CN105481858B - A kind of nitrogenous fused heterocyclic compound, preparation method, composition and application - Google Patents
A kind of nitrogenous fused heterocyclic compound, preparation method, composition and application Download PDFInfo
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- CN105481858B CN105481858B CN201410534512.6A CN201410534512A CN105481858B CN 105481858 B CN105481858 B CN 105481858B CN 201410534512 A CN201410534512 A CN 201410534512A CN 105481858 B CN105481858 B CN 105481858B
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- 150000002391 heterocyclic compounds Chemical class 0.000 title claims abstract description 24
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims description 34
- 239000000203 mixture Substances 0.000 title description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 248
- 238000006243 chemical reaction Methods 0.000 claims description 162
- 238000000034 method Methods 0.000 claims description 59
- -1 amino, hydroxyl Chemical group 0.000 claims description 56
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
- 239000001257 hydrogen Substances 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 11
- 125000004429 atom Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 230000022131 cell cycle Effects 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 150000001721 carbon Chemical group 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- 230000007704 transition Effects 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 238000007832 transition metal-catalyzed coupling reaction Methods 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000004069 aziridinyl group Chemical group 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 239000012453 solvate Substances 0.000 abstract description 10
- 230000002503 metabolic effect Effects 0.000 abstract description 9
- 239000002243 precursor Substances 0.000 abstract description 8
- 239000000651 prodrug Substances 0.000 abstract description 8
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- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 88
- 239000002904 solvent Substances 0.000 description 73
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 59
- 239000007787 solid Substances 0.000 description 58
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 239000002585 base Substances 0.000 description 41
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 33
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- 239000002994 raw material Substances 0.000 description 30
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 25
- 238000001914 filtration Methods 0.000 description 25
- 239000012044 organic layer Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000003208 petroleum Substances 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 15
- 238000003810 ethyl acetate extraction Methods 0.000 description 15
- 238000010511 deprotection reaction Methods 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 14
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
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- 239000000543 intermediate Substances 0.000 description 9
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
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- 239000003960 organic solvent Substances 0.000 description 8
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
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- 238000004519 manufacturing process Methods 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 6
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
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- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 6
- 102000020233 phosphotransferase Human genes 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
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- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
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- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- XUYJLQHKOGNDPB-UHFFFAOYSA-N phosphonoacetic acid Chemical compound OC(=O)CP(O)(O)=O XUYJLQHKOGNDPB-UHFFFAOYSA-N 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229960005141 piperazine Drugs 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000025053 regulation of cell proliferation Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of nitrogenous fused heterocyclic compounds shown in formula I, its pharmaceutically acceptable salt, or their enantiomter, diastereoisomer, tautomer, solvate, metabolic precursor thereof or prodrug, or pharmaceutical composition and its application containing it.Nitrogenous fused heterocyclic compound of the invention has preferable anti-tumor activity.
Description
Technical field
The present invention is specifically related to a kind of nitrogenous fused heterocyclic compound, preparation method, composition and application.
Background technique
Cyclin-dependent kinase (cyclin-dependent kinase, CDK) is a kind of serine (Ser)/Soviet Union's ammonia
Sour (Thr) kinases, the CDK-cyclin formed as intracellular important signal transducers and period plain (cyclin) are compound
Object participates in the growth of cell, proliferation, suspend mode or enters apoptosis.Cyclin plays in regulation of cell proliferation
Important function, in tumour cell, G1 period phase element and CDK it is not normal be it is most frequent, these changes may be participated in there are many mechanism
Change.These variations cause tumour often through the activation of oncogene and the silencing of tumor suppressor gene.Malignant cell is logical
It crosses heredity and gradually life system influences the expression of cell cycle regulating protein, cause the overexpression and the expression of CDK inhibitor of period element
Loss, consequent is CDK active out of control.
Cell cycle checkpoint (cell cycle checkpoint) refers to the speed limit position in control cell generation cycle
Point is responsible for determining the integrality of DNA synthesis, monitoring DNA replication dna, DNA damage reparation and resistance before DNA replication dna and mitosis
Disconnected cell enters m period, the accurate progress for adjusting the cell cycle, to prevent that mistake occurs in proliferating cycle.Cell response
DNA damage makes Cell cycle checkpoint be activated, and leads to Cell-Cycle Blockade, to repair the DNA of damage, or passes through cell
Apoptosis or the mode inducing cell death for terminating growth.Cell-Cycle Blockade frequently occurs in G1/S or G2/M intersection, cell
Cycle detection point regulatory molecule is also the novel targets of anti-tumor drug.
Early stage Cycle Regulation agent such as CDK inhibitor, Auro inhibitor etc. generally lead to poison because specificity is not high
Side effect is very big, and in recent years, selective CDK inhibitor etc. is reported in succession and enters clinical trial.Therefore, it finds and finds and is high
The specific cell periodic adjustment agent of effect, low toxicity is a popular domain of anti-tumor drug research.
Summary of the invention
The present invention is to overcome existing Cycle Regulation agent in the prior art due to specific not high, poor selectivity
Etc. reasons and show the defects of biggish clinical side effects, although the bad defect of the high activity of selectivity, and mention
Supplied a kind of nitrogenous fused heterocyclic compound, its pharmaceutically acceptable salt and their enantiomter, diastereoisomer,
Tautomer, solvate, metabolic precursor thereof or prodrug, preparation method, pharmaceutical composition and application containing it.Of the invention
Nitrogenous fused heterocyclic compound has preferable anti-tumor activity.
The present invention provides a kind of shown in formula I nitrogenous fused heterocyclic compound, its pharmaceutically acceptable salt or it
Enantiomter, diastereoisomer, tautomer, solvate, metabolic precursor thereof or prodrug；
Wherein, R1For hydrogen, halogen (preferably chlorine), C1~C6Alkyl (preferably methyl), C1~C6Alkoxy (preferably methoxyl group)
Or C3~C6Naphthenic base (preferably cyclopropyl)；
R2For hydrogen, halogen (preferably bromine), C1~C6The C that alkyl, hydroxyl replace1~C6Alkyl (preferably CH3-CH (OH) -), C1
~C6Alkyl oxygen-carbonyl-(preferably ethoxy-carbonyl), carboxyl, cyano, aldehyde radical (preferably carboxaldehyde radicals), C1~C6Acyl group (preferably second
Acyl group),Or substituted or unsubstituted C3~C12Heteroaryl；DescribedIn R5And R6Independently be hydrogen,
C1~C6Alkyl (preferably methyl) or C1~C6Alkoxy (preferably methoxyl group), alternatively, the R5And R6Atom connect cyclization,
WithIn N atom form unitary azepine C2~C6Naphthenic base (preferably unitary aziridinyl)；The substitution or not
Substituted C3~C12Hetero atom in heteroaryl is one of O, N and S or a variety of (preferably N)；The heteroatomic number
For 1~4 (preferably 2)；The substituted C3~C12Being substituted by by halogen (preferably F), C in heteroaryl1~C6Alkoxy
(preferably methoxyl group), trifluoromethyl, hydroxyl and C1~C6One of alkyl (preferably methyl) is a variety of replaced；
R3For hydrogen or C1~C6Alkyl (preferably methyl)；
R4For substituted or unsubstituted C1~C6Alkyl (preferably substituted or unsubstituted methyl, substituted or unsubstituted positive third
Base, substituted or unsubstituted tert-butyl, substituted or unsubstituted isopropyl or substituted or unsubstituted sec-butyl), replace or not
ReplaceSubstituted or unsubstituted C3~C6Naphthenic base (preferably substituted or unsubstituted C4、C5Or C6
Naphthenic base), C1~C6Alkyl oxygen-carbonyl-(preferably ethoxy-carbonyl -), substituted or unsubstituted C3~C12Aryl (preferably benzene
Base), substituted or unsubstituted C3~C12Heteroaryl or substituted or unsubstituted C2~C6Heterocyclylalkyl；Described h, i and the j is respectively
It is independently (the h preferably 2 or 3, the i preferably 1 or 2, the j preferably 2 or 3) of any integer in 1-5；Described
Substituted or unsubstituted C3~C12Hetero atom in heteroaryl is one of O, N and S or a variety of (preferably N), the substitution
Or unsubstituted C3~C12Heteroatomic number in heteroaryl is 1~4 (preferably 1)；Described is substituted or unsubstituted
C2~C6Hetero atom in Heterocyclylalkyl is one of O, N and S or a variety of (preferably N or O), and described is substituted or unsubstituted
C2~C6Heteroatomic number in Heterocyclylalkyl is 1~4 (preferably 1)；Described is substituted by by halogen (preferably F), C1~
C6Alkoxy (preferably methoxyl group), trifluoromethyl, hydroxyl and C1~C6One of alkyl (preferably methyl) is a variety of replaced；
Ar is W-L1-L2-Y-；
Wherein:
Y is selected from substituted or unsubstituted C3~C12Aryl, substituted or unsubstituted C3~C12Heteroaryl or substitution do not take
" the C in generation3~C6Heterocycloalkenyl and C3~C12Aryl " or substituted or unsubstituted " C3~C6Heterocycle heterocycloalkenyl and C3~C12It is miscellaneous
Aryl "；Substituted or unsubstituted " the C3~C6Heterocycloalkenyl and C3~C12Aryl " and substituted or unsubstituted " C3~C6
Heterocycle heterocycloalkenyl and C3~C12The hetero atom in heterocycloalkenyl in heteroaryl " it is independent for one of N, O or S or
A variety of (preferred N independent), heteroatomic number independent is 1~4 (preferably 1) independent；Described takes
Generation or unsubstituted " C3~C6Heterocycloalkenyl and C3~C12Aryl " and substituted or unsubstituted " C3~C6Heterocycle heterocycloalkenyl and C3
~C12The number of the alkenyl in heterocycloalkenyl in heteroaryl " independent is 1；The substituted or unsubstituted C3~C12
Heteroaryl and substituted or unsubstituted " C3~C6Heterocycle heterocycloalkenyl and C3~C12The hetero atom in heteroaryl in heteroaryl " is each
From being independently one of O, N and S or a variety of (preferred N independent), heteroatomic number independent is 1~4
(preferably 1) independent；Described is substituted by by halogen (preferably fluorine) or C1~C6Alkyl (preferably methyl) is replaced；
L2Selected from-(CH2)r,-O- ,-S- ,-C (=O)-or substituted or unsubstituted amino, r is any between 0~5
Integer (preferably 0 or 1)；Described is substituted by by C1~C3Replaced alkyl；
L1Selected from-(CH2)n, substituted or unsubstituted C3~C12Naphthenic base (preferably substituted or unsubstituted cyclohexyl) takes
Generation or unsubstituted C3~C12Heterocyclylalkyl；N is the arbitrary integer (preferably 0 or 1) between 0~5；Described is substituted by by C1~
C6Replaced alkyl (preferably methyl) or halogen；The substituted or unsubstituted C3~C12Hetero atom in Heterocyclylalkyl be O,
One of N and S or a variety of (preferably N), heteroatomic number are any integer (preferably 1 or 2) in 1~4；
W be hydrogen,Halogen (preferably bromine), hydroxyl, aldehyde radical,It is substituted or unsubstituted
Amino, substituted or unsubstituted C1~C6Alkyl (preferably substituted or unsubstituted methyl, alternatively, substituted or unsubstituted ethyl)
Or substituted or unsubstituted C1~C6Acyl group；DescribedIn X2For O, S orDescribedIn s be any integer (preferably s is 1 or 2) in 1~5, it is describedIn
T be any integer (preferably t is 0 or 1) in 0~5, it is describedIn m be 0~5 in any
Integer (preferably m is 1), it is describedIn X1For N, O ,-C (=O)-NH- orThe substitution
Amino refer on nitrogen only one hydrogen be substituted or nitrogen on two hydrogen be substituted, when substituted amino refers to that two hydrogen are substituted on nitrogen
When, two substituent groups are identical or different；Described is substituted by by C1~C6Alkyl (preferably methyl), C1~C6Alkyl sulphonyl
(preferably mesyl), C1~C6Alkoxy (preferably methoxyl group), C1~C6Alkylthio group (preferably methyl mercapto), C3~C6Naphthenic base,
The C that halogen, hydroxyl, amino, hydroxyl replace1~C6(ethyl, the hydroxyl that methyl, the hydroxyl that preferably hydroxyl replaces replace replace alkyl
Propyl), the N of 2-12 carbon atom, the N of N- dialkyl amido, 2-12 carbon atom, N- dialkyl amido-alkyl-, 2-12
Alkyl-, the C of the alkoxy substitution of a carbon atom3~C6Naphthenic base (preferably cyclopropyl) and C2~C6One of Heterocyclylalkyl or
It is a variety of replaced；The C2~C6Hetero atom in Heterocyclylalkyl is one of N, O and S or a variety of, and heteroatomic number is
Any integer in 1~4.
As the R2For substituted or unsubstituted C3~C12When heteroaryl, the substituted or unsubstituted C3~C12It is miscellaneous
Aryl is preferredDescribedIn A be oxygen, NH or substituted amino, taking in the substituted amino
On behalf of by C1~C6Alkyl replaces (preferably being replaced by methyl).
As the R4For substituted or unsubstituted C3~C12When heteroaryl, the substituted or unsubstituted C3~C12It is miscellaneous
Aryl is preferred
As the R4For substituted or unsubstituted C2~C6When Heterocyclylalkyl, the substituted or unsubstituted C2~C6It is miscellaneous
C in naphthenic base2~C6Heterocyclylalkyl is preferred
As the R2It is substituted or unsubstitutedWhen, described is substituted or unsubstitutedIt is preferred that
The R1It is preferred that hydrogen or methyl.
The R2It is preferred that acetyl group, cyano, bromine ,-CH (OH) CH3、C1~C6Alkyl oxygen-carbonyl-or
The R3It is preferred that hydrogen or methyl.
The R4It is preferred that methyl, tert-butyl, isopropyl, cyclopenta, cyclobutyl, phenyl, n-propyl or cyclohexyl.
The Y is preferred The Y preferably connects L in left end2, such as when Y isWhen
Connection type be
The L1It is preferred that
OrThe L1Group preferably left end connect W, right end connect L2, such as work as L1ForWhen
Connection type is
The Ar is preferred
Preferably, in the Formulas I compound represented, R1For hydrogen or methyl, R2For acetyl group, cyano, bromine ,-CH (OH)
CH3、C1~C6Alkyl oxygen-carbonyl-orR3For hydrogen, R4For methyl, tert-butyl, isopropyl, cyclopenta, cyclobutyl,
Phenyl, n-propyl or cyclohexyl, Ar areMore preferably, in the Formulas I compound represented, R1For
Methyl, R2For acetyl group or cyano, R3For hydrogen, R4For methyl, cyclopenta, isopropyl or tert-butyl, Ar isIt is optimal, in the Formulas I compound represented, R1For methyl, R2For acetyl group or cyano, R3
For hydrogen, R4For cyclopenta or isopropyl, Ar is
In the present invention, the pharmaceutically acceptable salt of the Formulas I compound represented is preferably chemical combination shown in Formulas I
Object and organic acid or inorganic acid are formed by salt or Formulas I compound represented and organic base or inorganic base is formed by salt.This
In invention, the solvate of the Formulas I compound represented be preferably hydrate or Formulas I compound represented with it is organic molten
Dosage form at solvate.
The organic acid can for this field it is conventional can at the various organic acids of salt, preferably methanesulfonic acid, p-methyl benzenesulfonic acid,
Maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, succinic acid,
Benzoic acid, isethionic acid, naphthalene sulfonic acids or salicylic acid etc..
The inorganic acid can for this field it is conventional can be at the various inorganic acids of salt, preferably hydrochloric acid, sulfuric acid or phosphoric acid etc..
The organic base can for this field it is conventional can be at the various organic bases of salt, preferably pyridines, imidazoles, pyrazine
One of organic bases such as class, indoles, fast quinoline class, tertiary amines, phenyl amines are a variety of.The tertiary amines organic base preferably three
Ethamine and/or N, N- diisopropylethylamine.The preferred N of phenyl amines organic base, accelerine.The pyridines have
One of the preferred pyridine of machine alkali, picoline, 4-dimethylaminopyridine and 2- methyl -5- ethylpyridine are a variety of.
The inorganic base can for this field it is conventional can be at the various inorganic bases of salt, preferred as alkali hydride, alkali gold
The hydroxide of category, the alkoxide of alkali metal, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, saleratus and sodium bicarbonate
One of or it is a variety of.The preferred sodium hydride of the alkali metal hydride and/or hydrofining.The hydroxide of the alkali metal
It is preferred that one of sodium hydroxide, potassium hydroxide and lithium hydroxide or a variety of.The preferred methanol of the alkoxide of the alkali metal
One of sodium, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide are a variety of.
In the present invention, the nitrogenous fused heterocyclic compound shown in formula I is preferably following any compound:
In the present invention, " x~y carbon atom ... base " (wherein x and y refer to number) being previously mentioned refers to the total of the group
Carbon number is that " x~y " is a.
For Formulas I compound represented of the present invention, organic synthesis and field of medicinal chemistry and technology people can be used
A variety of method preparations known to member.Methodologies described hereinafter can be used, with synthetic method known to organic chemistry filed
Together or variation on it understood by one of ordinary skill in the art synthesizes the compounds of this invention.
The preparation method of Formulas I compound represented of the present invention can use following from the starting material being easily obtained
General approach and process prepare the compound of the present invention.It will be appreciated that when providing typical or preferred technological operation
When condition (that is, reaction temperature, time, the molar ratio of reactant, solvent, pressure, etc.)；Other technological operations can also be used
Condition, unless otherwise indicated.Optimum reaction condition can change with specific reactant used or solvent, but these conditions can
To be determined by those skilled in the art by routine optimization process.
The method of Formulas I compound represented of the present invention described herein can be according to known in the art any suitable
Suitable method is monitored.For example, nuclear magnetic resonance, infrared spectroscopy, spectrophotometric or mass spectral analysis, HPLC or thin-layer chromatography are supervised
Control the generation of product.
The preparation of compound can be related to the protection and deprotection of multiple chemical groups.For the need protected and be deprotected
It wants, and the selection of protecting group appropriate can readily be determined by those skilled in the art, the chemical mistake of protecting group
Journey is in such as Greene et al., Protective Groups in Organic Synthesis, the second edition, Wiley&Sons,
1991, in find, be incorporated herein by reference herein in whole form.
Method reaction described herein can be carried out in suitable solvent, organic synthesis field technical staff is easily
Select the solvent.Suitable solvent substantially not with raw material, intermediate or product it is described react carry out at a temperature of from it is anti-
It answers, the temperature that the temperature that the reaction carries out can change in the boiling point temperature range from the freezing point of solvent to solvent,
Given reaction can carry out in the mixture of a kind of solvent or multi-solvents.According to specific reaction step, Ke Yixuan
Select the solvent for being suitable for specific reaction step.
In general, three kinds of reaction routes and technique at least as described below, which can be used, prepares the compounds of this invention, but not
The reagent and solvent being limited in reaction condition.
Therefore, the present invention also provides the preparation methods of the Formulas I compound represented, are following either method:
Method one:
The preparation method of the Formulas I compound represented includes the following steps: to take off Formula II compound represented
Except the reaction of protecting group, Formulas I compound represented is obtained, the PG in Formula II compound represented is the protecting group；
Wherein, described Ar, R1、R2、R3、R4As described above.
PG in the Formula II compound represented can be hydroxyl protection base, amino protecting group, carboxyl-protecting group or carbonyl
The various conventional protecting groups in this fields such as base protecting group, in order on the Ar group and Formula II compound represented
Amino can play the role of protecting certain reactive groups on Ar not react when being reacted and being linked together.
PG in the Formula II compound represented can for tertiary butyl oxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl group,
Acetyl group, allyl, allyl carbonyl etc..
The condition of the reaction of the deprotection base can be the conventional removing condition of the various protecting groups in this field, such as hydrolyze
Condition, the condition of aminolysis reaction, condition of hydrogenation of reaction etc..
When the W isAnd the X2When for NH, the PG is tertiary butyl oxycarbonyl, i.e. Formula II -1
Boc group on shown compound.
When the W isThe X2When for NH, and when the PG is tertiary butyl oxycarbonyl, preferably,
The preparation method of the Formulas I compound represented includes the following steps: -1 compound represented of Formula II carrying out deprotection
The Formulas I compound represented is made in the reaction of base；The L1、L2、Y、R1、R2、R3、R4As described above；
In the reaction of the deprotection base when the PG is tertiary butyl oxycarbonyl, the Y is preferred
In the reaction of the deprotection base when the PG is tertiary butyl oxycarbonyl, the L2It is preferred that-
(CH2) r-, and r is 0.
In the reaction of the deprotection base when the PG is tertiary butyl oxycarbonyl, the L1It is preferred that-
(CH2) n-, and n is 0.
In the reaction of the deprotection base when the PG is tertiary butyl oxycarbonyl, the R1It is preferred that methyl
Or hydrogen.
In the reaction of the deprotection base when the PG is tertiary butyl oxycarbonyl, the R2It is preferred that hydrogen,
Methyl, halogen, cyano, acetyl group ,-CO2CH2CH3、-CO2-N(CH3)-OCH3、-CO2NH2Or-CO2-N(CH3)2。
In the reaction of the deprotection base when the PG is tertiary butyl oxycarbonyl, the R3It is preferred that H or
Methyl.
In the reaction of the deprotection base when the PG is tertiary butyl oxycarbonyl, the R4It is preferred that first
Base, phenyl, cyclobutane base, pyridyl group ,-CO2CH2CH3, propyl, cyclopenta, butyl or cyclohexyl.
The process of the reaction of the deprotection base when the PG is tertiary butyl oxycarbonyl can use ability
Traditional test methods (such as TLC, HPLC, GC or NMR) in domain are monitored, generally with the disappearance of such as -1 compound represented of Formula II
Shi Zuowei reaction end.
The reaction of the described deprotection base when the PG is tertiary butyl oxycarbonyl, after, preferably, also
It can further include the operation of post-processing.The method and condition of the post-processing can be conventional for the such post-reaction treatment in this field
Method and condition, preferably: reaction system is washed, is dried, is filtered, solvent evaporated, then column chromatograph；
Alternatively, solvent, washing, filtering is evaporated off in reaction system；Alternatively, solvent, thin-layer chromatography is evaporated off in reaction system.
In the reaction of the deprotection base when the PG is tertiary butyl oxycarbonyl, preferably, also further
Include the following steps: in organic solvent, -1 compound represented of Formula V and 3 compound represented of formula are subjected to annulation, generated
- 2 compound represented of formula III；Then -2 compound represented of formula III is subjected to oxidation reaction, changed shown in production III-1
Close object；- 1 compound represented of formula III is reacted with 2 compound represented of formula, is changed shown in the obtained Formula II -1
Close object；
The L1、L2、Y、R1、R2、R3、R4As described above；
The X is halogen, preferably bromine, fluorine, chlorine, iodine, more preferable bromine.
Wherein, the condition of the method for each step reaction in reaction route can be according to the method for these reactions of this field
Normal condition carry out.
Organic solvent in the annulation can be the various conventional organic solvents of the such reaction in this field, preferably
Methanol, ethyl alcohol, isopropanol, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N-Methyl pyrrolidone, dioxane, four
One of hydrogen furans and methylene chloride are a variety of.
Method two:
The preparation method of the Formulas I compound represented includes the following steps: -3 compound represented of formula III and formula
4 compounds represented carry out substitution reaction or transition metal-catalyzed coupling reaction, generate chemical combination shown in the Formulas I
Object；LG group in -3 compound represented of formula III is leaving group；
The R1、R2、R3、R4As described above with Ar.
The leaving group can be the such various conventional leaving groups of reaction in this field, preferably halogen, methyl mercapto, first
Sulfuryl, OH, amino or sulphonic acid ester.
The condition of the substitution reaction or the transition metal-catalyzed coupling reaction can be such anti-for this field
The various normal conditions answered.The substitution reaction can by heat or pressurize or acid-base catalysis etc. under the conditions of carry out.
In the substitution reaction of the method two, the R1It is preferred that methyl or hydrogen.The R2It is preferred that hydrogen, methyl, halogen
Element, cyano, acetyl group ,-CO2CH2CH3、-CO2-N(CH3)-OCH3、-CO2NH2Or-CO2-N(CH3)2.The R3It is preferred that H or
Methyl.The R4It is preferred that methyl, phenyl, cyclobutane base, pyridyl group ,-CO2CH2CH3, propyl, cyclopenta, butyl or hexamethylene
Base.
In the method two of the preparation method of the Formulas I compound represented, preferably, still further comprising following step
It is rapid: -2 compound represented of Formula V and 3 compound represented of formula are subjected to annulation, production III-3 compound represented；
LG group in compound shown in Formula V -2 is leaving group；The leaving group is as described above；
The R1、R2、R3、R4As described above with Ar.
The condition of the annulation is as described above.
In method two, as the R2When for halogen, -2 compound represented of Formula V is to change shown in Formula V -2-1
Close object.As the R2When for acetyl group, -2 compound represented of Formula V is Formula V -2-2 compound represented.When described
R2When for halogen, -3 compound represented of formula III is formula III -3-1 compound represented.As the R2For acetyl
When base, -3 compound represented of formula III is formula III -3-2 compound represented.
In the method two of the preparation method of the Formulas I compound represented, preferably, still further comprising following step
It is rapid: the Formula V -2-1 compound represented can be generated by transition metal-catalyzed lower acylation reaction described in V-2-2
Compound represented.Formula III -3-1 the compound represented can give birth to by transition metal-catalyzed lower acylation reaction
At the III-3-2 compound represented.As the R2When for halogen, compound described in the Formulas I can pass through
Acylation reaction under transition metal-catalyzed, which generates, works as the R2Compound described in Formulas I when for acetyl group.
The R1、R3、R4, X, LG and Ar as described above.
Wherein, the condition of the method for each step reaction in reaction route can be according to the method for these reactions of this field
Normal condition carry out.
In the method two of the preparation method of the Formulas I compound represented, preferably, still further comprising following step
It is rapid: as the R2For C1~C6Alkyl oxygen-carbonyl-when, the Formulas I compound represented, in water and organic solvent (such as first
Alcohol, ethyl alcohol, isopropanol, tetrahydrofuran, dioxane) in the mixed solvent, (preferably under alkaline condition by hydrolysis
Hydrolysis, more preferably in sodium hydroxide, potassium hydroxide, the hydrolysis under the alkaline condition of lithium hydroxide) it can be generated and work as
The R2Formulas I compound represented when for carboxyl.As the R2When for carboxyl, the Formulas I compound represented and N,
It is available as the R that O- dimethyl hydroxylamine carries out condensation reaction2ForWhen Formulas I compound represented.Work as institute
The R stated2ForWhen, the Formulas I compound represented and grignard reagent or lithium reagent, in anhydrous organic solvent
In (such as tetrahydrofuran, methylene chloride), generation can be reacted as the R2Formulas I compound represented when for acetyl group.
The R1、R3、R4, X and Ar as described above.
Wherein, the condition of the method for each step reaction in reaction route can be according to the method for these reactions of this field
Normal condition carry out.
In the method two of the preparation method of the Formulas I compound represented, preferably, still further comprising following step
It is rapid: as the R2When for cyano, the Formulas I compound represented, in anhydrous solvent, with grignard reagent or lithium metal
Addition reaction occurs for reagent, and hydrolysis occurs again for obtained product, last available R2For C1~C6The formula of acyl group
I compound represented；
The R1、R3、R4, X and Ar as described above；The R14For C1~C6Alkyl.
Wherein, the condition of the method for each step reaction in reaction route can be according to the method for these reactions of this field
Normal condition carry out.
In the method two of the preparation method of the Formulas I compound represented, preferably, still further comprising following step
It is rapid: as the R2When for cyano, the Formulas I compound represented is in organic solvent, anti-with hydrazine, azanol or amine reagent
With acyl chlorides, acid or acid anhydrides the available R of ring closure reaction occurs for Ying Hou, obtained product again2For substituted or unsubstituted C3~C12
Formulas I compound represented when heteroaryl；
The R1、R3、R4, X and Ar as described above；The R15For substituted or unsubstituted C3~C12Heteroaryl；Institute
The substituted C stated3~C12Being substituted by by halogen (preferably F), C in heteroaryl1~C6Alkoxy (preferably methoxyl group), fluoroform
Base, hydroxyl and C1~C6One of alkyl (preferably methyl) is a variety of replaced.
Wherein, the condition of the method for each step reaction in reaction route can be according to the method for these reactions of this field
Normal condition carry out.
In the method two of the preparation method of the Formulas I compound represented, preferably, still further comprising following step
It is rapid: by -1 compound represented of Formula IV, (preferably tetrahydrofuran, methylene chloride or N, N- dimethyl formyl in anhydrous solvent
Amine), under the action of alkali (preferably sodium hydride, potassium hydroxide, sodium tert-butoxide or sodium methoxide), with cyano phosphite ester or its etc.
Effect object is reacted, production V-2-4 compound represented；
The R1And LG is as described above.
The condition of the method for the reaction of the production V-2-4 compound represented can be according to the such reaction in this field
Method normal condition carry out.
In the method two of the preparation method of the Formulas I compound represented, preferably, still further comprising following step
Rapid: by Formula V -2-4 compound represented, (preferably bromine, N- bromo-succinimide, C5H6Br2N2O2 cross bromine pyrrole with halogenating agent
Pyridine salt etc.) reaction, available Formula V -2-5 compound represented；
The R1, X and LG as described above.
The condition of the method for the reaction of the production V-2-5 compound represented can be according to the such reaction in this field
Method normal condition carry out.
In the method two of the preparation method of the Formulas I compound represented, preferably, still further comprising following step
It is rapid: by -2 compound represented of Formula IV, with the cyano compounds such as cyan-acetic ester, cyano propanone or the third dicyan in alkalinity or nothing
Under solvent condition, condensation reaction is carried out, Formula V -2-6 compound represented is obtained；
The R1And LG is as described above.
The condition of the method for the reaction of the production V-2-6 compound represented can be according to the such reaction in this field
Method normal condition carry out.
In the method two of the preparation method of the Formulas I compound represented, preferably, still further comprising following step
It is rapid: in organic solvent (preferably n,N-Dimethylformamide, N-Methyl pyrrolidone or alcohols solvent), will to change shown in Formula IV -3
Object is closed, is performed under heating conditions and reacts with amino-compound, available -4 compound represented of Formula IV；It will be shown in Formula IV -4
Compound in a solvent with halogenating agent (preferably bromine, N- bromo-succinimide, C5H6Br2N2O2 cross bromopyridine salt etc.)
It is reacted, available -5 compound represented of Formula IV；Functional group conversions by -5 compound represented of Formula IV by routine,
Available -6 compound represented of Formula IV；In a heated condition by -6 compound represented of Formula IV, with urea, guanidine, thiocarbamide etc.
Ring closure reaction occurs for reagent, carries out the operation such as functional group conversions or deprotection base again in the case of necessary, available
Formula V -2-7 compound represented；
The R1, X and LG as described above；The R16For C1~C6Alkyl.
Wherein, the condition of the method for each step reaction in reaction route can be according to the method for these reactions of this field
Normal condition carry out.
Method three:
As the R2When for halogen or acetyl group, the preparation method of the Formulas I compound represented includes following step
It is rapid: by formula III -3-4 compound represented and 5 compound represented of formula in transition metal-catalyzed lower generation coupling reaction, to generate
The Formulas I compound represented；
The R1、R3、R4, X and Ar as described above.
The condition of coupling reaction in the method three can be the various normal conditions of the such reaction in this field.
The present invention also provides containing nitrogenous fused heterocyclic compound, its pharmaceutically acceptable salt shown in above-mentioned Formulas I, or
Person their enantiomter, diastereoisomer, tautomer, solvate, metabolic precursor thereof or prodrug pharmaceutical composition
Object.
Wherein, the pharmaceutical composition nitrogenous fused heterocyclic compound as shown in one or more Formulas I, it pharmaceutically may be used
The salt of receiving or their enantiomter, diastereoisomer, tautomer, solvate, metabolic precursor thereof or prodrug
It is formed at least one pharmaceutic adjuvant.The selection of pharmaceutic adjuvant is different because of administration method and action character, generally can be filler,
Diluent, adhesive, wetting agent, disintegrating agent, lubricant, emulsifier or suspending agent etc..
Pharmaceutical composition of the invention can by oral, injection (vein, muscle, in subcutaneous and coronary artery), it is sublingual,
Buccal, per rectum, per urethra, Via vagina, intranasal, sucking or topic route application, optimization approach is oral.
The present invention also provides above-mentioned nitrogenous fused heterocyclic compounds shown in formula I, its pharmaceutically acceptable salt, or
Their enantiomter, diastereoisomer, tautomer, solvate, metabolic precursor thereof or prodrug preparation prevention or
Treat the application on the drug of the extremely relevant disease of cell cycle regulating.
The extremely relevant disease of cell cycle regulating of the disease preferred cycle protein dependent kinase regulation.
The cyclin-dependent kinase preferred CDK4 and/or CDK6.
The extremely relevant tumour of disease preferred cell cycle regulating.
The present invention also provides above-mentioned nitrogenous fused heterocyclic compounds shown in formula I, its pharmaceutically acceptable salt, or
Their enantiomter, diastereoisomer, tautomer, solvate, metabolic precursor thereof or prodrug is in manufacturing cycle egg
Application on white dependant kinase inhibitors.The cyclin-dependent kinase is as described above.
The present invention also provides above-mentioned nitrogenous fused heterocyclic compounds shown in formula I, its pharmaceutically acceptable salt, or
Their enantiomter, diastereoisomer, tautomer, solvate, metabolic precursor thereof or prodrug has swollen in preparation
Application on the drug of oncocyte inhibitory activity.
The preferred cancer cell of the tumour cell.The preferred breast cancer cell of the cancer cell.The breast cancer cell
It is preferred that breast cancer cell MCF-7.
On the basis of common knowledge of the art, above-mentioned each optimum condition, can any combination to get each preferable reality of the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: the present invention provides a kind of new structural nitrogenous fused heterocyclic compound,
Its pharmacodynamics and pharmacokinetics embodiment test data are shown: it has choosing to cyclin-dependent kinase in molecular level
Selecting property inhibiting effect, and specificity is high, activity is strong；In cellular level and animal level to active with cyclin-dependent kinase
Relevant tumour cell also has significant Inhibit proliferaton effect；The compounds of this invention stablizes the hepatomicrosome of people, mouse etc.
Property it is good, metabolic enzyme inhibits without obvious, and rats and mice body absorption property is good, and bioavilability is high, has preferable druggability.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
The structure of all compounds of the present invention can by nuclear magnetic resonance (1H NMR) and/or Mass Spectrometer Method (MS) identification.1H
Nmr chemical is displaced (δ) with PPM record (10-6).NMR is carried out by Bruker AVANCE-400 spectrometer.
LC-MS measures by Agilent 1200HPLC/6120 mass spectrograph
Thin layer silica gel plate is Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate.Column chromatography generally uses the Yantai Huanghai Sea
200-300 mesh silica gel is as carrier.
Embodiment 1 ' (preparation of intermediate):
Step 1:
Bis- chloro- 4- methyl 3-cyanopyridine (5g, 26.7mmol) (such as formula 1-a compound represented) of 2,6- is placed in seal pipe
In, tert-butylamine (3.12mL, 29.4mmol) and DIPEA (5.3mL, 32.1mmol) are added thereto, is heated to 120 DEG C of reactions
18h.Reaction solution is cooled to room temperature after reaction, and reaction solution is diluted with ethyl acetate, water washing, and organic phase anhydrous sodium sulfate is dry
Dry, silica gel column chromatography purifies (PE:EA=80:20 elution), obtains white solid 1.77g (such as formula 1-b compound represented).1H-
NMR(400MHz,CDCl3): δ=6.15 (1H, s), 5.00 (1H, s), 2.37 (3H, s), 1.44 (9H, s) .LC-MS m/z:(M
+H)+=224.10.
Step 2:
By (the change as shown in formula 1-b of the chloro- 4- methyl 3-cyanopyridine (1.77g, 7.94mmol) of 6- (tert-butyl amino) -2-
Close object) it is dissolved in 40mL glacial acetic acid, the bromine water (0.49ml, 9.53mmol) being dissolved in 5mL glacial acetic acid, room temperature reaction are added dropwise thereto
1h, solvent evaporated, residue are dissolved in ethyl acetate, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution after reaction
Washing, organic phase are dried, filtered with anhydrous sodium sulfate, solvent evaporated, and silica gel column chromatography purifies (PE:EA=90:10 elution), are obtained
White solid 1.723g (such as formula 1-c compound represented).1H-NMR(400MHz,CDCl3): δ=5.66 (1H, s), 2.51
(3H,s),1.49(9H,s).LC-MS m/z:(M+H)+=302.00.
Step 3:
By the chloro- 4- methyl 3-cyanopyridine (1g, 3.3mmol) of the bromo- 6- of 5- (tert-butyl amino) -2- (as shown in formula 1-c
Compound) be dissolved in 20mL anhydrous methylene chloride, be cooled to -78 DEG C under argon gas protection, be added dropwise thereto DIBAL-H (3.3ml,
3.3mmol, 1M in THF), -78 DEG C of reaction 2h rise back room temperature after reaction, and 1N hydrochloric acid solution is added thereto by pH value
It is adjusted to 2-3,0.5h is stirred at room temperature in reaction solution, and following reaction liquid is adjusted to alkalinity with 1N NaOH solution, and rear ethyl acetate extraction has
Machine is mutually dried, filtered with anhydrous sodium sulfate, solvent evaporated, and silica gel column chromatography purifies (PE:EA=90:10 elution), is obtained white solid
Body 0.943g (such as formula 1-d compound represented).1H-NMR(400MHz,CDCl3): δ=10.31 (1H, s), 5.81 (1H, s),
2.69(3H,s),1.52(9H,s).LC-MS m/z:(M+H)+=305.00.
Step 4:
By the chloro- 4- methyl nicotine aldehyde (261mg, 0.86mmol) of the bromo- 6- of 5- (tert-butyl amino) -2- (such as formula 1-d institute
The compound shown) and potassium tert-butoxide (290mg, 2.58mmol) be dissolved in 9ml NMP, thereto be added guanidine hydrochloride (411mg,
4.3mmol), microwave heating is cooled to room temperature after reaction to 180 DEG C of reaction 30min, 9ml water, reaction solution is added thereto
10min is stirred at room temperature, the solid filtering subsequently generated is washed with a small amount of methanol, and it is dry, yellow solid 86mg is obtained (such as formula 1-e institute
The compound shown).1H-NMR (400MHz, d-DMSO): δ=8.91 (1H, s), 6.87 (2H, s), 5.90 (1H, s), 2.56
(3H,s),1.50(9H,s).LC-MS m/z:(M+H)+=310.10.
Step 5:
By the bromo- N of 6-7(tert-butyl) -5- picoline simultaneously [2,3-d] pyrimidine -2,7- diamines (86mg, 0.28mmol)
(such as formula 1-e compound represented) is dissolved in 2.8ml trifluoroacetic acid and 0.3ml water, is heated to 80 DEG C of reaction 18h, and reaction terminates
After be cooled to room temperature, 3ml water is added in solvent evaporated thereto, after with ammonium hydroxide be adjusted to alkalinity, 10min is stirred at room temperature in reaction solution, with
The solid filtering generated afterwards, is washed with water, dry, obtains yellow solid 68mg (such as formula 1-f compound represented).LC-MS m/z:
(M+H)+=254.00.
Embodiment 2 ' (preparation of intermediate):
Step 1:
Sodium hydride (1.092g, 27.3mmol) is dissolved in 25ml anhydrous tetrahydro furan, is added thereto in the case where 0 DEG C of argon gas is protected
Enter cyanogen methyl acid phosphate diethylester (2.66ml, 16.38mmol), react at room temperature 0.5h, after be added be dissolved in 5ml THF thereto
1- (4- amino -2- (methyl mercapto) pyrimidine -5- base) ethyl ketone (1g, 5.46mmol) (such as Formulas I -16-e compound represented), room temperature
Reaction is overnight.After reaction, Shui temper is slowly added into reaction solution to go out, after be extracted with ethyl acetate, the anhydrous sulphur of organic phase
Sour sodium dries, filters, solvent evaporated, and silica gel column chromatography purifies (DCM:MeOH=97:3 elution), obtains yellow solid 635mg (such as
Formula 2-a compound represented).1H-NMR (400MHz, d-DMSO): δ=8.93 (1H, s), 7.33 (2H, s), 6.54 (1H, d, J
=1.2Hz), 2.51 (3H, s), 2.48 (3H, d, J=0.8Hz) .LC-MS m/z:(M+H)+=207.00.
Step 2:
By 5- methyl -2- (methyl mercapto) pyrido [2,3-d] pyrimidine -7- amine (650mg, 3.14mmol) (as shown in formula 2-a
Compound) be dissolved in 15ml anhydrous tetrahydro furan, be added and be dissolved in 15ml anhydrous methylene chloride thereto in the case where 0 DEG C of argon gas is protected
Sulfonic acid chloride (2.54ml, 31.4mmol), react at room temperature 1h.After reaction, unsaturated carbonate hydrogen is slowly added into reaction solution
Sodium Shui Rong Ye temper goes out, after be extracted with dichloromethane, organic phase is dried, filtered with anhydrous sodium sulfate, solvent evaporated, silica gel column chromatography
It purifies (DCM:MeOH=97:3 elution), obtains yellow solid 313mg (such as formula 2-b compound represented).1H-NMR(400MHz,
D-DMSO): δ=9.04 (1H, s), 7.67 (2H, s), 6.67 (1H, d, J=1.2Hz), 2.52 (3H, s) .LC-MS m/z:(M+
H)+=195.10.
Step 3:
By chloro--methylpyridine simultaneously [2,3-d] pyrimidine -7- amine (224mg, the 1.16mmol) (chemical combination as shown in formula 2-b
Object) it is dissolved in 10ml DMF, C5H6Br2N2O2 (363mg, 1.27mmol) is added thereto, room temperature reaction is overnight.After reaction, to
Slowly add water 30ml in reaction solution, the solid filtering of generation is dry, obtains the yellow solid 180mg (chemical combination as shown in formula 2-c
Object).LC-MS m/z:(M+H)+=272.90.
Embodiment 3 ' (preparation of intermediate):
Step 1:
By (the change as shown in Formulas I -16-e of 1- (4- amino -2- (methyl mercapto) pyrimidine -5- base) ethyl ketone (1g, 5.46mmol)
Close object) it is dissolved in ethyl acetoacetate (3ml, 27.85mmol), it is heated to 180 DEG C of reaction 3h and is cooled to room temperature after reaction,
Ethyl acetate 10ml is added into reaction solution, insoluble solid filtering is dry, obtains yellow solid 1.069g (as shown in formula 3-a
Compound).1H-NMR (400MHz, d-DMSO): δ=12.60 (1H, s), 9.02 (1H, s), 2.58 (3H, s), 2.44 (3H,
s),2.34(3H,s).LC-MS m/z:(M+H)+=250.05.
Step 2:
By 6- acetyl group -5- methyl -2- (methyl mercapto) pyrido [2,3-d] pyrimidine -7 (8H) -one (0.353g,
It 1.42mmol) is dissolved in phosphorus oxychloride (3ml, 32.77mmol) (such as formula 3-a compound represented), 110 DEG C is heated to and reacted
Night is cooled to room temperature after reaction, solvent evaporated, and residue is dissolved in saturated sodium bicarbonate solution, ethyl acetate extraction, nothing
Aqueous sodium persulfate dries organic phase, filtering, and solvent evaporated obtains yellow solid 400mg (such as formula 3-b compound represented), without pure
Change, direct plunges into next reaction.LC-MS m/z:(M+H)+=268.00.
Step 3:
By 1- (chloro- 5- methyl -2- (methyl mercapto) pyrido [2,3-d] pyrimidine -6- base of 7-) ethyl ketone (0.4g, 1.49mmol)
(such as formula 3-b compound represented) is dissolved in ammonium hydroxide (5ml), is heated to 100 DEG C of reactions overnight, after reaction, is cooled to room temperature,
Solvent evaporated, residue silica gel column chromatography purify (DCM:MeOH=95:5 elution), obtain yellow solid 200mg (as shown in formula 3-c
Compound).LC-MS m/z:(M+H)+=249.10.
Embodiment 4 ' (preparation of intermediate):
Step 1:
Potassium tert-butoxide (4.3g) is dispersed in anhydrous THF (150mL), ice-water bath is cooling, is slowly added under nitrogen protection
Phosphonoacetate (7mL), 0 DEG C is stirred to react 1h, and 2- methyl mercapto -4- amino-5-pyrimidine formaldehyde (5g) (such as Formulas I-is added
1-d compound represented), reaction 18h is stirred at room temperature.Water is added after reaction, ethyl acetate extraction merges organic layer, does
It is dry, solvent is evaporated off and obtains white solid (7g, 99%) (such as formula 4-a compound represented):1H NMR(CDCl3,400MHz):δ
1.35(t,3H),2.54(s,3H),4.28(q,2H),5.28(br,2H),6.33(d,1H),7.56(d,1H),8.29(s,
1H).ESI-MS m/z 239.7[M+H]+。
Step 2:
By (E)-ethyl -3- (4- amino -2- (methyl mercapto) pyrimidine -5- base) acryloyl group (14g) (as shown in formula 4-a
Compound) it is dissolved in methanol (200ml), it is added methanol solution of sodium methylate (21mL), 80 DEG C are stirred to react 6h.It is evaporated off after reaction
Solvent is added water dissolution, is adjusted to pH=8 with 2N hydrochloric acid, product is largely precipitated, and white solid (8g, 73%) is obtained by filtration (such as formula
4-b compound represented):1H NMR(DMSO-d6,400MHz):δ2.56(s,3H),6.50(d,1H),7.89(d,1H),8.84
(s,1H),12.37(br,1H).ESI-MS m/z 193.9[M+H]+。
Step 3:
Simultaneously [2,3-d] pyrimidin-7-ones (300mg) (such as formula 4-b compound represented) are dispersed in ice vinegar to 2- methylsulfanyl pyridine
Sour (10ml) is added bromine (0.16mL), and reaction 48h is stirred at room temperature.Methylene chloride is added after reaction, filters, uses methanol
Washing, obtains white solid (390mg, 92%) (such as formula 4-c compound represented):1H NMR(DMSO-d6,400MHz):δ
2.57(s,3H),8.48(s,1H),8.85(s,1H),12.91(br,1H).ESI-MS m/z 271.9[M+H]+。
Step 4:
By 2- methyl mercapto -6- bromopyridine, simultaneously [2,3-d] pyrimidin-7-ones (300mg) (such as formula 4-c compound represented) disperse
At phosphorus oxychloride (20mL), 110 DEG C are stirred to react 16h.Solvent is evaporated off after reaction, saturated sodium bicarbonate is added under ice-water bath
Solution is adjusted to pH=8, filters to obtain white solid (290mg) (such as formula 4-d compound represented), does not purify, be directly used in next
Step.
Step 5:
By the bromo- 7- chloropyridine of 2- methyl mercapto -6-, simultaneously [2,3-d] pyrimidine (290mg) (such as formula 4-d compound represented) is dissolved in
Reaction 72h is stirred at room temperature in 7N methanolic ammonia solution (50mL).Solvent is evaporated off after reaction, obtains crude white solid (310mg)
(such as Formulas I -6-c compound represented): ESI-MS m/z271.0 [M+H]+。
Embodiment 5 ' (preparation of intermediate):
Step 1:
Cyanogen methyl acid phosphate diethylester (12.5 grams, 70.6mmol) (such as Formulas I -16-e compound represented) is dissolved in tetrahydro furan
In muttering, ice bath is cooling, and sodium hydride (3 equivalent) is added in solution, stirs half an hour, 4- amido -2- methylthiopyrimidine -5- formaldehyde
(2.8 grams, 15mmol) are added at one time in solution, and the reaction solution that is stirred overnight at room temperature pours into extraction in ice water and goes out, ethyl acetate extraction
Take organic layer anhydrous magnesium sulfate dry, filtering is concentrated to dryness, gained grease rapid column chromatography (ethyl acetate: petroleum ether
=1:1) obtain target compound (such as formula 5-a compound represented).1H-NMR,DMSO,8.95(s,1H),7.40(brs,
2H),6.56(s,1H),2.50(s,3H)。LC-MS:C9H10N4S calcd[M+H]+207.065,found 207.0
Step 2:
By 5- methyl -7- amido -2- methylsulfanyl pyridine [2,3-d] pyrimidine (1.0 grams, 4.8mmol) (as shown in formula 5-a
Compound) it is dissolved in 20 milliliters of tetrahydrofurans, room temperature is in batches for bis- bromo- 5,5- Dimethyl Hydan (1.6 grams, 5.6mmol) of 1,3-
It is added, gained mixed liquor is stirred overnight at room temperature, and pours into extraction in ice water and goes out, ethyl acetate extraction, organic layer is done with anhydrous magnesium sulfate
Dry, filtering is concentrated to dryness, gained grease rapid column chromatography (methylene chloride: methanol=10:1) obtains target yellow solid
(300 milligrams) (such as Formulas I -5-d compound represented).1H-NMR,DMSO,9.19(s,1H),2.68(s,3H),2.57(s,
3H)。LC-MS:C9H9BrN4Scalcd[M+H]+283.97,found 284.1。
Embodiment 1:
Step 1:
By (the change as shown in Formulas I -16-e of 1- (4- amino -2- (methyl mercapto) pyrimidine -5- base) ethyl ketone (5.49g, 30mmol)
Close object) be dissolved in 2-methyl cellosolve (20mL), be added thereto malononitrile (5.94g, 90mmol) and ammonium acetate (11.55g,
150mmol), 130 DEG C of reaction 2h are heated to.Reaction solution is cooled to room temperature after reaction, the solid filtering of generation, with water and second
Alcohol washing, it is dry, 7- amino -5- methyl -2- (methyl mercapto) pyrido [2,3-d] pyrimidine -6- formonitrile HCN is obtained (such as Formulas I -16-d institute
The compound shown), it is yellow solid 4.905g.1H-NMR (400MHz, d-DMSO): δ=9.14 (1H, s), 7.84 (2H, s),
2.75(3H,s),2.54(3H,s)。LC-MS m/z:(M+H)+=232.00.
Step 2:
(such as by 7- amino -5- methyl -2- (methyl mercapto) pyrido [2,3-d] pyrimidine -6- formonitrile HCN (171mg, 0.74mmol)
Formulas I -16-d compound represented) it is dissolved in dry DMF (10mL), bromacetone (0.12mL, 1.47mmol) is added thereto, adds
Heat is to 80 DEG C of reaction 48h.Reaction solution Jia Ru Shui temper goes out after reaction, ethyl acetate extraction, the dry organic phase of anhydrous sodium sulfate,
Filtering, solvent evaporated, residue silica gel column chromatography purify to obtain 5,8- dimethyl -2- (methyl mercapto) imidazo [1', 2':1,6]
Pyrido [2,3-d] pyrimidine -6- formonitrile HCN (such as Formulas I -16-c compound represented) is yellow solid 100mg.1H-NMR
(400MHz,d-DMSO):δ9.44(1H,s),8.27(1H,s),2.83(3H,s),2.71(3H,s),2.40(3H,s)。LC-MS
m/z:(M+H)+=269.95.
Step 3:
By 5,8- dimethyl -2- (methyl mercapto) imidazo [1', 2':1,6] pyrido [2,3-d] pyrimidine -6- formonitrile HCN
(121mg, 0.45mmol) (such as Formulas I -16-c compound represented) be dissolved in chloroform (7mL) be added thereto m-CPBA (303mg,
1.35mmol, 77%), react at room temperature 2h.Reaction solution is washed with saturated sodium bicarbonate solution after reaction, and anhydrous sodium sulfate is dry
Dry organic phase, filtering, solvent evaporated obtain 5,8- dimethyl -2- (methylsulfonyl) imidazo [1', 2':1,6] pyrido [2,3-
D] pyrimidine -6- formonitrile HCN (such as Formulas I -16-b compound represented), it is yellow solid, direct plunges into and react in next step.1H-NMR
(400MHz,CDCl3): δ=9.53 (1H, s), 8.27 (1H, s), 3.49 (3H, s), 3.00 (3H, s), 2.57 (3H, s).LC-
MS m/z:(M+H)+=301.90.
Step 4:
By 5,8- dimethyl -2- (methylsulfonyl) imidazo [1', 2':1,6] pyrido [2,3-d] pyrimidine -6- formonitrile HCN
(135mg, 0.45mmol) (such as Formulas I -16-b compound represented) is dissolved in chloroform (7mL), and tert-butyl 4- (4- ammonia is added thereto
Base phenyl) piperazine -1- carboxylate (125mg, 0.45mmol), heated overnight at reflux.After reaction, solvent evaporated, residue
Silica gel column chromatography purifies to obtain tert-butyl 4- (4- ((6- cyano -5,8- dimethyl-imidazo [1', 2':1,6] pyrido [2,3-
D] pyrimidine -2-base) amino) phenyl) piperazine -1- carboxylate (such as Formulas I -16-a compound represented) is yellow solid 28mg.1H-NMR(400MHz,CDCl3):δ9.01(1H,s),7.89(1H,s),7.60(2H,d),7.01(2H,d),3.62(4H,t,J
=4.8Hz), 3.16 (4H, t, J=4.8Hz), 2.83 (3H, s), 2.51 (3H, s), 1.50 (9H, s).LC-MSm/z:(M+H)+
=499.00.
Step 5:
By tert-butyl 4- (4- ((6- cyano -5,8- dimethyl-imidazo [1', 2':1,6] pyrido [2,3-d] pyrimidine -
2- yl) amino) phenyl) piperazine -1- carboxylate (28mg, 0.056mmol) (such as Formulas I -16-a compound represented) is dissolved in dichloro
4M HCl/dioxane (0.5mL) is added thereto and reacts at room temperature 1h for methane (5mL).Reaction solution saturated carbon after reaction
Sour hydrogen sodium solution washing, the dry organic phase of anhydrous sodium sulfate, filtering, solvent evaporated, residue silica gel column chromatography purify to obtain formula
I-16 compound represented is Chinese red solid 21mg.1H-NMR (400MHz, d-DMSO): δ=10.54 (1H, s), 9.26
(1H, s), 8.00 (1H, s), 7.79 (2H, s), 7.04 (2H, d), 3.26 (4H, t, J=4.4Hz), 3.13 (4H, t, J=
4.8Hz),2.78(3H,s),2.40(3H,s).LC-MS m/z:(M+H) +=399.00.
Embodiment 2:
By 5,8- dimethyl -2- (methylsulfonyl) imidazo [1', 2':1,6] pyrido [2,3-d] pyrimidine -6- formonitrile HCN (such as formula
I-16-b compound represented) (135mg, 0.45mmol) be dissolved in chloroform (7mL), be added thereto 4- morpholine aniline (80mg,
0.45mmol), heated overnight at reflux.After reaction, solvent evaporated, residue silica gel column chromatography purify to obtain such as -17 institute of Formulas I
The compound shown is yellow solid 61mg.1H-NMR (400MHz, d-DMSO): δ=10.51 (1H, s), 9.25 (1H, s),
7.99 (1H, s), 7.77 (2H, s), 7.01 (2H, d), 3.76 (4H, t, J=4.0Hz), 3.10 (4H, t, J=4.4Hz), 2.77
(3H,s),2.39(3H,s)。LC-MS m/z:(M+H)+=400.00.
Embodiment 3:
Step 1:
By the bromo- 7- aminopyridine of 2- methyl mercapto -6- simultaneously [2,3-d] pyrimidine (such as Formulas I -6-c compound represented) crude product
(310mg) is dissolved in DMF (30mL), is added bromacetone (248 μ L), 80 DEG C are stirred to react 16h.Water, acetic acid are added after reaction
Ethyl ester extraction merges organic layer, dry, and solvent is evaporated off and obtains white solid 70mg, is such as Formulas I -6-b compound represented:
ESI-MS m/z 309.0[M+H]+。
Step 2:
Intermediate (such as Formulas I -6-b compound represented) (230mg) obtained by upper step is dissolved in chloroform (30mL), content is added
77% metachloroperbenzoic acid (340mg) is stirred at room temperature reaction 4h, 4- (4- tert-butoxycarbonyl-piperazine) aniline is added
(140mg), 70 DEG C are stirred to react 18h.Solvent is evaporated off after reaction, water is added, ethyl acetate extraction merges organic layer, does
It is dry, solvent is evaporated off, column chromatographic purifying (petroleum ether: ethyl acetate=10:1) obtains yellow solid (32mg) (as shown in Formulas I -6-a
Compound):1H NMR(CDCl3,400MHz):δ1.52(s,9H),2.56(s,3H),3.17(t,4H),3.63(t,4H),
7.03(d,2H),7.63(d,2H),7.64(s,1H),8.06(s,1H),8.81(s,1H).ESI-MS m/z 537.8 [M+
H]+。
Step 3:
Intermediate (such as Formulas I -6-a compound represented) (8mg) obtained by upper step is dissolved in methylene chloride (1mL), 4N is added
Reaction 5h is stirred at room temperature in the dioxane solution (1mL) of HCl.Solvent is evaporated off after reaction, is washed with methanol, is obtained by filtration
Red solid (6mg) (such as -6 compound represented of Formulas I):1H NMR(D2O,400MHz):δ2.32(s,3H),3.34(t,4H),
3.37(t,4H),6.61(d,2H),6.78(d,2H),7.53(s,1H),7.79(s,1H),8.56(s,1H).ESI-MS m/
z437.9[M+H]+。
Embodiment 4:
Starting material (such as Formulas I -6-a compound represented) (10mg) is dissolved in anhydrous dioxane (10mL), is added three
Butyl (1- ethoxy ethylene) tin (223 μ L), bi triphenyl phosphorus palladium chloride (6.5mg), lower 110 DEG C of nitrogen protection are stirred to react
14h.Potassium fluoride dihydrate (35mg) is added after reaction, 4N HCl dioxane (0.5ml) is stirred at room temperature 2h, is evaporated off
Solvent, Thin Layer Chromatography (methylene chloride: methanol=10:1) obtain yellow solid (4mg) (such as -7 compound represented of Formulas I)
:1H NMR(D2O,400MHz):δ2.31(s,3H),3.04(s,3H),3.34(t,4H),3.37(t,4H),6.60(d,2H),
6.79(d,2H),7.53(s,1H),7.79(s,1H),8.56(s,1H).ESI-MS m/z 402.0[M+H]+。
Embodiment 5:
Step 1:
Cyanogen methyl acid phosphate diethylester (2.5 grams, 14mmol) (such as Formulas I -1-d compound represented) is dissolved in tetrahydrofuran
In, ice bath is cooling, and potassium tert-butoxide (3 equivalent) is added in solution, stirs half an hour, 4- amido -2- methylthiopyrimidine -5- formaldehyde
(2.0 grams, 11.82mmol) are added at one time in solution, and the reaction solution that is stirred overnight at room temperature pours into extraction in ice water and goes out, acetic acid second
Ester extracts the anhydrous magnesium sulfate drying of organic layer, and filtering is concentrated to dryness, gained grease rapid column chromatography (methylene chloride: first
Alcohol=10:1) obtain target compound (such as Formulas I -1-c compound represented).1H-NMR,DMSO,8.82(s,1H),7.93(d,
1H, J=8.8Hz), 7.44 (brs, 1H), 6.73 (d, 1H, J=8.8Hz), 2.50 (s, 3H).LC-MS:C8H8N4S calcd
[M+H]+193.05,found 193.0.
Step 2:
By (the change as shown in Formulas I -1-c of 2- methyl mercapto -7- amido-pyridine [2,3-d] pyrimidine (500 milligrams, 2.6mmol)
Close object) it is dissolved in 2 milliliters of DMF, it is added 1- bromacetone (500 milligrams, 3.65mmol), gained reaction solution is heated to 50 DEG C of reactions
It 12 hours, pouring into ice water, solution is extracted with (50 milliliter * 3) of ethyl acetate, and gained organic layer anhydrous sodium sulfate is dry, it filters,
It is concentrated to dryness, gained crude product rapid column chromatography separation (ethyl acetate: petroleum ether=1:2) obtains target compound (120 milligrams)
(such as Formulas I -1-b compound represented).1H-NMR, MeOD, 9.11 (s, 1H), 8.19 (s, 1H), 7.66 (d, 1H, J=
9.6Hz), 7.44 (d, 1H, J=9.6Hz), 2.73 (s, 3H), 2.49 (s, 3H).LC-MS:C11H10N4S calcd[M+H]+
231.06,found 230.9.
Step 3:
Methyl mercapto compound (such as Formulas I -1-b compound represented) is dissolved in 5 milliliters of methylene chloride for 120 milligrams,
Metachloroperbenzoic acid (1.1 equivalent) is added in room temperature, is stirred at room temperature 3 hours, and LC-MS detection reaction is completed, saturated sodium bicarbonate
Solution extracts reaction of going out, and dichloromethane layer is separated, and anhydrous sodium sulfate is dry, filters, is concentrated to dryness, gained crude product (such as Formulas I-
1-a compound represented) it is directly used in next step
Step 4:
Crude product (such as Formulas I -1-a compound represented) obtained by upper step is dissolved in 5 milliliters of chloroform, 4- morpholine is added
Base-aniline (100 milligrams, 0.56mmol), gained dark solution heated overnight at reflux, for revolving to doing, gained crude product is directly quick
Column chromatography, obtains 30 milligrams of target compound (such as -1 compound represented of Formulas I).1H-NMR,DMSO,10.06(brs,1H),
9.07 (s, 1H), 8.02 (s, 1H), 7.77 (d, 2H, J=8.0Hz), 7.55 (d, 1H, J=9.2Hz), 7.24 (d, 1H, J=
9.6Hz), 7.01 (d, 2H, J=9.2Hz), 3.76 (t, 4H, J=4.8Hz), 3.10 (t, 4H, J=4.8Hz), 2.16 (s,
3H)。LC-MS:C20H20N6Ocalcd[M+H]+361.17,found 360.9
Embodiment 6:
Using the method for embodiment 5, compound I-1-a is first synthesized, is then closed using the method for the last two steps of embodiment 1
At obtaining such as Formulas I -2 compound represented 1H-NMR, DMSO, 9.18 (s, 1H), 8.90 (brs, 1H), 8.13 (s, 1H), 7.82-
7.76 (m, 3H), 7.37 (d, 1H, J=8.8Hz), 7.08-7.04 (m, 2H), 3.28-3.12 (m, 8H), 2.45 (s, 3H).LC-
MS:C20H21N7calcd[M+H]+360.1,found 360.0。
Embodiment 7:
Step 1:
By the bromo- 5- methyl -2- methyl mercapto -7- amido of 6--pyridine [2,3-d] pyrimidine (500 milligrams, 2.6mmol) (such as Formulas I -
5-d compound represented) it is dissolved in 5 milliliters of DMF, it is added 1- bromacetone (400 milligrams, 2.62mmol), gained reaction solution adds
Heat is reacted 12 hours to 50C, is poured into ice water, and solution is extracted with (50 milliliter * 3) of ethyl acetate, gained organic layer anhydrous slufuric acid
Sodium is dry, filters, is concentrated to dryness, and gained crude product rapid column chromatography separation (ethyl acetate: petroleum ether=1:2) obtains target chemical combination
Object (120 milligrams) (such as Formulas I -5-c compound represented).1H-NMR,DMSO,9.37(s,1H),8.29(s,1H),2.71(s,
3H),2.69(s,3H),2.39(s,3H)。LC-MS:C12H11BrN4Scalcd[M+H]+322.9,found322.8.
Step 2:
Above-mentioned 200 milligrams of methyl mercapto compound (such as Formulas I -5-c compound represented) is dissolved in 5 milliliters of chloroform
In, metachloroperbenzoic acid (1.1 equivalent) is added in room temperature, is stirred at room temperature 3 hours, and LC-MS detection reaction is completed, unsaturated carbonate hydrogen
Sodium solution extracts reaction of going out, and chloroform layer is separated, and anhydrous sodium sulfate is dry, filters, is concentrated to dryness, gained crude product is (such as formula
I-5-b compound represented) it is directly used in next step
Step 3:
Crude product (such as Formulas I -5-b compound represented) obtained by upper step is dissolved in 5 milliliters of chloroform, 4- (4- amine is added
Base phenyl) piperidines -1- carboxylic acid tert-butyl ester (200 milligrams, 0.72mmol), gained dark solution heated overnight at reflux, revolving to dry,
The direct rapid column chromatography of gained crude product obtains 80 milligrams of target compound (such as Formulas I -5-a compound represented)
1H-NMR, DMSO, 1017 (s, 1H), 9.21 (s, 1H), 8.07 (s, 1H), 7.75 (d, 2H, J=7.6Hz), 7.02
(d, 2H, J=9.2Hz), 3.39 (m, 4H), 3.07 (m, 4H), 2.69 (s, 3H), 2.40 (s, 3H), 1.46 (s, 9H).LC-MS:
C26H30BrN7O2calcd[M+H]+552.16,found 522.0
Step 4:
Above-mentioned 50 milligrams of boc-protected compound (such as Formulas I -5-a compound represented) is dissolved in 10 milliliters of dichloromethane
In alkane, 6N hydrochloric acid/1,4- dioxane solution is added, is stirred overnight at room temperature, is spin-dried for, water dissolution is transferred to PH7.0 with ammonium hydroxide, is revolved
Dry, rapid column chromatography separates (methylene chloride: methanol=10:1) and obtains 2.2 milligrams of (chemical combination as shown in Formulas I -5 of target compound
Object)
1H-NMR,DMSO,10.15(s,1H),9.18(s,1H),8.04(s,1H),7.80-7.73(m,2H),6.99-
6.88(m,2H),3.08(brs,4H),3.00(brs,4H),2.67(s,3H),2.39(s,3H).
LC-MS:C21H22BrN7calcd[M+H]+452.1,found 452.0
Embodiment 8:
Step 1:
Starting material (80 milligrams, 0.1448mmol) (such as Formulas I -5-a compound represented) is dissolved in 5 milliliters of 1,4- bis-
In six ring of oxygen, it is added tributyl ethoxy ethylene tin (200 milligrams, 0.5537mmol), Pd (PPh3) 2Cl2 (50 milligrams), argon gas
Protection is heated to 110 and spends night reaction solution to be cooled to room temperature, and is added potassium fluoride (500 milligrams), 6N hydrochloric acid, room temperature is then added
It is stirred overnight the rotation of reaction solution obtained by and removes organic solvent, aqueous solution is transferred to PH7.0 with ammonium hydroxide, and ethyl acetate extracts, and organic layer is anhydrous
Sodium sulphate is dry, filtering, is concentrated to dryness crude product rapid column chromatography (methylene chloride: methanol=10:1) obtained by and provides target chemical combination
Object (11 milligrams) (such as -3 compound represented of Formulas I).1H-NMR,DMSO,10.08(s,1H),9.19(s,1H),7.97(s,
1H), 7.80 (d, 2H), 7.04 (d, 2H, J=7.2Hz), 5.79 (brs, 1H), 5.55 (brs, 1H), 3.32-3.16 (m, 8H),
2.63(s,3H),2.40(s,3H),1.49(brs,3H)。LC-MS:C23H27N7Ocalcd[M+H]+418.2,found
418.0。
Embodiment 9:
Step 1:
By 2- methyl mercapto -5- methyl -7- amino -6- pyrido [2,3-d] pyrimidinecarboxylic acid ethyl ester (500mg) (such as Formulas I -20-
G compound represented) it is dissolved in DMF (20mL), it is added bromoacetophenone (715mg), 80 DEG C are stirred to react 16h.After reaction
Water is added, ethyl acetate extraction merges organic layer, dry, it is evaporated off solvent, column chromatographic purifying (petroleum ether: ethyl acetate=10:
1) yellow solid (90mg) (such as Formulas I -20-f compound represented) is obtained:1H NMR(CDCl3,400MHz):δ1.54(t,3H),
2.68(s,3H),2.77(s,3H),4.63(q,2H),7.28-7.38(m,1H),7.45-7.48(m,2H),8.04(d,2H),
8.58(s,1H),9.16(s,1H).ESI-MS m/z 378.9[M+H]+。
Second, three steps:
Raw material (180mg) (such as Formulas I -20-f compound represented) is dissolved in chloroform (20mL), is added between content 77%
Chloroperoxybenzoic acid (220mg) is stirred at room temperature reaction 4h, 4- (4- tert-butoxycarbonyl-piperazine) aniline (131mg) is added, 70 DEG C are stirred
Mix reaction 28h.Solvent is evaporated off after reaction, water is added, methylene chloride extraction merges organic layer, and it is dry, solvent, column is evaporated off
Chromatographic purifying (petroleum ether: ethyl acetate=1:1) obtains yellow solid (63mg) (such as Formulas I -20-d compound represented):1H
NMR(CDCl3,400MHz):δ1.52(s,9H),2.65(s,3H),3.19(t,4H),3.65(t,4H),4.61(q,2H),
7.05(d,2H),7.36(d,2H),7.44-7.48(m,3H),7.65(d,2H),8.03(d,2H),8.42(s,1H),9.04
(s,1H).ESI-MS m/z 608.0[M+H]+。
Step 4:
Raw material (55mg) (such as Formulas I -20-d compound represented) is dissolved in methanol (5mL), 4N NaOH solution is added
(2mL), 70 DEG C are stirred to react 1h.Solvent is evaporated off after reaction, is adjusted to pH=8 with 2N hydrochloric acid, product is largely precipitated, and filters
To yellow solid (50mg, 96%) (such as Formulas I -20-c compound represented): ESI-MS m/z 580.0 [M+H]+。
Step 5:
Raw material (50mg) (such as Formulas I -20-c compound represented) is dissolved in DMF (5mL), HATU (49mg) and DIPEA is added
N is added after reaction 0.5h is stirred at room temperature in (22 μ L), and reaction 12h is stirred at room temperature in O- dimethyl hydroxylamine hydrochloride (12.6mg).Instead
Water is added after answering, ethyl acetate extraction merges organic layer, and it is dry, solvent, column chromatographic purifying (petroleum ether: acetic acid second is evaporated off
Ester=1:1) obtain yellow solid (25mg) (such as Formulas I -20-b compound represented): ESI-MS m/z 623.0 [M+H]+。
Step 6:
Raw material (25mg) (such as Formulas I -20-b compound represented) is dissolved in super dry THF (2mL), is delayed under 0 DEG C of nitrogen protection
It is slow that 3N methyl-magnesium-bromide diethyl ether solution (0.1mL) is added dropwise.Solvent is evaporated off after reaction, water, ethyl acetate extraction is added, merges
Organic layer, it is dry, solvent is evaporated off, column chromatographic purifying (petroleum ether: ethyl acetate=1:1) obtains yellow solid (10mg) (such as formula
I-20-a compound represented): ESI-MS m/z 578.0 [M+H]+。
Step 7:
4N HCl dioxane solution (1mL) is added in raw material (10mg) (such as Formulas I -20-a compound represented), room temperature
It is stirred to react 5h.Solvent is evaporated off after reaction, is washed with ethyl acetate, yellow solid (4mg) is obtained by filtration (such as -20 institute of Formulas I
The compound shown):1H NMR(CD3OD,400MHz):δ2.84(s,3H),2.90(s,3H),3.44(s,4H),3.48(s,3H),
7.19(s,2H),7.62(d,3H),7.84(s,2H),7.97(d,2H),8.71(s,1H),9.52(s,1H).ESI-MS m/
z479.0[M+H]+。
Embodiment 10:
4NHCl dioxane solution (1mL) is added in raw material (20mg) (such as Formulas I -20-d compound represented), room temperature is stirred
Mix reaction 5h.Solvent is evaporated off after reaction, is washed with methanol, red solid (15mg, 89%) is obtained by filtration (such as -14 institute of Formulas I
The compound shown):1H NMR(DMSO-d6,400MHz):δ1.41(t,3H),2.58(s,3H),2.87(s,4H),3.05(s,
4H),4.48(q,2H),7.03(d,2H),7.35-7.38(m,1H),7.46-7.50(m,2H),7.81(s,2H),8.07(d,
2H),8.62(s,1H),9.23(s,1H).ESI-MS m/z 509.0[M+H]+。
Embodiment 11:
4N HCl dioxane solution (1mL) is added in raw material (10mg) (such as Formulas I -20-b compound represented), room temperature
It is stirred to react 5h.Solvent is evaporated off after reaction, is washed with ethyl acetate, yellow solid (5mg, 59%) is obtained by filtration (such as formula
I-19 compound represented):1H NMR(CD3OD,400MHz):δ2.82(s,3H),3.43(s,4H),3.51(s,4H),3.57
(s,3H),3.68(s,3H),7.22(s,2H),7.63(s,3H),7.85(s,2H),7.97(s,2H),8.74(s,1H),9.49
(s,1H).ESI-MS m/z 523.0[M+H]+。
Embodiment 12:
Step 1:
By 2- methyl mercapto -5- methyl -6- cyano -7- aminopyridine simultaneously [2,3-d] pyrimidine (500mg) (such as Formulas I -16-d institute
The compound shown) it is dissolved in DMF (20mL), it is added bromoacetophenone (861mg), 80 DEG C are stirred to react 16h.It is added after reaction
Water, ethyl acetate extraction merge organic layer, dry, and solvent is evaporated off, and column chromatographic purifying (petroleum ether: ethyl acetate=10:1) obtains
To yellow solid (140mg) (such as Formulas I -95-d compound represented): ESI-MS m/z 331.9 [M+H]+。
Second, three steps:
Raw material (140mg) (such as Formulas I -95-d compound represented) is dissolved in chloroform (20mL), is added between content 77%
Chloroperoxybenzoic acid (195mg) is stirred at room temperature reaction 4h, 4- (4- tert-butoxycarbonyl-piperazine) aniline (94mg) is added, 70 DEG C are stirred
Mix reaction 28h.Solvent is evaporated off after reaction, water is added, methylene chloride extraction merges organic layer, and it is dry, solvent, column is evaporated off
Chromatographic purifying (petroleum ether: ethyl acetate=1:1) obtains yellow solid (78mg) (such as Formulas I -95-b compound represented):1H
NMR(CDCl3,400MHz):δ1.52(s,9H),2.85(s,3H),3.20(t,4H),3.65(t,4H),7.05(d,2H),
7.39(d,2H),7.46-7.50(m,3H),7.63(s,2H),8.04(d,2H),8.38(s,1H),9.03(s,1H).ESI-MS
m/z 561.0[M+H]+。
Step 4:
Raw material (56mg) (such as Formulas I -95-b compound represented) is dissolved in methanol (5mL), 4N NaOH solution is added
(0.2mL) and hydrogen peroxide (0.23mL), 30 DEG C are stirred to react 5h.Na is added after reaction2S2O3Solution washing, uses dichloro
Methane extraction, is evaporated off solvent and obtains yellow solid (10mg) (such as Formulas I -95-a compound represented): ESI-MS m/z 579.0
[M+H]+。
Step 5:
4N HCl dioxane solution (1mL) is added in raw material (10mg) (such as Formulas I -95-a compound represented), room temperature
It is stirred to react 5h.Solvent is evaporated off after reaction, is washed with ethyl acetate, yellow solid (5mg) is obtained by filtration (such as -95 institute of Formulas I
The compound shown):1H NMR(DMSO-d6,400MHz):δ2.69(s,3H),3.26-3.40(m,8H),7.14(d,2H),
7.42-7.44(m,1H),7.50-7.54(s,2H),7.90(s,2H),8.10(d,2H),8.37(br,1H),8.71(s,1H),
9.35(s,1H),9.41(br,2H).ESI-MS m/z 479.0[M+H]+。
Embodiment 13:
4N HCl dioxane solution (1mL) is added in raw material (20mg) (such as Formulas I -95-b compound represented), room temperature
It is stirred to react 5h.Solvent is evaporated off after reaction, is washed with ethyl acetate, yellow solid (15mg, 91%) is obtained by filtration (such as formula
I-15 compound represented):1H NMR(DMSO-d6,400MHz):δ2.82(s,3H),2.86(s,3H),3.06(s,4H),
7.05(s,2H),7.37-7.41(m,1H),7.48-7.52(s,2H),7.85(s,2H),8.12(s,2H),8.64(s,1H),
9.28(s,1H).ESI-MS m/z 461.0[M+H]+。
Embodiment 14:
Step 1:
By 2- methyl mercapto -5- methyl -6- cyano -7- aminopyridine simultaneously [2,3-d] pyrimidine (500mg) (such as Formulas I -16-d institute
The compound shown) it is dissolved in DMF (20mL), it is added bromo ring fourth ethyl ketone (765mg), 80 DEG C are stirred to react 16h.After reaction plus
Entering water, ethyl acetate extraction merges organic layer, and it is dry, solvent, column chromatographic purifying (petroleum ether: ethyl acetate=10:1) is evaporated off
Obtain yellow solid (160mg) (such as Formulas I -21-c compound represented):1H NMR(DMSO-d6,400MHz):δ1.99-2.05
(m,2H),2.28-2.35(m,4H),2.73(s,3H),2.84(s,3H),3.67-3.71(m,1H),8.32(s,1H),9.45
(s,1H).ESI-MS m/z 310.0[M+H]+。
Second, three steps:
Raw material (160mg) (such as Formulas I -21-c compound represented) is dissolved in chloroform (20mL), is added between content 77%
Chloroperoxybenzoic acid (238mg) is stirred at room temperature reaction 4h, 4- (4- tert-butoxycarbonyl-piperazine) aniline (115mg) is added, 70 DEG C are stirred
Mix reaction 28h.Solvent is evaporated off after reaction, water is added, methylene chloride extraction merges organic layer, and it is dry, solvent, column is evaporated off
Chromatographic purifying (petroleum ether: ethyl acetate=1:1) obtains yellow solid (56mg) (such as Formulas I -21-a compound represented):1H
NMR(CDCl3,400MHz):δ1.52(s,9H),2.01-2.14(m,2H),2.32-2.47(m,4H),2.85(s,3H),3.19
(s,4H),3.64(s,4H),3.75-3.79(m,1H),7.04(d,2H),7.62(s,2H),7.94(s,1H),9.03(s,
1H).ESI-MS m/z 539.0[M+H]+。
Step 4:
4N HCl dioxane solution (1mL) is added in raw material (20mg) (such as Formulas I -21-a compound represented), room temperature
It is stirred to react 5h.Solvent is evaporated off after reaction, is washed with ethyl acetate, yellow solid (9mg) is obtained by filtration (such as -21 institute of Formulas I
The compound shown):1H NMR(CD3OD,400MHz):δ2.07-2.29(m,2H),2.44-2.48(m,2H),2.54-2.59(m,
2H),3.03(s,3H),3.46-3.52(m,8H),3.88-3.92(m,1H),7.14-7.25(m,2H),7.70-7.84(m,
2H),8.28(s,1H),9.49(s,1H).ESI-MS m/z 439.0[M+H]+。
Embodiment 15:
Step 1:
By 2- methyl mercapto -5- methyl -6- cyano -7- aminopyridine simultaneously [2,3-d] pyrimidine (chemical combination as shown in Formulas I -16-d
Object) (250mg) be dissolved in DMF (15mL), it is added pyridine bromide ethanone hydrobromide (550mg), 80 DEG C are stirred to react 46h.Reaction
After be added water, ethyl acetate extraction merges organic layer, dry, and solvent, column chromatographic purifying (petroleum ether: ethyl acetate is evaporated off
=10:1) obtain yellow solid (90mg) (such as Formulas I -22-c compound represented):1H NMR(DMSO-d6,400MHz):δ2.76
(s,3H),2.90(s,3H),7.40-7.44(m,1H),7.96-7.97(m,1H),8.17(d,1H),8.67(d,1H),8.91
(s,1H),9.16(s,1H).ESI-MS m/z 333.0[M+H]+。
Step 2:
Raw material (such as Formulas I -22-c compound represented) (120mg) is dissolved in chloroform (20mL), is added between content 77%
Chloroperoxybenzoic acid (330mg) is stirred at room temperature reaction 4h, 4- (4- tert-butoxycarbonyl-piperazine) aniline (80mg) is added, 70 DEG C are stirred
Mix reaction 28h.Solvent is evaporated off after reaction, water is added, methylene chloride extraction merges organic layer, and it is dry, solvent, column is evaporated off
Chromatographic purifying (petroleum ether: ethyl acetate=1:1) obtains yellow solid (10mg) (such as Formulas I -22-a compound represented): ESI-
MS m/z 562.0[M+H]+。
Step 3:
4N HCl dioxane solution (1mL) is added in raw material (10mg) (such as Formulas I -22-a compound represented), room temperature
It is stirred to react 5h.Solvent is evaporated off after reaction, is washed with ethyl acetate, yellow solid (5mg) is obtained by filtration (such as -22 institute of Formulas I
The compound shown):1H NMR(CDCl3,400MHz):δ3.03(s,3H),3.10(s,4H),3.22(s,4H),6.68(d,2H),
6.84(d,2H),7.07(s,1H),7.64(s,1H),7.85(s,1H),8.35(s,1H),8.69(s,1H),8.85(s,1H),
9.06(s,1H).ESI-MS m/z 461.0[M+H]+。
Embodiment 16:
Using the synthetic method in embodiment 7, after corresponding raw material is replaced, synthesis obtains boc-protected intermediate
Compound (such as Formulas I -23-a compound represented), then the compound (100mg) is dissolved in methylene chloride, 4N HCl dioxy is added
Reaction 5h is stirred at room temperature in six ring solution (3mL).Solvent is evaporated off after reaction, is washed with ethyl acetate, it is solid that yellow is obtained by filtration
Body (42mg) (such as -23 compound represented of Formulas I):1H NMR(DMSO-d6,400MHz):δ1.37(t,3H),2.82(s,3H),
3.25(s,8H),4.37(q,2H),7.08(s,2H),7.75(s,2H),8.57(s,1H),9.12(br,2H),9.32(s,
1H).ESI-MS m/z 457.0[M+H]+。
Embodiment 17:
Using the synthetic method in embodiment 7, after corresponding raw material is replaced, synthesis obtains yellow solid (45mg)
(such as -24 compound represented of Formulas I):1H NMR(DMSO-d6,400MHz):δ0.98(t,3H),1.76(q,2H),2.75-2.78
(m,2H),2.83(s,3H),3.25(s,4H),3.42(s,4H),7.10(d,2H),7.80(s,2H),8.11(s,1H),9.36
(s,1H),9.54(br,2H).ESI-MS m/z 427.0[M+H]+。
Embodiment 18:
First and second step:
It synthesizes to obtain raw material (such as Formulas I -27-f compound represented) using the similar method of embodiment 9, by the raw material
(650mg) is dissolved in chloroform (20mL), and the metachloroperbenzoic acid (405mg) of content 77% is added, and reaction 4h is stirred at room temperature, is added
4- (4- tert-butoxycarbonyl-piperazine) aniline (389mg), 70 DEG C are stirred to react 28h.It is evaporated off solvent after reaction, is added water, two
Chloromethanes extraction merges organic layer, dry, solvent is evaporated off, column chromatographic purifying (petroleum ether: ethyl acetate=1:1) obtains yellow
Solid (130mg) (such as Formulas I -27-d compound represented): ESI-MS m/z 600.3 [M+H]+。
Step 3:
Raw material (130mg) (such as Formulas I -27-d compound represented) is dissolved in ethyl alcohol (5mL), 4N NaOH solution is added
(2mL), 70 DEG C are stirred to react 1h.Solvent is evaporated off after reaction, is adjusted to pH=8 with 2N hydrochloric acid, product is largely precipitated, and filters
To yellow solid (50mg) (such as Formulas I -27-c compound represented): ESI-MS m/z 572.3 [M+H]+。
Step 4:
Raw material (50mg) (such as Formulas I -27-c compound represented) is dissolved in DMF (5mL), HATU (50mg) and DIPEA is added
N is added after reaction 0.5h is stirred at room temperature in (22 μ L), and reaction 12h is stirred at room temperature in O- dimethyl hydroxylamine hydrochloride (12.8mg).Instead
Water is added after answering, ethyl acetate extraction merges organic layer, and it is dry, solvent, column chromatographic purifying (petroleum ether: acetic acid second is evaporated off
Ester=1:1) obtain yellow solid (53mg) (such as Formulas I -27-b compound represented): ESI-MS m/z 615.3 [M+H]+。
Step 5:
Raw material (53mg) (such as Formulas I -27-b compound represented) is dissolved in super dry THF (2mL), in 0 DEG C under nitrogen protection
3N methyl-magnesium-bromide diethyl ether solution (0.3mL) is slowly added dropwise.Solvent is evaporated off after reaction, water, ethyl acetate extraction is added, closes
And organic layer, it is dry, solvent is evaporated off, column chromatographic purifying (petroleum ether: ethyl acetate=1:1) obtains yellow solid (22mg) (such as
Formulas I -27-a compound represented):1H NMR(CDCl3,400MHz):δ1.52(s,9H),1.72-1.74(m,2H),1.81-
1.86(m,4H),2.14-2.16(m,2H),2.58(s,3H),2.88(s,3H),3.17(t,4H),3.25-3.29(m,1H),
3.64(t,4H),7.03(d,2H),7.47(br,1H),7.64(d,2H),7.90(s,1H),9.04(s,1H).ESI-MS m/z
570.3[M+H]+。
Step 6:
4N HCl dioxane solution (1mL) is added in raw material (22mg) (such as Formulas I -27-a compound represented), room temperature
It is stirred to react 5h.Solvent is evaporated off after reaction, is washed with ethyl acetate, yellow solid (15mg) (such as Formulas I -27 is obtained by filtration
Compound represented):1H NMR(CDCl3,400MHz):δ1.73-1.75(m,2H),1.81-1.84(m,4H),2.12-2.18
(m,2H),2.58(s,3H),2.89(s,3H),3.11(s,4H),3.20(s,4H),3.25-3.30(m,1H),7.03(d,
2H),7.42(br,1H),7.63(d,2H),7.90(s,1H),9.04(s,1H).ESI-MS m/z 470.3[M+H]+。
Embodiment 19:
Using the synthetic method in embodiment 18, after corresponding raw material is replaced, synthesis is obtained as shown in Formulas I -13
Compound.1H-NMR,DMSO,10.22(s,1H),9.25(s,1H),7.93(s,1H),7.79(m,2H),7.05(m,2H),
3.33-3.29(m,5H),3.22-3.16(m,4H),2.76(s,3H),2.51(s,3H),1.40(d,6H).LC-MS:
C25H29N7Ocalcd[M+H]+444.24,found 444.0.
Embodiment 20:
Using the synthetic method in embodiment 18, after corresponding raw material is replaced, synthesis is obtained as shown in Formulas I -12
Compound.1H-NMR,DMSO(δ),10.25(s,1H),9.25(s,1H),7.88(s,1H),7.77(m,2H),7.05(m,
2H),3.29(m,4H),3.19(m,4H),2.51(s,3H),1.46(s,9H)。LC-MS:C26H31N7Ocalcd[M+H]+
458.26,found 458.0.
Embodiment 21:
Using the synthetic method in embodiment 18, after corresponding raw material is replaced, synthesis is obtained as shown in Formulas I -30
Compound.1H-NMR,DMSO(δ),10.22(s,1H),9.24(s,1H),7.91(s,1H),7.75(m,2H),7.03(m,
2H),3.15-3.09(m,4H),2.90-2.94(m,2H),2.75-2.72(m,4H),2.65-2.62(m,2H),2.51(s,
3H),2.07-2.04(m,2H),1.82-1.76(m,2H),1.52-1.24(m,6H).LC-MS:C28H33N7Ocalcd[M+
H]+484.27,found 484.2.
Embodiment 22:
Using the synthetic method in the first step of embodiment 18, second step and the 6th step, after corresponding raw material is replaced,
Synthesis is obtained such as -25 compound represented of Formulas I.1H-NMR,DMSO(δ),9.19(s,1H),7.88(s,1H),7.73(m,2H),
7.00(m,2H),4.45(q,2H),3.05(m,4H),2.86(m,4H),2.70(m,1H),2.52(s,3H),2.04-1.89
(m,2H),1.81-1.69(m,3H),1.48-1.17(m,8H).LC-MS:C29H35N7O2calcd[M]+513.29,found
513.2.
Embodiment 23:
It synthesizes to obtain as shown in Formulas I -94 using the synthetic method in the first step of embodiment 18, second step and the 6th step
Compound.1H-NMR,DMSO(δ),9.19(s,1H),7.88(s,1H),7.73(m,2H),7.00(m,2H),4.45(q,2H),
3.05(m,4H),2.86(m,4H),2.70(m,1H),2.52(s,3H),2.04-1.89(m,2H),1.81-1.69(m,3H),
1.48-1.17(m,8H).LC-MS:C28H34N8O2calcd[M]+515.28,found 515.3.
Embodiment 24:
Using the synthesis side of the synthetic method in embodiment 18 in the first step, second step, third step, the 4th step and the 6th step
Method, after corresponding raw material is replaced, synthesis is obtained such as -28 compound represented of Formulas I.1H-NMR,DMSO(δ),10.19(s,
1H),9.18(s,1H),7.89(s,1H),7.79(m,2H),7.05(m,2H),3.48(s,3H),3.38(s,3H),3.31-
3.30(m,4H),3.18-3.17(m.4H),2.72-2.68(m,1H),2.45(s,3H),2.02-1.96(m,2H),1.81-
1.1.70(m,3H),1.54-1.35(m,5H).LC-MS:C29H36N8O2calcd[M+H]+529.30,found 529.3.
Embodiment 25:
It, will be corresponding using the synthetic method in embodiment 18 in the first step, second step, third step, the 4th step and the 6th step
After raw material is replaced, synthesis is obtained such as -29 compound represented of Formulas I.1H-NMR,DMSO(δ),10.20(s,1H),9.19
(s,1H),7.89(s,1H),7.79(m,2H),7.06(m,2H),3.31(m,4H),3.22-3.17(m,5H),3.09(s,
3H),2.81(s,3H),2.43(s,3H),2.06-1.99(m,2H),1.82-1.79(m,3H),1.47-1.17(m,5H).LC-
MS:C29H36N8Ocalcd[M+H]+513.30,found 513.3.
Effect example 1 (activity data of the compound of the present invention in kinases and cellular level)
Test method:
1, CDK kinase inhibiting activity experiment usesUltra technology, when ATP concentration is Km, respectively
Test-compound is screened on CDK4/CycD3, CDK6/CycD3 kinases.In test process, test-compound is initially dense
Degree is selected as 3333nM, and each test-compound selects 10 gradient dilution concentration, and gradient dilution multiple is 3 times, every concentration 1
A multiple holes are detected.
CDK4/CycD3 and CDK6/CycD3 is purchased from Carna Biosciences, Inc.；Dimethyl sulfoxide, ATP, DTT
Solution is purchased from Sigma-Aldrich；EDTA solution is purchased from GIBCO；Detection Buffer, 10 × andUltra Europium-anti-phospho-eIF4E-binding protein 1 (Thr37/46) andUltra ULightTM- eIF4E-bindingprotein 1 (Thr37/46) Peptide, is purchased from
Perkinelmer。
Testing procedure: 1, using 1 × reaction buffer kinases, substrate, ATP is respectively configured to 2.5 × enzyme/substrate it is mixed
Close liquid and 2.5 × ATP solution.In experiment, CDK4/CycD3 kinases it is final concentration of: 0.76ng/ul, ATP are final concentration of:
80uM；CDK6/CycD3 kinases it is final concentration of: 0.5ng/ul, ATP are final concentration of: 50uM；Into 384 orifice plates be added 2.5 ×
Enzyme/Substrate cocktail, be incubated at room temperature 5 minutes；2.5 × ATP solution is added, is reacted at room temperature 30 minutes.2, it usesDetection Buffer, 1 × preparation 2 ×Ultra Europium-anti-phospho-
EIF4E-binding protein 1 (Thr37/46) is spare.After enzyme reaction carries out 30 minutes, 10mM is added into 384 orifice plates
EDTA, react at room temperature 5 minutes.It addsUltra Europium-anti-phospho-eIF4E-
Binding protein 1 (Thr37/46) is reacted at room temperature 1 hour.3,384 orifice plates are put in HERAEUS Multifuge
2000rpm is centrifuged 2 minutes in X1R centrifuge；According to surveying and determination in the enterprising line number of EnVisionTM, the laser of 337nM wavelength is selected to make
For exciting light, measure RFU665nM and RFU615nM, and using RFU665nM/RFU615nM × 10000 as final data into
Row analysis.4, Log (inhibitor) vs.response-Variable is carried out to data using Graphpad Prism 5.0
Slope (four parameters) curve matching, calculates corresponding IC50 (half maximal inhibitory
concentration)。
2, MCF-7 cell growth inhibition assay usesLuminescent Cell Viability
The measurement of Assay method.Experiment inhibits Mcf- on human breast carcinoma Mcf-7 cell, through the method detection compound of CellTiter
The effect of 7 cell Proliferations, in detection process, test-compound initial concentration is selected as 10 μM, and each embodiment compound selects 9
A gradient dilution concentration, gradient dilution multiple are 3 times, and 2 multiple holes of every concentration are detected.Mcf-7 cell is purchased from the triumphant base in Nanjing
Biotechnology Development Co., Ltd；Luminescence method cell viability detection kit is purchased from Promega, article No.:
G7573；Dimethyl sulfoxide is purchased from Sigma-Aldrich, article No.: D8418；384 porocyte culture plates, Corning, article No.:
3570。
Testing procedure: 1. normal culture human breast cancer cell Mcf-7, after digestion, by 675, every hole cell density kind plate in
384 orifice plates；2. after kind of plate 1d, one block of plate is used to survey background Celltiter value, it is denoted as Control D1.Remaining plate dosing: setting
Cell controls group.Test-compound initial concentration is 10 μM, successively 9 gradient dilution concentration, and gradient dilution multiple is 3 times, often
2 multiple holes of concentration are detected.3. after handling 7 days 25ul CellTiter detection liquid, oscillation is added in every hole in test-compound
2min is mixed well, centrifugation, is stood balance and is detected after ten minutes, record fluorescence signal, medicine group is denoted as Drug D7, cell pair
Control D7 is denoted as according to group.4. carrying out Log (inhibitor) to data using Graphpad Prism 5.0
Vs.response-Variable slope (four parameters) curve matching, calculates corresponding IC50(half
maximal inhibitory concentration)。
Test result is shown in Table 1.
The active testing result of table 1, kinases and cellular level
Claims (10)
1. a kind of nitrogenous fused heterocyclic compound or its pharmaceutically acceptable salt shown in formula I；
Wherein, R1For hydrogen, halogen, C1~C6Alkyl, C1~C6Alkoxy or C3~C6Naphthenic base；
R2For hydrogen, halogen, C1~C6The C that alkyl, hydroxyl replace1~C6Alkyl, C1~C6Alkyl oxygen-carbonyl-, carboxyl, cyano, aldehyde
Base, C1~C6Acyl group orDescribedIn R5And R6It independently is hydrogen, C1~C6Alkyl or C1~C6Alcoxyl
Base, alternatively, the R5And R6Atom connect cyclization, withIn N atom form unitary azepine C2~C6Naphthenic base；
R3For hydrogen；
R4For substituted or unsubstituted C1~C6Alkyl, substituted or unsubstituted C3~C6Naphthenic base, C1~C6Alkyl oxygen-carbonyl-,
Substituted or unsubstituted C3~C12Aryl, substituted or unsubstituted C3~C12Heteroaryl or substituted or unsubstituted C2~C6Heterocycle
Alkyl；The substituted or unsubstituted C3~C12Hetero atom in heteroaryl is one of O, N and S or a variety of, described
Substituted or unsubstituted C3~C12Heteroatomic number in heteroaryl is 1~4；The substituted or unsubstituted C2~C6
Hetero atom in Heterocyclylalkyl is one of O, N and S or a variety of, described substituted or unsubstituted C2~C6In Heterocyclylalkyl
Heteroatomic number be 1~4；Described is substituted by by halogen, C1~C6Alkoxy, trifluoromethyl, hydroxyl and C1~C6Alkane
One of base is a variety of replaced；
Ar is W-L1-L2-Y-；
Wherein:
Y is selected from
L2Selected from-(CH2)r,-O- ,-S- ,-C (=O)-or substituted or unsubstituted amino, r is 0 or 1；It is described be substituted by by
C1~C3Replaced alkyl；
L1Selected from-(CH2)n, substituted or unsubstituted C3~C12Naphthenic base, substituted or unsubstituted C3~C12Heterocyclylalkyl；N is
0 or 1；Described is substituted by by C1~C6Replaced alkyl or halogen；The substituted or unsubstituted C3~C12In Heterocyclylalkyl
Hetero atom be one of O, N and S or a variety of, heteroatomic number is any integer in 1~4；
W be hydrogen,Halogen, hydroxyl, aldehyde radical,Substituted or unsubstituted amino, substitution or
Unsubstituted C1~C6Alkyl or substituted or unsubstituted C1~C6Acyl group；DescribedIn X2For O, S or
DescribedIn s be 1~5 in any integer, it is describedIn t be 0
Any integer in~5, it is describedIn m be 0~5 in any integer, it is describedIn X1For N, O ,-C (=O)-NH- orThe substituted amino refers to only one hydrogen on nitrogen
Be substituted or nitrogen on two hydrogen be substituted, when substituted amino refers to that two hydrogen are substituted on nitrogen, two substituent groups be it is identical or
It is different；Described is substituted by by C1~C6Alkyl, C1~C6Alkyl sulphonyl, C1~C6Alkoxy, C1~C6Alkylthio group, C3~C6
The C that naphthenic base, halogen, hydroxyl, amino, hydroxyl replace1~C6The N of alkyl, 2-12 carbon atom, N- dialkyl amido, 2-12
The alkoxy alkyl-, the C that replace of the N of carbon atom, N- dialkyl amido-alkyl-, 2-12 carbon atom3~C6Naphthenic base and C2
~C6One of Heterocyclylalkyl is a variety of replaced；The C2~C6Hetero atom in Heterocyclylalkyl is one in N, O and S
Kind is a variety of, and heteroatomic number is any integer in 1~4.
2. nitrogenous fused heterocyclic compound or its pharmaceutically acceptable salt shown in formula I as described in claim 1, feature
It is:
As the R1When for halogen, the halogen is chlorine；As the R1For C1~C6When alkyl, the C1~C6Alkyl
For methyl；As the R1For C1~C6When alkoxy, the C1~C6Alkoxy is methoxyl group；As the R1For C3~C6
When naphthenic base, the C3~C6Naphthenic base is cyclopropyl；
And/or as the R2When for halogen, the halogen is bromine；As the R2The C replaced for hydroxyl1~C6When alkyl,
The C that the hydroxyl replaces1~C6Alkyl is CH3-CH(OH)-；As the R2For C1~C6Alkyl oxygen-carbonyl-when, it is described
C1~C6Alkyl oxygen-carbonyl-is ethoxy-carbonyl；As the R2When for aldehyde radical, the aldehyde radical is carboxaldehyde radicals；When described
R2For C1~C6When acyl group, the C1~C6Acyl group is acetyl group；As the R2ForWhen, and it is describedIn R5And R6It independently is C1~C6When alkyl, the C1~C6Alkyl is methyl；As the R2ForWhen, and it is describedIn R5And R6It independently is C1~C6When alkoxy, the C1~C6Alkoxy is
Methoxyl group；As the R2ForWhen, and the R5And R6Atom connect cyclization, withIn N atom
Form unitary azepine C2~C6When naphthenic base, the unitary azepine C2~C6Naphthenic base is unitary aziridinyl；
And/or as the R4For substituted or unsubstituted C1~C6When alkyl, the substituted or unsubstituted C1~C6Alkyl
For substituted or unsubstituted methyl, substituted or unsubstituted n-propyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted
Isopropyl or substituted or unsubstituted sec-butyl；As the R4For substituted or unsubstituted C3~C6When naphthenic base, described is taken
Generation or unsubstituted C3~C6Naphthenic base is substituted or unsubstituted C4、C5Or C6Naphthenic base；As the R4For C1~C6Alkyl
Oxygen-carbonyl-when, the C1~C6Alkyl oxygen-carbonyl-is ethoxy-carbonyl-；As the R4For substituted or unsubstituted C3
~C12When aryl, the C3~C12Aryl is phenyl；As the R4For substituted or unsubstituted C3~C12When heteroaryl, institute
The substituted or unsubstituted C stated3~C12Hetero atom in heteroaryl is O or N, and/or, the substituted or unsubstituted C3~
C12Heteroatomic number in heteroaryl is 1；As the R4For substituted or unsubstituted C2~C6It is described when Heterocyclylalkyl
Substituted or unsubstituted C2~C6Hetero atom in Heterocyclylalkyl is N or O, and/or, the substituted or unsubstituted C2~
C6Heteroatomic number in Heterocyclylalkyl is 1；
And/or as the L1For substituted or unsubstituted C3~C12When naphthenic base, the substituted or unsubstituted C3~C12
Naphthenic base is substituted or unsubstituted cyclohexyl；As the L1For substituted or unsubstituted C3~C12It is described when Heterocyclylalkyl
Substituted or unsubstituted C3~C12Hetero atom in Heterocyclylalkyl is N, and/or, heteroatomic number is 1 or 2；
And/or when the W is halogen, the halogen is bromine；When the W isWhen, it is described
S be 1 or 2, and/or, the t be 0 or 1, and/or, the m be 1；When the W is substituted or unsubstituted C1~C6
When alkyl, the substituted or unsubstituted C1~C6Alkyl is substituted or unsubstituted methyl, alternatively, substituted or unsubstituted
Ethyl.
3. nitrogenous fused heterocyclic compound or its pharmaceutically acceptable salt shown in formula I as claimed in claim 2, feature
It is:
As the R4For substituted or unsubstituted C3~C12When heteroaryl, the substituted or unsubstituted C3~C12Heteroaryl
ForAs the R4For substituted or unsubstituted C2~C6When Heterocyclylalkyl, the substituted or unsubstituted C2~
C6C in Heterocyclylalkyl2~C6Heterocyclylalkyl is
4. nitrogenous fused heterocyclic compound or its pharmaceutically acceptable salt shown in formula I as described in claim 1, feature
It is:
The R1For hydrogen or methyl；
And/or the R2For acetyl group, cyano, bromine ,-CH (OH) CH3、C1~C6Alkyl oxygen-carbonyl-or
And/or the R4For methyl, tert-butyl, isopropyl, cyclopenta, cyclobutyl, phenyl, n-propyl or cyclohexyl；
And/or the L1For
And/or the Ar is
5. nitrogenous fused heterocyclic compound or its pharmaceutically acceptable salt shown in formula I as described in claim 1, feature
It is: in the Formulas I compound represented, R1For hydrogen or methyl, R2For acetyl group, cyano, bromine ,-CH (OH) CH3、C1~C6
Alkyl oxygen-carbonyl-orR3For hydrogen, R4For methyl, tert-butyl, isopropyl, cyclopenta, cyclobutyl, phenyl, positive third
Base or cyclohexyl, Ar are
6. nitrogenous fused heterocyclic compound or its pharmaceutically acceptable salt shown in formula I as described in claim 1, feature
Be: the pharmaceutically acceptable salt of the Formulas I compound represented is Formulas I compound represented and organic acid or inorganic acid
It is formed by salt.
7. nitrogenous fused heterocyclic compound or its pharmaceutically acceptable salt shown in formula I as described in claim 1, feature
Be: the nitrogenous fused heterocyclic compound shown in formula I is following any compound:
8. a kind of preparation method such as Formulas I compound represented of any of claims 1-7, for it is following either one
Method:
Method one:
The preparation method of the Formulas I compound represented includes the following steps: Formula II compound represented carrying out removing guarantor
The reaction for protecting base, obtains Formulas I compound represented, and the PG in Formula II compound represented is the protecting group；
Wherein, described Ar, R1、R2、R3、R4With described in claim 1；
Method two:
The preparation method of the Formulas I compound represented includes the following steps: -3 compound represented of formula III and 4 institute of formula
The compound shown carries out substitution reaction or transition metal-catalyzed coupling reaction, generates the Formulas I compound represented；Formula
LG group in III-3 compound represented is leaving group；
The R1、R2、R3、R4With Ar with described in claim 1；
Method three:
As the R2When for halogen or acetyl group, the preparation method of the Formulas I compound represented include the following steps: by
Formula III -3-4 compound represented and 5 compound represented of formula generate described in transition metal-catalyzed lower generation coupling reaction
Formulas I compound represented；
The R1、R3、R4, X and Ar be the same as described in claim 1.
9. one kind containing the nitrogenous fused heterocyclic compound as shown in Formulas I of any of claims 1-7 or its pharmaceutically
The pharmaceutical composition of acceptable salt.
10. a kind of fused heterocyclic compound nitrogenous as shown in Formulas I of any of claims 1-7 or its can pharmaceutically connect
Application of the salt received on the drug of preparation prevention or the extremely relevant disease for the treatment of cell cycle regulating.
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| CN108727368B (en) * | 2017-04-14 | 2022-05-03 | 上海医药集团股份有限公司 | Nitrogen-containing fused heterocyclic compound, preparation method, intermediate, composition and application thereof |
| US11091485B2 (en) | 2017-05-23 | 2021-08-17 | Shengke Pharmaceuticals (Jiangsu) Ltd. | Imidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine compound as protein kinase inhibitor |
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