CN110117275A - A kind of amino-metadiazine compound and its application in anticancer medicine - Google Patents
A kind of amino-metadiazine compound and its application in anticancer medicine Download PDFInfo
- Publication number
- CN110117275A CN110117275A CN201910588232.6A CN201910588232A CN110117275A CN 110117275 A CN110117275 A CN 110117275A CN 201910588232 A CN201910588232 A CN 201910588232A CN 110117275 A CN110117275 A CN 110117275A
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- Prior art keywords
- compound
- amino
- alkyl
- nmr
- acid salt
- Prior art date
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- -1 amino-metadiazine compound Chemical class 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 title claims abstract description 12
- 230000001093 anti-cancer Effects 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 123
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 9
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims abstract description 8
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims abstract description 8
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims abstract description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 5
- 125000004103 aminoalkyl group Chemical group 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 3
- 125000005129 aryl carbonyl group Chemical group 0.000 claims abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 57
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 7
- 229940121647 egfr inhibitor Drugs 0.000 claims description 6
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims description 4
- 102000001301 EGF receptor Human genes 0.000 claims description 4
- 108060006698 EGF receptor Proteins 0.000 claims description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical class NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 claims description 3
- JVTAAEKCZFNVCJ-UWTATZPHSA-M (R)-lactate Chemical compound C[C@@H](O)C([O-])=O JVTAAEKCZFNVCJ-UWTATZPHSA-M 0.000 claims description 2
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical class OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical class OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 2
- 229940080296 2-naphthalenesulfonate Drugs 0.000 claims description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 claims description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical group F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical class OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229940116298 l- malic acid Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical class OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 claims description 2
- 235000001968 nicotinic acid Nutrition 0.000 claims description 2
- 239000011664 nicotinic acid Substances 0.000 claims description 2
- 229940049964 oleate Drugs 0.000 claims description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 2
- 150000003891 oxalate salts Chemical class 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 2
- 229940044551 receptor antagonist Drugs 0.000 claims description 2
- 239000002464 receptor antagonist Substances 0.000 claims description 2
- 229940071089 sarcosinate Drugs 0.000 claims description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 229940070710 valerate Drugs 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000017260 vegetative to reproductive phase transition of meristem Effects 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 1
- 229940082569 selenite Drugs 0.000 claims 1
- MCAHWIHFGHIESP-UHFFFAOYSA-L selenite(2-) Chemical compound [O-][Se]([O-])=O MCAHWIHFGHIESP-UHFFFAOYSA-L 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 50
- 238000012360 testing method Methods 0.000 description 37
- 238000005160 1H NMR spectroscopy Methods 0.000 description 33
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 31
- 238000000034 method Methods 0.000 description 29
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 28
- 239000002994 raw material Substances 0.000 description 28
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- 238000005406 washing Methods 0.000 description 8
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
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- 238000012546 transfer Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
A kind of application the present invention provides amino-metadiazine compound and its in anticancer medicine, the compound have logical formula (I) structure as follows:Wherein, it is 0~4 that m, which is 0~4, n,；R1Selected from amino, alkyl amino, aminoalkyl, alkyl amino-carbonyl；R2Selected from hydrogen, hydroxyl, nitro, halogen, amino, cyano, alkyl, alkenyl, halogenated alkyl, miscellaneous alkyl, alkyl amino, aminoalkyl, alkyl-carbonyl, alkyl amino-carbonyl, aryl carbonyl；X is selected from oxygen atom, amino or methylamino.EGFR can be improved in the compounds of this inventionT790MInhibiting rate has higher anticancer activity.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, more particularly, to a kind of amino-metadiazine compound and its in anticancer medicine
In application.
Background technique
Epidermal growth factor recipient tyrosine kinase (epidermal growth factor receptor tyrosine
Kinase, EGFR) it is one of the protein tyrosine kinase found earliest, the intracellular region of EGFR has ATP-binding site, and EGFR inhibits
Agent competitive can be combined with ATP-binding site, to inhibit the Phosphorylation events of EGFR, block the conduction of downstream signal,
And then inhibit growth, differentiation and the transfer of tumour cell.
It is the drug Gefitinib (gefitinib) of target spot, Tarceva (erlotinib), Ah cutting down for Buddhist nun using EGFR
(afatinib) etc. clinic has been applied to it, and with the further investigation of EGFR structure and activity relationship, many better effects are excellent
Elegant EGFR inhibitor (EP0566226, WO9961428, WO0051587, WO0375947, WO0132651, WO9633980,
WO9630347、US7709479、US6716847、US6593333、US6251912、CN201080060451.4、
CN201110191525.4 etc.) it has been found.These drugs are but inevitably present the problem of anti-drug resistance difference.Study table
Bright: the mutation (T790M) of amino acid The790 to Met790 is the main inducing of such drug resistant.There is clinical data
It has been shown that, about 60% patient's acquired resistance is caused by the mutation in the site T790M.Therefore exploitation anti-drug resistance is stronger, malicious
Property smaller, the stronger new E GFR inhibitor of activity there is extremely important realistic price.
Summary of the invention
In view of this, the present invention is directed to propose a kind of amino-metadiazine compound and its application in anticancer medicine,
To improve EGFRT790MInhibiting rate has higher anticancer activity.
In order to achieve the above objectives, the technical scheme of the present invention is realized as follows:
A kind of amino-metadiazine compound has logical formula (I) structure as follows:
Wherein, it is 0~4 that m, which is 0~4, n,；
R1Selected from amino, alkyl amino, aminoalkyl or alkyl amino-carbonyl；
R2Selected from hydrogen, hydroxyl, nitro, halogen, amino, cyano, alkyl, alkenyl, halogenated alkyl, miscellaneous alkyl, alkyl ammonia
Base, aminoalkyl, alkyl-carbonyl, alkyl amino-carbonyl or aryl carbonyl；
X is selected from oxygen atom, amino or methylamino.
Preferably, cyclic structure is 4-10 member ring.
Preferably, lead to formula (I) compound represented to be selected from one of flowering structure,
The present invention also provides a kind of EGFR inhibitor, including amino-metadiazine compound as described above or its pharmacy can
The salt of receiving.
Preferably, the pharmaceutical salt of amino-metadiazine compound includes inorganic acid salt or acylate, wherein inorganic acid
Salt is selected from hydrofluoride, hydrochloride, hydrobromate, hydriodate, sulfate, nitrate, phosphate, carbonate, borate, Asia
One or more of selenate, phosphomolybdate, phosphite, sulphite；The acylate be selected from citrate,
Maleate, D-malic acid salt, L MALIC ACID salt, DL-malic acid salt, Pfansteihl salt, D-lactate, DL- hydrochlorate, oxalates,
Mesylate, valerate, oleate, laruate, toluenesulfonate, 1-naphthalene sulfonic aicd salt, 2- naphthalene sulfonate, phthalate,
Tartrate, malonate, succinate, fumarate, glycollate, mercaptan hydrochlorate, glycinate, sarcosinate, sulfonic acid
One or more of salt, nicotinate, picoline hydrochlorate, isonicotinic acid salt, benzoate or substituted benzoic acid salt.
Present invention simultaneously provides a kind of amino-metadiazine compounds as described above or EGFR inhibitor as described above to exist
Prepare the application in epidermal growth factor receptor antagonists.
Also a kind of amino-metadiazine compound as described above or EGFR inhibitor as described above are anti-in preparation by the present invention
Application in cancer drug；Preferably, cancer is solid tumor.
Compared with the existing technology, amino-metadiazine compound of the present invention, has the advantage that
The present invention can be used for epidermal growth factor receptor specific combination by providing to aminopyrimidine structure of modification
Molecule, and have compared with high anti-cancer activity, improve to EGFRT790MInhibiting rate, and toxicity is smaller, is expected to be applied to anticarcinogen
Object.
Specific embodiment
In addition to being defined, technical term used in following embodiment has universal with those skilled in the art of the invention
The identical meanings of understanding.Test reagent used in following embodiment is unless otherwise specified conventional biochemical reagent；It is described
Experimental method is unless otherwise specified conventional method.
Below with reference to embodiment, the present invention will be described in detail.
The preparation of 1 compound 1 of embodiment
Compound 1
It is specific the preparation method comprises the following steps:
1) preparation of compound (1-1):
Compound (1-1)
The fluoro- 2- Nitroanisole (502.0mg, 2.94mmol) of 5- and N methyl piperazine (400mg, 4mmol) are dissolved in
In n,N-Dimethylformamide (5mL), potassium carbonate (609mg, 4.41mmol) is added in Xiang Shangshu mixed system, system room temperature is anti-
It answers 24 hours, saturated common salt water washing (10mL × 3), ethyl acetate extracts (10mL × 4), organic phase saturated common salt water washing
(10mL), dry concentration, column chromatographic purifying (petroleum ether: ethyl acetate=5:1) obtain compound (1-1) (yellow solid,
633.0mg, yield: 84%)；
The nuclear-magnetism test result of compound (1-1) are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.01 (d, J=9.4Hz, 1H), 6.23 (dd, J=9.4,2.5Hz,
1H), 6.10 (d, J=2.5Hz, 1H), 3.94 (s, 3H), 3.52 (t, J=7.4Hz, 2H), 3.08 (s, 3H), 2.49 (t, J=
7.3Hz,2H),2.29(s,6H).13C NMR(101MHz,Chloroform-d)δ156.78,154.26,129.27,103.35,
94.29,56.12,56.09,51.10,45.94,39.07.HRMS(ESI)calculated for HRMS(ESI)
calculated for C12H17N3O3Na+:274.1162,found 274.1160。
2) preparation of compound (1-2):
Compound (1-2)
Compound (1-1) (603.0mg, 2.38mmol) is dissolved in methanol (15mL), is added in Xiang Shangshu mixed system
Entering palladium carbon (100mg), hydrogen balloon, system reacts at room temperature 12 hours, filters, and concentration, saturated sodium bicarbonate washs (10mL × 3),
Ethyl acetate extracts (10mL × 4), and organic phase is with saturated common salt water washing (10mL), and dry to be concentrated to get compound (1-2) (black
Color solid, 567.0mg, yield: 94%)；
The nuclear-magnetism test result of compound (1-2) are as follows:
1H NMR (400MHz, Chloroform-d) δ 6.64 (d, J=8.3Hz, 1H), 6.51 (d, J=2.4Hz, 1H),
6.42 (dd, J=8.4,2.4Hz, 1H), 3.93 (s, 2H), 3.83 (s, 3H), 3.12 (t, J=4.9Hz, 4H), 2.66 (t, J=
4.8Hz,4H),2.40(s,3H).13C NMR(101MHz,Chloroform-d)δ147.98,144.67,130.33,115.44,
109.56,102.35,55.46,55.20,50.93,45.88.HRMS(ESI)calculated for C12H19N3O3Na+:
244.1420,found 244.1422。
3) preparation of compound (1-3):
Compound (1-3)
1- tertbutyloxycarbonyl -3- amido ring butylamine (532.0mg, 2.90mmol) is dissolved in 1,4- dioxane (15mL)
In, diisopropyl ethyl amine (0.716mL, 4.35mmol) is added in Xiang Shangshu mixed system, 2,4,5- trichloropyrimidines
60 DEG C of (500.0mg, 2.90mmol) system are reacted 12 hours, concentration, water washing (10mL × 3), ethyl acetate extraction (10mL ×
4), organic phase is concentrated with saturated common salt water washing (10mL), drying, and column chromatographic purifying (petroleum ether: ethyl acetate=5:1) obtains
Compound (1-3) (yellow liquid, 663.0mg, yield: 68.6%)；
The nuclear-magnetism test result of compound (1-3) are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.09 (s, 1H), 5.99 (d, J=6.6Hz, 1H), 4.83 (q, J=
6.5Hz, 1H), 4.36 (t, J=8.5Hz, 2H), 3.87 (dd, J=9.6,5.1Hz, 2H), 1.45 (s, 7H)13C NMR
(101MHz,Chloroform-d)δ172.60,165.00,164.30,153.69,112.46,78.59,65.62,65.42,
61.86,29.29,29.29,29.29.HRMS(ESI)calculated for C12H19N3O3Na+:295.0124,found
295.0122。
4) preparation of compound (1-4):
Compound (1-4)
The compound (1-3) (663.0mg, 1.99mmol) that step 3) obtains is dissolved in methylene chloride (2.5mL), to
Trifluoroacetic acid (2.5mL) is added in above-mentioned mixed system, reacts at room temperature half an hour, concentration is added methylene chloride (10mL), upwards
It states mixed system addition triethylamine and is adjusted to alkalinity, be added acryloyl chloride (180.0mg, 1.99mmol), system room temperature reaction 3 is small
When, concentration, saturated sodium bicarbonate solution washs (10mL × 3), and ethyl acetate extracts (10mL × 4), organic phase saturated common salt
Water washing (10mL), dry concentration, column chromatographic purifying (petroleum ether: ethyl acetate=1:1) obtain compound (1-4) (yellow liquid
Body, 325.0mg, yield: 60.0%)；
The nuclear-magnetism test result of compound (1-4) are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.07 (d, J=2.6Hz, 1H), 6.85 (d, J=7.0Hz, 1H),
6.34 (d, J=16.9Hz, 1H), 6.16 (td, J=8.5,6.6,2.5Hz, 1H), 5.70 (d, J=10.4Hz, 1H), 4.99
(dt, J=12.3,5.8Hz, 1H), 4.61 (t, J=8.6Hz, 1H), 4.46 (t, J=9.7Hz, 1H), 4.18-3.97 (m,
2H).13C NMR(101MHz,Chloroform-d)δ165.51,158.34,154.30,128.21,125.54,113.53,
57.93,54.59,40.79.HRMS(ESI)calculated for C10H10Cl2N4ONa+:295.0124,found
295.0122。
5) compound (1-2) (355mg, 1.537mmol) obtained by step 2) preparation of compound 1: is added to sec-butyl alcohol
In (15ml), compound (1-4) (320mg, 1.537mmol) obtained by step 4) is then added, is added in Xiang Shangshu mixed system
Trifluoroacetic acid (0.17mL, 2.3055mmol), 100 DEG C are reacted 24 hours, concentration, saturated sodium bicarbonate solution washing (10mL ×
3), ethyl acetate extraction (10mL × 4), organic phase saturated common salt water washing (10mL), dry concentration, column chromatographic purifying (two
Chloromethanes: methanol=20:1) obtain compound 1 (faint yellow solid, 211.0mg, yield: 30.0%)；
The nuclear-magnetism test result of compound 1 are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.09 (d, J=8.7Hz, 1H), 7.93 (s, 1H), 6.55 (d, J=
7.9Hz, 2H), 6.36 (d, J=16.9Hz, 1H), 6.23-6.15 (m, 1H), 5.69 (d, J=10.4Hz, 1H), 5.59 (d, J
=6.0Hz, 1H), 4.85 (q, J=6.5Hz, 1H), 4.55 (dt, J=36.8,8.9Hz, 2H), 4.15-3.99 (m, 2H),
3.87 (s, 3H), 3.64 (s, 1H), 3.18 (t, J=4.8Hz, 4H), 2.61 (t, J=4.7Hz, 4H), 2.37 (s, 3H)13C
NMR(101MHz,Chloroform-d)δ165.69,158.03,157.05,153.86,149.09,147.12,127.88,
125.74,122.27,119.63,107.96,104.10,100.49,58.06,55.65,55.15,54.96,50.06,
46.08,41.16.HRMS(ESI)calculated for C22H28ClN7O2Na+:480.1885,found 480.1883。
The preparation of 2 compound 2 of embodiment
Compound 2
It is specific the preparation method comprises the following steps:
1) preparation of compound (2-1):
Compound (2-1)
It is similar with the method for prepare compound (1-1)；Unlike, one of used raw material is N, N, N'- trimethyl
Ethylenediamine；
The nuclear-magnetism test result of compound (2-1) are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.01 (d, J=9.4Hz, 1H), 6.23 (dd, J=9.4,2.5Hz,
1H), 6.10 (d, J=2.5Hz, 1H), 3.94 (s, 3H), 3.52 (t, J=7.4Hz, 2H), 3.08 (s, 3H), 2.49 (t, J=
7.3Hz,2H),2.29(s,6H).13C NMR(101MHz,Chloroform-d)δ156.78,154.26,129.27,103.35,
94.29,56.12,56.09,51.10,45.94,39.07.HRMS(ESI)calculated for C12H19N3O3Na+:
276.1319,found 276.1315。
2) preparation of compound (2-2):
Compound (2-2)
It is similar with the method for prepare compound (1-2)；Unlike, one of used raw material is (2-1)；
The nuclear-magnetism test result of compound (2-2) are as follows:
1H NMR (400MHz, DMSO-d6) δ 6.52 (d, J=8.3Hz, 1H), 6.38-6.29 (m, 1H), 6.13 (d, J=
8.3Hz, 1H), 3.74 (s, 3H), 3.25 (s, 2H), 2.76 (s, 3H), 2.35 (t, J=7.2Hz, 2H), 2.18 (s, 6H)13C
NMR(101MHz,DMSO-d6)δ147.82,142.63,128.95,115.48,106.44,99.34,56.06,55.57,
51.93,45.97,39.66.HRMS(ESI)calculated for C12H21N3ONa+:244.1420,found 244.1422。
3) preparation of compound 2: similar with the method for prepare compound 1；Unlike, one of used raw material is
(2-1)；
The nuclear-magnetism test result of compound 2 are as follows:
1H NMR (400MHz, Chloroform-d) δ 7.97 (d, J=8.8Hz, 1H), 7.12 (s, 1H), 6.41-6.30
(m, 3H), 6.24-6.16 (m, 1H), 5.69 (dd, J=10.3,1.9Hz, 1H), 5.50 (d, J=6.0Hz, 1H), 4.90-
4.80 (m, 1H), 4.66-4.48 (m, 2H), 4.08 (ddd, J=24.8,9.8,5.3Hz, 2H), 3.88 (s, 3H), 3.52 (t, J
=7.4Hz, 2H), 2.95 (s, 3H), 2.63 (t, J=7.2Hz, 3H), 2.41 (s, 6H)13C NMR(101MHz,
Chloroform-d)δ167.10,165.72,158.30,157.04,153.91,140.60,127.77,125.80,122.75,
120.92,119.38,104.43,95.80,96.84,58.05,55.80,55.62,55.01,51.30,45.56,41.21,
39.16.HRMS(ESI)calculated for C22H28ClN7O2Na+:480.1885,found 480.1884。
The preparation of 3 compound 3 of embodiment
Compound 3
It is specific the preparation method comprises the following steps:
1) preparation of compound (3-1):
Compound (3-1)
It is similar with the method for prepare compound (1-3)；Unlike, one of used raw material is 1-BOC-3- methylamino
Azetidine；
The nuclear-magnetism test result of compound (3-1) are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.09 (s, 1H), 5.99 (d, J=6.6Hz, 1H), 4.83 (q, J=
6.5Hz, 1H), 4.36 (t, J=8.5Hz, 2H), 3.87 (dd, J=9.6,5.1Hz, 2H), 2.35 (s, 3H) 1.45 (s, 7H)
.13C NMR(101MHz,Chloroform-d)δ172.60,165.00,164.30,153.69,112.46,78.59,65.62,
65.42,61.86,35.80,29.29,29.29,29.29.HRMS(ESI)calculated for C12H19N3O3Na+:
295.0124,found 295.0122。HRMS(ESI)calculated for C13H18N4O2Na+:355.0699,found
355.0694。
2) preparation of compound (3-2):
Compound (3-2)
It is similar with the method for prepare compound (1-4)；Unlike, one of used raw material is (3-1)；
The nuclear-magnetism test result of compound (3-2) are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.10 (d, J=6.7Hz, 1H), 6.52-6.32 (m, 2H), 5.76-
5.62 (m, 1H), 5.13-5.03 (m, 1H), 4.03-3.76 (m, 2H), 3.67-3.42 (m, 2H), 3.12 (d, J=6.3Hz,
3H).13C NMR(101MHz,DMSO-d6)δ165.51,158.34,154.30,128.21,125.54,113.53,57.93,
54.59,40.79,35.80.HRMS(ESI)calculated for C11H12Cl2N4ONa+:309.0280,found
309.0282。
3) preparation of compound 3: similar with the method for prepare compound 1；Unlike, one of used raw material is
(3-2)；
The nuclear-magnetism test result of compound 3 are as follows:
1H NMR(400MHz,Chloroform-d)δ8.12–7.98(m,2H),6.56–6.32(m,4H),5.69(ddd,
J=12.6,8.2,4.0Hz, 1H), 5.05-4.95 (m, 1H), 3.59-3.42 (m, 2H), 3.18 (q, J=5.1Hz, 4H),
3.06 (d, J=7.5Hz, 3H), 2.64 (q, J=5.0Hz, 4H), 2.38 (d, J=2.6Hz, 3H), 2.33-2.05 (m, 2H)
.13C NMR(101MHz,Chloroform-d)δ171.10,168.60,168.20,157.60,148.30,141.10,
131.20,126.70,122.10,118.10,108.80,106.50,98.10,59.80,58.10,58.10,57.20,
53.10,53.10,51.20,51.20,47.50,36.20.HRMS(ESI)calculated for 23H30ClN7O2Na+:
497.2042,found 497.2040。
The preparation of 4 compound 4 of embodiment
Compound 4
It is specific the preparation method comprises the following steps:
1) preparation of compound (4-1):
Compound (4-1)
It is similar with the method for prepare compound (1-3)；Unlike, one of used raw material is (S) -1- tertiary butyloxycarbonyl
Base -3- amino-pyrrolidine；
The nuclear-magnetism test result of compound (4-1) are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.00 (s, 1H), 5.60 (d, J=7.1Hz, 1H), 4.66 (s,
1H), 3.72 (dd, J=11.5,6.3Hz, 1H), 3.56-3.39 (m, 3H), 3.24 (d, J=27.0Hz, 1H), 2.25 (dq, J
=13.6,7.0Hz, 1H), 1.92 (s, 1H), 1.42 (s, 9H), 1.32-1.18 (m, 1H), 0.88-0.72 (m, 1H)13C NMR
(101MHz,Chloroform-d)δ172.60,165.00,164.30,153.69,112.46,78.59,65.62,65.42,
61.86,58.30,29.29,29.29,29.29.HRMS(ESI)calculated for C13H18Cl2N4ONa+:332.0807,
found 332.0806。
2) preparation of compound (4-2):
Compound (4-2)
It is similar with the method for prepare compound (1-4)；Unlike, one of used raw material is (4-1)；
The nuclear-magnetism test result of compound (4-2) are as follows:
1H NMR (400MHz, DMSO-d6) δ 8.21 (d, J=3.4Hz, 1H), 7.96 (dd, J=10.3,6.8Hz, 1H),
6.57 (ddd, J=22.8,16.8,10.3Hz, 1H), 6.14 (ddd, J=16.8,4.1,2.5Hz, 1H), 5.76-5.64 (m,
1H), 4.68-4.54 (m, 1H), 3.97-3.52 (m, 3H), 3.41 (ddt, J=12.5,8.8,6.5Hz, 1H), 2.32-1.97
(m,2H).13C NMR(101MHz,DMSO-d6)δ163.77,158.96,157.68,154.72,129.91,127.16,
113.53,54.21,44.58,31.11,29.40.HRMS(ESI)calculated for C11H12Cl2N4ONa+:
309.0280,found 309.0282。
3) preparation of compound 4: similar with the method for prepare compound 1；Unlike, one of used raw material is
(4-2)；
The nuclear-magnetism test result of compound 4 are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.15 (t, J=8.5Hz, 1H), 7.91 (d, J=4.4Hz, 1H),
6.58-6.37 (m, 4H), 5.71 (ddd, J=18.7,8.5,3.8Hz, 1H), 5.30-5.17 (m, 1H), 4.71 (ddt, J=
15.7,10.8,5.9Hz, 1H), 4.13-3.84 (m, 4H), 3.87-3.42 (m, 3H), 3.20 (q, J=4.5Hz, 4H), 2.66
(q, J=5.2Hz, 4H), 2.48-1.94 (m, 6H)13C NMR(101MHz,Chloroform-d)δ164.74,158.07,
157.30,153.52,149.04,146.84,128.34,128.20,122.62,119.59,108.17,104.17,100.62,
55.65,55.03,52.17,51.33,50.38,45.87,44.62,44.00,32.11,29.94.HRMS(ESI)
calculated for C23H30ClN7O2Na+:494.2042,found 494.2040。
The preparation of 5 compound 5 of embodiment
Compound 5
It is specific the preparation method comprises the following steps:
1) preparation of compound (5-1):
Compound (5-1)
It is similar with the method for prepare compound (1-3)；Unlike, one of used raw material is (R) -1- tertiary butyloxycarbonyl
Base -3- amino-pyrrolidine；
The nuclear-magnetism test result of compound (5-1) are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.05 (s, 1H), 5.49 (d, J=7.2Hz, 1H), 4.70 (s,
1H), 4.17-4.07 (m, 1H), 3.85-3.67 (m, 1H), 3.28 (d, J=36.1Hz, 1H), 2.31 (dd, J=13.4,
7.0Hz, 1H), 1.47 (s, 8H), 1.25 (td, J=7.2,1.0Hz, 1H), 0.89-0.74 (m, 1H)13C NMR(101MHz,
Chloroform-d)δ158.31,154.47,153.87,113.27,79.86,51.50,51.04,43.74,31.71,
31.03,28.48,14.19.HRMS(ESI)calculated for C13H18Cl2N4ONa+:332.0807,found
332.0805。
2) preparation of compound (5-2):
Compound (5-2)
It is similar with the method for prepare compound (1-4)；Unlike, one of used raw material is (5-1)；
The nuclear-magnetism test result of compound (5-2) are as follows:
1H NMR (400MHz, DMSO-d6) δ 8.23 (d, J=3.4Hz, 1H), 7.97 (dd, J=10.3,6.8Hz, 1H),
6.58 (ddd, J=23.1,16.7,10.3Hz, 1H), 6.15 (ddd, J=16.8,4.2,2.4Hz, 1H), 5.68 (ddd, J=
10.6,8.4,2.4Hz, 1H), 4.61 (dq, J=42.6,6.5Hz, 1H), 3.94-3.49 (m, 3H), 3.42 (ddd, J=
12.1,9.6,5.6Hz,1H),2.27–1.87(m,2H).13C NMR(101MHz,DMSO-d6)δ163.78,159.02,
154.74,130.13,129.73,127.16,113.55,50.61,44.87,31.12,29.40.HRMS(ESI)
calculated for C11H12Cl2N4ONa+:309.0280,found 309.0282。
3) preparation of compound 5: similar with the method for prepare compound 1；Unlike, one of used raw material is
(5-2)；
The nuclear-magnetism test result of compound 5 are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.15 (t, J=8.6Hz, 1H), 7.91 (d, J=4.5Hz, 1H),
6.56-6.36 (m, 4H), 5.70 (ddd, J=18.6,8.3,4.0Hz, 1H), 5.27 (dd, J=17.6,6.4Hz, 1H), 4.69
(dq, J=19.4,5.8Hz, 1H), 4.09-3.82 (m, 4H), 3.81-3.67 (m, 2H), 3.68-3.58 (m, 1H), 3.51-
3.44 (m, 1H), 3.19 (dt, J=7.5,2.7Hz, 4H), 2.64 (dt, J=5.3,3.5Hz, 4H), 2.43-2.29 (m, 4H),
2.23–1.94(m,1H).13C NMR(101MHz,Chloroform-d)δ164.74,158.08,157.31,153.60,
153.43,149.06,146.93 130.37–127.58,122.54,119.62,108.10,104.15 100.58,55.65,
55.08,52.16,51.48,50.14–49.31,45.94,44.62,44.00,32.11,30.18.HRMS(ESI)
calculated for C23H30ClN7O2Na+:494.2042,found 494.2040。
Embodiment 6: the preparation of compound 6Compound 6
It is specific the preparation method comprises the following steps:
1) preparation of compound (6-1):
Compound (6-1)
It is similar with the method for prepare compound (1-3)；Unlike, one of used raw material is 1- tertbutyloxycarbonyl-
The nuclear-magnetism test result of 4- aminopiperidines (6-1) are as follows:
1H NMR(400MHz,Chloroform-d)δ8.00(s,1H),4.21–4.04(m,1H),3.65–3.20(m,
4H),1.97–1.51(m,2H),1.41(s,10H),1.35–1.18(m,1H),0.93–0.79(m,1H).13C NMR
(101MHz,Chloroform-d)δ170.78,159.26,159.20,158.20,119.27,73.35,54.29,46.12,
46.09,31.10,31.04,29.07,29.07,29.07.HRMS(ESI)calculated for C14H20Cl2N4O2Na+:
369.0856,found 369.0855。
2) preparation of compound (6-2):
Compound (6-2)
It is similar with the method for prepare compound (1-4)；Unlike, one of used raw material is (6-1)；
The nuclear-magnetism test result of compound (6-2) are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.04 (s, 1H), 6.59 (dd, J=16.8,10.5Hz, 1H),
6.29 (dd, J=16.8,1.9Hz, 1H), 5.77-5.61 (m, 1H), 5.37 (d, J=7.9Hz, 1H), 4.66 (d, J=
13.7Hz, 1H), 4.29 (tdt, J=11.6,8.2,4.2Hz, 1H), 4.02 (d, J=14.1Hz, 1H), 3.27 (t, J=
13.1Hz, 1H), 2.89 (t, J=12.8Hz, 1H), 2.14 (dd, J=25.5,12.7Hz, 2H), 1.56-1.34 (m, 2H)13C
NMR(101MHz,Chloroform-d)δ165.42,157.98,153.84,128.17,127.44,113.17,48.19,
44.56,40.93,32.49,31.52.HRMS(ESI)calculated for C12H14Cl2N4ONa+:323.0437,found
323.0436。
3) preparation of compound 6: similar with the method for prepare compound 1；Unlike, one of used raw material is
(6-2)；
The nuclear-magnetism test result of compound 6 are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.15 (d, J=8.8Hz, 1H), 7.87 (s, 1H), 6.64-6.41
(m, 3H), 6.28 (dd, J=16.8,1.9Hz, 1H), 5.69 (dd, J=10.5,2.0Hz, 1H), 5.08 (d, J=7.4Hz,
1H), 4.63 (d, J=13.6Hz, 1H), 4.22 (dtt, J=11.0,7.1,4.0Hz, 1H), 4.01 (d, J=13.7Hz, 1H),
3.85 (s, 3H), 3.17 (t, J=5.0Hz, 4H), 2.90 (t, J=12.6Hz, 1H), 2.61 (t, J=4.9Hz, 4H), 2.37
(s, 3H), 2.14 (d, J=12.5Hz, 3H), 1.48 (d, J=11.0Hz, 3H)13C NMR(101MHz,Chloroform-d)δ
165.48,158.38,156.94,153.46,149.77,145.68,127.94,127.63,120.68,119.50,104.18,
103.63,96.71,56.04,55.59,51.78,48.12,45.97,44.80,41.12,39.13,32.65,31.70,
29.72.HRMS(ESI)calculated for C24H32ClN7O2Na+:508.2198,found 508.2196。
The preparation of 7 compound 7 of embodimentCompound 7
It is specific the preparation method comprises the following steps:
The preparation of compound 7: similar with the method for prepare compound 1；Unlike, used raw material is (2-1),
(6-2)；
The nuclear-magnetism test result of compound 7 are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.04 (d, J=8.8Hz, 1H), 7.88 (s, 1H), 7.11 (s,
1H), 6.60 (dd, J=16.8,10.6Hz, 1H), 6.39-6.24 (m, 3H), 5.70 (dd, J=10.5,1.9Hz, 1H), 5.04
(d, J=7.4Hz, 1H), 4.64 (d, J=13.7Hz, 1H), 4.22 (dtt, J=11.3,8.1,4.1Hz, 1H), 4.07-3.98
(m, 1H), 3.86 (s, 3H), 3.42 (t, J=7.6Hz, 2H), 3.25 (t, J=12.7Hz, 1H), 2.93 (s, 4H), 2.48 (t,
J=7.5Hz, 2H), 2.29 (s, 6H), 2.16 (q, J=11.0,6.8Hz, 2H), 1.47 (t, J=11.6Hz, 2H)13C NMR
(101MHz,Chloroform-d)δ165.48,158.38,156.94,153.46,149.77,145.68,127.94,
127.63,120.68,119.50,104.18,103.63,96.71,56.04,55.59,51.78,48.12,45.97,44.80,
41.12,39.13,32.65,31.70,29.72.HRMS(ESI)calculated for C24H34ClN7O2Na+:510.2355,
found 510.2356。
Embodiment 8: the preparation of compound 8
Compound 8
It is specific the preparation method comprises the following steps:
1) preparation of compound (8-1):
Compound (8-1)
It is similar with the method for prepare compound (1-1)；Unlike, one of used raw material is morpholine；
The nuclear-magnetism test result of compound (8-1) are as follows:
1H NMR (400MHz, Chloroform-d) δ 7.99 (d, J=9.3Hz, 1H), 6.48-6.22 (m, 2H), 3.94
(s, 3H), 3.85 (d, J=5.6Hz, 4H), 3.46-3.21 (m, 4H)13C NMR(101MHz,Chloroform-d)δ
156.78,154.26,129.27,127.75,103.35,94.29,56.12,56.09,51.10,45.94,39.07.HRMS
(ESI)calculated for C11H14N2O4Na+:261.0846,found 261.0845。
2) preparation of compound (8-2):
Compound (8-2)
It is similar with the method for prepare compound (1-2)；Unlike, one of used raw material is (8-1)；
The nuclear-magnetism test result of compound (8-2) are as follows:
1H NMR (400MHz, Chloroform-d) δ 6.66 (d, J=8.3Hz, 1H), 6.50 (d, J=2.4Hz, 1H),
6.40 (dd, J=8.3,2.5Hz, 1H), 3.85 (d, J=5.7Hz, 7H), 3.56 (s, 2H), 3.03 (t, J=4.6Hz, 4H)
.13C NMR(101MHz,DMSO-d6)δ166.78,154.26,129.27,127.75,103.35,94.29,56.12,56.09,
51.10,45.94,39.07.HRMS(ESI)calculated for C11H16N2O2Na+:231.1140,found
231.1144。
3) preparation of compound 8: similar with the method for prepare compound 1；Unlike, used raw material is (8-1),
(6-2)；
The nuclear-magnetism test result of compound 8 are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.18 (d, J=8.7Hz, 1H), 7.89 (s, 1H), 7.33 (s,
1H), 6.68-6.41 (m, 3H), 6.30 (d, J=16.8Hz, 1H), 5.71 (d, J=10.6Hz, 1H), 5.09 (d, J=
7.3Hz, 1H), 4.65 (d, J=12.6Hz, 1H), 4.24 (ddt, J=14.7,11.2,5.1Hz, 1H), 4.08-3.98 (m,
1H), 3.87 (d, J=6.6Hz, 7H), 3.26 (t, J=12.9Hz, 1H), 3.11 (t, J=4.6Hz, 4H), 2.93 (t, J=
12.5Hz, 1H), 2.18 (d, J=10.7Hz, 2H), 1.48 (p, J=11.6,11.1Hz, 2H)13C NMR(101MHz,
Chloroform-d)δ165.53,158.05,156.99,153.27,149.09,146.98,128.06,127.56,122.90,
119.47,107.53,104.02,100.24,66.98,66.98,55.68,50.50,50.50,48.25,44.80,41.14,
32.60,31.68.HRMS(ESI)calculated for C23H29ClN6O3Na+:495.1882,found 495.1881。
The preparation of 9 compound 9 of embodiment
Compound 9
It is specific the preparation method comprises the following steps:
1) preparation of compound (9-1):
Compound (9-1)
It is similar with the method for prepare compound (1-3)；Unlike, one of used raw material is 1- tertbutyloxycarbonyl-
4- methylamino piperidine, the nuclear-magnetism test result of compound (9-1) are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.05 (d, J=1.0Hz, 1H), 4.48 (tt, J=11.3,
4.4Hz, 1H), 4.24 (s, 2H), 3.05 (d, J=1.1Hz, 3H), 2.79 (s, 2H), 1.85-1.63 (m, 4H), 1.46 (d, J
=1.1Hz, 9H)13C NMR(101MHz,Chloroform-d)δ160.31,158.17,157.37,154.59,113.71,
79.82,56.11,43.19,32.33,32.33,28.99,28.99,28.42,28.42,28.42.HRMS(ESI)
calculated for C15H22Cl2N4O2Na+:383.1012,found 383.1012。
2) preparation of compound (9-2):
Compound (9-2)
It is similar with the method for prepare compound (1-4)；Unlike, one of used raw material is (9-1)；
The nuclear-magnetism test result of compound (9-2) are as follows:
1H NMR (400MHz, DMSO-d6) δ 8.25 (s, 1H), 6.83 (dd, J=16.6,10.4Hz, 1H), 6.10 (dd,
J=16.7,2.5Hz, 1H), 5.67 (dd, J=10.4,2.5Hz, 1H), 4.65-4.42 (m, 2H), 4.17 (d, J=13.5Hz,
1H), 3.32 (s, 1H), 3.20-3.06 (m, 1H), 2.98 (s, 3H), 2.67 (t, J=12.5Hz, 1H), 2.50 (s, 1H),
1.75–1.61(m,1H).13C NMR(101MHz,DMSO-d6)δ164.61,160.48,158.67,156.79,128.88,
127.61,114.20,56.29,44.79,41.25,32.72,29.70,28.78.HRMS(ESI)calculated for
C13H16Cl2N4ONa+:337.0593,found 337.0592。
3) preparation of compound 9: similar with the method for prepare compound 1；Unlike, one of used raw material is
(9-2)；
The nuclear-magnetism test result of compound 9 are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.11 (d, J=8.7Hz, 1H), 7.95 (s, 1H), 6.69-6.42
(m, 3H), 6.31 (dd, J=16.8,2.0Hz, 1H), 5.72 (dd, J=10.5,2.0Hz, 1H), 4.86 (d, J=13.3Hz,
1H), 4.55 (tt, J=11.9,4.0Hz, 1H), 4.13 (d, J=13.5Hz, 1H), 3.87 (s, 3H), 3.19 (t, J=
5.0Hz, 5H), 3.01 (s, 3H), 2.72 (d, J=13.2Hz, 1H), 2.64 (t, J=5.0Hz, 4H), 2.39 (s, 3H),
1.97–1.86(m,2H),1.83–1.67(m,3H).13C NMR(101MHz,Chloroform-d)δ165.48,158.38,
156.94,153.46,149.77,145.68,127.94,127.63,120.68,119.50,104.18,103.63,96.71,
56.84,56.80,55.59,51.78,48.12,45.97,44.80,41.12,39.13,32.65,31.70,29.72.HRMS
(ESI)calculated for C25H34ClN7O2Na+:522.2355,found 522.2351。
The preparation of 10 compound 10 of embodiment
Compound 10
It is specific the preparation method comprises the following steps:
1) preparation of compound (10-1):
Compound (10-1)
It is similar with the method for prepare compound (1-3)；Unlike, one of used raw material is (R) -1- tertiary butyloxycarbonyl
Base -3- amino piperidine, the nuclear-magnetism test result of compound (10-1) are as follows:
1H NMR(400MHz,Chloroform-d)δ8.00(s,1H),4.21–4.04(m,1H),3.65–3.20(m,
4H),1.97–1.51(m,2H),1.41(s,10H),1.35–1.18(m,1H),0.93–0.79(m,1H).13C NMR
(101MHz,Chloroform-d)δ170.78,159.26,159.20,158.20,119.27,73.35,54.29,46.12,
46.09,31.10,31.04,29.07,29.07,29.07.HRMS(ESI)calculated for C14H20Cl2N4O2Na+:
369.0856,found 369.0854。
2) preparation of compound (10-2):
Compound (10-2)
It is similar with the method for prepare compound (1-4)；Unlike, one of used raw material is (10-1)；
The nuclear-magnetism test result of compound (10-2) are as follows:
1H NMR (400MHz, DMSO-d6) δ 8.20 (d, J=5.1Hz, 1H), 7.66 (dd, J=18.4,7.8Hz, 1H),
6.80 (dd, J=16.8,10.6Hz, 1H), 6.10 (dd, J=16.8,2.3Hz, 1H), 5.70-5.59 (m, 1H), 4.41-
3.82(m,3H),3.47–3.26(m,1H),3.11–2.94(m,1H),2.94–2.62(m,1H),1.99–1.66(m,3H),
1.43 (td, J=12.2,6.2Hz, 1H)13C NMR(101MHz,DMSO-d6)δ164.98,158.67,157.79,154.74,
128.94,127.77,113.44,49.15,47.51,45.74,29.87,24.18.HRMS(ESI)calculated for
C12H14Cl2N4ONa+:323.0437,found 323.0435。
3) preparation of compound 10: similar with the method for prepare compound 1；Unlike, one of used raw material is
(10-2)；
The nuclear-magnetism test result of compound 10 are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.16 (d, J=8.7Hz, 1H), 7.91 (s, 1H), 6.86-6.16
(m, 3H), 5.80-5.38 (m, 1H), 5.22 (d, J=61.5Hz, 1H), 4.08 (d, J=13.7Hz, 3H), 3.87 (s, 3H),
3.66-3.38 (m, 1H), 3.38-3.09 (m, 5H), 2.65 (t, J=4.9Hz, 4H), 2.40 (s, 3H), 2.06 (d, J=
35.6Hz,1H),1.90–1.53(m,3H).δ165.48,158.38,156.94,153.46,149.77,145.68,127.94,
127.63,120.68,119.50,104.18,103.63,96.71,56.04,55.59,51.78,48.12,45.97,44.80,
41.12,39.13,32.65,31.70,29.72.HRMS(ESI)calculated for C24H32ClN7O2Na+:508.2198,
found 508.2195。
The preparation of 11 compound 11 of embodimentCompound 11
It is specific the preparation method comprises the following steps:
1) preparation of compound (11-1):
Compound (11-1)
It is similar with the method for prepare compound (1-3)；Unlike, one of used raw material is (S) -1- tertiary butyloxycarbonyl
Base -3- amino piperidine, the nuclear-magnetism test result of (11-1) are as follows:
1H NMR(400MHz,Chloroform-d)δ8.00(s,1H),4.21–4.04(m,1H),3.65–3.20(m,
4H),1.97–1.51(m,2H),1.41(s,10H),1.35–1.18(m,1H),0.93–0.79(m,1H).13C NMR
(101MHz,Chloroform-d)δ170.78,159.26,159.20,158.20,119.27,73.35,54.29,46.12,
46.09,31.10,31.04,29.07,29.07,29.07.HRMS(ESI)calculated for C14H20Cl2N4O2Na+:
369.0856,found 369.0854。
2) preparation of compound (11-2):
Compound (11-2)
It is similar with the method for prepare compound (1-4)；Unlike, one of used raw material is (11-1)；
The nuclear-magnetism test result of compound (11-2) are as follows:
1H NMR (400MHz, DMSO-d6) δ 8.20 (d, J=5.1Hz, 1H), 7.66 (dd, J=18.4,7.8Hz, 1H),
6.80 (dd, J=16.8,10.6Hz, 1H), 6.10 (dd, J=16.8,2.3Hz, 1H), 5.70-5.59 (m, 1H), 4.41-
3.82(m,3H),3.47–3.26(m,1H),3.11–2.94(m,1H),2.94–2.62(m,1H),1.99–1.66(m,3H),
1.43 (td, J=12.2,6.2Hz, 1H)13C NMR(101MHz,DMSO-d6)δ164.98,158.67,157.79,154.74,
128.94,127.77,113.44,49.15,47.51,45.74,29.87,24.18.HRMS(ESI)calculated for
C12H14Cl2N4ONa+:323.0437,found 323.0434。
3) preparation of compound 11: similar with the method for prepare compound 1；Unlike, one of used raw material is
(11-2)；
The nuclear-magnetism test result of compound 11 are as follows:
1H NMR (400MHz, Chloroform-d) δ 8.16 (d, J=8.7Hz, 1H), 7.91 (s, 1H), 6.86-6.16
(m, 3H), 5.80-5.38 (m, 1H), 5.22 (d, J=61.5Hz, 1H), 4.08 (d, J=13.7Hz, 3H), 3.87 (s, 3H),
3.66-3.38 (m, 1H), 3.38-3.09 (m, 5H), 2.65 (t, J=4.9Hz, 4H), 2.40 (s, 3H), 2.06 (d, J=
35.6Hz,1H),1.90–1.53(m,3H).δ165.48,158.38,156.94,153.46,149.77,145.68,127.94,
127.63,120.68,119.50,104.18,103.63,96.71,56.04,55.59,51.78,48.12,45.97,44.80,
41.12,39.13,32.65,31.70,29.72.HRMS(ESI)calculated for C24H32ClN7O2Na+:508.2198,
found 508.2194。
Inhibiting effect test to EGFR-T790M enzyme
Compound is screened using established system, all compounds are all dissolved in 95%DMSO solution.
(1) each component in sieve medicine body system is diluted to required working concentration (diluting using enzyme activity buffer).
(2) 384 orifice plates, every hole sequentially add 5 μ L protein solutions, 2 μ L substrates, 1 μ L compound, are eventually adding 2 μ L ATP
Starting reaction.Blank control group changes 1 μ L compound into 1 μ L DMSO, and positive controls are positive drug.
(3) 384 orifice plates, incubation at room temperature 1h or so are sealed.
(4) what the metal Eu3+ and 5 μ L streptomysin Avidins marked to every hole 5 μ L-Tyr phospho-ABs of addition was marked
XL665 terminates reaction.Using stop buffer (Mg in enzyme activity buffer can be chelated containing EDTA2+, reach and terminate reaction
Purpose) it is diluted.
(5) it seals, is protected from light, incubation at room temperature 1h or so.
(6) with the fluorescent value at multi-function microplate reader detection two wavelength of 620nm and 665nm.
Following formula can be used for data processing, to obtain compound to the inhibiting rate of destination protein.
I%=(1-Fi/F0) * 100%
Wherein i% indicates that the inhibiting rate of the compound for protein under the conditions of a certain concentration, F0 indicate that blank control group exists
665nm and 620nm goes out the ratio of fluorescence intensity multiplied by the numerical values recited after 10000, Fi indicate experimental group in 665nm and
620nm goes out the ratio of fluorescence intensity multiplied by the numerical values recited after 10000.
The inhibiting effect test result of table 1 compound, 1~11 pair of EGFR-T790M enzyme
Compound is in vitro to the inhibiting effect of cancer cell
Using Methyl thiazoly tetrazolium assay (MTT) colorimetric determination compound to the inhibiting effect of cancer cell NCI-H1975: will
Cancer cell in logarithmic growth phase is according to every milliliter 5 × 104The density of cell number is seeded in 96 porocyte culture plates, zeroing
Hole is not celliferous normal incubation medium, the culture medium of the various concentration of the 1-21 containing compound is replaced after 24 hours, zeroing hole is more
Normal incubation medium is changed, each concentration gradient is arranged 5 multiple holes, is placed in 37 DEG C, 5%CO2It is cultivated in incubator, it is micro- after 24 hours
Microscopic observation cell state and growth change, it is molten that Methyl thiazoly tetrazolium assay (triumphant base biology, 5mg/mL) is added in every hole after 48 hours
Liquid continues at 37 DEG C, 5%CO2It is cultivated in incubator, culture medium is siphoned away after 4 hours, DMSO (dimethyl sulfoxide) is added in every hole
100 μ L measure absorbance value under 570 nano wave lengths using microplate reader, carry out data statistic analysis using Graphpad software,
Calculating medium effective concentration (IC50, unit: μM).(table 2)
The inhibiting effect test result of table 2 compound, 1~11 pair of cancer cell in vitro
As can be seen from the above table, the proliferation for the inhibition cancer cell that compound 1~11 in vitro can be different degrees of.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Within mind and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (7)
1. a kind of amino-metadiazine compound has logical formula (I) structure as follows:
Wherein, it is 0~4 that m, which is 0~4, n,；
R1Selected from amino, alkyl amino, aminoalkyl or alkyl amino-carbonyl；
R2Selected from hydrogen, hydroxyl, nitro, halogen, amino, cyano, alkyl, alkenyl, halogenated alkyl, miscellaneous alkyl, alkyl amino, ammonia
Base alkyl, alkyl-carbonyl, alkyl amino-carbonyl or aryl carbonyl；
X is selected from oxygen atom, amino or methylamino.
2. amino-metadiazine compound according to claim 1, it is characterised in that: cyclic structure is 4-10 member ring.
3. amino-metadiazine compound according to claim 1, it is characterised in that: logical formula (I) compound represented is selected from
With one of flowering structure,
4. a kind of EGFR inhibitor, it is characterised in that: including the described in any item amino-metadiazine compounds of claims 1 to 3
Or it is in pharmaceutically acceptable salt.
5. EGFR inhibitor according to claim 4, it is characterised in that: the pharmaceutical salt packet of amino-metadiazine compound
Include inorganic acid salt or acylate, wherein inorganic acid salt is selected from hydrofluoride, hydrochloride, hydrobromate, hydriodate, sulfuric acid
Salt, nitrate, phosphate, carbonate, one of borate, selenite, phosphomolybdate, phosphite, sulphite or
It is two or more；The acylate be selected from citrate, maleate, D-malic acid salt, L MALIC ACID salt, DL-malic acid salt,
Pfansteihl salt, D-lactate, DL- hydrochlorate, oxalates, mesylate, valerate, oleate, laruate, p-methyl benzenesulfonic acid
Salt, 1-naphthalene sulfonic aicd salt, 2- naphthalene sulfonate, phthalate, tartrate, malonate, succinate, fumarate, glycollate,
Mercaptan hydrochlorate, glycinate, sarcosinate, sulfonate, nicotinate, picoline hydrochlorate, isonicotinic acid salt, benzoate or substitution
One or more of benzoate.
6. a kind of amino-metadiazine compound as claimed in any one of claims 1 to 3 or EGFR described in claim 4 or 5
Inhibitor is preparing the application in epidermal growth factor receptor antagonists.
7. a kind of amino-metadiazine compound as claimed in any one of claims 1 to 3 or EGFR described in claim 4 or 5
Application of the inhibitor in preparation anticancer medicine；Preferably, cancer is solid tumor.
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| US20170226065A1 (en) * | 2014-08-03 | 2017-08-10 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Potent dual brd4-kinase inhibitors as cancer therapeutics |
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