratio thereof:
Wherein,
Z represents O, CH
2, NH or S; Especially, Z represents NH;
Y representative-C
3-9Alkyl-,-C
3-9Thiazolinyl-,-C
3-9Alkynyl-, by amino, single-or two (C
1-4Alkyl) amino or C
1-4Alkoxycarbonyl amino-optional the C that replaces
3-7Alkyl-CO-NH, by amino, single-or two (C
1-4Alkyl) amino or C
1-4Alkoxycarbonyl amino-optional the C that replaces
3-7Thiazolinyl-CO-NH, by amino, single-or two (C
1-4Alkyl) amino or C
1-4Alkoxycarbonyl amino-optional the C that replaces
3-7Alkynyl-CO-NH ,-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-, C
1-3Alkyl-NH-CS-Het
20,-C
1-3Alkyl-NH-CO-Het
20,-C
1-2Alkyl-CO-Het
21-CO-, Het
22-CH
2-CO-NH-C
1-3Alkyl-,-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-,-C
1-2Alkyl-NH-CO-CR
16R
17-NH-,-C
1-2Alkyl-CO-NH-CR
18R
19-CO-,-C
1-2Alkyl-CO-NR
20-C
1-3Alkyl-CO-,-C
1-2Alkyl-NR
21-CH
2-CO-NH-C
1-3Alkyl-or-NR
22-CO-C
1-3Alkyl-NH-;
X
1Represent connecting key, O ,-O-C
1-2Alkyl-, CO ,-CO-C
1-2Alkyl-, NR
11,-NR
11-C
1-2Alkyl-,-CH
2-,-O-N=CH-or C
1-2Alkyl-;
X
2Represent connecting 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
1Represent hydrogen, cyano group, halogen, hydroxyl, formoxyl, C
1-6Alkoxyl-, C
1-6Alkyl-, halogen-phenyl-carbonylamino-, the C that replaces of halogen
1-6Alkoxyl-, by one or may be two or more be selected from the C that the substituent groups of hydroxyl or halogen replace
1-4Alkyl;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group, Het
16-carbonyl, C
1-4Alkoxy carbonyl-, C
1-4Alkyl-carbonyl-, amino carbonyl-, single-or two (C
1-4Alkyl) amino carbonyl-, Het
1, formoxyl, C
1-4Alkyl-, C
2-6Alkynyl-, C
3-6Cycloalkyl-, C
3-6Cycloalkyloxy-, C
1-6Alkoxyl-, Ar
5, Ar
1-oxygen base-, the C that replaces of dihydroxy borine, halogen
1-6Alkoxyl-, by one or may two or more halogen, hydroxyl or NR of being selected from
5R
6The C that replaces of substituent group
1-4Alkyl; C
1-4Alkyl carbonyl-, this C wherein
1-4Alkyl is optional by one or two or more hydroxyl or the C of being selected from of possibility
1-4Alkyl-oxygen base-substituent group replace;
R
3Represent hydrogen, C
1-4Alkyl or be selected from halogen, C by one or more
1-4Alkoxyl-, amino-, single-or two (C
1-4Alkyl) amino-, C
1-4Alkyl-sulfonyl-or the C that replaces of the substituent group of phenyl
1-4Alkyl;
R
4Represent hydrogen, hydroxyl, Ar
3-oxygen base, Ar
4-C
1-4Alkoxyl-, C
1-4Alkoxyl-, optional by Het
12The C that replaces
2-4Alkene oxygen base-; Or R
4Representative is by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl, hydroxyl, halogen, Het
2-,-NR
7R
8,-carbonyl-NR
9R
10Or Het
3-carbonyl-the C that replaces of substituent group
1-4Alkoxyl;
R
5And R
6Independently be selected from hydrogen or C separately
1-4Alkyl;
R
7And R
8Independently be selected from hydrogen, C separately
1-4Alkyl, Het
8-, amino-sulfonyl-, single-or two (C
1-4Alkyl)-amino-sulfonyl-, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-, hydroxycarbonyl group-C
1-4Alkyl-, C
3-6Cycloalkyl, Het
9-carbonyl-C
1-4Alkyl-, Het
10-carbonyl-, polyhydroxy-C
1-4Alkyl-, Het
11-C
1-4Alkyl-or Ar
2-C
1-4Alkyl-; R
9And R
10Each independently is selected from hydrogen, C
1-4Alkyl, C
3-6Cycloalkyl, Het
4, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-;
R
11Represent 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 sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
12Represent hydrogen, C
1-4Alkyl, C
1-4Alkyl-oxygen base-carbonyl-, Het
18-C
1-4Alkyl-, phenyl-C
1-4Alkyl-oxygen base-carbonyl-, Het
17, optional by Het
19-C
1-4Alkyl amino-carbonyl-, C
2-4The thiazolinyl sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-the C that replaces of substituent group
2-4Alkenyl carbonyl-, or R
12Representative is optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
13Represent hydrogen, C
1-4Alkyl, Het
13, Het
14-C
1-4Alkyl-or optional be selected from hydrogen, hydroxyl, amino or C by one or possible two or more
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
14And R
15Independently be selected from hydrogen, C separately
1-4Alkyl, Het
15-C
1-4Alkyl-or C
1-4Alkoxy C
1-4Alkyl-;
R
16And R
17Independent separately hydrogen or the optional C that is replaced by phenyl, indyl, methyl mercapto (methylsulfide), hydroxyl, mercaptan (thiol), hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals of representing
1-4Alkyl;
R
18And R
19Independent separately hydrogen or the optional C that is replaced by phenyl, indyl, methyl mercapto, hydroxyl, mercaptan, hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals of representing
1-4Alkyl;
R
20And R
22The independent separately hydrogen or optional of representing by hydroxyl or C
1-4The C that alkoxyl replaces
1-4Alkyl;
R
21Represent hydrogen, C
1-4Alkyl, Het
23-C
1-4Alkyl-carbonyl, or R
21Representative is optional by hydroxyl, pyrimidine radicals, dimethyl amine or C
1-4The list that alkoxyl replaces-or two (C
1-4Alkyl) amino-C
1-4Alkyl-carbonyl-;
Het
1Represent heterocycle, described heterocycle is selected from piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, 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-list-or two (C
1-4Alkyl) amino-or amino carbonyl-replacement;
Het
2Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, thio-morpholinyl or dithian base (dithianyl), wherein said Het
2Optional by one or may two or a plurality of 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-substituent group replace;
Het
3, Het
4And Het
8Independently represent heterocycle, described heterocycle to be selected from morpholinyl, piperazinyl, piperidyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, wherein said Het separately
3, Het
4, Het
8Optional by one may two or a plurality of be selected from 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-substituent group replace;
Het
5Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
6And Het
7Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
9And Het
10Independently represent heterocycle, described heterocycle to be selected from furyl, piperidyl, morpholinyl, piperazinyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, wherein said Het separately
9Or Het
10Be the optional C that replaces
1-4Alkyl, C
3-6Cycloalkyl-C
1-4Alkyl-or amino-C
1-4Alkyl-;
Het
11Represent heterocycle, described heterocycle be selected from indyl or
Het
12Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, thio-morpholinyl or dithian base, wherein said Het
12Optional by one or possibility two or a plurality of hydroxyl, halogen, amino, C of being selected from
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-substituent group replace;
Het
13Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
14Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4The substituent group of alkyl replaces;
Het
15Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4The substituent group of alkyl replaces;
Het
16Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or 1,3,2-two oxa-bora Pentamethylene. base (dioxaborolane) or piperidyls, and wherein said heterocycle is optional to be selected from C by one or more
1-4The substituent group of alkyl replaces;
Het
17Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
18And Het
19Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4The substituent group of alkyl replaces; Het
20, Het
21And Het
22Independently represent heterocycle, described heterocycle to be selected from pyrrolidinyl, 2-Pyrrolidone base (2-pyrrolidinonyl), piperazinyl or piperidyl separately, optional by one or possibility two or a plurality of hydroxyl, C of being selected from
1-4Alkyl-, hydroxyl-C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
23Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Ar
1, Ar
2, Ar
3, and Ar
5The independent separately phenyl of representing, optional by cyano group, C
1-4Alkyl sulphonyl-, C
1-4Alkyl sulfonyl-amino-, amino-sulfonyl amino-, hydroxyl-C
1-4Alkyl, amino-sulfonyl-, hydroxyl, C
1-4Alkoxyl-or C
1-4Alkyl replaces;
As in front the definition and employed hereinafter:
-halogen is generally fluorine, chlorine, bromine and iodine;
-C
1-2Alkyl is defined as methyl or ethyl;
-C
1-3Alkyl is defined as the straight chain with 1-3 carbon atom and the saturated hydrocarbyl of side chain,
For example methyl, ethyl, propyl group etc.;
-C
1-4Alkyl is defined as the straight chain with 1-4 carbon atom and the saturated hydrocarbyl of side chain, as methyl, ethyl, propyl group, butyl, 1-Methylethyl, 2,2-dimethyl propyl, 2,2-dimethyl ethyl etc.;
-C
1-5Alkyl is defined as the straight chain with 1-5 carbon atom and the saturated hydrocarbyl of side chain, as methyl, ethyl, propyl group, butyl, amyl group, 1-methyl butyl, 2,2-dimethyl propyl, 2,2-dimethyl ethyl etc.;
-C
1-6Alkyl refers to comprise C
1-5Alkyl and have the higher homologues of 6 carbon atoms, as hexyl, 1,2-dimethylbutyl, 2-methyl amyl etc.;
-C
1-7Alkyl refers to comprise C
1-6Alkyl and have the higher homologues of 7 carbon atoms, as 1,2,3-dimethylbutyl, 2-methyl amyl etc.;
-C
3-9Alkyl is defined as the straight chain with 3-9 carbon atom and the saturated hydrocarbyl of side chain, as propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl etc.;
-C
2-4Thiazolinyl is defined as and comprises two keys and have the straight chain of 2-4 carbon atom and the alkyl of side chain, as vinyl, 2-acrylic, 3-cyclobutenyl, crotyl etc.;
-C
3-9Thiazolinyl is defined as and comprises two keys and have the straight chain of 3-9 carbon atom and the alkyl of side chain, as 2-acrylic, 3-cyclobutenyl, crotyl, pentenyl, 3-pentenyl, 3-methyl-2-butene base, 3-hexenyl etc.;
-C
2-6Alkynyl is defined as and comprises a triple bond and have the straight chain of 2-6 carbon atom and the alkyl of side chain, as 2-propynyl, 3-butynyl, 2-butyne base, 3-pentynyl, 3-methyl-2-butyne base, 3-hexin base etc.;
-C
3-6Cycloalkyl is generally cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl;
-C
1-4Alkoxyl is defined as the saturated hydrocarbyl of straight or branched, as methoxyl group, ethyoxyl, propoxyl group, butoxy, 1-methyl ethoxy, 2-methyl propoxyl group etc.;
-C
1-6Alkoxyl refers to C
1-4Alkoxyl and higher homologues are as methoxyl group, ethyoxyl, propoxyl group, butoxy, 1-methyl ethoxy, 2-methyl propoxyl group etc.;
-polyhydroxy-C
1-4Alkyl belongs to foregoing C
1-4Alkyl has two, three or may a plurality of hydroxyl substituents, for example trifluoromethyl.
As definition and employed hereinafter in front, the term formoxyl refers to formula-CH (=O) group.Work as X
1When representing divalent group-O-N=CH-, described group is with the R of band shape part in carbon atom and formula (I) chemical compound
3, R
4Link to each other, and work as X
2When representing divalent group-O-N=CH-, described group is with the R of band phenyl moiety in carbon atom and formula (I) chemical compound
3, R
4Link to each other.
Superincumbent definition and hereinafter mentioned heterocycle comprise its all possible isomeric form, and for example pyrrole radicals also comprises the 2H-pyrrole radicals; Triazolyl comprises 1,2,4-triazolyl and 1,3,4-triazolyl; The oxadiazole base comprises 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base and 1,3,4-oxadiazole base; Thiadiazolyl group comprises 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group and 1,3,4-thiadiazolyl group; Pyranose comprises 2H-pyranose and 4H-pyranose.
In addition, superincumbent definition and hereinafter mentioned heterocycle can link to each other with formula (I) molecule residue via any ring carbon or suitable hetero atom.Therefore, for example, when heterocycle is imidazole radicals, can be 1-imidazole radicals, 2-imidazole radicals, 3-imidazole radicals, 4-imidazole radicals and 5-imidazole radicals; When being thiazolyl, 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, 1,3,4-triazole-2-base; When being benzothiazolyl, can be 2-[4-morpholinodithio base, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl.
As hereinafter mentioned pharmaceutically acceptable addition salt refer to comprise formula (I) chemical compound the therapeutic activity that can form, the non-toxic acid addition salt form.The latter can be easily by adopting suitable acid treatment alkaline form to obtain.Suitably acid for example comprises, and inorganic acids is as halogen acids example hydrochloric acid or hydrobromic acid; Sulphuric acid, nitric acid, phosphoric acid and class acidoid; Organic acid, for example, acetic acid, propanoic acid, hydroxacetic acid, lactic acid, acetone acid, oxalic acid, malonic acid, succinic acid (being butane-diacid), maleic acid, maleic acid, malic acid, tartaric acid, Loprazolam, ethane sulfonic acid, benzenesulfonic acid, right-toluenesulfonic acid, cyclohexyl amine sulfonic acid (cyclamicacid), salicylic acid, right-aminosallcylic acid, pounce on class acidoids such as acid.
As hereinafter mentioned pharmaceutically acceptable addition salt refer to comprise therapeutic activity that formula (I) chemical compound can form, avirulence base addition salts form.The example of this type of base addition salts form, for example sodium, potassium, calcium salt; And and pharmaceutically acceptable amine, as ammonia, alkylamine, dibenzyl ethylenediamine benzyl (benzathine), N-methyl D-glycosamine, sea crust amine (hydrabamine), amino acids, as arginine, the formed salt of lysine.On the contrary, described salt form can be by changing into free acid or alkali form with suitable alkali or acid treatment.
Used as mentioned term addition salts also comprises the solvate that formula (I) chemical compound and its esters can form.This type of solvate such as hydrate, alcoholates for example.
Used as mentioned term stereoisomeric forms in any ratio is defined as formula (I) chemical compound may have different possible isomeries and conformation form.Except as otherwise noted or point out that the chemical name of chemical compound is represented the mixture of all possible solid and conformational isomerism form, described mixture comprises its all diastereomer of basic molecular structure, enantiomer and/or conformer.All stereoisomeric forms in any ratio intentions with formula (I) chemical compound of pure form or intermingling thing are included in the category of the present invention.
Also can there be tautomeric form in some formulas (I) chemical compound.Though this type of form is not clearly to point out in above-mentioned form, but still is intended to be included in the category of the present invention.
The N-oxide form of formula (I) chemical compound refer to comprise wherein one or several nitrogen-atoms be oxidized to formula (I) chemical compound of so-called N-oxide.
First group of chemical compound according to the present invention is made up of formula (I) chemical compound, wherein one or more following restriction in addition:
Z represents O, NH or S;
Y representative-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-,-C
1-2Alkyl-NH-CO-CH
2R
16-NH-;
X
1Represent connecting key, O ,-O-C
1-2Alkyl-, CO ,-CO-C
1-2Alkyl-, NR
11,-NR
11-C
1-2Alkyl-,-CH
2-,-O-N=CH-or C
1-2Alkyl-;
X
2Represent connecting 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
1Represent hydrogen, cyano group, halogen, hydroxyl, formoxyl, C
1-6Alkoxyl-, C
1-6Alkyl-, the C that replaces of halogen
1-6Alkoxyl-, by one or may two or the C that replaces of a plurality of substituent group that is selected from hydroxyl or halogen
1-4Alkyl;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group, Het
16-carbonyl, C
1-4Alkoxy carbonyl-, C
1-4Alkyl-carbonyl-, amino carbonyl-, single-or two (C
1-4Alkyl) amino carbonyl-, Het
1, formoxyl, C
1-4Alkyl-, C
2-6Alkynyl-, C
3-6Cycloalkyl-, C
3-6Cycloalkyloxy-, C
1-6Alkoxyl-, Ar
5, Ar
1-oxygen base-, dihydroxy borine, the C that replaced by halogen
1-6Alkoxyl-, by one or may two or a plurality of halogen, hydroxyl or NR of being selected from
5R
6The C that replaces of substituent group
1-4Alkyl, wherein said C
1-4Alkyl is by one or possibility two or a plurality of hydroxyl or C of being selected from
1-4Alkyl-oxygen base-the C that replaces of substituent group
1-4Alkyl-carbonyl-;
R
3Represent hydrogen, C
1-4Alkyl or be selected from halogen, C by one or more
1-4Alkoxyl-, amino-, single-or two (C
1-4Alkyl) amino-, C
1-4Alkyl-sulfonyl-or the C that replaces of the substituent group of phenyl
1-4Alkyl;
R
4Represent hydrogen, hydroxyl, AR
3-oxygen base, Ar
4-C
1-4Alkoxyl-, C
1-4Alkoxyl-, optional by Het
12The C that replaces
2-4Alkene oxygen base-; Or R
4Representative is by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl-, hydroxyl, halogen, Het
2,-NR
7R
8,-carbonyl-NR
9R
10Or Het
3-carbonyl-the C that replaces of substituent group
1-4Alkoxyl;
R
5And R
6Independently be selected from hydrogen or C separately
1-4Alkyl;
R
7And R
8Independently be selected from hydrogen, C separately
1-4Alkyl, Het
8, amino-sulfonyl-, single-or two (C
1-4Alkyl)-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-, polyhydroxy-C
1-4Alkyl-, Het
11-C
1-4Alkyl-or Ar
2-C
1-4Alkyl-;
R
9And R
10Independently be selected from hydrogen, C separately
1-4Alkyl, C
3-6Cycloalkyl, Het
4, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-;
R
11Represent 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 sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
12Represent 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 sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
13Represent hydrogen, C
1-4Alkyl, Het
13, Het
14-C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
14And R
15Independently be selected from hydrogen, C separately
1-4Alkyl, Het
15-C
1-4Alkyl-or C
1-4Alkoxy C
1-4Alkyl-;
R
16Represent hydrogen or C
1-4Alkyl, optional by phenyl, indyl, methyl mercapto, hydroxyl, mercaptan, hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals replacement;
Het
1Represent heterocycle, described heterocycle is selected from piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, 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-list-or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
Het
2Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, thio-morpholinyl or dithian base, wherein said Het
2Optional by one or possibility two or a plurality of hydroxyl, halogen, amino, C of being selected from
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-substituent group replace;
Het
3, Het
4And Het
8Independently represent heterocycle, described heterocycle to be selected from morpholinyl, piperazinyl, piperidyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, wherein said Het separately
3, Het
4And Het
8Optional by one or possibility two or a plurality of hydroxyl, amino, C of being selected from
1-4Alkyl-, C
3-6Cycloalkyl-C
1-4Alkyl-, amino-sulfonyl-, single-or two (C
1-4Alkyl) amino-sulfonyl-or amino-C
1-4Alkyl-substituent group replace;
Het
5Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
6And Het
7Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
9And Het
10Independently represent heterocycle, described heterocycle to be selected from furyl, piperidyl, morpholinyl, piperazinyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, wherein said Het separately
9Or Het
10Be the optional C that replaces
1-4Alkyl, C
3-6Cycloalkyl-C
1-4Alkyl-or amino-C
1-4Alkyl-;
Het
11Represent heterocycle, described heterocycle be selected from indyl or
Het
12Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, thio-morpholinyl or dithian base, wherein said Het
12Optional by one or possibility two or a plurality of hydroxyl, halogen, amino, C of being selected from
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-substituent group replace;
Het
13Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
14Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
15Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
16Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-two oxa-bora Pentamethylene. base or piperidyls, and wherein said heterocycle is optional to be selected from C by one or more
1-4The substituent group of alkyl replaces; And
Het
17Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
18And Het
19Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl-, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Ar
1, Ar
2, Ar
3, Ar
4And Ar
5The independent separately phenyl of representing, optional by cyano group, C
1-4Alkyl sulphonyl-, C
1-4Alkyl sulfonyl-amino-, amino-sulfonyl amino-, hydroxyl C
1-4Alkyl, amino-sulfonyl-, hydroxyl-, C
1-4Alkoxyl-or C
1-4Alkyl replaces.
One group of interesting chemical compound is made up of formula (I) chemical compound, wherein one or more following restriction in addition:
Z represents NH;
Y representative-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-,-NH-CO-C
1-6Alkyl-,-CO-C
1-7Alkyl-,-C
1-7Alkyl-CO-,-C
1-6Alkyl-CO-C
1-6Alkyl-,-C
1-2Alkyl-NH-CO-CR
16R
17-NH-,-C
1-2Alkyl-CO-N11-CR
18R
19-CO-,-C
1-2Alkyl-CO-NR
20-C
1-3Alkyl-CO-,-C
1-2Alkyl-NR
21-CH
2-CO-NH-C
1-3Alkyl-,-NR
22-CO-C
1-3Alkyl-NH-,-C
1-3Alkyl-NH-CO-Het
20,-C
1-2Alkyl-CO-Het
21-CO-or-Het
22-CH
2-CO-NH-C
1-3Alkyl-;
X
1Represent O ,-O-C
1-2Alkyl-,-O-N=CH-, NR
11,-NR
11-C
1-2Alkyl-; In a special embodiment, X
1Represent NR
11,-O-or-O-CH
2-;
X
2Represent connecting key, O ,-O-C
1-2Alkyl-,-O-N=CH-, NR
12Or-NR
12-C
1-2Alkyl-; In a special embodiment, X
2Represent connecting key ,-C
1-2Alkyl-, O-C
1-2Alkyl-,-O-or-O-CH
2-;
R
1Represent hydrogen, cyano group, halogen or hydroxyl, be preferably halogen;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-, C
1-4Alkoxy carbonyl-, Het
16-carbonyl, C
1-4Alkyl-, C
2-6Alkynyl-, Ar
5Or Het
1In another embodiment, R
2Represent hydrogen, cyano group, halogen, hydroxyl, C
2-6Alkynyl-or Het
1Especially, R
2Represent hydrogen, cyano group, halogen, hydroxyl or Ar
5
R
3Represent hydrogen;
R
4Represent hydrogen, hydroxyl, C
1-4Alkoxyl-; Or R
4Representative is by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl-or Het
2-the C that replaces of substituent group
1-4Alkoxyl;
R
12Represent hydrogen, C
1-4Alkyl or C
1-4Alkyl-oxygen base-carbonyl-;
R
13Represent hydrogen or Het
14-C
1-4Alkyl-, morpholinyl-C particularly
1-4Alkyl;
R
14And R
15Represent hydrogen;
R
16The C that represents hydrogen or replace with hydroxyl
1-4Alkyl;
R
17Represent hydrogen or C
1-4Alkyl, particularly hydrogen or methyl;
R
18Represent hydrogen or optional by the C of hydroxyl or phenyl replacement
1-4Alkyl;
R
19Represent hydrogen or C
1-4Alkyl, particularly hydrogen or methyl, even be more particularly hydrogen;
R
20Represent hydrogen or C
1-4Alkyl, particularly hydrogen or methyl;
R
21Represent hydrogen, C
1-4Alkyl, Het
23-C
1-4Alkyl-carbonyl, or R
21Represent single-or two (C
1-4Alkyl) amino-C
1-4Alkyl-carbonyl-, optional by hydroxyl, pyrimidine radicals, dimethyl amine or C
1-4Alkoxyl replaces;
R
22Represent hydrogen or C
1-4Alkyl, optional by hydroxyl or C
1-4Alkoxyl replaces;
Het
1Represent thiazolyl, optional by amino, C
1-4Alkyl, hydroxyl-C
1-4Alkyl-, phenyl, phenyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-list-or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
Het
2Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
2Optional by one or possibility two or a plurality of hydroxyl, amino or C of being selected from
1-4The substituent group of alkyl replaces; In another embodiment, Het
2Represent heterocycle, described heterocycle is selected from morpholinyl or piperidyl, and is optional by C
1-4Alkyl replaces, and is preferably methyl;
Het
3Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
3Optional by one or may two or a plurality of hydroxyl, amino-or C that is selected from
1-4Alkyl-substituent group replace;
Het
12Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
12Optional by one or possibility two or a plurality of hydroxyl, amino or C of being selected from
1-4Alkyl-substituent group replace;
Het
16Represent heterocycle, described heterocycle is selected from piperidyl or pyrrolidinyl;
Het
20Represent pyrrolidinyl, 2-Pyrrolidone base, piperidyl or hydroxyl-pyrrolidinyl, be preferably pyrrolidinyl or hydroxyl-pyrrolidinyl;
Het
21Represent pyrrolidinyl or hydroxyl-pyrrolidinyl;
Het
22Represent pyrrolidinyl, piperazinyl or piperidyl.
One group of special chemical compound is made up of formula (I) chemical compound, wherein one or more following restriction in addition:
Z represents NH;
Y representative-C
3-9Alkyl-,-C
2-9Thiazolinyl-, optional by amino, single-or two (C
1-4Alkyl) amino or C
1-4Alkoxycarbonyl amino-replacement-C
3-7Alkyl-CO-NH, optional by amino, single-or two (C
1-4Alkyl) amino or C
1-4The C of alkoxycarbonyl amino-replacement
3-7Thiazolinyl-CO-NH ,-C
1-5Alkyl-NR
13-C
1-5Alkyl-, C
1-5Alkyl-NH
14-CO-C
1-5Alkyl ,-C
1-6Alkyl-CO-NH-,-C
1-5Alkyl-CO-NR
15-C
1-5Alkyl ,-C
1-3Alkyl-NH-CO-Het
20-,-C
1-2Alkyl-CO-Het
21-CO-,-C
1-2Alkyl-NH-CO-CR
16R
17-NH-, C
1-2Alkyl-CO-NH-CR
18R
19-CO-, C
1-2Alkyl-CO-NR
20-C
1-3Alkyl-CO-or-NR
22-CO-C
1-3Alkyl-NH-; Even more particularly, Y representative-C
3-9Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-, C
1-5Alkyl-NR
14-CO-C
1-5Alkyl-,-C
1-3Alkyl-NH-CO-Het
20-,-C
1-2Alkyl-CO-Het
21-CO-or-C
1-2Alkyl-NH-CO-CR
16R
17-NH-;
X
1Represent connecting key, O or-O-C
1-2Alkyl-;
X
2Represent connecting key ,-CO-C
1-2Alkyl-, NR
12-NR
12-C
1-2Alkyl-,-O-N=CH-or-C
1-2Alkyl-; Even X more particularly
2Representative-CO-C
1-2Alkyl-or-NR
12-C
1-2Alkyl-;
R
1Represent hydrogen or halogen, be preferably hydrogen, chlorine, fluorine or bromine;
R
2Represent hydrogen or halogen, be preferably hydrogen, chlorine, fluorine or bromine;
R
3Represent hydrogen;
R
4Represent hydrogen or C
1-4Alkoxyl is preferably C
1-4Alkoxyl, even methoxyl group more preferably;
R
12Represent hydrogen or C
1-4Alkyl is preferably hydrogen or methyl;
R
13Represent hydrogen or C
1-4Alkyl;
R
14Represent hydrogen;
R
15Represent hydrogen;
R
16And R
17Independent separately hydrogen or the C of representing
1-4Alkyl;
R
18And R
19Independent separately hydrogen or the C of representing
1-4Alkyl, optional by hydroxyl or phenyl replacement;
R
20And R
21Independent separately hydrogen or the C of representing
1-4Alkyl, optional by C
1-4Alkoxyl replaces;
Het
20, Het
21And Het
22Independently represent heterocycle separately, described heterocycle is selected from pyrrolidinyl, 2-Pyrrolidone base or piperidyl, chooses wantonly to be replaced by hydroxyl.
One group of preferred chemical compound is made up of formula (I) chemical compound, wherein one or more following restriction in addition:
Z represents NH;
Y representative-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; Alkyl-NH-CO-Het
20-,-C
1-2Alkyl-CO-Het
21-CO-,-C
1-2Alkyl-NH-CO-CR
16R
17-NH-,-C
1-2Alkyl-NH-CO-CR
18R
19-CO-,-C
1-2Alkyl-CO-NR
20-C;
X
1Represent O ,-O-C
1-2Alkyl-,-O-N=CH-, NR
11Or-NR
11-C
1-2Alkyl-; In a special embodiment, X
1Represent NR
11,-O-or-O-CH
2-;
X
2Represent connecting key, O ,-O-C
1-2Alkyl-,-O-N=CH-, NR
12,-NR
12-C
1-2Alkyl-; In a special embodiment, X
2Represent connecting key ,-C
1-2Alkyl-,-O-C
1-2Alkyl-,-O-or-O-CH
2-;
R
1Represent hydrogen, cyano group, halogen or hydroxyl, be preferably halogen;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-, C
1-4Alkoxy carbonyl-, Het
16-carbonyl-, C
1-4Alkyl-, C
2-6Alkynyl-, Ar
5Or Het
1In a special embodiment, R
2Represent hydrogen, cyano group, halogen, hydroxyl, C
2-6Alkynyl or Het
1R especially
2Represent hydrogen, cyano group, halogen, hydroxyl or Ar
5
R
3Represent hydrogen;
R
4Represent hydrogen, hydroxyl, C
1-4Alkoxyl or R
4Represent C
1-4Alkoxyl, optional by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl-or Het
2Substituent group replace;
R
12Represent hydrogen, C
1-4Alkyl or C
1-4Alkyl-oxygen base-carbonyl-;
R
13Represent Het
14-C
1-4Alkyl, particularly morpholinyl-C
1-4Alkyl;
Het
1Represent thiazolyl, optional by amino, C
1-4Alkyl, hydroxyl-C
1-4Alkyl-, phenyl, phenyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-oxygen base-C
1-4Alkyl-list-or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
Het
2Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
2Optional by one or possibility two or a plurality of hydroxyl, amino or C of being selected from
1-4Alkyl-replacement; In another embodiment, Het
2Represent heterocycle, described heterocycle is selected from morpholinyl or piperidyl, and is optional by C
1-4Alkyl-replacement is preferably methyl;
Het
3Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
3Optional by one may two or a plurality of be selected from hydroxyl-, amino-or C
1-4Alkyl-substituent group replace;
Het
12Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
12Optional by one or possibility two or a plurality of hydroxyl, amino or C of being selected from
1-4Alkyl-substituent group replace;
Het
16Represent heterocycle, described heterocycle is selected from piperidyl or pyrrolidinyl.
Another group chemical compound is made up of formula (I) chemical compound, wherein in addition one or more following restriction:
Z represents NH;
Y representative-C
3-9Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-,-C
1-6Alkyl-NH-CO-,-CO-C
1-7Alkyl-or-C
1-7Alkyl-CO-;
X
1Represent NR
11,-O-or-O-CH
2-;
X
2Represent connecting key, NR
12,-NR
12-C
1-2Alkyl ,-CO-,-O-or-O-CH
2-;
R
1Represent halogen; R especially
1Represent chlorine, fluorine or bromine, and in 5 ' position;
R
2Represent hydrogen, cyano group, halogen, hydroxyl or Ar
5
R
3Represent hydrogen;
R
4Represent C
1-4Alkoxyl, optional by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl-or
Het
2-substituent group replace;
R
12Represent C
1-4Alkyl, or R
12Represent C
1-4Alkyl-oxygen base-carbonyl;
R
13Represent Het
4-C
1-4Alkyl;
Het
2Represent heterocycle, described heterocycle is selected from morpholinyl or piperidyl, and is optional by C
1-4Alkyl-replacement;
Het
3Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
3Optional by one may two or a plurality of be selected from hydroxyl-, amino-or C
1-4Alkyl-substituent group replace;
Het
12Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
12Optional by one may two or a plurality of be selected from hydroxyl, amino or
C
1-4Alkyl-substituent group replace;
Het
14Represent morpholinyl.
In another embodiment of the invention, formula (I) chemical compound is selected from:
1) 4,6-ethanetetrayl (ethanediylidene) pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 is because of (cyclopentadecine), 17-bromo-8,9,10,11,12,13,14, and 19-octahydro-20-methoxyl group-
2) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 is because of, 17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-13-methyl-
3) Benzoylamide, 4-fluoro-N-(8,9,10,11,12,13-six hydrogen-20-methoxyl group-4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 are because of-16-yl)-
4) 4,6-ethanetetrayl-8H, 14H-pyrimido [4,5-b] [6,12,1] benzo two oxa-azacyclo-s 16 be because of (cyclohexadecine), 18-chloro-9,10,11,12,15, and 20-six hydrogen-21-methoxyl group-
5) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,11] benzo oxa-diazacyclo 16 is because of-11 (12H)-ketone, 18-chloro-9,10,13,14,15, and 20-six hydrogen-21-methoxyl group-
6) 4,6-ethanetetrayl-14H-pyrimido [4,5-b] [6,9,12,1] benzo trioxa azacyclo-16 is because of, 18-chloro-8,9,11,12,15,20-six hydrogen-21-methoxyl group-
7) 4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[2,1, k] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 19-chloro-9,10, and 11a, 12,14,21-octahydro-22-methoxyl group-
8) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 17-chloro-9,10,12,13,14, and 19-six hydrogen-20-methoxyl group-13-methyl-
9) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 17-chloro-9,10,12,13,14, and 19-six hydrogen-20-methoxyl group-
10) 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 18-chloro-8,9,10,11,13,14,15, and 20-octahydro-21-methoxyl group-14-methyl-
11) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,13] benzo oxa-three azacyclo-s 16 are because of-11 (12H)-ketone, 18-chloro-9,10,13,14,15, and 20-six hydrogen-21-methoxyl group-
12) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,10,14] benzo oxa-three azacyclo-s 17 are because of (cycloheptadecin)-12 (13H)-ketone, 19-chloro-8,9,10,11,14,15,16, and 21-octahydro-22-methoxyl group-
13) 4,6-ethenylidene (etheno) pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 10,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-20-methoxyl group-
14) 4,6-ethenylidene-8H-pyrimido [4,5-b] pyrrolo-[2,1-1] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12,15 (14H)-diketone, 20-oxo-9,10,11, and 12a, 13,17,22-seven hydrogen-23-methoxyl group-
15) 4,6-ethanetetrayl-12H-pyrimido [4,5-b] pyrrolo-[2,1-1] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 20-chloro-8,9,10,11, and 12a, 13,14,15,17,22-decahydro-23-methoxyl group-
16) 4,6-ethenylidene pyrimido [4,5-b] [6,1,9,14] benzo oxa-three azacyclo-s 17 because of-9,14 (8H, 15H)-diketone, 19-chloro-10,11,12,13,16,21-six hydrogen-22-methoxyl group-
17) 4,6-ethenylidene-8H-pyrimido [4,5-b] [6,1,9,13] benzo oxa-three azacyclo-s 16 because of-9,13 (10H, 14H)-diketone, 18-chloro-11,12,15,20-tetrahydrochysene-21-methoxyl group-
18) 4,6-ethenylidene pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 because of-11,14 (8H, 15H)-diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-22-methoxyl group-
19) 4,6-ethenylidene pyrimido [4,5-b] [6,1,11,16] benzo oxa-three azacyclo-s 19 because of (cyclononadecine)-11,16 (8H, 17H)-diketone, 21-chloro-9,10,12,13,14,15,18,23-octahydro-24-methoxyl group-
20) 4,6-ethenylidene-8H-pyrimido [4,5-b] [6,1,11,15] benzo oxa-three azacyclo-s 18 because of (cyclooctadecine)-11,15 (12H, 16H)-diketone, 20-chloro-9,10,13,14,17,22-six hydrogen-23-methoxyl group-
21) 4,6-ethenylidene pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 is because of, 17-bromo-16-fluoro-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-
22) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-20-methoxyl group-11-methyl-
23) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-20-methoxyl group-11-methyl-(1-Methylethyl)-
24) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-20-methoxyl group-11-methyl-(1-phenylethyl)-
25) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-11, the 14-diketone, and 18-chloro-9,10,12,15,20-six hydrogen-21-methoxyl group-12-methyl-(1-Methylethyl)-
26) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-11, the 14-diketone, and 18-chloro-9,10,12,13,15,20-six hydrogen-21-methoxyl group-12, the 12-dimethyl-
27) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-11, the 14-diketone, and 18-chloro-9,10,12,13,15,20-six hydrogen-21-methoxyl group-12-(2-methyl-propyl)-
28) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12, the 15-diketone, and 19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxyl group-13-(2-methyl-propyl)-
29) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-11, the 14-diketone, and 18-chloro-9,10,12,13,15,20-six hydrogen-21-methoxyl group-
30) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 17 are because of-12, the 15-diketone, and 19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxyl group-
31) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H) diketone, 10,11,14,19-tetrahydrochysene-20-methoxyl group-1-methyl-
32) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H) diketone, 10,11,14,19-tetrahydrochysene-20-methoxyl group-11-(1-methyl-propyl)-
33) 9,11-ethanetetrayl pyrimido [4,5-b] pyrrolo-[1,2-i] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-14,19 (5H, 13H)-diketone, 16,17,18,18a, 20,21-six hydrogen-22-methoxyl group-
34) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H) diketone, 10,11,14,19-tetrahydrochysene-20-methoxyl group-
35) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,13] benzo oxa-three azacyclo-s 16 because of-9,13 (10H, 14H) diketone, 11,12,15,20-tetrahydrochysene-21-methoxyl group-
36) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,14] benzo oxa-three azacyclo-s 17 because of-9,14 (8H, 15H) diketone, 10,11,12,13,16,21-six hydrogen-22-methoxyl group-
37) 4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[2,1-k] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 19-chloro-18 fluoro-9,10, and 11a, 12,13,14,16,21-octahydro-22-methoxyl group-
38) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of, 18-chloro-9,10,11,12,13,14,15,20-octahydro-21-methoxyl group-14-methyl-
39) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 17-chloro-16-fluoro-9,10,12,13,14,19-six hydrogen-20-methoxyl group-13-methyl
40) 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 18-chloro-17-fluoro-8,9,10,11,13,14,15, and 20-octahydro-21-methoxyl group-14-methyl-
41) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 17-chloro-16 fluoro-9,10,12,13,14, and 19-six hydrogen-20-methoxyl group-
42) 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 18-chloro-17-fluoro-8,9,10,11,13,14,15, and 20-octahydro-21-methoxyl group-
43) 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 18-chloro-8,9,10,11,13,14,15, and 20-octahydro-21-methoxyl group-
44) 9,11-ethanetetrayl pyrimido [4,5-b] pyrrolo-[1,2-i] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-14,19 (5H, 13H)-diketone, 3-chloro-16,17,18a, 20,21-six hydrogen-22-methoxyl group-
45) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-20-methoxyl group-10-methyl-
46) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-11-(1-hydroxyethyl)-20-methoxyl group-
47) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 because of-11,14 (8H, 15H)-diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-22-methoxyl group-13-(1-methyl-propyl)-
48) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-11-(1-methylol)-20-methoxyl group-
49) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 because of-11,14 (8H, 15H)-diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-13-(methylol)-22-methoxyl group-
50) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 because of-11,14 (8H, 15H)-diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-22-methoxyl group-13-methyl-
51) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-9, the 12-diketone, and 18-chloro-10,11,13,14,15,20-six hydrogen-21-methoxyl group-
52) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,14] benzo oxa-three azacyclo-s 18 are because of-9, the 14-diketone, and 20-chloro-10,11,12,13,15,16,17,22-octahydro-23-methoxyl group-
53) 4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[2,1-k] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 19-chloro-9,10, and 11a, 12,13,14,16,21-octahydro-22-methoxyl group-
54) 4,6-ethanetetrayl-12H-pyrimido [4,5-b] pyrrolo-[2,1-1] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 20-chloro-8,9,10, and 12a, 13,14,15,17,22-decahydro-23-methoxyl group-
55) 4,6-ethanetetrayl-12H-pyrimido [4,5-b] pyrrolo-[2,1-1] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 20-chloro-19-fluoro-8,9,10, and 12a, 13,14,15,17,22-decahydro-23-methoxyl group-
56) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-13 (8H)-ketone, 19-chloro-9,10,11,12,13,14,15,16, and 21-octahydro-22-methoxyl group-
57) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8,9,10,11,14,15,16, and 21-octahydro-22-methoxyl group-10-methyl-
58) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-10-ethyl-8,9,10,11,14,15,16, and 21-octahydro-22-methoxyl group-
59) 1,22-ethanetetrayl-5H, 17H-pyrimido [4,5-b] pyrrolo-[2,1-h] [6,1,9,12] benzo oxa-three azacyclo-s 17 be because of-14 (15H)-ketone, 7-chloro-10,11,12,13,18, and 19a, 20-octahydro-24-methoxyl group-
60) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 18 are because of-13 (14H)-ketone, 20-chloro-9,10,11,12,15,16,17, and 22-octahydro-23-methoxyl group-
61) 14H-4,6-ethanetetrayl-9,13-methylene (methano)-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 20 are because of (cycloeicosin)-15 (16H)-ketone, 22-chloro-9,10,11,12,17,18,19,24-octahydro-26-methoxyl group-
62) 13H-4,6-ethanetetrayl-9,12-ethylidene (ethano) pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 20 be because of-14 (15H)-ketone, 21-chloro-9,10,11,12,16,17,18, and 23-octahydro-26-methoxyl group-
63) 14H-4,6-ethanetetrayl-10,13-ethylidene-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 20 be because of-15 (16H)-ketone, 22-chloro-9,10,11,12,17,18,19, and 24-octahydro-27-methoxyl group-
64) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8,9,10,11,14,15,16,21-octahydro-10-[[[2-hydroxyl-1-(methylol) ethyl] amino] acetyl group]-the 22-methoxyl group-
65) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8,9,10,11,14,15,16,21-octahydro-10-[[2-(methylol)-4-morpholinyl] acetyl group]-the 22-methoxyl group-
66) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8,9,10,11,14,15,16, and 21-octahydro-22-methoxyl group-
67) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8,9,10,11,14,15,16,21-octahydro-10-[[2-(ethoxy) methylamino] acetyl group]-the 22-methoxyl group-
68) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxyl group-10-[[[2-(4-pyridine radicals) ethyl] amino] acetyl group]-
69) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-10-[[[2-(dimethylamino) ethyl] methylamino] acetyl group]-8,9,10,11,14,15,16,21-octahydro-22-methoxyl group-
70) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxyl group-10-[[(2-methoxy ethyl) amino] acetyl group]-
71) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxyl group-10-[[(3-methoxy ethyl) amino] acetyl group]-
72) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8,9,10,11,14,15,16, and 21-octahydro-22-methoxyl group-10-(4-morpholinyl acetyl group)-
73) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxyl group-10-[(4-methyl isophthalic acid-piperazinyl) acetyl group]-
74) 13) 4,6-ethenylidene pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 is because of-13 (8H)-carboxylic acids, 17-bromo-9,10,11,12,14, and 19-six hydrogen-20-methoxyl group-, the phenyl methyl ester
75) 4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[2,1-m] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-13 (8H)-ketone, 21-chloro-9,10,11,12, and 13a, 14,15,16,18,23-decahydro-24-methoxyl group-
76) 4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[2,1-m] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-13 (8H)-ketone, 21-chloro-20-fluoro-9,10,11,12, and 13a, 14,15,16,18,23-decahydro-24-methoxyl group-
77) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,16] benzo oxa-diazacyclo 19 is because of-16 (17H)-ketone, 21-chloro-8,9,10,13,14,15,18, and 23-octahydro-24-methoxyl group-
78) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,16] benzo oxa-diazacyclo 19 is because of-16 (17H)-ketone, 21-chloro-8,9,10,13,14,15,18, and 23-octahydro-24-methoxyl group-
79) 4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[2,1-k] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-thioketone, 19-chloro-18-fluoro-9,10, and 11a, 12,13,14,16,21-octahydro-22-methoxyl group-
80) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of, 19-chloro-8,9,10,11,12,13,14,15,16,21-decahydro-22-methoxyl group-15-methyl-
81) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of, 17-chloro-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-13-methyl-
82) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of, 9,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-20-methoxyl group-11, the 11-dimethyl-
83) 9,11-ethanetetrayl pyrimido [4,5-b] pyrrolo-[1,2-i] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-14,19 (5H, 13H)-diketone, 3-chloro-16,17,18,18a, 20,21-six hydrogen-17-hydroxyl-22-methoxyl group-
84) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,14] benzo oxa-diazacyclo 18 is because of-15 (16H)-ketone, 20-chloro-9,12,13,14,17, and 22-six hydrogen-23-methoxyl group-
85) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 18 are because of, 20-chloro-9,10,11,12,13,14,15,16,17,22-decahydro-23-methoxyl group-16-methyl-
86) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-11, the 14-diketone, and 18-chloro-9,10,12,13,15,20-six hydrogen-21-methoxyl group-10-(2-methoxy ethyl)-
87) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,16] benzo oxa-three azacyclo-s 19 because of-12,16 (13H, 17H)-diketone, 21-chloro-8,9,10,14,15,18,23-octahydro-24-methoxyl group-
88) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,17] benzo oxa-three azacyclo-s 20 are because of-12,17 (18H)-diketone, 22-chloro-9,10,13,14,15,16,19, and 24-nine hydrogen-25-methoxyl group-
89) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] pyrrolo-[1,2-1] [6,1,12,15] benzo oxa-three azacyclo-s 18 are because of-12,17 (18H)-diketone, 22-chloro-9,10,11,14,15,16, and 16a, 19,24-nine hydrogen-25-methoxyl group-
90) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-9, the 12-diketone, and 18-chloro-10,11,13,14,15,20-six hydrogen-21-methoxyl group-11, the 11-dimethyl-
91) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] pyrrolo-[1,2-1] [6,1,12,15] benzo oxa-three azacyclo-s 18 are because of-12,17 (18H)-diketone, 22-chloro-9,10,11,14,15,16, and 16a, 19,24-nine hydrogen-15-hydroxyl-25-methoxyl group-
92) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 18 are because of-12,15 (16H)-diketone, 20-chloro-9,10,11,13,14,17, and 22-seven hydrogen-23-methoxyl group-13-methyl-
93) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 18 are because of-12,15 (16H)-diketone, 20-chloro-9,10,11,13,14,17, and 22-seven hydrogen-23-methoxyl group-14-(2-methyl-propyl)-
94) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 18 are because of-12,15 (16H)-diketone, 20-chloro-9,10,11,13,14,17, and 22-seven hydrogen-23-methoxyl group-14, the 14-dimethyl-
95) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 18 are because of-12,15 (16H)-diketone, 20-chloro-9,10,11,13,14,17, and 22-seven hydrogen-23-methoxyl group-14-(phenyl methyl)-
96) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 18 are because of-12,15 (16H)-diketone, 20-chloro-9,10,11,13,14,17, and 22-seven hydrogen-23-methoxyl group-14-methyl-
97) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-9, the 12-diketone, and 18-chloro-10,11,13,14,15,20-six hydrogen-21-methoxyl group-10-methyl-
98) 1,21-ethanetetrayl-5H-pyrimido [4,5-b] pyrrolo-[1,2-i] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-13,18 (19H)-diketone, 7-chloro-10,11, and 13a, 14,15,16-seven hydrogen-23-methoxyl group-
99) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-9, the 12-diketone, and 18-chloro-10,11,13,14,15,20-six hydrogen-21-methoxyl group-10-methyl-
100) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-9, the 12-diketone, and 18-chloro-10,11,13,14,15,20-six hydrogen-21-methoxyl group-11-(2-methyl-propyl)-
101) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-9, the 12-diketone, and 18-chloro-10,11,13,14,15,20-six hydrogen-11-(1-hydroxyethyl)-21-methoxyl group-
102) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 because of-11,14 (8H, 15H)-diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-22-methoxyl group-13-(2-methyl-propyl)-
103) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 because of-11,14 (8H, 15H)-diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-22-methoxyl group-13, the 13-dimethyl-
104) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 because of-11,14 (8H, 15H)-diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-22-methoxyl group-13-(phenyl propyl)-
105) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 because of-11,14 (8H, 15H)-diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-13-(1-hydroxyethyl)-22-(methoxyl group)-
106) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 18 are because of-12,15 (16H)-diketone, 20-chloro-9,10,11,13,14,17, and 22-seven hydrogen-14-(1-hydroxyethyl)-23-methoxyl group-
107) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-11,14-diketone, 18-chloro-9,10,12,13,15,20-six hydrogen-21-methoxyl group-10-[2-(4-morpholinyl) ethyl]-
108) carbamic acid, (6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,15] benzo oxa-diazacyclo 18 is because of-14-yl for 20-chloro-9,10,13,14,15,16,17,22-octahydro-23-methoxyl group-15-oxo-4)-, 1,1-dimethyl ethyl ester
109) carbamic acid, (6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,15] benzo oxa-diazacyclo 18 is because of-14-yl for 20-chloro-9,10,13,14,15,16,17,22-octahydro-23-methoxyl group-15-oxo-4)-, 1,1-dimethyl ethyl ester
110) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-9, the 12-diketone, and 18-chloro-10,11,13,14,15,20-six hydrogen-11-(methylol)-21-methoxyl group-
111) 1,21-ethanetetrayl-5H-pyrimido [4,5-b] pyrrolo-[1,2-i] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-13,18 (19H)-diketone, 7-chloro-10,11,12, and 13a, 14,15,16-seven hydrogen-15-hydroxyl-23-methoxyl group-
112) carbamic acid, (6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,15] benzo oxa-diazacyclo 18 is because of-14-yl for 20-chloro-9,10,12,13,14,15,16,17,22-decahydro-23-methoxyl group-15-oxo-4)-, 1,1-dimethyl ethyl ester
113) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,15] benzo oxa-diazacyclo 18 is because of-15 (16H)-ketone, 14-amino-20-chloro-9,10,11,12,13,14,17, and 21-octahydro-23-methoxyl group-
114) carbamic acid, (6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,13] benzo oxa-diazacyclo 16 is because of-12-yl for 18-chloro-11,12,13,14,15,20-six hydrogen-21-methoxyl group-13-oxo-4)-, 1,1-dimethyl ethyl ester
115) 4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[1,2-k] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 19-chloro-9,10, and 11a, 12,13,14,16,21-octahydro-13-hydroxyl-22-methoxyl group-
116) 4,6-ethanetetrayl-13,16-ethylidene-8H-pyrimido [4,5-b] [6,1,9,12,15] benzo oxa-tetraazacyclododecane 18 be because of-11 (12H)-ketone, 20-chloro-9,10,14,15,17, and 22-six hydrogen-25-methoxyl group-
117) 8H-4,6-ethanetetrayl-12,15-ethylidene pyrimido [4,5-b] [6,1,9,14] benzo oxa-three azacyclo-s 17 be because of-11 (12H)-ketone, 19-chloro-9,10,13,14,16, and 21-six hydrogen-24-methoxyl group-
118) 4,6-ethanetetrayl-12,16-methylene-6H-pyrimido [4,5-b] [6,1,9,15] benzo oxa-three azacyclo-s 18 be because of-11 (8H)-ketone, 20-chloro-9,10,12,13,14,15,17, and 22-octahydro-24-methoxyl group-
119) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 17-chloro-9,10,12,13,14, and 19-six hydrogen-20-methoxyl group-12, the 13-dimethyl-
120) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 17-chloro-13-ethyl-9,10,12,13,14, and 19-six hydrogen-20-methoxyl group-
121) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 17-chloro-9,10,12,13,14, and 19-six hydrogen-12 (hydroxymethyl)-20-methoxyl group-
122) 4,6-ethanetetrayl-12H-pyrimido [4,5-b] pyrrolo-[1,2-1] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 20-chloro-8,9,10,11, and 12a, 13,14,15,17,22-decahydro-14-hydroxyl-23-methoxyl group-
123) 4,6-ethanetetrayl-14,17-ethenylidene pyrimido [4,5-b] [6,1,10,13,16] benzo oxa-tetraazacyclododecane 19 be because of-12 (13H)-ketone, 21-chloro-8,9,10,11,15,16,18, and 23-octahydro-26-methoxyl group-
124) 4,6-ethanetetrayl-13,16-ethylidene-6H-pyrimido [4,5-b] [6,1,10,15] benzo oxa-three azacyclo-s 18 be because of-12 (13H)-ketone, 20-chloro-8,9,10,11,14,15,17, and 22-octahydro-25-methoxyl group-
125) 12H-4,6-ethanetetrayl-13,17-methylene pyrimido [4,5-b] [6,1,10,16] benzo oxa-three azacyclo-s 19 be because of-12-ketone, 21-chloro-8,9,10,11,13,14,15,16,18, and 23-decahydro-25-methoxyl group-
126) 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 18-chloro-8,9,10,11,13,14,15, and 20-octahydro-21-methoxyl group-13, the 14-dimethyl-
127) 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 18-chloro-14-ethyl-8,9,10,11,13,14,15, and 20-octahydro-21-methoxyl group-
128) 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 18-chloro-8,9,10,11,13,14,15, and 20-octahydro-13-(methylol)-21-methoxyl group-
129) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 17 are because of-13 (8H)-ketone, 19-chloro-15-ethyl-9,10,11,12,14,15,16,21-octahydro-22-methoxyl group
130) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-13 (8H)-ketone, 19-chloro-9,10,11,12,14,15,16, and 21-octahydro-22-methoxyl group-14, the 15-dimethyl-
131) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,16] benzo oxa-diazacyclo 19 is because of-16 (17H)-ketone, 21-chloro-8,9,10,11,12,13,14,15,18, and 23-decahydro-24-methoxyl group-
132) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,15] benzo oxa-diazacyclo 18 is because of-15 (16H)-ketone, 20-chloro-14-(dimethylamino)-9,10,11,12,13,14,17, and 22-octahydro-23-methoxyl group-.
In a special embodiment of the present invention, formula (I) chemical compound is to be selected from:
1) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 is because of, 17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-13-methyl-,
2) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 is because of, 17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-,
3) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 17 because of, 12,15-diketone-19-chloro-8,9,10,11,12,13,14,16,21-octahydro-22-methoxyl group-13-(2-methyl-propyl)-,
4) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 17 because of, 12, the 15-diketone, 19-chloro-8,9,10,11,12,13,14,16,21-octahydro-22-methoxyl group-,
5) 4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[2,1-k] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 19-chloro-18-fluoro-9,10, and 11a, 12,13,14,16,21-octahydro-22-methoxyl group-,
6) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of, 18-chloro-9,10,11,12,13,14,15,20-octahydro-21-methoxyl group-14-methyl-,
7) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of, 19-chloro-8,9,10,11,12,13,14,15,16,21-decahydro-22-methoxyl group-15-methyl-,
8) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of, 17-chloro-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-13-methyl-,
9) 12H-4,6-ethanetetrayl-13,17-methylene pyrimido [4,5-b] [6,1,10,16] benzo oxa-three azacyclo-s 19 be because of-12-ketone, 21-chloro-8,9,10,11,13,14,15,16,18, and 23-decahydro-25-methoxyl group-,
10) 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 18-chloro-8,9,10,11,13,14,15, and 20-octahydro-21-methoxyl group-13, the 14-dimethyl-,
11) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-13 (8H)-ketone, 19-chloro-15-ethyl-9,10,11,12,14,15,16, and 21-octahydro-22-methoxyl group-,
12) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-13 (8H)-ketone, 19-chloro-9,10,11,12,14,15,16, and 21-octahydro-22-methoxyl group-14, the 15-dimethyl-.
Another organizes special chemical compound:
-X wherein
1The formula of representative-O-(I) chemical compound;
-X wherein
1Representative-NR
11-, particularly-formula (I) chemical compound of NH-;
-R wherein
1Formula (I) chemical compound for fluorine, chlorine or bromine;
-R wherein
2Formula (I) chemical compound for fluorine, chlorine or bromine;
-R wherein
2Be Het
1, particularly optional by the formula of methyl substituted thiazolyl (I) chemical compound;
-R wherein
2Be C
2-6Alkynyl-, the formula of acetenyl (I) chemical compound particularly;
-R wherein
2Be Ar
5, formula (I) chemical compound of the particularly optional phenyl that is replaced by cyano group;
-R wherein
4Representation methoxy, and this methoxyl group is 7 formula (I) chemical compound in formula (I) structure;
-R wherein
4Representative is selected from C
1-4Alkoxyl or Het
2The C that replaces of substituent group
1-4Alkoxyl, particularly formula (I) chemical compound of the propoxyl group that is replaced by morpholinyl;
-R wherein
12Be hydrogen or C
1-4Alkyl-, especially methyl or R wherein
12Be C
1-4Formula (I) chemical compound of alkyl-oxygen base-carbonyl, the particularly tert-butyl group-oxygen base-carbonyl
-Het wherein
2Representative is by C
1-4Formula (I) chemical compound of the optional morpholinyl that replaces of alkyl, preferred morpholine links to each other with formula (I) chemical compound residue by nitrogen-atoms;
-wherein the Het3 representative is by formula (I) chemical compound of the optional morpholinyl that replaces of C1-4 alkyl, and preferred morpholinyl links to each other with formula (I) chemical compound residue by nitrogen-atoms;
-Het wherein
12Representative is by C
1-4Optional morpholinyl formula (I) chemical compound that replaces of alkyl, preferred morpholinyl links to each other with formula (I) chemical compound residue by nitrogen-atoms.
In the further embodiment of the present invention, X
2Substituent group is at 2 ' position, R
1Substituent group is represented hydrogen or halogen and 4 ' position, R
2Substituent group is represented halogen and 5 ' position, R
3Substituent group is at 2 and R
4Substituent group is at 7 of formula (I) structural formula.In addition, X
2Substituent group is at 3 ' position, R
1Substituent group is represented hydrogen or halogen and 4 ' position, R
1Substituent group is represented hydrogen or halogen and at 4 ', R
2Substituent group is represented halogen and 5 ' position, R
3Substituent group is at 2 and R
4Substituent group is at 7 of formula (I) structural formula.
According to another embodiment of the invention, formula (I) chemical compound is to be selected from:
Chemical compound of the present invention can by any organic chemistry filed technical staff general several standard synthetic methods prepare, and example is described in the following list of references: " Heterocyclic Compounds "-Vol.24 (part4) p 261-304Fused pyrimidines, Wiley-Interscience; Chem.Pharm.Bull., Vol 41 (2) 362-368 (1993); J.Chem.Soc., Perkin Trans.1,2001,130-137.
Y
1And Y
2The independent separately C that represents
1-5Alkyl, C
1-6Alkyl, CO-C
1-6Alkyl, CO-C
1-5Alkyl, Het
22-CH
2-CO-, CO-CR
16R
17-NH-, CR
18R
19-CO-, CH
2-CO-NH-C
1-3Alkyl-,-C
1-2Alkyl-NR
21-CH
2-CO-or CO-C
1-3Alkyl-NH-
X
3And X
4The functional group of the optional protection of representative, for example: firsts and seconds amine, hydroxyl, hydrogen or halogen (Cl, Br, I), itself and the Y that links to each other separately
1And Y
2Substituent group is together through reaction, the defined bivalence Y base of production (I).
Further enumerate as the test portion in the description, the special group chemical compound of formula (I) chemical compound is-X
1After this-representative-O-is called formula (I ') chemical compound, and it uses following synthetic schemes preparation usually.Chemical compound of the present invention can be from known 6-acetyl group oxygen base-4-chloro-7-methoxyl group quinazoline (II ') or from 6-acetyl group oxygen base-7-benzyl oxygen base-4-chloro-quinazoline (II
a) beginning preparation, its veratric acid that can get from commercialization respectively (veratric acid) and vanillic acid prepare.
The latter's chemical compound and the aniline that suitably replaces (the III ') coupling under standard conditions, for example, in propanol, under the intensification of 40-100 ℃ of scope, stirred 3-12 hour, can be successively according to the aniline of the prepared in reaction of Fig. 4-8, provide midbody compound (IV ', IV
a) (scheme 1).
Scheme 1
V=hydrogen or protecting group are as methyl carbonyl, the tert-butyl group, methyl, ethyl, benzyl or trialkylsilkl
R
23Represent Ar
3, Ar
4-C
1-4Alkyl, C
1-4Alkyl, optional by Het
12The C that replaces
2-6Thiazolinyl, or R
23Representative is by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl, hydroxyl, halogen, Het
2, NR
7R
8, NR
9R
10-carbonyl or Het
3The C that the substituent group of-carbonyl replaces
1-4Alkyl, wherein X
2, Ar
3, Ar
4, Het
12, Het
2, R
1, R
2, R
7, R
8, R
9, R
10, and Het
3As formula (I) chemical compound is defined
Formula (IV '-IVa) protection of intermediate is as T.W.Greene and P.G.M.Wuts; the third edition; blocking group (protective Groups in OrganicSynthesis) in the described organic synthesis in 1998; continue with the ring closure under the Mitsunobu condition, the generation target compound (I '-I '
a).(scheme 2-is V and R wherein
16Such as before this definition)
Scheme 2
In addition, Y representative-C wherein
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-NH-,-C
1-6Alkyl-CO-,-C
1-3Alkyl-NH-CO-Het
20-,-Het
22-CH
2-CO-NH-C
1-3Alkyl-,-C
1-2Alkyl-NH-CO-CR
16R
17-NH-,-C
1-2Alkyl-CO-NH-CR
18R
19-CO-,-C
1-2Alkyl-CO-NR
20-C
1-3Alkyl-CO-,-C
1-2Alkyl-NR
21-CH
2-CO-NH-C
1-3Alkyl or-NR
22-CO-C
1-3The formula of alkyl-NH (I '
b) chemical compound, be to use following synthetic schemes preparation.Formula (IV
b) intermediate is preparation as previously mentioned.Under standard conditions, use suitable ammonification alcohol deprotection and form corresponding ether subsequently, formula (XXVIII) intermediate is provided.Deprotection then ring is closed, provide the target formula (I '
b) chemical compound.
Scheme 3
V=hydrogen or protecting group as methyl carbonyl, the tert-butyl group, methyl, ethyl, benzyl or trialkylsilkl, or are the resin that links to each other with described molecule remainder under the solid state chemistry situation.
R
23Represent Ar
3, Ar
4-C
1-4Alkyl, C
1-4Alkyl, optional by Het
12The C that replaces
2-6Thiazolinyl, or R
23Representative is by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl, hydroxyl, halogen, Het
2, NR
7R
8, NR
9R
10-carbonyl or Het
3The C that the substituent group of-carbonyl replaces
1-4Alkyl, wherein X
2, Ar
3, Ar
4, Het
12, Het
2, R
1, R
2, R
7, R
8, R
9, R
10, and Het
3As formula (I) chemical compound is defined.
Y
1And Y
2The independent separately C that represents
1-5Alkyl, C
1-6Alkyl, CO-C
1-6Alkyl, CO-C
1-5Alkyl, Het
22-CH
2-CO-, CO-CR
16R
17-NH-, CR
18R
19-CO-, CH
2-CO-NH-C
1-3Alkyl-,-C
1-2Alkyl-NR
21-CH
2-CO-or CO-C
1-3Alkyl-NH-.
Be used for formula (I '
b) the synthetic more particular instance of chemical compound is provided among the reaction scheme 9-12.
To wherein-X
1The chemical compound of representative-O-, the suitably formula (III that replaces
a) aniline is usually from commercially available nitro-phenols (X) and α, ω-protected halogenation alcohols (XI), prepares under alkali condition, in the reaction of atent solvent, for example, uses dimethyl acetylamide (DMA), at K
2CO
3Exist down.Nitro-the phenyl derivatives of gained (XII) is reduced according to standard conditions subsequently, for example: use ferrum/acetic acid, production (III
a) the phenyl amines (scheme 4) of replacement.
Scheme 4
X represents halogen such as chlorine, bromine and iodine.
V represents hydrogen or protecting group such as methyl carbonyl.
X wherein
2Representative-NR
12-C
1-2Alkyl-chemical compound, usually reductive amination is carried out in alcohols (XIV) preparation that replaces from commercially available 2-nitro-benzaldehyde class (XIII) and amine under standard conditions, for example, in ethanol, use NaBH as solvent
4Reach titanium isopropoxide (iv) as Reducing agent, the nitro of production in first step (XV)-benzylamine class.
Next step, the one-level free alcohol uses step known in the art protected, for example, use and acetic anhydride, the esterification in the presence of pyridine.
Therefore, the formula that is obtained (XVI) intermediate by follow-up reduction, for example, uses hydrogenesis (H according to standard conditions
2, Pt/C, thiophene, MeOH) or stannic chloride (II) (SnCl
2, H
2O, EtOH), production (III
b) substituted phenyl amines (scheme 5).
Scheme 5
V represents protecting group such as methyl carbonyl.
Use aforesaid method, with two selective forms, 4-chloro-2-nitrobenzaldehyde is converted to the formula (III of suitable replacement
b) aniline.In first method (scheme 5a), the suitable formula (III that replaces
b) aniline is to obtain with one-level aminoacid reductive amination 4-chloro-2-nitrobenzaldehyde.
The methanol solution of 10mmol aldehyde 1,20mmol aminoacid 2,19mmolKF, 1mL4% thiophene (in DIPE) and 1g Pt/C (slurry in THF or MeOH), under 1 atmospheric pressure hydrogen, 50 ℃ stir down (scheme 5a).After consuming 4 equivalent hydrogen (generally after 48 hours), reactant mixture is filtered, and adds 3 normal Boc acid anhydrides.Next step, solution at room temperature is stirred 1-3 hour (LCMS monitoring), adds the ammonia of excessive 6N in MeOH then, and stirs and continue 1 hour to consume the reaction of excessive Boc acid anhydride.At last, evaporating liquid is to doing (observing the distillation of t-butyl carbamate), and gained through the N-benzyl amino acid 4 of Boc-protection with the HPLC purification.When R ' is not equal to hydrogen, is observed through the aniline 5 of Boc-protection and is primary product.In the case, method B can be used to obtain the aniline of type 4 (vide infra).
Scheme 5a.a) 1 atmospheric pressure H
2, Pt/C, KF, thiophene, methanol, 50 ℃, 1-2 days b) Boc
2O, methanol, room temperature, 1-3 hour.
Second kind obtains the suitably formula (III of replacement
b) method of aniline, be firsts and seconds aminoacid, aminoacid hydrogen chlorate, N-methacrylic amine and methylamino acetaldehyde dimethyl-acetal and 4-chloro-2-nitrobenzaldehyde 1 and 4-chloro-3-fluoro-2-nitrobenzaldehyde 6 (schemes 5
b) carry out reductive amination.Total recovery changes between 13-100%.
In containing the dichloromethane solution (suspension) of 5mmol amine 7,5mmol aldehyde 1 or 6,30mL adds the tert-butoxy titanium (IV) of 5mmol and the DIPEA of 5mmol (when 7 are the hydrogen chlorate)
1(
1Have titanium isopropoxide, in case 7 when being the aminoacid tert-butyl ester, observe the ester conversion reaction).Described to be reflected at its heat release in this case beyond expectation, and heating may cause this side reaction.After stirring 15 minutes, add the sodium triacetoxy borohydride of 12mmol and continue to stir 1-5 hour (LCMS monitoring).Next step, the saturated NaHCO of this solution and 10-20mL
3-solution effects and continuation are stirred and are stopped until bubbling.The gained milk filters by the P3 fritted glass filter, and with washed with dichloromethane.Organic layer is separated, and the water dichloromethane extraction.Merge organic layer with magnesium sulfate (or potassium carbonate) drying, filtration and evaporating solvent obtain crude product N-benzylamine 8, and its purity is enough to be used in the next step usually.
When R was hydrogen, secondary amine can Boc or Cbz radical protection, adds 3 normal Boc acid anhydrides or benzyl chloroformate and 3 normal DIPEA respectively in the dichloromethane solution of amine, and when at room temperature stirring 16-24.When R ' was huge, Boc protected normally slowly, and needed to prolong the return time in dichloromethane.Next step, excessive protective agent is by adding excessive 6 equivalent concentration ammonia among the MeOH, and at room temperature stirring consumption in 1 hour.After solvent was evaporated, products obtained therefrom was with RP HPLC purification.
1:X=H 7: one-level or secondary aminoacid are (if salt R_=Boc or Cbz R are H
The 6:X=F hydrochlorate) if, N-methacrylic R_=alkyl R is alkyl
Amine, methylamino acetyl group aldehyde 8
The base dimethyl-acetal
Scheme 5b.a) NaBH (OAC)
3, TI (OtBu) 4, (DIPEA when 7 be hydrochlorate), room temperature, 1-2 hour B) Boc
2O or CbzCl, DIPEA, CH
2Cl
2, room temperature to reflux, 16-24 hour.C) H
2, Pt/C, thiophene, methanol (or ethyl acetate or THF), 24-28 hour d) SnCl
2Water, ethanol, 50 ℃, 1.5 hours.
Therefore, the benzylamine 8 that is obtained passes through hydrogenolysis reducing subsequently, or under the double bond containing situation of R ' bag, with stannic chloride (II) reduction.
Nitroreduction by hydrogenolysis
Gained benzylamine 8 is dissolved in the methanol (or ethyl acetate or THF), adds 1gPt/C (slurry in EtOAc) and thiophene (1mL, 4% in DIPE), in 1atm hydrogen, 50 ℃ of following (scheme 3, step a) of stirring.After consuming 3 normal hydrogen, the gained mixture filters on dicalite, and removing desolvates obtains crude product aniline 9, depends on character and purity, and it can crystallization from heptane, be directly used in the next step through the HPLC purification or with crude product.
Nitroreduction by stannic chloride (II)
When R ' comprises two keys and adopts this method therefore can not be with hydrogenolysis reducing the time.
In the alcoholic solution of crude product nitro compound 8, add 5 normal stannic chloride (II) dihydrate (scheme 3, step b).This mixture stirred 1.5 hours at 50 ℃.Then, this solution is cooled to RT, adds saturated sodium bicarbonate and dichloromethane (generation bubble).The gained milk filters through sintered filter at P3.Tell organic layer, use the Anhydrous potassium carbonate drying, filter and remove to desolvate and obtain crude product aniline 9, it typically is enough pure to be used for the next step.
For X
2The chemical compound of representative-O-N=CH-, the suitably formula (III that replaces
c) aniline is usually according to reaction scheme 6 preparation.
In the first step, adopting as known in the art, the azanol condensation reaction is converted into corresponding oxime (XVIII) with known 2-nitro-benzaldehyde (XIII).
Next step reacts the oxime of described formula XVII and halogenated alkyl acetates under alkali condition, for example, use the K in DMSO
2CO
3, reduce nitro subsequently, for example, with hydrogenolysis (H
2, Pt/C, thiophene, MeOH) or stannic chloride (II) (SnCl
2Water, EtOH) so that the formula (III of suitable replacement to be provided
C) aniline.
Scheme 6
X represents halogen such as chlorine, bromine or iodine
For X
2Represent connecting key and Y representative-C
1-6The chemical compound of alkyl-NH-CO-, the suitably formula (III that replaces
d) aniline is usually according to reaction scheme 7 preparation.
In the first step, known 2-nitro-benzoic acid (XX) under known conditions, by the intermediate of an amidatioon accepted way of doing sth (XXII), for example, the hydroxylated amine of employing formula (XXI), 1,1 '-carbonyl is two-the 1H-imidazoles exists down, dropwise is added to CH
2Cl
2In (XX) mixture in.
Then, known program is protected in the one-level free alcohol employing field, for example, adopts and carry out esterification with acetic anhydride in the presence of pyridine.
Therefore, the formula that is obtained (XXIII) intermediate is reduced according to standard conditions subsequently, for example, adopts hydrogenolysis (H
2, Pt/C, thiophene, MeOH) or stannic chloride (II) (SnCl
2, H
2O, EtOH) formula (III that obtains replacing
d) aniline.
Scheme 7
V represents protecting group such as methyl carbonyl
For X
2Represent the chemical compound of connecting key, suitably (the III that replaces
c) aniline is usually according to reaction scheme 8 preparation.
In the first step, known 2-nitro-benzaldehyde (XIII) for example, adopts that (XXIV) De phosphonium salt carries out the Wittig reaction and carries out alkenyl and obtain formula (XXV) intermediate with suitable formula under condition known in the art.
Then free carboxy acid's esterification is to carry out under standard conditions, and for example, under acid condition, formula (XXVI) intermediate is reduced, and obtains required formula (III with ethanol
e) substituted aniline.
Scheme 8
Y
3Represent C
1-7Alkyl
Wherein-X
1-Y-X
2Formula (I) chemical compound that comprises amine-amide joint, that is :-X
1-Y-X
2-representative-O-C
1-5Alkyl-NR
14-CO-C
1-5Alkyl-NR
12-C
1-2Alkyl-,-O-C
1-3Alkyl-NH-CO-Het
20-C
1-2Alkyl-or-C
1-6Alkyl-NH-CO-CH
2-Het
22,-CO-C
1-2Alkyl-NH-CO-CR
16R
17-NH-C
1-2Alkyl-, be to be according to reaction scheme 9 preparations under 1,2 or 4 the situation at m, or be to be according to reaction scheme 10 preparations under 3 the situation at m.
Scheme 9a.a) iPrOH, 80 ℃, 2-24h b) 6N NH
3/ MeOH, RT, 1h c) Br (CH
2)
mCH
2NHBoc (m=1,2,
4), Cs
2CO
3, DMF, RT spends the night
The chloro-quinazoline 10 (scheme 9a) of monovalent is added in the aqueous isopropanol of N-benzyl aminoacid 4 or 9 (square case 5e and 5b).The gained reactant liquor stirs at 80 ℃ and obtained 11 (LCMS monitorings) in 2-24 hour.Then, this mixture is cooled to RT and adds the methanolic ammonia solution of 6N.After stirring 1 hour, the gained solution evaporation is to doing.Crude product phenol 12 is dissolved among the dry DMF subsequently again, and when adding 5 normal cesium carbonates, stirs 1 hour under RT.Add 1-1.2 normal (to avoid alkylation) Boc-aminoalkyl bromine subsequently in the gained phenolic ester, the gained mixture stirs under RT and spends the night, be evaporated to dried, be dissolved in the dichloromethane again and through the dicalite filtration to remove cesium salt.Obtain crude product Boc-aminoalkyl phenol 13 at this.
Scheme 9b.a) 6N HCl, dioxane, 60 ℃, spend the night (R=Me, Et), or TFA/CH
2Cl
2/ TIS (90: 8: 2) is b (R=tBu)) HBTU (or PyBop), DIPEA, DMF, RT, 1h c) 48%HBr, RT, 1-2h.
As shown in scheme 9b, by with 13 1, (R=Me is Et) or at TFA/CH in 60 ℃ in the presence of 6N HCl for the 4-dioxane solution
2Cl
2Spend the night in RT (R=tBu) stirring under/TIS (90: 8: 2) exists, ester functional group is hydrolyzed subsequently, and the Boc group is removed.Be evaporated to do after, after gained amino acid/11 4 is dissolved among the exsiccant DMF again and adds 6 normal DIPEA, it be added drop-wise to contain 3 equivalent HBTU (or PyBOP)
2(
2PyBOP produces three (pyrrolidinyl) phosphine oxide, is difficult to usually separate from macro ring).HBTU produces tetramethylurea, is easier to remove.In the exsiccant DMF solution.Stirred this solution 1 hour under RT, evaporating solvent obtains crude product macrocycle molecule 15a subsequently, and it uses RP HPLC purification.Prepurification can be by being dissolved in CH with residue
2Cl
2In and with saturated sodium bicarbonate aqueous solution washing, dry and remove solvent on potassium carbonate then.From aniline 4 or 9 these results' that begin yield is 10-65%.
If the Cbz group exists, can be before purification by with crude product macro ring 15a (R " "=Cbz) be dissolved in 48% the HBr aqueous solution and and removed this group in 1-2 hour in room temperature (RT) stirring.With reactant mixture is concentrated and with after the quencher of solid carbonic acid potassium, the macro ring 15b of deprotection is by using CH
2Cl
2(adding methanol having under the solubility situation) extraction obtains, and similarly by RP HPLC purification.The yield of Cbz deprotection is measured by LCMS.
The chloro-quinazoline 10 of monovalent is added in the aqueous isopropanol of N-benzyl aminoacid 4 or 9 (scheme 10a).Gained solution stirs at 80 ℃ and obtained 11 in 2-24 hour.Then, this mixture is cooled to RT and adds the methanolic ammonia solution of 6N.After stirring 1 hour, solution is evaporated to dried.Crude product phenol 12 is dissolved among the exsiccant DMF subsequently again and adds 5 normal cesium carbonates, stirs 1 hour down in RT.The 4-brombutyl nitrile that adds 0.8 equivalent (to avoid alkylation) in the gained phenates, gained mixture stir in RT and spend the night, and are evaporated to driedly, are dissolved in the dichloromethane again, and filter to remove cesium salt on decalite.
Scheme 10a.a) iPrOH, 80 ℃, 2-24h b) 6N NH
3/ MeOH, RT, 1hc) Br (CH
2)
3CN, Cs
2CO
3, DMF, RT,
Spend the night
Crude product 16 is completely dried then, is dissolved in 6N ammonia/MeOH (to avoid dimerization) again, adds some thiophene solution (to avoid dechlorination) afterwards in DIPE, uses wet Raney Ni in 1 atmospheric pressure hydrogen, 14 ℃ of processing (scheme 10b) down.After consuming 2 equivalent hydrogen (generally after 16-24 hour), mixture filters on dicalite and concentrates, so that crude product amine 17 to be provided.Then by (R=Me Et) exists to stir down and spends the night and make ester functional group be hydrolyzed into 18 (and if R_=Boc, the Boc group is removed) at 6N HCl with 17 dioxane solution.Be evaporated to do after, gained amino acid/11 8 is dissolved among the exsiccant DMF again and adds 6 normal DIPEA, drips the solution of 3 equivalent HBTU (or PyBOP) in dry DMF.Stirred this solution 1 hour under RT, continuing obtains crude product macrocycle molecule 19 with evaporating solvent, and it is by RP HPLC purification.Prepurification can be by being dissolved in CH with residue
2C1
2In and wash with saturated sodium bicarbonate aqueous solution.Since this result's of 4 or 9 aniline yield is 4-30%.
Scheme 10b.a) H
2, RaNi, 6N NH
3/ MeOH, 14 ℃, 16-24h b) 6NHCl, dioxane, 60 ℃, c spends the night)
HBTU (or PyBop), DIPEA, DMF, RT, 1h.
Wherein-X
1-Y-X
2-comprise formula (I) chemical compound of amine-amine joint, that is :-X
1-Y-X
2-representative-O-C
1-5Alkyl-NR
13-C
1-5Alkyl-NR
12-C
1-2Alkyl is usually according to reaction scheme 11 preparations.
n＝1、2、4
(to n=3, the butyl nitrile can provide required amine)
Scheme 11.a) iPrOH, 80 ℃, 7-8h b) NH
3/ MeOH, 1hc) BrCH
2(CH
2)
nNHBoc (n=
1,2,4),
*Cs
2CO
3, DMF spends the night.
*Remove the situation of n=3, use Br (CH
2)
3CN
D) 6N HCl, dioxane, 60 ℃, 24h e) NaBH (OAc)
3, CH
2Cl
2, RT, 1h.
To 5-chloro-2-{[(2,2-dimethoxy-ethyl) (methyl) amino] methyl } in the aqueous isopropanol of aniline 20 or corresponding dioxolanes (via the preparation of the reductive amination among the scheme 5b), add the chloro-quinazoline 10 of monovalent.Gained solution stirs down at 80 ℃ and obtained 21 in 7-8 hour.Then, mixture is cooled to RT, and adds the 6N methanolic ammonia solution to remove deacetylate.Stir after 1 hour, solution is evaporated to dried.In crude product phenol 22, add 5 normal cesium carbonates subsequently, and after stirring 1 hour, add Boc-aminoalkyl bromine (1.0-1.2 equivalent) or 5-bromine butyronitrile (0.8 equivalent), the gained mixture is evaporate to dryness after RT stirred liquid subsequently, is dissolved in the dichloromethane again and filters on dicalite to remove cesium carbonate.The phenols 23 that the aminoalkyl that is protected replaces.The phenol of butyronitrile-replacement at first is hydrogenated to corresponding amine under the above-mentioned condition of mentioning.
Then the gained compound dissolution is in 6N HCl and dioxane, and the gained mixture is in 60 ℃ of stir abouts 24 hours (formation of imines 24 is observed in the LCMS monitoring) (scheme 11).After reacting completely, in the ice-cooled sodium bicarbonate solution of the careful impouring of gained mixture or be evaporated to dried (lentamente, can cause decomposing).Under first kind of situation, this imines is with dichloromethane extraction, and with after the potassium carbonate drying, is reduced to corresponding amine immediately by adding sodium triacetoxy borohydride.Under latter event, this oily residue is dissolved in the dichloromethane again and adds excessive sodium triacetoxy borohydride and obtains corresponding amine.After adding saturated sodium carbonate,, can pass through RP HPLC purification with also obtaining crude product macrocycle molecule 25 with potassium carbonate is dry behind the dichloromethane extraction except that after desolvating.
Formula (I '
b) chemical compound, wherein-X
1-Y-X
2Comprise an amide-amide joint, promptly-X
1-Y-X
2Representative-O-C
1-4Alkyl-CO-NH-CR
18R
19-CO-NR
12-C
1-2Alkyl-,-O-C
1-4Alkyl-CO-NR
20-C
1-3Alkyl-CO-NR
12-C
1-2Alkyl-, or-O-C
1-4Alkyl-CO-Het
20-CO-NR
12-C
1-2Alkyl-usually according to reaction scheme 12 preparations.
Scheme 12
n＝1、2
m＝0、2、3
W=C
1-3Alkyl, CR
18R
19Or be Het with the N that connects them
21
Reagent and condition: a) i) PL-DCC resin, HoBt, DCM/DMF, RT, 5h; Ii) polystyrene-methyl isocyanate, polystyrene ylmethyl (polystylmethyl) trimethyl ammonium bicarbonate, RT, 12h; B) i) chloro-quinazoline, iPrOH, 55 ℃, 3h; Ii) 7N NH
3/ MeOH, room temperature, 2h; C) ClCH
2(CH
2)
mCO
2CH
3, potassium carbonate; D) concentrated hydrochloric acid, water, dioxane, 60 degree, 12 hours; E) PyBOP, DIPEA, DMF, RT, 3h.
In this operation, the known condition employing field in, the aminoacid coupling of gained aniline 26 (the embodiment A 42d that sees below) and suitable amido protecting obtains the amide of formula 27.Subsequently under standard conditions with the chloro-quinazoline coupling, for example, in propanol, stirred 3-12 hour down from the intensification of 40-100 ℃ of scope, obtain formula 28 intermediate.With deprotection and cyclization after the suitable halogen acetate alkylation, adopt promptly that known condition forms amide in the field, obtain formula 30 chemical compounds.The deprotection of formula 28 intermediate can be as T.W.Greene and P.G.M.Wuts, the third edition, the finishing of blocking group (the Protective Groupsin Organic Synthesis) narration in the organic synthesis in 1998.
In addition, formula (I) chemical compound is by preparing corresponding alkene cyclization double decomposition (metathesis) (scheme 13).This reaction is particularly useful for formula (I) chemical compound, wherein Y representative-C
3-9Thiazolinyl-,-C
3-9Alkyl, optional by amino, single-or two (C
1-4Alkyl) amino or C
1-4Alkoxycarbonyl amino-replacement-C
3-7Alkyl-CO-NH, or Y representative is optional by amino, single-or two (C
1-4Alkyl) amino or C
1-4Alkoxycarbonyl amino-replacement-C
3-7Thiazolinyl-CO-NH, hereinafter referred to as formula (I '
C) chemical compound.
In the first step, formula (III
e) aniline and 4-hydrogen quinazoline (II
b) coupling under standard conditions, for example, in propanol, under the intensification of 40-100 ℃ of scope, stirring 3-12 hour.Formula (IV
c) deprotection of intermediate can be as T.W.Greene and P.G.M.Wuts; the third edition; finishing of blocking group (Protective Groups in Organic Synthesis) narration in the organic synthesis in 1998; subsequently with suitable alkyl bromide (XXXII) under condition known in the art, as at Cs
2CO
3At reaction-inert solvent such as N, in the dinethylformamide (DMF), carry out alkylation under existing, obtain formula (XXXIII) alkene in stirred overnight at room temperature.Encircle closed double decomposition and be Advanced Organic Chemistry (the Advanced Organic Chemistry) third edition as J.March, 1985, the narration of 1036-1039 page or leaf, obtain formula (I '
c) for compound, it can adopt, and known method is optional in the field is reduced, for example, at H
2-air-flow, Pt/C exist down, at room temperature stirred 3-10 hour as solvent with oxolane (THF)/methanol.Formula (III
e) the similar synthetic method of aniline by synthesis type 27 (such scheme 12) amide, synthetic by the corresponding amine of acyl groupization.
Scheme 13
R
23Represent Ar
3, Ar
4-C
1-4Alkyl, C
1-4Alkyl, optional by Het
12The C that replaces
2-6Thiazolinyl, or R
23Representative is by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl, hydroxyl, halogen, Het
2, NR
7R
8, NR
9R
10-carbonyl or Het
3The C that the substituent group of-carbonyl replaces
1-4Alkyl, wherein Ar
3, Ar
4, Het
12, Het
2, R
7, R
8, R
9, R
10, X
2, R
1, R
2, and Het
3As formula (I) chemical compound is defined.
Y
3Represent C
1-5Alkyl, CO-C
1-5Alkyl or CO-CR
16R
17-NH-or the amino list of optional quilt-or two (C
1-4Alkyl) amino-or C
1-4The alkoxy amino carbonyl substituted
M represents 1,2,3 or 4
When necessary or when needing, any one or more following additional step can any order carry out:
(i) remove any surplus blocking group;
(ii), transform into further formula (I) chemical compound or its protected form with formula (I) chemical compound or its protected form;
(iii), transform into N-oxide, salt, quaternary ammonium or solvate or its protected form of formula (I) chemical compound with formula (I) chemical compound or its protected form;
(iv) N-oxide, salt, quaternary ammonium or solvate or its protected form with formula (I) chemical compound transforms into formula (I) chemical compound or its protected form;
(v) N-oxide, pharmaceutically acceptable addition salt, quaternary ammonium or solvate or its protected form that N-oxide, salt, quaternary ammonium or solvate or its protected form of formula (I) chemical compound transformed into formula (I) chemical compound;
(vi) wherein gained formula (I) chemical compound is (R) and (S) enantiomeric mixture, splits this mixture, to obtain desired enantiomer.
Formula (I) chemical compound, its N-oxide, addition of salts, quaternary ammonium and form of three-dimensional chemical isomer can be according to the present invention, use step known in the art and be converted to further chemical compound.
Those skilled in that art should figure out: in the said method, the functional group of midbody compound may need protected base sealing.
Want the functional group that protects, comprise hydroxyl, amino and carboxylic acid.The suitable blocking group of hydroxyl comprises trialkylsilkl group (as t-butyldimethylsilyl, t-butyldiphenylsilyl or TMS), phenyl and THP trtrahydropyranyl.Suitable amido protecting group comprises tert-butoxycarbonyl or benzyloxycarbonyl group.The suitable blocking group of carboxylic acid comprise C (
1-6) alkyl or benzyl ester.
The protection of functional group and deprotection can take place before or after a reactions steps.
In addition, the N-atom in formula (I) chemical compound can adopt CH by known method in the field
3-I methylates in suitable solvent such as 2-acetone, oxolane or dimethyl formamide.
Formula (I) chemical compound also can transform mutually by the mentioned functional group's method for transformation of some examples known in the field, hereinafter.
Formula (I) chemical compound also can be converted into corresponding N-oxide form by the known method that trivalent nitrogen is converted into its N-oxide form in the field.Described N-oxidation reaction usually can be by reacting with formula (I) initiation material and 3-phenyl-2-(benzenesulfonyl) oxa-aziridine (oxaziridine) or with a kind of suitable organic or inorganic peroxide.Suitable inorganic peroxide comprises, and for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxide are as sodium peroxide, potassium peroxide; Suitable organic peroxide can comprise peroxy acid, as the benzoyl hydroperoxide of benzoyl hydroperoxide or halogen replacement, as the 3-chloroperoxybenzoic acid; The peroxide bond alkanoic acid is as peracetic acid; Alkyl peroxide is as tert-butyl hydroperoxide.Suitable solvent is, for example, and the mixture of similar alcohol, hydro carbons such as toluene, ketone such as 2-butanone, halogenated hydrocarbon such as dichloromethane such as water, lower alcohol such as ethanol and this kind solvent.
The pure stereoisomer form of formula (I) chemical compound can obtain by the known method of application.Diastereomer can pass through physical method, as selective freezing and chromatographic process, distributes acquisitions such as liquid chromatography as adverse current.
Formulas more of the present invention (I) chemical compound and some intermediate can comprise asymmetric carbon atom.The pure three-dimensional chemical isomer of described chemical compound and described intermediate can obtain by known method in the application.For example, diastereomer can pass through physical method, as selective crystallization or chromatographic technique, distributes as adverse current, and liquid chromatography and similar approach are separated.Enantiomer can obtain from racemic mixture, be at first by described racemic mixture being converted into the salt or the chemical compound of its diastereomer, split the salt or the chemical compound of described diastereomer then by for example selective crystallization or chromatographic technique such as liquid chromatograph and similar approach physics with suitable resolving agent such as chiral acid effect; At last described isolating diastereomeric salt or chemical compound are converted into corresponding enantiomer.When if intermediary reaction is stereospecificity, pure form of three-dimensional chemical isomer can also obtain from the pure spatial chemistry simplified form of appropriate intermediate and starting material.
The method of another separate type (I) chemical compound and intermediate mapping form relates to liquid chromatography, particularly adopts the liquid chromatography of chiral stationary phase.
Use some intermediate and initiation material in the above mentioned course of reaction and be known compound and can commercially obtain or can be according to known method preparation in the field.Yet, in formula (I) chemical compound synthetic, the present invention further provides:
A) formula (III) intermediate and pharmaceutically acceptable addition salt and form of three-dimensional chemical isomer,
Wherein
V represents hydrogen or a blocking group, is preferably selected from methyl carbonyl, the tert-butyl group, methyl, ethyl, benzyl or trialkylsilkl;
Y representative-C
3-9Alkyl-,-C
3-9Thiazolinyl-, optional by amino, single-or two (C
1-4Alkyl) amino or C
1-4Alkoxycarbonyl amino-replacement-C
3-7Thiazolinyl-CO-NH ,-C
1-5Alkyl-oxygen base-C
1-5Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-, 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-,-C
1-3Alkyl-NH-CS-Het
20,-C
1-3Alkyl-NH-CO-Het
20,-C
1-2Alkyl-CO-Het
21-CO-,-Het
22-CH
2-CO-NH-C
1-3Alkyl-CO-NFH-C
1-6Alkyl-,-NH-CO-C
1-6Alkyl-,-CO-C
1-7Alkyl-,-C
1-7Alkyl-CO-,-C
1-6Alkyl-CO-C
1-6Alkyl ,-CO-Het
20,-C
1-2Alkyl-NH-CO-CR
16R
17-NH-,-C
1-2Alkyl-CO-NH-CR
18R
19-CO-,-C
1-2Alkyl-CO-NR
20-C
1-3Alkyl-CO-,-C
1-2Alkyl-NR
21-CH
2-CO-NH-C
1-3Alkyl-or-NR
22-CO-C
1-3Alkyl-NH-;
X
2Represent connecting 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
1Represent hydrogen, cyano group, halogen, hydroxyl, formoxyl, C
1-6Alkoxyl-, C
1-6Alkyl-, halogen-phenyl-carbonylamino-,
The C that is replaced by halogen
1-6Alkoxyl-,
By one or possibility two or a plurality of C that is selected from the substituent group replacement of hydroxyl or halogen
1-4Alkyl;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group, Het
16-carbonyl, C
1-4Alkoxy carbonyl-, C
1-4Alkyl-carbonyl-, amino carbonyl-, single-or two (C
1-4Alkyl) amino carbonyl-, Het
1, formoxyl, C
1-4Alkyl-,-C
2-6Alkynyl-, C
3-6Cycloalkyl-, C
3-6Cycloalkyloxy-, C
1-6Alkoxyl-, Ar
1-oxygen base-, dihydroxy borine, the C that replaced by halogen
1-6Alkoxyl-,
By one or possibility two or a plurality of halogen, hydroxyl or NR of being selected from
5R
6The C that replaces of substituent group
1-4Alkyl;
C
1-4Alkyl-carbonyl-, wherein said C
1-4Alkyl is optional by one or possibility two or a plurality of hydroxyl or C of being selected from
1-4Alkyl-oxygen base-substituent group replace;
R
5And R
6Independently be selected from hydrogen or C separately
1-4Alkyl;
R
12Represent hydrogen, C
1-4Alkyl, C
1-4Alkyl-oxygen base-carbonyl-, Het
18-C
1-4Alkyl-, phenyl-C
1-4Alkyl-oxygen base-carbonyl-, Het
17, optional by Het
19-C
1-4The C of alkyl amino-carbonyl-replacement
2-4Alkenyl carbonyl-, C
2-4The thiazolinyl sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
13Represent hydrogen, C
1-4Alkyl, Het
13, Het
14-C
1-4Alkyl or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
14And R
15Independently be selected from hydrogen, C separately
1-4Alkyl, optional by phenyl, indyl, methyl mercapto, hydroxyl, mercaptan, hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals replacement;
R
18And R
19Independent separately hydrogen or the C of representing
1-4Alkyl, optional by hydroxyl or C
1-4Alkoxyl replaces;
R
21Represent hydrogen, C
1-4Alkyl, Het
23-C
1-4Alkyl-carbonyl-or R
21Represent single-or two (C
1-4Alkyl) amino-C
1-4Alkyl-carbonyl-, optional by hydroxyl, pyrimidine radicals, dimethyl amine or C
1-4Alkoxyl replaces;
Het
1Represent heterocycle, described heterocycle is selected from piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, 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-list-or two (C
1-4Alkyl) amino-or amino carbonyl-replacement;
Het
13Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-, polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
14Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4The substituent group of alkyl replaces;
Het
15Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4The substituent group of alkyl replaces;
Het
16Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-two oxa-bora Pentamethylene. base or piperidyls, and wherein said heterocycle is optional to be selected from C by one or more
1-4The substituent group of alkyl replaces;
Het
17Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
18And Het
19Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4The substituent group of alkyl replaces;
Het
20, Het
21And Het
22Independently represent heterocycle separately, be selected from pyrrolidinyl, 2-Pyrrolidone base, piperazinyl or piperidyl, optional by one or possibility two or a plurality of hydroxyl, C of being selected from
1-4Alkyl-, hydroxyl-C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
23Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Ar
1, Ar
2, Ar
3, Ar
4And Ar
5The independent separately phenyl of representing, optional by cyano group, C
1-4Alkyl sulphonyl-, C
1-4Alkyl sulfonyl-amino-, amino-sulfonyl amino-, hydroxyl-C
1-4Alkyl, amino-sulfonyl-, hydroxyl, C
1-4Alkoxyl-or C
1-4Alkyl replaces;
In one embodiment, formula (III) intermediate is made up of the formula that wherein adds one or more following restriction (III) chemical compound;
V represents hydrogen or a blocking group, is preferably and is selected from methyl carbonyl, tert-butyl, methyl, ethyl, benzyl or trialkylsilkl;
Y representative-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-,-C
1-7Alkyl-CO-,-C
1-6Alkyl-CO-C
1-6Alkyl-;
X
2Represent connecting 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
1Represent hydrogen, cyano group, halogen, hydroxyl, formoxyl, C
1-6Alkoxyl-, C
1-6Alkyl-, the C that replaced by halogen
1-6Alkoxyl-, by one or may two or the C that replaces of a plurality of substituent group that is selected from hydroxyl or halogen
1-4Alkyl;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group, Het
16-carbonyl, C
1-4Alkoxy carbonyl-, C
1-4Alkyl-carbonyl-, amino carbonyl-, single-or two (C
1-4Alkyl) amino carbonyl-, Het
1, formoxyl, C
1-4Alkyl-,-C
2-6Alkynyl-, C
3-6Cycloalkyl-, C
3-6Cycloalkyloxy-, C
1-6Alkoxyl-, Ar
5, Ar
1-oxygen base-, dihydroxy borine, the C that replaced by halogen
1-6Alkoxyl-,
By one or possibility two or a plurality of halogen, hydroxyl or NR of being selected from
5R
6The C that replaces of substituent group
1-4Alkyl;
C
1-4Alkyl-carbonyl-, wherein said C
1-4Alkyl is optional by one or possibility two or a plurality of hydroxyl or C of being selected from
1-4Alkyl-oxygen base-substituent group replace;
R
5And R
6Independently be selected from C separately
1-4Alkyl;
R
12Represent hydrogen, C
1-4Alkyl, C
1-4Alkyl-oxygen base-carbonyl-, phenyl-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 sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-
Or it is optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
13Represent hydrogen, C
1-4Alkyl, Het
13, Het
14-C
1-4Alkyl or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
14And R
15Independently be selected from hydrogen, C separately
1-4Alkyl, Het
15-C
1-4Alkyl-or C
1-4Alkoxy C
1-4Alkyl-;
Het
1Represent heterocycle, described heterocycle is selected from piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, 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-list-or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
Het
13Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-, polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
14Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4The substituent group of alkyl replaces;
Het
15Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4The substituent group of alkyl replaces;
Het
16Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-two oxa-bora Pentamethylene. base or piperidyls, and wherein said heterocycle is optional to be selected from C by one or more
1-4The substituent group of alkyl replaces; And
Het
17Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
18And Het
19Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4The substituent group of alkyl replaces;
Ar
1, Ar
2, Ar
3, Ar
4And Ar
5The independent separately phenyl of representing, optional by cyano group, C
1-4Alkyl sulphonyl-, C
1-4Alkyl sulfonyl-amino-, amino-sulfonyl amino-, hydroxyl-C
1-4Alkyl, amino-sulfonyl-, hydroxyl, C
1-4Alkoxyl-or C
1-4Alkyl replaces;
Particularly wherein add formula (III) intermediate of the restriction that one or more is following:
I) V represents hydrogen, methyl or ethyl;
Ii) Y representative-C
3-9Alkyl-,-C
1-5Alkyl-oxygen base-C
1-5Alkyl-,-C
1-5Alkyl-NR
13-C
1-5Alkyl-, C
1-6Alkyl-NH-CO-;
Iii) Y representative-C
1-5Alkyl-oxygen base-C
1-5Alkyl-, C
1-2Alkyl-CO-Het
21-CO-,-CO-C
1-7Alkyl-or CO-Het
20
Iv) X
2Represent connecting key, O ,-O-C
1-2Alkyl-, NR
12,-NR
12-C
1-2Alkyl-,-CH
2-,-O-N=CH-or C
1-2Alkyl-;
V) X
2Representative-NR
12-C
1-2Alkyl-or-C
1-2Alkyl;
Vi) R
1Represent hydrogen, cyano group, halogen or hydroxyl, be preferably halogen;
Vii) R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-, C
1-4Alkoxy carbonyl-, Het
16-carbonyl, C
1-4Alkyl-, C
2-6Alkynyl-, Ar
5Or Het
1Be preferably halogen;
Viii) R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-or Het
1Especially, R
2Represent hydrogen, cyano group, halogen, hydroxyl or Ar
5
Ix) R
12Represent hydrogen, C
1-4Alkyl or C
1-4Alkoxy carbonyl-or phenyl
1-4Alkyl-oxygen base-carbonyl-;
X) R
13Represent Het
14-C
1-4Alkyl, particularly morpholinyl-C
1-4Alkyl;
Xi) Het
1Represent a thiazolyl, optional by amino, C
1-4Alkyl, hydroxyl-C
1-4Alkyl-, phenyl, phenyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-list-or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
Xii) Het
16Represent heterocycle, described heterocycle is selected from piperidyl or pyrrolidinyl;
Xiii) Het
20Represent piperidines, piperazine, pyrrolidinyl or 2-Pyrrolidone base, wherein said Het
20Choose wantonly and replaced by hydroxyl.
B) formula (XXX) intermediate and pharmaceutically acceptable addition salt and stereoisomeric forms in any ratio:
Wherein,
Y
1And Y
2The independent separately C that represents
1-5Alkyl, C
1-6Alkyl, CO-C
1-6Alkyl, CO-C
1-5Alkyl, Het
22-CH
2-CO, CO-CR
16R
17-NH-, Het
20, CR
18R
19-CO-, CH
2-CO-NH-C
1-3Alkyl-,-C
1-2Alkyl-NR
21-CH
2-CO-or CO-C
1-3Alkyl-NH-;
X
1Represent connecting key, O ,-O-C
1-2Alkyl-, CO ,-CO-C
1-2Alkyl-,-NR
11,-NR
11-C
1-2Alkyl-,-CH
2-,-O-N=CH-or C
1-2Alkyl-;
X
2Represent connecting 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
1Represent hydrogen, cyano group, halogen, hydroxyl, formoxyl, C
1-6Alkoxyl-, C
1-6Alkyl-, halogen-phenyl-carbonylamino-, the C that replaced by halogen
1-6Alkoxyl-,
By one or possibility two or a plurality of C that is selected from the substituent group replacement of hydroxyl or halogen
1-4Alkyl;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group, Het
16-carbonyl, C
1-4Alkoxy carbonyl-, C
1-4Alkyl-carbonyl-, amino carbonyl-, single-or two (C
1-4Alkyl) amino carbonyl-, Het
1, formoxyl, C
1-4Alkyl-,-C
2-6Alkynyl-, C
3-6Cycloalkyl-, C
3-6Cycloalkyloxy-, C
1-6Alkoxyl-, Ar
5, Ar
1-oxygen base-, dihydroxy borine, the C that replaced by halogen
1-6Alkoxyl-,
By one or possibility two or a plurality of halogen, hydroxyl or NR of being selected from
5R
6The C that replaces of substituent group
1-4Alkyl;
C
1-4Alkyl-carbonyl-, wherein said C
1-4Alkyl is optional by one or possibility two or a plurality of hydroxyl or C of being selected from
1-4Alkyl-oxygen base-substituent group replace;
R
3Represent hydrogen, C
1-4Alkyl or be selected from halogen, C by one or more
1-4Alkoxyl-, amino-, single-or two (C
1-4Alkyl) amino, C
1-4Alkyl-sulfonyl-or phenyl-the C that replaces of substituent group
1-4Alkyl;
R
5And R
6Independently be selected from hydrogen or C separately
1-4Alkyl;
R
7And R
8Independently be selected from hydrogen, C separately
1-4Alkyl, Het
8, amino-sulfonyl-, single-or two (C
1-4Alkyl)-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-, polyhydroxy-C
1-4Alkyl-, Het
11-C
1-4Alkyl-or Ar
2-C
1-4Alkyl-;
R
9And R
10Independently be selected from hydrogen, C separately
1-4Alkyl, C
3-6Cycloalkyl, Het
4, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-;
R
11Represent 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 sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
12Represent 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 sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
16And R
17Independent separately hydrogen or the optional C that is replaced by phenyl, indyl, methyl mercapto, hydroxyl, mercaptan, hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals of representing
1-4The C that alkyl replaces
1-4Alkyl;
R
18And R
19Independent separately hydrogen or the optional C that is replaced by phenyl, indyl, methyl mercapto, hydroxyl, mercaptan, hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals of representing
1-4Alkyl;
R
21Represent hydrogen, C
1-4Alkyl, Het
23-C
1-4Alkyl-carbonyl or R
21Represent single-or two (C
1-4Alkyl) amino-C
1-4Alkyl-carbonyl-, optional by hydroxyl, pyrimidine radicals, dimethyl amine or C
1-4Alkoxyl replaces;
R
23Represent Ar
3, Ar
4-C
1-4Alkyl, C
1-4Alkyl, optional by Het
12The C that replaces
2-6Thiazolinyl, or R
23Representative is by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl, hydroxyl, halogen, Het
2, NR
7R
8, NR
9R
10-carbonyl or Het
3The C that the substituent group of-carbonyl replaces
1-4Alkyl;
Het
1Represent heterocycle, described heterocycle is selected from piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, 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-list-or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
Het
2Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, thio-morpholinyl or dithian base, wherein said Het
2Choose wantonly by one or possible two and can a plurality ofly be selected from 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-substituent group replace; Het
3, Het
4And Het
8Independently represent heterocycle, described heterocycle to be selected from morpholinyl, piperazinyl, piperidyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, wherein said Het separately
3, Het
4, Het
8Optional by one may two or a plurality of be selected from 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-substituent group replace;
Het
5Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
6And Het
7Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
9And Het
10Independently represent heterocycle, described heterocycle to be selected from furyl, piperidyl, morpholinyl, piperazinyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, wherein said Het separately
9Or Het
10Be the optional C that replaces
1-4Alkyl, C
3-6Cycloalkyl-C
1-4Alkyl-or amino-C
1-4Alkyl-;
Het
11Represent heterocycle, described heterocycle be selected from indyl or
Het
12Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, thio-morpholinyl or dithian base, wherein said Het
12Choose wantonly by one or possible two and can a plurality ofly be selected from 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-substituent group replace;
Het
16Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-two oxa-bora Pentamethylene. base or piperidyls, and wherein said heterocycle is optional to be selected from C by one or more
1-4The substituent group of alkyl replaces; And
Het
17Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
18And Het
19Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl-, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
20, Het
21And Het
22Independently represent heterocycle separately, be selected from pyrrolidinyl, 2-Pyrrolidone base, piperazinyl or piperidyl, optional by one or possibility two or a plurality of hydroxyl, C of being selected from
1-4Alkyl-, hydroxyl-C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
23Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Ar
1, Ar
3, Ar
4And Ar
5The independent separately phenyl of representing, optional by cyano group, C
1-4Alkyl sulphonyl-, C
1-4Alkyl sulfonyl-amino-, amino-sulfonyl amino-, hydroxyl-C
1-4Alkyl, amino-sulfonyl-, hydroxyl, C
1-4Alkoxyl-or C
1-4Alkyl replaces.
In one embodiment, formula (XXX) intermediate is made up of the formula that wherein adds one or more following restriction (XXX) chemical compound:
Y
1And Y
2The independent separately C that represents
1-5Alkyl, CO-C
1-5Alkyl or CO-CH
2R
16-NH-;
X
1Represent connecting key, O ,-O-C
1-2Alkyl-, CO ,-CO-C
1-2Alkyl-,-NR
11,-NR
11-C
1-2Alkyl-,-CH
2-,-O-N=CH-or C
1-2Alkyl-;
X
2Represent connecting 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
1Represent hydrogen, cyano group, halogen, hydroxyl, formoxyl, C
1-6Alkoxyl-, C
1-6Alkyl-, the C that replaced by halogen
1-6Alkoxyl-,
By one or possibility two or a plurality of C that is selected from the substituent group replacement of hydroxyl or halogen
1-4Alkyl;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-, Het
16-carbonyl-, C
1-4Alkoxy carbonyl-, C
1-4Alkyl-carbonyl-, amino carbonyl-, single-or two (C
1-4Alkyl) amino carbonyl-, Het
1, formoxyl, C
1-4Alkyl-,-C
2-6Alkynyl-, C
3-6Cycloalkyl-, C
3-6Cycloalkyloxy-, C
1-6Alkoxyl-, Ar
5, Ar
1-oxygen base-, dihydroxy borine, the C that replaced by halogen
1-6Alkoxyl-,
By one or possibility two or a plurality of halogen, hydroxyl or NR of being selected from
5R
6The C that replaces of substituent group
1-4Alkyl;
C
1-4Alkyl-carbonyl-, wherein said C
1-4Alkyl is optional by one or possibility two or a plurality of hydroxyl or C of being selected from
1-4Alkyl-oxygen base-substituent group replace;
R
3Represent hydrogen;
R
5And R
6Independently be selected from hydrogen or C separately
1-4Alkyl;
R
7And R
8Independently be selected from hydrogen, C separately
1-4Alkyl, Het
8, amino-sulfonyl-, single-or two (C
1-4Alkyl)-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-, polyhydroxy-C
1-4Alkyl-, Het
11-C
1-4Alkyl-or Ar
2-C
1-4Alkyl-;
R
9And R
10Independently be selected from hydrogen, C separately
1-4Alkyl, C
3-6Cycloalkyl, Het
4, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-;
R
11Represent 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 sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
12Represent 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 sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
16Represent hydrogen or C
1-4Alkyl, optional by phenyl, indyl, methyl mercapto, hydroxyl, mercaptan, hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals replacement;
-R
23Represent Ar
3, Ar
4-C
1-4Alkyl, C
1-4Alkyl, optional by Het
12The C that replaces
2-6Thiazolinyl, or R
23Representative is by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl, hydroxyl, halogen, Het
2, NR
7R
8, NR
9R
10-carbonyl or Het
3The C that the substituent group of-carbonyl replaces
1-4Alkyl;
Het
1Represent heterocycle, described heterocycle is selected from piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, 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-list-or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
Het
2Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, thio-morpholinyl or dithian base, wherein said Het
2Choose wantonly by one or possible two and can a plurality ofly be selected from 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-substituent group replace;
Het
3, Het
4And Het
8Independently represent heterocycle, described heterocycle to be selected from morpholinyl, piperazinyl, piperidyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, wherein said Het separately
3, Het
4, Het
8Optional by one may two or a plurality of be selected from 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-substituent group replace;
Het
5Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
6And Het
7Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
9And Het
10Independently represent heterocycle, described heterocycle to be selected from furyl, piperidyl, morpholinyl, piperazinyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, wherein said Het separately
9Or Het
10Be the optional C that replaces
1-4Alkyl, C
3-6Cycloalkyl-C
1-4Alkyl-or amino-C
1-4Alkyl-;
Het
11Represent heterocycle, described heterocycle be selected from indyl or
Het
12Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, thio-morpholinyl or dithian base, wherein said Het
12Choose wantonly by one or possible two and can a plurality ofly be selected from 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-substituent group replace;
Het
16Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-two oxa-bora Pentamethylene. base or piperidyls, and wherein said heterocycle is optional to be selected from C by one or more
1-4The substituent group of alkyl replaces; And
Het
17Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
18And Het
19Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl-, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Ar
1, Ar
3, Ar
4And Ar
5The independent separately phenyl of representing, optional by cyano group, C
1-4Alkyl sulphonyl-, C
1-4Alkyl sulfonyl-amino-, amino-sulfonyl amino-, hydroxyl-C
1-4Alkyl, amino-sulfonyl-, hydroxyl, C
1-4Alkoxyl-or C
1-4Alkyl replaces.
Particularly wherein add formula (XXX) intermediate of one or more following restriction:
I) X
1Represent O ,-O-C
1-2Alkyl-,-O-N=CH-, NR
11Or-NR
11-C
1-2Alkyl-; In a special embodiment, X
1Representative-NR
11,-O-or-O-CH
2-;
Ii) X
2Represent connecting key, O ,-O-C
1-2Alkyl-,-O-N=CH-, NR
12Or-NR
12-C
1-2Alkyl-; In a special embodiment, X
2Represent connecting key ,-C
1-2Alkyl-,-O-C
1-2Alkyl-,-O-or-O-CH
2-;
Iii) R
1Represent hydrogen, cyano group, halogen or hydroxyl, be preferably halogen;
Iv) R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-, C
1-4Alkoxy carbonyl-, Het
16-carbonyl, C
1-4Alkyl-, C
2-6Alkynyl-, Ar
5Or Het
1In another embodiment, R
2Represent hydrogen, cyano group, halogen, hydroxyl, C
2-6Alkynyl-or Het
1Especially, R
2Represent hydrogen, cyano group, halogen, hydroxyl or Ar
5
V) R
23Represent hydrogen, C
1-4Alkyl or R
17Represent C
1-4Optional by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl-or Het
2-substituent group replace;
Vi) R
12Represent hydrogen, C
1-4Alkyl or C
1-4Alkyl-oxygen base-carbonyl-;
Vii) Het
1Represent thiazolyl, optional by amino, C
1-4Alkyl, hydroxyl-C
1-4Alkyl-, phenyl, phenyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-list-or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
Viii) Het
2Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
2Optional by one or possibility two or a plurality of hydroxyl, amino or C of being selected from
1-4Alkyl-substituent group replace; In another embodiment, Het
2Represent heterocycle, described heterocycle is selected from morpholinyl or piperidyl, and is optional by C
1-4Alkyl replaces, and is preferably methyl;
Ix) Het
3Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
3Optional by one or possibility two or a plurality of hydroxyl, amino or C of being selected from
1-4Alkyl-substituent group replace;
X) Het
12Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
12Optional by one or possibility two or a plurality of hydroxyl, amino or C of being selected from
1-4Alkyl-substituent group replace;
Xi) Het
16Represent heterocycle, described heterocycle is selected from piperidyl or pyrrolidinyl.
C) formula (XXXIII) intermediate and pharmaceutically acceptable addition salt and stereoisomeric forms in any ratio:
Wherein
M represents 1,2,3 or 4;
X
2Represent connecting 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-;
Y
3Represent C
1-5Alkyl, CO-C
1-5Alkyl or CO-CR
16R
17-NH-or C
1-5Alkyl-CO-, optional by amino, single-or two (C
1-4Alkyl) amino or C
1-4Alkoxycarbonyl amino replaces;
R
1Represent hydrogen, cyano group, halogen, hydroxyl, formoxyl, C
1-6Alkoxyl-, C
1-6Alkyl-, halogen-phenyl-carbonyl amino-,
The C that is replaced by halogen
1-6Alkoxyl-,
By one or possibility two or a plurality of C that is selected from the substituent group replacement of hydroxyl or halogen
1-4Alkyl;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group, Het
16-carbonyl, C
1-4Alkoxy carbonyl-, C
1-4Alkyl-carbonyl-, amino carbonyl-, single-or two (C
1-4Alkyl) amino carbonyl-, Het
1, formoxyl, C
1-4Alkyl-,-C
2-6Alkynyl-, C
3-6Cycloalkyl-, C
3-6Cycloalkyloxy-, C
1-6Alkoxyl-, Ar
5, Ar
1-oxygen base-, dihydroxy borine, the C that replaced by halogen
1-6Alkoxyl-,
By one or possibility two or a plurality of halogen, hydroxyl or NR of being selected from
5R
6The C that replaces of substituent group
1-4Alkyl;
C
1-4Alkyl-carbonyl-, wherein said C
1-4Alkyl is optional by one or possibility two or a plurality of hydroxyl or C of being selected from
1-4Alkyl-oxygen base-substituent group replace;
R
3Represent hydrogen, C
1-4Alkyl or be selected from halogen, C by one or more
1-4Alkoxyl-, amino-, single-or two (C
1-4Alkyl) amino, C
1-4Alkyl-sulfonyl-or phenyl-the C that replaces of substituent group
1-4Alkyl;
R
5And R
6Independently be selected from hydrogen or C separately
1-4Alkyl;
R
12Represent hydrogen, C
1-4Alkyl, C
1-4Alkyl-oxygen base-carbonyl-, Het
18-C
1-4Alkyl-, phenyl-C
1-4Alkyl-oxygen base-carbonyl-Het
17, optional by Het
19-C
1-4The C of alkyl amino-carbonyl-replacement
2-4Alkenyl carbonyl-, C
2-4The thiazolinyl sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
16And R
17Independent separately hydrogen or the optional C that is replaced by phenyl, indyl, methyl mercapto, hydroxyl, mercaptan, hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals of representing
1-4Alkyl;
Het
1Represent heterocycle, described heterocycle is selected from piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, 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-list-or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
Het
16Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-two oxa-bora Pentamethylene. base or piperidyls, and wherein said heterocycle is optional to be selected from C by one or more
1-4The substituent group of alkyl replaces;
Het
18And Het
19Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl-, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace; And
Ar
1And Ar
5The independent separately phenyl of representing, optional by cyano group, C
1-4Alkyl sulphonyl-, C
1-4Alkyl sulfonyl-amino-, amino-sulfonyl amino-, hydroxyl-C
1-4Alkyl, amino-sulfonyl-, hydroxyl, C
1-4Alkoxyl-or C
1-4Alkyl replaces.
Especially, formula (XXXIII) intermediate wherein adds the restriction that one or more is following:
I) X
2Represent connecting key, C
1-2Alkyl-, NR
12Or-NR
12-C
1-2Alkyl-; In a special embodiment, X
2Representative-NR
12-C
1-2Alkyl-or-C
1-2Alkyl-;
Ii) Y
3Represent C
1-5Alkyl, CO-CR
16R
17-NH-or C
1-5Alkyl-CO-, in a special embodiment, Y
3Represent C
1-5Alkyl-CO-;
Iii) R
1Represent hydrogen, cyano group, halogen or hydroxyl, be preferably halogen;
Iv) R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-, C
1-4Alkoxy carbonyl-, Het
16-carbonyl-, C
1-4Alkyl-, C
2-6Alkynyl-, Ar
5Or Het
1In another embodiment, R
2Represent hydrogen, cyano group, halogen or hydroxyl; Especially, R
2Represent hydrogen, cyano group, halogen, hydroxyl or Ar
5
V) R
3Represent hydrogen;
Vi) R
12Represent hydrogen or C
1-4Alkyl;
Vii) R
16The C that represents hydrogen or replaced by hydroxyl
1-4Alkyl;
Viii) R
17Represent hydrogen or C
1-4Alkyl, particularly hydrogen or methyl;
Ix) Het
1Represent thiazolyl, optional by amino, C
1-4Alkyl, hydroxyl-C
1-4Alkyl-, phenyl, phenyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-list-or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
X) Het
16Represent heterocycle, described heterocycle is selected from piperidyl or pyrrolidinyl;
Xi) Ar
5Represent phenyl.
One object of the present invention also provides formula (III), (XXX) or (XXXIII) application of intermediate in synthesis type (I) chemical compound.
Chemical compound of the present invention comprises formula (I) chemical compound and intermediate formula (III), (XXX) and (XXXIII), for useful, because they have pharmacologically active.Therefore they can be used as drug use.
As hereinafter experimental section is described, The compounds of this invention for example demonstrates inhibited proliferation and anti-tumor activity in the enzyme analysis of Lyn, YescSRC in extracorporeal receptor tyrosine kinase EGFR, ErbB2, ErbB4, FIT3, BLK or Sar kinases family.In another was analyzed, the inhibited proliferation of this chemical compound was measured in many cancerous cell lines, is among the A431 at ovarian cancer cell line SKOV3 and squamous cell carcinoma particularly, and known cytotoxicity analysis such as MIT analyze in the use field.
Therefore, the invention provides formula (I) chemical compound and their pharmaceutically acceptable N-oxides, addition salts, quaternary ammonium and the stereochemistry heterogeneous forms that is used for the treatment of.More particularly, in treatment or the prevention disease that cell proliferation mediated.After this formula (I) chemical compound and their pharmaceutically acceptable N-oxides, addition salts, quaternary ammonium and stereoisomeric forms in any ratio can be described as chemical compound of the present invention.
The useful especially disease of The compounds of this invention is: arteriosclerosis, restenosis, cancer and diabetic complication, for example retinopathy.
Viewpoint with the The compounds of this invention purposes, the method of a kind of treatment as the cell breeding disease of arteriosclerosis, restenosis and cancer is provided, this method comprises for example suffering cell breeding disease, needing comprising of this treatment of human mammiferous animal, gives the chemical compound of the present invention of effective dose.
Described method comprises comprising human animal, the The compounds of this invention of systematicness or topical administration effective dose.Those skilled in that art can understand: the EGFR inhibitor of the present invention of treatment effective dose is the amount that is enough to cause growth inhibitory effect, and especially this amount can change according to the size of tumor, kind, compound concentration in the treatment preparation and the state of sufferer.Generally, be used to as therapeutic agent, be used for treating amount, determine as the case may be by the attending doctor as the EGFR inhibitor of the cell breeding disease of arteriosclerosis, restenosis and cancer.
Generally, suitably dosage is to form the concentration range of EGFR inhibitor concentration at 0.5nM-200 μ M at therapentic part, and is more typically 5nM-10 μ M.In order to obtain to treat concentration, need the sufferer of treatment will give every kg body weight 0.01mg-300mg, particularly every kg body weight is from 10mg-100mg.As above annotate, above-mentioned amount may change as the case may be.In these Therapeutic Method, The compounds of this invention preferably is added into before administration.As described below, suitable pharmaceutical formulations can use the composition of knowing and being easy to get to prepare with known steps.
Because its high selectivity as the EGFR inhibitor, above-mentioned defined formula (I) chemical compound also can be used for labelling or differentiates kinases zone at receptor Tyrosine kinases receptors.For this purpose, chemical compound of the present invention can be labeled, and particularly partially or completely replaces one or more atom in molecule with its radiosiotope.The example of interesting labelled compound is to have at least one chemical compound for the radiosiotope halogen of iodine, bromine or fluorine; Or has at least one
11The chemical compound of C-atom or tritium atom.
A special group is made up of formula (I) chemical compound, wherein R
1It is a radioactivity halogen atom.In principle, any formula (I) chemical compound that contains halogen atom is the radioactive label that tends to suitable isotopic halogen atom.Suitably the halogen radiosiotope is a radioiodine for this purpose, for example
122I,
123I,
125I,
131I; Bromine radioactive, for example
75Br,
76Br,
77Br,
82Br, radioactive fluorine, for example
18F.The importing of radioactive halogen atom can or use the method for the halogen derivatives of any one preparation formula mentioned above (I) to carry out by suitable exchange reaction.
Radiolabeled another interesting form for by with
11C-atomic substitutions carbon atom or by tritium atomic substitutions hydrogen atom.
Therefore, described radioactive formula (I) chemical compound is used in the method for specific markers acceptor site in the biomaterial.The step that this method comprises is: (a) radio-labeled formula (I) chemical compound (b) gives this labelled compound to biomaterial and follows (c) from radio-labelled compound detection emitting substance.
The term biomaterial refers to comprise and has biogenetic each material.More particularly, this term refers to tissue specimen, blood plasma or body fluid, but also refers to animal, is in particular a part such as the organ of homoiothermic animal or animal.
When being used for the body inner analysis, radiolabeled chemical compound is to give in animal in an appropriate combination thing, and the position of this radio-labelled compound is to use imaging technique to survey, for example, single-photon emission computed tomography (SPECT) or positron emission computed tomography (PET) etc.In this way, the distribution of the special acceptor site of whole health can be detected, and contain the organ of described acceptor site can be above-mentioned imaging technique show.By giving the method that radiolabeled formula (I) chemical compound carries out the organ imaging and also constituting a part of the present invention from the detection of radioactive compound emitting substance.
On the other hand, the invention provides the purposes of The compounds of this invention on the medicine of preparation described cell breeding disease of treatment or symptom.
The compounds of this invention also refers to active component at this, and it need reach the amount of therapeutic effect, and age, disease and the particular obstacle that will treat or the disease with specific compound, route of administration, receptor changes in the nature of things.The day therapeutic dose that is fit to is from every kg body weight 0.01mg-300mg, particularly from every kg body weight 10mg-100mg.The method of treatment also is included under the scheme of taking to four every day and gives this active component.
When giving active component separately possibly, preferably occur with Pharmaceutical composition.Therefore, the present invention further provides a kind of pharmaceutical compositions that constitutes by The compounds of this invention and pharmaceutically acceptable carrier or diluent.Carrier or term be necessary for " acceptable " refer to compositions in other composition compatible and can be harmful to the receiver.
Pharmaceutical composition of the present invention can for example, use as people Remington ' s PharmaceuticalScience (18 such as Gennaro by the method preparation of knowing in any pharmaceutical field
ThEd.Mack Publishing Company 1990, sees particularly Part8:Pharmaceutical Preparations and their Manufacture) method narrated.The specilization compound of treatment effective dose with alkali form or addition salts form, makes up in well-mixed mixture as active component and pharmaceutically acceptable carrier, and this carrier can adopt the form of broad variety, depends on the drug-delivery preparation form of wanting.These Pharmaceutical compositions with suitable single dose form, preferably are applicable to systemic administration ideally, as oral, percutaneous or parenteral administration; Perhaps local application is as via suction, nasal spray, eye drop or via cream, gel, shampoo etc.For example, in the compositions of preparation peroral dosage form, under the oral liquid situation,, can use any pharmaceutical media commonly used as suspending agent, syrup, elixir and solution, as, water, glycols, oils, alcohols etc.; Or under powder agent, pill, capsule and tablet situation, use solid carrier, as starch, saccharide, kaolin, lubricant, binding agent, disintegrating agent etc.Because its easy administration, tablet and capsule are represented best oral dosage unit form, in the case, obviously use the solid pharmaceutical carriers.The compositions that is used for parenteral, carrier comprise sterilized water usually, and at least one major part although also can comprise other composition, for example, helps dissolved composition.Injection solution for example, can be prepared as the mixture that carrier wherein comprises saline solution, glucose solution or salt and glucose solution.Injectable suspensions also can use preparations such as suitable liquid-carrier, suspending agent in this case.In the compositions of suitable percutaneous dosing, optional penetration enhancers and/or the suitable wetting agent of comprising of carrier, the suitable additive combination of any character of optional and a small amount of ratio, this additive does not cause the great illeffects on any skin.This additive can promote percutaneous drug delivery, and/maybe can help to prepare desired compositions.The administration in a different manner of these compositionss, for example, percutaneous plaster is as patch (spot-on) or as ointment.
Particularly advantageous is to prepare aforementioned pharmaceutical compositions so that be easy to administration and make dosage even with dosage unit form.Description herein and the dosage unit form in claims refer to be suitable for the unit form of the physical separation of unit dose, and that constituent parts comprises is quantitative in advance, is calculated the active component of the required therapeutic effect of generation and required pharmaceutical carrier.The example of this dosage unit form is tablet (tablet that comprises impressed or coating), capsule, pill, powder packets, wafer, injection solution or suspending agent, teaspoon agent, soupspoon agent etc. and its isolating multiple dose.
Experimental section
Hereinafter, term " RT " refers to room temperature; " ADDP " refers to 1,1 '-(azo dicarbapentaborane) two piperidines; " DCM " refers to that dichloromethane, " DMA " refer to N, the N-dimethyl acetylamide, " DME " refer to that dimethyl ether, " DMF " refer to N, dinethylformamide, " DMSO " refer to that dimethyl sulfoxide, " DIPE " refer to that Di Iso Propyl Ether, " DIPEA " refer to that N-ethyl-N-(1-Methylethyl)-2-propylamine, " EtOH " refer to that ethanol, " EtOAc " refer to that ethyl acetate, " HBTU " refer to that also triazolium salt 3-oxide, " LAH " refer to lithium aluminium hydride, i.e. LiAlH to hexafluorophosphoric acid (1-)-[two (dimethylamino) methylene]-H-collection
4, " TFA " refers to that trifluoracetic acid and " THF " refer to that oxolane, " PyBOP " refer to hexafluorophosphoric acid (1-) (1-hydroxyl-1H-benzotriazole-O-) three-1-pyrrolidinyl (T-4)-phosphorus (1+) salt, " NaBH (OAc)
3" to refer to that triacetyl sodium borohydride, RP refer to anti-phase.
A. the preparation of intermediate
Embodiment A 1
A) preparation 6-(2-methyl-6-nitro-phenoxy)-methyl caproate (intermediate 1)
At N, 2-methyl-6-nitro-phenol (0.0065mol) and the K of N-dimethyl-Methanamide (DMF) in (80ml)
2CO
3(0.026mol) mixture drips 6-bromocaproic acid methyl ester (0.0195mol) after stirring 15 minutes under 50 ℃, the gained reactant mixture stirred 18 hours down in 50 ℃.Fully, this reaction frozen water quencher, the gained mixture extracts 3 times with toluene.Separated, the dry (MgSO of organic layer
4), filter and concentrate.Residue is directly used in down the step, gets 100% intermediate 1.
B) preparation 6-(2-amino-6-methylphenoxy) methyl caproate (intermediate 2)
Intermediate 1 (0.013mol) in THF (100ml) and ethamine (0.5g) mixture are that catalyst carries out hydrogenation with Pt/C 5% (2g).Absorbing H
2After (3 equivalent), reactant mixture is gone up filtration via a pillar Dicalite, gained filtrate concentrates, and gets 1.4g intermediate 2, can this be directly used in down the step.
C) preparation 6-[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-the 6-methylphenoxy] methyl caproate (intermediate 3)
The 4-chloro-6-methyl ketonic oxygen base-7-methoxyl group quinazoline (0.0045mol) in 2-propanol (40ml) and the mixture of intermediate 2 (0.0056mol) are stirred and refluxed 1 day.Concentrate this reactant mixture, gained is residual handles and stirs this mixture overnight with DIPE.Solid collected by filtration, washing and dry gets intermediate 3.
D) amino preparation 6-[2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl)]-the 6-methylphenoxy] methyl caproate (intermediate 4)
Intermediate 3 (0.0045mol) and NH
4Methanol (50m1) solution of OH (1.5m1) is evaporating solvent after RT stirs 18 hours down, gets intermediate 4 (impure, as to be directly used in the next step).
E) amino preparation 6-[2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl)]-the 6-methylphenoxy] caproic acid (intermediate 5)
With intermediate 4 (0.00024mol), LiOH (0.00047mol), THF (3ml), CH
3OH (1ml) and H
2O (1ml) mixture stirs, and heats 30 minutes down in 70 ℃, makes reactant mixture reduce to RT then.Organic solvent (THF/CH
3OH) be evaporated, aqueous concentrates neutralizes with HCI (1N), filters, washs the gained solid and in 65 ℃ down dry (vacuum), get 0.040g intermediate 5.
Embodiment A 2
A) preparation 6-(2-chloro-6-nitro-phenoxy)-methyl caproate (intermediate 6)
With the N of 2-chloro-6-nitro-phenol (0.046mol), after being heated to 50 ℃, dinethylformamide (150ml) solution adds K
2CO
3(0.069mol), the gained reactant mixture stirred 15 minutes.Add 6-bromocaproic acid methyl ester (0.069mol), the gained mixture stirs and spends the night.Reactant mixture is filtered, and filtrate concentrates, and the gained residue is directly used in the next step, gets 13.88g intermediate 6.
B) preparation 6-(2-amino-6-chlorophenoxy)-methyl caproate (intermediate 7)
Intermediate 6 (0.046mol) in THF (ml) and ethamine (2g) mixture are that catalyst carries out hydrogenation with Pt/C5% (3g) in the presence of DIPE (2ml).After absorbing hydrogen (3 equivalent), reactant mixture is filtered via a pillar Dicalite filler, filtrate concentrates, and gets intermediate 7.
C) preparation 6-[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazoline] amino]-the 6-chlorophenoxy]-methyl caproate (intermediate 8)
The 4-chloro-6-methyl ketonic oxygen base-7-methoxyl group quinazoline (0.022mol) in 2-isopropyl alcohol (170ml) and the mixture of intermediate 7 (0.022mol) stir and heated 2 hours at 80 ℃, concentrate, the gained residue is via (the eluent: DCM/CH of the chromatograph on silica gel
3OH 97/3) purification.Collect product section and evaporating solvent, get 5.1g intermediate 8 (being directly used in the next step).
D) preparation 6-quinazoline alcohol, 4-[[3-chloro-2-[(6-hydroxyl hexyl) the oxygen base] phenyl] amino]-7-methoxyl group-(intermediate 9)
LAH (0.0246mol) mixture in THF (40ml) at room temperature stirs, and drips THF (60ml) solution of intermediate 8 (0.006mol).The gained reactant mixture stirs after 1 day and adds other LAH (0.0123mol) more in batches.The mixture restir is crossed last dropping H of a week
2O (2ml) then drips 15%NaOH solution (2ml) and H
2O (6ml).This mixture stirs 15 minutes after-filtration, and filtrate concentrates.The gained residue is at ebullient CH
3Stir among the CN, filter, the gained solid is in 60 ℃ of dryings (vacuum).This solid is dissolved in CH again
3Among the OH/DCM (10/90), mixture neutralizes with HCl (1N).Separate organic facies, dry (MgSO
4), filter, concentrate, get 1g intermediate 9.
Embodiment A 3
A) preparation 6-(4-chloro-2-nitro-phenoxy)-methyl caproate (intermediate 10)
4-chloro-6-nitro-phenol (0.029mol) and K
2CO
3(0.035mol) mixture in DMA (80ml) drips 6-bromo-methyl caproate (0.035mol) in 50 ℃ of stirrings after 30 minutes, and the gained reactant mixture descended other restir 18 hours at 50 ℃.After finishing, mixture is filtered, filtrate is with HCI (1N) neutralization, in the impouring frozen water and stirred 30 minutes.Filter and collect the gained precipitation, washing is dissolved among the DCM, dry (MgSO
4), filter and concentrate, get intermediate 10 (being directly used in the next step).
B) preparation 6-(2-amino-4-chlorophenoxy)-methyl caproate (intermediate 11)
The intermediate 10 (0.026mol) in THF (100ml) and the mixture of ethamine (1g) are that catalyst carries out hydrogenation with Pt/C5% (5g) in the presence of DIPE (1ml).After absorbing hydrogen (3 equivalent), reactant mixture is filtered via a pillar Dicalite filler, filtrate concentrates, and gets intermediate 11.
C) preparation 6-[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-the 4-chlorophenoxy]-methyl caproate (intermediate 12)
To and stir 3 hours in the 4-chloro-6-methyl ketonic oxygen base-7-methoxyl group quinazoline (0.014mol) in the 2-propanol (120ml) and intermediate 11 (0.014mol) mixture heated to 80 ℃.This reactant mixture filters and concentrated filtrate.The gained residue is chromatogram purification (eluant: DCM/CH on silicagel column
3OH 96.5/3.5).Collect product component and evaporating solvent to doing, get 1.8g intermediate 12 (being directly used in the next step).
D) preparation 6-quinazoline alcohol, 4-[[5-chloro-2-[(6-hydroxyl hexyl) the oxygen base] phenyl] amino]-7-methoxyl group-(intermediate 13)
LAH (0.015mol) stirs then at N in THF (40ml)
2Drip the solution of the intermediate 12 (0.0037mol) in THF (80ml) down in RT.Reactant mixture stirs the last H that uses of a week
2O (0.9ml), NaOH aqueous solution (15%, 0.9ml) and H
2O (2.7ml) handles.Reactant mixture is filtered, the residue washing, filtrate decompression concentrates.The gained residue stirs in DIPE and solid collected by filtration, gets 0.8g (53%) intermediate 13.
Embodiment A 4
A) preparation 5-(4-chloro-2-nitro-phenoxy)-methyl valerate (intermediate 14)
4-chloro-6-nitrophenol (0.023mol), K
2CO
3(0.027mol) and N, dinethylformamide (80ml) mixture in 50 ℃ stir 30 minutes down after, Dropwise 5-bromo pentane acid A ester (0.027mol), the gained reactant mixture stirred 18 hours in 50 ℃.Mixture filters, and filtrate neutralizes with HCl (1N).In this mixture impouring frozen water and stirred 30 minutes.Filter and collect the gained precipitation, washing is dissolved in DCM/CH again
3Also dry (MgSO among the OH (95/5)
4), filter and concentrate, get 6.6g intermediate 14 (directly in the next step, using).
B) preparation 5-(2-amino-4-chlorophenoxy)-methyl valerate (intermediate 15)
The intermediate 14 (0.023mol) in THF (100ml) and the mixture of ethamine (1g) are that catalyst carries out hydrogenation with Pt/C 5% (5g) in the presence of DIPE (1ml).After absorbing hydrogen (3 equivalent), reactant mixture is filtered via a pillar Dicalite, filtrate concentrates, and gets intermediate 15.
C) preparation 5-[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-the 4-chlorophenoxy]-methyl valerate (intermediate 16)
The 4-chloro-6-methyl ketonic oxygen base-7-methoxyl group quinazoline (0.0067mol) in 2-propanol (60ml) and the mixture of intermediate 15 (0.0048mol) were in 80 ℃ of following agitating heating 4 hours.Reactant mixture is filtered washing gained solid and the dry 0.7g that gets.Filtrate concentrate and gained residue (grease) on silica gel through chromatograph (eluent: DCM/CH
3OH 96.5/3.
5) purification.Collect pure component and concentrated, get 1.5g intermediate 16.
D) preparation 6-quinazoline alcohol, 4-[[5-chloro-2-[(5-hydroxyl amyl group) the oxygen base] phenyl] amino]-7-methoxyl group-(intermediate 17)
LAH (0.013mol) mixture in THF (25m) is at N
2Stir in RT down, drip THF (45ml) solution of intermediate 16 (0.0032mol) and allow reactant mixture stir and spend the night.This reactant mixture water (0.8ml), NaOH (0.8ml, 15%) reach water (2.4ml) again and handled and stir this mixture 15 minutes.This mixture is filtered, and filtrate concentrates, and is dissolved in DCM/CH once more
3Among the OH (95/5),, concentrate back chromatogram purification (eluent: DCM/CH on silica gel with HCl (1N) neutralization
3OH 91.5/8.5).Collect product component and concentrated, get 0.400g intermediate 17.
Embodiment A 5
A) preparation 6-(2-nitro-phenoxy)-methyl caproate (intermediate 18)
At N, 2-nitro-phenol (0.014mol) and K in the dinethylformamide (50ml)
2CO
3(0.017mol) mixture stirred 15 minutes down in 50 ℃, dripped 6-bromo-methyl caproate (0.017mol), and the gained reactant mixture stirred 18 hours down in 50 ℃.In reactant mixture filtration and impouring frozen water.With gained sedimentation and filtration, washing and dry, get 3.0g intermediate 18 (being directly used in the next step).
B) preparation 6-(2-amino-benzene oxygen)-methyl caproate (intermediate 19)
Intermediate 18 (0.011mol) mixture in THF (100ml) is that catalyst carries out hydrogenation with Pt/C 5% (0.5g) in the presence of DIPE (0.5ml).After absorbing hydrogen (3 equivalent), reactant mixture is filtered via a pillar Dicalite, filtrate concentrates, and gets intermediate 19.
C) preparation 6-[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino] phenoxy group]-methyl caproate (intermediate 20)
4-chloro-6-methyl ketonic oxygen base-7-methoxyl group quinazoline (0.011.mol) in 2-propanol (100ml) and intermediate 19 (0.011mol) mixture were 80 ℃ of heated and stirred 5 hours, reactant mixture is concentrated, and gained residue (grease) is purification (eluant: DCM/CH on silica gel
3OH 96.5/3.5).Collect product component and concentrated, get 2,3g intermediate 20 (being directly used in the next step).
D) preparation 6-quinazoline alcohol, 4-[[2-[(6-hydroxyl hexyl) the oxygen base] phenyl] amino]-7-methoxyl group-(intermediate 21)
LAH (0.020mol) mixture in THF (30ml) stirs under RT, drips the solution of the intermediate 20 (0.005mol) in THF (50ml) then.Reactant mixture stirs and spends the night, water (1ml), NaOH aqueous solution (1ml, 15%) and water (3ml) processing again.This mixture is filtered, the wash residual thing, filtrate neutralizes with HCl (1N).Filtrate concentrates, and in 55 ℃ of dried residue (vacuum), gets 0.5g intermediate 21.
Embodiment A 6
A) preparation 6-(4-bromo-2-nitro-phenoxy)-methyl caproate (intermediate 22)
To after 4-bromo-2-nitrophenol (0.046mol) mixture heated to 40 among the DMA (100ml) ℃, add K
2CO
3(0.046mol), reactant mixture was stirred 15 minutes.Adding 6-bromo-methyl caproate (0.046mol) also spends the night this mixture in 40 ℃ of stirrings.Added other 6-bromo-methyl caproate (2g) and this reactant mixture restir 2 hours.Mixture is cooled in RT and the impouring frozen water (400ml).With the gained sedimentation and filtration, be dissolved among the DCM dry (MgSO
4) and filter once more.At last, evaporate this filtrate, get 14.24g (90%) intermediate 22.
B) preparation 6-(2-amino-4-bromine phenoxy group)-methyl caproate (intermediate 23)
Intermediate 22 (0.04mol) in THF (250ml) and ethamine (0.044mol) mixture are that catalyst carries out hydrogenation with Pt/C 5% (2g) in the presence of DIPE (2ml).Absorb H
2After (3 equivalent), reactant mixture is filtered via a pillar Dicalite, filtrate concentrates, and gets 12.8g intermediate 23 (98%).
C) preparation 6-[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-4-bromine phenoxy group]-methyl caproate (intermediate 24)
Will be in the mixture heated to 80 of 4-chloro-6-acetoxyl group-7-methoxyl group quinazoline hydrogen chlorate (0.00554mol) in the 2-propanol (10ml) and intermediate 23 (0.00554mol) ℃.After one hour, reactant mixture is homogeneous, and is black.This mixture stirs down in RT and spends the night, and concentrates back chromatogram purification on silica gel.Collect two kinds of product components and concentrated.Component 2 stirs in 2-propanol/DIPE (1/24), filters, and the gained solid drying gets intermediate 24.D) preparation 6-quinazoline alcohol, 4-[[5-bromo-2-[(6-hydroxyl hexyl) the oxygen base] phenyl] amino]-7-methoxyl group-(intermediate 25)
Will be at the mixture of the intermediate 24 (0.00188mol) among the THF (40ml), in 16 hours, under RT at N
2The LAH (0.0075mol) that is added drop-wise in-the air-flow in THF (20ml) stirs in the suspended matter.Reactant mixture is used H thereupon
2O (0.4ml) handles; Handle with NaOH aqueous solution (0.4ml, 15%) after 15 minutes; Use H at last
2O (1.2ml) handles (color becomes yellow from ash/green).Reactant mixture is filtered, and filtrate neutralizes with HCl (1N) and concentrates.Residue is at CH
3Stir among the CN/DIPE (24/1),, get intermediate 25 by solid collected by filtration and dry.
Embodiment A 7
A) preparation 7-(4-chloro-2-nitro-phenoxy)-cognac oil (intermediate 26)
4-chloro-6-nitro-phenol (0.017mol) and K in DMA (70ml)
2CO
3(0.019mol) mixture stirred 15 minutes down in 50 ℃, added 6-bromo-cognac oil (0.019mol) then and stirred this reactant mixture down in 50 ℃.With gained sedimentation and filtration and concentrating under reduced pressure filtrate, get intermediate 26 (being directly used in the next step).
B) preparation 7-(2-amino-4-chlorophenoxy)-cognac oil (intermediate 27)
It is that catalyst carries out hydrogenation that intermediate 26 (0.017mol) in THF (100ml) and dimethyl amine (1g) mixture exist with Pt/C 5% (2g) at DIPE (1ml).Absorb H
2After (3 equivalent), reactant mixture is filtered on a pillar Dicalite and concentrate, get intermediate 27.
C) preparation 7-[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-the 4-chlorophenoxy]-cognac oil (intermediate 28)
To stir at the mixture of 4-chloro-6-methyl ketonic oxygen base-7-methoxyl group quinazoline (0.0051mol) in the 2-isopropyl alcohol (50ml) and intermediate 27 (0.006mol), and in 80 ℃ of heating 6 hours, solvent evaporated under reduced pressure.Chromatograph (the eluent: DCM/CH of gained crude product on silica gel
3OH97.5/2.5) purification.Collect product component and concentrated, get 2.4g (92%) intermediate 28.
D) preparation 6-quinazoline alcohol, 4-[[5-chloro-2-[(7-hydroxyl heptyl) the oxygen base] phenyl] amino]-7-methoxyl group-(intermediate 29)
LAH (0.0186mol) mixture in THF (40ml) stirs the solution that the back drips the intermediate 28 (0.0047mol) among the THF (40ml) under RT.The gained reactant mixture stirs after 18 hours and adds other LAH (0.0092mol) again, gained mixture restir 1 day.This reactant mixture is used H thereupon
2O (1.5ml), appropriate amount of NaOH aqueous solution (15%, H 1.5ml) and then
2O (4.5ml) handles, and stirs this mixture 10 minutes.The gained mixture is filtered, and filtrate neutralizes, concentrates with HCl (1N), and the gained residue is by column chromatography purification (silica gel, eluant: DCM/CH
3OH 95/5).Collect product component and concentrated, get 0.5g (25%) intermediate 29.
Embodiment A 8
A) preparation acetic acid 8-(4-chloro-2-nitro-phenoxy)-1-monooctyl ester (ester) (intermediate 30)
With 4-chloro-6-nitro-phenol (0.0205mol), scintilla sieve (3.5g), DMA p.a. (50ml) and K
2CO
3Mixture (0.0238mol) stirred after 1 hour, added 8-bromo-1-capryl alcohol-acetate (0.0235mol) and also this mixture was stirred 16 hours down in 50 ℃.In mixture cooling and impouring frozen water, use toluene (2 150ml) extraction then.Merge organic layer, drying (MgSO
4), filter and evaporating solvent (vacuum).Residue is by chromatograph (eluant: the DCM/Hexane 80/20) purification on silica gel.Collection product component and steaming desolventize, and get 6.2g (87.9%) intermediate 30.
B) preparation 1-capryl alcohol, 8-(2-amino-4-chlorophenoxy)-, vinegar ester ester (intermediate 31)
Intermediate 30 (0.018mol) mixture in THF (100ml) is that catalyst carries out hydrogenation with Pt/C 5% (1g) in the presence of thiophene (1ml).After absorbing hydrogen (3 equivalent), reactant mixture filters the back via a pillar Dicalite and concentrates, and gets 5.6g intermediate 31 (being directly used in the next step).
C) preparation acetic acid 4-[[2-[[8-(acetoxyl group) octyl group] the oxygen base]-the 5-chlorphenyl] amino]-7-methoxyl group-6-quinazoline ester (intermediate 32)
4-chloro-6-methyl ketonic oxygen base-7-methoxyl group quinazoline (0.01mol) in 2-propanol (60ml) and intermediate 31 (0.01mol) mixture heated 2 hours down in 80 ℃, then with reactant mixture cooling, concentrated.Add DIPE and mixture was stirred 2 hours.Collect gained precipitation and dry, get 5.0g intermediate 32.
D) preparation 6-quinazoline alcohol, 4-[[5-chloro-2-[(8-hydroxyl octyl group) the oxygen base] phenyl] amino]-7-methoxyl group-(intermediate 33)
Intermediate 32 (0.0094mol) mixture in methanol (100ml) drips at H in 60 ℃ of heating down
2K among the O (10ml)
2CO
3(0.019mol) solution.The evaporation organic solvent, gained aqueous concentrates acetic acid treatment.Separate out precipitation is leached, use H
2O washs and in 60 ℃ of dryings (vacuum), gets 3.7g (88%) intermediate 33.
Embodiment A 9
A) preparation acetic acid 9-(4-chloro-2-nitro-phenoxy)-1-ester in the ninth of the ten Heavenly Stems (intermediate 34)
With 4-chloro-6-nitro-phenol (0.02mol), DMA p.a. (70ml) and K
2CO
3Mixture (0.0246mol) heated 1 hour down in 50 ℃, added the 9-bromine then, acetic acid 1 nonyl alcohol ester (0.024mol).The gained reactant mixture is heated after a weekend in the impouring frozen water (250ml).Filter and collect the gained solid, be dissolved among the DCM, dry (MgSO
4), filter and concentrate, 8.6g intermediate 34.
B) preparation acetic acid 9-(2-amino-4-chlorophenoxy)-1-ester in the ninth of the ten Heavenly Stems (intermediate 35)
The mixture of the intermediate 34 (0.023mol) in THF (200ml) is that catalyst carries out hydrogenation with Pt/C 5% (2g) in the presence of thiophene (2ml).After absorbing hydrogen (3 equivalent), reactant mixture filters the back via a pillar Dicalite and concentrates (vacuum), gets intermediate 35.
C) preparation 6-quinazoline alcohol, 4-[[2-[[9-(acetoxyl group) nonyl] the oxygen base]-the 5-chlorphenyl] amino]-the 7-methoxyl group-, acetate (intermediate 36)
The 4-chloro-6-methyl ketonic oxygen base-7-methoxyl group quinazoline (0.00099mol) in 2-propanol (15ml) and the mixture of intermediate 35 (0.0010mol) be in 80 ℃ of down heating 1.5 hours, then with reactant mixture at N
2Air-flow concentrates down.Add DIPE; Collect gained solid and dry.Get intermediate 36 (off-white color solid).Perhaps, will the 4-chloro-6-methyl ketonic oxygen base-7-methoxyl group quinazoline (0.051mol) in the 2-propanol (15ml) and intermediate 35 (0.0051mol) mixture in 80 ℃ down heating after 4 hours with reactant mixture at exsiccant N
2Air-flow concentrates down.Add DIPE; Collect gained solid and dry, get 2.38g (84.3%) intermediate 36.
D) preparation 6-quinazoline alcohol, 4-[[5-chloro-2-[(9-hydroxyl nonyl) the oxygen base] phenyl] amino]-7-methoxyl group-(intermediate 37)
With K
2CO
3(0.34g) be added in methanol (40ml) and H
2In the solution of the intermediate 36 (0.00437mol) among the O (8ml), after 2 hours, the gained precipitation is leached, get solid (1) and filtrate (I).Filtrate (I) evaporation is with H
2O joins (pH:10) in the residue.Adding acetic acid is until pH:5-6 and stirred this mixture 10 minutes, then solid is leached.These solids and solid (I) are at H
2O/CH
3Merge the back among the OH (20ml/100ml) and add K
2CO
3(0.380g).Reactant mixture is added other K in 60 ℃ of heating after 30 minutes again
2CO
3(0.400g), subsequently the stirring of gained mixture is spent the night.Solvent evaporation is also used H
2O and acetic acid are handled residue.The gained solid is leached, use CH
3OH washs and in 60 ℃ of vacuum dryings, gets 1.7g intermediate 37.
Embodiment A 10
A) preparation 5-hydroxyl-2-nitro-4-(benzyloxy)-benzoic acid (intermediate 38)
KOH (75g) is joined H
2Stir down among the O (175ml) and in RT, add 4-phenoxy group-5-methoxyl group-2-nitro-benzoic acid (0.031mol) in batches, the gained suspension was in 75 ℃ of heating 12 hours.This reactant mixture is filtered, and filtrate is used hydrochloric acid (dense) acidify.Gained precipitation is leached, in DIPE, stirs, filters and dry, 5.75g (65%) intermediate 38.
B) preparation 5-hydroxyl-2-nitro-4-(benzyloxy)-essence of Niobe (intermediate 39)
The mixture of the intermediate 38 (0.020mol) in thionyl chloride (50ml), stirring and refluxing is solvent evaporated under reduced pressure after 2 hours.The gained residue with methanol (50ml) quencher after this mixture stir a weekend.With the toluene coevaporation, get intermediate 39 behind the evaporating solvent.
C) preparation 5-(acetoxyl group)-2-nitro-4-(benzyloxy)-essence of Niobe (intermediate 40)
Intermediate 39 (0.020mol) mixture in acetic anhydride (40ml) and pyridine (6ml) is heated to 90 ℃ and stirred this reactant mixture 2 hours.Solvent evaporated under reduced pressure, the gained residue is via filtered through silica gel (eluent: DCM).Collect product component and evaporating solvent, get 5.4g (78%) intermediate 40.
D) preparation 5-(acetoxyl group)-2-amino-4-(phenyl methoxyl group)-essence of Niobe (intermediate 41)
The mixture of the intermediate 40 (0.015mol) in THF (100ml) is that catalyst carries out hydrogenation with Pt/C 5% (2g) in the presence of thiophene solution (1ml).After absorbing hydrogen (3 equivalent), catalyst is leached and evaporated filtrate, get 4.7g intermediate 41.
E) preparation 4 (3H)-quinazolinones, 6-hydroxyl-7-(phenyl methoxyl group)-(intermediate 42)
The mixture of intermediate 41 (0.015mol) in Methanamide (50ml) and ammonia and formic acid (0.0225mol) is heated to 150 ℃ and stirred this reactant mixture 4 hours, and mixture is cooled in RT and the impouring frozen water.Gained precipitation is leached, washes with water and in 60 ℃ of dryings (vacuum), 2.9g (72.5%) intermediate 42.
F) preparation 4 (3H)-quinazolinones, 6-(acetoxyl group)-7-(phenyl methoxyl group)-(intermediate 43)
1, the mixture of the intermediate 42 (0.011mol) in 1-ethylene glycol monoacetate (12ml) and the pyridine (2ml) is heated to 90 ℃, and this reactant mixture stirs after 3 hours in the mixture impouring frozen water.The gained precipitation is leached, washs and drying, get 3.3g (97%) intermediate 43.
G) preparation acetic acid 4-chloro-7-(phenyl methoxyl group)-6-quinazoline ester (intermediate 44)
Intermediate 43 (0.0032mol) and N, thionyl chloride (30ml) solution of dinethylformamide (catalytic amount), stirring and refluxing 6 hours, solvent evaporated under reduced pressure is also used the toluene coevaporation then.Residue is dissolved among the DCM and uses NaHCO
3Washing.With organic facies separation, dry (MgSO
4), filter and evaporating solvent.The gained residue is directly used in the next step, gets 0.6g (60%) intermediate 44.
H) preparation acetic acid 6-(4-bromo-2-nitro-phenoxy)-own ester of 1-(intermediate 44a)
4-bromo-2-nitrophenol (0.115mol) solution in DMA (250ml) adds K in 40 ℃ of following agitating heating
2CO
3(0.115mol) and stirred this reactant mixture 15 minutes.Add the 6-own ester of monobromo-acetic acid 1-(0.115mol), the gained mixture spends the night in 40 ℃ of stirrings.Add the other own ester of acetic acid 6-bromo-1-(4g) again, gained mixture stirring 2 hours is cooled to RT and stirring is spent the night.This mixture filters, and will extract with EtOAc then in the filtrate impouring frozen water (2000ml).With organic layer separation, dry (MgSO
4), filter and solvent evaporated under reduced pressure, 39.6g intermediate 44a.
I) preparation acetic acid 6-(2-amino-4-bromine phenoxy group)-own ester of 1-(intermediate 45)
Intermediate 44a (0.105mol) mixture in THF (250ml) is that catalyst carries out hydrogenation with Pt/C:5% (3g) in the presence of thiophene solution (3mol).After absorbing hydrogen (3 equivalent), catalyst is leached and reduction vaporization filtrate.The gained residue is dissolved among the DIPE, and is converted into hydrochlorate (1: 1) in HCl (20ml, 6N is in the 2-propanol).The gained precipitation is leached, washs and drying, get 36.91g (96%) intermediate 45.
J) preparation acetic acid 4-[[2-[[6-(acetoxyl group) hexyl] the oxygen base]-the 5-bromophenyl] amino]-7-(phenyl methoxyl group)-6-quinazoline ester (intermediate 46)
The intermediate 44 (0.0031mol) in 2-propanol (50ml) and the mixture of intermediate 45 (0.0031mol) are heated to 80 ℃, this reactant mixture are stirred make it to be cooled to RT after 6 hours and stir and spend the night.At last, solvent evaporated under reduced pressure gets 1.9g intermediate 46.
K) preparation 6-quinazoline alcohol, 4-[[5-bromo-2-[(6-hydroxyl hexyl) the oxygen base] phenyl] amino]-7-(phenyl methoxyl group)-(intermediate 47)
Intermediate 46 (0.0031mol) mixture in methanol (25ml) is heated to 60 ℃, is added in H
2K among the O (2.5ml)
2CO
3(0.0062mol) solution stirs this reactant mixture 18 hours then.Add other K again
2CO
3(0.0031mol) and with this mixture stirred 3 hours down in 60 ℃.Reduction vaporization organic solvent (CH
3OH) and with acetic acid handle the gained concentrated liquid.Gained precipitation leached, washs and in 60 ℃ of dryings (vacuum), 1.4g (84%) intermediate 47.
Embodiment A 11
A) preparation acetic acid 4-[[2-[[6-(acetoxyl group) hexyl] the oxygen base]-the 5-bromophenyl] amino]-6-quinazoline ester (intermediate 48)
Intermediate 45 (0.0045mol) in 2-propanol (50ml) and 4-chloro-6-quinazoline alcohol acetate (0.0045mol) mixture are heated to 80 ℃ and stirred this reactant mixture 2.5 hours.Solvent evaporated under reduced pressure, the gained residue is directly used in the next step, gets intermediate 48.
B) preparation 6-quinazoline alcohol, 4-[[5-bromo-2-[(6-hydroxyl hexyl) the oxygen base] phenyl] amino]-(intermediate 49)
At H
2Intermediate 48 (0.0045mol) and K in O (2.5ml) and the methanol (25ml)
2CO
3(0.0135mol) mixture, in 60 ℃ down stir 16 hours after with solvent evaporation, gained aqueous concentrates CH
3The OH/DCM extraction.Organic layer is isolated dry (MgSO
4), leach and evaporating solvent.Residue is in 60 ℃ of dryings (vacuum) and be directly used in the next step, intermediate 49.
Embodiment A 12
A) preparation 1-amylalcohol, 5-[[(4-bromo-2-nitrobenzophenone) methyl] amino]-(intermediate 50)
4-bromo-2-nitro-benzaldehyde (0.013mol) in ethanol (15ml), 5-amino-1-amylalcohol (0.013mol) and tetrakis (2-propoxyl group) (0.014mol) solution stirred 1 hour under RT, and reactant mixture is heated to 50 ℃ and stirred 30 minutes.Mixture is cooled to RT and drips NaBH
4(0.013mol).Reactant mixture stirs in the back impouring frozen water that spends the night (50ml).The gained mixture stirred 20 minutes, formed precipitation was leached (getting filtrate (I)), used H
2O washing is also stirred (dissolved product and remove from titanium salt it) in DCM.Mixture filters rear filtrate drying (MgSO
4) and filter the final evaporation solvent.Filtrate (I) evaporation is removed until EtOH, contains concentrated liquid and extracts 2 times with DCM.Organic layer separates, dry (MgSO
4), filter and evaporating solvent, 3.8g (93%) intermediate 50.
B) preparation [(4-bromo-2-nitrobenzophenone) methyl] (5-hydroxyl amyl group)-carbamic acid 1,1-dimethyl ethyl ester (intermediate 51)
Intermediate 50 (0.0032mol) in DMC (20ml) stirs under RT, and drips two (1, the 1-dimethyl ethyl) ester (0.0032mol) solution of two carbonic acid in DMC (5ml).The gained reactant mixture stirred 1 hour and H under RT
2O washing 2 times.Organic layer is told, dry (MgSO
4), filter and evaporating solvent, intermediate 51.
C) preparation [5-(acetoxyl group) amyl group] [(4-bromo-2-nitrobenzophenone) methyl]-carbamic acid 1,1-dimethyl ethyl ester (intermediate 52)
Intermediate 51 (0.0032mol) in acetic anhydride (15ml) and pyridine (0.032mol) solution after stirring 16 hours under the RT, solvent evaporated under reduced pressure and with the toluene coevaporation.Residue itself is used for the next step step, gets 1.47g (100%) intermediate 52.
D) preparation [5-(acetoxyl group) amyl group] [(2-amino-4-bromophenyl) methyl-carbamic acid 1,1-dimethyl ethyl ester (intermediate 53)
Intermediate 52 (0.0033mol) mixture in THF (50ml) carries out hydrogenation with Pt/C 5% (0.5g) as catalyst in the presence of thiophene solution.After absorbing hydrogen (3 equivalent), catalyst is leached and evaporated filtrate, get intermediate 53.
E) preparation [[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-4-bromophenyl] [5-(acetoxyl group) amyl group]-carbamic acid 1,1-dimethyl ethyl ester (intermediate 54)
Intermediate 53 (0.0028mol) in 2-propanol (50ml), 4-chloro-7-methoxyl group-, acetyl group-quinazoline alcohol (ester) (0.0028mol) mixture be heated to 60 ℃ and this reactant mixture stirred 1 hour.Solvent evaporated under reduced pressure, the gained residue itself is used for the next step step, gets intermediate 54.
F) preparation [[4-bromo-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] phenyl] methyl] (5-hydroxyl amyl group)-carbamic acid 1,1-dimethyl ethyl ester (intermediate 55)
The solution of the intermediate 54 (0.0028mol) in methanol (50ml) stirs under RT and adds H
2K among the O (5ml)
2CO
3(0.0056mol), reactant mixture is heated to 60 ℃ and stirred 18 hours.Remove organic solvent, aqueous concentrates acetic acid acidify.The gained precipitation is leached, be dissolved among the DCM, dry (MgSO
4), filter and evaporating solvent, get 1.2g intermediate 55.
Embodiment A 13
A) preparation 6-heptenoic acid, 7-(4-bromo-2-nitrobenzophenone)-, (6E)-(intermediate 56)
Will be at the NaH 60% (0.026mol among the exsiccant DMSO (15ml), no mineral oil) mixture heated to 65 ℃, and stir this mixture 1.5 hours (up to stopping to produce hydrogen), suspension (blackish green) is cooled to 15 ℃ thereupon, and drips bromo 5-carboxy pentyl triphenylphosphine (0.013mol) solution in DMSO (10ml).Gained solution (redness) stirred 10 minutes under RT, was added in the 4-bromo-2-nitrobenzaldehyde among the dry DMSO (8ml) immediately fast.Gained solution (pitchy) stirred 105 minutes, and used H
2O/Et
2O (25/75,100ml) quencher.Remove Et
2The O layer, water layer is also used ethyl acetate extraction with ethyl acetate extraction twice once more with HCl (37%) acidify (pH:1-2).Organic layer separates, dry (MgSO
4), filter and evaporating solvent, intermediate 56.
B) preparation 7-(4-bromo-2-nitrobenzophenone)-6-heptenoic acid methyl ester, (6E)-(intermediate 57)
Intermediate 56 (0.013mol) solution in concentrated hydrochloric acid (0.20ml) and methanol (10ml) stirs the back solvent evaporated under reduced pressure of spending the night under RT.Residue is dissolved among the DCM, uses NaHCO
3Solution washing.Organic layer separates, dry (MgSO
4), filter and evaporating solvent.Residue is via filtered through silica gel (eluant: DCM); Collect product component and evaporating solvent, get 0.800g intermediate 57.
C) preparation benzene 2-amino-4-bromo-methyl heptanoate (intermediate 58)
Intermediate 57 (0.0023mol) mixture Pt/C 5% (0.5g) with 5% concentration in the presence of thiophene solution (0.5ml) in THF (50ml) carries out hydrogenation as catalyst.After absorbing hydrogen (4 equivalent), catalyst is leached and evaporated filtrate, get 0.72g intermediate 58.
D) preparation benzene 2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-4-bromo-methyl heptanoate (intermediate 59)
Intermediate 58 (0.0023mol) in 2-propanol (40ml) and 4-chloro-7-methoxyl group-6-quinazoline alcohol acetic ester (0.0023mol) mixture be heated to 80 ℃ and stir 4 hours after, solvent evaporated under reduced pressure.The gained residue is at CH
3Stir among the OH/DIPE (1/9); Leach the gained precipitation,, get 0.55g intermediate 59 with the DIPE washing and in 60 ℃ of dryings (vacuum).
E) preparation 6-quinazoline alcohol, 4-[[5-bromo-2-(7-hydroxyl heptyl) phenyl] amino]-7-methoxyl group-(intermediate 60)
LAH (0.005mol) mixture in 2-propanol (20ml) stirs under RT, drips intermediate 59 (0.001mol) solution in the 2-propanol (30ml), and reactant mixture is stirred thereupon and spends the night.Add ethyl acetate (20ml), and excessive 4-chloro-7-methoxyl group-6-quinazoline alcohol acetic ester is decomposed by 10%HCl solution (5ml).Organic layer separates, and dry (MgSO4) filters and evaporating solvent.The gained residue itself is used for the next step step, gets intermediate 60.
Embodiment A 14
A) preparation 1-amylalcohol, 5-[[(4-bromo-2-nitrobenzophenone) methyl] methyl amine]-(intermediate 61)
Intermediate 50 (0.0047mol) in EtOH (150ml), formaldehyde (0.025mol) and four (2-propanol) titanium (0.0051mol) are heated in 50 ℃ and after stirring 1 hour, add NaBH under RT in batches
4(0.026mol).Reactant mixture stirs back water (100ml) quencher of spending the night.The gained mixture stirred 1 hour; Formed precipitation is leached and washs.Organic filtrate concentrates, and the aqueous concentrate is also dry with the DCM extraction immediately.Evaporating solvent, residue filter (eluant: DCM/CH on silica gel
3OH from 98/2 to 95/5).Collect product component and evaporating solvent, get 0.5g intermediate 61.
B) methyl preparation acetic acid 5-[[(4-bromo-2-nitrobenzophenone)] the methylbenzene propylhomoserin]-1-pentyl ester (intermediate 62)
Intermediate 61 (0.0015mol) in acetic anhydride (8ml) and pyridine (0.015mol) stir under the RT spend the night after, solvent evaporation and with the toluene coevaporation, intermediate 62.
C) methyl preparation acetic acid 5-[[(2-amino-4-bromophenyl)] methylamino]-1-pentyl ester (intermediate 63)
The mixture of the intermediate 62 (0.0015mol) in THF (50ml) carries out hydrogenation with Pt/C as catalyst in the presence of thiophene solution (1ml) [H179-034].At H
2After (3 equivalent) absorbed, catalyst filtered, and evaporated filtrate, got 0.5g intermediate 63.
D) preparation acetic acid 4-[[2-[[5-(acetoxyl group) amyl group] methylamino] methyl-5-bromophenyl]-7-methoxyl group-6-quinazoline ester (intermediate 64)
Intermediate 63 (0.0015mol) in 2-propanol (30ml) and 4-chloro-7-methoxyl group-6-quinazoline alcohol acetic ester (0.0015mol) mixture is heated to 80 ℃ and this reactant mixture and stirred 1 day.Solvent removed under reduced pressure, the gained residue itself is used for the next step step, gets 0.83g intermediate 64.
E) preparation 6-quinazoline alcohol, 4-[[5-bromo-2-[[(5-hydroxyl amyl group) methylamino] methyl] phenyl]]-7-methoxyl group-(intermediate 65)
Intermediate 64 (0.0015mol) solution in methanol (25ml) stirs and is added in H under RT
2K among the O (2.5ml)
2CO
3(0.003mol) solution is heated to reactant mixture 60 ℃ and stirred 18 hours subsequently.Evaporating solvent adds H
2O (20ml) with acetic acid this mixture that neutralizes, and leaches formed precipitation.Concentrating under reduced pressure filtrate, concentrate with DCM extraction, filter, dry (MgSO
4) and the concentrating under reduced pressure mixture, get 0.5g (70%) intermediate 65.
Embodiment A 15
A) preparation three fluoro-methanesulfonic acid 2-(4-chloro-2-nitrobenzophenone) ethyl ester (intermediate 66)
2-in Nitrocarbol. (30ml) (4-chloro-2-nitrobenzophenone) ethanol (0.01mol) and 2,6-two-tert-butyl pyridine (0.012mol) mixture is at N
2In 0 ℃ of stirring, at trifluoromethyl sulfonic acid anhydride (0.011mol) mixture of 0 ℃ of dropping in Nitrocarbol. (10ml), the homologation reaction mixture reaches RT and stirred 1 hour under the air-flow, gets intermediate 66.
B) preparation acetic acid 4-[2-(4-chloro-2-Nitrobenzol) ethyoxyl]-1-butyl ester (intermediate 67)
The mixture of the 1-ethyoxyl in Nitrocarbol. (10ml)-4-hydroxyl butane (0.01mol) is added drop-wise in the intermediate 66, and this this mixture stirred 1 hour down at 65 ℃ subsequently.The mixture cooling also adds entry.Layering, water layer DCM extracting twice.Organic layer separates, dry (MgSO
4), filter and evaporating solvent.The gained residue is column chromatography (eluant 1:DCM on silica gel; Eluant 2: twice of the purification of hexane/EtOAc90/10).Collect product component and evaporating solvent, get 0.800g (25%) intermediate 67.
C) preparation acetic acid 4-[2-(2-amino-4-chlorphenyl) ethyoxyl]-1-butyl ester (intermediate 68)
Dioxane (intermediate 67 in (40ml) in the presence of thiophene solution (0.3ml) with Pt/C (0.300g) as catalyst 40 ℃ of following hydrogenations.After absorbing hydrogen (3 equivalent), catalyst leaches, and evaporated filtrate gets intermediate 68.
D) preparation acetic acid 4-[[2-[2-[4-(acetoxyl group) butoxy] ethyl]-the 5-chlorphenyl] amino]-7-methoxyl group-6-quinazoline ester (intermediate 69)
4-chloro-6-acetoxyl group-7-methoxyl group quinazoline (0.00040mol) in dioxane (in right amount) and intermediate 68 (0.00035mol) be evaporating solvent after stirring 3 hours under 80 ℃, gets intermediate 69.
E) preparation 6-quinazoline alcohol, 4-[[5-chloro-2-[2-(4-hydroxyl butoxy) ethyl] phenyl] amino]-7-methoxyl group-(intermediate 70)
At H
2Intermediate 69 (residue) and K among O (25ml) and the EtOH (25ml)
2CO
3It is last that (0.0144mol) mixture stirs a week under RT, adds H
2O (150ml) and gained reactant mixture extract 3 times with DCM.Organic layer separates, dry (MgSO
4)
Embodiment A 16
A) preparation benzaldehyde, 4-chloro-2-nitro-, oxime (intermediate 71)
4-chloro-2-nitrobenzaldehyde (0.01077mol) in pyridine (20ml) and oxammonium hydrochloride. (1: 1) mixture (0.01184mol) in oil bath 80 ℃ of following heating solvent evaporated under reduced pressure after 2 hours.Residue is transferred to CH
3Among the OH/DCM (10/90) and with 1N HCl extraction gained mixture, use NaHCO subsequently
3Solution and water washing.Organic layer separates, dry (MgSO
4), overanxious and solvent evaporated under reduced pressure.Residue is dry under 50 ℃, gets 1.75g (81%) intermediate 71.
B) preparation benzaldehyde, 4-chloro-2-nitro-, O-[8-(acetoxyl group) octyl group] and oxime (intermediate 72)
With K
2CO
3(0.00887mol) join in intermediate 71 (0.00887mol) solution in DMSO (25ml) under the vigorous stirring, add 8-bromine octyl group acetas (0.00887mol) subsequently, the gained reactant mixture stirred 4 hours under RT.Mixture heats after 1 hour under 50-60 in oil bath, adds other 8-bromine octyl group acetas (0.669g) and K
2CO
3(0.369g).Reactant mixture stirs 4 hours postcooling under 50-60.With mixture impouring H2O/NH
4Extract among the Cl and with EtOAc.EtOAc layer drying (MgSO
4), filter and evaporating solvent (vacuum).Residual grease (4g) on silica gel via column chromatography purification (eluant: DCM/ hexane 70/30,80/20,100/0).Collect pure product component and solvent evaporated under reduced pressure, get 1.34g intermediate 72.
C) preparation benzaldehyde, 2-amino-4-chloro-, O-[8-(acetoxyl group) octyl group] oxime (intermediate 73)
Intermediate 72 (0.0036mol) in THF (100ml) in the presence of thiophene solution (1ml) with Pt/C 5% (0.5g) as catalyst under RT in hydrogen hydrogenation spend the night, reactant mixture is 50 ℃ of following heated overnight immediately.After absorbing hydrogen, mixture is filtered and evaporated filtrate.Residue moves among the THF (100ml) and this reactant mixture spends the night in hydrogenation under 50 ℃ as catalyst with Pt/C 5% (0.5g) in the presence of thiophene solution (0.1ml).This mixture in THF (100ml) with Pt/C 5% (0.5g) as catalyst under RT further hydrogenation spend the night.After absorbing hydrogen (3 equivalent), catalyst is filtered off, and filtrate is evaporated, and gets intermediate 73.
D) preparation benzaldehyde, 2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-the 4-chloro-, O-[8-(acetoxyl group) octyl group] oxime (intermediate 74)
4-chloro-6-acetoxyl group-7-methoxyl group quinazoline (0.0021mol) and intermediate 73 (0.0022mol) in 2-propanol p.a. (30ml), mixture heated 1 hour down in 80 ℃ in oil bath, and solvent is evaporated immediately.The gained residue on silica gel via column chromatography purification (eluant: DCM/CH
3OH 99.5/0.5 arrives and CH
3The gradient of OH).Collect pure component and evaporating solvent, get 0.300g intermediate 74.
E) preparation benzaldehyde, 4-chloro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino]-, O-(8-hydroxyl octyl group) oxime (intermediate 75)
At CH
3The mixture of the intermediate 74 (0.00026mol) among the OH (10ml) is used in H
2K among the O (1ml)
2CO
3(0.0011mol) mixture process, this reactant mixture stirs under RT and spends the night subsequently.Organic solvent (CH
3OH) the aqueous concentrates H of evaporation and gained
2O (30ml) dilution.Up to pH:4-5, this mixture stirred 1 hour and filtered the gained mixture subsequently with acidifying with acetic acid.Gained solid CH
3OH (5ml) washs and at 60 ℃ of following vacuum dryings, gets 0.199g (78%) intermediate 75.
Embodiment A 17
A) preparation acetic acid 8-(3-nitro-phenoxy)-1-monooctyl ester (intermediate 76)
3-nitrophenol (0.0144mol) and K in 2-propanol (20ml)
2CO
3(0.0144mol) mixture stirred 2.5 hours under RT, added 8-monobromo-acetic acid monooctyl ester (0.0144mol) then.Reactant mixture stirs after 3 hours restir and refluxed 18 hours under RT.Add other 8-monobromo-acetic acid monooctyl ester (0.004mol), gained mixture stirring and refluxing is 18 hours then.Mixture is cooled to RT, filters and filtering residue 2-propanol washing.Filtrate merges and concentrating under reduced pressure.Concentrated solution is immediately via column chromatography purification (eluant: hexane/EtOAc 85/15).Collect product component and evaporating solvent, get intermediate 76.
B) preparation acetic acid 8-(3-amino-benzene oxygen)-1-monooctyl ester (intermediate 77)
Intermediate 76 (0.0123mol) mixture in THF (50ml) is that catalyst is 50 ℃ of following hydrogenations with Pt/C 5% (2g) in the presence of thiophene solution (1ml).After absorbing hydrogen (3 equivalent), leach catalyst and evaporated filtrate, get 3.6g intermediate 77.
C) preparation acetic acid 4-[[3-[[8-(acetoxyl group) octyl group] the oxygen base] phenyl] amino]-7-methoxyl group-6-quinazoline ester (intermediate 78)
Heating is until dissolving fully down at 85 ℃ for intermediate 77 (0.0123mol) in 2-propanol (50ml) and 4-chloro-6-acetoxyl group-7-methoxyl group quinazoline (0.0123mol) mixture, and this reactant mixture is cooled to RT subsequently.The gained precipitation is leached,, get 5.33g (88%) intermediate 78 with DIPE washing and dry (vacuum).
D) preparation 6-quinazoline, 4-[[3-[(8-hydroxyl octyl group) the oxygen base] phenyl] amino]-7-methoxyl group-(intermediate 79)
At H
2O (8ml) and CH
3Intermediate 78 (0.00404mol) and K among the OH (80ml)
2CO
3(0.00807mol) mixture heated 18 hours down at 65 ℃, then the pressure reducing and steaming organic solvent.Residue H
2The O dilution, and the gained mixture is acidified to pH:4 with 1N HCl.Precipitation is leached and dry (vacuum), get 1.5g (90%) intermediate 79.
Embodiment A 18
A) preparation 2-acrylamide, 3-(4-chloro-2-nitrobenzophenone)-N-(3-hydroxypropyl)-, (intermediate 80)
With 1,1 '-carbonyl is two-1H-imidazoles (0.009mol) joins in the mixture of the 4-chloro-2-nitro-cinnamic acid (0.006mol) in THF (100ml) under RT, and the gained mixture stirred 2 hours under RT, must mixture (I).Mixture (I) joins in 3-amino-1-propanol (0.06mol) mixture in THF (100ml) in batches, and stirs this reactant mixture 2 hours under RT.Evaporating solvent is also transferred to residue in the water (100ml).Water layer merges organic layer, dry also filtration, reduction vaporization (requiring to carry out coevaporation several times with toluene) then with DCM (100ml3 time) extraction.Residue stirs in RT in toluene and spends the night and the gained precipitation is leached, subsequently by the column chromatography (eluant: DCM/CH on silica gel
3OH 100/0 to 97/3) purification.Collect product component and evaporating solvent, get the intermediate 80 of 1g (59%).
B) preparation 2-acrylamide, N-[3-(acetoxyl group) propyl group]-3-(4-chloro-2-nitrobenzophenone)-(intermediate 81)
In intermediate 80 (0.0035mol) mixture that under the RT pyridine (0.035mol) is added drop-wise in acetic anhydride (20ml), stir this reactant mixture down in RT then.At last, solvent evaporated under reduced pressure, the intermediate 81 of 1.1g (100%).
C) preparation hydrocinnamamide, the N-[3-acetoxyl group] propyl group]-2-amino-4-chloro-(intermediate 82)
Intermediate 81 (0.0033mol) mixture in THF (50ml) is catalyst hydrogenation 10 days under RT with Pt/C 5% (0.5g) in the presence of thiophene solution (0.5ml).After absorbing hydrogen (4 equivalent), catalyst is leached and filtrate evaporated under reduced pressure.The gained residue is by the column chromatography (eluant: purification DCM/CHsOH 99.5/0.5 to 95/5) on silica gel.Collect product component and solvent evaporated under reduced pressure, get 0.8g (81%) intermediate 82.
D) preparation hydrocinnamamide, 2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-N-[3-(acetoxyl group) propyl group]-4-chloro-(intermediate 83)
Intermediate 82 (0.0027mol) in 2-propanol (50ml) and 4-chloro-6-acetoxyl group-7-methoxyl group quinazoline (0.0027mol) mixture stirring and refluxing solvent evaporated under reduced pressure after 2 hours.The gained residue is by the column chromatography (eluant: DCM/CH on silica gel
3OH 99/1 to90/10) purification.Collect product component and solvent evaporated under reduced pressure, get 0.91g (65%) intermediate 83.
E) preparation hydrocinnamamide, 4-chloro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino]-N-(3-hydroxypropyl)-(intermediate 84)
Intermediate 83 (0.0017mol) in methanol (20ml) and water (2ml) and potassium carbonate (0.0072mol) mixture be solvent evaporated under reduced pressure after stirring 1 hour under the RT.The gained residue moves in the water, and water layer acetic acid acidify.The gained precipitation is leached and drying, get the intermediate 84 of 0.46g (63%).
Embodiment A 19
A) preparation acetic acid 4-chloro-7-methoxyl group-6-quinazoline alcohol ester (intermediate 85)
Mixture among 6-(acetoxyl group) in thionyl chloride (500ml)-7-methoxyl group-4 (1H)-quinazolone (0.23mol) and the DMF (1.ml), stirring and refluxing 5 hours is cooled to RT with reactant mixture then.Solvent evaporated under reduced pressure then with the toluene coevaporation.The gained residue is dissolved among the DCM and uses saturated NaHCO
3Solution washing.Organic layer separates, dry (MgSO
4), filter and solvent evaporated under reduced pressure.Residue stirs in DIPE then separating out sedimentation and filtration, 55.4g (95%) intermediate 85.
B) preparation 6-quinazoline alcohol, 4-[(4-chloro-2-hydroxy phenyl) the aniinol-7-methoxyl group-, 6-acetate mono-hydrochloric salts (intermediate 86)
Intermediate 85 (0.00696mol) in 2-propanol (100ml) and 2-amino-5-chloro-phenol (0.00696mol) mixture, 85 ℃ of following heated and stirred 4 hours, then reactant mixture is cooled to RT, the gained precipitation is leached, get intermediate 86, separate with mono-hydrochloric salts.
C) preparation 6-quinazoline alcohol, 4-[[4-chloro-2-[(6-hydroxyl hexyl) the oxygen base] phenyl] amino]-the 7-methoxyl group-, 6-acetas (intermediate 87)
The solution of the intermediate 86 (0.00076mol) in DMA (20ml) stirs under RT and adds sodium hydride (0.00091mol) in batches, and reaction stirred is 30 minutes subsequently, and drips 6-bromo-1-hexanol (0.00091mol) solution in DMA (2ml).The gained reactant mixture stirs under RT and spends the night, and adds NH subsequently
4Cl aqueous solution (1ml).With in the gained reactant mixture impouring frozen water and evaporating solvent.The gained residue is collected product component and evaporating solvent after via the HPLC purification, the intermediate 87 of 0.030g.
Embodiment A 20
Preparation boric acid, (8,9,10,11,12,13-six hydrogen-20-methoxyl group-4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 are because of-17-yl)-(intermediate 83)
Chemical compound 6 (0.0006mol), 4,4,4 ' in DMSO (5ml), 4 ', 5,5,5 ', 5-prestox-2,2 '-two-1,3,2-two-dihydro boron luxuriant (0.00066mol), dichloro [1,1 '-two (biphenyl phosphine) ferrocene] mixture of palladium (0.024g), potassium acetate (0.00092mol) and [1,1 '-biphenyl]-2-base dicyclohexyl-phosphine (0.024g) stirred 2 hours down at 80 ℃, in the frozen water of reactant mixture impouring subsequently and stirred 1 hour.Gained precipitation leached and with column chromatography purification (eluant: DCM/CH
3OH 98/2 to 90/10).Collect pure component and evaporating solvent, get 0.080g (33%) intermediate 88.
Embodiment A 21
A) preparation 1-amylalcohol, 5-[[(4-chloro-5-fluoro-2-nitro propyl group) methyl] amino]-(intermediate 89)
4-chloro-5-fluoro-2-nitro-benzaldehyde (0.0098mol) in EtOH (10ml), amylalcohol amine (0.0098mol) and four (2-propoxyl group) titanium (0.011mol) solution stirred 1 hour under RT, and adding sodium borohydride (0.015mol) in batches, reactant mixture stirring under RT is subsequently spent the night and is added H
2O.The gained mixture stirred 15 minutes, and precipitation is leached.Filtrate evaporation is dissolved in residue among the DCM then and uses H
2The O washing.Organic layer separates, dry (MgSO
4), filter and evaporating solvent.The gained residue on silica gel via the column chromatography purification.Collect product component and evaporating solvent, get the intermediate 89 of 2.3g (48%).
B) preparation carbamic acid, [5-(acetoxyl group) amyl group] [(4-chloro-5-fluoro-2-nitrobenzophenone) methyl]-, 1,1-dimethyl ethyl ester (intermediate 90)
Intermediate 89 (0.0079mol) solution in DCM (20ml) was used in uncle among the DCM (20ml)-butoxy carbonic anhydride (0.082mol) solution-treated 30 minutes, subsequently reactant mixture H
2O (2 * 20ml) washings.Organic layer separates, dry (MgSO
4), filter and evaporating solvent.Residue is dissolved in the acetic anhydride (30ml) subsequently this solution and handles and stir a weekend with pyridine (5ml).Evaporating solvent and with the toluene coevaporation.Residue on silica gel via column chromatography purification (eluant: DCM).Collect product component and evaporating solvent, get the intermediate 90 of 1.4g (40.9%).
C) preparation carbamic acid, [5-(acetoxyl group) amyl group] [(2-amino-4-chloro-5-fluorophenyl) methyl]-, 1,1-dimethyl ethyl ester (intermediate 91)
At toluene (40ml), CH
3OH (40ml) and H
2Intermediate 90 (0.0016mol) among the O (20ml), Fe (0.009mol) and NH
4The mixture of Cl (0.016mol), stirring and refluxing be after 2 hours, with the reactant mixture cooling and filter on dicalite.Filtrate evaporation back gained residue dilutes with DCM (50ml) and uses H
2The O washing.Organic layer separates, dry (MgSO
4), filter and evaporating solvent, get 0.513g (80%) intermediate 91.
D) preparation carbamic acid, [[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-4-chloro-5-fluorophenyl] methyl] [5-(acetoxyl group) amyl group]-, 1,1-dimethyl ethyl ester (intermediate 92)
Intermediate 91 (0.000379mol) in 2-propanol (10ml) and 4-chloro-6-acetoxyl group-7-methoxyl group quinazoline (0.000379mol) mixture, in oil bath in 80 ℃ of following heating evaporating solvents after 3 hours.The gained residue on silica gel via (the gradient elution agent: DCM/CH of column chromatography purification
3OH 100/0 to 99/1).Collect product component and evaporating solvent, get the intermediate 92 of 0.148g (63%).
E) preparation carbamic acid, [[4-chloro-5-fluoro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] phenyl] methyl] (5-hydroxyl amyl group)-, 1,1-dimethyl ethyl ester (intermediate 93)
At CH
3The solution of the intermediate 92 (0.000239mol) among the OH (10ml) is used in H
2K among the O (1ml)
2CO
2(0.00051mol) solution-treated.The gained reactant mixture stirs and to spend the night, subsequently with acetic acid neutralize this mixture and evaporating solvent.The gained residue is dissolved among the DCM and uses H
2The O washing.Organic layer separates, dry (MgSO
4), filter and evaporating solvent, the intermediate 93 of 0.120g (93,7%).
Embodiment A 22
A) preparation 1-butanols, 4-[[2-(4-chloro-2-nitrobenzophenone) ethyl] amino]-(intermediate 94)
At N
2In under RT, 1-amino-4-butanols (0.0300mol) is joined in the suspended matter of stirring of 1-propanol (30ml) and molecular sieve (8g), drip 4-chloro-2-nitro-benzaldehyde (0.0100mol) mixture in 2-propanol (10ml) subsequently.Mixture stirred 90 minutes, and dripped triacetyl oxygen base boron hydride (0.120mol) (generation gas).The reactant mixture stirring is spent the night, and be acidified to pH＜2 with 6N HCl.Add saturated NaHCO
3Solution is to pH 10, and the gained mixture filters on dicalite.Residue washs with the 2-propanol, and stirs in the EtOAc of heat, and this mixture filters on dicalite then, filtrate evaporated under reduced pressure.Residue is in middle absorption, and extracts this mixture with 1N HCl (250ml), and layering must reach organic layer (1).
Water layer (
*) separate, use K
2CO
3Neutralization also extracts with EtOAc.Organic layer separates, dry (MgSO
4), filter and solvent evaporated under reduced pressure, intermediate 94 (component 1).
Dry (the MgSO of organic layer (1)
4), filter and solvent evaporated under reduced pressure.The column chromatography purification of gained residue on silica gel.Collect product component and evaporating solvent, get intermediate 94 (component 2).Collect product component (100% yield)
B) preparation carbamic acid, [2-(4-chloro-2-nitrobenzophenone) ethyl] (4-hydroxyl butyl)-, 1,1-dimethyl ethyl ester (intermediate 95)
Intermediate 94 (0.0015mol) mixture in DCM (10ml), under RT, stir and drip two carbonic acid two (1 in DCM (5ml), 1-dimethyl ethyl ester (0.0015mol) solution, reactant mixture is stirred 1 hour then, and add (0.0015mol) solution of other two carbonic acid in DCM (5ml) two (1,1-dimethyl ethyl ester).Reactant mixture stirred 1 hour, and water washing 2 times.Organic layer separates, dry (MgSO
4), filter and evaporating solvent, the intermediate 95 of 0.56g.
C) preparation carbamic acid, [4-(acetoxyl group) butyl] [2-(4-chloro-2-nitrobenzophenone) ethyl]-, 1,1-dimethyl ethyl ester (intermediate 96)
The intermediate 95 (0.0015mol) in acetic anhydride (10ml) and the solution of pyridine (0.015mol) stirred under RT 18 hours, then solvent evaporated under reduced pressure and with the toluene coevaporation.The gained residue is (eluant: DCM/CH on silica gel
3OH 100/0 to 98/2) purification, collect product component and evaporating solvent, get 0.2g (33%) intermediate 96.
D) preparation carbamic acid, and [4-(acetoxyl group) butyl] [2-(2-amino-chlorphenyl) ethyl-, 1,1-dimethyl ethyl ester (intermediate 97)
The mixture of the intermediate 96 (0.0005mol) in THF (40ml) is that catalyst carries out hydrogenation with Pt/C 5% (0.1g) in the presence of thiophene solution (0.1ml).Absorbing H
2(3equiv.), catalyst filters and evaporating solvent, gets (quantitative yield) intermediate 97.
E) preparation carbamic acid, [4-(acetoxyl group) butyl] [2-[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-the 4-chlorphenyl] ethyl]-, 1,1-dimethyl ethyl ester (intermediate 98)
Intermediate 97 (0.0005mol) in 2-propanol (15ml) and 4-chloro-6-acetyl group-7-methoxyl group quinazoline (0.0005mol) solution stirred 2 hours down at 80 ℃, then solvent evaporated under reduced pressure.Flash column chromatography (the eluant: DCM/CH of crude product residue on silica gel
3OH99.8/0.2 to 96/4) purification.Collect product component and evaporating solvent, get 0.150g intermediate 98.
F) preparation carbamic acid, [2-[4-chloro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] phenyl] ethyl] (4-hydroxyl butyl)-, 1,1-dimethyl ethyl ester (intermediate 99)
Intermediate 98 (0.00025mol) and K in methanol (20ml) and water (2ml)
2CO
3(0.0005mol) mixture, 50 ℃ of following heated and stirred 18 hours, solvent evaporated under reduced pressure then.Water layer neutralizes with acetic acid, and uses the DCM extraction product.Extract washes with water, dry (MgSO
4), filter and evaporated filtrate, 0.130g intermediate 99.
Embodiment A 23
A) preparation benzene, 4-chloro-1-(3-chlorine propoxyl group)-2-nitro-(intermediate 100)
Under RT, potassium carbonate (0.15mol) is added in batches the 4-chloro-2-nitrophenol (0.1mol) in the 2-acetone (500ml).Mixture stirring and refluxing 30 minutes dripped 1-bromo-3-chloro-propane (0.11mol) and gained reactant mixture stirring and refluxing 45 minutes.Add other 1-bromo-3-chloro-propane (0.44mol), add potassium iodide (1g) again, this reactant mixture stirs and spends the night then.The gained mixture filters, and filtering residue 2-washing with acetone.Filtrate evaporated under reduced pressure solvent, gained residue on silica gel via column chromatography (eluant: hexane/EtOAc 80/20) purification.Collect product component and evaporating solvent, get 17.30g (69%) intermediate 100.
B) preparation ethanol, 2-[[3-(4-chloro-2-nitro-phenoxy) propyl group] [2-(4-morpholinyl) ethyl] amino]-(intermediate 101)
The mixture of the 2-in acetonitrile (150ml) (2-morpholine ethylamino)-ethanol (0.0083mol), intermediate 100 (0.0085mol) and sodium carbonate (0.016mol) stirred 92 hours filter reaction mixture in reflux temperature.Filtrate evaporated under reduced pressure solvent, residue be (eluant: DCM/ (CH on silica gel
3OH/NH
3) 99/1 to 95/5) purification.Collect product component and solvent evaporated under reduced pressure, get 1.4g (44%) intermediate 101.
C) preparation ethanol, 2-[[3-(4-chloro-2-nitro-phenoxy) propyl group] [2-(4-morpholinyl) ethyl] amino]-, acetate (intermediate 102)
Under RT, pyridine (0.036mol) is joined in the mixture of the intermediate 101 (0.0036mol) in acetic anhydride (25ml), then stirred reaction mixture 1 hour under RT.At last, the pressure reducing and steaming solvent gets 1.6g (100%) intermediate 102
D) preparation ethanol, 2-[[3-(2-amino-4-chlorophenoxy) propyl group] [2-(4-morpholinyl) ethyl] amino]-, acetas (intermediate 103)
Intermediate 102 (0.0037mol) mixture in THF (50ml) is that catalyst is 50 ℃ of following hydrogenations with Pt/C 5% (0.5g) in the presence of thiophene solution (0.5ml).Absorbing H
2After (3 equivalent), catalyst is leached and reduction vaporization filtrate.Residue on silica gel via column chromatography (eluant: DCM/CH
3OH 96/4) purification.Collect product component and solvent evaporated under reduced pressure, get 0.88g (60%) intermediate 103.
E) preparation 6-quinazoline alcohol, 4-[[2-[3-[[2-(acetoxyl group) ethyl]] [2-(4-morpholinyl) ethyl] amino] propoxyl group]-the 5-chlorphenyl] amino]-the 7-methoxyl group-, acetate (intermediate 104)
The mixture of the intermediate 103 (0.0021mol) in 2-propanol (100ml) and 4-chloro-6-acetoxyl group-7-methoxyl group quinazoline (0.0021mol), stirred 4 hours and add DIPEA (0.3ml) at reflux temperature, the reactant mixture stirring and refluxing is 2 hours then.At last, solvent evaporated under reduced pressure gets residue (I).Residue (I) (0.0021mol at most), three (α-[(1,2-α: 4,5-α)-(1E, 4E)-1,5-xenyl-1,4-pentadiene-3-ketone]) two-palladium (=Pd (DBA)
3) (0.00013mol), [1,1 '-dinaphthyl-2,2 '-two bases two [diphenyl-phosphine (=BINAP) mixture of (0.00026mol) and calcium oxide is disliked in luxuriant (40ml) two and was stirred 16 hours down at 130 ℃, this reactant mixture filters on dicalite then.Filtrate evaporated under reduced pressure, and residue column chromatography (eluant: DCM/CH on silica gel
3OH 98/2 to 90/10) purification.Collect product component and solvent evaporated under reduced pressure, get 0.480g (37%) intermediate 104.
F) preparation 6-quinazoline alcohol, 4-[[5-chloro-2-[3-[(2-ethoxy) [2-(4-morpholinyl) ethyl] amino] propoxyl group] phenyl] amino]-7-methoxyl group-(intermediate 105)
The intermediate 104 (0.00073mol) in methanol (20ml) and water (2ml) and the mixture of potassium carbonate (0.0057mol) stirred under RT 16 hours, then solvent evaporated under reduced pressure and residue is transferred in the water.Water layer washs with DCM, extracts to pH:7 and with DCM with acidifying with acetic acid.Organic layer drying (MgSO
4), filter and evaporating solvent, 0.250g (64%) intermediate 105.
Embodiment A 24
A) preparation Benzoylamide, 4-chloro-N-(6-hydroxyl hexyl)-2-nitro-(intermediate 106)
1,1 '-carbonyl is two-and 4-chloro-2-nitrobenzoic acid (0.01mol) mixture and this mixture that 1H-imidazoles (0.01mol) is added under RT among the DCM (40ml) in batches stirred 1 hour under RT, and dropping 6-hydroxyl hexylamine (0.01mol) and reactant mixture stirred 1 hour under RT under RT then.Mixture is with water (40ml) and HCl (1N, 40ml) washing.Organic layer separation, drying, filtration and solvent evaporated under reduced pressure get 1.7g (57%) intermediate 106.
B) preparation Benzoylamide, N-([6-(acetoxyl group) hexyl]-4-chloro-2-nitro-(intermediate 107)
Under the RT pyridine (0.057mol) is added drop-wise to the mixture of intermediate 106 (0.0057mol) in acetic anhydride (26.7ml), reactant mixture stirred 1 hour under RT then.Solvent evaporated under reduced pressure and gained residue are soluble in water, and mixture extracts with toluene then.Organic layer separation, drying, filtration and evaporating solvent get 1.8g (92%) intermediate 107.
C) preparation Benzoylamide, N-([6-(acetoxyl group) hexyl]-2-amino-4-chloro-(intermediate 108)
The mixture of intermediate 107 (0.0053mol) in THF (40ml) in the presence of thiazole solution (0.5ml) with Pt/C (0.5g) as catalyst 50 ℃ of following hydrogenations.Reactant mixture filters and filtrate evaporated under reduced pressure then.Residue hydrogenation and absorbing H once more
2After (3 equivalent), leach catalyst and reduction vaporization filtrate, get 1.56g (94%) intermediate 108
D) preparation Benzoylamide, N-[6-(acetoxyl group) hexyl]-2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-4-chloro-(intermediate 109)
The mixture of the intermediate 108 (0.0042mol) in 2-propanol (100ml) and 4-chloro-6-acetoxyl group-7-methoxyl group quinazoline (0.0042mol) stirred 16 hours down and solvent evaporated under reduced pressure then at 50 ℃.Residue on silica gel via column chromatography (eluant: DCM/CH
3OH from 99/1 to 90/10) purification.Collect pure component and evaporating solvent, get 1.3g (59%) intermediate 109.
E) preparation Benzoylamide, 4-chloro-N-(6-hydroxyl hexyl)-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino]-(intermediate 110)
Intermediate 109 (0.0023mol) stirred 16 hours down at 50 ℃ in water (2ml) and methanol (20ml) with potassium carbonate (0.0046mol), and reactant mixture is concentrated then.Residue extracts with DCM with acetic acid acidify and water layer.Organic layer separates, dry, filtration and solvent evaporated under reduced pressure, the intermediate 110 of 0.99g (97%).
Embodiment A 25
A) preparation carbamic acid, [(4-bromo-2-nitrobenzophenone) methyl] (5-hydroxyl amyl group)-, phenyl methyl ester (intermediate 111)
Under RT, benzyl chloro-carbonic acid (0.033mol) is added drop-wise in intermediate 50 (0.022mol at most) and the mixture of triethylamine (0.04mol) in DCM (100ml), and reactant mixture is levied stirring 1 hour at R.Adding entry (100ml) and mixture stirred 30 minutes under RT.Organic layer separation, drying, filtration and solvent evaporated under reduced pressure.Residue is via column chromatography (eluant: DCMlCH
3OH 99.5/0.5) purification.Collect product component and evaporating solvent, get 6.8g (68%) intermediate 111.
B) preparation carbamic acid, [(2-amino-4-bromophenyl) methyl] (5-hydroxyl amyl group)-, benzene methyl (intermediate 112)
The mixture of the intermediate 111 (0.015mol) in EtOAc (200ml) is catalyst hydrogenation 40 hours with Pt/C 5% (2g) in the presence of thiophene solution (3ml).Absorbing H
2After (3 equivalent), catalyst leaches and filtrate evaporated under reduced pressure.Get 6.3g intermediate 112.
C) preparation carbamic acid, [[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-4-bromophenyl] methyl (5-hydroxyl amyl group)-, benzene methyl .HCl (1: 1) (intermediate 113)
Under 60 ℃, will be in the 6-acetoxyl group in the 2-propanol (in right amount)-4-chloro-7-methoxyl group quinazoline (0.015mol) solution join intermediate 112 (0.015mol) solution in 2-propanol (in right amount), this reactant mixture stirred 1 hour at 70 ℃ then.Solvent removed under reduced pressure and gained residue stir in hexane.The gained precipitation leaches and is dry, gets 9.35g (98%) intermediate 113, separates with hydrogen chlorate (1: 1).
D) preparation carbamic acid, [[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-4-bromophenyl] methyl (5-chlorine amyl group)-, benzene methyl .HCl (1: 1) (intermediate 114)
Under RT, mesyl chloride (0.12mol) is added in the solution of the intermediate 113 (0.0125mol) in the 1-Methyl-2-Pyrrolidone (50ml), and reactant mixture stirred 1 hour down at 90 ℃.In the mixture impouring water (300ml) and water layer with EtOAc (3 * 100ml) extraction.Organic layer separates, water (2 * 200ml) washings, drying, filtration and solvent evaporated under reduced pressure.The gained residue is via column chromatography (eluant: DCM/CH
3OH 99.5/0.5 to 94/6) purification.Collect pure component and solvent evaporated under reduced pressure, get 3.9g intermediate 114.
Embodiment A 26
A) preparation glycine, N-[(4-chloro-2-nitrobenzophenone) acetyl group]-, ethyl ester (intermediate 115)
4-chloro-2-nitro-phenylacetic acid (0.0051mol) in DCM (50ml) and 1-hydroxyl-1H-benzotriazole (0.0051mol) slurry, with 1,1 '-carbonyl is two-and 1H-imidazoles (0.0051mol) handles, after spending 10 minutes, with DIPEA (0.0051mol), then handle earlier with ethyl aminoacetate hydrogen chlorate (0.0051mol).Reactant mixture stirred 2 hours and with water (50ml), with Na
2CO
3Solution (30ml) and 1N HCl washing.Organic layer separates, dry (MgSO
4), filter and evaporating solvent.DIPE (100ml) is added in the residue of gained and after stirring, collects the gained solid, 1.1g intermediate 115.
B) preparation glycine, N-[(2-amino-4-chlorphenyl) acetyl group]-, ethyl ester (intermediate 116)
The mixture of the intermediate 115 (0.023mol) in THF (250ml) in the presence of thiophene solution (1ml), with Pt/C (2.0g) as catalyst hydrogenation.Absorbing H
2After (3 equivalent), catalyst filters and evaporating solvent.The gained residue is suspended among the DIPE, and this suspension stirs, cools off and collect required product at boiling temperature then, gets 6.2g intermediate 116.
C) preparation glycine, N-[[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino-4-chlorphenyl] acetyl group]-, ethyl ester (intermediate 117)
The intermediate 85 (0.00050mol) in 2-acetone (5ml) and the mixture of intermediate 116 (0.00050mol), under 80 ℃ (oil bath temperatures), in manometer tube, stirred 16 hours, reactant mixture filtration and filtering residue are got 0.165g intermediate 117 by air drying then.
D) preparation glycine, N-[[4-chloro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] phenyl] acetyl group]-, ethyl ester (intermediate 118)
At NH
3/ CH
3OH (7N) (50ml) and the mixture of the intermediate 117 (0.0244mol) in the methanol (100ml) under RT, stir and spend the night and solvent reduction vaporization under RT then.At last, the gained residue spends the night 60 ℃ down dry (vacuum), gets the intermediate 118 of 8.2g (75%).
E) preparation glycine, N-[[4-chloro-2-[[6-[3-[[(1,1-dimethyl ethyoxyl) carbonyl] amino] propoxyl group]-7-methoxyl group-4-quinazolyl] amino] phenyl] acetyl group]-, ethyl ester (intermediate 119)
The intermediate 118 (0.00308mol) in DMA (20ml) and the mixture of cesium carbonate (0.0154mol) are levied at R and were stirred 1 hour, add N-(3-bromopropyl) carbamate (0.00308mol) and reactant mixture then and stir 1 hour under RT.Adding the stirring of other N-(3-bromopropyl) carbamate (0.00308mol) and gained mixture spends the night.Mixture filtration and filtering residue are washed with DMA.Merging filtrate and concentrating under reduced pressure.The crude product concentrate is via column chromatography (eluant: DCM/CH
3OH.100/0 to 95/5) purification.Collect pure product component and vapourisation under reduced pressure solvent, get intermediate 119.
F) preparation glycine, N-[[2-[[6-(the amino propoxyl group of 3-)-7-methoxyl group-4-quinazolyl] amino]-the 4-chlorphenyl] acetyl group, ethyl ester (intermediate 120)
The mixture of the intermediate 119 (0.003mol) in TFA (50ml) and DCM (50ml) stirred 1 hour under RT, reactant mixture under reduced pressure concentrates and concentrated solution so is used for next step reactions steps then, be not further purified and have, get intermediate 120.
G) preparation glycine, N-[[2-[[6-(the amino propoxyl group of 3-)-7-methoxyl group-4-quinazolyl] amino]-the 4-chlorphenyl] acetyl group, ethyl ester (intermediate 121)
Intermediate 120 (0.003mol) and LiOH.H in ethanol (15ml) and water (1ml)
2The mixture of O (0.018mol) stirred 2 hours and then this reactant mixture so be used for the next step step, be not further purified and have, intermediate 121.
Embodiment A 27
A) preparation 1-amylalcohol, 5-[[(4-bromo-5-fluoro-2-nitrobenzophenone) methyl] amino]-(intermediate 122)
At N
2Following reaction: 1, the 4-bromo-5-fluoro-2-nitro-benzaldehyde (0.0379mol) in the 2-two chloro-ethane (150ml) and 5-amino-1-amylalcohol (0.0379mol; 97%) mixture stirred 20 hours.Under RT, add NaBH (OAc)
3(0.0417mol), reactant mixture stirs to spend the night under RT and (after 2 hours, adds other NaBH (OAc) then
3(in right amount)).Mixture is with saturated NaHCO
3Solution washing.Organic layer separates, dry (MgSO
4), filter and evaporating solvent.Residue is via column chromatography (eluant: DCM/ (CH
3OH/NH
3) 90/10) purification.Collect pure product component and evaporating solvent, get 10.5g intermediate 122.
B) preparation carbamic acid, [(4-bromo-5-fluoro-2-nitrobenzophenone) methyl] (5-hydroxyl amyl group)-, 1,1-dimethyl ethyl ester (intermediate 123)
The drips of solution of two (1, the 1-dimethyl ethyl) the dihydroxy acid esters (0.034mol) in DCM (20ml) is added to the mixture of the intermediate 122 (0.031mol) in DCM (20ml), and the mixture reaction of gained is 4 hours then.Reactant mixture separates with water washing and organic layer.Organic layer drying (MgSO
4), filter and evaporating solvent.Residue is via column chromatography (eluant: DCM/CH
3OH 95/5) purification.Collect the product component, subsequently evaporating solvent and with the toluene coevaporation, 9.8g intermediate 123.
C) preparation carbamic acid, [(2-amino-4-bromo-5-fluorophenyl) methyl] (5-hydroxyl amyl group)-, 1,1-dimethyl ethyl ester (intermediate 124)
The mixture of the intermediate 123 (0.0022mol) in EtOAc (100ml) is catalyst hydrogenation with Pt/C 5% (0.5g) in the presence of thiophene solution (in right amount).Absorbing H
2After (3 equivalent), reactant mixture filters and evaporating solvent on dicalite.(the gradient elution agent: DCM is to DCM/CH via column chromatography for residue
3OH) purification.Collect pure product component and evaporating solvent, get 0.623g intermediate 124.
D) preparation carbamic acid, [[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-4-bromo-5-fluorophenyl] methyl (5-hydroxyl amyl group) (intermediate 125)
To be warmed to 60 ℃ at the mixture of the intermediate 85 (0.00154mol) in the acetonitrile (3ml), then at the solution of the intermediate 124 (0.00154mol) of 60 ℃ of droppings in acetonitrile (3ml).This reactant mixture stirred 30 minutes down at 60 ℃, was cooled to RT then.Solvent is evaporated, and residue is via (the gradient elution agent: DCM/CH of the column chromatography on the Biotage then
3OH) purification.Collect pure product component and evaporating solvent, get 0.800g intermediate 125.
E) preparation carbamic acid, [[4-bromo-5-fluoro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] phenyl] methyl] (5-hydroxyl amyl group)-, 1,1-dimethyl ethyl ester (intermediate 126)
To be added in the mixture of the intermediate 125 (0.00105mol) in methanol (50ml) in carbon ester potassium (0.00105mol) drips of solution in the water (5ml), reactant mixture stirred 1 hour under RT then.Solvent is evaporated and residue extracts with DCM.Separated, the dry (MgSO of organic layer
4), filtration and solvent be evaporated.Residue is via (the gradient elution agent: DCM/I/CH of the column chromatography on the Biotage
3OH) purification is collected pure product component and evaporating solvent, gets 0.590g intermediate 126.
F) preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 is because of-13 (8H)-carboxylic acids, 1-dimethyl ethyl ester (intermediate 127)
ADDP (0.00166mol) mixture in dry THF (70ml) is at N
2Be cooled to 5 ℃ with ice bath down, add tributylphosphine (0.00166mol) and gained mixture then and stirred 5 minutes at 5 ℃.Under 5 ℃, be added drop-wise to the solution of the intermediate 126 (0.00055mol) in the dry THF (10ml) in this reactant mixture lentamente and stirred 20 minutes, make it to be cooled to RT then.This mixture stirred under RT 3 hours and evaporating solvent.Residue is via (the gradient elution agent: DCM/CH of column chromatography purification
3OH).Collect pure product component and evaporating solvent, get intermediate 127.
Embodiment A 28
A) preparation glycine, N-[[2-[[6-(2-bromine oxethyl)-7-methoxyl group-4-quinazolyl] amino]-the 4-chlorophenyl] acetyl group]-, ethyl ester (intermediate 128)
The intermediate 118 (0.0138mol) in DMF (120ml) and the mixture of cesium carbonate (0.0690mol) stirred 30 minutes under RT, added 1 then, and 2-two bromo-ethane (0.117mol) and this reactant mixture stir under RT and spend the night.Solvent evaporated under reduced pressure and residue and toluene coevaporation.The gained residue stirs and leaches required product in DIPE, get 6.93g (91%) intermediate 128.
B) preparation glycine, N-[[4-chloro-2-[[7-methoxyl group-6-[2-[[2-(4-morpholinyl) ethyl] amino] ethyoxyl-4-quinazolyl] amino] phenyl] acetyl group]-, ethyl ester (intermediate 129)
100 ℃ of heating 90 minutes, reactant mixture was via the RP high-efficient liquid phase chromatogram purification then in microwave oven for the intermediate 128 (0.00181mol) in ethanol (20ml) and the mixture of 4-morpholinyl ethamine (0.00907mol).Collect product component and evaporating solvent, get 0.39g (36%) intermediate 129.
C) preparation glycine, N-[[4-chloro-2-[[7-methoxyl group-6-[2-[[2-(4-morpholinyl) ethyl] amino] ethyoxyl]-the 4-quinazolyl] amino] phenyl] acetyl group]-(intermediate 130)
Intermediate 129 (0.00065mol) and LiOH.H in ethanol (20ml) and water (2ml)
2The mixture of O (0.0032mol) stirred 2 hours under RT, and solvent evaporated under reduced pressure gets intermediate 130 (nothing is further purified and directly so is used for next step reactions steps) then.
Embodiment A 29
A) preparation benzoic acid, 4-fluoro-, 5-[4-fluorobenzoyl] amine]-2-nitrobenzophenone ester (intermediate 131)
The solution of the 5-amino in DCM (100ml)-2-nitrophenol (0.032mol) and triethylamine (0.065mol) stirs under RT, drip 4-fluoro-Benzenecarbonyl chloride. (0.065mol) solution in DCM (10ml) then, this reactant mixture stirred 1 day under RT.Mixture is with 1N HCl washing 2 times and water washing 1 time.Separated, the dry (MgSO of organic layer
4), filter and evaporating solvent.The gained residue stirs in ethanol/hexane (50/50), filters and be dry, gets 5.25g intermediate 131.
B) preparation Benzoylamide, 4-fluoro-N-(3-hydroxyl-4-nitrobenzophenone)-(intermediate 132)
The mixture of the intermediate 131 (0.0132mol) in methanol (80ml) stirs under RT, is added in the NaOCH in the methanol (10ml) then
330% methanol solution (0.0132mol).Reactant mixture stirs 30 minutes and reduction vaporization organic solvent.The gained concentrate stirs in 1NHCl, then with the gained sedimentation and filtration, wash with water and 60 ℃ down dry (vacuum), 3.3g intermediate 132.
C) preparation Benzoylamide, N-[3-[[6-(acetoxyl group) hexyl] the oxygen base]-the 4-nitrobenzophenone]-4-fluoro-(intermediate 133)
The intermediate 132 (0.011mol) in DMA (100ml) and the mixture of potassium carbonate (0.012mol) stirred 1 hour down at 60 ℃, added 6-bromine hexylacetic acid ester (0.012mol) then, and the gained reactant mixture stirred 18 hours down at 60 ℃.Add the many again stirrings of other 6-bromine hexyl acetonyl ester (0.300g) and this mixture 5 hours.Extract in the gained mixture impouring frozen water and with EtOAc.Separated, the dry (MgSO of organic layer
4), filter and evaporating solvent, 4.6g intermediate 133.
D) preparation Benzoylamide, N-[3-[[6-(acetoxyl group) hexyl] the oxygen base]-the 4-aminophenyl]-4-fluoro-(intermediate 134)
The mixture of the intermediate 133 (0.0024mol) in methanol (75ml) is that catalyst carries out hydrogenation at 50 ℃ in a hermetic container, in the presence of the thiophene solution (1ml), with Pd/C 10% (1g).Absorbing H
2After (3 equivalent), catalyst is leached, get filtrate (I).The mixture of the intermediate 133 (0.0024mol) in THF (75ml) is that catalyst carries out hydrogenation at 50 ℃ in a hermetic container, in the presence of the thiophene solution (1ml), with Pd/C 10% (1g).Absorbing H
2After (3 equivalent), catalyst is leached, get filtrate (II).Filtrate (I) and filtrate (II) are merged and reduction vaporization, get 1.85g intermediate 134.
E) preparation Benzoylamide, N-[3-[[6-(acetoxyl group) hexyl] the oxygen base]-4-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino] phenyl]-4-fluoro-(intermediate 135)
The intermediate 85 (0.0048mol) in 2-propanol (80ml) and the mixture of intermediate 134 (0.0048mol) stirred 1 hour at 80 ℃, and the gained mixture is filtered, washs and be dry then, gets 1.15g intermediate 135.
F) preparation Benzoylamide, 4-fluoro-N-[3-[(6-hydroxyl hexyl) the oxygen base]-4-[(6-hydroxyl-7-, methoxyl group-4-quinazolyl) amino] phenyl]-(intermediate 136)
The intermediate 135 (0.0019mol) in water (4ml) and methanol (40ml) and the solution of potassium carbonate (0.0038mol) stirred 1 hour down at 50 ℃, be added in the mixture of the potassium carbonate (0.26g) in the water (2ml) then, and this mixture stirred 4 hours.Solvent removed under reduced pressure and gained residue are dissolved in the acetic acid (100%).After stirring 30 minutes, solvent evaporation and crude product residue stir in DCM.Formed precipitation is filtered, washs then and stir in water.With gained sedimentation and filtration, washing and 60 ℃ down dry (vacuum), 0.650g (66%) intermediate 136.
Embodiment A 30
A) preparation alanine, N-[(4-chloro-2-nitrobenzophenone) acetoxyl group]-the 2-methyl-, ethyl ester (intermediate 137)
4-chloro-2-nitro-phenylacetic acid (0.00456mol) in DCM (20ml), 1-hydroxyl-177-benzotriazole (0.00456mol), 1,1 '-carbonyl is two-and the mixture of 1H-imidazoles (0.00456mol) and DIPEA (0.00456mol) stirred 15 minutes under RT, adds 2-methyl-alanine ethyl ester (0.00456mol) and this reactant mixture then and stir a weekend under RT.This mixture is with saturated potassium carbonate solution washing 2 times, with 1N HCl washing 2 times and with water washing 1 time.Separated, the dry (MgSO of organic layer
4), filter and evaporating solvent, intermediate 137.
B) preparation alanine, N-[(2-amino-4-chlorphenyl) acetoxyl group]-the 2-methyl-, ethyl ester (intermediate 138)
The mixture of the intermediate 137 (0.00456mol) in ethanol (25mol) and THF (25ml) in the presence of thiophene solution (0.3ml) with Pt/C 5% (0.5g) as catalyst 50 ℃ of hydrogenations.Absorbing H
2After (3 equivalent), catalyst is leached and evaporated filtrate, get 0.65g intermediate 138.
C) preparation alanine, N-[[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-the 4-chlorphenyl] acetoxyl group]-the 2-methyl-, ethyl ester (intermediate 139)
The intermediate 138 (0.0022mol) in acetonitrile (25ml) and the mixture of intermediate 85 (0.0022mol) were 80 ℃ of following heated and stirred 2 hours.Solvent evaporation and residue are via flash column chromatography (eluant: DCM/CH
3OH 100/0,95/5) purification, collect product component and evaporating solvent then, get 0.68g intermediate 139.
D) preparation alanine, N-[[4-chloro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] phenyl] acetyl group]-the 2-methyl-, ethyl ester (intermediate 140)
At CH
3OH/NH
3(7N) mixture of the intermediate 139 (0.0013mol) in (10ml) and the methanol (10ml) stirred 18 hours under RT, and solvent evaporated under reduced pressure gets 0.600g intermediate 140 then.
E) preparation alanine, N-[[4-chloro-2-[[6-[2-[[(1,1-dimethyl ethyoxyl) carbonyl] amino] ethyoxyl]-7-methoxyl group-4-quinazolyl] amino] phenyl] acetyl group]-the 2-methyl-, ethyl ester (intermediate 141)
The intermediate 140 (0.0013mol) in DMA (20ml) and the mixture of cesium carbonate (0.0063mol) stirred 45 minutes under RT, added (2-bromoethyl)-carbamic acid 1 then, 1-dimethyl ethyl ester (0.0014mol) and stirred this mixture 4 hours.Add other (2-bromoethyl)-carbamic acid 1,1-dimethyl ethyl ester (0.0014mol) and reactant mixture stir under RT and spend the night.The gained precipitation is leached and evaporated filtrate, get intermediate 141 (quantitative yield so is directly used in the next step step).
F) preparation alanine, N-[[24[6-(2-amino ethoxy)-7-methoxyl group-4-quinazolyl] amino]-the 4-chlorphenyl] acetyl group]-the 2-methyl-, ethyl ester (intermediate 142)
The solution of the intermediate 141 (0.0013mol) in TFA (15ml) and DCM (15ml) stirs 1 hour evaporating solvent then under RT, get 0.670g intermediate 142.
G) preparation alanine, N-[[2-[[6-(2-amino ethoxy)-7-methoxyl group-4-quinazolyl] amino]-the 4-chlorphenyl] acetyl group]-2-methyl-(intermediate 143)
Intermediate 142 (0.0013mol) and LiOH.H in ethanol (20ml) and water (1ml)
2The mixture of O (0.0039mol) adds other LiOH.H then 40 ℃ of heated and stirred 1 hour
2O (0.01192mol) and reactant mixture stirred 3 hours.Adding LiOH.H2O (0.00477mol) and gained mixture once more stirred 1 hour at 40 ℃.At last, solvent removed under reduced pressure gets intermediate 143 (quantitative yield)
Embodiment A 31
A) preparation Beta-alanine, N-[(2-amino-4-chlorphenyl) methyl]-, methyl ester (intermediate 144)
The mixture of the Beta-alanine methyl ester hydrogen chlorate (0.020mol) in methanol (100ml), 4-chlorine 2-nitro-benzaldehyde (0.010mol) and potassium fluoride (0.019mol) is at thiophene solution (1ml, 4% in the 2-propanol) in the presence of to be catalyst with Pt/C (1g, slurry in THF) change 24 hours at 50 ℃ following.Absorb H
2After (4 equivalent), reactant mixture is filtered on dicalite, filtering residue washs with DCM then, evaporating solvent.The gained residue is dissolved in the methanol and so is used for the next step step, gets intermediate 144.
B) preparation Beta-alanine, N-[(2-amino-4-chlorphenyl) methyl]-N-[(1,1-dimethyl ethyoxyl) carbonyl]-, methyl ester (intermediate 145)
Add tert-butyl two carbonic esters (0.060mol) in the intermediate 144 (0.020mol) and reactant mixture stirred 1 hour, add NH then
3/ CH
3OH and this mixture stirred 1 hour.It is eluant that solvent evaporation and dried residue filter on silica gel with DCM.Filtering residue is collected product component and evaporating solvent then via the RP high-efficient liquid phase chromatogram purification, gets 1.206g (36%) intermediate 145.
C) preparation Beta-alanine, N-[[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazoline amino]-the 4-chlorphenyl] methyl]-N-[(1,1-dimethyl ethyoxyl) carbonyl]-, methyl ester (intermediate 146)
The solution of the intermediate 145 (0.0035mol) in acetonitrile (40ml) is heated to 80 ℃, adds intermediate 85 (0.0035mol) and reactant mixture then and stirs 4 hours down at 80 ℃.At last, solvent evaporation gets intermediate 146 (so being used for the next step step) to doing.D) preparation Beta-alanine, N-[[4-chloro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] phenyl] methyl]-N-[(1,1-dimethyl ethyoxyl) carbonyl]-, methyl ester (intermediate 147)
With NH
3/ CH
3OH (7N) (0.035mol) is added in the solution of the intermediate 146 (0.0035mol) in the methanol (5ml), and reactant mixture stirred 30 minutes at RT.Solvent evaporation also is dissolved in the gained residue in the methanol.Add DIPE and the gained precipitation leached and dry, 0.9125g. for the second time crystallize can to filtrate, obtain by adding heptane, 0.8794g (total recovery: 93%) intermediate 147.
E) preparation Beta-alanine, N-[[4-chloro-2-[[6-[3-[[1,1-dimethyl ethyoxyl] carbonyl] amino] propoxyl group]-7-methoxyl group-4-quinazolyl] amino] phenyl] methyl]-N-[(1, l-dimethyl ethyoxyl) carbonyl]-, methyl ester (intermediate 148)
Cesium carbonate (0.00775mol) is added in the solution of the intermediate 147 (0.00155mol) among the dry DMF (15ml) and this mixture stirred 15 minutes under RT, add (3-bromopropyl)-carbamic acid 1 then, 1-dimethyl ethyl ester (0.00155mol) and reactant mixture stir under RT and spend the night.Solvent evaporation and residue are dissolved among the DCM.Slow filtration of this solution and filtering residue are washed with DCM, get intermediate 148 (so being directly used in the next step step).
F) preparation Beta-alanine, N-[[2-[[6-(the amino propoxyl group of 3-)-7-methoxyl group-4-quinazolyl] amino]-the 4-Chlorophenylmethyl]-hydroxyl, hydrogen chlorate (1: 1) (intermediate 149)
Water (4ml) is added in the solution of the intermediate 148 (0.00155mol) in the dioxane (10ml), add then hydrochloric acid (4ml, 36-38%) and reaction stirred until stopping to produce bubble.Add other hydrochloric acid (2ml, 36-38%) and reactant mixture in airtight bottle, stirred 8 hours.At last, evaporating solvent gets intermediate 149 (so being directly used in the next step step)
Embodiment A 32
A) preparation (R) proline, 1-[(4-chloro-2-nitrobenzophenone) methyl]-, 1,1-dimethyl ethyl ester (intermediate 150)
Four (2-propoxyl group) titaniums (0.010mol) are joined D-proline in DCM (30ml), 1,1-dimethyl ethyl ester, hydrogen chlorate (0.010mol) and 4-chloro-2-nitrobenzaldehyde (0.010mol), mixture stirred 1 hour under RT and adds NaBH (OAc) then
3(0.011mol).This reactant mixture stirs under RT and added entry in 2 hours then.Mixture filters on the P2 glass filter and with DCM washing, and the separated and water layer of organic layer is with DCM extraction 2 times then.Merge organic layer, drying, filtration and evaporating solvent, get intermediate 150 (so being directly used in the next step step)
B) preparation (R) proline, 1-[(2-amino-4-chlorphenyl) methyl]-, 1,1-dimethyl ethyl ester (intermediate 151)
Intermediate 150 (0.01mol) mixture in ethanol (100ml) and THF (50ml) is catalyst hydrogenation with Pt/C 5% (1g) in the presence of thiophene solution (1ml:4% is in DIPE).Absorbing H
2After (3 equivalent), catalyst is leached and evaporated filtrate.Residue is collected product component and evaporation organic solvent then via the RP high-efficient liquid phase chromatogram purification.The gained concentrate filters then, and filtering residue gets 1.0453g (34%) intermediate 151 with water washing and dry in stove.Extract with DCM with DCM washing filtering residue and water layer.Organic layer is dry and filtration on potassium carbonate, gets 0.0480g intermediate 151.
C) preparation (R) proline, the 1-[[2-[[6-acetoxyl group]-7-methoxyl group-4-quinazolyl] amino]-the 4-chlorphenyl] methyl]-, 1,1-dimethyl ethyl ester (intermediate 152)
Intermediate 85 (0.001mol) is added in the solution of the intermediate 151 (0.001mol) in the 2-propanol (in right amount), and reactant mixture stirred 2 hours and evaporating solvent subsequently.Other intermediate 85 (0.0185g) is added in the previous prepared reactant mixture, and this mixture stirred many 1 hour and evaporating solvent then, got intermediate 152.
D) preparation (R) proline, 1-[[4-chloro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] phenyl] methyl]-, 1,1-dimethyl ethyl ester (intermediate 153)
With NH
3/ CH
3OH (10ml) adds in the intermediate 152 (0.001mol) and this reactant mixture vibrated 1 hour, and evaporating solvent gets intermediate 153 (so being directly used in the next step step) then
E) preparation (R) proline, 1-[[4-chloro-2-[[6-(3-cyano group propoxyl group)-7-methoxyl group-4-quinazolyl] amino] phenyl] methyl]-, 1,1-dimethyl ethyl ester (intermediate 154)
The mixture of intermediate 153 (0.0005mol), 4-bromo-butyronitrile (0.04ml) and cesium carbonate (0.815g) stirs under RT and spends the night, and reactant mixture stirred 30 minutes down at 50 ℃ then.Adding other 4-bromo-butyronitrile (0.009ml) and this mixture stirs under RT after 4 hours again 50 ℃ of following stirrings 15 minutes.Solvent evaporation also is dissolved in residue among the DCM.This solution filters on dicalite and the filtrate evaporation, gets intermediate 154.
F) preparation (R) proline, 1-[[2-[[6-(the amino butoxy of 4-)-7-methoxyl group-4-quinazolyl] amino]-the 4-chlorphenyl] methyl]-, 1,1-dimethyl ethyl ester (intermediate 155)
At CH
3OH/NH
3Intermediate 154 (0.0005mol) mixture (40ml) is being catalyst, hydrogenation in the presence of thiophene solution (0.1ml) under 14 ℃, with raney nickel (catalytic amount).Absorbing H
2After (2 equivalent), catalyst is leached and evaporating solvent, get intermediate 155.
G) preparation (R) proline, 1-[[2-[[6-(the amino butoxy of 4-)-7-methoxyl group-4-quinazolyl] amino]-the 4-Chlorophenylmethyl]-.TFA (1: 1) (intermediate 156)
Solution stirring 7-8 hour of the intermediate 155 (residue) of TFA/1DCM/TIS (90/8/2) in (5ml), solvent evaporation and gained residue dried overnight in baking oven then, intermediate 156, separate with trifluoroacetate.
Embodiment A 33
A) preparation (S) proline, 1-[(4-chloro-5-fluoro-2-nitrobenzophenone) methyl]-, 1,1-, dimethyl ethyl ester (intermediate 157)
L-proline, 1 in DCM (30ml), the solution of 1-dimethyl ethyl ester (0.010mol) and 4-chloro-5-fluoro-2-nitro-benzaldehyde (0.010mol) is cooled to 0 ℃ and add four (2-propoxyl group) titaniums (0.010mol), and this mixture stirred 1 hour under RT and adds NaBH (Oac) then
3(0.011mol).The gained mixture stirred 6 hours under RT.Add entry and mixture is filtered.Organic layer is separated, dry, filter and evaporating solvent, intermediate 157 (so being directly used in the next step step).
B) preparation (S) proline, 1-[(2-amino-4-chloro-5-fluorophenyl) methyl]-, 1,1-dimethyl ethyl ester (intermediate 158)
The mixture of the intermediate 157 (0.009mol) in EtOAc (150ml) is that catalyst carries out hydrogenation with Pt/C 5% (1g) in the presence of thiophene solution (1ml:4% is in DIPE).When having absorbed H
2After (3 equivalent), catalyst is leached and evaporating solvent.Residue is via the RP high-efficient liquid phase chromatogram purification, collects the product component then and with organic solvent evaporation.Gained sedimentation and filtration, also dry with water washing gets 1.1286g (34%) intermediate 158.
C) preparation (S) proline, 1-[[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-4-chloro-5-fluorophenyl] methyl]-, 1,1-dimethyl ethyl ester (intermediate 159)
Intermediate 85 (0.001mol) is added in the solution of the intermediate 158 (0.001mol) in the 2-propanol (in right amount), reactant mixture stirs 2 hours and evaporating solvent then, gets intermediate 159 (so being used for the next step step)
D) preparation (S) proline, 1-[[4-chloro-5-fluoro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] phenyl] methyl]-, 1,1-dimethyl ethyl ester (intermediate 160)
With NH
3/ CH
3OH (10ml) adds in the intermediate 159 (0.001mol) and reactant mixture vibrated 1 hour, then with solvent evaporation, gets intermediate 160 (so being used for the next step step)
E) preparation (S) proline, 1-[[4-chloro-2-[[6-[3-[[(1,1-dimethyl ethyoxyl) carbonyl] amino] propoxyl group]-7-methoxyl group-4-quinazolyl] amino-5-fluorophenyl] methyl]-, 1,1-dimethyl ethyl ester (intermediate 161)
Intermediate 160 (0.0005mol), (3-bromopropyl)-carbamic acid, 1, the mixture of 1-dimethyl ethyl ester (0.12326ml) and carbon ester caesium (0.815g) stirs under RT and spends the night, and reactant mixture stirred 30 minutes down at 50 ℃ then.Add other (3-bromopropyl)-carbamic acid (0.013g), under RT, stir this mixture 4 hours and descend stirring 15 minutes at 50 ℃.Evaporating solvent and residue is dissolved among the DCM.This solution filters on dicalite and evaporating solvent, gets intermediate 161.
F) preparation (S) proline, 1-[[2-[[6-(the amino propoxyl group of 3-)-7-methoxyl group-4-quinazolyl] amino]-4-chloro-5-fluorophenyl] methyl]-.TFA salt (intermediate 162)
Solution stirring at the intermediate 161 (residue) of TFA/DCM/TIS (90/8/2) in (25ml) is spent the night, and evaporating solvent and gained residue be 80 ℃ of following dried overnight then, intermediate 162, separate with trifluoroacetate.
Embodiment A 34
A) preparation 5-hexene amide, N-[(2-amino-4-chlorphenyl) methyl]-(intermediate 163)
5-hexenoic acid (0.0075mol) in DCM (100ml) and PL-DCC resin (0.015mol; Polymer Laboratories:3417) mixture stirred 15 minutes under RT, added 2-amino-4-chloro-benzene methanamine (0.01125mol) and gained mixture then and stirred 3 hours.Added styrene methyl isocyanate (0.01125mol; Novabiochem:01-64-0169) after, reactant mixture stirred 4 hours, filtered and evaporating solvent, got 1.43g (76%) intermediate 163.
B) preparation 5-hexene amide, N-[(4-chloro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] phenyl) methyl]-(intermediate 164)
The intermediate 163 (0.0057mol) in 2-propanol (20ml) and the solution of intermediate 85 (0.0052mol) stirred 5 hours down at 60 ℃, then mixture were cooled off.Be added in the 7N NH in the methanol (20ml)
3, and reactant mixture stirred 2 hours under RT.At last, solvent evaporation gets 1.5g intermediate 164.
C) preparation 5-hexene amide, N-[(4-chloro-2-[(7-methoxyl group-6-(4-amylene oxygen base)-4-quinazolyl) amino] phenyl) methyl]-(intermediate 165)
Intermediate 164 (0.0018mol) in DMF (20ml) and the mixture of cesium carbonate (0.0090mol) stirred 15 minutes, added 5-bromo-1-amylene (0.0021mol) and mixture then and stirred under RT and spend the night.Add entry and DCM and layering.Organic layer washs with saline solution with 10% citric acid solution washing back, dry then (MgSO
4), filter and evaporating solvent.Residue (0.694g) is subsequently via the RP high-efficient liquid phase chromatogram purification.Collect product component and evaporating solvent, get 0.270g intermediate 165.
Embodiment A 35
A) preparation (S) carbamic acid, [1-[[[(4-chloro-2-nitrobenzophenone) methyl] amino] carbonyl]-the 3-cyclobutenyl]-, 1,1-dimethyl ethyl ester (intermediate 166)
With two (dimethylamino) methylene of 1-[]-the 1H-benzotriazole, hexafluoro phosphate ester (1-), 3-oxide (0.0056mol) is added in the 2-[[(1 among the DMF (25ml) lentamente, 1-dimethyl ethyoxyl) carbonyl] amino]-solution of 4-penetenoic acid (0.0046mol), 4-chloro-2-nitro-benzene methanamine (0.0056mol), 1-hydroxyl-1H-benzotriazole (0.0056mol) and DIPEA (0.93ml) in, this reactant mixture stirred 3 hours under RT then.This mixture is with EtOAc (200ml) dilution, then with 10%aq. citric acid solution (50ml), water (50ml), NaHCO
3Aqueous solution (50ml) and saline solution (50ml) washing.Separated, the dry (MgSO of organic layer
4), filter and evaporating solvent, 2.00g (100%) intermediate 166.
B) preparation (S) carbamic acid, [1-[[[(2-amino-4-chlorphenyl) methyl] amino] carbonyl]-the 3-cyclobutenyl]-, 1,1-dimethyl ethyl ester (intermediate 167)
Intermediate 166 (0.003mol) in ethanol (50ml) and tin chloride dihydrate (II) mixture (0.015mol) stirred 90 minutes down at 60 ℃, will extract 3 times in the reactant mixture impouring water and with toluene then.Separated, the dry (MgSO of organic layer
4), filter and evaporating solvent (vacuum), intermediate 167.
C) preparation (S) carbamic acid, [1-[[[[4-chloro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] benzyl] amino] carbonyl]-the 3-cyclobutenyl]-, 1,1-dimethyl ethyl ester (intermediate 168)
Intermediate 167 (0.003mol) in 2-propanol (150ml) and intermediate 85 (0.0025mol) solution cool off mixture after 55 ℃ stirring is spent the night down.Be added in methanol 50ml) in 7N NH
3And reactant mixture stirred 2 hours under RT.At last, evaporating solvent gets 2.17g intermediate 168.
D) preparation (S) carbamic acid, [1-[[[[4-chloro-2-[[7-methoxyl group-6-(4-amylene oxygen base)-4-quinazolyl] amino] phenyl] methyl] amino] carbonyl]-the 3-cyclobutenyl]-, 1,1-dimethyl ethyl ester (intermediate 169)
The intermediate 168 (0.0015mol) in DMF (30ml) and the solution of cesium carbonate (0.0075mol) stirred 15 minutes under RT, added 5-bromo-1-amylene (0.0018mol) and reactant mixture then and stirred 24 hours under RT.Add entry and DCM and layering.Organic layer washs with 10% citric acid solution, saline solution, dry then (MgSO
4), filter and evaporating solvent, intermediate 169.
Embodiment A 36
A) preparation 1-amylalcohol, 5-[2-(2-amino-4-chlorphenyl) ethyoxyl]-, ethyl ester (intermediate 170)
Reaction (I): in 1,20 dichloroethanes (30ml) 2, two (1, the 1-the dimethyl ethyl)-pyridines (0.012mol) of 6-and 4-chloro-2-nitro-phenethanol (0.01mol) are at N
2In 0 ℃ of stirring, the mixture of dropping trifluoroacetic anhydride (0.011mol) under 0 ℃, and reactant mixture then stirred 1 hour under RT, got mixture (I) down.
Reaction (II): 1,1 in the 2-two chloro-ethane (10ml), the 5-pentanediol, monoacetate (0.011mol) drips of solution is added in the mixture (I), and the gained mixture stirred 1 hour at 65 ℃.After the cooling, add entry and mixture distributes in ethanol/DCM.Organic layer is separated, dry, filtration and evaporating solvent.The gained residue is with by flash column chromatography (eluant: DCM/CH
3OH 100/0,98/2) purification.Collect product component and evaporating solvent, get mixture (II).The mixture of the mixture (II) in THF (50ml) is that catalyst is 50 ℃ of following hydrogenations with Pt/C (1g) in the presence of thiophene solution (1ml).When absorbing H
2After (3 equivalent), catalyst is leached and evaporated filtrate.Silica gel (eluant: hexane/EtOAc 80/20, the 70/30) purification of gained residue on glass funnel.Collect product component and evaporating solvent, get 1.5g intermediate 170.
B) preparation 6-quinazoline alcohol, 4-[[2-[2-[[5-(acetoxyl group) amyl group] the oxygen base] ethyl]-the 5-chlorphenyl] amino]-the 7-methoxyl group-, acetas (intermediate 171).
The intermediate 170 (0.005mol) in dioxane (20ml) and the mixture of intermediate 85 (0.005mol) were 80 ℃ of reactions 16 hours, and evaporating solvent gets intermediate 171 then.
C) preparation 6-quinazoline alcohol, 4-[[5-chloro-2-[2-[(5-hydroxyl amyl group) the oxygen base] ethyl] phenyl] amino]-7-methoxyl group-(intermediate 172)
The intermediate 1 (residue) in water (50ml) and methanol (50ml) and the mixture of potassium carbonate (5g) stir under RT and spend the night, and add entry then and mixture extracts with DCM.Organic layer is with water washing 2 times, and is dry then, filter and evaporating solvent.Add toluene and evaporating solvent once more, the intermediate 172 of 2g.
Embodiment A 37
A) preparation carbamic acid, [3-(4-chloro-2-nitrobenzophenone)-2-propyl group]-, 1,1-dimethyl ethyl ester (intermediate 173)
1-bromo-4-chloro-2-nitrobenzophenone (0.15mol) in triethylamine (300ml), dichloro two (triphenylphosphine) change palladium (0.0075mol) and Copper diiodide (I) mixture (0.0075mol) stirs down at 50 ℃, and add 2-propynyl-carbamic acid in batches, 1,1-dimethyl ethyl ester (0.375mol), reactant mixture stirred 2 hours down and evaporating solvent at 50 ℃ then.Residue is dissolved in the water and this mixture extracts with EtOAc.Organic layer is separated, dry, filtration and evaporating solvent.Residue is via column chromatography (eluant: hexane/EtOAc 80/20) purification 2 times.Collect product component and evaporating solvent.Gained residue (31.8g) stirs in hexane then the gained precipitation is leached and drying, gets 31.5g (67.6%) intermediate 173.
B) preparation carbamic acid, [3-(2-amino-4-chlorphenyl) propyl group]-, 1,1-dimethyl ethyl ester (intermediate 174)
The mixture of the intermediate 173 (0.04mol) in THF (200ml) is a catalyst in 50 ℃ following change (during, catalyst is changed 2 times) with Pt/C (3g) in the presence of thiophene solution (1ml).Absorbing H
2After (6 equivalent), catalyst is leached and evaporating solvent, get (66%) intermediate 174.
C) preparation carbamic acid, [3-[2-[[6-(acetoxyl group)-7-methoxyl group-4-quinazolyl] amino]-the 4-chlorphenyl] propyl group]-, 1,1-dimethyl ethyl ester (intermediate 175).
The intermediate 174 (0.04mol) in acetonitrile (100ml) and the mixture of intermediate 85 (0.035mol) reacted 3 hours down at 75 ℃, then reactant mixture were cooled off.The gained precipitation leaches and is dry, gets 12.2g (69.6%) intermediate 175.
D) preparation butanoic acid, 4-[[4-[[5-chloro-2-[3-[[(1,1-dimethyl ethyoxyl) carbon back] amino] propyl group] phenyl] amino]-7-methoxyl group-6-quinazolyl] the oxygen base]-, ethyl ester (intermediate 176)
The intermediate 175 (0.00020mol) in water (1ml) and methanol (1ml) and the mixture of potassium carbonate (0.00072mol) stirred 16 hours under RT, then evaporating solvent.Residue is dissolved in the water, and mixture extracts with the NaOAc neutralization and with DCM then.Organic layer is separated, dry, filter and evaporating solvent, 0.850g intermediate 176.
E) preparation butanoic acid, 4-[[4-[[2-(3-aminopropyl)-5-chlorphenyl] amino]-7-methoxyl group-6-quinazolyl] the oxygen base]-(intermediate 177)
The mixture of the intermediate 176 (0.00035mol) in THF (10ml)/HCl36% (2ml)/water (3ml) stirs 16 hours evaporating solvents then under RT.The gained residue stirs in acetonitrile, then the gained precipitation is leached and drying, gets 0.200g intermediate 177.
Embodiment A 38
A) preparation carbamic acid, [3-[4-chloro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] phenyl] propyl group]-, 1,1-dimethyl ethyl ester (intermediate 178)
Intermediate 175 (0.056mol) hydrogen chlorate in water (250ml) and methanol (200ml) and the mixture of potassium carbonate (25g) stirred under RT 6 hours and evaporating solvent then.Residue is dissolved in a spot of water, adds NaOAc (25g) and mixture then with DCM/CH
3The OH extraction.Organic layer is separated, dry, filter and evaporating solvent, 23.5g (91.5%) intermediate 178.
B) preparation 6-quinazoline alcohol, 4-[[2-(3-aminopropyl)-5-chlorphenyl] amino]-7-methoxyl group-.HCl (1: 1) (intermediate 179)
The mixture of the intermediate 178 (0.015mol) in methanol (50ml) and HCl/2-propanol (10ml) stirs 16 hours evaporating solvents then under RT.The gained residue is dry in DIPE, and after filtration, filter residue and drying gets 6.1g (94.6%) intermediate 179, separates with the hydrogen chlorate.
C) preparation acetamide, N-[3-[4-chloro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] phenyl] propyl group]-the 2-[(2-ethoxy) amino]-(intermediate 180)
Intermediate 179 (0.02mol), DMF (100ml) and DIPEA (0.1mol) stir down at 1-10 ℃, drip the mixture of the bromoacetyl chloride (0.05mol) in DCM (10ml) then, and reactant mixture stirred 2 hours under RT, must mixture (I).To be added drop-wise in the mixture (I) at the mixture of the 2-amino-ethanol (0.2mol) among the DMF (20ml), and this reactant mixture stirred 5 hours down at 60 ℃.Evaporating solvent and gained residue are via RP high performance liquid chromatography purification.Collect product component and evaporating solvent, get 10.7g intermediate 180.
D) preparation carbamic acid, [2-[[3-[4-chloro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] phenyl] propyl group] amino-2-oxygen ethyl] (2-ethoxy)]-, 1,1-dimethyl ethyl ester (intermediate 181)
To stir at the mixture of the intermediate 180 (0.0043mol) among DCM (50ml) and the THF (50ml), add two (1, the 1-dimethyl ethyl) esters (0.0046mol), reactant mixture stirs 2 hours and evaporating solvent then.Residue is dissolved in the low amounts of water and this mixture extracts with DCM.Separated and the evaporating solvent of organic layer.The gained residue is dissolved in and adds CH in the methanol then
3OH/NH
3The gained mixture stirred 2 hours and evaporating solvent.Residue is at glass filter (eluant: DCM/CH
sOH 90/10) last purification.Collect product component and evaporating solvent, get 0.500g intermediate 181.
Embodiment A 39
Preparation (intermediate 182)
The mixture of the intermediate 179 (0.016mol) in DMF (80ml) stirs and also to add DIPEA (0.040mol), solution (
*).In advance with the washed 2-(3 of DCM; 5-dimethoxy-4 '-formoxyl phenoxy group) (ethoxymethyl) base polystyrene (0.00528mol; Novabiochem:01-64-0261), in DCM (120ml), stir, add four (2-propoxyl group) titaniums (0.016mol) then and stir this mixture.Adding solution (
*) and the gained mixture stirred 2 hours.Add NaBH (OAc)
3(0.016mol), react turbid compound and stirred 16 hours and filtered.Filtering residue washs 3 times with DCM (200ml) at last with DCM (100ml)/THF (100ml) washing 2 times, wash continuously 3 times with DCM (200ml) and methanol (200ml).Washed residue was 50 ℃ of following dryings 16 hours and collect required product, got 9.46g (77%) intermediate 182.
Embodiment A 40
A) preparation 1,3-dioxolanes-2-methylamine, N-[(2-amino-4-chlorphenyl) methyl]-N-methyl-(intermediate 183)
N-methyl isophthalic acid in methanol (200ml), the solution of 3-dioxolanes-2-methylamine (0.020mol) and 4-chloro-2-nitro-benzaldehyde (0.010mol) is (an amount of at thiophene solution, 4% in THF) exist down, with Pt/C (catalytic amount, the serosity in EtOAc) is that catalyst is 50 ℃ of following hydrogenations.Absorbing H
2After (4 equivalent), reactant mixture is filtered on dicalite and evaporating solvent.Residue is via the RP high-efficient liquid phase chromatogram purification.Collect product component and evaporate organic component.Precipitation is leached, get 0.7879g (31%) intermediate 183.
B) preparation 6-quinazoline alcohol, 4-[[5-chloro-2-[[(1,3-dioxolanes-2-ylmethyl) methylamino] methyl] phenyl] amino]-the 7-methoxyl group-, acetas (intermediate 184)
Intermediate 85 (0.00156mol) in acetonitrile (15ml) and intermediate 183 (0.00156mol) solution stirred 3 hours down at 80 ℃, and reactant mixture allows cool overnight then.This mixture descended other restir 1 hour at 80 ℃, added 3 glacial acetic acids then.The gained mixture stirs and adds once more glacial acetic acid (1ml) down at 80 ℃.80 ℃ stir down spend the night after, this mixture is cooled to RT and with the gained sedimentation and filtration.Filtrate evaporation and residue are dry in baking oven, get intermediate 184 (so being used for next step reactions steps).
C) preparation 6-quinazolyl, 4-[[5-chloro-2-[[(1,3-dioxolanes-2-ylmethyl) methylamino] methyl] phenyl] amino]-7-methoxyl group-(intermediate 185)
At NH
3/ CH
3The solution of the intermediate 184 (0.00156mol) among the OH (in right amount) stirred 1 hour under RT, then reactant mixture is filtered filtering residue and filtrate.Filtrate is ground with acetonitrile, collects products obtained therefrom then, gets 0.1350g intermediate 185.
D) preparation carbamic acid, [3-[[4-[[5-chloro-2-[[(1,3-dioxolanes-2-ylmethyl) methylamino] methyl] phenyl] amino]-7-methoxyl group-6-quinazolyl] the oxygen base] propyl group]-, 1,1-dimethyl ethyl ester (intermediate 186)
Cesium carbonate (0.00464mol) is added in the solution of the intermediate 185 (0.00093mol) among the DMF (9ml), and mixture stirred 1 hour under RT.Add (3-bromopropyl)-carbamic acid, 1,1-dimethyl ethyl ester (0.00093mol) and reactant mixture stir under RT and spend the night, and evaporating solvent and residue are dissolved among the DCM then.This solution filters on dicalite and filtrate be evaporated to dried, intermediate 186 (so using in the infra step reactions steps)
Embodiment A 41
A) preparation benzene methanamine, 4-chloro-N-methyl-2-nitro-N-2-acrylic-(intermediate 187)
4-chloro-2-nitro-benzaldehyde (0.010mol) in DCM (in right amount) and N-methyl-2-acrylic-1-amine (0.010mol) stirred 15 hours under RT, added NaBH (OAc) then
3(0.011mol) and reactant mixture under RT, stirred 3.5 hours.Add other NaBH (OAc)
3(0.002mol) and mixture at silica gel (eluant: DCM) go up to filter.Secondary component on silica gel via column chromatography once more purification and with the first time gained component merge, evaporating solvent then, 2.0689g (86%) intermediate 187.
B) preparation benzene methanamine, 2-amino-4-chloro-N-methyl-N-2-propyl group-(intermediate 188)
Tin chloride dihydrate (II) (0.043mol) is added in the solution of the intermediate 187 (0.0086mol) in the ethanol (40ml), and after stirring, this reactant mixture heated 90 minutes down at 50 ℃.Add saturated NaHCO
3Aqueous solution adds DCM subsequently again, and the isolating organic layer of stratum disjunctum and institute filters then.Water layer filters once more with DCM extraction 3 times and isolating organic layer.Filtering residue is separated with the organic layer of DCM washing 3 times and filtrate, and drying, filtration and evaporating solvent get 1.3772g (76%) intermediate 188 then.
C) preparation 6-quinazoline alcohol, 4-[[5-chloro-2-[(methyl-2-acrylic amino) methyl] phenyl] amino]-the 7-methoxyl group-, acetas (intermediate 189)
Intermediate 85 (0.0016mol) is added in the solution of the intermediate 188 (0.0016mol) in the 2-propanol (20ml), then reactant mixture was stirred 3 hours down at 80 ℃, collect required product, get intermediate 189.
D) preparation 6-quinazoline alcohol, 4-[[5-chloro-2-[(methyl-2-acrylic amino) methyl] phenyl] amino]-7-methoxyl group-(intermediate 190)
At NH
3/ CH
3The solution vibration of the intermediate 189 (0.0016mol) among the OH (10ml) 1 hour, evaporating solvent gets intermediate 190 to doing then.
E) preparation 4-quinazoline amine, 6-(3-butoxy)-N-[5-chloro-2-[(methyl-2-acrylic-amino) methyl] phenyl]-7-methoxyl group-(intermediate 191)
The mixture of the intermediate 190 (0.00042mol) in DMF (in right amount), 4-bromo-1-butylene (0.0005mol) and cesium carbonate (in right amount) stirs under RT and spends the night, then evaporating solvent.The residue of doing is dissolved among the DCM and gained solution filters on dicalite, collects required product then, gets intermediate 191.
Embodiment A 42
A) preparation 1H-iso-indoles-1,3 (2H)-diketone, 2-[2-(4-chloro-2-nitrobenzophenone) ethyl]-(intermediate 192)
4-chloro-1-(2-chloroethyl)-2-nitro-benzene (0.37mol) and 1H-iso-indoles-1,3 (2H)-diketone in DMF (1000ml), the mixture of potassium carbonate (0.55mol) are 90 ℃ of reactions 2 hours, then with in reactant mixture cooling and the impouring ice-water.The gained mixture stirred 30 minutes under RT, and precipitation is leached.Filtering residue is dissolved in band MgSO
4DCM in, filter the rear filtrate evaporation.: 118g (96%) intermediate 192.
B) preparation phenethylamine, 4-chloro-2-nitro-(intermediate 193)
Hydrazine hydrate (2.0mol) slowly is added drop-wise in the mixture of the intermediate 192 (0.37mol) in methanol (1000ml), reactant mixture reacted 6 hours down at 55 ℃ then.After the filtration, filtrate is steamed and is added entry to the gained residue.This mixture extracts 3 times with toluene, then separated, the dry (MgSO of organic layer
4), filter and evaporating solvent, 61.5g intermediate 193.
C) preparation benzene phenethylamine, 2-amino-4-chloro-(intermediate 194)
The mixture of the intermediate 193 (0.225mol) in THF (500ml) carries out hydrogenation with Pt/C 5% (5g) as catalyst in the presence of thiophene solution (5ml).Absorbing H
2After (3 equivalent), catalyst is filtered off and solvent is evaporated.The gained residue adds sodium hydroxide until pH:9 after stirring 1 hour under 60 ℃ and cooling off.Separated and the water layer of organic layer is with toluene extraction 2 times.Organic layer is merged, dry (MgSO
4), filtration and solvent evaporation, 30g intermediate 194.
D) preparation (S) carbamic acid, [2-[[2-(2-amino-4-chlorphenyl) ethyl] amino-1-methyl-2-oxygen ethyl]-, 1,1-dimethyl ethyl ester (intermediate 195)
N[(1 in DCM (20ml), the 1-dimethyl ethyl) carbonyl]-L-alanine (0.0015mol) and PL-DCC resin (0.0030mol; Polymer Laboratories, Part No 3417) mixture stirred 30 minutes under RT.Be added in two (dimethylamine) methylene of 1-[among a small amount of DMF (5ml)]-1H-124 Triazole salt, hexafluoro phosphine (1-), the mixture of 3-oxide (0.0015mol).The mixture and the reactant mixture that are added in the intermediate 194 (0.00225mol) among the DCM (2ml) stirred 5 hours, added methyl Carbimide. polystyrene (0.00225mol then; NovaBiochem, No 01-64-0169), [two carbonic acid (polystyrene methyl) trimethyl ammonium (0.00450mol in addition; NovaBiochem, No 01-64-0419) also be added into.After 15 hours, reactant mixture is filtered and solvent evaporation, gets intermediate 195.
E) preparation (S) carbamic acid, [2-[[2-[4-chloro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] phenylethyl] amino-1-methyl-2-oxygen ethyl]-, 1,1-dimethyl ethyl ester (intermediate 196)
The intermediate 195 (0.00110mol) in 2-propanol (20ml) and the solution of intermediate 85 (0.00100mol) stirred 5 hours down at 50 ℃, then with the mixture cooling and be added in 7N NH in the methanol (10ml)
3Reactant mixture stirred 2 hours and evaporating solvent at RT, got intermediate 196.
F) preparation (S) acetic acid, [[4-[[2-[2-[(2-amino-1-oxopropyl) amino] ethyl]-the 5-chlorphenyl] amino]-7-methoxyl group-6-quinazolyl] the oxygen base]-HCl (1: 1) (intermediate 197)
Step I " carries out alkylation with chloracetate ": the intermediate 196 (0.001mol) in dry acetonitrile (20ml), chloro-acetic acid, the solution of methyl ester (0.002mol) and potassium carbonate (0.003mol) stirred 3 hours down at 75 ℃, add entry (2ml) and DCM (10ml) then, reactant mixture stirred 5 minutes under RT.This mixture filters via Isolute HM-N, and subsequently with the DCM eluting, evaporating solvent gets residue (I) then.Step II " deprotection ": the solution of the residue (I) in dense HCl (2.5ml), water (2.5ml) and dioxane (5.0ml) stirred 24 hours down at 60 ℃, and solvent evaporation then gets intermediate 197, separates with hydrogen chlorate (1: 1)
Embodiment A 43
A) preparation carbamic acid, [4-[[(4-chloro-2-nitrobenzophenone) methyl] amino]-4-oxidation butyl]-, 1,1-dimethyl ethyl ester (intermediate 198)
With N '-(ethyl carbon imines acyl)-N, N-dimethyl-1,3-propanediamine (0.0049mol) is added in the 4-[[(1 among the DMF (30ml) in batches, 1-dimethyl ethyoxyl) carbonyl] amino]-mixture of butanoic acid (0.0049rnol), 4-chloro-2-nitrobenzoyl alkanamine (0.0041mol) and DIPEA (0.0049mol), and reactant mixture stirred 3 hours under RT.Mixture is with EtOAc (150ml) dilution, the citric acid solution with 10%, water, NaHCO
3Aqueous solution and saline solution washing.Organic layer is separated, dry, filter and evaporating solvent, 1.225g intermediate 198.
B) preparation carbamic acid, [4-[[(2-amino-4-chlorphenyl) methyl] amino-4-oxo butyl]-, 1,1-dimethyl ethyl ester (intermediate 199)
The mixture of the intermediate 198 (0.003mol) in THF (25ml) and methanol (25ml) is that catalyst is 50 ℃ of following hydrogenations with Pt/C 5% (0.5g) in the presence of thiophene solution (0.5ml).Absorbing H
2After (3 equivalent), catalyst is leached and evaporating solvent, get intermediate 199.
C) preparation carbamic acid, [4-[[[4-chloro-2-[(6-hydroxyl-7-methoxyl group-4-quinazolyl) amino] phenyl] methyl] amino]-4-oxo butyl]-, 1,1-dimethyl ethyl ester (intermediate 120)
The intermediate 199 (0.0033mol) in 2-propanol (100ml) and the solution of intermediate 85 (0.00275mol) are at 50 ℃ of NH that stirred 3 hours down and be added in after cooling in the methanol (50ml)
3, 7N.Reactant mixture stirs evaporating solvent after 2 hours, gets intermediate 120.
D) preparation acetic acid, [[4-[[5-chloro-2-[[[4-[[(1,1-dimethyl ethyoxyl) carbonyl] amino]-1-oxidation butyl] amino] methyl] phenyl] amino]-7-methoxyl group-6-quinazolyl] the oxygen base]-, methyl ester (intermediate 121)
The mixture of the intermediate 120 (0.001mol) in acetonitrile (10ml), potassium carbonate (0.003mol) and methyl chloroacetate (0.003mol) stirred 3 hours down at 75 ℃, then reactant mixture on silica gel, filter and residue with the 2-washing with acetone.At last, the filtrate vapourisation under reduced pressure spends the night, and gets intermediate 121.
E) preparation acetic acid, [[4-[[2-[[(4-amino-1-oxo butyl) amino] methyl]-the 5-chlorophenyl] amino]-7-methoxyl group-6-quinazolyl] the oxygen base]-(intermediate 122)
The solution of the intermediate 121 (0.001mol) in dense HCl (3ml), THF (6ml) and water (3ml) stirred 24 hours down at 60 ℃, and evaporating solvent gets intermediate 122 then.
B. the preparation of chemical compound
Embodiment B 1
Preparation 4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 are because of-8 (9H)-ketone, and 10,11,12,13-tetrahydrochysene-20-methoxyl group-15-methyl-(chemical compound 1)
Intermediate 5 (0.00008mol), N '-(ethyl carbon imines acyl)-N, N-dimethyl-1, the solution of 3-propanediamine (0.00024mol) and DMC (5ml) stirs under RT, add N '-(ethyl carbon imines acyl)-N then, N-dimethyl-1, the single hydrogen chlorate (0.00008mol) of 3-propanediamine.Reactant mixture stirs a weekend under RT.React completely, mixture is with H
2O washing 2 times.Separated, the dry (MgSO of organic layer
4), filter and evaporating solvent.Residue is via the high performance liquid chromatography on RP-18 (positive) purification.Collect product component, evaporating solvent and residue get 0.009g chemical compound 1 65 ℃ down dry (vacuum).
Embodiment B 2
The preparation 4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 because of-, 15-chloro-8,9,10,11,12,13-six hydrogen-20-methoxyl group-(chemical compound 2)
The intermediate 9 (0.0024mol) in doing THF (100ml) and the solution of triphenylphosphine (0.0036mol) stir under RT, drip the solution of two (1-Methylethyl) esters (0.0036mol) of azoformic acid in THF (10ml) then.Reactant mixture stirred 6 hours and added two (1-Methylethyl) esters (0.35ml) of the other azoformic acid in THF (10ml).The mixture stirring is spent the night and is concentrated.Residue is via (the eluant: DCM/CH of the column chromatography on silica gel
3OH/THF 90/5/5) purification.Collect product component also further by the RP high-efficient liquid phase chromatogram purification.Collect product component and concentrated.Aqueous concentrate filters, and institute's solid retained is washed and 65 ℃ down dry (vacuum), get 0.065g chemical compound 2, fusing point 155.5-260.2 ℃.
Embodiment B 3
The preparation 4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 because of-, 17-chloro-8,9,10,11,12,13-six hydrogen-20-methoxyl group-(chemical compound 3)
THF (doing) in (50ml) intermediate 13 (0.0012mol) and the solution of tributylphosphine (0.0018mol) at N
2Under RT, stir under the condition, drip mixture then THF (doing) 1,1 '-(azo dicarbapentaborane) two-piperidines (0.0018mol) in (10ml).The reactant mixture stirring is spent the night and is added other tributylphosphine (0.30ml).Other 4 hours of mixture restir and evaporating solvent.Residue is via the RP high-efficient liquid phase chromatogram purification, collects the product component and concentrates, and aqueous concentrate filters, and institute's solid retained is washed, 65 ℃ down dry (vacuum), 0.040g chemical compound 3, fusing point: 241.5-242.7.
Embodiment B 4
Preparation 4,6-ethanetetrayl-8H, 18H-pyrimido [4,5-b] [6,12,1] benzo two oxa-azacyclo-s 14 be because of (cyclotetradecine), 16-chloro-9,10,11,12-tetrahydrochysene-19-methoxyl group-(chemical compound 4)
Intermediate 17 (0.001mol) in THF (40ml) and tributylphosphine (0.0012mol) solution are in N
2Stir at RT down, drip 1,1 ' among the THF (10ml)-(azo dicarbapentaborane) two-piperidines (0.0012mol) solution then.Reactant mixture stir add after 4 hours the tributylphosphine (1ml) that reenters other amount and, 1 '-(azo dicarbapentaborane) two-piperidines (1g).The gained compound that boils stirs and to spend the night and the concentrating under reduced pressure solvent.Residue is via the RP high-efficient liquid phase chromatogram purification.Collect product component and evaporate organic solvent.With gained sedimentation and filtration, washing and in 65 ℃ down dry (vacuum), 0.0065g chemical compound 4, fusing point 213.5-221.2 ℃.
Embodiment B 5
The preparation 4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 because of, 8,9,10,11,12,13-six hydrogen-20-methoxyl group-(chemical compound 5)
Intermediate 21 (0.0013mol) in THF (50ml) and tributylphosphine (0.002mol) solution stir under RT, add 1,1 ' among the THF (5ml)-(azo dicarbapentaborane) two-piperidines (0.002mol) solution then.Stirred reaction mixture 6 hours also reacts completely.Evaporating solvent and residue are by the RP high-efficient liquid phase chromatogram purification.Collect product component and evaporate organic solvent.Aqueous concentrate filters, and residual solids is washed and 65 ℃ down dry (vacuum), got 0.100g chemical compound 5, fusing point 243.3-251.2 ℃.
Embodiment B 6
The preparation 4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 because of, 17-bromo-8,9,10,11,12,13-six hydrogen-20-methoxyl group-(chemical compound 6)
Intermediate 25 (0.00079mol) in exsiccant THF (50ml) and tributylphosphine (0.00316mol) are at N
2Stir down in RT under the-air-flow, add 1,1 '-(azo dicarbapentaborane) two-piperidines (0.00316mol) solution among the THF (10ml) then.Reactant mixture is at N
2-air-flow stirred 12 hours down in RT.Evaporating solvent, residue stir and filtering mixt in DIPE.Filtrate and residue merge, and by the RP high-efficient liquid phase chromatogram purification.Collect product component and concentrated, get 0.180g (51%) chemical compound 6, fusing point 228.6-234.8 ℃.
Embodiment B 7
The preparation 4,6-ethanetetrayl-8H, 20H-pyrimido [4,5-b] [6,14,1] benzo two oxa-azacyclo-s-16 because of, 18-chloro-9,10,11,12,13,14-six hydrogen-21-methoxyl group-(chemical compound 7)
Intermediate 21 (0.0013mol) in THF (50ml) and tributylphosphine (0.002mol) solution stir under RT, add 1,1 ' among the THF (5ml)-(azo dicarbapentaborane) two-piperidines (0.002mol) solution then.Stirred reaction mixture 6 hours also reacts completely.Evaporating solvent and residue are by the RP high-efficient liquid phase chromatogram purification.Collect product component and evaporate organic solvent.Aqueous concentrate filters, and residual solids is washed and 65 ℃ down dry (vacuum), got 0.100g chemical compound 5, fusing point 243.3-251.2 ℃.
Embodiment B 8
The preparation 4,6-ethanetetrayl-21H-pyrimido [4,5-b] [6,15,1] benzo two oxa-azacyclo-s 17 because of, 19-chloro-8,9,10,11,12,13,14,15-octahydro-22-methoxyl group-(chemical compound 8)
The solution of the intermediate 33 (0.0045mol) in THF (200ml) stirs under RT, tributylphosphine (0.0047mol), and secondly 1,1 '-(azo dicarbapentaborane) two-piperidines (0.0047mol) successively is added.Reactant mixture stirred 4 hours, and evaporating solvent is until the initial volume that reaches 2/3.Mixture filters, and residue washs with THF in a small amount.Filtrate concentrates and residue is suspended in H
2Also stir among the O.Filter and collect the gained precipitation, wash with water and handle with boiling 2-propanol.Also filtration of mixture cooling, institute's solid retained is washed with 2-propanol and DIPE and 60 ℃ down dry (vacuum), is got the chemical compound 8 of 1.4g (74%), fusing point 147.7-151.1 ℃.
Embodiment B 9
The preparation 4,6-ethanetetrayl-8H, 22H-pyrimido [4,5-b] [6,16,1] benzo two oxa-azacyclo-s-18 because of, 20-chloro-9,10,11,12,13,14,15,16-octahydro-23-methoxyl group-(chemical compound 8)
The solution of the intermediate 37 (0.0022mol) in THF (100ml) stirs under RT, tributylphosphine (0.0023mol), and secondly 1,1 '-(azo dicarbapentaborane) two-piperidines (0.0023mol) successively is added.Reactant mixture stirred 4 hours, and evaporating solvent is until the initial volume that reaches 2/3.Mixture filters, and residue washs with THF in a small amount.Filtrate concentrates and residue is suspended in H
2Also stir among the O.Filter and collect the gained precipitation, wash with water and handle with boiling 2-propanol.Also filtration of mixture cooling, institute's solid retained is washed with 2-propanol and DIPE and 60 ℃ down dry (vacuum), is got the chemical compound 9 of 0.6g (63%), fusing point 177.4-183.8 ℃.
Embodiment B 10
A) preparation 4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 be because of-17-carboxylic acid, and 8,9,10,11,12,13-six hydrogen-20-methoxyl group-, methyl ester (chemical compound 10)
Chemical compound 6 (0.0005mol), Pd (OAC)
2(0.022g), 1,3-propane two base two [diphenyl-phosphine] (0.088g) and the mixture of potassium acetate (0.100g) reacts under 125 ℃, in the CO-gas (30atm).Solvent is evaporated.Residue is brought in the water and with DCM and is extracted this mixture.Isolating organic layer drying, filtration and evaporating solvent.Residue (is used eluent gradient elution: CH with the HPLC on X-Terra
3CN/CH
3OH/NH
4OAc) purification.Collect product component and evaporating solvent.Residue is brought in the water, uses K
2CO
3Alkalization extracts with DCM then.Isolating organic layer drying, filtration and evaporating solvent get 0.057g chemical compound 10.
B) preparation 4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 are because of-17-carboxylic acid, 8,9,10,11,12,13-six hydrogen-20-methoxyl group-(chemical compound 11)
At THF (3ml), methanol (3ml), NaOH 1N (1ml) and H
2The mixture of the chemical compound 10 among the O (2ml) stirred 3 hours down in 50 ℃.Evaporating solvent.Add entry (2ml).Add HCl (1N, 1ml) and mixture be stirred a little while.Precipitation is leached, wash with water, and then filter and in THF, stir, filter then and drying, get 0.036g chemical compound 11.
Embodiment B 11
The preparation pyrrolidine, 1-[(8,9,10,11,12,13-six hydrogen-20-methoxyl group-4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 are because of-17-yl) carbonyl] pyrrolidine (chemical compound 12)
Chemical compound 6 (0.0004mol), Pd (OAC) in THF (an amount of, drying)
2(0.011g), 1,3-propane two base two [diphenyl-phosphine] (0.044g) and the mixture of pyrrolidine (0.100g) reacted 16 hours under 125 ℃, in the CO-gas (30atm).Solvent is evaporated.Residue is brought in the water and with DCM and is extracted this mixture.Isolating organic layer drying, filtration and evaporating solvent.Residue (is used eluent gradient elution: CH with the HPLC on X-Terra
3CN/CH
3OH/NH
4OAc) purification.Collect product component and evaporating solvent.Residue is brought in the water, uses K
2CO
3Alkalization extracts with DCM then.Isolating organic layer drying, filtration and evaporating solvent get 0.057g chemical compound 12.
Embodiment B 12
4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 are because of-17-nitrile, 8,9,10,11,12,13-six hydrogen-20-methoxyl group-(chemical compound 13)
Chemical compound 6 (0.0002mol) in (2-OXo-1-pyrrolidine base)-methyl (2ml), three [μ-[(1,2-, η: 4,5-η)-(1E, 4E)-1,5-diphenyl-1,4-pentadiene-3-ketone]] two-palladium, (0.011g), 1,1 '-two (diphenylphosphine)-ferrocene (0.013g), zinc (0.005g) and Zn (CN)
2Mixture (0.045g) reacted 30 minutes in 150 ℃ in microwave in (2-OXo-1-pyrrolidine base)-methyl (2ml).Add entry (4ml) and with this mixture of ethyl acetate extraction 3 times.Merge the washing of organic layer and water (2x), drying, filter and evaporating solvent.Residue (is used eluant gradient elution: CH by the reversed-phase HPLC on X-Terra
3CN/CH
3OH/NH
4OAc) purification.Collect product component and evaporating solvent.Residue absorbs in water, uses K then
2CO
3Alkalization.This mixture extracts with DCM.Isolating organic layer drying, filtration and evaporating solvent get 0.063g (81%) chemical compound 13.
Embodiment B 13
The preparation morpholine, 4-[(8,9,10,11,12,13-six hydrogen-20-methoxyl group-4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 are because of-17-yl) carbonyl]-(chemical compound 14)
Chemical compound 6 (0.0002mol), Pd (OAc) in THF (an amount of, drying)
2(0.022g), 1,3-propane two base two [diphenylphosphine] (0.088g) and morpholine (0.200g) under CO-gas (30atm), reacted 24 hours down in 125 ℃.Solvent evaporation.Residue absorbs in water and this mixture extracts with DCM.Isolating organic layer drying, filtration and evaporating solvent.The HPLC of residue on X-Terra (uses eluant gradient elution: CH
3CN/CH
3OH/NH
4OAc) purification.Collect product component and evaporating solvent.Residue absorbs in water, uses K then
2CO
3Alkalization.This mixture extracts with DCM.Isolating organic layer drying, filtration and evaporating solvent get 0.005g chemical compound 14.
Embodiment B 14
A) preparation 4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 because of, 17-bromo-8,9,10,11,12,13-six hydrogen-20-benzyloxy-(chemical compound 15)
Intermediate 47 (0.0026mol) solution in THF (140ml) stirs under RT, adds tributylphosphine (0.0035mol) and adds ADDP (0.0035mol) subsequently.Reactant mixture stirred 6 hours and added other ADDP (0.0035mol) and tributylphosphine (0.0035mol).The gained mixture stirred 12 hours.Formed precipitation removes and solvent evaporated under reduced pressure.Residue is dissolved among the THF (100ml) of band molecular sieve.
Other ADDP (0.0035mol) and tributylphosphine (0.0035mol) are added into and this mixture stirred 2 hours.Gained sedimentation and filtration and solvent evaporated under reduced pressure.Residue filters (eluant: DCM/CH on silica gel
3OH 98/2).Collect product component and evaporating solvent, get 0.600g chemical compound 15.
B) preparation 4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 are because of-20-alcohol, 17-bromo-8,9,10,11,12,13-six hydrogen-(chemical compound 16)
The solution of the chemical compound 15 (0.0006mol) in trifluoracetic acid (6ml) and (sulphomethyl)-benzene (0.006mol) stirred 3 days under RT and evaporating solvent subsequently.Residue H
2Water layer extracts with DCM after the O quencher.Sedimentation and filtration between two-layer, washing and in 60 ℃ down dry (vacuum), chemical compound 16.
Embodiment B 15
The preparation 4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 because of, 17-bromo-8,9,10,11,12,13-six hydrogen-20-[3-(4-morpholinyl) propoxyl group]-acetic acid (chemical compound 17)
Chemical compound 16 (0.000065mol) and K in DMA (2ml)
2CO
3(0.00013mol) mixture stirred 30 minutes down at 60 ℃, added 4-(3-chloro-propyl group)-morpholine (0.000065mol) then, and reactant mixture stirred 1 day down at 60 ℃.Other 4-(3-chloro-propyl group)-morpholine (0.000065mol) is added into and this mixture 1 day.
After initiation material was consumed to the greatest extent, mixture was via the RP high-efficient liquid phase chromatogram purification.Collect product component and evaporate organic solvent.Aqueous concentrate DCM/CH
3OH (98/2) extraction and organic layer drying (MgSO
4), filtration, solvent evaporation, 0.004g chemical compound 17.
Embodiment B 16
A) preparation 4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 because of, 17-bromo-8,9,10,11,12,13-six hydrogen-(chemical compound 17)
The solution of the intermediate 49 (0.0012mol) in THF (50ml) under RT, N
2Following stirring also adds tributylphosphine (0.0017mol), adds 1,1 '-(azo dicarbapentaborane) two-piperidines (0.0017mol) and this reactant mixture then and stirs 1 hour.Solvent evaporation to initial volume 1/3 and formed precipitation leached washing then.Filtrate evaporation and gained residue H
2The O quencher.Mixture is with HCl (IN) acidify and use DCM/CH
3OH (99/1) extraction.Organic layer drying (MgSO
4), filter and evaporating solvent.Residue is by flash column chromatography (eluant: DCM/CH
3OH 99/1) purification.Collect product component and evaporating solvent.Residue stirs in ebullient 2-propanol, and gained sedimentation and filtration, usefulness 2-propanol and DIPE wash and in 60 ℃ of dryings (vacuum), get 0.111g chemical compound 18 then.
Embodiment B 17
A) preparation 4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 is because of-13 (8H)-carboxylic acids, 17-bromo-9,10,11,12,14,19-six hydrogen-20-methoxyl group-, 1,1-dimethyl ethyl ester (chemical compound 19)
Stir under RT at intermediate 55 (0.0021mol) solution of THF (drying) in (120ml), and add tributylphosphine (0.0032mol), and then add 1,1 '-(azo dicarbapentaborane) two-piperidines (0.0032mol), this reactant mixture stirred 3 hours.Evaporating solvent is to 1/3 of initial volume.The gained precipitation is leached and washs.Directly apply to the next step step before the filtrate evaporation.The part of residue (0.200g) is via the RP-high-efficient liquid phase chromatogram purification.Collect the product component and evaporate organic solvent.Aqueous concentrate extracts and organic layer drying (MgSO with DCM
4), filter, solvent evaporation then, 0.005g chemical compound 19.
B) preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 is because of-13 (8H)-carboxylic acids, 17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-(chemical compound 20)
Stirred 1 hour under RT at chemical compound 19 solution (0.00092mol) of list (trifluoro-acetate) in (20ml), then solvent evaporated under reduced pressure and with the toluene coevaporation.Residue stirs in boiling 2-propanol, then gained sedimentation and filtration, washing and dry.Filtrate evaporation and residue are via the RP-high-efficient liquid phase chromatogram purification.Collect product component and evaporating solvent.Aqueous concentrate filters, washs and 70 ℃ down dry (vacuum), gets 0.040g (5%) chemical compound 20
Embodiment B 18
The preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1] benzo oxa-azacyclo-15 because of, 17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-(chemical compound 20)
Intermediate 60 (0.0011mol) in exsiccant THF (50ml) stirs under RT and adds tributylphosphine (0.0016mol), add 1,1 then '-(azo dicarbapentaborane) two-piperidines (0.0016mol), this reactant mixture stirred 4 hours.Solvent evaporation is until 1/3 of initial volume.The gained precipitation leaches and washs.Filtrate evaporation and residue are via the RP high-efficient liquid phase chromatogram purification.Collect the product component and evaporate organic solvent.There is concentrate to filter, use H
2O washs and 65 ℃ down dry (vacuum), gets 0.037g (7.5%) chemical compound 21.
Embodiment B 19
A) preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 because of, 17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-13-methyl-(chemical compound 22)
The solution of the intermediate 65 (0.0011mol) in THF (50ml) stirs under RT and adds tributylphosphine (0.0016mol), adds 1,1 '-(azo dicarbapentaborane) two-piperidines (0.0016mol) then, and this reactant mixture stirred 2 hours.Solvent evaporation is until 1/3 of initial volume.The gained precipitation leaches and washs.Filtrate evaporation and residue are via the RP high-efficient liquid phase chromatogram purification.Collect the product component and evaporate organic solvent.Aqueous concentrate extracts 2 times and organic layer drying (MgSO with DCM
4), filter then.Solvent evaporation and gained residue get 0.004g (0.8%) chemical compound 22 50 ℃ down dry (vacuum).
Embodiment B 20
The preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,11,1] benzo two oxa-azacyclo-s 15 because of, 17-chloro-8,9,10,11,14,19-six hydrogen-20-methoxyl group-(chemical compound 23)
The mixture of the intermediate 70 (0.0007mol) in THF (50ml) stirs until dissolving fully and adding tributylphosphine (0.0014mol), and this mixture stirs and adding ADDP (0.0014mol) then.Reactant mixture stirs under RT and adds ADDP (in right amount) and tributylphosphine (in right amount) then.The gained mixture stirred 10 hours and adds once more other ADDP (in right amount) and tributylphosphine (in right amount) down at 60 ℃.Mixture stirred 16 hours down at 100 ℃.Solvent evaporation and residue HPLC purification.Collect product component and evaporating solvent, get 0.017g chemical compound 23.
Embodiment B 21
The preparation 4,6-ethanetetrayl-23H-pyrimido [4,5-b] [6,15,1,16] benzo two oxa-diazacyclos-19 because of, 21-chloro-8,9,10,11,12,13,14,15-octahydro-24-methoxyl group-(chemical compound 24)
Through molecular sieve (5ml) exsiccant in THF (20ml) and DMF p.a. intermediate 75 (0.000355mol) and the solution of tributylphosphine (0.000356mol), stir under RT with ADDP (0.000353mol) processing and reactant mixture, and then add other ADDP (in right amount) and tributylphosphine (in right amount) and this reactant mixture of stirring under RT.Solvent evaporation and residue HPLC purification.Collect product component and evaporating solvent, get 0.0274g (17%) chemical compound 24, fusing point 127.2-132.2 ℃.
Embodiment B 22
The preparation 22H-4,6-ethanetetrayl-21,17-methylene (metheno) pyrimido [5,4-d] [1,12,6] two oxa-azacyclo-s 20 because of, 8,9,10,11,12,13,14,15-octahydro-24-methoxyl group-(chemical compound 25)
The solution of the intermediate 79 (0.0012mol) in THF (75ml) stirs under RT and adds ADDP (0.0018mol) and tributylphosphine (0.0018mol) then.Reactant mixture stirred 3 hours and added other ADDP (0.0018mol) and tributylphosphine (0.0018mol).The gained mixture stirred 2 hours and solvent evaporated under reduced pressure.Residue stirs in the 2-propanol and filters, then filtrate evaporation and residue HPLC purification.Collect product component and evaporating solvent, get 0.0027g (72%) chemical compound 25.
Embodiment B 23
A) preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,10] benzo oxa-diazacyclo 15 is because of-12 (3H)-ketone, 17-chloro-8,9,10,11,14,19-six hydrogen-20-methoxyl group-(chemical compound 25)
Under RT, ADDP (0.00034mol) is added in the solution of intermediate 84 (0.00023mo1) among THF (20ml) and the DMF (20ml) and tributylphosphine (O.00042mo1) and reactant mixture stirred 1 hour under RT.Under RT, add again other ADDP and tributylphosphine then the gained mixture levy at R and stirred 1 hour.Solvent evaporation also adds other ADDP and tributylphosphine once more.Mixture is warmed to 100 ℃ and stirred 18 hours down at 100 ℃, and solvent evaporated under reduced pressure and residue are via the HPLC purification then.Collect product component and evaporating solvent, get 0.0094g (10%) chemical compound 26.
B) preparation 4,6-ethanetetrayl-23H-pyrimido [4,5-b] [6,1,12] benzo two oxa-azacyclo-s 15 are because of-14 (19H)-ketone, 17-chloro-8,9,10,11,12,13-six hydrogen-20-methoxyl group-(chemical compound 27) chemical compound 27 is synthetic with the similar approach of chemical compound 26.
Embodiment B 24
The preparation 4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 because of, 17-chloro-8,9,10,11,12,13-six hydrogen-20-(2-methoxy ethoxy)-(chemical compound 28)
Chemical compound 16 (0.00023mol) in DMA (10ml), 1-bromo-2-methoxyl group-ethane (0.0046mol) and K
2CO
3Mixture (0.00046mol) stirred 18 hours and this reactant mixture ice-water quencher subsequently at 60 ℃.Sedimentation and filtration, washing are also stirred in ebullient 2-propanol.The gained precipitation leaches, washs and 53 ℃ down dry (vacuum), gets 0.030g (74%) chemical compound 28.
Embodiment B 25
A) preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 is because of-13 (8H)-carboxylic acids, 17-chloro-16-fluoro-9,10,11,12,14,19-six hydrogen-20-methoxyl group-, 1,1-dimethyl ethyl ester (chemical compound 29)
Tributylphosphine (0.00044mol) is added in intermediate 93 (0.00022mol) among the THF (30ml) and the solution of ADDP (0.00044mol).Reactant mixture stirs and stirred a weekend and evaporating solvent.Add CH
3OH (5ml), the gained reactant mixture stirs, and filters then and evaporated filtrate.Residue is collected product component and evaporating solvent via the reversed-phase HPLC purification, gets 0.04g (35.2%) chemical compound 29.
B) preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,12] benzo two oxa-azacyclo-s 15 be because of, 17-chloro-16-fluoro-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-and, (chemical compound 30)
At CH
3The solution of the chemical compound 29 (0.000077mol) among the OH (5ml) (1ml) is handled then reactant mixture with HCl/2-propanol (6N) and is stirred under RT and spend the night.Solvent evaporation and residue DCM/NaHCO
3Dilution.Stir this mixture after 1 hour, organic layer separates, dry (MgSO
4), filter and evaporating solvent, 0.0089g (27.7%) chemical compound 30, fusing point 265.9-261.3 ℃.
Embodiment B 26
A) preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11] benzo oxa-diazacyclo 15 is because of-12 (13H)-carboxylic acids, 17-chloro-8,9,10,11,14,19-six hydrogen-20-methoxyl group-, 1,1-dimethyl ethyl ester (chemical compound 31)
Intermediate 99 (0.00025mol) in THF (20ml), ADDP (0.000375mol) and tributylphosphine (0.000375mol) solution stir 4 hours evaporating solvent 1/3 initial volumes most then under RT.The gained precipitation leaches and washs, and filtrate evaporation and residue are via the reversed-phase HPLC purification then.Collect product component and evaporating solvent, get 0.02g chemical compound 31.
B) preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11] benzo two oxa-azacyclo-s 15 because of, 17-chloro-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-(chemical compound 32)
Chemical compound 31 (0.00004mol) solution in TFA (5ml) stirred 4 hours under RT, then at N
2Remove in 40 ℃ down and desolvate.Residue is via the HPLC purification.Collect product component and evaporating solvent, get 0.0037g (69%) chemical compound 32.
Embodiment B 27
The preparation 4,6-ethanetetrayl-19H-pyrimido [5,4-k] [1,8,5,13] benzo two oxa-diazacyclos 15 because of, 17-chloro-8,9,10,11,12,13-six hydrogen-20-methoxyl group-10-[2-(4-morpholinyl) ethyl]-(chemical compound 33)
Under RT, ADDP (0.00068mol) and tributylphosphine (0.00085mol) are added in the solution of the intermediate 105 (0.00047mol) among the THF (30ml), and reactant mixture stirred 2 hours under RT.Solvent evaporated under reduced pressure and residue on silica gel via column chromatography (eluant: DCM/ (CH
3OH/NH
3) 99/1 to 80/20) purification.Pure component is collected solvent evaporated under reduced pressure.Residue (0.032g) is subsequently by the HPLC purification.Collect product component and evaporating solvent, get 0.0055g chemical compound 33.
Embodiment B 28
A) preparation 4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 because of, 8,9,10,11,12,13-six hydrogen-20-methoxyl group-17-phenyl-(chemical compound 34)
Intermediate 88 (0.0001mol) in DMSO (2ml), iodobenzene (0.0002mol), dichloro [1,1 '-two (biphenyl phosphine) ferrocene] palladium (catalytic amount, 5%), the mixture of 2M aqueous sodium carbonate (0.0003mol) stirred 3 hours down at 80 ℃, then in the reactant mixture impouring ice-water and water layer extract with DCM.Organic layer separation, drying, filtration and solvent evaporated under reduced pressure.Residue is via (the eluant: DCM/CH of the column chromatography on silica gel
3OH 98/2) purification.Collect product component and evaporating solvent, get .016g (36%) chemical compound 34.
B) preparation benzonitrile, the same way as that 3-(8,9,10,11,12,13-six hydrogen-20-methoxyl group-4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 are because of-17-yl)-(chemical compound 35) chemical compound 35 is pressed chemical compound 34 prepares
Embodiment B 29
Preparation 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,13] benzo oxa-diazacyclo 16 is because of-15 (20H)-ketone, 18-chloro-9,10,11,12,13,14-six hydrogen-21-methoxyl group-(chemical compound 36)
ADDP (0.0016mol) is added in the mixture of intermediate 110 (0.0011mol) among the THF (50ml) and tributylphosphine (0.0020mol) and this reactant mixture stirred 1 hour under RT.Solvent evaporated under reduced pressure, residue stirring and refluxing 1 hour in methanol (80ml) then.The gained precipitation leaches and is dissolved among the DMF (50ml).Solution concentrating under reduced pressure and gained residue once more stirs in methanol.At last, the gained precipitation leaches and is dry, gets 0.242g (52%) chemical compound 36.
Embodiment B 30
The preparation 4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 because of, 16-chloro-8,9,10,11,12,13-six hydrogen-20-methoxyl group (chemical compound 37)
Intermediate 87 (0.00007mol) solution in THF (3ml) stirs under RT and adds ADDP (0.0001mol) and tributylphosphine (0.0001mol) then.Reactant mixture stirred 18 hours and added other ADDP (0.0001mol) and tributylphosphine (0.0001mol).The gained mixture stirred 18 hours and evaporating solvent.Residue is via the HPLC purification and collect the product component, evaporating solvent and at 50 ℃ of following dry gained residues (vacuum) then, 0.002g chemical compound 37
Embodiment B 31
The preparation 4,6-ethanetetrayl-8H, 14H-pyrimido [4,5-b] [6,12,1] benzo two oxa-azacyclo-s 16 because of, 18-chloro-9,10,11,12,15,20-six hydrogen-21-methoxyl group (chemical compound 38)
The mixture of the intermediate 172 (0.0046mol) in THF (400ml) stirs under RT, adds tributylphosphine (0.0092mol) then, adds ADDP (0.0092mol) and this reactant mixture subsequently and stirs 2 hours.Solvent evaporation and residue are via reversed-phase high-performance liquid chromatography (Hypersil) (eluant: (0.5%NH
4Oac is in water)/CH
3CN 90/10) purification.
Collect product component and evaporating solvent.The gained residue absorbs this mixture K then in water
2CO
3Alkalization and DCM extraction.Organic layer separation, drying, filtration and evaporating solvent.Gained residue (1.1g) stirs in DIPE and precipitates and leaches drying then, gets 0.976g chemical compound 38.
Chemical compound 39 is pressed the same procedure preparation of chemical compound 38.
4,6-ethanetetrayl-14H-pyrimido [4,5-b] [6,9,12,1] benzo trioxa azacyclo-16 because of, 18-chloro-8,9,11,12,15,20-six hydrogen-21-methoxyl group (chemical compound 39)
Embodiment B 32
Preparation 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,11] benzo two oxa-azacyclo-s 16 are because of-11 (12H)-ketone, 18-chloro-9,10,13,14,15,20-six hydrogen-21-methoxyl group (chemical compound 40)
The mixture of intermediate 177 (0.00045mol), PyBOP (0.00135mol) and triethylamine (0.00135mol) is at 60 ℃ of reactions 3 hours and evaporating solvent.The gained residue is collected product component and evaporating solvent then via the RP high-efficient liquid phase chromatogram purification, gets 0.008g chemical compound 40.
Embodiment B 33
A) preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-10 (11H)-carboxylic acids, 19-chloro-8,9,12,13,14,15,16,21-octahydro-22-methoxyl group-12-oxo-, 1,1-dimethyl ethyl ester (chemical compound 41)
THF p.a. (150ml) and tributylphosphine (0.003mol) are at N
2, 50 ℃ stir and add ADDP (0.003mol) down, the mixture of the intermediate 181 (0.0009mol) in THF p.a. (15ml) is added into and the gained reactant mixture stirred 2 hours down at 60 ℃ then.Adding other tributylphosphine (0.003mol) and ADDP (0.003mol) and gained mixture stirred 2 hours at 60 ℃.At last, solvent evaporation gets chemical compound 41 (directly being used for the next step step with this)
B) preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxyl group (chemical compound 42)
The mixture of the chemical compound 41 in methanol (50ml) and 2-propanol/HCl (5ml) stirred 72 hours solvent evaporation then under RT.The gained residue absorbs in water and washs 3 times with DCM.Water layer K
2CO
3Alkalization and DCM extraction.The gained crude mixture is subsequently via a glass filter (eluant: DCM (CH
3OH/NH
3) 90/10) purification.Collect product component and evaporating solvent, get 0.322g chemical compound 42.
C) preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9; 12] benzo oxa-three azacyclo-s 15 are because of-12 (13H)-ketone, 19-chloro-8,9,10,11; 14,15,16,21-octahydro-10-[[(2-ethoxy) methyl amine] acetyl group]-22-methoxyl group (chemical compound 43)
The mixture of chemical compound 42 (0.0.000045mol), DMA (2ml) and DIPEA (0.00013mol) stirs and dripping bromine generation-chloroacetic chloride (0.00011mol), main 2-(methylamine)-ethanol (0.00044mol) and gained reactant mixture go up then 60 ℃ of following stirrings 16 hours, get 0.013g chemical compound 43.
Following compounds is corresponding to be produced:
| The chemical compound sequence number | Title |
| 44 | 4,6-ethanetetrayl pyrimido [4,5-b] [6; 1; 9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8; 910; 11,14,15; 16,21-octahydro-10-[[[2-hydroxyl-1-(methylol) ethyl] amino] acetyl group]-the 22-methoxyl group- |
| 45 | 4,6-ethanetetrayl pyrimido [4,5-b] [6; 1; 9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8; 910; 11,14,15; 16,21-octahydro-10-[[[2-methylol-4 morpholinyl] acetyl group]-the 22-methoxyl group- |
| 46 | 4,6-ethanetetrayl pyrimido [4,5-b] [6; 1; 9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8; 910; 11,14,15; 16,21-octahydro-22-methoxyl group-10-[[[2-(4-pyridine radicals) ethyl] amino] acetyl group]- |
| 47 | 4,6-ethanetetrayl pyrimido [4,5-b] [6; 1; 9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-10-[[[2 (dimethylamino) ethyl] methylamino] acetyl group]-8; 910; 11,14,15; 16,21-octahydro-22-methoxyl group- |
| 48 | 4,6-ethanetetrayl pyrimido [4,5-b] [6; 1; 9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8; 910; 11,14,15; 16,21-octahydro-22-methoxyl group-10-[[(2-methoxy ethyl) amino] acetyl group- |
| 49 | 4,6-ethanetetrayl pyrimido [4,5-b] [6; 1; 9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8; 910; 11,14,15; 16,21-octahydro-22-methoxyl group-10-[[(3-methoxy-propyl) amino] acetyl group]- |
| 50 | 4,6-ethanetetrayl pyrimido [4,5-b] [6; 1; 9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8; 910; 11,14,15; 16,21-octahydro-22-methoxyl group-10-(4-morpholinyl acetyl group)- |
| 51 | 4,6-ethanetetrayl pyrimido [4,5-b] [6; 1; 9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8; 910; 11,14,15; 16,21-octahydro-22-methoxyl group-10-[(4-methyl isophthalic acid-piperazinyl) acetyl group]- |
Embodiment B 34
Preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxyl group-10-methyl-(chemical compound 52)
4-goes on foot course of reaction step (I): vibration intermediate 182 (0.0002mol), DIPEA (0.0008mol) and DCM (7ml) also add bromoacetyl chloride (0.0008mol), and the gained reactant mixture stirs after 3 hours and washs 3 times with DCM, get resin (I).Step (II): resin (I), 2-(methylamino) ethanol (0.0020mol) and 1-Methyl-2-Pyrrolidone (6ml) were in 60 ℃ of vibrations 6 hours, and the gained reactant mixture with DCM washing 3 times, gets resin 4-(II) with DMF washing 3 times.Step-(III): in 60 ℃ of vibrations 6 hours, the gained mixture washed respectively 3 times with DMF and DCM then with resin (II), tri isopropyl silane (0.0020mol), ADDP (0.0020mol) and 1-Methyl-2-Pyrrolidone (8ml), got resin (III).Step (IV): with resin (III) and DCMITEA/ tri isopropyl silane (7ml) jolting 16 hours and filtration, washing filtering residue and evaporating solvent.The gained residue is via the reversed-phase high-performance liquid chromatography purification.Collect required product component and evaporating solvent, get 0.001g chemical compound 52.
Following compounds is by identical corresponding being produced of preparation method of chemical compound 52:
| The chemical compound sequence number | Title |
| 53 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,10,12] benzo oxa-three azacyclo-s 17 are because of-13 (14H)-ketone, 19-chloro-10-ethyl-8,9,10,11,14,15,16,21-octahydro-22-methoxyl group- |
| 54 | 1,22-ethanetetrayl-5H, 17H-pyrimido [4,5-b] pyrrolo-[2,1, h] [6,1,9,12] benzo oxa-three azacyclo-s 17 are because of-14 (15H)-ketone, 7-chloro-10,11,12,13,18,19,21-octahydro-22-methoxyl group- |
| 55 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 18 are because of-13 (14H)-ketone, 20-chloro-9,10,11,12,15,16,17,22-octahydro-23-methoxyl group- |
| 56 | 14H-4,6-ethanetetrayl-9,13-methylene-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 20 are because of-15 (16H)-ketone, 22-chloro-9,10,11,12,17,18,19,24-octahydro-26-methoxyl group- |
| 57 | 13H-4,6-ethanetetrayl-9,12-ethylidene pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 19 are because of-14 (15H)-ketone, 21-chloro-8,9,10,11,16,17,18,23-octahydro-26-methoxyl group- |
| 58 | 14H-4,6-ethanetetrayl-10,13-ethylidene-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 20 are because of-15 (16H)-ketone, 22-chloro-9,10,11,12,17,18,19,24-octahydro-27-methoxyl group- |
Embodiment B 35
Preparation 4,6-ethenylidene pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 is because of-13-(8H)-carboxylic acid, 17-bromo-9,10,11,12,14,19-six hydrogen-20-methoxyl group, benzene methyl (chemical compound 59)
Intermediate 114 (0.005mol) and K
2CO
3(0.025mol) mixture in DMA (25ml) under the microwave condition in 150 ℃ stir 30 minutes after solvent evaporated under reduced pressure.The gained residue stirs and leaches crystallize in EtOAc.Filtrate evaporated under reduced pressure, the gained residue is through column chromatography (eluant: DCM/CH
3OH 98/2 to 96/4) purification.Collect product component and evaporating solvent.Gained residue (1.1g-38%) is from CH
3Crystallization among the CN.Leach gained precipitation and dry.This component of a part is dry in addition, gets chemical compound 59.
Embodiment B 36
Preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 17 are because of-12,15-diketone, 19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxyl group-(chemical compound 60)
The mixture of intermediate 121 (0.00308mol) in DMF (300ml) is added drop-wise in DMF (300ml) mixture of PyBOP (0.00616mol) and DIPEA (0.0154mol) and spends the night, add other PyBOP (0.00616mol) and DIPEA (0.0154mol) again, the gained reactant mixture stirs a weekend.The pressure reducing and steaming solvent, the gained residue is dissolved in the 10%DCM methanol solution and washes with water then.Separate organic layer, dry (MgSO
4), filter and solvent evaporated under reduced pressure.Residuum reversed phase high-performance liquid chromatography purification.Collect pure product component and concentrated, get chemical compound 60 until there being solid to separate out.
Embodiment B 37
The preparation 4,6-ethenylidene pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 because of, 17-bromo-16-fluoro-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-(chemical compound 61)
TFA (2ml) is joined intermediate 127 (0.00055mol) in the mixture of DCM (10ml), and the gained reactant mixture stirred 3 hours and used the neutralization of NaOH solution in RT then.Separate organic layer, dry (MgSO
4), leach and evaporating solvent.Residue is by column chromatography (gradient eluent: DCM/CH
3OH) purification.Collect pure product component and evaporating solvent, get 0.042g chemical compound 61.
Embodiment B 38
Preparation 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-11,14-diketone, 18-chloro-9,10,12,13,15,20-six hydrogen-21-methoxyl group-10-[2-(4-morpholinyl) ethyl]-(chemical compound 62)
HBTU (0.00195mol) is joined under room temperature in DMA (250ml) solution of the intermediate 130 (0.00069mol) of stirring and DIPEA (0.00324mol), reactant mixture stirred 3 hours, under reduced pressure with solvent and toluene coevaporation.The gained residue is by reversed phase liquid chromatography purification (eluant 1:NH
4Oac; Eluant 2:NH
4HCO
3).Collect gained pure products component and solvent evaporated under reduced pressure.Gained residue (0.030g) crystallization from the 2-propanol leaches gained precipitation and dry (vacuum), gets 0.0165g chemical compound 62.
Following compounds 63 corresponding being produced: 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-11,14-diketone, 18-chloro-9,10,12,13,15,20-six hydrogen-21-methoxyl group-10-(2-methoxy ethyl)-(chemical compound 63)
Embodiment B 39
The preparation Benzoylamide, 4-fluoro-N-(8,9,10,11,12,13-six hydrogen-20-methoxyl group-4,6-ethanetetrayl-19H-pyrimido [4,5-b] [6,13,1] benzo two oxa-azacyclo-s 15 are because of-16-yl)-(chemical compound 64)
THF (20ml) solution of intermediate 136 (0.0002mol) stirs in RT and adds ADDP (0.0003mol) and tributylphosphine (0.0003mol) then.The gained reactant mixture adds other ADDP (0.0003mol) and tributylphosphine (0.0003mol) again after RT stirs 6 hours.The mixture of gained stirred 1 hour, solvent evaporated under reduced pressure.The gained residue stirs in methanol and filters.This filtering residue stirs in ebullient 2-propanol, and gained precipitation leaches and at CH
3OHHCl (1N)/H
2Stir in the O mixture.After the filtration, the gained filtering residue is at CH
3OH/NH
3Stir in the solution, the solid of separating out leaches and in 60 ℃ of dryings (vacuum), gets 0.015g chemical compound 64.
Embodiment B 40
Preparation 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-11,14-diketone, 18-chloro-9,10,12,13,15,20-six hydrogen-21-methoxyl group-12,12-dimethyl-(chemical compound 65)
DMA (70ml) solution of PyBOP (0.0013mol) and DIPEA (0.0065mol) stirs and drips DMA (70ml) solution of intermediate 143 (0.0013mol) in RT.This reactant mixture stirred 18 hours in RT, solvent evaporated under reduced pressure. and the gained residue is dissolved among the DCM, uses saturated NaHCO
3Twice of solution washing and washing with water 2 times.Tell organic facies, dry (MgSO
4), filter and evaporating solvent.The gained dried residue stirs in boiling 2-propanol, formed subsequently sedimentation and filtration, washing and in 60 ℃ of dryings (vacuum), 0.133g chemical compound 65,285 ℃ of fusing points.
Following compounds is according to the synthetic preparation of chemical compound 65:
| The chemical compound sequence number | Title |
| 66 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-11, the 14-diketone, 18-chloro-9,10,12,13,15,20-six hydrogen-21-methoxyl group-12-(1-Methylethyl)-, fusing point: 335 ℃ |
| 67 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-11,14-diketone, 18-chloro-9,10,12,13,15,20-six hydrogen-21-methoxyl group |
| -12-(2-methyl-propyl)- | |
| 68 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 17 are because of-12, the 15-diketone, 19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxyl group-13-(2-methyl-propyl)- |
| 69 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-11,14 diketone, 18-chloro-9,10,12,13,15,20-six hydrogen-21-methoxyl group-, fusing point: 292 ℃ |
Embodiment B 41
Preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,10,14] benzo oxa-three azacyclo-s 17 are because of-12 (13H)-ketone, 19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxyl group-(chemical compound 70)
DIPEA (0.00930mol) is joined in the solution of dry DMF (10ml) of intermediate 149 (0.00155mol), the gained mixture stirred 15 minutes.Subsequently this solution slowly sleeve go in DMF (40ml) solution of HBTU (0.00465mol), this reactant mixture stirred 30 minutes.Evaporation gained solution.The gained residue is by the reversed-phase high-performance liquid chromatography purification.Collect product component and evaporating solvent, get 0.258g chemical compound 70, fusing point 236.4-237.3 ℃.Following compounds is by corresponding preparation:
| The chemical compound sequence number | Title |
| 71 | 4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[2,1-k] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 19-chloro-9,10,11a, 12,13,14,16,21-octahydro-22-methoxyl group-, fusing point 261.2-265 ℃ |
| 72 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 17-chloro-9,10,12,13,14,19-six hydrogen-20-methoxyl group-13-methyl-, fusing point 288.5-290.5 ℃ |
| 73 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 17-chloro-9,10,12,13,14, and 19-six hydrogen-20-methoxyl group-, molten |
| Point: 294.2-295.2 ℃ | |
| 74 | 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 18-chloro-8,9,10,11,13,14,15,20-octahydro-21-methoxyl group-14-methyl-, fusing point: 240.0-240.3 ℃ |
| 75 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,13] benzo oxa-three azacyclo-s 16 are because of-11 (12H)-ketone, 18-chloro-9,10,13,14,15,20-six hydrogen-21-methoxyl group-, fusing point: 254.4-256.5 ℃ |
| 76 | 4,6-ethenylidene-8H-pyrimido [4,5-b] pyrrolo-[2,1-1] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12,15 (14H)-diketone, 20-chloro-9,10,11,12a, 13,17,22-seven hydrogen-23-methoxyl group-, fusing point: 350.5-352.5 ℃ |
| 77 | 4,6-ethanetetrayl-12H-pyrimido [4,5-b] pyrrolo-[2,1-1] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 20-chloro-8,9,10,11,12a, 13,14,15,17,22-decahydro-23-methoxyl group-, 132.8 ℃ of fusing point: 129.8- |
| 78 | 4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[2,1-k] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 19-chloro-18-fluoro-9,10,11a, 12,13,14,16,21-octahydro-22-methoxyl group-, fusing point: 261.4-264.0 ℃ |
| 79 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 17-chloro-16-fluoro-9,10,12,13,14,19-six hydrogen-20-methoxyl group-13-methyl-, fusing point: 306.3-307.4 ℃ |
| 80 | 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 18-chloro-17-fluoro-8,9,10,11,13,14,15,20-octahydro-21-methoxyl group-14-methyl-, fusing point 260.4-261.1 ℃ |
| 81 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 17-chloro-16-fluoro-9,10,12,13,14,19-six hydrogen-20-methoxyl group-, fusing point 304.2-304.4 ℃ |
| 82 | 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azepines |
| Encircle 16 because of-12-ketone, 18-chloro-17-fluoro-8,9,10,11,13,14,15,20-octahydro-21-methoxyl group-, fusing point: 311.0-311.9 ℃ | |
| 83 | 4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[2,1-k] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 19-chloro-9,10,11a, 12,13,14,16,21-octahydro-22-methoxyl group-, fusing point: 262.0-262.8 ℃ |
| 84 | 4,6-ethanetetrayl-12H-pyrimido [4,5-b] pyrrolo-[2,1-1] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 20-chloro-8,9,10,11,12a, 13,14,15,17,22-decahydro-23-methoxyl group-, 232.8 ℃ of fusing point: 231.9- |
| 85 | 4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[2,1-k] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 19-chloro-9,10,11a, 12,13,14,16,21-octahydro-13-hydroxyl-22-methoxyl group-, fusing point: 279.4-280.7 ℃ |
| 86 | 4,6-ethanetetrayl-13,16-ethylidene-8H-pyrimido [4,5-b] [6,1,9,12,15] benzo oxa-tetraazacyclododecane 18 is because of-11 (12H)-ketone, 20-chloro-9,10,14,15,17,22-six hydrogen-25-methoxyl group-, fusing point 296.4-297.0 ℃ |
| 87 | 8H-4,6-ethanetetrayl-12,15-ethylidene pyrimido [4,5-b] [6,1,9,14] benzo oxa-three azacyclo-s 17 are because of-11 (12H)-ketone, 19-chloro-9,10,13,14,16,21-six hydrogen-24-methoxyl group-, fusing point: 246.6-248.2 ℃ |
| 88 | 4,6-ethanetetrayl-12,16-methylene-6H-pyrimido [4,5-b] [6,1,9,15] benzo oxa-three azacyclo-s 18 are because of-11 (8H)-ketone, 20-chloro-9,10,12,13,14,15,17,22-octahydro-24-methoxyl group-, fusing point: 160-170 ℃ |
| 89 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 17-chloro-9,10,12,13,14,19-six hydrogen-20-methoxyl group-12, the 13-dimethyl-, fusing point: 265 ℃ |
| 90 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 17-chloro-13-ethyl-9,10,12,13,14,19-six hydrogen-20-methoxyl group-, fusing point: 261.1-262 ℃ |
| 91 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 |
| Because of-11 (8H)-ketone, 17-chloro-9,10,12,13,14,19-six hydrogen-12-(hydroxymethyl)-20-methoxyl group-, fusing point: 276.3-277.4 ℃ | |
| 92 | 4,6-ethanetetrayl-12H-pyrimido [4,5-b] pyrrolo-[2,1-1] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 20-chloro-8,9,10,11,12a, 13,14,15,17,22-decahydro-14-hydroxyl-23-methoxyl group-, fusing point: 267.8-268.5 ℃ |
| 93 | 4,6-ethanetetrayl-14,17-ethylidene pyrimido [4,5-b] [6,1,10,13,16] benzo oxa-tetraazacyclododecane 19 is because of-12 (13H)-ketone, 21-chloro-8,9,10,11,15,16,18,23-octahydro-26-methoxyl group-, fusing point: 286.8-287.6 ℃ |
| 94 | 4,6-ethanetetrayl-13,16-ethylidene-6H-pyrimido [4,5-b] [6,1,10,15] benzo oxa-three azacyclo-s 18 are because of-12 (13H)-ketone, 20-chloro-8,9,10,11,14,15,17,22-octahydro-25-methoxyl group-, fusing point: 253.1-255.9 ℃ |
| 95 | 12H-4,6-ethanetetrayl-13,17-methylene pyrimido [4,5-b] [6,1,10,16] benzo oxa-three azacyclo-s 19 are because of-12-ketone, 21-chloro-8,9,10,11,13,14,15,16,18,23-decahydro-25-methoxyl group-, 242.8 ℃ of fusing point: 240.1- |
| 96 | 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 18-chloro-8,9,10,11,13,14,15,20-octahydro-21-methoxyl group-13, the 14-dimethyl-, fusing point: 241.9-243.0 ℃ |
| 97 | 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 18-chloro-14-ethyl-8,9,10,11,13,14,15,20-octahydro-21-methoxyl group-, fusing point: 212.8-214.0 ℃ |
| 98 | 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 18-chloro-8,9,10,11,13,14,15,20-octahydro-13-(hydroxymethyl)-21-methoxyl group-, fusing point: 287.6-288.3 ℃ |
| 99 | 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 18-chloro-8,9,10,11,13,14,15,20-octahydro-21-methoxyl group-, fusing point: 304.6-304.8 ℃ |
| 166 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-13 (8H)-ketone, 19-chloro-15-ethyl-9,10,11,12,14,15,16,21-octahydro-22-methoxyl group- |
| 167 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-13 (8H)-ketone, 19-chloro-9,10,11,12,14,15,16,21-octahydro-22-methoxyl group-14, the 15-dimethyl- |
Embodiment B 42
Preparation 4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[2,1-m] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-13 (8H)-ketone, 21-chloro-9,10,11,12,13a, 14,15,16,18,23-decahydro-24-methoxyl group-(chemical compound 100)
Intermediate 156 (0.0005mol) and DIPEA (0.003mol) solution are joined among the HBTU (0.0015mol) and 1-hydroxyl-1H-benzotriazole (0.001mol) solution in dry DMF (125ml), and the reaction of gained reactant mixture is 1 hour then.The gained solvent steams and removes, the residue reversed-phase high-performance liquid chromatography purification of doing.Collect product component, add sodium carbonate and steaming except that organic solvent.DCM joined contain in the concentrated liquid, the gained mixture is with DCM extraction 3 times, and is dry and collect the gained organic extract, the chemical compound 100 of 0.0394g (16%), fusing point 226.3-227.7 ℃.
Following compounds is corresponding to be produced:
4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-13 (8H)-ketone, 19-chloro-9,10,11,12,14,15,16, fusing point 286.7-287.2 ℃ of 21-octahydro-22-methoxyl group-(chemical compound 101)
4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[2,1-m] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-13 (8H)-ketone, 21-chloro-20-fluoro-9,10,11,12,13a, 14,15,16,18, fusing point 234.7-236.8 ℃ of 23-decahydro-24-methoxyl group-(chemical compound 102).
Embodiment B 43
Preparation 4,6-ethanetetrayl-12H-pyrimido [4,5-b] pyrrolo-[2,1-1] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 20-chloro-19-fluoro-8,9,10,11,12a, 13,14,15,17,22-decahydro-23-methoxyl group-(chemical compound 103)
DMT (20ml) solution of intermediate 162 (0.001mol) and DIPEA (1.034mol) is added in DMF (200ml) solution of PyBOP (0.003mol) and 1-hydroxyl-1B-benzotriazole (0.001mol), and this reactant mixture is via reversed-phase high-performance liquid chromatography purification (acetonitrile/ammonium acetate buffer agent) then.Collect product component, add sodium carbonate, organic solvent is steamed remove (crystallize).Aqueous concentrates in refrigerator and cooled but filters and water washing: 0.2087g (43%) chemical compound 103, fusing point 241.6-242.6 ℃.
Following compounds is corresponding to be produced:
4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[2,1-k] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 19-chloro-18-fluoro-9,10,11a, 12,13,14,16,21-decahydro-22-methoxyl group-(chemical compound 104), fusing point: 211.3-212.7 ℃.
Embodiment B 44
A) preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,16] benzo oxa-diazacyclo 19 is because of-16 (17H)-ketone, 21-chloro-8,9,10,13,14,15,18,23-octahydro-24-methoxyl group-(B) (chemical compound 105) and 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,16] benzo oxa-diazacyclo 19 is because of-16 (17H)-ketone, 21-chloro-8,9,10,13,14,15,18, the intermediate of 23-octahydro-24-methoxyl group-(B)
The DCM mixture of 165 (0.000424mol) and Grubbs II catalyst (0.00042mol) is at N
2Stirred 6 hours in RT down, steam then and remove this solvent, gained residue reversed-phase high-performance liquid chromatography purification.Collect two kinds of components and steam and desolventize, 0.046g (23.3%) chemical compound 106 (A) and 0.078g (39.5%) chemical compound 105 (B).
B) preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,16] benzo oxa-diazacyclo 19 is because of-16 (17H)-ketone, 21-chloro-8,9,10,11,12,13,14,15,18,23-decahydro-24-methoxyl group-(chemical compound 107)
The hydrogenation 3 hours under Pt/C 5% (0.03g) catalyst of the mixture of chemical compound 105 (0.000064mol) in THF (15ml) and methanol (15ml).After inhaling hydrogen (1 equivalent), filtration catalizer also evaporates this filtrate, gets chemical compound 107.
Following compounds is corresponding to be produced:
4,6-ethanetetrayl-8H-pyrrolo-[4,5-b] [6,1,15] benzo oxa-diazacyclo 18 is because of-15 (16H)-ketone, 20-chloro-9,12,13,14,17,22-six hydrogen-23-methoxyl group-(chemical compound 108).
Embodiment B 45
A) carbamic acid, (20-chloro-9,10,13,14,15,16,17,22-octahydro-23-methoxyl group-15-oxo-4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,15] benzo oxa-diazacyclo 18 is because of-14-yl)-, 1, the preparation of 1-dimethyl ethyl ester (A) (chemical compound 109) and
Carbamic acid, (20-chloro-9,10,13,14,15,16,17,22-octahydro-23-methoxyl group-15-oxo-4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,15] benzo oxa-diazacyclo 18 is because of-14-yl)-, 1, the preparation of 1-dimethyl ethyl ester (B) (chemical compound 110)
DCM (150ml) solution of intermediate 169 (0.0015mol) and Gmbbs II catalyst (0.0015) stirs in RT and spends the night, and steaming desolventizes, and the gained residue is by the reversed-phase high-performance liquid chromatography purification.Collect two kinds of product components and steam and desolventize, 0.110g chemical compound 109 (A) and 0.064g chemical compound 110 (B).
B) preparation carbamic acid, (20-chloro-9,10,11,12,13,14,15,16,17,22-decahydro-23-methoxyl group-15-oxo-4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,15] benzo oxa-diazacyclo 18 is because of-14-yl)-, 1,1-dimethyl ethyl ester (chemical compound 111)
The hydrogenation 3 hours under Pt/C 5% (0.1g) catalyst of the mixture of chemical compound 109 (0.00025mol) in THF (15ml) and methanol (15ml).After inhaling hydrogen (1 equivalent), filtration catalizer and evaporate to dryness filtrate.Gained is residual through silicagel column DCM/CH
3OH filters, gained filtrate evaporate to dryness, and the gained solid is collected in the crystallization in methanol of gained residue, gets chemical compound 111.
Following compounds correspondingly is produced:
Carbamic acid, (6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,13] benzo oxa-diazacyclo 16 is because of-12-yl for 18-chloro-11,12,13,14,15,20-six hydrogen-21-methoxyl group-13-oxo-4)-, 1,1-dimethyl ethyl ester (chemical compound 165)
C) preparation 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,15] benzo oxa-diazacyclo 18 is because of-15 (16H)-ketone, 14-amino-20-chloro-9,10,11,12,13,14,17,22-octahydro-23-methoxyl group hydrochlorate (1: 2) (chemical compound 112)
6N 2-isopropyl alcohol hydrochloric acid (5ml) is joined in THF (in right amount) solution of chemical compound 111 (0.000088), the gained mixture stirs to steam after 1 hour in RT and desolventizes, and gets the chemical compound 112 of 0.050g, separates with hydrochlorate.
D) preparation 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,15] benzo oxa-diazacyclo 18 is because of-15 (16H)-ketone, 20-chloro-14-(dimethylamino)-9,10,11,12,13,14,17,22-octahydro-23-methoxyl group-(chemical compound 113)
Chemical compound 112 (0.000085mol) and formaldehyde (0.00052g) mixture are carried out hydrogenation with catalyst Pt/C 5% (0.04g) in the presence of thiophene solution (0.04ml) in methanol (20ml).After having absorbed 2 normal hydrogen, catalyst is leached and evaporate to dryness filtrate.The gained residue is via the reversed-phase high-performance liquid chromatography purification, and collection product component and steaming desolventize, and obtain chemical compound 113.
Embodiment B 46
The preparation 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 because of, 18-chloro-9,10,11,12,13,14,15,20-octahydro-21-methoxyl group-14-methyl-(chemical compound 114)
Will be at dioxane (10ml), intermediate 186 (0.00095) solution in water (5ml) and the concentrated hydrochloric acid (5ml) are in 50 ℃ of stirrings 27 hours, gained reactant mixture impouring one saturated NaHCO then
3In the aqueous solution and DCM extraction.Leach potassium carbonate after the gained organic extract drying.Add NaBH (OAc) 3 (0.00095mol) immediately.The gained reactant mixture stirred 1 hour in RT.This mixture is by the RP high-efficient liquid phase chromatogram purification, and collection product section and steaming desolventize, and obtain 0.0576g chemical compound 114, fusing point 202.8-203.6 ℃.Following compounds is corresponding to be produced:
| The chemical compound sequence number | Title |
| 115 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 because of, 19-chloro-8,9,10,11,12,13,14,15,16,21-decahydro-22-methoxyl group-15-methyl-, fusing point: 196.9-197.8 ℃ |
| 116 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of, 17-chloro-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-13-methyl-, fusing point: 195.8-196.6 ℃ |
| 117 | 4,6-ethanetetrayl 8-H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 18 because of, 20-chloro-9,10,11,12,13,14,15,16,17,22-decahydro-23-methoxyl group-16-methyl-, fusing point: 196.9-197.8 ℃ |
Embodiment B 47
Preparation 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 be because of, 17-chloro-8,9,12,13,14,19-six hydrogen-20-methoxyl group-13-methyl-± 75%E and ± 25%2 (compound 118)
Grubbs II catalyst (0.0012mol altogether) branch joins in DCM (100ml) solution of intermediate 191 (0.0016mol) gained reactant mixture stirring and refluxing totally 4 days several times.The gained mixture passes through reversed-phase high-performance liquid chromatography purification purification 2 times.Collection product component and steaming desolventize, and get the 0.0116g compound 118.
Embodiment B 48
4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-9,12-diketone, 18-chloro-10,11,13,14,15, the preparation of 20-six hydrogen-21-methoxyl group-11-methyl-hydrate (1: 1) (chemical compound 119)
Mixture in dry DMF (50ml) slowly joins two (dimethylamino) methylene of 1-[under RT with intermediate 197 (0.0010mol) and DIPEA (0.0040mol)]-1H-benzotriazole, hexafluoro phosphate (1-), in the dry DMF solution of 3-oxide (0.0025mol), reactant mixture water (5ml) cancellation of gained subsequently and steaming desolventize.The gained residue is by the reversed-phase high-performance liquid chromatography purification.Collect product section and boil off organic solvent, obtain 0.024g chemical compound 119.
Following compounds is by corresponding preparation:
| The chemical compound sequence number | Title |
| 120 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-20-methoxyl group-11-methyl- |
| 121 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-20-methoxyl group-11-(1-Methylethyl)- |
| 122 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-20-methoxyl group-11-(phenyl methyl)- |
| 123 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 10,11,14,19-tetrahydrochysene-20-methoxyl group-11-methyl |
| 124 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 10,11,14,19-tetrahydrochysene-20-methoxyl group-11-(1-methyl-propyl)- |
| 125 | 9,11-ethanetetrayl pyrimido [4,5-b] pyrrolo-[1,2-i] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-14,19 (5H, 13H)-diketone, 16,17,18,18a, 20,21-six hydrogen-22-methoxyl group- |
| 126 | 9,11-ethanetetrayl pyrimido [4,5-b] pyrrolo-[1,2-i] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-14,19 (5H, 13H)-diketone, 3-chloro-16,17,18,18a, 20,21-six hydrogen-22-methoxyl group- |
| 127 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-11-(1-hydroxyethyl)-20-methoxyl group- |
| 128 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-11,14 (8H, 15H)-and diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-22-methoxyl group-13-(1-methyl-propyl)- |
| 129 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-11-(hydroxymethyl)-20-methoxyl group- |
| 130 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-11,14 (8H, 15H)-and diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-13-(hydroxymethyl)-22-methoxyl group- |
| 131 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-11,14 (8H, 15H)-and diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-22-methoxyl group-13-methyl- |
| 132 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-9,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-20-methoxyl group-11, the 11-dimethyl- |
| 133 | 9,11-ethanetetrayl pyrimido [4,5-b] pyrrolo-[1,2-i] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-14,19 (5H, 13H)-diketone, 3-chloro-16,17,18,18a, 20,21-six hydrogen-17-hydroxyl-22-methoxyl group- |
| 134 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] pyrrolo-[1,2-I] [6,1,12,15] benzo oxa-three azacyclo-s 18 are because of-12,17 (18H)-diketone, 22-chloro-9,10,11,14,15,16,16a, 19,24-nine hydrogen-25-methoxyl group- |
| 135 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-9, the 12-diketone, 18-chloro-10,11,13,14,15,20-six hydrogen-21-methoxyl group-11, the 11-dimethyl- |
| 136 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 18 are because of-12,15 (16H)-diketone, 20-chloro-9,1.0,11,13,14,17,22-seven hydrogen-23-methoxyl group-14-(2-methyl-propyl)- |
| 137 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,153 benzo oxa-s, three azepines |
| Encircle 18 because of-12,15 (16H)-diketone, 20-chloro-9,10,11,13,14,17,22-seven hydrogen-23-methoxyl group-14, the 14-dimethyl- | |
| 138 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 18 are because of-12,15 (16H)-diketone, 20-chloro-9,10,11,13,14,17,22-seven hydrogen-23-methoxyl group-14-(phenyl methyl)- |
| 139 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 18 are because of-12,15 (16H)-diketone, 20-chloro-9,10,11,13,14,17,22-seven hydrogen-23-methoxyl group-14-methyl- |
| 140 | 1,21-ethanetetrayl-5H-pyrimido [4,5-b] pyrrolo-[1,2-i] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-13,18 (19H)-diketone, 7-chloro-10,11,12,13a, 14,15,16-seven hydrogen-23-methoxyl group- |
| 141 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-9, the 12-diketone, 18-chloro-10,11,13,14,15,20-six hydrogen-21-methoxyl group-11-(2-methyl-propyl)- |
| 142 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-9, the 12-diketone, 18-chloro-10,11,13,14,15,20-six hydrogen-11-(1-hydroxyethyl)-21-methoxyl group- |
| 143 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-11,14 (8H, 15H)-and diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-22-methoxyl group-13-(2-methyl-propyl)- |
| 144 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-11,14 (8H, 15H)-diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-22-methoxyl group-13, the 13-dimethyl- |
| 145 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-11,14 (8H, 15H)-and diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-22-methoxyl group-13-(phenyl methyl)- |
| 146 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 because of-11,14 (8H, 15H)-diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-13- |
| (1-hydroxyethyl)-22-methoxyl group- | |
| 147 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 18 are because of-12,15 (16H)-diketone, 20-chloro-9,10,11,13,14,17,22-seven hydrogen-14-(1-hydroxyethyl)-23-methoxyl group- |
| 148 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-9, the 12-diketone, 18-chloro-10,11,13,14,15,20-six hydrogen-11-(hydroxymethyl)-21-methoxyl group- |
| 149 | 1,21-ethanetetrayl-5H-pyrimido [4,5-b] pyrrolo-[1,2-i] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-13,18 (19H)-diketone, 7-chloro-, 10,11,12,13a, 14,15,16-seven hydrogen-15-hydroxyl-23-methoxyl group- |
Embodiment B 49
4,6-ethenylidene pyrimido [4,5-b] [6,1,9,14] benzo oxa-three azacyclo-s 17 because of-9,14 (8H, 15H)-diketone, 19-chloro-1,11,12,13,16, the preparation of 21-six hydrogen-22-methoxyl group-(chemical compound 150)
Intermediate 122 (0.001mol) and DIPEA (0.004mol) are joined in DMF (250ml) mixture of a PyBOP (0.003mol), and the gained reactant mixture stirs after 2 hours and adds entry, the solvent evaporate to dryness.Gained residue reversed-phase high-performance liquid chromatography purification.Collect product component and evaporate to dryness organic solvent.Contain concentrated liquid and place the precipitation of spending the night in refrigerator, the gained solid leaches, and obtains 0.093g (20%) chemical compound 150.
| The chemical compound sequence number | Title |
| 151 | 4,6-ethenylidene pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-20-methoxyl group- |
| 152 | 4,6-ethenylidene-8H-pyrimido [4,5-b] [6,1,9,13] benzo oxa-three azacyclo-s 16 because of-9,13 (10H, 14H)-diketone, 18-chloro-11,12,15,20-tetrahydrochysene-21-methoxyl group- |
| 153 | 4,6-ethenylidene pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 because of-11,14 (8H, 15H)-diketone, 19-chloro-9,10,12,13,16,21-six hydrogen-22- |
| Methoxyl group- | |
| 154 | 4,6-ethenylidene pyrimido [4,5-b] [6,1,11,16] benzo oxa-three azacyclo-s 19 are because of-11,16 (8H, 17H)-diketone, 21-chloro-9,10,12,13,14,15,18,23-octahydro-24-methoxyl group- |
| 155 | 4,6-ethenylidene-8H-pyrimido [4,5-b] [6,1,11,15] benzo oxa-three azacyclo-s 18 are because of-11,15 (12H, 16H)-and diketone, 20-chloro-D, 10,13,14,17,22-six hydrogen-23-methoxyl group- |
| 156 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 10,11,14,19-tetrahydrochysene-20-methoxyl group- |
| 157 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,13] benzo oxa-three azacyclo-s 16 because of-9,13 (10H, 14H)-diketone, 11,12,15,20-tetrahydrochysene-21-methoxyl group- |
| 158 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,14] benzo oxa-three azacyclo-s 17 because of-9,14 (8H, 15H)-diketone, 10,11,12,13,16,21-six hydrogen-22-methoxyl group- |
| 159 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,123 benzo oxa-s, three azacyclo-s 15 because of-9,12 (8H, 13H)-diketone, 17-chloro-10,11,14,19-tetrahydrochysene-20-methoxyl group-10-methyl- |
| 160 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-9,12-diketone, 18-chloro-10,11,13,14,15,20-six hydrogen-21-methoxyl group |
| 161 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,14] benzo oxa-three azacyclo-s 18 are because of-9, the 14-diketone, 20-chloro-10,11,12,13,15,16,17,22-octahydro-23-methoxyl group- |
| 162 | 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,12,16] benzo oxa-three azacyclo-s 19 are because of-12,16 (13H, 17H)-diketone, 21-chloro-8,9,10,11,14,15,18,23-octahydro-24-methoxyl group- |
| 163 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,17] benzo oxa-three azacyclo-s 20 are because of-12,17 (18H)-diketone, 22-chloro-9,10,11,13,14,15,16,19,24-nine hydrogen-25-methoxyl group- |
| 164 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 16 are because of-9, the 12-diketone, 18-chloro-10,11,13,14,15,20-six hydrogen-21-methoxyl group-10-methyl- |
| 168 | 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,12,15] benzo oxa-three azacyclo-s 18 are because of-12,15 (16H)-diketone, 20-chloro-9,10,11,13,14,17,22-seven hydrogen-23-methoxyl group-13-methyl- |
Compound identification
The gained chemical compound adopts the gradient elution system on the reversed-phase HPLC to identify by LC/MS.The gained chemical compound is by their specific retention time and their protonated molecular ion MH
+The peak is identified.The HPLC gradient provides by having the WattersAlliance HT2790 system that the post heater is set at 40 ℃.The flow point of coming from pillar branches to the Waters-Micromass ZQ mass spectrograph in electro-spray ionization source that the neutralization of a Waters 996 photodiode arrays (PDA) detector has cation and ionic forms operation.Reversed-phase HPLC has the Xterra MS C that flow velocity is 1.6ml/min one
8(3.5um carries out on 4.6 * 100mm) post.Adopt three kinds of mobile phases (mobile phase A: 95%25mM: ammonium acetate+5% acetonitrile; Mobile phase B: acetonitrile; Mobile phase C: methanol) Yun Hang gradient condition be in 6.5 minutes from 100%A to 50%B to 50%C, in 1 minute to 100%B and with 100%A reequilibrate 1.5 minutes.Volume injected is 10 μ L.
It is from 100 to 1000 scanning acquisitions in 1 second in 0.1 second that mass spectrum adopts life period.Capillary probe voltage is 3kV, and source temperature maintains 140 ℃.Nitrogen adopts atomization gas.The awl voltage 10V of cation mode, the awl voltage of anion pattern is 20V.Data are obtained by a Waters-Micromass MassLynx-Openlynx data system and are undertaken.
Table:Retention time (RT unit minute) and with MH
+The molecular weight of expression
| The chemical compound sequence number | Rt | MH + |
| 64 | 6.38 | 503 |
| 38 | 6.64 | 414 |
| 40 | 4.93 | 427 |
| 71 | 5.66 | 454 |
| 150 | 3.84 | 454 |
| 153 | 3.89 | 546 |
| 120 | 3.77 | 442 |
| The chemical compound sequence number | Rt | MH + |
| 121 | 4.32 | 470 |
| 122 | 4.84 | 518 |
| 60 | 4.53 | 456 |
| 123 | 3.05 | 408 |
| 124 | 4.08 | 450 |
| 125 | 3.56 | 434 |
| 156 | 2.83 | 394 |
| The chemical compound sequence number | Rt | MH + |
| 157 | 3.01 | 408 |
| 158 | 3.3 | 422 |
| 126 | 4.33 | 468 |
| 159 | 4.02 | 442 |
| 127 | 3.62 | 472 |
| 128 | 5.34 | 512 |
| 129 | 3.47 | 458 |
| 130 | 3.93 | 486 |
| 131 | 4.34 | 470 |
| 160 | 4.04 | 442 |
| 161 | 3.86 | 470 |
| 106 | 8.73 | 467 |
| 105 | 9.6 | 467 |
| 132 | 3.74 | 456 |
| 133 | 3.63 | 484 |
| 108 | 6.09 | 453 |
| 117 | 5.95 | 456 |
| 63 | 4.75 | 500 |
| 162 | 4 | 484 |
| 163 | 3.91 | 498 |
| 134 | 4.51 | 510 |
| 135 | 4.56 | 470 |
| The chemical compound sequence number | Rt | MH + |
| 168 | 4.17 | 484 |
| 136 | 4.62 | 526 |
| 137 | 4.18 | 498 |
| 138 | 4.62 | 560 |
| 139 | 3.88 | 456 |
| 119 | 4.5 | 456 |
| 140 | 5.03 | 482 |
| 164 | 4.74 | 456 |
| 141 | 5.41 | 498 |
| 142 | 4.17 | 486 |
| 143 | 5.16 | 512 |
| 144 | 4.42 | 484 |
| 145 | 5.18 | 546 |
| 147 | 4.3 | 514 |
| 110 | 6.2 | 568 |
| 109 | 6.14 | 56B |
| 148 | 3.92 | 472 |
| 149 | 4.45 | 498 |
| 111 | 6.26 | 570 |
| 165 | 5.82 | 540 |
C. pharmacological examples
Embodiment C .1: adopt flicker near algoscopy vitro inhibition EGFRIn current EGFR SPA kinase reaction, the kinase substrate of forming by biotinylated poly-(L-glutamic acid-L-tyrosine) (poly-(GT) biotin), with aforementioned mentioned albumen (
33P) radiolabeled ATP is hatched under existing together.Substrate (
33P) phosphorioization is covered with the streptavidin (Amersham Pharmacia Biotech) of SPA pearl subsequently as luminous energy emission use, measures with combining of radioactive substrates by the biotin of capturing and quantitatively being labeled.
Describe in detail
EGFR SPA kinase reaction carried out in 30 ℃ 60 minutes at 96-hole microtitration plate.Each detected chemical compound has all carried out 1.10
-6M to 1.10
-10The full dose response of M.IRESSA
_And Tarceva
TM(erlotinib) as reference compound.100 μ l reaction volumes contain 54.5mM Tris hydrochlorate, pH8.0,10mM 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
33P-ATP, poly-(GT) biotin in 0.35 μ g/ hole and hole, 0.5 μ g EGFR-kinases territory.
Stop this reaction by the streptavidin pearl (10mg/ml PBS+100mMEDTA+100 μ MATP) that in every hole, adds 100 μ l.Sheets thus obtained jolting 30 minutes in 300rpm is so that all biotinylation substrates are combined by pearl with the streptavidin bag.The gained pearl is deposited in the bottom 30 minutes of plate.Microtitration plate in 800rpm centrifugal 10 minutes, the amount of poly-(GT) biotin of phosphorylated (33P) is by determining by counting (30 minutes/hole) in the microtitration plate scintillation counter.
The vitro inhibition of Embodiment C .2:EGFR
Adopt Flash Plate technology or Davies, S.P. etc. are in Biochem J. (2000), 351; P.95-105 the glass fiber filter technology described in is assessed the vitro inhibition of EGFR.Flash Plate technology is usually at B.A.Brown etc. and in High ThroughputScreening (1997), p.317-328.Editor (s): Devlin describes among the John P.
During Flash Plate EGFR kinase reaction is analyzed, a kind of kinase substrate of forming by biotinylated poly-(L-glutamic acid-L-tyrosine) (poly-(GT) biotin) and the aforementioned protein of mentioning (
33P) radiolabeled ATP is hatched under existing.Substrate (
33P) phosphorioization is covered with the streptavidin (PerkinElmer Life Science) of Flash Plate subsequently as luminous energy emission use, measures with combining of radioactive substrates by the biotin of capturing and quantitatively being labeled.
Describe in detail
The EGFR kinase reaction is to go up at 96-hole microtitration Flash Plate (PerkinElmer LifeSciences) to carry out under 30 ℃ 60 minutes.Carried out 1.10 for each detected chemical compound
-6M to 1.10
-10The full dose response of M.IRESSA
_And Tarceva
TM(erlotinib) be used as reference compound.Comprise 54.5mM Tris HCl pH 8.0,10mM MgCl in the 100 μ l reaction volumes
2, 100 μ M Na
3VO
4, the unlabelled ATP of 5.0uM, 1mM DTT, 0.009%BSA, 0.8 μ Ci AT33P, 0.35 μ g/ hole poly-(GT) biotin and 0.5 μ g EGFR-kinases territory/hole.
By with the reactant mixture sucking-off and wash/stop 3 plates of buffer agent (PBS+100mM EDTA) washing with 200 μ l and come stopped reaction.To in every hole, add in the last washing step after the washing of 200 μ l/stop buffer agent, phosphorylated (
33P) amount of poly-(GT) biotin is determined (30 seconds/hole) by calculating the microtitration plate scintillation counter.
In glass fiber filter technical matters EGFR kinase reaction is analyzed, a kind of kinase substrate of forming by poly-(L-glutamic acid-L-tyrosine) (poly-(GT)), (
33P) hatch with aforementioned albumen under the existence of radioactive label ATP.Substrate (
33P) phosphorylated is detected as the radioactivity that is combined on the glass fibre filter subsequently.
Describe in detail
The EGFR kinase reaction is to carry out under 25 ℃ 10 minutes on one 96 hole microtitration plate.Carried out 1.10 for each detected chemical compound
-6M to 1.10
-10The full dose response of M.IRESSA_ and Tarceva
TM(erlotinib) be used as reference compound.Comprise 60mM Tris HCl pH 7.5,3mM MgCl in the 25 μ l reaction volumes
2, 3mM MnCl
2, 3 μ MNa
3VO
4, 50 μ g/ml PEG20000, the unlabelled ATP of 5.0 μ M, 1mM DTT, 0.1 μ Ci AT33P, 62.5ng/ hole poly-(GT) biotin and 0.5 μ g EGFR-kinases territory, every hole.
Come stopped reaction by 3% phosphoric acid solution that adds 55Itl.Extract in reactant mixture to the Filtermat A filter (Wallac) of 10 μ l, and reached before Typhoon (Amersham) upward adopts a LE phosphorage storage scanning in drying, in 75mM phosphoric acid, washed 3 times 5 minutes and in methanol, washed 1 time 5 minutes.
Embodiment C .3: the serum-free proliferation test on ovarian cancer SKOV3 cell
Adopt ovarian cancer cell line (SKOV3) to carry out the epidermal growth factor test that stimulates cellular proliferation, to assess the inhibitory action of chemical compound for the EGF in the full cell.
In the first step, the SKOV3 cell was hatched in the presence of 10%FCS serum 24 hours.In second step, above-mentioned cell is that the detected chemical compound of 100ng/ml is hatched 72 hours (37 ℃ and 5% (v/v) CO with ultimate density
2).The stimulation of chemical compound on EGF is finally with standard MTT cytoactive analysis and evaluation.
Perhaps, the SKOV3 cell was hatched in the presence of 10%FCS serum 24 hours.In second step, above-mentioned cell is hatched 72 hours with detected chemical compound, and the effect of chemical compound on cell proliferation is finally with standard MTT cytoactive analysis and evaluation.
Embodiment C .4:EGFR tyrosine kinase activity
EGFR ELISA is generally by Yang, E.B.et al., 2001, Biochimica etBiophysica Acta, 1550; Described in 144.
In order to determine the activity of EGFR tyrosine kinase, be applied to poly-(glutamic acid, the cheese amino) of the 0.4 μ g/ml in PBS of 100 μ l on each hole on the microtitration plate in a 96-hole, 37 ℃ of following overnight incubation.Nonspecific binding site is by at room temperature hatching blocking-up in 30 minutes with the BSA diluent (10mg/ml in PBS) of every hole 200 μ l.Behind 3 plates of PBS washing, can use immediately or storage under 4 ℃.
Before the activity of determining the EGFR tyrosine kinase, the plate of the shoe that is coated with is with PBS washing 2 times.Then, the ATP diluent (50mM Tris HCl pH 8.0, the 10mM MgCl that in every hole, add 88 μ l
2, 100FM Na
3VO
4, 1mM DTT, 5 μ M ATP) and 2 μ l have the test compound of various concentration.The EGFR of the dilution of EGFR tyrosine kinase-catalytic reaction by adding 10 μ l (the every hole of dilution → 0.05 μ g enzyme dilutes into 50mM TrisHCl pH 8.0+0.1%BSA) beginning.
After at room temperature hatching 10 minutes, stop this reaction 5 times by polysorbas20 washing with PBS and 0.1%.Adding the reorganization of 100ml in BSA (10mg/ml is at PBS) subsequently resists-phosphorylated kinases horseradish peroxidase conjugate (1: 2500).After at room temperature hatching 1 hour, microplate is with PBS/ polysorbas20 washing 5 times.(1-step Ultra TMB-ELISA Pierce) is hatched after colour developing, adds the 0.5M H of 100 μ l as the TMB-ELISA of microplate and 100 μ l
2SO
4Stop so that reacting, and it reads to read plate in 450-655nm wavelength place on the device at microplate.
Embodiment C .5: squamous cancer cell is the proliferation test on the A431 cell
In cell proliferation test, adopt squamous cancer cell system (A431), with the inhibitory action of assessment chemical compound in full cell.
In the first step, the A431 cell was hatched in the presence of 10%FCS serum 24 hours.In second step, above-mentioned cell is that the detected chemical compound of 100ng/ml was hatched 72 hours with ultimate density.The effect of chemical compound on cell proliferation is finally with standard MTT cell viability analysis and evaluation.
Following table provides the The compounds of this invention IC50 that adopts above-mentioned kinase assay gained value.
| Compound number | EGFR SPA (C1): the n of IC50 unit | Kinase activity (C2): pIC50 | SKOV3 cell (C3): pIC50 | A431 cell (C5): pIC50 | EGFR ELISA (C4): the nM of IC50 unit |
| 1 | ＞100 | ＜5.0 | ＜5.7 | ＜6.0 | ＞1000 |
| 2 | ＞100 | 7.0 | ＜5.7 | ＜6.0 | ＞1000 |
| 3 | 3.61 | 7.8 | 5.87 | ＜6.0 | ＞1000 |
| 4 | 32.58 | 7.3 | 5.54 | NT | 556 |
| 5 | 81.10 | 6.4 | 5.32 | NT | ＞1000 |
| 6 | 4.40 | 7.6 | 5.74 | NT | 359 |
| 7 | 6.64 | 7.1 | ＜5 | NT | ＞1000 |
| 8 | 3.97 | 7.5 | ＜5 | NT | 329 |
| 9 | 6.79 | 7.4 | NT | NT | ＞1000 |
| 16 | NT | 5.6 | NT | NT | ＞1000 |
| 18 | NT | 7.1 | ＜5 | NT | ＞1000 |
| 17 | NT | 7.4 | 5.08 | 5.6 | 269 |
| 10 | NT | 7.3 | ＜5 | ＜5.5 | ＞1000 |
| 12 | NT | ＜5 | ＜5 | ＜5.5 | ＞1000 |
| 14 | NT | ＜5 | ＜5 | ＜5.5 | ＞1000 |
| 11 | NT | ＜5 | ＜5 | ＜5.5 | ＞1000 |
| 13 | NT | 6.5 | ＜5 | ＜5.5 | ＞1000 |
| 20 | NT | 7.6 | 6.64 | 5.9 | NT |
| 19 | NT | 7.2 | 5.3 | ＜5.5 | NT |
| 21 | NT | 8.0 | 6.09 | ＜5.5 | 158 |
| 22 | NT | 7.8 | 6.59 | 5.8 | 38.4 |
| 23 | NT | 8.0 | 7.22 | 6.3 | NT |
| 24 | NT | 7.7 | 5.5 | ＜5.5 | NT |
| Compound number | EGFR SPA (C1): the n of IC50 unit | Kinase activity (C2): pIC50 | SKOV3 cell (C3): pIC50 | A431 cell (C5): pIC50 | EGFR ELISA (C4): the nM of IC50 unit |
| 25 | NT | 6.2 | ＜5 | ＜5.5 | NT |
| 26 | NT | 8.6 | 6.92 | 5.7 | NT |
| 28 | NT | 7.6 | 5.84 | 5.8 | NT |
| 29 | NT | 6.1 | ＜5 | ＜5.5 | NT |
| 30 | NT | 7.5 | 5.99 | ＜6.0 | NT |
| 32 | NT | 8.4 | 6.54 | NT | NT |
| 33 | NT | 7.6 | 5.76 | 5.8 | NT |
| 34 | NT | 7.2 | ＜5 | ＜5.5 | NT |
| 35 | NT | 5.4 | ＜5 | ＜5.5 | NT |
| 36 | NT | 7.8 | 6.78 | ＜5.5 | NT |
| 37 | NT | ＜5 | ＜5 | ＜5.5 | NT |
| 38 | NT | 7.7 | 6.9 | 5.9 | NT |
| 39 | NT | 7.7 | 6.7 | 5.8 | NT |
| 40 | NT | 7.5 | 7.3 | 6.2 | NT |
| Compound number | Kinase activity (C2): pIC50 | SKOV3 cell (C3): pIC50 | Embodiment number |
| 64 | 6.0 | 6.4 | B39 |
| 71 | 7.5 | 5.5 | B41 |
| 72 | 6.8 | 5.0 | B41 |
| 73 | 7.4 | 5.4 | B41 |
| 74 | 7.6 | 6.0 | B41 |
| 75 | 7.2 | 5.2 | B41 |
| 70 | 8.0 | 5.5 | B41 |
| 151 | 5.5 | 5.0 | B49 |
| 76 | 7.6 | 6.7 | B41 |
| 77 | 7.8 | 6.1 | B41 |
| Compound number | Kinase activity (C2): pIC50 | SKOV3 cell (C3): pIC50 | Embodiment number |
| 150 | 7.7 | 5.1 | B49 |
| 152 | 7.5 | 5.0 | B49 |
| 153 | 7.8 | 6.1 | B49 |
| 154 | 7.4 | 5.6 | B49 |
| 155 | 6.5 | 6.0 | B49 |
| 61 | 7.8 | 6.4 | B39 |
| 120 | 5.7 | 6.0 | B48 |
| 121 | 5.6 | 5.0 | B48 |
| 122 | 6.4 | 5.0 | B48 |
| 66 | 7.1 | 8.0 | B40 |
| Compound number | Kinase activity (C2): pIC50 | SKOV3 cell (C3): pIC50 | Embodiment number |
| 65 | 7.9 | 7.7 | B40 |
| 67 | 7.0 | 6.3 | B40 |
| 68 | 7.9 | 8.2 | B40 |
| 69 | 7.3 | 7.2 | B40 |
| 60 | 7.8 | 8.7 | B36 |
| 123 | 5.2 | 5.0 | B48 |
| 124 | 5.0 | 5.0 | B48 |
| 125 | 5.1 | 5.0 | B48 |
| 156 | 5.0 | 5.0 | B49 |
| 157 | 5.0 | 5.0 | B49 |
| Compound number | Kinase activity (C2): pIC50 | SKOV3 cell (C3): pIC50 | Embodiment number |
| 158 | 5.3 | 5.0 | B49 |
| 78 | 7.5 | 6.5 | B41 |
| 114 | 8.0 | 7.4 | B46 |
| 79 | 6.2 | 5.0 | B41 |
| 80 | 7.7 | 7.2 | B41 |
| 81 | 6.6 | 6.6 | B41 |
| 82 | 7.7 | 7.1 | B41 |
| 99 | 7.6 | 6.7 | B41 |
| 126 | 5.7 | 5.6 | B48 |
| 159 | 6.5 | 5.7 | B49 |
| Compound number | Kinase activity (C2): pIC50 | SKOV3 cell (C3): pIC50 | Embodiment number |
| 127 | 6.6 | 5.8 | B48 |
| 128 | 8.0 | 6.7 | B48 |
| 129 | 5.8 | 5.4 | 848 |
| 130 | 7.6 | 6.9 | B48 |
| 131 | 7.6 | 7.0 | B48 |
| 160 | 7.2 | 6.2 | B49 |
| 161 | 7.2 | 5.9 | B49 |
| 83 | 6.3 | 6.1 | B41 |
| 84 | 6.2 | 6.5 | B41 |
| 103 | 7.2 | 7.3 | B43 |
| Compound number | Kinase activity (C2): pIC50 | SKOV3 cell (C3): pIC50 | Embodiment number |
| 101 | 6.6 | 7.5 | B42 |
| 52 | 7.1 | 7 | B34 |
| 53 | 6.7 | 6.3 | B34 |
| 54 | 6.9 | 5.9 | B34 |
| 55 | 6.3 | 6.7 | B34 |
| 56 | 5.8 | 5.0 | B34 |
| 57 | 5.2 | 6.4 | B34 |
| 58 | 5.7 | 5.7 | B34 |
| 44 | 6.2 | 5.1 | B33 |
| 45 | 6.8 | 5.0 | B33 |
| Compound number | Kinase activity (C2): pIC50 | SKOV3 cell (C3): pIC50 | Embodiment number |
| 42 | 6.3 | 7.2 | B33 |
| 43 | 7.1 | 6.3 | B33 |
| 46 | 6.7 | 5.1 | B33 |
| 47 | 6.9 | 5.8 | B33 |
| 48 | 6.5 | 5.8 | B33 |
| 49 | 6.4 | 6.1 | B33 |
| 50 | 7.1 | 6.8 | B33 |
| 51 | 6.4 | B33 | |
| 100 | 8.1 | 6.9 | B42 |
| 102 | 6.7 | 7.3 | B42 |
| Compound number | Kinase activity (C2): pIC50 | SKOV3 cell (C3): pIC50 | Embodiment number |
| 106 | 7.0 | 7.2 | B44 |
| 105 | 6.8 | 7.6 | B44 |
| 104 | 6.0 | 6.5 | B43 |
| 115 | 8.2 | 6.9 | B46 |
| 116 | 6.7 | 7.2 | B46 |
| 132 | 5.0 | 5.0 | B48 |
| 133 | 5.8 | 5.1 | B48 |
| 108 | 6.4 | 6.8 | B44 |
| 117 | 6.7 | 5.4 | B46 |
| 63 | 6.9 | 5.7 | B38 |
| Compound number | Kinase activity (C2): pIC50 | SKOV3 cell (C3): pIC50 | Embodiment number |
| 162 | 6.8 | 7.3 | B49 |
| 163 | 7.0 | 6.4 | B49 |
| 134 | 6.4 | 6.1 | B48 |
| 135 | 5.4 | 6.0 | B48 |
| 136 | 6.2 | 6.6 | B48 |
| 137 | 6.6 | 6.6 | B48 |
| 138 | 5.7 | 6.2 | B48 |
| 139 | 6.4 | 6.8 | B48 |
| 119 | 6.0 | 5.8 | B48 |
| 140 | 6.7 | 6.7 | B48 |
| Compound number | Kinase activity (C2): pIC50 | SKOV3 cell (C3): pIC50 | Embodiment number |
| 164 | 6.3 | 6.8 | B49 |
| 141 | 6.1 | 5.8 | B48 |
| 142 | 7.0 | 6.2 | B48 |
| 143 | 6.3 | 6.7 | B48 |
| 144 | 6.8 | 6.9 | B48 |
| 145 | 6.7 | 6.6 | B48 |
| 146 | 6.7 | 6.2 | B48 |
| 147 | 6.9 | 6.6 | B48 |
| 62 | 6.4 | 5.3 | B48 |
| 110 | 5.4 | 5.0 | B45 |
| Compound number | Kinase activity (C2): pIC50 | SKOV3 cell (C3): pIC50 | Embodiment number |
| 109 | 5.7 | 6.5 | B45 |
| 148 | 6.6 | 5.0 | B48 |
| 149 | 6.9 | 5.8 | B48 |
| Compound number | Kinase activity (C2): pIC50 | SKOV3 cell (C3): pIC50 | Embodiment number |
| 111 | 5.8 | 5.0 | B45 |
D. compositions example
Following preparation illustration be suitable for the typical Pharmaceutical composition that systematicness gives animal or human experimenter according to of the present invention.
Be applied in " active component " that use in these examples and (A.I.) relate to formula (I) chemical compound or its pharmaceutically acceptable addition salt.
Embodiment is D.1: film coated tablet
The preparation label
With the mixture mix homogeneously of A.I. (100g), lactose (570g) and starch (200g), then with about 200ml aqueous solution moistening of sodium lauryl sulphate (5g) and polyvinylpyrrolidone (10g).With wet mixture of powders sieve, dry and sieve once more.Add microcrystalline Cellulose (100g) and hydrogenated vegetable oil (15g) then.With above-mentioned all material mix homogeneously and tablettings, get 10,000, every contains the 10mg active component.
Peplos
DCM (150ml) solution that in methylcellulose (10g) solution of denatured ethyl alcohol (75ml), adds ethyl cellulose (5g).Add DCM (75ml) and 1,2 then, 3-glycerol (2.5ml).With Polyethylene Glycol (10g) fusion and be dissolved in the dichloromethane (75ml).The latter solution added to add magnesium stearate (2.5g), polyvinyl-ketopyrrolidine (5g) among the former then and concentrate painted suspension (30ml) and make whole homogeneous phaseizations.In the coating instrument, use the gained mixture to the label coating.
Claims (23)
1. chemical compound and N-oxide form, pharmaceutically acceptable addition salt and stereochemistry heterogeneous forms with following formula:
Wherein,
Z represents O, CH
2, NH or S; Especially, Z represents NH;
Y representative-C
3-9Alkyl-,-C
3-9Thiazolinyl-,-C
3-9Alkynyl-, optional by amino, single-or two (C
1-4Alkyl) amino or C
1-4The C of alkoxycarbonyl amino-replacement
3-7Alkyl-CO-NH, optional by amino, single-or two (C
1-4Alkyl) amino or C
1-4The C of alkoxycarbonyl amino-replacement
3-7Thiazolinyl-CO-NH, optional by amino, single-or two (C
1-4Alkyl) amino or C
1-4The C of alkoxycarbonyl amino-replacement
3-7Alkynyl-CO-NH, 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-, C
1-3Alkyl-NH-CS-Het
20-,-C
1-3Alkyl-NH-CO-Het
20,-C
1-2Alkyl-CO-Het
21-CO-, Het
22-CH
2-CO-NH-C
1-3Alkyl-,-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-,-C
1-2Alkyl-NH-CO-CR
16R
17-NH-,-C
1-2Alkyl-CO-NH-CR
18R
19-CO-,-C
1-2Alkyl-CO-NR
20-C
1-3Alkyl-CO-,-C
1-2Alkyl-NR
21-CH
2-CO-NH-C
1-3Alkyl-or-NR
22-CO-C
1-3Alkyl-NH-;
X
1Represent connecting key, O ,-O-C
1-2Alkyl-, CO ,-CO-C
1-2Alkyl-, NR
11,-NR
11-C
1-2Alkyl-,-CH
2-,-O-N=CH-or C
1-2Alkyl-;
X
2Represent connecting 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
1Represent hydrogen, cyano group, halogen, hydroxyl, formoxyl, C
1-6Alkoxyl-, C
1-6Alkyl-, halogen-phenyl-carbonylamino-, the C that replaces of halogen
1-6Alkoxyl-, by one or may be two or more be selected from the C that the substituent groups of hydroxyl or halogen replace
1-4Alkyl;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group, Het
16-carbonyl, C
1-4Alkoxy carbonyl-, C
1-4Alkyl-carbonyl-, amino carbonyl-, single-or two (C
1-4Alkyl) amino carbonyl-, Het
1, formoxyl, C
1-4Alkyl-, C
2-6Alkynyl-, C
3-6Cycloalkyl-, C
3-6Cycloalkyloxy-, C
1-6Alkoxyl-, Ar
5, Ar
1-oxygen base-, the C that replaces of dihydroxy borine, halogen
1-6Alkoxyl-, by one or may two or more halogen, hydroxyl or NR of being selected from
5R
6The C that replaces of substituent group
1-4Alkyl;
C
1-4Alkyl-carbonyl-, wherein said C
1-4Alkyl is optional by one or two or more hydroxyl or the C of being selected from of possibility
1-4Alkyl-oxygen base-substituent group replace;
R
3Represent hydrogen, C
1-4Alkyl or be selected from halogen, C by one or more
1-4Alkoxyl-, amino-, single-or two (C
1-4Alkyl) amino-, C
1-4Alkyl-sulfonyl-or the C that replaces of the substituent group of phenyl
1-4Alkyl;
R
4Represent hydrogen, hydroxyl, Ar
3-oxygen base, Ar
4-C
1-4Alkoxyl-, C
1-4Alkoxyl-, optional by Het
12The C that replaces
2-4Alkene oxygen base-; Or R
4Representative is by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl, hydroxyl, halogen, Het
2-,-NR
7R
8,-carbonyl-NR
9R
10Or Het
3-carbonyl-the C that replaces of substituent group
1-4Alkoxyl;
R
5And R
6Independently be selected from hydrogen or C separately
1-4Alkyl;
R
7And R
8Independently be selected from hydrogen, C separately
1-4Alkyl, Het
8-, amino-sulfonyl-, single-or two (C
1-4Alkyl)-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-, polyhydroxy-C
1-4Alkyl-, Het
11-C
1-4Alkyl-or Ar
2-C
1-4Alkyl-;
R
9And R
10Each independently is selected from hydrogen, C
1-4Alkyl, C
3-6Cycloalkyl, Het
4, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-;
R
11Represent 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 sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
12Represent hydrogen, C
1-4Alkyl, C
1-4Alkyl-oxygen base-carbonyl-, Het
18-C
1-4Alkyl-, phenyl-C
1-4Alkyl-oxygen base-carbonyl-, Het
17, optional by Het
19-C
1-4The C of alkyl amino-carbonyl-replacement
2-4Alkenyl carbonyl-, C
2-4The thiazolinyl sulfonyl-, C
1-4Alkoxy C
1-4Alkyl, or R
12Representative is optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
13Represent hydrogen, C
1-4Alkyl, Het
13, Het
14-C
1-4Alkyl-or optional be selected from hydrogen, hydroxyl, amino or C by one or possible two or more
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
14And R
15Independently be selected from hydrogen, C separately
1-4Alkyl, Het
15-C
1-4Alkyl-or C
1-4Alkoxy C
1-4Alkyl-;
R
16And R
17Independent separately hydrogen or the optional C that is replaced by phenyl, indyl, methyl mercapto, hydroxyl, mercaptan, hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals of representing
1-4Alkyl;
R
18And R
19Independent separately hydrogen or the optional C that is replaced by phenyl, indyl, methyl mercapto, hydroxyl, mercaptan, hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals of representing
1-4Alkyl;
R
20And R
22The independent separately hydrogen or optional of representing by hydroxyl or C
1-4The C that alkoxyl replaces
1-4Alkyl;
R
21Represent hydrogen, C
1-4Alkyl, Het
23-C
1-4Alkyl-carbonyl or R
21Representative is optional by hydroxyl, pyrimidine radicals, dimethyl amine or C
1-4The list that alkoxyl replaces-or two (C
1-4Alkyl) amino-C
1-4Alkyl-carbonyl-;
Het
1Represent heterocycle, described heterocycle is selected from piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, 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-list-or two (C
1-4Alkyl) amino-or amino carbonyl-replacement;
Het
2Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, thio-morpholinyl or dithian base, wherein said Het
2Optional by one or possibility two or a plurality of hydroxyl, halogen, amino, C of being selected from
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-substituent group replace;
Het
3, Het
4And Het
8Independently represent heterocycle, described heterocycle to be selected from morpholinyl, piperazinyl, piperidyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, wherein said Het separately
3, Het
4Or Het
8Optional by one may two or a plurality of be selected from 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-substituent group replace;
Het
5Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
6And Het
7Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
9And Het
10Independently represent heterocycle, described heterocycle to be selected from furyl, piperidyl, morpholinyl, piperazinyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, wherein said Het separately
9Or Het
10Be the optional C that replaces
1-4Alkyl, C
3-6Cycloalkyl-C
1-4Alkyl-or amino-C
1-4Alkyl-;
Het
11Represent heterocycle, described heterocycle be selected from indyl or
Het
12Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, thio-morpholinyl or dithian base, wherein said Het
12Optional by one or possibility two or a plurality of hydroxyl, halogen, amino, C of being selected from
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-substituent group replace;
Het
13Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-, polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
14Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4The substituent group of alkyl replaces;
Het
15Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4The substituent group of alkyl replaces;
Het
16Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-two oxa-bora Pentamethylene. base or piperidyls, and wherein said heterocycle is optional to be selected from C by one or more
1-4The substituent group of alkyl replaces;
Het
17Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
18And Het
19Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4The substituent group of alkyl replaces;
Het
20, Het
21And Het
22Independently represent heterocycle, described heterocycle to be selected from pyrrolidinyl, 2-Pyrrolidone base, piperazinyl or piperidyl separately, optional by one or possibility two or a plurality of hydroxyl, C of being selected from
1-4Alkyl-, hydroxyl-C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
23Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Ar
1, Ar
2, Ar
3, Ar
4And Ar
5The independent separately phenyl of representing, optional by cyano group, C
1-4Alkyl sulphonyl-, C
1-4Alkyl sulfonyl-amino-, amino-sulfonyl amino-, hydroxyl-C
1-4Alkyl, amino-sulfonyl-, hydroxyl, C
1-4Alkoxyl-or C
1-4Alkyl replaces.
2. the chemical compound of claim 1, wherein
Z represents O, NH or S;
Y representative-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-,-C
1-2Alkyl-NH-CO-CH
2R
16-NH-;
X
1Represent connecting key, O ,-O-C
1-2Alkyl-, CO ,-CO-C
1-2Alkyl-, NR
11,-NR
11-C
1-2Alkyl-,-CH
2-,-O-N=CH-or C
1-2Alkyl-;
X
2Represent connecting 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
1Represent hydrogen, cyano group, halogen, hydroxyl, formoxyl, C
1-6Alkoxyl-, C
1-6Alkyl-, the C that replaces of halogen
1-6Alkoxyl-,
By one or possibility two or a plurality of C that is selected from the substituent group replacement of hydroxyl or halogen
1-4Alkyl;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group, Het
16-carbonyl, C
1-4Alkoxy carbonyl-, C
1-4Alkyl-carbonyl-, amino carbonyl-, single-or two (C
1-4Alkyl) amino carbonyl-, Het
1, formoxyl, C
1-4Alkyl-, C
2-6Alkynyl-, C
3-6Cycloalkyl-, C
3-6Cycloalkyloxy-, C
1-6Alkoxyl-, Ar
5, Ar
1-oxygen base-, the dihydroxy borine,
The C that is replaced by halogen
1-6Alkoxyl-,
By one or possibility two or a plurality of halogen, hydroxyl or NR of being selected from
5R
6The C that replaces of substituent group
1-4Alkyl,
C
1-4Alkyl-carbonyl-, wherein said C
1-4Alkyl is optional by one or possibility two or a plurality of hydroxyl or C of being selected from
1-4Alkyl-oxygen base-substituent group replace;
R
3Represent hydrogen, C
1-4Alkyl or be selected from halogen, C by one or more
1-4Alkoxyl-, amino-, single-or two (C
1-4Alkyl) amino-, C
1-4Alkyl-sulfonyl-or the C that replaces of the substituent group of phenyl
1-4Alkyl;
R
4Represent hydrogen, hydroxyl, Ar
3-oxygen base, Ar
4-C
1-4Alkoxyl-, C
1-4Alkoxyl-, optional by Het
12The C that replaces
2-4Alkene oxygen base-; Or R
4Representative is by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl-, hydroxyl, halogen, Het
2,-NR
7R
8,-carbonyl-NR
9R
10Or Het
3-carbonyl-the C that replaces of substituent group
1-4Alkoxyl;
R
5And R
6Independently be selected from hydrogen or C separately
1-4Alkyl;
R
7And R
8Independently be selected from hydrogen, C separately
1-4Alkyl, Het
8, amino-sulfonyl-, single-or two (C
1-4Alkyl)-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-, polyhydroxy-C
1-4Alkyl-, Het
11-C
1-4Alkyl-or Ar
2-C
1-4Alkyl-;
R
9And R
10Independently be selected from hydrogen, C separately
1-4Alkyl, C
3-6Cycloalkyl, Het
4, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-;
R
11Represent 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 sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
12Represent 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 sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
13Represent hydrogen, C
1-4Alkyl, Het
13, Het
14-C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
14And R
15Independently be selected from hydrogen, C separately
1-4Alkyl, Het
15-C
1-4Alkyl-or C
1-4Alkoxy C
1-4Alkyl-;
R
16Represent hydrogen or the optional C that is replaced by phenyl, indyl, methyl mercapto, hydroxyl, mercaptan, hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals
1-4Alkyl;
Het
1Represent heterocycle, described heterocycle is selected from piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, 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-list-or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
Het
2Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, thio-morpholinyl or dithian base, wherein said Het
2Optional by one or possibility two or a plurality of hydroxyl, halogen, amino, C of being selected from
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-substituent group replace;
Het
3, Het
4And Het
8Independently represent heterocycle, described heterocycle to be selected from morpholinyl, piperazinyl, piperidyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, wherein said Het separately
3, Het
4Or Het
8Optional by one or possibility two or a plurality of hydroxyl, amino, C of being selected from
1-4Alkyl-, C
3-6Cycloalkyl-C
1-4Alkyl-, amino-sulfonyl-, single-or two (C
1-4Alkyl) amino-sulfonyl-or amino-C
1-4Alkyl-substituent group replace;
Het
5Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
6And Het
7Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
9And Het
10Independently represent heterocycle, described heterocycle to be selected from furyl, piperidyl, morpholinyl, piperazinyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, wherein said Het separately
9Or Het
10Be the optional C that replaces
1-4Alkyl, C
3-6Cycloalkyl-C
1-4Alkyl-or amino-C
1-4Alkyl-;
Het
11Represent heterocycle, described heterocycle be selected from indyl or
Het
12Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, thio-morpholinyl or dithian base, wherein said Het
12Optional by one or possibility two or a plurality of hydroxyl, halogen, amino, C of being selected from
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-substituent group replace;
Het
13Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
14Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
15Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
16Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-two oxa-bora Pentamethylene. base or piperidyls, and wherein said heterocycle is optional to be selected from C by one or more
1-4The substituent group of alkyl replaces; And
Het
17Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
18And Het
19Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl-, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Ar
1, Ar
2, Ar
3, Ar
4And Ar
5The independent separately phenyl of representing, optional by cyano group, C
1-4Alkyl sulphonyl-, C
1-4Alkyl sulfonyl-amino-, amino-sulfonyl amino-, hydroxyl-C
1-4Alkyl, amino-sulfonyl-, hydroxyl-, C
1-4Alkoxyl-or C
1-4Alkyl replaces.
3. claim 1 or 2 chemical compound, wherein,
Z represents NH;
Y representative-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-,-NH-CO-C
1-6Alkyl-,-CO-C
1-7Alkyl-,-C
1-7Alkyl-CO-,-C
1-6Alkyl-CO-C
1-6Alkyl-,-C
1-2Alkyl-NH-CO-CR
16R
17-NH-,-C
1-2Alkyl-CO-NH-CR
18R
19-CO-,-C
1-2Alkyl-CO-NR
20-C
1-3Alkyl-CO-,-C
1-2Alkyl-NR
21-CH
2-CO-NH-C
1-3Alkyl-,-NR
22-CO-C
1-3Alkyl-NH-,-C
1-3Alkyl-NH-CO-Het
20,-C
1-2Alkyl-CO-Het
21-CO-or-Het
22-CH
2-CO-NH-C
1-3Alkyl-;
X
1Represent O ,-O-C
1-2Alkyl-,-O-N=CH-, NR
11Or-NR
11-C
1-2Alkyl-;
X
2Represent connecting key ,-C
1-2Alkyl-, O ,-O-C
1-2Alkyl-,-O-N=CH-, NR
12Or-NR
12-C
1-2Alkyl-;
R
1Represent hydrogen, cyano group, halogen or hydroxyl;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-, C
1-4Alkoxy carbonyl-, Het
16-carbonyl, C
1-4Alkyl-, C
2-6Alkynyl-, Ar
5Or Het
1
R
3Represent hydrogen;
R
4Represent hydrogen, hydroxyl, C
1-4Alkoxyl-; Or R
4Representative is by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl-or Het
2-the C that replaces of substituent group
1-4Alkoxyl;
R
12Represent hydrogen, C
1-4Alkyl-or C
1-4Alkyl-oxygen base-carbonyl-;
R
13Represent hydrogen or Het
14-C
1-4Alkyl-;
R
14And R
15Represent hydrogen;
R
16The C that represents hydrogen or replaced by hydroxyl
1-4Alkyl;
R
17Represent hydrogen or C
1-4Alkyl, particularly hydrogen or methyl;
R
18Represent hydrogen or optional by the C of hydroxyl or phenyl replacement
1-4Alkyl;
R
19Represent hydrogen or C
1-4Alkyl;
R
20Represent hydrogen or C
1-4Alkyl;
R
21Represent hydrogen, C
1-4Alkyl, Het
23-C
1-4Alkyl-carbonyl or R
21Represent single-or two (C
1-4Alkyl) amino-C
1-4Alkyl-carbonyl-, optional by hydroxyl, pyrimidine radicals, dimethyl amine or C
1-4Alkoxyl replaces;
R
22Represent hydrogen or optional by hydroxyl or C
1-4The C that alkoxyl replaces
1-4Alkyl;
Het
1Represent thiazolyl, optional by amino, C
1-4Alkyl, hydroxyl-C
1-4Alkyl-, phenyl, phenyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-list-or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
Het
2Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
2Optional by one or possibility two or a plurality of hydroxyl, amino or C of being selected from
1-4Alkyl-substituent group replace;
Het
3Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
3Optional by one or may two or a plurality of hydroxyl, amino-or C that is selected from
1-4Alkyl-substituent group replace;
Het
12Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
12Optional by one or possibility two or a plurality of hydroxyl, amino or C of being selected from
1-4Alkyl-substituent group replace;
Het
16Represent heterocycle, described heterocycle is selected from piperidyl or pyrrolidinyl;
Het
20Represent pyrrolidinyl, 2-Pyrrolidone base, piperidyl or hydroxyl-pyrrolidinyl, be preferably pyrrolidinyl or hydroxyl-pyrrolidinyl;
Het
21Represent pyrrolidinyl or hydroxyl-pyrrolidinyl;
Het
22Represent pyrrolidinyl, piperazinyl or piperidyl.
4. claim 1 or 2 chemical compound, wherein:
Z represents NH;
Y representative-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
1Represent O ,-O-C
1-2Alkyl-,-O-N=CH-, NR
11Or-NR
11-C
1-2Alkyl-;
X
2Represent connecting key, O ,-O-C
1-2Alkyl-,-O-N=CH-, NR
12Or-NR
12-C
1-2Alkyl-;
R
1Represent hydrogen, cyano group, halogen or hydroxyl, be preferably halogen;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group-, C
1-4Alkoxy carbonyl-, Het
16-carbonyl-, C
2-6Alkynyl-, Ar
5Or HetU;
R
3Represent hydrogen;
R
4Representation hydroxy, C
1-4Alkoxyl or R
4Represent C
1-4Alkoxyl, optional by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl-or Het
2Substituent group replace;
R
12Represent hydrogen, C
1-4Alkyl or C
1-4Alkyl-oxygen base-carbonyl-;
R
13Represent Het
14-C
1-4Alkyl;
Het
1Represent thiazolyl, optional by amino, C
1-4Alkyl, hydroxyl-C
1-4Alkyl-, phenyl, phenyl-C
1-4Alkyl-, C
1-4Alkyl-oxygen base-C
1-4Alkyl-list-or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
Het
2Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
2Optional by one or possibility two or a plurality of hydroxyl, amino or C of being selected from
1-4Alkyl-substituent group replace;
Het
3Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
3Optional by one or may two or a plurality of hydroxyl, amino-or C that is selected from
1-4Alkyl-substituent group replace;
Het
12Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
12Optional by one or possibility two or a plurality of hydroxyl, amino or C of being selected from
1-4Alkyl-substituent group replace;
Het
16Represent heterocycle, described heterocycle is selected from piperidyl or pyrrolidinyl.
5. the chemical compound of claim 1, wherein,
Z represents NH;
Y representative-C
3-9Alkyl-,-CO-C
1-7Alkyl-or-C
1-7Alkyl-CO-;
X
1Represent NR
11,-O-or-O-CH
2-;
X
2Represent connecting key, O ,-O-CH
2-;
R
1Represent halogen;
R
2Represent hydrogen, cyano group, halogen, hydroxyl or C
2-6Alkynyl-;
R
3Represent hydrogen;
R
4Representative is optional by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl-or Het
2The C that replaces of substituent group
1-4Alkoxyl;
R
12Represent C
1-4Alkyl or R
12Represent C
1-4Alkyl-oxygen base-carbonyl-;
Het
2Represent heterocycle, described heterocycle is selected from morpholinyl or piperidyl, and is optional by C
1-4Alkyl-replacement;
Het
3Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
3Optional by one may two or a plurality of be selected from hydroxyl-, amino-or C
1-4Alkyl-substituent group replace;
Het
12Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl or pyrrolidinyl, wherein said Het
12Optional by one or possibility two or a plurality of hydroxyl, amino or C of being selected from
1-4Alkyl-substituent group replace.
6. the chemical compound of claim 1, wherein,
Z represents NH;
Y representative-C
3-9Alkyl-,-C
2-9Thiazolinyl-, optional by amino, single-or two (C
1-4Alkyl) amino or C
1-4Alkoxycarbonyl amino-replacement-C
3-7Alkyl-CO-NH, optional by amino, single-or two (C
1-4Alkyl) amino or C
1-4The C of alkoxycarbonyl amino-replacement
3-7Thiazolinyl-CO-NH, C
1-5Alkyl-NR
13-C
1-5Alkyl-, C
1-5Alkyl-NH
14-CO-C
1-5Alkyl ,-C
1-6Alkyl-CO-NH-,-C
1-5Alkyl-CO-NR
15-C
1-5Alkyl ,-C
1-3Alkyl-NH-CO-Het
20,-C
1-2Alkyl-CO-Het
21-CO-,-C
1-2Alkyl-NH-CO-CR
16R
17-NH-, C
1-2Alkyl-CO-NH-CR
18R
19-CO-, C
1-2Alkyl-CO-NR
20-C
1-3Alkyl-CO-or-NR
22-CO-C
1-3Alkyl-NH-;
X
1Represent connecting key, O or-O-C
1-2Alkyl-;
X
2Represent connecting key ,-CO-C
1-2Alkyl-, NR
12,-NR
12-C
1-2Alkyl-,-O-N=CH-or-C
1-2Alkyl-;
R
1Represent hydrogen or halogen;
R
2Represent hydrogen or halogen;
R
3Represent hydrogen;
R
4Represent hydrogen or C
1-4Alkoxyl;
R
12Represent hydrogen or C
1-4Alkyl;
R
13Represent hydrogen or C
1-4Alkyl;
R
14Represent hydrogen;
R
15Represent hydrogen;
R
16And R
17Independent separately hydrogen or the C of representing
1-4Alkyl;
R
18And R
19The independent separately hydrogen or optional of representing by the C of phenyl or hydroxyl replacement
1-4Alkyl;
R
20And R
21The independent separately hydrogen or optional of representing by C
1-4The C that alkoxyl replaces
1-4Alkyl;
Het
20, Het
21And Het
22Independently represent heterocycle separately, described heterocycle is selected from pyrrolidinyl, 2-Pyrrolidone base or piperidyl, chooses wantonly to be replaced by hydroxyl.
7. the chemical compound of a formula (I), wherein said chemical compound is selected from:
1) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 is because of, 17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-13-methyl-,
2) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,12] benzo oxa-diazacyclo 15 is because of, 17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-,
3) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 17 are because of-12, the 15-diketone, and 19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxyl group-13-(2-methyl-propyl)-,
4) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 17 are because of-12, the 15-diketone, and 19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxyl group-,
5) 4,6-ethanetetrayl pyrimido [4,5-b] pyrrolo-[2,1-k] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of-11 (8H)-ketone, 19-chloro-18-fluoro-9,10, and 11a, 12,13,14,16,21-octahydro-22-methoxyl group-,
6) 4,6-ethanetetrayl-8H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of, 18-chloro-9,10,11,12,13,14,15,20-octahydro-21-methoxyl group-14-methyl-,
7) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of, 19-chloro-8,9,10,11,12,13,14,15,16,21-decahydro-22-methoxyl group-15-methyl-,
8) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,9,12] benzo oxa-three azacyclo-s 15 are because of, 17-chloro-8,9,10,11,12,13,14,19-octahydro-20-methoxyl group-13-methyl-,
9) 12H-4,6-ethanetetrayl-13,17-methylene pyrimido [4,5-b] [6,1,10,16] benzo oxa-three azacyclo-s 19 be because of-12-ketone, 21-chloro-8,9,10,11,13,14,15,16,18, and 23-decahydro-25-methoxyl group-,
10) 4,6-ethanetetrayl-12H-pyrimido [4,5-b] [6,1,10,13] benzo oxa-three azacyclo-s 16 are because of-12-ketone, 18-chloro-8,9,10,11,13,14,15, and 20-octahydro-21-methoxyl group-13, the 14-dimethyl-,
11) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-13 (8H)-ketone, 19-chloro-15-ethyl-9,10,11,12,14,15,16, and 21-octahydro-22-methoxyl group-,
12) 4,6-ethanetetrayl pyrimido [4,5-b] [6,1,11,14] benzo oxa-three azacyclo-s 17 are because of-13 (8H)-ketone, 19-chloro-9,10,11,12,14,15,16, and 21-octahydro-22-methoxyl group-14, the 15-dimethyl-.
8. each chemical compound, wherein X among the claim 1-6
2Substituent group is at the structural 2 ' position of formula (I), R
1Substituent group is at 4 ' position, R
2Substituent group is at 5 ' position, R
3Substituent group is at 3 and R
4Substituent group is at 7.
9. the inhibitors of kinases of a formula (I).
10. each claimed compounds among the claim 1-7, described chemical compound is as medicine.
11. the purposes of each claimed compounds on the medicine of preparation treatment cell breeding disease such as atherosclerosis, restenosis and cancer among the claim 1-7.
12. a Pharmaceutical composition, described Pharmaceutical composition comprise pharmaceutically acceptable carrier and effective each described chemical compound as active component among the claim 1-7 of kinase inhibition amount.
13. method for preparing each claimed compounds among the claim 1-7, comprise the 6-acetoxyl group-quinazoline that a) makes formula (II) and the intermediate of formula (III) aniline coupling that suitably replaces with acquisition formula (IV), and with the intermediate deprotection cyclization under optimum conditions subsequently of formula (IV);
B) with formula (IV
b) the intermediate deprotection after, under standard conditions, form the intermediate that corresponding ether obtains formula (XXVIII) by adopting suitable ammonification alcohol; Next step, deprotection encircle then closure obtain formula (I '
b) target compound;
The V=protecting group, as methyl carbonyl, the tert-butyl group, methyl, ethyl, benzyl or trialkylsilkl, or the resin that the V representative links to each other with described molecule remainder under the solid state chemistry situation;
R
17Represent Ar
3, Ar
4-C
1-4Alkyl, C
1-4Alkyl, optional by Het
12The C that replaces
2-6Thiazolinyl, or R
16Representative is by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl, hydroxyl, halogen, Het
2, NR
7R
8, NR
9R
10-carbonyl or Het
3The C that the substituent group of-carbonyl replaces
1-4Alkyl, wherein Ar
3, Ar
4, Het
12, Het
2, R
7, R
8, R
9, R
10And Het
3Define as chemical compound formula (I);
Y
1And Y
2The independent separately C that represents
1-5Alkyl, CO-C
1-5Alkyl or CO-CH
2R
16-NH-.
14. the intermediate of a formula (III) and pharmaceutically acceptable addition salt and stereochemistry heterogeneous forms:
Wherein,
V represents hydrogen or blocking group, is preferably selected from methyl carbonyl, the tert-butyl group, methyl, ethyl, benzyl or trialkylsilkl;
Y representative-C
3-9Alkyl-,-C
3-9Thiazolinyl-, optional by amino, single-or two (C
1-4Alkyl) amino or C
1-4Alkoxycarbonyl amino-replacement-C
3-7Alkyl-CO-NH, optional by amino, single-or two (C
1-4Alkyl) amino or C
1-4Alkoxycarbonyl amino-replacement-C
3-7Thiazolinyl-CO-NH, 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-,-C
1-3Alkyl-NH-CS-Het
20-,-C
1-3Alkyl-NH-CO-Het
20-,-C
1-2Alkyl-CO-Het
21-CO-,-Het
22-CH
2-CO-NH-C
1-3Alkyl-,-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 ,-CO-Het
20-,-C
1-2Alkyl-NH-CO-CR
16R
17-NH-,-C
1-2Alkyl-CO-NH-CR
18R
19-CO-,-C
1-2Alkyl-CO-NR
20-C
1-3Alkyl-CO-,-C
1-2Alkyl-NR
21-CH
2-CO-NH-C
1-3Alkyl-or-NR
22-CO-C
1-3Alkyl-NH-;
X
2Represent connecting 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
1Represent hydrogen, cyano group, halogen, hydroxyl, formoxyl, C
1-6Alkoxyl-, C
1-6Alkyl-, halogen-phenyl-carbonylamino-, the C that replaced by halogen
1-6Alkoxyl-, by one or may two or the C that replaces of a plurality of substituent group that is selected from hydroxyl or halogen
1-4Alkyl;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group, Het
16-carbonyl-, C
1-4Alkoxy carbonyl-, C
1-4Alkyl-carbonyl-, amino carbonyl-, single-or two (C
1-4Alkyl) amino carbonyl-, Het
1Formoxyl, C
1-4Alkyl-,-C
2-6Alkynyl-, C
3-6Cycloalkyl-, C
3-6Cycloalkyloxy-, C
1-6Alkoxyl-, Ar
5, Ar
1-oxygen base-, dihydroxy borine, the C that replaced by halogen
1-6Alkoxyl-, by one or may two or a plurality of halogen, hydroxyl or NR of being selected from
5R
6The C that replaces of substituent group
1-4Alkyl;
C
1-4Alkyl-carbonyl-, wherein said C
1-4Alkyl is optional by one or possibility two or a plurality of hydroxyl or C of being selected from
1-4Alkyl-oxygen base-substituent group replace;
R
5And R
6Independently be selected from hydrogen or C separately
1-4Alkyl;
R
12Represent hydrogen, C
1-4Alkyl, C
1-4Alkyl-oxygen base-carbonyl-, Het
18-C
1-4Alkyl-, phenyl-C
1-4Alkyl-oxygen base-carbonyl-, Het
17, optional by Het
19-C
1-4The C of alkyl amino-carbonyl-replacement
2-4Alkenyl carbonyl-, C
2-4The thiazolinyl sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or R
12Representative is optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
13Represent hydrogen, C
1-4Alkyl, Het
13, Het
14-C
1-4Alkyl or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
14And R
15Independently be selected from hydrogen, C separately
1-4Alkyl, Het
15-C
1-4Alkyl-or C
1-4Alkoxy C
1-4Alkyl-;
R
16And R
17Independent separately hydrogen or the optional C that is replaced by phenyl, indyl, methyl mercapto, hydroxyl, mercaptan, hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals of representing
1-4Alkyl;
R
18And R
19Independent separately hydrogen or the optional C that is replaced by phenyl, indyl, methyl mercapto, hydroxyl, mercaptan, hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals of representing
1-4Alkyl;
R
20And R
22The independent separately hydrogen or optional of representing by hydroxyl or C
1-4The C that alkoxyl replaces
1-4Alkyl;
R
21Represent hydrogen, C
1-4Alkyl, Het
23-C
1-4Alkyl-carbonyl-or R
21Represent single-or two (C
1-4Alkyl) amino-C
1-4Alkyl-carbonyl-, optional by hydroxyl, pyrimidine radicals, dimethyl amine or C
1-4Alkoxyl replaces;
Het
1Represent heterocycle, described heterocycle is selected from piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, 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-list-or two (C
1-4Alkyl) amino-or amino carbonyl-replacement;
Het
13Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
14Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4The substituent group of alkyl replaces;
Het
15Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4The substituent group of alkyl replaces;
Het
16Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-two oxa-bora Pentamethylene. base or piperidyls, and wherein said heterocycle is optional to be selected from C by one or more
1-4The substituent group of alkyl replaces;
Het
17Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
18And Het
19Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4The substituent group of alkyl replaces;
Het
20, Het
21And Het
22Independently represent heterocycle, described heterocycle to be selected from pyrrolidinyl, 2-Pyrrolidone base, piperazinyl or piperidyl separately, optional by one or possibility two or a plurality of hydroxyl, C of being selected from
1-4Alkyl-, hydroxyl-C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-substituent group replace;
Ar
1, Ar
2, Ar
3, Ar
4And Ar
5The independent separately phenyl of representing, optional by cyano group, C
1-4Alkyl sulphonyl-, C
1-4Alkyl sulfonyl-amino-, amino-sulfonyl amino-, hydroxyl-C
1-4Alkyl, amino-sulfonyl-, hydroxyl, C
1-4Alkoxyl-or C
1-4Alkyl replaces.
15. the purposes of intermediate in the chemical compound of synthesis type (I) of formula (III).
16. the intermediate of a formula (XXX) and pharmaceutically acceptable addition salt and stereochemistry heterogeneous forms,
Wherein,
Y
1And Y
2The independent separately C that represents
1-5Alkyl, C
1-6Alkyl, CO-C
1-6Alkyl, CO-C
1-5Alkyl, Het
22-CH
2-CO, CO-CR
16R
17-NH-, Het
20, CR
18R
19-CO-, CH
2-CO-NH-C
1-3Alkyl-,-C
1-2Alkyl-NR
21-CH
2-CO-or CO-C
1-3Alkyl-NH-;
X
1Represent connecting key, O ,-O-C
1-2Alkyl-, CO, CO-C
1-2Alkyl-,-NR
11,-NR
11-C
1-2Alkyl-,-CH
2-,-O-N=CH-or C
1-2Alkyl-;
X
2Represent connecting 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
1Represent hydrogen, cyano group, halogen, hydroxyl, formoxyl, C
1-6Alkoxyl-, C
1-6Alkyl-,
Halogen-phenyl-carbonylamino-, the C that replaced by halogen
1-6Alkoxyl-,
By one or possibility two or a plurality of C that is selected from the substituent group replacement of hydroxyl or halogen
1-4Alkyl;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group, Het
16-carbonyl, C
1-4Alkoxy carbonyl-, C
1-4Alkyl-carbonyl-, amino carbonyl-, single-or two (C
1-4Alkyl) amino carbonyl-, Het
1, formoxyl, C
1-4Alkyl-,-C
2-6Alkynyl-, C
3-6Cycloalkyl-, C
3-6Cycloalkyloxy-, C
1-6Alkoxyl-, Ar
5, Ar
1-oxygen base-, dihydroxy borine, the C that replaced by halogen
1-6Alkoxyl-,
By one or possibility two or a plurality of halogen, hydroxyl or NR of being selected from
5R
6The C that replaces of substituent group
1-4Alkyl;
C
1-4Alkyl-carbonyl-, wherein said C
1-4Alkyl is optional by one or possibility two or a plurality of hydroxyl or C of being selected from
1-4Alkyl-oxygen base-substituent group replace;
R
3Represent hydrogen, C
1-4Alkyl or be selected from halogen, C by one or more
1-4Alkoxyl-, amino-, single-or two (C
1-4Alkyl) amino, C
1-4Alkyl-sulfonyl-or phenyl-the C that replaces of substituent group
1-4Alkyl;
R
5And R
6Independently be selected from hydrogen or C separately
1-4Alkyl;
R
7And R
8Independently be selected from hydrogen, C separately
1-4Alkyl, Het
8, amino-sulfonyl-, single-or two (C
1-4Alkyl)-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-, polyhydroxy-C
1-4Alkyl-, Het
11-C
1-4Alkyl-or Ar
2-C
1-4Alkyl-;
R
9And R
10Independently be selected from hydrogen, C separately
1-4Alkyl, C
3-6Cycloalkyl, Het
4, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-;
R
11Represent 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 sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
12Represent 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 sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
16And R
17Independent separately hydrogen or the optional C that is replaced by phenyl, indyl, methyl mercapto, hydroxyl, mercaptan, hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals of representing
1-4Alkyl;
R
18And R
19Independent separately hydrogen or the optional C that is replaced by phenyl, indyl, methyl mercapto, hydroxyl, mercaptan, hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals of representing
1-4Alkyl;
R
21Represent hydrogen, C
1-4Alkyl, Het
23-C
1-4Alkyl-carbonyl or R
21Represent single-or two (C
1-4Alkyl) amino-C
1-4Alkyl-carbonyl-, optional by hydroxyl, pyrimidine radicals, dimethyl amine or C
1-4Alkoxyl replaces;
R
23Represent Ar
3, Ar
4-C
1-4Alkyl, C
1-4Alkyl, optional by Het
12The C that replaces
2-6Thiazolinyl, or R
17Representative is by one or possibility two or a plurality of C that is selected from
1-4Alkoxyl, hydroxyl, halogen, Het
2, NR
7R
8, NR
9R
10-carbonyl or Het
3The C that the substituent group of-carbonyl replaces
1-4Alkyl;
Het
1Represent heterocycle, described heterocycle is selected from piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, 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-list-or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
Het
2Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, thio-morpholinyl or dithian base, wherein said Het
2Choose wantonly by one or possible two and can a plurality ofly be selected from 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-substituent group replace;
Het
3, Het
4And Het
8Independently represent heterocycle, described heterocycle to be selected from morpholinyl, piperazinyl, piperidyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, wherein said Het separately
3, Het
4Or Het
8Optional by one may two or a plurality of be selected from 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-substituent group replace;
Het
5Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
6And Het
7Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl-, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
9And Het
10Independently represent heterocycle, described heterocycle to be selected from furyl, piperidyl, morpholinyl, piperazinyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, wherein said Het separately
9Or Het
10Be the optional C that replaces
1-4Alkyl, C
3-6Cycloalkyl-C
1-4Alkyl-or amino-C
1-4Alkyl-;
Het
11Represent heterocycle, described heterocycle be selected from indyl or
Het
12Represent heterocycle, described heterocycle is selected from morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, thio-morpholinyl or dithian base, wherein said Het
12Optional by one or possibility two or a plurality of hydroxyl, halogen, amino, C of being selected from
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-substituent group replace;
Het
16Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-two oxa-bora Pentamethylene. base or piperidyls, and wherein said heterocycle is optional to be selected from C by one or more
1-4The substituent group of alkyl replaces;
Het
17Represent heterocycle, described heterocycle is selected from pyrrolidinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
18And Het
19Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl-, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
20, Het
21And Het
22Independently represent heterocycle, described heterocycle to be selected from pyrrolidinyl, 2-Pyrrolidone base, piperazinyl or piperidyl separately, optional by one or possibility two or a plurality of hydroxyl, C of being selected from
1-4Alkyl-, hydroxyl-C
1-4Alkyl-or polyhydroxy-C
1-4Alkyl-substituent group replace;
Het
23Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Ar
1, Ar
3, Ar
4And Ar
5The independent separately phenyl of representing, optional by cyano group, C
1-4Alkyl sulphonyl-, C
1-4Alkyl sulfonyl-amino-, amino-sulfonyl amino-, hydroxyl-C
1-4Alkyl, amino-sulfonyl-, hydroxyl, C
1-4Alkoxyl-or C
1-4Alkyl replaces.
17. the intermediate of a formula (XXX), described intermediate is as medicine.
18. the intermediate of formula (XXX) is used for the treatment of the purposes on the medicine of cell breeding disease such as atherosclerosis, restenosis and cancer in production.
19. the application of intermediate in the chemical compound of synthesis type (I) of formula (XXX).
20. the intermediate of a formula (XXXIII) and pharmaceutically acceptable addition salt and stereochemistry heterogeneous forms,
Wherein,
M represents 1,2,3 or 4;
X
2Represent connecting 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-;
Y
3Represent C
1-5Alkyl, CO-C
1-5Alkyl or CO-CR
16R
17-NH-or C
1-5Alkyl-CO-, optional by amino, single-or two (C
1-4Alkyl) amino or C
1-4Alkoxycarbonyl amino replaces;
R
1Represent hydrogen, cyano group, halogen, hydroxyl, formoxyl, C
1-6Alkoxyl-, C
1-6Alkyl-, halogen-phenyl-carbonylamino-,
The C that is replaced by halogen
1-6Alkoxyl-,
By one or possibility two or a plurality of C that is selected from the substituent group replacement of hydroxyl or halogen
1-4Alkyl;
R
2Represent hydrogen, cyano group, halogen, hydroxyl, hydroxycarbonyl group, Het
16-carbonyl, C
1-4Alkoxy carbonyl-, C
1-4Alkyl-carbonyl-, amino carbonyl-, single-or two (C
1-4Alkyl) amino carbonyl-, Het
1, formoxyl, C
1-4Alkyl-,-C
2-6Alkynyl-, C
3-6Cycloalkyl-, C
3-6Cycloalkyloxy-, C
1-6Alkoxyl-, Ar
5, Ar
1-oxygen base-, dihydroxy borine, the C that replaced by halogen
1-6Alkoxyl-,
By one or possibility two or a plurality of halogen, hydroxyl or NR of being selected from
5R
6The C that replaces of substituent group
1-4Alkyl;
C
1-4Alkyl-carbonyl-, wherein said C
1-4Alkyl is optional by one or possibility two or a plurality of hydroxyl or C of being selected from
1-4Alkyl-oxygen base-substituent group replace;
R
3Represent hydrogen, C
1-4Alkyl or be selected from halogen, C by one or more
1-4Alkoxyl-, amino-, single-or two (C
1-4Alkyl) amino, C
1-4Alkyl-sulfonyl-or phenyl-the C that replaces of substituent group
1-4Alkyl;
R
5And R
6Independently be selected from hydrogen or C separately
1-4Alkyl;
R
12Represent hydrogen, C
1-4Alkyl, C
1-4Alkyl-oxygen base-carbonyl-, Het
18-C
1-4Alkyl-, phenyl-C
1-4Alkyl-oxygen base-carbonyl-Het
17, optional by Het
19-C
1-4The C of alkyl amino-carbonyl-replacement
2-4Alkenyl carbonyl-, C
2-4The thiazolinyl sulfonyl-, C
1-4Alkoxy C
1-4Alkyl-or optional by one or possibility two or a plurality of hydrogen, hydroxyl, amino or C of being selected from
1-4Alkoxyl-the phenyl that replaces of substituent group;
R
16And R
17Independent separately hydrogen or the optional C that is replaced by phenyl, indyl, methyl mercapto, hydroxyl, mercaptan, hydroxy phenyl, amino carbonyl, hydroxycarbonyl group, amine, imidazole radicals or guanidine radicals of representing
1-4Alkyl;
Het
1Represent heterocycle, described heterocycle is selected from piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolane base, thiazolyl, oxazolyl, imidazole radicals, isoxazolyl, oxadiazole base, pyridine radicals or pyrrolidinyl, 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-list-or two (C
1-4Alkyl) amino-or amino-carbonyl-replacement;
Het
16Represent heterocycle, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-two oxa-bora Pentamethylene. base or piperidyls, and wherein said heterocycle is optional to be selected from C by one or more
1-4The substituent group of alkyl replaces;
Het
18And Het
19Independently represent heterocycle separately, described heterocycle is selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidyl, and is optional by one or possibility two or a plurality of C that is selected from
1-4Alkyl, C
3-6Cycloalkyl-, hydroxyl-C
1-4Alkyl-, C
1-4Alkoxy C
1-4Alkyl or polyhydroxy-C
1-4Alkyl-substituent group replace;
Ar
1And Ar
5The independent separately phenyl of representing, optional by cyano group, C
1-4Alkyl sulphonyl-, C
1-4Alkyl sulfonyl-amino-, amino-sulfonyl amino-, hydroxyl-C
1-4Alkyl, amino-sulfonyl-, hydroxyl, C
1-4Alkoxyl-or C
1-4Alkyl replaces.
21. the intermediate of a formula (XXXIII), described intermediate is as medicine.
22. the intermediate of formula (XXXIII) is used for the treatment of purposes in the medicine of cell breeding disease such as atherosclerosis, restenosis and cancer in production.
23. the purposes of intermediate in the chemical compound of synthesis type (I) of formula (XXXIII).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210144221.7A CN102718775B (en) | 2003-05-27 | 2004-05-25 | As the Macrocyclic quinazoline derivatives of antiproliferative |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP0305723 | 2003-05-27 | ||
| EPPCT/EP03/05723 | 2003-05-27 | ||
| EPPCT/EP03/10266 | 2003-09-15 | ||
| EPPCT/EP03/51061 | 2003-12-18 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210144221.7A Division CN102718775B (en) | 2003-05-27 | 2004-05-25 | As the Macrocyclic quinazoline derivatives of antiproliferative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1794996A true CN1794996A (en) | 2006-06-28 |
Family
ID=34956895
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200480014512.8A Pending CN1794996A (en) | 2003-05-27 | 2004-05-25 | Macrocyclic quinazoline derivatives as antiproliferative agents |
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| Country | Link |
|---|---|
| CN (1) | CN1794996A (en) |
| ZA (1) | ZA200509541B (en) |
-
2004
- 2004-05-25 CN CN200480014512.8A patent/CN1794996A/en active Pending
-
2005
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