NZ620079B2 - Compounds for the treatment and prophylaxis of respiratory syncytial virus disease - Google Patents
Compounds for the treatment and prophylaxis of respiratory syncytial virus disease Download PDFInfo
- Publication number
- NZ620079B2 NZ620079B2 NZ620079A NZ62007912A NZ620079B2 NZ 620079 B2 NZ620079 B2 NZ 620079B2 NZ 620079 A NZ620079 A NZ 620079A NZ 62007912 A NZ62007912 A NZ 62007912A NZ 620079 B2 NZ620079 B2 NZ 620079B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- dihydro
- benzothiazepin
- dioxido
- methyl
- amino
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 242
- 230000000069 prophylaxis Effects 0.000 title claims description 8
- 208000001756 Virus Disease Diseases 0.000 title claims description 3
- 241000725643 Respiratory syncytial virus Species 0.000 title abstract description 26
- -1 carboxy, morpholinyl Chemical group 0.000 claims description 1451
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 255
- 239000001257 hydrogen Substances 0.000 claims description 236
- 229910052739 hydrogen Inorganic materials 0.000 claims description 236
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 155
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 130
- 150000002431 hydrogen Chemical group 0.000 claims description 116
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 114
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 113
- 229910052736 halogen Inorganic materials 0.000 claims description 105
- 150000001412 amines Chemical class 0.000 claims description 92
- 229910052757 nitrogen Inorganic materials 0.000 claims description 66
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 64
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 61
- 150000002367 halogens Chemical group 0.000 claims description 58
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 58
- 239000002253 acid Substances 0.000 claims description 56
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 56
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 52
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 48
- 125000001153 fluoro group Chemical group F* 0.000 claims description 46
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 43
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 41
- 239000011780 sodium chloride Substances 0.000 claims description 41
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 40
- 150000002829 nitrogen Chemical group 0.000 claims description 35
- 125000003566 oxetanyl group Chemical group 0.000 claims description 35
- 125000003386 piperidinyl group Chemical group 0.000 claims description 35
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 32
- XFNJVJPLKCPIBV-UHFFFAOYSA-N 1,3-Diaminopropane Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 claims description 31
- GCMNJUJAKQGROZ-UHFFFAOYSA-N 2-Aminoquinoline Chemical compound C1=CC=CC2=NC(N)=CC=C21 GCMNJUJAKQGROZ-UHFFFAOYSA-N 0.000 claims description 28
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 28
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 27
- 125000002393 azetidinyl group Chemical group 0.000 claims description 26
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 23
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 22
- 125000002757 morpholinyl group Chemical group 0.000 claims description 22
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 20
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 19
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 19
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 18
- 125000004193 piperazinyl group Chemical group 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 125000001188 haloalkyl group Chemical group 0.000 claims description 14
- CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical compound ON1CCCC1 CWLUFVAFWWNXJZ-UHFFFAOYSA-N 0.000 claims description 13
- 125000005959 diazepanyl group Chemical group 0.000 claims description 13
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 13
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 12
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 11
- ZXDUPDQEFOYLOM-UHFFFAOYSA-O propylideneazanium Chemical group [CH2-]CC=[NH2+] ZXDUPDQEFOYLOM-UHFFFAOYSA-O 0.000 claims description 11
- AOHJOMMDDJHIJH-UHFFFAOYSA-N 1,2-Diaminopropane Chemical compound CC(N)CN AOHJOMMDDJHIJH-UHFFFAOYSA-N 0.000 claims description 10
- XEHVFKKSDRMODV-UHFFFAOYSA-N Ethynyl radical Chemical group C#[C] XEHVFKKSDRMODV-UHFFFAOYSA-N 0.000 claims description 10
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 10
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 claims description 10
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 10
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 10
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 9
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 8
- 206010061603 Respiratory syncytial virus infection Diseases 0.000 claims description 8
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 8
- 125000002294 quinazolinyl group Chemical compound N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- NCZOVCDTUUZEEA-UHFFFAOYSA-N 3-methylquinolin-2-amine Chemical compound C1=CC=C2N=C(N)C(C)=CC2=C1 NCZOVCDTUUZEEA-UHFFFAOYSA-N 0.000 claims description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 239000000969 carrier Substances 0.000 claims description 7
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 7
- XOBKSJJDNFUZPF-UHFFFAOYSA-N methoxyethyl Chemical group CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 claims description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 7
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 7
- AYQMNFRCBKOMIA-UHFFFAOYSA-N 1-benzazepin-2-one Chemical compound O=C1C=CC=C2C=CC=CC2=N1 AYQMNFRCBKOMIA-UHFFFAOYSA-N 0.000 claims description 6
- AHHWIHXENZJRFG-UHFFFAOYSA-N Oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 claims description 6
- 239000004146 Propane-1,2-diol Substances 0.000 claims description 6
- 229960004063 Propylene glycol Drugs 0.000 claims description 6
- 125000003277 amino group Chemical compound 0.000 claims description 6
- YCRYJWJNPWZJSR-UHFFFAOYSA-O butylideneazanium Chemical group [CH2-]CCC=[NH2+] YCRYJWJNPWZJSR-UHFFFAOYSA-O 0.000 claims description 6
- 150000004985 diamines Chemical class 0.000 claims description 6
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 6
- 235000013772 propylene glycol Nutrition 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- KYUHNQVXADNNBQ-UHFFFAOYSA-N (1,1-dioxothietan-3-yl)methanamine Chemical compound NCC1CS(=O)(=O)C1 KYUHNQVXADNNBQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 5
- HNJBEVLQSNELDL-UHFFFAOYSA-N 2-Pyrrolidone Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- KWHDQPVGKVPPPS-UHFFFAOYSA-N quinazolin-5-amine Chemical compound C1=NC=C2C(N)=CC=CC2=N1 KWHDQPVGKVPPPS-UHFFFAOYSA-N 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- SIGSNYAYBSJATD-UHFFFAOYSA-N Ethadione Chemical group CCN1C(=O)OC(C)(C)C1=O SIGSNYAYBSJATD-UHFFFAOYSA-N 0.000 claims description 4
- BMVXCPBXGZKUPN-UHFFFAOYSA-N Hexylamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 claims description 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical group C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 claims description 3
- CHXUFRRQOZZSNV-UHFFFAOYSA-N 1-methylpiperidine Chemical group [CH2]N1CCCCC1 CHXUFRRQOZZSNV-UHFFFAOYSA-N 0.000 claims description 3
- KOFZWWMCDUHEEM-UHFFFAOYSA-N 1-methylpyrrolidine Chemical group [CH2]N1CCCC1 KOFZWWMCDUHEEM-UHFFFAOYSA-N 0.000 claims description 3
- MZBVNYACSSGXID-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1H-1-benzazepine Chemical compound N1CCCCC2=CC=CC=C21 MZBVNYACSSGXID-UHFFFAOYSA-N 0.000 claims description 3
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 3
- ZIANTQKRDKCYRV-UHFFFAOYSA-N 2H-1,3-oxazole Chemical group C1OC=C=N1 ZIANTQKRDKCYRV-UHFFFAOYSA-N 0.000 claims description 3
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 3
- RYECOJGRJDOGPP-UHFFFAOYSA-N ethylurea Chemical compound CCNC(N)=O RYECOJGRJDOGPP-UHFFFAOYSA-N 0.000 claims description 3
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 claims description 3
- GIIVBOCJNQMVRS-UHFFFAOYSA-O hexylideneazanium Chemical group [CH2-]CCCCC=[NH2+] GIIVBOCJNQMVRS-UHFFFAOYSA-O 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 3
- WGFGYCPJLDTZAU-UHFFFAOYSA-N oxetan-2-amine Chemical compound NC1CCO1 WGFGYCPJLDTZAU-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000002053 thietanyl group Chemical group 0.000 claims description 3
- YVBPNYXAQNAMLH-UHFFFAOYSA-N 1-hydroxy-2-methylpyrrolidine Chemical compound CC1CCCN1O YVBPNYXAQNAMLH-UHFFFAOYSA-N 0.000 claims description 2
- LLCNQKVFDFCGEO-UHFFFAOYSA-N 2-(6-chloroquinolin-2-yl)-1,3,4,5-tetrahydro-2-benzazepine Chemical compound C1CCC2=CC=CC=C2CN1C1=NC2=CC=C(Cl)C=C2C=C1 LLCNQKVFDFCGEO-UHFFFAOYSA-N 0.000 claims description 2
- HPZZTKGICNGATO-UHFFFAOYSA-N 6-chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-1H-quinazolin-2-one Chemical compound FC(F)(F)CN1C(=O)NC2=CC=C(Cl)C=C2C1(CC)C1=CC=C(F)C=C1 HPZZTKGICNGATO-UHFFFAOYSA-N 0.000 claims description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N Azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 2
- DNSISZSEWVHGLH-UHFFFAOYSA-N Butyramide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 2
- 101700055022 CR11 Proteins 0.000 claims description 2
- CBCKQZAAMUWICA-UHFFFAOYSA-N P-Phenylenediamine Chemical compound NC1=CC=C(N)C=C1 CBCKQZAAMUWICA-UHFFFAOYSA-N 0.000 claims description 2
- DHHVAGZRUROJKS-UHFFFAOYSA-N Phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 claims description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 2
- 125000005124 aminocycloalkyl group Chemical group 0.000 claims description 2
- GHWVXCQZPNWFRO-UHFFFAOYSA-N butane-2,3-diamine Chemical compound CC(N)C(C)N GHWVXCQZPNWFRO-UHFFFAOYSA-N 0.000 claims description 2
- 125000005350 hydroxycycloalkyl group Chemical group 0.000 claims description 2
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- OJEOJUQOECNDND-UHFFFAOYSA-N oxetan-3-amine Chemical compound NC1COC1 OJEOJUQOECNDND-UHFFFAOYSA-N 0.000 claims description 2
- LUBJCRLGQSPQNN-UHFFFAOYSA-N phenylurea Chemical compound NC(=O)NC1=CC=CC=C1 LUBJCRLGQSPQNN-UHFFFAOYSA-N 0.000 claims description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 2
- LCDCPQHFCOBUEF-UHFFFAOYSA-N pyrrolidine-1-carboxamide Chemical compound NC(=O)N1CCCC1 LCDCPQHFCOBUEF-UHFFFAOYSA-N 0.000 claims description 2
- IKWVYRACZMFUHI-UHFFFAOYSA-N quinoline-4,6-diamine Chemical compound N1=CC=C(N)C2=CC(N)=CC=C21 IKWVYRACZMFUHI-UHFFFAOYSA-N 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 125000004429 atoms Chemical group 0.000 claims 3
- RWDYNDCLJPWKJU-UHFFFAOYSA-N 4-methylquinazolin-2-amine Chemical compound C1=CC=C2C(C)=NC(N)=NC2=C1 RWDYNDCLJPWKJU-UHFFFAOYSA-N 0.000 claims 2
- ADJJYEZPSBDGGL-UHFFFAOYSA-N N'-[3-[(2-methoxyphenyl)methyl-methylamino]propyl]-N'-methylpropane-1,3-diamine Chemical compound COC1=CC=CC=C1CN(C)CCCN(C)CCCN ADJJYEZPSBDGGL-UHFFFAOYSA-N 0.000 claims 2
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims 2
- QKNFFJHHPCWXTH-VKHMYHEASA-N (2S)-2-(methylamino)propanamide Chemical compound CN[C@@H](C)C(N)=O QKNFFJHHPCWXTH-VKHMYHEASA-N 0.000 claims 1
- JCZPOYAMKJFOLA-ZXZARUISSA-N (3S,4R)-pyrrolidine-3,4-diol Chemical compound O[C@H]1CNC[C@H]1O JCZPOYAMKJFOLA-ZXZARUISSA-N 0.000 claims 1
- NGBHIADNEOTIAL-UHFFFAOYSA-N 1$l^{6},2-benzothiazepine 1,1-dioxide Chemical compound O=S1(=O)N=CC=CC2=CC=CC=C12 NGBHIADNEOTIAL-UHFFFAOYSA-N 0.000 claims 1
- BAVAZRNEAWBRLO-UHFFFAOYSA-N 1,2-benzodiazepin-4-one Chemical compound O=C1C=NN=C2C=CC=CC2=C1 BAVAZRNEAWBRLO-UHFFFAOYSA-N 0.000 claims 1
- WJAYFFRZPWPXLJ-UHFFFAOYSA-N 1-hydroxy-2,2-dimethylpyrrolidine Chemical compound CC1(C)CCCN1O WJAYFFRZPWPXLJ-UHFFFAOYSA-N 0.000 claims 1
- IXGLCDGZIPJEMW-UHFFFAOYSA-N 2,3-dihydro-1,3-oxazol-2-amine Chemical compound NC1NC=CO1 IXGLCDGZIPJEMW-UHFFFAOYSA-N 0.000 claims 1
- AFENDNXGAFYKQO-UHFFFAOYSA-N 2-Hydroxybutyric acid Chemical compound CCC(O)C(O)=O AFENDNXGAFYKQO-UHFFFAOYSA-N 0.000 claims 1
- ASQUQUOEFDHYGP-UHFFFAOYSA-N 2-methoxyethanolate Chemical group COCC[O-] ASQUQUOEFDHYGP-UHFFFAOYSA-N 0.000 claims 1
- YAXGBZDYGZBRBQ-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazol-2-amine Chemical compound NC1=NCCO1 YAXGBZDYGZBRBQ-UHFFFAOYSA-N 0.000 claims 1
- FQYRLEXKXQRZDH-UHFFFAOYSA-N 4-Aminoquinoline Chemical compound C1=CC=C2C(N)=CC=NC2=C1 FQYRLEXKXQRZDH-UHFFFAOYSA-N 0.000 claims 1
- VHRGRCVQAFMJIZ-UHFFFAOYSA-N Cadaverine Chemical compound NCCCCCN VHRGRCVQAFMJIZ-UHFFFAOYSA-N 0.000 claims 1
- NAQMVNRVTILPCV-UHFFFAOYSA-N Hexamethylenediamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 claims 1
- 229920000305 Nylon 6,10 Polymers 0.000 claims 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N Octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N Propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical compound 0.000 claims 1
- MNRNSFOFHFYHNP-UHFFFAOYSA-N cyclohexane-1,3-diamine Chemical compound NC1[CH]CCC(N)C1 MNRNSFOFHFYHNP-UHFFFAOYSA-N 0.000 claims 1
- FNFMQIWXTYFRKA-UHFFFAOYSA-N cyclohexane-1,4-diamine Chemical compound NC1[CH]CC(N)CC1 FNFMQIWXTYFRKA-UHFFFAOYSA-N 0.000 claims 1
- MYJQGGALXPHWLV-UHFFFAOYSA-N cyclopentane-1,2-diamine Chemical compound NC1CCCC1N MYJQGGALXPHWLV-UHFFFAOYSA-N 0.000 claims 1
- YQLZOAVZWJBZSY-UHFFFAOYSA-N decane-1,10-diamine Chemical compound NCCCCCCCCCCN YQLZOAVZWJBZSY-UHFFFAOYSA-N 0.000 claims 1
- 150000002009 diols Chemical class 0.000 claims 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims 1
- 125000001841 imino group Chemical group [H]N=* 0.000 claims 1
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims 1
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 claims 1
- 125000003431 oxalo group Chemical group 0.000 claims 1
- 125000002971 oxazolyl group Chemical group 0.000 claims 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 1
- 235000019260 propionic acid Nutrition 0.000 claims 1
- CZAAKPFIWJXPQT-UHFFFAOYSA-N quinazolin-2-amine Chemical compound C1=CC=CC2=NC(N)=NC=C21 CZAAKPFIWJXPQT-UHFFFAOYSA-N 0.000 claims 1
- 150000003246 quinazolines Chemical compound 0.000 claims 1
- XMIAFAKRAAMSGX-UHFFFAOYSA-N quinolin-5-amine Chemical compound C1=CC=C2C(N)=CC=CC2=N1 XMIAFAKRAAMSGX-UHFFFAOYSA-N 0.000 claims 1
- 150000008038 benzoazepines Chemical class 0.000 abstract description 9
- 150000007657 benzothiazepines Chemical class 0.000 abstract description 9
- ZCXLTWVZYXBHJS-UHFFFAOYSA-N 1,2-benzoxazepine Chemical class O1N=CC=CC2=CC=CC=C12 ZCXLTWVZYXBHJS-UHFFFAOYSA-N 0.000 abstract description 4
- QCXBGWWIZMNMGO-UHFFFAOYSA-N 2-(1,1-dioxo-3,5-dihydro-2H-1$l^{6},4-benzothiazepin-4-yl)-6-methyl-N-pyrrolidin-3-ylquinazolin-4-amine Chemical compound C12=CC(C)=CC=C2N=C(N2CC3=CC=CC=C3S(=O)(=O)CC2)N=C1NC1CCNC1 QCXBGWWIZMNMGO-UHFFFAOYSA-N 0.000 abstract 2
- 229940085242 Benzothiazepine derivative selective calcium channel blockers with direct cardiac effects Drugs 0.000 abstract 1
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- ZYJJPOJXZMSIHN-UHFFFAOYSA-O [amino(hydroxy)methylidene]-methylazanium;hexafluorophosphate Chemical compound C[NH+]=C(N)O.F[P-](F)(F)(F)(F)F ZYJJPOJXZMSIHN-UHFFFAOYSA-O 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CYKRMWNZYOIJCH-UHFFFAOYSA-N bromo(tripyrrolidin-1-yl)phosphanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1CCCN1[P+](N1CCCC1)(Br)N1CCCC1 CYKRMWNZYOIJCH-UHFFFAOYSA-N 0.000 description 1
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- ZZASRJYLQUPYFI-UHFFFAOYSA-N chloroform;N,N-dimethylformamide Chemical compound ClC(Cl)Cl.CN(C)C=O ZZASRJYLQUPYFI-UHFFFAOYSA-N 0.000 description 1
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- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- OPCPRUQQEJNFIV-UHFFFAOYSA-N disodium;cyanoboron(1-) Chemical compound [Na+].[Na+].[B-]C#N.[B-]C#N OPCPRUQQEJNFIV-UHFFFAOYSA-N 0.000 description 1
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- FIDDZFIGUIOGRU-UHFFFAOYSA-N methyl quinazoline-6-carboxylate Chemical class N1=CN=CC2=CC(C(=O)OC)=CC=C21 FIDDZFIGUIOGRU-UHFFFAOYSA-N 0.000 description 1
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- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
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- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
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- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 1
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 description 1
- KKEREYVOSKILFN-UHFFFAOYSA-N quinazolin-6-ylmethanol Chemical class N1=CN=CC2=CC(CO)=CC=C21 KKEREYVOSKILFN-UHFFFAOYSA-N 0.000 description 1
- OKXPYKHKJCATPX-UHFFFAOYSA-N quinazoline-2-carboxylic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=NC=C21 OKXPYKHKJCATPX-UHFFFAOYSA-N 0.000 description 1
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- POECFFCNUXZPJT-UHFFFAOYSA-M sodium;carbonic acid;hydrogen carbonate Chemical compound [Na+].OC(O)=O.OC([O-])=O POECFFCNUXZPJT-UHFFFAOYSA-M 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
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- 125000003666 tauryl group Chemical compound [H]N([H])C([H])([H])C([H])([H])S(*)(=O)=O 0.000 description 1
- DQQJBEAXSOOCPG-UHFFFAOYSA-N tert-butyl N-pyrrolidin-3-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNC1 DQQJBEAXSOOCPG-UHFFFAOYSA-N 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- OIRDBPQYVWXNSJ-FIBGUPNXSA-N trideuteriomethyl trifluoromethanesulfonate Chemical compound [2H]C([2H])([2H])OS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-FIBGUPNXSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- 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
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Abstract
Provided are heteroaryl substituted benzazepine, benzoxazepine and benzothiazepine derivatives of the general formula (I), where the variables are as defined in the specification. Examples of the compounds include N-[(3-Aminooxetan-3-yl)methyl]-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine and 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinazolin-4-amine. The compounds are useful in the treatment of respiratory syncytial virus (RSV). -4(5H)-yl)-6-methylquinolin-4-amine and 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinazolin-4-amine. The compounds are useful in the treatment of respiratory syncytial virus (RSV).
Description
Case 30569
Compounds for the Treatment and Prophylaxis of
Respiratory Syncytial Virus Disease
The invention relates to compounds which are respiratory syncytial virus (RSV) inhibitors
and which are useful in the treatment or laxis of RSV disease.
The ion relates in particular to (i) a compound of formula (I)
R3 Q
A Y R4 R6
R2 N N R7
R10 X R8
R9 (I)
Wherein
R1 is hydrogen, halogen, or C1-6alkyl;
R2 is hydrogen, halogen, or C1-6alkyl;
R3 is hydrogen, halogen, or C1-6alkyl;
R4 is hydrogen, or C1-6alkyl;
R5 is hydrogen, or halogen;
R6 is en, halogen, hydroxy, C1-6alkoxy, carboxy, morpholinyl, or 4-C0-
6alkylpiperazinyl;
R7 is hydrogen, n, C1-6alkyl, C1-6alkoxy, C1-6alkylaminocarbonyl, diC1-6
alkylaminocarbonyl, C1-6alkylsulfonyl, phenoxy, or hydroxy(CH2)2O-;
R8 is hydrogen, halogen, or C1-6alkoxy;
R9 is hydrogen, C1-6alkyl, or =O;
R10 is hydrogen, or =O, ed that R9 and R10 are not =O simultaneously;
JZ / 21.05.2012
A is nitrogen, or -C-R11 , wherein R11 is en, halogen, kyl, cycloalkyl, C1-
6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, C1-6alkoxy(CH 2)1O-,
difluoromethoxy, cyano, nitro, amino, vinyl, acetylenyl, aminocarbonyl, hydroxy(CH2)2O-, C1-
6alkylsulfinyl, C1-6alkylsulfonyl, y(CH2)1-6, deuteratedC1-6alkyl, carboxyl, C1-
6alkoxycarbonyl, hydroxy, difluoromethyl, droxy) C1-6alkyl, or C1-6alkylsulfanyl;
X is -CH2-, -O-, -NH-, -CF2-, -C(C1-6alkyl)(OH)-, -S-, -, -C(=NOC0-6alkyl)-, -
S(=O)-, -S(O2)- or -S(=O)(NH)-;
Y is -CH-, or nitrogen;
Q is en; halogen; C1-6alkyl, unsubstituted or once or twice substituted by amino or
hydroxy, provided that stitution is not on the same carbon; amino(CH2)2-
6aminosulfonyl; 2-amino-4,5-dihydro-1,3-oxazolyl(CH 2)1-6; carboxy(CH2)1-6;
phenylsulfonyl; piperidinyl-carbonyl; 1H-pyrazolyl; pyrrolidinyloxy; piperidin
yloxy; amino(CH2)2O-; orNR12R13 , wherein one of R12 and R13 is hydrogen, C1-6alkyl, or
hydroxy(CH 2)2-6;
and the other one is
{1-[amino(CH2)0-6]-3,3-difluorocyclobutyl}(CH 2)1-6; guanidino(CH2)2-6; (S-C1-
6alkylsulfonimidoyl)(CH 2)2-6; 2-oxaaza-spiro[3.4]octyl; {3-[amino(CH2)0-
6]tetrahydrofuranyl}(CH 2)1-6; 3-aminomethyl-1,1-dioxidothietanylmethyl; 3-amino-
1,1-dioxidothietanylmethyl; 3-(aminomethyl)thietanylmethyl; (1,1-
dioxidothiomorpholinyl)ethyl; C0-6alkyl(oxetanyl)N(CH 2)2-6; 4,5-dihydro-1H-imidazol-
2-yl; amino(CH2)2O-(CH 2)2-6; amino(CH2)2-10 ; amino(CH2)1-6difluoromethyl(CH 2)1-6;
amino(CH 2)1-6difluoromethyldifluoromethyl(CH 2)1-6; amino(CH2)1-6fluoromethyl(CH 2)1-6;
amino(CH 2)1-6oxetanyl(CH 2)0-6; amino(CH2)0-6oxetanyl(CH 2)1-6; amino(CH2)2-
6sulfanyl(CH 2)2-6; amino(CH2)2-6sulfonyl(CH 2)2-6; CH2)0-6carbonyl(CH 2)0-
6; aminocycloalkyl(CH2)0-6; 2-aminodihydrooxazolyl(CH2)1-6; odihydrooxazol
yl(CH 2)1-6; (2-aminomethyl-4,5-dihydro-1,3-oxazolyl)methyl; aminophenyl; 4-
aminotetrahydropyranyl(CH 2)1-6; inyl(CH2)1-6; azetidinyl(CH2)0-6;
azetidinylcarbonyl; C1-6alkoxy(CH 2)2-6; C1-6alkoxy(CH 2)2-6amino(CH 2)2-6; C1-6alkyl; C1-
6alkylamino(CH 2)2-6; C1-6alkylaminocarbonyl(CH 2)0-6; C1-6alkylaminooxetanyl(CH 2)1-6; C1-
6alkylcarbonyl; C1-6alkylcarbonylamino(CH 2)2-6; C1-6alkylcarbonylamino(CH 2)1-
6oxetanyl(CH 2)0-6; C1-6alkylsulfinyl(CH 2)2-6; C1-6alkylsulfonyl; carboxy(CH2)1-6;
cyano(CH 2)1-6; diC1-6alkylamino(CH 2)2-6; diC1-6alkylaminocarbonyl; difluoromethyl(CH2)1-
6amino(CH 2)2-6; hydrogen; hydroxy(CH2)2-10 ; hydroxy(CH2)2-6amino(CH 2)2-6;
y(CH 2)1-6carbonyl; hydroxy(CH2)0-6oxetanyl(CH 2)1-6; hydroxy(CH2)1-
nyl(CH 2)0-6; hydroxycycloalkyl; isoxazolyl; morpholinyl(CH2)1-6; morpholin
yl(CH2)2-6; oxetanyl(CH2)0-6; N-oxetanylpyrrolidinyl; oxo-pyrrolidinylcarbonyl;
phenylaminocarbonyl; phenyl(CH2)0-6aminooxetanyl(CH2)1-6; phenylcarbonyl;
piperazinyl(CH2)2-6; piperidinyl(CH2)2-6; piperidinyl(CH2)1-6; piperidinyl(CH2)0-6;
piperidinyl(CH2)0-6; piperidinylcarbonyl; pyrazinylcarbonyl; pyrazolyl;
pyridazinylcarbonyl; pyridinyl(CH2)0-6carbonyl; pyridinylamino(CH2)2-6; pyrrolidinyl,
unsubstituted or 4-substituted by halogen; pyrrolidinyl, unsubstituted or 3-substituted by
hydroxy or C1-6alkoxy; pyrrolidinyl(CH2)1-6; pyrrolidinylcarbonyl; tetrahydrofuranyl;
tetrahydropyranyl; tetrazolyl(CH2)2-6; trifluoromethylcarbonylamino(CH2)1-6oxetanyl;
-(CH2)1-6 C R15
trifluoromethylsulfonyl; R16 , wherein R14 is hydrogen, C1-6alkyl or
hydroxy(CH2)1-6; R15 is hydroxy, C1-6alkyl, hydroxy(CH2)1-6 or amino; and R16 is C1-6alkyl,
trifluoromethyl, hydroxy(CH2)1-6, amino(CH2)1-6, aminocarboxy or carboxy(CH2)1-6;
C R18
R19 , n R17 is hydrogen, C 18 is hydroxy(CH
1-6alkyl or hydroxy(CH2)1-6; R 2)1-6 or
C1-6alkyl; R19 is y(CH2)1-6, amino(CH2)1-6, carboxy or aminocarboxy(CH2)0-6;
C R21
or R22 , wherein R20 is hydrogen or C1-6alkyl; R21 is C1-6alkyl; R22 is C1-6alkoxy or
amino;
R12 and R13, with the nitrogen atom to which they are ed, may form a pyrrolidinyl,
zinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which
may be unsubstituted, once or twice substituted by a group selected from halogen, C1-
6alkyl, koxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, C1-
6alkylpiperazinyl, and amino(CH2)1-6;
R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a
spiral ring selected from 2-oxaaza-spiro[3.4]octanyl, 2-oxa-5,7-diazaspiro[3.4]octan-
6-oneyl, aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-
3aH-pyrrolo[3,4-d][1,3]oxazolyl, 2-aza-bicyclo[2.1.1]hexanyl, and 3-aza-
bicyclo[3.1.0]hexanyl; which may be unsubstituted or further substituted by amino;
and pharmaceutically acceptable salt and stereoisomers thereof.
Respiratory ial Virus (RSV) belongs to the family of Paramyxoviridae, ily of
Pneumovirinae. The human RSV is a major cause of acute upper and lower respiratory tract
ion in infants and en. Almost all children are infected by RSV at least once by age of
three. Natural human immunity against RSV is incomplete. In normal adults and older children,
RSV infection is mainly associated with upper respiratory track symptoms. Severe case of RSV
infection often leads to bronchiolitis and pneumonia, which requires hospitalization. isk
factors for lower respiratory track infections include premature birth, congenital heart disease,
chronic ary disease, and immuno-compromised conditions. A severe infection at young
age may lead to recurrent wheezing and asthma. For the elderly, RSV-related mortality rate
becomes higher with ing age.
There is no RSV vaccine available for human use, despite of many attempts in subunit
vaccine and live-attenuated vaccine approaches. Virazole®, the aerosol form of ribavirin, is the
only approved antiviral drug for treatment of RSV ion. However, it is rarely used clinically,
due to limited efficacy and potential side effects. Two marketed prophalyxis antibodies were
developed by une (CA, USA).
RSV-IGIV (brand name RespiGam) is polyclonal-concentrated RSV neutralizing antibody
administered through monthly on of 750 mg/kg in hospital (Wandstrat TL, Ann
cother. 1997 Jan;31(1):83-8). Subsequently, the usage of RSV-IGIV was largely replaced
by palivizumab (brand name Synagis®), a humanized monoclonal antibody against RSV fusion
(F) protein approved for laxis in high-risk s in 1998. When administered
intramuscularly at 15 mg/kg once a month for the duration of RSV season, palivizumab
demonstrated 45 – 55% ion of hospitalization rate caused by RSV infection in selected
infants (Pediatrics. 1998 Sep;102(3):531-7; Feltes TF et al, J r. 2003 Oct;143(4):532-40).
Unfortunately, zumab is not effective in the treatment of established RSV infection. A
newer version monoclonal dy, motavizumab, was designed as potential replacement of
palivizumab but failed to show additional t over palivizumab in recent Phase III clinical
trials (Feltes TF et al, Pediatr Res. 2011 Apr 25, Epub ahead of print).
A number of small molecule RSV inhibitors have been discovered. Among them, only a
few reached Phase I or II clinical trials. Arrow Therapeutics (now a group in AstraZeneca, UK)
completed a five-year Phase II trial of nucleocapsid (N) protein inhibitor RSV-604 in stem cell
transplantation patients by ry 2010 (www.clinicaltrials.gov), but has not released the final
results. Most of other small molecules were put on hold for s reasons.
RNAi therapeutics against RSV have also been thoroughly studied. ALN-RSV01 (Alnylam
ceuticals, MA, USA) is a siRNA targeting on RSV gene. A nasal spay administered for
two days before and for three days after RSV inoculation decreased infection rate among adult
volunteers (DeVincenzo J. et al, Proc Natl Acad Sci U S A. 2010 May 11;107(19):8800-5). In
another Phase II trial using naturally infected lung transplantation patients, results were not
sufficient for conclusion of antiviral efficacy, though certain health benefits have been observed
(Zamora MR et al, Am J Respir Crit Care Med. 2011 Feb 15;183(4):531-8). Additional Phase IIb
clinical trials in similar patient population for ALN-RSV01 are on-going
(www.clinicaltrials.gov).
Nevertheless, safe and effective treatment for RSV disease is needed urgently.
It has been found that the compounds of the t invention belong to a new chemical
class of RSV inhibitors for the treatment or prophylaxis of RSV infection. The compounds of the
invention are therefore useful in the treatment or prophylaxis of RSV disease.
As used herein, the term “C0-6alkyl” alone or in combination signifies a chemical bond, or
hydrogen, or saturated, linear- or ed chain alkyl group ning 1 to 6, preferably 1 to 4
carbon atoms, for example methyl, ethyl, propyl, pyl, 1-butyl, 2-butyl, tert -butyl and the
like. red “C0-6alkyl” groups are chemical bond, hydrogen, methyl, ethyl, isopropyl, tert -
butyl.
As used herein, the term “C1-6alkyl” alone or in combination signifies a saturated, linear- or
ed chain alkyl group containing 1 to 6, preferably 1 to 4 carbon atoms, for example
methyl, ethyl, propyl, isopropyl, 1-butyl, l, tert -butyl and the like. Preferred “C1-6alkyl”
groups are methyl, ethyl, isopropyl, tert -butyl.
As used herein, the term lkyl” alone or in ation signifies a saturated, linear- or
branched chain alkyl group containing 2 to 6, preferably 2 to 4 carbon atoms, for example ethyl,
propyl, isopropyl, 1-butyl, 2-butyl, tert -butyl and the like. Preferred lkyl” groups are ethyl,
isopropyl, tert -butyl.
As used herein, the term “-(CH2)0” signifies a chemical link, hydrogen, or a saturated,
linear alkyl chain containing from 1 to 6 carbon atoms, preferably, the term signifies hydrogen or
-(CH2)1.
As used herein, the term “-(CH2)1” signifies a saturated, linear alkyl chain containing
from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms.
As used herein, the term “-(CH2)2” signifies a saturated, linear alkyl chain containing
from 2 to 6 carbon atoms, ably from 2 to 4 carbon atoms.
As used herein, the term “-(CH2)2-10 -” ies a saturated, linear alkyl chain containing
from 2 to 10 carbon atoms, preferably from 2 to 4 carbon atoms.
The term “cycloalkyl”, alone or in combination, refers to a saturated carbon ring
containing from 3 to 7 carbon atoms, preferably from 3 to 6 carbon atoms, for example,
ropyl, utyl, cyclopentyl, exyl, cycloheptyl and the like. Preferred cycloalkyl
groups are ropyl, cyclopentyl and exyl.
The term “C1-6alkoxy” alone or in combination signifies a group C1-6alkyl-O-, n the
“C1-6alkyl” is as defined above; for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i-
butoxy, xy, t-butoxy and the like. Preferred C1-6alkoxy groups are methoxy and ethoxy
and more preferably methoxy.
The term “C2-6alkoxy” alone or in combination signifies a group C2-6alkyl-O-, wherein the
“C2-6alkyl” is as defined above; for example ethoxy, propoxy, isopropoxy, n-butoxy, xy, 2-
butoxy, t-butoxy and the like. Preferred koxy groups is ethoxy.
The term “halogen” means fluorine, chlorine, bromine or iodine. Halogen is preferably
fluorine or chlorine.
The term “hydroxy” alone or in combination refers to the group –OH.
The term “carbonyl” alone or in combination refers to the group -C(O)-.
The term “carboxy” alone or in combination refers to the group –COOH.
The term “amino”, alone or in combination, refers to primary (-NH2), secondary (-NH-
) or tertiary amino ( N ).
The term “sulfonyl” alone or in combination refers to the group -S(O)2-.
The term “C1-6alkylsulfanyl” alone or in combination refers to the group -S-C1-6alkyl.
The term “C1-6alkylsulfinyl” alone or in ation refers to the group -S(O) -C1-6alkyl.
The term “oxetanyl” alone or in combination refers to the group .
The compounds according to formula I does not include those in which the sp3 hybrid
carbon atom is disubstituted by two nitrogen atoms, or one nitrogen atom and one oxygen atom
simultaneously.The compounds according to the present invention may exist in the form of their
pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to
conventional acid-addition salts or base-addition salts that retain the ical effectiveness and
properties of the compounds of formula (I) and are formed from suitable non-toxic organic or
inorganic acids or organic or inorganic bases. Acid-addition salts include for example those
derived from inorganic acids such as hloric acid, hydrobromic acid, hydroiodic acid,
sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids
such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid,
citric acid, malic acid, lactic acid, fumaric acid, and the like. Base-addition salts include those
d from ammonium, potassium, sodium and, quaternary um hydroxides, such as for
example, ethyl ammonium hydroxide. The chemical cation of a pharmaceutical
compound into a salt is a que well known to ceutical chemists in order to obtain
improved physical and chemical ity, hygroscopicity, ility and solubility of
compounds. It is for example described in Bastin R.J., et. al., Organic Process Research &
Development 2000, 4, 5; or in Ansel, H., et. al., In: Pharmaceutical Dosage Forms and
Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Preferred are the sodium salts of
the compounds of formula (I).
"Pharmaceutically acceptable esters" means that compounds of general formula (I) may be
derivatised at functional groups to provide tives which are capable of conversion back to
the parent compounds in vivo. Examples of such compounds include physiologically acceptable
and metabolically labile ester derivatives, such as e, propionate and isobutyrate.
Additionally, any physiologically able equivalents of the compounds of general formula
(I), similar to the metabolically labile esters, which are e of producing the parent
compounds of general formula (I) in vivo, are within the scope of this invention. Preferred are
the methyl and ethyl esters of the compounds of formula (I).
Compounds of the general formula (I) which contain one or several chiral centers can
either be present as racemates, diastereomeric mixtures, or optically active single isomers. The
racemates can be separated according to known s into the enantiomers. Preferably,
diastereomeric salts which can be separated by crystallization are formed from the racemic
mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic
acid, malic acid, lactic acid or camphorsulfonic acid.
Another embodiment of present invention is (ii) a compound of formula (I) or a
pharmaceutically acceptable salt thereof, wherein
R1 is hydrogen, halogen or C1-6alkyl;
R2 is hydrogen, halogen or C1-6alkyl;
R3 is hydrogen, halogen or C1-6alkyl;
R4 is hydrogen or C1-6alkyl;
R5 is hydrogen;
R6 is hydrogen, halogen, hydroxy, C1-6 alkoxy, linyl or alkylpiperazinyl;
R7 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, phenoxy or hydroxy(CH2)2O-;
R8 is hydrogen, halogen or C1-6alkoxy;
R9 is en or C1-6alkyl;
R10 is hydrogen;
A is nitrogen or -C-R11 , wherein R11 is hydrogen, halogen, C1-6 alkyl, cycloalkyl, C1-
6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, C1-6alkoxy(CH O-,
romethoxy, cyano, nitro, amino, vinyl, acetylenyl, aminocarbonyl, hydroxy(CH2)2O-, C1-
6alkylsulfinyl, hydroxy(CH2)1-6, deuteratedC1-6alkyl, carboxyl, carbonyl, hydroxy,
difluoromethyl, -CH(hydroxy)C1-6alkyl or C1-6alkylsulfanyl;
X is S, S=O, SO2 or S(O)NH;
Y is -CH- or nitrogen;
Q is C1-6alkyl, unsubstituted or once substituted by amino; amino(CH 2)2-6aminosulfonyl;
2-amino-4,5-dihydro-1,3-oxazolylethyl; carboxy(CH2)1-6; phenylsulfonyl; piperidinyl-
carbonyl; 1H-pyrazolyl; pyrrolidinyloxy; piperidinyloxy; amino(CH2)2O-;
NR 12 R13 , wherein one of R12 and R13 is hydrogen, C 1-6alkyl or hydroxy(CH2)2-6;
and the other one is
{1-[amino(CH2)0-6]-3,3-difluorocyclobutyl}(CH 2)1-6; (S-C1-6alkylsulfonimidoyl)(CH 2)2-6;
{3-[amino(CH 2)0-6]tetrahydrofuranyl}(CH 2)1-6; (2-aminomethyl-4,5-dihydro-1,3-
oxazolyl)methyl; 3-aminomethyl-1,1-dioxidothietanylmethyl; 3-
(aminomethyl)thietanylmethyl; (1,1-dioxidothiomorpholinyl)ethyl; C0-
6alkyl(oxetanyl)N(CH 2)2-6; 4,5-dihydro-1H-imidazolyl; amino(CH2)2O-(CH 2)2-6;
amino(CH 2)2-10 ; amino(CH2)0-6carbonyl(CH 2)0-6; amino(CH2)1-6difluoromethyl(CH 2)1-6;
amino(CH 2)1-6difluoromethyldifluoromethyl(CH 2)1-6; CH2)1-6fluoromethyl(CH 2)1-6;
amino(CH 2)1-6oxetanyl(CH 2)0-6; amino(CH2)0-6oxetanyl(CH 2)1-6; amino(CH2)2-
nyl(CH 2)2-6; amino(CH2)2-6sulfonyl(CH 2)2-6; 1-aminocyclobutylmethyl; 2-
aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2-
aminocyclopentyl; ocyclopropylethyl; 1-aminocyclopropylmethyl; (2-amino-4,5-
dihydro-oxazolyl)(CH 2)1-6; (2-amino-4,5-dihydro-oxazolyl)(CH2)1-6; aminophenyl; 4-
aminotetrahydropyranyl(CH2)1-6; azetidinyl(CH2)1-6; azetidinyl(CH2)0-6; azetidin-
rbonyl; C1-6alkoxy(CH2)2-6; C1-6alkoxy(CH2)2-6amino(CH2)2-6; C1-6alkyl; C1-
6alkylamino(CH2)2-6; C1-6alkylaminooxetanyl(CH2)1-6; C1-6alkylcarbonyl; C1-
6alkylaminocarbonyl(CH2)0-6; C1-6alkylcarbonylamino(CH2)2-6; C1-
6alkylcarbonylamino(CH2)1-6oxetanyl(CH2)0-6; C1-6alkylsulfinyl(CH2)2-6; kylsulfonyl;
carboxy(CH2)1-6; cyano(CH2)1-6; alkylamino(CH2)2-6; diC1-6alkylaminocarbonyl;
difluoromethyl(CH2)1-6amino(CH2)2-6; hydrogen; hydroxy(CH2)2-10; hydroxy(CH2)2-
6amino(CH2)2-6; hydroxy(CH2)1-6carbonyl; hydroxy(CH2)1-6oxetanyl(CH2)0-6;
hydroxy(CH2)0-6oxetanyl(CH2)1-6; 4-hydroxycyclohexyl; isoxazolyl; morpholin
yl(CH2)1-6; morpholinyl(CH2)2-6; 2-oxaaza-spiro[3.4]octyl; oxetanyl(CH2)0-6; N-
oxetanylpyrrolidinyl; oxo-pyrrolidinylcarbonyl; phenylaminocarbonyl; phenyl(CH2)0-
6aminooxetanyl(CH2)1-6; phenylcarbonyl; piperazinyl(CH2)2-6; piperidinyl(CH2)2-6;
piperidinyl(CH2)1-6; piperidinyl(CH2)0-6; piperidinyl(CH2)0-6; piperidinylcarbonyl;
pyrazinylcarbonyl; pyrazolyl; pyridazinylcarbonyl; pyridinyl(CH2)0-6carbonyl;
nylamino(CH2)2-6; pyrrolidinyl, unsubstituted or 4-substituted by halogen;
pyrrolidinyl, unsubstituted or 3-substituted by hydroxy or C1-6alkoxy; pyrrolidin
yl(CH2)1-6; pyrrolidinylcarbonyl; tetrahydrofuranyl; tetrahydropyranyl;
tetrazolyl(CH2)2-6; trifluoromethylcarbonylamino(CH2)1-6oxetanyl; trifluoromethylsulfonyl;
-(CH2)1-6 C R15
R16 , wherein R14 is hydrogen or C1-6alkyl; R15 is hydroxy, kyl or amino; and
R16 is C1-6alkyl, oromethyl, hydroxy(CH2)1-6, amino(CH2)1-6, arbonyl or
C R18
carboxy(CH2)1-6; R19 , wherein R17 is hydrogen, C 18 is
1-6alkyl or hydroxy(CH2)1-6; R
hydroxy(CH2)1-6 or C1-6alkyl; R19 is hydroxy(CH2)1-6, amino(CH2)1-6, carboxy or
C R21
aminocarbonyl(CH2)0-6; or R22 , wherein R20 is hydrogen or C1-6alkyl; R21 is C1-
22 is C
6alkyl; R 1-6alkoxy or amino;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl,
piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which
may be unsubstituted, once or twice tuted by a group selected from n, C1-
6alkyl, C1-6alkoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, C1-
6alkylpiperazinyl, and amino(CH2)1-6;
R12 and R13, with the nitrogen atom to which they are may form a bridge ring or a spiral
ring selected from 6-aza-spiro[3.4]octanyl, 5,7-diazaspiro[3.4]octanone-
-yl, (4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-3aH-
pyrrolo[3,4-d][1,3]oxazolyl, 2-aza-bicyclo[2.1.1]hexanyl and 3-azabicyclo
[3.1.0]hexanyl; which may be unsubstituted or further tuted by amino.
Further embodiment of present invention is (iii) a compound of formula (I) or a
pharmaceutically able salt thereof, wherein
R1, R2 or R3 are hydrogen, fluoro, chloro or methyl;
R4 is hydrogen or methyl;
R5 is hydrogen;
R6 is hydrogen, fluoro, hydroxy, methoxy, morpholinyl or 4-(propanyl)piperazinyl;
R7 is hydrogen, fluoro, chloro, methyl, methoxy, ethoxy, hydroxyethoxy or phenoxy;
R8 is hydrogen, fluoro or methoxy;
R9 is hydrogen or methyl;
R10 is hydrogen;
A is nitrogen or -C-R11 , wherein R11 is hydrogen, fluoro, chloro, bromo, methyl, ethyl,
cyclopropyl, methoxy, trifluoromethyl, trifluoromethoxy, nyloxy, methoxyethoxy,
difluoromethoxy, cyano, nitro, amino, vinyl, acetylenyl, aminocarbonyl, yethoxy,
sulfanyl, sulfinyl, hydroxymethyl, atedmethyl, carboxyl, methoxycarbonyl,
hydroxy, difluoromethyl, methylCH(hydroxy)- or methylsulfonyl;
X is S, S=O, SO2 or S(O)NH;
Y is -CH- or en;
Q is 2-amino-4,5-dihydro-1,3-oxazolylethyl; aminoethoxy; aminoethylaminosulfonyl;
aminopropyl; carboxyethyl; methyl; phenylsulfonyl; dinyl-carbonyl; piperidin
yloxy; 1H-pyrazolyl; pyrrolidinyloxy; or
NR 12 R13 , wherein one of R12 and R13 is hydrogen, methyl or hydroxyethyl;
and the other one is
aminobutyl; aminocarbonylethyl; aminocarbonylmethyl; 1-aminocyclobutylmethyl; 2-
aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2-
aminocyclopentyl; 1-aminocyclopropylethyl; 1-aminocyclopropylmethyl; aminodecyl; (2-
amino-4,5-dihydro-oxazolyl)methyl; (2-amino-4,5-dihydro-oxazolyl)methyl;
aminoethoxyethyl; aminoethyl; aminoethylcarbonyl; aminoethylfluoromethylmethyl;
aminoethylsulfanylethyl; aminoethylsulfonylethyl; aminoheptyl; aminohexyl;
aminomethylcarbonyl; (1-aminomethyl-3,3-difluorocyclobutyl)methyl;
aminomethyldifluoromethyldifluoromethylmethyl; ethyldifluoromethylmethyl; (2-
aminomethyl-4,5-dihydro-1,3-oxazolyl)methyl; 3-aminomethyl-1,1-dioxidothietan
ylmethyl; aminomethylfluoromethylethyl; aminomethylfluoromethylmethyl;
aminomethyloxetanyl; aminomethyloxetanylmethyl; 3-(aminomethyl)thietanylmethyl;
aminononyl; aminooctyl; aminooxetanylethyl; aminooxetanylmethyl; aminopentyl;
aminophenyl; aminopropyl; 4-aminotetrahydropyranylmethyl; 3-aminotetrahydrofuran-
3-ylmethyl; azetidinyl; azetidinylcarbonyl; azetidinylmethyl; azetidinylmethyl;
carboxyethyl; carboxymethyl; cyanoethyl; difluoromethylmethylaminoethyl; 4,5-dihydro-
1H-imidazolyl; dimethylaminocarbonyl; dimethylaminoethyl; (1,1-
dioxidothiomorpholinyl)ethyl; ethyl; ethylaminocarbonyl; ethylaminoethyl;
minooxetanylmethyl; ethyl (oxetanyl)aminoethyl; en; 4-hydroxycyclohexyl;
hydroxyethyl; hydroxyethylaminoethyl; hydroxyethyloxetanyl; hydroxymethylcarbonyl;
hydroxymethyloxetanylmethyl; hydroxynonyl; ypropyl; isoxazolyl;
methoxyethyl; methoxyethylaminoethyl; methyl; methylaminocarbonylmethyl;
methylaminoethyl; methylcarbonyl; methylcarbonylaminoethyl;
methylcarbonylaminomethyloxetanylmethyl; carbonylaminopropyl;
methylsulfinylethyl; 2-(S-methylsulfonimidoyl)ethyl; methylsulfonyl; linylethyl;
morpholinylmethyl; 2-oxaaza-spiro[3.4]octyl; oxetanyl; oxetanylaminoethyl;
oxetanylaminopropyl; oxetanylmethyl; N-oxetanylpyrrolidinyl; oxo-pyrrolidin
ylcarbonyl; phenylaminocarbonyl; carbonyl; phenylmethylaminooxetanylmethyl;
piperazinylethyl; piperidinylcarbonyl; piperidinylcarbonyl; piperidinylcarbonyl;
piperidinyl; piperidinyl; piperidinylethyl; dinylmethyl; pyrazin
ylcarbonyl; pyrazolyl; pyridazinylcarbonyl; pyridineylmethylcarbonyl; ne
ylaminoethyl; pyridineylcarbonyl; pyridineylcarbonyl; pyrrolidinyl, unsubstituted
or 4-substituted by fluoro; idinyl, unsubstituted or 3-substituted by hydroxy or
methoxy; pyrrolidinylmethyl; pyrrolidinylcarbonyl; tetrahydrofuranyl;
tetrahydropyranyl; olylethyl; trifluoromethylsulfonyl;
-(CH2)1-6 C R15
oromethylcarbonylaminomethyloxetanyl; R16 , wherein R14 is hydrogen or
methyl; R15 is hydroxy, methyl or amino; and R16 is methyl, trifluoromethyl,
C R18
hydroxymethyl, hydroxyethyl, aminomethyl, aminocarbonyl or carboxymethyl; R19 ,
wherein R17 is hydrogen, methyl or hydroxymethyl; R18 is ymethyl or methyl; R19 is
hydroxymethyl, aminomethyl, carboxy, aminocarbonyl or aminocarbonylmethyl;
C R21
or R22 , wherein R20 is hydrogen or ; R21 is methyl or ethyl; R22 is methoxy or
amino;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl,
piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which
may be unsubstituted, once or twice substituted by a group selected from fluoro, methyl,
methoxy, gemdimethyl, amino, arbonyl, hydroxy, oxetanylamino,
methylpiperazinyl and aminomethyl;
R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a
spiral ring selected from 2-oxaaza-spiro[3.4]octanyl, 2-oxa-5,7-diazaspiro[3.4]octan-
6-oneyl, aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-
3aH-pyrrolo[3,4-d][1,3]oxazolyl, 2-aza-bicyclo[2.1.1]hexanyl or 3-azabicyclo
[3.1.0]hexanyl; which may be unsubstituted or further substituted by amino;
and all the remaining substituents are as defined above in embodiment (i) or (ii).
Another embodiment of present invention is (iv) a compound of formula (I) or a
ceutically acceptable salt f, wherein
R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are hydrogen;
A is -C-R11, wherein R11 is en, n or C1-6alkyl;
X is S;
Y is -CH- or nitrogen;
Q is NR12R13, n one of R12 and R13 is hydrogen; and the other one is
amino(CH2)2-6, amino(CH2)1-6difluoromethyl(CH2)1-6, amino(CH2)0-6oxetanyl(CH2)1-6 or
hydrogen;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring,
which may be once substituted by amino; and all the remaining substituents are as defined above
in embodiment (i) to (iii).
Further embodiment of present invention is (v) a compound of formula (I) or a
pharmaceutically acceptable salt thereof, wherein
R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are hydrogen;
A is -C-R11, wherein R11 is hydrogen, chloro or methyl;
Q is NR12R13, wherein one of R12 and R13 is hydrogen; and the other one is aminoethyl,
aminomethyldifluoromethylmethyl, ethyloxetanylmethyl, aminooxetanylmethyl or
hydrogen;
R12 and R13, with the nitrogen atom to which they are ed, may form a pyrrolidinyl
ring, which may be once substituted by amino; and all the remaining substituents are as defined
above in embodiment (iv).
Another further embodiment of present invention is (vi) a compound of formula (I) or a
pharmaceutically acceptable salt thereof, wherein
R1 R2 R3 R4 R5 R6 R7 R8, R9 and R10 are hydrogen;
A is -C-R11, wherein R11 is hydrogen, n, C1-6alkyl, hydroxy(CH2)1-6,
deuteratedmethyl or carboxyl;
X is S=O;
Y is -CH- or nitrogen;
Q is NR12R13, wherein one of R12 and R13 is hydrogen; and the other one is
amino(CH2)2-6; CH2)1-6difluoromethyl(CH2)1-6; amino(CH2)1-6fluoromethyl(CH2)1-6;
amino(CH2)1-6oxetanyl; amino(CH2)1-6oxetanyl(CH2)1-6; xetanyl(CH2)1-6; hydroxy(CH2)2-
; phenyl(CH2)1-6aminooxetanyl(CH2)1-6; pyrrolidinyl, 4-substituted by n;
-(CH2)1-6 C R15
or R16 , wherein R14 is hydrogen, R15 is hydroxy, and R16 is hydroxy(CH2)1-6;
R12 and R13, with the nitrogen atom to which they are ed, may form a pyrrolidinyl
ring, which may be once or twice substituted by a group selected from halogen, amino and
yl; and all the ing substituents are as defined above in embodiment (i) to (v).
More further embodiment of present invention is (vii) a compound of formula (I) or a
pharmaceutically acceptable salt thereof , wherein
R1 R2 R3 R4 R5 R6 R7 R8, R9 and R10 are hydrogen;
A is -C-R11, wherein R11 is hydrogen, chloro, methyl, hydroxymethyl, deuteratedmethyl
or carboxyl;
Q is NR12R13, wherein one of R12 and R13 is hydrogen; and the other one is thyl;
aminomethyldifluoromethylmethyl; aminomethylfluoromethylmethyl; ethyloxetanyl;
aminomethyloxetanylmethyl; aminooxetanylmethyl; aminopropyl; yethyl;
-(CH2)1-6 C R15
phenylmethylaminooxetanylmethyl; pyrrolidinyl, tituted by fluoro; or R16 ,
wherein R14 is hydrogen, R15 is hydroxy, and R16 is hydroxymethyl;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl
ring, which may be once or twice substituted by a group ed from fluoro, amino and
hydroxyl; and all the remaining substituents are as defined above in embodiment (vi).
Still further embodiment of present invention is (viii) a compound of formula (I) or a
pharmaceutically acceptable salt thereof, wherein
R1, R2, and R3 are hydrogen, halogen or C1-6alkyl;
R4 is hydrogen or C1-6alkyl;
R5 is hydrogen;
R6 is hydrogen, halogen, hydroxy, C1-6alkoxy, morpholinyl or 4-(propanyl)piperazin-
1-yl;
R7 is hydrogen, halogen, C1-6alkyl, koxy, hydroxy(CH2)2O-, or phenoxy;
R8 is hydrogen, n or C1-6alkoxy;
R9 is hydrogen or C1-6alkyl;
R10 is hydrogen;
A is nitrogen or -C-R11, wherein R11 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy,
trifluoromethyl, oromethoxy, pyridinyloxy, koxy(CH2)1O-, difluoromethoxy, nitro,
cycloalkyl, cyano, amino, vinyl, acetylenyl, aminocarbonyl, hydroxy(CH2)2O-, C1-
6alkylsulfanyl, C1-6alkylsulfinyl, hydroxy(CH2)1-6, deuteratedmethyl, carboxyl, C1-
6alkoxycarbonyl, hydroxy, difluoromethyl or methylCH(hydroxy)-;
X is SO2;
Y is -CH- or nitrogen;
Q is 2-amino-4,5-dihydro-1,3-oxazolylethyl; amino(CH2)2O-; amino(CH2)2-
6aminosulfonyl; C1-6alkyl, unsubstituted or once substituted by amino; carboxy(CH2)1-6;
phenylsulfonyl; piperidinyl-carbonyl; dinyloxy; 1H-pyrazolyl; idinyloxy;
or NR12R13, wherein one of R12 and R13 is hydrogen, C1-6alkyl or y(CH2)2-6; and the other
one is {1-[amino(CH2)0-6]-3,3-difluorocyclobutyl}(CH2)1-6; (S-C1-6alkylsulfonimidoyl)(CH2)2-6;
3-aminotetrahydrofuranyl(CH2)1-6; (2-aminomethyl-4,5-dihydro-1,3-oxazolyl)methyl; 3-
aminomethyl-1,1-dioxidothietanylmethyl; 3-(aminomethyl)thietanylmethyl; (1,1-
dioxidothiomorpholinyl)ethyl; kyl(oxetanyl)N(CH2)2-6; 4,5-dihydro-1H-imidazolyl;
amino(CH2)2O-(CH2)2-6; CH2)2-10; amino(CH2)1-6carbonyl; aminocarbonyl(CH2)1-6;
amino(CH2)1-6difluoromethyl(CH2)1-6; amino(CH2)1-6difluoromethyldifluoromethyl(CH2)1-6;
amino(CH2)1-6fluoromethyl(CH2)1-6; amino(CH2)1-6oxetanyl(CH2)0-6; amino(CH2)0-
6oxetanyl(CH2)1-6; amino(CH2)2-6sulfanyl(CH2)2-6; amino(CH2)2-6sulfonyl(CH2)2-6; 1-
aminocyclobutylmethyl; 2-aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1-
yclohexylmethyl; 2-aminocyclopentyl; 1-aminocyclopropylethyl; 1-
aminocyclopropylmethyl; (2-amino-4,5-dihydro-oxazolyl)(CH2)1-6; (2-amino-4,5-dihydrooxazolyl
) (CH2)1-6; aminophenyl; otetrahydropyranyl(CH2)1-6; azetidinyl(CH2)1-6;
azetidinyl(CH2)0-6; azetidinylcarbonyl; C1-6alkoxy(CH2)2-6; C1-6alkoxy(CH2)2-
6amino(CH2)2-6; kyl; C1-6alkylamino(CH2)2-6; C1-6alkylaminooxetanyl(CH2)1-6; C1-
6alkylcarbonyl; kylcarbonylamino(CH2)2-6; C1-6alkylcarbonylamino(CH2)1-6oxetanyl(CH2)0-
6; C1-6alkylsulfinyl(CH2)2-6; C1-6alkylsulfonyl; carboxy(CH2)1-6; cyano(CH2)1-6; C1-
6alkylaminocarbonyl(CH2)0-6; diC1-6alkylamino(CH2)2-6; diC1-6alkylaminocarbonyl;
difluoromethyl(CH2)1-6amino(CH2)2-6; hydrogen; hydroxy(CH2)2-10; hydroxy(CH2)2-
(CH2)2-6; hydroxy(CH2)1-6carbonyl; hydroxy(CH2)1-6oxetanyl(CH2)0-6; 4-
hydroxycyclohexyl; isoxazolyl; morpholinyl(CH2)1-6; morpholinyl(CH2)2-6; 2-oxa
aza-spiro[3.4]octyl; oxetanyl(CH2)0-6; N-oxetanylpyrrolidinyl; oxo-pyrrolidin
ylcarbonyl; phenylaminocarbonyl; phenyl(CH2)1-6aminooxetanyl(CH2)1-6; phenylcarbonyl;
piperazinyl(CH2)2-6; piperidinyl(CH2)2-6; dinyl(CH2)1-6; piperidinyl(CH2)0-6;
piperidinyl(CH2)0-6; piperidinylcarbonyl; piperidinylcarbonyl; piperidinylcarbonyl;
pyrazinylcarbonyl; pyrazolyl; pyridazinylcarbonyl; pyridineyl(CH2)0-6carbonyl;
pyridineyl(CH2)0-6carbonyl; pyridineylamino(CH2)2-6; pyrrolidinyl, unsubstituted or 4-
substituted by halogen; pyrrolidinyl, tituted or tituted by hydroxy or C1-6alkoxy;
pyrrolidinyl(CH2)1-6; pyrrolidinylcarbonyl; tetrahydrofuranyl; tetrahydropyranyl;
tetrazolyl(CH2)2-6; trifluoromethylcarbonylamino(CH2)1-6oxetanyl; trifluoromethylsulfonyl;
-(CH2)1-6 C R15
R16 , wherein R14 is hydrogen or C1-6alkyl; R15 is hydroxy, C1-6alkyl or amino; and R16
is C1-6alkyl, trifluoromethyl, hydroxy(CH2)1-6, amino(CH2)1-6, aminocarbonyl or carboxy(CH2)1-
C R18
R19 , wherein R17 is hydrogen, C 18 is hydroxy(CH
6; 1-6alkyl or hydroxy(CH2)1-6; R 2)1-6 or
C1-6alkyl; R19 is hydroxy(CH2)1-6, amino(CH2)1-6, y or aminocarbonyl(CH2)0-6;
C R21
or R22 , wherein R20 is hydrogen or kyl; R21 is C1-6alkyl; R22 is C1-6alkoxy or amino;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl,
piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may
be unsubstituted, once or twice substituted by a group selected from halogen, C1-6alkyl, C1-
6alkoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, ylamino, C1-6alkylpiperazinyl and
amino(CH2)1-6;
R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a
spiral ring selected from 2-oxaaza-spiro[3.4]octanyl, 5,7-diazaspiro[3.4]octanone-
5-yl, (4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-3aH-
pyrrolo[3,4-d][1,3]oxazolyl, 2-aza-bicyclo[2.1.1]hexanyl or 3-aza-bicyclo[3.1.0]hexan
yl; which may be unsubstituted or further substituted by amino; and all the remaining
substituents are as defined above in embodiment (i) to (vii).
Particular embodiment of present invention is (ix) a compound of formula (I) or a
pharmaceutically acceptable salt thereof, wherein R1, R2, and R3 are hydrogen, fluoro,
chloro or methyl;
R4 is hydrogen or methyl;
R5 is hydrogen;
R6 is hydrogen, fluoro, hydroxy, methoxy, morpholinyl or 4-(propanyl)piperazinyl;
R7 is hydrogen, fluoro, , methyl, methoxy, hydroxyethoxy, or phenoxy;
R8 is hydrogen, fluoro or methoxy;
R9 is en or ;
R10 is hydrogen;
A is nitrogen or -C-R11, wherein R11 is en, fluoro, chloro, bromo, methyl, ethyl,
methoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, methoxyethoxy, difluoromethoxy,
nitro, ropyl, cyano, amino, vinyl, acetylenyl, aminocarbonyl, hydroxyethoxy,
methylsulfanyl, methylsulfinyl, hydroxymethyl, deuteratedmethyl, carboxyl, ycarbonyl,
hydroxy, difluoromethyl or methylCH(hydroxy)-;
Y is -CH- or nitrogen;
Q is 2-amino-4,5-dihydro-1,3-oxazolylethyl; aminoethoxy; aminoethylaminosulfonyl;
aminopropyl; carboxyethyl; methyl; phenylsulfonyl; piperidinyl-carbonyl; piperidinyloxy;
1H-pyrazolyl; pyrrolidinyloxy; or NR12 R13 , wherein one of R12 and R13 is hydrogen,
methyl or hydroxyethyl, and the other one is aminobutyl; aminocarbonylethyl;
aminocarbonylmethyl; 1-aminocyclobutylmethyl; 2-aminocyclohexyl; 3-aminocyclohexyl; 4-
aminocyclohexyl; 1-aminocyclohexylmethyl; 2-aminocyclopentyl; 1-aminocyclopropylethyl; 1-
aminocyclopropylmethyl; aminodecyl; (2-amino-4,5-dihydro-oxazolyl)methyl; no-4,5-
dihydro-oxazolyl)methyl; aminoethoxyethyl; aminoethyl; aminoethylcarbonyl;
aminoethylfluoromethylmethyl; aminoethylsulfanylethyl; aminoethylsulfonylethyl;
aminoheptyl; exyl; aminomethylcarbonyl; (1-aminomethyl-3,3-
difluorocyclobutyl)methyl; ethyldifluoromethyldifluoromethylmethyl;
aminomethyldifluoromethylmethyl; (2-aminomethyl-4,5-dihydro-1,3-oxazolyl)methyl; 3-
aminomethyl-1,1-dioxidothietanylmethyl; aminomethylfluoromethylethyl;
aminomethylfluoromethylmethyl; aminomethyloxetanyl; aminomethyloxetanylmethyl; 3-
(aminomethyl)thietanylmethyl; onyl; aminooctyl; aminooxetanylethyl;
aminooxetanylmethyl; entyl; aminophenyl; aminopropyl; 4-aminotetrahydropyran
ylmethyl; 3-aminotetrahydrofuranylmethyl; azetidinyl; azetidinylcarbonyl; azetidin
ylmethyl; azetidinylmethyl; carboxyethyl; carboxymethyl; cyanoethyl;
difluoromethylmethylaminoethyl; 4,5-dihydro-1H-imidazolyl; dimethylaminocarbonyl;
dimethylaminoethyl; (1,1-dioxidothiomorpholinyl)ethyl; ethyl; ethylaminocarbonyl;
minoethyl; ethylaminooxetanylmethyl; ethyl (oxetanyl)aminoethyl; en; 4-
hydroxycyclohexyl; hydroxyethyl; hydroxyethylaminoethyl; hydroxyethyloxetanyl;
hydroxymethylcarbonyl; hydroxymethyloxetanylmethyl; hydroxynonyl; ypropyl;
olyl; methoxyethyl; methoxyethylaminoethyl; methyl; methylaminocarbonylmethyl;
methylaminoethyl; methylcarbonyl; methylcarbonylaminoethyl;
methylcarbonylaminomethyloxetanylmethyl; methylcarbonylaminopropyl; methylsulfinylethyl;
2-(S-methylsulfonimidoyl)ethyl; methylsulfonyl; morpholinylethyl; morpholinylmethyl; 2-
oxaaza-spiro[3.4]octyl; oxetanyl; oxetanylaminoethyl; ylaminopropyl;
oxetanylmethyl; N-oxetanylpyrrolidinyl; oxo-pyrrolidinylcarbonyl; phenylaminocarbonyl;
phenylcarbonyl; phenylmethylaminooxetanylmethyl; piperazinylethyl; piperidin
ylcarbonyl; piperidinylcarbonyl; piperidinylcarbonyl; piperidineyl; piperidineyl;
piperidinylethyl; piperidinylmethyl; pyrazinylcarbonyl; pyrazolyl; pyridazin
ylcarbonyl; pyridineylmethylcarbonyl; neylaminoethyl; pyridineylcarbonyl;
pyridineylcarbonyl; pyrrolidinyl, unsubstituted or tituted by fluoro; pyrrolidinyl,
unsubstituted or 3-substituted by y or methoxy; pyrrolidinylmethyl; pyrrolidin
ylcarbonyl; tetrahydrofuranyl; tetrahydropyranyl; tetrazolylethyl; trifluoromethylsulfonyl;
-(CH2)1-6 C R15
trifluoromethylcarbonylaminomethyloxetanyl; R16 , wherein R14 is hydrogen or methyl;
R15 is y, methyl or amino; and R16 is methyl, trifluoromethyl, hydroxymethyl,
C R18
yethyl, aminomethyl, aminocarbonyl or carboxymethyl; R19 , wherein R17 is
hydrogen, methyl or ymethyl; R18 is hydroxymethyl or methyl; R19 is hydroxymethyl,
C R21
aminomethyl, y, arbonyl or aminocarbonylmethyl; or R22 , wherein R20 is
hydrogen or methyl; R21 is methyl or ethyl; R22 is methoxy or amino;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl,
piperazinyl, dinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may
be unsubstituted, once or twice substituted by a group selected from fluoro, methyl, methoxy,
gemdimethyl, amino, aminocarbonyl, hydroxy, ylamino, methylpiperazinyl and
ethyl;
R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a
spiral ring selected from 2-oxaaza-spiro[3.4]octanyl, 2-oxa-5,7-diazaspiro[3.4]octanone-
-yl, (4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-3aH-
pyrrolo[3,4-d][1,3]oxazolyl, 2-aza-bicyclo[2.1.1]hexanyl or 3-aza-bicyclo[3.1.0]hexan
yl; which may be unsubstituted or further substituted by amino; and all the remaining
substituents are as defined above in embodiment (viii).
Another particular embodiment of present invention is (x) a compound of formula (I) or a
pharmaceutically acceptable salt thereof, wherein
R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are hydrogen;
A is -C-R11, wherein R11 is C1-6alkyl;
X is S(O)NH;
Y is -CH-;
Q is NR12R13, wherein one of R12 and R13 is hydrogen; and the other one is
amino(CH2)2-6;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl
ring, which may be twice substituted by a group selected from amino and yl; and all the
remaining substituents are as defined above in embodiment (i) to (ix).
Still another ular embodiment of invention is (xi) a compound of formula (I) or a
pharmaceutically acceptable salt thereof, n
R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are hydrogen;
A is -C-R11 , wherein R11 is methyl;
Q is NR12 R13 , wherein one of R12 and R13 is hydrogen; and the other one is aminoethyl;
R12 and R13 , with the nitrogen atom to which they are attached, may form a pyrrolidinyl
ring, which may be twice substituted by a group selected from amino and hydroxyl; and all the
remaining substituents are as defined above in ment (x).
ular embodiment of present invention is a compound of formula (I) or a
pharmaceutically acceptable salt thereof, selected from:
N-[(3-aminooxetanyl)methyl](8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetanyl)methyl](8-fluoro-1,1-dioxido-
2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetan
yl)methyl](7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin-
4-amine; N-[(3-aminooxetanyl)methyl](9-fluoro-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetanyl)methyl](7-
methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-
inooxetanyl)methyl](8-chloro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl)methylquinolinamine; N-[(3-aminooxetanyl)methyl](7-methoxy-1,1-dioxido-2,3-
o-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-[(3-aminotetrahydrofuran
yl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine;
N-[(3-aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinamine; N-[(4-aminotetrahydro-2H-pyranyl)methyl](1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetan
yl)methyl](8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine;
N-[(3-aminooxetanyl)methyl]methyl(8-methyl-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)quinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methyl-N-(2-oxaazaspiro[3.4]octyl)quinolinamine; N-[2-(3-aminooxetan
yl)ethyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinamine;
N-[(3-aminooxetanyl)methyl]methyl(5-methyl-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)quinolinamine; aminooxetanyl)methyl](8-methoxy-1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-[(3-aminooxetan
yl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-1,6-naphthyridinamine;
N-[(1-aminocyclohexyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}(8-fluoro-1,1-dioxido-2,3-
o-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-{[3-(benzylamino)oxetan
yl]methyl}chloro(7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin-
4-amine; N-[(3-aminooxetanyl)methyl]chloro(7-fluoro-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}(7-
methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3-
(aminomethyl)oxetanyl]methyl}(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methylquinolinamine; N-{[3-({[2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-
hiazepin-4(5 H)-yl)methylquinolinyl]amino}methyl)oxetanyl]methyl}acetamide;
(aminomethyl)oxetanyl]methyl}(8-methyl-1,1-dioxido-2,3-dihydro-1,4-
hiazepin-4(5 H)-yl)quinolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}methyl-
2-(8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; [3-({[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]amino}methyl)oxetanyl]methanol; (2S ){[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 methylquinolinyl]amino}propane-1,2-diol; (2R ){[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propane-1,2-
diol; N-{[1-(aminomethyl)-3,3-difluorocyclobutyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetanyl)methyl]chloro-
2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3-
(aminomethyl)oxetanyl]methyl}chloro(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinolinamine; trans-N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]cyclohexane-1,2-diamine; N-[2-(1,1-dioxido-
2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]cyclohexane-1,3-diamine;
(3R )[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-4,4-
dimethylpyrrolidinol; cis-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]cyclohexane-1,4-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]-2,2-difluoropropane-1,3-diamine; N-[6-chloro-
2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]-2,2-difluoropropane-1,3-
diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]
fluoropropane-1,3-diamine; N-[(3-aminooxetanyl)methyl]chloro(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; [4-{[(3-aminooxetan
yl)methyl]amino}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 quinolin
yl]methanol; N-[(3-aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)fluoromethylquinolinamine; aminooxetanyl)methyl](1,1-dioxido-
2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)fluoromethylquinolinamine; 6-chloro-
2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]methylpropane-1,2-
diamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(tetrahydro-2H-
pyranyl)quinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methyl-N-[2-(piperazinyl)ethyl]quinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methyl-N-(piperidinylmethyl)quinolinamine; N-[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]heptane-1,7-diamine;
1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'-
methylethane-1,2-diamine; N'-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinyl]-N,N-dimethylethane-1,2-diamine; -dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)-N,6-dimethylquinolinamine trifluoroacetate; (3S ,4S )[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]pyrrolidine-3,4-diol;
2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(pyrrolidin
ylmethyl)quinolinamine; 4-[4-(1,4-diazepanyl)methylquinolinyl]-2,3,4,5-tetrahydro-
1,4-benzothiazepine 1,1-dioxide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]-N'-ethylethane-1,2-diamine; 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}ethanol; -dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 methyl-N-(piperidinyl)quinolinamine; 2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(piperidinyl)quinolinamine; 2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(piperidinylmethyl)quinolin-
4-amine; 2-[(2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
no}ethyl)amino]ethanol; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]-2,2,3,3-tetrafluorobutane-1,4-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]-N'-(2-methoxyethyl)ethane-1,2-diamine; 1-[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]
methylpyrrolidinol; N-[6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
nolinyl]ethane-1,2-diamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-
6-methyl-N-(oxetanyl)quinolinamine; N-[(3-aminooxetanyl)methyl](1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methyl-N-[( 3R )-tetrahydrofuranyl]quinolinamine; N-{[3-
methyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}chloro(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3-(aminomethyl)oxetan
yl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; 2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(oxetanylmethyl)quinolin
amine; N-[(1-aminocyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl)methylquinolinamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]pentane-1,5-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methylquinolinyl]hexane-1,6-diamine; 1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]-1,1,1-trifluoromethanesulfonamide
hydrochloride; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]pyridazinecarboxamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]benzamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]acetamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]piperidinecarboxamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]piperidinecarboxamide; 3-[2-(1,1-dioxido-
2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-1,1-dimethylurea; 2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(1,2-oxazolyl)quinolin
amine; N-{[3-(aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-
hiazepin-4(5 H)-yl)(~2~ H_3_)methylquinolinamine; N-[(3-aminooxetan
yl)methyl]chloro(2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-[6-chloro-
2-(2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]ethane-1,2-diamine; N-[(3-
aminooxetanyl)methyl](2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
amine; 2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]pyrrolidin
amine; N-[2-(2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolinyl]-2,2-
ropropane-1,3-diamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-[2-
(1,1-dioxidothiomorpholinyl)ethyl]methylquinolinamine; N-[2-(2-aminoethoxy)ethyl]-
2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinamine; N~1~-[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]
methylpropane-1,2-diamine; N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl)quinolinyl]methylpropane-1,2-diamine; N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]propane-1,2-diamine; 4-[6-methyl(4-
piperazinyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide; 1-{[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propan
ol; (2S )-N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]propane-1,2-diamine; (2R )-N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-
6-methylquinolinyl]propane-1,2-diamine; N-[(3-aminooxetanyl)methyl](1,1-dioxido-
2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-7,8-difluoromethylquinolinamine; N-(2,2-
difluoroethyl)-N'-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolin
yl]ethane-1,2-diamine; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinyl]amino}oxetanethanol; (aminomethyl)thietanyl]methyl}(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-{[3-
(aminomethyl)-1,1-dioxidothietanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methylquinolinamine; N-(4,5-dihydro-1H-imidazolyl)(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; trans {[2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}cyclohexanol; (2S ){[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propan
ol; trans [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]
methoxypyrrolidinamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin+D154-4(5 H)-yl)-N-
[trans methoxypyrrolidinyl]methylquinolinamine; 4-{4-[(4aS ,7aR )-
hexahydropyrrolo[3,4-b][1,4]oxazin-6(2 methylquinolinyl}-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide; (3R ,4R )[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl)methylquinolinyl](4-methylpiperazinyl)pyrrolidinol; N-{2-[(2-
aminoethyl)sulfanyl]ethyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
quinolinamine; 1-{1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinyl]piperidinyl}methanamine; 2-{[2-(8-methoxy-1,1-dioxido-2,3-dihydro-
1,4-benzothiazepin-4(5 H)-yl)quinolinyl]amino}ethanol; N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]propane-1,3-diamine; ethyl
(morpholinyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; 3-{[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propanol; 2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-[2-(piperidin
yl)ethyl]quinolinamine; 1-amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl)methylquinolinyl]amino}propanol; N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 methylquinolinyl]glycine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)fluoroquinolinyl]ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)ethylquinolinyl]ethane-1,2-diamine; N-[7-chloro
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]propane-1,3-diamine; N-[8-
chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]propane-1,3-
diamine; N-[5-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin
yl]propane-1,3-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]-2,2-dimethylpropane-1,3-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)quinolinyl]ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]ethane-1,2-diamine; N~2~-[2-(1,1-dioxido-2,3-
o-1,4-benzothiazepin-4(5 methylquinolinyl]methylpropane-1,2-diamine;
N~2~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]propane-1,2-diamine; 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]butane-1,4-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)nitroquinolinyl]ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)fluoromethylquinolinyl]ethane-1,2-diamine; 2-{[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)fluoromethylquinolin
yl]amino}ethanol; 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)fluoro
methylquinolinyl]amino}ethanol; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)fluoromethylquinolinyl]ethane-1,2-diamine; 1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)-7,8-difluoromethylquinolinyl]ethane-1,2-diamine; 2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-N-(2-methoxyethyl)methylquinolin
amine; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]piperidinamine; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-1,6-
naphthyridinyl]pyrrolidinamine; N-[6-(difluoromethyl)(1,1-dioxido-2,3-dihydro-1,4-
hiazepin-4(5 H)-yl)quinolinyl]propane-1,3-diamine; 6-chloro(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)-N-ethylquinolinamine; 2-{[6-chloro(1,1-dioxido-
2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]amino}ethanol; N-[6-chloro(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]-N'-methylethane-1,2-diamine;
N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(methylsulfanyl)quinolin
yl]propane-1,3-diamine; N-[6-bromo(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl)quinolinyl]propane-1,3-diamine; {4-[(2-aminoethyl)amino](1,1-dioxido-2,3-dihydro-
1,4-benzothiazepin-4(5 H)-yl)quinolinyl}methanol; 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propane-1,3-diol; 2,2'-{[2-(1,1-dioxido-
2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]imino}diethanol; 4-{[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}
hydroxybutanoic acid; 1-amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinyl]amino}methylpropanol; 2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methyl-N-[2-(morpholinyl)ethyl]quinolinamine; 2-{[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-1,6-naphthyridinyl]amino}ethanol; N-[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]nonane-1,9-
diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
ane-1,10-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]octane-1,8-diamine; (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methylquinolinyl]amino}nonanol; N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]octane-1,8-diamine; cis amino[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]pyrrolidinol; N-[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-L-alanine; N-[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinyl]-beta-alanine; N-
[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinyl]benzene-1,3-
diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]benzene-1,4-diamine; (3S )[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinyl]pyrrolidinol; (3R )[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methylquinolinyl]pyrrolidinol; trans -N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]cyclopentane-1,2-diamine; 1-[2-(1,1-dioxido-
2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinyl]piperidinamine; 2-(1,1-
o-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-N,N,6-trimethylquinolinamine; N-[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)(trifluoromethoxy)quinolinyl]propane-
amine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
(trifluoromethyl)quinolinyl]propane-1,3-diamine; N-[6-(difluoromethoxy)(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]propane-1,3-diamine; N-[2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)methoxyquinolinyl]propane-1,3-diamine; N-[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]propane-1,3-diamine;
1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]propane-
amine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]propane-1,3-diamine; N-{[3-(aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-
1,4-benzothiazepin-4(5 H)-yl)fluoroquinolinamine; N-[(3-aminooxetanyl)methyl]
methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; (+)-N-[(3-
xetanyl)methyl]methyl[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl]quinolinamine; (-)-N-[(3-aminooxetanyl)methyl]methyl[1-oxido-2,3-dihydro-1,4-
hiazepin-4(5 H)-yl]quinolinamine; aminooxetanyl)methyl]chloro(1-
oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; 2,2-difluoro-N-[6-methyl
(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]propane-1,3-diamine; N-[6-
chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]-2,2-difluoropropane-
1,3-diamine; N-[6-chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin
yl]ethane-1,2-diamine; N-{[3-(aminomethyl)oxetanyl]methyl}methyl(1-oxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3-(aminomethyl)oxetan
yl]methyl}chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-
hyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]ethane-1,2-
diamine; methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin
yl]amino}ethanol; trans amino[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)quinolinyl]pyrrolidinol; (1R ,5S ,6S )[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]azabicyclo[3.1.0]hexanamine; trans
amino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]pyrrolidinol; 1-[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin
yl]pyrrolidinamine; trans [6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl)quinolinyl]fluoropyrrolidinamine; trans amino[6-chloro(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]pyrrolidinol; trans [6-chloro(1-
oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]fluoropyrrolidinamine; 2-[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]
azabicyclo[2.1.1]hexanamine; 2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 methylquinolinamine; 2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[2-(1-aminocyclopropyl)ethyl](1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; 2-(1,1-dioxido-
2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(morpholinylmethyl)quinolinamine;
N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N-
methylethane-1,2-diamine; N-(azetidinylmethyl)(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methyl-N-(pyrrolidinyl)quinolinamine; N-[(1-
aminocyclopropyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinamine; N-(azetidinyl)chloro(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)quinolinamine; 6-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methylquinolinyl]oxaazaspiro[3.4]octanamine; trans amino[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 -1,6-naphthyridinyl]pyrrolidinol; 1-[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]pyrrolidin
amine; N-(azetidinyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinamine; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinyl]azetidinamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)methylquinolinyl]prolinamide; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl)-N-(trans fluoropyrrolidinyl)methylquinolinamine; trans {[2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 quinolinyl]amino}pyrrolidinol; trans {[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}pyrrolidinol;
cis {[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]amino}pyrrolidinol; N-[trans fluoropyrrolidinyl]methyl(1-oxido-2,3-dihydro-
1,4-benzothiazepin-4(5 H)-yl)quinolinamine; 4-[(3-aminopropyl)amino](1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinol; 2-({4-[(3-aminopropyl)amino](1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl}oxy)ethanol; N-[2-(1,1-dioxido-
2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)(2-methoxyethoxy)quinolinyl]propane-1,3-
diamine; 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(pyridin
quinolinyl]propane-1,3-diamine; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methylquinolinyl]amino}propane-1,2-diol; 3-{[6-chloro(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]amino}propane-1,2-diol; 3-{[2-(8-chloro-
oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propane-
1,2-diol; 3-{[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin
yl]amino}propane-1,2-diol; 3-{[6-methyl(5-methyl-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)quinolinyl]amino}propane-1,2-diol; aminooxetan
hyl]methyl[7-(morpholinyl)-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl]quinolinamine; N-[(3-aminooxetanyl)methyl]{1,1-dioxido[4-(propan
yl)piperazinyl]-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl}methylquinolinamine; 3-{[4-
(4-aminoquinolinyl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepinyl]oxy}propan
ol; N-[(3-aminooxetanyl)methyl](1,1-dioxidophenoxy-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methylquinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methylquinolinyl]-beta-alaninamide; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}butanamide; 3-{[2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}methylpropanamide;
N~2~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-L-
alaninamide; N~2~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin-
4-yl]glycinamide; N~2~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinyl]-N-methylglycinamide; (2S )amino{[2-(1,1-dioxido-2,3-dihydro-1,4-
hiazepin-4(5 H)-yl)methylquinolinyl]amino}propanol; (2R )amino{[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinyl]amino}propanol;
N-[(2-amino-4,5-dihydro-1,3-oxazolyl)methyl](1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(2-aminomethyl-4,5-dihydro-1,3-
oxazolyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin-
4-amine; N-{[(4R )amino-4,5-dihydro-1,3-oxazolyl]methyl}(1,1-dioxido-2,3-dihydro-
1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-{[( 4S )amino-4,5-dihydro-1,3-
oxazolyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinamine; cis [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinyl]-4,5,6,6a-tetrahydro-3a H-pyrrolo[3,4-d][1,3]oxazolamine; 2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]glycinamide; N-[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]
methylalaninamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]alaninamide; 2-amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 methylquinolinyl]butanamide; 1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]methoxymethylpropanamide; N~1~-[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-4,4,4-
trifluorobutane-1,3-diamine; 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]-beta-alaninamide; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl)-N-{[3-(ethylamino)oxetanyl]methyl}methylquinolinamine; 2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-[1-(oxetanyl)pyrrolidinyl]quinolin
amine; (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-N-
ethyl-N-(oxetanyl)ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methylquinolinyl]-N'-(oxetanyl)propane-1,3-diamine; 1-[2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-N-(oxetanyl)pyrrolidin
amine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'-
(oxetanyl)ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
ylquinolinyl]-N'-(pyridinyl)ethane-1,2-diamine; (4R )[2-(1,1-dioxido-2,3-dihydro-
1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]hydroxypyrrolidinone; N-[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]oxopyrrolidine
carboxamide; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(1 H-
pyrazolyl)quinolinamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]pyridinecarboxamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]piperidinecarboxamide; N-[2-(1,1-dioxido-
2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl](pyridinyl)acetamide; N-
[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]methanesulfonamide trifluoroacetate; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methylquinolinyl]pyrazinecarboxamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinolinyl]hydroxyacetamide; N-[2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]pyridinecarboxamide; N-[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]azetidine
carboxamide; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]phenylurea; 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinyl]ethylurea; N-[6-cyclopropyl(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)quinolinyl]propane-1,3-diamine; 4-[(3-aminopropyl)amino](1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinecarbonitrile; N-[2-(1,1-dioxido-
hydro-1,4-benzothiazepin-4(5 H)-yl)ethenylquinolinyl]propane-1,3-diamine; N-[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)ethynylquinolinyl]propane-1,3-
diamine; N-[(3-aminooxetanyl)methyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)quinazolinamine; N-{[3-(benzylamino)oxetanyl]methyl}methyl(1-oxido-
2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; 2-fluoro-N-[6-methyl(1-oxido-
2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinyl]propane-1,3-diamine; N-{[3-
(aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinazolinamine; 2,2-difluoro-N-[6-methyl(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)quinazolinyl]propane-1,3-diamine; N-{[3-(aminomethyl)oxetan
yl]methyl}chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 quinazolin
amine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl]-
2,2-difluoropropane-1,3-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
6-methylquinazolinyl]fluoropropane-1,3-diamine; N-[6-methyl(1-oxido-2,3-dihydro-
1,4-benzothiazepin-4(5 H)-yl)quinazolinyl]propane-1,3-diamine; aminooxetan
yl)methyl](2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; N-[(3-aminooxetan-
3-yl)methyl](1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 quinazolinamine; N-[(3-
aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 quinazolin-
4-amine; N-[(3-aminooxetanyl)methyl]chloro(2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl)quinazolinamine; N-[(3-aminooxetanyl)methyl]chloro(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5 quinazolinamine; N-[(3-aminooxetanyl)methyl]chloro(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; 2-{[2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolinyl]amino}ethanol; 2-(2,3-dihydro-
1,4-benzothiazepin-4(5 H)-yl)methylquinazolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4-
hiazepin-4(5 H)-yl)methylquinazolinamine; N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinazolinyl]methylpropane-1,2-diamine; N-[(3-
aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinazolinamine; N-[(1-aminocyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinazolinamine; N-{[3-(aminomethyl)oxetan
yl]methyl}methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine;
(-)-N-{[3-(aminomethyl)oxetanyl]methyl}methyl[1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl]quinazolinamine; (+)-N-{[3-(aminomethyl)oxetanyl]methyl}
methyl[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl]quinazolinamine; N~4~-[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolinyl]fluorobutane-1,4-
diamine; N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolin
yl]fluorobutane-1,4-diamine; N-{[3-(aminomethyl)oxetanyl]methyl}(2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)methylquinazolinamine; trans fluoro[6-methyl(1-oxido-
2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]pyrrolidinamine; N-(Azetidinyl)-
6-methyl(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) quinazolinamine; N-(2-
{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}ethyl)acetamide; ({[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinyl]amino}methyl)oxetanyl]methyl}acetamide; N-(3-{[2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propyl)acetamide; N-[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolinyl]acetamide; 1-
[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]
methylpyrrolidinamine; N-[(3-aminooxetanyl)methyl](9-methoxy-1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; 4-(4-{[(3-aminooxetan
yl)methyl]amino}methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepinol 1,1-
dioxide; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]amino}methylpropane-1,2-diol; (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl)methylquinolinyl]amino}butane-1,3-diol; N-[6-methyl(2-methyl-1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 quinolinyl]ethane-1,2-diamine; N-[(3-aminooxetan
yl)methyl]methyl(2-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl)quinolinamine; N-[(3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
quinolinyl]amino}oxetanyl)methyl]-2,2,2-trifluoroacetamide; N-[3-
(aminomethyl)oxetanyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
quinolinamine; 2-(aminomethyl){[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methylquinolinyl]amino}propane-1,3-diol; 4-amino[2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]pyrrolidinone; 2-(1,1-dioxido-
2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-[2-(methylsulfinyl)ethyl]quinolin
amine; N-{2-[(2-aminoethyl)sulfonyl]ethyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 methylquinolinamine; N-[2-(1-iminooxido-1,2,3,5-tetrahydro-4H-
1lambda ~4~,4-benzothiazepinyl)methylquinolinyl]ethane-1,2-diamine; -dioxido-
2,3-dihydro-1,4-benzothiazepin-4(5 methyl-N-[2-(S-
methylsulfonimidoyl)ethyl]quinolinamine; trans amino[2-(1-iminooxido-1,2,3,5-
tetrahydro-4H-1lambda ~4~,4-benzothiazepinyl)methylquinolinyl]pyrrolidinol; trans -
1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]
fluoropyrrolidinamine; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinyl]pyrrolidinecarboxamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)(methylsulfinyl)quinolinyl]propane-1,3-diamine; 4-[(3-
ropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinoline
amide; 1-{4-[(3-aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)quinolinyl}ethanol; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinyl]amino}propanenitrile; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methyl-N-[2-(1 H-tetrazolyl)ethyl]quinolinamine; N~4~-(2-aminoethyl)(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinoline-4,6-diamine; 5-[2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]oxa-5,7-diazaspiro[3.4]octan
one; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolin
yl]amino}propane-1,2-diol; 3-{[6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl)quinazolinyl]amino}propane-1,2-diol; N-[2-(2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinazolinyl]ethane-1,2-diamine; N-[6-methyl(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)quinazolinyl]ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-
1,4-benzothiazepin-4(5 H)-yl)methylquinazolinyl]ethane-1,2-diamine; N-[3-
(aminomethyl)oxetanyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-
yl)quinazolinamine; N-(trans fluoropyrrolidinyl)methyl(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)quinazolinamine; N-(trans fluoropyrrolidinyl)methyl(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; 1-[6-methyl(1-oxido-
hydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinyl]pyrrolidinamine; N-(azetidinyl)-
6-methyl(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; (4R )
{2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]ethyl}-4,5-
o-1,3-oxazolamine; 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
ethylquinolinyl]propanoic acid; 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-
6-methylquinolinyl]propanamine; 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methylquinolinyl]oxy}ethanamine; 4-[6-methyl(pyrrolidinyloxy)quinolin-
2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; 4-[6-methyl(piperidin
yloxy)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide; 4-(4,6-
dimethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; [2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl](piperidinyl)methanone; 4-[6-
methyl(1 H-pyrazolyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; 4-
[6-methyl(phenylsulfonyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide;
minoethyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinoline-
4-sulfonamide; methyl 4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinecarboxylate; 4-({[3-(aminomethyl)oxetan
hyl}amino)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinoline
carboxylic acid; [4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-
1,4-benzothiazepin-4(5 H)-yl)quinolinyl]methanol; N-{[3-(aminomethyl)oxetanyl]methyl}-
6-(~2~ ethyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine;
4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5 quinazolinecarboxylic acid; 4-({[3-(aminomethyl)oxetan
yl]methyl}amino)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazoline
carboxylic acid; [4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5 H)-yl)quinazolinyl]methanol; [4-({[3-(aminomethyl)oxetan
yl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolin
yl]methanol; aminocyclopropyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methylquinazolinamine; and 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5 H)-yl)methyl-N-(pyrrolidinyl)quinazolinamine.
Another embodiment of invention is (xii) a compound of formula (I) or a pharmaceutically
acceptable salt thereof, wherein
R1 is hydrogen or halogen;
R2 and R4 are en;
R3 is en or halogen;
R5 is hydrogen or halogen;
R6 is hydrogen, halogen, hydroxy, C1-6alkoxy or carboxy;
R7 is hydrogen, halogen, C1-6alkoxy, C1-6alkylaminocarbonyl, diC1-6
alkylaminocarbonyl or C1-6alkylsulfonyl;
R8 is hydrogen or halogen;
R9 is hydrogen or =O;
R10 is hydrogen or =O, ed that R9 and R10 are not =O simultaneously;
A is -C-R11 , wherein R11 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, trifluoromethyl,
trifluoromethoxy, pyridinyloxy, difluoromethoxy or C ylsulfonyl;
X is -CH2-, -O-, –NH-, -CF2, -C(CH3)(OH)-, C=O, or -C(=N-C1-6alkoxy)-;
Y is -CH- or nitrogen;
Q is hydrogen; halogen; C1-6alkyl, once or twice tuted by hydroxy provided that
disubstitution of hydroxy is not on the same carbon; amino(CH2)2-6aminosulfonyl; 2-amino-4,5-
dihydro-1,3-oxazolylethyl; or NR12 R13 , wherein one of R12 and R13 is hydrogen, C1-6alkyl or
hydroxy(CH2)2-6, and the other one is guanidino(CH2)2-6; 3-aminomethyl-1,1-dioxidothietan
ylmethyl; 3-amino-1,1-dioxidothietanylmethyl; 3-(aminomethyl)thietanylmethyl;
amino(CH2)2O-(CH2)2-6; amino(CH2)2-10; amino(CH2)1-6carbonyl; amino(CH2)1-
6difluoromethyl(CH2)1-6; amino(CH2)1-6oxetanyl(CH2)1-6; amino(CH2)2-6sulfonyl(CH2)2-6; 3-
aminocyclohexyl; 4-aminocyclohexyl; 2-amino-4,5-dihydro-oxazolyl(CH2)1-6;
aminooxetanyl(CH2)1-6; C1-6alkylamino(CH2)2-6; kylaminocarbonyl; diC1-
-C1-6alkyl C R15
6alkylamino(CH2)2-6; hydroxy(CH2)2-6; zinyl(CH2)2-6; pyrrolidinyl; or ,
n R14 is hydrogen, C1-6alkyl or hydroxy(CH2)1-6; R15 is hydroxy, hydroxy(CH2)1-6 or
amino; and R16 is C1-6alkyl, y(CH2)1-6 or amino(CH2)1-6;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl,
piperazinyl or diazepanyl ring; which may be unsubstituted, once or twice substituted by a group
selected from C1-6alkyl, amino or hydroxy.
Another ular embodiment of invention is (xiii) a compound of formula (I) or a
pharmaceutically acceptable salt thereof, wherein
R1 is hydrogen or chloro;
R2 and R4 are hydrogen;
R3 is hydrogen or chloro;
R5 is hydrogen or fluoro;
R6 is hydrogen, fluoro, hydroxy, methoxy, ethoxy or carboxy;
R7 is en, fluoro, bromo, methoxy, dimethylaminocarbonyl, methylsulfonyl or
ulfonyl;
R8 is hydrogen or chloro.
A is CR11, wherein R11 is hydrogen, fluoro, chloro, bromo, methyl, methoxy,
trifluoromethyl, trifluoromethoxy, nyloxy, difluoromethoxy or methylsulfonyl;
Q is hydrogen; ; hydroxymethyl; hydroxymethyl(hydroxy)ethyl;
aminoethylaminosulfonyl; 2-amino-4,5-dihydro-1,3-oxazolylethyl; or NR12R13, wherein
one of R12 and R13 is hydrogen, methyl or yethyl, and the other one is aminobutyl; 3-
aminocyclohexyl; 4-aminocyclohexyl; 2-amino-4,5-dihydro-oxazolylmethyl; 3-amino-1,1-
dioxidothietanylmethyl; aminoethoxyethyl; aminoethyl; aminoethylsulfonylethyl;
aminomethylcarbonyl; aminomethyldifluoromethylmethyl; 3-aminomethyl-1,1-dioxidothietan
ylmethyl; nomethyl)thietanylmethyl; aminomethyloxetanylmethyl;
aminooxetanylmethyl; aminopropyl; dimethylaminoethyl; ethylaminocarbonyl; guanidinoethyl;
hydroxyethyl; hydroxypropyl; methylaminoethyl; piperazinylethyl; pyrrolidinyl; or
-C1-6alkyl C R15
R16 , wherein R14 is en, methyl or hydroxymethyl; R15 is hydroxy,
hydroxymethyl or amino; and R16 is methyl, hydroxymethyl or aminomethyl;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl,
piperazinyl or diazepanyl ring; which may be unsubstituted, once or twice substituted by a group
selected from methyl, amino or hydroxy; and all the remaining substituents are as defined above
in embodiment (xii).
A particular embodiment of present invention is a compound of formula (I) or a
pharmaceutically able salt thereof, selected from:
N-[(3-aminooxetanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)
quinolinamine; N-[2-(2-aminoethoxy)ethyl](5,5-difluoro-1,3,4,5-tetrahydro-2H
benzazepinyl)methylquinolinamine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H
benzazepinyl)methylquinolinyl]-N'-methylethane-1,2-diamine; 1-amino{[2-(5,5-
difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]amino}propanol; 3-
{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin
no}propane-1,2-diol; 3-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)
methylquinolinyl]amino}propanol; 2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepin
yl)methyl-N-[2-(piperazinyl)ethyl]quinolinamine; N~1~-[2-(5,5-difluoro-1,3,4,5-
tetrahydro-2Hbenzazepinyl)methylquinolinyl]propane-1,2-diamine; cis-N-[2-(5,5-
difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]cyclohexane-1,4-
diamine; 2-(9,9-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulenyl)methyl-N-(pyrrolidin
nolinamine; 2,2'-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)
methylquinolinyl]imino}diethanol; N~1~-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H
benzazepinyl)methylquinolinyl]methylpropane-1,2-diamine; 5,5-difluoro[6-
methyl(4-methylpiperazinyl)quinolinyl]-2,3,4,5-tetrahydro-1Hbenzazepine; 1-[2-
(9,9-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulenyl)methylquinolinyl]ethylurea;
N-{[3-(aminomethyl)oxetanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepin-
2-yl)methylquinolinamine; 5,5-difluoro[6-methyl(piperazinyl)quinolinyl]-
2,3,4,5-tetrahydro-1Hbenzazepine; 2-[4-(1,4-diazepanyl)methylquinolinyl]-5,5-
difluoro-2,3,4,5-tetrahydro-1Hbenzazepine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H
benzazepinyl)methylquinolinyl]-N-methylethane-1,2-diamine; 5,5-difluoro-
1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]pyrrolidinamine; 2-{[2-(5,5-
difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]amino}ethanol; N-[2-
(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]ethane-1,2-
diamine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin
yl]cyclohexane-1,3-diamine; N'-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)
methylquinolinyl]-N,N-dimethylethane-1,2-diamine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-
2Hbenzazepinyl)methylquinolinyl]propane-1,3-diamine; N-[2-(5,5-difluoro-1,3,4,5-
tetrahydro-2Hbenzazepinyl)methylquinolinyl]butane-1,4-diamine; trans amino
[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]pyrrolidinol;
N-{[3-(aminomethyl)-1,1-dioxidothietanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H
benzazepinyl)methylquinolinamine; N-{2-[(2-aminoethyl)sulfonyl]ethyl}(5,5-
difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinamine; N-{[3-
(aminomethyl)thietanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)
methylquinazolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}(5,5-difluoro-1,3,4,5-
tetrahydro-2Hbenzazepinyl)methylquinazolinamine; nomethyl)({[2-(5,5-
ro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinazolin
yl]amino}methyl)propane-1,3-diol; 2-(4-{[(3-aminooxetanyl)methyl]amino}
methylquinazolinyl)methyl-2,3,4,5-tetrahydro-1Hbenzazepinol; N-[(3-aminooxetan-
3-yl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinazolin
amine; N-[(3-amino-1,1-dioxidothietanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2H
benzazepinyl)methylquinazolinamine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H
benzazepinyl)methylquinazolinyl]-2,2-difluoropropane-1,3-diamine; N-[2-(7-bromo-
1,3,4,5-tetrahydro-2Hbenzazepinyl)chloroquinolinyl]ethane-1,2-diamine; 2-{4-[(2-
aminoethyl)amino]quinolinyl}-2,3,4,5-tetrahydro-1Hbenzazepinol; ethyl
(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; N-[2-(8-fluoro-
1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]ethane-1,2-diamine; N-[6-
chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; N-[6-
chloro(9-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine;
N-[2-(8-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; 1-
amino{[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]amino}propanol
trifluoroacetate; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-
diamine; N-[6-bromo(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-
e; N-[6-methoxy(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-
e; N-[2-(6-chloro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-
diamine; N-[2-(7-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin
yl]ethane-1,2-diamine; N-methyl-N'-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin
yl]ethane-1,2-diamine; 7-methoxy-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin
yl]ethane-1,2-diamine; N-[2-(7-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin
yl]ethane-1,2-diamine; N-[2-(8-methoxy-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin
ane-1,2-diamine; N-[6-(difluoromethoxy)(1,3,4,5-tetrahydro-2Hbenzazepin
nolinyl]ethane-1,2-diamine; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)
(trifluoromethyl)quinolinyl]ethane-1,2-diamine; N-[8-chloro(1,3,4,5-tetrahydro-2H
benzazepinyl)quinolinyl]ethane-1,2-diamine; N-[6-fluoro(1,3,4,5-tetrahydro-2H
epinyl)quinolinyl]ethane-1,2-diamine; N,N-dimethyl-N'-[2-(1,3,4,5-tetrahydro-2H-
2-benzazepinyl)quinolinyl]ethane-1,2-diamine; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepin-
2-yl)(trifluoromethoxy)quinolinyl]ethane-1,2-diamine; N-[6-(methylsulfonyl)(1,3,4,5-
tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; 2-{4-[(2-
aminoethyl)amino]quinolinyl}-2,3,4,5-tetrahydro-1Hbenzazepinecarboxylic acid; 2-(4-
chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine; N-[5-chloro(1,3,4,5-tetrahydro-
enzazepinyl)quinolinyl]ethane-1,2-diamine; N-{2-[7-(methylsulfonyl)-1,3,4,5-
tetrahydro-2Hbenzazepinyl]quinolinyl}ethane-1,2-diamine; N-{2-[7-(ethylsulfonyl)-
1,3,4,5-tetrahydro-2Hbenzazepinyl]quinolinyl}ethane-1,2-diamine; N-[2-(8-ethoxy-
1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; N-[6-(pyridin
yloxy)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; (2-
aminoethyl)amino]chloroquinolinyl}-N,N-dimethyl-2,3,4,5-tetrahydro-1Hbenzazepine-
7-carboxamide; 2-{4-[(2-aminoethyl)amino]quinolinyl}bromo-1,2,4,5-tetrahydro-3H
benzazepinone; 1-(2-{[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin
yl]amino}ethyl)guanidine trifluoroacetate; N-[(2-amino-4,5-dihydro-1,3-oxazolyl)methyl]
(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinamine trifluoroacetate; N-[(2-amino-4,5-
dihydro-1,3-oxazolyl)methyl]chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin-
4-amine; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]glycinamide; 3-[2-
(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propanamine; [2-(1,3,4,5-tetrahydro-
2Hbenzazepinyl)quinolinyl]methanol; 2-(6-chloroquinolinyl)-2,3,4,5-tetrahydro-1H-
2-benzazepine; 3-[6-chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propane-
ol; (4S ){2-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethyl}-4,5-
dihydro-1,3-oxazolamine; minoethyl)(1,3,4,5-tetrahydro-2Hbenzazepin
yl)quinolinesulfonamide trifluoroacetate; 4-{4-[(2-aminoethyl)amino]methylquinolin
yl}-1,3,4,5-tetrahydro-2H-1,4-benzodiazepinone; N-[6-methyl(1,2,3,5-tetrahydro-4H-1,4-
iazepinyl)quinolinyl]ethane-1,2-diamine; N-[2-(2,3-dihydro-1,4-benzoxazepin-
4(5 H)-yl)quinolinyl]ethane-1,2-diamine; N-[(3-aminooxetanyl)methyl][(5 E)
(methoxyimino)-1,3,4,5-tetrahydro-2Hbenzazepinyl]methylquinolinamine and 2-(4-
{[(3-aminooxetanyl)methyl]amino}methylquinazolinyl)-1,2,3,4-tetrahydro-5H
benzazepinone.
The compounds of the present invention can be prepared by any conventional means.
Suitable processes for synthesizing these compounds as well as their starting materials are
provided in the schemes below and in the examples. All substituents, in particular, R1 to R10 , A,
Q, X and Y are as defined above unless otherwise indicated. rmore, and unless explicitly
otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings
well known to a person of ordinary skill in organic chemistry.
Abbreviations
DMSO-d6: deuterated dimethylsulfoxide
FBS: fetal bovine serum
g: gram
µg: microgram
EC50: the concentration of a compound where 5 0% of its l protection effect
against viral induced CPE is observed
HPLC: high performance liquid chromatography
Hz: Hertz
CDCl3 deuterated form
CD3OD: deuterated methanol
mg: milligram
MHz: rtz
mL: milliliter
mmol: millimole
obsd. Observed
µL: microliter
µm: micrometer
µM: micromoles per liter
mm: millimeter
MS (ESI): mass spectroscopy (electron spray tion)
NMR: nuclear magnetic resonance
TLC: thin layer chromatography
General synthetic route for 2,4-dihalogen quinolines IIIa (Scheme 1)
Scheme 1
OH O
O OH R3 E
POE3
A VI A
R2 N E
R2 NH2
VII IIIa
E is Cl or Br
nds of st of formula IIIa can be prepared according to Scheme 1. Starting
with various VII, cyclization reaction with propanedioic acid in the presence of VI affords 2,4-
dihalogen-quinolines IIIa. The reaction can be d out at a temperature between 100 °C and
150 °C for 6 to 12 hours. VI can be phosphoryl trichloride or phosphoryl tribromide.
General synthetic route for 2,3,4,5-tetrahydro-1,4-benzothiazepines (Scheme 2)
Scheme 2
O O
OH NH2.HCl
R6 H
R6 R6
O N
SH R7
SH R7 S R7
R8 R8
VIIIa
X IXa
H H
N R6 N R6
N R6
S R7 S R7
S R7
R8 R8
O R8
N R6
S R7
O O R8
Compounds of interest IVa, IVb, IVc and IVd can be ed ing to Scheme 2.
Starting with 2-sulfanylbenzoic acids X, fication with methanol gives methyl 2-
sulfanylbenzoates IXa. Annulation of esters IXa with 2-bromo ethylamine affords 3,4-dihydro-
1,4-benzothiazepin-5(2H)-ones VIIIa. ion of VIIIa affords 2,3,4,5-tetrahydro-1,4-
benzothiazepines IVa. Acylation of IVa generates amides IVb. Oxidation of IVb followed by
deacylation affords compounds of interest IVc and IVd.
Methyl 2-sulfanylbenzoates IXa can be prepared by esterification of 2-sulfanylbenzoic
acids X. The conversion can be achieved by heating under reflux in the presence of sulfuric acid
in methanol overnight or stirring with thionyl chloride in methanol at room temperature for
several hours.
3,4-Dihydro-1,4-benzothiazepin-5(2 H)-ones VIIIa can be ed from methyl 2-
sulfanylbenzoates IXa by tion with 2-bromo-ethylamine hydrochloride. The reaction can
be carried out with a standard basic agent such as sodium hydride, potassium tert -butoxide in a
le organic solvent such as tetrahydrofuran, 1,4-dioxane, N,N -dimethylformamide or
mixtures thereof, lly at 0 ºC, followed by stirring at room temperature overnight.
2,3,4,5-Tetrahydro-1,4-benzothiazepines IVa can be prepared by reduction of 3,4-
dihydro-1,4-benzothiazepin-5(2 H)-ones VIIIa . The reaction can be d out with a standard
reducing agent such as lithium aluminium hydride, boron hydride or combination of sodium
borohydride and boron trifluoride in a suitable inert organic solvent such as tetrahydrofuran,
diethyl ether or mixtures thereof, typically at 0 ºC, followed by stirring at a temperature between
ºC and 70 ºC for several hours.
Amides IVb can be prepared by acylation of IVa with acetyl chloride or acetic anhydride.
The reaction can be carried out with a suitable base such as triethylamine or pyridine in a
suitable inert organic solvent such as dichloromethane, tetrahydrofuran or pyridine at 0 ºC,
ed by stirring at room temperature for 30 minutes.
Compounds IVc can be prepared by oxidation of IVb followed by deacylation. Oxidation
can be carried out with 1-2 lents of 3-chloroperoxybenzoic acid, in a suitable t such
as dichloromethane, chloroform, 1,2-dichloroethane, or the mixture thereof, lly at 0 ºC,
followed by stirring at room temperature for 10 to 20 minutes. Deacylation can be achieved by
stirring amides with a suitable base such as sodium hydroxide or potassium hydroxide in a
mixture of alcohol such as methanol or l and water under reflux overnight.
Compounds IVd can be prepared by oxidation of IVb followed by deacylation. Oxidation
can be d out with 4 equivalents of roperoxybenzoic acid, in a suitable solvent such as
dichloromethane, chloroform, 1,2-dichloroethane, or the mixture thereof, typically at 0 ºC,
followed by stirring at room ature for 1 to 2 hours. Deacylation can be ed by
stirring amides with a suitable base such as sodium hydroxide or potassium hydroxide in a
mixture of alcohol such as methanol or ethanol and water under reflux overnight.
General synthetic route for 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepines (Scheme 3)
Scheme 3
R6 N R6 H
O NH2.HCl N R6
SH R7 S R7
S R7
R8 R8
IXb VIIIb IVe
Compounds of st IVe can be ed ing to Scheme 3. Starting from 1-(2-
sulfanylphenyl)ethanones IXb, annulation of esters IXb with 2-bromo ethylamine hydrochloride
affords 5-methyl-2,3-dihydro-1,4-benzothiazepines VIIIb. Reduction of VIIIb affords 5-methyl-
2,3,4,5-tetrahydro-1,4-benzothiazepines IVe.
-Methyl-2,3-dihydro-1,4-benzothiazepine VIIIb can be prepared from 1-(2-
sulfanylphenyl)ethanones IXb by tion with 2-bromo-ethylamine. The reaction can be
carried out with a standard basic agent such as sodium hydride, potassium tert-butoxide in a
suitable organic solvent such as tetrahydrofuran, oxane, N,N-dimethylformamide or
mixtures thereof, typically at 0 ºC, followed by ng at room temperature overnight.
-Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepines IVe can be prepared from reduction of
-methyl-2,3-dihydro-1,4-benzothiazepines VIIIb. The reaction can be carried out with a
reducing reagent such as sodium borohydride in a suitable organic solvent such as methanol,
water or mixtures thereof at room temperature for several hours or ght, followed by
treatment with concentrated hydrochloric acid at room temperature for 30 minutes. After
neutralization with sodium carbonate or sodium hydroxide, free form of IVe is obtained.
General synthetic route for formulas Iaa (Scheme 4)
Scheme 4
R4 R6
R3 E
R3 E NH
R7 A R4 R6
S R8 R2 N N
IVf R7
R2 N E R1
IIac
R1 S
IIIa R8
N L1
N R3 E
R3 NH W1
NH W1
2 A R4 R6
A R4 R6 Va
R2 N N
R2 N N R7
R7 R1
R1 IIaa IIab S O
R8 O
R3 NH W1
A R6
R2 N N
E is Cl or Br,
W1 is (oxetanyl)C1-4 alkyl, (tetrahydrofuranyl)C1-4alkyl, hydro-2H-pyranyl)C1-4alkyl, or
(C3-6cycloalkyl)C1-4alkyl
L1 is H or benzyl,
or L1 and W1 with the nitrogen atom to which they are attached form 2-Oxaaza-spiro[3.4]octyl
Compounds of interest Iaa can be prepared ing to Scheme 4. Coupling of 2,4-
dihalogen quinolines IIIa with benzothiazepines IVf followed by oxidation gives 4-halogen
quinolines IIab. Coupling of 4-halogen quinolines IIab with various benzyl diamines Va
followed by debenzylation generates Iaa.
Quinolines IIac can be ed by ng of 2,4-dihalogen ines IIIa with
benzothiazepines IVf. The reaction can be carried out with or t a solvent such as
isopropanol, n-butanol, tert-butanol or the mixture thereof at a temperature between 120 oC and
180 oC, typically at 160 ºC under microwave irradiation for several hours.
Sulfones IIab can be prepared by oxidation of sulfides IIac. The reaction can be carried
out with a suitable oxidant such as 3-chloroperoxybenzoic acid in a suitable inert organic solvent
such as dichloromethane typically at 0 ºC, followed by stirring at room temperature for several
hours. Alternatively, the reaction can be d out with a suitable oxidant such as hydrogen
peroxide, sodium periodate or potassium permanganate, in a suitable solvent such as methanol,
tetrahydrofuran, water or the e thereof, typically at 0 ºC, followed by stirring at a
temperature between room temperature and 70 ºC for several hours.
4-Benzyl diamino quinolines IIaa can be prepared by coupling of quinolines IIab with
various benzyl es Va . The on can be carried out in the presence of a palladium
catalyst such as 1,1'-bis(diphenylphosphino)ferrocene-palladium (II), palladium (II) acetate,
tri(dibenzylideneacetone)dipalladium(0), or ium (II) chloride in the presence of a
phosphine ligand such as triphenyl phosphane, 1,1'-bis(diphenylphosphino)ferrocene, 9,9-
dimethyl-4,5-bis(diphenylphosphino)xanthene, or tricyclohexylphosphine, with a suitable base
such as sodium carbonate, potassium carbonate, cesium carbonate, sodium utoxide or
potassium tert -butoxide, in a suitable inert organic solvent such as toluene, 1,4-dioxane,
tetrahydrofuran or N,N -dimethylformamide at a temperature between 100 ºC and 160 ºC for 1 to
3 hours under microwave irradiation. Alternatively, the reactions can be carried out at a heated
ature such as between 100 ºC and 140 ºC for a longer reaction time without microwave
irradiation.
Compounds of interest Iaa can be prepared by standard debenzylation of IIaa . The
reaction can be carried out in the ce of palladium on carbon, palladium ide on
carbon or platinum oxide, typically with an acid such as hydrochloric acid, acetic acid or
trifluoroacetic acid in a suitable solvent such as methanol, ethanol, tetrahydrofuran, ethyl acetate
or the mixture thereof, at room temperature for several hours under hydrogen atmosphere.
General synthetic route for formula Iab and Iac (Scheme 5)
Scheme 5
R3 E R12 R13
R12 R13 R3 N
A R4 R6 N
H A R4 R6
R2 N N XI
R1 R2 N N
IIac R7
S R8 R1 Iab
R12 R13
R3 E
R12 R13 R3 N
A R4 R6 H A R4 R6
R2 N N
R7 R2 N N
R1 R1
IIab S O Iac
R8 S O
O O
E is Cl or Br
Compounds of interest Iab and Iac can be prepared according to Scheme 5. Coupling of
4-halogen quinolines IIac with various amines XI affords Iab. Coupling of 4-halogen quinolines
IIab and various amines XI affords 4-amino quinolines Iac. Alternatively, Iac can be obtained
by oxidation of the es Iab.
4-Amino ines Iab can be prepared by coupling of 4-halogen quinolines IIac with
various amines XI in the presence or absence of a palladium catalyst. Palladium-catalyzed
coupling reaction can be carried out in the presence of a palladium catalyst such as 1,1'-
phenylphosphino)ferrocene-palladium(II)dichloride, palladium acetate or
tris(dibenzylideneacetone) dipalladium(0), in combination with a phosphine ligand such as 1,1’-
bis(diphenylphosphino)ferrocene, 2,2’-bis(diphenylphosphino)-1,1’-binaphthalene, 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene or 2-dicyclohexylphosphino-2'-(N,N-
dimethylamino)biphenyl, and a base such as sodium tert-butoxide, cesium carbonate or
potassium phosphate in a suitable solvent such as 1,4-dioxane or toluene, at a temperature
between 100 °C and 140 °C for 1 to 2 hours under ave irradiation. atively,
palladium-catalyzed coupling reaction can be carried out at an ed temperature such as 110
°C or 120 °C without microwave irradiation for a longer on time. Coupling of 4-halogen
quinolines IIac with various amines XI in the absence of a ium catalyst can be carried out
with a suitable base such as N,N-diisopropylethylamine or without any base in a suitable solvent
such as n-butanol, 1-methylpyrrolidinone or phenol, at a temperature between 130 °C and 160
°C for 1.5 to 2 hours under microwave irradiation. Alternatively, the reaction can be carried out
at an elevated temperature between 150 °C and 180 °C t microwave irradiation for a
longer reaction time. Alternatively, the reaction can also be carried out without any base and
without any t at 160 °C for one to several hours under microwave irradiation.
4-Amino quinolines Iac can be prepared by coupling of 4-halogen quinolines IIab with
various amines XI in the presence of a metal catalyst such as a palladium catalyst or copper (I)
iodide, or absence of a metal catalyst. Coupling of 4-halogen quinolines IIab with various
amines XI in the presence of a palladium catalyst or in the e of any metal catalyst can be
carried out in analogy to coupling of 4-halogen quinolines IIac with various amines XI .
Copper(I) iodide catalyzed coupling of 4-halogen quinolines IIab with various amines XI can be
carried out in the ce of copper(I) iodide with a ligand such as N,N' -dimethylcyclohexane-
1,2-diamine or cyclohexane-1,3-diamine, and a base such as potassium ate or potassium
phosphate in a suitable solvent such as 1,4-dioxane or diethylene glycol dimethyl ether, at a
temperature between 140 °C and 150 °C for 2 to 3 hours under microwave irradiation.
Alternatively, the reaction can be d out at an elevated temperature without microwave
ation for a longer reaction time.
Alternatively, 4-Amino quinolines Iac can be prepared from oxidation of sulfides Iab .
The reaction can be d out in analogy to oxidation of ines IIac in Scheme 4.
General synthetic route for formula Iad (Scheme 6)
Scheme 6
R4 R6
R3 E
R3 E S R8
O A R4 R6
A m
IVg R2 N N
R2 N E R7
R1 IIIa IIad S
R12 R13
R12 R13
R3 N
A R4 R6
E is Cl or Br; R2 N N
m is 1 or 2. R1
Iad S
Compounds of interest Iad can be prepared according to Scheme 6. Coupling of 2,4-
halogen quinolines IIIa with benzothiazepines IVg affords 2-benzothiazepinhalogen
ines IIad. Coupling of IIad with various amines XI affords compounds of interest Iad.
2-Benzothiazepinhalogen quinolines IIad can be prepared from coupling of 2,4-
halogen quinolines IIIa with benzothiazepines IVg. The reaction can be carried out in the
absence of t or in a suitable solvent such as isopropanol, n-butanol, tert-butanol or the
mixtures thereof at a temperature between 120 oC and 180 oC, typically at 160 ºC under
microwave irradiation for several hours.
Compounds of interest of formula Iad can be prepared from coupling of 2-
benzothiazepinhalogen quinolines IIad with s amines XI. The on can be carried
out in the ce of a metal catalyst or in the absence of a metal catalyst in analogy to coupling
of 4-halogen ines IIab with various amines XI in Scheme 5.
General synthetic route for formula Iae, Iaf and Iag (Scheme 7)
Scheme 7
R3 NH2
R3 NH O
A R4 R6
A R4 R6
R2 N N
R2 N N R1
R7 X
R1 Iae R8
IIaf X R8
NH O L3 N
2 O
H L2
L3 N O
R3 E L2 O
R3 N
A R4 R6
H A R4 R6
R2 N N
R7 XII
R2 N N
R1 R7
IIae X R1
R8 IIag X R8
L5 O
L4 N
N W2
H O
XIII
L3 NH
R3 N
N O
A R4 R6
L4 W2
R3 N
R2 N N
A R4 R6 R1
Iaf X R8
R2 N N
R7 L5
R1 NH
IIah X L4
R8 W2
R3 N
A R4 R6
R2 N N
Iag X
E is Cl or Br;
L2 is hydrogen;
L3 is hydrogen, hydroxy or fluoro;
L2 and L3 are attached to form 3-oxetanyl;
L4 is hydrogen,or ; L5 is hydrogen;
W2 is ethyl, methylcyclopropyl, ethylcyclopropyl, or (morpholinyl)methyl
L4 and W2 with nitrogen they are attached to form azetidinyl, 2-azabicyclo[2.1.1]hexanyl or
(1R,5S,6S)azabicyclo[3,1,0]hexanyl
L5 and W2 with nitrogen they are attached to form pyrrolindinyl, azetidinyl, methylazetidinyl,
azetidinyl-carbonyl or pyrrolindinyl-carbonyl.
nds of st Iae, Iaf and Iag can be prepared according to Scheme 7. Coupling
of 4-halogen quinolines IIae with various protected amines affords intermediates IIaf, IIag and
IIah. Deprotection of IIaf, IIag and IIah affords compounds of interest Iae, Iaf and Iag.
Compounds of interest IIaf, IIag and IIah can be prepared from ng of 4-halogen
quinolines IIae with various protected amines. Coupling of 4-halogen quinolines IIae with
various amines such as tert-butyl carbamate, XII or XIII can be carried out in the presence of a
metal catalyst or in the absence of a metal catalyst in analogy to coupling of gen
quinolines IIab with various amines XI in Scheme 5.
Compounds of interest Iae, Iaf and Iag can be prepared from deprotection of tertbutyloxycarbonyl
of IIaf, IIag and IIah. The reaction can be carried out with a suitable acid
such as oroacetic acid or hydrochloric acid in a suitable solvent such as dichloromethane,
ethyl acetate or 1,4-dioxane, at 0 °C to room temperature for 4 to 16 hours.
General tic route for formula Iah (Scheme 8)
Scheme 8
L6 N Cbz
R3 E R3 NH
N Cbz
A R4 R6 NH
2 A R4 R6
R2 N N
R7 R2 N N
IIae R1
X IIai
R8 X R8
R3 NH
A R4 R6
Q is Cl or Br, R2 N N
L6 is hydroxy or fluoro
X R8
Compounds of st Iah can be prepared according to Scheme 8. Coupling of 4-
halogen quinolines IIae with s protected amines XIV affords intermediates IIai.
Deprotection of benzyloxycarbonyl of IIai affords compounds of interest Iah.
Compounds IIai can be prepared from coupling of 4-halogen quinolines IIae with
various amines XIV. The reaction can be carried out in the ce of a metal catalyst or in the
absence of a metal catalyst in analogy to coupling of 4-halogen quinolines IIab with s
amines XI in Scheme 5. Typically, the reaction can be carried out in the presence of
tris(dibenzylideneacetone)dipalladium(0) with 2-dicyclohexylphosphino-2'-(N,N-
dimethylamino)biphenyl, and sodium tert-butoxide in a suitable solvent such as 1,4-dioxane, at
120 °C for 2 hours under microwave irradiation.
Compounds of interest Iah can be prepared from deprotection of benzyloxycarbonyl of
IIai. The conversion can be achieved under strong acidic conditions, under basic conditions or
by hydrogenation. ng IIai with a mixture of aqueous solution of potassium hydroxide and
methanol under reflux for 30 minutes to several hours can generate Iah. Treating IIai under
strong acidic conditions such as reflux in 6 N hydrochloride in ol for several hours can
also generate Iah. Hydrogenation of IIai can be carried out in the presence of palladium on
carbon or palladium black, under hydrogen atmosphere or with a hydrogen donor such as formic
acid or ammonium formate, in a suitable solvent such as ol or ethanol, at a temperature
between room ature and 80 ºC for 15 minutes to several hours.
General synthetic route for formula Iai and Iaj (Scheme 9)
Scheme 9
R3 E
O R5
R4 R6
R2 N N
IIaj
X R8
R3 E R3 NH NH
OH R5
R4 R6 OH R5
R4 R6
NH NH
2 2
R2 N N
R7 R2 N N
R1 IIak R1
X R8 Iai X R8
L7 Br
L7 R3 E
L7 R3 N NH2
O R5
R4 R6 O R5
NH R4 R6
R2 N N
R7 R2 N N
R1 R7
IIam R1
X R8 Iaj X R8
E is Cl or Br,
L7 is hydroxyethyl, methoxyethyl or pyridinyl
Compounds of interest Iai and Iaj can be prepared according to Scheme 8. Demethylation
of 6-methoxy quinolines IIaj affords 6-hydroxy ines IIak. Reaction of IIak with bromides
XV s IIam. ng of 6-hydroxy quinolines IIak with propane-1,3-diamine affords
compounds of interest Iai. Coupling of IIam with e-1,3-diamine affords compounds of
interest Iaj.
6-Hydroxy quinolines IIak can be prepared by ylation of 6-methoxy quinolines
IIaj. The reaction can be carried out in an aqueous solution of hydrobromic acid by heating
under reflux for 2 days.
IIam can be prepared by reaction of IIak with bromides XV. When L7 is pyridinyl,
the reaction can be carried out in the presence of a metal catalyst such as Copper(I) iodide with a
ligand such as imethylcyclohexane-1,2-diamine and with a suitable base such as
potassium carbonate in a suitable solvent such as methoxyethane at 120 °C for 1 hours
under microwave irradiation. When L7 is substituted alkyl such as hydroxyethyl or
methoxyethyl, the reaction can be carried out in the presence of a suitable base such as potassium
carbonate in a suitable solvent such as acetone at room temperature overnight.
Compounds of interest Iai and Iaj can be prepared by coupling of IIak and IIam with
propane-1,3-diamine tely. The reaction can be carried out at 150 °C for 1.5 hours under
microwave irradiation.
General synthetic route for formula Iak (Scheme 10)
Scheme 10
O O
R3 E
R3 NH
A R4 R6 NH
2 A R4 R6
R2 N N
R7 R2 N N
R1 R7
IIae X R1
R8 IIan X R8
R3 NH
A R4 R6
R2 N N
E is Cl or Br, R7
Iak X R8
Compounds of interest Iak can be prepared according to Scheme 10. Coupling of 4-
halogen quinolines IIae with C-(2,2-dimethyl-[1,3]dioxolanyl)-methylamine ed by
deprotection s 4-(2,3-diol-propylamino)-quinolines Iak.
IIan can be obtained by coupling of 4-halogen quinolines IIae with C-(2,2-dimethyl-
[1,3]dioxolanyl)-methylamine. The reaction can be carried out in y to coupling of 4-
n quinolines IIab with various amines XI in Scheme 5. Typically the reaction can be
carried out by heating a mixture of 4-halogen quinolines IIae and C-(2,2-dimethyl-
[1,3]dioxolanyl)-methylamine at 160 oC for 16 hours.
4-(2,3-Diol-propylamino)-quinolines Iak can be prepared by ection of IIan. The
reaction can be carried out in the presence of an acid such as hydrochloric acid in a suitable
solvent such as methanol, ethanol, water or mixtures thereof at room temperature for several
hours.
General synthetic route for formula Ial (Scheme 11)
Scheme 11
O N O N
R3 NH
N R3 NH W3
A R4 F
XVI A R4 N
R2 N N
R7 R2 N N
IIao R1
S O IIap
R8 S O
O O
O NH
R3 NH W3
A R4 N
R2 N N
W3 is O or NCH(CH3) R7
2 R1
O
Compounds of interest Ial can be prepared according to Scheme 11. Coupling of fluorides
IIao with amines XVI followed by debenzylation affords compounds of interest Ial .
Quinolines IIap can be prepared from coupling of fluorides IIao (which can be prepared in
analogy to 4-benzyl o quinolines IIaa in Scheme 4) with amines XVI. The reaction can
be carried out by heating a mixture of fluorides IIao and amines XVI with a suitable solvent
such as N,N -dimethyl ide, N,N -dimethyl acetamide, N-methylpyrrolidinone, dimethyl
ide or the mixtures thereof, or without any solvent at a temperature between 100 oC and
150 oC, typically at 120 ºC under ave irradiation for several hours.
Compounds of interest Ial can be prepared by standard benzyl deprotection of IIap . The
reaction can be d out in analogy to debenzylation of IIaa in Scheme 4.
General synthetic route for formula Iam and Ian (Scheme 12)
Scheme 12
R3 E
A R4 R6
R2 N N
IIaq S O
R3 E
A R4 R6
R2 N N
IIar S O
R3 E
R3 E
A R4 R6
A R4 R6
R2 N N
O R2 N N
R1 O
IIas S O
R8 IIau S O
O R8
N O
R3 NH R3 NH O
R4 R6 A R4 R6
R2 N N R2 N N
O O
R1 R1
IIat S O IIav S O
R8 R8
O O
R3 NH
R3 NH
A R4 R6
A R4 R6
R2 N N
O R2 N N
R1 O
Iam S O R1
R8 Ian S O
O R8
E is Cl or Br,
Compounds of interest Iam and Ian can be prepared according to Scheme 12.
Demethylation of IIaq affords IIar. Coupling of IIar with iodobenzene affords 4-phenoxy
benzothiazepines IIas. ng of IIas with (3-aminomethyl-oxetanyl)-dibenzylamine
followed by debenzylation provides 4-[(3-amino-oxetanylmethyl)-amino]quinolines Iam .
Coupling of IIar with 3-bromo-propanol affords IIau . Coupling of 4-halogen quinolines IIau
with carbamic acid tert -butyl ester followed by deprotection of tert -butyloxycarbonyl s 4-
amino quinolines Ian .
IIar can be ed by demethylation of IIaq . The reaction can be carried out by
treating IIaq with a suitable Lewis acid such as tribromoborane, aluminum chloride, aluminum
bromide, and stannous chloride in a dry organic inert solvent such as dichloromethane,
chloroform, acetonitrile and N,N -dimethylformamide at a temperature between 0 and 80 °C,
lly at 0 oC, for a period of 5 minutes to 3 hours, typically for 1 hour.
IIas can be obtained by coupling of IIar with iodobenzene. The reaction can be carried
out by heating in the ce of copper(I) iodide or copper(I) bromide, with a ligand such as
N,N -dimethylglycine hydrochloride, (2-pyridyl)acetone or tris(hydroxymethyl)ethane, and
a base such as cesium ate, potassium carbonate, or potassium phosphate, in an organic
solvent such as dimethyl sulfoxide, N,N -dimethylformamide, acetonitrile or 1,4-dioxane at a
ature between 80 oC and 120 oC for 4 to 24 hours. Typically, the reaction can be d
out by g in the presence of copper(I) iodide, N,N -dimethylglycine hydrochloride and
potassium carbonate in dimethyl sulfoxide at 120 oC for 6 hours.
Iam can be obtained by coupling of IIas with (3-aminomethyl-oxetanyl)-dibenzylamine
followed by debenzylation. The reactions can be conducted in analogy to preparation of Iaa from
IIab in Scheme 4. Typically, coupling of IIas with (3-aminomethyl-oxetanyl)-dibenzylamine
can be carried out in the presence of bis(diphenylphosphino)-ferrocenedichloropalladium(II),
1,1'-bis(diphenylphosphino)-ferrocene and sodium-tert -butoxide in 1,4-dioxane at 120 oC for 2
hours under microwave irradiation. Debenzylation of IIat can be achieved by stirring a solution
of IIat in methanol in the presence of palladium hydroxide on carbon and oroacetic acid at
room temperature under 2 bar of hydrogen atmosphere for 14 hours.
IIau can be prepared by coupling of IIar with 3-bromo-propanol. The reaction can be
d out with a suitable base such as potassium ate, cesium carbonate, sodium tert -
butoxide, potassium tert -butoxide, sodium hydride or 1,8-diazabicyclo[5.4.0]undecene in an
inert organic solvent such as dichloromethane, N,N -dimethylformamide, dimethyl sulfoxide or 1-
methyl-pyrrolidinone at a temperature between room temperature and 100 oC, typically at 70
oC for several hours.
IIav can be prepared by coupling of 4-halogen quinolines IIau with carbamic acid tert-
butyl ester. The reaction can be carried out in the presence of a palladium catalyst in analogy to
coupling of 4-halogen quinolines IIab with various amines XI in Scheme 5. Typically the
reaction can be carried out by heating a mixture of 4-halogen quinolines IIau and carbamic acid
tert-butyl ester in the presence of bis(diphenylphosphino)ferrocenedichloropalladium(II), with
1,1'-bis(diphenylphosphino)ferrocene and sodium-tert-butoxide in 1,4-dioxane at 120 oC for 2
hours.
4-Amine quinolines Ian can be obtained by standard deprotection of tyloxycarbonyl
of IIav. The reaction can be carried out by treating IIav with a suitable acid
such as hydrochloric acid, oroacetic acid, or ic acid in a suitable t such as
methanol, ethyl acetate, romethane, 1,4-dioxane, water or the mixtures f at a
temperature between 0 ºC and room temperature for 30 minutes to several hours. Typically the
reaction can be carried out by treating IIav with trifluoroacetic acid in dichloromethane at room
temperature for 6 hours.
General synthetic route for formula Iao (Scheme 12)
Scheme 12
O OH
O OH
R3 E W4
W4 R3 NH
R4 R6 NH
A 2
XVII A R4 R6
R2 N N
R7 R2 N N
R1 R7
IIab S O R1
R8 IIaw
O S O
O N O O
W4 W4
R3 NH R3 NH
A R4 R6 A R4 R6
R2 N N R2 N N
R7 R7
R1 R1
Iao IIax
S O S O
R8 R8
O O
E is Cl or Br;
W is CH2, CH(CH3), CH2CH(CH3), or CH(CH3)CH2;
L8 is H or CH3.
Compounds of interest Iao can be prepared according to Scheme 13. Coupling of 4-
halogen quinolines IIab with various amino acids XVII gives acids IIaw . Esterification of acids
IIaw followed by aminolysis affords amides Iao .
Acids IIaw can be prepared by coupling of 4-halogen-quinolines IIab with amino acids
XVII . The reaction can be carried out in phenol, preferably at 150 °C in a sealed tube overnight.
Esters IIax can be ed by esterification of carboxylic acids IIaw . The reaction can
be carried out by heating IIaw and methanol in the presence of a suitable catalyst such as
concentrated sulfuric acid, dry hydrochloride gas, or thionyl chloride for several hours. Typically
the reaction can be d out by g IIaw and methanol in the presence of thionyl chloride
under reflux for 2 hours.
Amides Iao can be prepared by aminolysis of methyl esters IIax . The on can be
carried out by heating methyl esters IIax with various concentrated amines in alcohol, such as
7N ammonia in ol or 33% (wt%) methyl amine in absolute ethanol. The reaction can be
preferably carried out at 85 °C in a sealed tube overnight.
General tic route for formula Iap (Scheme 14)
Scheme 14
O N
R3 E O
R3 NH
A R4 R6 NH
A R4 R6
R2 N N
R7 R2 N N
R1 R7
IIab S O R1
O IIay S O
R3 NH
A R4 R6
R2 N N
Iap S O
Compounds of interest Iap can be prepared according to Scheme 14. Coupling of 4-
halogen quinolines IIab with 4-aminomethyl-2,2-dimethyl-oxazolidinecarboxylic acid tertbutyl
ester affords IIay. Cleavage of utyloxycarbonyl and acetal tes amino alcohols
Iap.
Oxazolidines can be prepared by coupling of 4-halogen quinolines IIab with 4-
aminomethyl-2,2-dimethyl-oxazolidinecarboxylic acid utyl ester. The reaction can be
carried out in the presence of a palladium catalyst in analogy to coupling of 4-halogen quinolines
IIab with various amines XI in Scheme 5. Typically the reaction can be carried out by heating a
mixture of 4-halogen quinolines IIab and 4-aminomethyl-2,2-dimethyl-oxazolidinecarboxylic
acid utyl ester in the presence of bis(diphenylphosphino)ferrocenedichloropalladium(II),
with 1,1'-bis(diphenylphosphino)ferrocene and sodium-tert-butoxide in 1,4-dioxane at 120 oC for
1.5 hours.
Amino ls Iap can be prepared by acid catalyzed cleavage of tert-butyloxycarbonyl
and acetal of acetonides IIay. The reaction is typically carried out in a solution of hydrochloride
in ethyl e for several hours at room temperature.
General synthetic route for formula Iar (Scheme 15)
Scheme 15
NH 2
2 N
R3 NH
R3 NH
A R4 R6 R5
A R4 R6
R2 N N
R7 R2 N N
R1 R7
Iaq X
R8 Iar X
L9 is H or CH3,
Compounds of interest Iar can be ed according to Scheme 15. Starting with amino
alcohols Iaq (prepared in ue to Idj in Scheme 56), ring closure with cyanogen bromide
gives oxazoles Iar. The reaction can be carried out with a suitable base such as sodium acetate,
sodium carbonate, potassium acetate or ium carbonate, in a suitable solvent such as
methanol, water, or the mixtures thereof, typically at 0 ºC, followed by stirring at room
temperature for several hours.
General synthetic route for formula Iat (Scheme 16)
Scheme 16
2 W5 N W5
R3 N
R3 N
A R4 R6
A R4 R6
R2 N N
R7 R2 N N
R1 R7
Ias S O R1
R8 Iat
O R8
L10 is H,
W5 is CH2,
or L10 is CH2 and W5 is CH, they attach and form a pyrrolidine ring.
Compounds of interest Iat can be prepared according to Scheme 16. Starting with amino
alcohols Ias (prepared in analogue to Iap in Scheme 14 and Iaf in Scheme 7), ation with
cyanogen e affords oxazoles Iat. Compounds of interest Iat can be prepared by
cyclization of amino ls Ias with a slight excess of cyanogen bromide. The reaction can be
carried out in the presence of a suitable base such as sodium acetate, sodium ate,
potassium acetate or potassium carbonate, in a suitable solvent such as methanol, water, or the
mixtures thereof, typically at 0 ºC, followed by stirring at room temperature for several hours.
General synthetic route for formula Iau (Scheme 17)
Scheme 17
O R6
O R6
N R7
S R8
R8 O
IVb IVh
R2 NH
XVIII
R3 NH R3
2 N
A R6 A R6
R2 N N R2 N N
R7 R7
R1 R1
S O S O
R8 R8
Iau O IIaz O
Compounds of interest Iau can be prepared according to Scheme 17. Starting with IVb,
oxidation of IVb gives sulfones IVh, which was coupled with 2-aminobenzonitriles XVIII to
afford imines IIaz. Ring closure of imines IIaz gives 4-amino quinolines Iau.
es IVh can be prepared by oxidation of IVb. The reaction can be carried out with a
suitable t such as 3-chloroperoxybenzoic acid, hydrogen peroxide, sodium periodate or
potassium permanganate, in a suitable solvent such as dichloromethane, acetic acid, water or the
mixtures f, lly at 0 ºC, followed by stirring at room temperature for several hours.
Imines IIaz can be prepared by heating a mixture of IVh, 2-aminobenzonitriles XVIII and
phosphorous oxychloride. The reaction can be carried out in a suitable inert organic solvent such
as dichloromethane, chloroform or the mixtures thereof, typically at 0-10 ºC, followed by stirring
at reflux for 24 hours.
Compounds of interest Iau can be ed by ring e of imines IIaz. The reaction
can be achieved by treatment of IIaz with Lewis acid such as zinc chloride in N,N-
dimethylacetamide at 120-180 ºC for several hours in an inert atmosphere.
General tic route for formula Iav and Iaw (Scheme 18)
Scheme 18
R3 NH
A R4 R6
R2 N N
Iae X R8
L11 L12
R3 NH
L11 L12
A R4 R6
R2 N N
IIba X R8
O O
N O
R3 NH R3 NH
L11 L12 L12
R5 L11 R5
A R4 R6 A R4 R6
R2 N N R2 N N
R7 R7
R1 R1
IIbb X Iav X
R8 R8
R3 NH
L11 R5
A R4 R6
R2 N N E is Cl or Br,
R7 L11 is H, or CH3,
Iaw X L12 is H, CH3 or CH2CH3
Compounds of st Iaw and Iav can be ed according to Scheme 18. Staring from
4-amino quinolines Iae, acylation of Iae with acyl chlorides XIX gives amides IIba. Reaction of
IIba with methanol affords methyl ethers Iav. Reaction of IIba with sodium azide followed by
hydrogenation of azides generates compounds of formula Iaw.
Amides IIba can be prepared from 4-amino quinolines Iae by acylation with acy chlorides
XIX. The reaction can be carried out with a suitable base such as potassium carbonate, cesium
carbonate, sodium hydride or 1,8-diazabicyclo[5.4.0]undecene in an inert organic t
such as dichloromethane, tetrahydrofuran or N,N-dimethylformamide, lly at room
temperature, followed by stirring at 50-100 ºC for several hours.
Methyl ethers Iav can be prepared by on of IIba with methanol. The reaction can
be realized by refluxing IIba in methanol in the presence of ethylamine overnight.
Azides IIbb can be prepared by reaction of amides IIba with sodium azide. The reaction
can be carried out in a suitable solvent such as acetonitrile, N,N-dimethylformamide, dimethyl
sulfoxide, water or mixtures thereof, typically at 25-70 ºC for several hours.
Amines Iaw can be prepared by enation of azides IIbb. The reaction can be
carried out in the presence of 10% palladium on carbon under hydrogen atmosphere in an
organic solvent such as ethyl acetate, methanol, or ethanol, lly at room ature for
several hours.
General synthetic route for formula Iax and Iay (Scheme 19)
Scheme 19
O L13O
O L13O
Cl N
R3 NH2
R3 NH N
R4 R6 XX O
A R4 O R6
R2 N N
R7 R2 N N
R1 R7
X R1
R8 IIbc
X R8
L13 L13
R3 NH NH2 R3 NH NH
A R4 R6
A R4 R6
R2 N N
R7 R2 N N
R1 R1
Iay X R8 Iax X R8
L13 is H or CF3
Compounds of interest Iax and Iay can be prepared according to Scheme 19. Starting
from 4-aminoquinolines Iae, acylation of Iae with acyl chlorides XX gives IIbc. Cleavage of
phthalic protecting group from IIbc generates amides Iax. Reduction of amides of Iax generates
Iay.
IIbc can be prepared by acylation of 4-aminoquinolines Iae. The reaction can be d
out by stirring a mixture of Iae and acyl chlorides XX with a suitable base such as N,N-
diisopropylethylamine or cesium carbonate, in a suitable organic solvent such as
romethane, N,N-dimethylformamide or the mixtures f, at room temperature for
several hours.
Amides Iax can be prepared by cleavage of phthalic protecting group from IIbc. The
reaction can be d out with a suitable base such as hydrazine, hydrazine e or low alkyl
amine such as methylamine or n-butylamine in an alcohol solvent such as ol or ethanol at
a ature between room temperature and 90 ºC for several hours. Typically, the reaction can
be carried out by heating IIbc with methylamine in ethanol, at 90 ºC for 2 hours.
Iay can be obtained by reduction of amides of Iax. The reaction can be carried out by
heating Iax in a solution of -methyl sulfide complex in diethyl ether at 80 ºC for several
hours.
General synthetic route for formula Iba (Scheme 20)
Scheme 20
L14 W6 L15 L14
R3 N N W6 L16
H R3 N N
A R4 R6 L15
A R4 R6
R2 N N
R7 R2 N N
Iaz R1
R8 Iba X
L14 is H,
L15 is H or ethyl,
L16 is CH2CH3 ,oxetanyl, or pyridinyl,
W6 is (CH2)2, (CH2)3, or methyl-oxetanyl,
L14 and W6 with nitrogen they are attached to form pyrrolidinyl,
L15 and W6 with nitrogen they are ed to form pyrrolidiny,
Compounds of interest Iba can be prepared according to Scheme 20. Starting with
amines Iaz (prepared in ue to Iac in Scheme 5 and Iaf, Iag in Scheme 7), reductive
amination with various aldehydes or ketones provides substituted amines Iba when L16 is ethyl
or oxetanyl; coupling of amines Iaz with 2-bromo-pyridine tes Iba when L16 is
pyridineyl.
Compounds of interest Iba can be prepared by reductive amination of Iaz with various
aldehydes or ketones. This reaction can be carried out with a suitable reducing agent such as
sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable organic solvent such as
dichloromethane, 1,2-dichloroethane, tetrahydrofuran, methanol or the mixtures thereof,
typically with the addition of molecular sieves or acetic acid, at a temperature between room
temperature and 70 oC for 2 to 12 hours.
Compounds of interest Iba can also be prepared by coupling of amines Iaz with 2-
bromo-pyridine. The reaction is typically performed in N-methylpyrolidinone with
tri(dibenzylideneacetone)dipalladium(0), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthe,
cesium carbonate at a temperature between 100 oC and 150 oC for several hours under inert
atmosphere.
l synthetic route for formula Ibb (Scheme 21)
Scheme 21
R3 NH2 R3 NH N L17
A R4 R6 O N L17 A R4 R6
R2 N N
R7 R2 N N
R1 R1
Iae X Ibb
R8 X
L17 is phenyl or ethyl
Compounds of a Ibb can be prepared as shown in Scheme 21. Ureas Ibb can be
prepared by reaction of 4-amino-quinolines Iae with isocyanides XXI. The reaction can be
d out by ng 4-amino-quinolines Iae with various isocyanide XXI in the presence of a
suitable base such as triethylamine in an organic solvent such as tetrahydrofuran at a ature
between 0 oC to 50 oC for several hours.
General synthetic route for formula Ibc (Scheme 22)
Scheme 22
R3 Cl
R3 Cl
R4 R6 L18
R4 R6
R2 N N
R7 R2 N N
R1 R7
IIbd R1
R8 IIbe X
2NH NH2
R3 NH NH
R4 R6
R2 N N
L18 is cyclopropyl, cyano, ethenyl, or ethynyl R1
X R8
Compounds of interest of formula Ibc can be prepared according to Scheme 22. on
of es IIbd with various organoboronic acids or various organometallic reagents affords
compounds IIbe. Coupling of IIbe with propane-1,3-diamine affords compounds of interest of
formula Ibc.
Compounds IIbe can be prepared from reaction of bromides IIbd with s
organoboronic acids or various metal reagents such as zinc cyanide or organostannic ts.
Reaction of bromides IIbd with various organoboronic acids can be d out in the presence
of a palladium catalyst such as tetra(triphenylphosphino)palladium or palladium acetate with a
phosphine ligand such as 2,2’-bis(diphenylphosphino)-1,1’-binaphthalene and a base such as
potassium carbonate in a suitable solvent such as toluene at 90 oC for 16 hours under argon
atmosphere. on of bromides IIbd with s organometallic reagents can be carried out
in the presence of a palladium catalyst such as tetra(tri-phenylphosphino)palladium in a suitable
solvent such as methylformamide under reflux for 1 to 2 hours under argon atmosphere.
Coupling of halogens IIbe with propane-1,3-diamine can be carried out in analogy to
coupling of 4-halogen quinolines IIab with various amines XI in Scheme 5. Typically, the
reaction can be carried out with a palladium catalyst such as
bis(diphenylphosphino)ferrocenedichloropalladium(II), with a phosphine ligand such as 1,1'-
bis(diphenylphosphino)ferrocene, and a suitable base such as sodium-tert-butoxide in a suitable
solvent such as 1,4-dioxane, heated at 120 oC for 2 hours under microwave irradiation.
l synthetic route for formula Ibd, Ibe and Ibf (Scheme 23)
Scheme 23
R4 R6
R3 OH
R3 OH NH A N R4 R6
A N
X R2 N N
IVi R8 R7
R2 N Cl R1 IIbg
R1 R8
IIIc
R12 R13
R3 Cl
A N R3 N
R2 N Cl A N R4 R6
R1 IIIb R2 N N
R12 R13 R8
H R4 R6
R12 NH
R13 R7
R3 N
A N IVi
R2 N Cl
IIbf
R4 R6
IVf R12
R12 R13
R13 R3 N
R3 N
A N R4 R6
A N R4 R6
R2 N N
R2 N N R7
R7 R1
Ibe Ibf S O
S R8
R8 O
Compounds of interest Ibd, Ibe and Ibf can be prepared ing to Scheme 23.
Hydrolysis of 2,4-dichloro-quinozalines IIIb affords 2-chlorohydroxy-quinozalines IIIc.
Coupling of 2,4-dichloro-quinozalines IIIb with various amines XI affords IIbf. Coupling of
IIIc with benzoazapines IVi followed by coupling with various amines XI affords compounds of
interest Ibd. Coupling of IIbf with benzoazapines IVi affords compounds of interest Ibd.
Coupling of IIbf with benzothioazapines IVf s compounds of st Ibe. Oxidation of
sulfides of Ibe affords compounds of interest Ibf.
2-Chlorohydroxy-quinozalines IIIc can be prepared by ysis of 2,4-dichloroquinozalines
IIIb . The reaction can be carried out in the presence of a le base such as
sodium hydroxide in a suitable solvent such as tetrahydrofuran, water or mixtures f at
room temperature for several hours.
4-Hydroxy quinozalines IIbg can be prepared by coupling of IIIc with zapines
IVi . The on can be carried out in the presence of a suitable base such as triethylamine in a
suitable solvent such as toluene or N,N -dimethylformamide at a temperature n 110 °C and
160 °C under microwave irradiation for 30 minutes to 2 hours. Alternatively, the reaction can be
carried out at an ed temperature such as under reflux overnight without microwave
irradiation.
2-Chloroamino quinozalines IIbf can be prepared by coupling of IIIb with various
amines XI . The reaction can be carried out in the presence of a suitable base such as
triethylamine in a suitable solvent such as methanol, tetrahydrofuran, dichloromethane or
es thereof at a temperature between 0 oC to room temperature for several hours.
Compounds of interest Ibd can be prepared by coupling of IIbg with various amines XI .
The reaction can be carried out in the presence of a suitable base such as 1,8-
diazabicyclo[5.4.0]undecene with a suitable ng reagents such as benzotriazol
yloxytris(dimethylamino)-phosphonium hexafluorophosphate, in a suitable solvent such as N,N -
dimethylformamide at room temperature for several hours.
Alternatively, compounds of interest Ibd can be obtained by the coupling of IIbf with
benzoazapines IVi . The reaction can be carried out with or without a base such as triethylamine,
in a suitable solvent such as n-butanol or N,N -dimethylformamide at a temperature between 130
°C and 160 °C for 30 minutes to several hours under microwave irradiation. Alternatively, this
reaction can be carried out with triethylamine in n-butanol in a sealed tube at a lower
temperature for several hours, lly at 100 °C for 4 hours.
Compounds of interest Ibe can be prepared by coupling of IIbf with hioazapines
IVf . The reaction can be carried out without any base or with a suitable base such as
triethylamine in a suitable solvent such as n-butanol or N,N -dimethylformamide at a ature
between 130 °C and 160 °C for several hours under microwave irradiation.
Compounds of interest Ibf can be prepared by oxidation of Ibe . The reaction can be
carried out with roperoxybenzoic acid in dichloromethane or oxone in a mixture solvent
such as ol and tetrahydrofuran at a temperature between 0 °C and room temperature for
several hours.
General synthetic route for formula Ibj (Scheme 24)
Scheme 24
L19 L19
W7 N W7 N
R3 NH R3 NH
A N R4 R6 A N R4 R6
R2 N N R2 N N
R7 R7
R1 R1
Ibh S
R8 Ibi S O R8
W7 NH2
R3 NH
A N R4 R6
W7 is O or CH2; R2 N N
L19 is H or benzyl R1
Ibj S O R8
O
Compounds of interest Ibj can be prepared according to Scheme 24. Starting with Ibh
(prepared in analogue to Ibe in Scheme 23), oxidation with a suitable oxidant provides Ibi.
Subsequent debenzylation generates amines Ibj.
Ibi can be prepared by oxidation of Ibh. The reaction can be carried out with a suitable
oxidant such as 3-chloroperoxybenzoic acid, hydrogen de, sodium periodate or ium
permanganate, in a suitable t such as dichloromethane, acetic acid, water or the e
thereof, typically at 0 ºC, followed by stirring at room temperature for several hours.
Compounds Ibj can be prepared by standard debenzylation of Ibi. The reaction can be
carried out with ium on carbon, palladium ide on carbon or platinum oxide,
typically with an acid such as acetic acid or trifluoroacetic acid in a suitable solvent such as
methanol, ethanol, tetrahydrofuran, ethyl acetate or the mixtures thereof, at room temperature
under hydrogen atmosphere for several hours.
General synthetic route for formula Ibl (Scheme 25)
Scheme 25
R3 NH NH2 W8
R3 NH N
A Y R4 R6
A Y R4 R6
R2 N N
R7 R2 N N
Ibk R1
X Ibl
R8 X
W8 is (CH2)2, (CH2)3 or oxetanylmethyl,
Compounds of interest Ibl can be prepared according to Scheme 25. Starting with amines Ibk
(prepared in analogue to Iac in Scheme 5 and Ibf in Scheme 23), acylation with acetic ide
or acetyl chloride gives acetamides Ibl. The reaction can be carried out with a suitable base such
as triethylamine or pyridine in a suitable inert organic t such as dichloromethane,
tetrahydrofuran or pyridine at 0 ºC, followed by stirring at room temperature for several hours.
General tic route for formula Ibm (Scheme 26)
Scheme 26
O H
R3 E N R3 N
A R4 R6
N A R4 R6
R2 N N
R7 R2 N N
R1 R7
IIab S O R1
R8 IIbh S O
O R8
R3 N
A R4 R6
R2 N N
E is Cl or Br R7
Ibm S O
Compounds of interest Ibm can be prepared according to Scheme 26. Coupling of 4-
halogen-quinolines IIab with N-(3-methyl-pyrrolidinyl)-acetamide affords compounds IIbh.
Deactylation of IIbh affords compounds of interest Ibm.
Compounds IIbh can be prepared by ng of 4-halogen-quinolines IIab with N-(3-
methyl-pyrrolidinyl)-acetamide. The reaction can be d out in the presence of a metal
st or in the absence of a metal catalyst in analogy to coupling of 4-halogen quinolines IIab
with various amines XI in Scheme 5. Typically, the reaction can be carried out with 1,1'-
bis(diphenylphosphino)ferrocene, is(diphenylphosphino)ferrocenedichloropalladium(II),
and sodium-tert-butoxide in 1,4-dioxane at 120 oC for 1.5 hours under microwave irradiation.
Compounds of interest Ibm can be prepared by lation of IIbh. The reaction can be
d out in 2 N hydrochloric acid at 100 oC for 16 hours.
General tic route for formula Ibo (Scheme 27)
Scheme 27
R12 R13 R12 R13
R3 N R3 N
A R4 R6 A R4 R6
R2 N N R2 N N
R7 R7
R1 Ib R1 Ibo
S O S O
F O
O O
Compounds of interest Ibo can be prepared according to Scheme 27. Starting with
fluorides Ibn, substitution of fluoro with methoxy group affords Ibo. The reaction can be carried
out by heating of fluorides with sodium methoxide in methanol, typically at 100 ºC for 20
minutes under microwave irradiation.
General synthetic route for formula Ibq (Scheme 28)
Scheme 28
R12 R13 R12 R13
R3 N R3 N
A R4 O A R4 OH
R2 N N R2 N N
R7 R7
R1 R1
Ibp S O
R8 Ibq S O
O O
Compounds of interest Ibq can be prepared according to Scheme 28. Demethylation of
methoxybenzenes Ibp affords phenols Ibq. The reaction can be carried out by heating of Ibp
with ium hydroxide in dimethylsulfoxide, typically at 100 ºC for 20 minutes under
microwave irradiation.
General synthetic route for formula Ibr and Ibs (Scheme 29)
Scheme 29
R3 Cl
R3 NH
A R4 R6
A R4 R6
R2 N N
R7 R2 N N
R1 R7
IIbi S O R1
R8 IIbk
O S O R8
OH OH OH
R3 NH R3 NH
A R4 R6
A R4 R6
R2 N N
R7 R2 N N
R1 R1
IIbj S Ibs
O R8 S O
O R8
OH OH
R3 NH
A R4 R6
R2 N N
R1 Ibr
O R8
Compounds of interest Ibr and Ibs can be ed according to Scheme 29. Coupling of
4-chloroquinolines IIbi with 4-aminohydroxy-butyric acid followed by ion of acids
IIbj affords 1,3-diols Ibr. Coupling of 4-chloroquinolines IIbi with 2-methyl-allyl1amine
followed by dihydroxylation of alkenes IIbk s 1,2-diols Ibs.
Acids IIbj can be obtained by coupling of 4-chloroquinolines IIbi with 4-amino
hydroxy-butyric acid. Alkenes IIbk can be obtained by ng of 4-chloro quinolines IIbi with
2-methyl-allylamine. ng reaction can be carried out by heating 4-chloroquinolines IIbi
with amines in a suitable organic solvent such as 1-methylpyrrolidinone at an elevated
temperature, typically at 160 oC for 16 hours.
1,3-Diols Ibr can be prepared by reduction of acids IIbj. The on can be carried out
by treating acids with sodium borohydride in the presence of iodine in tetrahydrofuran, typically
at 0 oC, followed by stirring at room temperature for 16 hours.
1,2-Diols Ibs can be prepared by dihydroxylation of alkenes IIbk. The reaction can be
accomplished by treating alkenes with 4-methylmorpholine N-oxide monohydrate and osmium
tetroxide in acetone at room temperature for 1 hour.
General tic route for formula Ibt (Scheme 30)
Scheme 30
R3 Cl R3 Cl
A R4 R6 A R4 R6
R2 N N
R7 R2 N N
R1 R1
IIbi S O IIbl
R8 S O
O O
R12 R13
R3 N
A R4 R6
R2 N N
Ibt S O
Compounds of interest Ibt can be prepared according to Scheme 30. Starting with IIbi,
tion with methyl iodide followed by coupling with various amines affords compounds of
interest Ibt.
nds IIbl can be prepared by alkylation of IIbi with methyl . ably,
compounds can be obtained by deprotonation of α-H of sulfone followed by reaction with
methyl iodide. Deprotonation of α-H of sulfone can be carried out by treating sulfone IIbi with
n-butyl lithium in ydrofuran at -78 °C under argon here for 1 hour. on with
methyl iodide can be accomplished by addition of methyl iodide to the above reaction e at
-78 oC, followed by stirring at room temperature overnight.
Compounds of interest Ibt can be prepared by coupling of IIbl with s amines. The
reaction can be carried out in analogy to coupling of 4-halogen quinolines IIab with various
amines XI in Scheme 5. The reaction preferably can be achieved by heating a mixture of IIbl
and various amines with or without organic solvent such as N,N-dimethylformamide, 1-
methylpyrrolidinone or n-butyl alcohol, under microwave irradiation at 140-160 ºC for 1-3
hours.
General tic route for formula Ibu, Ibv and Ibw (Scheme 31)
Scheme 31
H N CF3
N CF3
R3 Cl O
O R3 NH
NH O
A R4 R6 2 O
A R4 R6
R2 N N
R7 R2 N N
R1 R7
IIbi S O R1
R8 Ibu
O R8
NH NH
2 OH 2
R3 NH OH R3 NH
A R4 R6 A R4 R6
R2 N N R2 N N
R7 R7
R1 R1
Ibw S O Ibv
R8 R8
O O
Compounds of interest Ibu, Ibv and Ibw can be ed according to Scheme 31.
Coupling of 4-chloroquinolines IIbi with N-(3-amino-oxetanylmethyl)-2,2,2-trifluoro-
acetamide affords Ibu. Standard trifluoroacetyl deprotection of Ibu generates compounds Ibv.
Trifluoroacetyl deprotection and hydrolysis of Ibu affords Ibw.
Compounds Ibu can be prepared by coupling of 4-chloroquinolines IIbi with N-(3-aminooxetanylmethyl
)-trifluoro-acetamide. The reaction can be carried out in the presence of a
palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II),
(triphenylphosphine)dichloropalladium(II), palladium(II) acetate, or
tri(dibenzylideneacetone)dipalladium(0), in combination of a phosphine ligand such as
bis(diphenylphosphino)ferrocene, tricyclohexylphosphine, or 9,9-dimethyl-4,5-
bis(diphenylphosphino)xanthene, with a le base such as sodium tert ide, in a le
inert organic solvent such as 1,4-dioxane, or N,N -dimethylformamide, at 100-150 ºC for 1-3
hours under microwave irradiation. Alternatively, the reactions can be d out at an elevated
temperature such as 100-140 ºC for a longer reaction time without microwave irradiation.
Compounds Ibv can be prepared by standard trifluoroacetyl deprotection of Ibu . The
reaction can be d out with potassium carbonate, in a suitable solvent such as the mixture of
methanol and water, at room temperature for several hours.
Compounds Ibw can be prepared by trifluoroacetyl deprotection and hydrolysis of Ibu .
The reaction is typically carried out with ammonia solution in methanol for several hours at
room temperature.
General tic route for formula Ibx and Iby (Scheme 32)
Scheme 32
O OH
R3 E
A R4 R6 R3 N
R2 N N A R4 R6
IIab N N
X R2
R8 R7
R9 R1
IIbn
X R8
O O
NH Cl
R3 N O R3 N
A R4 R6 A R4 R6
R2 N N R2 N N
R7 R7
R1 R1
IIbm IIbo
X X
R8 R8
R9 R9
2 NH
R3 N O
R3 N
A R4 R6
A R4 R6
R2 N N
R7 R2 N N
R1 R7
Ibx X R8 Iby X
R9 R8
nds of interest Ibx and Iby can be prepared according to Scheme 32. Standard
coupling of IIab with 5-oxo-pyrrolidinecarboxylic acid amide generates IIbm, followed by
rearrangement of amides IIbm gives aminopyrrolidines Ibx. Coupling of halogens IIab with
pyrrolidinecarboxylic acid methyl ester affords compounds IIbn. Conversion of IIbn to
acylchlorides IIbo followed by treatment with ammonia affords compounds of interest Iby.
Amides IIbm can be prepared by copper-mediated coupling reaction of IIab with 5-oxopyrrolidinecarboxylic
acid amide. The on can be d out in the presence of a copper
source such as copper(I) iodide and a ligand such as 2,2'-bipyridine, L-proline, N,N-dimethyl
glycine, ethylene glycol or N,N'-dimethylcyclohexane-1,2-diamine, with a suitable base
such as triethylamine, sodium carbonate, ium carbonate, cesium carbonate, sodium tert -
butoxide, ium tert -butoxide, sodium hydride or 1,8-diazabicyclo[5.4.0]undecene. The
reaction can be carried out in a suitable organic t such as diethylene glycol dimethyl ether,
toluene, 1,4-dioxane, N,N -dimethylformamide, dimethyl sulfoxide or 1-methyl-pyrrolidinone
at a temperature n 100 ºC and 180 ºC for several hours under microwave irradiation.
Alternatively, the reactions can be carried out at a temperature such as 130 ºC for a longer
reaction time without microwave irradiation.
Aminopyrrolidines Ibx can be prepared by rearrangement of amides IIbm. The reaction
can be typically carried out in the presence of (diacetoxyiodo)benzene in a mixture of
acetonitrile and water for several hours at room temperature.
Acids IIbn can be ed by coupling of halogens IIab with idinecarboxylic
acid methyl ester. The reaction can be carried out with a suitable base such as
diisopropylethylamine without any solvent at 140 °C for 1.5 hours under microwave irradiation.
Acyl chlorides IIbo can be ed by chlorination of IIbn . The reaction can be carried
out with such as oxalyl dichloride in the presence of N,N -dimethylformamide, in a suitable
solvent such as dichloromethane at 0 oC to room ature for 16 hours.
Compounds of interest Iby can be prepared by reaction of IIbo with ammonia. The
reaction can be carried out in suitable solvent such as dichloromethane at 0 oC to room
temperature for 16 hours.
General synthetic route for formula Ibz and Ica (Scheme 33)
Scheme 33
R3 Cl
R3 NH
A R4 R6
A R4 R6
R2 N N
R7 R2 N N
R1 R7
IIbi S O R1
R8 IIbp S O
O R8
S NH S
R3 NH R3 NH
A R4 R6 A R4 R6
R2 N N R2 N N
R7 R7
R1 R1
Ica S O Ibz S O
R8 R8
O O
nds of interest Ibz and Ica can be prepared according to Scheme 33. Starting with
IIbi, coupling with 2-methylsulfanyl-ethylamine gives sulfides IIbp. Selective oxidation of
sulfides IIbi gives sulfoxides Ibz. Imination of sulfoxides, ed by hydrolyzation affords
nds of interest Ica.
es IIbp can be prepared from coupling of 2-benzoazapinchloroquinolines IIbi
with 2-methylsulfanyl-ethylamine. The reaction can be carried out in the presence of a palladium
catalyst in analogy to coupling of 4-halogen quinolines IIab with s amines XI in Scheme
. Typically the reaction can be carried out in the presence of
tri(dibenzylideneacetone)dipalladium(0), 2-(dicyclohexylphosphino)-2'-(N,N-
dimethylamino)biphenyl, and sodium-tert-butoxide in 1,4-dioxane under microwave irradiation
at 100 oC for 1.5 hours.
Sulfoxides Ibz can be prepared by oxidation of sulfides IIbp. The reaction preferably can
be carried out with a standard oxidant agent such as hydrogen de in a suitable organic
solvent such as acetic acid at room temperature for several hours.
Compounds of interest Ica can be prepared by metal-catalyzed imination of sulfoxides
ed by hydrolysis. Imination of sulfoxides can be carried out by treating ides with
rhodium (II) acetate and trifluoroacetamide or sulfonylamides in combination with iodobenzene
diacetate and magnesium oxide in dichloromethane at room temperature overnight, preferably
oroacetamide was used. Hydrolysis can be carried out in the presence of a suitable base,
such as potassium carbonate, sodium hydroxide or potassium hydroxide in methanol under reflux
for 30 minutes to several hours.
General synthetic route for formula Icc (Scheme 34)
Scheme 34
O O
R3 NH NH2 S
R3 NH NH2
A R4 R6 KMnO4 A R4 R6
R2 N N
R7 R2 N N
R1 R1
Icb S O Icc
R8 S O
O O
Compounds of interest Icc can be prepared according to Scheme 34. ng with sulfides
Icb (prepared in analogue to Iac in Scheme 5), oxidation of sulfides s compounds of
st Icc.
Compounds of interest Icc can be prepared by oxidation of sulfides Icb. The reaction can
be carried out in analogy to oxidation of quinolines IIac in Scheme 4. Typically the reaction can
be carried out by treating sufides with potassium permanganate in acetic acid at room
ature for 30 minutes to several hours.
General synthetic route for formula Icd (Scheme 35)
Scheme 35
R3 Cl R3 Cl
A R4 R6 A R4 R6
R2 N N
R7 R2 N N
IIbq R1
S IIbr
R8 S NH
O R8
R3 NH
A R4 R6
R2 N N
Icd S NH
Compounds of st Icd can be prepared according to Scheme 35. Starting with
sulfoxides IIbq, metal-catalyzed imination of sulfoxides followed by hydrolysis gives
sulfoximines IIbr. Coupling of IIbr with various amines affords nds of interest Icd.
Sulfoximines can be prepared from imination of sulfoxides IIbq followed by hydrolysis.
Imination of ides can be carried out by treating sulfoxides with rhodium (II) acetate and
trifluoroacetamide or sulfonylamides in combination with iodobenzene diacetate and magnesium
oxide in dichloromethane at room temperature overnight, preferably trifluoroacetamide was
used. Hydrolysis can be d out in the presence of a suitable base, such as potassium
carbonate, sodium hydroxide, potassium hydroxide or sodium methoxide in methanol under
reflux for 30 minutes to several hours.
Compounds of interest Icd can be prepared by coupling of IIbr with 1,2- nediamine.
The reaction can be carried out in analogy to coupling of 4-halogen quinolines IIac with various
amines XI in Scheme 5. Typically the reaction can be carried out with or without an organic
solvent such as methylformamide, 1-methylpyrrolidinone or n-butyl alcohol at a
ature between 140 ºC and 160 ºC under microwave irradiation for 1 to 3 hours.
General synthetic route for formula Ice e 36)
Scheme 36
R3 Cl
R3 Cl
R4 R6 S
O R4 R6
R2 N N
R7 R2 N N
R1 R7
IIbs S O R1
R8 IIbt S O
O R8
R3 NH NH
O R4 R6
R2 N N
Ice S O
Compounds of interest Ice can be prepared according to Scheme 36. Oxidation of
sulfides IIbs followed by coupling of IIbt with propane-1,3-diamine s compounds of
interest Ice.
Sulfoxides IIbt can be prepared by ion of sulfides IIbs . The reaction can be carried
out with a le oxidation reagent such as m-chloroperbenzoic acid in a suitable solvent such
as dichloromethane at 0 oC for 20 minutes.
Compounds of interest Ice can be prepared by coupling of IIbt with propane-1,3-
diamine. The reaction can be carried out in analogy to coupling of 4-halogen quinolines IIac
with various amines XI in Scheme 5. Typically, the reaction can be carried out by treating a
mixture of IIbt and propane-1,3-diamine without any base and without any solvent at 150 oC for
1 hour under microwave irradiation.
General tic route for a Icf and Icg (Scheme 37)
Scheme 37
O R3 Cl O R3 Cl
O R4 R6
O R4 R6
R2 N N
R7 R2 N N
R1 R1
IIbu S
R9 IIbv S O R8
O R3 Cl
NH2 R3 Cl
H R4 R6
O R4 R6
R2 N N
R2 N N R7
R7 R1
IIby S IIbw S O R8
R8 O
NH R3 OH R3 Cl
2 Cl
O R4 R6 R4 R6
R2 N N R2 N N
R7 R7
R1 R1
IIbz S S
O R8 IIbx O R8
O O
NH NH NH R3
2 R3 OH NH NH
2 2
O R4 R6 R4 R6
R2 N N R2 N N
R7 R7
R1 R1
Icg S Icf S
O R8 O R8
O O
Compounds of st Icg and Icf can be prepared according to Scheme 37. Amination of
IIbu affords amides IIby. Oxidation of sulfides IIby affords sulfones IIbz. Coupling of IIbz
with propane-1,3-diamine affords compounds of interest Icg. Oxidation of sulfides IIbu affords
sulfones IIbv. ion of carboxylic acid esters IIbv followed by Swern-oxidation affords
aldehydes IIbw. Methylation of IIbw followed by ng with propane-1,3-diamine affords
compounds of interest Icf.
Amides IIby can be prepared by amination of IIbu . The reaction can be carried out in a
solution of ammonia in a le solvent such as methanol, tetrahydrofuran or mixture thereof in
a sealed tube at a temperature between 100 oC and 150 oC for several hours, typically at 120 oC
for 16 hours.
Sulfones IIbz can be prepared by oxidation of sulfides IIby . The reaction can be d
out in y to oxidation of quinolines IIac in Scheme 4. Typically, the reaction can be carried
out with m-chloroperbenzoic acid in dichloromethane at 0 oC for 2 hours.
Compounds of interest Icg can be ed by coupling of IIbz with propane-1,3-
diamine. The reaction can be carried out in y to coupling of 4-halogen- quinolines IIac
with various amines XI in Scheme 5. Typically, the reaction can be carried out by treating a
mixture of IIbz and propane-1,3-diamine without any base and without any solvent at 120 oC for
1 hour under microwave irradiation.
Sulfones IIbv can be prepared by oxidation of es IIbu . The reaction can be carried
out in analogy to oxidation of quinolines IIac in Scheme 4. Typically, the reaction can be d
out with m-chloroperbenzoic acid in dichloromethane at 0 oC for 1 hour.
Aldehydes IIbw can be prepared by reduction of carboxylic acid esters IIbv followed by
Swern oxidation. Reduction can be carried out with a rd reducing agent such as sodium
ydride in a suitable solvent such as tetrahydrofuran, under reflux for several hours to
several days, typically 60 hours. Swern oxidation can be carried out with oxalyl dichloride and
dimethyl sulfoxide in the presence of triethylamine in a suitable solvent such as dichloromethane
at -78 oC, then at room temperature for 1 to several hours.
6-(1-Hydroxyethyl)quinolines IIbx can be prepared by methylation of IIbw . The reaction
can be carried out with a methylation reagent such as methyl magnesium bromide in
tetrahydrofuran at a temperature below 12 oC for 10 minutes to l hours.
Compounds of st Icg can be prepared by coupling of IIbw with propane-1,3-
diamine. The reaction can be carried out in analogy to coupling of 4-halogen quinolines IIac
with various amines XI in Scheme 5. Typically, the reaction can be carried out without any
metal catalyst and without any t at 150 oC for 1.5 hours under microwave irradiation.
General synthetic route for formula Ich and Ici (Scheme 38)
Scheme 38
R3 Cl R3 NH
A R4 R6 A R4 R6
R2 N N R2 N N
R7 R7
R1 R1
IIbi S O Ich S O
R8 R8
O O
R3 NH N
A R4 R6
R2 N N
Compounds of interest Ici can be prepared according to Scheme 38. Standard coupling of
IIbi with 3-amino-propionitrile generates Ich, cyclization of nitriles with sodium azide affords
tetrazoles Ici.
Nitriles Ich can be prepared by coupling reaction of chlorides IIbi with 3-aminopropionitrile.
The reaction can be carried out in analogy to coupling of 4-halogen quinolines IIac
with various amines XI in Scheme 5. Typically, the on can be carried out by heating with
tri(dibenzylideneacetone)dipalladium(0), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, and
sodium tert-butoxide in toluene at 110 ºC overnight.
Tetrazoles Ici can be prepared by cyclization of es Ich with sodium azide. The
reaction can be typically carried out in the presence of sodium azide and ammonium chloride in
N,N-dimethylformamide at a ature n 60 oC and 100 oC, lly at 80 oC for
several hours.
General synthetic route for formula Ick (Scheme 39)
Scheme 39
NH2 NH
O R3 NH R3 NH 2
N NH2
O R4 R6 R4 R6
R2 N N R2 N N
R7 R7
R1 R1
Icj S Ick
O S
R8 O R8
O O
Compounds of formula Ick can be prepared according to Scheme 39. ion of o
quinolines Icj generates 6-amino-quinolines Ick. The reaction can be carried out with stannous
chloride in methanol under reflux overnight.
General synthetic route for formula Icl (Scheme 40)
Scheme 40
H N
NH N
R3 Cl 2 O O
R3 N
A R4 R6
A R4 R6
R2 N N
R7 R2 N N
IIbi R1
S O Icl
R8 S O
O R8
Compounds of interest Icl can be prepared according to Scheme 40. Starting with IIbi,
coupling with (3-amino-oxetanylmethyl)-carbamic acid tert-butyl ester gives spiral
compounds Icl. This reaction can be carried out in the presence of a palladium st such as
(triphenylphosphine)dichloropalladium(II), [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II), palladium(II) acetate, or
benzylideneacetone)dipalladium(0), with a ine ligand such as 2,2'-
bis(diphenylphosphino)-1,1'-binaphthyl, bis(diphenylphosphino)ferrocene,
tricyclohexylphosphine, or 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, with a suitable
base such as sodium tert-butoxide, in a suitable inert organic solvent such as toluene, e, or
N,N-dimethylformamide, at a temperature between 100 ºC and 150 ºC for 1 to 3 hours under
microwave irradiation. Alternatively, the reactions can be carried out at a temperature such as
100 ºC to 140 ºC for a longer reaction time without microwave irradiation.
General synthetic route for formula Icm (Scheme 41)
Scheme 41
R3 Cl
H N O R3 NH
A N O
A N
R2 N Cl
R2 N Cl
IIIb R1
IIca
N R6
S R7
O R8
IVd O
OH O
R3 NH R3 NH
A N A N
R2 N N R6 R2 N N R6
R1 R1
S R7 S R7
Icm O IIcb
O R8 O
O R8
Compounds of interest Icm can be prepared according to Scheme 41. ng of 2,4-
roquinazolines IIIb with C-(2,2-dimethyl-[1,3]dioxolanyl)-methylamine affords IIca.
Reaction of 2-chloroaminoquinazolines IIca with 6,7,8,9-tetrahydrothiaaza-
benzocycloheptene oxides IVd followed by deprotection affords 4-(2,3-diol-propylamino)-
quinolines Iak.
IIca can be obtained by coupling of 2,4-dichloroquinazolines IIIb with C-(2,2-dimethyl-
[1,3]dioxolanyl)-methylamine. The on can be carried out with a base such as
triethylamine in a suitable solvent such as methanol or romethane at room temperature for
several hours.
Intermediates IIcb can be prepared by coupling of 2-chloroamino quinazolines IIca
with 6,7,8,9-tetrahydrothiaaza-benzocycloheptene 5,5-dioxides IVd. The reaction can be
carried out in the presence of a base such as triethylamine in N,N-dimethylformamide at a
temperature between 120 oC and 180 oC, typically at 160 oC for several hours.
4-(2,3-Diol-propylamino)-quinazolines Icm can be prepared by deprotection of IIcb. The
reaction can be carried out in the presence of an acid such as hydrochloric acid in a suitable
solvent such as ol, ethanol, water or mixtures thereof at room ature for several
hours.
General synthetic route for formula Icn (Scheme 42)
Scheme 42
O NH
N 2
R3 NH
R3 NH
A N
A N R4
R4 R6
R2 N N
R2 N N
R1 R7 R1
IIcc Icn S
S R8
H O NH2
R3 NH
R3 NH
A N
A N R4
R4 R6
R2 N N
R2 N N
R7 R1
R1 Ico
IIcd S
S R8
R8 O
m m
m is 1 or 2
Compounds of st Icn and Ico can be prepared ing to Scheme 42. Starting with
IIcc, cleavage of tert-butoxycarbonyl gives compounds of interest Icn. Oxidation of sulfides
IIcc generates oxides IIcd, followed by cleavage of tert-butoxycarbonyl generates nds of
interest Ico.
IIcd can be prepared by oxidation of thio group of compounds IIcc. The reaction can be
carried out with a suitable oxidant such as oxone, meta-chloroperoxybenzoic acid, hydrogen
peroxide, sodium periodate or potassium permanganate, in a suitable solvent such as methanol,
dichloromethane, acetic acid, water or the mixtures thereof, typically at 0 ºC, followed by stirring
at room temperature for several hours.
Amines Icn and Ico can be prepared by cleavage of tert-butoxycarbonyl of IIcc and IIcd
respectively. The reaction can be typically carried out with trifluoroacetic acid in
dichloromethane, or hydrogen chloride in methanol for several hours at room temperature.
General synthetic route for formula Icp (Scheme 43)
Scheme 43
O O
N CF NH
R3 NH 3 R3 NH 2
A N R4 R6 A N R4 R6
R2 N N R2 N N
R7 R7
R1 R1
IIce S Icp
R8 S
O O
Compounds of interest Icp can be ed according to Scheme 43. Starting with IIce,
removal of trifluoroacetyl generates amines Icp. The reaction can be carried out with ium
carbonate or sodium hydroxide, in a suitable solvent such as the mixture of ethanol and water, at
room ature for l hours.
General synthetic route for formula Icq and Icr (Scheme 44)
Scheme 44
H O
H O O
R3 OH N
O R3 N
A N R4 R6
H A N R4 R6
R2 N N
R1 R2 N N
IIbg R7
R8 R1
IIcf X
N Cbz
F NH
N Cbz
R3 NH R3 N
A N R4 R6 A N R4 R6
R2 N N R2 N N
R7 R7
R1 R1
IIcg X X
R8 Icq R8
R3 NH
A N R4 R6
R2 N N
Icr X
Compounds of interest Icq and Icr can be prepared according to Scheme 44. Starting
with quinazolinones IIbg, coupling reaction with amine gives IIcf, followed by cleavage of tertbutoxycarbonyl
of IIcf affords compounds of interest Icq. Starting with quinazolinones IIbg,
ng reaction with amine gives IIcg, followed by cleavage of benzoxycarbonyl of IIcg
affords nds of interest Icr.
IIcf and IIcg can be prepared from ng reaction of IIbg with 3-( tert-butoxycarbonyl-
amino)pyrrolidine and transaminofluoro-pyrrolidinecarboxylic acid benzyl ester
separately. The reaction can be carried out in the presence of benzotriazolyloxytris
(dimethylamino)phosphonium hexafluorophosphate, with a suitable base such as 1,8-
diazabicyclo[5.4.0]undecene, or yl amine, in a solvent such as N,N-dimethylformamide
or acetonitrile at room temperature overnight.
nds of interest Icq can be prepared by standard cleavage of tert-butoxycarbonyl of
IIcf. The on can be carried out by treating tert-butyl carbamates IIcf with a suitable acid
such as hloric acid, trifluoroacetic acid, or sulfuric acid in a suitable solvent such as
methanol, ethyl acetate, dichloromethane, 1,4-dioxane, water or the mixtures thereof at a
temperature between 0 ºC and room temperature for 30 minutes to several hours. Typically the
reaction can be carried out by ng tert-butyl carbamates IIaf with trifluoroacetic acid in
dichloromethane at room temperature for 6 hours.
Compounds of interest Icr can be prepared by cleavage of benzyl carbomates IIcg. The
sion can be achieved by hydrogenolysis or under strong acidic conditions. Hydrogenolysis
of IIcg can be carried out in the presence of palladium on carbon or palladium black, under
hydrogen atmosphere or with a hydrogen donor such as formic acid or ammonium formate, in a
le t such as methanol or ethanol, at a temperature between room temperature and 80
ºC for 15 minutes to several hours. Alternatively the conversion can also be achieved by treating
IIcg under strong acidic conditions such as reflux in 6 N hydrochloride in methanol for several
hours.
General synthetic route for formula Ics (Scheme 45)
Scheme 45
O O
R3 Cl
R5 O O R3
A R4 R6 N R5
O A R4 R6
R2 N N
R7 R2 N N
R1 R7
IIbi X R1
R8 IIch X
A R4 R6 R5
A R4 R6
R2 N N
R7 R2 N N
R1 R7
Ics X R1
R8 IIci X
Compounds of interest Ics can be prepared according to Scheme 45. Starting with 4-
chloro-quinolines IIbi , coupling with (R)-2,2-dimethylvinyl-oxazolidinecarboxylic acid
tert -butyl ester gives vinyl quinolines IIch . Subsequent reduction and deprotection of tert -
butyloxycarbonyl and acetal of IIch generates amino alcohols IIci , which are then cyclized to
compounds of interest Ics .
Vinyl ines IIch can be prepared by coupling of 4-chloro-quinolines IIbi with (R)-
2,2-dimethylvinyl-oxazolidinecarboxylic acid tert -butyl ester. The reaction can be lly
conducted in deoxygenated N,N hylformamide with triethylamine, bis(tri-tert -
butylphosphine)palladium(0), at a temperature between 100 ºC and 160 ºC for several hours
under microwave irradiation. Alternatively, the reactions can be carried out at an elevated
temperature such as between 100 and 140 ºC for a longer reaction time without microwave
irradiation.
Amino alcohols IIci can be prepared from vinyl quinolines IIch by hydrogenolysis and
deprotection of tert -butyloxycarbonyl and . The hydrogenolysis can be carried out in the
presence of 10% palladium on carbon under an atmospheric pressure of hydrogen, in an organic
solvent such as ethyl acetate, ol, or ethanol, typically at room temperature for several
hours. ection of ides is typically d out in a solution of hydrochloric acid in
ethyl acetate for several hours at room temperature.
Compounds Ics can be prepared from amino alcohols IIci by ring closure with cyanogen
bromide. The on can be carried out with a suitable base such as sodium acetate, sodium
carbonate, potassium acetate or potassium carbonate, in a suitable solvent such as methanol,
water, or the mixtures thereof, typically at 0 ºC, followed by stirring at room temperature for
several hours.
General synthetic route for formula Ict, Icu and Icv (Scheme 46)
Scheme 46
R3 Cl
A R4 R6 R5
A R4 R6
R2 N N
R7 R2 N N
R1 R7
IIbi X R1
R8 IIck
O O O NH
R3 R3
R5 R5
A R4 R6 A R4 R6
R2 N N R2 N N
R7 R7
R1 R1
IIcj R8 X
Icu R8
O OH 2
R5 A R4 R6
A R4 R6
R2 N N
R2 N N R7
R7 R1
R1 Icv X
Ict X R8
n is 0 or 1
Compounds of interest Ict, Icu and Icv can be prepared according to Scheme 46. Starting
with 4-chloro quinolines IIbi, coupling with ethyl acrylate gives alkenes IIcj. ion of
alkenes IIcj followed by hydrolysis of esters affords compounds of interest Ict. Heck reaction
coupling with acrylonitrile gives alkenes IIck. Hydrogenation of alkenes followed by hydrolysis
of nitriles affords amides Icu. atively, amides Icu can be formed by aminolysis of esters
IIcj. ion of amides Icu affords compounds of interest Icv.
Alkenes IIcj and IIck can be prepared by Heck coupling of 4-chloro-quinolines IIbi with
ethyl te and acrylonitrile separately. The reaction can be typically conducted in the
presence of bis(tri-tert-butylphosphine)palladium(0) with triethylamine in deoxygenated N,N-
dimethylformamide, at a ature between 100 ºC and 160 ºC for 30 minutes to several hours
under microwave irradiation. Alternatively, the reactions can be carried out at an elevated
ature such as between 100 ºC and 140 ºC for a longer reaction time t microwave
irradiation.
nds of interest Ict can be prepared by reduction of s IIcj followed by
hydrolysis. Reduction can be achieved by treating alkenes IIcj with 2-
enzenesulfonylhydrazide in the presence of triethylamine in dichloromethane at room
temperature for several hours. Hydrolysis can be carried out with a suitable base, such as lithium
hydroxide, or sodium hydroxide in a mixture of water and organic solvent, such as
tetrahydrofuran or methanol at room temperature for several hours.
Amides Icu can be prepared by hydrogenation of alkenes IIck followed by hydrolysis of
nitriles. Hydrogenation reaction can be carried out in the ce of palladium on carbon under
hydrogen atmosphere in methanol at room temperature for several hours. Hydrolysis can be
achieved by treating nitriles with a base such as potassium hydroxide in tert -butanol under reflux
for several hours.
Alternatively, amides Icu can be prepared by aminolysis of esters IIcj . The reaction can be
typically conducted in an ammonia on in tetrahydrofuran at a temperature between 25 ºC to
70 ºC for several hours.
Amines Icv can be prepared by reduction of amides Icu . The reaction can be achieved by
treating amides Icu with borane in tetrahydrofuran at an elevated temperature such as 65 °C for
several hours.
General synthetic route for formula Icw and Icx (Scheme 47)
Scheme 47
R3 E NHAc R3 O
A R4 R6 A R4 R6
R2 N N R2 N N
R7 R7
R1 R1
IIab S O IIcl S O
R8 R8
O O
O R3 O 2
m A R4 R6
R2 N N
XXII R1
Icw S O
N H
R3 O R3 O
A R4 R6
A R4 R6
R2 N N
R7 R2 N N
R1 R1
IIcm S O
R8 Icx S O
O R8
E is Br or cl,
m is 1 or 2
Compounds of interest Icw and Icx can be prepared according to Scheme 47. Coupling of 4-
halogen quinolines IIab with N-(2-hydroxyethyl)acetamide followed by deacylation of IIcl
affords compounds of interest Icw. Coupling of IIab with protected alcohol XXII followed by
cleavage of tert-butyloxycarbonyl affords compounds of interest Icx.
Ethers IIcl and IIcm can be prepared by coupling of 4-halogen quinolines IIab with N-
roxyethyl)acetamide and XXII separately. The reaction can be carried out with a
palladium st such as 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride in
combination with 1,1'-bis(diphenylphosphino)ferrocene and sodium tert-butoxide in a suitable
organic solvent such as 1,4-dioxane in a sealed microwave process vial at an ed
temperature such as 130 ºC under microwave ation for 1 to several hours.
2-Aminoethyl ethers Icw can be prepared by ation of IIcl. The reaction can be
carried out in an aqueous solution of hydrochloric acid at an elevated ature such as 80 ºC
for several hours.
Compounds of interest Icx can be prepared by cleavage of tert- butyloxycarbonyl. The
reaction can be carried out with trifluoroacetic acid in romethane or hloride in ethyl
acetate at room temperature for several hours.
General synthetic route for formula Icy (Scheme 48)
Scheme 48
O O
R3 Cl
R3 O O
R2 N Cl
R2 N Cl
IIId IIcn
R3 OH
A R4 R6
R2 N N R7
R2 N Cl
IIcp S R8 R1 IIco
A R4 R6
R2 N N R7
Icy S O R8
Compounds of interest Icy can be prepared according to Scheme 48. Starting with 2,4-
dichloro-quinolines IIId, regioselective phillic ement with diethyl malonate
followed by hydrolysis affords carboxylic acids IIco. Coupling of IIco with benzothiazepines
and decarboxylation in a tandem reaction affords 4-methyl-quinolines IIcp. Oxidation of sulfides
IIcp affords sulfones Icy.
IIcn can be prepared from regioselective nucleophillic replacement with diethyl malonate.
The reaction can be carried out in the presence of a suitable base such as sodium hydride or
potassium ate, in an organic solvent such as N,N-dimethylformamide, at an elevated
temperature, typically at 70 °C for several hours to overnight.
Carboxylic acids IIco can be prepared from hydrolysis of IIcn. The on can be carried
out with a suitable base such as lithium hydroxide or sodium hydroxide in a suitable mixed
solvent such as tetrahydrofuran and water or methanol and water, at room temperature for
several hours.
IIcp can be obtained by coupling of 2-chloroquinolines IIco with benzothiazepines and
decarboxylation in a tandem reaction. The reaction ably can be carried out with or without
an c solvent such as n-butanol under microwave irradiation at a temperature between 150
ºC and 170 ºC for several hours.
Compounds of interest Icy can be prepared by oxidation of IIcp. The reaction can be
carried out in analogy to oxidation of quinolines IIac in Scheme 4.
General synthetic route for formula Icz (Scheme 49)
Scheme 49
N O
R3 Br N O OH
O R3
A R4 R6
H A R4 R6
R2 N N
R7 R2 N N
R1 R7
IIcq S R1
R8 IIcr S
N O
R3 O
A R4 R6
A R4 R6
R2 N N
R7 R2 N N
R1 R7
Icz S O R8 IIcs S
O O R8
O
Compounds of interest Icz can be prepared according to Scheme 49. Starting with 4-
uinolines IIcq, on with a lithium alkylide followed by reaction with butoxycarbonylpiperidinecarboxaldehyde
provides the secondary alcohols IIcr. Dess-Martin
oxidation of IIcr followed by cleavage of tert-butyl carbamates affords compounds of interest
Icz.
IIcr can be obtained by reaction of oquinolines IIcq with a lithium alkylide
followed by reaction with 1-tert-butoxycarbonylpiperidinecarboxaldehyde. The conversion
can be achieved by ng 4-bromo-quinolines IIcq with llithium and 1-tertbutoxycarbonylpiperidinecarboxaldcehyde
in an inert c t such as tetrahydrofuran
at -78 °C, then at room temperature overnight.
Compounds of interest Icz can be obtained by Dess-Martin ion of IIcr followed by
cleavage of tert-butyl carbamates. Oxidation of IIcr can be carried out with a suitable oxidant
such as Dess-martin reagent in dichloromethane at room temperature overnight, or with
manganese dioxide in toluene under reflux for several hours. Cleavage of tert-butyl carbamates
can be achieved by treating tert-butyl carbamates IIcs with a suitable acid such as hydrochloric
acid, trifluoroacetic acid, or sulfuric acid in a le solvent such as methanol, ethyl acetate,
dichloromethane, 1,4-dioxane, water or the mixture thereof at a temperature between 0 ºC and
room temperature for 30 minutes to several hours. Typically the reaction can be carried out by
treating utyl carbamates IIcs with trifluoroacetic acid in dichloromethane at room
temperature for 6 hours.
General synthetic route for formula Ida (Scheme 50)
Scheme 50
OH N
B OH N
R3 Br R3
A R4 R6 N
N A R4 R6
R2 N N
R7 R2 N N
R1 R1
IIct S O
R8 Ida S O
O O
Compounds of interest Ida can be prepared according to Scheme 50. Coupling of bromides
IIct with 1H-pyrazoleboronic acid affords Ida. The reaction can be carried out in the ce
of a palladium catalyst such as (triphenylphosphine)palladium with sodium carbonate in a
suitable c solvent such as benzene or oxyethane, at a temperature between 80 ºC
and 120 ºC, typically at 80 ºC for 1 hour under microwave irradiation
General synthetic route for formula Ida (Scheme 51)
Scheme 51
R3 S
R3O S
A R4 R6 R5
A R4 R6
R2 N N
R7 R2 N N
R1 R7
IIcu X R1
R8 Idb X
R3 Cl R3 SH
R5 R5
A R4 R6 A R4 R6
R2 N N R2 N N
R7 R7
R1 R1
IIbi X IIcv X
R8 R8
NH 2 Cl
R3O S O R3O S O
R5 R5
A R4 R6 A R4 R6
R2 N N R2 N N
R7 R7
R1 R1
Idc X
R8 IIcw X
Compounds of interest Idb and Idc can be prepared according to Scheme 51. Coupling of
chlorides IIbi with ethiol affords IIcu. Oxidation of IIcu affords compounds of interest
Idb. Coupling of chlorides IIbi with sodium methanethiolate affords IIcv. Oxidation and
chlorination of IIcv affords sulfonyl chlorides IIcw. Coupling of sulfonyl chlorides IIcw with
1,2-diamine affords compounds of interest Idc.
nds of interest of a IIcu can be prepared by coupling of chlorides IIbi
with benzenethiol. The reaction can be carried out with a le base such as N,N-
dimethylpyridinamine in a le solvent such as ethanol at room temperature for several
days.
Sulfones Idb can be prepared by oxidation of IIcu. The reaction can be carried out with a
suitable oxidation reagent such as m-chloroperbenzoic acid in a suitable solvent such as
dichloromethane at a temperature between 0 ºC and room temperature for 1 to several hours.
Thiols IIcv can be prepared by coupling of chlorides IIbi with sodium methanethiolate.
The reaction can be carried out in a suitable solvent such as N,N-dimethylformamide under
reflux overnight.
Sulfonyl chlorides IIcw can be prepared by oxidation-chlorination of IIcv. The reaction
can be carried out in a le solvent such as hloric acid by bubbling of chlorine at a
temperature between 0 ºC and 10 ºC for 30 minutes.
Compounds of interest Idc can be prepared by coupling of chlorides IIcw with ethyl-1,2-
diamine. The reaction can be carried out with a suitable base such as triethylamine or ethyldiisopropyl-amine
in a suitable solvent such as dichloromethane at a temperature n 0 ºC
and room temperature overnight.
General synthetic route for a Idd, Ide and Idf (Scheme 52)
Scheme 52
O R3 Cl
NH NH
2 2 O R3 NH NH
O R4 R6 O
O O R4 R6
R2 N N
R7 R2 N N
R1 R7
IIbv S R1
O R8 Idd
O O R8
OH R3 Cl
OH R3 NH NH2
R4 R6
O O R4 R6
R2 N N
R1 R2 N N
IIcx S O R8 R1
O S O R8
NH NH
2 2
OH R3 NH NH2
O R4 R6
R2 N N
Idf S O R8
nds of interest Idd , Ide and Idf can be prepared according to Scheme 52.
Coupling of des IIbv with C-(3-aminomethyl-oxetanyl)-methylamine generates Idd .
Hydrolysis of esters affords carboxylic acids Ide . Reduction of esters IIbv followed by coupling
with C-(3-aminomethyl-oxetanyl)-methylamine generates compounds Idf .
Compounds Idd can be prepared by coupling of chlorides IIbv with C-(3-aminomethyloxetanyl
)-methylamine. The reaction can be carried in y to coupling of 4-halogen
quinolines IIab with various amines XI in Scheme 5. Typically the reaction can be carried out
with tris(dibenzylideneacetone)dipalladium(0), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and
sodium tert -butoxide in e at 110 ºC overnight under nitrogen atmosphere.
Acids Ide can be prepared from hydrolysis of methyl esters Idd . The reaction can be
carried out with a le base such as sodium hydroxide or lithium hydroxide in a mixture
solvent of tetrahydrofuran and water at a temperature between room temperature and 60 ºC,
typically at room temperature for several hours or ght.
Hydroxides IIcx can be prepared by reduction of esters IIbv . The reaction can be carried
out with a standard reduction agent such as m ium hydride in a suitable solvent such
as tetrahydrofuran, at a temperature between 0 ºC and room temperature for several hours,
typically at room temperature for 2 hours.
Compounds Idf can be prepared by coupling of IIcx with C-(3-aminomethyl-oxetan
yl)-methylamine. The reaction can be carried out in analogy to coupling of IIbv with C-(3-
aminomethyl-oxetanyl)-methylamine in this scheme.
General synthetic route for formula Idg (Scheme 53)
Scheme 53
Cl O
Br Br
N N
N Cl N Cl
R4 R6
IIId IIcy
S R8
O Br
CD N R6
3 N R6 CD O S CF R4
R4 3 3
O N N
N N R7
IIcz S
S R8
IIda R8
NH NH
2 2 NH NH2
O CD
CD3 N O R6
N R6 R4
N N
N N R7
Idg R8
IIdb S
R8 O
Compounds of interest Idg can be prepared according to Scheme 53. Starting with 2,4-
dichloro-quinazolines IIId, reaction with benzyl alcohol followed by coupling with
benzothiazepines IVf affords benzyloxy compounds IIcz. Substitution of bromo with -d3
followed by oxidation affords 6-methyl-d3-quinazolines IIdb. ng of IIdb with C-(3-
aminomethyl-oxetanyl)-methylamine affords compounds of interest Idg.
2-Chlorobenzoxy quinazolines IIcy can be prepared by reaction of 2,4-dichloroquinazolines
IIId with benzyl alcohol. The reaction can be carried out in the presence of a
suitable base such as sodium hydride in an organic solvent such as tetrahydrofuran, acetonitrile
or N,N-dimethylformamide at 0 °C followed by at room temperature for several hours.
IIcz can be prepared by coupling of IIcy with hiazepines IVf. The reaction can be
carried out t any base and without any solvent at a temperature between 80 °C and 160
°C, typically at 80 °C for 10 minutes to 2 hours.
6-Methyl-d3-quinazolines IIda can be prepared by substitution of bromo with methyl-d3.
The reaction can be carried out by treating IIcy with n-butyllithium in ous tetrahydrofuran
at -78 °C for several minutes under nitrogen followed by stirring with methyl-d3
trifluoromethanesulfonate at -78 °C and then at room temperature for 1 to several hours.
Sulfoxides IIdb can be prepared by oxidation of IIda. The reaction can be carried out by
treating IIda with 1-2 equivalents of 3-chloroperoxybenzoic acid in a le c solvent
such as dichloromethane, chloroform, 1,2-dichloroethane or the mixtures thereof, typically at 0
ºC, followed by stirring at room temperature for 10 to 20 minutes.
Compounds of interest Idg can be prepared by coupling of IIdb with C-(3-aminomethyloxetanyl
)-methylamine. The reaction can be carried out without any t and t any
base at an elevated temperature such as 170 °C for 20 minutes.
General synthetic route for formula Idh (Scheme 54)
Scheme 54
O O O
N R6 O N R6
R4 R4
N N N N
R7 R7
IIda S IIdc S
R8 R8
O O
OH O
O N R6
O N R6 R4
N N
N N R7
IIde S IIdd R8
R8 O
O m
NH NH
2 2
O NH NH
O N O R6
N N
Idh S
R8 m is 1 or 2
Compounds of interest Idh can be prepared according to Scheme 54. Starting with 6-
bromo-quinazolines IIda , carbonylation ed by esterification, oxidation and hydrolysis
affords acids IIde . Coupling of IIde with C-(3-aminomethyl-oxetanyl)-methylamine
generates compounds of interest Idh .
6-Methoxycarbonyl quinazolines IIdc can be prepared by carbonylation of 6-bromoquinazolines
IIda followed by esterification. ylation can be carried out with dry ice in the
presence of n-butyllithium in tetrahydrofuran at -78 °C under nitrogen atmosphere, followed by
stirring at room temperature for 1 to several hours. Methyl esterification can be d out in
methanol in the presence of sulfinyl chloride or concentrated sulfuric acid at a temperature
n room temperature and 70 °C for 1 to several hours
Compounds IIdd can be prepared by oxidation of IIdc . Oxidation can be carried out by
treating IIdc with 1-2 lent(s) of 3-chloroperoxybenzoic acid in a suitable organic solvent
such as dichloromethane, form, 1,2-dichloroethane or mixtures thereof, typically at 0 ºC,
followed by stirring at room temperature for 10 s to several hours.
Acids IIde can be prepared by hydrolysis of methyl esters IIdd . The reaction can be
d out with a suitable base such as sodium hydroxide or lithium hydroxide in a mixture of
tetrahydrofuran and water at a temperature between room temperature and 60 ºC, typically at
room ature for several hours or overnight.
Compounds of interest Idh can be ed by couplin, g of IIde with C-(3-
aminomethyl-oxetanyl)-methylamine. The reaction can be carried out without any solvent and
without any base at 170 °C for 30 minutes.
General synthetic route for formula Idi (Scheme 55)
Scheme 55
O H O
N R6 O N R6
R4 R4
N N N N
R7 R7
IIdf
IIda S S
R8 R8
OH O OH O
N R6 N R6
R4 R4
N N
R7 N N
IIdh S
R8 IIdg S
NH NH
2 2
OH NH NH
N O R6
N N
Idi S
O m is 1 or 2
Compounds of Idi can be prepared according to Scheme 55. Starting with 6-bromo
quinazolines IIda, Bouveault formylation followed by ion of aldehyde and ion of
sulfide affords 4-benzyloxyhydroxymethyl-quinazolines IIdh. Coupling of IIdh with C-(3-
aminomethyl-oxetanyl)-methylamine generates compounds of interest Idi.
Aldehydes IIdf can be prepared by ult formylation. The reaction can be carried
out by treating bromide with n-butyllithium in anhydrous tetrahydrofuran at -78 oC followed by
stirring with anhydrous N,N-dimethylformamide at -78 oC for 30 minutes to several hours .
6-Hydroxymethyl-quinazolines IIdg can be prepared by reduction of aldehydes. The
reaction can be carried out with sodium borohydride in a suitable organic solvent such as
methanol, tetrahydrofuran or the mixture thereof at 0 oC for 15 s to several hours.
IIdh can be ed by oxidation of sulfides. Oxidation can be carried out with 1-2
equivalents of 3-chloroperoxybenzoic acid in a suitable organic solvent such as dichloromethane,
chloroform, chloroethane or mixtures thereof, typically at 0 ºC, ed by stirring at
room temperature for 10 minutes to several hours.
Compounds of interest Idi can be prepared by coupling IIdh with C-(3-aminomethyloxetanyl
)-methylamine. The on can be d out without any solvent and without any
base at 160 °C for 30 minutes.
l synthetic route for formula Idj (Scheme 56)
Scheme 56
R4 R6
R3 E NH R3 E
A A R4 R6
R2 N E R2 N N
R1 R1
IIIa IIdi R8
R12 R13
R12 R13
R3 N
A R4 R6
R2 N N
E is Cl or Br R1
Idj R8
Compounds of interest Idj can be prepared according to Scheme 56. Starting with 2,4-
dihalogen-quinolines IIIa, coupling with benzoazepines IVi affords 2-benzoazepinhalogenqunolines
IIdi. Coupling of IIdi with various amines generates compounds of interest Idj.
2-Benzoazepinhalogen-qunolines IIdi can be prepared by ng of halogenquinolines
IIIa with benzoazepines IVi. The reaction can be carried out with or without a
solvent such as n-butanol at 160 oC for several hours under microwave irradiation.
Compounds of interest Idj can be prepared by ng of IIdi with various amines. The
reaction can be carried out in analogy to coupling of 4-halogen-quinolines IIab with various
amines XI in Scheme 5. Typically the reaction can be carried out in the presence of 1,1'-
bis(diphenylphosphino)ferrocene, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
and sodium tert-butoxide in 1,4-dioxane at 120 oC for 1.5 hours under microwave irradiation.
l synthetic route for formula Idk (Scheme 57)
Scheme 57
NH R3 OH
R3 OH
A N
A N O
R2 N N
R2 N Cl
R1 IIdj
IIIc O
NH2 R3 OH
R3 NH
A N
A N O
R2 N N
R2 N N
R1 OH
Idk OH IIdk
Compounds of interest Idk can be prepared according to Scheme 57. Starting with IIIc,
coupling with 1,2,3,4-tetrahydro-benzo[c]azepinone followed by reaction with methyl
magnesium bromide affords 5-methylhydroxy benzothiazepines IIdk. Coupling of IIdk with
omethyl-oxetanylamine generates compounds of st Idk.
2-Benzoazepin-quinolines IIdj can be prepared by coupling of IIIc with 1,2,3,4-
tetrahydro-benzo[c]azepinone. The reaction can be d out in the presence of an organic
base such as triethylamine in toluene under reflux overnight.
ylhydroxy benzothiazepines IIdk can be prepared by reaction of ketones IIdj
with methyl magnesium bromide. The conversion can be achieved by stirring of IIdj with
methyl magnesium bromide in tetrahydrofuran at 50 oC for several hours.
Compounds of interest Idk can be prepared by ng of IIdj with 3-aminomethyloxetanylamine.
The reaction can be carried out in the presence of a suitable base such as 1,8-
diazabicyclo[5.4.0]undecene with a suitable phosphine ligand such as benzotriazol
yloxytris(dimethylamino)-phosphonium hexafluorophosphate, in a suitable t such as N,N-
dimethylformamide at room temperature for several hours.
General synthetic route for formula Idl (Scheme 58)
Scheme 58
W9 N
W9 N
2NH R3 Cl R3 NH
A N A N
XXIII
R2 N Cl R2 N Cl
R1 R1
IIIb IIdl
W9 NH
W9 N
R3 NH
R3 NH
A N
A N
R2 N N
R1 R2 N N
Idl R1
F IIdm
W9 is O or SO2
Compounds of interest Idl can be prepared according to Scheme 58. Starting with IIIb,
reaction with various benzylamino mines XXIII affords IIdl. Substitution of 2-chloro with
,5-difluoro-2,3,4,5-tetrahydro-1H-benzo[c]azepine followed by deprotection of benzyl
generates compounds of st Idl.
2-Chloro-quinazolines IIdl can be prepared by coupling of IIIb with various amines
XXIII. The reaction can be carried out in the presence of a le base such as triethylamine in
a suitable t such as methanol, tetrahydrofuran, dichloromethane or mixtures thereof at a
temperature between 0 oC and room temperature for several hours or overnight.
Compounds Idl can be prepared by standard benzyl deprotection of IIdm. The reaction
can be carried out with palladium on carbon, palladium hydroxide on carbon or platinum oxide,
typically with on of acetic acid or trifluoroacetic acid in a suitable solvent such as
methanol, ethanol, tetrahydrofuran, ethyl acetate or the mixture thereof, at room temperature for
l hours under hydrogen atmosphere.
A. General synthetic route for formula Idm (Scheme 59)
Scheme 59
R5 R5 R5
H H
R6 O R6 N R6 N
R7 R7 R7
R8 R8 R8
XXIV IVj IVk
R3 E
R2 N E
IIIa
R3 N R12 R13 R3 E
R5 H R5
A A
R6 R6
R2 N N R2 N N
R7 R7
R1 R1
Idm R8 IIdn R8
E is chloro or bromo
Compounds of interest Idm can be prepared according to Scheme 59. ng with
naphthalenones XXIV, ring expansion with hydrazoic acid gives benzoazepinones IVj.
Reduction of lactams IVj to benzoazepines IVk followed by coupling of IVk with 2,4-dihalogen
quinolines IIIa gives 4-halogen quinolines IIdn. Coupling of IIdn with s amines XI
affords compounds of interest Idm.
zepinones IVj can be prepared from ring expansion of naphthalenones XXIV
by using sodium azide. The reaction can be carried out in toluene with a suitable acid such as
trifluoromethanesulfonic acid, trifluoroacetic acid or hydrochloric acid, typically at 0 ºC,
followed by ng at room temperature for several hours.
Benzoazepines IVk can be prepared from benzoazepinones IVj by reduction of lactams.
The reaction can be d out with standard reducing agent such as lithium aluminium hydride,
boron hydride or combination of sodium borohydride and boron trifluoride in a suitable inert
organic solvent such as tetrahydrofuran, diethyl ether or mixtures thereof, typically at 0 ºC,
followed by ng at a temperature between 25 ºC and 70 ºC for several hours.
gen quinolines IIdn can be prepared from coupling of zepines IVk and 2,4-
dihalogen quinolines IIIa. The reaction can be carried out with a suitable acid such as
hydrochloric acid or p-toluenesulfonic acid in a suitable organic solvent such as toluene,
dioxane, n-butyl alcohol or 2-methylpentanol at a temperature between 100 ºC and 120 ºC for
several hours. Alternatively, the reaction can be carried out without acid at a ature
between 100 ºC and 160 ºC for 1 to 3 hours under microwave irradiation.
Compounds of interest Idm can be prepared by coupling of 4-halogen quinolines IIdn
with various amines XI. The reaction can be achieved by microwave irradiation at a temperature
between 140 ºC and 160 ºC for 1 to 3 hours with or without organic solvent such as N,N-
dimethylformamide, 1-methylpyrrolidinone or l alcohol.
B. General tic route for formula Idm (Scheme 60)
Scheme 60
R5 R2 NH2
H R6
R6 N
N R1
XVIII
IVk IVm
R3 N R3 NH2
R5 R5
A R6 A R6
R2 N N R2 N N
R7 R7
R1 R1
IIdo R8 IIdp R8
R3 N R12 R13 R3 Cl
R5 H R5
A A
R6 R6
R2 N N R2 N N
R7 R7
R1 R1
Idm R8 IIdq R8
Compounds of interest Idm can be prepared according to Scheme 60. Acylation of
benzoazepines IVk, followed by ng with 2-aminobenzonitriles XVIII provides imines
IIdo. Ring closure of imines IIdo gives oquinolines IIdp. Sandmeyer reaction of 4-
aminoquinolines IIdp provides 4-halogen quinolines IIdq . ng of IIdq with various
amines XI generates compounds of st Idm .
Acetyl benzoazepines IVm can be prepared by acylation of benzoazepines IVk with acetyl
chloride or acetic ide. The reaction can be carried out with a suitable base such as
triethylamine or pyridine in a suitable inert organic solvent such as dichloromethane,
tetrahydrofuran or pyridine at 0 ºC, followed by stirring at room temperature for 30 minutes.
Imines IIdo can be prepared by g a mixture of IVm , 2-aminobenzonitriles XVIII
and phosphorous oxychloride. The reaction can be d out in a suitable inert c solvent
such as dichloromethane, chloroform or the mixtures thereof, lly at a temperature between
0 ºC and 10 ºC, followed by stirring under reflux for 24 hours.
Ring closure of imines IIdo to give 4-aminoquinolines IIdp can be achieved by treatment
of IIdo with Lewis acid such as zinc chloride in N,N -dimethyl-acetamide at a temperature
between 120 ºC and 180 ºC for several hours in an inert atmosphere.
Intermediates IIdq can be prepared from oquinolines IIdp by using Sandmeyer
reaction. The conversion is typically conducted in standard Sandmeyer reaction conditions such
as sodium nitrite, hydrochloric acid and sodium chloride or copper(I) chloride in a suitable
solvent such as water, typically at -10 ºC, followed by ng at room temperature for several
hours.
Compounds of interest Idm can be prepared by coupling of IIdq with various amines XI .
The reaction can be achieved by microwave irradiation at a temperature between 140 ºC and 160
ºC for 1-3 hours with or t organic solvent such as N,N -dimethylformamide, 1-methylpyrrolidinone
or n-butyl alcohol.
General synthetic route for formula Idn (Scheme 61)
Scheme 61
R3 E
H L20 S O Na H
N R2 N E
XXV O R1 IIIa
Br L20
IVn O IVo
R12 R13
H R12 R13
R3 E R3 N
A A
O O
R2 N N R2 N N
S S
R1 L20 R1 L20
IIdr O Idn O
L20 is C1-6 alkyl;
E is chloro or bromo.
nds of interest Idn can be prepared according to Scheme 61. Starting with 7-
bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine IVn, copper-catalyzed coupling with sodium
sulfinates XXV gives sulfonyls IVo. Coupling of IVo with 2,4-dihalogen quinolines IIIa gives
gen quinolines IIdr. ng of IIdr with various amines XI s compounds of
interest Idn.
The copper-mediated coupling reaction of 7-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine
IVn with sodium sulfinates XXV illustrated above can be carried out in the presence of a copper
source such as (I) iodide (CuI), and a ligand such as 2,2'-bipyridine, L-proline, N,N-
dimethyl glycine or ethylene glycol, with a suitable base such as triethylamine, sodium
carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tertbutoxide
, sodium hydride or 1,8-diazabicyclo[5.4.0]undecene. The reaction can be carried out
in a le organic t such as acetonitrile, toluene, 1,4-dioxane, N,N-dimethylformamide,
dimethyl sulfoxide or 1-methyl-pyrrolidinone at a temperature between 100 ºC and 180 ºC for
15 to 60 minutes under microwave irradiation. Alternatively, the reactions can be carried out at a
temperature such as 130 ºC for a longer reaction time without the use of microwave irradiation.
Compounds IIdr can be ed from coupling of benzoazepine IVo and halogen
quinolines IIIa. The reaction can be carried out with a suitable acid such as hydrochloric acid or
p-toluenesulfonic acid in a suitable organic solvent such as toluene, dioxane, n-butyl alcohol or
2-methylpentanol at a temperature between 100 ºC and 120 ºC for several hours.
Alternatively, the reaction can be carried out t acid at a temperature between 100 ºC and
160 ºC for 1-3 hours under microwave irradiation.
Compounds of interest Idn can be prepared by coupling of IIdr with various amines XI.
The reaction can be achieved by microwave irradiation at 140-160 ºC for 1-3 hours with or
without organic solvent such as N,N-dimethylformamide, 1-methyl-pyrrolidinone or n-butyl
alcohol.
D. General synthetic route for formula Ido (Scheme 62)
Scheme 62
R3 Cl R3 Cl
L21E
A OH XXVI A OL21
R2 N N R2 N N
R1 R1
IIds IIdt
R12 R13
R3 N
A OL21
R2 N N
L21 is C1-6 alkyl;
E is chloro or bromo. Ido
Compounds of interest Ido can be prepared according to Scheme 62. Starting with phenols
IIds, tion with various XXVI provides IIdt. ng of IIdt with various amines XI
affords compounds of interest Ido.
nds IIdt can be prepared by alkylation of phenols IIds with XXVI. The reaction
can be carried out with a le base such as cesium carbonate, sodium tert-butoxide,
potassium tert-butoxide, sodium hydride or azabicyclo[5.4.0]undecene in an inert
organic solvent such as dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide or 1-
methyl-pyrrolidinone, typically at room temperature for several hours.
Compounds of interest Ido can be prepared by coupling of IIdt with various amines XI.
The reaction can be achieved by microwave irradiation at a temperature between 140 ºC and 160
ºC for 1 to 3 hours with or without organic solvent such as N,N-dimethylformamide, ylpyrrolidinone
or n-butyl alcohol.
F. General synthetic route for a Idp (Scheme 63)
Scheme 63
R3 Cl R3 Cl
A A
R2 N N R2 N N O
R1 R1
IIdu IIdv O
L22 L23
R3 Cl H
R3 Cl
XXVII
L22 A
R2 N N N L23
R2 N N O
IIdx O R1
IIdw OH
R12 R13
R3 N
R2 N N N L23 L22 is hydrogen or C1-6 alkyl;
R1 L23 is hydrogen or C1-6 alkyl.
Idp O
Compounds of st Idp can be prepared according to Scheme 63. Starting with IIdu,
palladium-catalyzed carbonylation gives carboxylic acid methyl esters IIdv. Basic hydrolysis of
esters IIdv to acids IIdw ed by coupling with various amines XXVII to furnishes amides
IIdx. Coupling of IIdx with various amines XI affords compounds of interest Idp.
Palladium-catalyzed carbonylation of IIdu to the corresponding methyl esters IIdv can be
accomplished under an atmosphere of carbon monoxide (1 atmospheric pressure) in methanol.
The reaction can be carried out in the presence of a palladium catalyst such as
bis(triphenylphosphine)dichloropalladium(II), palladium(II) acetate,
tetrakis(triphenylphosphine)palladium(0), or tri(dibenzylideneacetone)dipalladium(0), in the
ce or absence of a phosphine ligand such as tricyclohexylphosphine or
nylphosphine, and a suitable base such as triethylamine, sodium carbonate or ium
carbonate at a temperature between 60 ºC and 120 ºC for several hours.
Hydrolysis of the methyl esters IIdv to acids IIdw can be d out in the presence of an
aqueous inorganic base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide in
a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several
hours.
Amides IIdx can be prepared by coupling various amines XXVII with carboxylic acids
IIdw . The reaction is typically conducted with standard peptide coupling reagents such as 1-
ethyl(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole, bromo-tris -
pyrrolidino-phosphoniumhexafluorophosphate and diisopropylethylamine, or O-(7-
azabenzotriazolyl)-N,N,N',N' methyluronium hexafluorophosphate and a base such as
triethylamine, or diisopropylethylamine in a suitable inert t such as dichloromethane or
N,N -dimethylformamide or mixtures f at room temperature for several hours.
Compounds of interest Idp can be prepared by coupling of amides IIdx with various
amines XI . The reaction can be conducted by ave irradiation at a temperature between
140 ºC and 160 ºC for 1 to 3 hours with or without organic solvent such as N,N -
dimethylformamide, 1-methyl-pyrrolidinone or n-butyl alcohol.
G. General synthetic route for formula Idq (Scheme 64)
Scheme 64
R6 N
R3 E
R3 E
R7 R5
A R6
A R8
IVp R2 N N
R2 N E R1
R1 R8
IIIa IIdy
R12 R13
R3 N
A R6
R2 N N
Compounds of interest Idq can be prepared according to Scheme 64. Palladium-catalyzed
coupling of lactams IVp with 2,4-dihalogenquinolines IIIa gives intermediates IIdy. ng
of IIdy with various amines XI generates nds of interest Idq.
Intermediates IIdy can be prepared from lactams IVp by coupling with 2,4-
dihhalogenquinolines IIIa. The reaction can be carried out typically in the presence of a
palladium catalyst such as iphenylphosphine)dichloropalladium(II), palladium(II) acetate,
tetrakis(triphenylphosphine)palladium(0), or tri(dibenzylideneacetone)dipalladium(0), in the
presence of a phosphine ligand such as tricyclohexylphosphine, or methyl-4,5-
bis(diphenylphosphino)xanthene, with a suitable base such as potassium ate tribasic,
sodium carbonate or potassium carbonate, in a suitable inert organic solvent such as dioxane, or
N,N-dimethylformamide, at a temperature between 100 ºC and 150 ºC for several hours.
Compounds of interest Idq can be prepared by coupling of IIdy with various amines XI.
The reaction can be achieved by microwave irradiation at a ature between 140 ºC and 160
ºC for 1 to 3 hours with or without organic solvent such as N,N-dimethylformamide, ylpyrrolidinone
or n-butyl alcohol.
H. General synthetic route for formula Ids(Scheme 65)
Scheme 65
O O
2NH NH
NH2 NH
NH NH2
R3 NH N R3 NH
R5 R5
A R6 A R6
R2 N N R2 N N
R7 R7
R1 R1
R8 R8
Idr Ids
Compounds of interest Ids can be prepared according to Scheme 65. Starting with
diamines Idr (prepared in analogue to Idm in Scheme 59 or Scheme 60), guanidation with 3,5-
dimethyl-1H-pyrazolecarboximidamide e gives guanidines Ids. The reaction can be
carried out in a suitable solvent such as ethanol, typically at a temperature between 70 ºC and 90
ºC for several hours.
L. General tic route for formula Idt (Scheme 66)
Scheme 66
CO Me
CO Me
H N Cl R5
R6 N XXVIII
N N
R8 IIdz R8
N N
Idt R8
Compounds of interest Idt can be prepared according to Scheme 66. Starting with
benzoazepines IVk, coupling with 2-chloro-quinolinecarboxylic acid methyl ester XXVIII
gives compounds IIdz, which are in turn reduced to compounds of interest Idt.
Esters IIdz can be ed from benzoazepines IVk by coupling with 2-chloro-quinoline-
oxylic acid methyl ester XXVIII. The reaction can be carried out with a suitable acid such
as hydrochloric acid or p-toluenesulfonic acid in a suitable organic solvent such as toluene,
dioxane, n-butyl alcohol or 2-methylpentanol at a temperature n 100 ºC and 120 ºC for
several hours. Alternatively, the reaction can be d out without acid at a temperature
between 100 ºC and 160 ºC for 1 to 3 hours under microwave irradiation.
Alcohols Idt can be prepared from methyl esters IIdz by reduction. The reaction is
typically conducted in a tetrahydrofuran solution of borane at 0 ºC, followed by stirring at reflux
temperature for several hours.
M. General synthetic route for formulas Idu and Idv (Scheme 67)
Scheme 67
A R6
R2 N N
O O R7
R3 E B R1
R5 R8
A R6
R2 N N
IIdn R8
A R6
R2 N N
IIea
R3 OH
A R6
R2 N N
R8
Compounds of interest Idu and Idv can be prepared ing to Scheme 67. Starting with
4-halogen quinolines IIdn, Suzuki reaction coupling with 2-allyl-4,4,5,5-tetramethyl-
]dioxaborolane gives 4-allyl-quinolines IIea and compounds Idv as a byproduct. 4-Allylquinolines
IIea are then converted to nds of interest Idu by Upjohn dihydroxylation.
4-Allyl-quinolines IIea and compounds Idv can be prepared from 4-halogen quinolines
IIdn by Suzuki coupling with 2-allyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane. The reaction is
typically conducted in 1,2-dimethoxyethane and water with potassium carbonate,
tetrakis(triphenylphosphine)palladium(0), at a temperature between 80 ºC and 140 ºC for several
hours under microwave irradiation. Alternatively, the reactions can be d out at a heated
temperature such as a temperature n 100 ºC and 140 ºC for a longer reaction time without
the use of microwave irradiation.
nds of interest Idu can be prepared from 4-allyl-quinolines IIea by Upjohn
oxylation. The reaction can be typically carried out in water with osmium tetroxide and N-
methyl morpholine-N-oxide at room temperature for several hours.
P. General synthetic route for formula Idw e 68)
Scheme 68
R3 E
A R3 E
R2 N E R5
R8 A R6
H L24
R1 IIIa
R7 N
R2 N N
R6 N N
H IIeb H R8
R5 L24
R12 R13
R3 N
A R6
R2 N N
Idw N
H R8
L24 is hydrogen or oxygen. L24
Compounds of interest Idw can be prepared according to Scheme 68. Starting with
diazepines IVq, coupling of 2,4-dihalogen quinolines IIIa with IVq furnishes IIeb. Subsequent
coupling of IIeb with various amines XI generates compounds of interest Idw.
Compounds IIeb can be prepared from coupling of 2,4-dihalogen ines IIIa with
diazepines IVq . The reaction can be carried out with a suitable acid such as hloric acid or
p-toluenesulfonic acid in a suitable organic solvent such as toluene, dioxane, n-butyl l or
2-methylpentanol at a temperature between 100 ºC and 120 ºC for several hours.
Alternatively, the on can be carried out without acid at a temperature between 100 ºC and
160 ºC for 1 to 3 hours under microwave irradiation.
Compounds of interest Idw can be prepared by coupling of compounds IIeb with various
amines XI . The reaction can be carried out typically in the presence of a palladium catalyst such
as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
(triphenylphosphine)dichloropalladium(II), palladium(II) acetate, or
tri(dibenzylideneacetone)dipalladium(0), in the presence of a phosphine ligand such
bis(diphenylphosphino)ferrocene, tricyclohexylphosphine, or 9,9-dimethyl-4,5-
bis(diphenylphosphino)xanthene, with a suitable base such as sodium tert -butoxide, in a suitable
inert organic solvent such as e, or N,N -dimethylformamide, at a ature between 100
ºC and 150 ºC for 1 to 3 hours under microwave irradiation. Alternatively, the reactions can be
carried out at a heated temperature such as a temperature n 100 ºC and 140 ºC for a
longer reaction time without the use of microwave irradiation.
R. General synthetic route for formula Idx (Scheme 69)
Scheme 69
R5 R5
R6 CN R6 CN
R7 OH R7 O CO Me
R8 XXIX R8 XXX
R3 E
R5 R5
H H R2 N E
R6 N R6 N
R1 IIIa
R7 O R7 O
R8 R8
IVr IVs
R3 E R12 R13 R13
N R3 N
R5 H
A R6 XI R5
A R6
R2 N N
R7 R2 N N
R1 R7
IIec O
R8 Idx O
Compounds of interest Idx can be prepared ing to Scheme 69. Starting with
hydroxybenzonitriles XXIX, alkylation with methyl bromoacetate gives esters XXX.
Intramolecular cyclization of compounds XXX gives benzooxazepinones IVr, which are in
turn converted to benzooxazepines IVs by reduction. Coupling of IVs with 2,4-dihalogen
quinolines IIIa furnishes IIec. Subsequent coupling of IIec with various amines XI affords
compounds of interest Idx.
Esters XXX can be prepared from alkylation of hydroxybenzonitriles XXIX with methyl
bromoacetate. The reaction is typically carried out in acetone with ium carbonate at room
temperature for several hours.
Benzooxazepinones IVr can be prepared from esters XXX by intramolecular
cyclization. The reaction can be carried out in methanol with Raney nickel at room temperature
for several hours under an atmospheric pressure of en.
Benzooxazepines IVs can be prepared from benzooxazepinones IVr by reduction of
lactam. The on is typically conducted in an inert solvent such as tetrahydrofuran, diethyl
ether or mixtures thereof with lithium aluminium hydride, typically at 0 ºC, followed by ng
at reflux temperature for several hours.
Substituted quinolines IIec can be prepared from coupling of benzooxazepines IVs with
2,4-dihalogen quinolines IIIa. The reaction can be carried out with a suitable base such as
potassium carbonate, cesium ate, diisopropylethylamine, triethylamine, or 1,8-
diazabicyclo[5.4.0]undecene in an inert organic t such as toluene, ydrofuran, 1-
methyl-pyrrolidinone or N,N-dimethylformamide, typically at a temperature between 100 ºC
and 180 ºC for 1 to 3 hours under microwave irradiation.
Compounds of interest Idx can be prepared by coupling of substituted quinolines IIec with
various amines XI. The reaction can be achieved by microwave irradiation at a temperature
between 140 ºC and 180 ºC for 1 to 3 hours with or t organic solvent such as N,N-
dimethylformamide, 1-methyl-pyrrolidinone or n-butyl alcohol.
General synthetic route for formula Idy (Scheme 70)
Scheme 70
O R6
O L25
L25 N N
N O
O W10 R7
W10 R3 NH S
R3 Cl NH
2 O R8
XXXI A N IVd
A N
R2 N Cl
R2 N Cl
R1 IIIb IIed
L25 L25
N NH
R3 NH W10
R3 NH
A N A N
R6 R6
R2 N N R2 N N
R1 R7
R1 R7
IIef S
O Idy S
R8 O R8
O O
.W10 is methylcyclopropyl and L25 is hydrogen,
or W10 and L25 with nitrogen they are attached with form pyrrolindi nyl.
nds of interest of formula Idy can be prepared according to Scheme 70.
Coupling of chloro-quinozalines IIIb with various amines XXXI followed by reaction
with 6,7,8,9-tetrahydrothiaaza-benzocycloheptene 5,5-dioxides IVd affords 2,4 -
disubstituted quinozalines IIef. Deprotection of utyloxycarbonyl of IIef generates the
target compounds Idy.
2-Chloroamino quinozalines IIed can be prepared by coupling of IIIb with various
amines XXXI . The reaction can be carried out in the presence of a suitable base such as
triethylamine in a suitable solvent such as methanol, ydrofuran, romethane or
mixture thereof at a temperature between 0 °C to room temperature for several hours.
4 - Disubstituted quinozalines IIef can be obtained by the coupling of IIed with 6,7,8,9-
ydrothiaaza-benzocycloheptene 5,5-dioxides IVd . The reaction can be carried out
with or without an acid such as 4-methylbenzenesulfonic acid and ammonium chloride, in a
le solvent such as ethanol or N,N -dimethylformamide at an elevated temperature between
50 oC and 120 oC for several hours, typically at 70 °C overnight.
Compounds of interest of formula Idy can be prepared from ection of tert -
butyloxycarbonyl of 4 – disubstituted quinozalines IIef . The reaction can be carried out with a
suitable acid such as trifluoroacetic acid or hydrochloric acid in a suitable solvent such as
dichloromethane, ethyl acetate or 1,4-dioxane, at 0 °C to room ature for 30 minutes to 16
hours.
The invention also s to a compound of formula (I) for use as therapeutically active
substance.
The invention relates to a compound of formula (I) for use as a medicament.
The invention also relates to a pharmaceutical composition comprising a compound of
formula (I) and a therapeutically inert carrier.
The invention relates in particular to the use of a compound of formula (I) for the
preparation of a medicament for the treatment or prophylaxis of respiratory syncytial virus
infection.
Said medicaments, e.g. in the form of ceutical ations, can be stered
orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft ne capsules,
solutions, emulsions or sions. The administration can, however, also be effected rectally,
e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions with an
effective amount of a compound as defined above.
The above-mentioned pharmaceutical composition can be obtained by processing the
compounds according to this invention with pharmaceutically inert inorganic or organic carriers.
For example, e, corn starch or derivatives thereof, talc, stearic acids or its salts and the like
can be used, as such carriers for tablets, coated tablets, dragées and hard gelatine capsules.
Suitable rs for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid
and liquid polyols and the like. Depending on the nature of the active substance no carriers
are, however, usually required in the case of soft ne capsules. Suitable carriers for the
production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and
the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats,
semi-liquid or liquid polyols and the like.
The pharmaceutical composition can, moreover, contain preservatives, solubilizers,
stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the
osmotic re, buffers, masking agents or antioxidants. They can also contain still other
therapeutically valuable substances.
The dosage depends on various factors such as manner of stration, species, age
and/or individual state of health. The doses to be administered daily are about 5-400 mg/kg,
preferably about 10-100 mg/kg, and can be taken singly or distributed over several
administrations.
A compound of formula (I) when manufactured ing to the above process is also an
embodiment of the invention.
This invention relates to the use of a compound of a (I) for the manufacture of a
medicament for treatment or prophylaxis of RSV infection.
Also described herein is a method for the treatment or prophylaxis of respiratory syncytial
virus ion, which method ses administering an effective amount of a nd of
formula (I).
The invention is illustrated by the following examples which have no ng character.
Unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols
have the meanings well known to a person of ry skill in organic chemistry.
Examples
Intermediates and final compounds were purified by flash chromatography using one of the
following instruments: i) Biotage SP1 system and the Quad 12/25 Cartridge . ii) ISCO
combi-flash chromatography instrument. Silica gel Brand and pore size: i) KP-SIL 60 Å, particle
size: 40-60 µM; ii) CAS registry NO: Silica Gel: 632314, particle size: 47-60 micron silica
gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 0 or 300-400.
Intermediates and final compounds were ed by ative HPLC on reversed phase
column using X BridgeTM Perp C18 (5 µm, OBDTM 30 × 100 mm) column or SunFireTM Perp C18
(5 µm, OBDTM 30 × 100 mm) column.
LC/MS spectra were obtained using a MicroMass Plateform LC (WatersTM alliance 2795-
ZQ2000). Standard LC/MS conditions were as follows (running time 6 minutes):
Acidic condition: A: 0.1% formic acid in H2O; B: 0.1% formic acid in acetonitrile;
Basic condition: A: 0.01% O in H2O; B: acetonitrile;
Neutral condition: A: H2O; B: acetonitrile.
Mass spectra (MS): generally only ions which indicate the parent mass are reported, and
unless otherwise stated the mass ion quoted is the positive mass ion (M+H)+.
The microwave assisted reactions were d out in a Biotage Initiator Sixty.
NMR Spectra were obtained using Bruker Avance 400MHz.
All reactions involving air-sensitive reagents were performed under an argon atmosphere.
Reagents were used as received from commercial suppliers without r purification unless
otherwise noted.
Intermediate 1-1
chloromethylquinoline
N Cl
To a three necks round bottom flask equipped with a reflux condenser and thermometer
containing phosphoryl chloride (400 mL) was added ylaniline (50 g, 0.47 mol) and
propanedioic acid (73 g, 0.7 mol). The mixture was heated and stirred at 95 oC for 16 hours and
then 145 oC for 1 hour. The volatiles were evaporated in vacuo and the residual black oil was
poured onto d ice with stirring. The resulting mixture was extracted with dichloromethane
(300 mL × 3). The combined organic layers were washed with a ted aqueous solution of
sodium bicarbonate until the water phase was pH 7~8, then washed with brine (300 mL), dried
over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash
column chromatography (3% ethyl acetate in petroleum ether) to afford 65 g of the pure t
(yield was 65.3%). MS obsd. (ESI+) [(M+H)+] 212.
Intermediate 1-2
2,4-Dichloro(methylsulfanyl)quinoline
N Cl
1-(Methylsulfanyl)nitrobenzene
To a suspension of p-nitrothiophenol (20 g, 0.129 mol) in water (150 mL) was added an aqueous
solution of sodium hydroxide (75 mL, 2 N) at room temperature. After the mixture was stirred
for 15 minutes and cooled to 10 oC, methyl iodide (57 g, 25 mL, 0.401 mol) was added .
The reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours. The
resulting mixture was extracted with diethyl ether (100 mL × 3). The organic layers were
combined, washed with water (200 mL) and brine (200 mL), dried over m sulfate and
trated in vacuo. The residue was purified by silica gel column chromatography to afford
11 g of 1-(methylsulfanyl)nitrobenzene as a yellow solid.
4-(Methylsulfanyl)aniline
A sion of 1-(methylsulfanyl)nitrobenzene (10.5 g, 0.062 mol) and Raney nickel (5 g) in
methanol (250 ml) was hydrogenated in a round flask equipped with a balloon filled with
hydrogen at room temperature for 16 hours. The resulting mixture was filtered and concentrated
in vacuo to afford 8.0 g of 4-(methylsulfanyl)aniline as colorless oil.
2,4-Dichloro(methylsulfanyl)quinoline
N Cl
Intermediate 1-2 can be prepared in analogy to Intermediate 1-1 by using 4-
(methylsulfanyl)aniline. MS obsd. (ESI+) [(M+H)+] 244.
Intermediate 1-3
6-Bromo-2,4-dichloroquinoline
N Cl
Intermediate 1-3 can be prepared in analogy to Intermediate 1-1 by using oaniline. MS
obsd. (ESI+) [(M+H)+] 276.
Intermediate 1-4
2,4-Dichloromethylquinoline
N Cl
Intermediate 1-4 can be prepared in y to intermediate 1-1 by using 3-methylaniline. MS
obsd. (ESI+) [(M+H)+] 212.
Intermediate 1-5
2,4-Dichloromethylquinoline
N Cl
ediate 1-5 can be prepared in analogy to intermediate 1-1 by using 3-methylaniline. MS
obsd. (ESI+) [(M+H)+] 212.
Intermediate 1-6
2,4-Dichlorofluoro-quinoline
N Cl
Intermediate 1-6 can be prepared in analogy to Intermediate 1-1 by using 4-fluoroaniline. MS
obsd. (ESI+) [(M+H)+] 216.
Intermediate 1-8
2,4-Dichlorotrideuteriomethyl-quinoline
D Cl
N Cl
Intermediate 1-8 can be prepared in analogy to Intermediate 1-1 by using 4-
trideuteriomethylaniline. MS obsd. (ESI+) [(M+H)+] 215.
Intermediate 1-9
Methyl chloro-quinolinecarboxylate
O Cl
N Cl
Intermediates 1-9 can be ed in analogy to Intermediate 1-1 by using methyl 4-
aminobenzoate. MS obsd. (ESI+) [(M+H)+] 256.
Intermediate 1-10
2,4-Dichloro-7,8-difluoromethylquinoline
F N Cl
ediate 1-10 can be prepared in analogy to Intermediate 1-1 by using 2,3-difluoro
methylaniline. MS obsd. (ESI+) [(M+H)+] 248.
Intermediate 1-11
2,4-Dichloro(trifluoromethoxy)quinoline
F O
N Cl
Intermediate 1-11 can be prepared in analogy to Intermediate 1-1 by using 4-
(trifluoromethoxy)aniline. MS obsd. (ESI+) +] 282.
Intermediate 1-12
2,4-Dichloro(difluoromethoxy)quinoline
H O
N Cl
Intermediate 1-12 can be prepared in analogy to Intermediate 1-1 by using 4-
(difluoromethoxy)aniline. MS obsd. (ESI+) [(M+H)+] 264.
Intermediate 1-13
chlorofluoromethylquinoline
F Cl
N Cl
Intermediate 1-13 can be prepared in analogy to Intermediate 1-1 by using 3-fluoro
methylaniline. MS obsd. (ESI+) [(M+H)+] 230.
Intermediate 1-14
2,4-Dichlorofluoromethylquinoline
F N Cl
Intermediate 1-14 can be prepared in analogy to Intermediate 1-1 by using 3-fluoro
methylaniline. MS obsd. (ESI+) [(M+H)+] 230.
Intermediate 1-15
bromomethylquinoline
N Br
Intermediate 1-15 can be prepared in analogy to Intermediate 1-1 by using 4-methylaniline,
propanedioic acid and oryl bromide. MS obsd. (ESI+) [(M+H)+] 300, 1H NMR (400 MHz,
CD3OD) δ ppm 7.92 (s, 1 H), 7.91 - 7.88 (d, J = 0.8 Hz, 1 H), 7.80 (s, 1 H), 7.62 -7.56 (dd, J =
2.0, 8.4 Hz, 1 H), 2.57 (s, 3 H).
Intermediate 1-16
2,4-Dichloro-1,6-naphthyridine
N Cl
Methyl 4-aminopyridinecarboxylate
N O
A mixture of compound 4-aminopyridinecarboxylic acid (100 g, 0.7 mol) and concentrated
sulfuric acid (400 g, 4.0 mol) in absolute methanol (1.5 L) was stirred under reflux for 24 hours.
The reaction mixture was concentrated in vacuo. The residue was diluted with ice-water (800
mL), ed with 2 N of aqueous solution of sodium hydroxide to about pH 10 and then
extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with water
(500 mL), dried over sodium sulfate and concentrated in vacuo to afford the crude t,
which was used for next step without r purification.
Methyl 4-(acetylamino)pyridinecarboxylate
N O
A mixture of methyl 4-aminopyridinecarboxylate (100 g, 0.6 mol) and acetic ide (240
g, 2.4 mol) in ous 1,4-dioxane (1.2 L) was stirred at room ature overnight. The
reaction mixture was concentrated in vacuo and diluted with water (800 mL). The mixture was
neutralized with a saturated aqueous solution of sodium bicarbonate to pH 7. The formed solid
was collected by filtration and dried in vacuo to afford 50 g of methyl 4-(acetylamino)pyridine-
3-carboxylate as a white solid.
1-Benzylhydroxy-1,6-naphthyridin-2(1H)-one
N O
A mixture of methyl 4-(acetylamino)pyridinecarboxylate (70 g, 0.36 mol) and sodium
hydride (50 g, 1.25 mol, 60% in mineral oil) in anhydrous ydrofuran (800 mL) was stirred
at room temperature for 30 minutes. To the above mixture was added bromomethylbenzene (60
g, 0.36 mmol) and the resulting e was stirred at room temperature ght. The reaction
mixture was poured onto crashed ice (600 mL), concentrated in vacuo, and washed with ethyl
acetate (400 mL). The aqueous layer was neutralized by addition of 3 N aqueous solution of
hydrochloric acid to pH 7. The formed solid was collected by filtration and dried in vacuo to
afford 24 g of 1-benzylhydroxy-1,6-naphthyridin-2(1H)-one as a pale yellow solid.
1,6-Naphthyridine-2,4(1H,3H)-dione
N O
A mixture of 1-benzylhydroxy-1,6-naphthyridin-2(1 H)-one (21 g, 0.08 mol) and
trifluoromethanesulfonic acid (100 mL) was heated with stirring at 120 oC overnight. The
reaction mixture was used for the next step directly.
2,4-Dichloro-1,6-naphthyridine
N Cl
A mixture of 1,6-naphthyridine-2,4(1H,3H)-dione (10 g, 0.06 mol) and oryl chloride (180
g) was heated with stirring at 100 oC for 3 hours. The reaction mixture was cooled to room
temperature and concentrated in vacuo. The residue was poured into ter (200 g) and
extracted with ethyl acetate (200 mL × 5). The combined organic layers were dried over sodium
sulfate, trated in vacuo to afford the crude product. 1H NMR (400 MHz, CD3OD) δ ppm
9.57 (s, 1 H), 8.90 - 8.89 (d, J = 5.6 Hz, 1 H), 8.12 (s, 1 H), 7.94 - 7.93 (d, J = 6.0 Hz, 1 H).
Intermediate 1-17
2,4-Dichlorodifluoromethylquinoline
F Cl
N Cl
4-Aminobenzaldehyde
H O
To a solution of 4-nitrobenzaldehyde (2.0 g, 0.133 mol) in acetic acid (150 mL) and water (15
mL) was added iron powder (1.48 g, 0.265 mol). The reaction was stirred overnight at room
temperature. The mixture was filtered and extracted with dichloromethane (50 mL × 3). Then the
organic layer was dried over sodium e, filtered and concentrated in vacuo. The residue was
purified by flash column chromatography (eluting with 10% ethyl acetate in petroleum ether) to
afford 1.2 g of the pure product (yield was 75%).
2,4-Dichloroquinolinecarbaldehyde
O Cl
N Cl
A e of 4-aminobenzaldehyde (14 g, 0.116 mol), propanedioic acid (14.4 g, 0.139 mol) and
phosphoryl chloride (180 g) was heated with stirring at 95 oC for 16 hours. The reaction mixture
was cooled to room temperature and concentrated in vacuo. The residue was purified by flash
column tography afford 150 mg of the pure product (yield was 0.57%).
2,4-Dichlorodifluoromethylquinoline
F Cl
N Cl
A mixture of 2,4-dichloroquinolinecarbaldehyde (45.2 mg, 0.2 mmol) and diethylaminosulfur
trifluoride (32.2 mg, 0.2 mmol) in 1,2-dichloroethane (15 mL) was refluxed overnight. The
reaction e was cooled to room temperature and concentrated in vacuo. The residue was
purified by thin layer chromatography to afford 20 mg of the desired product (yield was 40.3%),
MS obsd. (ESI+) [(M+H)+] 248, 1H NMR (400 MHz, CDCl3) δ ppm 8.28 (s, 1 H), 8.10 - 8.05 (d,
J = 8.8 Hz,1 H), 7.90 - 7.82 (d, J = 8.4 Hz,1 H), 7.53 (s, 1 H), 6.95 - 6.62 (t, J = 56 Hz ,1 H).
Intermediate 2-1
2,3,4,5-Tetrahydro-1,4-benzothiazepine
S
Methyl 2-sulfanylbenzoate
To a cooled solution of trated sulfuric acid (72 g) in methanol (1.5 L) at 0 oC, was added
2-sulfanylbenzoic acid (300 g, 1.95 mol) in portions under argon atmosphere. After being
refluxed with stirring for 18 hours, the reaction mixture was concentrated in vacuo. The residue
was diluted with water (800 mL), basified with a ted aqueous solution of sodium
bicarbonate to about pH 7, and extracted with dichloromethane (600 mL × 3). The combined
organic layers were washed with brine (800 mL), dried over sodium sulfate, filtered and
concentrated in vacuo to afford 300 g of methyl 2-sulfanylbenzoate (yield was 91%) as a light
yellow oil, which was used for the next step without further purification.
3,4-Dihydro-1,4-benzothiazepin-5(2H)-one
To a cooled on of methyl 2-sulfanylbenzoate (200 g, 1.19 mol) in tetrahydrofuran and N,N-
dimethylformamide (2 L, V/V = 1/1) was added 2-chloroethanamine hydrochloride (138 g, 1.19
mol) at 0 oC followed by sodium hydride (143 g, 3.57 mol, 60% in mineral oil) in ns.
After being stirred at room temperature overnight, the reaction mixture was poured into icewater
and extracted with ethyl acetate (900 mL × 4). The c layers were combined, washed
with brine (900 mL × 3), dried over sodium sulfate and concentrated in vacuo. The residue was
stirred in a e solution of ethyl acetate and petroleum ether (300 mL, V/V = 1/1) for 1 hour.
The solid was collected by filtration and dried in vacuo to afford 100 g of hydro-1,4-
benzothiazepin-5(2H)-one (yield was 47%).
2,3,4,5-Tetrahydro-1,4-benzothiazepine
To a bottle ning a cooled suspension of lithium aluminum hydride (44 g, 1.17 mol) in dry
tetrahydrofuran (1.5 L) was added 3,4-dihydro-1,4-benzothiazepin-5(2H)-one (150 g, 0.84 mol)
in portions at 0 oC. After being refluxed for 18 hours, the reaction mixture was cooled to 0 oC,
followed by addition of water (25 mL) dropwise. The reaction mixture was then filtered through
a pad of celite and washed with dichloromethane. The filtrate was dried over sodium sulfate and
evaporated in vacuo to afford 125 g of 2,3,4,5-tetrahydro-1,4-benzothiazepine (yield was 90%),
which was used for the next step without further purification.
Intermediate 2-2 and 2-3
8-Methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (Intermediate 2-2) and 8-Fluoro-2,3,4,5-
tetrahydro-1,4-benzothiazepine (Intermediate 2-3)
H H
N N
S O S F
4-Fluorosulfanylbenzoic acid
SH F
To a cooled on of 2-aminofluoro-benzoic acid (0.93 g, 6 mmol) in water (3 mL) was
added trated hydrochloric acid (1.2 mL), then a cold solution of sodium nitrite (0.41 g, 6
mmol) in water (2 mL) was added dropwise at 5 oC. After the addition, the mixture was stirred
for 30 minutes at that temperature. A cooled solution of um disulphide prepared with
boiled water (2 mL), sodium sulfide drate (1.57 g, 6.66 mmol), sulfur (0.2 g, 6.6 mmol)
and a solution of sodium hydroxide (0.6 mL, 10 mol/ L) was added dropwise into the above
e at 5 oC. After being stirred for 2 hours at room temperature, the mixture was acidified
with hydrochloric acid. The formed precipitate was filtered, washed with water, and dried in
vacuo to afford 1.4 g of the disulfide derivative as a yellow solid (yield was 70%). MS obsd.
(ESI-) [(M-H)-] 341.
A mixture of disulfide (1.4 g, 4.1 mmol) and zinc powder (0.18 g, 2.76 mmol) in acetic acid (5
mL) was refluxed for 4 hours, and then cooled to room temperature. The formed itate was
collected by filtration, and then boiled in an aqueous solution of sodium hydroxide (0.15 g in 1.2
mL of water) for 30 minutes. After being cooled to 0 oC, the mixture was acidified with
hydrochloric acid. The formed solid was collected by filtration, washed with water, and dried in
vacuo to afford 0.5 g of the product (yield was 36%). MS obsd. (ESI-) [(M-H)-] 171.
Methyl 4-fluorosulfanylbenzoate
SH F
A mixture of 4-fluorosulfanylbenzoic acid (6.0 g, 34.9 mmol), concentrated sulfuric acid (6
mL) in methanol (200 mL) was refluxed for 18 hours under argon atmosphere. The resulting
mixture was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with
water, basified with a saturated s solution of sodium bicarbonate to about pH 8. The
organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to
afford 4.54 g of the crude product as a brown oil (yield was 70%), which was used directly for
the next step without further purification. MS obsd. (ESI-) [(M-H) -]185.
8-Methoxy-3,4-dihydro-1,4-benzothiazepin-5(2H)-one and 8- Fluoro-3,4-dihydro-1,4-
benzothiazepin-5(2H)-one
O O
N H
S O S F
To a solution of methyl 4-fluorosulfanylbenzoate (3.0 g, 16 mmol) and 2-chloroethanamine
hydrochloride (1.88 g, 16 mmol) in N,N-dimethylformamide (30 mL), sodium hydride (1.94 g,
48 mmol, 60 % in l oil) was added in portions. The reaction mixture was stirred at 100 oC
overnight. The solvent was removed under reduced pressure. The e was diluted with water,
then a mixture of ethyl e and petroleum ether (1/10, V/V). The resulting mixture was
stirred for 1 hour. The resulting precipitate was collected by filtration, washed with diethyl ether
and petroleum ether, dried in vacuo to afford a mixture of 8-methoxy-3,4-dihydro-1,4-
benzothiazepin-5(2H)-one and 8-fluoro-3,4-dihydro-1,4-benzothiazepin-5(2H)-one. The above
mixture was purified by flash column to afford 0.75 g of the product 8-methoxy-3,4-dihydro-1,4-
benzothiazepin-5(2H)-one as a pale white solid (yield was 22%), MS obsd. (ESI+) [(M+H)+] 210
, and 0.75 g of the product 8-fluoro-3,4-dihydro-1,4-benzothiazepin-5(2H)-one as a pale white
solid (yield was 23%), MS obsd. (ESI+) [(M+H) +] 198.
Intermediate 2-2
8-Methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine
S O
ediate 2-2 can be prepared in analogy to intermediate 2-1 by using 8-methoxy-3,4-
dihydro-1,4-benzothiazepin-5(2H)-one (yield was 90%). MS obsd. (ESI+) [(M+H)+] 196.
Intermediate 2-3
8-Fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine
S F
Intermediate 2-3 can be prepared in analogy to intermediate 2-1 by using 8-fluoro-3,4-dihydro-
1,4-benzothiazepin-5(2H)-one (yield was 96%). MS obsd. (ESI+) [(M+H)+] 184.
Intermediate 2-4
7-Fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine
N F
S
Intermediate 2-4 can be prepared in analogy to intermediate 2-1 by using 5-fluoro
sulfanylbenzoic acid. MS obsd. (ESI+) [(M+H)+] 184.
Intermediate 2-5
9-Fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine
F
Intermediate 2-5 can be ed in analogy to intermediate 2-1 by using 3-fluoro
sulfanylbenzoic acid. MS obsd. (ESI+) [(M+H)+] 184.
Intermediate 2-6
8-Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine
S
Methyl 2-hydroxymethylbenzoate
A mixture of 2-hydroxymethylbenzoic acid (100.0 g, 657.2 mmol), trated sulfuric acid
(50 mL) in ol (1000 mL) was refluxed for 20 hours under nitrogen atmosphere. The
resulting mixture was concentrated in vacuo. The residue was poured into ice-water, extracted
with ethyl acetate (1000 mL). The organic layer was washed with saturated sodium bicarbonate,
brine, dried over sodium sulfate, concentrated in vacuo to afford 109 g of the crude product of
methyl 2-hydroxymethylbenzoate as light brown oil, which was used directly in the next step
without further purification.
Methyl 2-[(dimethylcarbamothioyl)oxy]methylbenzoate
To a solution of methyl 2-hydroxymethylbenzoate (109 g, 657.2 mmol) and 1,4-
diazabicyclo[2.2.2]octane (147.4 g, 1314.4 mmol) in N,N-dimethylformamide (300 mL) was
added a solution of N,N-dimethylcarbamothioyl chloride (97.5 g, 788.6 mmol) in N,N-
dimethylformamide (100 mL) at room temperature. After being heated at 60 oC for 4 hours, the
mixture was cooled and poured onto ice. The formed itate was collected by filtration,
washed with water (300 mL × 3) and dried in vacuo to afford 137 g of methyl 2-
[(dimethylcarbamothioyl)oxy]methylbenzoate as an off-white solid (yield was 82%).
Methyl methylcarbamoyl)sulfanyl]methylbenzoate
Methyl 2-[(dimethylcarbamothioyl)oxy]methylbenzoate (52.0 g, 205.5 mmol) in a round
bottle flask which was vacuumed and backfilled with nitrogen, was heated at 210 oC for 4 hours.
The mixture was then cooled to room temperature and used for next step without further
purification.
4-Methylsulfanylbenzoic acid
SH
A round bottle flask ning a mixture of methyl 2-[(dimethylcarbamoyl)sulfanyl]
methylbenzoate (50 g, 197.6 mmol) and an aqueous solution of sodium hydroxide (120 mL, 4 N)
was vacuumed and backfilled with nitrogen 3 times. After being refluxed for 2 hours, the
resulting mixture was cooled to 0 oC and acidified with an aqueous solution of hydrochloric acid
(45 mL, 6 N). The formed itate was collected by filtration, and then dissolved in ethyl
acetate (500 mL). The solution was dried over anhydrous sodium sulfate, and concentrated in
vacuo to afford 4-methylsulfanylbenzoic acid as a light yellow solid.
8-Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine
Intermediate 2-6 can be prepared in analogy to ediate 2-1 by using 4-methyl
sulfanylbenzoic acid. MS obsd. (ESI+) [(M+H)+] 180.
Intermediate 2-7
8-Chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine
S Cl
4-Chlorosulfanylbenzoic acid
SH Cl
To a cooled mixture of concentrated hydrochloric acid (6 mL) and ice (10 g) was added slowly a
solution of 2-aminochlorobenzoic acid ( 4 g, 23.3 mmol), sodium hydroxide (0.94 g, 23.5
mmol) and sodium nitrite ( 1.6 g, 23.3 mmol) in water (30 mL) in an ice bath. The resulting
mixture was stirred at 0 oC for 1 hour. A solution of potassium ethoxymethanedithioate (20.8 g,
65.2 mmol) in water (40 mL) in a beaker was heated to 65 oC. The cold ium salt solution
was added slowly to the above hot solution while evolution of gas was ed. After the
addition the mixture was cooled to room temperature and acidified to about pH 3 with an
aqueous on of hloric acid (4 N). The aqueous phase was decanted from the resulting
semisolid and the sludge was dissolved in 10% aqueous sodium ide (20 mL). The solution
was heated for 2 hours at 100 oC followed by addition of sodium hydrosulfite (2 g). The resulting
mixture was heated with stirring at 100 oC for an additional 10 minutes, then cooled to room
ature and filtered through a pad of celite. The filtrate was acidified to about pH 4 with
trated hydrochloric acid. The formed solid was collected by filtration, washed with water,
and dissolved in methanol (10 mL) and diethyl ether (150 mL). The solution was dried over
sodium sulfate and concentrated in vacuo to afford 2.8 g of 4-chlorosulfanylbenzoic acid as a
yellow solid (yield was 63%).
8-Chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine
S Cl
Intermediate 2-7 can be prepared in analogy to intermediate 2-1 by using 4-chloro
sulfanylbenzoic acid. MS obsd. (ESI+) [(M+H)+] 200.
Intermediate 3
-Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine
ulfanylphenyl)ethanone
To a stirred suspension of aluminium chloride (10.50 g, 78.8 mmol) in dry benzene (200 mL)
was added a solution of 1-[2-(benzylsulfanyl)phenyl]ethanone (11.93g, 49.2 mmol) in dry
benzene (100 mL) dropwise in an ice bath under argon atmosphere. After the reaction mixture
being stirred at room temperature overnight, the reaction was quenched by the cautious addition
of ter. The separated organic layer was washed with water and extracted with 5% aqueous
solution of sodium hydroxide (300 mL). The aqueous layer was ied to about pH 3 with
concentrated hydrochloric acid (12 N) and extracted with dichloromethane (300 mL × 3). The
combined organic layers were washed with brine, dried over anhydrous sodium sulfate,
concentrated in vacuo to afford 6.47 g of the crude product ulfanylphenyl)ethanone.
-Methyl-2,3-dihydro-1,4-benzothiazepine
To a solution of 1-(2-sulfanylphenyl)ethanone (6.40 g, 42.05 mmol) in ethanol (80 mL) was
added an aqueous solution of potassium hydroxide (7.08 g, 126.14 mmol in 30 mL of water) and
an aqueous solution of 2-bromoethanamine hydrobromide (9.48 g, 46.25 mmol in 30 mL of
water). After being stirred at room temperature for 6 hours, the reaction e was
concentrated in vacuo to remove most of ethanol and ted with dichloromethane (60 mL ×
3). The combined organic layers were washed with brine (100 mL), dried over anhydrous
sodium sulfate, and concentrated in vacuo. The residue was ed by flash column
chromatography to give 5.92 g of 5-methyl-2,3-dihydro-1,4-benzothiazepine.
5-Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine
To a solution of 5-methyl-2,3-dihydro-1,4-benzothiazepine (5.92 g, 33.40 mmol) in methanol
(100 mL) was added a on of sodium dride (3.16 g, 83.49 mmol) in water (60 mL).
After being stirred at room temperature ght, the reaction mixture was acidified with
concentrated hydrochloric acid, and then stirred at room temperature for 30 minutes. After being
adjusted to pH 9 with an aqueous solution of sodium hydroxide, the resulting mixture was
extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed by brine
(100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 5.6 g of 5-
methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, MS obsd. (ESI+) [(M+H)+] 180.
Intermediate 4
1-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone
O O
1-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone
To a on of 2,3,4,5-tetrahydro-1,4-benzothiazepine (5 g, 30.3 mmol) in dry dichloromethane
(100 mL) was added triethylamine (5.06 mL, 36.3 mmol) at room temperature, followed by the
dropwise addition of acetic anhydride (3.43 mL, 36.3 mmol) at 0 oC under nitrogen. The
resulting solution was stirred for 1 hour whilst allowing the temperature to rise slowly to room
temperature. The mixture was washed with brine (50 mL × 2), dried over sodium sulfate, ed
and concentrated in vacuo to afford 6.28 g of product as yellow oil, which was used for next step
without further purification.
1-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone
O O
To a cooled solution of 1-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (6.27 g, 30.2
mmol) in dichloromethane (100 mL) was added a suspension of 3-chloroperoxybenzoic acid
(20.9 g, 90.8 mmol, 75% purity) in dichloromethane (50 mL) at 10 oC. After the on, the
resulting mixture was stirred for 1 hour whilst allowing the temperature to rise slowly to room
temperature. The mixture was washed with a saturated aqueous solution of sodium carbonate
(100 mL × 2), a ted aqueous solution of sodium e (100 mL × 2) and brine (100 mL).
The organic layer was dried over sodium sulfate, ed and concentrated in vacuo. The residue
was stirred in diethyl ether (50 mL) and the solid was collected by filtration and dried in vacuo to
afford 6 g of 1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone as a white
powder.
Intermediate 5
2,3,4,5-Tetrahydro-1,4-benzothiazepine 1,1-dioxide
To a solution of 1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (240 g, 1.0
mol) in ethanol (1.0 L) was added sodium hydroxide (200 g, 5.0 mol) and water (700 mL). The
mixture was refluxed overnight and then concentrated in vacuo. The e was extracted by
ethyl acetate (1500 mL × 4). The combined organic layers were extracted by hydrochloric acid
(2000 mL, 3 N). The acidic s layer was washed with ethyl acetate (1500 mL × 2), then
basified with a saturated aqueous solution of sodium bicarbonate to pH > 7, and extracted with
ethyl acetate (1500 mL × 4). The combined organic layers were dried over sodium sulfate,
filtered and concentrated in vacuo to afford 151 g of 2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-
dioxide (yield was 76%), MS obsd. (ESI+) [(M+H)+] 198, 1H NMR (400 MHz, DMSO-d6) δ ppm
7.89 (dd, J = 1.2, 7.6 Hz, 1 H), 7.56 (t, J = 7.6 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.42 (d, J = 7.6
Hz, 1 H), 4.04 (s, 2 H), 3.32 - 3.30 (m, 2 H), 3.30 - 3.25 (m, 2 H), 2.64 (s, 1 H).
Intermediate 6
2,3,4,5-Tetrahydro-1,4-benzothiazepine 1-oxide
1-(1-Oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone
To a cooled solution of 1-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (70 g, 0.33 mol) in
dichloromethane (700 mL) was added a on of roperoxybenzoic acid (67 g, 0.33 mol)
in dichloromethane (800 mL) se at 0 oC. After the addition, the reaction was stirred at the
same temperature for 15 s. The resulting reaction mixture was washed with a saturated
aqueous solution of sodium carbonate (500 mL × 2) and a saturated aqueous solution of sodium
sulfite (500 mL × 2). The combined aqueous layers were extracted with dichloromethane (200
mL × 2), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash
chromatography (eluting with 1~2% ol in dichloromethane) to afford 57 g of the desired
product (yield was 77%).
2,3,4,5-Tetrahydro-1,4-benzothiazepine 1-oxide
Intermediate 6 was prepared in analogy to intermediate 5 by using 1-(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)ethanone (yield was 66%), MS obsd. (ESI+) +] 181, 1H NMR
(400 MHz, CD3OD) δ ppm 7.72 (dd, J = 1.6, 7.6 Hz, 1 H), 7.52 - 7.48 (m, 2 H), 7.33 (dd, J = 1.6,
7.2 Hz, 1 H), 4.21 - 4.11(m, 1 H), 3.82 - 3.80 (m, 1 H), 3.62 - 3.50 (m, 2 H), 3.22 - 3.19 (m, 2 H).
Intermediate 7
(5Z)-N-Methoxy-1,2,3,4-tetrahydro-5Hbenzazepinimine
A mixture of 4-tetrahydrobenzazepinone (500 mg, 2.530 mmol), O-methyl
hydroxylamine hydrochloride (211 mg, 2.530 mmol), sodium acetate (208 mg, 2.530 mmol) and
sodium carbonate (536 mg, 5.060 mmol) in ethanol was refluxed for 3 hours. The resulting
mixture was concentrated in vacuo to remove ethanol and to the residue was added water (15
mL). The residue in water was extracted with dichloromethane (15 mL × 3). The organic layers
were combined, dried over sodium sulfate, and concentrated in vacuo to afford 326 mg of the
desired product (yield was 67%).
Intermediate 8
fluoro-2,3,4,5-tetrahydro-1H-benzazepine
1-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)-2,2,2-trifluoroethanone
N F
O F F
To a cooled solution of 1,2,3,4-tetrahydrobenzazepinone hydrochloride (33.7 g, 0.17 mol)
in dichloromethane (500 mL) at 0 oC, was added ylamine (52 g, 0.51 mol) dropwise
followed by oroacetic anhydride (36 g, 0.17 mmol). After being stirred at room temperature
for 3 hours, the resulting mixture was diluted with water (300 mL). The aqueous layer was
extracted with dichloromethane (500 mL). The combined organic layers were washed with a
saturated aqueous solution of sodium bicarbonate (500 mL) and brine (500 mL), dried over
sodium sulfate and concentrated in vacuo. The e was purified by flash chromatography
(eluting with 16% ethyl acetate in eum ether) to afford 40 g of the desired product (yield
was 89%).
1-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)-2,2,2-trifluoroethanone
N F
O F F
A on of 2-(trifluoroacetyl)-1,2,3,4-tetrahydro-5Hbenzazepinone (40 g, 0.156 mol) in
N,N-diethylaminosuflur trifluoride (104 g, 0.468 mol) was heated at 70 oC for 3 hours. The
reaction mixture was poured into ice-water (600 mL) and extracted with dichloromethane (800
mL). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate
(500 mL) and brine (500 mL), dried over sodium sulfate, and concentrated in vacuo. The residue
was purified by flash chromatography (eluting with 16% ethyl acetate in petroleum ether) to give
33 g of the desired product (yield was 76%).
5,5-Difluoro-2,3,4,5-tetrahydro-1H-benzazepine
To a cooled solution of 1-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)-2,2,2-
trifluoroethanone (33 g, 0.184 mmol) in methanol was added an ammonia methanol solution
(300 mL, 7 M) at 0 oC. After being stirred at 0 oC for 2 hours, the reaction mixture was
concentrated in vacuo. The residue was purified by flash chromatography (eluting with 10~25%
ethyl acetate in petroleum ether) to afford 18 g of the desired t as a purple oil (yield was
83.3%), MS obsd. (ESI+) [(M+H)+] 184, 1H NMR (400 MHz, CDCl3) δ ppm 7.64 - 7.60 (m, 1
H), 7.34 - 7.25 (m, 2 H), 7.16 -7.14 (m, 1 H),7.01 (s, 2 H), 3.33 - 3.30 (m, 2 H), 2.33 - 2.24 (m, 2
H).
Intermediate 9-1
3-(Aminomethyl)-N,N-dibenzyltetrahydrofuranamine
NH2 O
3-(Dibenzylamino)tetrahydrofurancarbonitrile
To a cooled solution of dibenzylamine (31.9 g, 162 mmol) in acetic acid (100 mL) at 0 oC,
ofuran-3(2H)-one (7.0 g, 81 mmol) was added followed by trimethylsilyl-formonitrile
(14.4 g, 145.8 mmol). After being stirred at room temperature for 16 hours, the reaction mixture
was poured into water (100 mL), adjusted to pH 7 with sodium bicarbonate, d with ethyl
acetate (100 mL × 2). The combined organic layers were washed with brine (150 mL), dried over
sodium sulfate and concentrated in vacuo. The residue was ed by column chromatography
to afford 2.2 g of the desired product (yield was 9.28%).
3-(Aminomethyl)-N,N-dibenzyltetrahydrofuranamine
NH2 O
To a cooled solution of 3-(dibenzylamino)tetrahydrofurancarbonitrile (2.2 g, 7.5 mmol) in
tetrahydrofuran (50 mL) at 0 oC, was added lithium aluminium hydride (855 mg, 22.5 mmol).
After the mixture being stirred for 16 hours at room temperature, the reaction was quenched by
addition of water (5 mL). The resulting mixture was filtered and the filtrate was concentrated in
vacuo to afford 1.3 g of the crude product (yield was 58%).
Intermediate 9-2
3-(Aminomethyl)-N,N-dibenzyloxetanamine
Intermediate 9-2 can be prepared in y to intermediate 9-1 by using oxetanone. MS
obsd. (ESI+) [(M+H)+] 283.
Intermediate 9-3
1-(Aminomethyl)-N,N-dibenzylcyclobutanamine
ediate 9-3 can be prepared in analogy to intermediate 9-1 by using cyclobutanone. MS
obsd. (ESI+) [(M+H)+] 281.
Intermediate 9-4
3-(Aminomethyl)-N,N-dibenzylthietanamine
3,3-Dimethoxythietane
O O
To a solution of 1,3-dibromo-2,2-dimethoxy-propane (102 g, 389 mmol) in N,N-
dimethylformamide (1200 mL) was added sodium sulfide (66.8 g, 506 mmol), the mixture was
refluxed for 3 days. The mixture was cooled to room temperature, diluted with diethyl ether
(1200 mL), washed with water (1200 mL) and brine (1200 mL), dried over sodium sulphate and
concentrated in vacuo to afford 40 g of the product as a yellowish oil (yield was 77%).
Thietanone
To a solution of 3,3-dimethoxythietane (40 g, 600 mmol) in dichloromethane (2500 mL) was
added dioxosilane (160 g). The mixture was refluxed for 2 days. The mixture was cooled to
room temperature and filtered through a pad of celite. The filtrate was concentrated in vacuo to
afford the desired product.
nomethyl)-N,N-dibenzylthietanamine
ediate 9-4 can be ed in analogy to intermediate 9-1 by using thietanone. MS
obsd. (ESI+) [(M+H)+] 299, 1H NMR (400 MHz, CD3OD) δ ppm 7.21 - 7.14 (m, 8 H), 7.11 -
7.08 (m, 2 H), 3.74 (s, 4 H), 3.48 - 3.45 (m, 2 H), 3.26 (s, 2 H), 2.66 - 2.64 (m, 2 H), 1.49 (s, 2
Intermediate 9-5
1-(Aminomethyl)-N,N-dibenzylcyclohexanamine
Intermediate 9-5 can be prepared in analogy to intermediate 9-1 by using cyclohexanone. MS
obsd. (ESI+) [(M+H)+] 309.
Intermediate 9-6
(4-Aminomethyl-tetrahydropyranyl)-dibenzyl-amine
Intermediate 9-6 can be ed in analogy to intermediate 9-1 by using tetrahydropyranone.
MS obsd. (ESI+) [(M+H)+] 311.
Intermediate 10
Aminooxetanyl)methyl]-2,2,2-trifluoroacetamide
O O
NH H
2 F
F
N-{[3-(Dibenzylamino)oxetanyl]methyl}-2,2,2-trifluoroacetamide
N H
To a solution of 3-(aminomethyl)-N,N-dibenzyloxetanamine (3.0 g, 10.6 mmol) in
romethane (30 mL) in an ice bath was added dropwise trifluroacetic anhydride (2.5 g, 11.7
mmol). After the mixture being stirred at room temperature overnight, the reaction was quenched
by addition of a saturated aqueous solution of sodium onate at 0 oC. The resulting mixture
was extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo to
afford 4.0 g of the crude product as yellow oil.
N-[(3-Aminooxetanyl)methyl]-2,2,2-trifluoroacetamide
O O
H F
To a solution of (dibenzylamino)oxetanyl]methyl}-2,2,2-trifluoroacetamide (4.0 g,
.57 mmol) in methanol (80 mL) was added 20% palladium hydroxide on carbon (0.8 g) and
trifluoroacetic acid (one drop). The mixture was stirred at room temperature under hydrogen
overnight and then filtered. The te was concentrated in vacuo to afford the crude t as
a white solid.
Intermediate 11
tert-Butyl [(3-aminooxetanyl)methyl]carbamate
2NH O
tert-Butyl {[3-(dibenzylamino)oxetanyl]methyl}carbamate
N N
To a solution of 3-(aminomethyl)-N,N-dibenzyloxetanamine (10.0g, 35.41 mmol) in
tetrahydrofuran (100 mL) was added an aqueous solution of sodium onate (8.6 g, 102.4
mmol dissolved in 50 mL of water) and a solution of di-tert-butyl dicarbonate (8.9 g, 51.08
mmol) in tetrahydrofuran (30 mL). The mixture was stirred at room temperature overnight,
concentrated in vacuo to remove most of the organic solvent, and the aqueous residue was
extracted with dichloromethane (100 mL × 3). The organic layers were combined, washed with
brine (150 mL), dried over sodium sulfate and concentrated in vacuo to afford 13.0 g of the
crude product, which was used for the next step without any cation.
tert-Butyl [(3-aminooxetanyl)methyl]carbamate
2NH O
A mixture of tert-butyl ibenzylamino)oxetanyl]methyl}carbamate (13.0 g, crude), 20%
palladium ide on carbon (2.0 g) and oroacetic acid (0.5 mL) in methanol (20 mL)
was stirred overnight under hydrogen atmosphere (1 bar). After being basified with ammonia
solution in methanol, the resulting mixture was filtered and concentrated in vacuo to afford 5.8 g
of the crude product, which was used for the next step without any purification.
Intermediate 12
tert-Butyl [1-(2-aminoethyl)-cyclopropyl]carbamate
O N
H NH
3-(Benzyloxy)propanenitrile
To a e of benzyl alcohol (108 g, 1 mol) and 40% aqueous solution of sodium hydroxide
(10 mL) was added propenenitrile (58.3 g, 1.1 mol) and the mixture was stirred for 6 hours at
room ature. The mixture was neutralized with 1 N hydrochloric acid, and extracted with
dichloromethane (300 mL). The organic layer was washed with 5% on of sodium
hydroxide (300 mL) and brine (300 mL), dried over sodium sulfate and concentrated in vacuo to
afford 150 g of the desired compound (yield was 93%).
1-[2-(benzyloxy)ethyl]cyclopropanamine
To a solution of 3-(benzyloxy)propanenitrile (16.9 g 105 mmol) in diethyl ether (400 mL) were
added titanium isopropoxide (35.7 mL, 115 mmol) and ethyl magnesium bromide (210 mL, 1 M
in diethyl ether) successively at room ature. After being stirred for 0.5 hour, boron
trifluoride etherate (27 mL, 525 mmol) was added. After stirring for another 0.5 hour, 10%
aqueous solution of sodium hydroxide (ca. 5.5 mL) was introduced to the above mixture. The
resulting mixture was acidified with 1N hydrochloric acid to pH 3, and then washed with
dichloromethane. The s layer was basified with 5% aqueous solution of sodium hydroxide
to pH 8~9 and extracted with dichloromethane (100 mL). The organic layer was washed with
brine (100 mL), dried over sodium sulfate and concentrated in vacuo to afford 11 g of 1-[2-
loxy)ethyl]cyclopropanamine (yield was 55%).
2-(1-Aminocyclopropyl)ethanol hydrochloride
NH.HCl
To a mixture of 1-[2-(benzyloxy)ethyl]cyclopropanamine (13.2 g, 69 mmol), 10% palladium on
carbon (3.0 g) and propanol (100 mL) was added a solution of hydrochloride in propanol
(100 mL, 5-6 N). The mixture was shaken at 40 oC under hydrogen pressure of 4 atmospheres
until hydrogen uptake ceased. The catalyst was removed by filtration and washed with propan
ol. The filtrate was concentrated in vacuo to afford 8.8 g of the salt as a viscous oil (yield was
84.6%).
tert-Butyl hydroxyethyl)cyclopropyl]carbamate
O H OH
To a solution of 2-(1-amino-cyclopropyl)-ethanol hydrochloride (1:1) (8.8 g, 64.4 mmol) in
tetrahydrofuran (63 mL) was added water (1.5 mL), triethylamine (18.3 mL, 130 mmol) and a
solution of di-tert-butyl dicarbonate (15.46 g, 70.9 mmol) in tetrahydrofuran (21 mL). The
resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated in
vacuo and the e was ved in diethyl ether (100 mL). The organic solution was washed
with an aqueous hydrochloric acid solution (0.1 N, 50 mL) and brine (50 mL), dried over sodium
sulfate and concentrated in vacuo. The residue was triturated in water and ed to afford 9.3 g
of the pure product as a white solid (yield was 71%).
2-{1-[(tert-Butoxycarbonyl)amino]-cyclopropyl}ethyl methanesulfonate
N S
O H O
To a cooled solution of tert-butyl [1-(2-hydroxyethyl)cyclopropyl]carbamate (8.0 g, 0.04 mol)
and triethylamine (12.14 g) in ous tetrahydrofuran (120 mL) at -20 oC was added a
solution of mesyl chloride (17.8 g) in anhydrous tetrahydrofuran (30 mL). The ing mixture
was allowed to warm to room temperature and stirred at this temperature for 2 hours. The
resulting mixture was poured into ice-water (50 mL) and the ted organic layer was washed
with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The e was
triturated with petroleum ether and filtered to give 9.5 g of the pure product as an orange solid
(yield was 95%).
tert-Butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindolyl) ethyl] cyclopropylcarbamate
O N H N
To a solution of 2-{1-[(tert-butoxycarbonyl)amino]-cyclopropyl}ethyl methanesulfonate (9.5 g,
344.3 mmol) in anhydrous N,N-dimethylformamide (20 ml) was added potassium 2,3-dihydro-
1H-isoindole-1,3-dione (7.0 g, 37 mmol). After being d at 150 oC for 18 hours, the resulting
mixture was then filtered and washed with diethyl ether (50 mL). The filtrate was washed with
brine (50 mL × 3), dried over sodium sulfate and concentrated in vacuo. The residue was heated
with stirring in water and the precipitate was collected by filtration and dried in vacuo to afford
6.0 g of the pure product as an orange solid (yield was 53%).
utyl [1-(2-aminoethyl)-cyclopropyl]carbamate
O N
H NH
To a solution of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindolyl)ethyl]
cyclopropylcarbamate (3.3 g, 2.4 mmol) in ethanol (100 mL) was added hydrazine hydrate (5
mL) and the resulting mixture was heated under reflux for 16 hours. The mixture was filtered
and washed with diethyl ether. The filtrate was trated in vacuo to afford 1.5 g of the pure
compound as an orange oil (yield was 75%).
Intermediate 13
tert-Butyl [2-(1-aminocyclopropyl)ethyl]carbamate
2 N
H O
Methyl 1-aminocyclopropanecarboxylate
To a solution of 1-aminocyclopropanecarboxylic acid (1.0 g, 9.9 mmol) in methanol (30 mL)
was added thionyl chloride (3.5 g, 29.7 mmol) at 0 oC. The mixture was heated under reflux for 2
hours and then concentrated in vacuo to afford 1.1 g of the crude product (yield was 100%).
Methyl 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylate
O N
To a cooled mixture of methyl 1-aminocyclopropanecarboxylate (1.1 g, 9.6 mmol) and an
aqueous solution of potassium onate (2.88 g, 28.8 mmol dissolved in 10 mL of water) in
ethyl acetate (30 mL) was added a solution of di-tert-butyl dicarbonate (4.15 g, 19.2 mmol) in
ethyl acetate (10 mL) at 0 oC. The reaction mixture was allowed to warm to room temperature
and stirred at this ature overnight. The separated aqueous layer was extracted with ethyl
acetate (20 mL). The combined organic layers were dried over sodium sulfate and trated
in vauco to afford 2.0 g of the product (yield was 97%).
tert-Butyl [1-(hydroxymethyl)cyclopropyl]carbamate
O N
To a cooled solution of methyl 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylate (1.2 g,
5.6 mmol) in tetrahydrofuran (10 mL) at 0 oC was added dropwise a solution of lithium
borohydride (244 mg, 11.2 mmol) in tetrahydrofuran (10 mL) The on e was allowed
to warm to room temperature and stirred at this temperature overnight. The reaction was
quenched by on of water (10 mL) and the resulting mixture was extracted with
dichloromethane. The organic layer was dried over sodium e and concentrated in vacuo to
afford 0.8 g of the product (yield was 76.2%).
tert-Butyl [1-(azidomethyl)cyclopropyl]carbamate
O + N
O N
To a solution of tert-butyl [1-(hydroxymethyl)cyclopropyl]carbamate (1 g, 5.3 mmol) in N,N-
dimethylformamide (20 mL) was added azabicyclo[5.4.0]undecene (1.22 g, 8.0 mmol)
and diphenylphosphoryl azide (2.33 g, 8.00 mmol). After the mixture was stirred at 80 oC for 3
hours, another batch of azabicyclo[5.4.0]undecene (1.22 g, 8.0 mmol) and
diphenylphosphoryl azide (2.33 g, 8.00 mmol) was introduced and the mixture was stirred at 80
oC for another 2 hours. The resulting mixture was then diluted with water (20 mL) and extracted
with ethyl acetate (30 mL × 2). The combined organic layers were used for next step directly.
tert-Butyl [1-(aminomethyl)cyclopropyl]carbamate
O N 2
A solution of tert-butyl idomethyl)cyclopropyl]carbamate (60 mL, obtained from the
above step) was hydrogenated in the presence of 10% palladium on carbon (60 mg) at room
temperature overnight under hydrogen atmosphere with hydrogen balloon. The reaction was
filtered and concentrated in vacuo to afford 40 mg of the crude product (yield was 40%).
Intermediate 14
(1,1-Dioxidothietane-3,3-diyl)dimethanamine
NH NH2
O O
3,3-Bis(azidomethyl)thietane
+ N N +
N N
N N
To a mixture of 3,3-bis(bromomethyl)thietane (15.0 g, 0.058 mol) and tetrabutylazanium
bromide (0.93 g, 5%) in water (30 mL) was added sodium azide (9.0 g, 0.138 mol). The mixture
was stirred at 70 oC ght, then diluted with water (20 mL) and extracted with
romethane (50 mL × 3). The combined organic layers were dried over sodium sulfate and
concentrated in vacuo to remove most of dichloromethane. The residual solution (in 24 mL of
dichloromethane) was used for the next step.
3,3-Bis-azidomethyl-thietane 1,1-dioxide
+ N N +
N N
N N
O O
To a solution of 3,3-bis(azidomethyl)thietane (2.5 g, 13.59 mmol) in the mixture of formic acid
(5 mL) and romethane (6 mL) was added en peroxide (9.2 g, 81.54 mmol) slowly at
0 oC. After being warmed slowly to room temperature and stirred at room temperature
overnight, the mixture was diluted with water (10 mL) and extracted with dichloromethane (15
mL × 3). The combined organic layers were dried over sodium sulfate and concentrated in
vacuo. The e was purified by flash column tography to afford 2.8 g of the desired
product as a white solid (yield of two steps was 96%).
(1,1-Dioxidothietane-3,3-diyl)dimethanamine
NH NH
2 2
O O
A solution of 3,3-bis-azidomethyl-thietane 1,1-dioxide (1.0 g, 4.63 mmol) in methanol (10 mL)
was stirred in the presence of 10% palladium on carbon (0.2 g) under hydrogen atmosphere
overnight. The resulting reaction mixture was filtered and the filtrate was concentrated in vacuo
to afford 720 mg of the desired product.
Intermediate 15
Thietane-3,3-diyldimethanamine
NH NH
2 2
A solution of 3,3-bis(azidomethyl)thietane (2.5 g, 13.59 mmol) in romethane (6 mL) and
methanol (50 mL) was stirred in the presence of 10% palladium on carbon (0.8 g) under 25 psi of
hydrogen overnight. The resulting mixture was filtered and concentrated in vacuo to afford 1.8 g
of the d product.
Intermediate 16
ifluorocyclobutane-1,1-diyl)dimethanamine
F NH
F NH2
Dipropanyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate
O O
O O
To a stirred suspension of sodium hydride (96.5 g, 2.413 mol, 60% in mineral oil) in dry N,N-
dimethylformamide (900 ml) was added 1,3-bis(propanyl) propanedioate (363.3 g, 1.930 mol)
dropwise under nitrogen at a rate such that the ature was ined below 70 ºC. On
cessation of hydrogen evolution, the mixture was heated to 130 ºC, to 3-dibromo-2,2-
dimethoxypropane (252.8 g, 0.965 mol) was then introduced in one portion. The mixture was
heated under reflux for 48 hours. The cooled mixture was poured into a saturated aqueous
solution of ammonium chloride (300 mL) and extracted with methyl tert-butyl ether (300 mL).
The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and
brine, dried over sodium sulfate, and concentrated in vacuo. The residue was distilled in vacuo
(oil pump) to afford 52.7 g of dipropanyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate as a
ess oil (yield was 58.2%). 1H NMR (400 MHz, CDCl3) δ ppm 5.02 (m J = 6.4 Hz, 2 H),
3.12 (s, 6 H), 2.66 (s, 4 H), 1.11 (d, J = 6.4 Hz, 12 H).
Dipropanyl 3-oxocyclobutane-1,1-dicarboxylate
A solution of dipropanyl methoxycyclobutane-1,1-dicarboxylate (10.0 g, 34.6 mmol) in
hydrochloric acid (3 N, 55 mL) was heated at 50 ºC for 4 hours. The ing mixture was
neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl
acetate (100 mL). The ed organic layers were dried over sodium e and concentrated
in vacuo to afford 6.073 g of dipropanyl 3-oxocyclobutane-1,1-dicarboxylate as a light brown
oil (yield was 72.3%).
Dipropanyl 3,3-difluorocyclobutane-1,1-dicarboxylate
F O
F O
To a cooled solution of dipropanyl 3-oxocyclobutane-1,1-dicarboxylate (5.657 g, 23.3 mmol)
in dichloromethane (50 ml) at -78 ºC, was added dropwise a solution of N,N-diethylaminosuflur
trifluoride (9.25 ml, 70.05 mmol) in dichloromethane (25 ml) under nitrogen. After the addition,
the mixture was allowed to warm up to room temperature and stirred for 24 hours. The mixture
was diluted with dichloromethane (50 mL), and washed with 2 N aqueous solution of sodium
ide (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and
concentrated in vacuo to afford dipropanyl 3,3-difluorocyclobutane-1,1-dicarboxylate as a
yellow oil (yield was 68.8%).
3,3-Difluorocyclobutane-1,1-dicarboxylic acid
F OH
F OH
A mixture of 3,3-difluoro-cyclobutane-1,1-dicarboxylic acid diisopropyl ester (5.00 g, 18.9
mmol) and sodium hydroxide (3.00 g, 75.7 mmol) in methanol (20 ml) was stirred at room
ature overnight. The formed off-white solid was collected by filtration, washed with ethyl
acetate, and dissolved in water. The aqueous solution was acidified with hydrochloric acid (3 N)
to pH 3 - 4. The mixture was concentrated in vacuo to afford 6.293 g of the crude 3,3-
rocyclobutane-1,1-dicarboxylic acid as a white solid, which was used for next step without
further purification.
3,3-Difluorocyclobutane-1,1-dicarboxamide
F NH
F NH2
O
A solution of crude 3,3-difluorocyclobutane-1,1-dicarboxylic acid (6.293 g) in thionyl chloride
(50 mL) was heated under reflux for 2 hours. Then the solution was concentrated in vacuo to
remove thionyl chloride. To the residue was added dropwise ice-cold ammonium hydroxide (10
mL) and stirred for 0.5 hour. The formed ite precipitate was collected by filtration. The
filtrate was extracted with tetrahydrofuran (three times). The combined organic layers were dried
over magnesium sulfate and concentrated in vacuo. The solids were combined to afford 1.858 g
of 3,3-difluorocyclobutane-1,1-dicarboxamide as an off-white solid (yield of three steps was
55.2%).
(3,3-Difluorocyclobutane-1,1-diyl)dimethanamine
F NH
F NH
To a cooled solution of fluorocyclobutane-1,1-dicarboxamide (1.858 g, 10.4 mmol) in
tetrahydrofuran (25 mL) at -10 ºC, was added slowly lithium ium hydride (2.375 g, 62.58
mmol). The reaction was stirred at 0 ºC for 4 hours and then heated under reflux for 30 hours.
The mixture was cooled and quenched at 0 ºC by on of water (2.5 mL), 15% aqueous
solution of sodium hydroxide (7.5 mL) and water (2.5 mL) successively. The resulting mixture
was stirred at room ature for 0.5 hour. The mixture was filtered and the filtrate was
concentrated in vacuo to afford 1.137 g of the crude product of (3,3-difluorocyclobutane-1,1-
diyl)dimethanamine as a colorless oil (yield was 72.8%).
Intermediate 17
-Dioxo-1,3-dihydro-2H-isoindolyl)-4,4,4-trifluorobutanoyl chloride
O F F
N Cl
3-(1,3-Dioxo-1,3-dihydro-2H-isoindolyl)-4,4,4-trifluorobutanoic acid
O F F
N OH
A solution of phthalic de (378 mg, 2.54 mmol) and 3-amino-4,4,4-trifluorobutanoic acid
(200 mg, 1.27 mmol) in N,N-dimethylformamide (5 mL) was heated at 160 ºC under microwave
irradiation for 1 hour. The resulting mixture was cooled to room temperature, diluted with water,
and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with
brine (50 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by
flash chromatograph on silica gel (eluting with 50% ethyl e in hexane) to afford 270 mg of
the product of 3-(1,3-dioxo-1,3-dihydro-2H-isoindolyl)-4,4,4-trifluorobutanoic acid (yield
was 37%). MS obsd. (ESI+) [(M+H)+] 288.
3-(1,3-Dioxo-1,3-dihydro-2H-isoindolyl)-4,4,4-trifluorobutanoyl chloride
O F F
N Cl
To a solution of 3-(1,3-dioxo-1,3-dihydro-2H-isoindolyl)-4,4,4-trifluorobutanoic acid (270
mg, 0.94 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.16 mL, 1.8 8 mmol),
ed by N,N-dimethylformamide (1 drop). After the gas ceased to produce, the reaction
mixture was stirred at room ature for 2 hours. After the mixture was concentrated in
vacuo, the e was diluted with dichloromethane and concentrated in vacuo again to afford
280 mg of the product (yield was 90%), which was used for next step without purification.
Intermediate 18
2-Fluorobutane-1,4-diamine
NH 2
1,4-Dibromofluorobutane
To a solution of 1,4-dibromobutanol (6.0 g, 25.64 mmol) in dichloromethane (80 mL) was
added ethylaminosuflur trifluoride (6.25 mg, 38.79 mmol). The on mixture was
stirred at room temperature overnight. The mixture was diluted with ethyl acetate (15 mL),
washed with water (15 mL) and brine (15 mL), dried over sodium e, and concentrated in
vacuo to afford 4.0 g of 1,4-dibromofluoro-butane as a yellow oil.
2,2'-(2-Fluorobutane-1,4-diyl)bis(1H-isoindole-1,3(2H)-dione)
O F
To a solution of 1,4-dibromofluoro-butane (4.0 g, 17.09 mmol) in N,N-dimethylformamide
(60 mL) was added potassium 2,3-dihydro-1H-isoindole-1,3-dione (9.5 g, 51.27 mmol). The
reaction mixture was stirred at 100 ºC overnight. The mixture was cooled to room temperature,
diluted with ethyl acetate (60 mL), washed with water (60 mL), brine (60 mL), dried over
sodium sulfate, and concentrated in vacuo to afford 4.5 g of 2,2'-(2-fluorobutane-1,4-
diyl)bis(1H-isoindole-1,3(2H)-dione) as a white solid.
2-Fluorobutane-1,4-diamine
A mixture of 2,2'-(2-fluorobutane-1,4-diyl)bis(1H-isoindole-1,3(2H)-dione) (1.0 g, 2.73 mmol)
and hydrazine hydrate (0.68 g, 13.6 mmol) in ethanol (20 mL) was heated under reflux for 16
hours. The resulting mixture was cooled to room temperature and concentrated in vacuo to afford
the crude product, which was used for the next step.
Intermediate 19
utyl (4S)(aminomethyl)-2,2-dimethyl-1,3-oxazolidinecarboxylate
N O
tert-Butyl -[(benzylamino)methyl]-2,2-dimethyl-1,3-oxazolidinecarboxylate
N O
A mixture of tert-butyl (4S)formyl-2,2-dimethyl-1,3-oxazolidinecarboxylate (1.0 g, 4.36
mmol), phenylmethanamine (491 mg, 4.58 mmol) and toluene (8 mL) was heated under reflux
with ng for 2 hours. The mixture was concentrated in vacuo. The residue was dissolved in
1,2-dichloroethane (10 mL), to which sodium etyloxy)boranuidyl acetate (2.31 g, 10.91
mmol) was added. The mixture was stirred at room temperature for two days, then diluted with
water (25 mL), extracted with dichloromethane (25 mL × 3). The combined organic layers were
washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue
was purified by flash column chromatography to afford 849 mg of the product.
tert-Butyl (4S)(aminomethyl)-2,2-dimethyl-1,3-oxazolidinecarboxylate
N O
A mixture of tert-butyl (4S)[(benzylamino)methyl]-2,2-dimethyl-1,3-oxazolidine
carboxylate (810 mg, 2.53 mmol), palladium hydroxide on carbon (81 mg) and methanol (20
mL) was stirred at room temperature under hydrogen atmosphere ght. The catalyst was
removed by filtration. The filtrate was concentrated in vacuo. The residue was ed by SPE
(12 mL tube, 2 gram of DSC-SCX) to afford the pure product.
Intermediate 20
tert-Butyl 2-oxaazaspiro[3.4]octylcarbamate
O H
6-Benzylnitrooxaaza-spiro[3.4]octane
To a solution of benzyl-methoxymethyl-trimethylsilanylmethyl-amine (3.0 g, 12.6 mmol) and 3-
nitromethylene-oxetane (1.38 g, 12.0 mmol) in dichloromethane (60 mL) was added
trifluoroacetic acid (0.93 mL, 12.6 mmol) dropwise. The e was d at room
temperature for 2 hours, ed with sodium carbonate, ted with dichloromethane. The
organic layer was dried over sodium sulfate, concentrated in vacuo. The residue was purified by
column chromatography on silica gel to give 2 g of product as colorless oil. It was used for next
step without further purification.
6-Benzyloxaaza-spiro[3.4]octylamine
The mixture of 6-benzylnitrooxaaza-spiro[3.4]octane (2 g, 8.1 mmol), iron powder (2.3
g, 40.5 mmol), ammonium chloride (4.3 g, 81 mmol), methanol (40 mL) and 8 mL of water was
heated with stirring for 2 hours at 80 ºC. The reaction mixture was filtered by a pad of celite. The
filtrate was trated under reduced pressure, and the residue was used for next step without
further purification.
tert-Butyl (6-benzyloxaazaspiro[3.4]octyl)carbamate
To a mixture of 6-benzyloxaazaspiro[3.4]octylamine (prepared above), sodium
carbonate (1.46 g, 13.74 mmol), dichloromethane (20 mL) and water (20 mL) was added di-tert-
butyl dicarbonate (1.8 g, 8.24 mmol) at room temperature. The mixture was stirred at room
temperature overnight. The separated organic layer was dried over sodium sulfate, ed and
concentrated in vacuo. The residue was purified by column chromatography on silica gel to give
1.5 g of product as colorless oil, which was used for next step without further purification.
tert-Butyl 2-oxaazaspiro[3.4]octylcarbamate
O H
To a solution of 6-benzyloxaazaspiro[3.4]octylamine (1.5 g, 4.71 mmol) in methanol
(50 mL) was added ium hydroxide (20% on carbon, 300 mg). After being stirred at room
temperature for 4 hours under a hydrogen atmosphere, the resulting mixture was filtered. The
filtrate was concentrated in vacuo to give 900 mg of the product as colorless oil, which was used
for next step t further purification.
Intermediate 21
N-(3-Methylpyrrolidinyl)-acetamide
N O
N-(1-Benzylmethylpyrrolidinyl)-acetamide
N O
To a solution of 1-benzylmethylpyrrolidinol (1.0 g, 5.2 mmol) in acetonitrile (10 mL) at 0
ºC, was added concentrated sulfuric acid (10 mL) slowly. After being stirred for 16 hours at
room temperature, the on mixture was poured into ice-water. After the on mixture
was adjusted to pH 7 with a ted aqueous solution of potassium carbonate, the resulting
mixture was d with dichloromethane (200 mL × 3). The combined organic layers were
dried over sodium sulfate, and concentrated in vauo. The residue was purified by preparative
HPLC to afford 600 mg of the product (yield was 50%).
N-(3-Methylpyrrolidinyl)-acetamide
N O
A mixture of N-(1-benzylmethylpyrrolidinyl)-acetamide (600 mg, 2.6 mmol), palladium on
carbon (400 mg, 10%) and ethanol (20 mL) was stirred at 40 ºC under 50 Psi of hydrogen for 16
hours. The resulting mixture was ted. The filtrate was concentrated in vacuo to give 200 mg
of the desired product (yield was 54%), which was used for next step without any purification.
Intermediate 22
2-Fluoropropane-1,3-diamine
NH NH2
2-Fluoropropanediamide
NH NH2
O O
To a solution of 1,3-diethyl 2-difluoropropanedioate (25 g, 140.4 mmol) in methanol (100 mL)
under a nitrogen atmosphere was added a solution of ammonia in methanol (80 mL, 7 N, 560
mmol). The ing e was stirred at room temperature overnight and then concentrated in
vacuo. The residue was triturated in petroleum ether to afford 16.3 g of 2-fluoropropanediamide
as a white solid (yield was 97%). MS obsd. (ESI+) [(M+H)+] 121.
2-Fluoropropane-1,3-diamine
NH NH
2 2
To a solution of 2-fluoropropanediamide (16.3 g, 136 mmol) in tetrahydrofuran (200 mL) was
added a solution of boran-tetrahydrofuran complex (800 mL, 800 mmol, 1 M) in
tetrahydrofuran. The reaction mixture was heated at 70 °C with stirring overnight, then cooled in
an ice bath, stirred with ol (100 mL) further for 30 minutes, and concentrated in vacuo.
The residue was dissolved in methanol (100 mL) and the solution was concentrated in vacuo. To
the residue was added water (10 mL), ium hydroxide was added with cooling until the
aqueous solution was ted. The mixture was extracted by l ether (20 mL × 2), and the
combined organic layers was dried over potassium hydroxide and concentrated in vacuo to
afford 7.5 g of ropropane-1,3-diamine (yield was 60%). MS obsd. (ESI+) [(M+H)+] 93.
Intermediate 23
Benzyl 6-oxaazabicyclo[3.1.0]hexanecarboxylate
N O
To a solution of 1-benzyloxycarbonylpyrroline (2.5 g) in dichloromethane (60 mL) was added
3-chloroperoxybenzoic acid (6.08 g, 50-60% purity). The reaction was stirred at room
temperature for 72 hours, and then a saturated sodium thiosulfate solution (50 mL) was added.
After being stirred for additional 30 minutes, the e was extracted with chloroform (50 mL
× 2). The combined organic layers were washed successively with 2 N aqueous solution of
sodium hydroxide (50 mL × 2) and brine (50 mL), dried over magnesium sulfate and
concentrated in vacuo to afford 2.79 g of the crude benzyl 6-oxaazabicyclo[3.1.0]hexane
carboxylate as an oil. MS obsd. (ESI+) [(M+H)+] 220.
trans-(±)-Benzylaminohydroxypyrrolidinecarboxylate
O 2
A mixture of the crude benzyl 6-oxaazabicyclo[3.1.0]hexanecarboxylate obtained in the
above step (2.79 g) and 28% aqueous solution of ammonia (20 mL) was stirred at 40 °C for 2
days in a sealed tube, then 2 N aqueous solution of sodium hydroxide (25 mL) was introduced
and the mixture was extracted with chloroform (25 mL × 3). The combined organic layers were
dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 2.67 g of the crude
benzylaminohydroxypyrrolidinecarboxylate as oil. MS obsd. (ESI+) [(M+H)+]
237.
trans-(±)-Benzyl[(tert-butoxycarbonyl)amino]hydroxypyrrolidinecarboxylate
O OH
O NH
O O
To a cooled solution of trans-benzylaminohydroxypyrrolidinecarboxylate (2.67 g) in
chloroform (25 mL) was added dropwise a solution of di-tert-butyl dicarbonate (3.7 g) in
chloroform (10 mL) in an ice-water bath, and the mixture was stirred at room temperature for 19
hours. The reaction mixture was washed with water and the organic layer was dried over
anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a column
chromatography on silica gel to afford 2.7 g of trans-benzyl[(tert-butoxycarbonyl)amino]
hydroxypyrrolidinecarboxylate as crystals. MS obsd. (ESI+) [(M+H)+] 337.
trans-(±)-tert-Butyl [4-hydroxypyrrolidinyl]carbamate
H O
OH N
H
To a solution of 3-tert-butoxycarbonylaminohydroxy-pyrrolidinecarboxylic acid
benzyl ester (3.9 g) in methanol (31 mL) and tetrahydrofuran (7 mL) was added palladium
hydroxide (20 wt% Pd on , 500 mg) and the mixture was stirred at room temperature
under 40 - 45 psi of hydrogen atmosphere overnight. The resulting mixture was filtered and the
te was concentrated in vacuo. The e was triturated in the mixture of ethyl acetate and
diisopropylether and filtered to remove the insoluable materials. The te was trated in
vacuo to afford 2.0 g of trans-tert-butyl [4-hydroxypyrrolidinyl]carbamate (yield was 94%) as
a powder. MS obsd. (ESI+) [(M+H)+] 203.
Intermediate 24
trans-(±)-Benzyl 3-aminofluoroypyrrolidnecarobxylate
O NH
trans-(±)-Benzyl 3-azidofluoroypyrrolidnecarobxylate
O N +
In a solution of benzyloxaazabicyclo[3.1.0]hexanecarboxylate (2.5 g) in methanol (20
mL) was added water (5 mL), ammonium de (550 mg) and sodium azide (1.5 g). The
resulting mixture was heated at 65 °C for 21 hours. The solids were removed by filtration and the
filtrate was concentrated in vacuo. The residue was poured into 15% aqueous on of sodium
hydroxide (30 mL) and ted with dichloromethane (50 mL). The organic layers were
washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford 2.7 g of
trans-(±) benzylazidohydroxypyrrolidnecarobxylate. MS obsd. (ESI+) +] 250.
trans-(±)-Benzyl 3-azidofluoroypyrrolidnecarobxylate
O N +
N
To a cooled solution of trans-(±) benzylazidohydroxypyrrolidnecarobxylate (6.5 g) in
dichloromethane (110 mL) was added diethylaminosulfur trifluoride (6.8 mL) at -78 °C. The
mixture was stirred at room temperature for 16 hours, and then trated in vacuo. The
residue was dissolved in ethyl acetate (100 mL), and the solution was washed with a saturated
sodium bicarbonate (100 mL) and brine (100 mL), dried over magnesium e and
concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting
with 1% methanol in dichloromethane) to yield 5.7 g of trans-(±) benzylazido
fluoroypyrrolidnecarobxylate.
trans-(±)-Benzyl 3-aminofluoroypyrrolidnecarobxylate
O NH2
To a solution of trans-(±) benzylazidofluoroypyrrolidnecarobxylate (4.33 g) in
tetrahydrofuran (100 mL) and water (10 mL) was added triphenylphospine (4.5 g). The reaction
e was heated under reflux for 2 hours. The reaction mixture was concentrated in vacuo
and the residue was dissolved in ethyl acetate (50 mL). The solution was extracted with 15%
aqueous solution of citric acid (30 mL × 2) and the aqueous layers were combined, basified with
a concentrated aqueous ammonium hydroxide to about pH 9, then extracted with ethyl acetate
(50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over
magnesium sulfate and concentrated in vacuo to afford trans-(±)-benzyl 3-amino
fluoroypyrrolidnecarobxylate.
Intermediate 25
trans-(±)-tert-Butyl oropyrrolidinyl)carbamate
H O
F N
trans-(±)Benzyl[(tert-butoxycarbonyl)amino]fluoropyrrolidinecarboxylate
O O
To a cooled solution of trans-(±)-benzylaminofluoroypyrrolidnecarobxylate (2.39 g) in
chloroform (25 mL) was added dropwise a on of di-tert-butyl dicarbonate (3.7 g) in
chloroform (10 mL) in an ice-water bath. The mixture was stirred at room ature for 19
hours. The on mixture was washed with water and the organic layer was dried over
anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a column
tography on silica gel to afford 2.9 g of (±)benzyl[(tertbutoxycarbonyl
)amino]fluoropyrrolidinecarboxylate (yield was 90%) as crystals.
trans-(±)-tert-Butyl (4-fluoropyrrolidinyl) carbamate
H O
F N
To a solution of trans-(±)benzyl[(tert-butoxycarbonyl)amino]fluoropyrrolidine
carboxylate (3.39 g) in methanol (31 mL) and tetrahydrofuran (7 mL) was added palladium
hydroxide (20 wt% on carbon, 500 mg) and the mixture was stirred at room temperature under
40 - 45 psi of hydrogen atmosphere ght. The resulting mixture was filtered and the filtrate
was concentrated in vacuo. The residue was triturated in the mixture of ethyl acetate and
diisopropylether and filtered to remove the insoluable als. The filtrate was concentrated in
vacuo to afford 1.5 g of trans-(±)-tert-butyl (4-fluoropyrrolidinyl) carbamate (yield was 74%)
as a powder.
Intermediate 26
utyl (4S)ethenyl-2,2-dimethyl-1,3-oxazolidinecarboxylate
N O
3-tert-Butyl 4-methyl (4R)-2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate
N O
A solution of methyl (2R){[(tert-butoxy)carbonyl]amino}hydroxypropanoate (22 g, 0.1
mol), 2,2-dimethoxypropane (20.8 g, 0.2 mol) and 4-methylbenzenesulfonic acid (0.5 g) in
toluene was heated with stirring at 110 oC overnight. The solvent was removed under reduced
pressure. The e was treated with ethyl acetate, washed with water and brine. The organic
layer was dried over sodium sulfate, concentrated under reduced re. The residue distilled
at 0.6 mbar to give 16.5 g of 3-tert-butyl 4-methyl (4R)-2,2-dimethyl-1,3-oxazolidine-3,4-
dicarboxylate (yield was 63.6 %) as an amber oil.
tert-Butyl (4R)formyl-2,2-dimethyl-1,3-oxazolidinecarboxylate
N O
To a cooled solution of 3-tert-butyl 4-methyl (4R)-2,2-dimethyl-1,3-oxazolidine-3,4-
dicarboxylate (16.5 g, 63.6 mmol) in dry dichloromethane (300 mL) at -78 oC, was added a
cooled solution of 1.0 M diisobutylaluminium hydride in hexane (127.6 mL, 127.2 mmol) under
argon. The rate of addition was adjusted so as to keep the internal temperature below -65 oC and
take about 1 hour to complete. The reaction mixture was d for an additional 2 hours at -78
oC under argon. The reaction was quenched by slowly adding 60 mL of cold methanol (-78 oC)
so as to keep the internal temperature below -65 oC. The ing mixture was extracted with
ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated
under reduced pressure. The residue was distilled at 0.7 mbar to give tert-butyl (4R)formyl-
2,2-dimethyl-1,3-oxazolidinecarboxylate (10 g, 68.5 %) as colorless liquid.
tert-Butyl (4S)ethenyl-2,2-dimethyl-1,3-oxazolidinecarboxylate
N O
To a solution of methyltriphenylphosphonium bromide (3.1 g, 8.64 mmol) in dry ydrofuran
(30 mL) was add a solution of sodium bis(trimethylsilyl)amide in hexane (1.0 M, 8.64 mL, 8.64
mmol) under argon. After the reaction was stirred for further 20 minutes, a solution of -
-2,2-dimethyl-1,3-oxazolidinecarboxylate (1.8 g, 7.86 mmol) in dry ydrofuran
(20 mL) was added dropwise. The resulting mixture was stirred at room temperature ght.
The solvent was removed under reduced pressure. The residue was purified by flash column to
give tert-butyl (4S)ethenyl-2,2-dimethyl-1,3-oxazolidinecarboxylate (1.5 g, 83.9%) as
colorless liquid.
Intermediate 27
Pyridazinecarboxamide
O NH
N
To a cooled solution of pyridazinecarboxylic acid (1.0 g, 8.06 mmol) in tetrahydrofuran (40
mL) in a dry-ice bath was added 4-methyl-morpholine (0.9 g, 8.87 mmol) and isopropyl
chloroformate (1.1 g, 8.87 mmol) slowly. The reaction was stirred at -30 oC for 6 hours, then an
aqueous solution of ammonia (8 mL, 10% W/W) was added. The resulting mixture was stirred at
room temperature overnight, washed with a saturated aqueous solution of potassium ate (50
mL). The aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic
layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 202.5 mg of
the d product (yield was 20.4%). MS obsd. (ESI+) [(M+H)+] 124, 1H NMR (400 MHz,
CD3OD) δ ppm 9.45 - 9.35 (t, J = 1.6 Hz, 1 H), 8.58 (s, 1 H), 8.23 - 8.15 (d, J = 7.6 Hz, 1 H),
7.98 - 7.88 (m, 2 H).
Intermediate 28
Oxetane-3,3-diyldimethanamine
NH2 NH
3,3-Bis-azidomethyl-oxetane
N + + N
N N N N
A mixture of 3,3-bis(bromomethyl)oxetane (25 g, 100 mmol) and sodium azide (14.3 g, 220
mmol) in water (65 ml) was added tetrabutylazanium bromide (1.61 g, 5 mmol). The reaction
mixture was heated with stirring at 70 oC overnight. The reaction mixture was cooled to room
temperature and extracted with romethane (50 mL × 3). The combined organic layers were
washed with water, dried over sodium sulphate and concentrated in vacuo to afford 18.7 g of 3,3-
bis-azidomethyl-oxetane as a light yellow oil. The crude product was used for next step without
further purification.
Oxetane-3,3-diyldimethanamine
NH NH
2 2
A solution of s-azidomethyl-oxetane (18.7 g) in methanol (15 ml ) was stirred in the
presence of 10% palladium on carbon (1.8 g ) under hydrogen atmosphere at room ature
for 5 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford
oxetane-3,3-diyldimethanamine (12 g) as a light yellow solid.
Intermediate 29
Oxetanylidene-acetonitrile
To a on of oxetanone (5 g, 69.4 mmol ) in dry dichloromethane (150 ml ) was added
(triphenylphosphoranylidene)acetonitrile (20.9 g, 69.4 mmol) at room temperature. After being
d for 6 hours, the mixture was concentrated in vacuo and the residue was filtered through a
pad of silica gel (eluting with 30-50% diethyl ether in es) to afford 5.2 g of oxetan
ylidene-acetonitrile as a white solid (yield was 79%).
zylamino)oxetanacetonitrile
N CN
A mixture of oxetanylidene-acetonitrile (950 mg, 10 mmol) and phenylmethanamine (1.31
ml, 12 mmol) was heated with stirring at 60 oC for 5 hours under nitrogen. The mixture was
concentrated in vacuo. The e was purified by flash column (eluting with 0-50% ethyl
acetate in hexane) to afford 1.65 g of 3-(benzylamino)oxetanacetonitrile as a colorless oil
(yield was 81.7%).
3-(Aminoethyl)-N-benzyloxetanamine
H NH
To a cooled slurry of lithium aluminium hydride (327 mg, 8.6 mmol) in anhydrous diethyl
ether (40 mL), was added a solution of 3-(benzylamino)oxetanacetonitrile (1.0 g, 4.3
mmol) in anhydrous diethyl ether (10 mL) dropwise at 0 oC. After being stirred at 0 oC for
2 hours, the reaction was quenched by introducing disodium sulfate drate slowly.
After being stirred for 30 minutes, the mixture was filtered, and the filter cake was washed
with ethyl acetate. The filtrate was dried over sodium sulfate and concentrated in vacuo. The
residue was purified by flash column to afford 800 mg of 3-(aminoethyl)-N-benzyloxetan
amine as a light yellow oil (yield was 79%).
Intermediate 30
O O
The intermediate was prepared in analogy to 1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)ethanone in Intermediate 4 by oxidation of nomethyl)-N,N-dibenzylthietan
amine ( Intermediate 9-4) with 3-chloroperoxybenzoic acid.
The following examples were prepared by the general methods outlined in the schemes
above. They are intended to illustrate the meaning of the present invention but should by no
means represent a limitation within the g of the t invention.
Example 1-1
N-[(3-Aminooxetanyl)methyl](8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinolinamine
O NH
N N
4-(4-Chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine
N N
A mixture of 8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.63 g, 3.2 mmol), 2,4-
dichloromethylquinoline (0.68 g, 3.2 mmol) and n-butanol (4 mL) was heated with stirring in
a 5 mL of microwave process vial for 2.5 hours at 160 oC under microwave irradiation. The
t was removed by tration in vacuo. The residue was dissolved in a mixture solvent
of ethanol and dichloromethane and then concentrated in vacuo to remove dichloromethane. The
formed precipitate was collected by filtration, which was washed with diethyl ether and
petroleum ether, dried in vacuo to afford 0.59 g of the product as a pale white solid (yield was
50%). MS obsd. (ESI+) [(M+H)+] 371.
4-(4-Chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide
N N
A mixture of 4-(4-chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-
benzothiazepine (0.40 g, 1.1 mmol) and sodium metaperiodate (0.71 g, 3.3 mmol) in methanol
(15 mL) and water (6 mL) was d for 12 hours at room temperature. After removal of the
solvent by concentration in vacuo, the residue was dissolved in methanol (15 mL). A solution of
potassium permanganate (0.17 g, 1.1 mmol) in water (6 mL) was added dropwise to the above
solution which was cooled to 0 oC. After being stirred for 2 hours at 0 oC, the mixture was
extracted with ethyl acetate (10 mL). The organic layer was filtered through a short silica gel
. The filtrate was concentrated in vacuo to afford 0.40 g of the product as a white solid
(yield was 90%). MS obsd. (ESI+) +] 403.
N-{[3-(Dibenzylamino)oxetanyl]methyl}(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinamine
O N
N N
O
A mixture of 4-(4-chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide (50 mg, 0.13 mmol), cesium carbonate (80 mg, 0.26 mmol),
palladium acetate (2.8 mg, 0.013 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (11
mg, 0.019 mmol) and 3-(aminomethyl)-N,N-dibenzyloxetanamine (54 mg, 0.19 mmol) in
toluene (5 mL) was heated with stirring for 4 hours at 120 oC. After being cooled to room
temperature, the mixture was concentrated in vacuo. The residue was purified by flash
chromatography (eluting with 0.5% ylamine and 5% methanol in dichloromethane) to
afford 50 mg of the product as a white powder (yield was 59%). MS obsd. (ESI+) [(M+H)+] 649.
N-[(3-Aminooxetanyl)methyl](8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinolinamine
O NH
N N
A e of N-{[3-(dibenzylamino)oxetanyl]methyl}(8-methoxy-1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinamine (50 mg, 0.077 mmol), 10%
palladium hydroxide on carbon (100 mg) and trifluoroacetic acid (0.2 mL) in methanol (20 mL)
was d for 12 hours at room temperature under hydrogen here (1 bar). The resulting
mixture was basified with a saturated aqueous solution of sodium bicarbonate to pH >9 and then
extracted with dichloromethane (20 mL × 2). The combined organic layers were dried over
anhydrous sodium sulfate, and then concentrated in vacuo. The residue was purified by
preparative HPLC to afford 10 mg of the product (yield was 28%). MS obsd. (ESI+) [(M+H)+]
469, 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J = 8.34 Hz, 2 H), 7.56 (brs, 2 H), 7.44 (brs, 1
H), 7.18 (d, J = 8.59 Hz, 1 H), 6.22 (s, 1 H), 5.27 - 5.13 (m, 2 H), 4.74 - 4.55 (m, 4 H), 4.50 (brs,
2 H), 3.86 (s, 3 H), 3.81 - 3.72 (m, 2 H), 3.71 - 3.60 (m, 2 H), 2.46 (s, 3 H).
Example 1-2
N-[(3-Aminooxetanyl)methyl](8-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinolinamine
O NH
N N
The title compound was prepared in y to Example 1-1 in Scheme 4 by using 2,4-dichloro-
6-methylquinoline, 8-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and 3-(aminomethyl)-N,N-
dibenzyloxetanamine. MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm
7.95 (dd, J = 8.46, 5.18 Hz, 1 H), 7.77 - 7.64 (m, 2 H), 7.47 (d, J = 8.34 Hz, 1 H), 7.43 - 7.25 (m,
2 H), 6.20 (s, 1 H), 5.19 (brs, 2 H), 4.68 - 4.57 (m, 6 H), 3.70 (s, 2 H), 3.67 - 3.56 (m, 2 H), 2.44
(s, 3 H).
e 1-3
N-[(3-Aminooxetanyl)methyl](7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinolinamine
O NH
N N
The title compound was prepared in analogy to Example 1-1 in Scheme 4 by using 2,4-dichloro-
ylquinoline, 7-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and 3-(aminomethyl)-N,N-
dibenzyloxetanamine. MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm
8.02 (dd, J = 8.72, 5.43 Hz, 1 H), 7.79 - 7.65 (m, 2 H), 7.46 (d, J = 8.34 Hz, 1 H), 7.33 (d, J =
8.84 Hz, 1 H), 7.17 (td, J = 8.40, 2.65 Hz, 1 H), 6.17 (s, 1 H), 5.17 (brs, 2 H), 4.68 - 4.41 (m, 6
H), 3.72 - 3.64 (m, 2 H), 3.64 - 3.53 (m, 2 H), 2.44 (s, 3 H).
Example 1-4
N-[(3-Aminooxetanyl)methyl](9-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinolinamine
O NH
N N
S O
The title compound was prepared in analogy to Example 1-1 in Scheme 4 by using 2,4-dichloro-
6-methylquinoline, 9-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and 3-(aminomethyl)-N,N-
dibenzyloxetanamine. MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm
7.75 - 7.65 (m, 2 H), 7.60 (td, J = 7.96, 4.80 Hz, 1 H), 7.46 (d, J = 8.34 Hz, 1 H), 7.32 (dd, J =
8.59, 1.77 Hz, 1 H), 7.17 (dd, J = 10.36, 8.34 Hz, 1 H), 6.15 (s, 1 H), 5.20 (s, 2 H), 4.68 - 4.53
(m, 4 H), 4.45 (brs, 2 H), 3.86 - 3.73 (m, 2 H), 3.65 (s, 2 H), 2.43 (s, 3 H).
Example 1-5
N-[(3-Aminooxetanyl)methyl](7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinolinamine
O NH
N N
The title nd was prepared in analogy to Example 1-1 in Scheme 4 by using 2,4-dichloro-
6-methylquinoline, 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and 3-(aminomethyl)-
N,N-dibenzyloxetanamine. MS obsd. (ESI+) [(M+H)+] 469, 1H NMR (400 MHz, DMSO-d6) δ
ppm 7.79 (d, J = 8.84 Hz, 1 H), 7.68 (s, 1 H), 7.57 (d, J = 2.53 Hz, 1 H), 7.34 (d, J = 8.59 Hz, 1
H), 7.30 - 7.21 (m, 1 H), 6.96 (dd, J = 8.72, 2.65 Hz, 1 H), 6.35 (t, J = 5.31 Hz, 1 H), 6.19 (s, 1
H), 5.04 (brs, 2 H), 4.45 - 4.39 (m, 6 H), 3.92 - 3.75 (m, 3 H), 3.62 - 3.45 (m, 4 H), 2.37 (s, 3 H).
Example 1-6
N-[(3-Aminooxetanyl)methyl](8-chloro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
yl)methylquinolinamine
O NH
N N
The title compound was prepared in analogy to Example 1-1 in Scheme 4 by using 2,4-dichloro-
6-methylquinoline, 8-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine and 3-(aminomethyl)-N,N-
dibenzyloxetanamine. MS obsd. (ESI+) [(M+H)+] 473, 1H NMR (400 MHz, CD 3OD) δ ppm
7.99 - 7.88 (m, 2 H), 7.77 (s, 1 H), 7.64 (dd, J = 8.08, 2.27 Hz, 1 H), 7.53 (d, J = 8.59 Hz, 1 H),
7.40 (d, J = 8.59 Hz, 1 H), 6.19 (s, 1 H), 5.21 (brs, 2 H), 4.84 - 4.56 (m, 4 H), 4.53 (brs, 2 H),
3.75 (s, 2 H), 3.68 (brs, 2 H), 2.45 (s, 3 H).
Example 1-7
N-[(3-Aminooxetanyl)methyl](7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)-quinolinamine
O NH
N N
The title nd was prepared in analogy to Example 1-1 in Scheme 4 by using 2,4-
dichloroquinoline, 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and 3-(aminomethyl)-N,N-
dibenzyloxetanamine. MS obsd. (ESI+) [(M+H)+] 455, 1H NMR (400 MHz, CD3OD) δ ppm
7.79 (d, J = 8.84 Hz, 1 H), 7.68 (s, 1 H), 7.57 (d, J = 2.53 Hz, 1 H), 7.34 (d, J = 8.59 Hz, 1 H),
7.30 - 7.21 (m, 1 H), 6.96 (dd, J = 8.72, 2.65 Hz, 1 H), 6.35 (t, J = 5.31 Hz, 1 H), 6.19 (s, 1 H),
.04 (brs, 2 H), 4.45 (d, J = 5.81 Hz, 2 H), 4.39 (d, J = 5.81 Hz, 2 H), 3.92 - 3.75 (m, 3 H), 3.62 -
3.45 (m, 4 H), 2.37 (s, 3 H).
Example 2-1
N-[(3-Aminotetrahydrofuranyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinolinamine
N N
N-{[3-(Dibenzylamino) tetrahydrofuranyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinamine
N N
To a mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (400 mg, 1.08 mmol, prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-
tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 1-1 by using 2,3,4,5-tetrahydro-1,4-
hiazepine and chloromethylquinoline), 3-(aminomethyl)- N,N-dibenzyl
ydrofuranamine (385 mg, 1.3 mmol), sodium tert-butoxide (207 mg, 2.16 mmol), 1,1'-
bis(diphenylphosphino)ferrocene-palladium(II)dichloride (50 mg) and 1,1'-
bis(diphenylphosphino)ferrocene (200 mg) in 1,4-dioxane (5 mL) was heated with stirring in a
sealed 10 mL of microwave process vial for 1 hour at 120 ºC under microwave irradiation. The
resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to
afford 270 mg of the desired product (yield was 39.7%).
N-[(3-Aminotetrahydrofuranyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinolinamine
N N
A mixture of N-{[3-(dibenzylamino) tetrahydrofuranyl]methyl}(1,1-dioxido-2,3-dihydro-
1,4-benzothiazepin-4(5H)-yl)methylquinolinamine (270 mg, 0.43 mmol), 10% palladium
hydroxide on active carbon (300 mg) in methanol (20 mL) was stirred for 16 hours at room
ature under hydrogen atmosphere (1 bar). The resulting mixture was concentrated in
vacuo. The residue was purified by ative HPLC to afford 21 mg of the desired product
(yield was 10.8%). MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.06 -
7.98 (m, 2 H), 7.89 - 7.87 (d, J = 7.6 Hz, 1 H), 7.75 - 7.66 (m, 2 H), 7.59 - 7.56 (m, 2 H), 6.22 -
6.20 (d, J = 8.4 Hz, 1 H), 5.35 (s, 2 H), 4.5 (s, 2 H), 4.08 - 3.97 (m, 4 H), 3.88 - 3.73 (m, 3 H),
2.81 (s, 2 H), 2.46 (s, 3 H), 2.31 (s, 2 H).
Example 2-2
N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
6-methylquinolinamine
O NH
N N
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in e 2-1) and 3-(aminomethyl)-N,N-dibenzyloxetanamine. MS obsd. (ESI+)
[(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J = 1.2, 7.6 Hz, 1 H), 7.90 (d, J =
6.8 Hz, 1 H), 7.66 (s, 1 H), 7.62 (td, J = 1.2, 7.6 Hz, 1 H), 7.47 - 7.43 (m, 2 H), 7.30 (dd, J = 1.6,
8.4 Hz, 1 H), 6.20 (s, 1 H), 5.18 (s, 2 H), 4.63 (d, J = 6.4 Hz, 2 H), 4.59 (d, J = 6.8 Hz, 2 H), 4.59
(brs , 2 H), 3.68 (s, 2 H), 3.59 (t, J = 4.4 Hz, 2 H), 2.42 (s, 3 H).
Example 2-3
N-[(4-Aminotetrahydro-2H-pyranyl)methyl](1,1-dioxido-2,3-dihydro-1,4-
hiazepin-4(5H)-yl)methylquinolinamine
N N
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 4-(aminomethyl)-N,N-dibenzyltetrahydro-2H-pyranamine. MS
obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J = 7.2 Hz, 1 H), 7.87
(d, J = 7.6 Hz, 1 H), 7.68 (s, 1 H), 7.64 - 7.60 (m, 1 H), 7.44 (m, 2 H), 7.29 (dd, J = 2.0, 8.4 Hz,
1 H), 6.14 (s, 1 H), 5.16 (s, 2 H), 4.54 (brs, 2 H), 3.86 - 3.74 (m, 4 H), 3.58 (t, J = 4.8 Hz, 2 H),
2.42 (s, 3 H), 2.18 (dd, J = 2.4, 4.8 Hz, 2 H), 1.88 - 1.81 (m, 2 H), 1.57 (m, 2 H).
e 2-4
N-[(3-Aminooxetanyl)methyl](8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)-quinolinamine
O NH
N N
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-
chloroquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide red in
analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using 8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-
dichloroquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetanamine. MS (ESI+) [(M+H)+] 439,
1H NMR (400 MHz, CD
3OD) δ ppm 7.91 (d, J = 8.34 Hz, 1 H), 7.84 (d, J = 7.58 Hz, 1 H), 7.72 -
7.60 (m, 1 H), 7.49 - 7.35 (m, 3 H), 7.09 (ddd, J = 8.21, 5.18, 3.03 Hz, 1 H), 6.52 (t, J = 5.43 Hz,
1 H), 6.22 (s, 1 H), 5.06 (brs, 2 H), 4.45 (d, J = 6.06 Hz, 3 H), 4.38 (d, J = 6.06 Hz, 3 H), 3.61 (t,
J = 4.80 Hz, 2 H), 3.56 (d, J = 5.31 Hz, 2 H), 2.31 (s, 3 H).
Example 2-5
N-[(3-Aminooxetanyl)methyl]methyl(8-methyl-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinolinamine
O NH2
N N
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-
6-methylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared
in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in e 2-1 by using 8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-
dichloromethylquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetanamine. MS obsd.
(ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J = 7.83 Hz, 1 H), 7.68 (d, J
= 3.03 Hz, 2 H), 7.41 (d, J = 6.57 Hz, 1 H), 7.33 (d, J = 8.59 Hz, 1 H), 7.25 (dd, J = 8.59, 1.52
Hz, 1 H), 6.42 (t, J = 5.56 Hz, 1 H), 6.19 (s, 1 H), 5.05 (brs, 2 H), 4.45 (d, J = 5.81 Hz, 3 H),
4.39 (d, J = 6.06 Hz, 3 H), 3.60 (t, J = 4.55 Hz, 2 H), 3.55 (d, J = 5.31 Hz, 2 H), 2.37 (s, 3 H),
2.31 (s, 3 H).
Example 2-6
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(2-oxa
azaspiro[3.4]octyl)quinolinamine
N N
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using hloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and yloxaazaspiro[3.4]octylamine. MS obsd. (ESI+)
[(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 - 8.08 (m, 2 H), 7.90 - 7.88 ( d, J = 7.2,
1 H), 7.75 - 7.70 (m, 2 H), 7.65 - 7.59 (m, 2 H), 6.36 (s, 1 H), 5.38 - 5.36 (d, J = 8.8, 2 H), 5.20 -
5.10 (m, 1 H), 4.80 - 4.79 (m, 2 H), 4.74 - 4.72 (m, 2 H), 4.56 - 4.54 (d, J = 7.2, 2 H), 3.90 - 3.87
(m, 1 H), 3.81 - 3.75 (m, 4 H), 3.60 - 3.50 (m, 1 H), 2.48 (s, 3 H).
Example 2-7
N-[2-(3-Aminooxetanyl)ethyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
6-methylquinolinamine
NH NH
N N
O
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 3-(aminoethyl)-N-benzyloxetanamine. MS obsd. (ESI+)
+] 453, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 - 7.89 (t, 1 H), 7.89 - 7.87 (t, 1 H),
7.64 - 7.60 (m, 2 H), 7.49 - 7.45 (m, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 7.24 - 7.21 (m, 1 H), 6.87 (t,
J = 10.4 Hz, 1 H), 6.05 (s, 1 H), 5.08 (s, 2 H), 4.39 (m, 6 H), 3.63 (t, J = 9.2 Hz, 2 H), 3.41 - 3.36
(m, 2 H), 2.41 (s, 2 H), 2.35 (s, 3 H), 2.08 (t, J = 14.4 Hz, 2 H).
e 2-8
N-[(3-Aminooxetanyl)methyl]methyl(5-methyl-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinolinamine
N N
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-
6-methylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared
in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-
dichloromethylquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetanamine. MS obsd.
(ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (dd, J = 7.96, 1.39 Hz, 1 H),
7.90 (d, J = 6.57 Hz, 1 H), 7.71 - 7.64 (m, 2 H), 7.46 (ddd, J = 8.15, 6.63, 1.64 Hz, 2 H), 7.33
(dd, J = 8.59, 1.77 Hz, 1 H), 6.15 (s, 1 H), 5.86 (d, J = 6.82 Hz, 1 H), 4.64 - 4.53 (m, 4 H), 4.40 -
4.25 (brs, 2 H), 3.70 (d, J = 8.59 Hz, 1 H), 3.62 - 3.58 (m, 2 H), 3.57 - 3.49 (m, 1 H), 2.43 (s, 3
H), 2.00 (d, J = 7.07 Hz, 3 H).
e 2-9
N-[(3-Aminooxetanyl)methyl](8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinolinamine
2NH O
N N
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-
chloroquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in
analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using oxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-
dichloroquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetanamine. MS obsd. (ESI+)
[(M+H)+] 455, 1H NMR (400 MHz, CD3OD) δ ppm 7.91 - 7.74 (m, 2 H), 7.58 - 7.38 (m, 3 H),
7.22 - 7.03 (m, 2 H), 6.23 (s, 1 H), 5.12 (brs, 2 H), 4.70 - 4.46 (m, 6 H), 3.81 (s, 3 H), 3.70 (s, 2
H), 3.65 - 3.52 (m, 2 H).
Example 2-10
N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
1,6-naphthyridinamine
N N
The title compound was ed in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-
1,6-naphthyridinyl) ,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
e 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-1,6-
naphthyridine) and 3-(aminomethyl)-N,N-dibenzyloxetanamine. MS obsd. (ESI+) [(M+H)+]
426, 1H NMR (400 MHz, CD3OD) δ ppm 9.15 (s, 1 H), 8.28 - 8.80 (d, J = 6.4 Hz, 1 H), 8.00 -
7.95 (d, J = 1.2 Hz, 1 H), 7.95 - 7.90 (d, J = 7.2 Hz, 1 H), 7.62 - 7.58 (t, J = 0.8 Hz, 1 H), 7.50 -
7.40 (m, 2 H), 6.31 (s, 1 H), 5.35 (s, 2 H), 4.65 - 4.58 (m, 6 H), 3.80 (s, 2 H), 3.60 - 3.50 (t, J =
2.8 Hz, 2 H).
Example 2-11
N-[(1-Aminocyclohexyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinamine
N N
O
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 1-(aminomethyl)-N,N-dibenzylcyclohexanamine. MS obsd.
(ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CDCl3) δ ppm 8.02 - 7.99 (dd, J = 1.2 Hz, 8.0 Hz, 1
H), 7.65 - 7.63 (d, J = 7.6 Hz, 1 H), 7.48 - 7.46 (m, 2 H), 7.34 - 7.25 (m, 3 H), 5.86 (s, 1 H), 5.64
(s, 1 H), 5.10 (s, 2 H), 4.56 (s, 2 H), 3.55 (s, 2 H), 3.05 - 3.04 (d, J = 4.8 Hz, 2 H), 2.41 (s, 3 H),
1.98 (s, 4 H), 1.56 (m, 10 H).
Example 3-1
N-{[3-(Aminomethyl)oxetanyl]methyl}(8-fluoro-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinamine
N N
A mixture of 8-(4-chloromethylquinolinyl)fluoro-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide (200 mg, 0.51 mmol, prepared in analogy to 4-(4-chloro
methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by
using 8-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloromethylquinoline),
sodium tert-butoxide (96 mg, 1.02 mmol), is(diphenylphosphino)ferrocenepalladium
(II)dichloride (42 mg, 0.051 mmol), 1,1'-bis(diphenylphosphino)ferrocene (29 mg,
0.051 mmol), and oxetane-3,3-diyldimethanamine (89 mg, 0.77 mmol) in 1,4-dioxane (2 mL)
was heated with stirring in a sealed 5 mL of microwave process via for 1.5 hours at 120 ºC under
microwave irradiation. The resulting mixture was concentrated in vacuo. The residue was
ed by ative HPLC to afford 48 mg of the product as a white product (yield was 20%).
MS obsd. (ESI+) [(M+H)+] 471, 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (dd, J = 8.34, 5.05
Hz, 1 H), 7.74 (t, J = 5.56 Hz, 2 H), 7.54 (d, J = 8.59 Hz, 1 H), 7.46 - 7.29 (m, 2 H), 6.19 (s, 1
H), 5.23 (brs, 2 H), 4.69 - 4.58 (m, 8 H), 3.78 (s, 2 H), 3.69 (brs, 2 H), 3.41 (s, 2 H), 2.46 (s, 3
Example 3-2
N-{[3-(Benzylamino)oxetanyl]methyl}chloro(7-fluoro-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinolinamine
O N
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6-
dichloroquinolinyl)fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in
analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using 7-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4,6-
trichloroquinoline) and 3-(aminomethyl)-N-benzyloxetanamine. MS obsd. (ESI+) [(M+H)+]
567, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J = 8.72, 5.43 Hz, 1 H), 7.82 (d, J = 2.27 Hz,
1 H), 7.71 (dd, J = 9.09, 2. 53 Hz, 1 H), 7.50 (d, J = 8.84 Hz, 1 H), 7.39 (dd, J = 8.84, 2.27 Hz, 1
H), 7.33 (d, J = 7.07 Hz, 2 H), 7.25 - 7.16 (m, 2 H), 7.16 - 7.04 (m, 2 H), 6.13 (s, 1 H), 5.15 (brs,
2 H), 4.71 (d, J = 6.57 Hz, 2 H), 4.54 (d, J = 6.57 Hz, 4 H), 3.77 (s, 2 H), 3.72 (s, 2 H), 3.56 (t, J
= 4.93 Hz, 2 H).
Example 3-3
Aminooxetanyl)methyl]chloro(7-fluoro-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinolinamine
O NH2
N N
O
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6-
dichloroquinolinyl)fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in
analogy to the one in Example 3-2) and 3-(aminomethyl)oxetanamine. MS obsd. (ESI+)
[(M+H)+] 477, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 - 7.94 (m, 2 H), 7.72 (dd, J = 8.97, 2.65
Hz, 1 H), 7.53 (d, J = 8.84 Hz, 1 H), 7.43 (dd, J = 8.84, 2.27 Hz, 1 H), 7.15 (td, J = 8.46, 2.53
Hz, 1 H), 6.23 (s, 1 H), 5.18 (brs, 2 H), 4.73 - 4.60 (m, 4 H), 4.51 (brs, 2 H), 3.75 (s, 2 H), 3.59
(t, J = 4.67 Hz, 2 H).
Example 3-4
N-{[3-(Aminomethyl)oxetanyl]methyl}(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)-quinolinamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-
chloroquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in
analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-
dichloroquinoline) and e-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 469, 1H
NMR (400 MHz, CD3OD) δ ppm 8.41 (brs, 3 H), 8.02 (d, J = 8.08 Hz, 1 H), 7.97 (d, J = 8.84
Hz, 1 H), 7.68 (d, J = 8.08 Hz, 1 H), 7.60 (t, J = 7.71 Hz, 1 H), 7.44 (d, J = 2.53 Hz, 1 H), 7.31(t,
J = 7.20 Hz, 1 H), 7.01 (dd, J = 8.59, 2.53 Hz, 1 H), 6.19 (s, 1 H), 5.20 (br. s,2 H), 4.64 (s, 4 H),
4.54 (brs, 2 H), 3.92 (s, 3 H), 3.81 (s, 2 H), 3.69 - 3.55 (m, 2 H), 3.47 (s, 2 H).
Example 3-5
N-{[3-(Aminomethyl)oxetanyl]methyl}(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared
in analogy to hloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-
dichloromethylquinoline) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+]
483, 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (d, J = 8.59 Hz, 1 H), 7.64 (s, 1 H), 7.51 - 7.39
(m, 2 H), 7.31 (dd, J = 8.59, 1.77 Hz, 1 H), 6.91 (dd, J = 8.59, 2.53 Hz, 1 H), 6.14 (s, 1 H), 5.10
(brs, 2 H), 4.69 - 4.44 (m, 6 H), 3.90 (s, 3 H), 3.74 - 3.61 (m, 2 H), 3.57 - 3.52 (m, 2 H), 3.18 (s,
2 H), 2.42 (s, 3 H).
Example 3-6
N-{[3-({[2-(7-Methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]amino}methyl)oxetanyl]methyl}acetamide
N N
The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared
in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-
dichloromethylquinoline) and N-{[3-(aminomethyl)oxetanyl]methyl}acetamide. MS obsd.
(ESI+) +] 525, 1H NMR (400 MHz, CD3OD) δ ppm 7.91 (d, J = 8.59 Hz, 1 H), 7.70 (s, 1
H), 7.47 (d, J = 8.59 Hz, 1 H), 7.41 (d, J = 2.27 Hz, 1 H), 7.33 (dd, J = 8.46, 1.64 Hz, 1 H), 6.94
(d, J = 8.59 Hz, 1 H), 6.18 (s, 1 H), 5.12 (s, 2 H), 4.61 - 4.54 (m, 6 H), 3.90 (s, 3 H), 3.68 (s, 2
H), 3.67 - 3.63 (m, 2 H), 3.59 - 3.51 (m, 2 H), 2.44 (s, 3 H), 2.05 (s, 3 H).
Example 3-7
N-{[3-(Aminomethyl)oxetanyl]methyl}(8-methyl-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinamine
N N
The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4-
chloroquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in
analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using 8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-
dichloroquinoline) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 453, 1H
NMR (400 MHz, CD3OD) δ ppm 7.86 - 7.69 (m, 3 H), 7.57 - 7.49 (m, 1 H), 7.47 - 7.34 (m, 2 H),
7.19 - 7.06 (m, 1 H), 6.17 (s, 1 H), 5.11 (brs, 2 H), 4.68 - 4.39 (m, 6 H), 3.67 (s, 2 H), 3.63 (q, J
= 7.07 Hz, 1 H), 3.55 (t, J = 4.55 Hz, 2 H), 3.15 (s, 2 H), 2.33 (s, 3 H).
Example 3-8
N-{[3-(Aminomethyl)oxetanyl]methyl}methyl(8-methyl-1,1-dioxido-2,3-dihydro-
1,4-benzothiazepin-4(5H)-yl)quinolinamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared
in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using 8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-
dichloromethylquinoline) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+]
467, 1H NMR (400 MHz, CD3OD) 7.74 - 7.62 (m, 2 H), 7.58 (s, 1 H), 7.43 (d, J = 8.59 Hz, 1 H),
7.32 - 7.20 (m, 2 H), 6.07 (s, 1 H), 4.99 (brs, 2 H), 4.62 - 4.48 (m, 4 H), 4.48 - 4.18 (m, 2 H),
3.65 - 3.60 (m, 2 H), 3.44 (brs, 2 H), 3.11 (s, 2 H), 2.43 - 2.26 (m, 3 H), 2.14 (s, 3 H).
e 3-9
[3-({[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}methyl)oxetanyl]methanol
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 3-(aminomethyl)oxetanyl]methanol. MS obsd. (ESI+)
[(M+H)+] 454, 1H NMR (400 MHz, CD3OD) δ ppm 8.02 - 7.96 (m, 1 H), 7.90 (d, J = 7.33 Hz, 1
H), 7.68 - 7.54 (m, 2 H), 7.45 (d, J = 8.34 Hz, 2 H), 7.35 - 7.20 (m, 1 H), 6.19 (s, 1 H), 5.14 (s, 2
H), 4.60 (d, J = 6.06 Hz, 3 H), 4.51 (d, J = 6.06 Hz, 3 H), 3.98 (s, 2 H), 3.67 (s, 2 H), 3.58 (t, J =
4.67 Hz, 2 H), 2.42 (s, 3 H).
Example 3-10
-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}propane-1,2-diol
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using hloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and (2S)aminopropane-1,2-diol. MS obsd. (ESI+) [(M+H)+] 428,
1H NMR (400 MHz, CD
3OD) δ ppm 7.98 (dd, J = 7.83, 1.26 Hz, 1 H), 7.89 (d, J = 7.33 Hz, 1
H), 7.63 (td, J = 7.45, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.50 - 7.35 (m, 2 H), 7.29 (dd, J = 8.59, 1.77
Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2 H), 4.55 (brs, 2 H), 4.04 - 3.89 (m, 1 H), 3.69 (d, J = 5.56 Hz, 2
H), 3.64 - 3.49 (m, 4 H), 2.41 (s, 3 H).
e 3-11
(2R){[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}propane-1,2-diol
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in e 2-1) and (2R)aminopropane-1,2-diol. MS obsd. (ESI+) [(M+H)+] 428,
1H NMR (400 MHz, CD
3OD) δ ppm 7.98 (dd, J = 7.83, 1.26 Hz, 1 H), 7.89 (d, J = 7.33 Hz, 1
H), 7.63 (td, J = 7.45, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.50 - 7.35 (m, 2 H), 7.29 (dd, J = 8.59, 1.77
Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2 H), 4.55 (brs, 2 H), 4.04 - 3.89 (m, 1 H), 3.69 (d, J = 5.56 Hz, 2
H), 3.64 - 3.49 (m, 4 H), 2.41 (s, 3 H).
Example 3-12
N-{[1-(Aminomethyl)-3,3-difluorocyclobutyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy
to the one in Example 2-1) and (3,3-difluorocyclobutane-1,1-diyl)dimethanamine. MS obsd.
(ESI+) [(M+H)+] 487, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (dd, J = 7.83, 1.01 Hz, 1 H),
8.08 (s, 1 H), 7.89 (d, J = 7.07 Hz, 1 H), 7.80 - 7.68 (m, 2 H), 7.68 - 7.56 (m, 2 H), 6.15 (s, 1 H),
.37 (s, 2 H), 4.55 (brs, 2 H), 3.80 (s, 2 H), 3.79 - 3.67 (m, 2 H), 3.44 (s, 2 H), 2.76 (t, J = 12.25
Hz, 4 H), 2.51 (s, 3 H).
Example 3-13
N-[(3-Aminooxetanyl)methyl]chloro(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-
hiazepin-4(5H)-yl)quinolinamine
O NH2
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6-
dichloroquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared
in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using 8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4,6-
trichloroquinoline) and 3-(aminomethyl)oxetanamine. MS obsd. (ESI+) [(M+H)+] 489, 1H
NMR (400 MHz, CD3OD) δ ppm 7.95 (d, J = 2.27 Hz, 1 H), 7.83 - 7.74 (m, 1 H), 7.58 - 7.44 (m,
2 H), 7.44 - 7.33 (m, 1 H), 7.14 (dd, J = 8.34, 2.78 Hz, 1 H), 6.24 (s, 1 H), 5.11 (brs, 2 H), 4.61
(q, J = 6.74 Hz, 6 H), 3.82 (s, 3 H), 3.69 (s, 2 H), 3.63 - 3.50 (m, 2 H), 2.05 (s, 2 H).
Example 3-14
N-{[3-(Aminomethyl)oxetanyl]methyl}chloro(8-methoxy-1,1-dioxido-2,3-dihydro-
1,4-benzothiazepin-4(5H)-yl)quinolinamine
N N
O
The title compound was ed in y to Example 3-1 in Scheme 5 by using 4-(4,6-
dichloroquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared
in analogy to the one in Example 3-13) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+)
[(M+H)+] 503, 1H NMR (400 MHz, CD3OD) δ ppm 8.23 (s, 1 H), 7.88 (d, J = 8.59 Hz, 1 H),
7.73 (d, J = 8.84 Hz, 1 H), 7.65 - 7.51 (m, 2 H), 7.21 (dd, J = 8.34, 2.78 Hz, 1 H), 6.30 (s, 1 H),
.26 (brs, 2 H), 4.76 - 4.60 (m, 6 H), 4.56 (brs, 1 H), 3.91 (s, 2 H), 3.85 (s, 3 H), 3.69 (brs, 2 H),
3.52 (s, 2 H).
Example 3-15
trans-N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]cyclohexane -1,2-diamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and trans-cyclohexane-1,2-diamine. MS obsd. (ESI+) +] 451,
1H NMR (400 MHz, CD
3OD) δ ppm 8.06 - 7.96 (d, J = 7.8 Hz, 1 H), 7.83 (d, J = 7.33 Hz, 1 H),
7.70 (s, 1 H), 7.60 (td, J = 7.52, 1.14 Hz, 1 H), 7.50 - 7.38 (m, 2 H), 7.28 (dd, J = 8.46, 1.64 Hz,
1 H), 6.13 (s, 1 H), 5.20 - 5.11 (m, 2 H), 3.72 - 3.60 (m, 1 H), 3.58 - 3.49 (m, 1 H), 3.42 - 3.35
(m, 2 H), 3.35 - 3.30 (m, 1 H), 2.87 (td, J = 10.17, 3.92 Hz, 1 H), 2.42 (s, 3 H), 2.10 (d, J = 5.31
Hz, 1 H), 2.01 (d, J = 13.14 Hz, 1 H), 1.89 (d, J = 8.08 Hz, 2 H), 1.67 - 1.56 (m, 1 H), 1.51 - 1.41
(m, 2 H), 1.32 - 1.17 (m, 1 H).
Example 3-16
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-
cyclohexane-1,3-diamine
N N
The title compound was ed in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and exane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 451, 1H
NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J = 7.8 Hz, 1 H), 7.57 (d, J = 7.3 Hz, 1 H ), 7.53 - 7.47
(m, 2 H), 7.37 (t, J = 7.7 Hz, 1 H), 7.32 - 7.26 (m, 2 H), 5.86 (s, 1 H), 5.16 - 5.00 (m, 2 H), 3.65 -
3.50 (brs, 4 H), 3.16 (brs, 1 H), 2.42 (s, 3 H), 2.45 - 2.38 (m, 1 H), 2.29 (d, J = 11.1 Hz, 1 H),
2.03 - 1.85 (m, 3 H), 1.54 - 1.42 (m, 1 H), 1.40 - 1.24 (m, 3 H).
Example 3-17
[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-4,4-
dimethyl-pyrrolidinol
N N
The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and (3R)-4,4-dimethylpyrrolidinol. MS obsd. (ESI+) [(M+H)+]
452, 1H NMR (400 MHz, CD3OD) δ ppm 7.94 (dd, J = 7.83, 1.01 Hz, 1 H), 7.83 - 7.73 (m, 2 H),
7.58 (td, J = 7.58, 1.26 Hz, 1 H), 7.47 - 7.37 (m, 2 H), 7.23 (dd, J = 8.59, 1.77 Hz, 1 H), 6.03 (s,
1 H), 5.11 (s, 2 H), 4.02 (dd, J = 10.36, 5.31 Hz, 1 H), 3.93 (dd, J = 5.05, 3.79 Hz, 1 H), 3.61 -
3.47 (m, 4 H), 2.37 (s, 3 H), 1.15 (s, 3 H), 1.10 - 1.05 (m, 3 H).
Example 3-18
cis-N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-
cyclohexane-1,4-diamine
N N
The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and cis-cyclohexane-1,4-diamine. MS obsd. (ESI+) [(M+H)+] 451, 1H
NMR (400 MHz, DMSO- d6) δ ppm 7.91 - 7.85 (m, 2 H), 7.79 (s, 1 H), 7.58 (td, J = 7.45, 1.26
Hz, 1 H), 7.51 - 7.44 (m, 1 H), 7.29 (d, J = 8.59 Hz, 1 H), 7.21 (dd, J = 8.59, 1.52 Hz, 1 H), 6.17
(d, J = 7.58 Hz, 1 H), 6.03 (s, 1 H), 5.06 (brs, 2 H), 4.50 (brs, 1 H), 4.11 (d, J = 4.55 Hz, 1 H),
3.67 (d, J = 4.80 Hz, 1 H), 3.64 - 3.56 (m, 2 H), 3.16 (m, 2 H), 3.06 (brs, 1 H), 2.35 (s, 3 H), 1.83
- 1.44 (m, 8 H).
Example 3-19
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-2,2-
difluoropropane-1,3-diamine
F NH2
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and fluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+]
447, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 - 8.07 (d, 1 H), 7.95 (s, 1 H), 7.86 - 7.84 (d, 1 H),
7.77 - 7.69 (m, 2 H), 7.64 - 7.58 (m, 2 H), 6.26 (s, 1 H), 5.34 (s, 2 H), 4.53 (s, 2 H), 4.23 (t, 2 H),
3.74 - 3.66 (m, 4 H), 2.48 (s, 3 H).
Example 3-20
N-[6-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]-2,2-
difluoropropane-1,3-diamine
F NH
N N
The title compound was prepared in y to e 3-1 in Scheme 5 by using 4-(4,6-
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4,6-trichloroquinoline) and
2,2-difluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, DMSO-
d6) δ ppm 8.17 - 8.08 (m, 1 H), 7.94 (d, J = 7.07 Hz, 1 H), 7.88 (dd, J = 7.83, 1.26 Hz, 1 H), 7.62
(td, J = 7.45, 1.26 Hz, 1 H), 7.54 - 7.39 (m, 3 H), 7.14 (brs, 1 H), 6.33 (s, 1 H), 5.77 (s, 1 H),
.11 (brs, 2 H), 4.43 (brs, 2 H), 4.03 - 3.87 (m, 2 H), 3.61 (brs, 2 H), 3.13 - 3.29 (m, 2 H).
Example 3-21
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]
fluoropropane-1,3-diamine
N N
The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 2-fluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 429, 1H
NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J = 7.83, 1.01 Hz, 1 H), 7.84 (d, J = 7.58 Hz, 1 H),
7.65 - 7.57 (m, 2 H), 7.47 - 7.38 (m, 2 H), 7.29 (dd, J = 8.59, 1.77 Hz, 1 H), 6.10 (s, 1 H), 5.14
(s, 2 H), 4.69 (s, 2 H), 3.64 (d, J = 5.31 Hz, 1 H), 3.61 - 3.52 (m, 4 H), 3.04 - 2.91 (m, 2 H), 2.41
(s, 3 H).
Example 3-22
N-[(3-Aminooxetanyl)methyl]chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinolinamine
O NH2
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using -
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4,6-trichloroquinoline) and
3-(aminomethyl)oxetanamine. MS obsd. (ESI+) [(M+H)+] 459, 1H NMR (400 MHz, CD3OD)
δ ppm 8.34 (s, 1 H), 8.02 - 8.00 (t, J = 4.0, 2.4 Hz, 2 H), 7.92 - 7.90 (d, J = 7.2 Hz, 1 H), 7.65 -
7.62 (m, 1 H), 7.56 - 7.54 ( d, J = 9.2 Hz, 1 H), 7.49 - 7.44 (m, 2 H), 6.27 (s, 1 H), 5.22 (s, 2 H),
4.67 - 4.63 (m, 4 H), 4.56 (s, 1 H), 3.78 (s, 2 H), 3.63 - 3.60 (t, J = 4.8 Hz, 2 H).
Example 3-23
[4-{[(3-Aminooxetanyl)methyl]amino}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinolinyl]methanol
O NH
OH NH
N N
Methyl 4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline
carboxylate
O Cl
N N
To a cooled solution of methyl ro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-
6-carboxylate (2.0 g, 5.2 mmol, prepared in analogy to 4-(4-chloromethylquinolinyl)
methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in e 1-1 by using methyl 2,4-
dichoroquinolinecarboxylate and 2,3,4,5-tetrahydro-1,4-benzothiazepine) in dichloromethane
(30 mL) was added 3-chloroperoxybenzoic acid (2.63 g, 20.8 mmol) in an ice-bath. After being
stirred for 1 hour at 0 °C, the reaction mixture was washed with brine, dried over sodium e
and concentrated in vacuo to afford 2.0 g of the crude product.
4-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinemethanol
OH Cl
N N
To a solution of methyl 4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinecarboxylate (2.0 g, 4.8 mmol) in tetrahydrofuran (50 mL) was added sodium
borohydride (729 mg, 19.2 mmol). After being refluxed for 60 hours, the reaction mixture was
diluted with water (30 mL) and ted with dichloromethane (50 mL × 2). The combined
c layers were dried over sodium sulfate and concentrated in vacuo to afford 1.4 g of the
crude product.
[4-{[(3-Aminooxetanyl)methyl]amino}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinolinyl]methanol
O NH2
OH NH
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-chloro
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinemethanol and 3-
(aminomethyl)oxetanamine. MS obsd. (ESI+) [(M+H)+] 455, 1H NMR (400 MHz, CD3OD) δ
ppm 8.33 (s, 1 H), 8.08 - 8.05 (d, J = 11.2 Hz, 2 H), 7.94 - 7.92 (d, J = 7.2 Hz, 1 H), 7.74 - 7.68
(m, 3 H), 7.57 - 7.53 ( t, J = 7.6 Hz, 1 H), 6.26 (s, 1 H), 5.31 (s, 2 H), 4.72 (s, 2 H), 44.57 (s, 4
H), 4.44 (s, 1 H), 3.88 (s, 2 H), 3.77 - 3.71 (m, 2 H).
Example 3-24
N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
7-fluoromethylquinolinamine
O NH
F N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
7-fluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in
analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in e 2-1 by using 2,4-dichlorofluoromethylquinoline and 2,3,4,5-
tetrahydro-1,4-benzothiazepine) and 3-(aminomethyl)oxetanamine. MS obsd. (ESI+)
[(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 - 8.03 (d, J = 8.0 Hz, 1 H), 7.92 - 7.88
(t, J = 8.8, 8.0 Hz, 2 H), 7.68 - 7.65 (m, 1 H), 7.53 - 7.49 ( t, J = 7.6 Hz, 1 H), 7.28 - 7.25 (d, J =
11.6 Hz, 1 H), 6.20 (s, 1 H), 5.24 (s, 2 H), 4.66 - 4.48 (m, 6 H), 3.82 (s, 2 H), 3.66 - 3.64 (m, 2
H), 2.68 (s, 3 H).
Example 3-25
N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
-fluoromethylquinolinamine
O NH2
F NH
N N
O
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
-fluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in
analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using 2,4-dichlorofluoromethylquinoline and 2,3,4,5-
tetrahydro-1,4-benzothiazepine) and nomethyl)oxetanamine. MS obsd. (ESI+)
+] 457, 1H NMR (400 MHz, DMSO- d6) δ ppm 7.99 - 7.97 (d, J = 7.2 Hz, 1 H), 7.90 -
7.88 (m, 1 H), 7.66 - 7.62 (m, 1 H), 7.51 - 7.47 ( t, J = 7.6 Hz, 1 H), 7.29 - 7.24 (t, J = 8.8, 8.4
Hz, 1 H), 7.20 - 7.18 (d, J = 8.4 Hz, 1 H), 6.61 - 6.57 (d, J = 16.0 Hz, 1 H), 6.12 (s, 1 H), 5.11 (s,
2 H), 4.44 - 4.43 (d, J = 6.0 Hz, 2 H), 4.38 - 4.37 (d, J = 6.0 Hz, 2 H), 3.63 - 3.61 (t, J = 4.8, 4.4
Hz, 2 H), 3.53 (s, 2 H), 2.68 - 2.67 (t, J = 2.0, 1.6 Hz, 1 H), 2.34 - 2.33 (t, J = 2.0, 1.6, 1 H), 1.92
(s, 3 H).
Example 3-26
N~1~-[6-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]
methylpropane-1,2-diamine
N N
The title nd was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6-
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4,6-trichloroquinoline and 5-tetrahydro-1,4-benzothiazepine) and
2-methylpropane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, CD3OD) δ
ppm 7.98 (d, J = 8.0 Hz, 2 H), 7.87 (d, J = 7.2 Hz, 1 H), 7.61 (t, J = 7.2 Hz, 1 H), 7.49 -7.43 (m,
2 H), 7.38 (dd, J = 2.0, 8.8 Hz, 1 H), 6.13 (s, 1 H), 5.16 (s, 2 H), 4.54 (brs, 2 H), 3.57 (t, J = 4.4
Hz, 2 H), 3.27 (s, 2 H), 1.26 (s, 6 H).
Example 3-27
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(tetrahydro-2H-
pyranyl)quinolinamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in analogy
to the one in Example 2-1) and tetrahydro-2H-pyranylamine. MS obsd. (ESI+) [(M+H)+] 438,
1H NMR (400 MHz, DMSO- d6) δ ppm 7.89 (dd, J = 6.95, 3.41 Hz, 2 H), 7.78 (s, 1 H), 7.59 (t, J
= 7.07 Hz, 1 H), 7.47 (t, J = 7.58 Hz, 1 H), 7.31 (d, J = 8.59 Hz, 1 H), 7.23 (d, J = 8.59 Hz, 1
H), 6.33 (d, J = 8.08 Hz, 1 H), 6.09 (s, 1 H), 5.09 (brs, 2 H), 4.44 (brs, 1 H), 3.99 (d, J = 9.85 Hz,
2 H), 3.94 - 3.82 (m, 1 H), 3.69 - 3.52 (m, 4 H), 2.36 (s, 3 H), 1.85 (d, J = 11.87 Hz, 2 H), 1.69 -
1.44 (m, 2 H).
Example 3-28
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2-(piperazin
yl)ethyl]quinolinamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy
to the one in Example 2-1) and 2-(piperazinyl)ethanamine. MS obsd. (ESI+) [(M+H)+] 466, 1H
NMR (400 MHz, DMSO-d6) δppm 7.925 (d, J = 8.0 Hz, 1 H), 7.806 (d, J = 7.2 Hz, 1 H), 7.516 -
7.575 (m, 2 H), 7.359 - 7.395 (m, 2 H), 7.238 (m, 1 H), 5.98 (s, 1 H), 5.10 (s, 2 H), 4.49 (brs, 2
H), 3.538 (m, 2 H), 3.542 (m, 2 H), 3.44 (t, J = 6.57 Hz, 2 H), 3.32 (s, 2 H), 2.89 (t, J = 4.80 Hz,
4 H), 2.71 (t, J = 6.57 Hz, 2 H), 2.56 (brs, 4 H), 2.37 (s, 3 H).
e 3-29
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(piperidin
ylmethyl)quinolinamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy
to the one in Example 2-1) and 1-(piperidinyl)methanamine. MS obsd. (ESI+) [(M+H)+] 451,
1H NMR (400 MHz, DMSO- d6) δ ppm 9.89 (brs, 2 H), 7.875 (t, J = 8.0 Hz, 2 H), 7.76 (s, 1 H),
7.625 (t, J = 6.8Hz, 1 H), 7.48 (d, J = 7.6Hz, 1 H), 7.30 (d, J = 8.4Hz, 1 H), 7.226 (d, J = 1.6Hz
,1 H), 6.73 (t, J = 5.43 Hz, 1 H), 5.07 (brs, 2 H), 4.42 (brs, 2 H), 4.10 (d, J = 12.63 Hz, 2 H),
3.63(m, 2 H), 3.23 - 3.05 (m, 2 H), 2.50 (s, 2 H), 2.05(s, 3 H), 1.76 - 1.66 (m, 3 H), 1.15 - 0.98
(m, 2 H).
Example 3-30
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]heptane-1,7-diamine
NH NH
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in e 2-1) and heptane-1,7-diamine. MS obsd. (ESI+) [(M+H)+] 467, 1H NMR
(400 MHz, CD3OD) δ ppm 8.07 (dd, J = 1.2, 0.8 Hz, 1 H), 7.97 (s, 1 H), 7.92(d, J = 7.6 Hz, 1
H), 7.74 - 7.68 (m, 2 H), 7.61-7.56 (m, 2 H), 5.91 (s, 1 H), 5.32 (s, 2 H), 4.52 (brs, 2 H), 3.75 (d,
J = 4.80 Hz, 2 H), 3.31 (d, J = 1.60 Hz, 2 H), 2.94(m, 2 H), 2.45 (s, 3 H), 1.72 (m, 4 H), 1.50 (m,
6 H).
Example 3-31
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'-
methylethane-1,2-diamine
N N
O
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using hloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y
to the one in Example 2-1) and N-methylethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H
NMR (400 MHz, CD3OD) δ ppm 8.03 - 8.0 (m, 3 H), 7.87 - 7.84 (d, J = 8.8 Hz, 1 H), 7.71 - 7.70
(d, J = 1.2 Hz, 1 H), 7.57 - 7.53 (m, 2 H), 6.07 (s, 1 H), 5.40 (s, 2 H), 4.56 (s, 2 H), 3.96 - 3.93
(dd, J = 6.0, 6.4 Hz, 2 H), 3.75 - 3.73 (q, J = 4.4 Hz, 2 H), 3.43 - 3.40 (q, J = 6 Hz, 2 H), 2.80 (s,
3 H), 2.46 (s, 3 H).
Example 3-32
N'-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N,N-
dimethylethane-1,2-diamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and N,N-dimethylethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+]
425, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 - 8.01 (m, 3 H), 7.88 - 7.86 (d, J = 8.8 Hz, 1 H),
7.70 - 7.68 (d, J = 1.2 Hz, 1 H), 7.56 - 7.52 (m, 2 H), 6.05 (s, 1 H), 5.41 (s, 2 H), 4.56 (s, 2 H),
3.96 - 3.93 (dd, J = 6.0, 6.4 Hz, 2 H), 3.75-3.73 (q, J = 4.4 Hz, 2 H), 3.43 - 3.40 (q, J = 6.0 Hz,
2 H), 3.01 (s, 3 H), 2.45 (s, 3 H).
Example 3-33
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N,6-dimethylquinolinamine
trifluoroacetate
NH F F
N N
The title compound was prepared in y to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in analogy
to the one in Example 2-1) and amine. MS obsd. (ESI+) [(M+H)+] 368, 1H NMR (400
MHz, DMSO-d6) δ ppm 11.47 (s, 1 H), 8.45 (brs, 1 H), 7.99 (m, 3 H), 7.75 (m, 2 H), 7.60 (m, 2
H), 5.92 (s, 1 H), 5.33 (s, 2 H), 4.48 (s, 2 H), 3.91 (s, 2 H), 3.02 (s, 3 H), 2.33 (s, 3 H).
Example 3-34
(3S,4S)[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]pyrrolidine-3,4-diol
OH OH
N N
The title nd was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in e 2-1) and (3S,4S)-pyrrolidine-3,4-diol. MS obsd. (ESI+) [(M+H)+] 440, 1H
NMR (400 MHz, CD3OD) δ ppm 8.03 (s, 1 H),8.01 (s, 1 H), 7.80 - 7.78 (d, J = 7.6 Hz, 1 H),
7.67 - 7.63 (m, 2 H), 7.54 - 7.50 (m, 2 H), 5.83 (s, 1 H), 5.21 (s, 2 H), 4.45 (s, 2 H), 4.22 (s, 2 H),
4.18 - 4.15 (m, 2 H), 3.67 - 3.60 (m, 4 H), 2.41 (s, 3 H).
Example 3-35
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(pyrrolidin
ylmethyl)quinolinamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 1-(pyrrolidinyl)methanamine. MS obsd. (ESI+) [(M+H)+] 437,
1H NMR (400 MHz, CD
3OD) δ ppm 7.96 - 7.94 (m, 2 H), 7.90 (d, J = 7.6 Hz, 1 H), 7.70 (d, J =
8.4 Hz, 1 H), 7.61 (t, J = 7.6 Hz, 1 H), 7.47 - 7.45 (m, 2 H), 6.01 (s, 1 H), 5.33 - 5.25 (m, 2 H),
4.55 - 4.41 (m, 2 H), 3.96 - 3.73 (m, 3 H), 3.64 (s, 2 H), 3.38 - 3.31 (m, 1 H), 3.29 - 3.27 (m, 1
H), 2.37 (s, 3 H), 2.28 - 2.21 (m, 1 H), 2.13 - 1.96 (m, 2 H), 1.89 - 1.81 (m, 1 H).
Example 3-36
4-[4-(1,4-Diazepanyl)methylquinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide
N N
The title compound was ed in analogy to e 3-1 1 in Scheme 5 by using 4-(4-
chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in
analogy to the one in Example 2-1) and 1,4-diazepine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR
(400 MHz, CD3OD) δ ppm 7.99 (d, J = 7.2 Hz, 1 H), 7.86 (d, J = 7.2 Hz, 1 H), 7.81 (d, J = 8.8
Hz, 1 H), 7.72 - 7.68 (m, 2 H), 7.58 - 7.51 (m, 2 H), 6.31 (s, 1 H), 5.32 (s, 2 H), 4.54 (s, 2 H),
4.06 - 4.04 (m, 2 H), 3.90 - 3.87 (m, 2 H), 3.72 (s, 2 H), 3.63 - 3.61 (m, 2 H), 3.46 - 3.42 (m, 2
H), 2.45 (s, 3 H), 2.32 (s, 2 H).
Example 3-37
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'-
ethylethane-1,2-diamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and N-ethylethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 425, 1H
NMR (400 MHz, CD3OD) δ ppm 8.05 (d, J = 7.2 Hz, 1 H), 7.99 - 7.97 (m, 2 H), 7.81 (d, J = 8.4
Hz, 1 H), 7.67 (t, J = 7.2 Hz, 1 H), 7.51 - 7.46 (m, 2 H), 6.08 (s, 1 H), 5.37 (s, 2 H), 4.57 (s, 2 H),
3.91 (t, J = 6.4 Hz, 2 H), 3.69 (t, J = 4.8 Hz, 2 H), 3.37 (t, J = 6.4 Hz, 2 H), 3.15 (q, J = 7.2 Hz, 2
H), 2.43 (s, 3 H), 1.35 (t, J = 7.2 Hz, 3 H).
Example 3-38
2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}ethanol
N N
The title compound was prepared in y to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y
to the one in Example 2-1) and 2-aminoethanol. MS obsd. (ESI+) [(M+H)+] 398, 1H NMR (400
MHz, CD3OD) δ ppm 8.08 (d, J = 7.6 Hz, 1 H), 7.91 (s, 1 H), 7.85 (d, J = 7.6 Hz, 1 H), 7.74 -
7.67 (m, 2 H), 7.59 - 7.56 (m, 2 H), 6.09 (s, 1 H), 5.29 (s, 2 H), 4.51 (s, 2 H), 3.83 (t, J = 5.6 Hz,
2 H), 3.74 - 3.72 (m, 2 H), 3.62 (t, J = 5.6 Hz, 2 H), 2.47 (s, 3 H).
Example 3-39
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(piperidin
yl)quinolinamine
N N
S O
The title nd was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and piperidinamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR
(400 MHz, CD3OD) δ ppm 8.05 (t, J = 8 Hz, 2 H), 7.88 (d, J = 8 Hz, 1 H), 7.73 - 7.69 (m, 2 H),
7.59 - 7.57 (m, 2 H), 6.04 (s, 1 H), 5.33 (s, 2 H), 4.52 (s, 2 H), 4.18 - 4.11 (m, 1 H), 3.74 (s, 2 H),
3.61 - 3.57 (m, 2 H), 3.33 - 3.26 (m, 2 H), 2.46 (s, 3 H), 2.24 - 2.19 (m, 2 H), 2.01 - 1.91 (m, 2
Example 3-40
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(piperidin
yl)quinolinamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in e 2-1) and dinamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR
(400 MHz, CD3OD) δ ppm 8.09 - 8.07 (d, J = 8 Hz, 1 H), 7.99 (s, 1 H), 7.89 - 7.87 (q, J = 7.2
Hz, 1 H), 7.73 - 7.68 (q, J = 14 Hz, 2 H), 7.62 - 7.55 (m, 2 H), 6.14 (s, 1 H), 5.36 (s, 2 H), 4.58 -
4.51 (m, 2 H), 4.34 (s, 1 H), 3.75 (s, 2 H), 3.63 - 3.60 (d, J = 11.6 Hz, 1 H), 3.47 - 3.44 (m, 1 H),
3.07 - 3.02 (d, J = 11.6 Hz, 2 H), 2.47 (s, 3 H), 2.17 - 2.14 (m, 2 H), 2.05 - 2.00 (m, 1 H), 1.85 -
1.84 (m, 1 H).
Example 3-41
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(piperidin
ylmethyl)quinolinamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy
to the one in Example 2-1) and 1-(piperidinyl)methanamine. MS obsd. (ESI+) [(M+H)+] 451,
1H NMR (400 MHz, CD
3OD) δ ppm 8.07 (d, J = 7.6 Hz, 1 H), 7.93 (s, 1 H), 7.85 (d, J = 7.6 Hz,
1 H), 7.73 - 7.70 (m, 2 H), 7.62 - 7.58 (m, 2 H), 6.02 (s, 1 H), 5.35 (s, 2 H), 4.51 (s, 2 H), 3.75 -
3.71 (m, 4 H), 3.51 - 3.40 (m, 2 H), 2.98 - 2.92 (m, 1 H), 2.46 (s, 3 H), 2.11 - 2.05 (m, 1 H), 1.96
- 1.90 (m, 2 H), 1.78 - 1.56 (m, 3 H).
Example 3-42
2-[(2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}ethyl)amino]ethanol
NH OH
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy
to the one in Example 2-1) and 2-[(2-aminoethyl)amino]ethanol. MS obsd. (ESI+) [(M+H)+] 441,
1H NMR (400 MHz, CD
3OD) δ ppm 7.94 (d, J = 7.6 Hz, 1 H), 7.81 (d, J = 6.8 Hz, 1 H), 7.61 -
7.57 (m, 2 H), 7.43 - 7.38 (m, 2 H), 7.24 (d, J = 7.6 Hz, 1 H), 6.02 (s, 1 H), 5.12 (s, 2 H), 4.51
(brs, 2 H), 3.69 (t, J = 5.2 Hz, 2 H), 3.55 - 3.52 (m, 2 H), 3.49 (t, J = 6.0 Hz, 2 H), 3.01 (t, J = 6.0
Hz, 2 H), 2.83 (t, J = 5.6 Hz, 2 H), 2.38 (s, 3 H).
Example 3-43
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-2,2,3,3-
tetrafluorobutane-1,4-diamine
N N
S O
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 2,2,3,3-tetrafluorobutane-1,4-diamine. MS obsd. (ESI+)
[(M+H)+] 497, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (d, J = 6.8 Hz, 1 H), 7.78 (d, J = 6.4
Hz, 1 H), 7.58 - 7.62 (m, 2 H), 7.43 - 7.47 (m, 2 H), 7.30 - 7.32 (m, 1 H), 6.19 (s, 1 H), 5.13 (s, 2
H), 4.58 (brs, 2 H), 4.12 (t, J = 16 Hz, 2 H), 3.58 (t, J = 4.8 Hz 2 H), 3.34 - 3.20 (m, 2 H), 2.43
(s, 3 H).
e 3-44
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'-(2-
methoxyethyl)ethane-1,2-diamine
NH O
N N
The title compound was prepared in analogy to Example 3-1 1 in Scheme 5 by using 4-(4-
chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in
analogy to the one in Example 2-1) and N-(2-methoxyethyl)ethane-1,2-diamine. MS obsd. (ESI+)
[(M+H)+] 455, 1H NMR (400 MHz, CD3OD) δ ppm 8.06 - 8.04 (d, J = 7.6 Hz, 1 H), 7.88 - 7.86
(m, 2 H), 7.73 - 7.70 (m, 2 H), 7.59 - 7.56 (m, 2 H), 6.01 (s, 1 H), 5.33 (s, 2 H), 4.55 (s, 2 H),
3.88 - 3.78 (m, 2 H), 3.72 (s, 2 H), 3.67 - 3.65 (t, J = 4.8 Hz, 2 H), 3.45 - 3.42 (t, J = 6 Hz, 2 H),
3.38 (s, 3 H), 3.30 - 3.28 (m, 2 H), 2.45 (s, 3 H).
Example 3-45
1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinyl]
methylpyrrolidinol
N N
The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 3-methylpyrrolidinol. MS obsd. (ESI+) [(M+H)+] 438, 1H
NMR (400 MHz, CD3OD) δ ppm 8.06 - 8.01 (m, 2 H), 7.84 - 7.82 (d, J = 7.2 Hz, 1 H), 7.74 -
7.68 (m, 2 H), 7.57 - 7.53 (m, 2 H), 5.81 (s, 1 H), 5.26 (s, 2 H), 4.49 (s, 2 H), 4.12 –3.31 (m, 3
H), 3.27 -3.21 (m, 3 H), 2.44 (s, 3 H), 2.08 (s, 2 H), 1.50 (s, 3 H).
Example 3-46
N-[6-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]ethane-
1,2-diamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6-
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and
ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 417, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 -
7.99 (d, J = 8.8 Hz, 1 H), 7.90 (s, 1 H), 7.86 -7.84 (d, J = 7.2 Hz, 1 H), 7.53 - 7.38 (m, 4 H), 6.10
(s, 1 H), 5.18(s, 2 H), 3.59-3.40 (m, 4 H), 3.19 - 3.10 (m, 2 H).
.Example 3-47
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(oxetanyl)quinolin-
4-amine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in y
to the one in Example 2-1) and amine. MS obsd. (ESI+) [(M+H)+] 410, 1H NMR (400
MHz, CD3OD) δ ppm 7.97 (d, J = 1.9 Hz, 1 H), 7.79 (d, J = 1.9 Hz, 1 H), 7.72 (s, 1 H), 7.63 (t, J
= 3.8 Hz, 1 H), 7.44 (t, J = 4.3 Hz, 2 H), 7.29 (d, J = 2.1 Hz, 1 H), 5.72 (s, 1 H), 5.16 (t, J = 3.3
Hz, 2 H), 5.12 (s, 2 H), 4.86 (m, 1 H), 4.72 (t, J = 3.0 Hz, 2 H), 4.53 (brs, 2 H), 3.58 (t, J = 2.3
Hz, 2 H), 2.43 (s, 3 H).
Example 3-48
N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinamine
O NH
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-
chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to
4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide in
Example 2-1 by using 2,4-dichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and 3-
(aminomethyl)oxetanamine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ
ppm 7.96 (d, J = 1.8 Hz, 1 H), 7.89 (m, J = 5.5 Hz, 2 H), 7.63 (m, J = 4.0 Hz, 1 H), 7.44 (m, J =
7.6 Hz, 3 H), 7.12 - 7.08 (m, J = 4.1 Hz, 1 H), 6.58 (d, J = 0.8 Hz, 1 H), 6.22 (s, 1 H), 5.11 (s, 2
H ), 4.48 - 4.39 (m, J = 9.0 Hz, 6 H), 3.65 - 3.58 (m, J = 6.1 Hz, 4 H).
Example 3-49
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[(3R)-
tetrahydrofuranyl]quinolinamine
N N
The title compound was prepared in y to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and (3R)-tetrahydrofuranamine. MS obsd. (ESI+) [(M+H)+] 424,
1H NMR (400 MHz, CD
3OD) δ ppm 7.89 (t, J = 4.4 Hz, 2 H), 7.83 (s, 1 H), 7.65 (t, J = 3.7 Hz, 1
H), 7.47 (t, J = 3.8 Hz, 1 H), 7.31 (d, J = 2.1 Hz, 1 H), 7.24 (d, J = 2.1 Hz, 1 H), 6.56 (d, J = 1.5
Hz, 1 H), 6.01 (s, 1 H), 5.08 (s, 2 H), 4.40 (brs, 2 H), 4.02 (t, J = 3.6 Hz, 1 H), 3.88 (m, J = 7.2
Hz, 1 H), 3.80 (m, J = 5.4 Hz, 1 H), 3.64 (d, J = 4.5 Hz, 3 H), 2.30 (t, J = 3.7 Hz, 4 H).
Example 3-50
N-{[3-(Aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinolinamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 453,
1H NMR (400 MHz, CD
3OD) δ ppm 8.04 (d, J = 1.8 Hz, 1 H), 7.90 (d, J = 1.9 Hz, 1 H), 7.81 (s,
1 H), 7.67 (t, J = 3.6 Hz, 1 H), 7.57 (d, J = 2.1 Hz, 1 H), 7.52 (t, J = 3.8 Hz, 1 H),7.43 (d, J = 2.1
Hz, 1 H), 6.21 (s, 1 H), 5.26 (s, 2 H), 4.63 (s, 4 H), 4.55 (brs, 2 H), 3.82 (s, 2 H ), 3.67 (t, J = 2.4
Hz, 2 H ), 3.45 (brs, 2 H), 2.46 (s, 3 H).
Example 3-51
N-{[3-(Aminomethyl)oxetanyl]methyl}chloro(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinolinamine
N N
The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4,6-
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y
to hloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and
oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 473, 1H NMR (400 MHz, CD3OD) δ
ppm 8.00 (m, J = 2.2 Hz, 1 H), 7.89 (t, J = 2.9 Hz, 2 H), 7.63 (m, J = 4.1, 1 H), 7.45 (m, J = 6.5
Hz, 2 H), 7.37 (m, J = 2.8 Hz, 1 H), 6.21 (d, 1 H), 5.18 (s, 2 H), 4.56 (m, J = 4.6 Hz, 6 H), 3.67
(s, 2 H), 3.58 (t, J = 2.4 Hz, 2 H ), 3.15 (s, 2 H).
Example 3-52
(Aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinolinamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-
chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to
4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4-dichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and
oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ
ppm 8.32 (d, J = 2.1 Hz, 1 H), 8.11 (t, J = 2.0 Hz, 1 H), 8.04 (d, J = 1.9 Hz, 1 H), 7.93 (d, J = 2.0
Hz, 1 H), 7.77 (m, J = 8.3 Hz, 2 H), 7.63 (t, J = 3.7 Hz, 1 H), 7.53 (d, J = 3.8 Hz, 1 H), 6.30 (s, 1
H), 5.45 (s, 2 H ), 4.65 (m, J = 5.5 Hz, 6 H), 4.01 (s, 2 H) , 3.83 (t, J = 2.4 Hz, 2 H ), 3.51 (s, 2
Example 3-53
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(oxetan
ylmethyl)quinolinamine
N N
S O
The title compound was ed in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and tanyl)methanamine. MS obsd. (ESI+) [(M+H)+] 424, 1H
NMR (400 MHz, DMSO-d6) δ ppm 7.93 (d, 1 H), 7.89 - 7.87 (t, 1 H), 7.69 - 7.65 (m, 2 H), 7.50
- 7.46 (t, 1 H), 7.31 (d, 1 H), 7.24 - 7.21 (m, 1 H), 6.79 - 6.76 (t, 1 H), 6.04 (s, 1 H), 5.08 (s, 2 H),
4.74 - 4.70 (m, 2 H), 4.37 (t, 4 H), 3.61 (t, 4 H), 3.28 (m, 1 H), 2.35 (s, 3 H)
Example 3-54
N-[(1-Aminocyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinamine
N N
The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and nomethyl)cyclobutanamine. MS obsd. (ESI+) [(M+H)+]
437, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (m, J = 2.0 Hz, 1 H), 7.86 (d, J = 1.8 Hz, 1 H),
7.70 (s, 1 H), 7.61 (t, J = 3.6 Hz, 1 H), 7.45 (m, J = 3.0 Hz, 2 H), 7.30 (m, J = 2.5 Hz, 1 H), 6.13
(s, 1 H), 5.18 (s, 2 H), 4.53 (br. s., 2 H), 3.59 (t, J = 2.3 Hz, 2 H), 3.46 (s, 2 H), 2.43 (s, 3 H),
2.28 - 2.22 (m, J = 6.3 Hz, 2 H ), 2.12 - 2.03 (m, J = 9.2 Hz, 2 H ), 1.97 - 1.82 (m, J = 14.7 Hz, 2
Example 3-55
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]pentane-1,5-diamine
NH NH
N N
O
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in analogy
to the one in Example 2-1) and pentane-1,5-diamine. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR
(400 MHz, CDCl3) δ ppm 7.96 (d, J = 7.6 Hz, 1 H), 7.54 (d, J = 6.8 Hz 1 H), 7.42 (m, 2 H), 7.30
(d, J = 6.4 Hz, 1 H), 7.21 (m, 2 H), 5.81 (s, 1 H), 5.03 (s, 2 H), 4.61 (m, 2 H), 3.49 (brs, 2 H),
3.19 (m, 2 H), 2.71 (d, J = 6.40 Hz, 2 H), 2.94 (m, 2 H), 2.34 (s, 3 H), 1.61 (s, 2 H), 1.49 (m, 4
Example 3-56
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]hexane-
1,6-diamine
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and hexane-1,6-diamine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR
(400 MHz, CD3OD) δ ppm 8.07 (dd, J = 1.2, 0.8 Hz, 1 H), 7.97 (s, 1 H), 7.92 (d, J = 7.6 Hz, 1
H), 7.80 (d, J = 8.8 Hz, 1 H), 7.70 (d, J = 1.2 Hz, 1 H), 7.57 (dd, J = 7.20, 1.6 Hz, 2 H), 5.91 (s,
1 H), 5.32 (s, 2 H), 4.52 (brs, 2 H), 3.75 (d, J = 4.80 Hz, 2 H), 3.31 (d, J = 1.60 Hz, 2 H), 2.94
(m, 2 H), 2.45 (s, 3 H), 1.72 (m, 4 H), 1.50 (m, 4 H).
Example 3-57
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-1,1,1-
trifluoromethanesulfonamide hydrochloride
O F
NH F HCl
N N
The title compound was prepared in analogy to e 3-1 in Scheme 5 by using hloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y
to the one in Example 2-1) and 1,1,1-trifluoromethanesulfonamide. MS obsd. (ESI+) [(M+H)+]
486, 1H NMR (400 MHz, DMSO- d6) δ ppm 7.99 - 7.92 (m, 2 H), 7.85 - 7.80 (d, J = 7.2 Hz, 1
H), 7.78 - 7.73 (d, J = 2 Hz, 1 H), 7.72 - 7.65 (t, J = 7.6 Hz, 1 H), 7.62 - 7.51 (m, 2 H), 7.13 (s, 1
H), 5.07 (s, 2 H), 4.60 - 4.40 (m, 2 H), 3.98 - 3.91 (t, J = 2.8 Hz, 2 H), 2.39 (s, 3 H).
Example 3-58
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]pyridazinecarboxamide
NH N
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and pyridazinecarboxamide. MS obsd. (ESI+) [(M+H)+] 460, 1H
NMR (400 MHz, CD3OD) δ ppm 9.52 - 9.48 (d, J = 8 Hz, 1 H), 8.68 (s, 1 H), 8.62- 8.58 (d, J =
7.6 Hz ,1 H), 8.10 - 8.02 (m, 3 H), 7.94 (s, 1 H), 7.88 - 7.82 (d, J = 8 Hz ,1 H), 7.75 - 7.68 (t, J =
7.6 Hz , 2 H), 7.60 - 7.52 (t, J = 7.2 Hz, 1 H), 5.36 (s, 2 H), 4.80 - 4.55 (m, 2 H), 3.83 - 3.78 (t, J
= 2.8 Hz , 2 H), 2.56 (s, 3 H).
e 3-59
1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]benzamide
N N
S O
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and ide. MS obsd. (ESI+) [(M+H)+] 458, 1H NMR (400 MHz,
CD3OD) δ ppm 8.64 (s, 1 H), 8.09 - 8.04 (m, 5 H), 7.89 - 7.87 (d, J = 8.4 Hz, 1 H), 7.75 - 7.67
(m, 3 H), 7.62 - 7.55 (m, 3 H), 5.34 (s, 2 H), 4.62 (s, 2 H), 3.76 (s, 2 H), 2.53 (s, 3 H).
Example 3-60
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]acetamide
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide red in analogy
to the one in Example 2-1) and acetamide. MS obsd. (ESI+) [(M+H)+] 396, 1H NMR (400 MHz,
CD3OD) δ ppm 8.53 (s, 1 H), 8.10 - 8.06 (m, 2 H), 7.97 - 7.85 (d, J = 8.4 Hz, 1 H), 7.82 - 7.80
(d, J = 9.2 Hz, 1 H), 7.76 - 7.72 (m, 2 H), 7.58 - 7.54 (m, 2 H), 5.28 (s, 2 H), 4.60 (s, 2 H), 3.77 -
3.71 (m, 2 H), 2.52 (s, 3 H), 2.40 (s, 3 H).
Example 3-61
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]piperidinecarboxamide
NH NH
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-bromo-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 4,6-dibromoquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and
dinecarboxamide. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm
8.47 (s, 1 H), 8.11 (s, 1 H), 8.07 - 8.05 (d, J = 1.2 Hz, 1 H), 7.98 - 7.96 (d, J = 7.2 Hz, 1 H), 7.83
- 7.80 (d, J = 8.4 Hz, 1 H), 7.70 - 7.64 (m, 2 H), 7.58 - 7.54 (m, 1 H), 5.29 (s, 1 H), 4.61 (s, 2 H),
3.76 (s, 2 H), 3.55 - 3.52 (m, 2 H), 3.43 - 3.34 (m, 3 H), 3.22 - 3.15 (m, 1 H), 2.52 (s, 3 H), 2.29 -
2.27 (m, 1 H), 2.06 - 2.02 (m, 1 H), 1.97 - 1.89 (m, 2 H).
Example 3-62
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]piperidinecarboxamide
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y
to the one in Example 2-1) and piperidinecarboxamide. MS obsd. (ESI+) [(M+H)+] 465, 1H
NMR (400 MHz, CD3OD) δ ppm 8.50 (s, 1 H), 8.14 (s, 1 H), 8.01- 7.98 (d, J = 1.2 Hz, 1 H),
7.95 - 7.93 (d, J = 7.2 Hz, 1 H), 7.84 - 7.82 (d, J = 8.8 Hz, 1 H), 7.66 - 7.61 (m, 2 H), 7.52 - 7.51
(m, 1 H), 5.23 (s, 1 H), 4.59 (s, 2 H), 3.74 (s, 2 H), 3.57 - 3.54 (m, 2 H), 3.22 - 3.10 (m, 4 H),
2.50 (s, 3 H), 2.26 - 2.22 (m, 2 H), 2.14 - 2.08 (m, 2 H).
Example 3-63
3-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-1,1-
ylurea
NH N
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 1,1-dimethylurea. MS obsd. (ESI+) +] 425, 1H NMR (400
MHz, CD3OD) δ ppm 7.83 (d, J = 7.6 Hz, 1 H), 7.68 (t, J = 3.6 Hz, 2 H), 7.42 (q, J = 7.2 Hz, 2
H), 7.23 - 7.20 (m, 2 H), 7.15 (s, 1 H), 5.00 (s, 2 H), 4.45 (brs, 2 H), 3.42 (s, 2 H), 3.02 (s, 6 H),
2.30 (s, 3 H).
Example 3-64
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(1,2-oxazol
yl)quinolinamine
NH N
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-bromo-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 4,6-dibromoquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and
1,2-oxazolamine. MS obsd. (ESI+) [(M+H)+] 421, 1H NMR (400 MHz, CD3OD) δ ppm 8.72
(s, 1 H), 8.20 (s, 2 H), 8.14 (d, J = 7.2 Hz, 1 H), 8.07 (d, J = 7.6 Hz, 1 H), 7.83 (d, J = 8.8 Hz, 1
H), 7.63 -7.68 (m, 2 H), 7.56 (t, J = 7.6 Hz, 1 H), 6.65 (s, 1 H), 5.29 (s, 2 H), 4.61 (s, 2 H), 3.79
(s, 2 H), 2.54 (s, 3 H).
Example 3-65
N-{[3-(Aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl) trideuteriomethylquinolinamine
D NH NH
D 2
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-
6- trideuteriomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared
in y to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using chloro trideuteriomethylquinoline and 5-
tetrahydro-1,4-benzothiazepine) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+]
456, 1H NMR (400 MHz, CDCl 3) δ ppm 8.04 (d, 1 H), 7.68 (d, 1 H), 7.51 (m, 2 H), 7.36 (t, 1
H), 7.29 (s, 1 H), 7.22 (d, 1 H), 7.08 (s, 1 H), 5.92 (s, 1 H), 5.13 (s, 2 H), 4.57 (s, 6 H), 3.67 (s, 2
H ), 3.57 (s, 2 H ), 3.34 (s, 2 H).
Example 4-1
N-[(3-Aminooxetanyl)methyl]chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinamine
O NH
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6-
roquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (prepared in y to 4-(4-
chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1-
1) and 3-aminomethyl-oxetanylamine. MS obsd. (ESI+) [(M+H)+] 410, 1H NMR (400 MHz,
CD3OD) δ ppm 7.94 (s, 1 H), 7.93 - 7.70 (m, 1 H), 7.50 - 7.48 (d, J = 8.4 Hz, 2 H), 7.40 - 7.37
(m, 1 H), 7.26 - 7.22 (m, 1 H), 7.15 - 7.11 (m, 1 H), 6.20 (s, 1 H), 4.99 (s, 2 H), 4.63 - 4.61 (d, J
= 6.8 Hz, 2 H), 4.58 - 4.57 (d, J = 6.4 Hz, 2 H), 4.38 (s, 2 H), 3.65 (s, 2 H), 2.99 - 2.97 (t, J = 4.8
Hz, 2 H).
Example 4-2
hloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]ethane-1,2-diamine
N N
The title compound was prepared in analogy to Example 4-1 in Scheme 5 by using 4-(4,6-
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (prepared in analogy to the one in
Example 4-1) and ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 385, 1H NMR (400 MHz,
CD3OD) δ ppm 7.901 (s, 1 H), 7.70 - 7.60 (m, 1 H), 7.55 - 7.42 (m, 2 H), 7.378 - 3.350 (dd, J =
8.8, 2.4 Hz, 1 H), 7.28 - 7.16 (m, 1 H), 7.14 - 7.12 (m , 1 H), 6.05 (s, 1 H), 5.51 (s, 1 H), 4.97 (s,
2 H), 4.38 (s, 2 H), 3.43 - 3.39 (t, J = 6.4 Hz, 2 H), 2.99 - 2.95 (m, 4 H).
Example 4-3
N-[(3-Aminooxetanyl)methyl](2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinamine
O NH
N N
The title compound was prepared in analogy to Example 4-1 in Scheme 5 by using 4-(4-chloro-
ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (prepared in analogy to 4-(4-
chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1-
1) and 3-aminomethyl-oxetanylamine. MS obsd. (ESI+) [(M+H)+] 407, 1H NMR (400 MHz,
CD3OD) δ ppm 7.97 (s, 1 H), 7.74 - 7.67 (t, 2 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.55 (d, J = 7.6 Hz, 1
H), 7.32 (t, 1 H), 7.26 (t, 1 H), 6.27 (s, 1 H), 5.19 (s, 2 H), 4.77 - 4.70 (m, 4 H), 4.35 (s, 2 H),
4.12 (s, 2 H ), 3.16 (t, J = 9.6 Hz, 2 H ), 2.49 (s, 3 H).
Example 4-4
1-[2-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]pyrrolidinamine
N N
The title compound was prepared in analogy to Example 4-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (prepared in y to 4-(4-
chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1-
1) and pyrrolidinamine. MS obsd. (ESI+) [(M+H)+] 391, 1H NMR (400 MHz, CD3OD) δ ppm
8.07 (s, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 7.67 - 7.57 (m, 3 H), 7.38 -7.30 (m, 2 H), 5.96 (s, 1 H),
.17 (s, 2 H), 4.45 - 4.35 (m, 2 H), 4.30 - 4.25 (m, 1 H), 4.20 - 4.11 (m, 2 H), 4.05 - 3.91 (m, 2
H), 3.23 (t, J = 4.8 Hz, 2 H), 2.51 - 2.50 (m, 1 H), 2.53 (s, 3 H), 2.40 - 2.30 (m, 1 H).
Example 5-1
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-[2-(1,1-dioxidothiomorpholin
yl)ethyl]methylquinolinamine
N N
To a solution of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1) in 1,4-dioxane (4
mL) was added tris(dibenzylideneacetone) dipalladium (0) (40 mg, 0.04 mmol), 1,1'-
bis(diphenyphosphino)ferrocene (25 mg, 0.04 mmol), sodium tert-butoxide (77 mg, 0.80 mmol)
and 2-(1,1-dioxidothio-morpholinyl)ethanamine (107 mg, 0.60 mmol). The resulting mixture
was evacuated and refilled with nitrogen, sealed and heated at 120 oC ght. After being
cooled to room temperature, the mixture was filtered and washed with ethyl e, the organic
layers were combined and concentrated in vacuo, the residue was purified by flash
chromatography (eluenting with 2% methanol in dichloromethane) to afford 67 mg of the title
compound as a light solid (yield was 40%). MS obsd. (ESI+) [(M+H)+] 515, 1H NMR (400 MHz,
CDCl3) 8.05 (d, J = 7.6Hz, 1 H), 7.66 (d, J = 7.2 Hz, 1 H), 7.53 - 7.48 (m, 2 H), 7.37 - 7.28 (m,
2 H), 7.21 (s, 1 H), 5.88 (s, 1 H), 5.26 (m, 1 H), 5.12 (s, 1 H), 4.6 (brs, 1 H), 3.56 (m, 1 H), 3.33
(m, 2 H), 3.14 (m, 8 H), 2.99 (t, J = 4.8 Hz, 2 H), 2.46 (s, 3 H), 2.0 (d, J = 4.5 Hz, 2 H).
Example 5-2
N-[2-(2-Aminoethoxy)ethyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinamine
NH NH2
N N
The title compound was prepared in y to Example 5-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in e 2-1) and 2,2'-oxydiethanamine. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR
(400 MHz, CD3OD) δ ppm 8.08 (dd, J = 1.2, 7.6 Hz, 1 H), 7.92 (s, 1 H), 7.83 (d, J = 7.2 Hz, 1
H), 7.70 - 7.67 (m, 2 H), 7.59 - 7.55 (m, 2 H), 5.96 (s, 1 H), 5.28 (s, 2 H), 4.49 (s, 2 H), 3.81 (t, J
= 5.2 Hz, 2 H), 3.72 - 3.68 (m, 6 H), 3.13 (t, J = 4.8 Hz, 2 H), 2.45 (s, 3 H).
Example 5-3
N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]
methylpropane-1,2-diamine
NH 2
N N
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 2-methylpropane-1,2-diamine. MS obsd. (ESI+) +] 425,
1H NMR (400 MHz, CD
3OD) δ ppm 7.97 (d, J = 7.83 Hz, 1 H), 7.85 (d, J = 7.58 Hz, 1 H), 7.70
(s, 1 H), 7.60 (t, J = 7.33 Hz, 1 H), 7.48 - 7.38 (m, 2 H), 7.29 - 7.27 (m, 1 H), 6.09 (s, 1 H), 5.15
(brs, 2 H), 3.57 (brs, 2 H), 3.26 (s, 2 H), 2.43 (s, 3 H), 1.34 - 1.20 (m, 6 H).
Example 5-4
N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]
methylpropane-1,2-diamine
N N
S O
The title compound was prepared in analogy to e 5-1 in Scheme 5 by using 4-(4-
chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to
4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1by using and 2,4-dichloroquinoline 2,3,4,5-tetrahydro-1,4-benzothiazepine) and 2-
methylpropane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ
ppm 8.02 - 7.93 (m, 1 H), 7.87 (s, 2 H), 7.64 - 7.57 (m, 1 H), 7.56 - 7.48 (m, 1 H), 7.42 (s, 2 H),
7.19 -7.09 (m, 1 H), 6.11 (s, 1 H), 5.23 - 5.07 (m, 2 H), 3.63 - 3.51 (m, 2 H), 3.37 (s, 2 H), 3.33
(m, 2 H), 3.28 (s, 2 H), 1.26 (s, 6 H).
Example 5-5
N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]propane-1,2-diamine
N N
The title nd was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in y
to the one in Example 2-1) and propane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR
(400 MHz, CD3OD) δ ppm 7.91 (dd, J = 7.83, 1.01 Hz, 1 H), 7.83(d, J = 7.33 Hz, 1 H), 7.69 (s,
1 H), 7.58 (d, J = 1.26 Hz, 1 H), 7.44 (d, J = 8.59 Hz, 1 H), 7.38 - 7.31 (m, 1 H), 7.28 (dd, J =
8.59, 1.77 Hz, 1 H), 6.04 (s, 1 H), 5.13(brs, 2 H), 3.56 (t, J = 4.67 Hz, 2 H), 3.52 - 3.41 (m, 4 H),
3.37 (s, 1 H), 2.41 (s, 3 H), 1.38 (d, J = 6.06 Hz, 3 H).
Example 5-6
4-[6-Methyl(4-methylpiperazinyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide
N N
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 1-methylpiperazine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR
(400 MHz, CD3OD) δ ppm 7.90 (dd, J = 7.83, 1.01 Hz, 1 H), 7.79 (d, J = 7.07 Hz, 1 H), 7.60 -
7.45 (m, 3 H), 7.34 (td, J = 7.64, 1.14 Hz, 1 H), 7.28 (dd, J = 8.59, 1.77 Hz, 1 H), 6.54 (s, 1 H),
5.11 (s, 2 H), 3.61 - 3.50 (m, 2 H), 3.37 (s, 2 H), 3.17 (brs, 4 H), 2.80 (brs, 4 H), 2.46 (s, 3 H),
2.39 (s, 3 H).
Example 5-7
1-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}propanol
N N
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 1-1) and 1-aminopropanol. MS obsd. (ESI+) +] 412, 1H NMR
(400 MHz, CD3OD) δ ppm 7.99 (dd, J = 7.71, 1.14 Hz, 1 H), 7.84 (d, J = 7.07 Hz, 1 H), 7.71 (s,
1 H), 7.64 (td, J = 7.58, 1.26 Hz, 1 H), 7.55 (d, J = 8.59 Hz, 1 H), 7.50 - 7.41 (m, 1 H), 7.37 (dd,
J = 8.59, 1.52 Hz, 1 H), 6.03 (s, 1 H), 5.16 (s, 2 H), 4.08 (dd, J = 11.49, 6.44 Hz, 1 H), 3.62 (t, J
= 4.80 Hz, 2 H), 3.44 - 3.35 (m, 4 H), 2.42 (s, 3 H), 1.33 (d, J = 6.06 Hz, 3 H).
Example 5-8
~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]propane-1,2-diamine
NH 2
N N
The title compound was ed in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and (2S)-propane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H
NMR (400 MHz, CD3OD) δ ppm 7.86 (d, J = 7.58 Hz, 1 H), 7.71 (d, J = 7.33 Hz, 1 H), 7.67 -
7.60 (m, 1 H), 7.49 (t, J = 7.33 Hz, 1 H), 7.42 (d, J = 8.59 Hz, 1 H), 7.28 - 7.19 (m, 2 H), 6.07 -
5.83 (m, 1 H), 5.02 (brs, 2 H), 3.62 (s, 1 H), 3.56 - 3.46 (m, 2 H), 3.37 (s, 2 H), 3.28 - 3.11 (m, 4
H), 2.36 (s, 3 H), 0.92 - 0.80 (m, 2 H).
Example 5-9
(2R)-N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]propane-1,2-diamine
NH 2
N N
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y
to the one in Example 2-1) and (2R)-propane-1,2-diamine. MS obsd. (ESI+) +] 411, 1H
NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J = 7.83 Hz, 1 H), 7.82 (d, J = 7.58 Hz, 1 H), 7.70 -
7.55 (m, 2 H), 7.46 - 7.37 (m, 2 H), 7.33 - 7.22 (m, 2 H), 6.10 - 5.99 (m, 1 H), 5.13 (brs, 2 H),
3.65 - 3.52 (m, 3 H), 3.37 (m, 2 H), 3.31 - 3.20 (m, 2 H), 2.41 (s, 3 H), 1.32 - 1.22 (m, 2 H).
Example 5-10
N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
7,8-difluoromethylquinolinamine
O NH2
F N N
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-
6-methyl-7,8-difluoroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide
(prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide in Example 2-1 by using romethyl-7,8-dichloroquinoline
and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and 3-(aminomethyl)oxetanamine. MS obsd.
(ESI+) [(M+H)+] 475, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.04 (brs, 1 H), 7.88 (d, J = 7.83
Hz, 1 H), 7.62 (t, J = 6.82 Hz, 1 H), 7.47 (t, J = 7.58 Hz, 1 H), 7.18 (brs, 1 H), 6.31 (brs, 1 H),
.16 (brs, 1 H), 4.60 (d, J = 8.34 Hz, 2 H), 4.05 - 3.97 (m, 2 H), 3.82 (brs, 2 H), 3.62 (brs, 2 H),
3.17 (m, 2 H), 2.33 (s, 1 H), 1.28 - 1.13 (m, 3 H).
Example 5-11
N-(2,2-Difluoroethyl)-N'-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinyl]ethane-1,2-diamine
N N
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-
ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and N-(2,2-difluoroethyl)ethane-1,2-diamine. MS obsd. (ESI +)
[(M+H)+] 461, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (dd, J = 7.83, 1.26 Hz, 1 H), 7.83 (d, J
= 6.82 Hz, 1 H), 7.60 (td, J = 7.45, 1.26 Hz, 2 H), 7.46 - 7.38 (m, 2 H), 7.28 (dd, J = 8.59, 1.77
Hz, 1 H), 6.04 (s, 1 H), 5.13(s, 2 H), 3.58 (t, J = 4.80 Hz, 2 H), 3.46 (t, J = 6.19 Hz, 2 H), 3.37 (s,
3 H), 3.10 - 2.97 (m, 4 H), 2.41 (s, 3 H).
Example 5-12
3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}oxetanethanol
NH OH
N N
O
The title compound was prepared in y to Example 5-1 in Scheme 5 by using hloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 3-aminooxetanethanol. MS obsd. (ESI+) [(M+H)+] 454, 1H
NMR (400 MHz, DMSO-d6) δ ppm 7.97 (d, 1 H), 7.89 (d, 1 H), 7.64 (t, 1 H), 7.55 (s, 1 H), 7.49
- 7.42 (m, 2 H), 7.35 - 7.32 (m, 1 H), 6.63 (s, 1 H), 5.15 (s, 2 H), 4.50 (d, 2 H), 4.41(brs, 2 H),
4.39 (d, 4 H), 3.66 (d, 2 H), 2.33 (s, 3 H ), 2.27 (t, 2 H).
Example 6-1
N-{[3-(Aminomethyl)thietanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinolinamine
N N
A flask containing 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine
1,1-dioxide (250 mg, 0.67 mmol), thietane-3,3-diyldimethanamine (266 mg, 2.01 mmol ),
tris(dibenzylideneacetone)dipalladium(0) ( 61.8 mg, 0.067 mmol ), 2,2'-bis(diphenylphosphino)-
1,1'-binaphthyl ( 42 mg, 0.067 mmol), sodium tert-butoxide (160 mg, 1.66 mmol ) and toluene
(15 mL) was evacuated and then filled with nitrogen (balloon). After being stirred at 110 ºC
overnight, the resulting e was d with water (15 mL) and extracted with ethyl acetate
(15 mL × 4). The combined organic layers were dried over sodium sulfate and concentrated in
vacuo. The residue was purified by flash column tography and preparative HPLC to
afford 63 mg of the product as a white solid (yield was 20%). MS obsd. (ESI+) [(M+H)+] 469, 1H
NMR (400 MHz, CD3OD) δ ppm 7.96 - 7.94 (m, 1 H), 7.68 - 7.66 (d, J = 7.2 Hz, 1 H), 7.47 -
7.43 (m, 2 H), 7.31 - 7.27 (m, 1 H), 7.22 - 7.21 (d, J = 1.6 Hz, 1 H), 7.19 (s, 1 H), 5.88 (s, 1 H),
5.07 (s, 2 H), 4.50 (s, 2 H), 3.55 - 3.49 (m, 4 H), 3.11 (s, 2 H), 3.06 - 3.03 (d, J = 9.6 Hz, 2 H),
2.94 - 2.91 (d, J = 9.6 Hz, 2 H), 2.31 (s, 3 H).
Example 6-2
N-{[3-(Aminomethyl)-1,1-dioxidothietanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinamine
O NH
N N
O
The title compound was prepared in analogy to Example 6-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y
to the one in Example 2-1) and (1,1-dioxidothietane-3,3-diyl)dimethanamine. MS obsd. (ESI+)
[(M+H)+] 501, 1H NMR (400 MHz, CD3Cl) δ ppm 7.958 - 7.939 (d, J = 7.6 Hz, 1 H), 7.651 -
7.633 (d, J = 7.2 Hz, 1 H), 7.482 - 7.415 (m, 2 H), 7.308 - 7.270 (t, J = 7.2 Hz, 1 H), 7.235 -
7.215 (d, J = 8.0 Hz, 1 H), 7.134 (s, 1 H), 6.646 (s, 1 H), 5.065 (s, 2 H), 4.701 - 1.250 (brs, 2 H),
3.924 - 3.890 (m, 4 H), 3.659 -3.646 (d, J = 5.2 Hz, 2 H), 3.491 (s, 2 H), 3.320 (s, 2 H), 2.323 (s,
3 H).
Example 7
N-(4,5-Dihydro-1H-imidazolyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
ylquinolinamine
N N
N N
A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (150 mg, 0.40 mmol, prepared in y to the one in Example 2-1), hydrogen iodide
salt of 4,5-dihydro-1H-imidazolamine (110 mg, 0.515 mmol), 4,5-bis(diphenylphosphino)-
9,9-dimethylxanthene (25 mg, 0.043 mmol), tris(dibenzylideneacetone)dipalladium(0) (35 mg,
0.038 mmol), cesium carbonate (525 mg, 1.6 mmol) and 1,4-dioxane (3 mL) was heated with
stirring in a 5 mL of microwave process vial for 2 hours at 120 oC under microwave irradiation.
The resulting e was filtered and washed with ethyl acetate. The filtrate was washed with
brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by
preparative HPLC to afford the product as a solid. MS obsd. (ESI+) [(M+H)+] 422, 1H NMR (400
MHz, CD3OD) δ ppm 7.68 - 7.59 (m, 2 H), 7.56 (s, 1 H), 7.50 - 7.41 (m, 2 H), 7.08 (s,1 H), 5.23
(brs, 2 H), 4.62 (s, 3 H), 3.76 (s, 3 H), 3.61 (t, J = 4.93 Hz, 2 H), 2.68 (s, 4 H), 2.45 (s, 2 H).
Example 8-1
trans{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}cyclohexanol
N N
A e of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (140 mg, 0.38 mmol, prepared in analogy to the one in Example 2-1), trans
aminocyclohexanol (45 mg, 0.39 mmol), tris(dibenzylideneacetone)dipalladium(0) (35 mg,
0.038 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (15 mg, 0.038 mmol),
sodium tert-butoxide (38 mg, 0.39 mmol) and 1,4-dioxane (2 mL) was heated with stirring in a 5
mL of microwave process vial for 2 hours at 120 oC under ave irradiation. The mixture
was filtered and washed with ethyl e. The filtrate was washed with brine, dried over
sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to
afford the product as a solid. MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, DMSO-d6) δ
ppm 7.98 - 7.83 (m, 2 H), 7.76 (s, 1 H), 7.64 - 7.44 (m, 2 H), 7.29 (d, J = 8.34 Hz, 1 H), 7.21 (d,
J = 8.84 Hz, 1 H), 6.22 (d, J = 8.34 Hz, 1 H), 6.06 (s, 1 H), 5.09 (brs, 2 H), 4.68 (d, J = 4.29 Hz,
1 H), 3.62 (brs, 3 H), 3.49 (d, J = 4.55 Hz, 1 H), 2.34 (s, 3 H), 2.03 - 1.83 (m, 4 H), 1.63 - 1.45
(m, 2 H), 1.35 (brs, 2 H), 1.24 (brs, 1 H), 1.18 (brs, 1 H).
Example 8-2
(2S){[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}propanol
N N
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and (2S)aminopropanol. MS obsd. (ESI+) [(M+H)+] 412, 1H
NMR (400 MHz, DMSO-d6) δ ppm 7.89 (t, J = 6.32 Hz, 2 H), 7.75 (s, 1 H), 7.64 (t, J = 7.20 Hz,
1 H), 7.55 - 7.43 (m, 1 H), 7.38 - 7.27 (m, 1 H), 7.27 - 7.14 (m, 1 H), 6.16 (d, J = 8.08 Hz, 1 H),
6.07 (s, 1 H), 5.07 (brs, 2 H), 4.85 (brs, 1 H), 4.42 (brs, 1 H), 3.85 (dt, J = 12.82, 6.35 Hz, 1 H),
3.70 - 3.47 (m, 3 H), 2.36 (s, 3 H), 1.23 (d, J = 6.32 Hz, 3 H).
Example 8-3
trans[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]
methoxypyrrolidinamine
NH O
N N
S O
The title compound was prepared in y to Example 8-1 in Scheme 5 by using 4-(4-chloro-
ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and transmethoxymethylpyrrolidinamine. MS obsd. (ESI+)
[(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.00 (dd, J = 7.83, 1.26 Hz, 1 H), 7.89 -
7.78 (m, 2 H), 7.63 (td, J = 7.45, 1.26 Hz, 1 H), 7.53 (d, J = 8.59 Hz, 1 H), 7.47 (td, J = 7.71,
1.01 Hz, 1 H), 7.35 (dd, J = 8.59, 1.52 Hz, 1 H), 6.19 (s, 1 H), 5.19 (s, 2 H), 4.53 (brs, 2 H), 4.12
(dd, J = 11.12, 5.05 Hz, 1 H), 3.99 - 3.81 (m, 2 H), 3.73 (brs, 1 H), 3.67 - 3.56 (m, 2 H), 3.55 -
3.41 (m, 5 H), 2.43 (s, 3 H).
Example 8-4
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-[transmethoxypyrrolidin
yl]methylquinolinamine
N N
S O
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and transmethoxymethylpyrrolidinamine. MS obsd. (ESI+)
[(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.14 (d, J = 7.83 Hz, 1 H), 8.08 (s, 1 H),
7.87 (d, J = 7.33 Hz, 1 H), 7.79 - 7.73 (m, 2 H), 7.69 - 7.63 (m, 2 H), 6.10 (s, 1 H), 5.36 (q, J =
16.67 Hz, 2 H), 4.60 (brs, 2 H), 4.28 (brs, 1 H), 3.93 (dd, J = 12.63, 6.82 Hz, 1 H), 3.82 (t, J =
4.80 Hz, 2 H), 3.75 - 3.68 (m, 1 H), 3.68 - 3.59 (m, 2 H), 3.56 (s, 3 H), 2.51 (s, 3 H).
Example 8-5
4-{4-[(4aS,7aR)-Hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl]methylquinolinyl}-
2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide
O NH
H H
N N
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in y
to the one in Example 2-1) and (4aS,7aR)-octahydropyrrolo[3,4-b][1,4]oxazine. MS obsd. (ESI+)
[(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J = 7.83, 1.26 Hz, 1 H), 7.85 (d, J
= 7.33 Hz, 1 H), 7.81 (s, 1 H), 7.63 (td, J = 7.52, 1.39 Hz, 1 H), 7.50 - 7.41 (m, 2 H), 7.28 (dd, J
= 8.59, 1.77 Hz, 1 H), 6.09 (s, 1 H), 5.16 (s, 2 H), 4.51 (m, 2 H), 4.02 - 4.15 (m, 3 H), 3.86 (d, J
= 10.8 Hz, 1 H), 3.68 - 3.47 (m, 6 H), 3.238 (m, 1 H), 2.72 (m, 1 H), 2.41 (s, 3 H).
Example 8-6
(3R,4R)[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl](4-methylpiperazinyl)pyrrolidinol
N OH
N N
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using hloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and )(4-methylpiperazinyl)pyrrolidinol. MS obsd.
(ESI+) [(M+H)+] 522, 1H NMR (400 MHz, CD 3OD) δ ppm 7.99 - 7.86 (m, 1 H), 7.84 - 7.75 (m,
1 H), 7.73 (s, 1 H), 7.64 - 7.52 (m, 1 H), 7.47 (d, J = 8.59 Hz, 1 H), 7.43 - 7.32 (m, 1 H), 7.27 (d,
J = 8.59 Hz, 1 H), 6.27 - 6.09 (m, 1 H), 5.10 (brs, 2 H), 4.50 (brs, 1 H), 4.43 - 4.33 (m, 1 H), 3.81
- 3.62 (m, 2 H), 3.56 (dd, J = 9.85, 4.55 Hz, 3 H), 3.45 - 3.35 (m, 1 H), 3.02 - 2.92 (m, 1 H), 2.84
(brs, 2 H), 2.76 - 2.62 (m, 3 H), 2.57 (brs, 3 H), 2.39 (s, 3 H), 2.32 (s, 3 H).
Example 8-7
N-{2-[(2-Aminoethyl)sulfanyl]ethyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)methylquinolinamine
S NH2
N N
The title compound was prepared in analogy to e 8-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 2,2'-sulfanediyldiethanamine. MS obsd. (ESI+) [(M+H)+] 457,
1H NMR (400 MHz, CD
3OD) δ ppm 8.00 (dd, J = 7.83, 1.26 Hz, 1 H), 7.84 (d, J = 7.33 Hz, 1
H), 7.65 (td, J = 7.58, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.51 - 7.39 (m, 2 H), 7.29 (dd, J = 8.59, 1.77
Hz, 1 H), 6.03 (s, 1 H), 5.14 (s, 2 H), 3.65 - 3.50 (m, 4 H), 2.92 - 2.79 (m, 4 H), 2.78 - 2.68 (m, 2
H), 2.42 (s, 3 H).
Example 9-1
1-{1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]piperidinyl}methanamine
N N
A e of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (75 mg, 0.20 mmol, prepared in analogy to the one in e 2-1), piperidinylmethylamine
(3 mL) in a 2~5 mL of process vial was heated at 160 °C under microwave
irradiation for 1 hour. After being cooled to room ature, the mixture was concentrated in
vacuo to remove the solvent. The residue was purified by preparative HPLC to afford the
product as a solid. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 -
7.81 (m, 2 H), 7.66 (td, J = 7.58, 1.26 Hz, 1 H), 7.53 - 7.39 (m, 3 H), 7.28 (dd, J = 8.72, 1.89 Hz,
1 H), 6.58 (s, 1 H), 5.13 (brs, 2 H), 4.42 (brs, 2 H), 3.65 (t, J = 4.80 Hz, 2 H), 3.42 (d, J = 11.62
Hz, 2 H), 2.72 (t, J = 10.99 Hz, 2 H), 2.41 - 2.27 (m, 3 H), 1.95 - 1.74 (m, 2 H), 1.61 - 1.33 (m, 5
H).
Example 9-2
2-{[2-(8-Methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]amino}ethanol
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-
chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to
4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4-dichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and 2-
aminoethanol. MS obsd. (ESI+) [(M+H)+] 414, 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J =
8.08 Hz, 1 H), 7.76 (d, J = 8.34 Hz, 1 H), 7.53 (d, J = 2.78 Hz, 2 H), 7.51 - 7.41 (m, 1 H), 7.22 -
7.09 (m, 2 H), 6.10 (s, 1 H), 5.11 (s, 2 H), 4.62 (brs, 2 H), 3.83 (s, 3 H), 3.91 - 3.80 (m, 2 H),
3.61 (brs, 2 H), 3.52 (t, J = 5.81 Hz, 2 H).
Example 9-3
1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]propane-1,3-diamine
N N
The title nd was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR
(400 MHz, CD3OD) δ ppm 7.96 (dd, J = 7.83, 1.01 Hz, 1 H), 7.81(d, J = 7.07 Hz, 1 H), 7.64 -
7.54 (m, 2 H), 7.47 - 7.35 (m, 2 H), 7.26 (dd, J = 8.59, 1.77 Hz, 1 H), 5.98 (s, 1 H), 5.12 (s, 2 H),
3.56 (t, J = 4.93 Hz, 2 H), 3.39 (t, J = 6.82 Hz, 2 H), 2.82 (t, J = 6.95 Hz, 2 H), 2.39 (s, 3 H),
1.89 (t, J = 6.95 Hz, 2 H).
Example 9-4
4-[6-Methyl(morpholinyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using hloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y
to the one in Example 2-1) and morpholine. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz,
CDCl3) δ ppm 8.06 (d, J = 8.0 Hz, 1 H), 7.62 - 7.53 (m, 4 H), 7.40 (t, J = 7.6 Hz, 1 H), 7.32 (d, J
= 7.6 Hz, 1 H), 6.42 (s, 1 H), 5.51 (s, 2 H), 4.60 (brs, 2 H), 4.00 (t, J = 4.4 Hz, 4 H), 3.59 (s, 2
H), 3.10 (m, 4 H), 2.44 (s, 3 H).
Example 9-5
3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}propanol
NH OH
N N
S O
The title compound was prepared in analogy to e 9-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 3-propanol. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400
MHz, CDCl3) δ ppm 8.02 (d, J = 7.2 Hz, 1 H), 7.71 (m, 1 H), 7.53 - 7.49 (m, 2 H), 7.38 (t, J =
7.2 Hz, 1 H), 7.26 (m, 2 H), 5.31 (s, 1 H), 5.13 (s, 2 H), 4.60 (brs, 2 H), 3.92 (t, J = 4.2 Hz, 2 H),
3.52 (s, 2 H), 3.44 (m, 2 H), 2.40 (s, 3 H), 2.00 (m, 2 H).
Example 9-6
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2-(piperidin
yl)ethyl]quinolinamine
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and eridinyl)ethanamine. MS obsd. (ESI+) [(M+H)+] 465, 1H
NMR (400 MHz, CDCl3) δ ppm 8.04 (d, J = 7.6 Hz, 1 H), 7.67 (d, J = 7.6 Hz, 1 H), 7.51 (m, 2
H), 7.38 (t, J = 7.6 Hz, 1 H), 7.30 (m, 2 H), 5.74 (m, 1 H), 5.12 (s, 2 H), 4.6 (brs, 2 H), 3.58 (s, 2
H), 3.28 (m, 2 H), 2.75 (t, J = 8.4 Hz, 2 H), 2.46 (m, 7 H), 1.62 (m, 4 H), 1.52 (m, 2 H).
Example 9-7
o{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}propanol
NH NH
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using hloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in e 2-1) and aminopropanol. MS obsd. (ESI+) [(M+H)+] 427, 1H
NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J = 2.0 Hz, 1 H), 7.86 (d, J = 1.8 Hz, 1 H), 7.62 (t, J =
3.7 Hz, 1 H), 7.57 (s, 1 H), 7.44 (t, J = 3.8 Hz, 2 H), 7.30 - 7.27 (m, J = 2.5 Hz, 1 H), 6.09 (s, 1
H), 5.15 (s, 2 H), 4.53 (brs, 2 H), 3.97 - 3.91 (m, J = 5.8 Hz, 2 H ), 3.58 (t, J = 2.4 Hz, 2 H), 3.66
- 3.41 (m, J = 3.3 Hz, 2 H), 2.90 (dd, J = 4.2, 0.90 Hz, 1 H), 2.77 (dd, J = 5.2, 0.9 Hz, 1 H), 2.42
(s, 3 H).
Example 9-8
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]glycine
O OH
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and glycine. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz,
CD3OD) δ ppm 8.01 (d, J = 1.8 Hz, 1 H), 7.89 (d, J = 1.9 Hz, 1 H), 7.68 (t, J = 2.9 Hz, 2 H), 7.54
(d, J = 2.1 Hz, 1 H), 7.48 (t, J = 2.2 Hz, 1 H), 7.40 (d, J = 0.9 Hz, 1 H), 5.73 (s, 1 H), 5.09 (s, 2
H), 4.36 (brs , 2 H), 3.3 (s, 2 H ), 3.58 (s, 2 H), 2.41 (s, 3 H).
Example 9-9
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)fluoroquinolinyl]ethane-
1,2-diamine
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
6-fluoroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4-dichlorofluoroquinoline and 2,3,4,5-tetrahydro-1,4-
benzothiazepine) and ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 401, 1H NMR (400 MHz,
CD3OD) δ ppm 7.98 (d, J = 7.6 Hz, 1 H), 7.84 (d, J = 7.6 Hz, 1 H), 7.64 (t, J = 7.6 Hz, 1 H), 7.58
(dd, J = 2.8, 10.8 Hz, 1 H), 7.52 (dd, J = 6.4, 8.8 Hz, 1 H), 7.45 (t, J = 8.0 Hz, 1 H), 7.22 (td, J =
2.8, 8.8 Hz, 1 H), 6.09 (s, 1 H), 5.16 (s, 2 H), 4.55 (brs, 2 H), 3.63 - 3.57 (m, 2 H), 3.43 (t, J =
6.4 Hz, 2 H), 2.97 (t, J = 6.4 Hz, 2 H).
Example 9-10
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethylquinolinyl]ethane-
1,2-diamine
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
6-ethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to
4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using roehtylquinoline and 5-tetrahydro-1,4-benzothiazepine) and
ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.98
(d, J = 7.6 Hz, 1 H), 7.84 (d, J = 7.6 Hz, 1 H), 7.62 (m, 2 H), 7.44 (t, J = 8.4 Hz, 2 H), 7.32 (dd, J
= 1.6, 8.4 Hz, 1 H), 6.03 (s, 1 H), 5.14 (s, 2 H), 4.53 (brs, 2 H), 3.58 (s, 2 H), 3.44 (t, J = 6.0 Hz,
2 H), 2.97 (t, J = 6.4 Hz, 2 H), 2.72 (q, J = 7.6 Hz, 2 H), 1.27 (t, J = 7.6 Hz, 3 H).
Example 9-11
hloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]propane-1,3-diamine
NH NH
Cl N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4,7-
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and
propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 431, 1H NMR (400 MHz, CD3OD) δ ppm 8.10
- 8.05 (m, 2 H), 7.91 -7.82 (m, 2 H), 7.80 - 7.69 (m, 1 H), 7.61 - 7.50 (m, 1 H), 7.43 - 7.41 (d, J =
7.6 Hz, 1 H), 5.95 (s, 1 H), 5.30 (s, 2 H), 4.5 (s, 2 H), 3.72 (s, 2 H), 3.59 - 3.56 (t, J = 6.4 Hz, 2
H), 3.10 - 3.06 (t, J = 7.6 Hz, 2 H), 2.70 - 2.10 (t, J = 7.2 Hz, 2 H).
Example 9-12
N-[8-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]propane-1,3-diamine
NH NH
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4,8-
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4,8-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and
propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 431, 1H NMR (400 MHz, CD3OD) δ ppm 8.08
- 8.05 (m, 2 H), 7.94 - 7.92 (d, J = 7.6 Hz, 1 H), 7.85 - 7.83 (d, J = 7.6 Hz, 1 H), 7.71 - 7.70 (m,
1 H), 7.57 -7.56 (m, 1 H), 7.41 - 7.38 (m, 1 H), 6.00 (s, 1 H), 5.39 (s, 2 H), 4.55 (s, 2 H), 3.74 (s,
2 H), 3.60 - 3.56 (t, J = 6.8 Hz, 2 H), 3.09 - 3.05 (t, J = 7.6 Hz, 2 H), 2.11 - 2.07 (m, 2 H).
Example 9-13
N-[5-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]propane-1,3-diamine
Cl NH NH
N N
The title compound was prepared in y to Example 9-1 in Scheme 5 by using 4-(4,5-
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4,5-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and
propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 431, 1H NMR (400 MHz, CD3OD) δ ppm 8.08
- 8.06 (d, J = 7.6 Hz, 1 H), 7.94 - 7.92 (m, 2 H), 7.41 - 7.26 (m, 5 H), 5.99 (s, 1 H), 5.35 (s, 2 H),
4.55 (s, 2 H), 3.74 (s, 2 H), 3.63-3.61 (m, 2 H), 3.15 - 3.11 (t, J = 7.6 Hz, 2 H), 2.16 - 2.13 (m, 2
H ).
Example 9-14
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-2,2-
dimethylpropane-1,3-diamine
NH NH
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y
to the one in Example 2-1) and 2,2-dimethylpropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+]
439, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (d, J = 1.2 Hz, 1 H), 7.99 (s, 1 H), 7.88 (d, J = 7.2
Hz, 1H), 7.73 -7.70 (m, 2 H), 7.61 - 7.57 (m, 2 H), 6.07 (s, 1 H), 5.31 (s, 2 H), 4.50 (s, 2 H), 3.73
(s, 2 H), 3.49 (s, 2 H), 2.99 (s, 2 H), 2.47 (s, 3 H), 1.10 (s, 6 H).
Example 9-15
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]ethane-1,2-
diamine
N N
The title nd was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-
chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to
4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4-dichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and
ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 383, 1H NMR (400 MHz, CD3OD) δ ppm 7.87
(m, 1 H), 7.81 (d, J = 7.83 Hz, 2 H), 7.55 (m, 1 H), 7.47 (m, 1 H), 7.33 (m, 2 H), 7.04 (m, 1 H),
.94 (m,1 H), 5.12 (s, 2 H), 3.57 (t, J = 4.55 Hz, 2 H), 3.43 (t, J = 6.32 Hz, 2 H), 3.33 (m, 2 H),
2.97 (t, J = 6.44 Hz, 2 H).
Example 9-16
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]ethane-
amine
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy
to the one in Example 2-1) and ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR
(400 MHz, CD3OD) δ ppm 7.86 (m, 2 H), 7.65 - 7.50 (m, 2 H), 7.42 - 7.30 (m, 2 H), 7.28 - 7.16
(m, 1 H), 6.10 - 5.95 (m, 1 H), 5.09 (brs, 2 H), 3.64 - 3.42 (m, 2 H), 3.15 - 2.98 (m, 2 H), 2.84 (s,
2 H), 2.35 (s, 3 H), 1.20 (s, 2 H).
Example 9-17
N~2~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]
methylpropane-1,2-diamine
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 2-methylpropane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 425,
1H NMR (400 MHz, CD
3OD) δ ppm 7.98 (dd, J = 7.83, 1.26 Hz, 1 H), 7.86 (d, J = 6.82 Hz, 1
H), 7.70 (s, 1 H), 7.61 (td, J = 7.45, 1.26 Hz, 1 H), 7.47 - 7.42 (m, 2 H), 7.29 (dd, J = 8.59, 1.77
Hz, 1 H), 6.09 (s, 1 H), 5.16 (s, 2 H), 3.58 (t, J = 4.80 Hz, 2 H), 3.33 (m, 2 H), 3.27 (s, 2 H),
2.43 (s, 3 H), 1.27 (s, 6 H).
Example 9-18
N~2~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
pane-1,2-diamine
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in analogy
to the one in Example 2-1) and propane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR
(400 MHz, CD3OD) δ ppm 7.97 (dd, J = 7.83, 1.01 Hz, 1 H), 7.82 (d, J = 7.33 Hz, 1 H), 7.69 -
7.56 (m, 2 H), 7.46 - 7.38 (m, 2 H), 7.28 (dd, J = 8.46, 1.64 Hz, 1 H), 6.11 - 5.96 (m, 1 H), 5.13
(s, 2 H), 3.66 - 3.49 (m, 2 H), 3.30 - 3.20 (m, 3 H), 2.47 - 2.39 (m, 3 H), 2.24 - 2.19 (m, 2 H),
1.32 - 1.22 (m, 3 H).
Example 9-19
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]butane-
1,4-diamine
NH 2
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and butane-1,4-diamine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR
(400 MHz, CD3OD) δ ppm 8.01 - 7.95 (m, 1 H), 7.92 -7.86 (m, 1 H), 7.83 - 7.76 (m, 1 H), 7.69 -
7.61 (m, 1 H), 7.61 - 7.54 (m, 1 H), 7.50 - 7.42 (m, 1 H), 7.39 - 7.31 (m, 1 H), 5.96 (s, 1 H), 5.20
(brs, 2 H), 3.63 (brs, 2 H), 3.47 (brs, 2 H), 3.37 (s, 2 H), 2.42 (s, 3 H), 2.27 - 2.24 (m, 4 H), 1.86
(d, J = 3.28 Hz, 2 H).
Example 9-20
1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)nitroquinolinyl]ethane-
1,2-diamine
O NH
N N
The title compound was prepared in analogy to e 9-1 in Scheme 5 by using 4-(4-chloro-
6-nitroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to
hloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4-dichloronitroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine)
and ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm
9.07 (d, J = 2.53 Hz, 1 H), 8.13 (dd, J = 9.35, 2.53 Hz, 1 H), 7.96 (d, J = 7.58 Hz, 1 H), 7.91 (dd,
J = 7.71, 1.14 Hz, 1 H), 7.69 (t, J = 7.20 Hz, 1 H), 7.56 - 7.41 (m, 2 H), 6.09 (s, 1 H), 5.15 (brs, 2
H), 3.64 (brs, 2 H), 3.34 (brs, 4 H), 2.79 (t, J = 6.44 Hz, 2 H).
Example 9-21
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)fluoromethylquinolin
yl]ethane-1,2-diamine
F NH
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
-fluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in
analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using 2,4-dichlorofluoromethylquinoline and 5-
tetrahydro-1,4-benzothiazepine) and ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 415, 1H
NMR (400 MHz, CD3OD) δ ppm 7.98 - 7.83 (m, 2 H), 7.71 - 7.60 (m, 1 H), 7.53 - 7.43 (m, 1 H),
7.32 - 7.22 (m, 1 H), 7.21 - 7.11 (m, 1 H), 6.80 - 6.66 (m, 1 H), 6.01 (s, 1 H), 5.08 (brs, 2 H),
3.61 (t, J = 4.67 Hz, 2 H), 3.31 - 3.26 (m, 3 H), 2.87 (t, J = 6.19 Hz, 2 H), 2.22 (d, J = 2.53 Hz, 3
H).
Example 9-22
2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)fluoromethylquinolin
yl]amino}ethanol
F NH
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
-fluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in
y to the one in Example 9-21) and aminoethanol. MS obsd. (ESI+) [(M+H)+] 416, 1H
NMR (400 MHz, DMSO-d6) δ ppm 7.94 - 7.84 (m, 2 H), 7.66 (td, J = 7.45, 1.26 Hz, 1 H), 7.49
(td, J = 7.71, 1.26 Hz, 1 H), 7.32 - 7.21 (m, 1 H), 7.21 - 7.11 (m, 1 H), 6.48 (dt, J = 16.93, 4.67
Hz, 1 H), 6.04 (s, 1 H), 5.08 (brs, 2 H), 4.98 (t, J = 5.18 Hz, 1 H), 3.67 (q, J = 5.31 Hz, 2 H),
3.61 (t, J = 4.80 Hz, 2 H), 3.43 (m, 2 H), 2.22 (d, J = 2.53 Hz, 3 H).
Example 9-23
2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)fluoromethylquinolin
no}ethanol
F N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
7-fluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in
analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using 2,4-dichlorofluoromethylquinoline and 2,3,4,5-
tetrahydro-1,4-benzothiazepine) and aminoethanol. MS obsd. (ESI+) [(M+H)+] 416, 1H NMR
(400 MHz, DMSO-d6) δ ppm 7.93 - 7.87 (m, 2 H), 7.84 (d, J = 8.84 Hz, 1 H), 7.65 (td, J = 7.52,
1.14 Hz, 1 H), 7.53 - 7.43 (m, 1 H), 7.05 (d, J = 11.87 Hz, 1 H), 6.71 (t, J = 5.56 Hz, 1 H), 6.00
(s, 1 H), 5.07 (brs, 2 H), 4.83 (t, J = 5.56 Hz, 1 H), 3.67 - 3.55 (m, 4 H), 3.42 - 3.36 (m, 2 H),
2.27 (s, 3 H).
Example 9-24
1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)fluoromethylquinolin
ane-1,2-diamine
F N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
7-fluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in
analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using 2,4-dichlorofluoromethylquinoline and 2,3,4,5-
tetrahydro-1,4-benzothiazepine) and -1,2-diamine. MS obsd. (ESI+) [(M+H)+] 415, 1H
NMR (400 MHz, DMSO-d6) δ ppm 7.93 (d, J = 6.82 Hz, 1 H), 7.91 - 7.87 (m, 1 H), 7.82 (d, J =
8.84 Hz, 1 H), 7.66 (td, J = 7.52, 1.39 Hz, 1 H), 7.48 (td, J = 7.71, 1.01 Hz, 1 H), 7.09 - 7.03 (m,
1 H), 5.99 (s, 1 H), 5.09 (brs, 2 H), 3.61 (m, 2 H), 3.45 - 3.31 (m, 4 H), 2.90 (t, J = 6.32 Hz, 2 H),
2.27 (s, 3 H).
Example 9-25
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7,8-difluoromethylquinolin-
4-yl]ethane-1,2-diamine
F N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
fluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide
(prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide in e 2-1 by using 2,4-dichloro-7,8-difluoro
methylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and ethane-1,2-diamine. MS obsd.
(ESI+) [(M+H)+] 433, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.25 (m, 1 H), 8.08 (m, 1 H), 7.84
(m, 1 H), 7.76 (m, 1 H), 7.53 (m, 1 H), 5.99 (s, 1 H), 5.06 (brs, 2 H), 3.70 (m, 2 H), 3.49 -
3.30(m, 4 H), 3.01 (m, 2 H), 2.92 (s, 3 H).
Example 9-26
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-(2-methoxyethyl)
methylquinolinamine
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 2-methoxyethaneamine. MS obsd. (ESI+) [(M+H)+] 412, 1H
NMR (400 MHz, CD3OD) δ ppm 8.12 - 8.08 (d, J = 7.6 Hz, 1 H), 7.90 (s, 1 H), 7.35 - 7.30 (d, J
= 7.6 Hz, 1 H), 7.26 - 7.13 (m, 2 H), 7.11 - 7.05 (m, 2 H), 6.06 (s, 1 H), 5.27 (s, 2 H), 4.50 (s, 2
H), 4.78 - 4.62 (m, 6 H), 3.35 (s, 3 H), 2.45 (s, 3 H).
Example 9-27
1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]piperidinamine
N N
The title nd was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and dinamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR
(400 MHz, CD3OD) δ ppm 8.10 - 8.08 (m, 1 H), 7.84 - 7.71 (m, 3 H), 7.62 - 7.59 (m, 3 H), 6.50
(s, 1 H), 5.34 (s, 2 H), 4.57 - 4.55 (m, 2 H), 3.96 - 3.86 (m, 2 H), 3.78 - 3.76 (m, 2 H), 3.48 - 3.45
(m, 1 H), 3.13 - 3.08 (m, 2 H), 2.48 (s, 3 H), 2.27 - 2.23 (m, 2 H), 2.02 - 1.92 (m, 2 H).
Example 9-28
1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-1,6-naphthyridin
yl]pyrrolidinamine
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
phthyridinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-1,6-
naphthyridine) and pyrrolidinamine. MS obsd. (ESI+) [(M+H)+] 410, 1H NMR (400 MHz,
CD3OD) δ ppm 9.26 (s, 1 H), 8.28 - 8.20 (d, J = 6.4 Hz, 1 H), 8.05 - 7.98 (d, J = 8 Hz, 1 H), 7.90
- 7.82 (d, J = 7.2 Hz, 1 H), 7.70 - 7.60 (m, 2 H), 7.50 - 7.42 (t, J = 7.2 Hz, 1 H), 6.14 (s, 1 H),
.26 (s, 2 H), 4.70 - 4.50 (m, 2 H), 4.20 - 4.10 (m, 2 H), 4.10 - 4.00 (m, 1 H), 3.90 - 3.78 (m, 2
H), 3.60 - 3.52 (t, J = 2.8 Hz, 2 H), 2.60 - 2.48 (m, 1 H), 2.35 - 2.25 (m, 1 H).
Example 9-29
N-[6-(Difluoromethyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]propane-1,3-diamine
F NH NH
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
6-difluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in
analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using 2,4-dichlorodifluoromethylquinoline and 2,3,4,5-tetrahydro-
1,4-benzothiazepine) and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 447, 1H NMR (400
MHz, CD3OD) δ ppm 8.39 (s, 1 H), 8.12 - 8.08 (d, J = 7.6 Hz, 1 H), 7.95 - 7.85 (m, 3 H), 7.78 -
7.70 (t, J = 1.2 Hz, 1 H), 7.65 - 7.58 (t, J = 6.8 Hz, 1 H), 7.03 - 6.72 (t, J = 54.4 Hz, 1 H), 6.03 (s,
1 H), 5.35 (s, 2 H), 4.60 - 4.49 (m, 2 H), 3.80 - 3.72 (t, J = 2.8 Hz, 2 H), 3.68 - 3.60 (t, J = 6.8
Hz, 2 H), 3.15 - 3.09 (t, J = 7.6 Hz, 2 H), 2.16 - 2.05 (m, 2 H).
Example 9-30
6-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-ethylquinolin
amine
N N
O
The title compound was prepared in y to Example 9-1 in Scheme 5 by using 4-(4,6-
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide red in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and
ethaneamine. MS obsd. (ESI+) [(M+H)+] 402, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (s, 1
H), 7.90 (t, J = 4.2 Hz, 2 H), 7.65 (t, J = 3.5 Hz, 1 H), 7.48 (t, J = 3.7 Hz, 1 H), 7.38 (t, J = 3.8
Hz, 2 H), 6.03 (s, 1 H), 5.09 (s, 2 H), 4.42 (brs, 2 H), 3.62 (t, J = 2.4 Hz, 2 H), 3.3 (m, 2 H), 1.24
(t, 3 H).
Example 9-31
Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]amino}ethanol
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4,6-
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4,6-trichloroquinoline and 5-tetrahydro-1,4-benzothiazepine) and
aminoethanol. MS obsd. (ESI+) [(M+H)+] 418, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.06 (s, 1
H), 7.90 (t, J = 3.9 Hz, 2 H), 7.65 (t, J = 3.7 Hz, 1 H), 7.49 (t, J = 3.8 Hz, 1 H), 7.39 (t, J = 3.6
Hz, 2 H), 6.83 (t, J = 4.6 Hz, 1 H), 6.08 (s, 1 H), 5.08 (s, 2 H), 4.81 (t, J = 2.8 Hz, 1 H), 4.43
(brs, 2 H), 3.63 (m, 4 H), 3.85 (m, 2 H).
Example 9-32
N-[6-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]-N'-
methylethane-1,2-diamine
N N
O
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using -
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and
N-methylethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 431, 1H NMR (400 MHz, CD3OD) δ
ppm 7.98 (d, J = 2.0 Hz, 1 H), 7.90 (s, 1 H), 7.84 (d, J = 1.8 Hz, 1 H), 7.63 (t, J = 3.7 Hz, 1 H),
7.46 (t, J = 4.1 Hz, 2 H), 7.36 (m, J = 2.8 Hz, 1 H), 6.08 (s, 1 H), 5.17 (s, 2 H), 4.55 (brs, 2 H),
3.58 (t, J = 2.3 Hz, 2 H), 3.50 (t, J = 3.1 Hz, 2 H), 2.96 (t, J = 3.1 Hz, 2 H), 2.51 (s, 3 H).
Example 9-33
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(methylsulfanyl)quinolin
yl]propane-1,3-diamine
NH NH2
N N
The title compound was ed in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-
6-(methylsulfanyl)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared
in analogy to hloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 2-1 by using 2,4-dichloro(methylsulfanyl)quinoline and 2,3,4,5-
tetrahydro-1,4-benzothiazepine) and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 442, 1H
NMR (400 MHz, CD3OD) δ ppm 8.07 (dd, J = 1.2, 8.0 Hz, 1 H), 7.92 (d, J = 2.0 Hz, 1 H), 7.84
(d, J = 7.6 Hz, 1 H), 7.74 - 7.69 (m, 2 H), 7.64 (dd, J = 2.0, 8.8 Hz, 1 H), 7.57 (t, J = 8.0 Hz, 1
H), 5.95 (s, 1 H), 5.30 (s, 2 H), 4.50 (brs, 2 H), 3.72 (t, J = 4.8 Hz, 2 H), 3.59 (t, J = 6.8 Hz, 2 H),
3.08 (t, J = 7.6 Hz, 2 H), 2.55 (s, 3 H), 2.14 - 2.05 (m, 2 H).
Example 9-34
N-[6-Bromo(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]propane-1,3-diamine
NH NH
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(6-bromo-
roquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to hloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 6-bromo-2,4-dichloroquinoline and 2,3,4,5-tetrahydro-1,4-
benzothiazepine) and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 475, 1H NMR (400 MHz,
CD3OD) δ ppm 8.34 (s, 1 H), 8.05 - 8.04 (d, J = 7.6 Hz, 1 H), 7.88 - 7.86 (d, J = 7.6 Hz, 1 H),
7.81 - 7.79 (d, J = 9.2 Hz, 1 H), 7.75 - 7.69 (m, 2 H), 7.58 - 7.55 (t, J = 7.6 Hz, 1 H), 5.98 (s, 2
H), 5.34 (s, 2 H),4.52 (s, 2 H), 3.72 (s, 2 H), 3.60 - 3.57 (t, J = 7.2 Hz, 2 H), 3.12 - 3.08 (t, J =
7.6 Hz, 2 H), 2.15 - 2.08 (m, 2 H).
Example 10
{4-[(2-Aminoethyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinyl}methanol
OH NH
N N
4-Chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinemethanol
OH Cl
N N
The title compound was prepared in analogy to 4-chloro(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)-quinolinemethanol in Example 3-23 in Scheme 5 by using methyl
4-chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinecarboxylate (prepared in
analogy to 4-(4-chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-
benzothiazepine in Example 1-1 in Scheme 4 by using methyl 2,4-dichloro quinoline
carboxylate and 5-tetrahydro-1,4-benzothiazepine) and sodium borohydride.
{4-[(2-Aminoethyl)amino](2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl}methanol
OH NH
N N
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using [4-chloro
ihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]methanol and propane-1,3-diamine.
{4-[(2-Aminoethyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinyl}methanol
OH NH
N N
To a suspension of {4-[(2-aminoethyl)amino](2,3-dihydro-1,4-benzothiazepin-4(5H)-
nolinyl}methanol (370 mg, 1.04 mmol) in dichloromethane (10 mL) was added 3-
chloroperoxybenzoic acid (384 mg, 2.18 mmol). The resulting mixture was d at room
temperature for 2 hours. To the mixture was added an aqueous solution of saturated sodium
bicarbonate (1 mL) to quench the reaction, and resulting mixture was diluted with
dichloromethane (15 mL). The organic phase was separated, washed with saturated sodium
bicarbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was
purified by flash tography to afford 400 mg of the title compound as a yellow solid (yield
was 98%). MS obsd. (ESI+) [(M+H)+] 413, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.18 (s, 1 H),
7.93 (d, J = 7.6 Hz, 1 H), 7.87 - 7.84 (m, 2 H), 7.64 (m, 1 H), 7.45 (m, 1 H), 7.37 (s, 1 H), 7.33
(s, 1 H), 6.10 (s, 1 H), 5.09 (s, 2 H), 4.52 (brs, 2 H), 3.62 (s, 2 H), 3.37 - 3.28 (m, 4 H), 3.18 (m,
2 H).
Example 11-1
2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}propane-1,3-diol
N N
A solution of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide ( 200.0 mg, 0.54 mmol, prepared in analogy to the one in Example 2-1) and 2-
aminopropane-1,3-diol ( 420.0 mg, 4.6 mmol) in 1-methylpyrrolidinone (1.0 mL) was stirred
at 160 oC for 16 hours. After being cooled to room temperature and diluted with water (50 mL),
the resulting mixture was ted with ethyl acetate (100 mL), washed with brine (50 mL × 2),
dried over ous sodium sulfate and concentrated in vacuo. The e was purified by
preparative HPLC to afford 34.6 mg of the product as a white solid (yield was 15%). MS obsd.
(ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J = 7.83, 1.01 Hz, 1 H),
7.86 (d, J = 7.07 Hz, 1 H), 7.71 - 7.58 (m, 2 H), 7.51 - 7.40 (m, 2 H), 7.36 - 7.24 (m, 1 H), 6.16
(s, 1 H),5.16 (s, 2 H), 4.79 - 4.59 (m, 1 H), 4.54 (brs, 1 H), 3.81 (s, 5 H), 3.69 - 3.50 (m, 2 H),
2.42 (s, 3 H).
Example 11-2
2,2'-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]imino} diethanol
OH OH
N N
The title compound was prepared in analogy to Example 11-1 in Scheme 5 by using 4-(4-chloro-
ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 2,2'-iminodiethanol. MS obsd. (ESI+) [(M+H)+] 442, 1H NMR
(400 MHz, CD3OD) δ ppm 7.99 (dd, J = 7.83, 1.26 Hz, 1 H), 7.81 (s, 1 H), 7.83 (s, 1 H), 7.63
(td, J = 7.58, 1.26 Hz, 1 H), 7.56 - 7.39 (m, 2 H), 7.30 (dd, J = 8.46, 1.89 Hz, 1 H), 6.78 (s, 1 H),
.18 (s, 2 H), 4.57 (brs, 2 H), 3.73 - 3.56 (m, 6 H), 3.56 - 3.43 (m, 4 H), 2.42 (s, 3 H).
Example 11-3
4-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]amino}-
3-hydroxybutanoic acid
OH OH
N N
The title nd was ed in analogy to Example 11-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 4-aminohydroxybutanoic acid. MS obsd. (ESI+) [(M+H)+]
456. 1H NMR (400 MHz, CD3OD) δ ppm 8.10 (dd, J = 7.83, 1.26 Hz, 1 H), 7.83 - 8.00 (m, 2 H),
7.80 - 7.67 (m, 2 H), 7.67 - 7.52 (m, 2 H), 6.32 (s, 1 H), 5.43 - 5.27 (m, 2 H), 4.55 (brs, 2 H),
4.39 - 4.23 (m, 1 H), 3.86 - 3.66 (m, 3 H), 3.57 - 3.40 (m, 1 H), 2.78 - 2.63 (m, 2 H), 2.50 (s, 3
H).
Example 11-4
1-Amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
no}methylpropanol
N N
The title compound was prepared in analogy to Example 11-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 1,3-diaminomethylpropanol. MS obsd. (ESI+) [(M+H)+]
441, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J = 7.6 Hz, 1 H), 7.88 (d, J = 7.6 Hz, 1 H),
7.60 (t, J = 7.6 Hz, 1 H), 7.57 (s, 1 H), 7.43 (m, 2 H), 7.29 (dd, J = 1.2, 8.4 Hz, 1 H), 6.18 (s, 1
H), 5.15 (s, 2 H), 4.53 (brs, 2 H), 3.58 (t, J = 4.4 Hz, 2 H), 3.34 (m, 2 H), 2.85 - 2.76 (m, 2 H),
2.42 (s, 3 H), 1.32 (s, 3 H).
Example 12-1
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2-(morpholin
yl]quinolinamine
N N
S O
A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (50 mg, 0.134 mmol, prepared in analogy to the one in Example 2-1), 2-(morpholin
anamine (78 mg, 0.67 mmol) and n-butanol (5 mL) was heated with stirring in a 10 mL of
microwave process vial for 2 hours at 160 ºC under microwave irradiation. After being cooled to
room temperature, the mixture was diluted with dichloromethane and washed with brine. The
organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (eluting with 3% methanol in dichloromethane) to
afford 35 mg of the product as a light oil (yield was 56%). MS obsd. (ESI+) +] 467, 1H
NMR (400 MHz, CDCl3) δ ppm 8.05 (d, J = 7.6 Hz, 1 H), 7.66 (d, J = 7.2 Hz, 1 H), 7.53 - 7.51
(m, 2 H), 7.38 (m, 1 H), 7.32 (m, 1 H), 5.88 (s, 1 H), 5.56 (s, 2 H), 5.09 (s, 2 H), 4.6 (brs, 2 H)
3.76 (t, J = 4.8 Hz, 4 H), 3.50 (brs, 2 H), 3.33 (m, 2 H), 2.82 (m, 2 H), 2.56 (m, 4 H), 2.29 (s, 3
H).
Example 12-2
(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin
yl]amino}ethanol
N N
The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro-
1,6-naphthyridinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-1,6-
naphthyridine) and 2-aminoethanol. MS obsd. (ESI+) [(M+H)+] 385, 1H NMR (400 MHz,
CD3OD) δ ppm 9.66 (s, 1 H), 8.66 - 8.64 (d, J = 6.8 Hz, 1 H), 8.26 - 8.24 (d, J = 6.8 Hz, 1 H),
8.05 - 8.03 (d, J = 7.6 Hz, 1 H), 7.97 - 7.95 (d, J = 7.2 Hz, 1 H), 7.71 - 7.69 (d, J = 7.2 Hz, 1 H),
7.56 - 7.54 (d, J = 7.6 Hz, 1 H), 6.30 (s, 1 H), 5.38 (s, 1 H), 4.72 - 4.60 (m, 2 H), 3.87 - 3.86 (m,
2 H), 3.71 - 3.67 (m, 4 H).
Example 12-3
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]nonane-
1,9-diamine
NH NH
N N
The title compound was prepared in analogy to e 12-1 in Scheme 5 by using 4-(4-chloro-
8-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4-
benzothiazepine) and nonane-1,9-diamine. MS obsd. (ESI+) [(M+H)+] 495, 1H NMR (400 MHz,
CD3OD) δ ppm 8.04 - 8.03 (m, 1 H), 7.93 - 7.91 (m, 1 H), 7.82 - 7.80 (m, 1 H), 7.68 - 7.70 (m, 1
H), 7.58 - 7.56 (m, 2 H), 7.40 - 7.30 (m, 1 H), 5.87 (s, 1 H), 5.30 (s, 2 H), 4.49 (s, 2 H), 3.76 -
3.75 (m, 2 H), 3.42 - 3.40 (m, 2 H), 2.90 - 2.85 (m, 2 H), 2.61 (s, 3 H), 1.70 - 1.58 (m, 4 H), 1.48
- 1.31 (m, 10 H).
Example 12-4
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]decane-
1,10-diamine
NH 2
N N
O
The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using hloro-
8-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide red in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4-
benzothiazepine) and decane-1,10-diamine. MS obsd. (ESI+) [(M+H)+] 509, 1H NMR (400 MHz,
CD3OD) δ ppm 8.08 - 8.06 (m, 1 H), 7.94 - 7.93 (m, 1 H), 7.82 - 7.81 (m, 1 H), 7.72 - 7.70 (m, 1
H), 7.59 - 7.57 (m, 2 H), 7.42 - 7.32 (m, 1 H), 5.89 (s, 1 H), 5.31 (s, 2 H), 4.50 (s, 2 H), 3.78 -
3.77 (m, 2 H), 3.44 - 3.42 (m, 2 H), 2.91 - 2.87 (m, 2 H), 2.63 (s, 3 H), 1.70 - 1.58 (m, 4 H), 1.48
- 1.31 (m, 12 H).
Example 12-5
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]octane-
1,8-diamine
N N
The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro-
ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and octane-1,8-diamine. MS obsd. (ESI+) +] 481, 1H NMR
(400 MHz, CD3OD) δ ppm 8.10 - 8.08 (dd, J = 1.2 Hz, 1 H), 7.92 (s, 1 H), 7.86 - 7.84 (d, J = 7.6
Hz, 1 H), 7.71 - 7.67 (m, 2 H), 7.61 - 7.55 (m, 2 H), 5.92 (s, 1 H), 5.28 (s, 2 H), 4.52 (s, 2 H),
3.75 - 3.73 (m, 2 H), 3.50 - 3.46 (t, 2 H), 2.93 - 2.83 (t, 2 H), 2.46 (s, 3 H), 1.74 - 1.64 (m, 4 H),
1.51 - 1.40 (m, 8 H).
Example 12-6
9-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}nonanol
NH OH
N N
The title compound was ed in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and 9-aminononanol. MS obsd. (ESI+) [(M+H)+] 495, 1H NMR (400
MHz, CD3OD) δ ppm 8.11 - 8.09 (dd, J = 1.2 Hz, 1 H), 7.92 (s, 1 H), 7.85 -7.83 (d, J = 7.6 Hz, 1
H), 7.71 - 7.67 (m, 2 H), 7.61 - 7.57 (m, 2 H), 5.92 (s, 1 H), 5.28 (s, 2 H), 4.52 (s, 2 H), 3.74 (s, 2
H), 3.50 - 3.46 (t, 2 H), 2.92 - 2.89 (t, 2 H), 2.46 (s, 3 H), 1.73 - 1.63 (m, 4 H), 1.50 - 1.38 (m, 10
Example 12-7
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]octane-
1,8-diamine
N N
The title compound was prepared in y to Example 12-1 in Scheme 5 by using 4-(4-chloro-
8-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4-
benzothiazepine) and octane-1,8-diamine. MS obsd. (ESI+) [(M+H)+] 481, 1H NMR (400 MHz,
CD3OD) δ ppm 8.09 - 8.07 (d, J = 7.6 Hz, 1 H), 7.96 - 7.94 (d, J = 8.4 Hz, 1 H), 7.85 - 7.83 (d, J
= 7.6 Hz, 1 H), 7.73 - 7.70 (m, 2 H), 7.36 - 7.32 (m, 2 H), 5.90 (s, 1 H), 5.33 (s, 2 H), 4.52 - 4.51
(m, 2 H), 3.81 - 3.78 (t, 2 H), 3.47 - 3.42 (t, 2 H), 2.91 - 2.89 (t, 2 H), 2.64 (s, 3 H), 1.67 - 1.63
(m, 4 H), 1.50 - 1.37 (m, 8 H).
Example 13
cisamino[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin-
4-yl]pyrrolidinol
2NH OH
N N
A e of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (740 mg, 2.0 mmol, prepared in y to the one in Example 2-1) and cis
aminopyrrolidinol (600 mg, 6.0 mmol) in n-butanol (0.2 mL) was heated at 180 °C for 3 days.
After being cooled to room temperature, the mixture was purified by preparative HPLC to afford
the product as a solid. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.12
(dd, J = 7.83, 1.26 Hz, 1 H), 8.02 (s, 1 H), 7.87 (d, J = 7.07 Hz, 1 H), 7.82 - 7.71 (m, 2 H), 7.67 -
7.57 (m, 2 H), 5.93 (s, 1 H), 5.33 (s, 2 H), 4.66 (d, J = 2.02 Hz, 1 H), 4.56 (brs, 2 H), 4.28 - 4.17
(m, 2 H), 4.13 -3.99 (m, 2 H), 3.91 (s, 1 H), 3.76 (brs, 2 H), 3.37 (s, 3 H), 2.50 (s, 3 H).
e 14-1
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-L-
alanine
N N
The mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1) and L-alanine (360
mg, 4.0 mmol) in phenol (360 mg) was heated at 150°C ght. After being cooled to room
temperature, the mixture was purified by preparative HPLC to afford the pure product as a solid.
MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 8.16 - 7.92 (m, 3 H), 7.84
(d, J = 8.34 Hz, 1 H), 7.78 - 7.62 (m, 1 H), 7.61 - 7.42 (m, 2 H), 5.86 (s, 1 H), 5.24 (brs, 2 H),
4.65 - 4.35 (m, 3 H), 3.69 (brs, 2 H), 3.37 (s, 3 H), 2.53 - 2.39 (m, 3 H), 1.76 - 1.57 (m, 3 H).
Example 14-2
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinl]-beta-
alanine
N N
O
The title compound was prepared in analogy to Example 14-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and beta-alanine. MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400
MHz, CD3OD) δ ppm 8.14 - 8.08 (m, 1 H), 7.96 - 7.88 (m, 2 H), 7.77 - 7.68 (m, 2 H), 7.65 - 7.57
(m, 2 H), 6.09 (s, 1 H), 5.32 (s, 2 H), 4.56 (brs, 1 H), 3.84 - 3.71 (m, 4 H), 3.37 (s, 2 H), 2.76 (t, J
= 6.95 Hz, 2 H), 2.48 (s, 3 H).
Example 15-1
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]benzene-1,3-diamine
N N
O
A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
e (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1), benzene-1,3-
e (86 mg, 0.80 mmol), palladium acetate (18 mg, 0.04 mmol), 2,2'-
bis(diphenylphosphino)-1,1'-binaphthalene (50 mg, 0.04 mmol), potassium phosphate (169.6 mg,
0.8 mmol) and 1,4-dioxane (3 mL) in a 2~5 mL of process vial was heated at 140 °C under
microwave irradiation for 1.5 hours. After being cooled to room temperature, the mixture was
ed and washed with ethyl acetate. The filtrate was washed with brine, dried over sodium
sulfate, and concentrated in vacuo. The residue was ed by preparative HPLC to afford the
pure product as a solid. MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, DMSO-d6) δ ppm
8.31 (s, 1 H), 7.88 (dd, J = 6.06, 1.52 Hz, 2 H), 7.63 (td, J = 7.52, 1.14 Hz, 1 H), 7.54 - 7.46 (m,
1 H), 7.42 - 7.33 (m, 2 H), 7.33 - 7.27 (m, 1 H), 7.16 (t, J = 7.83 Hz, 1 H), 6.52 (t, J = 1.89 Hz, 1
H), 6.49 - 6.34 (m, 3 H), 5.23 (s, 2 H), 4.86 (s, 2 H), 3.60 (brs, 2 H), 2.38 (s, 3 H).
Example 15-2
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]benzene-1,4-diamine
N N
The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1 1) and benzene-1,4-diamine. MS obsd. (ESI+) [(M+H)+] 445, 1H NMR
(400 MHz, DMSO-d6) δ ppm 8.21 (s, 1 H), 7.92 - 7.83 (m, 2 H), 7.63 - 7.55 (m, 1 H), 7.53 -
7.46 (m, 1 H), 7.34 (d, J = 8.34 Hz, 1 H), 7.27 (dd, J = 8.59, 1.52 Hz, 1 H), 7.15 (d, J = 7.58 Hz,
1 H), 6.91 (m, J = 8.34 Hz, 2 H), 6.77 (m, J = 8.59 Hz, 2 H), 5.97 (s, 1 H), 5.20 - 5.12 (m, 2 H),
4.76 (brs, 2 H), 3.57 (brs, 2 H), 2.37 (s, 3 H).
Example 15-3
-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]pyrrolidinol
N N
The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and yrrolidinol. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR
(400 MHz, CD3OD) δ ppm 7.90 (dd, J = 7.83, 1.26 Hz, 1 H), 7.80 - 7.72 (m, 2 H), 7.54 (td, J =
7.52, 1.39 Hz, 1 H), 7.43 (d, J = 8.59 Hz, 1 H), 7.34 (td, J = 7.71, 1.01 Hz, 1 H), 7.23 (dd, J =
8.59, 1.77 Hz, 1 H), 6.05 (s, 1 H), 5.06 (s, 2 H), 4.55 - 4.43 (m, 1 H), 3.84 (dd, J = 10.48, 4.42
Hz, 2 H), 3.58 - 3.43 (m, 4 H), 3.35 (s, 2 H), 2.35 (s, 3 H), 2.11 (dd, J = 8.84, 4.55 Hz, 1 H), 2.06
- 1.97 (m, 1 H).
Example 15-4
(3R) [2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]pyrrolidinol
N N
The title nd was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and (3R)-pyrrolidinol. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR
(400 MHz, CD3OD) δ ppm 7.88 (dd, J = 7.83, 1.01 Hz, 1 H), 7.79 - 7.69 (m, 2 H), 7.52 (td, J =
7.52, 1.14 Hz, 1 H), 7.44 (d, J = 8.59 Hz, 1 H), 7.33 - 7.27 (m, 1 H), 7.23 (dd, J = 8.59, 1.77 Hz,
1 H), 6.02 (s, 1 H), 5.04 (s, 2 H), 4.55 - 4.42 (m, 2 H), 3.89 - 3.76 (m, 2 H), 3.59 - 3.42 (m, 4 H),
3.37 (s, 2 H), 2.35 (s, 3 H), 2.16 - 1.97 (m, 2 H).
Example 15-5
trans-N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]cyclopentane-1,2-diamine
N N
The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy
to the one in Example 2-1) and trans-cyclopentane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 437,
1H NMR (400 MHz, CD
3OD) δ ppm 8.03 (d, J = 7.83 Hz, 1 H), 7.93 - 7.81 (m, 2 H), 7.67 (t, J =
7.45 Hz, 1 H), 7.61 (d, J = 8.59 Hz, 1 H), 7.51 (t, J = 7.71 Hz, 1 H), 7.47 (d, J = 7.58 Hz, 1 H),
6.04 (s, 1 H), 5.25 (s, 2 H), 4.66 (brs, 1 H), 4.40 (brs, 1 H), 4.27 (d, J = 7.07 Hz, 1 H), 3.84 (q, J
= 7.66 Hz, 1 H), 3.75 - 3.65 (m, 2 H), 2.45 (s, 3 H), 2.40 - 2.24 (m, 2 H), 2.08 -1.79 (m, 3 H),
1.58 (dd, J = 13.01, 7.71 Hz, 1 H).
Example 16-1
1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]piperidinamine
N N
A e of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (0.2 g, 0.54 mmol, prepared in analogy to the one in Example 2-1), piperidinylamine
hydrochloric acid salt (0.275 g, 1.6 mmol) and N,N-diisopropylethylamine (1 mL) was heated at
160 °C under microwave irradiation for 1 hour. After being cooled to room temperature, the
mixture was purified by preparative HPLC and SPE. After SPE separation, the eluent was
concentrated in vacuo to remove the organic solution. The e was dried by lyophylization to
give 52.3 mg of the desired product (yield was 22.3%). MS obsd. (ESI+) [(M+H)+] 437, 1H NMR
(400 MHz, CD3OD) δ ppm 8.09 - 8.07 (d, J = 8 Hz, 1 H), 7.87 - 7.85 (q, J = 7.2 Hz, 1 H), 7.85 -
7.82 (m, 1 H), 7.73 - 7.68 (q, J = 14 Hz, 2 H), 7.62 - 7.55 (m, 2 H), 6.56 (s, 1 H), 5.37 (s, 2 H),
4.57 (s, 2 H), 3.90 - 3.88 (d, J = 9.6 Hz, 1 H), 3.75 (s, 2 H), 3.67-3.66 (m, 1 H), 3.51 - 3.48 (d, J
= 11.6 Hz, 1 H), 3.26 - 3.24 (d, J= 9.6 Hz, 1 H), 3.24 -3.14 (m, 1 H), 2.49 (s, 3 H), 2.26 - 2.22
(m, 1 H), 2.14 - 2.10 (m, 1 H), 1.99 - 1.92 (m, 1 H), 1.91 - 1.78 (m, 1 H).
e 16-2
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N,N,6-trimethylquinolinamine
N N
The title compound was prepared in analogy to Example 16-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y
to the one in Example 2-1) and dimethylamine. MS obsd. (ESI+) [(M+H)+] 382, 1H NMR (400
MHz, CD3OD) δ ppm 8.07 (d, J = 7.6 Hz, 1 H), 7.85 - 7.83 (m, 2 H), 7.73 - 7.70 (m, 2 H), 7.58 -
7.55 (m, 2 H), 6.14 (s, 1 H), 5.30 (s, 2 H), 4.51 (s, 2 H), 3.72 - 3.70 (m, 2 H), 3.29 (s, 6 H), 2.45
(s, 3 H).
Example 17-1
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(trifluoromethoxy)quinolin-
ropane-1,3-diamine
NH NH2
F O
N N
4-(4-Chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide
F O
N N
A mixture of 2,4-dichloro(trifluoromethoxy)quinoline (250 mg, 0.89 mmol), 2,3,4,5-
tetrahydro-1,4-benzothiazepine 1,1-dioxide (210 mg, 1.06 mmol) and n-butanol (2 mL) was
heated with stirring in a 5 mL of ave process vial for 3 hours at 150 oC under microwave
irradiation. The mixture was filtered. The formed solid was collected by filtration and washed
with 10 mL of mixture solution of petroleum ether and ethyl acetate (V/V=10/1) to afford 0.3 g
of the product (yield was 77%).
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(trifluoromethoxy)quinolin-
4-yl]propane-1,3-diamine
NH NH
F 2
F O
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using hloro-
6-(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and
propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 481, 1H NMR (400 MHz, CD3OD) δ ppm 8.16
- 8.15 (d, J = 2.4 Hz, 1 H), 8.09 - 8.07 (dd, J = 5.2, 8.0 Hz, 1 H), 7.94 - 7.92 (d, J = 10 Hz, 1 H),
7.90 - 7.88 (d, J = 8 Hz, 1 H), 7.72 - 7.70 (m, 2 H), 7.58 - 7.55 (m, 1 H), 6.03 (s, 1 H), 5.34 (s, 2
H), 4.55 (s, 2 H), 3.75 (s, 2 H), 3.62 - 3.59 (t, J = 6.8 Hz, 2 H), 3.14 - 3.10 (t, J = 8.0 Hz, 2 H),
2.15 - 2.11 (m, 2 H).
Example 17-2
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(trifluoromethyl)quinolin
yl]propane-1,3-diamine
F NH NH2
N N
The title compound was ed in analogy to Example 17-1 in Scheme 6 by using 4-(4-chloro-
6-(trifluoromethyl)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared
in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide in Example 17-1 by uisng 2,4-dichloro(trifluoromethyl)quinoline
and 2,3,4,5-tetrahydro-1,4-benzothiazepine oxide) and propane-1,3-diamine. MS obsd.
(ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 8.57 (s, 1 H), 8.09 - 8.07 (dd, J = 6.4,
7.6 Hz, 1 H), 7.98 - 9.97 (d, J = 1.6 Hz, 2 H), 7.95 - 7.87 (d, J = 7.2 Hz, 1 H), 7.74 - 7.70 (m, 1
H), 7.60 - 7.58 (m, 1 H), 6.04 (s, 1 H), 5.34 (s, 2 H), 4.55 (s, 2 H), 3.75 (s, 2 H), 3.62 - 3.59 (t, J
= 6.8 Hz, 2 H), 3.12 - 3.08 (t, J = 8 Hz, 2 H), 2.14 - 2.10 (t, J = 8 Hz, 2 H).
Example 17-3
N-[6-(Difluoromethoxy)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-
4-yl]propane-1,3-diamine
NH NH2
F O
N N
The title compound was prepared in y to Example 17-1 in Scheme 6 by using 4-(4-chloro-
6-(difluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared
in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloro
(difluoromethoxy)quinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide) and
propane-1,3-diamine. MS obsd. (ESI+) +] 463, 1H NMR (400 MHz, CD3OD) δ ppm 8.02
- 8.00 (d, J = 7.6 Hz, 1 H), 7.98 - 7.90 (d, J = 2 Hz, 1 H), 7.84 - 7.82 (d, J = 8.4 Hz, 2 H), 7.68 -
7.64 (t, J = 7.6 Hz, 1 H), 7.54 - 7.50 (m, 1 H), 7.05 - 6.68 (d, J = 73.6 Hz, 2 H), 5.95 (s, 1 H),
.28 (s, 2 H), 4.48 (s, 2 H), 3.68 (s, 2 H), 3.57 - 3.54 (t, J = 6.8 Hz, 2 H), 3.08 - 3.04 (t, J = 7.6
Hz, 2 H), 2.11 - 2.04 (m, 2 H).
Example 17-4
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methoxyquinolin
pane-1,3-diamine
NH NH
N N
The title compound was prepared in analogy to Example 17-1 in Scheme 6 by using 4-(4-chloro-
6-methoxyquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in
analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide in e 17-1 by using 2,4-dichloromethoxyquinoline and
2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide) and propane-1,3-diamine. MS obsd. (ESI+)
[(M+H)+] 427, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 - 7.99 (d, J = 8 Hz, 1 H), 7.83 - 7.81 (d,
J = 7.2 Hz, 1 H), 7.71 - 7.64 (m, 2 H), 7.52 - 7.50 (d, J = 7.6 Hz, 2 H), 7.30 - 7.27 (d, J = 9.2 Hz,
1 H), 5.90 (s, 1 H), 5.25 (s, 2 H), 4.46 (s, 2 H), 3.83 (s, 3 H), 3.66 (s, 2 H), 3.56 (s, 2 H), 3.08 -
3.07 (t, J = 7.2 Hz, 2 H), 2.09 - 2.06 (d, J = 5.2 Hz, 2 H).
Example 17-5
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]propane-1,3-diamine
NH NH
N N
The title compound was prepared in analogy to Example 17-1 in Scheme 6 by using hloro-
8-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide) and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H
NMR (400 MHz, CD3OD) δ ppm 8.33 (s, 1 H), 8.08 - 8.02 (m, 2 H), 7.83 - 7.86 (d, J = 7.2 Hz, 1
H), 7.74 - 7.72 (t, J = 8.4 Hz, 1 H), 7.62 - 7.58 (q, J = 7.2 Hz, 2 H), 7.34 - 7.28 (t, J = 7.6 Hz, 1
H), 5.98 (s, 2 H), 5.40 (s, 2 H), 4.58 (s, 2 H), 3.79 (s, 2 H), 3.64 - 3.61 (t, J = 6.8 Hz, 2 H), 3.09 -
3.05 (dd, J = 7.6, 8.4 Hz, 2 H), 2.67 (s, 3 H), 2.10 - 2.06 (d, J = 7.2 Hz, 2 H).
Exampe 17-6 and 17-7
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]propane-1,3-diamine and N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]propane-1,3-diamine
NH NH NH NH
2 2
N N N N
S O S O
O O
A mixture of the title compound prepared in y to Example 17-1 by using propane-1,3-
e and a mixture of 4-(4-chloromethylquinolin- 2-yl)- 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide and 4-(4-chloromethylquinolinyl)- 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolin
yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide in Example 17-1 by using a mixture of
2,4-dichloromethylquinoline and 2,4-dichloromethylquinoline and propane-1,3-diamine)
was purified by preparative HPLC and SPE to give the pure title compounds N-[2-(1,1-dioxido-
hydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]propane-1,3-diamine and N-[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]propane-1,3-
diamine.
1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]propane-
1,3-diamine, MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 8.15 - 7.98 (d,
J = 7.6 Hz ,1 H), 7.85 - 7.80 (d, J = 7.2 Hz ,1 H), 7.70 - 7.60 (q, J = 6.4 Hz ,2 H), 7.55 - 7.48 (t, J
= 7.6 Hz , 2 H), 7.21 - 7.18 (d, J = 6.8 Hz ,1 H), 5.87 (s, 1 H), 5.26 (s, 2 H), 4.70 - 4.40 (m, 2 H),
3.71 - 3.65 (t, J = 2.8 Hz , 2 H), 3.58 - 3.50 (t, J = 7.2 Hz ,2 H), 3.12 - 3.05 (t, J = 7.6 Hz, 2 H),
2.82 (s, 3 H), 2.12 - 2.03 (m, 2 H).
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]propane-
1,3-diamine, MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 8.10 - 8.02
(m, 1 H), 8.00 - 7.95 (d, J = 8.8 Hz ,1 H), 7.88 - 7.81 (d, J = 7.2 Hz, 1 H), 7.70 - 7.65 (t, J = 1.2
Hz , 1 H), 7.57 (s, 1 H), 7.57 - 7.50 (t, J = 16 Hz , 1 H), 7.30 - 7.22 (d, J = 8.4 Hz , 1 H), 5.88 (s,
1 H), 5.29 (s, 2 H), 4.60 - 4.40 (m, 2 H), 3.72 - 3.68 (t, J = 1.2 Hz ,2 H), 3.60 - 3.50 (t, J = 2.8 Hz
,2 H), 3.10 - 3.02 (t, J = 7.6 Hz ,2 H), 2.45 (s, 3 H), 2.11 - 2.02 (m, 2 H).
Example 17-8
N-{[3-(Aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)fluoroquinolinamine
NH NH2
N N
The title compound was ed in analogy to Example 17-1 in Scheme 6 by using 4-(4-chloro-
8-fluoroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1 by using 2,4-dichlorofluoroquinoline and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+]
457, 1H NMR (400 MHz, CD3OD) δ ppm 8.08 (d, J = 7.2 Hz, 1 H), 8.03 (dd, J = 2.4, 9.6 Hz, 1
H), 7.91 - 7.84 (m, 2 H), 7.70 (t, J = 7.2 Hz, 1 H), 7.57 (t, J = 7.6 Hz, 2 H), 6.23 (s, 1 H), 5.35 (s,
2 H), 4.63 (d, J = 7.2 Hz, 2 H), 4.56 - 4.51 (m, 4 H), 3.92 (s, 2 H), 3.74 (s, 2 H), 3.47 (s, 2 H).
e 18-1
N-[(3-Aminooxetanyl)methyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinolinamine
N N
4-(4-Chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide
N N
The title compound was prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-
2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1 in Scheme 6 by using 2,4-
romethylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide.
N-[(3-Aminooxetanyl)methyl](1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinamine
N N
A e of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide
(2 g, 5.6 mmol), 3-aminomethyloxetanylamine (572 mg, 5.6 mmol),
tri(dibenzylideneacetone)dipalladium(0) (256 mg, 0.28 mmol), 2,2'-bis(diphenylphosphino)-1,1'-
binaphthalene (348.7 mg, 0.56 mmol), sodium tert-butoxide (1.08 g, 11.2 mmol) and toluene (20
mL) was heated with ng in a 30 mL of sealed tube for 20 hours at 110 oC under nitrogen.
The resulting e was diluted with ethyl acetate and washed with water. The organic layer
was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by
column chromatography on silica gel to give 1.5 g of the product as off-white foam.
Example 18-2 and Example 18-3
(+)-N-[(3-Aminooxetanyl)methyl]methyl[1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl]quinolinamine and (-)-N-[(3-Aminooxetanyl)methyl]methyl[1-oxido-
2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolinamine
NH NH
NH 2 NH 2
O O
N N N N
S S
O O
(+) (-)
The chiral separation of Example 18-1 (column: IA; flow rate: 15mL/min; gradient: 50% hexane
in l with 0.4% of triethylamine) gives (+)-N-[(3-aminooxetanyl)methyl]methyl[1-
oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolinamine, MS obsd. (ESI+) [(M+H)+]
423, 1H NMR (400 MHz, CD3OD) δ ppm 7.74 (d, J = 7.6 Hz, 1 H), 7.70 - 7.66 (m, 2 H), 7.48 -
7.43 (m, 2 H), 7.39 (t, J = 7.2 Hz, 1 H), 7.29 (dd, J = 1.6, 8.4 Hz, 1 H), 6.16 (s, 1 H), 5.21 (d, J =
16.0 Hz, 1 H), 4.72 (brs, 2 H), 4.62 (d, J = 6.8 Hz, 2 H), 4.57 (dd, J = 2.4, 6.4 Hz, 2 H), 4.43
(brs, 1 H), 3.66 (s, 2 H), 3.42 (m, 2 H), 2.41 (s, 3 H); and (-)-N-[(3-aminooxetanyl)methyl]
methyl[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl]quinolinamine, MS obsd. (ESI+)
+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 7.70 (d, J = 7.6 Hz, 1 H), 7.65 (m, 2 H),
7.47 - 7.38 (m, 2 H), 7.33 (t, J = 7.2 Hz, 1 H), 7.27 (dd, J = 1.6, 8.4 Hz, 1 H), 6.12 (s, 1 H), 5.15
(d, J = 16.0 Hz, 1 H), 4.64 (brs, 2 H), 4.60 (d, J = 6.4 Hz, 2 H), 4.55 (dd, J = 2.8, 6.4 Hz, 2 H),
4.43 (brs, 1 H), 3.63 (s, 2 H), 3.34 (m, 2 H), 2.38 (s, 3 H).
Example 18-4
N-[(3-Aminooxetanyl)methyl]chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinolinamine
N N
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6-
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-
(4-chloromethylquinolinyl)- 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example
18-1 by using trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and
3-aminomethyloxetanylamine. MS obsd. (ESI+) [(M+H)+] 443, 1H NMR (400 MHz, CD3OD)
δ ppm 7.94 (d, J = 2.02 Hz, 1 H), 7.77 (d, J = 7.83 Hz, 1 H), 7.71 (d, J = 8.59 Hz, 1 H), 7.52 -
7.34 (m, 4 H), 6.22 (s, 1 H), 5.25 (d, J =15.92 Hz, 2 H), 4.78 (brs, 2 H), 4.65 - 4.52 (m, 4 H),
3.66 (s, 2 H), 3.47 - 3.38 (m, 2 H).
Example 18-5
N-[2-(1-Oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-2,2-
ropropane-1,3-diamine
F 2
N N
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in y to
the one in Example 18-1) and 2,2-difluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 431,
1H NMR (400 MHz, CD
3OD) δ ppm 7.93 (s, 1 H), 7.81 - 7.79 (m, 1 H), 7.76 - 7.74 (d, 2 H), 7.62
- 7.52 (m, 3 H), 6.25 (s, 1 H), 5.45 - 5.41 (d, 1 H), 5.05 (d, 1 H), 4.75 (m, 1 H), 4.45 (m, 1 H),
4.23 - 4.16 (m, 2 H), 3.72 - 3.64 (t, 2 H), 3.50 (m, 2 H), 2.47 (s, 3 H).
Example 18-6
N-[6-Chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]-2,2-
ropropane-1,3-diamine
F 2
N N
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6-
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-
(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18-
1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and 2,2-
difluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ
ppm 8.21 (s, 1 H), 7.86 - 7.81 (m, 2 H), 7.77 - 7.74 (m, 2 H), 7.58 (m, 2 H), 6.32 (s, 1 H), 5.45
(d, 1 H), 5.05 (d, 1 H), 4.75 (m, 1 H), 4.48 (m, 1 H), 4.20 (m, 2 H), 3.68 (t, 2 H), 3.50 (m, 2 H).
e 18-7
N-[6-Chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]ethane-1,2-
diamine
N N
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6-
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-
(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18-
1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine e) and
-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 401, 1H NMR (400 MHz, CD3OD) δ ppm 7.91
(d, J = 2.0 Hz, 1 H), 7.76 -7.74 (d, J = 7.8 Hz, 2 H), 7.53 - 7.38 (m, 4 H), 6.10 (s, 1 H), 5.29 -
.25 (d, J = 15.2 Hz, 1 H), 4.62 (s, 3 H), 3.57 (m, 4 H), 3.19 - 3.10 (m, 2 H).
Example 18-8
N-{[3-(Aminomethyl)oxetanyl]methyl}methyl(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinolinamine
N N
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to
the one in Example 18-1) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 437,
1H NMR (400 MHz, CD
3OD) δ ppm 8.11 (s, 1 H), 7.86 - 7 .75 (m, 3 H), 7.59 - 7.51 (m, 3 H),
7.67 (t, J = 3.6 Hz, 1 H), 7.57 (d, J = 2.1 Hz, 1 H), 6.22 (s, 1 H), 5.45 (d, J = 16.4 Hz, 1 H), 5.10
(brs, 1 H), 4.76 (brs, 1 H), 4.60 (m, 4 H), 3.94 (d, 2 H), 4.52 (s, 2 H), 3.47 (s, 2 H), 2.46 (s, 3 H).
Example 18-9
N-{[3-(Aminomethyl)oxetanyl]methyl}chloro(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinolinamine
N N
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6-
roquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-
(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in e 18-
1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and
oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ
ppm 8.31 (d, 1 H), 7.85 - 7.74 (m, 4 H), 7.60 - 7.55 (m, 2 H), 6.22 (s, 1 H), 5.45 (d, 1 H), 5.11(d,
1 H), 4.68(brs, 1 H), 4.65 - 4.56 (m, 4 H), 4.47 (d, 1 H), 3.91 (m, 2 H ), 3.55( m, 2 H ), 3.47 (s, 2
Example 18-10
N-[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]ethane-1,2-
diamine
N N
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in y to
the one in Example 18-1) and ethane-1,2-amine. MS obsd. (ESI+) [(M+H)+] 381, 1H NMR (400
MHz, CD3OD) δ ppm 7.89 (s, 1 H), 7.81 - 7.76 (m, 2 H), 7.73 - 7.70 (m, 1 H), 7.59 - 7.49 (m, 3
H), 6.02 (s, 1 H), 5.44 - 5.40 (m, 1 H), 5.04 - 5.01 (m, 1 H), 4.75 - 4.71 (m, 1 H), 4.48 - 4.44 (m,
1 H), 3.84 - 3.81 (t, 2 H), 3.51 (s, 2 H), 3.33 - 3.28 (m, 2 H), 2.45 (s, 3 H).
Example 18-11
2-{[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]amino}ethanol
N N
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in y to
the one in Example 18-1) and 2-amino-ethanol. MS obsd. (ESI+) [(M+H)+] 382, 1H NMR (400
MHz, CD3OD) δ ppm 7.92 (s, 1 H), 7.85 - 7.80 (d, J = 8.4 Hz, 1 H), 7.80 - 7.75 (d, J = 7.6 Hz, 1
H), 7.75 - 7.70 (d, J = 7.2 Hz, 1 H), 7.61 - 7.50 (m, 3 H), 6.10 (s, 1 H), 5.48 - 5.39 (m, 1 H), 5.08
- 4.95 (m, 1 H), 4.80 - 4.70 (m, 1 H), 4.52 - 4.42 (m, 1 H), 3.88 - 3.80 (t, J = 5.6 Hz, 2 H), 3.65 -
3.60 (t, J = 5.6 Hz, 2 H), 3.59 - 3.40 (m, 2 H ), 2.46 (s, 3 H).
Example 19-1
transAmino[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]pyrrolidinol
OH NH
N N
tert-Butyl [6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-
4-yl]hydroxypyrrolidinyl} carboxylate
H O
OH N
N N
A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide
(200 mg, 0.56 mmol, ed in analogy to the one in Example 18-1), utyl
hydroxypyrrolidinyl]carbamate (125 mg, 0.62 mmol), tris(2-benzylidene acetone)
palladium(II) (50 mg, 0.055 mmol), 2-dicyclohexylphosphino(N,N-dimethylamino)biphenyl
(30 mg, 0.076 mmol), sodium tert-butoxide (60 mg, 0.625 mmol) and 1,4-dioxane (3 mL) in a
2~5 mL of process vial was heated at 120°C under microwave irradiation for 2 hours. After
being cooled to room temperature, the mixture was ed and washed with ethyl acetate. The
filtrate was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue
was purified by flash column chromatography (eluting with 10% methanol in dichloromethane)
to afford 230 mg of the product as a white solid (yield was 80%).
transAmino[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]pyrrolidinol
OH NH2
N N
To a solution of tert-butyl {trans[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinyl]hydroxypyrrolidinyl}carboxylate (230 mg, 0.54 mmol) in
dichloromethane (5 mL) was added trifluoroacetic acid (2 mL). After being stirred at room
temperature for 3 hours, the resulting mixture was concentrated in vacuo. The residue was
ed by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+]
423, 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (s, 1 H), 7.80 - 7.76 (d, J = 7.2 Hz, 1 H), 7.76 -
7.70 (m, 2 H), 7.60 - 7.52 (m, 2 H), 7.52 - 7.43 (m, 1 H), 5.91 (s, 1 H), 5.42 - 5.30 (m, 1 H), 5.02
- 4.90 (m, 1 H), 4.80 - 4.68 (m, 1 H), 4.56 - 4.50 (m, 1 H), 4.50 - 4.20 (m, 3 H), 3.96 - 3.88 (m, 1
H), 3.86 - 3.80 (m, 1 H), 3.80 - 3.70 (m, 1 H), 3.56 - 3.38 (m, 2 H), 2.43 (s, 3 H ).
Example 19-2
(1R,5S,6S)[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]azabicyclo[3.1.0]hexanamine
H H
N N
The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide (prepared in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,2-dioxide ) and tert-butyl ,6S)azabicyclo[3.1.0]hexylcarbamate.
MS obsd. (ESI+) [(M+H)+] 435, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J = 7.83, 1.01
Hz, 1 H), 7.82 (d, J = 7.07 Hz, 1 H), 7.71 - 7.56 (m, 2 H), 7.51 - 7.39 (m, 2 H), 7.27 (dd, J =
8.59, 1.77 Hz, 1 H), 6.31 (s, 1 H), 5.15 (s, 2 H), rs, 2 H), 3.83(d, J = 9.60 Hz, 2 H), 3.58 (t,
J = 4.93 Hz, 2 H), 3.38 (d, J = 9.60 Hz, 2 H), 2.55 (s, 1 H), 2.40 (s, 3 H), 1.76 - 1.62 (m, 2 H).
Example 19-3
transAmino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]pyrrolidinol
H N OH
N N
The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,2-dioxide) and utyl trans-(4-hydroxypyrrolidinyl)carbamate. MS
obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 7.92 - 7.83 (m, 2 H), 7.76 (s, 1
H), 7.67 - 7.59 (m, 1 H), 7.47 (t, J = 7.45 Hz, 1 H), 7.37 (d, J = 8.59 Hz, 1 H), 7.23 (dd, J = 8.46,
1.39 Hz, 1 H), 6.03 (s, 1 H), 5.18 - 4.96 (m, 3 H), 4.41(brs, 2 H), 4.04 - 3.83 (m, 3 H), 3.62 (t, J =
4.80 Hz, 2 H), 3.35 - 3.25 (d, J = 9.85 Hz, 2 H), 2.35 (s, 3 H).
Example 19-4
1-[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]pyrrolidin-
3-amine
N N
The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine e (prepared in analogy to
the one in Example 18-1) and utyl pyrrolidinylcarbamate. MS obsd. (ESI+) [(M+H)+]
407, 1H NMR (400 MHz, CD3OD) δ ppm 7.81 (s, 1 H), 7.71 (t, J = 8.21 Hz, 2 H), 7.57 - 7.36
(m, 3 H), 7.27 (dd, J = 8.59, 1.77 Hz, 1 H), 6.11 (s, 1 H), 5.21 (d, J = 16.17 Hz, 1 H), 4.76 (d, J =
.92 Hz, 2 H), 4.50 (brs, 1 H), 3.88 - 3.71 (m, 2 H), 3.71 - 3.53 (m, 2 H), 3.53 - 3.36 (m, 3 H),
2.40 (s, 3 H), 2.26 (dq, J = 12.63, 6.23 Hz, 1 H), 1.98 - 1.78 (m, 1 H).
Example 19-5
trans[6-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]
fluoropyrrolidinamine
F NH
N N
The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4,6-
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
e 2-1) and tert-butyl trans-(4-fluoropyrrolidinyl) carbamate. MS obsd. (ESI+)
[(M+H)+] 461, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 - 7.96 (m, 2 H), 7.86 (d, J = 7.58 Hz, 1
H), 7.63 (td, J = 7.45, 1.26 Hz, 1 H), 7.54 (d, J = 9.09 Hz, 1 H), 7.46 (td, J = 7.71, 1.01 Hz, 1 H),
7.39 (dd, J = 9.09, 2.27 Hz, 1 H), 6.25 (s, 1 H), 5.14 - 5.25 (m, 2 H), 5.05 (brs, 1 H), 4.55 (brs, 2
H), 4.18 - 4.27 (dd, J = 12.25, 3.92 Hz, 1 H), 4.01 (dd, J = 8.97, 5.18 Hz, 1 H), 3.78 - 3.55 (m, 4
H), 3.40 - 3.30 (m, 1 H).
Example19-6
transAmino[6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinyl]pyrrolidinol
H N OH
N N
O
The title compound was prepared in y to Example 19-1 in Scheme 7 by using -
dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1 by using 2,4,6-trichloro-quinoline and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,2-dioxide) and tert-butyl (transhydroxypyrrolidinyl) carbamate. MS
obsd. (ESI+) [(M+H)+] 459, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 - 7.96 (m, 2 H), 7.85 (d, J
= 7.33 Hz, 1 H), 7.66 - 7.60 (m, 1 H), 7.53 (d, J = 9.09 Hz, 1 H), 7.49 - 7.42 (m, 1 H), 7.38 (dd, J
= 8.97, 2.15 Hz, 1 H), 6.20 (s, 1 H), 5.18 (brs, 2 H), 4.70 - 4.40 (b, 2 H), 4.21 (brs, 1 H), 4.10
(dd, J = 10.74, 4.93 Hz, 1 H), 3.97 (dd, J = 9.60, 5.56 Hz, 1 H), 3.59 (d, J = 3.28 Hz, 2 H), 3.54 -
3.49 (m, 1 H), 3.48 - 3.39 (m, 2 H).
Example 19-7
trans[6-Chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]
fluoropyrrolidinamine
NH F
N N
The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using -
roquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-
(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18-
1) and tert-butyl (transfluoropyrrolidinyl) carbamate. MS obsd. (ESI+) [(M+H)+] 445, 1H
NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J = 2.27 Hz, 1 H), 7.78 - 7.68 (m, 2 H), 7.55 (dd, J =
9.09, 1.52 Hz, 1 H), 7.52 - 7.42 (m, 2 H), 7.39 (dd, J = 9.09, 2.27 Hz, 1 H), 6.28 - 6.21 (m, 1 H),
.25 (d, J = 15.66 Hz, 1 H), 5.10 - 4.95 (m, 1 H), 4.90 - 4.54 (m, 2 H), 4.65 - 4.40 (m, 1 H), 4.30
- 4.10 (m, 1 H), 4.05 - 3.59 (m, 1 H), 3.55 - 3.51 (m, 2 H), 3.40 - 3.35 (m, 3 H).
Example 19-8
2-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]
azabicyclo[2.1.1]hexanamine
N N
The title compound was prepared in analogy to Example19-1 in Scheme 7 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,2-dioxide) and tert-butyl 2-azabicyclo[2.1.1]hexylcarbamate. MS obsd.
(ESI+) [(M+H)+] 435, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J = 7.83, 1.01 Hz, 1 H),
7.86 - 7.74 (m, 2 H), 7.61 (td, J = 7.58, 1.26 Hz, 1 H), 7.54 - 7.39 (m, 2 H), 7.33 (dd, J = 8.59,
1.77 Hz, 1 H), 6.43 (s, 1 H), 5.22 - 5.06 (m, 2 H), 4.38 (d, J = 6.32 Hz, 1 H), 3.95 (d, J = 8.59
Hz, 1 H), 3.67 - 3.52 (m, 2 H), 3.42 - 3.35 (m, 1 H), 3.05 (d, J = 8.59 Hz, 1 H), 2.91 - 2.77 (m, 1
H), 2.45 (s, 3 H), 1.67 (d, J = 7.83 Hz, 1 H), 1.39 - 1.26 (m, 2 H), 1.19 (d, J = 7.83 Hz, 1 H).
Example 20-1
2-(8-Methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
amine
N N
tert-Butyl [2-(8-Methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl] carbamate
NH O
N N
A mixture solution of 4-(4-chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-
benzothiazepine oxide (60.0 mg, 0.15 mmol, prepared in analogy to 4-(4-chloro
(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example
17-1 by using 2,4-dichloromethylquinoline and 8-methoxy-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,2-dioxide), tert-butyl carbamate (45.0 mg, 0.37 mmol), 1,1'-
bis(diphenylphosphino)ferrocene (11.2 mg, 0.02 mmol), 1,1'-
bis(diphenylphosphino)ferrocenedichloropalladium(II) (15.0 mg, 0.02 mmol), and sodium tert-
butoxide (75.0 mg, 0.72 mmol) in 1,4-dioxane (2.0 mL) was heated with stirring at 120 oC for 2
hours. After being cooled to room temperature, the reaction mixture was ted with ethyl
acetate (100 mL), washed with brine (50 mL × 2), dried over anhydrous sodium e and
concentrated in vacuo to afford 59.9 mg of the crude product as yellow oil. MS obsd. (ESI+)
[(M+H)+] 484.
2-(8-Methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
amine
N N
A mixture on of tert-butyl [2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinolinyl] carbamate (59.0 mg, 0.12 mmol) and trifluoroacetic acid (0.5
mL) in dichloromethane (2.0 mL) was stirred at room temperature for 6 hours. Then the reaction
mixture was extracted with ethyl e (100 mL). The organic layer was washed with brine (50
mL × 2), dried over anhydrous sodium sulfate and then concentrated in vacuo. The e was
purified by preparative HPLC to afford 10.2 mg of the product as a white solid (yield was
21.5%). MS obsd. (ESI+) [(M+H)+] 384, 1H NMR (400 MHz, CD3OD) δ ppm 7.72 (d, J = 8.34
Hz, 1 H), 7.58 (s, 1 H), 7.50 (d, J = 2.78 Hz, 1 H), 7.43 (d, J = 8.34 Hz, 1 H), 7.29 (dd, J = 8.46,
1.89 Hz, 1 H), 7.12 (dd, J = 8.34, 2.78 Hz, 1 H), 6.27 (s, 1 H), 5.02 (s, 2 H), 4.47 (brs, 2 H), 3.82
(s, 3 H), 3.56 (t, J = 4.80 Hz, 2 H), 2.42 (s, 3 H).
e 20-2
2-(7-Methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
amine
N N
O
The title compound was prepared in analogy to Example 20-1 in Scheme 7 by using 4-(4-chloro-
6-methylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared
in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 7-
methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) and tert-butyl carbamate. MS
obsd. (ESI+) [(M+H)+] 384, 1H NMR (400 MHz, CD3OD) δ ppm 7.87 (d, J = 8.84 Hz, 1 H), 7.59
(s, 1 H), 7.44 (d, J = 8.59 Hz, 1 H), 7.35 (d, J = 2.53 Hz, 1 H), 7.30 (dd, J = 8.59, 1.77 Hz, 1 H),
6.88 (dd, J = 8.72, 2.65 Hz, 1 H), 6.27 (s, 1 H), 5.04 (s, 2 H), 4.46 (brs, 2 H), 3.89 (s, 3 H), 3.52
(t, J = 4.67 Hz, 2 H), 2.42 (s, 3 H).
Example 20-3
[2-(1-Amino-cyclopropyl)-ethyl]-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
6-methylquinolinyl]-amine
NH 2NH
N N
The title compound was prepared in analogy to Example 20-1 in Scheme 7 by using 4-(4-
chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in
analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and
2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) and tert-butyl 1-(2-aminoethyl)-
cyclopropylcarbamate. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CDCl3) δ ppm 7.95
- 7.93 (dd, J = 1.2 , 8.0 Hz, 1 H), 7.59 - 7.57 (d, J = 6 Hz, 1 H), 7.42 - 7.38 (m, 2 H), 7.29 - 7.25
(m, 1 H), 7.21 - 7.18 (m, 2 H), 6.40 (s, 1 H), 5.79 (s, 1 H), 4.5 (s, 2 H), 3.48 (s, 2 H), 3.35 (s, 2
H), 2.44 (s, 3 H), 2.31 (s, 3 H), 1.77 - 1.74 (d, J = 6 Hz, 2 H), 1.54 (s, 2 H), 0.56 - 0.50 (m, 2 H).
e 21-1
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(morpholin
yl)quinolinamine
N N
tert-Butyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
ylamino]-methyl}-morpholinecarboxylate
N O
N N
A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (682 mg, 1.83 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolin
yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloro
methylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) in 1,4-dioxane (5 mL)
was added tert-butyl nomethyl)morpholinecarboxylate (395 mg, 1.83 mmol), 1,1'-
bis(diphenylphosphino)ferrocenedichloropalladium(II) (146 mg, 0.18 mmol), 1,1'-
bis(diphenylphosphino)ferrocene (100 mg, 0.18 mmol) and sodium tert-butoxide (350 mg, 3.66
mmol) under Argon protection. The mixture was heated with stirring under microwave
irridiation at 120 oC for 1.5 hours. The reaction mixture was concentrated in vacuo and the
residue was purified by preparative HPLC to give 100 mg of the d product (yield was
%).
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(morpholin
ylmethyl)quinolinamine
N N
O
To a solution of tert-butyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinylamino]-methyl}-morpholinecarboxylate (100 mg, 0.18 mmol) in ethyl
acetate (10 mL) was added a solution of hydrochloride in ethyl acetate (4 N, 30 mL) in an icewater
bath dropwise. After being stirred at room temperature for 4 hours, the mixture was
concentrated in vacuo. The residue was purified by preparative HPLC to afford oroacetic
acid salt of the d t. The trifluoroacetic acid salt was flashed through SPE column
with methanol to remove the trifluoroacetic acid. The solution was concentrated in vacuo and
then dried by ization to give 46.94 mg of the desired product (yield was 60%). MS obsd.
(ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J = 7.6 Hz, 1 H), 7.90 - 7.86
(m, 2 H), 7.72 - 7.68 (m, 2 H), 7.56 - 7.50 (m, 2 H), 6.11 (s, 1 H), 5.29 (s, 2 H), 4.55 - 4.49 (m, 2
H), 4.11 - 4.01 (m, 2 H), 3.88 - 3.81 (m, 1 H), 3.71 - 3.62 (m, 4 H), 3.42 - 3.39 (m, 1 H), 3.33 -
3.21 (s, 1 H), 3.28 - 3.01 (m, 2 H), 2.45 (s, 3 H).
Example 21-2
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N-
methylethane-1,2-diamine
N 2
N N
O
The title compound was prepared in analogy to e 21-1 in Scheme 7 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,2-dioxide) and tert-butyl N-[2-(methylamino)ethyl]carbamate. MS obsd.
(ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.92 (dd, J = 1.6, 7.6 Hz, 1 H), 7.86
(d, J = 7.6 Hz, 2 H), 7.74 (s, 1 H), 7.61 (t, J = 7.6 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 7.40 (t, J =
7.6 Hz, 1 H), 7.33 (dd, J = 2.0, 8.8 Hz, 1 H), 6.66 (s, 1 H), 5.20 (s, 2 H), 4.51 (brs, 2 H), 3.59 -
3.53 (m, 4 H), 3.24 (t, J = 6.4 Hz, 2 H), 2.93 (s, 3 H), 2.42 (s, 3 H).
Example 21-3
tidinylmethyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinamine
NH N
N N
The title compound was prepared in analogy to Example 21-1 in Scheme 7 by using 4-(4-chloro-
ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,2-dioxide) and tert-butyl 2-(aminomethyl)azetidinecarboxylate. MS obsd.
(ESI+) +] 423, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 - 8.02 (d, J = 4 Hz, 1 H), 7.89
(s, 1 H), 7.85 - 7.79 (d, J = 4 Hz, 1 H), 7.72 - 7.65 (m, 2 H), 7.60 - 7.50 (m, 2 H), 6.00 (s, 1 H),
.31 (s, 2 H), 4.85 - 4.75 (m, 1 H), 4.60 - 4.40 (m, 2 H), 4.13 - 3.95 (m, 3 H), 3.92 - 3.85 (dd, J =
2.8, 12.8 Hz, 1 H), 3.75 - 3.66 (t, J = 2.8 Hz, 2 H), 2.72 - 2.60 (m, 1 H), 2.52 - 2.42 (m, 1 H),
2.42 (s, 3 H).
Example 21-4
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(pyrrolidin
yl)quinolinamine
N N
The title compound was prepared in analogy to Example 21-1 in Scheme 7 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4-
benzothiazepine oxide) and tert-butyl 3-aminopyrrolidinecarboxylate. MS obsd. (ESI+)
+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 8.16 (s, 1 H), 8.12 - 8.10 (q, J = 1.2 Hz, 1
H), 7.96 - 7.94 (d, J = 7.6 Hz, 1 H), 7.80 - 7.74 (m, 2 H), 7.74 - 7.60 (m, 2 H), 6.04 (s, 1 H), 5.39
(s, 2 H), 4.84 - 4.82 (m, 2 H), 4.58 (s, 2 H), 3.81 - 3.77 (dd, J = 6.4, 4.4 Hz, 2 H), 3.62 - 3.52 (m,
3 H), 2.67 - 2.30 (m, 1 H), 2.61 - 2.54 (m, 1 H), 2.50 (s, 3 H).
Example 21-5
(1-Amino-cyclopropylmethyl)-[2-(5,5-dioxo-5,6,7,9-tetrahydro-5λ6-thiaazabenzocycloheptenyl
)methyl-quinolinyl]-amine
N N
The title compound was prepared in analogy to Example 21-1 in Scheme 7 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide red in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,2-dioxide) and tert-butyl 1-(aminomethyl)cyclopropane carbamate. MS obsd.
(ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 - 7.90 (d, J = 8 Hz, 1 H), 7.82 -
7.78 (d, J = 7.6 Hz, 1 H), 7.69 (s, 1 H), 7.60 - 7.52 (t, J = 1.2 Hz, 1 H), 7.42 - 7.36 (m, 2 H), 7.29
- 7.22 (d, J = 7.2 Hz, 1 H), 6.00 (s, 1 H), 5.11 (s, 2 H), 4.65 - 4.50 (m, 2 H), 3.60 - 3.50 (t, J = 2.8
Hz, 2 H), 3.40 - 3.30 (d, J = 4.4 Hz, 2 H), 2.39 (s, 3 H ), 0.70 - 0.60 (m, 4 H).
e 22
N-(Azetidinyl)chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinamine
N N
tert-Butyl 3-[6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin
ylamino]-azetidinecarboxylate
N O
N N
The title compound was prepared in analogy to tert-butyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinylamino]-methyl}-morpholinecarboxylate in
Example 21-1 by using 4-(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine
1,1-dioxide and utyl 3-aminoazetidinecarboxylate.
N-(Azetidinyl)chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinamine
N N
O
A mixture of tert-butyl 3-[6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
quinolinylamino]-azetidinecarboxylate (120 mg, 0.2 mmol) and a solution of hydrochloride
in 1,4-dioxane (4 N, 20 mL) was stirred at room temperature for 16 hours. The resulting e
was concentrated in vacuo. The residue was purified by preparative HPLC to afford 50 mg of the
desired product (yield was 51%). MS obsd. (ESI+) [(M+H)+] 429, 1H NMR (400 MHz, CD3OD)
δ ppm 8.31 (s, 1 H), 8.08 - 8.06 (d, J = 8 Hz, 1 H), 7.87 - 7.80 (m, 2 H), 7.73 - 7.68 (m, 2 H),
7.55 - 7.53 (m, 1 H), 5.84 (s, 1 H), 5.30 (s, 2 H), 4.99 - 4.96 (m, 1 H), 4.59 - 4.52 (m, 4 H), 4.32 -
4.27 (m, 2 H), 3.72 (s, 2 H).
Example 23
6-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]oxa
ro[3.4]octanamine
O NH
N N
tert-Butyl 6-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]oxaazaspiro[3.4]octancarbamate
O H O
N N
A mixture of tert-butyl 2-oxaazaspiro[3.4]octylcarbamate (459 mg, 2.0 mmol), 4-(4-
chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (500 mg, 1.34
mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-
1,4-benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and
2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide), tri(dibenzylideneacetone)dipalladium(0)
(61.3 mg, 0.067 mmol), 2'-(dicyclohexylphosphino)-N,N-dimethyl[1,1'-biphenyl]amine (52.7
mg, 0.134 mmol), sodium tert-butoxide (192.2 mg, 2.0 mmol) and 1,4-dioxane (6 mL) was
heated with ng in a 20 mL of microwave process vial for 3 hours at 100 oC. The mixture
was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium
sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica
gel to give 700 mg of the product as a white solid, which was used for next step without further
purification.
6-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]oxa
azaspiro[3.4]octanamine
O NH2
N N
To a solution of tert-butyl 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]oxaazaspiro[3.4]octancarbamate (700 mg, 1.24 mmol) in
dichloromethane (10 mL) was added trifluoroacetic acid (5 mL) at 0 oC. The resulting mixture
was d at room temperature for further 30 minutes. The reaction was ed with a
saturated aqueous solution of sodium carbonate, and the e was extracted with
dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in
vacuo. The residue was purified by preparative HPLC to give 80 mg of the product as a white
solid. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J = 7.6 Hz, 1
H), 7.83 (d, J = 7.6 Hz, 1 H), 7.79 (s, 1 H), 7.63 (m, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.44 (m, 1
H), 7.35 (m, 1 H), 6.10 (s, 1 H), 5.17 (s, 2 H), 4.95 (d, J = 6.8 Hz, 1 H), 4.68 - 4.62 (m, 3 H),
4.50 (brs, 2 H), 4.10 (d, J = 8.8 Hz, 1 H), 3.91 - 3.81 (m, 3 H), 3.60 (m, 2 H), 3.45 (m 1 H), 2.41
(s, 3 H).
Example 24
transAmino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-
naphthyridinyl]pyrrolidinol
OH NH
N N
tert-Butyl trans[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-
naphthyridinyl]hydroxypyrrolidincarbamate
OH N
N N
S O
To a solution of -(4-chloro-1,6-naphthyridinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (300 mg, 0.84 mmol, prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-
tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-1,4-
benzothiazepine and chloro-1,6-naphthyridine) in 1,4-dioxane (5 mL) was added tert-butyl
(transhydroxypyrrolidinyl)carbamate (204 mg, 1.02 mmol),
benzylideneacetone)dipalladium(0) (39 mg, 0.042 mmol), (2'-dicyclohexylphosphanylbiphenylyl
thyl-amine (24 mg, 0.063 mmol) and sodium tert-butoxide (114 mg, 1.17
mmol) under Ar protection. The reaction mixture was heated with stirring in a 10 mL of
microwave process vial for 2 hours at 120 oC. The reaction mixture was concentrated in vacuo.
The residue was purified by preparative HPLC to give 45 mg of the desired product (yield was
%).
transAmino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-
naphthyridinyl]pyrrolidinol
HO NH
N N
To a on of tert-butyl trans[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
phthyridinyl]hydroxypyrrolidincarbamate (45 mg, 0.08 mmol) in ethyl acetate (10
mL) was added a solution of hydrochloride in ethyl acetate (4 N, 30 mL) in an ice-water bath
dropwise. After being stirred at room temperature for 4 hours, the mixture was concentrated in
vacuo. The residue was purified by ative HPLC to give the trifluoroacetic acid salt of the
desired product. The trifluoroacetic acid salt was flashed through SPE column with methanol.
The solution was concentrated in vacuo and dried by lyopylization to afford 10.9 mg of the
d product (yield was 30%). MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD)
δ ppm 9.23 (s, 1 H), 8.23 (d, J = 7.2 Hz, 1 H), 7.99 (d, J = 7.6 Hz, 1 H), 7.87 (d, J = 7.2 Hz, 1 H),
7.66 - 7.64 (m, 2 H), 7.48 (t, J = 7.6 Hz, 1 H), 6.16 (s, 1 H), 5.25 (s, 2 H), 4.70 - 4.40 (m, 3 H),
4.26 - 4.18 (m, 2 H), 3.87 - 3.85 (m, 1 H), 3.81 - 3.78 (m, 1 H), 3.71 - 3.68 (m, 1 H), 3.55 (t, J =
4.8 Hz, 2 H).
Example 25
1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]pyrrolidinamine
N N
A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (0.3 g, 0.8 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-
2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloro
methylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) and tert-butyl
pyrrolidinecarbamate (0.3 g, 1.6 mmol) was heated with stirring in a 10 mL of microwave
process vial for 1 hour at 140 oC. The resuting mixture was purified by ative HPLC and
SPE. After SPE separation, the eluent was trated in vacuo to remove the c solution.
The residue was dried by lyophylization to afford 82.9 mg of the desired product (yield was 25
%). MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 - 8.08 (dd, J =
4.0, 8.0 Hz, 1 H), 8.02 (s, 1 H), 7.85 - 7.83 (q, J = 7.6 Hz, 1 H), 7.77 - 7.70 (m, 2 H), 7.61 - 7.56
(m, 2 H), 5.90 (s, 1 H), 5.30 (s, 2 H), 4.52 (s, 2 H), 4.30 - 4.26 (m, 1 H), 4.17 - 4.11 (m, 2 H)
3.99 - 3.96 (m, 2 H), 3.74 (s, 2 H), 2.57-2.52 (m, 1 H), 2.47 (s, 3 H), 2.35 - 2.28 (m, 1 H).
Example 26-1
N-(Azetidinyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinamine
N N
S O
tert-Butyl 3-[1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
ylamino]-azetidinecarboxylate
N O
N N
A mixture of 8-(4-bromomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (900 mg, 2.16 mmol, prepared in analogy to the one in Example 2-1) and tert-butyl 3-
aminoazetidinecarboxylate (1.86 g, 10.77 mmol) was heated with stirring in a 10 mL of
microwave s vial for 1 hour at 150 oC. The resuting mixture was purified by preparative
HPLC to afford 110 mg of the desired product (yield was 7%).
N-(Azetidinyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinamine
N N
S O
To a solution of tert-butyl 3-[1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinylamino]-azetidinecarboxylate (110 mg, 0.22 mmol) in ethyl acetate (10
mL) was added a solution of hydrochloride in ethyl acetate (4 N, 30 mL) in an ice-water bath
dropwise. After being stirred at room ature for 4 hours, the mixture was concentrated in
vacuo. The residue was purified by preparative HPLC to give the trifluoroacetic acid salt of the
desired product. The trifluoroacetic acid salt was flashed h SPE column with methanol.
The solution was trated in vacuo and dried by lyopylization to afford 29 mg of the desired
t (yield was 33%). MS obsd. (ESI+) [(M+H)+] 409, 1H NMR (400 MHz, CD3OD) δ ppm
8.09 (d, J = 7.2 Hz, 1 H), 8.02 (s, 1 H), 7.84 - 7.82 (m, 1 H), 7.76 - 7.72 (m, 2 H), 7.65 - 7.60 (m,
2 H), 5.79 (s, 1 H), 5.33 (s, 2 H), 4.96 - 4.92 (m, 1 H), 4.55 - 4.50 (m, 4 H), 4.31 - 4.28 (m, 2 H),
3.76 (s, 2 H), 2.49 (s, 3 H).
Example 26-2
1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]azetidin-
3-amine
N N
The title compound was prepared in analogy to Example 26-1 in Scheme 7 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and tert-butyl azetidinylcarbamate. MS obsd. (ESI+) [(M+H)+]
409, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 - 8.00 (d, J = 7.6 Hz, 1 H), 7.87 (s, 1 H), 7.80 -
7.78 (d, J = 7.6 Hz, 1 H), 7.67 - 7.62 (m, 2 H), 7.56 - 7.50 (m, 2 H), 6.00 (s, 1 H), 5.29 (s, 2 H),
4.47 (s, 2 H), 3.97 - 3.89 (m, 3 H), 3.82 - 3.69 (m, 4 H), 2.40 (s, 3 H).
Example 27
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]prolinamide
N N
tert-Butyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]carbamoyl}pyrrolidinecarboxylate
O O
N N
To a solution of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (0.60 g, 1.6 mmol, prepared in analogy to the one in Example 2-1), tert-butyl 2-
carbamoylpyrrolidinecarboxylate (0.34 g, 1.6 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium
(II)dichloride (0.13 g, 0.16 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0.089 g,
0.16 mmol) and sodium tert-butoxide (0.307 g, 3.2 mmol) in oxane (25 mL) was heated
with ng for 1.5 hours at 120 ºC under microwave irradiation. The reaction mixture was
filtered and concentrated in vacuo. The residue was ed by preparative TLC (eluting with
50% ethyl acetate in petroleum ether, V/V=1:1) to give 250 mg of the desired product (yield was
29%).
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]prolinamide
N N
To a solution of tert-butyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]carbamoyl}pyrrolidinecarboxylate (250 mg, 0.44 mmol) in ethyl acetate
(5 mL) was added a solution of hydrochloride in ethyl acetate (4 N, 20 mL) dropwise in an ice-
water bath. After being stirred at room temperature for 14 hours, the reaction mixture was
concentrated in vacuo. The residue was purified by ative TLC to give 104.8 mg of the
d product (yield was 48%). MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, DMSO-
d6) δ ppm 7.96 (s, 1 H), 7.88 - 7.84 (m, 2 H), 7.63 - 7.59 (m, 1 H), 7.54 (s, 1 H) 7.49 - 7.44 (m, 2
H), 7.39 - 7.37 (m, 2 H), 7.00 (s, 1 H), 5.04 (s, 2 H), 4.40 (s, 2 H), 4.16 - 4.12 (t, J = 5.2 Hz, 1
H), 3.64 (s, 2 H) 3.15 - 3.01 (m, 3 H), 2.39 (s, 3 H), 2.23 - 2.20 (m, 1 H), 1.95 - 1.90 (m, 1 H),
1.80 - 1.75 (m, 1 H).
Example 28-1
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-trans-(4-fluoropyrrolidinyl)-
6-methylquinolinamine
N N
O
Benzyl trans{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin-
4-yl]amino}fluoropyrrolidinecarboxylate
F O
N O
N N
The title nd was prepared in analogy to Example 8-1 in Scheme 7 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y
to the one in Example 2-1) and benzyl transaminofluoropyrrolidinecarboxylare.
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-(transfluoropyrrolidinyl)-
6-methylquinolinamine
N N
To a suspension of benzyl trans{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]amino}fluoropyrrolidinecarboxylate (320 mg, 0.557 mmol) in
methanol (5 mL) was added an aqueous solution of potassium hydroxide (40%, 5 mL). The
suspension was heated under reflux for 30 s. The organic solvent was removed by
concentration in vacuo. The residue was ed by preparative HPLC to afford the pure product
as a solid. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (d, J =
6.57 Hz, 1 H), 7.85 (d, J = 7.33 Hz, 1 H), 7.67 (s, 1 H), 7.63 (t, J = 7.07 Hz, 1 H), 7.53 - 7.40 (m,
2 H), 7.30 (d, J = 8.84 Hz, 1 H), 6.18 (s, 1 H), 5.15 (s, 2 H), 5.10 (brs, 1 H), 4.97 (brs, 1 H), 3.60
(dd, J = 12.00, 6.44 Hz, 3 H), 3.28 (brs, 1 H), 3.23 (dd, J = 8.84, 5.31 Hz, 1 H), 3.18 - 3.12 (m, 1
H), 3.04 (dd, J = 12.00, 4.67 Hz, 1 H), 2.42 (s, 3 H).
Example 28-2
trans{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]amino}pyrrolidinol
N N
O
The title compound was prepared in analogy to Example 28-1 in Scheme 8 by using 4-(4-
bromoquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to
4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1) and benzyl transaminohydroxypyrrolidinecarboxylate. MS obsd. (ESI+)
[(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.29 - 8.22 (d, J = 7.6 Hz, 1 H), 8.12 - 8.08
(d, J = 1.2 Hz, 1 H), 7.98 - 7.92 (d, J = 7.6 Hz, 1 H), 7.88- 7.82 (d, J = 0.8 Hz, 1 H), 7.80 - 7.71
(m, 2 H), 7.62 - 7.58 (t, J = 1.2 Hz, 1 H), 7.50 - 7.42 (t, J = 6.8 Hz, 1 H), 6.20 (s, 1 H), 5.45 -
5.30 (q, J = 7.2 Hz , 2 H), 4.62 - 4.52 (m, 2 H), 4.52 - 4.45 (m, 2 H), 4.05 - 3.95 (q, J = 4.4 Hz, 1
H), 3.80 - 3.75 (t, J = 2.8 Hz, 2 H), 3.75 - 3.68 (m, 1 H), 3.62 - 3.55 (dd, J = 2.8, 12.8 Hz,1 H),
3.48 - 3.40 (d, J = 7.6 Hz, 1 H).
Example 28-3
trans{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}pyrrolidinol
N N
The title nd was prepared in analogy to Example 28-1 in Scheme 8 by using 4-(4-bromo-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in analogy
to the one in Example 2-1) and benzyl (3S,4S)aminohydroxypyrrolidinecarboxylate. MS
obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.13 - 8.10 (d, J = 7.6 Hz ,1 H),
8.06 (s, 1 H), 7.95 - 7.90 (d, J = 7.2 Hz ,1 H), 7.78 - 7.70 (m, 2 H), 7.65 - 7.58 (m, 2 H), 6.16 (s,
1 H), 5.3 (q, J = 1.2 Hz , 2 H), 4.65 - 4.40 (m, 2 H), 4.50 - 4.40 (m, 2 H), 4.12 - 3.95 (m, 1 H),
3.80 - 3.68 (m, 3 H), 3.60 - 3.50 (m, 1 H), 3.48 - 3.40 (d, J = 7.2 Hz ,1 H), 2.47 (s, 3 H).
Example 28-4
cis{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}pyrrolidinol
N N
The title compound was prepared in y to e 28-1 in Scheme 8 by using 4-(4-bromo-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to the one in Example 2-1) and benzyl cisaminohydroxypyrrolidinecarboxylate. MS
obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.12 - 8.07 (m, 2 H), 7.98 -
7.90 (d, J = 7.6 Hz, 1 H), 7.78 - 7.70 (m, 2 H), 7.63 - 7.58 (m, 2 H), 6.16 (s, 1 H), 5.41 - 5.28 (m,
2 H), 4.61 - 4.50 (m, 2 H), 4.48 (s, 2 H), 4.02 - 3.93 (q, J = 6 Hz, 1 H), 3.78 - 3.68 (m, 3 H), 3.60
- 3.50 (dd, J = 2.8, 12.8 Hz, 1 H), 3.48 - 3.40 (d, J = 3.6 Hz, 1 H), 2.46 (s, 3 H).
Example 28-5
N-[transFluoropyrrolidinyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinolinamine
N N
The title compound was prepared in analogy to Example 28-1 in Scheme 8 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide red in analogy to
the one in Example 18-1) and benzyl transaminofluoropyrrolidinecarboxylare. MS
obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 7.75 (m, 3 H), 7.50 (m, 3 H),
7.35 (d, J = 8.4 Hz, 1 H), 6.16 (brs, 1 H), 5.28 - 4.97 (m, 3 H), 4.61 (s, 1 H), 4.28 (m, 1 H), 3.64
(m,1 H), 3.47 (s, 2 H), 3.30 - 3.08 (m, 2 H), 2.43 (s, 3 H).
Example 29
4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinol
NH NH2
N N
4-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinol
N N
A mixture of 4-(4-chloromethoxyquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (5.0 g, 12.85 mmol, prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-
tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichloro
methoxyquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and hydrobromic acid (350 mL,
48%) was refluxed for 2 days. The resulting e was basified with an aqueous solution of
sodium hydroxide (4 N) to about pH 9 and extracted with ethyl acetate (250 mL × 3). The
combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue
was ed by preparative HPLC to afford 3.0 g of the desired product (yield was 62.2%).
4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
nolinol
NH NH
N N
A mixture of ro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinol
(400 mg, 1.067 mmol) and propane-1,3-diamine (158 mg, 2.134 mmol) was heated with stirring
for 1.5 hours at 150 ºC under microwave irradiation. The reacting mixture was purified by
preparative HPLC and SPE to give 118.8 mg of the desired product (yield was 27%). MS obsd.
(ESI+)[(M+H)+] 413, 1H NMR (400 MHz, CD3OD) δ ppm 8.10 - 8.05 (d, J = 7.6 Hz, 1 H), 7.85 -
7.80 (d, J = 8 Hz, 1 H), 7.71 - 7.62 (m, 2 H), 7.60 - 7.52 (t, J = 7.2 Hz, 1 H), 7.40- 7.35 (m, 1 H),
7.26 - 7.20 (dd, J = 2.8 Hz, 12.8 Hz, 1 H), 5.91 (s, 1 H), 5.27 (s, 2 H), 4.52 - 4.42 (m, 2 H), 3.72 -
3.68 (t, J = 2.8 Hz, 2 H), 3.60 - 3.52 (t, J = 6.8 Hz, 2 0 - 3.02 (t, J = 7.2 Hz, 2 H), 2.10 -
2.00 (m, 2 H);
Example 30-1
2-({4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinyl}oxy)ethanol
NH NH
N N
2-[4-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinyloxy]-
ethanol
N N
A mixture of 4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinol
(250 mg, 0. 67 mmol, prepared in analogy to the one in Example 29), 2-bromo-ethanol (166.7
mg, 1.33 mmol), and potassium carbonate (277 mg, 2.01 mmol) in acetone (30 mL) was stirred
at room temperature overnight and then refluxed for 12 hours. The reacting mixture was filtered
and trated in vacuo. The residue was ed by preparative TLC to afford 230 mg of the
d product (yield was 82%).
2-({4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinyl}oxy)ethanol
NH NH2
N N
A mixture of 2-{[4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]oxy}ethanol (250 mg, 0.6 mmol) and propane-1,3-diamine (88.8 mg, 1.2 mmol) was heated
for 1.5 hours at 150 ºC under microwave ation. The reacting mixture was purified by
preparative HPLC and SPE to afford 98.2 mg of the desired product (yield was 35.8%). MS
obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.10 - 8.02 (d, J = 8 Hz, 1 H),
7.88 - 7.80 (d, J = 7.6 Hz, 1 H), 7.77 - 7.68 (q, J = 9.6 Hz, 2 H), 7.60 - 7.50 (m, 2 H), 7.42 - 7.38
(m, 1 H), 5.94 (s, 1 H), 5.29 (s, 2 H), 4.55 - 4.42 (m, 2 H), 4.18 - 4.10 (t, J = 4.4 Hz, 2 H), 3.90 -
3.85 (t, J = 4.4 Hz, 2 H), 3.76 - 3.68 (t, J = 4.4 Hz, 2 H), 3.62 - 3.55 (t, J = 6.8 Hz, 2 H), 3.12 -
3.05 (t, J = 7.6 Hz, 2 H), 2.15 - 2.00 (m, 2 H).
Example 30-2
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(2-methoxyethoxy)quinolin-
4-yl]propane-1,3-diamine
NH NH
N N
The title compound was prepared in analogy to Example 30-1 by using 4-chloro(1,1-dioxido-
2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinol red in analogy to the one in
Example 29), 1-bromomethoxyethane and propane-1,3-diamine. MS obsd. (ESI+) +]
471, 1H NMR (400 MHz, CD3OD) δ ppm 8.10 - 8.05 (d, J = 8 Hz, 1 H), 7.90 - 7.83 (d, J = 7.6
Hz, 1 H), 7.77 - 7.68 (q, J = 9.2 Hz, 2 H), 7.60 - 7.52 (m, 2 H), 7.42 - 7.36 (m, 1 H), 5.95 (s, 1
H), 5.30 (s, 2 H), 4.56 - 4.45 (m, 2 H), 4.22 - 4.18 (t, J = 2.8 Hz, 2 H), 3.80 - 3.75 (t, J = 2.8 Hz,
2 H), 3.75 - 3.70 (t, J = 4.4 Hz, 2 H), 3.65 - 3.58 (t, J = 6.8 Hz, 2 H), 3.42 (s, 3 H), 3.15 - 3.09 (t,
J = 7.6 Hz, 2 H), 2.16 - 2.05 (m, 2 H).
Example 31
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(pyridinyloxy)quinolin
yl]propane-1,3-diamine
NH NH2
N N
8-[4-Chloro(pyridinyloxy)-quinolinyl]- 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide
N N
A mixture of ro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinol
(400 mg, 1.067 mmol), 2-bromo-pyridine (337 mg, 2.134 mmol, prepared in analogy to the one
in Example 29), copper(I) iodide (40 mg, 0.107 mmol), N,N'-dimethyl-cyclohexane-1,2-diamine
(2.0 mg, 0.107 mmol) and potassium carbonate (250 mg, 2.134 mmol) in 1,2-dimethoxyethane
(5 mL) was heated at 120 °C for 1 hour under microwave irridiation. The resulting mixture was
filtered and concentrated in vacuo. The e was purified by preparative HPLC to afford 300
mg of the desired product (yield was 62.2%).
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(pyridinyloxy)quinolin
yl]propane-1,3-diamine
NH NH2
N N
O
The title compound was prepared in analogy to e 30-1 in Scheme 9 by using 8-[4-chloro-
6-(pyridinyloxy)-quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and
propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 490, 1H NMR (400 MHz, CD3OD) δ ppm 8.10
- 8.02 (m, 2 H), 7.92 - 7.90 (m, 1 H), 7.88 - 7.80 (m, 3 H), 7.71 - 7.65 (t, J = 7.2 Hz, 1 H), 7.60-
7.48 (m, 2 H), 7.15 - 7.09 (t, J = 0.8 Hz, 1 H), 7.06 - 7.00 (d, J = 8.4 Hz, 1 H), 5.96 (s, 1 H), 5.31
(s, 2 H), 4.55 - 4.42 (m, 2 H), 3.78 - 3.69 (t, J = 2.8 Hz, 2 H), 3.60 - 3.50 (t, J = 6.8 Hz, 2 H),
3.08 - 3.00 (t, J = 7.6 Hz, 2 H), 2.10 - 2.00 (m, 2 H).
Example 32-1
3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}propane-1,2-diol
N N
A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (200.0 mg, 0.54 mmol, prepared in analogy to the one in Example 2-1) and 1-(2,2-
dimethyl-1,3-dioxolanyl)methanamine (0.5 mL, 3.8 mmol) was heated with stirring at 160 oC
for 16 hours. After being cooled to room temperature, the resulting reaction mixture was diluted
with methanol (2.0 mL). Concentrated hydrochloric acid (12.0 N, 0.5 mL) was introduced to the
above mixture. The resulting mixture was stirred at room temperature for 1 hour, and then
extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL × 2),
dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by
preparative HPLC to afford 69.2 mg of the product as a white solid (yield was 30%). MS obsd.
(ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J = 7.83, 1.26 Hz, 1 H),
7.89 (d, J = 7.33 Hz, 1 H), 7.63 (td, J = 7.45, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.50 - 7.35 (m, 2 H),
7.29 (dd, J = 8.59, 1.77 Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2 H), 4.55 (brs, 2 H), 4.04 - 3.89 (m, 1
H), 3.69 (d, J = 5.56 Hz, 2 H), 3.64 - 3.49 (m, 4 H), 2.41 (s, 3 H).
Example 32-2
3-{[6-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]amino}propane-1,2-diol
N N
O
The title compound was prepared in analogy to e 32-1 in Scheme 10 by using 4-(4,6-
roquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in analogy
to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4,6-triochloroquinoline and 5-tetrahydro-1,4-benzothiazepine) and
1-(2,2-dimethyl-1,3-dioxolanyl)methanamine. MS obsd. (ESI+) [(M+H)+] 448. 1H NMR (400
MHz, CD3OD) δ ppm 8.23 (d, J = 2.02 Hz, 1 H), 8.12 (dd, J = 7.83, 1.01 Hz, 1 H), 7.97 (d, J =
6.82 Hz, 1 H), 7.87 - 7.80 (m, 1 H), 7.80 - 7.68 (m, 2 H), 7.66 - 7.54 (m, 1 H), 6.30 (s, 1 H), 5.32
(s, 2 H), 4.56 (brs, 2 H), 4.04 - 3.83 (m, 1 H), 3.83 - 3.60 (m, 5 H), 3.54 (dd, J = 14.27, 7.20 Hz,
1 H).
Example 32-3
3-{[2-(8-Chloro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}propane-1,2-diol
N N
The title compound was prepared in analogy to e 32-1 in Scheme 10 by using 4-(4-
chloromethylquinolinyl)chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide
(prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide in e 2-1 by using 2,4-dichloromethylquinoline and 8-
chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine) and 1-(2,2-dimethyl-1,3-dioxolan
yl)methanamine. MS obsd. (ESI+) [(M+H)+] 462. 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J
= 2.27 Hz, 1 H), 7.94 (d, J = 10.36 Hz, 2 H), 7.67 - 7.82 (m, 2 H), 7.61 (dd, J = 8.59, 1.26 Hz, 1
H), 6.21 (s, 1 H), 5.28 (s, 2 H), 4.54 (brs, 2 H), 4.02 - 3.90 (m, 1 H), 3.80 (brs, 2 H), 3.76 - 3.61
(m, 3 H), 3.54 (dd, J = 14.15, 7.33 Hz, 1 H), 2.50 (s, 3 H).
Example 32-4
3-{[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
no}propane-1,2-diol
N N
The title compound was prepared in analogy to Example 32-1 in Scheme 5 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to
the one in Example 18-1) and 1-(2,2-dimethyl-1,3-dioxolanyl)methanamine. MS obsd. (ESI+)
[(M+H)+] 412, 1H NMR (400 MHz, CD3OD) δ ppm 7.78 (d, J = 7.33 Hz, 1 H), 7.74 (dd, J =
7.58, 1.26 Hz, 1 H), 7.62 (s, 1 H), 7.55 - 7.39 (m, 3 H), 7.33 (dd, J = 8.34, 1.52 Hz, 1 H), 6.13 (s,
1 H), 5.24 (dd, J = 16.04, 2.91 Hz, 2 H), 4.82 (d, J = 7.58 Hz, 1 H), 4.76 (d, J = 14.15 Hz, 2 H),
4.06 - 3.83 (m, 1 H), 3.75 - 3.63 (m, 2 H), 3.63 - 3.52 (m, 1 H), 3.45 (d, J = 3.79 Hz, 2 H), 3.37
(td, J = 6.88, 4.42 Hz, 1 H), 2.43 (s, 3 H).
Example 32-5
3-{[6-Methyl(5-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]amino}propane-1,2-diol
N N
hloromethylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine
N N
A mixture of 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.0 g, 5.58 mmol) and 2,4-
dichloromethylquinoline (1.7 g, 8.02 mmol) was heated with stirring in a 2 mL of microwave
process vial for 5 hours at 170 oC under microwave irradiation. The t was removed by
concentration in vacuo. The residue was purified by flash column chromatography to give 560
mg of the mixture of 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and hloro
methylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine.
4-(4-Chloromethylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide
N N
To a solution of the above mixture of 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 4-(4-
chloromethylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (427 mg) in
dichloromethane was added a solution of 3-chloroperbenzoic acid (693 mg, 3.01 mmol) in
dichloromethane in an ice bath. After being d for 1.5 hours in an ice bath, the reaction
mixture was washed with a saturated aqueous solution of sodium bicarbonate and brine. The
organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue
was ed by flash column chromatography to give 130 mg of the product.
3-{[6-Methyl(5-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]amino}propane-1,2-diol
N N
The title compound was prepared in analogy to Example 32-1 in Scheme 10 by using 4-(4-
chloromethylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide and
1-(2,2-dimethyl-1,3-dioxolanyl)methanamine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400
MHz, CD3OD) δ ppm 8.03 (dd, J = 7.96, 1.39 Hz, 1 H), 7.90 (d, J = 6.57 Hz, 1 H), 7.71 - 7.64
(m, 2 H), 7.46 (ddd, J = 8.15, 6.63, 1.64 Hz, 2 H), 7.33 (dd, J = 8.59, 1.77 Hz, 1 H), 6.15 (s, 1 H),
.86 (d, J = 6.82 Hz, 1 H), 4.64 - 4.53 (m, 4 H), 3.70 (d, J = 8.59 Hz, 1 H), 3.62 - 3.58 (m, 2 H),
3.57 - 3.49 (m, 1 H), 2.43 (s, 3 H), 2.00 (d, J = 7.07 Hz, 3 H).
Example 33-1
N-[(3-Aminooxetanyl)methyl](7-morpholinyl-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinamine
O NH
NH O
N N
N-{[3-(Dibenzylamino)oxetanyl]methyl}methyl[7-(morpholinyl)-1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5H)-yl]quinolinamine
O N
N O
N N
A mixture of N-{[3-(dibenzylamino)oxetanyl]methyl}methyl[7-fluoro-1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5H)-yl]quinolinamine (100 mg, 0.16 mmol, prepared in
analogy to N-{[3-(dibenzylamino)oxetanyl]methyl}(8-methoxy-1,1-dioxido-2,3-dihydro-
1,4-benzothiazepin-4(5H)-yl)methylquinolinamine in Example 1-1 by using 2,4-dichloro-
ylquinoline, 7-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and nomethyl)-N,N-
dibenzyloxetanamine) and morpholine (0.5 mL) was heated with stirring in a sealed 2 mL of
microwave process via for 3 hours at 120 ºC under microwave irradiation. The resulting mixture
was concentrated in vacuo to afford 111 mg of the crude product which was used in next step
without purification. MS obsd. (ESI+) [(M+H)+] 704.
N-[(3-Aminooxetanyl)methyl][(7-morpholinyl)-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl]methylquinolinamine
O NH
NH O
N N
A mixture of N-{[3-(dibenzylamino)oxetanyl]methyl}methyl[7-(morpholinyl)-1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolinamine (100 mg, 0.14 mmol), 10%
palladium hydroxide on active carbon (100 mg) and trifluoroacetic acid (0.5 mL) in methanol
(20 mL) was stirred for 12 hours under hydrogen (1 bar). Then the mixture was basified with a
saturated aqueous solution of sodium bicarbonate, and extracted with romethane. The
organic layer was dried over anhydrous sodium e, and concentrated in vacuo. The e
was purified by preparative HPLC to afford 30 mg of the product (yield was 40%). MS obsd.
(ESI+) [(M+H)+] 524, 1HNMR ((400 MHz, CD3OD) δ ppm 7.72 - 7.60 (m, 2 H), 7.56 (d, J =
2.27 Hz, 1 H), 7.33 (d, J = 8.34 Hz, 1 H), 7.25 (dd, J = 8.46, 1.39 Hz, 1 H), 6.85 (dd, J = 8.84,
2.53 Hz, 1 H), 6.30 - 6.03 (m, 2 H), 5.00 (brs, 2 H), 4.53 - 4.31 (m, 4 H), 3.86 - 3.68 (m, 4 H),
3.51 (d, J = 14.40 Hz, 4 H), 3.33 - 3.19 (m, 6 H), 2.41 (brs, 1 H), 2.37 (s, 3 H).
Example 33-2
N-[(3-Aminooxetanyl)methyl]{1,1-dioxido[4-(propanyl)piperazinyl]-2,3-
dihydro-1,4-benzothiazepin-4(5H)-yl}methylquinolinamine
O NH2
N N
The title compound was prepared in analogy to Example 33-1 in Scheme 11 by using N-{[3-
(dibenzylamino)oxetanyl]methyl}methyl[7-fluoro-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl]quinolinamine (prepared in analogy to the one in Example 33-1) and
4-(propanyl)piperazine. MS obsd. (ESI+) [(M+H)+] 565, 1HNMR ((400 MHz, CD3OD) δ ppm
7.82 - 7.67 (m, 2 H), 7.58 (d, J = 8.59 Hz, 1 H), 7.46 (d, J = 2.53 Hz, 1 H), 7.35 (dd, J = 8.59,
1.52 Hz, 1 H), 6.72 (dd, J = 8.97, 2.15 Hz, 1 H), 6.14 (s, 1 H), 5.11 (brs, 2 H), 4.62 (q, J = 6.57
Hz, 4 H), 4.56 - 4.36 (m, 2 H), 3.82 - 3.65 (m, 2 H), 3.54 (brs, 2 H), 3.50 - 3.39 (m, 4 H), 2.90 -
2.88 (m, 1 H), 2.88 - 2.72 (m, 4 H), 2.50 - 2.40 (m, 3 H), 1.26 - 1.11 (m, 6 H).
e 34
3-{[4-(4-Aminoquinolinyl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepin
yl]oxy}propanol
N N
4-(4-Chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepinol 1,1-dioxide
N N
O
To a stirred solution of 4-(4-chloroquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide (2.0 g, 5.15 mmol, prepared in analogy to 4-(4-chloro
methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1) in dry
methylene chloride (70.0 mL) was added a solution of boron tribromide (2.5 ml, 25.7 mmol) in
dry methylene chloride (10 ml) at 0 oC. After being stirred at 0 oC for 1 hour, the reaction was
quenched by addition of a saturated aqueous sodium bicarbonate solution (30 mL). The mixture
was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with a
saturated aqueous sodium bicarbonate solution (20 mL × 3) and brine (20 mL × 3), dried over
anhydrous sodium sulfate and concentrated in vacuo to afford 1.95 g of the crude product as a
white solid. MS obsd. (ESI+) [(M+H)+] 375.
3-{[4-(4-Chloroquinolinyl)- 1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepin
yl]oxy}propanol
N N
A mixture of 4-(4-chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepinol 1,1-dioxide
(374.0 mg, 1.0 mmol), 3-bromo-propanol (0.37 mL, 3.0 mmol) and ium carbonate
(415.0 mg, 3.0 mmol) in N, N-dimethylformamide (1.5 mL) was heated with ng at 70 oC for
2 hours. After being cooled to room ature, the ing mixture was extracted with ethyl
e (150 mL × 2). The combined organic layers were washed with water (50 mL × 2) and a
saturated aqueous ammonium chloride solution (50 mL × 2), dried over anhydrous sodium
sulfate and then concentrated in vacuo to afford 421.6 mg of the crude product as a yellow oil
which was used for next step without further cation. MS obsd. (ESI+) [(M+H)+] 433.
tert-Butyl {2-[8-(3-hydroxypropoxy)-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl]quinolinyl}carbamate
NH O
N N
A mixture solution of 3-{[4-(4-chloroquinolinyl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4-
benzothiazepinyl]oxy}propanol (300.0 mg, 0.70 mmol), tert-butyl ate (175.0 mg,
1.5 mmol), 1,1'-bis(diphenylphosphino)ferrocene (70.0 mg, 0.113 mmol), 1,1'-
bis(diphenylphosphino)ferrocenedichloropalladium(II) (70.0 mg, 0.075 mmol) and sodium tert-
butoxide (232.0 mg, 2.25 mmol) in 1,4-dioxane (2.0 mL) was heated with stirring at 120 oC for 2
hours under microwave irridiation. After being cooled to room temperature, the on mixture
was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL ×
2), dried over anhydrous sodium e and concentrated in vacuo to afford 359.1 mg of the
crude product as yellow oil which was used for next step without further purification. MS obsd.
(ESI+) [(M+H)+] 514.
3-{[4-(4-Aminoquinolinyl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepin
yl]oxy}propanol
N N
A mixture solution of tert-butyl {2-[8-(3-hydroxypropoxy)-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl]quinolinyl}carbamate (359.1 mg, the crude product of the above
step) and oroacetic acid (1.0 mL) in dichloromethane (2.0 mL) was stirred at room
temperature for 6 hours. The reaction mixture was diluted with water (10 mL) and extracted with
ethyl e (100 mL). The organic layer was washed with brine (50 mL × 2), dried over
anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative
HPLC to afford 14.2 mg of the desired product as a white solid (yield was 4.9%). MS obsd.
(ESI+) [(M+H)+] 414, 1HNMR ((400 MHz, CD3OD) δ ppm 7.82 - 7.67 (m, 2 H), 7.54 - 7.48 (m,
2 H), 7.48 - 7.39 (m, 1 H), 7.19 - 7.06 (m, 2 H), 6.30 (s, 1 H), 5.04 (s, 2 H), 4.78 - 4.34 (m, 2 H),
4.11 (t, J = 6.32 Hz, 2 H), 3.71 (t, J = 6.19 Hz, 2 H), 3.62 - 3.49 (m, 2 H), 2.11 - 1.78 (m, 2 H).
Example 35
N-[(3-Aminooxetanyl)methyl](1,1-dioxidophenoxy-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinolinamine
2 O
N N
4-(4-Chloromethylquinolinyl)phenoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide
N N
A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepinol 1,1-
dioxide (250.0 mg, 0.65 mmol, prepared in analogy to 4-(4-chloroquinolinyl)-2,3,4,5-
tetrahydro-1,4-benzothiazepinol 1,1-dioxide in Example 34), iodo-benzene (0.1 mL, 0.089
mmol), copper(I) iodide (74.0 mg, 0.35 mmol), N, N-dimethylglycine hydrochloride (72.0 mg,
0.52 mmol) and potassium carbonate (267.0 mg, 1.9 mmol) in yl sulfoxide (1.5 mL). The
reaction mixture was heated with stirring at 120 oC for 6 hours. After being cooled to room
temperature, the reaction e was extracted with ethyl acetate (150 mL × 2), washed with
water (50 mL × 2) and a ted aqueous ammonium chloride solution (50 mL × 2), dried over
anhydrous sodium sulfate and then concentrated in vacuo to afford 298.0 mg of the crude
product as a yellow oil which was used for next step without r purification. MS obsd.
(ESI+) [(M+H)+] 465.
N-{[3-(Dibenzylamino)oxetanyl]methyl}(1,1-dioxidophenoxy-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinamine
N O
N N
A mixture solution of 4-(4-chloromethylquinolinyl)phenoxy-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide ( 167.0 mg, 0.36 mmol), (3-(aminomethyl)-N,N-dibenzyloxetan
amine ( 609.0 mg, 2.16 mmol), 1,1'-bis(diphenylphosphino)-ferrocenedichloropalladium(II)
(15.0 mg, 0.02 mmol), 1,1'-bis(diphenylphosphino)-ferrocene (11.2 mg, 0.02 mmol) and sodium
tert-butoxide (75.0 mg, 0.72 mmol) in 1,4-dioxane (2.0 mL) was heated with stirring at 120 oC
for 2 hours under microwave irridiation. After being cooled to room temperature, the reaction
mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50
mL × 2), dried over ous sodium sulfate and concentrated in vacuo. The residue was
purified by ISCO combi-flash chromatography (gradient elution, 20 - 60% ethyl acetate in
petroleum ether) to afford 134.6 mg of the desired product as a light yellow solid (yield was
52.6%). MS obsd. (ESI+) [(M+H)+] 711.
N-[(3-Aminooxetanyl)methyl](1,1-dioxidophenoxy-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinolinamine
2 O
N N
A mixture of N-{[3-(dibenzylamino)oxetanyl]methyl}(1,1-dioxidophenoxy-2,3-dihydro-
1,4-benzothiazepin-4(5H)-yl)methylquinolinamine (90 mg, 0.13 mmol), palladium
hydroxide on carbon (40 mg) and oroacetic acid (0.1 mL) in methanol (30.0 mL) was
stirred at room temperature under hydrogen (2 bar) for 14 hours. Then the reaction mixture was
ed and trated in vacuo. The residue was ed by preparative HPLC to afford 10.5
mg of the desired product as a white solid (yield was 15.2%). MS obsd. (ESI+) [(M+H)+] 531, 1H
NMR (400 MHz, CD3OD) δ ppm 7.86 (d, J = 8.34 Hz, 1 H), 7.69 (s, 1 H), 7.52 (d, J = 2.53 Hz,
1 H), 7.45 (d, J = 8.59 Hz, 1 H), 7.42 - 7.35 (m, 2 H), 7.31 (dd, J = 8.46, 1.64 Hz, 1 H), 7.25 -
7.13 (m, 2 H), 7.06 - 6.97 (m, 2 H), 6.21 (s, 1 H), 5.14 (brs, 2 H), 4.70 - 4.46 (m, 6 H), 3.68 (s, 2
H), 3.60 (brs, 2 H), 2.44 (s, 3 H).
Example 36-1
N~3~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-
beta-alaninamide
N N
Methyl N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-
beta-alaninate
N N
To a solution of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin-
4-yl]-beta-alanine (85 mg, 0.2 mmol, prepared in analogy to the one in Example 14-2) in
methanol (10 mL) at 0 °C was added thionyl chloride (1.5 mL) carefully. The mixture was
stirred at room ature for 20 minutes, and then refluxed at 80 °C for 2 hours. After being
cooled to room ature, the mixture was concentrated in vacuo. The residue was dissolved
in dichloromethane, washed with a saturated s solution of sodium onate, water and
brine, then dried over sodium sulfate, and concentrated in vacuo to afford the crude product
which was directly used for the next step without further purification.
N~3~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-
beta-alaninamide
N N
O
A mixture of methyl N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]-beta-alaninate and a solution of ammonia in methanol (7 N, 10 mL) was
heated with stirring at 85 °C in a sealed tube overnight. The resulting mixture was concentrated
in vacuo. The residue was purified by preparative HPLC to afford 59.2 mg of the d product
as a solid. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (d, J =
6.82 Hz, 1 H), 7.88 (dd, J = 7.83, 1.26 Hz, 1 H), 7.66 - 7.60 (m, 2 H), 7.50 - 7.42 (m, 2 H), 7.31
(d, J = 8.59 Hz, 1 H), 7.22 (dd, J = 8.46, 1.64 Hz, 1 H), 6.97 (brs, 1 H), 6.73 (t, J = 5.68 Hz, 1
H), 6.06 (s, 1 H), 5.06 (brs, 2 H), 4.40 (brs, 2 H), 3.68 - 3.56 (m, 2 H), 3.51 (q, J = 6.65 Hz, 2 H),
2.42 (t, J = 7.07 Hz, 2 H), 2.34 (s, 3 H).
Example 36-2
(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}butanamide
N N
O
The title compound was prepared in analogy to Example 36-1 in Scheme 13 by using 3-{[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]amino}butanoic acid
(prepared in analogy to N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]-beta-alanine in Example 14-2). MS obsd. (ESI+) [(M+H)+] 439, 1H NMR
(400 MHz, CD3OD) δ ppm 8.07 (dd, J = 7.83, 1.26 Hz, 1 H), 7.98 (d, J = 7.6 Hz, 1 H), 7.95 (brs,
1 H), 7.74 - 7.66 (m, 2 H), 7.62 - 7.51 (m, 2 H), 6.14 (s, 1 H), 5.29 (s, 2 H), 4.43 - 4.64 (m, 2 H),
4.38 (q, J = 8Hz, 1 H), 3.72 (brs, 2 H), 2.68 (dd, J = 14.65, 5.56 Hz, 1 H), 2.54 (dd, J = 14.65,
7.07 Hz, 1 H), 2.46 (s, 3 H), 1.41 (d, J = 6.32 Hz, 3 H).
Example 36-3
3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]amino}-
2-methylpropanamide
N N
The title compound was prepared in analogy to Example 36-1 by using 3-{[2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]amino}methylpropanoic acid
(prepared in analogy to N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]-beta-alanine in e 14-2). MS obsd. (ESI+) [(M+H)+] 439, 1H NMR
(400 MHz, DMSO-d6) δ ppm 8.17 (s, 1 H), 7.99 - 7.82 (m, 2 H), 7.72 - 7.57 (m, 2 H), 7.54 -
7.43 (m, 1 H), 7.38 (brs, 1 H), 7.32 (d, J = 8.34 Hz, 1 H), 7.23 (dd, J = 8.59,1.52 Hz, 1 H), 6.94
(s, 1 H), 6.03 (s, 1 H), 5.08 (brs, 2 H), 4.52 (brs, 3 H), 4.30 (brs, 1 H), 3.70 - 3.55 (m, 2 H), 3.50
(dt, J = 13.26, 6.51 Hz, 2 H), 3.25 - 3.15 (m, 2 H), 2.67 (q, J = 6.91 Hz, 1 H), 2.41 - 2.26 (m, 3
H), 1.13 (d, J = 7.07 Hz, 3 H).
Example 36-4
N~2~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-L-
alaninamide
N N
The title compound was prepared in analogy to Example 36-1 by using 1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-L-alanine (prepared in analogy to
N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-beta-
alanine in Example 14-2). MS obsd. (ESI+) +] 425, 1H NMR (400 MHz, DMSO-d6) δ
ppm 7.91 - 7.81 (m, 3 H), 7.68 (s, 1 H), 7.54 (brs, 1 H), 7.48 (d, J = 7.33 Hz, 1 H), 7.33 (d, J =
8.34 Hz, 1 H), 7.26 (d, J = 8.08 Hz, 1 H), 7.18 (brs, 1 H), 6.61 (d, J = 6.32 Hz, 1 H), 5.89 (s, 1
H), 4.99 (brs, 2 H), 4.08 (brs, 2 H), 3.59 (brs, 3 H), 2.35 (brs, 3 H), 1.49 (d, J = 6.82 Hz, 3 H).
Example 36-5
N~2~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]glycinamide
N N
The title nd was prepared in analogy to e 36-1 by using N~2~-[2-(1,1-Dioxido-
2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]glycine (prepared in analogy to
N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-beta-
alanine in Example 14-2). MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, DMSO-d6) δ
ppm 7.87 (d, J = 7.83 Hz, 1 H), 7.82 (d, J = 7.33 Hz, 1 H), 7.74 - 7.64 (m, 2 H), 7.52 - 7.41 (m,
2 H), 7.36 - 7.30 (m, 1 H), 7.30 - 7.19 (m, 2 H), 7.10 (t, J = 5.56 Hz, 1 H), 5.87 (s, 1 H), 5.00 (brs,
2 H), 3.86 (d, J = 5.81 Hz, 2 H), 3.59 (brs, 2 H), 3.32 (s, 2 H), 2.41 - 2.32 (s, 3 H).
Example 36-6
N~2~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N-
methylglycinamide
N N
The title compound was prepared in analogy to Example 36-1 by using 2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]glycine (prepared in analogy to N-
[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-beta-alanine
in Example 14-2) and a solution of methylamine in ethanol. MS obsd. (ESI+) [(M+H)+] 425, 1H
NMR (400 MHz, DMSO-d6) δ ppm 7.90 - 7.82 (m, 2 H), 7.77 (d, J = 7.58 Hz, 1 H), 7.70 (s, 1
H), 7.61 (td, J = 7.45, 1.52 Hz, 1 H), 7.51 - 7.46 (m, 1 H), 7.34 (d, J = 8.34 Hz, 1 H), 7.26 (dd, J
= 8.46, 1.64 Hz, 1 H), 7.15 (t, J = 5.94 Hz, 1 H), 5.86 (s, 1 H), 5.00 (brs, 2 H), 3.90 (d, J = 5.81
Hz, 2 H), 3.59 (brs, 2 H), 3.32 (s, 2 H), 2.62 (d, J = 4.55 Hz, 3 H), 2.37 (s, 3 H).
Example 37-1
(2S)Amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]amino}propanol
N N
tert-Butyl (2S)({[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]amino}methyl)-2,2-dimethyl-1,3-oxazolidinecarboxylate
N N
A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (332 mg, 0.890 mmol), tert-butyl (2S)aminomethyl-2,2-dimethyl-1,3-oxazolidine
carboxylate (205 mg, 0.890 mmol), 1,1'-bis(diphenylphosphino)ferrocene-
palladium(II)dichloride (73 mg, 0.089 mmol), 1,1'-bis(diphenylphosphino)ferrocene (49 mg,
0.089 mmol), sodium tert-butoxide (171.1 mg, 1.780 mmol) and 1,4-dioxane (4 mL) was heated
at 120 ºC for 1.5 hours under microwave irradiation. The reaction mixture was concentrated in
vacuo. The residue was purified by flash column tography to afford 251 mg of the
desired t.
(2S)Amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]amino}propanol
N N
A mixture of tert-butyl 4-({[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]amino}methyl)-2,2-dimethyl-1,3-oxazolidinecarboxylate (251 mg) and a
solution of hloride in ethyl acetate (13 mL, 4 N) was d at room temperature
overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved in water,
and basified with a saturated s solution of sodium bicarbonate to about pH 9, and
extracted with ethyl acetate ( 20 mL × 3). The combined organic layers were washed with brine,
dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by
preparative HPLC to give 74.6 mg of the desired product as a white solid. MS obsd. (ESI+)
[(M+H)+] 427, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (dd, J = 1.2, 8.0 Hz, 1 H), 7.98 (d, J =
7.2 Hz, 1 H), 7.86 (s, 1 H), 7.72 - 7.66 (m, 2 H), 7.55 - 7.46 (m, 2 H), 6.20 (s, 1 H), 5.31 (s, 2 H),
4.57 (s, 2 H), 3.93 - 3.62 (m, 7 H), 2.47 (s, 3 H).
Example 37-2
(2R)Amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]amino}propanol
N N
The title compound was prepared in analogy to e 37-1 in Scheme 14 by using 4-(4-
chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide, tert-butyl
(2R)aminomethyl-2,2-dimethyl-1,3-oxazolidinecarboxylate. MS obsd. (ESI+) [(M+H)+]
427, 1H NMR (400 MHz, CD3OD) δ ppm 8.02 (d, J = 6.8 Hz, 1 H), 7.96 (d, J = 8.4 Hz, 1 H),
7.80 (s, 1 H), 7.68 (dd, J = 6.0, 7.6 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.50 (m, 1 H), 7.41 (d, J =
8.4 Hz, 1 H), 6.19 (s, 1 H), 5.27 (s, 2 H), 4.57 (s, 2 H), 3.92 - 3.60 (m, 7 H), 2.45 (s, 3 H).
Example 38-1
N-[(2-Amino-4,5-dihydro-1,3-oxazolyl)methyl](1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinamine
N N
A mixture of 1-amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]amino}propanol (80 mg, 0.18 mmol, prepared in analogy to Example 9-
7) and potassium e (89 mg, 0.91 mmol ) in a mixture solution of methanol and water (7 ml,
V/V = 6/1) was added cyanogen bromide (89 mg, 0.84 mmol ) at 0 ºC. After being stirred at
room temperature for 3 hours, the mixture was stirred further with concentrated hloric
acid (3 mL) for 1 hour, and then concentrated in vacuo. The residue was dissolved in a saturated
aqueous solution of sodium bicarbonate (10 mL) and extracted with romethane (15 mL ×
3). The combined organic layers were dried over sodium e and concentrated in vacuo. The
residue was purified by flash column (10% methanol in dichloromethane) to afford 32 mg of the
desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, DMSO-
d6) δ ppm 7.92 - 7.87 (m, J = 4.6 Hz, 2 H), 7.72 (s, 1 H), 7.65 - 7.62 (t, J = 3.7 Hz, 1 H), 7.49 -
7.45 (t, J = 3.9 Hz, 1 H), 7.32 (d, J = 2.1 Hz, 1 H), 7.23 (d, J = 2.1 Hz, 1 H), 6.85 (t, J = 2.6 Hz,
1 H), 6.46 (brs, 2 H), 6.10 (s, 1 H), 5.10 (s, 2 H), 4.82 - 4.77 (m, J = 4.8 Hz, 1 H), 4.49 (brs, 2
H), 3.75 (m, 1 H), 3.63(s, 2 H), 3.52 (m, 3 H), 2.35 (s, 3 H).
Example 38-2
N-[(2-Aminomethyl-4,5-dihydro-1,3-oxazolyl)methyl](1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinamine
N 2
N N
To a mixture of 1-amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]amino}methylpropanol (200 mg, 0.45 mmol, prepared in analogy to
Example 11-4) and potassium acetate (240 mg, 2.4 mmol) in methanol (8 mL) and water (2 mL)
which was cooled to 0 ºC, a cooled solution of cyanogen bromide (52.3 mg, 0.5 mmol) in
methanol (2 mL) was added. After being stirred at room temperature for 4 hours, the reaction
e was concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL), washed
with water (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel to give 80 mg of the product as a white powder.
MS obsd. (ESI+) [(M+H)+] 466, 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (d, J = 7.6 Hz, 1 H),
7.83 (d, J = 7.2 Hz, 1 H), 7.60 (m, 2 H), 7.46 - 7.39 (m, 2 H), 7.29 (dd, J = 1.6, 8.8 Hz, 1 H),
6.19 (s, 1 H), 5.18 - 5.09 (m, 2 H), 4.51 (brs, 2 H), 3.82 (d, J = 11.2 Hz, 1 H), 3.65 (s, 2 H), 2.57
(m, 3 H), 2.41 (s, 3 H), 1.62 (s, 3 H).
Example 38-3
R)Amino-4,5-dihydro-1,3-oxazolyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-
hiazepin-4(5H)-yl)methylquinolinamine
N N
The title compound was prepared in analogy to Example 38-1 in Scheme 15 by using (2R)
amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}propanol red in analogy to Example 37-2). MS obsd. (ESI+) [(M+H)+] 452,
1H NMR (400 MHz, CD
3OD) δ ppm 7.98 (d, J = 7.2 Hz, 1 H), 7.87 (d, J = 7.2 Hz, 1 H), 7.64 -
7.58 (m, 2 H), 7.47 - 7.41 (m, 2 H), 7.28 (dd, J = 2.0, 8.8 Hz, 1 H), 6.09 (s, 1 H), 5.16 (s, 2 H),
4.58 (brs, 2 H), 4.40 (t, J = 8.0 Hz, 1 H), 4.29 (td, J = 5.6, 12.8 Hz, 1 H), 4.20 (dd, J = 6.0, 8.0
Hz, 1 H), 3.58 (t, J = 4.8 Hz, 2 H), 3.45 - 3.35 (m, 2 H), 2.42 (s, 3 H).
Example 38-4
N-{[(4S)Amino-4,5-dihydro-1,3-oxazolyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinamine
N N
The title compound was prepared in analogy to Example 38-1 in Scheme 15 by using (2S)
amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}propanol (prepared in y to Example 37-1). MS obsd. (ESI+) [(M+H)+] 452,
1H NMR (400 MHz, CD
3OD) δ ppm 7.98 (d, J = 7.2 Hz, 1 H), 7.87 (d, J = 7.2 Hz, 1 H), 7.64 -
7.58 (m, 2 H), 7.47 - 7.41 (m, 2 H), 7.28 (dd, J = 2.0, 8.8 Hz, 1 H), 6.09 (s, 1 H), 5.16 (s, 2 H),
4.58 (brs, 2 H), 4.40 (t, J = 8.0 Hz, 1 H), 4.29 (td, J = 5.6, 12.8 Hz, 1 H), 4.20 (dd, J = 6.0, 8.0
Hz, 1 H), 3.58 (t, J = 4.8 Hz, 2 H), 3.45 - 3.35 (m, 2 H), 2.42 (s, 3 H).
Example 38-5
cis[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-
4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazolamine
N O
N N
To a mixture of cisamino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]pyrrolidinol (90 mg 0.20 mmol, ed in analogy to Example 19-3 in
Scheme 7 by using 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine
1,1-dioxide and tert-butyl [cishydroxypyrrolidinyl]carbamate) and sodium acetate (82 mg,
1.0 mmol) in ol (10 mL) at 0 °C was added cyanogen bromide (105 mg, 1 mmol). The
mixture was stirred overnight gradually from 0 °C to room temperature, and then concentrated in
vacuo. The residue was purified by preparative HPLC to afford the pure product as a solid. MS
obsd. (ESI+) [(M+H)+] 464, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (d, J = 7.33 Hz, 1 H), 7.98
(d, J = 7.58 Hz, 1 H), 7.89 (brs, 1 H), 7.79 - 7.70 (m, 2 H), 7.66 - 7.56 (m, 2 H), 6.50 (s, 1 H),
.89 - 5.84 (m, 1 H), 5.41 (brs, 2 H), 4.97-5.02 (m, 1 H), 4.63 (brs, 2 H), 4.31 (brs, 1 H), 4.12
(brs, 1 H), 3.77 (brs, 2 H), 3.62 - 3.42 (b, 2 H), 2.54 - 2.48 (m, 3 H).
Example 39
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinamine
N N
2-{[(1E)(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethylidene]amino}
methylbenzonitrile
N N
To a d solution of 1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (6.0 g,
.0 mmol) in dry dichloromethane (100 mL) was added phosphorus oxychloride (2.5 mL, 27.3
mmol) at 10 ºC. After being stirred for 20 minutes at room temperature, a solution of 2-amino
methylbenzonitrile (3.3 g, 25.0 mmol) in dry dichloromethane (40 mL) was added and the
resulting suspension was heated under reflux for 24 hours. After being cooled to room
ature, the reaction mixture was diluted with water (50 mL), ed with a saturated
aqueous solution of sodium bicarbonate to about pH 8. The ted aqueous layer was
extracted with dichloromethane (100 mL). The combined organic layers were washed with brine,
dried over sodium sulfate and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (eluting with 16% ethyl acetate in petroleum ether) to give 1.5 g of
the product as a white solid.
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinamine
N N
A mixture of 2-{[(1E)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)ethylidene]amino}methylbenzonitrile (1.5 g, 4.24 mmol), zinc chloride (578 mg, 4.24
mmol) and N,N-dimethylacetamide (4 mL) was heated with stirring at 160 ºC for 3 hours under
argon. After the reaction e was cooled to about 40 ºC, an aqueous solution of sodium
hydroxide (2 N, 20 mL) was introduced. After being stirred for 10 minutes at room temperature,
the reaction mixture was poured into water. The formed solid was collected by filtration, and
dried in vacuo to give 1.5 g of the product as a brown powder. MS obsd. (ESI+) +] 354,
1H NMR (400 MHz, DMSO-d6) δ ppm 7.90 - 7.84 (m, 2 H), 7.66 - 7.62 (m, 2 H), 7.48 (t, J = 7.2
Hz, 1 H), 7.32 (d, J = 8.4 Hz, 1 H), 7.23 (dd, J = 1.6, 8.8 Hz, 1 H), 6.29 (s, 2 H), 6.23 (s, 1 H),
4.97 (s, 2 H), 4.36 (brs, 2 H), 3.60 (t, J = 4.8 Hz, 2 H), 2.34 (s, 3 H).
Example 40-1
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]glycinamide
N N
O
2-Chloro-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]acetamide
N N
To a on of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
amine (500 mg, 1.4 mmol) in chloroform (10 mL) was added 1,8-diazabicyclo[5.4.0]undec
ene (0.41 mL, 2.8 mmol) followed by chloroacetyl chloride (0.17 mL, 2.1 mmol) at room
temperature. The resulting on was heated with stirring at 70 ºC for 2 hours under nitrogen.
After being cooled to room temperature, the reaction was diluted with ethyl acetate (50 mL),
washed with water (50 mL × 3), dried over sodium sulfate and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (eluting with 25% ethyl acetate in
petroleum ether) to give 120 mg of the product as an ite solid.
2-Azido-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]acetamide
NH 3
N N
To a on of 2-chloro-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]acetamide (120 mg, 0.28 mmol) in acetonitrile (3 mL) was added sodium
azide (72 mg, 1.1 mmol). The resulting mixture was stirred at room temperature for 6 hours. The
reaction was d with ethyl acetate (20 mL), washed with water (10 mL), dried over sodium
sulfate, and trated in vacuo. The residue was purified by column chromatography on silica
gel (20% ethyl acetate in petroleum ether) to give 110 mg of the product as a white powder.
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]glycinamide
N N
To a solution of 2-azido-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]acetamide (110 mg, 0.25 mmol) in methanol was added 10% palladium on
carbon (507 mg). After being stirred at room temperature overnight under a hydrogen
atmosphere, the resulting mixture was filtered. The filtrate was concentrated in vacuo. The
residue was purified by preparative HPLC to afford 30 mg of the product as a white powder. MS
obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 8.51 (s, 1 H), 8.12 (s, 1 H),
8.07 (d, J = 7.6 Hz, 1 H), 8.00 (d, J = 7.6 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.67 - 7.12 (m, 2
H), 7.57 (t, J = 8.0 Hz, 1 H), 5.31 (s, 2 H), 4.66 (brs, 2 H), 4.25 (s, 2 H), 3.78 (s, 2 H), 2.52 (s, 3
H).
Example 40-2
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]
alaninamide
N N
2-Bromo-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]methylpropanamide
N N
To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
amine (200 mg, 0.566 mmol) in chloroform (10 mL) was added triethylamine (0.124 mL),
followed by 2-bromomethylpropionyl chloride (286 mg, 1.30 mmol). The resulting mixture
was heated at 110 ºC for 2 hours under microwave irradiation. After being cooled to room
temperature, the mixture was trated in vacuo. The residue was diluted with ethyl acetate
(35 mL), washed with brine and dried over sodium sulfate, and concentrated in vacuo. The
residue was purified by flash chromatography to afford 180 mg of the title compound as a light
solid (yield was 63%).
2-Azido-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]methylpropanamide
O N
N N
To a solution of 2-bromo-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]methylpropanamide (160 mg, 0.319 mmol) in actonitrile (15 mL) was
added sodium azide (62 mg, 0.958 mmol). After being refluxed ght, the ing mixture
was concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL), washed with
brine, dried over sodium sulfate, and concentrated in vacuo to afford 160 mg of the crude
product.
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]
methylalaninamide
N N
To a on 2-azido-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]methylpropanamide (160 mg, 0.345 mmol) in ethyl acetate (25 mL) was
added 10% palladium on carbon (100 mg), the flask was degassed and refilled with hydrogen
(repeated for three times). After being stirred at room temperature overnight under a hydrogen
here, the resulting mixture was filtered. The filtrate was concentrated in vacuo. The
residue was purified by flash chromatography to afford 110 mg of the title compound (yield was
73%). MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CDCl3) δ ppm 11.05 (s, 1 H), 8.30
(s, 1 H), 8.02 (dd, J = 0.8, 7.6 Hz, 1 H), 7.89 (d, J = 7.2 Hz, 1 H), 7.59 (d, J = 8.8 Hz, 1 H), 7.53
(t, J = 7.6 Hz, 1 H), 7.37 (m, 3 H), 5.17 (s, 2 H), 4.6 (brs., 2 H), 3.56 (s, 2 H), 2.48 (s, 3 H), 1.56
(s, 6 H).
Example 40-3
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]alaninamide
N N
The title compound was prepared in analogy to e 40-2 in Scheme 18 by using 2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinamine, 2-bromopropionyl
chloride and sodium azide. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm
8.07 - 7.85 (m, 3 H), 7.64 - 7.51 (m, 2 H), 7.46 - 7.35 (m, 2 H), 5.22 - 5.08 (m, 2 H), 4.51 - 4.42
(m, 1 H), 3.65 - 3.53 (m, 2 H), 3.37 (s, 3 H), 2.51 - 2.40 (m, 3 H), 1.73 (d, J = 7.07 Hz, 1 H),
1.30 (d, J = 2.78 Hz, 2 H).
Example 40-4
2-Amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]butanamide
N N
O
The title compound was prepared in analogy to Example 40-2 in Scheme 18 by using 2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinamine, 2-bromobutyryl
chloride and sodium azide. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm
8.07 (m, 3 H), 7.53 (m, 2 H), 7.45 (m, 2 H), 5.33 (m, 2 H), 4.32 (m, 1 H), 3.59 (m, 2 H), 3.37 (s,
3 H), 2.44 (m, 2 H), 1.70 (d, J = 8.02 Hz, 1 H), 1.38 (d, J = 2.56 Hz, 2 H), 1.22 (m, 3 H).
e 41
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]
methoxymethylpropanamide
N N
To a solution of 2-bromo-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]methylpropanamide (80 mg, 0.159 mmol, prepared in e 40-2) in
methanol (5 mL) was added ethylamine (1 mL), the resulting mixture was heated under reflux
overnight. After being cooled to room temperature, the resulting mixture was concentrated in
vacuo. The e was purified by preparative TLC (eluting with 33% ethyl e in hexanes)
to afford 15 mg of the title compound as a light powder (yield was 21%). MS obsd. (ESI+)
[(M+H)+] 454, 1H NMR (400 MHz, CD3OD) δ ppm 7.94 -7.89 (m, 3 H), 7.58 (m, 2 H), 7.43 -
7.39 (m, 3 H), 5.17 (s, 2 H), 4.50 (brs, 2 H), 3.59 (m, 2 H), 3.50 (s, 3 H), 2.46 (s, 3 H), 1.56 (s, 6
H).
Example 42-1
N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-
4,4,4-trifluorobutane-1,3-diamine
NH NH2
N N
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl](1,3-
dioxo-1,3-dihydro-2H-isoindolyl)-4,4,4-trifluorobutanamide
O N O
NH O
N N
To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
amine (200 mg, 0.565 mmol, prepared in analogy to the one in Example 2-1) in N,N-
dimethylformamide (6 mL) was added a solution of 3-(1,3-dioxo-1,3-dihydro-2H-isoindolyl)-
4,4,4-trifluorobutanoyl chloride (670 mg, 2.3 mmol) in dichloromethane (4 mL) followed by
isopropylethylamine (0.3 mL). The resulting mixture was stirred at room temperature for
1 hour and heated at 85 ºC for onal 2 hours. After being cooled to room temperature, the
resulting mixture was evaporated in vacuo. The residue was diluted with water and extracted
with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine, dried over
sodium sulfate and concentrated in vacuo. The residue was purified by flash tography to
afford 230 mg of the product as a solid (yield was 66%).
3-Amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]-4,4,4-trifluorobutanamide
NH O
N N
O
To a solution of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin-
4-yl](1,3-dioxo-1,3-dihydro-2H-isoindolyl)-4,4,4-trifluorobutanamide (25 mg, 0.04 mmol)
in ethanol (3 mL) was added a solution of methylamine (30% in ethanol, 0.3 mL). The resulting
mixture was heated at 90 ºC for 2 hours. After being cooled to room temperature, the mixture
was trated in vacuo. The residue was purified by flash chromatography (eluting with 50%
ethyl acetate in hexanes) to afford 15 mg of the title compound as light solid (yield was 80%).
N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-
4,4,4-trifluorobutane-1,3-diamine
NH NH
N N
To a solution of 3-amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
quinolinyl]-4,4,4-trifluorobutanamide (120 mg, 0.245 mmol) was added a solution of
borane-methyl sulfide complex in methyl sulfide (5 M, 1.0 mL). The ing solution was
heated at 85 ºC for 2 hours. After being cooled to room temperature, the mixture was acidified
by careful addition of an aqueous solution of hydrochloric acid (1 M) to about pH 4, and then
stirred at room temperature ght. The resulting mixture was concentrated in vacuo. The
residue was neutralized with a 10% aqueous solution of sodium hydroxide to pH >9, and then
extracted with romethane (20 mL × 3). The combined organic layers were washed with
brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash
chromatography to afford 60 mg of the title product as a solid (yield was 65%). MS obsd. (ESI+)
[(M+H)+] 479, 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (d, J = 7.6 Hz, 1 H), 7.65(d, J = 7.6 Hz,
1 H), 7.50 - 7.49 (m, 2 H), 7.38 (t, J = 7.2 Hz, 1 H), 7.30 (m, 1 H), 6.06 (s, 1 H), 5.93 (s, 1 H),
.12 (s, 1 H), 3.63 (m, 3 H), 4.62 (brs, 2 H), 3.45 (m, 1 H), 3.33 (m, 1 H), 2.42 (s, 3 H), 2.22 (m,
1 H), 2.03 (s, 1 H), 1.82 (m, 1 H).
Example 42-2
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-beta-
alaninamide
NH O
N N
The title compound was ed in analogy to 3-amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinyl]-4,4,4-trifluorobutanamide in Example 42-1 in
Scheme 19 by using 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin-
4-amine and 3-(1,3-dioxo-1,3-dihydro-2H-isoindolyl)propanoyl chloride. MS obsd. (ESI+)
[(M+H)+] 425, 1H NMR (400 MHz, CDCl3) δ ppm 8.00 (d, J = 7.83 Hz, 1 H), 8.29 (s, 1 H), 7.85
(d, J = 7.33 Hz, 1 H), 7.61 - 7.47 (m, 4 H), 7.34 (d, J = 12.13 Hz, 2 H), 5.12 (s, 2 H), 3.55 (brs, 2
H), 3.23 (d, J = 5.56 Hz, 2 H), 2.62 (brs, 2 H), 2.44 (brs, 3 H), 1.66 - 2.10 (m, 2 H).
Example 43
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-{[3-(ethylamino)oxetan
yl]methyl}methylquinolinamine
O N
N N
To a stirred solution of N-[(3-aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-
hiazepin-4(5H)-yl)methylquinolinamine (200 mg, 0.46 mmol, prepared in analogy
to Example 2-2), acetaldehyde (25.6 µL, 0.46 mmol) and acetic acid (270 µL) in methanol (8
mL) was added dropwize a solution of sodium cyanoborohydride (34 mg, 0.54 mmol) in
tetrahydrofuran (0.5 mL). After being stirred for 12 hours at room temperature, the on
mixture was diluted with ethyl acetate, washed with water and a saturated aqueous solution of
sodium bicarbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was
purified by preparative HPLC to afford 42 mg of the desired product as a white solid (yield was
%). MS obsd. (ESI+) [(M+H)+] 467, 1H NMR(400 MHz, 6) δ ppm 7.95 (d, J = 1.9
Hz, 1 H), 7.89 - 7.87 (t, J = 2.2 Hz, 1 H), 7.64 - 7.58 (m, J = 6.0 Hz, 2 H),7.49 - 7.45 (m, J = 4.0
Hz, 1 H), 7.35 (d, J = 2.1 Hz, 1 H), 7.27 - 7.24 (m, J = 2.5 Hz, 1 H), 6.17 (s, 1 H), 5.11 (s, 2 H),
4.52 (d, 2 H), 4.37 (d, 4 H), 3.62 - 3.45 (t, J = 2.4 Hz, 2 H ), 3.58 (d, 2 H ), 2.53 (m, 2 H), 2.37
(s, 3 H), 1.07 -1.03 (t, J = 3.6 Hz, 3 H ).
Example 44-1
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[1-(oxetan
yl)pyrrolidinyl]quinolinamine
N O
N N
To a solution of [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-
(pyrrolidinyl)quinolinamine (21 mg, 0.05 mmol, prepared in analogy to Example 21-4) and
oxetanone (7.2 mg, 0.10 mmol) in tetrahydrofuran (2 mL) was added acetic acid (8.6 µL, 0.15
mmol). After the mixture being stirred at 55 ºC for 1 hour, sodium triacetoxyborohydride (21
mg, 0.10 mmol) was added to the mixture. After being stirred for 2 hours at 65 ºC, the reaction
mixture was concentrated in vacuo. The residue was portioned between ethyl acetate and a
saturated aqueous solution of sodium carbonate. The ted organic layer was washed with
water, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by
ative HPLC to afford 10 mg of the t as a white solid. MS obsd. (ESI+) [(M+H)+]
479, 1H NMR (400 MHz, CD3OD) δ ppm 8.30 (d, J = 1.9 Hz, 1 H), 7.84 (d, J = 1.8Hz, 1 H),
7.78 (s, 1 H), 7.68 - 7.64 (t, J = 3.7 Hz, 1 H), 7.53 - 7.49 (t, J = 3.7 Hz, 2 H), 7.39 (d, J = 1.7 Hz,
1 H), 5.98 (s, 1 H), 5.20 (s, 2 H), 4.83 - 4.78 (m, J = 4.7 Hz, 2 H), 4.69 - 4.60 (m, J = 8.4 Hz, 2
H), 4.55 (brs, 2 H), 4.37 (s, 1 H), 3.80 - 3.74 (m, J = 4.1 Hz, 1 H), 3.65 - 3.61 (m, J = 4.2 Hz, 2
H), 2.96 - 2.89 (m, J = 6.6 Hz, 2 H), 2.75 - 2.72 (m, J = 3.3 Hz, 1 H), 2.63 - 2.47 (m, J = 15.9
Hz, 2 H), 2.45(s, 3 H), 1.95 (m, 1 H).
Example 44-2
N'-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-N-
ethyl-N-(oxetanyl)ethane-1,2-diamine
N N
The title compound was prepared in analogy to Example 44-1 in Scheme 20 by using N-[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'-ethylethane-1,2-
diamine (prepared in analogy to Example 3-37) and oxetanone. MS obsd. (ESI+) [(M+H)+]
481, 1H NMR (400 MHz, CD3OD) δ ppm 8.02 (d, J = 7.6 Hz, 1 H), 7.87 (d, J = 7.2 Hz, 1 H),
7.66 (t, 2 H), 7.50 (t, 2 H), 7.36 (d, J = 7.6 Hz, 1 H), 6.04 (s, 1 H), 5.20 (s, 2 H), 4.68 - 4.50 (m, 6
H), 4.07 - 4.00 (m, 1 H), 3.65 (s, 2 H), 3.45 (t, J = 12.4 Hz, 2 H), 2.84 (t, J = 12.8 Hz, 2 H), 2.73
- 2.67 (m, 2 H), 2.45 (s, 3 H), 1.07 (t, 3 H).
Example 45-1
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'-
(oxetanyl)propane-1,3-diamine
NH N
N N
To a stirred of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]propane-1,3-diamine (84 mg, 0.2 mmol, prepared in y to Example 9-3), oxetanone
(15 mg, 0.21 mmol ) and ethyldiisopropylamine (43 µL, 0.25 mmol ) in dichloromethane (10
mL) was added molecular sieves (4Å, 84 mg) followed by sodium triacetoxyborohydride (63.6
mg, 0.3 mmol). After being stirred at room temperature overnight, r batch of sodium
triacetoxyborohydride (63.6 mg, 0.3 mmol) was added and the mixture was heated under reflux
for 2 hours. The reaction mixture was cooled, washed with brine, dried over sodium sulfate and
concentrated in vacuo. The residue was purified by preparative HPLC to afford 26 mg of N-[2-
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'-(oxetan
yl)propane-1,3-diamine as a white solid. MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz,
CD3OD) δ ppm 8.05 (d, J = 7.6 Hz, 1 H), 7.87 (d, J = 7.6 Hz, 1 H), 7.34 (s, 1 H), 7.68 (t, J =
14.8 Hz, 1 H), 7.58 - 7.51 (m, 2 H), 7.45 (d, 1 H), 5.99 (s, 1 H), 5.24 (s, 2 H), 4.85 (t, J = 3.3 Hz,
2 H), 4.85 (t, J = 13.6 Hz, 2 H), 4.55 (m, 4 H), 4.06 - 4.00 (m, 1 H), 3.67 (s, 2 H), 3.50 (t, J =
13.2 Hz, 2 H), 2.74 (t, J = 13.6 Hz, 2 H), 2.45 (s, 3 H), 1.98 - 1.91 (m, 2 H).
Example 45-2
1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-N-
(oxetanyl)pyrrolidinamine
N N
The title compound was prepared in analogy to e 45-1 in Scheme 20 by using 1-[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]pyrrolidinamine
and oxetanone (prepared in analogy to e 25) and oxetanone. MS obsd. (ESI+)
[(M+H)+] 479, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 - 7.97 (m, J = 2.2 Hz, 1 H), 7.83 - 7.80
(t, J = 2.9 Hz, 2 H), 7.64 - 7.60 (m, J = 4.1 Hz, 1 H), 7.47 - 7.43 (m, J = 4.5 Hz, 2 H), 7.29 - 7.26
(m, J = 2.5 Hz, 1 H), 6.12 (s, 1 H), 5.15 (s, 2 H), 4.85 (m, 2 H), 4.56 (m, 4 H), 4.14 (m, 1 H ),
3.73 (m, 2 H), 3.60 (m, 3 H), 3.42 (m, 2 H), 2.40 (s, 3 H), 2.21 (m, 1 H), 1.87 (m, 1 H).
Example 45-3
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'-
(oxetanyl)ethane-1,2-diamine
N N
The title compound was prepared in analogy to Example 45-1 in Scheme 20 by using N-[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'-(oxetan
yl)ethane-1,2-diamine (prepared in analogy to Example 9-16) and oxetanone. MS obsd. (ESI+)
+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (t, J = 2.0 Hz, 1 H), 7.87 (d, J = 1.7 Hz,
2 H), 7.74 - 7.70 (m, J = 4.0 Hz, 1 H), 7.64 (d, J = 2.1 Hz, 1 H), 7.61 - 7.54 (m, J = 6.8 Hz, 2 H),
6.03 (s, 1 H), 5.29 (s, 2 H), 4.85 (t, J = 3.3 Hz, 2 H), 4.51 (t, J = 3.1 Hz, 4 H), 4.06 (brs, 1 H),
3.73 (s, 2 H), 3.57 (t, J = 3.0 Hz, 2 H), 2.93 (brs, 2 H), 2.48 (s, 3 H).
Example 46
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'-
(pyridinyl)ethane-1,2-diamine
N N
A e of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]ethane-1,2-diamine (150 mg, 0.38 mol, prepared in analogy to Example 9-16), 2-bromopyridine
(60 mg, 0.38 mol), tri(dibenzylideneacetone)dipalladium(0) (17.4 mg, 0.019 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthe (22 mg, 0.038 mmol), cesium ate (247.6
mg, 0.76 mmol) and N-methylpyrolidinone (3 mL) was heated with stirring at 150 ºC for 6 hours
under nitrogen. The mixture was diluted with ethyl acetate, washed with water, dried over
sodium sulfate, filtered, concentrated in vacuo. The residue was purified by preparative HPLC to
give 10 mg of produce as an off-white solid. MS obsd. (ESI+) [(M+H)+] 474, 1H NMR (400
MHz, DMSO-d6) δ ppm 8.1 (d, J = 6.4 Hz, 1 H), 7.96 (dd, J = 1.2, 8.0 Hz, 1 H), 7.81 (d, J = 6.8
Hz, 1 H), 7.54 - 7.39 (m, 5 H), 7.27 (dd, J = 2.0, 8.8 Hz, 1 H), 6.63 - 6.56 (m, 2 H), 6.07 (s, 1 H),
.10 (s, 2 H), 4.52 (brs, 2 H), 3.69 (t, J = 6.4 Hz, 2 H), 3.55 (m, 4 H), 2.40 (s, 3 H).
e 47-1
(4R)[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]
hydroxypyrrolidinone
O N
N N
A mixture of 4-(4-bromomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (400 mg, 0.96 mol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolin
yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1), (4R)
hydroxypyrrolidinone (116.3 mg, 1.15 mmol), copper(I) iodide (90 mg, 0.47 mmol),
potassium carbonate (265 mg, 1.92 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.1
mL, 0.63 mmol) and diethylene glycol dimethyl ether (10 mL) was heated with stirring in a 10
mL of microwave s vial for 2 hours at 140 ºC. The mixture was diluted with
dichloromethane, washed with water. The aqueous was back extracted with romethane.
The combined organic layer was dried over sodium sulfate, filtered, concentrated in vacuo. The
residue was purified by column chromatography on silica gel to give 160 mg of produce as a
gray solid. MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (d, J =
7.2 Hz, 1 H), 7.88 (dd, J = 1.2, 8.0 Hz, 1 H), 7.64 (td, J = 1.2, 7.6 Hz, 1 H), 7.56 (d, J = 8.8 Hz, 1
H), 7.48 (dd, J = 6.8, 7.6 Hz, 1 H), 7.40 (m, 2 H), 7.24 (s, 1 H), 5.51 (d, J = 3.6 Hz, 1 H), 5.13 (s,
2 H), 5.55 (d, J = 2.4 Hz, 1 H), 4.41 (brs, 2 H), 4.08 (dd, J = 4.8, 10.0 Hz, 1 H), 3.66 (s, 2 H),
3.52 (d, J = 9.6 Hz, 1 H), 2.87 (dd, J = 6.4, 16.8 Hz, 1 H), 2.36 (dd, J = 2.0, 16.8 Hz, 1 H), 2.36
(s, 3 H).
e 47-2
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]
oxopyrrolidinecarboxamide
O H
NH O
N N
A mixture of 4-(4-bromomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (500 mg, 1.19 mol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolin
yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1), 5-oxopyrrolidine
carboxamide (307 mg, 2.39 mmol), copper(I) iodide (23 mg, 0.12 mmol), potassium carbonate
(497 mg, 3.60 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.038 mL, 0.24 mmol) and
diethylene glycol dimethyl ether (10 mL) was heated with stirring in a 10 mL microwave process
vial for 3 hours at 140 oC under microwave irridiation. The e was d with
dichloromethane, washed with water. The aqueous layer was back extracted with
romethane. The combined c layers were dried over sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by column chromatography on silica gel to give
40 mg of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]
oxopyrrolidinecarboxamide as light brown solid. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR
(400 MHz, DMSO-d6) δ ppm 9.98 (s, 1 H), 7.88 (m, 3 H), 7.81 (s, 1 H), 7.70 (s, 1 H), 7.64 (td, J
= 1.2, 7.6 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 1 H), 7.46 (dd, J = 0.8, 7.6 Hz, 1 H), 7.38 (dd, J = 1.6,
8.4 Hz, 1 H), 5.08 (s, 2 H), 4.42 (brs, 2 H), 3.73 - 3.57 (m, 4 H), 3.43 (dd, J = 6.0, 9.6 Hz, 1 H),
3.32 (s, 1 H), 2.48 (m, 1 H), 2.42 (s, 3 H).
Example 47-3
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(1H-pyrazol
yl)quinolinamine
N N
The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo-
ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1) and 1H-pyrazolamine. MS obsd. (ESI+) [(M+H)+] 420, 1H NMR
(400 MHz, CD3OD) δ ppm 8.22 (s, 1 H), 8.15 - 8.14 (d, J = 2.8 Hz, 1 H), 8.04 - 8.02 (d, J = 8
Hz, 1 H), 7.90 - 7.88 (d, J = 7.2 Hz, 1 H), 7.85 -7.83 (d, J = 8.8 Hz, 1 H), 7.71 - 7.70 (m, 1 H),
7.64 - 7.61 (d, J = 8.4 Hz, 1 H), 7.60 - 7.51 (t, J = 8 Hz, 1 H), 7.30 (s, 1 H), 6.27 (s, 1 H), 5.34 (s,
2 H), 4.59 (s, 2 H), 3.74 (s, 2 H), 2.45 (s, 3 H).
Example 47-4
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]pyridinecarboxamide
NH O
N N
The title compound was ed in analogy to e 47-1 in Scheme 5 by using 4-(4-bromo-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1) and pyridinecarboxamide. MS obsd. (ESI+) [(M+H)+] 459, 1H NMR
(400 MHz, CD3OD) δ ppm 9.17 (s, 1 H), 8.80 (s, 1 H), 8.52 (s, 1 H), 8.44 - 8.42 (d, J = 8 Hz, 1
H), 8.08 - 8.06 (d, J = 8 Hz, 1 H), 7.99 - 7.96 (d, J = 9.6 Hz, 2 H), 7.90 - 7.88 (d, J = 8.4 Hz, 1
H), 7.70 - 7.48 (m, 4 H), 5.29 (s, 2 H), 4.72 (s, 2 H), 3.64 (s, 2 H), 2.49 (s, 3 H).
e 47-5
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]piperidinecarboxamide
NH O
N N
The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1) and piperidinecarboxamide. MS obsd. (ESI+) [(M+H)+] 465, 1H
NMR (400 MHz, CD3OD) δ ppm 8.33 (s, 1 H), 8.07 - 8.05 (d, J = 6.8 Hz, 1 H), 8.02 (s, 1 H),
7.95 - 7.93 (d, J = 7.6 Hz, 1 H), 7.80 - 7.78 (d, J = 8.4 Hz, 1 H), 7.66 - 7.62 (q, J = 8.8 Hz, 2 H),
7.56 - 7.52 (dd, J = 7.2, 15.6 Hz, 1 H), 5.28 (s, 2 H), 4.61 (s, 2 H), 4.34 - 4.31 (dd, J = 2.4, 12.8
Hz, 1 H), 3.74 (s, 2 H), 3.56 - 3.53 (d, J = 12.8 Hz, 1 H), 3.18 - 3.11 (m, 1 H), 2.51 (s, 3 H), 2.46
- 2.43 (d, J = 14 Hz, 1 H), 2.07 - 1.99 (m, 2 H), 1.88 - 1.76 (m, 1 H).
Example 47-6
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]
inyl)acetamide
O NH
N N
The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo-
ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1) and 2-(pyridinyl)acetamide. MS obsd. (ESI+) [(M+H)+] 473, 1H
NMR (400 MHz, CD3OD) δ ppm 8.53 (s, 1 H), 8.15 (s, 2 H), 8.06 - 8.04 (d, J = 7.6 Hz, 1 H),
7.85 - 7.54 (m, 8 H), 5.26 (s, 2 H), 4.61 (s, 2 H), 3.57 (s, 2 H), 2.56 (s, 3 H).
Example 47-7
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]methanesulfonamide trifluoroacetate
O F
NH F
O O
N N
The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
e in Example 17-1) and methanesulfonamide. MS obsd. (ESI+) [(M+H)+] 432, 1H NMR
(400 MHz, DMSO-d6) δ ppm 7.98 - 7.90 (m, 2 H), 7.88 - 7.82 (d, J = 7.2 Hz, 1 H), 7.72 - 7.65
(t, J = 2 Hz, 1 H), 7.65 - 7.58 (d, J = 7.6 Hz, 1 H), 7.58 - 7.51 (t, J = 2.4 Hz, 1 H), 7.48 - 7.42 (d,
J = 7.6 Hz, 1 H), 7.01 (s, 1 H), 5.10 (s, 2 H), 4.60 - 4.40 (m, 2 H), 3.82 - 3.75 (t, J = 2.8 Hz, 2 H),
3.10 (s, 3 H), 2.38 (s, 3 H).
Example 47-8
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
azinecarboxamide
NH O
N N
The title nd was prepared in y to Example 47-1 in Scheme 5 by using 4-(4-bromo-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1) and pyrazinecarboxamide. MS obsd. (ESI+) [(M+H)+] 460, 1H
NMR (400 MHz, CD3OD) δ ppm 9.53 (s, 1 H), 8.97 (s, 1 H), 8.86 (s, 1 H), 8.72 (s, 1 H), 8.10 -
8.08 (dd, J = 5.2, 11.2 Hz, 2 H), 7.94 - 7.90 (dd, J = 8.8, 14.8 Hz, 2 H), 7.76 - 7.72 (d, J = 7.6 Hz,
2 H), 7.60 - 7.56 (d, J = 8 Hz, 1 H), 5.37 (s, 2 H), 4.70 (s, 2 H), 3.81 (s, 2 H), 2.56 (s, 3 H).
Example 47-9
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]
hydroxyacetamide
NH O
N N
The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy
to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide in Example 17-1) and 2-hydroxyacetamide. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR
(400 MHz, CD3OD) δ ppm 8.54 (s, 1 H), 8.05 (dd, J = 1.2, 7.6 Hz, 1 H), 7.97 (d, J = 7.2 Hz, 1
H), 7.81 (s, 2 H), 7.70 - 7.66 (m, 2 H), 7.54 (t, J = 7.6 Hz, 1 H), 5.27 (s, 2 H), 4.62 (s, 2 H), 4.36
(s, 2 H), 3.76 (s, 2 H), 2.51 (s, 3 H).
e 48
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]pyridinecarboxamide
N N
A mixture of pyridinecarboxylic acid amide (99 mg, 0.8 mmol), hloro
methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (300 mg, 0.8 mmol,
prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide in Example 17-1), cyclohexane-1,3-diamine (90 mg, 0.08 mmol),
copper(I) iodide (1.5 mg, 0.008 mmol) and potassium phosphate (340 mg, 1.6 mmol) in 1,4-
dioxane (3 mL) was heated in a 5 mL of microwave process vial for 3 hours at 150 oC. The
reaction mixture was concentrated in vacuo. The e was purified by preparative HPLC and
SPE to give 26 mg of the desired product (yield was 7.1%). MS obsd. (ESI+) [(M+H)+] 451, 1H
NMR (400 MHz, CD3OD) δ ppm 8.90 - 8.82 (d, J = 8 Hz, 1 H), 8.77 (s, 1 H), 8.47 - 8.40 (d, J =
7.6 Hz, 1 H), 8.20 - 8.13 (t, J = 6.4 Hz, 1 H), 8.13 - 8.08 (d, J = 7.6 Hz, 2 H), 7.92 - 7.85 (m, 2
H), 7.80 - 7.70 (q, J = 8.4 Hz, 3 H), 7.62 - 7.56 (t, J = 7.2 Hz, 1 H), 5.37 (s, 2 H), 4.80 - 4.50 (m,
2 H), 3.82 - 3.78 (t, J = 2.8 Hz , 2 H), 2.60 (s, 3 H).
Example 49
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]azetidinecarboxamide
NH O
N N
utyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]carbamoyl}azetidinecarboxylate
NH O
N N
S O
The title compound was prepared in analogy to Example 48-1 in Scheme 5 by using 4-(4-
bromomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in
analogy to hloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine oxide in Example 17-1) and tert-butyl 2-carbamoylazetidine
carboxylate.
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]azetidinecarboxamide
NH O
N N
To a solution of tert-butyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]carbamoyl}azetidinecarboxylate (80 mg, 0.15 mmol) in ethyl e (10
mL) was added a solution of hydrochloride in ethyl acetate (4 N, 30 mL) dropwise in an icewater
bath. After being stirred at room temperature for 4 hours, the resulting mixture was
concentrated in vacuo and purified by preparative HPLC to give the trifluoroacetic acid salt of
the desired product. The trifluoroacetic acid salt was flashed through SPE column with methanol.
The eluent was concentrated in vacuo and dried by lyopylization to give 30.79 mg of the desired
product (yield was 47%). MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm
8.35 (s, 1 H), 8.04 (dd, J = 1.2, 7.6 Hz, 1 H), 7.98 (d, J = 7.6 Hz, 1 H), 7.93 (s, 1 H), 7.75 (d, J =
8.8 Hz, 1 H), 7.67 (t, J = 7.6 Hz, 1 H), 7.59 (d, J = 9.6 Hz, 1 H), 7.53 (t, J = 8.8 Hz, 1 H), 5.47 -
5.43 (m, 1 H), 5.28 (s, 2 H), 4.61 (brs, 2 H), 4.25 - 4.18 (m, 1 H), 4.14 - 4.10 (m, 1 H), 3.73 (s, 2
H), 3.04 - 2.98 (m, 1 H), 2.76 - 2.72 (m, 1 H), 2.49 (s, 3 H).
e 50-1
1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]
urea
NH N
N N
O
To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
amine (180 mg, 0.5 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolin
yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) and triethylamine (103
mg) in ydrofuran (15 mL) was added a solution of isocyanato-benzene (59.6 mg, 0.5
mmol) in tetrahydrofuran (5 mL) at 0 oC. The reaction was stirred at room temperature overnight
and then heated at 50 oC for additional 5 hours. The reaction mixture was concentrated in vacuo
and the residue was purified by preparative HPLC and SPE to give 17.6 mg of the d
product (yield was 7.5%). MS obsd. (ESI+) [(M+H)+] 473, 1H NMR (400 MHz, CD3OD) δ ppm
8.55 (s, 1 H), 8.12 - 8.03 (m, 2 H), 7.92 (s, 1 H), 7.86 - 7.81 (d, J = 8.4 Hz, 1 H), 7.76 - 7.68 (m,
2 H), 7.66 - 7.57 (m, 3 H), 7.45 - 7.38 (t, J = 7.6 Hz, 2 H), 7.20 - 7.12 (t, J = 2.0 Hz, 1 H), 5.32
(s, 2 H), 4.61 - 4.40 (m, 2 H), 3.82 - 3,75 (t, J = 2.8 Hz, 2 H), 2.56 (s, 3 H).
Example 50-2
1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]
ethylurea
NH N
N N
The title compound was prepared in analogy to Example 50-1 by using 2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinamine (prepared in analogy to 4-(4-
(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in
Example 17-1) and ethylisocyanate. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz,
CD3OD) δ ppm 8.44 (s, 1 H), 8.09 - 8.03 (d, J = 8 Hz, 1 H), 7.99 - 7.93 (d, J = 7.6 Hz, 1 H), 7.86
(s, 1 H), 7.80 - 7.74 (d, J = 8.8 Hz, 1 H), 7.72 - 7.62 (m, 2 H), 7.60 - 7.51 (t, J = 8.4 Hz, 1 H),
.24 (s, 2 H), 4.62 - 4.50 (m, 2 H), 3.78 - 3.70 (m, 2 H), 3.40 - 3.32 (q, J = 7.2 Hz, 2 H), 2.49 (s,
3 H), 1.28 - 1.20 (t, J = 7.2 Hz, 3 H).
Example 51
N-[6-Cyclopropyl(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]propane-1,3-diamine
NH NH2
N N
4-(4-Chlorocyclopropylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide
N N
O
To a solution of 4-(6-bromochloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
e (1.0 g, 2.3 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-
2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) in toluene (150 mL) was
added cyclopropylboronic acid (200 mg, 2.3 mmol), palladium acetate (52 mg, 0. 23 mmol), 2,2'-
bis(diphenylphosphino)-1,1'-binaphthyl (143 mg, 0.23 mmol) and potassium carbonate (320 mg,
2.3 mmol) under argon protection. After being heated at 90 oC for 16 hours, the reaction mixture
was concentrated in vacuo. The e was dissolved in dichloromethane (100 mL), and the
solution was washed with water (50 mL × 3), dried over sodium e, ed and
concentrated in vacuo. The residue was purified by column chromatography (eluting with 16%
ethyl acetate in petroleum ether) to afford 300 mg of the desired product (yield was 33%).
N-[6-Cyclopropyl(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]propane-1,3-diamine
NH NH2
N N
A mixture of 4-(4-chlorocyclopropylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine
1,1-dioxide (300 mg, 0.75 mmol) and propane-1,3-diamine (700 mg, 7.5 mmol) was heated with
stirring in a 10 mL of microwave process vial for 1.5 hours at 150 oC under microwave
irradiation. The reaction mixture was purified by preparative HPLC to give the oroacetic
acid salt of the desired product. The trifluoroacetic acid salt was flashed through SPE column
with methanol. The eluent was concentrated in vacuo and dried by lyopylization to give 119.4
mg of the desired product (yield was 36%). MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz,
CD3OD) δ ppm 8.05 (d, J = 7.6 Hz, 1 H), 7.84 (d, J = 7.2 Hz, 1 H), 7.81 (d, J = 1.2 Hz, 1 H),
7.67 - 7.69 (m, 2 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.46 (d, J = 8.8 Hz, 1 H), 5.92 (s, 1 H), 5.29 (s, 2
H), 4.48 (brs, 2 H), 3.70 (s, 2 H), 3.59 (t, J = 6.8 Hz, 2 H), 3.08 (t, J = 8.0 Hz, 2 H), 2.12 - 2.07
(m, 2 H), 2.05 - 1.98 (m,1 H), 1.03 (dd, J = 2.0 Hz, 8.4 Hz, 2 H), 0.78 - 0.76 (m, 2 H).
Example 52
4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinecarbonitrile
NH NH2
N N
4-(4-Chloroethynylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide
N N
To a degassed solution of 4-(6-bromochloroquinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide (880 mg, 2 mmol, prepared in analogy to 4-(4-chloro
(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example
17-1) in N,N-dimethylformamide (50 mL), zinc cyanide (280 mg, 2.4 mmol) and
tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) was added under argon. After
being refluxed for 2 hours, the reaction mixture was concentrated in vacuo and the residue was
portioned in ethyl acetate (100 mL) and water (100 mL). After being stirred vigorously for 1
hour, the separated aqueous layer was extracted with ethyl acetate (100 mL × 2). The combined
organic layers were dried over sodium sulfate and concentrated in vacuo to afford 0.6 g of the
crude product.
4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinecarbonitrile
NH NH2
N N
A mixture of 4-(4-chloroethynylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (300 mg, 0.7 mmol), propane-1,3-diamine (64 mg, 0.8 mmol), 1,1'-
bis(diphenylphosphino)ferrocene-palladium(II)dichloride (65 mg, 0.08 mmol), 1,1'-
phenylphosphino)ferrocene (45 mg, 0.08 mmol) and sodium tert-butoxide (307 mg, 3.2
mmol) in 1,4-dioxane (3 mL) was heated with stirring in a sealed 5 mL of microwave s
vial for 1.5 hours at 120 ºC under microwave irradiation. The resulting e was concentrated
in vacuo. The residue was purified by preparative HPLC and SPE. After SPE separation, the
eluent was concentrated in vacuo and the residue was dried by lization to afford 65.2 mg
of the desired product (yield was 20 %). MS obsd. (ESI+) [(M+H)+] 422, 1H NMR (400 MHz,
CD3OD) δ ppm 8.60 (s, 1 H), 8.10 - 8.08 (d, J = 8 Hz, 1 H), 7.99 - 7.86 (m, 3 H), 7.74 - 7.70 (t, J
= 7.2 Hz, 1 H), 7.61 - 7.57 (t, J = 7.6 Hz, 1 H), 6.05 (s, 2 H), 5.35 (s, 2 H), 4.56 (s, 2 H), 3.75 (s,
2 H), 3.62 - 3.59 (t, J = 6.8 Hz, 2 H), 3.14 - 3.10 (t, J = 8 Hz, 2 H), 2.15 - 2.11 (t, J = 7.6 Hz, 2
Example 53
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethenylquinolin
yl]propane-1,3-diamine
NH NH
N N
4-(4-Chloroethenylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide
N N
To a degassed solution of romochloroquinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide (880 mg, 2 mmol, prepared in analogy to 4-(4-chloro
uoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example
17-1) in N,N-dimethylformamide (50 mL), tributyl(vinyl)tin (760 mg, 2.4 mmol) and
tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) was added under argon. After
being refluxed for 2 hours, the reaction mixture was concentrated in vacuo and the residue was
portioned in ethyl acetate (100 mL) and a saturated aqueous solution of potassium fluoride (100
mL). After the mixture being stirred vigorously for 1 hour, the separated s layer was
ted with ethyl acetate (100 mL × 2). The combined organic layers were dried over sodium
sulfate and concentrated in vacuo to afford 0.4 g of the crude product.
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethenylquinolin
yl]propane-1,3-diamine
NH NH
N N
The title compound was prepared in analogy to Example 52 in Scheme 22 by using 4-(4-chloro-
6-ethenylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and propane-1,3-
diamine. MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 8.12 (s, 1 H), 8.05
- 8.02 (q, J = 8 Hz, 1 H), 7.89 - 7.81 (m, 2 H), 7.77 - 7.70 (m, 2 H), 7.56 - 7.54 (t, J = 4.4 Hz, 1
H), 6.80 - 6.74 (m, 1 H), 5.95 - 5.90 (m, 2 H), 5.36 - 5.30 (m, 3 H), 4.51 (s, 2 H), 3.71 (s, 2 H),
3.61 - 3.60 (t, J = 3.2 Hz, 2 H), 3.11 - 3.10 (t, J = 5.2 Hz, 2 H), 2.13 - 2.11 (t, J = 5.6 Hz, 2 H).
Example 54
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethynylquinolin
pane-1,3-diamine
NH NH2
N N
O
hloroethynylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide
N N
To a degassed solution of 4-(6-bromochloroquinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide (880 mg, 2 mmol, prepared in analogy to 4-(4-chloro
(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example
17-1) in N,N-dimethylformamide (50 mL), tributyl(ethynyl)tin (760 mg, 2.4 mmol) and
tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) was added under argon. After
being ed for 2 hours, the reaction mixture was trated in vacuo and the residue was
portioned in a mixture of ethyl acetate (100 mL) and a saturated aqueous solution of potassium
fluoride (100 mL). After the mixture being d vigorously for 1 hour, the separated aqueous
layer was extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried
over sodium sulfate and concentrated in vacuo to afford 0.45 g of the crude product.
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethynylquinolin
yl]propane-1,3-diamine
NH NH
N N
The title compound was prepared in analogy to Example 52 in Scheme 22 by using 4-(4-chloro-
6-ethynylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and propane-1,3-
diamine. MS obsd. (ESI+) [(M+H)+] 421, 1H NMR (400 MHz, CD3OD) δ ppm 8.25 (s, 1 H), 8.01
- 7.99 (d, J = 7.6 Hz, 1 H), 7.94 - 7.92 (d, J = 7.2 Hz, 1 H), 7.87 - 7.85 (d, J = 8.8 Hz, 1 H), 7.82
- 7.79 (m, 1 H), 7.65 - 7.61 (m, 1 H), 7.50 - 7.47 (m, 1 H), 7.32 (s, 1 H), 5.30 (s, 2 H), 3.65 - 3.60
(m, 6 H), 2.70 (s, 3 H), 2.14 - 2.11 (t, J = 5.2 Hz, 2 H).
Example 55-1
N-[(3-Aminooxetanyl)methyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinazolinamine
NH 2
N N
N-(3-Aminooxetanylmethyl)chloromethylquinazolinamine
N Cl
A solution of chloromethylquinazoline (645 mg, 3 mmol) and 3-(aminomethyl)oxetan-
3-amine (340 mg, 3.3 mmol) in ol (15 mL) was d at room temperature overnight.
After the resulting mixture was concentrated in vacuo, the residue was purified by column
chromatography (eluting with 10% methanol in dichloromethane) to afford the desired product.
N-[(3-Aminooxetanyl)methyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinazolinamine
NH 2
N N
A mixture of N-(3-aminooxetanylmethyl)chloromethylquinazolinamine (140 mg, 0.5
mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (270 mg, 1.5 mmol) in n-butanol (10
mL) was heated at 160 °C for 30 minutes. After the resulting mixture was concentrated in vacuo,
the residue was purified by preparative HPLC to afford the pure product as a solid. MS obsd.
(ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (s, 1 H), 7.83 - 7.79 (m, 2 H),
7.66 - 7.52 (m, 4 H), 5.45 - 5.41 (d, 1 H), 5.10 (brs, 1 H), 4.80 - 4.72 (m, 6 H), 4.39 (s, 2 H), 3.51
(s, 2 H), 2.45 (s, 3 H).
Example 55-2
(Benzylamino)oxetanyl]methyl}methyl(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinazolinamine
N N
The title compound was prepared in analogy to Example 55-1 in Scheme 23 by using 2,4-
romethylquinazoline, 3-(aminomethyl)-N-benzyloxetanamine and 2,3,4,5-tetrahydro-
1,4-benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 514, 1H NMR (400 MHz, CD3OD) δ
ppm 8.06 (s, 1 H), 7.81 - 7.77 (m, 2 H), 7.66 - 7.56 (m, 4 H), 7.47 - 7.45 (m, 2 H), 7.31 - 7.29
(m, 3 H), 5.45 - 5.35 (d, 1 H), 5.10 (brs, 1 H), 4.82 - 4.80 (m, 6 H), 4.71 - 4.69 (m, 2 H), 4.16 (s,
2 H), 3.51 (m, 2 H), 2.46 (s, 3 H).
Example 55-3
2-Fluoro-N-[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin
yl]propane-1,3-diamine
N N
The title compound was prepared in analogy to Example 55-1 in Scheme 23 by using 2,4-
romethylquinazoline, 2-fluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 414, 1H NMR (400 MHz, CD3OD) δ ppm
(d, J = 7.6 Hz, 1 H), 7.79 (s, 1 H), 7.70 - 7.20 (m, 6 H), 5.56 (m, 1 H), 4.85 - 4.55 (m, 3 H), 4.48
- 4.32 (brs, 1 H), 3.91 - 3.71 (brs, 2 H), 3.40 - 3.11 (m, 2 H), 2.93 - 2.72 (m, 2 H), 2.24 (s, 3 H),
1.68 (s, 2 H).
Example 55-4
N-[2-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl]-2,2-
ropropane-1,3-diamine
NH NH
N N
The title compound was prepared in analogy to Example 55-1 in Scheme 23 by using 2,4-
dichloromethylquinazoline, 2,2-difluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-
benzothiazepine. MS obsd. (ESI+) [(M+H)+] 416, 1H NMR (400 MHz, CD3OD) δ ppm 7.96 (s, 1
H), 7.80 -7.68 (m, 1 H), 7.60 -7.58 (m, 2 H), 7.51 - 7.49 (m, 1 H), 7.30 - 7.27 (t, 1 H), 7.24 - 7.20
(t, 1 H), 5.15 (s, 2 H), 4.37 - 4.31 (m, 4 H), 3.51 - 3.49 (m, 4 H), 3.14 (s, 2 H), 2.45 (s, 3 H).
Example 56-1
N-{[3-(Aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinazolinamine
N N
O
N-{[3-(Aminomethyl)oxetanyl]methyl}chloromethylquinazolinamine
N Cl
To a mixture of oxetane-3,3-diyldimethanamine (1.16 g, 10.0 mmol) and ylamine (1.4 mL,
mol) in dichloromethane (15 mL) was added dropwise of a solution of 2,4-dichloro
methylquinazoline (500 mg, 2.36 mmol) in romethane (5 mL). After being stirred at room
temperature overnight, the resulting mixture was diluted with water (50 mL), and extracted with
dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium
sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography
(eluting with 10% methanol in dichloromethane) to afford 300 mg of the desired product as a
white solid.
N-{[3-(Aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinazolinamine
N N
The title compound was prepared in analogy to e 55-1 in Scheme 23 by using N-{[3-
(aminomethyl)oxetanyl]methyl}chloromethylquinazolinamine and 2,3,4,5-
ydro-1,4-benzothiazepine 1,2-dioxide. MS obsd. (ESI+) [(M+H)+] 454, 1H NMR (400
MHz, CD3OD) δ ppm 7.99 (dd, J = 7.83, 1.26 Hz, 1 H), 7.88 (d, J = 7.33 Hz, 1 H), 7.67 (s, 1 H),
7.62 (td, J = 7.58, 1.26 Hz, 1 H), 7.50 - 7.37 (m, 2 H), 7.37 - 7.30 (m, 1 H), 5.21 (brs, 2 H), 4.66
(d, J = 6.06 Hz, 2 H), 4.57 (d, J = 6.06 Hz, 1 H), 4.51 (d, J = 6.32 Hz, 2 H), 4.06 (s, 2 H), 3.53 (t,
J = 5.05 Hz, 2 H), 3.05 (s, 2 H), 2.40 (s, 3 H).
Example 56-2
2,2-Difluoro-N-[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin
yl]propane-1,3-diamine
N N
The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4-
romethylquinazoline, 2,2-difluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 432, 1H NMR (400 MHz, CD3OD) δ ppm
7.98 (s, 1 H), 7.82 - 7.80 (d, 1 H), 7.74 - 7.69 (m, 2 H), 7.63 - 7.53 (m, 3 H), 5.40 (d, 1 H), 5.10
(m, 1 H), 4.75 (m, 1 H), 4.60 - 4.33 (m, 3 H), 3.63 (m, 4 H), 2.45 (s, 3 H).
Example 56-3
(aminomethyl)oxetanyl]methyl}chloro(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinazolinamine
N N
O
The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4,6-
trichloroquinazoline, oxetane-3,3-diyldimethanamine and 2,3,4,5-tetrahydro-1,4-benzothiazepine
1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 474, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (d, J =
6.82 Hz, 1 H), 7.94 (d, J = 2.53 Hz, 1 H), 7.88 (d, J = 7.07 Hz, 1 H), 7.66 - 7.59 (m, 1 H), 7.52 -
7.42 (m, 2 H), 7.42 - 7.36 (m, 1 H), 5.21 (brs, 2 H), 4.69 - 4.56 (m, 5 H), 4.51 (d, J = 6.32 Hz, 2
H), 4.05 (brs, 2 H), 3.52 (t, J = 5.05 Hz, 2 H), 3.04 (s, 2 H).
Example 56-4
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl]-2,2-
difluoropropane-1,3-diamine
N N
The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4-
dichloromethylquinazoline, 2,2-difluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 448, 1H NMR (400 MHz, CD3OD) δ
ppm 8.06 - 8.04 (dd, J = 1.2, 7.6 Hz, 1 H), 7.99 (s, 1 H), 7.84 - 7.82 (d, J = 7.6 Hz, 1 H), 7.72 -
7.67 (m, 2 H), 7.63 - 7.58 (m, 1 H), 7.56 - 7.54 (dd, J = 1.2, 8 Hz, 1 H), 5.35 (s, 2 H), 4.54 (s, 2
H), 4.44 - 4.37 (t, J =14 Hz, 2 H), 3.72 - 3.64 (m, 4 H), 2.46 (s, 3 H).
Example 56-5
1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl]
fluoropropane-1,3-diamine
NH NH
N N
The title compound was prepared in analogy to e 56-1 in Scheme 23 by using 2,4-
dichloromethylquinazoline, 2-fluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 430, 1H NMR (400 MHz, CD3OD) δ
ppm 8.06 - 8.04 (d, J = 7.6 Hz, 1 H), 7.93 (s, 1 H), 7.81 - 7.79 (d, J = 7.6 Hz, 1 H), 7.69 - 7.65 (t,
J = 8 Hz, 2 H), 7.60 - 7.53 (m, 2 H), 5.32 (s, 2 H), 5.17 - 5.03 (d, J = 28 Hz, 1 H), 4.52 (s, 2 H),
4.20 - 3.92 (m, 2 H), 3.67 (s, 2 H), 3.47 - 3.36 (m, 2 H), 2.44 (s, 3 H).
Example 56-6
N-[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]propane-
1,3-diamine
NH NH
N N
The title compound was ed in analogy to Example 56-1 in Scheme 23 by using 2,4-
dichloromethylquinazoline, propane-1,3-diamine and 5-tetrahydro-1,4-benzothiazepine
1-oxide. MS obsd. (ESI+) [(M+H)+] 396, 1H NMR (400 MHz, CD3OD) δ ppm 7.92 (s, 1 H),
7.81 - 7.79 (d, J = 7.6 Hz, 1 H), 7.74 - 7.72 (d, J = 7.6 Hz, 1 H), 7.64 - 7.50 (m, 4 H), 5.43 -
.39 (d, J = 15.6 Hz, 1 H), 5.12 - 5.05 (m, 1 H), 4.81 - 4.72 (m, 1 H), 4.53 - 4.46 (m, 2 H), 3.84
- 3.82 (m, 2 H), 3.52 - 3.48 (m, 2 H), 3.31 - 3.29 (m, 2 H), 2.43 (s, 3 H), 2.17 - 2.11 (m, 2 H).
Example 57-1
N-[(3-Aminooxetanyl)methyl](2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin
amine
N N
N-[(3-Aminooxetanyl)methyl]chloroquinazolinamine
N Cl
To a solution of 2,4-dichloroquinazoline (1.0 g, 5.024 mmol) in methanol (15 mL) was added 3-
(aminomethyl)oxetanamine (855 mg, 60%, 5.024 mmol) and triethylamine (101 mg, 1.005
mmol). After being stirred at room temperature overnight, the mixture was concentrated in
vacuo. The residue was purified by flash column chromatography to afford 1.2 g of the desired
product as a white solid (yield was 92%).
N-[(3-Aminooxetanyl)methyl](2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin
amine
N N
To a solution of N-[(3-aminooxetanyl)methyl]chloroquinazolinamine (200 mg, 0.756
mmol) in N,N-dimethylformamide (4 mL) was added 2,3,4,5-tetrahydro-1,4-benzothiazepine
(125 mg, 0.756 mmol) and triethylamine (230 mg, 2.268 mmol). After being heated at 130 oC for
4 hours under microwave ation, the reaction mixture was poured into water and extracted
with ethyl e. The organic layer was dried with sodium sulfate, and concentrated in vacuo.
The residue was purified by preparative HPLC to afford 42 mg of the desired product as a white
solid (yield was 14%). MS obsd. (ESI+) [(M+H)+] 394, 1H NMR (400 MHz, CD3OD) δ ppm 7.75
- 7.73 (t, J = 6.4, 1.2 Hz, 1 H), 7.56 - 7.53 (m, 1 H), 7.52 - 7.47 (m, 2 H), 7.43 - 7.41 (d, J = 8.0
Hz, 1 H), 7.24 - 7.20 (m, 1 H), 7.15 - 7.08 (m, 2 H), 5.06 (s, 2 H), 4.69 - 4.67 (d, J = 6.8 Hz, 2
H), 4.55 - 4.53 (d, J = 6.4 Hz, 2 H), 4.42 (s, 2 H), 4.09 (s, 2 H), 2.97 - 2.95 (t, J = 4.8, 4.4 Hz, 2
Example 57-2
N-[(3-Aminooxetanyl)methyl](1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
nazolinamine
N N
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4-
dichloroquinazoline, 3-(aminomethyl)oxetanamine and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 410, 1H NMR (400 MHz, CD3OD) δ ppm
7.91 - 7.90 (t, J = 7.2, 0.8 Hz, 1 H), 7.81 - 7.74 (m, 2 H), 7.58 - 7.54 (m, 1 H), 7.51 - 7.43 (m, 3
H), 7.16 - 7.12 (m, 1 H), 5.32 - 5.28 (d, J = 15.2 Hz, 2 H), 4.68 - 4.53 (m, 6 H), 4.10 (s, 2 H),
3.37 - 3.34 (m, 2 H).
Example 57-3
N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinazolinamine
N N
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4-
dichloroquinazoline, 3-(aminomethyl)oxetanamine and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ
ppm 7.98 - 7.93 (m, 1 H), 7.91 - 7.88 (m, 2 H), 7.64 - 7.60 (m, 1 H), 7.57 - 7.51 (m, 1 H), 7.48 -
7.41 (m, 2 H), 7.15 - 7.11 (m, 1 H), 5.24 (s, 2 H), 4.67 - 4.54 (m, 6 H), 4.09 (s, 2 H), 3.55 - 3.50
(m, 2 H).
Example 57-4
N-[(3-Aminooxetanyl)methyl]chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinazolinamine
Cl O
N N
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4,6-
trichloroquinazoline, nomethyl)oxetanamine and 5-tetrahydro-1,4-
benzothiazepine. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.18
(s, 1 H), 7.97 (s, 1 H), 7.70 (s, 1 H), 7.51 - 7.44 (m, 2 H), 7.27 - 7.21 (m, 2 H), 7.16 - 7.12 (t, J =
7.2 Hz, 1 H), 4.93 (s, 2 H), 4.50 - 4.35 (m, 5 H), 3.97 - 3.80 (m, 2 H), 2.96 - 2.87 (m, 2 H), 2.69
- 2.67 (m, 1 H), 2.35 - 2.33 (m, 1 H), 2.10 (s, 2 H).
Example 57-5
N-[(3-Aminooxetanyl)methyl]chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinazolinamine
Cl O
N N
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4,6-
trichloroquinazoline, 3-(aminomethyl)oxetanamine and 2,3,4,5-tetrahydro-1,4-
benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 444, 1H NMR (400 MHz, CD3OD) δ ppm
8.57 (s, 1 H), 8.01 - 7.73 (m, 2 H), 7.52 - 7.40 (m, 4 H), 5.31 - 5.28 (d, J = 15.2 Hz, 1 H), 4.66 -
4.53 (m, 6 H), 4.08 (s, 2 H), 3.51 - 3.50 (m, 2 H), 1.36 - 1.31 (m, 1 H).
Example 57-6
N-[(3-Aminooxetanyl)methyl]chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinazolinamine
Cl O
N N
The title compound was prepared in analogy to e 57-1 in Scheme 23 by using 2,4,6-
trichloroquinazoline, nomethyl)oxetanamine and 2,3,4,5-tetrahydro-1,4-
hiazepine 1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 460, 1H NMR (400 MHz, CD3OD) δ
ppm 8.00 - 7.98 (t, J = 2.0, 4.8 Hz, 2 H), 7.91 - 7.89 (d, J = 7.2 Hz, 1 H), 7.64 - 7.60 (t, J = 7.2
Hz , 1 H), 7.51 - 7.44 (m, 2 H), 7.40 - 7.38 (d, J = 9.2 Hz, 1 H), 5.22 (s, 2 H), 4.65 - 4.62 (t, J =
6.4, 5.6 Hz, 4 H), 4.56 - 4.54 (d, J = 6.4 Hz, 2 H), 4.08 (s, 2 H), 3.54 - 3.51 (t, J = 5.2, 4.8 Hz, 2
Example 57-7
2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin
yl]amino}ethanol
N N
O
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4-
diichloromethylquinazoline, 2-aminoethanol and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide. MS obsd. (ESI+) [(M+H)+] 410, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J = 1.2,
7.6 Hz, 1 H), 7.83 (d, J = 6.8 Hz, 1 H), 7.63 - 7.59 (m, 2 H), 7.44 (td, J = 0.8, 7.6 Hz, 1 H), 7.38
(dd, J = 1.6, 8.4 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 5.20 (s, 2 H), 4.58 (brs, 2 H), 3.82 - 3.78 (m,
4 H), 3.53 (t, J = 5.2 Hz, 2 H), 2.39 (s, 3 H).
Example 58
2-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinamine
N N
2-Chloromethylquinazolinamine
N Cl
A mixture of 2,4-dichloromethylquinazoline (500 mg, 2.348 mmol) and a solution of
ammonia in tetrahydrofuran (20 mL, 3.0 M) was d in an ice-bath for 2 hours. The resulting
mixture was concentrated in vauco to afford 454 mg of the crude product as a white solid.
2-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinamine
N N
To a solution of 2-chloromethylquinazolinamine (454 mg, 2.345 mmol) in nol (5
mL) was added 2,3,4,5-tetrahydro-1,4-benzothiazepine (388 mg, 2.345 mmol). After being
heated at 150 oC for 1.5 hours under microwave irradiation, the reaction mixture was filtered and
the ted solid was washed with ether to afford 756 mg of the product as a white solid. MS
obsd. (ESI+) [(M+H)+] 323, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (s, 1 H), 7.83 - 7.81 (d,
J = 8.0 Hz, 1 H), 7.62 - 7.60 (d, J = 8.0 Hz, 1 H), 7.53 - 7.49 (m, 2 H), 7.29 - 7.25 (m, 1 H), 7.22
- 7.19 (m, 1 H), 4.98 (s, 2 H), 4.25 (s, 2 H), 2.98 (s, 2 H), 2.35 (s, 3 H).
Example 59
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinamine
N N
To a solution of oxone (670 mg, 1.117 mmol) in water (2.5 mL), which was cooled below 0 oC
in an ice-bath, was added a solution of 2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinazolinamine (300 mg, 0.930 mmol) in methanol (15 mL) and tetrahydrofuran (3
mL) dropwise. The resulting mixture was d below 0 oC for 2 hours. The formed precipitate
was ted by filtration, washed with water and dried in vacuo to afford the desired product as
a white solid. MS obsd. (ESI+) [(M+H)+] 355, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.91 -7.86
(m, 2 H), 7.77 (s, 1 H), 7.64 - 7.60 (t, J = 16.0 Hz, 1 H), 7.51 - 7.48 (m, 2 H), 7.37 - 7.35 (d, J =
8.0 Hz, 1 H), 5.06 (s, 2 H), 4.37 (s, 2 H), 3.59 (s, 2 H), 2.31 (s, 3 H).
Example 60
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl]
methylpropane-1,2-diamine
N N
S O
2-Chloromethylquinazolinyl)methylpropane-1,2-diamine
NH 2
N Cl
A solution of 2,4-dichloromethylquinazoline (500 mg, 2.35 mmol) and 2-methylpropane-1,2-
diamine (365 µL, 3.52 mmol) in methanol (10 mL) was stirred at room temperature for 1 hour.
The reaction mixture was diluted with ethyl acetate (30 mL) and stirred for 30 minutes. The
formed solid was collected by filtration and dried in vacuo to afford 500 mg of the desired
product as a white solid (yield was 80.6%).
N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl]
methylpropane-1,2-diamine
NH 2
N N
A mixture of 2-chloromethylquinazolinyl)methylpropane-1,2-diamine (300 mg,
1.14 mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine (226 mg, 1.25 mmol) in n-butanol (3
mL) was heated in the microwave at 160 oC for 2 hours. The resulting mixture was concentrated
in vacuo. The residue was purified by flash column chromatography (eluting with 0 - 10%
ol in dichloromethane) to afford 300 mg of the desired product as a white solid (yield was
67%).
N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl]
methylpropane-1,2-diamine
N N
S O
O
To a stirred solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinazolinyl]methylpropane-1,2-diamine (240 mg, 0.61 mmol ) in dichloromethane
(15 mL) was added 3-chloroperoxybenzoic acid (263 mg, 1.53 mmol) at 0 oC. After being stirred
at 0 oC for 20 minutes, the reaction mixture was washed with a saturated aqueous solution of
sodium ate and brine, dried over sodium sulfate, and concentrated in vacuo. The residue
was purified by flash column chromatography (eluting with 10% methanol in dichloromethane)
to afford 100 mg of the desired product as a white solid (yield was 38.6%). MS obsd. (ESI+)
[(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (d, J = 1.9 Hz, 1 H), 7.86 (d, J = 1.8
Hz, 1 H), 7.73 (s, 1 H), 7.60 (t, J = 2.7 Hz, 1 H), 7.47 - 7.40 (m, J = 6.9 Hz, 2 H), 7.36 -7.33 (m,
1 H), 5.20 (s, 2 H), 4.58 (brs, 2 H), 3.72 (s, 2 H ), 3.52 (m, 2 H ), 2.41 (s, 3 H), 1.30 (s, 6 H).
Example 61-1
N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
6-methylquinazolinamine
O NH
N N
N-{[3-(Dibenzylamino)oxetanyl]methyl}(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinazolinamine
O N
N N
A mixture of (2-chloromethylquinazolinyl)-[3-(dibenzylamino)oxetanylmethyl]-amine
(2 g, 4.4 mmol, prepared in analogy to N-(3-aminooxetanylmethyl)chloro
methylquinazolinamine in Example 55-1), 2,3,4,5-tetrahydro-1,4-benzothiazepine (720 mg,
4.4 mmol), triethylamine (1.2 mL, 8.6 mmol) in N,N-dimethylformamide (20 mL) was heated
with stirring in a 30 mL of microwave process vial for 2 hours at 150 oC. The reaction mixture
was d with ethyl acetate, washed with water and brine. The c layer was dried over
sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column
tography on silica gel to give 1.7 g of the product as a white solid.
N-{[3-(Dibenzylamino)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinazolinamine
O N
N N
O
To a solution of N-{[3-(dibenzylamino)oxetanyl]methyl}(2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinazolinamine (1.7 g, 2.89 mmol) in dichloromethane (30 mL) was
added 3-chloroperbenzoic acid (75%, 1.33 g, 5.8 mmol) at 0 oC. The resulting mixture was
stirred for 1 hour whilst ng the temperature to rise slowly to room ature. The
reaction mixture was then washed with a ted aqueous solution of sodium carbonate, a
saturated aqueous solution of sodium sulfite and brine. The organic layer was dried over sodium
e, filtered, and trated in vacuo. The residue was purified by column chromatography
on silica gel to give 1.4 g of the product as a white solid.
N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
6-methylquinazolinamine
O NH
N N
To a solution of N-{[3-(dibenzylamino)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinazolinamine (1.4 g, 2.26 mmol) in methanol was
added palladium hydroxide (20% on carbon, 200 mg). After being stirred at room temperature
overnight under a hydrogen atmosphere, the resulting mixture was filtered. The filtrate was
concentrated in vacuo. The residue was purified by column chromatography on silica gel to
afford 300 mg of the product as off-white foam. MS obsd. (ESI+) [(M+H)+] 440, 1H NMR (400
MHz, CD3OD) δ ppm 7.97 (d, J = 7.6 Hz, 1 H), 7.86 (d, J = 7.2 Hz, 1 H), 7.69 (s, 1 H), 7.58 (t, J
= 7.2 Hz, 1 H), 7.44 - 7.34 (m, 3 H), 5.21 (s, 2 H), 4.66 (d, J = 6.4 Hz, 2 H), 4.60 (br.s., 2 H),
4.56 (d, J = 6.4 Hz, 2 H), 4.10 (s, 2 H), 3.52 (t, J = 5.2 Hz, 2 H), 2.39 (s, 3 H).
Example 61-2
N-[(1-Aminocyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinazolinamine
N N
Benzylamino-cyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinazolinamine
N N
The title compound was prepared in analogy to N-{[3-(dibenzylamino)oxetanyl]methyl}
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinamine in e
61-1 in Scheme 24 by using 2,4-dichloromethylquinazoline, 1-(aminomethyl)-N-
dibenzylcyclobutanamine and 5-tetrahydro-1,4-benzothiazepine.
N-[(1-Aminocyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)
methylquinazolinamine
N N
O
A mixture of N-[(1-benzylamino-cyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinazolinamine (220 mg, 0.417 mmol), 10% of palladium
hydroxide on carbon (30 mg), and trifluoroacetic acid (160 µL) in methanol (20 mL) was stirred
at room temperature for 24 hours under a en atmosphere. The resulting mixture was
filtered, and the filtrate was adjusted to pH 8-9 by the addition of a solution of ammonia in
methanol (7 M), and concentrated in vacuo. The residue was purified by preparative HPLC to
give 105 mg of the product as a white solid. MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400
MHz, CD3OD) δ ppm 7.98 (d, J = 7.6 Hz, 1 H), 7.86 (d, J = 7.6 Hz, 1 H), 7.73 (s, 1 H), 7.60 (t, J
= 7.6 Hz, 1 H), 7.47 - 7.32 (m, 3 H), 5.33 (s, 2 H), 4.58 (brs, 2 H), 3.84 (s, 2 H), 3.53 (t, J = 4.8
Hz, 2 H), 2.41 (s, 3 H), 2.21 (m, 2 H), 2.04 - 1.97 (m, 2 H), 1.91 - 1.82 (m, 2 H).
Example 62-1
(Aminomethyl)oxetanyl]methyl}methyl(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinazolinamine
NH NH
N N
2-Chloromethylquinazolin-4(3H)-one
N Cl
To a solution of 2,4-dichloromethylquinazoline (2.13 g, 10 mmol ) in tetrahydrofuran (20 mL)
was added sodium hydroxide (2 N, 20 mL). After being stirred at room temperature for 4 hours,
the reaction mixture was chilled and acidified to pH 5 with acetic acid. The formed solid was
collected by filtration, washed with water, and dried in vacuo to afford 1.7 g of the desired
product as a white solid (yield was 87.6%).
6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one
N N
To a stirred solution of 2-chloromethylquinazolin-4(3H)-one (15 g, 77.3 mmol) and 2,3,4,5-
tetrahydro-1,4-benzothiazepine e (16.8 g, 103 mmol) in toluene ( 200 mL) was added
triethylamine (16.1 mL, 116 mmol). After being refluxed overnight, the reaction e was
cooled to room temperature. The formed solid was collected by filtration, washed with ethanol
(50 mL ) and ethyl acetate( 100 mL), and then dried in vacuo to afford 21.0 g of the desired
product as a white solid (yield was 80%).
(Aminomethyl)oxetanyl]methyl}methyl(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinazolinamine
NH NH
N N
To a solution of 6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-
4(3H)-one (10 g, 29.5 mmol) and benzotriazolyloxytris(dimethylamino)phosphonium
hexafluorophosphate (16.9 g, 38.3 mmol) in N,N-dimethylformamide (140 mL) was added 1,8-
diazabicyclo[5.4.0]undecene (6.7 g, 44.2 mmol) at room temperature. After being stirred for
minutes, (3-aminomethyl-oxetanyl)-methylamine (5.1 g, 44.2 mmol) was added. The
mixture was stirred for 4 hours at room temperature and diluted with water (150 mL). The
ted aqueous layer was extracted with ethyl acetate (100 mL × 6 ). The organic layers were
ed and washed with brine, dried over sodium sulfate, and then concentrated in vacuo. The
residue was purified by flash column chromatography (eluting with 10% methanol in
dichloromethane) to afford 9.0 g of the impure product (purity was 90%). The impure t
was purified by preparative HPLC to afford 6.0 g of the desired product as a white solid. MS
obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, CD3OD) δ ppm 8.02 (s, 1 H), 7.82 - 7.79 (m, 2
H), 7.64 (d, J = 1.6 Hz, 1H), 7.60 - 7.57 (m, 3 H), 5.44 (d, 1 H), 5.13 (brs, 1 H), 4.77 (brs, 1 H),
4.66 - 4.59 (m, 4 H), 4.51 (brs, 1 H), 4.24 (s, 2 H), 3.55 (brs, 2 H), 3.44 (s, 2 H ), 2.44(s, 3 H).
Example 62-2 and Example 62-3
(-)-N-{[3-(Aminomethyl)oxetanyl]methyl}methyl[(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl]quinazolinamine and (+)-N-{[3-(Aminomethyl)oxetan
yl]methyl}methyl[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinazolin
amine
NH NH
2 NH NH
N O N O
N N N N
S S
O O
(-) (+)
The chiral separation of Example 62-1 n: IA; flow rate: 15 mL/min; gradient: 50% hexane
in ethanol with 0.4% of triethylamine) affords (-)- (aminomethyl)oxetanyl]methyl}
methyl[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl]quinazolinamine, MS obsd.
(ESI+) [(M+H)+] 438, and (+)-N-{[3-(aminomethyl)oxetanyl]methyl}methyl[1-oxido-
2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinazolinamine, MS obsd. (ESI+) [(M+H)+] 438.
Example 62-4 and e 62-5
N~4~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl]
fluorobutane-1,4-diamine and N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)methylquinazolinyl]fluorobutane-1,4-diamine
2 NH
NH NH 2
N N
N N N N
S O S O
O O
A B
The title compound was ed in analogy to Example 62-1 in Scheme 23 by using 2-chloro
methylquinazolin-4(3H)-one, 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and 2-
fluorobutane-1,4-diamine. 8.65 mg of compound A and 3.54 mg of compound B were obtained.
A: MS obsd. (ESI+) [(M+H)+] 444, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 - 7.90 (d, J = 3 Hz,
1 H), 7.65 (s, 1 H), 7.50 - 7.40 (t, 1 H), 7.40 - 7.30 (m, 3 H), 7.15 (s, 1 H), 5.95 (s, 1 H), 5.10 (s,
2 H), 4.75 - 4.50 (d, J = 52 Hz, 2 H), 3.75 (s, 2 H), 3.40 (s, 2 H), 2.97 - 2.87 (m, 2 H), 2.34 (s, 3
H), 1.90 (s, 2 H).
B: MS obsd. (ESI+) [(M+H)+] 444, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 - 7.90 (d, J = 4 Hz,
1 H), 7.70 (s, 1 H), 7.45 - 7.35 (t, 1 H), 7.33 - 7.25 (m, 3 H), 6.10 (s, 1 H), 5.15 (s, 2 H), 4.90 -
4.50 (m, 3 H), 4.00 - 3.65 (m, 2 H), 3.40 (s, 2 H), 2.95 - 2.70 (m, 2 H), 2.30 (s, 3 H), 2.11 - 1.65
(m, 2 H).
Example 62-6
N-{[3-(Aminomethyl)oxetanyl]methyl}(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinazolinamine
N N
The title compound was prepared in analogy to Example 62-1 in Scheme 23 by using 2-chloro
methylquinazolin-4(3H)-one, 2,3,4,5-tetrahydro-1,4-benzothiazepine and oxetane-3,3-
diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 422. 1H NMR (400 MHz, CD3OD) δ ppm 7.66
(dd, J = 1.6, 7.2 Hz, 1 H), 7.62 (s, 1 H), 7.44 (dd, J = 1.2, 7.6 Hz, 1 H), 7.34 - 7.29 (m, 2 H), 7.18
(m, 1 H), 7.08 (m, 1 H), 4.99 (s, 2 H), 4.63 (d, J = 6.4 Hz, 2 H), 4.45 (d, J = 6.4 Hz, 2 H), 4.34 (s,
2 H), 4.02 (s, 2 H), 2.98 (s, 2 H), 2.90 (m, 2 H), 2.36 (s, 3 H).
Example 62-7
transFluoro[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-
4-yl]pyrrolidinamine
F NH
N N
The title compound was prepared in analogy to Example 62-1 in Scheme 23 by using ro
methylquinazolin-4(3H)-one, 5-tetrahydro-1,4-benzothiazepine 1-oxide and trans
fluoropyrrolidinamine. MS obsd. (ESI+) [(M+H)+] 426. 1H NMR (400 MHz, CD3OD) 7.82 (s,
1 H), 7.71 (d, J = 6.8 Hz, 1 H), 7.42 (m, 4 H), 5.26 (d, J = 15.2 Hz, 1 H), 5.07 (d, J = 51.2 Hz, 1
H), 4.78 (brs, 1 H), 4.43 (m, 2 H), 4.29 (m, 1 H), 4.06 (t, J = 11.2 Hz, 1 H), 3.86 (d, J = 12 Hz, 1
H), 3.75 (m, 1 H), 3.40 (m, 2 H), 2.40 (s, 3 H).
Example 63-1
N-(2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}ethyl)acetamide
N N
To a solution of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin-
4-yl]ethane-1,2-diamine (39 mg, 0.1 mmol, prepared in analogy to Example 9-11) in
romethane (5 mL) was added acetic anhydride (12 mg, 0.12 mmol) at 0 oC. The reaction
mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue
was diluted with a saturated aqueous solution of sodium bicarbonate (5 mL), and extracted with
dichloromethane (10 mL × 2). The combined organic layers were washed with brine (10 mL),
dried over sodium sulfate, filtered and trated in vacuo. The e was purified by flash
column chromatography (eluting with 10% methanol in dichloromethane) to afford 21 mg of the
desired product as a white solid (yield was 48%). MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400
MHz, CD3OD) δ ppm 8.16 (s, 1 H), 7.95 (d, J = 1.8 Hz, 2 H), 7.86 (d, J = 1.9 Hz, 1 H), 7.62 (t, J
= 3.6 Hz, 2 H), 7.46 (t, J = 3.8 Hz, 1 H), 7.31 (d, J = 2.1 Hz, 1 H), 7.22 (d, J = 2.1 Hz, 1 H), 6.84
(s, 1 H), 6.20 (s, 1 H), 5.10 (s, 2 H), 4.43 (brs, 2 H), 3.62 (s, 2 H), 3.32 (m, 4 H), 2.34 (s, 3 H),
1.89 (s, 3 H).
Example 63-2
N-{[3-({[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}methyl)oxetanyl]methyl}acetamide
NH N
N N
The title compound was prepared in analogy to Example 63-1 in Scheme 25 by using N-{[3-
(aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinamine (prepared in y to Example 3-50) and acetic anhydride. MS obsd.
(ESI+) [(M+H)+] 495, 1H NMR (400 MHz, CD3OD) δ ppm 8.00 (d, J = 7.6 Hz, 1 H), 7.89 (d, J =
7.2 Hz, 1 H), 7.66 (t, 2 H), 7.46 (t, 2 H), 7.32 - 7.30 (m, 1 H), 6.22 (s, 1 H), 5.17 (s, 2 H), 4.56 -
4.51 (m, 6 H), 3.67 (d, 4 H), 3.60 (t, J = 9.6 Hz, 2 H ), 2.43 (s, 3 H), 2.06 (s, 3 H).
Example 63-3
N-(3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}propyl)acetamide
NH N
N N
The title nd was prepared in analogy to Example 63-1 in Scheme 25 by using N-[2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]propane-1,3-diamine
(prepared in analogy to Example 9-3) and acetic anhydride. MS obsd. (ESI+) [(M+H)+] 453, 1H
NMR (400 MHz, CD3OD) δ ppm 8.00 - 7.97 (m, 1 H), 7.81 (d, J = 7.2 Hz, 1 H), 7.76 - 7.64 (m,
2 H), 7.46 - 7.42 (m, 2 H), 7.30 - 7.28 (m, 1 H), 5.99 (s, 1 H), 5.14 (s, 2 H), 4.54 (brs, 2 H), 3.58
(t, 2 H), 3.36 (m, 4 H), 2.42 (s, 3 H), 2.00 (s, 3 H), 1.94 - 1.87 (m, 2 H).
Example 63-4
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin
tamide
N N
A mixture of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin
amine (50 mg, 0.14 mmol, prepared in analogy to Example 59) and acetic anhydride (2 mL) was
heated with stirring at 110 oC for 2 hours under nitrogen. The on mixture was diluted with
ethyl acetate, washed with a saturated s solution of sodium carbonate and brine, dried
over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column
chromatography on silica gel to give 30 mg of the product as a white powder. MS obsd. (ESI+)
[(M+H)+] 397, 1H NMR (400 MHz, CD3OD) δ ppm 7.87 (d, J = 7.6 Hz, 1 H), 7.80 (s, 1 H), 7.56
(m, 3 H), 7.28 (m, 1 H), 7.21 (m, 1 H), 5.11 (s, 2 H), 4.48 (s, 2 H), 2.99 (s, 2 H), 2.47 (s, 6 H).
Example 64
1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]
methylpyrrolidinamine
N N
N-{1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]
methylpyrrolidinyl}acetamide
N O
N N
The title compound was prepared in analogy to Example 3-1 in Scheme 26 by using 4-(4-chloro-
6-methylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared
in analogy to the one in Example 2-1) and N-(3-methylpyrrolidinyl)acetamide.
1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]
methylpyrrolidinamine
N N
A mixture of N-{1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin-
4-yl]methylpyrrolidinyl}acetamide (102 mg, 0.21 mmol) and hydrochloric acid (2 N, 120
mL) was heated with stirring at 100 oC for 16 hours. After being cooled to room temperature, the
reaction mixture was adjusted to pH 9 with a saturated aqueous solution of potassium carbonate
and exacted with romethane (200 mL × 3). The combined organic layers were dried over
sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to
afford 2.6 mg of the product (yield was 2.8%). MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400
MHz, CD3OD) δ ppm 8.10 - 8.08 (d, J = 7.6 Hz, 1 H), 8.01 (s, 1 H), 7.85 - 7.83 (d, J = 7.6 Hz, 1
H), 7.76 - 7.71 (m, 2 H), 7.60- 7.58 (m, 2 H), 5.92 (s, 1 H), 5.31 (s, 2 H), 4.51 (s, 2 H), 4.22 -
3.97 (m, 4 H), 3.75 - 3.73 (d, J = 8 Hz, 2 H), 2.47 (s, 3 H), 3.11- 3.08 (m, 2 H), 2.47 - 2.31 (m, 2
H), 1.63 (s, 3 H).
Example 65
N-[(3-Aminooxetanyl)methyl](9-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)methylquinolinamine
O NH2
N N
S O O
O
A mixture of N-[(3-aminooxetanyl)methyl](9-fluoro-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinamine (20 mg, 0.044 mmol, prepared in analogy
to Example 1-4) and sodium methoxide (24 mg, 0.44 mmol) in methanol (2 mL) was heated with
ng in a sealed 5 mL of microwave process via for 20 minutes at 100 ºC under microwave
irradiation. The resulting mixture was concentrated in vacuo. The residue was purified by
preparative HPLC to afford 6 mg of the t (yield was 29%). MS obsd. (ESI+) [(M+H)+]
469, 1HNMR (400 MHz, CD3OD) δ ppm 7.67 (s, 1 H), 7.62 - 7.52 (m, 1 H), 7.47 (d, J = 8.59
Hz, 1 H), 7.41 (d, J = 7.07 Hz, 1 H), 7.31 (dd, J = 8.46, 1.89 Hz, 1 H), 7.16 (d, J = 7.83 Hz, 1 H),
.99 (s, 1 H), 5.08 (s, 2 H), 4.63 - 4.49 (m, 4 H), 4.31 (t, J = 5.56 Hz, 2 H), 3.98 - 3.81 (m, 5 H),
3.54 (s, 2 H), 2.43 (s, 3 H).
Example 66
4-(4-{[(3-Aminooxetanyl)methyl]amino}methylquinolinyl)-2,3,4,5-tetrahydro-1,4-
hiazepinol 1,1-dioxide
O NH
N N
S O
A mixture of N-[(3-aminooxetanyl)methyl](7-methoxy-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinamine (20 mg, 0.044 mmol, prepared in analogy
to Example 1-5), potassium hydroxide (24 mg, 0.44 mmol) in dimethylsulfoxide (2 mL) was
heated with ng in a sealed 5 mL of microwave process via for 20 minutes at 100 ºC under
microwave irradiation. The resulting e was purified by preparative HPLC to afford 6 mg
of the product (yield was 30%). MS obsd. (ESI+) [(M+H)+] 455, 1HNMR (400 MHz, CD3OD) δ
ppm 7.77 (d, J = 8.59 Hz, 1 H), 7.67 (s, 1 H), 7.45 (d, J = 8.59 Hz, 1 H), 7.31 (dd, J = 8.46, 1.64
Hz, 1 H), 7.18 (d, J = 2.53 Hz, 1 H), 6.72 (dd, J = 8.59, 2.27 Hz, 1 H), 6.19 (s, 1 H), 5.03 (s, 2 H),
4.68 (d, J = 6.57 Hz, 2 H), 4.61 (d, J = 6.57 Hz, 2 H), 3.66 (s, 2 H), 3.50 (brs, 2 H), 3.30 (m, 2 H),
2.43 (s, 3 H).
Example 67
3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]amino}-
2-methylpropane-1,2-diol
N N
O
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(2-methylpropen
yl)quinolinamine
N N
A solution of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (372.0 mg, 1.0 mmol, ed in analogy to 4-(4-chloro(trifluoromethoxy)quinolin-
2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) and 2-methylprop
enamine (213.0 mg, 3.0 mmol) in 1-methylpyrrolidinone ( 1.0 mL) was heated with stirring
at 160 oC for 36 hours. The reaction mixture was cooled to room temperature, diluted with water
(10 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50
mL × 2), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 407.0 mg
of the product as a light yellow solid. MS obsd. (ESI +) [(M+H)+] 408.
3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]amino}-
2-methylpropane-1,2-diol
N N
A mixture solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(2-
propenyl)quinolinamine (200.0 mg, 0.49 mmol), 4-methylmorpholine N-oxide
monohydrate (67.2 mg, 0.58 mmol) and osmium ide (6.4 mg, 0.024 mmol) in acetone ( 10
mL) was stirred at room temperature for 1 hour. After being quenched by adding sodium
bisulfite, the resulting mixture was extracted with ethyl acetate (100 mL). The c layer was
washed with brine (50 mL × 2), dried over anhydrous sodium sulfate and then concentrated in
vacuo. The e was purified by preparative HPLC to afford 25.1 mg of the desired product as
a light yellow solid (yield was 11.6%), MS obsd. (ESI +) [(M+H)+] 442, 1H NMR (400 MHz,
CD3OD) δ ppm 7.96 (dd, J = 7.83, 1.01 Hz, 1 H), 7.89 (d, J = 7.33 Hz, 1 H), 7.60 (td, J = 7.45,
1.26 Hz, 1 H), 7.54 (s, 1 H), 7.50 - 7.34 (m, 2 H), 7.28 (dd, J = 8.59, 1.77 Hz, 1 H), 6.22 (s, 1 H),
5.13 (brs, 2 H), 4.52 (brs, 2 H), 3.66 - 3.46 (m, 4 H), 3.40 (s, 2 H), 3.33 (dt, J = 3.28, 1.64 Hz, 2
H), 2.41 (s, 3 H), 1.31 (s, 3 H).
Example 68
4-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}butane-1,3-diol
OH OH
N N
A solution of 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}hydroxybutanoic acid (50.0 mg, 0.11 mmol, prepared in analogy to Example 11-3),
sodium borohydride (100.0 g, 2.6 mmol) and iodine (300.0 mg, 1.2 mmol) in
tetrahydrofuran (10.0 mL) was stirred at room temperature for 16 hours. The reaction mixture
was diluted with water (20 mL) and extracted with ethyl acetate (100 mL). The organic layer was
washed with brine (50 mL × 2), dried over anhydrous sodium sulfate and then concentrated in
vacuo. The residue was purified by preparative HPLC to afford 20.0 mg of the desired product as
a light yellow solid (yield was 41.2%). MS obsd. (ESI +) [(M+H)+] 442, 1H NMR (400 MHz,
CD3OD) δ ppm 8.04 (d, J = 7.58 Hz, 1 H), 7.90 (d, J = 7.58 Hz, 1 H), 7.81 (brs, 1 H), 7.75 - 7.59
(m, 2 H), 7.59 - 7.41 (m, 2 H), 6.10 (s, 1 H), 5.25 (brs, 2 H), 4.53 (brs, 2 H), 4.12 (brs, 1 H), 3.82
(t, J = 5.94 Hz, 2 H), 3.68 (brs, 2 H), 3.55 (dd, J = 13.77, 4.17 Hz, 1 H), 3.44 (dd, J = 13.64, 7.33
Hz, 1 H), 2.45 (s, 3 H), 1.97 - 1.73 (m, 2 H).
e 69-1
N-[6-Methyl(2-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]ethane-1,2-diamine
N N
4-(4-Chloromethylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide
N N
O
To a cooled solution of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide (186 mg, 0.5 mmol, prepared in analogy to 4-(4-chloro
(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example
17-1) in dry tetrahydrofuran (10 mL) was added n-butyllithium (0.47 mL, 1.6 N) at -78 °C under
argon. After being stirred at -78 °C for 1 hour, a solution of methyl iodide in dry tetrahydrofuran
(5 mL) was added to the reaction mixture dropwise at -78°C. Then the mixture was stirred
overnight whilst allowing the temperature to rise slowly to room temperature. The resulting
reaction mixture was poured into a saturated aqueous solution of ammonium chloride (20 mL)
and extracted with ethyl e (50 mL). The organic layer was dried over sodium sulfate and
concentrated in vacuo. The residue was purified by flash column chromatography (eluting with
% ethyl acetate in petroleum ether) to afford the desired t.
N-[6-Methyl(2-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]ethane-1,2-diamine
N N
The title nd was prepared in analogy to Example 9-1 in Scheme 30 by using 4-(4-chloro-
6-methylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide and ethane
1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (d, J =
7.83 Hz, 1 H), 7.85 (brs, 1 H), 7.70 - 7.60 (m, 2 H), 7.52 - 7.40 (m, 2 H), 7.30 (dd, J = 8.59, 1.77
Hz, 1 H), 6.03 (s, 1 H), 5.13 (brs, 2 H), 3.67 - 3.57 (m, 1 H), 3.56 - 3.48 (m, 2 H), 3.31 - 3.30 (m,
3 H), 3.15 - 3.04 (m, 2 H), 2.42 (s, 3 H), 1.51 (brs, 2 H).
Example 69-2
Aminooxetanyl)methyl]methyl(2-methyl-1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinolinamine
NH 2
N N
The title compound was prepared in analogy to Example 69-1 in Scheme 30 by using 4-(4-
chloromethylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and
3-(aminomethyl)oxetanamine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD 3OD)
δ ppm 8.01 (d, J = 7.83 Hz, 1 H), 7.92 (brs, 1 H), 7.66 (s, 2 H), 7.52 - 7.41 (m, 2 H), 7.30 (dd, J
= 8.59, 1.77 Hz, 1 H), 6.19 (s, 1 H), 5.18 (brs, 1 H), 5.10 (brs, 1 H), 4.66 - 4.55 (m, 4 H), 3.68 (d,
J = 2.02 Hz, 2 H), 3.65 - 3.57 (m, 1 H), 3.35 - 3.30 (m, 3 H), 2.43 (s, 3 H), 1.60 - 1.40 (brs, 2 H).
Example 70
N-[(3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}oxetanyl)methyl]-2,2,2-trifluoroacetamide
H F
N F
NH O
N N
A solution of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (500 mg, 1.341 mmol, prepared in y to 4-(4-chloro(trifluoromethoxy)quinolin-
2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1), aminooxetan-
3-yl)methyl]-2,2,2-trifluoroacetamide (570 mg, 70%, 2.01 mmol), 1,1'-
bis(diphenylphosphino)ferrocene-palladium(II)dichloride (99 mg, 0.134 mmol), 1,1'-
phenylphosphino)ferrocene (75 mg, 0.134 mmol), and sodium tert-butoxide (258 mg,
2.682 mmol) in 1,4-dioxane (8 mL) was heated with stirring in a sealed 10 mL of microwave
process vial for 1.5 hours at 120 ºC under microwave irradiation. The reaction mixture was
poured into water and extracted with ethyl acetate. The organic layer was dried over sodium
sulfate and concentrated in vacuo. The residue was purified by flash column chromatography
(eluting with 1 - 10% methanol in dichloromethane) to afford 190 mg of the desired product
(yield was 26%). MS obsd. (ESI+) +] 535, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (m,
1 H), 7.82 (d, J = 6.8 Hz, 1 H), 7.66 (s, 1 H), 7.59 (td, J = 0.8, 7.6 Hz, 1 H), 7.47 - 7.42 (m, 2 H),
7.32 (dd, J = 1.6, 8.8 Hz, 1 H), 5.70 (s, 1 H), 5.18 (s, 2 H), 4.86 (m, 4 H), 4.52 (s, 2 H), 3.87 (s, 2
H), 3.60 (t, J = 4.8 Hz, 2 H), 2.43 (s, 3 H).
Example 71
N-[3-(Aminomethyl)oxetanyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
6-methylquinolinamine
N N
To a solution of N-[(3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]amino}oxetanyl)methyl]-2,2,2-trifluoroacetamide (190 mg, 0.355 mmol)
in methanol (15 mL) was added an aqueous solution of potassium carbonate (197 mg, 1.42
mmol, dissolved in 2 mL of water). After being stirred at room temperature overnight, the
ing mixture was concentrated in vacuo to remove methanol. The residue was diluted with
water (5 mL) and extracted with dichloromethane (15 mL). The organic layer was dried over
sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to give
23 mg of the desired product as a white solid (yield was 14.8%). MS obsd. (ESI+) [(M+H)+] 439,
1H NMR (400 MHz, CD
3OD) δ ppm 7.98 - 7.96 (m, 1 H), 7.58 - 7.56 (d, J = 6.8 Hz, 1 H), 7.44 -
7.40 (m, 2 H), 7.32 - 7.30 (t, 1 H), 7.19 (m, 2 H), 5.99 (s, 1 H), 5.54 (s, 1 H), 4.98 - 4.97 (d, J =
6.0, 4 H), 4.64 - 4.63 (m, 3 H), 3.51 (s, 2 H), 3.30 (s, 2 H), 2.34 (s, 3 H).
Example 72
2-(Aminomethyl){[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]amino}propane-1,3-diol
NH OH
N N
A mixture of N-[(3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]amino}oxetanyl)methyl]-2,2,2-trifluoroacetamide (269 mg, 0.503 mmol)
and a on of ammonia in methanol (7 M, 10 mL,) was stirred at room temperature ght.
The resulting mixture was concentrated in vacuo and the residue was ed by preparative
HPLC to afford 58 mg of the product as a white solid (yield was 25%). MS obsd. (ESI+)
[(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 - 8.09 (t, J = 6.4, 1.2 Hz, 1 H), 8.00 -
7.96 (m, 1 H), 7.86 (s, 1 H), 7.76 - 7.73 (m, 2 H), 7.64 - 7.60 (m, 2 H), 6.49 (s, 1 H), 5.33 (s, 2
H), 4.55 (s, 2 H), 3.82 (s, 2 H), 3.77 - 3.75 (m, 6 H), 2.49 (s, 3 H).
Example 73
4-Amino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]pyrrolidinone
O N
N N
To a solution of 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin-
4-yl]oxopyrrolidinecarboxamide (100 mg, 0.22 mmol, byproduct of Example 47-2) in
acetonitrile (2 mL) and water (2 mL) was added (diacetoxyiodo)benzene (91 mg, 0.28 mmol).
The mixture was stirred at room temperature overnight. The reaction mixture was diluted with
water, ied with concentrated hydrochloride acid (12 N), and extracted with
dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in
vacuo. The residue was ed by column chromatography on silica gel (eluting with 1 - 10%
methanol in dichloromethane) to give 10 mg of the product as a white solid. MS obsd. (ESI+)
+] 437, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94 - 7.87 (m, 2 H), 7.60 (td, J = 1.2, 7.2
Hz, 1 H), 7.55 (d, J = 8.8 Hz, 1 H), 7.47 - 7.43 (m, 2 H), 7.37 (dd, J = 2.0, 8.8 Hz, 1 H), 7.22 (s,
1 H), 5.13 (s, 2 H), 4.42 (brs, 2 H), 4.02 (dd, J = 2.0, 9.6 Hz, 1 H), 3.87 (td, J = 3.6, 6.8 Hz, 1 H),
3.62 (dd, J = 4.8, 9.6 Hz, 2 H), 3.45 (dd, J = 3.2, 9.6 Hz, 1 H), 3.14 - 3.13 (m, 1 H), 2.85 (dd, J =
7.2, 16.8 Hz, 1 H), 2.36 (s, 3 H).
Example 74
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2-
(methylsulfinyl)ethyl]quinolinamine
N N
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2-
(methylsulfanyl)ethyl]quinolinamine
N N
A dried microwave process vial capped with a rubber septum was purged with argon and
charged with ibenzylideneacetone)dipalladium(0) (2.88 mg, 0.005 mmol), 1-(N,N-
dimethylamino)-1′-(dicyclohexylphosphino)biphenyl (5.90 mg, 0.015 mmol) and sodium tert-
butoxide (134 mg, 1.4 mmol). The tube was purged with argon, and a solution of 4-(4-chloro
methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (370 mg, 1.0 mmol,
prepared in y to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine oxide in Example 17-1) and 2-(methylthio)ethylamine (128 mg, 1.4
mmol) in 1,4-dioxane (2.0 mL) was added. The mixture was heated with stirring in a sealed 5
mL of microwave process vial for 2 hour at 120 ºC under ave irradiation. After being
cooled to room temperature, the reaction mixture was diluted with ethyl acetate, filtered through
celite and concentrated in vacuo. The residue was purified by flash chromatography on silica gel
(eluting with 1 - 10% methanol in dichloromethane) to afford 341 mg of the desired product
(yield was 80%). MS obsd. (ESI+) [(M+H)+] 428.
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2-
(methylsulfinyl)ethyl]quinolinamine
N N
To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2-
(methylsulfanyl)ethyl]quinolinamine (300 mg, 0.70 mmol) in acetic acid (2 mL) was added
hydrogen peroxide (0.5 mL) at room temperature. The mixture was stirred at room temperature
for 2 hours. The resulting mixture was diluted with ethyl acetate (10 mL), washed with a
saturated s solution of sodium bicarbonate, dried over sodium sulfate, and trated in
vacuo. The residue was purified by preparative HPLC to afford the desired product. MS obsd.
(ESI+) [(M+H)+] 444, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d, J = 7.07 Hz, 1 H), 7.88
(dd, J = 7.83, 1.26 Hz, 1 H), 7.70 - 7.60 (m, 2 H), 7.47 (td, J = 7.64, 1.14 Hz, 1 H), 7.34 (d, J =
8.34 Hz, 1 H), 7.25 (dd, J = 8.34, 1.52 Hz, 1 H), 6.98 (t, J = 5.56 Hz, 1 H), 6.14 (s, 1 H), 5.09
(brs, 2 H), 4.5(brs, 2 H), 3.81 - 3.56 (m, 4 H), 3.20 - 3.07 (m, 1 H), 3.04 - 2.92 (m, 1 H), 2.65 (s,
3 H), 2.35 (s, 3 H).
Example 75
N-{2-[(2-Aminoethyl)sulfonyl]ethyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)methylquinolinamine
S NH
NH 2
N N
To a solution of N-{2-[(2-aminoethyl)sulfanyl]ethyl}(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinamine (40 mg, 0.087 mmol, prepared in analogy
to Example 3-1 by using hloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide and aminoethyl)sulfanyl]ethylamine) in acetic acid (2 mL),
potassiumpermanganate (15 mg, 0.08 mmol) was added. After being stirred at room temperature
for 30 minutes, the mixture was concentrated in vacuo. The residue was purified by preparative
HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 489, 1H NMR (400 MHz,
CD3OD) δ ppm 7.99 (dd, J = 7.83, 1.26 Hz, 1 H), 7.93 (d, J = 7.58 Hz, 1 H), 7.65 (td, J = 7.45,
1.26 Hz, 1 H), 7.54 (s, 1 H), 7.49 - 7.41 (m, 2 H), 7.30 (dd, J = 8.46, 1.64 Hz, 1 H), 6.13 (s, 1 H),
.16 (s, 2 H), 4.63 (brs, 1 H), 4.56 (brs, 1 H), 3.91 (t, J = 6.82 Hz, 2 H), 3.60 (t, J = 4.67 Hz, 2
H), 3.55 - 3.45 (m, 2 H), 3.31 - 3.27 (m, 2 H), 3.20 - 3.06 (m, 2 H), 2.41 (s, 3 H).
Example 76
N-[2-(1-Iminooxido-1,2,3,5-tetrahydro-4H-1lambda~4~,4-benzothiazepinyl)
methylquinolinyl]ethane-1,2-diamine
NH 2
N N
N-[4-(4-Chloromethylquinolinyl)oxido-2,3,4,5-tetrahydro-1H-1lambda~4~,4-
benzothiazepinylidene]-2,2,2-trifluoroacetamide
N N
N F
To a suspension of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine
1-oxide (357 mg, 1.0 mmol, prepared in analogy to the one in Example 18-1), trifluoroacetamide
(226 mg, 2.0 mmol), magnesium oxide (160 mg, 4.0 mmol) and rhodium(II) acetate (11 mg, 2.5
mol) in dichloromethane (10 mL) was added (diacetoxyiodo)benzene (483 mg, 1.5 mmol). After
being d at room ature overnight, the resulting mixture was concentrated in vacuo.
The residue was purified by flash column chromatography (eluting with 20 - 33% ethyl acetate
in petroleum ether) to afford 234 mg of the pure product (yield was 50%). MS obsd. (ESI+)
[(M+H)+] 468.
4-(4-Chloromethylquinolinyl)-2,3,4,5-tetrahydro-1H-1lambda~4~,4-benzothiazepin
imine 1-oxide
N N
To a solution of N-[4-(4-chloromethylquinolinyl)oxido-2,3,4,5-tetrahydro-1H-
1lambda~4~,4-benzothiazepinylidene]-2,2,2-trifluoroacetamide (234 mg, 0.50 mmol) in
methanol (10 mL) was added potassium carbonate (690 mg, 5.0 mmol).After being stirred at
room temperature for 30 minutes, the reaction e was concentrated in vacuo. The residue
was ed by column tography (eluting with 20 - 33% ethyl acetate in petroleum ether)
to afford the N-unsubstituted sulfoximines. MS obsd. (ESI+) [(M+H)+] 372.
N-[2-(1-Iminooxido-1,2,3,5-tetrahydro-4H-1lambda~4~,4-benzothiazepinyl)
methylquinolinyl]ethane-1,2-diamine
NH 2
N N
The title compound was ed in analogy to Example 9-1 in Scheme 35 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1H-1lambda~4~,4-benzothiazepinimine 1-oxide
and ethane 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 396, 1H NMR (400 MHz, DMSO-d6) δ ppm
7.91 (d, J = 8.08 Hz, 1 H), 7.83 (d, J = 7.58 Hz, 1 H), 7.70 (s, 1 H), 7.58 -7.52 (m, 1 H), 7.44 -
7.37 (m, 1 H), 7.30 (d, J = 8.59 Hz, 1 H), 7.21 (dd, J = 8.46, 1.64 Hz, 1 H), 6.63 (t, J = 5.43 Hz,
1 H), 6.01 (s, 1 H), 5.11 (brs, 2 H), 4.61 (brs,1 H), 4.10 (brs, 1 H), 3.49 - 3.36 (m, 2 H), 3.31 (q, J
= 6.23 Hz, 3 H), 2.86 - 2.76 (m, 3 H), 2.34 (s, 3 H).
Example 77
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2-(S-
methylsulfonimidoyl)ethyl]quinolinamine
S NH
N N
The title compound was prepared in analogy to Example 76 in Scheme 33 by using 2-(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2-
(methylsulfinyl)ethyl]quinolinamine (prepared in y to Example 74) and
trifluoroacetamide. MS obsd. (ESI+) [(M+H)+] 459, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d,
J = 7.33 Hz, 1 H), 7.96 (d, J = 7.33 Hz, 1 H), 7.73 - 7.66 (m, 2 H), 7.60 - 7.55 (m, 1 H), 7.52 (s,
1 H), 7.46 - 7.40 (m, 1 H), 6.17 (s, 1 H), 5.26 (brs, 2 H), 4.50 (brs, 2 H), 3.98 (t, J = 6.69 Hz, 2
H), 3.68 (brs, 2 H), 3.59 (t, J = 6.82 Hz, 2 H), 3.14 (s, 3 H), 2.45 (s, 3 H).
Example 78-1
transAmino[2-(1-iminooxido-1,2,3,5-tetrahydro-4H-1lambda~4~,4-benzothiazepin-
4-yl)methylquinolinyl]pyrrolidinol
H2N OH
N N
S NH
A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1H-1lambda~4~,4-
benzothiazepinimine 1-oxide (100 mg, 0.27 mmol), tert-butyl (transhydroxypyrrolidin
yl)carbamate (164 mg, 0.81 mmol) and n-butanol (0.2 mL) was stirred at 160 °C overnight. After
the mixture being cooled to room temperature, to the above mixture was added dichloromethane
(10 mL) and trifluoroacetic acid (10 mL). The mixture was stirred further until the on
finished monitoring by TLC, and then trated in vacuo. The residue was dissolved in
dichloromethane and the solution was washed with an aqueous on of sodium hydroxide
(10% W/W) and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was
purified by preparative HPLC to afford the product as a solid. MS obsd. (ESI+) [(M+H)+] 438,
1H NMR (400 MHz, CD
3OD) δ ppm 8.05 (d, J = 7.83 Hz, 1 H), 7.84 (s, 1 H), 7.81 (s, 1 H), 7.61
(t, J = 7.45 Hz, 1 H), 7.52 (d, J = 8.59 Hz, 1 H), 7.49 - 7.43 (m, 1 H), 7.36 - 7.30 (m, 1 H), 6.14
(s, 1 H), 5.31 - 5.16 (m, 2 H), 4.25 (brs, 1 H), 4.17 - 4.05 (m, 1 H), 4.05 - 3.94 (m, 1 H), 3.62 (d,
J = 10.61 Hz, 2 H), 3.70 - 3.58 (m, 2 H), 3.57 - 3.41 (m, 3 H), 2.43 (s, 3 H).
Example 78-2
trans[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]
fluoropyrrolidinamine
F NH2
N N
The title compound was prepared in analogy to Example 78-1 in Scheme 7 by using 4-(4-chloro-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide and tert-butyl (trans-
4-fluoropyrrolidinyl)carbamate. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz,
CD3OD) δ ppm 7.98 (dd, J = 7.71, 1.89 Hz, 1 H), 7.91 - 7.75 (m, 2 H), 7.62 (t, J = 7.45 Hz, 1 H),
7.52 (d, J = 8.59 Hz, 1 H), 7.45 (td, J = 7.58, 3.28 Hz, 1 H), 7.32(d, J = 8.59 Hz, 1 H), 6.19 (s, 1
H), 5.18 (brs, 2 H), 5.06 (m, 1 H), 4.53 (brs, 2 H), 4.17 (m, 1 H), 4.03 (dd, J = 9.98, 5.43 Hz, 1
H), 3.81 - 3.54 (m, 4 H), 3.45 - 3.35 (m, 1 H), 2.42 (s, 3 H).
e 79
1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]pyrrolidinecarboxamide
N N
1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]pyrrolidinecarboxylic acid
N N
A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (500 mg, 1.34 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolin
yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) and methyl pyrrolidine-
3-carboxylate (173 mg, 1.34 mmol) and N,N-diisopropylethylamine (346 mg, 2.68 mmol) was
heated with stirring in a sealed 10 mL of microwave process vial for 1.5 hours at 140 ºC under
microwave irradiation. The resulting mixture was purified by ative HPLC to afford 120
mg of the pure product (yield was 19.8%).
1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]pyrrolidinecarbonyl chloride
N N
To a cooled solution of 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]pyrrolidinecarboxylic acid (120 mg, 0.26 mmol) in dichloromethane (20
mL) was added two drops of N,N-dimethylformamide followed by oxalyl chloride (30.6 µL, 0.39
mmol) at 0 oC. After being stirred for 16 hours at room temperature, the reaction mixture was
concentrated in vacuo to afford 100 mg of the crude t which was used for the next step
without any further purification.
1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin
yl]pyrrolidinecarboxamide
N N
O
To a cooled solution of 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]pyrrolidinecarbonyl chloride (100 mg, 0.21 mmol) in dichloromethane
(20 mL) was added a saturated solution of ammonia in dichloromethane (10 mL) slowly at 0 oC.
After being stirred for 16 hours at room ature, the mixture was concentrated in vacuo. The
residue was purified by ative HPLC to afford 13 mg of the desired product (yield was
13.5%). MS obsd. (ESI+) +] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.08 - 8.05 (m, 2
H), 7.33 - 7.31 (d, J = 7.6 Hz, 1 H), 7.70 - 7.67 (m, 2 H), 7.57 - 7.55 (m, 2 H), 5.85 (s, 1 H), 5.25
(s, 2 H), 4.5 (s, 2 H), 4.03 - 3.94 (m, 4 H), 3.71 (s, 2 H), 3.29 - 3.21 (m, 1 H), 2.45 (s, 3 H), 2.41 -
2.32 (m, 1 H), 2.31 - 2,21 (m, 1 H).
Example 80
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(methylsulfinyl)quinolin
yl]propane-1,3-diamine
O NH NH
N N
4-[4-Chloro(methylsulfinyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
O Cl
N N
To a cooled solution of 4-[4-Chloro(methylsulfanyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide (800 mg, 1.98 mmol, prepared in analogy to 4-(4-chloro
quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide in e 17-1) in
dichloromethane (70 mL) was added a solution of 3-chloroperoxybenzoic acid (400 mg, 198
mmol, purity 85%) in romethane (30 mL) dropwise at 0 oC. After being stirred at 0 oC for
20 minutes, the reaction mixture was washed with a saturated aqueous solution of sodium
bicarbonate (100 mL), a saturated aqueous solution of sodium thiosulphate (100 mL × 3) and
brine (100 × 2). The organic layer was dried over sodium sulfate, filtered and trated in
vacuo to afford 500 mg of the desired product (yield was 60%).
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(methylsulfinyl)quinolin
yl]propane-1,3-diamine
O NH NH
N N
A mixture of 4-[4-chloro(methylsulfinyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide (300 mg, 0.71 mmol) and propane-1,3-diamine (67525 mg, 7.1
mmol) was heated with stirring in a sealed 10 mL of microwave process vial for 1 hour at 150 ºC
under microwave irradiation. The reaction mixture was purified by preparative HPLC to afford
the trifluoroacetic acid salt of the desired product. The trifluoroacetic acid salt was flashed
through SPE column with methanol. The eluent was concentrated in vacuo and dried by
lyopylization to afford 256.8 mg of the desired product (yield was 78%). MS obsd. (ESI+)
[(M+H)+] 459, 1H NMR (400 MHz, CD3OD) δ ppm 8.44 (s, 1 H), 8.05 - 7.96 (m, 3 H), 7.88 (d, J
= 7.6 Hz, 1 H), 7.71 (t, J = 7.6 Hz, 1 H), 7.55 (t, J = 7.6 Hz, 1 H), 6.02 (s, 1 H), 5.33 (s, 2 H),
4.54 (s, 2 H), 3.74 (s, 2 H), 3.61 (t, J = 6.0 Hz, 2 H), 3.11 (t, J = 8.0 Hz, 2 H), 2.82 (s, 3 H), 2.16
- 2.09 (m, 2 H).
Example 81
4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
nolinecarboxamide
O NH NH
N N
4-Chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinecarboxamide
O Cl
N N
S
To a mixture of methyl 4-chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline
carboxylate (400 mg, 1.04 mmol, prepared in y to 4-(4-chloromethylquinolinyl)
methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1-1) in ydrofuran (5 mL) and
a saturated solution of ammonia in methanol (30 mL) was heated with stirring for 16 hours at
120 ºC in a sealed tube. The reaction mixture was concentrated in vacuo to afford 300 mg of the
product (yield was 78%).
4-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinecarboxamide
O Cl
N N
To a cooled solution of 4-chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline
carboxamide (300 mg, 0.81 mmol) in dichloromethane (50 mL) was added 3-
chloroperoxybenzoic acid (418 mg, 70% purity, 1.70 mmol) at 0 oC. After being stirred for 2
hours at 0 oC, the reaction mixture was washed with a saturated aqueous solution of sodium
thiosulphate (50 mL), dried over sodium sulfate, and concentrated in vacuo to afford 300 mg of
the crude product.
4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinecarboxamide
O NH NH2
N N
O
A mixture of 4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline
carboxamide (300 mg, 0.75 mmol) and propane-1,3-diamine (306 mg, 4.14 mmol) was heated
with stirring in a sealed 10 mL of microwave process vial for 1 hour at 120 ºC under ave
irradiation. The reaction mixture was purified by preparative HPLC to afford 23.5 mg of the
desired t (yield was 7.2%). MS obsd. (ESI+) [(M+H)+] 440, 1H NMR (400 MHz, CD3OD)
δ ppm 8.70 - 8.69 (d, J = 1.6 Hz, 1 H), 8.18 - 8.15 (m, 1 H), 8.10 - 8.08 (dd, J = 1.2, 7.6 Hz, 1
H), 7.88 - 7.84 (t, J = 6.8 Hz, 2 H), 7.73 - 7.72 (m, 1 H), 7.60 - 7.59 (m, 1 H), 6.01 (s, 1 H), 5.34
(s, 2 H), 4.55 (s, 2 H), 3.75 (s, 2 H), 3.64 - 3.60 (t, J = 6.8 Hz, 1 H), 3.11 - 3.09 (m, 2 H), 2.18 -
2.09 (m, 2 H).
Example 82
1-{4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinyl}ethanol
OH NH NH
N N
4-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinecarbaldehyde
O Cl
N N
O
To a solution of oxalyl dichloride (36.3 mg, 0.29 mmol) in dichloromethane (10 mL) was added
a solution of dimethyl sulphoxide (0.1 mL, 0.57 mmol) in dichloromethane (10 mL) at -78 °C
dropwise. After the mixture being stirred for 10 minutes at -78 °C, a solution of 4-chloro(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinemethanol (100 mg, 0.26 mmol,
prepared in analogy to the one in Example 3-23) in dichloromethane (5 mL) was added
dropwise. After the mixture being stirred for further 1 hour at -78 °C, triethylamine (0.2 mL, 1.3
mmol) was. The resulting mixture was stirred at -78 °C for 1 hour and then at room temperature
for r 1 hour. The reaction was washed with brine, dried over sodium sulfate and
concentrated in vacuo to afford 70 mg of the product.
1-[4-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]ethanol
OH Cl
N N
To a cooled solution of 4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
inecarbaldehyde (100 mg, 0.26 mmol) in tetrahydrofuran (20 mL) was added a solution
of methyl magnesium bromide in tetrahydrofuran (0.13 mL, 0.39 mmol, 3 M) at 0 °C dropwise.
After being stirred for 20 s at the temperature below 12 °C, the mixture was concentrated
in vacuo. The residue was ed by preparative TLC to give 100 mg of the desired product
(yield was 96%).
1-{4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinyl}ethanol
OH NH NH
N N
O
A mixture of 1-[4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin
yl]ethanol (150 mg, 0.387 mmol) and propane-1,3-diamine (55 mg, 0.74 mmol) was heated with
stirring in a sealed 0.5 mL of microwave process vial for 1.5 hours at 150 ºC under microwave
irradiation. The on mixture was ed by preparative HPLC and SPE to afford 70.2 mg
of the desired t (yield was 41.2%). MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz,
CD3OD) δ ppm 8.10 - 8.05 (m, 2 H), 7.86 - 7.80 (d, J = 7.6 Hz, 1 H), 7.78 - 7.75 (m, 2 H), 7.72-
7.62 (t, J = 1.2 Hz, 1 H), 7.60 - 7.50 (t, J = 1.2 Hz, 1 H), 5.94 (s, 1 H), 5.30 (s, 2 H), 4.98 - 4.92
(m, 1 H), 4.58 - 4.45 (m, 2 H), 3.78 - 3.70 (t, J = 2.8 Hz, 2 H), 3.62 - 3.53 (t, J = 4.4 Hz, 2 H),
3.10 - 3.02 (t, J = 6.8 Hz, 2 H), 2.12 - 2.02 (m, 2 H), 1.50 - 1.40 (d, J = 6.4 Hz, 3 H).
Example 83
3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}propanenitrile
N N
A flask containing 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine
1,1-dioxide (500 mg, 1.34 mmol, prepared in analogy to 4-(4-chloro
(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example
17-1), 3-aminopropionitrile (140 mg, 2.01 mmol ), tris(dibenzylideneacetone)dipalladium(0) (
61.8 mg, 0.068 mmol ), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl ( 83.3 mg, 0.134 mmol ),
sodium tert-butoxide (257 mg, 2.68 mmol) and e (15 ml ) was evacuated and then filled
with nitrogen (balloon). After being stirred at 110 ºC overnight, the ing mixture was diluted
with water (15 mL), and extracted with ethyl acetate (15 mL × 4). The ed organic layers
were dried over sodium e and concentrated in vacuo. The residue was purified by flash
column chromatography (eluting with 10% methanol in dichloromethane) to afford 380 mg of
the product as a white solid (yield was 70%). MS obsd. (ESI+) [(M+H)+] 407, 1H NMR (400
MHz, CD3OD) δ ppm 8.02 - 8.00 (m, 1 H), 7.90 (d, J = 7.2 Hz, 1 H), 7.69 - 7.63 (m, 2 H), 7.51 -
7.45 (m, 2 H), 7.34 - 7.31 (m, 1 H), 6.10 (s, 1 H), 5.19 (s, 2 H), 4.55 (brs, 2 H), 3.73 (t, J = 13.2
Hz, 2 H), 3.63 (t, J = 10 Hz, 2 H ), 2.85 (t, 2 H), 2.44 (s, 3 H).
Example 84
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2-(1H-tetrazol
yl)ethyl]quinolinamine
NH N
N N
A mixture of 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]amino}propanenitrile (100 mg, 0.25 mmol), sodium azide (48 mg, 0.98 mmol), dimethyl
formamide (2 ml) and um chloride (52.6 mg, 0.98 mmol) was heated at 80 ºC in an oil
bath overnight. The resulting mixture was diluted with water and ted with romethane
(10 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate
and concentrated in vacuo. The residue was purified by flash column chromatography (eluting
with 10% methanol in dichloromethane) to afford 20 mg of the desired product as a white solid.
MS obsd. (ESI+) +] 450, 1H NMR (400 MHz, CD3OD) δ ppm 8.06 (m, 1 H), 7.92 (t, 1
H), 7.86 (s, 1 H), 7.60 (m, 1 H), 7.58 - 7.52 (m, 3 H), 5.89 (s, 1 H), 5.27 (s, 2 H), 4.52 (brs, 2 H),
3.86 (t, 2 H), 3.72 (t, 2 H ), 3.33 (t, 2 H), 2.47 (s, 3 H).
Example 85
N~4~-(2-Aminoethyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-4,6-
diamine
NH 2
N N
O
To a solution of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)nitroquinolin
yl]ethane-1,2-diamine (50 mg, 0.11 mmol, prepared in analogy to N-[2-(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]ethane-1,2-diamine in Example 9-
11) in methanol (20 mL) was added tin(II) chloride (102.8 mg, 0.55 mmol). After being refluxed
overnight, the resulting mixture was cooled to room temperature, diluted with dichloromethane,
washed with brine, dried over anhydrous sodium e and concentrated in vacuo. The residue
was purified by preparative HPLC to afford 11 mg of the desired product (yield was 25%). MS
obsd. (ESI+) [(M+H)+] 398, 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (d, J = 8.08 Hz, 1 H), 7.79
(d, J = 7.58 Hz, 1 H), 7.60 (t, J = 7.45 Hz, 1 H), 7.47 - 7.37 (m, 1 H), 7.35 (d, J = 8.84 Hz, 1 H),
7.06 - 6.95 (m, 2 H), 6.00 (s, 1 H), 5.10 (s, 2 H), 3.56 (brs, 2 H), 3.41 (t, J = 6.44 Hz, 2 H), 2.96
(t, J = 6.44 Hz, 2 H), 1.29 (brs, 2 H).
e 86
-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]oxa-
5,7-diazaspiro[3.4]octanone
N O
N N
A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
e (372 mg, 1.0 mmol, ed in analogy to the one in Example 17-1), tert-butyl [(3-
aminooxetanyl)methyl]carbamate (202 mg, 1.0 mmol),
tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.10 mmol), 2,2'-bis(diphenylphosphino)-1,1'-
binaphthyl (62 mg, 0.10 mmol) and sodium tert-buoxide (192 mg, 2.0 mmol) in toluene (10 mL)
was heated at 110 oC overnight. The resulting mixture was diluted with water (20 mL), and
extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with
brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by
preparative HPLC to afford 15 mg of the title compound. MS obsd. (ESI+) [(M+H)+] 465, 1H
NMR (400 MHz, DMSO-d6) δ ppm 8.15 (s, 1 H), 7.98 - 7.96 (d, J = 7.2 Hz, 1 H), 7.90 - 7.87
(m, 1 H), 7.68 - 7.64 (m, 1 H), 7.53 -7.46 (m, 2 H), 7.37 - 7.34 (m, 2 H), 7.17 (s, 1 H), 5.14 (s, 2
H), 4.80 - 4.74 (m, 4 H), 4.44 (s, 2 H), 4.27 (s, 2 H), 3.66 - 3.64 (t, J = 4.8, 4,4 Hz, 2 H), 2.36 (s,
3 H).
Example 87-1
3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin
yl]amino}propane-1,2-diol
N N
2-Chloro-N-[(2,2-dimethyl-1,3-dioxolanyl)methyl]methylquinazolinamine
N Cl
A solution of 2,4-dichloromethylquinazoline (300.0 mg, 1.4 mmol), triethylamine ( 0.5 mL)
and methyl-1,3-dioxolanemethanamine (0.2 mL, 1.5 mmol) in methanol ( 2.0 mL) was
stirred at room temperature for 16 hours. The on mixture was diluted with ethyl acetate
(100 mL), washed with brine (50 mL × 2), dried over anhydrous sodium sulfate and then
concentrated in vacuo to afford 431 mg of the crude product as a white solid. MS obsd. (ESI+)
[(M+H)+] 308.
3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin
yl]amino}propane-1,2-diol
N N
A solution of 2-chloro-N-[(2,2-dimethyl-1,3-dioxolanyl)methyl]methylquinazolinamine
(431.2 mg, 1.4 mmol) and triethylamine (0.8 mL), 5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (296.1 mg, 1.5 mmol) in N,N-dimethyl-formamide (1.0 mL) was stirred at 160 oC for 4
hours. After being cooled to room temperature, the reaction mixture was dissolved in methanol
(2.0 mL). To the above mixture, concentrated hydrochloric acid (0.5 mL) was added, and the
resulting mixture was stirred at room temperature for 1 hour, and then ted with ethyl
acetate (100 mL). The organic layer was washed with brine (50 mL × 2), dried over anhydrous
sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to
afford 59.2 mg of the t as a white solid (yield was 10%). MS obsd. (ESI+) [(M+H)+] 429,
1H NMR (400 MHz, CD
3OD) δ ppm 7.98 (dd, J = 7.83, 1.01 Hz, 1 H), 7.90 (d, J = 7.58 Hz, 1
H), 7.66 - 7.55 (m, 2 H), 7.50 - 7.35 (m, 2 H), 7.35 - 7.28 (m, 1 H), 5.21 (brs, 2 H), 4.56 (brs, 2
H), 4.05 - 3.95 (m, 1 H), 3.86 (dd, J = 13.26, 4.42 Hz, 1 H), 3.73 - 3.56 (m, 3 H), 3.53 (t, J =
5.05 Hz, 2 H), 2.39 (s, 3 H).
Example 87-2
3-[6-Chloro(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl))-quinazolin
ylamino]-propane-1,2-diol
N N
The title compound was prepared in analogy to Example 87-1 in Scheme 41 by using 2,4,6-
trichloroquinazoline, 2,2-dimethyl-1,3-dioxolanemethanamine and 2,3,4,5-tetrahydro-1,4-
benzothiazepine oxide. MS obsd. (ESI+) [(M+H)+] 449, 1H NMR (400 MHz, CD3OD) δ
ppm 7.98 (d, J = 7.83 Hz, 1 H), 7.95 - 7.84 (m, 2 H), 7.62 (t, J = 7.33 Hz, 1 H), 7.53 - 7.41 (m, 2
H), 7.37 (d, J = 8.84 Hz, 1 H), 5.21 (brs, 2 H), 4.61 (brs, 2 H), 4.01 (brs, 1 H), 3.85 (brs, 1 H),
3.65 (brs, 3 H), 3.52 (t, J = 4.67 Hz, 3 H).
Example 88-1
N-[2-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl]ethane-1,2-
diamine
N N
tert-Butyl {2-[(2-chloromethylquinazolinyl)amino]ethyl}carbamate
O O
N Cl
A mixture of 2,4-dichloromethylquinazoline (700 mg, 3.29 mmol), tert-butyl N-(2-
aminoethyl)carbamate (2.6 g, 16.4 mmol) and methanol (35 mL) was stirred at room ature
for 1 hour. The resulting mixture was concentrated in vacuo and the residue was purified by flash
column chromatography to afford 1.0 g of the t as a white solid (yield was 91%).
tert-Butyl {2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin
yl]aminoethyl}carbamate
O O
N N
To a solution of tert-butyl {2-[(2-chloromethylquinazolinyl)amino]ethyl}carbamate (460
mg, 1.366 mmol) in n-butanol (6 mL) was added 2,3,4,5-tetrahydro-1,4-benzothiazepine (248
mg, 1.50 mmol) and triethylamine (276 mg, 2.732 mmol). The mixture was heated with stirring
at 100 oC in a sealed tube for 4 hours, and then trated in vacuo. The residue was purified
by flash column chromatography to afford 350 mg of the desired product as a white solid (yield
was 55%).
N-[2-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl]ethane-1,2-
diamine
N N
To a cooled solution of trifluoroacetic acid in romethane (2 mL, V/V = 1/4) was added
tert-butyl {2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin
yl]aminoethyl}carbamate (120 mg, 0.258 mmol) in an ice bath. The mixture was stirred for 3
hours whilst allowing the temperature of the mixture rising naturally to room temperature, and
then concentrated in vacuo. The residue was dissolved in water (10 mL), and washed with
dichloromethane (10 mL). The aqueous layer was ed to pH 10 with a saturated aqueous
solution of sodium carbonate and extracted with ethyl acetate (20 mL × 2). The organic extracts
were dried with sodium sulfate, trated in vacuo to afford 68 mg of the product as a white
solid (yield was 72%). MS obsd. (ESI+) [(M+H)+] 366, 1H NMR (400 MHz, CD3OD) δ ppm 7.67
- 7.64 (t, J = 12.0 Hz, 2 H), 7.49 - 7.47 (d, J = 8.4 Hz, 1 H), 7.38 - 7.30 (m, 2 H), 7.23 - 7.19 (dd,
J = 8.4, 7.6 Hz, 2 H), 7.13 - 7.09 (dd, J = 8.8 Hz, 1 H), 5.04 (s, 2 H), 4.38 (s, 2 H), 3.75 - 3.72
(m, 2 H), 2.98 - 2.92 (m, 4 H), 2.39 (s, 3 H).
Example 88-2
(1-Amino-cyclopropylmethyl)-[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)-quinolinyl]-amine
N N
The title compound was prepared in analogy to Example 88-1 in Scheme 42 by using 2,4-
dichloromethylquinazoline, tert-butyl inomethyl)cyclopropyl]carbamate and 2,3,4,5-
tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI +) [(M+H)+] 408, 1H NMR (400 MHz,
CDCl3) δ ppm 7.766 - 7.748 (d, J = 7.2 Hz, 1 H),7.632 (s, 1 H), 7.410 - 7.328 (m, 5 H), 5.936 (s,
1 H), 5.333 - 5.295 (d, J = 15.2 Hz, 1 H), 4.924 (m, 2 H), 4.400 (s, 1 H), 3.644 (s, 2 H), 3.332 (s,
2 H), 2.398 (s, 3 H), 0.740 - 0.678 (m, 4 H).
Example 89
N-[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]ethane-
1,2-diamine
N N
tert-Butyl {2-[2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin
noethyl}carbamate
N O
N N
O
To a solution of oxone (120 mg, 0.200 mmol) in water (0.7 mL) which was cooled below 0 oC in
an ice bath, was added a solution of tert-butyl {2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
6-methylquinazolinyl]aminoethyl}carbamate (155 mg, 0.333 mmol) in methanol (3 mL)
dropwise. The mixture was stirred below 0 oC about 20 minutes. The formed precipitate was
collected by filtration, washed with water and purified by flash column chromatography to afford
124 mg of the product as a white solid (yield was 77%).
N-[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]ethane-
1,2-diamine
N N
The title compound was prepared in analogy to Example 88-1 in Scheme 42 by using tert-butyl
{2-[2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin
yl]aminoethyl}carbamate (150 mg, yield was 86%). MS obsd. (ESI+) [(M+H)+] 382, 1H NMR
(400 MHz, CD3OD) δ ppm 7.74 - 7.72 (t, J = 8.0 Hz, 2 H), 7.66 - 7.62 (d, J = 16.0 Hz, 1 H), 7.49
- 7.44 (m, 2 H), 7.42 - 7.40 (m, 1 H), 7.38 - 7.33 (m, 1 H), 5.29 - 5.25 (d, J = 16.0 Hz, 1 H ), 4.81
- 4.70 (m, 1 H), 4.58 - 4.51 (m, 1 H), 3.79 - 3.70 (m, 2 H), 3.53 - 3.34 (m, 4 H), 3.03 - 3.00 (m, 2
H), 2.40 (s, 3 H).
Example 90
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin
yl]ethane-1,2-diamine
N N
tert-Butyl {2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin-
4-yl]aminoethyl}carbamate
O O
N N
To a solution of tert-butyl {2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin-
4-yl]aminoethyl}carbamate (190 mg, 0.408 mmol) in dichloromethane (10 mL) was added
dropwise a solution of 3-chloroperbenzoic acid (228.6 mg, 1.02 mmol) in dichloromethane (6
mL) in an ice bath. After the mixture being stirred in an ice bath for 2 hours, the reaction was
quenched by the addition of a saturated aqueous solution of sodium thiosulphate. The ted
organic layer was washed by a saturated s solution of sodium bicarbonate and brine, dried
over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash
column chromatography (eluting with 20 - 40% ethyl acetate in petroleum ether) to give 170 mg
of the t.
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin
yl]ethane-1,2-diamine
N N
The title compound was prepared in analogy to Example 88-1 in Scheme 42 by using tert-butyl
{2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin
yl]aminoethyl}carbamate. MS obsd. (ESI+) [(M+H)+] 398, 1H NMR (400 MHz, CD3OD) δ ppm
7.98 (d, J = 6.8 Hz, 1 H), 7.83 (d, J = 7.6 Hz, 1 H), 7.65 (s, 1 H), 7.61 (dd, J = 6.8, 7.6 Hz, 1 H),
7.44 (t, J = 7.2 Hz, 1 H), 7.38 (dd, J = 1.6, 8.4 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 5.20 (s, 2 H),
4.58 (brs, 2 H), 3.73 (t, J = 6.4 Hz, 2 H), 3.54 - 3.48 (m, 2 H), 2.97 (t, J = 6.4 Hz, 2 H), 2.39 (s, 3
Example 91
N-[3-(Aminomethyl)oxetanyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinazolinamine
NH NH
N N
Trifluoro-N-[(3-{[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinazolinyl]amino}oxetanyl)methyl]acetamide
NH N
N O
N N
O
The title compound was prepared as a light white solid in analogy to Example 62-1 in Scheme 23
by using 2-chloromethylquinazolin-4(3H)-one, 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-
oxide and aminooxetanyl)methyl]-2,2,2-trifluoroacetamide (yield was 80%).
N-[3-(Aminomethyl)oxetanyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinazolinamine
NH NH
N N
To a stirred of 2,2,2-trifluoro-N-[(3-{[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinazolinyl]amino}oxetanyl)methyl]acetamide (70 mg, 0.135 mmol) in ethanol
(5 mL) was added an aqueous solution of sodium hydroxide (5 N, 1 mL). After being stirred at
room temperature overnight, the resulting mixture was diluted with water (15 mL), and extracted
with dichloromethane (15 mL × 3). The organic layers were combined, washed with brine, dried
over sodium sulfate, and concentrated in vacuo. The residue was ed by ative HPLC
to afford 7 mg of the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR
(400 MHz, CD3OD) δ ppm 7.97 (s, 1 H), 7.83 - 7.78 (m, 2 H), 7.71 - 7.68 (m, 1 H), 7.61 - 7.54
(m, 3 H), 5.45 (d, 1 H), 5.15 (brs, 1 H), 4.81 - 4.74 (m, 5 H), 4.51 (brs, 3 H), 3.54 (brs, 2 H), 2.45
(s, 3 H).
Example 92-1
N-(transFluoropyrrolidinyl)methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinazolinamine
N N
S
Benzyl transfluoro{[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinazolinyl]amino}pyrrolidinecarboxylate
N N
A suspension of 6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-
4(3H)-one (600 mg, 1.77 mmol, prepared in analogy to the one in Example 91), benzotriazol
yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.02 g, 2.3 mmol), and 1,8-
diazabicyclo[5.4.0]undecene (400 mg, 2.6 mmol) in anhydrous N,N-dimethylformamide (10
mL) was stirred at room ature for 10 minutes. Then a solution of benzyl transamino
fluoropyrrolidinecarboxylate (500 mg, 2.1 mmol) in N,N-dimethylformamide (5 mL) was
added dropwise. After being heated at 60 oC overnight, the mixture was diluted with water (50
mL), extracted with dichloromethane (50mL). The c layer was washed with brine, dried
over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash
column tography (gradient eluting with 10% to 25% ethyl acetate in romethane) to
afford 415 mg of the desired product as a yellow solid (yield was 41.8%).
N-(transFluoropyrrolidinyl)methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinazolinamine
N N
A mixture of benzyl transfluoro{[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinazolinyl]amino}pyrrolidinecarboxylate (200 mg, 0.35 mmol) and an aqueous
solution of hloric acid (5 mL, 6 N) was ed for 6 hours. The resulting mixture was
basified by adding an aqueous solution of sodium hydroxide (1 N) to pH 10, and then extracted
with dichloromethane (50 mL). The organic layer was washed with brine, dried over anhydrous
sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to
afford the desired compound as a yellow solid. MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400
MHz, CD3OD) δ ppm 7.76 (m, 3 H), 7.45 (m, 4 H), 5.32 (m, 3 H), 4.61(s, 3 H), 3.70 - 3.11 (m, 6
H), 2.41 (s, 3 H).
Example 92-2
N-(transFluoropyrrolidinyl)methyl(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinazolinamine
N N
The title compound was prepared in analogy to Example 92-1 in Scheme 44 by using yl-
2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one (prepared in
analogy to 6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one
in Example 91) and benzyl transaminofluoropyrrolidinecarboxylate. MS obsd. (ESI+)
[(M+H)+] 442, 1H NMR (400 MHz,CDCl3) δ ppm 8.40 - 8.02 (d, J = 7.6 Hz , 1 H), 7.83 - 7.81
(d, J = 7.2 Hz ,1 H), 7.52 - 7.49 (m, 1 H), 7.37 - 7.35 (d, J = 10.8 Hz, 3 H), 7.22 (s, 1 H), 5.41 (s,
1 H), 5.30 - 5.00 (brs, 2 H), 4.90 - 4.55 (brs, 2 H), 3.70 - 3.68 (d, J = 5.2 Hz, 1 H), 3.48 (s, 2 H),
3.31 - 3.25 (brs, 2 H) 2.95 (s, 1 H), 2.38 (s, 3 H), 2.20- 2.18 (d, J = 8.8 Hz, 1 H).
Example 93-1
1-[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin
yl]pyrrolidinamine
N N
tert-Butyl methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin
yl]pyrrolidinyl}carbamate
N N
The title compound was prepared in analogy to benzyl (3S,4S)fluoro{[6-methyl(1-
oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]amino}pyrrolidine
carboxylate in Example 92 by using 6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinazolin-4(3H)-one and tert-butyl (pyrrolidinyl)carbamate.
1-[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin
yl]pyrrolidinamine
N N
O
The title nd was prepared in analogy to Example 90 in Scheme 44 by using tert-butyl {1-
[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]pyrrolidin
yl}carbamate. MS obsd. (ESI+) [(M+H)+] 408, 1H NMR (400 MHz, CD3OD) δ ppm 7.73 (s, 1
H), 7.64 (dd, J = 7.2, 1.6 Hz, 2 H), 7.41 - 7.28 (m, 4 H), 5.16 (d, J = 15.2 Hz, 1 H), 4.70 (m, 2
H), 4.39 (s, 1 H), 3.86 (m, 2 H), 3.59 (m, 2 H), 3.37 (brs, 1 H), 2.31 (s, 3 H), 2.15 (m, 1 H), 1.82
(m, 1 H), 1.24 (brs, 1 H).
Example 93-2
N-(Azetidinyl)methyl(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
quinazolinamine
N N
O
The title nd was prepared in analogy to Example 93-1 in Scheme 44 by using 6-methyl-
2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one and tert-butyl 3-
aminoazetidinecarboxylate. MS obsd. (ESI+) [(M+H)+] 410.1, 1H NMR (400 MHz, DMSO-
d6) δ ppm 8.24 (s, 1 H), 7.87 (s, 2 H), 7.79 (s, 1 H), 7.62 (brs, 1 H), 7.45 (s, 1 H), 7.34 (d, J = 8.4
Hz, 1 H), 7.22 (brs, 1 H), 5.06 – 4.42 (m, 5 H), 3.85 (brs, 1 H), 3.59 (m, 5 H), 2.32 (s, 3 H).
Example 94
(4R){2-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]ethyl}-4,5-dihydro-1,3-oxazolamine
N N
tert-Butyl (4R){(2E)-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)
methylquinolinyl]-vinyl}-2,2-dimethyl-1,3-oxazolidinecarboxylate
N N
To a vial containing a mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide (200 mg, 0.536 mmol, prepared in analogy to 4-(4-chloro
uoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example
17-1), tert-butyl (4R)ethenyl-2,2-dimethyl-1,3-oxazolidinecarboxylate (146 mg, 0.643
mmol), triethylamine (0.5 mL) and N,N-dimethylformamide (1 mL), which was evacuated and
filled with argon, di(tri-tert-butylphosphine)palladium(0) (13.7 mg, 0.0268 mmol) was added.
The vial was caped and heated at 110 oC for 30 minutes under ave ation. The
reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3).
The c layers were combined, washed with brine, dried over sodium sulfate and
concentrated in vacuo. The residue was purified by flash column chromatography (eluting with
50% ethyl acetate in hexanes) to afford 180 mg of the desired product as a white solid (yield was
60%).
(3R)Amino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl))methyl-
quinolinyl]-butanol
N N
A solution of tert-butyl (4R){(2E)-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-
6-methylquinolinyl]-vinyl}-2,2-dimethyl-1,3-oxazolidinecarboxylate (180 mg, 0.32 mmol)
in methanol was hydrogenated over 10% palladium on carbon (30 mg) under atmospheric
pressure for 2 hours at room temperature. The reaction mixture was ed and the filtrate was
concentrated in vacuo. The residue was dissolved in a solution of hydrochloride in ethyl acetate
(2 N, 10 mL) and the solution was stirred at room ature for 2 hours. The reaction mixture
was basified with an aqueous on of sodium bicarbonate (2 N) to pH 8 and then extracted
with ethyl acetate (15 mL × 3). The combined layers was dried over sodium sulfate and
concentrated in vacuo. The residue was purified by flash column chromatography (eluting with
% methanol in dichloromethane) to afford 90 mg of the desired t as a white solid (yield
was 66.2%).
(4R){2-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]ethyl}-4,5-dihydro-1,3-oxazolamine
N N
O
The title compound was prepared in analogy to Example 38-1 in Scheme 45 by using (3R)
amino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl))methyl-quinolinyl]-
butanol and cyanogen e. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, DMSO-
d6) δ ppm 7.89 (m, J = 4.7 Hz, 2 H), 7.72 (s, 1 H), 7.63 (t, J = 3.7 Hz, 1 H), 7.47 (t, J = 3.9 Hz, 1
H), 7.32 (d, J = 2.1 Hz, 1 H), 7.23 (d, J = 2.1 Hz, 1 H), 6.85 (t, J = 2.6 Hz, 1 H), 6.10 (s, 1 H),
.15 (s, 2 H), 4.53 (brs, 2 H), 3.97 - 3.91 (m, J = 5.8 Hz, 2 H ), 3.58 (t, J = 2.4 Hz, 2 H), 3.66 -
3.41 (m, J = 3.3 Hz, 2 H), 2.90 (dd, J = 4.2, 0.9, Hz, 1 H), 2.77 (dd, J = 5.2, 0.9 Hz, 1 H), 2.42 (s,
3 H).
e 95
3-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)ethylquinolinyl]propanoic
acid
O OH
N N
Ethyl (2E)[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethylquinolin
yl]propenoate
O O
N N
A mixture of 4-(4-chloroethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (300 mg, 0.78 mmmol), ethyl propenoate (170 mg, 1.70 mmol), triethylamine (1 mL)
and N,N-dimethylformamide (2 mL), bis(tri-tert-butylphosphine)palladium(0) (15 mg, 0.02
mmol) was heated with ng in a 10 mL of microwave process vial for 30 minutes at 100 °C
under microwave irradiation. The reaction mixture was poured into water (5 mL) and extracted
with ethyl acetate (10 mL × 3). The organic layers were combined, washed with brine, dried over
sodium sulfate and concentrated in vacuo. The residue was purified by flash tography on
silica gel (eluting with 20 - 40% ethyl acetate in petroleum ether) to afford 280 mg of the product
as a white solid (yield was 80%). MS obsd. (ESI+) [(M+H)+] 451.
Ethyl 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethylquinolin
yl]propanoate
O O
N N
To a 25 mL of dry round bottom flask containing a solution of ethyl (2E)[2-(1,1-dioxido-2,3-
o-1,4-benzothiazepin-4(5H)-yl)ethylquinolinyl]propenoate (300 mg, 0.67 mmol)
in dichloromethane (5 mL) was added 2-nitrophenylsulfonylhydrazide (2.91 g, 13.4 mmol)
followed by a solution of triethylamine (5 mL) in dichloromethane (10 mL) under nitrogen. The
suspension was gently stirred for 6 hour at room ature under nitrogen, and then
trated in vacuo. The residue was purified by flash column chromatography on silica gel
(eluting with 20 - 40% ethyl acetate in petroleum ether) to afford 151 mg of the desired t
(yield was 50%). MS obsd. (ESI+) [(M+H)+] 453.
3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)ethylquinolinyl]propanoic
acid
O OH
N N
To a solution of ethyl 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
ethylquinolinyl]propanoate (100 mg, 0.22 mmol) in methanol (2 mL) was added an aqueous
solution of m hydroxide (20.6 mg in 2 mL of water) and the resulting mixture was stirred at
room temperature for 4 hours. The reacting mixture was acidified to pH 4 with an aqueous
solution of hydrochloric acid (5 N), and then extracted with ethyl acetate (10 mL × 3). The
organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was
purified by flash column chromatography (eluting with 1 - 10% methanol in dichlorometane) to
afford 50 mg of the t as a white solid. MS (ESI +) [(M+H)+] 425, 1H NMR (400 MHz,
DMSO-d6) δ ppm 8.08 (brs, 2 H), 7.94 (d, J = 7.58 Hz, 1 H), 7.80 (brs, 1 H), 7.72 (t, J = 7.07
Hz, 1 H), 7.57 (d, J = 7.33 Hz, 2 H), 7.37 (brs, 1 H), 5.38 (m, 2 H), 4.56 (brs, 2 H), 3.94 - 3.69
(m, 2 H), 3.26 (brs, 2 H), 2.81 - 2.64 (m, 4 H), 1.22 (t, J = 7.58 Hz, 3 H).
Example 96
3-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]propan-
1-amine
N N
O O
3-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-
propionitrile
N N
O O
The title compound was prepared in analogy to ethyl 3-[2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)ethylquinolinyl]propanoate in e 95 in Scheme 46 by using
4-(4-chloroethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and
acrylonitrile.
3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]propanamide
O NH
N N
O O
A solution of 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]-propionitrile (150 mg, 0.38 mmol), and powdered potassium hydroxide (172 mg, 3.07 mmol)
in tert-butanol (8 mL) was heated with stirring under reflux for 1.5 hours. After being cooled to
room ature, the reaction mixture was diluted with water (15 mL) and extracted with ethyl
acetate (15 mL × 3). The combined organic layers were dried over sodium sulfate and
concentrated in vacuo. The e was purified by flash column (eluting with 5% methanol in
dichloromethane) to afford 125 mg of the product as a white solid.
3-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]propan-
1-amine
N N
O O
To a solution of 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin-
4-yl]-propionamide (30 mg, 0.073 mmol) in tetrahydrofuran (2 mL) was added a solution of
borane in ydrofuran (1 mL, 2 M) in an ice bath. The mixture was stirred at 65 °C for 3
hours and then cooled naturally to room temperature. The reaction was quenched with methanol
and the e was concentrated in vacuo. The residue was purified by preparative HPLC to
afford 6.3 mg of the desired product. MS obsd. (ESI+) [(M+H)+] 396, 1H NMR (400 MHz,
CD3OD) δ ppm 7.99 (dd, J = 1.2, 8.0 Hz, 1 H), 7.88 (d, J = 7.2 Hz, 1 H), 7.64 - 7.56 (m, 3 H),
7.45 (dd, J = 6.8, 7.6 Hz, 1 H), 7.37 (dd, J = 1.6, 8.4 Hz, 1 H), 7.06 (s, 1 H), 5.22 (s, 2 H), 4.57
(brs, 2 H), 3.61 (t, J = 4.8 Hz, 2 H), 3.07 (t, J = 8.0 Hz, 2 H), 2.94 (t, J = 7.6 Hz, 2 H), 2.45 (s, 3
H), 2.04 - 1.96 (m, 2 H).
Example 97
2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]oxy}ethanamine
N N
O O
N-(2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]oxy}ethyl)acetamide
N O
N N
O O
A mixture of N-(2-hydroxyethyl)-acetamide (247 mg, 2.4 mmol), 4-(4-bromomethylquinolin-
2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (1000 mg, 2.4 mmol, prepared in
analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide in Example 17-1), 1,1'-bis(diphenylphosphino)ferrocenepalladium
(II)dichloride (190.4 mg, 0.24 mmol), 1,1'-bis(diphenylphosphino)ferrocene (129.3
mg, 0.24 mmol) and sodium tert-butoxide (460.8 mg, 4.8 mmol) in 1,4-dioxane (5 mL) was
heated with stirring in a sealed 10 mL of microwave process vial for 1 hour at 130 ºC under
microwave irradiation. The reaction mixture was trated in vacuo and the residue was
purified by preparative HPLC to afford 20 mg of the desired t (yield was 1.9%).
2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]oxy}ethanamine
N N
O O
A mixture of N-(2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin-
4-yl]oxy}ethyl)acetamide (15 mg, 0.03 mmol) and an s solution of hydrochloric acid (10
mL, 37% W/W) was heated with stirring at 80 ºC for 3 hours. The reaction mixture was purified
by preparative HPLC and SPE to give 9.3 mg of the desired product (yield was 68.5%). MS
obsd. (ESI+) [(M+H)+] 398, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (s, 1 H), 8.10 - 8.06 (d, J
= 7.6 Hz , 1 H), 7.93 - 7.88 (d, J = 7.2 Hz ,1 H), 7.82 - 7.76 (d, J = 8 Hz, 1 H), 7.73 - 7.68 (t, J =
7.6 Hz, 1 H), 7.65 - 7.60 (d, J = 6.8 Hz ,1 H), 7.60 - 7.53 (t, J = 7.2 Hz ,1 H), 6.68 (s, 1 H), 5.41
(s, 2 H), 4.70 - 4.65 (m, 2 H), 4.65 - 4.45 (m, 2 H), 3.80 - 3.72 (t, J = 2.8 Hz , 2 H), 3.62 - 3.58 (t,
J = 4.4 Hz , 2 H), 2.47 (s, 3 H).
Example 98-1
4-[6-Methyl(pyrrolidinyloxy)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine
1,1-dioxide
N N
tert-Butyl 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]oxy}pyrrolidinecarboxylate
N N
A mixture of tert-butyl 3-hydroxypyrrolidinecarboxylate (134.7 mg, 0.72 mmol), 4-(4-bromo-
6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (300 mg, 0.72 mmol,
prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide in Example 17-1), is(diphenylphosphino)ferrocenepalladium
(II)dichloride (57.12 mg, 0.07 mmol), 1,1'-bis(diphenylphosphino)ferrocene (38.78
mg, 0.07 mmol) and sodium tert-butoxide (138.24 mg, 1.44 mmol) in 1,4-dioxane (5 mL) was
heated with stirring in a sealed 10 mL of microwave process vial for 1 hour at 130 ºC under
ave irradiation. The reaction mixture was concentrated in vacuo and the residue was
purified by ative HPLC to afford 20 mg of the desired product (yield was 5.3%).
4-[6-Methyl(pyrrolidinyloxy)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine
1,1-dioxide
N N
A mixture of tert-butyl (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
quinolinyl]oxy}pyrrolidinecarboxylate (50 mg, 0.096 mmol) and a solution of
hydrochloride in ethyl acetate (30 mL, 4 M) was stirred at room temperature for 8 hours. The
resulting mixture was concentrated in vacuo and the residue was purified by preparative HPLC
and SPE to afford 18.4 mg of the desired product (yield was 45.3%). MS obsd. (ESI+) +]
424, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 - 8.08 (d, J = 6.4 Hz, 1 H), 7.95 - 7.88 (m, 2 H),
7.78 - 7.70 (m, 2 H), 7.68 - 7.56 (m, 2 H), 6.62 (s, 1 H), 5.75 - 5.70 (m, 1 H), 5.40 (s, 2 H), 4.70 -
4.50 (m, 2 H), 3.80 - 3.70 (m, 4 H), 3.65 - 3.48 (m, 2 H), 2.60 - 2.50 (m, 1 H), 2.46 (s, 3 H), 2.46
- 2.35 (m, 1 H).
e 98-2
8-[6-Methyl(piperidinyloxy)-quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine
1,1-dioxide
N N
The title compound was prepared in analogy to Example 98-1 in Scheme 47 by using 4-(4-
bromomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in
analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide in Example 17-1) and tert-butyl 4-hydroxypiperidinecarboxylate.
MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, CD3OD) δ ppm 8.10 - 8.05 (d, J = 8 Hz, 1
H), 7.92 (s, 1 H), 7.90 - 7.85 (d, J = 7.6 Hz ,1 H), 7.80 - 7.75 (d, J = 8.8 Hz, 1 H), 7.75 - 7.68 (t,
J = 7.6 Hz, 1 H), 7.68 - 7.62 (d, J = 9.2 Hz,1 H), 7.60 -7.55 (t, J = 7.6 Hz,1 H), 6.64 (s, 1 H),
.38 (s, 2 H), 5.32 - 5.26 (m, 1 H),4.65 - 4.40 (m, 2 H), 3.82 - 3.72 (t, J = 2.8 Hz , 2 H), 3.52 -
3.40 (m, 2 H), 3.40 - 3.30 (m, 2 H), 2.47 (s, 3 H), 3.36 - 3.28 (m, 2 H), 3.20 - 3.10 (m, 2 H).
Example 99
4-(4,6-Dimethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide
N N
Diethyl (2-chloromethylquinolinyl)propanedioate
O O
O O
N Cl
To a solution of 2,4-dichloromethylquinoline (2.11 g, 10 mmol) and 1,3-diethyl propanedioate
(2.64 g, 20 mmol) in N,N-dimethylformamide (40 mL) was added ous potassium
carbonate (2.8 g, 20 mmol). The mixture was stirred at 70 °C for 3 hours, then poured into
ter (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers
were washed with brine (150 mL × 2), dried over sodium sulfate. The residue was purified by
flash column chromatography on silica gel (eluting with 20 - 30% ethyl acetate in petroleum
ether) to afford 1.34 g of the desired product (yield was 40%). MS obsd. (ESI+) [(M+H)+] 336.
(2-Chloromethylquinolinyl)acetic acid
N Cl
To a solution of diethyl (2-chloromethylquinolinyl)propanedioate (100 mg, 0.30 mmol) in
methanol (2 mL) was added an s solution of sodium hydroxide (2 N, 2 mL) and the
resulting mixture was d at room temperature overnight. The reaction was then acidified to
pH 4 with an s solution of hydrochloric acid (5 N), and extracted with ethyl acetate (10
mL × 3). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford
the desired product as a white solid. MS (ESI+) [(M+H)+] 236.
4-(4,6-Dimethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine
N N
S
A on of (2-chloromethylquinolinyl)acetic acid (118 mg, 0.5 mmol ) and 2,3,4,5-
tetrahydro-1,4-benzothiazepine (247 mg, 1.5 mmol) in n-butanol (0.2 mL) was heated with
stirring in a sealed 0.5 mL of microwave process vial for 2 hours at 160 °C. After being cooled to
room temperature, the reaction mixture was diluted with dichloromethane (50 mL), washed with
a ted aqueous solution of sodium carbonate (50 mL) and brine (50 mL), dried over
anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (eluting with 20 - 30% ethyl acetate in petroleum ether) to afford
100 mg of the desired t (yield was 62%). MS (ESI+) [(M+H)+] 321.
4-(4,6-Dimethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide
N N
O
To a solution of 4-(4,6-dimethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (100 mg,
0.31 mmol) in dichloromethane (10 mL) was added 3-chloroperbenzoic acid (167 mg, 70%
purity, 0.78 mmol) at room temperature for 4 hours. The resulting mixture was washed with a
saturated aqueous solution of sodium carbonate (10 mL), dried over sodium sulfate and
concentrated in vacuo. The e was purified by preparative HPLC to afford the desired
product. MS (ESI+) [(M+H)+] 353, 1H NMR (400 MHz, 6) δ ppm 7.99 (d, J = 7.58 Hz,
1 H), 7.88 (d, J = 7.33 Hz, 1 H), 7.65 (t, J = 7.20 Hz, 1 H), 7.60 - 7.42 (m, 3 H), 7.35 (d, J = 8.34
Hz, 1 H), 7.18 (s, 1 H), 5.12 (brs, 2 H), 4.43 (brs, 2 H), 3.65 (brs, 2 H), 2.53 (s, 3 H), 2.39 (s, 3
Example 100
[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl](piperidin-
4-yl)methanone
N N
tert-Butyl 4-{[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl](hydroxy)methyl}piperidinecarboxylate
N O
N N
To a solution of 4-(4-bromomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (385
mg, 1.0 mmol, ed in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-
tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) in tetrahydrofuran (10 mL) which
was cooled to -78 °C, butyl lithium (0.8 mL, 1.3 mmol) was added slowly and the mixture was
stirred for 5 minutes, followed by the addition of a solution of tert-butyl 4-formylpiperidine
carboxylate (153 mg, 1.3 mmol ) in ydrofuran (5 mL) slowly. After being stirred further at
-78 °C for 2 hours, the reaction mixture was diluted with a saturated aqueous solution of
ammonium chloride (10 mL) and extracted with dichloromethane (20 mL × 2). The organic
layers were combined, dried over sodium e and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (eluting with 20 - 40% ethyl acetate in
petroleum ether) to afford 360 mg of the desired product (yield was 70%). MS (ESI+) [(M+H)+]
520.
tert-Butyl 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl](hydroxy)methyl}piperidinecarboxylate
N O
N N
To a solution of tert-butyl 4-{[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl](hydroxy)methyl}piperidinecarboxylate (519 mg, 1.0 mmol) in romethane (10 mL)
was added 3-chloroperbenzoic acid (537 mg, 70% purity, 2.2 mmol). After being stirred at room
temperature for 4 hours, to the above mixture was added a saturated aqueous solution of sodium
thiosulfate (3 mL). The separated organic layer was washed with a saturated s solution of
sodium carbonate (5 mL) and brine (5 mL), dried over sodium sulfate and concentrated in vacuo.
The residue was purified by flash column chromatography on silica gel (eluting with 20 - 50%
ethyl acetate in petroleum ether) to afford 300 mg of the desired product. MS (ESI+) [(M+H)+]
552.
tert-Butyl 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin
yl]carbonyl}piperidinecarboxylate
N O
N N
To a solution of tert-butyl 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl](hydroxy)methyl}piperidinecarboxylate (200 mg, 0.36 mmol) in
dichloromethane (10 mL) was added Dess-Martin reagents (226 mg, 0.54 mmol). The resulting
mixture was stirred at room temperature until the on was complete monitoring by LC/MS
and then concentrated in vacuo. The residue was purified by flash column chromatography on
silica gel (eluting with 20 - 30% ethyl acetate in petroleum ether) to afford 150 mg of the desired
t. MS (ESI+) +] 550.
[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl](piperidin-
4-yl)methanone
N N
To a solution of utyl 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinyl]carbonyl}piperidinecarboxylate (100 mg, 0.18 mmol) in
dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred
at room temperature until the reaction was te monitoring by LC/MS and then
concentrated in vacuo. The residue was purified by flash column tography on silica gel
(eluting with 1 - 10% methanol in dichloromethane) to afford 60 mg of the desired product. MS
(ESI+) [(M+H)+] 450, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (dd, J = 7.83, 1.26 Hz, 1 H),
7.90 (d, J = 7.07 Hz, 1 H), 7.68 - 7.56 (m, 2 H), 7.51 - 7.38 (m, 3 H), 7.34 (s, 1 H), 5.26 (brs, 2
H), 4.5 (brs, 2 H), 3.70 - 3.58 (m, 2 H), 3.37 (s, 2 H), 3.35 - 3.32 (m, 1 H), 3.14 - 3.03 (m, 2 H),
2.71 (td, J = 12.25, 2.78 Hz, 2 H), 2.40 (s, 3 H), 1.79 (m, 2 H), 1.69 - 1.51 (m, 2 H).
e 101
4-[6-Methyl(1H-pyrazolyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide
N N
To a solution of 8-(4-bromomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (115 mg, 0.28 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolin
yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) in dimethoxyethane (8
mL) was added enylphosphine) palladium (20 mg). After the mixture was stirred for 10
minutes, azoleboric acid (107 mg, 0.84 mmol) was added followed by an aqueous
solution of sodium carbonate (1 M, 0.5 mL). The resulting mixture was sealed and heated with
stirring in a sealed 10 mL of microwave process vial for 1 hour at 80 ºC under microwave
ation. The reaction mixture was then purified by preparative HPLC to afford 36.5 mg of the
desired product (yield was 10.8%). MS (ESI+) [(M+H)+] 405, 1H NMR (400 MHz, CD3OD) δ
ppm 8.41 (s, 1 H), 8.09 - 8.02 (m, 2 H), 7.95 (s, 2 H), 7.69 - 7.53 (m, 4 H), 6.99 (s, 1 H), 5.48 (s,
2 H), 4.67 (s, 2 H), 3.81 (s, 2 H), 3.34 (s, 1 H), 2.44 (s, 3 H).
Example 102
4-[6-Methyl(phenylsulfonyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide
O S O
N N
ethyl(phenylsulfanyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide
N N
A mixture of hloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide (1.8 g, 5.0 mmol, prepared in analogy to the one in Example 17-1), benzenethiol (0.66 g,
6.0 mmol) and N,N-dimethylpyridinamine (0.74 g, 6 mmol) in dry ethanol (40 mL) was
stirred at room temperature for 3 days. The reaction mixture was filtered and concentrated in
vacuo. The residue was purified by silica gel column (gradient eluting with 10 - 20 % ethyl
acetate in s) to afford 1.0 g of the desired product (yield was 45%).
4-[6-Methyl(phenylsulfonyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
dioxide
O S O
N N
A mixture solution of 4-[6-methyl(phenylsulfanyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-
benzothiazepine 1,1-dioxide (223 mg, 0.5 mmol) and roperbenzoic acid (340 mg, 2 mmol)
in dry dichloromethane (30 mL) was stirred at 0 ºC for 2 hours. After the reaction was quenched
with a saturated aqueous on of sodium thiosulphate (15 mL), the resulting mixture was
d further at room temperature for 15 minutes. The separated organic layer was washed with
a saturated aqueous solution of sodium bicarbonate (15 mL) and a saturated aqueous solution of
sodium thiosulphate (15 mL), dried over sodium sulfate and concentrated in vacuo. The residue
was purified by preparative HPLC to afford 168 mg of the desired product (yield was 70%). MS
(ESI+) [(M+H)+] 479, 1H NMR (400 MHz, CDCl3) δ ppm 8.11 - 8.08 (dd, J = 1.2, 8 Hz, 1 H),
8.05 (s, 1 H), 7.91 - 7.89 (t, J = 3.6 Hz, 3 H), 7.75 - 7.38 (d, J = 6.8 Hz, 1 H), 7.65 - 7.58 (m, 3
H), 7.53 - 7.45 (m, 3 H), 7.41 - 7.39 (dd, J = 1.6, 8.4 Hz, 1 H), 5.25 (s, 2 H), 5.15 - 4.20 (brs, 2
H), 3.58 (s, 2 H), 2.42 (s, 3 H).
Example 103
N-(2-Aminoethyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinesulfonamide
O S O
N N
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinethiol
N N
To a solution of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-
e (1.5 g, 4 mmol, prepared in analogy to the one in Example 17-1) in dry N,N-
dimethylformamide (100 mL) was added sodium methanethiolate (1.4 g, 20 mmol) under argon
protection. The reaction was stirred at 130 ºC for 16 hours. The reaction e was cooled to
50 ºC and concentrated in vacuo. The residue was dissolved in cooled water (150 mL) and
carefully acidified with 20% of hydrochloric acid to pH 4 ~ 5 under argon atmosphere. The
resultant solution was extracted with cooled romethane (150 mL × 3). The combined
organic layer was washed with cooled brine (100 mL × 2) and concentrated in vacuo at room
temperature to afford the crude product, which was used for next step without further
purification.
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinesulfonyl
chloride
O S O
N N
Gaseous chlorine was passed through a well stirred solution of 2-(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)methylquinolinethiol (the crude product from the above step) in
concentrated hydrochloric acid (10 mL) at -10 ºC at such a rate that temperature was maintained
between -5 ºC ~ -10 ºC. After been stirred for 30 minutes, the passage of ne was
discontinued and the mixture was poured onto ice (10 g) followed by the addition of sodium
bicarbonate (8 g) in small portions. The resulting mixture was extracted with cooled
dichloromethane (100 mL × 3). The combined organic layer was washed with cooled water (100
mL), dried over sodium sulfate and filtered. The te was used for the next step without
r purification.
N-(2-Aminoethyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
methylquinolinesulfonamide
O S O
N N
To a cooled solution of ethane-1,2-diamine (320 mg, 5.4 mmol) in dichloromethane (50 mL) was
added triethylamine (3 drops) followed by 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-
yl)methylquinolinesulfonyl de (the filtrate from the above step) at 0 ºC. The
resulting mixture was stirred at room temperature for 16 hours and concentrated in vacuo. The
residue was purified by preparative HPLC to afford 56.38 mg of the desired product (yield of
three steps was 3.1%). MS (ESI+) [(M+H)+] 461, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (s, 1
H), 7.99 - 7.97 (d, J = 8.4 Hz, 1 H), 7.85 - 7.83 (d, J = 7.6 Hz, 1 H), 7.67 - 7.63 (m, 3 H), 7.49 -
7.45 (m, 2 H), 5.25 (s, 2 H), 4.76 - 4.03 (m, 2 H), 3.63 - 3.59 (t, 2 H), 3.03 - 3.00 (m, 4 H), 2.46
(s, 3 H).
e 104
Methyl 4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinolinecarboxylate
O NH NH2
O O
N N
Methyl 4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline
carboxylate
O Cl
N N
To a d solution of methyl 4-chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-
oxylate (1.5 g, 3.9 mmol) in dichloromethane (20 ml) was added 3-chloroperbenzoic acid
(1.68 g, 9.7 mmol) at 0 oC. The reaction e was stirred at 0 oC for 20 minutes and the
reaction was quenched with a saturated aqueous solution of sodium carbonate (10 mL). The
separated organic layer was washed with a saturated aqueous solution of sodium carbonate (10
mL) and brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was
purified by flash column chromatography (eluting with 5% methanol in dichloromethane) to
afford 1.38 g of the desired product as a white solid (yield was 85%).
Methyl 4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-
hiazepin-4(5H)-yl)quinolinecarboxylate
O NH NH2
O O
N N
O
The title compound was prepared in analogy to Example 6-1 in Scheme 52 by using methyl 4-
chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinecarboxylate and
oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 497, 1H NMR (400 MHz, DMSO-
d6) δ ppm 8.57 (d, 1 H), 7.95 (d, 1 H), 7.85 (m, 2 H), 7.71 (t, 1 H), 7.61 (m, 1 H), 7.46 - 7.38 (m,
2 H), 6.18 (s, 1 H), 5.07 (s, 2 H), 4.32 (m, 6 H), 3.80 (s, 3 H), 3.55 (m, 4 H), 2.95 (s, 2 H).
Example 105
4-({[3-(Aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinolinecarboxylic acid
OH NH NH2
O O
N N
To a stirred solution of methyl 4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-
hydro-1,4-benzothiazepin-4(5H)-yl)quinolinecarboxylate (100 mg, 0.2 mmol) in
tetrahydrofuran and water (4 mL, V/V = 3/1) was added sodium hydroxide (40 mg, 1.0 mmol).
After being stirred at room ature overnight, the resulting mixture was concentrated in
vacuo to remove the organic solvent. The residual aqueous solution was acidified with an
aqueous solution of citric acid (5 mL, 20%) and extracted with dichloromethane (15 mL × 3).
The combined organic layers were dried over anhydrous sodium sulfate and concentrated in
vacuo to afford a sticky solid, which was purified by flash column chromatography (eluting with
% methanol in dichloromethane) to afford 20 mg of the desire t as a solid. MS obsd.
(ESI+) [(M+H)+] 483, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (s, 1 H), 8.01 (d, 1 H), 7.90
(m, 2 H), 7.61 (t, 1 H), 7.47 (t, 1 H), 7.32 (d, 1 H), 6.29 (s, 1 H), 5.76 (s, 2 H), 4.40 (m, 6 H),
3.78 (s, 2 H), 3.62 (s, 2 H), 3.17 (m, 2 H) .
Example 106
[4-({[3-(Aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinolinyl]methanol
OH NH NH2
N N
[4-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]methanol
OH Cl
N N
To a slurry of lithium aluminum e (46 mg, 1.21 mmol) in tetrahydrofuran (5 mL) was
added a solution of methyl 4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinolinecarboxylate (400 mg, 0.96 mmol) in tetrahydrofuran (10 mL) at 0 °C under a
nitrogen atmosphere. After being allowed to warm to room temperature and stirred for 2 hours,
the reaction mixture was cooled to 0 °C and treated with water (0.2 mL) to quench the reaction.
The resulting mixture was stirred for 30 minutes, dried over anhydrous sodium sulfate, filtered
and concentrated in vacuo to afford 321 mg of the desired product as a white solid (yield was
86%).
[4-({[3-(Aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinolinyl]methanol
OH NH NH2
N N
The title compound was prepared in analogy to Example 6-1 in Scheme 52 by using [4-chloro
(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]methanol and oxetane-3,3-
diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 469, 1H NMR (400 MHz, 6) δ ppm
7.93 (d, 1 H), 7.83 (m, 1 H), 7.75 (s, 1 H), 7.59 (m, 1 H), 7.42 (m, 1 H), 7.34 (s, 2 H), 7.25 (t, 1
H), 6.13 (s, 1 H), 5.10 (t, 1 H), 5.04 (s, 2 H), 4.47 (d, 2 H), 4.34 (m, 6 H), 3.58 (d, 2 H), 3.52 (d,
2 H), 2.96 (t, 2 H), 1.79 (m, 2 H).
e 107
(Aminomethyl)oxetanyl]methyl}trideuteriomethyl(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinazolinamine
D NH NH
D 2
N N
4-(Benzyloxy)bromochloroquinazoline
N Cl
To a cooled solution of 6-bromo-2,4-dichloroquinazoline (1.39g, 5 mmol) in tetrahydrofuran (50
mL) was added a solution of benzyl alcohol (0.52 mL, 5 mmol) and sodium hydride (210 mg,
.25 mmol, 60% in mineral oil) in tetrahydrofuran (15 mL) dropwise at 0 °C. After being stirred
at room temperature for 2 hours, the reaction e was poured into cold water (10 mL) and
then extracted with ethyl acetate (50 mL). The organic layer was dried over magnesium sulfate
and concentrated in vacuo to afford 1.73 g of the desired product as a yellow solid ( yield was
99%).
4-[4-(Benzyloxy)bromoquinazolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine
N N
S
A mixture of 4-(benzyloxy)bromochloroquinazoline (700 mg, 2.0 mmol) and 2,3,4,5-
ydro-1,4-benzothiazepine (990 mg, 6.0 mmol) was heated at 80 °C for 10 s. The
resulting reaction mixture was cooled to room temperature and purified by silica gel column
chromatography (eluting with dichloromethane) to afford 600 mg of the desired product as a
white solid (yield was .
4-[4-(Benzyloxy)trideuteriomethylquinazolinyl]-2,3,4,5-tetrahydro-1,4-
benzothiazepine
D O
N N
To a cooled solution of 4-[4-(benzyloxy)bromoquinazolinyl]-2,3,4,5-tetrahydro-1,4-
benzothiazepine (239 mg, 0.50 mmol) in anhydrous tetrahydrofuran (10 mL) was added nbutyllithium
(0.5 mL, 0.80 mmol) in tetrahydrofuran se over 5 minutes under a nitrogen
atmosphere at -78 °C, followed by addition of methyl-d3 trifluoromethanesulfonate(134 mg, 0.80
mmol) dropwise at -78 °C over 5 minutes. After being stirred for 1 hour at -78 °C, the reaction
mixture was allowed to warm to room ature and stirred for another 1 hour. The reaction
was quenched with deuterated water (5 mL). The resulting mixture was extracted with ethyl
acetate (20 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to
afford the desired compound.
4-[4-(Benzyloxy)trideuteriomethylquinazolinyl]-2,3,4,5-tetrahydro-1,4-
benzothiazepine e
D O
N N
To a solution of 4-[4-(benzyloxy)trideuteriomethylquinazolinyl]-2,3,4,5-tetrahydro-1,4-
benzothiazepine (417 mg, 1.0 mmol) in dichloromethane (10 mL) was added 3-
chloroperoxybenzoic acid (233 mg, 1.0 mmol, 75%). After being stirred for 1 hour, the mixture
was washed with a saturated aqueous solution of sodium thiosulphate (3 mL), 10% aqueous
solution of sodium hydroxide (5 mL) and brine (5 mL). The organic layer was dried over sodium
sulfate and trated in vacuo. The residue was purified by silica gel column tography
(eluting with 10% ethyl acetate in dichloromethane) to afford the desired product as a white
solid.
N-{[3-(aminomethyl)oxetanyl]methyl}trideuteriomethyl(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinazolinamine
D NH NH
D 2
N N
A e of 4-[4-(benzyloxy)trideuteriomethylquinazolinyl]-2,3,4,5-tetrahydro-1,4-
hiazepine 1-oxide (700 mg, 1.62 mmol) and oxetane-3,3-diyldimethanamine (752 mg, 6.5
mmol) was heated at 170 °C for 20 minutes, then the mixture was cooled to room temperature
and then purified by preparative HPLC to afford 60 mg of the desired product as a white solid
(yield was 8.4%). MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 7.78 -
7.73 (m, 2 H), 7.69 - 7.67 (m,1 H), 7.62 - 7.45 (m, 2 H), 7.44 - 7.40 (m, 1 H), 7.38 - 7.34 (m, 1
H), 5.27 (d, J = 16 Hz, 1H), 4.77 (brs, 1 H), 4.68 - 4.64 (m, 2 H), 4.52 - 4.47 (m, 2 H), 4.11 -
4.01 (m, 2 H), 3.49 - 3.35 (m, 2 H), 3.50 - 3.40 (m, 1 H), 3.40 - 3.34 (m, 1H), 3.04 (s, 2 H).
Example 108-1
4-({[3-(Aminomethyl)oxetanyl]methyl}amino)(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinazolinecarboxylic acid
OH NH NH
O N O
N N
Methyl 4-(benzyloxy)(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline
carboxylate
O O
O N
N N
To a solution of 4-(4-benzyloxybromoquinazolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine (239 mg, 0.5 mmol) in anhydrous tetrahydrofuran (10 mL) was added n-
butyllithium (0.5 mL, 0.8 mmol) in ydrofuran dropwise at -78 °C under nitrogen
atmosphere over 5 minutes followed by addition of dry ice ( 2.5 mmol) at -78 °C. After being
stirred for 1 hour at -78 °C, the reaction mixture was allowed to warm to room temperature and
stirred for another 1 hour. The reaction was quenched by addition of a saturated solution of
ammonium chloride (10 mL) and ted with ethyl acetate (25 mL). The organic layer was
dried over sodium e and concentrated in vacuo to afford the crude product of the acid. To a
solution of the above crude acid in methanol (15 mL) was added sulfinyl chloride (2 mL) at 0 °C,
then the mixture was heat at 70 °C for 1 hour. The reaction mixture was cooled to room
temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, and the
solution was washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium
e and trated in vacuo. The residue was purified by flash column chromatography
ng with 10% ethyl acetate in dichloromethane) to afford the desired methyl ester.
Methyl 4-(benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline
carboxylate and Methyl 4-(benzyloxy)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin
4(5H)-yl)quinazolinecarboxylate
O O
O O
O N
O N
N N
N N
O S O
To a solution of methyl 4-(benzyloxy)(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-
6-carboxylate (800 mg, 1.75 mmol) in dichloromethane was added m-chloroperoxybenzoic acid
(602 mg, 2.625 mmol, 75% purity) slowly, then the e was stirred at room temperature for
1 hour. The reaction mixture was washed with a saturated aqueous on of sodium
thiosulphate, and 10% aqueous solution of sodium ide, and brine. The resulting organic
layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash
column tography (eluting with 10% ethyl acetate in dichloromethane) to afford 350 mg of
methyl 4-(benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline
carboxylate and 400 mg of methyl 4-(benzyloxy)(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinazolinecarboxylate.
4-(Benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline
ylic acid
OH O
O N
N N
To the solution of methyl 4-(benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinazolinecarboxylate (350 mg, 0.74 mmol) in the mixture of tetrahydrofuran and water
(10 mL, V/V = 4:1) was added lithium hydroxide (178 mg, 7.4 mmol). The resulting mixture
was stirred at room temperature overnight and then acidified with hydrochloric acid (2 N),
extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in
vacuo. The residue was purified by flash column tography (eluting with 10% ethyl
acetate in dichloromethane) to afford 4-(benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)quinazolinecarboxylic MS obsd. (ESI+) [(M+H)+] 460.
4-({[3-(Aminomethyl)oxetanyl]methyl}amino)(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinazolinecarboxylic acid
OH NH NH
O N O
N N
A mixture of 4-(benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline
carboxylic acid (170 mg, 0.37 mmol) and oxetane-3,3-diyldimethanamine (128 mg, 1.11 mmol)
was heated at 170 °C for 30 minutes. Then the reaction mixture was cooled to room temperature
and ed by ative HPLC to afford 4-({[3-(Aminomethyl)oxetanyl]methyl}amino)
(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinecarboxylic acid, MS obsd.
(ESI+) [(M+H)+] 468, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 - 8.61 (m, 2 H), 8.09 - 8.00
(m, 1 H), 7.77 - 7.74 (m, 1 H), 7.68 - 7.65 (m, 1 H), 7.51 - 7.42 (m, 2 H), 7.27 -7.13 (m, 1 H),
.26 - 5.17 (m. 2 H), 4.89 - 4.68 (m, 4 H), 452 - 4.45 (m, 2 H), 4.40 - 4.31 (m, 2 H), 4.10 - 3.84
(m, 2 H), 3.20 - 3.01 (m, 2 H).
Example 108-2
4-({[3-(Aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinazolinecarboxylic acid
OH NH NH2
O N O
N N
The title compound was prepared in analogy to Example 108-1 in Scheme 54 by using 4-
(benzyloxy)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinecarboxylic
acid and oxetane-3,3-diyldimethanamine, MS obsd. (ESI +) [(M+H)+] 484, 1H NMR (400 MHz,
DMSO-d6) δ ppm 8.95 (brs, 1 H), 8.68 (m, 1H), 8.04 (d, J = 9.1 Hz, 1 H), 7.77 - 7.73 (m, 2 H),
7.68 - 7.63 (m, 1 H), 7.48 - 7.43 (m, 1 H), 7.24 - 7.19 (m, 1 H), 5.11 (brs, 2 H), 4.59-4.30 (brs, 6
H), 4.20 (m, 1H), 4.0 (m, 1H), 3.58 (brs, 2 H), 3.12 (m, 2 H).
e 109-1 and Example 109-2
[4-({[3-(Aminomethyl)oxetanyl]methyl}amino)(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinazolinyl]methanol and [4-({[3-(Aminomethyl)oxetan
yl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin
yl]methanol
OH NH NH2 OH NH NH2
N O N O
N N N N
S S O
zyloxy)(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinecarbaldehyde
H O
O N
N N
S
To a cooled on of 4-(4-benzyloxybromoquinazolinyl)-2,3,4,5-tetrahydro-1,4-
benzothiazepine (500 mg, 1.048 mmol) in anhydrous tetrahydrofuran (10 mL) was added
anhydrous N,N-dimethylformamide (150 µL, 1.94 mmol) at -78 oC. After being stirred at -78 oC
for 30 minutes, the mixture was warmed to room temperature, diluted with water (10 mL) and
extracted with ethyl e (20 mL × 3). The combined organic layers were washed with a
ted aqueous solution of ammonium chloride (40 mL) and brine (40 mL), dried over
anhydrous sodium sulfate, and concentrated in vacuo to afford 410 mg of the crude product as a
yellow solid. MS obsd. (ESI+) +] 428.
[4-(Benzyloxy)(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]methanol
OH O
N N
S
To a solution of 4-(benzyloxy)(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline
carbaldehyde (3.0 g, 7.0 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL) was added
sodium borohydride (270 mg, 7.13 mmol) at 0 oC. After being stirred at 0 oC for 15 minutes, the
resulting mixture was warmed to room temperature, diluted with water (10 mL) and extracted
with ethyl acetate (20 mL × 3). The combined organic layers were washed with a saturated
aqueous solution of ammonium chloride (40 mL) and brine (40 mL), dried over anhydrous
sodium sulfate, and trated in vacuo to afford 2.85 g of the desired product as a yellow
solid (yield was 95%), MS obsd. (ESI+) +] 430.
[4-(Benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin
yl]methanol and [4-(Benzyloxy)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinazolinyl]methanol
OH O
OH O
N N
N N
S O
O O
To a solution of [4-(benzyloxy)(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin
yl]methanol (1.0 g, 2.33 mmol) in romethane (20 mL) was added 3-chloroperoxybenzoic
acid (536 mg, 2.33 mmol, 75% purity) at 0 oC. After being stirred at 0 oC for 15 minutes, the
mixture was warmed to room temperature, diluted with water, extracted with dichloromethane
(20 mL × 3). The combined organic layers were washed with a saturated s solution of
sodium bicarbonate (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, and
concentrated in vacuo to afford 0.90 g of the mixture of [4-(benzyloxy)(1-oxido-2,3-dihydro-
1,4-benzothiazepin-4(5H)-yl)quinazolinyl]methanol and [4-(benzyloxy)(1,1-dioxido-2,3-
dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]methanol as a yellow solid.
[4-({[3-(Aminomethyl)oxetanyl]methyl}amino)(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinazolinyl]methanol and [4-({[3-(Aminomethyl)oxetan
yl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin
yl]methanol
OH NH NH2 OH NH NH2
N O N O
N N N N
S S O
O
A mixture of [4-(benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin
yl]methanol and [4-(benzyloxy)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)quinazolinyl]methanol (700 mg, about 1.57 mmol) and oxetane-3,3-diyldimethanamine
(700 mg, 6.03 mmol) was heated at 160 oC for 30 minutes. After being cooled to room
temperature, the on mixture was d with water (10 mL), extracted with
dichloromethane (20 mL × 3). The organic layers were washed with brine (40 mL), dried over
anhydrous sodium e and concentrated in vacuo. The residue was purified by preparative
HPLC to afford [4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1-oxido-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)quinazolinyl]methanol, MS obsd. (ESI+) [(M+H)+] 454, 1H NMR
(400 MHz, DMSO-d6) δ ppm 8.139 (s, 1 H), 7.918 (s, 1 H), 7.71 (m, 2 H), 7.48 (m, 3 H), 7.316
(d, J = 8 Hz, 1 H), 5.21 (m, 2 H), 4.75 (m, 2 H), 4.51 (m, 4 H), 4.369 (s, 3 H), 3.93 (brs, 1 H),
3.15 (brs, 2 H), 2.989 (s, 2 H), and [4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-
dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]methanol, MS obsd. (ESI+)
[(M+H)+] 470, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.197(s, 1 H), 7.789 (m, 3 H), 7.62 (t, J =
7.2 Hz, 1 H), 7.48 (m, 2 H), 7.316 (s, 1 H), 5.12 (m, 3 H), 4.48 (m, 8 H), 3.917 (s, 2 H), 3.569
(brs, 2 H), 2.951 (brs, 2 H).
Example 110-1
N-[(3-Aminooxetanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)-
ylquinolinamine
O NH
N N
2-(4-Chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzo[c]azepine
N N
A solution of 2,4-dichloromethylquinoline (500 mg, 2.358 mmol) and 5,5-difluoro-2,3,4,5-
tetrahydro-1H-benzazepine (432 mg, 2.358 mmol) in n-butanol (10 mL) was heated at 160 oC for
hours under microwave irradiation. The resulting reaction mixture was poured into water (10
mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over
sodium sulfate and concentrated in vacuo. The residue was purified by flash column
chromatography (eluting with 20% ethyl acetate in petroleum ether) to afford 550 mg of the
desired product as a solid (yield was 65 %).
N-[(3-Aminooxetanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)-
6-methylquinolinamine
O NH
N N
F
A solution of hloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-
benzazepine (250 mg, 0.697 mmol), nomethyl)oxetanamine (119 mg, 0.697 mmol,
purity: 60 %), 1,1'-bis(diphenylphosphino)ferrocene (39 mg, 0.0697 mmol), 1,1'-
bis(diphenylphosphino)ferrocene-palladium(II)dichloride (51 mg, 0.0697 mmol), sodium tert-
butoxide (134 mg, 1.394 mmol). in 1,4-dioxane (10 mL) was heated at 120 oC for 1.5 hours
under microwave irradiation. The resulting reaction mixture was poured into water (10 mL) and
extracted with dichloromethane (20 mL × 3), the combined c layers were dried over
sodium sulfate and concentrated in vacuo. The residue was purified by flash column
chromatography (eluting with 0 - 10% methanol in romethane) and preparative HPLC to
afford 14 mg of the product as a white solid (yield was 4.4%). MS obsd. (ESI+) [(M+H)+] 425,
1H NMR (400 MHz, CD
3OD) δ ppm 7.67 - 7.65 (d, J = 6.8 Hz, 2 H), 7.61 - 7.59 (d, J = 7.6 Hz ,
1 H), 7.46 - 7.39 (m, 2 H), 7.33 - 7.29 (m, 2 H), 6.15 (s, 1 H), 4.91 (s, 2 H), 4.63 - 4.61 (d, J =
6.4 Hz, 2 H), 4.58 - 4.56 (d, J = 6.4 Hz, 2 H), 4.32 - 4.29 (t, J = 5.5, 5.6 Hz, 2 H), 3.64 (s, 2 H),
2.55 - 2.45 (m, 2 H), 2.42 (s, 3 H).
Example 110-2
N-[2-(2-Aminoethoxy)ethyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)
methylquinolinamine
NH NH
N N
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 2-(2-
aminoethoxy)ethanamine. MS obsd. (ESI+) [(M+H)+] 427, 1H NMR (400 MHz, CD3OD) δ
ppm 7.60 -7.50 (d, J = 7.2 Hz 1 H), 7.50 - 7.40 (d, J = 9.2 Hz , 1 H), 7.40 - 7.30 (d, J = 7.6 Hz ,1
H), 7.30 - 7.15 (m, 5 H), 5.85 (s, 1 H), 5.05 (s, 1 H), 4.75 (s, 2 H), 4.30 (s, 2 H), 3.75 - 3.65 (m, 2
H), 3.55 - 3.45 (m, 2 H), 3.40 - 3.30 (m, 2 H), 2.90 - 2.80 (t, 2 H), 2.50 - 2.40 (m, 2 H), 2.35 (s, 3
Example 110-3
N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]-N'-
methylethane-1,2-diamine
N N
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and (2-
thyl)(methyl)amine. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR (400 MHz, CD3OD) δ ppm
7.60 - 7.50 (d, J = 7.2 Hz, 1 H), 7.45 - 7.30 (m, 2 H), 7.30 - 7.10 (m, 5 H), 5.85 (s, 1 H), 5.25 (s,
1 H), 4.80 (s, 2 H), 4.30 (s, 2 H), 3.35 - 3.20 (m, 2 H), 2.97 - 2.85 (m, 2 H), 2.50 - 2.40 (m, 5 H),
2.35 (s, 3 H).
Example 110-4
1-Amino{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin
yl]amino}propanol
NH NH
N N
The title compound was ed in analogy to Example 110-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 1,3-
diaminopropanol. MS obsd. (ESI+) [(M+H)+] 413, 1H NMR (400 MHz, CD3OD) δ ppm 7.60 -
7.50 (d, J = 7.6 Hz, 1 H), 7.45 - 7.35 (m, 2 H), 7.30 - 7.10 (m, 5 H), 5.85 (s, 1 H), 5.20 (s, 1 H),
4.78 (s, 2 H), 4.30 (s, 2 H), 3.85 - 3.75 (m, 1 H), 3.35 - 3.20 (m, 1 H), 3.20 - 3.10 (m, 1 H), 3.00 -
2.90 (m, 1 H), 2.75 - 2.65 (m,1 H), 2.45 - 2.35 (m, 2 H), 2.32 (s, 3 H).
Example 110-5
3-{[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin
yl]amino}propane-1,2-diol
NH OH
N N
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 3-
aminopropane-1,2-diol. MS obsd. (ESI+) [(M+H)+] 414, 1H NMR (400 MHz, CDCl3) δ ppm 7.60
- 7.50 (d, J = 7.6 Hz, 1 H), 7.50 - 7.40 (d, J = 8.4 Hz, 2 H), 7.35 - 7.25 (d, J = 8.4 Hz, 2 H), 7.25
- 7.10 (m, 2 H) 5.85 (s, 1 H), 5.20 (s, 1 H), 4.78 (s, 2 H), 4.20 (s, 2 H), 3.95 - 3.85 (m, 1 H), 3.70
- 3.50 (m, 2 H), 3.20 - 3.10 (m, 2 H), 2.50 - 2.40 (m, 2 H), 2.32 (s, 3 H).
Example 110-6
3-{[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin
yl]amino}propanol
NH OH
N N
The title compound was ed in analogy to Example 110-1 in Scheme 56 by using 2-(46-methylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 3-
aminopropaneol. MS obsd. (ESI+) [(M+H)+] 398, 1H NMR (400 MHz, CD3Cl) δ ppm 7.60 -
7.40 (m, 3 H), 7.35 - 7.25 (m, 4 H), 5.85 (s, 1 H), 4.80 (s, 2 H), 4.30 (s, 2 H), 3.90 - 3.80 (m, 2
H), 3.45 - 3.30 (m, 2 H), 2.55 - 2.45 (m, 2 H), 2.38 (s, 3 H).
e 110-7
2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methyl-N-[2-(piperazin
yl)ethyl]quinolinamine
N N
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 2-(piperazin-
1-yl)ethanamine. MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, CD3Cl) δ ppm 7.52 -
7.44 (d, J = 8.8 Hz, 1 H), 7.41 - 7.40 (m, 2 H), 7.25 - 7.10 (m, 4 H), 5.80 (s, 1 H), 5.51 (s, 1 H),
4.79 (s, 2 H), 4.26 (s, 2 H), 3.21 - 3.17 (m, 2 H), 2.86 - 2.84 (m, 4 H), 2.70 - 2.67 (m, 2 H), 2.44 -
2.42 (m, 6 H), 2.35 (s, 3 H).
Example 110-8
2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin
yl]propane-1,2-diamine
NH 2
N N
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and propane-1,2-
diamine. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR (400 MHz, CD3Cl) δ ppm 7.54 - 7.52 (d, J =
7.6 Hz, 1 H), 7.47 - 7.45 (d, J = 8.4 Hz, 1 H), 7.40 - 7.38 (d, J = 7.6 Hz, 1 H), 7.25 - 7.16 (m, 4
H) 5.85 (s, 1 H), 5.25 (s, 1 H), 4.78 (s, 2 H), 4.29 - 4.24 (m, 2 H), 3.22 - 3.17 (m, 2 H), 2.91 -
2.89 (m, 1 H), 2.46 - 2.33 (m, 2 H), 2.32 (s, 3 H) , 1.20 - 1.18 (m, 3 H).
Example 110-9
cis-N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin
yl]cyclohexane-1,4-diamine
N N
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and ciscyclohexane-1
,4-diamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm
7.60 - 7.50 (d, J = 7.6 Hz, 1 H), 7.50 - 7.40 (d, J = 8.4 Hz, 1 H), 7.40 - 7.30 (d, J = 7.6 Hz, 1 H),
7.30 - 7.15 (m, 5 H), 5.95 (s, 1 H), 4.80 - 4.70 (d, J = 4.0 Hz, 2 H), 4.60 (s, 2 H), 4.05 (s, 1 H),
3.10 (s, 1 H), 2.70 - 2.60 (m, 1 H), 2.50 - 2.40 (m, 2 H), 2.35 (s, 3 H), 2.05 (s, 2 H), 1.80 (s, 2 H),
1.50 - 1.30 (m, 4 H).
Example 110-10
2-(9,9-Difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulenyl)methyl-N-(pyrrolidin
yl)quinolinamine
N N
The title compound was ed in analogy to Example 110-1 in Scheme 56 by using 2-(4-
methylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and pyrrolidin
amine. MS obsd. (ESI+) [(M+H)+] 409, 1H NMR (400 MHz, CD3OD) δ ppm 7.60 - 7.50 (d, J =
7.6 Hz, 1 H), 7.50 - 7.40 (d, J = 8.8 Hz, 1 H), 7.40 - 7.30 (d, J = 7.2 Hz, 1 H), 7.30 - 7.20 (m, 4
H), 5.85 (s, 1 H), 4.75 (s, 2 H), 4.30 (s, 2 H), 4.05 (s, 1 H), 3.65 (s, 1 H), 3.30 - 3.20 (m, 1 H),
3.20 - 2.90 (m, 3 H) , 2.50 - 2.40 (m, 2 H), 2.35 (s, 3 H), 2.20 - 2.10 (m, 2 H).
Example 110-11
2,2'-{[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin
yl]imino}diethanol
OH OH
N N
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 2,2'-
iethanol. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.90 - 7.70
(m, 2 H), 7.70 - 7.60 (m, 2 H), 7.50 - 7.30 (m, 3 H), 6.40 (s, 1 H), 5.85 (s, 2 H), 4.65 (s, 2 H),
4.15 (s, 2 H), 3.85 (s, 3 H), 3.58 (s, 2 H), 3.25 (s, 2 H), 2.60 - 2.50 (m, 3 H) , 2.35 (s, 3 H).
Example 110-12
N~1~-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]
methylpropane-1,2-diamine
NH 2
N N
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4-
methylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 2-
methylpropane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ
ppm 8.06 (s, 1 H), 7.79 - 7.69 (m, 3 H), 7.61 - 7.58 (dd, J = 8.8, 1.6 Hz, 1 H), 7.53 - 7.49 (t, J =
7.6 Hz, 1 H), 7.46 - 7.42 (t, J = 7.6 Hz, 1 H), 6.13 (s, 1 H), 5.12 (s, 2 H), 4.24 - 4.21 (t, J = 5.6
Hz, 2 H), 3.76 (s, 2 H), 2.73 - 2.64 (m, 2 H), 2.48 (s, 3 H), 1.42 (s, 6 H).
Example 110-13
5,5-Difluoro[6-methyl(4-methylpiperazinyl)quinolinyl]-2,3,4,5-tetrahydro-1H
benzazepine
N N
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 1-
methylpiperazine. MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 7.93 -
7.91 (d, J = 8.4 Hz, 1 H), 7.77 - 7.75 (d, J = 7.6 Hz, 1 H), 7.71 - 7.69 (d, J = 7.6 Hz, 1 H), 7.69
(s, 1 H), 7.62 - 7.60 (d, J = 7.6 Hz, 1 H), 7.56 - 7.52 (t, J = 8 Hz, 1 H), 7.49 - 7.45 (t, J = 8 Hz, 1
H), 6.58 (s, 1 H), 5.18 (s, 2 H), 4.32 - 4.29 (t, J = 6 Hz, 2 H), 3.97 - 3.89 (m, 2 H), 3.77 - 3.68 (m,
2 H), 3.61 - 3.51 (m, 2 H), 3.50 - 3.39 (m, 2 H), 3.03 (s, 3 H), 2.79 - 2.67 (m, 2 H), 2.49 (s, 3 H).
e 110-14
1-[2-(9,9-Difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulenyl)methylquinolinyl]
ethylurea
NH N
N N
The title nd was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and ethylurea.
MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CDCl3) δ ppm 12.30 (s, 1 H), 9.62 - 9.55
(m, 1 H), 8.40 - 8.20 (m, 1 H), 7.82 - 7.70 (m, 2 H), 7.60 - 7.38 (m, 4 H), 7.12 (s, 1 H), 5.00 -
4.80 (m, 2 H), 4.50 - 4.10 (m, 2 H), 3.42 - 3.30 (m, 2 H), 2.70 - 2.50 (m, 2 H), 1.92 (s, 3 H), 1.31
- 1.20 (t, J = 7.2 Hz, 3 H).
Example 110-15
N-{[3-(Aminomethyl)oxetanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H
benzazepinyl)methylquinolinamine
NH NH
N N
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and oxetane-3,3-
diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (s,
1 H), 7.80 (m, 3 H), 7.67 (d, 1 H), 7.60 (t, 1 H), 7.54 (t, 1 H), 6.18 (s, 1 H), 5.16 (s, 2 H), 4.68 -
4.62 (m, 4 H), 4.32 (t, 2 H), 3.94 (s, 2 H), 3.54 (s, 2 H), 2.78 (m, 2 H), 2.54 (s, 3 H).
Example 111-1
,5-Difluoro[6-methyl(piperazinyl)quinolinyl]-2,3,4,5-tetrahydro-1H
benzazepine
N N
F
A mixture of 2-(4-chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-
benzazepine (100 mg, 0.279 mmol) and piperazine (300 mg, 3.488 mmol) was heated at 150 oC
for 2 hours under microwave irradiation. The ing reaction mixture was purified by
preparative HPLC followed by SPE. The eluent was concentrated in vacuo and the residue was
dried by lyophilization to afford 38.87 mg of the d product (yield was 34.1%). MS obsd.
(ESI+) [(M+H)+] 409, 1H NMR (400 MHz, CD3OD) δ ppm 7.65 - 7.58 (d, J = 7.6 Hz, 1 H ),
7.55 - 7.45 (t, 2 H), 7.40 - 7.30 (d, J = 7.6 Hz, 1 H), 7.38 - 7.25 (m, 2 H), 7.28 - 7.20 (m, 1 H),
6.35 (s, 1 H), 4.75 (s, 2 H), 4.34 (s, 2 H), 3.20 - 3.00 (m, 8 H), 2.60 - 2.45 (m, 2 H), 2.43 (s, 3 H).
e 111-2
2-[4-(1,4-Diazepanyl)methylquinolinyl]-5,5-difluoro-2,3,4,5-tetrahydro-1H
benzazepine
N N
The title nd was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and
[1,4]diazepane. MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3Cl) δ ppm 7.60 - 7.58
(d, J = 6.8 Hz, 1 H), 7.55 - 7.53 (m, 2 H), 7.45 - 7.43 (d, J = 7.2 Hz, 1 H), 7.34 - 7.24 (m, 3 H),
6.41 (s, 1 H), 4.85 (s, 2 H), 4.33 - 4.32 (d, J = 5.2 Hz ,2 H), 3.43 - 3.40 (m, 4 H), 3.17 - 3.14 (m,
4 H), 2.51 - 2.47 (m, 2 H), 2.41 (s, 3 H), 2.20 (brs, 1H), 2.04 -2.01 (m, 2 H).
Example 111-3
N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]-N-
methylethane-1,2-diamine
N N
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and (2-
aminoethyl)(methyl)amine. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR (400 MHz, CD3OD) δ ppm
7.60 - 7.50 (d, J = 7.2 Hz, 1 H), 7.45 - 7.35 (m, 2 H), 7.30 - 7.10 (m, 5 H), 5.85 (s, 1 H), 5.25 (s,
1 H), 4.78 (s, 2 H), 4.30 (s, 2 H), 3.35 - 3.20 (m, 2 H), 2.97 - 2.80 (m, 2 H), 2.50 - 2.35 (m, 5 H),
2.40 - 2.30 (s, 3 H).
e 111-4
1-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin
yl]pyrrolidinamine
N N
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and idin
amine. MS obsd. (ESI+) +] 409, 1H NMR (400 MHz, CD3OD) δ ppm 7.65 (s, 1 H), 7.62 -
7.55 (d, J = 7.6 Hz, 1 H), 7.55 - 7.45 (d, J = 8.8 Hz, 1 H), 7.45 - 7.40 (d, J = 7.2 Hz, 1 H), 7.40 -
7.30 (t, 1 H), 7.30 - 7.20 (m, 3 H), 5.85 (s, 1 H), 4.85 (s, 2 H), 4.30 (s, 2 H), 3.80 - 3.70 (m, 3 H),
3.60 - 3.50 (m, 2 H), 3.40 - 3.30 (m, 1 H), 2.50 - 2.40 (m, 2 H), 2.35 (s, 3 H), 2.30 - 2.10 (m, 1
Example 111-5
2-{[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin
yl]amino}ethanol
N N
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 2-
aminoethanol. MS obsd. (ESI+) [(M+H)+] 384, 1H NMR (400 MHz, CD3OD) δ ppm 7.60 - 7.40
(m, 3 H), 7.35 - 7.20 (m, 4 H), 5.87 (s, 1 H), 4.88 - 4.87 (d, J = 16.4 Hz, 2 H), 4.33 (s, 2 H), 3.90
- 3.87 (m, 2 H), 3.41 - 3.37 (m, 2 H), 2.52 - 2.47 (m, 2 H), 2.38 (s, 3 H), 2.00 - 1.97 (m, 2 H).
Example 111-6
N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]ethane-
1,2-diamine
N N
The title compound was prepared in analogy to e 111-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and ethane-1,2-
diamine. MS obsd. (ESI+) [(M+H)+] 383, 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (s, 1 H), 7.72
- 7.70 (d, J = 6.8 Hz, 1 H), 7.70 - 7.67 (d, J = 6.8 Hz, 2 H), 7.65 - 7.42 (m, 3 H), 6.00 (s, 1 H),
.02 (s, 2 H), 4.23 - 4.20 (t, 2 H), 3.88 - 3.78 (t, 2 H), 3.58 - 3.55 (t, 2 H), 2.71 - 2.61 (m, 2 H),
2.46 (s, 3 H).
Example 111-7
N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin
yl]cyclohexane-1,3-diamine
N N
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and cyclohexane-
1,3-diamine. MS obsd. (ESI+) [(M+H)+]437, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 - 7.97 (d,
J = 15.2 Hz, 1 H), 7.69 - 7.65 (m, 3 H), 7.55 - 7.41 (m, 3 H), 5.92 - 5.91 (d, J = 2.4 Hz, 2 H),
.02 - 4.92 (m, 2 H), 4.31 - 4.10 (m, 2 H), 3.83 - 3.60 (m, 1 H), 3.41 - 3.32 (m, 1 H), 2.69 - 2.63
(m, 2 H), 2.45 - 2.43 (m, 3 H), 2.38 - 2.32 (m, 1 H), 2.19 - 2.11 (m, 1 H), 2.10 - 1.98 (m, 2 H),
1.70 - 1.65 (m, 2 H), 1.44 - 1.29 (m, 2 H).
Example 111-8
(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]-N,N-
dimethylethane-1,2-diamine
N N
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and N,N-
dimethylethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CDCl3) δ
ppm 7.61 (s, 2 H), 7.59 (s, 1 H), 7.46 - 7.44 (d, J = 8.4 Hz, 1 H), 7.37 - 7.42 (m, 1 H), 7.31 - 7.29
(m, 2 H), 5.93 (s, 1 H), 4.88 (s, 2 H), 4.25 (m, 2 H), 3.45 - 3.41 (t, J = 6.4 Hz, 2 H), 2.69 - 2.65
(t, J = 6.4 Hz, 2 H), 2.53 - 2.44 (m, 2 H), 2.39 (s, 3 H), 2.34 (s, 3 H).
Example 111-9
N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin
yl]propane-1,3-diamine
N N
The title compound was prepared in analogy to e 111-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and propane-1,3-
diamine. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR (400 MHz, CD3OD) δ ppm 7.60 - 7.52 (m, 3
H), 7.40 - 7.32 (t, J = 2.4 Hz, 2 H), 7.30 - 7.20 (m, 2 H), 5.92 (s, 1 H), 4.30 - 4.20 (m, 2 H), 3.38
- 3.30 (t, J = 6.8 Hz, 2 H), 2.81 - 2.74 (t, J = 7.2 Hz, 2 H), 2.51 - 2.40 (m, 2 H), 2.37 (s, 3 H),
1.90 - 1.80 (m, 2 H), 1.32 - 1.25 (m, 2 H).
Example 111-10
,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]butane-
1,4-diamine
N N
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and butane-1,4-
diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.60 - 7.52 (m, 3
H), 7.40 - 7.35 (t, J = 2.4 Hz, 2 H), 7.32 - 7.20 (m, 2 H), 5.90 (s, 1 H), 4.30 - 4.20 (m, 2 H), 3.35
- 3.25 (m, 2 H), 2.78 - 2.68 (t, J = 7.2 Hz, 2 H), 2.51 - 2.40 (m, 2 H), 2.37 (s, 3 H), 1.78 - 1.68
(m, 2 H), 1.68 - 1.58 (m, 2 H), 1.32 - 1.25 (m, 2 H).
Example 111-11
transAmino[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)
methylquinolinyl]pyrrolidinol
OH NH2
N N
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4-
chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and utyl
[(3S,4S)hydroxypyrrolidinyl]carbamate. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400
MHz, CD3OD) δ ppm 7.75 (s, 1 H ), 7.65 - 7.55 (m, 2 H), 7.50 - 7.40 (d, J = 7.6 Hz, 1 H), 7.42 -
7.35 (t, 1 H), 7.35 - 7.25 (m, 2 H), 5.60 (s, 1 H), 4.80 (s, 2 H), 4.60 - 4.50 (m, 1 H), 4.25 - 4.15
(m, 1 H), 4.15 - 4.00 (m, 3 H), 3.90 - 3.80 (m, 1 H), 3.80 - , 1 H), 3.65 - 3.55 (m, 1 H),
3.30 (s, 2 H), 2.60 - 2.40 (m, 2 H), 2.30 (s, 3 H).
Example 112-1
N-{[3-(Aminomethyl)-1,1-dioxidothietanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-
2Hbenzazepinyl)methylquinolinamine
O NH
N N
A mixture solution of 2-(4-chloromethyl-quinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-
benzazepine (218 mg, 0.609 mmol), (1,1-dioxidothietane-3,3-diyl)dimethanamine (110 mg,
0.670 mmol), (tris(dibenzylideneacetone) adium(0) (56 mg, 0.061 mmol), 2,2’-
bis(diphenylphosphino)-1,1′-binaphthalene (38 mg, 0.061 mmol) and sodium tert-butoxide (117
mg, 1.218 mmol) in toluene (5 mL) was heated at 110 oC overnight. The resulting reaction
mixture was poured into water (10 mL) and extracted with dichloromethane (20 mL × 3), The
combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue
was purified by flash column chromatography and preparative HPLC to afford 50 mg of the
product as a white solid (yield was 17%). MS obsd. (ESI+) +] 487, 1H NMR (400 MHz,
CD3OD) δ ppm 7.970 (s, 1 H), 7.751 - 7.703 (m, 3 H), 7.618 - 7.593 (dd, J = 8.8, 1.2 Hz, 1 H),
7.533 - 7.497 (m, 2 H), 6.377 (s, 1 H), 5.107 (s, 1 H), 4.315 - 4.106 (m, 6 H), 3.993 (s, 1 H),
3.569 (s, 1 H), 2.708 - 2.645 (m, 2 H), 2.479 (s, 3 H).
Example 112-2
N-[(3-Aminooxetanyl)methyl][(5E)(methoxyimino)-1,3,4,5-tetrahydro-2H
benzazepinyl]methylquinolinamine
O NH
N N
(5E)(4-Chloromethylquinolinyl)-N-methoxy-1,2,3,4-tetrahydro-5Hbenzazepin
imine
N N
The title compound was prepared in analogy to 2-(4-chloromethylquinolinyl)-5,5-difluoro-
2,3,4,5-tetrahydro-1H-benzazepine in Example 110-1 in Scheme 56 by using 2,4-dichoro
methylquinoline and N-methoxy-1,2,3,4-tetrahydro-5Hbenzazepinimine.
N-[(3-Aminooxetanyl)methyl][(5E)(methoxyimino)-1,3,4,5-tetrahydro-2H
benzazepinyl]methylquinolinamine
O NH
N N
The title compound was ed in analogy to Example 112-1 in Scheme 56 by using (5E)(4-
chloromethylquinolinyl)-N-methoxy-1,2,3,4-tetrahydro-5Hbenzazepinimine and 3-
(aminomethyl)oxetanamine. MS obsd. (ESI+) [(M+H)+] 432, 1H NMR (400 MHz, CD3OD) δ
ppm 7.965 (s, 1 H), 7.706 - 7.684 (d, J = 8.8 Hz, 1 H), 7.609 - 7.586 (m, 3 H), 7.453 - 7.376 (m,
2 H), 6.100 (s, 1 H), 5.035 (s, 2 H), 4.695 - 4.623 (m, 4 H), 4.014 - 3.987 (m, 4 H), 3.928 (s, 3
H), 3.258 - 3.242 (m, 2 H), 2.471 (s, 3 H).
Example 113
(2-Aminoethyl)sulfonyl]ethyl}(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepin
yl)methylquinolinamine
O O
S NH
NH 2
N N
N-{2-[(2-Aminoethyl)sulfanyl]ethyl}(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepin
yl)methylquinolinamine
S NH
NH 2
N N
A mixture of hloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-
benzazepine (160 mg, 0.447 mmol) and 2-[(2-aminoethyl)sulfanyl]ethanamine (1.5 mL) was
heated at 150 oC for 8 hours. The resulting reaction mixture was concentrated in vacuo. The
residue was dissolved in dichloromethane (20 mL), washed with a saturated aqueous solution of
sodium bicarbonate (20 mL) and brine (20 mL), dried over sodium e and concentrated in
vacuo. The residue was purified by flash column chromatography (eluting with 10 - 20%
methanol in dichloromethane) to afford 180 mg of the desired product as oil (yield was 91.1%),
MS obsd. (ESI+) [(M+H)+] 443.
N-{2-[(2-Aminoethyl)sulfonyl]ethyl}(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepin
yl)methylquinolinamine
O O
S NH
NH 2
N N
To a solution of N-{2-[(2-aminoethyl)sulfanyl]ethyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H
benzazepinyl)methylquinolinamine (120 mg, 0.271 mmol) in acetic acid (2 mL) was
added potassium permanganate (60 mg, 0.38 mmol). After being stirred at room temperature for
minutes, the resulting mixture was concentrated in vacuo. The residue was ed by
preparative HPLC to afford 5 mg of the desired t as a solid. MS obsd. (ESI+) [(M+H)+]
475, 1H NMR (400 MHz, CD3OD) δ ppm 7.81 (s, 1 H), 7.77 - 7.68 (m, 2 H), 7.676 (s, 1 H), 7.56
(dd, J = 7.2, 1.2 Hz, 2 H), 7.47 (t, J = 7.6 Hz, 1 H), 6.08 (s, 1 H), 5.07 (brs, 2 H), 4.60 (brs, 2 H),
4.27 (t, J = 5.6 Hz, 2 H), 4.01 (t, J = 6.4 Hz, 2 H), 3.62 (t, J = 6.8 Hz, 2 H), 3.53 (m, 2 H), 3.42
(m, 2 H), 2.48 (s, 3 H).
Example 114-1
2-(4-{[(3-Aminooxetanyl)methyl]amino}methylquinazolinyl)-1,2,3,4-tetrahydro-
5Hbenzazepinone
O NH
N N
2-(4-Hydroxymethylquinazolinyl)-1,2,3,4-tetrahydro-5Hbenzazepinone
N N
O
To a stirred solution of ro-4(3H)-quinazolinone (580 mg, 3.0 mmol ) and 1,2,3,4-
tetrahydro-5Hbenzazepinone (591 mg, 3.0 mmol ) in toluene (20 mL) was added
triethylamine (626 µL, 4.5 mmol ). After being refluxed overnight, the resulting reaction mixture
was cooled and the formed solid was collected by filtration, washed with ethanol (10 mL) and
ethyl acetate (10 mL), and dried in vacuo to afford 775 mg of the d product as a white solid
(yield was 81%).
2-(4-{[(3-Aminooxetanyl)methyl]amino}methylquinazolinyl)-1,2,3,4-tetrahydro-
5Hbenzazepinone
O NH
N N
The title compound was prepared in analogy to Example 62-1 in Scheme 23 by using 2-(4-
ymethylquinazolinyl)-1,2,3,4-tetrahydro-5Hbenzazepinone and 3-
(aminomethyl)oxetanamine. MS obsd. (ESI+) [(M+H)+] 404, 1H NMR (400 MHz, CD3OD) δ
ppm 7.94 (s, 1 H), 7.90 (d, 1 H), 7.75 (d, 1 H), 7.65 - 7.55 (m, 3 H), 7.45 (t, 1 H), 5.40 (s, 2 H),
4.77 - 7.72 (m, 4 H), 4.40 (s, 2 H), 4.05 (brs, 2 H), 3.35 (t, 2 H), 2.43 (s, 3 H).
Example 114-2
N-{[3-(Aminomethyl)thietanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H
benzazepinyl)methylquinazolinamine
N N
The title compound was prepared in analogy to Example 114-1 in Scheme 23 by using 2-chloro-
4(3H)-quinazolinone, 5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and thietane-3,3-
methanamine. MS obsd. (ESI+) [(M+H)+] 456, 1H NMR (400 MHz, CD3OD) δ ppm 7.701
- 7.683 (d, J = 7.2 Hz, 1 H), 7.605 (s, 1 H), 7.574 - 7.554 (d, J = 8.0 Hz, 1 H), 7.392 - 7.336 (m,
2 H), 7.298 - 7.251 (t, J = 8.4, 10.4 Hz, 2 H), 4.990 (s, 2 H), 4.309 - 4.283 (t, J = 4.8, 5.6 Hz, 2
H), 4.035 (s, 2 H), 3.119 - 3.095 (d, J = 9.6 Hz, 2 H), 3.016 - 2.992 (d, J = 9.6 Hz, 2 H), 2.849 (s,
2 H), 2.478 - 2.413 (m, 2 H), 2.356 (s, 3 H).
Example 114-3
N-{[3-(Aminomethyl)oxetanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H
epinyl)methylquinazolinamine
N N
F
The title compound was prepared in analogy to Example 114-1 in Scheme 23 by using 2-chloro-
4(3H)-quinazolinone, 5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and oxetane-3,3-
diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 440, 1H NMR (400 MHz, CD3OD) δ ppm 8.00
(s, 1 H), 7.67 (m, 3 H), 7.56 (d, 1 H), 7.45 (m, 2 H), 5.14 (s, 2 H), 4.64 (d, 2 H), 4.58 (d, 2 H ),
4.21 (s, 4 H), 3.41 (s, 2 H), 2.63 (brs, 2 H), 2.44 (s, 3 H).
Example 114-4
2-(Aminomethyl)({[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)
methylquinazolinyl]amino}methyl)propane-1,3-diol
OH NH
N N
The title compound was formed when purification of Examle 114-3 by preparative HPLC in
acid condition. MS obsd. (ESI+) [(M+H)+] 458, 1H NMR (400 MHz, CD3OD) δ ppm 7.96 (s, 1
H), 7.63 - 7.75 (m, 4 H), 7.50 (t, 1 H), 7.43 (t, 1 H), 5.17 (s, 2 H), 4.27 (s, 2 H), 3.94 (s, 2 H),
3.76 (m, 4 H), 3.25 (s, 2 H), 2.68 (s, 2 H), 2.45 (s, 3 H).
Example 115
2-(4-{[(3-Aminooxetanyl)methyl]amino}methylquinazolinyl)methyl-2,3,4,5-
tetrahydro-1Hbenzazepinol
O NH
N N
2-(5-Hydroxymethyl-1,3,4,5-tetrahydro-benzoazepinyl)methyl-3H-quinazolin
N N
To a suspension of 2-(4-hydroxymethylquinazolinyl)-1,2,3,4-tetrahydro-5Hbenzazepin-
-one (500 mg, 1.57 mmol) in tetrahydrofuran (15 mL), a solution of methyl magnesium
bromide in ydrofuran (3 M, 0.57 ml, 1.72 mmol) was added at 0 oC. The reaction mixture
was heated at 50 oC for 4 hours, and then poured into a saturated aqueous on of ammonium
chloride (10 mL) and stirred for 10 minutes. The resulting e was extracted with
dichloromethane (15 mL × 3). The combined organic layers were dried over sodium sulfate and
concentrated in vacuo. The residue was purified by flash column chromatography (eluting with
50% ethyl acetate in hexanes) to afford 350 mg of the desired product as a white solid (yield was
66.5%).
2-(4-{[(3-Aminooxetanyl)methyl]amino}methylquinazolinyl)methyl-2,3,4,5-
tetrahydro-1Hbenzazepinol
O NH
N N
The title compound was prepared in analogy to Example 114-1 in Scheme 57 by using 2-(5-
hydroxymethyl-1,3,4,5-tetrahydro-benzoazepinyl)methyl-3H-quinazolinone and 3-
(aminomethyl)oxetanamine. MS obsd. (ESI+) [(M+H)+] 420, 1H NMR (400 MHz, CD 3OD) δ
ppm 7.95 (s, 1 H), 7.66 (d, 2 H), 7.57 (d, 1 H), 7.51 (d, 1 H), 7.30 (m, 2 H), 5.31 (d, 2 H), 4.80
(m, 4 H), 4.73 (d, 2 H), 4.39 (brs, 2 H), 3.97 (brs, 2 H), 2.45(s, 3 H), 1.64 (s, 3 H).
e 116-1
Aminooxetanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)-
6-methylquinazolinamine
O NH2
N N
2-Chloro-N-{[3-(dibenzylamino)oxetanyl]methyl}ethylquinazolinamine
O N
N Cl
A solution of 2,4-dichloromethylquinazoline (1.0 g, 4.69 mmol) in methanol (10 mL) was
added 3-(aminomethyl)-N,N-dibenzyloxetanamine (1.4 g, 5.16 mmol, 60% purity) and
triethylamine (0.1 g, 1 mmol). After being d at room temperature overnight, the mixture
was concentrated in vacuo. The residue was purified by flash column chromatography (eluting
with 20% ethyl acetate in petroleum ether) to afford 1.6 g of the t as a white solid (yield
was 76%).
N-{[3-(Dibenzylamino)oxetanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H
benzazepinyl)methylquinazolinamine
O N
N N
F
To a solution of 2-chloro-N-{[3-(dibenzylamino)oxetanyl]methyl}methylquinazolin
amine (200 mg, 0.436 mmol) in N,N-dimethylformamide (3 mL) was added 5,5-difluoro-1,3,4,5-
tetrahydro-2Hbenzazepine (80 mg, 0.436 mmol) and ylamine (89 mg, 0.872 mmol). The
mixture was heated at 120 oC for 30 minutes under microwave irradiation. The reaction was
poured into water (10 mL) and extracted with romethane (15 mL × 3). The combined
organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was
purified by flash column chromatography (eluting with 20% ethyl acetate in petroleum ether) to
afford 190 mg of the product as a brown solid (yield was 72%).
N-[(3-Aminooxetanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)-
6-methylquinazolinamine
O NH
N N
A solution of (dibenzylamino)oxetanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H-
2-benzazepinyl)methylquinazolinamine (190 mg, 0.314 mmol) and trifluororacetic acid
(1 drop) in ol was d in the presence of palladium hydroxide on carbon (50 mg) at
room temperature under hydrogen atmosphere overnight. The resulting mixture was filtered,
concentrated in vacuo. The residue was purified by preparative HPLC to afford 32 mg of the
product as a white solid (yield was 24%). MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz,
CD3OD) δ ppm 7.696 (s, 1 H), 7.654 - 7.636 (d, J = 7.2 Hz, 1 H), 7.607 - 7.588 ( d, J = 7.6 Hz, 1
H), 7.404 - 7.367 (m, 2 H), 7.341 - 7.283 (m, 2 H), 5.011 (s, 2 H), 4.683 - 4.626 (m, 2 H), 4.556
- 4.540 (d, J = 6.4 Hz, 2 H), 4.335 - 4.307 ( t, J = 5.6 Hz, 2 H), 4.084 (s, 2 H), 5.528 - 2.432 (m,
2 H), 2.398 (s, 3 H).
Example 116-2
N-[(3-Amino-1,1-dioxidothietanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2H
benzazepinyl)methylquinazolinamine
O NH
N N
F
The title compound was prepared in analogy to Example 116-1 in Scheme 57 by using 2,4-
dichloromethylquinazoline, 3-(aminomethyl)-N,N-dibenzyl(1,1-dioxido)thietanamine and
,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepine. MS obsd. (ESI+) [(M+H)+] 474, 1H NMR
(400 MHz, CD3OD) δ ppm 7.73 (s, 1 H), 7.65(d, 1 H), 7.60 (d, 1 H), 7.29- 7.45 (m, 4 H), 5.02 (s,
2 H), 4.04 - 4.62 (m, 2 H), 4.34 (t, 2 H ), 4.12 (t, 2 H ), 4.01 - 4.04 (m, 2 H), 2.47 (m, 2 H), 2.41
(s, 3 H).
Example 117
N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinazolinyl]-2,2-
difluoropropane-1,3-diamine
F F
N N
hloromethylquinazolinyl)-2,2-difluoropropane-1,3-diamine
F F
N Cl
To a solution of fluoropropane-1,3-diamine (1.1 g,10 mmol) and triethylamine (1.4 mL, 10
mol) in dichloromethane (15 mL) was added a solution of 2,4-dichloromethylquinazoline
(500 mg, 2.36 mmol) in dichloromethane (5 mL) dropwise. After being stirred at room
temperature ght, the resulting mixture was poured into water (50 mL) and extracted with
dichloromethane (50 mL × 2). The combined organic layers were washed with brine (50 mL),
dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by
flash column chromatography (eluting with 10 - 25% ol in dichloromethane) to afford
41.8 mg of the desired product as a white solid (yield was 62%). MS obsd. (ESI+) [(M+H)+] 287.
N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinazolinyl]-2,2-
difluoropropane-1,3-diamine
F F
N N
A solution of N-(2-chloromethylquinazolinyl)-2,2-difluoropropane-1,3-diamine (97 mg,
0.34 mmol) and 5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine (310 mg, 1.70 mmol) in nbutanol
(1 mL) was heated at 160 oC for 30 minutes. The resulting reaction mixture was purified
by preparative HPLC to afford 24.3 mg of the desired compound as a white solid. MS obsd.
(ESI+) [(M+H)+] 434, 1H NMR (400 MHz, CD3OD) δ ppm 7.96 (s, 1 H), 7.68 (d, J = 7.2 Hz, 2
H), 7.58 (m, 2 H), 7.46 (m, 2 H), 5.12 (s, 2 H), 4.36 (t, J = 13.6 Hz, 2 H), 4.23 (s, 2 H), 3.58 (t, J
= 16 Hz, 2 H), 2.67 (brs, 2 H), 2.44 (s, 3 H).
e 118-1
7-Bromo-1,3,4,5-tetrahydro-2Hbenzazepinyl)chloroquinolinyl]ethane-1,2-
diamine
N N
o-1,2,4,5-tetrahydro-3Hbenzazepinone
To a cooled solution of 6-bromo-3,4-dihydro-1H-naphthalenone (100 g, 0.44 mol) in toluene
was added sodium azide (150 g, 2.2 mol) followed by addition of trifluoromethanesulfonic acid
(200 mL) dropwise. When the addition was completed, the ice bath was removed and the
mixture was stirred at room temperature overnight. The reaction was poured into ice-water,
basified with potassium carbonate to pH>10 slowly, and then extracted with dichloromethane
(1000 mL × 3). The organic layers were combined and dried over sodium sulfate, and then
trated under reduced pressure to give a residue which was separated by column
chromatography on silica gel to give 35 g of crude product. It was used for next step without
further purification. MS obsd. (ESI+) +] 240.
7-Bromo-2,3,4,5-tetrahydro-1Hbenzazepine
To a solution of 7-bromo-1,2,4,5-tetrahydro-3Hbenzazepinone (35 g, 146 mmol) in 1,2-
dimethoxyethane (400 mL) was added a solution of borane dimethyl sulfide complex (1.0 M in
tetrahydrofuran, 40 mL) under nitrogen and the resulting mixture was stirred under reflux
overnight. The reaction was quenched with methanol, acidified with 2 M hydrochloric acid and
then d for further 2 hours. The resulting mixture was trated in vacuo and the residue
was purified by preparative HPLC to give 4.6 g of product. MS obsd. (ESI+) [(M+H)+] 226. 1H
NMR (400 MHz, CDCl3) δ ppm 7.21 (d, J = 5 Hz, 1 H), 7.15 - 7.13 (dd, J = 2.0, 8.0 Hz, 1 H),
6.89 (d, J = 8 Hz, 1 H), 3.79 (s, 2 H), 3.11 - 3.08 (m, 2 H), 2.82 - 2.79 (m, 2 H), 2.38 (brs, 1 H),
1.63 - 1.61 (m, 2 H).
7-Bromo(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine
N N
The mixture of 2,4,6-trichloroquinoline (300 mg, 1.29 mmol), 7-bromo-2,3,4,5-tetrahydro-1H
benzazepine (291 mg, 1.29 mmol) and n-butanol (3 mL) was heated with stirring in a 10 mL
microwave process vial for 1 hour at 160 ºC under microwave irradiation. The mixture was
cooled to room temperature and diluted with ethyl acetate (10 mL), and then washed with water
(10 mL). The organic layer was dried over sodium sulfate and evaporated to give a residue which
was purified by column chromatography on silica gel to give 222 mg of product as a white solid
(yield was 41%). MS obsd. (ESI+) [(M+H)+] 421.
N-[2-(7-Bromo-1,3,4,5-tetrahydro-2Hbenzazepinyl)chloroquinolinyl]ethane-1,2-
diamine
N N
The mixture of 7-bromo(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine
(200 mg, 0.47 mmol) and ethane-1,2-diamine (0.5 mL) was heated with ng in a 5 mL
microwave process vial for 2 hours at 160 ºC under microwave ation. The solvent was
removed under reduced pressure, and the residue was ed by preparative HPLC to give 38
mg of product (yield was 18%). MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, CD3OD) δ
ppm 7.90 (d, J = 2.4 Hz, 1 H), 7.49 (d, J = 8.8 Hz, 1 H), 7.41(m, 1 H) , 7.35 (m, 1 H), 7.31 (m, 2
H), 5.99 (s, 1 H), 4.80 (s, 2 H), 4.13 (m, 2 H), 3.40 (m, 2 H), 3.00 (m, 4 H), 1.90 (m, 2 H).
Example 118-2
2-{4-[(2-Aminoethyl)amino]quinolinyl}-2,3,4,5-tetrahydro-1Hbenzazepinol
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-
tetrahydro-1Hbenzazepineol (commercial available) and 2,4-dichloroquinoline
(commercial ble) instead of o-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6-
trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 349. 1H NMR (400 MHz, CD3OD) δ
ppm 7.82 (d, J = 8.0 Hz, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.43 (m, 1 H), 7.13 (m, 1 H), 6.96 (m, 2
H), 6.56 (m, 1 H), 6.00 (s, 1 H), 4.72 (s, 2 H), 4.13 (m, 2 H), 3.43 (t, J = 6.4 Hz, 2 H), 2.96 (m, 4
H), 1.87 (m, 2 H).
Example 118-3
N-[6-Methyl(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2 diamine
N N
The title compound was prepared in analogy to e 118-1 in Scheme 59 by using 2,3,4,5-
tetrahydro-1Hbenzazepine (commercial available) and 2,4-dichloromethylquinoline
(commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6-
trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 347. 1H NMR (400 MHz, DMSO-d6)
δ ppm 7.68 (s, 1 H), 7.55 (d, J = 6.8 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 7.21 (d, J = 6.8 Hz, 1 H),
7.13 - 7.05 (m, 3 H), 6.67 (brs, 1 H), 6.00 (s, 1 H), 4.79 (s, 2 H), 4.11 (brs, 2 H), 3.52 (s, 2 H),
3.05 - 2.99 (m, 4 H), 2.35 (s, 3 H), 1.77 (s, 2 H).
Example 118-4
N-[2-(8-Fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]ethane-1,2-
diamine
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 8-fluoro-
2,3,4,5-tetrahydro-1Hbenzazepine (commercial available) and 2,4-dichloromethylquinoline
(commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6-
oroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 365. 1H NMR (400 MHz, CD3OD) δ
ppm 7.68 (s, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.28 (m, 2 H), 7.12 (m, 1 H), 6.83 (m, 1 H), 5.93 (s,
1 H), 4.80 (s, 2 H), 4.09 (s, 2 H), 3.46 (t, J = 6.0 Hz, 2 H), 3.00 (m, 4 H), 2.40 (s, 3 H), 1.90 (m,
2 H).
Example 118-5
N-[6-Chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-
tetrahydro-1Hbenzazepine (commercial available) d of 7-bromo-2,3,4,5-tetrahydro-1H-
2-benzazepine. MS obsd. (ESI+) [(M+H)+] 367. 1H NMR (400 MHz, CD3OD) δ ppm 7.87 (d, J =
2.4 Hz, 1 H), 7.47 - 7.42 (m, 2 H), 7.34 (dd, J = 9.0, 2.2 Hz, 1 H), 7.15 - 7.09 (m, 3 H), 5.99 (s, 1
H), 4.76 (s, 2 H), 4.11 (brs, 2 H), 3.38 - 3.32 (m, 2 H), 3.00 - 2.93 (m, 4 H), 1.87 (t, J = 5.2 Hz, 2
Example 118-6
hloro(9-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-
diamine
Cl F
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 9-fluoro-
2,3,4,5-tetrahydro-1Hbenzazepine (commercial available) instead of o-2,3,4,5-
ydro-1Hbenzazepine. MS obsd. (ESI+) [(M+H)+] 385. 1H NMR (400 MHz, CD3OD) δ
ppm 7.90 (d, J = 2.0 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 1 H), 7.36 (dd, J = 8.8, 2.4 Hz, 1 H), 7.13 (m,
1 H), 7.00 (m, 2 H), 6.11 (s, 1 H), 4.91 (s, 2 H), 4.21 (s, 2 H), 3.45 (t, J = 6.0 Hz, 2 H), 3.10 (m,
2 H), 3.00 (t, J = 6.0 Hz, 2 H), 1.89 (m, 2 H).
Example 118-7
N-[2-(8-Fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine
N N
The title compound was prepared in analogy to e 118-1 in Scheme 59 by using 8-fluoro-
2,3,4,5-tetrahydro-1Hbenzazepine (commercial available) and 2,4-dichloroquinoline
(commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6-
trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 351. 1H NMR (400 MHz, CD3OD) δ
ppm 7.90 (d, J = 7.6 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.52 (t, J = 6.8, 1.2 Hz, 1 H), 7.19 (m, 2
H), 7.02 (m, 2 H), 6.07 (s, 1 H), 4.21 (s, 2 H), 3.52 (t, J = 6.0 Hz, 2 H), 4.91 (s, 2 H), 3.12 (m, 2
H), 3.06 (m, 2 H), 1.94 (m, 2 H).
Example 118-8
1-Amino{[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]amino}propanol
trifluoroacetate (salt)
NH F
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-
tetrahydro-1Hbenzazepine (commercial available), chloroquinoline (commercial
available) and 1,3-diamino-propanol (commercial available) instead of 7-bromo-2,3,4,5-
tetrahydro-1Hbenzazepine, 2,4,6-trichloroquinoline and ethane-1,2-diamine respectively. MS
obsd. (ESI+) +] 363. 1H NMR (400 MHz, CD3OD CD3OD) δ ppm 8.05 - 8.03 (d, J = 7.6
Hz, 1 H), 7.78 - 7.76 (d, J = 7.6 Hz, 1 H), 7.72 - 7.68 (m, 1 H), 7.52 - 7.50 (m, 1 H), 7.44 - 7.40
(m, 1 H), 7.23 - 7.19 (m, 3 H), 6.12 (s, 1 H), 4.97 (s, 2 H), 4.16 - 4.11 (m, 3 H), 3.56 - 3.55 (d, J
= 6 Hz, 2 H), 3.20 - 3.16 (dd, J = 2.8, 12.8 Hz, 1 H), 3.11 - 3.08 (m, 2 H), 2.99 - 2.94 (m, 1 H),
1.99 - 1.98 (m, 2 H).
e 118-9
N-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-
tetrahydro-1Hbenzazepine (commercial available) and chloroquinoline (commercial
available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6-trichloroquinoline
respectively. MS obsd. (ESI+) [(M+H)+] 333. 1H NMR (400 MHz, CD3OD) δ ppm 7.91 - 7.89
(m, 1 H), 7.62 - 7.60 (m, 1 H), 7.52 - 7.45 (m, 2 H), 7.21 - 7.12 (m, 3 H), 5.96 (s, 1 H), 4.10 (s, 2
H), 3.51 - 3.47 (t, J = 6.0 Hz, 1 H), 3.04 - 2.98 (m, 5 H), 2.84 (s, 2 H), 1.94 - 1.91 (m, 2 H).
Example 118-10
N-[6-Bromo(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-
tetrahydro-1Hbenzazepine (commercial available) and 6-bromo-2,4-dichloroquinoline
(commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6-
trichloroquinoline tively. MS obsd. (ESI+) +] 411. 1H NMR (400 MHz, CD3OD) δ
ppm 8.05 (d, J = 2.0 Hz, 1 H), 7.52 - 7.42 (m, 3 H), 7.16 - 7.12 (m, 3 H), 6.03 (s, 1 H), 4.83 (s, 2
H), 4.15 (brs, 2 H), 3.48 (t, J = 6.0 Hz, 2 H), 3.07 - 3.03 (m, 4 H), 1.94 (t, J = 5.2 Hz, 2 H).
Example 118-11
N-[6-Methoxy(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-
diamine
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-
tetrahydro-1Hbenzazepine (commercial available) and 2,4-dichloromethoxyquinoline
(commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6-
oroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 363. 1H NMR (400 MHz, CD3OD) δ
ppm 7.60 (d, J = 9.2 Hz, 1 H), 7.50 (d, J = 6.4 Hz, 1 H), 7.42 (d, J = 2.4 Hz, 1 H), 7.25 - 7.18 (m,
4 H), 6.01 (s, 1 H), 4.93 (s, 2 H), 4.13 (brs, 2 H), 3.89 (s, 3 H), 3.53 (t, J = 6.4 Hz, 2 H), 3.10 -
3.01 (m, 4 H), 1.96 (s, 2 H).
Example 118-12
N-[2-(6-Chloro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 5-chloro-
3,4-dihydro-1H-naphthalenone (commercial available) and 2,4-dichloroquinoline
rcial available) d of 6-bromo-3,4-dihydro-1H-naphthalenone and 2,4,6-
trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 367. 1H NMR (400 MHz, CD3OD) δ
ppm 7.82 (d, J = 8.0 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.43 (m, 2 H), 7.25 (d, J = 8.4 Hz, 1 H),
7.12 (m, 2 H), 5.96 (s, 1 H), 4.87 (s, 2 H), 4.10 (s, 2 H), 3.41 (m, 2 H), 3.25 (m, 2 H), 2.95 (m, 2
H), 1.94 (m, 2 H).
Example 118-13
N-[2-(7-Fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]ethane-1,2-
diamine
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using ro-
3,4-dihydro-1H-naphthalenone (commercial available) and 2,4-dichloromethylquinoline
(commercial available) instead of 6-bromo-3,4-dihydro-1H-naphthalenone and 2,4,6-
trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 365. 1H NMR (400 MHz, CD3OD) δ
ppm 7.82 (s, 1H), 7.58 (d, J = 8.4 Hz, 1 H), 7.45 (m, 1 H), 7.17 (m, 1 H), 6.94 (m, 1 H), 6.84 (m,
1 H), 6.03 (d, J = 4.0 Hz, 1 H), 4.87 (s, 2 H), 3.95 (m, 4 H), 3.56 (t, J = 6.4 Hz, 2 H), 3.10 (m, 4
H), 2.48 (s, 3 H).
Example 118-14
N-Methyl-N'-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-
tetrahydro-1Hbenzazepine (commercial available), chloroquinoline (commercial
available) and N-methyl-ethane-1,2-diamine (commercial available) instead of 7-bromo-2,3,4,5-
tetrahydro-1Hbenzazepine, 2,4,6-trichloroquinoline and ethane-1,2-diamine tively. MS
obsd. (ESI+) [(M+H)+] 347. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (brs, 2 H), 7.88 (s, 1 H),
7.55 (d, J = 6.4 Hz, 1 H), 7.47 (s, 2 H), 7.16 - 7.11 (m, 4 H), 6.01 (s, 1 H), 4.87 (s, 2 H), 4.14 (s,
2 H), 3.63 (s, 2 H), 3.20 (t, J = 5.6 Hz, 2 H), 3.02 (s, 2 H), 2.67 (s, 3 H), 1.80 (s, 2 H).
Example 118-15
7-Methoxy-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-
diamine
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 7-
methoxy-2,3,4,5-tetrahydro-1Hbenzazepine (commercial available) and 2,4-dichloroquinoline
(commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6-
oroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 363. 1H NMR (400 MHz, CD3OD) δ
ppm 8.00 (d, J = 6.0 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.63 (t, J = 6.0 Hz, 1 H), 7.43 (d, J = 8.0
Hz, 1 H), 7.34 (m, 1 H), 6.80 (m, 1 H), 6.76 (m, 1 H), 6.00 (s, 1 H), 4.87 (s, 2 H), 4.13 (m, 2 H),
3.76 (s, 3 H), 3.59 (m, 2 H), 3.09 (m, 4 H), 1.97 (m, 2 H).
Example 118-16
N-[2-(7-Fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine
N N
The title compound was ed in analogy to Example 118-1 in Scheme 59 by using 6-fluoro-
hydro-1H-naphthalenone (commercial available) and 2,4-dichloroquinoline
(commercial available) instead of 6-bromo-3,4-dihydro-1H-naphthalenone and 2,4,6-
trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 351. 1H NMR (400 MHz, CD3OD) δ
ppm 7.92 (d, J = 8.4 Hz, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.55 - 7.49 (m, 2 H), 7.24 (m, 1 H), 6.96
- 6.91 (m, 2 H), 5.97 (s, 1 H), 4.86 (s, 2 H), 4.12 (s, 2 H), 3.55 (t, J = 6.0 Hz, 2 H), 3.08 (m, 4 H),
1.95 (m, 2 H).
Example 118-17
8-Methoxy-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-
diamine
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 1 by using 8-
methoxy-2,3,4,5-tetrahydro-1Hbenzazepine (commercial available) and 2,4-dichloroquinoline
(commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6-
trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 363. 1H NMR (400 MHz, CD3OD) δ
ppm 8.08 (d, J = 8.4 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 1 H), 7.75 (t, J = 7.2 Hz, 1 H), 7.46 (t, J = 8.0
Hz, 1 H), 7.19 (m, 1 H), 7.13 (m, 1 H), 6.81 (m, 1 H), 6.05 (s, 1 H), 4.96 (s, 2 H), 4.15 (m, 2 H),
3.82 (m, 5 H), 3.29 (m, 2 H), 3.07 (m, 2 H), 1.99 (m, 2 H).
Example 118-18
N-[6-(Difluoromethoxy)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-
1,2-diamine
F F
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-
tetrahydro-1Hbenzazepine (commercial ble) and 2,4-dichloro
difluoromethoxyquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H
benzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 399. 1H NMR
(400 MHz, CD3OD) δ ppm 7.63 (d, J = 2.4 Hz, 1 H), 7.55 (d, J = 9.2 Hz, 1 H), 7.47 (d, J = 6.8
Hz, 1 H), 7.27 (dd, J = 8.8, 2.4 Hz, 1 H), 7.18 - 7.12 (m, 3 H), 6.79 (t, J = 74.4 Hz, 1 H, HCF2O-
), 6.03 (s, 1 H), 4.82 (s, 2 H), 4.15 (brs, 2 H), 3.46 (t, J = 6.2 Hz, 2 H), 3.06 - 3.00 (m, 4 H), 1.91
(t, J = 5.2 Hz, 2 H).
Example 118-19
N-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)(trifluoromethyl)quinolinyl]ethane-
1,2-diamine
F NH
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-
tetrahydro-1Hbenzazepine rcial ble) and 2,4-dichloro
trifluoromethylquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H
benzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 401. 1H NMR
(400 MHz, 6) δ ppm 8.36 (s, 1 H), 7.57 - 7.45 (m, 3 H), 7.12 (brs, 3 H), 6.99 (s, 1 H),
6.03 (s, 1 H), 4.81 (s, 2 H), 4.15 (brs, 2 H), 3.29 (brs, 2 H), 3.01 (s, 2 H), 2.82 (s, 2 H), 1.77 (s, 2
H).
Example 118-20
N-[8-Chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine
N N
The title nd was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-
tetrahydro-1Hbenzazepine (commercial available) and 2,4,8-trichloroquinoline (commercial
available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6-trichloroquinoline
respectively. MS obsd. (ESI+) [(M+H)+] 367. 1H NMR (400 MHz, CD3OD) δ ppm 7.24 (d, J =
8.0 Hz, 1 H), 7.60 (d, J = 6.8 Hz, 1 H), 7.55 (d, J = 7.6 Hz, 1 H), 7.13 - 7.09 (m, 3 H), 6.98 (t, J =
8.0 Hz, 1 H), 6.03 (s, 1 H), 4.89 (s, 2 H), 4.20 (brs, 2 H), 3.46 (t, J = 6.0 Hz, 2 H), 3.07 - 3.02 (m,
4 H), 1.92 (t, J = 5.2 Hz, 2 H).
Example 118-21
N-[6-Fluoro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine
N N
The title compound was ed in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-
tetrahydro-1Hbenzazepine rcial available) and 2,4-dichlorofluoroquinoline
(commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6-
trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 351. 1H NMR (400 MHz, CD3OD) δ
ppm 7.60 - 7.52 (m, 2 H), 7.47 (d, J = 6.8 Hz, 1 H), 7.26 - 7.21 (m, 1 H), 7.17 - 7.12 (m, 3 H),
6.04 (s, 1 H), 4.82 (s, 2 H), 4.15 (brs, 2 H), 3.45 (t, J = 6.4 Hz, 2 H), 3.06 - 2.99 (m, 4 H), 1.91 (t,
J = 5.4 Hz, 2 H).
Example 118-22
N,N-Dimethyl-N'-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-
diamine
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-
tetrahydro-1Hbenzazepine (commercial available), 2,4-dichloroquinoline rcial
available) and N,N-dimethyl-ethane-1,2-diamine (commercial available) instead of 7-bromo-
5-tetrahydro-1Hbenzazepine, 2,4,6-trichloroquinoline and ethane-1,2-diamine
respectively. MS obsd. (ESI+) [(M+H)+] 361. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90 (d, J =
3.6 Hz, 1 H), 7.56 - 7.46 (m, 3 H), 7.15 - 7.11 (m, 4 H), 5.89 (s, 1 H), 4.87 (s, 2 H), 4.14 (s, 2 H),
3.53 (s, 2 H), 3.05 (s, 2 H), 2.91 (s, 2 H), 2.53 (s, 6 H), 1.80 (s, 2 H).
Example 118-23
N-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)(trifluoromethoxy)quinolinyl]ethane-
1,2-diamine
N N
The title compound was prepared in y to Example 118-1 in Scheme 59 by using 2,3,4,5-
ydro-1Hbenzazepine (commercial available) and 2,4-dichloro
trifluoromethoxyquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H
benzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 417. 1H NMR
(400 MHz, CD3OD) δ ppm 7.80 (d, J = 2.0 Hz, 1 H), 7.56 (d, J = 9.2 Hz, 1 H), 7.48 (d, J = 6.8
Hz, 1 H), 7.33 (d, J = 10.0 Hz, 1 H), 7.18 - 7.12 (m, 3 H), 6.06 (s, 1 H), 4.83 (s, 2 H), 4.16 (brs, 2
H), 3.46 (t, J = 6.2 Hz, 2 H), 3.06 - 3.00 (m, 4 H), 1.91 (t, J = 5.2 Hz, 2 H).
Example 118-24
N-[6-(Methylsulfonyl)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-
diamine
O NH
N N
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-
tetrahydro-1Hbenzazepine (commercial available) and 2,4-dichloro
methanesulfonylquinoline (commercial ble) instead of 7-bromo-2,3,4,5-tetrahydro-1H
benzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 411. 1H NMR
(400 MHz, DMSO-d6) δ ppm 8.518 (s, 0.5 H), 8.514 (s, 0.5 H), 7.76 - 7.73 (m, 1 H), 7.61 (d, J =
6.4 Hz, 0.5 H), 7.52 (d, J = 6.8 Hz, 0.5 H), 7.47 - 7.34 (m, 1 H), 7.13 - 7.07 (m, 3 H), 6.23 (s, 0.5
H), 6.04 (s, 0.5 H). 4.83 (d, J = 6.4 Hz, 2 H), 4.34 (brs, 2 H), 3.15 (brs, 4 H), 3.00 (s, 2 H), 2.81
(t, J = 6.4 Hz, 1 H), 1.76 (brs, 2 H).
Example 118-25
(2-Aminoethyl)amino]quinolinyl}-2,3,4,5-tetrahydro-1Hbenzazepine
carboxylic acid
N N
The title nd was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-
tetrahydro-1Hbenzazepinecarboxylic acid (commercial available) and 2,4-
dichloroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H
benzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 377. 1H NMR
(400 MHz, CD3OD) δ ppm 8.57 (s, 1 H), 8.07 (s, 1 H), 7.84 (d, J = 7.6 Hz, 1 H), 7.74 (dd, J =
6.0 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.47 (m, 1 H), 7.18 (m, 2 H), 6.10 (s, 1 H), 4.24 (brs, 2
H), 3.62 (m, 2 H), 3.26 (m, 2 H), 3.16 (m, 4 H), 1.91 (m, 2 H).
Example 118-26
2-(4-Chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine
N N
The title compound was prepared in Scheme 1 by using 2,3,4,5-tetrahydro-1Hbenzazepine
rcial available) and chloroquinoline (commercial available) instead of 7-bromo-
2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+)
[(M+H)+] 309. 1H NMR (400 MHz, CDCl3) δ ppm 7.92 - 7.88 (dd, J = 1.2, 8.0 Hz, 1 H), 7.65 (d,
J = 8 Hz, 1 H), 7.53 - 7.45 (m, 2 H), 7.24 - 7.10 (m, 5 H), 4.81 (s, 2 H), 4.09 (brs, 2 H), 3.02 -
2.97 (m, 2 H), 1.94 - 1.88 (m, 2 H).
Example 119
N-[5-Chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine
Cl NH
N N
1-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)ethanone
A suspension of 2,3,4,5-tetrahydro-1Hbenzazepine hydrochloride (10 g, 54.4 mmol) in dry
dichloromethane (450 mL) was stirred at 0 ºC. Triethylamine (18.21 mL, 130.6 mmol) was
added followed by the dropwise addition of acetic anhydride (6.18 mL, 65.3 mmol) in dry
dichloromethane (50 mL). The reaction was then stirred for 1 hour whilst allowing the
temperature to rise slowly to room temperature. The resulting e was washed with 1 N
hydrochloric acid (200 mL) and brine (200 mL), dried over sodium sulfate and concentrated in
vacuo to give 10 g of t as colorless oil (yield was 97%). It was used in next step without
further purification. MS obsd. (ESI+) [(M+H)+] 190.
2-Chloro{[1-(1,3,4,5-tetrahydro-2Hbenzazepinyl)ethylidene]amino}benzonitrile
Cl N
N N
Phosphorus oxychloride (2.93 mL, 32.0 mmol) was added to a stirred solution of 1-(1,3,4,5-
tetrahydro-2Hbenzazepinyl)ethanone (5.5 g, 29.0 mmol) in dry dichloromethane (100 mL)
at 10 ºC. After that, the mixture was stirred for 20 minutes at room temperature. Then a solution
of 2-aminochloro-benzonitrile (4.43 g, 29.0 mmol) in dry dichloromethane (40 mL) was
added and the resulting suspension was heated under reflux for 24 hours. After the reaction
mixture was cooled to room temperature, water (50 mL) was added followed by saturated
sodium onate to pH 8. The organic layer was separated and the aqueous was extracted with
dichloromethane (100 mL). The organic fraction was washed with brine and dried over sodium
sulfate, and then evaporated in vacuo to give a residue which was precipitated in ether. The solid
was collected by filtration and dried in vacuo to give 6 g of t as a brown powder (yield
was 63.7%). It was used in the next step without further purification. MS obsd. (ESI+) [(M+H)+]
324.
ro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinamine
Cl NH2
N N
The mixture of 2-chloro{[1-(1,3,4,5-tetrahydro-2Hbenzazepin
ylidene]amino}benzonitrile (6 g, 18.5 mmol), zinc chloride (2.52 g, 18.5 mmol) and N,N-
dimethyl-acetamide (18 mL) was heated with stirring at 160 ºC for 3 hours under argon. After
the reaction was allowed to cool to about 40 ºC, sodium hydroxide (2 N, 20 mL) was added and
then d for 10 minutes at room temperature. The reaction mixture was poured into water and
the solid was collected by filtration, washed with water and dried in vacuo to give 5 g of product
as an off-white powder (yield was 83.3%). MS obsd. (ESI+) [(M+H)+] 324.
2-(4,5-Dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine
Cl Cl
N N
To the suspension of 5-chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinamine (1.5
g, 4.6 mmol) in concentrated hydrochloric acid (10 mL) was added a solution of sodium nitrite
(390 mg, 5.6 mmol) in water at -10 ºC. After the addition, the reaction mixture was stirred for
further 30 minutes, and then sodium chloride (2 g) was added. The resulting e was stirred
at room temperature overnight and neutralized with saturated sodium bicarbonate, extracted with
dichloromethane (50 mL × 2). The organic layers were combined and dried over sodium sulfate,
and then concentrated under reduced pressure to give the crude product. It was used in next step
without further purification.
N-[5-Chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine
Cl NH
N N
The mixture of 2-(4,5-dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine prepared
above and ethane-1,2-diamine (2 mL) was heated with stirring in a 10 mL microwave process
vial for 2 hours at 150 ºC under microwave irradiation. The reaction mixture was diluted with
ethyl acetate (20 mL), and then washed with water (20 mL). The c fraction was dried over
sodium sulfate, and concentrated under reduced pressure to give a e which was purified by
preparative HPLC to give 20 mg of t as a white . MS obsd. (ESI+) [(M+H)+] 367.
1H NMR (400 MHz, CD
3OD) δ ppm 7.46 - 7.42 (m, 2 H), 7.27 - 7.23 (m, 1 H), 7.16 - 7.11 (m, 3
H), 7.02 (66, J = 7.6, 1.2 Hz, 1 H), 5.97 (s, 1 H), 4.79 (s, 2 H), 4.13 (brs, 2 H), 3.38 - 3.21 (m, 2
H), 3.04 - 3.02 (m, 2 H), 2.96 (t, J = 6.0 Hz, 2 H), 1.91 - 1.86 (m, 2 H).
e 120-1
N-{2-[7-(Methylsulfonyl)-1,3,4,5-tetrahydro-2Hbenzazepinyl]quinolinyl}ethane-
1,2-diamine
N N
7-(Methylsulfonyl)-2,3,4,5-tetrahydro-1Hbenzazepine
The mixture of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine (226 mg, 1.0 mmol), sodium
methanesulfinate (120 mg, 1.2 mmol), copper(I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2
mmol), sodium hydroxide (8.0 mg, 0.2 mmol) and dimethyl sulfoxide (2 mL) was heated in a
sealed tube for 20 hours at 95 ºC. The resulting mixture was diluted with water, and extracted
with ethyl acetate (30 mL × 3). The organic layers were combined and washed with brine (40
mL × 3), and then dried over sodium sulfate. The solvent was removed under d pressure
and the residue was purified by column chromatography on silica gel
(methanol/dichloromethane, 1:20) to give 144 mg of t as a light-brown viscous oil (yield
was 63.9%). MS obsd. (ESI+) [(M+H)+] 226.
2-(4-Chloroquinolinyl)(methylsulfonyl)-2,3,4,5-tetrahydro-1Hbenzazepine
N N
The mixture of 2,4-dichloroquinoline (126 mg, 0.637 mmol), 7-(methylsulfonyl)-2,3,4,5-
ydro-1Hbenzazepine (144 mg, 0.637 mmol), triethylamine (0.106 mL, 0.765 mmol) and
N-methylpyrrolidone (2 mL) was heated with stirring in a sealed tube for 4 hours at 100 ºC.
The resulting mixture was diluted with water and extracted with ethyl acetate (15 mL × 3). The
organic layers were combined and washed with brine (15 mL × 3), and then dried over sodium
sulfate. The solvent was d under reduced pressure and the residue was purified by column
chromatography on silica gel (ethyl acetate/petroleum ether, 1:5) to afford 55.6 mg of product as
a white solid (yield was 22.5%). MS obsd. (ESI+) [(M+H)+] 387.
N-{2-[7-(Methylsulfonyl)-1,3,4,5-tetrahydro-2Hbenzazepinyl]quinolinyl}ethane-
1,2-diamine
N N
The mixture of 2-(4-chloroquinolinyl)(methylsulfonyl)-2,3,4,5-tetrahydro-1H
epine (55.6 mg, 0.144 mmol) and ethane-1,2-diamine (1 mL) was heated with stirring in a
mL microwave s vial for 2 hours at 150 ºC under microwave irradiation. The solvent
was removed in vacuo and the residue was purified by preparative HPLC to give 27.5 mg of
product as a light-yellow solid (yield was 46.5%). MS obsd. (ESI+) [(M+H)+] 411. 1H NMR (400
MHz, CD3OD) δ ppm 7.82 - 7.73 (m, 4 H), 7.53 (d, J = 7.6 Hz, 1 H), 7.45 - 7.40 (m, 1 H), 7.12 -
7.08 (m, 1 H), 5.98 (s, 1 H), 4.96 (s, 2 H), 4.16 (s, 2 H), 3.41 (t, J = 6.4 Hz, 2 H), 3.16 (brs, 2 H),
3.06 (s, 3 H), 2.97 (t, J = 6.4 Hz, 2 H), 1.96 (brs, 2 H).
Example 120-2
N-{2-[7-(Ethylsulfonyl)-1,3,4,5-tetrahydro-2Hbenzazepinyl]quinolinyl}ethane-1,2-
diamine
N N
The title compound was prepared in analogy to Example 120-1 by using sodium ethanesulfinate
(commercial available) d of sodium methanesulfinate. MS obsd. (ESI+) [(M+H)+] 424. 1H
NMR (400 MHz, CD3OD) δ ppm 7.81 - 7.76 (m, 2 H), 7.70 - 7.67 (m, 2 H), 7.53 (d, J = 7.6 Hz,
1 H), 7.43 - 7.39 (m, 1 H), 7.10 - 7.06 (m, 1 H), 5.97 (s, 1 H), 4.93 (s, 2 H), 4.14 (s, 2 H), 3.39 (t,
J = 6.4 Hz, 2 H), 3.16 - 3.10 (m, 4 H), 2.95 (t, J = 6.4 Hz, 2 H), 1.94 (brs, 2 H), 1.16 (t, J = 7.2
Hz, 3 H).
Example 121
N-[2-(8-Ethoxy-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine
N N O
2-(4-Chloroquinolinyl)ethoxy-2,3,4,5-tetrahydro-1Hbenzazepine
N N O
To a solution of 2-(4-chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepinol (36 mg, 0.11
mmol) in 5 mL of dry N,N-dimethylformamide was added sodium hydride (8 mg, 0.17 mmol),
then bromoethane (18.5 mg, 0.17 mmol) was added dropwise under nitrogen. After the addition,
the reaction was d at room temperature for r 1 hour. The resulting mixture was diluted
with dichloromethane (10 mL), washed with brine and then dried over sodium sulfate. The
solvent was removed in vacuo and the residue was ed by column chromatography on silica
gel to give 28 mg of product. MS obsd. (ESI+) [(M+H)+] 353.
N-[2-(8-Ethoxy-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine
N N O
The mixture of 2-(4-chloroquinolinyl)ethoxy-2,3,4,5-tetrahydro-1Hbenzazepine (28 mg,
0.79 mmol) and ethane-1,2-diamine (0.5 mL) was heated with stirring in a 5 mL microwave
process vial for 2 hours at 160 ºC under ave irradiation. The solvent was removed under
reduced pressure and the residue was purified by preparative HPLC to give 12 mg of product
(yield was 40%). MS obsd. (ESI+) [(M+H)+] 377. 1H NMR (400 MHz, CD3OD) δ ppm 7.88 (d, J
= 7.6 Hz, 1 H,), 7.62 (d, J = 8.0 Hz, 1 H), 7.57 (m, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 7.38 (m, 1 H),
7.19 (m, 2 H), 6.00 (s, 1 H), 4.78 (s, 2 H), 4.12 (m, 2 H), 3.99 (q, J = 6.8 Hz, 2 H), 3.48 (m, 2 H),
2.98 (m, 4 H), 1.94 (m, 2 H), 1.34 (t, J = 6.8 Hz, 3 H).
Example 122
N-[6-(Pyridinyloxy)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-
1,2-diamine
N N
4-Chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinol
N N
To a solution of 2-(4-chloromethoxy-quinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine
(800 mg, 2.37 mmol) in 15 mL of romethane was added slowly a on of boron
tribromide (0.558 mL, 5.9 mmol). The resulting mixture was stirred at room temperature for 30
minutes, followed by stirring at 40 ºC for 2 hours. After cooled to room temperature, the reaction
mixture was carefully quenched with sodium bicarbonate (20 mL), and then extracted with
dichloromethane (10 mL × 3). The organic layers were combined and washed with brine (20 ml),
then dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified
by flash column chromatography on silica gel (ethyl e/hexane, 1:5) to give 500 mg of
t (yield was 65%).
2-[4-Chloro(pyridinyloxy)quinolinyl]-2,3,4,5-tetrahydro-1Hbenzazepine
N N
The mixture of 4-chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinol (200 mg,
0.617 mmol), 2-fluoro-pyridine (180 mg, 1.85 mmol), ium carbonate (73 mg, 0.53 mmol)
and dry dimethylsulfoxide was heated with stirring in a sealed tube for 40 minutes at 130 ºC
under microwave irradiation. The resulting mixture was cooled to room temperature, then diluted
with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layer
was washed with brine (10 mL × 3), and then dried over sodium sulfate. The solvent was
removed in vacuo and the e was purified by column chromatography on silica gel (ethyl
acetate/petroleum ether, 1:5) to give 110 mg of product as a yellow solid (yield was 45%).
Pyridinyloxy)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-
1,2-diamine
N N
The mixture of 2-[4-chloro(pyridinyloxy)quinolinyl]-2,3,4,5-tetrahydro-1H
benzazepine (40 mg, 0.1 mmol) and ethane-1,2-diamine (2 mL) was heated with stirring in a 5
mL microwave process vial for 3 hours at 180 ºC under microwave irradiation. The solvent was
removed under reduced re and the residue was purified by preparative HPLC to give 7 mg
of product as a yellow powder. MS obsd. (ESI+) [(M+H)+] 426. 1H NMR (400 MHz, CD3OD) δ
ppm 8.12 (d, J = 3.2 Hz, 1 H), 7.82 - 7.78 (m, 1 H), 7.66 (d, J = 2.8 Hz, 1 H), 7.61 (d, J = 8.8 Hz,
1 H), 7.48 (d, J = 6.8 Hz, 1 H), 7.23 (dd, J = 5.2, 2.4 Hz, 1 H), 7.16 - 7.08 (m, 4 H), 6.90 (d, J =
8.4 Hz, 1 H), 6.04 (s, 1 H), 4.83 (s, 2 H), 4.16 (brs, 2 H), 3.41 (t, J = 6.2 Hz, 2 H), 3.05 (t, J = 4.8
Hz, 2 H), 2.94 (t, J = 6.2 Hz, 2 H), 1.96 - 1.91 (m, 2 H).
Example 123
2-{4-[(2-Aminoethyl)amino]chloroquinolinyl}-N,N-dimethyl-2,3,4,5-tetrahydro-1H
benzazepinecarboxamide
N N
Methyl 2-(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepinecarboxylate
N N
o(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1H-benzazepine (200 mg, 0.47
mmol), triethylamine ( 94 mg, 0.94 mmol) and tetrakis(triphenylphosphine)palladium(0) (49.2
mg, 0.047 mmol) were added into 10 mL of dry methanol. The resulting e was stirred
under reflux overnight under carbon monoxide. After cooled to room temperature, the reaction
was diluted with ethyl acetate (30 mL), and then washed with water. The organic fraction was
dried over sodium e and trated in vacuo to give a residue which was purified by
column chromatography on silica gel (ethyl acetate/petroleum ether, 1:5) to give 156 mg of
product (yield was 83%). MS obsd. (ESI+) [(M+H)+] 401.
2-(4,6-Dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepinecarboxylic acid
N N
Methyl 2-(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepinecarboxylate (156
mg, 0.39 mmol) was added into the mixture of methanol (5 mL) and sodium hydroxide (5 M, 2
mL). The reaction mixture was stirred at room temperature overnight. After that, the reaction
was diluted with 20 mL of water, acidified with 2 M of hydrochloric acid to pH 6 and diluted
with ethyl acetate (30 mL). The organic layer was separated and washed with water. The solvent
was dried over sodium sulfate and concentrated in vacuo to give a residue which was purified by
column chromatography on silica gel to give 135 mg of product. MS obsd. (ESI+) +] 387.
2-(4,6-Dichloroquinolinyl)-N,N-dimethyl-2,3,4,5-tetrahydro-1Hbenzazepine
carboxamide
N N
The mixture of 2-(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepinecarboxylic
acid (135 mg, 0.35 mmol), dimethylamine hydrochloride (34.2 mg, 0.42 mmol), triethylamine
(105 mg, 1.05 mmol), O-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium
uorophosphate (159 mg, 0.42 mmol) and 5 mL of dichloromethane was stirred at room
temperature overnight under nitrogen. The reaction was diluted with ethyl acetate (20 mL),
washed with water and dried over sodium sulfate. The solvent was removed in vacuo and the
residue was purified by column chromatography to give 133 mg of product as a white solid.
(yield was 92%). MS obsd. (ESI+) [(M+H)+] 414.
(2-Aminoethyl)amino]chloroquinolinyl}-N,N-dimethyl-2,3,4,5-tetrahydro-1H
benzazepinecarboxamide
N N
The mixture of -dichloroquinolinyl)-N,N-dimethyl-2,3,4,5-tetrahydro-1H
benzazepinecarboxamide (133 mg, 0.32 mmol) and ethane-1,2-diamine (2 mL) was heated
with stirring in a 5 mL microwave process vial for 3 hours at 180 ºC under microwave
irradiation. The solvent was removed under reduced pressure and the residue was purified by
ative HPLC to give 11 mg of product as a white solid. MS obsd. (ESI+) [(M+H)+] 438. 1H
NMR (400 MHz, CD3OD) δ ppm 7.89 (s, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.49 (d, J = 8.8 Hz, 1
H), 7.38 (m, 1 H), 7.22 (m, 2 H), 6.01 (s, 1 H), 4.80 (s, 2 H), 4.16 (m, 2 H), 3.44 (t, J = 6.4 Hz, 2
H), 3.11 - 2.97 (m, 10 H), 1.93 (m, 2 H).
Example 124
2-{4-[(2-Aminoethyl)amino]quinolinyl}bromo-1,2,4,5-tetrahydro-3Hbenzazepin
N N
7-Bromo(4-chloroquinolinyl)-1,2,4,5-tetrahydro-3Hbenzazepinone
N N
To a solution of chloroquinoline (196 mg, 1.0 mmol) in dioxane (4 mL) was added 7-
bromo-1,2,4,5-tetrahydro-3Hbenzazepinone (161 mg, 1.0 mmol), followed by
tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.03 mmol), 9,9-dimethyl-4,5-
bis(diphenylphosphino)xanthene (65 mg, 0.11 mmol), and potassium phosphate ic (212
mg, 1.0 mmol). The resultant mixture was refilled with nitrogen and heated at 130 ºC overnight.
After cooled to room temperature, the mixture was d with acetonitrile (10 mL), filtered,
and washed with acetonitrile. The filtrate was concentrated under reduced pressure to give a
residue which was purified by column chromatography on silica gel (hexane/ethyl
acetate/ammonium hydroxide solution, 80: 19:1) to give 165 mg of product as a white solid
(yield was 42%). MS obsd. (ESI+) [(M+H)+] 401.
2-{4-[(2-Aminoethyl)amino]quinolinyl}bromo-1,2,4,5-tetrahydro-3Hbenzazepin
one
N N
To a on of 7-bromo(4-chloroquinolinyl)-1,2,4,5-tetrahydro-3Hbenzazepinone
(40 mg, 0.1 mmol) was added ethane-1,2-diamine (0.5 mL) in a microwave vessel, which was
degassed and ed with nitrogen. The resultant mixture was heated at 170 ºC under
microwave irradiation for 30 minutes. After cooled to room temperature, the mixture was diluted
with methanol (10 mL) and concentrated under reduced pressure to give a residue which was
purified by preparative HPLC to afford 42 mg of product as a solid (yield was 98%). MS obsd.
(ESI+) [(M+H)+] 424. 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (d, J = 8.0 Hz, 1H), 7.73 (d, J =
8.0 Hz, 1 H), 7.58 (m, 2 H), 7.47 (s, 2 H), 7.32 (td, J = 1.2, 8.8 Hz, 1 H), 6.04 (s, 1 H), 5.48 (s, 2
H), 3.42 (t, J = 6.4 Hz, 2 H), 3.11 (t, J = 7.6 Hz, 2 H), 2.98 (t, J = 6.0 Hz, 2 H), 2.86 (t, J = 7.2
Hz, 2 H).
Example 125
1-(2-{[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]amino}ethyl)guanidine
oroacetate
NH NH
NH F
N N
To a solution of N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-
diamine (200 mg, 0.6 mmol) and methyl-1H-pyrazolecarboximidamide nitrate (122 mg,
0.6 mmol) in ethanol (15 mL) was ed by heating for overnight. After cooled to room
temperature, the reaction mixture was concentrated under reduced pressure, diluted with water
(15 mL), and then extracted with dichloromethane (50 mL × 2). The dichloromethane fractions
were combined and dried over sodium sulfate, and then concentrated under d pressure to
give a residue which was purified by preparative HPLC to give 35.78 mg of product as a white
solid. MS obsd. (ESI+) [(M+H)+] 375. 1H NMR (400 MHz, CD3OD) δ ppm 8.07 - 8.04 (brs, 1
H), 7.80 - 7.69 (m, 2 H), 7.51 - 7.41 (m, 2 H), 7.26 - 7.20 (m, 3 H), 6.00 (s, 1 H), 4.98 (s, 2 H),
4.14 (s, 2 H), 3.71 - 3.67 (m, 2 H), 3.58 - 3.55 (t, J = 6.4 Hz, 2 H), 3.13 - 3.10 (m, 2 H), 2.01 (s, 2
H).
Example 126-1
N-[(2-Amino-4,5-dihydro-1,3-oxazolyl)methyl](1,3,4,5-tetrahydro-2Hbenzazepin
yl)quinolinamine trifluoroacetate
NH F
N N
The mixture of 1-amino{[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin
no}propanol (690 mg, 1.9 mmol) and potassium acetate (490 mg, 5 mmol) in methanol
(7 mL) and water (1.75 mL) was d at 0 ºC. A cooled solution of cyanogen bromide (212
mg, 2 mmol) in methanol (1 mL) was added to the above mixture and the resultant mixture was
stirred at room temperature for 4 hours. The reaction mixture was concentrated and diluted with
ethyl acetate (50 mL), and then washed with water (50 mL). The organic on was dried over
sodium sulfate, and concentrated under d pressure to give a residue which was purified by
preparative HPLC to give 73 mg of product as a white powder (yield was 10%). MS obsd. (ESI+)
[(M+H)+] 388. 1H NMR (400 MHz, CD3OD) δ ppm 8.06 - 8.04 (dd, J = 8.4, 1.2 Hz, 1 H), 7.80 -
7.78 (d, J = 8.4 Hz, 1 H), 7.72 (m, 1 H), 7.50 (m, 1 H), 7.42 (m, 1 H), 7.23 (m, 3 H), 6.11 (s, 1
H), 5.42 (m, 1 H), 4.99 (s, 2 H), 4.11 (m, 3 H), 3.93 (d, J = 5.6 Hz, 2 H), 3.77 (dd, J = 9.6, 6.8
Hz, 1 H), 3.09 (m, 2 H), 2.00 (d, J = 5.6 Hz, 2 H).
Example 126-2
N-[(2-Amino-4,5-dihydro-1,3-oxazolyl)methyl]chloro(1,3,4,5-tetrahydro-2H
benzazepinyl)quinolinamine
N N
The title compound was prepared in y to Example 9-1 by using 1-amino{6-chloro-[2-
(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]amino}propanol [It was prepared in
Scheme 1 by using 2,3,4,5-tetrahydro-1Hbenzazepine (commercial available) and 1,3-
diamino-propanol (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H
benzazepine and ethane-1,2-diamine respectively.] instead of 1-amino{[2-(1,3,4,5-tetrahydro-
2Hbenzazepinyl)quinolinyl]amino}propanol. MS obsd. (ESI+) [(M+H)+] 422. 1H
NMR (400 MHz, CD3OD) δ ppm 8.17 (s, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.69 (m, 1 H), 7.52 (s,
1 H), 7.22 (m, 3 H), 6.15 (s, 1 H), 5.42 (m, 1 H), 4.99 (s, 2 H), 4.11 (m, 3 H), 3.94 (d, J = 5.6 Hz,
2 H), 3.77 (dd, J = 9.6, 6.8 Hz, 1 H), 3.09 (m, 2 H), 2.00 (d, J = 5.6 Hz, 2 H).
Example 127
1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]glycinamide
NH O
N N
2-Chloro-N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]acetamide
NH O
N N
To the solution of 2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinamine (500 mg, 1.73
mmol) was added 1,8-diazabicyclo[5.4.0]undecene (0.52 mL, 3.48 mmol) followed by
chloroacetyl chloride (0.21 mL, 2.64 mmol) at room temperature. The resulting solution was
heated with stirring at 70 ºC for 2 hours under nitrogen. After cooled to room temperature, the
reaction was diluted with ethyl e (50 mL), and then washed with water (50 mL × 3). The
organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a
residue which was purified by column chromatography on silica gel (ethyl acetate/petroleum
ether, 1:4) to give 140 mg of product as an off-white solid (yield was . MS obsd. (ESI+)
[(M+H)+] 366.
2-Azido-N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]acetamide
NH O
N N
To a solution of 2-chloro-N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin
yl]acetamide (70 mg, 0.19 mmol) in acetonitrile (2 mL) was added sodium azide (62 mg, 0.95
mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction was
diluted with ethyl acetate (20 mL), and then washed with water (10 mL). The ethyl acetate
fraction was dried over sodium sulfate, and then concentrated under reduced pressure to give a
residue which was purified by column chromatography on silica gel (ethyl acetate/petroleum
ether, 1:4) to give 65 mg of product as a white powder (yield was 91.8%). MS obsd. (ESI+)
[(M+H)+] 373.
N-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]glycinamide
NH O
N N
To a solution of 2-azido-N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]acetamide
(65 mg, 0.17 mmol) in methanol was added palladium (10% on carbon, 7 mg). After being
d at room temperature overnight under a hydrogen atmosphere, the resulting mixture was
ed. The te was concentrated in vacuo and the residue was purified by preparative
HPLC to afford 30 mg of product as a white powder (yield was 60.5%). MS obsd. (ESI+)
[(M+H)+] 347. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (s, 1 H), 7.78 (d, J = 8.0 Hz, 1 H),
7.55 - 7.49 (m, 3 H), 7.23 - 7.20 (m, 1 H), 7.15 - 7.08 (m, 3 H), 4.79 (s, 2 H), 4.13 (brs, 2 H),
3.45 (brs, 2 H), 3.04 (brs, 2 H), 1.79 (brs, 2 H).
e 128
3-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]propanamine
N N
Methyl -[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propenoate
O O
N N
The mixture of 2-(4-chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine (1.5 g, 4.86
mmol), acrylic acid methyl ester (0.88 ml, 9.7 mmol), ylamine (6 mL) and N,N-
dimethylformamide (6 mL), i-tert-butylphosphine)palladium(0) (124 mg, 0.243 mmol) was
heated with stirring in a 20 mL of microwave process vial for 30 minutes at 100 ºC under argon.
The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL ×
3). The organic layers were combined, washed with brine, dried over sodium sulfate and
concentrated in vacuo to give a residue which was purified by flash column to afford 1.41 g of
product as a white solid (yield was 81%). MS obsd. (ESI+) [(M+H)+] 359.
Methyl 3-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propanoate
O O
N N
To a solution of methyl (2E)[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]prop-
2-enoate (1.4 g, 3.91 mmol) in 30 mL of methanol was added 10% palladium on carbon (70 mg).
After being vigorously stirred under hydrogen (balloon) for 3 hours, the reaction was filtered and
the filtrate was concentrated in vacuo to give 1.4 g of t as a white solid (yield was 98%).
MS obsd. (ESI+) [(M+H)+] 361.
3-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]propanoic acid
O OH
N N
To a solution of methyl 3-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propanoate
(1.4 g, 3.89 mmol) in methanol (10 mL) was added an aqueous solution of sodium hydroxide (4
N, 16 mL) and the resulting mixture was stirred at room temperature for 4 hours. The reaction
was ied to pH 4 with 5 N hydrochloric acid, and then extracted with ethyl acetate (10 mL ×
3). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue
which was purified by flash column chromatography to afford 1.1 g of product as a white solid
(yield was 82%). MS obsd. (ESI+) [(M+H)+] 347.
3-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]propanamide
O NH
N N
To a solution of 3-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propanoic acid
(300 mg, 0.867 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.123 mL, 1.3
mmol ) and one drop of N,N-dimethylformamide at 0 ºC. The resulting mixture was warmed to
room ature and stirred for further 2 hours. The solvent was removed under reduced
re and the residue was dissolved in dichloromethane (5 mL), to which a tetrahydrofuran
on of ammonia (4 N, 5 mL) was added at 0 ºC, followed by stirring at room temperature
overnight. The reaction was concentrated in vacuo to dryness and purified by flash column to
afford 50 mg of t as a white solid. It was used in next step without further purification.
MS obsd. (ESI+) [(M+H)+] 346.
3-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]propanamine
N N
To the mixture of 3-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propanamide (50
mg, 0.145 mmol ) in tetrahydrofuran (5 mL) was added a tetrahydrofuran solution of borane (1.5
mL, 1.5 mmol) at 0 ºC, followed by stirring at 70 ºC for 4 hours. After being ed with
methanol (5 mL) at 0 ºC, the resulting mixture was concentrated in vacuo to give a residue which
was purified by flash column (ethyl acetate/hexane, 3:7) to afford 10 mg of product as a white
solid. MS obsd. (ESI+) [(M+H)+] 332. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (d, J = 7.2
Hz, 1 H), 7.57 - 7.52 (m, 2 H), 7.47 - 7.43 (m, 1 H), 7.18 - 7.04 (m, 5 H), 5.24 (brs, 2 H), 4.85 (s,
2 H), 4.14 (brs, 2 H), 3.03 (brs, 2 H), 2.93 (t, J = 7.2 Hz, 2 H), 1.89 - 1.82 (m, 4 H).
Example 129
3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]methanol
N N
Methyl 2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinecarboxylate
O O
N N
The mixture of 2-chloroquinolinecarboxylic acid methyl ester (3 g, 13.5 mmol), 5-
tetrahydro-1Hbenzazepine hydrochloride (3 g, 16.3 mmol), potassium carbonate (4.5 g, 32.6
mmol), tetrabutylammonium iodide (300 mg) and e (60 mL) was heated with stirring at
110 ºC for 5 days. The solvent was removed under reduced pressure to give a residue which was
purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1:4) to give 1.97
g of product as a yellow solid. MS obsd. (ESI+) [(M+H)+] 333.
[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]methanol
N N
To the mixture of methyl 2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinecarboxylate
(30 mg, 0.087 mmol ) in tetrahydrofuran (2 mL) was added a tetrahydrofuran solution of borane
(1.5 mL, 1.5 mmol) at 0 ºC. After being d at 70 ºC for 4 hours, the mixture was quenched
with methanol (5 mL) at 0 ºC. The solvent was removed in vacuo to give a e which was
purified by flash column (ethyl acetate/hexane, 3:7) to afford 16 mg of product as a white solid.
MS obsd. (ESI+) [(M+H)+] 305. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.70 (d, J = 8.0 Hz, 1
H), 7.56 - 7.44 (m, 3 H), 7.25 (s, 1 H), 7.16 - 7.07 (m, 4 H), 5.44 (t, J = 4.2 Hz, 1 H), 4.86 (s, 2
H), 4.85 (s, 2 H), 4.18 (brs, 2 H), 3.04 (brs, 2 H), 1.80 (brs, 2 H).
Example 130-1
2-(6-Chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine
N N
2-[6-Chloro(propenyl)quinolinyl]-2,3,4,5-tetrahydro-1Hbenzazepine
N N
The mixture of 2-(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine (200 mg,
0.58 mmol), 2-allyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.164 mL, 0.87 mmol),
tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.058 mmol), potassium carbonate (241 mg,
1.74 mmol), 1,2-dimethoxyethane (3 mL) and water (1 mL) was heated with stirring in a 10 mL
of microwave process vial for 3 hours at 120 ºC under microwave irradiation. The resulting
mixture was diluted with ethyl acetate (20 mL), and then washed with water (20 mL). The ethyl
acetate fraction was dried over sodium e, and then concentrated under reduced pressure to
give a residue which was separated by column tography on silica gel (ethyl
acetate/petroleum ether, 0.1:5) to afford 2-[6-chloro(propenyl)quinolinyl]-2,3,4,5-
tetrahydro-1Hbenzazepine (20 mg) and 2-(6-chloroquinolinyl)-2,3,4,5-tetrahydro-1H
benzazepine (50 mg).
hloro(propenyl)quinolinyl]-2,3,4,5-tetrahydro-1Hbenzazepine
MS obsd. (ESI+) [(M+H)+] 349.
2-(6-chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine
MS obsd. (ESI+) [(M+H)+] 309. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.93 (d, J = 9.2 Hz, 1
H), 7.72 (brs, 1 H), 7.56 - 7.51 (m, 2 H), 7.47 - 7.44 (m, 1 H), 7.29 (d, J = 9.6 Hz, 1 H), 7.14 -
7.08 (m, 3 H), 4.85 (brs, 2 H), 4.14 (brs, 2 H), 3.03 (brs, 2 H), 1.78 (brs, 2 H).
Example 130-2
3-[6-Chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propane-1,2-diol
N N
To a solution of 2-[6-chloro(propenyl)quinolinyl]-2,3,4,5-tetrahydro-1H
benzazepine (20 mg, 0.057 mmol) in acetone (2 mL) and water (1 mL) was added N-methyl
morpholine-N-oxide (50 % in water, 15.5 mg, 0.057 mmol) ed by osmium tetroxide (0.14
mg, 0.0005 mmol). The resulting mixture was stirred at room temperature overnight. The t
was removed under reduced pressure and the residue was purified by column chromatography on
silica gel (ethyl acetate/petroleum ether, 3:2) to give 14 mg of product as colorless oil. MS obsd.
(ESI+) [(M+H)+] 383. 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J = 2.0 Hz, 1 H), 7.58 (d, J =
8.8 Hz, 1 H), 7.50 (d, J = 6.8 Hz, 1 H), 7.40 (dd, J = 9.2, 2.4 Hz, 1 H), 7.14 - 7.08 (m, 4 H), 4.84
(brs, 2 H), 4.21 (brs, 1 H), 4.10 (brs, 1 H), 3.91 - 3.88 (m, 1 H), 3.58 - 3.55 (m, 2 H), 3.21 (dd, J
= 14.0, 4.4 Hz, 1 H), 3.04 (d, J = 6.4 Hz, 2 H), 2.87 (dd, J = 14.0, 8.4 Hz, 1 H), 1.91 - 1.86 (m, 2
Example 131
(4S){2-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]ethyl}-4,5-dihydro-
1,3-oxazolamine
N N
tert-Butyl (4S)-2,2-dimethyl{(E)[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin-
4-yl]ethenyl}-1,3-oxazolidinecarboxylate
N N
The mixture of 2-(4-chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine (310 mg, 1.0
mmol), (S)-2,2-dimethylvinyl-oxazolidinecarboxylic acid tert-butyl ester (273 mg, 1.2
mmol), bis(tri-tert-butylphosphine)palladium(0) (51 mg, 0.1 mmol), methyl dicyclohexylamine
(293 mg, 1.5 mmol) and N,N-dimethylformamide (6 mL) was heated with stirring in a 20 mL
microwave process vial for 2.5 hours at 120 ºC under microwave irradiation. The reaction
mixture was diluted with ethyl acetate and washed with brine. The c layer was dried over
sodium sulfate, and then concentrated under d pressure to give a residue which was
purified by flash column to give 380 mg of product as a white solid (yield was 76%). MS obsd.
(ESI+) [(M+H)+] 500.
tert-Butyl (4S)-2,2-dimethyl{2-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin
yl]ethyl}-1,3-oxazolidinecarboxylate
N N
The mixture of tert-butyl (4S)-2,2-dimethyl{(E)[2-(1,3,4,5-tetrahydro-2Hbenzazepin
yl)quinolinyl]ethenyl}-1,3-oxazolidinecarboxylate (380 mg, 0.76 mmol), palladium
hydroxide (20 % on carbon, 50 mg) and ethanol (15 mL) was stirred at room temperature for 4
hours under hydrogen. The solid was filtered by a pad of silica gel and the filtrate was
trated in vacuo to give 340 mg of product as a white solid (yield was 89%). MS obsd.
(ESI+) [(M+H)+] 502.
(2S)Amino[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]butanol
N N
To the solution of tert-butyl (4S)-2,2-dimethyl{2-[2-(1,3,4,5-tetrahydro-2Hbenzazepin
nolinyl]ethyl}-1,3-oxazolidinecarboxylate (340 mg, 0.68 mmol) in ethyl acetate was
introduced hydrochloric acid gas for 30 minutes. After being stirred at room temperature
overnight, the reaction was poured into ice-water then lized with saturated sodium
carbonate. The organic layer was separated, dried over sodium sulfate, and then concentrated in
vacuo to give the product. It was used in next step without further purification. MS obsd. (ESI+)
[(M+H)+] 362.
(4S){2-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]ethyl}-4,5-dihydro-
azolamine
N N
To the stirred mixture of (2S)amino[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin-
4-yl]butanol (110 mg, 0.3 mmol), ium acetate (90 mg, 0.91 mmol), methanol (8 mL)
and water (2 mL) was added a solution of cyanogen bromide (32.3 mg, 0.3 mmol) in cold
methanol (2 mL) at 0 ºC. After the addition, the resulting mixture was stirred at room
temperature for 24 hours. The solvent was removed under reduced pressure to give a residue
which was purified by preparative HPLC to give 40 mg of product as a white solid (yield was
. MS obsd. (ESI+) [(M+H)+] 387. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (d, J = 7.2
Hz, 1 H), 7.56 - 7.43 (m, 3 H), 7.17 - 7.04 (m, 4 H), 5.91 (brs, 1 H), 4.84 (s, 2 H), 4.21 (t, J = 8.0
Hz, 2 H), 4.13 (brs, 2 H), 3.87 (t, J = 7.2 Hz, 1 H), 3.77 (t, J = 7.2 Hz, 1 H), 3.01 (brs, 2 H), 2.94
- 2.89 (m, 1 H), 1.78 (brs, 2 H), 1.72 - 1.67 (m, 2 H).
Example 132
N-(2-Aminoethyl)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinesulfonamide
trifluoroacetate
O N
S NH F
O 2 F
N N
2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinethiol
N N
A mixture of 2-(4-chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine (2 g, 6.47 mmol)
and sodium thiomethoxide (2.4 g, 34 mmol) in dry N,N-dimethylformamide (20 mL) was heated
with stirring ght under reflux. The reaction mixture was cooled to 50 ºC and the volatile
ents were evaporated under reduced re to give a residue which was dissolved in 30
mL of chilled water and carefully acidified with 20% hydrochloride aid to pH 4-5 under argon.
The ant solution was extracted with chilled dichloromethane (30 mL × 3). The
dichloromethane fractions were combined and washed with chilled brine (30 mL × 2) and then
concentrated under reduced pressure at room temperature to give the crude product. It was used
in next step without further purification.
2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinesulfonyl chloride
O S O
N N
Gaseous chlorine was passed through a well stirred solution of 2-(1,3,4,5-tetrahydro-2H
benzazepinyl)quinolinethiol (2 g, 6.5 mmol) in concentrated hloric acid (17 mL) at -
ºC at such a rate that ature was maintained between -5 and -10 ºC. The passage of
chlorine was discontinued after 30 s. The mixture was poured into ice (30 g) followed by
addition of sodium bicarbonate (4 g) in small portions. The resultant mixture was extracted with
chilled dichloromethane (30 mL × 3). The dichloromethane fractions were combined and washed
with chilled water (20 mL), and then dried over sodium sulfate, filtered and the filtrate was used
in next step without further purification.
N-(2-Aminoethyl)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinesulfonamide
trifluoroacetate
O N
S NH F
O 2 F
N N
To a solution of ethane-1,2-diamine (500 mg, 8.3 mmol) in dichloromethane (20 mL) was added
a cold triethylamine (5 drops) in an ter bath, followed by the addition of the solution of 2-
(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinesulfonyl chloride (400 mg, 0.9 mmol) in
dichloromethane (20 mL) prepared above slowly. After being d overnight, the solvent was
removed under d pressure, and the residue was purified by preparative HPLC to give 43.6
mg of product (yield was 12.2%). MS obsd. (ESI+) [(M+H)+] 397. 1H NMR (400 MHz, CD3OD)
δ ppm 8.37 - 8.35 (m, 1 H), 7.88 - 7.82 (m, 2 H), 7.71 (m, 1 H), 7.48 - 7.42 (m, 2 H), 7.18 - 7.17
(m, 3 H), 5.02 (s, 2 H), 4.23 (s, 2 H), 3.09 - 3.03 (m, 6 H), 1.98 (s, 2 H).
Example 133-1
4-{4-[(2-Aminoethyl)amino]methylquinolinyl}-1,3,4,5-tetrahydro-2H-1,4-
benzodiazepinone
N N
O H
4-(4-Chloromethylquinolinyl)-1,3,4,5-tetrahydro-2H-1,4-benzodiazepinone
N N
O H
The mixture of 2,4-dichloromethyl-quinoline (422 mg, 2 mmol), 1,3,4,5-tetrahydro-2H-1,4-
benzodiazepinone (298 mg, 2 mmol) and l alcohol (15 mL) was heated with stirring in
a 20 mL microwave process vial for 3 hours at 160 ºC under microwave irradiation. After
cooling, the solvent was d in vacuo and the residue was purified by column
chromatography on silica gel (methanol/dichloromethane, 1:20) to give the product. MS obsd.
(ESI+) [(M+H)+] 338.
4-{4-[(2-Aminoethyl)amino]methylquinolinyl}-1,3,4,5-tetrahydro-2H-1,4-
benzodiazepinone
N N
O H
The mixture of 4-(4-chloromethylquinolinyl)-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin
one (60 mg, 1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), (8.2 mg,
0.01 mmol), bis(diphenylphosphino)ferrocene (6 mg, 0.01 mmol) and sodium tert-butoxide (20
mg, 0.2 mmol) and 1,4-dioxane (2 mL) was heated with stirring in a 10 mL microwave s
vial for 1 hour at 120 ºC under microwave irradiation. After cooling, the mixture was filtered and
washed with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate, and
concentrated in vacuo to give a e which was purified by preparative HPLC to afford the
product as a solid. MS obsd. (ESI+) [(M+H)+] 362. 1H NMR (400 MHz, CD3OD) δ ppm 7.64 (s,
1 H), 7.44 - 7.40 (m, 2 H), 7.28 (dd, J = 1.6, 8.4 Hz, 1 H), 7.18 (dd, J = 1.6, 8.0 Hz, 1 H), 7.09
(dd, J = 0.8, 8.0 Hz, 1 H), 6.98 (dd, J = 0.8, 8.0 Hz, 1 H), 6.00 (s, 1 H), 4.87 (s, 2 H), 4.72 (s, 2
H), 3.40 (t, J = 6.4 Hz, 2 H), 2.95 (t, J = 6.4 Hz, 2 H), 2.40 (s, 3 H).
e 133-2
N-[6-Methyl(1,2,3,5-tetrahydro-4H-1,4-benzodiazepinyl)quinolinyl]ethane-1,2-
diamine
N N
The title compound was prepared in analogy to Example 16-1 by using 2,3,4,5-tetrahydro-1H-
1,4-benzodiazepine (commercial available) instead of 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-
2-one. MS obsd. (ESI+) [(M+H)+] 348. 1H NMR (400 MHz, CD3OD) δ ppm 7.90 (s, 1 H), 7.67
(d, J = 8.4 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.42 (d, J = 7.2 Hz, 1 H), 7.12 (t, J = 8.0 Hz, 1 H),
6.88 (t, J = 7.2 Hz, 1 H), 6.82 (d, J = 8.0 Hz, 1 H), 5.95 (s, 1 H), 4.87 (s, 2 H), 4.00 (t, J = 4.8
Hz, 2 H), 3.72 (t, J = 6.0 Hz, 2 H), 3.46 (t, J = 4.8 Hz, 2 H), 3.18 (t, J = 6.0 Hz, 2 H), 2.49 (s, 3
Example 134
N-[2-(2,3-Dihydro-1,4-benzoxazepin-4(5H)-yl)quinolinyl]ethane-1,2-diamine
N N
Methyl (2-cyanophenoxy)acetate
O CO Me
To the mixture of 2-hydroxybenzonitrile (40 g, 0.34 mol) and potassium ate (51.6 g, 0.374
mol) in 850 mL of acetone was added methyl bromoacetate (51.7 g, 0.34 mol) slowly at room
temperature. After being d at room ature overnight, the solid was filtered off. The
filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate.
The organic layer was washed with water then brine, dried over sodium sulfate, filtered and
concentrated under reduced pressure to give a e which was recrystallized in methanol to
give 40 g of product as a white solid.
4,5-Dihydro-1,4-benzoxazepin-3(2H)-one
The methanol solution of methyl (2-cyanophenoxy)acetate (40 g, 0.209 mol) was added to the
mixture of Raney Ni (80 g) in 500 mL of methanol. The reaction mixture was d at room
temperature overnight under hydrogen atmosphere. Raney Ni was d by filtration, and the
filtrated was concentrated under reduced pressure to give a residue which was purified by
column chromatography on silica gel (methanol/dichloromethane, 1:50) to give 23 g of product.
MS obsd. (ESI+) [(M+H)+] 164.
2,3,4,5-Tetrahydro-1,4-benzoxazepine
O
To the suspension of lithium aluminium hydride (15.2 g, 0.4 mol) in 600 mL of ether was added
a on of 4,5-dihydro-1,4-benzoxazepin-3(2H)-one (16.3 g, 0.1 mol) in 60 mL of
tetrahydrofuran at room temperature. After being heated with stirring under reflux overnight,
water was added dropwise to quench the reaction at 0 ºC, The ing mixture was diluted with
ethyl acetate, and then filtered by a pad of celite. The filtrate was concentrated under reduced
pressure, followed by the addition of hydrochloric acid ethyl acetate solution. The hydrochloride
was collected by filtration, washed with ethyl e then ether, and then dried in vacuo to give
13.5 g of product. MS obsd. (ESI+) [(M+H)+] 150.
4-(4-Chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine
N N
O
The mixture of 2,4-dichloroquinoline (198 mg, 0.1 mmol), 2,3,4,5-tetrahydro-1,4-benzoxazepine
hydrochloride (186 mg, 0.1 mmol), diisopropylethylamine (0.4 mL) and 5 mL of N-methyl
pyrrolidone was heated with stirring at 100 ºC overnight. The mixture was cooled to room
temperature, diluted with brine, and extracted with ethyl acetate (30 mL × 3). The organic layers
were combined and washed with brine. The solvent was dried over sodium sulfate and removed
under reduced pressure to give a residue which was ed by column chromatography on silica
gel to give 119 mg of t as a white solid. MS obsd. (ESI+) [(M+H)+] 311.
N-[2-(2,3-Dihydro-1,4-benzoxazepin-4(5H)-yl)quinolinyl]ethane-1,2-diamine
N N
The mixture of 4-(4-chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (100 mg, 0.32
mmol) and 1.6 mL of ethane-1,2-diamine was heated with stirring in a 5 mL ave process
vial for 3 hours at 150 ºC under microwave irradiation. The mixture was concentrate in vacuo to
give a e which was purified by preparative HPLC to give 31 mg of product as a white
solid. MS obsd. (ESI+) [(M+H)+] 335. 1H NMR (400 MHz, CD3OD) δ ppm 8.61 (s, 1 H), 7.90
(d, J = 7.6 Hz, 1 H), 7.60 - 7.51 (m, 3 H), 7.23 (brs, 2 H), 7.09 - 6.98 (m, 2 H), 6.05 (s, 1 H), 4.89
(s, 2 H), 4.27 (s, 2 H), 4.25 (s, 2 H), 3.61 (s, 2 H), 3.15 (s, 2 H).
Example 135-1
N-[(1-Aminocyclopropyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-
6-methylquinazolinamine
N N
O
tert-Butyl (1-{[(2-chloromethylquinazolinyl)amino]methyl}cyclopropyl)carbamate
N O
N Cl
To a solution of tert-butyl [1-(aminomethyl)cyclopropyl]carbamate (0.92 g, 4.9 mmol) in
tetrahydrofuran (50 mL) was added triethylamine (1.3 mL, 9.4 mmol) followed by 2,4-dichloro-
6-methylquinazoline (1.0 g, 4.7 mmol) in portions at room ature. After being stirred at
room temperature overnight, the resultant mixture was concentrated in vacuo to remove 20 mL
of solvent and then stirred vigorously with water (200 mL). The formed solid was collected by
filtration and washed with water and ether, then dried in vacuo to afford 1.5 g of the t as a
white .
tert-Butyl [({2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)
quinazolinyl]amino}methyl)cyclopropyl]carbamate
N O
N N
A mixture of tert-butyl (1-{[(2-chloromethylquinazolinyl)amino]methyl}cyclopropyl)
carbamate (1.5 g, 4.1 mmol), 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (0.82 g, 4.1
mmol) and catalystic amount of ammonium chloride in ethanol (40 mL) was heated with stirring
at 70 oC overnight. The reaction mixture was then cooled to room temperature. The formed solid
was collected by filtration, then washed with ethanol and dried in vacuo. The crude solid (1.5 g)
was suspended in dichloromethane (50 mL) and ed with 1 N of sodium hydroxide. The
organic phase was separated and used for the next step directly.
(1-Amino-cyclopropylmethyl)-[2-(5,5-dioxo-5,6,7,9-tetrahydro-5lambda*6*-thiaaza-
benzocycloheptenyl)methyl-quinazolinyl]-amine
N N
To the solution obtained above was added trifluoroacetic acid (10 mL) and the mixture was
stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous
on of sodium carbonate. The organic layer was separated and dried over sodium sulfate,
filtrated and concentrated in vacuo. The residue was stirred with methanol. The ed white
solid was ted by filtration and dried in vacuo to afford 400 mg of the t as a white
powder. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 - 7.85 (m,
2 H), 7.74 (br. s., 2 H), 7.62 (t, J = 7.00 Hz, 1 H), 7.47 (t, J = 8.30 Hz, 1 H), 7.35 (dd, J = 8.53,
1.51 Hz, 1 H), 7.23 (d, J = 7.78 Hz, 1 H), 5.07 (br. s., 2 H), 4.44 (br. s., 2 H), 3.32 (s, 2 H), 2.35
(s, 3 H), 2.04 (s, 2 H), 0.52 (d, J = 30.62 Hz, 4 H).
Example 135-2
2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(pyrrolidin
yl)quinazolinamine
N N
O
The title compound was prepared in analogy to Example 135-1 in Scheme 70 by using 2,4-
dichloromethylquinazoline, tert-butyl 3-aminopyrrolidinecarboxylate, 2,3,4,5-tetrahydro-
1,4-benzothiazepine 1,1-dioxide and trifluoroacetic acid instead of 2,4-dichloro
methylquinazoline, tert-butyl [1-(aminomethyl)cyclopropyl]carbamate, 2,3,4,5-tetrahydro-1,4-
benzothiazepine oxide and trifluoroacetic acid. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR
(400 MHz, DMSO-d6) δ ppm 7.92 - 7.82 (m, 2 H), 7.78 (br. s., 1 H), 7.69 - 7.56 (m, 2 H), 7.48
(t, J = 7.53 Hz, 1 H), 7.34 (dd, J = 8.53, 1.25 Hz, 1 H), 7.22 (d, J = 6.78 Hz, 1 H), 5.08 (br. s., 2
H), 4.47 (br. s., 2 H), 3.48 - 2.54 (m, 7 H), 2.33 (s, 3 H), 2.25 - 2.00 (m, 1 H), 1.81 - 1.68 (m, 1
Example 136
Viral cytopathic effect (CPE) assay: To measure anti-RSV activity of compounds, 96-
well plates are seeded with 6x103 cells per well in Dulbecco’s modified Eagle’s medium
(DMEM) containing 10% fetal bovine serum (FBS). Cells are infected the next day with
sufficient RSV Long strain (ATCC) to produce an approximately 80-90% cytopathic effect after
6 days, in the presence of serial half-log diluted compound in a total volume of 200 µL per well.
The viability of cells is assessed after 6 days using Cell Counting kit-8 (Dojindo Molecular
Technologies). The absorbance at 450 nm and referenced at 630 nm is measured to determine
50% ive concentration (EC50).
The compounds of the t invention were tested for their anti-RSV activity, and the
activation as described herein. The Examples were tested in the above assay and found to have
EC50 of about 0.0001 µM to about 10 µM. ular compound of formula (I) were found to
have EC50 of about 0.0001 µM to about 1 µM. r particular compound of formula (I) were
found to have EC50 of about 0.0001 µM to about 0.1 µM.
Results of CPE assays are given in Table 1.
Table 1:
Example EC50 (µM, Example EC50 (µM, Example EC50 (µM,
Long Strain) Long Strain) Long Strain)
1-1 0.002 11-4 0.004 62-5 0.017
1-2 0.007 12-1 0.536 62-6 0.006
1-3 0.072 12-2 0.315 62-7 0.186
1-4 0.004 12-3 6.256 63-1 3.133
1-5 0.004 12-4 0.764 63-2 2.021
1-6 0.022 12-5 0.448 63-3 0.007
1-7 0.022 12-6 9.214 63-4 0.797
2-1 0.024 12-7 0.226 64 0.035
2-2 0.002 13 0.026 65 0.322
2-3 2.805 14-1 2.194 66 0.002
2-4 0.081 14-2 8.792 67 0.585
2-5 0.006 15-1 7.892 68 2.012
2-6 0.021 15-2 7.994 69-1 0.007
2-7 0.234 15-3 2.697 69-2 0.007
2-8 0.055 15-4 0.257 70 0.071
2-9 0.007 15-5 0.740 71 0.005
2-10 0.005 16-1 2.567 72 0.002
2-11 0.008 16-2 9.642 73 6.978
3-1 0.006 17-1 5.538 74 1.936
3-2 3.051 17-2 0.616 75 0.002
3-3 3.552 17-3 2.17 76 0.006
3-4 0.006 17-4 0.071 77 8.78
3-5 0.002 17-5 1.504 78-1 0.016
3-6 0.058 17-6 0.086 78-2 0.25
3-7 0.009 17-7 0.642 79 2.791
3-8 0.002 17-8 0.021 80 5.479
3-9 0.248 18-1 0.003 81 0.353
3-10 0.053 18-2 0.024 82 0.014
3-11 0.054 18-3 0.014 83 0.662
3-12 1.654 18-4 0.061 84 2.965
3-13 0.099 18-5 0.057 85 0.008
3-14 0.017 18-6 0.061 86 2.222
3-15 0.482 18-7 0.023 87-1 0.096
3-16 0.075 18-8 0.0007 87-2 9.31
3-17 5.053 18-9 0.005 88 0.007
3-18 0.024 18-10 0.011 89 0.007
3-19 0.009 18-11 0.619 90 0.005
3-20 0.507 19-1 0.043 91 0.004
3-21 0.006 19-2 0.011 92-1 0.009
3-22 0.032 19-3 0.006 92-2 0.019
3-23 0.002 19-4 0.02 93-1 0.005
3-24 0.021 19-5 3.073 93-2 0.009
3-25 0.022 19-6 0.054 94 6.527
3-26 0.876 19-7 6.856 95 3.039
3-27 1.394 19-8 2.749 96 2.833
3-28 0.149 20-1 0.073 97 0.177
3-29 0.022 20-2 0.31 98-1 0.778
3-30 7.81 20-3 0.093 98-2 3.163
3-31 0.014 21-1 0.023 99 2.999
3-32 0.037 21-2 0.161 100 9.191
3-33 0.426 21-3 0.015 101 8.579
3-34 0.085 21-4 0.004 102 9.76
3-35 0.013 21-5 0.007 103 0.202
3-36 0.092 22 0.036 104 0.89
3-37 0.017 23 5.185 105 1.084
3-38 0.0439 24 0.016 106 0.002
3-39 0.030 25 0.002 107 0.001
3-40 0.022 26-1 0.005 108-1 0.488
3-41 0.071 26-2 0.179 108-2 2.474
3-42 0.007 27 2.393 109-1 8
3-43 2.394 28-1 0.007 109-2 0.0015
3-44 0.012 28-2 0.007 110-1 0.017
3-45 5.229 28-3 0.001 110-2 2.607
3-46 0.053 28-4 0.001 110-3 0.161
3-47 0.101 28-5 0.003 110-4 0.06
3-48 0.023 29 0.042 110-5 1.655
3-49 0.099 30-1 0.317 110-6 4.278
3-50 0.0004 30-2 0.218 110-7 1.178
3-51 0.004 31 0.702 110-8 0.081
3-52 0.005 32-1 0.019 110-9 1.367
3-53 0.261 32-2 2.454 110-10 0.099
3-54 0.114 32-3 1.991 110-11 6.753
3-55 0.027 32-4 0.272 110-12 0.072
3-56 0.716 32-5 2.58 110-13 3.679
3-57 7.534 33-1 0.044 110-14 0.648
3-58 0.184 33-2 0.627 110-15 0.004
3-59 1.083 34 2.086 111-1 2.007
3-60 0.617 35 2.791 111-2 1.345
3-61 0.118 36-1 0.073 111-3 0.0768
3-62 0.589 36-2 1.474 111-4 0.066
3-63 9.899 36-3 2.153 111-5 1.64
3-64 0.874 36-4 0.138 111-6 0.062
3-65 0.002 36-5 0.026 111-7 0.873
4-1 0.269 36-6 0.264 111-8 0.283
4-2 0.098 37-1 0.005 111-9 0.047
4-3 0.026 37-2 0.043 111-10 0.107
4-4 0.208 38-1 0.01 111-11 0.588
4-5 5.258 38-2 0.302 112-1 3.739
-1 9.197 38-3 0.074 112-2 0.092
-2 0.211 38-4 0.064 113 0.733
-3 0.015 38-5 6.652 114-1 0.007
-4 0.326 39 0.092 114-2 0.975
-5 0.014 40-1 0.039 114-3 0.004
-6 2.062 40-2 4.655 114-4 0.186
-7 0.941 40-3 0.917 115 0.01
-8 0.022 40-4 2.646 116-1 0.005
-9 0.018 41 2.629 116-2 0.309
-10 0.397 42-1 8.947 117 5.97
-11 0.526 42-2 0.037 118-1 1.975
-12 6.249 43 0.017 118-2 0.048
6-1 0.025 44-1 0.084 118-3 0.063
6-2 0.908 44-2 1.547 118-4 0.104
7 1.418 45-1 0.021 118-5 0.178
8-1 5.513 45-2 0.253 118-6 0.173
8-2 0.817 45-3 0.031 118-7 0.166
8-3 0.9 46 0.682 118-8 0.223
8-4 0.064 47-1 7.881 118-9 0.202
8-5 0.074 47-2 5.822 118-10 0.289
8-6 3.767 47-3 5.692 118-11 0.323
8-7 0.322 47-4 0.993 118-12 0.448
9-1 2.35 47-5 0.835 118-13 0.463
9-2 4.77 47-6 2.312 118-14 0.616
9-3 0.001 47-7 3.4107 118-15 0.626
9-4 8.874 47-8 0.432 118-16 0.695
9-5 0.179 47-9 0.192 118-17 0.806
9-6 0.275 48 0.009 118-18 0.973
9-7 0.002 49 0.721 118-19 1.236
9-8 3.478 50-1 0.931 118-20 1.129
9-9 0.157 50-2 2.423 118-21 1.382
9-10 0.037 51 0.056 118-22 2.227
9-11 0.953 52 0.419 118-23 2.641
9-12 2.663 53 0.094 118-24 6.451
9-13 0.701 54 4.798 118-25 7.623
9-14 0.025 55-1 0.007 118-26 7.754
9-15 0.012 55-2 0.202 119 6.656
9-16 0.005 55-3 0.006 120-1 2.193
9-17 0.025 56-1 0.002 120-2 1.785
9-18 0.01 56-2 0.023 121 1.103
9-19 0.0007 56-3 0.004 122 3.125
9-20 0.760 56-4 0.027 123 3.144
9-21 0.021 56-5 0.022 124 6.102
9-22 0.872 56-6 0.002 125 2.521
9-23 3.022 57-1 0.067 126-1 0.790
9-24 0.024 57-2 0.018 126-2 0.638
9-25 4.084 57-3 0.023 127 6.249
9-26 7.204 57-4 0.239 128 7.174
9-27 0.797 57-5 0.027 129 7.875
9-28 0.003 57-6 0.037 130-1 6.836
9-29 0.024 57-7 0.081 130-2 7.269
9-30 8.591 58 2.772 131 2.523
9-31 2.427 59 0.746 132 7.814
9-32 0.063 60 0.018 133-1 0.31
9-33 0.057 61-1 0.005 133-2 0.186
9-34 0.024 61-2 0.097 134 0.25
0.003 62-1 0.0003 135-1 0.006
11-1 0.069 62-2 0.0017 135-2 0.018
11-2 7.022 62-3 0.0013
11-3 0.922 62-4 0.019
Example A
A compound of formula (I) can be used in a manner known per se as the active ingredient
for the production of s of the following composition:
Per tablet
Active ingredient 200 mg
Microcrystalline cellulose 155 mg
Corn starch 25 mg
Talc 25 mg
Hydroxypropylmethylcellulose 20 mg
425 mg
Example B
A compound of formula (I) can be used in a manner known per se as the active ingredient
for the production of capsules of the following composition:
Per capsule
Active ingredient 100.0 mg
Corn starch 20.0 mg
Lactose 95.0 mg
Talc 4.5 mg
ium stearate 0.5 mg
220.0 mg
Claims (5)
1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] fluoropyrrolidinamine; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]pyrrolidinecarboxamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4- 20 benzothiazepin-4(5 H)-yl)(methylsulfinyl)quinolinyl]propane-1,3-diamine; 4-[(3- aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinoline carboxamide; (3-aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)quinolinyl}ethanol; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]amino}propanenitrile; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 25 4(5 H)-yl)methyl-N-[2-(1 H-tetrazolyl)ethyl]quinolinamine; N~4~-(2-aminoethyl)(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinoline-4,6-diamine; 1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]oxa-5,7-diazaspiro[3.4]octan one; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolin no}propane-1,2-diol; 3-{[6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- 30 yl)quinazolinyl]amino}propane-1,2-diol; 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinazolinyl]ethane-1,2-diamine; N-[6-methyl(1-oxido-2,3-dihydro-1,4- hiazepin-4(5 H)-yl)quinazolinyl]ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)methylquinazolinyl]ethane-1,2-diamine; N-[3- (aminomethyl)oxetanyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- 35 yl)quinazolinamine; N-(trans fluoropyrrolidinyl)methyl(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinazolinamine; N-(trans fluoropyrrolidinyl)methyl(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; 1-[6-methyl(1-oxido- hydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinyl]pyrrolidinamine; N-(azetidinyl)- 6-methyl(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; (4R ) {2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]ethyl}-4,5- dihydro-1,3-oxazolamine; 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 ethylquinolinyl]propanoic acid; 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)- 5 6-methylquinolinyl]propanamine; 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]oxy}ethanamine; 4-[6-methyl(pyrrolidinyloxy)quinolin- 2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; 4-[6-methyl(piperidin quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; 4-(4,6- ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; [2-(1,1-dioxido-2,3- 10 o-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl](piperidinyl)methanone; 4-[6- methyl(1 H-pyrazolyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; 4- [6-methyl(phenylsulfonyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; N-(2-aminoethyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinoline- 4-sulfonamide; methyl 4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3- 15 dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinecarboxylate; 4-({[3-(aminomethyl)oxetan yl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinoline ylic acid; 3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)quinolinyl]methanol; N-{[3-(aminomethyl)oxetanyl]methyl}- 6-(~2~ H_3_)methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; 20 4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4- hiazepin-4(5 H)-yl)quinazolinecarboxylic acid; -(aminomethyl)oxetan yl]methyl}amino)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazoline carboxylic acid; [4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinazolinyl]methanol; [4-({[3-(aminomethyl)oxetan 25 yl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolin yl]methanol; N-[(1-aminocyclopropyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinazolinamine; and 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methyl-N-(pyrrolidinyl)quinazolinamine. 13. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein 30 R1 is hydrogen or halogen; R2 and R4 are hydrogen; R3 is hydrogen or halogen; R5 is hydrogen or halogen; R6 is hydrogen, halogen, hydroxy, C1-6alkoxy or carboxy; R7 is hydrogen, halogen, C1-6alkoxy, C1-6alkylaminocarbonyl, diC1-6 alkylaminocarbonyl or C1-6alkylsulfonyl; R8 is hydrogen or halogen; R9 is hydrogen or =O; 5 R10 is hydrogen or =O, provided that R9 and R10 are not =O simultaneously; A is -C-R11, wherein R11 is hydrogen, n, C1-6alkyl, C1-6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, difluoromethoxy or C 1-6alkylsulfonyl; X is -CH2-, -O-, –NH-, -CF2, -C(CH3)(OH)-, C=O, or -C(=N-C1-6alkoxy)-; Y is -CH- or nitrogen; 10 Q is hydrogen; halogen; C1-6alkyl, once or twice substituted by hydroxy provided that disubstitution of hydroxy is not on the same carbon; amino(CH2)2-6aminosulfonyl; 2- amino-4,5-dihydro-1,3-oxazolylethyl; or NR12R13, wherein one of R12 and R13 is hydrogen, C1-6alkyl or hydroxy(CH2)2-, and the other one is ino(CH2)2-6; 3- aminomethyl-1,1-dioxidothietanylmethyl; 3-amino-1,1-dioxidothietanylmethyl; 3- 15 (aminomethyl)thietanylmethyl; amino(CH2)2O-(CH2)2-6; amino(CH2)2-10; amino(CH2)1-6carbonyl; amino(CH2)1-6difluoromethyl(CH2)1-6; amino(CH2)1- 6oxetanyl(CH2)1-6; amino(CH2)2-6sulfonyl(CH2)2-6; 3-aminocyclohexyl; 4- aminocyclohexyl; 2-amino-4,5-dihydro-oxazolyl(CH2)1-6; aminooxetanyl(CH2)1-6; C1- 6alkylamino(CH2)2-6; C1-6alkylaminocarbonyl; diC1-6alkylamino(CH2)2-6; hydroxy(CH2)2-6; -C1-6alkyl C R15 20 zinyl(CH2)2-6; pyrrolidinyl; or R16 , wherein R14 is en, C1-6alkyl or hydroxy(CH2)1-6; R15 is y, hydroxy(CH2)1-6 or amino; and R16 is C1-6alkyl, hydroxy(CH2)1-6 or amino(CH2)1-6; R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl or diazepanyl ring; which may be tituted, once or twice tuted by a 25 group selected from C1-6alkyl, amino or hydroxy. 14. A compound according to claim 13 or a pharmaceutically acceptable salt f, n R1 is hydrogen or chloro; R2 and R4 are hydrogen; R3 is hydrogen or chloro; R5 is hydrogen or fluoro; R6 is hydrogen, fluoro, hydroxy, methoxy, ethoxy or carboxy; R7 is hydrogen, fluoro, bromo, methoxy, dimethylaminocarbonyl, methylsulfonyl or ethylsulfonyl; 5 R8 is hydrogen or chloro. A is CR11, wherein R11 is hydrogen, fluoro, , bromo, methyl, methoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, difluoromethoxy or methylsulfonyl; Q is hydrogen; chloro; hydroxymethyl; hydroxymethyl(hydroxy)ethyl; aminoethylaminosulfonyl; 2-amino-4,5-dihydro-1,3-oxazolylethyl; or NR12R13, 10 wherein one of R12 and R13 is hydrogen, methyl or hydroxyethyl;and the other one is aminobutyl; 3-aminocyclohexyl; ocyclohexyl; 2-amino-4,5-dihydro-oxazol ylmethyl; 3-amino-1,1-dioxidothietanylmethyl; aminoethoxyethyl; aminoethyl; aminoethylsulfonylethyl; aminomethylcarbonyl; aminomethyldifluoromethylmethyl; 3- aminomethyl-1,1-dioxidothietanylmethyl; 3-(aminomethyl)thietanylmethyl; 15 aminomethyloxetanylmethyl; aminooxetanylmethyl; ropyl; dimethylaminoethyl; ethylaminocarbonyl; guanidinoethyl; hydroxyethyl; hydroxypropyl; methylaminoethyl; piperazinylethyl; pyrrolidinyl; -C1-6alkyl C R15 or R16 , wherein R14 is en, methyl or hydroxymethyl; R15 is hydroxy, hydroxymethyl or amino; and R16 is methyl, hydroxymethyl or aminomethyl;R12 and R13, 20 with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl or diazepanyl ring; which may be unsubstituted, once or twice substituted by a group selected from methyl, amino or hydroxy. 15. A compound according to any one of claims 13 to 14 or a pharmaceutically acceptable salt thereof, selected from 25 N-[(3-aminooxetanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinolinamine; N-[2-(2-aminoethoxy)ethyl](5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinolinamine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H epinyl)methylquinolinyl]-N'-methylethane-1,2-diamine; 1-amino{[2-(5,5- ro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]amino}propanol; 3- 30 {[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin no}propane-1,2-diol; 3-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinolinyl]amino}propanol; 2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepin yl)methyl-N-[2-(piperazinyl)ethyl]quinolinamine; N~1~-[2-(5,5-difluoro-1,3,4,5- tetrahydro-2Hbenzazepinyl)methylquinolinyl]propane-1,2-diamine; cis (5,5- difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]cyclohexane-1,4- 5 diamine; 2-(9,9-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulenyl)methyl-N-(pyrrolidin yl)quinolinamine; 2,2'-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinolinyl]imino}diethanol; N~1~-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinolinyl]methylpropane-1,2-diamine; 5,5-difluoro[6- methyl(4-methylpiperazinyl)quinolinyl]-2,3,4,5-tetrahydro-1Hbenzazepine; 1-[2- 10 (9,9-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulenyl)methylquinolinyl]ethylurea; N-{[3-(aminomethyl)oxetanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepin- 2-yl)methylquinolinamine; fluoro[6-methyl(piperazinyl)quinolinyl]- 2,3,4,5-tetrahydro-1Hbenzazepine; 2-[4-(1,4-diazepanyl)methylquinolinyl]-5,5- difluoro-2,3,4,5-tetrahydro-1Hbenzazepine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H 15 benzazepinyl)methylquinolinyl]-N-methylethane-1,2-diamine; 1-[2-(5,5-difluoro- 1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]pyrrolidinamine; 2-{[2-(5,5- difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]amino}ethanol; N-[2- (5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]ethane-1,2- e; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin 20 yl]cyclohexane-1,3-diamine; (5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinolinyl]-N,N-dimethylethane-1,2-diamine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro- 2Hbenzazepinyl)methylquinolinyl]propane-1,3-diamine; N-[2-(5,5-difluoro-1,3,4,5- tetrahydro-2Hbenzazepinyl)methylquinolinyl]butane-1,4-diamine; trans amino [2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]pyrrolidinol; 25 N-{[3-(aminomethyl)-1,1-dioxidothietanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H epinyl)methylquinolinamine; N-{2-[(2-aminoethyl)sulfonyl]ethyl}(5,5- difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinamine; N-{[3- methyl)thietanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinazolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}(5,5-difluoro-1,3,4,5- 30 tetrahydro-2Hbenzazepinyl)methylquinazolinamine; 2-(aminomethyl)({[2-(5,5- difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinazolin yl]amino}methyl)propane-1,3-diol; 2-(4-{[(3-aminooxetanyl)methyl]amino} methylquinazolinyl)methyl-2,3,4,5-tetrahydro-1Hbenzazepinol; N-[(3-aminooxetan- 3-yl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinazolin 35 amine; N-[(3-amino-1,1-dioxidothietanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinazolinamine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinazolinyl]-2,2-difluoropropane-1,3-diamine; N-[2-(7-bromo- 1,3,4,5-tetrahydro-2Hbenzazepinyl)chloroquinolinyl]ethane-1,2-diamine; 2-{4-[(2- aminoethyl)amino]quinolinyl}-2,3,4,5-tetrahydro-1Hbenzazepinol; N-[6-methyl (1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; N-[2-(8-fluoro- 1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]ethane-1,2-diamine; N-[6- chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; N-[6- 5 chloro(9-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; N-[2-(8-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; 1- amino{[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]amino}propanol trifluoroacetate; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- diamine; N-[6-bromo(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- 10 diamine; N-[6-methoxy(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- diamine; N-[2-(6-chloro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- diamine; N-[2-(7-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin yl]ethane-1,2-diamine; N-methyl-N'-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin ane-1,2-diamine; N-[2-(7-methoxy-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin 15 yl]ethane-1,2-diamine; N-[2-(7-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin yl]ethane-1,2-diamine; N-[2-(8-methoxy-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin yl]ethane-1,2-diamine; N-[6-(difluoromethoxy)(1,3,4,5-tetrahydro-2Hbenzazepin yl)quinolinyl]ethane-1,2-diamine; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl) (trifluoromethyl)quinolinyl]ethane-1,2-diamine; N-[8-chloro(1,3,4,5-tetrahydro-2H 20 benzazepinyl)quinolinyl]ethane-1,2-diamine; N-[6-fluoro(1,3,4,5-tetrahydro-2H epinyl)quinolinyl]ethane-1,2-diamine; N,N-dimethyl-N'-[2-(1,3,4,5-tetrahydro-2H- 2-benzazepinyl)quinolinyl]ethane-1,2-diamine; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepin- 2-yl)(trifluoromethoxy)quinolinyl]ethane-1,2-diamine; N-[6-(methylsulfonyl)(1,3,4,5- tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; 2-{4-[(2- 25 thyl)amino]quinolinyl}-2,3,4,5-tetrahydro-1Hbenzazepinecarboxylic acid; 2-(4- chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine; N-[5-chloro(1,3,4,5-tetrahydro- 2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; 7-(methylsulfonyl)-1,3,4,5- tetrahydro-2Hbenzazepinyl]quinolinyl}ethane-1,2-diamine; N-{2-[7-(ethylsulfonyl)- 1,3,4,5-tetrahydro-2Hbenzazepinyl]quinolinyl}ethane-1,2-diamine; N-[2-(8-ethoxy- 30 1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; pyridin yloxy)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; 2-{4-[(2- aminoethyl)amino]chloroquinolinyl}-N,N-dimethyl-2,3,4,5-tetrahydro-1Hbenzazepine- oxamide; 2-{4-[(2-aminoethyl)amino]quinolinyl}bromo-1,2,4,5-tetrahydro-3H benzazepinone; 1-(2-{[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin 35 yl]amino}ethyl)guanidine trifluoroacetate; N-[(2-amino-4,5-dihydro-1,3-oxazolyl)methyl] (1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinamine trifluoroacetate; N-[(2-amino-4,5- dihydro-1,3-oxazolyl)methyl]chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin- 4-amine; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]glycinamide; 3-[2- (1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propanamine; [2-(1,3,4,5-tetrahydro- 2Hbenzazepinyl)quinolinyl]methanol; 2-(6-chloroquinolinyl)-2,3,4,5-tetrahydro-1H-
2-benzazepine;
3-[6-chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propane- 1,2-diol; (4S ){2-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethyl}-4,5- 5 dihydro-1,3-oxazolamine; N-(2-aminoethyl)(1,3,4,5-tetrahydro-2Hbenzazepin yl)quinolinesulfonamide trifluoroacetate; (2-aminoethyl)amino]methylquinolin yl}-1,3,4,5-tetrahydro-2H-1,
4-benzodiazepinone; N-[6-methyl(1,2,3,
5-tetrahydro-4H-1,4- benzodiazepinyl)quinolinyl]ethane-1,2-diamine; N-[2-(2,3-dihydro-1,4-benzoxazepin- 4(5 H)-yl)quinolinyl]ethane-1,2-diamine; N-[(3-aminooxetanyl)methyl][(5 E) 10 xyimino)-1,3,4,5-tetrahydro-2Hbenzazepinyl]methylquinolinamine and 2-(4- {[(3-aminooxetanyl)methyl]amino}methylquinazolinyl)-1,2,3,4-tetrahydro-5H benzazepinone. 16. A compound according to any one of claims 1 to 15 for use as a therapeutically active substance. 15 17. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 15 and a therapeutically inert carrier. 18. The use of a compound ing to any one of claims 1 to 15 for the preparation of a medicament for the treatment or laxis of respiratory syncytial virus infection. 19. A compound according to any one of claims 1 to 15 for the treatment or prophylaxis of 20 atory syncytial virus infection. 20. A pharmaceutical composition according to claim 17 substantially as herein described with reference to any example thereof. 21. A use according to claim 18 substantially as herein described with reference to any e thereof.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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CN2011078258 | 2011-08-11 | ||
CNPCT/CN2011/078258 | 2011-08-11 | ||
CNPCT/CN2012/078439 | 2012-07-10 | ||
CN2012078439 | 2012-07-10 | ||
PCT/EP2012/065499 WO2013020993A1 (en) | 2011-08-11 | 2012-08-08 | Compounds for the treatment and prophylaxis of respiratory syncytial virus disease |
Publications (2)
Publication Number | Publication Date |
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NZ620079A NZ620079A (en) | 2016-06-24 |
NZ620079B2 true NZ620079B2 (en) | 2016-09-27 |
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