CN102731492A - Cyclohexane derivative, its preparation method and its application in medicines - Google Patents
Cyclohexane derivative, its preparation method and its application in medicines Download PDFInfo
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- CN102731492A CN102731492A CN2011100834635A CN201110083463A CN102731492A CN 102731492 A CN102731492 A CN 102731492A CN 2011100834635 A CN2011100834635 A CN 2011100834635A CN 201110083463 A CN201110083463 A CN 201110083463A CN 102731492 A CN102731492 A CN 102731492A
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- Prior art keywords
- general formula
- compound
- alkyl
- aryl
- heterocyclic radical
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- 239000003814 drug Substances 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 125000000113 cyclohexyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 title abstract description 53
- 229940079593 drug Drugs 0.000 title abstract description 7
- AJJISMLYIMQAKP-OAHLLOKOSA-N 5-[4-[(2r)-4-(3-fluoro-4-methylsulfonylphenoxy)butan-2-yl]piperidin-1-yl]-3-propan-2-yl-1,2,4-oxadiazole Chemical compound CC(C)C1=NOC(N2CCC(CC2)[C@H](C)CCOC=2C=C(F)C(=CC=2)S(C)(=O)=O)=N1 AJJISMLYIMQAKP-OAHLLOKOSA-N 0.000 claims abstract description 17
- 229940100607 GPR119 agonist Drugs 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 112
- 238000006243 chemical reaction Methods 0.000 claims description 107
- -1 nitro, hydroxyl Chemical group 0.000 claims description 67
- 125000001072 heteroaryl group Chemical group 0.000 claims description 55
- 150000003839 salts Chemical class 0.000 claims description 44
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- 229910052760 oxygen Inorganic materials 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 claims description 34
- 125000003118 aryl group Chemical group 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000004429 atom Chemical group 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 4
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 4
- 239000004327 boric acid Substances 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 6
- 208000030159 metabolic disease Diseases 0.000 abstract description 3
- 125000001424 substituent group Chemical group 0.000 abstract 1
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 62
- 239000000047 product Substances 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 238000003756 stirring Methods 0.000 description 42
- 238000001819 mass spectrum Methods 0.000 description 33
- 239000000706 filtrate Substances 0.000 description 32
- 239000001301 oxygen Substances 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 239000012141 concentrate Substances 0.000 description 30
- 230000006837 decompression Effects 0.000 description 30
- 238000001035 drying Methods 0.000 description 30
- 238000005406 washing Methods 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 24
- 239000007864 aqueous solution Substances 0.000 description 22
- 125000000753 cycloalkyl group Chemical group 0.000 description 22
- 229910052799 carbon Inorganic materials 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 125000003545 alkoxy group Chemical group 0.000 description 18
- 125000000623 heterocyclic group Chemical group 0.000 description 17
- 238000003810 ethyl acetate extraction Methods 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000003480 eluent Substances 0.000 description 15
- 150000001721 carbon Chemical group 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 125000003003 spiro group Chemical group 0.000 description 14
- 210000004369 blood Anatomy 0.000 description 13
- 239000008280 blood Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 125000000304 alkynyl group Chemical group 0.000 description 12
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 12
- 125000002769 thiazolinyl group Chemical group 0.000 description 12
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 11
- 102000004877 Insulin Human genes 0.000 description 11
- 108090001061 Insulin Proteins 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 11
- 239000008103 glucose Substances 0.000 description 11
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 11
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 102100033839 Glucose-dependent insulinotropic receptor Human genes 0.000 description 9
- 101710163236 Glucose-dependent insulinotropic receptor Proteins 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 8
- 125000003282 alkyl amino group Chemical group 0.000 description 8
- 125000004414 alkyl thio group Chemical group 0.000 description 8
- 125000000000 cycloalkoxy group Chemical group 0.000 description 8
- 125000005366 cycloalkylthio group Chemical group 0.000 description 8
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 8
- IBGCXOFOCKCBNQ-UHFFFAOYSA-N nitro cyanate Chemical compound [O-][N+](=O)OC#N IBGCXOFOCKCBNQ-UHFFFAOYSA-N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- ZQWPRMPSCMSAJU-UHFFFAOYSA-N methyl cyclohexanecarboxylate Chemical class COC(=O)C1CCCCC1 ZQWPRMPSCMSAJU-UHFFFAOYSA-N 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 6
- 102100040918 Pro-glucagon Human genes 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 238000010171 animal model Methods 0.000 description 5
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229960001866 silicon dioxide Drugs 0.000 description 5
- KRRTXVSBTPCDOS-UHFFFAOYSA-N 5-bromopyrazin-2-amine Chemical compound NC1=CN=C(Br)C=N1 KRRTXVSBTPCDOS-UHFFFAOYSA-N 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- WJPYCSQNYMMSQK-UHFFFAOYSA-N 5-(4-methylsulfonylphenyl)pyrazin-2-amine Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CN=C(N)C=N1 WJPYCSQNYMMSQK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 3
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 3
- PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-UHFFFAOYSA-N 0.000 description 3
- 241000892865 Heros Species 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229910007857 Li-Al Inorganic materials 0.000 description 3
- 229910008447 Li—Al Inorganic materials 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- JJOYCHKVKWDMEA-UHFFFAOYSA-N ethyl cyclohexanecarboxylate Chemical compound CCOC(=O)C1CCCCC1 JJOYCHKVKWDMEA-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 3
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 2
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 2
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 2
- 0 CC(C)c1nc(*)n[o]1 Chemical compound CC(C)c1nc(*)n[o]1 0.000 description 2
- WEAXIIDEOCIAKR-UHFFFAOYSA-N CS(=O)(=O)C1=CC=C(C=C1)OB(O)O Chemical compound CS(=O)(=O)C1=CC=C(C=C1)OB(O)O WEAXIIDEOCIAKR-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 description 2
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
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- OWMZNFCDEHGFEP-NFBCVYDUSA-N secretin human Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(N)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 OWMZNFCDEHGFEP-NFBCVYDUSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000013293 zucker diabetic fatty rat Methods 0.000 description 1
Abstract
The invention relates to a cyclohexane derivative, its preparation method and its application in medicines. Concretely speaking, the invention relates to the novel cyclohexane derivative shown in a general formula (I), its preparation method, a pharmaceutical composition containing the derivative and a use of the derivative as a therapeutic agent, especially a GPR119 agonist, and an application of the derivative in preparing drugs for treating diabetes, metabolic disorders, and other diseases. Various substituents in the formula (I) are the same as the definitions in the instruction.
Description
Technical field
The pharmaceutical composition that the present invention relates to a kind of new cyclohexanes verivate, its preparation method and contain this verivate with and as therapeutical agent particularly as the GPR119 agonist with in the purposes of the medicine of diseases such as preparation treatment mellitus and metabolic disorder.
Background technology
A classical symptom of type ii diabetes is that pancreatic beta cell can't secrete the Regular Insulin of q.s when following the patient to show insulin resistant.Can the medicine of treating type ii diabetes clinically be divided into two types based on this point, a kind of is the medicine that is used for improving the insulin resistant symptom of organ-tissues such as liver, muscle; Second kind is to act on the medicine that pancreatic beta cell promotes its excreting insulin.At present; Develop multiple medicine and be used for realizing this purpose; Like glucagon kind polypeptide-1 analogue (GLP-1 mimetics); Because its mechanism of action is the glucose dependency, maybe not can in the clinical treatment use makes the patient hypoglycemic symptom occur, thereby become the ideal medicine simultaneously.On to GLP-1 research basis, developed DPP IV (DPPIV) suppressor factor again, also success becomes the medicine for treatment of novel I type i diabetes.Along with further going deep into of research,, make a kind of g protein coupled receptor GPR119 become the novel targets of a potential type ii diabetes treatment especially to the research of pancreatic beta cell excreting insulin process.
G protein coupled receptor 119 (GPR119) is a kind of orphan receptor of finding through the Human genome sequencing analysis, and its assignment of genes gene mapping mainly is expressed in beta Cell of islet and intestinal cell in the pancreatic tissue in X chromosome.Through further research, find that Oleoyl monoethanolamide (OEA) and derivative of fatty acid oleoyl SUNLECITHIN A are the endogenic ligands of GPR119.Through combining with GPR119 and exciting GPR119, can improve the intracellular cyclic monophosphate of β (cAMP) concentration, the stimulus-secretion coupling in the activated cell promotes flow of calcium ions, thereby promotes the Regular Insulin vesicle secretion outside born of the same parents.
Histocyte expression characteristic and the function of GPR119 are all pointed out, and activate this receptor and can promote GLP-1 and insulin secretion, help glycemic control.This notion has been used in the pharmaceutical research relevant with mellitus.In the isolated perfusion test to the isolated from rat pancreas islet, the GPR119 agonist can stimulate to be secreted with second o'clock in first o'clock of Regular Insulin mutually mutually, and this promoting insulin secretion has the glucose dependency.In addition, the GPR119 agonist also can promote mouse intestinal L clone secretion GLP-1.The GPR119 agonist has obtained demonstration to the treatment of diabetes effect in experimentation on animals.Can significantly improve Regular Insulin, GLP-1 and GIP level in the blood circulation for the oral GPR119 agonist of rat, reduce the blood sugar concentration of rat after accepting carbohydrate tolerance test simultaneously.Give diabetes rat 4 weeks of oral GPR119 agonist continued treatment (ZDF rat) every day; Its fasting blood glucose level obviously reduces, and the tolerance of carbohydrate tolerance test significantly improves, and the glycolated hemoglobin level is significantly improved; Significantly increase with insulin content simultaneously, the prompting islet function makes moderate progress.Above-mentioned test-results all shows, uses the diabetic symptom that the GPR119 agonist can improve experimental animal.
As the new formulation of treatment type ii diabetes, the main advantage of GPR119 agonist is that secretin's (comprising GLP-1 and GIP) and pancreas islet are have multiple secretomotor effect.This characteristic is that the GLP-1 analogue and the DPP-IV suppressor factor of anti-DPP-IV degraded is not available.In addition, the animal experiment prompting, the GPR119 agonist also has the potential of management of body weight.This novel mechanism of action possibly bring renewal, stronger hypoglycemic effect for treating diabetes, thereby helps to increase the variety of diabetes drug treatment, to satisfy requirement of different patients.
The patented claim of a series of GPR119 agonist is disclosed at present, comprising WO2005007658 and WO2009012275.
Although disclose the GPR119 agonist of diseases such as a series of treatment mellitus and metabolic disease at present; But still need the new compound of exploitation with better drug effect; Through continuous effort; The compound that the present invention's design has the structure shown in the general formula (I), and find that the compound with this class formation shows excellent effect and effect.
Summary of the invention
The object of the present invention is to provide the compound shown in a kind of general formula (I), and their tautomer, enantiomorph, diastereomer, raceme and pharmaceutically useful salt, and meta-bolites and metabolic precursor thereof or prodrug.
Wherein:
Ring A is selected from C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl or heteroaryl, wherein said C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl or heteroaryl are optional independently of one another further by one or more halogen, cyanic acid, nitro, C of being selected from
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl, heteroaryl ,-OR
3,-NR
4R
5,-C (O) R
3,-C (O) OR
3,-C (O) NR
4R
5,-NR
4C (O) R
5,-NR
4SO
2R
5,-S (O)
mR
3Or-SO
2NR
4R
5Substituting group replace;
Ring B is selected from heterocyclic radical or heteroaryl, and wherein said heterocyclic radical or heteroaryl are optional independently of one another further by one or more halogen, C of being selected from
1-6Alkyl or-OR
3Substituting group replace;
L be selected from a singly-bound or-(CH
2)
1-4-, one-CH arbitrarily wherein
2-optional independently of one another by one or more O, N (R
6) or S replace all the other CH
2Choose wantonly and further be selected from halogen or C by one or two
1-6The substituting group of alkyl replaces;
R
1Be selected from C
3-10Naphthenic base, C
6-10Aryl, heterocyclic radical or heteroaryl, wherein said C
3-10Naphthenic base, C
6-10Aryl, heterocyclic radical or heteroaryl are optional further by one or more halogen, cyanic acid, nitro, C of being selected from
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl, heteroaryl ,-OR
3,-NR
4R
5,-C (O) R
3,-C (O) OR
3,-C (O) NR
4R
5,-NR
4C (O) R
5,-NR
4SO
2R
5,-S (O)
mR
3Or-SO
2NR
4R
5Substituting group replace;
R
2Be selected from halogen, cyanic acid, nitro, C
1-6Alkyl ,-OR
3Or-NR
4R
5, wherein said C
1-6Alkyl is optional further by one or more halogen, cyanic acid, nitro, hydroxyl, C of being selected from
1-6Alkoxyl group, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10The substituting group of aryl or heteroaryl replaces;
R
3Be selected from Wasserstoffatoms, C
1-6Alkyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl or heteroaryl, wherein said C
1-6Alkyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl or heteroaryl are optional further by one or more halogen, cyanic acid, nitro, hydroxyl, C of being selected from
1-6Alkyl, C
1-6Alkoxyl group, C
3-10Naphthenic base, heterocyclic radical, C
6-10The substituting group of aryl or heteroaryl replaces;
R
4And R
5Be selected from Wasserstoffatoms, C independently of one another
1-6Alkyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl or heteroaryl, wherein said C
1-6Alkyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl or heteroaryl are independently optional separately further by one or more halogen, cyanic acid, nitro, hydroxyl, C of being selected from
1-6Alkyl, C
1-6Alkoxyl group, C
3-10Naphthenic base, heterocyclic radical, C
6-10The substituting group of aryl or heteroaryl replaces;
Perhaps, R
4And R
5Nitrogen-atoms with being connected forms heterocyclic radical, and wherein said heterocyclic radical contains one or more N, O or S (O)
mHeteroatoms, and said heterocyclic radical is optional further by one or more halogen, cyanic acid, nitro, hydroxyl, C of being selected from
1-6Alkyl, C
1-6Alkoxyl group, C
3-10Naphthenic base, heterocyclic radical, C
6-10The substituting group of aryl or heteroaryl replaces;
R
6Be selected from Wasserstoffatoms, C
1-6Alkyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl or heteroaryl;
M is 0,1 or 2; And
N is 0,1,2 or 3.
Preferred version of the present invention provides the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, comprising the compound shown in the general formula (II) or its pharmaceutically useful salt:
Wherein:
L, R
1Described in the definition such as claim 1 that encircle A;
D, E, F or G independently are selected from C atom or N atom separately, and adjacent 3 or 4 atoms among D, E, F or the G are not the N atom simultaneously.
Preferred version of the present invention provides the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, comprising the compound shown in the general formula (III) or its pharmaceutically useful salt:
Wherein:
L, R
1Described in the definition such as claim 1 that encircle A;
E, F or G independently are selected from C atom or N atom separately, and 3 the adjacent atoms among E, F or the G are not the N atom simultaneously;
R
7Be selected from C
1-6Alkyl, halogen, hydroxyl, cyanic acid, C
1-6Alkoxyl group, nitro, C
3-10Naphthenic base or heterocyclic radical, perhaps 2 R
7Form carbonyl;
P is 1,2 or 3;
Q is 1,2 or 3.
Preferred version of the present invention provides the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein encircles A C
6-10Aryl, wherein said C
6-10Aryl optional further by one or more halogens or-SO
2R
3Substituting group replace.
Preferred version of the present invention provides the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein R
1Be heteroaryl, wherein said heteroaryl is optional further by one or more C
1-6Alkyl replaces.
Preferred version of the present invention provides the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein R
1For
R
8Be selected from C
1-6Alkyl or C
3-10Naphthenic base.
Preferred version of the present invention provides the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, and wherein n is 0.
Preferred version of the present invention provides the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein L be-O-,-O-CH
2-or-O-CH (CH
3)-.
Typical compound of the present invention includes, but are not limited to:
Or its pharmaceutically useful salt.
The present invention relates to the method for the compound or pharmaceutically acceptable salt thereof shown in a kind of preparation general formula (I), this method comprises:
With general formula (IA) compound and the reaction of general formula (IB) compound, obtain general formula (I) compound;
Wherein:
PG is hydroxyl or leavings group, be preferably halogen or-O-S (O)
mR
9
R
9Be C
1-6Alkyl or aryl;
Ring A, ring B, m, n, R
1, R
2With described in the definition such as general formula (I) of L.
The present invention relates to the method for the compound or pharmaceutically acceptable salt thereof shown in a kind of preparation general formula (I), this method comprises:
With general formula (IC) compound and the reaction of general formula (ID) compound, obtain general formula (I) compound;
Wherein:
PG is hydroxyl or leavings group, be preferably halogen or-O-S (O)
mR
9
R
9Be C
1-6Alkyl or aryl;
Ring A, ring B, m, n, R
1, R
2With described in the definition such as general formula (I) of L.
The present invention relates to the method for the compound or pharmaceutically acceptable salt thereof shown in a kind of preparation general formula (I), this method comprises:
With of the boric acid ester reaction of general formula (IE) compound, obtain general formula (I) compound with ring A;
Wherein:
X is selected from halogen;
Ring A, ring B, n, R
1, R
2With described in the definition such as general formula (I) of L.
Another aspect of the present invention relates to The compounds of this invention or the purposes of its pharmaceutically useful salt in the medicine of preparation GPR119 agonist.
Another aspect of the present invention relates to The compounds of this invention or its pharmaceutically useful salt, as the medicine of GPR119 agonist.
The invention still further relates to The compounds of this invention or its pharmaceutically useful salt in the medicine of the disease of preparation treatment mellitus and metabolic syndrome purposes.
Further, another aspect of the present invention relates to a kind of pharmaceutical composition, and it contains The compounds of this invention or its pharmaceutically useful salt and the pharmaceutically useful carrier or the vehicle of treating effective dose.This pharmaceutical composition is as the medicine of GPR119 agonist.The purposes of this pharmaceutical composition in the medicine of preparation treatment GPR119 agonist.
Another aspect of the present invention relates to a kind of method of treating the disease of mellitus and metabolic syndrome, and this method comprises The compounds of this invention or its pharmaceutically useful salt of the effective therapeutic dose of patient that needs treatment.
Another aspect of the present invention relates to The compounds of this invention or its pharmaceutically useful salt as the medicine of the disease of treatment mellitus and metabolic syndrome.
Another aspect of the present invention relates to a kind of method of regulating Regular Insulin, and this method comprises The compounds of this invention or its pharmaceutically useful salt of the effective therapeutic dose of patient of needs treatment.
Another aspect of the present invention relates to The compounds of this invention or its pharmaceutically useful salt as the medicine of regulating Regular Insulin.
Detailed description of the invention
Only if the phase counter-statement is arranged, otherwise the following term that is used in specification sheets and claims has following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group, comprises the straight chain and the branched group of 1 to 20 carbon atom.The alkyl that preferably contains 1 to 10 carbon atom more preferably contains the alkyl of 1 to 6 carbon atom.Non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec.-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2; 2-dimethyl propyl, 1-ethyl propyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl-propyl, 1,1,2-trimethylammonium propyl group, 1; 1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1; 3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl, n-heptyl, 2-methyl hexyl, 3-methyl hexyl, 4-methyl hexyl, 5-methyl hexyl, 2,3-dimethyl-amyl group, 2; 4-dimethyl-amyl group, 2,2-dimethyl-amyl group, 3,3-dimethyl-amyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2; 3-dimethyl-hexyl, 2,4-dimethyl-hexyl, 2,5-dimethyl-hexyl, 2; 2-dimethyl-hexyl, 3,3-dimethyl-hexyl, 4,4-dimethyl-hexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2; 2-diethylammonium amyl group, positive decyl, 3; 3-diethylhexyl, 2, the 2-diethylhexyl, and various branched chain isomers etc.The low alkyl group that more preferably contains 1 to 6 carbon atom, non-limiting example comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec.-butyl, n-pentyl, 1,1-dimethyl propyl, 1; 2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl-propyl, 1,1; 2-trimethylammonium propyl group, 1; 1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1; 3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl etc.Alkyl can be substituted or unsubstituted; When being substituted; Substituting group can be substituted on any spendable tie point; Be preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo ,-OR
3,-NR
4R
5,-C (O) R
3,-C (O) OR
3,-C (O) NR
4R
5,-NR
4C (O) R
5,-NR
4SO
2R
5,-S (O)
mR
3Or-SO
2NR
4R
4
" naphthenic base " refers to saturated or the unsaturated monocycle of part or encircle the cyclic hydrocarbon substituting group more, and it comprises 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably cycloalkyl ring comprises 3 to 10 carbon atoms.The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc.The polycyclic naphthene base comprises volution, condensed ring and endocyclic naphthenic base.
" spiro cycloalkyl group " refers to 5 to 20 yuan, many cyclic groups of a shared carbon atom (title spiro atom) between the monocycle, and these can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to shared spiro atom between ring and the ring is divided into single spiro cycloalkyl group, two spiro cycloalkyl group base or many spiro cycloalkyl group with spiro cycloalkyl group, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises
" condensed ring alkyl " refers to 5 to 20 yuan; Each ring in the system and other rings in the system are shared the many cyclic groups of full carbon of a pair of carbon atom that adjoins; Wherein one or more rings can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or polycyclic fused ring alkyl, is preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic alkyls.The non-limiting example of condensed ring alkyl comprises
" bridge ring alkyl " refers to 5 to 20 yuan, shared two the many cyclic groups of full carbon of direct-connected carbon atom not of any two rings, and these can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or encircle bridge ring alkyl more, is preferably dicyclo, three ring or Fourth Rings, more elects dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises
Said cycloalkyl ring can condense on aryl, heteroaryl or heterocycloalkyl ring, and the ring that wherein links together with precursor structure is a naphthenic base, and non-limiting example comprises indanyl, tetralyl, benzocyclohepta alkyl etc.Naphthenic base can be optional substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo ,-OR
3,-NR
4R
5,-C (O) R
3,-C (O) OR
3,-C (O) NR
4R
5,-NR
4C (O) R
5,-NR
4SO
2R
5,-S (O)
mR
3Or-SO
2NR
4R
5
" thiazolinyl " refers to the alkyl as defined above be made up of at least two carbon atoms and at least one carbon-to-carbon double bond.The thiazolinyl that preferably contains 1 to 10 carbon atom more preferably contains the thiazolinyl of 1 to 6 carbon atom.For example vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-crotonyl etc.Thiazolinyl can be substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-OR
3,-NR
4R
5,-C (O) R
3,-C (O) OR
3,-C (O) NR
4R
5,-NR
4C (O) R
5,-NR
4SO
2R
5,-S (O)
mR
3Or-SO
2NR
4R
5
" alkynyl " refers to the as above defined alkyl that at least two carbon atoms and at least one carbon-to-carbon triple bond are formed.The alkynyl that preferably contains 1 to 10 carbon atom more preferably contains the alkynyl of 1 to 6 carbon atom.For example ethynyl, 1-proyl, 2-propynyl, 1-, 2-or 3-butynyl etc.Alkynyl can be substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-OR
3,-NR
4R
5,-C (O) R
3,-C (O) OR
3,-C (O) NR
4R
5,-NR
4C (O) R
5,-NR
4SO
2R
5,-S (O)
mR
3Or-SO
2NR
4R
5
" heterocyclic radical " refers to saturated or the unsaturated monocycle of part or encircle the cyclic hydrocarbon substituting group more, and it comprises 3 to 20 annular atomses, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O)
mThe heteroatoms of (wherein m is an integer 0 to 2), but do not comprise-O-O-,-O-S-or-loop section of S-S-, all the other annular atomses are carbon.Preferably include 3 to 12 annular atomses, wherein 1～4 is heteroatoms, and more preferably cycloalkyl ring comprises 3 to 10 annular atomses.The non-limiting example of monocyclic cycloalkyl comprises pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, high piperazinyl etc.The polycyclic naphthene base comprises volution, condensed ring and endocyclic heterocyclic radical." spiro heterocyclic radical " refers to 5 to 20 yuan, many rings heterocyclic group of a shared atom (title spiro atom) between the monocycle, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O)
pThe heteroatoms of (wherein p is an integer 0 to 2), all the other annular atomses are carbon.These can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to shared spiro atom between ring and the ring is divided into single spiro heterocyclic radical, two spiro heterocyclic radical or many spiro heterocyclic radicals with spiro cycloalkyl group, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises
" fused heterocycle base " refers to 5 to 20 yuan; Each ring in the system and other rings in the system are shared many rings heterocyclic group of a pair of atom that adjoins; One or more rings can contain one or more pairs of keys; But the none ring has the πDian Zi system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O)
pThe heteroatoms of (wherein p is an integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or encircle the fused heterocycle alkyl more, is preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan fused bicyclic heterocycle bases.The non-limiting example of fused heterocycle base comprises
" bridge heterocyclic radical " refers to 5 to 14 yuan; Shared two the many rings heterocyclic groups of direct-connected atom not of any two rings; These can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O)
mThe heteroatoms of (wherein m is an integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or encircle bridge ring alkyl more, is preferably dicyclo, three ring or Fourth Rings, more elects dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises:
Said heterocyclic ring can condense on aryl, heteroaryl or cycloalkyl ring, and the ring that wherein links together with precursor structure is a heterocyclic radical, and non-limiting example comprises:
Deng.Heterocyclic radical can be optional substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo ,-OR
3,-NR
4R
5,-C (O) R
3,-C (O) OR
3,-C (O) NR
4R
5,-NR
4C (O) R
5,-NR
4SO
2R
5,-S (O)
mR
3Or-SO
2NR
4R
5
" aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (just share and adjoin the right ring of carbon atom) group, and many rings (being its ring that the has phase adjacency pair carbon atom) group with conjugated πDian Zi system is preferably 6 to 10 yuan, for example phenyl and naphthyl.Said aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring that wherein links together with precursor structure is an aryl rings, and non-limiting example comprises:
Aryl can be substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-OR
3,-NR
4R
5,-C (O) R
3,-C (O) OR
3,-C (O) NR
4R
5,-NR
4C (O) R
5,-NR
4SO
2R
5,-S (O)
mR
3Or-SO
2NR
4R
5
" heteroaryl " refers to comprise 1 to 4 heteroatoms, the heteroaromatic system of 5 to 14 annular atomses, and wherein heteroatoms comprises oxygen, sulphur and nitrogen.Be preferably 5 to 10 yuan.It is 5 yuan or 6 yuan that heteroaryl is preferably, for example furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Said heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring that wherein links together with precursor structure is a heteroaryl ring, and non-limiting example comprises:
Heteroaryl can be optional substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, ,-OR
3,-NR
4R
5,-C (O) R
3,-C (O) OR
3,-C (O) NR
4R
5,-NR
4C (O) R
5,-NR
4SO
2R
5,-S (O) mR
3Or-SO
2NR
4R
5
" alkoxyl group " refer to-O-(alkyl) and-O-(unsubstituted naphthenic base), wherein the definition of alkyl is as stated.Non-limiting example comprises methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Alkoxyl group can be optional substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from into alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-OR
3,-NR
4R
5,-C (O) R
3,-C (O) OR
3,-C (O) NR
4R
5,-NR
4C (O) R
5,-NR
4SO
2R
5,-S (O)
mR
3Or-SO
2NR
4R
5
" haloalkyl " refers to that alkyl is replaced by one or more halogens.
" hydroxyl " refers to-the OH group.
" hydroxyalkyl " refers to that alkyl is replaced by hydroxyl.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" amino " refers to-NH
2
" cyanic acid " refers to-CN.
" nitro " refers to-NO
2
" benzyl " refers to-CH
2-phenyl.
" oxo " refers to=O.
" carboxylic acid " refers to-C (O) OH.
" carboxylicesters " refers to-C (O) O (alkyl) or (naphthenic base).
" choose wantonly " or " randomly " mean describe subsequently ground incident or environment can but needn't take place, this explanation comprises that this incident or environment take place or spot occasion not.For example, " optional by the substituted heterocyclic group of alkyl " mean alkyl can but must not exist, this explanation comprise heterocyclic group by the substituted situation of alkyl and heterocyclic group not by the substituted situation of alkyl.
" substituted " refers to the one or more Wasserstoffatomss in the group, is preferably maximum 5, and more preferably 1～3 Wasserstoffatoms is replaced by the substituting group of respective number independently of one another.Self-evident, substituting group only is in their possible chemical position, and those skilled in the art can confirm (through experiment or theoretical) possibility or impossible replacement under the situation of not paying too much effort.For example, amino or the hydroxyl that has a free hydrogen possibly be unsettled when combining with the carbon atom with unsaturated (like olefinic) key.
" pharmaceutical composition " expression contains on one or more compounds described herein or its physiology/mixture of pharmaceutically useful salt or prodrug and other chemical compositions, and other components physiology/pharmaceutically useful carrier and vehicle for example.The purpose of pharmaceutical composition is the administration that promotes organism, is beneficial to the absorption and then the performance biological activity of activeconstituents.
M and R
3～R
5Definition such as general formula (I) compound described in.
The compound method of The compounds of this invention
In order to accomplish the object of the invention, the present invention adopts following technical scheme:
The preparation method of the described compound or its salt of general formula of the present invention (I) may further comprise the steps:
With general formula (IA) compound and the reaction of general formula (IB) compound, obtain general formula (I) compound;
The preferred version of this compound method:
General formula (IA) compound and general formula (IB) compound under the triphenylphosphine condition and condensation reagent, are preferably diisopropyl azodiformate, obtain general formula (I) compound;
Perhaps, general formula (IA) compound and general formula (IB) compound under alkaline condition, are preferably carbonate or sodium hydride, obtain general formula (I) compound;
Wherein:
PG is hydroxyl or leavings group, be preferably halogen or-O-S (O)
mR
9
R
9Be C
1-6Alkyl or aryl;
Ring A, ring B, m, n, R
1, R
2With described in the definition such as general formula (I) of L.
The preparation method of the described compound or its salt of general formula of the present invention (I) may further comprise the steps:
With general formula (IC) compound and the reaction of general formula (ID) compound, obtain general formula (I) compound;
The preferred version of this compound method:
General formula (IA) compound and general formula (IB) compound under the triphenylphosphine condition and condensation reagent, are preferably diisopropyl azodiformate, obtain general formula (I) compound;
Perhaps, general formula (IA) compound and general formula (IB) compound under alkaline condition, are preferably carbonate or sodium hydride, obtain general formula (I) compound;
Wherein:
PG is hydroxyl or leavings group, be preferably halogen or-O-S (O)
mR
9
R
9Be C
1-6Alkyl or aryl;
Ring A, ring B, m, n, R
1, R
2With described in the definition such as general formula (I) of L.
The preparation method of the described compound or its salt of general formula of the present invention (I) may further comprise the steps:
With the boric acid ester of general formula (IE) compound with ring A, in the presence of palladium catalyst, be preferably the reaction of two (triphenylphosphine) palladium chloride, obtain general formula (I) compound;
Wherein:
X is selected from halogen;
Ring A, ring B, n, R
1, R
2With described in the definition such as general formula (I) of L.
Embodiment
Be used to further describe the present invention below in conjunction with embodiment, but these embodiment and unrestricted scope of the present invention.
Embodiment
The structure of compound through nucleus magnetic resonance (NMR) or/and mass spectrum (MS) come to confirm.NMR displacement (δ) is with 10
-6(ppm) unit provides.The mensuration of NMR is with Bruker AVANCE-400 nuclear magnetic resonance spectrometer, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d
6), deuterochloroform (CDCl
3), deuterated methanol (CD
3OD), be designated as TMS (TMS) in.
The mensuration of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
The mensuration of HPLC is used Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 * 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 * 4.6mm chromatographic column).
The tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, and the specification that the silica-gel plate that tlc (TLC) is used adopts is 0.15mm～0.2mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm～0.5mm.
Column chromatography generally uses Huanghai Sea silica gel 200～300 order silica gel in Yantai to be carrier.
Known starting raw material of the present invention can adopt or synthesize according to methods known in the art; Maybe can buy Co.KG from ABCR GmbH &; Acros Organics; Aldrich Chemical Company, reaches company such as auspicious chemical at splendid chemistry science and technology far away (Accela Chem Bio Inc).
Argon atmospher or nitrogen atmosphere are meant that reaction flask connects an about 1L volumetrical argon gas or nitrogen balloon.
Nitrogen atmosphere is meant that reaction flask connects an about 1L volumetrical hydrogen balloon.
Parr 3916EKX type hydrogenation appearance and clear blue QL-500 type steam iron generator or HC2-SS type hydrogenation appearance are used in the pressure hydration reaction.
Hydrogenation vacuumizes usually, charges into hydrogen, repeatable operation 3 times.
Microwave reaction uses CEM Discover-S 908860 type microwave reactors.
Do not have specified otherwise among the embodiment, be reflected under nitrogen atmosphere or the argon atmospher and carry out.
Do not have specified otherwise among the embodiment, solution is meant the aqueous solution.
Do not have specified otherwise among the embodiment, the temperature of reaction is a room temperature.
Room temperature is optimum temperature of reaction, is 20 ℃～30 ℃.
Tlc (TLC) is adopted in the monitoring of the reaction process among the embodiment, and the system of reacting employed developping agent has: methylene dichloride and methanol system, and normal hexane and ethyl acetate system, the volume ratio of solvent is according to different adjusting of polarity of compound.
The system of the eluent of the column chromatography that purifying compounds adopts and the developping agent system of tlc comprise: A: methylene dichloride and methanol system; B: normal hexane and ethyl acetate system; The volume ratio of solvent is regulated according to the polarity of compound is different, also can add alkalescence such as a spot of triethylamine and acetic acid or acid reagent and regulate.
Embodiment 1
3-sec.-propyl-5-[trans-4-[[5-(4-methylsulfonyl phenyl) pyrazine-2-yl] oxygen methyl] cyclohexyl]-1,2, the 4-oxadiazole
The first step
Trans-4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexane carboxylic acid ethyl ester
(153mg 1.50mmol) is dissolved in the 15mL THF, adds (1R successively with N '-hydroxy-2-methyl-propylamine 1a; 4R)-and 4-ethoxy carbonyl cyclohexane carboxylic acid (301mg, 1.50mmol), triethylamine (455mg; 4.50mmol), the 1-hydroxy benzo triazole (223mg, 1.65mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (317mg; 1.65mmol), stirring reaction 12 hours.The concentrating under reduced pressure reaction solution adds 20mL toluene, is heated to backflow, stirring reaction 2 hours.The reaction solution concentrating under reduced pressure adds 30mL ETHYLE ACETATE, with water washing (30mL * 2); Anhydrous magnesium sulfate drying filters, and filtrate decompression concentrates; With eluent system B purifying gained resistates, obtain title product trans-4-(3-sec.-propyl-1,2 with silica gel column chromatography; 4-oxadiazole-5-yl) cyclohexane carboxylic acid ethyl ester 1b (260mg, colorless oil), productive rate: 65.2%.
MS?m/z(ESI)：267.2[M+1]
Second step
Trans-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl] methyl alcohol
Will (1R, 4R)-4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexane carboxylic acid ethyl ester 1b (260mg 1mmol) is dissolved in the 20mL THF, and the adding Li-Al hydrogen (74mg, 2mmol), stirring reaction 1 hour.Slowly splash into the 0.2mL saturated ammonium chloride solution, filter, with washed with dichloromethane (5mL); Filtrating is used anhydrous magnesium sulfate drying, filters, and filtrate decompression concentrates; Obtain bullion title product trans-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl] methyl alcohol 1c (240mg; Colorless oil), product is not purified directly carries out next step reaction.
MS?m/z(ESI)：225.1[M+1]
The 3rd step
5-bromo-pyrazine-2-amine
Under the ice bath, with pyrazine-2-amine 1d (11.87g 12.50mmol) is dissolved in the 300mL methylene dichloride, add in batches the N-bromo-succinimide (22.20g, 125mmol), stirring reaction 2 hours.Add 100mL saturated sodium carbonate solution cancellation reaction, separatory, organic phase is used saturated sodium carbonate solution (50mL * 1) successively; Water washing (50mL * 2), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 5-bromo-pyrazine-2-amine 1e (13g with silica gel column chromatography; Yellow solid), productive rate: 60.0%.
MS?m/z(ESI)：173.9[M+1]
The 4th step
5-(4-methylsulfonyl phenyl) pyrazine-2-amine
With 5-bromo-pyrazine-2-amine 1e (0.50g; 2.79mmol), (4-methylsulfonyl phenyl) boric acid (0.57g, 2.79mmol); Two (triphen phosphino-) palladium chloride (65mg; 0.06mmol) and 4mL 2M sodium carbonate solution be dissolved in 14mL 1, the mixed solvent of 4-dioxane and methyl alcohol (V/V=5: 2), rise to 100 ℃ of stirring reactions 3 hours.Add 100mL water, suction filtration, filter cake is with water washing (50mL * 2); Filter cake stirred suction filtration 20 minutes with the making beating of 50mL ETHYLE ACETATE; Obtain bullion title product 5-(4-methylsulfonyl phenyl) pyrazine-2-amine 1f (570mg, yellow solid), bullion is not purified directly to carry out next step reaction.
MS?m/z(ESI)：250.1[M+1]
The 5th step
5-(4-methylsulfonyl phenyl) pyrazine-2-alcohol
Cryosel is bathed down, and (230mg 3mmol) adds the 1.5mL vitriol oil in batches with Sodium Nitrite; Rise to 50 ℃ of stirrings, solid is dissolved entirely, reduce to 0 ℃ again; (temperature is at 0 ℃-5 ℃ in keeping for 560mg, concentrated sulfuric acid solution 2.20mmol) to drip 4.5mL 5-(4-methylsulfonyl phenyl) pyrazine-2-amine 1f; Finish stirring at room reaction 15 minutes, 45 ℃ of stirring reactions 45 minutes.Pour reaction solution into the 50mL frozen water, stir, dripping 12.5M sodium hydroxide solution conditioned reaction liquid pH is 4; Filter; Collect solid, with eluent system A purifying gained resistates, obtain title product 5-(4-methylsulfonyl phenyl) pyrazine-2-alcohol 1g (330mg with silica gel column chromatography; Faint yellow solid), productive rate: 60.0%.
MS?m/z(ESI)：251.1[M+1]
The 6th step
3-sec.-propyl-5-[trans-4-[[5-(4-methylsulfonyl phenyl) pyrazine-2-yl] oxygen methyl] cyclohexyl]-1,2, the 4-oxadiazole
With bullion trans-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl] methyl alcohol 1c (240mg; 1mmol) be dissolved in the 20mL toluene, add 5-(4-methylsulfonyl phenyl) pyrazine-2-alcohol 1g (250mg, 1mmol) and triphenylphosphine (394mg; 1.50mmol); Slowly splash into diisopropyl azodiformate (242mg, 1.20mmol), stirring reaction 2 hours.The reaction solution concentrating under reduced pressure with eluent system B purifying gained resistates, obtains title product 3-sec.-propyl-5-[trans-4-[[5-(4-methylsulfonyl phenyl) pyrazine-2-yl] oxygen methyl] cyclohexyl]-1 with silica gel column chromatography; 2; 4-oxadiazole 1 (60mg, white solid), productive rate: 13.3%.
MS?m/z(ESI)：467.2[M+1]
1H?NMR(400MHz，CDCl
3)δ8.58(d，1H)，8.34(d，1H)，8.12-8.16(m，2H)，8.03-8.07(m，2H)，4.26(d，2H)，3.10(s，3H)，3.05-3.13(m，1H)，2.89-2.98(m，1H)，2.21-2.29(m，2H)，2.05-2.13(m，2H)，1.65-1.76(m，2H)，1.35(d，6H)，1.25-1.31(m，3H).
Embodiment 2
3-sec.-propyl-5-[trans-4-[[6-(4-methylsulfonyl phenyl)-3-pyridine] oxygen methyl] cyclohexyl]-1,2, the 4-oxadiazole
The first step
Trans-4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexane carboxylic acid methyl esters
(817mg 8mmol) is dissolved in the 60mL THF, adds trans-4-methoxycarbonyl cyclohexane carboxylic acid (1.49g with N '-hydroxy-2-methyl-propylamine 1a; 8mmol), add successively again triethylamine (3.3mL, 24mmol); 1-hydroxy benzo triazole (1.19g; 8.80mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1.68g, 8.80mmol), stirring reaction 12 hours.The concentrating under reduced pressure reaction solution adds 60mL toluene, is heated to backflow, stirring reaction 4 hours.The reaction solution concentrating under reduced pressure adds 100mL ETHYLE ACETATE, with water washing (50mL * 2); Anhydrous magnesium sulfate drying filters, and filtrate decompression concentrates; Obtain bullion title product trans-4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexane carboxylic acid methyl esters 2a (1.95g; Brown oily), product is not purified directly carries out next step reaction.
MS?m/z(ESI)：253.1[M+1]
Second step
Trans-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl] methyl alcohol
With bullion trans-4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexane carboxylic acid methyl esters 2a (252mg 1mmol) is dissolved in the 20mL THF, add Li-Al hydrogen (74mg, 2mmol), stirring reaction 1 hour.Slowly splash into the 0.2mL saturated ammonium chloride solution, filter, with THF wash solids (10mL * 2), merging filtrate; Use anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates; With eluent system B purifying gained resistates, obtain title product trans-[4-(3-sec.-propyl-1,2 with silica gel column chromatography; 4-oxadiazole-5-yl) cyclohexyl] methyl alcohol 2b (120mg, colorless oil), productive rate: 54.0%.
MS?m/z(ESI)：225.2[M+1]
The 3rd step
Trans-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl] methyl methylsulfonate
With trans-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl] methyl alcohol 2b (200mg; 0.90mmol) be dissolved in the 10mL methylene dichloride, the adding triethylamine (0.4mL, 2.70mmol); Add again methylsulfonyl chloride (154mg, 1.35mmol), stirring reaction 1 hour.The reaction solution concentrating under reduced pressure adds 20mL water, with dichloromethane extraction (40mL * 2), merges organic phase; With water washing (20mL * 1), anhydrous magnesium sulfate drying filters; Filtrate decompression concentrates, and obtains bullion title product trans-[4-(3-sec.-propyl-1,2; 4-oxadiazole-5-yl) cyclohexyl] methyl methylsulfonate 2c (250mg, colorless oil), product is not purified directly to carry out next step reaction.
MS?m/z(ESI)：303.0[M+1]
The 4th step
6-(4-methylsulfonyl phenyl) pyridine-3-alcohol
With 6-chloropyridine-3-alcohol 2d (0.65g; 5mmol) (1g 5mmol) is dissolved in the 30mL dme, adds tetrakis triphenylphosphine palladium (288mg with (4-methylsulfonyl phenyl) boric acid; 0.25mmol) and 7.5mL 2M sodium carbonate solution, 100 ℃ of stirring reactions of microwave 30 minutes.The reaction solution concentrating under reduced pressure adds 150mL water, and using Hydrogen chloride conditioned reaction liquid pH is 5～6; With ethyl acetate extraction (150mL * 3), merge organic phase, anhydrous magnesium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 6-(4-methylsulfonyl phenyl) pyridine-3-alcohol 2e (420mg, white solid), productive rate: 37.5%.
MS?m/z(ESI)：249.6[M+1]
The 5th step
3-sec.-propyl-5-[trans-4-[[6-(4-methylsulfonyl phenyl)-3-pyridine] oxygen methyl] cyclohexyl]-1,2, the 4-oxadiazole
With bullion trans-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl] methyl methylsulfonate 2c (242mg; 0.80mmol) be dissolved in 10mL N, in N '-N, add 6-(4-methylsulfonyl phenyl) pyridine-3-alcohol 2e (199mg; 0.80mmol) and salt of wormwood (221mg; 1.60mmol), be heated to 80 ℃, stirring reaction 1.5 hours.Cooling adds 60mL water, with ethyl acetate extraction (60mL * 3); Merge organic phase, with water washing (30mL * 1), with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; Obtain title product 3-sec.-propyl-5-[trans-4-[[6-(4-methylsulfonyl phenyl)-3-pyridine] oxygen methyl] cyclohexyl]-1,2,4-oxadiazole 2 (80mg; White solid), productive rate: 30.0%.
MS?m/z(ESI)：456.0[M+1]
1H?NMR(400MHz，CDCl
3)δ8.42(d，1H)，8.15(d，2H)，8.02(d，2H)，7.75(d，1H)，7.31-7.34(m，1H)，5.30(s，1H)，3.93(d，2H)，3.04-3.11(m，3H)，2.90-2.94(m，1H)，2.25(d，2H)，2.10(d，2H)，1.65-1.67(m，2H)，1.33-1.35(m，9H).
Embodiment 3
3-sec.-propyl-5-[cis-4-[[5-(4-methylsulfonyl phenyl) pyrazine-2-yl] oxygen methyl] cyclohexyl]-1,2, the 4-oxadiazole
The first step
5-bromo-pyrazine-2-alcohol
Under the ice bath, (2g 11.50mmol) is dissolved in the 6rnL vitriol oil with 5-bromo-pyrazine-2-amine 1e; Be heated to 45 ℃ of hydrotropies, ice bath drips 8mL Sodium Nitrite (1.07g, concentrated sulfuric acid solution 15.50mmol) down; Stirring at room reaction 15 minutes is warming up to 45 ℃ of reactions 1 hour again.Reaction solution is added in the 20mL frozen water, and dripping the 12.50M sodium hydroxide solution is 4～5 to reaction solution pH, ethyl acetate extraction (50mL * 3); Merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 5-bromo-pyrazine-2-alcohol 3a (1.30g, yellow solid), productive rate: 65.0%.
MS?m/z(ESI)：176.9[M+1]
Second step
Cis-hexanaphthene-1,4-carboxylic acid dimethyl ester
With cis-hexanaphthene-1, (10g 5.80mmol) is dissolved in the 80mL methyl alcohol 4-dicarboxylicacid 3b, adds the 0.4mL vitriol oil, is heated to back flow reaction 5 hours.The reaction solution concentrating under reduced pressure adds 50mL ETHYLE ACETATE, uses saturated sodium bicarbonate solution (50mL * 1) successively; Water (50mL * 1), saturated nacl aqueous solution washing (50mL * 1), anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains bullion title product cis-hexanaphthene-1; 4-carboxylic acid dimethyl ester 3c (12.40g, colorless oil), product is not purified directly to carry out next step reaction.
MS?m/z(ESI)：218.1[M+18]
The 3rd step
(1S, 4S)-4-methoxycarbonyl cyclohexane carboxylic acid
With bullion cis-hexanaphthene-1, (11.60g 57.90mmol) is dissolved in the 100mL methyl alcohol 4-carboxylic acid dimethyl ester 3c, is heated to backflow, slowly adds 30mL Pottasium Hydroxide (3.25g, methanol solution 57.90mmol), back flow reaction 5 hours.The reaction solution concentrating under reduced pressure adds 100mL water, and extracted with diethyl ether (40mL * 3) is removed raw material; Dripping the 1M hydrogen chloride solution is 5～6 to water pH, and ethyl acetate extraction (30mL * 3) is with saturated nacl aqueous solution washing (50mL * 1); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; Obtain bullion title product cis-4-methoxycarbonyl cyclohexane carboxylic acid 3d (5.60g, white solid), product is not purified directly to carry out next step reaction.
MS?m/z(ESI)：187.1[M+1]
The 4th step
Cis-4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexane carboxylic acid methyl esters
(3.07g 30mmol) is dissolved in the 60mL THF, adds bullion (1S with N '-hydroxy-2-methyl-propylamine 1a; 4S)-(5.60g 30mmol), adds triethylamine (12.5mL to 4-methoxycarbonyl cyclohexane carboxylic acid 3d more successively; 90mmol), and the 1-hydroxy benzo triazole (4.46g, 33mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (6.33g; 33mmol), stirring reaction is 5 hours.The concentrating under reduced pressure reaction solution adds 80mL toluene, is heated to backflow, stirring reaction 12 hours.The reaction solution concentrating under reduced pressure adds 100mL water, ethyl acetate extraction (50mL * 3); With saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and obtains bullion title product cis-4-(3-sec.-propyl-1,2; 4-oxadiazole-5-yl) cyclohexane carboxylic acid methyl esters 3e (6.70g, yellow oily), product is not purified directly to carry out next step reaction.
MS?m/z(ESI)：253.1[M+1]
The 5th step
Cis-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl] methyl alcohol
Under the ice bath, (630mg 16.60mmol) is dissolved in the 50mL THF with Li-Al hydrogen; Dropping 20mL bullion (1S, 4S)-4-(3-sec.-propyl-1,2; 4-oxadiazole-5-yl) cyclohexane carboxylic acid methyl esters 3e (2g, tetrahydrofuran solution 8.30mmol), stirring at room reaction 5 hours.Slowly splash into the 1.3mL saturated ammonium chloride solution, filter, with THF washing leaching cake (10mL * 2), merging filtrate is used anhydrous magnesium sulfate drying; Filter, filtrate decompression concentrates, and adds 50mL ETHYLE ACETATE, with saturated nacl aqueous solution washing (50mL * 2); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, and obtains bullion title product cis-[4-(3-sec.-propyl-1; 2,4-oxadiazole-5-yl) cyclohexyl] methyl alcohol 3f (1.6g, yellow oil), product is not purified directly to carry out next step reaction.
MS?m/z(ESI)：225.1[M+1]
The 6th step
Cis-5-[4-[(5-bromo-pyrazine-2-yl) oxygen methyl] cyclohexyl]-3-sec.-propyl-1,2, the 4-oxadiazole
Under the ice bath, will (1S, 4S)-[4-(3-sec.-propyl-1; 2,4-oxadiazole-5-yl) cyclohexyl] (224mg is 1mmol) with 5-bromo-pyrazine-2-alcohol 3a (175mg for methyl alcohol 3f; 1mmol) be dissolved in the 10mL THF, and the adding triphenylphosphine (524mg, 2mmol); Dissolving in ultrasonic 1 minute drips 297 μ L diisopropyl azodiformates, ultrasonic reaction 20 minutes.Add the 20mL methylene dichloride; The concentrating under reduced pressure reaction solution with eluent system B purifying gained resistates, obtains title product cis-5-[4-[(5-bromo-pyrazine-2-yl) oxygen methyl] cyclohexyl]-3-sec.-propyl-1 with silica gel column chromatography; 2; 4-oxadiazole 3g (250mg, colorless oil), productive rate: 65.6%.
MS?m/z(ESI)：383.0[M+1]
The 7th step
Cis-3-sec.-propyl-5-[4-[[5-(4-methyl sulfenyl phenyl) pyrazine-2-yl] oxygen methyl] cyclohexyl]-1,2, the 4-oxadiazole
With cis-5-[4-[(5-bromo-pyrazine-2-yl) oxygen methyl] cyclohexyl]-3-sec.-propyl-1,2,4-oxadiazole 3g (250mg; 0.65mmol), (4-methyl sulfenyl phenyl) boric acid (110mg, 0.65mmol); Two (triphen phosphino-) palladium chloride (9.20mg; 0.01mmol) and 1mL 2M sodium carbonate solution be dissolved in 3.5mL 1, the mixed solvent of 4-dioxane and methyl alcohol (V/V=5: 2), rise to 95 ℃ of stirring reactions 12 hours.Add 5mL water, ethyl acetate extraction (30mL * 3) merges organic phase; With saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and obtains bullion title product cis-3-sec.-propyl-5-[4-[[5-(4-methyl sulfenyl phenyl) pyrazine-2-yl] oxygen methyl] cyclohexyl]-1,2; 4-oxadiazole 3h (220mg, yellow solid), product is not purified directly to carry out next step reaction.
MS?m/z(ESI)：425.1[M+1]
The 8th step
3-sec.-propyl-5-[cis-4-[[5-(4-methylsulfonyl phenyl) pyrazine-2-yl] oxygen methyl] cyclohexyl]-1,2, the 4-oxadiazole
With bullion cis-3-sec.-propyl-5-[4-[[5-(4-methyl sulfenyl phenyl) pyrazine-2-yl] oxygen methyl] cyclohexyl]-1; 2; (220mg 0.52mmol) is dissolved in the mixed solvent (V/V=2: 1), add potassium hydrogen persulfate composite salts (955mg again of 15mL acetone and water to 4-oxadiazole 3h; 1.55mmol), stirring reaction 12 hours.Dripping saturated sodium bicarbonate solution is 7 to reaction solution pH, and the concentrating under reduced pressure reaction solution adds 30mL water, with ethyl acetate extraction (50mL * 2); Merge organic phase, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With eluent system B purifying gained resistates, obtain title product 3-sec.-propyl-5-[cis-4-[[5-(4-methylsulfonyl phenyl) pyrazine-2-yl] oxygen methyl] cyclohexyl]-1,2 with silica gel column chromatography; 4-oxadiazole 3 (80mg, white solid), productive rate: 33.7%.
MS?m/z(ESI)：[M+1]
1H?NMR(400MHz，CDCl
3)δ8.60(s，1H)，8.34(s，1H)，8.17(d，2H)，8.08(d，2H)，4.32(d，2H)，3.32-3.22(m，1H)，3.20-3.07(m，4H)，2.33-2.20(m，2H)，2.18-2.05(m，1H)，1.98-1.80(m，4H)，1.64-1.51(m，2H)，1.39(d，6H).
Embodiment 4
3-sec.-propyl-5-[trans-4-[1-[5-(4-methylsulfonyl phenyl) pyrazine-2-yl] oxygen ethyl] cyclohexyl]-1,2, the 4-oxadiazole
The first step
Trans-4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexane carboxylic acid
(440mg 1.74mmol) is dissolved in the 5mL methyl alcohol, and (139mg 3.50mmol), was warming up to 30 ℃ of stirring reactions 16 hours to add sodium hydroxide with bullion trans-4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexane carboxylic acid methyl esters 2a.The reaction solution concentrating under reduced pressure adds 10mL water, ethyl acetate extraction (10mL * 2), drip the 2M hydrogen chloride solution to water pH be 3; With ethyl acetate extraction (20mL * 4), merge organic phase, with saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains bullion title product trans-4-(3-sec.-propyl-1,2; 4-oxadiazole-5-yl) cyclohexane carboxylic acid 4a (400mg, white solid), product is not purified directly to carry out next step reaction.
MS?m/z(ESI)：237.1[M-1]
Second step
Trans-4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl)-N-methoxyl group-N-methyl-cyclohexyl base methane amide
With bullion (1R, 4R)-4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexane carboxylic acid 4a (200mg; 0.84mmol), the 1-hydroxy benzo triazole (113mg, 0.84mmol); 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (177mg, 0.92mmol), N-methoxy methyl amine hydrochlorate (123mg; 1.26mmol) and triethylamine (254mg 2.50mmol) is dissolved in the 15mL methylene dichloride, stirring reaction 16 hours.Add 20mL water, dichloromethane extraction (30mL * 3) merges organic phase; With saturated nacl aqueous solution washing (20mL * 1), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and obtains bullion title product trans-4-(3-sec.-propyl-1,2; 4-oxadiazole-5-yl)-and N-methoxyl group-N-methyl-cyclohexyl base methane amide 4b (200mg, colorless oil), product is not purified directly to carry out next step reaction.
The 3rd step
Trans-1-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl] ethyl ketone
With bullion (1R, 4R)-4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl)-N-methoxyl group-(200mg 0.71mmol) is dissolved in the 10mL ether N-methyl-cyclohexyl base methane amide 4b, slowly is added dropwise to 0.5mL 3M methyl-magnesium-bromide, stirring reaction 2 hours.Be added dropwise to 20mL saturated ammonium chloride solution cancellation reaction, ethyl acetate extraction (30mL * 3) merges organic phase, with saturated nacl aqueous solution washing (20mL * 1); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With eluent system B purifying gained resistates, obtain title product trans-1-[4-(3-sec.-propyl-1,2 with silica gel column chromatography; 4-oxadiazole-5-yl) cyclohexyl] ethyl ketone 4c (140mg, colorless oil), productive rate: 83.8%.
The 4th step
Trans-1-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl] ethanol
With trans-1-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl] ethyl ketone 4c (140mg 0.59mmol) is dissolved in the 5mL methyl alcohol, add Peng Qinghuana (45mg, 1.18mmol), stirring reaction 1 hour.Add 5mL saturated ammonium chloride solution cancellation reaction,, merge organic phase with ethyl acetate extraction (20mL * 3); With saturated nacl aqueous solution washing (20mL * 1), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and obtains bullion title product trans-1-[4-(3-sec.-propyl-1,2; 4-oxadiazole-5-yl) cyclohexyl] ethanol 4d (140mg, colorless oil), product is not purified directly to carry out next step reaction.
MS?m/z(ESI)：239.1[M+1]
The 5th step
Trans-1-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl] ethyl methane sulfonate
With bullion trans-1-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl] ethanol 4d (140mg; 0.59mmol) be dissolved in the 5mL methylene dichloride, the adding triethylamine (0.3mL, 1.76mmol); Add again methylsulfonyl chloride (0.1mL, 0.88mmol), stirring reaction 1 hour.Add 10mL water,, merge organic phase with dichloromethane extraction (20mL * 3); With saturated nacl aqueous solution washing (20mL * 1), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and obtains bullion title product trans-1-[4-(3-sec.-propyl-1,2; 4-oxadiazole-5-yl) cyclohexyl] ethyl methane sulfonate 4e (160mg, white solid), product is not purified directly to carry out next step reaction.
The 6th step
3-sec.-propyl-5-[trans-4-[1-[5-(4-methylsulfonyl phenyl) pyrazine-2-yl] oxygen ethyl] cyclohexyl]-1,2, the 4-oxadiazole
With bullion trans-1-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl] ethyl methane sulfonate 4e (160mg; 0.51mmol) be dissolved in 5mL N; In N '-N, add 5-(4-methylsulfonyl phenyl) pyrazine-2-alcohol 1g (140mg, 0.56mmol) and cesium carbonate (332mg; 1.02mmol), be warming up to 90 ℃ of stirring reactions 5 hours.Add 15mL water, with ethyl acetate extraction (30mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 2); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With developping agent system B purifying gained resistates, obtain title product 3-sec.-propyl-5-[trans-4-[1-[5-(4-methylsulfonyl phenyl) pyrazine-2-yl] oxygen ethyl] cyclohexyl]-1,2 with the thin-layer chromatography chromatography; 4-oxadiazole 4 (35mg, white solid), productive rate: 14.6%.
MS?m/z(ESI)：471.1[M+1]
1H?NMR(400MHz，CDCl
3)δ8.60(s，1H)，8.32(s，1H)，8.17(d，2H)，8.08(d，2H)，5.25-5.14(m，1H)，3.72-3.59(m，1H)，3.18-3.06(m，5H)，2.91(dd，2H)，2.31-2.20(m，4H)，2.10(dd，2H)，2.04(s，1H)，1.90(d，1H)，1.70(d，1H)，1.40(d，6H).
Embodiment 5,6
Trans-5-[4-[[7-(2-fluoro-4-methylsulfonyl-phenyl)-5,6-pyrrolin [2,3-d] pyrimidine-4-yl] oxygen base] cyclohexyl]-3-sec.-propyl-1,2, the 4-oxadiazole
Cis-5-[4-[[7-(2-fluoro-4-methylsulfonyl-phenyl)-5,6-pyrrolin [2,3-d] pyrimidine-4-yl] oxygen base] cyclohexyl]-3-sec.-propyl-1,2, the 4-oxadiazole
The first step
The silica-based cyclohexane carboxylic acid of 4-triethyl
With 4-hydroxy-cyclohexyl carboxylic acid 5a (2.90g 20mmol) is dissolved in the 50mL THF, add imidazoles (1.43g, 21mmol) and TERT-BUTYL DIMETHYL CHLORO SILANE (3.02g, 20mmol), stirring reaction 3 hours.Add 200mL ETHYLE ACETATE, with water washing (150mL * 2), anhydrous magnesium sulfate drying; Filter, filtrate decompression concentrates, and obtains the silica-based cyclohexane carboxylic acid 5b (4.80g of bullion title product 4-tertiary butyl dimethyl chloride; Colourless liquid), product is not purified directly carries out next step reaction.
MS?m/z(ESI)：259.1[M+1]
Second step
Trans-4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl alcohol
Cis-4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl alcohol
(1.90g 18.50mmol) is dissolved in the 150mL THF, adds the silica-based cyclohexane carboxylic acid 5b (4.80g of 4-tertiary butyl dimethyl chloride with N '-hydroxy-2-methyl-propylamine 1a; 18.50mmol), add again triethylamine (5.62g, 55.50mmol); 1-hydroxy benzo triazole (3g; 22.20mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (4.26g, 22.20mmol), stirring reaction 12 hours.The concentrating under reduced pressure reaction solution adds 150mL toluene, is heated to backflow, stirring reaction 5 hours.The reaction solution concentrating under reduced pressure with eluent system B purifying gained resistates, obtains a pair of diastereomer product with silica gel column chromatography; Be respectively trans-4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl alcohol 5c (800mg; Light yellow oily), cis-4-(3-sec.-propyl-1,2; 4-oxadiazole-5-yl) cyclohexyl alcohol 5d (1.50g, light yellow oily).
The 3rd step
5-allyl group pyrimidine-4, the 6-glycol
Under the ice bath, (1.20g 22mmol) is dissolved in the 30mL methyl alcohol, and (885mg 11mmol), drips 10mL 2-allyl group propyl group diethyl ester 5e (2g, methanol solution 1mmol), stirring reaction 12 hours again to add the hydrochloric acid carbonamidine with 50% sodium methylate.The reaction solution concentrating under reduced pressure adds 60mL water, drip the 6M hydrogen chloride solution to reaction solution pH be 3, separate out a large amount of solids; Filter, washing (30mL * 2), vacuum-drying obtains title product 5-allyl group pyrimidine-4; 6-glycol 5f (880mg, white solid), productive rate: 58.0%.
MS?m/z(ESI)：151.1[M-1]
The 4th step
5-allyl group-4,6-two chloro-pyrimidines
With 5-allyl group pyrimidine-4, (4.30g 28mmol) places reaction flask to 6-glycol 5f, slowly adds the 30mL POCl3, is heated to refluxing and stirring reaction 2 hours.Reaction solution is poured in the 200g ice, and under the ice bath, using the 4M sodium hydroxide solution is 7 to reacting liquid pH value, ethyl acetate extraction (150mL * 3); Merge organic phase, saturated nacl aqueous solution washing (200mL * 2), anhydrous magnesium sulfate drying; Filter, filtrate decompression concentrates, and obtains bullion title product 5-allyl group-4; 6-two chloro-pyrimidine 5g (5g, brown liquid), productive rate: 93.6%.
MS?m/z(ESI)：190.9[M+1]
The 5th step
2-(4,6-dichloro pyrimidine-5-yl) acetaldehyde
With bullion 5-allyl group-4, (5g 26mmol) is dissolved in the mixed solvent (V/V=1: 1) of 100mL acetone and water to 6-two chloro-pyrimidine 5g; Under the ice bath, and the adding perosmic anhydride (500mg, 1.90mmol); Add sodium periodate (7.20g more in batches; 33.80mmol), guarantee that temperature is lower than 40 ℃, finish stirring at room reaction 1 hour.Filter, filter cake is poured in the saturated sodium thiosulfate solution fast, and filtrating is with saturated sodium thiosulfate solution washing (30mL * 2), concentrating under reduced pressure; Water merges organic phase with dichloromethane extraction (20mL * 5), saturated nacl aqueous solution washing (20mL * 2), anhydrous magnesium sulfate drying; Filter, filtrate decompression concentrates, and obtains bullion title product 2-(4; 6-dichloro pyrimidine-5-yl) acetaldehyde 5h (2.60g, brown solid), productive rate: 51.7%.
The 6th step
4-chloro-7-(2-fluoro-4-methylsulfonyl-phenyl)-5,6-pyrrolin [2,3-d] pyrimidine
The 10mL trifluoroacetic acid is placed there-necked flask, be cooled to-10 ℃, add 2-fluoro-4-methylsulfonyl-aniline (446mg; 2.40mmol), under-15 ℃, add triacetyl Peng Qinghuana (763mg; 3.60mmol), stirred 10 minutes, add 10mL bullion 2-(4 again; 6-dichloro pyrimidine-5-yl) acetaldehyde 5h (500mg, dichloromethane solution 2.60mmol), stirring at room reaction 12 hours.Add the 50mL methylene dichloride, dripping saturated sodium carbonate solution is 8 to reaction solution pH, the extraction separatory, and water is with dichloromethane extraction (20mL * 3); Merge organic phase, saturated nacl aqueous solution washing (40mL), anhydrous magnesium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 4-chloro-7-(2-fluoro-4-methylsulfonyl-phenyl)-5,6-pyrrolin [2 with silica gel column chromatography; 3-d] pyrimidine 5i (100mg, white solid), productive rate: 13.0%.
MS?m/z(ESI)：328.0[M+1]
The 7th step
Trans-5-[4-[[7-(2-fluoro-4-methylsulfonyl-phenyl)-5,6-pyrrolin [2,3-d] pyrimidine-4-yl] oxygen base] cyclohexyl]-3-sec.-propyl-1,2, the 4-oxadiazole
Cis-5-[4-[[7-(2-fluoro-4-methylsulfonyl-phenyl)-5,6-pyrrolin [2,3-d] pyrimidine-4-yl] oxygen base] cyclohexyl]-3-sec.-propyl-1,2, the 4-oxadiazole
With 60% sodium hydride (90mg 2.34mmol) is dissolved in the 10mL THF, add (1R, 4R)-4-(3-sec.-propyl-1; 2,4-oxadiazole-5-yl) cyclohexyl alcohol 5c (55mg, 0.26mmol), reflux 1.5 hours; Be cooled to room temperature, add 4-chloro-7-(2-fluoro-4-methylsulfonyl-phenyl)-5 again, 6-pyrrolin [2,3-d] pyrimidine 5i (85mg; 0.26mmol), refluxing and stirring reaction 4 hours, 60 ℃ were reacted 16 hours again.Add the 50mL shrend reaction of going out, drip the 2M hydrogen chloride solution to reaction solution pH be 8, with dichloromethane extraction (30mL * 3), the merging organic phase; Anhydrous magnesium sulfate drying filters, and filtrate decompression concentrates; With developping agent system B purifying gained resistates, obtaining a pair of diastereomer product with the thin-layer chromatography chromatography, is respectively trans-5-[4-[[7-(2-fluoro-4-methylsulfonyl-phenyl)-5; 6-pyrrolin [2,3-d] pyrimidine-4-yl] the oxygen base] cyclohexyl]-3-sec.-propyl-1,2; 4-oxadiazole 5 (45mg, white solid), productive rate: 34.6%; Cis-5-[4-[[7-(2-fluoro-4-methylsulfonyl-phenyl)-5,6-pyrrolin [2,3-d] pyrimidine-4-yl] oxygen base] cyclohexyl]-3-sec.-propyl-1,2,4-oxadiazole 6 (30mg, white solid), productive rate: 23.1%.
MS?m/z(ESI)：502.1[M+1]
5：
1H?NMR(400MHz，CDCl
3)δ8.29(s，1H)，8.02-8.08(m，1H)，7.68-7.77(m，2H)，5.16-5.26(m，1H)，4.21(t，2H)，3.13(t，2H)，3.04-3.10(m，1H)，3.06(s，3H)，2.93-3.02(m，1H)，2.21-2.33(m，4H)，1.79-1.92(m，2H)，1.48-1.58(m，2H)，1.34(d，6H).
6：
1H?NMR(400MHz，CDCl
3)δ8.30(s，1H)，8.03-8.09(m，1H)，7.69-7.76(m，2H)，5.41-5.47(m，1H)，4.21(t，2H)，3.15(t，2H)，3.02-3.11(m，2H)，3.05(s，3H)，2.06-2.16(m，4H)，1.97-2.05(m，2H)，1.75-1.87(m，2H)，1.35(d，6H).
Embodiment 7
Cis-5-[4-[[6-(3-fluoro-4-pyridine)-3-pyridine] oxygen methyl] cyclohexyl]-3-sec.-propyl-1,2, the 4-oxadiazole
The first step
Tributyl-(3-fluoro-4-pyridine) tin
Under the dry ice bath, (0.7mL 5.25mmol) is dissolved in the 20mL THF, adds the n-Butyl Lithium (2mL of 1M with diisopropylamine 1e; 5.00mmol) hexane solution, stirring reaction 30 minutes adds 10mL 3-fluorine pyridine 7a (0.51g; 5.25mmol) tetrahydrofuran solution, stirring reaction 90 minutes adds tributyl chlorine tin (1.63g; 5.00mmol), rise to room temperature, stirring reaction 2 hours.Add 50mL water, extracted with diethyl ether (40mL * 3) merges organic phase; With saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain bullion title product tributyl-(3-fluoro-4-pyridine) tin 7b (1.93g, colourless liquid), product is not purified directly to carry out next step reaction.
Second step
6-(3-fluoro-4-pyridine) pyridine-3-alcohol
With tributyl-(1.93g 5.00mmol) is dissolved in 10mL N, in the dinethylformamide to (3-fluoro-4-pyridine) tin 7b; Adding 6-bromopyridine-3-alcohol 7c (0.87g, 5.00mmol), triphenyl phosphorus palladium chloride (175mg; 0.25mmol) and the inferior ketone (95mg of iodate; 0.50mmol), be heated to 150 ℃, stirring reaction 5 hours.The reaction solution concentrating under reduced pressure adds 50mL water, ethyl acetate extraction (40mL * 3); Merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 6-(3-fluoro-4-pyridine) pyridine-3-alcohol 7d (0.50g, light yellow solid), productive rate: 65.6%.
MS?m/z(ESI)：191.0[M+1]
The 3rd step
Cis-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) hexanaphthene] methylmethanesulfonate ester
With cis-[4-(3-sec.-propyl-1,2,4-oxadiazole-5-yl) cyclohexyl] methyl alcohol 3f (0.80g 3.57mmol) is dissolved in the 20mL methylene dichloride, add triethylamine (1.5mL, 10.71mmol) and methylsulfonyl chloride (0.6mL, 7.13mmol), stirring reaction 5 hours.The reaction solution concentrating under reduced pressure adds 50mL water, and ethyl acetate extraction (30mL * 3) merges organic phase; With saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and obtains title product cis-[4-(3-sec.-propyl-1,2; 4-oxadiazole-5-yl) hexanaphthene] methylmethanesulfonate ester 7e (1.00g, yellow liquid), productive rate: 93.45%.
MS?m/z(ESI)：303.1[M+1]
The 4th step
Cis-5-[4-[[6-(3-fluoro-4-pyridine)-3-pyridine] oxygen methyl] cyclohexyl]-3-sec.-propyl-1,2, the 4-oxadiazole
With 6-(3-fluoro-4-pyridine) pyridine-(0.10g 0.526mmol) is dissolved in 5mL N to 3-alcohol 7d, in the N-dimethyl-formyl; Add (1S, 4S)-[4-(3-sec.-propyl-1,2; 4-oxadiazole-5-yl) hexanaphthene] methylmethanesulfonate ester 7e (0.16g, 0.526mmol) and salt of wormwood (0.22g, 1.58mmol); Be heated to 85 ℃, stirring reaction 5 hours.The reaction solution concentrating under reduced pressure adds 50mL water, and ethyl acetate extraction (30mL * 3) merges organic phase; With saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With eluent system A purifying gained resistates, obtain title product cis-5-[4-[[6-(3-fluoro-4-pyridine)-3-pyridine] oxygen methyl] cyclohexyl]-3-sec.-propyl-1,2 with silica gel column chromatography; 4-oxadiazole 7 (0.08g, white solid), productive rate: 38.5%.
MS?m/z(ESI)：397.1[M+1]
1H?NMR(400MHz，CDCl
3)δ8.53(d，1H)，8.49(d，1H)，8.43(dd，1H)，8.00(m，1H)，7.88(m，1H)，3.93(d，2H)，3.07(m，1H)，2.93(m，1H)，2.24(m，2H)，2.09(m，2H)，1.86(m，2H)，1.70(m，2H)，1.52(m，1H)，1.35(d，6H).
Test case:
Biological assessment
Following method is used for measuring the agonist activity of The compounds of this invention to GPR119.Experimental technique is summarized as follows:
Inoculation hamster beta islet cells (HIT-T15) (purchasing in ATCC article No. CRL-1777) in 96 orifice plates, inoculating cell density is 2x10
4Cell is at 37 ℃, 5%CO
2Cultivate under the condition after 48 hours, remove nutrient solution, adding 100 μ L stimulates damping fluid (0.5mM IBMX, 0.1%BSA, pH 7.4 for Hanks, 5mM HEPES), and in incubated at room 15 minutes.In the hole, add the different concns medicine, hatch 30 minutes after, remove damping fluid, add the lysate of 75 μ L precoolings, and hatched 20 minutes, suitably vibration on ice.Lysate is transferred in the 1.5mL centrifuge tube centrifugal 10 minutes with the rotating speed of 13000rpm.Get 50 μ L sample supernatants, (Cell Biolabs, Inc.) standard step detects cAMP content, the EC of compound according to the cAMPELISA test kit
50Value can draw through the cAMP cubage.
The EC of test-compound
50Be worth as shown in the table:
| Compound number | EC 50(HIT-T15)/(μM) |
| Embodiment 1 | 0.047 |
| Embodiment 2 | 0.035 |
| Embodiment 3 | 0.075 |
| Embodiment 5 | 0.036 |
Conclusion: 1,2,3 and 5 couples of GPR119 of embodiment of the invention compound have tangible agonist activity.
Pharmacokinetics is estimated
The pharmacokinetics test of test case 1 The compounds of this invention
1, summary
Study the drug level in the different blood plasma constantly behind the oral embodiment of the invention 5 compounds.The research The compounds of this invention is estimated its characteristics of pharmacokinetics in the pharmacokinetics in rats behavior.
2, testing program
2.1 test drug
Embodiment 5 compounds
2.2 experimental animal
4 of healthy adult SD rats, male and female half and half are available from west, Shanghai pul-Bi Kai laboratory animal ltd, animal production licence number: SCXK (Shanghai) 2008-0016.
2.3 medicine preparation
Take by weighing a certain amount of medicine, add 0.5%CMC-Na, the ultrasonic 1.0mg/ml suspension of processing.
2.4 administration and sample collecting
Fasting is distinguished gastric infusion after one night, and dosage is 10.0mg/kg, administration volume 10ml/kg.Each blood sampling constantly in 24 hours before administration and after the administration, anticoagulant heparin, separated plasma is in-20 ℃ of preservations.Feed in 2 hours after the administration.
3. analytical procedure
Set up the LC/MS/MS method and measured embodiment 5 compounds, the linearity range of method is 1.00～2000ng/ml, and plasma sample is analyzed after protein precipitation is handled.
4, pharmacokinetic parameter result
The pharmacokinetic parameter of The compounds of this invention such as following table:
Conclusion: embodiment 5 compounds behind oral administration in the rat body Plasma Concentration and exposure level all higher, have good medicine dynamic characteristic.
The pharmacodynamics test
1. research purpose
With the ICR mouse is animal subject, observes the influence of embodiment 5 compound single multiple dose administrations to glucose load mouse blood sugar value.
2. test-compound
Embodiment 1 and embodiment 5 compounds
3. experimental animal
Healthy ICR mouse (about body weight 20-24g) 40, male and female half and half are available from west, Shanghai pul-Bi Kai laboratory animal ltd, animal production licence number: SCXK (Shanghai) 2008-0016.
4. medicine preparation
Take by weighing an amount of compound with the 0.5% sodium cellulose glycolate aqueous solution be mixed with 1 with the suspension of 3mg/ml, positive compound is mixed with the suspension of 3mg/ml, ultrasonic suspending before the administration.
5. TP
5.1 divide into groups
Totally 40 of male and female mouse, overnight fast 16 hours.Measuring basic blood glucose value after weighing, is the 30mg/kg group (5 female 5 heros) of Blank group (5 female 5 heros), embodiment 1 compound according to blood sugar height random packet, 10 and the 30mg/kg group of embodiment 5 compounds (5 female 5 heros respectively).
5.2 dosage setting
Dosage is 10 and 30mg/kg, and the Blank group gives the 0.5% sodium cellulose glycolate aqueous solution.
5.3 medication
Gastric infusion, administration give 20% glucose solution (every mouse gives 0.4ml) by 4g/kg after 15 minutes.
5.4 the mensuration of blood glucose value
Blood glucose value (15 minutes) is measured in administration according to dosage.
Administration gives 20% glucose solution by 4g/kg after 15 minutes, and in the time of 0,15,30,45,60 and 120 minute, use the full blood sugar detection appearance of Luo Shi Luo Kang to measure the blood glucose value of each mouse.
5.5 data statistics
Use the Excel statistical software: MV calculates with avg; The SD value is calculated with STDEV; Group difference P value is calculated with TTEST.
The AUC calculation formula:
AUC＝(t
15min+t
0min)x0.25/2+(t
30min+t
15min)x0.25/2+(t
45min+t
30min)x0.25/2+(t
60min+t
45min)x0.25/2+(t
120min+t
60min)x1/2
T wherein
0min, t
15min, t
30min, t
45min, t
60min, t
120minThe blood glucose value that records for different time points.
6. test-results
The blood sugar rate of descent of TG-AUC (AUC) is 12.16% when giving the administration in 30 minutes behind embodiment 1 compound of 30mg/kg (P=0.011); The blood sugar rate of descent of TG-AUC (AUC) is respectively 12.27% and 15.91% when giving the administration in 30 minutes behind the embodiment compound of 10mg/kg and 30mg/kg (P=0.031), and the result shows the effect that embodiment 1 and 5 compounds all have tangible reduction mouse blood sugar to raise.
Claims (15)
1. the compound shown in the general formula (I) or its pharmaceutically useful salt:
Wherein:
Ring A is selected from C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl or heteroaryl, wherein said C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl or heteroaryl are optional independently of one another further by one or more halogen, cyanic acid, nitro, C of being selected from
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl, heteroaryl ,-OR
3,-NR
4R
5,-C (O) R
3,-C (O) OR
3,-C (O) NR
4R
5,-NR
4C (O) R
5,-NR
4SO
2R
5,-S (O)
mR
3Or-SO
2NR
4R
5Substituting group replace;
Ring B is selected from heterocyclic radical or heteroaryl, and wherein said heterocyclic radical or heteroaryl are optional independently of one another further by one or more halogen, C of being selected from
1-6Alkyl or-OR
3Substituting group replace;
L be selected from a singly-bound or-(CH
2)
1-4-, one-CH arbitrarily wherein
2-optional independently of one another by one or more O, N (R
6) or S replace all the other CH
2Choose wantonly and further be selected from halogen or C by one or two
1-6The substituting group of alkyl replaces;
R
1Be selected from C
3-10Naphthenic base, C
6-10Aryl, heterocyclic radical or heteroaryl, wherein said C
3-10Naphthenic base, C
6-10Aryl, heterocyclic radical or heteroaryl are optional further by one or more halogen, cyanic acid, nitro, C of being selected from
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl, heteroaryl ,-OR
3,-NR
4R
5,-C (O) R
3,-C (O) OR
3,-C (O) NR
4R
5,-NR
4C (O) R
5,-NR
4SO
2R
5,-S (O)
mR
3Or-SO
2NR
4R
5Substituting group replace;
R
2Be selected from halogen, cyanic acid, nitro, C
1-6Alkyl ,-OR
3Or-NR
4R
5, wherein said C
1-6Alkyl is optional further by one or more halogen, cyanic acid, nitro, hydroxyl, C of being selected from
1-6Alkoxyl group, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10The substituting group of aryl or heteroaryl replaces;
R
3Be selected from Wasserstoffatoms, C
1-6Alkyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl or heteroaryl, wherein said C
1-6Alkyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl or heteroaryl are optional further by one or more halogen, cyanic acid, nitro, hydroxyl, C of being selected from
1-6Alkyl, C
1-6Alkoxyl group, C
3-10Naphthenic base, heterocyclic radical, C
6-10The substituting group of aryl or heteroaryl replaces;
R
4And R
5Be selected from Wasserstoffatoms, C independently of one another
1-6Alkyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl or heteroaryl, wherein said C
1-6Alkyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl or heteroaryl are independently optional separately further by one or more halogen, cyanic acid, nitro, hydroxyl, C of being selected from
1-6Alkyl, C
1-6Alkoxyl group, C
3-10Naphthenic base, heterocyclic radical, C
6-10The substituting group of aryl or heteroaryl replaces;
Perhaps, R
4And R
5Nitrogen-atoms with being connected forms heterocyclic radical, and wherein said heterocyclic radical contains one or more N, O or S (O)
mHeteroatoms, and said heterocyclic radical is optional further by one or more halogen, cyanic acid, nitro, hydroxyl, C of being selected from
1-6Alkyl, C
1-6Alkoxyl group, C
3-10Naphthenic base, heterocyclic radical, C
6-10The substituting group of aryl or heteroaryl replaces;
R
6Be selected from Wasserstoffatoms, C
1-6Alkyl, C
3-10Naphthenic base, heterocyclic radical, C
6-10Aryl or heteroaryl;
M is 0,1 or 2; And
N is 0,1,2 or 3.
2. the compound shown in the general formula according to claim 1 (I) or its pharmaceutically useful salt, comprising the compound shown in the general formula (II) or its pharmaceutically useful salt:
Wherein:
L, R
1Described in the definition such as claim 1 that encircle A;
D, E, F or G independently are selected from C atom or N atom separately, and adjacent 3 or 4 atoms among D, E, F or the G are not the N atom simultaneously.
3. the compound shown in the general formula according to claim 1 (I) or its pharmaceutically useful salt, comprising the compound shown in the general formula (III) or its pharmaceutically useful salt:
Wherein:
L, R
1Described in the definition such as claim 1 that encircle A;
E, F or G independently are selected from C atom or N atom separately, and 3 the adjacent atoms among E, F or the G are not the N atom simultaneously;
R
7Be selected from C
1-6Alkyl, halogen, hydroxyl, cyanic acid, C
1-6Alkoxyl group, nitro, C
3-10Naphthenic base or heterocyclic radical, perhaps 2 R
7Form carbonyl;
P is 1,2 or 3;
Q is 1,2 or 3.
4. the compound shown in the general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein encircling A is C
6-10Aryl, wherein said C
6-10Aryl optional further by one or more halogens or-SO
2R
3Substituting group replace.
5. according to compound or its pharmaceutically useful salt, the wherein R shown in each described general formula (I) of claim 1～4
1Be heteroaryl, wherein said heteroaryl is optional further by one or more C
1-6Alkyl replaces.
6. the compound shown in the general formula according to claim 5 (I) or its pharmaceutically useful salt, wherein R
1For
R
8Be selected from C
1-6Alkyl or C
3-10Naphthenic base.
7. the compound shown in the general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein n is 0.
8. the compound shown in the general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein L be-O-,-O-CH
2-or-O-CH (CH
3)-.
9. according to compound or its pharmaceutically useful salt shown in each described general formula (I) of claim 1～8, wherein this compound is:
10. method for preparing the compound or pharmaceutically acceptable salt thereof shown in the general formula according to claim 1 (I), this method comprises:
With general formula (IA) compound and the reaction of general formula (IB) compound, obtain general formula (I) compound;
Wherein:
PG is hydroxyl or leavings group, be preferably halogen or-O-S (O)
mR
9
R
9Be C
1-6Alkyl or aryl;
Ring A, ring B, m, n, R
1, R
2With described in the definition such as claim 1 of L.
11. a method for preparing the compound or pharmaceutically acceptable salt thereof shown in the general formula according to claim 1 (I), this method comprises:
With general formula (IC) compound and the reaction of general formula (ID) compound, obtain general formula (I) compound;
Wherein:
PG is hydroxyl or leavings group, be preferably halogen or-O-S (O)
mR
9
R
9Be C
1-6Alkyl or aryl;
Ring A, ring B, m, n, R
1, R
2With described in the definition such as claim 1 of L.
12. a method for preparing the compound or pharmaceutically acceptable salt thereof shown in the general formula according to claim 1 (I), this method comprises:
With of the boric acid ester reaction of general formula (IE) compound, obtain general formula (I) compound with ring A;
Wherein:
X is selected from halogen;
Ring A, ring B, n, R
1, R
2With described in the definition such as claim 1 of L.
13. a pharmaceutical composition, said pharmaceutical composition contain the treatment effective dose according to the compound shown in any one described general formula (I) or its pharmaceutically useful salt and pharmaceutically useful carrier in the claim 1～9.
14. according to compound or its pharmaceutically useful salt shown in any one described general formula (I) of claim 1～9, or the purposes of pharmaceutical composition according to claim 13 in preparation GPR119 agonist.
15. according to compound or its pharmaceutically useful salt shown in any one described general formula (I) of claim 1～9, or the purposes of pharmaceutical composition according to claim 13 in the medicine of the disease of preparation treatment mellitus and metabolic syndrome.
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