US20120208998A1 - Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity - Google Patents
Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity Download PDFInfo
- Publication number
- US20120208998A1 US20120208998A1 US13/428,242 US201213428242A US2012208998A1 US 20120208998 A1 US20120208998 A1 US 20120208998A1 US 201213428242 A US201213428242 A US 201213428242A US 2012208998 A1 US2012208998 A1 US 2012208998A1
- Authority
- US
- United States
- Prior art keywords
- optionally substituted
- lower alkyl
- och
- aryl
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 230000002401 inhibitory effect Effects 0.000 title abstract description 14
- 108010002459 HIV Integrase Proteins 0.000 title abstract description 6
- -1 Polycyclic carbamoylpyridone derivative Chemical class 0.000 title description 271
- 150000001875 compounds Chemical class 0.000 claims abstract description 200
- 125000000217 alkyl group Chemical group 0.000 claims description 277
- 125000000623 heterocyclic group Chemical group 0.000 claims description 123
- 125000003107 substituted aryl group Chemical group 0.000 claims description 103
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 86
- 125000003545 alkoxy group Chemical group 0.000 claims description 84
- 229910052739 hydrogen Inorganic materials 0.000 claims description 81
- 239000001257 hydrogen Substances 0.000 claims description 79
- 150000002367 halogens Chemical group 0.000 claims description 72
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 69
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 68
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 61
- 229910052736 halogen Inorganic materials 0.000 claims description 50
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 45
- 125000005842 heteroatom Chemical group 0.000 claims description 42
- 150000002431 hydrogen Chemical group 0.000 claims description 40
- 125000003342 alkenyl group Chemical group 0.000 claims description 38
- 125000004104 aryloxy group Chemical group 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 229910052760 oxygen Inorganic materials 0.000 claims description 32
- 229910052717 sulfur Inorganic materials 0.000 claims description 31
- 125000002947 alkylene group Chemical group 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 24
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 21
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 17
- 125000004450 alkenylene group Chemical group 0.000 claims description 17
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 17
- 125000003277 amino group Chemical group 0.000 claims description 15
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 15
- UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 13
- 150000003585 thioureas Chemical class 0.000 claims description 13
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 abstract description 10
- 229940124411 anti-hiv antiviral agent Drugs 0.000 abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 5
- 230000000840 anti-viral effect Effects 0.000 abstract description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 639
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 442
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 396
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 304
- 238000005481 NMR spectroscopy Methods 0.000 description 232
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 231
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 208
- QDZZDVQGBKTLHV-UHFFFAOYSA-N (2,4-difluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1F QDZZDVQGBKTLHV-UHFFFAOYSA-N 0.000 description 204
- 238000005160 1H NMR spectroscopy Methods 0.000 description 124
- 239000000243 solution Substances 0.000 description 109
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 104
- 238000006243 chemical reaction Methods 0.000 description 94
- 125000001424 substituent group Chemical group 0.000 description 91
- 238000002844 melting Methods 0.000 description 66
- 230000008018 melting Effects 0.000 description 66
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
- 239000000126 substance Substances 0.000 description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 239000013078 crystal Substances 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 43
- 0 *N1ccN2C([3*])=C(C(=O)N([1*])C[2*])C(=O)C(O)=C2C1=O Chemical compound *N1ccN2C([3*])=C(C(=O)N([1*])C[2*])C(=O)C(O)=C2C1=O 0.000 description 38
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000002904 solvent Substances 0.000 description 36
- 230000002829 reductive effect Effects 0.000 description 35
- 239000000203 mixture Substances 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
- 238000000034 method Methods 0.000 description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 238000001816 cooling Methods 0.000 description 24
- 125000000753 cycloalkyl group Chemical group 0.000 description 22
- 239000012453 solvate Substances 0.000 description 20
- 230000035484 reaction time Effects 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000003795 chemical substances by application Substances 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 239000007810 chemical reaction solvent Substances 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 125000003282 alkyl amino group Chemical group 0.000 description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 15
- 125000004043 oxo group Chemical group O=* 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 102100034343 Integrase Human genes 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 108010061833 Integrases Proteins 0.000 description 9
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 9
- 241000700605 Viruses Species 0.000 description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 230000002194 synthesizing effect Effects 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
- 125000004442 acylamino group Chemical group 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 description 7
- 239000008363 phosphate buffer Substances 0.000 description 7
- 208000030507 AIDS Diseases 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000725303 Human immunodeficiency virus Species 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 238000005576 amination reaction Methods 0.000 description 6
- 125000005129 aryl carbonyl group Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 5
- 125000004414 alkyl thio group Chemical group 0.000 description 5
- 230000036436 anti-hiv Effects 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 150000001728 carbonyl compounds Chemical class 0.000 description 5
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 230000010534 mechanism of action Effects 0.000 description 5
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 4
- 239000007993 MOPS buffer Substances 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 125000006203 morpholinoethyl group Chemical group [H]C([H])(*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 4
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000003003 spiro group Chemical group 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 241001430294 unidentified retrovirus Species 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- GTPHFPQRKCCTTO-UHFFFAOYSA-N CC.CC.CC1N2C=C(C(=O)CCC3=CC=CC=C3)C(=O)C(O)=C2C(=O)N2CCCCN12 Chemical compound CC.CC.CC1N2C=C(C(=O)CCC3=CC=CC=C3)C(=O)C(O)=C2C(=O)N2CCCCN12 GTPHFPQRKCCTTO-UHFFFAOYSA-N 0.000 description 3
- NGXLQSDDEIUGJI-UHFFFAOYSA-N CC.CC1CN2C(=O)C3=C(O)C(=O)C(C(=O)CCC4=CC=CC=C4)=CN3C(C)N2C1 Chemical compound CC.CC1CN2C(=O)C3=C(O)C(=O)C(C(=O)CCC4=CC=CC=C4)=CN3C(C)N2C1 NGXLQSDDEIUGJI-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 238000007126 N-alkylation reaction Methods 0.000 description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000012888 bovine serum Substances 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical group 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000002373 plant growth inhibitor Substances 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- AAZYNPCMLRQUHI-UHFFFAOYSA-N propan-2-one;2-propan-2-yloxypropane Chemical compound CC(C)=O.CC(C)OC(C)C AAZYNPCMLRQUHI-UHFFFAOYSA-N 0.000 description 1
- XYKIUTSFQGXHOW-UHFFFAOYSA-N propan-2-one;toluene Chemical compound CC(C)=O.CC1=CC=CC=C1 XYKIUTSFQGXHOW-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- DIRYBTPIWDRSDJ-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate;toluene Chemical compound CC1=CC=CC=C1.CC(C)OC(=O)N=NC(=O)OC(C)C DIRYBTPIWDRSDJ-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical class CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005300 thiocarboxy group Chemical group C(=S)(O)* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
Definitions
- the present invention relates to novel compounds possessing an antiviral activity, more particularly, polycyclic carbamoylpyridone derivatives having a HIV integrase inhibitory activity and a pharmaceutical composition, particularly an anti-HIV agent containing the same.
- HIV human immunodeficiency virus
- AIDS acquired immunodeficiency syndrome
- the therapeutic agent for AIDS is mainly selected from a group of reverse transcriptase inhibitors (e.g., AZT, 3TC) and protease inhibitors (e.g., Indinavir), but they are proved to be accompanied by side effects such as nephropathy and the emergence of resistant viruses.
- AZT reverse transcriptase inhibitors
- Indinavir protease inhibitors
- the development of anti-HIV agents having the other mechanism of action has been desired.
- an integrase inhibitor has been focused on as an anti-HIV agent having a novel mechanism of action (Ref: Patent Documents 1 and 2).
- an anti-HIV agent having such a mechanism of action known are carbamoyl-substituted hydroxypyrimidinone derivative (Ref: Patent Documents 3 and 4) and carbamoyl-substituted hydroxypyrrolidione derivative (Ref: Patent Document 5).
- a patent application concerning carbamoyl-substituted hydroxypyridone derivative has been filed (Ref: Patent Document 6, Example 8).
- carbamoylpyridone derivatives include 5-alkoxypyridine-3-carboxamide derivatives and ⁇ -pyrone-3-carboxamide derivatives, which are a plant growth inhibitor or herbicide (Ref: Patent Documents 7-9).
- HIV integrase inhibitors include N-containing condensed cyclic compounds (Ref: Patent Document 10).
- the present inventors intensively studied to find that a novel polycyclic carbamoylpyridone derivative possesses a potent HIV integrase inhibitory activity. Moreover, the present inventors have discovered that a compound of the present compound and a pharmaceutical composition containing the same are useful as an antiviral agent (e.g. antiretroviral agent, anti-HIV agent, anti-HTLV-1 (Human T cell leukemia virus type 1) agent, anti-FIV (Feline immunodeficiency virus) agent, anti-SIV (Simian immunodeficiency virus) agent), especially an anti-HIV agent, an anti-AIDS agent, or a therapeutic for associated diseases, to accomplish the present invention shown below.
- an antiviral agent e.g. antiretroviral agent, anti-HIV agent, anti-HTLV-1 (Human T cell leukemia virus type 1) agent, anti-FIV (Feline immunodeficiency virus) agent, anti-SIV (Simian immunodeficiency virus) agent
- R 1 is hydrogen or lower alkyl
- X is a single bond, a heteroatom group selected from O, S, SO, SO 2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
- R 2 is optionally substituted aryl
- R 3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino,
- R 4 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO 2 , NR a (R a is hydrogen or
- the broken line represents the presence or absence of a bond
- B 1 and B 2 is CR 20 R 21 and another is NR 22 , where the broken line represents the absence of a bond;
- R 4 and R 22 taken together may form optionally substituted heterocycle
- R 4 and R 21 taken together may form optionally substituted heterocycle
- B 1 and B 2 are each independently C, CR 23 or N, where B 1 and B 2 taken together may form optionally substituted heterocycle;
- R 20 , R 21 , R 22 and R 23 are each independently, hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO
- G ring is optionally substituted heterocycle
- R 1 is hydrogen or lower alkyl
- X is a single bond, a heteroatom group selected from O, S, SO, SO 2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
- R 2 is optionally substituted aryl
- R 3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino,
- R 14 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO 2 , NR 5 (R 5 is independently selected
- R 1 is hydrogen or lower alkyl
- X is a single bond, a heteroatom group selected from O, S, SO, SO 2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
- R 2 is optionally substituted aryl
- R 3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino;
- R 4 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO 2 , NR a (R a is selected hydrogen
- B 1 and B 2 is CR 20 R 21 and another is NR 22 ;
- R 20 , R 21 and R 22 are each independently, hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substitute
- B 1 is NR 22 (R 22 is hydrogen, optionally substituted lower alkyl, lower alkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted lower alkylcarbonyl, optionally substituted aryl carbonyl, substituted thiourea or substituted sulfonyl), and B 2 is CH 2 .
- R 22 is hydrogen, optionally substituted lower alkyl, lower alkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted lower alkylcarbonyl, optionally substituted aryl carbonyl, substitute
- R 4 is optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl.
- B 1 is NR 22 (R 22 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted lower alkylcarbonyl, optionally substituted aryl carbonyl, substituted thiourea or substituted sulfonyl), B 2 is CH 2 and R 4 is optionally substituted lower alkyl, optionally substituted cyclo alkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl.
- B 1 is NR 22 (R 22 is hydrogen, optionally substituted lower alkyl (substituent: amino, lower alkylamino, lower alkoxy, aryloxy, cyano, halogen, optionally substituted carbamoyl, acylamino lower alkynyl, hydroxy), cycloalkyl, cycloalkyl lower alkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted 5- to 6-membered aromatic heterocyclic group, optionally substituted 5- to 6-membered heterocycle lower alkyl, optionally substituted lower alkylcarbonyl (substituent: lower alkoxy), optionally substituted benzoyl (substituent: lower alkoxy), substituted sulfonyl (substituent; lower alkyl, aryl, heterocyclic group)), B 2 is CH 2 and R 4 is optionally substituted lower alkyl (substituent: amino, lower alkylamino
- R 1 is hydrogen or lower alkyl
- X is a single bond, a heteroatom group selected from O, S, SO, SO 2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
- R 2 is optionally substituted aryl
- R 3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino,
- C ring is optionally substituted heterocycle or optionally substituted carbocycle
- B 1 and B 2 are independently C, CR 23 or N;
- R 23 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocycle lower alkylcarbonyl,
- the broken line represents the presence or absence of a bond
- R 4 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from CO, O, S, SO, SO 2 , NR a (R a is
- R 1 is hydrogen or lower alkyl
- X is a single bond, a heteroatom group selected from O, S, SO, SO 2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
- R 2 is optionally substituted aryl
- R 3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino,
- H ring is optionally substituted heterocycle
- R 24 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocycle lower alkylcarbonyl,
- R 3 is hydrogen.
- a pharmaceutical composition comprising a compound according to any one of (1) to (16), or a pharmaceutically acceptable salt, or solvate thereof.
- the present invention further provides a method for treating a virus infectious disease comprising administering the aforementioned compound. Further, the present invention provides a process for producing an agent for treating a virus infectious disease comprising the aforementioned compound.
- the present invention compounds possess an integrase inhibitory activity and/or a cell-growth inhibitory activity against virus, especially HIV. Accordingly, they are useful for the prevention or treatment of various diseases mediated by integrase or virus infection diseases (e.g., AIDS).
- a preferable compound is also effective to a resistant strain.
- a preferable compound has good pharmacokinetic in a body.
- “Lower alkylene” means a straight or branched C1 to C6 lower alkylene such as methylene, ethylene, trimethylene, propylene, tetramethylene, ethylethylene, pentamethylene, or hexamethylene, preferably C1 to C4 lower straight alkylene such as methylene, ethylene, trimethylene, and tetramethylene, more preferably methylene or ethylene.
- “Lower alkenylene” means a straight or branched C2 to C6 lower alkenylene, which consists of the above “Lower alkylene” having one or more double bonds, such as vinylene, propylene, or butenylene, preferably a straight C2 to C3 lower alkenylene such as vinylene or propylene.
- Alkyl means a straight or branched C1 to C10 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
- C1 to C6 lower alkyl Preferred is C1 to C6 lower alkyl, more preferred is C1 to C4 lower alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, and isohexyl.
- C1 to C6 lower alkyl more preferred is C1 to C4 lower alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, and isohexyl.
- the lower alkyl When lower alkyl is intervened with “—N ⁇ ” or “ ⁇ N—”, the lower alkyl may have a double bond to form —CH 2 —N ⁇ CH 2 , —CH ⁇ N—CH 3 , etc.
- Alkenyl means a straight or branched C2 to C8 alkenyl, which consists of the above “alkyl” having one or more double bonds, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, and 3-methyl-2-butenyl, preferably C2 to C6 lower alkenyl, and more preferably C2 to C4 lower alkenyl.
- “Lower alkenyloxy” means oxy attached to the above “lower alkenyl”, such as vinyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 1,3-butadienyloxy, and 3-methyl-2-butenyloxy.
- Cycloalkyl means C3 to C20, preferably C3 to C15, more preferably C3 to C10 cyclic saturated hydrocarbon, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, adamantyl, and polyhedron (e.g. cubane, dodecahedrane), further preferably C3 to C6 cycloalkyl.
- Cycloalkyl lower alkyl means lower alkyl substituted with the above cycloalkyl, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and cyclohexylethyl, and preferably C3 to C6 cycloalkyl lower alkyl.
- Aryl means monocyclic aromatic hydrocarbon (phenyl) and polycyclic aromatic hydrocarbon (e.g., 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl etc.), preferably phenyl or naphthyl (e.g., 1-napthyl, 2-naphthyl).
- Alkyl or “aryl lower alkyl” means the above “lower alkyl” substituted with 1 to 3 of the above “aryl”, such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl, 1-napthylmethyl, 2-napthylmethyl, preferably benzyl.
- Aryloxy means oxy attached to the above “aryl”, such as 1-naphthyloxy, 2-naphthyloxy, 1-anthryloxy, 2-anthryloxy, 9-anthryloxy, 1-phenanthryloxy, 2-phenanthryloxy, 3-phenanthryloxy, 4-phenanthryloxy, and 9-phenanthryloxy, preferably phenyloxy or naphthyloxy (e.g., 1-napthyloxy, 2-naphthyloxy).
- Heterocyclic group means “heteroring” or “heteroaryl”.
- Heteroring means a non-aromatic heterocyclic group which has at least one of N, O, P and/or S in the ring and may be bonded at any substitutable position, preferably 5- to 7-membered ring, such as 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperadinyl, 2-piperadinyl, 2-morpholinyl, 3-morpholinyl,
- Heteroaryl means monocyclic aromatic heterocyclic group or condensed aromatic heterocyclic group.
- Monocyclic aromatic heterocyclic group means a group induced from a 5- to 8-membered aromatic ring optionally containing 1 to 4 of O, S, P and/or N in the ring wherein the group may be bonded at any substitutable position.
- Condensed aromatic heterocyclic group means a group wherein a 5- to 8-membered aromatic ring optionally containing 1 to 4 of O, S, P and/or N in the ring is condensed with 1 to 4 of 5- to 8-membered aromatic carbocycle(s) or the other 5- to 8-membered aromatic heteroring(s), and may be bonded at any substitutable position.
- heteroaryl examples include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), e
- Heterocycle lower alkyl means lower alkyl substituted with the above “heterocyclic group”.
- Heterocycleoxy means an oxy attached to the above “heterocyclic group”.
- Heterocycle means a heterocycle which can form the heterocyclic group.
- “Lower alkoxy” means oxy attached to the above “lower alkyl”, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.
- Substituent group B examples include hydroxy, carboxy, halogen (F, Cl, Br, I), halo lower alkyl (e.g., CF 3 , CH 2 CF 3 , CH 2 CCl 3 ), halo lower alkoxy (e.g., OCF 3 , OCH 2 CF 3 , OCH 2 CCl 3 ), lower alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), lower alkenyl (e.g., vinyl), lower alkynyl (e.g., ethynyl), cycloalkyl (e.g., cyclopropyl), cycloalkenyl (e.g., cyclopropenyl), lower alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), lower alkenyloxy (e.g., vinyloxy, allyloxy), lower alkoxycarbonyl (
- substituents of “optionally substituted amino” or “optionally substituted carbamoyl” include mono- or di-lower alkyl, lower alkylcarbonyl, or lower alkylsulfonyl, optionally substituted lower alkyl (e.g., methyl, ethyl, isopropyl, benzyl, carbamoylalkyl (e.g., carbamoylmethyl), mono- or di-lower alkylcarbamoyl lower alkyl (e.g., dimethylcarbamoylethyl), hydroxy lower alkyl, heteroring lower alkyl (e.g., morpholinoethyl, tetrahydropyranylethyl), alkoxycarbonyl lower alkyl (e.g., ethoxycarbonylmethyl, ethoxycarbonylethyl), mono- or di-lower alkylamino lower alkyl (e.g., dimethylamino
- two substituents on the amino together with the neighboring N atom may form an N-containing heteroring which optionally contains S and/or O in the ring (preferably 5- to 7-membered ring or saturated ring) and the ring is optionally substituted with oxo or hydroxy.
- the S atom forming the ring may be substituted with oxo.
- a 5- or 6-membered ring such as piperazinyl, piperidino, morpholino, pyrrolidino, thiadinan-2-yl, 2-oxopiperidino, 2-oxopyrrolidino, 1,1-dioxido-1,2-thiadinan-2-yl, and 4-hydroxymorpholino is preferable.
- Phosphoric acid residue means a group shown of the formula: —PO(OH) 2 .
- Optionally substituted phosphoric acid residue means a phosphoric acid residue wherein the OH part and/or hydrogen of the OH is optionally substituted with a phosphoric acid residue, preferably shown by the formula:
- R A and R B each are independently OR C or NR D R E (wherein R C , R D and R E each are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic group, or R D and R E taken together with the neighboring N atom may form an optionally substituted heterocycle (preferably 5- to 6-membered ring)) or R A and R B taken together with the neighboring P atom may form an optionally substituted heterocycle (preferably 5- to 6-membered ring)).
- R A and R B are both OR C , or one of them is OR C and the other is NR D R E .
- R C , R D and R E each are preferably, independently, lower alkyl (e.g., methyl, ethyl).
- the optionally substituted heterocycle formed by R A and R B taken together with the neighboring P atom may be the following structure:
- Hydroxy substituted with optionally substituted phosphoric acid residue is preferably hydroxy substituted with a phosphoric acid residue substituted with di lower alkyls, and more preferably a group of the following formula:
- Amino substituted with optionally substituted phosphoric acid residue is preferably amino substituted with a phosphoric acid residue substituted with di lower alkyls, and more preferably a group of the following formula:
- a ring is optionally substituted heterocycle.
- the heterocycle is preferably a 5- to 7-membered ring containing 1 to 3, preferably 2 to 3 of O, S and/or N atoms, and is more preferably selected from the above heteroring.
- 1 or 2 heteroatoms can be present on an arc of A ring, and a position thereof is not limited.
- One of preferable embodiments of A ring is the following ring which is optionally substituted.
- Z is Z ⁇ O or NR 19 .
- R 19 is preferably 1) hydrogen, 2) optionally substituted lower alkyl (example of substituent: amino optionally substituted with mono- or di-lower alkyl, cycloalkyl, hydroxy, optionally substituted heterocyclic group (heterocycle is preferably 5- to 7-membered, e.g. furyl, thienyl, thiazolyl, pyridyl, morpholino, imidazole; example of substituent lower alkyl, halogen), optionally substituted heterocyclecarbonyl (heterocycle is preferably 5- to 7-membered, e.g.
- morpholinocarbonyl optionally substituted phenyl (substituent: lower alkyl, amino, lower alkylamino, hydroxy, halogen, halogenated lower alkyl, lower alkoxy, halogenated lower alkoxy, lower alkylthio, lower alkylsulfonyl), acetylamino, carbamoyl, mono- or di-lower alkyl substituted carbamoyl, lower alkylsulfonylamino, lower alkoxy, carbonyl, halogen, thiol, lower alkylthio), 3) lower alkenyl, 4) acyl (e.g. lower alkylcarbonyl), 5) lower alkylsulfonyl.
- phenyl substituted phenyl
- acetylamino carbamoyl, mono- or di-lower alkyl substituted carbamoyl, lower alkylsulfonylamino, lower alk
- substituent on the A ring same or different one or more substituents selected from Substituent group S2 are exemplified, preferably lower alkyl and the like.
- a substituent part on A ring may be connected with a neighboring atom to further form a fused ring or a spiro ring, preferably an optionally substituted carbocylcle (preferably 5- to 6-membered ring) or an optionally substituted heterocycle (preferably 5- to 6-membered ring).
- Substituent Group S2 hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkylcarbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocyclic lower al
- R 1 is hydrogen or lower alkyl, preferable hydrogen.
- X is a single bond, a heteroatom group (hereinafter, referred to as M in some cases) selected from O, S, SO, SO 2 and NH, or lower alkylene or lower alkenylene, each may be intervened by the heteroatom.
- M a heteroatom group
- “intervene” means the case where the heteroatom 1) is present between carbon atoms constituting alkylene or alkenylene, 2) is bound to a N atom of carbamoyl group adjacent to X, and/or 3) is bound to R 2 adjacent to X.
- the heteroatom group (M) may be same or different one or more groups.
- the case where lower alkylene is intervened by the heteroatom includes -M-CH 2 —, —CH 2 -M-CH 2 —, —CH 2 -M-, and —CH 2 -M-M-CH 2 —.
- X is preferably a spacer in which 1 to 3 atoms are connected.
- X is more preferably lower alkylene, or lower alkenylene which may be intervened by a heteroatom, or O, further preferably C1 to C3 lower alkylene or C2 to C3 lower alkenylene, or O, particularly preferably methylene or O.
- R 2 is optionally substituted aryl, preferably phenyl.
- a substituent on aryl preferably include same or different 1 to 3, preferably 1 to 2 substituents selected from the group consisting of halogen, hydroxy, amino, lower alkylamino, cyano, carboxy, formyl, oxo, lower alkyl, lower alkoxy, lower alkylthio, carbamoyl, and lower alkylcarbamoyl, and Substituent group S1 (: optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from group consisting O, S, SO, SO 2 , NR
- the substituent is a group more preferably selected from halogen, hydroxy, amino, cyano, lower alkyl, and lower alkoxy, and Substituent group S1, particularly preferably selected from halogen (e.g. F) and/or Substituent group S1.
- halogen e.g. F
- Substituent group S1 particularly preferably selected from halogen (e.g. F) and/or Substituent group S1.
- R 2 is more preferably phenyl, or phenyl substituted with at least halogen, particularly preferably 4-halogenophenyl (e.g. 4-F-phenyl) or 2,4-dihalogenophenyl (e.g. 2,4-F-phenyl).
- R 2 is more preferably phenyl optionally substituted with 1 to 3 Rs described later.
- a —X—R 2 part is preferably represented by the following formula.
- R's are each independently a group selected from the group consisting of halogen and Substituent group S1.
- Substituent group S1 optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from group consisting CO, O, S, SO, SO 2 , NR a (R a is hydrogen or lower alkyl), —N ⁇ and ⁇ N—), lower alkoxy lower alkyl, optionally substituted amino lower alkyl (substituent: mono- or di-lower alkyl, lower alkylcarbonyl, or lower alkylsulfonyl), halogenated lower alkyl, lower alkoxy, optionally substituted carbamoyl (substituent: mono- or di-lower alkyl
- m is an integer of 0 to 3, preferably 0, or 1 to 2.
- R is preferably halogen and, when m is 2, R is preferably two halogens, or halogen and other group.
- R is preferably present at a 4-position and, optionally, other position (e.g. 2-position) on a benzene ring.
- R is more preferably same or different groups selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkoxy lower alkyl, halogenated lower alkyl; halogenated lower alkoxy, lower alkylsulfonylamino, carbamoyl, and lower alkylcarbamoyl, particularly preferably two Fs.
- R 3 may be a variety of substituents as far as they do not adversely affect on the pharmacological activity of Compound (I), and examples include hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino.
- Examples of a substituent of “optionally substituted” include halogen, hydroxy, amino, lower alkylamino, cyano, carboxy, formyl, oxo, lower alkyl, lower alkoxy, lower alkylthio, carbamoyl, lower alkylcarbamoyl, aryl, heterocyclic group, lower alkylcarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyl, halogenated lower alkyl, and halogenated lower alkoxy, more preferably halogen, hydroxy, amino, lower alkylamino, lower alkyl, and lower alkoxy.
- R 3 is more preferably hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino, further preferably hydrogen or lower alkyl (e.g. methyl), particularly preferably hydrogen.
- the present invention provides the following compounds (in each of the following formulas, each symbol is as defined above unless otherwise is indicated).
- R 1 is hydrogen or lower alkyl, preferably hydrogen.
- X is a single bond, a heteroatom group selected from O, S, SO, SO 2 and NH, or lower alkylene or lower alkenylene which may be intervened by the heteroatom group; preferably a single bond, O, S, or lower alkylene (more preferably C1 to C3) which may be intervened by O or S.
- R 2 is optionally substituted aryl
- R 3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy group, or optionally substituted amino, more preferably hydrogen or optionally substituted lower alkyl.
- R 4 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocyclic lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from the group consisting of O, S, SO, SO 2 , NR a
- a broken line indicates the presence or absence of a bond.
- B 1 and B 2 are such that any one of them is CR 20 R 21 , and the other is NR 22 and, in this case, a broken line is not present.
- R 4 and R 22 may be connected together to form an optionally substituted heterocycle (e.g. G ring);
- R 4 and R 21 may be connected together to form an optionally substituted heterocycle (e.g. H ring).
- B 1 and B 2 are independently C, CR 23 , or N.
- B 1 and B 2 parts may be connected together to form an optionally substituted heterocycle (e.g. C ring) and, in this case, when B 1 and B 2 are independently CR 23 or N, a broken line indicates the absence of a bond.
- an optionally substituted heterocycle e.g. C ring
- R 20 , R 21 , R 22 and R 23 are independently selected from hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocyclic lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from the group consist
- R 2 , R 21 , R 22 and R 22 are more preferably selected from hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic lower alkyl, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkylcarbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocyclic lower alkylcarobnyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, substituted thiourea, and substituted sulfon
- the Compound (I) includes Compounds (I-10), (I-6), (I-9) and (I-12) shown below.
- G ring is a 5- to 7-membered ring containing 2 to 3 of O, S and/or N atoms, and contains at least 2 N atoms. More preferably, the ring is selected from the aforementioned heterorings, and the following rings are exemplified.
- a substituent on the G ring same or different one or more substituents selected from the Substituent group S2 are exemplified.
- a substituent part on the G ring may be connected with a neighboring atom to further form a fused ring or a spiro ring, preferably an optionally substituted carbocycle (preferably 5- to 6-membered ring) or an optionally substituted heterocycle (preferably 5- to 6-membered ring).
- One of preferable aspects of a substituent on the G ring is lower alkyl (e.g. methyl, isopropyl), lower alkoxy lower alkyl (e.g. 2-methoxyethyl), or optionally substituted amino (example of substituent lower alkyl (e.g. methyl), lower alkylcarbonyl (e.g. acetyl)).
- lower alkyl e.g. methyl, isopropyl
- lower alkoxy lower alkyl e.g. 2-methoxyethyl
- optionally substituted amino example of substituent lower alkyl (e.g. methyl), lower alkylcarbonyl (e.g. acetyl)).
- R 3 is preferably hydrogen or optionally substituted lower alkyl, more preferably hydrogen.
- R 14 is preferably hydrogen, optionally substituted lower alkyl (substituent: amino, lower alkylamino, lower alkoxy, aryloxy, cyano, halogen, (substituted) carbamoyl, acylamino, lower alkynyl, hydroxy), cycloalkyl, cycloalkyl lower alkyl, phenyl, benzyl, 5- to 6-membered aromatic heterocyclic group, 5- to 6-membered heterocyclic lower alkyl, optionally substituted lower alkylcarbonyl (substituent: lower alkoxy), optionally substituted benzoyl (substituent: lower alkoxy), substituted sulfonyl (substituent: lower alkyl, aryl, heterocyclic group), more preferably hydrogen or optionally substituted lower alkyl.
- B 1 is CR 20 R 21
- B 2 is NR 22 (R 20 , R 21 and R 22 are as defined above).
- B 1 is NR 22
- B 2 is CR 20 R 20 (R 20 , R 21 and R 22 are as defined above).
- R 3 is preferably hydrogen or optionally substituted lower alkyl, more preferably hydrogen.
- R 20 , R 21 and R 22 are preferably independently hydrogen, optionally substituted lower alkyl (example of substituent: amino, lower alkylamino, lower carbonylamino, lower alkoxy, aryloxy, cyano, halogen, acylamino (e.g.
- lower carbonylamino lower alkynyl, hydroxy, lower alkoxycarbonyl, optionally substituted heterocyclecarbonyl (example of substituent: lower alkyl, lower alkoxy), lower alkenyl, optionally substituted carbamoyl (example of substituent lower alkyl), lower alkylcarbonyloxy, lower alkyloxycarbonyl, lower alkylcarobnyl amino, oxo, lower alkynyl), cycloalkyl, cycloalkyl lower alkyl, optionally substituted aryl (example of substituent: lower alkyl, halogen, lower alkyloxy, nitro), optionally substituted aryl lower alkyl (example of substituent: lower alkyl, halogen, lower alkyloxy, nitro, oxo), optionally substituted heterocyclic group (example of substituent lower alkyl, halogen, lower alkyloxy, nitro), optionally substituted heterocyclic lower al
- R 20 and R 21 are both hydrogen.
- R 1 is hydrogen or lower alkyl, more preferably hydrogen;
- X is lower alkylene;
- R 2 is phenyl, or phenyl substituted with at least halogen, more preferably phenyl substituted with 1 to 2 halogens (e.g. F);
- R 3 is hydrogen;
- B 1 is CH 2 or NR 22 ;
- B 2 is NR 22 or CH 2 , more preferably B 1 is NR 22 ;
- B 2 is CH 2 .
- R 4 is preferably optionally substituted lower alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl; example of substituent: hydroxy, amino, lower alkylamio, lower alkoxy, aryloxy, oxo, lower alkoxycarbonyl, optionally substituted heterocyclecarbonyl (example of substituent: lower alkyl, lower alkoxy)), specifically lower alkylamino lower alkyl (e.g. 2-dimethylaminoethyl, 2-diethylaminoethyl), lower alkoxy lower alkyl (e.g.
- lower alkyl e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl
- substituent hydroxy, amino, lower alkylamio, lower alkoxy, aryloxy, oxo, lower alkoxycarbonyl, optionally substituted heterocycle
- aryl e.g. phenyl; example of substituent; lower alkyl, halogen, lower alkyloxy, nitro, or a substituent part may be lower alkylene which may be intervened by a heteroatom (e.g. O)); optionally substituted aryl lower alkyl (e.g. benzyl; example of substituent: lower alkyl, halogen, lower alkyloxy, nitro, or a substituent part may be lower alkylene which may be intervened by a heteroatom (e.g.
- optionally substituted heterocyclic group preferably 5- to 6-membered ring
- optionally substituted heterocyclic group preferably 5- to 6-membered ring
- optionally substituted heterocyclic group preferably 5- to 6-membered ring lower alkyl (e.g.
- R 22 is preferably optionally substituted alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, neopentyl; example of substituent: amino, lower alkylamino, lower alkoxy, aryloxy, cyano, halogen, (substituted) carbamoyl, acylamino, oxo), specifically lower alkylamino lower alkyl (e.g. 2-dimethylaminoethyl, 2-diethylaminoethyl), lower alkoxy lower alkyl (e.g.
- aryloxy lower alkyl e.g. 2-phenoxyethyl, 3-phenoxypropyl
- cyano lower alkyl e.g. cyanomethyl
- halogenated lower alkyl e.g. fluoromethyl, 2,2,2-trifluoromethyl
- carboranemethyl e.g.
- 2-acetamideethyl lower alkenyl (e.g. allyl, propargyl, crotyl); cycloalkyl lower alkyl (e.g. 3-cyclopropyl, cyclopropylmethyl, 1-adamantylmethyl, 2-adamantylmethyl, dodecahedranemethyl, cubanemethyl); optionally substituted aryl (e.g. phenyl; a substituent part may be lower alkylene which may be intervened by a heteroatom (e.g. O)); optionally substituted aryl lower alkyl (e.g. benzyl; a substituent part may be lower alkylene which may be intervened by a heteroatom (e.g.
- optionally substituted heterocyclic group e.g. picolyl pyridyl; example of substituent lower alkyl
- optionally substituted heterocyclic lower alkyl e.g. piperonylmethyl, morpholinoethyl, furanmethyl, tetrahydrofuranmethyl, dioxanemethyl, tetrahydropyranmethyl, triazolemethyl, tetrazolemethyl, thiazolemethyl, oxazolemethyl, 1,2,4-oxadiazolemethyl, 1,3,4-oxadiazolemethyl, isoxazolemethyl, imidazolemethyl, methylpyrrolemethyl, 18-crownethermethyl; example of substituent: lower alkyl); optionally substituted lower alkylcarbonyl (e.g.
- acetyl example substituent lower alkoxy (e.g. methoxy)); optionally substituted arylcarbonyl (e.g. benzoyl; example of substituent; lower alkoxy); substituted thiourea (e.g. urea, lower alkylurea (e.g. dimethylurea), dimethylthiourea); or substituted sulfonyl (e.g. alkylsulfonyl (e.g. methanesulfonyl), arylsulfonyl (e.g. benzenesulfonyl), heterocyclic sulfonyl (e.g. thiophenesulfonyl)).
- substituted thiourea e.g. urea, lower alkylurea (e.g. dimethylurea), dimethylthiourea
- substituted sulfonyl e.g. alkylsulfonyl (e.g. me
- C ring indicates an optionally substituted carbocycle or an optionally substituted heterocycle.
- B 1 and B 2 are independently C, CH or N.
- B 1 and B 2 are independently CR 23 or N, a broken line indicates the presence of a bond.
- the C ring is a heterocycle, the same heterocycles as the A ring and the G ring are exemplified, and a substituent on the C ring is also exemplified similarly. That is, as a substituent on the C ring, same or different one or more substituents selected from Substituent group S2 are exemplified.
- a substituent part on the C ring may be taken together with a neighboring atom to further form a fused ring or a spiro ring, preferably an optionally substituted carbocycle (preferably 5- to 6-membered ring) or an optionally substituted heterocycle (preferably 5- to 6-membered ring).
- B 1 and B 2 are independently C or CH and, as the carbocycle, a 5- to 7-membered ring is exemplified.
- a broken line indicates the presence or absence of a bond, preferably the absence of a bond.
- the C ring includes the following rings, preferably (i) and (l).
- One of preferable aspects as a substituent on the C ring is lower alkyl (e.g. methyl, isopropyl), lower alkoxy lower alkyl (e.g. 2-methoxyethyl), and optionally substituted amino (example of substituent: lower alkyl (e.g. methyl), lower alkylcarbonyl (e.g. acetyl)).
- lower alkyl e.g. methyl, isopropyl
- lower alkoxy lower alkyl e.g. 2-methoxyethyl
- optionally substituted amino example of substituent: lower alkyl (e.g. methyl), lower alkylcarbonyl (e.g. acetyl)).
- R 19 is more preferably hydrogen, lower alkyl, or lower alkoxy lower alkyl.
- R 3 is preferably hydrogen, or optionally substituted lower alkyl, more preferably hydrogen.
- H ring means a heterocycle having the same meaning as that of the A ring, is preferably a 5- to 7-membered ring and, as a substituent on each ring, the same substituents as those in the case of the A ring are exemplified. That is, as a substituent on the H ring, same or different one or more substituents selected from the Substituent group S2 are exemplified.
- a substituent part on the H ring may be connected with a neighboring atom to further form a fused ring or a spiro ring, preferably an optionally substituted carbocycle (preferably 5- to 6-membered ring) or an optionally substituted heterocycle (preferably 5- to 6-membered ring).
- R 3 is preferably hydrogen, or optionally substituted lower alkyl, more preferably hydrogen.
- R 24 is preferably hydrogen, optionally substituted lower alkyl (substituent: amino, lower alkylamino, lower alkoxy, aryloxy, cyano, halogen, (substituted) carbamoyl, acylamino, lower alkynyl, hydroxy), cycloalkyl, cycloalkyl lower alkyl, phenyl, benzyl, 5- to 6-membered aromatic heterocyclic group, 5- to 6-membered heterocyclic lower alkyl, optionally substituted lower alkylcarbonyl (substituent: lower alkoxy, halogen), optionally substituted benzoyl (substituent: lower alkoxy, halogen), or substituted sulfonyl (substituent: lower alkyl, aryl, heterocyclic group (preferably 5- to 6-membered
- Compound (I) has at least the following characteristics as its chemical structure.
- Compound (1) exhibits a remarkably potent integrase inhibitory activity and/or cell-growth inhibitory activity against virus including HIV.
- a preferable compound is also effective to a resistant strain.
- other partial structures have a relatively large freedom degree, may have a variety of substituents, and may form a condensed ring, and the condensed ring may be further substituted.
- the present invention provides a pharmaceutically acceptable salt or a solvate of Compound (I). All theoretically possible tautomer, geometrical isomer, optically active compound, and racemate thereof of the present compound are within the scope of the invention.
- Pharmaceutically acceptable salts of a compound of the present invention include, as basic salts, for example, alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine, meglumine, diethanolamine, or ethylenediamine salts; aralkyl amine salts such as N, N-dibenzylethylenediamine or benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts,
- Acid salts include, for example, mineral acid salts such as hydrochloride, sulfates salts, nitrate salts, phosphates salts, carbonates salts, hydrogencarbonates or perchlorate; organic acid salts such as acetates, propionates, lactates, maleates, fumarates, tararates, malates, citrates salts, or ascorbates; sulfonates such as methanesulfonates, isethionates, benzenesulfonates, or p-toluenesulfonates; and acidic amino acid salts such as aspartates or glutamates are exemplified.
- mineral acid salts such as hydrochloride, sulfates salts, nitrate salts, phosphates salts, carbonates salts, hydrogencarbonates or perchlorate
- organic acid salts such as acetates, propionates, lactates, maleates, fumarates, tararate
- Solvates of a compound of the present invention include alcholates and hydrates.
- L 1 is a leaving group (e.g.; halogen); P 1 and P 2 are a hydroxy protecting group; P 3 is a carboxy protecting group (e.g.: lower alkyl); R a and R b are hydrogen or a substituent on an amino group)
- Examples of a hydroxy protecting group (P 1 , P 2 ) include acyl (e.g.: acetyl, pivaloyl, benzoyl), aralkyl (e.g.: benzyl), lower alkyl (e.g.: methyl), alkoxyalkyl (e.g.: methoxymethyl, methoxyethyl), lower alkylsulfonyl (e.g.: methanesulfonyl), arylsulfonyl (e.g.: benzenesulfonyl, toluenesulfonyl), alkoxycarbonyl (e.g.: methoxycarbonyl) and the like.
- acyl e.g.: acetyl, pivaloyl, benzoyl
- aralkyl e.g.: benzyl
- lower alkyl e.g.: methyl
- alkoxyalkyl e.
- lower alkyl e.g.; methyl, ethyl
- aralkyl e.g.: benzyl
- the present step is a reaction for condensing a compound (II) and a compound (III) to synthesize a compound (IV).
- the reaction may be performed according to the condition for a reaction of amidating carboxylic acid which is generally performed.
- a compound (II) may be reacted as it is, or may be reacted after converted into corresponding acid chloride or active ester.
- the reaction is performed in a suitable solvent in the presence of a condensing agent.
- dicyclohexylcarbodiimide 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like may be used.
- a reagent such as 1-hydroxybenzotriazole and N-hydroxysuccinimide, or a base such as triethylamine, N-methylmorpholine, and pyridine may be added.
- a reaction temperature is 0 to 150° C., preferably room temperature to 70° C.
- an aprotic solvent can be broadly used, and tetrahydrofuran (THF), 1,4-dioxane, dimethylformamide (DMF), methylene chloride, chloroform and the like are preferable.
- a reaction time is a few minutes to a few tens hours, preferably 9 to 17 hours.
- the present step is a reaction for introducing a protected hydroxy group (OP 1 ) into a compound (IV) to produce a compound (V).
- the reaction may be performed according to the condition for an alkoxylating reaction which is generally performed.
- a compound (V) in which P 1 is methyl can be synthesized by reacting a compound (IV) with metal alkoxide (e.g.: sodium methoxide).
- metal alkoxide e.g.: sodium methoxide
- a reaction temperature is 0 to 200° C., preferably 80 to 120° C.
- reaction solvent alcohol, dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) are exemplified.
- a reaction time is a few minutes to a few tens hours, preferably 5 to 10 hours.
- the present step is a reaction for protecting a hydroxy group of a compound (V) to produce a compound (VI).
- the reaction may be performed according to the condition for a reaction of protecting a hydroxy group which is generally performed. For example, by using diisopropyl azodicarboxylate or diethyl azodicarboxylate together with an alcohol and various phosphines, a compound (VI) in which P 2 is alkyl can be synthesized.
- a reaction temperature is 0 to 100° C., preferably 0° C. to room temperature.
- reaction solvent THF, toluene, dichloromethane and the like are exemplified.
- a reaction time is a few minutes to a few tens hours, preferably 1 to 3 hours.
- the present step is a reaction of oxidizing a nitrogen atom of a compound (VI) to produce a compound (VII).
- the reaction may be performed according to the condition for an oxidation reaction using an oxidizing agent which is generally performed.
- a reaction temperature is 0 to 100° C., preferably under ice-cooling to room temperature.
- reaction solvent chloroform, methylene chloride, acetic acid and the like are exemplified.
- an oxidizing agent examples include metachloroperbenzoic acid, hydrogen peroxide and the like.
- a reaction time is a few minutes to a few tens hours, preferably 1 to 5 hours.
- the present step is a reaction for hydroxylating a methyl group of a compound (VII).
- reaction temperature 0 to 150° C., preferably 120 to 140° C.
- this may be hydrolyzed (e.g.: treatment with a base (e.g.: alkali metal hydroxide)).
- a reaction time is a few minutes to a few tens hours, preferably 0.5 to 2 hours for acetoxylation, and 0.5 to 1 hour for hydrolysis.
- the present step is a reaction for oxidizing a hydroxy group of a compound (VIII) to synthesize a compound (IX).
- a reaction temperature is 0 to 150° C., preferably room temperature to 70° C.
- reaction solvent chloroform and the like are exemplified.
- dimethyl sulfoxide As an oxidizing agent, dimethyl sulfoxide and the like are exemplified.
- a reaction time is a few minutes to a few tens hours, preferably 0.1 to 1 hour.
- the present step is a reaction for oxidizing a formyl group of a compound (IX) to synthesize a compound (X).
- a reaction temperature is 0 to 150° C., preferably under ice-cooling to room temperature.
- reaction solvent an alcohol and the like are exemplified.
- potassium hydroxide and iodine are exemplified.
- a reaction time is a few minutes to a few tens hours, preferably 0.5 to 3 hours.
- the present step is a reaction for deprotecting an OP 2 part of a compound (X) to synthesize a compound (XI).
- the reaction may be performed according to the condition for a reaction of deprotecting a hydroxy protecting group which is generally performed.
- a reaction temperature is 0 to 150° C., preferably under ice-cooling to room temperature.
- reaction solvent acetonitrile, methylene chloride, THF and the like are exemplified.
- a reaction time is a few minutes to a few tens hours, preferably 1 to 3 hours.
- the present step is a reaction for deprotecting an OP 1 part of a compound (XI) to synthesize a compound (I-A).
- the reaction may be treated preferably with a Lewis acid (e.g.: aluminum chloride).
- a reaction temperature is 0 to 150° C., preferably 10 to 50° C.
- reaction solvent methylene chloride, THF and the like are exemplified.
- a reaction time is a few minutes to a few tens hours, preferably 1 to 3 hours.
- the present step is a reaction for deprotecting an ester part (COOP 3 ) of a compound (X) to synthesize carboxylic acid (XII).
- COOP 3 ester part
- XII carboxylic acid
- hydrolysis with an alkali e.g.: NaOH
- an alkali e.g.: NaOH
- a reaction temperature is 0 to 150° C., preferably 10 to 50° C.
- reaction solvent methanol, water and the like are exemplified.
- a reaction time is a few minutes to a few tens hours, preferably a few minutes to 2 hours.
- Carboxylic acid (XII) can be converted into various derivatives (e.g.; amide).
- the present step is a reaction for reacting a compound (XII) with various amines to synthesize a compound (XIII).
- the reaction may be performed according to the condition for a reaction of amidating carboxylic acid which is generally performed and, for example, the reaction may be performed as in the first step.
- a reaction temperature is 0 to 150° C., preferably room temperature to 70° C.
- an aprotic solvent can be broadly used, and tetrahydrofuran (THF), 1,4-dioxane, dimethylformamide (DMF), methylene chloride, chloroform and the like are preferable.
- a reaction time is a few minutes to a few tens hours, preferably a few minutes to 3 hours.
- An amide part of the resulting compound (XIII) may be further chemically modified (e.g.: N-alkylation).
- the present step is a reaction for deprotecting OP 1 and OP 2 parts of a compound (XIII) to synthesize a compound (I-B).
- the reaction may be performed according to the condition for a reaction of deprotecting a hydroxy protecting group which is generally performed.
- a reaction temperature is 0 to 200° C., preferably 150 to 180 degree.
- a reaction time is a few minutes to a few tens hours, preferably 1 to 5 minutes.
- the present step is a reaction for deprotecting an ester part (COOP 3 ) of a compound (XI) to synthesize carboxylic acid (XIV).
- COOP 3 ester part
- XIV carboxylic acid
- hydrolysis with an alkali e.g.: lithium hydroxide
- an alkali e.g.: lithium hydroxide
- a reaction temperature is 0 to 150° C., preferably 10 to 50° C.
- reaction solvent methanol, water and the like are exemplified.
- a reaction time is a few minutes to a few tens hours, preferably a few minutes to 3 hours.
- the present step is a reaction for deprotecting an OP 1 part of a compound (XIV) to synthesize a compound (I-C).
- the reaction may be treated preferably with a Lewis acid (e.g.: boron tribromide).
- a reaction temperature is 0 to 150° C., preferably under ice-cooling to room temperature.
- reaction solvent dichloromethane and the like are exemplified.
- a reaction time is a few minutes to a few tens hours, preferably a few minutes to 5 hours.
- the monocyclic carbamoylpyridone derivative obtained above is derived into a bicyclic compound by the following method.
- a compound (XIV) is reacted with a protected hydrazine reagent according to a general amidation reaction to obtain a compound (XIV-1).
- the protected hydrazine reagent can be synthesized, for example, according to the method described in Pol. J. Chem. 2003.77.315-319.
- a compound (XIV) may be reacted as it is, or may be reacted after it is converted into corresponding acid chloride or active ester.
- the reaction is performed in a suitable solvent in the presence of a condensing agent.
- dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like can be used.
- a reagent such as 1-hydroxybenzotriazole and N-hydroxysuccinimide and the like, and a base such as triethylamine, N-methylmorpholine, and pyridine may be added.
- a reaction temperature is about 0 to 150° C., preferably room temperature to 70° C.
- an aprotic solvent can be broadly used, and tetrahydrofuran (THF), 1,4-dioxane, dimethylformamide (DMF), methylene chloride, chloroform and the like are preferable.
- a reaction time is a few minutes to a few tens hours, preferably 10 minutes to 5 hours.
- a reaction temperature is usually 0 to 150° C., preferably room temperature to 60° C.
- reaction solvent ethyl acetate, 1,4-dioxane, and THF are exemplified.
- a reaction time is usually a few minutes to a few tens hours, preferably a few minutes to 5 hours.
- a compound (XIV-2) is reacted with a carbonyl compound according to a general aminal forming reaction to obtain a compound (XIV-3).
- a reaction temperature is usually about 0 to 100° C., preferably room temperature to 60° C.
- reaction solvent methylene chloride, THF, and toluene are exemplified.
- a reaction time is usually a few minutes to a few tens hours, preferably a few minutes to 5 hours.
- the present reaction is preferably performed in the presence of an acid catalyst (e.g. acetic acid, p-toluenesulfonic acid).
- an acid catalyst e.g. acetic acid, p-toluenesulfonic acid.
- a reaction temperature is usually about 0 to 180° C., preferably room temperature to 60° C.
- reaction solvent THF, 1,4-dioxane, and methylene chloride are exemplified.
- a reaction time is usually a few minutes to a few hours, preferably a few minutes to 5 hours.
- a compound (XIV) is reacted with an amine reagent according to the thirty-fifth step to obtain a compound (XIV-5).
- a compound (XIV-5) is reacted with an N-amination reagent to obtain a compound (XIV-6).
- Preparation of an N-amination reagent and an N-amination reaction are performed, for example, according to the method described in J. Med. Chem. 1984, 27.1103-1108.
- a compound (XIV-6) is reacted with a carbonyl compound according to the thirty-seventh step to obtain a compound (XIV-7).
- An NH part of a compound (XIV-6) is variously modified to obtain a compound (XIV-8).
- modification method general N-alkylation, alkylation using a halogenated compound, reductive amination using a carbonyl compound, acylation, and sulfonylation are exemplified.
- a P 1 part of a compound (XIV-8) is deprotected according to the thirty-eighth step to obtain a compound (XIV-9).
- n is an integer of 1 to 4; R and R′ are an arbitrary substituent; respective X 1 s are the same or different, and an X 1 ( ⁇ C, N) may be substituted; n is preferably an integer of 1 to 4).
- a compound (XIV-10) is subjected to a general acetal deprotection reaction to obtain a compound (XIV-11).
- the present reaction is preferably performed under the acidic condition.
- a reaction temperature is usually about 0 to 120° C., preferably room temperature to 60° C.
- reaction solvent THF, 1,4-dioxane, water, and methanol are exemplified.
- a reaction time is usually a few minutes to a few tens hours, preferably a few minutes to 5 hours.
- a compound (XIV-10) is obtained by reacting a compound (VIV) with a hydrazine reagent having a protected aldehyde-type substituent according to the thirty-fifth step.
- a P 1 part of a compound (XIV-11) is deprotected according to the thirty-eighth step to obtain a compound (XIV-12) (C ring formation).
- a compound (XIV-6) is reacted with a carbonyl compound according to a general aminal forming reaction to obtain a compound (XIV-13).
- a compound (XIV-13) is cyclized in a molecule to obtain a compound (XIV-14).
- a reaction is performed according to a general alkylation reaction or the similar condition.
- a P 1 part of a compound (XIV-14) is deprotected according to the thirty-eighth step to obtain a compound (XIV-15) (C ring formation).
- a compound (XIV) is reacted with an amine reagent according to the thirty-fifth step to obtain a compound (XIV-19).
- a compound (XIV-19) is reacted with an N-amination reagent to obtain a compound (XIV-20).
- Preparation of an N-amination reagent and an N-amination reaction are performed, for example, according to the method described in J. Med. Chem. 1984, 27, 1103-1108.
- a compound (XIV-20) is subjected to a general acetal deprotection reaction according to the forty-fourth step to obtain a compound (XIV-21).
- An NH part of a compound (XIV-21) is variously modified to obtain a compound (XIV-22).
- modification method general N-alkylation, alkylation using a halogenated compound, reductive amination using a carbonyl compound, acylation, and sulfonation are exemplified.
- a P 1 part of a compound (XIV-22) is deprotected according to the thirty-eighth step to obtain a compound (XIV-23).
- the present compound obtained above may be further chemically modified to synthesize another compound.
- a reactive functional group e.g.: OH, COOH, NH 2
- the group may be protected before the reaction and may be deprotected after the reaction, if desired.
- the present compound is useful, for example, as a drug such as an anti-viral drug.
- the present compound has the remarkable inhibitory action on integrase of a virus. Therefore, the present compound can be expected to have the preventive or therapeutic effect for various diseases derived from a virus which produces at least integrase, and is grown at infection in an animal cell, and is useful as an integrase inhibiting agent for retrovirus (e.g. HIV-1, HIV-2, HTLV-1, SIV, FIV etc.), and is useful as an anti-HIV drug etc.
- retrovirus e.g. HIV-1, HIV-2, HTLV-1, SIV, FIV etc.
- the present compound may be used in a combination therapy by combining an anti-HIV drug having the different action mechanism such as a reverse transcriptase inhibiter and/or a protease inhibiting agent.
- an integrase inhibiter is not marketed, and it is useful to use in a combination therapy by combining the present compound with a reverse transcriptase inhibiter and/or a protease inhibiter.
- the above use includes not only use as a medical mixture for anti-HIV, but also use as a joint use agent for increasing the anti-HIV activity of other anti-HIV drug such as cocktail therapy.
- the present compound can be used in order to prevent infection with a retrovirus vector from spreading into a tissue other than an objective tissue, upon use of a retrovirus vector based on HIV or MLV in the field of gene therapy.
- a retrovirus vector based on HIV or MLV in the field of gene therapy.
- the present compound can be administered orally or parenterally.
- the present compound can be also used as a conventional preparation, for example, as any dosage form of a solid agent such as tablets, powders, granules, capsules and the like; an aqueous agent; an oily suspension; or a liquid agent such as syrup and elixir.
- the present compound can be used as an aqueous or oily suspension injectable, or a nasal drop.
- conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like may be arbitrarily used.
- an anti-HIV-drug particularly, an oral agent is preferable.
- a preparation of the present invention is prepared by combining (e.g. mixing) a therapeutically effective amount of the present compound with a pharmaceutically acceptable carrier or diluent.
- a dose of the present invention is different depending on an administration method, an age, a weight and condition of a patient, and a kind of a disease and, usually, in the case of oral administration, about 0.05 mg to 3000 mg, preferably about 0.1 mg to 1000 mg may be administered per adult a day, if necessary, by dividing the dose. In addition, in the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg is administered per adult a day.
- the extract was washed with a 5% aqueous potassium carbonate solution, an aqueous saturated ammonium chloride solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure to obtain a mixture (175 g) of 10 and 11.
- the resulting mixture was dissolved in acetic acid (1050 ml) and water (1050 ml), and zinc (31.1 g, 475 mmol) was added, followed by heating to reflux for 1 hour. After the reaction solution was cooled to room temperature, a 10% aqueous potassium carbonate solution was added, followed by extraction with ethyl acetate.
- the extract was washed with an aqueous saturated ammonium chloride solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, this was washed with diethyl ether to obtain 5-benzyloxy-N-(4-fluoro-benzyl)-4-hydroxy-6-hydroxymethyl-nicotinic acid amide 10 (107 g, 59%) as a colorless crystal.
- the reaction solution was diluted with ethyl acetate, washed with an aqueous saturated sodium bicarbonate solution, a 10% aqueous citric acid solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain 3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-hydroxy-pyridine-2-carboxylic acid methyl ester 14 (141 mg, 69%) as a colorless crystal.
- the organic layer was washed with water, a 5% aqueous sodium hydrogen sulfite solution and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain 3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-oxo-1-(2-oxo-ethyl)-1,4-dihydro-pyridine-2-carboxylic acid methyl ester 16 (5.39 g, 71%) as a colorless crystal.
- Example compounds A-2 to A-29, and A-31 to A-32 were synthesized.
- the solvent was distilled off under reduced pressure, to the residue were added toluene (100 ml) and hexane (2000 ml), and precipitated crystals were filtered.
- the solvent was distilled off under reduced pressure, to the residue were added diethyl ether (200 ml) and hexane (2000 ml), and precipitated crystals were filtered.
- the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). 4-Benzyloxy-N-(4-fluorobenzyl)-5-methoxy-6-methylnicotinamide 23 (68.5 g, 52%) was obtained as a colorless crystal.
- Example A-30 (86 mg, 93%).
- Example B-1 According to the same manner as that of Example B-1, the following Examples compounds B-2 to B-28 were synthesized.
- N′-(4-fluoro-benzyl)-hydrazinecarboxylic acid tert-butyl ester was synthesized by the method described in the literature (J. Med. Chem. 1996, 39, 3203-3216).
- To the compound 59 (597 mg, 0.996 mmol) was added 4N hydrochloric acid (ethyl acetate solution) at 0° C., and a temperature was raised to room temperature, followed by stirring for 1 hour.
- An aqueous sodium bicarbonate solution was added to neutralize it, followed by extraction with ethyl acetate.
- the organic layer was washed with water, dried with anhydrous sodium sulfate, and the solvent was distilled off to obtain a compound 60 (500 mg) at a yield of 100%.
- Example compound K-1 was obtained.
- Example compounds K-2 to K-6 were synthesized.
- the present invention further includes the following compounds.
- Example compounds K-7 to K41 were synthesized according to the same manner as that of Example K-1.
- Example N-1 (44.3 mg, 69%) was obtained from Compound 70 (76.3 mg).
- Example O-1 According to the method of synthesizing Example A-1, Example O-1 (54.3 mg, 66%) was obtained form Compound 69 (100 g).
- Example Compounds N-2 to N-57 were synthesized.
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Abstract
Description
- The present invention relates to novel compounds possessing an antiviral activity, more particularly, polycyclic carbamoylpyridone derivatives having a HIV integrase inhibitory activity and a pharmaceutical composition, particularly an anti-HIV agent containing the same.
- Among viruses, human immunodeficiency virus (hereafter, referred to as HIV), a kind of retrovirus, is known to cause acquired immunodeficiency syndrome (hereafter, referred to as AIDS). The therapeutic agent for AIDS is mainly selected from a group of reverse transcriptase inhibitors (e.g., AZT, 3TC) and protease inhibitors (e.g., Indinavir), but they are proved to be accompanied by side effects such as nephropathy and the emergence of resistant viruses. Thus, the development of anti-HIV agents having the other mechanism of action has been desired.
- On the other hand, currently, a combination therapy is reported to be efficient in treatment for AIDS because of the frequent emergence of the resistant mutant. Two kinds of reverse transcriptase inhibitors and protease inhibitors are clinically used as an anti-HIV agent; however agents having the same mechanism of action often exhibit cross-resistance or only an additional activity. Therefore, development of anti-HIV agents having the other mechanism of action is desired.
- Under the circumstances above, an integrase inhibitor has been focused on as an anti-HIV agent having a novel mechanism of action (Ref: Patent Documents 1 and 2). As an anti-HIV agent having such a mechanism of action, known are carbamoyl-substituted hydroxypyrimidinone derivative (Ref: Patent Documents 3 and 4) and carbamoyl-substituted hydroxypyrrolidione derivative (Ref: Patent Document 5). Further, a patent application concerning carbamoyl-substituted hydroxypyridone derivative has been filed (Ref: Patent Document 6, Example 8).
- Other known carbamoylpyridone derivatives include 5-alkoxypyridine-3-carboxamide derivatives and γ-pyrone-3-carboxamide derivatives, which are a plant growth inhibitor or herbicide (Ref: Patent Documents 7-9).
- Other HIV integrase inhibitors include N-containing condensed cyclic compounds (Ref: Patent Document 10).
- In addition, the present applicant filed a dicyclic carbamoylpyridone derivative as a HIV integrase inhibiting agent (Ref: Patent Document 11).
- [Patent Document 1] WO03/016275
- [Patent Document 2] WO2004/024693
- [Patent Document 3] WO03/035076
- [Patent Document 4] WO03/035076
- [Patent Document 5] WO2004/004657
- [Patent Document 6] JP Patent Application 2003-32772
- [Patent Document 7] JP Patent Publication 1990-108668
- [Patent Document 8] JP Patent Publication 1990-108683
- [Patent Document 9] JP Patent Publication 1990-96506
- [Patent Document 10] WO2005/016927
- [Patent Document 11] WO2006/088173
- Under such the circumstances, the development of a novel integrase inhibitor has been desired.
- The present inventors intensively studied to find that a novel polycyclic carbamoylpyridone derivative possesses a potent HIV integrase inhibitory activity. Moreover, the present inventors have discovered that a compound of the present compound and a pharmaceutical composition containing the same are useful as an antiviral agent (e.g. antiretroviral agent, anti-HIV agent, anti-HTLV-1 (Human T cell leukemia virus type 1) agent, anti-FIV (Feline immunodeficiency virus) agent, anti-SIV (Simian immunodeficiency virus) agent), especially an anti-HIV agent, an anti-AIDS agent, or a therapeutic for associated diseases, to accomplish the present invention shown below.
- (1) A compound of the formula:
- (wherein,
- R1 is hydrogen or lower alkyl;
- X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
- R2 is optionally substituted aryl;
- R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino,
- R4 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO2, NRa (Ra is hydrogen or lower alkyl), —N═ and ═N—));
- the broken line represents the presence or absence of a bond;
- one of B1 and B2 is CR20R21 and another is NR22, where the broken line represents the absence of a bond;
- When B2 is NR22, R4 and R22 taken together may form optionally substituted heterocycle;
- When B2 is CHR21, R4 and R21 taken together may form optionally substituted heterocycle; or
- B1 and B2 are each independently C, CR23 or N, where B1 and B2 taken together may form optionally substituted heterocycle;
- R20, R21, R22 and R23 are each independently, hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO2, NR5 (R5 is independently selected from the same substitution group as R4), —N═ and ═N—), hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, substituted thiourea or substituted sulfonyl),
- a pharmaceutically acceptable salt, or a solvate thereof.
(2) A compound of the formula: - (wherein,
G ring is optionally substituted heterocycle - R1 is hydrogen or lower alkyl;
- X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
- R2 is optionally substituted aryl;
- R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino,
- R14 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO2, NR5 (R5 is independently selected from the same substitution group as R4), —N═ and ═N—), hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, substituted thiourea or substituted sulfonyl),
- according to (1), or a pharmaceutically acceptable salt, or a solvate thereof.
(3) A compound of the formula: - (wherein,
- R1 is hydrogen or lower alkyl;
- X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
- R2 is optionally substituted aryl;
- R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino;
- R4 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO2, NRa (Ra is selected hydrogen or lower alkyl), —N═ and ═N—));
- one of B1 and B2 is CR20R21 and another is NR22;
- R20, R21 and R22 are each independently, hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, substituted thiourea or substituted sulfonyl), according to (1), or a pharmaceutically acceptable salt, or a solvate thereof.
- (4) A compound according to (3), pharmaceutically acceptable salt, or solvate thereof, wherein B1 is CR20R21 and B2 is NR22 (R20, R21 and R22 are the same as defined in (3)).
(5) A compound according to (3), pharmaceutically acceptable salt, or solvate thereof, wherein B1 is NR22 and B2 is CR20R21 (R20, R21 and R22 are the same as defined in (3)).
(6) A compound according to (3), pharmaceutically acceptable salt, or solvate thereof, wherein B1 is NR22 (R22 is the same as defined in (3)) and B2 is CH2.
(7) A compound according to (3), pharmaceutically acceptable salt, or solvate thereof, wherein B1 is NR22 (R22 is hydrogen, optionally substituted lower alkyl, lower alkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted lower alkylcarbonyl, optionally substituted aryl carbonyl, substituted thiourea or substituted sulfonyl), and B2 is CH2.
(8) A compound according to (3), pharmaceutically acceptable salt, or solvate thereof, wherein R4 is optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl.
(9) A compound according to (3), pharmaceutically acceptable salt, or solvate thereof, wherein B1 is NR22 (R22 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted lower alkylcarbonyl, optionally substituted aryl carbonyl, substituted thiourea or substituted sulfonyl), B2 is CH2 and R4 is optionally substituted lower alkyl, optionally substituted cyclo alkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl.
(10) A compound according to (3), pharmaceutically acceptable salt, or solvate thereof, wherein B1 is NR22 (R22 is hydrogen, optionally substituted lower alkyl (substituent: amino, lower alkylamino, lower alkoxy, aryloxy, cyano, halogen, optionally substituted carbamoyl, acylamino lower alkynyl, hydroxy), cycloalkyl, cycloalkyl lower alkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted 5- to 6-membered aromatic heterocyclic group, optionally substituted 5- to 6-membered heterocycle lower alkyl, optionally substituted lower alkylcarbonyl (substituent: lower alkoxy), optionally substituted benzoyl (substituent: lower alkoxy), substituted sulfonyl (substituent; lower alkyl, aryl, heterocyclic group)), B2 is CH2 and R4 is optionally substituted lower alkyl (substituent amino, lower alkylamino, lower alkoxy, aryloxy), cycloalkyl, cycloalkyl lower alkyl, phenyl, benzyl,
5- to 6-membered aromatic heterocyclic group, 5- to 6-membered heterocycle lower alkyl).
(11) A compound of the formula: - (wherein,
- R1 is hydrogen or lower alkyl;
- X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
- R2 is optionally substituted aryl;
- R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino,
- C ring is optionally substituted heterocycle or optionally substituted carbocycle;
- B1 and B2 are independently C, CR23 or N;
- R23 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, substituted thiourea or substituted sulfonyl),
- the broken line represents the presence or absence of a bond;
- R4 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from CO, O, S, SO, SO2, NRa (Ra is selected hydrogen or lower alkyl), —N═ and ═N—));
- according to (1), or a pharmaceutically acceptable salt, or solvate thereof.
(12) A compound of the formula: - (wherein,
- R1 is hydrogen or lower alkyl;
- X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
- R2 is optionally substituted aryl;
- R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino,
- H ring is optionally substituted heterocycle;
- R24 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, substituted thiourea or substituted sulfonyl),
- according to (1), or a pharmaceutically acceptable salt, or solvate thereof.
(13) A compound according to any one of (1) to (12), pharmaceutically acceptable salt, or solvate thereof, wherein R1 is hydrogen or lower alkyl.
(14) A compound according to any one of (1) to (12), pharmaceutically acceptable salt, or solvate thereof, wherein X is lower alkylene R2 is phenyl or phenyl substituted with at least halogen.
(15) A compound according to any one of (1) to (12), pharmaceutically acceptable salt, or solvate thereof, wherein R3 is hydrogen.
(16) A compound according to any one of (1) to (12), pharmaceutically acceptable salt, or solvate thereof, wherein R1 is hydrogen or lower alkyl; X is lower alkylene; R2 is phenyl or phenyl substituted with 1 to 2 halogen; R3 is hydrogen.
(17) A pharmaceutical composition comprising a compound according to any one of (1) to (16), or a pharmaceutically acceptable salt, or solvate thereof.
(18) A pharmaceutical composition according to (17), which is an anti-HIV agent. - The present invention further provides a method for treating a virus infectious disease comprising administering the aforementioned compound. Further, the present invention provides a process for producing an agent for treating a virus infectious disease comprising the aforementioned compound.
- The present invention compounds possess an integrase inhibitory activity and/or a cell-growth inhibitory activity against virus, especially HIV. Accordingly, they are useful for the prevention or treatment of various diseases mediated by integrase or virus infection diseases (e.g., AIDS). A preferable compound is also effective to a resistant strain. In addition, a preferable compound has good pharmacokinetic in a body.
- The terms used herein are explained below. Each term, alone or in combination with another term, means as follows.
- “Lower alkylene” means a straight or branched C1 to C6 lower alkylene such as methylene, ethylene, trimethylene, propylene, tetramethylene, ethylethylene, pentamethylene, or hexamethylene, preferably C1 to C4 lower straight alkylene such as methylene, ethylene, trimethylene, and tetramethylene, more preferably methylene or ethylene.
- “Lower alkenylene” means a straight or branched C2 to C6 lower alkenylene, which consists of the above “Lower alkylene” having one or more double bonds, such as vinylene, propylene, or butenylene, preferably a straight C2 to C3 lower alkenylene such as vinylene or propylene.
- “Alkyl” means a straight or branched C1 to C10 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. Preferred is C1 to C6 lower alkyl, more preferred is C1 to C4 lower alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, and isohexyl.
- When lower alkyl is intervened with “—N═” or “═N—”, the lower alkyl may have a double bond to form —CH2—N═CH2, —CH═N—CH3, etc.
- “Alkenyl” means a straight or branched C2 to C8 alkenyl, which consists of the above “alkyl” having one or more double bonds, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, and 3-methyl-2-butenyl, preferably C2 to C6 lower alkenyl, and more preferably C2 to C4 lower alkenyl.
- “Lower alkenyloxy” means oxy attached to the above “lower alkenyl”, such as vinyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 1,3-butadienyloxy, and 3-methyl-2-butenyloxy.
- “Cycloalkyl” means C3 to C20, preferably C3 to C15, more preferably C3 to C10 cyclic saturated hydrocarbon, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, adamantyl, and polyhedron (e.g. cubane, dodecahedrane), further preferably C3 to C6 cycloalkyl.
- “Cycloalkyl lower alkyl” means lower alkyl substituted with the above cycloalkyl, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and cyclohexylethyl, and preferably C3 to C6 cycloalkyl lower alkyl.
- “Aryl” means monocyclic aromatic hydrocarbon (phenyl) and polycyclic aromatic hydrocarbon (e.g., 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl etc.), preferably phenyl or naphthyl (e.g., 1-napthyl, 2-naphthyl).
- “Aralkyl” or “aryl lower alkyl” means the above “lower alkyl” substituted with 1 to 3 of the above “aryl”, such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl, 1-napthylmethyl, 2-napthylmethyl, preferably benzyl.
- “Aryloxy” means oxy attached to the above “aryl”, such as 1-naphthyloxy, 2-naphthyloxy, 1-anthryloxy, 2-anthryloxy, 9-anthryloxy, 1-phenanthryloxy, 2-phenanthryloxy, 3-phenanthryloxy, 4-phenanthryloxy, and 9-phenanthryloxy, preferably phenyloxy or naphthyloxy (e.g., 1-napthyloxy, 2-naphthyloxy).
- “Heterocyclic group” means “heteroring” or “heteroaryl”.
- “Heteroring” means a non-aromatic heterocyclic group which has at least one of N, O, P and/or S in the ring and may be bonded at any substitutable position, preferably 5- to 7-membered ring, such as 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperadinyl, 2-piperadinyl, 2-morpholinyl, 3-morpholinyl, morpholino, and tetrahydropyranyl. The “non-aromatic heterocyclic group” may be saturated or unsaturated as far as it is non-aromatic.
- “Heteroaryl” means monocyclic aromatic heterocyclic group or condensed aromatic heterocyclic group.
- Monocyclic aromatic heterocyclic group means a group induced from a 5- to 8-membered aromatic ring optionally containing 1 to 4 of O, S, P and/or N in the ring wherein the group may be bonded at any substitutable position.
- Condensed aromatic heterocyclic group means a group wherein a 5- to 8-membered aromatic ring optionally containing 1 to 4 of O, S, P and/or N in the ring is condensed with 1 to 4 of 5- to 8-membered aromatic carbocycle(s) or the other 5- to 8-membered aromatic heteroring(s), and may be bonded at any substitutable position.
- Examples of “heteroaryl” include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanyl (e.g., 3-furazanyl), pyrazinyl (e.g., 2-pyrazinyl), oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), benzofuryl (e.g., 2-benzo[b]furyl, 3-benzo[b]furyl, 4-benzo[b]furyl, 5-benzo[b]furyl, 6-benzo[b]furyl, 7-benzo[b]furyl), benzothienyl (e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl), benzoimidazolyl (e.g., 1-benzoimidazolyl, 2-benzoimidazolyl, 4-benzoimidazolyl, 5-benzoimidazolyl), dibenzofuryl, benzooxazolyl, quinoxalinyl (e.g., 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl (e.g., 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolinyl (e.g., 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (e.g., 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), purinyl, pteridinyl (e.g., 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (e.g., 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, phenandinyl (e.g., 1-phenandinyl, 2-phenandinyl) or phenothiadinyl (e.g., 1-phenothiadinyl, 2-phenothiadinyl, 3-phenothiadinyl, 4-phenothiadinyl).
- “Heterocycle lower alkyl” means lower alkyl substituted with the above “heterocyclic group”.
- “Heterocycleoxy” means an oxy attached to the above “heterocyclic group”.
- “Heterocycle” means a heterocycle which can form the heterocyclic group.
- “Lower alkoxy” means oxy attached to the above “lower alkyl”, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.
- “Lower alkylcarbonyl”, “cycloalkylcarbonyl”, “cycloalkyl lower alkylcarbonyl”, “lower alkoxycarbonyl”, “arylcarbonyl”, “aryl lower alkylcarbonyl”, “aryloxycarbonyl”, “heterocyclecarbonyl”, “heterocycle lower alkylcarbonyl”, and “heterocycleoxy carbonyl”, each means a carbonyl attached to the above “lower alkyl”, “cycloalkyl”, “cycloalkyl lower alkyl”, “lower alkoxy”, “aryl”, “aryl lower alkyl”, “aryloxy”, “heterocyclic group”, and “heterocycle lower alkyl”, respectively.
- When a substituent(s) is/are present on “optionally substituted lower alkyl”, “optionally substituted cycloalkyl”, “optionally substituted cycloalkyl lower alkyl”, “optionally substituted lower alkenyl”, “optionally substituted lower alkoxy”, “optionally substituted aryl”, “optionally substituted aryl lower alkyl”, “optionally substituted aryloxy”, “optionally substituted aryloxy lower alkyl”, “optionally substituted heterocyle”, “optionally substituted heterocyclic group”, “optionally substituted heterocycle lower alkyl”, “optionally substituted heterocycleoxy”, “optionally substituted lower alkenyloxy”, “optionally substituted lower alkylcarbonyl”, “optionally substituted cycloalkylcarbonyl”, “optionally substituted cycloalkyl lower alkylcarbonyl”, “optionally substituted lower alkoxycarbonyl”, “optionally substituted arylcarbonyl”, “optionally substituted aryl lower alkylcarbonyl”, “optionally substituted aryloxycarbonyl”, “optionally substituted heterocyclecarbonyl”, “optionally substituted heterocycle lower alkylcarbonyl”, “optionally substituted heterocycleoxy carbonyl”, “optionally substituted lower alkylene”, “optionally substituted lower alkenylene”, “optionally substituted phosphoric acid residue”, “optionally substituted carbocycle” or “optionally substituted heterocycle”, each may be substituted with the same or different, 1 to 4 group(s) selected from Substituent group B at any position.
- Examples of Substituent group B include hydroxy, carboxy, halogen (F, Cl, Br, I), halo lower alkyl (e.g., CF3, CH2CF3, CH2CCl3), halo lower alkoxy (e.g., OCF3, OCH2CF3, OCH2CCl3), lower alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), lower alkenyl (e.g., vinyl), lower alkynyl (e.g., ethynyl), cycloalkyl (e.g., cyclopropyl), cycloalkenyl (e.g., cyclopropenyl), lower alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), lower alkenyloxy (e.g., vinyloxy, allyloxy), lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), nitro, nitroso, optionally substituted amino (e.g., alkylamino (e.g., methylamino, ethylamino, dimethylamino), acylamino (e.g., acetylamino, benzoylamino), aralkylamino (e.g., benzylamino, trithylamino), hydroxyamino)), azido, aryl (e.g., phenyl), aralkyl (e.g., benzyl), cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio (e.g., methylthio), alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl), optionally substituted alkylsulfonylamino (e.g., methanesulfonylamino, ethanesulfonylamino, N-methylsulfonyl-N′-methylamino), optionally substituted carbamoyl (e.g., alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl)), sulfamoyl, acyl (e.g., formyl, acetyl), formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, azido, ureido, amidino, guanidino, phthalimido, oxo, phosphoric acid residue, lower alkyl which is substituted with a phosphoric acid residue and may be intervened with a heteroatom group(s), aryl substituted with a phosphoric acid residue, aralkyl substituted with a phosphoric acid residue, and hydroxy lower alkyl, more preferably hydroxy, carboxy, halogen (F, Cl, Br, I), halo lower alkyl (e.g., CF3, CH2CF3, CH2CCl3), halo lower alkoxy (e.g., OCF3, OCH2CF3, OCH2CCl3), lower alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), lower alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), optionally substituted amino (e.g., alkylamino (e.g., methylamino, ethylamino, dimethylamino)), oxo, or phosphoric acid residue.
- Examples of a substituent of “optionally substituted amino” or “optionally substituted carbamoyl” include mono- or di-lower alkyl, lower alkylcarbonyl, or lower alkylsulfonyl, optionally substituted lower alkyl (e.g., methyl, ethyl, isopropyl, benzyl, carbamoylalkyl (e.g., carbamoylmethyl), mono- or di-lower alkylcarbamoyl lower alkyl (e.g., dimethylcarbamoylethyl), hydroxy lower alkyl, heteroring lower alkyl (e.g., morpholinoethyl, tetrahydropyranylethyl), alkoxycarbonyl lower alkyl (e.g., ethoxycarbonylmethyl, ethoxycarbonylethyl), mono- or di-lower alkylamino lower alkyl (e.g., dimethylaminoethyl)), lower alkoxy lower alkyl (e.g., methoxyethyl, ethoxymethyl, ethoxyethyl, isopropoxyethyl), acyl (e.g., formyl, optionally substituted lower alkylcarbonyl (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, methoxyethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, ethoxycarbonylmethylcarbonyl), lower alkoxy lower alkylcarbonyl (e.g., methoxyethylcarbonyl), lower alkylcarbamoyl lower alkylcarbonyl (e.g., methylcarbamoylethylcarbonyl), alkoxycarbonylacetyl), optionally substituted arylcarbonyl (e.g., benzoyl, toluoyl), optionally substituted aralkyl (e.g., benzyl, 4-fluorobenzyl), hydroxy, optionally substituted lower alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, isopropylsulfonyl, 2,2,2-trifluoroethanesulfonyl, benzylsulfonyl, methoxyethylsulfonyl), arylsulfonyl optionally substituted with lower alkyl or halogen (e.g., benzenesulfonyl, toluenesulfonyl, 4-fluorobenzenesulfonyl), cycloalkyl (e.g., cyclopropyl), aryl optionally substituted with lower alkyl (e.g., phenyl, trityl), lower alkylaminosulfonyl (e.g., methylaminosulfonyl, dimethylaminosulfonyl), lower alkylaminocarbonyl (e.g., dimethylaminocarbonyl), lower alkoxycarbonyl (e.g., ethoxycarbonyl), cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclohexylcarbonyl), optionally substituted sulfamoyl (e.g., sulfamoyl, methylsulfamoyl, dimethylsulfamoyl), lower alkylcarbonylamino (e.g., methylcarbonylamino), heteroring (e.g., morpholino, tetrahydropyranyl), optionally substituted amino (e.g., mono- or di-alkylamino (e.g., dimethylamino), formylamino), and the like.
- As to amino of “optionally substituted amino”, “optionally substituted carbamoyl”, or “optionally substituted carbamoylcarbonyl”, two substituents on the amino together with the neighboring N atom may form an N-containing heteroring which optionally contains S and/or O in the ring (preferably 5- to 7-membered ring or saturated ring) and the ring is optionally substituted with oxo or hydroxy. The S atom forming the ring may be substituted with oxo. A 5- or 6-membered ring such as piperazinyl, piperidino, morpholino, pyrrolidino, thiadinan-2-yl, 2-oxopiperidino, 2-oxopyrrolidino, 1,1-dioxido-1,2-thiadinan-2-yl, and 4-hydroxymorpholino is preferable.
- Phosphoric acid residue means a group shown of the formula: —PO(OH)2. Optionally substituted phosphoric acid residue means a phosphoric acid residue wherein the OH part and/or hydrogen of the OH is optionally substituted with a phosphoric acid residue, preferably shown by the formula:
- (wherein, RA and RB each are independently ORC or NRDRE (wherein RC, RD and RE each are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic group, or RD and RE taken together with the neighboring N atom may form an optionally substituted heterocycle (preferably 5- to 6-membered ring)) or RA and RB taken together with the neighboring P atom may form an optionally substituted heterocycle (preferably 5- to 6-membered ring)).
- More preferably, RA and RB are both ORC, or one of them is ORC and the other is NRDRE.
- RC, RD and RE each are preferably, independently, lower alkyl (e.g., methyl, ethyl).
- The optionally substituted heterocycle formed by RA and RB taken together with the neighboring P atom may be the following structure:
- (wherein, the broken line means a part of the ring)
- Hydroxy substituted with optionally substituted phosphoric acid residue is preferably hydroxy substituted with a phosphoric acid residue substituted with di lower alkyls, and more preferably a group of the following formula:
- Amino substituted with optionally substituted phosphoric acid residue is preferably amino substituted with a phosphoric acid residue substituted with di lower alkyls, and more preferably a group of the following formula:
- A ring is optionally substituted heterocycle. The heterocycle is preferably a 5- to 7-membered ring containing 1 to 3, preferably 2 to 3 of O, S and/or N atoms, and is more preferably selected from the above heteroring. Optionally, 1 or 2 heteroatoms can be present on an arc of A ring, and a position thereof is not limited. One of preferable embodiments of A ring is the following ring which is optionally substituted.
- One of preferable embodiments of Z is Z═O or NR19.
- When Z═NR19, R19 is preferably 1) hydrogen, 2) optionally substituted lower alkyl (example of substituent: amino optionally substituted with mono- or di-lower alkyl, cycloalkyl, hydroxy, optionally substituted heterocyclic group (heterocycle is preferably 5- to 7-membered, e.g. furyl, thienyl, thiazolyl, pyridyl, morpholino, imidazole; example of substituent lower alkyl, halogen), optionally substituted heterocyclecarbonyl (heterocycle is preferably 5- to 7-membered, e.g. morpholinocarbonyl), optionally substituted phenyl (substituent: lower alkyl, amino, lower alkylamino, hydroxy, halogen, halogenated lower alkyl, lower alkoxy, halogenated lower alkoxy, lower alkylthio, lower alkylsulfonyl), acetylamino, carbamoyl, mono- or di-lower alkyl substituted carbamoyl, lower alkylsulfonylamino, lower alkoxy, carbonyl, halogen, thiol, lower alkylthio), 3) lower alkenyl, 4) acyl (e.g. lower alkylcarbonyl), 5) lower alkylsulfonyl.
- As other substituent on the A ring, same or different one or more substituents selected from Substituent group S2 are exemplified, preferably lower alkyl and the like. Alternatively, a substituent part on A ring may be connected with a neighboring atom to further form a fused ring or a spiro ring, preferably an optionally substituted carbocylcle (preferably 5- to 6-membered ring) or an optionally substituted heterocycle (preferably 5- to 6-membered ring).
- Substituent Group S2: hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkylcarbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocyclic lower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from group consisting CO, O, S, SO, SO2, NR5 (R5 is selected independently from the same substituent group of R4), —N═ and ═N—), oxo.
- R1 is hydrogen or lower alkyl, preferable hydrogen.
- X is a single bond, a heteroatom group (hereinafter, referred to as M in some cases) selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene, each may be intervened by the heteroatom. Herein, “intervene” means the case where the heteroatom 1) is present between carbon atoms constituting alkylene or alkenylene, 2) is bound to a N atom of carbamoyl group adjacent to X, and/or 3) is bound to R2 adjacent to X. The heteroatom group (M) may be same or different one or more groups. For example, the case where lower alkylene is intervened by the heteroatom includes -M-CH2—, —CH2-M-CH2—, —CH2-M-, and —CH2-M-M-CH2—. X is preferably a spacer in which 1 to 3 atoms are connected. X is more preferably lower alkylene, or lower alkenylene which may be intervened by a heteroatom, or O, further preferably C1 to C3 lower alkylene or C2 to C3 lower alkenylene, or O, particularly preferably methylene or O.
- R2 is optionally substituted aryl, preferably phenyl. Examples of a substituent on aryl preferably include same or different 1 to 3, preferably 1 to 2 substituents selected from the group consisting of halogen, hydroxy, amino, lower alkylamino, cyano, carboxy, formyl, oxo, lower alkyl, lower alkoxy, lower alkylthio, carbamoyl, and lower alkylcarbamoyl, and Substituent group S1 (: optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from group consisting O, S, SO, SO2, NR5 (R5 is selected independently from the same substituent group of R4), —N═ and ═N—), lower alkoxy lower alkyl, amino lower alkyl optionally substituted with mono- or di-lower alkyl, halogenated lower alkyl, lower alkoxy, carbamoyl optionally substituted with mono- or di-lower alkyl, optionally substituted lower alkylsulfonylamino, halogenated lower alkoxy, hydroxy lower alkyl). The substituent is a group more preferably selected from halogen, hydroxy, amino, cyano, lower alkyl, and lower alkoxy, and Substituent group S1, particularly preferably selected from halogen (e.g. F) and/or Substituent group S1. When one substituent is present on aryl, its position is preferably a 4-position. R2 is more preferably phenyl, or phenyl substituted with at least halogen, particularly preferably 4-halogenophenyl (e.g. 4-F-phenyl) or 2,4-dihalogenophenyl (e.g. 2,4-F-phenyl).
- R2 is more preferably phenyl optionally substituted with 1 to 3 Rs described later.
- In all compounds of the present invention, a —X—R2 part is preferably represented by the following formula.
- R's are each independently a group selected from the group consisting of halogen and Substituent group S1.
- Substituent group S1: optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from group consisting CO, O, S, SO, SO2, NRa (Ra is hydrogen or lower alkyl), —N═ and ═N—), lower alkoxy lower alkyl, optionally substituted amino lower alkyl (substituent: mono- or di-lower alkyl, lower alkylcarbonyl, or lower alkylsulfonyl), halogenated lower alkyl, lower alkoxy, optionally substituted carbamoyl (substituent: mono- or di-lower alkyl, lower alkylcarbonyl, or lower alkylsulfonyl), optionally substituted lower alkylsulfonylamino, halogenated lower alkoxy, and hydroxy lower alkyl.
- And, m is an integer of 0 to 3, preferably 0, or 1 to 2. When m is 1, R is preferably halogen and, when m is 2, R is preferably two halogens, or halogen and other group.
- R is preferably present at a 4-position and, optionally, other position (e.g. 2-position) on a benzene ring.
- When m=2, R is more preferably same or different groups selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkoxy lower alkyl, halogenated lower alkyl; halogenated lower alkoxy, lower alkylsulfonylamino, carbamoyl, and lower alkylcarbamoyl, particularly preferably two Fs.
- R3 may be a variety of substituents as far as they do not adversely affect on the pharmacological activity of Compound (I), and examples include hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino. Examples of a substituent of “optionally substituted” include halogen, hydroxy, amino, lower alkylamino, cyano, carboxy, formyl, oxo, lower alkyl, lower alkoxy, lower alkylthio, carbamoyl, lower alkylcarbamoyl, aryl, heterocyclic group, lower alkylcarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyl, halogenated lower alkyl, and halogenated lower alkoxy, more preferably halogen, hydroxy, amino, lower alkylamino, lower alkyl, and lower alkoxy. R3 is more preferably hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino, further preferably hydrogen or lower alkyl (e.g. methyl), particularly preferably hydrogen.
- The present invention provides the following compounds (in each of the following formulas, each symbol is as defined above unless otherwise is indicated).
- R1 is hydrogen or lower alkyl, preferably hydrogen.
- X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene which may be intervened by the heteroatom group; preferably a single bond, O, S, or lower alkylene (more preferably C1 to C3) which may be intervened by O or S.
- R2 is optionally substituted aryl;
- R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy group, or optionally substituted amino, more preferably hydrogen or optionally substituted lower alkyl.
- R4 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocyclic lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from the group consisting of O, S, SO, SO2, NRa (Ra is hydrogen or lower alkyl), —N═ and ═N—), more preferably hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted heterocyclic group, or optionally substituted heterocyclic lower alkyl.
- A broken line indicates the presence or absence of a bond.
- B1 and B2 are such that any one of them is CR20R21, and the other is NR22 and, in this case, a broken line is not present.
- When B2 is NR22, R4 and R22 may be connected together to form an optionally substituted heterocycle (e.g. G ring);
- When B2 is CHR21, R4 and R21 may be connected together to form an optionally substituted heterocycle (e.g. H ring).
- Alternatively, B1 and B2 are independently C, CR23, or N. B1 and B2 parts may be connected together to form an optionally substituted heterocycle (e.g. C ring) and, in this case, when B1 and B2 are independently CR23 or N, a broken line indicates the absence of a bond.
- R20, R21, R22 and R23 are independently selected from hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocyclic lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from the group consisting of O, S, SO, SO2, NR5 (R5 is selected independently from the same substituent group of R4), —N═ and ═N—), hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkylcarbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycabronyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocyclic lower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, substituted thiourea, and substituted sulfonyl.
- R2, R21, R22 and R22 are more preferably selected from hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic lower alkyl, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkylcarbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocyclic lower alkylcarobnyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, substituted thiourea, and substituted sulfonyl.
- The Compound (I) includes Compounds (I-10), (I-6), (I-9) and (I-12) shown below.
- G ring is a 5- to 7-membered ring containing 2 to 3 of O, S and/or N atoms, and contains at least 2 N atoms. More preferably, the ring is selected from the aforementioned heterorings, and the following rings are exemplified.
- (Z is CH2, O, S, SO, SO2, or NR19 described later)
- As a substituent on the G ring, same or different one or more substituents selected from the Substituent group S2 are exemplified. Alternatively, a substituent part on the G ring may be connected with a neighboring atom to further form a fused ring or a spiro ring, preferably an optionally substituted carbocycle (preferably 5- to 6-membered ring) or an optionally substituted heterocycle (preferably 5- to 6-membered ring).
- One of preferable aspects of a substituent on the G ring is lower alkyl (e.g. methyl, isopropyl), lower alkoxy lower alkyl (e.g. 2-methoxyethyl), or optionally substituted amino (example of substituent lower alkyl (e.g. methyl), lower alkylcarbonyl (e.g. acetyl)).
- R3 is preferably hydrogen or optionally substituted lower alkyl, more preferably hydrogen.
- As R14, the same groups as those in the case of R20, R21, R22 and R23 are exemplified. R14 is preferably hydrogen, optionally substituted lower alkyl (substituent: amino, lower alkylamino, lower alkoxy, aryloxy, cyano, halogen, (substituted) carbamoyl, acylamino, lower alkynyl, hydroxy), cycloalkyl, cycloalkyl lower alkyl, phenyl, benzyl, 5- to 6-membered aromatic heterocyclic group, 5- to 6-membered heterocyclic lower alkyl, optionally substituted lower alkylcarbonyl (substituent: lower alkoxy), optionally substituted benzoyl (substituent: lower alkoxy), substituted sulfonyl (substituent: lower alkyl, aryl, heterocyclic group), more preferably hydrogen or optionally substituted lower alkyl.
- Preferably, B1 is CR20R21, and B2 is NR22 (R20, R21 and R22 are as defined above).
- In addition, preferably, B1 is NR22, and B2 is CR20R20 (R20, R21 and R22 are as defined above).
- R3 is preferably hydrogen or optionally substituted lower alkyl, more preferably hydrogen.
- R20, R21 and R22 are preferably independently hydrogen, optionally substituted lower alkyl (example of substituent: amino, lower alkylamino, lower carbonylamino, lower alkoxy, aryloxy, cyano, halogen, acylamino (e.g. lower carbonylamino), lower alkynyl, hydroxy, lower alkoxycarbonyl, optionally substituted heterocyclecarbonyl (example of substituent: lower alkyl, lower alkoxy), lower alkenyl, optionally substituted carbamoyl (example of substituent lower alkyl), lower alkylcarbonyloxy, lower alkyloxycarbonyl, lower alkylcarobnyl amino, oxo, lower alkynyl), cycloalkyl, cycloalkyl lower alkyl, optionally substituted aryl (example of substituent: lower alkyl, halogen, lower alkyloxy, nitro), optionally substituted aryl lower alkyl (example of substituent: lower alkyl, halogen, lower alkyloxy, nitro, oxo), optionally substituted heterocyclic group (example of substituent lower alkyl, halogen, lower alkyloxy, nitro), optionally substituted heterocyclic lower alkyl (example substituent: lower alkyl, halogen, lower alkyloxy, nitro, oxo), optionally substituted lower alkylcarbonyl (substituent: lower alkoxy, halogen), cycloalkylcarbonyl, optionally substituted benzoyl (substituent: lower alkoxy, halogen), substituted sulfonyl (substituent: lower alkyl, aryl, heterocyclic group (preferably 5- to 6-membered aromatic heterocyclic group)).
- More preferably, R20 and R21 are both hydrogen.
- In Compound (I-6), more preferably, R1 is hydrogen or lower alkyl, more preferably hydrogen; X is lower alkylene; R2 is phenyl, or phenyl substituted with at least halogen, more preferably phenyl substituted with 1 to 2 halogens (e.g. F); R3 is hydrogen; B1 is CH2 or NR22; B2 is NR22 or CH2, more preferably B1 is NR22; B2 is CH2.
- R4 is preferably optionally substituted lower alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl; example of substituent: hydroxy, amino, lower alkylamio, lower alkoxy, aryloxy, oxo, lower alkoxycarbonyl, optionally substituted heterocyclecarbonyl (example of substituent: lower alkyl, lower alkoxy)), specifically lower alkylamino lower alkyl (e.g. 2-dimethylaminoethyl, 2-diethylaminoethyl), lower alkoxy lower alkyl (e.g. 1-methoxyethyl, 2-methoxypropyl, 2-methoxyethyl, 3-methoxyprpopyl, 4-methoxybutyl, 2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 2-propoxyethyl, 3-propoxypropyl, 4-propoxybutyl) or aryloxy lower alkyl (e.g. 2-phenoxyethyl, 3-phenoxypropyl); optionally substituted cycloalkyl (e.g. cyclopropyl); optionally substituted cycloalkyl lower alkyl (e.g. cyclopropylmethyl, 1-adamantylmethyl, 2-adamantylmethyl, dodecahedranemethyl, cudanemethyl); optionally substituted aryl (e.g. phenyl; example of substituent; lower alkyl, halogen, lower alkyloxy, nitro, or a substituent part may be lower alkylene which may be intervened by a heteroatom (e.g. O)); optionally substituted aryl lower alkyl (e.g. benzyl; example of substituent: lower alkyl, halogen, lower alkyloxy, nitro, or a substituent part may be lower alkylene which may be intervened by a heteroatom (e.g. O)); optionally substituted heterocyclic group (preferably 5- to 6-membered ring) (e.g. picolyl, pyridyl; example of substituent lower alkyl, halogen, lower alkyloxy, nitro); or optionally substituted heterocyclic group (preferably 5- to 6-membered ring) lower alkyl (e.g. piperonylmethyl, 2-morpholinoethyl, thiophenemethyl, furanmethyl, tetrahydrofuranmethyl, dioxanemethyl, tetrahydropyranmethyl, thiazolemethyl, oxazolemethyl, 1,2,4-oxadiazolemethyl, 1,3,4-oxadiazolemethyl; example of substituent lower alkyl, halogen, lower alkyloxy, nitro; the heterocycle may be fused with a benzene ring).
- R22 is preferably optionally substituted alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, neopentyl; example of substituent: amino, lower alkylamino, lower alkoxy, aryloxy, cyano, halogen, (substituted) carbamoyl, acylamino, oxo), specifically lower alkylamino lower alkyl (e.g. 2-dimethylaminoethyl, 2-diethylaminoethyl), lower alkoxy lower alkyl (e.g. 1-methoxyethyl, 2-methoxypropyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 2-propoxyethyl, 3-propoxypropyl, 4-propoxybutyl), aryloxy lower alkyl (e.g. 2-phenoxyethyl, 3-phenoxypropyl), cyano lower alkyl (e.g. cyanomethyl), halogenated lower alkyl (e.g. fluoromethyl, 2,2,2-trifluoromethyl), or carboranemethyl, acylamino lower alkyl (e.g. 2-acetamideethyl); lower alkenyl (e.g. allyl, propargyl, crotyl); cycloalkyl lower alkyl (e.g. 3-cyclopropyl, cyclopropylmethyl, 1-adamantylmethyl, 2-adamantylmethyl, dodecahedranemethyl, cubanemethyl); optionally substituted aryl (e.g. phenyl; a substituent part may be lower alkylene which may be intervened by a heteroatom (e.g. O)); optionally substituted aryl lower alkyl (e.g. benzyl; a substituent part may be lower alkylene which may be intervened by a heteroatom (e.g. O)); optionally substituted heterocyclic group (e.g. picolyl pyridyl; example of substituent lower alkyl); optionally substituted heterocyclic lower alkyl (e.g. piperonylmethyl, morpholinoethyl, furanmethyl, tetrahydrofuranmethyl, dioxanemethyl, tetrahydropyranmethyl, triazolemethyl, tetrazolemethyl, thiazolemethyl, oxazolemethyl, 1,2,4-oxadiazolemethyl, 1,3,4-oxadiazolemethyl, isoxazolemethyl, imidazolemethyl, methylpyrrolemethyl, 18-crownethermethyl; example of substituent: lower alkyl); optionally substituted lower alkylcarbonyl (e.g. acetyl; example substituent lower alkoxy (e.g. methoxy)); optionally substituted arylcarbonyl (e.g. benzoyl; example of substituent; lower alkoxy); substituted thiourea (e.g. urea, lower alkylurea (e.g. dimethylurea), dimethylthiourea); or substituted sulfonyl (e.g. alkylsulfonyl (e.g. methanesulfonyl), arylsulfonyl (e.g. benzenesulfonyl), heterocyclic sulfonyl (e.g. thiophenesulfonyl)).
- C ring indicates an optionally substituted carbocycle or an optionally substituted heterocycle. When the C ring is a heterocycle, B1 and B2 are independently C, CH or N. Provided that, when B1 and B2 are independently CR23 or N, a broken line indicates the presence of a bond. When the C ring is a heterocycle, the same heterocycles as the A ring and the G ring are exemplified, and a substituent on the C ring is also exemplified similarly. That is, as a substituent on the C ring, same or different one or more substituents selected from Substituent group S2 are exemplified. Alternatively, a substituent part on the C ring may be taken together with a neighboring atom to further form a fused ring or a spiro ring, preferably an optionally substituted carbocycle (preferably 5- to 6-membered ring) or an optionally substituted heterocycle (preferably 5- to 6-membered ring).
- When the C ring is a carbocycle, B1 and B2 are independently C or CH and, as the carbocycle, a 5- to 7-membered ring is exemplified.
- A broken line indicates the presence or absence of a bond, preferably the absence of a bond.
- The C ring includes the following rings, preferably (i) and (l).
- (Z is CH2, O, S, SO, SO2, or NR19 described later)
- One of preferable aspects as a substituent on the C ring is lower alkyl (e.g. methyl, isopropyl), lower alkoxy lower alkyl (e.g. 2-methoxyethyl), and optionally substituted amino (example of substituent: lower alkyl (e.g. methyl), lower alkylcarbonyl (e.g. acetyl)).
- R19 is more preferably hydrogen, lower alkyl, or lower alkoxy lower alkyl.
- R3 is preferably hydrogen, or optionally substituted lower alkyl, more preferably hydrogen.
- In Compound (I-9), as R4, the same groups as those for R4 of Compound (I-6) are preferably exemplified.
- H ring means a heterocycle having the same meaning as that of the A ring, is preferably a 5- to 7-membered ring and, as a substituent on each ring, the same substituents as those in the case of the A ring are exemplified. That is, as a substituent on the H ring, same or different one or more substituents selected from the Substituent group S2 are exemplified. Alternatively, a substituent part on the H ring may be connected with a neighboring atom to further form a fused ring or a spiro ring, preferably an optionally substituted carbocycle (preferably 5- to 6-membered ring) or an optionally substituted heterocycle (preferably 5- to 6-membered ring).
- R3 is preferably hydrogen, or optionally substituted lower alkyl, more preferably hydrogen.
- As R24, the same groups as those in the case of R20, R21, R22 and R23 are exemplified. R24 is preferably hydrogen, optionally substituted lower alkyl (substituent: amino, lower alkylamino, lower alkoxy, aryloxy, cyano, halogen, (substituted) carbamoyl, acylamino, lower alkynyl, hydroxy), cycloalkyl, cycloalkyl lower alkyl, phenyl, benzyl, 5- to 6-membered aromatic heterocyclic group, 5- to 6-membered heterocyclic lower alkyl, optionally substituted lower alkylcarbonyl (substituent: lower alkoxy, halogen), optionally substituted benzoyl (substituent: lower alkoxy, halogen), or substituted sulfonyl (substituent: lower alkyl, aryl, heterocyclic group (preferably 5- to 6-membered aromatic heterocyclic group)), more preferably hydrogen, or optionally substituted lower alkyl.
- Compound (I) has at least the following characteristics as its chemical structure.
- (1) The main structure, condensed heterocycle, is substituted with oxo (═O), hydroxy (OH) and oxo (═O).
(2) A substituted carbamoyl group (—CONR1XR2) is attached to the position neighboring to the oxo group on the heterocycle. - Particularly, by possession of such the structure, Compound (1) exhibits a remarkably potent integrase inhibitory activity and/or cell-growth inhibitory activity against virus including HIV. A preferable compound is also effective to a resistant strain. In contrast, other partial structures have a relatively large freedom degree, may have a variety of substituents, and may form a condensed ring, and the condensed ring may be further substituted.
- The present invention provides a pharmaceutically acceptable salt or a solvate of Compound (I). All theoretically possible tautomer, geometrical isomer, optically active compound, and racemate thereof of the present compound are within the scope of the invention.
- Pharmaceutically acceptable salts of a compound of the present invention include, as basic salts, for example, alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine, meglumine, diethanolamine, or ethylenediamine salts; aralkyl amine salts such as N, N-dibenzylethylenediamine or benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts or lysine salts. Acid salts include, for example, mineral acid salts such as hydrochloride, sulfates salts, nitrate salts, phosphates salts, carbonates salts, hydrogencarbonates or perchlorate; organic acid salts such as acetates, propionates, lactates, maleates, fumarates, tararates, malates, citrates salts, or ascorbates; sulfonates such as methanesulfonates, isethionates, benzenesulfonates, or p-toluenesulfonates; and acidic amino acid salts such as aspartates or glutamates are exemplified.
- Solvates of a compound of the present invention include alcholates and hydrates.
- A general process for producing the present compound will be exemplified below.
-
- (wherein L1 is a leaving group (e.g.; halogen); P1 and P2 are a hydroxy protecting group; P3 is a carboxy protecting group (e.g.: lower alkyl); Ra and Rb are hydrogen or a substituent on an amino group)
- Examples of a hydroxy protecting group (P1, P2) include acyl (e.g.: acetyl, pivaloyl, benzoyl), aralkyl (e.g.: benzyl), lower alkyl (e.g.: methyl), alkoxyalkyl (e.g.: methoxymethyl, methoxyethyl), lower alkylsulfonyl (e.g.: methanesulfonyl), arylsulfonyl (e.g.: benzenesulfonyl, toluenesulfonyl), alkoxycarbonyl (e.g.: methoxycarbonyl) and the like.
- As a carboxy protecting group (P3), lower alkyl (e.g.; methyl, ethyl), and aralkyl (e.g.: benzyl) are exemplified.
- The present step is a reaction for condensing a compound (II) and a compound (III) to synthesize a compound (IV). The reaction may be performed according to the condition for a reaction of amidating carboxylic acid which is generally performed. A compound (II) may be reacted as it is, or may be reacted after converted into corresponding acid chloride or active ester. Preferably, the reaction is performed in a suitable solvent in the presence of a condensing agent.
- As a condensing agent, dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like may be used. If necessary, a reagent such as 1-hydroxybenzotriazole and N-hydroxysuccinimide, or a base such as triethylamine, N-methylmorpholine, and pyridine may be added.
- A reaction temperature is 0 to 150° C., preferably room temperature to 70° C.
- As a reaction solvent, an aprotic solvent can be broadly used, and tetrahydrofuran (THF), 1,4-dioxane, dimethylformamide (DMF), methylene chloride, chloroform and the like are preferable.
- A reaction time is a few minutes to a few tens hours, preferably 9 to 17 hours.
- The present step is a reaction for introducing a protected hydroxy group (OP1) into a compound (IV) to produce a compound (V). The reaction may be performed according to the condition for an alkoxylating reaction which is generally performed.
- For example, a compound (V) in which P1 is methyl can be synthesized by reacting a compound (IV) with metal alkoxide (e.g.: sodium methoxide).
- A reaction temperature is 0 to 200° C., preferably 80 to 120° C.
- As a reaction solvent, alcohol, dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) are exemplified.
- A reaction time is a few minutes to a few tens hours, preferably 5 to 10 hours.
- The present step is a reaction for protecting a hydroxy group of a compound (V) to produce a compound (VI). The reaction may be performed according to the condition for a reaction of protecting a hydroxy group which is generally performed. For example, by using diisopropyl azodicarboxylate or diethyl azodicarboxylate together with an alcohol and various phosphines, a compound (VI) in which P2 is alkyl can be synthesized.
- A reaction temperature is 0 to 100° C., preferably 0° C. to room temperature.
- As a reaction solvent, THF, toluene, dichloromethane and the like are exemplified.
- A reaction time is a few minutes to a few tens hours, preferably 1 to 3 hours.
- The present step is a reaction of oxidizing a nitrogen atom of a compound (VI) to produce a compound (VII). The reaction may be performed according to the condition for an oxidation reaction using an oxidizing agent which is generally performed.
- A reaction temperature is 0 to 100° C., preferably under ice-cooling to room temperature.
- As a reaction solvent, chloroform, methylene chloride, acetic acid and the like are exemplified.
- Examples of an oxidizing agent include metachloroperbenzoic acid, hydrogen peroxide and the like.
- A reaction time is a few minutes to a few tens hours, preferably 1 to 5 hours.
- The present step is a reaction for hydroxylating a methyl group of a compound (VII). Preferably, after acetoxylation by a reaction with acetic anhydride (reaction temperature: 0 to 150° C., preferably 120 to 140° C.), this may be hydrolyzed (e.g.: treatment with a base (e.g.: alkali metal hydroxide)).
- A reaction time is a few minutes to a few tens hours, preferably 0.5 to 2 hours for acetoxylation, and 0.5 to 1 hour for hydrolysis.
- The present step is a reaction for oxidizing a hydroxy group of a compound (VIII) to synthesize a compound (IX).
- A reaction temperature is 0 to 150° C., preferably room temperature to 70° C.
- As a reaction solvent, chloroform and the like are exemplified.
- As an oxidizing agent, dimethyl sulfoxide and the like are exemplified.
- A reaction time is a few minutes to a few tens hours, preferably 0.1 to 1 hour.
- The present step is a reaction for oxidizing a formyl group of a compound (IX) to synthesize a compound (X).
- A reaction temperature is 0 to 150° C., preferably under ice-cooling to room temperature.
- As a reaction solvent, an alcohol and the like are exemplified.
- As an oxidizing agent, potassium hydroxide and iodine are exemplified.
- A reaction time is a few minutes to a few tens hours, preferably 0.5 to 3 hours.
- The present step is a reaction for deprotecting an OP2 part of a compound (X) to synthesize a compound (XI). The reaction may be performed according to the condition for a reaction of deprotecting a hydroxy protecting group which is generally performed.
- A reaction temperature is 0 to 150° C., preferably under ice-cooling to room temperature.
- As a reaction solvent, acetonitrile, methylene chloride, THF and the like are exemplified.
- A reaction time is a few minutes to a few tens hours, preferably 1 to 3 hours.
- The present step is a reaction for deprotecting an OP1 part of a compound (XI) to synthesize a compound (I-A). The reaction may be treated preferably with a Lewis acid (e.g.: aluminum chloride).
- A reaction temperature is 0 to 150° C., preferably 10 to 50° C.
- As a reaction solvent, methylene chloride, THF and the like are exemplified.
- A reaction time is a few minutes to a few tens hours, preferably 1 to 3 hours.
- The present step is a reaction for deprotecting an ester part (COOP3) of a compound (X) to synthesize carboxylic acid (XII). Preferably, hydrolysis with an alkali (e.g.: NaOH) may be performed.
- A reaction temperature is 0 to 150° C., preferably 10 to 50° C.
- As a reaction solvent, methanol, water and the like are exemplified.
- A reaction time is a few minutes to a few tens hours, preferably a few minutes to 2 hours.
- Carboxylic acid (XII) can be converted into various derivatives (e.g.; amide).
- The present step is a reaction for reacting a compound (XII) with various amines to synthesize a compound (XIII). The reaction may be performed according to the condition for a reaction of amidating carboxylic acid which is generally performed and, for example, the reaction may be performed as in the first step.
- A reaction temperature is 0 to 150° C., preferably room temperature to 70° C.
- As a reaction solvent, an aprotic solvent can be broadly used, and tetrahydrofuran (THF), 1,4-dioxane, dimethylformamide (DMF), methylene chloride, chloroform and the like are preferable.
- A reaction time is a few minutes to a few tens hours, preferably a few minutes to 3 hours.
- An amide part of the resulting compound (XIII) may be further chemically modified (e.g.: N-alkylation).
- The present step is a reaction for deprotecting OP1 and OP2 parts of a compound (XIII) to synthesize a compound (I-B). The reaction may be performed according to the condition for a reaction of deprotecting a hydroxy protecting group which is generally performed.
- For example, when pyridine hydrochloride is used, a reaction temperature is 0 to 200° C., preferably 150 to 180 degree.
- A reaction time is a few minutes to a few tens hours, preferably 1 to 5 minutes.
- The present step is a reaction for deprotecting an ester part (COOP3) of a compound (XI) to synthesize carboxylic acid (XIV). Preferably, hydrolysis with an alkali (e.g.: lithium hydroxide) may be performed.
- A reaction temperature is 0 to 150° C., preferably 10 to 50° C.
- As a reaction solvent, methanol, water and the like are exemplified.
- A reaction time is a few minutes to a few tens hours, preferably a few minutes to 3 hours.
- The present step is a reaction for deprotecting an OP1 part of a compound (XIV) to synthesize a compound (I-C). The reaction may be treated preferably with a Lewis acid (e.g.: boron tribromide).
- A reaction temperature is 0 to 150° C., preferably under ice-cooling to room temperature.
- As a reaction solvent, dichloromethane and the like are exemplified.
- A reaction time is a few minutes to a few tens hours, preferably a few minutes to 5 hours.
- The monocyclic carbamoylpyridone derivative obtained above is derived into a bicyclic compound by the following method.
-
- (wherein each symbol is as defined above)
- A compound (XIV) is reacted with a protected hydrazine reagent according to a general amidation reaction to obtain a compound (XIV-1). The protected hydrazine reagent can be synthesized, for example, according to the method described in Pol. J. Chem. 2003.77.315-319. A compound (XIV) may be reacted as it is, or may be reacted after it is converted into corresponding acid chloride or active ester. Preferably, the reaction is performed in a suitable solvent in the presence of a condensing agent.
- As condensing agent, dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like can be used. If necessary, a reagent such as 1-hydroxybenzotriazole and N-hydroxysuccinimide and the like, and a base such as triethylamine, N-methylmorpholine, and pyridine may be added.
- A reaction temperature is about 0 to 150° C., preferably room temperature to 70° C.
- As a reaction solvent, an aprotic solvent can be broadly used, and tetrahydrofuran (THF), 1,4-dioxane, dimethylformamide (DMF), methylene chloride, chloroform and the like are preferable.
- A reaction time is a few minutes to a few tens hours, preferably 10 minutes to 5 hours.
- A P2 part of a compound (XIV-1) is deprotected to obtain a compound (XIV-2).
- A reaction temperature is usually 0 to 150° C., preferably room temperature to 60° C.
- As a reaction solvent, ethyl acetate, 1,4-dioxane, and THF are exemplified.
- A reaction time is usually a few minutes to a few tens hours, preferably a few minutes to 5 hours.
- A compound (XIV-2) is reacted with a carbonyl compound according to a general aminal forming reaction to obtain a compound (XIV-3).
- A reaction temperature is usually about 0 to 100° C., preferably room temperature to 60° C.
- As a reaction solvent, methylene chloride, THF, and toluene are exemplified.
- A reaction time is usually a few minutes to a few tens hours, preferably a few minutes to 5 hours.
- The present reaction is preferably performed in the presence of an acid catalyst (e.g. acetic acid, p-toluenesulfonic acid).
- A P1 part of a compound (XIV-3) is deprotected to obtain a compound (XIV-4).
- A reaction temperature is usually about 0 to 180° C., preferably room temperature to 60° C.
- As a reaction solvent, THF, 1,4-dioxane, and methylene chloride are exemplified.
- A reaction time is usually a few minutes to a few hours, preferably a few minutes to 5 hours.
- In the above reaction, by using a compound in which R4 and R22 taken together form a ring, as a protected hydrazine reagent, a tricyclic compound such as the compound (I-10) may be synthesized (G ring formation).
-
- (wherein each symbol is as defined above)
- A compound (XIV) is reacted with an amine reagent according to the thirty-fifth step to obtain a compound (XIV-5).
- A compound (XIV-5) is reacted with an N-amination reagent to obtain a compound (XIV-6). Preparation of an N-amination reagent and an N-amination reaction are performed, for example, according to the method described in J. Med. Chem. 1984, 27.1103-1108.
- A compound (XIV-6) is reacted with a carbonyl compound according to the thirty-seventh step to obtain a compound (XIV-7).
- An NH part of a compound (XIV-6) is variously modified to obtain a compound (XIV-8). As the modification method, general N-alkylation, alkylation using a halogenated compound, reductive amination using a carbonyl compound, acylation, and sulfonylation are exemplified.
- A P1 part of a compound (XIV-8) is deprotected according to the thirty-eighth step to obtain a compound (XIV-9).
-
- (wherein each symbol is defined above; n is an integer of 1 to 4; R and R′ are an arbitrary substituent; respective X1s are the same or different, and an X1 (═C, N) may be substituted; n is preferably an integer of 1 to 4).
- A compound (XIV-10) is subjected to a general acetal deprotection reaction to obtain a compound (XIV-11). The present reaction is preferably performed under the acidic condition.
- A reaction temperature is usually about 0 to 120° C., preferably room temperature to 60° C.
- As a reaction solvent, THF, 1,4-dioxane, water, and methanol are exemplified.
- A reaction time is usually a few minutes to a few tens hours, preferably a few minutes to 5 hours.
- A compound (XIV-10) is obtained by reacting a compound (VIV) with a hydrazine reagent having a protected aldehyde-type substituent according to the thirty-fifth step.
- A P1 part of a compound (XIV-11) is deprotected according to the thirty-eighth step to obtain a compound (XIV-12) (C ring formation).
-
- (wherein each symbol is as defined above; L is a leaving group; R and R′ are an arbitrary substituent)
- A compound (XIV-6) is reacted with a carbonyl compound according to a general aminal forming reaction to obtain a compound (XIV-13).
- A compound (XIV-13) is cyclized in a molecule to obtain a compound (XIV-14). A reaction is performed according to a general alkylation reaction or the similar condition.
- A P1 part of a compound (XIV-14) is deprotected according to the thirty-eighth step to obtain a compound (XIV-15) (C ring formation).
-
- (wherein each symbol is as defined above)
- A compound (XIV) is reacted with an amine reagent according to the thirty-fifth step to obtain a compound (XIV-19).
- A compound (XIV-19) is reacted with an N-amination reagent to obtain a compound (XIV-20). Preparation of an N-amination reagent and an N-amination reaction are performed, for example, according to the method described in J. Med. Chem. 1984, 27, 1103-1108.
- A compound (XIV-20) is subjected to a general acetal deprotection reaction according to the forty-fourth step to obtain a compound (XIV-21).
- An NH part of a compound (XIV-21) is variously modified to obtain a compound (XIV-22). As the modification method, general N-alkylation, alkylation using a halogenated compound, reductive amination using a carbonyl compound, acylation, and sulfonation are exemplified.
- A P1 part of a compound (XIV-22) is deprotected according to the thirty-eighth step to obtain a compound (XIV-23).
- In addition, the present compound obtained above may be further chemically modified to synthesize another compound. In addition, when there is a reactive functional group (e.g.: OH, COOH, NH2) on a side chain part etc. in the above reaction, the group may be protected before the reaction and may be deprotected after the reaction, if desired.
- The present compound is useful, for example, as a drug such as an anti-viral drug. The present compound has the remarkable inhibitory action on integrase of a virus. Therefore, the present compound can be expected to have the preventive or therapeutic effect for various diseases derived from a virus which produces at least integrase, and is grown at infection in an animal cell, and is useful as an integrase inhibiting agent for retrovirus (e.g. HIV-1, HIV-2, HTLV-1, SIV, FIV etc.), and is useful as an anti-HIV drug etc.
- In addition, the present compound may be used in a combination therapy by combining an anti-HIV drug having the different action mechanism such as a reverse transcriptase inhibiter and/or a protease inhibiting agent. Particularly, currently, an integrase inhibiter is not marketed, and it is useful to use in a combination therapy by combining the present compound with a reverse transcriptase inhibiter and/or a protease inhibiter.
- Further, the above use includes not only use as a medical mixture for anti-HIV, but also use as a joint use agent for increasing the anti-HIV activity of other anti-HIV drug such as cocktail therapy.
- In addition, the present compound can be used in order to prevent infection with a retrovirus vector from spreading into a tissue other than an objective tissue, upon use of a retrovirus vector based on HIV or MLV in the field of gene therapy. Particularly, when a cell is infected with a vector in vitro, and the cell is returned into a body, if the present compound is administered in advance, unnecessary infection can be prevented in a body.
- The present compound can be administered orally or parenterally. In the case of oral administration, the present compound can be also used as a conventional preparation, for example, as any dosage form of a solid agent such as tablets, powders, granules, capsules and the like; an aqueous agent; an oily suspension; or a liquid agent such as syrup and elixir. In the case of parenteral administration, the present compound can be used as an aqueous or oily suspension injectable, or a nasal drop. Upon preparation of it, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like may be arbitrarily used. As an anti-HIV-drug, particularly, an oral agent is preferable. A preparation of the present invention is prepared by combining (e.g. mixing) a therapeutically effective amount of the present compound with a pharmaceutically acceptable carrier or diluent.
- A dose of the present invention is different depending on an administration method, an age, a weight and condition of a patient, and a kind of a disease and, usually, in the case of oral administration, about 0.05 mg to 3000 mg, preferably about 0.1 mg to 1000 mg may be administered per adult a day, if necessary, by dividing the dose. In addition, in the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg is administered per adult a day.
- Examples are shown below.
-
- 1) Maltol 1 (189 g, 1.5 mol) was dissolved in dimethylformamide (1890 ml), and benzyl bromide (184 ml, 1.5 mol) was added. After the solution was stirred at 80° C. for 15 minutes, potassium carbonate (228 g, 1.65 mol) was added, and the mixture was stirred for 1 hour. After the reaction solution was cooled to room temperature, an inorganic salt was filtered, and the filtrate was distilled off under reduced pressure. To the again precipitated inorganic salt was added tetrahydrofuran (1000 ml), this was filtered, and the filtrate was distilled off under reduced pressure to obtain the crude product (329 g, >100%) of 3-benzyloxy-2-methyl-pyran-4-one 2 as a brown oil.
- NMR (CDCl3) δ: 2.09 (3H, s), 5.15 (2H, s), 6.36 (1H, d, J=5.6 Hz), 7.29-7.41 (5H, m), 7.60 (1H, d, J=5.6 Hz).
- 2) The compound 2 (162.2 g, 750 mmol) was dissolved in ethanol (487 ml), and aqueous ammonia (28%, 974 ml) and a 6N aqueous sodium hydroxide solution (150 ml, 900 mmol) were added. After the reaction solution was stirred at 90° C. for 1 hour, this was cooled to under ice-cooling, and ammonium chloride (58 g, 1080 mmol) was added. To the reaction solution was added chloroform, this was extracted, and the organic layer was washed with an aqueous saturated sodium bicarbonate solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, isopropyl alcohol and diethyl ether were added to the residue, and precipitated crystals were filtered to obtain 3-benzyloxy-2-methyl-1H-pyridine-4-one 3 (69.1 g, 43%) as a pale yellow crystal.
- NMR (DMSO-d6) δ: 2.05 (3H, s), 5.04 (2H, s), 6.14 (1H, d, J=7.0 Hz), 7.31-7.42 (5H, m), 7.46 (1H, d, J=7.2 Hz), 11.29 (1H, brs).
- 3) The above compound 3 (129 g, 599 mmol) was suspended in acetonitrile (1300 ml), and N-bromosuccinic acid imide (117 g, 659 mmol) was added, followed by stirring at room temperature for 90 minutes. Precipitated crystals were filtered, and washed with acetonitrile and diethyl ether to obtain 3-benzyloxy-5-bromo-2-methyl-pyridine-4-ol 4 (154 g, 88%) as a colorless crystal.
- NMR (DMSO-d6) δ: 2.06 (3H, s), 5.04 (2H, s), 7.32-7.42 (5H, m), 8.03 (1H, d, J=5.5 Hz), 11.82 (1H, brs).
- 4) To a solution of the compound 4 (88 g, 300 mmol), palladium acetate (13.4 g, 60 mmol) and 1,3-bis(diphenylphosphino)propane (30.8 g, 516 mmol) in dimethylformamide (660 ml) were added methanol (264 ml) and triethylamine (210 ml, 1.5 mol) at room temperature. The interior of a reaction vessel was replaced with carbon monoxide, and the material was stirred at room temperature for 30 minutes, and stirred at 80 degree for 18 hours. A vessel to which ethyl acetate (1500 ml), an aqueous saturated ammonium chloride solution (1500 ml) and water (1500 ml) had been added was stirred under ice-cooling, and the reaction solution was added thereto. Precipitates were filtered, and washed with water (300 ml), ethyl acetate (300 ml) and diethyl ether (300 ml) to obtain 5-benzyloxy-4-hydroxy-6-methyl-nicotinic acid methyl ester 5 (44.9 g, 55%) as a colorless crystal.
- NMR (DMSO-d6) δ: 2.06 (3H, s), 3.72 (3H, s), 5.02 (2H, s), 7.33-7.42 (5H, m), 8.07 (1H, s).
- 5) After a solution of the compound 5 (19.1 g, 70 mmol) in acetic anhydride (134 ml) was stirred at 130° C. for 40 minutes, the solvent was distilled off under reduced pressure to obtain 4-acetoxy-5-benzyloxy-6-methyl-nicotinic acid methyl ester 6 (19.9 g, 90%) as a flesh colored crystal.
- NMR (CDCl3) δ: 2.29 (3H, s), 2.52 (3H, s), 3.89 (3H, s), 4.98 (2H, s), 7.36-7.41 (5H, m), 8.85 (1H, s).
- 6) To a solution of the compound 6 (46.2 g, 147 mmol) in chloroform (370 ml) was added metachloroperbenzoic acid (65%) (42.8 g, 161 mmol) in portions under ice-cooling, and this was stirred at room temperature for 90 minutes. To the reaction solution was added a 10% aqueous potassium carbonate solution, and this was stirred for 10 minutes, followed by extraction with chloroform. The organic layer was washed with successively with a 10% aqueous potassium carbonate solution, an aqueous saturated ammonium chloride solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with diisopropyl ether to, obtain 4-acetoxy-5-benzyloxy-6-methyl-1-oxy-nicotinic acid methyl ester 7 (42.6 g, 87%) as a colorless crystal.
- NMR (CDCl3) δ: 2.30 (3H, s), 2.41 (3H, s), 3.90 (3H, s), 5.02 (2H, s), 7.37-7.39 (5H, m), 8.70 (1H, s).
- 7) To acetic anhydride (500 ml) which had been heated to stir at 130° C. was added the compound 7 (42.6 g, 129 mmol) over 2 minutes, and this was stirred for 20 minutes. The solvent was distilled off under reduced pressure to obtain 4-acetoxy-6-acetoxymethyl-5-benzyloxy-nicotinic acid methyl ester 8 (49.6 g, >100%) as a black oil.
- NMR (CDCl3) δ: 2.10 (3H, s), 2.28 (3H, s), 3.91 (3H, s), 5.07 (2H, s), 5.20 (2H, s), 7.35-7.41 (5H, m), 8.94 (1H, s).
- 8) To a solution of the compound 8 (46.8 g, 125 mmol) in methanol (140 ml) was added a 2N aqueous sodium hydroxide solution (376 ml) under ice-cooling, and this was stirred at 50° C. for 40 minutes. To the reaction solution were added diethyl ether and 2N hydrochloric acid under ice-cooling, and precipitated crystals were filtered. Resulting crystals were washed with water and diethyl ether to obtain 5-benzyloxy-4-hydroxy-6-hydroxymethyl-nicotinic acid 9 (23.3 g, 68%) as a colorless crystal.
- NMR (DMSO-d6) δ: 4.49 (2H, s), 5.19 (2H, s), 5.85 (1H, brs), 7.14-7.20 (2H, m), 7.33-7.43 (7H, m), 8.30 (1H, s), 10.73 (1H, t, J=5.8 Hz), 11.96 (1H, brs).
- 9) To a solution of the compound 9 (131 g, 475 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (219 g, 1140 mmol) and 1-hydroxybenzotriazole (128 g, 950 mmol) in dimethylformamide (1300 ml) was added 4-fluorobenzylamine (109 ml, 950 mmol), and this was stirred at 80° C. for 1.5 hours. After the reaction solution was cooled to room temperature, hydrochloric acid was added, followed by extraction with ethyl acetate. The extract was washed with a 5% aqueous potassium carbonate solution, an aqueous saturated ammonium chloride solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a mixture (175 g) of 10 and 11. The resulting mixture was dissolved in acetic acid (1050 ml) and water (1050 ml), and zinc (31.1 g, 475 mmol) was added, followed by heating to reflux for 1 hour. After the reaction solution was cooled to room temperature, a 10% aqueous potassium carbonate solution was added, followed by extraction with ethyl acetate. The extract was washed with an aqueous saturated ammonium chloride solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, this was washed with diethyl ether to obtain 5-benzyloxy-N-(4-fluoro-benzyl)-4-hydroxy-6-hydroxymethyl-nicotinic acid amide 10 (107 g, 59%) as a colorless crystal.
- NMR (DMSO-d6) δ: 4.45 (2H, d, J=4.3 Hz), 4.52 (2H, d, J=5.8 Hz), 5.09 (2H, s), 6.01 (1H, brs), 7.36-7.43 (5H, m), 8.31 (1H, s), 12.63 (1H, brs).
- 10) After manganese dioxide (49 g) was added to a suspension of the compound 10 (9.8 g, 25.6 mmol) in chloroform (490 ml), the mixture was stirred at room temperature for 1 hour. After the reaction solution was stirred at 60° C. for 20 minutes, Celite filtration was performed, and this was washed with chloroform heated at 50° C. The filtrate was distilled off under reduced pressure to obtain 5-benzyloxy-N-(4-fluoro-benzyl)-6-formyl-4-hydroxy-nicotinic acid amide 12 (8.2 g, 84%) as a pale yellow crystal.
- NMR (DMSO-d6) δ: 4.53 (2H, d, J=5.8 Hz), 5.38 (2H, s), 7.15-7.21 (2H, m), 7.35-7.46 (7H, m), 8.33 (1H, s), 9.90 (1H, s), 10.35 (1H, t, J=5.8 Hz), 12.49 (1H, brs).
- 11) To an aqueous solution (105 ml) of sodium chlorite (7.13 g, 78.8 mmol), and sulfamic acid (7.65 g, 78.8 mmol) was added a solution of the compound 12 (15.0 g, 39.4 mmol) in tetrahydrofuran (630 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After water (2500 ml) was added to the reaction solution, precipitated crystals were filtered. Washing with diethyl ether afforded 3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-hydroxy-pyridine-2-carboxylic acid 13 (14.0 g, 90%) as a colorless crystal.
- NMR (DMSO-d6) δ: 4.52 (2H, d, J=5.8 Hz), 5.13 (2H, s), 7.14-7.19 (2H, m), 7.31-7.40 (5H, m), 7.47-7.49 (2H, m), 8.31 (1H, d, J=4.5 Hz), 10.44 (1H, t, J=5.9 Hz), 12.47 (1H, brs).
- 12) A solution of the compound 13 (198 mg, 0.500 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115 mg, 0.600 mmol) and 1-hydroxybenzotriazole (81 mg, 0.600 mmol) in dimethylformamide (3 ml) was stirred at room temperature for 1.5 hours. Then, methanol (3 ml) and triethylamine (153 ul, 1.10 mmol) were added, and the mixture was heated to reflux for 1.5 hours. The reaction solution was diluted with ethyl acetate, washed with an aqueous saturated sodium bicarbonate solution, a 10% aqueous citric acid solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain 3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-hydroxy-pyridine-2-carboxylic acid methyl ester 14 (141 mg, 69%) as a colorless crystal.
- NMR (DMSO-d6) δ: 3.85 (3H, s), 4.52 (2H, d, J=6.0 Hz), 5.15 (2H, s), 7.13-7.21 (2H, m), 7.31-7.47 (7H, m), 8.33 (1H, s), 10.41 (1H, t, J=6.0 Hz), 12.59 (1H, brs).
- 13) After 3-bromopropene (2.15 ml, 24.8 mmol) was added to a solution of the compound 14 (6.79 g, 16.5 mmol), and cesium carbonate (8.09 g, 24.8 mmol) in dimethylformamide (54 ml), the mixture was stirred at room temperature for 4.5 hours. To the reaction solution was added an aqueous ammonium chloride solution, and this was extracted with ethyl acetate, washed with water and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain 1-allyl-3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methyl ester 15 (6.15 g, 83%) as a colorless crystal.
- NMR (CDCl3) δ: 3.76 (3H, s), 4.54 (2H, d, J=6.0 Hz), 4.60 (2H, d, J=6.0 Hz), 5.20-5.37 (2H, m), 5.25 (2H, s), 5.80-5.93 (1H, m), 6.98-7.04 (2H, m), 7.31-7.35 (7H, m), 8.45 (1H, s), 10.41 (1H, m).
- 14) To a solution of the compound 15 (7.6 g, 16.9 mmol) in 1,4-dioxane (228 ml) was added an aqueous solution (38 ml) of potassium osmate dihydrate (372 mg, 1.01 mmol), and sodium metaperiodate (14.5 g, 67.6 mmol) was further added, followed by stirring at room temperature for 2 hours. The reaction solution was added to a vessel to which ethyl acetate (300 ml) and water (300 ml) had been added, while stirring. The organic layer was washed with water, a 5% aqueous sodium hydrogen sulfite solution and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain 3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-oxo-1-(2-oxo-ethyl)-1,4-dihydro-pyridine-2-carboxylic acid methyl ester 16 (5.39 g, 71%) as a colorless crystal.
- NMR (CDCl3) δ: 3.74 (3H, s), 4.60 (2H, d, J=5.9 Hz), 4.87 (2H, s), 5.27 (2H, s), 6.98-7.04 (2H, m), 7.30-7.40 (7H, m), 8.39 (1H, s), 9.58 (1H, s), 10.38 (1H, s).
- 15) To a solution of the compound 16 (400 mg, 0.884 mmol) in methylene chloride (12 ml) were added 2-methoxyethylamine (77 ul, 0.884 mmol) and acetic acid (18 ul), and the mixture was stirred at room temperature for 5 minutes. Thereafter, the reaction was performed at 140° C. for 30 minutes in a microwave reaction apparatus. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and fractions eluting with toluene-acetone were concentrated under reduced pressure to obtain 9-benzyloxy-2-(2-methoxy-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrid[1,2-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide 17-1 (226 mg, 54%) as a yellow solid.
- NMR (CDCl3) δ: 3.35 (3H, s), 3.65 (2H, t, J=5.1 Hz), 3.97 (2H, t, J=4.5 Hz), 4.63 (2H, d, J=5.7 Hz), 5.28 (2H, s), 6.56 (2H, m), 7.01 (2H, t, J=8.7 Hz), 7.38-7.30 (5H, m), 7.65 (2H, d, J=6.6 Hz), 10.63 (1H, s).
- According to the similar method, the following compounds were synthesized.
- NMR (CDCl3) δ: 2.68 (6H, s), 3.33 (2H, t, J=6.6 Hz), 4.28 (2H, t, J=6.6 Hz), 4.62 (2H, d, J=6.0 Hz), 5.25 (2H, s), 6.85-6.92 (2H, m), 7.03 (2H, t, J=8.7 Hz), 7.31-7.40 (5H, m), 7.62 (2H, d, J=6.3 Hz), 8.65 (1H, s), 10.63 (1H, t, J=6.0 Hz).
- NMR (CDCl3) δ: 2.59 (4H, s), 2.74 (2H, s), 3.73 (4H, s), 3.95 (2H, s), 4.62 (2H, d, J=6.0 Hz), 5.28 (1H, s), 6.53 (1H, d, J=6.0 Hz), 6.63 (1H, d, J=6.0 Hz), 7.01 (2H, t, J=8.7 Hz), 7.26-7.38 (5H, m), 7.64 (2H, d, J=6.9 Hz), 8.61 (1H, s), 10.61 (1H, t, J=5.4 Hz).
- NMR (CDCl3) δ: 1.55-1.76 (6H, m), 2.71-2.87 (6H, m), 4.13 (2H, brs), 4.62 (2H, d, J=6 Hz), 5.28 (2H, s), 6.62 (1H, d, J=6.2 Hz), 6.77 (1H, m), 6.97-7.04 (2H, m), 7.30-7.39 (5H, m), 7.62-7.63 (2H, m), 8.59 (1H, s), 10.56-10.61 (1H, m).
- NMR (CDCl3) δ: 0.92-0.99 (6H, m), 1.17-1.26 (1H, m), 1.44-1.50 (1H, m), 1.88-1.92 (1H, m), 3.52-3.59 (1H, m), 3.68-3.75 (1H, m), 4.62 (2H, d, J=6 Hz), 5.29 (2H, s), 6.36 (1H, d, J=6 Hz), 6.59 (1H, d, J=6 Hz), 6.98-7.04 (2H, m), 7.29-7.37 (5H, m), 7.62-7.65 (2H, m), 8.57 (1H, s), 10.62 (1H, m).
- NMR (CDCl3) δ: 1.12 (6H, d, J=6 Hz), 3.51-3.59 (1H, m), 3.68 (2H, t, J=4.8 Hz), 3.96 (2H, t, J=4.8 Hz), 4.62 (2H, d, J=6 Hz), 5.28 (2H, s), 6.58-6.64 (2H, m), 6.98-7.04 (2H, m), 7.30-7.39 (5H, m), 7.64-7.66 (2H, m), 8.59 (1H, brs), 10.63 (1H, brs).
- NMR (CDCl3) δ: 1.31 (6H, d, J=6.9 Hz), 4.62 (2H, d, J=6.0 Hz), 5.08-5.17 (1H, m), 5.27 (2H, s), 6.39 (1H, d, J=6.3 Hz), 6.73 (1H, d, J=6.3 Hz), 6.98-7.04 (2H, m), 7.16-7.39 (5H, m), 7.66-7.68 (2H, m), 8.66 (1H, s), 10.67 (1H, t, J=5.5 Hz).
- NMR (CDCl3) δ: 1.15-1.92 (10H, m), 4.62 (2H, d, J=6.1 Hz), 4.70-4.78 (1H, m), 5.27 (2H, s), 6.43 (1H, d, J=6.4 Hz), 6.69 (1H, d, J=6.3 Hz), 7.01-7.16 (2H, m), 7.18-7.37 (5H, m), 7.66-7.68 (2H, m), 8.63 (1H, s), 10.67 (1H, t, J=5.5 Hz).
- NMR (CDCl3) δ: 4.61 (2H, d, J=6.0 Hz), 4.92 (2H, s), 5.31 (2H, s), 6.28 (1H, d, J=6.1 Hz), 6.62 (1H, d, J=6.3 Hz), 6.97-7.09 (4H, m), 7.25-7.38 (7H, m), 7.62-7.66 (2H, m), 8.60 (1H, s), 10.59 (1H, t, J=6.0 Hz).
- NMR (CDCl3) δ: 1.09 (31-1, t, J=6.6 Hz), 2.29 (3H, s), 3.28-3.32 (2H, m), 3.61-3.65 (2H, m), 3.94-3.98 (2H, m), 4.62 (2H, d, J=5.7 Hz), 5.31 (2H, s), 6.21 (1H, d, J=6.0 Hz), 6.49 d, J=6.0 Hz), 6.54 (3H, brs), 6.89-7.04 (2H, m), 7.08-7.39 (6H, m), 7.66 (2H, d, J=6.3 Hz), 8.54 (1H, s), 10.57-10.62 (1H, m).
- NMR (CDCl3) δ: 1.96 (2H, t, J=6.6 Hz), 2.07 (2H, t, J=7.5 Hz), 2.42 (2H, t, J=7.8 Hz), 3.36 (2H, t, J=6.6 Hz), 3.43 (2H, t, J=6.9 Hz), 3.76 (2H, t, J=6.6 Hz), 4.62 (2H, d, J=6.0 Hz), 5.28 (2H, s), 6.62 (1H, d, J=6.3 Hz), 6.78 (1H, d, J=6.3 Hz), 6.98-7.04 (2H, m), 7.30-7.38 (5H, m), 7.63-7.65 (2H, m), 8.59 (1H, s), 10.59-10.63 (1H, m).
- NMR (CDCl3) δ: 1.48-1.62 (1H, m), 1.87-1.98 (2H, m), 2.05-2.17 (1H, m), 3.47 (1H, dd, J=14.1, 8.1 Hz), 3.73-3.82 (1H, m), 3.84-3.92 (1H, m), 4.12-4.21 (1H, m), 4.21 (1H, dd, J=13.8, 2.4 Hz), 4.62 (2H, d, J=6.0 Hz), 5.28 (2H, s), 6.58 (1H, d, J=6.2 Hz), 6.67 (1H, d, J=6.2 Hz), 6.97-7.05 (2H, m), 7.28-7.39 (5H, m), 7.62-7.66 (2H, m), 8.58 (1H, m), 10.60-10.68 (1H, m).
- NMR (CDCl3) δ: 4.63 (2H, d, J=6.0 Hz), 5.00 (2H, s), 5.31 (2H, s), 6.37 (1H, d, J=6.1 Hz), 6.68 (1H, d, J=6.1 Hz), 6.97-7.06 (2H, m), 7.28-7.38 (7H, m), 7.56-7.61 (2H, m), 8.61 (1H, s), 8.62-8.66 (2H, m), 10.50 (1H, t, J=6.0 Hz).
- NMR (CDCl3) δ: 1.26 (3H, t, J=7.0 Hz), 1.62-1.69 (2H, m), 1.84-1.87 (2H, m), 2.88-2.96 (2H, m), 4.16 (2H, q, J=7.0 Hz), 4.35 (2H, brs), 4.62 (2H, d, J=5.9 Hz), 5.27 (2H, s), 6.37 (1H, d, J=6.3 Hz), 6.69 (1H, d, J=5.6 Hz), 6.98-7.04 (2H, m), 7.16-7.40 (5H, m), 7.64-7.67 (2H, m), 8.62 (1H, brs), 10.59 (1H, brs).
- NMR (CDCl3) δ: 3.40 (3H, s), 4.62 (2H, d, J=6.0 Hz), 5.27 (2H, s), 6.37 (1H, d, J=6.0 Hz), 6.64 (1H, d, J=6.0 Hz), 6.97-7.05 (2H, m), 7.28-7.40 (5H, m), 7.63-7.68 (2H, m), 8.60 (1H, brs), 10.61 (1H, brs).
- NMR (DMSO-d6) δ: 1.76 (3H, s), 3.33 (2H, s), 3.79 (2H, s), 4.55 (2H, d, J=5.1 Hz), 5.05 (2H, s), 6.89 (1H, d, J=6.0 Hz), 7.17 (2H, t, J=8.4 Hz), 7.30-7.50 (5H, m), 7.61 (2H, d, J=5.1 Hz), 7.96 (1H, s), 8.93 (1H, s), 10.61 (1H, s).
- NMR (CDCl3) δ: 1.15 (6H, d, J=6.1 Hz), 1.93-2.02 (2H, m), 3.45 (2H, t, J=5.7 Hz), 3.55 (1H, sep, J=6.1 Hz), 3.90 (2H, d, J=6.8 Hz), 4.62 (2H, d, J=6.0 Hz), 5.28 (2H, s), 6.49 (1H, d, J=6.3 Hz), 6.59 (1H, d, J=6.3 Hz), 6.97-7.05 (2H, m), 7.27-7.38 (5H, m), 7.62-7.65 (2H, m), 8.58 (1H, s), 10.58-10.65 (1H, m).
- NMR (CDCl3) δ: 2.98 (6H, s), 4.62 (2H, d, J=6.0 Hz), 4.88 (2H, s), 5.31 (2H, s), 6.35 (1H, d, J=6.2 Hz), 6.54 (1H, d, J=6.2 Hz), 6.77 (2H, brs), 6.87-7.05 (2H, m), 7.19-7.25 (2H, m), 7.29-7.41 (2H, m), 7.65-7.70 (2H, m), 8.54 (1H, s), 10.62 (1H, t, J=5.6 Hz).
- NMR (CDCl3) δ: 4.62 (2H, s), 5.04 (2H, s), 5.28 (2H, s), 6.51 (1H, d, J=6.3 Hz), 6.87 (1H, d, J=6.3 Hz), 7.00-7.06 (2H, m), 7.20-7.40 (5H, m), 7.44-7.47 (2H, m), 7.59-7.62 (2H, m), 7.90-7.93 (2H, m), 8.63 (1H, s).
- NMR (CDCl3) δ: 1.87-1.97 (2H, m), 2.34 (3H, s), 2.42 (2H, d, J=6.8 Hz), 2.54 (8H, brs), 3.85 (2H, d, J=6.9 Hz), 4.62 (2H, d, J=5.9 Hz), 5.28 (2H, s), 6.52 (1H, d, J=6.3 Hz), 6.60 (1H, d, J=6.3 Hz), 6.95-7.05 (2H, m), 7.28-7.38 (5H, m), 7.61-7.66 (2H, m), 8.59 (1H, s), 10.61 (1H, t, J=5.9 Hz).
- NMR (CDCl3) δ: 1.99 (2H, quin, J=5.7 Hz), 3.34 (3H, s), 3.60 (2H, t, J=6.3 Hz), 3.95 (2H, t, J=6.3 Hz), 4.62 (2H, d, J=5.7 Hz), 5.28 (2H, s), 6.45 (1H, d, J=6.3 Hz), 6.61 (1H, d, J=6.3 Hz), 7.01 (2H, t, J=6.6 Hz), 7.28-7.38 (5H, m), 7.64 (2H, d, J=6.6 Hz), 8.59 (1H, s), 10.62 (1H, s).
- NMR (CDCl3) δ: 0.89 (3H, t, J=7.5 Hz), 1.55 (2H, m), 3.38 (2H, t, J=6.6 Hz), 3.68 (2H, t, J=4.8 Hz), 3.98 (2H, t, J=4.5 Hz), 4.62 (2H, d, J=5.7 Hz), 5.28 (2H, s), 6.57 (1H, d, J=5.7 Hz), 6.60 (1H, d, J=5.7 Hz), 7.01 (2H, t, J=8.7 Hz), 7.30-7.38 (5H, m), 7.65 (2H, d, J=6.9 Hz), 8.59 (1H, s), 10.63 (1H, s).
- NMR (CDCl3) δ: 4.17-4.20 (2H, m), 4.25-4.28 (2H, m), 4.62 (2H, d, J=5.6 Hz), 5.28 (2H, s), 6.60-6.66 (1H, m), 6.86 (2H, d, J=8.0 Hz), 6.95-7.04 (2H, m), 7.28-7.37 (8H, m), 7.64 (2H, d, J=7.0 Hz), 8.59 (1H, s), 10.60 (1H, brs).
- NMR (CDCl3) δ: 3.04 (2H, t, J=7.2 Hz), 4.00 (2H, t, J=7.2 Hz), 4.62 (2H, d, J=6.0 Hz), 5.29 (2H, s), 6.10 (1H, d, J=6.3 Hz), 6.52 (1H, d, J=6.3 Hz), 7.01 (2H, m), 7.24 (1H, m), 7.30-7.39 (5H, m), 7.53 (1H, m), 7.62-7.66 (2H, m), 8.46 (1H, m), 8.52 (1H, dd, J=1.5 Hz, 4.5 Hz), 8.56 (1H, s), 10.57 (1H, brt, J=6.0 Hz).
- NMR (CDCl3) δ: 3.01 (3H, s), 3.13 (3H, s), 4.59 (2H, s), 4.63 (2H, d, J=6.0 Hz), 5.26 (2H, s), 6.42 (1H, d, J=6.0 Hz), 6.64 (1H, d, J=6.0 Hz), 7.01 (2H, m), 7.29-7.36 (5H, m), 7.64 (2H, m), 8.60 (1H, s), 10.59 (1H, brt, J=6.0 Hz).
- NMR (CDCl3) δ: 1.18 (3H, t, J=7.0 Hz), 3.49 (2H, q, J=7.0 Hz), 3.66-3.71 (2H, m), 3.96-4.00 (2H, m), 4.63 (2H, d, J=6.0 Hz), 5.28 (2H, s), 6.57 (1H, d, J=5.9 Hz), 6.61 (1H, d, J=5.9 Hz), 6.98-7.06 (2H, m), 7.29-7.40 (5H, m), 7.63-7.67 (2H, m), 8.59 (1H, s), 10.60-10.68 (1H, m).
- NMR (DMSO-d6) δ: 4.55 (2H, d, J=5.7 Hz), 4.99 (2H, s), 5.07 (2H, s), 6.44 (1H, dd, J=1.8 Hz, 3.0 Hz), 6.51 (1H, dd, J=0.9 Hz, 3.0 Hz), 6.99 (1H, d, J=6.3 Hz), 7.17 (2H, m), 7.31-7.41 (4H, m), 7.46 (1H, d, J=6.6 Hz), 7.58-7.62 (2H, m), 7.65 (1H, dd, J=0.9 Hz, 1.8 Hz), 8.89 (1H, s), 10.57 (1H, brt, J=5.7 Hz).
- NMR (CDCl3) δ: 3.00 (2H, t, J=7.2 Hz), 3.98 (2H, t, J=7.2 Hz), 4.62 (2H, d, J=5.4 Hz), 5.30 (2H, s), 6.06 (1H, d, J=6.3 Hz), 6.46 (1H, d, J=6.3 Hz), 7.01 (2H, m), 7.11 (2H, m), 7.17-7.40 (9H, m), 7.64 (2H, m), 8.53 (1H, s), 10.58 (1H, brt, J=5.4 Hz).
- NMR (CDCl3) δ: 1.75 (1H, m), 2.21 (1H, m), 2.44-2.55 (2H, m), 2.87 (1H, brd, J=10.8 Hz), 3.15 (1H, brt, J=8.7 Hz), 3.56 (1H, d, J=9.9 Hz), 3.69 (1H, d, J=9.9 Hz), 4.62 (2H, d, J=5.7 Hz), 5.25 (2H, s), 6.66 (1H, d, J=6.3 Hz), 6.98 (1H, d, J=6.3 Hz), 7.00 (2H, m), 7.15-7.38 (10H, m), 7.62-7.66 (2H, m), 8.58 (1H, s), 10.63 (1H, brt, J=5.7 Hz).
- NMR (CDCl3) δ: 4.63 (2H, d, J=5.2 Hz), 5.13 (2H, s), 5.32 (2H, s), 6.43-6.44 (1H, m), 6.58-6.60 (1H, m), 6.98-7.04 (3H, m), 7.13-7.14 (1H, m), 7.28-7.39 (6H, m), 7.65-7.67 (2H, m), 8.56 (1H, s), 10.58 (1H, brs).
- NMR (CDCl3) δ: 0.99 (6H, brs), 1.62 (1H, brs), 2.22 (1H, brs), 2.33 (6H, brs), 3.83 (2H, brs), 4.62 (2H, d, J=6.0 Hz), 5.29 (2H, s), 6.56 (1H, d, J=6.3 Hz), 6.64 (1H, brs), 7.01 (2H, t, J=8.1 Hz), 7.27-7.36 (5H, m), 7.62 (2H, d, J=8.1 Hz), 8.57 (1H, s), 10.62 (1H, t, J=5.7 Hz).
- NMR (CDCl3) δ: 1.92 (2H, tt, J=6.6 Hz, 6.9 Hz), 2.39 (2H, t, J=6.6 Hz), 2.43 (4H, brt, J=4.8 Hz), 3.70 (4H, brt, J=4.8 Hz), 3.86 (2H, t, J=6.9 Hz), 4.62 (2H, d, J=6.0 Hz), 5.28 (2H, s), 6.50 (1H, d, J=6.3 Hz), 6.61 (1H, d, J=6.3 Hz), 7.01 (2H, m), 7.29-7.38 (5H, m), 7.62-7.65 (2H, m), 8.60 (1H, s), 10.62 (1H, brt, J=6.0 Hz).
- 16) To the compound 17-1 (140 mg, 0.293 mmol) was added trifluoroacetic acid (1.4 ml) under ice-cooling, and the mixture was stirred at 0° C. for 5 minutes and, then, at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and this was diluted with chloroform, and added to ice water. This was washed with an aqueous saturated sodium bicarbonate solution, a 10% aqueous citric acid solution and water, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized with methylene chloride-ethanol to obtain Example A-1 (89 mg, 79%) as a yellow crystal.
- melting point: 223-224° C. NMR (DMSO-d6) δ: 3.25 (3H, s), 3.58 (2H, t, J=5.4 Hz), 3.92 (2H, t, J=5.1 Hz), 4.53 (2H, d, J=5.7 Hz), 6.87 (1H, d, 6.3 Hz), 7.14 (2H, t, J=9.0 Hz), 7.33-7.38 (2H, m), 7.47 (1H, d, J=6.0 Hz), 8.77 (1H, s), 10.56 (1H, t, J=6.0 Hz), 12.00 (1H, brs).
- 17) The compound 17-1 (157 mg, 0.329 mmol) was dissolved in dimethylformamide (18 ml) and methanol (1 ml), 10% palladium-carbon powder (31 mg) was added, and the mixture was stirred at room temperature for 20 hours under the hydrogen atmosphere. The reaction solution was filtered with Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, this was filtered with Celite again, and the filtrate was concentrated under reduced pressure. The residue was recrystallized with methylene chloride-methanol to obtain Example B-1 (66 mg, 52%) as a brown crystal.
- melting point: 197-199° C. NMR (DMSO-d6) δ: 3.27 (3H, s), 3.55 (2H, t, J=5.1 Hz), 3.68 (2H, t, J=5.1 Hz), 3.79 (2H, s), 4.36 (2H, s), 4.51 (2H, d, J=5.7 Hz), 7.15 (2H, t, J=8.7 Hz), 7.32-7.37 (2H, m), 8.38 (1H, s), 10.46 (1H, t, J=5.4 Hz), 12.41 (1H, s).
- According to the same manner as that of Example A-1, the following Example compounds A-2 to A-29, and A-31 to A-32 were synthesized.
- melting point: 224-225° C. NMR (DMSO-d6) δ: 2.24 (6H, s), 2.59 (2H, t, J=6.0 Hz), 3.87 (2H, t, J=6.0 Hz), 4.55 (2H, d, J=6.0 Hz), 6.94 (1H, d, J=6.3 Hz), 7.17 (2H, t, J=6.9 Hz), 7.35-7.40 (2H, m), 7.50 (1H, d, J=6.3 Hz), 8.80 (1H, s), 10.59 (1H, t, J=6.0 Hz), 12.05 (1H, s).
- melting point: 212-215° C. NMR (DMSO-d6) δ: 2.51 (4H, s), 2.38 (3H, s), 3.55 (4H, s), 3.90 (2H, s), 4.55 (2H, d, J=6.0 Hz), 6.95 (1H, d, J=6.3 Hz), 7.17 (2H, t, J=8.7 Hz), 7.35-7.40 (2H, m), 7.50 (1H, d, J=6.3 Hz), 10.58 (1H, t, J=6.3 Hz), 12.10 (1H, s).
- melting point: 217-218° C. Elementary analysis for C23H25FN4O4 Cal'd (%): C, 62.72; H, 5.72; F, 4.31; N, 12.72. Found (%): C, 58.98; H, 5.46; F, 6.16; N, 11.66. NMR (DMSO-d 6) δ: 1.41-1.51 (6H, m), 2.49-2.73 (6H, m), 3.91 (2H, m), 4.54 (2H, d, J=6 Hz), 6.93 (1H, d, J=6 Hz), 7.13-7.19 (2H, m), 7.35-7.39 (2H, m), 7.50 (1H, d, J=6 Hz), 8.80 (1H, s), 10.57 (1H, t, J=5.7 Hz), 12.14 (1H, brs).
- melting point: 242-243° C. Elementary analysis for C21H22FN3O4 Cal'd (%): C, 63.15; H, 5.55; F, 4.76; N, 10.52. Found (%); C, 63.14; H, 5.57; F, 4.63; N, 10.54. NMR (DMSO-d 6) δ: 0.86-0.94 (6H, m), 1.08-1.20 (1H, m), 1.33-1.55 (1H, m), 1.81-1.90 (1H, m), 3.51-3.58 (1H, m), 3.65-3.71 (1H, m), 4.54 (2H, d, J=6 Hz), 6.92 (1H, d, J=6.3 Hz), 7.13-7.20 (2H, m), 7.34-7.39 (2H, m), 7.50 (1H, d, J=6.3 Hz), 8.79 (1H, s), 10.60 (1H, t, J=5.7 Hz), 12.13 (1H, brs).
- melting point: 209-210° C. Elementary analysis for C21H22FN3O5 Cal'd (%); C, 60.72; H, 5.34; F, 4.57; N, 10.12. Found (%); C, 60.78; H, 5.29; F, 4.34; N, 10.11. NMR (DMSO-d 6) δ: 1.06 (61-1, d, J=6.3 Hz), 3.54-3.64 (3H, m), 3.90 (2H, t, J=5.4 Hz), 6.89 (1H, d, J=6.3 Hz), 7.13-7.19 (2H, m), 7.35-7.39 (2H, m), 7.47 (1H, d, J=6.3 Hz), 8.77 (1H, s), 10.58 (1H, t, J=5.7 Hz), 12.04 (1H, brs).
- melting point: 282-283° C. NMR (DMSO-d6) δ: 1.29 (6H, d, J=6.9 Hz), 4.54 (2H, d, J=5.9 Hz), 4.83-4.92 (1H, m), 7.04 (1H, d, J=6.4 Hz), 7.13-7.19 (2H, m), 7.35-7.40 (2H, m), 7.56 (1H, d, J=6.4 Hz), 8.80 (1H, s), 10.61 (1H, t, J=5.8 Hz), 12.26 (1H, brs).
- melting point: >300° C. NMR (DMSO-d6) δ: 1.15-1.84 (10H, m), 4.43-4.49 (1H, m), 4.53 (2H, d, J=5.8 Hz), 7.05 (1H, d, J=6.4 Hz), 7.13-7.19 (2H, m), 7.34-7.39 (2H, m), 7.53 (1H, d, J=6.4 Hz), 8.79 (1H, s), 10.61 (1H, t, J=5.8 Hz), 12.23 (1H, brs).
- melting point: 190-192° C. NMR (CDCl3) δ: 1.10-1.16 (3H, m), 2.29 (3H, s), 3.29-3.38 (2H, m), 3.63-3.69 (2H, m), 3.94-3.99 (2H, m), 4.62 (2H, d, J=6.0 Hz), 6.13-6.19 (1H, m), 6.52-6.61 (4H, m), 6.96-7.40 (2H, m), 6.96-7.04 (2H, m), 7.04-7.17 (1H, m), 7.29-7.36 (2H, m), 8.47 (1H, s), 10.56 (1H, brs), 11.89 (1H, brs).
- melting point: 262-264° C. NMR (CDCl3) δ: 1.93-2.04 (2H, m), 2.04-2.15 (2H, m), 2.39-2.46 (2H, m), 3.35-3.46 (4H, m), 3.75-3.81 (2H, m), 4.62 (2H, d, J=5.7 Hz), 6.69 (1H, d, J=6.3 Hz), 6.78 (1H, d, J=6.3 Hz), 6.95-7.04 (2H, m), 7.29-7.37 (2H, m), 8.53 (1H, s), 10.58 (1H, brs), 11.89 (1H, brs).
- melting point: 248-249° C. NMR (CDCl3) δ: 1.52-1.66 (1H, m), 1.90-2.00 (2H, m), 2.06-2.18 (1H, m), 3.52-3.61 (1H, m), 3.71-3.83 (1H, m), 3.85-3.94 (1H, m), 4.12-4.24 (1H, m), 4.63 (2H, d, J=6.0 Hz), 6.59 (1H, d, J=6.5 Hz), 6.66 (1H, d, J=6.5 Hz), 6.96-7.04 (2H, m), 7.29-7.37 (2H, m), 8.52 (1H, s), 10.61 (1H, brs), 11.97 (1H, brs).
- melting point: 265-268° C. NMR (DMSO-d6) δ: 4.55 (2H, d, J=5.4 Hz), 5.02 (2H, s), 7.02 (1H, d, J=6.5 Hz), 7.13-7.22 (2H, m), 7.34-7.42 (4H, m), 7.56 (1H, d, J=6.51 Hz), 8.54-8.57 (2H, m), 8.83 (1H, s), 10.54-10.56 (1H, m), 11.78 (1H, s).
- melting point: 288-289° C. NMR (CDCl3) δ: 1.29 (3H, t, J=7.0 Hz), 1.64-1.75 (2H, m), 1.86-1.92 (2H, m), 2.89-2.97 (2H, m), 4.16 (2H, q, J=7.0 Hz), 4.30-4.50 (2H, m), 4.62 (2H, d, J=5.8 Hz), 4.80-4.88 (1H, m), 6.33 (1H, d, J=6.6 Hz), 6.76 (1H, d, J=6.6 Hz), 6.97-7.03 (2H, m), 7.31-7.35 (2H, m), 8.56 (1H, s), 10.57 (1H, brs), 11.98 (1H, brs).
- melting point: 276-279° C. NMR (CDCl3) δ: 3.43 (3H, s), 4.63 (2H, d, J=5.7 Hz), 6.33 (1H, d, J=6.2 Hz), 6.71 (1H, d, J=6.2 Hz), 6.86-7.05 (2H, m), 7.30-7.37 (2H, m), 8.53 (1H, s), 10.59 (1H, brs), 11.95 (1H, brs).
- melting point: >300° C. NMR (DMSO-d6) δ: 1.76 (3H, s), 3.37 (2H, t, J=5.7 Hz), 3.79 (2H, t, J=5.7 Hz), 4.54 (2H, d, J=5.7 Hz), 6.85 (1H, d, J=6.3 Hz), 7.16 (2H, m), 7.37 (2H, m), 7.48 (1H, d, J=6.3 Hz), 7.95 (1H, brt, J=5.7 Hz), 8.82 (1H, s), 10.58 (1H, brt, J=5.7 Hz), 12.07 (1H, s).
- melting point: 180-181° C. NMR (CDCl3) δ: 1.14 (6H, d, J=6.1 Hz), 1.94-2.04 (2H, m), 3.48 (2H, t, J=5.7 Hz), 3.55 (1H, sep, J=6.1 Hz), 3.92 (2H, t, J=6.6 Hz), 4.63 (2H, d, J=6.0 Hz), 6.42 (1H, d, J=6.2 Hz), 6.67 (1H, d, J=6.2 Hz), 6.96-7.04 (2H, m), 7.30-7.37 (2H, m), 8.52 (1H, s), 10.61 (1H, brs), 12.05 (1H, brs).
- melting point: 245-247° C. NMR (CDCl3) δ: 2.98 (6H, s), 4.62 (2H, d, J=5.7 Hz), 4.87 (2H, s), 6.32 (1H, d, J=6.2 Hz), 6.63 (1H, d, J=6.2 Hz), 6.79 (2H, brs), 6.96-7.23 (2H, m), 7.21-7.25 (2H, m), 7.30-7.36 (2H, m), 8.49 (1H, s), 10.61 (1H, t, J=5.7 Hz), 12.08 (1H, brs).
- melting point: 197-199° C. NMR (CDCl3) δ: 1.96-2.04 (2H, m), 3.34 (3H, s), 3.45 (2H, t, J=5.4 Hz), 3.90 (2H, t, J=6.9 Hz), 4.62 (2H, d, J=5.7 Hz), 5.11 (2H, s), 6.38 (1H, d, J=6.0 Hz), 6.70 (1H, d, J=6.0 Hz), 6.97-7.03 (2H, m), 7.31-7.35 (2H, m), 8.55 (1H, s), 10.61 (1H, brs), 12.03 (1H, brs).
- melting point: 215-217° C. NMR (CDCl3) δ: 0.90 (31-1, t, J=7.5 Hz), 1.58 (2H, m), 3.41 (2H, t, J=6.6 Hz), 3.69 (2H, t, J=4.7 Hz), 3.97 (2H, t, J=4.6 Hz), 4.63 (2H, d, J=5.8 Hz), 6.53 (1H, d, J=6.3 Hz), 6.67 (1H, d, J=6.3 Hz), 6.97-7.03 (2H, m), 7.31-7.36 (2H, m), 8.54 (1H, s), 10.62 (1H, brs), 11.97 (1H, brs).
- melting point: 237-239° C. NMR (CDCl3) δ: 4.18-4.21 (2H, m), 4.26-4.29 (2H, m), 4.62 (2H, d, J=5.8 Hz), 6.57 (1H, d, J=6.3 Hz), 6.71 (1H, d, J=6.3 Hz), 6.86 (2H, d, J=8.1 Hz), 6.97-7.02 (3H, m), 7.29-7.35 (4H, m), 8.56 (1H, s), 10.58 (1H, t, J=5.7 Hz), 11.84 (1H, brs).
- melting point: 256-257° C. NMR (CDCl3) δ: 3.00 (2H, t, J=7.5 Hz), 4.02 (2H, t, J=7.5 Hz), 4.54 (2H, d, J=6.0 Hz), 6.89 (1H, d, J=6.3 Hz), 7.16 (2H, m), 7.30-7.39 (3H, m), 7.48 (1H, d, J=6.3 Hz), 7.70 (1H, m), 8.44 (1H, dd, J=1.8 Hz, 5.1 Hz), 8.48 (1H, m), 8.78 (1H, s), 10.56 (1H, t, J=6.0 Hz), 11.98 (1H, s).
- melting point: >300° C. NMR (DMSO-d6) δ: 2.87 (3H, s), 3.03 (3H, s), 4.55 (2H, d, J=6.0 Hz), 4.71 (2H, s), 6.80 (1H, d, J=6.3 Hz), 7.16 (2H, m), 7.38 (2H, m), 7.48 (1H, d, J=6.3 Hz), 8.82 (1H, s), 10.54 (1H, brt, J=6.0 Hz), 11.83 (1H, s).
- melting point: 212-214° C. NMR (CDCl3) δ: 1.19 (3H, t, J=7.0 Hz), 3.51 (2H, q, J=7.0 Hz), 3.67-3.72 (2H, m), 3.95-4.01 (2H, m), 4.63 (2H, d, J=5.7 Hz), 6.54 (1H, d, J=6.0 Hz), 6.65 (1H, d, J=6.0 Hz), 6.96-7.02 (2H, m), 7.29-7.36 (2H, m), 8.52 (1H, s), 10.62 (1H, brs), 11.97 (1H, brs).
- melting point: 234-237° C. NMR (DMSO-d6) δ: 4.54 (2H, d, J=6.0 Hz), 4.98 (2H, s), 6.45 (1H, dd, J=2.1 Hz, 3.3 Hz), 6.53 (1H, dd, J=0.6 Hz, 3.3 Hz), 6.93 (1H, d, J=6.3 Hz), 7.16 (2H, m), 7.36 (2H, m), 7.47 (1H, d, J=6.3 Hz), 7.65 (1H, dd, J=0.6 Hz, 2.1 Hz), 8.74 (1H, s), 10.56 (1H, brt, J=6.0 Hz), 11.85 (1H, s).
- melting point: 288-291° C. NMR (DMSO-d6) δ: 2.96 (2H, t, J=7.5 Hz), 2.98 (2H, t, J=7.5 Hz), 4.54 (2H, d, J=6.0 Hz), 6.87 (1H, d, J=6.3 Hz), 7.16 (2H, m), 7.30 (2H, m), 7.34-7.39 (4H, m), 7.47 (1H, d, J=6.3 Hz), 8.78 (1H, s), 10.57 (1H, brt, J=6.0 Hz), 12.01 (1H, s).
- melting point: 218-219° C. NMR (CDCl3) δ: 1.82 (1H, m), 2.24 (1H, q, J=8.4 Hz), 2.36 (1H, m), 2.56 (1H, m), 2.83 (1H, m), 3.00 (1H, m), 3.63 (2H, s), 4.54 (2H, d, J=6.0 Hz), 5.19 (1H, m), 7.11 (1H, d, J=6.3 Hz), 7.16 (2H, m), 7.23-7.39 (7H, m), 7.56 (1H, d, J=6.3 Hz), 8.78 (1H, s), 10.58 (1H, t, J=6.0 Hz), 12.14 (1H, s).
- melting point: 233-236° C. NMR (CDCl3) δ: 4.61 (2H, d, J=6.0 Hz), 5.11 (2H, s), 6.37 (1H, d, J=6.3 Hz), 6.72 (1H, d, J=6.3 Hz), 6.96-7.04 (3H, m), 7.15 (1H, d, J=3.3 Hz), 7.32-7.36 (3H, m), 8.56 (1H, s), 10.56 (1H, brs), 11.87 (1H, brs).
- melting point: 208-210° C. NMR (DMSO-d6) δ: 0.91 (6H, s), 2.17 (2H, s), 2.25 (6H, s), 3.70 (2H, s), 4.54 (2H, d, J=5.7 Hz), 6.84 (1H, d, J=6M Hz), 7.14-7.19 (2H, m), 7.35-7.39 (2H, m), 7.46 (1H, d, J=6.0 Hz), 8.81 (1H, s), 10.60 (1H, t, J=6.3 Hz), 12.18 (1H, brs).
- melting point: 197-198° C. NMR (CDCl3) δ: 1.81 (2H, tt, J=6.3 Hz, 6.9 Hz), 2.31 (4H, brs), 2.33 (2H, t, J=6.3 Hz), 3.49 (4H, brt, J=4.5 Hz), 3.80 (2H, t, J=6.9 Hz), 4.54 (2H, d, J=6.0 Hz), 6.95 (1H, d, J=6.3 Hz), 7.16 (2H, m), 7.34 (2H, m), 7.50 (1H, d, J=6.3 Hz), 8.80 (1H, s), 10.59 (1H, t, J=6.0 Hz), 12.16 (1H, s).
-
- 1) 4-Hydroxy-6-methylnicotinic acid 19 (95.6 g, 0.625 mol) was dissolved in acetic acid (950 ml) and water (190 ml), and bromine (39 ml, 0.750 mol) was added over 15 minutes. After the solution was stirred at 60° C. for 5 hours, the solvent was distilled off under reduced pressure, methanol (200 ml) was added and, crystals were collected by filtration. The solution was distilled off under reduced pressure, methanol was added again to the residue, and crystals were collected by filtration. A total of 142.2 g (98%) of 5-bromo-4-hydroxy-6-methylnicotinic acid 20 was obtained as a colorless crystal.
- NMR (DMSO-d6) δ: 2.53 (3H, s), 8.56 (1H, s), 13.45 (1H, brs), 14.80 (1H, brs).
- 2) The compound 20 (138 g, 0.596 mol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (148 g, 0.775 mol), and 1-hydroxybenzotriazole (100 g, 0.656 mol) were dissolved in dimethylformamide (970 ml), and 4-fluorobenzylamine (79 ml, 0.715 mol) was added. After the reaction solution was stirred at room temperature for 9 hours, water (2000 ml) was added, and crystals were collected by filtration, followed by washing with ether. 5-Bromo-N-(4-fluorobenzyl)-4-hydroxy-6-methylnicotinamide 21 (156 g, 77%) was obtained as a colorless crystal.
- NMR (DMSO-d6) δ: 2.47 (3H, s), 4.50 (2H, d, J=5.9 Hz), 7.12-7.20 (m, 2H), 7.32-7.39 (m, 2H), 8.38 (1H, s), 10.50 (1H, t, J=5.9 Hz), 12.72 (1H, brs).
- 3) The compound 21 (75.2 g, 222 mmol) and copper (I) iodide (21.1 g, 111 mmol) were dissolved in dimethylformamide (750 ml), a 28% sodium methoxide-methanol solution (216 ml, 888 mmol) was added, and the mixture was stirred at 105° C. for 100 minutes. After cooling, ice-water (800 ml) was added, and unnecessary matters were filtered. To the solution was added 2 M hydrochloric acid (443 ml), and crystals were collected by filtration. N-(4-fluorobenzyl)-4-hydroxy-5-methoxy-6-methylnicotinamide 22 (56.0 g, 87%) was obtained as a colorless crystal.
- NMR (DMSO-d6) δ: 2.26 (3H, s), 3.74 (3H, s), 4.49 (2H, d, J=6.0 Hz), 7.10-7.19 (2H, m), 7.30-7.38 (2H, m), 8.24 (1H, s), 10.68 (1H, t, J=6.0 Hz), 12.21 (1H, brs).
- 4) To a solution of the compound 22 (100 g, 344 mmol), benzyl alcohol (46 ml, 447 mmol), and tributylphosphine (128 ml, 516 mmol) in tetrahydrofuran (1000 ml) was added a 40% diisopropyl azodicarboxylate-toluene solution (280 ml, 516 mmol) under ice-cooling over 30 minutes. After stirred for 30 minutes under ice-cooling, a temperature was raised to room temperature, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, to the residue were added toluene (100 ml) and hexane (2000 ml), and precipitated crystals were filtered. The solvent was distilled off under reduced pressure, to the residue were added diethyl ether (200 ml) and hexane (2000 ml), and precipitated crystals were filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). 4-Benzyloxy-N-(4-fluorobenzyl)-5-methoxy-6-methylnicotinamide 23 (68.5 g, 52%) was obtained as a colorless crystal.
- NMR (CDCl3) δ: 2.58 (3H, s), 3.86 (3H, s), 4.40 (2H, d, J=5.7 Hz), 5.21 (2H, s), 6.91-7.00 (2H, m), 7.08-7.14 (2H, m), 7.19-7.27 (2H, m), 7.32-7.40 (3H, m), 7.87 (1H, brs), 8.97 (1H, s).
- 5) To a solution of the compound 23 (67.5 g, 177 mmol) in chloroform (350 ml) was added a solution of metachloroperbenzoic acid (65%) (49.5 g, 186 mmol) in chloroform (350 ml) over 30 minutes under ice-cooling. After stirred for 45 minutes under ice-cooling, a temperature was raised to room temperature, followed by stirring for 75 minutes. To the reaction solution was added an aqueous saturated sodium bicarbonate solution, followed by extraction with chloroform. The organic layer was washed with an aqueous saturated sodium bicarbonate solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, to the residue was added diethyl ether (200 ml), and precipitated crystals (47.8 g) were collected by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (toluene/acetone) to obtain 2.65 g of crystals. A total of 50.5 g (72%) of 4-benzyloxy-N-(4-fluorobenzyl)-5-methoxy-6-methyl-1-oxynicotinamide 24 was obtained as a colorless crystal.
- NMR (CDCl3) δ: 2.55 (3H, s), 3.90 (3H, s), 4.40 (2H, d, J=5.7 Hz), 5.16 (2H, s), 6.93-6.70 (2H, s), 6.90-7.19 (5H, m), 7.30-7.38 (2H, m), 7.94 (1H, brs), 8.81 (1H, s).
- 6) The compound 24 (49.4 g, 125 mmol) was dissolved in acetic anhydride (350 ml), and this was stirred at 80° C. for 30 minutes. The solvent was distilled off under reduced pressure, this was dissolved in methanol (500 ml), and a 28% sodium methoxide-methanol solution (7.5 ml, 31.3 mmol) was added under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction solution was added Amberlite (registered trade mark) IR-120B until the solution became neutral, and a solid matter was filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). 4-Benzyloxy-N-(4-fluorobenzyl)-6-hydroxymethyl-5-methoxynicotinamide 25 (25.4 g, 51%) was obtained as a colorless crystal.
- NMR (CDCl3) δ: 3.42 (1H, brs), 3.89 (3H, s), 4.41 (2H, d, J=5.7 Hz), 4.83 (2H, s), 5.23 (2H, s), 6.92-6.99 (2H, m), 7.09-7.14 (2H, m), 7.19-7.23 (2H, m), 7.28-7.37 (3H, m), 7.85 (1H, brs), 9.03 (1H, s).
- 7) To a solution of the compound 25 (25.0 g, 63.1 mmol), dimethyl sulfoxide (44.8 ml, 631 mmol), and triethylamine (44.3 ml, 378 mmol) in chloroform (250 ml) was added a sulfur trioxide pyridine complex (50.2 g, 315 mmol) under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. To the reaction solution was added water, chroloform was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with water, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, to the residue was added diethyl ether, and crystals (17.7 g) were collected by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3.16 g of crystals. A total of 20.9 g (84%) of 4-benzyloxy-N-(4-fluorobenzyl)-6-formyl-5-methoxynicotinamide 26 was obtained as a colorless crystal.
- NMR (CDCl3) δ: 4.02 (3H, s), 4.41 (2H, d, J=5.7 Hz), 5.30 (2H, s), 6.93-6.70 (2H, m), 7.09-7.15 (2H, m), 7.20-7.27 (2H, m), 7.31-7.40 (3H, m), 7.83 (1H, brs), 9.20 (1H, s), 10.26 (1H, s).
- 8) To a solution of the compound 26 (300 mg, 0.761 mmol) in methanol (1 ml) was added a solution of potassium hydroxide (111 mg, 1.99 mmol) in methanol (1 ml) under ice-cooling, and a solution of iodine (251 mg, 1.00 mmol) in methanol (4 ml) was further added, followed by stirring at the same temperature for 1 hour. To the reaction solution were added a 5% aqueous sodium hydrogen sulfite solution and water, and precipitated crystals were collected by filtration. Methyl 4-benzyloxy-5-(4-fluorobenzylcarbamoyl)-3-methoxypyridine-2-carboxylate 27 (275 mg, 85%) was obtained as a colorless crystal.
- NMR (CDCl3) δ: 3.99 (3H, s), 4.02 (3H, s), 7.40 (2H, d, J=5.7 Hz), 5.26 (2H, s), 6.92-6.99 (2H, m), 7.10-7.15 (2H, m), 7.19-7.23 (2H, m), 7.25-7.39 (3H, m), 7.81 (1H, brs), 9.09 (1H, s).
- 9) To a suspension of sodium iodide (5.51 g, 36.8 mmol) in acetonitrile (50 ml) was added chlorotrimethylsilane (4.66 ml, 36.8 mmol), and the mixture was stirred at room temperature for 10 minutes. After to this solution was added the compound 27 (2.60 g, 6.13 mmol) under ice-cooling, this was stirred at the same temperature for 20 minutes. To the reaction solution was added a 5% sodium hydrogen sulfite solution, followed by extraction with ethyl acetate. The extract was washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chlorite solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting solid matter was recrystallized to obtain (acetone-diisopropyl ether) and methyl 5-(4-fluorobenzylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate 28 (1.73 g, 84%) as a colorless crystal.
- NMR (CDCl3) δ: 4.04 (6H, s), 4.60 (2H, d, J=6.0 Hz), 6.96-7.03 (2H, m), 7.29-7.35 (2H, m), 8.63 (1H, s), 9.68 (1H, brs), 10.34 (1H, brs).
- 10) The compound 28 (900 mg, 2.12 mmol) was dissolved in methanol (8 ml), and a 2N aqueous sodium hydroxide solution (4 ml) was added. The solution was stirred at room temperature for 2 hours, 2 M hydrochloric acid (3 ml) was added, and crystals were collected by filtration. 4-Benzyloxy-5-(4-fluoro-benzylcarbamoyl)-3-methoxy-pyridine-2-carboxylic acid 29 (474 mg, 54%) was obtained as a colorless crystal.
- NMR (CDCl3) δ: 4.05 (3H, s), 4.40 (2H, d, J=5.6 Hz), 5.36 (2H, s), 6.94-7.01 (2H, m), 7.08-7.12 (2H, m), 7.21-7.24 (2H, m), 7.29-7.41 (3H, m), 7.87 (1H, brs), 9.03 (1H, s).
- 11) From the compound 29 (641 mg, 2 mmol), a crude compound 30 (932 mg) was obtained according to the method of the step 21. To this dioxane (6 ml) solution was added 2N hydrochloric acid (3 ml) at room temperature, thereafter, this was warmed to 70° C. for 30 minutes, and cooled to room temperature, and sodium hydrogen carbonate was added. Precipitated crystals were washed with water, and dried to obtain a compound 31 (513 mg, 61%).
- 1H-NMR (DMSO-d6) δ: 3.58 (1H, brs), 3.82 (3H, s), 3.83 (1H, brs), 4.51 (2H, d, J=6.0 Hz), 4.60 (1H, brs), 4.70 (1H, brs), 5.84 (1H, brs), 7.10-7.20 (4H, m), 7.30-7.42 (4H, m), 7.68 (1H, brs), 8.57 (1H, s), 10.41 (1H, brs).
- 12) To a solution of the compound 31 (513 mg, 1.1 mmol) in acetonitrile (5 ml) was added a Burgess reagent (520 mg, 2.2 mmol), and this was warmed at 70° C. for 1.5 hours. After cooled to room temperature, water was added to stop the reaction, and this was extracted with chloroform, washed with water, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and fractions eluted with chloroform-methanol were concentrated under reduced pressure to obtain a compound 32 (95 mg, 19%).
- 1H-NMR (CDCl3) δ: 4.08 (3H, s), 4.60 (2H, d, J=5.8 Hz), 4.95 (2H, s), 6.38 (1H, d, J=6.1 Hz), 6.62 (1H, d, J=6.1 Hz), 6.95-7.10 (4H, m), 7.27-7.40 (4H, m), 8.57 (1H, s), 10.54 (1H, brs).
- 13) To the compound 32 (95 mg, 0.2 mmol) was added pyridine hydrochloride (2 g), and this was warmed at 180° C. for 5 minutes. After cooled to room temperature, water was added, and precipitated crystals were washed with water, and dried to obtain Example A-30 (86 mg, 93%).
- melting point: 290-293° C. Elementary analysis for C23H17F2N3O4 Cal'd (%): C, 63.16; H, 3.92; F, 8.69; N, 9.61. Found (%): C, 62.97; H, 3.87; F, 8.36; N, 9.65.
- 1H-NMR (DMSO-d6) δ: 4.54 (2H, d, J=5.6 Hz), 4.95 (2H, s), 7.02 (1H, d, J=5.6 Hz), 7.10-7.22 (4H, m), 7.30-7.57 (5H, m), 8.78 (1H, s), 10.57 (1H, t, J=5.9 Hz), 11.9 (1H, brs).
- melting point: 281-283° C.
- NMR (DMSO-d6) δ: 1.97-2.00 (2H, m), 3.43-3.51 (2H, m), 3.83 (2H, t, J=6.8 Hz), 4.54 (2H, d, J=5.6 Hz), 6.97 (1H, d, J=6.0 Hz), 7.14-7.18 (2H, m), 7.30 (1H, t, J=5.2 Hz), 7.35-7.39 (2H, m), 7.50 (1H, d, J=6.0 Hz), 7.93 (1H, s), 8.27 (1H, s), 8.78 (1H, s), 10.58 (1H, t, J=5.6 Hz), 12.05 (1H, s).
- melting point: 191° C. NMR (DMSO-d6) δ: 3.76 (2H, t, J=5.0 Hz), 3.98 (2H, t, J=5.2 Hz), 4.52 (2H, s), 4.63 (2H, d, J=5.8 Hz), 6.49 (1H, d, J=6.4 Hz), 6.63 (1H, d, J=6.3 Hz), 6.98-7.03 (2H, m), 7.25-7.36 (7H, m), 8.53 (1H, s), 10.60-10.64 (1H, m), 11.92 (1H, brs).
- melting point: 287° C. NMR (DMSO-d6) δ: 3.63-3.68 (2H, m), 3.81-3.84 (2H, m), 4.54 (2H, d, J=5.8 Hz), 4.95 (1H, t, J=5.5 Hz), 6.90 (1H, d, J=5.9 Hz), 7.14-7.20 (2H, m), 7.35-7.38 (2H, m), 7.48 (1H, d, J=5.8 Hz), 8.81 (1H, s), 10.60 (1H, t, J=5.9 Hz), 12.12 (1H, brs).
- According to the same manner as that of Example B-1, the following Examples compounds B-2 to B-28 were synthesized.
- melting point: 218-220° C. NMR (DMSO-d6) δ: 2.19 (6H, s), 3.60 (2H, t, J=6.3 Hz), 3.79 (2H, s), 4.37 (2H, s), 4.52 (2H, d, J=4.5 Hz), 7.15 (2H, t, J=9.0 Hz), 7.32-7.37 (2H, m), 8.40 (1H, s), 10.45 (1H, t, J=6.3 Hz), 12.40 (1H, s).
- melting point: 205-207° C. NMR (DMSO-d6) δ: 2.43 (2H, s), 2.50 (4H, s), 3.54 (4H, s), 3.63 (2H, s), 3.81 (2H, s), 4.40 (2H, s), 4.52 (2H, d, J=6.0 Hz), 7.16 (2H, t, J=9.0 Hz), 7.33-7.37 (2H, m), 8.43 (1H, s), 10.45 (1H, t, J=5.7 Hz), 12.48 (1H, s).
- melting point: 232-235° C. Elementary analysis for C23H27FN4O4 Cal'd (%): C, 62.43; H, 6.15; F, 4.29; N, 12.66. Found (%): C, 61.78; H, 5.76; F, 4.04; N, 12.50. NMR (DMSO-d 6) δ: 1.37-1.46 (6H, m), 2.38-2.50 (6H, m), 3.61 (2H, t, J=6.6 Hz), 3.79 (2H, m), 4.37 (2H, m), 4.52 (2H, d, J=6 Hz), 7.12-7.18 (2H, m), 7.32-7.37 (2H, m), 8.41 (1H, s), 10.44 (1H, t, J=6 Hz), 12.50 (1H, brs).
- melting point: 278-280° C. Elementary analysis for C21H24FN3O4 Cal'd (%): C, 62.83; H, 6.03; F, 4.73; N, 10.47. Found (%); C, 62.45; H, 6.00; F, 4.50; N, 10.43. NMR (DMSO-d 6) δ: 0.86-0.93 (6H, m), 1.08-1.18 (1H, m), 1.37-1.44 (1H, m), 1.78-1.84 (1H, m), 3.30-3.38 (2H, m), 3.73-3.77 (2H, m), 4.37-4.44 (2H, m), 4.52 (2H, d, J=6 Hz), 7.12-7.18 (2H, m), 7.32-7.37 (2H, m), 8.41 (1H, s), 10.46 (1H, t, J=6 Hz), 12.54 (1H, brs).
- melting point: 210-212° C. Elementary analysis for C21H24FN3O5 Cal'd (%): C, 60.42; H, 5.80; F, 4.55; N, 10.07. Found (%); C, 59.77; H, 5.66; F, 4.42; N, 10.01. NMR (DMSO-d 6) δ: 1.08 (6H, d, J=6 Hz), 3.54-3.66 (5H, m), 3.79-3.83 (2H, m), 4.35-4.39 (2H, m), 4.52 (2H, d, J=6 Hz), 7.12-7.18 (2H, m), 7.32-7.37 (2H, m), 8.40 (1H, s), 10.44 (1H, t, J=6 Hz), 12.42 (1H, brs).
- melting point: 286-287° C. NMR (DMSO-d6) δ: 1.17 (6H, d, J=6.9 Hz), 3.64-3.70 (2H, m), 4.36-4.38 (2H, m), 4.52 (2H, d, J=6.0 Hz), 4.70-4.79 (1H, m), 7.13-7.19 (2H, m), 7.33-7.37 (2H, m), 8.43 (1H, s), 10.47 (1H, t, J=6.0 Hz), 12.60 (1H, brs).
- melting point: >300° C. NMR (DMSO-d6) δ: 1.03-1.81 (10H, m), 3.69-3.72 (2H, m), 4.29-4.36 m), 4.52 (2H, d, J=6.1 Hz), 7.13-7.19 (2H, m), 7.33-7.37 (2H, m), 8.43 (1H, s), 10.47 (1H, t, J=5.8 Hz), 12.59 (1H, brs).
- melting point: 271-272° C. NMR (DMSO-d6) δ: 3.71-3.75 (2H, m), 4.37-4.41 (2H, m), 4.52 (2H, d, J=6.0 Hz), 4.71 (2H, s), 7.13-7.23 (4H, m), 7.33-7.45 (4H, m), 8.41 (1H, s), 10.44 (1H, t, J=5.9 Hz), 12.36 (1H, brs).
- melting point: 185-188° C. NMR (CDCl3) δ: 1.12-1.18 (3H, m), 2.26 (3H, s), 3.30-4.40 (10H, m), 4.60 (2H, d, J=5.4 Hz), 6.57 (2H, brs), 6.97-7.02 (2H, m), 7.04-7.16 (1H, m), 7.26-7.34 (3H, m), 8.23 (1H, s), 10.43 (1H, brs), 12.29. (1H, brs).
- melting point: 207-209° C. NMR (CDCl3) δ: 1.92-1.96 (2H, m), 2.05-2.10 (2H, m), 2.40 (2H, t, J=8.1 Hz), 3.35 (2H, t, J=6.6 Hz), 3.43 (2H, t, J=6.9 Hz), 3.55 (2H, t, J=6.6 Hz), 3.82-3.86 (2H, m), 4.26-4.30 (2H, m), 4.60 (2H, d, J=6.0 Hz), 6.96-7.02 (2H, m), 7.30-7.35 (2H, m), 8.32 (1H, s), 10.43-10.47 (1H, m), 12.26 (1H, brs).
- melting point: 250-251° C. NMR (CDCl3) δ: 1.50-1.59 (2H, m), 1.89-1.98 (2H, m), 2.03-2.14 (1H, m), 3.25 (1H, dd, J=8.4 Hz, 13.8 Hz), 4.25-3.73 (7H, m), 4.59 (2H, d, J=5.1 Hz), 7.00 (2H, d, J=8.4 Hz), 7.32 (2H, dd, J=5.4 Hz, 8.4 Hz), 8.31 (1H, s), 10.47 (1H, t, 5.1 Hz), 12.29 (1H, brs).
- melting point: 258-260° C. NMR (CDCl3) δ: 1.28 (31-1, t, J=7.2 Hz), 1.54-1.92 (4H, m), 4.14-4.43 (6H, m), 4.60 (2H, d, J=5.4 Hz), 6.97-7.05 (2H, m), 7.29-7.34 (2H, m), 8.32 (1H, s), 10.43 (1H, t, J=5.4 Hz), 12.27 (1H, brs).
- melting point: 249-251° C. NMR (CDCl3) δ: 1.93 (3H, s), 3.48-3.52 (2H, m), 3.67-3.71 (2H, m), 3.82-3.86 (2H, m), 4.28-4.32 (2H, m), 4.59 (2H, s), 6.99-7.04 (2H, m), 7.30-7.33 (2H, m), 8.30 (1H, s).
- melting point: 239-241° C. NMR (CDCl3) δ: 1.10 (6H, d, J=6.0 Hz), 1.88-1.96 (2H, m), 3.48-3.57 (3H, m), 3.69 (2H, t, J=6.6 Hz), 3.77-3.81 (2H, m), 4.21-4.24 (2H, m), 4.60 (2H, d, J=5.7 Hz), 6.96-7.02 (2H, m), 7.30-7.35 (2H, m), 8.30 (1H, s), 10.45-10.49 (1H, m), 12.42 (1H, brs).
- melting point: 260-262° C. NMR (CDCl3) δ: 2.97 (6H, s), 3.59-3.63 (2H, m), 4.09-4.13 (2H, m), 4.59 (2H, d, J=5.7 Hz), 4.67 (2H, s), 6.70-6.78 (2H, m), 6.96-7.02 (2H, m), 7.19 (2H, d, J=8.7 Hz), 7.29-7.34 (2H, m), 8.27 (1H, s), 10.46 (1H, t, J=5.7 Hz), 12.45 (1H, brs).
- melting point: 266-270° C. NMR (DMSO-d6) δ: 3.75-3.81 (2H, m), 4.41-4.45 (2H, m), 4.52 (2H, d, J=6.0 Hz), 4.80 (2H, s), 7.13-7.19 (2H, m), 7.33-7.37 (4H, m), 7.56 (2H, d, J=8.1 Hz), 7.81 (2H, d, J=8.1 Hz), 8.44 (1H, s), 10.44 (1H, t, J=6.0 Hz), 12.28 (1H, brs).
- melting point: 238-240° C. NMR (CDCl3) δ: 1.93 (2H, quin, J=5.7 Hz), 3.31 (3H, s), 3.47 (2H, t, J=5.7 Hz), 3.68 (2H, t, J=6.9 Hz), 3.75-3.79 (2H, m), 4.21-4.24 (2H, m), 4.60 (2H, d, J=5.7 Hz), 6.97-7.02 (2H, m), 7.30-7.35 (2H, m), 8.31 (1H, s), 10.46 (1H, t, J=7.8 Hz), 12.38 (1H, brs).
- melting point: 196-197° C. NMR (CDCl3) δ: 0.91 (3H, t, J=7.5 Hz), 1.52-1.63 (2H, m), 3.41 (2H, t, J=7.5 Hz), 3.67 (2H, t, J=4.2 Hz), 3.76 (2H, t, J=4.2 Hz), 3.88-3.92 (2H, m), 4.19-4.23 (2H, m), 4.60 (2H, d, J=6.0 Hz), 6.97-7.03 (2H, m), 7.30-7.35 (2H, m), 8.32 (1H, s), 10.47 (1H, t, J=5.7 Hz), 12.29 (1H, brs).
- melting point: 200-201° C. NMR (CDCl3) δ: 3.96-4.02 (4H, m), 4.20-4.28 (4H, m), 4.60 (2H, d, J=6.0 Hz), 6.86-6.89 (2H, m), 6.96-7.02 (3H, m), 7.28-7.34 (4H, m), 8.31 (1H, s), 10.43 (1H, brs), 12.15 (1H, brs).
- melting point: 245° C. NMR (CDCl3) δ: 3.00 (3H, s), 3.08 (3H, s), 3.83-3.87 (2H, m), 4.37-4.41 (2H, m), 4.42 (2H, s), 4.60 (2H, s), 6.98-7.04 (2H, m), 7.30-7.34 (2H, m), 8.33 (1H, s).
- melting point: 201-202° C. NMR (CDCl3) δ: 1.19 (3H, t, J=7.2 Hz), 3.51 (2H, q, J=7.2 Hz), 3.67 (2H, t, J=5.4 Hz), 3.76 (2H, t, J=5.4 Hz), 3.88-3.92 (2H, m), 4.20-4.23 (2H, m), 4.60 (2H, d, J=5.7 Hz), 6.96-7.02 (2H, m), 7.30-7.34 (2H, m), 8.31 (1H, s), 10.46 (1H, brs), 12.28 (1H, brs).
- melting point: 241° C. NMR (CDCl3) δ: 3.00 (2H, t, J=6.3 Hz), 3.41 (2H, brs), 3.82 (2H, t, J=6.6 Hz), 3.97 (2H, brs), 4.59 (2H, d, J=5.1 Hz), 6.96-7.02 (2H, m), 7.22-7.36 (7H, m), 8.24 (1H, brs), 10.45 (1H, brs), 12.31 (1H, brs).
- melting point: 212-214° C. NMR (CDCl3) δ: 1.03 (6H, s), 2.25 (2H, brs), 2.37 (6H, s), 3.55 (2H, s), 3.86-3.90 (2H, m), 4.20-4.24 (2H, m), 4.60 (2H, d, J=6.0 Hz), 6.96-7.02 (2H, m), 7.29-7.34 (2H, m), 8.30 (1H, s), 10.46 (1H, t, J=4.5 Hz), 12.43 (1H, brs).
- melting point: 181-185° C. NMR (CDCl3) δ: 2.08 (2H, brs), 2.73 (6H, brs), 3.67 (2H, t, J=6.6 Hz), 3.80-3.84 (6H, m), 4.22-4.26 (2H, m), 4.61 (2H, d, J=6.0 Hz), 6.98-7.04 (2H, m), 7.33-7.38 (2H, m), 8.28 (1H, s), 10.41 (1H, t, J=6.0 Hz), 12.19 (1H, brs).
- Diethyl {2-[7-(4-fluorobenzylcarbamoyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydropyrid[1,2-a]pyrazin-2-yl]ethyl}phosphonate
- NMR (DMSO-d6) δ: 1.24 (6H, d, J=7.0 Hz), 2.1-2.23 (2H, m), 3.64-3.72 (2H, m), 3.79-3.82 (2H, m), 3.99-4.06 (4H, m), 4.37-4.41 (2H, m), 7.52 (2H, d, J=5.7 Hz), 7.12-7.18 (2H, m), 7.33-7.38 (2H, m), 8.42 (1H, s), 10.43 (1H, t, J=5.7 Hz), 12.34 (1H, s).
- melting point: 216° C. NMR (DMSO-d6) δ: 1.40 (9H, s), 2.18 (2H, s), 2.92 (2H, s), 3.40 (2H, s), 3.90 (2H, s), 4.39 (2H, s), 4.59 (2H, s), 7.01 (2H, t, J=11.6 Hz), 7.31 (2H, m), 8.34 (1H, s), 10.48 (1H, s).
- melting point: 213° C. NMR (DMSO-d6) δ: 3.57-3.63 (4H, m), 3.80-3.84 (2H, m), 4.36-4.41 (2H, m), 4.52 (2H, d, J=5.8 Hz), 4.89 (1H, t, J=5.5 Hz), 7.13-7.20 (2H, m), 7.32-7.38 (2H, m), 8.42 (1H, s), 10.46 (1H, t, J=5.8 Hz), 12.52 (1H, brs).
-
- 1) To a solution of a compound 13 (3.00 g, 7.57 mmol) in dichloromethane (30 ml) were added oxalyl chloride (0.79 ml, 9.08 mmol) and dimethylformamide (catalytic amount) at room temperature, and the mixture was stirred for 1.5 hours as it was. A solution of N′-(4-fluoro-benzyl)-hydrazinecarboxylic acid tert-butyl ester (2.00 g, 8.33 mmol) and triethylamine (1.16 ml, 8.33 mmol) in dichloromethane (30 ml) was added at 0° C., and a temperature was raised to room temperature, followed by stirring for 1.5 hours. An aqueous ammonium chloride solution was added, this was extracted with chloroform, and the organic layer was washed with water. This was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate) to obtain a compound 59 (133 mg) at a yiled of 85%.
- NMR (CDCl3) δ: 4.20 (1H, brs), 4.61 (2H, d, J=6.0 Hz), 5.00 (2H, brs), 5.60 (1H, brs), 6.82 (1H, s), 6.91 (2H, t, J=8.4 Hz), 7.01 (2H, t, J=8.7 Hz), 7.10 (2H, dd, J=5.4 Hz, 8.7 Hz), 7.22-7.36 (7H, m), 8.52 (1H, d, J=6.6 Hz), 10.24 (1H, s), 10.47 (1H, t, J=5.7 Hz).
- 2) N′-(4-fluoro-benzyl)-hydrazinecarboxylic acid tert-butyl ester was synthesized by the method described in the literature (J. Med. Chem. 1996, 39, 3203-3216). To the compound 59 (597 mg, 0.996 mmol) was added 4N hydrochloric acid (ethyl acetate solution) at 0° C., and a temperature was raised to room temperature, followed by stirring for 1 hour. An aqueous sodium bicarbonate solution was added to neutralize it, followed by extraction with ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate, and the solvent was distilled off to obtain a compound 60 (500 mg) at a yield of 100%.
- NMR (CDCl3) δ: 4.53 (4H, s), 5.20 (2H, s), 6.81-7.35 (13H, m), 8.48 (1H, s), 10.60 (1H, s), 11.80 (1H, s).
- 3) To a solution of a compound 61 (180 mg, 0.347 mmol) in dichloromethane (1.8 ml) were added acetaldehyde (26 μl, 0.417 mmol) and acetic acid (40 μl, 0.694 mmol) at 0° C., and a temperature was raised to room temperature, followed by stirring for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain a compound 61 (165 mg) at a yield of 87%.
- NMR (CDCl3) δ: 0.83 (3H, s), 3.46 (1H, s), 4.31 (1H, s), 4.58 (2H, d, J=5.4 Hz), 4.89 (1H, s), 5.11 (2H, s), 6.07 (1H, s), 6.96-7.67 (13H, m), 8.00 (1H, s), 10.22 (1H, s).
- 4) According to the method of synthesizing Example B-1, Example compound K-1 was obtained.
- melting point: 247-249° C. NMR (CDCl3) δ: 1.24 (3H, m), 4.54 (3H, m), 4.80 (2H, m), 6.22 (1H, s), 7.06 (4H, m), 7.37 (4H, m), 8.03 (1H, s), 10.09 (1H, s), 11.57 (1H, s).
- According to the same manner as that of Example K-1, the following Example compounds K-2 to K-6 were synthesized.
- melting point: >300° C. NMR (DMSO-d6) δ: 4.50 (2H, d, J=5.7 Hz), 4.68 (2H, s), 5.16 (2H, d, J=7.2 Hz), 6.83 (1H, t, J=7.8 Hz), 7.14 (4H, m), 7.36 (4H, m), 8.38 (1H, s), 10.39 (1H, t, J=5.7 Hz), 11.20 (1H, s).
- melting point: 206° C. NMR (DMSO-d6) δ: 0.64 (3H, d, J=6.0 Hz), 0.80 (3H, d, J=6.0 Hz), 1.23 (2H, s), 1.55 (1H, t, J=9.3 Hz), 4.50 (3H, m), 4.89 (1H, d, 14.1 Hz), 5.50 (1H, s), 7.06 (1H, s), 7.33-7.44 (4H, m), 8.43 (1H, s), 10.40 (1H, t, J=5.7 Hz), 11.44 (1H, s).
- melting point: 207° C. NMR (DMSO-d6) δ: 0.64 (3H, d, J=6.6 Hz), 0.69 (3H, d, J=6.6 Hz), 1.89 (1H, m), 4.51 (2H, d, J=6.3 Hz), 4.60 (1H, d, J=14.4 Hz), 4.79 (1H, d, J=14.4 Hz), 5.10 (1H, d, J=8.1 Hz), 7.01 (1H, s), 7.13-7.22 (4H, m), 7.33-7.44 (4H, m), 8.40 (1H, s), 10.42 (1H, t, J=6.0 Hz), 11.44 (1H, s).
- melting point: 235° C. NMR (DMSO-d6) δ: 0.30-0.57 (4H, m), 1.09 (1H, m), 4.51 (2H, d, J=6.0 Hz), 4.60 (1H, d, J=14.4 Hz), 4.78 (1H, s), 4.83 (1H, d, J=14.4 Hz), 7.10-7.22 (4H, m), 7.33-7.46 (4H, m), 8.52 (1H, s), 10.38 (1H, t, J=6.0 Hz), 11.39 (1H, s).
- melting point: 270° C. NMR (DMSO-d6) δ: 0.91 (9H, s), 4.45 (1H, d, J=14.4 Hz), 4.52 (2H, d, J=6.0 Hz), 5.03 (1H, d, J=14.4 Hz), 5.27 (1H, d, J=3.3 Hz), 7.05 (1H, d, J=3.3 Hz), 7.13-7.24 (4H, m), 7.33-7.46 (4H, m), 8.41 (1H, s), 10.40 (1H, t, J=5.7 Hz), 11.51 (1H, s).
- The present invention further includes the following compounds.
-
[Chemical formula 77] (I-9) No (R)m Rb R4 1 4-F —CH3 CH3 2 4-F —CH(CH3)2 CH3 3 4-F —CH2CH2OCH3 CH3 4 4-F —N(CH3)CO CH3 CH3 5 4-F —N(CH3)2 CH3 6 2,4-F —CH3 CH3 7 2,4-F —CH(CH3)2 CH3 8 2,4-F —CH2CH2OCH3 CH3 9 2,4-F —N(CH3)CO CH3 CH3 10 2,4-F —N(CH3)2 CH3 11 2-F, —CH3 CH3 3-Cl 12 2-F, —CH(CH3)2 CH3 3-Cl 13 2-F, —CH2CH2OCH3 CH3 3-Cl 14 2-F, —N(CH3)CO CH3 3-Cl CH3 15 2-F, —N(CH3)2 CH3 3-Cl 16 4-F —CH3 CH2CH2OCH3 17 4-F —CH(CH3)2 CH2CH2OCH3 18 4-F —CH2CH2OCH3 CH2CH2OCH3 19 4-F —N(CH3)CO CH2CH2OCH3 CH3 20 4-F —N(CH3)2 CH2CH2OCH3 21 2,4-F —CH3 CH2CH2OCH3 22 2,4-F —CH(CH3)2 CH2CH2OCH3 23 2,4-F —CH2CH2OCH3 CH2CH2OCH3 24 2,4-F —N(CH3)CO CH2CH2OCH3 CH3 25 2,4-F —N(CH3)2 CH2CH2OCH3 26 2-F, —CH3 CH2CH2OCH3 3-Cl 27 2-F, —CH(CH3)2 CH2CH2OCH3 3-Cl 28 2-F, —CH2CH2OCH3 CH2CH2OCH3 3-Cl 29 2-F, —N(CH3)CO CH2CH2OCH3 3-Cl CH3 30 2-F, —N(CH3)2 CH2CH2OCH3 3-Cl 31 4-F —CH3 —CH2(4-F—Ph) 32 4-F —CH(CH3)2 —CH2(4-F—Ph) 33 4-F —CH2CH2OCH3 —CH2(4-F—Ph) 34 4-F —N(CH3)CO —CH2(4-F—Ph) CH3 35 4-F —N(CH3)2 —CH2(4-F—Ph) 36 2,4-F —CH3 —CH2(4-F—Ph) 37 2,4-F —CH(CH3)2 —CH2(4-F—Ph) 38 2,4-F —CH2CH2OCH3 —CH2(4-F—Ph) 39 2,4-F —N(CH3)CO —CH2(4-F—Ph) CH3 40 2,4-F —N(CH3)2 —CH2(4-F—Ph) 41 2-F, —CH3 —CH2(4-F—Ph) 3-Cl 42 2-F, —CH(CH3)2 —CH2(4 -F—Ph) 3-Cl 43 2-F, —CH2CH2OCH3 —CH2(4-F—Ph) 3-Cl 44 2-F, —N(CH3)CO —CH2(4-F—Ph) 3-Cl CH3 45 2-F, —N(CH3)2 —CH2(4-F—Ph) 3-Cl 46 4-F H CH3 47 2,4-F H CH3 48 2-F, 3-Cl H CH3 49 4-F H CH2CH2OCH3 50 2,4-F H CH2CH2OCH3 51 2-F, 3-Cl H CH2CH2OCH3 52 4-F H —CH2(4-F—Ph) -
[Chemical formula 78] (I-9) No (R)m Ra R4 1 4-F —CH3 CH3 2 4-F —CH(CH3)2 CH3 3 4-F —CH2CH2OCH3 CH3 4 4-F —N(CH3)CO CH3 CH3 5 4-F —N(CH3)2 CH3 6 2,4-F —CH3 CH3 7 2,4-F —CH(CH3)2 CH3 8 2,4-F —CH2CH2OCH3 CH3 9 2,4-F —N(CH3)CO CH3 CH3 10 2,4-F —N(CH3)2 CH3 11 2-F, —CH3 CH3 3-Cl 12 2-F, —CH(CH3)2 CH3 3-Cl 13 2-F, —CH2CH2OCH3 CH3 3-Cl 14 2-F, —N(CH3)CO CH3 CH3 3-Cl 15 2-F, —N(CH3)2 CH3 3-Cl 16 4-F —CH3 CH2CH2OCH3 17 4-F —CH(CH3)2 CH2CH2OCH3 18 4-F —CH2CH2OCH3 CH2CH2OCH3 19 4-F —N(CH3)CO CH3 CH2CH2OCH3 20 4-F —N(CH3)2 CH2CH2OCH3 21 2,4-F —CH3 CH2CH2OCH3 22 2,4-F —CH(CH3)2 CH2CH2OCH3 23 2,4-F —CH2CH2OCH3 CH2CH2OCH3 24 2,4-F —N(CH3)CO CH3 CH2CH2OCH3 25 2,4-F —N(CH3)2 CH2CH2OCH3 26 2-F, —CH3 CH2CH2OCH3 3-Cl 27 2-F, —CH(CH3)2 CH2CH2OCH3 3-Cl 28 2-F, —CH2CH2OCH3 CH2CH2OCH3 3-Cl 29 2-F, —N(CH3)CO CH2CH2OCH3 3-Cl CH3 30 2-F, —N(CH3)2 CH2CH2OCH3 3-Cl 31 4-F —CH3 —CH2(4-F—Ph) 32 4-F —CH(CH3)2 —CH2(4-F—Ph) 33 4-F —CH2CH2OCH3 —CH2(4-F—Ph) 34 4-F —N(CH3)CO —CH2(4-F—Ph) CH3 35 4-F —N(CH3)2 —CH2(4-F—Ph) 36 2,4-F —CH3 —CH2(4-F—Ph) 37 2,4-F —CH(CH3)2 —CH2(4-F—Ph) 38 2,4-F —CH2CH2OCH3 —CH2(4-F—Ph) 39 2,4-F —N(CH3)CO —CH2(4-F—Ph) CH3 40 2,4-F —N(CH3)2 —CH2(4-F—Ph) 41 2-F, —CH3 —CH2(4-F—Ph) 3-Cl 42 2-F, —CH(CH3)2 —CH2(4-F—Ph) 3-Cl 43 2-F, —CH2CH2OCH3 —CH2(4-F—Ph) 3-Cl 44 2-F, —N(CH3)CO —CH2(4-F—Ph) 3-Cl CH3 45 2-F, —N(CH3)2 —CH2(4-F—Ph) 3-Cl -
[Chemical formula 79] (I-9) No (R)m Rb R4 1 4-F —CH3 CH3 2 4-F —CH(CH3)2 CH3 3 4-F —CH2CH2OCH3 CH3 4 4-F —N(CH3)CO CH3 CH3 5 4-F —N(CH3)2 CH3 6 2,4-F —CH3 CH3 7 2,4-F —CH(CH3)2 CH3 8 2,4-F —CH2CH2OCH3 CH3 9 2,4-F —N(CH3)CO CH3 CH3 10 2,4-F —N(CH3)2 CH3 11 2-F, —CH3 CH3 3-Cl 12 2-F, —CH(CH3)2 CH3 3-Cl 13 2-F, —CH2CH2OCH3 CH3 3-Cl 14 2-F, —N(CH3)CO CH3 CH3 3-Cl 15 2-F, —N(CH3)2 CH3 3-Cl 16 4-F —CH3 CH2CH2OCH3 17 4-F —CH(CH3)2 CH2CH2OCH3 18 4-F —CH2CH2OCH3 CH2CH2OCH3 19 4-F —N(CH3)CO CH3 CH2CH2OCH3 20 4-F —N(CH3)2 CH2CH2OCH3 21 2,4-F —CH3 CH2CH2OCH3 22 2,4-F —CH(CH3)2 CH2CH2OCH3 23 2,4-F —CH2CH2OCH3 CH2CH2OCH3 24 2,4-F —N(CH3)CO CH3 CH2CH2OCH3 25 2,4-F —N(CH3)2 CH2CH2OCH3 26 2-F, —CH3 CH2CH2OCH3 3-Cl 27 2-F, —CH(CH3)2 CH2CH2OCH3 3-Cl 28 2-F, —CH2CH2OCH3 CH2CH2OCH3 3-Cl 29 2-F, —N(CH3)CO CH2CH2OCH3 3-Cl CH3 30 2-F, —N(CH3)2 CH2CH2OCH3 3-Cl 31 4-F —CH3 —CH2(4-F—Ph) 32 4-F —CH(CH3)2 —CH2(4-F—Ph) 33 4-F —CH2CH2OCH3 —CH2(4-F—Ph) 34 4-F —N(CH3)CO —CH2(4-F—Ph) CH3 35 4-F —N(CH3)2 —CH2(4-F—Ph) 36 2,4-F —CH3 —CH2(4-F—Ph) 37 2,4-F —CH(CH3)2 —CH2(4-F—Ph) 38 2,4-F —CH2CH2OCH3 —CH2(4-F—Ph) 39 2,4-F —N(CH3)CO —CH2(4-F—Ph) CH3 40 2,4-F —N(CH3)2 —CH2(4-F—Ph) 41 2-F, —CH3 —CH2(4-F—Ph) 3-Cl 42 2-F, —CH(CH3)2 —CH2(4-F—Ph) 3-Cl 43 2-F, —CH2CH2OCH3 —CH2(4-F—Ph) 3-Cl 44 2-F, —N(CH3)CO —CH2(4-F—Ph) 3-Cl CH3 45 2-F, —N(CH3)2 —CH2(4-F—Ph) 3-Cl 46 4-F H CH3 47 2,4-F H CH3 48 2-F, 3-Cl H CH3 49 4-F H CH2CH2OCH3 50 2,4-F H CH2CH2OCH3 51 2-F, 3-Cl H CH2CH2OCH3 52 4-F H —CH2(4-F—Ph) -
[Chemical formula 80] (I-9) No (R)m Ra R4 1 4-F —CH3 CH3 2 4-F —CH(CH3)2 CH3 3 4-F —CH2CH2OCH3 CH3 4 4-F —N(CH3)CO CH3 CH3 5 4-F —N(CH3)2 CH3 6 2,4-F —CH3 CH3 7 2,4-F —CH(CH3)2 CH3 8 2,4-F —CH2CH2OCH3 CH3 9 2,4-F —N(CH3)CO CH3 CH3 10 2,4-F —N(CH3)2 CH3 11 2-F, —CH3 CH3 3-Cl 12 2-F, —CH(CH3)2 CH3 3-Cl 13 2-F, —CH2CH2OCH3 CH3 3-Cl 14 2-F, —N(CH3)CO CH3 CH3 3-Cl 15 2-F, —N(CH3)2 CH3 3-Cl 16 4-F —CH3 CH2CH2OCH3 17 4-F —CH(CH3)2 CH2CH2OCH3 18 4-F —CH2CH2OCH3 CH2CH2OCH3 19 4-F —N(CH3)CO CH3 CH2CH2OCH3 20 4-F —N(CH3)2 CH2CH2OCH3 21 2,4-F —CH3 CH2CH2OCH3 22 2,4-F —CH(CH3)2 CH2CH2OCH3 23 2,4-F —CH2CH2OCH3 CH2CH2OCH3 24 2,4-F —N(CH3)CO CH3 CH2CH2OCH3 25 2,4-F —N(CH3)2 CH2CH2OCH3 26 2-F, —CH3 CH2CH2OCH3 3-Cl 27 2-F, —CH(CH3)2 CH2CH2OCH3 3-Cl 28 2-F, —CH2CH2OCH3 CH2CH2OCH3 3-Cl 29 2-F, —N(CH3)CO CH2CH2OCH3 3-Cl CH3 30 2-F, —N(CH3)2 CH2CH2OCH3 3-Cl 31 4-F —CH3 —CH2(4-F—Ph) 32 4-F —CH(CH3)2 —CH2(4-F—Ph) 33 4-F —CH2CH2OCH3 —CH2(4-F—Ph) 34 4-F —N(CH3)CO —CH2(4-F—Ph) CH3 35 4-F —N(CH3)2 —CH2(4-F—Ph) 36 2,4-F —CH3 —CH2(4-F—Ph) 37 2,4-F —CH(CH3)2 —CH2(4-F—Ph) 38 2,4-F —CH2CH2OCH3 —CH2(4-F—Ph) 39 2,4-F —N(CH3)CO —CH2(4-F—Ph) CH3 40 2,4-F —N(CH3)2 —CH2(4-F—Ph) 41 2-F, —CH3 —CH2(4-F—Ph) 3-Cl 42 2-F, —CH(CH3)2 —CH2(4-F—Ph) 3-Cl 43 2-F, —CH2CH2OCH3 —CH2(4-F—Ph) 3-Cl 44 2-F, —N(CH3)CO —CH2(4-F—Ph) 3-Cl CH3 45 2-F, —N(CH3)2 —CH2(4-F—Ph) 3-Cl -
[Chemical formula 81] (I-9) No (R)m Rb R4 1 4-F —CH3 CH3 2 4-F —CH(CH3)2 CH3 3 4-F —CH2CH2OCH3 CH3 4 4-F —N(CH3)CO CH3 CH3 5 4-F —N(CH3)2 CH3 6 2,4-F —CH3 CH3 7 2,4-F —CH(CH3)2 CH3 8 2,4-F —CH2CH2OCH3 CH3 9 2,4-F —N(CH3)CO CH3 CH3 10 2,4-F —N(CH3)2 CH3 11 2-F, —CH3 CH3 3-Cl 12 2-F, —CH(CH3)2 CH3 3-Cl 13 2-F, —CH2CH2OCH3 CH3 3-Cl 14 2-F, —N(CH3)CO CH3 CH3 3-Cl 15 2-F, —N(CH3)2 CH3 3-Cl 16 4-F —CH3 CH2CH2OCH3 17 4-F —CH(CH3)2 CH2CH2OCH3 18 4-F —CH2CH2OCH3 CH2CH2OCH3 19 4-F —N(CH3)CO CH3 CH2CH2OCH3 20 4-F —N(CH3)2 CH2CH2OCH3 21 2,4-F —CH3 CH2CH2OCH3 22 2,4-F —CH(CH3)2 CH2CH2OCH3 23 2,4-F —CH2CH2OCH3 CH2CH2OCH3 24 2,4-F —N(CH3)CO CH3 CH2CH2OCH3 25 2,4-F —N(CH3)2 CH2CH2OCH3 26 2-F, —CH3 CH2CH2OCH3 3-Cl 27 2-F, —CH(CH3)2 CH2CH2OCH3 3-Cl 28 2-F, —CH2CH2OCH3 CH2CH2OCH3 3-Cl 29 2-F, —N(CH3)CO CH2CH2OCH3 3-Cl CH3 30 2-F, —N(CH3)2 CH2CH2OCH3 3-Cl 31 4-F —CH3 —CH2(4-F—Ph) 32 4-F —CH(CH3)2 —CH2(4-F—Ph) 33 4-F —CH2CH2OCH3 —CH2(4-F—Ph) 34 4-F —N(CH3)CO —CH2(4-F—Ph) CH3 35 4-F —N(CH3)2 —CH2(4-F—Ph) 36 2,4-F —CH3 —CH2(4-F—Ph) 37 2,4-F —CH(CH3)2 —CH2(4-F—Ph) 38 2,4-F —CH2CH2OCH3 —CH2(4-F—Ph) 39 2,4-F —N(CH3)CO —CH2(4-F—Ph) CH3 40 2,4-F —N(CH3)2 —CH2(4-F—Ph) 41 2-F, —CH3 —CH2(4-F—Ph) 3-Cl 42 2-F, —CH(CH3)2 —CH2(4-F—Ph) 3-Cl 43 2-F, —CH2CH2OCH3 —CH2(4-F—Ph) 3-Cl 44 2-F, —N(CH3)CO —CH2(4-F—Ph) 3-Cl CH3 45 2-F, —N(CH3)2 —CH2(4-F—Ph) 3-Cl 46 4-F H CH3 47 2,4-F H CH3 48 2-F, 3-Cl H CH3 49 4-F H CH2CH2OCH3 50 2,4-F H CH2CH2OCH3 51 2-F, 3-Cl H CH2CH2OCH3 52 4-F H —CH2(4-F—Ph) -
[Chemical formula 82] (I-9) No (R)m Ra R4 1 4-F —CH3 CH3 2 4-F —CH(CH3)2 CH3 3 4-F —CH2CH2OCH3 CH3 4 4-F —N(CH3)CO CH3 CH3 5 4-F —N(CH3)2 CH3 6 2,4-F —CH3 CH3 7 2,4-F —CH(CH3)2 CH3 8 2,4-F —CH2CH2OCH3 CH3 9 2,4-F —N(CH3)CO CH3 CH3 10 2,4-F —N(CH3)2 CH3 11 2-F, —CH3 CH3 3-Cl 12 2-F, —CH(CH3)2 CH3 3-Cl 13 2-F, —CH2CH2OCH3 CH3 3-Cl 14 2-F, —N(CH3)CO CH3 CH3 3-Cl 15 2-F, —N(CH3)2 CH3 3-Cl 16 4-F —CH3 CH2CH2OCH3 17 4-F —CH(CH3)2 CH2CH2OCH3 18 4-F —CH2CH2OCH3 CH2CH2OCH3 19 4-F —N(CH3)CO CH3 CH2CH2OCH3 20 4-F —N(CH3)2 CH2CH2OCH3 21 2,4-F —CH3 CH2CH2OCH3 22 2,4-F —CH(CH3)2 CH2CH2OCH3 23 2,4-F —CH2CH2OCH3 CH2CH2OCH3 24 2,4-F —N(CH3)CO CH3 CH2CH2OCH3 25 2,4-F —N(CH3)2 CH2CH2OCH3 26 2-F, —CH3 CH2CH2OCH3 3-Cl 27 2-F, —CH(CH3)2 CH2CH2OCH3 3-Cl 28 2-F, —CH2CH2OCH3 CH2CH2OCH3 3-Cl 29 2-F, —N(CH3)CO CH2CH2OCH3 3-Cl CH3 30 2-F, —N(CH3)2 CH2CH2OCH3 3-Cl 31 4-F —CH3 —CH2(4-F—Ph) 32 4-F —CH(CH3)2 —CH2(4-F—Ph) 33 4-F —CH2CH2OCH3 —CH2(4-F—Ph) 34 4-F —N(CH3)CO —CH2(4-F—Ph) CH3 35 4-F —N(CH3)2 —CH2(4-F—Ph) 36 2,4-F —CH3 —CH2(4-F—Ph) 37 2,4-F —CH(CH3)2 —CH2(4-F—Ph) 38 2,4-F —CH2CH2OCH3 —CH2(4-F—Ph) 39 2,4-F —N(CH3)CO —CH2(4-F—Ph) CH3 40 2,4-F —N(CH3)2 —CH2(4-F—Ph) 41 2-F, —CH3 —CH2(4-F—Ph) 3-Cl 42 2-F, —CH(CH3)2 —CH2(4-F—Ph) 3-Cl 43 2-F, —CH2CH2OCH3 —CH2(4-F—Ph) 3-Cl 44 2-F, —N(CH3)CO —CH2(4-F—Ph) 3-Cl CH3 45 2-F, —N(CH3)2 —CH2(4-F—Ph) 3-Cl -
[Chemical formula 83] (I-9) No (R)m Rb R4 1 4-F —CH3 CH3 2 4-F —CH(CH3)2 CH3 3 4-F —CH2CH2OCH3 CH3 4 4-F —N(CH3)CO CH3 CH3 5 4-F —N(CH3)2 CH3 6 2,4-F —CH3 CH3 7 2,4-F —CH(CH3)2 CH3 8 2,4-F —CH2CH2OCH3 CH3 9 2,4-F —N(CH3)CO CH3 CH3 10 2,4-F —N(CH3)2 CH3 11 2-F, —CH3 CH3 3-Cl 12 2-F, —CH(CH3)2 CH3 3-Cl 13 2-F, —CH2CH2OCH3 CH3 3-Cl 14 2-F, —N(CH3)CO CH3 CH3 3-Cl 15 2-F, —N(CH3)2 CH3 3-Cl 16 4-F —CH3 CH2CH2OCH3 17 4-F —CH(CH3)2 CH2CH2OCH3 18 4-F —CH2CH2OCH3 CH2CH2OCH3 19 4-F —N(CH3)CO CH3 CH2CH2OCH3 20 4-F —N(CH3)2 CH2CH2OCH3 21 2,4-F —CH3 CH2CH2OCH3 22 2,4-F —CH(CH3)2 CH2CH2OCH3 23 2,4-F —CH2CH2OCH3 CH2CH2OCH3 24 2,4-F —N(CH3)CO CH3 CH2CH2OCH3 25 2,4-F —N(CH3)2 CH2CH2OCH3 26 2-F, —CH3 CH2CH2OCH3 3-Cl 27 2-F, —CH(CH3)2 CH2CH2OCH3 3-Cl 28 2-F, —CH2CH2OCH3 CH2CH2OCH3 3-Cl 29 2-F, —N(CH3)CO CH2CH2OCH3 3-Cl CH3 30 2-F, —N(CH3)2 CH2CH2OCH3 3-Cl 31 4-F —CH3 —CH2(4-F—Ph) 32 4-F —CH(CH3)2 —CH2(4-F—Ph) 33 4-F —CH2CH2OCH3 —CH2(4-F—Ph) 34 4-F —N(CH3)CO —CH2(4-F—Ph) CH3 35 4-F —N(CH3)2 —CH2(4-F—Ph) 36 2,4-F —CH3 —CH2(4-F—Ph) 37 2,4-F —CH(CH3)2 —CH2(4-F—Ph) 38 2,4-F —CH2CH2OCH3 —CH2(4-F—Ph) 39 2,4-F —N(CH3)CO —CH2(4-F—Ph) CH3 40 2,4-F —N(CH3)2 —CH2(4-F—Ph) 41 2-F, —CH3 —CH2(4-F—Ph) 3-Cl 42 2-F, —CH(CH3)2 —CH2(4-F—Ph) 3-Cl 43 2-F, —CH2CH2OCH3 —CH2(4-F—Ph) 3-Cl 44 2-F, —N(CH3)CO —CH2(4-F—Ph) 3-Cl CH3 45 2-F, —N(CH3)2 —CH2(4-F—Ph) 3-Cl 46 4-F H CH3 47 2,4-F H CH3 48 2-F, 3-Cl H CH3 49 4-F H CH2CH2OCH3 50 2,4-F H CH2CH2OCH3 51 2-F, 3-Cl H CH2CH2OCH3 52 4-F H —CH2(4-F—Ph) -
[Chemical formula 84] (I-9) No (R)m Ra R4 1 4-F —CH3 CH3 2 4-F —CH(CH3)2 CH3 3 4-F —CH2CH2OCH3 CH3 4 4-F —N(CH3)CO CH3 CH3 5 4-F —N(CH3)2 CH3 6 2,4-F —CH3 CH3 7 2,4-F —CH(CH3)2 CH3 8 2,4-F —CH2CH2OCH3 CH3 9 2,4-F —N(CH3)CO CH3 CH3 10 2,4-F —N(CH3)2 CH3 11 2-F, —CH3 CH3 3-Cl 12 2-F, —CH(CH3)2 CH3 3-Cl 13 2-F, —CH2CH2OCH3 CH3 3-Cl 14 2-F, —N(CH3)CO CH3 CH3 3-Cl 15 2-F, —N(CH3)2 CH3 3-Cl 16 4-F —CH3 CH2CH2OCH3 17 4-F —CH(CH3)2 CH2CH2OCH3 18 4-F —CH2CH2OCH3 CH2CH2OCH3 19 4-F —N(CH3)CO CH3 CH2CH2OCH3 20 4-F —N(CH3)2 CH2CH2OCH3 21 2,4-F —CH3 CH2CH2OCH3 22 2,4-F —CH(CH3)2 CH2CH2OCH3 23 2,4-F —CH2CH2OCH3 CH2CH2OCH3 24 2,4-F —N(CH3)CO CH3 CH2CH2OCH3 25 2,4-F —N(CH3)2 CH2CH2OCH3 26 2-F, —CH3 CH2CH2OCH3 3-Cl 27 2-F, —CH(CH3)2 CH2CH2OCH3 3-Cl 28 2-F, —CH2CH2OCH3 CH2CH2OCH3 3-Cl 29 2-F, —N(CH3)CO CH2CH2OCH3 3-Cl CH3 30 2-F, —N(CH3)2 CH2CH2OCH3 3-Cl 31 4-F —CH3 —CH2(4-F—Ph) 32 4-F —CH(CH3)2 —CH2(4-F—Ph) 33 4-F —CH2CH2OCH3 —CH2(4-F—Ph) 34 4-F —N(CH3)CO —CH2(4-F—Ph) CH3 35 4-F —N(CH3)2 —CH2(4-F—Ph) 36 2,4-F —CH3 —CH2(4-F—Ph) 37 2,4-F —CH(CH3)2 —CH2(4-F—Ph) 38 2,4-F —CH2CH2OCH3 —CH2(4-F—Ph) 39 2,4-F —N(CH3)CO —CH2(4-F—Ph) CH3 40 2,4-F —N(CH3)2 —CH2(4-F—Ph) 41 2-F, —CH3 —CH2(4-F—Ph) 3-Cl 42 2-F, —CH(CH3)2 —CH2(4-F—Ph) 3-Cl 43 2-F, —CH2CH2OCH3 —CH2(4-F—Ph) 3-Cl 44 2-F, —N(CH3)CO —CH2(4-F—Ph) 3-Cl CH3 45 2-F, —N(CH3)2 —CH2(4-F—Ph) 3-Cl -
[Chemical formula 85] (I-9) No (R)m Rb R4 1 4-F —CH3 CH3 2 4-F —CH(CH3)2 CH3 3 4-F —CH2CH2OCH3 CH3 4 4-F —N(CH3)CO CH3 CH3 5 4-F —N(CH3)2 CH3 6 2,4-F —CH3 CH3 7 2,4-F —CH(CH3)2 CH3 8 2,4-F —CH2CH2OCH3 CH3 9 2,4-F —N(CH3)CO CH3 CH3 10 2,4-F —N(CH3)2 CH3 11 2-F, —CH3 CH3 3-Cl 12 2-F, —CH(CH3)2 CH3 3-Cl 13 2-F, —CH2CH2OCH3 CH3 3-Cl 14 2-F, —N(CH3)CO CH3 CH3 3-Cl 15 2-F, —N(CH3)2 CH3 3-Cl 16 4-F —CH3 CH2CH2OCH3 17 4-F —CH(CH3)2 CH2CH2OCH3 18 4-F —CH2CH2OCH3 CH2CH2OCH3 19 4-F —N(CH3)CO CH3 CH2CH2OCH3 20 4-F —N(CH3)2 CH2CH2OCH3 21 2,4-F —CH3 CH2CH2OCH3 22 2,4-F —CH(CH3)2 CH2CH2OCH3 23 2,4-F —CH2CH2OCH3 CH2CH2OCH3 24 2,4-F —N(CH3)CO CH3 CH2CH2OCH3 25 2,4-F —N(CH3)2 CH2CH2OCH3 26 2-F, —CH3 CH2CH2OCH3 3-Cl 27 2-F, —CH(CH3)2 CH2CH2OCH3 3-Cl 28 2-F, —CH2CH2OCH3 CH2CH2OCH3 3-Cl 29 2-F, —N(CH3)CO CH2CH2OCH3 3-Cl CH3 30 2-F, —N(CH3)2 CH2CH2OCH3 3-Cl 31 4-F —CH3 —CH2(4-F—Ph) 32 4-F —CH(CH3)2 —CH2(4-F—Ph) 33 4-F —CH2CH2OCH3 —CH2(4-F—Ph) 34 4-F —N(CH3)CO —CH2(4-F—Ph) CH3 35 4-F —N(CH3)2 —CH2(4-F—Ph) 36 2,4-F —CH3 —CH2(4-F—Ph) 37 2,4-F —CH(CH3)2 —CH2(4-F—Ph) 38 2,4-F —CH2CH2OCH3 —CH2(4-F—Ph) 39 2,4-F —N(CH3)CO —CH2(4-F—Ph) CH3 40 2,4-F —N(CH3)2 —CH2(4-F—Ph) 41 2-F, —CH3 —CH2(4-F—Ph) 3-Cl 42 2-F, —CH(CH3)2 —CH2(4-F—Ph) 3-Cl 43 2-F, —CH2CH2OCH3 —CH2(4-F—Ph) 3-Cl 44 2-F, —N(CH3)CO —CH2(4-F—Ph) 3-Cl CH3 45 2-F, —N(CH3)2 —CH2(4-F—Ph) 3-Cl 46 4-F H CH3 47 2,4-F H CH3 48 2-F, 3-Cl H CH3 49 4-F H CH2CH2OCH3 50 2,4-F H CH2CH2OCH3 51 2-F, 3-Cl H CH2CH2OCH3 52 4-F H —CH2(4-F—Ph) -
[Chemical formula 86] (I-9) No (R)m Ra R4 1 4-F —CH3 CH3 2 4-F —CH(CH3)2 CH3 3 4-F —CH2CH2OCH3 CH3 4 4-F —N(CH3)CO CH3 CH3 5 4-F —N(CH3)2 CH3 6 2,4-F —CH3 CH3 7 2,4-F —CH(CH3)2 CH3 8 2,4-F —CH2CH2OCH3 CH3 9 2,4-F —N(CH3)CO CH3 CH3 10 2,4-F —N(CH3)2 CH3 11 2-F, —CH3 CH3 3-Cl 12 2-F, —CH(CH3)2 CH3 3-Cl 13 2-F, —CH2CH2OCH3 CH3 3-Cl 14 2-F, —N(CH3)CO CH3 CH3 3-Cl 15 2-F, —N(CH3)2 CH3 3-Cl 16 4-F —CH3 CH2CH2OCH3 17 4-F —CH(CH3)2 CH2CH2OCH3 18 4-F —CH2CH2OCH3 CH2CH2OCH3 19 4-F —N(CH3)CO CH3 CH2CH2OCH3 20 4-F —N(CH3)2 CH2CH2OCH3 21 2,4-F —CH3 CH2CH2OCH3 22 2,4-F —CH(CH3)2 CH2CH2OCH3 23 2,4-F —CH2CH2OCH3 CH2CH2OCH3 24 2,4-F —N(CH3)CO CH3 CH2CH2OCH3 25 2,4-F —N(CH3)2 CH2CH2OCH3 26 2-F, —CH3 CH2CH2OCH3 3-Cl 27 2-F, —CH(CH3)2 CH2CH2OCH3 3-Cl 28 2-F, —CH2CH2OCH3 CH2CH2OCH3 3-Cl 29 2-F, —N(CH3)CO CH2CH2OCH3 3-Cl CH3 30 2-F, —N(CH3)2 CH2CH2OCH3 3-Cl 31 4-F —CH3 —CH2(4-F—Ph) 32 4-F —CH(CH3)2 —CH2(4-F—Ph) 33 4-F —CH2CH2OCH3 —CH2(4-F—Ph) 34 4-F —N(CH3)CO —CH2(4-F—Ph) CH3 35 4-F —N(CH3)2 —CH2(4-F—Ph) 36 2,4-F —CH3 —CH2(4-F—Ph) 37 2,4-F —CH(CH3)2 —CH2(4-F—Ph) 38 2,4-F —CH2CH2OCH3 —CH2(4-F—Ph) 39 2,4-F —N(CH3)CO —CH2(4-F—Ph) CH3 40 2,4-F —N(CH3)2 —CH2(4-F—Ph) 41 2-F, —CH3 —CH2(4-F—Ph) 3-Cl 42 2-F, —CH(CH3)2 —CH2(4-F—Ph) 3-Cl 43 2-F, —CH2CH2OCH3 —CH2(4-F—Ph) 3-Cl 44 2-F, —N(CH3)CO —CH2(4-F—Ph) 3-Cl CH3 45 2-F, —N(CH3)2 —CH2(4-F—Ph) 3-Cl -
[Chemical formula 87] (I-9) No (R)m Ra R4 1 4-F —CH3 CH3 2 4-F —CH(CH3)2 CH3 3 4-F —CH2CH2OCH3 CH3 4 4-F —N(CH3)CO CH3 CH3 5 4-F —N(CH3)2 CH3 6 2,4-F —CH3 CH3 7 2,4-F —CH(CH3)2 CH3 8 2,4-F —CH2CH2OCH3 CH3 9 2,4-F —N(CH3)CO CH3 CH3 10 2,4-F —N(CH3)2 CH3 11 2-F, —CH3 CH3 3-Cl 12 2-F, —CH(CH3)2 CH3 3-Cl 13 2-F, —CH2CH2OCH3 CH3 3-Cl 14 2-F, —N(CH3)CO CH3 CH3 3-Cl 15 2-F, —N(CH3)2 CH3 3-Cl 16 4-F —CH3 CH2CH2OCH3 17 4-F —CH(CH3)2 CH2CH2OCH3 18 4-F —CH2CH2OCH3 CH2CH2OCH3 19 4-F —N(CH3)CO CH3 CH2CH2OCH3 20 4-F —N(CH3)2 CH2CH2OCH3 21 2,4-F —CH3 CH2CH2OCH3 22 2,4-F —CH(CH3)2 CH2CH2OCH3 23 2,4-F —CH2CH2OCH3 CH2CH2OCH3 24 2,4-F —N(CH3)CO CH3 CH2CH2OCH3 25 2,4-F —N(CH3)2 CH2CH2OCH3 26 2-F, —CH3 CH2CH2OCH3 3-Cl 27 2-F, —CH(CH3)2 CH2CH2OCH3 3-Cl 28 2-F, —CH2CH2OCH3 CH2CH2OCH3 3-Cl 29 2-F, —N(CH3)CO CH2CH2OCH3 3-Cl CH3 30 2-F, —N(CH3)2 CH2CH2OCH3 3-Cl 31 4-F —CH3 —CH2(4-F—Ph) 32 4-F —CH(CH3)2 —CH2(4-F—Ph) 33 4-F —CH2CH2OCH3 —CH2(4-F—Ph) 34 4-F —N(CH3)CO —CH2(4-F—Ph) CH3 35 4-F —N(CH3)2 —CH2(4-F—Ph) 36 2,4-F —CH3 —CH2(4-F—Ph) 37 2,4-F —CH(CH3)2 —CH2(4-F—Ph) 38 2,4-F —CH2CH2OCH3 —CH2(4-F—Ph) 39 2,4-F —N(CH3)CO —CH2(4-F—Ph) CH3 40 2,4-F —N(CH3)2 —CH2(4-F—Ph) 41 2-F, —CH3 —CH2(4-F—Ph) 3-Cl 42 2-F, —CH(CH3)2 —CH2(4-F—Ph) 3-Cl 43 2-F, —CH2CH2OCH3 —CH2(4-F—Ph) 3-Cl 44 2-F, —N(CH3)CO —CH2(4-F—Ph) 3-Cl CH3 45 2-F, —N(CH3)2 —CH2(4-F—Ph) 3-Cl -
[Chemical formula 88] (I-9) No (R)m Ra R4 1 4-F —CH3 CH3 2 4-F —CH(CH3)2 CH3 3 4-F —CH2CH2OCH3 CH3 4 4-F —N(CH3)CO CH3 CH3 5 4-F —N(CH3)2 CH3 6 2,4-F —CH3 CH3 7 2,4-F —CH(CH3)2 CH3 8 2,4-F —CH2CH2OCH3 CH3 9 2,4-F —N(CH3)CO CH3 CH3 10 2,4-F —N(CH3)2 CH3 11 2-F, —CH3 CH3 3-Cl 12 2-F, —CH(CH3)2 CH3 3-Cl 13 2-F, —CH2CH2OCH3 CH3 3-Cl 14 2-F, —N(CH3)CO CH3 CH3 3-Cl 15 2-F, —N(CH3)2 CH3 3-Cl 16 4-F —CH3 CH2CH2OCH3 17 4-F —CH(CH3)2 CH2CH2OCH3 18 4-F —CH2CH2OCH3 CH2CH2OCH3 19 4-F —N(CH3)CO CH3 CH2CH2OCH3 20 4-F —N(CH3)2 CH2CH2OCH3 21 2,4-F —CH3 CH2CH2OCH3 22 2,4-F —CH(CH3)2 CH2CH2OCH3 23 2,4-F —CH2CH2OCH3 CH2CH2OCH3 24 2,4-F —N(CH3)CO CH3 CH2CH2OCH3 25 2,4-F —N(CH3)2 CH2CH2OCH3 26 2-F, —CH3 CH2CH2OCH3 3-Cl 27 2-F, —CH(CH3)2 CH2CH2OCH3 3-Cl 28 2-F, —CH2CH2OCH3 CH2CH2OCH3 3-Cl 29 2-F, —N(CH3)CO CH2CH2OCH3 3-Cl CH3 30 2-F, —N(CH3)2 CH2CH2OCH3 3-Cl 31 4-F —CH3 —CH2(4-F—Ph) 32 4-F —CH(CH3)2 —CH2(4-F—Ph) 33 4-F —CH2CH2OCH3 —CH2(4-F—Ph) 34 4-F —N(CH3)CO —CH2(4-F—Ph) CH3 35 4-F —N(CH3)2 —CH2(4-F—Ph) 36 2,4-F —CH3 —CH2(4-F—Ph) 37 2,4-F —CH(CH3)2 —CH2(4-F—Ph) 38 2,4-F —CH2CH2OCH3 —CH2(4-F—Ph) 39 2,4-F —N(CH3)CO —CH2(4-F—Ph) CH3 40 2,4-F —N(CH3)2 —CH2(4-F—Ph) 41 2-F, —CH3 —CH2(4-F—Ph) 3-Cl 42 2-F, —CH(CH3)2 —CH2(4-F—Ph) 3-Cl 43 2-F, —CH2CH2OCH3 —CH2(4-F—Ph) 3-Cl 44 2-F, —N(CH3)CO —CH2(4-F—Ph) 3-Cl CH3 45 2-F, —N(CH3)2 —CH2(4-F—Ph) 3-Cl -
[Chemical formula 89] (I-9) No (R)m Ra R4 1 4-F —CH3 CH3 2 4-F —CH(CH3)2 CH3 3 4-F —CH2CH2OCH3 CH3 4 4-F —N(CH3)CO CH3 CH3 5 4-F —N(CH3)2 CH3 6 2,4-F —CH3 CH3 7 2,4-F —CH(CH3)2 CH3 8 2,4-F —CH2CH2OCH3 CH3 9 2,4-F —N(CH3)CO CH3 CH3 10 2,4-F —N(CH3)2 CH3 11 2-F, —CH3 CH3 3-Cl 12 2-F, —CH(CH3)2 CH3 3-Cl 13 2-F, —CH2CH2OCH3 CH3 3-Cl 14 2-F, —N(CH3)CO CH3 CH3 3-Cl 15 2-F, —N(CH3)2 CH3 3-Cl 16 4-F —CH3 CH2CH2OCH3 17 4-F —CH(CH3)2 CH2CH2OCH3 18 4-F —CH2CH2OCH3 CH2CH2OCH3 19 4-F —N(CH3)CO CH3 CH2CH2OCH3 20 4-F —N(CH3)2 CH2CH2OCH3 21 2,4-F —CH3 CH2CH2OCH3 22 2,4-F —CH(CH3)2 CH2CH2OCH3 23 2,4-F —CH2CH2OCH3 CH2CH2OCH3 24 2,4-F —N(CH3)CO CH3 CH2CH2OCH3 25 2,4-F —N(CH3)2 CH2CH2OCH3 26 2-F, —CH3 CH2CH2OCH3 3-Cl 27 2-F, —CH(CH3)2 CH2CH2OCH3 3-Cl 28 2-F, —CH2CH2OCH3 CH2CH2OCH3 3-Cl 29 2-F, —N(CH3)CO CH2CH2OCH3 3-Cl CH3 30 2-F, —N(CH3)2 CH2CH2OCH3 3-Cl 31 4-F —CH3 —CH2(4-F—Ph) 32 4-F —CH(CH3)2 —CH2(4-F—Ph) 33 4-F —CH2CH2OCH3 —CH2(4-F—Ph) 34 4-F —N(CH3)CO —CH2(4-F—Ph) CH3 35 4-F —N(CH3)2 —CH2(4-F—Ph) 36 2,4-F —CH3 —CH2(4-F—Ph) 37 2,4-F —CH(CH3)2 —CH2(4-F—Ph) 38 2,4-F —CH2CH2OCH3 —CH2(4-F—Ph) 39 2,4-F —N(CH3)CO —CH2(4-F—Ph) CH3 40 2,4-F —N(CH3)2 —CH2(4-F—Ph) 41 2-F, —CH3 —CH2(4-F—Ph) 3-Cl 42 2-F, —CH(CH3)2 —CH2(4-F—Ph) 3-Cl 43 2-F, —CH2CH2OCH3 —CH2(4-F—Ph) 3-Cl 44 2-F, —N(CH3)CO —CH2(4-F—Ph) 3-Cl CH3 45 2-F, —N(CH3)2 —CH2(4-F—Ph) 3-Cl -
[Chemical formula 90] (I-9) No (R)m Ra R4 1 4-F —CH3 CH3 2 4-F —CH(CH3)2 CH3 3 4-F —CH2CH2OCH3 CH3 4 4-F —N(CH3)CO CH3 CH3 5 4-F —N(CH3)2 CH3 6 2,4-F —CH3 CH3 7 2,4-F —CH(CH3)2 CH3 8 2,4-F —CH2CH2OCH3 CH3 9 2,4-F —N(CH3)CO CH3 CH3 10 2,4-F —N(CH3)2 CH3 11 2-F, —CH3 CH3 3-Cl 12 2-F, —CH(CH3)2 CH3 3-Cl 13 2-F, —CH2CH2OCH3 CH3 3-Cl 14 2-F, —N(CH3)CO CH3 CH3 3-Cl 15 2-F, —N(CH3)2 CH3 3-Cl 16 4-F —CH3 CH2CH2OCH3 17 4-F —CH(CH3)2 CH2CH2OCH3 18 4-F —CH2CH2OCH3 CH2CH2OCH3 19 4-F —N(CH3)CO CH3 CH2CH2OCH3 20 4-F —N(CH3)2 CH2CH2OCH3 21 2,4-F —CH3 CH2CH2OCH3 22 2,4-F —CH(CH3)2 CH2CH2OCH3 23 2,4-F —CH2CH2OCH3 CH2CH2OCH3 24 2,4-F —N(CH3)CO CH3 CH2CH2OCH3 25 2,4-F —N(CH3)2 CH2CH2OCH3 26 2-F, —CH3 CH2CH2OCH3 3-Cl 27 2-F, —CH(CH3)2 CH2CH2OCH3 3-Cl 28 2-F, —CH2CH2OCH3 CH2CH2OCH3 3-Cl 29 2-F, —N(CH3)CO CH2CH2OCH3 3-Cl CH3 30 2-F, —N(CH3)2 CH2CH2OCH3 3-Cl 31 4-F —CH3 —CH2(4-F—Ph) 32 4-F —CH(CH3)2 —CH2(4-F—Ph) 33 4-F —CH2CH2OCH3 —CH2(4-F—Ph) 34 4-F —N(CH3)CO —CH2(4-F—Ph) CH3 35 4-F —N(CH3)2 —CH2(4-F—Ph) 36 2,4-F —CH3 —CH2(4-F—Ph) 37 2,4-F —CH(CH3)2 —CH2(4-F—Ph) 38 2,4-F —CH2CH2OCH3 —CH2(4-F—Ph) 39 2,4-F —N(CH3)CO —CH2(4-F—Ph) CH3 40 2,4-F —N(CH3)2 —CH2(4-F—Ph) 41 2-F, —CH3 —CH2(4-F—Ph) 3-Cl 42 2-F, —CH(CH3)2 —CH2(4-F—Ph) 3-Cl 43 2-F, —CH2CH2OCH3 —CH2(4-F—Ph) 3-Cl 44 2-F, —N(CH3)CO —CH2(4-F—Ph) 3-Cl CH3 45 2-F, —N(CH3)2 —CH2(4-F—Ph) 3-Cl -
[Chemical formula 91] (I-9) No (R)m Ra R4 1 4-F —CH3 CH3 2 4-F —CH(CH3)2 CH3 3 4-F —CH2CH2OCH3 CH3 4 4-F —N(CH3)CO CH3 CH3 5 4-F —N(CH3)2 CH3 6 2,4-F —CH3 CH3 7 2,4-F —CH(CH3)2 CH3 8 2,4-F —CH2CH2OCH3 CH3 9 2,4-F —N(CH3)CO CH3 CH3 10 2,4-F —N(CH3)2 CH3 11 2-F, —CH3 CH3 3-Cl 12 2-F, —CH(CH3)2 CH3 3-Cl 13 2-F, —CH2CH2OCH3 CH3 3-Cl 14 2-F, —N(CH3)CO CH3 CH3 3-Cl 15 2-F, —N(CH3)2 CH3 3-Cl 16 4-F —CH3 CH2CH2OCH3 17 4-F —CH(CH3)2 CH2CH2OCH3 18 4-F —CH2CH2OCH3 CH2CH2OCH3 19 4-F —N(CH3)CO CH3 CH2CH2OCH3 20 4-F —N(CH3)2 CH2CH2OCH3 21 2,4-F —CH3 CH2CH2OCH3 22 2,4-F —CH(CH3)2 CH2CH2OCH3 23 2,4-F —CH2CH2OCH3 CH2CH2OCH3 24 2,4-F —N(CH3)CO CH3 CH2CH2OCH3 25 2,4-F —N(CH3)2 CH2CH2OCH3 26 2-F, —CH3 CH2CH2OCH3 3-Cl 27 2-F, —CH(CH3)2 CH2CH2OCH3 3-Cl 28 2-F, —CH2CH2OCH3 CH2CH2OCH3 3-Cl 29 2-F, —N(CH3)CO CH2CH2OCH3 3-Cl CH3 30 2-F, —N(CH3)2 CH2CH2OCH3 3-Cl 31 4-F —CH3 —CH2(4-F—Ph) 32 4-F —CH(CH3)2 —CH2(4-F—Ph) 33 4-F —CH2CH2OCH3 —CH2(4-F—Ph) 34 4-F —N(CH3)CO —CH2(4-F—Ph) CH3 35 4-F —N(CH3)2 —CH2(4-F—Ph) 36 2,4-F —CH3 —CH2(4-F—Ph) 37 2,4-F —CH(CH3)2 —CH2(4-F—Ph) 38 2,4-F —CH2CH2OCH3 —CH2(4-F—Ph) 39 2,4-F —N(CH3)CO —CH2(4-F—Ph) CH3 40 2,4-F —N(CH3)2 —CH2(4-F—Ph) 41 2-F, —CH3 —CH2(4-F—Ph) 3-Cl 42 2-F, —CH(CH3)2 —CH2(4-F—Ph) 3-Cl 43 2-F, —CH2CH2OCH3 —CH2(4-F—Ph) 3-Cl 44 2-F, —N(CH3)CO —CH2(4-F—Ph) 3-Cl CH3 45 2-F, —N(CH3)2 —CH2(4-F—Ph) 3-Cl -
[Chemical formula 92] (I-10) No Ra Rb 1 H H 2 —CH3 H 3 —CH(CH3)2 H 4 —CH2CH2OCH3 H 5 H —CH3 6 —CH3 —CH3 7 —CH(CH3)2 —CH3 8 —CH2CH2OCH3 —CH3 9 H —CH(CH3)2 10 —CH3 —CH(CH3)2 11 —CH(CH3)2 —CH(CH3)2 12 —CH2CH2OCH3 —CH(CH3)2 13 H —CH2CH2OCH3 14 —CH3 —CH2CH2OCH3 15 —CH(CH3)2 —CH2CH2OCH3 16 —CH2CH2OCH3 —CH2CH2OCH3 17 H —N(CH3)2 18 —CH3 —N(CH3)2 19 —CH(CH3)2 —N(CH3)2 20 —CH2CH2OCH3 —N(CH3)2 21 H —N(CH3)CO CH3 22 —CH3 —N(CH3)CO CH3 23 —CH(CH3)2 —N(CH3)CO CH3 24 —CH2CH2OCH3 —N(CH3)CO CH3 -
[Chemical formula 93] (I-10) No Ra Rb 1 H H 2 —CH3 H 3 —CH(CH3)2 H 4 —CH2CH2OCH3 H 5 H —CH3 6 —CH3 —CH3 7 —CH(CH3)2 —CH3 8 —CH2CH2OCH3 —CH3 9 H —CH(CH3)2 10 —CH3 —CH(CH3)2 11 —CH(CH3)2 —CH(CH3)2 12 —CH2CH2OCH3 —CH(CH3)2 13 H —CH2CH2OCH3 14 —CH3 —CH2CH2OCH3 15 —CH(CH3)2 —CH2CH2OCH3 16 —CH2CH2OCH3 —CH2CH2OCH3 17 H —N(CH3)2 18 —CH3 —N(CH3)2 19 —CH(CH3)2 —N(CH3)2 20 —CH2CH2OCH3 —N(CH3)2 21 H —N(CH3)CO CH3 22 —CH3 —N(CH3)CO CH3 23 —CH(CH3)2 —N(CH3)CO CH3 24 —CH2CH2OCH3 —N(CH3)CO CH3 -
[Chemical formula 94] (I-10) No Ra Rb 1 H H 2 —CH3 H 3 —CH(CH3)2 H 4 —CH2CH2OCH3 H 5 H —CH3 6 —CH3 —CH3 7 —CH(CH3)2 —CH3 8 —CH2CH2OCH3 —CH3 9 H —CH(CH3)2 10 —CH3 —CH(CH3)2 11 —CH(CH3)2 —CH(CH3)2 12 —CH2CH2OCH3 —CH(CH3)2 13 H —CH2CH2OCH3 14 —CH3 —CH2CH2OCH3 15 —CH(CH3)2 —CH2CH2OCH3 16 —CH2CH2OCH3 —CH2CH2OCH3 17 H —N(CH3)2 18 —CH3 —N(CH3)2 19 —CH(CH3)2 —N(CH3)2 20 —CH2CH2OCH3 —N(CH3)2 21 H —N(CH3)CO CH3 22 —CH3 —N(CH3)CO CH3 23 —CH(CH3)2 —N(CH3)CO CH3 24 —CH2CH2OCH3 —N(CH3)CO CH3 -
[Chemical formula 95] (I-10) No Ra Rb 1 H H 2 —CH3 H 3 —CH(CH3)2 H 4 —CH2CH2OCH3 H 5 H —CH3 6 —CH3 —CH3 7 —CH(CH3)2 —CH3 8 —CH2CH2OCH3 —CH3 9 H —CH(CH3)2 10 —CH3 —CH(CH3)2 11 —CH(CH3)2 —CH(CH3)2 12 —CH2CH2OCH3 —CH(CH3)2 13 H —CH2CH2OCH3 14 CH3 —CH2CH2OCH3 15 —CH(CH3)2 —CH2CH2OCH3 16 —CH2CH2OCH3 —CH2CH2OCH3 17 H —N(CH3)2 18 —CH3 —N(CH3)2 19 —CH(CH3)2 —N(CH3)2 20 —CH2CH2OCH3 —N(CH3)2 21 H —N(CH3)CO CH3 22 —CH3 —N(CH3)CO CH3 23 —CH(CH3)2 —N(CH3)CO CH3 24 —CH2CH2OCH3 —N(CH3)CO CH3 -
[Chemical formula 96] (I-10) No Ra Rb 1 H H 2 —CH3 H 3 —CH(CH3)2 H 4 —CH2CH2OCH3 H 5 H —CH3 6 —CH3 —CH3 7 —CH(CH3)2 —CH3 8 —CH2CH2OCH3 —CH3 9 H —CH(CH3)2 10 —CH3 —CH(CH3)2 11 —CH(CH3)2 —CH(CH3)2 12 —CH2CH2OCH3 —CH(CH3)2 13 H —CH2CH2OCH3 14 —CH3 —CH2CH2OCH3 15 —CH(CH3)2 —CH2CH2OCH3 16 —CH2CH2OCH3 —CH2CH2OCH3 17 H —N(CH3)2 18 —CH3 —N(CH3)2 19 —CH(CH3)2 —N(CH3)2 20 —CH2CH2OCH3 —N(CH3)2 21 H —N(CH3)CO CH3 22 —CH3 —N(CH3)CO CH3 23 —CH(CH3)2 —N(CH3)CO CH3 24 —CH2CH2OCH3 —N(CH3)CO CH3 -
[Chemical formula 97] (I-10) No Ra Rb 1 H H 2 —CH3 H 3 —CH(CH3)2 H 4 —CH2CH2OCH3 H 5 H —CH3 6 —CH3 —CH3 7 —CH(CH3)2 —CH3 8 —CH2CH2OCH3 —CH3 9 H —CH(CH3)2 10 —CH3 —CH(CH3)2 11 —CH(CH3)2 —CH(CH3)2 12 —CH2CH2OCH3 —CH(CH3)2 13 H —CH2CH2OCH3 14 —CH3 —CH2CH2OCH3 15 —CH(CH3)2 —CH2CH2OCH3 16 —CH2CH2OCH3 —CH2CH2OCH3 17 H —N(CH3)2 18 —CH3 —N(CH3)2 19 —CH(CH3)2 —N(CH3)2 20 —CH2CH2OCH3 —N(CH3)2 21 H —N(CH3)CO CH3 22 —CH3 —N(CH3)CO CH3 23 —CH(CH3)2 —N(CH3)CO CH3 24 —CH2CH2OCH3 —N(CH3)CO CH3 - Further, the following compounds were synthesized.
- One aspect of Compound (I-10)
- One aspect of Compound (I-6)
- Specific compounds are as follows. “Ex No.” indicates Example No.
-
Ex No. [Chemical formula 106] K-08 K-07 K-31 K-32 K-33 [Chemical formula 107] K-34 K-35 K-09 K-10 K-11 [Chemical formula 108] K-36 K-12 K-13 K-14 K-15 K-37 [Chemical formula 109] K-16 K-17 K-19 K-18 K-20 K-21 [Chemical formula 110] K-22 K-23 K-24 K-25 K-38 K-26 [Chemical formula 111] K-27 K-28 K-39 K-29 K-30 K-40 [Chemical formula 112] K-41 N-01 O-02 N-02 Q-15 Q-02 [Chemical formula 113] Q-03 O-03 N-03 Q-14 N-57 N-56 [Chemical formula 114] Q-13 N-55 N-24 N-25 Q-04 Q-01 [Chemical formula 115] Q-05 O-04 N-54 N-53 N-52 N-51 [Chemical formula 116] N-50 N-49 Q-06 Q-07 O-05 N-04 [Chemical formula 117] N-05 N-07 N-08 N-06 Q-08 Q-09 [Chemical formula 118] N-09 N-10 N-11 N-12 N-13 N-26 [Chemical formula 119] N-14 N-15 N-27 N-28 N-16 [Chemical formula 120] N-17 N-48 N-47 N-46 N-29 O-07 [Chemical formula 121] O-06 O-08 O-09 O-10 N-30 N-45 [Chemical formula 122] N-44 N-43 O-11 O-13 N-31 [Chemical formula 123] N-32 Q-10 Q-11 N-33 [Chemical formula 124] N-42 O-01 Q-12 N-18 N-19 N-20 [Chemical formula 125] N-41 N-34 N-35 N-36 [Chemical formula 126] N-37 N-21 O-12 N-22 N-23 [Chemical formula 127] N-38 N-39 N-40 P-1 N-59 [Chemical formula 128] N-60 N-58 - Physical properties of the above compounds are shown below. Example compounds K-7 to K41 were synthesized according to the same manner as that of Example K-1.
- NMR (DMSO-d6) δ: 1.68 (1H, dd, J=6.6 Hz, 12.3 Hz), 3.15 (2H, m), 4.51 (2H, d, J=6.3 Hz), 4.55 (1H, d, J=14.7 Hz), 4.64 (1H, s), 4.83 (1H, d, J=14.7 Hz), 5.47 (1H, m), 7.01 (1H, d, 2.7 Hz), 7.13-7.43 (8H, m), 8.34 (1H, s), 10.39 (1H, t, J=6.0 Hz).
- NMR (DMSO-d6) δ: 1.69 (2H, m), 1.78 (3H, s), 2.87 (1H, m), 4.52 (1H, s), 4.72 (1H, s), 5.42 (1H, s), 7.02 (1H, s), 7.16-7.43 (8H, m), 7.82 (1H, s), 8.48 (1H, s), 10.40 (1H, s), 11.57 (1H, s).
- NMR (DMSO-d6) δ: 0.92 (6H, t, J=6.0 Hz), 1.46-1.86 (7H, m), 2.75-3.08 (3H, m), 4.41 (1H, m), 4.52 (2H, m), 5.56 (1H, m), 7.16 (2H, t, J=9.0 Hz), 7.35 (2H, dd, J=6.0 Hz, 8.7 Hz), 8.39 (1H, s), 10.44 (1H, t, J=6.0 Hz), 11.88 (1H, s).
- NMR (DMSO-d6) δ: 1.56 (2H, m), 1.79 (2H, m), 2.94 (2H, t, J=4.5 Hz), 3.70 (2H, m), 4.52 (2H, d, J=6.0 Hz), 5.38 (1H, s), 7.16 (2H, t, J=6.0 Hz), 7.34 (2H, dd, J=5.4 Hz, 8.7 Hz), 8.40 (1H, s), 10.40 (1H, t, J=6.0 Hz), 11.73 (1H, s).
- NMR (DMSO-d6) δ: 2.19 (2H, t, J=6.6 Hz), 3.19 (2H, t, J=6.0 Hz), 7.06 (1H, m), 7.25 (1H, m), 7.41 (1H, m), 8.49 (1H, s), 10.37 (1H, t, J=5.7 Hz), 11.63 (1H, s).
- NMR (DMSO-d6) δ: 1.05 (6H, t, J=5.4 Hz), 4.20-4.43 (3H, m), 5.01 (1H, d, J=12.6 Hz), 5.38 (1H, d, J=13.2 Hz), 6.01 (1H, s), 6.89 (1H, m), 7.07 (1H, m), 7.23 (1H, m), 8.14 (1H, s), 10.30 (1H, s).
- NMR (DMSO-d6) δ: 2.61 (3H, s), 3.33 (3H, s), 3.54 (3H, m), 3.98 (1H, s), 4.55 (1H, s), 5.19 (1H, m), 5.38 (1H, s), 7.08 (1H, m), 7.24 (1H, m), 7.42 (1H, m), 8.41 (1H, s), 10.39 (1H, t, J=6.0 Hz), 11.10 (1H, s).
- NMR (DMSO-d6) δ: 3.21 (3H, s), 3.26 (3H, s), 3.43 (7H, m), 4.07 (1H, m), 4.55 (1H, s), 5.15 (1H, d, J=12.6 Hz), 5.46 (1H, d, J=13.2 Hz), 7.07 (1H, m), 7.24 (1H, m), 7.42 (1H, m), 8.39 (1H, s), 10.39 (1H, t, J=5.4 Hz), 10.97 (1H, s).
- NMR (DMSO-d6) δ: 2.19 (2H, quint, J=7.5 Hz), 3.19 (2H, t, J=6.6 Hz), 3.76 (2H, t, J=6.9 Hz), 4.52 (2H, d, J=6.0 Hz), 5.17 (2H, s), 7.15 (1H, t, J=9.0 Hz), 7.35 (2H, dd, J=5.7 Hz, 8.7 Hz), 8.47 (1H, s), 10.35 (1H, t, J=5.7 Hz), 11.61 (1H, s).
- NMR (DMSO-d6) δ: 3.18 (3H, s), 3.70 (2H, s), 4.54 (2H, d, J=6.0 Hz), 5.42 (2H, s), 7.06 (1H, m), 7.23 (1H, m), 7.40 (1H, m), 8.43 (1H, s), 10.36 (1H, t, J=5.7 Hz), 11.10 (1H, s).
- NMR (DMSO-d6) δ: 3.16 (3H, s), 3.55 (4H, s), 3.84 (2H, s), 4.54 (2H, d, J=4.5 Hz), 5.39 (2H, s), 7.07 (1H, m), 7.29 (1H, m), 7.41 (1H, m), 8.35 (1H, s), 10.41 (1H, t, J=4.5 Hz), 11.19 (1H, s).
- NMR (DMSO-d6) δ: 2.81 (3H, s), 2.90 (3H, s), 3.16 (3H, s), 3.81 (2H, s), 4.54 (2H, d, J=5.7 Hz), 5.41 (2H, s), 7.07 (1H, m), 7.25 (1H, m), 7.40 (1H, m), 8.37 (1H, s), 10.39 (1H, t, J=6.3 Hz), 11.10 (1H, s).
- NMR (DMSO-d6) δ: 2.16 (3H, s), 2.25 (2H, m), 3.15 (3H, s), 3.40 (2H, s), 3.81 (1H, s), 4.54 (2H, d, J=6.0 Hz), 5.38 (2H, s), 7.07 (1H, m), 7.28 (1H, m), 7.41 (1H, m), 8.32 (1H, s), 10.43 (1H, t, J=6.0 Hz), 11.08 (1H, s).
- NMR (DMSO-d6) δ: 3.11 (2H, t, J=6.3 Hz), 3.14 (3H, s), 3.34 (2H, t, J=6.3 Hz), 4.07 (1H, s), 4.15 (1H, s), 4.56 (2H, d, J=6.0 Hz), 5.42 (2H, s), 7.06 (1H, m), 7.25 (1H, m), 7.41 (1H, m), 8.42 (1H, s), 10.40 (1H, t, J=6.0 Hz), 11.04 (1H, s).
- NMR (DMSO-d6) δ: 2.90 (2H, s), 3.17 (3H, s), 3.53 (2H, d, J=4.2 Hz), 4.54 (2H, d, J=5.7 Hz), 4.81 (1H, t, J=4.8 Hz), 5.37 (1H, br s), 5.42 (1H, br s), 7.06 (1H, m), 7.24 (1H, m), 7.42 (1H, m), 8.40 (1H, s), 10.39 (1H, t, J=5.7 Hz), 11.10 (1H, s).
- NMR (DMSO-d6) δ: 2.00 (3H, s), 2.61 (3H, s), 3.47 (1H, m), 4.22 (3H, m), 4.55 (2H, br s), 5.22 (1H, br s), 5.37 (1H, br s), 7.06 (1H, m), 7.24 (1H, m), 7.40 (1H, m), 8.40 (1H, s), 10.38 (1H, t, J=6.3 Hz), 11.00 (1H, s).
- NMR (DMSO-d6) δ: 2.61 (3H, s), 3.20 (1H, br s), 3.62 (2H, br s), 3.89 (1H, br s), 4.55 (2H, d, J=5.4 Hz), 4.83 (1H, t, J=5.7 Hz), 5.27 (1H, br s), 5.34 (1H, br s), 7.06 (1H, m), 7.23 (1H, m), 7.42 (1H, m), 8.39 (1H, s), 10.41 (1H, t, J=6.0 Hz), 11.22 (1H, s).
- NMR (DMSO-d6) δ: 3.26 (3H, s), 3.55 (2H, m), 4.15 (1H, br s), 4.51 (2H, m), 4.53 (1H, d, J=6.0 Hz), 5.21 (1H, br s), 5.57 (1H, br s), 6.11 (1H, t, J=7.2 Hz), 7.05 (1H, m), 7.23 (1H, m), 7.42 (1H, m), 8.35 (1H, s), 10.41 (1H, t, J=6.0 Hz), 11.12 (1H, s).
- NMR (DMSO-d6) δ: 2.63 (3H, s), 4.28 (1H, br s), 4.56 (1H, br s), 4.56 (1H, d, J=5.7 Hz), 5.34 (1H, br s), 5.35 (1H, br s), 7.07 (1H, m), 7.25 (1H, m), 7.42 (1H, m), 8.41 (1H, s), 10.34 (1H, t, J=5.7 Hz), 10.60 (1H, s).
- NMR (DMSO-d6) δ: 1.09 (3H, t, J=6.6 Hz), 3.03 (2H, br s), 3.37 (2H, q, J=6.6 Hz), 3.47 (2H, s), 4.54 (1H, d, J=6.0 Hz), 5.36 (1H, br s), 5.38 (1H, br s), 7.07 (1H, m), 7.25 (1H, m), 7.41 (1H, m), 8.38 (1H, s), 10.39 (1H, t, J=6.0 Hz), 11.09 (1H, br s).
- NMR (DMSO-d6) δ: 1.72 (2H, br s), 2.86 (2H, br s), 3.16 (3H, s), 3.21 (2H, br s), 4.55 (1H, d, J=5.7 Hz), 5.37 (1H, br s), 5.43 (1H, br s), 7.06 (1H, m), 7.25 (1H, m), 7.41 (1H, m), 8.50 (1H, s), 10.37 (1H, t, J=5.7 Hz), 11.10 (1H, br s).
- NMR (DMSO-d6) δ: 1.80 (3H, s), 2.86 (2H, t, J=6.6 Hz), 3.15 (3H, s), 3.21 (2H, t, J=6.6 Hz), 4.54 (2H, d, J=4.8 Hz), 5.36 (2H, br s), 7.06 (1H, m), 7.24 (1H, m), 7.42 (1H, m), 7.93 (1H, t, J=5.1 Hz), 8.42 (1H, s), 10.42 (1H, t, J=4.8 Hz), 11.18 (1H, br s).
- NMR (DMSO-d6) δ: 2.10 (6H, s), 2.38 (2H, s), 2.85 (2H, s), 3.16 (3H, s), 4.54 (2H, d, J=5.7 Hz), 5.31 (1H, br s), 5.45 (1H, br s), 7.07 (1H, m), 7.25 (1H, m), 7.40 (1H, m), 8.35 (1H, s), 10.46 (1H, t, J=5.7 Hz), 11.03 (1H, br s).
- NMR (DMSO-d6) δ: 0.89 (3H, t, J=7.2 Hz), 1.64 (2H, m), 3.00 (2H, t, J=5.14 Hz), 3.07 (1H, m), 3.20 (3H, s), 3.20 (1H, m), 3.42 (2H, m), 4.54 (2H, s), 5.22 (1H, d, 12.6 Hz), 5.48 (1H, d, 12.6 Hz), 7.09 (1H, m), 7.24 (1H, m), 7.40 (1H, m), 8.39 (1H, s), 10.39 (1H, t, J=5.7 Hz), 11.13 (1H, br s).
- NMR (CDCl3) δ: 2.72 (3H, s), 3.26 (3H, s), 4.61 (2H, d, J=2.7 Hz), 6.97-7.03 (2H, m), 7.26-7.35 (2H, m), 8.32 (1H, s), 10.40 (1H, brs).
- 1H-NMR (DMSO-d6) δ: 1.60-1.70 (1H, m), 3.15 (3H, d, J=7.1 Hz), 3.14-3.83 (m), 4.49-4.53 (2H, m) 5.40-5.50 (1H, m), 7.12-7.18 (2H, m), 7.33-7.38 (2H, m), 8.43 and 8.53 (1H, s), 10.30-10.40 (1H, brt), 11.30 (1H, brs).
- 1H-NMR (DMSO-d6) δ: 2.79 (3H, s), 3.27 (3H, s), 4.03-3.66 (m), 4.58 (2H, d, J=5.71 Hz), 6.09 (1H, s), 7.26-7.16 (2H, m), 7.45-7.36 (2H, m), 8.57 (1H, s), 10.34 (1H, t, J=6.04 Hz), 11.44 (1H, br s).
- 1H-NMR (DMSO-d6) δ: 2.72 (3H, s), 3.15-3.52 (m), 4.53 (2H, d, J=2.7 Hz), 7.11-7.18 (2H, m), 7.32-7.37 (2H, m), 8.31 (1H, s), 8.51 (1H, brs), 10.29 (1H, brs)
- 1H-NMR (DMSO-d6) δ: 0.70 and 1.02 (each 3H, d, J=6.2 Hz), 2.63 (3H, s), 3.16 (3H, s), 3.25-3.52 (1H, m), 4.51 (2H, m), 5.18 (1H, d, J=8.4 Hz), 7.12-7.18 (2H, m), 7.33-7.38 (2H, m), 8.46 (1H, s), 10.30-10.40 (1H, m), 11.27 (1H, brs).
- 1H-NMR (DMSO-d6) δ: 3.18 (3H, s), 4.50-4.70 (3H, m), 5.47 (1H, brs), 6.13 (1H, t, J=7.0 Hz), 7.03-7.09 (1H, m), 7.19-7.27 (1H, m), 7.36-7.44 (1H, m), 8.36 (1H, s), 10.41 (1H, t, J=5.9 Hz), 11.26 (1H, brs).
- 1H-NMR (DMSO-d6) δ: 2.98-3.14 (2H, m), 3.27 (3H, s), 3.33 (3H, s), 3.46-3.62 (2H, m), 4.64 (2H, d, J=5.9 Hz), 5.20-5.27 (2H, m), 6.75-6.90 (2H, m), 7.26-7.41 (1H, m), 8.26 (1H, s) 10.30-10.40 (1H, brt)
- NMR (CDCl3) δ: 1.21 (3H, t, J=7.0 Hz), 2.85-3.08 (2H, m), 3.31 (3H, s), 4.64 (2H, d, J=5.9 Hz), 4.83-5.37 (2H, m), 6.75-6.87 (2H, m), 7.32-7.43 (1H, m), 8.34 (1H, brs), 10.30-10.45 (1H, m), 11.13-11.31 (1H, m)
- 1H-NMR (CDCl3) δ: 1.35 (1H, t, J=7.13 Hz), 3.28-2.90 (1H, m), 3.37 (3H, s), 3.53 (3H, s), 3.75-3.58 (1H, m), 4.28-4.08 (1H, m), 4.69 (2H, d, J=5.88 Hz), 5.48-5.05 (2H, m), 6.90-6.80 (2H, m), 7.47-7.36 (1H, m), 8.31 (1H, s), 0.50-10.41 (1H, m).
- 1H-NMR (CDCl3) δ: 3.41 (2H, br s), 3.82 (2H, br s), 4.12 (2H, br s), 4.55 (2H, br s), 4.64 (2H, d, J=6.0 Hz), 4.95 (1H, br s), 5.32 (1H, br s), 6.75-6.83 (2H, m), 7.31-7.41 (1H, m), 10.39 (1H, t, J=6.0 Hz), 11.31 (1H, br s).
- 1H-NMR (CDCl3) δ: 1.68 (1H, br s), 1.91 (4H, br s), 2.92 (1H, br s), 3.00 (1H, br s), 3.21 (1H, br s), 4.39 (1H, br s), 4.63 (2H, d, J=6.0 Hz), 4.82 (1H, br s), 5.22 (1H, br 6.79-6.82 (2H, m), 7.27-7.40 (1H, m), 8.30 (1H, s), 10.40 (1H, t, J=6.0 Hz), 11.39 (1H, br s).
-
- 1) Using Compound 67 synthesized according to the method of synthesizing Compound 65, Compound 68 was synthesized by the following procedure.
- To a solution of the Compound 67 (23.3 g, 49.4 mmol) in DMF (230 ml) was added potassium carbonate (13.7 g, 98.8 mmol), and the mixture was stirred at room temperature for 90 minutes. Then, O-(2,4-dinitrophenyl)-hydroxylamine (10.8 g, 54.4 mmol) was added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added water, this was extracted ethyl acetate, and dried with sodium sulfate. The solvent was distilled off, and the resulting crystal was washed with diethyl ether to obtain 21.7 g (yield 90%) of 1-amino-3-benzyloxy-5-[3-(2,4-difluoro-phenyl)-propyl]-4-oxo-1,4-dihydro-pyridine-2-car boxylic acid (2-methoxy-ethyl)-amide 68.
- NMR (CDCl3) δ: 3.25 (3H, s), 3.42 (2H, t, J=4.9 Hz), 3.48 (2H, t, J=4.9 Hz), 4.60 (2H, d, J=4.8 Hz), 4.60 (2H, br s), 5.27 (3H, s), 6.74-6.84 (2H, m), 7.34-7.43 (6H, m), 7.77 (1H, br s), 9.37 (1H, br s), 10.38 (1H, t, J=4.8 Hz).
- 2) To a solution of the Compound 68 (10 g, 20.6 mmol) in toluene (300 ml) were added peraformaldehyde (790 mg, 26.3 mmol) and acetic acid (3.16 g, 52.6 mmol), and the mixture was heated and stirred at 80° C. for 40 minutes. After cooling, the solvent was distilled off. Further, the not-purified residue was dissolved in DMF (500 ml), and cesium carbonate (25.7 g, 78.9 mmol) was added under ice-cooling, followed by stirring for 30 minutes. To the reaction solution was added water, and this was extracted with ethyl acetate, washed with water, and dried with sodium sulfate. The solvent was distilled off, and the resulting crystal was washed with diethyl ether to obtain 9.85 g (yield 96%) of 5-benzyloxy-7-[3-(2,4-difluoro-phenyl)-propyl]-3-(2-methoxy-ethyl)-2,3-dihydro-1H-pyrid[2,1-f][1,2,4]triazine-4,6-dione 69.
- NMR (CDCl3) δ: 3.34 (3H, s), 3.55 (2H, t, J=4.7 Hz), 3.62 (2H, t, J=4.7 Hz), 4.51 (2H, d, J=7.9 Hz), 4.62 (2H, d, J=5.9 Hz), 5.29 (2H, s), 5.88 (1H, br s), 6.76-6.86 (2H, m), 7.29-7.42 (4H, m), 7.54-7.58 (2H, m), 8.51 (1H, s) 10.41 (1H, t, J=5.9 Hz).
- 3) According to the method of synthesizing Compound 15, 5-benzyloxy-7-[3-(2,4-difluoro-phenyl)-propyl]-3-(2-methoxy-ethyl)-1-pyridin-2-ylmethyl-2,3-dihydro-1H-pyrid[2,1-f][1,2,4]triazine-4,6-dione 70 (76.3 mg, 89%) was obtained from Compound 69 (72.2 g).
- NMR (CDCl3) δ: 3.28 (3H, s), 3.66 (2H, s), 3.80 (2H, br s), 3.30 (2H, br s), 4.61 (2H, d, J=6.0 Hz), 4.69 (2H, br s), 5.35 (1H, br s), 6.76-6.86 (2H, m), 7.29-7.39 (7H, m), 7.59-7.62 (2H, m), 7.74 (1H, d, J=1.9 Hz, 7.7 Hz), 8.32 (1H, s), 8.62 (1H, d, J=4.2 Hz), 10.38 (1H, t, J=6.0 Hz).
- 4) According to the method of synthesizing Example A-1, Example N-1 (44.3 mg, 69%) was obtained from Compound 70 (76.3 mg).
- 1H-NMR (CDCl3) δ: 3.32 (3H, s), 3.64 (2H, t, J=4.8 Hz), 3.79 (2H, br s), 4.41 (2H, br 4.59 (2H, d, J=5.9 Hz), 4.88 (2H, br s), 6.75-6.84 (2H, m), 7.28-7.42 (2H, m), 7.84 (1H, dd, J=7.6 Hz, 7.6 Hz), 8.21 (1H, s), 8.63 (1H, d, J=4.4 Hz), 10.28 (1H, t, J=5.9 Hz), 11.67 (1H, br s).
- 5) According to the method of synthesizing Example A-1, Example O-1 (54.3 mg, 66%) was obtained form Compound 69 (100 g).
- 1H-NMR (CDCl3) δ: 3.37 (3H, s), 3.59 (2H, t, J=4.5 Hz), 3.70 (2H, t, J=4.5 Hz), 4.62 (2H, d, J=6.0 Hz), 4.72 (2H, d, J=8.2 Hz), 5.91 (1H, t, J=8.2 Hz), 6.76-6.84 (2H, m), 7.32-7.40 (1H, m), 8.43 (1H, s), 10.29 (1H, t, J=6.0 Hz).
- According to the same manner as that of Example N-1, the following Example Compounds N-2 to N-57 were synthesized.
- NMR (DMSO-d6) δ: 2.71 (3H, s), 4.53 (2H, d, J=5.7 Hz), 4.68 (2H, s), 4.80 (2H, br s), 7.02-7.48 (7H, m), 8.24 (1H, s), 10.34 (1H, t, J=5.7 Hz), 11.58 (1H, br s).
- NMR (DMSO-d6) δ: 1.19 (6H, d, J=6.9 Hz), 2.83 (3H, s), 4.53 (2H, d, J=5.7 Hz), 4.66 (1H, m), 4.79 (2H, s), 7.07 (1H, m), 7.27 (1H, m), 7.40 (1H, m), 8.28 (1H, s), 10.37 (1H, t, J=5.7 Hz), 11.94 (1H, br s).
- NMR (DMSO-d6) δ: 2.67 (3H, s), 4.53 (2H, d, J=5.7 Hz), 4.87 (4H, br s), 7.00-7.50 (5H, m), 7.52 (1H, d, J=1.5 Hz), 8.27 (1H, s), 10.28 (1H, t, J=5.7 Hz), 11.40 (1H, br s).
- NMR (DMSO-d6) δ: 1.82 (2H, quint, J=6.6 Hz), 2.86 (3H, s), 3.24 (3H, s), 3.40 (2H, t, J=6.0 Hz), 3.52 (2H, t, J=7.5 Hz), 4.53 (2H, d, J=6.0 Hz), 4.80 (2H, br s), 7.06 (1H, m), 7.23 (1H, m), 7.36 (1H, m), 8.26 (1H, s), 10.35 (1H, t, J=5.4 Hz), 11.79 (1H, br s).
- NMR (DMSO-d6) δ: 1.54-1.97 (4H, m), 2.88 (3H, s), 3.49 (1H, dd, J=7.8 Hz, 14.4 Hz), 3.68 (2H, m), 3.79 (1H, dd, J=8.1 Hz, 15.0 Hz), 4.07 (1H, m), 4.53 (2H, d, J=6.0 Hz), 4.84 (2H, br s), 7.06 (1H, m), 7.26 (1H, m), 7.36 (1H, m), 8.26 (1H, s), 10.35 (1H, t, J=6.0 Hz), 11.69 (1H, br s).
- NMR (DMSO-d6) δ: 1.06 (6H, d, J=6.0 Hz), 2.88 (3H, s), 3.37 (1H, m), 3.60 (4H, m), 4.53 (2H, d, J=6.0 Hz), 4.82 (2H, br s), 7.06 (1H, m), 7.23 (1H, m), 7.41 (1H, m), 8.28 (1H, s), 10.33 (1H, t, J=5.7 Hz), 11.74 (1H, br s).
- NMR (DMSO-d6) δ: 1.07 (6H, d, J=6.0 Hz), 1.81 (2H, m), 2.87 (3H, s), 3.38 (1H, m), 3.43 (2H, t, J=6.0 Hz), 3.53 (2H, t, J=6.3 Hz), 4.53 (2H, d, J=6.0 Hz), 4.81 (2H, br s), 7.06 (1H, m), 7.23 (1H, m), 7.39 (1H, m), 8.27 (1H, s), 10.35 (1H, t, J=6.0 Hz), 11.84 (1H, br s).
- NMR (DMSO-d6) δ: 2.70 (3H, s), 4.53 (2H, d, J=6.0 Hz), 4.74 (1H, s), 4.83 (2H, br s), 6.45 (1H, d, J=3.0 Hz), 6.50 (1H, d, J=2.4 Hz), 7.06 (1H, m), 7.21 (1H, m), 7.44 (1H, m), 7.61 (s, 1H), 8.28 (1H, s), 10.29 (1H, t, J=6.0 Hz), 11.50 (1H, br s).
- NMR (DMSO-d6) δ: 1.52 (8H, m), 1.94 (3H, br s), 2.88 (3H, s), 3.28 (2H, br s), 4.53 (2H, d, J=6.0 Hz), 4.84 (2H, br s), 7.06 (1H, m), 7.24 (1H, m), 7.38 (1H, m), 8.24 (1H, s), 10.38 (1H, t, J=6.0 Hz), 11.71 (1H, br s).
- NMR (DMSO-d6) δ: 0.81 (4H, m), 2.80 (1H, m), 2.81 (3H, s), 4.53 (2H, d, J=5.7 Hz), 4.72 (2H, br s), 7.05 (1H, m), 7.23 (1H, m), 7.39 (1H, m), 8.26 (1H, s), 10.34 (1H, t, J=6.0 Hz), 11.87 (1H, br s).
- NMR (DMSO-d6) δ: 2.81 (3H, s), 4.53 (2H, d, J=6.0 Hz), 4.80 (2H, s), 4.88 (2H, br s), 7.03-7.59 (6H, m), 8.31 (1H, s), 10.28 (1H, t, J=65.7 Hz), 11.46 (1H, br s).
- NMR (DMSO-d6) δ: 0.33 (2H, d, J=4.8 Hz), 0.51 (2H, d, J=6.6 Hz), 1.12 (1H, m), 2.89 (3H, s), 3.36 (2H, d, J=7.2 Hz), 4.53 (2H, d, J=5.4 Hz), 4.88 (2H, br s), 7.09 (1H, m), 7.23 (1H, m), 7.41 (1H, m), 8.28 (1H, s), 10.34 (1H, t, J=5.7 Hz), 11.76 (1H, br s).
- NMR (DMSO-d6) δ: 0.31-1.09 (6H, m), 3.33 (4H, br s), 4.54 (2H, d, J=5.4 Hz), 4.97 (2H, br s), 7.08 (1H, m), 7.22 (1H, m), 7.39 (1H, m), 8.31 (1H, s), 10.34 (1H, t, J=5.1 Hz), 11.80 (1H, br s).
- NMR (DMSO-d6) δ: 1.56-1.90 (4H, m), 3.44-4.07 (5H, m), 4.53 (2H, d, J=6.0 Hz), 4.82 (2H, br s), 7.09 (1H, m), 7.28 (1H, m), 7.41 (1H, m), 8.23 (1H, s), 10.39 (1H, t, J=6.0 Hz), 11.71 (1H, br s).
- NMR (DMSO-d6) δ: 1.54-1.97 (4H, m), 2.88 (3H, s), 3.49 (1H, dd, J=7.8 Hz, 14.4 Hz), 3.68 (2H, m), 3.79 (1H, dd, J=8.1 Hz, 15.0 Hz), 4.07 (1H, m), 4.53 (2H, d, J=6.0 Hz), 4.84 (2H, br s), 7.06 (1H, m), 7.26 (1H, m), 7.36 (1H, m), 8.26 (1H, s), 10.35 (1H, t, J=6.0 Hz), 11.69 (1H, br s).
- NMR (DMSO-d6) δ: 2.71 (3H, s), 4.54 (2H, d, J=5.7 Hz), 4.60 (2H, s), 4.77 (2H, br s), 6.00 (2H, s), 6.90 (2H, s), 6.98 (1H, s), 7.05 (1H, m), 7.28 (1H, m), 7.40 (1H, m), 8.22 (1H, s), 10.37 (1H, t, J=5.7 Hz), 11.65 (1H, br s).
- NMR (DMSO-d6) δ: 1.10 (3H, t, J=6,9 Hz), 2.88 (3H, s), 3.46 (2H, q, J=6.6 Hz), 3.60 (2H, d, J=4.8 Hz), 3.66 (2H, br s), 4.53 (2H, d, J=5.7 Hz), 4.83 (2H, br s), 7.05 (1H, m), 7.24 (1H, m), 7.41 (1H, m), 8.31 (1H, s), 10.31 (1H, t, J=5.7 Hz), 11.72 (1H, br s).
- NMR (DMSO-d6) δ: 1.79 (2H, m), 1.93 (2H, m), 2.22 (2H, t, J=8.1 Hz), 2.90 (3H, s), 3.23 (2H, t, J=6.6 Hz), 3.42 (4H, m), 4.54 (2H, d, J=6.0 Hz), 4.84 (2H, br s), 7.06 (1H, m), 7.21 (1H, m), 7.41 (1H, m), 8.32 (1H, s), 10.32 (1H, t, J=5.7 Hz), 11.76 (1H, br s).
- NMR (DMSO-d6) δ: 0.85 (3H, t, J=6.3 Hz), 1.22 (20H, br s), 1.44 (2H, m), 1.82 (2H, m), 2.88 (3H, s), 3.39 (2H, t, J=6.0 Hz), 3.54 (2H, t, J=5.7 Hz), 4.53 (2H, d, J=6.0 Hz), 4.82 (2H, br s), 7.07 (1H, m), 7.25 (1H, m), 7.41 (1H, m), 8.31 (1H, s), 10.32 (1H, t, J=6.0 Hz), 11.85 (1H, br s).
- NMR (DMSO-d6) δ: 2.89 (3H, s), 3.25-3.81 (9H, m), 4.54 (2H, d, J=5.7 Hz), 4.84 (2H, br s), 7.06 (1H, m), 7.27 (1H, m), 7.42 (1H, m), 8.31 (1H, s), 10.31 (1H, t, J=6.0 Hz), 11.64 (1H, br s).
- NMR (DMSO-d6) δ: 2.72 (3H, s), 4.23 (4H, s), 4.54 (2H, m), 4.55 (2H, s), 4.78 (1H, br s), 6.78-7.41 (6H, m), 8.25 (1H, s), 10.35 (1H, s), 11.66 (1H, br s).
- NMR (DMSO-d6) δ: 0.82-1.40 (17H, m), 1.82 (2H, m), 2.88 (3H, s), 3.24 (2H, d, 5.7 Hz), 3.41 (2H, t, J=6.0 Hz), 3.54 (2H, t, J=7.2 Hz), 4.53 (2H, d, J=5.7 Hz), 4.82 (2H, br s), 7.06 (1H, m), 7.25 (1H, m), 7.41 (1H, m), 8.31 (1H, s), 10.32 (1H, t, J=5.7 Hz), 11.85 (1H, br s).
- 1H-NMR (CDCl3) δ: 0.99 (3H, t, J=7.39 Hz), 1.79-1.34 (4H, m), 3.14-3.00 (2H, m), 3.41 (3H, s), 3.83-3.62 (4H, m), 4.69 (2.2H, d, J=6.21 Hz), 4.95-4.71 (1H, m), 6.92-6.79 (1H, m), 7.49-7.37 (1H, m), 8.51 (1H, s), 10.47 (1H, brt, J=6.21 Hz), 11.82-11.53 (1H, brs)
- 1H-NMR (CDCl3) δ: 1.19-1.01 (6H, brm), 3.38 (3H, s), 3.48 (1H, s), 3.68-3.61 (2H, m), 3.76-3.70 (2H, m), 4.67 (2H, d, J=6.88 Hz), 4.91-4.83 (2H, m), 6.90-6.77 (2H, m), 7.46-7.35 (1H, m), 8.44 (1.4H, s), 10.40 (1H, brt, J=6.88 Hz), 11.58 (1H, brs)
- 1H-NMR (CDCl3) δ: 1.79 (2H, br s), 3.19 (1H, br s), 3.35 (3H, s), 3.38 (3H, s), 3.47 (2H, t, J=5.77 Hz), 3.65 (2H, t, J=4.53 Hz), 3.74 (2H, br s), 4.66 (2H, d, J=5.77 Hz), 4.94-4.70 (2H, m), 6.91-6.76 (2H, m), 7.45-7.34 (1H, m), 8.46 (1H, s), 10.39 (1H, br s), 11.77-11.46 (1H, m)
- 1H-NMR (CDCl3) δ: 1.97 (2H, br s), 2.96 (2H, t, J=7.22 Hz), 3.32 (3H, s), 3.73-3.57 (4H, m), 4.06 (2H, br s), 4.67 (2H, d, J=4.20 Hz), 5.03-4.60 (2H, m), 6.19 (2H, t, J=2.0 Hz), 6.65 (2H, t, J=2.0 Hz), 6.91-6.79 (2H, m), 7.47-7.34 (1H, m), 8.46 (1H, s), 10.43-10.31 (1H, m), 11.68-11.47 (1H, m)
- 1H-NMR (CDCl3) δ: 2.50 (3H, s), 3.38 (3H, s), 3.87-3.60 (6H, m), 4.27 (1H, br s), 4.66 (2H, d, J=6.04 Hz), 4.77 (1H, br s), 6.13 (1H, s), 6.92-6.75 (2H, m), 7.49-7.32 (2H, m), 8.45 (1H, s), 10.37 (1H, br s), 11.69 (1H, br s)
- 1H-NMR (DMSO-d6) δ: 3.22 (2H, br s), 3.36 (3H, s), 3.60 (2H, br s), 4.55 (2H, d, J=9.40 Hz), 5.41 (2H, br s), 7.12-7.03 (1H, m), 7.26 (1H, d, J=9.74 Hz), 7.31-7.21 (1H, m), 7.49-7.36 (1H, m), 8.47-8.38 (1H, m), 8.49 (1H, s), 9.01 (1H, d, J=9.74 Hz), 10.23-10.20 (1H, m), 11.56 (1H, br
- 1H-NMR (CDCl3) δ: 1.19 (3H, t, J=7.60 Hz), 1.99-1.91 (2H, m), 3.13 (2H, q, J=15.19, 7.60 Hz), 3.35 (3H, s), 3.49 (2H, t, J=5.62 Hz), 3.66 (2H, t, J=7.22 Hz), 4.67 (2H, d, J=7.72 Hz), 8.49 (1H, s), 10.41 (1H, br s), 11.73 (1H, br s)
- 1H-NMR (CDCl3) δ: 2.94 (3H, s), 3.39-3.32 (2H, m), 3.66 (2H, br s), 4.62 (2H, d, J=6.21 Hz), 6.87-6.77 (3H, m), 7.41-7.31 (1H, m), 7.48 (1H, dt, J=10.63, 3.99 Hz), 7.60 (1H, td, J=7.76, 1.62 Hz), 8.09 (1H, dd, J=8.14, 1.59 Hz), 8.42 (1H, s), 10.26 (1H, t, J=6.21 Hz)
- 1H-NMR (CDCl3) δ: 3.39 (3H, s), 3.72-3.41 (3H, m), 4.14-4.01 (2H, m), 4.71 (2H, d, J=5.37 Hz), 5.25 (1H, d, J=13.60 Hz), 6.15 (1H, d, J=13.60 Hz), 6.92-6.81 (2H, m), 7.13 (1H, t, J=4.11 Hz), 7.50-7.40 (1H, m), 8.57 (2H, d, J=4.11 Hz), 8.60 (1H, s), 10.51-10.37 (1H, m), 11.49 (1H, br s)
- 1H-NMR (CDCl3) δ: 0.42-0.33 (2H, m), 0.70-0.60 (2H, m), 1.22-1.02 (1H, m), 3.54 (2H, d, J=7.05 Hz), 4.41 (2H, br s), 4.65 (2H, d, J=6.29 Hz), 4.93 (2H, br s), 6.90-6.79 (2H, m), 7.46-7.33 (3H, m), 7.84 (1H, td, J=7.76, 1.79 Hz), 8.34 (1H, s), 8.66 (1H, d, J=4.87 Hz), 10.36 (1H, t, J=6.29 Hz), 11.83 (1H, br s)
- 1H-NMR (CDCl3) δ: 1.07-0.94 (4H, m), 2.90-2.80 (1H, m), 4.24 (2H, s), 4.64 (2H, d, J=6.21 Hz), 4.74 (2H, br s), 6.91-6.77 (2H, m), 7.46-7.32 (3H, m), 7.80 (1H, td, J=7.68, 1.73 Hz), 8.38 (1H, s), 8.64 (1H, d, J=5.87 Hz), 10.36 (1H, t, J=5.71 Hz), 12.06-11.70 (1H, m)
- 1H-NMR (DMSO-d6) δ: 3.07 (3H, s), 3.37-3.30 (2H, m), 3.56 (2H, br s), 4.58 (1H, d, J=5.87 Hz), 5.84-5.41 (2H, m), 7.15-7.07 (1H, m), 7.18 (2H, d, J=10.24 Hz), 7.36-7.24 (1H, m), 7.52-7.42 (1H, m), 8.24 (2H, d, J=−9.40 Hz), 8.35 (1H, s), 10.37-10.21 (1H, m), 11.63-11.34 (1H, m)
- 1H-NMR (CDCl3) δ: 2.14-1.92 (4H, m), 3.35-3.15 (1H, m), 3.37 (3H, s), 3.63-3.48 (2H, m), 3.95-3.73 (2H, m), 4.19-3.98 (2H, m), 4.67 (1H, d, J=5.54 Hz), 4.84 (1H, br s), 4.98 (1H, br s), 6.91-6.77 (1H, m), 7.47-7.32 (1H, m), 8.54 (1H, s), 10.46-10.36 (1H, m), 11.91-11.45 (1H, m)
- 1H-NMR (CDCl3) δ: 3.24-3.01 (2H, m), 3.34 (3H, s), 3.55-3.49 (2H, m), 4.66 (2H, d, J=7.22 Hz), 4.81 (2H, br s), 4.85 (2H, br s), 6.89-6.77 m), 7.20-7.13 m), 7.49-7.32 (2H, m), 8.51 (1H, s), 10.44-10.28 (1H, m)
- 1H-NMR (CDCl3) δ: 2.14-1.92 (4H, m), 3.35-3.15 (1H, m), 3.37 (3H, s), 3.63-3.48 (2H, m), 3.95-3.73 (2H, m), 4.19-3.98 (2H, m), 4.67 (1H, d, J=5.54 Hz), 4.84 (1H, br s), 4.98 (1H, br s), 6.91-6.77 (1H, m), 7.47-7.32 (1H, m), 8.54 (1H, s), 10.46-10.36 (1H, m), 11.91-11.45 (1H, m)
- 1H-NMR (CDCl3) δ: 3.06 (2H, br s), 3.33 (3-H, s), 3.46 (4H, t, J=5.00 Hz), 4.72-4.62 (2H, m), 6.01 (2H, s), 6.89-6.78 (2H, m), 7.45-7.32 (1H, m), 8.49 (1H, s), 10.39-10.36 m), 11.93-11.50 (1H, m)
- 1H-NMR (CDCl3) δ: 1.17 (6H, d, J=6.21 Hz), 3.38 (3H, s), 3.82-3.50 (5H, m), 4.67 (2H, d, J=5.87 Hz), 4.89 (2H, br s), 6.88-6.78 (2H, m), 7.44-7.34 (1H, m), 8.53 (1H, s), 10.41 (1H, t, J=5.87 Hz)
- 1H-NMR (CDCl3) δ: 3.34 (3H, s), 3.54 (3H, br s), 4.03 (1H, br s), 4.66 (2H, d J=5.7 Hz), 5.30 (1H, br s), 5.92 (1H, s), 6.78-6.88 (2H, m), 6.96-7.03 (1H, m), 7.19-7.23 (1H, m), 7.35-7.43 (1H, m), 8.64 (1H, s), 10.17 (1H, t, J=5.7 Hz), 11.52 (1H, s).
- 1H-NMR (CDCl3) δ: 2.49 (1H, t, J=2.5 Hz), 3.38 (3H, s), 3.69 (2H, t, J=4.5 Hz), 3.77 (2H, t, J=4.5 Hz), 3.96 (2H, d, J=2.5 Hz), 4.68 (2H, d, J=5.9 Hz), 4.88 (2H, s), 6.80-6.90 (2H, m), 7.37-7.45 (1H, m), 8.53 (1H, s), 10.32 (1H, t, J=5.9 Hz), 11.62 (1H, br s).
- 1H-NMR (CDCl3) δ: 3.35 (3H, s), 3.63 (2H, d, J=3.9 Hz), 3.70 (2H, br s), 4.06 (2H, br s), 4.62 (2H, d, J=6.0 Hz), 4.74 (2H, br s), 6.45 (1H, s), 6.76-6.85 (2H, m), 7.31-7.39 (1H, m), 7.48 (1H, t, J=L8 Hz), 10.31 (1H, t, J=6.0 Hz), 11.60 (1H, br s).
- 1H-NMR (CDCl3) δ: 3.34 (3H, s), 3.62 (2H, t, J=3.9 Hz), 3.69 (2H, br s), 4.20 (2H, br s), 4.61 (2H, d, J=6.2 Hz), 4.78 (2H, br s), 6.76-6.85 (2H, m), 7.09 (1H, dd, J=1.3 Hz, 5.0 Hz), 7.14 (1H, dd, J=2.9 Hz, 5.0 Hz), 8.22 (1H, s), 10.28 (1H, J=6.2 Hz), 11.60 (1H, br s).
- 1H-NMR (CDCl3) δ: 3.36 (3H, s), 3.64 (2H, t, J=4.8 Hz), 3.74 (2H, br s), 4.20 (2H, s), 4.61 (2H, d, J=6.0 Hz), 4.76 (2H, br s), 6.27 (1H, d, J=3.2 Hz), 6.34 (1H, dd, J=1.9 Hz, 3.2 Hz), 6.76-6.84 (2H, m), 7.30-7.38 (1H, m), 7.45 (1H, dd, J=0.8 Hz, 1.9 Hz), 8.20 (1H, s), 10.29 (1H, t, J=6.0 Hz).
- 1H-NMR (CDCl3) δ: 3.49 (3H, s), 3.67 (2H, t, J=4.5 Hz), 3.76 (2H, br s), 4.43 (2H, br s), 4.67 (2H, d, J=5.5 Hz), 4.78 (2H, br s), 6.80-6.90 (2H, m), 6.96-7.04 (2H, m), 7.36-7.44 m), 7.44 (1H, dd, J=1.5 Hz, 5.1 Hz), 8.41 (1H, br s), 10.37 (1H, br s).
- 1H-NMR (CDCl3) δ: 2.89 (3H, d, J=4.5 Hz), 3.35 (3H, s), 3.63 (2H, t, J=4.8 Hz), 3.72 (2H, br s), 4.61 (2H, d, J=5.7 Hz), 4.87 (2H, br s), 6.72 (1H, br s), 6.76-6.85 (2H, m), 7.31-7.39 (1H, m), 8.49 (1H, s), 10.23 (1H, t, J=5.7 Hz), 11.63 (1H, br s).
- 1H-NMR (CDCl3) δ: 3.44 (3H, s), 3.72 (4H, br s), 4.61 (2H, d, J=5.4 Hz), 4.80 (2H, s), 4.90 (2H, s), 4.77-4.87 (2H, m), 7.36-7.44 (1H, m), 8.52 (1H, s), 10.10 (1H, s), 11.65 (1H, br s).
- 1H-NMR (CDCl3) δ: 3.32 (3H, s), 3.61 (2H, br s), 3.68 (2H, br s), 4.15 (2H, s), 4.60 (2H, d, J=5.7 Hz), 4.81 (2H, br s), 6.75-6.85 (2H, m), 7.07 (2H, t, J=5.6 Hz), 7.23-7.36 (3H, m), 8.27 (1H, s), 10.24 (1H, t, J=5.7 Hz), 11.60 (1H, br s).
- 1H-NMR (CDCl3) δ: 3.32 (3H, s), 3.59 (2H, t, J=4.5 Hz), 3.68 (2H, br s), 3.80 (3H, s), 4.61 (2H, d, J=5.7 Hz), 4.65 (2H, br s), 6.75-6.85 (2H, m), 6.89 (2H, d, J=8.6 Hz), 7.17 (2H, d, J=8.6 Hz), 7.29-7.37 (1H, m), 8.28 (1H, s), 10.30 (1H, t, J=5.7 Hz), 11.61 (1H, br s).
- 1H-NMR (CDCl3) δ: 3.31 (3H, s), 3.60 (2H, t, J=4.2 Hz), 3.68 (2H, br s), 4.17 (2H, s), 4.60 (2H, d, J=5.7 Hz), 4.68 (2H, br s), 6.75-6.85 (2H, m), 7.25-7.39 (6H, m), 8.27 (1H, s), 10.28 (1H, t, J=5.7 Hz), 11.61 (1H, br s).
- 1H-NMR (CDCl3) δ: 3.34 (3H, s), 3.35 (3H, s), 3.54 (2H, t, J=4.5 Hz), 3.61 (2H, t, J=4.5 Hz), 3.72 (2H, br s), 4.64 (2H, d, J=5.9 Hz), 4.84 (2H, br s), 6.75-6.84 (2H, m), 7.32-7.40 (1H, m), 8.51 (1H, s), 10.38 (1H, br s), 11.62 (1H, br s).
- 1H-NMR (CDCl3) δ: 3.04 (3H, s), 3.05 (3H, s), 3.35 (3H, s), 3.65 (2H, t, J=4.6 Hz), 3.77 (2H, br s), 3.96 (2H, br s), 4.68 (2H, d, J=5.9 Hz), 5.02 (2H, s), 6.80-6.89 (2H, m), 7.37-7.45 (1H, m), 8.56 (1H, s), 10.39 (1H, br s), 11.60 (1H, br s).
- 1H-NMR (CDCl3) δ: 3.25 (2H, br s), 3.37 (3H, s), 3.66 (2H, t, J=4.2 Hz), 3.73 (2H, br s), 3.82 (2H, t, J=4.2 Hz), 4.63 (2H, d, J=5.7 Hz), 4.90 (2H, s), 6.76-6.85 (2H, m), 7.33-7.41 (1H, m), 8.63 (1H, br s), 10.45 (1H, br s), 11.6 (1H, br s).
- 1H-NMR (CDCl3) δ: 0.00 (2H, br s), 0.60 (2H, m), 0.94 (1H, m), 2.93 (2H, br s), 3.38 (3H, s), 3.65 (2H, t, J=4.5 Hz), 3.74 (2H, t, J=4.5 Hz), 4.67 (2H, d, J=5.9 Hz), 4.83 (2H, br s), 6.79-6.88 (2H, m), 7.36-7.44 (1H, m), 8.56 (1H, s), 10,42 (1H, J=5.9 Hz), 11.61 (1H, br s).
- 1H-NMR (CDCl3) δ: 3.37 (3H, s), 3.68 (2H, br s), 3.75 (2H, br s), 4.38 (2H, br s), 4.63 (2H, d, J=5.9 Hz), 4.88 (2H, br s), 6.79-6.88 (2H, m), 7.32-7.41 (1H, m), 7.56-7.61 (1H, m), 7.94-7.97 (1H, m), 8.34 (1H, s), 8.74 (1H, br s), 10.26 (1H, t, J=5.9 Hz).
- 1H-NMR (CDCl3) δ: 1.17 (3H, t, 7.13), 3.11 (2H, q, J=7.1 Hz), 3.36 (3H, s), 3.63 (2H, t, J=4.5 Hz), 3.71 (2H, br s), 4.64 (2H, d, J=5.9 Hz), 4.78 (2H, br s), 6.76-6.85 (2H, m), 7.33-7.41 (1H, m), 8.45 (1H, s), 10.38 (1H, t, J=5.9 Hz), 11.59 (1H, br s).
- According to the sme manner as that of Example O-1, the following Example Compounds O-2 to O-13 were synthesized.
- NMR (DMSO-d6) δ: 4.52 (2H, d, J=5.4 Hz), 4.64 (4H, br s), 7.02-7.44 (7H, m), 7.64 (1H, t, J=5.4 Hz), 7.98 (1H, s), 10.52 (1H, s).
- NMR (DMSO-d6) δ: 1.19 (6H, d, J=6.9 Hz), 4.62 (1H, m), 4.68 (2H, d, J=8.1 Hz), 7.06 (1H, m), 7.26 (1H, m), 7.40 (1H, m), 7.53 (1H, t, J=7.2 Hz), 8.12 (1H, s), 10.41 (1H, t, J=5.7 Hz), 11.94 (1H, br s).
- NMR (DMSO-d6) δ: 4.52 (2H, d, J=5.7 Hz), 4.68 (4H, s), 6.44 (2H, m), 7.06 (1H, m), 7.27 (2H, m), 7.40 (2H, m), 7.64 (2H, s), 8.06 (1H, s), 10.43 (1H, t, J=5.7 Hz), 11.56 (1H, br s).
- NMR (DMSO-d6) δ: 4.53 (1H, d, J=3.8 Hz), 4.76 (2H, d, J=7.8 Hz), 4.85 (2H, s), 7.00-7.40 (5H, m), 7.50 (1H, d, J=3.6 Hz), 7.65 (1H, t, J=7.8 Hz), 8.15 (1H, s), 10.32 (1H, t, J=5.7 Hz), 11.58 (1H, br s).
- NMR (DMSO-d6) δ: 1.52-1.94 (4H, m), 3.46 (1H, dd, J=7.5 Hz, 14.1 Hz), 3.66 (2H, m), 3.79 (1H, dd, J=6.9 Hz, 14.4 Hz), 4.04 (1H, m), 4.54 (2H, d, J=5.7 Hz), 6.75 (2H, d, J=16.0 Hz), 7.07 (1H, m), 7.25 (1H, m), 7.39 (1H, m), 7.61 (1H, t, J=8.1 Hz), 8.15 (1H, s), 10.37 (1H, t, J=5.7 Hz), 11.72 (1H, br s).
- NMR (DMSO-d6) δ: 2.43 (2H, br s), 3.55 (4H, br s), 3.60 (2H, t, J=5.7 Hz), 4.54 (2H, d, J=6.0 Hz), 4.78 (2H, d, J=8.1 Hz), 7.07 (1H, m), 7.24 (1H, m), 7.40 (1H, m), 7.55 (1H, t, J=8.1 Hz), 8.18 (1H, s), 10.35 (1H, t, J=6.2 Hz), 11.79 (1H, br s).
- NMR (DMSO-d6) δ: 1.52-1.94 (4H, m), 3.46 (1H, dd, J=7.5 Hz, 14.1 Hz), 3.66 (2H, m), 3.79 (1H, dd, J=6.9 Hz, 14.4 Hz), 4.04 (1H, m), 4.54 (2H, d, J=5.7 Hz), 6.75 (2H, d, J=16.0 Hz), 7.07 (1H, m), 7.25 (1H, m), 7.39 (1H, m), 7.61 (1H, t, J=8.1 Hz), 8.15 (1H, s), 10.37 (1H, t, J=5.7 Hz), 11.72 (1H, br s).
- NMR (DMSO-d6) δ: 1.08 (2H, d, J=6.0 Hz), 3.56 (2H, t, J=5.7 Hz), 3.58 (1H, m), 3.60 (2H, t, J=5.7 Hz), 4.54 (2H, d, J=6.0 Hz), 4.75 (2H, d, J=8.1 Hz), 7.06 (1H, m), 7.28 (1H, m), 7.38 (1H, m), 7.55 (1H, t, J=8.4 Hz), 8.17 (1H, s), 10.36 (1H, t, J=5.7 Hz), 11.73 (1H, br s).
- NMR (DMSO-d6) δ: 1.06 (6H, d, J=6.3 Hz), 1.78 (2H, m); 3.43 (2H, t, J=6.3 Hz), 3.53 (3H, m), 4.53 (2H, d, J=6.3 Hz), 4.72 (2H, d, J=13.5 Hz), 7.09 (1H, m), 7.24 (1H, m), 7.38 (1H, m), 7.57 (1H, t, J=8.1 Hz), 8.17 (1H, s), 10.36 (1H, t, J=6.3 Hz), 11.87 (1H, br s).
- NMR (DMSO-d6) δ: 1.59 (1H, m), 3.01 (3H, s), 3.15 (2H, t, J=8.1 Hz), 3.28 (2H, t, J=8.1 Hz), 4.31 (2H, d, J=5.7 Hz), 4.50 (2H, d, J=8.1 Hz), 6.85 (1H, m), 7.03 (1H, m), 7.19 (1H, m), 7.36 (1H, t, J=8.1 Hz), 7.95 (1H, s), 10.14 (1H, t, J=6.0 Hz), 11.63 (1H, br s).
- NMR (DMSO-d6) δ: 4.52 (6H, br s), 5.98 (2H, s), 6.84-7.77 (7H, m), 10.73 (1H, br s).
- 1H-NMR (DMSO-d6) δ: 2.62-2.50 (2H, m), 3.10 (1H, t, J=7.30 Hz), 3.87 (1H, t, J=7.39 Hz), 4.49 (1H, d, J=6.88 Hz), 4.57 (3H, d, J=5.88 Hz), 4.75 (2H, d, J=7.89 Hz), 6.59-6.57 (1H, m), 7.12-7.09 (2H, m), 7.33-7.23 (1H, m), 7.48-7.36 (1H, m), 7.58 (1H, t, J=7.89 Hz) 7.76 (1H, td, J=7.64, 1.85 Hz), 8.18 (1H, s), 8.54 (1H, d, J=3.86 Hz), 10.42 (1H, t, J=5.71 Hz), 11.71 (1H, br s)
-
- 1) Using Compound 71 synthesized according to the method of synthesizing Compound 70, Compound 72 was synthesized by the following procedure.
- To a solution of Compound 71 (200 mg, 0.369 mmol) in THF (10 ml) were added triphenylphosphine (145 mg, 0.553 mmol), a diethyl azodicarboxylate 40 wt % toluene solution (251 μl, 0.553 mmol), and N-methyl-o-nitrobenzenesulfonamide (120 mg, 0.553 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, and the resulting residue was purified by subjecting to silica gel chromatography. From fractions eluting with hexane-ethyl acetate (1:19 v/v), 143 mg (yield 52%) of N-{2-[5-benzyloxy-7-[3-(2,4-difluoro-phenyl)-propyl]-3-(2-methoxy-ethyl)-4,6-dioxo-2,3,4,6-tetrahydro-pyrid[2,1-f][1,2,4]triazin-1-yl]-ethyl}-N-methyl-o-nitro-benzenesulfonamide 72 was obtained as an oil.
- NMR (CDCl3) δ: 2.94 (3H, s), 3.13 (1H, br s), 3.34 (1H, br s), 3.37 (3H, s), 3.62 (6H, br s), 4.64 (2H, d, J=6.0 Hz), 4.72 (2H, s), 5.29 (1H, br s), 5.35 (1H, br s), 6.77-6.87 (2H, m), 7.30-7.42 (4H, m), 7.57 (2H, dd, J=1.5 Hz, 7.9 Hz), 7.64-7.70 (1H, m), 7.71-7.77 (2H, m), 8.08-8.05 (1H, m), 8.55 (1H, s), 10.40 (1H, t, J=6.0 Hz).
- 2) To a solution of Compound 72 (106.6 mg, 0.144 mmol) and potassium carbonate (99.5 mg, 0.72 mmol) in DMF (5 ml) was added benzenethiol (23.8 mg, 0.216 mmol) at room temperature, and the mixture was stirred for 16 hours. To the reaction solution was addd water, and this was extracted with ethyl acetate, washed with water, and dried with magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by subjecting to silica gel chromatography. From fractions eluting with chloroform-methanol (85:15 v/v), 39.1 mg (yield 49%) of 5-benzyloxy-7-[3-(2,4-difluoro-phenyl)-propyl]-3-(2-methoxy-ethyl)-1-(2-methylamino-eth yl)-2,3-dihydro-1H-pyrid[2,1-f][1,2,4]triazine-4,6-dione 73 was obtained as an oil.
- NMR (CDCl3) δ: 2.56 (3H, s), 3.29 (2H, br s), 3.33 (3H, s), 3.65 (6H, br s), 4.62 (2H, d, J=6.6 Hz), 4.72 (2H, br s), 5.32 (2H, br s), 6.76-6.88 (2H, m), 7.29-7.40 (4H, m), 7.55-7.61 (2H, m), 8.61 (1H, s), 10.47 (1H, t, J=6.6 Hz).
- 3) To a solution of Compound 73 (45 mg, 0.081 mmol) in dichloromethane (5 ml) were added triethylamine (24.6 mg, 0.243 mmol) and acetic anhydride (16.5 mg, 0.162 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off, and the resulting residue was purified by subjecting to silica gel chromatography. From fractions eluting with chloroform-methanol (95:5 v/v), 48.0 mg (yield 100%) of N-{2-[5-benzyloxy-7-[3-(2,4-difluoro-pheynl)-propyl]-3-(2-methoxy-ethyl)-4,6-dioxo-2,3,4,6-tetrahydro-pyrid[2,1-f][1,2,4]triazin-1-yl]-ethyl}-N-methyl-acetamide 74 was obtained as an oil.
- NMR (CDCl3) δ: 2.14 (3H, s), 3.10 (3H, s), 3.34 (3H, s), 3.36 (4H, br s), 3.61 (2H, br s), 3.70 (2H, br s), 4.63 (2H, d, J=5.9 Hz), 4.73 (2H, s), 5.31 (2H, br s), 6.77-6.87 (2H, m), 7.29-7.41 (4H, m), 7.55-7.58 (2H, m), 10.43 (1H, t, J=5.9 Hz).
- 4) According to the method of synthesizing Example A-1, Example P-1 (46. 1 mg, 75%) was obtained from Compound 74 (72.2 mg).
-
- 1) To a solution of Compound 69 (150 mg, 0.301 mmol) in THF (2 ml) were added methoxyacetyl chloride (327 mg, 3.010 mmol) and pyridine (47.6 mg, 0.602 mmol) at room temperature, and the mixture was stirred at 60° C. for 30 minutes. This was quenched with an aqueous saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with an aqueous saturated sodium chloride solution, and dried with sodium sulfate. The solvent was distilled off, and the resulting residue was purified by subjecting to silica gel chromatography. From fractions eluting with chloroform-methanol (97:3 v/v), 168.0 mg (yield 98%) of the title Compound 75 was obtained as an oil.
- 1H-NMR (CDCl3) δ: 3.37 (3H, s), 3.46 (3H, s), 3.60 (3H, br s), 3.86 (1H, br s), 4.27 (2H, br s), 4.67 (2H, d, J=6.04 Hz), 5.06-4.88 (2H, m), 5.51-5.20 (2H, m), 5.73-5.56 (1H, m), 6.92-6.79 (4H, m), 7.47-7.31 (4H, m), 7.64-7.57 (2H, m), 8.43 (1H, s), 10.28 (1H, t, J=5.96 Hz)
- 2) According to the method of synthesizing Example A-1, Example Q-1 (80 g, 57%) was obtained from Compound 75 (168 mg).
- 1H-NMR (CDCl3) δ: 3.42 (3H, s), 3.49 (3H, s), 3.49 (3H, s), 3.69-3.60 (2H, m), 3.87-3.70 (2H, m), 4.27 (2H, s), 4.69 (2H, d, J=5.88 Hz), 5.25-5.04 (1H, br m), 5.88-5.69 (1H, br m), 6.93-6.79 (2H, m), 7.48-7.35 (1H, m), 8.42 (1.3H, s), 10.23 (1H, br s), 11.55-11.27 (1H, m)
- According to the same manner as that of Example Q-1, the following Example Compounds Q-2 to Q-15 were synthesized.
- NMR (DMSO-d6) δ: 2.00 (3H, s), 4.45 (2H, d, J=5.7 Hz), 4.63 (1H, br s), 4.71 (1H, br s), 5.29 (1H, br s), 5.55 (1H, br s), 7.03-7.44 (7H, m), 8.26 (1H, s), 10.25 (1H, t, J=6.3 Hz), 11.23 (1H, br s).
- NMR (DMSO-d6) δ: 3.21 (3H, s), 4.02 (2H, m), 4.53 (2H, d, J=6.0 Hz), 4.72 (2H, m), 5.22 (1H, br s), 5.38 (1H, br s), 7.04-7.46 (7H, m), 8.11 (1H, s), 10.39 (1H, t, J=6.0 Hz).
- 1H-NMR (CDCl3) δ: 3.05 (3H, s), 3.65-3.31 (4H, m), 4.69 (2H, d, J=4.87 Hz), 5.58-5.22 (2H, m), 6.93-6.79 (2H, m), 7.48-7.36 (2H, m), 7.67-7.56 (2H, m), 7.78-7.69 (2H, m) 7.88-7.76 (2H, m), 8.46 (1H, s), 10.28 brt, J=4.87 Hz), 11.58-11.34 (1H, m)
- 1H-NMR (CDCl3) δ: 3.04 (3H, s), 3.61-3.31 (4H, m), 3.92 (3H, s), 4.65 (1H, d, J=7.32 Hz), 5.55-5.27 (2H, m), 6.90-6.75 (2H, m), 7.03 (2H, d, J=8.69 Hz), 7.45-7.29 (1H, m), 7.76 (2H, d, J=8.69 Hz), 8.39 (1H, s), 10.29 (1H, br s), 11.61-11.30 (1H, m)
- 1H-NMR (CDCl3) δ: 3.09 (3H, s), 3.44 (2H, br s), 3.57 (2H, br s), 4.69 (0.9H, d, J=5.29 Hz), 5.49-5.34 (0.8H, m), 6.91-6.80 (2H, m), 7.35-7.26 (2H, m), 7.47-7.36 (1H, m) 7.92-7.79 (2H, m), 8.45 (1H, s), 10.27 (1H, t, J=5.29 Hz), 11.44 (1H, br s)
- 1H-NMR (CDCl3) δ: 2.51 (3H, s), 3.07 (2.9H, s), 3.46-3.36 (2H, m), 3.63-3.49 (2H, m), 4.69 (1H, d, J=6.04 Hz), 5.42 (1H, br s), 6.91-6.79 (1.1H, m), 7.40 (2H, d, J=8.23 Hz), 7.45-7.39 (1H, m), 7.70 (2H, d, J=8.23 Hz), 8.46 (1H, s), 10.31 (1H, t, J=6.04 Hz), 11.47 (1H, br s)
- 1H-NMR (CDCl3) δ: 1.29-1.19 (4H, m), 2.81 (1H, t, J=6.97 Hz), 3.41 (3H, s), 3.74-3.59 (3H, m), 3.96-3.82 (1H, m), 4.68 (2H, d, J=5.71 Hz), 5.09 (0H, d, J=10.91 Hz), 5.65 (1H, d, J=12.09 Hz), 6.93-6.80 (2H, m), 7.47-7.36 (1H, m), 8.44 (1H, s), 10.24 (1H, t, J=12.09 Hz), 11.39 (1H, br s)
- 1H-NMR (CDCl3) δ: 1.17-0.96 (6H, m), 1.51 (1H, s), 3.40 (3H, s), 3.62 (3H, br s), 4.08-3.96 (1H, m), 4.69 (1H, d, J=7.39 Hz), 5.07-5.02 (1H, br m), 5.81-5.78 (1H, br m), 6.92-6.80 (2H, m), 7.48-7.36 (1H, m), 8.58 (1H, s), 10.25 (1H, t, J=7.39 Hz), 11.47 (1H, br s)
- 1H-NMR (CDCl3) δ: 3.16 (3H, s), 3.51 (2H, br s), 3.68 (2H, br s), 4.67 (2H, d, J=6.71 Hz), 5.36 (1H, br s), 6.02 (1H, br s), 6.68 (1H, s), 6.90-6.78 (2H, m), 7.46-7.34 (1H, m), 7.68 (1H, s), 8.43 (1H, s), 10.27 (1H, br s), 11.41 (1H, br s)
- 1H-NMR (CDCl3) δ: 3.12 (3H, s), 3.54-3.44 (2H, m), 3.69-3.61 (2H, m), 4.67 (2H, d, J=6.55 Hz), 5.53-5.25 (1H, m), 5.88-5.62 (1H, m), 6.94-6.76 (2H, m), 7.25 (1H, dd, J=5.04, 4.40 Hz), 7.45-7.34 (1H, m), 7.71 (1H, dd, J=4.40, 1.10 Hz), 7.81 (1H, dd, J=5.04, 1.10 Hz), 8.43 (1H, s), 10.30-10.24 (1H, m)
- 1H-NMR (CDCl3) δ: 3.11 (3H, s), 3.52 (2H, br s), 3.70 (1H, br s), 3.78 (1H, br s), 4.64 (2H, d, J=5.9 Hz), 5.28 (1H, br s), 5.75 (1H, br s), 6.77-6.87 (2H, m), 7.25-7.27 (1H, m), 7.33-7.41 (1H, m), 7.95 (1H, d, J=4.9 Hz), 8.04 (1H, br s), 8.44 (3H, s), 10,20 (1H, br s).
- 1H-NMR (CDCl3) δ: 3.08 (6H, s), 3.35 (3H, s), 3.57 (2H, t, J=4.5 Hz), 3.69 (2H, br s), 4.63 (2H, d, J=5.7 Hz), 5.07 (2H, s), 6.76-6.85 (2H, m), 7.31-7.39 (1H, m), 8.30 (1H, s), 10.33 (1H, t, J=5.7 Hz), 11.40 (1H, br s).
- 1H-NMR (CDCl3) δ: 3.18 (3H, s), 3.38 (3H, s), 3.64 (2H, s), 3.70 (1H, br s), 3.87 (1H, m), 4.64 (2H, d, J=5.7 Hz), 5.15 (1H, d, J=13.2 Hz), 5.49 (1H, d, J=13.2 Hz), 6.77-6.86 (2H, m), 7.33-7.41 (1H, m), 8.55 (1H, s), 10.10 (1H, t, 5.7 Hz), 11.55 (1H, br s).
- 1H-NMR (CDCl3) δ: 2.20 (3H, s), 3.37 (3H, s), 3.60 (2H, br s), 3.67 (1H, br s), 3.81 (1H, br s), 4.64 (2H, d, J=5.9 Hz), 5.02 (1H, br s), 5.61 (1H, br s), 6.77-6.86 (2H, m), 7.33-7.41 (1H, m), 8.43 (1H, s), 10.17 (1H, t, J=5.9 Hz), 11.39 (1H, br s).
- The present invention further provides the following compounds.
- Chemical names and physical properties of above compounds are shown below.
- 1H-NMR (CDCl3) δ: 1.28 (6.0H, s), 1.60-1.78 (2.0H, m), 3.27 (2.0H, br s), 3.41 (3.0H, s), 3.63-3.82 (4.0H, m), 4.68 (2.0H, d, J=5.71 Hz), 4.83 (2.0H, br s), 6.80-6.90 (2.0H, m), 7.38-7.45 (1.0H, m), 8.50 (1.0H, s), 10.41 (1.0H, t, J=5.62 Hz).
- 1H-NMR (CDCl3) δ: 1.56-1.62 (1.0H, m), 1.92-2.01 (2.0H, m), 2.07-2.15 (1.0H, m), 2.50 (3.0H, s), 3.26 (1.0H, br s), 3.70-3.80 (1.0H, m), 3.82-3.92 (1.0H, m), 4.01-4.19 (3.0H, m), 4.30 (1.0H, br s), 4.66 (1.0H, br s), 4.67 (2.0H, d, J=5.37 Hz), 4.91 (1.0H, br s), 6.12 (1.0H, s), 6.79-6.90 (2.0H, m), 7.35-7.43 (1.0H, m), 8.44 (1.0H, s), 10.30-10.40 (1.0H, m), 11.70 (1.0H, br s).
- 1H-NMR (CDCl3) δ: 1.54-1.61 (1.0H, m), 1.92-2.01 (2.0H, m), 2.06-2.20 (1.0H, m), 2.51 (1.0H, t, J=2.47 Hz), 3.20 (2.0H, dd, J=13.73, 8.52 Hz), 3.75-3.83 (1.0H, m), 3.88-3.96 (2.0H, m), 4.03-4.20 (2.0H, m), 4.67 (2.0H, d, J=5.77 Hz), 4.87 (1.0H, d, J=13.46 Hz), 5.02 (1.0H, d, J=13.46 Hz), 6.78-6.88 (2.0H, m), 7.35-7.43 (1.0H, m), 8.58 (1.0H, s), 10.36 (1.0H, t, J=7.00 Hz).
- 1H-NMR (CDCl3) δ: 1.55-1.63 (2.0H, m), 1.75-1.87 (1.0H, m), 1.90-2.00 (2.0H, m), 2.05-2.17 (1.0H, m), 3.17-3.28 (2.0H, m), 3.35 (3.0H, s), 3.70-4.15 (6.0H, m), 4.67 (2.0H, d, J=5.71 Hz), 4.78 (1.0H, br s), 4.93 (1.0H, br s), 6.79-6.90 (2.0H, m), 7.35-7.44 (1.0H, m), 8.47 (1.0H, s), 10.41 (1.0H, t, J=7.00 Hz)
- 1H-NMR (CDCl3) δ: 1.15 (6.0H, d, J=6.04 Hz), 2.50 (3.0H, s), 3.48-3.55 (1.0H, m), 3.59-3.65 (2.0H, m), 3.65-3.72 (2.0H, m), 3.77 (1.0H, br s), 4.28 (1.0H, br s), 4.67 (2.0H, d, J=5.71 Hz), 4.67 (1.0H, br s), 4.79 (1.0H, br s), 6.12 (1.0H, s), 6.80-6.90 (2.0H, m), 7.37-7.42 (1.0H, m), 8.44 (1.0H, br s), 10.36 (1.0H, br s).
- 1H-NMR (CDCl3) δ: 1.93-2.01 (2.0H, m), 2.51 (3.0H, s), 3.33 (3.0H, s), 3.50 (2.0H, t, J=7.00 Hz), 3.69 (2.0H, br s), 4.26 (1.0H, br s), 4.60-4.70 (1.0H, m), 4.68 (2.0H, d, J=6.04 Hz), 6.14 (1.0H, s), 6.80-6.90 (2.0H, m), 7.35-7.46 (1.0H, m), 8.50 (1.0H, s), 10.37 (1.0H, br s), 11.80 (1.0H, br s).
- 1H-NMR (CDCl3) δ: 1.92-2.01 (2.0H, m), 2.08-2.16 (1.0H, m), 3.31 (1.0H, br s), 3.75 (1.0H, q, J=7.50 Hz), 3.86 (1.0H, q, J=7.39 Hz), 4.05-4.21 (2.0H, m), 4.39 (1.0H, s), 4.64 (2.0H, d, J=5.71 Hz), 4.73-4.92 (2.0H, m), 4.95-5.06 (2.0H, m), 6.80-6.88 (2.0H, m), 7.28-7.42 (3.0H, m), 7.81 (1.0H, t, J=6.88 Hz), 8.26 (1.0H, s), 8.65 (1.0H, d, J=4.03 Hz), 10.32-10.35 (1.0H, m).
- 1H-NMR (CDCl3) δ: 2.62 (3.0H, s), 3.37 (3.0H, s), 3.69 (2.0H, t, J=4.62 Hz), 3.81 (2.0H, br s), 4.35 (2.0H, br s), 4.64 (2.0H, d, J=5.71 Hz), 4.90 (2.0H, br s), 6.81-6.88 (2.0H, m), 7.15 (1.0H, d, J=7.72 Hz), 7.23 (1.0H, d, J=7.72 Hz), 7.32-7.42 (1.0H, m), 7.69 (1.0H, t, J=7.81 Hz), 8.21 (1.0H, s), 10.33 (1.0H, s).
- 1H-NMR (CDCl3) δ: 1.56-1.62 (1.0H, m), 1.92-2.01 (2.0H, m), 2.07-2.15 (1.0H, m), 2.50 (3.0H, s), 3.26 (1.0H, br s), 3.70-3.80 (1.0H, m), 3.82-3.92 (1.0H, m), 4.01-4.19 (3.0H, m), 4.30 (1.0H, br s), 4.66 (1.0H, br s), 4.67 (2.0H, d, J=5.37 Hz), 4.91 (1.0H, br s), 6.12 (1.0H, s), 6.79-6.90 (2.0H, m), 7.35-7.43 (1.0H, m), 8.44 (1.0H, s), 10.30-10.40 (1.0H, m), 11.70 (1.0H, br s).
- 1H-NMR (CDCl3) δ: 1.54-1.61 (1.0H, m), 1.92-2.01 (2.0H, m), 2.06-2.20 (1.0H, m), 2.51 (1.0H, t, J=2.47 Hz), 3.20 (2.0H, dd, J=13.73, 8.52 Hz), 3.75-3.83 (1.0H, m), 3.88-3.96 (2.0H, m), 4.03-4.20 (2.0H, m), 4.67 (2.0H, d, J=5.77 Hz), 4.87 (1.0H, d, J=13.46 Hz), 5.02 (1.0H, d, J=13.46 Hz), 6.78-6.88 (2.0H, m), 7.35-7.43 (1.0H, m), 8.58 (1.0H, a), 10.36 (1.0H, t, J=7.00 Hz).
- 1H-NMR (CDCl3) δ: 1.55-1.63 (2.0H, m), 1.75-1.87 (1.0H, m), 1.90-2.00 (2.0H, m), 2.05-2.17 (1.0H, m), 3.17-3.28 (2.0H, m), 3.35 (3.0H, s), 3.70-4.15 (6.0H, m), 4.67 (2.0H, d, J=5.71 Hz), 4.78 (1.0H, br s), 4.93 (1.0H, br s), 6.79-6.90 (2.0H, m), 7.35-7.44 (1.0H, m), 8.47 (1.0H, s), 10.41 (1.0H, t, J=7.00 Hz)
- 1H-NMR (CDCl3) δ: 1.52-1.61 (1.0H, m), 1.90-2.00 (2.0H, m), 2.05-2.19 (1.0H, m), 2.57 (3.0H, s), 3.75 (1.0H, q, J=7.23 Hz), 3.85 (1.0H, q, J=7.42 Hz), 4.00-4.20 (2.0H, m), 4.34 (1.0H, br s), 4.62 (2.0H, d, J=5.77 Hz), 4.77-5.05 (4.0H, m), 6.78-6.86 (2.0H, m), 7.12 (1.0H, d, J=7.69 Hz), 7.18 (1.0H, d, J=7.97 Hz), 7.25-7.40 (1.0H, m), 7.64 (1.0H, t, J=7.83 Hz), 8.20 (1.0H, br s), 10.33 (1.0H, br s).
- 1H-NMR (CDCl3) δ: 1.92-2.01 (2.0H, m), 2.08-2.16 (1.0H, m), 3.31 (1.0H, br s), 3.75 (1.0H, q, J=7.50 Hz), 3.86 (1.0H, q, J=7.39 Hz), 4.05-4.21 (2.0H, m), 4.39 (1.0H, s), 4.64 (2.0H, d, J=5.71 Hz), 4.73-4.92 (2.0H, m), 4.95-5.06 (2.0H, m), 6.80-6.88 (2.0H, m), 7.28-7.42 (3.0H, m), 7.81 (1.0H, t, J=6.88 Hz), 8.26 (1.0H, s), 8.65 (1.0H, d, J=4.03 Hz), 10.32-10.35 (1.0H, m).
- 1H-NMR (CDCl3) δ: 1.52-1.61 (1.0H, m), 1.90-2.00 (2.0H, m), 2.05-2.19 (1.0H, m), 2.57 (3.0H, s), 3.75 (1.0H, q, J=7.23 Hz), 3.85 (1.0H, q, J=7.42 Hz), 4.00-4.20 (2.0H, m), 4.34 (1.0H, br s), 4.62 (2.0H, d, J=5.77 Hz), 4.77-5.05 (4.0H, m), 6.78-6.86 (2.0H, m), 7.12 (1.0H, d, J=7.69 Hz), 7.18 (1.0H, d, J=7.97 Hz), 7.25-7.40 (1.0H, m), 7.64 (1.0H, t, J=7.83 Hz), 8.20 (1.0H, br s), 10.33 (1.0H, br s).
- 1H-NMR (CDCl3) δ: 1.13 (6.0H, d, J=6.21 Hz), 3.56-3.64 (1.0H, m), 3.68-3.71 (2.0H, m), 3.81 (2.0H, br s), 4.41 (2.0H, br s), 4.62 (2.0H, d, J=6.21 Hz), 4.92 (2.0H, br s), 6.79-6.86 (2.0H, m), 7.31-7.42 (3.0H, m), 7.83 (1.0H, t, J=7.97 Hz), 8.21 (1.0H, s), 8.65-8.67 (1.0H, m), 10.31 (1.0H, t, J=10.00 Hz).
- 1H-NMR (CDCl3) δ: 1.14 (3.0H, t, J=6.97 Hz), 1.90-2.00 (2.0H, m), 2.50 (3.0H, s), 3.46 (2.0H, q, J=7.05 Hz), 3.53 (2.0H, t, J=5.62 Hz), 3.70 (2.0H, br s), 4.26 (2.0H, br s), 4.60-4.71 (2.0H, m), 4.66 (2.0H, d, J=6.04 Hz), 6.14 (1.0H, s), 6.78-6.88 (2.0H, m), 7.35-7.44 (1.0H, m), 8.49 (1.0H, br s), 10.39 (1.0H, br s).
- 1H-NMR (CDCl3) δ: 1.50-1.66 (1.0H, m), 1.89-2.03 (2.0H, m), 2.06-2.21 (1.0H, m), 3.20 (1.0H, br s), 3.78 (1.0H, dd, J=15.19, 6.97 Hz), 3.83-3.93 (1.0H, m), 3.97-4.18 (2.0H, m), 4.25 (2.0H, br s), 4.59-4.66 (1.0H, m), 4.65 (2.0H, d, J=5.54 Hz), 4.89 (1.0H, br s), 6.79-6.90 (2.0H, m), 7.13 (1.0H, d, J=5.04 Hz), 7.19 (1.0H, d, J=2.01 Hz), 7.33-7.41 (1.0H, m), 7.41-7.46 (1.0H, m), 8.25 (1.0H, br s), 10.30-10.34 (1.0H, br m), 11.69 (1.0H, br s).
- 1H-NMR (CDCl3) δ: 1.50-1.66 (1.0H, m), 1.89-2.03 (2.0H, m), 2.06-2.21 (1.0H, m), 3.20 (1.0H, br s), 3.78 (1.0H, dd, J=15.19, 6.97 Hz), 3.83-3.93 (1.0H, m), 3.97-4.18 (2.0H, m), 4.25 (2.0H, br s), 4.59-4.66 (1.0H, m), 4.65 (2.0H, d, J=5.54 Hz), 4.89 (1.0H, br s), 6.79-6.90 (2.0H, m), 7.13 (1.0H, d, J=5.04 Hz), 7.19 (1.0H, d, J=2.01 Hz), 7.33-7.41 (1.0H, m), 7.41-7.46 (1.0H, m), 8.25 (1.0H, br s), 10.30-10.34 (1.0H, br m), 11.69 (1.0H, br s).
- 1H-NMR (CDCl3) δ: 1.51-1.68 (1.0H, m), 1.91-2.02 (2.0H, m), 2.06-2.20 (1.0H, m), 3.22 (1.0H, s), 3.79 (1.0H, dd, J=15.36, 6.97 Hz), 3.85-3.95 (1.0H, m), 4.01-4.35 (4.0H, m), 4.64 (2.0H, d, J=5.87 Hz), 4.94 (2.0H, br s), 6.29 (1.0H, d, J=3.02 Hz), 6.35 (1.0H, d, J=1.85 Hz), 6.78-6.87 (2.0H, m), 7.32-7.42 (1.0H, m), 7.47 (1.0H, d, J=1.85 Hz), 8.20 (1.0H, s), 10.31 (1.0H, t, J=7.00 Hz).
- 1H-NMR (CDCl3) δ: 1.51-1.68 (1.0H, m), 1.91-2.02 (2.0H, m), 2.06-2.20 (1.0H, m), 3.22 (1.0H, s), 3.79 (1.0H, dd, J=15.36, 6.97 Hz), 3.85-3.95 (1.0H, m), 4.01-4.35 (4.0H, m), 4.64 (2.0H, d, J=5.87 Hz), 4.94 (2.0H, br s), 6.29 (1.0H, d, J=3.02 Hz), 6.35 (1.0H, d, J=1.85 Hz), 6.78-6.87 (2.0H, m), 7.32-7.42 (1.0H, m), 7.47 (1.0H, d, J=1.85 Hz), 8.20 (1.0H, s), 10.31 (1.0H, t, J=7.00 Hz).
- 1H-NMR (CDCl3) δ: 1.22 (3.0H, t, J=6.97 Hz), 3.55 (2.0H, q, J=6.99 Hz), 3.68-3.84 (3.0H, m), 4.26 (2.0H, s), 4.65 (2.0H, d, J=5.88 Hz), 4.85 (2.0H, br s), 6.30 (1.0H, d, J=3.36 Hz), 6.38 (1.0H, t, J=2.43 Hz), 6.79-6.90 (2.0H, m), 7.33-7.43 (1.0H, m), 7.48 (1.0H, t, J=0.92 Hz), 8.22 (1.0H, s), 10.32 (1.0H, t, J=7.00 Hz), 11.66 (1.0H, br s).
- 1H-NMR (CDCl3) δ: 1.16 (3.0H, t, J=7.05 Hz), 1.90-2.01 (2.0H, m), 3.47 (2.0H, q, J=6.99 Hz), 3.54 (2.0H, t, J=5.62 Hz), 3.70 (2.0H, br s), 4.23 (2.0H, s), 4.65 (2.0H, d, J=5.54 Hz), 6.32 (1.0H, d, J=2.85 Hz), 6.38 (1.0H, dd, J=3.27, 1.76 Hz), 6.79-6.87 (2.0H, m), 7.32-7.44 (1.0H, m), 7.48 (1.0H, dd, J=1.93, 0.76 Hz), 8.29 (1.0H, s), 10.34 (1.0H, t, J=7.00 Hz).
- 1H-NMR (CDCl3) δ: 0.92 (3.0H, t, J=7.39 Hz), 1.53-1.65 (2.0H, m), 1.92-2.03 (2.0H, m), 3.39 (2.0H, t, J=6.71 Hz), 3.55 (2.0H, t, J=5.54 Hz), 3.71 (2.0H, br s), 4.24 (2.0H, s), 4.61-4.85 (2.0H, m), 4.66 (2.0H, d, J=5.88 Hz), 6.33 (1.0H, d, J=3.36 Hz), 6.39 (1.0H, br s), 6.80-6.91 (2.0H, m), 7.33-7.44 (1.0H, m), 7.49 (1.0H, br s), 8.30 (1.0H, s), 10.33-10.36 (1.0H, br m).
- 1H-NMR (CDCl3) δ: 2.22 (2H, t), 2.24 (3H, s), 2.74 (2H, br), 3.40 (3H, s), 3.68 (2H, t, J=3.68 Hz), 3.78 (2H, t, J=3.68 Hz), 4.68 (2H, s, J=5.71 Hz), 4.77 (2H, br), 6.77-6.91 (2H, m), 7.36 (1.0H, m), 8.40 (1.0H, s), 10.35 (1.0H, s), 11.66 (1.0H, br)
- 1H-NMR (CDCl3) δ: 1.16 (6H, d, J=6.2 Hz), 1.21 (3H, t, J=7.22 Hz), 1.91-1.99 (2H, m), 3.15 (2H, q, J=7.16 Hz), 3.58 (2H, t, J=5.71 Hz), 3.59 (1H, q, J=6.2 Hz), 3.70 (2H, t, J=6.71 Hz), 4.71 (2H, d, J=5.88 Hz), 4.74 (2H, br), 6.81-6.90 (2H, m), 7.38-7.46 (1H, m), 8.50 (1.0H, s), 10.43 (1H, s), 11.74 (1H, s).
- 1H-NMR (CDCl3) δ: 4.21 (2H, s), 4.64 (2H, d, J=5.88 Hz), 4.79 (2H, s), 5.01 (1H, s), 6.82-6.86 (1.0H, m), 7.03 (1H, dd, J=5.20, 3.53 Hz), 7.11-7.12 (1H, m), 7.20 (1H, d, J=7.72 Hz), 7.36-7.38 (2.0H, m), 7.77 (1H, td, J=7.68, 1.73 Hz), 8.28 (1H, s), 8.65 (1H, d, J=5.04 Hz), 10.30 (1H, t, J=6.04 Hz).
- 1H-NMR (CDCl3) δ: 4.24 (2H, s), 4.64 (2H, d, J=5.88 Hz), 4.82 (2H, br), 4.85 (2H, s) 6.40 (1H, dd, J=3.27, 1.93 Hz), 6.45 (1H, d, J=3.36 Hz), 6.80-6.89 (2H, m), 7.27 (1H, d, J=7.72 Hz), 7.34-7.39 (2H, m), 7.41-7.42 (1H, m), 7.77 (1H, td, J=7.72, 1.68 Hz), 8.28 (1.0H, s), 8.65 (1H, d, J=4.70 Hz), 10.30 (0.6H, t, J=5.71 Hz).
- 1H-NMR (CDCl3) δ: 1.58-1.77 (15H, m), 2.03 (2H, s), 4.34 (2H, s), 4.64 (2H, d, J=5.88 Hz), 4.80 (2H, br), 6.79-6.88 (2H, m), 7.33-7.40 (3H, m), 7.78 (1H, dt, J=7.55, 1.68 Hz), 8.32 (1H, s), 8.63-8.66 (1H, m), 10.36 (1H, t, J=5.88 Hz), 11.73 (1H, br).
- 1H-NMR (CDCl3) δ: 1.37 (6H, t, J=7.14 Hz), 2.00 (2H, s), 3.34 (2H, br) 3.41 (3H, s), 3.66 (2H, br), 3.74 (2H, br), 4.15 (4H, q, J=7.14 Hz), 4.67 (2H, d, J=6.04 Hz), 4.82 (2H, s), 6.79-6.88 (2.1H, m), 7.37-7.42 (1.0H, m), 8.51 (1.0H, s), 10.36 (1.0H, t, J=5.91 Hz), 11.58 (1H, br).
- 1H-NMR (CDCl3) δ: 4.18 (2H, s), 4.64 (2H, d, J=5.88 Hz), 4.69 (2H, br), 4.73 (2H, s), 6.01 (2H, s), 6.80 (1H, s), 6.83-6.88 (2H, m), 7.21 (1H, d, J=7.72 Hz), 7.32-7.45 (3H, m), 7.75 (1H, td, J=7.68, 1.79 Hz), 8.30 (1H, s), 8.63 (1H, d, J=5.04 Hz), 10.32 (1H, t, J=5.88 Hz).
- 1H-NMR (CDCl3) δ: 3.22 (2H, t, J=8.73 Hz), 4.19 (2H, s), 4.60 (2.0H, t, J=8.64 Hz), 4.73 (4H, s), 6.75 (1H, d, J=7.39 Hz), 6.78-6.87 (2H, m), 7.07 (1H, d, J=8.06 Hz), 7.17-7.22 (2H, m), 7.31-7.41 (2H, m), 7.78 (1H, t, J=7.30 Hz), 8.24 (1H, s), 8.63 (1H, d, J=4.70 Hz), 10.29 (1H, t, J=8.73 Hz), 11.78 (1H, br).
- 1H-NMR (CDCl3) δ: 4.23 (3H, s), 4.27 (4H, s), 4.62 (2H, d, J=6.04 Hz), 4.71 (4H, s), 6.78-6.87 (5H, m), 7.22 (1H, d, J=7.72 Hz), 7.34-7.42 (2H, m), 7.79 (1H, d, J=6.71 Hz), 8.23 (1H, s), 8.65 (1H, d, J=4.87 Hz), 10.30 (1H, d, J=6.04 Hz), 11.81 (1H, br).
- 1H-NMR (CDCl3) δ: 3.32-3.98 (9H, m), 4.43 (2H, br), 4.63 (2H, d, J=5.87 Hz), 4.94 (2H, br), 6.80-6.88 (2H, m), 7.32-7.45 (3H, m), 7.86 (1H, t, J=8.73 Hz), 8.27 (1H, s), 8.66 (1H, d, J=4.87 Hz), 10.30 (1.0H, d, J=5.87 Hz), 11.60 (1H, br).
- 1H-NMR (CDCl3) δ: 1.03 (6.0H, t, J=7.05 Hz), 2.56 (4H, q, J=7.23 Hz), 2.66 (2H, t, J=4.89 Hz), 3.16 (2H, br), 3.38 (3H, s), 3.65 (2H, t, J=5.20 Hz), 3.76 (2H, br), 4.66 (2H, d, J=5.87 Hz), 4.90 (2H, s), 6.79-6.88 (2H, m), 7.35-7.43 (1H, m), 8.54 (1H, s), 10.40 (1.0H, t, J=5.79 Hz).
- 1H-NMR (CDCl3) δ: 1.13 (6H, d, J=6.04 Hz), 1.91-1.99 (2H, m), 2.55 (1H, t, J=2.52 Hz), 3.54 (2H, t, J=5.71 Hz), 3.58 (1H, t, J=6.21 Hz), 3.70 (2H, t, J=6.71 Hz), 3.94 (2H, d, J=2.35 Hz), 4.67 (2H, d, J=5.87 Hz), 4.85 (2H, s), 6.79-6.88 (2H, m), 7.36-7.44 (1H, m), 8.57 (1H, s), 10.38 (1H, br), 11.74 (1H, br).
- 1H-NMR (CDCl3) δ: 0.89 (6H, t, J=7.39 Hz), 1.50 (4H, q, J=7.39 Hz), 1.46-1.57 (4H, m), 3.09 (2H, br), 3.39 (3H, s), 3.66 (2H, t, J=4.12 Hz), 3.74 (2H, br), 4.67 (2H, d, J=5.54 Hz), 4.80 (2H, br), 6.80-6.87 (2H, m), 7.36-7.43 (1H, m), 8.50 (1H, s), 10.41 (1.0H, t, J=5.54 Hz), 11.60 (1H, br).
- 1H-NMR (CDCl3) δ: 1.13 (6H, d, J=6.13 Hz), 1.92-2.01 (2H, m), 3.52-3.60 (3H, m), 3.75 (2H, br), 4.36 (2H, br), 4.66 (2H, d, J=5.88 Hz), 4.81 (2H, br), 6.81-6.90 (2.0H, m), 7.35-7.43 (3H, m), 7.77-7.84 (1H, m), 8.36 (1.0H, s), 8.66 (1H, d, J=4.03 Hz), 10.38 (1H, s), 11.87 (1H, br).
- 1H-NMR (CDCl3) δ: 3.39 (3H, s), 3.70 (2H, t, J=4.53 Hz), 3.83 (2H, t, J=4.03 Hz), 4.43 (2H, br), 4.65 (2H, d, J=5.88 Hz), 4.90 (2H, br), 6.81-6.88 (2H, m), 7.34-7.42 (1H, m), 8.23 (1H, s), 8.90 (1H, d, J=1.51 Hz), 10.32 (1H, t, J=5.21 Hz), 11.68 (1H, br).
- 1H-NMR (CDCl3) δ: 3.34 (3H, s), 3.66 (2H, t, J=4.50 Hz), 3.75 (2H, br), 4.44 (2H, br), 4.62 (2H, d, J=5.95 Hz), 4.89 (2H, br), 6.78-6.85 (2H, m), 7.31-7.38 (1H, m), 8.39 (1H, s), 8.80 (1H, s), 10.25 (1H, t, J=5.64 Hz).
- 1H-NMR (CDCl3) δ: 2.74 (3H, s), 3.35 (3H, s), 3.65 (2H, t, J=4.50 Hz), 3.76 (2H, t, J=4.27 Hz), 4.27 (2H, br), 4.60 (2H, d, J=5.80 Hz), 4.86 (2H, br), 6.76-6.85 (2H, m), 6.98 (1H, s), 7.29-7.37 (1H, m), 8.16 (1.0H, s), 10.26 (1H, t, J=5.95 Hz), 11.65 (1H, br).
- 1H-NMR (CDCl3) δ: 2.26 (3H, s), 2.31 (3H, s), 3.35 (3H, s), 3.63 (3H, br), 3.97 (3H, br), 4.62 (2H, d, J=5.64 Hz), 4.75 (2H, br), 6.77-6.86 (2H, m), 7.31-7.39 (1H, m), 8.21 (1H, s), 10.22 (1H, t, J=5.64 Hz), 11.57 (1H, br).
- 1H-NMR (CDCl3) δ: 0.00 (2H, br), 0.58 (2H, br), 0.84-0.97 (1H, m), 1.10 (3H, s), 1.12 (3H, s), 1.86-1.94 (2H, m), 2.91 (2H, br), 3.47-3.57 (3H, m), 3.65 (2H, br), 4.64 (2H, d, J=5.80 Hz), 4.77 (2H, br), 6.76-6.85 (2H, m), 7.32-7.40 (1H, m), 8.52 (1H, s), 10.38 (1H, t, J=5.80 Hz), 11.70 (1H, br).
- 1H-NMR (CDCl3) δ: 1.13 (6H, d, J=6.04 Hz), 1.93-2.01 (2H, m), 3.4-3.59 (3H, m), 3.75 (2H, br), 4.49 (2H, br), 4.67 (2H, d, J=5.54 Hz), 4.86 (2H, br), 6.82-6.89 (2H, m), 7.37-7.45 (1H, m), 8.48 (1H, s), 8.85 (1H, s), 10.32 (1H, br).
- 1H-NMR (CDCl3) δ: 1.13 (6H, d, J=6.04 Hz), 1.88-1.97 (2H, m), 3.25 (2H, br), 3.38 (3H, s), 3.52 (2H, t, J=5.54 Hz), 3.56-3.60 (2H, m), 3.67 (2H, br), 4.67 (2H, d, J=6.21 Hz), 4.82 (2H, br), 6.79-6.88 (2H, m), 7.35-7.43 (1H, m), 8.51 (1H, s), 10.42 (1H, t, J=6.04 Hz), 11.79 (1H, br).
- 1H-NMR (CDCl3) δ: 1.12 (6H, d, J=6.04 Hz), 1.91-2.00 (2H, m), 3.52-3.59 (3H, m), 3.74 (2H, br), 4.40 (2H, br), 4.64 (2H, d, J=5.71 Hz), 4.82 (2H, br), 6.80-6.87 (2H, m), 7.31-7.41 (1H, m), 8.26 (1H, s), 8.89 (1H, s), 10.34 (1H, t, J=5.71 Hz), 11.84 (1H, br).
- 1H-NMR (CDCl3) δ: 1.09 (6H, d, J=6.21 Hz), 1.87-1.95 (2H, m), 2.30 (3H, s), 3.34 (3H, s), 3.49-3.57 (3H, m), 3.99 (2H, br), 4.65 (2H, d, J=5.71 Hz), 4.65 (2H, br), 6.79-6.89 (2H, m), 7.34-7.42 (1H, m), 8.29 (1H, s), 10.29 (1H, t, J=5.71 Hz), 11.77 (1H, br).
- 1H-NMR (CDCl3) δ: 1.14 (6H, d, J=6.04 Hz), 1.78 (2H, br), 1.88-1.97 (2H, m), 3.17 (2H, t, J=6.71 Hz), 3.35 (3H, s), 3.46-3.58 (5H, m), 3.68 (2H, br), 4.66 (2H, d, J=6.04 Hz), 4.71 (2H, br), 6.80-6.87 (2.4H, m), 7.36-7.44 (1H, m), 8.46 (1H, s), 10.41 (1H, t, J=6.71 Hz), 11.75 (1H, br).
- 1H-NMR (CDCl3) δ: 1.10 (6H, d, J=6.04 Hz), 1.88-1.96 (2H, m), 2.50 (3H, s), 3.50-3.56 (3H, m), 3.71 (2H, br), 4.25 (2H, br), 4.66 (2H, d, J=6.21 Hz), 4.66 (2H, br), 6.79-6.89 (2H, m), 7.35-7.43 (1H, m), 8.48 (1H, s), 10.37 (1H, t, J=6.21 Hz), 11.85 (1H, br).
- 1H-NMR (CDCl3) δ: 1.30 (6H, d, J=6.71 Hz), 4.27 (2H, br), 4.60 (2H, d, J=5.80 Hz), 4.76 (2H, s), 4.90 (1H, q, J=6.71 Hz), 6.75-6.84 (2H, m), 7.28-7.37 (3H, m), 7.77 (1H, dd, J=8.54, 6.86 Hz), 8.22 (1H, s), 8.61 (1H, d, J=4.12 Hz), 10.31 (1H, t, J=6.71 Hz), 11.89 (1H, br).
- 1H-NMR (CDCl3) δ: 1.32 (6H, d, J=6.71 Hz), 4.35 (2H, br), 4.62 (2H, d, J=5.80 Hz), 4.78 (2H, br), 4.92 (1H, q, J=6.79 Hz), 6.76-6.85 (2H, m), 7.31-7.39 (1H, m), 8.43 (1H, s), 8.82 (1H, s), 10.27 (1H, t, J=6.79 Hz).
- 1H-NMR (CDCl3) δ: 1.09 (6H, d, J=6.10 Hz), 1.83-1.91 (2H, m), 3.48-3.55 (3H, m), 3.62 (2H, br), 4.06 (2.5H, s), 4.62 (2H, d, J=5.80 Hz), 4.62 (2H, br), 6.45 (1H, s), 6.76-6.84 (2H, m), 7.31-7.39 (3H, m), 7.48 (1H, d, J=1.68 Hz), 8.38 (1H, s), 10.33 (1H, t, J=5.80 Hz), 11.75 (2H, br).
- 1H-NMR (CDCl3) δ: 1.85-1.94 (2H, m), 3.30 (3H, s), 3.46 (2H, t, J=5.64 Hz), 3.61 (2H, br), 4.05 (2H, br), 4.62 (2H, d, J=5.80 Hz), 4.62 (2H, br), 6.45 (1H, d, J=1.07 Hz), 6.76-6.85 (2H, m), 7.30-7.40 (3H, m), 7.48 (1H, t, J=1.68 Hz), 8.37 (1H, s), 10.31 (1H, t, J=5.80 Hz), 11.70 (1H, br).
- 1H-NMR (CDCl3) δ: 1.15 (3.0H, t, J=7.02 Hz), 2.46 (3H, s), 3.48 (2.4H, q, J=7.02 Hz), 3.65 (2H, t, J=4.12 Hz), 3.75 (2H, br), 4.23 (2H, br), 4.63 (2H, d, J=5.95 Hz), 4.74 (2H, br), 6.09 (1H, s), 6.76-6.85 (2H, m), 7.31-7.39 (1H, m), 8.40 (1H, s), 10.31 (1H, t, J=5.95 Hz), 11.66 (1H, br).
- 1H-NMR (CDCl3) δ: 1.33 (6H, d, J=7.22 Hz), 2.52 (3H, s), 4.22 (2H, br), 4.67 (2H, d, J=5.88 Hz), 4.67 (2H, br), 4.91 (1H, q, J=7.22 Hz), 6.15 (1H, s), 6.80-6.90 (2H, m), 7.36-7.44 (1H, m), 8.48 (1H, s), 10.38 (1H, t, J=5.54 Hz), 11.89 (1H, br).
- 1H-NMR (CDCl3) δ: 1.93-2.03 (3H, m), 2.09-2.18 (1H, m), 3.19 (1H, br), 3.76-3.84 (1H, m), 3.87-3.94 (1H, m), 4.02-4.17 (4H, m), 4.66 (2H, d, J=5.54 Hz), 4.66 (1H, br), 4.89 (1H, br), 6.49 (1H, s), 6.80-6.89 (2H, m), 7.35-7.44 (2H, m), 7.54 (1H, s), 8.38 (1H, s), 10.35 (1H, br), 11.67 (1H, br).
- 1H-NMR (CDCl3) δ: 2.47 (3H, s), 4.12 (2H, br), 4.65 (2H, d, J=5.54 Hz), 4.65 (2H, br), 4.96 (2H, br), 6.01 (1H, s), 6.79-6.88 (2H, m), 7.01 (1H, dd, J=5.20, 3.36 Hz), 7.10 (1H, d, J=2.85 Hz), 7.21-7.41 (2H, m), 8.41 (1H, s), 10.31 (1H, br), 11.56 (1H, br).
- 1H-NMR (CDCl3) δ: 2.48 (3H, s), 4.17 (2H, br), 4.67 (2H, d, J=6.21 Hz), 4.73 (2H, br), 4.81 (2H, br), 6.07 (1. H, s), 6.40 (1H, dd, J=3.36, 1.85 Hz), 6.45 (1H, d, J=3.36 Hz), 6.81-6.90 (2H, m), 7.35-7.43 (2H, m), 8.44 (1H, s), 10.32 (1H, br), 11.58 (1H, br).
- 1H-NMR (CDCl3) δ: 1.93-2.03 (3H, m), 2.09-2.18 (1H, m), 3.19 (1H, br), 3.76-3.84 (1H, m), 3.87-3.94 (1H, m), 4.02-4.17 (4H, m), 4.66 (2H, d, J=5.54 Hz), 4.66 (1H, br), 4.89 (1H, br), 6.49 (1H, s), 6.80-6.89 (2H, m), 7.35-7.44 (2H, m), 7.54 (1H, s), 8.38 (1H, s), 10.35 (1H, br), 11.67 (1H, br).
- 1H-NMR (CDCl3) δ: 1.12 (61-1, d, J=6.04 Hz), 1.90-1.98 (2H, m), 3.51-3.59 (3H, m), 3.70 (2H, br), 4.24 (2H, s), 4.65 (2H, d, J=5.71 Hz), 4.70 (2H, br), 6.32 (1H, d, J=3.19 Hz), 6.37-6.39 (1H, m), 6.79-6.88 (2H, m), 7.34-7.42 (1H, m), 7.48 (1H, d, J=1.68 Hz), 8.30 (1H, s), 10.35 (1H, br), 11.80 (2H, br).
- NMR (DMSO-d6) δ: 1.85 (2H, m), 3.24 (3H, s), 3.40 (2H, t, J=6.0 Hz), 3.54 (2H, t, J=7.2 Hz), 4.46 (2H, d), 4.47 (2H, s), 4.98 (2H, br s), 6.98-7.59 (6H, m), 7.81 (1H, s), 10.17 (1H, t, J=5.9 Hz), 11.86 (1H, s).
- NMR (DMSO-d6) δ: 0.85 (3H, t, J=7.3 Hz), 1.49 (2H, q, J=7.1 Hz), 1.82 (2H, t, J=6.7 Hz), 2.87 (3H, s), 3.29 (2H, t, J=10 Hz), 3.42 (2H, t, J=5.8 Hz), 3.51-3.55 (2H, m), 4.53 (2H, d, J=6.0 Hz), 4.80 (2H, s), 7.08 (01H, d, J=8.8 Hz), 7.24 (1H, s), 7.40 (1H, d, J=7.1 Hz), 8.27 (1H, s), 10.37 (1H, s).
- NMR (DMSO-d6) δ: 2.69 (3H, s), 3.16 (2H, t, J=8.8 Hz), 4.54 (6H, m), 4.76 (2H, s), 6.73 (1H, d, J=8.06 Hz), 7.10 (2H, m), 7.23 (2H, m), 7.39 (1H, m), 8.22 (1H, s), 10.35 (1H, s).
- NMR (DMSO-d6) δ: 1.61 (1H, m), 1.91-2.01 (1H, m), 2.61 (1H, m), 2.88 (3H, s), 3.42-3.51 (6H, m), 4.54 (2H, d, J=5.7 Hz), 4.84 (2H, s), 7.04-7.10 (1H, m), 7.20-7.28 (1H, m), 7.41 (1H, m), 8.25 (1H, s), 10.38 (1H, s).
- NMR (DMSO-d6) δ: 2.72 (3H, s), 4.52 (2H, s), 4.56 (2H, s), 4.80 (1H, s), 6.54 (1H, s), 7.06 (1H, td, J=8.5, 2.6 Hz), 7.20-7.29 (1H, m), 7.40 (1.0H, dd, J=15.4, 8.6 Hz), 7.67 (1H, s), 7.75 (1H, s), 8.24 (1H, s), 10.30 (1H, t, J=6.0 Hz).
- NMR (DMSO-d6) δ: 2.82 (3H, s), 3.01 (1H, dd, J=16.2, 6.6 Hz), 3.56-3.85 (2H, m), 4.50 (2H, d, J=5.7 Hz), 4.78-5.12 (4H, m), 6.77-6.86 (2H, m), 7.03-7.12 (2H, m), 7.24 (2H, m), 7.40 (1H, dd, J=15.3, 8.6 Hz), 8.21 (1H, s), 10.39 (1H, s), 11.59 (1H, br s).
- NMR (DMSO-d6) δ: 2.06 (2H, dd, J=10.6, 4.0 Hz), 2.88 (3H, s), 3.65 (2H, t, J=7.0 Hz), 4.04 (2H, t, J=6.1 Hz), 4.53 (2H, d, J=5.9 Hz), 4.84 (2H, s), 6/90-7.30 (m, 8H), 8.26 (1H, s), 10.36 (1H, s).
- NMR (DMSO-d6) δ: 1.24 (2H, m), 1.58 (1H, d, J=12.4 Hz), 1.91 (1H, m), 2.91 (3H, s), 3.36 (4H, m), 3.85 (2H, d, J=9.4 Hz), 4.53 (2H, d, J=5.5 Hz), 4.83 (2H, s), 7.06 (1H, dd, J=9.5, 7.1 Hz), 7.19-7.27 (1H, m), 7.40 (1H, dd, J=15.4, 8.6 Hz), 8.29 (1H, s), 10.35 (1H, t, J=5.5 Hz).
- NMR (DMSO-d6) δ: 0.84 (3H, t, J=7.8 Hz), 1.48 (2H, m), 2.87 (3H, s), 3.35 (2H, m), 3.60 (2H, m), 4.53 (2H, d, J=5.7 Hz), 4.83 (2H, s), 7.09 (1H, m), 7.26 (1H, m), 7.41 (1H, m), 8.28 (1H, s), 10.34 (1H, t, J=5.7 Hz), 11.73 (1H, br s).
- NMR (DMSO-d6) δ: 2.87 (3H, s), 3.89 (2H, s), 4.21 (2H, t, J=4.7 Hz), 4.53 (2H, d, J=6.4 Hz), 4.95 (2H, s), 7.18 (8H, m), 8.31 (1H, s), 10.32 (1H, t, J=6.0 Hz).
- NMR (DMSO-d6) δ: 1.08 (3H, t, J=6.9 Hz), 1.82 (2H, t, J=6.6 Hz), 2.87 (3H, s), 3.42 (4H, m), 3.53 (2H, t, J=7.2 Hz), 4.53 (2H, d, J=6.0 Hz), 4.82 (2H, s), 7.06 (1H, m), 7.24 (1H, m), 7.40 (1H, m), 8.30 (1H, s), 10.33 (1H, t, J=6.0 Hz).
- NMR (DMSO-d6) δ: 2.10 (6H, s), 2.82 (3H, s), 3.59 (2H, s), 4.54 (2H, d, J=5.9 Hz), 4.85 (2H, s), 7.04-7.10 (1H, m), 7.25 (1H, m), 7.41 (1H, m), 8.31 (1H, s), 10.32 (1H, t, J=5.9 Hz), 11.81 (1H, br s).
- NMR (DMSO-d6) δ: 1.81-1.90 (2H, m), 3.24 (3.6H, s), 3.39 (2H, t, J=7.13 Hz), 3.55 (2H, t, J=7.13 Hz), 4.35 (2H, s), 4.47 (2H, d, J=5.7 Hz), 4.93 (2H, s), 7.04-7.10 (1H, m), 7.19-7.36 (3H, m), 7.50 (1H, d, J=7.7 Hz), 7.81 (2H, td, J=7.6, 1.7 Hz), 8.49 (1H, dd, J=4.9, 0.8 Hz), 10.18 (1H, t, J=6.0 Hz), 11.80 (1H, br s).
- NMR (DMSO-d6) δ: 1.85 (2H, m), 3.22 (3H, s), 3.38 (2H, t, J=6.0 Hz), 3.51 (2H, t, J=7.5 Hz), 3.53 (1H, s), 4.12 (2H, s), 4.54 (2H, d, J=5.9 Hz), 4.93 (2H, s), 7.07 (1H, m), 7.20-7.28 (1H, m), 7.40 (1H, dd, J=15.36, 8.64 Hz), 8.34 (1H, s), 10.28 (1H, t, J=5.9 Hz), 11.79 (1H, br s).
- NMR (DMSO-d6) δ: 1.07 (3H, t, J=7.1 Hz), 3.39-3.70 (6H, m), 4.36 (2H, s), 4.47 (2H, d, J=6.0 Hz), 4.97 (2H, s), 7.04-7.10 (1H, m), 7.19-7.36 (3H, m), 7.50 (1H, d, J=7.7 Hz), 7.77 (1H, s), 7.81 (1H, t, J=8.0, 2.2 Hz), 8.49 (1H, dd, J=4.9, 0.8 Hz), 10.16 (1H, t, J=5.9 Hz), 11.73 (1H, s).
- NMR (DMSO-d6) δ: 1.08 (3H, t, J=7.0 Hz), 1.80-1.89 (2H, m), 3.39-3.45 (4H, m), 3.56 (2H, t, J=7.1 Hz), 4.35 (2H, s), 4.46 (2H, d, J=5.8 Hz), 4.93 (1H, s), 7.06 (1H, dt, J=11.6, 4.3 Hz), 7.27 (3H, m), 7.49 (1H, d, J=7.8 Hz), 7.80 (2H, td, J=7.7, 1.8 Hz), 8.48 (1H, d, J=4.0 Hz), 10.17 (1H, t, J=5.9 Hz), 11.81 (1H, s).
- NMR (DMSO-d6) δ: 0.00 (2H, m), 0.37 (2H, s), 0.88 (1H, m), 1.76-1.85 (2H, m), 3.36 (3H, s), 3.49 (2H, dd, J=13.7, 6.4 Hz), 4.53 (2H, d, J=5.8 Hz), 4.89 (2H, s), 7.06 (1H, m), 7.24 (1H, m), 7.39 (1H, m), 8.30 (1H, s), 10.30 (1H, t, J=5.9 Hz).
- NMR (DMSO-d6) δ: 1.76-1.85 (2H, m), 3.16 (3H, s), 3.21 (3H, s), 3.33 (6H, m), 3.49 (2H, dd, J=12.2, 5.0 Hz), 4.53 (2H, d, J=5.6 Hz), 4.84 (2H, s), 7.02-7.09 (1H, m), 7.20-7.27 (1H, m), 7.38 (1H, dd, J=15.3, 8.6 Hz), 8.20 (1H, s), 10.34 (1H, s).
- NMR (DMSO-d6) δ: 1.66 (2H, m), 1.76-1.85 (2H, m), 3.0 (2H, m), 3.18 (3H, s), 3.23 (3H, s), 3.35-3.62 (6H, m), 4.53 (2H, d, J=5.4 Hz), 4.87 (2H, s), 7.04-7.10 (1H, m), 7.21-7.28 (1H, m), 7.36-7.44 (1H, m), 8.19 (1H, s), 10.33 (1H, t, J=5.5 Hz).
- NMR (DMSO-d6) δ: 1.15 (3H, d, J=6.9 Hz), 2.78 (3H, s), 3.25 (3H, s), 3.33-3.43 (3H, m), 4.52 (2H, d, J=5.7 Hz), 4.81 (2H, m), 7.05 (1H, td, J=8.3, 2.1 Hz), 7.23 (1H; dt, J=13.7, 5.2 Hz), 7.39 (1H, dd, J=15.3, 8.5 Hz), 8.23 (1H, s), 10.38 (1H, s), 11.82 (1H, s).
- NMR (DMSO-d6) δ: 1.88 (2H, m), 3.24 (3H, s), 3.40 (2H, t, J=6.0 Hz), 3.56 (2H, t, J=, 7.1 Hz), 4.42 (s, 2H), 4.45 (2H, d, J=5.7 Hz), 4.96 (2H, s), 7.07 (1H, m), 7.19-7.27 (1H, m), 7.33 (1H, dd, J=15.3, 8.6 Hz), 7.68 (1H, s), 7.69 (1H, s), 9.10 (1H, d, J=1.7 Hz), 10.17 (1H, t, J=6.0 Hz), 11.84 (1H, s).
- NMR (DMSO-d6) δ: 1.20 (3H, br s), 3.25 (3H, s), 3.32 (2H, m), 3.44 (1H, m), 4.31 (1H, br s), 4.45 (2H, d, J=5.6 Hz), 4.79 (1H, m), 4.95 (2H, s), 7.04-7.09 (1H, m), 7.19-7.34 (3H, m), 7.48 (1H, d, J=7.6 Hz), 7.67 (1H, s), 7.80 (1H, td, J=7.6, 1.8 Hz), 8.48 (1H, d, J=4.0 Hz), 10.14 (1H, t, J=6.0 Hz), 11.88 (1H, s).
- NMR (DMSO-d6) δ: 1.18 (3H, br s), 2.38 (3H, s), 3.21 (3H, s), 3.42-3.54 (3H, m), 4.30 (2H, br s), 4.50 (2H, d, J=5.7 Hz), 4.82 (2H, m), 6.41 (1H, s), 7.04-7.09 (1H, m), 7.24 (1H, dt, J=13.7, 5.3 Hz), 7.37 (1H, dd, J=15.4, 8.7 Hz), 8.00 (1H, s), 10.19 (1H, t, J=6.0 Hz), 11.84 (1H, s).
- NMR (DMSO-d6) δ: 1.84 (2H, m), 3.25 (3H, s), 3.40 (2H, t, J=6.1 Hz), 3.55 (2H, t, J=7.2 Hz), 4.27 (2H, s), 4.48 (2H, d, J=5.9 Hz), 4.84 (2H, br s), 7.04-7.39 (5H, m), 7.57 (1H, dd, J=4.9, 2.9 Hz), 7.79 (1H, s), 10.19 (1H, t, J=5.9 Hz), 11.85 (1H, s).
- NMR (DMSO-d6) δ: 1.46 (6H, d, J=6.0 Hz), 1.76-1.84 (2H, m), 3.49 (4H, m), 4.26 (2H, s), 4.47 (2H, d, J=5.7 Hz), 4.83 (2H, m), 7.03-7.39 (6H, m), 7.56 (1H, dd, J=5.0, 2.9 Hz), 7.80 (1H, s), 10.19 (1H, t, J=5.9 Hz), 11.90 (1H, s).
- NMR (DMSO-d6) δ: 1.19 (3H, s), 3.27 (3H, s), 3.37-3.62 (3H, m), 4.21 (2H, s), 4.46 (2H, d, J=6.0 Hz), 4.74-4.90 (2H, m), 7.02-7.35 (5H, m), 7.57 (1H, dd, J=5.0, 2.9 Hz), 7.68 (1H, s), 10.16 (1H, t, J=5.9 Hz), 11.92 (1H, s).
- NMR (DMSO-d6) δ: 1.26 (2H, m), 1.61 (2H, d, J=12.4 Hz), 1.95 (1H, m), 3.23 (4H, m), 3.85 (2H, d, J=9.7 Hz), 4.37 (2H, s), 4.47 (2H, d, J=5.4 Hz), 4.96 (2H, br s), 7.07 (1H, t, J=7.7 Hz), 7.29 (3H, m), 7.54 (1H, d, J=7.7 Hz), 7.82 (1H, s), 7.85 (1H, s), 8.52 (1H, d, J=3.9 Hz), 10.18 (1H, t, J=6.0 Hz), 11.80 (1H, s).
- NMR (DMSO-d6) δ: 1.76-1.98 (4H, m), 2.22 (2H, t, J=8.1 Hz), 3.22-3.44 (6H, m), 4.28 (2H, s), 4.47 (2H, d, J=5.7 Hz), 4.95 (2H, br s), 7.02-7.38 (5H, m), 7.56 (1H, dd, J=5.0, 2.9 Hz), 7.76 (1H, s), 10.16 (1H, t, J=6.0 Hz), 11.82 (1H, s).
- NMR (DMSO-d6) δ: 1.06 (3H, t, J=6.9 Hz), 1.15 (3H, d, J=6.9 Hz), 3.05 (2H, m), 3.26 (3H, s), 3.43-3.56 (3H, m), 4.55 (2H, d, J=5.9 Hz), 4.75 (1H, m), 4.84 (2H, s), 7.08 (1H, td, J=8.6, 2.6 Hz), 7.21-7.29 (1H, m), 7.42 (1H, dd, J=15.4, 8.6 Hz), 8.23 (1H, d, J=13.6 Hz), 10.31 (1H, t, J=5.8 Hz), 11.85 (1H, s).
- NMR (DMSO-d6) δ: 3.10-3.78 (3H, m), 3.07-3.75 (11H, m), 4.51 (2H, d, J=6.0 Hz), 4.84 (2H, s), 7.05-7.11 (1H, m), 7.21-7.28 (1H, m), 7.41 (1H, dd, J=15.4, 8.6 Hz), 8.20 (1H, s), 10.35 (1H, t, J=6.0 Hz).
- NMR (DMSO-d6) δ: 1.15-1.29 (2H, m), 1.57 (2H, d, J=12.4 Hz), 1.91 (1H, m), 3.19 (3H, s), 3.25 (8H, m), 3.84 (2H, d, J=11.3 Hz), 4.51 (2H, d, J=5.7 Hz), 4.90 (2H, br s), 7.06 (1H, dt, J=11.6, 4.2 Hz), 7.20-7.27 (1H, m), 7.39 (1H, dd, J=15.4, 8.6 Hz), 8.26 (1H, s), 10.28 (1H, t, J=6.0 Hz), 11.73 (1H, s).
- NMR (DMSO-d6) δ: 3.20 (3H, s), 3.40-3.79 (13H, m), 4.53 (2H, d, J=5.7 Hz), 4.89 (2H, m), 7.03-7.44 (3H, m), 8.25 (1H, s), 10.28 (1H, t, J=6.0 Hz), 11.58 (1H, s).
- NMR (DMSO-d6) δ: 0.84 (3H, t, J=7.4 Hz), 1.48 (2H, td, J=14.0, 7.2 Hz), 1.82 (2H, m), 3.31 (2H, t, J=6.6 Hz), 3.42 (2H, t, J=6.0 Hz), 3.55 (2H, s), 4.26 (2H, s), 4.47 (2H, d, J=5.6 Hz), 4.68-5.00 (2H, br s), 7.02-7.39 (5H, m), 7.56 (1H, dd, J=4.9, 2.9 Hz), 7.79 (1H, s), 10.18 (1H, t, J=6.0 Hz), 11.87 (1H, s).
- NMR (DMSO-d6) δ: 0.84 (3H, s), 1.48 (2H, s), 3.64 (4H, m), 4.26 (2H, s), 4.47 (2H, s), 7.25-7.37 (5H, m), 7.56 (1H, s), 7.76 (1H, s), 10.17 (1H, s), 11.79 (1H, s).
- 1H-NMR (CDCl3) δ: 1.18 (6.0H, d, J=6.21 Hz), 2.23 (3.0H, s), 3.59-3.67 (4.0H, m), 3.96 (1.0H, br s), 4.67 (2.0H, d, J=5.71 Hz), 4.95-5.11 (2.0H, m), 6.80-6.88 (2.0H, m), 7.35-7.45 (1.0H, m), 8.47 (1.0H, s), 10.21 (1.0H, t, J=7.00 Hz).
- 1H-NMR (CDCl3) δ: 1.12 (6H, d, J=6.21 Hz), 1.88-1.96 (2H, m), 2.15 (3H, s), 3.49-3.59 (3H, m), 3.58 (1H, br), 4.67 (2H, d, J=5.87 Hz), 4.93 (1H, br), 5.63 (1H, br), 6.81-6.89 (2H, m), 7.36-7.44 (1H, br), 8.51 (1H, s), 10.22 (1H, t, J=5.87 Hz), 11.62 (1H, br).
- NMR (DMSO-d6) δ: 1.47-1.59 (1H, m), 1.79-1.99 (3H, m), 2.51 (3H, s), 3.40-3.49 (1H, m), 3.64-3.73 (2H, m), 3.77-3.85 (1H, m), 4.06 (1H, br), 4.55 (2H, d, J=5.64 Hz), 5.37 (1H, br), 5.63 (1H, br), 7.07 (1H, t, J=8.54 Hz), 7.25 (1H, dd, J=16.40, 6.02 Hz), 7.41 (1H, dd, J=15.56, 8.54 Hz), 8.32 (1H, s), 10.20 (1H, t, J=5.72 Hz), 11.38 (1H, br).
- NMR (DMSO-d6) δ: 1.16 (3H, br s), 2.27 (3H, br s), 3.24 (3H, s), 3.38 (2H, m), 4.54 (2H, d, J=5.8 Hz), 4.67 (1H, br s), 5.12 (1H, br s), 5.68 (1H, br s), 7.03-7.44 (3H, m), 8.28 (1H, s), 10.28 (1H, s).
- NMR (DMSO-d6) δ: 1.21 (2H, m), 1.52 (2H, m), 1.89 (1H, m), 2.25 (3H, br s), 3.21 (4H, m), 3.84 (2H, d, J=9.0 Hz), 4.54 (2H, d, J=5.88 Hz), 5.31-5.65 (2H, m), 7.04-7.10 (1H, m), 7.20-7.28 (1H, m), 7.41 (1H, dd, J=15.3, 8.6 Hz), 8.38 (1H, s), 10.22 (1H, t, J=5.8 Hz), 11.44 (1H, s).
- NMR (DMSO-d6) δ: 2.30 (3H, s), 3.19-3.77 (9H, m), 4.54 (2H, d, J=5.7 Hz), 5.31-5.44 (2H, m), 7.04-7.45 (3H, m), 8.25 (1H, s), 10.27 (1H, s).
- NMR (DMSO-d6) δ: 1.79 (2H, m), 2.24 (3H, m), 3.21 (3H, s), 3.52 (2H, m), 4.54 (2H, d, J=5.5 Hz), 5.24-5.61 (2H, m), 7.06 (1H, m), 7.24 (1H, m), 7.41 (1H, m), 8.37 (1H, s), 10.26 (1H, s).
- NMR (DMSO-d6) δ: 1.47-1.59 (1H, m), 1.79-1.99 (3H, m), 2.51 (3H, s), 3.40-3.49 (1H, m), 3.64-3.73 (2H, m), 3.77-3.85 (1H, m), 4.06 (1H, br), 4.55 (2H, d, J=5.64 Hz), 5.37 (1H, br), 5.63 (1H, br), 7.07 (1H, t, J=8.54 Hz), 7.25 (1H, dd, J=16.40, 6.02 Hz), 7.41 (1H, dd, J=15.56, 8.54 Hz), 8.32 (1H, s), 10.20 (1H, t, J=5.72 Hz), 11.38 (1H, br).
- The present invention further provides the following compound.
- In Compound (I-6), R4 and R22 are selected from the following substituents, and the present invention provides all compounds which are formed from those combinations.
- methyl, ethyl, n-propyl, ipropyl, n-butyl, cyclopropyl, cyclopropylmethyl, 1-adamantylmethyl, 2-adamantylmethyl, dodecahedranemethyl, methoxyethyl, methoxypropyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxyethyl, propoxypropyl, porpoxybutyl, phenyl, picolyl, piperonylmethyl, benzyl, dimethylanimoethyl, diethylaminoethyl, morpholinoethyl, phenoxyethyl, phenoxypropyl, cubanemethyl, thiophenemethyl, furanemethyl, tetrahydrofuranmethyl, dioxanemethyl, tetrahydropyranmethyl, pyridyl, thiazolemethyl, oxazolemethyl, 1,2,4-oxadiazolemethyl, 1,3,4-oxadiazolemethyl
- methyl, ethyl, n-propyl, i-propyl, n-butyl, cyclopropyl, cyclopropylmethyl, 1-adamantylmethyl, 2-adamantylmethyl, dodecahedranemethyl, methoxyethyl, methoxypropyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxyethyl, propoxypropyl, propoxybutyl, phenyl, picolyl, piperonylmethyl, benzyl, dimethylaminoethyl, diethylaminoethyl, morpholinoethyl, phenoxyethyl, phenoxypropyl, cubanemethyl, thiophenemethyl, furanemethyl, tetrahydrofuranmethyl, dioxane methyl, tetrahydrapyranmethyl, pyridyl, acetyl, methoxyacetyl, benzoyl, cyanomethyl, 2,2,2-trifluoromethyl, triazolemethyl, tetrazolemethyl, thiazolemethyl, oxazolemethyl, 1,2,4-oxadiazolemethyl, 1,3,4-oxadiazolemethyl, neopentyl, carboranemethyl, fluoromethyl, dimethylurea, methanesulfonyl, benzenesulfonyl, thiophenesulfonyl, acetamidoethyl, allyl, propargyl, isoxazolemethyl, dimethylthiourea, chrotyl, methoxymethyl, 18-crownethermethyl, imidazolemethyl, methylpyrrolemethyl
- The HIV integrase inhibitory activity was investigated based on the following assay method.
- By the same method as that described in Experimental Example 1 of WO 2004/024693, a substrate DNA solution (2 pmol/μl) and a target DNA solution (5 pmol/μl) were prepared. After each target DNA solution was once boiled, a temperature was slowly lowered to anneal complementary chains, which was used. Each sequence of a substrate DNA and a target DNA is as described in the same Experimental Example.
- Streptavidin (manufactured by Vector Laboratories) was dissolved in a 0.1 M carbonate buffer solution (composition: 90 mM Na2CO3, 10 mM NaHCO3) to a concentration of 40 μg/ml. Each 50 μl of this solution was added to a well of an immunoplate (manufactured by NUNC), and this is allowed to stand at 4° C. overnight to adsorb. Then, each well was washed with a phosphate buffer (composition: 13.7 mM NaCl, 0.27 mM KCl, 0.43 mM Na2HPO4, 0.14 mM KH2PO4) two times, and 300 μl of a phosphate buffer containing 1% skim milk was added to block it for 30 minutes. Further, each well was washed with a phosphate buffer two times, 50 ml of a substrate DNA solution (2 pmol/μl) was added to adsorb at room temperature for 30 minutes while shaking, and this was washed with a phosphate buffer two times and, then, distilled water once.
- Then, to each well prepared as described above were added 12 μl of a buffer (composition: 150 mM MOPS (pH7.2), 75 mM MnCl2, 50 mM 2-mercaptoethanol, 25% glycerol, 500 μg/ml bovine serum albumin-fraction V), and 51 μl of a reaction solution prepared from 39 ml of distilled water. Then, 9 μl of an integrase solution (30 pmol) was added, and the mixture was mixed well. To a well as a negative control (NC) was added 9 μl of a diluting solution (composition: 20 mM MOPS (pH7.2), 400 mM potassium glutamete, 1 mM EDTA, 0.1% NP-40, 20% glycerol, 1 mM DTT, 4 M urea), and this was mixed well using a plate mixer.
- After the plate was incubated at 30° C. for 60 minutes, the reaction solution was discarded, followed by washing with 250 μl of a washing buffer (composition: 150 mM MOPS (pH7.2), 50 mM 2-mercaptoethanol, 25% glycerol, 500 μg/ml bovine serum albumin-fraction V) three times.
- Then, to each well were added 12 μl of a buffer (composition: 150 mM MOPS (pH7.2), 75 mM MgCl2, 50 mM 2-mercaptoethanol, 25% glycerol, 500 μg/ml bovine serum albumin-fraction V), and 53 μl of a reaction solution prepared from 41 μl of distilled water. Further, 6 μl of a solution of a test compound in DMSO was added to each well, and 6 μl of DMSO was added to a well as a positive control (PC), followed by mixing well using a plate mixer. After the plate was incubated at 30° C. for 30 minutes, 1 μl of a target DNA (5 pmol/μl) was added, and this was mixed well using a plate mixer.
- After each plate was incubated at 30° C. for 10 minutes, the reaction solution was discarded, followed by washing with a phosphate buffer two times. Then, an anti-digoxigenin antibody labeled with alkaline phosphatase (sheep Fab fragment: manufactured by Boehringer) was diluted 2000-fold with an antibody diluting solution, 100 μl of the diluent was added to bind at 30° C. for 1 hour, and this was washed successively with a phosphate buffer containing 0.05% Tween20 two times, and a phosphate buffer once. Then, 150 μl of an alkaline phosphatase coloring buffer (composition: 10 mM paranitrophenyl phosphate (manufactured by Vector Laboratories), 5 mM MgCl2, 100 mM NaCl, 100 mM Tris-HCl (pH 9.5)) was added to react at 30° C. for 2 hours, 50 μl of a 1N NaOH solution was added to stop the reaction, an absorbance (OD405 nm) of each well was measured, and an inhibition rate (IC50) was obtained according to the following calculation equation.
-
Inhibition rate (%)=100[1−{(C abs.−NC abs.)/(PC abs.−NC abs.)}] - C abs.; absorbance of well of compound
- NC abs.: absorbance of NC
- PC abs.: absorbance of PC
- The present compound showed the strong integrase inhibitory activity against HIV.
-
TABLE 1 Ex No. IC50 (nM) O-07 4.8 O-06 3.8 N-15 3.3 N-16 2.6 - A term “active ingredient” means the present compound, a tautomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
- A hard gelatin capsule is prepared using the following ingredients:
-
dose (mg/capsule) Active ingredient 250 Starch (dried) 200 Magnesium stearate 10 Total 460 mg - A tablet is prepared using the following ingredients:
-
dose (mg/tablet) Active ingredient 250 Cellulose (microcrystalline) 400 Silicon dioxide (fumed) 10 Stearic acid 5 Total 665 mg - Ingredients are mixed, and compressed to obtain tablets, each weighing 665 mg.
Claims (6)
1. (canceled)
2. A compound of the formula:
(wherein,
G ring is optionally substituted heterocycle
R1 is hydrogen or lower alkyl;
X is a single bond, a heteroatom group selected from the group consisting of O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
R2 is optionally substituted aryl;
R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino,
R14 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from the group consisting of O, S, SO, SO2, NR5 (R5 is independently selected from the same substitution group as R4), —N═ and ═N—), hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, substituted thiourea or substituted sulfonyl),
or a pharmaceutically acceptable salt thereof.
3-10. (canceled)
11. A compound of the formula:
(wherein,
R1 is hydrogen or lower alkyl;
X is a single bond, a heteroatom group selected from the group consisting of O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
R2 is optionally substituted aryl;
R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino,
C ring is optionally substituted heterocycle or optionally substituted carbocycle;
B1 and B2 are independently C, CR23 or N;
R23 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, substituted thiourea or substituted sulfonyl),
the broken line represents the presence or absence of a bond;
R4 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from the group consisting of CO, O, S, SO, SO2, NRa (Ra is hydrogen or lower alkyl), —N═ and ═N—));
or a pharmaceutically acceptable salt thereof.
12. A compound of the formula:
(wherein,
R1 is hydrogen or lower alkyl;
X is a single bond, a heteroatom group selected from the group consisting of O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
R2 is optionally substituted aryl;
R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino,
H ring is optionally substituted heterocycle;
R24 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, substituted thiourea or substituted sulfonyl),
or a pharmaceutically acceptable salt thereof.
13-18. (canceled)
Priority Applications (1)
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US13/428,242 US20120208998A1 (en) | 2005-10-27 | 2012-03-23 | Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity |
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JP2005-312076 | 2005-10-27 | ||
JP2005312076 | 2005-10-27 | ||
JP2006-223875 | 2006-08-21 | ||
JP2006223875 | 2006-08-21 | ||
PCT/JP2006/321335 WO2007049675A1 (en) | 2005-10-27 | 2006-10-26 | Polycyclic carbamoylpyridone derivative having inhibitory activity on hiv integrase |
US8412808A | 2008-06-16 | 2008-06-16 | |
US13/428,242 US20120208998A1 (en) | 2005-10-27 | 2012-03-23 | Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity |
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PCT/JP2006/321335 Division WO2007049675A1 (en) | 2005-10-27 | 2006-10-26 | Polycyclic carbamoylpyridone derivative having inhibitory activity on hiv integrase |
US8412808A Division | 2005-10-27 | 2008-06-16 |
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US20120208998A1 true US20120208998A1 (en) | 2012-08-16 |
Family
ID=37967785
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US12/084,128 Active 2029-04-29 US8188271B2 (en) | 2005-10-27 | 2006-10-26 | Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity |
US13/428,242 Abandoned US20120208998A1 (en) | 2005-10-27 | 2012-03-23 | Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity |
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US12/084,128 Active 2029-04-29 US8188271B2 (en) | 2005-10-27 | 2006-10-26 | Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity |
Country Status (15)
Country | Link |
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US (2) | US8188271B2 (en) |
EP (1) | EP1950212B1 (en) |
JP (1) | JP5131689B2 (en) |
KR (1) | KR20080064182A (en) |
AU (1) | AU2006307101A1 (en) |
BR (1) | BRPI0617842A2 (en) |
CA (1) | CA2626956A1 (en) |
EA (1) | EA200801144A1 (en) |
ES (1) | ES2569357T3 (en) |
IL (1) | IL190879A0 (en) |
MA (1) | MA29879B1 (en) |
MX (1) | MX2008005137A (en) |
NO (1) | NO20081892L (en) |
TW (1) | TW200800988A (en) |
WO (1) | WO2007049675A1 (en) |
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-
2006
- 2006-10-26 MX MX2008005137A patent/MX2008005137A/en not_active Application Discontinuation
- 2006-10-26 BR BRPI0617842-1A patent/BRPI0617842A2/en not_active IP Right Cessation
- 2006-10-26 AU AU2006307101A patent/AU2006307101A1/en not_active Abandoned
- 2006-10-26 EA EA200801144A patent/EA200801144A1/en unknown
- 2006-10-26 KR KR1020087012320A patent/KR20080064182A/en not_active Application Discontinuation
- 2006-10-26 US US12/084,128 patent/US8188271B2/en active Active
- 2006-10-26 EP EP06822311.4A patent/EP1950212B1/en active Active
- 2006-10-26 JP JP2007542639A patent/JP5131689B2/en active Active
- 2006-10-26 ES ES06822311.4T patent/ES2569357T3/en active Active
- 2006-10-26 CA CA002626956A patent/CA2626956A1/en not_active Abandoned
- 2006-10-26 TW TW095139466A patent/TW200800988A/en unknown
- 2006-10-26 WO PCT/JP2006/321335 patent/WO2007049675A1/en active Application Filing
-
2008
- 2008-04-15 IL IL190879A patent/IL190879A0/en unknown
- 2008-04-22 NO NO20081892A patent/NO20081892L/en not_active Application Discontinuation
- 2008-04-23 MA MA30862A patent/MA29879B1/en unknown
-
2012
- 2012-03-23 US US13/428,242 patent/US20120208998A1/en not_active Abandoned
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Also Published As
Publication number | Publication date |
---|---|
CA2626956A1 (en) | 2007-05-03 |
MX2008005137A (en) | 2008-09-29 |
IL190879A0 (en) | 2008-11-03 |
US8188271B2 (en) | 2012-05-29 |
EP1950212B1 (en) | 2016-02-24 |
EA200801144A1 (en) | 2008-10-30 |
EP1950212A4 (en) | 2010-08-04 |
AU2006307101A1 (en) | 2007-05-03 |
KR20080064182A (en) | 2008-07-08 |
NO20081892L (en) | 2008-06-23 |
ES2569357T3 (en) | 2016-05-10 |
MA29879B1 (en) | 2008-10-03 |
JPWO2007049675A1 (en) | 2009-04-30 |
BRPI0617842A2 (en) | 2011-08-09 |
EP1950212A1 (en) | 2008-07-30 |
US20090143356A1 (en) | 2009-06-04 |
JP5131689B2 (en) | 2013-01-30 |
TW200800988A (en) | 2008-01-01 |
WO2007049675A1 (en) | 2007-05-03 |
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