JP5767393B2 - 新規二環式ピリジノン - Google Patents
新規二環式ピリジノン Download PDFInfo
- Publication number
- JP5767393B2 JP5767393B2 JP2014501751A JP2014501751A JP5767393B2 JP 5767393 B2 JP5767393 B2 JP 5767393B2 JP 2014501751 A JP2014501751 A JP 2014501751A JP 2014501751 A JP2014501751 A JP 2014501751A JP 5767393 B2 JP5767393 B2 JP 5767393B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- methyl
- dihydro
- mmol
- fluoro
- 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.)
- Expired - Fee Related
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- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title description 5
- 125000002619 bicyclic group Chemical group 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 205
- -1 2- {2- [2- (bicyclo [1.1.1] pent-1-yl) -4-chlorophenoxy ] Ethyl} -7- (4-methyl-1H-imidazol-1-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,6-dione Compound Chemical class 0.000 claims description 160
- 125000000217 alkyl group Chemical group 0.000 claims description 88
- 150000003839 salts Chemical class 0.000 claims description 59
- 125000003118 aryl group Chemical group 0.000 claims description 48
- 239000001257 hydrogen Substances 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 43
- 125000001072 heteroaryl group Chemical group 0.000 claims description 40
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 38
- 229910052799 carbon Inorganic materials 0.000 claims description 37
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 37
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 36
- 125000001153 fluoro group Chemical group F* 0.000 claims description 35
- 150000002367 halogens Chemical class 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 125000005842 heteroatom Chemical group 0.000 claims description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 15
- 125000000304 alkynyl group Chemical group 0.000 claims description 15
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
- 208000024827 Alzheimer disease Diseases 0.000 claims description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 11
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 8
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 claims description 8
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 8
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 8
- IYYZUPMFVPLQIF-UHFFFAOYSA-N dibenzothiophene Chemical compound C1=CC=C2C3=CC=CC=C3SC2=C1 IYYZUPMFVPLQIF-UHFFFAOYSA-N 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 claims description 8
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 6
- 208000012902 Nervous system disease Diseases 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- 208000020016 psychiatric disease Diseases 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000001118 alkylidene group Chemical group 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 claims description 4
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 claims description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 4
- USQJUMKNJWUXHW-UHFFFAOYSA-N [1]benzofuro[3,2-c]pyridine Chemical compound C1=NC=C2C3=CC=CC=C3OC2=C1 USQJUMKNJWUXHW-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- UMIVXZPTRXBADB-UHFFFAOYSA-N benzocyclobutene Chemical compound C1=CC=C2CCC2=C1 UMIVXZPTRXBADB-UHFFFAOYSA-N 0.000 claims description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 4
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000003981 vehicle Substances 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims description 3
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical compound C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 claims description 3
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 3
- ZGSNZVRXASCXRP-UHFFFAOYSA-N 5-methoxy-1h-pyrazole Chemical compound COC=1C=CNN=1 ZGSNZVRXASCXRP-UHFFFAOYSA-N 0.000 claims description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 3
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical compound C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 claims description 3
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 3
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 2
- IVDMVAFKQDDZGH-AWEZNQCLSA-N 2-[(2s)-1-[4-chloro-2-(trifluoromethyl)phenoxy]propan-2-yl]-7-(4-methylimidazol-1-yl)-3,4-dihydropyrido[1,2-a]pyrazine-1,6-dione Chemical compound C([C@H](C)N1C(C=2N(C(C(N3C=C(C)N=C3)=CC=2)=O)CC1)=O)OC1=CC=C(Cl)C=C1C(F)(F)F IVDMVAFKQDDZGH-AWEZNQCLSA-N 0.000 claims description 2
- CZEVSRPJHTVIAG-AWEZNQCLSA-N 2-[(2s)-1-[4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-yl]-7-(4-methylimidazol-1-yl)-3,4-dihydropyrido[1,2-a]pyrazine-1,6-dione Chemical compound C([C@H](C)N1C(C=2N(C(C(N3C=C(C)N=C3)=CC=2)=O)CC1)=O)OC1=CC=C(F)C=C1C(F)(F)F CZEVSRPJHTVIAG-AWEZNQCLSA-N 0.000 claims description 2
- WNKIZPPVGKAWKE-UHFFFAOYSA-N 2-[2-[(2,2-difluoro-1,3-benzodioxol-4-yl)oxy]ethyl]-7-(4-methylimidazol-1-yl)-3,4-dihydropyrido[1,2-a]pyrazine-1,6-dione Chemical compound C1=NC(C)=CN1C(C1=O)=CC=C2N1CCN(CCOC=1C=3OC(F)(F)OC=3C=CC=1)C2=O WNKIZPPVGKAWKE-UHFFFAOYSA-N 0.000 claims description 2
- LEHPUPBPVUBARN-UHFFFAOYSA-N 2-[2-[(2,2-difluoro-1,3-dihydroinden-4-yl)oxy]ethyl]-7-(4-methylimidazol-1-yl)-3,4-dihydropyrido[1,2-a]pyrazine-1,6-dione Chemical compound C1=NC(C)=CN1C(C1=O)=CC=C2N1CCN(CCOC=1C=3CC(F)(F)CC=3C=CC=1)C2=O LEHPUPBPVUBARN-UHFFFAOYSA-N 0.000 claims description 2
- HTPYICLKDABRCS-UHFFFAOYSA-N 2-[2-[2-(3,3-difluorocyclobutyl)-4-fluorophenoxy]ethyl]-7-(4-methylimidazol-1-yl)-3,4-dihydropyrido[1,2-a]pyrazine-1,6-dione Chemical compound C1=NC(C)=CN1C(C1=O)=CC=C2N1CCN(CCOC=1C(=CC(F)=CC=1)C1CC(F)(F)C1)C2=O HTPYICLKDABRCS-UHFFFAOYSA-N 0.000 claims description 2
- WOARPCISPWAXFG-UHFFFAOYSA-N 2-[2-[2-(3-bicyclo[1.1.1]pentanyl)phenoxy]ethyl]-7-(4-methylimidazol-1-yl)-3,4-dihydropyrido[1,2-a]pyrazine-1,6-dione Chemical compound C1=NC(C)=CN1C(C1=O)=CC=C2N1CCN(CCOC=1C(=CC=CC=1)C13CC(C1)C3)C2=O WOARPCISPWAXFG-UHFFFAOYSA-N 0.000 claims description 2
- XNTCGZXHDJPICB-UHFFFAOYSA-N 2-[2-[4-fluoro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]ethyl]-7-(4-methylimidazol-1-yl)-3,4-dihydropyrido[1,2-a]pyrazine-1,6-dione Chemical compound C1=NC(C)=CN1C(C1=O)=CC=C2N1CCN(CCOC=1C(=CC(F)=CC=1)C(C)(C)C(F)(F)F)C2=O XNTCGZXHDJPICB-UHFFFAOYSA-N 0.000 claims description 2
- YQSXKNVPEQLXJQ-UHFFFAOYSA-N 2-[2-[[4-fluoro-2-(trifluoromethyl)-1,3-benzothiazol-7-yl]oxy]ethyl]-7-(4-methylimidazol-1-yl)-3,4-dihydropyrido[1,2-a]pyrazine-1,6-dione Chemical compound C1=NC(C)=CN1C(C1=O)=CC=C2N1CCN(CCOC=1C=3SC(=NC=3C(F)=CC=1)C(F)(F)F)C2=O YQSXKNVPEQLXJQ-UHFFFAOYSA-N 0.000 claims description 2
- AHERSACVYXVWEK-UHFFFAOYSA-N 7-(4-methylimidazol-1-yl)-2-[2-[2-[2-(trifluoromethyl)-1,3-thiazol-4-yl]phenoxy]ethyl]-3,4-dihydropyrido[1,2-a]pyrazine-1,6-dione Chemical compound C1=NC(C)=CN1C(C1=O)=CC=C2N1CCN(CCOC=1C(=CC=CC=1)C=1N=C(SC=1)C(F)(F)F)C2=O AHERSACVYXVWEK-UHFFFAOYSA-N 0.000 claims description 2
- XNBWJMQONCSXNL-UHFFFAOYSA-N 7-(4-methylimidazol-1-yl)-2-[2-[2-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]phenoxy]ethyl]-3,4-dihydropyrido[1,2-a]pyrazine-1,6-dione Chemical compound C1=NC(C)=CN1C(C1=O)=CC=C2N1CCN(CCOC=1C(=CC=CC=1)C=1SN=C(N=1)C(F)(F)F)C2=O XNBWJMQONCSXNL-UHFFFAOYSA-N 0.000 claims description 2
- WANTWYYPVUJSRC-UHFFFAOYSA-N 7-(4-methylimidazol-1-yl)-2-[2-[2-[3-(trifluoromethyl)-1,2-oxazol-5-yl]phenoxy]ethyl]-3,4-dihydropyrido[1,2-a]pyrazine-1,6-dione Chemical compound C1=NC(C)=CN1C(C1=O)=CC=C2N1CCN(CCOC=1C(=CC=CC=1)C=1ON=C(C=1)C(F)(F)F)C2=O WANTWYYPVUJSRC-UHFFFAOYSA-N 0.000 claims description 2
- VVMAQBKWLDOZMB-UHFFFAOYSA-N 7-(4-methylimidazol-1-yl)-2-[2-[[2-(trifluoromethyl)-1,3-benzothiazol-7-yl]oxy]ethyl]-3,4-dihydropyrido[1,2-a]pyrazine-1,6-dione Chemical compound C1=NC(C)=CN1C(C1=O)=CC=C2N1CCN(CCOC=1C=3SC(=NC=3C=CC=1)C(F)(F)F)C2=O VVMAQBKWLDOZMB-UHFFFAOYSA-N 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 239000000544 cholinesterase inhibitor Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- JNODQFNWMXFMEV-UHFFFAOYSA-N latrepirdine Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CCC1=CC=C(C)N=C1 JNODQFNWMXFMEV-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 16
- 229940122041 Cholinesterase inhibitor Drugs 0.000 claims 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 claims 1
- 239000003693 atypical antipsychotic agent Substances 0.000 claims 1
- 229940127236 atypical antipsychotics Drugs 0.000 claims 1
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 claims 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 claims 1
- 239000008024 pharmaceutical diluent Substances 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 219
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 174
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 117
- 239000000203 mixture Substances 0.000 description 111
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 82
- 238000005481 NMR spectroscopy Methods 0.000 description 77
- 230000015572 biosynthetic process Effects 0.000 description 76
- 238000003786 synthesis reaction Methods 0.000 description 76
- 239000000243 solution Substances 0.000 description 75
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 69
- 125000001424 substituent group Chemical group 0.000 description 68
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 65
- 239000007787 solid Substances 0.000 description 62
- 238000006243 chemical reaction Methods 0.000 description 59
- 238000000746 purification Methods 0.000 description 50
- 229920006395 saturated elastomer Polymers 0.000 description 48
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 47
- 239000011541 reaction mixture Substances 0.000 description 47
- 238000000034 method Methods 0.000 description 44
- 239000012044 organic layer Substances 0.000 description 43
- 238000010898 silica gel chromatography Methods 0.000 description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 41
- 235000019341 magnesium sulphate Nutrition 0.000 description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 36
- 239000000047 product Substances 0.000 description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 239000002904 solvent Substances 0.000 description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 26
- 238000002360 preparation method Methods 0.000 description 24
- 239000011780 sodium chloride Substances 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- 125000004432 carbon atom Chemical group C* 0.000 description 23
- 239000000543 intermediate Substances 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 239000002253 acid Substances 0.000 description 20
- 150000001721 carbon Chemical group 0.000 description 20
- 239000003814 drug Substances 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 18
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Classifications
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- 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
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- 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
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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-
- A—HUMAN NECESSITIES
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- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
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Description
Xは、1〜3個のヘテロ原子を含有する5〜14員ヘテロアリールであり、
R1は、水素、ハロゲン、C1〜6アルキル、C3〜6シクロアルキル、C2〜6アルケニルまたはC2〜6アルキニルであり、前記アルキル、シクロアルキル、アルケニルまたはアルキニルは、フルオロ、シアノ、−CF3、ヒドロキシル、またはC1〜6アルコキシ基1〜3個で独立して置換されていてもよく、
各出現についてのR2aおよびR2bは、各々独立して、水素、フルオロ、シアノ、−CF3、C1〜6アルキル、C3〜6シクロアルキル、(C4〜10)ビシクロアルキル、C2〜6アルケニル、C2〜6アルキリデン、またはC2〜6アルキニルであり、前記アルキル、シクロアルキル、ビシクロアルキル、アルケニル、アルキリデンまたはアルキニルは、シアノ、C1〜3アルキルまたは1〜3個のフルオロで独立して置換されていてもよいか、R2aおよびR2bは、それらが結合している炭素と一緒に、1〜3個のR8で置換されていてもよい3〜5員シクロアルキルを形成し、
R3は、−(C(R11)2)t−(C6〜10アリール)または−(C(R11)2)t−(5〜14員ヘテロアリール)であり、前記アリールまたはヘテロアリール部分は、1〜5個のR10で独立して置換されていてもよく、
R4aおよびR4bは、各々独立して、水素、−CF3、またはC1〜6アルキルであり、前記アルキルは、1〜3個の−CF3、シアノまたはフルオロで置換されていてもよいか、R4aおよびR4bは、それらが結合している炭素と一緒に、3〜5員シクロアルキルを形成し、前記シクロアルキルは、−CF3、シアノ、フルオロまたはC1〜6アルキル1〜3個で置換されていてもよく、
各出現についてのR5aおよびR5bは、各々独立して、水素、−CF3、またはC1〜6アルキルであり、前記アルキルは、1〜3個の−CF3、シアノまたはフルオロで置換されていてもよいか、R5aおよびR5bは、それらが結合している炭素と一緒に、3〜5員シクロアルキルを形成し、前記シクロアルキルは、1〜3個の−CF3、シアノ、フルオロまたはC1〜6アルキルで置換されていてもよく、
R6、R7およびR8は、独立して、水素、−CF3、シアノ、ハロゲン、C1〜6アルキルまたは−OR9であり、ただし、R6およびR7は、両方同時に−OHとはならず、
R9は、水素、C1〜6アルキル、C3〜6シクロアルキル、C3〜6アルケニルまたはC3〜6アルキニルであり、前記アルキル、シクロアルキル、アルケニルまたはアルキニルは、シアノ、または1〜3個のフルオロで独立して置換されていてもよく、
各R10は、独立して、水素、ハロゲン、シアノ、−CF3、C1〜6アルキル、−(C(R11)2)m−(C3〜6シクロアルキル)、−(C(R11)2)m−((C4〜10)ビシクロアルキル)、−(C(R11)2)m−(4〜10員ヘテロシクロアルキル)、−(C(R11)2)m−(C6〜10アリール)、−(C(R11)2)m−(5〜10員ヘテロアリール)、−(C(R11)2)m−OR12、−C(O)R13、−SF5または−Si(CH3)3であり、前記アルキル、シクロアルキル、ビシクロアルキル、ヘテロシクロアルキル、アリールまたはヘテロアリール部分は、1〜3個のR14で独立して置換されていてもよく、
各R11は、独立して、水素、C1〜6アルキル、C2〜6アルケニル、C2〜6アルキニル、C3〜4シクロアルキル、フルオロ、−CF3、−CHF2または−OR12であり、前記アルキル、アルケニル、アルキニルまたはシクロアルキル部分は、1〜3個のフルオロまたはシアノで独立して置換されていてもよく、
各R12は、独立して、水素、C1〜6アルキル、−CF3、−(C(R14)2)n−(C3〜6シクロアルキル)、−(C(R14)2)n−(4〜10員ヘテロシクロアルキル)、−(C(R14)2)n−(C6〜10アリール)または−(C(R14)2)n−(5〜10員ヘテロアリール)であり、前記アルキル、シクロアルキル、ヘテロシクロアルキル、アリールまたはヘテロアリール部分は、1〜3個のR16で独立して置換されていてもよく、
各R13は、独立して、C1〜6アルキル、−(C(R16)2)p−(C3〜6シクロアルキル)、−(C(R16)2)p−(4〜10員ヘテロシクロアルキル)、−(C(R16)2)p−(C6〜10アリール)または−(C(R16)2)p−(5〜10員ヘテロアリール)であり、前記アルキル、シクロアルキル、ヘテロシクロアルキル、アリールまたはヘテロアリール部分は、1〜3個のR16で独立して置換されていてもよく、
各R14は、独立して、水素、C1〜6アルキル、C2〜6アルケニル、C2〜6アルキニル、ハロゲン、シアノ、−CF3、−CHF2、−OR9または−OCF3であり、
R16は、独立して、水素、−CF3、シアノ、ハロゲン、C1〜6アルキルまたは−OR9であり、前記アルキル部分は、1〜3個のR17で置換されていてもよく、
R17は、独立して、水素、ヒドロキシル、−CF3、シアノ、フルオロ、C2〜6アルケニルまたはC2〜6アルキニルであり、前記アルケニルまたはアルキニル部分は、1〜3個の水素、フルオロまたはC1〜6アルキルで置換されていてもよく、
各t、m、nまたはpは、0、1、2、3、および4から独立して選択される整数であり、
zは、1および2から選択される整数であり、
yは、1、2、3および4から選択される整数である)、
および薬学的に許容できるその塩を対象とする。
R4a、R4b、R5a、R5b、R6、R7およびR8は、各々独立して、水素またはC1〜6アルキルであり、
R14は、独立して、水素、C1〜6アルキル、クロロ、ブロモもしくはフルオロ、−CF3、−CHF2または−OR9であり、
R17は、独立して、水素または−CF3またはフェニルであり、前記フェニルおよびC1〜6アルキル部分は、1〜3個の水素またはハロゲンで独立して置換されていてもよく、
または薬学的に許容できるその塩。
7−(4−メチル−1H−イミダゾール−1−イル)−2−(2−{2−[2−(トリフルオロメチル)−1,3−チアゾール−4−イル]フェノキシ}エチル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[4−フルオロ−2−(トリフルオロメチル)フェノキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−(2−{2−[3−(トリフルオロメチル)イソオキサゾール−5−イル]フェノキシ}エチル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−(2−{[4−フルオロ−2−(トリフルオロメチル)−1,3−ベンゾチアゾール−7−イル]オキシ}エチル)−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[2−(3,3−ジフルオロシクロブチル)−4−フルオロフェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−(2−{[2−(トリフルオロメチル)−1,3−ベンゾチアゾール−7−イル]オキシ}エチル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン、トリフルオロ酢酸塩;
7−(4−メチル−1H−イミダゾール−1−イル)−2−(2−{2−[3−(トリフルオロメチル)−1,2,4−チアジアゾール−5−イル]フェノキシ}エチル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[4−フルオロ−2−(1,1,1−トリフルオロ−2−メチルプロパン−2−イル)フェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[2−(ビシクロ[1.1.1]ペンタ−1−イル)フェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(2S)−1−[4−クロロ−2−(トリフルオロメチル)フェノキシ]プロパン−2−イル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(2,2−ジフルオロ−2,3−ジヒドロ−1H−インデン−4−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(2,2−ジフルオロ−1,3−ベンゾジオキソール−4−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;および
2−{2−[2−(ビシクロ[1.1.1]ペンタ−1−イル)−4−クロロフェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン
からなる群から選択される好ましい化合物、
または上記のいずれかの薬学的に許容できる塩に関する。
(i)塩酸ドネペジル(ARICEPT、MEMAC)、サリチル酸フィゾスチグミン(ANTILIRIUM)、硫酸フィゾスチグミン(ESERINE)、メトリホナート、ネオスチグミン、ガンスチグミン、ピリドスチグミン(MESTINON)、アンベノニウム(MYTELASE)、デマルカリウム(demarcarium)、Debio 9902(ZT−1としても知られている;Debiopharm)、リバスチグミン(EXELON)、ラドスチギル、NP−0361、臭化水素酸ガランタミン(RAZADYNE、RIMINYL、NIVALIN)、タクリン(COGNEX)、トルセリン、マレイン酸ベルナクリン、メモキン(memoquin)、ヒューペルジンA(HUP−A;NeuroHitech)、フェンセリン、エドロホニウム(ENLON、TENSILON)、およびINM−176などのアセチルコリンエステラーゼ阻害薬;
(ii)汎HLA DR結合エピトープとコンジュゲートしているAβ1〜15(PADRE)、ACC−001(Elan/Wyeth)、ACI−01、ACI−24、AN−1792、Affitope AD−01、CAD106、およびV−950などのアミロイド−β(または、そのフラグメント);
(iii)ポネズマブ、ソラネズマブ、バピネオズマブ(AAB−001としても知られている)、AAB−002(Wyeth/Elan)、ACI−01−Ab7、BAN−2401、静脈内Ig(GAMMAGARD)、LY2062430(ヒト化m266;Lilly)、R1450(Roche)、ACU−5A5、huC091、および国際特許公開第WO04/032868号、第WO05/025616号、第WO06/036291号、第WO06/069081号、第WO06/118959号に、米国特許公開第US2003/0073655号、第US2004/0192898号、第US2005/0048049号、第US2005/0019328号に、欧州特許公開第EP0994728号および1257584号に、ならびに米国特許第5,750,349号に開示されているものなどのアミロイド−βに対する抗体(または、それらのフラグメント);
(iv)ディメボン、ダブネチド、エプロジセート、ロイプロリド、SK−PC−B70M、セレコキシブ、ロバスタチン、アナプソス(anapsos)、オキシラセタム、プラミラセタム、バレニクリン、ニセルゴリン、コロストリニン、ビスノルシムセリン(bisnorcymserine)(BNCとしても知られている)、NIC5−15(Humanetics)、E−2012(Eisai)、ピオグリタゾン、クリオキノール(PBT1としても知られている)、PBT2(Prana Biotechnology)、フルルビプロフェン(ANSAID、FROBEN)およびそのR−エナンチオマータレンフルルビル(FLURIZAN)、ニトロフルルビプロフェン、フェノプロフェン(FENOPRON、NALFON)、イブプロフェン(ADVIL、MOTRIN、NUROFEN)、イブプロフェンリシネート、メクロフェナム酸、メクロフェナム酸ナトリウム(MECLOMEN)、インドメタシン(INDOCIN)、ジクロフェナクナトリウム(VOLTAREN)、ジクロフェナクカリウム、スリンダク(CLINORIL)、スリンダクスルフィド、ジフルニサル(DOLOBID)、ナプロキセン(NAPROSYN)、ナプロキセンナトリウム(ANAPROX、ALEVE)、ARC031(Archer Pharmaceuticals)、CAD−106(Cytos)、LY450139(Lilly)、インスリン分解酵素(インスリシン(insulysin)としても知られている)、イチョウ葉エキスEGb−761(ROKAN、TEBONIN)、トラミプロセート(CEREBRIL、ALZHEMED)、エプロジセート(FIBRILLEX、KIACTA)、化合物W(3,5−ビス(4−ニトロフェノキシ)安息香酸)、NGX−96992、ネプリライシン(中性エンドペプチダーゼ(NEP)としても知られている)、シロ−イノシトール(シリトールとしても知られている)、アトルバスタチン(LIPITOR)、シンバスタチン(ZOCOR)、KLVFF−(EEX)3、SKF−74652、メシル酸イブタモレン、ASP−1702、SCH−745966、JNJ−715754、AMG−0683、AZ−12304146、BMS−782450、GSK−188909、NB−533、E2609およびTTP−854などのBACE阻害薬;ELND−007などのガンマセクレターゼモジュレーター;ならびにTTP488(Transtech)とTTP4000(Transtech)、およびPTI−777を包含する米国特許第7,285,293号に開示されているものなどのRAGE(最終糖化産物受容体)阻害薬などのアミロイド低下剤またはアミロイド阻害剤(アミロイド産生、蓄積および線維化を低減するものを包含する);
(v)グアンファシン(INTUNIV、TENEX)、クロニジン(CATAPRES)、メタラミノール(ARAMINE)、メチルドパ(ALDOMET、DOPAMET、NOVOMEDOPA)、チザニジン(ZANAFLEX)、フェニレフリン(ネオシネフリンとしても知られている)、メトキサミン、シラゾリン、グアンファシン(INTUNIV)、ロフェキシジン、キシラジン、モダフィニル(PROVIGIL)、アドラフィニル、およびアルモダフィニル(NUVIGIL)などのアルファ−アドレナリン受容体作動薬;
(vi)カルテオロール、エスモロール(BREVIBLOC)、ラベタロール(NORMODYNE、TRANDATE)、オクスプレノロール(LARACOR、TRASACOR)、ピンドロール(VISKEN)、プロパノロール(propanolol)(INDERAL)、ソタロール(BETAPACE、SOTALEX、SOTACOR)、チモロール(BLOCADREN、TIMOPTIC)、アセブトロール(SECTRAL、PRENT)、ナドロール(CORGARD)、酒石酸メトプロロール(LOPRESSOR)、コハク酸メトプロロール(TOPROL−XL)、アテノロール(TENORMIN)、ブトキサミン、およびSR 59230A(Sanofi)などのベータ−アドレナリン受容体遮断剤(ベータ遮断薬);
(vii)アミトリプチリン(ELAVIL、ENDEP)、ブトリプチリン、メシル酸ベンズトロピン(COGENTIN)、トリヘキシフェニジル(ARTANE)、ジフェンヒドラミン(BENADRYL)、オルフェナドリン(NORFLEX)、ヒヨスチアミン、アトロピン(ATROPEN)、スコポラミン(TRANSDERM−SCOP)、臭化メチルスコポラミン(PARMINE)、ジシクロベリン(BENTYL、BYCLOMINE、DIBENT、DILOMINE)、トルテロジン(DETROL)、オキシブチニン(DITROPAN、LYRINEL XL、OXYTROL)、臭化ペンチエネート、プロパンテリン(PRO−BANTHINE)、シクリジン、塩酸イミプラミン(TOFRANIL)、マレイン酸イミプラミン(SURMONTIL)、ロフェプラミン、デシプラミン(NORPRAMIN)、ドキセピン(SINEQUAN、ZONALON)、トリミプラミン(SURMONTIL)、およびグリコピロレート(ROBINUL)などの抗コリン薬;
(viii)カルバマゼピン(TEGRETOL、CARBATROL)、オクスカルバゼピン(TRILEPTAL)、フェニトインナトリウム(PHENYTEK)、フォスフェニトイン(CEREBYX、PRODILANTIN)、ジバルプロエクスナトリウム(DEPAKOTE)、ガバペンチン(NEURONTIN)、プレガバリン(LYRICA)、トピリメート(topirimate)(TOPAMAX)、バルプロ酸(DEPAKENE)、バルプロ酸ナトリウム(DEPACON)、1−ベンジル−5−ブロモウラシル、プロガビド、ベクラミド、ゾニサミド(TRERIEF、EXCEGRAN)、CP−465022、レチガバイン、タランパネル、およびプリミドン(MYSOLINE)などの抗痙攣薬;
(ix)ルラシドン(LATUDA、SM−13496としても知られている;Dainippon Sumitomo)、アリピプラゾール(ABILIFY)、クロルプロマジン(THORAZINE)、ハロペリドール(HALDOL)、イロペリドン(FANAPTA)、デカン酸フルペンチキソール(DEPIXOL、FLUANXOL)、レセルピン(SERPLAN)、ピモジド(ORAP)、デカン酸フルフェナジン、塩酸フルフェナジン、プロクロルペラジン(COMPRO)、アセナピン(SAPHRIS)、ロキサピン(LOXITANE)、モリンドン(MOBAN)、ペルフェナジン、チオリダジン、チオチキシン(thiothixine)、トリフルオペラジン(STELAZINE)、ラメルテオン、クロザピン(CLOZARIL)、ノルクロザピン(ACP−104)、リスペリドン(RISPERDAL)、パリペリドン(INVEGA)、メルペロン、オランザピン(ZYPREXA)、クエチアピン(SEROQUEL)、タルネタント、アミスルプリド、ジプラシドン(GEODON)、ブロナンセリン(LONASEN)、およびACP−103(Acadia Pharmaceuticals)などの抗精神病薬;
(x)ロメリジン、ジコノチド、ニルバジピン(ESCOR、NIVADIL)、ジペルジピン、アムロジピン(NORVASC、ISTIN、AMLODIN)、フェロジピン(PLENDIL)、ニカルジピン(CARDENE)、ニフェジピン(ADALAT、PROCARDIA)、MEM 1003およびその親化合物ニモジピン(NIMOTOP)、ニソルジピン(SULAR)、ニトレンジピン、ラシジピン(LACIPIL、MOTENS)、レルカニジピン(ZANIDIP)、リファリジン、ジルチアゼム(CARDIZEM)、ベラパミル(CALAN、VERELAN)、AR−R 18565(AstraZeneca)、ならびにエネカジンなどのカルシウムチャネル遮断薬;
(xi)ニテカポン、トルカポン(TASMAR)、エンタカポン(COMTAN)、およびトロポロンなどのカテコールO−メチルトランスフェラーゼ(COMT)阻害薬;
(xii)アトモキセチン、レボキセチン、ヨヒンビン、カフェイン、フェンメトラジン、フェンジメトラジン、ペモリン、フェンカムファミン(GLUCOENERGAN、REACTIVAN)、フェネチリン(CAPTAGON)、ピプラドール(MERETRAN)、デアノール(ジメチルアミノエタノールとしても知られている)、メチルフェニデート(DAYTRANA)、塩酸メチルフェニデート(RITALIN)、デクスメチルフェニデート(FOCALIN)、アンフェタミン(単独で、または他のCNS刺激薬、例えば、ADDERALL(アスパラギン酸アンフェタミン、硫酸アンフェタミン、デキストロアンフェタミンサッカレート、および硫酸デキストロアンフェタミン)と組み合わせて)、硫酸デキストロアンフェタミン(DEXEDRINE、DEXTROSTAT)、メタンフェタミン(DESOXYN)、リスデクスアンフェタミン(VYVANSE)、およびベンズフェタミン(DIDREX)などの中枢神経系刺激薬;
(xiii)プレドニゾン(STERAPRED、DELTASONE)、プレドニゾロン(PRELONE)、酢酸プレジゾロン(predisolone)(OMNIPRED、PRED MILD、PRED FORTE)、リン酸プレドニゾロンナトリウム(ORAPRED ODT)、メチルプレドニゾロン(MEDROL);酢酸メチルプレドニゾロン(DEPO−MEDROL)、およびコハク酸メチルプレドニゾロンナトリウム(A−METHAPRED、SOLU−MEDROL)などのコルチコステロイド;
(xiv)アポモルヒネ(APOKYN)、ブロモクリプチン(PARLODEL)、カベルゴリン(DOSTINEX)、ジヒドレキシジン、ジヒドロエルゴクリプチン、フェノルドパム(CORLOPAM)、リスリド(DOPERGIN)、テルグリド スペルゴリド(spergolide)(PERMAX)、ピリベジル(TRIVASTAL、TRASTAL)、プラミペキソール(MIRAPEX)、キンピロール、ロピニロール(REQUIP)、ロチゴチン(NEUPRO)、SKF−82958(GlaxoSmithKline)、カリプラジン、パルドプルノクスおよびサリゾタンなどのドーパミン受容体作動薬;
(xv)クロルプロマジン、フルフェナジン、ハロペリドール、ロキサピン(loxzpine)、レスペリドン(resperidone)、チオリダジン、チオチキセン、トリフルオペラジン、テトラベナジン(NITOMAN、XENAZINE)、7−ヒドロキシアモキサピン、ドロペリドール(INAPSINE、DRIDOL、DROPLETAN)、ドンペリドン(MOTILIUM)、L−741742、L−745870、ラクロプリド、SB−277011A、SCH−23390、エコピパム、SKF−83566、およびメトクロプラミド(REGLAN)などのドーパミン受容体拮抗薬;
(xvi)ブプロピオン、サフィナミド、マレイン酸ノミフェンシン(MERITAL)、バノキセリン(GBR−12909としても知られている)およびそのデカン酸エステルDBL−583、ならびにアミネプチンなどのドーパミン再取り込み阻害薬;
(xvii)バクロフェン(LIORESAL、KEMSTRO)、シクロフェン(siclofen)、ペントバルビタール(NEMBUTAL)、プロガビド(GABRENE)、およびクロメチアゾールなどのガンマ−アミノ−酪酸(GABA)受容体作動薬;
(xviii)シプロキシファン、チプロリサント(tiprolisant)、S−38093、イルダビサント、ピトリサント、GSK−239512、GSK−207040、JNJ−5207852、JNJ−17216498、HPP−404、SAR−110894、トランス−3−フルオロ−3−(3−フルオロ−4−ピロリジン−1−イルメチル−フェニル)−シクロブタンカルボン酸エチルアミド(PF−3654746および米国特許公開第US2005−0043354号、第US2005−0267095号、第US2005−0256135号、第US2008−0096955号、第2007−1079175号、および第US2008−0176925号;国際特許公開第WO2006/136924号、第WO2007/063385号、第WO2007/069053号、第WO2007/088450号、第WO2007/099423号、第WO2007/105053号、第WO2007/138431号、および第WO2007/088462号;ならびに米国特許第7,115,600号に記載されているもの)などのヒスタミン3(H3)拮抗薬;
(xix)酢酸グラチラマー(コポリマー−1としても知られている;COPAXONE)、MBP−8298(合成ミエリン塩基性タンパク質ペプチド)、フマル酸ジメチル、フィンゴリモド(FTY720としても知られている)、ロキニメクス(LINOMIDE)、ラキニモド(ABR−215062およびSAIK−MSとしても知られている)、ABT−874(ヒト抗−IL−12抗体;Abbott)、リツキシマブ(RITUXAN)、アレムツズマブ(CAMPATH)、ダクリズマブ(ZENAPAX)、およびナタリズマブ(TYSABRI)などの免疫調節薬;
(xx)メトトレキサート(TREXALL、RHEUMATREX)、ミトキサントロン(NOVANTRONE)、ミコフェノール酸モフェチル(CELLCEPT)、ミコフェノール酸ナトリウム(MYFORTIC)、アザチオプリン(AZASAN、IMURAN)、メルカプトプリン(PURI−NETHOL)、シクロホスファミド(NEOSAR、CYTOXAN)、クロラムブシル(LEUKERAN)、クラドリビン(LEUSTATIN、MYLINAX)、アルファ−フェトプロテイン、エタネルセプト(ENBREL)、および4−ベンジルオキシ−5−((5−ウンデシル−2H−ピロール−2−イリデン)メチル)−2,2’−ビ−1H−ピロール(PNU−156804としても知られている)などの免疫抑制薬;
(xxi)インターフェロンベータ−1a(AVONEX、REBIF)およびインターフェロンベータ−1b(BETASERON、BETAFERON)を包含するインターフェロン;
(xxii)単独か、またはDOPAデカルボキシラーゼ阻害薬(例えば、カルビドパ(SINEMET、CARBILEV、PARCOPA)、ベンセラジド(MADOPAR)、α−メチルドパ、モノフルロメチルドパ(monofluromethyldopa)、ジフルオロメチルドパ、ブロクレシン、またはm−ヒドロキシベンジルヒドラジン)と組み合わせたレボドパ(または、そのメチルもしくはエチルエステル);
(xxiii)メマンチン(NAMENDA、AXURA、EBIXA)、アマンタジン(SYMMETREL)、アカンプロセート(CAMPRAL)、ベソンプロジル、ケタミン(KETALAR)、デルセミン、デキサナビノール、デキセファロキサン、デキストロメトルファン、デキストロルファン、トラキソプロジル、CP−283097、ヒマンタン(himantane)、イダンタドール(idantadol)、イペノキサゾン、L−701252(Merck)、ランシセミン(lancicemine)、レボルファノール(DROMORAN)、LY−233536およびLY−235959(共にLilly)、メタドン、(DOLOPHINE)、ネラメキサン、ペルジンホテル、フェンシクリジン、チアネプチン(STABLON)、ジゾシルピン(MK−801としても知られている)、EAB−318(Wyeth)、イボガイン、ボアカンギン、チレタミン、リルゾール(RILUTEK)、アプチガネル(CERES0TAT)、ガベスチネル、ならびにレマシミド(remacimide)などのN−メチル−D−アスパラギン酸(NMDA)受容体拮抗薬;
(xxiv)セレギリン(EMSAM)、塩酸セレギリン(l−デプレニル、ELDEPRYL、ZELAPAR)、ジメチルセレギレン(dimethylselegilene)、ブロファロミン、フェネルジン(NARDIL)、トラニルシプロミン(PARNATE)、モクロベミド(AURORIX、MANERIX)、ベフロキサトン、サフィナミド、イソカルボキサジド(MARPLAN)、ニアラミド(NIAMID)、ラサギリン(AZILECT)、イプロニアジド(MARSILID、IPROZID、IPRONID)、CHF−3381(Chiesi Farmaceutici)、イプロクロジド、トロキサトン(HUMORYL、PERENUM)、ビフェメラン、デソキシペガニン(desoxypeganine)、ハルミン(テレパシンまたはバナステリン(banasterine)としても知られている)、ハルマリン、リネゾリド(ZYVOX、ZYVOXID)、およびパージリン(EUDATIN、SUPIRDYL)などのモノアミンオキシダーゼ(MAO)阻害薬;
(xxv)セビメリン、レベチラセタム、塩化ベタネコール(DUVOID、URECHOLINE)、イタメリン、ピロカルピン(SALAGEN)、NGX267、アレコリン、L−687306(Merck)、L−689660(Merck)、ヨウ化フルトレトニウム(FURAMON、FURANOL)、ベンゼンスルホン酸フルトレトニウム、p−トルエンスルホン酸フルトレトニウム、McN−A−343、オキソトレモリン、サブコメリン、AC−90222(Acadia Pharmaceuticals)、およびカルバコール(CARBASTAT、MIOSTAT、CARBOPTIC)などのムスカリン様受容体(特に、M1サブタイプ)作動薬;
(xxvi)ボスチニブ、コンドリアーゼ、アリモクロモール(airmoclomol)、ラモトリジン、ペランパネル、アニラセタム、ミナプリム(minaprime)、ビルゾール(viluzole) 2,3,4,9−テトラヒドロ−1H−カルバゾール−3−オンオキシム、デスモテプラーゼ、アナチバント、アスタキサンチン、ニューロペプチドNAP(例えば、AL−108およびAL−208;共にAllon Therapeutics)、ニューロストロール(neurostrol)、ペランペネル(perampenel)、イスプロニクリン、ビス(4−β−D−グルコピラノシルオキシベンジル)−2−β−D−グルコピラノシル−2−イソブチルタルトレート(ダクチロリン(dactylorhin)BまたはDHBとしても知られている)、ホルモバクチン、キサリプロデン(XAPRILA)、ラクタシスチン、塩酸ジメボリン(dimeboline)(DIMEBON)、ジスフェントン(CEROVIVE)、アルンジン酸(ONO−2506、PROGLIA、CEREACT)、シチコリン(シチジン5’−ジホスホコリンとしても知られている)、エダラボン(RADICUT)、AEOL−10113およびAEOL−10150(共にAeolus Pharmaceuticals)、AGY−94806(SA−450およびMsc−1としても知られている)、顆粒球コロニー刺激因子(AX−200としても知られている)、BAY−38−7271(KN−387271としても知られている;Bayer AG)、アンクロド(VIPRINEX、ARWIN)、DP−b99(D−Pharm Ltd)、HF−0220(17−β−ヒドロキシエピアンドロステロン;Newron Pharmaceuticals)、HF−0420(オリゴトロピン(oligotropin)としても知られている)、ピリドキサール5’−リン酸(MC−1としても知られている)、マイクロプラスミン、S−18986、ピクロゾタン、NP031112、タクロリムス、L−セリル−L−メチオニル−L−アラニル−L−リシル−L−グルタミル−グリシル−L−バリン、AC−184897(Acadia Pharmaceuticals)、ADNF−14(National Institutes of Health)、スチルバズレニル(stilbazulenyl)ニトロン、SUN−N8075(Daiichi Suntory Biomedical Research)、ならびにゾナンパネル(zonampanel)などの神経保護薬;
(xxvii)エピバチジン、ブプロピオン、CP−601927、バレニクリン、ABT−089(Abbott)、ABT−594、AZD−0328(AstraZeneca)、EVP−6124、R3487(MEM3454としても知られている;Roche/Memory Pharmaceuticals)、R4996(MEM63908としても知られている;Roche/Memory Pharmaceuticals)、TC−4959およびTC−5619(共にTargacept)、ならびにRJR−2403などのニコチン様受容体作動薬;
(xxviii)アトモキセチン(STRATTERA)、ドキセピン(APONAL、ADAPIN、SINEQUAN)、ノルトリプチリン(AVENTYL、PAMELOR、NORTRILEN)、アモキサピン(ASENDIN、DEMOLOX、MOXIDIL)、レボキセチン(EDRONAX、VESTRA)、ビロキサジン(VIVALAN)、マプロチリン(DEPRILEPT、LUDIOMIL、PSYMION)、ブプロピオン(WELLBUTRIN)、およびラダキサフィン(radaxafine)などのノルエピネフリン(ノルアドレナリン)再取り込み阻害薬;
(xxix)(a)PDE1阻害薬(例えば、ビンポセチン(CAVINTON、CERACTIN、INTELECTOL)および米国特許第6,235,742号に開示されているもの)、(b)PDE2阻害薬(例えば、エリスロ−9−(2−ヒドロキシ−3−ノニル)アデニン(EHNA)、BAY 60−7550、および米国特許第6,174,884号に開示されているもの)、(c)PDE3阻害薬(例えば、アナグレリド、シロスタゾール、ミルリノン、オルプリノン、パログレリル、およびピモベンダン)、(d)PDE4阻害薬(例えば、アプレミラスト、イブジラスト、ロフルミラスト、ロリプラム、Ro20−1724、イブジラスト(KETAS)、ピクラミラスト(RP73401としても知られている)、CDP840、シロミラスト(ARIFLO)、ロフルミラスト、トフィミラスト、オグレミラスト(GRC3886としても知られている)、テトミラスト(OPC−6535としても知られている)、リリミファスト(lirimifast)、テオフィリン(UNIPHYL、THEOLAIR)、アロフィリン(LAS−31025としても知られている)、ドキソフィリン、RPR−122818、またはメセンブリン)、および(e)PDE5阻害薬(例えば、シルデナフィル(VIAGRA、REVATIO)、タダラフィル(CIALIS)、バルデナフィル(LEVITRA、VIVANZA)、ウデナフィル、アバナフィル、ジピリダモール(PERSANTINE)、E−4010、E−4021、E−8010、ザプリナスト、イオデナフィル(iodenafil)、ミロデナフィル、DA−8159、ならびに国際特許出願WO2002/020521、WO2005/049616、WO2006/120552、WO2006/126081、WO2006/126082、WO2006/126083、およびWO2007/122466に開示されているもの)、(f)PDE9阻害薬(例えば、BAY 73−6691(Bayer AG)ならびに米国特許公開第US2003/0195205号、第US2004/0220186号、第US2006/0111372号、第US2006/0106035号、およびUSSN 12/118,062(2008年5月9日出願)に開示されているもの)、ならびに(g)2−[4−(1−メチル−4−ピリジン−4−イル−1H−ピラゾール−3−イル)フェノキシメチル]キノリン(PF−2545920)、およびSCH−1518291などのPDE10阻害薬を包含するホスホジエステラーゼ(PDE)阻害薬;
(xxx)キニーネ(その塩酸塩、二塩酸塩、硫酸塩、重硫酸塩およびグルコン酸塩を包含する)、クロロキン、ソントキン(sontoquine)、ヒドロキシクロロキン(PLAQUENIL)、メフロキン(LARIAM)、およびアモジアキン(CAMOQUIN、FLAVOQUINE)などのキノリン;
(xxxi)ASP−1702、SCH−745966、JNJ−715754、AMG−0683、AZ−12304146、BMS−782450、GSK−188909、NB−533、LY−2886721、E−2609、HPP−854、(+)−酒石酸フェンセリン(POSIPHEN)、LSN−2434074(LY−2434074としても知られている)、KMI−574、SCH−745966、Ac−rER(N2−アセチル−D−アルギニル−L−アルギニン)、ロキシスタチン(loxistatin)(E64dとしても知られている)、およびCA074Meなどのβ−セクレターゼ阻害薬;
(xxxii)BMS−708163(Avagacest)、WO20060430064(Merck)、DSP8658(Dainippon)、ITI−009、L−685458(Merck)、ELAN−G、ELAN−Z、4−クロロ−N−[2−エチル−1(S)−(ヒドロキシメチル)ブチル]ベンゼンスルホンアミドなどのγ−セクレターゼ阻害薬およびモジュレーター;
(xxxiii)スピペロン、レボ−ピンドロール、BMY 7378、NAD−299、S(−)−UH−301、NAN190、レコゾタンなどのセロトニン(5−ヒドロキシトリプタミン)1A(5−HT1A)受容体拮抗薬;
(xxxiv)バビカセリン、およびジクロナピンなどのセロトニン(5−ヒドロキシトリプタミン)2C(5−HT2c)受容体作動薬;
(xxxv)PRX−03140(Epix)などのセロトニン(5−ヒドロキシトリプタミン)4(5−HT4)受容体作動薬;
(xxxvi)A−964324、AVI−101、AVN−211、ミアンセリン(TORVOL、BOLVIDON、NORVAL)、メチオテピン(メチテピンとしても知られている)、リタンセリン、ALX−1161、ALX−1175、MS−245、LY−483518(SGS518としても知られている;Lilly)、MS−245、Ro 04−6790、Ro 43−68544、Ro 63−0563、Ro 65−7199、Ro 65−7674、SB−399885、SB−214111、SB−258510、SB−271046、SB−357134、SB−699929、SB−271046、SB−742457(GlaxoSmithKline)、Lu AE58054(Lundbeck A/S)、およびPRX−07034(Epix)などのセロトニン(5−ヒドロキシトリプタミン)6(5−HT6)受容体拮抗薬;
(xxxvii)アラプロクレート(alaproclate)、シタロプラム(CELEXA、CIPRAMIL)、エスシタロプラム(LEXAPRO、CIPRALEX)、クロミプラミン(ANAFRANIL)、デュロキセチン(CYMBALTA)、フェモキセチン(MALEXIL)、フェンフルラミン(PONDIMIN)、ノルフェンフルラミン、フルオキセチン(PROZAC)、フルボキサミン(LUVOX)、インダルピン、ミルナシプラン(IXEL)、パロキセチン(PAXIL、SEROXAT)、セルトラリン(ZOLOFT、LUSTRAL)、トラゾドン(DESYREL、MOLIPAXIN)、ベンラファキシン(EFFEXOR)、ジメリジン(NORMUD、ZELMID)、ビシファジン、デスベンラファキシン(PRISTIQ)、ブラソフェンシン、ビラゾドン、カリプラジン、ニューラルステム(neuralstem)およびテソフェンシンなどのセロトニン(5−HT)再取り込み阻害薬;
(xxxviii)神経成長因子(NGF)、塩基性線維芽細胞成長因子(bFGF;ERSOFERMIN)、ニューロトロフィン−3(NT−3)、カルディオトロフィン−1、脳由来神経栄養因子(BDNF)、ニューブラスチン(neublastin)、メテオリン(meteorin)、およびグリア由来神経栄養因子(GDNF)などの栄養因子ならびにプロペントフィリン、イデベノン、PYM50028(COGANE;Phytopharm)、およびAIT−082(NEOTROFIN)などの栄養因子の産生を刺激する薬剤;
(xxxix)パリフルチン(paliflutine)、ORG−25935、JNJ−17305600、およびORG−26041などのグリシン輸送体−1阻害薬;
(xl)ペランパネル、ミバンパトル(mibampator)、セルランパネル(selurampanel)、GSK−729327、およびN−((3S,4S)−4−(4−(5−シアノチオフェン−2−イル)フェノキシ)テトラヒドロフラン−3−イル)プロパン−2−スルホンアミドなどのAMPA型グルタミン酸受容体モジュレーター;
などを包含するが、それらに限定されるものではない。
「アルキル」という用語は、1〜20個の炭素原子、一実施形態において、1〜12個の炭素原子、別の実施形態において、1〜10個の炭素原子、別の実施形態において、1〜6個の炭素原子、別の実施形態において、1〜4個の炭素原子を含有する直鎖または分岐鎖の飽和ヒドロカルビル置換基(すなわち、水素の除去により炭化水素から得られる置換基)を指す。そのような置換基の例は、メチル、エチル、プロピル(n−プロピルおよびイソプロピルを包含する)、ブチル(n−ブチル、イソブチル、sec−ブチルおよびtert−ブチルを包含する)、ペンチル、イソアミル、ヘキシルなどを包含する。一部の場合に、ヒドロカルビル部分(すなわち、アルキル、シクロアルキルなど)中の炭素原子の数は、接頭語「Cx〜y」により指示され、xは、置換基中の炭素原子の最小数であり、yは、置換基中の炭素原子の最大数である。したがって、例えば、「C1〜6アルキル」とは、1〜6個の炭素原子を含有するアルキル置換基を指す。
下記は、本発明の様々な化合物の合成を例示している。本発明の範囲内にある追加の化合物は、単独でか、または当技術分野において一般的に知られている技法と組み合わせて、これらの実施例に例示されている方法を使用して調製することができる。
実験は、一般的に、特に、酸素または水分に敏感な試薬または中間体が用いられる場合、不活性雰囲気(窒素またはアルゴン)下で行った。適切な場合に無水溶媒(一般的に、Aldrich Chemical Company、Milwaukee、WisconsinからのSure−Seal(商標)製品)を包含する市販の溶媒および試薬は、一般的に、さらなる精製なしに使用した。生成物は、一般的に、さらなる反応に続けるか生物学的試験に供する前に真空下で乾燥した。質量分析データは、液体クロマトグラフィー−質量分析(LCMS)、大気圧化学イオン化(APCI)またはガスクロマトグラフィー−質量分析(GCMS)計測器から報告される。核磁気共鳴(NMR)データについての化学シフトは、用いられる重水素化溶媒からの残留ピークを基準とした百万分率(ppm、δ)で表される。
調製1
5−(4−メチル−1H−イミダゾール−1−イル)−6−オキソ−1,6−ジヒドロピリジン−2−カルボン酸、臭化水素酸塩(P1)
J=7.6Hz, 1H), 9.58-9.60(m, 1H), 12.6(v br s, 1H).
2−(2−クロロエチル)−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン(P2)
8.04(d, J=7.5Hz, 1H), 9.50(d, J=1.6Hz, 1H).
1H), 7.27(d, J=7.6Hz, 1H), 7.45(d, J=7.6Hz, 1H), 8.24(d, J=1.0Hz, 1H).
2−[(2−{2−[2−(トリフルオロメチル)−1,3−チアゾール−4−イル]フェノキシ}エチル)アミノ]エタノール(P3)
J=8, 7, 2Hz, 1H), 7.64(dd, J=7.8, 1.6Hz, 1H), 7.81(s, 1H), 10.47(s, 1H).
d, J=8.4Hz, 1H), 7.13(ddd, J=7.7, 7.4, 1.1Hz, 1H), 7.35(ddd, J=8.3, 7.3, 1.8Hz,
1H), 8.31(dd, J=7.8, 1.8Hz, 1H), 8.37(s, 1H).
J=5, 5Hz, 2H), 4.25(dd, J=5, 5Hz, 2H), 7.03(br d, J=8.3Hz, 1H), 7.08-7.12(m,
1H), 7.33-7.38(m, 1H), 8.18(s, 1H), 8.21(br d, J=7.9Hz, 1H).
2−({(2S)−1−[4−フルオロ−2−(トリフルオロメチル)フェノキシ]プロパン−2−イル}アミノ)エタノール、塩酸塩(P4)
δ 1.31(d, J=6.8Hz, 3H), 1.45(s, 9H), 3.98-4.03(m, 2H),
4.04-4.13(m, 1H), 6.95(dd, J=9.2, 4.2Hz, 1H), 7.16-7.22(m, 1H), 7.30(dd, J=8.3,
3.0Hz, 1H).
3.94(dd, J=8.5, 4.0Hz, 1H), 6.93(dd, J=9.1, 4.2Hz, 1H), 7.18(br ddd, J=9, 8,
3Hz, 1H), 7.30(dd, J=8.4, 3.1Hz, 1H).
3.11-3.19(m, 1H), 3.74(dd, J=5.6, 5.4Hz, 2H), 3.92(d, J=5.5Hz, 2H), 6.94(dd,
J=9.0, 4.0Hz, 1H), 7.15-7.21(m, 1H), 7.29(dd, J=8.4, 3.1Hz, 1H).
J=10.6, 4.0Hz, 1H), 7.30(dd, J=9.0, 4.2Hz, 1H), 7.38-7.45(m, 2H).
2−[3−(トリフルオロメチル)−1,2−オキサゾール−5−イル]フェノール(P5)
δ 3.96(s, 3H), 6.99(s, 1H), 7.02(br d, J=8.5Hz, 1H),
7.08(ddd, J=8, 7, 1.0Hz, 1H), 7.55(ddd, J=8.4, 7.4, 1.8Hz, 1H), 7.99(dd, J=7.9,
1.9Hz, 1H).
δ 4.00(s, 3H), 7.01(s, 1H), 7.05(dd, J=8.4, 0.9Hz, 1H),
7.11(ddd, J=7.8, 7.4, 1.1Hz, 1H), 7.48(ddd, J=8.4, 7.4, 1.8Hz, 1H), 8.00(dd,
J=7.8, 1.7Hz, 1H).
8Hz, 1H), 7.39(ddd, J=8, 8, 1.6Hz, 1H), 7.89(dd, J=7.9, 1.7Hz, 1H).
4−フルオロ−2−(トリフルオロメチル)−1,3−ベンゾチアゾール−7−オール(P6)
7.63(br s, 1H).
δ 6.90(dd, J=8.7, 3.3Hz, 1H), 7.21(dd, J=10.2, 8.7Hz,
1H).
2−(3,3−ジフルオロシクロブチル)−4−フルオロフェノール(P7)
1.0Hz, 1H), 6.74(dd, J=8.8, 4.7Hz, 1H), 6.82-6.95(m, 2H), 7.10(dd, J=9.5,
3.0Hz, 1H).
δ 5.08(s, 2H), 5.33(dd, J=11.1, 1.0Hz, 1H), 5.76(dd,
J=17.8, 1.0Hz, 1H), 6.85-6.95(m, 2H), 7.11(ddd, J=17.8, 11.1, 1.5Hz, 1H),
7.23(dd, J=9.4, 2.9Hz, 1H), 7.33-7.48(m, 5H).
3.65(dd, ABXパターンの半分, J=18.0, 9.4Hz, 1H), 4.49(dd,
J=10.1, 9.8Hz, 1H), 5.14(AB四重線, JAB=12.0Hz, ΔνAB=12.2Hz, 2H), 6.91-6.95(m, 2H),
7.01(ddd, J=9.0, 7.8, 2.9Hz, 1H), 7.32-7.44(m, 3H), 7.45-7.49(m, 2H).
NMR(400MHz, CDCl3) δ 3.22-3.31(m, 2H),
3.36-3.46(m, 2H), 3.75-3.85(m, 1H), 5.08(s, 2H), 6.87-6.95(m, 2H), 6.99(dd,
J=9.2, 2.7Hz, 1H), 7.33-7.44(m, 5H).
δ 2.58-2.73(m, 2H), 2.90-3.03(m, 2H), 3.53-3.64(m, 1H),
5.06(s, 2H), 6.83-6.94(m, 3H), 7.34-7.45(m, 5H).
δ 2.60-2.78(m, 2H), 2.92-3.07(m, 2H), 3.46-3.58(m, 1H),
6.61-6.95(m, 3H).
2−[2−(2−ブロモフェノキシ)エチル]−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン(P8)
6.87-6.94(m, 2H), 7.25-7.30(m, 1H), 7.56(dd, J=7.9, 1.6Hz, 1H).
J=5.3, 5.3Hz, 2H), 4.14(dd, J=5.1, 5.1Hz, 2H), 6.85(ddd, J=7.6, 7.6, 1.3Hz,
1H), 6.91(dd, J=8.2, 1.2Hz, 1H), 7.26(ddd, J=8.2, 7.6, 1.5Hz, 1H), 7.54(dd,
J=8.0, 1.6Hz, 1H).
1H), 7.08(d, J=7.8Hz, 1H), 7.15(br d, J=8Hz, 1H), 7.34(dd, J=8, 8Hz, 1H),
7.40(br s, 1H), 7.58(br d, J=8Hz, 1H), 7.78(d, J=7.9Hz, 1H), 8.25(s, 1H).
2−(トリフルオロメチル)−1,3−ベンゾチアゾール−7−オール(P9)
J=8.0, 8.0Hz, 1H).
δ 3.94(s, 3H), 6.81(dd, J=8.4, 1.2Hz, 1H), 7.35(dd,
J=8.4, 8.3Hz, 1H), 7.97(dd, J=8.3, 1.3Hz, 1H), 8.59(br s, 1H).
1H), 8.28(dd, J=8.2, 0.8Hz, 1H), 9.75(br s, 1H).
δ 4.03(s, 3H), 6.97(br d, J=7.9Hz, 1H), 7.56(dd, J=8.3,
8.0Hz, 1H), 7.82(dd, J=8.3, 0.6Hz, 1H).
δ 6.44(br s, 1H), 6.95(d, J=7.8Hz, 1H), 7.47(dd, J=8.2,
8.0Hz, 1H), 7.82(d, J=8.2Hz, 1H).
2’−メチル−2−オキソ−1,2−ジヒドロ−3,4’−ビピリジン−6−カルボン酸、塩酸塩(P10)
1H).
1H).
1H).
NMR(400MHz, CDCl3) δ 1.37(s, 12H), 3.97(s,
3H), 4.06(s, 3H), 7.67(d, J=7.3Hz, 1H), 8.09(d, J=7.3Hz, 1H).第二クロップの材料(1.13g、13%)も、精製から得られた;これは、NMR分析により少量の不純物を含有していた。
s, 1H), 7.79(AB四重線, JAB=7.3Hz, ΔνAB=24.1Hz, 2H), 8.57(d, J=5.0Hz, 1H).
8.31-8.38(m, 2H), 8.76(d, J=6.0Hz, 1H), 12.2(v br s, 1H).
4−(4−クロロ−1H−イミダゾール−1−イル)−6−オキソ−1,6−ジヒドロピリジン−2−カルボン酸、塩酸塩(P11)
δ 7.00(d, J=1.2Hz, 1H), 7.57(br s, 1H), 11.3(v br s,
1H).
J=1.6Hz, 1H), 7.67(d, J=7.8Hz, 1H), 7.82-7.83(m, 1H), 7.84(d, J=7.8Hz, 1H).
メタンスルホン酸(2S)−2−[(tert−ブトキシカルボニル)アミノ]プロピル(P12)
1H), 4.16(dd, ABXパターンの半分, J=10.1, 4.2Hz, 1H),
4.19-4.28(br m, 1H), 4.62(br s, 1H).
(2S)−1−[4−フルオロ−2−(1,1,1−トリフルオロプロパン−2−イル)フェノキシ]プロパン−2−アミン(P13)
4.5Hz, 1H), 6.98(br dd, J=8.8, 3.1Hz, 1H), 7.05(ddd, J=9.0, 7.8, 3.1Hz, 1H).
J=9.0. 4.5Hz, 1H), 6.98(ddd, J=9.0, 7.8, 3.1Hz, 1H), 7.06-7.11(m, 1H).
6.74(dd, J=8.8, 4.5Hz, 1H), 6.85-6.91(m, 1H), 7.04-7.09(m, 1H).
6.79-6.84(m, 1H), 6.92-6.98(m, 1H), 7.05-7.11(m, 1H).より高いRfのジアステレオマーに富んだ材料(1.10g、4.15mmol、14%)およびより低いRfのジアステレオマーに富んだ材料(324mg、1.22mmol、4%)も得られた。
7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロピリド[2,1−c][1,4]オキサジン−1,6−ジオン(P14)
7.15-7.17(m, 1H), 7.43(AB四重線, JAB=7.7Hz, ΔνAB=33.4Hz, 2H), 8.33(d, J=1.4Hz, 1H).
1−フルオロ−4−ニトロ−2−(ペンタフルオロ−λ6−スルファニル)ベンゼン(P15)
8.72(dd, J=5.8, 2.7Hz, 1H).
2−{2−[4−フルオロ−2−(トリフルオロメチル)フェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン(1)
J=9.0, 4.1Hz, 1H), 7.18-7.24(m, 1H), 7.32(br dd, J=8.3, 3.2Hz, 1H).
dd, J=5.6, 5.4Hz, 2H), 4.20(dd, J=5.3, 5.3Hz, 2H), 7.22(br dd, J=8.8, 4.2Hz,
1H), 7.30-7.37(m, 2H).
4.32-4.37(m, 4H), 7.21-7.26(m, 1H), 7.25(d, J=7.8Hz, 1H), 7.30-7.32(m, 1H),
7.32-7.39(m, 2H), 7.76(d, J=7.8Hz, 1H), 8.30(d, J=1.3Hz, 1H).
2−{2−[(7−フルオロナフタレン−1−イル)オキシ]エチル}−7−(2−メチル−1,3−オキサゾール−5−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン(2)
A.6−メトキシ−5−(2−メチル−1,3−オキサゾール−5−イル)ピリジン−2−カルボン酸メチル(C37)の合成。1,4−ジオキサン(11.6mL)中の2−メチル−1,3−オキサゾール(2.41g、29.0mmol)、5−ブロモ−6−メトキシピリジン−2−カルボン酸メチル(C30)(1.51g、5.81mmol)、炭酸カリウム(細かく粉砕した、2.41g、17.4mmol)、およびアリルパラジウムクロリド二量体(224mg、0.58mmol)の混合物を、一晩にわたって100℃まで加熱した。混合物を、セライトに通して濾過し、セライトパッドを、酢酸エチルと、続いて、エタノールで洗浄した。合わせた濾液および洗浄物を、真空中で濃縮した。シリカゲルクロマトグラフィー(グラジエント:ヘプタン中10%〜100%酢酸エチル)を介して精製すると、固体として表題化合物が得られた。収量:267mg、1.02mmol、18%。1H NMR(400MHz, CD3OD) δ 1.42(t, J=7.1Hz, 3H), 2.56(s, 3H), 4.17(s, 3H), 4.43(q, J=7.1Hz,
2H), 7.59(s, 1H), 7.83(d, J=7.8Hz, 1H), 8.17(d, J=7.7Hz, 1H).
8.07(d, J=7.7Hz, 1H).
A.1−(2−クロロエトキシ)−7−フルオロナフタレン(C40)の合成。メチルエチルケトン(7.71mL)中の7−フルオロナフタレン−1−オール(500mg、3.08mmol)の溶液に、炭酸カリウム(682mg、4.93mmol)および1−ブロモ−2−クロロエタン(1.46mL、17.0mmol)を加えた。反応物を、18時間にわたって還流状態で加熱したら直ぐに、室温まで冷却した。飽和炭酸カリウム水溶液を加え、混合物を、酢酸エチルで3回抽出した。合わせた有機層を、硫酸ナトリウム上で乾燥し、真空中で濃縮した。シリカゲルクロマトグラフィー(グラジエント:ヘプタン中10%〜50%酢酸エチル)を介して精製すると、油として表題化合物が得られた。収量:429mg、1.59mmol、52%。1H NMR(400MHz, CDCl3) δ 3.79(t, J=6.2Hz, 2H), 4.48(t, J=6.2Hz, 2H), 6.84(d, J=7.6Hz, 1H),
7.28(ddd, J=8.9, 8.4, 2.7Hz, 1H), 7.34(br dd, J=8.2, 7.7Hz, 1H), 7.47(br d,
J=8.3Hz, 1H), 7.80(dd, J=9.0, 5.7Hz, 1H), 7.91(br dd, J=10.6, 2.6Hz, 1H).
4.27(dd, J=5.3, 5.1Hz, 2H), 6.87(d, J=7.6Hz, 1H), 7.25-7.30(m, 1H, 推定; 溶媒ピークにより一部不明確), 7.34(dd, J=8.1, 7.7Hz,
1H), 7.44(d, J=8.2Hz, 1H), 7.80(dd, J=9.1, 5.6Hz, 1H), 7.85(dd, J=10.5, 2.5Hz,
1H).
6.85(d, J=7.6Hz, 1H), 7.26-7.31(m, 1H, 推定; 溶媒ピークにより一部不明確), 7.31-7.36(m, 2H), 7.46(d, J=8.2Hz, 1H), 7.71(dd, J=10.3, 2.5Hz,
1H), 7.81(dd, J=9.0, 5.5Hz, 1H), 7.89(d, J=7.6Hz, 1H), 8.00(s, 1H).
2−{(2S)−1−[4−クロロ−2−(1,1,1−トリフルオロ−2−メチルプロパン−2−イル)フェノキシ]プロパン−2−イル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン(117)
δ 1.76(br s, 3H), 3.94(s, 3H), 5.88(br s, 1H), 6.94(d,
J=8.8Hz, 1H), 7.30-7.35(m, 2H).
生成物のピークのみ: δ 2.27(br s, 3H),
3.86(s, 3H), 6.90(d, J=8.8Hz, 1H), 7.33(dd, J=8.8, 2.5Hz, 1H), 7.69-7.73(m,
1H).
J=8.8, 2.6Hz, 1H), 7.35-7.37(m, 1H).
δ 1.67(br s, 6H), 5.37(br s, 1H), 6.71(d, J=8.6Hz, 1H),
7.14(dd, J=8.6, 2.5Hz, 1H), 7.33-7.36(m, 1H).
δ 1.24(d, J=6.4Hz, 3H), 1.67(br s, 6H), 2.13(br s, 2H),
3.41-3.50(m, 1H), 3.79(dd, ABXパターンの半分, J=8.8, 7.2Hz,
1H), 3.86(dd, ABXパターンの半分, J=8.9, 4.4Hz, 1H), 6.86(d,
J=8.8Hz, 1H), 7.23(dd, J=8.8, 2.5Hz, 1H), 7.36-7.39(m, 1H).
δ 1.41(d, J=6.8Hz, 3H), 1.69(br s, 6H), 2.23(d,
J=1.0Hz, 3H), 3.85(t, J=5.8Hz, 2H), 4.05(dd, ABXパターンの半分,
J=9.6, 5.4Hz, 1H), 4.14(dd, ABXパターンの半分, J=9.6, 6.6Hz,
1H), 4.41(t, J=5.8Hz, 2H), 4.48-4.57(m, 1H), 6.54(d, J=7.5Hz, 1H), 7.10(d,
J=8.9Hz, 1H), 7.24-7.26(m, 1H), 7.31(dd, J=8.8, 2.6Hz, 1H), 7.37-7.40(m, 1H),
7.67(d, J=7.5Hz, 1H), 8.19(d, J=1.4Hz, 1H).
δ 1.41(d, J=7.0Hz, 3H), 1.59-1.62(m, 6H), 2.35(d,
J=1.0Hz, 3H), 3.59-3.72(m, 2H), 4.03(dd, ABXパターンの半分,
J=10.0, 4.7Hz, 1H), 4.11(dd, ABXパターンの半分, J=10.0, 8.9Hz,
1H), 4.25(ddd, J=14.2, 8.1, 4.4Hz, 1H), 4.46(ddd, J=14.3, 6.4, 4.3Hz, 1H),
5.16-5.26(m, 1H), 6.86(d, J=8.8Hz, 1H), 7.17-7.19(m, 1H), 7.25(dd, J=8.8,
2.5Hz, 1H), 7.30(d, J=7.8Hz, 1H), 7.36(br d, J=2.5Hz, 1H), 7.54(d, J=7.6Hz,
1H), 8.48(br s, 1H).
2−[(2S)−1−{4−フルオロ−2−[(2R)−1,1,1−トリフルオロプロパン−2−イル]フェノキシ}プロパン−2−イル]−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン(118)
4.01-4.19(m, 3H), 4.22-4.37(m, 2H), 5.11-5.25(m, 1H), 6.99-7.12(m, 3H),
7.25-7.33(m, 2H), 7.76-7.82(m, 1H), 8.27-8.32(m, 1H).この材料を、より高いRfの生成物ジアステレオマーを含有する分画、ならびに前のステップおよびこの光延反応に同様にして供されたP13のより上のRfのジアステレオマー(調製13のステップ4を参照;1.10g、4.15mmol)に富んだ出発材料に由来する関連材料と合わせた。[1H NMR(400MHz, CDCl3), 特徴的ピーク: δ 1.38-1.49(m, 6H), 2.32-2.35(m, 3H),
6.79-6.85(m, 1H), 6.95-7.01(m, 1H), 7.03-7.11(m, 1H), 7.15-7.19(m, 1H),
7.29-7.34(m, 1H), [7.52(d, J=7.6Hz)および7.52(d, J=7.8Hz),
計1H], 8.40-8.45(m, 1H)].超臨界流体クロマトグラフィー(カラム:Chiral Technologies Chiralpak(登録商標)AD−H、5μm;溶離液:35:65メタノール/二酸化炭素、0.2%イソプロピルアミンを含有する)を介してこの混合物を精製すると、材料(150mg)が得られ、次いで、これを、ジエチルエーテル(5mL)でスラリー化し、濾過すると、生成物が得られた。収量:98mg、0.20mmol、2ステップで4%。トリフルオロメチル部分に隣接するメチル基の立体化学は、関連する様態で調製されたサンプルでの単結晶X線結晶学により確立された。LCMS m/z 493.3(M+1). 1H NMR(400MHz, CD3OD) δ 1.36-1.40(m, 6H), 2.24(d, J=1.2Hz, 3H), 3.64(ddd, J=13.6, 8.1,
4.2Hz, 1H), 3.80(ddd, J=13.6, 6.9, 4.1Hz, 1H), 4.01-4.17(m, 3H), 4.22-4.37(m,
2H), 5.15-5.25(m, 1H), 7.02-7.05(m, 2H), 7.06-7.11(m, 1H), 7.30(d, J=7.8Hz,
1H), 7.31-7.33(m, 1H), 7.80(d, J=7.8Hz, 1H), 8.31(d, J=1.2Hz, 1H).
2−{(2S)−1−[4−クロロ−2−(ペンタフルオロ−λ6−スルファニル)フェノキシ]プロパン−2−イル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン(119)
3.59-3.66(m, 2H), 3.89-4.01(m, 1H), 4.18-4.29(m, 2H), 4.80(t, J=5.8Hz, 1H),
4.94(t, J=5.4Hz, 1H), 6.45(d, J=7.5Hz, 1H), 7.32-7.34(m, 1H), 7.69(d, J=7.5Hz,
1H), 8.13(d, J=1.3Hz, 1H), 8.67(br d, J=8.3Hz, 1H).
3.59-3.65(m, 2H), 4.14-4.28(m, 2H), 4.53-4.62(m, 1H), 4.83(t, J=5.7Hz, 1H),
7.07(d, J=7.7Hz, 1H), 7.40-7.42(m, 1H), 7.79(d, J=7.8Hz, 1H), 8.25(d, J=1.4Hz,
1H).
4H), 4.99-5.08(m, 1H), 7.16-7.21(m, 2H), 7.28(d, J=7.7Hz, 1H), 7.52(d, J=7.7Hz,
1H), 8.40(dd, J=9.2, 2.7Hz, 1H), 8.44(br s, 1H), 8.71(d, J=2.6Hz, 1H).
3.85-3.92(m, 1H), 4.05(dd, J=9.6, 5.5Hz, 1H), 4.99-5.08(m, 1H), 6.80(dd, ABXパターンの半分, J=8.8, 2.6Hz, 1H), 6.86(br d, AB四重線の半分,
J=8.8Hz, 1H), 7.06(d, J=2.6Hz, 1H).
2H), 4.39(ddd, ABXYパターンの半分, J=14.3, 7.2, 4.2Hz, 1H),
4.99-5.08(m, 1H), 6.99(d, J=9.0Hz, 1H), 7.16-7.18(m, 1H), 7.28(d, J=7.7Hz, 1H),
7.46(dd, J=8.9, 2.5Hz, 1H), 7.51(d, J=7.7Hz, 1H), 7.74(d, J=2.5Hz, 1H),
8.40-8.42(m, 1H).
方法A
2−[2−(アリールオキシ)エチル]および2−[2−(ヘテロアリールオキシ)エチル]7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオンの調製
a)カラム:Waters Sunfire C18、5μm;移動相A:水中0.05%トリフルオロ酢酸(v/v);移動相B:アセトニトリル中0.05%トリフルオロ酢酸(v/v);
b)カラム:Waters XBridge C18、5μm;移動相A:水中0.03%水酸化アンモニウム(v/v);移動相B:アセトニトリル中0.03%水酸化アンモニウム(v/v);
c)カラム:Waters Sunfire C18 19×100、5μm;移動相A:水中0.05%ギ酸(v/v);移動相B:アセトニトリル中0.05%ギ酸(v/v)。
鈴木カップリングを介するオルト−置換7−(4−メチル−1H−イミダゾール−1−イル)−2−(2−フェノキシエチル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオンの調製
下に列挙されているものなどの本発明の範囲にある追加化合物は、単独でか、または当技術分野において一般的に知られている技法と組み合わせて、これらの実施例で例示されている方法を使用して、当業者により調製することができる。
2−{2−[4−クロロ−2−(トリフルオロメチル)フェノキシ]エチル}−7−(1−メチル−1H−ピラゾール−4−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[4−クロロ−2−(トリフルオロメチル)フェノキシ]エチル}−7−(3−メチル−1H−1,2,4−トリアゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(3−クロロ−1H−1,2,4−トリアゾール−1−イル)−2−{2−[4−クロロ−2−(トリフルオロメチル)フェノキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[4−クロロ−2−(トリフルオロメチル)フェノキシ]エチル}−7−(3−メチルイソチアゾール−5−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[4−クロロ−2−(トリフルオロメチル)フェノキシ]エチル}−7−(2−メチル−1,3−チアゾール−5−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[4−クロロ−2−(トリフルオロメチル)フェノキシ]エチル}−7−(3−メチルイソオキサゾール−5−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−(2−{4−フルオロ−2−[1−(トリフルオロメチル)シクロプロピル]フェノキシ}エチル)−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−[(1S)−2−{4−フルオロ−2−[1−(トリフルオロメチル)シクロプロピル]フェノキシ}−1−メチルエチル]−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[2−(2,2−ジフルオロ−1−メチルシクロプロピル)−4−フルオロフェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[4−フルオロ−2−(トリメチルシリル)フェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[2−(2,2−ジフルオロシクロプロピル)−4−フルオロフェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−(2−{[7−フルオロ−2−(トリフルオロメチル)−2,3−ジヒドロ−1−ベンゾフラン−4−イル]オキシ}エチル)−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−(2−{[7−フルオロ−3−メチル−3−(トリフルオロメチル)−2,3−ジヒドロ−1H−インデン−4−イル]オキシ}エチル)−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−(2−{[5−フルオロ−8−メチル−8−(トリフルオロメチル)ビシクロ[4.2.0]オクタ−1,3,5−トリエン−2−イル]オキシ}エチル)−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[2−(2,2−ジフルオロ−1−メチルシクロプロピル)−4−フルオロフェノキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[4−フルオロ−2−(トリメチルシリル)フェノキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[2−(2,2−ジフルオロシクロプロピル)−4−フルオロフェノキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−[(1S)−2−{[7−フルオロ−2−(トリフルオロメチル)−2,3−ジヒドロ−1−ベンゾフラン−4−イル]オキシ}−1−メチルエチル]−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−[(1S)−2−{[7−フルオロ−3−メチル−3−(トリフルオロメチル)−2,3−ジヒドロ−1H−インデン−4−イル]オキシ}−1−メチルエチル]−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−[(1S)−2−{[5−フルオロ−8−メチル−8−(トリフルオロメチル)ビシクロ[4.2.0]オクタ−1,3,5−トリエン−2−イル]オキシ}−1−メチルエチル]−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−(2−{[7−フルオロ−3−メチル−3−(トリフルオロメチル)−1,3−ジヒドロ−2−ベンゾフラン−4−イル]オキシ}エチル)−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−[(1S)−2−{[7−フルオロ−3−メチル−3−(トリフルオロメチル)−1,3−ジヒドロ−2−ベンゾフラン−4−イル]オキシ}−1−メチルエチル]−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−(2−{[7−フルオロ−2−メチル−2−(トリフルオロメチル)−2,3−ジヒドロ−1−ベンゾフラン−4−イル]オキシ}エチル)−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−[(1S)−2−{[7−フルオロ−2−メチル−2−(トリフルオロメチル)−2,3−ジヒドロ−1−ベンゾフラン−4−イル]オキシ}−1−メチルエチル]−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−(2−{[7−フルオロ−3−メチル−3−(トリフルオロメチル)−2,3−ジヒドロ−1−ベンゾフラン−4−イル]オキシ}エチル)−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−[(1S)−2−{[7−フルオロ−3−メチル−3−(トリフルオロメチル)−2,3−ジヒドロ−1−ベンゾフラン−4−イル]オキシ}−1−メチルエチル]−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−(2−{[7−フルオロ−3−(トリフルオロメチル)−2,3−ジヒドロ−1−ベンゾフラン−4−イル]オキシ}エチル)−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−[(1S)−2−{[7−フルオロ−3−(トリフルオロメチル)−2,3−ジヒドロ−1−ベンゾフラン−4−イル]オキシ}−1−メチルエチル]−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−[2−(2−ビシクロ[1.1.1]ペンタ−1−イル−4−クロロフェノキシ)エチル]−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−[2−(2−ビシクロ[1.1.1]ペンタ−1−イル−4−フルオロフェノキシ)エチル]−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−[(1S)−2−(2−ビシクロ[1.1.1]ペンタ−1−イル−4−クロロフェノキシ)−1−メチルエチル]−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−[(1S)−2−(2−ビシクロ[1.1.1]ペンタ−1−イル−4−フルオロフェノキシ)−1−メチルエチル]−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[4−クロロ−2−(3−フルオロビシクロ[1.1.1]ペンタ−1−イル)フェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[4−フルオロ−2−(3−フルオロビシクロ[1.1.1]ペンタ−1−イル)フェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[4−クロロ−2−(3−フルオロビシクロ[1.1.1]ペンタ−1−イル)フェノキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[4−フルオロ−2−(3−フルオロビシクロ[1.1.1]ペンタ−1−イル)フェノキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−(2−{4−フルオロ−2−[3−(トリフルオロメチル)ビシクロ[1.1.1]ペンタ−1−イル]フェノキシ}エチル)−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−[(1S)−2−{4−フルオロ−2−[3−(トリフルオロメチル)ビシクロ[1.1.1]ペンタ−1−イル]フェノキシ}−1−メチルエチル]−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{2−[(2,2,7−トリフルオロ−2,3−ジヒドロ−1H−インデン−4−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{2−[(2,2,7−トリフルオロ−2,3−ジヒドロ−1−ベンゾフラン−4−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(2,2−ジフルオロ−2,3−ジヒドロ−1−ベンゾフラン−4−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{2−[(2,2,3,3,7−ペンタフルオロ−2,3−ジヒドロ−1−ベンゾフラン−4−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{2−[(2,2,3,3−テトラフルオロ−2,3−ジヒドロ−1−ベンゾフラン−4−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[4−フルオロ−2−(2,2,2−トリフルオロ−1−ヒドロキシ−1−メチルエチル)フェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[4−フルオロ−2−(2,2,2−トリフルオロ−1−メチルエチル)フェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(7−クロロ−2,2−ジフルオロ−2,3−ジヒドロ−1H−インデン−4−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{2−[(2,2,8−トリフルオロ−3,4−ジヒドロ−2H−クロメン−5−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{2−[(2,2,8−トリフルオロ−2H−クロメン−5−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{2−[(2,2,5−トリフルオロ−3,4−ジヒドロ−2H−クロメン−8−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{2−[(2,2,5−トリフルオロ−2H−クロメン−8−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{2−[(4,4,8−トリフルオロ−3,4−ジヒドロ−2H−クロメン−5−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{2−[(3,3,8−トリフルオロ−3,4−ジヒドロ−2H−クロメン−5−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{(1S)−1−メチル−2−[(2,2,7−トリフルオロ−2,3−ジヒドロ−1H−インデン−4−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{(1S)−1−メチル−2−[(2,2,7−トリフルオロ−2,3−ジヒドロ−1−ベンゾフラン−4−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[(2,2−ジフルオロ−2,3−ジヒドロ−1−ベンゾフラン−4−イル)オキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{(1S)−1−メチル−2−[(2,2,3,3,7−ペンタフルオロ−2,3−ジヒドロ−1−ベンゾフラン−4−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{(1S)−1−メチル−2−[(2,2,3,3−テトラフルオロ−2,3−ジヒドロ−1−ベンゾフラン−4−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[4−フルオロ−2−(2,2,2−トリフルオロ−1−ヒドロキシ−1−メチルエチル)フェノキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[4−フルオロ−2−(2,2,2−トリフルオロ−1−メチルエチル)フェノキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[(7−クロロ−2,2−ジフルオロ−2,3−ジヒドロ−1H−インデン−4−イル)オキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{(1S)−1−メチル−2−[(2,2,8−トリフルオロ−3,4−ジヒドロ−2H−クロメン−5−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{(1S)−1−メチル−2−[(2,2,8−トリフルオロ−2H−クロメン−5−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{(1S)−1−メチル−2−[(2,2,5−トリフルオロ−3,4−ジヒドロ−2H−クロメン−8−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{(1S)−1−メチル−2−[(2,2,5−トリフルオロ−2H−クロメン−8−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{(1S)−1−メチル−2−[(4,4,8−トリフルオロ−3,4−ジヒドロ−2H−クロメン−5−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{(1S)−1−メチル−2−[(3,3,8−トリフルオロ−3,4−ジヒドロ−2H−クロメン−5−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{2−[(3,3,7−トリフルオロ−2,3−ジヒドロ−1H−インデン−4−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(3,3−ジフルオロ−2,3−ジヒドロ−1H−インデン−4−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{2−[(2,2,3,3,7−ペンタフルオロ−2,3−ジヒドロ−1H−インデン−4−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{2−[(2,2,3,3−テトラフルオロ−2,3−ジヒドロ−1H−インデン−4−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(2,2−ジフルオロ−3,4−ジヒドロ−2H−クロメン−5−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(2,2−ジフルオロ−2H−クロメン−5−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(2,2−ジフルオロ−3,4−ジヒドロ−2H−クロメン−8−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(2,2−ジフルオロ−2H−クロメン−8−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(4,4−ジフルオロ−3,4−ジヒドロ−2H−クロメン−5−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(3,3−ジフルオロ−3,4−ジヒドロ−2H−クロメン−5−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(4,4−ジフルオロ−4H−クロメン−5−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(8,8−ジフルオロ−5,6,7,8−テトラヒドロナフタレン−1−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{2−[(4,8,8−トリフルオロ−5,6,7,8−テトラヒドロナフタレン−1−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(7,7−ジフルオロ−5,6,7,8−テトラヒドロナフタレン−1−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{(1S)−1−メチル−2−[(3,3,7−トリフルオロ−2,3−ジヒドロ−1H−インデン−4−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[(3,3−ジフルオロ−2,3−ジヒドロ−1H−インデン−4−イル)オキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{(1S)−1−メチル−2−[(2,2,3,3,7−ペンタフルオロ−2,3−ジヒドロ−1H−インデン−4−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{(1S)−1−メチル−2−[(2,2,3,3−テトラフルオロ−2,3−ジヒドロ−1H−インデン−4−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[(2,2−ジフルオロ−3,4−ジヒドロ−2H−クロメン−5−イル)オキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[(2,2−ジフルオロ−2H−クロメン−5−イル)オキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[(2,2−ジフルオロ−3,4−ジヒドロ−2H−クロメン−8−イル)オキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[(2,2−ジフルオロ−2H−クロメン−8−イル)オキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[(4,4−ジフルオロ−3,4−ジヒドロ−2H−クロメン−5−イル)オキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[(3,3−ジフルオロ−3,4−ジヒドロ−2H−クロメン−5−イル)オキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[(4,4−ジフルオロ−4H−クロメン−5−イル)オキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[(8,8−ジフルオロ−5,6,7,8−テトラヒドロナフタレン−1−イル)オキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{(1S)−1−メチル−2−[(4,8,8−トリフルオロ−5,6,7,8−テトラヒドロナフタレン−1−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[(7,7−ジフルオロ−5,6,7,8−テトラヒドロナフタレン−1−イル)オキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{(1S)−1−メチル−2−[(2,2,4−トリフルオロ−2,3−ジヒドロ−1−ベンゾフラン−7−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[(2,2−ジフルオロ−2,3−ジヒドロ−1−ベンゾフラン−7−イル)オキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−{2−[(2,2,4−トリフルオロ−2,3−ジヒドロ−1−ベンゾフラン−7−イル)オキシ]エチル}−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(2,2−ジフルオロ−2,3−ジヒドロ−1−ベンゾフラン−7−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
ペンタフルオロ(5−フルオロ−2−{2−[7−(4−メチル−1H−イミダゾール−1−イル)−1,6−ジオキソ−1,3,4,6−テトラヒドロ−2H−ピリド[1,2−a]ピラジン−2−イル]エトキシ}フェニル)硫黄;
ペンタフルオロ[5−フルオロ−2−({(2S)−2−[7−(4−メチル−1H−イミダゾール−1−イル)−1,6−ジオキソ−1,3,4,6−テトラヒドロ−2H−ピリド[1,2−a]ピラジン−2−イル]プロピル}オキシ)フェニル]硫黄;
ペンタフルオロ(2−{2−[7−(4−メチル−1H−イミダゾール−1−イル)−1,6−ジオキソ−1,3,4,6−テトラヒドロ−2H−ピリド[1,2−a]ピラジン−2−イル]エトキシ}フェニル)硫黄;および
ペンタフルオロ[2−({(2S)−2−[7−(4−メチル−1H−イミダゾール−1−イル)−1,6−ジオキソ−1,3,4,6−テトラヒドロ−2H−ピリド[1,2−a]ピラジン−2−イル]プロピル}オキシ)フェニル]硫黄。
アミロイドベータタンパク質Aβ(1〜42)の産生を調節する化合物の能力を、ヒトWT−APP過剰発現CHO細胞を使用して決定した。細胞を、DMEM/F12ベースの培地において96ウェルの組織培養処理した透明プレート(Falcon)中に22,000細胞/100μLウェルにてプレートし、37℃において24時間にわたってインキュベートした。試験するための化合物を、100%DMSO中で希釈し、IC50決定のための11点半対数用量応答を達成した。化合物を、新鮮な培地に添加し、1%最終DMSOを達成した。適切なビヒクルまたは阻害薬対照を、アッセイシグナルウィンドウについて、それぞれ、最小阻害値または最大阻害値を得るために対照ウェル中に個別に添加した後、プレートを、37℃において約24時間にわたってインキュベートした。この手順は、次に記載されているELISA検出ステップにおいてAβ(1〜42)レベルについて試験される各ウェル中の馴化培地を生成する。各ウェル中の残りの細胞培養物も、下に記載されているように細胞毒性について試験される。
Claims (20)
- 式Iの構造を有する化合物
(式中、
Xは、1〜3個のヘテロ原子を含有する5〜14員ヘテロアリールであり、
R1は、水素、ハロゲン、C1〜6アルキル、C3〜6シクロアルキル、C2〜6アルケニルまたはC2〜6アルキニルであり、前記アルキル、シクロアルキル、アルケニルまたはアルキニルは、フルオロ、シアノ、−CF3、ヒドロキシル、またはC1〜6アルコキシ基1〜3個で独立して置換されていてもよく、
各出現についてのR2aおよびR2bは、各々独立して、水素、フルオロ、シアノ、−CF3、C1〜6アルキル、C3〜6シクロアルキル、(C4〜10)ビシクロアルキル、C2〜6アルケニル、C2〜6アルキリデン、またはC2〜6アルキニルであり、前記アルキル、シクロアルキル、ビシクロアルキル、アルケニル、アルキリデンまたはアルキニルは、シアノ、C1〜3アルキルまたは1〜3個のフルオロで独立して置換されていてもよいか、R2aおよびR2bは、それらが結合している炭素と一緒に、1〜3個のR8で置換されていてもよい3〜5員シクロアルキルを形成し、
R3は、−(C(R11)2)t−(C6〜10アリール)または−(C(R11)2)t−(5〜14員ヘテロアリール)であり、前記アリールまたはヘテロアリール部分は、1〜5個のR10で独立して置換されていてもよく、
R4aおよびR4bは、各々独立して、水素、−CF3、またはC1〜6アルキルであり、前記アルキルは、1〜3個の−CF3、シアノまたはフルオロで置換されていてもよいか、R4aおよびR4bは、それらが結合している炭素と一緒に、3〜5員シクロアルキルを形成し、前記シクロアルキルは、−CF3、シアノ、フルオロまたはC1〜6アルキル1〜3個で置換されていてもよく、
各出現についてのR5aおよびR5bは、各々独立して、水素、−CF3、またはC1〜6アルキルであり、前記アルキルは、1〜3個の−CF3、シアノまたはフルオロで置換されていてもよいか、R5aおよびR5bは、それらが結合している炭素と一緒に、3〜5員シクロアルキルを形成し、前記シクロアルキルは、1〜3個の−CF3、シアノ、フルオロまたはC1〜6アルキルで置換されていてもよく、
R6、R7およびR8は、独立して、水素、−CF3、シアノ、ハロゲン、C1〜6アルキルまたは−OR9であり、ただし、R6およびR7は、両方同時に−OHとはならず、
R9は、水素、C1〜6アルキル、C3〜6シクロアルキル、C3〜6アルケニルまたはC3〜6アルキニルであり、前記アルキル、シクロアルキル、アルケニルまたはアルキニルは、シアノ、または1〜3個のフルオロで独立して置換されていてもよく、
各R10は、独立して、水素、ハロゲン、シアノ、−CF3、C1〜6アルキル、−(C(R11)2)m−(C3〜6シクロアルキル)、−(C(R11)2)m−((C4〜10)ビシクロアルキル)、−(C(R11)2)m−(4〜10員ヘテロシクロアルキル)、−(C(R11)2)m−(C6〜10アリール)、−(C(R11)2)m−(5〜10員ヘテロアリール)、−(C(R11)2)m−OR12、−C(O)R13、−SF5または−Si(CH3)3であり、前記アルキル、シクロアルキル、ビシクロアルキル、ヘテロシクロアルキル、アリールまたはヘテロアリール部分は、1〜3個のR14で独立して置換されていてもよく、
各R11は、独立して、水素、C1〜6アルキル、C2〜6アルケニル、C2〜6アルキニル、C3〜4シクロアルキル、フルオロ、−CF3、−CHF2または−OR12であり、前記アルキル、アルケニル、アルキニルまたはシクロアルキル部分は、1〜3個のフルオロまたはシアノで独立して置換されていてもよく、
各R12は、独立して、水素、C1〜6アルキル、−CF3、−(C(R14)2)n−(C3〜6シクロアルキル)、−(C(R14)2)n−(4〜10員ヘテロシクロアルキル)、−(C(R14)2)n−(C6〜10アリール)または−(C(R14)2)n−(5〜10員ヘテロアリール)であり、前記アルキル、シクロアルキル、ヘテロシクロアルキル、アリールまたはヘテロアリール部分は、1〜3個のR16で独立して置換されていてもよく、
各R13は、独立して、C1〜6アルキル、−(C(R16)2)p−(C3〜6シクロアルキル)、−(C(R16)2)p−(4〜10員ヘテロシクロアルキル)、−(C(R16)2)p−(C6〜10アリール)または−(C(R16)2)p−(5〜10員ヘテロアリール)であり、前記アルキル、シクロアルキル、ヘテロシクロアルキル、アリールまたはヘテロアリール部分は、1〜3個のR16で独立して置換されていてもよく、
各R14は、独立して、水素、C1〜6アルキル、C2〜6アルケニル、C2〜6アルキニル、ハロゲン、シアノ、−CF3、−CHF2、−OR9または−OCF3であり、
R16は、独立して、水素、−CF3、シアノ、ハロゲン、C1〜6アルキルまたは−OR9であり、前記アルキル部分は、1〜3個のR17で置換されていてもよく、
R17は、独立して、水素、ヒドロキシル、−CF3、シアノ、フルオロ、C2〜6アルケニルまたはC2〜6アルキニルであり、前記アルケニルまたはアルキニル部分は、1〜3個の水素、フルオロまたはC1〜6アルキルで置換されていてもよく、
各t、m、nまたはpは、0、1、2、3、および4から独立して選択される整数であり、
zは、1および2から選択される整数であり、
yは、1、2、3および4から選択される整数である)、
および薬学的に許容できるその塩。 - Xが、イミダゾリル、ピラゾリル、イソチアゾリル、チアゾリル、イソオキサゾリル、オキサゾリルまたはピリジルである、請求項1に記載の化合物、または薬学的に許容できるその塩。
- Xが、イミダゾリルである、請求項2に記載の化合物、または薬学的に許容できるその塩。
- R1が、C1〜6アルキルである、請求項3に記載の化合物、または薬学的に許容できるその塩。
- R1が、1個のヒドロキシルもしくはC1〜6アルコキシまたは1〜3個のフルオロで置換されていてもよいメチルであり、yが、2または3であり、zが、1である、請求項4に記載の化合物、または薬学的に許容できるその塩。
- R10が、独立して、水素、ハロゲン、シアノ、−CF3、C1〜6アルキル、(C4〜10)ビシクロアルキル、−(C(R11)2)m−(C3〜6シクロアルキル)、−(C(R11)2)m−(4〜10員ヘテロシクロアルキル)、−(C(R11)2)m−(C6〜10アリール)、−(C(R11)2)m−(5〜10員ヘテロアリール)、−(C(R11)2)m−OR12または−C(O)R13であり、アルキル、シクロアルキル、ビシクロアルキル、ヘテロシクロアルキル、アリールまたはヘテロアリール部分が、1〜3個のR14で独立して置換されていてもよい、請求項5に記載の化合物、または薬学的に許容できるその塩。
- R11が、独立して、水素、C1〜6アルキル、フルオロ、−CF3、−CHF2または−OR12であり、R12が、水素、C1〜6アルキル、−CF3またはC6〜10アリールである、請求項6に記載の化合物、または薬学的に許容できるその塩。
- R3が、フェニル、ナフタレン、2,3−ジヒドロ−1H−インデン、キノリン、イソキノリン、ピラゾール、ベンゾ[b]フラン、2,3−ジヒドロベンゾフラン、1,2−ベンゾイソチアゾール、1,3−ベンゾチアゾール、ベンゾフロ[3,2−c]ピリジン、ピリジン、カルバゾール、ベンゾ[d]イソオキサゾール、ベンゾシクロブタン、1,2,3,4−テトラヒドロナフタレン、ジベンゾ[b,d]チオフェン、ジベンゾ[b,d]フランまたはシンノリンである、請求項7に記載の化合物、または薬学的に許容できるその塩。
- R10が、水素、クロロ、フルオロ、ブロモ、シアノ、−CF3、−OCF3、メチル、エチル、プロピル、イソプロピル、ブチル、tert−ブチル、シクロプロピル、シクロブチル、ビシクロアルキル、ヒドロキシル、メトキシ、ピラゾール、イソチアゾール、チアゾール、1,3,4−チアジアゾール、イソオキサゾール、オキサゾール、ピリジン、ピペリジン、ベンゾフラン、ベンゾ[d][1,3]ジオキソール、テトラヒドロピランまたはフェニルであり、前記C1〜6アルキル、ビシクロアルキル、シクロアルキル、ヘテロシクロアルキル、ヘテロアリールまたはアリール部分が、1〜3個のR14で独立して置換されていてもよい、請求項8に記載の化合物、または薬学的に許容できるその塩。
- R2aおよびR2bが、水素またはC1〜6アルキルであり、tが、0であり、mが、0である、請求項9に記載の化合物、または薬学的に許容できるその塩。
- R3が、C6〜10アリールまたは5〜14員ヘテロアリールであり、
R4a、R4b、R5a、R5b、R6、R7およびR8が、各々独立して、水素またはC1〜6アルキルであり、
R14が、独立して、水素、C1〜6アルキル、クロロ、ブロモもしくはフルオロ、−CF3、−CHF2または−OR9であり、
R17が、独立して、水素または−CF3またはフェニルであり、前記フェニル部分が、水素または1〜3個のハロゲンで独立して置換されていてもよい、請求項5に記載の化合物、
または薬学的に許容できるその塩。 - R3が、フェニル、ナフタレン、2,3−ジヒドロ−1H−インデン、キノリン、イソキノリン、ピラゾール、ベンゾ[b]フラン、2,3−ジヒドロベンゾフラン、1,2−ベンゾイソチアゾール、1,3−ベンゾチアゾール、ベンゾフロ[3,2−c]ピリジン、ピリジン、カルバゾール、ベンゾ[d]イソオキサゾール、1,2,3,4−テトラヒドロナフタレン、ジベンゾ[b,d]チオフェン、ジベンゾ[b,d]フラン、ベンゾシクロブタンまたはシンノリンである、請求項11に記載の化合物、
または薬学的に許容できるその塩。 - R10が、水素、クロロ、フルオロ、ブロモ、シアノ、−CF3、−OCF3、メチル、エチル、プロピル、イソプロピル、ブチル、tert−ブチル、シクロプロピル、シクロブチル、ビシクロアルキル、ヒドロキシル、メトキシ、ピラゾール、イソチアゾール、チアゾール、1,3,4−チアジアゾール、イソオキサゾール、オキサゾール、ピリジン、ピペリジン、ベンゾフラン、ベンゾ[d][1,3]ジオキソール、テトラヒドロピランまたはフェニルであり、前記アルキル、シクロアルキル、ビシクロアルキル、ヘテロシクロアルキル、ヘテロアリールまたはアリール部分が、1〜3個の水素、フルオロまたは−CF3で置換されていてもよい、請求項12に記載の化合物、
または薬学的に許容できるその塩。 - 7−(4−メチル−1H−イミダゾール−1−イル)−2−(2−{2−[2−(トリフルオロメチル)−1,3−チアゾール−4−イル]フェノキシ}エチル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(1S)−2−[4−フルオロ−2−(トリフルオロメチル)フェノキシ]−1−メチルエチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−(2−{2−[3−(トリフルオロメチル)イソオキサゾール−5−イル]フェノキシ}エチル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−(2−{[4−フルオロ−2−(トリフルオロメチル)−1,3−ベンゾチアゾール−7−イル]オキシ}エチル)−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[2−(3,3−ジフルオロシクロブチル)−4−フルオロフェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
7−(4−メチル−1H−イミダゾール−1−イル)−2−(2−{[2−(トリフルオロメチル)−1,3−ベンゾチアゾール−7−イル]オキシ}エチル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン、トリフルオロ酢酸塩;
7−(4−メチル−1H−イミダゾール−1−イル)−2−(2−{2−[3−(トリフルオロメチル)−1,2,4−チアジアゾール−5−イル]フェノキシ}エチル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[4−フルオロ−2−(1,1,1−トリフルオロ−2−メチルプロパン−2−イル)フェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[2−(ビシクロ[1.1.1]ペンタ−1−イル)フェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{(2S)−1−[4−クロロ−2−(トリフルオロメチル)フェノキシ]プロパン−2−イル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(2,2−ジフルオロ−2,3−ジヒドロ−1H−インデン−4−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;
2−{2−[(2,2−ジフルオロ−1,3−ベンゾジオキソール−4−イル)オキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン;および
2−{2−[2−(ビシクロ[1.1.1]ペンタ−1−イル)−4−クロロフェノキシ]エチル}−7−(4−メチル−1H−イミダゾール−1−イル)−3,4−ジヒドロ−2H−ピリド[1,2−a]ピラジン−1,6−ジオン
からなる群から選択される化合物、
または上記のいずれかの薬学的に許容できる塩。 - 請求項1から14のいずれか一項に記載の化合物または薬学的に許容できるその塩を含む、神経学的障害および精神医学的障害からなる群から選択される疾患または状態を治療するための、医薬組成物。
- 疾患または状態が、ニーマンピックC型である、請求項15に記載の医薬組成物。
- 疾患または状態が、アルツハイマー病である、請求項15に記載の医薬組成物。
- 請求項1から14のいずれか一項に記載の化合物または薬学的に許容できるその塩および薬学的に許容できるビヒクル、希釈剤または担体を含む医薬組成物。
- 請求項1に記載の式Iの化合物または薬学的に許容できるその塩である第一の化合物、
非定型抗精神病薬、コリンエステラーゼ阻害薬、ディメボン(Dimebon)、またはNMDA受容体拮抗薬である第二の化合物、および任意選択の医薬担体、賦形剤または希釈剤
を含む、医薬組成物。
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CA2830027A1 (en) | 2012-10-04 |
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