CN110372720A - 一类激酶抑制剂 - Google Patents
一类激酶抑制剂 Download PDFInfo
- Publication number
- CN110372720A CN110372720A CN201910743940.2A CN201910743940A CN110372720A CN 110372720 A CN110372720 A CN 110372720A CN 201910743940 A CN201910743940 A CN 201910743940A CN 110372720 A CN110372720 A CN 110372720A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- heterocycle
- heteroaryl
- aryl
- base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229940043355 kinase inhibitor Drugs 0.000 title abstract description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 111
- 101000715943 Caenorhabditis elegans Cyclin-dependent kinase 4 homolog Proteins 0.000 claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 159
- 125000000623 heterocyclic group Chemical group 0.000 claims description 139
- 229910052757 nitrogen Inorganic materials 0.000 claims description 134
- -1 aryl-C1-4Alkyl Chemical group 0.000 claims description 107
- 125000001072 heteroaryl group Chemical group 0.000 claims description 100
- 125000003118 aryl group Chemical group 0.000 claims description 97
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 79
- 150000003839 salts Chemical class 0.000 claims description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- 229910052799 carbon Inorganic materials 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- 239000001257 hydrogen Substances 0.000 claims description 42
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 31
- 239000003814 drug Substances 0.000 claims description 29
- 150000001721 carbon Chemical group 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 229910004749 OS(O)2 Inorganic materials 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 15
- 125000000304 alkynyl group Chemical group 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 239000005864 Sulphur Substances 0.000 claims description 12
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 12
- 125000004429 atom Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- FPEAARFNXIWCTP-UHFFFAOYSA-N 5,6,7,8-tetrahydro-1,6-naphthyridine Chemical group C1=CC=C2CNCCC2=N1 FPEAARFNXIWCTP-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 229940124597 therapeutic agent Drugs 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 238000006467 substitution reaction Methods 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 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 208000024891 symptom Diseases 0.000 claims description 5
- 230000004663 cell proliferation Effects 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000002619 bicyclic group Chemical group 0.000 claims description 3
- 125000002147 dimethylamino group Chemical class [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000000350 glycoloyl group Chemical group O=C([*])C([H])([H])O[H] 0.000 claims description 2
- 125000000250 methylamino group Chemical class [H]N(*)C([H])([H])[H] 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000005936 piperidyl group Chemical group 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 150000001345 alkine derivatives Chemical class 0.000 claims 1
- 125000002393 azetidinyl group Chemical group 0.000 claims 1
- 230000001276 controlling effect Effects 0.000 claims 1
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- 230000001105 regulatory effect Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 36
- 239000002585 base Substances 0.000 description 346
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 126
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 101
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 88
- HKSQZEGSMBFHGC-UHFFFAOYSA-N pyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=N1 HKSQZEGSMBFHGC-UHFFFAOYSA-N 0.000 description 68
- 239000000243 solution Substances 0.000 description 64
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- 229960005141 piperazine Drugs 0.000 description 44
- VFWVWPWWZVTJDG-UHFFFAOYSA-N thieno[3,2-d]pyrimidine-6-carboxamide Chemical compound C1=NC=C2SC(C(=O)N)=CC2=N1 VFWVWPWWZVTJDG-UHFFFAOYSA-N 0.000 description 44
- 238000006243 chemical reaction Methods 0.000 description 41
- 235000002639 sodium chloride Nutrition 0.000 description 40
- 239000012043 crude product Substances 0.000 description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 27
- HBWGDGHGYGHWKD-UHFFFAOYSA-N 1-methyl-4-pyridin-3-ylpiperazine Chemical compound C1CN(C)CCN1C1=CC=CN=C1 HBWGDGHGYGHWKD-UHFFFAOYSA-N 0.000 description 26
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- 238000005406 washing Methods 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 23
- 239000002253 acid Substances 0.000 description 23
- 201000010099 disease Diseases 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 21
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 235000019439 ethyl acetate Nutrition 0.000 description 19
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 238000010828 elution Methods 0.000 description 18
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
- 239000012071 phase Substances 0.000 description 16
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical compound C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 150000002576 ketones Chemical class 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 238000011282 treatment Methods 0.000 description 13
- 206010028980 Neoplasm Diseases 0.000 description 12
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 12
- RLNCTIUJEJXMBZ-UHFFFAOYSA-N pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide Chemical compound C1=NC=NN2C=C(C(=O)N)C=C21 RLNCTIUJEJXMBZ-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000000470 constituent Substances 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 11
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 229910021529 ammonia Inorganic materials 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000005457 ice water Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 239000003513 alkali Substances 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 239000012895 dilution Substances 0.000 description 9
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- 239000000284 extract Substances 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 230000002062 proliferating effect Effects 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 229960001866 silicon dioxide Drugs 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- CELPHAGZKFMOMR-UHFFFAOYSA-N azanium;dichloromethane;methanol;hydroxide Chemical compound [NH4+].[OH-].OC.ClCCl CELPHAGZKFMOMR-UHFFFAOYSA-N 0.000 description 8
- 229960000443 hydrochloric acid Drugs 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 239000007832 Na2SO4 Substances 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 150000002240 furans Chemical class 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
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- 125000006239 protecting group Chemical group 0.000 description 7
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- 229920006395 saturated elastomer Polymers 0.000 description 7
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- VIROYRDWRZNPKD-UHFFFAOYSA-N 1,2,4-triazine-6-carboxamide Chemical compound NC(=O)C1=CN=CN=N1 VIROYRDWRZNPKD-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 238000003810 ethyl acetate extraction Methods 0.000 description 6
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 230000002969 morbid Effects 0.000 description 6
- YPOXGDJGKBXRFP-UHFFFAOYSA-N pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=N1 YPOXGDJGKBXRFP-UHFFFAOYSA-N 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 5
- GXWNSJYVSIJRLS-UHFFFAOYSA-N 6-bromo-8-methylimidazo[1,2-a]pyrazine Chemical compound CC1=NC(Br)=CN2C=CN=C12 GXWNSJYVSIJRLS-UHFFFAOYSA-N 0.000 description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 5
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- 125000001931 aliphatic group Chemical group 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 5
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Substances BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000000908 ammonium hydroxide Substances 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 230000022131 cell cycle Effects 0.000 description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 4
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000002024 ethyl acetate extract Substances 0.000 description 4
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- 125000005456 glyceride group Chemical group 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
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- 230000007170 pathology Effects 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 150000003866 tertiary ammonium salts Chemical class 0.000 description 1
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- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 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
- 231100000331 toxic Toxicity 0.000 description 1
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- DPUOLQHDNGRHBS-MDZDMXLPSA-N trans-Brassidic acid Chemical compound CCCCCCCC\C=C\CCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-MDZDMXLPSA-N 0.000 description 1
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- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- 210000004291 uterus Anatomy 0.000 description 1
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract
本发明涉及作为CDK4/6激酶抑制剂的如式(I)的化合物、药学组合物,以及其使用方法。
Description
本申请是2015年5月27日提交的发明名称为“一类激酶抑制剂”的第201580027559.6号中国专利申请的分案申请。
技术领域
本发明涉及可抑制CDK4/6激酶活性的一类化合物和/或药学可接受的盐,以及作为药物治疗增生性疾病,如癌症和炎症。
背景技术
增生性疾病如癌症和炎症吸引着学术界为其提供有效治疗手段。并在这方面已做出努力,识别并靶向了在增殖性疾病中发挥作用的特定机制。
肿瘤的发展与周期蛋白依赖性激酶(cyclin-dependent kinase,CDK)及其调控蛋白的基因变异和调控异常密切相关,表明CDK抑制剂可能是有效的抗癌疗法。
CDK是丝氨酸/苏氨酸蛋白激酶,其是细胞周期和细胞增殖的原动力。CDK调节哺乳动物细胞周期的启动、进展和完成,并且对细胞生长很关键。大部分已知的CDK,包括CDK1至CDK9,都直接或间接参与细胞周期进展过程。直接参与细胞周期进展的CDK,如CDK1-4和CDK6,可分为G1、S或G2M期酶。异常增殖是癌症细胞的特征,CDK功能异常在许多实体瘤中高频发生。
CDK及其相关蛋白在增殖细胞中协调和驱动细胞周期的作用十分关键。因此,靶向多个CDK或特定CDK治疗增生异常疾病,如癌症的疗法具有极大潜力。CDK抑制剂也可被用于治疗如病毒感染,自身免疫性疾病和神经退行性疾病等其他疾病。CDK靶向疗法也可与其他治疗药物联合使用用于上述疾病的治疗。
因此,具有CDK抑制活性的化合物对癌症的预防和治疗具有重要意义。虽然许多CDK4/6抑制剂被披露半衰期短或有毒性,如WO 2010020675和WO 2012064805。因此,对于新型CDK4/6抑制剂的需求将越来越迫切,其在疗效、稳定性、选择性、安全性、药效学特征和药代动力学特征至少有一方面具有优势。本发明涉及一类新型CDK4/6抑制剂。
发明内容
本发明涉及一类新型6-5元稠环衍生物及其药学组合物,以及作为药物的应用。
在一个方面,本发明提供至少一个式(I)所示的化合物:
和/或其至少一个药学上可接受的盐,其中
X为C或N;
Y为CR11、O、S或NR12;
6-5元稠环系统A-B选自:
Q选自芳基或杂芳基;
R1选自:氢、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、C3-10环烷基-C1-4烷基、杂环基、杂环基-C1-4烷基、芳基、芳基-C1-4烷基、杂芳基和杂芳基-C1-4烷基,其中每个烷基、烯基、炔基、环烷基和杂环基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6a的取代基取代,其中每个芳基和杂芳基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6b的取代基取代;
R2选自:氢、卤素、羟基、CN、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、C3-10环烷基-C1-4烷基、杂环基、杂环基-C1-4烷基、芳基、芳基-C1-4烷基、杂芳基和杂芳基-C1-4烷基,其中每个烷基、烯基、炔基、环烷基和杂环基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6a的取代基取代,其中每个芳基和杂芳基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6b的取代基取代;
R3和R4分别选自:氢、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基;其中每个烷基、烯基、炔基和环烷基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6a的取代基取代;或R3和R4连同与它们相连的N原子一起形成一个含0、1、2或3个杂原子的4-12元环,其中杂原子独立选自氧、硫和氮,并任选由1-2个R6a取代基取代;
附带条件是,当R3和R4均为氢时,R2不是芳基或杂芳基;
每个R5独立地选自:氢、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、-OR8、-NR7S(O)rR8、-NO2、-卤素、-S(O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CR7(N-OR8)、-CHF2、-CF3、-OCHF2和-OCF3;其中每个C1-10烷基、C2-10烯基、C2-10炔基和C3-10环烷基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6a的取代基取代;
每个R6a独立地选自:C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、-OR8、-NR7S(O)rR8、-NO2、-卤素、-S(O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CR7(NOR8)、-CHF2、-CF3、-OCHF2和-OCF3;
每个R6b独立地选自:R6a、芳基、芳基-C1-4烷基、杂芳基、和杂芳基-C1-4烷基;
R7和R8独立地选自:氢、C1-10烷基、C2-10烯基、C2-10炔基、环烷基、环烷基-C1-4烷基、杂环基、杂环基C1-4烷基、芳基、杂芳基、芳基-C1-4烷基、杂芳基和杂芳基-C1-4烷基;其中每个烷基、烯基、炔基、环烷基和杂环基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6a的取代基取代,其中每个芳基和杂芳基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6b的取代基取代;或R7和R8一起连同与它们相连的单个或多个原子共同构成一个含有0、1或2个额外的独立选自氧,硫和N的杂原子的4-12元杂环,该环可以是未被取代的或被1-2个选自R6b的取代基取代;
R9和R10独立地选自:氢、C1-10烷基、C2-10烯基、C2-10炔基、环烷基、环烷基-C1-4烷基、杂环基、杂环基-C1-4烷基、芳基、芳基-C1-4烷基、杂芳基和杂芳基-C1-4烷基;或R9和R10一起连同与它们相连的单个或多个碳原子共同构成含有0、1或2个独立选自氧,硫和氮的杂原子的3-7元环,该环可以是未被取代的或被1-2个选自R6a的取代基取代;
R11选自:氢、C1-10烷基、C3-10环烷基、C3-10环烷基烷基、杂环基、杂环基-C1-4烷基、芳基、芳基-C1-4烷基、杂芳基、杂芳基-C1-4烷基、-OR7、-NR7S(O)rR8、-S(O)rR7、-SR7、-S(O)2OR7、-OS(O)2R7、-S(O)rNR7R8、-NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CHF2、-CF3、-OCHF2和-OCF3;
R12选自:氢、C1-10烷基、C3-10环烷基、C3-10环烷基-C1-4烷基、杂环基、杂环基-C1-4烷基、芳基、芳基-C1-4烷基、杂芳基、杂芳基-C1-4烷基、-S(O)rR7、-C(O)R7、-CO2R7、-CO2(CR9R10)tCONR7R8和-C(O)NR7R8;
m独立选自0、1、2和3;
每个r独立选自1和2;
每个t独立选自1、2和3。
另一方面,本发明提供药物组合物,其包括至少一个式(I)化合物和/或其至少一个药学上可接受的盐,和至少一个药学上可接受的载体。
另一方面,本发明提供用于调节CDK4/6的方法,该方法包括对有需要的系统或个体给予治疗有效量的至少一个式(1)化合物和/或至少一个药学上可接受的盐或药学组合物,从而调节CDK4/6。本发明还提供了治疗、改善或预防对抑制CDK4/6响应的病症的方法,包括给予有需要的系统或个体有效量的至少一个式(I)化合物和/或至少一个药学上可接受的盐或药学组合物,或与另一治疗药物联合使用,治疗上述病症。或者,本发明提供了至少一个式(I)化合物和/或至少一个药学上可接受的盐,用于治疗CDK4/6介导病症的药物制造的用途。在特定实施例中,所述化合物可单独或与另一治疗药物联合使用治疗CDK4/6介导病症,其中所述病症为自身免疫性疾病、移植疾病、感染性疾病或细胞增殖紊乱。
此外,本发明提供了治疗细胞增殖性病症的方法,该方法包括给予有需要的系统或个体有效量的至少一个式(I)化合物和/或至少一个药学上可接受的盐或药学组合物,或与另一治疗药物联合使用,治疗上述病症。
或者,本发明提供了至少一个式(I)化合物和/或至少一个药学上可接受的盐,用于制造治疗细胞增殖性病症的药物的用途。在特定实施例中,所述化合物可单独或与另一治疗药物联合使用治疗细胞增殖性病症,其中所述病症包括但不限于淋巴瘤、骨肉瘤、黑素瘤、或乳腺、肾、前列腺、结肠直肠、甲状腺、卵巢、胰腺、神经元、肺、子宫或胃肠道肿瘤。
在使用本发明所述化合物的上述方法中,至少一个式(I)化合物和/或至少一个药学上可接受的盐可被用于由细胞或组织构成的系统,或哺乳动物,如人或动物受试者。
具体实施方式
此处所用的术语定义如下:
“烷基”是指具有特定碳原子数的支链和直链饱和脂肪族烃基团。除另有注明外,“烷基”是指C1-C6烷基。例如,“C1-C6烷基”中的“C1-C6”指的是有1、2、3、4、5或6个碳原子的直线或分枝排列的基团。例如,“C1-C8烷基”包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基、庚基、辛基、壬基、癸基等。
“环烷基”是指具有特定碳原子数的饱和脂肪族环状烃基团。除另有注明外,“环烷基”是指C3-C10环烷基。例如,“环烷基”包括但不限于环丙基、甲基-环丙基、2,2-二甲基-环丁基、环戊基、2-乙基-环戊基、环己基和反式-4-甲基环己基等。
“烯基”是指含有2-10个碳原子且至少有一个碳碳双键的非芳香直链、分支或环状烃基。在一些实施例中,存在1个碳碳双键,多达4个非芳香性的碳碳双键可能存在。因此,“C2-6烯基”是指含有2-6个碳原子的烯基。烯基基团包括但不限于乙烯基、丙烯基、丁烯基、2-甲基丁烯基和环己烯基。烯基中的直链、分枝或环状部分可能含有双键,且若标明取代烯基表示其可能被取代。
“炔基”是指含有2-10个碳原子且至少一个碳碳三键的直链、分枝或环状烃基。在一些实施例中,可存在3个碳碳三键。因此,“C2-6炔基”指含有2-6个碳原子的炔基。炔基基团包括但不限于乙炔基、丙炔基、丁炔基、3-甲基丁炔基等。炔基中的直链、分枝或环状部分可能含有三键,若标明取代炔基表示其可能被取代。
“芳基”包括:5元和6元芳香碳环,例如苯基;至少有一个芳香碳环的双环,例如萘基、茚满和1,2,3,4-四氢喹啉和至少有一个芳香碳环的三环,例如芴。若芳基取代基为二环或三环且其中至少有一环为非芳香环,那么应认为是通过芳环联接。
例如,芳基包括5元和6元芳香碳环,这些芳香碳环与含有一个或多个选自N、O和S的杂原子的5-7元杂环稠合,条件是联接位点是芳香碳环。由取代的苯类衍生物形成的且在环原子上存在自由价电子的二价自由基,被命名为取代的亚苯基自由基。衍生自一价多环烃自由基的其名字以“-基”结尾的二价自由基,其是在含有自由价电子上的碳原子上再去掉一个氢原子而得到的,其名称为在单价自由基名字加上“-亚(-idene)”,例如,有两个连接位点的萘基就被称为亚萘基。然而芳基的定义不包含杂芳基,也不与之重叠,单独定义如下。因此,如果一个或多个芳香碳环与杂芳环稠合,所形成的环系应被认为是杂芳基,而不是此处定义的芳基。
“卤素”是指氟、氯、溴和碘。
“杂芳基”是指
5元到8元的芳香单环,该环含有选自N、O和S的,数目为1到4个,在某些实施例中为1到3个的杂原子,其余均为碳原子;
8元到12元双环,该环含有选自N、O和S的,数目为1到4个,在某些实施例中为1到3个的杂原子,其余均为碳原子,且其中至少有一个杂原子出现在芳环中;和
11元到14元三环。该环含有选自N、O和S的,数目为1到4个,在某些实施例中为1到3个的杂原子,其余均为碳原子,且其中至少有一个杂原子出现在芳环中。
当杂芳基中S和O的总数大于1时,这些杂原子彼此不相邻。在一些实施例中,杂芳基中S和O的总数不大于2。在一些实施例中,杂芳基中S和O的总数不大于1。
杂芳基的例子包括但不限于(连接位点的编号优先,指定为1位)2-吡啶基、3-吡啶基、4-吡啶基、2,3-吡嗪基、3,4-吡嗪基、2,4-嘧啶基、3,5-嘧啶基、1-吡唑基、2,3-吡唑基、2,4-咪唑啉基、异噁唑基、噁唑基、噻唑基、噻重氮基、四唑基、噻吩基、苯并噻吩基、呋喃基、苯并呋喃基、苯并咪唑啉基、二氢吲哚基、吡地嗪基、三唑基、喹啉基、吡唑基和5,6,7,8-四氢异喹啉基。
进一步地,杂芳基包括但不限于吡咯基、异噻唑基、三嗪基、吡嗪基、哒嗪基、吲哚基、苯并三氮唑基、喹诺啉基和异喹啉基。如下述对杂环基的定义,“杂芳基”包括含氮杂芳基的N氧化衍生物。
一价杂芳基自由基的命名以“-基”结尾,其衍生的二价自由基的就是在含有自由价电子上的碳原子上再去掉一个氢原子而得到的,该二价自由基的命名系在一价自由基的名称加上“-亚(-idene)”,例如,有两个连接位点的吡啶基被称为吡啶亚基。杂芳基的定义不包含如上定义的芳基,也不与之重叠。
若杂芳基取代基为二环或三环,并且其中至少一环为非芳香性的或不含杂原子,那么通常认为分别是通过芳香环或含杂原子的环联接的。
“杂环”(和由此衍变的如“杂环的”或“杂环基”)泛指单一的环状脂肪烃,通常有3至12个环原子,至少含2个碳原子,此外还含有1-3个独立地选自O、S、N的杂原子,亦指含有至少一个上述杂原子的组合。或者,上述定义中的杂环可以是多环体系(例如,二环),其中两个或两个以上环通过稠合或桥接或螺合方式连接,其中至少一个环中含有一个或多个独立选自氧、硫、氮和硫的杂原子。“杂环”亦指与5元和6元芳香碳环稠合的含有一个或多个选自N、O和S的杂原子的5元到7元杂环,条件是连接位点在杂环上。杂环可以是饱和的或含有一到多个双键(即部分不饱和)。杂环可以被氧代(oxo)取代。杂环上的碳原子或杂原子均可是联接位点,前提是形成一个稳定的结构。当杂环上有取代基时,该取代基可以和杂环上的任何杂原子或碳原子连接,前提是形成一个稳定的化学结构。此处所述的杂环与杂芳基定义不重叠。
适宜的杂环包括,例如(连接位点优先排序为1)1-吡咯烷基、2-吡咯烷基,2,4-咪唑烷基、2,3-吡唑烷酮基、1-哌啶基、2-哌啶基、3-哌啶基、4-哌啶基、2,5-哌嗪基、1,4-哌嗪基和2,3-哒嗪基。也包括2-吗啉基和3-吗啉基(氧原子位置编号优先为1)。含取代基的杂环也包括被一个或多个氧代取代的环系,如哌啶基-N-氧化物,吗啉基-N-氧化物,1-氧代-1-硫代吗啉基和1,1-二氧代-1-硫代吗啉基。双杂环化合物包括,例如:
此处所用的“芳烷基”是指芳基取代的烷基。示例的芳烷基包括苄基,苯乙基和萘甲基等。在一些实施中,芳烷基含7-20或7-11个碳原子。当使用“芳基C1-4烷基”时,其中“C1-4”是指烷基部分而不是芳基部分的碳原子数。同样地,当使用“芳基C1-10烷基”时,其中“C1-10”是指烷基部分而不是芳基部分的碳原子数。
此处所用的“杂环基烷基”是指杂环基取代的烷基。当使用“杂环基C1-6烷基”时,其中“C1-6”是指烷基部分而不是杂环基部分的碳原子数。
此处所用的“环烷基烷基”是指环烷基取代的烷基。当使用“C3-10环烷基烷基”时,其中“C3-10”是指环烷基部分而不是烷基部分的碳原子数。当使用“C3-7环烷基烷基”时,其中“C3-7”是指环烷基部分而不是烷基部分的碳原子数。当使用“C3-8环烷基烷基”时,其中“C3-8”是指环烷基部分而不是烷基部分的碳原子数。当使用“环烷基C1-10烷基”时,其中“C1-10”是指烷基部分而不是环烷基部分的碳原子数。
此处所用的“杂芳基烷基”是指杂芳基取代的烷基。当使用“杂芳基C1-4烷基”时,其中“C1-4”是指环烷基部分而不是杂芳基部分的碳原子数。同样地,当使用“杂芳基C1-10烷基”时,其中“C1-10”是指烷基部分而不是杂芳基部分的碳原子数。
为避免歧义,例如:当提到烷基、环烷基、杂环基烷基、芳基和/或其杂芳基取代时,其意是指每个这些基团单独地取代,或是指这些基团混合取代。亦即:如果R1是芳烷基,芳基部分可为未被取代的或被至少一个,如1个,2个,3个或4个独自选自R6b的取代基取代,烷基部分也可为未被取代的或被至少一个,如1个、2个、3个或4个独自选自R6a的取代基。
“药学上可接受的盐”是指与药学上可接受的无毒的碱或酸,包括无机或有机碱和无机或有机酸制成的盐。无机碱的盐可以选自,例如:铝、铵、钙、铜、铁、亚铁、锂、镁、锰、二价锰、钾、钠、锌盐。进一步,药学上可接受的无机碱的盐可选自铵、钙、镁、钾和钠盐。在固体盐中可能存在一个或多个晶体结构,也有可能存在水合物的形式。药学上可接受的有机无毒碱的盐可选自,例如:伯胺、仲胺和叔胺盐,取代胺包括自然存在的取代胺、环胺和碱性离子交换树脂如精氨酸、甜菜碱、咖啡碱、胆碱、N,N-二苄基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸,海巴明胺、异丙胺、赖氨酸、甲葡糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺和氨丁三醇。
当本专利所指化合物是碱时,需要与至少一种药学上可接受的无毒酸制备其盐,这些酸选自无机和有机酸。例如,选自醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙烷磺酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、粘酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸和对甲苯磺酸。在一些实施例中,可选择这些酸,例如:柠檬酸、氢溴酸、盐酸、马来酸、磷酸、硫酸、富马酸和酒石酸。
“保护基”(Pg)是指一类用于与化合物上其它官能团反应而阻隔或保护特定官能团的取代基。例如,“氨基保护基”是指联接在氨基上阻隔或保护化合物上氨基官能团的取代基。适合的氨基保护基团包括但不限于乙酰基、三氟乙酰基、叔丁氧羰基(BOC)、苄氧羰基(CBZ)和-9-芴甲氧羰基(Fmoc)。同样,“羟基保护基”是指一类羟基取代基可有效阻挡或保护羟基功能。适当的保护基包括但不限于乙酰基和硅烷基。“羧基保护基”是指一类羧基取代基能有效阻挡或保护羧基的功能。常用羧基保护基包括但不限于-CH2CH2SO2Ph、氰乙基、2-(三甲硅基)乙基、2-(三甲硅基)乙氧基甲基、2-(对甲苯磺酰基)乙基、2-(对硝基苯硫基)乙基、2-(二苯基膦)-乙基和硝基乙基等。对于保护基的一般描述和使用说明,见T.W.Greene,Protective Groupsin Organic Synthesis,John Wiley&Sons,New York,1991。
至少一个化合物和/或其至少一个药学上可接受的盐的“给与”或“给药”是指为需要治疗的个体提供本发明中的化合物或其药学可接受的盐。
“有效量”是指目标化合物或其药学上可接受的盐能够引起组织、系统、动物或人类出现可被研究人员、兽医、临床医生或其他临床人员观察到的生物学或医学反应的剂量。
“组合物”包括:包含特定量的特定成分的产品,以及任何直接或间接这些特定量的特定成分的组合而成的产品。药学组合物包含:包含有效成分和作为载体的惰性成分的产品,以及任何两个或两个以上的成分直接或间接,通过组合、复合或聚集而制成的产品,或通过一个或更多的成分分解产生的产品,或通过一个或更多的成分发生其他类型反应或相互作用产生的产品。
“药学可接受”是指与制剂中的其它组分相容,并且对服用者无不可接受的毒害。
本发明提供至少一个式(I)所示的化合物:
和/或其至少一个药学上可接受的盐,其中
X为C或N;
Y为CR11,O,S,或NR12;
6-5元稠环系统A-B选自:
Q选自芳基或杂芳基;
R1选自:氢、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、C3-10环烷基-C1-4烷基、杂环基、杂环基-C1-4烷基、芳基、芳基-C1-4烷基、杂芳基和杂芳基-C1-4烷基,其中每个烷基、烯基、炔基、环烷基和杂环基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6a的取代基取代,其中每个芳基和杂芳基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6b的取代基取代;
R2选自:氢、卤素、羟基、CN、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、C3-10环烷基-C1-4烷基、杂环基、杂环基-C1-4烷基、芳基、芳基-C1-4烷基,杂芳基,和杂芳基-C1-4烷基,其中每个烷基、烯基、炔基、环烷基和杂环基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6a的取代基取代,其中每个芳基和杂芳基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6b的取代基取代;
R3和R4分别选自:氢、C1-10烷基、C2-10烯基、C2-10炔基和C3-10环烷基;其中每个烷基,烯基,炔基,和环烷基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6a的取代基取代;或R3和R4连同与它们相连的N原子一起形成一个含0、1、2或3个杂原子的4-12元环,其中杂原子独立选自氧、硫和氮,并任选由1-2个R6a取代基取代;
附带条件是,当R3和R4均为氢时,R2不是芳基或杂芳基;
每个R5独立地选自:氢、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、-OR8、-NR7S(O)rR8、-NO2、-卤素、-S(O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CR7(N-OR8)、-CHF2、-CF3、-OCHF2、和-OCF3;其中每个C1-10烷基、C2-10烯基、C2-10炔基和C3-10环烷基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6a的取代基;
每个R6a独立地选自:C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、-OR8、-NR7S(O)rR8、-NO2、-卤素、-S(O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CR7(NOR8)、-CHF2、-CF3、-OCHF2和-OCF3;
每个R6b独立地选自:R6a、芳基、芳基-C1-4烷基、杂芳基、和
杂芳基-C1-4烷基;
R7和R8独立地选自:氢、C1-10烷基、C2-10烯基、C2-10炔基、环烷基、环烷基-C1-4烷基、杂环基、杂环基C1-4烷基、芳基、杂芳基、芳基-C1-4烷基、杂芳基和
杂芳基-C1-4烷基;其中每个烷基、烯基、炔基、环烷基和杂环基是未被取代的或被至
少一个,如1、2、3或4个,独立选自R6a的取代基取代,其中每个芳基和杂芳基是
未被取代的或被至少一个,如1、2、3或4个,独立选自R6b的取代基取代;或R7和
R8一起连同与它们相连的单个或多个原子共同构成一个含有0、1或2个额外的独立
选自O,S和N的杂原子的4-12元杂环,该环可以是未被取代的或被1-2个选自R6b
的取代基取代;
R9和R10独立地选自:氢、C1-10烷基、C2-10烯基、C2-10炔基、环烷基、环烷基-C1-4烷基、杂环基、杂环基-C1-4烷基、芳基、芳基-C1-4烷基、杂芳基和杂芳基-C1-4烷基;或R9和R10一起连同与它们相连的单个或多个碳原子共同构成含有0、1或2个独立选自氧,硫和氮的杂原子的3-7元环,该环可以是未被取代的或被1-2个选自R6a的取代基取代;
R11选自:氢、C1-10烷基、C3-10环烷基、C3-10环烷基烷基、杂环基、杂环基-C1-4烷基、芳基、芳基-C1-4烷基、杂芳基、杂芳基-C1-4烷基、-OR7、-NR7S(O)rR8、-S(O)rR7、-SR7、-S(O)2OR7、-OS(O)2R7、-S(O)rNR7R8、-NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CHF2、-CF3、-OCHF2和-OCF3;
R12选自:氢、C1-10烷基、C3-10环烷基、C3-10环烷基-C1-4烷基、杂环基、杂环基-C1-4烷基、芳基、芳基-C1-4烷基、杂芳基、杂芳基-C1-4烷基、-S(O)rR7、-C(O)R7、-CO2R7、-CO2(CR9R10)tCONR7R8和-C(O)NR7R8;
m独立选自0、1、2和3;
每个r独立选自1和2;
每个t独立选自1、2和3。
在一些实施例中,6-5元稠环系统A-B是 其中每个R12和每个R11独立选自氢和C1-10烷基。最好每个R12和每个R11独立选自氢和甲基。
在一些实施例中,Q选自杂芳基。
在一些实施例中,Q选自吡啶基、哒嗪基和5,6,7,8-四氢-1,6-萘啶基。最好Q选自吡啶-2-基,哒嗪-3-基和5,6,7,8-四氢-1,6-萘啶-2-基。最好Q是吡啶-2-基.
在一些实施例中,R1选自于氢、C1-10烷基、杂环基、杂环基-C1-4烷基,其中杂环基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6a的取代基取代,其中每个R6a独立选自C1-10烷基、-NR7R8、-(CR9R10)tOR8、-OR8、-C(O)R7和-(CR9R10)tS(O)rR8,其中R7、R8、R9、R10、t和r如前所述。
在一些实施例中,Q选自吡啶-2-基,哒嗪-3-基,R1选自杂环基、杂环基-C1-4烷基,包括,例如:
其中杂环基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6a的取代基取代,其中每个R6a独立选自C1-10烷基、-NR7R8、-(CR9R10)tOR8、-OR8、-C(O)R7、-C(O)NR7R8和-(CR9R10)tS(O)rR8,其中R7、R8、R9、R10、t和r如前所述。
优选地,R6a独立选自于氢、甲基、乙基、羟基、羟甲基、羟乙基、乙酰基、羟乙酰基、甲氧基甲基、甲氧乙基、(甲磺酰基)乙基、氨基、氨基甲酰基、甲氨基和二甲氨基。
在一些实施例中,Q选自5,6,7,8-四氢-1,6-萘啶基,R1选自氢,C1-10烷基。
在一些实施例中,R2选自C3-10环烷基,其中环烷基是未被取代的或被至少一个,如1、2、3或4个,独立选自R6a的取代基取代.
在一些实施例中,R2选自环戊基和环己基,其中环己基是未被取代的或被甲基取代。最好R2选自环戊基和4-甲基环己基。
在一些实施例中,R3和R4是独立选自氢、C1-10烷基和C3-10环烷基,附加条件是当R3和R4均为氢时,R2不是芳基和杂芳基。最好R3和R4独立选自氢、甲基、乙基和环丙基,附加条件是当R3和R4均为氢时,R2不是芳基和杂芳基。
在一些实施例中,R3和R4与氮原子相连形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基和吗啉基,其中所形成的环是未被取代的或被甲基、羟基和甲氧基取代。
在一些实施例中,R5独立选自氢,C1-10烷基和-C(O)R7。其中R7选自甲基和羟甲基。
在一些实施例中,Q选自吡啶-2-基,哒嗪-3-基,R5是氢。
在一些实施例中,Q选自5,6,7,8-四氢-1,6-萘啶基,R5独立选自氢,C1-10烷基和-C(O)R7。其中R7选自甲基和羟甲基。
至少一个化合物选自:
7-环戊基-N,N-二甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)-5H-吡咯并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)-5H-吡咯并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)呋喃并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)呋喃并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N,5-三甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)-5H-吡咯并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N,5-三甲基-2-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)-5H-吡咯并[3,2-d]嘧啶-6-甲酰胺,
(S)-7-环戊基-N,N-二甲基-2-((5-(3-氧代四氢-3H-噁唑并[3,4-a]吡嗪-7(1H)-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
(R)-7-环戊基-N,N-二甲基-2-((5-(3-氧代四氢-3H-噁唑并[3,4-a]吡嗪-7(1H)-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
(R)-7-环戊基-N,N-二甲基-2-((5-(吗啉-2-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
2-((5-(4-氨基哌啶-1-基)吡啶-2-基)氨基)-7-环戊基-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((5-(4-(甲氨基)哌啶-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-2-((5-(4-(二甲基氨基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
(S)-7-环戊基-2-((5-(3-(甲氧基甲基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
(S)-7-环戊基-2-((5-(3-(甲氧基甲基)-4-甲基哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
(S)-7-环戊基-2-((5-(4-乙基-3-(甲氧基甲基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
(S)-7-环戊基-2-((5-(3-(羟甲基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
(S)-7-环戊基-2-((5-(3-(羟甲基)-4-甲基哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
(S)-7-环戊基-2-((5-(4-乙基-3-(羟甲基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
(R)-7-环戊基-2-((5-(3-(甲氧基甲基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
(R)-7-环戊基-2-((5-(3-(甲氧基甲基)-4-甲基哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
(R)-7-环戊基-2-((5-(4-乙基-3-(甲氧基甲基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
(R)-7-环戊基-2-((5-(3-(羟甲基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
(R)-7-环戊基-2-((5-(3-(羟甲基)-4-甲基哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
(R)-7-环戊基-2-((5-(4-乙基-3-(羟甲基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((5-(1-甲基哌啶-4-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
2-((5-(6-氨基-3-氮杂双环[3.1.0]己酰-3-基)吡啶-2-基)氨基)-7-环戊基-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((5-(哌嗪-1-基甲基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((5-((4-甲基哌嗪-1-基)甲基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-2-((5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
2-((5-((1S,4S)-2,5-二氮杂二环并[2.2.1]庚烷-2-基)吡啶-2-基)氨基)-7-环戊基-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((5-((1S,4S)-5-甲基-2,5-二氮杂二环并[2.2.1]庚烷-2-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
(R)-7-环戊基-2-((5-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
(S)-7-环戊基-2-((5-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
2-((5-((1R,4R)-2,5-二氮杂二环并[2.2.1]庚烷-2-基)吡啶-2-基)氨基)-7-环戊基-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
2-((5-(3,6-二氮杂二环并[3.1.1]庚烷-3-基)吡啶-2-基)氨基)-7-环戊基-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((5-(6-甲基-3,6-二氮杂二环并[3.1.1]庚烷-3-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-2-((5-(6-乙基-3,6-二氮杂二环并[3.1.1]庚烷-3-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-2-((5-((7R,8aR)-7-羟基六氢吡咯并[1,2-a]吡嗪-2(1H)-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-2-((5-((7S,8aR)-7-羟基六氢吡咯并[1,2-a]吡嗪-2(1H)-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-2-((5-((7R,8aS)-7-羟基六氢吡咯并[1,2-a]吡嗪-2(1H)-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
2-((5-(3,6-二氮杂二环并[3.2.0]庚烷-3-基)吡啶-2-基)氨基)-7-环戊基-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((5-(6-甲基-3,6-二氮杂二环并[3.2.0]庚烷-3-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-2-((5-(6-乙基-3,6-二氮杂二环并[3.2.0]庚烷-3-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((6-(哌嗪-1-基)哒嗪-3-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
2-((6-(4-乙酰哌嗪-1-基)哒嗪-3-基)氨基)-7-环戊基-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-2-((6-(4-(2-羟基乙酰)哌嗪-1-基)哒嗪-3-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((6-(4-(2-(甲磺酰基)乙基)哌嗪-1-基)哒嗪-3-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((5,6,7,8-四氢-1,6-萘啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((6-甲基-5,6,7,8-四氢-1,6-萘啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-2-((5-(4-(2-羟基乙基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-2-((5-(4-(2-甲氧基乙基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N,N-二甲基-2-((5-(4-(2-(甲磺酰基)乙基)哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-2-((5-(4-乙基哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-2-((5-((3S,5R)-3,5-二甲基哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺
7-环戊基-N,N-二甲基-2-((5-((3S,5R)-3,4,5-三甲基哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺
7-环戊基-2-((5-((3S,5R)-4-乙基-3,5-二甲基哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺
7-环戊基-N,N-二甲基-2-((5-(1-甲基-2,4-二氧代-1,3,8-三唑螺环[4.5]癸烷-8-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺
2-((5-(4-氨甲酰基-4-(甲基氨基)哌啶-1-基)吡啶-2-基)氨基)-7-环戊基-N,N-二甲基噻吩并[3,2-d]嘧啶-6-甲酰胺
氮杂环丁烷-1-基(7-环戊基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-基)甲酮,
(7-环戊基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-基)(3-甲氧基氮杂环丁烷-1-基)甲酮,
(7-环戊基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-基)(3-羟基氮杂环丁烷-1-基)甲酮,
(7-环戊基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-基)(哌啶-1-基)甲酮,
(7-环戊基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-基)(4-甲基哌嗪-1-基)甲酮,
(7-环戊基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-基)(哌嗪-1-基)甲酮,
7-环戊基-N-环丙基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
(7-环戊基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-基)(吡咯烷-1-基)甲酮,
7-环戊基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N-甲基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
7-环戊基-N-乙基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
(7-环戊基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-基)(吗啉)甲酮,
氮杂环丁烷-1-基(7-环戊基-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-基)甲酮,
(7-环戊基-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-基)(3-甲氧基氮杂环丁烷-1-基)甲酮,
(7-环戊基-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-基)(哌啶-1-基)甲酮,
(7-环戊基-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-基)(4-甲基哌嗪-1-基)甲酮,
7-环戊基-N-环丙基-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
(7-环戊基-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-基)(吡咯烷-1-基)甲酮,
7-环戊基-N-甲基-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
(7-环戊基-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-基)(吗啉)甲酮,
N,N-二甲基-7-((1r,4r)-4-甲基环己基)-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
N,N-二甲基-7-((1r,4r)-4-甲基环己基)-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
N,N-二甲基-7-((1r,4r)-4-甲基环己基)-2-((5,6,7,8-四氢-1,6-萘啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
N,N-二甲基-2-((6-甲基-5,6,7,8-四氢-1,6-萘啶-2-基)氨基)-7-((1r,4r)-4-甲基环己基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
2-((6-乙酰-5,6,7,8-四氢-1,6-萘啶-2-基)氨基)-N,N-二甲基-7-((1r,4r)-4-甲基环己基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
2-((6-(2-羟基乙酰)-5,6,7,8-四氢-1,6-萘啶-2-基)氨基)-N,N-二甲基-7-((1r,4r)-4-甲基环己基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
N,N-二甲基-7-((1r,4r)-4-甲基环己基)-2-((6-(哌嗪-1-基)哒嗪-3-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
N,N-二甲基-7-((1r,4r)-4-甲基环己基)-2-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
2-((6-(4-乙酰哌嗪-1-基)哒嗪-3-基)氨基)-N,N-二甲基-7-((1r,4r)-4-甲基环己基)噻吩并[3,2-d]嘧啶-6-甲酰胺,
2-((6-(4-(2-羟基乙酰)哌嗪-1-基)哒嗪-3-基)氨基)-N,N-二甲基-7-((1r,4r)-4-甲基环己基)噻吩并[3,2-d]嘧啶-6-甲酰胺;和/或其药学可接受的盐。
在另一方面,本发明提供了一种包含上述任何一个实施例及其变化形式的化合物的药物组合,其中组合物的给药途径包括口服、胃肠道外、腹腔内、静脉注射、动脉注射、透皮、舌下、肌内、直肠、口腔、鼻内、脂质体,经由吸入、阴道、眼内,通过局部给药(例如通过导管或支架),皮下、脂肪内、关节内或鞘内。
在另一方面,本发明提供了包含上述任何一个实施例及其变化形式的化合物的药盒;以及包括以下一项或多项信息的说明书:组合物应用于何种疾病、组合物储存信息、剂量信息以及如何使用组合物的说明。在一个特殊变化中,药盒包含多剂量形式的化合物。
在另一方面,本发明提供了包含上述任何一个实施例及其变化形式的化合物的制品;以及包装材料。在一种变化中,包装材料包括一个容器。在一个特殊变化中,所诉容器包括标签,其标明一项或多项以下内容:化合物应用于何种疾病、储存信息、剂量信息和/或如何使用组合物的说明。在另一种变化中,制品包括多剂量形式的化合物。
在另一方面,本发明提供了一种治疗方法,包含向某个体给予上述任何一个实施例及其变化形式的化合物。
在另一方面,本发明提供了一种通过上述任何一个实施例及其变化形式的化合物与CDK4/6作用从而抑制CDK4/6的方法。
在另一方面,本发明提供了一种抑制CDK4/6的方法,包括使上述任何一个实施例及其变化形式的化合物出现在某个体内,以抑制体内CDK4/6活性的方法。
在另一方面,本发明提供了一种抑制CDK4/6的方法,包括对某个体给药一个化合物,此化合物在体内转化为另一化合物,转化而成的化合物可以抑制体内CDK4/6活性,且该化合物为上述任何一个实施例及其变化形式的化合物。
在另一方面,本发明提供了一种治疗疾病状态的方法,CDK4/6活性造成了该疾病的病理和/或症状,该方法包含使治疗有效量的上述任何一个实施例及其变化形式的化合物出现在某个体体内,改善其疾病状态。
在另一方面,本发明提供了一种治疗疾病状态的方法,CDK4/6活性造成了该疾病的病理和/或症状,该方法包含对某个体给药一个化合物,此化合物在体内转化为另一化合物,转化而成的化合物可以抑制体内CDK4/6活性。值得注意的是,本发明所述化合物可以是转化前或转化后的化合物。
上述每个方法的变化中,疾病状态选自:癌性增殖性疾病(例如脑、肺、鳞状细胞、膀胱、胃、胰腺、乳腺、头、颈、肾、卵巢、前列腺、结肠、表皮、食道、睾丸、妇科或甲状腺癌);非癌性增殖性疾病(例如良性皮肤增生(如银屑病)、再狭窄和良性前列腺肥大(BPH));胰腺炎;肾脏疾病;疼痛;防止胚细胞植入;治疗与血管发生或血管生成相关疾病(例如肿瘤血管生成、急性和慢性感染性疾病如类风湿性关节炎、动脉粥样硬化、炎性肠病、皮肤病如银屑病、湿疹和硬皮病、糖尿病、糖尿病性视网膜病变、早产儿视网膜病变、老年性黄斑变性、血管瘤、神经胶质瘤、黑色素瘤、卡波济氏肉瘤和卵巢癌、乳腺癌、肺癌、胰腺癌、前列腺癌、结肠癌和表皮样癌);哮喘;中性粒细胞趋化性(例如,心肌梗死和中风的再灌注损伤和炎症性关节炎);感染性休克;T细胞接到的疾病,其中免疫抑制很有价值(如预防器官移植排斥、移植物抗宿主病、系统性红斑狼疮、多发性硬化和类风湿关节炎);动脉粥样硬化;抑制对生长因子混合物反应的角质细胞;肺慢性阻塞性疾病(COPD)和其他疾病。
在另一方面,本发明提供了一种治疗疾病状态的方法,CDK4/6基因突变造成了该疾病的病理和/或症状,例如黑色素瘤、肺癌、结肠癌和其他类型肿瘤。
在另一方面,本发明涉及上述任何一个实施例及其变化形式的化合物作为药物的用途。在另一方面,本发明涉及上述任何一个实施例及其变化形式的化合物作为抑制CDK4/6药物生产的用途。
在另一方面,本发明涉及上述任何一个实施例及其变化形式的化合物作为治疗CDK4/6活性造成的病理和/或症状的疾病状态的药物的生产。
给药和药学组合物
一般地,本发明所述化合物将以治疗有效量经由任何本领域已知的普通及可接受的方式,单独或与一个或多个治疗药物合用给药。治疗有效量可以广泛变化,取决于受试者的疾病严重性、年龄和相对健康状况,所用化合物的药效以及其他本领域已知的一般技能。例如,对于肿瘤性疾病和免疫系统疾病的治疗,所需剂量将根据给药模式,待治疗的具体病症和所需效果而异。
一般地,每日剂量为0.001至100mg/kg体重时可达到满意的结果,具体来说,从约0.03至2.5mg/kg体重。较大型哺乳动物的日剂量,如人类,可从约0.5mg至约2000mg,或更具体来说,从0.5mg至1000mg,以方便的形式给药,例如,以分剂量最多每日四次或以缓释形式。合适的口服给药的单位剂量形式包含约1至50mg活性成分。
本发明所述化合物可以以药学组合物形式给药,通过任何常规途径给药;例如经肠,例如口服,例如以片剂或胶囊形式,肠胃外,例如以可注射溶液或混悬液形式;或局部给药,例如以洗剂,凝胶剂,软膏剂或乳膏剂,或者以鼻或栓剂形式。
含有本发明所述的以游离碱或药学可接受盐型的化合物与至少一种药学可接受的载体或稀释剂的药学组合物,可以常规方式通过混合、制粒、包衣、溶解或冷冻干燥流程来制造。例如,药学组合物包含一个本发明所述化合物与至少一个药学可接受载体或稀释剂组合,可以以常规方式通过与药学可接受载体或稀释剂混合制成。用于口服的单位剂量形式包含,例如,从约0.1mg至约500mg活性物质。
在一个实施例中,药学组合物为活性成分的溶液,包含混悬剂或分散物,如等张水溶液。在仅包含活性成分或与如甘露醇的载体混合的冻干组合物的情况下,分散体或悬浮液可在使用前进行补充。药学组合物可以被灭菌和/或含有佐剂,如防腐剂、稳定剂、湿润剂或乳化剂、溶解促进剂、调节渗透压的盐和/或缓冲剂。合适的防腐剂包括但不仅限于抗氧化剂如抗坏血酸,杀微生物剂,如山梨酸或苯甲酸。溶液或悬浮液还可以包含增粘剂,包括但不仅限于羧甲基纤维素钠、羧甲基纤维素、葡聚糖、聚乙烯吡咯烷酮、明胶,或增溶剂,例如吐温80(聚氧乙烯(20)失水山梨醇单油酸酯)。
悬浮液在油中可能包含作为油性成分的植物油,合成或半合成的油,常用于注射目的。实施例包括含有作为酸组分的具有8至22个碳原子,或在一些实施方案中,从12至22个碳原子的长链脂肪酸的液体脂肪酸酯。合适的液体脂肪酸酯包括但不限于月桂酸、十三烷酸、肉豆蔻酸、十五烷酸、棕榈酸、十七烷酸、硬脂酸、花生酸、山萮酸或相应的不饱和酸,例如油酸、反油酸、芥酸、巴西烯酸和亚油酸,如果需要,可以含有抗氧化剂,例如维生素E、3-胡萝卜素或3,5-二-叔丁基羟基甲苯。这些脂肪酸酯的醇组分可以具有六个碳原子,并且可以是单价或多价的,例如单-,二-或三价的醇。合适的醇组分包括但不限于甲醇、乙醇、丙醇、丁醇或戊醇或者其异构体、乙二醇和甘油。
其它合适的脂肪酸酯包括但不限于油酸乙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、M2375(聚氧乙烯甘油)、M1944CS(通过醇解杏仁油的不饱和聚乙二醇化甘油酯和含有甘油酯和聚乙二醇酯)、LABRASOLTM(通过醇解TCM制备的饱和聚乙二醇化甘油酯和包含甘油酯和聚乙二醇酯;均可从法国GaKefosse公司获得)、和/或812(德国Hüls AG公司的链长为C8至C12的饱和脂肪酸甘油三酯),以及植物油如棉子油、杏仁油、橄榄油、蓖麻油、芝麻油、豆油或花生油。
用于口服给药的药物组合物可以通过,例如,通过将活性成分与一种或多种固体载体混合,如果需要,颗粒化所得的混合物,并通过加入另外的赋形剂加工所述混合物或颗粒,以形式片剂或片芯。
合适的载体包括但不限于填充剂,例如糖,例如乳糖、蔗糖,甘露醇或山梨醇,纤维素制剂和/或磷酸钙,例如磷酸三钙或磷酸氢钙,和还有粘合剂,例如淀粉,例如玉米,小麦,大米或马铃薯淀粉,甲基纤维素,羟丙基甲基纤维素,羧甲基纤维素钠和/或聚乙烯吡咯烷酮,和/或,如果需要的话,崩解剂,如上述淀粉,羧甲基淀粉,交联聚乙烯吡咯烷酮,藻酸或其盐,如藻酸钠。另外的赋形剂包括流动调节剂和润滑剂,例如硅酸,滑石粉,硬脂酸或其盐,如硬脂酸镁或硬脂酸钙,和/或聚乙二醇,或其衍生物。
可以为片剂芯提供合适的,可选肠溶的包衣,通过使用特别是,浓缩的糖溶液,其可包括阿拉伯树胶,滑石,聚乙烯吡咯烷酮,聚乙二醇和/或二氧化钛,或者荣誉合适有机溶剂或溶剂混合物的涂层溶液,或者,对于肠溶衣,合适的纤维素制品,如乙酰纤维素邻苯二甲酸酯或羟丙基甲基纤维素邻苯二甲酸酯溶液的制备。染料或颜料可以加入片剂或片剂包衣中,例如用于标识目的或指示不同剂量的活性成分。
用于口服给药的药物组合物还可以包括硬胶囊,包括明胶或含有明胶和增塑剂,如甘油或山梨醇的软密封胶囊。硬胶囊剂可含有活性成分的颗粒的形式,例如与填充剂如玉米淀粉,粘合剂和/或助流剂如滑石粉或硬脂酸镁,和任选的稳定剂混合。在软胶囊中,活性成分可以溶解或悬浮于合适的液体赋形剂如脂肪油,石蜡油或液体聚乙二醇或者乙二醇或丙二醇的脂肪酸酯中,向其中稳定剂和洗涤剂,例如聚氧乙烯山梨糖醇的脂肪酸酯型,也可加入。
适用于直肠给药的药物组合物,例如栓剂,其包含活性成分和栓剂基质的组合。合适的栓剂基质是,例如,天然或合成的甘油三酯、石蜡烃、聚乙二醇或高级链烷醇。
适于胃肠外给药的药物组合物可包含水溶性形式的活性成分,例如水溶性盐或包含增加粘度的物质的含水注射悬浮液,例如羧甲基纤维素钠,山梨糖醇的水溶液和/或葡聚糖,如果需要,和稳定剂。将活性成分,任选地与赋形剂,也可以是在一个冷冻干燥的形式,并且可在非肠道给药前通过加入合适的溶剂制成的溶液。使用的解决方案,例如,用于胃肠外给药,也可以用作输注溶液。注射制剂的制备通常在无菌条件下,填充进,例如,安瓿或小瓶,和密封的容器中。
本发明所述化合物可以作为唯一的活性成分,或与其它在免疫调节疗法有用的或抗肿瘤性疾病有用的药物一起给药。例如,本发明所述化合物与对上述各种疾病有效的药学组合物一起使用,例如,可以使用本发明所述化合物与环磷酰胺、5-氟尿嘧啶、氟达拉滨、吉西他滨、顺铂、卡铂、长春新碱、长春碱、依托泊苷、伊立替康、紫杉醇、多西他赛、利妥昔单抗、多柔比星、吉非替尼或伊马替尼;或者也与环孢菌素、雷帕霉素、子囊霉素或它们的免疫抑制类似物,例如环孢菌素A、环孢菌素G、FK-506、西罗莫司和依维莫司,糖皮质激素,如:泼尼松、环磷酰胺、硫唑嘌呤、甲氨蝶呤、金盐、柳氮磺吡啶、抗疟药、布喹那、来氟米特、咪唑立宾、麦考酚酸、麦考酚酸、酚酸酯和15-脱氧精胍菌素,免疫抑制单克隆抗体,例如单克隆抗体白细胞受体,例如MHC、CD2、CD3、CD4、CD7、CD25、CD28、I CD40、CD45、CD58、CD80、CD86、CD152、CD137、CD154、ICOS、LFA-1、VLA-4或它们的配体,或其它免疫调节化合物,例如CTLA41g。
本发明还提供了药物组合,例如一种药盒,其包含a)是本发明所公开的化合物,可以为游离形式或药学可接受的盐形式,和b)至少一种共同药物。该药盒可以包含其使用说明书。
实施例
化合物或其至少一个药学可接受的盐合成方法有多种,在本实例中列举出的是具有代表性的方法。然而,需要指出的是,至少一个式I的化合物或其至少一个药学可接受的盐也可能通过其它合成路线的合成得到。
式I的某化合物中,原子与其它原子之间的连接可能导致存在特殊的立体异构体(如手性中心)。合成至少一个式I的化合物或其至少一个药学可接受的盐可能产生不同异构体(对映异构体,非对映异构体)的混合物。除非特别说明是某个特定的立体构型,所列举的化合物均包括了其可能存在的不同立体异构体。
至少一个式I的化合物也可以制成药学可接收的酸加成盐,例如,通过将本发明化合物的游离碱的形式与药学可接受的无机或有机酸反应。或者将至少一个式I的化合物以游离酸的形式与药学可接受的无机或有机碱反应,将其制成药学可接受的碱加成盐。适宜于制备式I化合物的药学可接受盐的无机和有机的酸和碱已在本申请书的定义部分做了说明。此外,式I化合物盐的形式也可以通过使用起始原料或中间体的盐进行制备。
式I化合物的游离酸或游离碱可以通过其相应的碱加成盐或者酸加成盐制备得到。式I化合物的酸加成盐形式可转化成相应的游离碱,例如通过用合适的碱(如氢氧化铵溶液、氢氧化钠等)处理。式I化合物的碱加成盐形式可转化为相应的游离酸,例如通过用合适的酸(如盐酸等)处理。
至少一个式I的化合物或其至少一个药学可接受的盐的N-氧化物可通过本领域已知的方法制得。例如,N-氧化物可以通过将式I化合物的非氧化形式在接近0℃的条件下与氧化剂(如三氟过氧乙酸,过氧马来酸(permaleic acid),过氧苯甲酸,过氧乙酸,间氯过氧苯甲酸等)在惰性有机溶剂(如二氯甲烷等卤化烃)中反应得到。备择地,式I化合物的N-氧化物也可通过起始原料的N-氧化物制备得到。
非氧化形式的式I化合物可通过将其N-氧化物与还原剂(如硫、二氧化硫、三苯基膦、硼氢化锂、硼氢化钠、三氯化磷和三溴化磷等)在0~80℃的条件下在相应的惰性有机溶剂(如乙腈、乙醇和水合二氧六环等)中反应制得。
式I化合物的保护衍生物可以通过本领域人员熟知的方法制备得到。关于保护基团的加入和去除的详细技术描述参见:T.W.Greene,Protecting Groups in OrganicSynthesis,3rd edition,John Wiley&Sons,Inc.1999。
这些反应中所使用的标志和常识,图表与实例均与现行的科学文献相一致,例如,美国化学协会杂志或生物化学杂志。除非另有说明,标准的单字母或三字母的缩写通常指L型氨基酸残基。除非另有说明,所有使用的起始原料均从市场供应商购买得到,使用时并未进一步纯化。例如,在实例及整个说明书中会用到以下缩写:g(克),mg(毫克),L(升),mL(毫升),μL(微升),psi(磅每平方英寸),M(摩尔),mM(毫摩尔),i.v.(静脉注射),Hz(赫兹),MHz(兆赫),mol(摩尔),mmol(毫摩尔),RT(环境温度),min(分钟),h(小时),mp(熔点),TLC(薄层色谱法),Rt(保留时间),RP(反相),MeOH(甲醇),i-PrOH(异丙醇),TEA(三乙胺),TFA(三氟乙酸),TFAA(三氟乙酸酐),THF(四氢呋喃),DMSO(二甲基亚砜),EtOAc(乙酸乙酯),DME(1,2-二甲醚),DCM(二氯甲烷),DCE(二氯乙烷),DMF(N,N-二甲基甲酰胺),DMPU(N,N-二甲基丙烯基脲),CDI(1,1-羰基二咪唑),IBCF(氯甲酸异丁酯),HOAc(乙酸),HOSu(N-羟基琥珀酰亚胺),HOBT(1-羟基苯并三氮唑),Et2O(乙醚),EDCI(1-(3-二甲基氨基丙基)3-乙基碳亚胺盐酸盐),BOC(叔丁氧羰基),FMOC(9-芴基甲氧羰基),DCC(二环己基碳二亚胺),CBZ(氯甲酸苄酯),Ac(乙酰基),atm(大气压),TMSE(2-(三甲基硅基)乙基),TMS(三甲硅基),TIPS(三异丙基硅烷基),TBS(叔丁基二甲基硅基),DMAP(二甲基氨基吡啶),Me(甲基),OMe(甲氧基),Et(乙基),tBu(叔丁基),HPLC(高效液相色谱法),BOP(双(2-氧代-3-噁唑烷基)次磷酰氯),TBAF(四丁基氟化铵),mCPBA(间氯过氧苯甲酸)。
醚或Et2O均是指乙醚;盐水则是指饱和NaCl水溶液。除非另有说明,所有的温度均是指℃温度(摄氏度),所有的反应都是在室温下的惰性氛围中反应。
1H NMR谱采用Bruker Avance 400核磁共振光谱仪记录。化学位移为以ppm表示。耦合常数均以赫兹为单位(Hz)。以分割模式描述表观多样性,并定为s(单峰),d(双峰),t(三重峰),q(四重峰),m(多重峰),br(泛峰)。
低分辨质谱(MS)和化合物纯度数据来自Waters ZQ液质联用色谱的单极杆系统,该系统配备有电喷雾离子检测器(ESI),紫外探测器(220和254nm)及蒸发光散射检测器(ELSD)。薄层层析法使用的是0.25mmE.Merck公司的硅胶板(60F-254),5%的磷钼酸乙醇溶液,茚三酮或p-氧化苯基溶液并在紫外灯下观察。快速柱层析使用的是硅胶(230-400目,Merck公司)
合成路线
至少一个式I化合物和/或其至少一个药学上可接受的盐可由不同方法合成,一些示例性方法提供如下和实施例。其他合成方法可由本领域技术人员根据本发明披露的信息容易地提出。
实施例1
7-环戊基-N,N-二甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)噻吩并[3,2-d]嘧啶-
6-甲酰胺(1)
(5-溴-2-(甲硫基)嘧啶-4-基)(环戊基)甲醇(1a)
将5-溴-2-(甲巯基)嘧啶-4-羧酸(2.49g,10.0mmol),环戊甲醛(4.23g,43.2mmol)与苯甲醚(40mL)的混合物加热至140℃反应7小时。减压浓缩,残余物用硅胶柱层析纯化(洗脱剂:20-30%乙酸乙酯/石油醚)得标题化合物(5-溴-2-(甲硫基)嘧啶-4-基)(环戊基)甲醇(1a)为淡黄色液体(1.22g,40%)。MS-ESI(m/z):303and 305(1:1,100%),[M+1]+。
(5-溴-2-(甲硫基)嘧啶-4-基)(环戊基)甲酮(1b)
于0℃下,向1a(1.15g,3.79mmol)的无水二氯甲烷溶液(40mL)中加入Dess-Martin试剂(2.90g,6.83mmol)。升至室温并搅拌2小时,将反应混合物倒入饱和碳酸氢钠水溶液(100mL)中,乙酸乙酯(2×50mL)萃取。萃取液用饱和食盐水洗涤,无水硫酸镁干燥并减压浓缩。残余物用硅胶柱层析纯化(洗脱剂:10-20%乙酸乙酯/石油醚)得标题化合物(5-溴-2-(甲硫基)嘧啶-4-基)(环戊基)甲酮(1b)为淡黄色液体(1.10g,96%)。MS-ESI(m/z):301和303(1:1,100%),[M+1]+。
7-环戊基-2-(甲硫基)噻吩并[3,2-d]嘧啶-6-羧酸(1c)
室温下,向1b(73.6mg,0.244mmol)和巯基乙酸甲酯(27.2mg,0.256mmol)的DMF溶液(1mL)中加入NaH(60%,19.5mg,0.488mmol),混合物在室温下搅拌反应15分钟,然后加热到60℃反应3小时。冷却到室温,将5N NaOH(0.2mL)加入到反应液中,搅拌1小时。然后用水稀释,用1N HCl调节pH=3~4。乙酸乙酯(2×5mL)萃取。萃取液用饱和食盐水洗涤,无水硫酸镁干燥并减压浓缩得到标题化合物7-环戊基-2-(甲硫基)噻吩并[3,2-d]嘧啶-6-羧酸(1c)为白色固体(72.0mg,100%)。MS-ESI(m/z):295(100%),[M+1]+。直接用于下一步。
7-环戊基-N,N-二甲基-2-(甲硫基)噻吩并[3,2-d]嘧啶-6-甲酰胺(1d)
向1c(71.9mg,0.244mmol),二甲胺盐酸盐(39.8mg,0.488mmol),EDCI(70.3mg,0.366mmol),HOBT水合物(56.0mg,0.366mmol)和无水DMF(2mL)的混合物中加入DIPEA(127μL,0.732mmol)。室温下,搅拌反应17小时。将反应混合物倒入水中,乙酸乙酯(2×5mL)萃取,萃取液用饱和食盐水洗涤,无水硫酸镁干燥并减压浓缩。残余物用硅胶柱层析纯化(洗脱剂:50%乙酸乙酯/石油醚)得标题化合物7-环戊基-N,N-二甲基-2-(甲硫基)噻吩并[3,2-d]嘧啶-6-甲酰胺(1d)为无色油状物(63.8mg,81%)。MS-ESI(m/z):322(100%),[M+1]+。
7-环戊基-N,N-二甲基-2-(甲基磺酰)噻吩并[3,2-d]嘧啶-6-甲酰胺(1e)
于0℃下,向1d(63.0mg,0.196mmol)的二氯甲烷溶液(4mL)中加入mCPBA(75%,113mg,0.490mmol)。升至室温并搅拌1小时。加入饱和NaHSO3(2mL),搅拌10分钟。将反应混合物倒入饱和NaHCO3(10mL)水溶液中,二氯甲烷(2×10mL)萃取。减压干燥浓缩得标题化合物7-环戊基-N,N-二甲基-2-(甲基磺酰)噻吩并[3,2-d]嘧啶-6-甲酰胺(1e)(69.3mg,100%)为白色固体。MS-ESI(m/z):354[M+1]+。
叔丁基4-(6-(7-环戊基-6-(二甲基甲酰胺)噻吩并[3,2-d]嘧啶-2-基氨基)吡啶-
3-基)哌嗪-1-羧酸酯(1f)
在室温下,向叔丁基4-(6-甲酰胺基吡啶-3-基)哌嗪-1羧酸酯(48.8mg,0.159mmol)的DMF溶液(0.5mL)中加入NaH(60%,10mg,0.25mmol),并在此温度下反应20分钟,然后加入1e(51.2mg,0.145mmol)的DMF溶液(0.5mL)。室温反应1小时。将甲醇(3mL)加入到反应液中,搅拌半小时。然后用水稀释,乙酸乙酯(2×10mL)萃取,饱和食盐水洗涤,减压干燥浓缩得标题化合物叔丁基4-(6-(7-环戊基-6-(二甲基甲酰胺)噻吩并[3,2-d]嘧啶-2-基氨基)吡啶-3-基)哌嗪-1-羧酸酯(1f)为白色固体(90mg)。MS-ESI(m/z):552[M+1]+。
7-环戊基-N,N-二甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)噻吩并[3,2-d]嘧啶e-
6-甲酰胺(1)
向1f(80mg)的二氯甲烷溶液(3mL)中加入TFA(3mL)。室温搅拌1小时。减压干燥浓缩,残余物用硅胶柱层析纯化(洗脱剂:94:5:1二氯甲烷-甲醇-氨水)得标题化合物7-环戊基-N,N-二甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)噻吩并[3,2-d]嘧啶e-6-甲酰胺(1)为淡黄色固体(32.8mg,50%,2步)。MS-ESI(m/z):452[M+1]+。
实施例2
7-环戊基-N,N-二甲基-2-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)噻吩并[3,2-d]
嘧啶-6-甲酰胺(2)
将1(15.3mg,0.034mmol),甲醛(37%水溶液,14mg,0.17mmol),NaBH(OAc)3(9.3mg,0.044mmol)和二氯甲烷(1mL)的混合物在室温下搅拌反应0.5小时,将反应混合物用NaHCO3溶液(5mL)稀释,二氯甲烷(2×5mL)萃取。干燥浓缩,残余物用硅胶柱层析纯化(洗脱剂:96:3:1二氯甲烷-甲醇-氨水)得标题化合物7-环戊基-N,N-二甲基-2-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺(2)为淡黄色固体。MS-ESI(m/z):466[M+1]+。
实施例3
7-环戊基-N,N-二甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)-5H-吡咯[3,2-d]嘧
啶-6-甲酰胺(3)
叔丁基2-(4-(环戊烷甲酰)-2-(甲硫基)嘧啶-5-基氨基)醋酸酯(3a)
在氮气保护下,将化合物(1b,752mg,2.50mmol),甘氨酸叔丁酯盐酸盐(502mg,3.00mmol),Pd2(dba)3(229mg,0.25mmol),Xantphos(145mg,0.25mmol)以及碳酸铯(2.61g,8.00mmol)在二氧六环(25mL)加热16小时。冷至室温后用水稀释,乙酸乙酯萃取(2×)。有机相用饱和食盐水洗涤。干燥(Na2SO4)后浓缩除去溶剂。粗产物用硅胶柱层析纯化,20-30%乙酸乙酯-己烷洗脱得产物(3a,460mg,52%,黄色固体)。MS-ESI(m/z):352[M+1]+。
叔丁基2-(N-(4-(环戊烷甲酰)-2-(甲硫基)嘧啶-5-基)乙酰氨基)醋酸酯(3b)
向化合物3a(272mg,0.775mmol)的无水二氯甲烷(8mL)溶液中室温下加入吡啶(135mg,1.71mmol)和DMAP(4.7mg,0.04mmol)。然后滴加乙酰氯(183mg,2.33mmol),室温搅拌16小时。水(30mL)稀释,二氯甲烷萃取(2×15mL)。萃取物用饱和食盐水洗涤。干燥(MgSO4)后浓缩除去溶剂。粗产物用硅胶柱层析纯化,30-50%乙酸乙酯-己烷洗脱得产物叔丁基2-(N-(4-(环戊烷甲酰)-2-(甲硫基)嘧啶-5-基)乙酰氨基)醋酸酯(3b,298mg,98%,淡黄色油状物)。MS-ESI(m/z):394[M+1]+。
叔丁基5-乙酰基-7-环戊基-7-羟基-2-(甲硫基)-6,7-二氢-5H-吡咯[3,2-d]嘧
啶-6-羧酸酯(3c)
向化合物3b(412mg,1.05mmol)的DMF(8mL)溶液中加入K2CO3(362mg,2.62mmol)。将该混合物在60℃加热2小时。冷至室温后用水稀释,乙酸乙酯萃取(2×20mL))。有机相用饱和食盐水洗涤。干燥(Na2SO4)后浓缩除去溶剂。得粗产物叔丁基5-乙酰基-7-环戊基-7-羟基-2-(甲硫基)-6,7-二氢-5H-吡咯[3,2-d]嘧啶-6-羧酸酯(3c,412mg,100%,黄色油状物)。MS-ESI(m/z):394[M+1]+。直接用于下一步反应。
5-乙酰基-7-环戊基-7-羟基-2-(甲硫基)-6,7-二氢-5H-吡咯[3,2-d]嘧啶-6-羧
酸(3d)
向3c(412mg,1.05mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(5mL)。室温搅拌2小时。蒸干溶剂的粗产物5-乙酰基-7-环戊基-7-羟基-2-(甲硫基)-6,7-二氢-5H-吡咯[3,2-d]嘧啶-6-羧酸(3d,353mg,100%,黄色油状物)。MS-ESI(m/z):338[M+1]+。直接用于下一步反应。
5-乙酰基-7-环戊基-7-羟基-N,N-二甲基-2-(甲硫基)-6,7-二氢-5H-吡咯[3,2-
d]嘧啶-6-甲酰胺(3e)
向化合物3d(220mg,0.651mmol),二甲胺盐酸盐(106mg,1.30mmol),EDCI(187mg,0.977mmol)以及HOBT单水合物(150mg,0.977mmol)的无水二甲基甲酰胺(4mL)溶液中加入DIPEA(567μL,3.26mmol)。混合物室温搅拌17小时。用水稀释,乙酸乙酯萃取(2×)。有机相用饱和食盐水洗涤。干燥(Na2SO4)后浓缩除去溶剂。粗产物用硅胶柱层析纯化,50-100%乙酸乙酯-己烷洗脱得产物5-乙酰基-7-环戊基-7-羟基-N,N-二甲基-2-(甲硫基)-6,7-二氢-5H-吡咯[3,2-d]嘧啶-6-甲酰胺(3e,127mg,54%,白色固体)。MS-ESI(m/z):365[M+1]+。
5-乙酰-7-环戊基-7-羟基-N,N-二甲基-2-(甲基磺酰)-6,7-二氢-5H-吡咯[3,2-
d]嘧啶-6-甲酰胺(3f)
0℃下,向化合物3e(169mg,0.465mmol)的二氯甲烷(10mL)溶液中加入mCPBA(75%,267mg,1.16mmol)。室温搅拌2小时。加入饱和NaHSO3(3mL),搅拌10分钟。用饱和NaHCO3(20mL)稀释,二氯甲烷萃取(2×15mL)。萃取物干燥(Na2SO4)后蒸去溶剂得粗产物5-乙酰-7-环戊基-7-羟基-N,N-二甲基-2-(甲基磺酰)-6,7-二氢-5H-吡咯[3,2-d]嘧啶-6-甲酰胺(3f,184mg,100%,白色固体)。MS-ESI(m/z):397[M+1]+。
叔丁基4-(6-(5-乙酰基-7-环戊基-6-(二甲基甲酰胺)-7-羟基-6,7-二氢-5H-吡
咯[3,2-d]嘧啶-2-基氨基)吡啶-3-基)哌嗪-1-羧酸酯(3g)
室温下,向4-(6-甲酰氨基吡啶-3-基)哌嗪-1-碳酸叔丁酯(69.0mg,0.225mmol)的DMF(1mL)溶液中加入NaH(60%,15mg,0.36mmol)。室温搅拌20分钟。加入化合物3f(85.0mg,0.215mmol)的DMF(1mL)溶液。室温搅拌1小时。加入甲醇(3mL)并搅拌30分钟。用水稀释(1mL),乙酸乙酯萃取(2×)。干燥(Na2SO4)后浓缩除去溶剂。粗产物用硅胶柱层析,50-100%乙酸乙酯-己烷洗脱然后用5%甲醇-乙酸乙酯洗脱得产物叔丁基4-(6-(5-乙酰基-7-环戊基-6-(二甲基甲酰胺)-7-羟基-6,7-二氢-5H-吡咯[3,2-d]嘧啶-2-基氨基)吡啶-3-基)哌嗪-1-羧酸酯(3g,39.0mg,30%,白色固体)。MS-ESI(m/z):595[M+1]+。
7-环戊基-N,N-二甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)-5H-吡咯[3,2-d]嘧
啶-6-甲酰胺(3)
化合物3g(14.3mg)的0.5M H2SO4/甲醇(1mL)溶液于50℃加热16小时。冷至室温后加入NaHCO3(90mg),搅拌10分钟。旋蒸溶剂。粗产物用硅胶柱层析,94:5:1二氯甲烷-甲醇-氨水洗脱得产物7-环戊基-N,N-二甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)-5H-吡咯[3,2-d]嘧啶-6-甲酰胺(3,3.0mg,29%,淡黄色固体)。MS-ESI(m/z):435[M+1]+。
实施例4
7-环戊基-N,N-二甲基-2-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)-5H-吡咯[3,2-
d]嘧啶-6-甲酰胺(4)
5-乙酰基-7-环戊基-7-羟基-N,N-二甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)-6,
7-二氢-5H-吡咯[3,2-d]嘧啶-6-甲酰胺(4a)
向化合物3g(24.7mg,0.0416mmol)的二氯甲烷(1mL)溶液中加入三氟乙酸(1.5mL)。室温搅拌1.5小时。浓缩除去溶剂。粗产物用硅胶柱层析,92:7:1二氯甲烷-甲醇-氨水(28%)洗脱得产物5-乙酰基-7-环戊基-7-羟基-N,N-二甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)-6,7-二氢-5H-吡咯[3,2-d]嘧啶-6-甲酰胺(4a,7.0mg,34%,淡黄色固体)。MS-ESI(m/z):495[M+1]+。
5-乙酰基-7-环戊基-7-羟基-N,N-二甲基-2-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨
基)-6,7-二氢-5H-吡咯[3,2-d]嘧啶-6-甲酰胺(4b)
向化合物4a(7.0mg,0.014mmol)的1,2-二氯乙烷(0.3mL)溶液中加入甲醛(37%水溶液,14mg,0.17mmol)和NaBH(OAc)3(4.5mg,0.021mmol)。室温搅拌1小时。用饱和NaHCO3(5mL)稀释,二氯甲烷萃取(2×)。干燥(Na2SO4)后浓缩除去溶剂。粗产物纯化用硅胶柱层析,96:3:1二氯甲烷-甲醇-氨水洗脱得产物5-乙酰基-7-环戊基-7-羟基-N,N-二甲基-2-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)-6,7-二氢-5H-吡咯[3,2-d]嘧啶-6-甲酰胺(4b,5.5mg,76%,黄色固体)。MS-ESI(m/z):509[M+1]+。
7-环戊基-N,N-二甲基-2-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)-5H-吡咯[3,2-
d]嘧啶-6-甲酰胺(4)
将化合物4b(5.5mg)的0.5M H2SO4/甲醇(1mL)溶液于50℃加热14小时。冷却至室温后加入NaHCO3(90mg),搅拌10分钟。浓缩除去溶剂。粗产物用硅胶柱层析,94:5:1二氯甲烷-甲醇-氨水洗脱得产物7-环戊基-N,N-二甲基-2-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)-5H-吡咯[3,2-d]嘧啶-6-甲酰胺(4,4.3mg,89%,淡黄色固体)。MS-ESI(m/z):449[M+1]+。
实施例5
7-环戊基-N,N-二甲基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)吡咯并[2,1-f][1,
2,4]三嗪-6-甲酰胺(5)
6-甲基-3-硫基-3,4-二氢-1,2,4-三嗪-5(2H)-酮(5a)
室温下,向丙酮酸(18.4g,0.2mol)的水溶液(400mL)中加入硫代氨基脲(18.4g,0.2mol)。加热反应体系至70℃搅拌1小时。待冷却至室温后,于搅拌状态下分批加入碳酸钠(21.2g,0.2mol),反应体系再次加热回流3小时。待冷却至室温后,用冰醋酸调节pH至5。该混悬体系用乙酸乙酯萃取(500mL×2),有机相经水和饱和食盐水洗涤,无水硫酸钠干燥后,过滤浓缩得浅黄色固体6-甲基-3-硫基-3,4-二氢-1,2,4-三嗪-5(2H)-酮(5a,23.6g)。MS-ESI(m/z):144[M+1]+。
6-甲基-3-(甲硫基)-1,2,4-三嗪-5(4H)-酮(5b)
室温下,向5a(23.6g,165mmol)的1N氢氧化钠水溶液(330mL)中滴加碘甲烷(10.3mL,165mmol),反应体系在室温搅拌1小时后用冰醋酸中和至pH 5。该混悬体系经减压过滤,用水洗涤(500mL×2),干燥得产物6-甲基-3-(甲硫基)-1,2,4-三嗪-5(4H)-酮(5b,14.5g)。MS-ESI(m/z):158[M+1]+。
5-氯-6-甲基-3-(甲硫基)-1,2,4-三嗪(5c)
将5b(14.5g,92mmol)和三氯氧磷(120mL)的混合物加热至回流反应1小时,待反应体系冷却至50℃后,减压浓缩至1/5体积量。浓缩液经二氯甲烷(500mL)稀释,冰水(500mL×5)和饱和食盐水(500mL×2)洗涤,无水硫酸钠干燥。有机相经减压过滤,滤液浓缩得黑色浆状物5-氯-6-甲基-3-(甲硫基)-1,2,4-三嗪(5c,9.6g)。MS-ESI(m/z):176[M+1]+。
6-甲基-3-(甲硫基)-1,2,4-三嗪(5d)
向冰水冷却的5c(9.6g,55mmol)的异丙醇(210mL)混悬液中分批缓慢加入硼氢化钠(10.5g,275mmol),反应体系在0-5℃搅拌1小时后过滤,滤饼经冷的异丙醇(20mL)洗涤,滤液合并,浓缩至干。粗品与二氯甲烷(300mL)混合搅拌,缓慢分批加入DDQ(12.5g,55mmol),并于室温搅拌16小时,反应体系经过滤,二氯甲烷洗涤,滤液浓缩至干。粗品经硅胶柱层析(洗脱相:石油醚/乙酸乙酯=50:1→10:1)纯化得6-甲基-3-(甲硫基)-1,2,4-三嗪(5d,2.3g)。MS-ESI(m/z):142[M+1]+。
6-(溴甲基)-3-(甲硫基)-1,2,4-三嗪(5e)
向5d(2.3g,16.3mmol)的四氯化碳CCl4(80mL)溶液中加入N-溴代丁二酰亚胺(3.2g,17.9mmol)和过氧苯甲酸酐(395mg,1.63mmol)。该体系加热至回流反应1小时后补加N-溴代丁二酰亚胺(3.2g,17.9mmol)和过氧苯甲酸酐(395mg,1.63mmol)。该体系再次回流反应1小时。体系冷却至室温后过滤,二氯甲烷(20mL)洗涤。合并的滤液经饱和亚硫酸钠水溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,硅胶柱层析(洗脱相:石油醚/乙酸乙酯=50:1→25:1)纯化得6-(溴甲基)-3-(甲硫基)-1,2,4-三嗪(5e,0.88g)。MS-ESI(m/z):220,222[M+1]+。
乙基3-环戊基-2-((3-(甲硫基)-1,2,4-三嗪-6-基)甲基)-3-丙酮酸酯(5f)
向冰水冷却的环戊基甲酰乙酸乙酯(1.47g,8.0mmol)的N,N-二甲基甲酰胺(8.0mL)溶液中加入60%氢化钠(160mg,4.0mmol),升至室温搅拌10分钟后,再次冷却至0-5℃,加入5e(0.88g,4.0mmol)的N,N-二甲基甲酰胺(4.0mL)溶液。该体系缓慢升至室温反应1小时后用饱和氯化铵水溶液淬灭,乙酸乙酯萃取。有机相经水和饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,硅胶柱层析(洗脱相:石油醚/乙酸乙酯=50:1→10:1)纯化得乙基-3-环戊基-2-((3-(甲硫基)-1,2,4-三嗪-6-基)甲基)-3-丙酮酸酯(5f,0.75g)。MS-ESI(m/z):324[M+1]+。
乙基7-环戊基-2-(甲硫基)吡咯并[2,1-f][1,2,4]三嗪-6-羧酸酯(5g)
将5f(0.75g,2.3mmol)和三氯氧磷(23mL)混合加热至回流反应16小时,待体系冷却至50℃后浓缩至干,粗品乙基-7-环戊基-2-(甲硫基)吡咯并[2,1-f][1,2,4]三嗪-6-羧酸酯(5g)直接用于下一步反应。MS-ESI(m/z):306[M+1]+。
7-环戊基-2-(甲硫基)吡咯并[2,1-f][1,2,4]三嗪-6-羧酸(5h)
向5g(700mg,2.3mmol)的四氢呋喃/甲醇/水混合溶液(36mL,v:v:v=1:1:1)中加入氢氧化锂一水合物(1.45g,34.5mmol),该体系于室温反应16小时后,用1N盐酸水溶液中和至pH 2-3,用乙酸乙酯萃取。有机相经水和饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩至干。粗品7-环戊基-2-(甲硫基)吡咯并[2,1-f][1,2,4]三嗪-6-羧酸(5h)直接用于下一步反应。MS-ESI(m/z):278[M+1]+。
7-环戊基-N,N-二甲基-2-(甲硫基)吡咯并[2,1-f][1,2,4]三嗪-6-甲酰胺(5i)
5h(554mg,2.0mmol)与HOBT(540mg,4.0mmol),EDCI(575mg,3.0mmol),二甲胺盐酸盐(489mg,6.0mmol),三乙胺(1.39mL,10.0mmol)以及分子筛(2.0g)的N,N-二甲基甲酰胺(20mL)溶液于室温搅拌16小时。反应液经水和乙酸乙酯萃取,有机相经水,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩至干得粗品5i,直接用于下一步反应。MS-ESI(m/z):305[M+1]+.
7-环戊基-N,N-二甲基-2-(甲基硫代)吡咯并[2,1-f][1,2,4]三嗪-6-甲酰胺(5j)
向5i(630mg,2.0mmol)的二氯甲烷溶液(20mL)中加入间氯过氧苯甲酸(460mg,2.0mmol),反应体系在室温条件下搅拌1小时后,用饱和碳酸氢钠水溶液淬灭。有机相经水,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩至干得粗品7-环戊基-N,N-二甲基-2-(甲基硫代)吡咯并[2,1-f][1,2,4]三嗪-6-甲酰胺(5j),直接用于下一步反应。MS-ESI(m/z):321[M+1]+。
7-环戊基-2-((4-甲氧基苄基)氨基)-N,N-二甲基吡咯并[2,1-f][1,2,4]三嗪-6-
甲酰胺(5k)
向5j(665mg,2.0mmol)的N-甲基吡咯烷酮溶液中(20mL)加入对甲基苄胺(1.30mL,10.0mmol),反应液加热至80℃,搅拌16小时。待冷至室温后用水和乙酸乙酯萃取。经水,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩至干得粗品7-环戊基-2-((4-甲氧基苄基)氨基)-N,N-二甲基吡咯并[2,1-f][1,2,4]三嗪-6-甲酰胺(5k),直接用于下一步反应。MS-ESI(m/z):394[M+1]+。
2-氨基-7-环戊基-N,N-二甲基吡咯并[2,1-f][1,2,4]三嗪-6-甲酰胺(5l)
向5k(≈500mg,1.0mmol)的二氯甲烷溶液中(10mL)缓慢滴加三氟乙酸(10mL),反应体系在室温下搅拌5小时,浓缩至干,经氨水碱化至pH 9-10,再次浓缩至干。粗品经硅胶柱层析纯化(洗脱相:二氯甲烷/甲醇=100:1→10:1)得2-氨基-7-环戊基-N,N-二甲基吡咯并[2,1-f][1,2,4]三嗪-6-甲酰胺(5l)(136mg)。MS-ESI(m/z):274[M+1]+。
叔丁基4-(6-((7-环戊基-6-(二甲基氨基甲酰基)吡咯并[2,1-f][1,2,4]三嗪-2-
基)氨基)吡啶-3-基)哌嗪-1-羧酸酯(5m)
将5l(10mg,0.03663mmol)、2-氯-5-(4′-叔丁氧羰基哌嗪基)-吡啶(22mg,0.07326mmol)、Pd2dba3(12.8mg,0.01832mmol)、Xphos(21.2mg,0.03663mmol)和叔丁醇钠(10.5mg,0.11mmol)混合于1,4-二氧六环(0.72mL)中,于氮气保护下加热至105℃搅拌16小时。待冷至室温后,用乙酸乙酯稀释,经硅藻土过滤,滤液浓缩至干。粗品经硅胶柱层析纯化(洗脱相:二氯甲烷/甲醇=100:1→10:1)得到叔丁基4-(6-((7-环戊基-6-(二甲基氨基甲酰基)吡咯并[2,1-f][1,2,4]三嗪-2-基)氨基)吡啶-3-基)哌嗪-1-羧酸酯(5m,7.0mg)。MS-ESI(m/z):535[M+1]+。
7-环戊基-N,N-二甲基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)吡咯并[2,1-f][1,
2,4]三嗪-6-甲酰胺(5)
将5m(7.0mg,0.0131mmol)溶于4N氯化氢/乙酸乙酯混合液在室温下搅拌3小时,浓缩至干后用氨水碱化至pH 9-10,再次浓缩至干,粗品经硅胶柱层析纯化(洗脱相:二氯甲烷/甲醇=10:1)得标题化合物7-环戊基-N,N-二甲基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-6-甲酰胺(5,4.6mg)。MS-ESI(m/z):435[M+1]+。
实施例6
7-环戊基-N,N-二甲基-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)吡咯并[2,1-
f][1,2,4]三嗪-6-甲酰胺(6)
将5l(11mg,0.040mmol)、1-(6-氯吡啶-3-基)-4-甲基哌嗪(15mg,0.071mmol)、Pd2dba3(7.0mg,0.010mmol)、Xphos(11.6mg,0.020mmol)和叔丁醇钠(19.2mg,0.20mmol)混合于1,4-二氧六环(1.2mL)中,于氮气保护下加热至105℃搅拌16小时。待冷至室温后,用乙酸乙酯稀释,经硅藻土过滤,滤液浓缩至干。粗品经硅胶柱层析纯化(洗脱相:二氯甲烷/甲醇=10:1)得7-环戊基-N,N-二甲基-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-6-甲酰胺(6)(5.0mg)。MS-ESI(m/z):449[M+1]+。
实施例7
7-环戊基-N,N-二甲基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)呋喃并[3,2-d]嘧
啶-6-甲酰胺(7)
5-溴-4-(((叔丁基二甲基硅烷基)氧基)(环戊基)甲基)-2-(甲硫基)嘧啶(7a)
于氮气保护下,0-5℃下,向1a(1.6g,5.28mmol)的乙腈(26mL)溶液中加入DBU(4.74mL,31.7mmol)和TBSCl(3.98g,26.4mmol)。反应体系缓慢升至室温搅拌5小时,后经乙酸乙酯(50mL)稀释,1N HCl水溶液(20mL),水(25mL),饱和NaHCO3水溶液(20mL)和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩至干,粗品经硅胶柱层析纯化(洗脱相:正己烷/乙酸乙酯=100:1)得5-溴-4-(((叔丁基二甲基硅烷基)氧基)(环戊基)甲基)-2-(甲硫基)嘧啶(7a)(2.2g).MS-ESI(m/z):417,419[M+1]+。
(4-(((叔丁基二甲基硅烷基)氧基)(环戊基)甲基)-2-(甲硫基)嘧啶-5-基)硼酸
(7b)
在冷至-78℃,氮气保护下,向冰水冷却的7a(2.2g,5.2mmol)的无水四氢呋喃(52mL)溶液中滴加硼酸三甲酯(4.0mL,36mmol)和正丁基锂(2.5M正己烷溶液,12mL)。反应液经2小时缓慢升至0℃,经3N盐酸水溶液(13mL)淬灭,乙酸乙酯(50mL)萃取,饱和食盐水洗,无水硫酸钠干燥,过滤浓缩得无色残余物(4-(((叔丁基二甲基硅烷基)氧基)(环戊基)甲基)-2-(甲硫基)嘧啶-5-基)硼酸(7b),直接用于下一步反应。MS-ESI(m/z):383[M+1]+。
4-(((叔丁基二甲基硅烷基)氧基)(环戊基)甲基)-2-(甲硫基)嘧啶-5-基-醇(7c)
向冰水冷却的7b(粗品,约5.2mmol)四氢呋喃/水(60mL,v:v=1:1)溶液中分批加入硼酸钠四水合物(2.3g,15mmol),反应液升至室温搅拌5小时,经1N盐酸中和至pH 2-3,乙酸乙酯萃取,水和饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩至干。粗品经硅胶柱层析纯化(洗脱相:正己烷/乙酸乙酯=20:1)得4-(((叔丁基二甲基硅烷基)氧基)(环戊基)甲基)-2-(甲硫基)嘧啶-5-基-醇(7c)(1.6g).MS-ESI(m/z):355[M+1]+。
乙基2-((4-(((叔丁基二甲基硅烷基)氧基)(环戊基)甲基)-2-(甲硫基)嘧啶-5-
基)氧基)醋酸酯(7d)
向7c(1.6g,4.5mmol)和溴乙酸乙酯(0.5mL,4.5mmol)的N,N-二甲基甲酰胺溶液中(23mL)加入碳酸铯(2.2g,6.8mmol),体系在室温下搅拌1小时,经饱和氯化铵水溶液淬灭,乙酸乙酯萃取,水和饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩至干得乙基2-((4-(((叔丁基二甲基硅烷基)氧基)(环戊基)甲基)-2-(甲硫基)嘧啶-5-基)氧基)醋酸酯(7d),粗品直接用于下一步反应。MS-ESI(m/z):441[M+1]+。
乙基2-((4-(环戊基(羟基)甲基)-2-(甲硫基)嘧啶-5-基)氧基)醋酸酯(7e)
氮气保护下,向冰水冷却的7d(粗品,约4.5mmol)的乙腈溶液中(45mL)中滴加三氟化硼乙醚(3.0mL),反应液升至室温搅拌30分钟后经饱和碳酸氢钠水溶液中和至pH 8-9,乙酸乙酯萃取,水和饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩至干得乙基2-((4-(环戊基(羟基)甲基)-2-(甲硫基)嘧啶-5-基)氧基)醋酸酯(7e)(1.1g)。MS-ESI(m/z):327[M+1]+。
乙基2-((4-(环戊烷甲酰基)-2-(甲硫基)嘧啶-5-基)氧基)醋酸酯(7f)
向冰水冷却的7e(490mg,1.5mmol)二氯甲烷溶液中(20mL)加入戴斯-马丁氧化剂(1.28g,3.0mmol),反应液升至室温搅拌1小时后经饱和碳酸氢钠水溶液(10mL)淬灭,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩至干。粗品经硅胶柱层析纯化(洗脱相:正己烷/乙酸乙酯=20:1)得乙基2-((4-(环戊烷甲酰基)-2-(甲硫基)嘧啶-5-基)氧基)醋酸酯(7f)(320mg)。MS-ESI(m/z):325[M+1]+。
7-环戊基-2-(甲硫基)呋喃并[3,2-d]嘧啶-6-羧酸(7g)
向冰水冷却的7f(290mg,0.9mmol)四氢呋喃(11mL)溶液中加入60%氢化钠(125mg,3.2mmol),反应体系升至室温搅拌30分钟后经1N盐酸中和至pH 2-3,乙酸乙酯萃取,饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩至干得7-环戊基-2-(甲硫基)呋喃并[3,2-d]嘧啶-6-羧酸(7g)。MS-ESI(m/z):279[M+1]+。
7-环戊基-N,N-二甲基-2-(甲硫基)呋喃并[3,2-d]嘧啶-6-甲酰胺(7h)
将7g(粗品,0.90mmol)、HOBT(243mg,1.59mmol)、EDCI(228mg,1.19mmol)、二甲胺盐酸盐(194mg,2.38mmol)与DIPEA(0.65mL,3.97mmol)溶于N,N-二甲基甲酰胺(16mL),反应液在室温搅拌16小时后经1N盐酸中和至pH 2-3,乙酸乙酯萃取,水和饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩至干得7-环戊基-N,N-二甲基-2-(甲硫基)呋喃并[3,2-d]嘧啶-6-甲酰胺(7h)。MS-ESI(m/z):306[M+1]+。
7-环戊基-N,N-二甲基-2-(甲磺酰基)呋喃并[3,2-d]嘧啶-6-甲酰胺(7i)
向7h(粗品)的二氯甲烷溶液中(16mL)加入间氯过氧苯甲酸(355mg,1.59mmol),反应液在室温搅拌1小时后经饱和碳酸氢钠水溶液淬灭,水和饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩至干。粗品经硅胶柱层析纯化(洗脱相:正己烷/丙酮=2:1)得7-环戊基-N,N-二甲基-2-(甲磺酰基)呋喃并[3,2-d]嘧啶-6-甲酰胺(7i)(69mg)。MS-ESI(m/z):338[M+1]+。
叔丁基4-(6-((7-环戊基-6-(二甲基氨基甲酰基)呋喃并[3,2-d]嘧啶-2-基)氨
基)吡啶-3-基)哌嗪-1-羧酸酯(7j)
向冰水冷却的7i(33.7mg,0.1mmol)和叔丁基-4-(6-甲磺酰基吡啶-3-基)-哌嗪-1-羧酸(30.6mg,0.1mmol)的N,N-二甲基甲酰胺(2mL)溶液中加入60%氢化钠(8.0mg,0.2mmol),反应液缓慢升至室温搅拌2小时后经饱和氯化铵水溶液淬灭,乙酸乙酯萃取,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩至干。粗品经硅胶柱层析纯化(洗脱相:二氯甲烷/甲醇=50:1)得叔丁基4-(6-((7-环戊基-6-(二甲基氨基甲酰基)呋喃并[3,2-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-羧酸酯(7j)(5.3mg)。MS-ESI(m/z):536[M+1]+。
7-环戊基-N,N-二甲基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)呋喃并[3,2-d]嘧
啶-6-甲酰胺(7)
向7j(5.3mg,0.01mmol)的二氯甲烷(0.5mL)溶液中加入三氟乙酸(0.5mL),反应液在室温搅拌40分钟后减压浓缩至干,经氨水碱化至pH 9-10,再次浓缩至干。粗品经硅胶柱层析纯化(洗脱相:二氯甲烷/甲醇=10:1)得7-环戊基-N,N-二甲基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)呋喃并[3,2-d]嘧啶-6-甲酰胺(7)(2.8mg)。MS-ESI(m/z):436[M+1]+。
实施例8
7-环戊基-N,N-二甲基-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)呋喃并[3,2-
d]嘧啶-6-甲酰胺(8)
向冰水冷却的7i(33.7mg,0.1mmol)和N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)甲酰胺(22.0mg,0.1mmol)的N,N-二甲基甲酰胺(2mL)溶液中加入60%氢化钠(8.0mg,0.2mmol),反应液缓慢升至室温搅拌2小时后经饱和氯化铵水溶液淬灭,乙酸乙酯萃取,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩至干。粗品经硅胶柱层析纯化(洗脱相:二氯甲烷/甲醇=10:1)得7-环戊基-N,N-二甲基-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)呋喃并[3,2-d]嘧啶-6-甲酰胺(8)(2.4mg)。MS-ESI(m/z):450[M+1]+。
实施例9
7-环戊基-N,N,5-三甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)-5H-吡咯并[3,2-d]
嘧啶-6-甲酰胺(9)
叔丁基4-(6-(7-环戊基-6-(二甲基甲酰胺)-5H-吡咯并[3,2-d]嘧啶-2-基氨基)
吡啶-3-基)哌嗪-1-羧酸酯(9a)
向3(11.2mg)的二氯甲烷(0.5mL)溶液中加入Boc2O(6.1mg)和TEA(5.4μL)。室温搅拌2小时。蒸干溶剂得粗产物,用硅胶柱层析纯化,95:5二氯甲烷-甲醇洗脱得产物叔丁基4-(6-(7-环戊基-6-(二甲基甲酰胺)-5H-吡咯并[3,2-d]嘧啶-2-基氨基)吡啶-3-基)哌嗪-1-羧酸酯(9a,12.0mg,87%,淡黄色固体)。MS-ESI(m/z):535.5[M+1]+。
叔丁基4-(6-(7-环戊基-6-(二甲基甲酰胺)-5-甲基-5H-吡咯并[3,2-d]嘧啶-2-
基氨基)吡啶-3-基)哌嗪-1-羧酸酯(9b)
室温下,向9a(12.0mg,0.0225mmol)的THF(0.5mL)溶液中加入NaH(60%,2.0mg,0.050mmol)。室温搅拌10分钟。加入碘甲烷(3.2mg,0.0225mmol)的THF(0.25mL)溶液。室温搅拌2.5小时。蒸干溶剂。粗产物用硅胶柱层析纯化,3%甲醇-二氯甲烷洗脱得产物叔丁基4-(6-(7-环戊基-6-(二甲基甲酰胺)-5-甲基-5H-吡咯并[3,2-d]嘧啶-2-基氨基)吡啶-3-基)哌嗪-1-羧酸酯(9b,7.9mg,64%,黄色固体)。MS-ESI(m/z):549.5[M+1]+。
7-环戊基-N,N,5-三甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)-5H-吡咯并[3,2-d]
嘧啶-6-甲酰胺(9)
向化合物9b(7.8mg)的二氯甲烷(0.5mL)溶液中加入TFA(0.5mL)。室温搅拌1小时。蒸干溶剂。粗产物用硅胶柱层析纯化,91:8:1二氯甲烷-甲醇-氨水洗脱得产物7-环戊基-N,N,5-三甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)-5H-吡咯并[3,2-d]嘧啶-6-甲酰胺(9,6.4mg,100%,淡黄色固体)。MS-ESI(m/z):449.4[M+1]+。
实施例10
7-环戊基-N,N,5-三甲基-2-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)-5H-吡咯[3,
2-d]嘧啶-6-甲酰胺(10)
向化合物9(3.9mg,0.014mmol)的1,2-二氯乙烷(0.3mL)溶液中加入甲醛(37%水溶液,9.2mg,0.11mmol)和NaBH(OAc)3(2.4mg,0.011mmol)。室温搅拌1小时。用饱和NaHCO3(1mL)稀释,二氯甲烷萃取(2×1mL)。干燥(Na2SO4)后蒸干溶剂。粗产物用硅胶柱层析,95:4:1二氯甲烷-甲醇-氨水洗脱得产物7-环戊基-N,N,5-三甲基-2-(5-(4-甲基哌嗪-1-基)吡啶-2-基氨基)-5H-吡咯[3,2-d]嘧啶-6-甲酰胺(10,2.6mg,65%,淡黄色固体)。MS-ESI(m/z):463.4[M+1]+。
表1中列出的实施例11-64是使用实施例1中所述的方法,通过替换叔丁基4-(6-甲酰胺基吡啶-3-基)哌嗪-1羧酸酯为相应的氨基吡啶或氨基哒嗪并进行必要的修饰而制备得到的,如酰化、还原胺化反应,或用类似的合成策略或方法。表1中给出了实施例11-64的名称及结构。
表1
表2中列出的实施例65-76是使用实施例1中所述的方法,通过替换二甲氨基盐酸盐为相应的氨基而制备得到,而表2中列出的实施例77-84是使用实施例2中所述的方法而制备得到,表2中给出了实施例65-84的名称及结构。
表2
实施例85
N,N-二甲基-7-((1r,4r)-4-甲基环己基)-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)噻吩并[3,2-d]嘧啶-6-甲酰胺(85)
标题化合物(实施例85)(10mg,98%)是使用实施例1中所述的方法,通过替换环戊基甲醛为(1r,4r)-4-甲基环己酰-1-甲醛而制备得到。MS-ESI(m/z):480[M+1]+。
表3中列出的实施例86-94是使用实施例85中所述的方法,通过替换叔丁基4-(6-甲酰胺基吡啶-3-基)哌嗪-1羧酸酯为相应的氨基吡啶或氨基哒嗪并进行必要的修饰而制备得到的,如酰化、还原胺化反应。表3中给出了实施例86-94的名称及结构。
表3
生物活性检测
通过测定化合物对COLO-205细胞增殖的抑制作用,检测化合物对CDK4/6的抑制作用。COLO-205细胞培养于含10%胎牛血清的RPMI-1640培养基中。取处于对数生长期的COLO-205细胞按2000/孔的密度接种至96孔培养板中,37℃,5%CO2孵育过夜。96孔板中加入不同浓度(终浓度10000、3333.3、1111.1、270.4、123.5、41.2、13.7、4.6和1.5nM)的化合物,于37℃,5%CO2孵育72小时。弃去培养基,每孔20μlMTS/100μl培养基。孵育1.5h后,每孔加入25μl 10%SDS终止反应。用酶标仪测量490nm和650nm处的吸收。用GraphPad Prism5.0计算IC50。
取处于对数生长期的BE(2)-C细胞按5000/孔/150μl的密度接种至96孔培养板中,37℃,5%CO2孵育过夜。化合物分别用DMSO配置成浓度为20mM的化合物储液,用培养基现用现配成不同浓度的工作液(4×终浓度)。BE(2)-C细胞接种后24小时,每孔加入50μl化合物工作液。孵育72小时后用MTS方法测定细胞增殖活性。
根据本文中所述的生物学方法对上述制备的所选化合物进行试验。其结果见表4。
表4
实施例 | COLO205IC<sub>50</sub>(nM) | BE(2)-C IC<sub>50</sub>(nM) |
1 | 1106 | 38.5 |
2 | 339 | 24.1 |
5 | 517 | 601 |
7 | 711 | / |
73 | 624 | / |
87 | 450 | |
88 | 855 | / |
89 | 389 | / |
90 | 270 | / |
91 | 223 | / |
Claims (18)
1.式(I)所示的化合物或其药学上可接受的盐:
其中
X为C或N;
Y为CR11或S;
6-5元稠环系统A-B选自:
Q选自芳基或杂芳基;
R1选自:氢、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、C3-10环烷基-C1-4烷基、杂环基、杂环基-C1-4烷基、芳基、芳基-C1-4烷基、杂芳基和杂芳基-C1-4烷基,其中每个烷基、烯基、炔基、环烷基和杂环基是未被取代的或被至少一个独立选自C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、-OR8、-NR7S(O)rR8、-NO2、-卤素、-S(O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CR7(NOR8)、-CHF2、-CF3、-OCHF2和-OCF3的取代基取代,其中每个芳基和杂芳基是未被取代的或被至少一个独立选自C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、-OR8、-NR7S(O)rR8、-NO2、-卤素、-S(O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CR7(NOR8)、-CHF2、-CF3、-OCHF2、-OCF3、芳基、芳基-C1-4烷基、杂芳基和杂芳基-C1-4烷基的取代基取代;
R2选自:氢、卤素、羟基、CN、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、C3-10环烷基-C1-4烷基、杂环基、杂环基-C1-4烷基、芳基、芳基-C1-4烷基、杂芳基和杂芳基-C1-4烷基,其中每个烷基、烯基、炔基、环烷基和杂环基是未被取代的或被至少一个独立选自C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、-OR8、-NR7S(O)rR8、-NO2、-卤素、-S(O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CR7(NOR8)、-CHF2、-CF3、-OCHF2和-OCF3的取代基取代,其中每个芳基和杂芳基是未被取代的或被至少一个独立选自C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、-OR8、-NR7S(O)rR8、-NO2、-卤素、-S(O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CR7(NOR8)、-CHF2、-CF3、-OCHF2、-OCF3、芳基、芳基-C1-4烷基、杂芳基和杂芳基-C1-4烷基的取代基取代;
R3和R4分别选自:氢、C1-10烷基、C2-10烯基、C2-10炔基和C3-10环烷基;其中每个烷基、烯基、炔基和环烷基是未被取代的或被至少一个独立选自C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、-OR8、-NR7S(O)rR8、-NO2、-卤素、-S(O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CR7(NOR8)、-CHF2、-CF3、-OCHF2和-OCF3的取代基取代;
或R3和R4连同与它们相连的N原子一起形成一个含1、2或3个杂原子的4-12元环,其中杂原子独立选自氧、硫和氮,并任选由1-2个选自C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、-OR8、-NR7S(O)rR8、-NO2、-卤素、-S(O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CR7(NOR8)、-CHF2、-CF3、-OCHF2和-OCF3的取代基取代;
附带条件是,当R3和R4均为氢时,R2不是芳基或杂芳基;
每个R5独立地选自:C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、-OR8、-NR7S(O)rR8、-NO2、-卤素、-S(O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CR7(N-OR8)、-CHF2、-CF3、-OCHF2和-OCF3;其中每个C1-10烷基,C2-10烯基,C2-10炔基和C3-10环烷基是未被取代的或被至少一个独立选自C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、-OR8、-NR7S(O)rR8、-NO2、-卤素、-S(O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CR7(NOR8)、-CHF2、-CF3、-OCHF2和-OCF3的取代基取代;
R7和R8独立地选自:氢、C1-10烷基、C2-10烯基、C2-10炔基、环烷基、环烷基-C1-4烷基、杂环基、杂环基C1-4烷基、芳基、芳基-C1-4烷基、杂芳基和杂芳基-C1-4烷基;其中每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基是未被取代的或被至少一个独立选自C1-10烷基、C3-10环烷基、-OH、-O-C1-10烷基、-O-C3-10环烷基、-O-C3-10环烷基-C1-4烷基、-O-杂环基、-O-杂环基C1-4烷基、-O-芳基、-O-芳基-C1-4烷基、-O-杂芳基、-O-杂芳基-C1-4烷基、-NO2、-卤素、-NH2、-NH(C1-10烷基)、-N(C1-10烷基)2、-NH(C3-10环烷基)、-N(C3-10环烷基)2、-NH(C3-10环烷基-C1-4烷基)、-N(C3-10环烷基-C1-4烷基)2、-NH(杂环基)、-N(杂环基)2、-NH(杂环基C1-4烷基)、-N(杂环基C1-4烷基)2、-NH(芳基)、-N(芳基)2、-NH(芳基-C1-4烷基)、-N(芳基-C1-4烷基)2、-NH(杂芳基)、-N(杂芳基)2、-NH(杂芳基-C1-4烷基)、-N(杂芳基-C1-4烷基)2、-N(C1-10烷基)(C3-10环烷基)、-N(C1-10烷基)(C3-10环烷基-C1-4烷基)、-N(C1-10烷基)(杂环基)、-N(C1-10烷基)(杂环基C1-4烷基)、-N(C1-10烷基)(芳基)、-N(C1-10烷基)(芳基-C1-4烷基)、-N(C1-10烷基)(杂芳基)、-N(C1-10烷基)(杂芳基-C1-4烷基)、-N(C3-10环烷基)(C3-10环烷基-C1-4烷基)、-N(C3-10环烷基)(杂环基)、-N(C3-10环烷基)(杂环基C1-4烷基)、-N(C3-10环烷基)(芳基)、-N(C3-10环烷基)(芳基-C1-4烷基)、-N(C3-10环烷基)(杂芳基)、-N(C3-10环烷基)(杂芳基-C1-4烷基)、-N(C3-10环烷基-C1-4烷基)(杂环基)、-N(C3-10环烷基-C1-4烷基)(杂环基C1-4烷基)、-N(C3-10环烷基-C1-4烷基)(芳基)、-N(C3-10环烷基-C1-4烷基)(芳基-C1-4烷基)、-N(C3-10环烷基-C1-4烷基)(杂芳基)、-N(C3-10环烷基-C1-4烷基)(杂芳基-C1-4烷基)、-N(杂环基)(杂环基C1-4烷基)、-N(杂环基)(芳基)、-N(杂环基)(芳基-C1-4烷基)、-N(杂环基)(杂芳基)、-N(杂环基)(杂芳基-C1-4烷基)、-N(杂环基C1-4烷基)(芳基)、-N(杂环基C1-4烷基)(芳基-C1-4烷基)、-N(杂环基C1-4烷基)(杂芳基)、-N(杂环基C1-4烷基)(杂芳基-C1-4烷基)、-N(芳基)(芳基-C1-4烷基)、-N(芳基)(杂芳基)、-N(芳基)(杂芳基-C1-4烷基)、-N(芳基-C1-4烷基)(杂芳基)、-N(芳基-C1-4烷基)(杂芳基-C1-4烷基)、-N(杂芳基)(杂芳基-C1-4烷基)、-(CR9R10)tOH、-(CR9R10)tO-C1-10烷基、-(CR9R10)tO-C3-10环烷基、(CR9R10)tO-C3-10环烷基-C1-4烷基、-(CR9R10)tO-杂环基、-(CR9R10)tO-杂环基C1-4烷基、-(CR9R10)tO-芳基、-(CR9R10)tO-芳基-C1-4烷基、-(CR9R10)tO-杂芳基、-(CR9R10)tO-杂芳基-C1-4烷基、-(CR9R10)tS(O)rH、-(CR9R10)tS(O)r-C1-10烷基、-(CR9R10)tS(O)r-C3-10环烷基、-(CR9R10)tS(O)r-C3-10环烷基-C1-4烷基、-(CR9R10)tS(O)r-杂环基、-(CR9R10)tS(O)r-杂环基C1-4烷基、-(CR9R10)tS(O)r-芳基、-(CR9R10)tS(O)r-芳基-C1-4烷基、-(CR9R10)tS(O)r-杂芳基、-(CR9R10)tS(O)r-杂芳基-C1-4烷基、-C(O)H、-C(O)-C1-10烷基、-C(O)-C3-10环烷基、-C(O)-C3-10环烷基-C1-4烷基、-C(O)-杂环基、-C(O)-杂环基C1-4烷基、-C(O)-芳基、-C(O)-芳基-C1-4烷基、-C(O)-杂芳基、-C(O)-杂芳基-C1-4烷基、-CN、-C(O)NH2、-C(O)NH(C1-10烷基)、-C(O)N(C1-10烷基)2、-C(O)NH(C3-10环烷基)、-C(O)N(C3-10环烷基)2、-C(O)NH(C3-10环烷基-C1-4烷基)、-C(O)N(C3-10环烷基-C1-4烷基)2、-C(O)NH(杂环基)、-C(O)N(杂环基)2、-C(O)NH(杂环基C1-4烷基)、-C(O)N(杂环基C1-4烷基)2、-C(O)NH(芳基)、-C(O)N(芳基)2、-C(O)NH(芳基-C1-4烷基)、-C(O)N(芳基-C1-4烷基)2、-C(O)NH(杂芳基)、-C(O)N(杂芳基)2、-C(O)NH(杂芳基-C1-4烷基)、-C(O)N(杂芳基-C1-4烷基)2、-C(O)N(C1-10烷基)(C3-10环烷基)、-C(O)N(C1-10烷基)(C3-10环烷基-C1-4烷基)、-C(O)N(C1-10烷基)(杂环基)、-C(O)N(C1-10烷基)(杂环基C1-4烷基)、-C(O)N(C1-10烷基)(芳基)、-C(O)N(C1-10烷基)(芳基-C1-4烷基)、-C(O)N(C1-10烷基)(杂芳基)、-C(O)N(C1-10烷基)(杂芳基-C1-4烷基)、-C(O)N(C3-10环烷基)(C3-10环烷基-C1-4烷基)、-C(O)N(C3-10环烷基)(杂环基)、-C(O)N(C3-10环烷基)(杂环基C1-4烷基)、-C(O)N(C3-10环烷基)(芳基)、-C(O)N(C3-10环烷基)(芳基-C1-4烷基)、-C(O)N(C3-10环烷基)(杂芳基)、-C(O)N(C3-10环烷基)(杂芳基-C1-4烷基)、-C(O)N(C3-10环烷基-C1-4烷基)(杂环基)、-C(O)N(C3-10环烷基-C1-4烷基)(杂环基C1-4烷基)、-C(O)N(C3-10环烷基-C1-4烷基)(芳基)、-C(O)N(C3-10环烷基-C1-4烷基)(芳基-C1-4烷基)、-C(O)N(C3-10环烷基-C1-4烷基)(杂芳基)、-C(O)N(C3-10环烷基-C1-4烷基)(杂芳基-C1-4烷基)、-C(O)N(杂环基)(杂环基C1-4烷基)、-C(O)N(杂环基)(芳基)、-C(O)N(杂环基)(芳基-C1-4烷基)、-C(O)N(杂环基)(杂芳基)、-C(O)N(杂环基)(杂芳基-C1-4烷基)、-C(O)N(杂环基C1-4烷基)(芳基)、-C(O)N(杂环基C1-4烷基)(芳基-C1-4烷基)、-C(O)N(杂环基C1-4烷基)(杂芳基)、-C(O)N(杂环基C1-4烷基)(杂芳基-C1-4烷基)、-C(O)N(芳基)(芳基-C1-4烷基)、-C(O)N(芳基)(杂芳基)、-C(O)N(芳基)(杂芳基-C1-4烷基)、-C(O)N(芳基-C1-4烷基)(杂芳基)、-C(O)N(芳基-C1-4烷基)(杂芳基-C1-4烷基)、-C(O)N(杂芳基)(杂芳基-C1-4烷基)、-CHF2和-CF3的取代基取代;
或R7和R8一起连同与它们相连的单个或多个原子共同构成一个含有0、1或2个额外的独立选自氧、硫和氮的杂原子的4-12元杂环,该环可以是未被取代的或被1-2个选自C1-10烷基、C3-10环烷基、-OH、-O-C1-10烷基、-O-C3-10环烷基、-O-C3-10环烷基-C1-4烷基、-O-杂环基、-O-杂环基C1-4烷基、-O-芳基、-O-芳基-C1-4烷基、-O-杂芳基、-O-杂芳基-C1-4烷基、-NO2、-卤素、-NH2、-NH(C1-10烷基)、-N(C1-10烷基)2、-NH(C3-10环烷基)、-N(C3-10环烷基)2、-NH(C3-10环烷基-C1-4烷基)、-N(C3-10环烷基-C1-4烷基)2、-NH(杂环基)、-N(杂环基)2、-NH(杂环基C1-4烷基)、-N(杂环基C1-4烷基)2、-NH(芳基)、-N(芳基)2、-NH(芳基-C1-4烷基)、-N(芳基-C1-4烷基)2、-NH(杂芳基)、-N(杂芳基)2、-NH(杂芳基-C1-4烷基)、-N(杂芳基-C1-4烷基)2、-N(C1-10烷基)(C3-10环烷基)、-N(C1-10烷基)(C3-10环烷基-C1-4烷基)、-N(C1-10烷基)(杂环基)、-N(C1-10烷基)(杂环基C1-4烷基)、-N(C1-10烷基)(芳基)、-N(C1-10烷基)(芳基-C1-4烷基)、-N(C1-10烷基)(杂芳基)、-N(C1-10烷基)(杂芳基-C1-4烷基)、-N(C3-10环烷基)(C3-10环烷基-C1-4烷基)、-N(C3-10环烷基)(杂环基)、-N(C3-10环烷基)(杂环基C1-4烷基)、-N(C3-10环烷基)(芳基)、-N(C3-10环烷基)(芳基-C1-4烷基)、-N(C3-10环烷基)(杂芳基)、-N(C3-10环烷基)(杂芳基-C1-4烷基)、-N(C3-10环烷基-C1-4烷基)(杂环基)、-N(C3-10环烷基-C1-4烷基)(杂环基C1-4烷基)、-N(C3-10环烷基-C1-4烷基)(芳基)、-N(C3-10环烷基-C1-4烷基)(芳基-C1-4烷基)、-N(C3-10环烷基-C1-4烷基)(杂芳基)、-N(C3-10环烷基-C1-4烷基)(杂芳基-C1-4烷基)、-N(杂环基)(杂环基C1-4烷基)、-N(杂环基)(芳基)、-N(杂环基)(芳基-C1-4烷基)、-N(杂环基)(杂芳基)、-N(杂环基)(杂芳基-C1-4烷基)、-N(杂环基C1-4烷基)(芳基)、-N(杂环基C1-4烷基)(芳基-C1-4烷基)、-N(杂环基C1-4烷基)(杂芳基)、-N(杂环基C1-4烷基)(杂芳基-C1-4烷基)、-N(芳基)(芳基-C1-4烷基)、-N(芳基)(杂芳基)、-N(芳基)(杂芳基-C1-4烷基)、-N(芳基-C1-4烷基)(杂芳基)、-N(芳基-C1-4烷基)(杂芳基-C1-4烷基)、-N(杂芳基)(杂芳基-C1-4烷基)、-(CR9R10)tOH、-(CR9R10)tO-C1-10烷基、-(CR9R10)tO-C3-10环烷基、-(CR9R10)tO-C3-10环烷基-C1-4烷基、-(CR9R10)tO-杂环基、-(CR9R10)tO-杂环基C1-4烷基、-(CR9R10)tO-芳基、-(CR9R10)tO-芳基-C1-4烷基、-(CR9R10)tO-杂芳基、-(CR9R10)tO-杂芳基-C1-4烷基、-(CR9R10)tS(O)rH、-(CR9R10)tS(O)r-C1-10烷基、-(CR9R10)tS(O)r-C3-10环烷基、-(CR9R10)tS(O)r-C3-10环烷基-C1-4烷基、-(CR9R10)tS(O)r-杂环基、-(CR9R10)tS(O)r-杂环基C1-4烷基、-(CR9R10)tS(O)r-芳基、-(CR9R10)tS(O)r-芳基-C1-4烷基、-(CR9R10)tS(O)r-杂芳基、-(CR9R10)tS(O)r-杂芳基-C1-4烷基、-C(O)H、-C(O)-C1-10烷基、-C(O)-C3-10环烷基、-C(O)-C3-10环烷基-C1-4烷基、-C(O)-杂环基、-C(O)-杂环基C1-4烷基、-C(O)-芳基、-C(O)-芳基-C1-4烷基、-C(O)-杂芳基、-C(O)-杂芳基-C1-4烷基、-CN、-C(O)NH2、-C(O)NH(C1-10烷基)、-C(O)N(C1-10烷基)2、-C(O)NH(C3-10环烷基)、-C(O)N(C3-10环烷基)2、-C(O)NH(C3-10环烷基-C1-4烷基)、-C(O)N(C3-10环烷基-C1-4烷基)2、-C(O)NH(杂环基)、-C(O)N(杂环基)2、-C(O)NH(杂环基C1-4烷基)、-C(O)N(杂环基C1-4烷基)2、-C(O)NH(芳基)、-C(O)N(芳基)2、-C(O)NH(芳基-C1-4烷基)、-C(O)N(芳基-C1-4烷基)2、-C(O)NH(杂芳基)、-C(O)N(杂芳基)2、-C(O)NH(杂芳基-C1-4烷基)、-C(O)N(杂芳基-C1-4烷基)2、-C(O)N(C1-10烷基)(C3-10环烷基)、-C(O)N(C1-10烷基)(C3-10环烷基-C1-4烷基)、-C(O)N(C1-10烷基)(杂环基)、-C(O)N(C1-10烷基)(杂环基C1-4烷基)、-C(O)N(C1-10烷基)(芳基)、-C(O)N(C1-10烷基)(芳基-C1-4烷基)、-C(O)N(C1-10烷基)(杂芳基)、-C(O)N(C1-10烷基)(杂芳基-C1-4烷基)、-C(O)N(C3-10环烷基)(C3-10环烷基-C1-4烷基)、-C(O)N(C3-10环烷基)(杂环基)、-C(O)N(C3-10环烷基)(杂环基C1-4烷基)、-C(O)N(C3-10环烷基)(芳基)、-C(O)N(C3-10环烷基)(芳基-C1-4烷基)、-C(O)N(C3-10环烷基)(杂芳基)、-C(O)N(C3-10环烷基)(杂芳基-C1-4烷基)、-C(O)N(C3-10环烷基-C1-4烷基)(杂环基)、-C(O)N(C3-10环烷基-C1-4烷基)(杂环基C1-4烷基)、-C(O)N(C3-10环烷基-C1-4烷基)(芳基)、-C(O)N(C3-10环烷基-C1-4烷基)(芳基-C1-4烷基)、-C(O)N(C3-10环烷基-C1-4烷基)(杂芳基)、-C(O)N(C3-10环烷基-C1-4烷基)(杂芳基-C1-4烷基)、-C(O)N(杂环基)(杂环基C1-4烷基)、-C(O)N(杂环基)(芳基)、-C(O)N(杂环基)(芳基-C1-4烷基)、-C(O)N(杂环基)(杂芳基)、-C(O)N(杂环基)(杂芳基-C1-4烷基)、-C(O)N(杂环基C1-4烷基)(芳基)、-C(O)N(杂环基C1-4烷基)(芳基-C1-4烷基)、-C(O)N(杂环基C1-4烷基)(杂芳基)、-C(O)N(杂环基C1-4烷基)(杂芳基-C1-4烷基)、-C(O)N(芳基)(芳基-C1-4烷基)、-C(O)N(芳基)(杂芳基)、-C(O)N(芳基)(杂芳基-C1-4烷基)、-C(O)N(芳基-C1-4烷基)(杂芳基)、-C(O)N(芳基-C1-4烷基)(杂芳基-C1-4烷基)、-C(O)N(杂芳基)(杂芳基-C1-4烷基)、-CHF2和-CF3的取代基取代;
R9和R10独立地选自:氢、C1-10烷基、C2-10烯基、C2-10炔基、环烷基、环烷基-C1-4烷基、杂环基、杂环基-C1-4烷基、芳基、芳基-C1-4烷基、杂芳基和杂芳基-C1-4烷基;或R9和R10一起连同与它们相连的单个或多个碳原子共同构成含有0、1或2个独立选自氧,硫和氮的杂原子的3-7元环,该环可以是未被取代的或被1-2个选自C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、-OR8、-NR7S(O)rR8、-NO2、-卤素、-S(O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CR7(NOR8)、-CHF2、-CF3、-OCHF2和-OCF3的取代基取代;
R11选自:氢、C1-10烷基、C3-10环烷基、C3-10环烷基烷基、杂环基、杂环基-C1-4烷基、芳基、芳基-C1-4烷基、杂芳基、杂芳基-C1-4烷基、-OR7、-NR7S(O)rR8、-S(O)rR7、-SR7、-S(O)2OR7、-OS(O)2R7、-S(O)rNR7R8、-NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CHF2、-CF3、-OCHF2和-OCF3;
R12选自:氢、C1-10烷基、C3-10环烷基、C3-10环烷基-C1-4烷基、杂环基、杂环基-C1-4烷基、芳基、芳基-C1-4烷基、杂芳基、杂芳基-C1-4烷基、-S(O)rR7、-C(O)R7、-CO2R7、-CO2(CR9R10)tCONR7R8和-C(O)NR7R8;
m独立选自0、1、2和3;
每个r独立选自1和2;
每个t独立选自1、2和3;
其中杂芳基是
5元到8元的芳香单环,该环含有选自N、O和S的,数目为1到3个的杂原子,其余均为碳原子;或
8元到12元双环,该环含有选自N、O和S的,数目为1到3个的杂原子,其余均为碳原子,且其中至少有一个杂原子出现在芳环中;
其中杂环基是
单一的环状脂肪烃,其具有3至12个环原子,至少含2个碳原子,含有1-3个独立地选自O、S、N的杂原子;或
二环体系,其具有3至12个环原子,含有一个或多个独立地选自O、S、N的杂原子;
其中杂环基任选地被氧代取代。
2.如权利要求1所述的化合物或其药学上可接受的盐,其中6-5元稠环系统A-B是
3.如权利要求1所述的化合物或其药学上可接受的盐,其中R11选自氢和甲基。
4.如权利要求1-3中任一项所述的化合物或其药学上可接受的盐,其中Q选自杂芳基。
5.如权利要求1-4中任一项所述的化合物或其药学上可接受的盐,其中Q选自吡啶基,哒嗪基和5,6,7,8-四氢-1,6-萘啶基。
6.如权利要求5所述的化合物或其药学上可接受的盐,其中Q选自吡啶-2-基,哒嗪-3-基和5,6,7,8-四氢-1,6-萘啶-2-基。
7.如权利要求1-6中任一项所述的化合物或其药学上可接受的盐,其中R1选自氢、C1-10烷基、杂环基和杂环基-C1-4烷基,其中杂环基是未被取代的或被至少一个独立选自C1-10烷基、-NR7R8、-(CR9R10)tOR8、-OR8、-C(O)R7、-C(O)NR7R8和-(CR9R10)tS(O)rR8的取代基取代,其中R7、R8、R9、R10、t和r如权利要求1所述。
8.如权利要求7所述的化合物或其药学上可接受的盐,其中Q选自吡啶-2-基,哒嗪-3-基,R1选自由以下组成的杂环基和杂环基-C1-4烷基:
其中杂环基是未被取代的或被至少一个独立选自C1-10烷基、-NR7R8、-(CR9R10)tOR8、-OR8、-C(O)R7、-C(O)NR7R8和-(CR9R10)tS(O)rR8的取代基取代,其中R7,R8,R9,R10,t和r如权利要求1所述。
9.如权利要求7-8中任一项所述的化合物或其药学上可接受的盐,其中杂环基是未被取代的或被至少一个独立选自甲基、乙基、羟基、羟甲基、羟乙基、乙酰基、羟乙酰基、甲氧基甲基,甲氧乙基、(甲磺酰基)乙基、氨基、氨基甲酰基、甲氨基和二甲氨基的基团取代。
10.如权利要求1-9中任一项所述的化合物或其药学上可接受的盐,其中R2选自C3-10环烷基,其中环烷基是未被取代的或被至少一个独立选自C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、-OR8、-NR7S(O)rR8、-NO2、-卤素、-S(O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8、-CR7(NOR8)、-CHF2、-CF3、-OCHF2和-OCF3的取代基取代。
11.如权利要求10所述的化合物或其药学上可接受的盐,其中R2选自环戊基和环己基,其中环己基是未被取代的或被甲基取代。
12.如权利要求1-11中任一项所述的化合物或其药学上可接受的盐,其中R3和R4独立选自氢、C1-10烷基和环丙烷基。
13.如权利要求1-11中任一项所述的化合物或其药学上可接受的盐,其中R3和R4连同与它们相连的N原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基和吗啉基,其中所形成的环是未被取代的或被甲基、羟基和甲氧基取代。
14.如权利要求1-13中任一项所述的化合物或其药学上可接受的盐,其中R5独立选自C1-10烷基和-C(O)R7,其中R7选自甲基和羟甲基。
15.药物组合物,包含权利要求1-14中任一项所述的化合物或其药学上可接受的盐,和至少一种药学上可接受的载体。
16.权利要求1-14中任一项所述的化合物或其药学上可接受的盐,或权利要求15的药物组合物在制备用于调控CDK4/6的药物中的用途。
17.权利要求1-14中任一项所述的化合物或其药学上可接受的盐,或权利要求15的药物组合物,可选择性与另一治疗药物组合,在制备用于治疗、改善或预防对抑制CDK4/6有响应的症状的药物中的用途。
18.权利要求1-14中任一项所述的化合物或其药学上可接受的盐,或权利要求15的药物组合物,可选择性与另一治疗药物组合,在制备用于治疗细胞增殖异常的药物中的用途。
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