NZ742484B2 - Polycyclic compounds as inhibitors of bruton's tyrosine kinase - Google Patents
Polycyclic compounds as inhibitors of bruton's tyrosine kinase Download PDFInfo
- Publication number
- NZ742484B2 NZ742484B2 NZ742484A NZ74248416A NZ742484B2 NZ 742484 B2 NZ742484 B2 NZ 742484B2 NZ 742484 A NZ742484 A NZ 742484A NZ 74248416 A NZ74248416 A NZ 74248416A NZ 742484 B2 NZ742484 B2 NZ 742484B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- oxo
- dihydro
- triazaacenaphthylenecarboxamide
- 3hthia
- methylphenoxyphenyl
- Prior art date
Links
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 title claims description 9
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 title claims 2
- 239000003112 inhibitor Substances 0.000 title description 4
- 125000003367 polycyclic group Chemical group 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 428
- 125000000217 alkyl group Chemical group 0.000 claims description 986
- -1 3-hydroxyadamantanyl Chemical group 0.000 claims description 747
- 102100021850 Nardilysin Human genes 0.000 claims description 262
- 108090000970 Nardilysin Proteins 0.000 claims description 262
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 248
- 125000001188 haloalkyl group Chemical group 0.000 claims description 241
- 125000001424 substituent group Chemical group 0.000 claims description 201
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 159
- 229910052799 carbon Inorganic materials 0.000 claims description 147
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 128
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 103
- 125000004076 pyridyl group Chemical group 0.000 claims description 97
- PRHPGHJWMIDPMQ-UHFFFAOYSA-O NC([S+](C=C1NC(N2)=O)C3=C1C2=CC=N3)=O Chemical compound NC([S+](C=C1NC(N2)=O)C3=C1C2=CC=N3)=O PRHPGHJWMIDPMQ-UHFFFAOYSA-O 0.000 claims description 87
- 229910052736 halogen Inorganic materials 0.000 claims description 87
- 150000002367 halogens Chemical class 0.000 claims description 87
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 79
- 229910052739 hydrogen Inorganic materials 0.000 claims description 72
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 67
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 59
- 150000003857 carboxamides Chemical class 0.000 claims description 55
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 53
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 48
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 37
- 229910052801 chlorine Inorganic materials 0.000 claims description 35
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 33
- 229910052731 fluorine Inorganic materials 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 28
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 27
- 208000035475 disorder Diseases 0.000 claims description 23
- 230000000155 isotopic effect Effects 0.000 claims description 22
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 20
- YGMDBALTLRGFBZ-UHFFFAOYSA-O NC([S+](C=C1NCN2)C3=C1C2=CC=N3)=O Chemical compound NC([S+](C=C1NCN2)C3=C1C2=CC=N3)=O YGMDBALTLRGFBZ-UHFFFAOYSA-O 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 229960002685 biotin Drugs 0.000 claims description 13
- 239000011616 biotin Substances 0.000 claims description 13
- 206010028980 Neoplasm Diseases 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 12
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 12
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 11
- TZNINXJVCNXDIG-UHFFFAOYSA-O NC([S+](CC1=NC=N2)C3=C1C2=CC=N3)=O Chemical compound NC([S+](CC1=NC=N2)C3=C1C2=CC=N3)=O TZNINXJVCNXDIG-UHFFFAOYSA-O 0.000 claims description 11
- 201000011510 cancer Diseases 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 9
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 7
- 101150065749 Churc1 gene Proteins 0.000 claims description 7
- 102100038239 Protein Churchill Human genes 0.000 claims description 7
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 7
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 7
- FKQFYCTZRLGVSY-UHFFFAOYSA-N CC1=CC(OC2=NC(C)=CC=C2)=NC=C1 Chemical compound CC1=CC(OC2=NC(C)=CC=C2)=NC=C1 FKQFYCTZRLGVSY-UHFFFAOYSA-N 0.000 claims description 6
- VKTFBHYPOYETQR-UHFFFAOYSA-O NC([S+](C=C1NC=N2)C3=C1C2=CC=N3)=O Chemical compound NC([S+](C=C1NC=N2)C3=C1C2=CC=N3)=O VKTFBHYPOYETQR-UHFFFAOYSA-O 0.000 claims description 6
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 4
- GJAUFPRNRJUPAQ-UHFFFAOYSA-O CC(C=CC=C1)=C1OC(C=CC=C1)=C1C([S+](C(NC1CCCC1)=O)C1=C2C(N3)=CC=N1)=C2NC3=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1C([S+](C(NC1CCCC1)=O)C1=C2C(N3)=CC=N1)=C2NC3=O GJAUFPRNRJUPAQ-UHFFFAOYSA-O 0.000 claims description 4
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 4
- 208000034578 Multiple myelomas Diseases 0.000 claims description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 4
- RCCYSVYHULFYHE-UHFFFAOYSA-N pentanediamide Chemical compound NC(=O)CCCC(N)=O RCCYSVYHULFYHE-UHFFFAOYSA-N 0.000 claims description 4
- ZBDBRFFGEREUQT-UHFFFAOYSA-N 2-methyl-3-(2-methylpyridin-3-yl)oxypyridine Chemical compound CC1=NC=CC=C1OC1=CC=CN=C1C ZBDBRFFGEREUQT-UHFFFAOYSA-N 0.000 claims description 3
- RFSRKULPMSHMDC-UHFFFAOYSA-N 2-methyl-3-(4-methylpyridin-2-yl)oxypyridine Chemical compound CC1=CC(=NC=C1)OC2=C(N=CC=C2)C RFSRKULPMSHMDC-UHFFFAOYSA-N 0.000 claims description 3
- PXQJVHZACANXMG-UHFFFAOYSA-N 2-methyl-3-(6-methylpyridin-2-yl)oxypyridine Chemical compound Cc1cccc(Oc2cccnc2C)n1 PXQJVHZACANXMG-UHFFFAOYSA-N 0.000 claims description 3
- ILBJSUFQMNARKT-SFHVURJKSA-N CC(C=CC=C1)=C1OC(C=CC=C1)=C1C(SC1=C2C(N3)=CC=N1)=C2N(C(N(CC1)C[C@H]1N(C)C)=O)C3=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1C(SC1=C2C(N3)=CC=N1)=C2N(C(N(CC1)C[C@H]1N(C)C)=O)C3=O ILBJSUFQMNARKT-SFHVURJKSA-N 0.000 claims description 3
- XTVVGHOUGNQISV-INIZCTEOSA-N CC(C=CC=C1)=C1OC(C=CC=C1)=C1C(SC1=C2C(N3)=CC=N1)=C2N(C(N(CC1)C[C@H]1N)=O)C3=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1C(SC1=C2C(N3)=CC=N1)=C2N(C(N(CC1)C[C@H]1N)=O)C3=O XTVVGHOUGNQISV-INIZCTEOSA-N 0.000 claims description 3
- HIXJZAYJQNFGNM-UHFFFAOYSA-O CC(C=CC=C1)=C1OC(C=CC=C1)=C1C([S+](C(NC1CCCCC1)=O)C1=C2C(N3)=CC=N1)=C2NC3=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1C([S+](C(NC1CCCCC1)=O)C1=C2C(N3)=CC=N1)=C2NC3=O HIXJZAYJQNFGNM-UHFFFAOYSA-O 0.000 claims description 3
- GWVIAIBRJQEEHQ-URMDRURSSA-O CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(N(CCC2)[C@@H]2NC(/C(\C2CC2)=C/C#N)=O)=O)C1=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(N(CCC2)[C@@H]2NC(/C(\C2CC2)=C/C#N)=O)=O)C1=O GWVIAIBRJQEEHQ-URMDRURSSA-O 0.000 claims description 3
- GWVIAIBRJQEEHQ-GSZLRSJXSA-O CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(N(CCC2)[C@H]2NC(/C(\C2CC2)=C/C#N)=O)=O)C1=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(N(CCC2)[C@H]2NC(/C(\C2CC2)=C/C#N)=O)=O)C1=O GWVIAIBRJQEEHQ-GSZLRSJXSA-O 0.000 claims description 3
- CSPZEUZNJPQXET-OQMUSNMJSA-O CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(N(CCC2)[C@H]2NC(C=C)=O)=O)C1=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(N(CCC2)[C@H]2NC(C=C)=O)=O)C1=O CSPZEUZNJPQXET-OQMUSNMJSA-O 0.000 claims description 3
- VMRGFQKAFZFKOH-MIQTYRAGSA-O CC(N[C@H](CCC1)N1C([S+](C=C1NC(N2C(C=CC=C3)=C3OC3=C(C)C=CC=C3)=O)C3=C1C2=CC=N3)=O)=O Chemical compound CC(N[C@H](CCC1)N1C([S+](C=C1NC(N2C(C=CC=C3)=C3OC3=C(C)C=CC=C3)=O)C3=C1C2=CC=N3)=O)=O VMRGFQKAFZFKOH-MIQTYRAGSA-O 0.000 claims description 3
- DIKAGYQULWFJNF-ONZSSFSLSA-O CCC(N[C@H](CCC1)N1C([S+](C=C1NC(N2C(C=CC=C3)=C3OC3=C(C)C=CC=C3)=O)C3=C1C2=CC=N3)=O)=O Chemical compound CCC(N[C@H](CCC1)N1C([S+](C=C1NC(N2C(C=CC=C3)=C3OC3=C(C)C=CC=C3)=O)C3=C1C2=CC=N3)=O)=O DIKAGYQULWFJNF-ONZSSFSLSA-O 0.000 claims description 3
- DTRHJVQMJZBJCG-UHFFFAOYSA-O O=C(NC1CCCCC1)[S+](C1=C2C(N3)=CC=N1)C(C(C=C1)=CC=C1OC1=CC=CC=C1)=C2NC3=O Chemical compound O=C(NC1CCCCC1)[S+](C1=C2C(N3)=CC=N1)C(C(C=C1)=CC=C1OC1=CC=CC=C1)=C2NC3=O DTRHJVQMJZBJCG-UHFFFAOYSA-O 0.000 claims description 3
- 206010034277 Pemphigoid Diseases 0.000 claims description 3
- 241000721454 Pemphigus Species 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 201000000564 macroglobulinemia Diseases 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- XLMOKYOYVFIABX-UHFFFAOYSA-N NC(C1=CC2=NC=NC3=CC=NC1=C23)=O Chemical compound NC(C1=CC2=NC=NC3=CC=NC1=C23)=O XLMOKYOYVFIABX-UHFFFAOYSA-N 0.000 claims 8
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims 1
- FWVNJWIDTVFHBH-UHFFFAOYSA-N C1=CC2=NC(NC3=CC=NC1=C23)=O Chemical compound C1=CC2=NC(NC3=CC=NC1=C23)=O FWVNJWIDTVFHBH-UHFFFAOYSA-N 0.000 claims 1
- ZUMUEPYCVCIPIO-UHFFFAOYSA-O N#CC(C=CC=C1)=C1OCC1=CC=CC(OCC(C=C2)=CC=C2N(C2=CC=NC3=C2C(N2)=C[S+]3C(NC3CCCCC3)=O)C2=O)=C1 Chemical compound N#CC(C=CC=C1)=C1OCC1=CC=CC(OCC(C=C2)=CC=C2N(C2=CC=NC3=C2C(N2)=C[S+]3C(NC3CCCCC3)=O)C2=O)=C1 ZUMUEPYCVCIPIO-UHFFFAOYSA-O 0.000 claims 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims 1
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 76
- 238000002360 preparation method Methods 0.000 abstract description 6
- 229940043355 kinase inhibitor Drugs 0.000 abstract 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 abstract 1
- 125000004043 oxo group Chemical group O=* 0.000 description 241
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 164
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- 239000000543 intermediate Substances 0.000 description 106
- 238000000132 electrospray ionisation Methods 0.000 description 102
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 85
- 150000001721 carbon Chemical group 0.000 description 83
- 238000001819 mass spectrum Methods 0.000 description 69
- 239000000243 solution Substances 0.000 description 68
- 238000005481 NMR spectroscopy Methods 0.000 description 64
- 238000006243 chemical reaction Methods 0.000 description 61
- 239000000460 chlorine Substances 0.000 description 52
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- 238000003818 flash chromatography Methods 0.000 description 44
- 239000007787 solid Substances 0.000 description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 36
- DVTKYLOSVTXGCT-UHFFFAOYSA-N CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C([O-])=O)C1=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C([O-])=O)C1=O DVTKYLOSVTXGCT-UHFFFAOYSA-N 0.000 description 35
- 238000011282 treatment Methods 0.000 description 35
- 239000002904 solvent Substances 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 125000001544 thienyl group Chemical group 0.000 description 24
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 23
- 229940086542 triethylamine Drugs 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000003795 chemical substances by application Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 125000004432 carbon atom Chemical group C* 0.000 description 21
- 238000000746 purification Methods 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 20
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 17
- 239000002253 acid Substances 0.000 description 17
- 239000002585 base Substances 0.000 description 17
- 125000004429 atom Chemical group 0.000 description 16
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 16
- 125000004093 cyano group Chemical group *C#N 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- 125000003342 alkenyl group Chemical group 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 125000003226 pyrazolyl group Chemical group 0.000 description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- 125000003118 aryl group Chemical group 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- 208000006673 asthma Diseases 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 238000000926 separation method Methods 0.000 description 13
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 12
- 238000012746 preparative thin layer chromatography Methods 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 10
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 description 10
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- 229920006395 saturated elastomer Chemical group 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 9
- 125000002877 alkyl aryl group Chemical group 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 125000003386 piperidinyl group Chemical group 0.000 description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 8
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 8
- 229910002091 carbon monoxide Inorganic materials 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- DPHPCAFHGURMOR-UHFFFAOYSA-O CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(Cl)=O)C1=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(Cl)=O)C1=O DPHPCAFHGURMOR-UHFFFAOYSA-O 0.000 description 7
- 239000007821 HATU Substances 0.000 description 7
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 7
- 239000012346 acetyl chloride Substances 0.000 description 7
- 125000000304 alkynyl group Chemical group 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 210000003719 b-lymphocyte Anatomy 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 208000027866 inflammatory disease Diseases 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- 208000023504 respiratory system disease Diseases 0.000 description 6
- 238000004808 supercritical fluid chromatography Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 5
- 208000023275 Autoimmune disease Diseases 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 229930040373 Paraformaldehyde Natural products 0.000 description 5
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 5
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000005304 joining Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 201000008482 osteoarthritis Diseases 0.000 description 5
- 239000001301 oxygen Chemical group 0.000 description 5
- 229920002866 paraformaldehyde Polymers 0.000 description 5
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000009424 thromboembolic effect Effects 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 208000009386 Experimental Arthritis Diseases 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- LHWGZYKNCVWOIG-UHFFFAOYSA-N N#CC1(NC=CC=C1I)Cl Chemical compound N#CC1(NC=CC=C1I)Cl LHWGZYKNCVWOIG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 125000004069 aziridinyl group Chemical group 0.000 description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 229910052740 iodine Chemical group 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
- 125000004193 piperazinyl group Chemical group 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- ARJOQCYCJMAIFR-UHFFFAOYSA-N prop-2-enoyl prop-2-enoate Chemical compound C=CC(=O)OC(=O)C=C ARJOQCYCJMAIFR-UHFFFAOYSA-N 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 3
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 3
- AUHFWLUBEJKXLN-UHFFFAOYSA-N 2-fluoro-4-methyl-3-nitropyridine Chemical compound CC1=CC=NC(F)=C1[N+]([O-])=O AUHFWLUBEJKXLN-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 201000004624 Dermatitis Diseases 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000864342 Homo sapiens Tyrosine-protein kinase BTK Proteins 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- TZGHAMKIRCMTET-UHFFFAOYSA-N N#CC1(NC=CC=C1NC1=CC=C(COC2CCCCC2)C=C1)Cl Chemical compound N#CC1(NC=CC=C1NC1=CC=C(COC2CCCCC2)C=C1)Cl TZGHAMKIRCMTET-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 125000003725 azepanyl group Chemical group 0.000 description 3
- 125000002393 azetidinyl group Chemical group 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 125000002632 imidazolidinyl group Chemical group 0.000 description 3
- 210000001503 joint Anatomy 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 125000005961 oxazepanyl group Chemical group 0.000 description 3
- 125000003566 oxetanyl group Chemical group 0.000 description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 3
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 102220240796 rs553605556 Human genes 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- PAXDIBGWURAVIH-YUMQZZPRSA-N tert-butyl n-[(1s,2s)-2-aminocyclopentyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N PAXDIBGWURAVIH-YUMQZZPRSA-N 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 description 2
- FHOJHXQSKYIENH-AATRIKPKSA-N (E)-2-[(2-methylpropan-2-yl)oxycarbonylamino]but-2-enoic acid Chemical compound C\C=C(\NC(=O)OC(C)(C)C)C(O)=O FHOJHXQSKYIENH-AATRIKPKSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 2
- ULOYFTVVYHGIHI-UHFFFAOYSA-N 2-(chloromethyl)-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CN=C1CCl ULOYFTVVYHGIHI-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- YRXIMPFOTQVOHG-UHFFFAOYSA-N 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]acetic acid Chemical compound OC(=O)CN(C)C(=O)OC(C)(C)C YRXIMPFOTQVOHG-UHFFFAOYSA-N 0.000 description 2
- UUOLETYDNTVQDY-UHFFFAOYSA-N 2-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CN=C1Cl UUOLETYDNTVQDY-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- XWZZKTXNWNTQLR-UHFFFAOYSA-N 2-methyl-1-nitro-3-phenoxybenzene Chemical compound C1=CC=C([N+]([O-])=O)C(C)=C1OC1=CC=CC=C1 XWZZKTXNWNTQLR-UHFFFAOYSA-N 0.000 description 2
- AAEJMRFPMLLTIX-UHFFFAOYSA-N 3-[tert-butyl(dimethyl)silyl]oxybenzaldehyde Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=CC(C=O)=C1 AAEJMRFPMLLTIX-UHFFFAOYSA-N 0.000 description 2
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 2
- QIORDSKCCHRSSD-UHFFFAOYSA-N 3-methyl-2-nitrophenol Chemical compound CC1=CC=CC(O)=C1[N+]([O-])=O QIORDSKCCHRSSD-UHFFFAOYSA-N 0.000 description 2
- MUNOBADFTHUUFG-UHFFFAOYSA-N 3-phenylaniline Chemical compound NC1=CC=CC(C=2C=CC=CC=2)=C1 MUNOBADFTHUUFG-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- QFKLIYCFIWOUMY-UHFFFAOYSA-N 4-(4-methylphenoxy)pyrimidin-2-amine Chemical compound C1=CC(C)=CC=C1OC1=CC=NC(N)=N1 QFKLIYCFIWOUMY-UHFFFAOYSA-N 0.000 description 2
- TUSUZVYPJNMGGJ-UHFFFAOYSA-N 4-bromo-N-(fluoromethyl)aniline Chemical compound C1=CC(=CC=C1NCF)Br TUSUZVYPJNMGGJ-UHFFFAOYSA-N 0.000 description 2
- RQMWVVBHJMUJNZ-UHFFFAOYSA-N 4-chloropyridin-2-amine Chemical compound NC1=CC(Cl)=CC=N1 RQMWVVBHJMUJNZ-UHFFFAOYSA-N 0.000 description 2
- YHWQJTNMKZWBBN-UHFFFAOYSA-N 4-ethyl-n-methylaniline Chemical compound CCC1=CC=C(NC)C=C1 YHWQJTNMKZWBBN-UHFFFAOYSA-N 0.000 description 2
- ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 208000011691 Burkitt lymphomas Diseases 0.000 description 2
- RUVUEELPNFMXPS-UHFFFAOYSA-N CC(C(OC1OCCCC1)=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C([O-])=O)C1=O Chemical compound CC(C(OC1OCCCC1)=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C([O-])=O)C1=O RUVUEELPNFMXPS-UHFFFAOYSA-N 0.000 description 2
- QILSPDWMMBVMIB-UHFFFAOYSA-N CC(C)C(C=C1)=CC(C)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C([O-])=O)C1=O Chemical compound CC(C)C(C=C1)=CC(C)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C([O-])=O)C1=O QILSPDWMMBVMIB-UHFFFAOYSA-N 0.000 description 2
- IVBIFPAFHWFCPN-UHFFFAOYSA-N CC(C)C1(N)NC=CC=C1 Chemical compound CC(C)C1(N)NC=CC=C1 IVBIFPAFHWFCPN-UHFFFAOYSA-N 0.000 description 2
- BGAOLNJKYLMKPR-UHFFFAOYSA-N CC(C)CC1=CC=C(C)C(N)=N1 Chemical compound CC(C)CC1=CC=C(C)C(N)=N1 BGAOLNJKYLMKPR-UHFFFAOYSA-N 0.000 description 2
- MNBBIQTZYQUHOM-UHFFFAOYSA-N CC(C)CC1=CC=C(C)C(NC2=C(C(N)=C(C(OC)=O)S3)C3=NC=C2)=N1 Chemical compound CC(C)CC1=CC=C(C)C(NC2=C(C(N)=C(C(OC)=O)S3)C3=NC=C2)=N1 MNBBIQTZYQUHOM-UHFFFAOYSA-N 0.000 description 2
- DRTHUOJETDXOOT-KRWDZBQOSA-N CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=C(C(N(CC2)C[C@H]2NC)=O)SC2=C1C(N1)=CC=N2)C1=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=C(C(N(CC2)C[C@H]2NC)=O)SC2=C1C(N1)=CC=N2)C1=O DRTHUOJETDXOOT-KRWDZBQOSA-N 0.000 description 2
- CSPZEUZNJPQXET-ONZSSFSLSA-O CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(N(CCC2)[C@@H]2NC(C=C)=O)=O)C1=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(N(CCC2)[C@@H]2NC(C=C)=O)=O)C1=O CSPZEUZNJPQXET-ONZSSFSLSA-O 0.000 description 2
- LZKQOSYKAUNXMV-UHFFFAOYSA-O CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(NC(CC2)CCC2NC)=O)C1=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(NC(CC2)CCC2NC)=O)C1=O LZKQOSYKAUNXMV-UHFFFAOYSA-O 0.000 description 2
- WLZFKDNXYIQOEP-UHFFFAOYSA-O CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(NC(CCCC2)C2NC)=O)C1=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(NC(CCCC2)C2NC)=O)C1=O WLZFKDNXYIQOEP-UHFFFAOYSA-O 0.000 description 2
- IZPDZOJNCOJKAO-UHFFFAOYSA-N CCC(C=C1)=CC(C)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C([O-])=O)C1=O Chemical compound CCC(C=C1)=CC(C)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C([O-])=O)C1=O IZPDZOJNCOJKAO-UHFFFAOYSA-N 0.000 description 2
- FBXMWVPRCPXXDX-UHFFFAOYSA-N COCC(C=C1)=CC=C1NC1=CC=CNC1(C#N)Cl Chemical compound COCC(C=C1)=CC=C1NC1=CC=CNC1(C#N)Cl FBXMWVPRCPXXDX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- VFBUUSULDXMISG-ZZXKWVIFSA-N N#C/C=C(\C1CC1)/C(O)=O Chemical compound N#C/C=C(\C1CC1)/C(O)=O VFBUUSULDXMISG-ZZXKWVIFSA-N 0.000 description 2
- MMCURZDBOGASQX-UHFFFAOYSA-N N#CC1(NC=CC(I)=C1)Cl Chemical compound N#CC1(NC=CC(I)=C1)Cl MMCURZDBOGASQX-UHFFFAOYSA-N 0.000 description 2
- FPGAHNJCBMRVTQ-UHFFFAOYSA-N N#CC1(NC=CC=C1NC1=CC=C(CO)C=C1)Cl Chemical compound N#CC1(NC=CC=C1NC1=CC=C(CO)C=C1)Cl FPGAHNJCBMRVTQ-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- OALBJXNBOOOZGI-UHFFFAOYSA-O OC1(CNC([S+](C2=C3C(N4)=CC=N2)C(C(C=C2)=CC=C2OC2=CC=CC=C2)=C3NC4=O)=O)CCCCC1 Chemical compound OC1(CNC([S+](C2=C3C(N4)=CC=N2)C(C(C=C2)=CC=C2OC2=CC=CC=C2)=C3NC4=O)=O)CCCCC1 OALBJXNBOOOZGI-UHFFFAOYSA-O 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 206010038563 Reocclusion Diseases 0.000 description 2
- 206010039710 Scleroderma Diseases 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108010009978 Tec protein-tyrosine kinase Proteins 0.000 description 2
- SIGXMQNKJVKPQJ-UHFFFAOYSA-N [3-[tert-butyl(dimethyl)silyl]oxyphenyl]methanol Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=CC(CO)=C1 SIGXMQNKJVKPQJ-UHFFFAOYSA-N 0.000 description 2
- JLSLLJXYCISJHL-UHFFFAOYSA-N [O-]C([S+](C1=C2C(N3)=CC=N1)C(C1=NC(OC4=CC=CC=C4)=CC=C1)=C2NC3=O)=O Chemical compound [O-]C([S+](C1=C2C(N3)=CC=N1)C(C1=NC(OC4=CC=CC=C4)=CC=C1)=C2NC3=O)=O JLSLLJXYCISJHL-UHFFFAOYSA-N 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000002399 angioplasty Methods 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000006880 cross-coupling reaction Methods 0.000 description 2
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 2
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 2
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 2
- BSEXNZMHLUMQKR-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1.NC(=O)C1CC1 BSEXNZMHLUMQKR-UHFFFAOYSA-N 0.000 description 2
- 239000012024 dehydrating agents Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 2
- 108700003601 dimethylglycine Proteins 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000011737 fluorine Chemical group 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- TXXHDPDFNKHHGW-UHFFFAOYSA-N muconic acid Chemical group OC(=O)C=CC=CC(O)=O TXXHDPDFNKHHGW-UHFFFAOYSA-N 0.000 description 2
- 229940078490 n,n-dimethylglycine Drugs 0.000 description 2
- HAGXGPBANMKVAK-UHFFFAOYSA-N n-(2-methylphenoxy)aniline Chemical compound CC1=CC=CC=C1ONC1=CC=CC=C1 HAGXGPBANMKVAK-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- RQZGOIJRSJWNRB-UHFFFAOYSA-N n-methyl-4-propan-2-ylaniline Chemical compound CNC1=CC=C(C(C)C)C=C1 RQZGOIJRSJWNRB-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- KVGZFBRRQJWLJO-UHFFFAOYSA-N oxan-2-yl methanesulfonate Chemical compound CS(=O)(=O)OC1CCCCO1 KVGZFBRRQJWLJO-UHFFFAOYSA-N 0.000 description 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000012877 positron emission topography Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical group OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000004576 sand Substances 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000008117 stearic acid Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- DSDCDMKASWVZHI-UHFFFAOYSA-M zinc;2-methanidylpropane;bromide Chemical compound Br[Zn+].CC(C)[CH2-] DSDCDMKASWVZHI-UHFFFAOYSA-M 0.000 description 2
- GEQHKFFSPGPGLN-OLQVQODUSA-N (1r,3s)-cyclohexane-1,3-diamine Chemical compound N[C@H]1CCC[C@@H](N)C1 GEQHKFFSPGPGLN-OLQVQODUSA-N 0.000 description 1
- PAWSVPVNIXFKOS-NSCUHMNNSA-N (2E)-2-aminobut-2-enoic acid zwitterion Chemical compound C\C=C(\N)C(O)=O PAWSVPVNIXFKOS-NSCUHMNNSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- DQLQXXICPMREOT-SNAWJCMRSA-N (e)-2-(dimethylamino)but-2-enoic acid Chemical compound C\C=C(\N(C)C)C(O)=O DQLQXXICPMREOT-SNAWJCMRSA-N 0.000 description 1
- YKIKDQYYTAOTPL-NSCUHMNNSA-N (e)-2-bromobut-2-enoic acid Chemical compound C\C=C(\Br)C(O)=O YKIKDQYYTAOTPL-NSCUHMNNSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 125000005962 1,4-oxazepanyl group Chemical group 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 description 1
- BVJYDVKFDDPCAW-UHFFFAOYSA-N 1-aminocyclopentan-1-ol Chemical compound NC1(O)CCCC1 BVJYDVKFDDPCAW-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 1
- CEEGZYQFCDHVSO-UHFFFAOYSA-N 1-fluoro-3-(nitromethyl)benzene Chemical compound [O-][N+](=O)CC1=CC=CC(F)=C1 CEEGZYQFCDHVSO-UHFFFAOYSA-N 0.000 description 1
- BSXPDVKSFWQFRT-UHFFFAOYSA-N 1-hydroxytriazolo[4,5-b]pyridine Chemical compound C1=CC=C2N(O)N=NC2=N1 BSXPDVKSFWQFRT-UHFFFAOYSA-N 0.000 description 1
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- AMMPLVWPWSYRDR-UHFFFAOYSA-N 1-methylbicyclo[2.2.2]oct-2-ene-4-carboxylic acid Chemical compound C1CC2(C(O)=O)CCC1(C)C=C2 AMMPLVWPWSYRDR-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- GFMMXOIFOQCCGU-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC1=C(F)C(F)=CC=C1C(=O)NOCC1CC1 GFMMXOIFOQCCGU-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- RJEOLFWWPFSFFM-UHFFFAOYSA-N 2-[[3-[tert-butyl(dimethyl)silyl]oxyphenyl]methoxy]benzonitrile Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=CC(COC=2C(=CC=CC=2)C#N)=C1 RJEOLFWWPFSFFM-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- LDVAIJZDACHGML-UHFFFAOYSA-N 2-fluoro-n-methylaniline Chemical compound CNC1=CC=CC=C1F LDVAIJZDACHGML-UHFFFAOYSA-N 0.000 description 1
- CHZCERSEMVWNHL-UHFFFAOYSA-N 2-hydroxybenzonitrile Chemical compound OC1=CC=CC=C1C#N CHZCERSEMVWNHL-UHFFFAOYSA-N 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical group C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- SALIGPAVMVFEJN-UHFFFAOYSA-N 2h-benzotriazol-4-yloxy(tripyrrolidin-1-yl)phosphanium Chemical compound C1CCCN1[P+](N1CCCC1)(N1CCCC1)OC1=CC=CC2=NNN=C12 SALIGPAVMVFEJN-UHFFFAOYSA-N 0.000 description 1
- XLZYKTYMLBOINK-UHFFFAOYSA-N 3-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(=O)C=2C=CC(O)=CC=2)=C1 XLZYKTYMLBOINK-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical compound NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- COPMASWDWLENMV-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-prop-1-enyl-1,3,2-dioxaborolane Chemical compound CC=CB1OC(C)(C)C(C)(C)O1 COPMASWDWLENMV-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ASSMPDZEDVTRKG-UHFFFAOYSA-N 4-(bromomethyl)aniline Chemical compound NC1=CC=C(CBr)C=C1 ASSMPDZEDVTRKG-UHFFFAOYSA-N 0.000 description 1
- FCQCSCFHFSBKRM-UHFFFAOYSA-N 4-(iodomethyl)aniline Chemical compound NC1=CC=C(CI)C=C1 FCQCSCFHFSBKRM-UHFFFAOYSA-N 0.000 description 1
- URSADVDNUKPSIK-UHFFFAOYSA-N 4-(methoxymethyl)aniline Chemical compound COCC1=CC=C(N)C=C1 URSADVDNUKPSIK-UHFFFAOYSA-N 0.000 description 1
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
- DBGFGNCFYUNXLD-UHFFFAOYSA-N 4-chloropyrimidin-2-amine Chemical group NC1=NC=CC(Cl)=N1 DBGFGNCFYUNXLD-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical group NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 1
- QLRTVZKXTUGXHT-UHFFFAOYSA-N 6-(bromomethyl)pyridin-2-amine Chemical compound NC1=CC=CC(CBr)=N1 QLRTVZKXTUGXHT-UHFFFAOYSA-N 0.000 description 1
- QRWMZMCNUKMMJL-UHFFFAOYSA-N 6-chloro-3-methyl-2-nitropyridine Chemical compound Cc1ccc(Cl)nc1[N+]([O-])=O QRWMZMCNUKMMJL-UHFFFAOYSA-N 0.000 description 1
- JEAVIRYCMBDJIU-UHFFFAOYSA-N 6-methyl-1h-pyridin-2-one Chemical compound CC1=CC=CC(O)=N1 JEAVIRYCMBDJIU-UHFFFAOYSA-N 0.000 description 1
- TVEXGJYMHHTVKP-UHFFFAOYSA-N 6-oxabicyclo[3.2.1]oct-3-en-7-one Chemical compound C1C2C(=O)OC1C=CC2 TVEXGJYMHHTVKP-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 206010001767 Alopecia universalis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-OUBTZVSYSA-N Ammonia-15N Chemical compound [15NH3] QGZKDVFQNNGYKY-OUBTZVSYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000033309 Analgesic asthma syndrome Diseases 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010002412 Angiocentric lymphomas Diseases 0.000 description 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 1
- 208000032467 Aplastic anaemia Diseases 0.000 description 1
- 206010003011 Appendicitis Diseases 0.000 description 1
- 206010003557 Asthma exercise induced Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 206010003840 Autonomic nervous system imbalance Diseases 0.000 description 1
- 208000032568 B-cell prolymphocytic leukaemia Diseases 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- 208000027496 Behcet disease Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 206010051728 Bone erosion Diseases 0.000 description 1
- 206010006448 Bronchiolitis Diseases 0.000 description 1
- 208000023611 Burkitt leukaemia Diseases 0.000 description 1
- 206010006811 Bursitis Diseases 0.000 description 1
- BOUQJYKABBZOIK-UHFFFAOYSA-N CC(C)C1=NC=CC=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C([O-])=O)C1=O Chemical compound CC(C)C1=NC=CC=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C([O-])=O)C1=O BOUQJYKABBZOIK-UHFFFAOYSA-N 0.000 description 1
- AEYPJUVIENZNIG-UHFFFAOYSA-O CC(C)CC1=CC=C(C)C(N(C2=CC=NC3=C2C(N2)=C[S+]3C(OC)=O)C2=O)=N1 Chemical compound CC(C)CC1=CC=C(C)C(N(C2=CC=NC3=C2C(N2)=C[S+]3C(OC)=O)C2=O)=N1 AEYPJUVIENZNIG-UHFFFAOYSA-O 0.000 description 1
- MWKHKNYHIVTCOB-UHFFFAOYSA-N CC(C)CC1=CC=C(C)C(N(C2=CC=NC3=C2C(N2)=C[S+]3C([O-])=O)C2=O)=N1 Chemical compound CC(C)CC1=CC=C(C)C(N(C2=CC=NC3=C2C(N2)=C[S+]3C([O-])=O)C2=O)=N1 MWKHKNYHIVTCOB-UHFFFAOYSA-N 0.000 description 1
- JLZJNUTWLXRDEZ-UHFFFAOYSA-N CC(C)COCC1=CC=CC(N(C2=CC=NC3=C2C(N2)=C[S+]3C([O-])=O)C2=O)=N1 Chemical compound CC(C)COCC1=CC=CC(N(C2=CC=NC3=C2C(N2)=C[S+]3C([O-])=O)C2=O)=N1 JLZJNUTWLXRDEZ-UHFFFAOYSA-N 0.000 description 1
- KYSADPMFCGJWRL-UHFFFAOYSA-N CC(C)OCC(C=C1)=CC=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C([O-])=O)C1=O Chemical compound CC(C)OCC(C=C1)=CC=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C([O-])=O)C1=O KYSADPMFCGJWRL-UHFFFAOYSA-N 0.000 description 1
- GNBNBCCKCLVKGK-UHFFFAOYSA-N CC(C)OCC1=CC=CC(N(C2=CC=NC3=C2C(N2)=C[S+]3C([O-])=O)C2=O)=N1 Chemical compound CC(C)OCC1=CC=CC(N(C2=CC=NC3=C2C(N2)=C[S+]3C([O-])=O)C2=O)=N1 GNBNBCCKCLVKGK-UHFFFAOYSA-N 0.000 description 1
- ABSRXYUPBNYJAD-UHFFFAOYSA-N CC(C=C1)=CC=C1OC1=NC(N(C2=CC=NC3=C2C(N2)=C[S+]3C([O-])=O)C2=O)=NC=C1 Chemical compound CC(C=C1)=CC=C1OC1=NC(N(C2=CC=NC3=C2C(N2)=C[S+]3C([O-])=O)C2=O)=NC=C1 ABSRXYUPBNYJAD-UHFFFAOYSA-N 0.000 description 1
- FXPUPQWVDPWKBY-UHFFFAOYSA-O CC(C=CC=C1)=C1OC(C=CC=C1)=C1C([S+](C(N)=O)C1=C2C(N3)=CC=N1)=C2NC3=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1C([S+](C(N)=O)C1=C2C(N3)=CC=N1)=C2NC3=O FXPUPQWVDPWKBY-UHFFFAOYSA-O 0.000 description 1
- PXIZQYCCLLGQGP-UHFFFAOYSA-O CC(C=CC=C1)=C1OC(C=CC=C1)=C1C([S+](C(NC(CCCC1)C1O)=O)C1=C2C(N3)=CC=N1)=C2NC3=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1C([S+](C(NC(CCCC1)C1O)=O)C1=C2C(N3)=CC=N1)=C2NC3=O PXIZQYCCLLGQGP-UHFFFAOYSA-O 0.000 description 1
- URNHVFOFAMQAOD-JXLGBODESA-O CC(C=CC=C1)=C1OC(C=CC=C1)=C1C([S+](C(N[C@@H](CCC1)[C@H]1N)=O)C1=C2C(N3)=CC=N1)=C2NC3=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1C([S+](C(N[C@@H](CCC1)[C@H]1N)=O)C1=C2C(N3)=CC=N1)=C2NC3=O URNHVFOFAMQAOD-JXLGBODESA-O 0.000 description 1
- LWVPDPKPPUFTRQ-GNQLYUGHSA-O CC(C=CC=C1)=C1OC(C=CC=C1)=C1C([S+](C(N[C@@H](CCCC1)[C@H]1NC=O)=O)C1=C2C(N3)=CC=N1)=C2NC3=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1C([S+](C(N[C@@H](CCCC1)[C@H]1NC=O)=O)C1=C2C(N3)=CC=N1)=C2NC3=O LWVPDPKPPUFTRQ-GNQLYUGHSA-O 0.000 description 1
- GMANTTUIQBAIPA-UHFFFAOYSA-N CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C(C(NC(CC3)CCC3=O)=O)S2)C1=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C(C(NC(CC3)CCC3=O)=O)S2)C1=O GMANTTUIQBAIPA-UHFFFAOYSA-N 0.000 description 1
- SDBMQTRMPOMDGB-UHFFFAOYSA-N CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C(C(NC(CCCC3)C3=O)=O)S2)C1=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C(C(NC(CCCC3)C3=O)=O)S2)C1=O SDBMQTRMPOMDGB-UHFFFAOYSA-N 0.000 description 1
- SHYYPPCFIDHSJY-UHFFFAOYSA-O CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(NC(CC2)CCC2=O)=O)C1=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(NC(CC2)CCC2=O)=O)C1=O SHYYPPCFIDHSJY-UHFFFAOYSA-O 0.000 description 1
- ZQBJDRUXKFQKGS-UHFFFAOYSA-O CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(NC(CCCC2)C2=O)=O)C1=O Chemical compound CC(C=CC=C1)=C1OC(C=CC=C1)=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C(NC(CCCC2)C2=O)=O)C1=O ZQBJDRUXKFQKGS-UHFFFAOYSA-O 0.000 description 1
- JOAXQYQXTHVKFI-UHFFFAOYSA-N CC(C=CC=C1)=C1OC1=CC=CN=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C([O-])=O)C1=O Chemical compound CC(C=CC=C1)=C1OC1=CC=CN=C1N(C1=CC=NC2=C1C(N1)=C[S+]2C([O-])=O)C1=O JOAXQYQXTHVKFI-UHFFFAOYSA-N 0.000 description 1
- QYXWTKCWIKSIDN-UHFFFAOYSA-N CC(C=CC=C1)=C1ON(C1=CC=CNC1(C#N)Cl)C1=CC=CC=C1 Chemical compound CC(C=CC=C1)=C1ON(C1=CC=CNC1(C#N)Cl)C1=CC=CC=C1 QYXWTKCWIKSIDN-UHFFFAOYSA-N 0.000 description 1
- ANIJZWYOMWCKQK-UHFFFAOYSA-N CC(OC(C1=CC=C2)(OC(C)=O)OC(OC(C)=O)=C1C2=O)=O Chemical compound CC(OC(C1=CC=C2)(OC(C)=O)OC(OC(C)=O)=C1C2=O)=O ANIJZWYOMWCKQK-UHFFFAOYSA-N 0.000 description 1
- CSMZFQDUPQYKIR-UHFFFAOYSA-N CC1=CC=CC(OC(C=C2)=CC=C2N(C2=CC=NC3=C2C(N2)=C[S+]3C([O-])=O)C2=O)=N1 Chemical compound CC1=CC=CC(OC(C=C2)=CC=C2N(C2=CC=NC3=C2C(N2)=C[S+]3C([O-])=O)C2=O)=N1 CSMZFQDUPQYKIR-UHFFFAOYSA-N 0.000 description 1
- VWMMETSBYRUTBJ-UHFFFAOYSA-N CC=CC1=NC=CC([N+]([O-])=O)=C1 Chemical compound CC=CC1=NC=CC([N+]([O-])=O)=C1 VWMMETSBYRUTBJ-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 102000000503 Collagen Type II Human genes 0.000 description 1
- 108010041390 Collagen Type II Proteins 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 208000009011 Cytochrome P-450 CYP3A Inhibitors Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Chemical group OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 206010011841 Dacryoadenitis acquired Diseases 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 208000004145 Endometritis Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 201000011275 Epicondylitis Diseases 0.000 description 1
- 208000004657 Exercise-Induced Asthma Diseases 0.000 description 1
- 206010016228 Fasciitis Diseases 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 208000007465 Giant cell arteritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Chemical group OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 1
- 208000001718 Immediate Hypersensitivity Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000005615 Interstitial Cystitis Diseases 0.000 description 1
- 208000000209 Isaacs syndrome Diseases 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical group OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- CZQHHVNHHHRRDU-UHFFFAOYSA-N LY294002 Chemical compound C1=CC=C2C(=O)C=C(N3CCOCC3)OC2=C1C1=CC=CC=C1 CZQHHVNHHHRRDU-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- 201000008197 Laryngitis Diseases 0.000 description 1
- 206010052178 Lymphocytic lymphoma Diseases 0.000 description 1
- 201000003791 MALT lymphoma Diseases 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Chemical group OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000003926 Myelitis Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- VLUQULVIFHMNTG-UHFFFAOYSA-N NC1(CCl)N=CC=CN1 Chemical compound NC1(CCl)N=CC=CN1 VLUQULVIFHMNTG-UHFFFAOYSA-N 0.000 description 1
- LYPFSTOIOFMWLB-UHFFFAOYSA-N NCC(C=C1)=CC=C1OC1=CC=CC(COC(C=CC=C2)=C2C#N)=C1 Chemical compound NCC(C=C1)=CC=C1OC1=CC=CC(COC(C=CC=C2)=C2C#N)=C1 LYPFSTOIOFMWLB-UHFFFAOYSA-N 0.000 description 1
- 238000006411 Negishi coupling reaction Methods 0.000 description 1
- 206010072359 Neuromyotonia Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010029461 Nodal marginal zone B-cell lymphomas Diseases 0.000 description 1
- FBQROKBQPZZWCN-UHFFFAOYSA-N O=C(C(SC1=C2C(N3)=CC=N1)=C2N(C(C=C1)=CC=C1OC1=CC=CC=C1)C3=O)Cl Chemical compound O=C(C(SC1=C2C(N3)=CC=N1)=C2N(C(C=C1)=CC=C1OC1=CC=CC=C1)C3=O)Cl FBQROKBQPZZWCN-UHFFFAOYSA-N 0.000 description 1
- TUBFBCAFVBTHGM-UHFFFAOYSA-O O=C([S+](C1=C2C(N3)=CC=N1)C(C1=NC(OC4=CC=CC=C4)=CC=C1)=C2NC3=O)Cl Chemical compound O=C([S+](C1=C2C(N3)=CC=N1)C(C1=NC(OC4=CC=CC=C4)=CC=C1)=C2NC3=O)Cl TUBFBCAFVBTHGM-UHFFFAOYSA-O 0.000 description 1
- 208000005225 Opsoclonus-Myoclonus Syndrome Diseases 0.000 description 1
- 208000003435 Optic Neuritis Diseases 0.000 description 1
- 206010031149 Osteitis Diseases 0.000 description 1
- 208000005141 Otitis Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 206010034038 Parotitis Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 206010035742 Pneumonitis Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010065857 Primary Effusion Lymphoma Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 206010036711 Primary mediastinal large B-cell lymphomas Diseases 0.000 description 1
- 206010036774 Proctitis Diseases 0.000 description 1
- 208000035416 Prolymphocytic B-Cell Leukemia Diseases 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 102100036164 Putative phospholipase B-like 2 Human genes 0.000 description 1
- 101710200837 Putative phospholipase B-like 2 Proteins 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 208000033464 Reiter syndrome Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 241001303601 Rosacea Species 0.000 description 1
- APTGPWJUOYMUCE-UHFFFAOYSA-N S-Ethyl thioacetate Chemical compound CCSC(C)=O APTGPWJUOYMUCE-UHFFFAOYSA-N 0.000 description 1
- ZQUSFAUAYSEREK-WKILWMFISA-N SB-239063 Chemical compound COC1=NC=CC(C=2N(C=NC=2C=2C=CC(F)=CC=2)[C@@H]2CC[C@@H](O)CC2)=N1 ZQUSFAUAYSEREK-WKILWMFISA-N 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 208000007893 Salpingitis Diseases 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 108010016672 Syk Kinase Proteins 0.000 description 1
- 102000000551 Syk Kinase Human genes 0.000 description 1
- 208000001106 Takayasu Arteritis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 206010045240 Type I hypersensitivity Diseases 0.000 description 1
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 208000006374 Uterine Cervicitis Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 206010046914 Vaginal infection Diseases 0.000 description 1
- 201000008100 Vaginitis Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000003728 Vulvodynia Diseases 0.000 description 1
- 206010069055 Vulvovaginal pain Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- BBKCOQYMKGEAAJ-UHFFFAOYSA-M [Br-].[Zn+]C1CCC1 Chemical compound [Br-].[Zn+]C1CCC1 BBKCOQYMKGEAAJ-UHFFFAOYSA-M 0.000 description 1
- DBTPSOCEDCHBPY-UHFFFAOYSA-N [O-]C([S+](C1=C2C(N3)=CC=N1)C(C(C=C1)=CC=C1OC1=CC=CC=C1)=C2NC3=O)=O Chemical compound [O-]C([S+](C1=C2C(N3)=CC=N1)C(C(C=C1)=CC=C1OC1=CC=CC=C1)=C2NC3=O)=O DBTPSOCEDCHBPY-UHFFFAOYSA-N 0.000 description 1
- BYAGCOSOTXHNLT-UHFFFAOYSA-N [O-]C([S+](C1=C2C(N3)=CC=N1)C(C(C=C1)=NC=C1C1=CC=CC=C1)=C2NC3=O)=O Chemical compound [O-]C([S+](C1=C2C(N3)=CC=N1)C(C(C=C1)=NC=C1C1=CC=CC=C1)=C2NC3=O)=O BYAGCOSOTXHNLT-UHFFFAOYSA-N 0.000 description 1
- FHJGVZCCIRMSQF-UHFFFAOYSA-N [O-]C([S+](C1=C2C(N3)=CC=N1)C(C1=CC=CN=C1C1=CC=CC=C1)=C2NC3=O)=O Chemical compound [O-]C([S+](C1=C2C(N3)=CC=N1)C(C1=CC=CN=C1C1=CC=CC=C1)=C2NC3=O)=O FHJGVZCCIRMSQF-UHFFFAOYSA-N 0.000 description 1
- UKUCVZIWVQCNPP-UHFFFAOYSA-N [O-]C([S+](C1=C2C(N3)=CC=N1)C(C1=NC(C4=CC=CC=C4)=CC=N1)=C2NC3=O)=O Chemical compound [O-]C([S+](C1=C2C(N3)=CC=N1)C(C1=NC(C4=CC=CC=C4)=CC=N1)=C2NC3=O)=O UKUCVZIWVQCNPP-UHFFFAOYSA-N 0.000 description 1
- PIKXYSCDGMOPEA-UHFFFAOYSA-N [O-]C([S+](C=C1NC(N2C(C=CC=C3)=C3C3=CC=CC=C3)=O)C3=C1C2=CC=N3)=O Chemical compound [O-]C([S+](C=C1NC(N2C(C=CC=C3)=C3C3=CC=CC=C3)=O)C3=C1C2=CC=N3)=O PIKXYSCDGMOPEA-UHFFFAOYSA-N 0.000 description 1
- QQHVEYWHVJJOSZ-UHFFFAOYSA-N [O-]C([S+](C=C1NC(N2C(C=CC=C3)=C3OC(C=CC=C3)=C3F)=O)C3=C1C2=CC=N3)=O Chemical compound [O-]C([S+](C=C1NC(N2C(C=CC=C3)=C3OC(C=CC=C3)=C3F)=O)C3=C1C2=CC=N3)=O QQHVEYWHVJJOSZ-UHFFFAOYSA-N 0.000 description 1
- PPZCAQMSEYNVSF-UHFFFAOYSA-N [O-]C([S+](C=C1NC(N2C(C=CC=C3)=C3OC3=C(CF)C=CC=C3)=O)C3=C1C2=CC=N3)=O Chemical compound [O-]C([S+](C=C1NC(N2C(C=CC=C3)=C3OC3=C(CF)C=CC=C3)=O)C3=C1C2=CC=N3)=O PPZCAQMSEYNVSF-UHFFFAOYSA-N 0.000 description 1
- FIUMGVSRKPNHIP-UHFFFAOYSA-N [O-]C([S+](C=C1NC(N2C3=CC=C(COC4CCCCC4)C=C3)=O)C3=C1C2=CC=N3)=O Chemical compound [O-]C([S+](C=C1NC(N2C3=CC=C(COC4CCCCC4)C=C3)=O)C3=C1C2=CC=N3)=O FIUMGVSRKPNHIP-UHFFFAOYSA-N 0.000 description 1
- RTEXJSAQVRWGSW-UHFFFAOYSA-N [O-]C([S+](C=C1NC(N2C3=NC(COC4CCC4)=CC=C3)=O)C3=C1C2=CC=N3)=O Chemical compound [O-]C([S+](C=C1NC(N2C3=NC(COC4CCC4)=CC=C3)=O)C3=C1C2=CC=N3)=O RTEXJSAQVRWGSW-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 208000002552 acute disseminated encephalomyelitis Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 208000032775 alopecia universalis congenita Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 235000010210 aluminium Nutrition 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- ACPOUJIDANTYHO-UHFFFAOYSA-N anthra[1,9-cd]pyrazol-6(2H)-one Chemical compound C1=CC(C(=O)C=2C3=CC=CC=2)=C2C3=NNC2=C1 ACPOUJIDANTYHO-UHFFFAOYSA-N 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 150000001543 aryl boronic acids Chemical class 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 208000024744 aspirin-induced respiratory disease Diseases 0.000 description 1
- 208000010216 atopic IgE responsiveness Diseases 0.000 description 1
- 208000024998 atopic conjunctivitis Diseases 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 208000010217 blepharitis Diseases 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000018339 bone inflammation disease Diseases 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 206010008323 cervicitis Diseases 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 201000001352 cholecystitis Diseases 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000023819 chronic asthma Diseases 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 201000004897 cough variant asthma Diseases 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- KFGVRWGDTLZAAO-UHFFFAOYSA-N cyclopenta-1,3-diene dicyclohexyl(cyclopenta-1,3-dien-1-yl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.C1CCC(CC1)P(C1CCCCC1)c1ccc[cH-]1 KFGVRWGDTLZAAO-UHFFFAOYSA-N 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 201000004400 dacryoadenitis Diseases 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical group CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 208000019479 dysautonomia Diseases 0.000 description 1
- 208000019258 ear infection Diseases 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 208000010227 enterocolitis Diseases 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 201000010063 epididymitis Diseases 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 208000024695 exercise-induced bronchoconstriction Diseases 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- UHCBBWUQDAVSMS-UHFFFAOYSA-N fluoroethane Chemical compound CCF UHCBBWUQDAVSMS-UHFFFAOYSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000000174 gluconic acid Chemical group 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000004220 glutamic acid Chemical group 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 208000002557 hidradenitis Diseases 0.000 description 1
- 201000007162 hidradenitis suppurativa Diseases 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 208000000122 hyperventilation Diseases 0.000 description 1
- 230000000870 hyperventilation Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 208000026876 intravascular large B-cell lymphoma Diseases 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 208000006116 lymphomatoid granulomatosis Diseases 0.000 description 1
- 201000007919 lymphoplasmacytic lymphoma Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 208000004396 mastitis Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- MKIJJIMOAABWGF-UHFFFAOYSA-N methyl 2-sulfanylacetate Chemical compound COC(=O)CS MKIJJIMOAABWGF-UHFFFAOYSA-N 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- VLZLOWPYUQHHCG-UHFFFAOYSA-N nitromethylbenzene Chemical compound [O-][N+](=O)CC1=CC=CC=C1 VLZLOWPYUQHHCG-UHFFFAOYSA-N 0.000 description 1
- 208000024696 nocturnal asthma Diseases 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 208000007892 occupational asthma Diseases 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 208000005963 oophoritis Diseases 0.000 description 1
- 239000008008 oral excipient Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 201000005737 orchitis Diseases 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- CELWCAITJAEQNL-UHFFFAOYSA-N oxan-2-ol Chemical compound OC1CCCCO1 CELWCAITJAEQNL-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Chemical group OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 208000008494 pericarditis Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008196 pharmacological composition Substances 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 208000008423 pleurisy Diseases 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 208000018290 primary dysautonomia Diseases 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- CYOHGALHFOKKQC-UHFFFAOYSA-N selumetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1Cl CYOHGALHFOKKQC-UHFFFAOYSA-N 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 235000021391 short chain fatty acids Nutrition 0.000 description 1
- 150000004666 short chain fatty acids Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- 206010062113 splenic marginal zone lymphoma Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 108010087686 src-Family Kinases Proteins 0.000 description 1
- 102000009076 src-Family Kinases Human genes 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000008409 synovial inflammation Effects 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- FEYLUKDSKVSMSZ-UHFFFAOYSA-N tert-butyl n-(4-aminocyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(N)CC1 FEYLUKDSKVSMSZ-UHFFFAOYSA-N 0.000 description 1
- AKVIZYGPJIWKOS-DTWKUNHWSA-N tert-butyl n-[(1r,2s)-2-aminocyclohexyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N AKVIZYGPJIWKOS-DTWKUNHWSA-N 0.000 description 1
- OBSACSBMTRJNPH-BDAKNGLRSA-N tert-butyl n-[(1s,3r)-3-aminocyclohexyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](N)C1 OBSACSBMTRJNPH-BDAKNGLRSA-N 0.000 description 1
- MEQMNSLPRLOIMT-UHFFFAOYSA-N tert-butyl tert-butylcarbamoyl carbonate tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate Chemical compound C(OC(NC(C)(C)C)=O)(OC(C)(C)C)=O.C(OC(=O)OC(C)(C)C)(OC(C)(C)C)=O MEQMNSLPRLOIMT-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000009959 type I hypersensitivity Effects 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 208000002003 vulvitis Diseases 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 1
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 1
Abstract
The present disclosure is directed to compounds of Formula (I) as Bruton's kinase inhibitors and their preparation, as well as compositions comprising compounds of Formula (I).
Description
(12) Granted patent specificaon (19) NZ (11) 742484 (13) B2 (47) Publicaon date: 2022.01.28 (54) POLYCYCLIC COMPOUNDS AS INHIBITORS OF BRUTON'S TYROSINE KINASE (51) Internaonal Patent Classificaon(s): C07D 495/16 C07D 519/00 A61K 31/519 A61P 35/00 A61P 37/00 A61P 19/00 (22) Filing date: (73) Owner(s): 2016.12.09 JANSSEN PHARMACEUTICA NV POLYCYCLIC COMPOUNDS AS INHIBITORS OF BRUTON'S TYROSINE KINASE TECHNICAL FIELD The present disclosure is directed to small molecule tyrosine kinase inhibitors.
BACKGROUND Rheumatoid arthritis ("RA") is a chronic, autoimmune, inflammatory disorder that affects the lining of the joints, causing painful swelling that can result in bone erosion and joint deformation. RA presents a significant societal impact – it has a relatively high prevalence (about 1% of the United States population suffers from RA), produces irreversible joint damage, and has a widespread occurrence of co-morbities. While many patients benefit from currently marketed biologic and small molecule medicines, most patients still suffered from the chronic pain and inflammation of the disease.
Cancer, in particular mantle cell lymphoma, chronic lymphocytic leukemia, macroglobulinemia, and multiple myeloma, continues to afflict patients. Alternative, effective treatments of cancer are still needed.
Human Bruton’s tyrosine kinase ("Btk") is a ~76 kDa protein belonging to the Tec family of non-receptor tyrosine kinases. Tec kinases form the second largest family of cytoplasmic tyrosine kinases in mammalian cells, which consists of four other members in addition to BTK: the eponymous kinase TEC, ITK, TXK/RLK and BMX. Tec kinases are evolutionarily conserved throughout vertebrates. They are related to, but structurally distinct from, the larger Src and Syk kinase families. Tec family proteins are abundantly expressed in hematopoietic tissues and play important roles in the growth and differentiation of blood and endothelial cells in mammals.
Based upon Btk expression from IHC studies described in the art, Btk inhibition has the potential to modulate biology associated with B cells, macrophages, mast cells, osteoclasts, and platelet microparticles. Corneth, O.B., et al. Curr. Top. Microbiol. Immunol. BTK Signaling in B Cell Differentiation and Autoimmunity. 2015 Sept. 5. The role of B cells in RA is supported by the therapeutic benefit exhibited in the clinic upon B cell depletion with Rituximab™. Since auto-reactive antibodies play such a critical role in synovial inflammation, therapeutic modulation of the B cell compartment is an attractive mechanism to treat early RA and potentially modulate disease at the earliest stages. B cell depletion in murine models such as collagen-induced arthritis (CIA) prevents arthritis development. Svensson, et al. (1998) B cell- deficient mice do not develop type II collagen-induced arthritis (CIA). Clin Exp Immunol 111, 521-526.
SUMMARY In a first aspect the present invention provides a compound of Formula (I): wherein R is H; R is selected from the group consisting of: CH -cyclohexyl, wherein the cyclohexyl is optionally substituted with OH; 3-hydroxyadamantanyl; and C cycloalkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: OH, 6 7 8 8 halogen, C alkyl, C haloalkyl, OC alkyl, CN, NR R , NR -C(O)H, NR -C(O)-C 1-6 1-6 1-6 1- 8 8 8 8 alkyl, NR -C(O)-C haloalkyl, NR -C(O)-O-C alkyl, NR -C(O)-C alk-OH, NR - 6 1-6 1-6 1-6 6 7 8 3 4 5 C(O)-C alk-NR R , and NR -C(O)-C(R )=CR (R ); wherein R is selected from the group consisting of: H, CN, halogen, C haloalkyl, and C alkyl; R and R are each independently selected from the group consisting of: H; C alk-NR R ; C alk-O-C alkyl; C cycloalkyl; heterocycloalkyl 6 1-6 1-6 3-6 optionally substituted with C alkyl; and -linker-PEG-Biotin; R and R are each independently selected from the group consisting of: H, C alkyl, C(O)H, and CN; and R is H; or R and R , together with the nitrogen atom to which they are attached, form a pyrrolidinyl ring 6 7 6 7 optionally substituted with NR R , wherein R and R are each independently selected from the group consisting of H; C alkyl; NR -C(O)-C alkyl; and NR -C(O)- 1-6 1-6 3 4 5 3 4 5 C(R )=CR (R ), wherein R is H or CN; R is H; and R is H or cyclopropyl; A is selected from the group consisting of: pyridyl; phenyl; pyrimidinyl; pyrazinyl; pyridin- 2(1H)-one; and pyridazinyl; wherein the A is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halogen, C alkyl, C haloalkyl, and OC alkyl; 1-6 1-6 E is selected from the group consisting of: O, a bond, and CH ; G is selected from the group consisting of: H; halogen; C alkyl; C haloalkyl; NH(C alkyl); 1-6 1-6 1-6 C cycloalkyl; phenyl; pyrimidinyl; pyridyl; pyridazinyl; pyridin-2(1H)-one; heterocycloalkyl that contains an oxygen heteroatom; and phenyl-CH -O-phenyl, wherein the -O-phenyl is substituted with CN; wherein the phenyl; pyridyl; pyridazinyl; and pyridin-2(1H)-one is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halogen, C alkyl, C haloalkyl, 1-6 1-6 OC haloalkyl, and OC alkyl; 1-6 1-6 a stereoisomer thereof; an isotopic variant thereof; or a pharmaceutically acceptable salt thereof.
In a second aspect the present invention provides a compound selected from the group consisting of: N-((1S,4S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Hydroxycyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(Dimethylamino)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Hydroxycyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,4R)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,4R)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,4R)Methoxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)((E)Cyanocyclopropylacrylamido)cyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1S,2S)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)-N-((1R,2R)(methylamino)cyclopentyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Cyanamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1R,2R)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,2RS)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-Cyclopentyl(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2R)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1r,3s,5R,7S)Hydroxyadamantanyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)-N-(2-(methylamino)cyclohexyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1R,2S)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1R,2S)propionamidocyclohexyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,2RS)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1S,2R)propionamidocyclohexyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1S,2S)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)-N-((1S,2S)(methylamino)cyclopentyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)-N-((1S,2R)(methylamino)cyclohexyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1R,2R)propionamidocyclohexyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Formamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acrylamidocyclopentyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2R)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1S,2S)propionamidocyclohexyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Hydroxycyclopentyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)-N-(4-(methylamino)cyclohexyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1S,4S)propionamidocyclohexyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)oxo-N-((1S,3R)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)-N-((1S,3R)(2-(methylamino)acetamido)cyclopentyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)(2-Aminoacetamido)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)((E)(Dimethylamino)butenamido)cyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; -(2-Methylphenoxyphenyl)-N-((1S,4S)((E)(methylamino)but enamido)cyclohexyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1S,4S)((E)Aminobutenamido)cyclohexyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)-N-((1S)(methylamino)cyclopentyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-Cyclopentyl(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-Cyclopentyl(*R)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,4S)Hydroxycyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Hydroxycyclohexyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,4R)Hydroxycyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,4R)Hydroxycyclohexyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxyphenyl)oxo-N-((1S,3R)propionamidocyclopentyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)((*E)Cyanocyclopropylacrylamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1S,4S)((*E)Cyanocyclopropylacrylamido)cyclohexyl)(*R)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,2R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxyphenyl)oxo-N-((1S,4S)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*R)-(2-Methylphenoxyphenyl)oxo-N-((1S,4S)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acetamidocyclohexyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-(rac-(1,3-cis)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,2R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,4S)(Dimethylamino)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)(Dimethylamino)cyclohexyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)(2-(dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; -(*S)-(2-Methylphenoxyphenyl)-N-((1S,3R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2S)acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -([1,1'-Biphenyl]yl)-N-((1 R,2 S)acrylamidocyclohexyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,3RS)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)(4-isopropoxymethylphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; -(*S)-(2-Methylphenoxyphenyl)-N-((1R,2R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2R)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acrylamidocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxyphenyl)-N-((1R,2S)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,2S)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1S,2R)Acrylamidocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxyphenyl)-N-((1R,2S)(2-(methylamino)acetamido)cyclohexyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,2R)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,2S)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; -(*S)-(2-Methylphenoxyphenyl)-N-((1S,2S)(2-(methylamino)acetamido)cyclopentyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(3-chlorophenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2S)Hydroxycyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 5-([1,1'-Biphenyl]yl)-N-((1R,2S)aminocyclohexyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,3S)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; -([1,1'-Biphenyl]yl)-N-((1R,2R)hydroxycyclopentyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-(trans-(1R,4R)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; trans-N-((1RS,3RS)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; tert-Butyl ((1R,3S)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclopentyl)carbamate; tert-Butyl trans-((1R,4R)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclohexyl)carbamate; N-((1-Hydroxycyclohexyl)methyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,3R)((E)(Dimethylamino)butenamido)cyclopentyl)(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; -(*S)-(2-Methylphenoxyphenyl)-N-((1S,2R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,3R)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(4-isopropoxymethylphenyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 4-Oxo(2-phenylpyridinyl)-N-((1S,2R)propionamidocyclopentyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(4-isopropoxymethylphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -(4-Isopropoxymethylphenyl)-N-((1S,3R)(2-(methylamino)acetamido)cyclopentyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; tert-Butyl ((1S,4S)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclohexyl)carbamate; N-((1S,3R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenylpyrimidinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-cyclobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-cyclobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(4-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)(3-chlorophenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -([1,1'-Biphenyl]yl)-N-((1R,2S)acrylamidocyclopentyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenoxypyrazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenylpyridazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-cyclobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-isopropoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((tetrahydro-2H-pyran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-isopropylpyridinyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(3-Chloropropanamido)cyclopentyl)(*S)-(4-methylphenoxypyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-isopropoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,3RS)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,3RS)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-cyclobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-isopropoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-(cyclopentyloxy)methylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)-N-((1R,3R)(2-(methylamino)acetamido)cyclopentyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(4-methylphenoxypyridinyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(4-((tetrahydro-2H-pyranyl)oxy)phenyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)(2-Aminoacetamido)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-cyclobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)(2-(Dimethylamino)acetamido)cyclopentyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)-N-((1S,3S)(2-(methylamino)acetamido)cyclopentyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; -(3-Chlorophenoxyphenyl)-N-((1S,3R)((E)(dimethylamino)but enamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; -([1,1'-Biphenyl]yl)-N-((1R,2S)aminocyclopentyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxyphenyl)-N-((1R,3S)(2-(methylamino)acetamido)cyclohexyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,3S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acetamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-cyclobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(4-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Hydroxycyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(2-isopropylpyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(4-isopropoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*S)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S, S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(6-phenylpyridazinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(6-phenylpyrimidinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(5-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(2-(Methylamino)acetamido)cyclopentyl)oxo(2-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(2-methyl((tetrahydro-2H-pyranyl)oxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(4-((tetrahydro-2H-pyranyl)oxy)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; racemic cisN-((1RS,3RS)Aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; racemic transN-((1RS,3RS)Aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,2RS)Acrylamidocyclopentyl)(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,3RS)Aminocyclopentyl)(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,3RS)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyrazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)acrylamidocyclopentyl)oxo(5-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(*S)-(4-(pyridinyloxy)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((tetrahydro-2H-pyran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridazinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*S,3*S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(5-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*S,3*S)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(5-phenoxypyrazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*S,3*S)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -([2,3'-Bipyridin]yl)-N-((1R,2S)acrylamidocyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,2*S)Aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenylpyridazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*S,3*S)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -([2,2'-Bipyridin]yl)-N-((1R,2S)acrylamidocyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -([2,3'-Bipyridin]yl)-N-((1R,2R)acrylamidocyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*S)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(6-(isopropylamino)methylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*R)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*R)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*R)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(2-isopropylpyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(2-isopropylpyridinyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-(cyclopentyloxy)methylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -([2,2'-Bipyridin]yl)-N-((1R,2R)acrylamidocyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2S)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*R)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2S)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((tetrahydro-2H-pyran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(5-phenylpyridazinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2R)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3S)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2R)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((2-methylpyridinyl)oxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6-methylpyridinyl)oxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-((6-methylpyridinyl)oxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-((6-methylpyridinyl)oxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-((2-methylpyridinyl)oxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-cyclobutylpyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(2-cyclobutylpyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxyphenyl)oxo-N-((1R,2S)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,2S)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(((S)-tetrahydrofuran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6-methylpyridinyl)oxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3S)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(((R)-tetrahydrofuran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(4-(pyridazinyloxy)phenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3R)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3R)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Hydroxycyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 4-Oxo(4-phenoxyphenyl)-N-((1R,2S)propionamidocyclopentyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3S)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(2-methyl(pyridinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3S)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclopentyl)(*S)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(2-methyl(pyridazinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(4-(pyridazinyloxy)phenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1S,3S)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acetamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1S,3R)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3R)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; (S)(2-Methylphenoxyphenyl)(3-(methylamino)pyrrolidinecarbonyl)-3Hthia- 3,5,8-triazaacenaphthylen-4(5H)-one; (S)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)propionamide; (S)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)acetamide; (S)(3-Aminopyrrolidinecarbonyl)(2-methylphenoxyphenyl)-3Hthia-3,5,8- triazaacenaphthylen-4(5H)-one; (S)(3-(Dimethylamino)pyrrolidinecarbonyl)(2-methylphenoxyphenyl)-3Hthia- 3,5,8-triazaacenaphthylen-4(5H)-one; N-((1R,3R)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3R)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl(pyridazinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl(pyridazinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Aminocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1r,4r)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; (S)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide; (R)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide; (S,E)Cyanocyclopropyl-N-(1-(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide; (R,E)Cyanocyclopropyl-N-(1-(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(4-(pyridinyloxy)phenyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(3-isopropylphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(4-(pyridinyloxy)phenyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxyphenyl)-N-((1S,2R)(2-(methylamino)acetamido)cyclohexyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2R)(2-(methylamino)acetamido)cyclohexyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1S,2R)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(4-isopropoxymethylphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclopentyl)(4-isopropoxymethylphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(3-isopropylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2R)Hydroxycyclopentyl)(4-isopropoxymethylphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,2S)Acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(4-(3-((2-Cyanophenoxy)methyl)phenoxy)methylphenyl)-N-cyclohexyloxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-(5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)methylphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenyl)cyclopropanecarboxamide; N-Cyclohexyl(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-Cyclohexyloxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N1-((E)(((1S,2R)(5-(6-isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamido)cyclopentyl)amino)oxobutenyl)-N5- (15-oxo((3aS,4S,6aR)oxohexahydro-1H-thieno[3,4-d]imidazolyl)-4,7,10- trioxaazanonadecyl)glutaramide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyrimidinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)((E)Cyanocyclopropylacrylamido)cyclopentyl)(*S)-(6-isobutyl methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,2S)Acrylamidocyclohexyl)(4-methyl(pyridazinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methyloxo(pyridazinyl)-1,6- dihydropyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(4-methyloxo(pyridazinyl)-1,6- dihydropyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridazinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(2-methyl(pyridazinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridazinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((2-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridazinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(6'-methyloxo-2H-[1,2'-bipyridin]-5'-yl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(5-((6-methylpyridinyl)oxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(5-((6-methylpyridinyl)oxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((6-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyrimidinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyrimidinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyrimidinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((6-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridinyloxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((2-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide ; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridinyloxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(5-((2-methylpyridinyl)oxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((2-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((2-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl(pyrimidinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl(pyrimidinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl(pyridinyloxy)phenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl(pyridinyloxy)phenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)((E)Cyano(3-methyloxetanyl)acrylamido)cyclopentyl)(*S)-(6- isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide; N-((1R,2S)((E)Cyanoethoxymethylpentenamido)cyclopentyl)(*S)-(6- isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide; N-((1R,2S)acrylamidocyclopentyl)oxo(4-(pyrimidinyloxy)phenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; an isotopic variant thereof, or a pharmaceutically acceptable salt thereof.
In a third aspect the present invention provides a pharmaceutical composition comprising: an effective amount of at least one compound according to the first aspect and at least one pharmaceutically acceptable excipient.
In a fourth aspect the present invention provides a pharmaceutical composition comprising an effective amount of at least one compound of the second aspect and at least one pharmaceutically acceptable excipient.
In a fifth aspect the present invention provides a use of at least one compound of the first aspect, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by Bruton’s tyrosine kinase activity.
In a sixth aspect the present invention provides a use of at least one compound of the first aspect, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject in need thereof.
In a seventh aspect the present invention provides a use of at least one compound of the first aspect, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating systemic lupus erythematosus in a subject in need thereof.
In an eighth aspect the present invention provides a use of at least one compound of the first aspect, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a pemphigus disorder or a pemphigoid disorder in a subject in need thereof.
In a ninth aspect the present invention proivides a use of at least one compound of the first aspect, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating rheumatoid arthritis in a subject in need thereof.
In a tenth aspect the present invention provides a compound having the structure of Formula (IIc), a stereoisomer, isotopic variant, or pharmaceutically acceptable salt thereof, (IIc) wherein G-E-A is selected from the group consisting of: and ; where G is selected from the group consisting of: C alkyl, phenyl, pyrimidinyl, pyridyl, pyridyl substituted with CH , and C cycloalkyl; and R is H or CH ; 3 3-6 3 Ring B is selected from the group consisting of: and R is selected from the group consisting of: OH, OCH , NH , NH(CH ), N(CH ) , NH(CO - 3 2 3 3 2 2 tert-butyl), NH(C=O)C alkyl, NH(C=O)CH=CH , NH(C=O)CH NH , 1-3 2 2 2 NH(C=O)CH NH(CH ), NH(C=O)CH N(CH ) , and NH(C=O)CH=CHCH N(CH ) . 2 3 2 3 2 2 3 2 In an eleventh aspect the present invention provides a method of making a compound of the first aspect, or a pharmaceutically acceptable salt thereof, comprising the method steps set out in the Examples.
Also described are compounds of Formula (I): (I) wherein R is H or C alkyl; R is selected from the group consisting of:C alk-cycloalkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: NR -C(O)- 3 4 5 6 7 C(R )=CR (R ); NR R ; OH; CN; oxo; O-C alkyl; halogen; C alkyl; C haloalkyl; 1-6 1-6 1-6 C alk-OH; C cycloalkyl; C alkaryl; SO C alkyl; SO C alkenyl; NR -C(O)-C 1-6 3-6 1-6 2 1-6 2 2-6 1- 6 7 8 8 8 8 alk-NR R ; NR -C(O)-C alkyl; NR -C(O)-O-C alkyl; NR -C(O)-C cycloalkyl; NR - 6 1-6 1-6 3-6 8 8 8 C(O)H; NR -C(O)-C cycloalkyl; NR -C(O)-C haloalkyl; NR -C(O)-alkynyl; 3-6 1-6 8 8 8 NR -C(O)-C aryl; NR -C(O)-heteroaryl; NR -C(O)-C alk-CN; 6-10 1-6 NR -C(O)-C alk-OH; NR -C(O)-C alk-SO -C alkyl; 1-6 1-6 2 1-6 8 6 7 8 NR -C(O)-C alk-NR R ; NR -C(O)-C alk-O-C alkyl wherein the 1-6 1-6 1-6 C alk is optionally substituted with OH, OC alkyl, or NR R ; and 1-6 1-6 NR -C(O)-C alk-heterocycloalkyl wherein the C alk is optionally substituted with oxo 0-6 0-6 and the heterocycloalkyl is optionally substituted with C alkyl; wherein R and R are each independently selected from the group consisting of: H; C alkyl; C cycloalkyl; C(O)H;and CN; 1-6 3-6 R is selected from the group consisting of: H, CN, halogen, C haloalkyl, and C alkyl; R and R are each independently selected from the group consisting of: H; C alk-NR R ; C alk-OH; C alk-C cycloalkyl optionally substituted with 6 1-6 0-6 3-6 C alkyl; halogen; C alkyl; OC alkyl; C alk-O-C alkyl; 1-6 1-6 1-6 1-6 1-6 C alk-NH-C alk-O-C alkyl; C alk-heterocycloalkyl optionally 1-6 0-6 1-6 0-6 substituted with C(O)C alkyl or C alkyl; C alk-NHSO -C alkyl; 1-6 1-6 1-6 2 1-6 C alk-SO -C alkyl; -NHC(O)-C alkyl; and -linker-PEG-Biotin; 1-6 2 1-6 1-6 R is H or C alkyl; or R and R , together with the nitrogen atom to which they are attached, form a pyrrolidinyl ring 6 7 6 7 optionally substituted with NR R , wherein R and R are each independently selected from the group consisting of H; C alkyl; NR -C(O)-C alkyl; and NR -C(O)- 1-6 1-6 3 4 5 8 3 4 5 C(R )=CR (R ), wherein R is H; R is H or CN; R is H; and R is H or cyclopropyl A is selected from the group consisting of: a bond; pyridyl; phenyl; napthalenyl; pyrimidinyl; pyrazinyl; pyridazinyl; benzo[d][1,3]dioxolyl optionally substituted with halogen; benzothiophenyl; and pyrazolyl; wherein the A is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: C alkyl; halogen; SF ; OC alkyl; C(O)-C alkyl; and C haloalkyl; 1-6 1-6 1-6 E is selected from the group consisting of: O, a bond, C(O)-NH, CH , and CH -O; G is selected from the group consisting of: H; C cycloalkyl; phenyl; thiophenyl; C alkyl; 3-6 1-6 pyrimidinyl; pyridyl; pyridazinyl; benzofuranyl; C haloalkyl; heterocycloalkyl that contains an oxygen heteroatom; phenyl-CH -O-phenyl; C alk-O-C alkyl; NR R ; 2 1-6 1-6 SO C alkyl; and OH; wherein the phenyl; pyridyl; pyridazinyl; benzofuranyl; or 2 1-6 thiophenyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halogen; C alkyl; C haloalkyl; OC haloalkyl; 1-6 1-6 1-6 C cycloalkyl; OC alkyl; CN; OH; C alk-O-C alkyl; C(O)-NR R ; and C(O)-C 3-6 1-6 1-6 1-6 1- alkyl; and stereoisomers and isotopic variants thereof; and pharmaceutically acceptable salts thereof.
Compositions comprising compounds of Formula (I) are also described. Methods of using compounds of Formula (I) are also within the scope of the disclosure.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS The disclosure may be more fully appreciated by reference to the following description, including the following glossary of terms and the concluding examples. It is to be appreciated that certain features of the disclosed compositions and methods which are, for clarity, described herein in the context of separate aspects, may also be provided in combination in a single aspect.
Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.
The term "alkyl," when used alone or as part of a substituent group, refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms ("C "), preferably 1 to 6 carbons 1-12 atoms ("C "), in the chain. Examples of alkyl groups include methyl (Me, C alkyl) ethyl (Et, 1-6 1 C alkyl), n-propyl (C alkyl), isopropyl (C alkyl), butyl (C alkyl), isobutyl (C alkyl), sec-butyl 2 3 3 4 4 (C alkyl), tert-butyl (C alkyl), pentyl (C alkyl), isopentyl (C alkyl), tert-pentyl (C alkyl), hexyl 4 4 5 5 5 (C alkyl), isohexyl (C alkyl), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
When a range of carbon atoms is used herein, for example, C , all ranges, as well as individual numbers of carbon atoms are encompassed. For example, "C " includes C , C , 1-3 1-3 1-2 C , C , C , and C . 2-3 1 2 3 The term "C alk" refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, CH , CH(CH ), CH(CH )-CH , and C(CH ) -. The term "-C alk-" refers 2 3 3 2 3 2 0 to a bond. In some aspects, the C alk can be substituted with an oxo group or an OH group.
The term "alkenyl," when used alone or as part of a substituent group, refers to straight and branched carbon chains having from 2 to 12 carbon atoms ("C "), preferably 2 to 6 carbon 2-12 atoms ("C "), wherein the carbon chain contains at least one, preferably one to two, more preferably one double bond. For example, alkenyl moieties include, but are not limited to allyl, 1-propenyl, 1-butenyl, propa-1,2-dienyl, and the like.
The term "alkynyl," when used alone or as part of a substituent group, refers to straight and branched carbon chains having from 2 to 12 carbon atoms ("C "), preferably 2 to 6 carbon 2-12 atoms ("C "), wherein the carbon chain contains at least one, preferably one to two, more preferably one triple bond. For example, alkynyl moieties include, but are not limited to vinyl, 1- propynyl, 2-butynyl, and the like.
The term "aryl" refers to carbocylic aromatic groups having from 6 to 10 carbon atoms ("C ") such as phenyl, naphthyl, and the like. 6-10 The term "cycloalkyl" refers to monocyclic, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms ("C "), preferably from 3 to 6 carbon atoms ("C "). Examples of 3-10 3-6 cycloalkyl groups include, for example, cyclopropyl (C ), cyclobutyl (C ), cyclopentyl (C ), 3 4 5 cyclohexyl (C ), 1-methylcyclopropyl (C ), 2-methylcyclopentyl (C ), adamantanyl (C ) and the 6 4 4 10 like.
The term "heterocycloalkyl" refers to any five to ten membered monocyclic or bicyclic, saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Examples of suitable heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahyofuranyl, tetrahydropyranyl, piperazinyl, hexahydro-5H-[1,4]dioxino[2,3-c]pyrrolyl, benzo[d][1,3]dioxolyl, and the like.
The term "heteroaryl" refers to a mono-or bicyclic aromoatic ring structure including carbon atoms as well as up to four heteroatoms selected from nitrogen, oxygen, and sulfur.
Heteroaryl rings can include a total of 5, 6, 9, or 10 ring atoms ("C "). Examples of heteroaryl -10 groups include but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the like.
The term "halogen" represents chlorine, fluorine, bromine, or iodine. The term "halo" represents chloro, fluoro, bromo, or iodo.
The term "haloalkyl" refers to an alkyl moiety wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms. One exemplary substitutent is fluoro.
Preferred haloalkyl groups of the disclosure include trihalogenated alkyl groups such as trifluoromethyl groups.
The term "oxo" refers to a =O moiety, wherein two hydrogens from the same carbon atom have be replaced with a carbonyl. For example, an oxo-substituted pyrrolidinyl moiety could be a pyrrolidinone moiety or a pyrrolidinone moiety.
The term "benzofuranyl" represents the following moiety: The benzofuranyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, 6-, or 7- carbon atoms.
The term "benzo[d][1,3]dioxolyl" represents the following moiety: The benzo[d][1,3]dioxolyl moiety can be attached through any one of the 2-, 4-, 5-, 6-, or 7- carbon atoms. In those aspects wherein the" benzo[d][1,3]dioxolyl moiety is substituted with halogen," the following moieties are preferred: The term "benzothiophenyl" represents the following moiety: The benzothiophenyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, 6-, or 7- carbon atoms.
The term "phenyl" represents the following moiety: The phenyl moiety can be attached through any of the carbon atoms.
The term "napthalenyl" (i.e., naphthyl) represents the following moiety: The naphthalenyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-position carbon atoms.
The term "pyridyl" represents the following moiety: The pyridyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, or 6-position carbon atoms.
The term "pyrimidinyl" represents the following moiety: The pyrimidinyl moiety can be attached through any one of the 2-, 4-, 5-, or 6-position carbon atoms.
The term "pyrazinyl" represents the following moiety: The pyrazinyl moiety can be attached through any one of the 2-, 3-, 5-, or 6-position carbon atoms.
The term "pyridazinyl" represents the following moiety: The pyridazinyl moiety can be attached through any one of the 3-, 4-, 5-, or 6-position carbon atoms.
The term "pyrazolyl" represents the following moiety: The pyrazolyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, or 5-position carbon atoms.
The term "thiophenyl" represents the following moiety: The thiophenyl moiety can be attached through any one of the 2-, 3-, 4-, or 5-position carbon atoms.
The term "linker-PEG-Biotin" refers to a moiety comprising –linker-PEG-CH -NH-biotinyl. Compounds of the disclosure that include a linker-PEG-Biotin moiety can be used according to any of the methods described herein. Alternatively, compounds of the disclosure that include a linker-PEG-Biotin moiety can be used as diagnostic probes according to methods known in the art. Preferred linkers are known in the art, with the linker – CH -NHC(O)-(CH ) -C(O)-NH-CH - being particularly preferred. Preferred PEG moieties 2 2 3 2 include at least two or three repeating –CH -CH -O- moieties. A preferred linker-PEG-Biotin moiety is The term "piperidinyl" represents the following moiety: When the piperidinyl moiety is a substituent, it can be attached through any one of the 1-, 2-, 3-, 4-, 5-, or 6-position atoms, as permitted.
The term "pyrrolidinyl" represents the following moiety: When the piperidinyl moiety is a substituent, it can be attached through any one of the 1-, 2-, 3-, 4-, or 5- position atoms, as permitted.
The term "oxazepanyl" refers to a 7-membered heterocycloalkyl moiety having one ring nitrogen atom and one ring oxygen atom. Examples include 1,3-oxazepanyl and 1,4-oxazepanyl moieties 1,3-oxazepanyl 1,4-oxazepanyl When the oxazepanyl moiety is a substituent, it can be attached through any ring carbon atom or through the nitrogen atom, as permitted The term "aziridinyl" represents a 3-membered heterocycloalkyl moiety having one ring nitrogen. When the aziridinyl moiety is a substituent, it can be attached through any ring carbon atom or through the nitrogen atom, as permitted.
The term "azetidinyl" represents a 4-membered heterocycloalkyl moiety having one ring nitrogen. When the azetidinyl moiety is a substituent, it can be attached through any carbon atom or through the nitrogen atom, as permitted.
The term "azepanyl" represents a 7-membered heterocycloalkyl moiety having one ring nitrogen. When the azepanyl moiety is a substitutent, it can be attached through any carbon atom or through the nitrogen atom, as permitted The term "quinuclidinyl" represents the following moiety: Within the disclosure, when the quinuclidinyl moiety is a substituent, it can be attached to the compound of Formula (I) through any one of the ring carbon atoms.
The term "imidazolidinyl" represents the following moiety: When the imidazolidinyl moiety is a substituent, it can be attached through any one of the 1-, 2-, 3-, 4-, or 5-position atoms., as permitted The term "piperazinyl" represents the following moiety: When the piperazinyl moiety is a substituent, it can be attached through any one of the 1-, 2-, 3-, 4-, 5-, or 6-position atoms, as permitted The term "morpholinyl" represents the following moiety: When the morpholinyl moiety is a substituent, it can be attached through any one of the 2-, 3-, 4-, 5-, or 6-position atoms, as permitted.
The term "tetrahydropyranyl" represents a 6-membered heterocycloalkyl moiety having one ring oxygen. The tetrahydropyranyl moiety can be attached through any carbon atom on the ring.
The term "tetrahydrofuranyl" represents a 5-membered heterocycloalkyl moiety having one ring oxygen. The tetrahydrofuranyl moiety can be attached through any carbon atom on the ring.
As used herein, the term "compound(s) of Formula (I)" includes those compounds of "Formula (I)," as well as compounds of any of the Formula (I) subgenera.
"Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
"Pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-octenecarboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
"Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient or carrier with which a compound of the disclosure is administered. A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
"Subject" includes humans. The terms "human," "patient," and "subject" are used interchangeably herein.
"Treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.
"Compounds of the present disclosure," and equivalent expressions, are meant to embrace compounds of the Formula (I) as described herein, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, where the context so permits.
Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
As used herein, the term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an "isotopic variant" of a compound can be radiolabeled, that is, contain one or more non- 2 13 radioactive isotopes, such as for example, deuterium ( H or D), carbon-13 ( C), nitrogen-15 ( N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be 2 13 15 H/D, any carbon may be C, or any nitrogen may be N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the disclosure may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.
Radiolabeled compounds of the disclosure can be used in diagnostic methods such as Single- photon emission computed tomography (SPECT). The radioactive isotopes tritium, i.e. H, and carbon-14, i.e. C, are particularly useful for their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting 11 18 15 13 isotopes, such as C, F, O and N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
All isotopic variants of the compounds of the disclosure, radioactive or not, are intended to be encompassed within the scope of the disclosure.
It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers," for example, diastereomers, enantiomers, and atropisomers.
Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R-and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture." "Atropisomers" refer to stereoisomers that arise because of hindered rotation around a single bond.
"Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H).
For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci-and nitro-forms of phenyl nitromethane, that are likewise formed by treatment with acid or base.
Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
The compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)-or (S)-stereoisomers or as mixtures thereof.
Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. Within the present disclosure, any open valency appearing on a carbon, oxygen, or nitrogen atom in any structure described herein indicates the presence of a hydrogen atom. Where a chiral center exists in a structure, but no specific stereochemistry is shown for that center, both enantiomers, separately or as a mixture, are encompassed by that structure. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
The present disclosure is directed to compounds of Formula (I): wherein R is H or C alkyl; R is selected from the group consisting of: C alk-cycloalkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: NR -C(O)- 3 4 5 6 7 C(R )=CR (R ); NR R ; OH; CN; oxo; O-C alkyl; halogen; C alkyl; C haloalkyl; 1-6 1-6 1-6 C alk-OH; C cycloalkyl; C alkaryl; SO C alkyl; SO C alkenyl; NR -C(O)-C 1-6 3-6 1-6 2 1-6 2 2-6 1- 6 7 8 8 8 8 alk-NR R ; NR -C(O)-C alkyl; NR -C(O)-O-C alkyl; NR -C(O)-C cycloalkyl; NR - 6 1-6 1-6 3-6 8 8 8 C(O)H; NR -C(O)-C cycloalkyl; NR -C(O)-C haloalkyl; NR -C(O)-alkynyl; 3-6 1-6 8 8 8 8 NR -C(O)-C aryl; NR -C(O)-heteroaryl; NR -C(O)-C alk-CN; NR -C(O)-C alk- 6-10 1-6 1-6 8 8 8 6 7 OH; NR -C(O)-C alk-SO -C alkyl; NR -C(O)-O-C alkyl; NR -C(O)-C alk-NR R ; 1-6 2 1-6 1-6 1-6 NR -C(O)-C alk-O-C alkyl, wherein the C alk- is optionally substituted with a 1-6 1-6 1-6 member selected from the group consisting of: OH, OC alkyl, and NR R ; and NR -C(O)-C alk-heterocycloalkyl wherein the C alk is optionally substituted with oxo 0-6 0-6 and the heterocycloalkyl is optionally substituted with C alkyl; wherein R and R are each independently selected from the group consisting of: H; C alkyl, C cycloalkyl, C(O)H, and CN; 1-6 3-6 R is selected from the group consisting of: H, CN, halogen, C haloalkyl, and C alkyl; R and R are each independently selected from the group consisting of: H; C alk-NR R ; C alk-OH; C alk-C cycloalkyl optionally substituted with 6 1-6 0-6 3-6 C alkyl; halogen; C alkyl; OC alkyl; NR R ; C alk-O-C alkyl; 1-6 1-6 1-6 1-6 1-6 C alk-NH-C alk-O-C alkyl; C alk-heterocycloalkyl optionally 1-6 0-6 1-6 0-6 substituted with C(O)C alkyl or C alkyl; C alk-NHSO -C alkyl; 1-6 1-6 1-6 2 1-6 C alk-SO -C alkyl; NHC(O)-C alkyl; and linker-PEG-Biotin; 1-6 2 1-6 1-6 R is H or C alkyl; A is selected from the group consisting of: a bond; pyridyl; phenyl; napthalenyl; pyrimidinyl; pyrazinyl; pyridazinyl; benzo[d][1,3]dioxolyl optionally substituted with halogen; benzothiophenyl; and pyrazolyl; optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: C alkyl; halogen; SF ; OC alkyl; 1-6 5 1-6 C(O)-C alkyl; and C haloalkyl; 1-6 1-6 E is selected from the group consisting of: O, a bond, C(O)-NH, CH , and CH -O; G is selected from the group consisting of: H; C cycloalkyl; phenyl; thiophenyl; C alkyl; 3-6 1-6 pyrimidinyl; pyridyl; pyridazinyl; benzofuranyl; C haloalkyl; heterocycloalkyl that contains an oxygen heteroatom; phenyl-CH -O-phenyl; C alk-O-C alkyl; NR R ; 2 1-6 1-6 SO C alkyl; and OH; wherein the phenyl, pyridyl, pyridazinyl, benzofuranyl, or 2 1-6 thiophenyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halogen; C alkyl, C haloalkyl, OC haloalkyl, 1-6 1-6 1-6 C cycloalkyl, OC alkyl, CN, OH, C alk-O-C alkyl, C(O)-NR R , and C(O)-C 3-6 1-6 1-6 1-6 1- alkyl; and stereoisomers and isotopic variants thereof; and pharmaceutically acceptable salts thereof.
The present disclosure is also directed to compounds of Formula (I): wherein R is H or C alkyl; R and R , together with the nitrogen atom to which they are attached, form an optionally substituted ring that is a pyrrolidinyl ring or a piperidinyl ring; wherein the pyrrolidinyl ring or piperidinyl ring formed from the joining of R and R are optionally substituted with 1, 2, or 3 substituents each independently selected from the 8 3 4 5 6 7 group consisting of: NR -C(O)-C(R )=CR (R ); NR R ; OH; CN; oxo; O-C alkyl; halogen; C alkyl; C haloalkyl; C alk-OH; C cycloalkyl; C alkaryl; SO C alkyl; 1-6 1-6 1-6 3-6 1-6 2 1-6 8 6 7 8 8 SO C alkenyl; -NR -C(O)-C alk-NR R ; NR -C(O)-C alkyl; NR -C(O)-O-C alkyl; 2 2-6 1-6 1-6 1-6 8 8 8 8 NR -C(O)-C cycloalkyl; NR -C(O)H; NR -C(O)-C alkyl; NR -C(O)-C 3-6 1-6 3- 8 8 8 8 cycloalkyl;NR -C(O)-C haloalkyl; NR -C(O)-alkynyl; NR -C(O)-C aryl; NR -C(O)- 6 1-6 6-10 8 8 8 heteroaryl; NR -C(O)-C alk-CN; NR -C(O)-C alk-OH; NR -C(O)-C alk-SO -C 1-6 1-6 1-6 2 1- 8 8 6 7 8 alkyl; NR -C(O)-O-C alkyl; NR -C(O)-C alk-NR R ; NR -C(O)-C alk-O-C alkyl 6 1-6 1-6 1-6 1-6 wherein the C alk- is optionally substituted with OH, OC alkyl, or NR R ; and 1-6 1-6 NR -C(O)-C alk-heterocycloalkyl wherein the C alk is optionally substituted with oxo 0-6 0-6 and the heterocycloalkyl is optionally substituted with C alkyl; wherein R and R are each independently selected from the group consisting of: H, C alkyl, C cycloalkyl, C(O)H, and -CN; 1-6 3-6 R is selected from the group consisting of: H, CN, halogen, C haloalkyl, and C alkyl; R and R are each independently selected from the group consisting of: H; C alk-NR R ; C alk-OH; C alk-C cycloalkyl optionally substituted with 6 1-6 0-6 3-6 C alkyl; halogen; C alkyl; -OC alkyl; NR R ; C alk-O-C alkyl; 1-6 1-6 1-6 1-6 1-6 C alk-NH-C alk-O-C alkyl; C alk-heterocycloalkyl optionally 1-6 0-6 1-6 0-6 substituted with C(O)C alkyl or C alkyl; C alk-NHSO -C alkyl; 1-6 1-6 1-6 2 1-6 C alk-SO -C alkyl; NHC(O)-C alkyl; or linker-PEG-Biotin; 1-6 2 1-6 1-6 R is H or C alkyl; A is selected from the group consisting of: a bond; pyridyl; phenyl; napthalenyl; pyrimidinyl; pyrazinyl; pyridazinyl; benzo[d][1,3]dioxolyl optionally substituted with halogen; benzothiophenyl; or pyrazolyl; optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C alkyl, halogen, SF , OC alkyl, 1-6 5 1-6 C(O)-C alkyl, and C haloalkyl; 1-6 1-6 E is selected from the group consisting of: O, a bond, C(O)-NH, CH , and CH -O; G is selected from the group consisting of: H; C cycloalkyl; phenyl; thiophenyl; C alkyl; 3-6 1-6 pyrimidinyl; pyridyl; pyridazinyl; benzofuranyl; -C haloalkyl; heterocycloalkyl that contains an oxygen heteroatom; phenyl-CH -O-phenyl; C alk-O-C alkyl; NR R ; 2 1-6 1-6 SO C alkyl; or OH; wherein the phenyl, pyridyl, pyridazinyl, benzofuranyl, or 2 1-6 thiophenyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halogen, C alkyl, C haloalkyl, OC haloalkyl, 1-6 1-6 1-6 C cycloalkyl, OC alkyl, CN, OH, C alk-O-C alkyl, C(O)-NR R , and C(O)-C 3-6 1-6 1-6 1-6 1- alkyl; and stereoisomers and isotopic variants thereof; and pharmaceutically acceptable salts thereof.
The present disclosure is also directed to compounds of Formula (I): wherein R is H; R is selected from the group consisting of: CH -cyclohexyl, wherein the cyclohexyl is optionally substituted with OH; 3-hydroxyadamantanyl; and C cycloalkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: OH, 6 7 8 8 halogen, C alkyl, C haloalkyl, OC alkyl, CN, NR R , NR -C(O)H, NR -C(O)-C 1-6 1-6 1-6 1- 8 8 8 8 alkyl, NR -C(O)-C haloalkyl, NR -C(O)-O-C alkyl, NR -C(O)-C alk-OH, NR - 6 1-6 1-6 1-6 6 7 8 3 4 5 C(O)-C alk-NR R , and NR -C(O)-C(R )=CR (R ); wherein R is selected from the group consisting of: H, CN, halogen, C haloalkyl, and C alkyl; R and R are each independently selected from the group consisting of: H; C alk-NR R ; C alk-O-C alkyl; C cycloalkyl; heterocycloalkyl 6 1-6 1-6 3-6 optionally substituted with C alkyl; and -linker-PEG-Biotin; R and R are each independently selected from the group consisting of: H, C alkyl, C(O)H, and CN; and R is H; or R and R , together with the nitrogen atom to which they are attached, form a pyrrolidinyl ring 6 7 6 7 optionally substituted with NR R , where R and R are each independently selected from the group consisting of H; C alkyl; NR -C(O)-C alkyl; and NR -C(O)- 1-6 1-6 3 4 5 3 4 5 C(R )=CR (R ), wherein R is H or CN, R is H and R is H or cyclopropyl; A is selected from the group consisting of: pyridyl; phenyl; pyrimidinyl; pyrazinyl; pyridin- 2(1H)-one; and pyridazinyl; wherein the A is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halogen, C alkyl, C haloalkyl, and OC alkyl; 1-6 1-6 E is selected from the group consisting of: O, a bond, and CH ; G is selected from the group consisting of: H; halogen; C alkyl; C haloalkyl; NH(C alkyl); 1-6 1-6 1-6 C cycloalkyl; phenyl; pyrimidinyl; pyridyl; pyridazinyl; pyridin-2(1H)-one; heterocycloalkyl that contains an oxygen heteroatom; and phenyl-CH -O-phenyl, wherein the -O-phenyl is substituted with CN; wherein the phenyl, pyridyl, pyridazinyl, and pyridin-2(1H)-one is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halogen, C alkyl, C haloalkyl, 1-6 1-6 OC haloalkyl, and OC alkyl; and 1-6 1-6 stereoisomers or isotopic variant thereof; and pharmaceutically acceptable salts thereof.
According to the disclosure, R is H or C alkyl. In some aspects, R is C alkyl, for 1-6 1-6 example, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, or t-butyl. In preferred aspects, R is H.
According to the disclosure, R is a C alk-cycloalkyl moiety that can be unsubstituted.
In other aspects of the disclosure, R is a C alk-cycloalkyl moiety substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent. In those embodiments wherein R is C alk-cycloalkyl, the cycloalkyl is directly attached to the compound of Formula (I) through a bond. In those aspects wherein R is a C alk-cycloalkyl moiety, the cycloalkyl moiety is attached to the compound of Formula (I) through an aliphatic linker having 1, 2, 3, 4, , or 6 carbon atoms, wherein the C alk includes, for example, –CH -, –CH(CH )-, CH(CH )- 1-6 2 3 3 CH -, and –C(CH ) -. In preferred aspects, R is C alk-cycloalkyl, for example C alk- 2 3 2 0-1 0 cycloalkyl (i.e., cycloalkyl) or C alk-cycloalkyl (i.e., CH -cycloalkyl).
In preferred aspects, the R cycloalkyl moiety is a 3-, 4-, 5-, 6-, or 10-membered cycloalkyl, preferably a 5- or 6-membered cycloalkyl, with a 5-membered cycloalkyl being most preferred.
In some aspects of the disclosure, R is C alk-cylopropyl, preferably C alk-cylopropyl or C alk-cylopropyl, optionally substituted with 1, 2, or 3 substituents as recited herein. In more preferred aspects, R is C alk-cylopropyl, preferably C alk-cylopropyl or C alk-cylopropyl, substituted with 1 or 2 substituents as recited herein. The substituents can be attached through any position on the cylopropyl ring.
In some aspects of the disclosure, R is C alk-cylobutyl, preferably C0 alk-cylobutyl or C1 alk-cylobutyl, optionally substituted with 1, 2, or 3 substituents as recited herein. In more preferred aspects, R is C alk-cylobutyl, preferably C0 alk-cylobutyl or C1 alk-cylobutyl, substituted with 1 or 2 substituents as recited herein. The substituents can be attached through any position on the cylobutyl ring.
In preferred aspects of the disclosure, R is C alk-cyclopentyl, preferably C alk-cyclopentyl or C alk-cyclopentyl, optionally substituted with 1, 2, or 3 substituents as recited herein. In more preferred aspects, R is C alk-cyclopentyl, preferably C alk-cyclopentyl or C alk-cyclopentyl, substituted with 1 or 2 substituents as recited herein.
The substituents can be attached through any position on the cyclopentyl ring.
In some aspects of the disclosure, R is C alk-cyclohexyl, preferably C alk-cyclohexyl or C alk-cyclohexyl, optionally substituted with 1, 2, or 3 substituents as recited herein. In more preferred aspects, R is C alk-cyclohexyl, preferably C alk-cyclohexyl or C alk-cyclohexyl, substituted with 1 or 2 substituents as recited herein.
The substituents can be attached through any position on the cyclohexyl ring.
In some aspects of the disclosure, R is C alk-adamantanyl, preferably C alk-adamantanyl or C alk-adamantanyl, optionally substituted with 1, 2, or 3 substituents as recited herein. In more preferred aspects, R is C alk-adamantanyl, preferably C alk-adamantanyl or C alk-adamantanyl, substituted with 1 or 2 substituents as recited herein.
The substituents can be attached through any position on the adamantanyl ring.
According to the disclosure, the R cycloalkyl can be unsubstituted. In some aspects, the R cycloalkyl is substituted with 1, 2, or 3 substituents. In preferred aspects, the R cycloalkyl is substituted with 1 or 2 substituents, more preferably 1 substituent. In those aspects wherein the R cycloalkyl is substituted, the substituents may be independently selected from the group 8 3 4 5 6 7 consisting of NR -C(O)-C(R )=CR (R ); NR R ; OH; CN; oxo; O-C alkyl; halogen; C alkyl; C haloalkyl; C alk-OH; C cycloalkyl; C alkaryl; SO C alkyl; 1-6 1-6 1-6 3-6 1-6 2 1-6 8 6 7 8 8 SO C alkenyl; NR -C(O)-C alk-NR R ; NR -C(O)-C alkyl; NR -C(O)-O-C alkyl; 2 2-6 1-6 1-6 1-6 8 8 8 NR -C(O)-C cycloalkyl; NR -C(O)H; NR -C(O)-C cycloalkyl; 3-6 3-6 8 8 8 8 NR -C(O)-C haloalkyl; NR -C(O)-alkynyl; NR -C(O)-C aryl; NR -C(O)-heteroaryl; 1-6 6-10 8 8 8 NR -C(O)-C alk-CN; NR -C(O)-C alk-OH; NR -C(O)-C alk-SO -C alkyl; 1-6 1-6 1-6 2 1-6 8 6 7 8 NR -C(O)-C alk-NR R ; NR -C(O)-C alk-O-C alkyl wherein the C alk- is optionally 1-6 1-6 1-6 1-6 6 7 8 substituted with OH, OC alkyl, or NR R ; NR -C(O)-C alk-heterocycloalkyl wherein the – 1-6 0-6 alk- is optionally substituted with oxo and the heterocycloalkyl is optionally substituted with 3 4 5 6 7 8 C1-6alkyl; and wherein R , R , R , R , R , and R are as defined herein.
In some aspects, the R cycloalkyl is substituted with an oxo moiety, for example one oxo moiety. In those aspects wherein the R cycloalkyl is substituted with an oxo moiety, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with a halogen, for example a fluorine or chlorine or bromine. In some aspects, the R cycloalkyl is substituted with one or two halogens, preferably one halogen. In those aspects wherein the R cycloalkyl is substituted with a halogen, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with CN. In some aspects, the R cycloalkyl is substituted with one or two CN, preferably one CN. In those aspects wherein the R cycloalkyl is substituted with CN, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with OH. In some aspects, the R cycloalkyl is substituted with one or two OH, preferably one OH. In those aspects wherein the R cycloalkyl is substituted with OH, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents. 2 6 7 6 7 In some aspects, the R cycloalkyl is substituted with NR R wherein R and R are each independently H; C alkyl, C cycloalkyl; C(O)H; or CN. In preferred aspects, R and R are 1-6 3-6 each independently H or C alkyl. In those aspects wherein the R cycloalkyl is substituted with NR R , the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. In some aspects, the R cycloalkyl is 1-5 1-4 1-3 1-2 1 substituted with one or two C alkyl, preferably one C alkyl. In those aspects wherein the R 1-6 1-6 cycloalkyl is substituted with C alkyl, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with C alk-OH, for example, C alk-OH, C alk-OH, C alk-OH, C alk-OH, or C alk-OH, wherein the –OH moiety can be 1-5 1-4 1-3 1-2 1 attached to any carbon of the C alk group, preferably the ω carbon. In some aspects, the R cycloalkyl is substituted with one or two C alk-OH, preferably one C alk-OH. In those aspects wherein the R cycloalkyl is substituted with C alk-OH, the 1-6 1-6 cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with OC alkyl, for example, OC alkyl, OC alkyl, OC alkyl, OC alkyl, or OC alkyl. In some aspects, the R cycloalkyl 1-5 1-4 1-3 1-2 1 is substituted with one or two OC alkyl, preferably one OC alkyl. In those aspects wherein 1-6 1-6 the R cycloalkyl is substituted with OC alkyl, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with a C cycloalkyl moiety, for example, a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl moiety. In some aspects, the R cycloalkyl is substituted with one or two C cycloalkyl, preferably one C cycloalkyl. In those 3-6 3-6 aspects wherein the R cycloalkyl is substituted with C cycloalkyl, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with C alkaryl, for example, benzyl (i.e., CH -phenyl). In some aspects, the R cycloalkyl is substituted with one or two C alkaryl, preferably one C alkaryl. In those aspects wherein the R cycloalkyl is substituted 1-6 1-6 with C alkaryl, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with SO C alkyl, for example, 2 1-6 SO C alkyl, SO C alkyl, SO C alkyl, SO C alkyl, or SO C alkyl. In some aspects, the R 2 1-5 2 1-4 2 1-3 2 1-2 2 1 cycloalkyl is substituted with one or two SO C alkyl, preferably one 2 1-6 SO C alkyl. In those aspects wherein the R cycloalkyl is substituted with 2 1-6 SO C alkyl, the cycloalkyl ring may optionally be substituted with one or two additional 2 1-6 substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with SO C alkenyl, for example, 2 2-6 -SO C alkenyl, SO C alkenyl, SO C alkenyl, or SO C alkenyl. In some aspects, the R 2 2-5 2 2-4 2 2-3 2 2 cycloalkyl is substituted with one or two SO C alkenyl, preferably one SO C alkenyl. In 2 2-6 2 2-6 those aspects wherein the R cycloalkyl is substituted with SO C alkenyl, the cycloalkyl ring 2 2-6 may optionally be substituted with one or two additional substituents as defined herein for the R substituents. 2 8 8 In some aspects, the R cycloalkyl is substituted with NR -C(O)H wherein R is H or C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. In preferred aspects, 1-6 1-5 1-4 1-3 1-2 1 8 2 8 R is H. In some aspects, the R cycloalkyl is substituted with one or two NR -C(O)H, preferably one NR -C(O)H. In those aspects wherein the R cycloalkyl is substituted with NR -C(O)H, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with NR -C(O)-C alkyl, for example, 8 8 8 8 NR -C(O)-C1-5alkyl, NR -C(O)-C1-4alkyl, NR -C(O)-C1-3alkyl, NR -C(O)-C1-2alkyl, or NR -C(O)-C alkyl, wherein R is H or C alkyl, for example, C alkyl, C alkyl, C alkyl, 1 1-6 1-5 1-4 1-3 C alkyl, or C alkyl. In preferred aspects, R is H. In some aspects, the R cycloalkyl is 1-2 1 substituted with one or two NR –C(O)-C alkyl, preferably one NR -C(O)-C alkyl. In those 1-6 1-6 aspects wherein the R cycloalkyl is substituted with NR -C(O)-C alkyl, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with NR -C(O)-C cycloalkyl, for 8 8 8 example, NR -C(O)-cyclopropyl, NR -C(O)-cyclobutyl, NR -C(O)-cyclopentyl, or NR -C(O)-cyclohexyl, wherein R is H or C alkyl, for example, C alkyl, C alkyl, 1-6 1-5 1-4 C alkyl, C alkyl, or C alkyl. In preferred aspects, R is H. In some aspects, the R cycloalkyl 1-3 1-2 1 is substituted with one or two NR -C(O)-C cycloalkyl, preferably one NR -C(O)-C cycloalkyl. In those aspects wherein the R cycloalkyl is substituted with NR -C(O)-C cycloalkyl, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with C haloalkyl, for example, C haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or C haloalkyl, including CF , 1-5 1-4 1-3 1-2 1 3 CH CH F, and the like. In some aspects, the R cycloalkyl is substituted with one or two C haloalkyl, preferably one C haloalkyl. In those aspects wherein the R cycloalkyl is 1-6 1-6 substituted with C haloalkyl, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with NR -C(O)-C haloalkyl, for 8 8 8 example, NR -C(O)–C haloalkyl, NR -C(O)–C haloalkyl, NR -C(O)–C haloalkyl, 1-5 1-4 1-3 8 8 8 NR -C(O)–C haloalkyl, or NR -C(O)–C haloalkyl, including NR -C(O)–CF , 1-2 1 3 NR -C(O)–CH CH F, and the like, wherein R is H or C alkyl, for example, C alkyl, 2 2 1-6 1-5 C alkyl, C alkyl, C alkyl, or C alkyl. In preferred aspects, R is H. In some aspects, the R 1-4 1-3 1-2 1 cycloalkyl is substituted with one or two NR -C(O)-C haloalkyl, preferably one NR -C(O)-C haloalkyl. In those aspects wherein the R cycloalkyl is substituted with NR -C(O)-C haloalkyl, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with NR -C(O)-C alkynyl, for 8 8 8 example, NR -C(O)-C2-5alkynyl, NR -C(O)-C2-4alkynyl, NR -C(O)-C2-3alkynyl, or NR -C(O)-C alkynyl, wherein R is H or C alkyl, for example, C alkyl, C alkyl, C alkyl, 2 1-6 1-5 1-4 1-3 C1-2alkyl, or C1alkyl. In preferred aspects, R is H. In some aspects, the R cycloalkyl is substituted with one or two NR -C(O)-C alkynyl, preferably one NR -C(O)-C alkynyl. In 2-6 2-6 those aspects wherein the R cycloalkyl is substituted with NR -C(O)-C alkynyl, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with NR -C(O)-C aryl, for example, 6-10 8 8 8 NR -C(O)-phenyl or NR -C(O)-napthalenyl, wherein R is H or C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. In preferred aspects, R is H. In some 1-5 1-4 1-3 1-2 1 aspects, the R cycloalkyl is substituted with one or two NR -C(O)-C aryl, preferably one 6-10 NR -C(O)-C aryl. In those aspects wherein the R cycloalkyl is substituted with 6-10 NR -C(O)-C aryl, the cycloalkyl ring may optionally be substituted with one or two additional 6-10 substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with NR -C(O)-heteroaryl, for example, 8 8 8 8 8 NR -C(O)-pyrrolyl, NR -C(O)-thienyl, NR -C(O)-oxazolyl, NR -C(O)-pyrazolyl, NR -C(O)- pyridyl, NR -C(O)-pyrimidinyl, and the like, wherein R is H or C alkyl, for example, C 1-6 1- alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. In preferred aspects, R is H. In some aspects, 1-4 1-3 1-2 1 2 8 8 the R cycloalkyl is substituted with one or two NR -C(O)-heteroaryl, preferably one NR -C(O)- heteroaryl. In those aspects wherein the R cycloalkyl is substituted with NR -C(O)-heteroaryl, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with NR -C(O)-C alk-CN, for example, 8 8 8 NR -C(O)-C alk-CN, NR -C(O)-C alk-CN, NR -C(O)-C alk-CN, 1-5 1-4 1-3 8 8 8 NR -C(O)-C alk-CN, or NR -C(O)-C alk-CN, wherein R is H or C alkyl, for example, 1-2 1 1-6 C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. In preferred aspects, R is H. In some 1-5 1-4 1-3 1-2 1 aspects, the R cycloalkyl is substituted with one or two NR -C(O)-C alk-CN, preferably one NR -C(O)-C alk-CN. In those aspects wherein the R cycloalkyl is substituted with NR -C(O)-C alk-CN, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with NR -C(O)-C alk-OH, for 8 8 8 example, NR -C(O)-C1-5alk-OH, NR -C(O)-C1-4alk-OH, NR -C(O)-C1-3alk-OH, 8 8 8 NR -C(O)-C alk-OH, or NR -C(O)-C alk-OH, wherein R is H or C alkyl, for example, C 1-2 1 1-6 1- 5alkyl, C1-4alkyl, C1-3alkyl, C1-2alkyl, or C1alkyl. In preferred aspects, R is H. In some aspects, 2 8 8 the R cycloalkyl is substituted with one or two NR -C(O)-C alk-OH, preferably one NR - C(O)-C1-6alk-OH. In those aspects wherein the R cycloalkyl is substituted with NR -C(O)-C alk-OH, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with NR -C(O)-C alk-SO -C alkyl, 1-6 2 1-6 for example, NR -C(O)-C alk-SO -C alkyl, NR -C(O)-C alk-SO -C alkyl, 1-5 2 1-5 1-4 2 1-4 8 8 8 NR -C(O)-C alk-SO -C alkyl, NR -C(O)-C alk-SO -C alkyl, or NR -C(O)-C alk-SO - 1-3 2 1-3 1-2 2 1-2 1 2 C alkyl, wherein R is H or C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or 1 1-6 1-5 1-4 1-3 1-2 C alkyl. In preferred aspects, R is H. In some aspects, the R cycloalkyl is substituted with one or two NR -C(O)-C alk-SO -C alkyl, preferably one NR -C(O)-C alk-SO -C alkyl. In 1-6 2 1-6 1-6 2 1-6 those aspects wherein the R cycloalkyl is substituted with NR -C(O)-C alk-SO -C alkyl, the 1-6 2 1-6 cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with NR -C(O)-O-C alkyl, for 8 8 8 example, NR -C(O)-O-C alkyl, NR -C(O)-O-C alkyl, NR -C(O)-O-C alkyl, 1-5 1-4 1-3 8 8 8 NR -C(O)-O-C alkyl, or NR -C(O)-O-C alkyl, wherein R is H or C alkyl, for example, 1-2 1 1-6 C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. In preferred aspects, R is H. In some 1-5 1-4 1-3 1-2 1 aspects, the R cycloalkyl is substituted with one or two NR -C(O)-O-C alkyl, preferably one NR -C(O)-O-C alkyl. In those aspects wherein the R cycloalkyl is substituted with NR -C(O)-O-C alkyl, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents. 2 8 6 7 In some aspects, the R cycloalkyl is substituted with NR -C(O)-C alk-NR R , for 8 6 7 8 6 7 8 6 7 example, NR -C(O)-C alk-NR R , NR -C(O)-C alk-NR R , NR -C(O)-C alk-NR R , 1-5 1-4 1-3 8 6 7 8 6 7 6 7 NR -C(O)-C alk-NR R , or NR -C(O)-C alk-NR R , wherein R and R are each independently 1-2 1 H; C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl; C cycloalkyl, for 1-6 1-5 1-4 1-3 1-2 1 3-6 example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; C(O)H, or CN. In preferred aspects, R and R are each independently H, C alkyl; or C cycloalkyl, with H and C alkyl being preferred, and H and C alkyl being more preferred. 3-6 1-6 1-2 In these embodiments, R is H or C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, 1-6 1-5 1-4 1-3 1-2 or C alkyl. In preferred aspects, R is H. In some aspects, the R cycloalkyl is substituted with 8 6 7 8 6 7 one or two NR -C(O)-C1-6alk-NR R , preferably one NR -C(O)-C1-6alk-NR R . In those aspects 2 8 6 7 wherein the R cycloalkyl is substituted with NR -C(O)-C alk-NR R , the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with NR -C(O)-C alk-O-C alkyl, for 1-6 1-6 example, NR -C(O)-C alk-O-C alkyl, NR -C(O)-C alk-O-C alkyl, 1-5 1-5 1-4 1-4 8 8 8 NR -C(O)-C alk-O-C alkyl, NR -C(O)-C alk-O-C alkyl, or NR -C(O)-C alk-O-C alkyl, 1-3 1-3 1-2 1-2 1 1 wherein R is H or C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. In 1-6 1-5 1-4 1-3 1-2 1 8 2 8 preferred aspects, R is H. In certain aspects wherein the R cycloalkyl is substituted with NR - C(O)-C alk-O-C alkyl, the C alk- is optionally substituted with OH; OC alkyl, for 1-6 1-6 1-6 1-6 6 7 6 example, OC alkyl, OC alkyl, OC alkyl, OC alkyl, or OC alkyl; or NR R , wherein R and 1-5 1-4 1-3 1-2 1 R are each independently H; C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or 1-6 1-5 1-4 1-3 1-2 C alkyl; C cycloalkyl; C(O)H ;or CN. In preferred aspects, R and R are each independently 1 3-6 H, C alkyl; or C cycloalkyl, with H and C alkyl being preferred, and H and C alkyl being 1-6 3-6 1-6 1-2 more preferred. In some aspects, the C alk- of the NR -C(O)-C alk-O-C alkyl moiety is 1-6 1-6 1-6 substituted with OH. In other aspects, the C alk- is substituted with OC alkyl, for example, 1-6 1-6 OC alkyl, OC alkyl, OC alkyl, OC alkyl, or OC alkyl. In some aspects, the R cycloalkyl 1-5 1-4 1-3 1-2 1 is substituted with one or two NR -C(O)-C alk-O-C alkyl, preferably one NR -C(O)-C alk- 1-6 1-6 1-6 O-C alkyl. In those aspects wherein the R cycloalkyl is substituted with NR -C(O)-C alk-O- 1-6 1-6 C alkyl, the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents.
In some aspects, the R cycloalkyl is substituted with NR -C(O)-C alk-heterocycloalkyl, for example, NR -C(O)-C alk-heterocycloalkyl, 0-6 0-5 NR -C(O)-C alk-heterocycloalkyl, NR -C(O)-C alk-heterocycloalkyl, 0-4 0-3 NR -C(O)-C alk-heterocycloalkyl, NR -C(O)-C alk-heterocycloalkyl, 0-2 0-1 8 8 8 NR -C(O)-C alk-heterocycloalkyl, or NR -C(O)-C alk-heterocycloalkyl, wherein R is H or C 1 0 1- alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. In preferred aspects, R 6 1-5 1-4 1-3 1-2 1 is H. Preferred substituent heterocycloalkyl groups include tetrahydrofuranyl, piperidinyl, pyrrolidinyl, and the like. In certain aspects wherein the R cycloalkyl is substituted with NR - C(O)-C alk-heterocycloalkyl the C alk- is optionally substituted with oxo. In certain aspects 1-6 1-6 wherein the R cycloalkyl is substituted with NR -C(O)-C alk-heterocycloalkyl, the substituent heterocycloalkyl moiety can be unsubstituted or substituted with C alkyl, for example, C 1-6 1- 5alkyl, C1-4alkyl, C1-3alkyl, C1-2alkyl, or C1alkyl. In those aspects wherein the R cycloalkyl is substituted with C(O)-C alk-heterocycloalkyl, the R cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents. 2 8 3 4 5 In some aspects, the R cycloalkyl is substituted with NR -C(O)-C(R )=CR (R ), wherein 3 4 5 8 R , R , and R are as described herein and R is H or C1-6alkyl, for example, C1-5alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. In preferred aspects, R is H. In these aspects, R is H; 1-4 1-3 1-2 1 CN; halogen; C haloalkyl; or C alkyl. In some embodiments, R is H. In other aspects, R is 1-6 1-6 CN. In still other aspects, R is halogen, for example F or Cl. In yet other aspects, R is C haloalkyl, for example, C haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or 6 1-5 1-4 1-3 1-2 C haloalkyl, including CF , CH CH F, and the like. In further aspects, R is C alkyl, for 1 3 2 2 1-6 example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. In those aspects wherein the R 1-5 1-4 1-3 1-2 1 8 3 4 5 cycloalkyl is substituted with NR -C(O)-C(R )=CR (R ), the cycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R substituents. 2 8 3 4 5 In preferred aspects, the R cycloalkyl is substituted with NR -C(O)-C(R )=CR (R ); 8 6 7 8 6 7 2 NR -C(O)-C alk-NR R ; NR -C(O)-C alkyl; or NR R . In more preferred aspects, the R 1-6 1-6 8 3 4 5 2 cycloalkyl is substituted with NR -C(O)-C(R )=CR (R ). In other preferred aspects, the R 8 6 7 8 6 7 cycloalkyl is substituted with NR -C(O)-C alk-NR R ; NR -C(O)-C alkyl; or NR R ; wherein 1-6 1-6 R and R are each independently H or C alkyl.
In some preferred aspects, R is CH -cyclohexyl, wherein the cyclohexyl is optionally substituted with OH; 3-hydroxyadamantanyl; or C cycloalkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: OH, halogen, C 6 7 8 8 8 alkyl, C haloalkyl, OC alkyl, CN, NR R , NR -C(O)H, NR -C(O)-C alkyl, NR -C(O)-C 6 1-6 1-6 1-6 1- 8 8 8 6 7 8 haloalkyl, NR -C(O)-O-C alkyl, NR -C(O)-C alk-OH, NR -C(O)-C alk-NR R , and NR - 6 1-6 1-6 1-6 3 4 5 3 C(O)-C(R )=CR (R ); wherein R is selected from the group consisting of: H, CN, halogen, C haloalkyl, and C alkyl; R and R are each independently selected from the group consisting 6 1-6 of: H; C alk-NR R ; C alk-O-C alkyl; C cycloalkyl; heterocycloalkyl optionally 0-6 1-6 1-6 3-6 substituted with C alkyl; and -linker-PEG-Biotin; R and R are each independently selected from the group consisting of: H, C alkyl, C(O)H, and CN; and R is H. In some aspects, the R is substituted with 1 or 2 substituents. In some aspects, the R is substituted with at least one substituent, preferably 1 or 2 substituents, independently selected from the group consisting of OH, halogen, C alkyl, C haloalkyl, OC alkyl, and CN. 1-6 1-6 1-6 In some preferred aspects, R is CH -cyclohexyl. In other preferred aspects, R is CH - cyclohexyl wherein the cyclohexyl is substituted with OH.
In some preferred aspects, R is 3-hydroxyadamantanyl.
In other preferred aspects, R is C cycloalkyl. In some other preferred aspects, R is C 3-6 3- 6cycloalkyl substituted with 1, 2, or 3 substituents. Those substituents can be independently selected from the group consisting of OH, halogen, C alkyl, C haloalkyl, OC alkyl, CN, 1-6 1-6 1-6 6 7 8 8 8 8 8 NR R , NR -C(O)H, NR -C(O)-C alkyl, NR -C(O)-C haloalkyl, NR -C(O)-O-C alkyl, NR - 1-6 1-6 1-6 8 6 7 8 3 4 5 C(O)-C alk-OH, NR -C(O)-C alk-NR R , and NR -C(O)-C(R )=CR (R ). 1-6 1-6 4 5 2 In those embodiments employing R and R , that is, those aspects wherein the R 8 3 4 5 4 5 cycloalkyl is substituted with NR -C(O)-C(R )=CR (R ), R and R are each independently H; halogen; C alk-NR R ; C alkyl; OC alkyl; C alk-C cycloalkyl optionally substituted with 0-6 1-6 1-6 0-6 3-6 C alkyl; C alk-heterocycloalkyl optionally substituted with –C(O)C alkyl or C alkyl; C 1-6 0-6 1-6 1-6 1- alk-OH; C alk-O-C alkyl; C alk-NH-C alk-O-C alkyl; C alk-NHSO -C alkyl; 6 1-6 1-6 1-6 0-6 1-6 1-6 2 1-6 -C alk-SO -C alkyl; -NHC(O)-C alkyl; or linker-PEG-Biotin. 1-6 2 1-6 1-6 Within the scope of this disclosure, the double bond present in 8 3 4 5 -NR -C(O)-C(R )=CR (R ) may be of the Z or E configuration.
In some aspects, neither R nor R is H.
In most preferred aspects, each of R and R is H. 4 5 4 5 In some aspects, one of R and R is H. In certain of these aspects, the other of R and R is halogen, for example F or Cl. 4 5 4 5 In some aspects, one of R and R is H. In certain of these aspects, the other of R and R is C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. 1-6 1-5 1-4 1-3 1-2 1 4 5 4 5 In some aspects, one of R and R is H. In certain of these aspects, the other of R and R is OC alkyl, for example, OC alkyl, OC alkyl, OC alkyl, OC alkyl, or OC alkyl. 1-6 1-5 1-4 1-3 1-2 1 4 5 4 5 In some aspects, one of R and R is H. In certain of these aspects, the other of R and R is C alk-C cycloalkyl, for example, C alk-C cycloalkyl, C alk-C cycloalkyl, 0-6 3-6 0-5 3-5 0-4 3-4 C alk-C cycloalkyl, C alk-C cycloalkyl, C alk-C cycloalkyl, C alk-C cycloalkyl or 0-3 3 0-2 3-6 0-1 3-6 0 3-6 C alk-C cycloalkyl. In these aspects, the cycloalkyl moiety can be unsubstituted or can be 1 3-6 substituted with C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. The 1-6 1-5 1-4 1-3 1-2 1 substitution can be a spiro-substitution or a non-spiro-substitution. 4 5 4 5 In some aspects, one of R and R is H. In certain of these aspects, the other of R and R is C alk-heterocycloalkyl, for example, C alk-heterocycloalkyl, C alk-heterocycloalkyl, 0-6 1-6 0-4 C alk-heterocycloalkyl, C alk-heterocycloalkyl, C alk-heterocycloalkyl, 0-3 0-2 0-1 C alk-heterocycloalkyl, or C alk-heterocycloalkyl. In these aspects, the substituent heterocycloalkyl is preferably an oxygen-containing heterocycloalkyl, for example, tetrahydropyranyl, tetrahydrofuranyl, or oxetanyl. In other aspects, the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, for example, pyrrolidinyl, aziridinyl, or piperidinyl. In certain of these aspects, the substituent heterocycloalkyl can be substituted with C(O)C alkyl, for example, C(O)C1-5alkyl, C(O)C1-4alkyl, C(O)C1-3alkyl, C(O)C1-2alkyl, or C(O)C1alkyl. In other aspects, the substituent heterocycloalkyl can be substituted with C alkyl, for example, C 1-6 1- alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. 1-4 1-3 1-2 1 4 5 4 5 In some aspects, one of R and R is H. In certain of these aspects, the other of R and R is C alk-OH, for example, C alk-OH, C alk-OH, C alk-OH, C alk-OH, or 1-6 1-5 1-4 1-3 1-2 C alk-OH. The OH moiety can be attached to any carbon of the C alk group, preferably the ω 1 1-6 carbon. 4 5 4 5 In some aspects, one of R and R is H. In certain of these aspects, the other of R and R 6 7 6 7 6 7 6 7 is C alk-NR R , for example, C alk-NR R , C alk-NR R , C alk-NR R , 0-6 0-5 0-4 0-3 6 7 6 7 6 7 6 7 6 7 C alk-NR R , C alk-NR R , C alk-NR R , or C alk-NR R , wherein R and R are each 0-2 0-1 1 0 independently H; C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or 1-6 1-5 1-4 1-3 1-2 C alkyl; C cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; 1 3-6 C(O)H; or CN. In preferred aspects, R and R are each independently H; C alkyl; or C cycloalkyl, more preferably, R and R are each independently H or C alkyl. 3-6 1-6 4 5 4 5 In some aspects, one of R and R is H. In certain of these aspects, the other of R and R is C alk-O-C alkyl, for example, C alk-O-C alkyl, C alk-O-C alkyl, 1-6 1-6 1-5 1-5 1-4 1-4 C alk-O-C alkyl, C alk-O-C alkyl, or C alk-O-C alkyl. 1-3 1-3 1-2 1-2 1 1 4 5 4 5 In some aspects, one of R and R is H. In certain of these aspects, the other of R and R is C alk-NH-C alk-O-C alkyl, for example, C alk-NH-C alk-O-C alkyl, 1-6 0-6 1-6 1-5 0-6 1-5 C alk-NH-C alk-O-C alkyl, C alk-NH-C alk-O-C alkyl, 1-4 0-6 1-4 1-3 0-6 1-3 C alk-NH-C alk-O-C alkyl, C alk-NH-C alk-O-C alkyl, 1-2 0-6 1-2 1 0-6 1 C alk-NH-C alk-O-C alkyl, C alk-NH-C alk-O-C alkyl, 1-5 0-6 1-5 1-4 1-5 1-4 C alk-NH-C alk-O-C alkyl, C alk-NH-C alk-O-C alkyl, C alk-NH-C alk-O-C alky, or 1-3 1-4 1-3 1-2 1-3 1-2 1 1-2 1 C alk-NH-C alk-O-C alkyl. 1-6 0 1-6 4 5 4 5 In some aspects, one of R and R is H. In certain of these aspects, the other of R and R is C alk-NHSO -C alkyl, for example, C alk-NHSO -C alkyl C alk-NHSO -C alkyl, 1-6 2 1-6 1-5 2 1-5 1-4 2 1-4 C alk-NHSO -C alkyl, C alk-NHSO -C alkyl, or C alk-NHSO -C alkyl. 1-3 2 1-3 1-2 2 1-2 1 2 1 4 5 4 5 In some aspects, one of R and R is H. In certain of these aspects, the other of R and R is C alk-SO -C alkyl, for example, C alk-SO -C alkyl, C alk-SO -C alkyl, 1-6 2 1-6 1-5 2 1-5 1-4 2 1-4 C alk-SO -C alkyl, C alk-SO -C alkyl, or C alk-SO -C alkyl. 1-3 2 1-3 1-2 2 1-2 1 2 1 4 5 4 5 In some aspects, one of R and R is H. In certain of these aspects, the other of R and R is NHC(O)-C alkyl, for example, NHC(O)-C alkyl, NHC(O)-C alkyl, NHC(O)-C alkyl, 1-6 1-5 1-4 1-3 NHC(O)-C alkyl, or NHC(O)-C alkyl. 1-2 1 4 5 4 5 In some aspects, one of R and R is H. In certain of these aspects, the other of R and R is linker-PEG-Biotin, preferably 4 5 4 5 In preferred aspects, one of R and R is H and the other of R and R is C alkyl (e.g., methyl, t-butyl); cycloalkyl (e.g., cyclopropyl); C alk-NR R (e.g., CH -NH , CH -NHCH , 1-6 2 2 2 3 CH -N(CH ) , C(CH ) -NH , C(CH ) -NHCH , C(CH ) -N(CH ) ; C alk-O-C alkyl (e.g., 2 3 2 3 2 2 3 2 3 3 2 3 2 1-6 1-6 C(CH ) -OCH , C(CH ) -OCH CH ); C alk-heterocycloalkyl substituted with 3 2 3 3 2 2 3 0-6 C alkyl (e.g., C(CH )-oxetanyl). 1-6 3 In some embodiments, or R and R , together with the nitrogen atom to which they are attached, form an optionally substituted ring that is a pyrrolidinyl ring or a piperidinyl ring, for example, compounds of Formula (I)’ or Formula (I)": (I’) (I") In these aspects, ring formed by the joining of R and R can be unsubstituted. In some aspects, the ring formed by the joining of R and R is substituted with 1, 2, or 3 substituents. In preferred aspects, the ring formed by the joining of R and R is substituted with 1 or 2 substituents, more preferably 1 substituent. In those aspects wherein the ring formed by the joining of R and R is substituted, the substituents may be independently selected from the 8 3 4 5 6 7 group consisting of NR -C(O)-C(R )=CR (R ); NR R ; OH; CN; oxo; O-C alkyl; halogen; C 1-6 1- alkyl; C haloalkyl; C alk-OH; C cycloalkyl; C alkaryl; SO C alkyl; SO C alkenyl;- 6 1-6 1-6 3-6 1-6 2 1-6 2 2-6 8 6 7 8 8 NR -C(O)-C alk-NR R ; NR -C(O)-C alkyl; NR -C(O)-O-C alkyl; 1-6 1-6 1-6 8 8 8 NR -C(O)-C cycloalkyl; NR -C(O)H; NR -C(O)-C cycloalkyl; 3-6 3-6 8 8 8 8 NR -C(O)-C haloalkyl; NR -C(O)-alkynyl; NR -C(O)-C aryl; NR -C(O)-heteroaryl; 1-6 6-10 8 8 8 NR -C(O)-C alk-CN; NR -C(O)-C alk-OH; NR -C(O)-C alk-SO -C alkyl; 1-6 1-6 1-6 2 1-6 8 6 7 8 NR -C(O)-C alk-NR R ; NR -C(O)-C alk-O-C alkyl wherein the C alk- is optionally 1-6 1-6 1-6 1-6 6 7 8 substituted with –OH, OC alkyl, or NR R ; NR -C(O)-C alk-heterocycloalkyl wherein the – 1-6 0-6 C alk- is optionally substituted with oxo and the heterocycloalkyl is optionally substituted with 3 4 5 6 7 8 C alkyl; and wherein R , R , R , R , R , and R are as defined herein.
A preferred subgenus of Formula (I) is a compound of Formula (IA): (I-A) wherein the cyclopentyl ring is substituted at the 2 position with any of the R substituents defined herein.
Other preferred subgenera of Formula (I) are: (I-B-1) (I-B-2) Within the scope of the disclosure, A can be a bond. Also within the scope of the disclosure, A can be pyridyl; phenyl; napthalenyl; pyrimidinyl; pyrazinyl; pyridazinyl; benzo[d][1,3]dioxolyl optionally substituted with halogen; benzothiophenyl; or pyrazolyl. Also within the disclosure, A can be pyridyl; phenyl; pyrimidinyl; pyrazinyl; pyridine-2(1H)-one, or pyridazinyl. Also according to the disclosure, any of the A moieties (excluding a bond) can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl; halogen, for example F or Cl; SF ; 1-5 1-4 1-3 1-2 1 5 OC alkyl, for example, OC alkyl, OC alkyl, OC alkyl, OC alkyl, or OC alkyl; 1-6 1-5 1-4 1-3 1-2 1 C(O)-C alkyl, for example, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, or 1-6 1-5 1-4 1-3 1-2 C(O)-C alkyl; and C haloalkyl, for example, C haloalkyl, C haloalkyl, 1 1-6 1-5 1-4 C haloalkyl, C haloalkyl, or C haloalkyl, including CF , CH CH F, and the like. Preferably, 1-3 1-2 1 3 2 2 the A moieties can be substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, independently selected from the group consisting of halogen, C alkyl, C haloalkyl, and OC 1-6 1-6 1- alkyl.
In some aspects, A is pyridyl. The pyridyl can be attached to any of the compounds of Formula (I) (or its subgenera) through any ring carbon atom, but preferably it attached through the 2- or 3-position carbon. Preferably, the pyridyl is substituted with one or two substituents, preferably one substituent. The pyridyl substituent can be attached to any ring carbon atom of the pyridyl ring. In those embodiments wherein the pyridyl is attached to the compound of Formula (I) through the 3-position carbon, the substituent is preferably attached to the pyridyl at the 2- or 4-position. The pyridyl can be substituted at any available ring carbon atom with C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. The pyridyl can be 6 1-5 1-4 1-3 1-2 1 substituted at any available ring carbon atom with halogen, for example F or Cl. The pyridyl can be substituted at any available ring carbon atom with SF The pyridyl can be substituted at any available ring carbon atom with OC alkyl, for example, OC alkyl, OC alkyl, OC alkyl, 1-6 1-5 1-4 1-3 OC alkyl, or OC alkyl. The pyridyl can be substituted at any available ring carbon atom with 1-2 1 C(O)-C alkyl, for example, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, or 1-6 1-5 1-4 1-3 1-2 C(O)-C alkyl. The pyridyl can be substituted at any available ring carbon atom with C 1 1- haloalkyl, for example, C haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or 6 1-5 1-4 1-3 1-2 C haloalkyl, including CF , CH CH F, and the like. Preferred substituents wherein A is pyridyl 1 3 2 2 include C alkyl, with C alkyl being most preferred, and with one C alkyl substituent being 1-6 1 1 more preferred. Other preferred substituents include halogen, in particular F and Cl.
In some aspects, A is phenyl. Preferably, the phenyl is substituted with one or two substituents, preferably one substituent. The phenyl can be substituted at any available ring carbon atom with C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or 1-6 1-5 1-4 1-3 1-2 C alkyl. The phenyl can be substituted at any available ring carbon atom with halogen, for example F or Cl. The phenyl can be substituted at any available ring carbon atom with -SF .
The phenyl can be substituted at any available ring carbon atom with OC1-6alkyl, for example, OC alkyl, OC alkyl, OC alkyl, OC alkyl, or OC alkyl. The phenyl can be substituted at 1-5 1-4 1-3 1-2 1 any available ring carbon atom with C(O)-C1-6alkyl, for example, C(O)-C1-5alkyl, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, or C(O)-C alkyl. The phenyl can be substituted 1-4 1-3 1-2 1 at any available ring carbon atom with C1-6haloalkyl, for example, C1-5haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or C haloalkyl, including CF , CH CH F, and the 1-4 1-3 1-2 1 3 2 2 like. The phenyl’s substituent can be attached to any ring carbon atom of the phenyl ring, preferably ortho to the phenyl moiety’s point of attachment to the compound of Formula (I).
Preferred substituents wherein A is phenyl include C alkyl, with C alkyl being most preferred. 1-6 1 Other preferred substituents include halogen, in particular F and Cl.
In some aspects, A is napthalenyl. Preferably, the napthalenyl is substituted with one or two substituents, preferably one substituent. The napthalenyl can be substituted at any available ring carbon atom with C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or 1-6 1-5 1-4 1-3 1-2 C alkyl. The napthalenyl can be substituted at any available ring carbon atom with halogen, for example F or Cl. The napthalenyl can be substituted at any available ring carbon atom with SF . The napthalenyl can be substituted at any available ring carbon atom with OC alkyl, for 1-6 example, OC alkyl, OC alkyl, OC alkyl, OC alkyl, or OC alkyl. The napthalenyl can be 1-5 1-4 1-3 1-2 1 substituted at any available ring carbon atom with C(O)-C alkyl, for example, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, or C(O)-C alkyl. The 1-5 1-4 1-3 1-2 1 napthalenyl can be substituted at any available ring carbon atom with C haloalkyl, for example, C haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or C haloalkyl, including CF , 1-5 1-4 1-3 1-2 1 3 CH CH F, and the like. The napthalenyl can be attached through any of its carbon atoms to the compound of Formula (I). The napthalenyl substituent can be attached to any ring carbon atom of the napthalenyl ring, preferably ortho to the napthalenyl moiety’s point of attachment to the compound of Formula (I). Preferred substituents wherein A is napthalenyl include C alkyl, with C alkyl being most preferred. Other preferred substituents include halogen, in particular F and Cl.
In some aspects, A is pyrimidinyl. The pyrimidinyl can be attached to any of the compounds of Formula (I) (or its subgenera) through any ring carbon atom through any ring carbon atom. Preferably, the pyrimidinyl is substituted with one or two substituents, preferably one substituent. The pyrimidinyl can be substituted at any available ring carbon atom with C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. The pyrimidinyl can be 6 1-5 1-4 1-3 1-2 1 substituted at any available ring carbon atom with halogen, for example F or Cl. The pyrimidinyl can be substituted at any available ring carbon atom with SF5. The pyrimidinyl can be substituted at any available ring carbon atom with OC alkyl, for example, OC alkyl, 1-6 1-5 OC1-4alkyl, OC1-3alkyl, OC1-2alkyl, or OC1alkyl. The pyrimidinyl can be substituted at any available ring carbon atom with C(O)-C alkyl, for example, C(O)-C alkyl, C(O)-C alkyl, 1-6 1-5 1-4 C(O)-C1-3alkyl, C(O)-C1-2alkyl, or C(O)-C1alkyl. The pyrimidinyl can be substituted at any available ring carbon atom with C haloalkyl, for example, C haloalkyl, C haloalkyl, 1-6 1-5 1-4 C haloalkyl, C haloalkyl, or C haloalkyl, including CF , CH CH F, and the like. Preferred 1-3 1-2 1 3 2 2 substituents wherein A is pyrimidinyl include C alkyl, with C alkyl being most preferred. 1-6 1 Other preferred substituents include halogen, in particular F and Cl.
In some aspects, A is pyrazinyl. The pyrazinyl can be attached to any of the compounds of Formula (I) (or its subgenera) through any ring carbon atom. Preferably, the pyrazinyl is substituted with one or two substituents, preferably one substituent. The pyrazinyl can be substituted at any available ring carbon atom with C alkyl, for example, C alkyl, C alkyl, C 1-6 1-5 1-4 1- alkyl, C alkyl, or C alkyl. The pyrazinyl can be substituted at any available ring carbon atom 3 1-2 1 with halogen, for example F or Cl. The pyrazinyl can be substituted at any available ring carbon atom with SF . The pyrazinyl can be substituted at any available ring carbon atom with OC alkyl, for example, OC alkyl, OC alkyl, OC alkyl, OC alkyl, or OC alkyl. The 1-6 1-5 1-4 1-3 1-2 1 pyrazinyl can be substituted at any available ring carbon atom with C(O)-C alkyl, for example, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, or C(O)-C alkyl. The pyrazinyl 1-5 1-4 1-3 1-2 1 can be substituted at any available ring carbon atom with C haloalkyl, for example, C haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or C haloalkyl, including CF , 1-5 1-4 1-3 1-2 1 3 CH CH F, and the like. Preferred substituents wherein A is pyrazinyl include C alkyl, with 2 2 1-6 C alkyl being most preferred. Other preferred substituents include halogen, in particular F and In some aspects, A is pyridazinyl. The pyridazinyl can be attached to any of the compounds of Formula (I) (or its subgenera) through any ring carbon atom. Preferably, the pyridazinyl is substituted with one or two substituents, preferably one substituent. The pyridazinyl can be substituted at any available ring carbon atom with C alkyl, for example, -C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. The pyridazinyl can be substituted at any 1-5 1-4 1-3 1-2 1 available ring carbon atom with halogen, for example F or Cl. The pyridazinyl can be substituted at any available ring carbon atom with SF . The pyridazinyl can be substituted at any available ring carbon atom with OC alkyl, for example, OC alkyl, OC alkyl, 1-6 1-5 1-4 OC alkyl, OC alkyl, or OC alkyl. The pyridazinyl can be substituted at any available ring 1-3 1-2 1 carbon atom with C(O)-C1-6alkyl, for example, C(O)-C1-5alkyl, C(O)-C1-4alkyl, C(O)-C1-3alkyl, C(O)-C alkyl, or C(O)-C alkyl. The pyridazinyl can be substituted at any available ring carbon 1-2 1 atom with C1-6haloalkyl, for example, C1-5haloalkyl, C1-4haloalkyl, C haloalkyl, C haloalkyl, or C haloalkyl, including CF , CH CH F, and the like. Preferred 1-3 1-2 1 3 2 2 substituents wherein A is pyridazinyl include C alkyl, with C alkyl being most preferred. 1-6 1 Other preferred substituents include halogen, in particular F and Cl.
In some aspects, A is benzo[d][1,3]dioxolyl. The benzo[d][1,3]dioxolyl can be attached to any of the compounds of Formula (I) (or its subgenera) through any ring carbon atom. The benzo[d][1,3]dioxolyl can be unsubstituted or can be substituted with one or two halogen, preferably F. Preferably, the benzo[d][1,3]dioxolyl is substituted with one or two other substituents. The benzo[d][1,3]dioxolyl can be substituted at any available ring carbon atom with C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. The 1-6 1-5 1-4 1-3 1-2 1 benzo[d][1,3]dioxolyl can be substituted at any available ring carbon atom with halogen, for example F or Cl. The benzo[d][1,3]dioxolyl can be substituted at any available ring carbon atom with -SF . The benzo[d][1,3]dioxolyl can be substituted at any available ring carbon atom with OC alkyl, for example, OC alkyl, OC alkyl, OC alkyl, OC alkyl, or OC alkyl. The 1-6 1-5 1-4 1-3 1-2 1 benzo[d][1,3]dioxolyl can be substituted at any available ring carbon atom with C(O)-C alkyl, for example, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, or 1-5 1-4 1-3 1-2 C(O)-C alkyl. The benzo[d][1,3]dioxolyl can be substituted at any available ring carbon atom with C haloalkyl, for example, C haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or 1-6 1-5 1-4 1-3 1-2 C haloalkyl, including CF , CH CH F, and the like. 1 3 2 2 In some aspects, A is benzothiophenyl. The benzothiophenyl can be attached to any of the compounds of Formula (I) (or its subgenera) through any ring carbon atom. Preferably, the benzothiophenyl is substituted with one or two substituents, preferably one substituent. The benzothiophenyl can be substituted at any available ring carbon atom with C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. The benzothiophenyl can be 1-5 1-4 1-3 1-2 1 substituted at any available ring carbon atom with halogen, for example F or Cl. The benzothiophenyl can be substituted at any available ring carbon atom with SF . The benzothiophenyl can be substituted at any available ring carbon atom with OC alkyl, for example, OC alkyl, OC alkyl, OC alkyl, OC alkyl, or OC alkyl. The benzothiophenyl can 1-5 1-4 1-3 1-2 1 be substituted at any available ring carbon atom with C(O)-C alkyl, for example, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, or C(O)-C alkyl. The 1-5 1-4 1-3 1-2 1 benzothiophenyl can be substituted at any available ring carbon atom with C1-6haloalkyl, for example, C haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or C haloalkyl, including 1-5 1-4 1-3 1-2 1 CF3, CH2CH2F, and the like.
In some aspects, A is pyrazolyl. The pyrazolyl can be attached to any of the compounds of Formula (I) (or its subgenera) through any ring carbon atom. Preferably, the pyrazolyl is substituted with one or two substituents, preferably one substituent. The pyrazolyl can be substituted at any available ring carbon atom with C alkyl, for example, C alkyl, C alkyl, C 1-6 1-5 1-4 1- alkyl, C alkyl, or C alkyl. The pyrazolyl can be substituted at any available ring carbon atom 3 1-2 1 with halogen, for example F or Cl. The pyrazolyl can be substituted at any available ring carbon atom with SF . The pyrazolyl can be substituted at any available ring carbon atom with OC alkyl, for example, OC alkyl, OC alkyl, OC alkyl, OC alkyl, or OC alkyl. The 1-6 1-5 1-4 1-3 1-2 1 pyrazolyl can be substituted at any available ring carbon atom with C(O)-C alkyl, for example, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, or C(O)-C alkyl. The pyrazolyl 1-5 1-4 1-3 1-2 1 can be substituted at any available ring carbon atom with C haloalkyl, for example, C haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or C haloalkyl, including CF , 1-5 1-4 1-3 1-2 1 3 CH CH F, and the like.
In preferred aspects, A is an unsubstituted or substituted phenyl, pyridyl, pyrimidyl, or pyrazinyl moiety, with pyridyl being particularly preferred. In those aspects wherein the phenyl, pyridyl, pyrimidyl, or pyrazinyl moiety is substituted, the preferred substituents include C alkyl (e.g., methyl) and halogen (e.g., F or Cl).
Additional preferred subgenera of Formula (I) are: (I-D) wherein the phenyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
(I-E) wherein the pyridyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
(I-F) wherein the pyridyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
According to the disclosure, E is O, a bond, C(O)-NH, CH , or CH -O. The E moiety can be attached through any available carbon atom on the A moiety. The E moiety can also be attached through any available carbon atom on the G moiety.
In some aspects, E is O, a bond, or CH . In preferred aspects, E is O. In other preferred aspects, E is a bond.
In some aspects of the disclosure, E is C(O)-NH, wherein the A-E-G moiety is A-C(O)-NH-G.
In other aspects of the disclosure, E is CH .
In yet other aspects of the disclosure, E is CH -O, wherein the A-E-G moiety is A-CH -O-G.
Additional preferred subgenera of Formula (I) are: (I-G-1) wherein the phenyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
(I-G-2) wherein the phenyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
(I-H-1) wherein the pyridyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
(I-H-2) wherein the pyridyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
G O N (I-J-1) wherein the pyridyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
(I-J-2) wherein the pyridyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
Other preferred subgenera of Formula (I) are: G O A G O A (I-K-1) (I-K-2) G A G A (I-L-1) (I-L-2) According to the disclosure, G is H; halogen; C alkyl; C haloalkyl; NH(C alkyl); C 1-6 1-6 1-6 3- cycloalkyl; phenyl; pyrimidinyl; pyridyl; pyridazinyl; pyridin-2(1H)-one; heterocycloalkyl that contains an oxygen heteroatom; and phenyl-CH -O-phenyl, wherein the -O-phenyl is substituted with CN; wherein the phenyl; pyridyl; pyridazinyl; and pyridin-2(1H)-one is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halogen, C alkyl, C haloalkyl, OC haloalkyl, and OC alkyl, 1-6 1-6 1-6 1-6 Also according to the disclosure, G is H; C cycloalkyl; phenyl; thiophenyl; C alkyl; 3-6 1-6 pyrimidinyl; pyridyl; pyridazinyl; benzofuranyl; C haloalkyl; heterocycloalkyl that contains an oxygen heteroatom; phenyl-CH -O-phenyl; C alk-O-C alkyl; NR R ; 2 1-6 1-6 SO C alkyl; or OH; wherein the phenyl; pyridyl; pyridazinyl; pyrimidinyl; benzofuranyl; or 2 1-6 thiophenyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen; C alkyl; C haloalkyl; OC haloalkyl; C cycloalkyl; 1-6 1-6 1-6 3-6 OC alkyl; CN; OH; C alk-O-C alkyl; C(O)-NR R ; and C(O)-C alkyl. 1-6 1-6 1-6 1-6 In some aspects, G is H.
In other aspects, G is C cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
In some aspects, G is C alkyl, for example, C alkyl, C lkyl, C alkyl, C alkyl, or 1-6 1-5 1-4 1-3 1-2 C alkyl.
In some aspects, G is C haloalkyl, for example, C haloalkyl, 1-6 1-5 C haloalkyl, C haloalkyl, C haloalkyl, or C haloalkyl, including CF , CH CH F, and the 1-4 1-3 1-2 1 3 2 2 like.
In other aspects, G is a heterocycloalkyl that contains an oxygen heteroatom, for example, tetrahydropyranyl, tetrahydrofuranyl, or oxetanyl.
In preferred aspects, G is phenyl-CH -O-phenyl. In these aspects, the phenyl-CH -O-phenyl can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of halogen; C alkyl; C haloalkyl; OC haloalkyl; C cycloalkyl; OC alkyl; 1-6 1-6 1-6 3-6 1-6 CN; OH; C alk-O-C alkyl; C(O)-NR R ; and C(O)-C alkyl. The one or both of the phenyl 1-6 1-6 1-6 rings of the phenyl-CH -O-phenyl moiety can be substituted with halogen, for example F or Cl.
The one or both of the phenyl rings of the -phenyl-CH -O-phenyl moiety can be substituted with C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. The one or both of 1-6 1-5 1-4 1-3 1-2 1 the phenyl rings of the phenyl-CH -O-phenyl moiety can be substituted with C haloalkyl, for 2 1-6 example, C haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or 1-5 1-4 1-3 1-2 C haloalkyl. The one or both of the phenyl rings of the phenyl-CH -O-phenyl moiety can be substituted with OC haloalkyl, for example, OC haloalkyl, OC haloalkyl, OC haloalkyl, 1-6 1-5 1-4 1-3 OC haloalkyl, or OC haloalkyl. The one or both of the phenyl rings of the 1-2 1 phenyl-CH -O-phenyl moiety can be substituted with C cycloalkyl, for example, cyclopropyl, 2 3-6 cyclobutyl, cyclopentyl, or cyclohexyl. The one or both of the phenyl rings of the phenyl-CH -O-phenyl moiety can be substituted with OC alkyl, for example, OC alkyl, 2 1-6 1-5 OC alkyl, OC alkyl, OC alkyl, or OC alkyl. The one or both of the phenyl rings of the 1-4 1-3 1-2 1 phenyl-CH -O-phenyl moiety can be substituted with CN. The one or both of the phenyl rings of the phenyl-CH -O-phenyl moiety can be substituted with OH. The one or both of the phenyl rings of the phenyl-CH -O-phenyl moiety can be substituted with C alk-O-C alkyl, for 2 1-6 1-6 example, C alk-O-C alkyl, C alk-O-C alkyl, C alk-O-C alkyl, C alk-O-C alkyl, or 1-5 1-5 1-4 1-4 1-3 1-3 1-2 1-2 C alk-O-C alkyl. The one or both of the phenyl rings of the phenyl-CH -O-phenyl moiety can 1 1 2 6 7 6 7 be substituted with C(O)-NR R , wherein R and R are preferably each independently H; C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl; or C cycloalkyl, for 6 1-5 1-4 1-3 1-2 1 3-6 example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. More preferably, R and R are each independently H or C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or 1-6 1-5 1-4 1-3 1-2 C1alkyl. The one or both of the phenyl rings of the phenyl-CH2-O-phenyl moiety can be substituted with C(O)-C alkyl, for example, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, 1-6 1-65 1-4 1-3 C(O)-C1-2alkyl, or C(O)-C1alkyl.
In some aspects, G is C alk-O-C alkyl, for example, C alk-O-C alkyl, 1-6 1-6 1-5 1-5 C1-4alk-O-C1-4alkyl, C1-3alk-O-C1-3alkyl, C1-2alk-O-C1-2alkyl, or C1alk-O-C1alkyl. 6 7 6 7 In other aspects, G is NR R , wherein R and R are each independently H; C alkyl; C cycloalkyl; C(O)H, or CN. In these aspects, R and R are preferably each independently H; C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl; or 1-6 1-5 1-4 1-3 1-2 1 C cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. More preferably, R and R are each independently H or C alkyl, for example, C alkyl, C alkyl, C 1-6 1-5 1-4 1- alkyl, C alkyl, or C alkyl. 3 1-2 1 In some aspects, G is SO C alkyl, for example, SO C alkyl, SO C alkyl, 2 1-6 2 1-5 2 1-4 -SO C alkyl, SO C alkyl, or SO C alkyl. 2 1-3 2 1-2 2 1 In some aspects, G is OH.
In preferred aspects, G is phenyl. In these aspects, the phenyl can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of halogen; C alkyl; C haloalkyl; OC haloalkyl; C cycloalkyl; OC alkyl; CN; OH; C alk-O-C alkyl; 1-6 1-6 3-6 1-6 1-6 1-6 C(O)-NR R ; and C(O)-C alkyl. The phenyl can be substituted with halogen, for example F or Cl. The phenyl can be substituted with C alkyl, for example, C alkyl, C alkyl, 1-6 1-5 1-4 C alkyl, C alkyl, or C alkyl. The phenyl can be substituted with C haloalkyl, for example, 1-3 1-2 1 1-6 C haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or C haloalkyl. The phenyl can be 1-5 1-4 1-3 1-2 1 substituted with OC haloalkyl, for example, OC haloalkyl, OC haloalkyl, 1-6 1-5 1-4 OC haloalkyl, OC haloalkyl, or OC haloalkyl. The phenyl can be substituted with 1-3 1-2 1 C cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The phenyl can be substituted with OC alkyl, for example, OC alkyl, OC alkyl, OC alkyl, 1-6 1-5 1-4 1-3 OC alkyl, or OC alkyl. The phenyl can be substituted with CN. The phenyl can be substituted 1-2 1 with OH. The phenyl can be substituted with C alk-O-C alkyl, for example, 1-6 1-6 C alk-O-C alkyl, C alk-O-C alkyl, C alk-O-C alkyl, C alk-O-C alkyl, or 1-5 1-5 1-4 1-4 1-3 1-3 1-2 1-2 6 7 6 7 C alk-O-C alkyl. The phenyl can be substituted with C(O)-NR R , wherein R and R are preferably each independently H; C alkyl, for example, C alkyl, C alkyl, C alkyl, 1-6 1-5 1-4 1-3 C alkyl, or C alkyl; or C cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or 1-2 1 3-6 cyclohexyl. More preferably, R and R are each independently H or C alkyl, for example, C 1-6 1- 5alkyl, C1-4alkyl, C1-3alkyl, C1-2alkyl, or C1alkyl. The phenyl can be substituted with C(O)-C1- alkyl, for example, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, or C(O)- 6 1-65 1-4 1-3 1-2 C1alkyl.
In some aspects, G is pyridyl. In these aspects, the pyridyl can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of halogen; C alkyl; C haloalkyl; OC haloalkyl; C cycloalkyl; OC alkyl; CN; OH; C alk-O-C alkyl; 1-6 1-6 3-6 1-6 1-6 1-6 C(O)-NR R ; and C(O)-C alkyl. The pyridyl can be substituted with halogen, for example F or Cl. The pyridyl can be substituted with C alkyl, for example, C alkyl, C alkyl, 1-6 1-5 1-4 C alkyl, C alkyl, or C alkyl. The pyridyl can be substituted with C haloalkyl, for example, 1-3 1-2 1 1-6 C haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or C haloalkyl. The pyridyl can be 1-5 1-4 1-3 1-2 1 substituted with OC haloalkyl, for example, OC haloalkyl, OC haloalkyl, 1-6 1-5 1-4 OC haloalkyl, OC haloalkyl, or OC haloalkyl. The pyridyl can be substituted with 1-3 1-2 1 C cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The pyridyl can be substituted with OC alkyl, for example, OC alkyl, OC alkyl, OC alkyl, 1-6 1-5 1-4 1-3 OC alkyl, or OC alkyl. The pyridyl can be substituted with CN. The pyridyl can be substituted 1-2 1 with –OH. The pyridyl can be substituted with C alk-O-C alkyl, for example, 1-6 1-6 C alk-O-C alkyl, C alk-O-C alkyl, C alk-O-C alkyl, C alk-O-C alkyl, or C alk-O- 1-5 1-5 1-4 1-4 1-3 1-3 1-2 1-2 1 6 7 6 7 C alkyl. The pyridyl can be substituted with C(O)-NR R , wherein R and R are preferably each independently H; C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl; or 1-6 1-5 1-4 1-3 1-2 1 C cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. More preferably, R and R are each independently H or C alkyl, for example, C alkyl, 1-6 1-5 C alkyl, C alkyl, C alkyl, or C alkyl. The pyridyl can be substituted with C(O)-C alkyl, for 1-4 1-3 1-2 1 1-6 example, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, or 1-65 1-4 1-3 1-2 C(O)-C alkyl.
In some aspects, G is pyridazinyl. In these aspects, the pyridazinyl can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of halogen; C alkyl; C haloalkyl; OC haloalkyl; C cycloalkyl; OC alkyl; CN; OH; C alk-O-C alkyl; 1-6 1-6 3-6 1-6 1-6 1-6 C(O)-NR R ; and C(O)-C alkyl. The pyridazinyl can be substituted with halogen, for example F or Cl. The pyridazinyl can be substituted with C alkyl, for example, C alkyl, 1-6 1-5 C alkyl, C alkyl, C alkyl, or C alkyl. The pyridazinyl can be substituted with 1-4 1-3 1-2 1 C haloalkyl, for example, C haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or 1-6 1-5 1-4 1-3 1-2 C1haloalkyl. The pyridazinyl can be substituted with OC1-6haloalkyl, for example, OC1- haloalkyl, OC haloalkyl, OC haloalkyl, OC haloalkyl, or OC haloalkyl. The pyridazinyl 1-4 1-3 1-2 1 can be substituted with C3-6cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The pyridazinyl can be substituted with OC alkyl, for example, OC1-5alkyl, OC1-4alkyl, OC1-3alkyl, OC1-2alkyl, or OC1alkyl. The pyridazinyl can be substituted with CN. The pyridazinyl can be substituted with OH. The pyridazinyl can be substituted with C alk-O-C alkyl, for example, C alk-O-C alkyl, C alk-O-C alkyl, 1-6 1-6 1-5 1-5 1-4 1-4 C alk-O-C alkyl, C alk-O-C alkyl, or C alk-O-C alkyl. The pyridazinyl can be substituted 1-3 1-3 1-2 1-2 1 1 6 7 6 7 with C(O)-NR R , wherein R and R are preferably each independently H; C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl; or C cycloalkyl, for example, 1-5 1-4 1-3 1-2 1 3-6 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. More preferably, R and R are each independently H or C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. 1-6 1-5 1-4 1-3 1-2 1 The pyridazinyl can be substituted with C(O)-C alkyl, for example, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, or C(O)-C alkyl. 1-65 1-4 1-3 1-2 1 In some aspects, G is pyrimidinyl. In these aspects, the pyrimidinyl can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of halogen; C alkyl; C haloalkyl; OC haloalkyl; C cycloalkyl; OC alkyl; CN; OH; C alk-O-C alkyl; 1-6 1-6 3-6 1-6 1-6 1-6 C(O)-NR R ; and C(O)-C alkyl. The pyrimidinyl can be substituted with halogen, for example F or Cl. The pyrimidinyl can be substituted with C alkyl, for example, C alkyl, 1-6 1-5 C alkyl, C alkyl, C alkyl, or C alkyl. The pyrimidinyl can be substituted with 1-4 1-3 1-2 1 C haloalkyl, for example, C haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or 1-6 1-5 1-4 1-3 1-2 C haloalkyl. The pyrimidinyl can be substituted with OC haloalkyl, for example, 1 1-6 OC haloalkyl, OC haloalkyl, OC haloalkyl, OC haloalkyl, or OC haloalkyl. The 1-5 1-4 1-3 1-2 1 pyrimidinyl can be substituted with C cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The pyrimidinyl can be substituted with OC alkyl, for example, OC alkyl, OC alkyl, OC alkyl, OC alkyl, or OC alkyl. The pyrimidinyl can be substituted 1-5 1-4 1-3 1-2 1 with CN. The pyrimidinyl can be substituted with OH. The pyrimidinyl can be substituted with C alk-O-C alkyl, for example, C alk-O-C alkyl, C alk-O-C alkyl, 1-6 1-6 1-5 1-5 1-4 1-4 C alk-O-C alkyl, C alk-O-C alkyl, or C alk-O-C alkyl. The pyrimidinyl can be substituted 1-3 1-3 1-2 1-2 1 1 6 7 6 7 with C(O)-NR R , wherein R and R are preferably each independently H; C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl; or C cycloalkyl, for example, 1-5 1-4 1-3 1-2 1 3-6 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. More preferably, R and R are each independently H or C1-6alkyl, for example, C1-5alkyl, C1-4alkyl, C1-3alkyl, C1-2alkyl, or C1alkyl.
The pyrimidinyl can be substituted with C(O)-C alkyl, for example, C(O)-C1-65alkyl, C(O)-C1-4alkyl, C(O)-C1-3alkyl, C(O)-C1-2alkyl, or C(O)-C1alkyl.
In some aspects, G is benzofuranyl. In these aspects, the benzofuranyl can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of halogen; C alkyl; C haloalkyl; OC haloalkyl; C cycloalkyl; OC alkyl; CN; OH; C alk-O-C alkyl; 1-6 1-6 3-6 1-6 1-6 1-6 C(O)-NR R ; and C(O)-C alkyl. The benzofuranyl can be substituted with halogen, for example F or Cl. The benzofuranyl can be substituted with C alkyl, for example, C alkyl, 1-6 1-5 C alkyl, C alkyl, C alkyl, or C alkyl. The benzofuranyl can be substituted with 1-4 1-3 1-2 1 C haloalkyl, for example, C haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or 1-6 1-5 1-4 1-3 1-2 C haloalkyl. The benzofuranyl can be substituted with OC haloalkyl, for example, 1 1-6 OC haloalkyl, OC haloalkyl, OC haloalkyl, OC haloalkyl, or OC haloalkyl. The 1-5 1-4 1-3 1-2 1 benzofuranyl can be substituted with C cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The benzofuranyl can be substituted with OC alkyl, for example, OC alkyl, OC alkyl, OC alkyl, OC alkyl, or OC alkyl. The benzofuranyl can be 1-5 1-4 1-3 1-2 1 substituted with CN. The benzofuranyl can be substituted with OH. The benzofuranyl can be substituted with C alk-O-C alkyl, for example, C alk-O-C alkyl, C alk-O-C alkyl, 1-6 1-6 1-5 1-5 1-4 1-4 C alk-O-C alkyl, C alk-O-C alkyl, or C alk-O-C alkyl. The benzofuranyl can be 1-3 1-3 1-2 1-2 1 1 6 7 6 7 substituted with C(O)-NR R , wherein R and R are preferably each independently H; C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl; or C cycloalkyl, for example, 1-5 1-4 1-3 1-2 1 3-6 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. More preferably, R and R are each independently H or C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. 1-6 1-5 1-4 1-3 1-2 1 The benzofuranyl can be substituted with C(O)-C alkyl, for example, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, C(O)-C alkyl, or C(O)-C alkyl. 1-65 1-4 1-3 1-2 1 In some aspects, G is thiophenyl. In these aspects, the thiophenyl can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of halogen; C alkyl; C haloalkyl; OC haloalkyl; C cycloalkyl; OC alkyl; CN; OH; C alk-O-C alkyl; 1-6 1-6 3-6 1-6 1-6 1-6 C(O)-NR R ; and C(O)-C alkyl. The thiophenyl can be substituted with halogen, for example F or Cl. The thiophenyl can be substituted with C alkyl, for example, C alkyl, 1-6 1-5 C alkyl, C alkyl, C alkyl, or C alkyl. The thiophenyl can be substituted with 1-4 1-3 1-2 1 C haloalkyl, for example, C haloalkyl, C haloalkyl, C haloalkyl, C haloalkyl, or 1-6 1-5 1-4 1-3 1-2 C1haloalkyl. The thiophenyl can be substituted with OC1-6haloalkyl, for example, OC haloalkyl, OC haloalkyl, OC haloalkyl, OC haloalkyl, or OC haloalkyl. The 1-5 1-4 1-3 1-2 1 thiophenyl can be substituted with C3-6cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The thiophenyl can be substituted with OC alkyl, for example, OC1-5alkyl, OC1-4alkyl, OC1-3alkyl, OC1-2alkyl, or OC1alkyl. The thiophenyl can be substituted with CN. The thiophenyl can be substituted with OH. The thiophenyl can be substituted with C alk-O-C alkyl, for example, C alk-O-C alkyl, C alk-O-C alkyl, 1-6 1-6 1-5 1-5 1-4 1-4 C alk-O-C alkyl, C alk-O-C alkyl, or C alk-O-C alkyl. The thiophenyl can be substituted 1-3 1-3 1-2 1-2 1 1 6 7 6 7 with C(O)-NR R , wherein R and R are preferably each independently H; C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl; or C cycloalkyl, for example, 1-5 1-4 1-3 1-2 1 3-6 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. More preferably, R and R are each independently H or C alkyl, for example, C alkyl, C alkyl, C alkyl, C alkyl, or C alkyl. 1-6 1-5 1-4 1-3 1-2 1 The thiophenyl can be substituted with C(O)-C alkyl, for example, C(O)-C alkyl, C(O)-C 1-6 1-65 1- alkyl, C(O)-C alkyl, C(O)-C alkyl, or C(O)-C alkyl. 4 1-3 1-2 1 In preferred aspects, G is unsubstituted or substituted pyridyl, pyridizinyl, or pyrazinyl.
In those aspects wherein G is substituted pyridyl, pyridizinyl, or pyrazinyl, preferred substituents include C alkyl (e.g., methyl). In other preferred aspects, G is C alkyl (e.g., isopropyl). 1-6 1-6 In preferred aspects, G is unsubstituted or substituted pyridyl, pyridizinyl, or pyrazinyl and E is CH or O. In those aspects wherein G is substituted pyridyl, pyridizinyl, or pyrazinyl and E is CH or O, preferred substituents include C alkyl (e.g., methyl). In other preferred 2 1-6 aspects, G is C alkyl (e.g., isopropyl) and E is CH or O. 1-6 2 In some preferred aspects, A-E-G is: , , or . is H; R is cyclopentyl Preferred compounds of the Formula I include those wherein R 8 3 4 5 substituted with 1 or 2 substituents wherein one of the substituents is NR -C(O)-C(R )=CR (R ), 3 4 5 wherein R , R , and R are each H; A is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with CH E is O or a bond; and G is phenyl or C alkyl. In more preferred aspects, 3; 1-6 2 8 3 4 5 R is substituted with 1 substituent that is NR -C(O)-C(R )=CR (R ). In preferred aspects, A-E- G is , , or .
Preferred subgenera of Formula (I) include: wherein the A phenyl is unsubstituted or substituted, preferably with C alkyl; C alkyl (I-P-2) wherein the A phenyl is unsubstituted or substituted, preferably with C alkyl; wherein the A pyridyl is unsubstituted or substituted, preferably with C alkyl; wherein the A pyridyl is unsubstituted or substituted, preferably with C alkyl; wherein the A pyridyl is unsubstituted or substituted, preferably with C alkyl; C alkyl (I-U-2) wherein the A pyridyl is unsubstituted or substituted, preferably with C alkyl; (I-X-1) wherein the A pyridyl is unsubstituted or substituted, preferably with C alkyl; (I-XU-2) wherein the A pyridyl is unsubstituted or substituted, preferably with C alkyl; (I-Y-1) wherein the A phenyl is unsubstituted or substituted, preferably with C alkyl; and (I-Y-2) wherein the A phenyl is unsubstituted or substituted, preferably with C alkyl.
An additional embodiment described herein is a compound selected from the group consisting of: N-((1S,4S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Hydroxycyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(Dimethylamino)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Hydroxycyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,4R)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,4R)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,4R)Methoxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)((E)Cyanocyclopropylacrylamido)cyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1S,2S)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)-N-((1R,2R)(methylamino)cyclopentyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Cyanamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1R,2R)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,2RS)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-Cyclopentyl(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2R)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1r,3s,5R,7S)Hydroxyadamantanyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)-N-(2-(methylamino)cyclohexyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)oxo-N-((1R,2S)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1R,2S)propionamidocyclohexyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,2RS)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1S,2R)propionamidocyclohexyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2S)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)-N-((1S,2S)(methylamino)cyclopentyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)-N-((1S,2R)(methylamino)cyclohexyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1R,2R)propionamidocyclohexyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Formamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acrylamidocyclopentyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1S,2R)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1S,2S)propionamidocyclohexyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Hydroxycyclopentyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)-N-(4-(methylamino)cyclohexyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1S,4S)propionamidocyclohexyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)oxo-N-((1S,3R)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)-N-((1S,3R)(2-(methylamino)acetamido)cyclopentyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)(2-Aminoacetamido)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)((E)(Dimethylamino)butenamido)cyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; -(2-Methylphenoxyphenyl)-N-((1S,4S)((E)(methylamino)but enamido)cyclohexyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1S,4S)((E)Aminobutenamido)cyclohexyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)-N-((1S)(methylamino)cyclopentyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-Cyclopentyl(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-Cyclopentyl(*R)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,4S)Hydroxycyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Hydroxycyclohexyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,4R)Hydroxycyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,4R)Hydroxycyclohexyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxyphenyl)oxo-N-((1S,3R)propionamidocyclopentyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)((*E)Cyanocyclopropylacrylamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1S,4S)((*E)Cyanocyclopropylacrylamido)cyclohexyl)(*R)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,2R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxyphenyl)oxo-N-((1S,4S)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*R)-(2-Methylphenoxyphenyl)oxo-N-((1S,4S)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acetamidocyclohexyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-(rac-(1,3-cis)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,2R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,4S)(Dimethylamino)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)(Dimethylamino)cyclohexyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)(2-(dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; -(*S)-(2-Methylphenoxyphenyl)-N-((1S,3R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2S)acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-([1,1'-Biphenyl]yl)-N-((1 R,2 S)acrylamidocyclohexyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,3RS)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)(4-isopropoxymethylphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; -(*S)-(2-Methylphenoxyphenyl)-N-((1R,2R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2R)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acrylamidocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxyphenyl)-N-((1R,2S)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,2S)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1S,2R)Acrylamidocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2S)(2-(methylamino)acetamido)cyclohexyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,2R)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,2S)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,2S)(2-(methylamino)acetamido)cyclopentyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(3-chlorophenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2S)Hydroxycyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; -([1,1'-Biphenyl]yl)-N-((1R,2S)aminocyclohexyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,3S)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; -([1,1'-Biphenyl]yl)-N-((1R,2R)hydroxycyclopentyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-(trans-(1R,4R)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; trans-N-((1RS,3RS)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; tert-Butyl ((1R,3S)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclopentyl)carbamate; tert-Butyl trans-((1R,4R)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclohexyl)carbamate; N-((1-Hydroxycyclohexyl)methyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,3R)((E)(Dimethylamino)butenamido)cyclopentyl)(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; -(*S)-(2-Methylphenoxyphenyl)-N-((1S,2R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,3R)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(4-isopropoxymethylphenyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 4-Oxo(2-phenylpyridinyl)-N-((1S,2R)propionamidocyclopentyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(4-isopropoxymethylphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -(4-Isopropoxymethylphenyl)-N-((1S,3R)(2-(methylamino)acetamido)cyclopentyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; tert-Butyl ((1S,4S)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclohexyl)carbamate; N-((1S,3R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenylpyrimidinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-cyclobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-cyclobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(4-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)(3-chlorophenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -([1,1'-Biphenyl]yl)-N-((1R,2S)acrylamidocyclopentyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenoxypyrazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenylpyridazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-cyclobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-isopropoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((tetrahydro-2H-pyran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-isopropylpyridinyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(3-Chloropropanamido)cyclopentyl)(*S)-(4-methylphenoxypyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-isopropoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,3RS)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,3RS)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-cyclobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-isopropoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-(cyclopentyloxy)methylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)-N-((1R,3R)(2-(methylamino)acetamido)cyclopentyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(4-methylphenoxypyridinyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(4-((tetrahydro-2H-pyranyl)oxy)phenyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)(2-Aminoacetamido)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-cyclobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)(2-(Dimethylamino)acetamido)cyclopentyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(2-Methylphenoxyphenyl)-N-((1S,3S)(2-(methylamino)acetamido)cyclopentyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; -(3-Chlorophenoxyphenyl)-N-((1S,3R)((E)(dimethylamino)but enamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 5-([1,1'-Biphenyl]yl)-N-((1R,2S)aminocyclopentyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxyphenyl)-N-((1R,3S)(2-(methylamino)acetamido)cyclohexyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,3S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acetamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-cyclobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(4-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Hydroxycyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(2-isopropylpyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(4-isopropoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*S)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S, S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(6-phenylpyridazinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(6-phenylpyrimidinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(5-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(2-(Methylamino)acetamido)cyclopentyl)oxo(2-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(2-methyl((tetrahydro-2H-pyranyl)oxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(4-((tetrahydro-2H-pyranyl)oxy)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; racemic cisN-((1RS,3RS)Aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; racemic transN-((1RS,3RS)Aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,2RS)Acrylamidocyclopentyl)(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,3RS)Aminocyclopentyl)(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,3RS)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyrazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)acrylamidocyclopentyl)oxo(5-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(*S)-(4-(pyridinyloxy)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((tetrahydro-2H-pyran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridazinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*S,3*S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(5-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*S,3*S)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(5-phenoxypyrazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*S,3*S)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -([2,3'-Bipyridin]yl)-N-((1R,2S)acrylamidocyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,2*S)Aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenylpyridazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*S,3*S)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -([2,2'-Bipyridin]yl)-N-((1R,2S)acrylamidocyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5-([2,3'-Bipyridin]yl)-N-((1R,2R)acrylamidocyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*S)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(6-(isopropylamino)methylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*R)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*R)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*R)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(2-isopropylpyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(2-isopropylpyridinyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-(cyclopentyloxy)methylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-([2,2'-Bipyridin]yl)-N-((1R,2R)acrylamidocyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2S)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*R)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2S)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((tetrahydro-2H-pyran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(5-phenylpyridazinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2R)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3S)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2R)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((2-methylpyridinyl)oxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6-methylpyridinyl)oxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-((6-methylpyridinyl)oxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-((6-methylpyridinyl)oxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-((2-methylpyridinyl)oxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-cyclobutylpyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(2-cyclobutylpyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxyphenyl)oxo-N-((1R,2S)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,2S)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(((S)-tetrahydrofuran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6-methylpyridinyl)oxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3S)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(((R)-tetrahydrofuran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(4-(pyridazinyloxy)phenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3R)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3R)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Hydroxycyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 4-Oxo(4-phenoxyphenyl)-N-((1R,2S)propionamidocyclopentyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3S)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(2-methyl(pyridinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3S)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclopentyl)(*S)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(2-methyl(pyridazinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(4-(pyridazinyloxy)phenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1S,3S)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acetamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1S,3R)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3R)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; (S)(2-Methylphenoxyphenyl)(3-(methylamino)pyrrolidinecarbonyl)-3Hthia- 3,5,8-triazaacenaphthylen-4(5H)-one; (S)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)propionamide; (S)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)acetamide; (S)(3-Aminopyrrolidinecarbonyl)(2-methylphenoxyphenyl)-3Hthia-3,5,8- triazaacenaphthylen-4(5H)-one; (S)(3-(Dimethylamino)pyrrolidinecarbonyl)(2-methylphenoxyphenyl)-3Hthia- 3,5,8-triazaacenaphthylen-4(5H)-one; N-((1R,3R)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3R)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl(pyridazinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl(pyridazinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Aminocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1r,4r)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; (S)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide; (R)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide; (S,E)Cyanocyclopropyl-N-(1-(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide; (R,E)Cyanocyclopropyl-N-(1-(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(4-(pyridinyloxy)phenyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(3-isopropylphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(4-(pyridinyloxy)phenyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,2R)(2-(methylamino)acetamido)cyclohexyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; -(*S)-(2-Methylphenoxyphenyl)-N-((1R,2R)(2-(methylamino)acetamido)cyclohexyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1S,2R)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(4-isopropoxymethylphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclopentyl)(4-isopropoxymethylphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(3-isopropylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2R)Hydroxycyclopentyl)(4-isopropoxymethylphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,2S)Acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; -(4-(3-((2-Cyanophenoxy)methyl)phenoxy)methylphenyl)-N-cyclohexyloxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-(5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)methylphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenyl)cyclopropanecarboxamide; N-Cyclohexyl(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-Cyclohexyloxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N1-((E)(((1S,2R)(5-(6-isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamido)cyclopentyl)amino)oxobutenyl)-N5- (15-oxo((3aS,4S,6aR)oxohexahydro-1H-thieno[3,4-d]imidazolyl)-4,7,10- trioxaazanonadecyl)glutaramide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyrimidinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)((E)Cyanocyclopropylacrylamido)cyclopentyl)(*S)-(6-isobutyl methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,2S)Acrylamidocyclohexyl)(4-methyl(pyridazinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methyloxo(pyridazinyl)-1,6- dihydropyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(4-methyloxo(pyridazinyl)-1,6- dihydropyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridazinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(2-methyl(pyridazinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridazinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((2-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(5-(pyridazinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridazinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(6'-methyloxo-2H-[1,2'-bipyridin]-5'-yl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(5-((6-methylpyridinyl)oxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(5-((6-methylpyridinyl)oxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((6-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyrimidinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyrimidinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyrimidinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((6-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridinyloxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((2-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide ; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridinyloxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(5-((2-methylpyridinyl)oxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((2-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((2-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl(pyrimidinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl(pyrimidinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl(pyridinyloxy)phenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl(pyridinyloxy)phenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)((E)Cyano(3-methyloxetanyl)acrylamido)cyclopentyl)(*S)-(6- isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide; N-((1R,2S)((E)Cyanoethoxymethylpentenamido)cyclopentyl)(*S)-(6- isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide; N1-((E)(((1S,2R)(5-(6-isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamido)cyclopentyl)amino)oxobutenyl)-N5- (15-oxo((3aS,4S,6aR)oxohexahydro-1H-thieno[3,4-d]imidazolyl)-4,7,10- trioxaazanonadecyl)glutaramide; and N-((1R,2S)acrylamidocyclopentyl)oxo(4-(pyrimidinyloxy)phenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; and isotopic variants, and pharmaceutically acceptable salts thereof.
An additional embodiment described herein is a compound selected from the group consisting of: N-((1R,2S)Acrylamidocyclopentyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenoxypyrazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyrimidinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; and N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((2-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; and isotopic variants, and pharmaceutically acceptable salts thereof.
An additional embodiment described herein is a compound of Formula (I) having the Formula (IIa): (IIa) wherein R is selected from the group consisting of: H, Cl and CH ; n is 0 or1; E is O; G is selected from the group consisting of: C alkyl, phenyl, pyridyl, pyridyl substituted with CH , pyrimidinyl, pyridazinyl, tetrahydrofuranyl, tetrahydropyranyl, and Ring B is selected from the group consisting of: R is selected from the group consisting of: OH, OCH , NH , NH(CH ), N(CH ) , NH(CO - 3 2 3 3 2 2 tert-butyl), NH(C=O)C alkyl, NH(C=O)CH=CH , NH(C=O)CH NH , 1-3 2 2 2 NH(C=O)CH NH(CH ), NH(C=O)CH N(CH ) , and NH(C=O)CH=CHCH N(CH ) ; 2 3 2 3 2 2 3 2 R is selected from the group consisting of: OH, OCH , CN, NH , NH(CH ), N(CH ) , 3 2 3 3 2 NH(CO -tert-butyl), NH(C=O)C alkyl, and NH(C=O)CH=CH ; 2 1-3 2 R is H or CN; and R is selected from the group consisting of: CH NH , CH NH(CH ), CH N(CH ) , and 2 2 2 3 2 3 2 cyclopropyl.
An additional embodiment described herein is a compound of Formula (I) having the Formula (IIa) wherein: R is H or CH ; n is 1; E is O; G is selected from the group consisting of: C1-3alkyl, phenyl, pyridyl, and pyridyl substituted with CH3; Ring B is selected from the group consisting of: and R is NH(C=O)CH=CH2.
An additional embodiment described erein is a compound of Formula (I) having the Formula (IIb): (IIb) wherein G-A is selected from the group consisting of: G is selected from the group consisting of: C alkyl, C cycloalkyl, phenyl, 1-6 3-6 and pyridyl.
R is selected from the group consisting of: R is selected from the group consisting of: OH, OCH , NH , NH(CH ), N(CH ) , NH(CO - 3 2 3 3 2 2 tert-butyl), NH(C=O)C alkyl, NH(C=O)CH=CH , NH(C=O)CH NH , 1-3 2 2 2 NH(C=O)CH NH(CH ), NH(C=O)CH N(CH ) , and NH(C=O)CH=CHCH N(CH ) . 2 3 2 3 2 2 3 2 An additional embodiment described herein is a compound of Formula (I) having the Formula (IIb) wherein: G-A is G is phenyl or pyridyl; R is selected from the group consisting of: and R is NH(C=O)CH=CH .
An additional embodiment described herein is a compound of Formula (I) having the Formula (IIc): (IIc) wherein G-E-A is selected from the group consisting of: and ; where G is selected from the group consisting of: C alkyl, phenyl, pyrimidinyl, pyridyl, pyridyl substituted with CH , and C cycloalkyl; and R is H or CH ; 3 3-6 3 Ring B is selected from the group consisting of: R is selected from the group consisting of: OH, OCH , NH , NH(CH ), N(CH ) , NH(CO - 3 2 3 3 2 2 tert-butyl), NH(C=O)C1-3alkyl, NH(C=O)CH=CH2, NH(C=O)CH2NH2, NH(C=O)CH NH(CH ), NH(C=O)CH N(CH ) , and NH(C=O)CH=CHCH N(CH ) . 2 3 2 3 2 2 3 2 An additional embodiment described herein is a compound of Formula (I) having the Formula (IIc) wherein: An additional embodiment described herein is a compound of Formula (I) having the Formula (IIc): wherein G-E-A is 2c 2c 2c G O m m R 2c ; G is C alkyl, phenyl, or pyridyl; R is H or CH ; Ring B is and R is NH(C=O)CH=CH .
The disclosure also relates to methods of using the compounds described herein to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated by Bruton’s tyrosine kinase. These methods are accomplished by administering to the subject a compound of the disclosure in an amount sufficient to inhibit Bruton’s tyrosine kinase.
In a further aspect, described herein are methods for inhibiting Bruton's tyrosine kinase in a subject in need of treatment by administering to the subject a composition containing a therapeutically effective amount of at least one compound of Formula (I). Some aspects of the disclosure are directed to methods of treating a subject suffering from an autoimmune disease by administering to the subject a composition containing a therapeutically effective amount of at least one compound of Formula (I). In some aspects, the autoimmune disease is, e.g., inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome, multiple sclerosis, Guillain- Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus- myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia.
When used for the treatment of an autoimmune disease, the compounds of Formula (I) can be administered as single agents. Alternatively, when used for the treatment of an autoimmune disease, the compounds of Formula (I) can be administered in combination with other agents known to be useful for the treatment of autoimmune diseases.
Other embodiments of the disclosure are directed to methods of treating a subject suffering from a heteroimmune condition by administering to the subject a composition containing a therapeutically effective amount of at least one compound of Formula (I). In some aspects, the heteroimmune condition or disease is, e.g., graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis. When used for the treatment of a heteroimmune condition, the compounds of Formula (I) can be administered as single agents. Alternatively, when used for the treatment of a heteroimmune condition, the compounds of Formula (I) can be administered in combination with other agents known to be useful for the treatment of heteroimmune diseases.
Other embodiments of the disclosure are directed to methods of treating a subject suffering from an inflammatory disease by administering to the subject a composition containing a therapeutically effective amount of at least one compound of Formula (I). In certain embodiments, the inflammatory disease is, e.g., asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis. When used for the treatment of an inflammatory disease, the compounds of Formula (I) can be administered as single agents. Alternatively, when used for the treatment of an inflammatory disease, the compounds of Formula (I) can be administered in combination with other agents known to be useful for the treatment of inflammatory diseases.
Other embodiments of the disclosure are directed to methods of treating a subject suffering from cancer by administering to the subject a composition containing a therapeutically effective amount of at least one compound of Formula (I). In one embodiment, the cancer is a B- cell proliferative disorder, e.g., diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, or lymphomatoid granulomatosis. Cancers that are particularly suited to being treated with compounds of the disclosure include mantle cell lymphoma and chronic lymphocytic leukemia and macroglobulinemia, as well as multiple myeloma. In some embodiments, where the subject is suffering from a cancer, an anti-cancer agent is administered to the subject in addition to one of the above-mentioned compounds. In one embodiment, the anti-cancer agent is an inhibitor of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002. When used for the treatment of cancer, the compounds of Formula (I) can be administered as single agents. Alternatively, when used for the treatment of cancer, the compounds of Formula (I) can be administered in combination with other agents known to be useful for the treatment of cancer.
Other embodiments of the disclosure are directed to methods of treating a subject suffering from a thromboembolic disorder by administering to the subject a composition containing a therapeutically effective amount of at least one compound of Formula (I). In further embodiments, thromboembolic disorder is, e.g., myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, or deep venous thrombosis. When used for the treatment of a thromboembolic disorder, the compounds of Formula (I) can be administered as single agents.
Alternatively, when used for the treatment of a thromboembolic disorder, the compounds of Formula (I) can be administered in combination with other agents known to be useful for the treatment of thromboembolic disorders.
Other embodiments of the disclosure are directed to methods of treating a subject suffering from a respiratory disease by administering to the subject a composition containing a therapeutically effective amount of at least one compound of Formula (I). In some aspects, the respiratory disease is asthma. In a further embodiment of this aspect, the respiratory disease includes, but is not limited to, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma. When used for the treatment of a respiratory disease, the compounds of Formula (I) can be administered as single agents. Alternatively, when used for the treatment of a respiratory disease, the compounds of Formula (I) can be administered in combination with other agents known to be useful for the treatment of respiratory diseases.
In another aspect are methods for preventing rheumatoid arthritis and osteoarthritis comprising administering to the subject, at least once, an effective amount of at least one compound of Formula (I). When used for the treatment of rheumatoid arthritis or osteoarthritis, the compounds of Formula (I) can be administered as single agents. Alternatively, when used for the treatment of rheumatoid arthritis or osteoarthritis, the compounds of Formula (I) can be administered in combination with other agents known to be useful for the treatment of rheumatoid arthritis or osteoarthritis.
In another aspect are methods for treating inflammatory responses of the skin comprising administering to the subject, at least once, an effective amount of at least one compound of Formula (I). Such inflammatory responses of the skin include, by way of example, dermatitis, contact dermatitis, eczema, urticaria, rosacea, and scarring. In another aspect are methods for reducing psoriatic lesions in the skin, joints, or other tissues or organs, comprising administering to the mammal an effective amount of a compound of Formula (I). When used for the treatment of these conditions, the compounds of Formula (I) can be administered as single agents.
Alternatively, when used for the treatment of these conditions, the compounds of Formula (I) can be administered in combination with other agents known to be useful for the treatment of these conditions.
In preferred aspects, compounds of the disclosure can be used to treat rheumatoid arthritis.
Compounds of the disclosure can also be used to treat systemic lupus erythematosus.
Compounds of the disclosure can also be used to treat pemphigus disorders and pemphigoid disorders.
In some aspects, the compounds of Formula (I) can be administered in combination with a CYP 3A4 inhibitor, according to methods known in the art.
In treatment methods according to the disclosure, an effective amount of a pharmaceutical agent according to the disclosure is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition. An "effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic benefit in patients in need of such treatment for the designated disease, disorder, or condition. Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.
In addition, the compounds of the disclosure may be used in combination with additional active ingredients in the treatment of the above conditions. The additional active ingredients may be coadministered separately with a compound of the disclosure or included with such an agent in a pharmaceutical composition according to the disclosure. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the disclosure), decrease one or more side effects, or decrease the required dose of the active agent according to the disclosure.
The compounds of the disclosure are used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions of the disclosure. A pharmaceutical composition of the disclosure comprises: (a) an effective amount of at least one compound in accordance with the disclosure; and (b) a pharmaceutically acceptable excipient.
Delivery forms of the pharmaceutical compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. The compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.
The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, the compositions are formulated for intravenous infusion, topical administration, or oral administration.
For oral administration, the compounds of the disclosure can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds may be formulated to yield a dosage of, e.g., from about 0.05 to about 100 mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about 0.1 to about 10 mg/kg daily. For example, a total daily dosage of about 5 mg to 5 g daily may be accomplished by dosing once, twice, three, or four times per day.
Oral tablets may include a compound according to the disclosure mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin.
The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, compounds of the disclosure may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the compound of the disclosure with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
The active agents of this disclosure may also be administered by non-oral routes. For example, the compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses may range from about 1 to 1000 µ.g/kg/minute of compound, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
For topical administration, the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the compounds of the disclosure may utilize a patch formulation to affect transdermal delivery.
Compounds of the disclosure may alternatively be administered in methods of this disclosure by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.
Exemplary compounds useful in methods of the disclosure will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, the variables are as defined above in reference to Formula (I). Reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0 °C and the reflux temperature of the solvent. Reactions may be heated employing conventional heating or microwave heating. Reactions may also be conducted in sealed pressure vessels above the normal reflux temperature of the solvent.
Compounds of the disclosure can be prepared using the knowledge of one skilled in the art in combination with the present disclosure. For example, compounds of the disclosure can be prepared according to the following schemes and examples.
Abbreviations Table 3. Abbreviations and acronyms used herein include the following.
Table 3.
Term Acronym/Abbreviation Acetonitrile ACN, MeCN tert-Butylcarbamoyl BOC Di-tert-butyl dicarbonate (Boc) O Benzotriazolyloxytris(dimethylamino)-phosphonium BOP hexafluorophosphate 1,1'-Carbonyldiimidazole CDI Diatomaceous Earth CELITE 545, (1-Cyanoethoxyoxoethylidenaminooxy)dimethylamino- COMU morpholino-carbenium hexafluorophosphate 1,8-Diazabicyclo[5.4.0]undecene DBU Methylene chloride, dichloromethane DCM Diisopropyl azodiformate DIAD N, N-Diisopropylethylamine DIPEA, DIEA, Hunig’s base Term Acronym/Abbreviation N,N-Dimethylformamide DMF 4-Dimethylaminopyridine DMAP Dimethyl sulfoxide DMSO Deutero-dimethyl sulfoxide DMSO-d Diphenylphosphino ferrocene dppf Bis[(2-diphenylphosphino)phenyl] ether DPEphos Di-tert-butylphosphino ferrocene dtbpf 1-Ethyl(3-dimethylaminopropyl)carbodiimide EDCI, EDC, EDAC Electrospray Ionisation ESI Ethyl Acetate EtOAc, or EA, or AcOEt Ethanol EtOH Flash Column Chromatography FCC 2-(1HAzobenzotriazoleyl)-1,1,3,3-tetramethylaminium HATU hexafluorophosphate Acetic Acid HOAc, AcOH 1-Hydroxyazabenzotriazole HOAT, HOAt 1-Hydroxy-benzotriazole HOBt High-pressure liquid chromatography HPLC Isopropyl Alcohol IPA Deteromethanol MeOD-d Methanol MeOH Methanesulfonyl chloride MsCl Term Acronym/Abbreviation Methyl tert-butyl ether MTBE Sodium methoxide NaOMe Tetrakis(triphenylphosphine)palladium(0) Pd(PPh ) Palladium(II) acetate Pd(OAc) [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl Palladium(II)bis(triphenylphosphine) dichloride, PdCl2(PPh3)2 bis(triphenylphosphine)palladium(II) dichloride Triphenylphosphine PPh Precipitate ppt p-Toluenesulfonic acid p-TsOH, PTSA (benzotriazolyl-oxytripyrrolidinophosphonium PyBOP hexafluorophosphate) Bromotripyrrolidinophosphonium hexafluorophosphate PyBrOP Room temperature rt Supercritical Fluid Chromatography SFC Thionyl chloride SOCl Tetrabutylammonium fluoride TBAF tert-Butyl(chloro)dimethylsilane TBSCl Triethyl amine TEA Trifluoroacetic acid TFA Trifluoroacetic anhydride TFAA Tetrahydrofuran THF Term Acronym/Abbreviation Thin Layer Chromatography TLC PREPARATIVE EXAMPLES Exemplary compounds useful in methods of the invention will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples to follow.
SCHEME 1 According to SCHEME 1, a compound of formula (VI), where ring B is a C cycloalkyl, Y is OH or NH , and PG is a suitable nitrogen protecting group such as BOC, is commercially available or is synthetically accessible employing conditions known to one skilled in the art, from a compound of formula (V). Acylation of a compound of formula (VI), where Y is NH , with a suitable acylating agent such as the anhydrides and halides of carboxylic acids such as acetic anhydride, propionic anhydride, propenoyl chloride, C alkyl(C=O)Cl, and the like, in the presence of a suitable base such as TEA, DIPEA, and the like, with or without the presence of a reagent such as DMAP, in a suitable solvent such as THF, DCM, and the like, at temperatures ranging from 0 °C to 25 °C, for a period of 2 to 6 h, to provide a compound of where Y is NH , and R is (C=O)CH=CH , and (C=O)C alkyl. In cases where the amine 2 2 1-6 compound has a tert-butylcarbamate (BOC) protecting group (PG), removal of the tert- butylcarbamate (BOC) protecting group (PG), is accomplished by using an acid such as HCl, TFA, p-toluenesulfonic acid, in a solvent sich as MeOH, dioxane, or DCM. In a preferred embodiment, deprotection is achieved with HCl/MeOH or TFA/DCM.
A compound of formula (VI), where ring B is a C cycloalkyl, and Y is NH is prepared -6 2 from a compound of formula (VI), where ring B is a C cycloalkyl, and Y is OH under Mitsonobu conditions. In two steps, reaction of a compound of formula (VI), where Y is OH, with triphenylphosphane, DIAD, and, phthalimide, followed by hydrazinolysis with hydrazine hydrate in a solvent such as EtOH, provides a compound of formula (VI), where ring B is a C cycloalkyl, PG is BOC, and Y is NH .
A compound of formula (VI), where ring B is a C cycloalkyl, PG is BOC, and Y is CO H, is reacted with diphenyl phosphorazidate (DPPA), phenylmethanol, and a base such as TEA, in a solvent such as toluene, at a temperature of about 100 °C, for a period of 18-24 h, to provide a compound (VI) where PG is BOC, and Y is NH-(C=O)OCH phenyl. Deprotection of the CBz, under conditions known to one skilled in the art, for example, hydrogenation using (H , psi) using Pd(OH) , affords a compound of formula (VI), where PG is BOC, and Y is NH .
SCHEME 2 According to SCHEME 2, a synthetically accessible or commercially available compound of formula (VIII), where A is phenyl, or a six membered heteroaryl ring containing one or two nitrogen members, HAL is Br or F, and R is independently H, halo, and CH , is reacted in an aromatic nucleophilic substitution reaction with a commercially available or synthetically accessible alcohol of formula G -OH (X), where G is phenyl, C cycloalkyl, or C 3-6 1- alkyl, a suitable base such as NaH, Na CO , NaHCO , K CO , Cs CO , and the like, in a 6 2 3 3 2 3 2 3 suitable solvent such as DMF, DMA, THF, dioxane, and the like, to provide a compound of formula (XII), where E is O.
In an alternate method, a compound of formula (XII), where E is O, is prepared from a compound of formula (VIII), where HAL is F, and R is OH, in a coupling reaction. For example, reaction of a compound of formula (VIII) with a commercially available or synthetically accessible aryl or heteroaryl boronic acid or ester such as phenyl boronic acid a metal catalyst such as copper (II) acetate, a base such as trimethylamine, in a solvent such as DCM, and the like, for a period of about 16 h, provides a compound of formula (XII) where R is F and E is O.
A compound of formula (IX), where R is C alkyl, is reacted with a commercially available or synthetically accessible compound of formula LG-G (XI), where LG is a leaving group such as Cl, Br, I, or methanesulfonate, and G is C alkyl, C cycloalkyl or C 1-6 3-6 3- heterocycloalkyl, a suitable base such as NaH, Na CO , NaHCO , K CO , Cs CO , and the like, 6 2 3 3 2 3 2 3 in a suitable solvent such as DMF, DMA, THF, dioxane, and the like, to provide a compound of formula (XII), where E is O, and G is C alkyl, C cycloalkyl or C heterocycloalkyl. 1-6 3-6 3-6 A compound of formula (XII), where ring A is pyridyl, E is N-PG, and G is C alkyl, is prepared from a compound of formula (VII), where HAL is Cl, and R is C alkyl. For example, 2-chloromethylnitropyridine is reacted with an amine such as propanamine, followed by reaction with DMAP, di-tert-butyl dicarbonate, in a solvent such as THF, to provide a compound of formula (XII), where ring A is pyridyl, E is N, substituted with a protecting group (BOC), and G is C alkyl.
Reduction of the nitro moiety of a compound of formula (XII), where E is O or N-PG, G is phenyl, C alkyl, C cycloalkyl, pyridyl, employing conditions known to one skilled in the 1-6 3-6 art, for example, reduction with iron (Fe), in a solvent such as EtOH/water, in the presence of NH Cl or concentrated HCl, at a temperatures ranging from 0 °C to 25 °C, for a period of 2 to 6 h, provides the corresponding aniline of formula (XIII). Reduction of a nitro compound of formula (VII), is also achieved using hydrogenation conditions, for example, reaction with a palladium catalyst such as Pd/C, Pd(OH) , Pt/C and the like, in a suitable solvent such as THF, MeOH, EtOAc, or a mixture thereof, in the presence of H (for example at atmospheric pressure or at 30 to 50 PSI), at temperatures ranging from rt to 50 °C, to provide an amine compound of formula (XIII). Reduction of a nitro compound of formula (XII), is also achieved employing Zn, ammonium chloride, in a suitable solvent or solvent mixture such as acetone/water, at a temperature ranging from 0 °C to rt, for a period of about 2-6 h, to provide an amine compound of formula (XIII).
SCHEME 3 According to SCHEME 3, a compound of formula (XIV), where ring A is a suitably substituted phenyl or heteroaryl containing 1-2 nitrogen members, and HAL is I, Cl, or Br, and R is C alkyl, is reacted in a Copper-Catalyzed Cross-Coupling reaction with a compound of formula G -OH, where G is phenyl, or heteroaryl containing 1-2 nitrogen members. For example, a compound of formula (XV) such as 2-chloromethylpyrimidinamine, is reacted with a compound of formula (X), such as phenol, a copper catalyst such as Cu, CuI, and the like, N,N-dimethylglycine, a base such as K CO , Cs CO , and the like, in a suitable solvent such as 2 3 2 3 dioxane, DMSO, and the like, at a temperature of about 90 °C, for a period of 1 to 3 days, provides 4-methylphenoxypyrimidinamine. In an alternate method, coupling reactions are performed in the absence of a catalyst, employing microwave or conventional heating, with a base such as K CO , in a solvent such as DMSO.
A compound of formula (XVI) is also prepared from a compound of formula (IX) in two steps. In a first step, coupling with a compound of formula (IX), where ring A is phenyl, or a heteroaryl ring containing 1-2 nitrogen members, R is C alkyl, is reacted with a compound of formula LG-G , where LG is Cl, and G is C alkyl, or 6 membered heteroaryl ring containing 1 to 2 nitrogen members as previously described. In a second step, reduction of the nitro moiety employing conditions known to one of skill in the art provides a compound of formula (XVI).
SCHEME 4 According to SCHEME 4, an aryl halide compound of formula (XIV), where ring A is phenyl, or a heteroaryl ring containing 1-2 nitrogen members, HAL is Cl, Br, and R is H or C1- alkyl, undergo a transition metal catalyzed cross-coupling reaction such as Suzuki, Negishi, and Grignard reactions. For example, reaction of a compound of formula (XIV) with a commercially available or synthetically accessible alkyl or aryl boronic acid or ester, in the presence of a suitable palladium catalyst such as Pd(PPh3)4, Pd(OAc)2, Pd(dppf)Cl2, and the like, a base such as Cs CO , K CO , Na CO , and the like, in a suitable solvent such as ACN, THF, MeOH, 2 3 2 3 2 3 EtOH, toluene, dioxane, water, or a mixture thereof, employing conventional or microwave heating, at temperatures ranging from 80 °C to 120 °C, for a period of 12, to 24 h, to provide a compound of formula (XVII), where G is C alkyl, or phenyl.
In a similar fashion, an aryl an aryl halide compound of formula (XIV), where ring A is phenyl, or a heteroaryl ring containing 1-2 nitrogen members, HAL is Cl, Br, and R is H or C alkyl, is reacted with a Grignard reagent such as such as isopropylmagnisium chloride, or an organozinc reagent such as isobutylzinc(II) bromide, cyclobutylzinc(II) bromide, and the like, in the presence of a palladium catalyst such as Pd(dppf)Cl · DCM, Pd(dppf) Cl , and the like, in a 2 2 2 suitable solvent such THF, at temperatures ranging from -78 °C to the reflux temperature of the solvent, to provide a compound of formula (XVII), where G is C alkyl.
SCHEME 5 According to SCHEME 5, aryl halides of formula (XVIII), where HAL is I, Cl or Br, undergo a palladium catalyzed arylation with a compound of formula (XVI) or (XVII), where G is phenyl, and C cycloalkyl, R is H or C alkyl, in the presence of a palladium catalyst such as 3-6 1-6 Pd(OAc) , Pd (dba) , and the like, a ligand such as Xantphos, S-Phos, BINAP, DPEPhos, a 2 2 3 suitable base such as NaOtBu, Cs CO , K PO , and the like, in a suitable solvent such as ACN, 2 3 3 4 THF, toluene, dioxane, and the like, employing conventional or microwave heating, at temperatures ranging from 60 to 120 °C, to provide a compound of formula (XIX), where E is a bond, or O.
SCHEME 6 G E G E N NH NH NH 1. CDI S Ar CN N Cyclization CO H CO CH Cyclization 2. Hydrolysis S N Cl N (XIX) (XX) (XXI) According to SCHEME 6, a nitrile compound of formula (XIX) is reacted in a nucleophilic aromatic substitution reaction with ethyl thioacetate, under basic conditions, followed by ring closure, to afford a thienopyridine-carboxylate compound of formula (XX). A compound of formula (XXI) is prepared in two steps from a compound of formula (XX). In a first step, reaction of a compound of formula (XX) with CDI; in suitable solvent such as 1,dioxane, and the like; at reflux temperature; for a period of 12-24 h. In a second step, hydrolysis of the ester moiety, with a suitable base such as NaOH, LiOH, and the like, in a solvent such as MeOH, and the like, at temperatures ranging from rt to 50 °C, for a period of 12 to 24 h, affords an acid compound of formula (XXI).
SCHEME 7 According to SCHEME 7, an acid compound of formula (XXI), as described above, is first converted to an acid chloride compound of formula (XXII). For example, a compound of formula (XXI) is treated with a chlorinating agent such as thionyl chloride and the like; in a solvent such as toluene, and the like, to form a compound of formula (XXII).
Coupling reactions are achieved by conventional amide bond forming techniques which are well known to one of skill in the art as depicted in SCHEME 5. For example, an acyl halide (e.g., chloride) compound of formula (XXI), is reacted with (1s,3r,5R,7S)aminoadamantan ol, or an amine of formula (V), (VI), or (VII) in the presence of an excess of a tertiary amine, such as TEA, pyridine, and the like, optionally in the presence of a suitable catalyst such as DMAP, in a suitable solvent such as DCM or THF, at a temperature ranging from room temperature to the reflux temperature of the solvent, to provide a compound of Formula (I). A variety of other amino acid coupling methodologies are used to couple the compounds of formula (XXI). Reaction of a commercially available or synthetically accessible amine of formula (V), (VI), or (VII); with a suitably substituted acid of formula (XXI) under amide bond forming conditions provides a compound of Formula (I). In a preferred embodiment, a compound of formula (V), (VI), or (VII), either as a free base or as an acid salt, is reacted with an acid compound of formula (XXI), in the presence of a dehydrating agent such as HOBt/EDAC, HATU, HOAT, T3P , and the like; a suitably selected base such as DIPEA, TEA, and the like; in an organic solvent or mixture thereof such as toluene, acetonitrile, ethyl acetate, DMF, THF, methylene chloride, and the like; to afford a compound of Formula (I). In a particularly preferred embodiment, the dehydrating agent is HATU and the base is TEA or DIPEA. In cases where the amine compound of formula (V), (VI), or (VII) has a tert- butylcarbamate (BOC) protecting group (PG), removal of the tert-butylcarbamate (BOC) protecting group (PG), is accomplished by using an acid such as HCl, TFA, p-toluenesulfonic acid, in a solvent such as MeOH, dioxane, or DCM. In a preferred embodiment, deprotection is achieved with HCl/MeOH or TFA/DCM.
A compound of Formula (I), where R is C cycloalkyl substituted with NH , is reacted -6 2 under reductive amination conditions with an suitable aldehyde such as formaldehyde, paraformaldehyde, a reducing agent such as NaBH , NaBH(OAc) , and the like, in a suitable solvent such as DCM, MeOH, THF, and the like, to afford a compound of Formula (I), where R is C cycloalkyl substituted with N(CH ) . In an alternate method, a compound of Formula (I), -6 3 2 where R is C cycloalkyl substituted with NH , is reacted in a two-step synthesis, with -6 2 paraformaldehyde, to form the imine in a first step, followed by hydrogenation with H and Pd/C to afford a compound of Formula (I), where R is C cycloalkyl substituted with NH(CH ). -6 3 A compound of Formula (I), where R is C cycloalkyl substituted with NH , is reacted -6 2 with acylating agent such as the anhydrides and halides of carboxylic acids such as acetic anhydride, propenoyl propenoate, propionic anhydride, C alkyl(C=O)Cl, and the like, under conditions previously described, to provide a compound of Formula (I), where R is C cycloalkyl substituted with NH(C=O)C alkyl, and NH(C=O)CH=CH . 6 1-3 2 A compound of Formula (I), where R is C cycloalkyl substituted with NH is reacted -6 2 with a suitable acid of such as 2-(dimethylamino)acetic acid, Boc-sarcosine, 2-(tert- butoxycarbonylamino)acetic acid, (E)(dimethylamino)butenoic acid, acrylic acid, and the like, under amide bond forming conditions previously described conditions to provide a compound of Formula (I), where R is C cycloalkyl substituted with NH(C=O)CH NH ; -6 2 2 NH(C=O)CH NH(CH ); and NH(C=O)CH N(CH ) . A deprotection step, employing conditions 2 3 2 3 2 previously described is employed where applicable.
A compound of Formula (I), where R is C cycloalkyl substituted with NH is reacted -6 2 with an N-cyanating reagent such as BrCN, a base such as TEA, in a solvent such as DCM, to provide a compound of Formula (I), where R is C cycloalkyl substituted with NH-CN.
A compound of Formula (I), where R is C cycloalkyl substituted with NH(CH ) is -6 3 formed in two steps from a compound of Formula (I), where R is C cycloalkyl substituted with OH. In a first step, oxidation with an oxidizing agent such as Dess-Martin periodinane and the like, in a suitable solvent such as DCM, for a period of about 16 h. In a second step, reaction of the keto compound under reductive amination conditions previously described, provides a compound of Formula (I), where R is C5-6cycloalkyl substituted with NH(CH3).
A compound of Formula (I), where R is C cycloalkyl substituted with NH(CH ) may -6 3 be formed in two steps from a compound of Formula (I), where R is C5-6cycloalkyl substituted with OH. In a first step, conversion of the OH to the 4-methylbenzenesulfonate, by reaction with a suitable base such as DIEA, 4-methylbenzenesulfonyl chloride, in a suitable solvent such as DCM may provide the 4-methylbenzenesulfonate. Subsequent reaction with a suitable amine such as methyl amine, and the like, may provide a compound of Formula (I), where R is C cycloalkyl substituted with NH(CH ).
Compounds of Formula (I) may be converted to their corresponding salts using methods known to one of ordinary skill in the art. For example, an amine of Formula (I) is treated with trifluoroacetic acid, HCl, or citric acid in a solvent such as Et O, CH Cl , THF, MeOH, 2 2 2 chloroform, or isopropanol to provide the corresponding salt form. Alternately, trifluoroacetic acid or formic acid salts are obtained as a result of reverse phase HPLC purification conditions.
Cyrstalline forms of pharmaceutically acceptable salts of compounds of Formula (I) may be obtained in crystalline form by recrystallization from polar solvents (including mixtures of polar solvents and aqueous mixtures of polar solvents) or from non-polar solvents (including mixtures of non-polar solvents).
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
Compounds prepared according to the schemes described above may be obtained as single forms, such as single enantiomers, by form-specific synthesis, or by resolution.
Compounds prepared according to the schemes above may alternately be obtained as mixtures of various forms, such as racemic (1:1) or non-racemic (not 1:1) mixtures. Where racemic and non- racemic mixtures of enantiomers are obtained, single enantiomers may be isolated using conventional separation methods known to one of ordinary skill in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation. Where regioisomeric or diastereomeric mixtures are obtained, as applicable, single isomers may be separated using conventional methods such as chromatography or crystallization.
The following specific examples are provided to further illustrate the invention and various preferred embodiments.
EXAMPLES In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.
Unless otherwise stated, reaction mixtures were magnetically stirred at rt (rt) under a nitrogen atmosphere. Where solutions were "dried," they were generally dried over a drying agent such as Na SO or MgSO . Where mixtures, solutions, and extracts were "concentrated", 2 4 4 they were typically concentrated on a rotary evaporator under reduced pressure. Reactions under microwave irradiation conditions were carried out in a Biotage Initiator or CEM (Microwave Reactor) Discover instrument.
Normal-phase silica gel chromatography (FCC) was performed on silica gel (SiO ) using prepacked cartridges.
Preparative reverse-phase high performance liquid chromatography (RP HPLC) was performed on either: An Agilent HPLC with an Xterra Prep RP18 column (5 µM, 30 x 100 or 50 x 150mm) or an XBridge C18 OBD column (5 µM, 30 x 100 or 50 x 150mm), and a mobile phase of 5% ACN in 20mM NH OH was held for 2 min, then a gradient of 5-99% ACN over 15 min, then held at 99% ACN for 5 min, with a flow rate of 40 or 80 mL/min.
A Shimadzu LC-8A Series HPLC with an Inertsil ODS-3 column (3 μm, 30 x 100mm, T = 45 °C), mobile phase of 5% ACN in H O (both with 0.05% TFA) was held for 1 min, then a gradient of 5-99% ACN over 6 min, then held at 99% ACN for 3 min, with a flow rate of 80 mL/min.
A Shimadzu LC-8A Series HPLC with an XBridge C18 OBD column (5 μm, 50 x 100mm), mobile phase of 5% ACN in H O (both with 0.05% TFA) was held for 1 min, then a gradient of 5-99% ACN over 14 min, then held at 99% ACN for 10 min, with a flow rate of 80 mL/min.
A Gilson HPLC with an XBridge C18 column (5µm, 100 x 50mm), mobile phase of 5- 99% ACN in 20 mM NH4OH over 10 min and then hold at 99 ACN for 2 min, at a flow rate of 80 mL/min.
Quality control testing includes identity, chemical, and radiochemical purity by HPLC using an XBridge C18 (5µm, 4.6 x 250 mm) column eluted with a mixture of methanol/ammonium acetate 5 mM, 65/35, v/v at a flow rate of 1 mL/min equipped with serial UV (280 nm) and gamma detection.
Preparative supercritical fluid high performance liquid chromatography (SFC) was performed either on a Jasco preparative SFC system, an APS 1010 system from Berger instruments, or a SFC-PICLAB-PREP 200 (PIC SOLUTION, Avignon, France). The separations were conducted at 100-150 bar with a flow rate ranging from 40-60 mL/min. The column was heated to 35-40 °C.
Mass spectra (MS) were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) mass corresponds to the exact mass.
Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers. Definitions for multiplicity are as follows: s = singlet, d = doublet, t= triplet, q = quartet, m = multiplet, br = broad. It will be understood that for compounds comprising an exchangeable proton, said proton may or may not be visible on an NMR spectrum depending on the choice of solvent used for running the NMR spectrum and the concentration of the compound in the solution.
Chemical names were generated using ChemDraw Ultra 12.0, ChemDraw Ultra 14.0 (CambridgeSoft Corp., Cambridge, MA) or ACD/Name Version 10.01 (Advanced Chemistry).
Compounds designated as *R or *S are enantiopure compounds where the absolute configuration was not determined.
CHIRAL SEPARATION METHOD 1. The atropisomers were chromatographed to isolate the two separate atropisomers, with the respective single atropisomers arbitrarily labeled as *S or *R to indicate that the compound is a single atropisomer of unknown absolute configuration. In cases for which absolute configuration of a single atropisomeric compound was determined, the atropisomers are named as either S or R throughout (with S corresponding to the alternate designations aS, Sa, or P; and with R corresponding to the alternate designations aR, Ra, or M).
The purification was performed on a chiral SFC column (Stationary phase: Whelk O1 (S,S), 5 µm, 250 × 21.1mm column. The mobile phase was: 40% CO2, 60% MeOH (0.2% formic acid)).
CHIRAL SEPARATION METHOD 2. The atropisomers were chromatographed to isolate the two separate atropisomers, with the respective single atropisomers arbitrarily labeled as *S or *R to indicate that the compound is a single atropisomer of unknown absolute configuration. In cases for which absolute configuration of a single atropisomeric compound was determined, the atropisomers are named as either S or R throughout (with S corresponding to the alternate designations aS, S , or P; and with R corresponding to the alternate designations aR, R , or M).
The purification was performed on a chiral SFC column (Stationary phase: Chiralpak AD-H, 5 µm, 250 × 21.1mm column. The mobile phase was: 60% CO , 40% EtOH (0.3% iPrNH ).
Intermediate 1. 5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
Step A: 2-Methylnitrophenoxybenzene. To a round bottom flask were added phenol (42.5 g, 452 mmol), K CO (125 g, 905 mmol), and DMF (500 mL). To the reaction mixture was added 5-fluoronitrotoluene (70.2 g, 452 mmol) and the reaction was stirred at 80 °C for 16 h under N . The reaction was diluted with saturated NH Cl and extracted with MTBE (3 × 400 mL). The organic layers were combined, dried (Na SO ), filtered, and concentrated to dryness to yield the title compound (100 g, 92% yield) as a brown oil.
Step B: 2-Methylphenoxyaniline. To a solution of 2-methylnitrophenoxybenzene (100 g, 436 mmol) in EtOH/H2O (3:1 ratio, 2000 mL) were sequentially added NH4Cl (117 g, 2180 mmol) and Fe (97 g, 1700 mmol). The reaction mixture was heated to reflux for 2 h, then the reaction was cooled to 25 °C and concentrated to dryness. To the residue was added water and EtOAc and the organic layer was separated, washed with saturated NaHCO and saturated brine, dried (MgSO4), filtered, and concentrated to dryness to yield the title compound (82 g, 90% yield).
Step C: 2-Chloro(2-methylphenoxyanilino)pyridinecarbonitrile. To a round bottom flask under a N atmosphere were added 2-methylphenoxyaniline (30 g, 150 mmol), 2-chloro- 4-iodopyridinecarbonitrile (51.6 g, 195 mmol), and dioxane (200 mL), followed by bis(2- diphenylphosphinophenyl)ether (DPEphos) (16 g, 30 mmol), Pd(OAc) (3.36 g, 15 mmol), and K PO (89 g, 420 mmol). The reaction mixture was stirred at 100 °C overnight. The reaction mixture was filtered and purified flash column chromatography to yield the title compound (32 g, 63% yield) as a yellow solid.
Step D: Methyl 3-amino(2-methylphenoxyanilino)thieno[2,3-b]pyridinecarboxylate. To a round bottom flask were added 2-chloro(2-methylphenoxyanilino)pyridinecarbonitrile (36 g, 107 mmol) in MeOH (150 mL). To this solution was added NaOMe (14.5 g, 268 mmol) in MeOH (30 mL), followed by methyl 2-sulfanylacetate (23 g, 217 mmol). The reaction mixture was refluxed overnight. The reaction mixture was cooled and the yellow precipitate was filtered off, washed with MeOH, and dried to yield the title compound (30 g, 75% yield) as a yellow solid.
Step E: Methyl 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylate. To a round bottom flask were added methyl 3-amino(2- methylphenoxyanilino)thieno[2,3-b]pyridinecarboxylate (30.6 g, 75.5 mmol), carbonyldiimidazole (CDI, 49 g, 300 mmol), and 1,4-dioxane (500 ml). The reaction was stirred at reflux overnight. Then the reaction mixture was concentrated to dryness and to the residue was added to MeOH (200 mL) and the precipitate that formed was filtered off and dried to yield the title compound (28.1 g) as a yellow solid.
Step F: 5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. To a round bottom flask were added methyl 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylate (9.2 g, 21 mmol), lithium hydroxide (4.47 g, 106 mmol), THF (200 mL), MeOH (200 mL), and water (50 mL). The reaction mixture was stirred at 50 °C for 15 h. The mixture was concentrated to dryness and diluted with H O. The pH was adjusted to 2 with 1 M HCl and the precipitate was filtered and dried to yield the title compound (8.1 g, 91% yield) as yellow solid. MS (ESI): mass calcd. for C H N O S, 417.08; m/z found, 418.0 [M+H] . 22 15 3 4 Intermediate 2: 4-Oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxylic acid.
Step A. 1-Nitrophenoxybenzene. The title compound was prepared in a manner analogous to Intermediate 1, Step A, using 4-fluoronitrobenzene and phenol, and substituting sodium carbonate for potassium carbonate.
Step B. 4-Phenoxyaniline. The title compound was prepared in a manner analogous to Intermediate 16, Step B using 1-nitrophenoxybenzene. In an alternate method, the title compound was prepared using Pt/C, in THF, at 50 atm of H .
Step C. 4-Oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-F, using 4-phenoxyaniline and 2-chloroiodopyridinecarbonitrile in Step C. MS (ESI): mass calcd. for C H N O S, 403.41; m/z found, 404.0 [M+H] . H NMR (400 MHz, 21 13 3 4 DMSO-d ): δ 10.07 (br. s., 1H), 8.38 (d, J=5.2 Hz, 1H), 7.51 - 7.42 (m, 4H), 7.26 - 7.11 (m, 5H), 6.11 (d, J=5.2 Hz, 1H).
Intermediate 3. 5-(2-Fluoromethylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
Step A: 4-Bromofluoromethylaniline. To a round bottom flask were added 2-fluoro methylaniline (7 g, 56 mmol) and anhydrous DMF (100 mL). The reaction mixture was cooled in an ice bath, placed under a nitrogen atmosphere, and treated with N-bromosuccinimide (10 g, 56 mmol). The reaction was allowed to warm to rt and was stirred at rt for 10 min. The reaction mixture was poured into a water solution of diluted brine and extracted with EtOAc. The combined organic extracts were washed with diluted brine (3X), dried (MgSO ), filtered through a pad of silica, and concentrated to dryness. The residue was purified by flash column chromatography yield the title compound (6.84 g, 60% yield) as a yellow foam.
Step B: 5-(2-Fluoromethylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps A and C-F, using 4-bromofluoromethylaniline in Step A. MS (ESI): mass calcd. for C H FN O S, 435.07; m/z found, 436.1 [M+H] . 22 14 3 4 Intermediate 4: 2-Chloro[4-(cyclohexoxy)methylanilino]pyridinecarbonitrile.
Step A: 2-Chloro(4-methoxymethylanilino)pyridinecarbonitrile. A mixture of 2-chloro- 4-iodopyridinecarbonitrile (1.7 g, 6.4 mmol), 4-methoxymethylaniline (880 mg, 6.4 mmol), DPEPhos [bis(2-diphenylphosphinophenyl)ether] 690 mg, 1.3 mmol), palladium(II) acetate (145 mg, 0.646 mmol), and K PO (3.7 mg, 0.017 mmol) in dioxane (20 mL) was degassed under vacuum and heated at 120 °C overnight. The mixture was cooled to rt, concentrated to dryness, and purified by flash column chromatography to yield the title compound (1.1 g, 63% yield) as a brown solid.
Step B: 2-Chloro(4-hydroxymethylanilino)pyridinecarbonitrile. To a solution of 2- chloro(4-methoxymethylanilino)pyridinecarbonitrile (1.1 g, 4.0 mmol) in anhydrous DCM (15 mL) was carefully added a solution of boron tribromide in DCM (1 M, 12 mL 3.0 equiv, 12 mmol) at 0 °C, and was stirred at rt for 4 h. The reaction was quenched with water (20 mL), extracted with ethyl ether, and concentrated to dryness. The residue was purified by flash column chromatography to yield the title compound (900 mg, 86% yield) as yellow solid.
Step C: 2-Chloro[4-(cyclohexoxy)methylanilino]pyridinecarbonitrile. To a mixture of 2-chloro(4-hydroxymethylanilino)pyridinecarbonitrile (1.0 g, 3.9 mmol), cyclohexanol (1.16 g, 11.6 mmol), and PPh (1.5 g, 5.7 mmol) in THF (20 mL) at 0 °C was added DIAD (1.17 g, 5.79 mmol). The mixture was stirred at rt overnight. The mixture was concentrated to dryness and the residue was purified by flash column chromatography to yield the title compound (400 mg, 30% yield) as yellow solid. MS (ESI): mass calcd. for C H ClN O, 19 20 3 341.13; m/z found, 342 [M+H] .
Intermediate 5: 5-(4-(Cyclohexyloxy)methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
The title compound was prepared in a manner analogous to Intermediate 1, Steps D-F, using, 2- chloro[4-(cyclohexoxy)methylanilino]pyridinecarbonitrile (Intermediate 4, product from Step D) in Step D. MS (ESI): mass calcd. for C H N O S, 423.13; m/z found, 424.1 [M+H] . 22 21 3 4 Intermediate 6. 5-(2-Fluorophenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
Step A. 2-Fluoronitrophenoxybenzene. A solution of phenylboronic acid (1 g, 8.2 mmol), 3-fluoronitrophenol (2.6 g, 16.5 mmol), copper (II) acetate (1.9 g, 10.5 mmol), trimethylamine (2.5 g, 24.7 mmol), molecular sieves, in DCM (50 mL) was stirred at rt for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. Purification (FCC, SiO , Petroleum ether: Ethyl acetate = 100: 1 - 50: 11) afforded the title compound (400 mg, 21%).
Step B. 5-(2-Fluorophenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 25, Steps B-C using 2-Fluoronitrophenoxybenzene in Step B. MS (ESI): mass calcd. for C H FN O S, 421.05; m/z found, 422.1 [M+H] . 21 12 3 4 Intermediate 7: 5-(4-Isopropoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
Step A. 1-Isopropoxynitrobenzene. The title compound was prepared in a manner analogous to Intermediate 1, Step A using 3-methylnitrophenol and 2-iodopropane.
Step B. 5-(4-Isopropoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 25, Steps B-C using 1-isopropoxynitrobenzene in Step B. MS (ESI): mass calcd. for C H N O S, 369.08; m/z found, 370.3 [M+H] . 18 15 3 4 Intermediate 8: 5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl chloride.
To a solution of 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Intermediate 1, 500 mg, 1.20 mmol) in anhydrous DCM (20 mL) was added 2-drops of DMF and cooled to 0 °C. Then oxalyl dichloride (760 mg, 6.0 mmol) was added slowly and it was stirred at 40 °C overnight. The reaction mixture was concentrated to dryness to give the title compound (260 mg), which was used in the next step without purification.
Intermediate 9: 4-Oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carbonyl chloride.
To a 200 mL round bottom flask with a stir bar were added 4-oxo(4-phenoxyphenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 2, 3.9 g, 9.7 mmol) and thionyl chloride (50 mL, 680 mmol) and was warmed in a 90 °C sand bath to reflux for 90 min. The reaction mixture was concentrated to dryness. DCM (75 mL) was added and the reaction mixture was concentrated to dryness (repeated twice) to give the title compound as a stock solution in THF (0.1 M, 100 mL), which was used without further purification.
Intermediate 10. 4-Oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl chloride.
N NH The title compound was prepared in a manner analogous to Intermediate 9, using 4-oxo(6- phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 28).
Intermediate 11: 5-(4-Ethylmethylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
Step A: 4-Ethylmethylaniline. To a solution of 4-bromomethylaniline (1.86 g, 10.0 mmol), Cs CO (9.77 g, 30.0 mmol), and Pd(dppf)Cl (146 mg, 0.200 mmol) in a Schlenk tube under a 2 3 2 N atmosphere was added dry THF (30 mL). To the stirred suspension was added triethylborane (30 mL, 1 M solution in THF, 30 mmol) in one portion, and the mixture was refluxed for 5 h.
The reaction was cooled to 0 °C and quenched by the addition of 10% aqueous NaOH and 30% aqueous H O . After stirring for 30 min at rt, the mixture was extracted with EtOAc, the combined organic layer washed successively with aqueous FeSO and brine, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound as a white solid (1.1 g, 83% yield). MS (ESI): mass calcd. for C H N, 135.21; m/z found, 136.2 [M+H] . 9 13 Step B: 5-(4-Ethylmethylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-F, using 4-ethylmethylaniline and 2-chloroiodopyridinecarbonitrile in Step C.
MS (ESI): mass calcd. for C H N O S, 353.08; m/z found, 353.9 [M+H] . 18 15 3 3 Intermediate 12: 5-(2-Methyl((tetrahydro-2H-pyranyl)oxy)phenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxylic acid.
Step A: Tetrahydropyranyl methanesulfonate. A solution of tetrahydropyranol (2.0 g, 20 mmol) and diisopropylethylamine (3.00 g, 23.5 mmol) in DCM (20 mL) was cooled to 0 °C and methanesulfonyl chloride (2.50 g, 21.5 mmol) was added dropwise and stirred at rt for 2 h. The mixture was concentrated to dryness to give the title compound (3.72 mg, 100% yield), which was used in the next step directly.
Step B: 5-(2-Methyl((tetrahydro-2H-pyranyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps A-F using tetrahydropyranyl methanesulfonate and 3- methylnitrophenol in Step A. MS (ESI): mass calcd. for C H N O S, 425.10; m/z found, 21 19 3 5 426.1 [M+H] .
Intermediate 13: 5-(4-Methylphenoxypyrimidinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
Step A: 4-Methylphenoxypyrimidinamine. A mixture of 2-chloromethylpyrimidin amine (4.96 g, 34.55 mmol), phenol (4.35 g, 46.22 mmol), CuI (1.35 g, 7.09 mmol), N,N- dimethylglycine (747 mg, 7.24 mmol) in dioxane (40 mL), and Cs CO (17.13 g, 52.58 mmol) was degassed and heated at 90 °C under N for 3 days. The reaction was cooled to room temperature and diluted with water (100 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over anhydrous Na S O , filtered, and concentrated to 2 2 4 dryness. The residue was purified by flash column chromatography to give the title compound (40.07 g, 57.64% yield) as a white solid. MS (ESI): mass calcd. for C H N O, 201.2; m/z 11 11 3 found, 202.1 [M+H] .
Step B. 5-(4-Methylphenoxypyrimidinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-F, using 4-Methylphenoxypyrimidinamine and 2- chloroiodopyridinecarbonitrile in Step C. MS (ESI): mass calcd. for C H N O S, 419.07; 13 5 4 m/z found, 419.9 [M+H] .
Intermediate 14: 4-Oxo(5-phenoxypyrimidinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
The title compound was prepared in a manner analogous to Intermediate 13, using 5- bromopyrimidinamine and phenol in Step A. MS (ESI): mass calcd. for C H N O S, 405.05; 19 11 5 4 m/z found, 406.0 [M+H] .
Intermediate 15: 5-(2-Methyl(pyrimidinyloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
Step A. 2-(3-Methylnitrophenoxy)pyrimidine. A solution of 3-methylnitrophenol (3 g, 19.5 mmol), 2-chloropyrimidine (2.2 g, 19.5 mmol), Cu (125 mg, 1.9 mmol), K CO (5.4 g, 39.1 mmol) in DMSO (20 mL), was stirred at 90 C for 24 h. Water was added and the resulting precipitate was filtered to give the title compound as a yellow solid which was used crude without further purification.
Step B. 2-Methyl(pyrimidinyloxy)aniline. 2-(3-Methylnitrophenoxy)pyrimidine (From Step A) was dissolved in MeOH (150 mL). Pd/C was added (2 g) and the reaction mixture was stirred under H for 16 h. The resulting mixture was filtered and concentrated under reduced pressure to afford the title compound as a pale yellow solid (2.8 g, 71 % over 2 steps).
Step C. 5-(2-Methyl(pyrimidinyloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-F using 2-methyl(pyrimidinyloxy)aniline in Step C.
MS (ESI): mass calcd. for C H N O S, 419.07; m/z found, 420.1 [M+H] . 13 5 4 Intermediate 16: 5-(2-Isopropylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
Step A: 4-Nitro(propenyl)pyridine. A solution of 2-chloronitropyridine (2.50 g, 15.8 mmol), 4,4,5,5-tetramethyl(propenyl)-1,3,2-dioxaborolane (3.557 mL, 18.92 mmol), Pd(dppf)Cl (0.643 g, 0.788 mmol), and K CO (3.27 g, 23.7 mmol) in dioxane (40 mL) and 2 2 3 H O (10 mL) was stirred at 80 °C overnight. The reaction was concentrated to dryness and the residue was purified by flash column chromatography to give the title compound (2.2 g, 85% yield). MS (ESI): mass calcd. for C H N O , 164.16; m/z found, 165.1 [M+H] . 8 8 2 2 Step B. 2-Isopropylpyridinamine. To a solution of 4-nitro(propenyl)pyridine (2.2 g, 13.4 mmol) in MeOH (50 mL), was added 10% Pd/C (200 mg). The reaction mixture was stirred under 1 atm of H for 18 h. The reaction mixture was filtered thru a pad of Celite®, and concentrated under reduced pressure to afford the title compound (1.8 g, 99.8 %).
Step C: 5-(2-Isopropylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-F, using 2-isopropylpyridinamine Step C. MS (ESI): mass calcd. for C H N O S, 17 14 4 3 354.08; m/z found, 355.0 [M+H] .
Intermediate 17: 5-(4-Isopropylmethylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
Step A: 4-Isopropylmethyl-aniline. To a solution of 4-iodomethylaniline (4.0 g, 17 mmol) and Pd(dppf) Cl (140 mg, 0.17 mmol) in THF (50 mL) was added isopropylmagnisium chloride (25.5 mL, 51.0 mmol) at -78 °C and was reacted at reflux for 4 h. The reaction was quenched with a saturated solution of NH Cl, extracted with EtOAc, dried over anhydrous Na SO , 4 2 4 filtered, and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound as a brown solid (320 mg).
Step B: 5-(4-Isopropylmethylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-F, using 4-isopropylmethyl-aniline and 2-chloro iodopyridinecarbonitrile in Step C.
Intermediate 18: 5-(6-Isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
Step A: 6-Isobutylmethylpyridinamine. To a 200 mL round bottom flask were added 6- bromomethylpyridinamine (5.42 g, 29.0 mmol) and 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (520 mg, 0.631 mmol). The vessel was evacuated then back filled with nitrogen. THF (20 mL) was added, followed by isobutylzinc(II) bromide (0.5 M in THF, 80 mL, 40 mmol) via syringe, then the reaction mixture was heated to 60 °C for 2 h. The reaction mixture was treated with saturated aqueous sodium bicarbonate (300 mL) and extracted with EtOAc (2 × 300 mL). The combined organic layers were dried (MgSO ), concentrated under vacuum, and the residue was purified by FCC (SiO , 40-80% EtOAc/hexanes) to give the title compound (3.646 g, 77% yield) as a brown solid.
Step B: Methyl 3-amino((6-isobutylmethylpyridinyl)amino)thieno[2,3-b]pyridine carboxylate. To a round bottom flask under a N atmosphere were added 6-isobutyl methylpyridinamine (53.5 g, 326 mmol), 2-chloroiodopyridinecarbonitrile (94.8 g, 358 mmol) and dioxane (1000 mL), followed by bis(2-diphenylphosphinophenyl)ether (DPEphos) (10.5 g, 19.5 mmol), Pd(OAc) (2.92 g, 13.0 mmol), and Cs CO (265 g, 814 mmol). The 2 2 3 reaction mixture was stirred at 105 °C for 3 h. Methyl 2-mercaptoacetate (51.9 g, 489 mmol) was added, and the reaction was stirred at 105 °C overnight. The reaction mixture was filtered and concentrated. The residue was suspended in MeOH (400 mL) and stirred for 2 h at room temperature. The resulting precipitate was isolated by filtration and dried under vacuum to give the title compound (75.3 g, 62% yield) as a yellow solid.
Step C: Methyl 5-(6-isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylate. To a round bottom flask were added methyl 3-amino((6- isobutylmethylpyridinyl)amino)thieno[2,3-b]pyridinecarboxylate (30.0 g, 81 mmol), carbonyldiimidazole (CDI, 39.4 g, 243 mmol), triethylamine (24.6 g, 243 mmol) and 1,4-dioxane (300 mL). The reaction was stirred at 100 °C for 6 h, then cooled to 50 °C. The resulting precipitate was collected by filtration, rinsed with MeOH and dried under vacuum to yield the title compound (27 g, 84%) as an off-white solid.
Step D: 5-(6-Isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. To a round bottom flask were added methyl 5-(6- isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylate (68.0 g, 172 mmol), lithium hydroxide (36.0 g, 858 mmol), and a mixture of 5:2:2 THF:MeOH:H O (4 L). The reaction mixture was stirred at 80 °C for 4.5 h. The mixture was concentrated to dryness and diluted with H O. The solution was acidified by the addition of 1 M HCl and the resulting precipitate was filtered and dried under vacuum to yield the title compound (63 g, 96% yield) as yellow solid. MS (ESI): mass calcd. for C H N O S, 417.08; m/z found, 22 15 3 4 418.0 [M+H] .
Intermediate 19: 5-([1,1'-Biphenyl]yl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
Step A: 3-Phenylaniline. To a solution of phenylboronic acid (12.19 g, 100 mmol) in MeOH (150 mL) were added Na CO (21.2 g, 200 mmol) and 3-bromoaniline (17.2 g, 100 mmol) sequentially. To the suspension was added Pd(OAc) (562 mg, 2.50 mmol) and the reaction was heated to reflux until a black suspension appeared. The suspension was cooled to room temperature, diluted with MeOH, and the black precipitate was removed by filtration. The filtrate was concentrated to dryness and the residue was taken up in water and DCM. The organic phase was collected, dried over anhydrous Na CO , and concentrated to dryness to give the title compound as a brown oil (18.37 g, 100.0% yield).
Step B: 5-([1,1'-Biphenyl]yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-F, using 3-phenylaniline and 2-chloroiodopyridinecarbonitrile in Step C. MS (ESI): mass calcd. for C H N O S, 387.07; m/z found, 388.1 [M+H] 21 13 3 3 Intermediate 20: 4-Oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
Step A. 2-Phenylpyridinamine. A mixture of 4-chloropyridinamine (64 g, 498 mmol), phenyl boronic acid (61 g, 500 mmol), Na CO (159 g, 1.5 mol), Pd(PPh ) (6.4 g) in 2 3 3 4 H O/EtOH/toluene (500 mL) was heated to 90 °C in sealed vessel for 14 h. The crude mixture was cooled, filtered, and concentrated under reduced pressure. Purification (FCC, SiO , PE:EtOAc (100:1) afforded the title compound (64 g, 75%).
Step B. 4-Oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-F, using 2-phenylpyridinamine and 2-chloroiodopyridinecarbonitrile in Step C.
MS (ESI): mass calcd. for C H N O S, 388.06; m/z found, 388.8 [M+H] . 12 4 3 Intermediate 21: 4-Oxo(4-phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
The title compound was prepared in a manner analogous to Intermediate 20, substituting 4- bromopyridinamine for 4-chloropyridinamine, and substituting Pd(dppf)Cl CH Cl for 2 2 2 Pd(PPh ) in Step A. MS (ESI): mass calcd. for C H N O S, 388.06; m/z found, 389.0 [M+H] . 3 4 20 12 4 3 Intermediate 22. 4-Oxo(5-phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
The title compound was prepared in a manner analogous to Intermediate 20, substituting 5- bromopyridinamine for 4-chloropyridinamine in Step A. MS (ESI): mass calcd. for C H N O S, 388.06; m/z found, 388.8 [M+H] . 12 4 3 Intermediate 23: 4-Oxo(6-phenylpyrimidinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
The title compound was prepared in a manner analogous to Intermediate 20, substituting 6- chloropyrimidinamine for 4-chloropyridinamine, and substituting Pd(dppf)Cl -CH Cl for 2 2 2 Pd(PPh ) in Step A. MS (ESI): mass calcd. for C H N O S, 389.06; m/z found, 390.2 [M+H] . 3 4 19 11 5 3 Intermediate 24: 5-(6-Cyclobutoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
Step A. 2-Cyclobutoxymethylnitropyridine. To a solution of cyclobutanol (2 g, 28.8 mmol), Cs CO (12.5 g, 38.4 mmol) in ACN (19.2 mL) was added dropwise 2-fluoromethyl- 5-nitropyridine (3 g, 19.2 mmol). The reaction mixture was stirred at rt for 20 h. H2O (300 mL) and DCM (200 mL) were added to the reaction mixture. The reaction mixture was extracted with DCM. The combined organics were separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude title compound, as a red oil, was used without further purification.
Step B. 6-Cyclobutoxymethylpyridinamine. Crude 2-cyclobutoxymethyl nitropyridine, from step A, was dissolved in 5:1 Acetone/water (96 mL), and ammonium chloride (5 g), and cooled in an ice bath. To the reaction mixture was added Zn (12.5 g, 192 mmol) in chunks. The cooled mix was stirred for 5 minutes at 0 °C then at room temperature for 2.5 h. To the reaction mixture was added Mg SO (40 g) and EtOAc (300 mL), and the reaction mix was stirred for an additional 2-3 h. The reaction mixture was filtered thru Celite®, and the resulting organics were concentrated under reduced pressure to afford the title compound (3 g, 89% over 2 steps).
Step C. Methyl 5-(6-cyclobutoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylate. The title compound was prepared in a manner analogous to Intermediate 1, Step C, using 6-cyclobutoxymethylpyridinamine, and substituting Cs CO for K PO 3 4.
Step D. 5-(6-Cyclobutoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps D-F. MS (ESI): mass calcd. for C H N O S, 396.09; m/z 19 16 4 4 found, 397.1 [M+H] .
Intermediate 25. 5-(6-(cyclopentyloxy)methylpyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid.
Step A. 2-Cyclopentyloxymethylnitropyridine. The title compound was prepared in a manner analogous to Intermediate 24, Step A, using 2-fluoromethylnitropyridine and cyclopentanol.
Step B. 6-Cyclopentyloxymethylpyridinamine. The title compound was prepared in a manner analogous to Intermediate 16, Step B, using 2-cyclopentyloxymethylnitropyridine.
Step C. 5-(6-(Cyclopentyloxy)methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-F, using 6-cyclopentyloxymethylpyridinamine in Step C. MS (ESI): mass calcd. for C H N O S, 410.10; m/z found, 411.0 [M+H] . 18 4 4 Intermediate 26: 4-Oxo(5-phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
The title compound was prepared in a manner analogous to Intermediate 25, using 5-bromo nitropyridine and phenol in Step A. MS (ESI): mass calcd. for C H N O S, 404.06; m/z found, 12 4 4 404.7 [M+H] .
Intermediate 27: 5-(4-Methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
The title compound was prepared in a manner analogous to Intermediate 25, using 2-fluoro methylnitropyridine or 2-chloromethylnitropyridine and phenol, and DMF or ACN in Step A. MS (ESI): mass calcd. for C H N O S, 418.07; m/z found, 419 [M+H] . 21 14 4 4 Intermediate 28: 4-Oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
The title compound was prepared in a manner analogous to Intermediate 25, using 2-chloro nitropyridine and phenol in Step A. MS (ESI): mass calcd. for C H N O S, 404.06; m/z found, 12 4 4 405.0 [M+H] .
Intermediate 29: 5-(2-Methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
The title compound was prepared in a manner analogous to Intermediate 25, using 6-chloro methylnitropyridine and phenol in Step A. MS (ESI): mass calcd. for C H N O S, 418.07; 21 14 4 4 m/z found, 419.0 [M+H] .
Intermediate 30. 5-(6-Isopropoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
The title compound was prepared in a manner analogous to Intermediate 25, using 2-fluoro methylnitropyridine and propanol in Step A. MS (ESI): mass calcd. for C H N O S, 18 16 4 4 384.09; m/z found, 385.0 [M+H] .
Intermediate 31: 5-(4-Isopropoxymethylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
The title compound was prepared in a manner analogous to Intermediate 25, using 3-methyl nitrophenol and 2-iodopropane in Step A. MS (ESI): mass calcd. for C19H17N3O4S, 383.09; m/z found, 384.1 [M+H] .
Intermediate 32. 5-(4-((6-Methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
The title compound was prepared in a manner analogous to Intermediate 25, using 1-fluoro nitrobenzene and 6-methylpyridinol Step A. MS (ESI): mass calcd. for C H N O S, 418.07; 21 14 4 4 m/z found, 419.0 [M+H] .
Intermediate 33. 5-(6-Isobutoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid.
The title compound was prepared in a manner analogous to Intermediate 25, using 2-fluoro methylnitropyridine and 2-methylpropanol Step A. MS (ESI): mass calcd. for C H N O S, 398.10; m/z found, 399.0 [M+H] . 19 18 4 4 Intermediate 34: (E)(tert-Butoxycarbonylamino)butenoic acid.
Step A: (E)Aminobutenoic acid. To a solution of (E)bromobutenoic acid (1.0 g, 6.1 mmol) in THF (20 mL) in an ice-bath was added aqueous NH4OH (10 mL) and was stirred at room temperature for 6 hours. The mixture was concentrated to dryness to give the title compound (0.613 g, 100% yield), which was used in the next step without further purification.
Step B: (E)(tert-Butoxycarbonylamino)butenoic acid. A solution of (E)aminobut enoic acid (0.613 g, 6.06 mmol), (Boc)2O (1.587 g, 7.272 mmol), K2CO3 (1.675 g, 12.12 mmol), THF (30 mL), and water (15 mL) was stirred at room temperature overnight. The mixture was dispersed between EtOAc and water. The organic layer was collected, concentrated to dryness to give the title compound (0.305 g, 25.0% yield), which was used in the nest step without further purification. MS (ESI): mass calcd. for C H NO , 201.10; m/z found, 102 [M –Boc +H] . 9 15 4 Intermediate 35: tert-Butyl ((1S,4S)aminocyclohexyl)carbamate.
Step A: tert-Butyl ((1R,4R)hydroxycyclohexyl)carbamate. To a solution of di-tert-butyl dicarbonate (4.087 mL, 21.01 mmol) and diisopropylethylamine (2.87 mL, 17.4 mmol) in THF (60 mL) was added (1R,4R)aminocyclohexanol (2.00 g, 17.4 mmol) and was stirred at rt for 4 h. The reaction was concentrated to dryness and the residue was dried under reduced pressure to yield the title compound as a white solid (3.49 g, 87.0% yield), which was used without further purification.
Step B: tert-Butyl ((1S,4S)(1,3-dioxoisoindolinyl)cyclohexyl)carbamate. To a stirred solution of tert-butyl ((1R,4R)hydroxycyclohexyl)carbamate (3.49 g, 16.2 mmol), phthalimide (2.50 g, 17.0 mmol), and triphenylphosphine (6.38 g, 24.3 mmol) in THF (50 mL) under nitrogen at 0 °C was added diisopropyl azodicarboxylate (4.82 g, 24.3 mmol) and was stirred at rt overnight. The reaction was concentrated to dryness and the residue was purified by flash column chromatography to yield the title compound (2.24 g, 40.1% yield) as a white solid. MS (ESI): mass calcd. for C H N O , 344.40; m/z found, 345.0 [M+H] . 19 24 2 4 Step C: tert-Butyl ((1S,4S)aminocyclohexyl)carbamate. A solution of tert-butyl ((1S,4S) (1,3-dioxoisoindolinyl)cyclohexyl)carbamate (2.238 g, 6.498 mmol) and hydrazine hydrate (1.104 mL, 19.49 mmol) in EtOH (20 mL) was stirred at 80 °C for 2 hours. The mixture was diluted with 1M NaOH and extracted with DCM. The organic layer was separated, dried (MgSO ), filtered, and concentrated to dryness. The residue was diluted with toluene and distilled at reduced pressure twice to yield the title compound (1.342 g, 96.00% yield), which was used without further purification. MS (ESI): mass calcd. for C H N O , 214.30; m/z 11 22 2 2 found, 215.0 [M+H] .
Intermediate 36. N-((1S,2R)Aminocyclopentyl)acrylamide.
Method A: Step A: tert-Butyl ((1R,2S)acrylamidocyclopentyl)carbamate. To a solution of tert-butyl ((1R,2S)aminocyclopentyl)carbamate (15 g, 75 mmol) in DCM (300 mL) was added triethylamine (13.53 mL, 97.36 mmol), followed by propenoyl chloride (6.97 mL, 86.1 mmol) at 0 °C with stirring. The cooling bath was removed, and the mixture was stirred for 60 minutes at room temperature. The reaction was quenched with aqueous 1% HCl and extracted with DCM. The organic phases were combined and washed consecutively with aqueous NaHCO and brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated to dryness, and the residue was purified by recrystallization from DCM to give the title compound (14.5 g, 75.1% yield) as a white solid. MS (ESI): mass calcd. for C H N O , 254.32; m/z 13 22 2 3 found, 155.1 (minus Boc group) [M+H] . H NMR (400 MHz, DMSO-d ): δ 7.68-7.50 (m, 1H), 6.47-6.31 (m, 1H), 6.28-6.16 (m, 1H), 6.12-5.96 (m, 1H), 5.60-5.46 (m, 1H), 4.13-3.98 (m, 1H), 3.88-3.68 (m, 1H), 1.87- 1.58 (m, 3H), 1.55-1.37 (m, 3H), 1.32 (s, 9H).
Step B: N-((1S,2R)Aminocyclopentyl)acrylamide. To a solution of tert-butyl ((1R,2S) acrylamidocyclopentyl)carbamate (800 mg, 3.146 mmol) in DCM (20 mL) was added methanesulfonic acid (1.208 g, 12.58 mmol) and was stirred at room temperature for 30 minutes.
The reaction was concentrated to dryness to give the title compound (485 mg, 100% yield) as a yellow oil, which was used without further purification.
Method B: Step A: tert-Butyl ((1R,2S)acrylamidocyclohexyl)carbamate. To a solution of tert-butyl ((1R,2S)aminocyclohexyl)carbamate (1.0 g, 5.0 mmol) and triethylamine (0.606 g, 5.99 mmol) in DCM (10 mL) was added acrylic anhydride (824 mg, 6.53 mmol) dropwise in an ice bath and was stirred at room temperature for 1 h. The reaction was diluted with DCM, washed with HCl (1.0 M), saturated aqueous NaHCO , and aqueous NaCl successively. The organic phase was collected, dried over anhydrous Na SO , and concentrated to dryness to give the title compound (1.1 g, 87% yield) as a white solid, which was used without further purification in next reaction. MS (ESI): mass calcd. for C H N O , 254.32; m/z found, 255.0 [M+H] . 13 22 2 3 Step B: N-((1S,2R)Aminocyclopentyl)acrylamide. A solution of tert-butyl ((1R,2S) acrylamidocyclohexyl)carbamate (800 mg, 1.90 mmol) in 4 M HCl in MeOH (2 mL) was stirred at room temperature for 60 minutes. The reaction was concentrated to dryness to give the title compound which was used without further purification.
Intermediate 37: tert-Butyl N-[(1R,3S)aminocyclopentyl]carbamate.
Step A: tert-Butyl N-[(1R,3S)(benzyloxycarbonylamino)cyclopentyl]carbamate. To a solution of (1S,3R)(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (10.0 g, 43.6 mmol), phenylmethanol (9.04 mL), and triethylamine (9 mL) in toluene (100 mL) was added diphenyl phosphorazidate (9.7 mL). The reaction was warmed to 100 °C and reacted overnight. The mixture was washed with saturated NaHCO and extracted with ethyl acetate. The organic phase was evaporated to dryness and was purified by flash column chromatography to yield the title compound (9.6 g, 66% yield).
Step B: tert-Butyl N-[(1R,3S)aminocyclopentyl]carbamate. A mixture of tert-butyl N- [(1R,3S)(benzyloxycarbonylamino)cyclopentyl]carbamate (9.6 g, 29 mmol) in ethanol (100 mL) was hydrogenated at room temperature (H , 30 psi) using Pd(OH) (20% on carbon, 2 g).
The reaction was stirred overnight and the catalyst was filtered off and the filtrate was evaporated to dryness to yield the crude title compound (5.4 g, 94% yield).
Intermediate 38: tert-Butyl ((1R,2S)acrylamidocyclohexyl)carbamate.
To a solution of tert-butyl ((1R,2S)aminocyclohexyl)carbamate (411.5 mg, 1.92 mmol) and triethylamine (291, 2.88 mmol) in DCM (5 mL) was added acrylic anhydride (208.5 mg, 2.304 mmol) dropwise in an ice bath and was stirred at room temperature for 30 minutes. The reaction was diluted with DCM, washed with HCl (1 M), saturated aqueous NaHCO3, and brine successively. The organic phase was collected and concentrated to dryness. The residue was dissolved in DCM (2 mL) and methanesulfonic acid (369 mg, 3.84 mmol) was added and was stirred at room temperature for 5 h. The reaction was concentrated to dryness to give the title compound (611 mg, 189% yield), which was used without further purification in next reaction.
Intermediate 39: N-((1S,4S)aminocyclohexyl)acrylamide.
The title compound was prepared in a manner analogous to Intermediate 36, using tert-butyl ((1s,4s)aminocyclohexyl)carbamate in Step A.
Intermediate 40: N-[(1S,2R)aminocyclohexyl]propenamide.
Step A: tert-Butyl ((1R,2S)acrylamidocyclohexyl)carbamate. To a solution of tert-butyl ((1R,2S)aminocyclohexyl)carbamate (1.4 g, 6.5 mmol) and triethylamine (1.32 g, 13.1 mmol) in DCM (15 mL) was added acrylic anhydride (824 mg, 6.53 mmol) dropwise in an ice bath and was stirred at room temperature for 1 h. The reaction was washed with HCl (0.5 M), aqueous NaHCO , and aqueous NaCl. The organic phase was collected, dried over anhydrous Na SO , 3 2 4 and concentrated to dryness to give the title compound (1.3 g, 74% yield) as a yellow solid, which was used without further purification in next reaction.
Step B: N-((1S,2R)Aminocyclohexyl)acrylamide. To a solution of tert-butyl ((1R,2S) acrylamidocyclohexyl)carbamate (Intermediate 38) in MeOH (2 mL) was added HCl (1 mL) and was stirred at room temperature for 30 min. The reaction was concentrated to dryness to give the title compound (72 mg), which was used in next step without further purification. MS (ESI): mass calcd. for C H N O, 168.24; m/z found, 169.1 [M+H] . 9 16 2 Intermediate 41: N-((1R,2R)aminocyclohexyl)acrylamide.
The title compound was prepared in a manner analogous to Intermediate 36, using tert-butyl ((1R,2R)aminocyclohexyl)carbamate in Step A.
Intermediate 42: 2-((3-(4-Aminomethylphenoxy)benzyl)oxy)benzonitrile.
Step A: 3-((tert-butyldimethylsilyl)oxy)benzaldehyde. To a mixture of 3-hydroxybenzaldehyde (24.4 g, 200 mmol) in DCM (500 mL) was added Et N (30.3 g, 300 mmol) and TBSCl (33.1 g, 220 mmol) and stirred room temperature for 3 hours. The reaction was dispersed between DCM and saturated NH Cl aq solution. The organic layer was collected, condensed and was purified by flash column chromatography (PE/EA) to give the title compound (47.3 g, 100% yield).
Step B: (3-((tert-butyldimethylsilyl)oxy)phenyl)methanol. To a mixture of 3-((tert- butyldimethylsilyl)oxy)benzaldehyde (47.3 g, 200 mmol) in MeOH (30 mL) cooled to 0 °C was added portion wise NaBH (3.78 g, 100 mmol). After the addition was completed the reaction was stirred at room temperature for 2 hours. Volatiles were removed under vacuo. Water and EtOAc were added to the residue, the organic layer was separated, washed with brine, dried over Na SO , filtered and concentrated under vacuo to provide target product as yellow oil, which was used forward next step without further purification.
Step C: 2-((3-((tert-butyldimethylsilyl)oxy)benzyl)oxy)benzonitrile. To a mixture of (3-((tert- butyldimethylsilyl)oxy)phenyl)methanol (13.94 g, 60 mmol) in THF (200 mL) were sequentially added 2-hydroxybenzonitrile (8.58 g, 72 mmol), Ph P (18.88 g, 72 mmol) and DIAD (14.56 g, 72 mmol) dropwise at room temperature and the reaction was stirred for one hour. Saturated aqueous NH Cl and EtOAc were added, the organic layer was separated, washed with brine, dried over Na SO , filtered, condensed under vacuo and was purified by flash column chromatography(PE/EA) to give the title compound (17.0 g, 83% yield).
Step D: 2-((3-hydroxybenzyl)oxy)benzonitrile. To a mixture of 2-((3-((tert- butyldimethylsilyl)oxy)benzyl)oxy)benzonitrile (17.0 g, 50 mmol) in THF (250 mL) was added a 1M solution TBAF (60 mL, 60 mmol) and the reaction was stirred at room temperature for 30 minutes. A saturated aqueous NH4Cl solution and EtOAc were added, the organic layer was separated, washed with brine, dried over Na SO , filtered, condensed and was purified by flash column chromatography(MeOH/DCM) to give the title compound (11.3 g, 100% yield).
Step E: 2-((3-(3-methylnitrophenoxy)benzyl)oxy)benzonitrile. To a mixture of 2-((3- hydroxybenzyl)oxy)benzonitrile (11.3 g, 50 mmol), 4-fluoromethylnitrobenzene (7.8 g, 50 mmol), K CO (13.8 g, 100 mmol) in 200 mL of DMSO was stirred under N at 150 °C for 4 2 3 2 hours. The mixture was condensed and was purified by flash column chromatography (PE/EA) to give the title compound (15.1 g, 84% yield).
Step F: 2-((3-(4-aminomethylphenoxy)benzyl)oxy)benzonitrile. To a mixture of 2-((3-(3- methylnitrophenoxy)benzyl)oxy)benzonitrile (15.1 g, 42 mmol) in EtOH ( 420mL ) and water ( 140 mL ) were sequentially added NH Cl (11.2 g, 210 mmol), iron (9.38 g, 168 mmol) and the reaction mixture was stirred at reflux for 4 hours and then cooled to room temperature, The mixture was diluted with DCM ( 500 mL ) and water ( 200 mL ), the organic layer was collected, condensed and was purified by flash column chromatography (MeOH/water) to give the title compound (13.9 g, 100% yield). MS (ESI): mass calcd. for C H N O , 330.14; m/z found, 21 18 2 2 331.1 [M+H] .
Intermediate 43: Methyl 5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)methylphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylate.
The title compound was prepared in a manner analogous to Intermediate 1 Steps C-E, using 2- ((3-(4-aminomethylphenoxy)benzyl)oxy)benzonitrile (Intermediate 42) in place of 2-methyl- 4-phenoxyaniline in Step C.
Intermediate 44: (E)Cyanocyclopropylacrylic acid.
To a 50 mL round bottom flask fitted with a stir bar under N were added cyanoacetic acid (1.70 g, 20 mmol), cyclopropanecarbaldehyde (1.40 g, 20 mmol), ammonium acetate (60 mg, 0.8 mmol), and toluene (20 mL) and was warmed in a sand bath set at 110 °C. The reaction mixture was cooled to room temperature, the solid was filtered and dried to give the title compound as a light yellow solid (2.02 g, 73% yield).
Intermediate 45: N-[(1S,3R)Aminocyclopentyl]propenamide.
To a cooled (-20 °C) solution of tert-butyl ((1R,3S)aminocyclopentyl)carbamate (235.7 mg, 1.17 mmol) and TEA (.245 mL, 1.76 mmol) in DCM (10 mL) was added dropwise acryloyl chloride (0.12 mL, 1.41 mmol). The reaction mixture was allowed to warm to rt, and in the same vessel was added 2 mL of TFA. The reaction mixture was concentrated under reduced pressure and 2M NH /MeOH (5 mL) was added. The crude reaction mixture was dissolved in DCM (5 mL) and passed thru a silica gel plug. The tile compound was used without further purification.
Intermediate 46: N-[(1R,2R)Aminocyclopentyl]propenamide.
The title compound was prepared in a manner analogous to Intermediate 36, using tert-butyl ((1R,2R)aminocyclopentyl)carbamate. H NMR (400 MHz, CDCl ) δ 7.05 (s, 1H), 6.27 (dd, J = 17.1, 1.6 Hz, 1H), 6.11 (dd, J = 17.0, 10.2 Hz, 1H), 5.61 (dd, J = 10.3, 1.6 Hz, 1H), 5.25 - 4.96 (m, 1H), 4.36 - 4.20 (m, 1H), 3.95 - 3.72 (m, 1H), 2.50 - 2.32 (m, 1H), 2.13 (s, 1H), 1.98 - 1.62 (m, 5H).
Example 1: N-((1S,4S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1S,4S)aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a round bottom flask were added 5- (*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer , 42 mg, 0.10 mmol), tert-butyl ((1S,4S)aminocyclohexyl)carbamate (Intermediate 35, 32 mg, 0.15 mmol), triethylamine (20 mg, 0.20 mmol), HATU (57 mg, 0.15 mmol), and DMF (1 mL). The reaction mixture was stirred at rt for 2 h. The intermediate was purified by flash column chromatography. The intermediate was dissolved in MeOH (15 mL) and saturated aqueous HCl (5 mL) was added. The resulting mixture was concentrated to dryness. The residue was dispersed between DCM and 10% aqueous NH . The organic layer was collected and concentrated to dryness to yield the title compound (51.4 mg, 100% yield), which was used in the next step without further purification.
Step B: N-((1S,4S)acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of N-((1S,4S) aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (51.4 mg, 0.100 mmol), and triethylamine (20 mg, 0.20 mmol), in DCM (15 mL) was added propenoyl chloride (9.0 mg, 0.10 mmol) dropwise at 0 °C. The reaction mixture was stirred at rt for 5 min. The reaction was dispersed between DCM and water, the organic layer was collected, and concentrated to dryness. The residue was purified by flash column chromatography to yield the title compound (25 mg, 42% yield). MS (ESI): mass calcd. for C H N O S, 567.66; m/z found, 568.3 [M+H] . H NMR (400 MHz, 31 29 5 4 DMSO-d ): δ 10.15 (br, 1H), 8.35-8.21 (m, 1H), 8.18-7.85 (m, 2H), 7.45-7.39 (m, 2H), 7.36-7.27 (m, 1H), 7.20-7.15 (m, 1H), 7.13-7.07 (m, 2H), 7.07-7.03 (m, 1H), 6.98-6.92 (m, 1H), 6.37-6.25 (m, 1H), 6.10-6.03 (m, 1H), 5.98-5.84 (m, 1H), 5.58-5.51 (m, 1H), 3.85-3.76 (m, 2H), 2.03 (s, 3H), 1.76-1.55 (m, 8H).
Example 2: N-((1R,3S)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1 using tert-butyl ((1S,3R)- 3-aminocyclohexyl)carbamate and 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1). MS (ESI): mass calcd. for C H N O S, 567.7; m/z found, 568.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.32 (d, J = 31 29 5 4 3 .4 Hz, 1H), 7.45-7.36 (m, 2H), 7.34-7.26 (m, 1H), 7.22-7.15 (m, 1H), 7.12-7.03 (m, 3H), 7.01- 6.93 (m, 1H), 6.25-6.17 (m, 2H), 6.07 (d, J = 5.3 Hz, 1H), 5.67-5.60 (m, 1H), 4.04-3.95 (m, 1H), 3.91-3.80 (m, 1H), 2.22-2.08 (m, 5H), 2.01-1.83 (m, 4H), 1.51-1.43 (m, 1H), 1.24-1.16 (m, 1H).
Example 3: N-((1S,4S)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: 5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl chloride. To a solution of 5-(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, 500 mg, 1.20 mmol) in anhydrous DCM (20 mL) was added 2-drops of DMF and cooled to 0 °C.
Then oxalyl dichloride (760 mg, 6.0 mmol) was added slowly and it was stirred at 40 °C overnight. The reaction mixture was concentrated to dryness to give the title compound (260 mg), which was used in the next step without purification.
Step B: N-((1S,4S)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of 5-(2-Methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (372.2 mg, 0.854 mmol), trimethylamine (259 mg, 2.5 mmol), in DCM (50 mL), was added N- ((1S,4S)aminocyclohexyl)acrylamide (252 mg, 1.5 mmol). The reaction mixture was stirred at room temp for 5 minutes, then concentrated under reduced pressure. Purification (FCC, SiO2, (MeOH/water), then by preparative TLC (DCM/MeOH = 15/1) afforded the title compound (74 mg, 15%). MS (ESI): mass calcd. for C H N O S, 567.7; m/z found, 568.3 31 29 5 4 [M+H] . H NMR (400 MHz, DMSO-d ): δ 8.34-7.88 (m, 2H), 7.47-7.38 (m, 2H), 7.30-7.14 (m, 2H), 7.12-7.08 (m, 2H), 7.07-7.02 (m, 1H), 6.97-6.90 (m, 1H), 6.38-6.27 (m, 1H), 6.10-6.01 (m, 1H), 5.89-5.65 (m, 1H), 5.56-5.49 (m, 1H), 3.92-3.75 (m, 2H), 2.02 (s, 3H), 177-1.73 (s, 8H).
Example 4: N-((1R,2R)Hydroxycyclopentyl)(S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and (1R,2R)aminocyclopentanol. Absolute stereochemical configuration of the title compound was confirmed via X-ray analysis after cocrystallization with BTK protein. MS (ESI): mass calcd. for C H N O S, 500.6; m/z found, 501.2 [M+H] . H NMR (400 MHz, 27 24 4 4 CDCl ): δ 9.53 (s, 1H), 8.40-8.29 (m, 1H), 7.42-7.35 (m, 2H), 7.20-7.14 (m, 2H), 7.11-7.06 (m, 2H), 7.01-6.97 (m, 1H), 6.96-6.92 (m, 1H), 6.02-5.98 (m, 1H), 5.86-5.79 (m, 1H), 4.40 (s, 1H), 4.13-3.98 (m, 2H), 2.30-2.17 (m, 1H), 2.15-2.03 (m, 4H), 1.91-1.81 (m, 1H), 1.77-1.66 (m, 2H), 1.62-1.48 (m, 1H).
Example 5: N-((1R,2S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: tert-Butyl ((1S,2R)(5-(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamido)cyclohexyl)carbamate. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N- [(1S,2R)aminocyclohexyl]carbamate, HCl/MeOH deprotection done in next step.
Step B: N-((1R,2S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A mixture of tert-butyl ((1S,2R)- 2-(5-(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclohexyl)carbamate (644 mg, 1.05 mmol), concentrated HCl (3 mL), and MeOH (20 mL) was stirred at rt for 2 h. The mixture was condensed under reduced pressure. The residue was dispersed between DCM and 10% NH aq. The organic layer was collected, dried, and concentrated under reduced pressure. Purification (reverse phase eluting with gradient MeOH/water (ratio: 0-100%) afforded the title compound (455 mg, 84%) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 513.6; m/z found, 514.2 [M+H] . 28 27 5 3 H NMR (400 MHz, CDCl ): d 8.39-8.30 (m, 1H), 7.44-7.36 (m, 2H), 7.21-7.15 (m, 2H), 7.14- 7.07 (m, 2H), 7.03-6.99 (m, 1H), 6.98-6.94 (m, 1H), 6.52-6.41 (m, 1H), 6.04-5.96 (m, 1H), 4.05- 3.97 (m, 1H), 3.14-3.07 (m, 1H), 2.13 (s, 3H), 1.84-1.77 (m, 1H), 1.71-1.63 (m, 3H), 1.55-1.43 (m, 4H).
Example 6: N-((1R,2S)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 3, Step B, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 8) and (1S,2R)aminocyclopentanol. MS (ESI): mass calcd. for C H N O S, 500.6; m/z found, 501.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.34-8.27 (m, 27 24 4 4 3 1H), 7.44-7.34 (m, 2H), 7.33-7.25 (m, 1H), 7.20-7.13 (m, 1H), 7.11-7.02 (m, 3H), 7.00-6.92 (m, 1H), 6.10-6.03 (m, 1H), 4.27-4.17 (m, 1H), 4.17-4.09 (m, 1H), 2.12 (s, 3H), 2.05-1.87 (m, 3H), 1.79-1.53 (m, 3H).
Example 7: N-((1R,2S)(Dimethylamino)cyclohexyl)(*S)-(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1R,2S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 5, Steps A-B, using 5-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2R) aminocyclohexyl]carbamate, in Step A.
Step B: N-((1R,2S)(Dimethylamino)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of N-((1R,2S)- 2-aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (60 mg, 0.12 mmol) in MeOH (5 mL) was added formaldehyde (1 mL) slowly. The reaction was stirred for 10 min, then NaBH (OAc) (64 mg, 0.30 mmol) was added slowly and the mixture was stirred for 2 h. The reaction was quenched by addition of NaOH (2 mL) and was purified by flash column chromatography to yield the title compound (12 mg) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 541.7; m/z 31 5 3 found, 542.2 [M+H] .
Example 8: N-((1R,2S)Hydroxycyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: 5-(*S)-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl chloride. To a mixture of 5-(*S)-(2-methylphenoxyphenyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer, 50 mg, 0.12 mmol) in DCM (10 mL) was added oxalyl dichloride (2 mL) and was reacted at 60 °C overnight.
The reaction mixture was concentrated to dryness to yield the title compound (60 mg) as a brown solid.
Step B: N-((1R,2S)Hydroxycyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a mixture of (1S,2R) aminocyclopentanol (40 mg, 0.29 mmol) and triethylamine (30 mg, 0.30 mmol) in DCM (4 mL) was added 5-(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl chloride (50 mg, 0.12 mmol) and was reacted at rt for 20 min.
The reaction was quenched by the addition of H O (10 mL), extracted with DCM, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash column chromatography to yield the title compound (18 mg) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 500.6; m/z found, 501.2 [M+H] . 27 24 4 4 Example 9: N-((1R,2R)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and (1R,2R)aminocyclopentanol. MS (ESI): mass calcd. for H N O S, 500.6; m/z found, 501.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.34-8.27 (m, C27 24 4 4 3 1H), 7.44-7.34 (m, 2H), 7.33-7.25 (m, 1H), 7.20-7.13 (m, 1H), 7.11-7.02 (m, 3H), 7.00-6.92 (m, 1H), 6.10-6.03 (m, 1H), 4.18-4.07 (m, 2H), 2.16-2.06 (m, 4H), 2.03-1.94 (m, 1H), 1.82-1.70 (m, 2H), 1.64-1.54 (m, 2H).
Example 10: N-((1R,2S)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 5, Step A-B, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1S,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C28H27N5O3S, 513.6; m/z found, 514.2 [M+H] .
Example 11: N-((1R,2R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1R,2R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 5, Step A-B, using 5-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1R,2R)aminocyclopentyl]carbamate, in Step A.
Step B: N-((1R,2R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step B, using N-((1R,2R)aminocyclopentyl)(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide and acetyl chloride. MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 29 27 5 4 542.4 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.20 (s, 1H), 8.32-8.23 (m, 1H), 8.18 (br, 1H), 8.03-7.91 (m, 1H), 7.45-7.37 (m, 2H), 7.36-7.28 (m, 1H), 7.20-7.14 (m, 1H), 7.14-7.02 (m, 3H), 6.98-6.89 (m, 1H), 5.99-5.82 (m, 1H), 4.22-3.97 (m, 2H), 2.03 (s, 3H), 1.98-1.89 (m, 2H), 1.75 (s, 3H), 1.68-1.58 (m, 2H), 1.55-1.46 (m, 1H), 1.42-1.33 (m, 1H).
Example 12: N-((1R,2S)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 5, Step A-B, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate in Step A. The resulting HCl salt was converted to the free base using 2 M NaOH to yield the title compound (44 mg). MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, 500.2 [M+H] . H NMR 27 25 5 3 (400 MHz, CD OD): δ 8.07 (d, J = 3.8, 1H), 7.42-7.33 (m, 2H), 7.21-7.16 (m, 1H), 7.15-7.10 (m, 1H), 7.10-7.05 (m, 2H), 7.05-7.00 (m, 1H), 6.98-6.92 (m, 1H), 5.84-5.77 (m, 1H), 4.4-4.31 (m, 1H), 3.46-3.35 (m, 1H), 2.16-2.01 (m, 5H), 1.94-1.80 (m, 2H), 1.69-1.54 (m, 2H).
Example 13: N-((1R,4R)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: tert-Butyl ((1R,4R)(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamido)cyclohexyl)carbamate. The title compound was prepared in a manner analogous to Example 5, Step A-B, using 5-(2-methylphenoxyphenyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-(4-aminocyclohexyl)carbamate.
Step B: N-((1R,4R)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step B, using tert-butyl ((1R,4R)(5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamido)cyclohexyl)carbamate and propenoyl chloride . MS (ESI): mass calcd. for C H N O S, 567.7; m/z found, 568.4 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.15 (br, 31 29 5 4 6 1H), 8.34-8.23 (m, 1H), 8.15-7.97 (m, 2H), 7.47-7.39 (m, 2H), 7.37-7.28 (m, 1H), 7.20-7.15 (m, 1H), 7.14-7.08 (m, 2H), 7.08-7.03 (m, 1H), 6.99-6.92 (m, 1H), 6.21-6.13 (m, 1H), 6.08-6.02 (m, 1H), 5.96-5.87 (m, 1H), 5.57-5.51 (m, 1H), 3.80-3.69 (m, 2H), 2.03 (s, 3H), 1.89-1.80 (m, 4H), 1.50-1.39 (m, 2H), 1.33-1.24 (m, 2H).
Example 14: N-((1R,2S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 7, Step B, using N- ((1R,2S)aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 10). MS (ESI): mass calcd. for C H N O S, 541.7; m/z found, 542.2 [M+H] . H NMR (400 MHz, CD OD): δ 12.38-12.24 31 5 3 3 (m, 1H), 9.70 -9.58 (m, 1H), 8.40-8.32 (m, 1H), 7.41-7.36 (m, 2H), 7.20-7.12 (m, 2H), 7.11-7.07 (m, 2H), 7.00-6.98 (m, 1H), 6.97-6.93 (m, 1H), 6.08-5.99 (m, 1H), 4.94-4.84 (m, 1H), 3.13-3.01 (m, 1H), 2.99-2.74 (m, 6H), 2.74-2.65 (m, 1H), 2.36-2.28 (m, 1H), 2.25-2.15 (m, 2H), 2.12-2.08 (m, 3H), 2.06-2.01 (m, 1H), 1.66-1.45 (m, 3H).
Example 15: N-((1R,4R)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and (1R,4R)aminocyclohexanol. MS (ESI): mass calcd. for C H N O S, 514.6; m/z found, 515.80 [M+H] . 28 26 4 4 Example 16: N-((1S,4S)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and (1S,4S)aminocyclohexanol. MS (ESI): mass calcd. for C H N O S, 514.6; m/z found, 515.70 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.34-10.21 28 26 4 4 6 (m, 1H), 8.38 -8.24 (m, 1H), 8.16-7.89 (m, 1H), 7.49-7.42 (m, 2H), 7.40-7.34 (m, 1H), 7.24-7.17 (m, 1H), 7.16-7.11 (m, 2H), 7.10-7.07 (m, 1H), 7.01-6.95 (m, 1H), 6.03-5.84 (m, 1H), 4.43-4.36 (m, 1H), 3.84-3.74 (m, 2H), 2.07 (s, 3H), 1.85-1.67 (m, 4H), 1.56-1.44 (m, 4H).
Example 17: N-((1R,2S)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 7 using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate in Step A.
MS (ESI): mass calcd. for C H N O S, 527.6; m/z found, 528.2 [M+H] . H NMR (400 MHz, 29 29 5 3 CD OD): δ 8.21-8.13 (m, 1H), 7.42-7.34 (m, 2H), 7.28-7.18 (m, 1H), 7.17-7.11 (m, 1H), 7.09- 7.06 (m, 2H), 7.05-7.01 (m, 1H), 6.99-6.91 (m, 1H), 5.95-5.83 (m, 1H), 4.58-4.44 (m, 1H), 2.63- 2.52 (m, 1H), 2.41-2.32 (m, 6H), 2.14-2.10 (m, 3H), 2.07-1.97 (m, 3H), 1.87-1.79 (m, 2H), 1.75- 1.65 (m, 1H).
Example 18: N-((1R,4R)Methoxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and (1R,4R)methoxycyclohexanamine. MS (ESI): mass calcd. for C H N O S, 528.6; m/z found, 529.2 [M+H] . H NMR (400 MHz, DMSO-d and CD OD): δ 29 28 4 4 6 3 8.24 (d, J = 5.2 Hz, 1H), 7.40-7.29 (m, 2H), 7.27-7.20 (m, 1H), 7.14-7.06 (m, 1H), 7.06-7.00 (m, 2H), 7.00-6.96 (m, 1H), 6.94-6.84 (m, 1H), 5.95 (d, J = 5.3 Hz, 1H), 3.83-3.68 (m, 1H), 3.22 (s, 3H), 3.12-3.05 (m, 1H), 2.11-1.95 (m, 5H), 1.91-1.80 (m, 2H), 1.44-1.30 (m, 2H), 1.21-1.15 (m, 2H).
Example 19: N-((1S,4S)((E)Cyanocyclopropylacrylamido)cyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1S,4S)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1 Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl ((1S,4S) aminocyclohexyl)carbamate.
Step B: N-((1S,4S)((E)Cyanocyclopropylacrylamido)cyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of (E)cyanocyclopropylpropenoic acid (27 mg, 0.20 mmol), HATU (114 mg, 0.300 mmol), and triethylamine (40 mg, 0.40 mmol) in DMF (2 mL) was added N-((1S,4S) aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (also Example 25, 103 mg, 0.200 mmol) and was stirred at rt for 4 hours. The mixture was purified by flash column chromatography, then by preparative TLC to yield the title compound (43 mg, 33% yield). MS (ESI): mass calcd. for C H N O S, 32 6 4 632.7; m/z found, 633.2 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.17 (br, 1H), 8.40-8.24 (m, 1H), 7.94-7.78 (m, 1H), 7.76-7.61 (m, 1H), 7.46-7.40 (m, 2H), 7.39-7.28 (m, 1H), 7.21-7.15 (m, 1H), 7.13-7.03 (m, 3H), 6.99-6.88 (m, 2H), 6.04-5.86 (m, 1H), 3.92-3.81 (m, 1H), 3.79-3.72 (m, 1H), 2.04 (s, 3H), 1.85-1.50 (m, 9H), 1.20-1.08 (m, 2H), 0.99-0.81 (m, 2H).
Example 20: N-((1S,2S)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and (1S,2S)aminocyclopentanol. MS (ESI): mass calcd. for C27H24N4O4S, 500.6; m/z found, 501.1 [M+H] . H NMR (400 MHz, CD3OD): δ 8.34-8.27 (m, 1H), 7.44-7.34 (m, 2H), 7.33-7.25 (m, 1H), 7.20-7.13 (m, 1H), 7.11-7.02 (m, 3H), 7.00-6.92 (m, 1H), 6.10-6.03 (m, 1H), 4.17-4.07 (m, 2H), 2.19-2.09 (m, 4H), 2.03-1.95 (m, 1H), 1.80-1.72 (m, 2H), 1.64-1.55 (m, 2H).
Example 21: 5-(2-Methylphenoxyphenyl)-N-((1R,2R)(methylamino)cyclopentyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1R,2R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 5, Step A-B, using 5-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1R,2R)aminocyclopentyl]carbamate, in Step A.
Step B: 5-(2-Methylphenoxyphenyl)-N-((1R,2R)(methylamino)cyclopentyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of N-((1R,2R) aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (248 mg, 0.463 mmol), paraformaldehyde (2 g), 4A molecular Sieve (4 g) in DCM (75 mL) was stirred at rt under N for 16 h. The mixture was filtered and concentrated to dryness to yield the title compound (19 mg, 8% yield). MS (ESI): mass calcd. for C H N O S, 513.6; m/z found, 514.7 [M+H] . 28 27 5 3 Example 22: N-((1R,2R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 5, Step A-B, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1R,2R)aminocyclopentyl]carbamate, in Step A. MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, 500.1 [M+H] . H NMR (400 MHz, 27 25 5 3 and CD OD): δ 8.05-7.98 (m, 1H), 7.38-7.28 (m, 2H), 7.12-7.05 (m, 2H), 7.05-6.98 DMSO-d6 3 (m, 2H), 6.98-6.94 (m, 1H), 6.89-6.84 (m, 1H), 5.70-5.65 (m, 1H), 4.04-3.86 (m, 2H), 3.29-3.22 (m, 1H), 2.10-2.00 (m, 2H), 1.99-1.96 (m, 3H), 1.74-1.62 (m, 3H), 1.56-1.47 (m, 1H).
Example 23: N-((1S,4S)Cyanamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of N-((1S,4S)aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 25, 103 mg, 0.200 mmol) and triethylamine (40 mg, 0.4 mmol) in DCM (5 mL) was added BrCN (21 mg, 0.20 mmol) and was stirred at rt for 2 h. The mixture was purified by flash column chromatography to yield the title compound (30 mg, 28% yield). MS (ESI): mass calcd. for C H N O S, 538.6; 29 26 6 3 m/z found, 539.3 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.22 (br, 1H), 8.37-8.21 (m, 1H), 8.15-7.89 (m, 1H), 7.46-7.40 (m, 2H), 7.40-7.29 (m, 1H), 7.20-7.16 (m, 1H), 7.13-7.09 (m, 2H), 7.08-7.04 (m, 1H), 6.99-6.93 (m, 1H), 6.80-6.70 (m, 1H), 6.04-5.83 (m, 1H), 3.87-3.76 (m, 1H), 3.37-3.35 (m, 1H), 2.04 (s, 3H), 1.75-1.57 (m, 8H).
Example 24: N-((1R,3S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1R,3S)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and (1S,3R)-cyclohexane-1,3- diamine.
Step B: N-((1R,3S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 7, Step B. MS (ESI): mass calcd. for C H N O S, 541.7; 31 5 3 m/z found, 542.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.17 (d, J = 5.6 Hz, 1H), 7.42-7.35 (m, 2H), 7.25-7.20 (m, 1H), 7.17-7.12 (m, 1H), 7.11-7.06 (m, 2H), 7.05-7.02 (m, 1H), 7.00-6.93 (m, 1H), 5.91 (d, J = 5.6 Hz, 1H), 3.98-3.89 (m, 1H), 2.59-2.49 (m, 1H), 2.37 (s, 6H), 2.24-2.18 (m, 1H), 2.11 (s, 3H), 2.02-1.97 (m, 1H), 1.95-1.86 (m, 2H), 1.49-1.39 (m, 2H), 1.35-1.30 (m, 2H).
Example 25: N-((1S,4S)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound is Example 19, product from Step A. MS (ESI): mass calcd. for C H N O S, 513.6; m/z found, 514.3 [M+H] . 28 27 5 3 Example 26: 5-(2-Methylphenoxyphenyl)oxo-N-((1R,2R)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 11, Step B, using N- ((1R,2R)aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 11, product from Step A) and propanoyl chloride. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.6 [M+H] . H NMR 29 5 4 (400 MHz, DMSO-d ): δ 10.20 (s, 1H), 8.39-8.03 (m, 2H), 7.92-7.83 (m, 1H), 7.46-7.37 (m, 2H), 7.37-7.27 (m, 1H), 7.19-7.13 (m, 1H), 7.12-7.03 (m, 3H), 6.98-6.91 (m, 1H), 5.98-5.80 (m, 1H), 4.16-4.02 (m, 2H), 2.05-1.98 (m, 5H), 1.97-1.89 (m, 2H), 1.68-1.59 (m, 2H), 1.56-1.47 (m, 1H), 1.42-1.34 (m, 1H), 0.92 (t, J = 7.6 Hz, 3H).
Example 27: N-((1RS,2RS)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 3, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 8) and (1RS,2RS)aminocyclohexanol in Step B. MS (ESI): mass calcd. for C H N O S, 514.6; m/z found, 515.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.36-8.31 (m, 28 26 4 4 3 1H), 7.44-7.34 (m, 2H), 7.33-7.25 (m, 1H), 7.20-7.13 (m, 1H), 7.11-7.02 (m, 3H), 7.00-6.92 (m, 1H), 6.10-6.03 (m, 1H), 4.06-3.90 (m, 2H), 2.13 (s, 3H), 1.87-1.76 (m, 3H), 1.67-1.59 (m, 3H), 1.50-1.38 (m, 2H).
Example 28: N-Cyclopentyl(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and cyclopentanamine, no HCl/MeOH deprotection. MS (ESI): mass calcd. for C H N O S, 484.6; m/z found, 485.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.32 27 24 4 3 3 (d, J = 5.6 Hz, 1H), 7.45-7.36 (m, 2H), 7.34-7.27 (m, 1H), 7.22-7.14 (m, 1H), 7.12-7.03 (m, 3H), 7.02-6.92 (m, 1H), 6.06 (d, J = 5.5 Hz, 1H), 4.35-4.26 (m, 1H), 2.12 (s, 3H), 2.06-1.98 (m, 2H), 1.83-1.75 (m, 2H), 1.67-1.56 (m, 4H).
Example 29: N-((1R,2R)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 7, Step B, using N- ((1R,2R)aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 22). MS (ESI): mass calcd. for C H N O S, 527.6; m/z found, 528.0 [M+H] . 29 29 5 3 Example 30: N-((1r,3s,5R,7S)Hydroxyadamantanyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and (1s,3r,5R,7S)aminoadamantanol. MS (ESI): mass calcd. for C H N O S, 566.7; m/z found, 567.0 [M+H] . 32 30 4 4 Example 31: 5-(2-Methylphenoxyphenyl)-N-(2-(methylamino)cyclohexyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: 5-(2-Methylphenoxyphenyl)oxo-N-(2-oxocyclohexyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide. To a solution of N-(2-hydroxycyclohexyl)(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide (Example 36, 800 mg, 1.55 mmol) in DCM (10 mL) was added Dess-Martin periodinane (988 mg, 2.33 mmol) and was reacted at rt for 4 h, concentrated to dryness, and purified by flash column chromatography to give the title compound as a yellow solid (500 mg).
Step B: 5-(2-Methylphenoxyphenyl)-N-(2-(methylamino)cyclohexyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of 5-(2-methyl phenoxyphenyl)oxo-N-(2-oxocyclohexyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide (500 mg, 0.98 mmol) in DCM (5 mL) were added methylamine (5 mL) and NaBH(OAc) (500 mg, 0.98 mmol) and was reacted at rt for 4 h. The reaction was quenched by the addition of H O (20 mL), extracted with DCM, dried over anhydrous Na SO , filtered, and 2 2 4 concentrated to dryness. The residue was purified by flash column chromatography to give the title compound as a yellow solid (200 mg). MS (ESI): mass calcd. for C H N O S, 527.6; m/z 29 29 5 3 found, 528.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.38 (s, 1H), 8.35-8.29 (m, 1H), 7.44- 7.34 (m, 2H), 7.30-7.25 (m, 1H), 7.20-7.13 (m, 1H), 7.11-7.02 (m, 3H), 7.00-6.92 (m, 1H), 6.12- 6.05 (m, 1H), 4.72-4.02 (m, 1H), 3.38-3.01 (m, 1H), 2.77-2.64 (m, 3H), 2.29-2.15 (m, 1H), 2.15- 2.05 (m, 3H), 2.04-1.73 (m, 4H), 1.65-1.38 (m, 3H).
Example 32: N-((1S,2S)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 7, Step B, using N-((1S,2S)- 2-aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 41). MS (ESI): mass calcd. for C H N O S, 29 29 5 3 527.6; m/z found, 528.1 [M+H] .
Example 33: N-((1R,2S)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 11, Steps A-B, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1S,2R)aminocyclohexyl]carbamate, in Step A. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.2 [M+H] . H NMR (400 MHz, 29 5 4 CDCl ): δ 9.55-9.38 (m, 1H), 8.37-8.27 (m, 1H), 7.41-7.33 (m, 2H), 7.19-7.13 (m, 2H), 7.11- 7.05 (m, 2H), 7.01-6.89 (m, 3H), 6.18-6.04 (m, 1H), 6.01-5.93 (m, 1H), 4.20-4.07 (m, 2H), 2.12- 2.09 (m, 3H), 2.07 (s, 3H), 2.02-1.98 (m, 1H), 1.88-1.75 (m, 3H), 1.65-1.56 (m, 4H).
Example 34: 5-(2-Methylphenoxyphenyl)oxo-N-((1R,2S)propionamidocyclopentyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 11, Steps A-B, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate, in Step A, and propanoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.2 29 5 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.29 (d, J = 5.0, 1H), 7.45-7.35 (m, 2H), 7.32-7.25 (m, 1H), 7.20-7.14 (m, 1H), 7.12-7.03 (m, 3H), 7.01-6.92 (m, 1H), 6.04 (d, J = 5.3, 1H), 4.44- 4.30 (m, 2H), 2.25-2.17 (m, 2H), 2.11 (s, 3H), 2.08-1.97 (m, 2H), 1.93-1.84 (m, 1H), 1.78-1.60 (m, 3H), 1.08 (t, J = 7.6, 3H).
Example 35: 5-(2-Methylphenoxyphenyl)oxo-N-((1R,2S)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of N-((1R,2S)aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 10, 150 mg, 0.29 mmol) in DCM was added triethylamine , then propanoyl propanoate (38 mg, 0.29 mmol) in DCM was added dropwise and was stirred at rt for 2 h. The reaction was concentrated to dryness and purified by flash column chromatography, then preparative TLC to give the title compound as a yellow solid (55 mg). MS (ESI): mass calcd. for C H N O S, 569.7; m/z found, 570.3 [M+H] . 31 31 5 4 H NMR (400 MHz, CDCl ): δ 9.72-9.60 (m, 1H), 8.45-8.30 (m, 1H), 7.41-7.37 (m, 3H), 7.23- 7.14 (m, 2H), 7.10-7.06 (m, 2H), 7.00-6.93 (m, 2H), 6.52-6.31 (m, 1H), 6.26-6.06 (m, 1H), 4.31- 4.22 (m, 1H), 4.16-4.08 (m, 1H), 2.43-2.25 (m, 2H), 2.16-2.05 (m, 3H), 1.97-1.89 (m, 1H), 1.78- 1.68 (m, 3H), 1.62-1.41 (m, 4H), 1.21-1.13 (m, 3H).
Example 36: N-((1RS,2RS)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and (1RS,2RS)aminocyclohexanol. MS (ESI): mass calcd. for C H N O S, 514.6; m/z found, 515.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.35-8.26 (m, 28 26 4 4 3 1H), 7.46-7.35 (m, 2H), 7.31-7.28 (m, 1H), 7.19-7.12 (m, 1H), 7.08-7.04 (m, 3H), 7.00-6.93 (m, 1H), 6.09-6.02 (m, 1H), 3.85-3.74 (m, 1H), 3.56-3.43 (m, 1H), 2.11 (s, 3H), 2.05-1.93 (m, 2H), 1.82-1.66 (m, 2H), 1.39-1.27 (m, 4H).
Example 37: N-((1R,2S)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 11, Steps A-B, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate in Step A, and acetyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.2 29 27 5 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.31 (d, J = 5.6, 1H), 7.43-7.36 (m, 2H), 7.32-7.24 (m, 1H), 7.19-7.13 (m, 1H), 7.11-7.03 (m, 3H), 7.00-6.93 (m, 1H), 6.08-6.03 (m, 1H), 4.44-4.28 (m, 2H), 2.14-2.09 (m, 3H), 2.09-1.97 (m, 2H), 1.95-1.92 (m, 3H), 1.92-1.81 (m, 1H), 1.77-1.59 (m, 3H).
Example 38: N-((1R,2R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: tert-Butyl ((1R,2R)(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamido)cyclohexyl)carbamate. A solution of 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 8, 980 mg, 2.25 mmol), tert-butyl N-[(1R,2R)aminocyclohexyl]carbamate (1.0 g, 4.7 mmol), and triethylamine (227 mg, 2.25 mmol) in DCM (10 mL) was reacted at rt for 2 h, then quenched with H O (10 mL), extracted with DCM, dried over anhydrous Na SO , filtered, 2 2 4 and concentrated to dryness to give the title compound as a yellow solid (1.3 g, 94% yield).
Step B: N-((1R,2R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of tert-butyl ((1R,2R)(5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamido)cyclohexyl)carbamate (1.3 g, 2.1 mmol) in MeOH (10 mL) was added concentrated HCl (2 mL) and was stirred at rt for 20 min. The reaction was quenched by the addition of H2O (10 mL), extracted with DCM, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound as a yellow solid (800 mg, 74% yield). MS (ESI): mass calcd. for C28H27N5O3S, 513.6; m/z found, 514.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.16-8.12 (m, 1H), 7.42-7.33 (m, 2H), 7.27-7.12 (m, 2H), 7.09-7.01 (m, 3H), 7.00-6.92 (m, 1H), 5.91-5.85 (m, 1H), 3.91-3.81 (m, 1H), 3.11-2.96 (m, 1H), 2.13-2.01 (m, 5H), 1.85-1.77 (m, 2H),1.55-1.35 (m, 4H).
Example 39: N-((1S,2R)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 3, Steps A-B, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride and (1R,2S)aminocyclopentanol in Step B. MS (ESI): mass calcd. for C H N O S, 27 24 4 4 500.6; m/z found, 501.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.34-8.27 (m, 1H), 7.44-7.34 (m, 2H), 7.33-7.25 (m, 1H), 7.20-7.13 (m, 1H), 7.11-7.02 (m, 3H), 7.00-6.92 (m, 1H), 6.10-6.03 (m, 1H), 4.26-4.11 (m, 2H), 2.12 (s, 3H), 2.05-1.87 (m, 3H), 1.79-1.60 (m, 3H).
Example 40: N-((1S,2S)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 11, Steps A-B, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1S,2S)aminocyclopentyl]carbamate in Step A, and acetyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.4 29 27 5 4 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.21 (s, 1H), 8.29 (d, J = 5.3 Hz, 1H), 8.20-8.05 (m, 1H), 8.03-7.90 (m, 1H), 7.47-7.38 (m, 2H), 7.38-7.32 (m, 1H), 7.21-7.15 (m, 1H), 7.12-7.07 (m, 2H), 7.07-7.02 (m, 1H), 6.98-6.90 (m, 1H), 5.93 (d, J = 5.1 Hz, 1H), 4.21-3.98 (m, 2H), 2.03 (s, 3H), 1.99-1.89 (m, 2H), 1.75 (s, 3H), 1.71-1.60 (m, 2H), 1.59-1.45 (m, 1H), 1.4-1.34 (m, 1H).
Example 41: N-((1S,2S)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1S,2S)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, 500.1 [M+H] . 27 25 5 3 Example 42: 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2R)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1S,2R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 5, Step A-B, using 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1R,2S) aminocyclohexyl]carbamate, in Step A.
Step B: 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2R)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of N-((1S,2R) aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (120 mg, 0.22 mmol) in DCM (30 mL) were added propionic anhydride (34 mg, 0.26 mmol) and DMAP (2.7 mg, 0.022 mmol). The reaction was stirred at rt for 30 min, concentrated to dryness, and purified by flash column chromatography to give the title compound as a yellow solid (81 mg, 64% yield). MS (ESI): mass calcd. for C H N O S, 569.7; m/z found, 570.3 [M+H] . H NMR (400 MHz, DMSO-d ): δ 9.98 (d, J = 31 31 5 4 6 11.8 Hz, 1H), 8.32 (d, J = 5.4 Hz, 1H), 7.80-7.64 (m, 1H), 7.57-7.47 (m, 1H), 7.47-7.40 (m, 2H), 7.39-7.32 (m, 1H), 7.24-7.14 (m, 1H), 7.14-7.03 (m, 3H), 7.02-6.88 (m, 1H), 5.97 (d, J = 5.4 Hz, 1H), 4.20-4.05 (m, 1H), 4.04-3.92 (m, 1H), 2.26-2.12 (m, 2H), 2.05 (s, 3H), 1.72-1.60 (m, 4H), 1.58-1.47 (m, 2H), 1.42-1.28 (m, 2H), 1.03-0.92 (m, 3H).
Example 43: N-((1R,2R)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH To a solution of N-((1R,2R)aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 38, 100 mg, 0.2 mmol) in DCM (4 mL) were added formaldehyde (1 mL) and NaBH(OAc)3 (200 mg, 0.94 mmol) and was reacted at rt overnight. The reaction was quenched by the addition of H O (10 mL), extracted with DCM, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound as a yellow solid (41 mg, 39% yield). MS (ESI): mass calcd. for C H N O S, 541.7; m/z found, 542.2 31 5 3 [M+H] . H NMR (400 MHz, CD OD): δ 8.31-8.27 (m, 1H), 7.43-7.35 (m, 2H), 7.32-7.23 (m, 1H), 7.20-7.13 (m, 1H), 7.11-7.03 (m, 3H), 7.00-6.94 (m, 1H), 6.09-6.02 (m, 1H), 4.33-4.17 (m, 1H), 3.44-3.31 (m, 1H), 2.82 (s, 3H), 2.81 (s, 3H), 2.21-2.11 (m, 1H), 2.10-2.06 (m, 3H), 2.05- 2.00 (m, 1H),1.98-1.91 (m, 1H), 1.87-1.79 (m, 1H), 1.71-1.51 (m, 2H), 1.49-1.36 (m, 2H).
Example 44: N-((1S,2R)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 11, Steps A-B, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl, in Step A, and using acetyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.2 [M+H] . H NMR (400 MHz, DMSO- 29 5 4 d ): δ 9.98 (s, 1H), 8.32 (d, J = 5.4 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.68-7.56 (m, 1H), 7.49- 7.32 (m, 3H), 7.23-7.14 (m, 1H), 7.14-7.05 (m, 3H), 7.02-6.88 (m, 1H), 5.97 (d, J = 5.5 Hz, 1H), 4.17-4.04 (m, 1H), 4.04-3.90 (m, 1H), 2.05 (s, 3H), 1.89 (s, 3H), 1.74-1.59 (m, 4H), 1.58-1.46 (m, 2H), 1.42-1.30 (m, 2H).
Example 45: 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2S)propionamidocyclopentyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1S,2S)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 5, Step A-B, using 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1S,2S)- 2-aminocyclopentyl]carbamate, in Step A.
Step B: 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2S)propionamidocyclopentyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 42, Step B. To a solution of N-((1S,2S)aminocyclopentyl)- 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide (100 mg, 0.2 mmol) in DCM (25 mL) was added propionic anhydride (31 mg, 0.24 mmol), followed by DMAP . The reaction was stirred at rt for 30 min, concentrated to dryness, and purified by flash column chromatography to give the title compound as a yellow solid (68 mg, 61% yield). MS (ESI): mass calcd. for C30H29N5O4S, 555.6; m/z found, 556.5 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.19 (s, 1H), 8.28 (d, J = 5.3 Hz, 1H), 8.20-8.04 (m, 1H), 7.95- 7.80 (m, 1H), 7.52 – 7.25 (m, 3H), 7.25 – 7.01 (m, 4H), 6.99-6.85 (m, 1H), 5.93 (d, J = 5.1 Hz, 1H), 4.30-3.95 (m, 2H), 2.14 – 1.79 (m, 7H), 1.70-1.58 (m, 2H), 1.57-1.33 (m, 2H), 0.92 (t, J = 6.8 Hz, 3H).
Example 46: 5-(2-Methylphenoxyphenyl)-N-((1S,2S)(methylamino)cyclopentyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1S,2S)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 5, Step A-B, using 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1S,2S)- 2-aminocyclopentyl]carbamate, in Step A.
Step B: 5-(2-Methylphenoxyphenyl)-N-((1S,2S)(methylamino)cyclopentyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To an oven dried round bottom flask under an N atmosphere fitted with a reflux condenser were added N-((1S,2S) aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (300 mg, 0.60 mmol), paraformaldehyde (200 mg, 2.2 mmol), and activated 4A molecular sieves in anhydrous DCM (50 mL) and the reaction was refluxed for 16 hours. The reaction mixture was filtered, washed with DCM, the organic phases combined, and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound as a slight yellow solid (20 mg, 6.3% yield). MS (ESI): mass calcd. for C H N O S, 513.6; m/z found, 514.3 [M+H] . H NMR (400 MHz, 28 27 5 3 CD3OD): δ 8.44 (s, 1H), 8.33 (d, J = 5.4 Hz, 1H), 7.46-7.35 (m, 2H), 7.34-7.26 (m, 1H), 7.22- 7.13 (m, 1H), 7.12-7.03 (m, 3H), 7.02-6.92 (m, 1H), 6.13-6.01 (m, 1H), 4.42-4.30 (m, 1H), 3.56- 3.38 (m, 1H), 2.87-2.74 (m, 3H), 2.31-2.15 (m, 2H), 2.13-2.07 (m, 3H), 1.97-1.70 (m, 4H).
Example 47: N-((1R,2R)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 3, Steps A-B, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1R,2R)aminocyclohexyl]carbamate in Step A, and using acetyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 29 5 4 556.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.30 (d, J = 5.5Hz, 1H), 7.46-7.34 (m, 2H), 7.30-7.23 (m, 1H), 7.19-7.10 (m, 1H), 7.10-7.01 (m, 3H), 6.99-6.91 (m, 1H), 6.05 (d, J = 5.5Hz, 1H), 3.85-3.71 (m, 2H), 2.14-2.08 (m, 3H), 2.07-1.98 (m, 1H), 1.98-1.91 (m, 1H), 1.86 (s, 3H), 1.83-1.72 (m, 2H), 1.48-1.28 (m, 4H).
Example 48: N-((1S,2R)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH Step A: N-((1S,2R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 3, Step B, using 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 20) and tert-butyl N-[(1R,2S)- 2-aminocyclohexyl]carbamate; followed by deprotection with HCl/MeOH.
Step B: N-((1S,2R)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of N-((1S,2R) aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (150 mg, 0.27 mmol) and formaldehyde (0.5 mL) in MeOH (5 mL) was added NaBH(OAc) (174 mg, 0.819 mmol) and was stirred at rt for 16 h, concentrated to dryness, and purified by flash column chromatography to give the title compound as a yellow solid (40 mg, 26% yield). MS (ESI): mass calcd. for C H N O S, 31 5 3 541.7; m/z found, 542.0 [M+H] . H NMR (400 MHz, DMSO-d and CD OD): δ 8.26-8.20 (m, 1H), 8.18 (s, 1H), 7.49-7.35 (m, 2H), 7.31-7.20 (m, 1H), 7.19-7.13 (m, 1H), 7.11-7.01 (m, 3H), 6.97-6.90 (m, 1H), 5.92-5.83 (m, 1H), 4.71-4.57 (m, 1H), 2.85-2.68 (m, 1H), 2.61 (s, 3H), 2.57 (s, 3H), 2.07-2.03 (m, 3H), 1.90-1.77 (m, 2H), 1.75-1.63 (m, 1H), 1.64-1.38 (m, 4H), 1.35-1.25 (m, 1H).
Example 49: N-((1S,2R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was is Example 48, product from Step A. MS (ESI): mass calcd. for C28H27N5O3S, 513.6; m/z found, 514.1 [M+H] .
Example 50: 5-(2-Methylphenoxyphenyl)-N-((1S,2R)(methylamino)cyclohexyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH Step A: N-((1S,2R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound is Example 48, product from Step A.
Step B: 5-(2-Methylphenoxyphenyl)-N-((1S,2R)(methyleneamino)cyclohexyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To an oven dried round bottom flask under an argon atmosphere fitted with a reflux condenser were added N-((1S,2R) aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (100 mg, 0.20 mmol), paraformaldehyde (53 mg, 0.59 mmol), activated 4A molecular sieves (100 mg), and anhydrous DCM (30 mL) and was refluxed for 16 hours. The reaction mixture was filtered and the residue washed with DCM. The organic phases were combined and concentrated to dryness to give the title compound as a yellow solid (100 mg, 100% yield).
Step C: (1R,2S)-N-Methyl(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)-N-methylenecyclohexanaminium. To a solution of 5-(2- methylphenoxyphenyl)-N-((1S,2R)(methyleneamino)cyclohexyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide (410 mg, 0.78 mmol) and Pd/C (10% on carbon, 200 mg) in MeOH/EtOAc (1/3, 30 mL) was reflux under H for 72 h, then cooled to rt, filtered, and concentrated to dryness to give the title compound as a yellow solid (280 mg, 66% yield).
Step D: 5-(2-Methylphenoxyphenyl)-N-((1S,2R)(methylamino)cyclohexyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of (1R,2S)-N- methyl(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)-N-methylenecyclohexanaminium (280 mg, 0.52 mmol) in 6.0 M HCl/MeOH (15 mL) was heated at reflux overnight, then concentrated to dryness and purified by flash column chromatography to give the title compound as a yellow solid (162 mg, 59.3 % yield). MS (ESI): mass calcd. for C H N O S, 527.6; m/z found, 528.1 [M+H] . 29 29 5 3 Example 51: N-((1S,2R)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1S,2R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1 Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1R,2S) aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 499.58; m/z found, 27 25 5 3 500.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.08 (d, J = 5.6 Hz, 1H), 7.40-7.34 (m, 2H), 7.21-7.15 (m, 1H), 7.15-7.10 (m, 1H), 7.10-7.05 (m, 2H), 7.04-7.01 (m, 1H), 6.97-6.93 (m, 1H), 5.81 (d, J = 5.6 Hz, 1H), 4.45-4.36 (m, 1H), 3.50-3.38 (m, 1H), 2.13-2.01 (m, 5H), 1.92-1.80 (m, 2H), 1.68-1.58 (m, 2H).
Step B: N-((1S,2R)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of N-((1S,2R) aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (150 mg, 0.30 mmol) in MeOH (5 mL) was added formaldehyde (98 mg, 3.3 mmol) and was stirred at rt for 10 min, then NaBH(OAc) (318 mg, 1.50 mmol) was added and was stirred at rt overnight. The pH was adjusted to pH >7 with 2 M aqueous NaOH. The reaction mixture was concentrated to dryness and the residue was purified by flash column chromatography and preparative TLC to give the title compound as a yellow solid (56 mg, 35% yield). MS (ESI): mass calcd. for C H N O S, 527.6; m/z found, 528.2 29 29 5 3 [M+H] . H NMR (400 MHz, CD OD): δ 8.25 (d, J = 5.4 Hz, 1H), 7.44-7.32 (m, 2H), 7.29-7.19 (m, 1H), 7.19-7.11 (m, 1H), 7.11-7.01 (m, 3H), 6.99-6.92 (m, 1H), 6.04-5.95 (m, 1H), 4.54-4.43 (m, 1H), 2.76-2.60 (m, 1H), 2.53-2.33 (m, 6H), 2.15-1.99 (m, 5H), 1.96-1.82 (m, 2H), 1.80-1.66 (m, 2H).
Example 52: 5-(2-Methylphenoxyphenyl)oxo-N-((1R,2R)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: tert-Butyl ((1R,2R)(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamido)cyclohexyl)carbamate. A solution of 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 8, 980 mg, 2.25 mmol), tert-butyl N-[(1R,2R)aminocyclohexyl]carbamate (1.0 g, 4.7 mmol), and triethylamine (227 mg, 2.25 mmol) in DCM (10 mL) was reacted at rt for 2 h.
The reaction was quenched with H O (10 mL), extracted with DCM, dried over anhydrous Na SO , filtered, and concentrated to dryness to give the title compound as a yellow solid (1.3 g, 94% yield ). MS (ESI): mass calcd. for C H N O S, 613.73; m/z found, 614.1 [M+H] . 33 35 5 5 Step B: N-((1R,2R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of tert-butyl ((1R,2R)(5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamido)cyclohexyl)carbamate (1.3 g, 2.1 mmol) in MeOH (10 mL), was added concentrated HCl (2 mL) and was reacted at rt for 20 min. The reaction was quenched with H O (10 mL), extracted with DCM, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound (800 mg, 73.5% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 513.61; m/z 28 27 5 3 found, 514.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.16-8.12 (m, 1H), 7.42-7.33 (m, 2H), 7.27-7.12 (m, 2H), 7.09-7.01 (m, 3H), 7.00-6.92 (m, 1H), 5.91-5.85 (m, 1H), 3.91-3.81 (m, 1H), 3.11-2.96 (m, 1H), 2.13-2.01 (m, 5H), 1.85-1.77 (m, 2H),1.55-1.35 (m, 4H).
Step C: 5-(2-Methylphenoxyphenyl)oxo-N-((1R,2R)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of N-((1R,2R) aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (150 mg, 0.29 mmol) and triethylamine (50 mg, 0.50 mmol) in DCM (5 mL) was added propanoyl propanoate (38 mg, 0.29 mmol) and was reacted at rt for 20 min. The reaction was quenched with H O (10 mL), extracted with DCM, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound as a yellow solid (108 mg, 65.0% yield). MS (ESI): mass calcd. for C H N O S, 569.7; m/z found, 570.1 [M+H] . H NMR (400 MHz, 31 31 5 4 CD OD): δ 8.30 (d, J = 5.5Hz, 1H), 7.45-7.34 (m, 2H), 7.31-7.24 (m, 1H), 7.20-7.11 (m, 1H), 7.11-7.01 (m, 3H), 7.00-6.90 (m, 1H), 6.05 (d, J = 5.5Hz, 1H), 3.87-3.74 (m, 2H), 2.18-2.07 (m, 5H), 2.06-1.99 (m, 1H), 1.97-1.89 (m, 1H), 1.82-1.73 (m, 2H), 1.50-1.29 (m, 4H), 1.06-0.96 (m, 3H).
Example 53: N-((1S,2R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound is the product from Step A, Example 51. MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, 500.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.08 (d, J = 27 25 5 3 3 5.6 Hz, 1H), 7.40-7.34 (m, 2H), 7.21-7.15 (m, 1H), 7.15-7.10 (m, 1H), 7.10-7.05 (m, 2H), 7.04- 7.01 (m, 1H), 6.97-6.93 (m, 1H), 5.81 (d, J = 5.6 Hz, 1H), 4.45-4.36 (m, 1H), 3.50-3.38 (m, 1H), 2.13-2.01 (m, 5H), 1.92-1.80 (m, 2H), 1.68-1.58 (m, 2H).
Example 54: N-((1S,2S)Formamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1S,2S)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1S,2S) aminocyclohexyl]carbamate, in Step A. MS (ESI): mass calcd. for C H N O S, 513.61; m/z 28 27 5 3 found, 514.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.37-8.28 (m, 1H), 7.46-7.35 (m, 2H), 7.32-7.23 (m, 1H), 7.21-7.12 (m, 1H), 7.13-7.02 (m, 3H), 7.01-6.93 (m, 1H), 6.11-6.02(m, 1H), 4.07-3.97 (m, 1H), 3.16-3.03 (m, 1H), 2.17-2.12 (m, 1H), 2.11-2.04 (m, 3H), 2.02-1.95 (m, 1H), 1.91-1.80 (m, 2H), 1.64-1.47 (m, 2H), 1.46-1.35 (m, 2H).
Step B: N-((1S,2S)Formamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of N-((1S,2S) aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 58, 130 mg, 0.25 mmol) and DMAP (10 mg, 0.082 mmol) in DCM (5 mL) was added propanoyl propanoate (33 mg, 0.25 mmol) and was stirred at rt for 1 h, concentrated to dryness, and purified by flash column chromatography to give the title compound as a yellow solid (63 mg, 46% yield) and 5-(2-methyl phenoxyphenyl)oxo-N-((1S,2S)propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 60). MS (ESI): mass calcd. for C29H27N5O4S, 541.6; m/z found, 542.2 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.20 (s, 1H), 8.42-8.26 (m, 1H), 8.14-7.87(m, 3H), 7.52-7.33 (m, 3H), 7.25-7.16 (m, 1H), 7.17-7.05 (m, 3H), 7.04-6.92 (m, 1H), 6.05-5.89 (m, 1H), 3.94-3.66 (m, 2H), 2.07 (s, 3H), 1.92-1.79 (m, 2H), 1.76-1.63 (m, 2H), 1.56-1.40 (m, 1H), 1.31-1.21(m, 3H).
Example 55: N-((1S,2S)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 11, Steps A-B, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1S,2S)aminocyclohexyl]carbamate , in Step A, and acetyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.1 29 5 4 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.17 (s, 1H), 8.40-8.20 (m, 1H), 8.05-7.78 (m, 2H), 7.48-7.31 (m, 3H), 7.27-7.05 (m, 4H), 7.04-6.91 (m, 1H), 6.04-5.85 (m, 1H), 3.75-3.65 (m, 2H), 2.06 (s, 3H), 1.90-1.79 (m, 2H), 1.76 (s, 3H), 1.72-1.63 (m, 2H), 1.48-1.40(m, 1H), 1.31- 1.23 (m, 3H).
Example 56: N-((1S,2S)Acrylamidocyclopentyl)(*R)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1S,2S)Aminocyclopentyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *R atropisomer) and tert-butyl N-[(1S,2S)- 2-aminocyclopentyl]carbamate.
Step B: N-((1S,2S)Acrylamidocyclopentyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step B. MS (ESI): mass calcd. for C H N O S, 553.6; 27 5 4 m/z found, 554.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.38-8.23 (m, 1H), 7.46-7.35 (m, 2H), 7.33-7.25 (m, 1H), 7.23-7.12 (m, 1H), 7.12-7.02 (m, 3H), 6.99-6.94 (m, 1H), 6.28-6.17 (m, 2H), 6.09-6.00 (m, 1H), 5.67-5.54 (m, 1H), 4.31-4.18 (m, 2H), 2.23-2.07 (m, 5H), 1.88-1.76 (m, 2H), 1.72-1.55 (m, 2H).
Example 57: N-((1S,2R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 11, Step B, using N- ((1S,2R)aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide, Example 51, product from Step A, and acetyl chloride. MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.1 [M+H] . H NMR 29 27 5 4 (400 MHz, CD OD): δ 8.29 (d, J = 5.4 Hz, 1H), 7.45-7.34 (m, 2H), 7.33-7.24 (m, 1H), 7.21-7.12 (m, 1H), 7.12-7.02 (m, 3H), 7.02-6.92 (m, 1H), 6.04 (d, J = 5.3 Hz, 1H), 4.45-4.30 (m, 2H), 2.11 (s, 3H), 2.08-1.99 (m, 2H), 1.94 (s, 3H), 1.90-1.84 (m, 1H), 1.78-1.56 (m, 3H).
Example 58: N-((1S,2S)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound is the product from Step A, Example 54. MS (ESI): mass calcd. for C H N O S, 513.6; m/z found, 514.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.37-8.28 (m, 28 27 5 3 3 1H), 7.46-7.35 (m, 2H), 7.32-7.23 (m, 1H), 7.21-7.12 (m, 1H), 7.13-7.02 (m, 3H), 7.01-6.93 (m, 1H), 6.11-6.02(m, 1H), 4.07-3.97 (m, 1H), 3.16-3.03 (m, 1H), 2.17-2.12 (m, 1H), 2.11-2.04 (m, 3H), 2.02-1.95 (m, 1H), 1.91-1.80 (m, 2H), 1.64-1.47 (m, 2H), 1.46-1.35 (m, 2H).
Example 59: 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2R)propionamidocyclopentyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 11, Step B, using N- ((1S,2R)aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide, Example 51, product from Step A, and propanoyl chloride. MS ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.2 [M+H] . H NMR ( 30 29 5 4 (400 MHz, cd3od) d 8.30 (d, J = 5.3 Hz, 1H), 7.43-7.35 (m, 2H), 7.33-7.24 (m, 1H), 7.20-7.12 (m, 1H), 7.12-7.02 (m, 3H), 7.01-6.93 (m, 1H), 6.05 (d, J = 5.4 Hz, 1H), 4.43-4.30 (m, 2H), 2.24-2.17 (m, 2H), 2.11 (s, 3H), 2.07-1.98 (m, 2H), 1.92-1.82 (m, 1H), 1.76-1.58 (m, 3H), 1.08 (t, J = 7.6 Hz, 3H).
Example 60: 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2S)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of N-((1S,2S)aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 58, 130 mg, 0.25 mmol) and DMAP (10 mg, 0.082 mmol) in DCM (5 mL) was added propanoyl propanoate (33 mg, 0.25 mmol) and was stirred at rt for 1 h, concentrated to dryness, and purified by flash column chromatography to give the title compound as a yellow solid (36 mg 25% yield) and N-((1S,2S)- 2-Formamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 54). MS (ESI): mass calcd. for C H N O S, 31 31 5 4 569.7; m/z found, 570.2 [M+H] .
Example 61: N-((1R,2R)Hydroxycyclopentyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Steps A-B, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *R atropisomer) and (1R,2R)aminocyclopentanol in Step A. MS (ESI): mass calcd. for C H N O S, 500.6; m/z found, 501.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.33-8.25 (m, 27 24 4 4 3 1H), 7.43-7.34 (m, 2H), 7.32-7.26 (m, 1H), 7.21-7.14 (m, 1H), 7.11-7.02 (m, 3H), 7.00-6.92 (m, 1H), 6.06-6.00 (m, 1H), 4.19-4.06 (m, 2H), 2.18-2.13 (m, 1H), 2.11 (s, 3H), 2.05-1.93 (m, 1H), 1.81-1.70 (m, 2H), 1.67-1.55 (m, 2H).
Example 62: N-((1S,2S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of N-((1S,2S)aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 58, 63 mg, 0.12 mmol) and formaldehyde (0.3 mL) in MeOH (5 mL) was added NaBH(OAc) (78 mg, 0.37 mmol) and was stirred at rt for 1 h, concentrated to dryness, and purified by flash column chromatography to give the title compound as a yellow solid (45 mg, 63% yield). MS (ESI): mass calcd. for C H N O S, 541.7; m/z found, 542.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.48 (s, 1H), 31 5 3 3 8.40-8.24 (m, 1H), 7.46-7.34 (m, 2H), 7.31-7.23 (m, 1H), 7.21-7.13 (m, 1H), 7.13-7.02 (m, 3H), 7.01-6.95 (m, 1H), 6.13-6.01 (m, 1H), 4.31-4.17 (m, 1H), 3.28-3.17 (m, 1H), 2.89-2.76 (m, 6H), 2.20-2.12 (m, 1H), 2.12-2.06(m, 3H), 2.06-2.00 (m, 1H), 2.00-1.92 (m, 1H), 1.88-1.79 (m, 1H), 1.66-1.53 (m, 2H), 1.49-1.36 (m, 2H).
Example 63: 5-(2-Methylphenoxyphenyl)-N-(4-(methylamino)cyclohexyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: 5-(2-Methylphenoxyphenyl)oxo-N-(4-oxocyclohexyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide. A solution of N-((1R,4R)hydroxycyclohexyl) (2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide (Example 15, 150 mg, 0.30 mmol) and (1,1-diacetoxyoxo-isobenzofuranyl) acetate (250 mg, 0.60 mmol) in DCM (20 mL) was stirred at rt for 16 hours. To the mixture was added water and DCM and was filtered. The organic layer was collected, concentrated to dryness, and purified by flash column chromatography to give the title compound (138 mg, 90.0% yield).
Step B: 5-(2-Methylphenoxyphenyl)-N-(4-(methylamino)cyclohexyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of 5-(2-methyl phenoxyphenyl)oxo-N-(4-oxocyclohexyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide (154 mg, 0.301 mmol) and methylamine in MeOH (0.5 mL) in DCM (5 mL) was added NaBH(OAc) (200 mg, 0.94 mmol) and stirred at rt for 16 hours. To the mixture was added a 1 M aqueous solution of NH and DCM. The organic layer was collected, concentrated to dryness, and purified by flash column chromatography, then by preparative TLC to give the title compound (36 mg, 22% yield). MS (ESI): mass calcd. for C H N O S, 527.6; m/z found, 29 29 5 3 528.3 [M+H] . H NMR (400 MHz, a mixture of CD OD and DMSO-d ): δ 8.09-8.03 (m, 1H), 7.39-7.31 (m, 2H), 7.16-7.08 (m, 2H), 7.07-7.01 (m, 2H), 7.00-6.96 (m, 1H), 6.91-6.86 (m, 1H), 5.75-5.67 (m, 1H), 3.74-3.66 (m, 1H), 2.78-2.66 (m, 1H), 2.45 (s, 3H), 2.04-1.94 (m, 7H), 1.43- 1.24 (m, 4H).
Example 64: N-((1S,4S)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of N-((1S,4S)aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 25, 150 mg, 0.30 mmol) and triethylamine (340 mg, 0.90 mmol) in DCM (10 mL) was added acetic anhydride (30 mg, 0.30 mmol) and stirred at rt for 2 hours. The mixture was purified by flash column chromatography, then by preparative TLC to give the title compound (103 mg, 62.0% yield).
MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 553.4 [M+H] . H NMR (400 MHz, 29 5 4 DMSO-d ): δ 10.17 (br, 1H), 8.37-8.24 (m, 1H), 7.96-7.82 (m, 1H), 7.69-7.58 (m, 1H), 7.49-7.39 (m, 2H), 7.39-7.32 (m, 1H), 7.22-7.15 (m, 1H), 7.15-7.03 (m, 3H), 7.01-6.92 (m, 1H), 6.02-5.89 (m, 1H), 3.87-3.72 (m, 1H), 3.72-3.60 (m, 1H), 2.05 (s, 3H), 1.81 (s, 3H), 1.76-1.65 (m, 4H), 1.64-1.48 (m, 4H).
Example 65: 5-(2-Methylphenoxyphenyl)oxo-N-((1S,4S)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of N-((1S,4S)aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 25, 154 mg, 0.300 mmol) and triethylamine (342 mg, 0.900 mmol) in DCM (10 mL) was added propanoyl propanoate (28 mg, 0.21 mmol) and was stirred at room temperature for 2 hours. The mixture was purified by flash column chromatography, then by preparative TLC to give the title compound (76 mg, 44% yield). MS (ESI): mass calcd. for C H N O S, 569.7; m/z found, 31 31 5 4 570.3 [M+H] . H NMR (400 MHz, a mixture of CD OD and DMSO-d ): δ 8.33-8.20 (m, 1H), 7.59-7.46 (m, 1H), 7.42-7.33 (m, 2H), 7.32-7.25 (m, 1H), 7.16-7.11 (m, 1H), 7.09-6.98 (m, 3H), 6.95-6.89 (m, 1H), 6.02-5.85 (m, 1H), 3.85-3.79 (m, 1H), 3.74-3.70 (m, 1H), 2.12-2.06 (m, 2H), 2.03 (s, 3H), 1.71-1.50 (m, 8H), 0.99 (t, J = 7.5 Hz, 3H).
Example 66: N-((1S,4S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of N-((1S,4S)aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 25,150 mg, 0.30 mmol), formaldehyde (37% in water) in DCM was added NaBH(OAc) and was stirred at room temperature for 16 hours. To the mixture was added a 1 M aqueous solution of NH and DCM.
The organic layer was collected, concentrated to dryness, and purified by flash column chromatography, then by preparative TLC to give the title compound (100 mg, 61% yield). MS (ESI): mass calcd. for C H N O S, 541.7; m/z found, 542.3 [M+H] . 31 5 3 Example 67: N-((1R,2R)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1R,2R)aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2R) aminocyclopentyl]carbamate.
Step B: N-((1R,2R)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of N-((1R,2R) aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (28.5 mg, 0.0570 mmol) and triethylamine (65 mg, 0.17 mmol) in DCM (10 mL) was added acetic anhydride (5.8 mg, 0.57 mmol) and stirred at room temperature for 15 minutes. The mixture was purified by flash column chromatography, then by preparative TLC to give the title compound (25 mg, 81% yield). MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.3 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.21 (br, 29 27 5 4 6 1H), 8.35-7.99 (m, 2H), 7.98-7.93 (m, 1H), 7.45-7.40 (m, 2H), 7.38-7.27 (m, 1H), 7.20-7.16 (m, 1H), 7.12-7.08 (m, 2H), 7.07-7.05 (m, 1H), 6.97-6.93 (m, 1H), 5.98-5.80 (m, 1H), 4.17-4.01 (m, 2H), 2.04 (s, 3H), 2.00-1.91 (m, 2H), 1.77 (s, 3H), 1.69-1.61 (m, 2H), 1.57-1.49 (m, 1H), 1.44- 1.36 (m, 1H).
Example 68: N-((1S,3R)acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1S,3R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, using 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1R,3S) aminocyclopentyl]carbamate, in Step A.
Step B: N-((1S,3R)acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step B. MS (ESI): mass calcd. for C H N O S, 27 5 4 553.6; m/z found, 554.4 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.21-10.10 (m, 1H), 8.34- 8.28 (m, 1H), 8.27-8.11 (m, 2H), 7.46-7.40 (m, 2H), 7.39-7.32 (m, 1H), 7.21-7.16 (m, 1H), 7.13- 7.08 (m, 2H), 7.08-7.05 (m, 1H), 6.99-6.93 (m, 1H), 6.26-6.16 (m, 1H), 6.12-6.04 (m, 1H), 6.00- 5.89 (m, 1H), 5.59-5.52 (m, 1H), 4.26-4.15 (m, 1H), 4.08-3.99 (m, 1H), 2.31-2.23 (m, 1H), 2.05 (s, 3H), 1.95-1.85 (m, 2H), 1.77-1.66 (m, 1H), 1.64-1.47 (m, 2H).
Example 69: 5-(2-Methylphenoxyphenyl)oxo-N-((1S,3R)propionamidocyclopentyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of N-((1S,3R)aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 68, product from Step A, 150 mg, 0.30 mmol) and triethylamine (91 mg, 0.90 mmol) in DCM (10 mL) was added propanoyl propanoate (39 mg, 0.30 mmol) and was stirred at room temperature for 2 hours. The mixture was purified by flash column chromatography, then by preparative TLC to give the title compound (140 mg, 83% yield). MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 29 5 4 556.3 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.14 (br, 1H), 8.34-8.16 (m, 2H), 7.84-7.77 (m, 1H), 7.45-7.40 (m, 2H), 7.37-7.31 (m, 1H), 7.21-7.16 (m, 1H), 7.13-7.08 (m, 2H), 7.08-7.05 (m, 1H), 6.98-6.93 (m, 1H), 5.98-5.86 (m, 1H), 4.24-4.12 (m, 1H), 4.01-3.90 (m, 1H), 2.26-2.17 (m, 1H), 2.09-2.01 (m, 5H), 1.94-1.78 (m, 2H), 1.74-1.63 (m, 1H), 1.61-1.42 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H).
Example 70: N-((1S,3R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of N-((1S,3R)aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 68, product from Step A, 150 mg, 0.30 mmol) and triethylamine (91 mg, 0.90 mmol) in DCM (10 mL) was added acetic anhydride (30 mg, 0.29 mmol) and was stirred at room temperature for 2 hours. The mixture was purified by flash column chromatography, then by preparative TLC to give the title compound (130 mg, 32% yield). MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 29 27 5 4 542.3 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.14 (s, 1H), 8.34-8.28 (m, 1H), 8.22-8.12 (m, 1H), 7.93-7.86 (m, 1H), 7.46-7.40 (m, 2H), 7.38-7.33 (m, 1H), 7.21-7.16 (m, 1H), 7.14-7.09 (m, 2H), 7.09-7.05 (m, 1H), 6.99-6.94 (m, 1H), 5.99-5.92 (m, 1H), 4.25-4.13 (m, 1H), 4.00-3.88 (m, 1H), 2.25-2.17 (m, 1H), 2.05 (s, 3H), 1.92-1.81 (m, 2H), 1.79 (s, 3H), 1.72-1.64 (m, 1H), 1.59-1.43 (m, 2H).
Example 71: N-((1S,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of N-((1S,3R)aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 68, product from Step A, 150 mg, 0.30 mmol), HATU (137 mg, 0.360 mmol), and triethylamine (91 mg, 0.90 mmol) in DMF (3 mL) was added 2-(dimethylamino)acetic acid (37 mg, 0.36 mmol) and was stirred at rt for 4 hours. The mixture was purified by flash column chromatography, then by preparative TLC to give the title compound (70 mg, 39% yield). MS (ESI): mass calcd. for C H N O S, 31 32 6 4 584.7; m/z found, 585.3 [M+H] . H NMR (400 MHz, CD OD and DMSO-d ): δ 8.28-8.21 (m, 1H), 7.40-7.32 (m, 2H), 7.28-7.23 (m, 1H), 7.15-7.09 (m, 1H), 7.07-7.02 (m, 2H), 7.02-6.99 (m, 1H), 6.93-6.88 (m, 1H), 5.97-5.89 (m, 1H), 4.24-4.20 (m, 1H), 4.06-4.02 (m, 1H), 2.89-2.84 (m, 2H), 2.30-2.24 (m, 1H), 2.20 (s, 6H), 2.02 (s, 3H), 1.89-1.79 (m, 2H), 1.76-1.68 (m, 1H), 1.66- 1.58 (m, 1H), 1.57-1.50 (m, 1H).
Example 72: 5-(2-Methylphenoxyphenyl)-N-((1S,3R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide.
Step A: tert-butyl methyl(2-(((1S,3R)(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamido)cyclopentyl)amino)oxoethyl)carbamate. To a solution of N-Boc-N-methylglycine (0.14 g, 0.74 mmol), HATU (0.274 g, 0.720 mmol), and triethylamine (0.182 g, 1.80 mmol) in DMF (3 mL) was added N-((1S,3R)aminocyclopentyl)- -(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide (Example 68, product from Step A, 0.30 g, 0.60 mmol) and stirred at rt for 1 hour.
The mixture was purified by flash column chromatography to give the title compound (362 mg, 90.0% yield).
Step B: 5-(2-Methylphenoxyphenyl)-N-((1S,3R)(2-(methylamino)acetamido)cyclopentyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of tert- butyl methyl(2-(((1S,3R)(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclopentyl)amino)oxoethyl)carbamate (362 mg, 0.540 mmol), concentrated HCl (1.0 mL), and MeOH (5 mL) was stirred for 5 min at rt and then concentrated to dryness. The residue was dispersed between a 1 M aqueous NH OH solution and DCM. The organic layer was collected and concentrated to dryness to give the title compound (267 mg, 82% yield). MS (ESI): mass calcd. for C H N O S, 570.7; m/z found, 30 6 4 571.3 [M+H] . H NMR (400 MHz, CD OD/DMSO-d ): δ 8.21-8.14 (m, 1H), 7.38-7.32 (m, 2H), 7.24-7.19 (m, 1H), 7.14-7.09 (m, 1H), 7.06-7.01 (m, 2H), 7.01-6.98 (m, 1H), 6.92-6.88 (m, 1H), 5.87-5.81 (m, 1H), 4.24-4.20 (m, 1H), 4.07-4.03 (m, 1H), 3.38-3.27 (m, 2H), 2.35 (s, 3H), 2.29-2.21 (m, 1H), 2.02 (s, 3H), 1.96-1.83 (m, 2H), 1.77-1.68 (m, 1H), 1.68-1.59 (m, 1H), 1.59- 1.51 (m, 1H).
Example 73: N-((1S,3R)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of N-((1S,3R)aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 68, product from Step A,150 mg, 0.30 mmol) and formaldehyde (37% in water, 1.0 mL) in DCM (10 mL) was added NaBH(OAc) (318 mg, 1.50 mmol) and was stirred at room temperature for 6 hours. To the mixture was added 1 M aqueous NH and DCM. The organic layer was collected, concentrated to dryness, and purified by flash column chromatography, then by preparative TLC to give the title compound (109 mg, 67.0% yield). MS (ESI): mass calcd. for C H N O S, 527.6; m/z 29 29 5 3 found, 528.2 [M+H] . H NMR (400 MHz, DMSO-d /CD OD): δ 8.23-8.17 (m, 1H), 7.40-7.31 (m, 2H), 7.26-7.21 (m, 1H), 7.15-7.08 (m, 1H), 7.07-6.98 (m, 2H), 7.00 (d, J = 2.5 Hz, 1H), 6.93-6.88 (m, 1H), 5.91-5.85 (m, 1H), 4.25-4.22 (m, 1H), 2.69-2.60 (m, 1H), 2.26 (s, 6H), 2.21- 2.13 (m, 1H), 2.02 (s, 3H), 1.93-1.77 (m, 2H), 1.70-1.59 (m, 2H), 1.56-1.48 (m, 1H).
Example 74: N-((1S,3R)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and (1R,3S)aminocyclopentanol. MS (ESI): mass calcd. for C H N O S, 500.6; m/z found, 501.3 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.15 (s, 27 24 4 4 6 1H), 8.35-8.25 (m, 1H), 8.11-7.97 (m, 1H), 7.46-7.39 (m, 2H), 7.38-7.32 (m, 1H), 7.21-7.15 (m, 1H), 7.15-7.04 (m, 3H), 6.99-6.92 (m, 1H), 5.98-5.91 (m, 1H), 4.75-4.67 (m, 1H), 4.24-4.14 (m, 1H), 4.13-4.05 (m, 1H), 2.16-2.08 (m, 1H), 2.04 (s, 3H), 1.89-1.81 (m, 1H), 1.78-1.66 (m, 2H), 1.64-1.49 (m, 2H).
Example 75: N-((1S,3R)(2-Aminoacetamido)cyclopentyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: tert-Butyl (2-(((1R,3S)(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamido)cyclopentyl)amino)oxoethyl)carbamate. A solution of N-((1S,3R)aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 68, product from Step A, 0.15 g, 0.30 mmol), N-Boc-glycine (0.037 g, 0.21 mmol), HATU (0.137 g, 0.360 mmol), and triethylamine (0.091 g, 0.91 mmol) in DMF (3 mL) was stirred at rt for 1 hour. The mixture was purified by flash column chromatography to give the title compound (177 mg, 90.0% yield).
Step B: N-((1S,3R)(2-Aminoacetamido)cyclopentyl)(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of tert-butyl (2- (((1R,3S)(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclopentyl)amino)oxoethyl)carbamate (177 mg, 0.270 mmol) in concentrated HCl (1 mL) and MeOH (5 mL) was concentrated to dryness. The residue was dispersed between 1 M aqueous NH OH solution and DCM. The organic layer was collected and purified by flash column chromatography, then by preparative TLC to give the title compound (130 mg, 85% yield). MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 29 28 6 4 557.2 [M+H] . H NMR (400 MHz, CD OD and DMSO-d ): δ 8.24-8.16 (m, 1H), 7.40-7.31 (m, 2H), 7.24-7.20 (m, 1H), 7.14-7.08 (m, 1H), 7.07-7.01 (m, 2H), 7.01-6.97 (m, 1H), 6.92-6.87 (m, 1H), 5.92-5.83 (m, 1H), 4.27-4.22 (m, 1H), 4.07-4.02 (m, 1H), 3.47-3.34 (m, 2H), 2.33-2.20 (m, 1H), 2.02 (s, 3H), 1.95-1.85 (m, 2H), 1.78-1.68 (m, 1H), 1.68-1.59 (m, 1H), 1.59-1.50 (m, 1H).
Example 76: N-((1S,3R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1R,3S)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, 500.3 [M+H] . H NMR (400 MHz, CD OD and 27 25 5 3 3 DMSO-d ): δ 8.06-8.03 (m, 1H), 7.37-7.32 (m, 2H), 7.15-7.07 (m, 2H), 7.05-7.01 (m, 2H), 6.99- 6.96 (m, 1H), 6.90-6.86 (m, 1H), 5.73-5.69 (m, 1H), 4.23-4.20 (m, 1H), 3.52-3.42 (m, 1H), 2.43- 2.34 (m, 1H), 2.00 (s, 3H), 1.97-1.88 (m, 2H), 1.87-1.79 (m, 1H), 1.76-1.68 (m, 1H), 1.62-1.53 (m, 1H).
Example 77: N-((1S,4S)((E)(Dimethylamino)butenamido)cyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: tert-Butyl ((E)(((1S,4S)(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamido)cyclohexyl)amino)oxobuten yl)carbamate. To a solution of (E)(tert-butoxycarbonylamino)butenoic acid (Intermediate 34, 150 mg, 0.75 mmol), HATU (190 mg, 0.50 mmol), and triethylamine (101 mg, 1.00 mmol) in DMF (2 mL) was added N-((1S,4S)aminocyclohexyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 25, 154 mg, 0.300 mmol) and was stirred at rt for 4 hours. The mixture was purified by flash column chromatography to give the title compound (30 mg, 14% yield).
Step B: N-((1S,4S)((E)Aminobutenamido)cyclohexyl)(2-methylphenoxyphenyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of tert- butyl ((E)(((1S,4S)(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclohexyl)amino)oxobutenyl)carbamate (56 mg, 0.080 mmol) in MeOH (2 mL) was added concentrated aqueous HCl (0.2 mL). The mixture was concentrated to dryness and was purified by preparative TLC to give the title compound (48 mg, 99% yield).
Step C: N-((1S,4S)((E)(Dimethylamino)butenamido)cyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of N-((1S,4S)((E)aminobutenamido)cyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (32 mg, 0.054 mmol) and formaldehyde (37% in water, 1.0 mL) in DCM (10 mL) was added NaBH(OAc) (200 mg, 0.94 mmol) and was stirred at room temperature for 16 hours. To the mixture was added a 1 M aqueous NH OH solution and DCM. The organic layer was collected, concentrated to dryness, and purified by flash column chromatography, then by preparative TLC to give the title compound (15 mg, 43% yield). MS (ESI): mass calcd. for C H N O S, 624.8; 34 36 6 4 m/z found, 625.3 [M+H] .
Example 78: 5-(2-Methylphenoxyphenyl)-N-((1S,4S)((E)(methylamino)but enamido)cyclohexyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: tert-Butyl methyl((E)(((1S,4S)(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamido)cyclohexyl)amino)oxobuten yl)carbamate. A solution of N-((1S,4S)aminocyclohexyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 25, 100 mg, 0.20 mmol), (E)(tert-butoxycarbonylamino)butenoic acid (Intermediate 34, 43 mg, 0.20 mmol), HATU (114 mg, 0.300 mmol), and triethylamine (40 mg, 0.40 mmol) in DMF (2 mL) was stirred at rt for 4 hours. The reaction mixture was purified by flash column chromatography to give the title compound (71 mg, 50% yield).
Step B: 5-(2-Methylphenoxyphenyl)-N-((1S,4S)((E)(methylamino)but enamido)cyclohexyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of tert-butyl methyl((E)(((1S,4S)(5-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamido)cyclohexyl)amino)oxobut enyl)carbamate (71 mg, 0.10 mmol) in MeOH (3 mL) was added concentrated aqueous HCl (0.5 mL). The mixture was concentrated to dryness and the residue was dispersed between DCM and 10% aqueous NH OH. The organic layer was collected, concentrated to dryness, and purified by flash column chromatography, then by preparative TLC to give the title compound (22 mg, 35% yield). MS (ESI): mass calcd. for C H N O S, 610.7; m/z found, 611.3 [M+H] . 33 34 6 4 Example 79: N-((1S,4S)((E)Aminobutenamido)cyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound is the product from Step B, Example 77. MS (ESI): mass calcd. for C32H32N6O4S, 596.7; m/z found, 597.3 [M+H] .
Example 80: 5-(2-Methylphenoxyphenyl)-N-((1S)(methylamino)cyclopentyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: (S)(2-Methylphenoxyphenyl)oxo-N-(3-oxocyclopentyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide. A solution of N-((1S,3R)hydroxycyclopentyl) (2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide (Example 74, 250 mg, 0.50 mmol) and Dess-Martin periodinane (424 mg, 1.00 mmol) in DCM (20 mL) was stirred at room temperature for 16 hours. Water and DCM were added to the mixture and then it was filtered. The organic layer was collected, concentrated to dryness, and purified by flash column chromatography to give the title compound (249 mg, 100% yield).
Step B: 5-(2-Methylphenoxyphenyl)-N-((1S)(methylamino)cyclopentyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of (S)(2-methyl- 4-phenoxyphenyl)oxo-N-(3-oxocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (249 mg, 0.499 mmol) and a methanolic solution of methylamine (1.0 mL) in DCM (8 mL) was added NaBH(OAc) (318 mg, 1.50 mmol) and was stirred at room temperature for 6 hours. The mixture was dispersed between DCM and water.
The organic layer was collected, concentrated to dryness and purified by flash column chromatography and then by preparative TLC to give the title compound (20 mg, 8% yield). MS (ESI): mass calcd. for C H N O S, 513.6; m/z found, 514.3 [M+H] . H NMR (400 MHz, 28 27 5 3 CD OD and DMSO-d ): δ 8.09-8.03 (m, 1H), 7.38-7.30 (m, 2H), 7.16-7.12 (m, 1H), 7.12-7.07 (m, 1H), 7.05-7.01 (m, 2H), 6.99-6.96 (m, 1H), 6.90-6.86 (m, 1H), 5.76-5.69 (m, 1H), 4.42-4.34 (m, 1H), 3.46-3.40 (m, 1H), 2.43 (s, 3H), 2.14-2.04 (m, 2H), 2.00 (s, 3H), 1.95-1.90 (m, 2H), 1.64-1.57 (m, 1H), 1.54-1.46 (m, 1H).
Example 81: N-Cyclopentyl(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide.
A chiral purification was performed on N-cyclopentyl(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 28; 794 mg) via chiral SFC (Stationary phase: CHIRALCEL OJ-H, 5 µm, 250 x 20 mm, Mobile phase: 60% CO , 40% MeOH) to give the title compound (as the *S atropisomer; 67 mg). MS (ESI): mass calcd. for C H N O S, 484.6; m/z found, 484.1 [M+H] . H NMR (600 MHz, CDCl ): δ 9.53 (s, 1H), 27 24 4 3 3 8.33 (d, J = 5.5 Hz, 1H), 7.47 - 7.33 (m, 2H), 7.23 - 6.88 (m, 6H), 6.01 (d, J = 5.4 Hz, 1H), 5.71 (d, J = 7.2 Hz, 1H), 4.36 (q, J = 7.1 Hz, 1H), 2.18 - 2.02 (m, 5H), 1.81 - 1.59 (m, 4H), 1.51 (ddq, J = 13.5, 8.6, 6.7 Hz, 2H).
Example 82: N-Cyclopentyl(*R)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide.
A chiral purification was performed on N-cyclopentyl(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 28; 794 mg) via chiral SFC (Stationary phase: CHIRALCEL OJ-H, 5 µm, 250 x 20 mm, Mobile phase: 60% CO , 30% MeOH) to give the title compound (as the *R atropisomer; 67 mg). MS (ESI): mass calcd. for C H N O S, 484.6; m/z found, 484.1 [M+H] . H NMR (600 MHz, CDCl ): δ 9.53 (s, 1H), 27 24 4 3 3 8.32 (d, J = 5.5 Hz, 1H), 7.45 - 7.33 (m, 2H), 7.25 - 6.91 (m, 6H), 6.00 (d, J = 5.4 Hz, 1H), 5.79 (d, J = 7.0 Hz, 1H), 4.36 (h, J = 7.1 Hz, 1H), 2.17 - 2.02 (m, 5H), 1.79 - 1.62 (m, 4H), 1.62 - 1.40 (m, 2H).
Example 83: N-((1S,4S)Hydroxycyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
A chiral purification was performed on N-cyclopentyl(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 16, 843 mg) via chiral SFC (Stationary phase: CHIRALCEL OJ-H, 5 µm, 250 x 20 mm, Mobile phase: 55% CO , 45% MeOH) to give the title compound (as the *S atropisomer; 37 mg). MS (ESI): mass calcd. for C H N O S, 514.6; m/z found, 514.2 [M+H] . H NMR (600 MHz, CDCl ): δ 9.44 (s, 1H), 28 26 4 4 3 8.34 (d, J = 5.4 Hz, 1H), 7.46 - 7.34 (m, 2H), 7.27 - 6.91 (m, 7H), 6.01 (d, J = 5.4 Hz, 1H), 5.67 (d, J = 7.9 Hz, 1H), 4.14 - 3.93 (m, 2H), 2.13 (s, 3H), 1.84 - 1.66 (m, 8H).
Example 84: N-((1S,4S)Hydroxycyclohexyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
A chiral purification was performed on N-cyclopentyl(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 16, 843 mg) via chiral SFC (Stationary phase: CHIRALCEL OJ-H, 5 µm, 250 x 20 mm, Mobile phase: 55% CO , 45% MeOH) to give the title compound (as the *R atropisomer; 35 mg). MS (ESI): mass calcd. for C H N O S, 514.6; m/z found, 514.2 [M+H] . 28 26 4 4 Example 85: N-((1R,4R)Hydroxycyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
A chiral purification was performed on N-((1R,4R)hydroxycyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 15; 843 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H, 5 µm, 250 x 20 mm, Mobile phase: 70% CO , 30% EtOH) to give the title compound (as the *S atropisomer; 18 mg). MS (ESI): mass calcd. for C H N O S, 514.6; m/z found, 514.2 [M+H] . H NMR (500 28 26 4 4 MHz, CDCl ): δ 9.47 (s, 1H), 8.35 (d, J = 5.5 Hz, 1H), 7.46 - 7.34 (m, 2H), 7.21 - 7.07 (m, 4H), 7.07 - 6.91 (m, 2H), 6.02 (d, J = 5.5 Hz, 1H), 5.38 (d, J = 7.9 Hz, 1H), 4.05 - 3.85 (m, 1H), 3.76 - 3.59 (m, 1H), 2.20 - 2.00 (m, 7H), 1.53 - 1.42 (m, 2H), 1.42 - 1.28 (m, 2H), 1.28 - 1.20 (m, 1H).
Example 86: N-((1R,4R)Hydroxycyclohexyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
A chiral purification was performed on N-((1R,4R)hydroxycyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 15; 843 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H, 5 µm, 250 x 20 mm, Mobile phase: 70% CO , 30% EtOH) to give the title compound (as the *R atropisomer; 18 mg). MS (ESI): mass calcd. for C H N O S, 514.6; m/z found, 514.2 [M+H] . H NMR (500 28 26 4 4 MHz, CDCl ): δ 9.47 (s, 1H), 8.35 (d, J = 5.5 Hz, 1H), 7.50 - 7.35 (m, 2H), 7.23 - 7.07 (m, 4H), 7.06 - 6.90 (m, 2H), 6.02 (d, J = 5.5 Hz, 1H), 5.37 (d, J = 7.9 Hz, 1H), 4.02 - 3.85 (m, 1H), 3.75 - 3.67 (m, 1H), 2.14 - 2.02 (m, 7H), 1.54 - 1.42 (m, 2H), 1.42 - 1.29 (m, 2H), 1.27 - 1.21 (m, 1H).
Example 87: 5-(*S)-(2-Methylphenoxyphenyl)oxo-N-((1S,3R) propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1S,3R)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 5, using 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,3S) aminocyclopentyl]carbamate, in Step A.
Step B: 5-(*S)-(2-Methylphenoxyphenyl)oxo-N-((1S,3R)propionamidocyclopentyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of N-((1S,3R) aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (90 mg, 0.18 mmol) and triethylamine (57 mg, 0.56 mmol) in DCM (5 mL) was added propanoyl propanoate (24 mg, 0.18 mmol) and was stirred at room temperature for 2 hours. The mixture was purified by flash column chromatography, then by preparative TLC to give the title compound (53 mg, 51% yield). MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.4 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.15 (s, 29 5 4 6 1H), 8.33-8.26 (m, 1H), 8.25-8.12 (m, 1H), 7.86-7.78 (m, 1H), 7.46-7.39 (m, 2H), 7.38-7.29 (m, 1H), 7.20-7.15 (m, 1H), 7.12-7.08 (m, 2H), 7.08-7.04 (m, 1H), 6.98-6.93 (m, 1H), 5.98-5.89 (m, 1H), 4.23-4.12 (m, 1H), 4.00-3.88 (m, 1H), 2.26-2.17 (m, 1H), 2.08-2.01 (m, 5H), 1.91-1.78 (m, 2H), 1.73-1.62 (m, 1H), 1.58-1.41 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H).
Example 88: N-((1S,3R)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of N-((1S,3R)aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 87, product from Step A, 90 mg, 0.18 mmol) and triethylamine (57 mg, 0.56 mmol) in DCM (5 mL) was added acetic anhydride (24 mg, 0.24 mmol) and was stirred at room temperature for 2 hours. The mixture was purified by flash column chromatography, then by preparative TLC to give the title compound (53 mg, 53% yield). MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 29 27 5 4 542.4 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.16 (s, 1H), 8.37-8.12 (m, 2H), 7.95-7.87 (m, 1H), 7.45-7.39 (m, 2H), 7.36-7.29 (m, 1H), 7.20-7.15 (m, 1H), 7.12-7.08 (m, 2H), 7.08-7.05 (m, 1H), 6.98-6.93 (m, 1H), 5.97-5.87 (m, 1H), 4.24-4.12 (m, 1H), 3.99-3.90 (m, 1H), 2.25-2.17 (m, 1H), 2.03 (s, 3H), 1.91-1.80 (m, 2H), 1.78 (s, 3H), 1.72-1.62 (m, 1H), 1.60-1.50 (m, 1H), 1.49-1.40 (m, 1H).
Example 89: N-((1S,4S)((*E)Cyanocyclopropylacrylamido)cyclohexyl)(*S)-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide.
Step A: N-((1S,4S)((*E)Cyanocyclopropylacrylamido)cyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 7 using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl ((1S,4S)aminocyclohexyl)carbamate in Step A.
Step B: N-((1S,4S)((*E)Cyanocyclopropylacrylamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A chiral purification was performed on N-((1S,4S)((*E)cyano cyclopropylacrylamido)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide (29.5 mg) via chiral SFC (Stationary phase: CHIRALCEL OJ-H, 5 µm, 250 x 20 mm, Mobile phase: 60% CO , 40% MeOH) to give the title compound (as the *S atropisomer; 10 mg). MS (ESI): mass calcd. for C H N O S, 632.7; m/z 32 6 4 found, 632.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.33 (d, J = 5.5 Hz, 1H), 7.49 - 6.84 (m, 9H), 6.08 (d, J = 5.5 Hz, 1H), 4.14 - 3.88 (m, 2H), 2.17 - 1.68 (m, 12H), 1.38 - 1.18 (m, 3H), 1.03 - 0.79 (m, 2H).
Example 90: N-((1S,4S)((*E)Cyanocyclopropylacrylamido)cyclohexyl)(*R)-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide.
Step A: N-((1S,4S)((*E)Cyanocyclopropylacrylamido)cyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared using steps A-B in Example 19 (43 mg).
Step B: N-((1S,4S)((*E)Cyanocyclopropylacrylamido)cyclohexyl)(*R)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A chiral purification was performed on N-((1S,4S)((*E)cyano cyclopropylacrylamido)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide (Example 19; 29.5 mg) via chiral SFC (Stationary phase: CHIRALCEL OJ-H, 5 µm, 250 x 20 mm, Mobile phase: 60% CO , 40% MeOH) to give the title compound (as the *R atropisomer; 11 mg). MS (ESI): mass calcd. for C35H32N6O4S, 632.7; m/z found, 632.2 [M+H] . H NMR (400 MHz, CD3OD): δ 8.33 (d, J = .6 Hz, 1H), 7.49 - 6.87 (m, 9H), 6.07 (d, J = 5.5 Hz, 1H), 4.11 - 3.89 (m, 2H), 2.17 - 1.68 (m, 12H), 1.37 - 1.23 (m, 3H), 1.05 - 0.77 (m, 3H).
Example 91: N-((1R,2R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide.
To a dry scintillation vial under Ar with a stir bar containing (1R,2R)-trans-N-Boc-1,2- cyclopentanediamine (306.6 mg, 1.531 mmol), diisopropylethylamine (0.525 mL, 3.00 mmol), and THF (4 mL) was slowly added at room temperature 4-oxo(4-phenoxyphenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9, 10 mL, 0.1 M, 1 mmol) dropwise via syringe and was stirred at rt. A precipitate formed in the reaction solution, which was filtered and rinsed with ether. The residue was dissolved in DCM and an excess of HCL in dioxane (4 M, 5 mL) was added and was stirred for 90 min at 50 °C. The reaction mixture was concentrated to dryness and the residue was dissolved in DMSO and purified by HPLC to give the title compound (189.1 mg, 38.94% yield). MS (ESI): mass calcd. for C H N O S, 485.6; m/z found, 486.1 [M+H] . 26 23 5 3 Example 92: 5-(*S)-(2-Methylphenoxyphenyl)oxo-N-((1S,4S)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
A chiral purification was performed on 5-(2-methylphenoxyphenyl)oxo-N-((1S,4S) propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 65; 76 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H, 5 µm, 250 x 20 mm, Mobile phase: 50% CO , 50% EtOH) to give the title compound (as the *S atropisomer; 33 mg, 17% yield). MS (ESI): mass calcd. for C H N O S, 569.7; m/z found, 569.2 [M+H] . 31 31 5 4 Example 93: 5-(*R)-(2-Methylphenoxyphenyl)oxo-N-((1S,4S) propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
A chiral purification was performed on 5-(2-methylphenoxyphenyl)oxo-N-((1S,4S) propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 65; 76 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H, 5 µm, 250 x 20 mm, Mobile phase: 50% CO , 50% EtOH) to give the title compound (as the *R atropisomer; 30 mg, 16% yield). MS (ESI): mass calcd. for C H N O S, 569.7; m/z found, 569.2 [M+H] . 31 31 5 4 Example 94: N-((1S,4S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
A chiral purification was performed on N-((1S,4S)acetamidocyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 64; 103 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H, 5 µm, 250 x 20 mm, Mobile phase: 50% CO , 50% EtOH) to give the title compound (as the *S atropisomer; 36 mg, 19% yield). MS (ESI): mass calcd. for C H N O S, 555.7; m/z found, 555.2 [M+H] . 29 5 4 Example 95: N-((1S,4S)Acetamidocyclohexyl)(*R)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
A chiral purification was performed on N-((1S,4S)acetamidocyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 64; 103 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H, 5 µm, 250 x 20 mm, Mobile phase: 50% CO , 50% EtOH) to give the title compound (as the *R atropisomer; 36 mg, 19% yield). MS (ESI): mass calcd. for C H N O S, 555.7; m/z found, 555.2 [M+H] . H 29 5 4 NMR (600 MHz, CDCl ): δ 9.48 (s, 1H), 8.36 (d, J = 5.5 Hz, 1H), 7.49 - 7.34 (m, 2H), 7.22 - 7.14 (m, 2H), 7.13 - 7.05 (m, 2H), 7.05 - 6.91 (m, 2H), 6.03 (d, J = 5.4 Hz, 1H), 5.62 (dd, J = 49.6, 7.4 Hz, 2H), 4.20 - 3.87 (m, 2H), 2.13 (s, 3H), 2.01 (s, 3H), 1.93 - 1.81 (m, 4H), 1.81 - 1.76 (m, 2H), 1.74 - 1.68 (m, 2H).
Example 96: N-(rac-(1,3-cis)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: Racemic-tert-butyl (3-(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclopentyl)carbamate. To a dry scintillation vial under Ar with a stir bar containing tert-butyl rac-[(1S,3R)aminocyclopentyl]carbamate (295 mg, 1.48 mmol), THF (4 mL), and DIPEA (0.525 mL, 3 mmol) was added slowly (dropwise) at rt 4-oxo- -(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9, 10 mL, 0.1 M, 1 mmol). When LCMS showed that the reaction had gone to completion, the reaction was concentrated to dryness and dissolved in DCM.
Step B: N-(rac-(1,3-cis)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide. A solution of racemic-tert-butyl (3-(4-oxo(4- phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamido)cyclopentyl)carbamate in HCl in dioxane (4 M, 5 mL) was stirred at 50 °C for 2 hrs. The reaction mixture was concentrated to dryness, dissolved in DMF and purified by HPLC to give the title compound (231.6 mg, 47.70% yield). MS (ESI): mass calcd. for C H N O S, 26 23 5 3 485.6; m/z found, 486.1 [M+H] . H NMR (500 MHz, CD OD): δ 8.14 (d, J = 5.7 Hz, 1H), 7.47 - 7.26 (m, 4H), 7.22 - 7.02 (m, 5H), 6.01 (d, J = 5.7 Hz, 1H), 4.45 - 4.30 (m, 1H), 3.61 - 3.51 (m, 1H), 2.60 - 2.46 (m, 1H), 2.21 - 1.60 (m, 5H).
Example 97: N-((1R,2S)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: tert-butyl ((1S,2R)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclopentyl)carbamate. To a dry scintillation vial under Ar with a stir bar containing tert-butyl ((1S,2R)aminocyclopentyl)carbamate (301.2 mg, 1.504 mmol), THF (4 mL), and diisopropylethylamine (0.525 mL, 3.00 mmol) was added slowly (dropwise) at rt 4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carbonyl chloride (Intermediate 9, 10 mL, 0.1 M, 1 mmol). The reaction progress was monitored by LCMS. A precipitate formed that was filtered and rinsed with ether.
Step B: N-((1R,2S)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide. The precipitate from Step A was dissolved in DCM and an excess of HCl in dioxane (4 M, 5 mL) was added and was stirred at 50 °C for 90 min.
The reaction mixture was concentrated to dryness and the residue was dissolved in DMF and purified by HPLC to give the title compound (142.3 mg, 29.31% yield). MS (ESI): mass calcd. for C H N O S, 485.6; m/z found, 486.1 [M+H] . H NMR (500 MHz, CD OD): δ 8.24 (s, 26 23 5 3 3 1H), 7.48 - 7.27 (m, 4H), 7.24 - 7.03 (m, 6H), 6.11 (s, 1H), 4.59 - 4.38 (m, 1H), 3.78 - 3.58 (m, 1H), 2.22 - 2.06 (m, 2H), 1.98 - 1.65 (m, 4H).
Example 98: N-((1S,2R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: tert-Butyl ((1R,2S)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclopentyl)carbamate. To a dry scintillation vial under Ar with a stir bar containing (1R,2S)amino(N-Boc-amino)cyclopentane (296.5 mg, 1.480 mmol), THF (4 mL), and diisopropylethylamine (0.525 mL, 3.00 mmol) was added slowly (dropwise) at rt 4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carbonyl chloride (Intermediate 9, 10 mL, 0.1 M, 1 mmol). The reaction progress was monitored by LCMS. A precipitate formed that was filtered and rinsed with ether.
Step B: N-((1S,2R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide. The precipitate, from Step A, was dissolved in DCM and an excess of HCl in dioxane (4 M, 5 mL) was added and was stirred at 50 °C for 90 min.
The reaction mixture was concentrated to dryness and the residue was dissolved in DMF and purified by HPLC to give the title compound (126.6 mg, 26.07% yield). MS (ESI): mass calcd. for C H N O S, 485.6; m/z found, 486.1 [M+H] . H NMR (500 MHz, CD OD): δ 8.15 (d, J = 26 23 5 3 3 .6 Hz, 1H), 7.48 - 7.24 (m, 4H), 7.21 - 7.04 (m, 5H), 6.02 (d, J = 5.7 Hz, 1H), 4.56 - 4.43 (m, 1H), 3.62 (s, 1H), 2.28 - 2.05 (m, 2H), 2.04 - 1.58 (m, 4H).
Example 99: N-((1S,4S)(Dimethylamino)cyclohexyl)(*S)-(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
A chiral purification was performed on N-((1S,4S)(dimethylamino)cyclohexyl)(2-methyl- 4-phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 66; 100 mg) via chiral SFC (Stationary phase: CHIRALCEL OJ-H, 5 µm, 250 x 20 mm, Mobile phase: 70% CO , 30% EtOH) to give the title compound (as the *S atropisomer; 30 mg, 17% yield). MS (ESI): mass calcd. for C H N O S, 541.7; m/z found, 541.2 [M+H] . H 31 5 3 NMR (600 MHz, CDCl ): δ 8.35 (d, J = 5.5 Hz, 1H), 7.46 - 7.35 (m, 2H), 7.27 (s, 0H), 7.23 - 7.06 (m, 4H), 7.03 - 6.89 (m, 2H), 6.01 (d, J = 5.5 Hz, 1H), 5.82 (d, J = 7.9 Hz, 1H), 4.18 (dq, J = 6.7, 3.8 Hz, 1H), 2.33 (s, 6H), 2.13 (s, 4H), 1.92 - 1.55 (m, 8H).
Example 100: N-((1S,4S)(Dimethylamino)cyclohexyl)(*R)-(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
A chiral purification was performed on N-((1S,4S)(dimethylamino)cyclohexyl)(2-methyl- 4-phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 66; 100 mg) via chiral SFC (Stationary phase: CHIRALCEL OJ-H, 5 µm, 250 x 20 mm, Mobile phase: 70% CO , 30% EtOH) to give the title compound (as the *R atropisomer; 32 mg, 18% yield). MS (ESI): mass calcd. for C H N O S, 541.7; m/z found, 541.2 [M+H] . H 31 5 3 NMR (600 MHz, CDCl ): δ 8.35 (d, J = 5.4 Hz, 1H), 7.49 - 7.35 (m, 2H), 7.27 (s, 1H), 7.25 - 7.06 (m, 4H), 7.06 - 6.92 (m, 2H), 6.01 (d, J = 5.4 Hz, 1H), 5.70 (d, J = 7.9 Hz, 1H), 4.22 - 4.08 (m, 1H), 2.31 (s, 6H), 2.13 (s, 4H), 1.92 - 1.63 (m, 8H).
Example 101: N-((1S,3R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,3S)aminocyclopentyl]carbamate (Intermediate 37) in Step A. MS (ESI): mass calcd. for C H N O S, 553.6; m/z found, 554.4 [M+H] . H NMR (400 MHz, 27 5 4 DMSO-d ): δ 10.16 (s, 1H), 8.33-8.27 (m, 1H), 8.26-8.10 (m, 2H), 7.45-7.40 (m, 2H), 7.38-7.32 (m, 1H), 7.21-7.15 (m, 1H), 7.13-7.08 (m, 2H), 7.08-7.05 (m, 1H), 6.98-6.94 (m, 1H), 6.25-6.16 (m, 1H), 6.10-6.04 (m, 1H), 5.97-5.90 (m, 1H), 5.58-5.52 (m, 1H), 4.26-4.15 (m, 1H), 4.09-3.98 (m, 1H), 2.31-2.22 (m, 1H), 2.04 (s, 3H), 1.94-1.83 (m, 2H), 1.75-1.65 (m, 1H), 1.64-1.56 (m, 1H), 1.56-1.47 (m, 1H).
Example 102: N-((1S,3R)(2-(dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a mixture of 2-(dimethylamino)acetic acid (32 mg, 0.31 mmol), HATU (119 mg, 0.313 mmol), and triethylamine (95 mg, 0.94 mmol) in DMF (3 mL) was added N-((1S,3R) aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 87, product from Step A, 156 mg, 0.312 mmol) and was stirred at rt for 1 hour. The mixture was purified by flash column chromatography and then by preparative TLC to yield the title compound (59 mg, 96% yield). MS (ESI): mass calcd. for C H N O S, 584.7; m/z found, 585.4 [M+H] . 31 32 6 4 Example 103: 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,3R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide.
Step A: tert-Butyl methyl(2-(((1R,3S)(5-(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamido)cyclopentyl)amino) oxoethyl)carbamate. To a mixture of Boc-sarcosine (31 mg, 0.16 mmol), HATU (61 mg, 0.16 mmol), and triethylamine (49 mg, 0.48 mmol) in DMF (3 mL) was added N-((1S,3R) aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 87, product from Step A, 80 mg, 0.16 mmol) and was stirred at rt for 1 hour. The mixture was purified by flash column chromatography to yield the title compound (107 mg, 100% yield).
Step B: 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,3R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide. A solution of tert-butyl methyl(2-(((1R,3S)(5-(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamido)cyclopentyl)amino)oxoethyl)carbamate (107 mg, 0.16 mmol) in concentrated HCl (1 mL) and MeOH (5 mL) was concentrated to dryness. The residue was dispersed between an aqueous 1 M NH solution and DCM. The organic layer was collected and purified by flash column chromatography to yield the title compound (57 mg, 63% yield). MS (ESI): mass calcd. for C H N O S, 570.7; m/z found, 571.4 [M+H] . 30 6 4 Example 104: N-((1R,2S)acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: tert-Butyl ((1S,2R)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclopentyl)carbamate. To a dry scintillation vial under Ar containing a stir bar were added tert-butyl N-((1S,2R)aminocyclopentyl)carbamate (301.2 mg, 1.504 mmol), THF (4 mL), and diisopropylethylamine (0.525 mL, 3.00 mmol). 4-Oxo(4- phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9, 10 mL, 0.1 M, 1 mmol) was added dropwise to the above reaction solution. A solid precipitate that formed was filtered and rinsed with ether. The crude product was used in the next step without further purification.
Step B: N-((1R,2S)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide. tert-Butyl ((1S,2R)(5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamido)cyclopentyl)carbamate was dissolved in DCM and an excess of HCl in dioxane (4 M, 5 mL) was added and was reacted for 90 min at 50 °C. The reaction mixture was concentrated to dryness and the residue was dissolved in DMF and was purified by basic reverse phase HPLC to yield the title compound (142 mg, 29.3% yield).
Step C: N-((1R,2S)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide. To a small oven dried microwave vial under argon were added N-((1R,2S)aminocyclopentyl)(4-phenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide (45.8 mg, 0.094 mmol), DCM (1.0 mL), and triethylamine (0.067 mL, 0.47 mmol). The vial was cooled to -20 °C in an ice/acetone bath and a 0.17 mL solution of propenoyl chloride in DCM (0.5 mL in 10 mL DCM) was added dropwise over 10-15 min and then allowed to warm to rt slowly over 5 min. The reaction mixture was purified by flash column chromatography, and then by reverse phase basic HPLC to yield the title compound (7.6 mg, 15% yield). MS (ESI): mass calcd. for C H N O S, 539.6; 29 25 5 4 m/z found, 540.2 [M+H] . H NMR (500 MHz, CD OD): δ 8.26 (s, 1H), 7.49 - 7.27 (m, 4H), 7.27 - 7.04 (m, 5H), 6.38 - 6.04 (m, 3H), 5.61 (dd, J = 10.2, 1.9 Hz, 1H), 4.51 - 4.38 (m, 2H), 2.16 - 1.99 (m, 2H), 1.99 - 1.55 (m, 4H).
Example 105: N-((1R,2R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,3R)aminocyclopentyl]carbamate in place of tert-butyl ((1S,4S) aminocyclohexyl)carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 553.6; m/z 27 5 4 found, 554.4 [M+H] . H NMR (400 MHz, CD OD): δ 8.30 (d, J = 5.5 Hz, 1H), 7.45-7.35 (m, 2H), 7.30-7.24 (mz, 1H), 7.21-7.12 (m, 1H), 7.11-7.02 (m, 3H), 7.00-6.93 (m, 1H), 6.29-6.15 (m, 2H), 6.05 (d, J = 5.5 Hz, 1H), 5.65-5.58 (m, 1H), 4.33-4.16 (m, 2H), 2.23-2.09 (m, 5H), 1.87- 1.75 (m, 2H), 1.72-1.51 (m, 2H).
Example 106: 5-([1,1'-Biphenyl]yl)-N-((1 R,2 S)acrylamidocyclohexyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-([1,1'-biphenyl]- 3-yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 19) and tert-butyl N-[(1S,2R)aminocyclohexyl]carbamate in Step A. MS (ESI): mass calcd. for C30H27N5O3S, 537.6; m/z found, 538.2 [M+H] . H NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 8.33-8.22 (m, 1H), 7.87-7.73 (m, 4H), 7.70-7.64 (m, 3H), 7.48-7.40 (m, 3H), 7.39-7.34 (m, 1H), 6.45-6.34 (m, 1H), 6.16-6.08 (m, 1H), 6.08-6.01 (m, 1H), 5.62-5.52 (m, 1H), 4.27-4.11 (m, 1H), 4.07-3.96 (m, 1H), 1.76-1.60 (m, 4H), 1.59-1.50 (m, 2H), 1.44-1.31 (m, 2H).
Example 107: N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 553.6; m/z found, 554.5 [M+H] . H NMR (400 MHz, CD OD): δ 8.30 (d, J = 27 5 4 3 .6 Hz, 1H), 7.44-7.33 (m, 2H), 7.30-7.24 (m, 1H), 7.20-7.13 (m, 1H), 7.12-7.02 (m, 3H), 7.00- 6.92 (m, 1H), 6.31-6.14 (m, 2H), 6.04 (d, J = 5.6 Hz, 1H), 5.65-5.56 (m, 1H), 4.48-4.33 (m, 2H), 2.17-2.03 (m, 5H), 1.95-1.85 (m, 1H), 1.80-1.60 (m, 3H).
Example 108: N-((1R,2S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2R)aminocyclohexyl]carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 567.7; m/z found, 568.2 [M+H] . H NMR (400 MHz, DMSO-d ): δ 9.97 (s, 1H), 31 29 5 4 6 8.36-8.24 (m, 1H), 7.96-7.71 (m, 2H), 7.45-7.39 (m, 2H), 7.38-7.32 (m, 1H), 7.20-7.15 (m, 1H), 7.13-7.04 (m, 3H), 6.99-6.93 (m, 1H), 6.45-6.33 (m, 1H), 6.18-6.08 (m, 1H), 6.00-5.88 (m, 1H), .62-5.53 (m, 1H), 4.28-4.12 (m, 1H), 4.06-3.98 (m, 1H), 2.04 (s, 3H), 1.76-1.61 (m, 4H), 1.59- 1.51 (m, 2H), 1.43-1.32 (m, 2H).
Example 109: N-((1RS,3RS)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, using 4-oxo(4- phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and tert-butyl rac-[(1S,3R)aminocyclopentyl]carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 539.6; m/z found, 540.2 [M+H] . H NMR (500 MHz, 29 25 5 4 CDCl ): δ 9.54 (s, 1H), 8.34 (d, J = 5.5 Hz, 1H), 7.50 - 7.34 (m, 3H), 7.31 - 7.27 (m, 2H), 7.23 - 7.10 (m, 5H), 6.41 (dd, J = 16.8, 1.3 Hz, 1H), 6.16 - 6.04 (m, 2H), 5.69 (dd, J = 10.3, 1.4 Hz, 1H), 4.41 - 4.35 (m, 1H), 4.27 - 4.04 (m, 1H), 3.79 - 3.49 (m, 1H), 2.46 - 1.75 (m, 6H).
Example 110: N-((1S,3R)Acrylamidocyclopentyl)(4-isopropoxymethylphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31) and tert-butyl N-[(1R,3S)aminocyclopentyl]carbamate in Step A. MS (ESI): mass calcd. for C27H29N5O4S, 519.6; m/z found, 520.5 [M+H] . H NMR (400 MHz, CD3OD): δ 8.29 (d, J = 5.4 Hz, 1H), 7.29-7.11 (m, 1H), 7.06-6.82 (m, 2H), 6.37-6.15 (m, 2H), 6.02 (d, J = .5 Hz, 1H), 5.76-5.52 (m, 1H), 4.72-4.58 (m, 1H), 4.44-4.11 (m, 2H), 2.58-2.40 (m, 1H), 2.19- 1.95 (m, 5H), 1.88-1.71 (m, 2H), 1.68- 1.54 (m, 1H), 1.40-1.30 (m, 6H).
Example 111: N-((1R,2R)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a stirred solution of N-((1R,2R)aminocyclopentyl)(*S)-(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 67, product from Step A, 100 mg, 0.2 mmol) in DMF (3 mL) were added 2-(dimethylamino)acetic acid (22 mg, 0.16 mmol), HATU (75 mg, 0.20 mmol), and triethylamine (40 mg, 0.40 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness and the residue was partitioned between ethyl acetate and water. The organic layer was separated, shaken with brine and dried over anhydrous Na SO . The residue was purified by flash column chromatography to give the title compound as yellow solid (59 mg, 50% yield). MS (ESI): mass calcd. for C H N O S, 584.7; m/z found, 585.2 [M+H] . H 31 32 6 4 NMR (400 MHz, CD OD): δ 8.29 (d, J = 5.5 Hz, 1H), 7.45-7.35 (m, 2H), 7.32-7.24 (m, 1H), 7.20-7.12 (m, 1H), 7.12-7.03 (m, 3H), 7.00-6.92 (m, 1H), 6.04 (d, J = 5.5 Hz, 1H), 4.39-4.11 (m, 2H), 3.04-2.88 (m, 2H), 2.29-2.25 (m, 6H), 2.18-2.06 (m, 5H), 1.87-1.74 (m, 2H), 1.75-1.50 (m, 2H).
Example 112: 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide.
Step A: tert-Butyl methyl(2-(((1R,2R)(5-(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamido)cyclopentyl)amino) oxoethyl)carbamate. To a stirred solution of N-((1R,2R)aminocyclopentyl)(*S)-(2-methyl- 4-phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 67, Product from Step A, 80 mg, 0.16 mmol) in DMF (3 mL) were added 2-[tert- butoxycarbonyl(methyl)aminoacetic acid (36 mg, 0.16 mmol), HATU (73 mg, 0.19 mmol), and diisopropylethylamine (45 mg, 0.35 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness and the residue was partitioned between ethyl acetate and water. The organic layer was separated, shaken with brine and dried over anhydrous Na SO . The residue was purified by flash column chromatography to give the title compound as yellow solid (70 mg, 65% yield).
Step B: 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide. A solution of tert-butyl methyl(2-(((1R,2R)(5-(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamido)cyclopentyl)amino)oxoethyl)carbamate (70 mg, 0.10 mmol) in concentrated HCl (2 mL) and MeOH (15 mL) was stirred at room temperature for about 2 hours. The reaction mixture was concentrated to dryness and the residue was purified by flash column chromatography to give the title compound as yellow solid (56 mg, 87% yield). MS (ESI): mass calcd. for C H N O S, 570.7; m/z found, 571.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.46 30 6 4 3 (s, 1H), 8.32 (d, J = 5.5 Hz, 1H), 7.45-7.35 (m, 2H), 7.32-7.24 (m, 1H), 7.19-7.13 (m, 1H), 7.12- 7.03 (m, 3H), 7.01-6.92 (m, 1H), 6.07 (d, J = 5.5 Hz, 1H), 4.32-4.16 (m, 2H), 3.66 (s, 2H), 2.61 (s, 3H), 2.21-2.04 (m, 5H), 1.91- 1.76 (m, 2H), 1.75-1.52 (m, 2H).
Example 113: N-((1R,2R)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 112, using 2-(tert- butoxycarbonylamino)acetic acid in Step A. MS (ESI): mass calcd. for C H N O S, 556.6; m/z 29 28 6 4 found, 557.5 [M+H] . H NMR (400 MHz, CD OD): δ 8.49 (s, 1H), 8.31 (d, J = 5.5 Hz, 1H), 7.48-7.35 (m, 2H), 7.32-7.25 (m, 1H), 7.22-7.13 (m, 1H), 7.12-7.02 (m, 3H), 7.00-6.92 (m, 1H), 6.06 (d, J = 5.5 Hz, 1H), 4.29-4.15 (m, 2H), 3.57 (s, 2H), 2.25-2.05 (m, 5H), 1.90-1.76 (m, 2H), 1.72-1.52 (m, 2H).
Example 114: N-((1S,2R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2S)aminocyclopentyl]carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 553.6; m/z found, 554.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.28 (d, J = 27 5 4 3 .0 Hz, 1H), 7.46-7.31 (m, 2H), 7.30-7.20 (m, 1H), 7.19-7.10 (m, 1H), 7.09-6.98 (m, 3H), 6.97- 6.89 (m, 1H), 6.35-6.12 (m, 2H), 6.03 (d, J = 5.5 Hz, 1H), 5.68-5.52 (m, 1H), 4.48-4.32 (m, 2H), 2.24 – 1.99 (m, 5H), 1.96 – 1.81 (m, 1H), 1.81 – 1.54 (m, 3H).
Example 115: N-((1R,2S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, 500.3 [M+H] . H NMR (400 MHz, CD OD): δ 8.49 (s, 27 25 5 3 3 1H), 8.30 (d, J = 5.5 Hz, 1H), 7.44-7.35 (m, 2H), 7.34-7.24 (m, 1H), 7.19-7.13 (m, 1H), 7.12- 7.02 (m, 3H), 7.02-6.93(m, 1H), 6.04 (d, J = 5.6 Hz, 1H), 4.52-4.43(m, 1H), 3.78-3.69 (m, 1H), 2.21-2.11 (m, 2H), 2.09 (s, 3H), 2.01-1.86 (m, 2H), 1.80-1.67 (m, 2H).
Example 116: N-((1S,2S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2S)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 553.6; m/z found, 554.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.30 (d, J = 27 5 4 3 .5Hz, 1H), 7.44-7.34 (m, 2H), 7.31-7.23 (m, 1H), 7.18-7.13 (m, 1H), 7.11-7.01 (m, 3H), 6.99- 6.92 (m, 1H), 6.27-6.16 (m, 2H), 6.04 (d, J = 5.5Hz, 1H), 5.66-5.57 (m, 1H), 4.33-4.15 (m, 2H), 2.23-2.05 (m, 5H), 1.86-1.72 (m, 2H), 1.70-1.52 (m, 2H).
Example 117: N-((1S,3R)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. tert-Butyl ((1R,3S)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclopentyl)carbamate. To a dry scintillation vial under Ar containing a stir bar were added tert-butyl ((1R,3S)aminocyclopentyl)carbamate (309.3 mg, 1.544 mmol), diisopropylethylamine (0.50 mL, 2.9 mmol), and THF (4 mL). Next, 4-oxo(4- phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9, 10 mL, 0.1 M, 1 mmol) was slowly added via a syringe at room temperature for 1 hour. The reaction was purified by gilson reverse phase acidic HPLC.
Step B. N-((1S,3R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide. tert-Butyl ((1R,3S)(4-oxo(4-phenoxyphenyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamido)cyclopentyl)carbamate was dissolved in DCM (5 mL) and 2 M HCl in ether (5 mL) and was stirred over night (20 hours) at rt. The reaction was filtered and the precipitate was rinsed with DCM. The residue was dissolved in methanol and acetonitrile was added. The reaction was concentrated to dryness and lyophilized to give the title compound (252.1 mg, 51.9% over two steps). MS (ESI): mass calcd. for C H N O S, 485.57; m/z found, 486.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.35 (d, J 26 23 5 3 3 = 5.6 Hz, 1H), 7.48 - 7.36 (m, 4H), 7.24 - 7.08 (m, 6H), 6.21 (d, J = 5.6 Hz, 1H), 4.38 - 4.30 (m, 1H), 3.73 - 3.62 (m, 1H), 2.61 - 2.49 (m, 1H), 2.21 - 1.76 (m, 5H).
Step C: N-((1S,3R)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide. To a dry scintillation vial under Ar containing a stir bar were added N-((1S,3R)aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide (112.7 mg, 0.232 mmol), DCM (3.38 mL), and triethylamine (0.225 mL, 1.62 mmol). The white suspension was cooled to ~ -20 °C in an ice/acetone bath. To the solution was slowly added propenoyl chloride (0.0187 mL, 0.22 mmol) as a solution in DCM (0.5 mL in 10 mL, adding 0.37 mL of this solution). The reaction was allowed to warm to rt with stirring and was stirred for 10 minutes. The reaction was concentrated to dryness and the residue was dissolved in methanol and was purified by reverse phase basic HPLC on a dionex column to give the title compound (16.3 mg, 13.0% yield). MS (ESI): mass calcd. for C H N O S, 539.6; m/z found, 540.1 [M+H] . H NMR (400 MHz, 29 25 5 4 CDCl ): δ 9.54 (s, 1H), 8.35 (d, J = 5.5 Hz, 1H), 7.46 - 7.36 (m, 3H), 7.29 (s, 1H), 7.25 - 7.04 (m, 6H), 6.48 - 6.25 (m, 2H), 6.21 - 6.03 (m, 2H), 5.70 (d, J = 10.3 Hz, 1H), 4.48 - 4.00 (m, 2H), 2.57 - 2.40 (m, 1H), 2.05 (d, J = 4.3 Hz, 1H), 1.99 - 1.81 (m, 4H).
Example 118: N-((1R,2S)Acrylamidocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, using 4-oxo(4- phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and tert-butyl ((1S,2R)aminocyclohexyl)carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 553.6; m/z found, 554.1 [M+H] . H NMR (500 MHz, CD OD): δ 27 5 4 3 8.30 (d, J = 7.7 Hz, 1H), 7.41 (dddd, J = 10.7, 8.7, 6.4, 2.1 Hz, 4H), 7.22 - 7.05 (m, 5H), 6.49 - 6.35 (m, 1H), 6.27 (dd, J = 17.0, 1.9 Hz, 1H), 6.23 - 6.09 (m, 1H), 5.67 (dd, J = 10.3, 1.8 Hz, 1H), 4.41 (s, 1H), 4.18 (s, 1H), 1.89 - 1.44 (m, 9H).
Example 119: N-((1S,4S)Acrylamidocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, using 4-oxo(4- phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and 1-N-boc-cis-1,4-cyclohexyldiamine in Step A. MS (ESI): mass calcd. for C H N O S, 553.6; m/z found, 554.1 [M+H] . H NMR (500 MHz, CD OD): δ 8.36 - 8.24 (m, 27 5 4 3 1H), 7.43 - 7.36 (m, 4H), 7.20 - 7.13 (m, 3H), 7.13 - 7.09 (m, 2H), 6.38 - 6.28 (m, 1H), 6.27 - 6.14 (m, 2H), 5.75 - 5.57 (m, 1H), 4.05 - 3.88 (m, 1H), 1.92 - 1.64 (m, 8H).
Example 120: N-((1R,2R)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2R)aminocyclopentyl]carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, 500.4 [M+H] . H NMR (400 MHz, CD OD): δ 8.50 (s, 1H), 27 25 5 3 3 8.33 (d, J = 5.6 Hz, 1H), 7.45-7.35 (m, 2H), 7.32-7.25 (m, 1H), 7.21-7.13 (m, 1H), 7.11-7.04 (m, 3H), 7.01-6.94 (m, 1H), 6.07 (d, J = 5.6 Hz, 1H), 4.31-4.18 (m, 1H), 3.52-3.40 (m, 1H), 2.31- 2.15 (m, 2H), 2.10 (s, 3H), 1.94-1.82 (m, 3H), 1.79-1.67 (m, 1H).
Example 121: N-((1R,3S)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Step A using 4-oxo (4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and N-[(1S,3R)aminocyclopentyl]propenamide (Intermediate 45). MS (ESI): mass calcd. for C H N O S, 539.6; m/z found, 540.0 [M+H] . H NMR (500 MHz, 29 25 5 4 CDCl ): δ 9.54 (s, 1H), 8.35 (d, J = 5.5 Hz, 1H), 7.47 - 7.34 (m, 2H), 7.29 - 7.28 (m, 1H), 7.27 (s, 2H), 7.25 - 7.02 (m, 6H), 6.41 (dd, J = 16.9, 1.3 Hz, 1H), 6.19 - 5.91 (m, 2H), 5.70 (dd, J = .3, 1.3 Hz, 1H), 4.47 - 4.31 (m, 1H), 4.18 - 4.00 (m, 1H), 2.74 - 1.77 (m, 6H).
Example 122: 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2S)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide.
Step A. N-((1R,2S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2R) aminocyclopentyl]carbamate.
Step B: 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2S)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide. A solution of N-((1R,2S)aminocyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (70 mg, 0.14 mmol), 2-[tert-butoxycarbonyl(methyl)amino]acetic acid (26 mg, 0.14 mmol), triethylamine (28 mg, 0.28 mmol), and HATU (53 mg, 0.14 mmol) in DMF (3 mL) was stirred at rt for 3 h. Water was added and the precipitate was filtered to give a pale yellow solid. The solid was dissolved in MeOH (2 mL) and HCl (2 mL) and was heated at 50 °C for 30 min. The reaction mixture was concentrated to dryness and the residue was purified by flash column chromatography to give the title compound (62 mg, 98% yield). MS (ESI): mass calcd. for C H N O S, 570.7; m/z found, 571.4 [M+H] . H NMR (400 MHz, CD OD): δ 8.45 (s, 1H), 30 6 4 3 8.28 (d, J = 5.5 Hz, 1H), 7.46-7.34 (m, 2H), 7.30-7.24 (m, 1H), 7.20-7.12 (m, 1H), 7.12-7.03 (m, 3H), 7.01-6.93 (m, 1H), 6.02 (d, J = 5.5 Hz, 1H), 4.49-4.35 (m, 2H), 3.68 (s, 2H), 2.62 (s, 3H), 2.14-1.99 (m, 5H), 1.96-1.86 (m, 1H), 1.80-1.61 (m, 3H).
Example 123: N-((1S,2S)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 122 using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2S)aminocyclopentyl]carbamate in Step A, and 2-(dimethylamino)acetic acid in Step B. MS (ESI): mass calcd. for C H N O S, 584.7; m/z found, 585.2 [M+H] . H 31 32 6 4 NMR (400 MHz, CD OD): δ 8.30 (d, J = 5.6 Hz, 1H), 7.43-7.33 (m, 2H), 7.30-7.22 (m, 1H), 7.21-7.12 (m, 1H), 7.11-7.02 (m, 3H), 7.01-6.89 (m, 1H), 6.04 (d, J = 5.6 Hz, 1H), 4.33-4.22 (m, 1H), 4.22-4.12 (m, 1H), 3.02-2.89 (m, 2H), 2.26 (s, 6H), 2.16-2.07 (m, 5H), 1.86-1.75 (m, 2H), 1.75-1.66 (m, 1H), 1.62-1.51 (m, 1H).
Example 124: N-((1S,2R)Acrylamidocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, using 4-oxo(4- phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and tert-butyl N-[(1R,2S)aminocyclohexyl]carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 553.6; m/z found, 554.1 [M+H] . H NMR (500 MHz, CD OD): δ 27 5 4 3 8.31 (d, J = 5.6 Hz, 1H), 7.46 - 7.34 (m, 4H), 7.22 - 7.06 (m, 5H), 6.49 - 6.36 (m, 1H), 6.31 - 6.25 (m, 1H), 6.18 (d, J = 5.6 Hz, 1H), 5.67 (dd, J = 10.2, 1.8 Hz, 1H), 4.45 - 4.37 (m, 1H), 4.21 - 4.08 (m, 1H), 1.89 - 1.41 (m, 9H).
Example 125: 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2S)(2- (methylamino)acetamido)cyclohexyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide.
N NH Step A. N-((1R,2S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2S) aminocyclohexyl]carbamate.
Step B. 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2S)(2- (methylamino)acetamido)cyclohexyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide. The title compound was prepared in a manner analogous to Example 122, Step B, using 2-[tert-butoxycarbonyl(methyl)amino]acetic acid. MS (ESI): mass calcd. for C H N O S, 584.7; m/z found, 585.2 [M+H] . 31 32 6 4 Example 126: N-((1R,2S)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Step A-B, using 4- oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and tert-butyl N-[(1S,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, 500.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.54 27 25 5 3 3 (s, 1H), 8.15 (d, J = 5.6 Hz, 1H), 7.49 - 7.24 (m, 4H), 7.19 - 7.08 (m, 3H), 7.08 - 7.03 (m, 2H), 6.01 (d, J = 5.5 Hz, 1H), 4.33 - 4.24 (m, 1H), 3.66 - 3.53 (m, 1H), 1.93 - 1.38 (m, 9H).
Example 127: N-((1S,2R)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, using 4-oxo(4- phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and tert-butyl N-[(1R,2S)aminocyclopentyl]carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 539.6; m/z found, 540.1 [M+H] . 29 25 5 4 Example 128: N-((1R,2S)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 122, using 2- (dimethylamino)acetic acid in Step B. MS (ESI): mass calcd. for C H N O S, 584.7; m/z 31 32 6 4 found, 585.4 [M+H] . H NMR (400 MHz, CD OD): δ 8.30 (d, J = 5.5 Hz, 1H), 7.43-7.35 (m, 2H), 7.31-7.21 (m, 1H), 7.19-7.13 (m, 1H), 7.10-7.03 (m, 3H), 7.00-6.92 (m, 1H), 6.04 (d, J = .5 Hz, 1H), 4.47-4.34 (m, 2H), 3.16 (s, 2H), 2.36 (s, 6H), 2.13-2.02 (m, 5H), 1.95-1.85 (m, 1H), 1.79-1.59 (m, 3H).
Example 129: N-((1R,2S)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 122, Step B, using N- ((1R,2S)aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 125, product from Step A), and 2-(tert- butoxycarbonylamino)acetic acid. MS (ESI): mass calcd. for C H N O S, 570.7; m/z found, 30 6 4 571.2 [M+H] .
Example 130: N-((1S,2S)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 122 using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2S)aminocyclopentyl]carbamate in Step A, and (2-tert-butoxyoxo- ethyl)carbamic acid in Step B. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.2 29 28 6 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.03 (d, J = 5.6 Hz, 1H), 7.42-7.29 (m, 2H), 7.20-7.06 (m, 4H), 7.04-6.99 (m, 1H), 6.98-6.91 (m, 1H), 5.76 (d, J = 5.6 Hz, 1H), 4.35-4.26 (m, 1H), 4.20-4.09 (m, 1H), 3.25-3.19 (m, 2H), 2.27-2.13 (m, 2H), 2.10 (s, 3H), 1.88-1.74 (m, 3H), 1.64- 1.50 (m, 1H).
Example 131: N-((1R,2S)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of N-((1R,2S)aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 115, 52.0 mg, 0.104 mmol) and triethylamine (21 mg, 0.21 mmol) in DCM (10 mL) was added (2,5-dioxopyrrolidin- 1-yl) 2-(tert-butoxycarbonylamino)acetate (57 mg, 0.21 mmol) in an ice bath, then stirred at rt for 1h. The reaction mixture was concentrated to dryness and the residue was dissolved in HCl (2 mL) and MeOH ( mL) and heated to 50 °C and stirred for 30 min. The reaction mixture was concentrated to dryness and was purified by flash column chromatography to give the title compound (43 mg, 97% yield). MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 29 28 6 4 557.4 [M+H] . H NMR (400 MHz, CD OD): δ 8.48 (s, 1H), 8.26 (d, J = 5.5 Hz, 1H), 7.44-7.35 (m, 2H), 7.29-7.24 (m, 1H), 7.20-7.13(m, 1H), 7.11-7.03 (m, 3H), 6.99-6.93 (m, 1H), 6.00 (d, J = 5.6 Hz, 1H), 4.47-4.35 (m, 2H), 3.60 (s, 2H), 2.16-2.08 (m, 4H), 2.07-2.00 (m, 1H), 1.96-1.85 (m, 1H), 1.78-1.64 (m, 3H).
Example 132: N-((1R,2S)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 122, Step B, using N- ((1R,2S)aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 125, product from Step A) and 2- (dimethylamino)acetic acid. MS (ESI): mass calcd. for C H N O S, 598.7; m/z found, 599.3 32 34 6 4 [M+H] . H NMR (400 MHz, DMSO-d ): δ 8.24-8.20 (m, 1H), 8.20-8.09 (m, 1H), 7.77-7.70 (m, 1H), 7.44-7.39 (m, 2H), 7.32-7.36 (m, 1H), 7.19-7.14 (m, 1H), 7.11-7.07 (m, 2H), 7.06-7.03 (m, 1H), 6.95-6.91 (m, 1H), 5.88-5.82 (m, 1H), 4.13-4.03 (m, 2H), 3.22-3.19 (m, 1H), 3.12-3.07 (m, 1H), 2.29 (s, 6H), 2.02 (s, 3H), 1.74-1.59 (m, 4H), 1.55-1.49 (m, 1H), 1.47-1.33 (m, 3H).
Example 133: 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,2S)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide.
The title compound was prepared in a manner analogous to Example 122 using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2S)aminocyclopentyl]carbamate in Step A, and 2-[tert- butoxycarbonyl(methyl)amino]acetic acid in Step B. MS (ESI): mass calcd. for C H N O S, 30 6 4 570.7; m/z found, 571.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.03 (d, J = 5.6 Hz, 1H), 7.43-7.30 (m, 2H), 7.17-7.11 (m, 2H), 7.10-7.06 (m, 2H), 7.06-6.99 (m, 1H), 6.97-6.91 (m, 1H), .75 (d, J = 5.7 Hz, 1H), 4.37-4.23 (m, 1H), 4.22-4.04 (m, 1H), 3.17-3.13 (m, 2H), 2.31 (s, 3H), 2.26-2.12 (m, 2H), 2.09 (s, 3H), 1.91-1.74 (m, 3H), 1.61-1.49 (m, 1H).
Example 134: N-((1S,2S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2S)aminocyclopentyl]carbamate in Step A, and acetyl chloride Step B.
MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.1 [M+H] . H NMR (400 MHz, 29 27 5 4 CD OD): δ 8.23 (d, J = 5.5Hz, 1H), 7.44-7.31 (m, 2H), 7.30-7.19 ( m, 1H), 7.18-7.12 (m, 1H), 7.10-7.00 (m, 3H), 6.97-6.92 (m, 1H), 5.97 (d, J = 5.6Hz, 1H), 4.25-4.08 (m, 2H), 2.18-2.08 (m, 5H), 1.91 (s, 3H), 1.86-1.74 (m, 2H), 1.73-1.63 (m, 1H), 1.61-1.43 (m, 1H).
Example 135: N-((1S,2S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2S)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, 500.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.03 (d, J = 27 25 5 3 3 .7Hz, 1H), 7.41-7.31 (m, 2H), 7.19-7.04 (m, 4H), 7.04-7.00 (m, 1H), 6.98-6.89 (m, 1H), 5.76 (d, J = 5.6Hz, 1H), 4.03-3.91 (m, 1H), 3.26-3.19 (m, 1H), 2.22-2.13 (m, 1H), 2.10 (s, 3H), 2.07- 1.99 (m, 1H), 1.82-1.66 (m, 3H), 1.50-1.39 (m, 1H).
Example 136: N-((1R,2S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of N-((1R,2S)aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 125, product from Step A, 77 mg, 0.15 mmol) and triethylamine (46 mg, 0.45 mmol) in DCM (5 mL) was added acetic anhydride (15 mg, 0.15 mmol) and was stirred at room temperature for 2 hours. The mixture was purified by flash column chromatography, then by preparative TLC to give the title compound (64 mg, 77% yield). MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 29 5 4 556.2 [M+H] . H NMR (400 MHz, DMSO-d ): δ 9.96 (s, 1H), 8.36-8.22 (m, 1H), 7.82-7.64 (m, 1H), 7.63-7.57 (m, 1H), 7.44-7.39 (m, 2H), 7.39-7.28 (m, 1H), 7.19-7.14 (m, 1H), 7.12-7.07 (m, 2H), 7.07-7.04 (m, 1H), 6.97-6.92 (m, 1H), 6.01-5.86 (m, 1H), 4.14-4.01 (m, 1H), 4.01-3.93 (m, 1H), 2.03 (s, 3H), 1.87 (s, 3H), 1.70-1.58 (m, 4H), 1.55-1.44 (m, 2H), 1.40-1.29 (m, 2H).
Example 137: N-((1R,2S)Aminocyclohexyl)(3-chlorophenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 5-(3-Chlorophenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, using 2-chlorofluoronitrobenzene in Step A.
Step B. N-((1R,2S)Aminocyclohexyl)(3-chlorophenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(3-chlorophenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and tert-butyl N-[(1S,2R) aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H ClN O S, 534.0; m/z found, 27 24 5 3 534.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.16-8.10 (m, 1H), 7.57-7.49 (m, 1H), 7.42- 7.34 (m, 2H), 7.30-7.23 (m, 1H), 7.18-7.11 (m, 2H), 7.08-7.02 (m, 2H), 6.05-6.00 (m, 1H), 4.45- 4.38 (m, 1H), 3.42-3.33 (m, 1H), 1.91-1.77 (m, 4H), 1.76-1.66 (m, 2H), 1.62-1.54 (m, 1H), 1.52- 1.43 (m, 1H).
Example 138: N-((1R,2S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 136 using N-((1R,2S) aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 115). MS (ESI): mass calcd. for C H N O S, 29 27 5 4 541.6; m/z found, 542.5 [M+H] . H NMR (400 MHz, CD OD): δ 8.30 (d, J = 5.5 Hz, 1H), 7.45-7.33 (m, 2H), 7.31-7.24 (m, 1H), 7.20-7.12m, 1H), 7.12 -7.02 (m, 3H), 6.99-6.93 (m, 1H), 6.04 (d, J = 5.4 Hz, 1H), 4.40-4.29(m, 2H), 2.11 (s, 3H), 2.08-1.99 (m, 2H), 1.93 (s, 3H), 1.89- 1.82 (m, 1H), 1.75-1.62 (m, 3H).
Example 139: N-((1R,3R)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Step A, using 4-oxo (4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and (1R,3R)aminocyclohexanol. MS (ESI): mass calcd. for C H N O S, 27 24 4 4 500.6; m/z found, 501.1 [M+H] . H NMR (500 MHz, CDCl ): δ 9.55 (s, 1H), 8.36 (s, 1H), 7.47 - 7.35 (m, 2H), 7.29 - 7.26 (m, 1H), 7.23 - 7.04 (m, 5H), 6.21 (s, 1H), 5.43 (d, J = 7.8 Hz, 1H), 4.49 - 4.29 (m, 1H), 4.29 - 4.13 (m, 2H), 3.82 - 3.56 (m, 0H), 2.66 - 2.28 (m, 1H), 2.12 - 1.80 (m, 3H), 1.77 - 1.52 (m, 4H), 1.47 - 1.17 (m, 1H).
Example 140: N-((1R,2S)Hydroxycyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Step A, using 4-oxo (4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and (1S,2R)aminocyclopentanol. MS (ESI): mass calcd. for C26H22N4O4S, 486.6; m/z found, 487 [M+H] . H NMR (500 MHz, CD OD): δ 8.30 (d, J = 5.6 Hz, 1H), 7.47 - 7.32 (m, 4H), 7.26 - 7.03 (m, 5H), 6.17 (d, J = 5.6 Hz, 1H), 4.31 - 4.05 (m, 2H), 2.11 - 1.53 (m, 7H).
Example 141: 5-([1,1'-Biphenyl]yl)- N-((1R,2S)aminocyclohexyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-([1,1'- biphenyl]yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 19) and tert-butyl N-[(1S,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 483.6; m/z found, 484.2 [M+H] . 27 25 5 2 Example 142: N-((1R,3S)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Step A, using 4-oxo (4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and (1R,3R)aminocyclohexanol. MS (ESI): mass calcd. for C H N O S, 27 24 4 4 500.6; m/z found, 501.0 [M+H] . H NMR (500 MHz, CDCl ): δ 9.52 (s, 1H), 8.38 (s, 1H), 7.48 - 7.38 (m, 2H), 7.32 - 7.27 (m, 1H), 7.23 - 7.07 (m, 5H), 6.21 (s, 1H), 4.19 (s, 1H), 4.05 (s, 1H), 3.42 (s, 3H), 2.14 - 2.01 (m, 1H), 1.98 - 1.40 (m, 7H).
Example 143: N-((1S,3S)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Step A, using 4-oxo (4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and (1S,3S)aminocyclohexanol. MS (ESI): mass calcd. for C27H24N4O4S, 500.6; m/z found, 501.1 [M+H] . H NMR (500 MHz, CDCl ): δ 9.64 (s, 1H), 8.35 (d, J = 5.9 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.30 - 7.26 (m, 1H), 7.25 (d, J = 3.5 Hz, 1H), 7.24 - 7.08 (m, 5H), 6.25 (d, J = 5.9 Hz, 1H), 5.65 (d, J = 7.8 Hz, 1H), 4.44 - 4.29 (m, 1H), 4.21 (s, 1H), 2.16 - 1.29 (m, 9H).
Example 144: 5-([1,1'-Biphenyl]yl)-N-((1R,2R)hydroxycyclopentyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-([1,1'- biphenyl]yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 19) and (1R,2R)aminocyclopentanol, no deprotection with HCl necessary as (1R,2R)aminocyclopentanol was used. MS (ESI): mass calcd. for C H N O S, 470.5; m/z 26 22 4 3 found, 471.1 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.10 (s, 1H), 8.31-8.26 (m, 1H), 8.05-7.97 (m, 1H), 7.84-7.80 (m, 1H), 7.79-7.76 (m, 1H), 7.70-7.67 (m, 2H), 7.67-7.63 (m, 1H), 7.48-7.43 (m, 3H), 7.39-7.34 (m, 1H), 6.07-6.03 (m, 1H), 4.80-4.73 (m, 1H), 4.02-3.94 (m, 2H), 2.01-1.93 (m, 1H), 1.89-1.79 (m, 1H), 1.67-1.59 (m, 2H), 1.53-1.41 (m, 2H).
Example 145: N-((1S,4S)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Step A-B, using 4- oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and tert-butyl N-(4-aminocyclohexyl)carbamate. MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, [M+H] . 27 25 5 3 Example 146: N-(trans-(1R,4R)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Step A-B, using 4- oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and trans-N-Boc-1,4-cyclohexanediamine. MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, [M+H] . H NMR (500 MHz, CD OD): δ 8.31 (d, J = 5.6 Hz, 27 25 5 3 3 1H), 7.49 - 7.35 (m, 4H), 7.23 - 7.05 (m, 5H), 6.18 (d, J = 5.6 Hz, 1H), 3.90 (ddt, J = 11.7, 7.7, 4.0 Hz, 1H), 3.17 - 3.02 (m, 1H), 2.10 (dq, J = 13.9, 4.3 Hz, 4H), 1.68 - 1.39 (m, 4H).
Example 147: trans-N-((1RS,3RS)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Step A-B, using 4- oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and trans-tert-butyl N-[(1R,3R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 485.6; m/z found, 486.1 [M+H] . H NMR (400 MHz, CD OD): δ 26 23 5 3 3 8.21 (d, J = 5.6 Hz, 1H), 7.47 - 7.30 (m, 4H), 7.25 - 7.03 (m, 5H), 6.09 (d, J = 5.6 Hz, 1H), 4.60 - 4.43 (m, 1H), 3.90 - 3.59 (m, 1H), 2.35 - 2.05 (m, 4H), 1.84 - 1.56 (m, 2H).
Example 148: N-((1S,2S)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Step A-B, using 4- oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and tert-butyl N-[(1S,2S)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 485.6; m/z found, 486.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.43 (s, 26 23 5 3 3 1H), 8.30 (d, J = 5.6 Hz, 1H), 7.86 – 7.79 (m, 1H), 7.73 – 7.62 (m, 4H), 7.47 – 7.38 (m, 3H), 7.37-7.31 (m, 1H), 6.19 (d, J = 5.6 Hz, 1H), 4.67-4.50 (m, 1H), 3.70-3.58 (m, 1H), 3.55-3.45 (m, 2H), 3.27-3.15 (m, 1H), 2.92 (s, 3H), 2.60-2.45 (m, 1H), 2.30-2.15 (m, 1H).
Example 149: N-((1R,2R)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Step A-B, using 4- oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and tert-butyl N-[(1R,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, 500.1 [M+H] . H NMR (500 MHz, CD OD): δ 8.17 27 25 5 3 3 (d, J = 5.6 Hz, 1H), 7.50 - 7.23 (m, 4H), 7.23 - 6.97 (m, 5H), 6.04 (d, J = 5.7 Hz, 1H), 4.01 - 3.79 (m, 1H), 3.08 - 2.94 (m, 1H), 2.22 - 1.75 (m, 4H), 1.62 - 1.23 (m, 4H).
Example 150: tert-Butyl ((1R,3S)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclopentyl)carbamate.
The title compound was prepared in a manner analogous to Example 104, Step A, using 4-oxo- -(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and tert-butyl N-[(1R,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 585.7; m/z found, 486.1 (minus Boc) [M+H] . H NMR (400 MHz, 31 31 5 5 CDCl ): δ 8.34 (d, J = 5.6 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.31 - 7.27 (m, 2H), 7.23 - 7.06 (m, 5H), 6.13 (d, J = 5.3 Hz, 1H), 5.03 - 4.96 (m, 1H), 4.48 - 4.34 (m, 1H), 3.85 - 3.72 (m, 1H), 2.53 - 2.35 (m, 1H), 2.04 - 1.64 (m, 6H), 1.50 (s, 9H), 1.45 - 1.43 (m, 1H).
Example 151: tert-Butyl trans-((1R,4R)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamido)cyclohexyl)carbamate.
The title compound was prepared in a manner analogous to Example 104, Step A, using 4-oxo- 5-(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and trans-N-Boc-1,4-cyclohexanediamine. MS (ESI): mass calcd. for C H N O S, 599.7; m/z found, 600.2 [M+H] . H NMR (400 MHz, CDCl ): δ 9.48 (s, 1H), 32 33 5 5 3 8.35 (d, J = 5.5 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.23 - 7.08 (m, 5H), 6.17 (d, J = 5.6 Hz, 1H), 5.35 (d, J = 7.9 Hz, 1H), 4.51 - 4.31 (m, 1H), 3.90 (s, 1H), 3.47 (s, 1H), 2.19 - 1.99 (m, 5H), 1.52 - 1.15 (m, 14H).
Example 152: N-((1-Hydroxycyclohexyl)methyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using oxo(4- phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 2) and 1-aminomethylcyclohexanol hydrochloride, no deprotection step with HCl used in Step A. MS (ESI): mass calcd. for C H N O S, 514.6; m/z found, 515.0 [M+H] . 28 26 4 4 H NMR (400 MHz, CDCl ): δ 9.55 (s, 1H), 8.33 (s, 1H), 8.02 (s, 1H), 7.45 – 7.34 (m, 2H), 7.36 – 7.25 (m, 2H), 7.23 – 7.06 (m, 5H), 6.39 (t, J = 5.9 Hz, 1H), 6.14 (s, 1H), 3.46 (d, J = 5.7 Hz, 2H), 2.96 (s, 2H), 1.63 – 1.45 (m, 7H), 1.35 (q, J = 10.0, 8.3 Hz, 1H).
Example 153: N-((1S,3R)((E)(Dimethylamino)butenamido)cyclopentyl)(4- isopropoxymethylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide.
The title compound was prepared in a manner analogous to Example 122 using 5-(4-isopropoxy- 2-methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31) and tert-butyl N-[(1R,2S)aminocyclopentyl]carbamate in Step A, and (E) (dimethylamino)butenoic acid in Step B. MS (ESI): mass calcd. for C H N O S, 576.7; 36 6 4 m/z found, 577.6 [M+H] . H NMR (400 MHz, CD OD): δ 8.48 (s, 1H), 8.28 (d, J = 5.5 Hz, 1H), 7.28-7.13 (m, 1H), 7.01-6.86 (m, 2H), 6.84-6.68 (m, 1H), 6.34-6.16 (m, 1H), 6.01 (d, J = .5 Hz, 1H), 4.74 -4.58 (m, 1H), 4.43-4.29 (m, 1H), 4.25-4.13 (m, 1H), 3.67-3.51 (m, 2H), 2.60 (s, 6H), 2.55-2.40 (m, 1H), 2.10 (s, 3H), 2.07-1.95 (m, 2H), 1.92-1.71 (m, 2H), 1.68-1.57 (m, 1H), 1.42-1.27 (m, 6H).
Example 154: N-((1S,2R)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 122 using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2S)aminocyclopentyl]carbamate in Step A, and using 2-(tert- butoxycarbonylamino)acetic acid in Step B. MS (ESI): mass calcd. for C29H28N6O4S, 556.6; m/z found, 557.4 [M+H] . H NMR (400 MHz, CD OD): δ 8.41 (s, 1H), 8.29 (d, J = 5.5 Hz, 1H), 7.45-7.33 (m, 2H), 7.28-7.23(m, 1H), 7.22-7.13 (m, 1H), 7.11-7.02 (m, 3H), 7.00-6.91 (m, 1H), 6.04 (d, J = 5.6 Hz, 1H), 4.51 – 4.31 (m, 2H), 3.77-3.55 (m, 2H), 2.19 – 1.99 (m, 5H), 1.98-1.83 (m, 1H), 1.80-1.60 (m, 3H).
Example 155: N-((1S,2R)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 122 using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2S)aminocyclopentyl]carbamate in Step A, and using 2- (dimethylamino)acetic acid in Step B. MS (ESI): mass calcd. for C H N O S, 584.7; m/z 31 32 6 4 found, 585.5 [M+H] . H NMR (400 MHz, CD OD): δ 8.36 (s, 1H), 8.33-8.24 (m, 1H), 7.46- 7.31 (m, 2H), 7.28-7.20 (m, 1H), 7.19-7.11(m, 1H), 7.11 – 6.99 (m, 3H), 6.99 – 6.89 (m, 1H), 6.13-5.95 (m, 1H), 4.50 – 4.27 (m, 2H), 3.61 – 3.38 (m, 2H), 2.70-2.38 (m, 6H), 2.20-1.95 (m, 5H), 1.94 – 1.53 (m, 4H).
Example 156: 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,2R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide.
The title compound was prepared in a manner analogous to Example 122 using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2S)aminocyclopentyl]carbamate in Step A, and using 2-[tert- butoxycarbonyl(methyl)amino]acetic acid in Step B. MS (ESI): mass calcd. for C H N O S, 30 6 4 570.7; m/z found, 571.4 [M+H] . H NMR (400 MHz, CD OD): δ 8.42 (s, 1H), 8.29 (d, J = 5.4 Hz, 1H), 7.46-7.33 (m, 2H), 7.28-7.21 (m, 1H), 7.20-7.13 (m, 1H), 7.12–7.01 (m, 3H), 6.99-6.91 (m, 1H), 6.04 (d, J = 5.6 Hz, 1H), 4.51-4.33 (m, 2H), 3.77-3.55 (m, 2H), 2.63 (s, 3H), 2.17-1.98 (m, 5H), 1.97-1.84 (m, 1H), 1.80-1.60 (m, 3H).
Example 157: N-((1S,3R)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Step A, using 4-oxo (4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and (1R,3S)amino-cyclohexanol hydrochloride. MS (ESI): mass calcd. for C H N O S, 500.6; m/z found, 501.1 [M+H] . H NMR (500 MHz, CDCl ): δ 9.47 (s, 1H), 27 24 4 4 3 8.31 (d, J = 5.6 Hz, 1H), 7.45 - 7.27 (m, 4H), 7.22 - 6.99 (m, 5H), 6.75 (s, 1H), 6.13 (d, J = 5.4 Hz, 1H), 4.27 - 3.94 (m, 2H), 2.18 - 1.20 (m, 9H).
Example 158: N-((1S,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 122 using 5-(4-isopropoxy- 2-methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31) and tert-butyl N-[(1R,2S)aminocyclopentyl]carbamate in Step A, and 2- (dimethylamino)acetic acid in Step B. MS (ESI): mass calcd. for C H N O S, 550.7; m/z 28 34 6 4 found, 552.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.45 (s, 1H), 8.29 (d, J = 4.9 Hz, 1H), 7.29-7.16 (m, 1H), 7.01-6.95 (m, 1H), 6.91 (dd, J = 8.6, 2.4 Hz, 1H), 6.02 (d, J = 5.0 Hz, 1H), 4.73-4.60 (m, 1H), 4.38-4.10 (m, 2H), 3.47 (s, 2H), 2.63 (s, 6H), 2.51 – 2.37 (m, 1H), 2.11 (s, 3H), 2.07-1.93 (m, 2H), 1.91 – 1.71 (m, 2H), 1.70-1.58(m, 1H), 1.41-1.29 (m, 6H).
Example 159: 4-Oxo(2-phenylpyridinyl)-N-((1S,2R)propionamidocyclopentyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1S,2R)Aminocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and tert-butyl N-[(1R,2S) aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 470.55; m/z found, 22 6 2 471.1 [M+H] .
Step B: 4-Oxo(2-phenylpyridinyl)-N-((1S,2R)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of N-((1S,2R) aminocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (50 mg, 0.11 mmol) and a catalytic amount of DMAP in DCM (25 mL) was added propionic anhydride (21 mg, 0.16 mmol) and was stirred at rt for 20 min. The reaction was concentrated to dryness and the residue was purified by flash column chromatography to give the title compound as a light yellow solid (28 mg, 48% yield). MS (ESI): mass calcd. for C H N O S, 526.6; m/z found, 527.6 [M+H] . H NMR (400 MHz, 28 26 6 3 CD OD): δ 8.85 (d, J = 5.2 Hz, 1H), 8.31 (d, J = 5.6 Hz, 1H), 8.10-7.95 (m, 3H), 7.57 – 7.36 (m, 4H), 6.29 (d, J = 5.6 Hz, 1H), 4.45-4.25 (m, 2H), 2.27-2.15 (m, 2H), 2.13 – 1.94 (m, 2H), 1.93 – 1.81 (m, 1H), 1.79 – 1.54 (m, 3H), 1.08 (t, J = 7.6 Hz, 3H).
Example 160: N-((1R,2S)Aminocyclohexyl)(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4- isopropoxymethylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 31) and tert-butyl N-[(1S,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 479.6; m/z found, 480.5 [M+H] . H NMR (400 MHz, 29 5 3 CD OD): δ 8.46 (s, 1H), 8.29 (d, J = 5.5 Hz, 1H), 7.29-7.13 (m, 1H), 7.01-6.86 (m, 2H), 6.06- .96 (m, 1H), 4.73-4.58 (m, 1H), 4.47-4.31 (m, 1H), 3.68-3.53 (m, 1H), 2.19-1.98 (m, 3H), 1.95- 1.65 (m, 6H), 1.61-1.47 (m, 2H), 1.42-1.29 (m, 6H).
Example 161: 5-(4-Isopropoxymethylphenyl)-N-((1S,3R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide.
The title compound was prepared in a manner analogous to Example 122 using 5-(4-isopropoxy- 2-methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31) and tert-butyl N-[(1R,3S)aminocyclopentyl]carbamate in Step A and 2-[tert- butoxycarbonyl(methyl)amino]acetic acid in Step B. MS (ESI): mass calcd. for C H N O S, 27 32 6 4 536.6; m/z found, 537.6 [M+H] . H NMR (400 MHz, CD OD): δ 8.46 (s, 1H), 8.30 (d, J = 5.4 Hz, 1H), 7.30-7.12 (m, 1H), 7.04-6.83 (m, 2H), 6.02 (d, J = 5.4 Hz, 1H), 4.70-4.62 (m, 1H), 4.47-4.26 (m, 1H), 4.22-4.08 (m, 1H), 3.70 (s, 2H), 2.67 (s, 3H), 2.55-2.40 (m, 1H), 2.17-1.97 (m, 5H), 1.90-1.58 (m, 3H), 1.39-1.27 (m, 6H).
Example 162: N-((1S,2R)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1S,2R)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2S) aminocyclopentyl]carbamate.
Step B. N-((1S,2R)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 159 , step B, using acetic anhydride. MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.37-8.25 29 27 5 4 3 (m, 1H), 7.45-7.34 (m, 2H), 7.30-7.23 (m, 1H), 7.22-7.13 (m, 1H), 7.12-7.02 (m, 3H), 7.00-6.95 (m, 1H), 6.12 – 6.02 (m, 1H), 4.42-4.27 (m, 2H), 2.14-2.09 (m, 3H), 2.08-1.96 (m, 2H), 1.95- 1.91 (m, 3H), 190-1.81 (m, 1H), 1.79 – 1.58 (m, 3H).
Example 163: tert-Butyl ((1S,4S)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclohexyl)carbamate.
The title compound was prepared in a manner analogous to Example 104, Step A, using 4-oxo- -(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and 1-N-Boc-cis-1,4-cyclohexyldiamine. MS (ESI): mass calcd. for C H N O S, 599.7; m/z found, 600.1 [M+H] . H NMR (400 MHz, CDCl ): δ 9.46 (s, 1H), 32 33 5 5 3 8.36 (d, J = 5.5 Hz, 1H), 7.46 - 7.35 (m, 2H), 7.29 - 7.27 (m, 1H), 7.22 - 7.02 (m, 5H), 6.16 (d, J = 5.5 Hz, 1H), 5.46 (d, J = 7.6 Hz, 1H), 4.69 - 4.52 (m, 1H), 4.19 - 3.95 (m, 1H), 3.82 - 3.62 (m, 1H), 1.95 - 1.60 (m, 9H), 1.46 (s, 9H).
Example 164: N-((1S,3R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Steps A-B, using 4- oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9) and tert-butyl ((1R,3S)aminocyclopentyl)carbamate. MS (ESI): mass calcd. for C H N O S, 485.6; m/z found, 486.1 [M+H] . H NMR (500 MHz, CD OD): δ 8.35 (d, J = 26 23 5 3 3 .6 Hz, 1H), 7.48 - 7.36 (m, 4H), 7.24 - 7.08 (m, 6H), 6.21 (d, J = 5.6 Hz, 1H), 4.38 - 4.30 (m, 1H), 3.73 - 3.62 (m, 1H), 2.61 - 2.49 (m, 1H), 2.21 - 1.76 (m, 5H).
Example 165: N-((1R,2S)Acrylamidocyclopentyl)(*R)-(4-isopropoxymethylphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31, including CHIRAL SEPARATION METHOD 1 to obtain the *R atropisomer) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 519.6; m/z found, 520.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.28-8.22 (m, 27 29 5 4 3 1H), 7.24-7.18 (m, 1H), 6.97-6.87 (m, 2H), 6.32-6.14 (m, 2H), 6.01-5.95 (m, 1H), 5.63-5.57 (m, 1H), 4.71-4.61 (m, 1H), 4.46-4.34 (m, 2H), 2.16-1.99 (m, 5H), 1.97-1.84 (m, 1H), 1.82-1.59 (m, 3H), 1.37-1.29 (m, 6H).
Example 166: N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyrimidin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: tert-Butyl ((1R,2S)(5-(*S)-(4-methylphenoxypyrimidinyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamido)cyclopentyl)carbamate. To a solution of -(4-methylphenoxypyrimidinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxylic acid (Intermediate 13, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer; 400 mg, 0.95mmol), tert-butyl ((1S,2R)aminocyclopentyl)carbamate (382 mg, 1.9 mmol) DIPEA (1.6 mL, 9.5 mmol) in DMF (3.8 mL) was added dropwise 1- propanephosphonic anhydride (T3P ) (3.17 mL, 4.76 mmol). The reaction mixture was stirred at room temperature for 1 h. To the reaction mixture was added water and EtOAc. The organics were separated, washed with water, and brine. The aq was back extracted with EtOAc, and the combined organics were dried (Na SO ), filtered, and concentrated under reduced pressure.
Purification (FCC, SiO , 20-100% EtOAc/hexane) afforded the title compound (395 mg, 68%).
Step B. N-((1R,2S)Aminocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of tert-butyl ((1R,2S)(5-(4-methylphenoxypyrimidinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclopentyl)carbamate (395 mg, 0.65 mmol) in HCl (4 M in dioxane, 0.82 mL) was stirred at room temperature for 1 h. Ether was added and the reaction mixture was stirred for 15 min. The resulting solids were filtered and dried under reduced pressure to afford the title compound (272 mg, 77%). MS (ESI): mass calcd. for C H N O S, 23 7 3 501.56; m/z found, 502.0 [M+H] . H NMR (500 MHz, CD OD): δ 8.57 (s, 1H), 8.51 (d, J = 5.9 Hz, 1H), 7.50 – 7.42 (m, 2H), 7.32 – 7.27 (m, 1H), 7.27 – 7.24 (m, 2H), 6.50 (d, J = 6.0 Hz, 1H), 4.50 (q, J = 6.6 Hz, 1H), 3.78 (q, J = 6.9 Hz, 1H), 2.34 (s, 3H), 2.23 – 2.13 (m, 2H), 2.05 – 1.91 (m, 2H), 1.84 – 1.72 (m, 2H).
Step C: N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a 40 mL vial containing N-((1R,2S)aminocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 254, 100 mg, 0.186 mmol), DMF (1.86 mL), acrylic acid (0.103 mL, 1.49 mmol), and diisopropylethylamine (0.16 mL, 0.93 mmol), stirred under N , was added dropwise 2,4,6-tripropyl-1,3,5,2,4,6- trioxatriphosphorinane-2,4,6-trioxide (1.11 mL, 1.86 mmol, 5 eq). After 1 h, another 5 eq 2,4,6- tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.11 mL, 1.86 mmol) was added.
After 15 min, the reaction was extracted with EtOAc, and washed with water and brine. The aqueous solution was extracted with more EtOAc, the combined organic phases were dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound (23.9 mg, 23.1% yield). MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.0 [M+H] . H NMR (500 MHz, CD OD): δ 8.52 28 25 7 4 3 (s, 1H), 8.40 – 8.31 (m, 1H), 7.48 – 7.43 (m, 2H), 7.30 – 7.26 (m, 1H), 7.26 – 7.23 (m, 2H), 6.29 (dd, J = 17.1, 10.0 Hz, 2H), 6.23 – 6.17 (m, 1H), 5.62 (d, J = 11.9 Hz, 1H), 4.48 – 4.37 (m, 2H), 2.33 (s, 3H), 2.14 – 2.04 (m, 2H), 1.97 – 1.86 (m, 1H), 1.83 – 1.63 (m, 3H).
Example 167: N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenylpyrimidinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (6-phenylpyrimidinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 23) and N-[(1S,2R)aminocyclopentyl]propenamide (Intermediate 36), no deprotection step with HCl was used. MS (ESI): mass calcd. for C H N O S, 525.6; m/z 27 23 7 3 found, 526.5 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.26 (s, 1H), 9.38 (s, 1H), 8.42-8.32 (m, 2H), 8.25-8.16 (m, 2H), 7.93-7.74 (m, 2H), 7.62-7.54 (m, 3H), 6.57-6.49 (m, 1H), 6.27-6.16 (m, 1H), 6.10-6.02 (m, 1H), 5.60-5.49 (m, 1H), 4.37-4.19 (m, 2H), 1.96-1.85 (m, 2H), 1.80-1.70 (m, 2H), 1.67-1.57 (m, 2H).
Example 168: N-((1R,2S)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(2- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and tert-butyl N-[(1S,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 538.6; m/z found, 539.2 [M+H] . H NMR (400 MHz, CD OD): δ 29 26 6 3 3 8.90-8.82 (m, 1H), 8.36-8.27 (m, 1H), 8.06-8.01 (m, 3H), 7.52-7.43 (m, 4H), 6.47-6.36 (m, 1H), 6.33-6.22 (m, 2H), 5.69-5.63 (m, 1H), 4.47-4.36 (m, 1H), 4.22-4.10 (m, 1H), 1.83-1.62 (m, 6H), 1.58-1.46 (m, 2H).
Example 169: N-((1R,2S)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(2- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 524.6; m/z found, 525.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.84 28 24 6 3 3 (d, J = 5.2 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 8.09 – 7.95 (m, 3H), 7.54-7.40 (m, 4H), 6.41 – 6.10 (m, 3H), 5.60 (dd, J = 9.8, 2.2 Hz, 1H), 4.49 – 4.29 (m, 2H), 2.17-1.98 (m, 2H), 1.97-1.83 (m, 1H), 1.82 – 1.57 (m, 3H).
Example 170: N-((1R,2S)Aminocyclopentyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, Step A-B, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,2R)aminocyclopentyl)carbamate. MS (ESI): mass calcd. for C H N O S, 500.6; m/z found, 501.1 [M+H] . H NMR (500 MHz, CDCl ): δ 8.29 (d, J = 26 24 6 3 3 .4 Hz, 1H), 8.07 (s, 1H), 7.46 – 7.38 (m, 2H), 7.27 – 7.15 (m, 3H), 6.95 (s, 2H), 5.99 (d, J = 5.4 Hz, 1H), 5.28 (s, 1H), 4.17 (q, J = 6.9 Hz, 1H), 4.04 – 3.99 (m, 4H), 3.49 – 3.42 (m, 1H), 2.22 (s, 3H), 1.86 – 1.75 (m, 1H), 1.71 – 1.47 (m, 3H).
Example 171: N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,2R)aminocyclopentyl)carbamate in Step A. MS (ESI): mass calcd. for H N O S, 554.6; m/z found, 555.2 [M+H] . H NMR (500 MHz, CDCl ): δ 9.58 (s, 1H), C29 26 6 4 3 8.33 (d, J = 5.5 Hz, 1H), 8.05 (s, 1H), 7.48 – 7.40 (m, 2H), 7.29 – 7.16 (m, 3H), 6.97 – 6.93 (m, 1H), 6.84 (d, J = 6.3 Hz, 1H), 6.57 (d, J = 6.8 Hz, 1H), 6.35 (dd, J = 16.9, 1.5 Hz, 1H), 6.21 – 6.10 (m, 1H), 6.02 (d, J = 5.5 Hz, 1H), 5.66 (dd, J = 10.3, 1.4 Hz, 1H), 4.44 – 4.29 (m, 2H), 4.12 (q, J = 7.2 Hz, 1H), 2.30 – 2.08 (m, 3H), 1.93 – 1.82 (m, 2H), 1.80 – 1.64 (m, 3H).
Example 172: N-((1R,2S)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, using 4-oxo(6- phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 28) and tert-butyl ((1S,2R)aminocyclohexyl)carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.2 [M+H] . H NMR (400 MHz, CDCl ): δ 29 26 6 4 3 8.29 (d, J = 5.4 Hz, 1H), 8.24 – 8.17 (m, 1H), 7.77 (ddd, J = 20.3, 8.3, 2.9 Hz, 1H), 7.49 – 7.39 (m, 2H), 7.31 – 6.98 (m, 4H), 6.37 (dd, J = 17.0, 1.8 Hz, 1H), 6.30 – 6.17 (m, 1H), 6.11 (d, J = 5.5 Hz, 1H), 5.66 (dd, J = 10.0, 1.8 Hz, 1H), 4.30 (d, J = 7.9 Hz, 1H), 4.13 (dq, J = 14.3, 7.1, 6.5 Hz, 2H), 2.04 (s, 3H), 1.90 – 1.80 (m, 1H), 1.71 (d, J = 15.2 Hz, 1H), 1.60 (dd, J = 19.0, 9.7 Hz, 3H), 1.25 (t, J = 7.1 Hz, 1H), 1.08 (d, J = 6.7 Hz, 1H).
Example 173: N-((1R,2S)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH O HN The title compound was prepared in a manner analogous to Example 166, Step A, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and N-((1S,2R)aminocyclohexyl)acrylamide. MS (ESI): mass calcd. for C H N O S, 568.7; m/z found, 569.1 [M+H] . H NMR (500 MHz, CDCl ): δ 9.53 (s, 1H), 28 6 4 3 8.35 (d, J = 5.4 Hz, 1H), 8.04 (s, 1H), 7.48 - 7.39 (m, 2H), 7.28 - 7.16 (m, 3H), 7.05 (s, 1H), 6.97 - 6.93 (m, 1H), 6.41 (dd, J = 16.9, 1.4 Hz, 1H), 6.20 (dd, J = 16.9, 10.3 Hz, 1H), 6.02 (d, J = 5.5 Hz, 1H), 5.73 (dd, J = 10.2, 1.4 Hz, 1H), 4.30 (tt, J = 6.5, 3.0 Hz, 1H), 4.16 (h, J = 4.3, 3.8 Hz, 1H), 2.89 (d, J = 0.6 Hz, 1H), 2.21 (d, J = 0.8 Hz, 3H), 2.08 - 1.99 (m, 1H), 1.92 (ddd, J = 13.9, 10.2, 3.8 Hz, 1H), 1.77 - 1.54 (m, 6H).
Example 174: N-((1R,2S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31, including CHIRAL SEPARATION METHOD 1 to obtain the *R atropisomer) and tert-butyl N-[(1S,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 533.6; m/z found, 534.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.33-8.22 (m, 28 31 5 4 3 1H), 7.21-7.16 (m, 1H), 6.98-6.95 (m, 1H), 6.93-6.89 (m, 1H), 6.46-6.36 (m, 1H), 6.28-6.22 (m, 1H), 6.02-5.96 (m, 1H), 5.68-5.63 (m, 1H), 4.69-4.62 (m, 1H), 4.46-4.38 (m, 1H), 4.18-4.12 (m, 1H), 2.10 (s, 3H), 1.82-1.72 (m, 4H), 1.71-1.60 (m, 2H), 1.58-1.48 (m, 2H), 1.34 (d, J = 6.0 Hz, 6H).
Example 175: N-((1R,3R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including step F2 to obtain the *S atropisomer), and tert-butyl N-[(1R,3R) aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 553.6; m/z found, 554.4 27 5 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.31 (d, J = 5.6 Hz, 1H), 7.43-7.35 ( m, 2H), 7.33- 7.24 (m, 1H), 7.18-7.12 (m, 1H), 7.12 – 7.01 (m, 3H), 6.99-6.90 (m, 1H), 6.26 – 6.18 (m, 2H), 6.06 (d, J = 5.6 Hz, 1H), 5.68-5.55 (m, 1H), 4.57 – 4.45 (m, 1H), 4.44 – 4.30 (m, 1H), 2.28-2.14 (m, 2H), 2.11 (s, 3H), 2.04-1.86 (m, 2H), 1.73 – 1.45 (m, 2H).
Example 176: N-((1S,3R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including step F2 to obtain the *S atropisomer), and tert-butyl N-[(1R,3S) aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 567.7; m/z found, 568.2 31 29 5 4 [M+H] . H NMR (400 MHz, CD OD:DMSO-d = 2:1): δ 8.43-8.35 (m, 1H), 7.54-7.45 (m, 2H), 7.42-7.36 (m, 1H), 7.30-7.22 (m, 1H), 7.21-7.11 (m, 3H), 7.08-7.01 (m, 1H), 6.31-6.21 (m, 2H), 6.13-6.07 (m, 1H), 5.73-5.62 (m, 1H), 4.08-3.97 (m, 1H), 3.89-3.79 (m, 1H), 2.20-2.16 (m, 4H), 1.98-1.89 (m, 3H), 1.52-1.36 (m, 4H).
Example 177: N-((1R,2R)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using oxo(6- phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 28) and tert-butyl N-[(1R,2R)aminocyclopentyl]carbamate and BOC deprotection using TFA in Step A. MS (ESI): mass calcd. for C H N O S, 540.6; m/z found, 28 24 6 4 541.0 [M+H] . H NMR (500 MHz, CDCl ): δ 9.58 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 8.18 (s, 1H), 7.73 (t, J = 11.1 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.29 – 7.17 (m, 3H), 7.10 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 6.2 Hz, 1H), 6.29 (d, J = 16.9 Hz, 2H), 6.18 – 6.03 (m, 2H), 5.62 (d, J = 10.4 Hz, 1H), 4.15 (dq, J = 40.1, 7.9 Hz, 2H), 2.28 (ddd, J = 27.6, 12.4, 5.9 Hz, 2H), 1.81 (dd, J = 14.7, 7.6 Hz, 2H), 1.67 – 1.45 (m, 2H).
Example 178: N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using oxo(6- phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 28) and tert-butyl ((1S,2R)aminocyclopentyl)carbamate and BOC deprotection using TFA in Step A. MS (ESI): mass calcd. for C28H24N6O4S, 540.6; m/z found, 541.0 [M+H] .
H NMR (500 MHz, CDCl ): δ 8.27 (d, J = 5.5 Hz, 1H), 8.17 (s, 1H), 7.76 – 7.67 (m, 1H), 7.47 – 7.39 (m, 2H), 7.28 – 7.15 (m, 3H), 7.08 (d, J = 8.7 Hz, 1H), 7.00 (s, 1H), 6.84 (d, J = 18.9 Hz, 1H), 6.29 (d, J = 16.9 Hz, 1H), 6.20 – 6.06 (m, 2H), 6.00 (s, 1H), 5.59 (d, J = 9.8 Hz, 1H), 4.36 (q, J = 7.1, 6.3 Hz, 2H), 2.19 (dt, J = 11.9, 6.6 Hz, 1H), 2.13 – 2.02 (m, 1H), 1.89 – 1.61 (m, 4H).
Example 179: N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(5- phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 26) and tert-butyl ((1S,2R)aminocyclopentyl)carbamate. MS (ESI): mass calcd. for C H N O S, 540.6; m/z found, 541.0 [M+H] . H NMR (400 MHz, CDCl ): δ 9.27 (s, 1H), 28 24 6 4 3 8.38 (dd, J = 16.8, 4.2 Hz, 2H), 7.56 - 7.31 (m, 4H), 7.24 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 7.9 Hz, 2H), 6.66 (d, J = 5.6 Hz, 1H), 6.37 (d, J = 16.8 Hz, 1H), 6.27 - 6.06 (m, 3H), 5.69 (d, J = 10.3 Hz, 1H), 4.44 - 4.24 (m, 2H), 2.43 - 2.03 (m, 2H), 1.96 - 1.67 (m, 4H).
Example 180: N-((1S,3R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,3S)aminocyclohexyl]carbamate in Step A, and acetic anhydride in Step B. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.2 [M+H] . H NMR (400 29 5 4 MHz, CD OD): δ 8.34-8.29 (m, 1H), 7.43-7.35 (m, 2H), 7.31-7.25 (m, 1H), 7.20-7.13 (m, 1H), 7.11-7.03 (m, 3H), 7.01-6.93 (m, 1H), 6.09-6.03 (m, 1H), 4.02-3.89 (m, 1H), 3.81-3.71 (m, 1H), 2.17-2.08 (m, 4H), 1.97-1.83 (m, 6H), 1.47-1.15 (m, 4H).
Example 181: N-((1R,3R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,3R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 513.6; m/z found, 514.2 [M+H] . 28 27 5 3 Example 182: N-((1R,3R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,3R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 567.7; m/z found, 568.5 [M+H] . H NMR (400 MHz, CD OD): δ 8.33 (d, J = 31 29 5 4 3 .6 Hz, 1H), 7.43-7.37 (m, 2H), 7.31-7.27 (m, 1H), 7.20-7.15 (m, 1H), 7.11-7.03 (m, 3H), 7.01- 6.95 (m, 1H), 6.41-6.31 (m, 1H), 6.27-6.19 (m, 1H), 6.08 (d, J = 5.7 Hz, 1H), 5.68-5.62 (m, 1H), 4.25-4.15 (m, 2H), 2.12 (s, 3H), 1.95-1.78 (m, 3H), 1.74-1.54 (m, 5H).
Example 183: N-((1R,2S)Acrylamidocyclohexyl)(6-cyclobutoxymethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(6- cyclobutoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 24) and N-[(1S,2R)aminocyclohexyl]propenamide (Intermediate 40), no MeOH/HCl deprotection. MS (ESI): mass calcd. for C H N O S, 546.6; 28 30 6 4 m/z found, 547.2 [M+H] . H NMR (500 MHz, CD OD): δ 8.32 (d, J = 5.5 Hz, 1H), 8.05 (d, J = 3.8 Hz, 1H), 6.84 (s, 1H), 6.42 (dd, J = 17.0, 10.3 Hz, 1H), 6.32 – 6.22 (m, 1H), 6.10 (d, J = 5.4 Hz, 1H), 5.71 – 5.64 (m, 1H), 5.25 – 5.14 (m, 1H), 4.44 (s, 1H), 4.17 (s, 1H), 2.52 – 2.43 (m, 2H), 2.22 – 2.10 (m, 5H), 1.89 – 1.63 (m, 8H), 1.60 – 1.46 (m, 2H).
Example 184: N-((1R,3R)Acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1R,3R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 553.6; m/z found, 554.2 [M+H] . 27 5 4 Example 185: N-((1R,2R)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(5- phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 26) and tert-butyl N-[(1R,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 540.6; m/z found, 541.0 [M+H] . H NMR (500 MHz, CDCl ): δ 9.45 28 24 6 4 3 (s, 1H), 8.45 - 8.30 (m, 2H), 7.50 - 7.36 (m, 4H), 7.26 - 7.21 (m, 1H), 7.17 - 7.09 (m, 2H), 6.80 (d, J = 5.8 Hz, 1H), 6.42 (d, J = 6.4 Hz, 1H), 6.36 - 6.07 (m, 3H), 5.67 (dd, J = 10.3, 1.4 Hz, 1H), 4.25 - 4.03 (m, 2H), 2.40 - 2.26 (m, 2H), 1.92 - 1.79 (m, 2H), 1.65 - 1.58 (m, 1H), 1.58 - 1.48 (m, 1H).
Example 186: N-((1S,3R)Acrylamidocyclopentyl)(*R)-(4-isopropoxymethylphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31, including CHIRAL SEPARATION METHOD 1 to obtain the *R atropisomer) and tert-butyl N-[(1R,3S)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C27H29N5O4S, 519.6; m/z found, 520.2 [M+H] . H NMR (400 MHz, CD3OD): δ 8.35-8.23 (m, 1H), 7.25-7.13 (m, 1H), 6.99-6.95 (m, 1H), 6.94-6.89 (m, 1H), 6.27-6.19 (m, 2H), 6.06-5.98 (m, 1H), 5.68-5.61 (m, 1H), 4.70-4.63 (m, 1H), 4.41-4.30 (m, 1H), 4.25-4.15 (m, 1H), 2.52-2.43 (m, 1H), 2.11 (s, 3H), 2.08-1.98 (m, 2H), 1.83-1.73 (m, 2H), 1.65-1.58 (m, 1H), 1.34 (d, J = 6.0 Hz, 6H).
Example 187: N-((1R,2S)Acrylamidocyclohexyl)(6-cyclobutoxymethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 5-(6-Cyclobutoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 24, using 6-fluoromethylnitropyridine in Step A.
Step B. N-((1R,2S)Acrylamidocyclohexyl)(6-cyclobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(6-cyclobutoxymethylpyridin- 3-yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and N-[(1S,2R)- 2-aminocyclohexyl]propenamide (Intermediate 40), no MeOH/HCl deprotection. MS (ESI): H N O S, 546.6; m/z found, 547.2 [M+H] . H NMR (500 MHz, CD OD): δ mass calcd. for C28 30 6 4 3 8.32 (d, J = 5.3 Hz, 1H), 7.61 (dd, J = 8.6, 2.3 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 6.42 (dd, J = 17.0, 10.3 Hz, 1H), 6.27 (d, J = 17.0 Hz, 1H), 6.08 (d, J = 5.4 Hz, 1H), 5.67 (dd, J = 10.2, 1.7 Hz, 1H), 5.26 – 5.16 (m, 1H), 4.44 (s, 1H), 4.22 – 4.12 (m, 1H), 2.55 – 2.45 (m, 2H), 2.25 (s, 3H), 2.21 – 2.11 (m, 2H), 1.90 – 1.62 (m, 8H), 1.60 – 1.45 (m, 2H).
Example 188: N-((1RS,3RS)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Step B, using N- ((1RS,3RS)aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 289) and acryloyl chloride. MS (ESI): mass calcd. for C H N O S, 540.6; m/z found, 541.1 [M+H] . H NMR (500 MHz, CDCl ): δ 9.54 28 24 6 4 3 (s, 1H), 8.32 (s, 1H), 8.20 (d, J = 12.1 Hz, 1H), 7.78 – 7.68 (m, 1H), 7.57 – 7.49 (m, 1H), 7.49 – 7.40 (m, 2H), 7.30 – 7.17 (m, 3H), 7.11 (d, J = 8.7 Hz, 1H), 6.84 – 6.77 (m, 1H), 6.42 – 6.34 (m, 1H), 6.16 – 6.05 (m, 2H), 5.69 – 5.62 (m, 1H), 4.38 (dh, J = 7.6, 4.1 Hz, 1H), 4.11 (tt, J = 13.9, 11.3, 5.3 Hz, 1H), 3.52 – 3.44 (m, 1H), 2.46 (dt, J = 14.3, 8.7 Hz, 1H), 2.07 – 1.80 (m, 4H).
Example 189: N-((1R,2S)Acrylamidocyclopentyl)oxo(4-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(4- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 21) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 524.6; m/z found, 525.1 [M+H] . H NMR (400 MHz, CD OD): δ 28 24 6 3 3 8.73-8.67 (m, 1H), 8.34-8.29 (m, 1H), 7.93-7.87 (m, 2H), 7.84-7.80 (m, 2H), 7.54-7.48 (m, 3H), 6.31-6.14 (m, 3H), 5.64-5.59 (m, 1H), 4.58-4.54 (m, 1H), 4.45-4.41 (m, 1H), 2.21-1.98 (m, 2H), 1.97-1.56 (m, 4H).
Example 190: N-((1S,3R)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31, including CHIRAL SEPARATION METHOD 1 to obtain the *R atropisomer), tert-butyl N-[(1R,3S)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 28 31 5 4 533.6; m/z found, 534.7 [M+H] . H NMR (400 MHz, CD OD): δ 8.28 (d, J = 5.5 Hz, 1H), 7.30-7.14 (m, 1H), 7.05-6.80 (m, 2H), 6.34-6.14 (m, 2H), 6.00 (d, J = 5.5 Hz, 1H), 5.71-5.54 (m, 1H), 4.71-4.57 (m, 1H), 4.08-3.75 (m, 2H), 2.21-2.14 (m, 1H), 2.10 (s, 3H), 2.00-1.82 (m, 3H), 1.55-1.37 (m, 2H), 1.36-1.31 (m, 6H), 1.30-1.11 (m, 2H).
Example 191: N-((1S,3R)Acrylamidocyclopentyl)(3-chlorophenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(3-chloro phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 137, product from Step A) and tert-butyl N-[(1R,3S)aminocyclopentyl]carbamate.
MS (ESI): mass calcd. for C H ClN O S, 574.1; m/z found, 574.1 [M+H] . H NMR (400 29 24 5 4 MHz, CD OD): δ 8.33-8.29 (m, 1H), 7.70-7.64 (m, 1H), 7.43-7.33 (m, 3H), 7.20-7.12 (m, 2H), 7.09-7.02 (m, 2H), 6.26-6.18 (m, 3H), 5.67-5.60 (m, 1H), 4.38-4.28 (m, 1H), 4.23-4.14 (m, 1H), 2.51-2.42 (m, 1H), 2.09-1.96 (m, 2H), 1.84-1.70 (m, 2H), 1.64-1.55 (m, 1H).
Example 192: N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(5- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 22) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 524.6; m/z found, 525.1 [M+H] . H NMR (400 MHz, CD OD): δ 28 24 6 3 3 9.00-8.96 (m, 1H), 8.65-8.61 (m, 1H), 8.35-8.29 (m, 1H), 8.27-8.23 (m, 1H), 7.78-7.71 (m, 2H), 7.56-7.42 (m, 3H), 6.33-6.14 (m, 3H), 5.65-5.58 (m, 1H), 4.49-4.37 (m, 2H), 2.16-2.00 (m, 2H), 1.98-1.87 (m, 1H), 1.78-1.63 (m, 3H).
Example 193: 5-([1,1'-Biphenyl]yl)-N-((1R,2S)acrylamidocyclopentyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-([1,1'-biphenyl]- 3-yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 19) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 523.6; m/z found, 524.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.28-8.15 (m, 29 25 5 3 3 1H), 7.80-7.76 (m, 1H), 7.69-7.63 (m, 4H), 7.46-7.41 (m, 2H), 7.38-7.32 (m, 2H), 6.33-6.06 (m, 3H), 5.64-5.56 (m, 1H), 4.47-7.38 (m, 2H), 2.14-2.02 (m, 2H), 1.94-1.85 (m, 1H), 1.83-1.72 (m, 2H), 1.69-1.61 (m, 1H).
Example 194: N-((1R,2S)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 4-Oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-G , using 3-(2-pyridyl)aniline in place of 2-methylphenoxyaniline in step C.
Step B. N-((1R,2S)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, using 4-oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 524.6; m/z found, 525.5 [M+H] . H NMR 28 24 6 3 (400 MHz, CD OD): δ 8.69-8.52 (m, 1H), 8.23 (d, J = 5.5 Hz, 1H), 8.17-8.10 (m, 1H), 8.08-8.02 (m, 1H), 7.97-7.85 (m, 2H), 7.77-7.66 (m, 1H), 7.55-7.44 (m, 1H), 7.41- 7.30 (m, 1H), 6.44-6.09 (m, 3H), 5.70-5.48 (m, 1H), 4.50-4.32 (m, 2H), 2.16-1.99 (m, 2H), 1.94-1.85 (m, 1H), 1.81-1.55 (m, 3H).
Example 195: N-((1R,3R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,3R)aminocyclohexyl]carbamate, in Step A, and acetic anhydride in Step B. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.2 [M+H] . 29 5 4 Example 196: N-((1R,3S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 553.6; m/z found, 554.5 [M+H] . H NMR (400 MHz, CD OD): δ 8.30 (d, J = 27 5 4 3 .1 Hz, 1H), 7.51-7.36 (m, 2H), 7.33-7.25 (m, 1H), 7.22-7.14 (m, 1H), 7.13-7.03 (m, 3H), 7.00- 6.94 (m, 1H), 6.31-6.19 (m, 2H), 6.04 (d, J = 4.9 Hz, 1H), 5.73-5.59 (m, 1H), 4.48-4.33 (m, 1H), 4.29-4.12 (m, 1H), 2.57-2.42 (m, 1H), 2.12(s, 3H), 2.09-1.96 (m, 2H), 1.88-1.70 (m, 2H), 1.68- 1.54 (m, 1H).
Example 197: N-((1R,2R)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(2- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and tert-butyl N-[(1R,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 524.6; m/z found, 525.4 [M+H] . H NMR (400 MHz, CD OD): δ 8.85 28 24 6 3 3 (d, J = 5.3 Hz, 1H), 8.32 (d, J = 5.6 Hz, 1H), 8.08-8.00 (m, 3H), 7.54-7.41 (m, 4H), 6.30 (d, J = .6 Hz, 1H), 6.24-6.18 (m, 2H), 5.68-5.58 (m, 1H), 4.35-4.17 (m, 2H), 2.26-2.08 (m, 2H), 1.91- 1.75 (m, 2H), 1.73-1.47 (m, 2H).
Example 198: N-((1S,3R)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(2- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and tert-butyl N-[(1R,3S)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 524.6; m/z found, 525.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.88- 28 24 6 3 3 8.82 (m, 1H), 8.33-8.27 (m, 1H), 8.05-7.99 (m, 3H), 7.50-7.42 (m, 4H), 6.30-6.26 (m, 1H), 6.26- 6.21 (m, 2H), 5.66-5.60 (m, 1H), 4.39-4.30 (m, 1H), 4.23-4.14 (m, 1H), 2.51-2.42 (m, 1H), 2.08- 2.96 (m, 2H), 1.84-1.71 (m, 2H), 1.65-1.57 (m, 1H).
Example 199: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 3-(3-Methylnitrophenoxy)pyridine. The title compound was prepared using analogous conditions described in Intermediate 1, Step A, using 4-fluoromethylnitrobenzene and pyridinol. MS (ESI): mass calcd. for C12H10N2O3, 230.07; m/z found, 231.1 [M+H] .
Step B. 5-(2-Methyl(pyridinyloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 25, Steps B-C, using 3-(3-methylnitrophenoxy)pyridine. In an alternate method, Intermediate 1, Step B is used. MS (ESI): mass calcd. for C H N O S, 418.07, m/z 21 14 4 4 found, 419.0 [M+H] .
Step C. N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)phenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl(pyridinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and N-[(1S,2R)aminocyclopentyl]propenamide (Intermediate 36) in Step A (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.3 [M+H] . H 29 26 6 4 NMR (400 MHz, CD OD): δ 8.55 (s, 1H), 8.50-8.41 (m, 1H), 8.33 (d, J = 5.5 Hz, 1H), 7.91-7.84 (m, 1H), 7.77-7.66 (m, 1H), 7.47-7.38 (m, 1H), 7.29-7.20 (m, 1H), 7.19-7.12 (m, 1H), 34-6.1623 ( m, 2H), 6.15-6.06 (m, 1H), 5.68-5.57 (m, 1H), 4.49-4.35 (m, 2H), 2.20-2.15 (m, 3H), 2.14 -2.03 (m, 2H), 1.97-1.87 (m, 1H), 1.82-1.63 (m, 3H).
Example 200: N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1R,2R)aminocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2R) aminocyclopentyl]carbamate.
Step B. N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 166, Step C. MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.2 [M+H] . H NMR (400 MHz, CDCl ): δ 8.34 (d, J = 5.4 29 26 6 4 3 Hz, 1H), 8.05 (s, 1H), 7.48 – 7.36 (m, 2H), 7.29 – 7.14 (m, 3H), 7.06 (d, J = 5.6 Hz, 1H), 6.95 (s, 1H), 6.87 (d, J = 5.9 Hz, 1H), 6.29 (ddd, J = 17.0, 3.1, 1.6 Hz, 1H), 6.11 – 5.97 (m, 2H), 5.61 (dd, J = 10.2, 1.6 Hz, 1H), 4.26 – 4.07 (m, 3H), 2.39 – 2.18 (m, 5H), 2.04 (s, 1H), 1.81 (ddd, J = .4, 10.7, 6.7 Hz, 2H), 1.50 (dq, J = 12.6, 9.5 Hz, 1H).
Example 201: N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenoxypyrazinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 4-Oxo(5-phenoxypyrazinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 13, using 5-bromopyrazinamine and phenol in Step A.
Step B. N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenoxypyrazinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo(5-phenoxypyrazinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and N-[(1S,2R) aminocyclopentyl]propenamide (Intermediate 36) (no deprotection HCl/MeOH). MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.1 [M+H] . H NMR (400 MHz, DMSO- 27 23 7 4 d ): δ 10.20 (s, 1H), 8.66-8.59 (m, 1H), 8.45-8.39 (m, 1H), 8.34 (d, J = 5.5 Hz, 1H), 7.94-7.85 (m, 1H), 7.83-7.74 (m, 1H), 7.56-7.42 (m, 2H), 7.36- 7.23 (m, 3H), 6.35 (d, J = 5.5 Hz, 1H), 6.29-6.15 (m, 1H), 6.13-5.98 (m, 1H), 5.61-5.48 (m, 1H), 4.34-4.20 (m, 2H), 2.00-1.84 (m, 2H), 1.82-1.69 (m, 2H), 1.67-1.58 (m, 1H), 1.56-1.47 (m, 1H).
Example 202: N-((1R,2S)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH Step A. 4-Oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-F, using 3-(3-pyridyl)aniline and 2-chloroiodopyridinecarbonitrile, and substituting Cs2CO3 for K PO in Step C.
Step B. N-((1R,2S)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid and N-[(1S,2R)aminocyclopentyl]prop enamide (Intermediate 36) (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 524.6; m/z found, 525.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.90-8.83 (m, 28 24 6 3 3 1H), 8.57-8.52 (m, 1H), 8.33-8.26 (m, 1H), 8.18-8.12 (m, 1H), 7.90-7.83 (m, 1H), 7.81-7.72 (m, 2H), 7.56-7.44 (m, 2H), 6.35-6.14(m, 3H), 5.66-5.56 (m, 1H), 4.47-4.34 (m, 2H), 2.20-2.00 (m, 2H), 1.96-1.84 (m, 1H), 1.82-1.60 (m, 3H).
Example 203: N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenylpyridazinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 6-Phenylpyridazinamine. The title compound was prepared in manner analogous to Intermediate 20, Step A, using 6-chloropyridazinamine and phenyl boronic acid and substituting Pd(dppf) Cl2 for Pd(PPh3)4.
Step B. 4-Oxo(6-phenylpyridazinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-F, using 6-phenylpyridazinamine and 2-chloroiodopyridinecarbonitrile in Step Step C. N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenylpyridazinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, using 4-oxo(6-phenylpyridazinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid and tert-butyl N-[(1S,2R) aminocyclopentyl]carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 525.6; m/z 27 23 7 3 found, 526.5 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.28 (s, 1H), 9.39 (s, 1H), 8.55 (s, 1H), 8.40-8.30 (m, 1H), 8.20-8.16 (m, 2H), 7.92-7.83 (m, 1H), 7.82-7.75 (m, 1H), 7.60-7.55 (m, 3H), 6.48-6.41 (m, 1H), 6.27-6.18 (m, 1H), 6.09-6.02 (m, 1H), 5.60-5.51 (m, 1H), 4.33-4.24 (m, 2H), 1.98-1.86 (m, 2H), 1.82-1.70 (m, 2H), 1.68-1.49 (m, 2H).
Example 204: N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-cyclobutoxymethylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC (Stationary phase: Chiralpak AS-H 5µm 250*20mm, Mobile phase: 70% CO2, 30% MeOH) of N-((1R,2S)Acrylamidocyclohexyl)(6-cyclobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 187) afforded the title compound. MS (ESI): mass calcd. for C H N O S, 546.7; m/z found, 547.2 [M+H] . H 28 30 6 4 NMR (400 MHz, CD OD): δ 8.30 (d, J = 5.1 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 6.42 (dd, J = 17.0, 10.2 Hz, 1H), 6.26 (d, J = 17.0 Hz, 1H), 6.05 (d, J = 5.2 Hz, 1H), .66 (d, J = 10.2 Hz, 1H), 5.28 – 5.14 (m, 1H), 4.42 (s, 1H), 4.22 – 4.11 (m, 1H), 2.54 – 2.44 (m, 2H), 2.24 (s, 3H), 2.19 – 2.07 (m, 2H), 1.91 – 1.60 (m, 8H), 1.59 – 1.45 (m, 2H).
Example 205: N-((1R,2S)Acrylamidocyclopentyl)(4-isopropoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4- isopropoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 7) and N-[(1S,2R)aminocyclopentyl]propenamide (Intermediate 36), no deprotection step with HCl. MS (ESI): mass calcd. for C26H27N5O4S, 505.6; m/z found, 506.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.27 (d, J = 5.6 Hz, 1H), 7.36-7.23 (m, 2H), 7.17-7.03 (m, 2H), 6.35-6.15 (m, 2H), 6.12 (d, J = 5.6 Hz, 1H), 5.66-5.57 (m, 1H), 4.74-4.62 (m, 1H), 4.50-4.32 (m, 2H), 2.18-2.01 (m, 2H), 1.96-1.85 (m, 1H), 1.8-1.57 (m, 3H), 1.38-1.33 (m, 6H).
Example 206: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((tetrahydro-2H-pyran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl ((tetrahydro-2H-pyranyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Intermediate 12) and tert-butyl N-[(1S,2R) aminocyclopentyl]carbamate in step A. MS (ESI): mass calcd. for C H N O S, 561.7; m/z 29 31 5 5 found, 562.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.29-8.23 (m, 1H), 7.24-7.16 (m, 1H), 7.06-7.00 (m, 1H), 6.99-6.93 (m, 1H), 6.32-6.14 (m, 2H), 6.02-5.96 (m, 1H), 5.63-5.56 (m, 1H), 4.68-4.56 (m, 1H), 4.46-4.33 (m, 2H), 3.99-3.89 (m, 2H), 3.66-3.54 (m, 2H), 2.18-1.98 (m, 7H), 1.96-1.83 (m, 1H), 1.81-1.61 (m, 5H) Example 207: N-((1R,2S)Acrylamidocyclopentyl)(2-isopropylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2- isopropylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 16) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 490.6; m/z found, 491.2 [M+H] . H NMR (400 MHz, CD OD): δ 26 6 3 3 8.65 (d, J = 5.3 Hz, 1H), 8.16-8.02 (m, 1H), 7.48-7.38 (m, 1H), 7.35-7.28 (m, 1H), 6.37-7.24 (m, 1H), 6.22-6.10 (m, 1H), 6.00 (d, J = 5.5 Hz, 1H), 5.62-5.51(m, 1H), 4.57-4.47 (m, 1H), 4.44-4.33 (m, 1H), 3.21-3.09 (m, 1H), 2.12-1.97 (m, 2H), 1.92-1.74 (m, 3H), 1.670-1.57 (m, 1H), 1.35 (d, J = 6.9 Hz, 6H).
Example 208: N-((1R,3S)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(2- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and tert-butyl N-[(1S,3R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 524.6; m/z found, 525.2 [M+H] . H NMR (400 MHz, CD OD): δ 28 24 6 3 3 8.90-8.82 (m, 1H), 8.37-8.28 (m, 1H), 8.07-8.00 (m, 3H), 7.52-7.43 (m, 4H), 6.33-6.28 (m, 1H), 6.27-6.20 (m, 2H), 5.68-5.60 (m, 1H), 4.41-4.29 (m, 1H), 4.24-4.14 (m, 1H), 2.53-2.43 (m, 1H), 2.09-1.96 (m, 2H), 1.87-1.73 (m, 2H), 1.65-1.56 (m, 1H).
Example 209: N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isopropoxymethylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC purification (Stationary phase: Chiralpak AS-H 5µm 250*20mm, Mobile phase: 70% CO2, 30% MeOH) of N-((1R,2S)Acrylamidocyclohexyl)(6-isopropoxymethylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 211) afforded the title compound. MS (ESI): mass calcd. for C H N O S, 534.6; m/z found, 535.2 27 30 6 4 [M+H] . H NMR (500 MHz, CD OD): δ 8.31 (d, J = 4.5 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H), 6.42 (dd, J = 17.0, 10.2 Hz, 1H), 6.30 – 6.24 (m, 1H), 6.12 – 6.02 (m, 1H), 5.67 (dd, J = 10.3, 1.6 Hz, 1H), 5.40 – 5.29 (m, 1H), 4.43 (s, 1H), 4.23 – 4.10 (m, 1H), 2.26 (s, 3H), 1.86 – 1.61 (m, 6H), 1.59 – 1.47 (m, 2H), 1.37 (dd, J = 6.1, 2.8 Hz, 6H).
Example 210: N-((1R,2S)(3-Chloropropanamido)cyclopentyl)(*S)-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, Step A, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and N-[(1S,2R)aminocyclopentyl]chloropropanamide. MS (ESI): mass calcd. for C H ClN O S, 591.1; m/z found, 591.0 [M+H] . H NMR (400 MHz, CDCl ): d 29 27 6 4 3 9.65 (s, 1H), 8.35 (d, J = 5.5 Hz, 1H), 8.04 (d, J = 6.5 Hz, 3H), 7.44 (dd, J = 8.3, 7.1 Hz, 2H), 7.31 – 7.15 (m, 2H), 6.98 – 6.87 (m, 3H), 6.04 (d, J = 5.4 Hz, 1H), 4.38 (tt, J = 14.0, 6.7 Hz, 2H), 3.81 (qt, J = 10.6, 6.4 Hz, 2H), 2.68 (t, J = 6.4 Hz, 2H), 2.20 (s, 3H), 2.10 (dd, J = 13.9, 7.2 Hz, 1H), 1.90 – 1.65 (m, 4H).
Example 211: N-((1R,2S)Acrylamidocyclohexyl)(6-isopropoxymethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 5-(6-Isopropoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 24, using 6-fluoromethylpyridinamine, 2-propanol in Step A.
Step B. N-((1R,2S)Acrylamidocyclohexyl)(6-isopropoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 166, Step A, using and using N-[(1S,2R) aminocyclohexyl]propenamide (Intermediate 40) and 5-(6-isopropoxymethylpyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid. MS (ESI): mass H N O S, 534.6; m/z found, 535.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.33 calcd. for C27 30 6 4 3 (d, J = 5.5 Hz, 1H), 7.58 (dd, J = 8.6, 2.1 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H), 6.42 (dd, J = 17.0, .2 Hz, 1H), 6.31 – 6.23 (m, 1H), 6.09 (d, J = 5.4 Hz, 1H), 5.67 (dd, J = 10.2, 1.8 Hz, 1H), 5.41 – 5.29 (m, 1H), 4.44 (s, 1H), 4.17 (d, J = 8.1 Hz, 1H), 2.26 (s, 3H), 1.88 – 1.46 (m, 8H), 1.37 (dd, J = 6.2, 2.2 Hz, 6H).
Example 212: N-((1R,3R)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(2- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and tert-butyl N-[(1R,3R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 524.6; m/z found, 525.1 [M+H] . H NMR (400 MHz, CD OD): δ 28 24 6 3 3 8.87-8.79 (m, 1H), 8.27-8.19 (m, 1H), 8.05-8.00 (m, 2H), 8.00-7.95 (m, 1H), 7.52-7.43 (m, 4H), 6.27-6.16 (m, 3H), 5.68-5.59 (m, 1H), 4.55-4.46 (m, 1H), 4.44-4.36 (m, 1H), 2.26-2.15 (m, 2H), 2.06-1.94 (m, 2H), 1.76-1.65 (m, 1H), 1.61-1.52 (m, 1H).
Example 213: N-((1R,2R)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 568.7; m/z found, 569.0 [M+H] . H NMR (500 MHz, CDCl ): δ 9.73 (s, 1H), 28 6 4 3 8.33 (d, J = 5.4 Hz, 1H), 8.04 (s, 1H), 7.47 – 7.39 (m, 2H), 7.28 – 7.14 (m, 3H), 6.95 (s, 1H), 6.75 (d, J = 7.3 Hz, 1H), 6.56 – 6.49 (m, 1H), 6.28 (dd, J = 17.0, 1.5 Hz, 1H), 6.09 – 5.98 (m, 2H), 5.59 (dd, J = 10.3, 1.5 Hz, 1H), 3.96 – 3.77 (m, 2H), 2.20 (s, 3H), 2.04 (s, 2H), 1.83 – 1.76 (m, 2H), 1.45 – 1.21 (m, 4H).
Example 214: N-((1RS,3RS)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a cooled solution, 0 °C, of 4-oxo(5-phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Intermediate 26, 911.4 mg, 2.25 mmol), N-[(1RS,3RS)- 3-aminocyclopentyl]propenamide (382.3 mg, 2.48 mmol), and diisopropylethylamine (1.9 mL) in DMF (10 mL) was added propylphosphonic anhydride ((T3P®), 50 wt. % in ethyl acetate, 2 mL, 9.29 mmol) dropwise. Upon completion by LCMS, the reaction mixture was partitioned with EtOAc and sat. aq. NaHCO . The organics were dried (Na SO ), filtered, and 3 2 4 concentrated under reduced pressure. The resulting crude title compound was triturated with DCM to provide the title compound as a white solid. Chiral SFC (Stationary phase: Chiralpak IA 5µm 250*20mm, Mobile phase: 55% CO , 45% iPrOH) afforded the title compound, N- ((1S,3R)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 313) and N-((1*R,3*S) Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 328). MS (ESI): mass calcd. for C H N O S, 28 24 6 4 540.6; m/z found, 541.0 [M+H] .
Example 215: N-((1R,3R)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31, including CHIRAL SEPARATION METHOD 1 to obtain the *R atropisomer) and tert-butyl N-[(1R,3R)(propenoylamino)cyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 533.6; m/z found, 534.5 [M+H] . H NMR (400 MHz, CD OD): δ 8.31 (d, J = 28 31 5 4 3 5.6 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 6.99-6.95 (m, 1H), 6.94-6.88 (m, 1H), 6.41-6.31 (m, 1H), 6.27-6.18 (m, 1H), 6.06 – 6.00 (m, 1H), 5.70-5.62 (m, 1H), 4.71-4.60 (m, 1H), 4.26 – 4.10 (m, 2H), 2.11 (s, 3H), 1.98 – 1.75 (m, 3H), 1.75 – 1.50 (m, 5H), 1.34 (d, J = 6.0 Hz, 6H).
Example 216: N-((1RS,3RS)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, using 4-oxo(5- phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 26) and tert-butyl N-[(1R,3R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.0 [M+H] . H NMR (400 MHz, DMSO-d ): δ 29 26 6 4 6 .23 (s, 1H), 8.50 - 8.28 (m, 2H), 8.03 (dd, J = 53.5, 7.6 Hz, 2H), 7.73 - 7.55 (m, 2H), 7.55 - 7.42 (m, 2H), 7.38 - 7.16 (m, 3H), 6.39 (dd, J = 17.1, 10.2 Hz, 1H), 6.21 (d, J = 5.5 Hz, 1H), 6.09 (dd, J = 17.1, 2.4 Hz, 1H), 5.57 (dd, J = 10.1, 2.4 Hz, 1H), 4.28 - 4.04 (m, 2H), 1.91 - 1.46 (m, 8H).
Example 217: N-((1R,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1R,3R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1R,3R)aminocyclopentyl]carbamate.
Step B. N-((1R,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 2- (dimethylamino)acetic acid, no deprotection step with HCl needed. MS (ESI): mass calcd. for C H N O S, 584.7; m/z found, 585.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.34-8.27 (m, 31 32 6 4 3 1H), 7.44-7.34 (m, 2H), 7.31-7.26 (m, 1H), 7.19-7.13 (m, 1H), 7.12-7.06 (m, 2H), 7.06-7.03 (m, 1H), 6.99-6.94 (m, 1H), 6.09-6.01 (m, 1H), 4.54-4.43 (m, 1H), 4.40-4.30 (m, 1H), 3.03-2.94 (m, 2H), 2.30 (s, 6H), 2.22-2.14 (m, 2H), 2.11 (s, 3H), 2.03-1.89 (m, 2H), 1.71-1.61 (m, 1H), 1.60- 1.50 (m, 1H).
Example 218: N-((1R,2R)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
NN NH The title compound was prepared in a manner analogous to Example 166, using 4-oxo(5- phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 26) and tert-butyl N-[(1R,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.1 [M+H] . H NMR (500 MHz, CDCl ): δ 9.51 29 26 6 4 3 (s, 1H), 8.45 - 8.31 (m, 2H), 7.51 - 7.33 (m, 4H), 7.26 - 7.19 (m, 1H), 7.18 - 7.08 (m, 2H), 6.52 (d, J = 7.2 Hz, 1H), 6.33 - 6.13 (m, 3H), 6.10 - 5.99 (m, 1H), 5.62 (dd, J = 10.3, 1.4 Hz, 1H), 3.96 - 3.73 (m, 2H), 2.31 - 2.06 (m, 2H), 1.89 - 1.77 (m, 2H), 1.46 - 1.24 (m, 4H).
Example 219: N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyrimidin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyrimidinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 13, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer and tert-butyl N-[(1R,2R)aminocyclopentyl]carbamate, and substituting diisopropylethylamine for trimethylamine. MS (ESI): mass calcd. for C H N O S, 555.6; m/z 28 25 7 4 found, 556.0 [M+H] . H NMR (600 MHz, CD OD): δ 8.54 – 8.53 (s, 1H), 8.38 – 8.36 (d, J = .6 Hz, 1H), 7.48 – 7.43 (m, 2H), 7.31 – 7.22 (m, 3H), 6.31 – 6.27 (d, J = 5.5 Hz, 1H), 6.25 – 6.20 (m, 2H), 5.66 – 5.62 (m, 1H), 4.32 – 4.19 (m, 2H), 2.35 – 2.31 (s, 3H), 2.22 – 2.10 (m, 2H), 1.88 – 1.77 (m, 2H), 1.72 – 1.56 (m, 2H).
Example 220: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 5-(2-Methyl(pyridinyloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps A, and C-F, using 2-fluoropyridine and 4-amino methylphenol in place of 5-fluoronitrotoluene and phenol in Step A.
Step B. N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)phenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using N-[(1S,2R) aminocyclopentyl]propenamide (Intermediate 36) and 5-(2-methyl(pyridin yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.2 29 26 6 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.33 (d, J = 5.5 Hz, 1H), 8.21-8.13 (m, 1H), 7.92-7.81 (m, 1H), 7.43-7.31 (m, 1H), 7.25-7.20 (m, 1H), 7.19-7.11 (m, 2H), 7.09-7.04 (m, 1H), 6.33-6.16 (m, 3H), 5.67-5.55 (m, 1H), 4.48-4.35 (m, 2H), 2.20-2.14 (m, 3H), 2.13-2.01 (m, 2H), 1.97-1.87 (m, 1H), 1.83-1.61 (m, 3H).
Example 221: N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-cyclobutoxymethylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral separation of (chiral SFC (Stationary phase: Chiralpak AS-H 5µm 250*20mm, Mobile phase: 70% CO2, 30% MeOH) N-((1R,2S)Acrylamidocyclohexyl)(6-cyclobutoxy methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 183) provides the title compound. MS (ESI): mass calcd. for C H N O S, 546.7; m/z 28 30 6 4 found, 547.1 [M+H] . H NMR (500 MHz, CD OD): δ 8.31 (d, J = 5.5 Hz, 1H), 8.06 (s, 1H), 6.84 (s, 1H), 6.42 (dd, J = 17.0, 10.3 Hz, 1H), 6.26 (dd, J = 17.0, 1.7 Hz, 1H), 6.09 (d, J = 5.5 Hz, 1H), 5.67 (dd, J = 10.3, 1.7 Hz, 1H), 5.23 – 5.13 (m, 1H), 4.44 (s, 1H), 4.15 (d, J = 10.3 Hz, 1H), 2.53 – 2.45 (m, 2H), 2.22 – 2.10 (m, 5H), 1.90 – 1.61 (m, 8H), 1.59 – 1.46 (m, 2H).
Example 222: N-((1R,2S)Acrylamidocyclohexyl)(6-isopropoxymethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, Step A, using 5-(6- isopropoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 30) and N-[(1S,2R)aminocyclohexyl]propenamide (Intermediate 40). MS (ESI): mass calcd. for C H N O S, 534.6; m/z found, 535.2 [M+H] . 27 30 6 4 H NMR (500 MHz, CD OD): δ 8.33 (d, J = 5.6 Hz, 1H), 8.05 (d, J = 3.3 Hz, 1H), 6.81 (s, 1H), 6.42 (dd, J = 17.0, 10.2 Hz, 1H), 6.32 – 6.23 (m, 1H), 6.12 (d, J = 5.5 Hz, 1H), 5.70 – 5.64 (m, 1H), 5.34 – 5.26 (m, 1H), 4.44 (s, 1H), 4.22 – 4.13 (m, 1H), 2.14 (s, 3H), 1.86 – 1.61 (m, 6H), 1.59 – 1.46 (m, 2H), 1.36 (dd, J = 6.1, 3.8 Hz, 6H).
Example 223: N-((1R,2S)Acrylamidocyclohexyl)(6-(cyclopentyloxy)methylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, Step A, using 5-(6- (cyclopentyloxy)methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Intermediate 25) and N-[(1S,2R) aminocyclohexyl]propenamide (Intermediate 40). MS (ESI): mass calcd. for C H N O S, 29 32 6 4 560.7; m/z found, 561.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.33 (d, J = 5.4 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 6.83 (s, 1H), 6.47 – 6.38 (m, 1H), 6.33 – 6.24 (m, 1H), 6.11 (d, J = 5.3 Hz, 1H), 5.70 – 5.65 (m, 1H), 5.44 – 5.37 (m, 1H), 4.44 (s, 1H), 4.21 – 4.13 (m, 1H), 2.14 (s, 3H), 2.05 – 1.94 (m, 2H), 1.90 – 1.75 (m, 8H), 1.73 – 1.63 (m, 4H), 1.61 – 1.45 (m, 2H).
Example 224: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)phenyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using N- [(1S,2R)aminocyclopentyl]propenamide (Intermediate 36) and 5-(2-methyl(pyrimidin yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 15), no deprotection with HCl/MeOH. MS (ESI): mass calcd. for C H N O S, 28 25 7 4 555.6; m/z found, 556.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.69-8.58 (m, 2H), 8.39-8.25 (m, 1H), 7.45-7.36 (m, 1H), 7.33-7.19 (m, 3H), 6.37-6.14 (m, 3H), 5.64-5.56 (m, 1H), 4.48-4.40 (m, 2H), 2.21-2.14 (m, 3H), 2.13-2.01 (m, 2H), 1.96-1.87 (m, 1H), 1.85-1.70 (m, 2H), 1.68-1.58 (m, 1H).
Example 225: N-((1R,2S)Acrylamidocyclohexyl)(6-isobutoxymethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, Step A, using 5-(6- isobutoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 33) and N-[(1S,2R)aminocyclohexyl]propenamide (Intermediate 40). MS (ESI): mass calcd. for C H N O S, 548.7; m/z found, 549.1 [M+H] . 28 32 6 4 H NMR (400 MHz, CD OD): δ 8.33 (s, 1H), 8.06 (s, 1H), 6.90 (s, 1H), 6.48 – 6.37 (m, 1H), 6.32 – 6.24 (m, 1H), 6.12 (s, 1H), 5.67 (d, J = 10.5 Hz, 1H), 4.44 (s, 1H), 4.21 – 4.13 (m, 1H), 4.13 – 4.08 (m, 2H), 2.16 (s, 3H), 2.13 – 2.04 (m, 1H), 1.88 – 1.62 (m, 6H), 1.61 – 1.46 (m, 2H), 1.04 (d, J = 6.6 Hz, 6H).
Example 226: N-((1S,3S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,3S)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 553.6; m/z found, 554.5 [M+H] . 27 5 4 Example 227: N-((1R,2R)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH O HN The title compound was prepared in a manner analogous to Example 1, using 4-oxo(2- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and tert-butyl N-[(1R,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 538.6; m/z found, 539.1 [M+H] . H NMR (400 MHz, CD OD): δ 29 26 6 3 3 8.90-8.79 (m, 1H), 8.32-8.28 (m, 1H), 8.05-8.00 (m, 3H), 7.51-7.43 (m, 4H), 6.31-6.25 (m, 1H), 6.21-6.15 (m, 2H), 5.61-5.54 (m, 1H), 3.91-3.78 (m, 2H), 2.07-1.93 (m, 2H), 1.84-1.71 (m, 2H), 1.54-1.32 (m, 4H).
Example 228: N-((1R,3R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1R,3R)aminocyclopentyl]carbamate, in Step A, and acetic anhydride in Step B. MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.2 [M+H] . 29 27 5 4 H NMR (400 MHz, CD OD): δ 8.34-8.30 (m, 1H), 7.43-7.36 (m, 2H), 7.31-7.27 (m, 1H), 7.19- 7.14 (m, 1H), 7.11-7.06 (m, 2H), 7.06-7.03 (m, 1H), 6.98-6.94 (m, 1H), 6.08-6.05 (m, 1H), 4.52- 4.44 (m, 1H), 4.31-4.24 (m, 1H), 2.21-2.13 (m, 2H), 2.12 (s, 3H), 1.99-1.93 (m, 1H), 1.92 (s, 3H), 1.91-1.85 (m, 1H), 1.69-1.58 (m, 1H), 1.56-1.45 (m, 1H).
Example 229: 5-(2-Methylphenoxyphenyl)-N-((1R,3R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using N- ((1R,3R)aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 217, product from Step A) and 2-[tert- butoxycarbonyl(methyl)amino]acetic acid. MS (ESI): mass calcd. for C H N O S, 570.7; m/z 30 6 4 found, 571.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.31-8.24 (m, 1H), 7.43-7.35 (m, 2H), 7.31-7.23 (m, 1H), 7.18-7.13 (m, 1H), 7.11-7.06 (m, 2H), 7.06-7.03 (m, 1H), 6.98-6.94 (m, 1H), 6.05-5.99 (m, 1H), 4.52-4.44 (m, 1H), 4.38-4.30 (m, 1H), 3.26-3.23 (m, 2H), 2.40 (s, 3H), 2.23- 2.14 (m, 2H), 2.11 (s, 3H), 2.04-1.89 (m, 2H), 1.72-1.61 (m, 1H), 1.60-1.48 (m, 1H).
Example 230: N-((1S,3R)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,3S)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 513.6; m/z found, 514.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.45(s, 28 27 5 3 3 1H), 8.36-8.30 (m, 1H), 7.45-7.37 (m, 2H), 7.31-7.25 (m, 1H), 7.20-7.14 (m, 1H), 7.12-7.03 (m, 3H), 7.00-6.94 (m, 1H), 6.10-6.06 (m, 1H), 4.07-3.91 (m, 1H), 3.26-3.14 (m, 1H), 2.34-2.23 (m, 1H), 2.12 (s, 3H), 2.07-1.88 (m, 3H), 1.57-1.27 (m, 4H).
Example 231: N-((1S,3S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Steps A-B, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,3S)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 567.7; m/z found, 568.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.32 (d, J = 31 29 5 4 3 .6 Hz, 1H), 7.45-7.35 (m, 2H), 7.31-7.24 (m, 1H), 7.21-7.14 (m, 1H), 7.11-7.02 (m, 3H), 7.01- 6.92 (m, 1H), 6.39-6.18 (m, 2H), 6.06 (d, J = 5.6 Hz, 1H), 5.69-5.59 (m, 1H), 4.24-4.13 (m, 2H), 2.12 (s, 3H), 1.95-1.77 (m, 3H), 1.76-1.62 (m, 4H), 1.59-1.51 (m, 1H).
Example 232: N-((1R,3R)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(2- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and tert-butyl N-[(1R,3R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 538.6; m/z found, 539.4 [M+H] . H NMR (400 MHz, DMSO-d ): δ 29 26 6 3 6 .24 (s, 1H), 8.89 (d, J = 5.2 Hz, 1H), 8.32 (d, J = 5.5 Hz, 1H), 8.18- 7.93 (m, 5H), 7.54-7.44 (m, 4H), 6.42-6.31 (m, 1H), 6.21 (d, J = 5.5 Hz, 1H), 6.12-6.02 (m, 1H), 5.59-5.51 (m, 1H), 4.25-4.09(m, 2H), 1.82-1.41 (m, 8H).
Example 233: N-((1R,2R)Aminocyclopentyl)(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 166, Steps A-B, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and (1R,2R)-trans-N-Boc-1,2-cyclopentanediamine, in Step A. MS (ESI): mass calcd. for C H N O S, 500.6; m/z found, 501.1 [M+H] . H NMR (400 MHz, CDCl ): δ 8.31 26 24 6 3 3 (dt, J = 5.4, 1.3 Hz, 1H), 8.06 (s, 1H), 7.49 - 7.38 (m, 2H), 7.29 - 7.16 (m, 3H), 6.95 (s, 1H), 6.11 (d, J = 10.7 Hz, 1H), 6.01 (dd, J = 5.3, 1.4 Hz, 1H), 4.00 (p, J = 7.5 Hz, 1H), 3.46 (s, 4H), 3.18 (q, J = 7.7 Hz, 1H), 2.21 (s, 3H), 2.05 (dtd, J = 12.7, 7.7, 4.9 Hz, 1H), 1.76 (dddd, J = 20.6, 13.4, 9.5, 5.2 Hz, 2H), 1.60 - 1.38 (m, 2H).
Example 234: N-((1R,2S)Acrylamidocyclopentyl)oxo(4-((tetrahydro-2H-pyran yl)oxy)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methyl((tetrahydro-2H-pyranyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Intermediate 12) and N-[(1S,2R) aminocyclopentyl]propenamide (Intermediate 36) (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 547.6; m/z found, 548.5 [M+H] . 28 29 5 5 Example 235: N-((1R,3R)(2-Aminoacetamido)cyclopentyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using N- ((1R,3R)aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 217, product from Step A) and 2-(tert- butoxycarbonylamino)acetic acid. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 29 28 6 4 557.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.31-8.24 (m, 1H), 7.42-7.36 (m, 2H), 7.29- 7.25 (m, 1H), 7.18-7.13 (m, 1H), 7.11-7.06 (m, 2H), 7.06-7.03 (m, 1H), 6.98-6.95 (m, 1H), 6.06- .99 (m, 1H), 4.53-4.44 (m, 1H), 4.38-4.30 (m, 1H), 3.28-3.21 (m, 2H), 2.23-2.15 (m, 2H), 2.11 (s, 3H), 2.03-1.92 (m, 2H), 1.73-1.61 (m, 1H), 1.60-1.48 (m, 1H).
Example 236: N-((1R,3R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, Step A-B, using 4- oxo(5-phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 26) and tert-butyl N-[(1R,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, 500.4 [M+H] . H NMR (400 MHz, CD OD): δ 27 25 5 3 3 8.15-8.09 (m, 1H), 7.41-7.34 (m, 2H), 7.22-7.18 (m, 1H), 7.16-7.00 (m, 1H), 7.11-7.05 (m, 2H), 7.04-7.02 (m, 1H), 6.98-6.94 (m, 1H), 5.89-5.83 (m, 1H), 4.56-4.47 (m, 1H), 3.80-3.70 (m, 1H), 2.33-2.20 (m, 2H), 2.20-2.12 (m, 1H), 2.10 (s, 3H), 2.02-1.94 (m, 1H), 1.86-1.75 (m, 1H), 1.64- 1.53 (m, 1H).
Example 237: N-((1R,3S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and using tert-butyl N-[(1S,3R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C31H29N5O4S, 567.7; m/z found, 568.2 [M+H] . H NMR (400 MHz, CD3OD): δ 8.34-8.28 (m, 1H), 7.44-7.36 (m, 2H), 7.33-7.26 (m, 1H), 7.20-7.13 (m, 1H), 7.11-7.04 (m, 3H), 6.99-6.93 (m, 1H), 6.23-6.17 (m, 2H), 6.08-6.04 (m, 1H), 5.66-5.58 (m, 1H), 4.04-3.94 (m, 1H), 3.91-3.77 (m, 1H), 2.23-2.15 (m, 1H), 2.12 (s, 3H), 1.99-1.83 (m, 3H), 1.51-1.18 (m, 4H).
Example 238: N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-isopropoxymethylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC purification (Stationary phase: Chiralpak AS-H 5µm 250*20mm, Mobile phase: 70% CO2, 30% MeOH) of N-((1R,2S)Acrylamidocyclohexyl)(6-isopropoxymethylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 211) afforded the title compound. MS (ESI): mass calcd. for C H N O S, 534.6; m/z found, 535.2 27 30 6 4 [M+H] . H NMR (500 MHz, CD3OD): δ 8.32 (d, J = 5.5 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H), 6.42 (dd, J = 17.0, 10.3 Hz, 1H), 6.27 (dd, J = 17.0, 1.5 Hz, 1H), 6.08 (d, J = 5.4 Hz, 1H), 5.67 (dd, J = 10.3, 1.6 Hz, 1H), 5.39 – 5.30 (m, 1H), 4.42 (s, 1H), 4.17 (d, J = 10.2 Hz, 1H), 2.26 (s, 3H), 1.89 – 1.60 (m, 6H), 1.59 – 1.45 (m, 2H), 1.37 (dd, J = 6.1, 2.7 Hz, 6H).
Example 239: N-((1R,2R)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH O HN The title compound was prepared in a manner analogous to Example 166, using 4-oxo(6- phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 28) and tert-butyl N-[(1R,2R)aminocyclohexyl]carbamate in Step A. MS (ESI): mass calcd. for C29H26N6O4S, 554.6; m/z found, 555.2 [M+H] . H NMR (400 MHz, CDCl ): δ 9.73 (s, 1H), 8.30 (d, J = 4.8 Hz, 1H), 8.18 (d, J = 2.7 Hz, 1H), 7.75 (td, J = 8.6, 8.1, 3.1 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.20 (dd, J = 19.5, 7.6 Hz, 3H), 7.10 (d, J = 8.7 Hz, 1H), 7.04 – 6.92 (m, 2H), 6.24 (d, J = 17.1 Hz, 1H), 6.14 – 5.96 (m, 2H), 5.55 (dd, J = 10.0, 1.6 Hz, 1H), 4.11 (q, J = 7.1 Hz, 1H), 3.87 (dt, J = 22.2, 10.5 Hz, 2H), 2.52 (s, 1H), 2.20 (d, J = 12.0 Hz, 1H), 2.04 (s, 3H), 1.30 (dt, J = 36.2, 6.5 Hz, 2H).
Example 240: N-((1R,3S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,3R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, 500.4 [M+H] . H NMR (400 MHz, CD OD): δ 8.52 (s, 27 25 5 3 3 1H), 8.32 (d, J = 5.6 Hz, 1H), 7.49-7.36 (m, 2H), 7.33-7.25 (m, 1H), 7.23-7.14 (m, 1H), 7.14- 7.04 (m, 3H), 7.02-6.93 (m, 1H), 6.07 (d, J = 5.5 Hz, 1H), 4.37-4.20 (m, 1H), 3.74-3.60 (m, 1H), 2.64-2.49 (m, 1H), 2.23-1.98 (m, 6H), 1.97-1.70 (m, 2H).
Example 241: N-((1S,3S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,3S)aminocyclopentyl]carbamate in Step A, and acetic anhydride in Step B. MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.5 [M+H] . H NMR (400 29 27 5 4 MHz, CD OD): δ 8.32 (d, J = 5.1 Hz, 1H), 7.45-7.35 (m, 2H), 7.34-7.24 (m, 1H), 7.23-7.14 (m, 1H), 7.13 – 7.02 (m, 3H), 7.01-6.91 (m, 1H), 6.06 (d, J = 5.0 Hz, 1H), 4.55 – 4.40 (m, 1H), 4.35- 4.21 (m, 1H), 2.24-2.06 (m, 5H), 2.02 – 1.85 (m, 5H), 1.73-1.57 (m, 1H), 1.57-1.44 (m, 1H).
Example 242: N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-cyclobutoxymethylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC (Stationary phase: Chiralpak AS-H 5µm 250*20mm, Mobile phase: 70% CO , 30% MeOH) of N-((1R,2S)acrylamidocyclohexyl)(6-cyclobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 187) afforded the title compound. MS (ESI): mass calcd. for C H N O S, 546.7; m/z found, 547.2 [M+H] . H 28 30 6 4 NMR (500 MHz, CD OD): δ 8.31 (d, J = 5.2 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 6.42 (dd, J = 17.0, 10.2 Hz, 1H), 6.27 (dd, J = 17.0, 1.5 Hz, 1H), 6.07 (d, J = 5.0 Hz, 1H), 5.67 (dd, J = 10.3, 1.6 Hz, 1H), 5.26 – 5.14 (m, 1H), 4.42 (s, 1H), 4.17 (d, J = 9.3 Hz, 1H), 2.54 – 2.45 (m, 2H), 2.25 (s, 3H), 2.21 – 2.10 (m, 2H), 1.91 – 1.61 (m, 8H), 1.59 – 1.45 (m, 2H).
Example 243: N-((1S,3S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,3S)aminocyclohexyl]carbamate in Step A, and acetyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.2 [M+H] . H NMR (400 29 5 4 MHz, CD OD): δ 8.32 (d, J = 5.5 Hz, 1H), 7.44-7.35 (m, 2H), 7.32-7.26 (m, 1H), 7.20-7.14 (m, 1H), 7.11-7.03 (m, 3H), 7.00-6.93 (m, 1H), 6.07 (d, J = 5.6 Hz, 1H), 4.20-4.07 (m, 2H), 2.12 (s, 3H), 1.97 (s, 3H), 1.92-1.81 (m, 2H), 1.77-1.66 (m, 3H), 1.64-1.48 (m, 3H).
Example 244: N-((1R,3S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,3R)aminocyclopentyl]carbamate in Step A, and acetic anhydride in Step B. MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.5 [M+H] . H NMR (400 29 27 5 4 MHz, CD OD): δ 8.30 (d, J = 5.6 Hz, 1H), 7.48-7.36 (m, 2H), 7.33-7.25 (m, 1H), 7.22-7.14 (m, 1H), 7.13-7.03 (m, 3H), 7.00-6.92 (m, 1H), 6.05 (d, J = 5.6 Hz, 1H), 4.41-4.24 (m, 1H), 4.20- 4.04 (m, 1H), 2.54- 2.35 (m, 1H), 2.12 (s, 3H), 2.08-1.95 (m, 2H), 1.93 (s, 3H), 1.84-1.65 (m, 2H), 1.61-1.49 (m, 1H).
Example 245: N-((1S,3S)(2-(Dimethylamino)acetamido)cyclopentyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1S,3S)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(1S,3S) aminocyclopentyl]carbamate.
Step B. N-((1S,3S)(2-(Dimethylamino)acetamido)cyclopentyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using N-((1S,3S) aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide and 2-(dimethylamino)acetic acid. MS (ESI): mass calcd. for C H N O S, 584.7; m/z found, 585.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.41 (s, 31 32 6 4 3 1H), 8.32 (d, J = 5.5 Hz, 1H), 7.46-7.35 (m, 2H), 7.34-7.23 (m, 1H), 7.20-7.13 (m, 1H), 7.11 – 7.02 (m, 3H), 7.00-6.93 (m, 1H), 6.07 (d, J = 5.6 Hz, 1H), 4.58 – 4.43 (m, 1H), 4.43 – 4.30 (m, 1H), 3.48 (s, 2H), 2.64 (s, 6H), 2.26 – 2.14 (m, 2H), 2.12 (s, 3H), 2.05-1.89 (m, 2H), 1.75-1.46 (m, 2H).
Example 246: 5-(2-Methylphenoxyphenyl)-N-((1S,3S)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using N- ((1S,3S)aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 245, product from Step A) and 2-[tert- butoxycarbonyl(methyl)amino]acetic acid. MS (ESI): mass calcd. for C H N O S, 570.7; m/z 30 6 4 found, 571.5 [M+H] . H NMR (400 MHz, CD OD): δ 8.43 (s, 1H), 8.33 (d, J = 5.5 Hz, 1H), 7.45-7.35 (m, 2H), 7.34-7.25 (m, 1H), 7.23-7.12 (m, 1H), 7.10-7.01 (m, 3H), 7.00-6.92 (m, 1H), 6.07 (d, J = 5.6 Hz, 1H), 4.57 – 4.43 (m, 1H), 4.40 – 4.26 (m, 1H), 3.70 (s, 2H), 2.69 (s, 3H), 2.27 – 2.13 (m, 2H), 2.12 (s, 3H), 2.04-1.90 (m, 2H), 1.71 – 1.47 (m, 2H).
Example 247: N-((1S,3S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH O NH The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,3S)aminocyclohexyl]carbamate in place of tert-butyl ((1S,4S)aminocyclohexyl)carbamate in step G (400 mg). MS (ESI): mass calcd. for C H N O S, 513.6; m/z found, 514.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.03 (d, J = 28 27 5 3 3 .7 Hz, 1H), 7.42-7.33 (m, 2H), 7.19-7.11 (m, 2H), 7.10-7.06 (m, 2H), 7.05-7.00 (m, 1H), 6.97- 6.90 (m, 1H), 5.75 (d, J = 5.2 Hz, 1H), 4.36-4.27 (m, 1H), 3.23-3.13 (m, 1H), 2.11 (s, 3H), 2.02- 1.94 (m, 1H), 1.85-1.63 (m, 5H), 1.59-1.52 (m, 1H), 1.32-1.23 (m, 1H).
Example 248: 5-(3-Chlorophenoxyphenyl)-N-((1S,3R)((E)(dimethylamino)but enamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1S,3R)Aminocyclopentyl)(3-chlorophenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(3-chlorophenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 137, product from Step A) and tert- butyl N-[(1R,3S)aminocyclopentyl]carbamate.
Step B. 5-(3-Chlorophenoxyphenyl)-N-((1S,3R)((E)(dimethylamino)but enamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using N-((1S,3R)aminocyclopentyl)(3-chlorophenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide and (E)(dimethylamino)butenoic acid, no HCl/MeOH deprotection. MS (ESI): mass calcd. for C H ClN O S, 631.1; m/z found, 631.2 32 31 6 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.18-8.12 (m, 1H), 7.58-7.53 (m, 1H), 7.42-7.36 (m, 2H), 7.31-7.25 (m, 1H), 7.18-7.12 (m, 2H), 7.08-7.04 (m, 2H), 6.78-6.68 (m, 1H), 6.16-6.09 (m, 1H), 6.08-6.01 (m, 1H), 4.42-4.33 (m, 1H), 4.28-4.20 (m, 1H), 3.11-3.06 (m, 2H), 2.46-2.37 (m, 1H), 2.21 (s, 6H), 2.11-1.96 (m, 2H), 1.92-1.84 (m, 1H), 1.83-1.74 (m, 1H), 1.73-1.64 (m, 1H).
Example 249: 5-([1,1'-Biphenyl]yl)-N-((1R,2S)aminocyclopentyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-([1,1'- biphenyl]yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 19) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 469.6; m/z found, 470.4 [M+H] . H NMR (400 MHz, CD OD): δ 26 23 5 2 3 8.16-8.11 (mz, 1H), 7.79-7.74 (m, 1H), 7.68-7.63 (m, 3H), 7.62-7.57 (m, 1H), 7.46-7.41 (m, 2H), 7.38-7.29 (m, 2H), 6.05-6.01 (m, 1H), 4.52-4.44 (m, 1H), 3.62-3.56 (m, 1H), 2.18-2.08 (m, 2H), 1.97-1.81 (m, 2H), 1.77-1.61 (m, 2H).
Example 250: 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,3S)(2- (methylamino)acetamido)cyclohexyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide.
Step A. N-((1R,3S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,3R) aminocyclohexyl]carbamate.
Step B. 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,3S)(2- (methylamino)acetamido)cyclohexyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using N-((1R,3S)aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide and 2-[tert- butoxycarbonyl(methyl)amino]acetic acid. MS (ESI): mass calcd. for C H N O S, 584.7; m/z 31 32 6 4 found, 585.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.45 (s, 1H), 8.35-8.29 (m, 1H), 7.44- 7.35 (m, 2H), 7.31-7.24 (m, 1H), 7.20-7.13 (m, 1H), 7.11-7.04 (m, 3H), 6.99-6.93 (m, 1H), 6.10- 6.04 (m, 1H), 4.04-3.91 (m, 1H), 3.88-3.73 (m, 1H), 3.66 (s, 2H), 2.67 (s, 6H), 2.23-2.15 (m, 1H), 2.12 (s, 3H), 1.99-1.83 (m, 3H), 1.53-1.18 (m, 4H).
Example 251: N-((1R,3S)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using N- ((1R,3S)aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 250, product from Step A) and 2-(tert- butoxycarbonylamino)acetic acid. MS (ESI): mass calcd. for C H N O S, 570.7; m/z found, 30 6 4 571.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.38 (s, 1H), 8.34-8.30 (m, 1H), 7.43-7.36 (m, 2H), 7.31-7.25 (m, 1H), 7.20-7.13 (m, 1H), 7.10-7.03 (m, 3H), 6.99-6.93 (m, 1H), 6.10-6.05 (m, 1H), 4.05-3.90 (m, 1H), 3.88-3.75 (m, 1H), 3.60 (s, 2H), 2.22-2.15 (m, 1H), 2.12 (s, 3H), 1.98- 1.83 (m, 3H), 1.52-1.13 (m, 4H).
Example 252: N-((1R,3S)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using N- ((1R,3S)aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 250, product from Step A) and 2- (dimethylamino)acetic acid. MS (ESI): mass calcd. for C H N O S, 598.7; m/z found, 599.2 32 34 6 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.35 (s, 1H), 8.34-8.29 (m, 1H), 7.44-7.35 (m, 2H), 7.32-7.26 (m, 1H), 7.20-7.13 (m, 1H), 7.10-7.03 (m, 3H), 6.99-6.93 (m, 1H), 6.10-6.04 (m, 1H), 4.03-3.91 (m, 1H), 3.87-3.73 (m, 1H), 3.56 (s, 2H), 2.69 (s, 6H), 2.21-2.15 (m, 1H), 2.12 (s, 3H), 1.98-1.82 (m, 3H), 1.49-1.16 (m, 4H).
Example 253: N-((1R,3S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step B, using N- ((1R,3S)aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 250, product from Step A) and acetic anhydride. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.2 [M+H] . H NMR 29 5 4 (400 MHz, CD OD): δ 8.35-8.29 (m, 1H), 7.44-7.35 (m, 2H), 7.32-7.26 (m, 1H), 7.19-7.12 (m, 1H), 7.11-7.04 (m, 3H), 6.99-6.93 (m, 1H), 6.09-6.04 (m, 1H), 4.02-3.91 (m, 1H), 3.80-3.67 (m, 1H), 2.17-2.07 (m, 4H), 1.95-1.84 (m, 6H), 1.51-1.37 (m, 1H), 1.35-1.26 (m, 2H), 1.21-1.07 (m, 1H).
Example 254: N-((1R,2S)Aminocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, Steps A-B, using 5-(4- methylphenoxypyrimidinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 13, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,2R)aminocyclopentyl)carbamate in Step A. MS (ESI): mass calcd. for C25H23N7O3S, 501.6; m/z found, 502.0 [M+H] . H NMR (500 MHz, CD3OD): δ 8.57 (s, 1H), 8.51 (d, J = 5.9 Hz, 1H), 7.50 – 7.42 (m, 2H), 7.32 – 7.27 (m, 1H), 7.27 – 7.24 (m, 2H), 6.50 (d, J = 6.0 Hz, 1H), 4.50 (q, J = 6.6 Hz, 1H), 3.78 (q, J = 6.9 Hz, 1H), 2.34 (s, 3H), 2.23 – 2.13 (m, 2H), 2.05 – 1.91 (m, 2H), 1.84 – 1.72 (m, 2H).
Example 255: N-((1R,2R)Aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH O H N The title compound was prepared in a manner analogous to Example 166, Step A-B, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 514.6; m/z found, 515.1 [M+H] . H NMR (500 MHz, CDCl ): δ 8.19 27 26 6 3 3 (d, J = 5.3 Hz, 1H), 8.13 (s, 1H), 7.47 – 7.39 (m, 2H), 7.28 – 7.16 (m, 3H), 7.06 (s, 1H), 6.93 (s, 1H), 5.87 (s, 1H), 4.68 (s, 4H), 3.71 (d, J = 10.6 Hz, 1H), 3.46 (s, 2H), 2.74 (s, 1H), 2.21 (s, 3H), 2.07 (dd, J = 14.0, 10.0 Hz, 2H), 1.39 – 1.30 (m, 2H), 1.16 (s, 1H).
Example 256: N-((1R,2R)Aminocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, Steps A-B, using 5-(4- methylphenoxypyrimidinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 13, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2R)aminocyclopentyl]carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 501.6; m/z found, 502.0 [M+H] . H NMR (400 MHz, CD OD): δ 23 7 3 3 8.55 – 8.45 (m, 1H), 8.24 – 8.13 (m, 1H), 7.50 – 7.37 (m, 2H), 7.32 – 7.19 (m, 3H), 6.11 – 6.00 (m, 1H), 4.28 – 4.15 (m, 1H), 3.58 – 3.44 (m, 1H), 2.33 – 2.17 (m, 5H), 1.94 – 1.81 (m, 2H), 1.79 – 1.61 (m, 2H).
Example 257: N-((1R,2S)Aminocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (6-phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 28) and tert-butyl N-[(1S,2R)aminocyclohexyl]carbamate, and substituting diisopropylethylamine for triethylamine. MS (ESI): mass calcd. for C H N O S, 500.6; m/z 26 24 6 3 found, 501.1 [M+H] . H NMR (500 MHz, CDCl ): δ 8.26 (q, J = 5.9, 5.4 Hz, 3H), 8.15 (s, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.49 – 7.41 (m, 4H), 7.30 – 7.18 (m, 2H), 7.12 (dd, J = 15.5, 8.7 Hz, 2H), 6.45 (s, 2H), 6.12 – 6.04 (m, 2H), 3.21 (s, 1H), 1.73 – 1.37 (m, 4H), 1.21 (t, J = 7.0 Hz, 1H).
Example 258: N-((1S,2R)Acetamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(2- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and using tert-butyl N-[(1R,2S)aminocyclopentyl]carbamate in Step A, and acetic anhydride and DMAP in Step B. MS (ESI): mass calcd. for C H N O S, 512.6; m/z 27 24 6 3 found, 513.5 [M+H] . H NMR (400 MHz, CD OD): δ 8.86 (d, J = 5.1 Hz, 1H), 8.31 (d, J = 5.2 Hz, 1H), 8.14 – 7.95 (m, 3H), 7.60 – 7.38 (m, 4H), 6.30 (d, J = 5.6 Hz, 1H), 4.43-4.25 (m, 2H), 2.10 – 1.81 (m, 6H), 1.79 – 1.51 (m, 3H).
Example 259: N-((1S,3S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,3S)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C27H25N5O3S, 499.6; m/z found, 500.3 [M+H] . H NMR (400 MHz, CD3OD): δ 8.49 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 7.47-7.36 (m, 2H), 7.33-7.25 (m, 1H), 7.22-7.13 (m, 1H), 7.12- 7.03 (m, 3H), 7.02-6.92 (m, 1H), 6.08 (d, J = 5.5 Hz, 1H), 4.62-4.47 (m, 1H), 3.88 – 3.70 (m, 1H), 2.39 – 2.19 (m, 2H), 2.16 – 2.03 (m, 5H), 1.83 – 1.57 (m, 2H).
Example 260: N-((1R,2S)Aminocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(2- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and tert-butyl N-[(1S,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 484.6; m/z found, 485.2 [M+H] . H NMR (400 MHz, CD OD): δ 26 24 6 2 3 8.83-8.78 (m, 1H), 8.14-8.09 (m, 1H), 8.03-7.99 (m, 2H), 7.92-7.89 (m, 1H), 7.51-7.44 (m, 3H), 7.42-7.39 (m, 1H), 6.13-6.10 (m, 1H), 4.47-4.42 (m, 1H), 3.42-3.35 (m, 1H), 1.92-1.69 (m, 6H), 1.62-1.55 (m, 1H), 1.51-1.42 (m, 1H).
Example 261: N-((1R,3S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,3R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 513.6; m/z found, 514.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.47 (s, 28 27 5 3 3 1H), 8.36-8.30 (m, 1H), 7.43-7.36 (m, 2H), 7.30-7.24 (m, 1H), 7.20-7.13 (m, 1H), 7.10-7.03 (m, 3H), 6.99-6.93 (m, 1H), 6.11-6.04 (m, 1H), 4.05-3.93 (m, 1H), 3.25-3.16 (m, 1H), 2.33-2.23 (m, 1H), 2.12 (s, 3H), 2.06-1.91 (m, 3H), 1.57-1.31 (m, 4H).
Example 262: N-((1R,2S)Aminocyclopentyl)(*R)-(4-isopropoxymethylphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4- isopropoxymethylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 31, including CHIRAL SEPARATION METHOD 1 to obtain the *R atropisomer) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 465.6; m/z found, 466.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.46 24 27 5 3 3 (s, 1H), 8.33-8.29 (m, 1H), 7.24-7.18 (m, 1H), 7.00-6.89 (m, 2H), 6.06-6.01 (m, 1H), 4.71-4.61 (m, 1H), 4.51-4.42 (m, 1H), 3.80-3.70 (m, 1H), 2.22-2.09 (m, 2H), 2.04 (s, 3H), 2.01-1.85 (m, 2H), 1.83-1.65 (m, 2H), 1.38-1.31 (m, 6H).
Example 263: N-((1R,2S)Aminocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (2-phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 470.5; m/z found, 471.3 [M+H] . H NMR (400 MHz, CD OD): δ 8.81 22 6 2 3 (d, J = 5.3 Hz, 1H), 8.12 (d, J = 5.6 Hz, 1H), 8.07-7.96 (m, 2H), 7.94-7.89 (m, 1H), 7.55 – 7.36 (m, 4H), 6.11 (d, J = 5.7 Hz, 1H), 4.61-4.46 (m, 1H), 3.70-3.58 (m, 1H), 2.26 – 2.05 (m, 2H), 2.01 – 1.61 (m, 4H).
Example 264: N-((1R,2R)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31, including CHIRAL SEPARATION METHOD 1 to obtain the *R atropisomer) and tert-butyl N-[(1R,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for H N O S, 533.6; m/z found, 534.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.32-8.24 (m, C28 31 5 4 3 1H), 7.22-7.15 (m, 1H), 7.00-6.94 (m, 1H), 6.94-6.86 (m, 1H), 6.21-6.16 (m, 2H), 6.03-5.98 (m, 1H), 5.62-5.55 (m, 1H), 4.70-4.61 (m, 1H), 3.91-3.81 (m, 2H), 2.10 (s, 3H), 2.07-1.96 (m, 2H), 1.84-1.76 (m, 2H), 1.50-1.36 (m, 4H), 1.36-1.32 (m, 6H).
Example 265: N-((1R,2S)Aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using oxo(6- phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 28) and tert-butyl ((1S,2R)aminocyclopentyl)carbamate. MS ESI): mass calcd. for C H N O S, 486.6; m/z found, 486.9 [M+H] . H NMR (500 MHz, Chloroform-d) d 8.27 22 6 3 (s, 1H), 8.03 (s, 1H), 7.45 (td, J = 7.3, 1.6 Hz, 2H), 7.30 - 7.18 (m, 2H), 7.11 (d, J = 8.7 Hz, 2H), 6.82 - 6.56 (m, 3H), 6.12 (s, 1H), 4.16 (s, 2H), 3.52 - 3.44 (m, 2H), 1.84 - 1.61 (m, 4H), 1.56 - 1.46 (m, 2H).
Example 266: N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-cyclobutoxymethylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral separation of (chiral SFC (Stationary phase: Chiralpak AS-H 5µm 250*20mm, Mobile phase: 70% CO2, 30% MeOH) N-((1R,2S)Acrylamidocyclohexyl)(6-cyclobutoxy methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 183) provides the title compound. MS (ESI): mass calcd. for C28H30N6O4S, 546.7; m/z found, 547.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.32 (d, J = 5.5 Hz, 1H), 8.04 (s, 1H), 6.84 (s, 1H), 6.48 – 6.38 (m, 1H), 6.28 (dd, J = 17.0, 1.8 Hz, 1H), 6.09 (d, J = 5.5 Hz, 1H), 5.67 (dd, J = 10.2, 1.9 Hz, 1H), 5.25 – 5.12 (m, 1H), 4.47 – 4.37 (m, 1H), 4.17 (d, J = 10.3 Hz, 1H), 2.54 – 2.43 (m, 2H), 2.23 – 2.09 (m, 5H), 1.91 – 1.63 (m, 8H), 1.60 – 1.46 (m, 2H).
Example 267: N-((1R,2S)Aminocyclopentyl)oxo(4-phenylpyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (4-phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 21) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 470.5; m/z found, 471.1 [M+H] . H NMR (400 MHz, CD OD): δ 22 6 2 3 8.73-8.67 (m, 1H), 8.42(s, 1H), 8.36-8.29 (m, 1H), 7.93-7.87 (m, 2H), 7.85-7.78 (m, 2H), 7.56- 7.48 (m, 3H), 6.27-6.23 (m, 1H), 4.52-4.44 (m, 1H), 3.80-3.69 (m, 1H), 2.22-2.08 (m, 2H), 2.04- 1.85 (m, 2H), 1.81-1.68 (s, 2H).
Example 268: N-((1R,2R)Hydroxycyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using oxo(2- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and (1R,2R)aminocyclopentanol in place of tert-butyl ((1S,4S) aminocyclohexyl)carbamate in step G (91 mg). MS (ESI): mass calcd. for C25H21N5O3S, 471.5; m/z found, 472.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.90-8.79 (m, 1H), 8.36-8.24 (m, 1H), 8.07-7.98 (m, 3H), 7.51-7.41 (m, 4H), 6.32-6.22 (m, 1H), 4.16-4.07 (m, 2H), 2.18-2.07 (m, 1H), 2.04-1.94 (m, 1H), 1.82-1.70 (m, 2H), 1.66-1.54 (m, 2H).
Example 269: N-((1R,2R)Aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 1, Step A, using oxo(6- phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 28) and tert-butyl N-[(1R,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C25H22N6O3S, 486.6; m/z found, 487.1 [M+H] . H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 2.6 Hz, 1H), 7.70 (dd, J = 8.8, 2.7 Hz, 1H), 7.46 (t, J = 7.9 Hz, 2H), 7.32 – 7.17 (m, 3H), 7.11 (d, J = 8.7 Hz, 1H), 6.18 (d, J = 5.5 Hz, 1H), 3.96 (q, J = 8.1 Hz, 1H), 3.46 – 3.36 (m, 3H), 3.14 (q, J = 7.8 Hz, 1H), 2.82 – 2.75 (m, 5H), 1.78 (dt, J = 14.7, 7.6 Hz, 2H).
Example 270: N-((1R,2S)Aminocyclopentyl)(2-isopropylpyridinyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- isopropylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 16) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 436.5; m/z found, 437.1 [M+H] . 22 24 6 2 Example 271: N-((1R,2S)Aminocyclopentyl)(4-isopropoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4- isopropoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for H N O S, 451.5; m/z found, 452.4 [M+H] . H NMR (400 MHz, CD OD): δ 8.52 (s, 1H), C23 25 5 3 3 8.26 (d, J = 5.6 Hz, 1H), 7.35-7.22 (m, 2H), 7.14-7.02 (m, 2H), 6.10 (d, J = 5.6 Hz, 1H), 4.72- 4.65 (m, 1H), 4.53-4.42 (m, 1H), 3.79-3.64 (m, 1H), 2.23-2.09 (m, 2H), 2.05-1.82 (m, 2H), 1.81- 1.66 (m, 2H), 1.41-1.32 (m, 6H).
Example 272: N-((1S,2S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31, including CHIRAL SEPARATION METHOD 1 to obtain the *R atropisomer) and tert-butyl N-[(1S,2S)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for H N O S, 533.6; m/z found, 534.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.30-8.26 (m, C28 31 5 4 3 1H), 7.21-7.15 (m, 1H), 7.00-6.94 (m, 1H), 6.94-6.86 (m, 1H), 6.21-6.16 (m, 2H), 6.03-5.98 (m, 1H), 5.62-5.55 (m, 1H), 4.70-4.61 (m, 1H), 3.91-3.81 (m, 2H), 2.10 (s, 3H), 2.07-1.96 (m, 2H), 1.84-1.76 (m, 2H), 1.54-1.36 (m, 4H), 1.36-1.32 (m, 6H).
Example 273: N-((1R,2R)Acrylamidocyclohexyl)(*S)-(4-isopropoxymethylphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 533.6; m/z found, 534.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.30-8.24 (m, 28 31 5 4 3 1H), 7.20-7.15 (m, 1H), 7.00-6.94 (m, 1H), 6.94-6.86 (m, 1H), 6.21-6.16 (m, 2H), 6.03-5.98 (m, 1H), 5.62-5.55 (m, 1H), 4.72-4.59 (m, 1H), 3.93-3.82 (m, 2H), 2.11 (s, 3H), 2.07-1.94 (m, 2H), 1.84-1.74 (m, 2H), 1.54-1.36 (m, 4H), 1.36-1.32 (m, 6H).
Example 274: N-((1S, S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31, including CHIRAL SEPARATION METHOD 1 to obtain the *R atropisomer) and tert-butyl N-[(1S,3S)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 533.6; m/z found, 534.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.30 (d, J = 28 31 5 4 3 .6 Hz, 1H), 7.23-7.16 (m, 1H), 6.99-6.96 (m, 1H), 6.94-6.87 (m, 1H), 6.41-6.29 (m, 1H), 6.27- 6.18 (m, 1H), 6.02 (d, J = 5.6 Hz, 1H), 5.69-5.59 (m, 1H), 4.71-4.62 (m, 1H), 4.25-4.13 (m, 2H), 2.11 (s, 3H), 1.94-1.77 (m, 3H), 1.74-1.61 (m, 4H), 1.59-1.51 (m, 1H), 1.34 (d, J = 6.0 Hz, 6H).
Example 275: N-((1R,3S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: tert-Butyl N-[(1R,3S)(propenoylamino)cyclohexyl]carbamate. To a solution of tert-butyl N-[(1R,3S)aminocyclohexyl]carbamate (200 mg, 0.798 mmol) in DCM (50 mL) was added triethylamine (0.403 g, 3.99 mmol), followed by the addition of propenoyl chloride (0.0794 g, 0.877 mmol) in an ice-bath and the reaction was stirred at rt for 1 h. The reaction was concentrated to dryness and purified by flash column chromatography to give the title compound (155 mg, 72.4% yield) as a light yellow solid.
Step B. N-((1S,3R)aminocyclohexyl)acrylamide. The title compound was prepared in a manner analogous to Example 5, step B.
Step C: N-((1R,3S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, using 5-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31, including CHIRAL SEPARATION METHOD 1 to obtain the *R atropisomer) and using N-((1S,3R) aminocyclohexyl)acrylamide. MS (ESI): mass calcd. for C H N O S, 533.6; m/z found, 534.7 28 31 5 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.30 (d, J = 5.5 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.99-6.95 (m, 1H), 6.94-6.86 (m, 1H), 6.25 – 6.17 (m, 2H), 6.02 (d, J = 5.6 Hz, 1H), 5.67-5.57 (m, 1H), 4.71-4.60 (m, 1H), 4.05-3.92 (m, 1H), 3.91 – 3.78 (m, 1H), 2.21-2.13 (m, 1H), 2.11 (s, 3H), 1.99 – 1.80 (m, 3H), 1.56 – 1.36 (m, 2H), 1.34 (d, J = 6.0 Hz, 6H), 1.31-1.12 (m, 2H).
Example 276: N-((1R,3S)Acrylamidocyclopentyl)(*R)-(4-isopropoxymethylphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31, including CHIRAL SEPARATION METHOD 1 to obtain the *R atropisomer) and tert-butyl N-[(1S,3R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 519.6; m/z found, 520.4 [M+H] . H NMR (400 MHz, CD OD): δ 8.29 (d, J = 27 29 5 4 3 .6 Hz, 1H), 7.29-7.13 (m, 1H), 7.02-6.79 (m, 2H), 6.36-6.18 (m, 2H), 6.02 (d, J = 5.5 Hz, 1H), .71-5.59 (m, 1H), 4.74-4.57 (m, 1H), 4.45-4.30 (m, 1H), 4.25 -4.11 (m, 1H), 2.55-2.40 (m, 1H), 2.11 (s, 3H), 2.08-1.96 (m, 2H), 1.88- 1.69 (m, 2H), 1.69-1.53 (m, 1H), 1.40-1.30 (m, 6H).
Example 277: N-((1R,2R)Aminocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH O H N The title compound was prepared in a manner analogous to Example 166, Steps A-B, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27) and tert-butyl N-[(1R,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 500.6; m/z found, 501.1 [M+H] . H NMR (400 MHz, 26 24 6 3 CDCl ): δ 8.45 (d, J = 2.8 Hz, 1H), 8.21 (d, J = 2.7 Hz, 1H), 8.03 (dd, J = 8.7, 2.7 Hz, 1H), 7.95 (dd, J = 5.8, 2.5 Hz, 2H), 7.69 (dd, J = 9.0, 2.8 Hz, 1H), 7.45 (q, J = 7.2 Hz, 4H), 7.10 (d, J = 8.7 Hz, 1H), 6.04 (s, 1H), 6.00 - 5.92 (m, 1H), 5.80 (dd, J = 42.2, 5.5 Hz, 2H), 3.77 (qd, J = 11.4, .4, 3.7 Hz, 2H), 3.45 (s, 1H), 1.82 (dd, J = 23.7, 10.9 Hz, 2H), 1.40 - 1.15 (m, 4H).
Example 278: N-((1R,2S)Aminocyclopentyl)oxo(6-phenylpyridazinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (6-phenylpyridazinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 203, product from Step B) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 471.5; m/z found, 472.2 [M+H] . H NMR 24 21 7 2 (400 MHz, CD OD and DMSO-d ): δ 9.28 (d, J = 2.2 Hz, 1H), 8.45-8.38(m, 1H), 8.22-8.18 (m, 4H), 7.64-7.53 (m, 3H), 6.33- 6.23 (m, 1H), 4.42-4.36 (m, 1H), 3.62-3.56 (m, 1H), 2.12-1.97 (m, 2H), 1.90-1.77 (m, 2H), 1.75-1.56 (m, 2H).
Example 279: N-((1S,3S)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(2- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and tert-butyl N-[(1S,3S)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 538.6; m/z found, 539.2 [M+H] . H NMR (400 MHz, DMSO-d ): δ 29 26 6 3 6 .28 (s, 1H), 8.89 (d, J = 5.2 Hz, 1H), 8.38-8.28 (m, 1H), 8.17 (s, 1H), 8.14-8.07 (m, 3H), 8.02- 7.93 (m, 1H), 7.55-7.41 (m, 4H), 6.43-6.31 (m, 1H), 6.22 (d, J = 5.5 Hz, 1H), 6.12-6.03 (m, 1H), .61-5.51 (m, 1H), 4.21-4.08 (m, 2H), 1.82-1.59 (m, 5H), 1.53-1.36 (m, 3H).
Example 280: N-((1R,2S)Acetamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(2- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate in Step A, and substituting acetic anhydride for propenoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 512.6; m/z found, 513.4 [M+H] . H NMR (400 MHz, CD OD): δ 8.85 (d, J = 27 24 6 3 3 .3 Hz, 1H), 8.31 (d, J = 5.6 Hz, 1H), 8.07-8.00 m, 3H), 7.55-7.43 (m, 4H), 6.29 (d, J = 5.5 Hz, 1H), 4.42-4.28 (m, 2H), 2.11-1.96 (m, 2H), 1.94 (s, 3H), 1.92-1.82(m, 1H), 1.79-1.57 (m, 3H).
Example 281: N-((1R,2S)Aminocyclopentyl)oxo(6-phenylpyrimidinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (6-phenylpyrimidinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 23) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 471.5; m/z found, 472.2 [M+H] . H NMR (400 MHz, CD OD): δ 24 21 7 2 3 9.35-9.26 (m, 1H), 8.40-8.36 (m, 2H), 8.27-8.20 (m, 3H), 7.61-7.52 (m, 3H), 6.62-6.56 (m, 1H), 4.57-4.41 (m, 1H), 3.80-3.68 (m, 1H), 2.28-2.10 (m, 2H), 2.08-1.85 (m, 2H), 1.81-1.65 (m, 2H).
Example 282: N-((1S,3S)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(2- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and tert-butyl N-[(1S,3S)aminocyclopentyl]carbamate, in Step A, and acetic anhydride in Step B. MS (ESI): mass calcd. for C H N O S, 524.6; m/z found, 525.4 [M+H] . 28 24 6 3 H NMR (400 MHz, CD OD): δ 8.81 (d, J = 5.0 Hz, 1H), 8.26 (d, J = 5.4 Hz, 1H), 8.12 – 7.94 (m, 3H), 7.55-7.30 (m, 4H), 6.31-6.12(m, 3H), 5.72 – 5.48 (m, 1H), 4.53 – 4.23 (m, 2H), 2.23 – 2.07 (m, 2H), 2.07 – 1.79 (m, 2H), 1.71-1.41 (m, 2H).
Example 283: N-((1R,3S)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 4-oxo(2- phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and tert-butyl N-[(1S,3R)aminocyclohexyl]carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 538.6; m/z found, 539.2 [M+H] . H NMR (400 MHz, DMSO- 29 26 6 3 d ): δ 10.26 (s, 1H), 8.91-8.85 (m, 1H), 8.35-8.27 (m, 1H), 8.19-8.11 (m, 1H), 8.10-8.03 (m, 4H), 7.52-7.45 (m, 4H), 6.23-6.12 (m, 2H), 6.10-5.98 (m, 1H), 5.58-5.50 (m, 1H), 3.89-3.79 (m, 1H), 3.73-3.59 (m, 1H), 2.03-1.95 (m, 1H), 1.80-1.73 (m, 3H), 1.37-1.27 (m, 3H), 1.13-1.08 (m, 1H).
Example 284: N-((1R,2S)Aminocyclopentyl)oxo(5-phenylpyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (5-phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 22) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 470.5; m/z found, 471.1 [M+H] . H NMR (400 MHz, CD OD): δ 22 6 2 3 9.00-8.96 (m, 1H), 8.65-8.58 (m, 1H), 8.45-8.39 (m, 1H), 8.36-8.30 (m, 1H), 8.26-8.21 (m, 1H), 7.77-7.69 (m, 2H), 7.55-7.47 (m, 2H), 7.47-7.41 (m, 1H), 6.31-6.23 (m, 1H), 4.54-4.42 (m, 1H), 3.78-3.70 (m, 1H), 2.21-2.11 (m, 2H), 2.04-1.85 (m, 2H), 1.83-1.69 (m, 2H).
Example 285: N-((1R,2S)Aminocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (3-(pyridinyl)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 194, product from Step A) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate.
MS (ESI): mass calcd. for C H N O S, 470.5; m/z found, 471.4 [M+H] . H NMR (400 MHz, 22 6 2 CD OD): δ 8.65-8.57 (m, 1H), 8.20-8.07 (m, 2H), 8.04-7.98 (m, 1H), 7.96-7.84 (m, 2H), 7.77- 7.65 (m, 1H), 7.52-7.41 (m, 1H), 7.41-7.32 (m, 1H), 6.03 (d, J = 5.6 Hz, 1H), 4.55-4.44 (m, 1H), 3.71-3.56 (m, 1H), 2.22-2.06 (m, 2H), 1.97-1.82 (m, 2H), 1.80-1.62 (m, 2H).
Example 286: N-((1S,2R)(2-(Methylamino)acetamido)cyclopentyl)oxo(2-phenylpyridin- 4-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1S,2R)Aminocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and using tert-butyl N-[(1R,2S)- 2-aminocyclopentyl]carbamate.
Step B. N-((1S,2R)(2-(Methylamino)acetamido)cyclopentyl)oxo(2-phenylpyridinyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 2-[tert- butoxycarbonyl(methyl)amino]acetic acid and HATU, no deprotection HCl/MeOH. MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.5 [M+H] . H NMR (400 MHz, CD OD): δ 28 27 7 3 3 8.84 (d, J = 5.2 Hz, 1H), 8.41 (s, 1H), 8.27 (d, J = 5.6 Hz, 1H), 8.08 – 7.96 (m, 3H), 7.52-7.41 (m, 4H), 6.24 (d, J = 5.6 Hz, 1H), 4.50 – 4.36 (m, 2H), 3.75 (s, 2H), 2.65 (s, 3H), 2.16 – 1.96 (m, 2H), 1.95-1.82 (m, 1H), 1.80-1.58 (m, 3H).
Example 287: N-((1R,2S)Aminocyclopentyl)(2-methyl((tetrahydro-2H-pyran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methyl((tetrahydro-2H-pyranyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Intermediate 12) and tert-butyl N-[(1S,2R) aminocyclopentyl]carbamate in place of tert-butyl ((1S,4S)aminocyclohexyl)carbamate. MS (ESI): mass calcd. for C H N O S, 507.6; m/z found, 508.2 [M+H] . H NMR (400 MHz, 26 29 5 4 CD OD): δ 8.50 (s, 1H), 8.33-8.27 (m, 1H), 7.25-7.15 (m, 1H), 7.06-6.94 (m, 2H), 6.04-5.99 (m, 1H), 4.70-4.60 (m, 1H), 4.52-4.41 (m, 1H), 4.01-3.90 (m, 2H), 3.79-3.69 (m, 1H), 3.65-3.56 (m, 2H), 2.19-2.02 (m, 7H), 2.01-1.86 (m, 2H), 1.81-1.66 (m, 4H).
Example 288: N-((1R,2S)Aminocyclopentyl)oxo(4-((tetrahydro-2H-pyran yl)oxy)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
NH R The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methyl((tetrahydro-2H-pyranyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Intermediate 12) and tert-butyl N-[(1S,2R) aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 493.6; m/z found, 494.4 27 5 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.46 (s, 1H), 8.29 (d, J = 5.6 Hz, 1H), 7.37 – 7.21 (m, 2H), 7.19-7.12 (m, 2H), 6.14 (d, J = 5.6 Hz, 1H), 4.71-4.60 (m, 1H), 4.52-4.41 (m, 1H), 4.04 – 3.90 (m, 2H), 3.80-3.68 (m, 1H), 3.67-3.52 (m, 2H), 2.25 – 2.02 (m, 4H), 2.02 – 1.84 (m, 2H), 1.81 – 1.63 (m, 4H).
Example 289: racemic cis N-((1RS,3RS)Aminocyclopentyl)oxo(6-phenoxypyridin yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Steps A-B, using 4- oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 10) and racemic tert-butyl ((1S,3R)aminocyclopentyl)carbamate. MS (ESI): mass calcd. for C H N O S, 486.6; m/z found, 486.9 [M+H] . H NMR (500 MHz, 22 6 3 CDCl ): δ 8.31 (d, J = 5.5 Hz, 1H), 8.22 – 8.16 (m, 1H), 7.85 – 7.79 (m, 1H), 7.71 (t, J = 6.4 Hz, 1H), 7.48 – 7.40 (m, 2H), 7.29 – 7.17 (m, 3H), 7.10 (dd, J = 8.7, 0.7 Hz, 1H), 6.12 (d, J = 5.5 Hz, 1H), 4.55 (q, J = 7.1 Hz, 1H), 3.94 (s, 3H), 3.75 (tt, J = 5.5, 2.2 Hz, 2H), 3.48 (s, 1H), 2.11 – 1.89 (m, 4H).
Example 290: racemic trans N-((1RS,3RS)Aminocyclopentyl)oxo(6-phenoxypyridin yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 104, Steps A-B, using 4- oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 10) and racemic tert-butyl N-[(1R,3R)aminocyclopentyl]carbamate.
MS (ESI): mass calcd. for C H N O S, 486.6; m/z found, 486.9 [M+H] . H NMR (500 MHz, 22 6 3 CDCl ): δ 8.33 (d, J = 5.5 Hz, 1H), 8.18 (q, J = 2.8, 2.3 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.46 (t, J = 7.9 Hz, 2H), 7.29 (d, J = 7.4 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.7 Hz, 1H), 6.17 (d, J = 5.6 Hz, 1H), 4.52 (p, J = 7.1 Hz, 1H), 3.84 – 3.68 (m, 5H), 2.28 (dq, J = 18.3, 7.2 Hz, 2H), 2.19 – 2.04 (m, 2H), 1.71 (tt, J = 13.1, 4.7 Hz, 2H).
Example 291: N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1R,2S)aminocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 166, Steps A-B, using 4-oxo(5-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 26) and using tert-butyl ((1S,2R)aminocyclohexyl)carbamate.
Step B. N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 337 using N-((1R,2S)aminocyclohexyl)oxo(5-phenoxypyridin yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.1 [M+H] . H NMR (400 MHz, CDCl ): δ 9.48 (s, 1H), 29 26 6 4 3 8.47 - 8.33 (m, 2H), 7.58 - 7.35 (m, 4H), 7.25 - 7.21 (m, 1H), 7.20 - 6.90 (m, 2H), 6.48 - 6.06 (m, 4H), 5.73 (dd, J = 10.3, 1.4 Hz, 1H), 4.38 - 4.10 (m, 2H), 1.97 - 1.47 (m, 9H).
Example 292: N-((1RS,2RS)Acrylamidocyclopentyl)(2-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 337, using racemic trans N- ((1RS,3RS)aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 290). MS (ESI): mass calcd. for C H N O S, 29 26 6 4 554.6; m/z found, 555.0 [M+H] . H NMR (600 MHz, CD OD): δ 8.34 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.51 - 7.35 (m, 2H), 7.29 - 7.15 (m, 3H), 6.90 (d, J = 8.5 Hz, 1H), 6.36 - 6.07 (m, 3H), 5.73 - 5.53 (m, 1H), 4.49 - 4.37 (m, 2H), 2.24 (s, 3H), 2.19 - 1.64 (m, 8H).
Example 293: N-((1RS,3RS)Aminocyclopentyl)(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, Step A-B, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,3R)aminocyclopentyl]carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 500.6; m/z found, 500.9 [M+H] . H NMR (400 MHz, CDCl ): δ 26 24 6 3 3 8.24 (dd, J = 5.1, 2.8 Hz, 1H), 8.06 (d, J = 7.5 Hz, 1H), 7.45 – 7.35 (m, 2H), 7.26 – 7.11 (m, 3H), 6.90 (s, 1H), 6.68 (s, 1H), 5.99 – 5.92 (m, 1H), 4.97 (s, 2H), 4.57 – 4.48 (m, 1H), 3.64 (s, 1H), 3.43 (s, 4H), 2.24 (s, 1H), 2.16 (d, J = 3.6 Hz, 3H), 1.98 (d, J = 19.7 Hz, 2H).
Example 294: N-((1RS,3RS)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step B, using N- ((1RS,3RS)aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 290). MS (ESI): mass calcd. for C H N O S, 28 24 6 4 540.6; m/z found, 541.0 [M+H] . H NMR (500 MHz, CDCl ): δ 8.26 (d, J = 68.3 Hz, 1H), 7.76 (d, J = 9.3 Hz, 1H), 7.65 – 7.02 (m, 4H), 6.18 (p, J = 6.3, 4.9 Hz, 1H), 4.65 – 4.08 (m, 7H), 3.70 – 3.33 (m, 5H), 2.50 (dt, J = 125.7, 7.2 Hz, 1H), 2.24 (ddq, J = 24.3, 13.3, 7.4, 6.3 Hz, 1H), 2.11 – 1.82 (m, 1H), 1.74 – 1.40 (m, 1H), 1.41 – 1.15 (m, 1H).
Example 295: N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyrazinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A using 4-oxo(5- phenoxypyrazinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 201, product from Step A) and N-[(1S,2R)aminocyclohexyl]propenamide (Intermediate 40) (no deprotection HCl/MeOH). MS (ESI): mass calcd. for C H N O S, 555.6; 28 25 7 4 m/z found, 556.2 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.15 (s, 1H), 8.61 (s, 1H), 8.47- 8.25 (m, 2H), 7.97-7.77 (m, 2H), 7.56-7.40 (m, 2H), 7.36-7.18 (m, 3H), 6.54-6.28 (m, 2H), 6.20- 6.04 (m, 1H), 5.66-5.50 (m, 1H), 4.29-4.14 (m, 1H), 4.08-3.94 (m, 1H), 1.77-1.61 (m, 4H), 1.59- 1.49 (m, 2H), 1.45-1.28 (m, 2H).
Example 296: N-((1R,2S)acrylamidocyclopentyl)oxo(5-phenoxypyrimidinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A using 4-oxo(5- phenoxypyrimidinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 14) and N-[(1S,2R)aminocyclopentyl]propenamide (Intermediate 36) (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.4 27 23 7 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.68 (s, 2H), 8.30-8.26 (m, 1H), 7.55-7.46 (m, 2H), 7.33-7.22 (m, 3H), 6.30-6.15 (m, 3H), 5.63-5.57 (m, 1H), 4.49-4.33 (m, 2H), 2.22-1.99 (m, 2H), 1.97-1.82 (m, 1H), 1.79-1.59 (m, 3H).
Example 297: N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyrimidinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (5-phenoxypyrimidinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 14) and N-[(1S,2R)aminocyclohexyl]propenamide (Intermediate 40), no HCl/MeOH deprotection. MS (ESI): mass calcd. for C28H25N7O4S, 555.6; m/z found, 556.4 [M+H] . H NMR (400 MHz, CD OD): δ 8.68(s, 2H), 8.32-8.26 (m, 1H), 7.55-7.46 (m, 2H), 7.35-7.22 (m, 3H), 6.47-6.35 (m, 1H), 6.31-6.21 (m, 2H), 5.69-5.59 (m, 1H), 4.58-4.37 (m, 1H), 4.21-4.09 (m, 1H), 1.83-1.49 (m, 8H).
Example 298: N-((1R,2S)Acrylamidocyclopentyl)(S)-(6-isobutylmethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: 5-(*S)-(6-Isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared by treating 5-(6- isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 18) with CHIRAL SEPARATION METHOD 2 to obtain the *S atropisomer as the isopropylamine salt. Salt removal procedure: The isopropylamine salt of 5- (*S)-(6-Isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxylic acid (73 g, 165 mmol) was dissolved in MeOH (438 mL) and H O (219 mL).
LiOH-H O (34.7 g, 826 mmol) was added and the mixture was stirred at rt for 1 h. The mixture was concentrated to removed half of the original volume, the solution was cooled to 0 °C, and the pH was adjusted to 4-5 by adding 1 N HCl slowly. The resulting precipitate was filtered and dried under vacuum to give the title compound (56.1 g, 88%) as a yellow solid.
Step B: N-((1R,2S)Acrylamidocyclopentyl)(S)-(6-isobutylmethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a round bottom flask were added 5-(*S)-(6-isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (1.0 g, 2.62 mmol), HATU (1.29 g, 3.40 mmol), TEA (0.397 g, 3.93 mmol) and DMF (10 mL). The mixture was stirred for 10 minutes at room temperature, and then added to a stirred solution N-((1S,2R)aminocyclopentyl)acrylamide (Intermediate 36, 0.53 g, 3.44 mmol) and TEA (0.529 mg, 5.24 mmol) in DMF (4 mL) and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was treated with water (50 mL), the precipitate was isolated by filtration and dried under vacuum. The crude product was purified by FCC (SiO2, eluting with a 3:100 mixture of MeOH:DCM) to afford the title compound (0.81 g, 58%) as a white solid. Absolute stereochemical configuration of the title compound was confirmed via single crystal X-ray analysis. MS (ESI): mass calcd. for C H N O S, 518.6; m/z found, 519.1 [M+H] . H NMR (400 MHz, CDCl ): δ 9.65 (s, 1H), 27 30 6 3 3 8.40 (s, 1H), 8.33 (d, J = 5.5 Hz, 1H), 7.19 (s, 1H), 7.05-6.95 (m, 2H), 6.32 (dd, J = 17.0, 1.7 Hz, 1H), 6.19 (dd, J = 17.0, 10.1 Hz, 1H), 5.93 (d, J = 5.5 Hz, 1H), 5.64 (dd, J = 10.2, 1.6 Hz, 1H), 4.50-4.30 (m, 2H), 2.70 (d, J = 7.1 Hz, 2H), 2.27 – 2.02 (m, 6H), 1.92 – 1.61 (m, 4H), 0.99 (d, J = 6.6 Hz, 6H).
Example 299: N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isopropoxymethylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC purification of N-((1R,2S)Acrylamidocyclohexyl)(6-isopropoxy methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 222) afforded the title compound (Stationary phase: Chiralpak AS-H 5µm 250*20mm, Mobile phase: 70% CO2, 30% MeOH). MS (ESI): mass calcd. for C H N O S, 534.6; m/z 27 30 6 4 found, 535.2 [M+H] . H NMR (500 MHz, CD OD): δ 8.33 (d, J = 5.5 Hz, 1H), 8.06 (s, 1H), 6.81 (s, 1H), 6.42 (dd, J = 17.0, 10.2 Hz, 1H), 6.27 (dd, J = 17.0, 1.8 Hz, 1H), 6.11 (d, J = 5.5 Hz, 1H), 5.67 (dd, J = 10.3, 1.8 Hz, 1H), 5.35 – 5.25 (m, 1H), 4.44 (s, 1H), 4.16 (d, J = 10.6 Hz, 1H), 2.14 (s, 3H), 1.86 – 1.61 (m, 6H), 1.60 – 1.46 (m, 2H), 1.36 (dd, J = 6.1, 3.8 Hz, 6H).
Example 300: N-((1R,2S)Acrylamidocyclopentyl)oxo(*S)-(4-(pyridinyloxy)phenyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 3-(4-Nitrophenoxy)pyridine. The title compound was prepared using analogous conditions described in Intermediate 1, Step A, using1-fluoronitrobenzene and pyridinol.
Step B. 4-Oxo(4-(pyridinyloxy)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 25, Steps B-C, using 3-(4-nitrophenoxy)pyridine.
Step C. N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)phenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo(4-(pyridin yloxy)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and N- [(1S,2R)aminocyclopentyl]propenamide (Intermediate 36) (no HCl/MeOH deprotection).
MS (ESI): mass calcd. for C H N O S, 540.6; m/z found, 541.1 [M+H] . H NMR (400 MHz, 28 24 6 4 CD OD): δ 8.44-8.40 (m, 1H), 8.38-8.34 (m, 1H), 8.33-8.28 (m, 1H), 7.62-7.57 (m, 1H), 7.50- 7.44 (m, 3H), 7.29-7.25 (m, 2H), 6.32-6.24 (m, 1H), 6.23-6.16 (m, 2H), 5.64-5.59 (m, 1H), 4.47- 4.37 (m, 2H), 2.16-2.01 (m, 2H), 1.97-1.86 (m, 1H), 1.82-1.61 (m, 3H).
Example 301: N-((1R,2R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1R,2R)Aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 29, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2R) aminocyclopentyl]carbamate, and substituting diisopropylethylamine for triethylamine.
Step B. N-((1R,2R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 337, using N-((1R,2R)aminocyclopentyl)(2- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide. MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.0 [M+H] . H 29 26 6 4 NMR (500 MHz, CDCl ): δ 9.55 (s, 1H), 8.37 (d, J = 5.4 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.26 - 7.10 (m, 3H), 6.93 - 6.73 (m, 2H), 6.45 - 6.26 (m, 2H), 1.72 - 1.70 (m, 0H), 6.19 - 5.96 (m, 2H), 5.67 (dd, J = 10.3, 1.4 Hz, 1H), 4.27 - 3.98 (m, 2H), 2.43 - 2.33 (m, 1H), 2.33 - 2.22 (m, 4H), 1.91 - 1.81 (m, 2H), 1.66 - 1.43 (m, 2H).
Example 302: N-((1R,2S)Acrylamidocyclohexyl)oxo(2-phenoxypyrimidinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 5-Nitrophenoxypyrimidine. The title compound was prepared in a manner analogous to Intermediate 24, Step A, using 2-chloronitropyrimidine and phenol, and substituting TEA or DIEA for Cs CO .
Step B. 4-Oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 16, steps B-C, using 5-nitrophenoxypyrimidine in Step B.
Step C. N-((1R,2S)Acrylamidocyclohexyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using N-[(1S,2R)aminocyclohexyl]propenamide (Intermediate 40) and 4-oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.3 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.12 (s, 28 25 7 4 6 1H), 8.76 (s, 2H), 8.37-8.32 (m, 1H), 7.90-7.81 (m, 2H), 7.50-7.42 (m, 2H), 7.31-7.24 (m, 3H), 6.44-6.33 (m, 2H), 6.16-6.07 (m, 1H), 5.62-5.56 (m, 1H), 4.24-4.17 (m, 1H), 4.05-3.97 (m, 1H), 1.74-1.52 (m, 6H), 1.45-1.31 (m, 2H).
Example 303: N-((1R,2S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1R,2S)aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 29, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2R) aminocyclohexyl]carbamate and diisopropylethylamine.
Step B. N-((1R,2S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 337. MS (ESI): mass calcd. for C30H28N6O4S, 568.7; m/z found, 569.1 [M+H] . H NMR (500 MHz, CDCl ): δ 9.52 (s, 1H), 8.36 (d, J = 5.4 Hz, 1H), 7.60 - 7.37 (m, 3H), 7.26 - 7.18 (m, 3H), 7.14 - 7.01 (m, 1H), 6.81 (dd, J = 8.5, 0.8 Hz, 1H), 6.42 (dd, J = 16.9, 1.4 Hz, 1H), 6.31 (s, 1H), 6.19 (dd, J = 16.9, 10.3 Hz, 1H), 6.00 (d, J = .5 Hz, 1H), 5.74 (dd, J = 10.2, 1.4 Hz, 1H), 4.33 - 4.25 (m, 1H), 4.21 - 4.08 (m, 1H), 2.29 (s, 3H), 2.10 - 1.88 (m, 2H), 1.75 - 1.67 (m, 4H), 1.60 - 1.56 (m, 2H).
Example 304: N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((tetrahydro-2H-pyran- 4-yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl ((tetrahydro-2H-pyranyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Intermediate 12) and tert-butyl N-[(1S,2R) aminocyclopentyl]carbamate, and substituting diisopropylethylamine for triethylamine in Step A.
Chiral SFC purification (Stationary phase: CHIRALCEL OD-H 5µm 250x20mm, Mobile phase: 65% CO2, 35% MeOH) afforded the title compound and N-((1R,2S)Acrylamidocyclopentyl)- -(*R)-(2-methyl((tetrahydro-2H-pyranyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 347). MS (ESI): mass calcd. for C H N O S, 29 31 5 5 561.7; m/z found, 562.3 [M+H] . H NMR (400 MHz, CD OD): δ 8.29-8.23 (m, 1H), 7.24-7.16 (m, 1H), 7.06-7.00 (m, 1H), 6.99-6.93 (m, 1H), 6.32-6.14 (m, 2H), 6.02-5.96 (m, 1H), 5.63-5.56 (m, 1H), 4.68-4.56 (m, 1H), 4.46-4.33 (m, 2H), 3.99-3.89 (m, 2H), 3.66-3.54 (m, 2H), 2.18-1.98 (m, 7H), 1.96-1.83 (m, 1H), 1.81-1.61 (m, 5H).
Example 305: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridazinyloxy)phenyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 5-(2-Methyl(pyridazinyloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 3,6-dichloropyridazine, 3-methylnitrophenol Step A, (no Cu).
Step B. N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridazinyloxy)phenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methyl(pyridazin yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and N-[(1S,2R)aminocyclopentyl]propenamide (Intermediate 36) (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.1 [M+H] . H 28 25 7 4 NMR (400 MHz, CD OD): δ 8.95 (d, J = 4.0 Hz, 1H), 8.31 (d, J = 5.5 Hz, 1H), 7.82-7.71 (m, 1H), 7.53-7.38 (m, 2H), 7.35-7.29(m, 1H), 7.29-7.20 (m, 1H), 6.34-6.14 (m, 3H), 5.65-5.55 (m, 1H), 4.50-4.35 (m, 2H), 2.22-2.14 (m, 3H), 2.14-2.02 (m, 2H), 1.96-1.86 (m, 1H), 1.80-1.62 (m, 3H).
Example 306: N-((1*S,3*S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, Step C, using N- ((1RS,3RS)aminocyclopentyl)(4-methylphenoxypyridinyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide (Example 293); purification was performed via chiral SFC (Stationary phase: Chiralpak IA, 5 µm, 250 x 20 mm, Mobile phase: 50% CO , 50% iPrOH). MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.3 [M+H] . H NMR 29 26 6 4 (400 MHz, CDCl3): δ 9.51 (s, 1H), 8.37 (d, J = 5.4 Hz, 1H), 8.05 (s, 1H), 7.50 – 7.39 (m, 2H), 7.30 – 7.15 (m, 3H), 6.95 (d, J = 1.1 Hz, 1H), 6.29 (dd, J = 16.9, 1.5 Hz, 1H), 6.14 – 6.01 (m, 2H), 5.87 (d, J = 7.2 Hz, 1H), 5.77 (d, J = 7.4 Hz, 1H), 5.66 (dd, J = 10.3, 1.4 Hz, 1H), 4.52 (dh, J = 10.3, 7.2 Hz, 2H), 2.39 – 2.18 (m, 4H), 2.03 (qdd, J = 13.9, 7.9, 6.6 Hz, 2H), 1.69 – 1.46 (m, 2H), 1.21 (d, J = 6.1 Hz, 1H).
Example 307: N-((1R,2R)Acrylamidocyclopentyl)oxo(5-phenoxypyrimidinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (5-phenoxypyrimidinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 14) and N-[(1R,2R)aminocyclopentyl]propenamide (Intermediate 46), no deprotection with MeOH/HCl. MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.1 27 23 7 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.69(s, 2H), 8.35-8.30 (m, 1H), 7.55-7.45 (m, 2H), 7.34-7.23 (m, 3H), 6.33-6.28 (m, 1H), 6.24-6.20 (m, 2H), 5.65-5.58 (m, 1H), 4.34-4.17 (m, 2H), 2.23-2.13 (m, 2H), 1.86-1.79 (m, 2H), 1.69-1.47 (m, 2H).
Example 308: N-((1*S,3*S)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1RS,3RS)aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 166, Step A-B, using 5-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl rac-[(1R,3R)aminocyclohexyl]carbamate.
Step B. N-((1*S,3*S)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 166, Step C, using N-((1RS,3RS) aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; chiral SFC purification afforded the title compound and N- ((1*R,3*R)acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 332) (Stationary phase: CHIRALPAK AD-H, 5 µm, 250 x 20 mm, Mobile phase: 60% CO , 40% iPrOH) (387 mg). MS (ESI): mass calcd. for C H N O S, 568.7; m/z found, 569.3 [M+H] . H NMR (500 MHz, 28 6 4 CDCl ): δ 9.42 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 8.07 (s, 1H), 7.48 – 7.40 (m, 2H), 7.29 – 7.16 (m, 3H), 6.98 – 6.93 (m, 1H), 6.30 (dd, J = 17.0, 1.5 Hz, 1H), 6.17 – 6.02 (m, 2H), 5.84 (d, J = 7.8 Hz, 1H), 5.72 (d, J = 7.5 Hz, 1H), 5.65 (dd, J = 10.3, 1.5 Hz, 1H), 4.27 (dqt, J = 19.9, 7.5, 3.9 Hz, 2H), 2.21 (d, J = 0.8 Hz, 3H), 1.92 – 1.63 (m, 4H), 1.54 (dtd, J = 12.2, 7.8, 4.0 Hz, 1H), 1.21 (d, J = 6.1 Hz, 3H).
Example 309: N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-(cyclopentyloxy) methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, Step A, using 5-(6- (cyclopentyloxy)methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Intermediate 25, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and using N-[(1S,2R)aminocyclohexyl]prop enamide (Intermediate 40). MS (ESI): mass calcd. for C H N O S, 560.7; m/z found, 561.2 29 32 6 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.32 (d, J = 5.5 Hz, 1H), 8.06 (s, 1H), 6.83 (s, 1H), 6.42 (dd, J = 17.0, 10.2 Hz, 1H), 6.27 (dd, J = 17.0, 1.8 Hz, 1H), 6.11 (d, J = 5.6 Hz, 1H), 5.67 (dd, J = 10.2, 1.9 Hz, 1H), 5.44 – 5.37 (m, 1H), 4.49 – 4.41 (m, 1H), 4.16 (d, J = 10.3 Hz, 1H), 2.14 (s, 3H), 2.07 – 1.94 (m, 2H), 1.89 – 1.77 (m, 8H), 1.74 – 1.63 (m, 4H), 1.60 – 1.48 (m, 2H).
Example 310: N-((1R,2S)Acrylamidocyclopentyl)oxo(2-phenoxypyrimidinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using N- [(1S,2R)aminocyclopentyl]propenamide (Intermediate 36) and N-[(1S,2R) aminocyclohexyl]propenamide (Intermediate 40) and 4-oxo(2-phenoxypyrimidinyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 302, product from Step B) (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 541.6; m/z 27 23 7 4 found, 542.3 [M+H] . H NMR (400 MHz, a mixture of DMSO-d and CD OD): δ 8.70 (s, 2H), 8.33-8.29 (m, 1H), 7.90-7.64 (m, 1H), 7.46-7.39 (m, 2H), 7.28-7.20 (m, 3H), 6.34-6.29 (m, 1H), 6.25-6.15 (m, 1H), 6.09-6.01 (m, 1H), 5.56-5.49 (m, 1H), 4.33-4.21 (m, 2H), 1.99-1.63 (m, 2H), 1.79-1.57 (m, 3H), 1.58-1.45 (m, 1H).
Example 311: N-((1R,2R)Acrylamidocyclopentyl)oxo(5-phenoxypyrazinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 1, Step A and 4-oxo(5- phenoxypyrazinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 201, product from Step A) and N-[(1R,2R)aminocyclopentyl]propenamide (Intermediate 46) (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 541.6; 27 23 7 4 m/z found, 542.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.50-8.45 (m, 1H), 8.36-8.29 (m, 2H), 7.56-7.40 (m, 2H), 7.32-7.18 (m, 3H), 6.33 (d, J = 5.6 Hz, 1H), 6.24-6.16 (m, 2H), 5.67- .57 (m, 1H), 4.37-4.15 (m, 2H), 2.26-2.07 (m, 2H), 1.89-1.76 (m, 2H), 1.73-1.50 (m, 2H).
Example 312: N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isobutoxymethylpyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC (Stationary phase: Chiralpak AS-H 5µm 250*20mm, Mobile phase: 70% CO , 30% MeOH) of N-((1R,2S)Acrylamidocyclohexyl)(6-isobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 225) afforded the title compound and N-((1R,2S)acrylamidocyclohexyl)(*R)-(6-isobutoxymethylpyridin- 3-yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 352).
MS (ESI): mass calcd. for C H N O S, 548.7; m/z found, 549.2 [M+H] . H NMR (500 MHz, 28 32 6 4 CD OD): δ 8.39 – 8.29 (m, 1H), 8.06 (s, 1H), 6.89 (s, 1H), 6.42 (dd, J = 16.9, 10.1 Hz, 1H), 6.27 (d, J = 18.0 Hz, 1H), 6.16 – 6.06 (m, 1H), 5.67 (d, J = 11.0 Hz, 1H), 4.48 – 4.41 (m, 1H), 4.22 – 4.15 (m, 1H), 4.14 – 4.06 (m, 2H), 2.16 (s, 3H), 2.14 – 2.06 (m, 1H), 1.87 – 1.77 (m, 3H), 1.75 – 1.61 (m, 3H), 1.59 – 1.47 (m, 2H), 1.04 (d, J = 6.7 Hz, 6H).
Example 313: N-((1S,3R)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was isolated by Chiral SFC from Example 214. MS (ESI): mass calcd. for C H N O S, 540.6; m/z found, 541.3 [M+H] . H NMR (400 MHz, CDCl ): δ 9.53 (s, 1H), 28 24 6 4 3 8.53 - 8.26 (m, 2H), 7.59 - 7.33 (m, 5H), 7.26 - 7.22 (m, 1H), 7.21 - 7.08 (m, 2H), 6.54 - 6.45 (m, 1H), 6.44 - 6.34 (m, 1H), 6.26 - 6.20 (m, 1H), 6.10 (dd, J = 16.9, 10.3 Hz, 1H), 5.67 (dd, J = .2, 1.5 Hz, 1H), 4.44 - 4.31 (m, 1H), 4.18 - 4.06 (m, 1H), 2.54 - 2.40 (m, 1H), 2.10 - 1.57 (m, 4H), 0.86 - 0.82 (m, 1H).
Example 314: N-((1R,2R)Acrylamidocyclopentyl)oxo(2-phenoxypyrimidinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using N- [(1R,2R)aminocyclopentyl]propenamide (Intermediate 46) in place of tert-butyl ((1S,4S)- 4-aminocyclohexyl)carbamate and N-[(1S,2R)aminocyclohexyl]propenamide (Intermediate 40) and 4-oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxylic acid (Example 302, product from Step B) (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.4 [M+H] . H NMR (400 MHz, DMSO-d ): 27 23 7 4 6 δ 10.28 (s, 1H), 8.75 (s, 2H), 8.44 – 8.00 (m, 3H), 7.53 – 7.36 (m, 2H), 7.36 – 7.18 (m, 3H), 6.34 (d, J = 5.5 Hz, 1H), 6.23-6.10 (m, 1H), 6.09-5.97 (m, 1H), 5.60-5.50 (m, 1H), 4.27-4.17 (m, 1H), 4.17-4.06 (m, 1H), 2.08 – 1.90 (m, 2H), 1.76 – 1.37 (m, 4H).
Example 315: N-((1*S,3*S)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC Purification of N-((1RS,3RS)Acrylamidocyclohexyl)oxo(5-phenoxypyridin- 2-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 216), (Stationary phase: Chiralpak IA, 5 µm, 250 x 20 mm, Mobile phase: 50% CO , 50% iPrOH) afforded the title compound and N-((1*R,3*R)Acrylamidocyclohexyl)oxo(5- phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 344). MS (ESI): mass calcd. for C29H26N6O4S, 554.6; m/z found, 555.3 [M+H] . H NMR (400 MHz, CDCl ): δ 9.44 (s, 1H), 8.46 - 8.30 (m, 2H), 7.58 - 7.35 (m, 4H), 7.26 - 7.22 (m, 1H), 7.19 - 7.06 (m, 2H), 6.34 - 6.22 (m, 2H), 6.16 - 6.06 (m, 1H), 5.94 - 5.86 (m, 1H), 5.71 (d, J = 7.5 Hz, 1H), 5.68 - 5.61 (m, 1H), 9.41 - 9.24 (m, 0H), 4.35 - 4.19 (m, 2H), 1.97 - 1.88 (m, 2H), 1.85 - 1.77 (m, 5H), 1.59 - 1.49 (m, 1H).
Example 316: N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-isopropoxymethylphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4- isopropoxymethylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 31, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and N-[(1R,2R)aminocyclopentyl]propenamide (Intermediate 46), no HCl/MeOH deprotection. MS (ESI): mass calcd. for C H N O S, 519.6; m/z found, 520.3 27 29 5 4 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.13 (s, 1H), 8.32-8.23 (m, 2H), 8.22-8.12(br, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.97-6.91 (m, 1H), 6.89-6.82 (m, 1H), 6.22-6.11 (m, 1H), 6.08-6.01 (m, 1H), 5.86 (d, J = 5.4 Hz, 1H), 5.60-5.50 (m, 1H), 4.67-4.56 (m, 1H), 4.27-4.08 (m, 2H), 2.07 – 1.90 (m, 5H), 1.72-1.61 (m, 2H), 1.61-1.50 (m, 1H), 1.49-1.36 (m, 1H), 1.26 (d, J = 6.0 Hz, 6H).
Example 317: 5-([2,3'-Bipyridin]yl)-N-((1R,2S)acrylamidocyclopentyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 5-([2,3'-Bipyridin]yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 19, Method A, using pyridinylboronic acid and 2-chloropyridinamine, and substituting PdCl (PPh ) for Pd(OAc) , in Step A. 2 3 2 2 Step B. 5-([2,3'-Bipyridin]yl)-N-((1R,2S)acrylamidocyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-([2,3'-bipyridin]yl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid and N-((1S,2R)aminocyclopentyl)acrylamide (Intermediate 36), no HCl/MeOH deprotection. MS (ESI): mass calcd. for C H N O S, 525.6; 27 23 7 3 m/z found, 526.2 [M+H] . H NMR (400 MHz, CD3OD): δ 9.31-9.19 (m, 1H), 8.98-8.86 (m, 1H), 8.65-8.56 (m, 1H), 8.54-8.47 (m, 1H), 8.35-8.26 (m, 1H), 8.21-8.11 (m, 1H), 7.61-7.51 (m, 2H), 6.34-6.23 (m, 2H), 6.23-6.16 (m, 1H), 5.67-5.55 (m, 1H), 4.46-4.35 (m, 2H), 2.13-2.00 (m, 2H), 1.96-1.85 (m, 1H), 1.80-1.60 (m, 3H).
Example 318: N-((1*R,2*S)Aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 29, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,2R)aminocyclopentyl)carbamate. MS (ESI): mass calcd. for C H N O S, 26 24 6 3 500.6; m/z found, 501.0 [M+H] . H NMR (500 MHz, CDCl3): δ 9.53 (s, 1H), 8.36 (d, J = 5.5 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.46 - 7.36 (m, 2H), 7.28 - 7.16 (m, 2H), 6.97 (s, 1H), 6.84 - 6.76 (m, 1H), 6.00 (d, J = 5.5 Hz, 1H), 4.69 - 4.60 (m, 1H), 4.27 - 4.14 (m, 1H), 4.12 - 4.04 (m, 1H), 2.29 (s, 3H), 2.12 - 2.01 (m, 1H), 1.91 - 1.55 (m, 5H), 1.49 (s, 9H).
Example 319: N-((1S,3R)Acrylamidocyclopentyl)oxo(2-phenoxypyrimidinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 337, using tert-butyl N- [(1R,3S)aminocyclopentyl]carbamate and 4-oxo(2-phenoxypyrimidinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 302, product from Step B).
MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.3 [M+H] . 27 23 7 4 Example 320: N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenylpyridazinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: 3-Chlorophenyl-pyridazine. A solution of 3,5-dichloropyridazine (2.00 g, 13.4 mmol), phenylboronic acid (1.64 g, 13.4 mmol), Pd(OAc) (0.301 g, 1.34 mmol), 1,2,3,4,5- pentaphenyl-1'-(di-tert-butylphosphino)ferrocene (1.906 g, 2.685 mmol), KF (1.947 g, 33.56 mmol), dioxane (50 mL), and water (12 mL) was stirred at reflux for 15 h under N . The mixture was diluted with EtOAc, washed with brine, dried over anhydrous Na SO , and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound (1.53 g, 59.8% yield) as white solid. MS (ESI): mass calcd. for C H ClN , 190.63; m/z found, 7 2 190.0 [M+H] .
Step B: tert-Butyl (5-phenylpyridazinyl)carbamate. A mixture of 3-chlorophenyl- pyridazine (1.53 g, 8.03 mmol), tert-butyl carbamate (1.88 g, 16.1 mmol), Pd(dppf)Cl (0.592 g, 0.803 mmol), Xphos (0.928 g, 1.61 mmol), and Cs CO (6.54 g, 20.1 mmol) in dioxane (30 mL) was stirred at 100 °C for 16 hours. The mixture was diluted with EtOAc and filtered. The filtrate was partitioned between EtOAc and water, the organic layer was washed with water and brine, and dried over anhydrous Na SO , and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound (0.96 g, 44% yield) as light yellow solid. MS (ESI): mass calcd. for C H N O , 271.31; m/z found, 272.0 [M+H] . 7 3 2 Step C: Methyl 3-amino((tert-butoxycarbonyl)(5-phenylpyridazinyl)amino)thieno[2,3- b]pyridinecarboxylate. The title compound was prepared using analogous conditions described in Intermediate 1, steps C-D, and using tert-butyl (5-phenylpyridazinyl)carbamate and Cs CO in place of 5-fluoronitrotoluene and K CO in step C (1.05 g). MS (ESI): mass 2 3 2 3 calcd. for C H N O S, 477.54; m/z found, 478.3 [M+H] . 24 23 5 4 Step D: Methyl 3-amino((5-phenylpyridazinyl)amino)thieno[2,3-b]pyridinecarboxylate.
A solution of methyl 3-amino((tert-butoxycarbonyl)(5-phenylpyridazin yl)amino)thieno[2,3-b]pyridinecarboxylate (1.05 g, 2.20 mmol) in TFA (4 mL) and DCM (12 mL) was stirred at rt for 3 h. The mixture was concentrated to dryness to give the title compound (0.79 g, 95% yield) as yellow solid, which was used in the next step directly. MS (ESI): mass calcd. for C H N O S, 377.42; m/z found, 378.3 [M+H] . 19 15 5 2 Step E. 4-Oxo(5-phenylpyridazinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps E-F, using methyl 3-amino((5-phenylpyridazinyl)amino)thieno[2,3-b]pyridine carboxylate.
Step F: N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenylpyridazinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo(5-phenylpyridazinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and N-[(1S,2R) aminocyclopentyl]propenamide (Intermediate 36) (no HCl/MeOH deprotection. MS (ESI): mass calcd. for C H N O S, 525.6; m/z found, 526.1 [M+H] . H NMR (400 MHz, DMSO- 27 23 7 3 d ): δ 10.27 (s, 1H), 9.86-9.83 (m, 1H), 8.40-8.33 (m, 2H), 7.99-7.93 (m, 2H), 7.90-7.85 (m, 1H), 7.82-7.77 (m, 1H), 7.62-7.55 (m, 3H), 6.34-6.28 (m, 1H), 6.28-6.18 (m, 1H), 6.11-6.02 (m, 1H), 5.58-5.52 (m, 1H), 4.34-4.19 (m, 2H), 2.00-1.84 (m, 2H), 1.82-1.67 (m, 2H), 1.67-1.47 (m, 2H).
Example 321: N-((1*S,3*S)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was purified from N-((1RS,2RS)Acrylamidocyclopentyl)(2-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 292) chiral SFC (Stationary phase: Chiralpak IA, 5 µm, 250 x 20 mm, Mobile phase: 50% CO , 50% iPrOH) afforded the title compound and N-((1*R,3*R) Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 334) . MS (ESI): mass calcd. for C H N O S, 28 24 6 4 540.6; m/z found, 541.2 [M+H] . H NMR (500 MHz, CDCl ): δ 8.38 – 8.32 (m, 1H), 8.17 (t, J = 2.2 Hz, 1H), 7.73 – 7.66 (m, 1H), 7.50 – 7.41 (m, 2H), 7.32 – 7.17 (m, 4H), 7.11 (dd, J = 8.8, 1.7 Hz, 1H), 6.98 (p, J = 5.3 Hz, 1H), 6.29 (dq, J = 16.9, 1.4 Hz, 1H), 6.20 – 6.07 (m, 2H), 5.65 (dq, J = 10.3, 1.4 Hz, 1H), 4.44 (dp, J = 27.6, 6.8 Hz, 2H), 2.65 (d, J = 5.1 Hz, 1H), 2.25 (tdd, J = 12.2, 7.3, 3.5 Hz, 2H), 1.96 (dq, J = 23.9, 6.7 Hz, 2H), 1.67 – 1.48 (m, 2H).
Example 322: N-((1R,2R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1R,2R)Aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 29, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2R) aminocyclohexyl]carbamate and substituting diisopropylethylamine for triethylamine.
Step B. N-((1R,2R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 337, using N-((1R,2R)aminocyclohexyl)(*S)- (2-methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide. MS (ESI): mass calcd. for C H N O S, 568.7; m/z found, 569.0 [M+H] . H 28 6 4 NMR (500 MHz, CDCl ): δ 9.61 (s, 1H), 8.35 (d, J = 5.4 Hz, 1H), 7.58 - 7.38 (m, 3H), 7.26 - 7.14 (m, 3H), 6.81 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 7.2 Hz, 1H), 6.39 - 6.19 (m, 2H), 6.17 - 5.93 (m, 2H), 5.62 (dd, J = 10.3, 1.4 Hz, 1H), 4.04 - 3.74 (m, 2H), 2.33 - 1.36 (m, 11H).
Example 323: N-((1S,3S)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, using 4-oxo(6- phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 28) and tert-butyl racemic-[(1R,3R)aminocyclohexyl]carbamate in Step A.
Chiral SFC purification of racemic N-((1RS,3RS)acrylamidocyclohexyl)oxo(6- phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Stationary phase: Chiralpak IA, 5 µm, 250 x 20 mm, Mobile phase: 50% CO , 50% iPrOH) afforded the title compound and N-((1*R,3*R)Acrylamidocyclohexyl)oxo(6- phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 331). MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.2 [M+H] . H 29 26 6 4 NMR (500 MHz, CDCl ): δ 8.36 (tt, J = 4.8, 1.8 Hz, 1H), 8.21 – 8.15 (m, 1H), 7.75 – 7.69 (m, 1H), 7.56 – 7.43 (m, 3H), 7.36 (dt, J = 4.3, 1.8 Hz, 1H), 7.29 (dd, J = 7.6, 3.8 Hz, 1H), 7.22 (t, J = 5.8 Hz, 2H), 7.13 (ddd, J = 9.0, 5.9, 2.7 Hz, 1H), 6.32 – 6.21 (m, 2H), 6.21 (ddt, J = 7.0, 4.8, 2.1 Hz, 1H), 5.67 (ddd, J = 9.6, 4.9, 2.2 Hz, 1H), 4.23 (dd, J = 7.2, 3.5 Hz, 1H), 4.15 (dq, J = 9.6, 4.8 Hz, 1H), 3.45 – 3.35 (m, 2H), 1.90 (td, J = 13.7, 6.9 Hz, 2H), 1.77 (dd, J = 9.4, 4.6 Hz, 2H), 1.66 – 1.59 (m, 2H), 1.54 (q, J = 9.4 Hz, 1H).
Example 324: N-((1R,2R)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (3-(pyridinyl)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 202, product from Step A) and N-[(1R,2R)aminocyclopentyl]propenamide (Intermediate 46) (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C28H24N6O3S, 524.6; m/z found, 525.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.94-8.79 (m, 1H), 8.60-8.49 (m, 1H), 8.33-8.24 (m, 1H), 8.20-8.09 (m, 1H), 7.92-7.80 (m, 2H), 7.76-7.68 (m, 1H), 7.56-7.46 (m, 2H), 6.25-6.12 (m, 3H), 5.66-5.56 (m, 1H), 4.33-4.13 (m, 2H), 2.23-2.04 (m, 2H), 1.86-1.72 (m, 2H), 1.72-1.47 (m, 2H).
Example 325: 5-([2,2'-Bipyridin]yl)-N-((1R,2S)acrylamidocyclopentyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 4-Nitro-2,2'-bipyridine. The title compound was prepared in a manner analogous to Intermediate 20, Step A, using 2-(trimethylstannyl)pyridine and 2-chloronitropyridine, no base, and DMF as the solvent.
Step B. 5-([2,2'-Bipyridin]yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 25, Steps B-C, using 4-nitro-2,2'-bipyridine in Step B.
Step C. 5-([2,2'-Bipyridin]yl)-N-((1R,2S)acrylamidocyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-([2,2'-bipyridin]yl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid and N-[(1S,2R)aminocyclopentyl]prop enamide (Intermediate 36) (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 525.6; m/z found, 526.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.92-8.82 (m, 27 23 7 3 3 1H), 8.64-8.59 (m, 1H), 8.49-8.44 (m, 1H), 8.44-8.39 (m, 1H), 8.30-8.23 (m, 1H), 7.97-7.91 (m, 1H), 7.57-7.50 (m, 1H), 7.45-7.40 (m, 1H), 6.33-6.24 (m, 2H), 6.23-6.18 (m, 1H), 5.64-5.60 (m, 1H), 4.46-4.39 (m, 2H), 2.15-2.01 (m, 2H), 1.96-1.86 (m, 1H), 1.83-1.61 (m, 3H).
Example 326: 5-([2,3'-Bipyridin]yl)-N-((1R,2R)acrylamidocyclopentyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-([2,3'- bipyridin]yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 317, product from Step A) and N-((1R,2R)aminocyclopentyl)acrylamide (Intermediate 46) (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 525.6; 27 23 7 3 m/z found, 526.1 [M+H] . H NMR (400 MHz, CD OD): δ 9.27-9.22 (m, 1H), 8.94-8.88 (m, 1H), 8.62-8.57 (m, 1H), 8.53-8.47 (m, 1H), 8.32-8.27 (m, 1H), 8.21-8.15 (m, 1H), 7.59-7.52 (m, 2H), 6.31-6.26 (m, 1H), 6.22-6.16 (m, 2H), 5.63-5.56 (m, 1H), 4.29-4.17 (m, 2H), 2.19-2.09 (m, 2H), 1.84-1.73 (m, 2H), 1.70-1.60 (m, 1H), 1.60-1.51 (m, 1H).
Example 327: N-((1R,2R)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (3-(pyridinyl)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 194, product from Step A) and N-[(1R,2R)aminocyclopentyl]propenamide (Intermediate 46) in place of tert-butyl ((1S,4S)aminocyclohexyl)carbamate in step G. MS (ESI): mass calcd. for C H N O S, 524.6; m/z found, 525.1 [M+H] . H NMR (400 MHz, 28 24 6 3 CD OD): δ 8.65-8.56 (m, 1H), 8.30-8.25 (m, 1H), 8.18-8.12 (m, 1H), 8.08-8.04 (m, 1H), 7.94- 7.85 (m, 2H), 7.75-7.69 (m, 1H), 7.54-7.45 (m, 1H), 7.40-7.33 (m, 1H), 6.24-6.20 (m, 2H), 6.19- 6.15 (m, 1H), 5.65-5.58 (m, 1H), 4.31-4.16 (m, 2H), 2.25-2.05 (m, 2H), 1.90-1.76 (m, 2H), 1.72- 1.50 (m, 2H).
Example 328: N-((1*R,3*S)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was isolated by Chiral SFC from Example 214. MS (ESI): mass calcd. for C H N O S, 540.6; m/z found, 541.0 [M+H] . H NMR (400 MHz, CDCl ): δ 9.53 (s, 1H), 28 24 6 4 3 8.50 - 8.21 (m, 2H), 7.56 - 7.33 (m, 5H), 7.25 - 7.22 (m, 1H), 7.16 - 7.11 (m, 2H), 6.48 - 6.33 (m, 1H), 6.23 (d, J = 5.5 Hz, 1H), 6.17 - 6.03 (m, 1H), 5.68 (dd, J = 10.4, 1.4 Hz, 1H), 4.38 (s, 1H), 4.18 - 4.05 (m, 1H), 2.53 - 2.41 (m, 1H), 2.11 - 1.77 (m, 5H), 0.94 - 0.80 (m, 1H).
Example 329: N-((1*R,3*R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, Step C, using N- ((1RS,3RS)aminocyclopentyl)(4-methylphenoxypyridinyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide (Example 293); purification was performed via chiral SFC (Stationary phase: Chiralpak IA, 5 µm, 250 x 20 mm, Mobile phase: 50% CO , 50% iPrOH). MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.3 [M+H] . H NMR 29 26 6 4 (400 MHz, CDCl ): δ 9.51 (s, 1H), 8.37 (d, J = 5.4 Hz, 1H), 8.05 (s, 1H), 7.50 – 7.39 (m, 2H), 7.30 – 7.15 (m, 3H), 6.95 (d, J = 1.1 Hz, 1H), 6.29 (dd, J = 16.9, 1.5 Hz, 1H), 6.14 – 6.01 (m, 2H), 5.87 (d, J = 7.2 Hz, 1H), 5.77 (d, J = 7.4 Hz, 1H), 5.66 (dd, J = 10.3, 1.4 Hz, 1H), 4.52 (dh, J = 10.3, 7.2 Hz, 2H), 2.39 – 2.18 (m, 4H), 2.03 (qdd, J = 13.9, 7.9, 6.6 Hz, 2H), 1.69 – 1.46 (m, 2H), 1.21 (d, J = 6.1 Hz, 1H).
Example 330: N-((1R,2S)Acrylamidocyclopentyl)(6-(isopropylamino)methylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. tert-Butyl isopropyl(4-methylnitropyridinyl)carbamate. A solution of 2-chloro methylnitropyridine (2.5 g, 14.5 mmol) and propanamine (10 mL) was stirred at reflux overnight. The reaction mix was cooled and the solvent was removed under reduced pressure.
THF (50 mL), DMAP (178 mg, 1.4 mmol), and di-tert-butyl dicarbonate (3.47 g, 15.9 mmol) were added to the crude mix and the reaction was stirred at reflux overnight. Purification by FCC afforded the title compound.
Step B. tert-Butyl (5-aminomethylpyridinyl)(isopropyl)carbamate. The title compound was prepared in a manner analogous to Intermediate 16, Step B, using tert-Butyl isopropyl(4-methyl- -nitropyridinyl)carbamate.
Step C. 5-(6-(Isopropylamino)methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-F, using 2-chloroiodonicotinonitrile and tert-butyl (5- aminomethylpyridinyl)(isopropyl)carbamate in Step C.
Step D. N-((1R,2S)Acrylamidocyclopentyl)(6-(isopropylamino)methylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(6-(isopropylamino) methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and N-[(1S,2R)aminocyclopentyl]propenamide (Intermediate 36) (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 519.6; m/z found, 520.2 [M+H] . H 26 29 7 3 NMR (400 MHz, CD OD): δ 8.35-8.24 (m, 1H), 7.89-7.80 (m, 1H), 6.50 (s, 1H), 6.33-6.12 (m, 3H), 5.65 -5.55 (m, 1H), 4.47-4.34 (m, 2H), 4.04-3.95 (m, 1H), 2.14-1.99 (m, 5H), 1.95-1.85(m, 1H), 1.80-1.59 (m, 3H), 1.25-1.17 (m, 6H).
Example 331: N-((1*R,3*R)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was isolated as a product from Example 323. MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.3 [M+H] . H NMR (500 MHz, CDCl ): δ 8.35 (dd, J = 29 26 6 4 3 .5, 2.1 Hz, 1H), 8.18 (d, J = 2.8 Hz, 1H), 7.71 (dd, J = 8.6, 2.9 Hz, 1H), 7.51 – 7.37 (m, 3H), 7.37 – 7.18 (m, 4H), 7.12 (dd, J = 8.8, 2.1 Hz, 1H), 6.35 – 6.17 (m, 3H), 5.66 (dt, J = 9.9, 1.9 Hz, 1H), 4.27 – 4.20 (m, 1H), 3.21 (s, 1H), 1.89 (tt, J = 13.2, 4.9 Hz, 2H), 1.80 – 1.59 (m, 6H), 1.52 (td, J = 9.4, 3.6 Hz, 1H).
Example 332: N-((1*R,3*R)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared by chiral purification from Example 308. MS (ESI): mass calcd. for C H N O S, 568.7; m/z found, 569.3 [M+H] . H NMR (500 MHz, CDCl ): δ 9.42 28 6 4 3 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 8.07 (s, 1H), 7.48 – 7.40 (m, 2H), 7.29 – 7.16 (m, 3H), 6.98 – 6.93 (m, 1H), 6.30 (dd, J = 17.0, 1.5 Hz, 1H), 6.17 – 6.02 (m, 2H), 5.84 (d, J = 7.8 Hz, 1H), 5.72 (d, J = 7.5 Hz, 1H), 5.65 (dd, J = 10.3, 1.5 Hz, 1H), 4.27 (dqt, J = 19.9, 7.5, 3.9 Hz, 2H), 2.21 (d, J = 0.8 Hz, 3H), 1.92 – 1.63 (m, 4H), 1.54 (dtd, J = 12.2, 7.8, 4.0 Hz, 1H), 1.21 (d, J = 6.1 Hz, 3H).
Example 333: N-((1R,2S)Aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 29, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2R)aminocyclohexyl]carbamate, and substituting diisopropylethylamine for triethylamine. MS (ESI): mass calcd. for C H N O S, 514.6; m/z 27 26 6 3 found, 515.0 [M+H] . H NMR (500 MHz, CD OD): δ 8.51 (dd, J = 6.3, 2.1 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.56 - 7.40 (m, 2H), 7.36 - 7.13 (m, 3H), 6.95 (dd, J = 8.7, 1.1 Hz, 1H), 6.41 (d, J = 7.1 Hz, 1H), 4.54 - 4.38 (m, 1H), 3.73 - 3.55 (m, 1H), 2.26 (s, 3H), 1.96 - 1.48 (m, 8H).
Example 334: N-((1*R,3*R)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Isolated from chiral purification from Example 321. MS (ESI): mass calcd. for C H N O S, 28 24 6 4 540.6; m/z found, 541.2 [M+H] . H NMR (500 MHz, CDCl ): δ 8.35 (dd, J = 5.6, 1.0 Hz, 1H), 8.20 – 8.15 (m, 1H), 7.70 (ddd, J = 8.8, 2.8, 1.1 Hz, 1H), 7.46 (tt, J = 7.5, 1.0 Hz, 2H), 7.33 – 7.18 (m, 4H), 7.15 – 7.02 (m, 2H), 6.29 (dt, J = 17.0, 1.2 Hz, 1H), 6.21 – 6.08 (m, 2H), 5.66 (dt, J = 10.3, 1.2 Hz, 1H), 4.51 – 4.36 (m, 2H), 2.74 (s, 1H), 2.30 – 2.19 (m, 2H), 2.04 – 1.87 (m, 2H), 1.67 – 1.48 (m, 2H).
Example 335: N-((1R,2S)Aminocyclohexyl)(*S)-(6-isobutylmethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(6- isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 18, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2R)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 478.6; m/z found, 479.1 [M+H] . H NMR (500 MHz, CDCl ): δ 9.81 (s, 1H), 30 6 2 3 8.42 (s, 1H), 8.26 (d, J = 5.5 Hz, 1H), 8.13 (s, 4H), 7.20 (s, 1H), 6.93 (s, 1H), 5.88 (d, J = 5.5 Hz, 1H), 4.42 (dd, J = 7.7, 4.1 Hz, 1H), 3.56 (s, 1H), 2.74 – 2.66 (m, 2H), 2.14 (s, 3H), 1.87 – 1.75 (m, 3H), 1.55 – 1.49 (m, 2H), 1.47 – 1.35 (m, 2H), 0.98 (dd, J = 6.6, 2.4 Hz, 6H).
Example 336: N-((1R,2R)Aminocyclopentyl)(2-isopropylpyridinyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- isopropylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 16) and tert-butyl N-[(1R,2R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 436.5; m/z found, 437.2 [M+H] . H NMR (400 MHz, CD OD): δ 22 24 6 2 3 8.62 (d, J = 5.3 Hz, 1H), 8.13-8.03 (m, 1H), 7.37-7.32 (m, 1H), 7.30-7.23 (m, 1H), 5.97 (d, J = .7 Hz, 1H), 4.05-3.91 (m, 1H), 3.28-3.19 (m, 1H), 3.18-3.06 (m, 1H), 2.22-2.12 (m, 1H), 2.11- 1.99 (m, 1H), 1.84-1.63 (m, 3H), 1.51-1.41 (m, 1H), 1.34 (d, J = 6.9 Hz, 6H).
Example 337: N-((1R,2R)Acrylamidocyclopentyl)(2-isopropylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a cooled (0 °C) solution of N-((1R,2R)aminocyclopentyl)(2-isopropylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 336, 270 mg, 0.62 mmol) and DIPEA (0.08 mL, 0.74 mmol) in DCM (5 mL) was added propenoyl prop enoate (0.08 mL, 0.74 mmol). The reaction mix was stirred for 5 min. The solvent was removed under reduced pressure and the crude mix was purified (FCC, SiO , MeOH/H O) to afford the title compound (160 mg, 52%). MS (ESI): mass calcd. for C H N O S, 490.6; m/z found, 26 6 3 491.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.73-8.64 (m, 1H), 8.36-8.25 (m, 1H), 7.54- 7.44 (m, 1H), 7.40-7.35 (m, 1H), 6.25-6.15 (m, 3H), 5.67-5.59 (m, 1H), 4.33-4.16 (m, 2H), 3.21- 3.10 (m, 1H), 2.23-2.08 (m, 2H), 1.87-1.77 (m, 2H), 1.72-1.51 (m, 2H), 1.34 (d, J = 6.9 Hz, 6H).
Example 338: N-((1R,2R)Acrylamidocyclohexyl)oxo(2-phenoxypyrimidinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using tert-butyl N- [(1R,2R)aminocyclohexyl]carbamate and 4-oxo(2-phenoxypyrimidinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 302, product from Step B).
MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.3 [M+H] . H NMR (400 MHz, 28 25 7 4 DMSO-d ): δ 10.31 (s, 1H), 8.76 (s, 2H), 8.37-8.30 (m, 1H), 8.20-8.13 (m, 1H), 8.04-7.96 (m, 1H), 7.50-7.42 (m, 2H), 7.31-7.24 (m, 3H), 6.37-6.30 (m, 1H), 6.22-6.02 (m, 2H), 5.56-5.50 (m, 1H), 3.83-3.57 (m, 2H), 1.90-1.80 (m, 2H), 1.73-1.64 (m, 2H), 1.47-1.23 (m, 4H).
Example 339: N-((1R,2R)Aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 29, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2R)aminocyclopentyl]carbamate and diisopropylethylamine. MS (ESI): mass calcd. for C H N O S, 500.6; m/z found, 501.1 26 24 6 3 [M+H] . H NMR (500 MHz, CD OD): δ 8.53 (d, J = 6.2 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.51 - 7.37 (m, 2H), 7.36 - 7.16 (m, 3H), 6.96 (d, J = 8.6 Hz, 1H), 6.45 (d, J = 6.2 Hz, 1H), 4.36 - 4.23 (m, 1H), 3.59 - 3.46 (m, 1H), 2.35 - 2.14 (m, 5H), 1.96 - 1.65 (m, 4H).
Example 340: N-((1R,2S)Acetamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1R,2S)aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A using 5-(2-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 29, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,2R) aminocyclohexyl]carbamate and diisopropylethylamine in Step A.
Step B. N-((1R,2S)Acetamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step B using and acetic anhydride. MS (ESI): mass calcd. for C29H28N6O4S, 556.6; m/z found, 557.0 [M+H] . H NMR (500 MHz, CDCl3): δ 9.51 (s, 1H), 8.36 (d, J = 5.5 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.27 - 7.17 (m, 3H), 7.07 (s, 1H), 6.81 (d, J = 8.6 Hz, 1H), 6.22 - 5.91 (m, 2H), 4.31 - 4.05 (m, 2H), 2.29 (s, 3H), 2.09 (s, 3H), 1.93 - 1.39 (m, 8H).
Example 341: N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-(cyclopentyloxy) methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, Step A, using 5-(6- (cyclopentyloxy)methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Intermediate 25, including CHIRAL SEPARATION METHOD 1 to obtain the *R atropisomer) and N-[(1S,2R)aminocyclohexyl]propenamide (Intermediate 40). MS (ESI): mass calcd. for C H N O S, 560.7; m/z found, 561.2 [M+H] . 29 32 6 4 H NMR (400 MHz, CD OD): δ 8.33 (d, J = 5.5 Hz, 1H), 8.05 (s, 1H), 6.83 (s, 1H), 6.42 (dd, J = 17.0, 10.1 Hz, 1H), 6.28 (dd, J = 17.0, 1.8 Hz, 1H), 6.11 (d, J = 5.6 Hz, 1H), 5.68 (dd, J = 10.1, 1.9 Hz, 1H), 5.45 – 5.37 (m, 1H), 4.43 (s, 1H), 4.24 – 4.12 (m, 1H), 2.14 (s, 3H), 2.06 – 1.94 (m, 2H), 1.88 – 1.77 (m, 8H), 1.74 – 1.63 (m, 4H), 1.60 – 1.48 (m, 2H).
Example 342: 5-([2,2'-Bipyridin]yl)-N-((1R,2R)acrylamidocyclopentyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-([2,2'- bipyridin]yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 325, product from Step B) and N-[(1R,2R)aminocyclopentyl]propenamide (Intermediate 46) (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 525.6; 27 23 7 3 m/z found, 526.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.90-8.85 (m, 1H), 8.63-8.59 (m, 1H), 8.48-8.44 (m, 1H), 8.43-8.39 (m, 1H), 8.30-8.23 (m, 1H), 7.96-7.91 (m, 1H), 7.56-7.51 (m, 1H), 7.45-7.40 (m, 1H), 6.30-6.20 (m, 3H), 5.66-5.59 (m, 1H), 4.32-4.21 (m, 2H), 2.22-2.11 (m, 2H), 1.89-1.77 (m, 2H), 1.75-1.65 (m, 1H), 1.63-1.52 (m, 1H).
Example 343: 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2S) propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step B, using N- ((1R,2S)aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide (Example 333), propanoyl propanoate, and substituting diisopropylethylamine for triethylamine. MS (ESI): mass calcd. for C H N O S, 30 6 4 570.7; m/z found, 571.1 [M+H] . H NMR (400 MHz, CDCl ): δ 9.51 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 7.68 - 7.39 (m, 3H), 7.25 - 7.09 (m, 3H), 6.81 (d, J = 8.5 Hz, 1H), 6.00 (dd, J = 7.0, 2.1 Hz, 2H), 4.29 - 4.07 (m, 2H), 2.43 - 1.16 (m, 17H).
Example 344: N-((1*R,3*R)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC Purification of N-((1RS,3RS)Acrylamidocyclohexyl)oxo(5-phenoxypyridin- 2-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 216), (Stationary phase: Chiralpak IA, 5 µm, 250 x 20 mm, Mobile phase: 50% CO , 50% iPrOH) afforded the title compound. MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.3 29 26 6 4 [M+H] . H NMR (400 MHz, CDCl ): δ 9.45 (s, 1H), 8.46 - 8.26 (m, 2H), 7.59 - 7.38 (m, 4H), 7.26 - 7.09 (m, 3H), 6.40 - 6.01 (m, 4H), 5.89 (d, J = 7.4 Hz, 1H), 5.71 - 5.56 (m, 1H), 4.43 - 4.13 (m, 2H), 2.35 - 1.77 (m, 6H), 1.63 - 1.44 (m, 1H), 1.29 - 1.16 (m, 1H).
Example 345: N-((1R,2S)Acetamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 1, Step B, using N- ((1*R,2*S)aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 318) and substituting acetic anhydride and diisopropylethylamine for propenoyl chloride and triethylamine. MS (ESI): mass calcd. for C28H26N6O4S, 542.6; m/z found, 543.0 [M+H] . H NMR (500 MHz, CDCl3): δ 9.53 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 7.61 - 7.36 (m, 3H), 7.27 - 7.14 (m, 3H), 6.86 - 6.70 (m, 2H), 6.27 - 5.90 (m, 2H), 4.37 - 4.00 (m, 2H), 2.28 (s, 3H), 2.20 - 1.62 (m, 9H).
Example 346: 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2S) propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step B, using N- ((1*R,2*S)aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 318) and propanoyl propanoate and diisopropylethylamine for propenoyl chloride and triethylamine. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.0 [M+H] . H NMR (500 MHz, Methanol-d4) d 8.34 29 28 6 4 (d, J = 5.6 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.50 - 7.38 (m, 2H), 7.33 - 7.08 (m, 3H), 6.91 (d, J = 8.6 Hz, 1H), 6.13 (d, J = 5.5 Hz, 1H), 4.50 - 4.27 (m, 2H), 2.30 - 2.14 (m, 5H), 2.14 - 1.55 (m, 6H), 1.09 (t, J = 7.6 Hz, 3H).
Example 347: N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((tetrahydro-2H-pyran- 4-yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl ((tetrahydro-2H-pyranyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Intermediate 12) and tert-butyl N-[(1S,2R) aminocyclopentyl]carbamate, and substituting diisopropylethylamine for triethylamine in Step A.
Chiral SFC purification (Stationary phase: CHIRALCEL OD-H 5µm 250x20mm, Mobile phase: 65% CO , 35% MeOH) afforded the title compound and N-((1R,2S)acrylamidocyclopentyl)- -(*S)-(2-methyl((tetrahydro-2H-pyranyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 304) MS (ESI): mass calcd. for C H N O S, 29 31 5 5 561.7; m/z found, 562.3 [M+H] . H NMR (400 MHz, CD OD): δ 8.29-8.23 (m, 1H), 7.24-7.16 (m, 1H), 7.06-7.00 (m, 1H), 6.99-6.93 (m, 1H), 6.32-6.14 (m, 2H), 6.02-5.96 (m, 1H), 5.63-5.56 (m, 1H), 4.68-4.56 (m, 1H), 4.46-4.33 (m, 2H), 3.99-3.89 (m, 2H), 3.66-3.54 (m, 2H), 2.18-1.98 (m, 7H), 1.96-1.83 (m, 1H), 1.81-1.61 (m, 5H).
Example 348: N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-isopropoxymethylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH Chiral SFC purification of N-((1R,2S)acrylamidocyclohexyl)(6-isopropoxy methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 222) afforded the title compound (Stationary phase: Chiralpak AS-H 5µm 250*20mm, Mobile phase: 70% CO2, 30% MeOH). MS (ESI): mass calcd. for C H N O S, 534.6; m/z 27 30 6 4 found, 535.2 [M+H] . H NMR (500 MHz, CD OD): δ 8.32 (d, J = 5.5 Hz, 1H), 8.05 (s, 1H), 6.81 (s, 1H), 6.42 (dd, J = 17.0, 10.2 Hz, 1H), 6.28 (dd, J = 17.0, 1.7 Hz, 1H), 6.10 (d, J = 5.5 Hz, 1H), 5.67 (dd, J = 10.2, 1.8 Hz, 1H), 5.35 – 5.25 (m, 1H), 4.42 (s, 1H), 4.18 (d, J = 10.2 Hz, 1H), 2.14 (s, 3H), 1.88 – 1.61 (m, 6H), 1.59 – 1.46 (m, 2H), 1.36 (dd, J = 6.1, 3.9 Hz, 6H).
Example 349: N-((1R,2S)Aminocyclopentyl)oxo(5-phenylpyridazinyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (5-phenylpyridazinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 320, product from Step E) and tert-butyl N-[(1S,2R)aminocyclopentyl]carbamate.
MS (ESI): mass calcd. for C H N O S, 471.5; m/z found, 472.2 [M+H] . H NMR (400 MHz, 24 21 7 2 a mixture of CD OD and DMSO-d ): δ 9.66-9.61 (m, 1H), 8.38-8.34 (m, 1H), 8.24-8.16 (m, 2H), 7.90-7.83 (m, 2H), 7.55-7.45 (m, 3H), 6.26-6.19 (m, 1H), 4.40-4.34 (m, 1H), 3.67-3.58 (m, 1H), 2.12-1.97 (m, 2H), 1.90-1.77 (m, 2H), 1.74-1.52 (m, 2H).
Example 350: N-((1R,2R)Aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 29, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2R)aminocyclohexyl]carbamate and diisopropylethylamine. MS (ESI): mass calcd. for C27H26N6O3S, 514.6; m/z found, 515.1 [M+H] . H NMR (600 MHz, CD OD): δ 8.62 (d, J = 6.6 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.54 - 7.45 (m, 2H), 7.37 - 7.22 (m, 3H), 7.01 (d, J = 8.8 Hz, 1H), 6.63 (d, J = 6.6 Hz, 1H), 4.06 (ddd, J = 12.0, 10.5, 4.3 Hz, 1H), 3.20 (td, J = 11.3, 4.2 Hz, 1H), 2.34 (s, 3H), 2.21 - 2.15 (m, 1H), 1.94 - 1.31 (m, 7H).
Example 351: N-((1S,3R)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (2-phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 20) and N-[(1R,3S)aminocyclohexyl]propenamide (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 538.6; m/z found, 539.4 [M+H] . H 29 26 6 3 NMR (400 MHz, DMSO-d ): δ 8.88 (d, J = 5.1 Hz, 1H), 8.35-7.98 (m, 6H), 7.59-7.37 (m, 4H), 6.29-5.99 (m, 3H), 5.62-5.48 (m, 1H), 3.93-3.79 (m, 1H), 3.74-3.62 (m, 1H), 2.08-1.95 (m, 1H), 1.87-1.68 (m, 3H), 1.47- 1.19 (m, 3H), 1.15-1.02 (m, 1H).
Example 352: N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-isobutoxymethylpyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC (Stationary phase: Chiralpak AS-H 5µm 250*20mm, Mobile phase: 70% CO2, 30% MeOH) of N-((1R,2S)Acrylamidocyclohexyl)(6-isobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 225) afforded the title compound and N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isobutoxymethylpyridin- 3-yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 312).
MS (ESI): mass calcd. for C H N O S, 548.7; m/z found, 549.2 [M+H] . H NMR (500 MHz, 28 32 6 4 CD OD): δ 8.38 – 8.27 (m, 1H), 8.05 (s, 1H), 6.89 (s, 1H), 6.42 (dd, J = 17.0, 10.2 Hz, 1H), 6.28 (d, J = 15.8 Hz, 1H), 6.14 – 6.07 (m, 1H), 5.72 – 5.64 (m, 1H), 4.43 (s, 1H), 4.25 – 4.15 (m, 1H), 4.13 – 4.07 (m, 2H), 2.16 (s, 3H), 2.13 – 2.07 (m, 1H), 1.86 – 1.78 (m, 3H), 1.76 – 1.62 (m, 3H), 1.60 – 1.46 (m, 2H), 1.04 (d, J = 6.7 Hz, 6H).
Example 353: 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2R) propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 29, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,2R)aminocyclopentyl]carbamate, and substituting diisopropylethylamine for triethylamine in Step A, and using propanoyl propanoate and diisopropylethylamine in place of propenoyl chloride and triethylamine in Step B. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.0 [M+H] . H NMR (500 MHz, DMSO- 29 28 6 4 d ): δ 10.28 (s, 1H), 8.52 - 8.01 (m, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.48 - 7.44 (m, 2H), 7.27 - 7.20 (m, 3H), 7.01 (d, J = 8.7 Hz, 1H), 6.09 (s, 1H), 4.32 - 4.02 (m, 2H), 2.14 (s, 3H), 2.11 - 1.01 (m, 7H), 0.96 (t, J = 7.6 Hz, 3H).
Example 354: N-((1R,2S)Aminocyclopentyl)(*S)-(6-isobutylmethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(6- isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 18, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,2R)aminocyclopentyl)carbamate. MS (ESI): mass calcd. for C H N O S, 464.6; m/z found, 465.1 [M+H] . H NMR (500 MHz, CDCl ): δ 8.36 (d, J = 24 28 6 2 3 3.0 Hz, 1H), 8.29 (t, J = 4.2 Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 5.92 (t, J = 4.2 Hz, 1H), 5.11 (s, 1H), 3.66 (q, J = 6.4 Hz, 1H), 3.43 – 3.38 (m, 6H), 2.72 (dd, J = 7.4, 3.1 Hz, 2H), 2.22 – 2.07 (m, 4H), 1.98 – 1.78 (m, 2H), 1.74 (ddd, J = 11.0, 7.8, 5.5 Hz, 1H), 1.64 (tt, J = 11.3, 8.1 Hz, 1H), 1.00 (t, J = 4.8 Hz, 6H).
Example 355: N-((1R,3S)Aminocyclopentyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, Step A-B, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1S,3R)aminocyclopentyl]carbamate. MS (ESI): mass calcd. for C H N O S, 500.6; m/z found, 501.0 [M+H] . H NMR (400 MHz, CDCl ): δ 8.34 26 24 6 3 3 (d, J = 5.4 Hz, 1H), 8.04 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.49 – 7.39 (m, 2H), 7.29 – 7.15 (m, 3H), 6.95 (s, 1H), 6.01 (d, J = 5.4 Hz, 1H), 4.60 (dt, J = 9.1, 6.1 Hz, 1H), 3.75 (tt, J = 5.3, 2.2 Hz, 1H), 3.48 (s, 1H), 2.83 – 2.64 (m, 5H), 2.11 – 1.86 (m, 4H), 1.59 (dp, J = 13.6, 2.2 Hz, 2H).
Example 356: N-((1R,3S)Aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, Step A-B, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl N-[(1R,3S)aminocyclohexyl]carbamate. MS (ESI): mass calcd. for C H N O S, 514.6; m/z found, 515.0 [M+H] . H NMR (400 MHz, CDCl ): δ 8.35 (dd, J = 27 26 6 3 3 .4, 1.4 Hz, 1H), 8.05 (s, 1H), 7.49 – 7.39 (m, 2H), 7.92 (d, J = 8.4 Hz, 1H), 7.30 – 7.15 (m, 3H), 6.95 (s, 1H), 6.03 (d, J = 5.5 Hz, 1H), 4.60 (dt, J = 9.1, 6.1 Hz, 1H), 3.75 (tt, J = 5.3, 2.2 Hz, 1H), 3.14 (s, 1H), 2.83 – 2.64 (m, 5H), 2.11 – 1.86 (m, 4H), 1.88 (ddd, J = 12.6, 6.3, 2.9 Hz, 1H), 1.50 – 1.29 (m, 3H).
Example 357: N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isobutylmethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 337 using N-((1R,2S) aminocyclohexyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 335). MS (ESI): mass calcd. for C H N O S, 28 32 6 3 532.7; m/z found, 533.1 [M+H] . H NMR (500 MHz, CDCl ): δ 9.53 (s, 1H), 8.40 - 8.31 (m, 2H), 7.19 (s, 1H), 7.07 (s, 1H), 6.45 - 6.37 (m, 2H), 6.21 (dd, J = 16.9, 10.3 Hz, 1H), 5.94 (d, J = .4 Hz, 1H), 5.76 - 5.70 (m, 1H), 4.32 (d, J = 6.4 Hz, 1H), 4.12 (q, J = 7.2 Hz, 1H), 2.71 (d, J = 7.0 Hz, 2H), 2.04 (s, 3H), 1.96 - 1.84 (m, 3H), 1.58 (td, J = 30.3, 28.1, 18.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 4H), 0.99 (d, J = 6.5 Hz, 6H).
Example 358: N-((1R,2R)Acetamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step B, using N- ((1R,2R)aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide (Example 301, product from Step A) and replacing acetic anhydride and diisopropylethylamine for propenoyl chloride and triethylamine. MS (ESI): mass calcd. for C H N O S, 542.6; m/z found, 543.0 [M+H] . H 28 26 6 4 NMR (600 MHz, CDCl ): δ 8.42 - 8.31 (m, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.26 - 7.18 (m, 3H), 6.96 (d, J = 5.8 Hz, 1H), 6.81 (dd, J = 8.5, 0.8 Hz, 1H), 6.18 (d, J = 6.6 Hz, 1H), 6.00 (d, J = 5.3 Hz, 1H), 4.24 - 3.92 (m, 3H), 2.41 - 2.30 (m, 1H), 2.28 (s, 3H), 2.26 - 2.15 (m, 1H), 1.99 (s, 3H), 1.83 (tdd, J = 9.2, 6.3, 4.7 Hz, 2H), 1.64 - 1.45 (m, 2H).
Example 359: N-((1R,3S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 337, using N-((1R,3S) aminocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 355). MS (ESI): mass calcd. for C H N O S, 29 26 6 4 554.6; m/z found, 555.00 [M+H] . H NMR (400 MHz, CDCl3): δ 8.31 (d, J = 5.4 Hz, 1H), 8.06 (s, 1H), 7.79 (d, J = 7.3 Hz, 1H), 7.48 – 7.38 (m, 2H), 7.32 – 7.14 (m, 4H), 6.95 (s, 1H), 6.37 (dd, J = 17.0, 1.6 Hz, 1H), 6.12 (dd, J = 16.9, 10.2 Hz, 1H), 6.01 (d, J = 5.5 Hz, 1H), 5.63 (dd, J = 10.1, 1.6 Hz, 1H), 4.39 (tq, J = 8.8, 4.4 Hz, 1H), 2.44 (dt, J = 14.2, 8.6 Hz, 1H), 2.10 – 1.83 (m, 9H), 1.17 (dd, J = 10.1, 6.9 Hz, 1H).
Example 360: N-((1R,3S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, step B, using N-((1R,3S)- 3-aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 356) and substituting acetic anhydride and diisopropylethylamine for propenoyl chloride and triethylamine. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.00 [M+H] . H NMR (500 MHz, CDCl ): δ 9.62 (s, 1H), 29 28 6 4 3 8.34 (d, J = 5.4 Hz, 1H), 8.05 (s, 1H), 7.48 – 7.40 (m, 2H), 7.29 – 7.15 (m, 3H), 6.94 (s, 1H), 6.04 (d, J = 5.4 Hz, 1H), 5.97 (d, J = 7.7 Hz, 1H), 5.88 (d, J = 7.8 Hz, 1H), 4.05 – 3.94 (m, 2H), 3.88 (dtd, J = 12.4, 8.5, 8.0, 4.0 Hz, 1H), 3.54 - 347 (m, 2H), 2.35 (d, J = 11.6 Hz, 1H), 2.19 (s, 3H), 2.11 – 1.95 (m, 5H), 1.89 – 1.81 (m, 1H), 1.47 (ddd, J = 14.1, 10.3, 4.1 Hz, 1H).
Example 361: 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3S) propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 35, using N-((1R,3S) aminocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 355), and substituting diisopropylethylamine for triethylamine. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.00 [M+H] . H 29 28 6 4 NMR (500 MHz, CDCl ): δ 9.64 (s, 1H), 8.33 (d, J = 5.4 Hz, 1H), 8.06 (s, 1H), 7.63 (d, J = 7.3 Hz, 1H), 7.47 – 7.39 (m, 2H), 7.29 – 7.15 (m, 3H), 6.95 (s, 1H), 6.66 (d, J = 6.4 Hz, 1H), 6.02 (d, J = 5.5 Hz, 1H), 5.29 (s, 1H), 4.37 (tt, J = 7.7, 2.9 Hz, 1H), 4.16 – 3.99 (m, 1H), 2.47 – 2.30 (m, 1H), 2.26 – 2.15 (m, 3H), 2.04 (s, 2H), 1.98 – 1.85 (m, 4H), 1.26 (t, J = 7.2 Hz, 3H).
Example 362: N-((1R,2R)Acetamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step B, using N- ((1R,2R)aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide (Example 350), substituting acetic anhydride and diisopropylethylamine for propenoyl chloride and triethylamine. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.0 [M+H] . H NMR (600 MHz, CDCl ): δ 9.49 (s, 1H), 29 28 6 4 3 8.37 (d, J = 5.4 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.25 - 7.18 (m, 3H), 6.81 (d, J = 8.6 Hz, 1H), 6.58 (d, J = 7.1 Hz, 1H), 5.99 (d, J = 5.4 Hz, 1H), 3.88 - 3.68 (m, 2H), 2.28 (s, 3H), 2.27 - 2.20 (m, 1H), 2.10 - 2.04 (m, 1H), 2.03 - 1.95 (m, 3H), 1.85 - 1.76 (m, 2H), 1.42 - 1.28 (m, 5H).
Example 363: N-((1R,3S)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 337, using N-((1R,3S) aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 356). MS (ESI): mass calcd. for C30H28N6O4S, 568.7; m/z found, 569.00 [M+H] . H NMR (500 MHz, CDCl ): δ 9.54 (s, 1H), 8.34 (d, J = 5.4 Hz, 1H), 8.04 (s, 1H), 7.48 – 7.39 (m, 2H), 7.28 – 7.15 (m, 3H), 6.94 (s, 1H), 6.27 (dd, J = 16.9, 1.5 Hz, 1H), 6.12 – 6.01 (m, 2H), 5.80 (t, J = 8.6 Hz, 2H), 5.63 (dd, J = 10.2, 1.5 Hz, 1H), 5.30 (s, 2H), 3.48 (s, 1H), 2.45 – 2.38 (m, 1H), 2.06 (q, J = 8.7, 5.5 Hz, 3H), 1.86 (dt, J = 7.2, 3.6 Hz, 1H), 1.51 (qt, J = 13.6, 3.6 Hz, 1H), 1.29 – 1.07 (m, 4H).
Example 364: 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2R) propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 35, using N-((1R,2R) Aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 350Example 350: N-((1R,2R) Aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide. MS (ESI): mass calcd. for C H N O S, 570.7; m/z 30 6 4 found, 571.0 [M+H] . H NMR (500 MHz, CDCl ): δ 9.57 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 7.64 - 7.36 (m, 3H), 7.26 - 7.18 (m, 3H), 6.81 (dd, J = 8.5, 0.7 Hz, 1H), 6.73 (d, J = 7.2 Hz, 1H), .99 (d, J = 5.4 Hz, 1H), 5.90 (d, J = 8.0 Hz, 1H), 3.89 - 3.70 (m, 2H), 2.28 (s, 3H), 2.27 - 2.11 (m, 3H), 1.89 - 1.77 (m, 3H), 1.45 - 1.32 (m, 4H), 1.10 (t, J = 7.6 Hz, 3H).
Example 365: N-((1R,3S)Acrylamidocyclopentyl)(6-isobutoxymethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1R,3S)Aminocyclopentyl)(*S)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 166, Step A, using 5-(6-isobutoxymethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 33, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,3R)aminocyclopentyl)carbamate (with a TFA/DCM deprotection).
Step B. N-((1R,3S)Acrylamidocyclopentyl)(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step B, using N-((1R,3S)aminocyclopentyl)(*S)-(6- isobutoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide, acrylic anhydride and diisopropylethylamine in place of propenoyl chloride and triethylamine in step B. MS (ESI): mass calcd. for C H N O S, 534.6; m/z found, 535.0 27 30 6 4 [M+H] . H NMR (500 MHz, CDCl ): δ 9.63 (s, 1H), 8.33 (d, J = 5.5 Hz, 1H), 8.02 (s, 1H), 7.58 (d, J = 7.3 Hz, 1H), 6.87 (d, J = 7.1 Hz, 1H), 6.83 – 6.78 (m, 1H), 6.39 (dd, J = 17.0, 1.4 Hz, 1H), 6.11 (dd, J = 16.9, 10.3 Hz, 1H), 6.02 (d, J = 5.4 Hz, 1H), 5.66 (dd, J = 10.3, 1.4 Hz, 1H), 4.40 (ddt, J = 11.5, 7.7, 3.6 Hz, 1H), 4.18 – 4.04 (m, 3H), 2.51 – 2.40 (m, 1H), 2.16 – 1.82 (m, 9H), 1.03 (dd, J = 6.8, 1.3 Hz, 6H).
Example 366: N-((1R,3S)Acrylamidocyclopentyl)(*S)-(6-(cyclopentyloxy) methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step B, using N- ((1R,3S)Aminocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 394), and acrylic anhydride and diisopropylethylamine in place of propenoyl chloride and triethylamine in step B. MS (ESI): mass calcd. for C H N O S, 546.7; m/z found, 547.0 [M+H] . H NMR (500 28 30 6 4 ): δ 8.32 (d, J = 5.4 Hz, 1H), 8.03 (s, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.19 (d, J = 7.2 MHz, CDCl3 Hz, 1H), 6.73 (s, 1H), 6.37 (dd, J = 17.0, 1.5 Hz, 1H), 6.12 (dd, J = 16.9, 10.3 Hz, 1H), 6.02 (d, J = 5.4 Hz, 1H), 5.64 (dd, J = 10.2, 1.5 Hz, 1H), 5.46 – 5.35 (m, 1H), 4.21 – 3.99 (m, 1H), 2.44 (s, 0H), 2.13 (s, 3H), 2.54 – 2.37 (m, 1H), 2.13 (s, 3H), 2.04 – 1.95 (m, 3H), 1.94 - 1.86 (m, 5H), 1.64 (dq, J = 7.0, 2.7, 2.2 Hz, 4H).
Example 367: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((2-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 2-Methyl(3-methylnitrophenoxy)pyridine. The title compound was prepared in a manner analogous to Intermediate 1, Step A, using 4-fluoromethylnitrobenzene and 2- methylpyridinol.
Step B. 5-(2-Methyl((2-methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 25, Steps B-C, using 2-methyl(3-methylnitrophenoxy)pyridine in Step B.
Step C: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((2-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methyl ((2-methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid and N-((1S,2R)aminocyclopentyl)acrylamide (Intermediate 36), no HCl/MeOH deprotection. MS (ESI): mass calcd. for C H N O S, 568.6; m/z found, 569.2 28 6 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.35-8.28 (m, 1H), 8.28-8.22 (m, 1H), 7.50-7.43 (m, 1H), 7.36-7.28 (m, 2H), 7.10-7.02 (m, 1H), 6.99-6.93 (m, 1H), 6.32-6.16 (m, 2H), 6.09-6.01 (m, 1H), 5.64-5.58 (m, 1H), 4.46-4.36 (m, 2H), 2.50 (s, 3H), 2.13 (s, 3H), 2.11-2.01 (m, 2H), 1.96- 1.86 (m, 1H), 1.81-1.61 (m, 3H).
Example 368: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 2-Methyl((6-methylpyridinyl)oxy)aniline. The title compound was prepared in a manner analogous to Intermediate 1, Step A, using 4-aminomethylphenol and 2-fluoro methylpyridine.
Step B. 5-(2-Methyl((6-methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-F, using 2-methyl((6-methylpyridinyl)oxy)aniline in Step C.
Step C. N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A using 5-(2-methyl ((6-methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid and N-((1S,2R)aminocyclopentyl)acrylamide (Intermediate 36), no HCl/MeOH deprotection . MS (ESI): mass calcd. for C H N O S, 568.6; m/z found, 569.2 28 6 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.36-8.24 (m, 1H), 7.76-7.65 (m, 1H), 7.44-7.29 (m, 1H), 7.20-7.15 (m, 1H), 7.13-7.06 (m, 1H), 7.06-6.97 (m, 1H), 6.82-6.72 (m, 1H), 6.34-6.15 (m, 2H), 6.14-6.05 (m, 1H), 5.66-5.55(m, 1H), 4.48-4.34 (m, 2H), 2.42 (s, 3H), 2.20-2.00 (m, 5H), 1.98-1.84 (m, 1H), 1.82-1.61 (m, 3H).
Example 369: N-((1R,2S)Acrylamidocyclopentyl)(4-((6-methylpyridinyl)oxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 368, using 4-aminophenol and 2-fluoromethylpyridine in Step A. MS (ESI): mass calcd. for C29H26N6O4S, 554.6; m/z found, 555.1 [M+H] . H NMR (400 MHz, DMSO-d ): δ 9.98 (s, 1H), 8.30 (d, J = 5.5 Hz, 1H), 7.92-7.81 (m, 1H), 7.81-7.62 (m, 2H), 7.52-7.40 (m, 2H), 7.34-7.21 (m, 2H), 7.08-6.97 (m, 1H), 6.89-6.80 (m, 1H), 6.30-6.15 (m, 1H), 6.11-5.96 (m, 2H), 5.62-5.47 (m, 1H), 4.42-4.14 (m, 2H), 2.35 (s, 3H), 2.02-1.82 (m, 2H), 1.80-1.68 (m, 2H), 1.66-1.44 (m, 2H).
Example 370: N-((1R,2S)Acrylamidocyclopentyl)(4-((6-methylpyridinyl)oxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-((6- methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 32) and tert-butyl ((1S,2R)aminocyclopentyl)carbamate in Step A, and using acrylic anhydride in place of propenoyl chloride in Step B. MS (ESI): mass H N O S, 554.6; m/z found, 555.1 [M+H] . H NMR (400 MHz, CD OD): δ calcd. for C29 26 6 4 3 8.34-8.24 (m, 2H), 7.54-7.46 (m, 1H), 7.45-7.38 (m, 2H), 7.37-7.30 (m, 1H), 7.24-7.18 (m, 2H), 6.31-6.12 (m, 3H), 5.68-5.53 (m, 1H), 4.47-4.32 (m, 2H), 2.52 (s, 3H), 2.14-1.99 (m, 2H), 1.97- 1.85 (m, 1H), 1.80-1.61 (m, 3H).
Example 371: N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-(cyclopentyloxy) methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in manner analogous to Example 1, Step B, using N-((1R,2S)- 2-aminocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide (Example 374) and acrylic anhydride and diisopropylethylamine in place of propenoyl chloride and triethylamine. MS (ESI): mass calcd. for C H N O S, 546.7; m/z found, 547.0 [M+H] . H NMR (500 MHz, CDCl ): δ 9.48 28 30 6 4 3 (s, 1H), 8.33 (d, J = 5.4 Hz, 1H), 8.02 (s, 1H), 6.86 (d, J = 6.1 Hz, 1H), 6.80 (d, J = 6.4 Hz, 1H), 6.72 (s, 1H), 6.33 (d, J = 16.8 Hz, 1H), 6.16 (dd, J = 16.9, 10.1 Hz, 1H), 6.02 (d, J = 5.3 Hz, 1H), .65 (d, J = 10.3 Hz, 1H), 5.41 (dq, J = 6.5, 3.4, 3.0 Hz, 1H), 4.38 (dq, J = 19.3, 6.8 Hz, 2H), 2.28 – 2.17 (m, 1H), 2.11 (s, 4H), 1.98 (dq, J = 15.8, 7.9, 7.2 Hz, 2H), 1.92 – 1.65 (m, 10H).
Example 372: N-((1R,2S)Acrylamidocyclopentyl)(4-((2-methylpyridinyl)oxy)phenyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 368, using 4- fluoronitrobenzene and 2-methylpyridinol in Step A. MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.2 [M+H] . H NMR (400 MHz, CD3OD) d 8.33-8.22 (m, 29 26 6 4 2H), 7.51-7.39 (m, 3H), 7.34-7.28 (m, 1H), 7.19-7.12 (m, 2H), 6.32-6.13 (m, 3H), 5.64-5.57 (m, 1H), 4.46-4.35 (m, 2H), 2.51 (s, 3H), 2.14-2.01 (m, 2H), 1.95-1.85 (m, 1H), 1.81-1.61 (m, 3H).
Example 373: N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-isobutoxymethylpyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1R,2S)aminocyclopentyl)(*S)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 166, Step A, using 5-(6-isobutoxymethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 33, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,2R)aminocyclopentyl)carbamate.
Step B. N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-isobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step B, using N-((1R,2S)aminocyclopentyl) (*S)-(6-isobutoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide, acrylic anhydride and diisopropylethylamine in place of propenoyl chloride and triethylamine in step B. MS (ESI): mass calcd. for C H N O S, 27 30 6 4 534.6; m/z found, 535.0 [M+H] . H NMR (400 MHz, CDCl ): δ 9.49 (s, 1H), 8.33 (d, J = 5.4 Hz, 1H), 8.02 (s, 1H), 6.94 (dd, J = 22.5, 5.8 Hz, 2H), 6.79 (s, 1H), 6.33 (dd, J = 17.1, 1.7 Hz, 1H), 6.17 (dd, J = 16.9, 10.2 Hz, 1H), 6.02 (d, J = 5.5 Hz, 1H), 5.63 (dd, J = 10.2, 1.7 Hz, 1H), 4.40 (hept, J = 6.5 Hz, 2H), 4.09 (dt, J = 6.7, 3.7 Hz, 2H), 3.53 – 3.43 (m, 1H), 2.28 – 2.03 (m, 6H), 1.92 – 1.68 (m, 3H), 1.03 (d, J = 6.7 Hz, 6H).
Example 374: N-((1R,2S)Aminocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, using 5-(6- (cyclopentyloxy)methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Intermediate 25, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,2R) aminocyclopentyl)carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 492.6; m/z 28 6 3 found, 493.0 [M+H] . H NMR (500 MHz, CDCl3): δ 8.34 (d, J = 5.5 Hz, 1H), 8.01 (s, 1H), 6.77 – 6.71 (m, 2H), 6.03 (d, J = 5.5 Hz, 1H), 5.42 (tt, J = 6.2, 2.9 Hz, 1H), 4.15 (p, J = 7.1 Hz, 1H), 3.48 – 3.26 (m, 5H), 2.81 (s, 3H), 2.20 – 2.09 (m, 2H), 2.10 – 1.91 (m, 3H), 1.91 – 1.74 (m, 4H), 1.72 – 1.46 (m, 4H).
Example 375: N-((1R,2S)Aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and (1S,2R)-(2-aminocyclohexyl)carbamic acid tert-butyl ester, and diisopropylethylamine. MS (ESI): mass calcd. for C H N O S, 514.6; m/z found, 515.0 27 26 6 3 [M+H] . H NMR (400 MHz, CD OD): δ 8.55 (s, 1H), 8.16 (s, 1H), 7.58 - 7.40 (m, 2H), 7.39 - 7.01 (m, 4H), 6.49 (d, J = 6.3 Hz, 1H), 4.54 - 4.39 (m, 1H), 3.73 - 3.56 (m, 1H), 2.24 (s, 3H), 1.86 - 1.54 (m, 8H).
Example 376: N-((1R,2S)Acrylamidocyclopentyl)(2-cyclobutylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 2-Cyclobutylpyridinamine. To a solution of 2-bromopyridinamine (17.3 g, 100 mmol) and Pd(dppf)Cl2 (4.08 g, 5 mmol) in THF (600 mL), was added via syringe cyclobutylzinc(II) bromide (200 mL, 100 mmol). The reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was treated with saturated aqueous sodium bicarbonate (300mL), then extracted with EtOAc (2X300mL). The combined organic layers were dried (Na SO ) and concentrated under reduced pressure. Purification (FCC, SiO , PE/EA) afforded the title compound as a brown oil (4.4 g, 30%).
Step B. 5-(2-Cyclobutylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-G, using 2-cyclobutylpyridinamine.
Step C. N-((1R,2R)Acrylamidocyclopentyl)(2-cyclobutylpyridinyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-cyclobutylpyridinyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and N-((1S,2R) aminocyclopentyl)acrylamide (Intermediate 36), no HCl/MeOH deprotection step. MS (ESI): mass calcd. for C H N O S, 502.6; m/z found, 503.3 [M+H] . H NMR (400 MHz, CD OD): δ 26 26 6 3 3 8.70 (d, J = 5.3 Hz, 1H), 8.30 (d, J = 5.6 Hz, 1H), 7.46 (s, 1H), 7.38-7.32 (m, 1H), 6.33-6.15 (m, 3H), 5.65-5.58 (m, 1H), 4.50-4.33 (m, 2H), 3.88-3.71 (m, 1H), 2.46-2.28 (m, 4H), 2.17-1.99 (m, 3H), 1.97-1.84 (m, 2H), 1.81-1.57 (m, 3H).
Example 377: N-((1R,2S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and (1S,2R)-(2-aminocyclohexyl)carbamic acid tert-butyl ester and diisopropylethylamine in Step A, and using acetic anhydride and diisopropylethylamine in place of propenoyl chloride and triethylamine in Step B. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.0 29 28 6 4 [M+H] . H NMR (500 MHz, CD OD): δ 8.39 - 8.31 (m, 1H), 8.09 (s, 1H), 7.53 - 7.36 (m, 2H), 7.33 - 7.11 (m, 3H), 7.05 (s, 1H), 6.29 - 6.00 (m, 1H), 4.35 (s, 1H), 4.11 (d, J = 7.1 Hz, 1H), 2.21 (s, 3H), 2.02 (s, 3H), 1.82 - 1.45 (m, 8H).
Example 378: N-((1R,2S)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,2R)aminocyclopentyl)carbamate and diisopropylethylamine in Step A, and using acetic anhydride and diisopropylethylamine in place of propenoyl chloride and triethylamine in Step B. MS (ESI): mass calcd. for C H N O S, 542.6; m/z found, 543.0 28 26 6 4 [M+H] . H NMR (500 MHz, CDCl ): δ 9.54 (s, 1H), 8.35 (d, J = 5.5 Hz, 1H), 8.05 (s, 1H), 7.52 - 7.39 (m, 2H), 7.26 - 7.23 (m, 1H), 7.23 - 7.17 (m, 2H), 6.99 - 6.94 (m, 1H), 6.72 (d, J = 6.0 Hz, 1H), 6.08 (d, J = 6.6 Hz, 1H), 6.05 - 6.02 (m, 1H), 4.35 - 4.23 (m, 2H), 2.29 - 2.22 (m, 1H), 2.20 (d, J = 0.8 Hz, 3H), 2.14 - 2.07 (m, 1H), 2.04 (s, 3H), 1.91 - 1.81 (m, 4H).
Example 379: N-((1R,2R)Acrylamidocyclopentyl)(2-cyclobutylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- cyclobutylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 376, product from Step B) and N-((1R,2R)aminocyclopentyl)acrylamide (Example 382, product from Step A), no HCl/MeOH deprotection step. MS (ESI): mass calcd. for C H N O S, 502.6; m/z found, 503.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.69 (d, J = 26 26 6 3 3 .3 Hz, 1H), 8.26 (d, J = 5.5 Hz, 1H), 7.49 (s, 1H), 7.38 (dd, J = 5.2, 1.7 Hz, 1H), 6.24-6.10 (m, 3H), 5.61-5.54 (m, 1H), 4.29-4.15 (m, 2H), 3.84-3.69 (m, 1H), 2.44-2.29 (m, 4H), 2.20-2.02 (m, 3H), 1.95-1.86 (m, 1H), 1.83-1.72 (m, 2H), 1.68-1.49 (m, 2H).
Example 380: 5-(*S)-(2-Methylphenoxyphenyl)oxo-N-((1R,2S) propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1R,2S)aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 166, using 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,2R) aminocyclohexyl)carbamate.
Step B. 5-(*S)-(2-Methylphenoxyphenyl)oxo-N-((1R,2S)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in manner analogous to Example 1, Step B, using propionic anhydride and diisopropylethylamine in place of propenoyl chloride and triethylamine. MS (ESI): mass calcd. for C H N O S, 569.7; m/z found, 570.0 [M+H] . H NMR (500 MHz, CD OD): δ 8.33 31 31 5 4 3 (d, J = 5.6 Hz, 1H), 7.47 - 7.36 (m, 2H), 7.30 (d, J = 8.6 Hz, 1H), 7.23 - 6.96 (m, 5H), 6.07 (d, J = 5.6 Hz, 1H), 4.37 - 4.29 (m, 1H), 4.16 - 4.06 (m, 1H), 2.38 - 2.19 (m, 2H), 2.13 (s, 3H), 1.83 - 1.49 (m, 8H), 1.14 (t, J = 7.6 Hz, 3H).
Example 381: 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,2S) propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,2R)aminocyclohexyl)carbamate and diisopropylethylamine in Step A, and using propionic anhydride and diisopropylethylamine in place of propenoyl chloride and triethylamine in Step B. MS (ESI): mass calcd. for C H N O S, 570.7; m/z found, 571.0 30 6 4 [M+H] .
Example 382: N-((1R,2R)Acrylamidocyclopentyl)(*S)-(6-isobutylmethylpyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1R,2R)aminocyclopentyl)acrylamide. The title compound was prepared in a manner analogous to Intermediate 36, using tert-butyl ((1R,2R)aminocyclopentyl)carbamate.
Step B. N-((1R,2R)Acrylamidocyclopentyl)(*S)-(6-isobutylmethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(6-isobutylmethylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 18, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and N-((1R,2R) aminocyclopentyl)acrylamide, no HCl/MeOH deprotection step. MS (ESI): mass calcd. for C H N O S, 518.6; m/z found, 519 [M+H] . H NMR (400 MHz, CD OD): δ 8.39 (s, 1H), 27 30 6 3 3 8.33-8.28 (m, 1H), 7.39 (s, 1H), 6.27-6.16 (m, 2H), 6.03-5.97 (m, 1H), 5.67-5.55 (m, 1H), 4.30- 4.18 (m, 2H), 2.73-2.67 (m, 2H), 2.20 (s, 3H), 2.18-2.06 (m, 3H), 1.87-1.75 (m, 2H), 1.71-1.51 (m, 2H), 0.97 (d, J = 6.6 Hz, 6H).
Example 383: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(((S)-tetrahydrofuran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. (S)(2-methyl((tetrahydrofuranyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 7, using 4-fluoromethylnitrobenzene and (S)-tetrahydrofuran ol Step A.
Step B. N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(((S)-tetrahydrofuran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using N-((1S,2R) aminocyclopentyl)acrylamide (Intermediate 36) and (S)(2-methyl((tetrahydrofuran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid, no HCl/MeOH deprotection step. MS (ESI): mass calcd. for C H N O S, 547.6; m/z found, 548.2 28 29 5 5 [M+H] . H NMR (400 MHz, CD OD): δ 8.28 (d, J = 5.6 Hz, 1H), 7.26-7.18 (m, 1H), 7.02-6.89 (m, 2H), 6.34-6.16 (m, 2H), 6.06-5.96 (m, 1H), 5.68-5.55 (m, 1H), 5.11-5.05 (m, 1H), 4.48-4.35 (m, 2H), 4.05-3.92 (m, 3H), 3.90-3.85 (m, 1H), 2.35-2.23 (m, 1H), 2.18-2.02 (m, 6H), 1.98-1.86 (m, 1H), 1.80-1.62 (m, 3H).
Example 384: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 5-(2-methyl((6-methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 7, using 4-fluoromethylnitrobenzene and 6-methylpyridinol Step A.
Step B. N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using N-((1S,2R) aminocyclopentyl)acrylamide (Intermediate 36) and 5-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid, no HCl/MeOH deprotection step. MS (ESI): mass calcd. for C H N O S, 568.6; m/z found, 569.2 28 6 4 [M+H] . H NMR (400 MHz, DMSO-d and CD OD): δ 8.25 (d, J = 5.5 Hz, 1H), 8.23-8.17 (m, 1H), 7.46-7.36 (m, 1H), 7.33-7.22 (m, 2H), 7.07-7.00 (m, 1H), 6.97-6.91 (m, 1H), 6.26-6.05 (m, 2H), 5.96 (d, J = 5.5 Hz, 1H), 5.56-5.48 (m, 1H), 4.30-4.26 (m, 1H), 4.10-4.03 (m, 1H), 2.44 (s, 3H), 2.04 (s, 3H), 2.00-1.91 (m, 2H), 1.84-1.75 (m, 1H), 1.72-1.61 (m, 2H), 1.60-1.50 (m, 1H).
Example 385: 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3S) propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,3R)aminocyclohexyl)carbamate in Step A, and using propionic anhydride in place of propenoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 570.7; m/z 30 6 4 found, 571 [M+H] . H NMR (400 MHz, CD OD:DMSO-d = 2:1): δ 8.30-8.24 (m, 1H), 8.04- 8.02 (m, 1H), 7.40-7.32 (m, 2H), 7.21-7.09 (m, 3H), 7.02-6.98 (m, 1H), 6.07-6.01 (m, 1H), 3.90- 3.78 (m, 1H), 3.70-3.55 (m, 1H), 2.11 (s, 3H), 2.09-2.02 (m, 2H), 2.01-1.96 (m, 1H), 1.83-1.71 (m, 3H), 1.39-1.19 (m, 3H), 1.12-1.03 (m, 1H), 1.01-0.97 (m, 3H).
Example 386: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(((R)-tetrahydrofuran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. (R)(2-methyl((tetrahydrofuranyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 7, using 4-fluoromethylnitrobenzene and (R)-tetrahydrofuran ol Step A.
Step B. N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(((R)-tetrahydrofuran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using N-((1S,2R) aminocyclopentyl)acrylamide (Intermediate 36) and (R)(2-methyl((tetrahydrofuran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid. MS (ESI): mass calcd. for C H N O S, 547.6; m/z found, 548.1 [M+H] . H NMR (400 MHz, 28 29 5 5 CD OD): δ 8.28 (d, J = 5.5 Hz, 1H), 7.29-7.16 (m, 1H), 7.05-6.97 (m, 1H), 6.95-6.88 (m, 1H), 6.36-6.14 (m, 2H), 6.06-5.93 (m, 1H), 5.71-5.57 (m, 1H), 5.15-5.04 (m, 1H), 4.51-4.34 (m, 2H), 4.05 – 3.79 (m, 4H), 2.39-2.24 (m, 1H), 2.20-2.01 (m, 6H), 1.9-1.86 (m, 1H), 1.84-1.56 (m, 3H).
Example 387: N-((1R,2S)Acrylamidocyclopentyl)oxo(4-(pyridazinyloxy)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 4-Oxo(4-(pyridazinyloxy)phenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 3,6-dichloropyridazine, 4-nitrophenol in Step A, (no Cu).
Step B. N-((1R,2S)Acrylamidocyclopentyl)oxo(4-(pyridazinyloxy)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using N-((1S,2R)aminocyclopentyl)acrylamide (Intermediate 36) and 4-oxo(4-(pyridazinyloxy)phenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid, no HC/MeOH deprotection. MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.1 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.01 (s, 27 23 7 4 6 1H), 9.06-9.01 (m, 1H), 8.35-8.30 (m, 1H), 7.88-7.83 (m, 1H), 7.82-7.76 (m, 1H), 7.74-7.68 (br, 1H), 7.55-7.48 (m, 3H), 7.45-7.37 (m, 2H), 6.27-6.17 (m, 1H), 6.10-6.02 (m, 2H), 5.57-5.51 (m, 1H), 4.33-4.22 (m, 2H), 1.98-1.85 (m, 2H), 1.81-1.70 (m, 2H), 1.65-1.50 (m, 2H).
Example 388: 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3R) propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,3R)aminocyclopentyl)carbamate in Step A, and using propionic anhydride in place of propenoyl chloride Step B. MS (ESI): mass calcd. for C H N O S, 556.6; m/z 29 28 6 4 found, 557 [M+H] . H NMR (400 MHz, CD OD): δ 8.30 (d, J = 5.5 Hz, 1H), 8.09 (s, 1H), 7.49-7.37 (m, 2H), 7.29-7.19 (m, 1H), 7.18-7.11 (m, 2H), 7.01 (s, 1H), 6.12 (d, J = 5.5 Hz, 1H), 4.54- 4.39 (m, 1H), 4.36-4.21 (m, 1H), 2.22-2.10 (m, 7H), 2.06-1.84 (m, 2H), 1.73-1.41 (m, 2H), 1.19-1.02 (m, 3H).
Example 389: N-((1S,4S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1s,4s)aminocyclohexyl)carbamate in Step A, and using acetic anhydride in place of propenoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 556.6; m/z 29 28 6 4 found, 557 [M+H] . H NMR (400 MHz, CD OD): δ 8.34 (d, J = 5.3 Hz, 1H), 8.14 (s, 1H), 7.52-7.39 (m, 2H), 7.31-7.23 (m, 1H), 7.22-7.15 (m, 2H), 7.05 (s, 1H), 6.15 (d, J = 5.5 Hz, 1H), 4.11-3.77(m, 2H), 2.22 (s, 3H), 2.00 (s, 3H), 1.86-1.68 (m, 8H).
Example 390: 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3R) propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,3S)aminocyclopentyl)carbamate in Step A, and using propionic anhydride in place of propenoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 556.6; m/z 29 28 6 4 found, 557.3 [M+H] . H NMR (400 MHz, CD OD) : δ 8.34 (d, J = 5.6 Hz, 1H), 8.08 (s, 1H), 7.51 – 7.36 (m, 2H), 7.27-7.13 (m, 1H), 7.19 – 7.12 (m, 2H), 7.03 (s, 1H), 6.15 (d, J = 5.5 Hz, 1H), 4.41 – 4.23 (m, 1H), 4.18 – 4.00 (m, 1H), 2.51 – 2.34 (m, 1H), 2.24 – 2.13 (m, 5H), 2.09 – 1.91 (m, 2H), 1.82-1.63 (m, 2H), 1.60-1.48 (m, 1H), 1.12 (t, J = 7.6 Hz, 3H).
Example 391: N-((1S,3R)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,3S)aminocyclopentyl)carbamate in Step A, and using acetic anhydride in place of propenoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 542.6; m/z 28 26 6 4 found, 543.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.34 (d, J = 5.5 Hz, 1H), 8.08 (s, 1H), 7.49 – 7.37 (m, 2H), 7.29 – 7.21 (m, 1H), 7.21 – 7.12 (m, 2H), 7.03 (s, 1H), 6.15 (d, J = 5.6 Hz, 1H), 4.38 – 4.27 (m, 1H), 4.19 – 4.03 (m, 1H), 2.50 – 2.37 (m, 1H), 2.19 (s, 3H), 2.10-1.94 (m, 2H), 1.93 (s, 3H), 1.83 – 1.64 (m, 2H), 1.59-1.49 (m, 1H).
Example 392: N-((1R,3R)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,3R)aminocyclopentyl)carbamate in Step A, and using acetic anhydride in place of propenoyl chloride Step B. MS (ESI): mass calcd. for C H N O S, 542.61; m/z 28 26 6 4 found, 543.0 [M+H] . H NMR (400 MHz, CD OD): δ 8.37-8.31 (m, 1H), 8.11-8.04 (m, 1H), 7.45-7.38 (m, 2H), 7.27-7.20 (m, 1H), 7.19-7.12 (m, 2H), 7.05-6.99 (m, 1H), 6.18-6.11 (m, 1H), 4.55-4.39 (m, 1H), 4.33-4.20 (m, 1H), 2.20-2.10 (m, 5H), 2.01-1.84 (m, 5H), 1.70-1.58 (m, 1H), 1.53-1.41 (m, 1H).
Example 393: N-((1R,2R)Hydroxycyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide.
To a dry scintillation vial under Ar containing a stir bar were added (1R,2R)-trans aminocyclopentanol hydrochloride (1.5 mmol), and diisopropylethylamine (0.525 mL, 3.00 mmol) in THF (4 mL). To this reaction solution was added slowly by syringe 4-oxo(4- phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9, 10 mL, 0.1 M, 1 mmol) at room temperature. The reaction was monitored by LCMS and when it had gone to completion, the reaction was concentrated to dryness, the residue dissolved in DMF, and was purified by basic reverse phase HPLC to give the title compound (91.4 mg, 18.8% yield). MS (ESI): mass calcd. for C H N O S, 486.6; m/z found, 487.1 26 22 4 4 [M+H] . H NMR (500 MHz, CD OD): δ 8.31 (d, J = 5.6 Hz, 1H), 7.49 - 7.27 (m, 4H), 7.27 - 7.03 (m, 5H), 6.18 (d, J = 5.6 Hz, 1H), 4.18 - 4.06 (m, 2H), 2.25 - 2.07 (m, 1H), 2.07 - 1.93 (m, 1H), 1.93 - 1.72 (m, 2H), 1.72 - 1.54 (m, 2H).
Example 394: N-((1R,3S)Aminocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, using 5-(6- (cyclopentyloxy)methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Intermediate 25, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,3R) aminocyclopentyl)carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 492.6; m/z 28 6 3 found, 493.0 [M+H] . H NMR (500 MHz, CDCl ): δ 8.32 (d, J = 5.5 Hz, 1H), 8.01 (s, 1H), 7.91 (d, J = 8.3 Hz, 1H), 6.72 (t, J = 0.8 Hz, 1H), 6.02 (d, J = 5.4 Hz, 1H), 5.41 (td, J = 6.0, 3.0 Hz, 1H), 4.59 (tdd, J = 9.1, 6.3, 2.7 Hz, 1H), 3.73 (tt, J = 5.5, 2.5 Hz, 1H), 3.48 (d, J = 6.2 Hz, 4H), 3.37 – 3.29 (m, 5H), 2.13 (s, 3H), 2.10 – 1.88 (m, 2H), 1.90 – 1.74 (m, 3H), 1.70 – 1.54 (m, 3H).
Example 395: N-((1S,3S)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,3S)aminocyclopentyl)carbamate in Step A, and using acetic anhydride Step B. MS (ESI): mass calcd. for C H N O S, 542.6; m/z found, 543 [M+H] . H NMR (400 28 26 6 4 MHz, CD OD): δ 8.41-8.28 (m, 1H), 812-8.04 (m, 1H), 7.49-7.36 (m, 2H), 7.28-7.21 (m, 1H), 7.20-7.13 (m, 2H), 7.06-6.98 (m, 1H), 6.19-6.09 (m, 1H), 4.51-4.44 (m, 1H), 4.33-4.23 (m, 1H), 2.24-2.09 (m, 5H), 2.01-1.85 (m, 5H), 1.72-1.59 (m, 1H), 1.57-1.46 (m, 1H).
Example 396: N-((1R,2S)Acetamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1R,2S)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide. To a dry scintillation vial under Ar containing a stir bar were added tert-butyl ((1S,2R)aminocyclopentyl)carbamate (301 mg, 1.50 mmol), and diisopropylethylamine (0.525 mL, 3.00 mmol) in THF (4 mL). To this reaction solution was added slowly by syringe 4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl chloride (Intermediate 9, 10 mL, 0.1 M, 1 mmol) at room temperature. The reaction was monitored by LCMS and when it had gone to completion, the reaction was concentrated to dryness, the residue dissolved in DMF, and was purified by basic reverse phase HPLC to give the title compound (142.3 mg, 29.31% yield).
Step B: N-((1R,2S)Acetamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound in a manner analogous to Example 1, Step B, using N-((1R,2S)aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide, acetic anhydride and diisopropylethylamine. MS (ESI): mass calcd. for C H N O S, 527.6; m/z found, 528.0 28 25 5 4 [M+H] . H NMR (400 MHz, CDCl ): δ 8.33 (d, J = 5.5 Hz, 1H), 7.47 - 7.34 (m, 2H), 7.34 - 7.27 (m, 2H), 7.24 - 7.01 (m, 6H), 6.61 (d, J = 5.6 Hz, 1H), 6.23 - 6.07 (m, 2H), 4.36 - 4.25 (m, 2H), 2.33 - 2.21 (m, 1H), 2.19 - 2.06 (m, 1H), 2.03 (s, 3H), 1.94 - 1.71 (m, 4H).
Example 397: N-((1R,2S)Aminocyclopentyl)(*S)-(6-isobutoxymethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 166, Step A, using 5-(6- isobutoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 33, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,2R)aminocyclopentyl)carbamate (with a TFA/DCM deprotection). MS (ESI): mass calcd. for C H N O S, 480.6; m/z found, 481.0 [M+H] . H 24 28 6 3 NMR (500 MHz, CDCl ): δ 8.27 (d, J = 5.4 Hz, 1H), 8.00 (s, 1H), 6.94 (s, 1H), 6.79 (d, J = 0.9 Hz, 1H), 5.99 (d, J = 5.5 Hz, 1H), 5.30 (s, 1H), 4.20 (p, J = 7.1 Hz, 1H), 4.12 – 4.02 (m, 2H), 3.54 – 3.46 (m, 3H), 2.19 – 2.01 (m, 5H), 1.84 (dddd, J = 13.2, 8.8, 6.1, 3.0 Hz, 1H), 1.74 – 1.50 (m, 4H), 1.03 (dd, J = 6.7, 1.7 Hz, 6H).
Example 398: 4-Oxo(4-phenoxyphenyl)-N-((1R,2S)propionamidocyclopentyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step B, using N- ((1R,2S)aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide (Example 396, product from Step A), propionic anhydride and diisopropylethylamine in place of propenoyl chloride and triethylamine. MS (ESI): mass calcd. for C H N O S, 541.62; m/z found, 542.0 [M+H] . H NMR (400 MHz, CDCl ): δ 9.48 29 27 5 4 3 (s, 1H), 8.34 (d, J = 5.5 Hz, 1H), 7.53 - 7.36 (m, 2H), 7.31 - 7.27 (m, 1H), 7.23 - 7.08 (m, 5H), 6.67 (d, J = 5.6 Hz, 1H), 6.14 (d, J = 5.5 Hz, 1H), 5.92 (d, J = 6.2 Hz, 1H), 4.41 - 4.10 (m, 2H), 2.36 - 2.20 (m, 3H), 2.19 - 2.05 (m, 1H), 1.91 - 1.68 (m, 5H), 1.19 (t, J = 7.6 Hz, 3H).
Example 399: 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3S) propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,3S)aminocyclopentyl)carbamate in Step A, and using propionic anhydride in place of propenoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557 [M+H] . H NMR (400 MHz, CD OD): δ 8.33 (d, J = 5.5 29 28 6 4 3 Hz, 1H), 8.08 (s, 1H), 7.48-7.37 (m, 2H), 7.27-7.20 (m, 1H), 7.19-7.13 (m, 2H), 7.02 (s, 1H), 6.14 (d, J = 5.6 Hz, 1H), 4.53- 4.41 (m, 1H), 4.36-4.22 (m, 1H), 2.24-2.10 (m, 7H), 2.05-1.83 (m, 2H), 1.71-1.59 (m, 1H), 1.56-1.43 (m, 1H), 1.15-1.05 (m, 3H).
Example 400: N-((1S,3S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,3S)aminocyclohexyl)carbamate in place of tert-butyl ((1S,4S)aminocyclohexyl)carbamate Step A, and using acetic anhydride in place of prop enoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.0 29 28 6 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.36-8.32 (m, 1H), 8.10-8.06 (m, 1H), 7.45-7.38 (m, 2H), 7.27-7.20 (m, 1H), 7.19-7.12 (m, 2H), 7.05-6.99 (m, 1H), 6.18-6.12 (m, 1H), 4.21-4.08 (m, 2H), 2.19 (s, 3H), 1.85 (s, 3H), 1.90-1.81 (m, 2H), 1.77-1.56 (m, 6H).
Example 401: N-((1R,2S)Acrylamidocyclohexyl)(2-methyl(pyridinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methyl(pyridinyloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Example 220, product from Step A) and N-((1S,2R) aminocyclohexyl)acrylamide (Intermediate 40), no HCl/MeOH deprotection. MS (ESI): mass calcd. for C H N O S, 568.6; m/z found, 569.3 [M+H] . H NMR (400 MHz, CD OD): δ 28 6 4 3 8.36-8.26 (m, 1H), 8.19-8.10 (m, 1H), 7.92-7.80 (m, 1H), 7.39-7.32 (m, 1H), 7.24-7.17 (m, 1H), 7.17-7.09 (m, 2H), 7.08-7.01 (m, 1H), 6.45-6.35 (m, 1H), 6.30-6.17 (m, 2H), 5.70-5.59 ( m, 1H), 4.47-4.35 (m, 1H), 4.20-4.05 (m, 1H), 2.15 (s, 3H), 1.83-1.60 (m, 6H), 1.58-1.45 (m, 2H).
Example 402: 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3S) propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,3S)aminocyclohexyl)carbamate in Step A, and using propionic anhydride in place of propenoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 570.7; m/z found, 571.0 [M+H] . H NMR (400 MHz, CD OD): δ 8.36-8.32 (m, 30 6 4 3 1H), 8.10-8.06 (m, 1H), 7.45-7.38 (m, 2H), 7.27-7.20 (m, 1H), 7.19-7.12 (m, 2H), 7.05-6.99 (m, 1H), 6.18-6.12 (m, 1H), 4.22-4.05 (m, 2H), 2.27-2.20 (m, 2H), 2.19 (s, 3H), 1.91-1.79 (m, 2H), 1.78-1.55 (m, 6H), 1.15-1.08 (m, 3H).
Example 403: N-((1R,3S)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,3R)aminocyclopentyl)carbamate in Step A, and using acetic anhydride in place of propenoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 542.6; m/z found, 542.9 [M+H] . H NMR (400 MHz, DMSO-d and CD OD): δ 28 26 6 4 6 3 8.26 (d, J = 5.5 Hz, 1H), 8.02 (s, 1H), 7.42-7.31 (m, 2H), 7.19-7.13 (m, 1H), 7.12-7.07(m, 2H), 7.00 (s, 1H), 6.04 (d, J = 5.6 Hz, 1H), 4.30-4.18 (m, 1H), 4.05-3.91 (m, 1H), 2.35-2.23 (m, 1H), 2.11 (s, 3H), 1.98-1.83 (m, 2H), 1.81 (s, 3H), 1.74-1.53 (m, 2H), 1.52-1.40 (m, 1H).
Example 404: N-((1R,2R)Acrylamidocyclohexyl)(*S)-(6-isobutylmethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(6- isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 18, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and N-((1R,2R)aminocyclohexyl)acrylamide (Intermediate 41), no HCl/MeOH deprotection. MS (ESI): mass calcd. for C H N O S, 532.7; m/z found, 533.0 28 32 6 3 [M+H] . H NMR (400 MHz, CD OD): δ 8.38 (s, 1H), 8.32-8.24 (m, 1H), 7.38 (s, 1H), 6.24- 6.09 (m, 2H), 6.04-5.93 (m, 1H), 5.66-5.48 (m, 1H), 3.93-3.77 (m, 2H), 2.75-2.65 (m, 2H), 2.19 (s, 3H), 2.12-1.94 (m, 3H), 1.85-1.73 (m, 2H), 1.51-1.32 (m, 4H), 0.96 (d, J = 5.9 Hz, 6H).
Example 405: N-((1R,3S)Aminocyclopentyl)(*S)-(6-isobutoxymethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(6- isobutoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 33, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,3R)aminocyclopentyl)carbamate. MS (ESI): mass calcd. for C H N O S, 480.6; m/z found, 481.0 [M+H] . H NMR (500 MHz, CDCl ): δ 8.33 (d, J = 24 28 6 3 3 .5 Hz, 1H), 8.01 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 6.81 – 6.77 (m, 1H), 6.01 (d, J = 5.5 Hz, 1H), 4.65 – 4.55 (m, 1H), 4.09 (qd, J = 10.1, 6.6 Hz, 2H), 3.74 (tt, J = 5.5, 2.4 Hz, 1H), 3.48 (s, 3H), 2.17 – 1.87 (m, 8H), 1.63 – 1.53 (m, 2H), 1.03 (dd, J = 6.7, 1.4 Hz, 6H).
Example 406: N-((1R,2S)Acrylamidocyclohexyl)(2-methyl(pyridazinyloxy)phenyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methyl(pyridazinyloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxylic acid (Example 305, product from Step A) and N-((1S,2R) aminocyclohexyl)acrylamide (Intermediate 40), no HCl/MeOH deprotection. MS (ESI): mass calcd. for C H N O S, 569.6; m/z found, 570.2 [M+H] . H NMR (400 MHz, CD OD): δ 29 27 7 4 3 8.96-8.92 (m, 1H), 8.32-8.28 (m, 1H), 7.79-7.73 (m, 1H), 7.50-7.42 (m, 2H), 7.34-7.30 (m, 1H), 7.27-7.21 (m, 1H), 6.48-6.36 (m, 1H), 6.31-6.22 (m, 1H), 6.21-6.16 (m, 1H), 5.69-5.62 (m, 1H), 4.46-4.39 (m, 1H), 4.17-4.08 (m, 1H), 2.20-2.14 (m, 3H), 1.83-1.48 (m, 8H).
Example 407: N-((1S,3R)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and N-((1R,3S)aminocyclohexyl)acetamide, no deprotection with HCl/MeOH. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.0 [M+H] . H 29 28 6 4 NMR (400 MHz, CD OD): δ 8.36-8.31 (m, 1H), 8.10-8.06 (m, 1H), 7.46-7.38 (m, 2H), 7.27- 7.20 (m, 1H), 7.19-7.12 (m, 2H), 7.05-6.99 (m, 1H), 6.16-6.12 (m, 1H), 4.03-3.88 (m, 1H), 3.78- 3.68 (m, 1H), 2.19 (s, 3H), 2.15-2.06 (m, 1H), 1.96-1.80 (m, 6H), 1.47-1.25 (m, 3H), 1.20-1.09 (m, 1H).
Example 408: N-((1R,2S)Acrylamidocyclohexyl)oxo(4-(pyridazinyloxy)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (4-(pyridazinyloxy)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 387, product from Step A) and N-((1S,2R)aminocyclohexyl)acrylamide (Intermediate 40), no HCl/MeOH deprotection. MS (ESI): mass calcd. for C H N O S, 555.6; 28 25 7 4 m/z found, 556.1 [M+H] . H NMR (400 MHz, CD3OD): δ 8.99-8.94 (m, 1H), 8.35-8.29 (m, 1H), 7.82-7.74 (m, 1H), 7.55-7.49 (m, 3H), 7.46-7.42 (m, 2H), 6.47-6.37 (m, 1H), 6.33-6.23 (m, 2H), 5.70-5.62 (m, 1H), 4.45-4.39 (m, 1H), 4.20-4.10 (m, 1H), 1.85-1.74 (m, 4H), 1.69-1.48 (m, 4H).
Example 409: 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1S,3S) propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 29) and tert-butyl ((1S,3S)aminocyclopentyl)carbamate and diisopropylethylamine in Step A, and propionic anhydride in place of propenoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.0 [M+H] . H NMR 29 28 6 4 (500 MHz, CDCl ): δ 12.31 (d, J = 5.5 Hz, 1H), 11.74 (d, J = 8.6 Hz, 1H), 11.49 - 11.32 (m, 2H), 11.29 - 11.09 (m, 3H), 10.86 (d, J = 8.6 Hz, 1H), 10.10 (d, J = 5.5 Hz, 1H), 8.54 - 8.34 (m, 1H), 8.34 - 8.18 (m, 1H), 6.20 (s, 3H), 6.20 - 6.08 (m, 4H), 5.94 - 5.80 (m, 2H), 5.73 - 5.41 (m, 2H), 5.08 (t, J = 7.6 Hz, 3H).
Example 410: N-((1S,3S)Acetamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step B, using N-((1S,3S)- 3-aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 415) and acetic anhydride in place of prop- 2-enoyl chloride. MS (ESI): mass calcd. for C H N O S, 542.6; m/z found, 543.1 [M+H] . H 28 26 6 4 NMR (400 MHz, CD OD): δ 8.35 (d, J = 5.6 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.52 - 7.38 (m, 2H), 7.31 - 7.15 (m, 3H), 6.90 (d, J = 8.5 Hz, 1H), 6.20 - 6.08 (m, 1H), 4.58 - 4.39 (m, 1H), 4.35 - 4.11 (m, 2H), 2.38 - 1.43 (m, 12H).
Example 411: N-((1S,3R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step B, using N- ((1S,3R)aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide (Example 414), acrylic anhydride and diisopropylethylamine, in place of propenoyl chloride and trimethylamine. MS (ESI): mass calcd. for C30H28N6O4S, 568.7; m/z found, 569.0 [M+H] . H NMR (500 MHz, CD3OD): δ 8.36 (d, J = 5.6 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.53 - 7.37 (m, 2H), 7.35 - 7.14 (m, 3H), 6.91 (d, J = 8.6 Hz, 1H), 6.32 - 6.08 (m, 3H), 5.64 (dd, J = 7.2, 4.8 Hz, 1H), 4.09 - 3.81 (m, 2H), 2.25 (s, 3H), 2.22 - 2.14 (m, 1H), 2.00 - 1.88 (m, 3H), 1.54 - 1.14 (m, 4H).
Example 412: 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1S,3R) propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step B, using N- ((1S,3R)aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide (Example 414), propionic anhydride and diisopropylethylamine in place of propenoyl chloride and triethylamine. MS (ESI): mass calcd. for C H N O S, 570.7; m/z found, 571.0 [M+H] . H NMR (500 MHz, CD OD): δ 8.36 30 6 4 3 (d, J = 5.5 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.55 - 7.37 (m, 2H), 7.32 - 7.12 (m, 3H), 6.91 (d, J = 8.6 Hz, 1H), 6.15 (d, J = 5.5 Hz, 1H), 4.03 - 3.67 (m, 2H), 2.25 (s, 3H), 2.23 - 2.09 (m, 3H), 1.97 - 1.82 (m, 3H), 1.53 - 1.41 (m, 1H), 1.39 - 1.27 (m, 2H), 1.23 - 1.14 (m, 1H), 1.12 (t, J = 7.6 Hz, 3H).
Example 413: N-((1S,3R)Acetamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step B, using N- ((1S,3R)aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide (Example 414), acetic anhydride and diisopropylethylamine in place of propenoyl chloride and triethylamine. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.0 [M+H] . H NMR (500 MHz, CD OD): δ 8.35 29 28 6 4 3 (d, J = 5.6 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.53 - 7.34 (m, 2H), 7.32 - 7.13 (m, 3H), 7.00 - 6.76 (m, 1H), 6.14 (d, J = 5.5 Hz, 1H), 4.08 - 3.92 (m, 1H), 3.84 - 3.69 (m, 1H), 2.25 (s, 3H), 2.15 (d, J = 12.1 Hz, 1H), 2.00 - 1.79 (m, 5H), 1.54 - 1.41 (m, 1H), 1.40 - 1.27 (m, 3H), 1.23 - 1.11 (m, 1H).
Example 414: N-((1S,3R)Aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 29, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,3S)aminocyclohexyl)carbamate, and diisopropylethylamine. MS (ESI): mass calcd. for C H N O S, 514.6; m/z found, 515.1 27 26 6 3 [M+H] . H NMR (500 MHz, CD OD): δ 8.57 (d, J = 6.2 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.55 - 7.38 (m, 2H), 7.34 - 7.20 (m, 3H), 6.97 (d, J = 8.4 Hz, 1H), 6.59 - 6.45 (m, 1H), 4.13 - 3.49 (m, 1H), 3.28 - 3.16 (m, 1H), 2.41 - 2.27 (m, 4H), 2.16 - 1.93 (m, 3H), 1.64 - 1.13 (m, 4H).
Example 415: N-((1S,3S)Aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 29, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and using tert-butyl ((1S,3S)aminocyclopentyl)carbamate. MS (ESI): mass calcd. for C H N O S, 500.6; m/z found, 501.0 [M+H] . H NMR (600 MHz, CDCl ): δ 8.37 26 24 6 3 3 (d, J = 5.5 Hz, 1H), 7.58 - 7.33 (m, 3H), 7.26 - 7.17 (m, 3H), 6.81 (d, J = 8.5 Hz, 1H), 6.02 (d, J = 5.4 Hz, 1H), 5.53 (d, J = 7.2 Hz, 1H), 4.65 - 4.50 (m, 1H), 3.62 - 3.52 (m, 1H), 2.40 - 2.30 (m, 1H), 2.28 (s, 3H), 2.14 - 2.05 (m, 1H), 1.88 - 1.83 (m, 2H), 1.59 - 1.47 (m, 1H), 1.47 - 1.36 (m, 1H).
Example 416: 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3R) propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and N-((1R,3S)aminocyclohexyl)propionamide in Step A. MS (ESI): mass calcd. for C H N O S, 570.7; m/z found, 571.0 [M+H] . H NMR (400 MHz, CD OD): δ 8.35-8.30 (m, 30 6 4 3 1H), 8.10-8.07 (m, 1H), 7.45-7.38 (m, 2H), 7.27-7.20 (m, 1H), 7.19-7.12 (m, 2H), 7.05-6.99 (m, 1H), 6.15-6.11 (m, 1H), 4.01-3.87 (m, 1H), 3.79-3.66 (m, 1H), 2.19 (s, 3H), 2.18-2.08 (m, 3H), 1.94-1.80 (m, 3H), 1.51-1.38 (m, 1H), 1.37-1.26 (m, 2H), 1.21-1.12 (m, 1H), 1.11-1.06 (m, 3H).
Example 417: (S)(2-Methylphenoxyphenyl)(3-(methylamino)pyrrolidinecarbonyl)- 3Hthia-3,5,8-triazaacenaphthylen-4(5H)-one.
S NH N NH Step A: (R)(3-Hydroxypyrrolidinecarbonyl)(2-methylphenoxyphenyl)-3Hthia- 3,5,8-triazaacenaphthylen-4(5H)-one. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Intermediate 1) and (3R)-pyrrolidinol, no deprotection with HCl/MeOH.
Step B: (R)(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl 4-methylbenzenesulfonate. To a round bottom flask were added (R)(3-hydroxypyrrolidinecarbonyl)(2-methylphenoxyphenyl)-3H thia-3,5,8-triazaacenaphthylen-4(5H)-one (152 mg, 0.312 mmol), diisopropylethylamine (80 mg, 0.62 mmol), DCM (10 mL), and 4-methylbenzenesulfonyl chloride (77 mg, 0.41 mmol) sequentially and stirred at reflux for 3 h. The mixture was concentrated to dryness and used in the next step without purification (203 mg).
Step C: (S)(2-Methylphenoxyphenyl)(3-(methylamino)pyrrolidinecarbonyl)-3H thia-3,5,8-triazaacenaphthylen-4(5H)-one. A solution of (R)(5-(2-methylphenoxyphenyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl)pyrrolidinyl 4- methylbenzenesulfonate (203 mg, 0.317 mmol) and methyl amine (5 mL) was added to a sealed tube and stirred at 80 °C for 15 h. The mixture was concentrated to dryness and purified by flash column chromatography, then by prep-TLC to give the title compound as a light yellow solid (10 mg, 6.3% yield). MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, 500.4 [M+H] . H 27 25 5 3 NMR (400 MHz, CD OD): δ 8.35-8.31 (m, 1H), 7.43-7.36 (m, 2H), 7.32-7.25 (m, 1H), 7.20- 7.13 (m, 1H), 7.13-7.03 (m, 3H), 7.02-6.95 (m, 1H), 6.09-6.05 (m, 1H), 4.10-3.87 (m, 3H), 3.84- 3.76 (m, 1H), 2.87-2.82 (m, 1H), 2.73 (s, 3H), 2.52-2.40 (m, 1H), 2.10 (s, 3H), 2.08-1.91 (m, 1H).
Example 418: (S)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)propionamide.
A solution of (S)(3-aminopyrrolidinecarbonyl)(2-methylphenoxyphenyl)-3Hthia- 3,5,8-triazaacenaphthylen-4(5H)-one (Example 420, 150 mg, 0.31 mmol), propionic acid (46 mg, 0.62 mmol), HATU (153 mg, 0.402 mmol), and diisopropylethylamine (60 mg, 0.46 mmol) in DMF (5 mL) was stirred at rt for 2 h. The mixture was purified by HPLC to give the title compound as a light yellow solid (75 mg, 44% yield). MS (ESI): mass calcd. for C H N O S, 29 27 5 4 541.6; m/z found, 542.6 [M+H] . H NMR (400 MHz, CD OD): δ 8.32-8.27 (m, 1H), 7.42-7.35 (m, 3H), 7.19-7.12 (m, 1H), 7.10-7.01 (m, 3H), 6.99-6.93 (m, 1H), 6.06-6.01 (m, 1H), 4.49-4.37 (m, 1H), 4.00-3.53 (m, 4H), 2.28-2.15 (m, 3H), 2.13-2.09 (m, 3H), 2.06-1.94 (m, 1H), 1.11 (t, J = 7.6 Hz, 3H).
Example 419: (S)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)acetamide.
N NH The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(3S)-pyrrolidinyl]carbamate in Step A, and acetyl chloride in place of propenoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 527.6; m/z 28 25 5 4 found, 528.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.34-8.30 (m, 1H), 7.42-7.32 (m, 3H), 7.19-7.12 (m, 1H), 7.11-7.02 (m, 3H), 6.99-6.94 (m, 1H), 6.08-6.04 (m, 1H), 4.47-4.39 (m, 1H), 4.07-3.73 (m, 3H), 3.69-3.54 (m, 1H), 2.30-2.19 (m, 1H), 2.15-2.08 (m, 3H), 2.06-1.98 (m, 1H), 1.95 (s, 3H).
Example 420: (S)(3-Aminopyrrolidinecarbonyl)(2-methylphenoxyphenyl)-3Hthia- 3,5,8-triazaacenaphthylen-4(5H)-one.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl N-[(3S)-pyrrolidinyl]carbamate. MS (ESI): mass calcd. for C H N O S, 485.6; m/z found, 486.0 [M+H] . H NMR (400 MHz, CD OD): δ 8.34-8.28 26 23 5 3 3 (m, 1H), 7.44-7.32 (m, 3H), 7.20-7.13 (m, 1H), 7.12-7.02 (m, 3H), 7.01-6.94 (m, 1H), 6.09-6.03 (m, 1H), 3.98-3.63 (m, 4H), 3.59-3.44 (m, 1H), 2.30-2.17 (m, 1H), 2.12 (s, 3H), 1.98-1.84 (m, 1H).
Example 421: (S)(3-(Dimethylamino)pyrrolidinecarbonyl)(2-methylphenoxyphenyl)- 3Hthia-3,5,8-triazaacenaphthylen-4(5H)-one.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and (3S)-N,N-dimethylpyrrolidinamine, no deprotection step with HCl/MeOH. MS (ESI): mass calcd. for C H N O S, 513.6; m/z found, 514.1 [M+H] . H 28 27 5 3 NMR (400 MHz, CD OD): δ 8.36-8.32 (m, 1H), 8.31 (s, 1H), 7.43-7.36 (m, 2H), 7.34-7.29 (m, 1H), 7.19-7.13 (m, 1H), 7.11-7.03 (m, 3H), 7.00-6.96 (m, 1H), 6.10-6.06 (m, 1H), 4.12-3.98 (m, 2H), 3.82-3.67 (m, 1H), 3.66-3.57 (m, 1H), 2.56 (s, 6H), 2.42-2.33 (m, 1H), 2.12 (s, 3H), 2.08- 1.99 (m, 1H).
Example 422: N-((1R,3R)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,3R)aminocyclohexyl)carbamate in Step A, and acetic anhydride in place of propenoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 29 28 6 4 557.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.36-8.31 (m, 1H), 8.11-8.06 (m, 1H), 7.48- 7.39 (m, 2H), 7.27-7.20 (m, 1H), 7.19-7.14 (m, 2H), 7.06-7.00 (m, 1H), 6.17-6.10 (m, 1H), 4.19- 4.04 (m, 2H), 2.20 (s, 3H), 1.97 (s, 3H), 1.88-1.58 (m, 8H).
Example 423: 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3R) propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,3R)aminocyclohexyl)carbamate in Step A, and propionic anhydride in place of propenoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 570.7; m/z 30 6 4 found, 571.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.42-8.32 (m, 1H), 8.15-8.06 (m, 1H), 7.50-7.37 (m, 2H), 7.29-7.10 (m, 3H), 7.07-7.00 (m, 1H), 6.24-6.15 (m, 1H), 4.21-4.06 (m, 2H), 2.17-2.06 (m, 5H), 1.86-1.57 (m, 8H), 1.19-1.05 (m, 3H).
Example 424: N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl(pyridazin yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC purification (Stationary phase: CHIRALCEL AS-H, 5 µm, 250 × 20 mm, Mobile phase: 60% CO , 40% MeOH) of N-((1R,2S)Acrylamidocyclopentyl)(2-methyl (pyridazinyloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide (Example 305) afforded the title compound. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.2 [M+H] . H NMR (500 MHz, CDCl ): δ 9.06 - 8.92 (m, 28 25 7 4 3 1H), 8.36 (d, J = 5.5 Hz, 1H), 7.66 - 7.48 (m, 1H), 7.31 - 7.27 (m, 3H), 7.26 - 7.21 (m, 1H), 6.77 - 6.60 (m, 1H), 6.48 - 6.26 (m, 2H), 6.26 - 5.94 (m, 2H), 5.87 - 5.57 (m, 1H), 4.48 - 4.26 (m, 2H), 2.35 - 2.22 (m, 1H), 2.19 (s, 4H), 1.96 - 1.81 (m, 1H), 1.79 - 1.73 (m, 3H).
Example 425: N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl(pyridazin yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC purification (Stationary phase: CHIRALCEL AS-H, 5 µm, 250 × 20 mm, Mobile phase: 60% CO , 40% MeOH) of N-((1R,2S)Acrylamidocyclopentyl)(2-methyl (pyridazinyloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide (Example 305) afforded the title compound. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.2 [M+H] . H NMR (500 MHz, CDCl ): δ 9.50 (s, 1H), 28 25 7 4 3 9.00 (dd, J = 4.5, 1.4 Hz, 1H), 8.45 - 8.27 (m, 1H), 7.66 - 7.44 (m, 1H), 7.31 - 7.27 (m, 3H), 7.26 - 7.22 (m, 1H), 6.80 - 6.63 (m, 1H), 6.50 - 6.33 (m, 1H), 6.33 - 5.95 (m, 3H), 5.84 - 5.56 (m, 1H), 4.50 - 4.19 (m, 2H), 2.35 - 2.22 (m, 1H), 2.18 (s, 3H), 2.04 - 1.83 (m, 1H), 1.78 - 1.68 (m, 4H).
Example 426: N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-isopropoxymethylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step B, using acrylic anhydride and N-((1R,2S)aminocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 428). MS (ESI): mass calcd. for C H N O S, 520.6; m/z found, 521.2 [M+H] . H NMR (500 MHz, 26 28 6 4 CDCl ): δ 8.34 (d, J = 5.5 Hz, 1H), 8.01 (s, 1H), 6.79 (d, J = 6.2 Hz, 1H), 6.72 (s, 1H), 6.64 (d, J = 6.5 Hz, 1H), 6.38 - 6.31 (m, 1H), 6.15 (dd, J = 16.9, 10.2 Hz, 1H), 6.04 (d, J = 5.4 Hz, 1H), .66 (d, J = 10.4 Hz, 1H), 5.32 (hept, J = 6.1 Hz, 1H), 4.36 (tt, J = 13.3, 6.5 Hz, 2H), 2.30 - 2.06 (m, 6H), 1.87 (qd, J = 8.4, 7.8, 4.1 Hz, 1H), 1.73 (dtd, J = 19.7, 10.4, 9.1, 4.8 Hz, 3H), 1.37 (dd, J = 13.1, 6.1 Hz, 6H).
Example 427: N-((1R,3S)Acrylamidocyclopentyl)(*S)-(6-isopropoxymethylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH S HN The title compound was prepared in a manner analogous to Example 1, Step B, using acrylic anhydride and N-((1R,3S)aminocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 429). MS (ESI): mass calcd. for C H N O S, 520.6; m/z found, 521.2 [M+H] . H NMR (400 MHz, 26 28 6 4 CDCl3): δ 8.32 (d, J = 5.6 Hz, 1H), 8.03 (s, 1H), 7.70 (d, J = 7.3 Hz, 1H), 7.24 (s, 1H), 6.72 (s, 1H), 6.37 (d, J = 16.9 Hz, 1H), 6.12 (dd, J = 17.0, 10.2 Hz, 1H), 6.03 (d, J = 5.5 Hz, 1H), 5.64 (d, J = 10.4 Hz, 1H), 5.31 (d, J = 4.6 Hz, 2H), 4.39 (p, J = 5.4, 4.8 Hz, 1H), 4.14 (dq, J = 14.4, 6.9 Hz, 2H), 2.45 (dt, J = 14.4, 8.8 Hz, 1H), 2.13 (s, 3H), 2.07 - 1.79 (m, 6H), 1.40 - 1.32 (m, 4H).
Example 428: N-((1R,2S)Aminocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, using 5-(6- isopropoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 30, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,2R)aminocyclopentyl)carbamate in Step A, and TFA/DCM deprotection in Step B. MS (ESI): mass calcd. for C H N O S, 466.6; m/z found, 23 26 6 3 467.2 [M+H] . H NMR (400 MHz, CDCl ): δ 7.93 (d, J = 16.3 Hz, 3H), 6.65 (s, 1H), 5.84 (d, J = 5.5 Hz, 1H), 5.19 - 4.95 (m, 1H), 4.78 - 4.45 (m, 1H), 3.70 (q, J = 6.7, 6.2 Hz, 1H), 2.25 (d, J = 28.5 Hz, 4H), 2.16 - 1.97 (m, 1H), 1.96 - 1.70 (m, 3H), 1.53 (d, J = 9.2 Hz, 1H), 1.31 (d, J = 6.1 Hz, 3H), 1.27 (dd, J = 27.9, 6.1 Hz, 6H).
Example 429: N-((1R,3S)Aminocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 166, using 5-(6- isopropoxymethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 30, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1S,3R)aminocyclopentyl)carbamate in Step A, and TFA/DCM deprotection in Step B. MS (ESI): mass calcd. for C H N O S, 466.6; m/z found, 23 26 6 3 467.2 [M+H] . H NMR (400 MHz, CDCl ): δ 8.30 (d, J = 5.5 Hz, 1H), 8.00 (d, J = 25.9 Hz, 2H), 6.71 (d, J = 1.0 Hz, 1H), 6.01 (d, J = 5.5 Hz, 1H), 5.39 - 5.25 (m, 1H), 4.59 (dtt, J = 8.7, 6.3, 2.5 Hz, 1H), 4.07 (s, 3H), 3.73 (tt, J = 5.2, 2.2 Hz, 1H), 2.14 (d, J = 0.9 Hz, 3H), 2.12 - 1.87 (m, 4H), 1.66 - 1.56 (m, 2H), 1.37 (dd, J = 10.5, 6.2 Hz, 6H).
Example 430: N-((1S,3R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and in Step A and acrylic anhydride in place of propenoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.3 [M+H] . H NMR (400 MHz, CD OD): δ 8.33 29 26 6 4 3 (d, J = 5.5 Hz, 1H), 8.08 (s, 1H), 7.50-7.37 (m, 2H), 7.27-7.20 (m, 1H), 7.19-7.13 (m, 2H), 7.02 (s, 1H), 6.27-6.20 (m, 2H), 6.14 (d, J = 5.5 Hz, 1H), 5.68-5.57 (m, 1H), 4.41 – 4.29 (m, 1H), 4.25 – 4.12 (m, 1H), 2.55 – 2.40 (m, 1H), 2.19 (s, 3H), 2.10-1.95 (m, 2H), 1.89 – 1.71 (m, 2H), 1.67 – 1.53 (m, 1H).
Example 431: N-((1S,3R)Aminocyclopentyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4- methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,3S)aminocyclopentyl)carbamate. MS (ESI): mass calcd. for C H N O S, 500.6; m/z found, 501.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.13 (d, J = 26 24 6 3 3 5.6 Hz, 1H), 7.98 (s, 1H), 7.46 – 7.38 (m, 2H), 7.25 – 7.14 (m, 3H), 7.02 – 6.97 (m, 1H), 5.91 (d, J = 5.6 Hz, 1H), 4.43 – 4.28 (m, 1H), 3.65 – 3.55 (m, 1H), 2.59-2.48 (m, 1H), 2.17 (s, 3H), 2.13 – 2.03 (m, 2H), 2.02-1.93 (m, 1H), 1.91-1.82 (m, 1H), 1.75 – 1.67 (m, 1H).
Example 432: N-((1r,4r)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(4-methyl phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 27, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1r,4r)aminocyclohexyl)carbamate in Step A, and acetic anhydride in place of propenoyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 29 28 6 4 557.0 [M+H] . H NMR (400 MHz, CD OD): δ 8.33 (d, J = 5.6 Hz, 1H), 8.08 (s, 1H), 7.46-7.39 (m, 2H), 7.26-7.20 (m, 1H), 7.19-7.14 (m, 2H), 7.04-7.00 (m, 1H), 6.13 (d, J = 5.6 Hz, 1H), 3.95 -3.79 (m, 1H), 3.69-3.58 (m, 1H), 2.19 (s, 3H), 2.01-1.93 (m, 4H), 1.90 (s, 3H), 1.58-1.44 (m, 2H), 1.41-1.28 (m, 2H).
Example 433: (S)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide.
The title compound was prepared in a manner analogous to Example 1 using tert-butyl (S)- pyrrolidinylcarbamate and 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) in Step A. MS (ESI): mass calcd. for C29H25N5O4S, 539.6; m/z found, 540.4 [M+H] . H NMR (400 MHz, a mixture of DMSO-d6 and CD OD): δ 8.35-8.28 (m, 1H), 7.44-7.33 (m, 3H), 7.21-7.02 (m, 4H), 6.99-6.91 (m, 1H), 6.27-6.06 (m, 2H), 6.02-5.97 (m, 1H), 5.62-5.55 (m, 1H), 4.48-4.38 (m, 1H), 3.85-3.70 (m, 2H), 3.65-3.51 (m, 2H), 2.26-2.15 (m, 1H), 2.07 (s, 3H), 2.01-1.91 (m, 1H).
Example 434: (R)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide.
The title compound was prepared in a manner analogous to Example 1, using tert-butyl (R)- pyrrolidinylcarbamate and 5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) in Step A. MS (ESI): mass calcd. for C H N O S, 539.6; m/z found, 540.4 [M+H] . H NMR (400 MHz, a mixture of DMSO-d 29 25 5 4 6 and CD OD): δ 8.37-8.32 (m, 1H), 7.45-7.38 (m, 2H), 7.38-7.32 (m, 1H), 7.21-7.14 (m, 1H), 7.13-7.05 (m, 3H), 7.00-6.94 (m, 1H), 6.27-6.08 (m, 2H), 6.02-5.98 (m, 1H), 5.64-5.57 (m, 1H), 4.47-4.37 (m, 1H), 3.86-3.71 (m, 2H), 3.58-3.51 (m, 2H), 2.26-2.16 (m, 1H), 2.07 (s, 3H), 2.00- 1.90 (m, 1H).
Example 435: (S,E)Cyanocyclopropyl-N-(1-(5-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide.
Step A: tert-butyl (S)-(1-(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)carbamate. A mixture of 5-(2-Methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, 500 mg, 1.2 mmol), tert-butyl (S)-pyrrolidinylcarbamate (0.43 g, 2.4 mmol), HATU (0.59 g, 1.56 mmol), DIEA (0.23 g, 1.8 mmol) in DMF (5 mL) was stirred at room temperature for one hour. The mixture was quenched with water, the solid was filtered and dried to afford the title compound.
Step B: (S)(3-Aminopyrrolidinecarbonyl)(2-methylphenoxyphenyl)-3Hthia-3,5,8- triazaacenaphthylen-4(5H)-one.
Tert-butyl (S)-(1-(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)carbamate was dissolved in a solution of 10 mL con HCl in MeOH (10mL), stirred at room temperature for one hour. The mixture was concentrated to give the title compound (0.29 g, 50% yield).
Step C: (S,E)cyanocyclopropyl-N-(1-(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide A mixture of (S) (3-aminopyrrolidinecarbonyl)(2-methylphenoxyphenyl)-3Hthia-3,5,8- triazaacenaphthylen-4(5H)-one (200 mg, 0.41 mmol), (E)cyanocyclopropylacrylic acid (Intermediate 44, 113 mg, 0.82 mmol), HATU (201 mg, 0.53 mmol), DIEA (132 mg, 1.03 mmol) in DMF (5 mL) was stirred at room temperature for two hours. The mixture was purified by flash column chromatography (MeOH/water) to afford the title compound (85 mg, 34% yield). MS (ESI): mass calcd. for C H N O S, 604.7; m/z found, 605.4 [M+H] . H NMR 33 28 6 4 (400 MHz, a mixture of DMSO-d and CD OD) δ 8.34-8.31 (m, 1H), 7.43-7.36 (m, 2H), 7.34- 7.30 (m, 1H), 7.18-7.12 (m, 1H), 7.11-7.03 (m, 3H), 6.98-6.92 (m, 1H), 6.90-6.84 (m, 1H), 6.03- 5.98 (m, 1H), 4.48-4.39 (m, 1H), 3.98-3.86 (m, 1H), 3.86-3.75 (m, 2H), 3.66-3.56 (m, 1H), 2.25- 2.15 (m, 1H), 2.02 (s, 3H), 2.04-1.98 (m, 1H), 1.97-1.87 (m, 1H), 1.23-1.17 (m, 2H), 0.95-0.87 (m, 2H).
Example 436: (R,E)Cyanocyclopropyl-N-(1-(5-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide.
The title compound was prepared in a manner analogous to Example 435, using tert-butyl (R)- pyrrolidinylcarbamate in place of tert-butyl (S)-pyrrolidinylcarbamate in Step A. MS (ESI): mass calcd. for C H N O S, 604.7; m/z found, 605.4 [M+H] . H NMR (400 MHz, a 33 28 6 4 mixture of DMSO-d and CD OD) δ 8.34-8.31 (m, 1H), 7.43-7.36 (m, 2H), 7.34-7.30 (m, 1H), 7.18-7.12 (m, 1H), 7.11-7.03 (m, 3H), 6.98-6.92 (m, 1H), 6.90-6.84 (m, 1H), 6.03-5.98 (m, 1H), 4.48-4.39 (m, 1H), 3.98-3.86 (m, 1H), 3.86-3.75 (m, 2H), 3.66-3.56 (m, 1H), 2.25-2.15 (m, 1H), 2.02 (s, 3H), 2.04-1.98 (m, 1H), 1.97-1.87 (m, 1H), 1.23-1.17 (m, 2H), 0.95-0.87 (m, 2H).
Example 437: N-((1R,2S)Acrylamidocyclopentyl)oxo(4-(pyridinyloxy)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 4-Oxo(4-(pyridinyloxy)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, Step A and C, using 2-fluoropyridine and 4-aminophenol, in Step A, (no Cu).
Step B: N-((1R,2S)Acrylamidocyclopentyl)oxo(4-(pyridinyloxy)phenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo(4-(pyridinyloxy)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and N-((1S,2R) aminocyclopentyl)acrylamide (Intermediate 36), no HCl/MeOH deprotection step. MS (ESI): mass calcd. for C H N O S, 540.6; m/z found, 541.1 [M+H] . H NMR (400 MHz, DMSO- 28 24 6 4 d ): δ 10.00 (s, 1H), 8.34-8.26 (m, 1H), 8.23-8.14 (m, 1H), 7.93-7.83 (m, 2H), 7.76-7.63 (m, 1H), 7.50-7.39 (m, 2H), 7.35-7.27 (m, 2H), 7.20-7.15 (m, 1H), 7.14-7.06 (m, 1H), 6.26-6.14 (m, 1H), 6.10-6.01 (m, 2H), 5.58-5.50 (m, 1H), 4.36-4.18 (m, 2H), 1.99-1.83 (m, 2H), 1.80-1.68 (m, 2H), 1.63-1.47 (m, 2H).
Example 438: N-((1R,2S)Acrylamidocyclopentyl)(3-isopropylphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 5-(3-Isopropylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps C-F, using 3-isopropylaniline in Step C.
Step B. N-((1R,2S)Acrylamidocyclopentyl)(3-isopropylphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, using 5-(3-isopropylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid and tert-butyl ((1S,2R)aminocyclopentyl)carbamate.
MS (ESI): mass calcd. for C H N O S, 489.6; m/z found, 490.5 [M+H] . H NMR (400 MHz, 26 27 5 3 CD OD): δ 8.26 (d, J = 5.6Hz, 1H), 7.57-7.49 (m, 1H), 7.46-7.39 (m, 1H), 7.32-7.26 (m, 1H), 7.24-7.16 (m, 1H), 6.33-6.16 (m, 2H), 6.06 (d, J = 5.6Hz, 1H), 5.66-5.57 (m, 1H), 4.48-4.35 (m, 2H), 3.04 -2.95 (m, 1H), 2.14-2.03 (m, 2H), 1.95-1.87 (m, 1H), 1.81-1.62 (m, 3H), 1.30-1.27 (m, 6H).
Example 439: N-((1R,2R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step B, using N- ((1R,2R)aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 440). MS (ESI): mass calcd. for C H N O S, 567.7; m/z found, 568.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.32-8.26 (m, 31 29 5 4 3 1H), 7.43-7.33 (m, 2H), 7.29-7.24 (m, 1H), 7.19-7.12 (m, 1H), 7.10-7.03 (m, 3H), 6.98-6.93 (m, 1H), 6.22-6.15 (m, 2H), 6.05-6.01 (m, 1H), 5.62-5.54 (m, 1H), 3.91-3.76 (m, 2H), 2.10 (s, 3H), 2.08-1.98 (m, 2H), 1.83-1.75 (m, 2H), 1.50-1.36 (m, 4H).
Example 440: N-((1R,2R)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,2R)aminocyclohexyl)carbamate. MS (ESI): mass calcd. for C H N O S, 513.6; m/z found, 514.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.19-8.14 (m, 28 27 5 3 3 1H), 7.42-7.33 (m, 2H), 7.24-7.18 (m, 1H), 7.16-7.11 (m, 1H), 7.08-7.01 (m, 3H), 6.98-6.93 (m, 1H), 5.92-5.88 (m, 1H), 3.92-3.82 (m, 1H), 3.09-2.98 (m, 1H), 2.13-1.98 (m, 5H), 1.87-1.75 (m, 2H), 1.52-1.39 (m, 4H).
Example 441: N-((1R,2R)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: tert-Butyl (2-(((1R,2R)(5-(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamido)cyclohexyl)amino)oxoethyl)carbamate. A solution of N-((1R,2R)aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 440, 65.0 mg, 0.127 mmol), 2-((tert-butoxycarbonyl)amino)acetic acid (50 mg, 0.28 mmol), triethylamine (50 mg, 0.50 mmol), and HATU (95 mg, 0.25 mmol) in DMF (5 mL) was reacted at room temperature for 2 h. The reaction was quenched with 10 mL of H O, extracted with DCM, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash column chromatography to yield the title compound (80 mg, 94% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S. 670.78; m/z found, 671.2 [M+H] . 38 6 6 Step B: N-((1R,2R)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of tert- butyl (2-(((1R,2R)(5-(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclohexyl)amino)oxoethyl)carbamate (80 mg, 0.12 mmol) in MeOH (2.0 mL) was added HCl (1.0 mL) and was reacted at 60 °C for 30 minutes.
The reaction was concentrated to dryness and the residue was purified by flash column chromatography and preparative TLC to yield the title compound (51 mg) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 570.7; m/z found, 571.2 [M+H] . H NMR (400 MHz, 30 6 4 CD OD): δ 8.31-8.26 (m, 1H), 7.44-7.34 (m, 2H), 7.28-7.21 (m, 1H), 7.16-7.11 (m, 1H), 7.10- 7.01 (m, 3H), 6.98-6.93 (m, 1H), 6.05-5.98 (m, 1H), 3.89-3.77 (m, 2H), 3.24 (s, 2H), 2.11 (s, 3H), 2.08-1.93 (m, 2H), 1.85-1.73 (m, 2H), 1.52-1.36 (m, 4H).
Example 442: N-((1R,2S)Acrylamidocyclohexyl)oxo(4-(pyridinyloxy)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (4-(pyridinyloxy)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 437, product from Step A) and N-((1S,2R)aminocyclohexyl)acrylamide (Intermediate 40), no HCl/MeOH deprotection. MS (ESI): mass calcd. for C H N O S, 554.6; 29 26 6 4 m/z found, 555.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.33-8.28 (m, 1H), 8.19-8.13 (m, 1H), 7.90-7.83 (m, 1H), 7.50-7.43 (m, 2H), 7.36-7.30 (m, 2H), 7.19-7.12 (m, 1H), 7.10-7.04 (m, 1H), 6.46-6.36 (m, 1H), 6.33-6.23 (m, 2H), 5.69-5.63 (m, 1H), 4.45-4.35 (m, 1H), 4.20-4.10 (m, 1H), 1.85-1.64 (m, 6H), 1.60-1.48 (m, 2H).
Example 443: 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,2R)(2- (methylamino)acetamido)cyclohexyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide.
Step A: N-((1S,2R)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,2S) aminocyclohexyl). MS (ESI): mass calcd. for C H N O S, 513.61; m/z found, 514.2 [M+H] . 28 27 5 3 H NMR (400 MHz, CD OD): δ 8.53 (d, J = 6.2Hz, 1H), 7.47-7.38 (m, 2H), 7.38-7.31 (m, 1H), 7.24-7.16 (m, 1H), 7.15-7.07 (m, 3H), 7.05-6.97 (m, 1H), 6.40 (d, J = 6.2Hz, 1H), 4.51-4.43 (m, 1H), 3.70-3.59 (m, 1H), 2.16 (s, 3H), 1.97-1.74 (m, 6H), 1.66-1.53 (m, 2H).
Step B: 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,2R)(2- (methylamino)acetamido)cyclohexyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide. To a solution of N-((1S,2R)aminocyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (150 mg, 0.292 mmol) and Boc-sarcosine (207 mg, 0.438 mmol) in anhydrous DMF (3 mL) were added HATU (166 mg, 0.438 mmol) and DIPEA (76 mg, 0.58 mmol) and was stirred overnight at rt. The reaction was purified by flash column chromatography to get 120 mg of a yellow solid. The solid was dissolved in MeOH (2 mL) and concentrated HCl (1 mL) and was stirred at room temperature for 2 h. The reaction was concentrated to dryness and was purified by preparative TLC (DCM/MeOH; 20/1) to give the title compound (51 mg, 30% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 584.7; m/z found, 585.2 [M+H] . H NMR (400 31 32 6 4 MHz, CD OD): δ 8.17 (d, J = 5.6Hz, 1H), 7.42-7.33 (m, 2H), 7.24-7.19 (m, 1H), 7.18-7.11 (m, 1H), 7.11-7.00 (m, 3H), 6.99-6.91 (m, 1H), 5.90 (d, J = 5.6Hz, 1H), 4.38-4.28 (m, 1H), 4.26-4.15 (m, 1H), 3.67-3.57 (m, 1H), 3.56-3.46 (m, 1H), 2.51 (s, 3H), 2.10 (s, 3H), 1.83-1.67 (m, 5H), 1.61-1.47 (m, 3H).
Example 444: N-((1S,2R)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1S,2R)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,2S) aminocyclohexyl)carbamate. MS (ESI): mass calcd. for C H N O S, 513.61; m/z found, 514.2 28 27 5 3 [M+H] . H NMR (400 MHz, CD OD): δ 8.53 (d, J = 6.2Hz, 1H), 7.47-7.38 (m, 2H), 7.38-7.31 (m, 1H), 7.24-7.16 (m, 1H), 7.15-7.07 (m, 3H), 7.05-6.97 (m, 1H), 6.40 (d, J = 6.2Hz, 1H), 4.51- 4.43 (m, 1H), 3.70-3.59 (m, 1H), 2.16 (s, 3H), 1.97-1.74 (m, 6H), 1.66-1.53 (m, 2H).
Step B: N-((1S,2R)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of N- ((1S,2R)aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (150 mg, 0.292 mmol) and Boc-glycine (192 mg, 0.438 mmol) in anhydrous DMF (3 mL) were added HATU (166 mg, 0.438 mmol) and DIPEA (76 mg, 0.58 mmol) and was stirred overnight at rt. The reaction was purified by flash column chromatography to get 130 mg of a yellow solid. The solid was dissolved in MeOH (2 mL) and concentrated HCl (1 mL) and was stirred at room temperature for 2 h. The reaction was concentrated to dryness and was purified by preparative TLC (DCM/MeOH; 20/1) to give the title compound (82 mg, 49% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 30 6 4 570.7; m/z found, 571.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.14 (d, J = 5.6Hz, 1H), 7.42- 7.35 (m, 2H), 7.24-7.18 (m, 1H), 7.18-7.11 (m, 1H), 7.10-7.05 (m, 2H), 7.05-7.00 (m, 1H), 6.98- 6.91 (m, 1H), 5.87 (d, J = 5.6Hz, 1H), 4.35-4.28 (m, 1H), 4.26-4.17 (m, 1H), 3.69-3.61 (m, 1H), 3.56-3.47 (m, 1H), 2.10 (s, 3H), 1.87-1.64 (m, 5H), 1.64 – 1.42 (m, 3H).
Example 445: N-((1R,2R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of N-((1R,2R)aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 440, 120 mg, 0.234 mmol) in DCM (2 mL), were added acetic anhydride (24 mg, 0.23 mmol) and triethylamine (36 mg, 0.35 mmol) and was reacted at room temperature for 20 minutes. The reaction was concentrated to dryness and the residue was purified by flash column chromatography to get the title compound (100 mg, 77% yield) as a gray solid. MS (ESI): mass calcd. for C30H29N5O4S, 555.6; m/z found, 556.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.34-8.27 (m, 1H), 7.44-7.35 (m, 2H), 7.31-7.24 (m, 1H), 7.19-7.12 (m, 1H), 7.11-7.02 (m, 3H), 6.98-6.93 (m, 1H), 6.08-6.02 (m, 1H), 3.85-3.74 (m, 2H),2.11 (s, 3H), 2.06-1.98 (m, 1H), 1.97-1.90 (m, 1H), 1.88 (s, 3H), 1.82-1.75 (m, 2H), 1.50-1.33 (m, 4H).
Example 446: N-((1S,2R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,2S)aminocyclohexyl)carbamate, in Step A, and acetyl chloride in Step B.
MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.2 [M+H] . H NMR (400 MHz, 29 5 4 CD OD): δ 8.31 (d, J = 5.5 Hz, 1H), 7.44-7.34 (m, 2H), 7.31-7.23 (m, 1H), 7.20-7.12 (m, 1H), 7.11-7.01 (m, 3H), 7.00-6.91 (m, 1H), 6.05 (d, J = 5.5 Hz, 1H), 4.36-4.26 (m, 1H), 4.17-4.08 (m, 1H), 2.11 (s, 3H), 2.00 (s, 3H), 1.79-1.45 (m, 8H).
Example 447: N-((1R,2R)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using N- ((1R,2R)aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide (Example 440) and 2-(dimethylamino)acetic acid, no MeOH/HCl deprotection step necessary. MS (ESI): mass calcd. for C H N O S, 598.7; m/z 32 34 6 4 found, 599.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.35-8.29 (m, 2H), 7.42-7.38 (m, 2H), 7.31-7.24 (m, 1H), 7.19-7.12 (m, 1H), 7.11-7.02 (m, 3H), 6.98-6.93 (m, 1H), 6.09-6.04 (m, 1H), 3.95-3.77 (m, 2H), 3.35 (s, 2H), 2.48 (s, 6H), 2.10 (s, 3H), 2.04-1.98 (m, 2H), 1.85-1.74 (m, 2H), 1.58-1.36 (m, 4H).
Example 448: 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2R)(2- (methylamino)acetamido)cyclohexyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide.
Step A: tert-Butyl methyl(2-(((1R,2R)(5-(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamido)cyclohexyl)amino) oxoethyl)carbamate. A solution of N-((1R,2R)aminocyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 440, 120 mg, 0.234 mmol), 2-((tert-butoxycarbonyl)(methyl)amino)acetic acid (65 mg, 0.34 mmol), triethylamine (50 mg, 0.50 mmol), and HATU (95 mg, 0.25 mmol) in DMF (5 mL) was reacted at room temperature for 2 h. The reaction was quenched with H O (10 mL), extracted with DCM, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash column chromatography to yield the title compound (120 mg, 75% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S. 684.80; m/z found, 685.2 36 40 6 6 [M+H] .
Step B: 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2R)(2- (methylamino)acetamido)cyclohexyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide. A solution of tert-butyl methyl(2-(((1R,2R)(5-(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamido)cyclohexyl)amino)oxoethyl)carbamate (120 mg, 0.175 mmol) in HCl (1 mL) and MeOH (2 mL) was reacted at 60 °C for 30 minutes. The reaction was concentrated to dryness and the residue was purified by flash column chromatography and preparative TLC to yield the title compound (95 mg, 93% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 584.7; m/z found, 585.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.05-7.99 (m, 31 32 6 4 3 1H), 7.40-7.33 (m, 2H), 7.18-7.10 (m, 2H), 7.09-7.05 (m, 2H), 7.03-6.99 (m, 1H), 6.96-6.91 (m, 1H), 5.77-5.73 (m, 1H), 3.97-3.85 (m, 1H), 3.84-3.72 (m, 1H), 3.16-3.02 (m, 2H), 2.21 (s, 3H), 2.09 (s, 3H), 2.07-2.01 (m, 2H), 1.81-1.66 (m, 2H), 1.47-1.25 (m, 4H).
Example 449: N-((1S,2R)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1S,2R)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,2S) aminocyclohexyl)carbamate in place of tert-butyl ((1s,4s)aminocyclohexyl)carbamate in step G (1100 mg). MS (ESI): mass calcd. for C H N O S, 513.6; m/z found, 514.2 [M+H] . H 28 27 5 3 NMR (400 MHz, CD3OD): δ 8.12 (d, J = 5.6 Hz, 1H), 7.42-7.33 (m, 2H), 7.23-7.18 (m, 1H), 7.16-7.11 (m, 1H), 7.10-7.04 (m, 2H), 7.04-7.01 (m, 1H), 6.98-6.93 (m, 1H), 5.85 (d, J = 5.6 Hz, 1H), 4.44-4.38 (m, 1H), 3.40-3.34 (m, 1H), 2.09 (s, 3H), 1.90-1.68 (m, 6H), 1.60-1.43 (m, 2H).
Step B: N-((1S,2R)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of N-((1S,2R)aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (80 mg, 0.16 mmol) and 2- (dimethylamino)acetic acid (60 mg, 0.23 mmol) in anhydrous DMF (2 mL) was added HATU (89 mg, 0.23 mmol) and DIPEA (40 mg, 0.31 mmol) and the reaction was stirred overnight at rt.
The reaction was purified by flash column chromatography to yield the title compound (66 mg, 71% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 598.7; m/z found, 599.2 32 34 6 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.32-8.26 (m, 1H), 7.43-7.34 (m, 2H), 7.29-7.23 (m, 1H), 7.19-7.12 (m, 1H), 7.11-7.02 (m, 3H), 6.99-6.93 (m, 1H), 6.05-6.00 (m, 1H), 4.39-4.29 (m, 1H), 4.23-4.13 (m, 1H), 3.11 (s, 2H), 2.36 (s, 6H), 2.11 (s, 3H), 1.83-1.67 (m, 5H), 1.60-1.47 (m, 3H).
Example 450: N-((1S,2R)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,2S)aminocyclohexyl)carbamate. MS (ESI): mass calcd. for C H N O S, 513.6; m/z found, 514.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.12 (d, J = 28 27 5 3 3 .6 Hz, 1H), 7.42-7.33 (m, 2H), 7.23-7.18 (m, 1H), 7.16-7.11 (m, 1H), 7.10-7.04 (m, 2H), 7.04- 7.01 (m, 1H), 6.98-6.93 (m, 1H), 5.85 (d, J = 5.6 Hz, 1H), 4.44-4.38 (m, 1H), 3.40-3.34 (m, 1H), 2.09 (s, 3H), 1.90-1.68 (m, 6H), 1.60-1.43 (m, 2H).
Example 451: N-((1S,2R)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,2S)aminocyclohexyl)carbamate. MS (ESI): mass calcd. for C H N O S, 31 29 5 4 567.7; m/z found, 568.5 [M+H] . H NMR (400 MHz, CD OD): δ 8.30 (d, J = 5.5 Hz, 1H), 7.44-7.34 (m, 2H), 7.30-7.23 (m, 1H), 7.19-7.12 (m, 1H), 7.11-7.02 (m, 3H), 6.99-6.92 (m, 1H), 6.47-6.34 (m, 1H), 6.31-6.21 (m, 1H), 6.05 (d, J = 5.5 Hz, 1H), 5.69-5.60 (m, 1H), 4.46-4.35 (m, 1H), 4.21-4.10 (m, 1H), 2.11 (s, 3H), 1.84-1.47 (m, 8H).
Example 452: N-((1S,2R)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH S HN The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1, including CHIRAL SEPARATION METHOD 1 to obtain the *S atropisomer) and tert-butyl ((1R,2S)aminocyclopentyl)carbamate. MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, 500.4 [M+H] . H NMR (400 MHz, CD OD): δ 8.33 (d, J = 27 25 5 3 3 .9 Hz, 1H), 7.45-7.33 (m, 2H), 7.28-7.23 (m, 1H), 7.20-7.13 (m, 1H), 7.10-7.04 (m, 3H), 7.00- 6.93 (m, 1H), 6.07 (d, J = 5.8 Hz, 1H), 4.52-4.42 (m, 1H), 3.80-3.68 (m, 1H), 2.24-2.13 (m, 2H), 2.11 (s, 3H), 2.00-1.85 (m, 2H), 1.80-1.64 (m, 2H).
Example 453: N-((1R,2S)Aminocyclopentyl)(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4- isopropoxymethylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 31) and tert-butyl ((1S,2R)aminocyclopentyl)carbamate. MS (ESI): mass calcd. for C H N O S, 465.6; m/z found, 466.2 [M+H] . H NMR (400 MHz, 24 27 5 3 CD OD): δ 8.19-8.06 (m, 1H), 7.16-7.06 (m, 1H), 6.98-6.84 (m, 2H), 5.89-5.79 (m, 1H), 4.69- 4.59 (m, 1H), 4.53-4.43 (m, 1H), 3.65-3.52 (m, 1H), 2.20-2.03 (m, 5H), 1.97-1.81 (m, 2H), 1.78- 1.60 (m, 2H), 1.38-1.28 (m, 6H).
Example 454: N-((1S,3R)Acetamidocyclopentyl)(4-isopropoxymethylphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH S HN The title compound was prepared in a manner analogous to Example 1, using 5-(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 31) and using tert-butyl ((1R,3S)aminocyclopentyl)carbamate in Step A, and acetyl chloride in Step B. MS (ESI): mass calcd. for C H N O S, 507.6; m/z found, 508.2 26 29 5 4 [M+H] . H NMR (400 MHz, CD3OD): δ 8.30 (d, J = 5.6 Hz, 1H), 7.22-7.15 (m, 1H), 6.99-6.95 (m, 1H), 6.94-6.88 (m, 1H), 6.02 (d, J = 5.6 Hz, 1H), 4.70-4.61 (m, 1H), 4.39-4.26 (m, 1H), 4.17-4.05 (m, 1H), 2.48-2.38 (m, 1H), 2.10 (s, 3H), 2.08-1.88 (m, 5H), 1.81-1.64 (m, 2H), 1.62- 1.48 (m, 1H), 1.35-1.32 (m, 6H).
Example 455: N-((1R,2S)Aminocyclopentyl)(3-isopropylphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(3- isopropylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Example 428, product from Step A, tert-butyl ((1S,2R)aminocyclopentyl)carbamate. MS (ESI): mass calcd. for C H N O S, 435.17; m/z found, 436.2 [M+H] . H NMR (400 MHz, 23 25 5 2 CD OD): δ 8.17 (d, J = 5.6 Hz, 1H), 7.54-7.46 (m, 1H), 7.42-7.36 (m, 1H), 7.25-7.19 (m, 1H), 7.20-7.11 (m, 1H), 5.97 (d, J = 5.6 Hz, 1H), 4.52-4.44 (m, 1H), 3.71-3.54 (m, 1H), 3.03-2.94 (m, 1H), 2.19-2.09 (m, 2H), 1.98-1.82 (m, 2H), 1.78-1.64 (m, 2H), 1.30-1.27 (m, 6H).
Example 456: N-((1R,2R)Hydroxycyclopentyl)(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH S HN The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4- isopropoxymethylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (Intermediate 31) and (1R,2R)aminocyclopentanol, no MeOH/HCl deprotection. MS (ESI): mass calcd. for C H N O S, 466.6; m/z found, 467.1 [M+H] . H 24 26 4 4 NMR (400 MHz, CD OD): δ 8.29 (d, J = 5.6 Hz, 1H), 7.22 -7.15 (m, 1H), 7.00-6.94 (m, 1H), 6.94-6.87 (m, 1H), 6.02 (d, J = 5.6 Hz, 1H), 4.70-4.61 (m, 1H), 4.18-4.01 (m, 2H), 2.18-2.08 (m, 4H), 2.04-1.95 (m, 1H), 1.83-1.72 (m, 2H), 1.65-1.55 (m, 2H), 1.37-1.30 (m, 6H).
Example 457: N-((1S,2R)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide.
To a dry scintillation vial under Ar were added tert-butyl (1R,2S)aminocyclohexylcarbamate (191 mg, 0.891 mmol), THF (2.097 mL), and DIPEA (0.262 mL, 1.50 mmol). To this solution was added dropwise slowly over 10 min was 4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarbonyl chloride (Intermediate 9, 13.11 mL, 0.04 M, 0.5240 mmol) and was stirred for 2 hours. The reaction was quenched with water, which caused a precipitate to form. The solution was filtered to isolate the solid and the solid was treated with DCM (5 mL) and HCl (5 mL, in ether, 2M). The reaction was warmed to 60 °C for 10 min, and then stirred at room temperature overnight. The reaction was concentrated to dryness and dissolved in methanol and purified by Gilson reverse phase HPLC to give the title compound (8.3 mg, 2.9% yield). MS (ESI): mass calcd. for C H N O S, 499.6; m/z found, 500.0 [M+H] . 27 25 5 3 H NMR (400 MHz, CD OD): δ 8.21 (d, J = 5.6 Hz, 1H), 7.49 - 7.25 (m, 4H), 7.25 - 7.02 (m, 5H), 6.08 (d, J = 5.7 Hz, 1H), 4.48 - 4.31 (m, 1H), 3.53 (q, J = 6.6, 5.4 Hz, 1H), 2.01 - 1.41 (m, 8H).
Example 458: N-((1S,2S)Acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl ((1S,2S)aminocyclopentyl)carbamate in step A. MS (ESI): mass calcd. for C H N O S, 553.6; m/z found, 554.2 [M+H] . H NMR (400 MHz, a mixture 27 5 4 of DMSO-d6 and CD3OD): δ 8.26 (d, J = 5.3 Hz, 1H), 7.42-7.32 (m, 2H), 7.31-7.24 (m, 1H), 7.16-7.08 (m, 1H), 7.08-6.98 (m, 3H), 6.95-6.87 (m, 1H), 6.20-6.11 (m, 1H), 6.10-6.01 (m, 1H), .93 (d, J = 5.4 Hz, 1H), 5.56-5.44 (m, 1H), 4.26-4.16 (m, 1H), 4.16-4.12 (m, 1H), 2.10-1.86 (m, 5H), 1.73-1.60 (m, 2H), 1.60-1.50 (m, 1H), 1.48-1.40 (m, 1H).
Example 459: N-((1S,2R)Acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, using 5-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and tert-butyl ((1R,2S)aminocyclopentyl)carbamate in Step A. MS (ESI): mass calcd. for C H N O S, 553.6; m/z found, 554.2 [M+H] . H NMR (400 MHz, DMSO- 27 5 4 d6): δ 10.03 (s, 1H), 8.30 (d, J = 5.5 Hz, 1H), 7.92-7.81 (m, 1H), 7.79-7.67 (m, 1H), 7.48-7.39 (m, 2H), 7.39-7.30 (m, 1H), 7.22-7.14 (m, 1H), 7.13-7.04 (m, 3H), 6.99-6.92 (m, 1H), 6.27-6.16 (m, 1H), 6.09-6.02 (m, 1H), 5.94 (d, J = 5.4 Hz, 1H), 5.60-5.49 (m, 1H), 4.33-4.19 (m, 2H), 2.03 (s, 3H), 1.97-1.82 (m, 2H), 1.78-1.68 (m, 2H), 1.66-1.46 (m, 2H).
Example 460: 5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)methylphenyl)-N-cyclohexyl oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
N NH To a mixture of cyclohexanamine (67 mg, 0.67 mmol) in 10 mL of dry THF was added 1M Me Al (2 mL, 2.0mmol) at room temperature and stirred at room temperature for 30 minutes, then was added methyl 5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)methylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylate (Intermediate 43, 187 mg, 0.33 mmol) and stirred under N2 at reflux for 16 hours. The reaction was quenched by adding MeOH (3 mL), diluted with CH Cl , filtered through Celite®. The filtrate was condensed, purified by preparative TLC (MeOH/DCM=1/50). (69 mg, 33% yield). MS (ESI): mass calcd. for C H N O S, 629.7; m/z found, 630.3 [M+H] . H NMR (400 MHz, DMSO-d ): δ 8.31-8.20 36 31 5 4 6 (m, 1H), 8.20-8.15 (m, 1H), 7.74-7.69 (m, 1H), 7.68-7.61 (m, 1H), 7.50-7.42 (m, 1H), 7.34-7.29 (m, 1H), 7.29-7.24 (m, 2H), 7.24-7.20 (m, 1H), 7.12-7.04 (m, 3H), 6.98-6.92 (m, 1H), 5.84-5.79 (m, 1H), 5.32 (s, 2H), 3.80-3.69 (m, 1H), 2.03 (s, 3H), 1.87-1.78 (m, 2H), 1.76-1.67 (m, 2H), 1.63-1.53 (m, 1H), 1.37-1.23 (m, 5H).
Example 461: N-(5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)methylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenyl)cyclopropanecarboxamide.
Step A: 5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)methylphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxylic acid.
The title compound was prepared in a manner analogous to Intermediate 1, Step F, using methyl -(4-(3-((2-cyanophenoxy)methyl)phenoxy)methylphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylate (Intermediate 43).
Step B: tert-butyl (5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)methylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenyl)carbamate. To the suspension of 5-(4-(3-((2- cyanophenoxy)methyl)phenoxy)methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (1.7 g, 3.1 mmol) in 60 ml of CH Cl was added oxalyl chloride and one drop of DMF, then was stirred at room temperature for 3 hours. then concentrated, acetone was added and cooled to 0 °C under ice bath, a solution of NaN in water was added and stirred for 30 minutes, diluted in EtOAc, washed with water, brine, dried and concentrated. The residue was diluted in toluene and reflux for one hour, then n-BuOH was added and reflux for two hours, then concentrated, and purified by flash chromatography with DCM/MeOH to get a yellow solid. (950 mg, 49% yield).
Step C: 2-((3-(4-(2-aminooxo-3,4-dihydro-5Hthia-3,5,8-triazaacenaphthylenyl) methylphenoxy)benzyl)oxy)benzonitrile. To a solution of tert-butyl (5-(4-(3-((2- cyanophenoxy)methyl)phenoxy)methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenyl)carbamate (750 mg, 1.21 mmol) in 2,2,2-trifluoroethanol (50 mL) was heated in microwave at 120 °C for one hour, then concentrated and purified by purified by flash chromatography with DCM/MeOH to get a yellow solid. (450 mg, 72% yield).
Step D: N-(5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)methylphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenyl)cyclopropanecarboxamide. To a solution of 2-((3-(4-(2- aminooxo-3,4-dihydro-5Hthia-3,5,8-triazaacenaphthylenyl) methylphenoxy)benzyl)oxy)benzonitrile (35.0 mg, 0.0673 mmol) and 4-methylmorpholine (6.8 mg, 0.0673 mmol) in CH Cl (20 mL) was added cyclopropanecarbonyl chloride (7.0 mg, 0.0673 mmol). The reaction was stirred at room temperature for 30 minutes, then concentrated and purified by flash column chromatography (MeOH/water) to afford the title compound (15 mg, 38% yield). MS (ESI): mass calcd. for C33H25N5O4S, 587.6; m/z found, 588.1 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.45 (s, 1H), 10.12 (s, 1H), 8.08 (d, J = 5.4 Hz, 1H), 7.73-7.68 (m, 1H), 7.67-7.60 (m, 1H), 7.50-7.40 (m, 1H), 7.36-7.24 (m, 3H), 7.23-7.17 (m, 1H), 7.11-7.02 (m, 3H), 6.98-6.92(m, 1H), 5.80 (d, J = 5.4 Hz, 1H), 5.30 (s, 2H), 2.04 (s, 3H), 1.73-1.65 (m, 1H), 0.87-0.81(m, 4H).
Example 462: N-Cyclohexyl(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (Intermediate 1) and cyclohexanamine, no HCl/MeOH deprotection. MS (ESI): mass calcd. for C H N O S, 498.6; m/z found, 499.2 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.14 (s, 28 26 4 3 6 1H), 8.36-8.32 (m, 1H), 7.95-7.89 (m, 1H), 7.49-7.41 (m, 2H), 7.41-7.36 (m, 1H), 7.24-7.17 (m, 1H), 7.17-7.08 (m, 3H), 7.02-6.97 (m, 1H), 6.00-5.96 (m, 1H), 3.80-3.76 (m, 1H), 2.07 (s, 3H), 1.86-1.78 (m, 2H), 1.78-1.70 (m, 2H), 1.66-1.57 (m, 1H), 1.42-1.21 (m, 4H), 1.14-1.03 (m, 1H).
Example 463: N-Cyclohexyloxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide.
To the suspension of 4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Intermediate 2, 109 mg, 0.27 mmol ) in 10 mL of CH Cl was added oxalyl chloride (70 mg, 0.54 mmol ) and one drop of DMF, then was stirred at 40 °C for 2 hours. After concentration under vacuo to dryness, the residue was dissolved in 10 mL of CH Cl and was added a solution of cyclohexanamine (55 mg, 0.54 mmol ) in 5 mL of CH2Cl2, stirred at room temperature for 5 minutes. The mixture was concentrated and purified by ISCO using MeOH/H O as eluent to get the title compound as yellow solid. (46 mg, 35% yield).
MS (ESI): mass calcd. for C27H24N4O3S, 484.6; m/z found, 485.2 [M+H] . H NMR (400 MHz, DMSO-d ): δ 8.29 (d, J = 5.1 Hz, 1H), 7.94-7.92 (m, 1H), 7.42-7.40 (m, 4H), 7.30-7.04 (m, 5H), 6.04 (d, J = 5.2 Hz, 1H), 3.78-3.68 (m, 1H), 1.85-1.52 (m, 5H), 1.34-1.08 (m, 5H).
Example 464: N1-((E)(((1S,2R)(5-(6-isobutylmethylpyridinyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamido)cyclopentyl)amino)oxobutenyl)- N5-(15-oxo((3aS,4S,6aR)oxohexahydro-1H-thieno[3,4-d]imidazolyl)-4,7,10-trioxa- 14-azanonadecyl)glutaramide.
Step A: tert-Butyl ((E)(((1S,2R)(5-(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamido)cyclopentyl)amino)oxobut enyl)carbamate. The mixture of (E)((tert-butoxycarbonyl)amino)butenoic acid (Intermediate 23, 333.5 mg, 1.657 mmol), N-((1R,2S)aminocyclopentyl)(6-isobutyl methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 298, product from Step A, 700.0 mg, 1.507 mmol), HATU (744.6 mg,1.959 mmol), triethylamine (456.5 mg, 4.52 mmol) in DMF (10.0 mL ) was stirred at room temperature for 15 minutes and TLC showed reaction completed. The mixture was purified by column chromatography eluting with water/ methanol to get target compound as a light yellow solid (500 mg, 60% yield).
Step B: N1-((E)(((1S,2R)(5-(*S)-(6-isobutylmethylpyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamido)cyclopentyl)amino)oxobutenyl)-N5- (15-oxo((3aS,4S,6aR)oxohexahydro-1H-thieno[3,4-d]imidazolyl)-4,7,10-trioxa azanonadecyl)glutaramide. Tert-butyl ((E)(((1S,2R)(5-(6-isobutylmethylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamido)cyclopentyl)amino) oxobutenyl)carbamate (500 mg, 0.772 mmol) was dissolved in 4 N HCl in methanol (10.0 mL), then stirred at room temperature for one hour, concentrated to give de-Boc product. The mixture of 5,21-dioxo((3aS,4S,6aR)oxohexahydro-1H-thieno[3,4-d]imidazolyl)- ,13,16-trioxa-6,20-diazapentacosanoic acid (432.8 mg, 0.772 mmol), HATU (440.1 mg, 1.158 mmol), triethylamine (312.2 mg, 3.087 mmol) in DMF(5.0 mL) was stirred at room temperature for 5 minutes to give activated-ester solution. De-Boc product was dissolved in DMF (5.0 mL), then to it was added activated-ester solution. The mixture was stirred at room temperature for 10 minutes and TLC showed reaction was completed. Then, the mixture was purified by column chromatography eluting with water/methanol to get target compound as a white solid. (350 mg, 41.5% yield).MS (ESI): mass calcd. for C H N O S , 1090.4; m/z found, 1090.5 [M+H] . H 53 75 11 10 2 NMR (400 MHz, CD OD): δ 8.41 (s, 1H), 8.33 (d, J = 5.5 Hz, 1H), 7.42 (s, 1H), 6.75-6.66 (m, 1H), 6.12-6.00 (m, 1H), 6.03 (d, J = 5.5 Hz, 1H), 4.52-4.37 (m, 3H), 4.32-4.26 (m, 1H), 3.92- 3.87 (m, 2H), 3.64-3.59 (m, 4H), 3.59-3.54 (m, 4H), 3.53-3.47 (m, 4H), 3.27-3.15 (m, 5H), 2.94- 2.87 (m, 1H), 2.75-2.65 (m, 3H), 2.25-2.16 (m, 9H), 2.15-2.01 (m, 3H), 1.96-1.83(m, 3H), 1.82- 1.67 (m, 8H), 1.66-1.53 (m, 3H), 1.46-1.36 (m, 2H), 1.03-0.96 (m, 6H).
Example 465: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyrimidinyloxy)pyridin- 3-yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 5-(4-Methyl(pyrimidinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1 Steps A, and C-F, using aminomethylpyridinol and 2-chloropyrimidine Step A.
Step B: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyrimidinyloxy)pyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4-methyl(pyrimidin yloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and N-((1S,2R)aminocyclopentyl)acrylamide (Intermediate 36), no HCl/MeOH deprotection.
MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.1 [M+H] . H NMR (400 MHz, 27 24 8 4 CD OD): δ 8.73-8.66 (m, 2H), 8.39-8.34 (m, 1H), 8.32-8.28 (m, 1H), 7.42-7.28 (m, 2H), 6.34- 6.17 (m, 3H), 5.67-5.58 (m, 1H), 4.50-4.37 (m, 2H), 2.30-2.24 (m, 3H), 2.15-2.02 (m, 2H), 1.97- 1.86 (m, 1H),1.81-1.63 (m, 3H).
Example 466: N-((1R,2S)((E)Cyanocyclopropylacrylamido)cyclopentyl)(*S)-(6- isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide.
To a solution of (E)cyanocyclopropylacrylic acid (25 mg, 0.18 mmol), HATU (68 mg, 0.18 mmol), and triethylamine (46 mg, 0.45 mmol) in DMF (1 mL) was added a solution of N- ((1R,2S)aminocyclopentyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide (Example 298, product from Step A, 70 mg, 0.15 mmol) in DMF (1 mL) and was stirred at room temperature for 10 minutes. The mixture was purified by flash column chromatography and then by preparative TLC (MeOH/DCM = 1/20) to yield the title compound (31 mg, 34% yield) as yellow solid. MS (ESI): mass calcd. for C H N O S, 583.70; m/z found, 584.2 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.31-9.98 31 33 7 3 6 (br, 1H), 8.45-8.26 (m, 2H), 8.10-7.81 (m, 2H), 7.34 (s, 1H), 6.96-6.86 (m, 1H), 5.96-5.82 (m, 1H), 4.41-4.22 (m, 2H), 2.66-2.61 (m, 2H), 2.15-2.05 (m, 4H), 1.97-1.88 (m, 2H), 1.84-1.72 (m, 3H), 1.71-1.62 (m, 1H), 1.52-1.42 (m, 1H), 1.16-1.07 (m, 2H), 0.92 (d, J = 6.6 Hz, 6H), 0.85- 0.75 (m, 2H).
Example 467: N-((1R,2S)Acrylamidocyclohexyl)(4-methyl(pyridazinyloxy)pyridin- 3-yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 5-(4-Methyl(pyridazinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 25, using 3,6-dichloropyridazine and 5-aminomethylpyridinol in Step A.
Step B: N-((1R,2S)Acrylamidocyclohexyl)(4-methyl(pyridazinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4-methyl(pyridazin yloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and N-((1S,2R)aminocyclohexyl)acrylamide (Intermediate 40), no HCl/MeOH deprotection.
MS (ESI): mass calcd. for C H N O S, 570.6; m/z found, 571.2 [M+H] . H NMR (400 MHz, 28 26 8 4 CD OD): δ 9.12 – 8.95 (m, 1H), 8.33 – 8.19 (m, 2H), 7.87-7.76 (m, 1H), 7.67-7.56 (m, 1H), 7.35 (s, 1H), 6.47-6.34 (m, 1H), 6.28 – 6.12 (m, 2H), 5.69-5.57 (m, 1H), 4.46-4.33 (m, 1H), 4.16-4.01 (m, 1H), 2.26 (d, J = 7.6 Hz, 3H), 1.85 – 1.38 (m, 8H).
Example 468: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)pyridin- 3-yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 5-(2-Methyl(pyrimidinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1 Steps A, and C-F, using 5-aminomethylpyridinol and 2- chloropyrimidine in Step A.
Step C: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)pyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methyl(pyrimidin yloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and N-((1S,2R)aminocyclopentyl)acrylamide (Intermediate 36), no HCl/MeOH deprotection.
MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.0 [M+H] . H NMR (400 MHz, 27 24 8 4 CD3OD): δ 8.72-8.67 (m, 2H), 8.36-8.32 (m, 1H), 8.02-7.92 (m, 1H), 7.37-7.32 (m, 1H), 7.31- 7.25 (m, 1H), 6.33-6.16 (m, 3H), 5.66-5.60 (m, 1H), 4.48-4.35 (m, 2H), 2.34-2.27 (m, 3H), 2.18- 2.02 (m, 2H), 1.97-1.86 (m, 1H),1.84-1.63 (m, 3H).
Example 469: N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methyloxo(pyridazinyl)- 1,6-dihydropyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide.
Step A. N-((1S,2R)aminocyclopentyl)acrylamide. A solution of tert-butyl ((1R,2S) acrylamidocyclopentyl)carbamate (363 mg, 1.42 mmol) in 4.0 N HCl/MeOH was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure and used crude in Step C without further purification.
Step B. 5-(4-methyloxo(pyridazinyl)-1,6-dihydropyridinyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 25, using 3,6-dichloropyridazine and 5-amino methylpyridinol in Step A.
Step C. N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methyloxo(pyridazinyl)-1,6- dihydropyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(4- methyloxo(pyridazinyl)-1,6-dihydropyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid and N-((1S,2R)aminocyclopentyl)acrylamide (Step A), no HCl/MeOH deprotection, purification using flash column chromatography afforded the title compound as the *S atropisomer. MS (ESI): mass calcd. for C H N O S, 556.6; m/z 27 24 8 4 found, 557.2 [M+H] . H NMR (400 MHz, CD OD): δ 9.25 (d, J = 4.6 Hz, 1H), 8.44-8.39 (m, 1H), 8.31 (s, 1H), 8.25 (d, J = 9.0 Hz, 1H), 7.95 – 7.83 (m, 1H), 6.72 (s, 1H), 6.61-6.55 (m, 1H), 6.34 – 6.09 (m, 2H), 5.61 (d, J = 9.7 Hz, 1H), 4.50-4.35 (m, 2H), 2.14 (s, 3H), 2.11 – 2.00 (m, 2H), 1.98-1.84 (m, 1H), 1.81 – 1.59 (m, 3H).
Example 470: N-((1R,2S)Acrylamidocyclopentyl)(*R)-(4-methyloxo(pyridazinyl)- 1,6-dihydropyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide.
Flash column chromatography of Example 469, Step B afforded the *R atropisomer. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.2 [M+H] . H NMR (400 MHz, CD OD): δ 27 24 8 4 3 9.24 (d, J = 4.6 Hz, 1H), 8.40 (d, J = 5.5 Hz, 1H), 8.36 (s, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.93- 7.86 (m, 1H), 6.71 (s, 1H), 6.56 (d, J = 5.5 Hz, 1H), 6.32-6.12 (m, 2H), 5.61 (d, J = 9.7 Hz, 1H), 4.48 – 4.29 (m, 2H), 2.13 (s, 3H), 2.11-2.00 (m, 2H), 1.98-1.83 (m, 1H), 1.81 – 1.58 (m, 3H).
Example 471: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridazinyloxy)pyridin- 3-yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1S,2R)Aminocyclopentyl)acrylamide. A solution of tert-butyl ((1R,2S) acrylamidocyclohexyl)carbamate (800 mg, 1.90 mmol) in 4 M HCl in MeOH (2 mL) was stirred at room temperature for 60 minutes. The reaction was concentrated to dryness to give N- ((1S,2R)aminocyclopentyl)acrylamide, which was used without further purification.
Step B: 5-(4-Methyl(pyridazinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 25, Step A and C, using 3,6-dichloropyridazine and 5-amino methylpyridinol in Step A. MS (ESI): mass calcd. for C H N O S, 420.40; m/z found, 19 12 6 4 421.0 [M+H] .
Step C: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridazinyloxy)pyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of 5-(4- methyl(pyridazinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (800 mg, 1.90 mmol), triethylamine (384 mg, 3.80 mmol), and HATU (940 mg, 2.47 mmol) in DMF was stirred at room temperature for 15 minutes to give activated-ester solution. N-((1S,2R)aminocyclopentyl)acrylamide from Step A, was dissolved in DMF and triethylamine (384 mg, 3.80 mmol) and was added to the activated-ester solution. The reaction was stirred at room temperature for 10 minutes. The reaction was purified by flash column chromatography to give the title compound (441 mg, 41.5% yield) as a light yellow solid. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.2 [M+H] . 27 24 8 4 H NMR (400 MHz, CD OD): δ 9.07 (d, J = 4.6 Hz, 1H), 8.35 (d, J = 5.6 Hz, 1H), 8.21 (d, J = 4.0 Hz, 1H), 7.88-7.80 (m, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.39 (s, 1H), 6.35 – 6.14 (m, 3H), 5.62 (d, J = 9.6 Hz, 1H), 4.52 – 4.31 (m, 2H), 2.29 (s, 3H), 2.17-2.00 (m, 2H), 1.97-1.82 (m, 1H), 1.83 – 1.60 (m, 3H).
Example 472: N-((1R,2S)Acrylamidocyclohexyl)(2-methyl(pyridazinyloxy)pyridin- 3-yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 5-(2-Methyl(pyridazinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 25, using 5-aminomethylpyridinol and 3,6-dichloropyridazine in Step A.
Step B: N-((1R,2S)Acrylamidocyclohexyl)(2-methyl(pyridazinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2-methyl(pyridazin yloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and N-((1S,2R)aminocyclohexyl)acrylamide (Intermediate 40), no HCl/MeOH deprotection.
MS (ESI): mass calcd. for C H N O S, 570.6; m/z found, 571.2 [M+H] . H NMR (400 MHz, 28 26 8 4 CD OD): δ 9.11-9.04 (m, 1H), 8.38-8.35 (m, 1H), 7.98-7.91 (m, 1H), 7.90-7.82 (m, 1H), 7.70- 7.63 (m, 1H), 7.32-7.25 (m, 1H), 6.47-6.38 (m, 1H), 6.32-6.22 (m, 2H), 5.73-5.63 (m, 1H), 4.50- 4.40 (m, 1H), 4.20-4.14 (m, 1H), 2.29-2.24 (m, 3H), 1.85-1.59 (m, 8H).
Example 473: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridazinyloxy)pyridin- 3-yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 5-(2- methyl(pyridazinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (Example 472, product from Step A) and N-((1S,2R) aminocyclopentyl)acrylamide (Intermediate 36), no HCl/MeOH deprotection. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.1 [M+H] . H NMR (400 MHz, CD OD): δ 27 24 8 4 3 9.08-9.04 (m, 1H), 8.36-8.32 (m, 1H), 7.97-7.92 (m, 1H), 7.87-7.82 (m, 1H), 7.68-7.63 (m, 1H), 7.31-7.25 (m, 1H), 6.32-6.15 (m, 3H), 5.65-5.56 (m, 1H), 4.53-4.34 (m, 2H), 2.27-2.21 (m, 3H), 2.15-2.02 (m, 2H), 1.97-1.86 (m, 1H),1.80-1.63 (m, 3H).
Example 474: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((2-methylpyridin yl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1S,2R)aminocyclopentyl)acrylamide. To a solution of tert-butyl ((1R,2S) acrylamidocyclohexyl)carbamate (500 mg, 1.97 mmol) in DCM (3 mL) was added methanesulfonic acid (0.387 mL) and was stirred at room temperature for 2 h. The reaction was concentrated to dryness to give N-((1S,2R)aminocyclopentyl)acrylamide, which was used without further purification.
Step B: 5-(2-Methyl((2-methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 6-chloromethylnitropyridine and 2-methylpyridinol in Step A, no Cu. MS (ESI): mass calcd. for C21H15N5O4S, 433.44; m/z found, 434.0 [M+H] .
Step C: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((2-methylpyridin yl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of 5-(2-methyl((2-methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxylic acid (736 mg, 1.34 mmol), triethylamine (0.474 mL, 3.40 mmol), and HATU (742 mg, 1.95 mmol) in DMF (3 mL) was stirred at room temperature for 15 minutes to give activated-ester solution. N-((1S,2R) aminocyclopentyl)acrylamide (From Step A), was dissolved in DMF (3 mL) and triethylamine (0.474 mL, 3.40 mmol) and was added to the activated-ester solution. The reaction was stirred at room temperature for 2 h. The reaction was purified by flash column chromatography to give the title compound (580 mg, 99.1% yield) as a grey solid. MS (ESI): mass calcd. for C H N O S, 569.6; m/z found, 570.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.40-8.25 (m, 29 27 7 4 3 2H), 7.99-7.77 (m, 1H), 7.70-7.51 (m, 1H), 7.44-7.22 (m, 1H), 7.17-6.99 (m, 1H), 6.36-6.15 (m, 2H), 6.15-6.04 (m, 1H), 5.69-5.54 (m, 1H), 4.50-4.29 (m, 2H), 2.43 (s, 3H), 2.25-2.12 (m, 3H), 2.11-1.99 (m, 2H), 1.98-1.85 (m, 1H), 1.80-1.58 (m, 3H).
Example 475: N-((1R,2S)Acrylamidocyclohexyl)oxo(5-(pyridazinyloxy)pyridin yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 4-Oxo(5-(pyridazinyloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Steps A, and C-F, using 6-aminopyridinol and 3,6- dichloropyridazine in place of phenol and 5-fluoronitrotoluene in step A.
Step B: N-((1R,2S)Acrylamidocyclohexyl)oxo(5-(pyridazinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo(5-(pyridazinyloxy)pyridinyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid and N-((1S,2R) aminocyclohexyl)acrylamide (Intermediate 40), no HCl/MeOH deprotection. MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.2 [M+H] . H NMR (400 MHz, DMSO-d ): δ 27 24 8 4 6 .10 (s, 1H), 9.09-9.05 (m, 1H), 8.64 (s, 1H), 8.36-8.30 (m, 1H), 8.10-8.02 (m, 1H), 7.90-7.80 (m, 3H), 7.76-7.69 (m, 1H), 7.68-7.62 (m, 1H), 6.46-6.34 (m, 1H), 6.21-6.08 (m, 2H), 5.64-5.54 (m, 1H), 4.25-4.18 (m, 1H), 4.07-3.96 (m, 1H), 1.78-1.60 (m, 4H), 1.60-1.48 (m, 2H), 1.46-1.29 (m, 2H).
Example 476: N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridazinyloxy)pyridin yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
The title compound was prepared in a manner analogous to Example 1, Step A, using 4-oxo (5-(pyridazinyloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid and N-((1S,2R)aminocyclopentyl)acrylamide (Intermediate 36), (no HCl/MeOH deprotection). MS (ESI): mass calcd. for C H N O S, 542.6; m/z found, 543.2 26 22 8 4 [M+H] . H NMR (400 MHz, CD OD): δ 9.03-8.98 (m, 1H), 8.68-8.61 (m, 1H), 8.37-8.30(m, 1H), 8.07-8.00 (m, 1H), 7.86-7.79 (m, 1H), 7.75-7.68 (m, 1H), 7.64-7.57(m, 1H), 6.40-6.33 (m, 1H), 6.32-6.19 (m, 2H), 5.67-5.59(m, 1H), 4.46-4.40 (m, 2H), 2.15-2.03 (m, 2H), 1.98-1.85 (m, 1H), 1.82-1.65 (m, 3H).
Example 477: N-((1R,2S)Acrylamidocyclopentyl)(6'-methyloxo-2H-[1,2'-bipyridin]-5'- yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1S,2R)aminocyclopentyl)acrylamide. A solution of tert-butyl ((1R,2S) acrylamidocyclopentyl)carbamate (582 mg, 2.29 mmol) in 4 M HCl in dioxane was stirred at room temperature for 60 minutes. The reaction was concentrated to dryness to give N-((1S,2R)- 2-aminocyclopentyl)acrylamide, which was used without further purification.
Step B. 5-(6'-Methyloxo-2H-[1,2'-bipyridin]-5'-yl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, using 6-fluoromethylnitropyridine and pyridinol in place of -fluoronitrotoluene and phenol in step A. MS (ESI): mass calcd. for C H N O S, 419.41; 13 5 4 m/z found, 420.1 [M+H] .
Step C: N-((1R,2S)Acrylamidocyclopentyl)(6'-methyloxo-2H-[1,2'-bipyridin]-5'-yl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of 5-(6'- methyloxo-2H-[1,2'-bipyridin]-5'-yl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (686 mg, 1.64 mmol), triethylamine (0.456 mL, 3.26 mmol), and HATU (808 mg, 2.13 mmol) in DMF (4 mL) was stirred at room temperature for 15 minutes to give activated-ester solution. N-((1S,2R)Aminocyclopentyl)acrylamide (From Step A), was dissolved in DMF (4 mL) and triethylamine (0.456 mL, 3.26 mmol) and was added to the activated-ester solution. The reaction was stirred at room temperature for 10 minutes. The reaction was purified by flash column chromatography to give the title compound (370 mg, 98.5% yield) as a white solid. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.2 28 25 7 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.34 (d, J = 5.6 Hz, 1H), 8.07 – 7.93 (m, 2H), 7.87- 7.80 (m, 1H), 7.69 – 7.59 (m, 1H), 6.66 (d, J = 9.2 Hz, 1H), 6.58-6.47 (m, 1H), 6.33 – 6.16 (m, 3H), 5.62 (d, J = 9.7 Hz, 1H), 4.49 – 4.34 (m, 2H), 2.44 (s, 3H), 2.17-2.00 (m, 2H), 1.99-1.85 (m, 1H), 1.82 – 1.57 (m, 3H).
Example 478: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1S,2R)aminocyclopentyl)acrylamide. A solution of tert-butyl ((1R,2S) acrylamidocyclopentyl)carbamate (497 mg, 1.95 mmol) in 4 M HCl in dioxane was stirred at room temperature for 60 minutes. The reaction was concentrated to dryness to give N-((1S,2R)- 2-aminocyclopentyl)acrylamide, which was used without further purification.
Step B: 5-(2-Methyl(pyridinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 6-fluoromethylnitropyridine and pyridinol Step A, no Cu. MS (ESI): mass calcd. for C H N O S, 419.41; m/z found, 420.1 [M+H] . 13 5 4 Step C: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of 5-(2- methyl(pyridinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (630 mg, 1.50 mmol), triethylamine (304 mg, 3.00 mmol), and HATU (742 mg, 1.95 mmol) in DMF (2.5 mL) was stirred at room temperature for minutes to give activated-ester solution. N-((1S,2R)aminocyclopentyl)acrylamide (From Step A), was dissolved in DMF (2.5 mL) and triethylamine (304 mg, 3.00 mmol) and was added to the activated-ester solution. The reaction was stirred at room temperature for 10 minutes. The reaction was purified by flash column chromatography to give the title compound (450 mg, 53.9% yield) as a white solid. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.2 28 25 7 4 [M+H] . H NMR (400 MHz, CD OD): δ 8.35 (d, J = 5.5 Hz, 1H), 8.30-8.23 (m, 1H), 7.97- 7.91(m, 1H), 7.90-7.84 (m, 1H), 7.31 – 7.24 (m, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 6.36 – 6.13 (m, 3H), 5.61 (d, J = 9.5 Hz, 1H), 4.48-4.35 (m, 2H), 2.25 (s, 3H), 2.15- 1.99 (m, 2H), 1.96-1.85 (m, 1H), 1.82 – 1.57 (m, 3H).
Example 479: N-((1R,2S)Acrylamidocyclopentyl)(5-((6-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1S,2R)aminocyclopentyl)acrylamide. To a solution of tert-butyl ((1R,2S) acrylamidocyclopentyl)carbamate (958 mg, 3.78 mmol) in DCM (15 mL) was added methanesulfonic acid (402 mg, 4.19 mmol) and was stirred at room temperature for 1 h. The reaction was concentrated to dryness to give N-((1S,2R)aminocyclopentyl)acrylamide, which was used without further purification.
Step B: 5-(5-((6-Methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, using Steps A, C-F, and using 2-fluoromethylpyridine and 6- aminopyridinol in place of 5-fluoronitrotoluene and phenol in Step A. MS (ESI): mass calcd. for C H N O S, 419.41; m/z found, 420.1 [M+H] . 13 5 4 Step C: N-((1R,2S)Acrylamidocyclopentyl)(5-((6-methylpyridinyl)oxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of 5-(5-((6- methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxylic acid (1000 mg, 1.88 mmol), triethylamine (483 mg, 4.78 mmol), and HATU (1.43 g, 3.77 mmol) in DMF (5 mL) was stirred at room temperature for 15 minutes to give activated- ester solution. N-((1S,2R)aminocyclopentyl)acrylamide (From Step A), was dissolved in DMF (5 mL) and triethylamine (483 mg, 4.78 mmol) and was added to the activated-ester solution. The reaction was stirred at room temperature for 30 minutes. The reaction was purified by flash column chromatography to give the title compound (532 mg, 48.4% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.1 [M+H] . H 28 25 7 4 NMR (400 MHz, DMSO-d ): δ10.10 (s, 1H), 8.58-8.48 (m, 1H), 8.33 (d, J = 5.2 Hz, 1H), 8.00- 7.73 (m, 4H), 7.69-7.59 (m, 1H), 7.13-7.04 (m, 1H), 7.00-6.92 (m, 1H), 6.30-5.99 (m, 3H), 5.61- 5.48 (m, 1H), 4.42-4.17 (m, 2H), 2.35 (s, 3H), 2.03-1.82 (m, 2H), 1.80-1.47 (m, 4H).
Example 480: N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridinyloxy)pyridinyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1S,2R)aminocyclopentyl)acrylamide. To a solution of tert-butyl ((1R,2S) acrylamidocyclopentyl)carbamate (504 mg, 1.98 mmol) in DCM (15 mL) was added methanesulfonic acid (381 mg, 3.97 mmol) and was stirred at room temperature for 2 h. The reaction was concentrated to dryness to give N-((1S,2R)aminocyclopentyl)acrylamide, which was dissolved in DMF (2.5 mL) and used without further purification.
Step B: 4-Oxo(5-(pyridinyloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, using Steps A, C-F, and using 2-fluoropyridine and 6-aminopyridin- 3-ol in place of 5-fluoronitrotoluene and phenol in Step A. MS (ESI): mass calcd. for C H N O S, 405.39; m/z found, 406.0 [M+H] . 19 11 5 4 Step C: N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of 4-oxo(5- (pyridinyloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (670 mg, 1.65 mmol), triethylamine, and HATU (817 mg, 2.15 mmol) in DMF (2.5 mL) was added N-((1S,2R)aminocyclopentyl)acrylamide (From Step A). The reaction mixture was stirred at room temperature until LCMS showed the reaction had gone to completion. The reaction was poured into water and the precipitate that formed was collected by filtration. The solid was purified by flash column chromatography to give the title compound (190 mg, 21.2% yield) as a grey solid. MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.0 [M+H] . 27 23 7 4 H NMR (400 MHz, DMSO-d ): δ 10.28 (br, 1H), 8.58-8.48 (m, 1H), 8.35-8.28 (m, 1H), 8.23- 8.16 (m, 1H), 7.98-7.84 (m, 3H), 7.82-7.73 (m, 1H), 7.69-7.62 (m, 1H), 7.26-7.14 (m, 2H), 6.29- 6.00 (m, 3H), 5.60-5.49 (m, 1H), 4.35-4.19 (m, 2H), 2.01-1.83 (m, 2H), 1.81-1.68 (m, 2H), 1.67- 1.48 (m, 2H).
Example 481: N-((1R,2S)Acrylamidocyclopentyl)(5-((6-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1S,2R)aminocyclopentyl)acrylamide. To a solution of tert-butyl ((1R,2S) acrylamidocyclopentyl)carbamate (554 mg, 2.19 mmol) in DCM (3 mL) was added methanesulfonic acid (837 mg, 8.71 mmol) and was stirred at room temperature for 1 h. The reaction was concentrated to dryness to give N-((1S,2R)aminocyclopentyl)acrylamide, which was dissolved in DMF (2.0 mL) and used without further purification.
Step B: 5-(5-((6-Methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 5-bromopyrimidine and 6-methylpyridinol in Step A, no Cu. MS (ESI): mass calcd. for C H N O S, 419.41; m/z found, 420.0 [M+H] . 13 5 4 Step C: N-((1R,2S)Acrylamidocyclopentyl)(5-((6-methylpyridinyl)oxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of 5-(5-((6- methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxylic acid (1.096 g, 2.614 mmol), triethylamine (1.168 g, 11.54 mmol), and HATU (1.077 g, 2.83 mmol) in DMF (3.0 mL) was stirred at room temperature for 15 minutes to form the activated ester. To this solution was added N-((1S,2R)aminocyclopentyl)acrylamide (From Step A) in DMF (2.5 mL) and was stirred at room for 30 minutes. The reaction was purified by flash column chromatography (MeOH /H O) and again by flash column chromatography (DCM/ MeOH) to give the title compound (420 mg, 34.1% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.1 [M+H] . H NMR (400 28 25 7 4 MHz, CD OD): δ 8.49-8.38 (m, 1H), 8.38-8.30 (m, 1H), 8.30-8.21 (m, 1H), 7.75-7.64 (m, 1H), 7.64-7.50 (m, 2H), 7.42-7.32 (m, 1H), 6.32-6.12 (m, 3H), 5.69-5.52 (m, 1H), 4.47-4.34 (m, 2H), 2.54 (s, 3H), 2.13-2.00 (m, 2H), 1.95-1.85 (m, 1H), 1.81-1.62 (m, 3H).
Example 482: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)phenyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1S,2R)aminocyclopentyl)acrylamide. To a solution of tert-butyl ((1R,2S) acrylamidocyclopentyl)carbamate (479 mg, 1.88 mmol) in DCM (15 mL) was added methanesulfonic acid (201 mg, 2.09 mmol) and was stirred at room temperature for 1 h. The reaction was concentrated to dryness to give N-((1S,2R)aminocyclopentyl)acrylamide, which was used without further purification.
Step B:5-(2-Methyl(pyrimidinyloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, using Steps A-F, using 4-fluoromethylnitrobenzene and pyrimidinol in Step A. MS (ESI): mass calcd. for C H N O S, 419.41; m/z found, 420.0 13 5 4 [M+H] .
Step C: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)phenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of 5-(2-methyl (pyrimidinyloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (500 mg, 0.942 mmol), triethylamine (242 mg, 2.39 mmol), and HATU (716 mg, 1.88 mmol) in DMF (3.0 mL) was stirred at room temperature for 15 minutes to form the activated ester. To this solution was added N-((1S,2R)aminocyclopentyl)acrylamide (From Step A), triethylamine (242 mg, 2.39 mmol) in DMF (3.0 mL). The reaction mixture was stirred at room temperature until LCMS showed the reaction had gone to completion. The reaction was purified by flash column chromatography to give the title compound (189 mg, 34.8% yield) as a white solid. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.1 [M+H] . H 28 25 7 4 NMR (400 MHz, CD OD): δ 8.95 (s, 1H), 8.70-8.61 (m, 2H), 8.32 (d, J = 4.7 Hz, 1H), 7.51-7.34 (m, 1H), 7.26 (s, 1H), 7.21-7.11 (m, 1H), 6.37-6.16 (m, 2H), 6.13-6.05 (m, 1H), 5.68-5.57 (m, 1H), 4.50-4.35 (m, 2H), 2.17 (s, 3H), 2.13-2.01 (m, 2H), 1.96-1.85 (m, 1H), 1.84-1.60 (m, 3H).
Example 483: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((6-methylpyridin yl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1S,2R)aminocyclopentyl)acrylamide. To a solution of tert-butyl ((1R,2S) acrylamidocyclopentyl)carbamate (417 mg, 1.64 mmol) in DCM (15 mL) was added methanesulfonic acid (233 mg, 2.43 mmol) and was stirred at room temperature for 1 h. The reaction was concentrated to dryness to give N-((1S,2R)aminocyclopentyl)acrylamide, which was used without further purification.
Step B: 5-(4-Methyl((6-methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 2-fluoromethylnitropyridine and 6-methylpyridinol in place of 5-fluoronitrotoluene and phenol in Step A, and no Cu. MS (ESI): mass calcd. for C H N O S, 433.44; m/z found, 434.0 [M+H] . 21 15 5 4 Step C: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((6-methylpyridin yl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of 5-(4-methyl((6-methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxylic acid (600 mg, 1.09 mmol), triethylamine (280 mg, 1.22 mmol), and HATU (748 mg, 1.97 mmol) in DMF (3.0 mL) was stirred at room temperature for 15 minutes to form the activated ester. To this solution was added the N-((1S,2R) aminocyclopentyl)acrylamide (from Step A) in DMF (3.0 mL) and triethylamine (280 mg, 1.22 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction was purified by flash column chromatography to give the title compound (525 mg, 82.0% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 569.6; m/z found, 570.1 [M+H] . H 29 27 7 4 NMR (400 MHz, CD OD): δ 8.34 (d, J = 5.4 Hz, 1H), 8.22-8.12 (m, 1H), 7.88-7.75 (m, 1H), 7.21 (s, 1H), 7.18-7.12 (m, 1H), 7.04-6.95 (m, 1H), 6.3-6.13 (m, 3H), 5.68-5.57 (m, 1H), 4.5- 4.37 (m, 2H), 2.48 (s, 3H), 2.30-2.20 (m, 3H), 2.16-2.03 (m, 2H), 1.99-1.87 (m, 1H), 1.83-1.62 (m, 3H).
Example 484: N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyrimidinyloxy)pyridin yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1S,2R)aminocyclopentyl)acrylamide. A solution of tert-butyl ((1R,2S) acrylamidocyclopentyl)carbamate (407 mg, 1.60 mmol) in 4.0 M HCl in dioxane (50 mL) was stirred at room temperature for 1 h. The reaction was concentrated to dryness to give N- ((1S,2R)aminocyclopentyl)acrylamide, which was used without further purification.
Step B: 4-Oxo(5-(pyrimidinyloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, using Steps A, C-F, and using 2-chloropyrimidine and 6- aminopyridinol in place of 5-fluoronitrotoluene and phenol in Step A. MS (ESI): mass calcd. for C H N O S, 406.38; m/z found, 407.0 [M+H] . 18 10 6 4 Step C: N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyrimidinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of 4-oxo(5- (pyrimidinyloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (500 mg, 1.23 mmol), triethylamine (257 mL, 1.84 mmol), and HATU (608 mg, 1.60 mmol) in DMF (100 mL) was stirred at room temperature for 15 minutes to form the activated ester. To this solution was added the N-((1S,2R)aminocyclopentyl)acrylamide (from Step A) in DMF (50 mL) and triethylamine (257 mL, 1.84 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction was purified by flash column chromatography to give the title compound (365 mg, 54.8% yield) as a white solid. MS (ESI): mass calcd. for C H N O S, 542.6; m/z found, 543.1 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.13 (s, 26 22 8 4 6 1H), 8.77-8.67 (m, 2H), 8.66-8.58 (m, 1H), 8.38-8.30 (m, 1H), 8.08-7.99 (m, 1H), 7.93-7.84 (m, 1H), 7.81-7.73 (s, 1H), 7.73-7.65 (m, 1H), 7.44 – 7.28 (m, 1H), 6.29 – 5.97 (m, 3H), 5.62-5.47 (m, 1H), 4.36-4.17 (m, 2H), 2.01-1.82 (m, 2H), 1.80 – 1.45 (m, 4H).
Example 485: N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyrimidinyloxy)pyridin yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: 4-Oxo(5-(pyrimidinyloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, using Steps A-F, using 5-chloronitropyridine and pyrimidinol in place of 5-fluoronitrotoluene and phenol in Step A. MS (ESI): mass calcd. for C H N O S, 406.38; m/z found, 407.0 [M+H] . 18 10 6 4 Step B: N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyrimidinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of 4-oxo(5- (pyrimidinyloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (400 mg, 0.984 mmol), triethylamine (149 mg, 1.48 mmol), and HATU (486 mg, 1.28 mmol) in DMF (4 mL) was stirred at room temperature for 10 minutes to form the activated ester. To this solution was added a solution of N-((1S,2R)aminocyclopentyl)acrylamide (Intermediate 36, 197 mg, 1.28 mmol) in DMF (1 mL) and triethylamine (248 mg, 2.46 mmol) and was stirred at room temperature for 30 minutes. The reaction was purified by reverse phase HPLC to give the title compound (266 mg, 49.8% yield). MS (ESI): mass calcd. for C H N O S, 542.6; m/z found, 543.1 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.08 (s, 26 22 8 4 6 1H), 9.07 (s, 1H), 8.82 (s, 2H), 8.60-8.55 (m, 1H), 8.35-8.30 (m, 1H), 7.92-7.84 (m, 2H), 7.78- 7.70 (m, 1H), 7.68-7.62 (m, 1H), 6.31-6.16 (m, 2H), 6.11-5.99 (m, 1H), 5.59-5.50 (m, 1H), 4.34- 4.19 (m, 2H), 2.01-1.83 (m, 2H), 1.82-1.68 (m, 2H), 1.67-1.58 (m, 1H), 1.57-1.46 (m, 1H).
Example 486: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyrimidinyloxy)pyridin- 3-yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: 5-(4-Methyl(pyrimidinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 2-chloromethylnitropyridine and pyrimidinol in Step A, no Cu. MS (ESI): mass calcd. for C H N O S, 420.40; m/z found, 421.1 [M+H] . 19 12 6 4 Step B: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyrimidinyloxy)pyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of 5-(4- methyl(pyrimidinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (800 mg, 1.90 mmol), triethylamine (289 mg, 2.85 mmol), and HATU (9.41 mg, 2.47 mmol) in DMF (8 mL) was stirred at room temperature for 10 minutes to form the activated ester. To this solution was added a solution of N-((1S,2R) aminocyclopentyl)acrylamide (Intermediate 36, 382 mg, 2.47 mmol) in DMF (2 mL) and triethylamine (481 mg, 4.76 mmol) and was stirred at room temperature for 30 minutes. The reaction was purified by reverse phase HPLC to give the title compound (551 mg, 52.0% yield).
MS (ESI): mass calcd. for C27H24N8O4S, 556.6; m/z found, 557.2 [M+H] . H NMR (400 MHz, DMSO-d ): δ 10.15 (s, 1H), 9.06 (s, 1H), 8.84 (s, 2H), 8.34-8.28 (m, 1H), 8.18-8.12 (m, 1H), 7.90-7.83 (m, 1H), 7.80-7.70 (m, 1H), 7.36 (s, 1H), 6.27-6.15 (m, 1H), 6.13-6.01 (m, 2H), 5.59- .50 (m, 1H), 4.33-4.20 (m, 2H), 2.17 (s, 3H), 1.98-1.82 (m, 2H), 1.82-1.67 (m, 2H), 1.67-1.56 (m, 1H), 1.56-1.44 (m, 1H).
Example 487: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((6-methylpyridin yl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. N-((1S,2R)aminocyclopentyl)acrylamide. To a solution of tert-butyl ((1R,2S) acrylamidocyclopentyl)carbamate (700 mg, 2.75 mmol) in DCM (4 mL) was added methanesulfonic acid (1.058 g, 11.01 mmol) and was stirred at room temperature for 1 h. The reaction was concentrated to dryness to give N-((1S,2R)aminocyclopentyl)acrylamide, which was used without further purification.
Step B: 5-(4-Methyl((6-methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 2-bromomethylnitropyridine and 6-methylpyridinol in Step A, no Cu. MS (ESI): mass calcd. for C H N O S, 433.44; m/z found, 434.0 [M+H] . 21 15 5 4 Step C: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((6-methylpyridin yl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. .
A solution of 4-oxo(5-(pyrimidinyloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (1.432 g, 3.303 mmol), triethylamine (1.476 g, 14.59 mmol), and HATU (1.361 g, 3.578 mmol) in DMF (5 mL) was stirred at room temperature for minutes to form the activated ester. To this solution was added N-((1S,2R) aminocyclopentyl)acrylamide (from Step A) in DMF (3 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction was purified by flash column chromatography to give the title compound (600 mg, 37.9% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 569.6; m/z found, 570.1 [M+H] . H NMR (400 MHz, CD OD): δ 8.37-8.26 (m, 29 27 7 4 3 2H), 8.10-8.01 (m, 1H), 7.63-7.56 (m, 1H), 7.39-7.32 (m, 1H), 7.20-7.14 (m, 1H), 6.33-6.09 (m, 3H), 5.65-5.56 (m, 1H), 4.47-4.35 (m, 2H), 2.54 (s, 3H), 2.22 (s, 3H), 2.13-2.01 (m, 2H), 1.95- 1.85 (m, 1H), 1.81-1.60 (m, 3H).
Example 488: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridinyloxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: N-((1S,2R)aminocyclopentyl)acrylamide. To a solution of tert-butyl ((1R,2S) acrylamidocyclopentyl)carbamate (509 mg, 2.00 mmol) in DCM (10 mL) was added methanesulfonic acid (385 mg, 4.01 mmol) and was stirred at room temperature for 2 h. The reaction was concentrated to dryness to give N-((1S,2R)aminocyclopentyl)acrylamide, which was dissolved in DMF (2 mL).
Step B: 5-(4-Methyl(pyridinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 2-fluoromethylnitropyridine and pyridinol in Step A, no Cu. MS (ESI): mass calcd. for C H N O S, 419.41; m/z found, 420.1 [M+H] . 13 5 4 Step C: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of 5-(4- methyl(pyridinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (700 mg, 1.67 mmol), triethylamine, and HATU (825 mg, 2.17 mmol) in DMF (3 mL) was stirred at room temperature for 15 minutes to form the activated ester. To this solution was added the N-((1S,2R)aminocyclopentyl)acrylamide (From Step A) and was stirred at room temperature until LCMS showed the reaction had gone to completion. The reaction was poured into H O and the precipitate that formed was collected by filtration. The residue was purified by flash column chromatography to give the title compound (380 mg, 41% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 555.6; m/z 28 25 7 4 found, 556.1 [M+H] . H NMR (400 MHz, DMSO-d ): δ10.22 (br, 1H), 8.40-8.19 (m, 3H), 7.95-7.84 (m, 2H), 7.82-7.69 (m, 1H), 7.29-7.23 (m, 2H), 7.22-7.16 (m, 1H), 6.28-6.14 (m, 1H), 6.11-6.02 (m, 2H), 5.60-5.46 (m, 1H), 4.34-4.19 (m, 2H), 2.15 (s, 3H), 1.98-1.83 (m, 2H), 1.82- 1.68 (m, 2H), 1.67-1.48 (m, 2H).
Example 489: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((2-methylpyridin yl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide .
Step A: 5-(4-Methyl((2-methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 2-fluoromethylnitropyridine and 2-methylpyridinol in Step A, no Cu. MS (ESI): mass calcd. for C H N O S, 433.44; m/z found, 434.0 [M+H] . 21 15 5 4 Step B: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((2-methylpyridin yl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of tert-butyl ((1R,2S)acrylamidocyclopentyl)carbamate (500 mg, 1.97 mmol) in DCM (3 mL) was added methanesulfonic acid (0.387 g, 5.96 mmol) and was stirred at room temperature for 2 h. The reaction was concentrated to dryness to give N-((1S,2R) aminocyclopentyl)acrylamide, which was dissolved in DMF (2 mL) and triethylamine (0.474 mL, 3.40 mmol). A solution of 5-(4-methyl((2-methylpyridinyl)oxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxylic acid (736 mg, 1.34 mmol), triethylamine (0.474 mL, 3.40 mmol), and HATU (742 mg, 1.95 mmol) in DMF (4 mL) was stirred at room temperature for 15 minutes to form the activated ester. To this solution was added the N-((1S,2R)aminocyclopentyl)acrylamide solution from above and was stirred at room temperature for 2 h. The reaction was purified by flash column chromatography (MeOH/H O) and again using flash column chromatography (DCM/MeOH) to give the title compound (636 mg, 99.5% yield) as a white solid. MS (ESI): mass calcd. for C H N O S, 29 27 7 4 569.6; m/z found, 570.2 [M+H] . H NMR (400 MHz, CD OD): δ 8.29 (s, 2H), 8.15-8.04 (m, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.40-7.28 (m, 1H), 7.19 (s, 1H), 6.32-6.14 (m, 2H), 6.13-6.05 (m, 1H), 5.59 (d, J = 9.7 Hz, 1H), 4.47-4.28 (m, 2H), 2.41 (s, 3H), 2.26-2.18 (m, 3H), 2.11-1.98 (m, 2H), 1.94-1.82 (m, 1H), 1.76-1.55 (m, 3H).
Example 490: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridinyloxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: 5-(4-Methyl(pyridinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 2-fluoromethylnitropyridine and pyridinol in Step A, no Cu. MS (ESI): mass calcd. for C H N O S, 419.41; m/z found, 420.0 [M+H] . 13 5 4 Step B: N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of tert- butyl ((1R,2S)acrylamidocyclopentyl)carbamate (500 mg, 1.97 mmol) in DCM (3 mL) was added methanesulfonic acid (0.387 g, 5.96 mmol) and was stirred at room temperature for 2 h.
The reaction was concentrated to dryness to give N-((1S,2R)aminocyclopentyl)acrylamide, which was dissolved in DMF (2 mL) and triethylamine (0.474 mL, 3.40 mmol). A solution of 5- (4-methyl((2-methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (712 mg, 1.34 mmol), triethylamine (0.474 mL, 3.40 mmol), and HATU (742 mg, 1.95 mmol) in DMF (4 mL) was stirred at room temperature for 15 minutes to form the activated ester. To this solution was added the N-((1S,2R) aminocyclopentyl)acrylamide solution from above and was stirred at room temperature for 2 h.
The reaction was purified by flash column chromatography (MeOH/H O) and again using flash column chromatography (DCM/MeOH) to give the title compound (742 mg, 99.6% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.1 [M+H] . H 28 25 7 4 NMR (400 MHz, CD OD): δ 8.46 (s, 1H), 8.43-8.35 (m, 1H), 8.32-8.23 (m, 1H), 8.16-8.04 (m, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.56-7.41 (m, 1H), 7.18 (s, 1H), 6.31-6.15 (m, 2H), 6.14-6.06 (m, 1H), 5.58 (d, J = 9.6 Hz, 1H), 4.48-4.29 (m, 2H), 2.26-2.16 (m, 3H), 2.11-1.96 (m, 2H), 1.95- 1.82 (m, 1H), 1.78-1.58 (m, 3H).
Example 491: N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridinyloxy)pyridinyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: 4-Oxo(5-(pyridinyloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 5-bromonitropyridine and pyridinol in Step A, no Cu.
MS (ESI): mass calcd. for C H N O S, 405.39; m/z found, 406.0 [M+H] . 19 11 5 4 Step B: N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of tert-butyl ((1R,2S)acrylamidocyclopentyl)carbamate (350 mg, 1.38 mmol) in DCM (2 mL) was added methanesulfonic acid (0.271 mL, 4.17 mmol) and was stirred at room temperature for 2 h. The reaction was concentrated to dryness to give N-((1S,2R)aminocyclopentyl)acrylamide, which was dissolved in DMF (2 mL) and triethylamine (0.332 mL, 2.38 mmol). A solution of 4-oxo (5-(pyridinyloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxylic acid (482 mg, 0.939 mmol), triethylamine (0.332 mL, 2.38 mmol), and HATU (520 mg, 1.37 mmol) in DMF (2 mL) was stirred at room temperature for 15 minutes to form the activated ester. To this solution was added the N-((1S,2R)aminocyclopentyl)acrylamide solution from above and was stirred at room temperature for 30 minutes. The reaction was purified by flash column chromatography (MeOH/H O) and again using flash column chromatography (DCM/MeOH) to give the title compound (210 mg, 40.6% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.1 [M+H] . H NMR (400 27 23 7 4 MHz, DMSO-d ): δ 10.09 (s, 1H), 8.58-8.52 (m, 1H), 8.52-8.40 (m, 2H), 8.37-8.27 (m, 1H), 7.95-7.83 (m, 1H), 7.83-7.71 (m, 2H), 7.69-7.59 (m, 2H), 7.54-7.39 (m, 1H), 6.27-6.13 (m, 2H), 6.13-5.96 (m, 1H), 5.60-5.48 (m, 1H), 4.33-4.20 (m, 2H), 2.00-1.86 (m, 2H), 1.80-1.68 (m, 2H), 1.65-1.46 (m, 2H).
Example 492: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)pyridin- 3-yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: 5-(2-Methyl(pyrimidinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 6-chloromethylnitropyridine and 2-chloropyrimidin ol in Step A, no Cu. MS (ESI): mass calcd. for C H N O S, 420.40; m/z found, 421.0 [M+H] . 19 12 6 4 Step B: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)pyridinyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of 5-(2- methyl(pyrimidinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (800 mg, 1.90 mmol), triethylamine (289 mg, 2.85 mmol), and HATU (941 mg, 2.47 mmol) in DMF (8 mL) was stirred at room temperature for 15 minutes to form the activated ester. To this solution was added a solution of N-((1S,2R) aminocyclopentyl)acrylamide (376 mg, 2.44 mmol) and triethylamine (481 mg, 4.76 mmol) in DMF (2 mL) and was stirred at room temperature for 30 minutes. The reaction was purified by flash column chromatography (MeOH/H O) to give the title compound (560 mg, 52.9% yield).
MS (ESI): mass calcd. for C H N O S, 556.6; m/z found, 557.1 [M+H] . H NMR (400 MHz, 27 24 8 4 CD OD): δ 9.01 (s, 1H), 8.80 (s, 2H), 8.34-8.28 (m, 1H), 7.95-7.85 (m, 1H), 7.23-7.16 (m, 1H), 6.31-6.10 (m, 3H), 5.64-5.54 (m, 1H), 4.47-4.32 (m, 2H), 2.23-2.16 (m, 3H), 2.13-2.01 (m, 2H), 1.96-1.84 (m, 1H), 1.80-1.59 (m, 3H).
Example 493: N-((1R,2S)Acrylamidocyclopentyl)(5-((2-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: 5-(5-((2-Methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 5-bromonitropyridine and 2-methylpyridinol in Step A, no Cu. MS (ESI): mass calcd. for C H N O S, 419.41; m/z found, 420.0 [M+H] . 13 5 4 Step B: N-((1R,2S)Acrylamidocyclopentyl)(5-((2-methylpyridinyl)oxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of tert- butyl ((1R,2S)acrylamidocyclopentyl)carbamate (300 mg, 1.18 mmol) in DCM (2 mL) was added methanesulfonic acid (0.232 mL, 3.58 mmol) and was stirred at room temperature for 2 h.
The reaction was concentrated to dryness to give N-((1S,2R)aminocyclopentyl)acrylamide, which was dissolved in DMF (2 mL) and triethylamine (0.284 mL, 2.04 mmol). A solution of 5- (5-((2-methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (428 mg, 0.805 mmol), triethylamine (0.284 mL, 2.04 mmol), and HATU (445 mg, 1.17 mmol) in DMF (2 mL) was stirred at room temperature for 15 minutes to form the activated ester. To this solution was added the N-((1S,2R) aminocyclopentyl)acrylamide solution from above and was stirred at room temperature for 2 h.
The reaction was purified by flash column chromatography (MeOH/H O) and again using flash column chromatography (DCM/MeOH) to give the title compound (400 mg, 87.9% yield) as a white solid. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.1 [M+H] . H 28 25 7 4 NMR (400 MHz, a mixture of DMSO-d and CD OD): δ 8.40-8.33 (m, 1H), 8.33-8.26 (m, 2H), 7.60-7.53 (m, 2H), 7.51-7.46 (m, 1H), 7.32-7.25 (m, 1H), 6.26-6.15 (m, 2H), 6.12-6.06 (m, 1H), .56-5.51 (m, 1H), 4.32-4.28 (m, 2H), 2.45 (s, 3H), 2.01-1.88 (m, 2H), 1.84-1.74 (m, 1H), 1.73- 1.60 (m, 2H), 1.59-1.48 (m, 1H).
Example 494: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: 5-(2-Methyl(pyridinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 6-chloromethylnitropyridine and pyridinol in Step A, no Cu. MS (ESI): mass calcd. for C H N O S, 419.41; m/z found, 420.1 [M+H] . 13 5 4 Step B: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. To a solution of 5-(2- methyl(pyridinyloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid (650 mg, 1.55 mmol), triethylamine (313 mg, 3.10 mmol), and HATU (331 mg, 0.870 mmol) in DMF (5 mL) was stirred at room temperature for minutes to form the activated ester. To this solution was added a solution of N-((1S,2R) aminocyclopentyl)acrylamide (303 mg, 1.97 mmol) and triethylamine (894 mg, 8.85 mmol) in DMF (5 mL) and was stirred at room temperature for 10 minutes. The reaction was purified by flash column chromatography (MeOH/H O) and again by flash column chromatography (DCM/MeOH) to give the title compound (480 mg, 55.7% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.1 [M+H] . H NMR (400 MHz, CD OD): δ 28 25 7 4 3 8.52-8.45 (m, 1H), 8.43-8.37 (m, 1H), 8.36-8.30 (m, 1H), 7.85-7.79 (m, 1H), 7.78-7.70 (m, 1H), 7.54-7.46 (m, 1H), 7.15-7.06 (m, 1H), 6.31-6.10 (m, 3H), 5.65-5.56 (m, 1H), 4.50-4.27 (m, 2H), 2.18 (s, 3H), 2.10-1.88 (m, 3H), 1.78-1.60 (m, 3H).
Example 495: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6-methylpyridin yl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A: 5-(2-Methyl((6-methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 15, using 6-chloromethylnitropyridine and 6-methylpyridinol in Step A, no Cu. MS (ESI): mass calcd. for C H N O S, 419.41; m/z found, 420.1 [M+H] . 13 5 4 Step B: N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6-methylpyridin yl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
To a solution of 5-(2-methyl((6-methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxylic acid (1000 mg, 2.31 mmol), triethylamine (466 mg, 4.61 mmol), and HATU (1315 mg, 3.460 mmol) in DMF (5 mL) was stirred at room temperature for 15 minutes to form the activated ester. To this solution was added a solution of N-((1S,2R)aminocyclopentyl)acrylamide (485 mg, 3.15 mmol) and triethylamine (1472 mg, 14.57 mmol) in DMF (5 mL) and was stirred at room temperature for 10 minutes. The reaction was purified by flash column chromatography (MeOH/H O) and again by flash column chromatography (DCM/MeOH) to give the title compound (781 mg, 59.4% yield) as a yellow solid. MS (ESI): mass calcd. for C H N O S, 569.6; m/z found, 570.1 [M+H] . H NMR (400 29 27 7 4 MHz, CD OD): δ 8.36-8.29 (m, 2H), 7.86-7.78 (m, 1H), 7.65-7.58 (m, 1H), 7.40-7.33 (m, 1H), 7.10-7.01 (m, 1H), 6.33-6.15 (m, 2H), 6.13-6.08 (m, 1H), 5.65-5.56 (m, 1H), 4.53-4.32 (m, 2H), 2.55 (s, 3H), 2.22-2.16 (m, 3H), 2.15-2.00 (m, 2H), 1.96-1.83 (m, 1H), 1.81-1.59 (m, 3H).
Example 496: N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC purification (Stationary phase: CHIRALCEL AS-H, 5 µm, 250 × 20 mm, Mobile phase: 60% CO , 40% MeOH) of N-((1R,2S)acrylamidocyclopentyl)(2-methyl((6- methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide (Example 368) afforded the *S atropisomer. MS (ESI): mass calcd. for C H N O S, 568.7; m/z found, 569.3 [M+H] . H NMR (400 MHz, CDCl ): δ 9.52 (s, 1H), 28 6 4 3 8.34 (d, J = 5.5 Hz, 1H), 7.67 - 7.56 (m, 1H), 7.27 - 7.08 (m, 3H), 6.95 (d, J = 7.4 Hz, 1H), 6.80 - 6.63 (m, 2H), 6.49 - 6.28 (m, 2H), 6.20 - 6.01 (m, 2H), 5.67 (dd, J = 10.2, 1.4 Hz, 1H), 4.47 - 4.26 (m, 2H), 2.49 (s, 3H), 2.34 - 2.09 (m, 5H), 1.92 - 1.73 (m, 4H).
Example 497: N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC purification (Stationary phase: CHIRALCEL AS-H, 5 µm, 250 × 20 mm, Mobile phase: 60% CO , 40% MeOH) of N-((1R,2S)acrylamidocyclopentyl)(2-methyl((6- methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide (Example 368) afforded the *R atropisomer. MS (ESI): mass calcd. for C H N O S, 568.7; m/z found, 569.3 [M+H] . H NMR (400 MHz, CDCl ): δ 9.51 (s, 1H), 28 6 4 3 8.42 - 8.28 (m, 1H), 7.70 - 7.55 (m, 1H), 7.25 - 7.02 (m, 4H), 6.94 (d, J = 7.2 Hz, 2H), 6.81 - 6.65 (m, 3H), 6.46 - 6.29 (m, 3H), 6.26 - 5.99 (m, 3H), 5.79 - 5.60 (m, 1H), 4.45 - 4.24 (m, 3H), 2.49 (s, 3H), 2.40 - 1.82 (m, 9H).
Example 498: N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC column (Stationary phase: CHIRALCEL AS-H, 5 µm, 250 × 20 mm, Mobile phase: 60% CO , 40% MeOH) of N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6- methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide (Example 384) affords the title compound as the *S atropisomer. MS (ESI): mass calcd. for C H N O S, 568.7; m/z found, 569.3 [M+H] . H NMR (400 MHz, CDCl ): δ 9.49 28 6 4 3 (s, 1H), 8.36 (dd, J = 13.0, 4.2 Hz, 2H), 7.39 - 7.30 (m, 1H), 7.24 - 7.12 (m, 2H), 7.07 - 6.86 (m, 2H), 6.73 - 6.62 (m, 1H), 6.47 - 6.24 (m, 2H), 6.14 (dd, J = 16.8, 10.3 Hz, 1H), 5.98 (d, J = 5.4 Hz, 1H), 5.68 (d, J = 10.1 Hz, 1H), 4.46 - 4.24 (m, 2H), 2.58 (s, 3H), 2.37 - 1.58 (m, 9H).
Example 499: N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC column (Stationary phase: CHIRALCEL AS-H, 5 µm, 250 × 20 mm, Mobile phase: 60% CO , 40% MeOH) of N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6- methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide (Example 384) affords the title compound as the *R atropisomer. MS (ESI): mass calcd. for C H N O S, 568.7; m/z found, 569.3 [M+H] . H NMR (400 MHz, CDCl ): δ 9.50 28 6 4 3 (s, 1H), 8.44 - 8.21 (m, 2H), 7.33 (dd, J = 8.4, 2.8 Hz, 1H), 7.19 (d, J = 8.5 Hz, 2H), 7.03 - 6.85 (m, 2H), 6.74 (d, J = 5.8 Hz, 1H), 6.45 - 6.33 (m, 1H), 6.31 - 6.08 (m, 2H), 6.02 - 5.93 (m, 1H), .69 (d, J = 10.2 Hz, 1H), 4.42 - 4.22 (m, 2H), 2.58 (s, 3H), 2.37 - 1.73 (m, 9H).
Example 500: N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((2-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC purification (Stationary phase: CHIRALCEL AS-H, 5 µm, 250 × 20 mm, Mobile phase: 60% CO , 40% MeOH) of N-((1R,2S)acrylamidocyclopentyl)(2-methyl((2- methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide (Example 367) afforded the *S atropisomer. MS (ESI): mass calcd. for C H N O S, 568.7; m/z found, 569.3 [M+H] . H NMR (400 MHz, CDCl ): δ 9.54 (s, 0H), 28 6 4 3 8.42 - 8.27 (m, 2H), 7.39 - 7.11 (m, 4H), 6.99 - 6.49 (m, 3H), 6.46 - 5.90 (m, 3H), 5.66 (d, J = .2 Hz, 1H), 5.30 (d, J = 2.1 Hz, 1H), 4.45 - 4.24 (m, 2H), 2.71 - 1.23 (m, 11H).
Example 501: N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((2-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC purification (Stationary phase: CHIRALCEL AS-H, 5 µm, 250 × 20 mm, Mobile phase: 60% CO , 40% MeOH) of N-((1R,2S)acrylamidocyclopentyl)(2-methyl((2- methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide (Example 367) afforded the *R atropisomer. MS (ESI): mass calcd. for C H N O S, 568.7; m/z found, 569.3 [M+H] . H NMR (400 MHz, CDCl ): δ 9.64 - 5.57 (m, 28 6 4 3 13H), 5.36 - 5.23 (m, 1H), 4.46 - 4.22 (m, 2H), 2.54 (s, 3H), 2.34 - 2.04 (m, 5H), 1.95 - 1.60 (m, 4H).
Example 502: N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl(pyrimidin yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral separation of N-((1R,2S)acrylamidocyclopentyl)(2-methyl(pyrimidin yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 224) using chiral SFC column (Stationary phase: CHIRALCEL AS-H, 5 µm, 250 × 20 mm, Mobile phase: 60% CO , 40% MeOH) to give the *S atropisomer. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.2 [M+H] . H NMR (400 MHz, CDCl ): δ 8.60 (d, J = 28 25 7 4 3 4.7 Hz, 2H), 8.36 (d, J = 5.5 Hz, 1H), 7.38 - 7.19 (m, 5H), 7.12 - 7.05 (m, 1H), 6.72 - 6.61 (m, 1H), 6.44 - 6.31 (m, 1H), 6.26 - 6.00 (m, 2H), 5.69 (d, J = 10.3 Hz, 1H), 4.41 - 4.26 (m, 2H), 2.37 - 2.25 (m, 1H), 2.20 (s, 3H), 1.97 - 1.81 (m, 1H), 1.81 - 1.68 (m, 4H).
Example 503: N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl(pyrimidin yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral separation of N-((1R,2S)acrylamidocyclopentyl)(2-methyl(pyrimidin yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 224) using chiral SFC column (Stationary phase: CHIRALCEL AS-H, 5 µm, 250 × 20 mm, Mobile phase: 60% CO , 40% MeOH) to give the *R atropisomer. MS (ESI): mass calcd. for C H N O S, 555.6; m/z found, 556.2 [M+H] . H NMR (400 MHz, CDCl ): δ 9.50 (s, 1H), 28 25 7 4 3 8.60 (d, J = 4.7 Hz, 2H), 8.36 (d, J = 5.6 Hz, 1H), 7.33 - 7.18 (m, 3H), 7.15 - 7.02 (m, 1H), 6.72 (d, J = 5.3 Hz, 1H), 6.42 - 6.34 (m, 1H), 6.25 - 6.19 (m, 1H), 6.19 - 6.09 (m, 1H), 6.07 (d, J = 5.4 Hz, 1H), 5.70 (dd, J = 10.4, 1.5 Hz, 1H), 4.38 - 4.27 (m, 2H), 2.35 - 2.23 (m, 1H), 2.20 (s, 3H), 1.93 - 1.84 (m, 1H), 1.81 - 1.66 (m, 4H).
Example 504: N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl(pyridin yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC column purification (Stationary phase: CHIRALCEL AS-H, 5 µm, 250 × 20 mm, Mobile phase: 60% CO , 40% MeOH) of N-((1R,2S)acrylamidocyclopentyl)(2-methyl (pyridinyloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide (Example 220) provides the title compound. MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.3 [M+H] . H NMR (400 MHz, CDCl ): δ 9.69 - 9.42 (m, 29 26 6 4 3 1H), 8.45 - 8.17 (m, 2H), 7.86 - 7.64 (m, 1H), 7.22 - 6.92 (m, 5H), 6.82 - 6.63 (m, 1H), 6.63 - 6.47 (m, 1H), 6.40 - 6.30 (m, 1H), 6.20 - 6.00 (m, 2H), 5.66 (d, J = 10.0 Hz, 1H), 4.50 - 4.24 (m, 2H), 2.33 - 1.75 (m, 9H).
Example 505: N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl(pyridin yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Chiral SFC column purification (Stationary phase: CHIRALCEL AS-H, 5 µm, 250 × 20 mm, Mobile phase: 60% CO2, 40% MeOH) of N-((1R,2S)acrylamidocyclopentyl)(2-methyl (pyridinyloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide (Example 220) provides the title compound. MS (ESI): mass calcd. for C H N O S, 554.6; m/z found, 555.3 [M+H] . H NMR (400 MHz, CDCl ): δ 9.60 - 9.48 (m, 29 26 6 4 3 1H), 8.41 - 8.18 (m, 2H), 7.85 - 7.65 (m, 1H), 7.24 - 6.93 (m, 5H), 6.80 - 6.43 (m, 1H), 6.41 - 6.31 (m, 1H), 6.20 - 6.03 (m, 2H), 5.67 (d, J = 10.1 Hz, 1H), 4.35 (d, J = 6.6 Hz, 2H), 2.40 - 1.65 (m, 10H).
Example 506: N-((1R,2S)((E)Cyano(3-methyloxetanyl)acrylamido)cyclopentyl) (*S)-(6-isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide.
N NH Step A: N-((1R,2S)(2-Cyanoacetamido)cyclopentyl)(*S)-(6-isobutylmethylpyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. A solution of N- ((1R,2S)aminocyclopentyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide (Example 298, product from Step A, 500 mg, 0.998 mmol), 2,5-dioxopyrrolidinyl 2-cyanoacetate (273 mg, 1.50 mmol), triethylamine (202 mg, 2.00 mmol), and DCM (20 mL) was stirred at room temperature for 2 h. The reaction was concentrated to dryness and purified by flash column chromatography to yield the title compound (359 mg, 67.7% yield) as light yellow solid. MS (ESI): mass calcd. for C H N O S, 27 29 7 3 531.63; m/z found, 532.3 [M+H] .
Step B: N-((1R,2S)((E)Cyano(3-methyloxetanyl)acrylamido)cyclopentyl)(*S)-(6- isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide. A solution of N-((1R,2S)(2-cyanoacetamido)cyclopentyl)(*S)-(6-isobutyl methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (120 mg, 0.226 mmol), 3-methyloxetanecarbaldehyde (68 mg, 0.68 mmol), piperidine (0.3 mL), acetic acid (0.1 mL), 4A molecular sieves (0.5 g), and dioxane (5 mL) was stirred at reflux for 1 h. The reaction was filtered and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography to yield the title compound (99 mg, 71% yield) as white solid. MS (ESI): mass calcd. for C H N O S, 613.73; m/z found, 614.3 [M+H] . H 32 35 7 4 NMR (400 MHz, CD OD): δ 8.42-8.36 (m, 1H), 8.35-8.31 (m, 1H), 7.56 (s, 1H), 7.41 (s, 1H), 6.05-6.00 (m, 1H), 4.80-4.57 (m, 2H), 4.53-4.32 (m, 4H), 2.76-2.70 (m, 2H), 2.25-2.19 (m, 3H), 2.19-2.03 (m, 3H), 2.01-1.75 (m, 3H), 1.71-1.54 (m, 4H), 1.03-0.94 (m, 6H).
Example 507: N-((1R,2S)((E)Cyanoethoxymethylpentenamido)cyclopentyl) (*S)-(6-isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide.
To a solution of N-((1R,2S)(2-cyanoacetamido)cyclopentyl)(*S)-(6-isobutyl methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide (Example 506, product from Step A, 250 mg, 0.470 mmol), 2-ethoxymethylpropanal (109 mg, 0.941 mmol), and acetic acid (50 μL) in dioxane (5 mL) was added piperidine (150 μL) and heated at reflux for 1 h. The reaction was concentrated to dryness and purified by flash column chromatography to yield the title compound (71 mg, 23% yield) as pale yellow solid. H NMR (400MHz, CD OD): d 8.42 (s, 1H), 8.32 (d, J = 5.5 Hz, 1H), 7.41 (s, 1H), 7.31 (s, 1H), 6.02 (d, J = 5.5 Hz, 1H), 4.54-4.44(m, 1H), 4.40-4.32 (m, 1H), 3.35 (q, J = 7.0 Hz, 2H), 2.72 (d, J = 7.3 Hz, 2H), 2.21 (s, 3H), 2.16-2.06 (m, 3H), 1.97-1.73 (m, 3H), 1.68-1.58 (m, 1H), 1.34 (s, 3H),1.34(s,3H), 1.09 (t, J = 7.0 Hz, 3H), 1.01-0.96 (m, 6H).
Example 508: N-((1R,2S)acrylamidocyclopentyl)oxo(4-(pyrimidinyloxy)phenyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide.
Step A. 4-Oxo(4-(pyrimidinyloxy)phenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1 Steps A, C-F, using 5-bromopyrimidine and 4-aminophenol in Step Step B. N-((1R,2S)acrylamidocyclopentyl)oxo(4-(pyrimidinyloxy)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide. tert-Butyl ((1R,2S) acrylamidocyclopentyl)carbamate (Intermediate 36, product from Step A, 301 mg, 1.18 mmol) was dissolved in CH Cl , MsOH ( 227.6 mg, 2.37 mmol) was added and the mixture was stirred for two hours, then the solvent was removed in vacuum, the residue was dissolved in DMF, it was added into the solvent of 4-oxo(4-(pyrimidinyloxy)phenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxylic acid (400 mg, 0.98 mmol) and HATU (488 mg, 1.28 mmol) and triethylamine in DMF, after LCMS show the reaction was finished, it was poured into water, the solid formed was filtered and purified by silica gel column (DCM/EA/MeOH=2000/1000/20) to afford the title compound as brown solid. (310 mg, 58%).
MS (ESI): mass calcd. for C H N O S, 541.6; m/z found, 542.1 [M+H] . H NMR (400 MHz, 27 23 7 4 DMSO-d ): δ 9.06 (s, 1H), 8.76 (s, 2H), 8.35-8.26 (m, 1H), 7.93-7.86 (m, 1H), 7.86-7.77 (m, 1H), 7.57-7.44 (m, 2H), 7.40-7.30 (m, 2H), 6.31-6.19 (m, 1H), 6.15-6.04 (m, 2H), 5.61-5.50 (m, 1H), 4.35-4.23 (m, 2H), 2.00-1.86 (m, 2H), 1.84-1.70 (m, 2H), 1.70-1.51 (m, 2H).
BTK kinase lanthascreen binding assay: A BTK kinase lanthascreen binding assay monitors compound binding to unphosphorylated-BTK kinase domain (UP-BTK), by competing with a fluorescent labeled tracer. UP-BTK, consisting of the kinase domain of non- phosphorylated BTK protein (389-659aa), was produced in a Baculovirus/insect cell expression system. Into a 384-well plate, 2 ng of GST-tagged human BTK (389-659aa) was incubated with compound, 50 nM of Tracer 236 and 2 nM anti-GST antibody for 60 minutes using an optimized Lanthascreen assay. After 60 minutes, plates were read at 340 nM and 615/665 nM in an Infinite F500 (Tecan). Data were analyzed using Xlfit™ version 5.3 from ID Business Solutions (Guildford), Microsoft Excel add-in. pIC refers to the negative log of the IC in molar. 50 50 Ex # Compound Name BTK_I_ binding pIC50 1 N-((1S,4S)Acrylamidocyclohexyl)(*S)-(2-methyl 7.61 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 2 N-((1R,3S)Acrylamidocyclohexyl)(2-methyl 7.36 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 3 N-((1S,4S)Acrylamidocyclohexyl)(2-methyl 7.42 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 4 N-((1R,2R)Hydroxycyclopentyl)(S)-(2-methyl 7.73 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(*S)-(2-methyl 7.69 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 6 N-((1R,2S)Hydroxycyclopentyl)(2-methylphenoxyphenyl)- 7.48 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 7 N-((1R,2S)(Dimethylamino)cyclohexyl)(*S)-(2-methyl 7.31 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 8 N-((1R,2S)Hydroxycyclopentyl)(*S)-(2-methyl 7.95 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 9 N-((1R,2R)Hydroxycyclopentyl)(2-methylphenoxyphenyl)- 7.41 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,2S)Aminocyclohexyl)(2-methylphenoxyphenyl) 7.35 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 11 N-((1R,2R)Acetamidocyclopentyl)(2-methyl 7.24 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 12 N-((1R,2S)Aminocyclopentyl)(2-methylphenoxyphenyl) 7.03 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 13 N-((1R,4R)Acrylamidocyclohexyl)(2-methyl 6.94 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 14 N-((1R,2S)(Dimethylamino)cyclohexyl)(2-methyl 7.30 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,4R)Hydroxycyclohexyl)(2-methylphenoxyphenyl)- 7.21 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 16 N-((1S,4S)Hydroxycyclohexyl)(2-methylphenoxyphenyl)- 7.14 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 17 N-((1R,2S)(Dimethylamino)cyclopentyl)(2-methyl 6.92 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 18 N-((1R,4R)Methoxycyclohexyl)(2-methylphenoxyphenyl)- 6.99 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; Ex # Compound Name BTK_I_ binding pIC50 19 N-((1S,4S)((E)Cyanocyclopropylacrylamido)cyclohexyl)- 6.63 -(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,2S)Hydroxycyclopentyl)(2-methylphenoxyphenyl)- 7.02 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 21 5-(2-Methylphenoxyphenyl)-N-((1R,2R) 6.85 (methylamino)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 22 N-((1R,2R)Aminocyclopentyl)(2-methylphenoxyphenyl) 7.13 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 23 N-((1S,4S)Cyanamidocyclohexyl)(2-methyl 6.77 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 24 N-((1R,3S)(Dimethylamino)cyclohexyl)(2-methyl 6.59 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,4S)Aminocyclohexyl)(2-methylphenoxyphenyl) 6.66 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 26 5-(2-Methylphenoxyphenyl)oxo-N-((1R,2R) 6.69 propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 27 N-((1RS,2RS)Hydroxycyclohexyl)(2-methyl 6.96 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 28 N-Cyclopentyl(2-methylphenoxyphenyl)oxo-4,5-dihydro- 6.67 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 29 N-((1R,2R)(Dimethylamino)cyclopentyl)(2-methyl 6.81 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 N-((1r,3s,5R,7S)Hydroxyadamantanyl)(2-methyl 6.36 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 31 5-(2-Methylphenoxyphenyl)-N-(2-(methylamino)cyclohexyl) 6.66 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 32 N-((1S,2S)(Dimethylamino)cyclopentyl)(2-methyl 7.12 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 33 N-((1R,2S)Acetamidocyclohexyl)(2-methyl 6.98 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 34 5-(2-Methylphenoxyphenyl)oxo-N-((1R,2S) 6.91 propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)oxo-N-((1R,2S) 6.87 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 36 N-((1RS,2RS)Hydroxycyclohexyl)(2-methyl 6.72 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 37 N-((1R,2S)Acetamidocyclopentyl)(2-methyl 6.68 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 38 N-((1R,2R)Aminocyclohexyl)(2-methylphenoxyphenyl) 6.68 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 39 N-((1S,2R)Hydroxycyclopentyl)(2-methylphenoxyphenyl)- 6.51 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 40 N-((1S,2S)Acetamidocyclopentyl)(2-methyl 6.40 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 41 N-((1S,2S)Aminocyclopentyl)(2-methylphenoxyphenyl) 6.37 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 42 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2R) 6.24 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 43 N-((1R,2R)(Dimethylamino)cyclohexyl)(2-methyl 6.23 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 44 N-((1S,2R)Acetamidocyclohexyl)(2-methyl 6.17 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 45 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2S) 6.14 propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 46 5-(2-Methylphenoxyphenyl)-N-((1S,2S) 6.14 (methylamino)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 47 N-((1R,2R)Acetamidocyclohexyl)(2-methyl 6.12 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 48 N-((1S,2R)(Dimethylamino)cyclohexyl)(2-methyl 6.12 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 49 N-((1S,2R)Aminocyclohexyl)(2-methylphenoxyphenyl) 6.12 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 50 5-(2-Methylphenoxyphenyl)-N-((1S,2R) 6.07 (methylamino)cyclohexyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 51 N-((1S,2R)(Dimethylamino)cyclopentyl)(2-methyl 6.01 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 52 5-(2-Methylphenoxyphenyl)oxo-N-((1R,2R) 6.01 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 53 N-((1S,2R)Aminocyclopentyl)(2-methylphenoxyphenyl) 5.95 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 54 N-((1S,2S)Formamidocyclohexyl)(2-methyl 5.90 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 55 N-((1S,2S)Acetamidocyclohexyl)(2-methyl 5.88 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 56 N-((1S,2S)Acrylamidocyclopentyl)(*R)-(2-methyl 5.77 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 57 N-((1S,2R)Acetamidocyclopentyl)(2-methyl 5.65 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 58 N-((1S,2S)Aminocyclohexyl)(2-methylphenoxyphenyl) 5.51 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 59 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2R) 5.46 propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 60 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2S) 5.40 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 61 N-((1R,2R)Hydroxycyclopentyl)(*R)-(2-methyl 5.36 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 62 N-((1S,2S)(Dimethylamino)cyclohexyl)(2-methyl 5.29 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 63 5-(2-Methylphenoxyphenyl)-N-(4-(methylamino)cyclohexyl) 6.85 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 64 N-((1S,4S)Acetamidocyclohexyl)(2-methyl 7.28 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 65 5-(2-Methylphenoxyphenyl)oxo-N-((1S,4S) 7.20 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 66 N-((1S,4S)(Dimethylamino)cyclohexyl)(2-methyl 6.56 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 67 N-((1R,2R)Acetamidocyclopentyl)(*S)-(2-methyl 7.41 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 68 N-((1S,3R)acrylamidocyclopentyl)(2-methyl 7.78 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 69 5-(2-Methylphenoxyphenyl)oxo-N-((1S,3R) 7.73 propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 70 N-((1S,3R)Acetamidocyclopentyl)(2-methyl 7.69 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 71 N-((1S,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(2- 7.38 methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 72 5-(2-Methylphenoxyphenyl)-N-((1S,3R)(2- 7.02 (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 73 N-((1S,3R)(Dimethylamino)cyclopentyl)(2-methyl 7.00 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 74 N-((1S,3R)Hydroxycyclopentyl)(2-methylphenoxyphenyl)- 7.07 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 75 N-((1S,3R)(2-Aminoacetamido)cyclopentyl)(2-methyl 7.30 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 76 N-((1S,3R)Aminocyclopentyl)(2-methylphenoxyphenyl) 6.88 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 77 N-((1S,4S)((E)(Dimethylamino)butenamido)cyclohexyl) 6.61 (2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 78 5-(2-Methylphenoxyphenyl)-N-((1S,4S)((E) 6.55 (methylamino)butenamido)cyclohexyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 79 N-((1S,4S)((E)Aminobutenamido)cyclohexyl)(2-methyl- 6.47 4-phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 80 5-(2-Methylphenoxyphenyl)-N-((1S) 6.42 (methylamino)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 81 N-Cyclopentyl(*S)-(2-methylphenoxyphenyl)oxo-4,5- 7.03 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 82 N-Cyclopentyl(*R)-(2-methylphenoxyphenyl)oxo-4,5- 5.35 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 83 N-((1S,4S)Hydroxycyclohexyl)(*S)-(2-methyl 7.60 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 84 N-((1S,4S)Hydroxycyclohexyl)(*R)-(2-methyl 6.21 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 85 N-((1R,4R)Hydroxycyclohexyl)(*S)-(2-methyl 7.67 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 86 N-((1R,4R)Hydroxycyclohexyl)(*R)-(2-methyl 6.64 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 87 5-(*S)-(2-Methylphenoxyphenyl)oxo-N-((1S,3R) 7.87 propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 88 N-((1S,3R)Acetamidocyclopentyl)(*S)-(2-methyl 7.89 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 91 N-((1R,2R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5- 7.31 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 92 5-(*S)-(2-Methylphenoxyphenyl)oxo-N-((1S,4S) 6.91 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 93 5-(*R)-(2-Methylphenoxyphenyl)oxo-N-((1S,4S) 6.99 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 94 N-((1S,4S)Acetamidocyclohexyl)(*S)-(2-methyl 7.59 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 95 N-((1S,4S)Acetamidocyclohexyl)(*R)-(2-methyl 6.14 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 96 N-(rac-(1,3-cis)Aminocyclopentyl)oxo(4-phenoxyphenyl)- 7.11 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 97 N-((1R,2S)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5- 7.70 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 98 N-((1S,2R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5- 6.10 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 99 N-((1S,4S)(Dimethylamino)cyclohexyl)(*S)-(2-methyl 7.03 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 100 N-((1S,4S)(Dimethylamino)cyclohexyl)(*R)-(2-methyl 5.86 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 101 N-((1S,3R)Acrylamidocyclopentyl)(*S)-(2-methyl 7.95 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 102 N-((1S,3R)(2-(dimethylamino)acetamido)cyclopentyl)(*S)-(2- 7.50 methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 103 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,3R)(2- 7.40 (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 104 N-((1R,2S)acrylamidocyclopentyl)oxo(4-phenoxyphenyl)- 8.37 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 105 N-((1R,2R)Acrylamidocyclopentyl)(*S)-(2-methyl 8.11 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 106 5-([1,1'-Biphenyl]yl)-N-((1 R,2 S)acrylamidocyclohexyl) 8.06 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 107 N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl 8.25 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 108 N-((1R,2S)Acrylamidocyclohexyl)(*S)-(2-methyl 7.56 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 109 N-((1RS,3RS)Acrylamidocyclopentyl)oxo(4- 7.85 phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide; 110 N-((1S,3R)Acrylamidocyclopentyl)(4-isopropoxy 7.23 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 111 N-((1R,2R)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)- 7.68 (2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 112 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2R)(2- 8.04 (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 113 N-((1R,2R)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methyl 7.88 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 114 N-((1S,2R)Acrylamidocyclopentyl)(*S)-(2-methyl 6.81 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 115 N-((1R,2S)Aminocyclopentyl)(*S)-(2-methyl 7.57 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 116 N-((1S,2S)Acrylamidocyclopentyl)(*S)-(2-methyl 7.30 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 117 N-((1S,3R)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)- 7.80 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 118 N-((1R,2S)Acrylamidocyclohexyl)oxo(4-phenoxyphenyl)- 8.12 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 119 N-((1S,4S)Acrylamidocyclohexyl)oxo(4-phenoxyphenyl)- 7.61 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 120 N-((1R,2R)Aminocyclopentyl)(*S)-(2-methyl 7.54 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 121 N-((1R,3S)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)- 6.57 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 122 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2S)(2- 7.18 (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 123 N-((1S,2S)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2- 7.07 methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 124 N-((1S,2R)Acrylamidocyclohexyl)oxo(4-phenoxyphenyl)- 6.71 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 125 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2S)(2- 7.11 (methylamino)acetamido)cyclohexyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 126 N-((1R,2S)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5- 7.13 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 127 N-((1S,2R)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)- 6.56 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 128 N-((1R,2S)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)- 7.10 (2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 129 N-((1R,2S)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methyl 7.39 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 130 N-((1S,2S)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methyl 7.17 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 131 N-((1R,2S)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methyl 7.40 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 132 N-((1R,2S)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2- 7.27 methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 133 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,2S)(2- 7.13 (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 134 N-((1S,2S)Acetamidocyclopentyl)(*S)-(2-methyl 6.76 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 135 N-((1S,2S)Aminocyclopentyl)(*S)-(2-methyl 6.82 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 136 N-((1R,2S)Acetamidocyclohexyl)(*S)-(2-methyl 7.52 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 137 N-((1R,2S)Aminocyclohexyl)(3-chlorophenoxyphenyl) 7.49 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 138 N-((1R,2S)Acetamidocyclopentyl)(*S)-(2-methyl 7.49 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 139 N-((1R,3R)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5- 7.23 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 140 N-((1R,2S)Hydroxycyclopentyl)oxo(4-phenoxyphenyl)- 7.15 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 141 5-([1,1'-Biphenyl]yl)- N-((1R,2S)aminocyclohexyl)oxo- 7.01 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 142 N-((1R,3S)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5- 6.87 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 143 N-((1S,3S)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5- 6.75 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 144 5-([1,1'-Biphenyl]yl)-N-((1R,2R)hydroxycyclopentyl)oxo- 6.69 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 145 N-((1S,4S)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5- 6.69 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 146 N-(trans-(1R,4R)Aminocyclohexyl)oxo(4-phenoxyphenyl)- 6.66 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 147 trans-N-((1RS,3RS)Aminocyclopentyl)oxo(4- 6.63 phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide; 148 N-((1S,2S)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5- 6.47 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 149 N-((1R,2R)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5- 6.45 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 150 tert-Butyl ((1R,3S)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3H- 6.40 1-thia-3,5,8-triazaacenaphthylene carboxamido)cyclopentyl)carbamate; 151 tert-Butyl trans-((1R,4R)(4-oxo(4-phenoxyphenyl)-4,5- 6.33 dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamido)cyclohexyl)carbamate; 152 N-((1-Hydroxycyclohexyl)methyl)oxo(4-phenoxyphenyl)-4,5- 6.25 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 153 N-((1S,3R)((E)(Dimethylamino)butenamido)cyclopentyl)- 6.44 -(4-isopropoxymethylphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 154 N-((1S,2R)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methyl 6.36 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 155 N-((1S,2R)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)- 6.35 (2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 156 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,2R)(2- 6.26 (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 157 N-((1S,3R)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5- 6.19 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 158 N-((1S,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(4- 6.11 isopropoxymethylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 159 4-Oxo(2-phenylpyridinyl)-N-((1S,2R) <6 propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 160 N-((1R,2S)Aminocyclohexyl)(4-isopropoxymethylphenyl)- <6 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 161 5-(4-Isopropoxymethylphenyl)-N-((1S,3R)(2- <6 (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 162 N-((1S,2R)Acetamidocyclopentyl)(*S)-(2-methyl <6 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 163 tert-Butyl ((1S,4S)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3H- 5.43 1-thia-3,5,8-triazaacenaphthylene carboxamido)cyclohexyl)carbamate; Ex # Compound Name BTK_I_ binding pIC50 164 N-((1S,3R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5- 5.19 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 165 N-((1R,2S)Acrylamidocyclopentyl)(*R)-(4-isopropoxy 8.30 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 166 N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methyl 8.13 phenoxypyrimidinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 167 N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenylpyrimidin- 8.34 4-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 168 N-((1R,2S)Acrylamidocyclohexyl)oxo(2-phenylpyridin 8.10 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 169 N-((1R,2S)Acrylamidocyclopentyl)oxo(2-phenylpyridin 8.26 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 170 N-((1R,2S)Aminocyclopentyl)(*S)-(4-methyl 7.02 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 171 N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methyl 8.19 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 172 N-((1R,2S)Acrylamidocyclohexyl)oxo(6-phenoxypyridin- 8.35 3-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 173 N-((1R,2S)Acrylamidocyclohexyl)(*S)-(4-methyl 8.02 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 174 N-((1R,2S)Acrylamidocyclohexyl)(*R)-(4-isopropoxy 8.28 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 175 N-((1R,3R)Acrylamidocyclopentyl)(*S)-(2-methyl 8.05 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 176 N-((1S,3R)Acrylamidocyclohexyl)(*S)-(2-methyl 7.78 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 177 N-((1R,2R)Acrylamidocyclopentyl)oxo(6-phenoxypyridin- 7.49 3-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 178 N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenoxypyridin- 8.28 3-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 179 N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenoxypyridin- 8.37 2-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 180 N-((1S,3R)Acetamidocyclohexyl)(*S)-(2-methyl 7.94 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 181 N-((1R,3R)Aminocyclohexyl)(2-methylphenoxyphenyl) 7.33 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 182 N-((1R,3R)Acrylamidocyclohexyl)(*S)-(2-methyl 7.66 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 183 N-((1R,2S)Acrylamidocyclohexyl)(6-cyclobutoxy 7.58 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 184 N-((1R,3R)Acrylamidocyclopentyl)(2-methyl 7.55 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 185 N-((1R,2R)Acrylamidocyclopentyl)oxo(5-phenoxypyridin- 7.56 2-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; Ex # Compound Name BTK_I_ binding pIC50 186 N-((1S,3R)Acrylamidocyclopentyl)(*R)-(4-isopropoxy 7.62 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 187 N-((1R,2S)Acrylamidocyclohexyl)(6-cyclobutoxy 7.30 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 188 N-((1RS,3RS)Acrylamidocyclopentyl)oxo(6- 7.11 phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 189 N-((1R,2S)Acrylamidocyclopentyl)oxo(4-phenylpyridin 8.23 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 190 N-((1S,3R)Acrylamidocyclohexyl)(*R)-(4-isopropoxy 7.10 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 191 N-((1S,3R)Acrylamidocyclopentyl)(3-chloro 7.95 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 192 N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenylpyridin 7.92 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 193 5-([1,1'-Biphenyl]yl)-N-((1R,2S)acrylamidocyclopentyl) 8.09 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 194 N-((1R,2S)Acrylamidocyclopentyl)oxo(3-(pyridin 7.89 yl)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 195 N-((1R,3R)Acetamidocyclohexyl)(*S)-(2-methyl 7.55 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 196 N-((1R,3S)Acrylamidocyclopentyl)(*S)-(2-methyl 7.12 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 197 N-((1R,2R)Acrylamidocyclopentyl)oxo(2-phenylpyridin 7.48 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 198 N-((1S,3R)Acrylamidocyclopentyl)oxo(2-phenylpyridin 7.98 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 199 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridin 8.13 yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 200 N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-methyl 8.18 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 201 N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenoxypyrazin- 8.32 2-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 202 N-((1R,2S)Acrylamidocyclopentyl)oxo(3-(pyridin 7.90 yl)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 203 N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenylpyridazin- 8.06 4-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 204 N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-cyclobutoxy 8.03 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 205 N-((1R,2S)Acrylamidocyclopentyl)(4-isopropoxyphenyl) 7.62 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 206 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((tetrahydro- 7.33 2H-pyranyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 207 N-((1R,2S)Acrylamidocyclopentyl)(2-isopropylpyridinyl)- 7.53 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; Ex # Compound Name BTK_I_ binding pIC50 208 N-((1R,3S)Acrylamidocyclopentyl)oxo(2-phenylpyridin <6 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 209 N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isopropoxy 7.31 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 210 N-((1R,2S)(3-Chloropropanamido)cyclopentyl)(*S)-(4- 7.19 methylphenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 211 N-((1R,2S)Acrylamidocyclohexyl)(6-isopropoxy 6.92 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 212 N-((1R,3R)Acrylamidocyclopentyl)oxo(2-phenylpyridin 7.49 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 213 N-((1R,2R)Acrylamidocyclohexyl)(*S)-(4-methyl 7.30 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 214 N-((1RS,3RS)Acrylamidocyclopentyl)oxo(5- 7.85 phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 215 N-((1R,3R)Acrylamidocyclohexyl)(*R)-(4-isopropoxy 7.13 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 216 N-((1RS,3RS)Acrylamidocyclohexyl)oxo(5- 7.44 phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 217 N-((1R,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(2- 7.44 methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 218 N-((1R,2R)Acrylamidocyclohexyl)oxo(5-phenoxypyridin- 6.76 2-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; Ex # Compound Name BTK_I_ binding pIC50 219 N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-methyl 7.94 phenoxypyrimidinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 220 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridin 8.16 yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 221 N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-cyclobutoxy 8.29 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 222 N-((1R,2S)Acrylamidocyclohexyl)(6-isopropoxy 7.91 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 223 N-((1R,2S)Acrylamidocyclohexyl)(6-(cyclopentyloxy) 7.81 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 224 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidin 7.46 yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 225 N-((1R,2S)Acrylamidocyclohexyl)(6-isobutoxy 7.66 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 226 N-((1S,3S)Acrylamidocyclopentyl)(*S)-(2-methyl 6.85 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 227 N-((1R,2R)Acrylamidocyclohexyl)oxo(2-phenylpyridin 6.76 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 228 N-((1R,3R)Acetamidocyclopentyl)(2-methyl 7.34 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 229 5-(2-Methylphenoxyphenyl)-N-((1R,3R)(2- 7.29 (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 230 N-((1S,3R)Aminocyclohexyl)(*S)-(2-methyl 7.24 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 231 N-((1S,3S)Acrylamidocyclohexyl)(*S)-(2-methyl 6.56 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 232 N-((1R,3R)Acrylamidocyclohexyl)oxo(2-phenylpyridin 7.05 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 233 N-((1R,2R)Aminocyclopentyl)(4-methylphenoxypyridin 6.85 yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 234 N-((1R,2S)Acrylamidocyclopentyl)oxo(4-((tetrahydro-2H- 6.76 pyranyl)oxy)phenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 235 N-((1R,3R)(2-Aminoacetamido)cyclopentyl)(2-methyl 7.44 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 236 N-((1R,3R)Aminocyclopentyl)(2-methylphenoxyphenyl) 7.00 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 237 N-((1R,3S)Acrylamidocyclohexyl)(*S)-(2-methyl 6.56 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 238 N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-isopropoxy 6.95 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 239 N-((1R,2R)Acrylamidocyclohexyl)oxo(6-phenoxypyridin- 6.47 3-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 240 N-((1R,3S)Aminocyclopentyl)(*S)-(2-methyl 6.72 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 241 N-((1S,3S)Acetamidocyclopentyl)(*S)-(2-methyl 7.26 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 242 N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-cyclobutoxy 7.04 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 243 N-((1S,3S)Acetamidocyclohexyl)(*S)-(2-methyl 6.85 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 244 N-((1R,3S)Acetamidocyclopentyl)(*S)-(2-methyl 6.66 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 245 N-((1S,3S)(2-(Dimethylamino)acetamido)cyclopentyl)(2- 6.73 methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 246 5-(2-Methylphenoxyphenyl)-N-((1S,3S)(2- 6.84 (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 247 N-((1S,3S)Aminocyclohexyl)(*S)-(2-methyl 6.66 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 248 5-(3-Chlorophenoxyphenyl)-N-((1S,3R)((E) 6.98 (dimethylamino)butenamido)cyclopentyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 249 5-([1,1'-Biphenyl]yl)-N-((1R,2S)aminocyclopentyl)oxo- 6.90 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 250 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,3S)(2- 6.75 (methylamino)acetamido)cyclohexyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 251 N-((1R,3S)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methyl 6.71 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 252 N-((1R,3S)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2- 6.63 methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 253 N-((1R,3S)Acetamidocyclohexyl)(*S)-(2-methyl 6.63 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 254 N-((1R,2S)Aminocyclopentyl)(*S)-(4-methyl 6.55 phenoxypyrimidinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 255 N-((1R,2R)Aminocyclohexyl)(*S)-(4-methyl 6.51 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 256 N-((1R,2R)Aminocyclopentyl)(*S)-(4-methyl 6.48 phenoxypyrimidinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 257 N-((1R,2S)Aminocyclohexyl)oxo(6-phenoxypyridinyl)- 6.47 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 258 N-((1S,2R)Acetamidocyclopentyl)oxo(2-phenylpyridin <6 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 259 N-((1S,3S)Aminocyclopentyl)(*S)-(2-methyl 6.45 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 260 N-((1R,2S)Aminocyclohexyl)oxo(2-phenylpyridinyl)- 6.45 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 261 N-((1R,3S)Aminocyclohexyl)(*S)-(2-methyl 6.42 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 262 N-((1R,2S)Aminocyclopentyl)(*R)-(4-isopropoxy 6.39 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 263 N-((1R,2S)Aminocyclopentyl)oxo(2-phenylpyridinyl)- 6.38 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 264 N-((1R,2R)Acrylamidocyclohexyl)(*R)-(4-isopropoxy 6.26 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 265 N-((1R,2S)Aminocyclopentyl)oxo(6-phenoxypyridinyl)- 6.24 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 266 N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-cyclobutoxy 6.21 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 267 N-((1R,2S)Aminocyclopentyl)oxo(4-phenylpyridinyl)- 6.21 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 268 N-((1R,2R)Hydroxycyclopentyl)oxo(2-phenylpyridin 6.20 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 269 N-((1R,2R)Aminocyclopentyl)oxo(6-phenoxypyridinyl)- 6.00 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 270 N-((1R,2S)Aminocyclopentyl)(2-isopropylpyridinyl) <6 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 271 N-((1R,2S)Aminocyclopentyl)(4-isopropoxyphenyl)oxo- <6 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 272 N-((1S,2S)Acrylamidocyclohexyl)(*R)-(4-isopropoxy <6 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 273 N-((1R,2R)Acrylamidocyclohexyl)(*S)-(4-isopropoxy <6 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 274 N-((1S, S)Acrylamidocyclohexyl)(*R)-(4-isopropoxy <6 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 275 N-((1R,3S)Acrylamidocyclohexyl)(*R)-(4-isopropoxy <6 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 276 N-((1R,3S)Acrylamidocyclopentyl)(*R)-(4-isopropoxy <6 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 277 N-((1R,2R)Aminocyclohexyl)oxo(6-phenoxypyridinyl)- <6 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 278 N-((1R,2S)Aminocyclopentyl)oxo(6-phenylpyridazin <6 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 279 N-((1S,3S)Acrylamidocyclohexyl)oxo(2-phenylpyridin <6 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 280 N-((1R,2S)Acetamidocyclopentyl)oxo(2-phenylpyridin <6 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 281 N-((1R,2S)Aminocyclopentyl)oxo(6-phenylpyrimidin <6 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 282 N-((1S,3S)Acrylamidocyclopentyl)oxo(2-phenylpyridin <6 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 283 N-((1R,3S)Acrylamidocyclohexyl)oxo(2-phenylpyridin <6 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 284 N-((1R,2S)Aminocyclopentyl)oxo(5-phenylpyridinyl)- <6 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 285 N-((1R,2S)Aminocyclopentyl)oxo(3-(pyridinyl)phenyl)- <6 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 286 N-((1S,2R)(2-(Methylamino)acetamido)cyclopentyl)oxo(2- <6 phenylpyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 287 N-((1R,2S)Aminocyclopentyl)(2-methyl((tetrahydro-2H- <6 pyranyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 288 N-((1R,2S)Aminocyclopentyl)oxo(4-((tetrahydro-2H- <6 pyranyl)oxy)phenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 289 racemic cis N-((1RS,3RS)Aminocyclopentyl)oxo(6- 5.77 phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 290 racemic trans N-((1RS,3RS)Aminocyclopentyl)oxo(6- 5.65 phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 291 N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyridin- 8.60 2-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 292 N-((1RS,2RS)Acrylamidocyclopentyl)(2-methyl 8.38 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 295 N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyrazin- 8.39 2-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 296 N-((1R,2S)acrylamidocyclopentyl)oxo(5- 8.39 phenoxypyrimidinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 297 N-((1R,2S)Acrylamidocyclohexyl)oxo(5- 8.53 phenoxypyrimidinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 298 N-((1R,2S)Acrylamidocyclopentyl)(S)-(6-isobutyl 8.09 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 299 N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isopropoxy 8.19 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 300 N-((1R,2S)Acrylamidocyclopentyl)oxo(*S)-(4-(pyridin 8.27 yloxy)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 301 N-((1R,2R)Acrylamidocyclopentyl)(*S)-(2-methyl 7.97 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 302 N-((1R,2S)Acrylamidocyclohexyl)oxo(2- 8.23 phenoxypyrimidinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 303 N-((1R,2S)Acrylamidocyclohexyl)(*S)-(2-methyl 8.40 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 304 N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl 7.48 ((tetrahydro-2H-pyranyl)oxy)phenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 305 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridazin 7.84 yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 306 N-((1*S,3*S)Acrylamidocyclopentyl)(*S)-(4-methyl 8.04 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 307 N-((1R,2R)Acrylamidocyclopentyl)oxo(5- 7.58 phenoxypyrimidinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 308 N-((1*S,3*S)Acrylamidocyclohexyl)(*S)-(4-methyl 7.78 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 309 N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-(cyclopentyloxy)- 7.91 4-methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 310 N-((1R,2S)Acrylamidocyclopentyl)oxo(2- 8.04 phenoxypyrimidinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 311 N-((1R,2R)Acrylamidocyclopentyl)oxo(5-phenoxypyrazin- 7.57 2-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 312 N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isobutoxy 8.01 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 313 N-((1S,3R)Acrylamidocyclopentyl)oxo(5-phenoxypyridin- 7.83 2-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 314 N-((1R,2R)Acrylamidocyclopentyl)oxo(2- 7.14 phenoxypyrimidinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 315 N-((1*S,3*S)Acrylamidocyclohexyl)oxo(5- 7.50 phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 316 N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-isopropoxy 7.33 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 317 5-([2,3'-Bipyridin]yl)-N-((1R,2S)acrylamidocyclopentyl) 7.74 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 318 N-((1*R,2*S)Aminocyclopentyl)(*S)-(2-methyl 6.46 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 319 N-((1S,3R)Acrylamidocyclopentyl)oxo(2- 7.21 phenoxypyrimidinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 320 N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenylpyridazin- 7.23 3-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 321 N-((1*S,3*S)Acrylamidocyclopentyl)oxo(6- 7.71 phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 322 N-((1R,2R)Acrylamidocyclohexyl)(*S)-(2-methyl 6.81 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 323 N-((1S,3S)Acrylamidocyclohexyl)oxo(6-phenoxypyridin- 7.13 3-yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 324 N-((1R,2R)Acrylamidocyclopentyl)oxo(3-(pyridin 6.90 yl)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 325 5-([2,2'-Bipyridin]yl)-N-((1R,2S)acrylamidocyclopentyl) 7.07 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 326 5-([2,3'-Bipyridin]yl)-N-((1R,2R)acrylamidocyclopentyl) 6.72 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 327 N-((1R,2R)Acrylamidocyclopentyl)oxo(3-(pyridin 6.98 yl)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 328 N-((1*R,3*S)Acrylamidocyclopentyl)oxo(5- 6.58 phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 329 N-((1*R,3*R)Acrylamidocyclopentyl)(*S)-(4-methyl 6.85 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 330 N-((1R,2S)Acrylamidocyclopentyl)(6-(isopropylamino) 6.69 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 331 N-((1*R,3*R)Acrylamidocyclohexyl)oxo(6- 6.66 phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 332 N-((1*R,3*R)Acrylamidocyclohexyl)(*S)-(4-methyl 6.60 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 333 N-((1R,2S)Aminocyclohexyl)(*S)-(2-methyl 6.50 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 334 N-((1*R,3*R)Acrylamidocyclopentyl)oxo(6- 6.81 phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 335 N-((1R,2S)Aminocyclohexyl)(*S)-(6-isobutyl 6.38 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 336 N-((1R,2R)Aminocyclopentyl)(2-isopropylpyridinyl) 6.01 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 337 N-((1R,2R)Acrylamidocyclopentyl)(2-isopropylpyridinyl)- 6.42 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 338 N-((1R,2R)Acrylamidocyclohexyl)oxo(2- 6.39 phenoxypyrimidinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 339 N-((1R,2R)Aminocyclopentyl)(*S)-(2-methyl 6.28 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 340 N-((1R,2S)Acetamidocyclohexyl)(*S)-(2-methyl 6.26 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 341 N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-(cyclopentyloxy)- 6.23 4-methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 342 5-([2,2'-Bipyridin]yl)-N-((1R,2R)acrylamidocyclopentyl) 6.12 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 343 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2S) 6.11 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 344 N-((1*R,3*R)Acrylamidocyclohexyl)oxo(5- 6.11 phenoxypyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 345 N-((1R,2S)Acetamidocyclopentyl)(*S)-(2-methyl 6.09 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 346 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2S) 6.07 propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 347 N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl 6.06 ((tetrahydro-2H-pyranyl)oxy)phenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 348 N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-isopropoxy 6.00 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 349 N-((1R,2S)Aminocyclopentyl)oxo(5-phenylpyridazin <6 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 350 N-((1R,2R)Aminocyclohexyl)(*S)-(2-methyl <6 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 351 N-((1S,3R)Acrylamidocyclohexyl)oxo(2-phenylpyridin <6 yl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 352 N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-isobutoxy <6 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 353 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2R) <6 propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 354 N-((1R,2S)Aminocyclopentyl)(*S)-(6-isobutyl methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 355 N-((1R,3S)Aminocyclopentyl)(*S)-(4-methyl 6.61 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 356 N-((1R,3S)Aminocyclohexyl)(*S)-(4-methyl <6 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 357 N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isobutyl 7.98 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 358 N-((1R,2R)Acetamidocyclopentyl)(*S)-(2-methyl 6.44 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 359 N-((1R,3S)Acrylamidocyclopentyl)(*S)-(4-methyl 8.05 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 360 N-((1R,3S)Acetamidocyclohexyl)(*S)-(4-methyl 6.26 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 361 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3S) 7.94 propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 362 N-((1R,2R)Acetamidocyclohexyl)(*S)-(2-methyl <6 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 363 N-((1R,3S)Acrylamidocyclohexyl)(*S)-(4-methyl 6.31 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 364 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2R) <6 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 365 N-((1R,3S)Acrylamidocyclopentyl)(6-isobutoxy 7.93 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 366 N-((1R,3S)Acrylamidocyclopentyl)(*S)-(6-(cyclopentyloxy)- 8.07 4-methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 367 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((2- 7.54 methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 368 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6- 8.13 methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 369 N-((1R,2S)Acrylamidocyclopentyl)(4-((6-methylpyridin 8.06 yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 370 N-((1R,2S)Acrylamidocyclopentyl)(4-((6-methylpyridin 7.79 yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 371 N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-(cyclopentyloxy)- 8.23 4-methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 372 N-((1R,2S)Acrylamidocyclopentyl)(4-((2-methylpyridin 7.93 yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 373 N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-isobutoxy 8.25 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 374 N-((1R,2S)Aminocyclopentyl)(*S)-(6-(cyclopentyloxy) 6.82 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 375 N-((1R,2S)Aminocyclohexyl)(*S)-(4-methyl 6.92 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 376 N-((1R,2S)Acrylamidocyclopentyl)(2-cyclobutylpyridinyl)- 7.81 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 377 N-((1R,2S)Acetamidocyclohexyl)(*S)-(4-methyl 6.83 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 378 N-((1R,2S)Acetamidocyclopentyl)(*S)-(4-methyl 6.39 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 379 N-((1R,2R)Acrylamidocyclopentyl)(2-cyclobutylpyridin 6.80 yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 380 5-(*S)-(2-Methylphenoxyphenyl)oxo-N-((1R,2S) 7.20 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 381 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,2S) 6.75 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 382 N-((1R,2R)Acrylamidocyclopentyl)(*S)-(6-isobutyl 7.68 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 383 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(((S)- 7.45 tetrahydrofuranyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 384 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6- 7.54 methylpyridinyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 385 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3S) 7.98 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 386 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(((R)- 7.09 tetrahydrofuranyl)oxy)phenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 387 N-((1R,2S)Acrylamidocyclopentyl)oxo(4-(pyridazin 7.16 yloxy)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 388 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3R) 7.64 propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 389 N-((1S,4S)Acetamidocyclohexyl)(*S)-(4-methyl 7.30 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 390 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3R) 8.04 propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 391 N-((1S,3R)Acetamidocyclopentyl)(*S)-(4-methyl 7.86 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 392 N-((1R,3R)Acetamidocyclopentyl)(*S)-(4-methyl 7.34 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 393 N-((1R,2R)Hydroxycyclopentyl)oxo(4-phenoxyphenyl)- 6.74 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 394 N-((1R,3S)Aminocyclopentyl)(*S)-(6-(cyclopentyloxy) 6.70 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 395 N-((1S,3S)Acetamidocyclopentyl)(*S)-(4-methyl 6.66 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 396 N-((1R,2S)Acetamidocyclopentyl)oxo(4-phenoxyphenyl)- 6.66 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 397 N-((1R,2S)Aminocyclopentyl)(*S)-(6-isobutoxy 6.62 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 398 4-Oxo(4-phenoxyphenyl)-N-((1R,2S) 6.56 propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 399 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3S) 6.51 propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 400 N-((1S,3S)Acetamidocyclohexyl)(*S)-(4-methyl 6.46 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 401 N-((1R,2S)Acrylamidocyclohexyl)(2-methyl(pyridin 6.39 yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 402 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3S) 6.38 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 403 N-((1R,3S)Acetamidocyclopentyl)(*S)-(4-methyl 6.26 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 404 N-((1R,2R)Acrylamidocyclohexyl)(*S)-(6-isobutyl 6.21 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 405 N-((1R,3S)Aminocyclopentyl)(*S)-(6-isobutoxy 6.16 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 406 N-((1R,2S)Acrylamidocyclohexyl)(2-methyl(pyridazin 6.13 yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 407 N-((1S,3R)Acetamidocyclohexyl)(*S)-(4-methyl 6.05 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 408 N-((1R,2S)Acrylamidocyclohexyl)oxo(4-(pyridazin <6 yloxy)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 409 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1S,3S) <6 propionamidocyclopentyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 410 N-((1S,3S)Acetamidocyclopentyl)(*S)-(2-methyl <6 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 411 N-((1S,3R)Acrylamidocyclohexyl)(*S)-(2-methyl <6 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 412 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1S,3R) <6 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 413 N-((1S,3R)Acetamidocyclohexyl)(*S)-(2-methyl <6 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 414 N-((1S,3R)Aminocyclohexyl)(*S)-(2-methyl <6 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 415 N-((1S,3S)Aminocyclopentyl)(*S)-(2-methyl <6 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 416 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3R) <6 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 417 (S)(2-Methylphenoxyphenyl)(3-(methylamino)pyrrolidine- 5.89 1-carbonyl)-3Hthia-3,5,8-triazaacenaphthylen-4(5H)-one; 418 (S)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3H 5.80 thia-3,5,8-triazaacenaphthylenecarbonyl)pyrrolidin yl)propionamide; Ex # Compound Name BTK_I_ binding pIC50 419 (S)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3H 5.79 thia-3,5,8-triazaacenaphthylenecarbonyl)pyrrolidin yl)acetamide; 420 (S)(3-Aminopyrrolidinecarbonyl)(2-methyl 5.73 phenoxyphenyl)-3Hthia-3,5,8-triazaacenaphthylen-4(5H)-one; 421 (S)(3-(Dimethylamino)pyrrolidinecarbonyl)(2-methyl 5.66 phenoxyphenyl)-3Hthia-3,5,8-triazaacenaphthylen-4(5H)-one; 422 N-((1R,3R)Acetamidocyclohexyl)(*S)-(4-methyl 7.72 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 423 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3R) 7.75 propionamidocyclohexyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 424 N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl 7.76 (pyridazinyloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 425 N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl 6.67 (pyridazinyloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 426 N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-isopropoxy 8.20 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 427 N-((1R,3S)Acrylamidocyclopentyl)(*S)-(6-isopropoxy 7.88 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 428 N-((1R,2S)Aminocyclopentyl)(*S)-(6-isopropoxy 6.67 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 429 N-((1R,3S)Aminocyclopentyl)(*S)-(6-isopropoxy <6 methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 430 N-((1S,3R)Acrylamidocyclopentyl)(*S)-(4-methyl 8.17 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 431 N-((1S,3R)Aminocyclopentyl)(*S)-(4-methyl 6.68 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 432 N-((1r,4r)Acetamidocyclohexyl)(*S)-(4-methyl 7.45 phenoxypyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 433 (S)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3H 7.01 thia-3,5,8-triazaacenaphthylenecarbonyl)pyrrolidin yl)acrylamide; 434 (R)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3H 6.29 thia-3,5,8-triazaacenaphthylenecarbonyl)pyrrolidin yl)acrylamide; 435 (R,E)Cyanocyclopropyl-N-(1-(5-(2-methyl 6.15 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide; 436 (S,E)Cyanocyclopropyl-N-(1-(5-(2-methylphenoxyphenyl)- 6.09 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carbonyl)pyrrolidinyl)acrylamide; 437 N-((1R,2S)Acrylamidocyclopentyl)oxo(4-(pyridin 8.38 yloxy)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 438 N-((1R,2S)Acrylamidocyclopentyl)(3-isopropylphenyl) 8.02 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 439 N-((1R,2R)Acrylamidocyclohexyl)(*S)-(2-methyl 7.53 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 440 N-((1R,2R)Aminocyclohexyl)(*S)-(2-methyl 7.07 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 441 N-((1R,2R)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methyl 7.01 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 442 N-((1R,2S)Acrylamidocyclohexyl)oxo(4-(pyridin 6.84 yloxy)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 443 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,2R)(2- 6.74 (methylamino)acetamido)cyclohexyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 444 N-((1S,2R)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methyl 6.73 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 445 N-((1R,2R)Acetamidocyclohexyl)(*S)-(2-methyl 6.73 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 446 N-((1S,2R)Acetamidocyclohexyl)(*S)-(2-methyl 6.72 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 447 N-((1R,2R)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2- 6.67 methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 448 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2R)(2- 6.66 (methylamino)acetamido)cyclohexyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 449 N-((1S,2R)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2- 6.51 methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 450 N-((1S,2R)Aminocyclohexyl)(*S)-(2-methyl 6.47 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 451 N-((1S,2R)Acrylamidocyclohexyl)(2-methyl 6.40 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 452 N-((1S,2R)Aminocyclopentyl)(*S)-(2-methyl 6.38 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 453 N-((1R,2S)Aminocyclopentyl)(4-isopropoxy 6.32 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 454 N-((1S,3R)Acetamidocyclopentyl)(4-isopropoxy 6.21 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 455 N-((1R,2S)Aminocyclopentyl)(3-isopropylphenyl)oxo-4,5- <6 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 456 N-((1R,2R)Hydroxycyclopentyl)(4-isopropoxy <6 methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 457 N-((1S,2R)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5- 5.81 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 458 N-((1S,2S)Acrylamidocyclopentyl)(2-methyl 7.53 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 459 N-((1S,2R)Acrylamidocyclopentyl)(2-methyl 7.13 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 460 5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)methylphenyl)-N- 6.78 cyclohexyloxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 461 N-(5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)methylphenyl) 6.46 oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylen yl)cyclopropanecarboxamide; 462 N-Cyclohexyl(2-methylphenoxyphenyl)oxo-4,5-dihydro- 6.33 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 463 N-Cyclohexyloxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 6.22 3,5,8-triazaacenaphthylenecarboxamide; 464 N1-((E)(((1S,2R)(5-(6-isobutylmethylpyridinyl)oxo- 6.64 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamido)cyclopentyl)amino)oxobutenyl)-N5-(15-oxo- 19-((3aS,4S,6aR)oxohexahydro-1H-thieno[3,4-d]imidazolyl)- 4,7,10-trioxaazanonadecyl)glutaramide; 465 N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyrimidin 7.25 yloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 466 N-((1R,2S)((E)Cyanocyclopropylacrylamido)cyclopentyl)- 7.63 -(*S)-(6-isobutylmethylpyridinyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 467 N-((1R,2S)Acrylamidocyclohexyl)(4-methyl(pyridazin <6 yloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 468 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidin 6.52 yloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 476 N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridazin 6.20 yloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 477 N-((1R,2S)Acrylamidocyclopentyl)(6'-methyloxo-2H-[1,2'- 6.85 bipyridin]-5'-yl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 478 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridin 7.64 yloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 479 N-((1R,2S)Acrylamidocyclopentyl)(5-((6-methylpyridin 7.54 yl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 480 N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridin 7.59 yloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 481 N-((1R,2S)Acrylamidocyclopentyl)(5-((6-methylpyridin 7.33 yl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 482 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidin 7.79 yloxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 483 N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((6- 7.49 methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 484 N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyrimidin 6.93 yloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 485 N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyrimidin 6.59 yloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 486 N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyrimidin 7.39 yloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 487 N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((6- 6.87 methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 488 N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridin 7.62 yloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 489 N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((2- 7.03 methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide ; 490 N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridin 7.40 yloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 491 N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridin 7.43 yloxy)pyridinyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; Ex # Compound Name BTK_I_ binding pIC50 492 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidin 6.66 yloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 493 N-((1R,2S)Acrylamidocyclopentyl)(5-((2-methylpyridin 7.32 yl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 494 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridin 7.37 yloxy)pyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 495 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6- 6.63 methylpyridinyl)oxy)pyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; and 508 N-((1R,2S)acrylamidocyclopentyl)oxo(4-(pyrimidin 7.48 yloxy)phenyl)-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide.
The term "comprising" as used in this specification and claims means "consisting at least in part of". When interpreting statements in this specification, and claims which include the term "comprising", it is to be understood that other features that are additional to the features prefaced by this term in each statement or claim may also be present. Related terms such as "comprise" and "comprised" are to be interpreted in similar manner.
In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.
In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.
ASPECTS The disclosure is also directed to the following aspects: Aspect 1. A compound of formula I: wherein R is H or C1-6alkyl; R –C alk-cycloalkyl optionally substituted with 1, 2, or 3 substituents selected from the group 8 3 4 5 6 7 consisting of –NR -C(O)-C(R )=CR (R ); -NR R ; -OH; -CN; oxo; -O-C1-6alkyl; halogen; -C alkyl; –C haloalkyl; -C alk-OH; -C cycloalkyl; -C alkaryl; 1-6 1-6 1-6 3-6 1-6 8 6 7 8 -SO2C1-6alkyl; -SO2C2-6alkenyl; -NR -C(O)-C1-6alk-NR R ; -NR -C(O)-C1-6alkyl; 8 8 8 -NR -C(O)-O-C alkyl; -NR -C(O)-C cycloalkyl; -NR -C(O)H; 1-6 3-6 8 8 8 -NR -C(O)-C cycloalkyl; -NR -C(O)-C haloalkyl; -NR -C(O)-alkynyl; 3-6 1-6 8 8 8 -NR -C(O)-C aryl; -NR -C(O)-heteroaryl; -NR -C(O)-C alk-CN; 6-10 1-6 -C(O)-C alk-OH; -NR -C(O)-C alk-SO -C alkyl; -NR 1-6 1-6 2 1-6 8 6 7 8 -NR -C(O)-C alk-NR R ; -NR -C(O)-C alk-O-C alkyl wherein the 1-6 1-6 1-6 alk- is optionally substituted with –OH, -OC alkyl, or -NR R ; and –C1-6 1-6 -NR -C(O)-C alk-heterocycloalkyl wherein the -C alk- is optionally substituted with 0-6 0-6 alkyl; oxo and the heterocycloalkyl is optionally substituted with -C1-6 wherein R and R are each independently H; -C alkyl; -C cycloalkyl, -C(O)H, 1-6 3-6 -CN; R is H, -CN; halogen; -C haloalkyl; or -C alkyl; 1-6 1-6 4 5 6 7 and R each independently H, -C alk-NR R ; -C alk-OH; R 0-6 1-6 -C alk-C cycloalkyl optionally substituted with C alkyl; halogen; 0-6 3-6 1-6 -C alkyl; -OC alkyl; -C alk-O-C alkyl; 1-6 1-6 1-6 1-6 -C alk-NH-C alk-O-C alkyl; -C alk-heterocycloalkyl optionally 1-6 0-6 1-6 0-6 substituted with –C(O)C alkyl or –C alkyl; -C alk-NHSO -C alkyl; 1-6 1-6 1-6 2 1-6 -C alk-SO -C alkyl; -NHC(O)-C alkyl; or -linker-PEG-Biotin; 1-6 2 1-6 1-6 R is H or C alkyl; A is a bond; pyridyl; phenyl; napthalenyl; pyrimidinyl; pyrazinyl; pyridazinyl; benzo[d][1,3]dioxolyl optionally substituted with halogen; benzothiophenyl; or pyrazolyl; wherein the A is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -C alkyl; halogen; -SF ; -OC alkyl; -C(O)-C alkyl; and 1-6 5 1-6 1-6 -C haloalkyl; E is –O-; a bond; -C(O)-NH-; -CH -; or -CH -O-; G is H; -C cycloalkyl; -phenyl; -thiophenyl; -C alkyl; -pyrimidinyl; -pyridyl; -pyridazinyl; 3-6 1-6 -benzofuranyl; -C haloalkyl; -heterocycloalkyl that contains an oxygen heteroatom; -phenyl-CH -O-phenyl; -C alk-O-C alkyl; -NR R ; -SO C alkyl; or 2 1-6 1-6 2 1-6 –OH; wherein the phenyl; pyridyl; pyridazinyl; benzofuranyl; or thiophenyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen; -C alkyl; -C haloalkyl; -OC haloalkyl; -C cycloalkyl; -OC alkyl; 1-6 1-6 1-6 3-6 1-6 -CN; -OH; -C alk-O-C alkyl; -C(O)-NR R ; or -C(O)-C alkyl; 1-6 1-6 1-6 or a stereoisomer or isotopic variant thereof; or a pharmaceutically acceptable salt thereof.
Aspect 2. The compound of aspect 1, wherein R is H.
Aspect 3. The compound of any one of the preceding aspects, wherein R is cyclopentyl.
Aspect 4. The compound of any one of the preceding aspects, wherein R is substituted with 1 or 2 substituents, preferably R is substituted with 1 substituent.
Aspect 5. The compound of aspect 4, wherein R is substituted with oxo.
Aspect 6. The compound of aspect 4 or aspect 5, wherein R is substituted with halogen; - CN; -OH; -CN; -C alkyl; -C alk-OH; -OC alkyl; -C cycloalkyl; or -C alkaryl. 1-6 1-6 1-6 3-6 1-6 Aspect 7. The compound of any one of aspects 4 to 6, wherein R is substituted with –NR - 8 8 8 C(O)H; -NR -C(O)-C alkyl; -NR -C(O)-C cycloalkyl; -NR -C(O)-C haloalkyl; 1-6 3-6 1-6 8 8 8 8 -NR -C(O)-alkynyl; -NR -C(O)-C aryl; -NR -C(O)-C alk-CN; -NR -C(O)-C alk-OH; 6-10 1-6 1-6 8 8 8 6 7 -NR -C(O)-C alk-SO -C alkyl; -NR -C(O)-O-C alkyl; -NR -C(O)-C alk-NR R ; or 1-6 2 1-6 1-6 1-6 -NR -C(O)-C alk-O-C alkyl wherein the –C alk- is optionally substituted with –OH, 1-6 1-6 1-6 -OC alkyl, or -NR R .
Aspect 8. The compound of any one of aspects 4 to 7, wherein R is substituted with -NR -C(O)-heteroaryl or –NR -C(O)-C alk-heterocycloalkyl wherein the heterocycloalkyl is optionally substituted with -C alkyl.
Aspect 9. The compound of any one of aspects 4 to 8, wherein R is substituted with - SO C alkyl; -NR -C(O)-C alk-SO -C alkyl; or -SO C alkenyl. 2 1-6 1-6 2 1-6 2 2-6 Aspect 10. The compound of any one of aspects 4 to 9, wherein R is substituted with 8 3 4 5 -NR -C(O)-C(R )=CR (R ).
Aspect 11. The compound of aspect 10, wherein R is H.
Aspect 12. The compound of aspect 10 or aspect 11, wherein R is H.
Aspect 13. The compound of aspect 10 or aspect 11, wherein R is –CN.
Aspect 14. The compound of aspect 10 or aspect 11, wherein R is F or Cl.
Aspect 15. The compound of any one of aspects 10 to 14, wherein one of R and R is H.
Aspect 16. The compound of any one of aspect 10 to 15, wherein R is H and R is H.
Aspect 17. The compound of any one of aspect 10 to 14, wherein one of R and R is halogen; -C alkyl; -OC alkyl; -C alk-C cycloalkyl optionally substituted with C 1-6 1-6 0-6 3-6 1- alkyl; or -C alk-OH. 6 1-6 Aspect 18. The compound of any one of aspects 10 to 14, wherein one of R and R is –C 6 7 6 7 alk-NR R , -C alk-NR R , or -C alk-NH-O-C alkyl. 6 1-6 1-6 1-6 Aspect 19. The compound of any one of aspects 10 to 14, wherein one of R and R is -C alk-heterocycloalkyl optionally substituted with –C(O)C alkyl or –C(O)C alkyl; or 0-6 1-6 1-6 -C alk-O-C alkyl. 1-6 1-6 Aspect 20. The compound of any one of aspects 10 to 14, wherein one of R and R is - NHC(O)-C alkyl.
Aspect 21. The compound of any one of aspects 10 to 14, wherein one of R and R is -C1-6alk-NHSO2-C1-6alkyl or -C1-6alk-SO2-C1-6alkyl.
Aspect 22. The compound of any one of the preceding aspects, wherein A is phenyl.
Aspect 23. The compound of any one of aspects 1-21, wherein A is pyridyl.
Aspect 24. The compound of any one of aspects 1-21, wherein A is pyrimidinyl.
Aspect 25. The compound of any one of aspects 1-21, wherein A is pyrazinyl.
Aspect 26. The compound of any one of aspects 1-21, wherein A is pyridazinyl.
Aspect 27. The compound of any one of aspects 22 to 26, wherein A is substituted with 1 or 2 substitutents.
Aspect 28. The compound of aspect 27, wherein A is substituted with -C1-6alkyl, preferably – CH .
Aspect 29. The compound of any one of the preceding aspects, wherein E is O.
Aspect 30. The compound of any one of aspects 1-28, wherein E is a bond.
Aspect 31. The compound of any one of aspects 1-30, wherein G is -C alkyl; -C haloalkyl; 1-6 1-6 -C alk-O-C alkyl; or -C cycloalkyl. 1-6 1-6 3-6 Aspect 32. The compound of any one of aspects 1-30, wherein G is -C alkyl or -C 1-6 3- cycloalkyl.
Aspect 33. The compound of any one of aspects 1-30, wherein G is -NR R or –OH.
Aspect 34. The compound of any one of aspects 1-30, wherein G is -heterocycloalkyl that contains an oxygen heteroatom.
Aspect 35. The compound of any one of aspects 1-30, wherein G is -SO C alkyl. 2 1-6 Aspect 36. The compound of any one of aspects 1-30, wherein G is –phenyl.
Aspect 37. The compound of any one of aspects 1-30, wherein G is –pyridyl.
Aspect 38. The compound of any one of aspects 1-30, wherein G is –pyrimidinyl or pyridazinyl.
Aspect 39. The compound of any one of aspects 1-30, wherein G is –benzofuranyl or – thiophenyl.
Aspect 40. The compound of any one of aspects 1-30, wherein G is -phenyl-CH -O-phenyl.
Aspect 41. The compound of any one of aspects 36-40, wherein G is substituted with 1 or 2 substitutents.
Aspect 42. The compound of aspect 41, wherein G is substituted with halogen.
Aspect 43. The compound of aspect 41 or 42, wherein G is substituted with -C alkyl; -C 1-6 1- 6haloalkyl; -OC1-6haloalkyl; -C3-6cycloalkyl; -OC1-6alkyl; -C1-6alk-O-C1-6alkyl; or -C(O)-C1- alkyl.
Aspect 44. The compound of any one of aspects 41-43, wherein G is substituted with –CN.
Aspect 45. The compound of any one of aspects 41-44, wherein G is substituted with –OH.
Aspect 46. The compound of any one of aspects 41-45, wherein G is substituted with -C(O)- NR R .
Aspect 47. The compound of any one of aspects 1-21, wherein A-E-G is , , or .
Aspect 48. The compound of aspect 1, wherein R is H; R is C alk-cyclopentyl substituted 8 3 4 5 with 1 or 2 substituents wherein one of the substituents is -NR -C(O)-C(R )=CR (R ), 3 4 5 wherein R , R , and R are each H; A is phenyl or pyridyl substituted with –CH E is O or a bond; and G is phenyl or C1-6 alkyl.
Aspect 49. The compound of aspect 48, wherein R is substituted with 1 substituent that is - 8 3 4 5 NR -C(O)-C(R )=CR (R ).
Aspect 50. The compound of aspect 48 or 49, wherein A-E-G is , , or .
Aspect 51. The compound of any one of aspects 48, 49, or 50, wherein the compound of formula I is , or Aspect 52. The compound of any one of the preceding aspects that is a pharmaceutically acceptable salt.
Aspect 53. A pharmaceutical composition comprising a compound of any one of aspects 1- 51, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
Aspect 54. A method of inhibiting Bruton’s tyrosine kinase comprising contacting the kinase with a compound of any one of aspects 1-51.
Aspect 55. A method of treating cancer in a patient comprising administering to the patient a compound of any one of aspects 1-51, or a pharmaceutically acceptable salt thereof.
Aspect 56. The method of aspect 55, wherein the cancer is mantle cell lymphoma, chronic lymphocytic leukemia, macroglobulinemia, or multiple myeloma.
Aspect 57. A method of treating systemic lupus erythematosus in a patient comprising administering to the patient a compound of any one of aspects 1-51, or a pharmaceutically acceptable salt thereof.
Aspect 58. A method of treating a pemphigus disorder or a pemphigoid disorder in a patient comprising administering to the patient a compound of any one of aspects 1-51, or a pharmaceutically acceptable salt thereof.
Aspect 59. A method of treating rheumatoid arthritis in a patient comprising administering to the patient a compound of any one of aspects 1-51, or a pharmaceutically acceptable salt thereof.
Aspect 60. A method of making a compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof.
Aspect 61. A compound as depicted in this disclosure.
Claims (58)
1. A compound of Formula (I): 5 wherein R is H; R is selected from the group consisting of: CH -cyclohexyl, wherein the cyclohexyl is optionally substituted with OH; 3-hydroxyadamantanyl; and C cycloalkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: OH, 6 7 8 8 10 halogen, C alkyl, C haloalkyl, OC alkyl, CN, NR R , NR -C(O)H, NR -C(O)-C 1-6 1-6 1-6 1- 8 8 8 8 alkyl, NR -C(O)-C haloalkyl, NR -C(O)-O-C alkyl, NR -C(O)-C alk-OH, NR - 6 1-6 1-6 1-6 6 7 8 3 4 5 C(O)-C alk-NR R , and NR -C(O)-C(R )=CR (R ); wherein R is selected from the group consisting of: H, CN, halogen, C haloalkyl, and C alkyl; 15 R and R are each independently selected from the group consisting of: H; C alk-NR R ; C alk-O-C alkyl; C cycloalkyl; heterocycloalkyl 6 1-6 1-6 3-6 optionally substituted with C alkyl; and -linker-PEG-Biotin; R and R are each independently selected from the group consisting of: H, C alkyl, C(O)H, and CN; and 20 R is H; or R and R , together with the nitrogen atom to which they are attached, form a pyrrolidinyl ring 6 7 6 7 optionally substituted with NR R , wherein R and R are each independently selected from the group consisting of H; C alkyl; NR -C(O)-C alkyl; and NR -C(O)- 1-6 1-6 3 4 5 3 4 5 C(R )=CR (R ), wherein R is H or CN; R is H; and R is H or cyclopropyl; 25 A is selected from the group consisting of: pyridyl; phenyl; pyrimidinyl; pyrazinyl; pyridin- 2(1H)-one; and pyridazinyl; wherein the A is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halogen, C alkyl, C haloalkyl, and OC alkyl; 1-6 1-6 E is selected from the group consisting of: O, a bond, and CH ; G is selected from the group consisting of: H; halogen; C alkyl; C haloalkyl; NH(C alkyl); 1-6 1-6 1-6 C cycloalkyl; phenyl; pyrimidinyl; pyridyl; pyridazinyl; pyridin-2(1H)-one; heterocycloalkyl that contains an oxygen heteroatom; and phenyl-CH -O-phenyl, wherein the -O-phenyl is substituted with CN; wherein the phenyl; pyridyl; pyridazinyl; and 5 pyridin-2(1H)-one is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halogen, C alkyl, C haloalkyl, 1-6 1-6 OC haloalkyl, and OC alkyl; 1-6 1-6 a stereoisomer thereof; an isotopic variant thereof; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein R is cyclopentyl.
3. The compound of claim 1 or 2, wherein R is substituted with 1 or 2 substituents.
4. The compound of any one of the preceding claims, wherein R is substituted with OH.
5. The compound of any one of claims 1 to 3, wherein R is substituted with OH, halogen, C 15 alkyl, C haloalkyl, OC alkyl, or CN. 6 1-6 1-6 2 8 8
6. The compound of any one of claims 1 to 3, wherein R is substituted with NR -C(O)H, NR - 8 8 8 C(O)-C alkyl, NR -C(O)-C haloalkyl, NR -C(O)-C alk-CN, NR -C(O)-C alk-OH, 1-6 1-6 1-6 1-6 8 8 6 7 NR -C(O)-O-C alkyl, or NR -C(O)-C alk-NR R . 1-6 1-6
7. The compound of any one of claims 1 to 3, wherein R is substituted with NR -C(O)- 3 4 5 20 C(R )=CR (R ).
8. The compound of any one of claims 1 to 3, 6, or 7, wherein R is H.
9. The compound of any one of claims 1 to 3, 6 or 7, wherein R is CN.
10. The compound of any one of claims 1 to 3, 6 or 7, wherein R is F or Cl.
11. The compound of any one of claims 1 to 3, or 6 to 10, wherein one of R and R is H. 25
12. The compound of any one of claims 1 to 3, or 6 to 11, wherein R is H and R is H.
13. The compound of any one of claims 1 to 3, or 6 to 10, wherein one of R and R is C alk- NR R .
14. The compound of any one of claims 1 to 3, or 6 to 10, wherein one of R and R is heterocycloalkyl optionally substituted with C alkyl.
15. The compound of any one of claims 1 to 14, wherein A is phenyl.
16. The compound of any one of claims 1 to 14, wherein A is pyridyl. 5
17. The compound of any one of claims 1 to 14, wherein A is pyrimidinyl.
18. The compound of any one of claims 1 to 14, wherein A is pyrazinyl.
19. The compound of any one of claims 1 to 18, wherein A is substituted with 1 or 2 substitutents.
20. The compound of any one of claims 1 to 19, wherein A is substituted with C alkyl. 10
21. The compound of any one of claims 1 to 20, wherein E is O.
22. The compound of any one of claims 1 to 20wherein E is a bond.
23. The compound of any one of claims 1 to 22, wherein G is C alkyl, C haloalkyl, or C 1-6 1-6 3- cycloalkyl.
24. The compound of any one of claims 1 to 22, wherein G is C alkyl or C cycloalkyl. 1-6 3-6 15
25. The compound of any one of claims 1 to 22, wherein G is NH(C alkyl).
26. The compound of any one of claims 1 to 22, wherein G is heterocycloalkyl that contains an oxygen heteroatom.
27. The compound of any one of claims 1 to 22, wherein G is phenyl.
28. The compound of any one of claims 1 to 22, wherein G is pyridyl. 20
29. The compound of any one of claims 1 to 22, wherein G is pyrimidinyl or pyridazinyl.
30. The compound of any one of claims 1 to 22, wherein G is phenyl-CH -O-phenyl, wherein the -O-phenyl is substituted with CN.
31. The compound of any one of claims 1 to 30, wherein G is substituted with 1 or 2 substitutents.
32. The compound of any one of claims 1 to 31, wherein G is substituted with C alkyl.
33. The compound of any one of claims 1 to 14, wherein A-E-G is , , or .
34. The compound of claim 1, wherein R is H; R is cyclopentyl substituted with 1 or 2 8 3 4 5 3 4 5 substituents wherein one of the substituents is NR -C(O)-C(R )=CR (R ), wherein R , R , and R are each H; A is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with CH E is O or a bond; and G is phenyl or C alkyl. 3; 1-6
35. The compound of claim 34, wherein R is substituted with 1 substituent that is 8 3 4 5 NR -C(O)-C(R )=CR (R ). 10
36. The compound of claim 34, wherein A-E-G is , , or .
37. A compound selected from the group consisting of: N-((1S,4S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- 15 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 20 N-((1R,2R)Hydroxycyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,2S)(Dimethylamino)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Hydroxycyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 10 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,2S)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,4R)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- 20 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,4R)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2S)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,4R)Methoxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)((E)Cyanocyclopropylacrylamido)cyclohexyl)(2-methyl 30 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1S,2S)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)-N-((1R,2R)(methylamino)cyclopentyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1S,4S)Cyanamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H 10 thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)oxo-N-((1R,2R)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,2RS)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-Cyclopentyl(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2R)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1r,3s,5R,7S)Hydroxyadamantanyl)(2-methylphenoxyphenyl)oxo-4,5- 20 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)-N-(2-(methylamino)cyclohexyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2S)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)oxo-N-((1R,2S)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)oxo-N-((1R,2S)propionamidocyclohexyl)-4,5-dihydro- 30 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,2RS)Hydroxycyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1S,2R)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H 10 thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2R)propionamidocyclohexyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1S,2R)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2S)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)-N-((1S,2S)(methylamino)cyclopentyl)oxo-4,5-dihydro- 20 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1S,2R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)-N-((1S,2R)(methylamino)cyclohexyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- 30 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)oxo-N-((1R,2R)propionamidocyclohexyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Formamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1S,2S)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acrylamidocyclopentyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 10 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2R)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 5-(2-Methylphenoxyphenyl)oxo-N-((1S,2S)propionamidocyclohexyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Hydroxycyclopentyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- 20 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)-N-(4-(methylamino)cyclohexyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acetamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 25 5-(2-Methylphenoxyphenyl)oxo-N-((1S,4S)propionamidocyclohexyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)(Dimethylamino)cyclohexyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- 30 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)oxo-N-((1S,3R)propionamidocyclopentyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1S,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)-N-((1S,3R)(2-(methylamino)acetamido)cyclopentyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)(Dimethylamino)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- 10 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Hydroxycyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)(2-Aminoacetamido)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1S,3R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)((E)(Dimethylamino)butenamido)cyclohexyl)(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 20 5-(2-Methylphenoxyphenyl)-N-((1S,4S)((E)(methylamino)but enamido)cyclohexyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1S,4S)((E)Aminobutenamido)cyclohexyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 5-(2-Methylphenoxyphenyl)-N-((1S)(methylamino)cyclopentyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-Cyclopentyl(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-Cyclopentyl(*R)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- 30 triazaacenaphthylenecarboxamide; N-((1S,4S)Hydroxycyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Hydroxycyclohexyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,4R)Hydroxycyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,4R)Hydroxycyclohexyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxyphenyl)oxo-N-((1S,3R)propionamidocyclopentyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- 10 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)((*E)Cyanocyclopropylacrylamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1S,4S)((*E)Cyanocyclopropylacrylamido)cyclohexyl)(*R)-(2-methyl 15 phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,2R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxyphenyl)oxo-N-((1S,4S)propionamidocyclohexyl)-4,5- 20 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*R)-(2-Methylphenoxyphenyl)oxo-N-((1S,4S)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1S,4S)Acetamidocyclohexyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-(rac-(1,3-cis)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- 30 triazaacenaphthylenecarboxamide; N-((1S,2R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,4S)(Dimethylamino)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)(Dimethylamino)cyclohexyl)(*R)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1S,3R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)(2-(dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 10 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,3R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2S)acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,2R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-([1,1'-Biphenyl]yl)-N-((1 R,2 S)acrylamidocyclohexyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- 20 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,3RS)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1S,3R)Acrylamidocyclopentyl)(4-isopropoxymethylphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 30 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2R)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,2S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 10 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acrylamidocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,2R)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2S)(2- 20 (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,2S)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 25 N-((1S,2R)Acrylamidocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2S)(2-(methylamino)acetamido)cyclohexyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- 30 triazaacenaphthylenecarboxamide; N-((1S,2R)Acrylamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,2S)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 5 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 10 N-((1R,2S)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,2S)(2-(methylamino)acetamido)cyclopentyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1S,2S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- 20 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(3-chlorophenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,3R)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2S)Hydroxycyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 5-([1,1'-Biphenyl]yl)-N-((1R,2S)aminocyclohexyl)oxo-4,5-dihydro-3Hthia- 30 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,3S)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 5-([1,1'-Biphenyl]yl)-N-((1R,2R)hydroxycyclopentyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1S,4S)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-(trans-(1R,4R)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; trans-N-((1RS,3RS)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3H 10 thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 15 tert-Butyl ((1R,3S)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclopentyl)carbamate; tert-Butyl trans-((1R,4R)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclohexyl)carbamate; N-((1-Hydroxycyclohexyl)methyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- 20 triazaacenaphthylenecarboxamide; N-((1S,3R)((E)(Dimethylamino)butenamido)cyclopentyl)(4-isopropoxy methylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(2-Aminoacetamido)cyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1S,2R)(2-(Dimethylamino)acetamido)cyclopentyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,2R)(2- (methylamino)acetamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8- 30 triazaacenaphthylenecarboxamide; N-((1S,3R)Hydroxycyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(4-isopropoxymethylphenyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 4-Oxo(2-phenylpyridinyl)-N-((1S,2R)propionamidocyclopentyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,2S)Aminocyclohexyl)(4-isopropoxymethylphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(4-Isopropoxymethylphenyl)-N-((1S,3R)(2-(methylamino)acetamido)cyclopentyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- 10 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; tert-Butyl ((1S,4S)(4-oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamido)cyclohexyl)carbamate; N-((1S,3R)Aminocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 15 N-((1R,2S)Acrylamidocyclopentyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenylpyrimidinyl)-4,5-dihydro-3H 20 thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2S)Aminocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H 30 thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1S,3R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H 10 thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,3R)Aminocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-cyclobutoxymethylpyridinyl)oxo-4,5- 20 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1S,3R)Acrylamidocyclopentyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-cyclobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H 30 thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(4-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)(3-chlorophenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5-([1,1'-Biphenyl]yl)-N-((1R,2S)acrylamidocyclopentyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3H 10 thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,2R)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)phenyl)oxo-4,5- 20 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenoxypyrazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2S)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(6-phenylpyridazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-cyclobutoxymethylpyridinyl)oxo- 30 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-isopropoxyphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((tetrahydro-2H-pyran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-isopropylpyridinyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,3S)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)(3-Chloropropanamido)cyclopentyl)(*S)-(4-methylphenoxypyridin 10 yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-isopropoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,2R)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,3RS)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- 20 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,3RS)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)(2-(Dimethylamino)acetamido)cyclopentyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2R)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)phenyl)oxo-4,5- 30 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-cyclobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-isopropoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-(cyclopentyloxy)methylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acrylamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- 10 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acetamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 5-(2-Methylphenoxyphenyl)-N-((1R,3R)(2-(methylamino)acetamido)cyclopentyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- 20 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(4-methylphenoxypyridinyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2S)Acrylamidocyclopentyl)oxo(4-((tetrahydro-2H-pyranyl)oxy)phenyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)(2-Aminoacetamido)cyclopentyl)(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Aminocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H 30 thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,3S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-cyclobutoxymethylpyridinyl)oxo- 10 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acetamidocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1S,3S)(2-(Dimethylamino)acetamido)cyclopentyl)(2-methylphenoxyphenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(2-Methylphenoxyphenyl)-N-((1S,3S)(2-(methylamino)acetamido)cyclopentyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 20 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(3-Chlorophenoxyphenyl)-N-((1S,3R)((E)(dimethylamino)but enamido)cyclopentyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 5-([1,1'-Biphenyl]yl)-N-((1R,2S)aminocyclopentyl)oxo-4,5-dihydro-3Hthia- 25 3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,3S)(2-(methylamino)acetamido)cyclohexyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 30 N-((1R,3S)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,3S)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,2R)Aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia- 10 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acetamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,2S)Aminocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5-dihydro- 20 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2S)Aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-cyclobutoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(4-phenylpyridinyl)-4,5-dihydro-3Hthia- 30 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Hydroxycyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(2-isopropylpyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,2S)Aminocyclopentyl)(4-isopropoxyphenyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*S)-(4-isopropoxymethylphenyl)oxo-4,5- 10 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S, S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,3S)Acrylamidocyclopentyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(6-phenylpyridazinyl)-4,5-dihydro-3Hthia- 20 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2S)Aminocyclopentyl)oxo(6-phenylpyrimidinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acrylamidocyclopentyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H 30 thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(5-phenylpyridinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(2-(Methylamino)acetamido)cyclopentyl)oxo(2-phenylpyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,2S)Aminocyclopentyl)(2-methyl((tetrahydro-2H-pyranyl)oxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(4-((tetrahydro-2H-pyranyl)oxy)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; racemic cisN-((1RS,3RS)Aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5- 10 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; racemic transN-((1RS,3RS)Aminocyclopentyl)oxo(6-phenoxypyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1RS,2RS)Acrylamidocyclopentyl)(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,3RS)Aminocyclopentyl)(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1RS,3RS)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H- 20 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyrazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)acrylamidocyclopentyl)oxo(5-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isopropoxymethylpyridinyl)oxo- 30 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(*S)-(4-(pyridinyloxy)phenyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,2S)Acrylamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((tetrahydro-2H-pyran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridazinyloxy)phenyl)oxo-4,5- 10 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*S,3*S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(5-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1*S,3*S)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3H- 20 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(5-phenoxypyrazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1S,3R)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*S,3*S)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H 30 thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-([2,3'-Bipyridin]yl)-N-((1R,2S)acrylamidocyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,2*S)Aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1S,3R)Acrylamidocyclopentyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenylpyridazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*S,3*S)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H- 10 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,2R)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5-([2,2'-Bipyridin]yl)-N-((1R,2S)acrylamidocyclopentyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5-([2,3'-Bipyridin]yl)-N-((1R,2R)acrylamidocyclopentyl)oxo-4,5-dihydro-3H 20 thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)oxo(3-(pyridinyl)phenyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*S)Acrylamidocyclopentyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1*R,3*R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(6-(isopropylamino)methylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*R)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H- 30 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*R)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*R)Acrylamidocyclopentyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,2S)Aminocyclohexyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(2-isopropylpyridinyl)oxo-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(2-isopropylpyridinyl)oxo-4,5-dihydro-3H 10 thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)oxo(2-phenoxypyrimidinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,2S)Acetamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-(cyclopentyloxy)methylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-([2,2'-Bipyridin]yl)-N-((1R,2R)acrylamidocyclopentyl)oxo-4,5-dihydro-3H 20 thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2S)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1*R,3*R)Acrylamidocyclohexyl)oxo(5-phenoxypyridinyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2S)Acetamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2S)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((tetrahydro-2H-pyran 30 yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)oxo(5-phenylpyridazinyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1S,3R)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2R)propionamidocyclopentyl)- 10 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,3S)Aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- 20 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3S)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- 30 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1R,2R)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((2-methylpyridinyl)oxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6-methylpyridinyl)oxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-((6-methylpyridinyl)oxy)phenyl)oxo-4,5- 10 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-((6-methylpyridinyl)oxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,2S)Acrylamidocyclopentyl)(4-((2-methylpyridinyl)oxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl)oxo- 20 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-cyclobutylpyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(2-cyclobutylpyridinyl)oxo-4,5-dihydro-3H- 30 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxyphenyl)oxo-N-((1R,2S)propionamidocyclohexyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,2S)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclopentyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(((S)-tetrahydrofuran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6-methylpyridinyl)oxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3S)propionamidocyclohexyl)- 10 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(((R)-tetrahydrofuran yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(4-(pyridazinyloxy)phenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3R)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,4S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3R)propionamidocyclopentyl)- 20 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3R)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2R)Hydroxycyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclopentyl)(*S)-(6-(cyclopentyloxy)methylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- 30 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acetamidocyclopentyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia- 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 4-Oxo(4-phenoxyphenyl)-N-((1R,2S)propionamidocyclopentyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; 5 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3S)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(2-methyl(pyridinyloxy)phenyl)oxo-4,5- 10 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3S)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acetamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,2R)Acrylamidocyclohexyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclopentyl)(*S)-(6-isobutoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(2-methyl(pyridazinyloxy)phenyl)oxo-4,5- 20 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(4-(pyridazinyloxy)phenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1S,3S)propionamidocyclopentyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3S)Acetamidocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- 30 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxypyridinyl)oxo-N-((1S,3R)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Aminocyclohexyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1S,3S)Aminocyclopentyl)(*S)-(2-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1S,3R)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; (S)(2-Methylphenoxyphenyl)(3-(methylamino)pyrrolidinecarbonyl)-3Hthia- 10 3,5,8-triazaacenaphthylen-4(5H)-one; (S)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)propionamide; (S)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)acetamide; 15 (S)(3-Aminopyrrolidinecarbonyl)(2-methylphenoxyphenyl)-3Hthia-3,5,8- triazaacenaphthylen-4(5H)-one; (S)(3-(Dimethylamino)pyrrolidinecarbonyl)(2-methylphenoxyphenyl)-3Hthia- 3,5,8-triazaacenaphthylen-4(5H)-one; N-((1R,3R)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- 20 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(4-Methylphenoxypyridinyl)oxo-N-((1R,3R)propionamidocyclohexyl)- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl(pyridazinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl(pyridazinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Acrylamidocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl)oxo- 30 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,3S)Aminocyclopentyl)(*S)-(6-isopropoxymethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1S,3R)Aminocyclopentyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1r,4r)Acetamidocyclohexyl)(*S)-(4-methylphenoxypyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; (S)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- 10 triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide; (R)-N-(1-(5-(2-Methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide; (S,E)Cyanocyclopropyl-N-(1-(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide; 15 (R,E)Cyanocyclopropyl-N-(1-(5-(2-methylphenoxyphenyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarbonyl)pyrrolidinyl)acrylamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(4-(pyridinyloxy)phenyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(3-isopropylphenyl)oxo-4,5-dihydro-3Hthia- 20 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acrylamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2R)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(4-(pyridinyloxy)phenyl)-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide; 5-(*S)-(2-Methylphenoxyphenyl)-N-((1S,2R)(2-(methylamino)acetamido)cyclohexyl)- 30 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)(2-Aminoacetamido)cyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acetamidocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,2R)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 5-(*S)-(2-Methylphenoxyphenyl)-N-((1R,2R)(2-(methylamino)acetamido)cyclohexyl)- 4-oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 10 N-((1S,2R)(2-(Dimethylamino)acetamido)cyclohexyl)(*S)-(2-methyl phenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1S,2R)Aminocyclohexyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1S,2R)Acrylamidocyclohexyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Aminocyclopentyl)(*S)-(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(4-isopropoxymethylphenyl)oxo-4,5-dihydro-3H- 20 1-thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,3R)Acetamidocyclopentyl)(4-isopropoxymethylphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Aminocyclopentyl)(3-isopropylphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; 25 N-((1R,2R)Hydroxycyclopentyl)(4-isopropoxymethylphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Aminocyclohexyl)oxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-((1S,2S)Acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 30 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1S,2R)Acrylamidocyclopentyl)(2-methylphenoxyphenyl)oxo-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)methylphenyl)-N-cyclohexyloxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-(5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)methylphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenyl)cyclopropanecarboxamide; 5 N-Cyclohexyl(2-methylphenoxyphenyl)oxo-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N-Cyclohexyloxo(4-phenoxyphenyl)-4,5-dihydro-3Hthia-3,5,8- triazaacenaphthylenecarboxamide; N1-((E)(((1S,2R)(5-(6-isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia- 10 3,5,8-triazaacenaphthylenecarboxamido)cyclopentyl)amino)oxobutenyl)-N5- (15-oxo((3aS,4S,6aR)oxohexahydro-1H-thieno[3,4-d]imidazolyl)-4,7,10- trioxaazanonadecyl)glutaramide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyrimidinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,2S)((E)Cyanocyclopropylacrylamido)cyclopentyl)(*S)-(6-isobutyl methylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,2S)Acrylamidocyclohexyl)(4-methyl(pyridazinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 20 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methyloxo(pyridazinyl)-1,6- dihydropyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; 25 N-((1R,2S)Acrylamidocyclopentyl)(*R)-(4-methyloxo(pyridazinyl)-1,6- dihydropyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene carboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridazinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 30 N-((1R,2S)Acrylamidocyclohexyl)(2-methyl(pyridazinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridazinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((2-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridazinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,2S)Acrylamidocyclopentyl)(6'-methyloxo-2H-[1,2'-bipyridin]-5'-yl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(5-((6-methylpyridinyl)oxy)pyridinyl)oxo- 10 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(5-((6-methylpyridinyl)oxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)phenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((6-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyrimidinyloxy)pyridinyl)-4,5- 20 dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyrimidinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyrimidinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((6-methylpyridinyl)oxy)pyridin yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridinyloxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl((2-methylpyridinyl)oxy)pyridin 30 yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide ; N-((1R,2S)Acrylamidocyclopentyl)(4-methyl(pyridinyloxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-(pyridinyloxy)pyridinyl)-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyrimidinyloxy)pyridinyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 5 N-((1R,2S)Acrylamidocyclopentyl)(5-((2-methylpyridinyl)oxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl(pyridinyloxy)pyridinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(2-methyl((6-methylpyridinyl)oxy)pyridin 10 yl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 15 N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((6-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((2-methylpyridin 20 yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl((2-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl(pyrimidinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 25 N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl(pyrimidinyloxy)phenyl) oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl(pyridinyloxy)phenyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*R)-(2-methyl(pyridinyloxy)phenyl)oxo- 30 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)((E)Cyano(3-methyloxetanyl)acrylamido)cyclopentyl)(*S)-(6- isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide; N-((1R,2S)((E)Cyanoethoxymethylpentenamido)cyclopentyl)(*S)-(6- isobutylmethylpyridinyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylene- 2-carboxamide; 5 N-((1R,2S)acrylamidocyclopentyl)oxo(4-(pyrimidinyloxy)phenyl)-4,5-dihydro- 3Hthia-3,5,8-triazaacenaphthylenecarboxamide; an isotopic variant thereof, or a pharmaceutically acceptable salt thereof.
38. A compound as claimed in claim 1 selected from the group consisting of: 10 N-((1R,2S)Acrylamidocyclopentyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(2-phenylpyridinyl)-4,5-dihydro-3Hthia- 15 3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(6-phenoxypyridinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*R)-(4-isopropoxymethylphenyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; 20 N-((1R,2R)Acrylamidocyclopentyl)(*S)-(4-methylphenoxypyrimidinyl)oxo- 4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)oxo(5-phenoxypyrazinyl)-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)oxo(5-phenoxypyrimidinyl)-4,5-dihydro-3H 25 thia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclopentyl)(S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; N-((1R,2S)Acrylamidocyclohexyl)(*S)-(6-isobutylmethylpyridinyl)oxo-4,5- dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; and 30 N-((1R,2S)Acrylamidocyclopentyl)(*S)-(2-methyl((2-methylpyridin yl)oxy)phenyl)oxo-4,5-dihydro-3Hthia-3,5,8-triazaacenaphthylenecarboxamide; an isotopic variant thereof, or a pharmaceutically acceptable salt thereof.
39. A pharmaceutical composition comprising: an effective amount of at least one compound according to any one of claims 1-38 and at least one pharmaceutically acceptable excipient.
40. A pharmaceutical composition comprising an effective amount of at least one compound of 5 claim 37 and at least one pharmaceutically acceptable excipient.
41. A use of at least one compound as claimed in any one of claims 1-38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by Bruton’s tyrosine kinase activity. 10
42. A use of at least one compound as claimed in any one of claims 1-38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject in need thereof.
43. The use of claim 42, wherein the cancer is mantle cell lymphoma, chronic lymphocytic leukemia, macroglobulinemia, or multiple myeloma. 15
44. A use of at least one compound as claimed in any one of claims 1-38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating systemic lupus erythematosus in a subject in need thereof.
45. A use of at least one compound as claimed in any one of claims 1-38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a pemphigus disorder 20 or a pemphigoid disorder in a subject in need thereof.
46. A use of at least one compound as claimed in any one of claims 1-38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating rheumatoid arthritis in a subject in need thereof.
47. A method of making a compound of claim 1, or a pharmaceutically acceptable salt thereof, 25 comprising the method steps set out in the Examples.
48. A compound of claim 1 having the structure of Formula (IIa), or a pharmaceutically acceptable salt thereof, (IIa) wherein R is selected from the group consisting of: H, Cl and CH ; 5 n is 0 or1; E is O; G is selected from the group consisting of: C alkyl, phenyl, pyridyl, pyridyl substituted with CH , pyrimidinyl, pyridazinyl, tetrahydrofuranyl, tetrahydropyranyl, and 10 Ring B is selected from the group consisting of: 15 R is selected from the group consisting of: OH, OCH , NH , NH(CH ), N(CH ) , NH(CO - 3 2 3 3 2 2 tert-butyl), NH(C=O)C alkyl, NH(C=O)CH=CH , NH(C=O)CH NH , 1-3 2 2 2 NH(C=O)CH NH(CH ), NH(C=O)CH N(CH ) , and NH(C=O)CH=CHCH N(CH ) ; 2 3 2 3 2 2 3 2 R is selected from the group consisting of: OH, OCH , CN, NH , NH(CH ), N(CH ) , 3 2 3 3 2 NH(CO -tert-butyl), NH(C=O)C alkyl, and NH(C=O)CH=CH ; 2 1-3 2 R is H or CN; and R is selected from the group consisting of: CH NH , CH NH(CH ), CH N(CH ) , and 2 2 2 3 2 3 2 cyclopropyl. 5
49. A compound of claim 1 having the structure of Formula (IIb), or a pharmaceutically acceptable salt thereof, (IIb) wherein 10 G-A is selected from the group consisting of: G is selected from the group consisting of: C alkyl, C cycloalkyl, phenyl, and pyridyl. 1-6 3-6 R is selected from the group consisting of: 15 and R is selected from the group consisting of: OH, OCH , NH , NH(CH ), N(CH ) , NH(CO - 3 2 3 3 2 2 tert-butyl), NH(C=O)C alkyl, NH(C=O)CH=CH , NH(C=O)CH NH , 1-3 2 2 2 NH(C=O)CH NH(CH ), NH(C=O)CH N(CH ) , and NH(C=O)CH=CHCH N(CH ) . 2 3 2 3 2 2 3 2 5
50. A compound having the structure of Formula (IIc), a stereoisomer, isotopic variant, or pharmaceutically acceptable salt thereof, (IIc) wherein 10 G-E-A is selected from the group consisting of: and ; where G is selected from the group consisting of: C alkyl, phenyl, pyrimidinyl, pyridyl, pyridyl substituted with CH , and C cycloalkyl; and R is H or CH ; 3 3-6 3 Ring B is selected from the group consisting of: R is selected from the group consisting of: OH, OCH , NH , NH(CH ), N(CH ) , NH(CO - 3 2 3 3 2 2 tert-butyl), NH(C=O)C alkyl, NH(C=O)CH=CH , NH(C=O)CH NH , 1-3 2 2 2 NH(C=O)CH NH(CH ), NH(C=O)CH N(CH ) , and NH(C=O)CH=CHCH N(CH ) . 2 3 2 3 2 2 3 2
51. A compound according to claim 1, characterized in that it is N-((1R,2S) 5 Acrylamidocyclopentyl)(S)-(6-isobutylmethylpyridinyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide, an isotopic variant, or a pharmaceutically acceptable salt thereof.
52. A compound according to claim 1, characterized in that it is N-((1R,2S) 10 Acrylamidocyclohexyl)(*S)-(6-isopropoxymethylpyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide, an isotopic variant, or a pharmaceutically acceptable salt thereof.
53. A compound according to claim 1, characterized in that it is N-((1R,2S) 15 Acrylamidocyclohexyl)(*S)-(6-isobutoxymethylpyridinyl)oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylenecarboxamide, an isotopic variant, or a pharmaceutically acceptable salt thereof.
54. A compound according to claim 1, characterized in that it is N-((1R,2R) 20 Acrylamidocyclopentyl)(*S)-(4-isopropoxymethylphenyl)oxo-4,5-dihydro-3H thia-3,5,8-triazaacenaphthylenecarboxamide, an isotopic variant, or a pharmaceutically acceptable salt thereof.
55. A compound as claimed in any one of claims 1-38 and 48-54 substantially as herein 25 described and with reference to any example thereof.
56. A pharmaceutical composition as claimed in claim 39 or 40 sustantially as herein described and with reference to any example thereof. 30
57. A use as claimed in any one of claims 41-46 substantially as herein described and with reference to any example thereof.
58. A method as claimed in claim 47 substantially as herein described and with reference to any example thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562265836P | 2015-12-10 | 2015-12-10 | |
| US62/265,836 | 2015-12-10 | ||
| PCT/US2016/065954 WO2017100662A1 (en) | 2015-12-10 | 2016-12-09 | Polycyclic compounds as inhibitors of bruton's tyrosine kinase |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ742484A NZ742484A (en) | 2021-09-24 |
| NZ742484B2 true NZ742484B2 (en) | 2022-01-06 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11319329B2 (en) | Inhibitors of Bruton's tyrosine kinase and methods of their use | |
| WO2018103060A1 (en) | Inhibitors of bruton's tyrosine kinase and methods of their use | |
| US10822348B2 (en) | Inhibitors of Bruton's tyrosine kinase and methods of their use | |
| WO2018103058A1 (en) | Inhibitors of bruton's tyrosine kinase and methods of their use | |
| NZ742484B2 (en) | Polycyclic compounds as inhibitors of bruton's tyrosine kinase |