JP2017502027A - Gpr6のテトラヒドロピリドピラジンモジュレーター - Google Patents
Gpr6のテトラヒドロピリドピラジンモジュレーター Download PDFInfo
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- JP2017502027A JP2017502027A JP2016541330A JP2016541330A JP2017502027A JP 2017502027 A JP2017502027 A JP 2017502027A JP 2016541330 A JP2016541330 A JP 2016541330A JP 2016541330 A JP2016541330 A JP 2016541330A JP 2017502027 A JP2017502027 A JP 2017502027A
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- JP
- Japan
- Prior art keywords
- piperidin
- pyrazin
- dihydropyrido
- difluorophenoxy
- isopropylamino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 102100033861 G-protein coupled receptor 6 Human genes 0.000 title abstract description 37
- 101001069613 Homo sapiens G-protein coupled receptor 6 Proteins 0.000 title abstract description 37
- HOFCYSNYAFJTSI-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrido[2,3-b]pyrazine Chemical compound C1=CC=C2NCCNC2=N1 HOFCYSNYAFJTSI-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 447
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- -1 hydroxy, amino Chemical group 0.000 claims description 415
- 125000000217 alkyl group Chemical group 0.000 claims description 86
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 55
- 239000001257 hydrogen Substances 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 49
- 229910052799 carbon Inorganic materials 0.000 claims description 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 48
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 43
- 125000001424 substituent group Chemical group 0.000 claims description 34
- 150000001408 amides Chemical class 0.000 claims description 32
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- 229920006395 saturated elastomer Polymers 0.000 claims description 31
- 125000005843 halogen group Chemical group 0.000 claims description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 29
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 19
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- IUVCECHSUQJXMM-UHFFFAOYSA-N cyclobutyl acetate Chemical compound CC(=O)OC1CCC1 IUVCECHSUQJXMM-UHFFFAOYSA-N 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 7
- 125000006311 cyclobutyl amino group Chemical group [H]N(*)C1([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- GONMCTNGCPLRCY-UHFFFAOYSA-N 1-[3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-2-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone Chemical compound FC1=C(OC2CCN(CC2)C2=C(N=C3C(=N2)CN(CC3)C(C)=O)NC(C)C)C=CC(=C1)F GONMCTNGCPLRCY-UHFFFAOYSA-N 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 4
- FSUXDPIOBQLEKO-UHFFFAOYSA-N 1-[2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-(propan-2-ylamino)-7,8-dihydro-5h-pyrido[3,4-b]pyrazin-6-yl]ethanone Chemical compound CC(C)NC1=NC=2CN(C(C)=O)CCC=2N=C1N(CC1)CCC1OC1=CC=C(F)C=C1F FSUXDPIOBQLEKO-UHFFFAOYSA-N 0.000 claims description 3
- PEDBETLWIDHFSD-UHFFFAOYSA-N 1-[3-(2,2-difluoroethylamino)-2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-2,2-difluoroethanone Chemical compound FC(CNC1=C(N=C2C(=N1)CN(CC2)C(C(F)F)=O)N2CCC(CC2)OC2=C(C=C(C=C2)F)F)F PEDBETLWIDHFSD-UHFFFAOYSA-N 0.000 claims description 3
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 3
- CJEZYFCOYOMTCD-UHFFFAOYSA-N tert-butyl 4-[6-acetyl-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-2-yl]piperazine-1-carboxylate Chemical compound C(C)(=O)N1CC2=NC(=C(N=C2CC1)N1CCN(CC1)C(=O)OC(C)(C)C)NC(C)C CJEZYFCOYOMTCD-UHFFFAOYSA-N 0.000 claims description 3
- CNIJPVCRGBRADO-LOACHALJSA-N (2S)-1-[2-(2,2-difluoroethylamino)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-7-methyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-2-methoxypropan-1-one Chemical compound FC(CNC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)CN(C(C2)C)C([C@H](C)OC)=O)F CNIJPVCRGBRADO-LOACHALJSA-N 0.000 claims description 2
- NNCMDNRHJDTQBI-UHFFFAOYSA-N (5-chloro-2-fluorophenyl)-[1-[6-methyl-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-2-yl]piperidin-4-yl]methanone Chemical compound ClC=1C=CC(=C(C1)C(=O)C1CCN(CC1)C=1N=C2C(=NC1NC(C)C)CN(CC2)C)F NNCMDNRHJDTQBI-UHFFFAOYSA-N 0.000 claims description 2
- QJRXHWYPTZIIMW-UHFFFAOYSA-N 1-[2-(2,2-difluoroethylamino)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5-methyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone Chemical compound FC(CNC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)C(N(CC2)C(C)=O)C)F QJRXHWYPTZIIMW-UHFFFAOYSA-N 0.000 claims description 2
- NCBHSJWWCRASPE-UHFFFAOYSA-N 1-[2-(2,2-difluoroethylamino)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-2,2-difluoroethanone Chemical compound FC(CNC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)CN(CC2)C(C(F)F)=O)F NCBHSJWWCRASPE-UHFFFAOYSA-N 0.000 claims description 2
- GDLRFXBQKYAJKF-UHFFFAOYSA-N 1-[2-(2,2-difluoroethylamino)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-2-methoxyethanone Chemical compound FC(CNC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)CN(CC2)C(COC)=O)F GDLRFXBQKYAJKF-UHFFFAOYSA-N 0.000 claims description 2
- BEIMMJQYRZFALE-UHFFFAOYSA-N 1-[2-(2,2-difluoroethylamino)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-7-methyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone Chemical compound FC(CNC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)CN(C(C2)C)C(C)=O)F BEIMMJQYRZFALE-UHFFFAOYSA-N 0.000 claims description 2
- KKVIHTPXMOCKPD-UHFFFAOYSA-N 1-[2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-2,2-difluoroethanone Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)C(C(F)F)=O)C=CC(=C1)F KKVIHTPXMOCKPD-UHFFFAOYSA-N 0.000 claims description 2
- WIDYNDYFLUIBHH-UHFFFAOYSA-N 1-[2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-2-methoxyethanone Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)C(COC)=O)C=CC(=C1)F WIDYNDYFLUIBHH-UHFFFAOYSA-N 0.000 claims description 2
- BOKJSHWVCIWGHN-UHFFFAOYSA-N 1-[2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]propan-1-one Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)C(CC)=O)C=CC(=C1)F BOKJSHWVCIWGHN-UHFFFAOYSA-N 0.000 claims description 2
- CLOSQPDXGHYOFH-OAHLLOKOSA-N 1-[2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-[[(2R)-1-methoxypropan-2-yl]amino]-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2N[C@@H](COC)C)CN(CC3)C(C)=O)C=CC(=C1)F CLOSQPDXGHYOFH-OAHLLOKOSA-N 0.000 claims description 2
- CLOSQPDXGHYOFH-HNNXBMFYSA-N 1-[2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-[[(2S)-1-methoxypropan-2-yl]amino]-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2N[C@H](COC)C)CN(CC3)C(C)=O)C=CC(=C1)F CLOSQPDXGHYOFH-HNNXBMFYSA-N 0.000 claims description 2
- JRJLPTCUEBFMPA-KRWDZBQOSA-N 1-[2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-[[(3S)-oxolan-3-yl]amino]-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]propan-1-one Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2N[C@@H]2COCC2)CN(CC3)C(CC)=O)C=CC(=C1)F JRJLPTCUEBFMPA-KRWDZBQOSA-N 0.000 claims description 2
- XIOKGNQYBGJUAK-UHFFFAOYSA-N 1-[2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5-methyl-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-2,2-difluoroethanone Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2NC(C)C)C(N(CC3)C(C(F)F)=O)C)C=CC(=C1)F XIOKGNQYBGJUAK-UHFFFAOYSA-N 0.000 claims description 2
- IWFKEJLLLIHOQD-UHFFFAOYSA-N 1-[2-[4-[(2,4-difluorophenyl)methyl]piperazin-1-yl]-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-2-methylpropan-1-one Chemical compound FC1=C(CN2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)C(C(C)C)=O)C=CC(=C1)F IWFKEJLLLIHOQD-UHFFFAOYSA-N 0.000 claims description 2
- OZCTVPBBFJSIPB-UHFFFAOYSA-N 1-[2-[4-[(2,4-difluorophenyl)methyl]piperazin-1-yl]-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone Chemical compound FC1=C(CN2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)C(C)=O)C=CC(=C1)F OZCTVPBBFJSIPB-UHFFFAOYSA-N 0.000 claims description 2
- TZLIJUSGPVQVEO-JOCHJYFZSA-N 1-[2-[4-[(R)-(2,4-difluorophenyl)-fluoromethyl]piperidin-1-yl]-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone Chemical compound FC1=C(C=CC(=C1)F)[C@@H](C1CCN(CC1)C=1N=C2C(=NC1NC(C)C)CN(CC2)C(C)=O)F TZLIJUSGPVQVEO-JOCHJYFZSA-N 0.000 claims description 2
- TZLIJUSGPVQVEO-QFIPXVFZSA-N 1-[2-[4-[(S)-(2,4-difluorophenyl)-fluoromethyl]piperidin-1-yl]-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone Chemical compound FC1=C(C=CC(=C1)F)[C@H](C1CCN(CC1)C=1N=C2C(=NC1NC(C)C)CN(CC2)C(C)=O)F TZLIJUSGPVQVEO-QFIPXVFZSA-N 0.000 claims description 2
- DEVKCOJYOBVAJW-UHFFFAOYSA-N 1-[3-(2,2-difluoroethylamino)-2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5-methyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone Chemical compound FC(CNC1=C(N=C2C(=N1)C(N(CC2)C(C)=O)C)N2CCC(CC2)OC2=C(C=C(C=C2)F)F)F DEVKCOJYOBVAJW-UHFFFAOYSA-N 0.000 claims description 2
- RXQZHPDNUHUQAQ-UHFFFAOYSA-N 1-[3-(2,2-difluoroethylamino)-2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone Chemical compound FC(CNC1=C(N=C2C(=N1)CN(CC2)C(C)=O)N2CCC(CC2)OC2=C(C=C(C=C2)F)F)F RXQZHPDNUHUQAQ-UHFFFAOYSA-N 0.000 claims description 2
- OLCPSLUHIDGRAC-UHFFFAOYSA-N 1-[3-(cyclobutylamino)-2-[4-[(2,4-difluorophenyl)methyl]piperazin-1-yl]-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone Chemical compound C1(CCC1)NC1=C(N=C2C(=N1)CN(CC2)C(C)=O)N2CCN(CC2)CC2=C(C=C(C=C2)F)F OLCPSLUHIDGRAC-UHFFFAOYSA-N 0.000 claims description 2
- KCSNHUSEVYLGAW-UHFFFAOYSA-N 1-[3-[(3,3-difluorocyclobutyl)amino]-2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone Chemical compound FC1(CC(C1)NC1=C(N=C2C(=N1)CN(CC2)C(C)=O)N2CCC(CC2)OC2=C(C=C(C=C2)F)F)F KCSNHUSEVYLGAW-UHFFFAOYSA-N 0.000 claims description 2
- MBPOFZZJKYHBRS-UHFFFAOYSA-N 1-[3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-2-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-2-methoxyethanone Chemical compound FC1=C(OC2CCN(CC2)C2=C(N=C3C(=N2)CN(CC3)C(COC)=O)NC(C)C)C=CC(=C1)F MBPOFZZJKYHBRS-UHFFFAOYSA-N 0.000 claims description 2
- QDVKQXNZCPPZFC-UHFFFAOYSA-N 1-[3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5-methyl-2-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-2-methoxyethanone Chemical compound FC1=C(OC2CCN(CC2)C2=C(N=C3C(=N2)C(N(CC3)C(COC)=O)C)NC(C)C)C=CC(=C1)F QDVKQXNZCPPZFC-UHFFFAOYSA-N 0.000 claims description 2
- NBYHCUZRCFOGAJ-UHFFFAOYSA-N 1-[3-[4-(3-methoxyphenyl)sulfonylpiperidin-1-yl]-2-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone Chemical compound C(C)(C)NC=1N=C2C(=NC1N1CCC(CC1)S(=O)(=O)C1=CC(=CC=C1)OC)CN(CC2)C(C)=O NBYHCUZRCFOGAJ-UHFFFAOYSA-N 0.000 claims description 2
- DATMUIHVACAMGB-UHFFFAOYSA-N 1-[3-[4-(4-fluorophenyl)sulfonylpiperidin-1-yl]-2-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone Chemical compound FC1=CC=C(C=C1)S(=O)(=O)C1CCN(CC1)C1=C(N=C2C(=N1)CN(CC2)C(C)=O)NC(C)C DATMUIHVACAMGB-UHFFFAOYSA-N 0.000 claims description 2
- WQBBZAUSIBHYSV-UHFFFAOYSA-N 2-(2,2-difluoroethylamino)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-N,N,5-trimethyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound FC(CNC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)C(N(CC2)C(=O)N(C)C)C)F WQBBZAUSIBHYSV-UHFFFAOYSA-N 0.000 claims description 2
- QPASDCWRWVFGHR-UHFFFAOYSA-N 2-(2,2-difluoroethylamino)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-N,N,7-trimethyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound FC(CNC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)CN(C(C2)C)C(=O)N(C)C)F QPASDCWRWVFGHR-UHFFFAOYSA-N 0.000 claims description 2
- PFHQZVCJRTUASF-UHFFFAOYSA-N 2-(2,2-difluoroethylamino)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-N,N-dimethyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound FC(CNC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)CN(CC2)C(=O)N(C)C)F PFHQZVCJRTUASF-UHFFFAOYSA-N 0.000 claims description 2
- BHSOKSOYTDIJFH-UHFFFAOYSA-N 2-(cyclopropylamino)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-N,N,5-trimethyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound C1(CC1)NC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)C(N(CC2)C(=O)N(C)C)C BHSOKSOYTDIJFH-UHFFFAOYSA-N 0.000 claims description 2
- HJXSCEBDNXRAEY-UHFFFAOYSA-N 2-(tert-butylamino)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-N,N-dimethyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound C(C)(C)(C)NC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)CN(CC2)C(=O)N(C)C HJXSCEBDNXRAEY-UHFFFAOYSA-N 0.000 claims description 2
- VEJYSDDQSCHEPV-UHFFFAOYSA-N 2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5-methyl-6-methylsulfonyl-N-propan-2-yl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-3-amine Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2NC(C)C)C(N(CC3)S(=O)(=O)C)C)C=CC(=C1)F VEJYSDDQSCHEPV-UHFFFAOYSA-N 0.000 claims description 2
- HTZPLPXSOKGAHL-UHFFFAOYSA-N 2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-6-(2-fluoroethyl)-N-propan-2-yl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-3-amine Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)CCF)C=CC(=C1)F HTZPLPXSOKGAHL-UHFFFAOYSA-N 0.000 claims description 2
- WVNJJQCGMGXTTA-UHFFFAOYSA-N 2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-6-methyl-N-propan-2-yl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-3-amine Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)C)C=CC(=C1)F WVNJJQCGMGXTTA-UHFFFAOYSA-N 0.000 claims description 2
- ZQSQANVLMIZGFW-UHFFFAOYSA-N 2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-6-methylsulfonyl-N-propan-2-yl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-3-amine Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)S(=O)(=O)C)C=CC(=C1)F ZQSQANVLMIZGFW-UHFFFAOYSA-N 0.000 claims description 2
- NNRCOKXZVAPOJH-UHFFFAOYSA-N 2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-N,N,5-trimethyl-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2NC(C)C)C(N(CC3)C(=O)N(C)C)C)C=CC(=C1)F NNRCOKXZVAPOJH-UHFFFAOYSA-N 0.000 claims description 2
- SZPUFGYPZNGJJQ-UHFFFAOYSA-N 2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-N-(2-methoxyethyl)-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)C(=O)NCCOC)C=CC(=C1)F SZPUFGYPZNGJJQ-UHFFFAOYSA-N 0.000 claims description 2
- HARGAPZWEJDNCT-UHFFFAOYSA-N 2-[4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl]-N,N-dimethyl-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)C(=O)N(C)C)C=CC(=C1)OC HARGAPZWEJDNCT-UHFFFAOYSA-N 0.000 claims description 2
- PHVACLPWVCZBQR-UHFFFAOYSA-N 2-[4-(4-cyano-2-fluorophenoxy)piperidin-1-yl]-N,N-dimethyl-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound C(#N)C1=CC(=C(OC2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)C(=O)N(C)C)C=C1)F PHVACLPWVCZBQR-UHFFFAOYSA-N 0.000 claims description 2
- LACYCIZBHVBIAT-UHFFFAOYSA-N 2-[4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl]-N,N-dimethyl-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound ClC=1C=CC(=C(C(=O)C2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)C(=O)N(C)C)C1)F LACYCIZBHVBIAT-UHFFFAOYSA-N 0.000 claims description 2
- LNHWNOWSQBYDGD-UHFFFAOYSA-N 2-[4-[(2,4-difluorophenyl)-fluoromethyl]piperidin-1-yl]-6-methyl-N-propan-2-yl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-3-amine Chemical compound FC1=C(C=CC(=C1)F)C(C1CCN(CC1)C=1N=C2C(=NC1NC(C)C)CN(CC2)C)F LNHWNOWSQBYDGD-UHFFFAOYSA-N 0.000 claims description 2
- WEWPKQJONYAZFF-UHFFFAOYSA-N 2-[4-[(2,4-difluorophenyl)-fluoromethyl]piperidin-1-yl]-N,N-dimethyl-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound FC1=C(C=CC(=C1)F)C(C1CCN(CC1)C=1N=C2C(=NC1NC(C)C)CN(CC2)C(=O)N(C)C)F WEWPKQJONYAZFF-UHFFFAOYSA-N 0.000 claims description 2
- LLDFGRFJUUBZCG-UHFFFAOYSA-N 2-[4-[(2,4-difluorophenyl)methyl]piperazin-1-yl]-6-methylsulfonyl-N-propan-2-yl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-3-amine Chemical compound FC1=C(CN2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)S(=O)(=O)C)C=CC(=C1)F LLDFGRFJUUBZCG-UHFFFAOYSA-N 0.000 claims description 2
- KCNUCXSMWFOXEY-UHFFFAOYSA-N 3-(2,2-difluoroethylamino)-2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-N,N-dimethyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound FC(CNC1=C(N=C2C(=N1)CN(CC2)C(=O)N(C)C)N2CCC(CC2)OC2=C(C=C(C=C2)F)F)F KCNUCXSMWFOXEY-UHFFFAOYSA-N 0.000 claims description 2
- GENCHWDTLHDGDV-UHFFFAOYSA-N 3-(cyclobutylamino)-2-[4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl]-N,N-dimethyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound C1(CCC1)NC1=C(N=C2C(=N1)CN(CC2)C(=O)N(C)C)N2CCC(CC2)OC2=C(C=C(C=C2)OC)F GENCHWDTLHDGDV-UHFFFAOYSA-N 0.000 claims description 2
- SSSAAZHGVHRQMQ-UHFFFAOYSA-N 3-[2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-3-oxopropanenitrile Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)C(CC#N)=O)C=CC(=C1)F SSSAAZHGVHRQMQ-UHFFFAOYSA-N 0.000 claims description 2
- OLWFSHRVTXHOAB-UHFFFAOYSA-N 3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-6-methyl-N-propan-2-yl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-2-amine Chemical compound FC1=C(OC2CCN(CC2)C2=C(N=C3C(=N2)CN(CC3)C)NC(C)C)C=CC(=C1)F OLWFSHRVTXHOAB-UHFFFAOYSA-N 0.000 claims description 2
- WBUGZKCCSZPEPZ-UHFFFAOYSA-N 3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-N,N-dimethyl-2-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound FC1=C(OC2CCN(CC2)C2=C(N=C3C(=N2)CN(CC3)C(=O)N(C)C)NC(C)C)C=CC(=C1)F WBUGZKCCSZPEPZ-UHFFFAOYSA-N 0.000 claims description 2
- XZFFAYWJIHTJHD-UHFFFAOYSA-N 3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-N-(2-methoxyethyl)-2-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound FC1=C(OC2CCN(CC2)C2=C(N=C3C(=N2)CN(CC3)C(=O)NCCOC)NC(C)C)C=CC(=C1)F XZFFAYWJIHTJHD-UHFFFAOYSA-N 0.000 claims description 2
- LPDQCOZZDLFEPF-UHFFFAOYSA-N 3-[4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl]-6-methyl-N-propan-2-yl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-2-amine Chemical compound FC1=C(OC2CCN(CC2)C2=C(N=C3C(=N2)CN(CC3)C)NC(C)C)C=CC(=C1)OC LPDQCOZZDLFEPF-UHFFFAOYSA-N 0.000 claims description 2
- IRGNVXRGFACSOX-UHFFFAOYSA-N 3-[4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl]-N,N-dimethyl-2-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound FC1=C(OC2CCN(CC2)C2=C(N=C3C(=N2)CN(CC3)C(=O)N(C)C)NC(C)C)C=CC(=C1)OC IRGNVXRGFACSOX-UHFFFAOYSA-N 0.000 claims description 2
- FZEZEAHOJXPJIL-UHFFFAOYSA-N 3-[4-(4-cyano-2-fluorophenoxy)piperidin-1-yl]-N,N-dimethyl-2-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound C(#N)C1=CC(=C(OC2CCN(CC2)C2=C(N=C3C(=N2)CN(CC3)C(=O)N(C)C)NC(C)C)C=C1)F FZEZEAHOJXPJIL-UHFFFAOYSA-N 0.000 claims description 2
- JOAGWBROEFGAGV-UHFFFAOYSA-N 3-[4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl]-N,N-dimethyl-2-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound ClC=1C=CC(=C(C(=O)C2CCN(CC2)C2=C(N=C3C(=N2)CN(CC3)C(=O)N(C)C)NC(C)C)C1)F JOAGWBROEFGAGV-UHFFFAOYSA-N 0.000 claims description 2
- BJKRRQIZQPWPHY-UHFFFAOYSA-N 3-[4-[(2,4-difluorophenyl)-fluoromethyl]piperidin-1-yl]-N,N-dimethyl-2-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-carboxamide Chemical compound FC1=C(C=CC(=C1)F)C(C1CCN(CC1)C1=C(N=C2C(=N1)CN(CC2)C(=O)N(C)C)NC(C)C)F BJKRRQIZQPWPHY-UHFFFAOYSA-N 0.000 claims description 2
- HQTYXSQIQIYKQC-UHFFFAOYSA-N 3-fluoro-4-[1-[6-(2-methoxyacetyl)-2-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-3-yl]piperidin-4-yl]oxybenzonitrile Chemical compound FC=1C=C(C#N)C=CC1OC1CCN(CC1)C1=C(N=C2C(=N1)CN(CC2)C(COC)=O)NC(C)C HQTYXSQIQIYKQC-UHFFFAOYSA-N 0.000 claims description 2
- BKXPUXJJHDYHSD-UHFFFAOYSA-N 3-fluoro-4-[1-[6-methyl-2-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-3-yl]piperidin-4-yl]oxybenzonitrile Chemical compound FC=1C=C(C#N)C=CC1OC1CCN(CC1)C1=C(N=C2C(=N1)CN(CC2)C)NC(C)C BKXPUXJJHDYHSD-UHFFFAOYSA-N 0.000 claims description 2
- ZJNCJRGONKKQPM-UHFFFAOYSA-N 3-fluoro-4-[1-[6-methyl-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-2-yl]piperidin-4-yl]oxybenzonitrile Chemical compound FC=1C=C(C#N)C=CC1OC1CCN(CC1)C=1N=C2C(=NC1NC(C)C)CN(CC2)C ZJNCJRGONKKQPM-UHFFFAOYSA-N 0.000 claims description 2
- AUPDVTRYLMDISN-UHFFFAOYSA-N 4-[1-[6-(cyclopropanecarbonyl)-2-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-3-yl]piperidin-4-yl]oxy-3-fluorobenzonitrile Chemical compound C1(CC1)C(=O)N1CC2=NC(=C(N=C2CC1)NC(C)C)N1CCC(CC1)OC1=C(C=C(C#N)C=C1)F AUPDVTRYLMDISN-UHFFFAOYSA-N 0.000 claims description 2
- QHAYDSAORNBIBU-UHFFFAOYSA-N 4-[1-[6-acetyl-2-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-3-yl]piperidin-4-yl]oxy-3-fluorobenzonitrile Chemical compound C(C)(=O)N1CC2=NC(=C(N=C2CC1)NC(C)C)N1CCC(CC1)OC1=C(C=C(C#N)C=C1)F QHAYDSAORNBIBU-UHFFFAOYSA-N 0.000 claims description 2
- JGQSUMBLQLYGMA-UHFFFAOYSA-N 4-[[4-[6-acetyl-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-2-yl]piperazin-1-yl]methyl]-3-fluorobenzonitrile Chemical compound C(C)(=O)N1CC2=NC(=C(N=C2CC1)N1CCN(CC1)CC1=C(C=C(C#N)C=C1)F)NC(C)C JGQSUMBLQLYGMA-UHFFFAOYSA-N 0.000 claims description 2
- ZATIEATULNKCIF-UHFFFAOYSA-N 6-(2,2-difluoroethyl)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-N-propan-2-yl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-2-amine Chemical compound FC(CN1CC2=NC(=C(N=C2CC1)NC(C)C)N1CCC(CC1)OC1=C(C=C(C=C1)F)F)F ZATIEATULNKCIF-UHFFFAOYSA-N 0.000 claims description 2
- WWPMMCYXCUAIQH-UHFFFAOYSA-N N-(2,2-difluoroethyl)-2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5-methyl-6-methylsulfonyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-3-amine Chemical compound FC(CNC1=C(N=C2C(=N1)C(N(CC2)S(=O)(=O)C)C)N2CCC(CC2)OC2=C(C=C(C=C2)F)F)F WWPMMCYXCUAIQH-UHFFFAOYSA-N 0.000 claims description 2
- OPFNFNXTVSGTOP-UHFFFAOYSA-N N-(2,2-difluoroethyl)-2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-6-methyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-3-amine Chemical compound FC(CNC1=C(N=C2C(=N1)CN(CC2)C)N2CCC(CC2)OC2=C(C=C(C=C2)F)F)F OPFNFNXTVSGTOP-UHFFFAOYSA-N 0.000 claims description 2
- WFSTYLJLIRNPTM-UHFFFAOYSA-N N-(2,2-difluoroethyl)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5-methyl-6-methylsulfonyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-2-amine Chemical compound FC(CNC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)C(N(CC2)S(=O)(=O)C)C)F WFSTYLJLIRNPTM-UHFFFAOYSA-N 0.000 claims description 2
- WEPYKHOJTKMFPG-UHFFFAOYSA-N N-(2,2-difluoroethyl)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-6,7-dimethyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-2-amine Chemical compound FC(CNC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)CN(C(C2)C)C)F WEPYKHOJTKMFPG-UHFFFAOYSA-N 0.000 claims description 2
- OGDJAPZFQNICMB-UHFFFAOYSA-N N-(2,2-difluoroethyl)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-6-methylsulfonyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-2-amine Chemical compound FC(CNC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)CN(CC2)S(=O)(=O)C)F OGDJAPZFQNICMB-UHFFFAOYSA-N 0.000 claims description 2
- BNECLYPVBLBWJE-UHFFFAOYSA-N N-(2,2-difluoroethyl)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-7-methyl-6-methylsulfonyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-2-amine Chemical compound FC(CNC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)CN(C(C2)C)S(=O)(=O)C)F BNECLYPVBLBWJE-UHFFFAOYSA-N 0.000 claims description 2
- RJZHGBONFGIONP-UHFFFAOYSA-N N-cyclobutyl-2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-6-methylsulfonyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-3-amine Chemical compound C1(CCC1)NC1=C(N=C2C(=N1)CN(CC2)S(=O)(=O)C)N2CCC(CC2)OC2=C(C=C(C=C2)F)F RJZHGBONFGIONP-UHFFFAOYSA-N 0.000 claims description 2
- WMVKEICVMPCBFH-UHFFFAOYSA-N N-cyclopropyl-2-[4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl]-6-methyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-3-amine Chemical compound C1(CC1)NC1=C(N=C2C(=N1)CN(CC2)C)N2CCC(CC2)OC2=C(C=C(C=C2)OC)F WMVKEICVMPCBFH-UHFFFAOYSA-N 0.000 claims description 2
- MAJHVWJNIPAICG-UHFFFAOYSA-N N-cyclopropyl-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5,6-dimethyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-2-amine Chemical compound C1(CC1)NC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)C(N(CC2)C)C MAJHVWJNIPAICG-UHFFFAOYSA-N 0.000 claims description 2
- WWWODUMJPXCYHV-UHFFFAOYSA-N N-cyclopropyl-3-[4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl]-6-methyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-2-amine Chemical compound C1(CC1)NC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)OC)F)CN(CC2)C WWWODUMJPXCYHV-UHFFFAOYSA-N 0.000 claims description 2
- GZJWUTGKWXOMFU-NRFANRHFSA-N N-cyclopropyl-3-[4-[(S)-(2,4-difluorophenyl)-fluoromethyl]piperidin-1-yl]-6-methyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-2-amine Chemical compound C1(CC1)NC=1N=C2C(=NC1N1CCC(CC1)[C@H](F)C1=C(C=C(C=C1)F)F)CN(CC2)C GZJWUTGKWXOMFU-NRFANRHFSA-N 0.000 claims description 2
- DFRPGOORGHJXGT-UHFFFAOYSA-N [2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-(1,2-oxazol-5-yl)methanone Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)C(=O)C3=CC=NO3)C=CC(=C1)F DFRPGOORGHJXGT-UHFFFAOYSA-N 0.000 claims description 2
- FOEDAKAYIRFINY-QHCPKHFHSA-N [2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-[(2S)-1-methylpyrrolidin-2-yl]methanone Chemical compound CC(C)NC1=C(N=C2CCN(CC2=N1)C(=O)[C@@H]1CCCN1C)N1CCC(CC1)OC1=C(F)C=C(F)C=C1 FOEDAKAYIRFINY-QHCPKHFHSA-N 0.000 claims description 2
- OMKDIIHTEGCEDV-UHFFFAOYSA-N [2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-(propan-2-ylamino)-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-pyrrolidin-1-ylmethanone Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC2NC(C)C)CN(CC3)C(=O)N3CCCC3)C=CC(=C1)F OMKDIIHTEGCEDV-UHFFFAOYSA-N 0.000 claims description 2
- MTQHWKKEVIZVTJ-UHFFFAOYSA-N cyclopropyl-[2-(2,2-difluoroethylamino)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5-methyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]methanone Chemical compound C1(CC1)C(=O)N1C(C2=NC(=C(N=C2CC1)NCC(F)F)N1CCC(CC1)OC1=C(C=C(C=C1)F)F)C MTQHWKKEVIZVTJ-UHFFFAOYSA-N 0.000 claims description 2
- VJBZTVUXYAULIV-UHFFFAOYSA-N cyclopropyl-[3-(2,2-difluoroethylamino)-2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5-methyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]methanone Chemical compound C1(CC1)C(=O)N1C(C2=NC(=C(N=C2CC1)N1CCC(CC1)OC1=C(C=C(C=C1)F)F)NCC(F)F)C VJBZTVUXYAULIV-UHFFFAOYSA-N 0.000 claims description 2
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims 6
- JTNXLHFGSOWSSM-UHFFFAOYSA-N 1-[2-(2,2-difluoroethylamino)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5-methyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-2,2-difluoroethanone Chemical compound FC(CNC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)C(N(CC2)C(C(F)F)=O)C)F JTNXLHFGSOWSSM-UHFFFAOYSA-N 0.000 claims 2
- BBNYLDSWVXSNOQ-UHFFFAOYSA-N oxolane-2-carbaldehyde Chemical compound O=CC1CCCO1 BBNYLDSWVXSNOQ-UHFFFAOYSA-N 0.000 claims 2
- RDXSNOSVIFKOPG-CQSZACIVSA-N (2R)-1-[3-(2,2-difluoroethylamino)-2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-2-methoxypropan-1-one Chemical compound FC(CNC1=C(N=C2C(=N1)CN(CC2)C([C@@H](C)OC)=O)N2CCC(CC2)OC2=C(C=C(C=C2)F)F)F RDXSNOSVIFKOPG-CQSZACIVSA-N 0.000 claims 1
- FQWWKVZBYLUHMI-AWEZNQCLSA-N (2S)-1-[2-(2,2-difluoroethylamino)-3-[4-(2,4-difluorophenoxy)piperidin-1-yl]-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-2-methoxypropan-1-one Chemical compound FC(CNC=1N=C2C(=NC1N1CCC(CC1)OC1=C(C=C(C=C1)F)F)CN(CC2)C([C@H](C)OC)=O)F FQWWKVZBYLUHMI-AWEZNQCLSA-N 0.000 claims 1
- RDXSNOSVIFKOPG-AWEZNQCLSA-N (2S)-1-[3-(2,2-difluoroethylamino)-2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]-2-methoxypropan-1-one Chemical compound FC(CNC1=C(N=C2C(=N1)CN(CC2)C([C@H](C)OC)=O)N2CCC(CC2)OC2=C(C=C(C=C2)F)F)F RDXSNOSVIFKOPG-AWEZNQCLSA-N 0.000 claims 1
- KZKRRZFCAYOXQE-UHFFFAOYSA-N 1$l^{2}-azinane Chemical group C1CC[N]CC1 KZKRRZFCAYOXQE-UHFFFAOYSA-N 0.000 claims 1
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- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- FXYXJKWVTFZJGZ-UHFFFAOYSA-N tert-butyl 4-(2,4-difluorobenzoyl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C(=O)C1=CC=C(F)C=C1F FXYXJKWVTFZJGZ-UHFFFAOYSA-N 0.000 description 1
- DAWIORDJWWVXOJ-UHFFFAOYSA-N tert-butyl 4-(2,4-difluorophenyl)sulfonylpiperidine-1-carboxylate Chemical compound FC1=C(C=CC(=C1)F)S(=O)(=O)C1CCN(CC1)C(=O)OC(C)(C)C DAWIORDJWWVXOJ-UHFFFAOYSA-N 0.000 description 1
- YGGDBIBTWAGGKQ-MBBUEALLSA-N tert-butyl 4-[(2,4-difluorophenyl)-fluoromethyl]piperidine-1-carboxylate 4-[(R)-(2,4-difluorophenyl)-fluoromethyl]piperidine Chemical compound F[C@H](C1CCNCC1)c1ccc(F)cc1F.CC(C)(C)OC(=O)N1CCC(CC1)C(F)c1ccc(F)cc1F YGGDBIBTWAGGKQ-MBBUEALLSA-N 0.000 description 1
- ITCQNWXLNZGEHP-UHFFFAOYSA-N tert-butyl 4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate Chemical compound CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1 ITCQNWXLNZGEHP-UHFFFAOYSA-N 0.000 description 1
- 125000006318 tert-butyl amino group Chemical group [H]N(*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 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
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
Classifications
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- 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
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- 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
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
Description
本発明は、Gタンパク質共役受容体6(G-Protein-Coupled Receptor 6)(以下、GPR6という)モジュレーターである化合物を提供する。GPR6は、Gs経路を介してシグナルを送るGPCRである。GPR6受容体は、中枢神経系(CNS)、特に線条体の中型有棘ニューロン(MSNs)にて高度に発現しており、末梢組織で最小の発現となる。ドーパミン作動性神経支配の主要な線条体ターゲットは、線条体淡蒼球系(間接)および線条体黒質系(直接)出力路の中型有棘ニューロン(MSNs)に存在する。直接出力路のMSNsがドーパミンD1受容体を発現する一方、間接路のものはD2受容体を発現する。GPR6は、線条体におけるD2受容体発現MSNsで豊富であり、ここでは、GPR6活性が、D2受容体シグナリングと機能的に対立する。Gs結合GPR6の拮抗作用または逆活性作用は、MSNsにおいてcAMPを低下させ、ドーパミン媒介性のD2受容体活性化に対する機能的代替を提供する。従って、本発明の化合物は、パーキンソン病を含む様々な神経学的および精神医学的障害を治療するのに有用である。
R1は、置換されていてもよいC3−8シクロアルキル、置換されていてもよいC3−6ヘテロシクリル、置換されていてもよいC6−10アリール、および置換されていてもよいC1−10ヘテロアリールからなる群より選ばれ;
X1はNであり、およびX2はCHであるか;または
X1はCHであり、およびX2はNであるか;または
X1はNであり、およびX2はNであり;
X1がNである場合、Zは、C1−6アルキレン、C1−6ハロアルキレン、−C(O)−、および−S(O)2−からなる群より選ばれ;
X1がCHである場合、Zは、C1−6アルキレン、C1−6ハロアルキレン、−O−、−C(O)−、−NH−、−S−、−S(O)−、および−S(O)2−からなる群より選ばれ;
qは、0、1、または2であり;
sは、0、1、または2であり;
R2は、−OR5または−NR6R7であり;
R3は、それぞれ独立して、C1−6アルキル、C3−8シクロアルキル、およびトリフルオロメチルからなる群より選ばれ;
pは、0、1、または2であり;
R4は、それぞれ独立して、C1−6アルキル、ヒドロキシ、およびハロからなる群より選ばれ;
rは、0または1であり;
R5は、C1−6アルキルおよびC3−8シクロアルキルからなる群より選ばれ;
R6は、水素およびC1−6アルキルからなる群より選ばれ;
R7は、置換されていてもよいC1−6アルキル、C3−8シクロアルキル、置換されていてもよいC6−10アリール、置換されていてもよいC1−10ヘテロアリール、および置換されていてもよいC3−6ヘテロシクリルからなる群より選ばれ;
X3は、CHおよびCR4からなる群より選ばれ、並びにX4はNR8であるか;または
X3は、NR8であり、並びにX4はCHおよびCR4からなる群より選ばれ;
R8は、C1−6アルキル、C1−6ハロアルキル、C3−8シクロアルキル、−S(O)2−R9、−C(O)−R10、−C(O)−N(R11)(R12)、および−C(O)−OR13からなる群より選ばれ;
R9は、C1−6アルキル、C3−8シクロアルキル、および置換されていてもよいフェニルからなる群より選ばれ;
R10は、水素、置換されていてもよいC1−6アルキル、C3−8シクロアルキル、置換されていてもよいC6−10アリール、置換されていてもよいC1−10ヘテロアリール、および置換されていてもよいC3−6ヘテロシクリルからなる群より選ばれ;
R11は、水素およびC1−6アルキルからなる群より選ばれ;
R12は、水素、C1−6アルキルおよびC3−8シクロアルキルからなる群より選ばれるか;または
R11およびR12は、それらが結合している窒素と一緒になって、N、O、およびSの群より選ばれる1個の追加の環ヘテロ原子を有していてもよく、並びにいずれかの環炭素原子上でシアノ、ハロ、ヒドロキシ、アミノ、置換されていてもよいC3−6ヘテロシクリル、C1−9アミド(C1-9 amide)、置換されていてもよいC1−6アルキル、およびC1−4アルコキシからなる群より独立して選ばれる1〜5個の置換基で置換されていてもよく、並びにいずれかの追加の環窒素上で水素、C3−8シクロアルキル、および置換されていてもよいC1−6アルキルからなる群より選ばれる置換基で置換されていてもよい、4〜7員の飽和環を形成し;
R13は、C1−6アルキルおよびC3−8シクロアルキルからなる群より選ばれる)
で示される化合物またはその薬学上許容し得る塩を提供する。
用語「C1−4アルキル」とは、炭素原子が1〜4個である直鎖または分枝のアルキル鎖を指す。
R1は、置換されていてもよいC3−8シクロアルキル、置換されていてもよいC3−6ヘテロシクリル、置換されていてもよいC6−10アリール、および置換されていてもよいC1−10ヘテロアリールからなる群より選ばれ;
X1はNであり、およびX2はCHであるか;または
X1はCHであり、およびX2はNであるか;または
X1はNであり、およびX2はNであり;
X1がNである場合、Zは、C1−6アルキレン、C1−6ハロアルキレン、−C(O)−、および−S(O)2−からなる群より選ばれ;
X1がCHである場合、Zは、C1−6アルキレン、C1−6ハロアルキレン、−O−、−C(O)−、−NH−、−S−、−S(O)−、および−S(O)2−からなる群より選ばれ;
qは、0、1、または2であり;
sは、0、1、または2であり;
R2は、−OR5または−NR6R7であり;
R3は、それぞれ独立して、C1−6アルキル、C3−8シクロアルキル、およびトリフルオロメチルからなる群より選ばれ;
pは、0、1、または2であり;
R4は、それぞれ独立して、C1−6アルキル、ヒドロキシ、およびハロからなる群より選ばれ;
rは、0または1であり;
R5は、C1−6アルキルおよびC3−8シクロアルキルからなる群より選ばれ;
R6は、水素およびC1−6アルキルからなる群より選ばれ;
R7は、置換されていてもよいC1−6アルキル、C3−8シクロアルキル、置換されていてもよいC6−10アリール、置換されていてもよいC1−10ヘテロアリール、および置換されていてもよいC3−6ヘテロシクリルからなる群より選ばれ;
X5は、CHおよびCR4からなる群より選ばれ、並びにX6は、NHおよびN−CH2−(置換されていてもよいフェニル)からなる群より選ばれるか;または
X5は、NHおよびN−CH2−(置換されていてもよいフェニル)からなる群より選ばれ、並びにX6は、CHおよびCR4からなる群より選ばれる)
で示される化合物またはその薬学上許容し得る塩を提供する。
(5-クロロ-2-フルオロフェニル)(ピペリジン-4-イル)メタノン
ESI-MS m/z [M+Na]+ 364.20.
ESI-MS m/z [M+H]+ 242.20.
4-(2,4-ジフルオロフェノキシ)ピペリジン
1H NMR (400 MHz, DMSO-d6)δ ppm 1.84 (m, 2H), 2.08 (m, 2H), 3.05 (m, 2H), 3.20 (m, 2H), 4.57 (m, 1H), 7.04 (m, 1H), 7.31 (m, 2H), 8.95 (br d, 2H).
3-フルオロ-4-(ピペリジン-4-イルオキシ)ベンゾニトリル
1H NMR (400 MHz, DMSO-d6)δppm 1.89 (m, 2H), 2.14 (m, 2H);3.08 (m, 2H), 3.21 (m, 2H), 4.86 (m, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.89 (m, 1H); ESI-MS m/z [M+H]+ 220.7.
6 4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン
(R)-4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン
tert-ブチル 4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-カルボキシレート(無色油状物)
tert-ブチル 4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-カルボキシレートをキラルSFC分割に付して、(R)-tert-ブチル 4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-カルボキシレートを得た。
(R)-tert-ブチル 4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-カルボキシレート(2.8 g, 8.50 mmol)をEtOAc(20 mL)に溶か、HCl(EtOAc中 4 M, 21 mL)を加えた。反応混合物を23℃で2時間撹拌した。溶媒の留去で、表題化合物をそのHCl塩(2.1 g, 93%)として得た。
ESI-MS m/z [M+H]+ 229.9.
(S)-4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン
tert-ブチル 4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-カルボキシレートをキラルSFC分割に付し、(R)-tert-ブチル 4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-カルボキシレートを得た。
表題化合物のHCl塩を、製造5aと同様のやり方で(S)-tert-ブチル 4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-カルボキシレートを使用して製造した。
ESI-MS m/z [M+H]+229.9.
4-((2-フルオロフェニル)スルホニル)ピペリジン
ESI-MS m/z [M+H]+243.95.
4-((2-フルオロ-4-メトキシフェニル)スルホニル)ピペリジン
2,4-ジフルオロベンゼンチオール(0.810 mL, 7.15 mmol)、tert-ブチル 4-((メチルスルホニル)オキシ)ピペリジン-1-カルボキシレート(1.816 g, 6.5 mmol)、およびK2CO3(1.348 g, 9.75 mmol)のACN(16.25 mL)中の混合物を、80℃で一晩加熱した。反応混合物を水に注ぎ、EtOAcで2回抽出した。有機層をNa2SO4で乾燥し、ろ過し、減圧下で濃縮して、tert-ブチル 4-((2,4-ジフルオロフェニル)チオ)ピペリジン-1-カルボキシレート(2.141 g)を黄色油状物として得た。これを精製せずに次に進めた。
ESI-MS m/z [M+Na]+ 383.80.
ESI-MS m/z [M+H]+274.00.
4-((3-フルオロフェニル)スルホニル)ピペリジン
ESI-MS m/z [M+H]+ 255.9.
ESI-MS m/z [M+Na]+ 365.9.
ESI-MS m/z [M+H]+243.9.
4-((3-メトキシフェニル)スルホニル)ピペリジン
ESI-MS m/z [M+H]+255.9.
4-((4-フルオロフェニル)スルホニル)ピペリジン
ESI-MS m/z [M+H]+ 243.95.
1-(2,4-ジフルオロベンジル)ピペラジン
ESI-MS m/z [M+H]+ 213.04.
4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン
ESI-MS m/z [M+Na]+ 348.2.
ESI-MS m/z [M+H]+226.20.
3-クロロ-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)ピリド[3,4-b]ピラジン
ESI-MS m/z [M+H]+ 377.4.
4-((1-(3-クロロピリド[3,4-b]ピラジン-2-イル)ピペリジン-4-イル)オキシ)-3-フルオロベンゾニトリル
ESI-MS m/z [M+H]+ 384.3.
(R)-3-クロロ-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)ピリド[3,4-b]ピラジン
ESI-MS m/z [M+H]+ 393.4.
(S)-3-クロロ-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)ピリド[3,4-b]ピラジン
E-MS m/z [M+H]+ 393.4.
3-クロロ-2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)ピリド[3,4-b]ピラジン
ESI-MS m/z [M+H]+ 376.0.
3-クロロ-2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)ピリド[3,4-b]ピラジン
ESI-MS m/z [M+H]+ 389.2.
tert-ブチル 4-(3-クロロピリド[3,4-b]ピラジン-2-イル)ピペラジン-1-カルボキシレート
1H NMR (500 MHz, DMSO-d6)δ ppm 1.44 (s, 9H), 3.51-3.58 (m, 4H), 3.62-3.68 (m, 4H), 7.67 (d, J = 1.0 Hz, 1H), 8.66 (d, J = 5.9 Hz, 1H), 9.15 (d, J = 1.0 Hz, 1H); ESI-MS m/z [M+H]+ 350.5.
tert-ブチル 4-(3-(イソプロピルアミノ)ピリド[3,4-b]ピラジン-2-イル)ピペラジン-1-カルボキシレート
1H NMR (500 MHz, DMSO-d6)δ ppm 1.26 (d, J = 6.8 Hz, 6H), 1.43 (s, 9H), 3.30-3.33 (m, 4H), 3.52-3.60 (m, 4H), 4.32-4.42 (m, 1H), 6.54 (d, J = 7.8 Hz, 1H), 7.43-7.46 (m, 1H), 8.29 (d, J = 5.4 Hz, 1H), 8.78 (s, 1H); ESI-MS m/z [M+H]+ 373.0.
(1s,3s)-3-((2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)ピリド[3,4-b]ピラジン-3-イル)アミノ)シクロブタン-1-オール
1H NMR (500 MHz, DMSO-d6)δ ppm 1.92-2.02 (m, 2H), 2.61-2.70 (m, 6H), 3.38 (br s, 4H), 3.60 (s, 2H), 3.90-3.98 (m, 1H), 3.99-4.07 (m, 1H), 5.08 (d, J = 5.9 Hz, 1H), 6.93-6.98 (m, 1H), 7.09 (td, J = 8.4, 2.7 Hz, 1H), 7.20-7.25 (m, 1H), 7.41-7.45 (m, 1H), 7.47-7.53 (m, 1H), 8.28 (d, J = 5.9 Hz, 1H), 8.75 (s, 1H); ESI-MS m/z [M+H]+ 427.0.
(1s,3s)-3-((2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)ピリド[3,4-b]ピラジン-3-イル)アミノ)シクロブタン-1-オール
3-クロロ-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)ピリド[3,4-b]ピラジン(0.75 g, 1.991 mmol)、(1s,3s)-3-アミノシクロブタノール塩酸塩(0.738 g, 5.97 mmol)、およびフッ化カリウム(0.150 g, 2.59 mmol)をDMSO(7.5 mL)中で組み合わせ、DIPEA(1.734 mL, 9.95 mmol)を23℃で加えた。反応混合物を23℃で5日間撹拌し、水(30 mL)で希釈して、黄色ないしオレンジ色の懸濁液を得た。得られた固体をろ過し、水ですすぎ、真空乾燥して、表題化合物(784 mg, 92%)を黄色ないしオレンジ色の固体として得た。
1H NMR (500 MHz, DMSO-d6)δ ppm 1.87-2.03 (m, 4H), 2.07-2.18 (m, 2H), 2.61-2.73 (m, 2H), 3.19-3.29 (m, 2H), 3.63-3.73 (m, 2H), 3.89-3.99 (m, 1H), 3.99-4.10 (m, 1H), 4.62 (tt, J = 7.9, 3.8 Hz, 1H), 5.08 (d, J = 5.9 Hz, 1H), 6.99-7.10 (m, 2H), 7.26-7.38 (m, 2H), 7.44 (d, J = 5.4 Hz, 1H), 8.28 (d, J = 5.4 Hz, 1H), 8.76 (s, 1H); ESI-MS m/z [M+H]+ 427.9.
(1r,3r)-3-((2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)ピリド[3,4-b]ピラジン-3-イル)アミノ)シクロブタン-1-オール
3-クロロ-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)ピリド[3,4-b]ピラジン(0.75 g, 1.991 mmol)、(1r,3r)-3-アミノシクロブタノール塩酸塩(0.738 g, 5.97 mmol)、およびフッ化カリウム(0.150 g, 2.59 mmol)をDMSO(7.5 mL)中で組み合わせ、DIPEA(1.734 mL, 9.95 mmol)を23℃で加えた。反応を23℃で5日間撹拌し、水(30 mL)で希釈して、茶色の粘着性懸濁液を得た。懸濁液を氷で冷却し、0℃で30分撹拌し、ろ過し、水ですすぎ、得られた固体を真空乾燥して、表題化合物(802 mg, 94%)を薄い茶色の固体として得た。
1H NMR (500 MHz, DMSO-d6)δ ppm 1.86-1.96 (m, 2H), 2.07-2.15 (m, 2H), 2.23 (ddd, J = 12.6, 7.9, 4.4 Hz, 2H), 2.33-2.40 (m, 2H), 3.23-3.30 (m, 2H), 3.67-3.74 (m, 2H), 4.30-4.37 (m, 1H), 4.56-4.65 (m, 2H), 5.03 (d, J = 4.9 Hz, 1H), 7.00-7.07 (m, 2H), 7.29-7.37 (m, 2H), 7.44 (d, J = 4.9 Hz, 1H), 8.28 (d, J = 5.4 Hz, 1H), 8.77 (s, 1H); ESI-MS m/z [M+H]+ 427.9.
N-シクロブチル-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)ピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+ 412.1.
N-(3,3-ジフルオロシクロブチル)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)ピリド[3,4-b]ピラジン-3-アミン
3-クロロ-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)ピリド[3,4-b]ピラジン(0.46 g, 1.221 mmol)、3,3-ジフルオロシクロブタンアミン塩酸塩(0.526 g, 3.66 mmol)、およびフッ化カリウム(0.092 g, 1.587 mmol)をDMSO(5 mL)中で組み合わせ、DIPEA(1.063 mL, 6.10 mmol)を23℃で加えた。反応を23℃で5日間撹拌し、水(20 mL)で希釈して、黄色ないしオレンジ色の懸濁液を得た。得られた固体をろ過し、水ですすぎ、真空乾燥して、表題化合物(516.4 mg, 95%)を黄色ないしオレンジ色の固体として得た。
1H NMR (500 MHz, DMSO-d6)δ ppm 1.87-1.98 (m, 2H), 2.07-2.18 (m, 2H), 2.77-2.91 (m, 2H), 2.96-3.07 (m, 2H), 3.23-3.32 (m, 2H), 3.69-3.78 (m, 2H), 4.35-4.45 (m, 1H), 4.63 (tt, J = 7.9, 3.8 Hz, 1H), 7.00-7.07 (m, 1H), 7.24-7.40 (m, 3H), 7.48 (d, J = 5.4 Hz, 1H), 8.33 (d, J = 5.4 Hz, 1H), 8.82 (s, 1H); ESI-MS m/z [M+H]+ 447.9.
2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピルピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+ 400.00.
9(S)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-(テトラヒドロフラン-3-イル)ピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+428.1.
(R)-2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-N-(テトラヒドロフラン-3-イル)ピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+ 427.1.
(S)-2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-N-(テトラヒドロフラン-3-イル)ピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+ 427.1.
2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-N-イソプロピルピリド[3,4-b]ピラジン-3-アミン
1H NMR (500 MHz, DMSO-d6)δ ppm 1.24 (d, J = 6.4 Hz, 6H), 2.62 (t, J = 4.9 Hz, 4H), 3.34-3.41 (m, 4H), 3.59 (s, 2H), 4.22-4.42 (m, 1H), 6.46 (d, J = 7.8 Hz, 1H), 7.04-7.17 (m, 1H), 7.22 (td, J = 10.0, 2.4 Hz, 1H), 7.40-7.44 (m, 1H), 7.49 (td, J = 8.5, 6.8 Hz, 1H), 8.27 (d, J = 5.9 Hz, 1H), 8.76 (s, 1H); ESI-MS m/z [M+H]+399.0.
N-シクロブチル-2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)ピリド[3,4-b]ピラジン-3-アミン
1H NMR (500 MHz, DMSO-d6)δ ppm 1.68-1.77 (m, 2H), 2.12 (quind, J = 9.3, 2.7 Hz, 2H), 2.27-2.35 (m, 2H), 2.56-2.68 (m, 4H), 3.35-3.42 (m, 4H), 3.60 (s, 2H), 4.57 (sextet, J = 8.0 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 7.06-7.12 (m, 1H), 7.22 (td, J = 9.9, 2.7 Hz, 1H), 7.43 (d, J = 5.4 Hz, 1H), 7.46-7.53 (m, 1H), 8.27 (d, J = 5.4 Hz, 1H), 8.76 (s, 1H); ESI-MS m/z [M+H]+ 411.0.
6-ベンジル-3-クロロ-2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン
ESI-MS m/z [M+H]+ 483.3.
3-クロロ-2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン
ESI-MS m/z [M+H]+ 407.3.
6-ベンジル-3-クロロ-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン
4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン塩酸塩(247 mg, 0.929 mmol)、2,3-ジクロロピリド[3,4-b]ピラジン(169 mg, 0.845 mmol)およびDIPEA(441μL, 2.53 mmol)のDCM(1.69 mL)中の混合物を、0℃で5分、次いでrtで30分撹拌した。次いで混合物を、EtOAcおよび飽和NH4Cl水溶液で分配した。有機層を塩水で洗浄し、Na2SO4で乾燥し、ろ過し、留去した。残留物をEtOAc中に溶かし、シリカパッドに通してろ過した。ろ液を濃縮して、3-クロロ-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)ピリド[3,4-b]ピラジン(338.4 mg)を黄色発泡体として得た。
ESI-MS m/z [M+H]+ 393.2.
ESI-MS m/z [M+H]+ 487.3.
6-ベンジル-3-クロロ-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン
6-ベンジル-3-クロロ-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン
ESI-MS m/z [M+H]+ 471.4.
4-((1-(6-ベンジル-3-クロロ-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-イル)ピペリジン-4-イル)オキシ)-3-フルオロベンゾニトリル
ESI-MS m/z [M+H]+ 478.5.
(R)-6-ベンジル-3-クロロ-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン
ESI-MS m/z [M+H]+ 487.4.
(S)-6-ベンジル-3-クロロ-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン
表題化合物を、製造46と同様のやり方で(S)-3-クロロ-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)ピリド[3,4-b]ピラジンを使用して製造した。生成物を、ヘプタン中のEtOAcの10%〜50%グラジエントを使用するフラッシュシリカゲルクロマトグラフィーで2回精製した。
ESI-MS m/z [M+H]+ 487.3.
6-ベンジル-N-(2,2-ジフルオロエチル)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+516.4.
6-ベンジル-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+ 494.10.
6-ベンジル-N-シクロブチル-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
表題化合物を、TFA塩として、製造51と同様のやり方でシクロブタンアミンを2,2-ジフルオロエタンアミンの代わりに使用し、およびHPLC方法Aを使用して製造した。
ESI-MS m/z [M+H]+ 506.00.
(S)-6-ベンジル-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-(1-メトキシプロパン-2-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+ 524.00.
(R)-6-ベンジル-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-(1-メトキシプロパン-2-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+ 524.00.
(S)-6-ベンジル-N-(sec-ブチル)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+ 508.00.
(R)-6-ベンジル-N-(sec-ブチル)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+ 508.00.
4-((1-(6-ベンジル-3-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-イル)ピペリジン-4-イル)オキシ)-3-フルオロベンゾニトリル
ESI-MS m/z [M+H]+ 501.5.
(R)-6-ベンジル-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+ 510.4.
(S)-6-ベンジル-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+ 510.4.
3-フルオロ-4-((1-(3-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-イル)ピペリジン-4-イル)オキシ)ベンゾニトリル
ESI-MS m/z [M+H]+ 411.5.
N-(2,2-ジフルオロエチル)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+426.5.
N-シクロブチル-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
反応を水素雰囲気下で2時間撹拌したこと以外は製造66と同様のやり方で、TFA塩として表題化合物を製造した。
ESI-MS m/z [M+H]+ 416.5.
(R)-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+ 420.5.
(S)-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+ 420.5.
N-シクロブチル-2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
ESI-MS m/z [M+H]+ 518.4
ESI-MS m/z [M+H]+ 428.4.
1-(3-(イソプロピルアミノ)-2-(ピペラジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
ESI-MS m/z [M+H]+ 319.5.
2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-5-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
N-(2,2-ジフルオロエチル)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
(5-クロロ-2-フルオロフェニル)(1-(3-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-イル)ピペリジン-4-イル)メタノン
ESI-MS m/z [M+H]+ 405.2.
ESI-MS m/z [M+H]+ 499.2.
ESI-MS m/z [M+H]+ 522.4.
ESI-MS m/z [M+H]+ 432.3.
3-クロロ-N-イソプロピルピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, DMSO-d6)δ ppm 1.28 (d, J = 6.6 Hz, 6H), 4.39-4.49 (m, 1H), 7.49 (dd, J = 5.8, 0.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.95 (d, J = 0.8 Hz, 1H); ESI-MS m/z [M+H]+ 223.1.
3-クロロ-N-シクロプロピルピリド[3,4-b]ピラジン-2-アミン
ESI-MS m/z [M+H]+ 221.1.
3-クロロ-N-(2,2-ジフルオロエチル)ピリド[3,4-b]ピラジン-2-アミン
6-ベンジル-3-クロロ-N-シクロプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
ESI-MS m/z [M+H]+ 315.2.
3-クロロ-N-シクロプロピル-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
ESI-MS m/z [M+H]+ 239.2.
6-ベンジル-3-クロロ-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
ESI-MS m/z [M+H]+ 317.3.
6-ベンジル-3-クロロ-N-(2,2-ジフルオロエチル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
6-ベンジル-N-(tert-ブチル)-3-クロロ-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
2,3-ジクロロピリド[3,4-b]ピラジン(1 g, 5.00 mmol)およびDIPEA(1.75 mL, 10.00 mmol)をDCM(10.00 mL)中で組み合わせ、0℃に冷却し、tert-ブチルアミン(1.590 mL, 15.00 mmol)を加え、48時間撹拌した。反応混合物を飽和NH4Cl水溶液に注ぎ、EtOAcで2回抽出した。有機抽出物を組み合わせ、MgSO4に通してろ過し、真空で濃縮した。残留物をEtOAc中に再溶解させ、EtOAcで洗浄しながら、シリカの1インチプラグに通してろ過し、濃縮して、N-(tert-ブチル)-3-クロロピリド[3,4-b]ピラジン-2-アミン(1.04 g, 88%)を得た。
6-ベンジル-3-(4-((2-フルオロフェニル)スルホニル)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
ESI-MS m/z [M+H]+ 523.90.
6-ベンジル-N-シクロプロピル-3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 0.53-0.60 (m, 2H), 0.78-0.85 (m, 2H), 1.84 - 1.95 (m, 2H), 1.99-2.09 (m, 2H), 2.65-2.73 (m, 1H), 2.90-2.98 (m, 1H), 3.08-3.23 (m, 3H), 3.33 - 3.42 (m, 2H), 3.55-3.68 (m, 2H), 3.75 (s, 3H), 4.16-4.24 (m, 1H), 4.28-4.40 (m, 2H), 4.50-4.59 (m, 2H), 6.67 (s, 1H), 6.73 (dd, J = 12.9, 3.0 Hz, 1H), 7.01-7.09 (m, 1H), 7.52-7.61 (m, 5H); ESI-MS m/z [M+H]+ 504.4.
6-ベンジル-N-シクロプロピル-2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 0.50-0.55 (m, 2H), 0.76 (dd, J = 7.0, 1.9 Hz, 2H), 1.86-1.96 (m, 2H), 2.01-2.10 (m, 2H), 2.63 (tt, J = 7.0, 3.6 Hz, 1H), 2.93-3.01 (m, 2H), 3.07 (br s, 2H), 3.34-3.41 (m, 2H), 3.56 (br s, 2H), 3.75 (s, 3H), 4.23 (br s, 2H), 4.30-4.37 (m, 1H), 4.53 (br s, 2H,)6.63-6.68 (m, 1H), 6.73 (dd, J = 12.8, 2.9 Hz, 1H), 7.05 (t, J = 9.2 Hz, 1H), 7.52-7.61 (m, 5H); ESI-MS m/z [M+H]+ 504.4.
N-シクロプロピル-3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
ESI-MS m/z [M+H]+ 414.4.
N-シクロプロピル-2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 0.52-0.59 (m, 2H), 0.75-0.83 (m, 2H), 1.84-1.97 (m, 2H), 2.02-2.12 (m, 2H), 2.64-2.71 (m, 1H), 2.93-3.16 (m, 4H), 3.35 (s, 2H), 3.52-3.63 (m, 2H), 3.75 (s, 3H), 4.20-4.31 (m, 2H), 4.32-4.40 (m, 1H), 6.63-6.69 (m, 1H), 6.73 (dd, J = 12.9, 3.0 Hz, 1H), 7.03-7.10 (m, 1H); ESI-MS m/z [M+H]+ 414.3.
6-ベンジル-N-シクロプロピル-3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 0.55 (dt, J = 3.5, 1.4 Hz, 2H), 0.77-0.84 (m, 2H), 1.35-1.43 (m, 1H), 1.50-1.71 (m, 2H), 1.91-2.11 (m, 2H), 2.56-2.72 (m, 3H), 3.06-3.15 (m, 2H), 3.36-3.51 (m, 3H), 3.52-3.76 (m, 1H), 4.17 (br s, 2H), 4.52 (s, 2H), 5.50 (dd, J = 46.2, 7.6 Hz, 1H)6.96-7.07 (m, 2H), 7.44-7.60 (m, 6H); ESI-MS m/z [M+H]+ 508.4.
6-ベンジル-N-シクロプロピル-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 0.48-0.54 (m, 2H), 0.71-0.78 (m, 2H), 1.36-1.45 (m, 1H), 1.50-1.72 (m, 2H), 1.92-2.12 (m, 2H), 2.57-2.71 (m, 3H), 2.97-3.10 (m, 2H), 3.39-3.55 (m, 3H), 3.75-3.89 (m, 1H), 4.22 (br s, 2H), 4.53 (br s, 2H), 5.50 (dd, J = 46.5, 7.6 Hz, 1H), 6.96-7.07 (m, 2H), 7.45-7.61 (m, 6H); ESI-MS m/z [M+H]+508.4.
N-シクロプロピル-3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 0.55-0.61 (m, 2H), 0.80-0.86 (m, 2H), 1.41 (br d, J = 12.4 Hz, 1H), 1.52-1.73 (m, 2 H), 1.93-2.13 (m, 2H), 2.60-2.73 (m, 3H), 3.05 (t, J = 6.3 Hz, 2H), 3.39-3.52 (m, 2H), 3.55 (t, J = 6.3 Hz, 2H), 3.98 (s, 1H), 4.17 (s, 2H), 5.51 (dd, J = 46.7, 7.6 Hz, 1H), 6.97-7.08 (m, 2H), 7.45-7.54 (m, 1H); ESI-MS m/z [M+H]+ 418.3.
N-シクロプロピル-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 0.51-0.57 (m, 2H), 0.75-0.81 (m, 2H), 1.43 (br d, J = 13.1 Hz, 1H), 1.52-1.72 (m, 2H), 1.94-2.13 (m, 2H), 2.59-2.72 (m, 3H), 2.97 (t, J = 6.3 Hz, 2H), 3.40-3.50 (m, 2H), 3.51-3.56 (m, 2H), 3.98 (s, 1H), 4.22 (s, 2H), 5.51 (dd, J = 46.2, 7.3 Hz, 1H), 6.96-7.08 (m, 2H), 7.46-7.54 (m, 1H); ESI-MS m/z [M+H]+ 418.3.
6-ベンジル-3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.24 (d, J = 6.6 Hz, 6H), 1.86-1.97 (m, 2H), 2.03-2.12 (m, 2H), 2.95 (br s, 2H), 3.01-3.12 (m, 2H), 3.33-3.38 (m, 2H), 3.53 (br s, 2H), 3.75 (s, 3H), 4.13-4.24 (m, 3H), 4.31-4.38 (m, 1H), 4.52 (s, 2H), 6.63-6.69 (m, 1H), 6.73 (dd, J = 12.8, 2.9 Hz, 1H), 7.06 (t, J = 9.2 Hz, 1H), 7.51-7.60 (m, 5H); ESI-MS m/z [M+H]+ 506.4.
6-ベンジル-3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.23 (dd, J = 6.4, 2.4 Hz, 6H), 1.39-1.47 (m, 1H), 1.51-1.72 (m, 2H), 1.95-2.12 (m, 2H), 2.58-2.70 (m, 2H), 3.04 (br s, 2H), 3.36-3.83 (m, 4H), 4.09-4.21 (m, 3H), 4.51 (br s, 2H), 5.52 (dd, J = 46.2, 7.3 Hz, 1H), 6.97-7.07 (m, 2H), 7.45-7.59 (m, 6H); ESI-MS m/z [M+H]+ 510.4.
3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.25 (d, J = 6.6 Hz, 6H), 1.88-1.98 (m, 2H), 2.04-2.13 (m, 2H), 2.93-3.03 (m, 4H), 3.35-3.41 (m, 3H), 3.54 (t, J = 6.3 Hz, 2H), 3.76 (s, 3H), 4.14-4.18 (m, 2H), 4.18-4.23 (m, 1H), 4.32-4.40 (m, 1H), 6.67 (ddd, J = 9.0, 3.0, 1.4 Hz, 1H), 6.74 (dd, J = 12.9, 3.0 Hz, 1H), 7.07 (t, J = 9.2 Hz, 1H); ESI-MS m/z [M+H]+ 416.3.
3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.24 (dd, J = 6.6, 2.3 Hz, 6H), 1.41-1.48 (br m, 1H), 1.52-1.74 (m, 2H), 1.97-2.14 (m, 2H), 2.61-2.73 (m, 2H), 2.99 (t, J = 6.3 Hz, 2H), 3.38-3.49 (m, 2H), 3.50-3.55 (m, 2H), 4.14 (s, 2H), 4.14-4.21 (m, 1H), 5.53 (dd, J = 46.5, 7.3 Hz, 1H), 6.95-7.10 (m, 2H), 7.46-7.55 (m, 1H); ESI-MS m/z [M+H]+ 420.3.
6-ベンジル-2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.22 (d, J = 6.6 Hz, 6H), 1.87-2.13 (m, 4H), 2.94-3.10 (m, 4H), 3.35-3.53 (m, 3H), 3.75 (s, 3H), 3.79-3.88 (m, 1H), 4.07-4.27 (m, 3H), 4.31-4.39 (m, 1H), 4.52 (br s, 2H), 6.66 (ddd, J = 8.9, 3.0, 1.5 Hz, 1H), 6.73 (dd, J = 12.9, 3.0 Hz, 1H), 7.03-7.10 (m, 1H), 7.51-7.60 (m, 5H); ESI-MS m/z [M+H]+ 506.4.
6-ベンジル-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.21 (dd, J = 6.4, 2.4 Hz, 6H), 1.40-1.48 (m, 1H), 1.51-1.74 (m, 2H), 1.95-2.16 (m, 2H), 2.61-2.73 (m, 2H), 3.00 (br s, 2H), 3.40-3.57 (m, 3H), 4.06-4.13 (m, 2H), 4.15- 4.20 (br m, 1H), 4.51 (br s, 2H), 5.52 (dd, J = 46.0, 7.3 Hz, 1H), 6.97-7.08 (m, 2H), 7.46-7.62 (m, 6H); ESI-MS m/z [M+H]+ 510.4.
2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.24 (d, J = 6.6 Hz, 6H), 1.88-1.98 (m, 2H), 2.05-2.14 (m, 2H), 2.94-3.03 (m, 4H), 3.35-3.43 (m, 2H), 3.54 (t, J = 6.3 Hz, 2H), 3.76 (s, 3H), 4.10-4.21 (m, 3H), 4.32-4.39 (m, 1H), 6.67 (ddd, J = 8.9, 3.0, 1.5 Hz, 1 H), 6.74 (dd, J = 12.8, 2.9 Hz, 1H), 7.07 (t, J = 9.2 Hz, 1H); ESI-MS m/z [M+H]+ 416.3.
2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.23 (dd, J = 6.4, 2.4 Hz, 6H), 1.41-1.49 (m, 1H), 1.52-1.74 (m, 2H), 1.98-2.14 (m, 2H), 2.68 (qd, J = 12.6, 2.5 Hz, 2H), 2.96 (t, J = 6.3 Hz, 2H), 3.40-3.51 (m, 2H), 3.52 (t, J = 6.3 Hz, 2H), 4.10-4.16 (m, 1H), 4.16 (s, 2H), 5.53 (dd, J = 46.5, 7.6 Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]+420.3.
2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.24 (d, J = 6.4 Hz, 6H), 1.89-1.99 (m, 2H), 2.09-2.17 (m, 2H), 2.74 (t, J = 5.9 Hz, 2H), 2.95 (ddd, J = 12.3, 8.7, 3.4 Hz, 2H), 3.11 (t, J = 6.1 Hz, 2H), 3.82 (s, 2H), 4.14 (septet, J = 6.4 Hz, 1H), 4.46 (tt, J = 7.7, 3.5 Hz, 1H), 6.85-6.92 (m, 1H), 6.99 (ddd, J = 11.4, 8.4, 3.2 Hz, 1H), 7.18 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 404.0.
2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (500 MHz, DMSO-d6)δ ppm 1.15 (d, J = 6.8 Hz, 6H), 2.42 (br s, 1H), 2.51-2.61 (m, 6H), 2.89-3.00 (m, 6H), 3.58 (s, 2H), 3.63 (s, 2H), 4.00-4.10 (m, 1H), 5.15 (d, J = 8.3 Hz, 1H), 7.04-7.11 (m, 1H), 7.21 (td, J = 10.0, 2.4 Hz, 1H), 7.44-7.52 (m, 1H); ESI-MS m/z [M+H]+ 403.0.
4-((1-(6-ベンジル-2-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)ピペリジン-4-イル)オキシ)-3-フルオロベンゾニトリル
1H NMR (400 MHz, DMSO-d6)δ ppm 1.05-1.33 (m, 6H), 1.81-1.96 (m, 2H), 2.08-2.18 (m, 2H), 2.84-3.00 (m, 3H), 3.01-3.17 (m, 1H), 3.18-3.32 (m, 2H), 3.33-3.46 (m, 1H), 3.65-3.77 (m, 1H), 3.95-4.06 (m, 1H), 4.08-4.30 (m, 2H), 4.43-4.57 (m, 2H), 4.80-4.87 (m, 1H), 5.91 (d, J = 8.1 Hz, 1H), 7.44-7.60 (m, 6H), 7.66-7.70 (m, 1H), 7.84-7.90 (m, 1H), 10.13 (br s, 1H); ESI-MS m/z [M+H]+ 501.5.
3-フルオロ-4-((1-(2-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)ピペリジン-4-イル)オキシ)ベンゾニトリル
ESI-MS m/z [M+H]+ 411.4.
(5-クロロ-2-フルオロフェニル)(1-(2-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)ピペリジン-4-イル)メタノン
ESI-MS m/z [M+H]+ 523.4.
ESI-MS m/z [M+H]+ 432.3.
3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
ESI-MS m/z [M+H]+ 494.4.
ESI-MS m/z [M+H]+ 404.3.
N-(2,2-ジフルオロエチル)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
N-(tert-ブチル)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
N-シクロブチル-3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
ESI-MS m/z [M+H]+ 235.2.
ESI-MS m/z [M+H]+ 329.3.
ESI-MS m/z [M+H]+ 518.4.
ESI-MS m/z [M+H]+ 428.4.
N-シクロプロピル-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-5-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
濃縮して、表題化合物をTFA塩(132 mg)として得た。
N-(2,2-ジフルオロエチル)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
N-(2,2-ジフルオロエチル)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
シクロプロピル(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)メタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 0.81-0.96 (m, 4H), 1.29 (m, 7H), 1.90-2.18 (m, 4H), 2.73 (m, 0.7H), 2,87 (m, 1.3H), 3.07 (m, 2H), 3.42 (m, 2H), 3.88 (m, 0.7H), 4.06 (t, J = 5.7 Hz, 1.3H), 4.14 (m, 1H), 4.49 (m, 1H), 4.62 (s, 1.3H), 4.80 (s, 0.7H), 6.88 (m, 1H), 6.99 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.18 ppm (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+472.5.
1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシエタン-1-オン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.30 (m, 6H), 1.96 (m, 2H), 2.13 (m, 2H), 2.75 (t, J = 5.7 Hz, 0.7H), 2.83 (t, J = 5.7 Hz, 1.3H), 3.08 (m, 2H), 3.44 (m, 5H), 3.77 (t, J = 5.8 Hz, 1.3H), 3.88 (t, J = 5.9 Hz, 0.7H), 4.14 (m, 1H), 4.24 (s, 0.7H), 4.28 (s, 1.3H), 4.49 (td, J = 7.1, 3.5 Hz, 1H), 4.56 (s, 0.7H), 4.63 (s, 1.3H), 6.88 (m, 1H), 6.99 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 476.5.
2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (500 MHz, DMSO-d6)1.18 (d, J = 6.3 Hz, 6H), 1.88 (m, 2H), 2.07 (m, 2H), 2.75 (t, J = 5.9 Hz, 2H), 2.89 (m, 2H), 2.97 (s, 3H), 3.29 (m, 2H), 3.45 (t, J = 5.9 Hz, 2H), 4.09 (m, 1H), 4.16 (s, 2H), 4.52 (tt, J = 8.1, 3.9 Hz, 1H), 5.57 (d, J = 8.3 Hz, 1H), 7.01 (m, 1H), 7.30 (m, 2H); ESI-MS m/z [M+H]+ 481.90.
2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-N-(2-メトキシエチル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.32 (d, J = 6.6 Hz, 6H), 1.97 (m, 2H), 2.14 (m, 2H), 2.77 (t, J = 5.8 Hz, 2H), 3.12 (m, 2H), 3.37 (m, 5H), 3.46 (m, 4H), 3.71 (t, J = 5.8 Hz, 2H), 4.13 (m, 1H), 4.50 (m, 3H), 6.88 (m, 1H), 6.98 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 505.6.
(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)(テトラヒドロフラン-2-イル)メタノン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.31 (m, 6H), 1.97 (m, 4H), 2.16 (m, 4H)2.82 (m, 2H), 3.10 (m, 2H), 3.45 (m, 2H), 3.89 (m, 4H), 4.14 (m, 1H), 4.44-4.87 (m, 4H), 6.88 (m, 1H), 6.99 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J = 9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 502.6.
3-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-3-オキソプロパンニトリル
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.27 (m, 6H), 1.96 (m, 2H), 2.12 (m, 2H), 2.75 (t, J = 5.9 Hz, 0.8H), 2.85 (m, 1.2H), 3.01 (m, 2H), 3.39 (m, 2H), 3.75 (t, J = 5.8 Hz, 1.2H), 3.89 (t, J = 5.9 Hz, 0.8H), 4.00 (m, 2H);4.14 (m, 1H), 4.48 (m, 1H), 4.50 (s, 0.8H), 4.60 (s, 1.2H), 6.88 (m, 1H), 6.98 (ddd, J = 11.4, 8.6, 3.0 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 471.5.
4-((1-(6-アセチル-3-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-イル)ピペリジン-4-イル)オキシ)-3-フルオロベンゾニトリル
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.31 (m, 6H), 2.02 (m, 2H), 2.20 (m, 5H), 2.74 (t, J = 5.9 Hz, 0.7H), 2.85 (m, 1.3H), 3.14 (m, 2H), 3.43 (m, 2H), 3.83 (t, J = 5.9 Hz, 1.3H), 3.87 (t, J = 5.9 Hz, 0.7H), 4.14 (m, 1H), 4.60 (s, 0.7H), 4.64 (s, 1.3H), 4.80 (m, 1H), 7.34 (m, 1H), 7.54 (m, 2H); ESI-MS m/z [M+H]+ 453.5.
1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシプロパン-1-オン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.36 (m, 9H), 1.98 (m, 2H), 2.14 (m, 2H), 2.83 (m, 2H), 3.16 (m, 2H), 3.35 (s, 3H), 3.49 (m, 2H), 3.90 (m, 1H), 3.93 (t, J = 5.8 Hz, 1H), 4.12 (m, 1H), 4.35 (m, 1H), 4.52 (m, 1H), 4.59-4.79 (m, 2H), 6.88 (m, 1H), 6.99 (ddd, J = 11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 490.5.
シクロプロピル(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)メタノン
1H NMR (400 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 0.67-0.81 (m, 4H), 1.19 (d, J = 6.3 Hz, 6H), 1.80-1.95 (m, 2H), 2.01-2.07 (m, 2H), 2.51-2.56 (m, 1H), 2.57-2.66 (m, 0.9H), 2.72-2.79 (m, 1.1H), 2.84-2.94 (m, 2H), 3.23-3.33 (m, 2H), 3.70-3.79 (m, 0.9H), 3.92-3.98 (m, 1.1H), 4.08-4.18 (m, 1H), 4.42 (br s, 1.1H), 4.48-4.56 (m, 1H), 4.67 (br s, 0.9H), 5.71 (br s, 1H), 6.99-7.05 (m, 1H), 7.26-7.34 (m, 2H); ESI-MS m/z [M+H]+ 472.5.
1-(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシエタン-1-オン
1H NMR (400 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.18 (d, J = 6.6 Hz, 6H), 1.83-1.93 (m, 2H), 2.03-2.11 (m, 2H), 2.63 (t, J = 5.8 Hz, 0.9H), 2.72 (t, J = 5.3 Hz, 1.1H), 2.84-2.93 (m, 2H), 3.22-3.36 (m, 5H), 3.66 (t, J = 5.8 Hz, 1.1H), 3.74 (t, J = 6.1 Hz, 0.9H), 4.10-4.16 (m, 1H), 4.17 (br s, 0.9H), 4.19 (s, 1.1H), 4.49-4.56 (m, 1H), 5.65-5.72 (m, 1H), 6.99-7.05 (m, 1H), 7.26-7.35 (m, 2H); ESI-MS m/z [M+H]+ 476.5.
3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, DMSO-d6)δ ppm 1.19 (d, J = 6.6 Hz, 6H), 1.82-1.93 (m, 2H), 2.02-2.08 (m, 2H), 2.77 (t, J = 5.7 Hz, 2H), 2.84-2.93 (m, 2H), 2.98 (s, 3H), 3.24-3.32 (m, 2H), 3.45 (t, J = 5.9 Hz, 2H), 4.10-4.18 (m, 3H), 4.50-4.55 (m, 1H), 5.67 (br s, 1H), 6.99-7.04 (m, 1H), 7.26-7.35 (m, 2H); ESI-MS m/z [M+H]+ 482.4.
2-(4-(4-シアノ-2-フルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.29 (m, 6H), 2.02 (m, 2H), 2.19 (m, 2H), 2.81 (t, J = 5.3 Hz, 2H), 2.91 (s, 5H), 3.17 (m, 3H), 3.43 (m, 2H), 3.56 (t, J = 5.6 Hz, 2H), 4.13 (m, 1H), 4.32 (s, 2H), 4.80 (m, 1H), 7.34 (m, 1H), 7.54 (t, J = 10.9 Hz, 2H); ESI-MS m/z [M+H]+ 482.5.
3-フルオロ-4-((1-(3-(イソプロピルアミノ)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-イル)ピペリジン-4-イル)オキシ)ベンゾニトリル
1H NMR (400 MHz, メタノール-d4)δ ppm 1.24 (d, J = 6.6 Hz, 6H), 1.98 (m, 2H), 2.19 (m, 2H), 3.08 (m, 7H), 3.38 (m, 3H), 3.76 (br s, 1H), 4.16 (m, 1H), 4.29 (m, 2H), 4.79 (m, 1H), 7.34 (m, 1H), 7.53 (m, 2H); ESI-MS m/z [M+H]+ 425.5.
(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)(モルホリノ)メタノン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.31 (d, J = 6.6 Hz, 6H), 1.96 (m, 2H), 2.13 (m, 2H), 2.81 (t, J = 5.8 Hz, 2H), 3.10 (m, 2H), 3.33 (m, 4H), 3.45 (m, 2H), 3.59 (t, J = 5.9 Hz, 2H), 3.70 (m, 4H), 4.13 (m, 1H), 4.37 (s, 2H), 4.50 (tt, J = 7.2, 3.5 Hz, 1H), 6.88 (m, 1H), 6.99 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 517.5.
3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-N-(2-メトキシエチル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, DMSO-d6)δ ppm 1.18 (d, J = 6.3 Hz, 6H), 1.83-1.93 (m, 2H), 2.02-2.11 (m, 2H), 2.61 (t, J = 5.6 Hz, 2H), 2.82-2.93 (m, 2H), 3.14-3.21 (m, 2H), 3.23 (s, 3H), 3.24-3.31 (m, 2H), 3.31-3.37 (m, 2H), 3.60 (t, J = 5.8 Hz, 2H), 4.08-4.17 (m, 1H), 4.29 (s, 2H), 4.49-4.56 (m, 1H), 5.61-5.70 (m, 1H), 6.66-6.73 (m, 1H), 6.99-7.05 (m, 1H), 7.26-7.34 (m, 2H); ESI-MS m/z [M+H]+ 505.0.
(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)(テトラヒドロフラン-2-イル)メタノン
1H NMR (400 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.19 (d, J = 6.3 Hz, 6H), 1.78-1.94 (m, 4H), 1.97-2.13 (m, 4H), 2.63 (t, J = 5.7 Hz, 0.9H), 2.71-2.77 (m, 1.1H), 2.85-2.95 (m, 2H), 3.24-3.33 (m, 2H), 3.69-3.85 (m, 4H), 4.11 (dt, J = 12.9, 6.4 Hz, 1H), 4.38-4.57 (m, 3H), 4.75 (ddd, J = 14.0, 7.8, 5.7 Hz, 1H), 5.81 (br s, 1H), 6.99-7.05 (m, 1H), 7.25-7.34 (m, 2H); ESI-MS m/z [M+H]+ 502.5.
3-(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-3-オキソプロパンニトリル
1H NMR (400 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.19 (d, J = 6.6 Hz, 6H), 1.80-1.96 (m, 2H), 2.00-2.17 (m, 2H), 2.64 (t, J = 5.6 Hz, 0.9H), 2.76 (t, J = 5.7 Hz, 1.1H), 2.84-2.97 (m, 2H), 3.22-3.34 (m, 2H), 3.64 (t, J = 5.8 Hz, 1.1H), 3.75 (t, J = 5.9 Hz, 0.9H), 4.08-4.14 (m, 1H), 4.16 (s, 0.9H), 4.17 (s, 1.1H), 4.37 (s, 0.9H), 4.43 (s, 1.1H), 4.48-4.57 (m, 1H), 5.76 (br s, 1H), 6.98-7.06 (m, 1H), 7.24-7.36 (m, 2H); ESI-MS m/z [M+H]+ 471.5.
(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)(イソオキサゾール-5-イル)メタノン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.30 (m, 6H), 1.96 (m, 2H), 2.13 (m, 2H), 2.89 (m, 2H), 3.11 (m, 2H), 3.46 (m, 2H), 3.91-4.21 (m, 3H), 4.49 (m, 1H), 4.78 (br s, 2H), 6.87 (m, 1H), 6.92 (s, 1H), 6.98 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H), 8.55 (s, 1H); ESI-MS m/z [M+H]+ 499.5.
4-((1-(6-アセチル-2-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)ピペリジン-4-イル)オキシ)-3-フルオロベンゾニトリル
1H NMR (400 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.18 (d, J = 6.6 Hz, 6H), 1.86-1.96 (m, 2H), 2.08 (s, 1.3H), 2.09 (s, 1.7H), 2.10-2.21 (m, 2H), 2.61 (t, J = 5.6 Hz, 0.9H), 2.73 (t, J = 5.2 Hz, 1.1H), 2.88-2.98 (m, 2H), 3.23-3.31 (m, 2H), 3.66-3.76 (m, 2H), 4.09-4.17 (m, 1H), 4.40 (s, 1.1H), 4.43 (s, 0.9H)4.80-4.87 (m, 1H), 5.59-5.67 (m, 1H), 7.50 (t, J = 8.6 Hz, 1H), 7.68 (dq, J = 8.6, 1.7 Hz, 1H), 7.86 (dt, J = 11.2, 1.7 Hz, 1H); ESI-MS m/z [M+H]+ 453.5.
4-((1-(6-(シクロプロパンカルボニル)-2-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)ピペリジン-4-イル)オキシ)-3-フルオロベンゾニトリル
1H NMR (400 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 0.69-0.79 (m, 4H), 1.18 (d, J = 6.6 Hz, 6H), 1.91 (dd, J = 19.5, 5.6 Hz, 2H), 2.13 (dd, J = 14.3, 6.2 Hz, 2H), 2.52-2.53 (m, 1H), 2.57-2.64 (m, 0.9H), 2.75 (t, J = 6.2 Hz, 1.1H), 2.88-2.99 (m, 2H), 3.22-3.31 (m, 2H), 3.72-3.77 (m, 0.9H), 3.95 (t, J = 5.8 Hz, 1H), 4.10-4.16 (m, 1H), 4.42 (br s, 1.1H), 4.67 (br s, 0.9H), 4.80-4.87 (m, 1H), 5.61-5.67 (m, 1H), 7.50 (t, J = 8.5 Hz, 1H), 7.65-7.70 (m, 1H), 7.86 (dd, J = 11.2, 1.9 Hz, 1H); ESI-MS m/z [M+H]+ 479.5.
2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-6-(イソプロピルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.29 (d, J = 6.6 Hz, 6H), 1.35 (d, J = 6.8 Hz, 6H), 1.95 (m, 2H), 2.13 (m, 2H), 2.82 (t, J = 5.9 Hz, 2H), 3.07 (m, 2H), 3.42 (m, 3H), 3.67 (t, J = 5.8 Hz, 2H), 4.12 (septet, J = 6.5 Hz, 1H), 4.41 (s, 2H), 4.48 (dt, J = 7.5, 3.6 Hz, 1H)6.87 (m, 1H), 6.98 (ddd, J = 11.3, 8.5, 2.9 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 510.5.
2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-6-(メチル-L-プロリル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.26 (dd, J = 6.6, 4.5 Hz, 6H), 1.97 (m, 4H), 2.09 (m, 3H), 2.24 (m, 1H), 2.76 (m, 3H), 2.93(app d, J = 7.6 Hz, 3H), 3.03 (m, 2H), 3.20 (m, 1H), 3.40 (m, 2H), 3.69-4.19 (m, 4H), 4.48 (m, 2H), 4.66 (m, 2H), 6.87 (m, 1H), 6.98 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 515.6.
(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)(ピロリジン-1-イル)メタノン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.33 (d, J = 6.3 Hz, 6H), 1.89 (m, 4H), 1.97 (m, 2H), 2.14 (m, 2H), 2.81 (t, J = 5.8 Hz, 2H), 3.13 (m, 2H), 3.46 (m, 6H), 3.61 (t, J = 5.8 Hz, 2H), 4.12 (septet, J = 6.4 Hz, 1H), 4.38 (s, 2H), 4.51 (tt, J = 7.2, 3.6 Hz, 1H), 6.88 (m, 1H), 6.99 (ddd, J = 11.4, 8.5, 3.0 Hz, 1H), 7.18 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 501.6.
1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタン-1-オン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.28 (m, 6H), 1.96 (m, 2H), 2.12 (m, 2H), 2.79 (t, J = 5.9 Hz, 0.7H), 2.85 (t, J = 5.8 Hz, 1.3H), 3.05 (m, 2H), 3.42 (m, 2H), 3.92 (dt, J = 11.3, 5.8 Hz, 2H), 4.15 (m, 1H), 4.48 (m, 1H), 4.65 (s, 2H), 6.56 (m, 1H), 6.88 (m, 1H), 6.98 (ddd, J = 11.3, 8.5, 2.9 Hz, 1H), 7.17 (td, J = 9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 482.5.
3-フルオロ-4-((1-(2-(イソプロピルアミノ)-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)ピペリジン-4-イル)オキシ)ベンゾニトリル
1H NMR (400 MHz, DMSO-d6)δ ppm 1.18 (d, J = 6.3 Hz, 6H), 1.88-1.96 (m, 2H), 2.09-2.16 (m, 2H), 2.76 (t, J = 5.9 Hz, 2H), 2.89-2.96 (m, 2H), 2.97 (s, 3H), 3.24-3.30 (m, 2H), 3.45 (t, J = 5.9 Hz, 2H), 4.10-4.16 (m, 3H), 4.81-4.85 (m, 1H), 5.66 (d, J = 8.3 Hz, 1H), 7.50 (t, J = 8.7 Hz, 1H), 7.68 (ddd, J = 8.6, 2.0, 1.3 Hz, 1H), 7.86 (dd, J = 11.4, 2.0 Hz, 1H); ESI-MS m/z [M+H]+ 489.5.
3-フルオロ-4-((1-(2-(イソプロピルアミノ)-6-(2-メトキシアセチル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)ピペリジン-4-イル)オキシ)ベンゾニトリル
1H NMR (400 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.18 (d, J = 6.6 Hz, 6H), 1.87-1.97 (m, 2H), 2.08-2.16 (m, 2H), 2.62 (t, J = 5.8 Hz, 0.9H), 2.72 (t, J = 6.1 Hz, 1.1H), 2.89-2.97 (m, 2H), 3.22-3.28 (m, 1H), 3.29 (br s, 1.3H), 3.30 (s, 1.7H), 3.64-3.67 (m, 1.1H), 3.72-3.75 (m, 0.9H), 4.10-4.16 (m, 1H), 4.17 (br s, 0.9H), 4.19 (s, 1.1H), 4.36 (br s, 0.9H), 4.41 (s, 1.1H), 4.80-4.86 (m, 1H), 5.58-5.63 (m, 1H), 7.50 (t, J = 8.7 Hz, 1H), 7.66-7.70 (m, 1H), 7.87 (dd, J =11.2, 1.9 Hz, 1H); ESI-MS m/z [M+H]+ 483.5.
3-フルオロ-4-((1-(2-(イソプロピルアミノ)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)ピペリジン-4-イル)オキシ)ベンゾニトリル
1H NMR (400 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.16-1.24 (m, 6H), 1.87-1.96 (m, 2H), 2.08-2.16 (m, 2H), 2.74-2.85 (m, 0.9H), 2.85-2.92 (m, 1.1H), 2.95 (br s, 1.3H), 2.96 br s, 1.7H), 2.97-3.00 (m, 1H), 3.25-3.42 (m, 3H), 3.65-3.71 (m, 1H), 4.12-4.19 (m, 2H), 4.25-4.31 (m, 1H), 4.82-4.88 (m, 1H), 5.89 (d, J = 8.3 Hz, 1H), 7.50 (t, J = 8.6 Hz, 1H), 7.66-7.71 (m, 1H), 7.87 (dd, J = 11.4, 2.0 Hz, 1H), 9.96 (br s, 1H); ESI-MS m/z [M+H]+ 425.5.
3-(4-(4-シアノ-2-フルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, DMSO-d6)δ ppm 1.13-1.26 (m, 6H), 1.87-1.96 (m, 2H), 2.08-2.16 (m, 2H), 2.81-2.99 (m, 6H), 3.25-3.42 (m, 3H), 3.65-3.71 (m, 1H), 4.12-4.19 (m, 2H), 4.25-4.31 (m, 1H), 4.82-4.88 (m, 1H), 5.89 (d, J = 8.3 Hz, 1H), 7.50 (t, J = 8.6 Hz, 1H), 7.66-7.71 (m, 1H), 7.87 (dd, J = 11.4, 2.0 Hz, 1H), 9.96 (br s, 1H); ESI-MS m/z [M+H]+ 482.5.
1-(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.45 (d, J = 6.8 Hz, 1.9H), 1.58 (d, J = 6.8 Hz, 1.1H), 1.93-2.02 (m, 2H), 2.14 (dd, J = 12.7, 3.4 Hz, 2H), 2.19-2.23 (m, 3H), 2.62-2.83 (m, 1.5H), 2.87-3.08 (m, 3.2H), 3.35-3.43 (m, 2H), 3.48-3.55 (m, 0.7H), 3.78(sxtd, J = 14.4, 4.2 Hz, 2H), 4.06 (dd, J = 14.2, 5.4 Hz, 0.6H), 4.46 (dt, J = 7.6, 3.5, Hz, 1H), 4.73 (dd, J = 13.2, 5.4 Hz, 0.4H), 5.34 (q, J = 6.8 Hz, 0.6H), 5.92-5.97 (m, 1H), 6.06 (dt, J = 9.0, 4.3, Hz, 1H), 6.15-6.20 (m, 1H), 6.86-6.91 (m, 1H), 6.99 (ddd, J = 11.2, 8.5, 3.2 Hz, 1H), 7.18 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 482.
N-(2,2-ジフルオロエチル)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (500 MHz, メタノール-d4)δ ppm 1.54 (d, J = 6.8 Hz, 3H), 1.91-2.02 (m, 2H), 2.07-2.19 (m, 2H), 2.66 (dd, J = 16.8, 3.2 Hz, 1H), 2.91 (s, 3H), 2.93-3.06 (m, 3H), 3.34-3.48 (m, 3H), 3.68-3.88 (m, 2H), 3.98 (dd, J = 14.2, 6.4 Hz, 1H), 4.45 (dt, J = 7.4, 3.8, Hz, 1H), 4.77 (q, J = 6.8 Hz, 1H), 5.87-6.21 (m, 1H), 6.82-6.92 (m, 1H), 6.98 (ddd, J = 11.4, 8.7, 2.9 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 518.80.
1-(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシエタノン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.47 (d, J = 6.8 Hz, 2H), 1.58 (d, J = 6.8 Hz, 1H), 1.93-2.03 (m, 2H), 2.10-2.18 (m, 2H), 2.63-3.06 (m, 4.1H), 3.12 (td, J = 12.9, 3.9 Hz, 0.3H), 3.36-3.51 (m, 5.6H), 3.70-3.88 (m, 2H), 4.02 (dd, J = 13.9, 5.6 Hz, 0.7H), 4.18-4.33 (m, 2H), 4.46 (dt, J = 7.3, 3.7 Hz, 1H), 4.71 (dd, J = 13.4, 5.6 Hz, 0.3H), 4.79-4.84 (m, 0.3H), 5.30 (q, J = 6.8 Hz, 0.7H), 5.91-6.21 (m, 1H), 6.85-6.92 (m, 1H), 6.99 (ddd, J = 11.3, 8.7, 2.9 Hz, 1H), 7.18 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 512.85.
1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.43 (d, J = 6.8 Hz, 1.8H), 1.56 (d, J = 6.8 Hz, 1.2H), 1.95-2.03 (m, 2H), 2.10-2.23 (m, 5H), 2.63-2.83 (m, 1.6H), 2.88-3.10 (m, 3.2H), 3.35-3.47 (m, 2H), 3.48-3.57 (m, 0.5H), 3.78 (td, J = 14.4, 4.4 Hz, 2H), 4.05 (dd, J = 13.9, 5.6 Hz, 0.6H), 4.42-4.51 (m, 1H), 4.73 (dd, J = 13.7, 5.9 Hz, 0.6H), 5.35 (q, J = 6.7 Hz, 0.5H), 5.92-6.20 (m, 1H), 6.84-6.93 (m, 1H), 6.96-7.04 (m, 1H), 7.14-7.23 (m, 1H); ESI-MS m/z [M+H]+ 482.
N-(2,2-ジフルオロエチル)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (500 MHz, メタノール-d4)δ ppm 1.52 (d, J = 6.8 Hz, 3H), 1.91-2.01 (m, 2H), 2.08-2.19 (m, 2H), 2.66 (dd, J = 17.1, 2.9 Hz, 1H), 2.91 (s, 3H), 2.93-3.08 (m, 3H), 3.34-3.48 (m, 3H), 3.77 (td, J = 14.4, 4.4 Hz, 2H), 3.97 (dd, J = 14.2, 6.4 Hz, 1H), 4.40-4.51 (m, 1H), 4.78 (q, J = 6.7 Hz, 1H), 5.88-6.21 (m, 1H), 6.82-6.92 (m, 1H), 6.98 (ddd, J = 11.2, 8.3, 2.9 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 518.80.
1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシエタノン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.45 (d, J = 6.8 Hz, 2H), 1.56 (d, J = 6.8 Hz, 1H), 1.93-2.02 (m, 2H), 2.11-2.18 (m, 2H), 2.63-3.18 (m, 4.5H), 3.35-3.51 (m, 5.5H), 3.78 (td, J = 14.5, 4.1 Hz, 2H), 4.01 (dd, J = 13.7, 5.4 Hz, 0.7H), 4.19-4.33 (m, 2H), 4.47 (dd, J = 7.3, 3.9 Hz, 1H), 4.70 (dd, J = 13.2, 5.9 Hz, 0.3H), 4.80-4.84 (m, 0.3H), 5.31 (q, J = 6.7 Hz, 0.7H), 5.93-6.20 (m, 1H), 6.85-6.92 (m, 1 H), 6.99 (ddd, J = 11.3, 8.7, 2.9 Hz, 1H), 7.18 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 512.80.
1-(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.30-1.36 (m, 6H), 1.45 (d, J = 6.8 Hz, 1.8H), 1.58 (d, J = 6.8 Hz, 1.2H), 1.98 (d, J = 6.8 Hz, 2H), 2.15 (dd, J = 8.5, 4.6 Hz, 2H), 2.19-2.23 (m, 3H), 2.70-2.85 (m, 1.4H), 2.91-3.17 (m, 3.3H), 3.44-3.57 (m, 2.7H), 4.06-4.19 (m, 1.6H), 4.48-4.55 (m, 1H), 4.76 (dd, J = 13.7, 5.4 Hz, 0.4H), 5.35 (q, J = 6.8 Hz, 0.6H), 6.86-6.92 (m, 1H), 7.00 (ddd, J = 11.3, 8.7, 2.9 Hz, 1H), 7.19 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 460.2.
3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-5-メチル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (500 MHz, メタノール-d4)δ ppm 1.25-1.31 (m, 6H), 1.52 (d, J = 6.4 Hz, 3H), 1.90-2.02 (m, 2H), 2.09-2.19 (m, 2H), 2.70 (dd, J = 17.3, 3.2 Hz, 1H), 2.88-3.13 (m, 6H), 3.37-3.50 (m, 3H), 3.98 (dd, J = 14.2, 6.4 Hz, 1H), 4.15 (dt, J = 13.1, 6.4 Hz, 1H), 4.48 (dt, J=7.4, 3.8 Hz, 1H), 4.77 (q, J = 7.0 Hz, 1H), 6.84-6.92 (m, 1H), 6.99 (ddd, J = 11.4, 8.7, 2.9 Hz, 1H), 7.18 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+496.90.
1-(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシエタノン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.29-1.37 (m, 6H), 1.47 (d, J = 6.8 Hz, 2H), 1.58 (d, J = 6.8 Hz, 1H), 1.98 (d, J =9.8 Hz, 2H), 2.14 (br s, 2H), 2.72-2.88 (m, 1.5H), 2.92-3.00 (m, 0.8H), 3.09-3.17 (m, 2.5H), 3.41-3.53 (m, 5.7H), 4.06 (dd, J = 14.2, 5.4 Hz, 0.8H), 4.10-4.33 (m, 3.2H), 4.52 (d, J = 3.4 Hz, 1H), 4.72 (dd, J = 13.4, 5.6 Hz, 0.4H), 4.80-4.84 (m, 0.4H), 5.31 (q, J = 6.3 Hz, 0.7H), 6.89 (t, J = 8.5 Hz, 1H), 7.00 (ddd, J = 11.2, 8.5, 3.2 Hz, 1H), 7.19 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 490.95.
シクロプロピル(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)メタノン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 0.81-1.05 (m, 4H), 1.45 (d, J = 6.8 Hz, 1.6H), 1.64 (d, J = 6.8 Hz, 1.4H), 1.94-2.18 (m, 5.4H), 2.61-2.83 (m, 1.6H), 2.89-3.12 (m, 3.2H), 3.35-3.44 (m, 2.1H), 3.51-3.60 (m, 0.6H), 3.71-3.86 (m, 2H), 4.42-4.51 (m, 1.6H), 4.70 (dd, J = 13.2, 4.9 Hz, 0.5H), 5.21-5.37 (m, 1H), 5.91-6.20 (m, 1H), 6.85-6.91 (m, 1H), 6.99 (ddd, J = 11.3, 8.7, 2.9 Hz, 1H), 7.18 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 508.85.
シクロプロピル(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)メタノン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 0.80-1.06 (m, 4H), 1.43 (d, J = 6.8 Hz, 1.5H), 1.62 (d, J = 6.8 Hz, 1.5H), 1.91-2.20 (m, 5.5H), 2.62-2.83 (m, 1.6H), 2.90-3.13 (m, 3.2H), 3.35-3.48 (m, 2.1H), 3.52-3.61 (m, 0.5H), 3.78 (td, J = 14.4, 3.9 Hz, 2H), 4.46 (dd, J = 8.3, 4.4 Hz, 1.6H), 4.69 (dd, J = 13.2, 4.9 Hz, 0.5H), 5.21-5.38 (m, 1H), 5.92-6.20 (m, 1H), 6.88 (t, J = 8.5 Hz, 1H), 6.96-7.03 (m, 1H), 7.18 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 508.85.
シクロプロピル(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)メタノン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 0.79-1.05 (m, 4H), 1.30 (t, J = 6.3 Hz, 6H), 1.44 (d, J = 6.8 Hz, 1.5H), 1.63 (d, J = 6.8 Hz, 1.5H), 1.92-2.18 (m, 5.1H), 2.67-2.84 (m, 1.5H), 2.91-3.13 (m, 3H), 3.44 (td, J = 7.9, 3.7 Hz, 2H), 3.53-3.61 (m, 0.5H), 4.16 (dt, J = 11.8, 6.0 Hz, 1H), 4.49 (d, J = 7.3 Hz, 1.5H), 4.70 (dd, J = 12.9, 5.1 Hz, 0.4H), 5.21-5.37 (m, 1H), 6.89 (t, J = 8.3 Hz, 1H), 6.96-7.04 (m, 1H), 7.19 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 486.90.
1-(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.51 (d, J = 6.8 Hz, 2.1H), 1.62 (d, J = 6.8 Hz, 0.9H), 1.94-2.02 (m, 2H), 2.10-2.18 (m, 2H), 2.68-2.78 (m, 1H), 2.82-3.06 (m, 3.2H), 3.36-3.44 (m, 2H), 3.53-3.61 (m, 0.7H), 3.71-3.88 (m, 2.1H), 4.16 (dd, J = 14.2, 5.4 Hz, 0.7H), 4.46 (dt, J = 7.4, 3.8 Hz, 1H), 4.67 (dd, J = 13.2, 5.9 Hz, 0.3H), 4.97 (q, J = 6.7 Hz, 0.3H), 5.27 (q, J = 6.8 Hz, 0.7H), 5.93-6.20 (m, 1H), 6.43-6.70 (m, 1H), 6.85-6.92 (m, 1H), 6.99 (ddd, J = 11.3, 8.4, 3.2 Hz, 1H), 7.18 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 518.80.
1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.50 (d, J = 6.8 Hz, 2.1H), 1.60 (d, J = 6.8 Hz, 0.9H), 1.92-2.03 (m, 2H), 2.11-2.18 (m, 2H), 2.68-2.77 (m, 1H), 2.82-3.08 (m, 3H), 3.26 (td, J = 12.9, 12.9, 3.9 Hz, 0.4H), 3.36-3.47 (m, 2H), 3.53-3.62 (m, 0.6H), 3.78 (td, J = 14.4, 4.4 Hz, 2H), 4.15 (dd, J = 13.9, 5.6 Hz, 0.7H), 4.43-4.49 (m, 1H), 4.66 (dd, J = 13.2, 5.9 Hz, 0.3H), 4.98 (q, J = 6.8 Hz, 0.3H), 5.28 (q, J = 6.8 Hz, 0.7H), 5.93-6.19 (m, 1H), 6.43-6.69 (m, 1H), 6.86-6.91 (m, 1H), 6.99 (ddd, J = 11.2, 8.3, 2.9 Hz, 1H), 7.18 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 518.85.
1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.25-1.30 (m, 6H), 1.49 (d, J = 6.8 Hz, 2H), 1.60 (d, J = 6.3 Hz, 1H), 1.91-2.01 (m, 2H), 2.10-2.18 (m, 2H), 2.70-2.80 (m, 1H), 2.81-3.09 (m, 3H), 3.22-3.30 (m, 0.5H), 3.37-3.47 (m, 2H), 3.54-3.62 (m, 0.6H), 4.12-4.21 (m, 1.6H), 4.45-4.52 (m, 1H), 4.66 (dd, J = 13.4, 6.1 Hz, 0.3H), 4.93-4.99 (m, 0.3H), 5.26 (q, J = 6.5 Hz, 0.7H), 6.43-6.69 (m, 1H), 6.86-6.92 (m, 1H), 7.00 (ddd, J = 11.3, 8.7, 2.9 Hz, 1H), 7.19 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 496.90.
1-(3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.32 (d, J = 6.6 Hz, 6H), 1.89-2.00 (m, 2H), 2.06-2.15 (m, 2H), 2.19 (s, 1.4H), 2.21 (s, 1.6H), 2.77-2.83 (m, 0.9H), 2.87-2.93 (m, 1.1H), 3.04-3.14 (m, 2H), 3.42-3.50 (m, 2H), 3.75 (s, 3H), 3.80-3.85 (m, 1.1H), 3.85-3.90 (m, 0.9H), 4.09-4.19 (m, 1H), 4.35-4.42 (m, 1H), 4.55 (br s, 2H), 6.67 (dt, J = 9.0, 1.4 Hz, 1H), 6.74 (dd, J = 12.8, 2.9 Hz, 1H), 7.08 (t, J = 9.2 Hz, 1H); ESI-MS m/z [M+H]+ 458.4.
1-(2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
ESI-MS m/z [M+H]+ 458.40.
2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.27-1.32 (m, 6H), 1.89-1.99 (m, 2H), 2.06-2.15 (m, 2H), 2.81 (s, 2H), 2.91 (s, 6H), 3.00-3.09 (m, 2H), 3.39-3.46 (m, 2H), 3.55 (t, J = 5.8 Hz, 2H), 3.75 (s, 3H), 4.13 (quin, J = 6.4 Hz, 1H), 4.30 (s, 2H), 4.34-4.40 (m, 1H), 6.67 (ddd, J = 8.9, 3.0, 1.5 Hz, 1H), 6.74 (dd, J = 12.8, 2.9 Hz, 1 H), 7.08 (t, J = 9.2 Hz, 1H); ESI-MS m/z [M+H]+487.4.
1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.23 (d, J = 6.6 Hz, 3.3H), 1.24 (d, J = 6.6 Hz, 2.7H), 1.93 (m, 2H), 2.11 (m, 2H), 2.18 (s, 1.3H), 2.20 (s, 1.7H), 2.71 (t, J = 6.1 Hz, 0.9H), 2.80 (t, J = 6.1 Hz, 1.1H), 2.95 (m, 2H), 3.34 (m, 2H), 3.79 (t, J = 5.9 Hz, 1.1H), 3.84 (t, J = 6.1 Hz, 0.9H), 4.15 (m, 1H), 4.44 (tt, J = 7.5, 3.7 Hz, 1H), 4.53 (s, 0.9H), 4.54 (s, 1.1H), 6.86 (m, 1H), 6.97 (ddd, J = 11.2, 8.5, 3.2 Hz, 1H), 7.16 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 446.00.
2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.92-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.81-2.86 (m, 2H), 2.90 (s, 6H), 2.96-3.04 (m, 2H), 3.34-3.42 (m, 2H), 3.54 (t, J = 5.9 Hz, 2H), 3.74-3.84 (m, 2H), 4.28 (s, 2H), 4.46 (tt, J = 7.7, 3.9 Hz, 1H), 5.90-6.22 (m, 1H), 6.88 (dddd, J = 9.1, 8.1, 3.2, 1.9 Hz, 1H), 6.99 (ddd, J = 11.4, 8.6, 3.0 Hz, 1 H), 7.18 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 497.4.
1-(2-((2,2-ジフルオロエチル)アミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシエタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.92-2.03 (m, 2H), 2.09-2.18 (m, 2H), 2.77 (t, J = 5.8 Hz, 0.9H), 2.84 (t, J = 5.8 Hz, 1.1H), 2.96-3.04 (m, 2H), 3.37 (d, J = 10.4 Hz, 2H), 3.41 (s, 1.5H), 3.42 (s, 1.5H), 3.73-3.83 (m, 3H), 3.88 (t, J = 5.9 Hz, 1H), 4.24 (s, 0.9H), 4.27 (s, 1.1H), 4.41-4.49 (m, 1H), 4.50 (s, 0.9H), 4.53 (s, 1.1H), 5.89-6.21 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 498.3.
(R)-1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシプロパン-1-オン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.32 (d, J = 6.8 Hz, 1.3 H), 1.38 (d, J = 6.6 Hz, 1.7H), 1.92-2.03 (m, 2H), 2.09-2.18 (m, 2H), 2.78 (t, J = 6.2 Hz, 0.9H), 2.86 (m, 1.1H), 2.97-3.06 (m, 2H), 3.33 (s, 3H), 3.35-3.43 (m, 2H), 3.79 (td, J = 14.5, 4.3 Hz, 2H), 3.85-3.97 (m, 2H), 4.36 (dq, J = 12.7, 6.5 Hz, 1H), 4.42-4.49 (m, 1H), 4.58 (m, 0.9H), 4.68 (m, 1.1H), 5.90-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J = 11.4, 8.5, 3.0 Hz, 1 H), 7.18 (td, J = 9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 512.4.
1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.24-1.31 (m, 6H), 1.46 (d, J = 6.8 Hz, 2H), 1.59 (d, J = 6.8 Hz, 1H), 1.92-2.00 (m, 2H), 2.09-2.17 (m, 2H), 2.19-2.23 (m, 3H), 2.61-2.82 (m, 1.5H), 2.87-2.96 (m, 0.7H), 2.99-3.09 (m, 2.4H), 3.40 (td, J = 7.7, 3.7 Hz, 2H), 3.49-3.57 (m, 0.6H), 4.06 (dd, J = 13.9, 5.6 Hz, 0.6H), 4.13-4.20 (m, 1H), 4.48 (td, J = 7.2, 3.7 Hz, 1H), 4.73 (dd, J = 13.4, 5.6 Hz, 0.4H), 4.84 (br s, 0.2H), 5.39 (q, J = 6.5 Hz, 0.6H), 6.85-6.91 (m, 1H), 6.99 (ddd, J = 11.2, 8.3, 2.9 Hz, 1H), 7.18 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 460.90.
1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.27 (dd, J = 7.6, 6.6 Hz, 6H), 1.51 (d, J = 6.8 Hz, 2.1H), 1.62 (d, J = 6.8 Hz, 0.9H), 1.90-2.00 (m, 2H), 2.09-2.17 (m, 2H), 2.65-2.75 (m, 1H), 2.80-3.03 (m, 3H), 3.25 (td, J = 12.9, 3.9 Hz, 0.3H), 3.34-3.42 (m, 2H), 3.52-3.61 (m, 0.7H), 4.11-4.21 (m, 1.7H), 4.46 (dt, J = 7.3, 3.7 Hz, 1H), 4.66 (dd, J = 13.4, 5.6 Hz, 0.3H), 4.91-4.98 (m, 0.3H), 5.25 (q, J =6.7 Hz, 0.7H), 6.44-6.69 (m, 1H), 6.84-6.92 (m, 1H), 6.99 (ddd, J = 11.3, 8.4, 3.2 Hz, 1H), 7.18 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 496.90.
2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-5-メチル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (500 MHz, メタノール-d4)δ ppm 1.26 (dd, J = 10.7, 6.4 Hz, 6H), 1.54 (d, J = 6.8 Hz, 3H), 1.88-2.00 (m, 2H), 2.07-2.18 (m, 2H), 2.64 (dd, J = 16.6, 2.9 Hz, 1H), 2.89-2.92 (m, 4H), 2.94-3.03 (m, 3H), 3.34-3.48 (m, 3H), 3.97 (dd, J = 14.2, 6.4 Hz, 1H), 4.15 (quin, J = 6.5 Hz, 1H), 4.46 (dt, J = 7.4, 3.8 Hz, 1H), 4.76 (q, J = 6.7 Hz, 1H), 6.81-6.92 (m, 1H), 6.98 (ddd, J = 11.4, 8.4, 3.2 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 496.95.
2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-N,N,5-トリメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (500 MHz, メタノール-d4)δ ppm 1.26 (dd, J = 9.3, 6.4 Hz, 6H), 1.50 (d, J = 6.8 Hz, 3H), 1.89-1.98 (m, 2H), 2.12 (dq, J = 13.2, 3.6 Hz, 2H), 2.55-2.64 (m, 1H), 2.88 (s, 6H), 2.94-3.03 (m, 3H), 3.34-3.41 (m, 3H), 3.72-3.82 (m, 1H), 4.14 (quin, J = 6.5 Hz, 1H), 4.45 (dt, J = 7.4, 3.8 Hz, 1H), 4.67 (q, J = 6.8 Hz, 1H), 6.83-6.91 (m, 1H), 6.98 (ddd, J =11.4, 8.4, 3.2 Hz, 1H), 7.17 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 489.90.
3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-N,N,5-トリメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (500 MHz, メタノール-d4)δ ppm 1.34 (dd, J = 6.4, 5.4 Hz, 6H), 1.51 (d, J = 6.8 Hz, 3H), 1.91-2.03 (m, 2H), 2.10-2.18 (m, 2H), 2.70 (dd, J = 17.1, 2.9 Hz, 1H), 2.89 (s, 6H), 3.03 (s, 1H), 3.09-3.19 (m, 2H), 3.33-3.39 (m, 1H), 3.43-3.53 (m, 2H), 3.79 (dd, J = 14.2, 5.8 Hz, 1H), 4.08-4.18 (m, 1H), 4.46-4.57 (m, 1H), 4.62 (d, J = 6.8 Hz, 1H), 6.84-6.93 (m, 1H), 6.99 (ddd, J = 11.2, 8.3, 2.9 Hz, 1H), 7.18 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 489.95.
2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N,N,5-トリメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (500 MHz, メタノール-d4)δ ppm 1.47 (d, J = 6.8 Hz, 3H), 1.96 (d, J = 8.3 Hz, 2H), 2.12 (d, J = 3.4 Hz, 2H), 2.64 (s, 1H), 2.88 (s, 6H), 2.97 (d, J = 11.7 Hz, 3H), 3.34-3.45 (m, 3H), 3.71-3.83 (m, 3H), 4.41-4.49 (m, 1H), 4.67 (d, J = 6.8 Hz, 1H), 6.05 (s, 1H), 6.87 (s, 1H), 6.95-7.02 (m, 1H), 7.13-7.21 (m, 1H); ESI-MS m/z [M+H]+ 511.90.
3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-N-イソプロピル-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.25 (d, J = 6.3 Hz, 6H), 1.88-1.98 (m, 2H), 2.04-2.14 (m, 2H), 2.93-3.05 (m, 3H), 3.07 (br s, 4H), 3.33-3.40 (m, 2H), 3.41-3.69 (m, 2H), 3.75 (s, 3H), 4.15-4.32 (m, 3H), 4.32-4.39 (m, 1H), 6.66 (ddd, J = 8.9, 3.0, 1.5 Hz, 1 H), 6.73 (dd, J = 12.8, 2.9 Hz, 1H), 7.07 (t, J = 9.2 Hz, 1H); ESI-MS m/z [M+H]+ 430.4.
1-(3-((2,2-ジフルオロエチル)アミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.96 (m, 2H), 2.12 (m, 2H), 2.18 (s, 1.3H), 2.20 (s, 1.7H), 2.73 (t, J = 5.9 Hz, 0.8H), 2.83 (t, J = 5.9Hz, 1.2H), 3.01 (m, 2H), 3.39 (m, 2H), 3.80 (m, 4H), 4.45 (dt, J = 7.0, 3.6 Hz, 1H), 4.57 (app d, 2H), 6.05 (m, 1H), 6.86 (m, 1H), 6.96 (ddd, J = 11.2, 8.5, 3.2 Hz, 1H), 7.15 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+468.4.
N-(2,2-ジフルオロエチル)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (500 MHz, メタノール-d4)δ ppm 1.95 (m, 2H), 2.12 (m, 2H), 2.47 (s, 3H), 2.79 (m, 4H), 2.96 (ddd, J = 12.4, 8.8, 3.2 Hz, 2H), 3.35 (m, 2H), 3.49 (s, 2H), 3.75 (td, J = 14.6, 4.4 Hz, 2H), 4.43 (tt, J = 7.7, 3.5 Hz, 1H), 6.03 (m, 1H), 6.86 (m, 1H), 6.97 (ddd, J = 11.2, 8.5, 3.2 Hz, 1H), 7.16 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 440.4.
メチル 3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキシレート
1H NMR (500 MHz, DMSO-d6)δ ppm 1.18 (d, J = 6.8 Hz, 6H), 1.82-1.94 (m, 2H), 2.02-2.12 (m, 2H), 2.65 (t, J = 5.9 Hz, 2H), 2.83-2.93 (m, 2H), 3.21-3.33 (m, 2H), 3.63 (s, 3H), 3.64-3.68 (m, 2H), 4.06-4.17 (m, 1H), 4.34 (br s, 2H), 4.51 (tt, J = 8.1, 3.9 Hz, 1H), 5.51-5.65 (m, 1H), 6.99-7.05 (m, 1H), 7.25-7.35 (m, 2H); ESI-MS m/z [M+H]+ 462.4.
3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-6-(2-フルオロエチル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.19 (d, J = 6.8 Hz, 6H), 1.83-1.92 (m, 2H), 2.02-2.13 (m, 2H), 2.79-2.96 (m, 3H), 2.96-3.11 (m, 0.9H), 3.24-3.36 (m, 2H), 3.38-3.55 (m, 1.1 H)3.65 (br s, 1.1H), 3.71 (m, 0.9H), 3.73-3.84 (m, 1H), 4.12-4.19 (m, 1H), 4.28 (br s, 0.9H), 4.30 (br s, 1.1H), 4.54 (ddd, J = 11.7, 7.8, 3.9 Hz, 1H), 4.87 (t, J = 4.4 Hz, 0.9H), 4.88-4.95 (m, 1H), 4.97 (t, J = 4.4 Hz, 1.1H), 5.86 (d, J = 8.3 Hz, 1H), 6.97-7.08 (m, 1H), 7.25-7.37 (m, 2H); ESI-MS m/z [M+H]+ 450.5.
(R)-1-(2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.28 (m, 6H), 1.45 (d, J = 12.7 Hz, 1H), 1.65 (m, 2H), 2.01 (m, 1H), 2.09 (m, 1H), 2.18 (s, 1.1H), 2.20 (s, 1.9H), 2.76 (m, 4H), 3.49 (m, 2H), 3.81 (t, J = 6.1 Hz, 1.3H), 3.85 (t, J = 5.9 Hz, 0.7H), 4.13 (m, 1H), 4.57 (s, 0.7H), 4.61 (s, 1.3H), 5.52 (m, 1H), 7.02 (m, 2H), 7.50 (m, 1H); ESI-MS m/z [M+H]+462.4.
N-シクロプロピル-2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 0.53-0.58 (m, 2H), 0.75-0.81 (m, 2H), 1.86-1.96 (m, 2H), 2.02-2.12 (m, 2H), 2.64-2.70 (m, 1H), 2.94-3.02 (m, 1H), 3.08-3.12 (m, 3H), 3.17-3.27 (m, 3H), 3.34-3.42 (m, 2H), 3.59-3.68 (m, 2H), 3.75 (s, 3H), 4.25-4.41 (m, 3H), 6.64-6.69 (m, 1H), 6.70-6.76 (m, 1H), 7.03-7.10 (m, 1H); ESI-MS m/z [M+H]+ 428.4.
N-シクロプロピル-3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 0.56-0.62 (m, 2H), 0.79-0.87 (m, 2H), 1.85-1.96 (m, 2H), 2.02-2.11 (m, 2H), 2.66-2.75 (m, 1H), 2.94-3.02 (m, 2H), 3.08-3.12 (m, 3H), 3.13-3.27 (m, 2H), 3.33-3.43 (m, 2H), 3.53-3.69 (m, 2H), 3.75 (s, 3H), 4.19-4.42 (m, 3H), 6.63-6.69 (m, 1H)6.73 (dd, J = 12.9, 3.0 Hz, 1H), 7.02-7.09 (m, 1H); ESI-MS m/z [M+H]+ 428.4.
N-シクロプロピル-3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 0.57 (dt, J = 3.5, 1.4 Hz, 2H), 0.78-0.85 (m, 2H), 1.36-1.45 (m, 1H), 1.52-1.73 (m, 2H), 1.93-2.15 (m, 2H), 2.60-2.87 (m, 3H), 3.08 (s, 3H), 3.09 - 3.15 (m, 2H), 3.38-3.74 (m, 4H), 4.26 (br s, 2H), 5.51 (dd, J = 46.2, 7.3 Hz, 1H), 6.96-7.08 (m, 2H), 7.45-7.53 (m, 1H); ESI-MS m/z [M+H]+ 432.4.
(S)-N-シクロプロピル-3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 0.56-0.63 (m, 2H), 0.84 (m, J = 6.8 Hz, 2H), 1.40 (d, J = 12.9 Hz, 1H), 1.52-1.74 (m, 2H), 1.92-2.14 (m, 2H), 2.61-2.75 (m, 3H), 3.08 (s, 3H), 3.09-3.16 (m, 2H), 3.40-3.55 (m, 2H), 3.55-3.80 (m, 2H), 4.31 (br s, 2H), 5.50 (dd, J = 46.0, 7.6 Hz, 1H), 6.96-7.08 (m, 2H), 7.45-7.54 (m, 1H); ESI-MS m/z [M+H]+ 432.4.
(R)-N-シクロプロピル-3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 0.55-0.62 (m, 2H), 0.79-0.87 (m, 2H), 1.40 (br d, J = 12.4 Hz, 1H), 1.52-1.73 (m, 2H), 1.93-2.14 (m, 2H), 2.61-2.74 (m, 3H), 3.08 (s, 3H), 3.10-3.15 (m, 2H), 3.40-3.54 (m, 2H), 3.55-3.81 (m, 2H), 4.26 (br s, 2H), 5.50 (dd, J = 46.2, 7.8 Hz, 1H), 6.97-7.08 (m, 2H), 7.45-7.53 (m, 1H); ESI-MS m/z [M+H]+ 432.3.
3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-N-イソプロピル-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.24 (dd, J = 6.4, 2.2 Hz, 6H), 1.40-1.48 (m, 1H), 1.53-1.74 (m, 2H), 1.96-2.14 (m, 2H), 2.60-2.73 (m, 2H), 2.93-3.06 (br m, 2H), 3.06 (s, 3H), 3.39-3.54 (m, 3H), 3.69-3.81 (m, 1H), 4.18 (dt, J = 13.1, 6.4 Hz, 2H), 4.16-4.36 (br m, 1H), 5.52 (dd, J = 46.2, 7.6 Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.54 (m, 1H); ESI-MS m/z [M+H]+ 434.4.
1-(3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.29 (dd, J = 6.4, 1.9 Hz, 6H), 1.46 (br s, 1H), 1.56-1.77 (m, 2H), 2.00 (d, J = 12.9 Hz, 1H), 2.04-2.15 (m, 1H), 2.18 (s, 1.3H), 2.20 (s, 1.7H), 2.76 (qd, J = 12.8, 2.4 Hz, 3H), 2.87 (t, J = 5.9 Hz, 1H), 3.40-3.56 (m, 2H), 3.78-3.83 (m, 1.1H), 3.83-3.89 (m, 0.9H), 4.09-4.17 (m, 1H), 4.52 (s, 2H), 5.53 (dd, J = 46.7, 7.6 Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]+ 462.4.
3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.31 (dd, J = 6.6, 1.8 Hz, 6H), 1.40-1.48 (m, 1H), 1.58-1.78 (m, 2H), 1.95-2.03 (m, 1H), 2.03-2.18 (m, 1H), 2.71-2.88 (m, 4H), 2.90 (s, 6H), 3.42-3.52 (m, 2H), 3.54 (t, J = 5.7 Hz, 2H), 4.07-4.16 (m, 1H), 4.22-4.27 (m, 2H), 5.53 (dd, J = 46.5, 7.3 Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]+ 491.4.
3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.33 (d, J = 6.3 Hz, 6H), 1.89-2.00 (m, 2H), 2.06-2.16 (m, 2H), 2.85-2.89 (m, 2H), 2.90 (s, 6H), 3.04-3.13 (m, 2H), 3.41-3.50 (m, 2H), 3.55 (t, J = 5.8 Hz, 2H), 3.76 (s, 3H), 4.08-4.18 (m, 1H), 4.27 (s, 2H), 4.35-4.42 (m, 1H), 6.67 (ddd, J = 9.0, 2.9, 1.5 Hz, 1H), 6.74 (dd, J = 12.9, 3.0 Hz, 1H), 7.08 (t, J = 9.2 Hz, 1H); ESI-MS m/z [M+H]+ 487.4.
2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-N-イソプロピル-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.24 (d, J = 6.3 Hz, 6H), 1.88-1.99 (m, 2H), 2.04-2.14 (m, 2H), 2.93-3.04 (m, 3H), 3.08 (br s, 4H), 3.35-3.53 (m, 3H), 3.76 (br s, 4H), 4.10-4.19 (m, 1H), 4.20-4.40 (m, 3H), 6.64-6.69 (m, 1H), 6.74 (dd, J = 12.8, 2.1 Hz, 1H), 7.07 (t, J = 9.2 Hz, 1H); ESI-MS m/z [M+H]+ 430.4.
2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-N-イソプロピル-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.23 (dd, J = 6.4, 2.4 Hz, 6H), 1.41-1.49 (m, 1H), 1.52-1.74 (m, 2H), 1.97-2.15 (m, 2H), 2.61-2.75 (m, 2H), 2.89-3.04 (m, 2H), 3.07 (s, 3H), 3.40-3.56 (m, 3H), 3.75 (br s, 1H), 4.13 (quin, J = 6.5 Hz, 1H), 4.18-4.38 (m, 2H), 5.53 (dd, J = 46.2, 7.6 Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.54 (m, 1H); ESI-MS m/z [M+H]+ 434.4.
1-(2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.23-1.31 (m, 6H), 1.45 (d, J = 12.9 Hz, 1H), 1.53-1.76 (m, 2H), 1.96-2.15 (m, 2H), 2.18 (s, 1.2H), 2.21 (s, 1.8H), 2.67-2.84 (m, 4H), 3.38-3.55 (m, 2H), 3.78-3.83 (m, 1.2H), 3.83-3.87 (m, 0.8H), 4.13 (dq, J = 12.6, 6.3 Hz, 1H), 4.56 (s, 0.8H), 4.59 (s, 1.2H), 5.53 (dd, J = 46.2, 7.6 Hz, 1H), 6.97-7.09 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]+ 462.4.
2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.29 (dd, J = 6.4, 1.9 Hz, 6H), 1.40-1.49 (m, 1H), 1.55-1.77 (m, 2H), 2.01 (d, J = 13.1 Hz, 2H), 2.70-2.84 (m, 4H), 2.87-2.94 (m, 6H), 3.40-3.52 (m, 2H), 3.53-3.57 (m, 2H), 4.11 (quin, J = 6.4 Hz, 1H)4.29 (s, 2H)5.53 (dd, J = 46.2, 7.3 Hz, 1H), 6.97-7.09 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]+ 491.4.
(5-クロロ-2-フルオロフェニル)(1-(2-(イソプロピルアミノ)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)ピペリジン-4-イル)メタノン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.24 (d, J = 6.6 Hz, 6H), 1.81-1.94 (m, 2H), 1.96-2.05 (m, 2H), 2.85 (t, J = 11.5 Hz, 2H), 3.00 (d, J = 6.3 Hz, 2H), 3.07 (s, 3H), 3.44-3.53 (m, 4H), 3.71-3.82 (m, 1H), 4.14-4.23 (m, 2H), 4.28-4.37 (m, 1H), 7.28 (dd, J = 10.6, 8.8 Hz, 1H), 7.61 (ddd, J = 8.8, 4.1, 2.8 Hz, 1H), 7.75 (dd, J = 6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 446.3.
1-(3-(4-(5-クロロ-2-フルオロベンゾイル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.30-1.34 (m, 6H), 1.88-2.04 (m, 4H), 2.19 (s, 1.4H), 2.21 (s, 1.6H), 2.77-2.83 (m, 0.9H), 2.87-2.92 (m, 1.1H), 2.93-3.02 (m, 2H), 3.34-3.43 (m, 1H), 3.50-3.59 (m, 2H), 3.80-3.85 (m, 1.1H), 3.85-3.90 (m, 0.9H), 4.08-4.17 (m, 1H), 4.54 (br s, 2H), 7.25-7.32 (m, 1H), 7.59-7.63 (m, 1H), 7.76 (dd, J = 6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 474.3.
3-(4-(5-クロロ-2-フルオロベンゾイル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.31-1.34 (m, 6H), 1.89-2.06 (m, 4H), 2.85-2.89 (m, 2H), 2.90-2.92 (m, 6H), 2.93-3.02 (m, 2H), 3.35-3.41 (m, 1H), 3.50-3.58 (m, 4H), 4.08-4.16 (m, 1H), 4.27 (s, 2H), 7.29 (dd, J = 10.6, 8.8 Hz, 1H), 7.61 (ddd, J = 8.8, 4.0, 2.8 Hz, 1H), 7.76 (dd, J = 6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 504.4.
3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.25 (d, J = 6.6 Hz, 6H), 1.90-2.00 (m, 2H), 2.07-2.16 (m, 2H), 2.96-3.05 (m, 3H), 3.08 (br s, 4H), 3.33-3.42 (m, 2H), 3.43-3.85 (m, 2H), 4.14-4.38 (m, 3H), 4.44-4.51 (m, 1H), 6.84-6.91 (m, 1H), 6.95-7.02 (m, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 418.3.
1-(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.33 (d, J = 6.6 Hz, 6H), 1.91-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.19 (s, 1.4H), 2.21 (s, 1.6H), 2.77-2.83 (m, 0.9H), 2.88-2.94 (m, 1.1H), 3.12 (td, J = 8.5, 4.0 Hz, 2H), 3.43-3.51 (m, 2H), 3.80-3.85 (m, 1.1H), 3.86-3.91 (m, 0.9H), 4.10-4.18 (m, 1H), 4.47-4.54 (m, 1H), 4.55 (br s, 2H), 6.85-6.92 (m, 1H), 6.99 (ddd, J = 11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 446.4.
3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.31 (d, J = 6.3 Hz, 6H), 1.91-2.01 (m, 2H), 2.09-2.18 (m, 2H), 2.86 (t, J = 5.7 Hz, 2H), 2.90 (s, 6H), 3.03-3.11 (m, 2H), 3.39-3.47 (m, 2H), 3.55 (t, J = 5.7 Hz, 2H), 4.14 (quin, J = 6.4 Hz, 1H), 4.27 (s, 2H), 4.49 (tt, J = 7.3, 3.6 Hz, 1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 475.4.
2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.24 (d, J = 6.3 Hz, 6H), 1.90-2.00 (m, 2H), 2.08-2.17 (m, 2H), 2.95-3.06 (m, 3H), 3.12 (br s, 4H), 3.35-3.53 (m, 3H), 3.76 (br s, 1H), 4.15 (dt, J = 13.1, 6.5, 6.5 Hz, 1H), 4.19-4.38 (m, 2H), 4.48 (tt, J = 7.3, 3.7 Hz, 1H), 6.85-6.92 (m, 1H), 6.99 (ddd, J = 11.4, 8.5, 3.0 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 418.3.
2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.28 (d, J = 6.6 Hz, 6H), 1.90-2.00 (m, 2H), 2.08-2.17 (m, 2H), 2.77-2.84 (m, 2H), 2.91 (s, 6H), 2.99-3.08 (m, 2H), 3.35-3.44 (m, 2H), 3.55 (t, J = 5.8 Hz, 2H), 4.09-4.17 (m, 1H), 4.29 (s, 2H), 4.44-4.51 (m, 1H), 6.84-6.91 (m, 1H), 6.99 (s, 1H), 7.18 (td, J = 9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 475.4.
(5-クロロ-2-フルオロフェニル)(1-(3-(イソプロピルアミノ)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-イル)ピペリジン-4-イル)メタノン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.24 (d, J = 6.6 Hz, 6H), 1.82-1.93 (m, 2H), 1.97-2.05 (m, 2H), 2.81-3.05 (m, 4H), 3.08 (s, 3H), 3.35-3.54 (m, 4H), 3.72-3.83 (m, 1H), 4.10-4.18 (m, 1H), 4.19-4.40 (m, 2H), 7.25-7.32 (m, 1H), 7.61 (ddd, J = 8.8, 4.3, 2.8 Hz, 1H), 7.75 (dd, J = 6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 446.3.
1-(2-(4-(5-クロロ-2-フルオロベンゾイル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.26-1.32 (m, 6H), 1.84-1.96 (m, 2H), 1.97-2.06 (m, 2H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.70-2.76 (m, 0.7H), 2.80-2.86 (m, 1.3H), 2.87-3.00 (m, 2H), 3.34-3.41 (m, 1H), 3.46-3.56 (m, 2H), 3.79-3.84 (m, 1.3H), 3.84-3.89 (m, 0.7H), 4.07-4.18 (m, 1H), 4.57 (s, 1.1H), 4.62 (s, 0.9H), 7.28 (dd, J = 10.4, 8.8 Hz, 1H), 7.61 (ddd, J = 8.9, 4.2, 2.9 Hz, 1H), 7.76 (dd, J = 6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 474.3.
2-(4-(5-クロロ-2-フルオロベンゾイル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.31 (d, J = 6.6 Hz, 6H), 1.85-2.05 (m, 4H), 2.77-2.84 (m, 2H), 2.91 (s, 6H), 2.93-3.01 (m, 2H), 3.36-3.41 (m, 1H), 3.51-3.59 (m, 4H), 4.07-4.15 (m, 1H), 4.31 (s, 2H), 7.28 (dd, J = 10.4, 8.8 Hz, 1H), 7.61 (ddd, J = 8.8, 4.3, 2.8 Hz, 1H), 7.76 (dd, J = 6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 504.4.
1-(2-(tert-ブチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.48 (s, 9H), 1.87-1.98 (m, 2H), 2.07-2.17 (m, 2H), 2.19 (s, 1.3H), 2.21 (s, 1.7H), 2.74 (t, J = 5.9 Hz, 0.9H), 2.84 (t, J = 5.9 Hz, 1.1H), 2.97 (ddd, J = 12.4, 8.6, 3.3 Hz, 2H), 3.33-3.37 (m, 2H), 3.80 (t, J = 5.9 Hz, 1.1H), 3.85 (t, J = 5.9 Hz, 0.9H), 4.43-4.51 (m, 1H), 4.53 (d, J = 1.3 Hz, 2H), 6.88 (ddddd, J = 9.1, 8.1, 2.9, 1.9, 0.8 Hz, 1H), 6.95-7.02 (m, 1H), 7.18 (td, J = 9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 460.4.
2-(tert-ブチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.48 (s, 9H), 1.87-1.97 (m, 2H), 2.07-2.17 (m, 2H), 2.82 (t, J = 5.9 Hz, 2H), 2.90 (s, 6H), 2.95 (ddd, J = 12.2, 8.5, 3.3 Hz, 2H), 3.29-3.35 (m, 2H), 3.53 (t, J = 5.8 Hz, 2H), 4.25 (s, 2H), 4.46 (tt, J = 7.5, 3.8 Hz, 1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J = 11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 489.4.
1-(2-((2,2-ジフルオロエチル)アミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.91-2.03 (m, 2H), 2.09-2.17 (m, 2H), 2.19 (s, 1.3H), 2.21 (s, 1.7H), 2.75 (t, J = 5.9 Hz, 0.9H), 2.85 (t, J = 5.9 Hz, 1.1H), 2.95-3.05 (m, 2H), 3.34-3.42 (m, 2H), 3.73-3.79 (m, 2H), 3.81 (t, J = 5.9 Hz, 1.2H), 3.86 (t, J = 6.1 Hz, 0.8H), 4.46 (tq, J = 7.9, 3.9 Hz, 1H), 4.56 (d, J = 0.8 Hz, 2H), 5.89-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (dddd, J = 11.4, 8.5, 3.0, 1.0 Hz, 1H), 7.17 (td, J = 9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 468.3.
1-(2-(シクロブチルアミノ)-3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.76-1.86 (m, 2H), 1.89-2.00 (m, 2H), 2.01-2.15 (m, 4H), 2.19 (s, 1.4H), 2.20 (s, 1.6H), 2.38-2.48 (m, 2H), 2.73-2.79 (m, 0.9H), 2.81-2.88 (m, 1.1H), 2.99-3.08 (m, 2H), 3.38-3.47 (m, 2H), 3.76 (s, 3H), 3.78-3.83 (m, 1.1H), 3.83-3.88 (m, 0.9H), 4.32-4.48 (m, 2H), 4.54 (s, 2H), 6.64-6.70 (m, 1H), 6.74 (dd, J = 12.8, 2.9 Hz, 1H), 7.08 (t, J = 9.2 Hz, 1H); ESI-MS m/z [M+H]+ 470.4.
2-(シクロブチルアミノ)-3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.77-1.87 (m, 2H), 1.90-2.00 (m, 2H), 2.03-2.15 (m, 4H), 2.39-2.49 (m, 2H), 2.81-2.87 (m, 2H), 2.90 (s, 6H), 2.98-3.08 (m, 2H), 3.38-3.47 (m, 2H), 3.54 (t, J = 5.8 Hz, 2H), 3.76 (s, 3H), 4.26 (s, 2H), 4.33-4.47 (m, 2H), 6.67 (dd, J = 9.1, 1.5 Hz, 1H), 6.74 (dd, J = 12.8, 2.9 Hz, 1H), 7.08 (t, J = 9.2 Hz, 1H); ESI-MS m/z [M+H]+ 499.4.
1-(3-(シクロブチルアミノ)-2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.78-1.87 (m, 2H), 1.91-2.01 (m, 2H), 2.03-2.16 (m, 4H), 2.19 (s, 1.2H), 2.21 (s, 1.8H), 2.38-2.50 (m, 2H), 2.70-2.76 (m, 0.8H), 2.80-2.87 (m, 1.2H), 3.00-3.11 (m, 2H), 3.40-3.50 (m, 2H), 3.76 (s, 3H), 3.79-3.83 (m, 1.2H), 3.84-3.88 (m, 0.8H), 4.34-4.48 (m, 2H), 4.57 (s, 0.8H), 4.61 (s, 1.2H), 6.64-6.69 (m, 1H), 6.74 (dd, J = 12.8, 2.9 Hz, 1H), 7.08 (t, J = 9.2 Hz, 1H); ESI-MS m/z [M+H]+ 470.4.
3-(シクロブチルアミノ)-2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.74-1.84 (m, 2H), 1.89-2.04 (m, 4H), 2.06-2.15 (m, 2H), 2.36-2.46 (m, 2H), 2.79 (t, J = 5.7 Hz, 2H), 2.90 (s, 6H), 2.94-3.02 (m, 2H), 3.34-3.43 (m, 2H), 3.51-3.56 (m, 2H), 3.76 (s, 3H), 4.26 (s, 2H), 4.43 (s, 2H), 6.64-6.69 (m, 1H), 6.74 (dd, J = 12.9, 3.0 Hz, 1H), 7.08 (t, J = 9.2 Hz, 1H); ESI-MS m/z [M+H]+ 499.4.
3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.92-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.82 (t, J = 5.8 Hz, 2H), 2.90 (s, 6H), 2.99 (ddd, J = 12.4, 8.6, 3.4 Hz, 2H), 3.34-3.41 (m, 2H), 3.55 (t, J = 5.8 Hz, 2H), 3.77 (td, J = 14.5, 4.3 Hz, 2H), 4.28 (s, 2H), 4.42-4.49 (m, 1H), 5.89-6.21 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J = 11.4, 8.6, 3.0 Hz, 1H), 7.17 (td, J = 9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 497.4.
N-(2,2-ジフルオロエチル)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.92-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.88 (t, J = 5.9 Hz, 2H), 2.93 (s, 3H), 3.00 (ddd, J = 12.4, 8.8, 3.3 Hz, 2H), 3.34-3.42 (m, 2H), 3.57 (t, J = 5.9 Hz, 2H), 3.78 (td, J = 14.5, 4.3 Hz, 2H), 4.28 (s, 2H), 4.46 (tt, J = 7.5, 3.6 Hz, 1H), 5.89-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J = 11.4, 8.6, 3.0 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 504.3.
1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.92-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.81 (t, J = 5.9 Hz, 0.8H), 2.87 (t, J = 5.9 Hz, 1.2H), 2.97-3.05 (m, 2H), 3.35-3.43 (m, 2H), 3.78 (td, J = 14.5, 4.3 Hz, 2H), 3.87-3.96 (m, 2H), 4.42-4.50 (m, 1H), 4.60 (s, 1.2H), 4.62 (s, 0.8H), 5.89-6.22 (m, 1H), 6.41-6.71 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J = 11.4, 8.6, 3.0 Hz, 1H), 7.17 (td, J = 9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 504.3.
(S)-1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシプロパン-1-オン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.32 (d, J = 6.6 Hz, 1.3H), 1.38 (d, J = 6.6 Hz, 1.7H), 1.91-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.77 (t, J = 5.8 Hz, 0.9H), 2.85 (t, J = 4.9 Hz, 1.1H), 2.96-3.05 (m, 2H), 3.33 (s, 3H), 3.35-3.43 (m, 2H), 3.78 (td, J = 14.5, 4.3 Hz, 2H), 3.84-3.97 (m, 2H), 4.31-4.40 (m, 1H), 4.42-4.49 (m, 1H), 4.59 (m, 0.9H), 4.67 (m, 1.1H), 5.90-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J = 11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J = 9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 512.4.
1-(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.92-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.87 (t, J = 5.9 Hz, 2H), 2.93 (s, 3H), 2.96-3.04 (m, 2H), 3.34-3.42 (m, 2H), 3.57 (t, J = 5.8 Hz, 2H), 3.76 (td, J = 14.5, 4.3 Hz, 2H), 4.28 (s, 2H), 4.42-4.49 (m, 1H), 5.89-6.21 (m, 1H), 6.85-6.91 (m, 1H), 6.98 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J =9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 504.4.
1-(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.92-2.02 (m, 2H), 2.09-2.17 (m, 2H), 2.80 (t, J = 5.9 Hz, 0.8H), 2.86 (t, J = 5.4 Hz, 1.2H), 2.96-3.04 (m, 2H), 3.34-3.43 (m, 2H), 3.77 (td, J = 14.3, 4.0 Hz, 2H), 3.90 (t, J = 5.8 Hz, 1.2H), 3.93 (t, J = 6.1 Hz, 0.8H), 4.46 (tt, J = 7.6, 3.7 Hz, 1H), 4.61 (s, 0.8H), 4.63 (s, 1.2H), 5.89-6.21 (m, 1H), 6.42-6.71 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 504.4.
(S)-1-(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシプロパン-1-オン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.32 (d, J = 6.6 Hz, 1.3H), 1.38 (d, J = 6.6 Hz, 1.7H), 1.91-2.04 (m, 2H), 2.09-2.19 (m, 2H), 2.76 (t, J = 6.2 Hz, 0.9H), 2.84 (t, J = 5.4 Hz, 1.1H), 2.95-3.05 (m, 2H), 3.33 (s, 3H), 3.35-3.43 (m, 2H), 3.78 (td, J = 14.6, 4.3 Hz, 2H), 3.83-3.98 (m, 2H), 4.32-4.41 (m, 1H), 4.42-4.49 (m, 1H), 4.56 (m, 1.1H), 4.68 (m, 0.9H), 5.89-6.22 (m, 1H), 6.85-6.91 (m, 1H), 6.98 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+512.4.
(R)-1-(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシプロパン-1-オン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.32 (d, J = 6.8 Hz, 1.3H), 1.38 (d, J = 6.6 Hz, 1.6H), 1.90-2.04 (m, 2H), 2.09-2.18 (m, 2H), 2.76 (t, J = 6.6 Hz, 0.9H), 2.84 (t, J = 6.1 Hz, 1.1H), 3.00 (ddd, J = 12.3, 8.6, 3.3 Hz, 2H), 3.33 (s, 3H), 3.34-3.43 (m, 2H), 3.72-3.84 (m, 2H), 3.84-3.98 (m, 2H), 4.32-4.41 (m, 1H), 4.42-4.50 (m, 1H), 4.51-4.55 (m, 0.6H), 4.62-4.69 (m, 1.4H), 5.89-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 512.4.
1-(2-(シクロプロピルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 0.78-0.84 (m, 2H), 1.01-1.07 (m, 2H), 1.47 (d, J = 6.8 Hz, 2H), 1.60 (d, J = 6.8 Hz, 1H), 1.90-2.03 (m, 2H), 2.09-2.19 (m, 2H), 2.23 (s, 3H), 2.76 (tt, J = 6.9, 3.5 Hz, 1H), 2.85-2.96 (m, 2H), 2.99-3.20 (m, 3H), 3.46-3.60 (m, 3H), 4.14 (dd, J = 13.6, 5.6 Hz, 0.5H), 4.52 (td, J = 7.4, 3.4 Hz, 1H), 5.38 (q, J = 6.6 Hz, 0.5H), 6.86-6.94 (m, 1H), 7.01 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.19 (td, J = 9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 458.35.
2-(シクロプロピルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N,N,5-トリメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 0.82-0.89 (m, 1H), 1.05-1.12 (m, 1H), 1.53-1.58 (m, 3H), 1.92-2.04 (m, 2H), 2.10-2.20 (m, 2H), 2.63-2.87 (m, 2H), 2.91-2.94 (m, 5H), 3.02-3.25 (m, 3H), 3.35-3.59 (m, 3H), 3.78-3.86 (m, 1H), 4.49-4.57 (m, 1H), 4.66 (q, J = 6.8 Hz, 1H), 6.86-6.94 (m, 1H), 6.97-7.05 (m, 1H), 7.15-7.25 (m, 1H); ESI-MS m/z [M+H]+ 487.40.
N-シクロプロピル-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5,6-ジメチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 0.60-0.67 (m, 2H), 0.83-0.92 (m, 2H), 1.64-1.80 (m, 3H), 1.87-2.04 (m, 2H), 2.05-2.21 (m, 2H), 2.74 (tt, J = 7.0, 3.6 Hz, 1H), 2.98-3.21 (m, 7H), 3.35-3.51 (m, 2H), 3.59 (d, J = 6.6 Hz, 1H), 3.78 (br s, 1H), 4.42 (br s, 1H), 4.49 (td, J = 7.4, 3.7 Hz, 1H), 6.86-6.93 (m, 1H), 6.96-7.05 (m, 1H), 7.18 (td, J = 9.2, 5.3 Hz, 1H).
1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.13 (d, J = 6.8 Hz, 1.4H), 1.23 (d, J = 6.8 Hz, 1.6H), 1.92-2.03 (m, 2H), 2.09-2.17 (m, 2H), 2.18 (s, 1.4H), 2.22 (s, 1.6H), 2.54-2.67 (m, 1H), 2.95-3.04 (m, 2.4H), 3.13 (dd, J = 16.7, 6.3 Hz, 0.6H), 3.34-3.44 (m, 2H), 3.74-3.83 (m, 2.4H), 3.99 (d, J = 18.2 Hz, 0.6H), 4.40-4.49 (m, 1H), 4.55 (quin, J = 6.6 Hz, 0.5H), 4.66 (d, J = 16.7 Hz, 0.5H), 5.07 (d, J = 17.7 Hz, 0.5H), 5.18 (m, 0.5H), 5.90-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J = 9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 481.9.
2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N,N,7-トリメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド
1H NMR (400 MHz, メタノール-d4)δ ppm 1.19 (d, J = 6.8 Hz, 3H), 1.92-2.02 (m, 2H), 2.09-2.19 (m, 2H), 2.53 (d, J = 17.2 Hz, 1H), 2.88 (s, 6H), 3.00 (ddd, J = 12.3, 8.6, 3.3 Hz, 2H), 3.15 (dd, J = 16.8, 5.9 Hz, 1H), 3.34-3.42 (m, 2H), 3.73-3.84 (m, 2H), 4.2 -4.34 (m, 3H), 4.46 (tt, J = 7.6, 3.6 Hz, 1H), 5.89-6.22 (m, 1H), 6.85-6.91 (m, 1H), 6.98 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J =9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 511.1.
N-(2,2-ジフルオロエチル)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-6,7-ジメチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.39-1.57 (m, 3H), 1.92-2.03 (m, 2H), 2.08-2.18 (m, 2H), 2.82-3.09 (m, 6H), 3.16 (d, J =14.9 Hz, 1H), 3.35-3.44 (m, 2H), 3.67-3.85 (m, 3H), 4.11-4.29 (m, 1H), 4.37-4.44 (m, 1H), 4.44-4.52 (m, 1H), 5.90-6.22 (m, 1H), 6.85-6.91 (m, 1H), 6.98 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J = 9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 453.9.
1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7-メチル-7,8-ジヒドロピリド[4,3-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.21 (d, J = 7.1 Hz, 1.2H), 1.29 (d, J = 6.6 Hz, 1.8H), 1.92-2.03 (m, 2H), 2.09-2.19 (m, 2H), 2.58-2.69 (m, 1H), 2.98-3.07 (m, 2.4H), 3.11-3.17 (m, 0.6H), 3.35-3.44 (m, 2H), 3.78 (td, J = 14.5, 4.3 Hz, 2H), 4.11 (d, J = 17.2 Hz, 1H), 4.42-4.51 (m, 1H), 4.60-4.67 (m, 0.6H), 4.73-4.77 (m, 0.4H), 5.05 (d, J = 17.7 Hz, 0.6H), 5.11-5.18 (m, 0.4H), 5.89-6.22 (m, 1H), 6.39-6.73 (m, 1H), 6.85-6.91 (m, 1H), 6.99 (ddd, J = 11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 517.9.
1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシエタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.16 (d, J = 6.8 Hz, 1.4H), 1.24 (d, J = 6.6 Hz, 1.6H), 1.91-2.04 (m, 2H), 2.09-2.19 (m, 2H), 2.59 (dd, J = 16.9, 10.6 Hz, 1H), 2.97-3.00 (m, 2.4H), 3.09-3.15 (m, 0.6H), 3.35-3.41 (m, 2H), 3.43 (s, 3H), 3.78 (td, J = 14.6, 4.3 Hz, 2H), 4.03 (d, J = 17.9 Hz, 0.6H), 4.19-4.27 (m, 1.4H), 4.29-4.39 (m, 1H), 4.46-4.52 (m, 1.5H), 4.58-4.62 (m, 0.5H), 5.07 (d, J = 18.8 Hz, 0.5H), 5.18 (t, J = 5.3 Hz, 0.5H), 5.89-6.22 (m, 1H), 6.85-6.91 (m, 1H), 6.99 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 511.9.
N-(2,2-ジフルオロエチル)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7-メチル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (400 MHz, メタノール-d4)δ ppm 1.25 (d, J = 6.8 Hz, 3H), 1.92-2.03 (m, 2H), 2.09-2.19 (m, 2H), 2.57 (d, J = 16.9 Hz, 1H), 2.94 (s, 3H), 3.01 (t, J = 10.9 Hz, 2H), 3.14 (dd, J = 16.7, 6.3 Hz, 1H), 3.34-3.43 (m, 2H), 3.78 (td, J = 14.5, 4.3 Hz, 2H), 4.17-4.25 (m, 1H), 4.43-4.55 (m, 3H), 5.89-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J = 9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 517.9.
(2S)-1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシプロパン-1-オン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.17 (t, J = 6.7 Hz, 1.4H), 1.27 (dd, J = 6.7, 2.7 Hz, 1.6H), 1.33 (dd, J = 11.5, 6.7 Hz, 1.4H), 1.38 (dd, J = 6.7, 2.7 Hz, 1.6H), 1.92-2.03 (m, 2H), 2.09-2.19 (m, 2H), 2.58 (m, 0.6H), 2.64 (m, 0.4H), 2.95-3.05 (m, 2H), 3.08-3.10 (m, 0.5H), 3.12-3.14 (m, 0.5H), 3.35 (s, 3H), 3.37-3.44 (m, 2H), 3.71-3.86 (m, 2H), 4.03 (t, J = 18.3 Hz, 1H), 4.30-4.41 (m, 1H), 4.43-4.50 (m, 1H), 4.70-4.83 (m, 1H), 5.08 (m, 0.5H), 5.21 (m, 0.5H), 5.89-6.21 (m, 1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J = 11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J = 9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 525.9.
(2R)-1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシプロパン-1-オン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.17 (t, J = 6.6 Hz, 1.4H), 1.27 (dd, J = 6.7, 2.7 Hz, 1.6H), 1.33 (dd, J = 11.6, 6.8 Hz, 1.4H), 1.38 (dd, J = 6.7, 2.7 Hz, 1.6H), 1.92-2.03 (m, 2H), 2.09-2.18 (m, 2H), 2.53-2.68 (m, 1H), 2.94-3.05 (m, 2H), 3.08-3.10 (m, 0.5H), 3.12-3.14 (m, 0.5H), 3.35 (s, 3H), 3.37-3.42 (m, 2H), 3.78 (td, J = 14.5, 4.2 Hz, 2H), 4.03 (t, J = 18.8 Hz, 1H), 4.30-4.41 (m, 1H), 4.43-4.51 (m, 1H), 4.70-4.82 (m, 1H), 5.03-5.14 (m, 0.5H), 5.18-5.23 (m, 0.5H), 5.90-6.22 (m, 1H), 6.85-6.91 (m, 1H), 6.99 (ddd, J = 11.3, 8.5, 2.9 Hz, 1H), 7.18 (td, J = 9.2, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 525.9.
シクロプロピル(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)メタノン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 0.80-1.01 (m, 4H), 1.13 (d, J = 6.6 Hz, 1.4H), 1.27 (d, J = 6.3 Hz, 1.6H), 1.91-2.04 (m, 2H), 2.06-2.20 (m, 2H), 2.56-2.60 (m, 0.5H), 2.66-2.70 (m, 0.5H), 3.02 (br s, 2H), 3.13-3.15 (m, 0.5H), 3.16-3.20 (m, 0.5H), 3.34-3.46 (m, 2H), 3.72-3.87 (m, 2H), 4.04 (d, J = 18.2 Hz, 1H), 4.41-4.58 (m, 2H), 5.02 (d, J = 17.4 Hz, 1.4H), 5.15-5.19 (m, 0.6H), 5.90-6.23 (m, 1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J = 11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J = 9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 507.9.
6-(2,2-ジフルオロエチル)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン
1H NMR (500 MHz, DMSO-d6)δ ppm 1.19 (d, J = 6.4 Hz, 6H), 1.82-1.93 (m, 2H), 2.03-2.10 (m, 2H), 2.79-2.98 (m, 4H), 3.24-3.32 (m, 2H), 3.33-3.75 (m, 4H), 4.05-4.18 (m, 3H), 4.52-4.55 (m, 1H), 5.76-5.82 (m, 1H), 6.39-6.72 (m, 1H), 7.00-7.04 (m, 1H), 7.25-7.34 (m, 2H); ESI-MS m/z [M+H]+ 468.3.
(S)-1-(2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.31 (m, 6H), 1.45 (d, J = 11.7 Hz, 1H), 1.67 (m, 2H), 2.00 (m, 1H), 2.11 (m, 1H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.80 (m, 4H), 3.53 (m, 2H), 3.82 (t, J = 5.9 Hz, 1.3H), 3.86 (t, J = 5.9 Hz, 0.7H), 4.11 (m, 1H), 4.60 (s, 0.7H), 4.64 (s, 1.3H), 5.53 (m, 1H), 7.02 (m, 2H), 7.50 (m, 1H); ESI-MS m/z [M+H]+462.5.
(S)-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルバルデヒド
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.29 (m, 6H), 1.45 (d, J = 12.7 Hz, 1H), 1.66 (m, 2H), 2.00 (m, 1H), 2.10 (m, 1H), 2.77 (m, 4H), 3.49 (m, 2H), 3.76 (t, J = 5.9Hz, 1.4H), 3.82 (t, J = 6.1 Hz, 0.6H), 4.12 (m, 1H), 4.48 (s, 0.6H), 4.52 (s, 1.4H), 5.53 (m, 1H), 7.02 (m, 2H), 7.50 (td, J = 8.3, 6.3 Hz, 1H), 8.18 (s, 0.7H), 8.24 (s, 0.3H); ESI-MS m/z [M+H]+ 447.90.
(R)-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルバルデヒド
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.30 (m, 7H), 1.45 (d, J = 13.2 Hz, 1H), 1.67 (m, 2H), 2.01 (m, 1H), 2.11 (m, 1H), 2.79 (m, 4H), 3.51 (m, 2H), 3.77 (t, J = 5.9 Hz, 1.4H), 3.83 (t, J = 6.1 Hz, 0.6H), 4.13 (m, 1H), 4.51 (s, 0.6H), 4.56 (s, 1.4H), 5.53 (m, 1H), 7.02 (m, 2H), 7.50 (m, 1H), 8.19 (s, 0.7H), 8.24 (s, 0.3H); ESI-MS m/z [M+H]+ 447.95.
1-(3-(4-(3-フルオロフェニルスルホニル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (500 MHz, メタノール-d4)δ ppm 0.85-0.94 (m, 3H), 1.21-1.24 (m, 6H), 1.90-1.99 (m, 2H), 2.19 (d, J = 13.7 Hz, 3H), 2.67-2.76 (m, 3H), 2.81 (t, J = 5.9 Hz, 1 H), 3.34-3.42 (m, 1 H), 3.46-3.55 (m, 2H), 3.78 (t, J = 6.1 Hz, 1H), 3.84 (t, J = 5.9 Hz, 1 H), 4.16 (td, J = 6.5, 3.7 Hz, 1H), 4.49 (d, J = 2.4 Hz, 2H), 7.51-7.57 (m, 1H), 7.68-7.75 (m, 2H), 7.76-7.80 (m, 1H); ESI-MS m/z [M+H]+ 476.90.
1-(2-(イソプロピルアミノ)-3-(4-(3-メトキシフェニルスルホニル)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (500 MHz, メタノール-d4)δ ppm 0.82-0.94 (m, 2H), 1.21-1.24 (m, 6H), 1.87-1.98 (m, 4H), 2.19 (d, J = 13.2 Hz, 3H), 2.66-2.75 (m, 3H), 2.81 (t, J = 6.1 Hz, 1H), 3.46-3.54 (m, 2H), 3.78 (t, J = 5.9 Hz, 1H), 3.84 (t, J = 5.9 Hz, 1H), 3.91 (s, 3H), 4.15 (dd, J = 10.7, 4.4 Hz, 1H), 4.46-4.50 (m, 2H), 7.29-7.34 (m, 1H), 7.42-7.44 (m, 1H), 7.48-7.52 (m, 1H), 7.56-7.61 (m, 1H); ESI-MS m/z [M+H]+ 488.90.
1-(3-(4-((2-フルオロフェニル)スルホニル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
1H NMR (500 MHz, DMSO-d6)δ ppm 1.16 (d, J = 6.8 Hz, 6H), 1.95 (m, 4H), 2.07 (app d, 3H), 2.65 (m, 4H), 3.49 (m, 3H), 3.69 (m, 2H), 4.13 (m, 1H), 4.37 (app d, 2H), 5.69 (br s, 1H), 7.52 (m, 2H), 7.87 (m, 2H); ESI-MS m/z [M+H]+ 476.00.
1-(3-(4-(4-フルオロフェニルスルホニル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (500 MHz, メタノール-d4)δ ppm 0.90 (d, J = 6.8 Hz, 1H), 1.20-1.24 (m, 6H), 1.90-1.99 (m, 2H), 1.99-2.06 (m, 2H), 2.19 (d, J = 13.7 Hz, 3H), 2.67-2.76 (m, 3H), 2.82 (t, J = 5.9 Hz, 1H), 3.45-3.55 (m, 2H), 3.79 (t, J = 5.9 Hz, 1H), 3.84 (t, J = 5.9 Hz, 1H), 4.12-4.20 (m, 1H), 4.49 (s, 2H), 4.58 (s, 1H), 7.42 (td, J = 8.7, 1.7 Hz, 2H), 7.97-8.02 (m, 2H); ESI-MS m/z [M+H]+ 476.90.
3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルバルデヒド
1H NMR (500 MHz, メタノール-d4)δ ppm 1.29 (d, J = 6.4 Hz, 6H), 1.90-2.01 (m, 2H), 2.07-2.18 (m, 2H), 2.78-2.89 (m, 2H), 3.02-3.10 (m, 2H), 3.39-3.45 (m, 2H), 3.76-3.86 (m, 2H), 4.14 (quin, J = 6.4 Hz, 1H), 4.46-4.49 (m, 3H), 6.85-6.91 (m, 1H), 6.95-7.01 (m, 1H), 7.14-7.21 (m, 1H), 8.16-8.27 (m, 1H); ESI-MS m/z [M+H]+ 432.4.
1-(3-(4-(2-フルオロ-4-メトキシフェニルスルホニル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[4,3-b]ピラジン-6(5H)-イル)エタノン
1H NMR (500 MHz, メタノール-d4)δ ppm 0.87-0.90 (m, 2H), 1.23 (dd, J = 6.8, 1.0 Hz, 6H), 1.95-2.02 (m, 3H), 2.19 (d, J = 12.2 Hz, 3H), 2.69-2.79 (m, 3H), 2.82 (t, J = 5.9 Hz, 1H), 3.35-3.42 (m, 1H), 3.52 (td, J = 8.3, 4.4 Hz, 2H), 3.79 (t, J = 5.9 Hz, 1H), 3.85 (t, J = 6.1 Hz, 1H), 3.93 (s, 3H), 4.17(dtt, J = 9.8, 6.4, 3.3 Hz, 1H), 4.50 (s, 2H), 6.95-7.02 (m, 2H), 7.78-7.84 (m, 1H); ESI-MS m/z [M+H]+506.90.
(S)-1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-((1-メトキシプロパン-2-イル)アミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
ESI-MS m/z [M+H]+ 434.5.
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.27 (m, 3H), 1.95 (m, 2H), 2.13 (m, 2H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.79 (app t, 0.7H), 2.84 (app t, 1.3H), 3.05 (m, 2H), 3.39 (m, 3H), 3.43 (m, 2H), 3.51 (dt, J = 5.5, 3.5 Hz, 2H), 3.82 (app t, 1.3H), 3.86 (app t, 0.7H), 4.25 (m, 1H), 4.49 (m, 1H), 4.57 (s, 0.7H), 4.60 (s, 1.3H), 6.88 (m, 1H), 6.99 (ddd, J = 11.2, 8.3, 2.9 Hz, 1H), 7.18 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 476.00.
(R)-1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-((1-メトキシプロパン-2-イル)アミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
ESI-MS m/z [M+H]+ 434.5.
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.29 (m, 3H), 1.95 (m, 2H), 2.13 (m, 2H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.74 (t, J = 5.9 Hz, 0.7H), 2.84 (app t, 1.3H), 3.09 (m, 2H), 3.38 (m, 3H), 3.47 (m, 4H), 3.82 (t, J = 6.1 Hz, 1.3H), 3.86 (t, J = 5.9 Hz, 0.7H), 4.26 (m, 1H), 4.49 (m, 1H), 4.59 (br s, 0.7H), 4.62 (s, 1.3H), 6.87 (m, 1H), 6.98 (ddd, J = 11.3, 8.7, 2.9 Hz, 1H), 7.27 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 476.00.
1-(3-(シクロブチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.82 (m, 2H), 1.97 (m, 2H), 2.11 (m, 4H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.45 (m, 2H), 2.73 (t, J = 5.9 Hz, 0.7H), 2.84 (t, J = 5.9 Hz, 1.3H), 3.11 (m, 2H), 3.47 (m, 2H), 3.81 (t, J = 5.9 Hz, 1.3 H), 3.85 (t, J = 5.9 Hz, 0.7H), 4.40 (m, 1H), 4.49 (m, 1H), 4.59 (s, 0.7H), 4.63 (s, 1.3H), 6.87 (m, 1H), 6.97 (ddd, J = 11.2, 8.5, 3.2 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+458.00.
1-(3-(シクロブチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.57-1.74 (m, 2H), 1.85-1.95 (m, 2H), 1.97-2.08 (m, 4H), 2.08 (s, 1.3H), 2.09 (s, 1.7H), 2.19-2.30 (m, 2H), 2.58 (t, J = 5.9 Hz, 0.9H), 2.71 (t, J = 5.9 Hz, 1.1H), 2.88 (t, J = 10.5 Hz, 2H), 3.23-3.33 (m, 2H), 3.70 (dt, J = 11.7, 5.9 Hz, 2H), 4.32-4.47 (m, 3H), 4.52 (tt, J = 8.1, 3.8 Hz, 1H), 6.05 (d, J = 7.8 Hz, 0.4H), 6.08 (d, J = 8.3 Hz, 0.6H 6.96-7.07 (m, 1H), 7.24-7.36 (m, 2H); ESI-MS m/z [M+H]+458.00.
(S)-1-(3-(sec-ブチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
ESI-MS m/z [M+H]+ 418.5.
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 0.98 (m, 3H), 1.27 (m, 3H), 1.68 (m, 2H), 1.97 (m, 2H), 2.13 (m, 2H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.74 (td, J = 5.9, 1.5 Hz, 0.7H), 2.84 (td, J = 5.9, 1.5 Hz, 1.3H), 3.11 (m, 2H), 3.45 (m, 2H), 3.82 (t, J = 5.9 Hz, 1.3H), 3.86 (m, 0.7H), 3.97 (m, 1H), 4.50 (m, 1H), 4.61 (d, J = 3.9 Hz, 0.7H), 4.64 (s, 1.3H), 6.87 (m, 1H), 6.97 (ddd, J = 11.3, 8.7, 2.9 Hz, 1H), 7.17 (td, J = 9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 460.00.
(R)-1-(3-(sec-ブチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
ESI-MS m/z [M+H]+ 418.5.
1H NMR (500 MHz, メタノール-d4)δ ppm 0.98 (m, 3H), 1.26 (m, 3H), 1.67 (m, 2H), 1.96 (m, 2H), 2.13 (m, 2H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.73 (td, J = 5.9, 1.5 Hz, 0.7H), 2.84 (td, J = 5.9, 1.5 Hz, 1.3H), 3.08 (m, 2H), 3.43 (m, 2H), 3.82 (t, J = 5.9 Hz, 1.3H), 3.86 (m, 0.7H), 3.97 (m, 1H), 4.49 (m, 1H), 4.59 (m, 0.7H), 4.63 (s, 1.3H), 6.87 (m, 1H), 6.98 (ddd, J = 11.3, 8.4, 3.2 Hz, 1H), 7.17 (td, J = 9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 460.0.
1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)プロパン-1-オン
1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1H NMR (400 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 1.10-1.20 (m, 3H), 1.25 (d, J = 6.8 Hz, 3H), 1.26 (d, J = 6.8 Hz, 3H), 1.90-2.00 (m, 2H), 2.09-2.18 (m, 2H), 2.47-2.58 (m, 2H), 2.72 (t, J = 5.9 Hz, 0.8 H), 2.81 (t, J = 5.9 Hz, 1.2H), 2.92-3.01 (m, 2H), 3.81 (t, J = 5.9 Hz, 1.2H), 3.87 (t, J = 6.1 Hz, 0.8H), 4.13-4.21 (m, 1H), 4.46 (tt, J = 7.5, 3.7 Hz, 1H), 4.55 (s, 0.8H), 4.56 (s, 1.2H), 6.85-6.92 (m, 1H), 6.99 (m, 1H), 7.18 (m, 1H); ESI-MS m/z [M+Na]+ 482.9.
メチル 2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキシレート
1H NMR (500 MHz, DMSO-d6)δ ppm 1.17-1.19 (m, 6H), 1.80-1.94 (m, 2H), 2.06 (ddd, J = 9.5, 5.9, 3.2 Hz, 2H), 2.64 (t, J = 5.9 Hz, 2H), 2.82-2.94 (m, 2H), 3.19-3.31 (m, 2H), 3.64 (s, 3H), 3.64-3.69 (m, 2H), 4.07-4.17 (m, 1H), 4.35 (br s, 2H), 4.51 (tt, J = 8.1, 3.9 Hz, 1H), 5.53 (d, J = 8.3 Hz, 1H), 7.01 (dddd, J = 9.3, 8.1, 3.2, 1.5 Hz, 1H), 7.26-7.35 (m, 2H); ESI-MS m/z [M+H]+ 461.9.
2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-6-(2-フルオロエチル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.17 (d, J = 6.8 Hz, 6H), 1.82-1.93 (m, 2H), 2.02-2.11 (m, 2H), 2.62-2.69 (m, 2H), 2.73-2.80 (m, 3H), 2.81-2.91 (m, 3H), 3.20-3.29 (m, 2H), 3.48 (s, 2H), 4.04-4.12 (m, 1H), 4.47-4.54 (m, 1H), 4.56 (t, J = 4.9 Hz, 1H), 4.66 (t, J = 4.9 Hz, 1H), 5.38 (d, J = 7.8 Hz, 1H), 6.98-7.05 (m, 1H), 7.26-7.34 (m, 2H); ESI-MS m/z [M+H]+ 450.0.
1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.14-1.19 (m, 6H), 2.08 (s, 1.2H), 2.09 (s, 1.8H), 2.52-2.65 (m, 5H), 2.70 (t, J = 5.9 Hz, 1H), 2.98 (br s, 4H), 3.58 (s, 2H), 3.70 (dt, J = 12.0, 5.7 Hz, 2H), 4.00-4.15 (m, 1H), 4.40 (s, 0.8H), 4.43 (s, 1.2H), 5.35 (d, J = 7.8 Hz, 0.4H), 5.38 (d, J = 8.3 Hz, 0.6H)7.08 (td, J = 8.3, 2.4 Hz, 1H), 7.21 (td, J = 10.0, 2.4 Hz, 1H), 7.44-7.51 (m, 1H); ESI-MS m/z [M+H]+ 445.0.
1-(3-(シクロブチルアミノ)-2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.56-1.72 (m, 2H), 1.97-2.06 (m, 2H), 2.07 (s, 1.3H), 2.08 (s, 1.7H), 2.18-2.27 (m, 2H), 2.52-2.66 (m, 4.9H), 2.69 (t, J = 5.9 Hz, 1.1H), 2.99 (br s, 4H), 3.59 (s, 2H), 3.69 (dt, J = 11.5, 6.0 Hz, 2H), 4.27-4.46 (m, 3H), 5.89 (d, J = 7.3 Hz, 0.4H), 5.93 (d, J = 7.8 Hz, 0.6H), 7.02-7.13 (m, 1H), 7.17-7.27 (m, 1H), 7.41-7.55 (m, 1H); ESI-MS m/z [M+H]+ 457.0.
2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-N-イソプロピル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (500 MHz, DMSO-d6)δ ppm 1.12-1.19 (m, 6H), 2.53-2.61 (m, 4H), 2.74 (t, J = 5.9 Hz, 2H), 2.97 (s, 3H), 3.00 (d, J = 7.3 Hz, 4H), 3.44-3.48 (m, 1H), 3.59 (s, 2H), 4.02-4.10 (m, 1H), 4.16 (s, 2H), 5.41 (d, J = 7.8 Hz, 1H), 7.08 (td, J = 8.4, 2.2 Hz, 1H), 7.22 (td, J = 9.9, 2.7 Hz, 1H), 7.44-7.54 (m, 1H); ESI-MS m/z [M+H]+ 480.9.
1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)プロパン-1-オン
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 0.94-1.05 (m, 3H), 1.16-1.18 (m, 6H), 2.41 (quin, J = 7.8 Hz, 2H), 2.52-2.65 (m, 5H), 2.69 (t, J = 5.6 Hz, 1H), 2.98 (br s, 3H), 3.58 (s, 2H), 3.70 (t, J = 5.9 Hz, 1.1H), 3.73 (t, J = 5.9 Hz, 0.9H), 4.03 (q, J = 7.2 Hz, 2H), 4.06-4.15 (m, 1H), 4.42 (br s, 2H), 5.34 (d, J = 7.8 Hz, 0.6H), 5.37 (d, J = 8.3 Hz, 0.4H), 7.08 (td, J = 8.5, 2.4 Hz, 1H), 7.21 (td, J = 9.9, 2.7 Hz, 1H), 7.44-7.52 (m, 1 H); ESI-MS m/z [M+H]+ 459.0.
tert-ブチル 4-(6-アセチル-3-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-イル)ピペラジン-1-カルボキシレート
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.16-1.21 (m, 6H), 1.42 (s, 9H), 2.08 (s, 1.3H), 2.09 (s, 1.7H), 2.58 (t, J = 5.9 Hz, 0.9H), 2.70 (t, J = 5.6 Hz, 1.1H), 2.87-2.98 (m, 4H), 3.51 (br s, 4H), 3.67-3.75 (m, 2H), 4.06-4.15 (m, 1H), 4.41 (s, 1.1H), 4.44 (s, 0.9H), 5.50 (d, J = 7.8 Hz, 1H), 5.53 (d, J = 7.8 Hz, 1H); ESI-MS m/z [M+H]+ 419.0.
(1s,3s)-3-((6-アセチル-2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)アミノ)シクロブチル アセテート
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.97-2.00 (m, 3H), 2.07 (s, 1.3H), 2.08 (s, 1.7H), 2.10-2.17 (m, 2H), 2.55-2.63 (m, 5H), 2.67-2.74 (m, 3H), 2.90-3.10 (m, 4H), 3.59 (s, 2H), 3.66-3.74 (m, 2H), 4.02-4.12 (m, 1H), 4.39 (s, 1.1H), 4,42 (s, 0.9H), 4.68 (quind, J = 7.3, 3.4 Hz, 1H), 6.11 (d, J = 7.8 Hz, 0.6H), 6.15 (d, J = 7.8 Hz, 0.4H), 7.08 (td, J = 8.5, 2.4 Hz, 1H), 7.19-7.24 (m, 1H), 7.45-7.51 (m, 1H); ESI-MS m/z [M+H]+ 515.0.
1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(((1s,3s)-3-ヒドロキシシクロブチル)アミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.80-1.88 (m, 2H), 2.07 (s, 1.3H), 2.08 (s, 1.7H), 2.54-2.64 (m, 7H), 2.69 (t, J = 5.9 Hz, 1H), 2.99 (br s, 4H), 3.59 (s, 2H), 3.69 (dt, J = 11.5, 6.0 Hz, 2H), 3.77-3.91 (m, 2H), 4.38 (s, 1.1H), 4.41 (s, 0.9H), 4.95-5.00 (m, 1H), 5.82 (d, J = 7.3 Hz, 1H), 5.85 (d, J = 7.8 Hz, 1H)7.08 (td, J = 8.4, 2.2 Hz, 1H), 7.19-7.24 (m, 1H), 7.45-7.51 (m, 1H); ESI-MS m/z [M+H]+ 473.0.
1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-d3-エタン-1-オン
1H NMR (400 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.19 (d, J = 6.4 Hz, 2.7H), 1.21 (d, J = 6.4 Hz, 3.3H), 1.82-1.92 (m, 2H), 2.03-2.11 (m, 2H), 2.59 (t, J = 5.9 Hz, 0.9H), 2.71 (t, J = 5.9 Hz, 1.1H), 2.87 (m, 2H), 3.22-3.30 (m, 2H), 3.67-3.74 (m, 2H), 4.06-4.16 (m, 1H), 4.41 (s, 1.1H), 4.43 (s, 0.9H), 4.51 (m, 1H), 5.50 (d, J = 8.3 Hz, 1.1H), 5.54 (d, J = 7.8 Hz, 0.9H), 6.92-7.06 (m, 1H), 7.21-7.35 (m, 2H); ESI-MS m/z [M+H]+ 449.0.
(1s,3s)-3-((6-アセチル-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)アミノ)シクロブチル アセテート
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.86-1.96 (m, 2H), 1.98-2.01 (m, 3H), 2.01-2.08 (m, 2H), 2.08 (s, 1.3H), 2.09 (s, 1.7H), 2.11-2.20 (m, 2H), 2.59 (t, J = 5.9 Hz, 0.9H), 2.67-2.77 (m, 3.1H), 2.83-2.91 (m, 2H), 3.29 (d, J = 10.3 Hz, 2H), 3.70 (dt, J = 11.4, 5.8 Hz, 2H), 4.06-4.13 (m, 1H), 4.40 (s, 1H), 4.43 (s, 1H), 4.52 (dt, J = 8.2, 4.0 Hz, 1H), 4.69 (td, J = 7.3, 2.9 Hz, 1H), 6.24 (d, J = 7.3 Hz, 0.6H), 6.28 (d, J=7.8 Hz, 0.4H), 6.98-7.05 (m, 1H), 7.26-7.34 (m, 2H); ESI-MS m/z [M+H]+ 516.0.
1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メチルプロパン-1-オン
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 0.99 (d, J = 6.8 Hz, 2.7H), 1.03 (d, J = 6.8 Hz, 3H), 1.11-1.22 (m, 6H), 2.58 (br s, 3.8H), 2.69 (t, J = 5.4 Hz, 1.2H), 2.88-3.13 (m, 5H), 3.58 (s, 2H), 3.75 (dt, J = 10.9, 5.6 Hz, 2H), 4.05-4.17 (m, 1H), 4.41 (s, 1.1H), 4.49 (s, 0.9H), 5.29-5.42 (m, 1H), 7.08 (td, J = 8.5, 2.4 Hz, 1H), 7.21 (td, J = 9.9, 2.7 Hz, 1H), 7.44-7.52 (m, 1H); ESI-MS m/z [M+H]+ 473.0.
1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(((1s,3s)-3-ヒドロキシシクロブチル)アミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.84-1.93 (m, 4H), 2.04-2.11 (m, 5H), 2.56-2.65 (m, 2.9H), 2.71 (t, J = 5.9 Hz, 1.1H), 2.87 (t, J = 10.3 Hz, 2H), 3.27 (dd, J = 8.1, 4.2 Hz, 2H), 3.70 (dt, J = 11.5, 6.0 Hz, 2H), 3.79-3.91 (m, 2H), 4.40 (s, 1.1H), 4.42 (s, 0.9H), 4.51 (tt, J = 8.2, 4.0 Hz, 1H), 4.99-5.04 (m, 1H), 5.99 (d, J = 7.3 Hz, 1.1H), 6.03 (d, J = 7.8 Hz, 1H), 6.99-7.04 (m, 1H), 7.26-7.33 (m, 2H); ESI-MS m/z [M+H]+ 473.9.
1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(((1r,3r)-3-フルオロシクロブチル)アミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
1H NMR (500 MHz, メタノール-d4, 回転異性体の混合物)δ ppm 2.18-2.23 (m, 3H), 2.36-2.50 (m, 2H), 2.55-2.69 (m, 2H), 2.73 (t, J = 5.4 Hz, 0.9H), 2.80-2.86 (m, 1.1H), 3.26-3.30 (m, 4H), 3.47-3.72 (m, 4H), 3.81 (t, J = 5.6 Hz, 1.1H), 3.87 (t, J = 6.1 Hz, 0.9H), 4.49 (s, 2H), 4.55-4.59 (m, 2H), 4.83 (s, 2H), 5.15-5.21 (m, 0.6H), 5.26-5.33 (m, 0.4H), 7.65-7.71 (m, 1H); ESI-MS m/z [M+H]+ 474.9.
4-((4-(6-アセチル-3-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-イル)ピペラジン-1-イル)メチル)-3-フルオロベンゾニトリル
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.13-1.28 (m, 6H), 2.08 (s, 1.3H), 2.09 (s, 1.7H), 2.59 (t, J = 5.9 Hz, 0.9H), 2.67-2.75 (m, 1.1H), 2.90-3.21 (m, 2H), 3.28-3.63 (m, 6H), 3.67-3.77 (m, 2H), 4.06-4.19 (m, 1H), 4.42 (s, 1.1H), 4.45 (s, 0.9H), 4.50 (br s, 2H), 5.68-5.77 (m, 1H), 7.83-7.87 (m, 1H), 7.87-7.92 (m, 1H), 8.01-8.22 (m, 1H), 10.22 (br s, 1H); ESI-MS m/z [M+H]+ 452.0.
(1r,3r)-3-((6-アセチル-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)アミノ)シクロブチル アセテート
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.83-1.97 (m, 2H), 2.03 (s, 3H), 2.04-2.12 (m, 5H), 2.33-2.41 (m, 2H), 2.41-2.49 (m, 2H), 2.59 (t, J = 5.9 Hz, 0.9H), 2.71 (t, J = 5.6 Hz, 1.1H), 2.89 (t, J = 10.0 Hz, 2H), 3.20-3.34 (m, 4H), 3.56-3.79 (m, 2H), 4.40 (s, 1.1H), 4.43 (s, 0.9H), 4.47-4.59 (m, 2H), 5.05 (td, J = 6.9, 3.2 Hz, 1H), 6.24 (d, J = 6.8 Hz, 0.6 H), 6.27 (d, J=6.8 Hz, 0.4H), 6.94-7.11 (m, 1H), 7.22-7.43 (m, 2H); ESI-MS m/z [M+H]+ 515.9.
1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(((1r,3r)-3-ヒドロキシシクロブチル)アミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.87-1.93 (m, 2H), 2.00-2.12 (m, 5H), 2.12-2.20 (m, 2H), 2.21-2.32 (m, 2H), 2.55-2.62 (m, 0.9H), 2.71 (t, J = 5.1 Hz, 1.1H), 2.88 (t, J = 10.0 Hz, 2H), 3.28 (br s, 2H), 3.63-3.80 (m, 2H), 4.29 (d, J = 3.9 Hz, 1H), 4.40 (s, 1.1H)4.43 (s, 0.9H), 4.47-4.62 (m, 1H), 4.95 (d, J = 4.9 Hz, 1H), 5.99 (d, J = 6.3 Hz, 1H), 6.03 (d, J = 6.8 Hz, 1H), 6.96-7.08 (m, 1H), 7.23-7.36 (m, 2H); ESI-MS m/z (M+H)+474.0.
(S)-1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(テトラヒドロフラン-3-イルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, DMSO-d6)δ ppm 1.88-1.89 (m, 4H), 2.05-2.09 (m, 4H), 2.60-2.90 (m, 4H), 3.30-3.40 (m, 4H), 3.55-3.57 (m, 1H), 3.68-3.74 (m, 2H), 3.85-3.95 (m, 2H), 4.38-4.51 (m, 4H), 5.91 (dd, J = 6.0, 4.4 Hz, 1H), 7.01 (m, 1H), 7.25-7.31 (m, 2H); ESI-MS m/z [M+H]+ 474.3.
(S)-1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(テトラヒドロフラン-3-イルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)プロパン-1-オン
1H NMR (400 MHz, DMSO-d6)δ ppm 0.97-1.03 (m, 3H), 1.87-2.04 (m, 6H), 2.15-2.25 (m, 1H), 2.40-2.43 (m, 2H), 2.58-2.60 (m, 1H), 2.69-2.73 (m, 1H), 2.88 (q, J = 9.6 Hz, 2H), 3.30-3.34 (m, 2H), 3.50-3.60 (m, 1H), 3.70-3.74 (m, 2H), 3.84-3.90 (m, 2H), 4.35-4.60 (m, 4H), 5.88-5.92 (m, 1H), 6.98-7.02 (m, 1H), 7.27-7.30 (m, 2H); ESI-MS m/z [M+H]+ 488.3.
1-(3-((3,3-ジフルオロシクロブチル)アミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン
1H NMR (500 MHz, DMSO-d6, 回転異性体の混合物)δ ppm 1.80-1.95 (m, 2H), 2.03-2.08 (m, 2H), 2.0 (s, 1.3H), 2.09 (s, 1.7H), 2.60 (t, J = 5.6 Hz, 0.9H), 2.67-2.80 (m, 3.1H), 2.83-2.98 (m, 4H), 3.31-3.38 (m, 2H), 3.71 (dt, J = 11.2, 5.6 Hz, 2H), 4.14-4.27 (m, 1H), 4.42 (s, 1.1H), 4.45 (s, 0.9H), 4.53 (tt, J = 8.2, 3.8 Hz, 1H), 6.46 (dd, J = 14.6, 6.8 Hz, 1H), 6.98-7.06 (m, 1H), 7.25-7.36 (m, 2H); ESI-MS m/z 493.9(M+H)+ 493.9.
N-シクロブチル-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン
1H NMR (500 MHz, DMSO-d6)δ ppm 1.55-1.75 (m, 2H), 1.84-1.96 (m, 2H), 1.96-2.14 (m, 4H), 2.18-2.32 (m, 2H), 2.75 (t, J = 5.9 Hz, 2H), 2.84-2.95 (m, 2H), 2.95-3.03 (m, 3H), 3.26-3.33 (m, 2H), 3.45 (t, J = 5.9 Hz, 2H), 4.16 (s, 2H), 4.30-4.44 (m, 1H), 4.52 (tt, J = 8.1, 3.8 Hz, 1H), 6.12 (d, J = 7.8 Hz, 1H), 6.95-7.08 (m, 1H), 7.23-7.37 (m, 2H); ESI-MS m/z (M+H)+ 494.0.
(R)-1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(テトラヒドロフラン-3-イルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, CDCl3)δ ppm 1.82-1.86 (m, 1H), 2.20 (s, 3H), 2.33-2.36 (m, 1H), 2.59-2.66 (m, 4H), 2.79 (m, 2H), 3.05-3.15 (m, 4H), 3.63 (s, 1H), 3.69-3.72 (m, 2H), 3.85-3.88 (m, 2H), 3.95-3.99 (m, 2H), 4.46-4.64 (m, 3H), 4.87-4.90 (m, 1H), 6.79-6.90 (m, 2H), 7.39-7.41 (m, 1H); ESI-MS m/z [M+H]+ 473.1.
(S)-1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(テトラヒドロフラン-3-イルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (400 MHz, CDCl3)δ ppm 1.82-1.86 (m, 1H), 2.20 (s, 3H), 2.33-2.36 (m, 1H), 2.59-2.66 (m, 4H), 2.79 (dt, J = 21.6, 5.6 Hz, 2H), 3.05-3.15 (m, 4H), 3.63 (s, 1H), 3.69-3.72 (m, 2H), 3.85-3.88 (m, 2H), 3.98-4.00 (m, 2H), 4.48-4.64 (m, 3H), 4.88-4.92 (m, 1H), 6.82 (t, J = 9.6 Hz, 1H), 6.84 (t, J = 12.8 Hz, 1H), 7.39 (q, J = 7.2 Hz, 1H); ESI-MS m/z [M+H]+ 473.1.
(S)-1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(テトラヒドロフラン-3-イルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)プロパン-1-オン
1H NMR (400 MHz, CDCl3)δ ppm 1.18 (q, J = 7.2 Hz, 3H), 1.75-1.85 (m, 1H), 2.25-2.46 (m, 3H), 2.55-2.65 (m, 4H), 2.75-2.80 (m, 2H), 3.00-3.10 (m, 4H), 3.59-3.70 (m, 4H), 3.87-3.90 (m, 2H), 3.96-3.98 (m, 2H), 4.46-4.62 (m, 3H), 4.85-4.95 (m, 1H), 6.75-6.90 (m, 2H), 7.35-7.45 (m, 1H); ESI-MS m/z [M+H]+ 487.3.
1-(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン
1H NMR (500 MHz, メタノール-d4)δ ppm 0.85-0.93 (m, 1H), 1.25 (d, J = 6.4 Hz, 6H), 1.95 (ddd, J = 12.1, 8.2, 3.7 Hz, 2H), 2.09-2.17 (m, 2H), 2.20 (d, J = 8.8 Hz, 3H), 2.74 (t, J = 5.9 Hz, 1H), 2.84 (t, J = 5.6 Hz, 1H), 2.92-3.02 (m, 2H), 3.35 (dd, J = 8.3, 3.9 Hz, 2H), 3.81 (t, J = 5.6 Hz, 1H), 3.86 (t, J = 5.9 Hz, 1H), 4.12-4.21 (m, 1H), 4.46 (dd, J = 7.1, 3.7 Hz, 1H), 4.54 (s, 2H), 6.85-6.91 (m, 1H), 6.96-7.02 (m, 1H), 7.18 (td, J = 8.8, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 446.90.
GPR6のcAMP活性の阻害in vitroアッセイ
GPR6のcAMP活性の阻害in vitroアッセイ
ハロペリドール誘導性カタレプシー - in vivoげっ歯類パーキンソン病モデル
6-ヒドロキシドーパミン病変モデル - in vivoげっ歯類パーキンソン病モデル
Claims (12)
- 式I
(式中、
R1は、置換されていてもよいC3−8シクロアルキル、置換されていてもよいC3−6ヘテロシクリル、置換されていてもよいC6−10アリール、および置換されていてもよいC1−10ヘテロアリールからなる群より選ばれ;
X1はNであり、およびX2はCHであるか;または
X1はCHであり、およびX2はNであるか;または
X1はNであり、およびX2はNであり;
X1がNである場合、Zは、C1−6アルキレン、C1−6ハロアルキレン、−C(O)−、および−S(O)2−からなる群より選ばれ;
X1がCHである場合、Zは、C1−6アルキレン、C1−6ハロアルキレン、−O−、−C(O)−、−NH−、−S−、−S(O)−、および−S(O)2−からなる群より選ばれ;
qは、0、1、または2であり;
sは、0、1、または2であり;
R2は、−OR5または−NR6R7であり;
R3は、それぞれ独立して、C1−6アルキル、C3−8シクロアルキル、およびトリフルオロメチルからなる群より選ばれ;
pは、0、1、または2であり;
R4は、それぞれ独立して、C1−6アルキル、ヒドロキシ、およびハロからなる群より選ばれ;
rは、0または1であり;
R5は、C1−6アルキルおよびC3−8シクロアルキルからなる群より選ばれ;
R6は、水素およびC1−6アルキルからなる群より選ばれ;
R7は、置換されていてもよいC1−6アルキル、C3−8シクロアルキル、置換されていてもよいC6−10アリール、置換されていてもよいC1−10ヘテロアリール、および置換されていてもよいC3−6ヘテロシクリルからなる群より選ばれ;
X3は、CHおよびCR4からなる群より選ばれ、並びにX4はNR8であるか;または
X3は、NR8であり、並びにX4はCHおよびCR4からなる群より選ばれ;
R8は、C1−6アルキル、C1−6ハロアルキル、C3−8シクロアルキル、−S(O)2−R9、−C(O)−R10、−C(O)−N(R11)(R12)、および−C(O)−OR13からなる群より選ばれ;
R9は、C1−6アルキル、C3−8シクロアルキル、および置換されていてもよいフェニルからなる群より選ばれ;
R10は、水素、置換されていてもよいC1−6アルキル、C3−8シクロアルキル、置換されていてもよいC6−10アリール、置換されていてもよいC1−10ヘテロアリール、および置換されていてもよいC3−6ヘテロシクリルからなる群より選ばれ;
R11は、水素およびC1−6アルキルからなる群より選ばれ;
R12は、水素、C1−6アルキルおよびC3−8シクロアルキルからなる群より選ばれるか;または
R11およびR12は、それらが結合している窒素と一緒になって、N、O、およびSの群より選ばれる1個の追加の環ヘテロ原子を有していてもよく、並びにいずれかの環炭素原子上でシアノ、ハロ、ヒドロキシ、アミノ、置換されていてもよいC3−6ヘテロシクリル、C1−9アミド、置換されていてもよいC1−6アルキル、およびC1−4アルコキシからなる群より独立して選ばれる1〜5個の置換基で置換されていてもよく、並びにいずれかの追加の環窒素上で水素、C3−8シクロアルキル、および置換されていてもよいC1−6アルキルからなる群より選ばれる置換基で置換されていてもよい、4〜7員の飽和環を形成し;
R13は、C1−6アルキルおよびC3−8シクロアルキルからなる群より選ばれる)
で示される化合物またはその薬学上許容し得る塩。 - X1がCHであり、およびX2がNである請求項1に記載の化合物またはその薬学上許容し得る塩。
- X1がNであり、およびX2がNである、請求項1に記載の化合物またはその薬学上許容し得る塩。
- X3がCHおよびCR4からなる群より選ばれ、並びにX4がNR8である、請求項3に記載の化合物またはその薬学上許容し得る塩。
- R1が置換されていてもよいC6−10アリールである、請求項1〜4のいずれか1項に記載の化合物またはその薬学上許容し得る塩。
- ZがC1−6アルキレンである、請求項1〜5のいずれか1項に記載の化合物またはその薬学上許容し得る塩。
- Zが−O−である、請求項1〜5のいずれか1項に記載の化合物またはその薬学上許容し得る塩。
- Zが−C(O)−である、請求項1〜5のいずれか1項に記載の化合物またはその薬学上許容し得る塩。
- R2が−NR6R7である、請求項1〜8のいずれか1項に記載の化合物またはその薬学上許容し得る塩。
- シクロプロピル(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)メタノン;1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシエタン-1-オン;2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン;2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-N-(2-メトキシエチル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)(テトラヒドロフラン-2-イル)メタノン;3-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-3-オキソプロパンニトリル;4-((1-(6-アセチル-3-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-イル)ピペリジン-4-イル)オキシ)-3-フルオロベンゾニトリル;1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシプロパン-1-オン;シクロプロピル(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)メタノン;1-(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシエタン-1-オン;3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;2-(4-(4-シアノ-2-フルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;3-フルオロ-4-((1-(3-(イソプロピルアミノ)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-イル)ピペリジン-4-イル)オキシ)ベンゾニトリル;(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)(モルホリノ)メタノン;3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-N-(2-メトキシエチル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)(テトラヒドロフラン-2-イル)メタノン;3-(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-3-オキソプロパンニトリル;(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)(イソオキサゾール-5-イル)メタノン;4-((1-(6-アセチル-2-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)ピペリジン-4-イル)オキシ)-3-フルオロベンゾニトリル;4-((1-(6-(シクロプロパンカルボニル)-2-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)ピペリジン-4-イル)オキシ)-3-フルオロベンゾニトリル;2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-6-(イソプロピルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン;2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-6-(メチル-L-プロリル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン;(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)(ピロリジン-1-イル)メタノン;1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタン-1-オン;3-フルオロ-4-((1-(2-(イソプロピルアミノ)-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)ピペリジン-4-イル)オキシ)ベンゾニトリル;3-フルオロ-4-((1-(2-(イソプロピルアミノ)-6-(2-メトキシアセチル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)ピペリジン-4-イル)オキシ)ベンゾニトリル;3-フルオロ-4-((1-(2-(イソプロピルアミノ)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)ピペリジン-4-イル)オキシ)ベンゾニトリル;3-(4-(4-シアノ-2-フルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;1-(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;N-(2,2-ジフルオロエチル)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン;1-(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシエタノン;1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;N-(2,2-ジフルオロエチル)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシエタノン;1-(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-5-メチル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;1-(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシエタノン;シクロプロピル(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)メタノン;シクロプロピル(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)メタノン;シクロプロピル(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)メタノン;1-(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン;1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン;1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン;1-(3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;1-(2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;1-(2-((2,2-ジフルオロエチル)アミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシエタノン;(R)-1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシプロパン-1-オン;1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン;2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-5-メチル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン;2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-N,N,5-トリメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-N,N,5-トリメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N,N,5-トリメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-N-イソプロピル-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;1-(3-((2,2-ジフルオロエチル)アミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;N-(2,2-ジフルオロエチル)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン;メチル 3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキシレート;3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-6-(2-フルオロエチル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;(R)-1-(2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;
1-(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;N-シクロプロピル-2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン;N-シクロプロピル-3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;N-シクロプロピル-3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;(S)-N-シクロプロピル-3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;(R)-N-シクロプロピル-3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-N-イソプロピル-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;1-(3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;3-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-N-イソプロピル-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン;2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-N-イソプロピル-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン;1-(2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;(5-クロロ-2-フルオロフェニル)(1-(2-(イソプロピルアミノ)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)ピペリジン-4-イル)メタノン;1-(3-(4-(5-クロロ-2-フルオロベンゾイル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;3-(4-(5-クロロ-2-フルオロベンゾイル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;1-(3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン;2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;(5-クロロ-2-フルオロフェニル)(1-(3-(イソプロピルアミノ)-6-メチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-イル)ピペリジン-4-イル)メタノン;1-(2-(4-(5-クロロ-2-フルオロベンゾイル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;2-(4-(5-クロロ-2-フルオロベンゾイル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;1-(2-(tert-ブチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;2-(tert-ブチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;1-(2-((2,2-ジフルオロエチル)アミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;1-(2-(シクロブチルアミノ)-3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;2-(シクロブチルアミノ)-3-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;1-(3-(シクロブチルアミノ)-2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;3-(シクロブチルアミノ)-2-(4-(2-フルオロ-4-メトキシフェノキシ)ピペリジン-1-イル)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N,N-ジメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;N-(2,2-ジフルオロエチル)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン;(S)-1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシプロパン-1-オン;1-(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン;1-(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン;(S)-1-(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシプロパン-1-オン;(R)-1-(3-(2,2-ジフルオロエチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシプロパン-1-オン;1-(2-(シクロプロピルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;2-(シクロプロピルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N,N,5-トリメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;N-シクロプロピル-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5,6-ジメチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N,N,7-トリメチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキサミド;N-(2,2-ジフルオロエチル)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-6,7-ジメチル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7-メチル-7,8-ジヒドロピリド[4,3-b]ピラジン-6(5H)-イル)-2,2-ジフルオロエタノン;1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシエタノン;N-(2,2-ジフルオロエチル)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7-メチル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;(2S)-1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシプロパン-1-オン;(2R)-1-(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メトキシプロパン-1-オン;シクロプロピル(2-(2,2-ジフルオロエチルアミノ)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7-メチル-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)メタノン;6-(2,2-ジフルオロエチル)-3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-アミン;(S)-1-(2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;(S)-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルバルデヒド;(R)-2-(4-((2,4-ジフルオロフェニル)フルオロメチル)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルバルデヒド;1-(3-(4-(3-フルオロフェニルスルホニル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;1-(2-(イソプロピルアミノ)-3-(4-(3-メトキシフェニルスルホニル)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;1-(3-(4-((2-フルオロフェニル)スルホニル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;1-(3-(4-(4-フルオロフェニルスルホニル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;3-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルバルデヒド;1-(3-(4-(2-フルオロ-4-メトキシフェニルスルホニル)ピペリジン-1-イル)-2-(イソプロピルアミノ)-7,8-ジヒドロピリド[4,3-b]ピラジン-6(5H)-イル)エタノン;(S)-1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-((1-メトキシプロパン-2-イル)アミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;
(R)-1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-((1-メトキシプロパン-2-イル)アミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;1-(3-(シクロブチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;(S)-1-(3-(sec-ブチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;(R)-1-(3-(sec-ブチルアミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)プロパン-1-オン;メチル2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-カルボキシレート;2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-6-(2-フルオロエチル)-N-イソプロピル-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン;1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;1-(3-(シクロブチルアミノ)-2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-N-イソプロピル-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン;1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)プロパン-1-オン;tert-ブチル 4-(6-アセチル-3-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-イル)ピペラジン-1-カルボキシレート;(1s,3s)-3-((6-アセチル-2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)アミノ)シクロブチル アセテート;1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(((1s,3s)-3-ヒドロキシシクロブチル)アミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-d3-エタン-1-オン;(1s,3s)-3-((6-アセチル-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)アミノ)シクロブチル アセテート;1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(イソプロピルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)-2-メチルプロパン-1-オン;1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(((1s,3s)-3-ヒドロキシシクロブチル)アミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(((1r,3r)-3-フルオロシクロブチル)アミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;4-((4-(6-アセチル-3-(イソプロピルアミノ)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-2-イル)ピペラジン-1-イル)メチル)-3-フルオロベンゾニトリル;(1r,3r)-3-((6-アセチル-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-イル)アミノ)シクロブチル アセテート;1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(((1r,3r)-3-ヒドロキシシクロブチル)アミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;(S)-1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(テトラヒドロフラン-3-イルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;(S)-1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-(テトラヒドロフラン-3-イルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)プロパン-1-オン;1-(3-((3,3-ジフルオロシクロブチル)アミノ)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オン;N-シクロブチル-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-6-(メチルスルホニル)-5,6,7,8-テトラヒドロピリド[3,4-b]ピラジン-3-アミン;(R)-1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(テトラヒドロフラン-3-イルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;(S)-1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(テトラヒドロフラン-3-イルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタノン;および(S)-1-(2-(4-(2,4-ジフルオロベンジル)ピペラジン-1-イル)-3-(テトラヒドロフラン-3-イルアミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)プロパン-1-オンからなる群より選ばれる請求項1に記載の化合物または前記化合物の薬学上許容し得る塩。 - 請求項1〜10のいずれか1項に記載の化合物または薬学上許容し得る塩および薬学上許容し得る賦形剤を含む医薬組成物。
- 医薬としての請求項1〜10のいずれか1項に記載の化合物または薬学上許容し得る塩の使用。
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US201361919661P | 2013-12-20 | 2013-12-20 | |
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PCT/US2014/071543 WO2015095728A1 (en) | 2013-12-20 | 2014-12-19 | Tetrahydropyridopyrazines modulators of gpr6 |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2020523287A (ja) * | 2017-06-15 | 2020-08-06 | 武田薬品工業株式会社 | Gpr6のテトラヒドロピリドピラジンモジュレーター |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SG10201608528YA (en) | 2011-12-21 | 2016-12-29 | Novira Therapeutics Inc | Hepatitis b antiviral agents |
EP2882722B1 (en) | 2012-08-13 | 2016-07-27 | Takeda Pharmaceutical Company Limited | Quinoxaline derivatives as gpr6 modulators |
CR20200276A (es) | 2012-08-28 | 2021-01-27 | Janssen Sciences Ireland Uc | Sulfamoilarilamidas y su uso como medicamentos para el tratamientos de la hepatitis b (divisional exp. 2015-0059) |
JP6466348B2 (ja) | 2013-02-28 | 2019-02-06 | ヤンセン・サイエンシズ・アイルランド・アンリミテッド・カンパニー | スルファモイル−アリールアミドおよびb型肝炎を処置するための医薬品としてのその使用 |
CA2922302C (en) | 2013-04-03 | 2021-08-03 | Janssen Sciences Ireland Uc | N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
JO3603B1 (ar) | 2013-05-17 | 2020-07-05 | Janssen Sciences Ireland Uc | مشتقات سلفامويل بيرولاميد واستخدامها كادوية لمعالجة التهاب الكبد نوع بي |
CN105960400B (zh) | 2013-05-17 | 2019-05-31 | 爱尔兰詹森科学公司 | 氨磺酰基噻吩酰胺衍生物及其作为药物用于治疗乙型肝炎的用途 |
CA2935719C (en) | 2013-07-25 | 2021-11-02 | Janssen Sciences Ireland Uc | Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
AP2016009122A0 (en) | 2013-10-23 | 2016-03-31 | Janssen Sciences Ireland Uc | Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
JO3466B1 (ar) * | 2013-12-20 | 2020-07-05 | Takeda Pharmaceuticals Co | مواد ضابطة لتترا هيدرو بيريدوبيرازينات من gpr6 |
US9169212B2 (en) | 2014-01-16 | 2015-10-27 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
US10392349B2 (en) | 2014-01-16 | 2019-08-27 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
KR20160128305A (ko) | 2014-02-05 | 2016-11-07 | 노비라 테라퓨틱스, 인코포레이티드 | Hbv 감염의 치료를 위한 병용 요법 |
PL3102572T3 (pl) | 2014-02-06 | 2019-04-30 | Janssen Sciences Ireland Uc | Pochodne sulfamoilopirolamidu i ich zastosowanie jako leki do leczenia wirusowego zapalenia wątroby typu B |
EP3105230B1 (en) * | 2014-02-14 | 2021-04-07 | Takeda Pharmaceutical Company Limited | Pyridopyrazines modulators of gpr6 |
WO2016149581A1 (en) | 2015-03-19 | 2016-09-22 | Novira Therapeutics, Inc. | Azocane and azonane derivatives and methods of treating hepatitis b infections |
US10875876B2 (en) | 2015-07-02 | 2020-12-29 | Janssen Sciences Ireland Uc | Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
AU2016330964B2 (en) | 2015-09-29 | 2021-04-01 | Novira Therapeutics, Inc. | Crystalline forms of a hepatitis B antiviral agent |
AU2017248828A1 (en) | 2016-04-15 | 2018-11-01 | Janssen Sciences Ireland Uc | Combinations and methods comprising a capsid assembly inhibitor |
EA202092171A1 (ru) | 2018-03-14 | 2020-12-01 | Янссен Сайенсиз Айрлэнд Анлимитед Компани | Схема дозирования модулятора сборки капсида |
KR20210130753A (ko) | 2019-02-22 | 2021-11-01 | 얀센 사이언시즈 아일랜드 언리미티드 컴퍼니 | Hbv 감염 또는 hbv-유발성 질환의 치료에 유용한 아미드 유도체 |
CN113795486A (zh) | 2019-05-06 | 2021-12-14 | 爱尔兰詹森科学公司 | 用于治疗hbv感染或hbv诱发的疾病的酰胺衍生物 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004515449A (ja) * | 1999-02-26 | 2004-05-27 | アリーナ・フアーマシユーチカルズ・インコーポレーテツド | 第6gタンパク質共役型受容体の小分子調節物質 |
JP2009534368A (ja) * | 2006-04-21 | 2009-09-24 | ファイザー・プロダクツ・インク | ピリジン[3,4−b]ピラジノン |
JP2015524843A (ja) * | 2012-08-13 | 2015-08-27 | エンヴォイ セラピューティクス インコーポレイテッド | Gpr6モジュレーターとしてのキノキサリン誘導体 |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1101854C (zh) * | 1994-08-11 | 2003-02-19 | 武田药品工业株式会社 | G蛋白偶联受体蛋白质及其产生方法和用途 |
US20030229113A1 (en) | 2000-03-24 | 2003-12-11 | Koji Hashimoto | Keratinocyte growth inhibitors and hydroxamic acid derivatives |
AU2003274005A1 (en) * | 2002-10-24 | 2004-05-13 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with human g-protein coupled receptor 6 (gpr6) |
CA2513684A1 (en) | 2003-01-31 | 2004-08-19 | Merck & Co., Inc. | 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
SE0400285D0 (sv) * | 2004-02-10 | 2004-02-10 | Astrazeneca Ab | Pyrroloquinoline and piperidoquinoline derivatives, preparation thereof, compositions containing them and uses thereof |
US20070054916A1 (en) | 2004-10-01 | 2007-03-08 | Amgen Inc. | Aryl nitrogen-containing bicyclic compounds and methods of use |
JP2009535393A (ja) | 2006-05-01 | 2009-10-01 | ファイザー・プロダクツ・インク | 置換2−アミノ縮合複素環式化合物 |
US8145966B2 (en) | 2007-06-05 | 2012-03-27 | Astrium Limited | Remote testing system and method |
GB0710844D0 (en) | 2007-06-06 | 2007-07-18 | Lectus Therapeutics Ltd | Potassium ion channel modulators & uses thereof |
GB2449929A (en) | 2007-06-08 | 2008-12-10 | Snell & Wilcox Ltd | Hierarchical spatial resolution building processes to fill holes in an interpolated image |
WO2010143169A2 (en) | 2009-06-12 | 2010-12-16 | Société Splicos | Compounds useful for treating aids |
WO2013087815A1 (en) | 2011-12-15 | 2013-06-20 | Merz Pharma Gmbh & Co. Kgaa | Liquid pharmaceutical composition containing a pyrazolopyrimidine derivative and pharmaceutical uses thereof |
WO2013087808A1 (en) | 2011-12-15 | 2013-06-20 | Merz Pharma Gmbh & Co. Kgaa | Pharmaceutical composition comprising a pyrazolopyrimidme and cyclodextrin |
CA2872883A1 (en) | 2012-05-09 | 2013-11-14 | Sunovion Pharmaceuticals Inc. | Heteroaryl compounds and methods of use thereof |
FR2995937B1 (fr) | 2012-09-21 | 2014-09-26 | Exoes | Ensemble de production d'electricite a moteur a pression de vapeur |
JO3466B1 (ar) * | 2013-12-20 | 2020-07-05 | Takeda Pharmaceuticals Co | مواد ضابطة لتترا هيدرو بيريدوبيرازينات من gpr6 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004515449A (ja) * | 1999-02-26 | 2004-05-27 | アリーナ・フアーマシユーチカルズ・インコーポレーテツド | 第6gタンパク質共役型受容体の小分子調節物質 |
JP2009534368A (ja) * | 2006-04-21 | 2009-09-24 | ファイザー・プロダクツ・インク | ピリジン[3,4−b]ピラジノン |
JP2015524843A (ja) * | 2012-08-13 | 2015-08-27 | エンヴォイ セラピューティクス インコーポレイテッド | Gpr6モジュレーターとしてのキノキサリン誘導体 |
Cited By (4)
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---|---|---|---|---|
JP2020523287A (ja) * | 2017-06-15 | 2020-08-06 | 武田薬品工業株式会社 | Gpr6のテトラヒドロピリドピラジンモジュレーター |
JP2022188199A (ja) * | 2017-06-15 | 2022-12-20 | 武田薬品工業株式会社 | Gpr6のテトラヒドロピリドピラジンモジュレーター |
JP7460369B2 (ja) | 2017-06-15 | 2024-04-02 | 武田薬品工業株式会社 | Gpr6のテトラヒドロピリドピラジンモジュレーター |
JP7497400B2 (ja) | 2017-06-15 | 2024-06-10 | 武田薬品工業株式会社 | Gpr6のテトラヒドロピリドピラジンモジュレーター |
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