WO2009076337A1 - Gamma secretase modulators - Google Patents
Gamma secretase modulators Download PDFInfo
- Publication number
- WO2009076337A1 WO2009076337A1 PCT/US2008/086030 US2008086030W WO2009076337A1 WO 2009076337 A1 WO2009076337 A1 WO 2009076337A1 US 2008086030 W US2008086030 W US 2008086030W WO 2009076337 A1 WO2009076337 A1 WO 2009076337A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- substituted
- another embodiment
- effective amount
- compound
- Prior art date
Links
- VHNYOQKVZQVBLC-RTCGXNAVSA-N (4r,7e,9as)-7-[[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]methylidene]-4-(3,4,5-trifluorophenyl)-1,3,4,8,9,9a-hexahydropyrido[2,1-c][1,4]oxazin-6-one Chemical compound C1([C@@H]2COC[C@@H]3CC\C(C(N32)=O)=C/C=2C=C(C(=CC=2)N2C=C(C)N=C2)OC)=CC(F)=C(F)C(F)=C1 VHNYOQKVZQVBLC-RTCGXNAVSA-N 0.000 title claims description 13
- 229940124648 γ-Secretase Modulator Drugs 0.000 title claims description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 1059
- 238000000034 method Methods 0.000 claims abstract description 116
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 88
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 claims abstract description 28
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 claims abstract description 28
- 230000000694 effects Effects 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 568
- 125000003118 aryl group Chemical group 0.000 claims description 158
- 125000000217 alkyl group Chemical group 0.000 claims description 141
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 141
- 125000001153 fluoro group Chemical group F* 0.000 claims description 117
- -1 heteroaryi Chemical group 0.000 claims description 107
- 238000011282 treatment Methods 0.000 claims description 102
- 125000005843 halogen group Chemical group 0.000 claims description 93
- 239000008194 pharmaceutical composition Substances 0.000 claims description 75
- 239000003112 inhibitor Substances 0.000 claims description 71
- 125000001072 heteroaryl group Chemical group 0.000 claims description 69
- 239000003937 drug carrier Substances 0.000 claims description 64
- 150000003839 salts Chemical class 0.000 claims description 64
- 239000012453 solvate Substances 0.000 claims description 60
- 125000002883 imidazolyl group Chemical group 0.000 claims description 54
- 150000002148 esters Chemical class 0.000 claims description 50
- 229910052799 carbon Inorganic materials 0.000 claims description 44
- 125000003107 substituted aryl group Chemical group 0.000 claims description 41
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 39
- 239000003814 drug Substances 0.000 claims description 38
- 229940079593 drug Drugs 0.000 claims description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
- 239000004480 active ingredient Substances 0.000 claims description 28
- 125000000304 alkynyl group Chemical group 0.000 claims description 28
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 125000004122 cyclic group Chemical group 0.000 claims description 26
- 229940044551 receptor antagonist Drugs 0.000 claims description 25
- 239000002464 receptor antagonist Substances 0.000 claims description 25
- 125000005842 heteroatom Chemical group 0.000 claims description 24
- 239000000556 agonist Substances 0.000 claims description 22
- 230000002401 inhibitory effect Effects 0.000 claims description 22
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 201000010374 Down Syndrome Diseases 0.000 claims description 18
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 18
- 125000004429 atom Chemical group 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- 102000009091 Amyloidogenic Proteins Human genes 0.000 claims description 17
- 108010048112 Amyloidogenic Proteins Proteins 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 230000008021 deposition Effects 0.000 claims description 17
- 230000004770 neurodegeneration Effects 0.000 claims description 17
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 17
- 206010044688 Trisomy 21 Diseases 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- XWAIAVWHZJNZQQ-UHFFFAOYSA-N donepezil hydrochloride Chemical compound [H+].[Cl-].O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 XWAIAVWHZJNZQQ-UHFFFAOYSA-N 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 15
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 15
- 230000000926 neurological effect Effects 0.000 claims description 15
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 13
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 239000000018 receptor agonist Substances 0.000 claims description 13
- 229940044601 receptor agonist Drugs 0.000 claims description 13
- 102100021257 Beta-secretase 1 Human genes 0.000 claims description 12
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 claims description 12
- 239000000544 cholinesterase inhibitor Substances 0.000 claims description 12
- 239000003540 gamma secretase inhibitor Substances 0.000 claims description 12
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 11
- 229960003135 donepezil hydrochloride Drugs 0.000 claims description 11
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 claims description 9
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 claims description 9
- 239000002439 beta secretase inhibitor Substances 0.000 claims description 9
- 208000010877 cognitive disease Diseases 0.000 claims description 9
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 208000027061 mild cognitive impairment Diseases 0.000 claims description 9
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 9
- 229960001685 tacrine Drugs 0.000 claims description 9
- 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 8
- 206010012289 Dementia Diseases 0.000 claims description 8
- 208000010412 Glaucoma Diseases 0.000 claims description 8
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 8
- 208000025698 brain inflammatory disease Diseases 0.000 claims description 8
- 206010014599 encephalitis Diseases 0.000 claims description 8
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 8
- 230000007436 olfactory function Effects 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 108091005435 5-HT6 receptors Proteins 0.000 claims description 7
- 102100040243 Microtubule-associated protein tau Human genes 0.000 claims description 7
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims description 7
- 229940043355 kinase inhibitor Drugs 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 7
- 229960002965 pravastatin Drugs 0.000 claims description 7
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims description 7
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 7
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 claims description 6
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 6
- 239000003149 muscarinic antagonist Substances 0.000 claims description 6
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 claims description 6
- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 claims description 5
- 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 claims description 5
- 108091007911 GSKs Proteins 0.000 claims description 5
- 102000004103 Glycogen Synthase Kinases Human genes 0.000 claims description 5
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims description 5
- 229930003427 Vitamin E Natural products 0.000 claims description 5
- 230000006933 amyloid-beta aggregation Effects 0.000 claims description 5
- 239000003242 anti bacterial agent Substances 0.000 claims description 5
- 230000003115 biocidal effect Effects 0.000 claims description 5
- 230000001906 cholesterol absorption Effects 0.000 claims description 5
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 claims description 5
- 229940125753 fibrate Drugs 0.000 claims description 5
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 5
- 239000003324 growth hormone secretagogue Substances 0.000 claims description 5
- 239000003395 histamine H3 receptor antagonist Substances 0.000 claims description 5
- 230000007388 microgliosis Effects 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 5
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 5
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 5
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 claims description 5
- 239000002469 receptor inverse agonist Substances 0.000 claims description 5
- 235000019165 vitamin E Nutrition 0.000 claims description 5
- 229940046009 vitamin E Drugs 0.000 claims description 5
- 239000011709 vitamin E Substances 0.000 claims description 5
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 claims description 4
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 4
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000012824 ERK inhibitor Substances 0.000 claims description 4
- 102000004878 Gelsolin Human genes 0.000 claims description 4
- 108090001064 Gelsolin Proteins 0.000 claims description 4
- 102000004384 Histamine H3 receptors Human genes 0.000 claims description 4
- 108090000981 Histamine H3 receptors Proteins 0.000 claims description 4
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 4
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 claims description 4
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 claims description 4
- 102100024448 Prostaglandin E2 receptor EP2 subtype Human genes 0.000 claims description 4
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims description 4
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 4
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 4
- 229960005370 atorvastatin Drugs 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 4
- CXQGFLBVUNUQIA-UHFFFAOYSA-N clofibride Chemical compound CN(C)C(=O)CCCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 CXQGFLBVUNUQIA-UHFFFAOYSA-N 0.000 claims description 4
- 229960005049 clofibride Drugs 0.000 claims description 4
- 125000004367 cycloalkylaryl group Chemical group 0.000 claims description 4
- XXRVYAFBUDSLJX-UHFFFAOYSA-N etofibrate Chemical compound C=1C=CN=CC=1C(=O)OCCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 XXRVYAFBUDSLJX-UHFFFAOYSA-N 0.000 claims description 4
- 229960003501 etofibrate Drugs 0.000 claims description 4
- 229960004844 lovastatin Drugs 0.000 claims description 4
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims description 4
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims description 4
- 229940127592 mGluR2/3 antagonist Drugs 0.000 claims description 4
- 229950009116 mevastatin Drugs 0.000 claims description 4
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 claims description 4
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 claims description 4
- 150000003180 prostaglandins Chemical class 0.000 claims description 4
- 229960000672 rosuvastatin Drugs 0.000 claims description 4
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims description 4
- 229960002855 simvastatin Drugs 0.000 claims description 4
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims description 4
- USWVMPGQVYZHCA-UHFFFAOYSA-K Aluminum clofibrate Chemical compound C=1C=C(Cl)C=CC=1OC(C)(C)C(=O)O[Al](O)OC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 USWVMPGQVYZHCA-UHFFFAOYSA-K 0.000 claims description 3
- 101150053721 Cdk5 gene Proteins 0.000 claims description 3
- 102000019058 Glycogen Synthase Kinase 3 beta Human genes 0.000 claims description 3
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 claims description 3
- 102100021496 Insulin-degrading enzyme Human genes 0.000 claims description 3
- 108090000828 Insulysin Proteins 0.000 claims description 3
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 claims description 3
- 102100039418 Plasminogen activator inhibitor 1 Human genes 0.000 claims description 3
- 229960002996 aluminium clofibrate Drugs 0.000 claims description 3
- 239000003529 anticholesteremic agent Substances 0.000 claims description 3
- 229940127226 anticholesterol agent Drugs 0.000 claims description 3
- 125000004350 aryl cycloalkyl group Chemical group 0.000 claims description 3
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 3
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 3
- 229940121372 histone deacetylase inhibitor Drugs 0.000 claims description 3
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims description 3
- 239000003446 ligand Substances 0.000 claims description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 claims description 2
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 claims description 2
- 235000012000 cholesterol Nutrition 0.000 claims description 2
- 229960001214 clofibrate Drugs 0.000 claims description 2
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 claims description 2
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 2
- 238000002255 vaccination Methods 0.000 claims description 2
- 102000003914 Cholinesterases Human genes 0.000 claims 2
- 108090000322 Cholinesterases Proteins 0.000 claims 2
- 229940048961 cholinesterase Drugs 0.000 claims 2
- 125000005114 heteroarylalkoxy group Chemical group 0.000 claims 2
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims 1
- 229960000815 ezetimibe Drugs 0.000 claims 1
- 125000005349 heteroarylcycloalkyl group Chemical group 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 52
- 0 CC1=NC=CNc(ncc(*CC=C)c2)c2OC1 Chemical compound CC1=NC=CNc(ncc(*CC=C)c2)c2OC1 0.000 description 47
- 239000000203 mixture Substances 0.000 description 32
- 229910007161 Si(CH3)3 Inorganic materials 0.000 description 29
- 125000004432 carbon atom Chemical group C* 0.000 description 27
- 239000000651 prodrug Substances 0.000 description 21
- 229940002612 prodrug Drugs 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 17
- 125000006413 ring segment Chemical group 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- 229910052760 oxygen Inorganic materials 0.000 description 13
- 238000002648 combination therapy Methods 0.000 description 12
- 229910052731 fluorine Inorganic materials 0.000 description 12
- 239000001301 oxygen Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 229940126540 compound 41 Drugs 0.000 description 11
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 11
- 229910052717 sulfur Inorganic materials 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 10
- 210000004556 brain Anatomy 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 239000005557 antagonist Substances 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 208000006011 Stroke Diseases 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 6
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 229940126086 compound 21 Drugs 0.000 description 6
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 125000004434 sulfur atom Chemical group 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 229940039856 aricept Drugs 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Natural products O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000011593 sulfur Substances 0.000 description 5
- 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 4
- WRWPPGUCZBJXKX-UHFFFAOYSA-N Cc(cc1)ccc1F Chemical compound Cc(cc1)ccc1F WRWPPGUCZBJXKX-UHFFFAOYSA-N 0.000 description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 208000012902 Nervous system disease Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
- 208000015114 central nervous system disease Diseases 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229960004136 rivastigmine Drugs 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 108010064397 amyloid beta-protein (1-40) Proteins 0.000 description 3
- 230000003042 antagnostic effect Effects 0.000 description 3
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 3
- 125000005110 aryl thio group Chemical group 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- ZUFVXZVXEJHHBN-UHFFFAOYSA-N hydron;1,2,3,4-tetrahydroacridin-9-amine;chloride Chemical compound [Cl-].C1=CC=C2C([NH3+])=C(CCCC3)C3=NC2=C1 ZUFVXZVXEJHHBN-UHFFFAOYSA-N 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- UHIGHLGTNVYXOP-UHFFFAOYSA-N Cc(cc1F)cc(F)c1F Chemical compound Cc(cc1F)cc(F)c1F UHIGHLGTNVYXOP-UHFFFAOYSA-N 0.000 description 2
- UWQNGXALQJBCIS-UHFFFAOYSA-N Cc(nc1)c[n]1-c(ccc(C)c1)c1F Chemical compound Cc(nc1)c[n]1-c(ccc(C)c1)c1F UWQNGXALQJBCIS-UHFFFAOYSA-N 0.000 description 2
- SBABGOSVPNOWPL-UHFFFAOYSA-N Cc1c2nc[s]c2c(C)cc1 Chemical compound Cc1c2nc[s]c2c(C)cc1 SBABGOSVPNOWPL-UHFFFAOYSA-N 0.000 description 2
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N Cc1c[nH]c[n]1 Chemical compound Cc1c[nH]c[n]1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 102000003729 Neprilysin Human genes 0.000 description 2
- 108090000028 Neprilysin Proteins 0.000 description 2
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 241000534944 Thia Species 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000005206 alkoxycarbonyloxymethyl group Chemical group 0.000 description 2
- 125000002877 alkyl aryl group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 125000005038 alkynylalkyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 150000001649 bromium compounds Chemical class 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000003636 conditioned culture medium Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 238000003795 desorption Methods 0.000 description 2
- 230000006806 disease prevention Effects 0.000 description 2
- 208000037765 diseases and disorders Diseases 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 229940108366 exelon Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 125000004404 heteroalkyl group Chemical group 0.000 description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 description 2
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 150000004694 iodide salts Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- OBWFJXLKRAFEDI-UHFFFAOYSA-N methyl cyanoformate Chemical compound COC(=O)C#N OBWFJXLKRAFEDI-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000003959 neuroinflammation Effects 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 150000002923 oximes Chemical group 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000004007 reversed phase HPLC Methods 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
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical class CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- PAORVUMOXXAMPL-SECBINFHSA-N (2s)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride Chemical compound CO[C@](C(Cl)=O)(C(F)(F)F)C1=CC=CC=C1 PAORVUMOXXAMPL-SECBINFHSA-N 0.000 description 1
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 230000006269 (delayed) early viral mRNA transcription Effects 0.000 description 1
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
- 125000005846 1-(alkanoyloxy)ethyl group Chemical group 0.000 description 1
- 125000005848 1-(alkoxycarbonyloxy)ethyl group Chemical group 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical class CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- VUQPJRPDRDVQMN-UHFFFAOYSA-N 1-chlorooctadecane Chemical class CCCCCCCCCCCCCCCCCCCl VUQPJRPDRDVQMN-UHFFFAOYSA-N 0.000 description 1
- 125000001088 1-naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical class BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010065040 AIDS dementia complex Diseases 0.000 description 1
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 108010017640 Aspartic Acid Proteases Proteins 0.000 description 1
- 102000004580 Aspartic Acid Proteases Human genes 0.000 description 1
- 101500024073 Bos taurus Corticotropin Proteins 0.000 description 1
- 101001011741 Bos taurus Insulin Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- KAYQPNUSSBMZBM-WTKPLQERSA-N C/C=C(/C)\N=C/NC1C=CC(N)=CC1OC Chemical compound C/C=C(/C)\N=C/NC1C=CC(N)=CC1OC KAYQPNUSSBMZBM-WTKPLQERSA-N 0.000 description 1
- YUZPZCMPPYKFLC-UHFFFAOYSA-N CC(C)c(ccc(C)c1)c1S(F)(F)(F)(F)F Chemical compound CC(C)c(ccc(C)c1)c1S(F)(F)(F)(F)F YUZPZCMPPYKFLC-UHFFFAOYSA-N 0.000 description 1
- YDXMRHZAXWAPKC-UHFFFAOYSA-N CC(CC[Cs])Cc1cc(F)cc(F)c1 Chemical compound CC(CC[Cs])Cc1cc(F)cc(F)c1 YDXMRHZAXWAPKC-UHFFFAOYSA-N 0.000 description 1
- UYDZUCNMZXCLJI-UHFFFAOYSA-N COc(cc(cc1)O)c1Br Chemical compound COc(cc(cc1)O)c1Br UYDZUCNMZXCLJI-UHFFFAOYSA-N 0.000 description 1
- AZNKKZHZGDZSIF-UHFFFAOYSA-N COc(cc(cc1)[N+]([O-])=O)c1F Chemical compound COc(cc(cc1)[N+]([O-])=O)c1F AZNKKZHZGDZSIF-UHFFFAOYSA-N 0.000 description 1
- DVRLCHPMBFOIDM-UHFFFAOYSA-N CS1=CC1c(cc1F)cc(F)c1F Chemical compound CS1=CC1c(cc1F)cc(F)c1F DVRLCHPMBFOIDM-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229910052686 Californium Inorganic materials 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- HZCVONJWZPKKBI-UHFFFAOYSA-N Cc(c(F)cc(F)c1)c1F Chemical compound Cc(c(F)cc(F)c1)c1F HZCVONJWZPKKBI-UHFFFAOYSA-N 0.000 description 1
- DMEPVFSJYHJGCD-UHFFFAOYSA-N Cc(cc1C)cc(N)c1N Chemical compound Cc(cc1C)cc(N)c1N DMEPVFSJYHJGCD-UHFFFAOYSA-N 0.000 description 1
- WYUIWKFIFOJVKW-UHFFFAOYSA-N Cc(cc1Cl)ccc1Cl Chemical compound Cc(cc1Cl)ccc1Cl WYUIWKFIFOJVKW-UHFFFAOYSA-N 0.000 description 1
- GPHHVUOLHZANSW-UHFFFAOYSA-N Cc(cc1F)cc(C)c1F Chemical compound Cc(cc1F)cc(C)c1F GPHHVUOLHZANSW-UHFFFAOYSA-N 0.000 description 1
- ZTAGGIJNCKYXFJ-UHFFFAOYSA-N Cc(cc1F)cc(F)c1[I]=C Chemical compound Cc(cc1F)cc(F)c1[I]=C ZTAGGIJNCKYXFJ-UHFFFAOYSA-N 0.000 description 1
- YEBJIVQWMFRFDN-UHFFFAOYSA-N Cc(ccc(C)c1O2)c1OC2(F)F Chemical compound Cc(ccc(C)c1O2)c1OC2(F)F YEBJIVQWMFRFDN-UHFFFAOYSA-N 0.000 description 1
- NLCKMGDTJGNGSO-UHFFFAOYSA-N Cc(nc1)c[n]1-c(c(OC)c1)ccc1O Chemical compound Cc(nc1)c[n]1-c(c(OC)c1)ccc1O NLCKMGDTJGNGSO-UHFFFAOYSA-N 0.000 description 1
- ICAHLESVLLFSSB-UHFFFAOYSA-N Cc(nc1)c[n]1-c(ccc(C)c1)c1OC Chemical compound Cc(nc1)c[n]1-c(ccc(C)c1)c1OC ICAHLESVLLFSSB-UHFFFAOYSA-N 0.000 description 1
- DRTPQDZLNJUSSX-UHFFFAOYSA-N Cc(nc1)c[n]1-c(ccc(C)c1)c1OC(F)(F)F Chemical compound Cc(nc1)c[n]1-c(ccc(C)c1)c1OC(F)(F)F DRTPQDZLNJUSSX-UHFFFAOYSA-N 0.000 description 1
- HVTDTGZLCRILTI-UHFFFAOYSA-N Cc(nc1COc2c3)c[n]1-c2ncc3I Chemical compound Cc(nc1COc2c3)c[n]1-c2ncc3I HVTDTGZLCRILTI-UHFFFAOYSA-N 0.000 description 1
- GJOQZTLJKFMBPW-UHFFFAOYSA-N Cc1c(C(CO2)(F)F)c2c(C)cc1 Chemical compound Cc1c(C(CO2)(F)F)c2c(C)cc1 GJOQZTLJKFMBPW-UHFFFAOYSA-N 0.000 description 1
- SIZDXQWOSMNNEW-UHFFFAOYSA-N Cc1c(CC[Si]2(C)C)c2c(C)cc1 Chemical compound Cc1c(CC[Si]2(C)C)c2c(C)cc1 SIZDXQWOSMNNEW-UHFFFAOYSA-N 0.000 description 1
- FAUDJBISFFZJGS-UHFFFAOYSA-N Cc1c(cn[o]2)c2c(C)cc1 Chemical compound Cc1c(cn[o]2)c2c(C)cc1 FAUDJBISFFZJGS-UHFFFAOYSA-N 0.000 description 1
- FANULIRKCKNWIT-UHFFFAOYSA-N Cc1c2nc[o]c2c(C)cc1 Chemical compound Cc1c2nc[o]c2c(C)cc1 FANULIRKCKNWIT-UHFFFAOYSA-N 0.000 description 1
- FKKLHLZFSZGXBN-UHFFFAOYSA-N Cc1cc(Cl)cc(C)c1 Chemical compound Cc1cc(Cl)cc(C)c1 FKKLHLZFSZGXBN-UHFFFAOYSA-N 0.000 description 1
- PGFCSLSLIRDOSK-UHFFFAOYSA-N Cc1ccc(C)c2c1CC=NO2 Chemical compound Cc1ccc(C)c2c1CC=NO2 PGFCSLSLIRDOSK-UHFFFAOYSA-N 0.000 description 1
- JRULHTKYHFWWNR-UHFFFAOYSA-N Cc1ccc(C)c2c1[n](C)nn2 Chemical compound Cc1ccc(C)c2c1[n](C)nn2 JRULHTKYHFWWNR-UHFFFAOYSA-N 0.000 description 1
- BGVTUIRPHLSMJU-UHFFFAOYSA-N Cc1ccc(C)nn1 Chemical compound Cc1ccc(C)nn1 BGVTUIRPHLSMJU-UHFFFAOYSA-N 0.000 description 1
- LCZUOKDVTBMCMX-UHFFFAOYSA-N Cc1cnc(C)cn1 Chemical compound Cc1cnc(C)cn1 LCZUOKDVTBMCMX-UHFFFAOYSA-N 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- ILUBKROSBGNQFA-UHFFFAOYSA-N Fc(cc1)cc(C2SC2)c1F Chemical compound Fc(cc1)cc(C2SC2)c1F ILUBKROSBGNQFA-UHFFFAOYSA-N 0.000 description 1
- OKIHXNKYYGUVTE-UHFFFAOYSA-N Fc(cc1)ccc1S Chemical compound Fc(cc1)ccc1S OKIHXNKYYGUVTE-UHFFFAOYSA-N 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- 150000000994 L-ascorbates Chemical class 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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- RVOLLAQWKVFTGE-UHFFFAOYSA-N Pyridostigmine Chemical compound CN(C)C(=O)OC1=CC=C[N+](C)=C1 RVOLLAQWKVFTGE-UHFFFAOYSA-N 0.000 description 1
- 101000746366 Rattus norvegicus Granulocyte-macrophage colony-stimulating factor Proteins 0.000 description 1
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 1
- 229910006024 SO2Cl2 Inorganic materials 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 102100038968 WAP four-disulfide core domain protein 1 Human genes 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical class C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 1
- 125000005513 benzoazaindolyl group Chemical group 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 150000005347 biaryls Chemical class 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
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- IXIBAKNTJSCKJM-BUBXBXGNSA-N bovine insulin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 IXIBAKNTJSCKJM-BUBXBXGNSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000025434 cerebellar degeneration Diseases 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical group O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000003493 decenyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- LMEDOLJKVASKTP-UHFFFAOYSA-N dibutyl sulfate Chemical class CCCCOS(=O)(=O)OCCCC LMEDOLJKVASKTP-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005049 dihydrooxadiazolyl group Chemical group O1N(NC=C1)* 0.000 description 1
- 125000005056 dihydrothiazolyl group Chemical group S1C(NC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 125000005072 dihydrothiopyranyl group Chemical group S1C(CCC=C1)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 239000002329 esterase inhibitor Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 229960003765 fluvastatin Drugs 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- 125000005643 gamma-butyrolacton-4-yl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000643 heteroaryl-fused-heterocycloalkyl group Chemical group 0.000 description 1
- 125000004447 heteroarylalkenyl group Chemical group 0.000 description 1
- 125000005368 heteroarylthio group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 229930005346 hydroxycinnamic acid Natural products 0.000 description 1
- 235000010359 hydroxycinnamic acids Nutrition 0.000 description 1
- 125000005945 imidazopyridyl group Chemical group 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- SNWQUNCRDLUDEX-UHFFFAOYSA-N inden-1-one Chemical compound C1=CC=C2C(=O)C=CC2=C1 SNWQUNCRDLUDEX-UHFFFAOYSA-N 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 238000001906 matrix-assisted laser desorption--ionisation mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000004370 n-butenyl group Chemical group [H]\C([H])=C(/[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960002362 neostigmine Drugs 0.000 description 1
- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000007138 neurofibrillary change Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229960002797 pitavastatin Drugs 0.000 description 1
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 229960002290 pyridostigmine Drugs 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 208000002320 spinal muscular atrophy Diseases 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- NGSWKAQJJWESNS-ZZXKWVIFSA-N trans-4-coumaric acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C=C1 NGSWKAQJJWESNS-ZZXKWVIFSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical class OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention relates to certain heterocyclic compounds useful as gamma secretase modulators (including inhibitors, antagonists and the like), pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat various diseases including central nervous system disorders such as, for example, neurodegenerative diseases such as Alzheimer's disease and other diseases relating to the deposition of amyloid protein. They are especially useful for reducing Amyloid beta (hereinafter referred to as A ⁇ ) production which is effective in the treatment of diseases caused by A/? such as, for example, Alzheimers and Down Syndrome.
- a ⁇ Amyloid beta
- Alzheimer's disease is a disease characterized by degeneration and loss of neurons and also by the formation of senile plaques and neurofibrillary change.
- a symptom-improving agent represented by an acetylcholinesterase inhibitor
- a method of controlling the cause of onset of pathologic conditions needs to be developed for creation of the basic remedy of Alzheimer's disease.
- a ⁇ protein which is a metabolite of amyloid precursor protein (hereinafter referred to as APP), is considered to be greatly involved in degeneration and loss of neurons as well as onset of demential conditions (for example, see Kiein W L, et al Proceeding National Academy of Science USA t Sep. 2, 2003, 100(18), p. 10417-22, suggest a molecular basis for reversible memory loss.
- APP amyloid precursor protein
- senile plaques for example, (Glenner GG, et at, Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochemical and Biophysical Research Communications, May 16, 1984, 120(3), p. 885-90. See also Masters C L, et al, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proceeding National Academy of Science USA, June 1985, 82(12), p. 4245-4249.).
- A/?40 and A7?42 are expected to be agents for controlling progress of Alzheimer's disease or for preventing the disease.
- These A ⁇ s are produced when APP is cleaved by beta secretase and subsequently cleaved by gamma secretase. Jn consideration of this, creation of inhibitors of ⁇ -secretase and ⁇ -secretase has been attempted for the purpose of reducing production of A/?s.
- Many of these known secretase inhibitors are peptides or peptidomimetics such as L-685,458.
- L-685,458 an aspartyl protease transition state mimic, is a potent inhibitor of ⁇ -secretase activity, Biochemistry, Aug. 1, 2000, 39(30), p. 8698-8704).
- the present invention provides a novel cloid of compounds as gamma secretase modulators (including inhibitors, antagonists and the like), methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with the AjS using such compounds or pharmaceutical compositions.
- This invention provides novel compounds, that are gamma secretase modulators, of the formula:
- This invention also provides compounds of formula (I) in pure and isolated form.
- This invention also provides compounds of formula (!) selected from the group consisting of: compounds of formulas IA to IH, 2 to 9, 12 to 18, 20, 21 , 40 to 43, 55, 2A to 9A, 12A to 18A, 20A ( 21A 1 4OA to 43A, 55A, 2B to 9B, 12B to 18B, 208, 21B, 408 to 43B, 55B, 2C to 9C 1 12C to 18C 1 2OC, 21 C, 4OC to 43C 1 55C, 6.2, 9.1, 10,1, 10.2, 10.3, 14.1, 16.1, 16.2, 18.1, 19.1, 20.2, 21.2, 23.2, 25.1, 26.1, 27.1, 28.1, 30.1, 36.1, 37,1, 38.1, 39.1, 41.1, 43.1, 45.1, 46.1, 47.1, 48.1, 49.1, 50.1, 51.1, 52.1, 59.1, 60.1, 61.1, 64.1, 65.1, 68.1, 70.1, E1, E2, and E3.
- This invention also provides compounds of formula (!) selected from the group consisting of: compounds of formulas IA to IH.
- This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas 2 to 9, 12 to 18, 20, 21, 40 to 43, and 55.
- This invention also provides compounds of formula (! selected from the group consisting of: compounds of formulas 2A to 9A, 12A to 18A, 2OA, 21 A, 4OA to 43A, and 55A.
- This invention also provides compounds of formula (i) selected from the group consisting of: compounds of formulas 2B to 9B, 12B to 18B, 2OB, 21 B, 4OB to 43B 1 and55B.
- This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas 2C to 9C, 12C to 18C, 2OC, 21 C, 4OC to 43C, and 55C.
- This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas 6.2, 9.1, 10.1, 10.2, 10.3, 14.1, 16.1, 16.2,
- This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas E1, E2, and E3.
- This invention also provides pharmaceutical compositions comprising an effective amount of one or more (e.g., one) compounds of formula (I), or a pharmaceutically acceptable salt, ester or solvate thereof, and a pharmaceutically acceptable carrier.
- This invention also provides pharmaceutical compositions comprising an effective amount of one or more (e.g., one) compounds of formula (I), or a pharmaceutically acceptable salt, ester or solvate thereof, and an effective amount of one or more (e.g., one) other pharmaceutically active ingredients (e.g., drugs), and a pharmaceutically acceptable carrier.
- the compounds of formuta (I) can be useful as gamma secretase modulators and can be useful in the treatment and prevention of diseases such as, for example, centra! nervous system disorders such as Afeheimers disease and Downs Syndrome.
- this invention also provides methods for: (1) method for modulating (including inhibiting, antagonizing and the like) gamma-secretase; (2) treating one or more neurodegenerative diseases; (3) inhibiting the deposition of amyloid protein (e.g., amyfoid beta protein) in, on or around neurological tissue (e.g., the brain); (4) Alzheimer's disease; and (5) treating Downs syndrome; wherein each method comprises administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of such treatment.
- amyloid protein e.g., amyfoid beta protein
- each method comprises administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of such treatment.
- This invention also provides combination therapies for (1) modulating gamma- secretase, or (2) treating one or more neurodegenerative diseases, or (3) inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (4) treating Alzheimer's disease.
- the combination therapies are directed to methods comprising the administration of an effective amount of one or more (e.g. one) compounds of formula (I) and the administration of an effective amount of one or more (e.g., one) other pharmaceutical active ingredients (e.g., drugs).
- This invention also provides methods for. (1) treating mild cognitive impairment; (2) treating glaucoma; (3) treating cerebral amyloid angiopathy; (4) treating stroke; (5) treating dementia; (6) treating microgliosis; (7) treating brain inflammation; and (8) treating olfactory function loss; wherein wherein each method comprises administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of such treatment.
- each method comprises administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of such treatment.
- This invention also provides a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of formula (f) in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described beiow), the combined quantities of the compound of formula (1) and the other pharmaceutically active ingredient being effective to treat the diseases or conditions mentioned in any of the above methods.
- This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds of formulas IA to IH, 6.2, 10,2, 10.3, 20.2, 21.2, 23.2, 2 to 9, 12 to 18, 20, 21. 40 to 43, 55, 2A to 9A 1 12A to 18A 1 20A, 21 A, 4OA to 43A, 55A, 2B to 9B, 12B to 18B 1 2OB, 21 B, 4OB to 43B, 55B 1 2C to 9C, 12C to 18C, 2OC, 21C 1 4OC to 43C, 55C, E1, E2 S and E3.
- This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (!) is selected from the group consisting of: compounds IA to IH.
- This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (!) is selected from the group consisting of: compounds 6.2, 10.2, 10.3, 20.2, 21.2, and 23.2.
- This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formuia (() is selected from the group consisting of: compounds 2 to 9, 12 to 18, 20, 21, 40 to 43, and 55.
- This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds 2A to 9A 1 12A to 18A, 2OA, 21A, 40A to 43A, and 55A.
- This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds 2B to 9B, 12B to 18B, 2OB, 21 B, 4OB to 43B, and 55B.
- This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds 2C to 9C, 12C to 1 ⁇ C, 2OC, 21 C, 4OC to 43C, and 55C.
- This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds E1 , E2, and E3.
- This invention provides compounds, useful as gamma secretase modulators, of formula (i): or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
- R 1A , G 1 , G 2 , G 3 , G 4 , (B) 5 G 1 R 9 , R 10 , and W are independently selected; letters (A) and (B) in formula (I) are reference letters to identify the rings present in formula (I); the numbers (1), (2), (3), (4), and (5) are reference numbers to identify positions of the Ring (A); G 4 is at position (1), G 3 is at position (2), G 2 is at position (3), G 1 is at position (4) and the N is at position (5); the moiety -G-R 10 -R 9 is bound through G to G 4 (i.e., position (1)) or G 3 (i.e., position (2)), and when G is bound to G 4 then G 4 is a -C-, and when G is bound to G 3 then G 3 is a -C-; the dotted line between G 1 and G 2 represents an optional bond;
- Ring (B) is the ring formed from the N at position (5) and G 1 , and G 1 is carbon or N (i.e., -N(R 2 ) d - wherein d is 0), and when G 1 is N the optional bond between G 1 and G 2 is absent; said Ring (B) is a 4 to 8 (and in one example 5 to 6) membered heterocycfoalkyl, heteroaryl, or heterocycloalkenyl ring; said heterocycloalkyl, heterocycloalkenyi, or a heteroaryl ring Ring (B), in addition to the nitrogen common to Ring (A) and Ring (B), optionally comprises, at least one (e.g., 1 to 3, or 1 to 2, or 1 ) other heteroatom selected from the group consisting of: -NR 2 -, -O- , -S-, -S(O)-, and -S(O) 2 -; said Ring (B) is optionally substituted with 1 to 6 independently selected R 21
- G 1 is selected from the group consisting of: (1) -C(R 2t J q - wherein q is O when the optional bond is present (i.e., G 1 is C), (2) -C(R 21 ) q - wherein q is 1 when the optional bond is absent,
- G 2 is selected from the group consisting of: a direct bond (i.e., G 3 is bonded directly to G 1 , and Ring A is a five membered ring), -C(R 21 ) ⁇ -N ⁇ R 2 ) d -,
- G 2 is not -C(N(R 2 ) 2 )-
- G 3 is selected from the group consisting of: (a) -C(R 21 ) q wherein q is 0 (i.e., the is C and there are no valences to fill with a H atom), (b) -CH- (i.e., q is 0 and there is a valence to fill with a H), (c) -C(R 21 ) q wherein q is 1 , and (d) -N(R 2 ) d wherein d is 0 (and there is no H on the N due to the double bond between G 3 and G 4 ); and with the proviso that: when moiety G is bound to G 3 , then G 3 is carbon (i.e., the group G 3 is the group -C(R 21 ) q wherein q is 0 and there is no valence to fili with a H atom);
- G 4 is selected from the group consisting of: (a) -C(R 21 ) q wherein q is 0 (i.e., the -C(R 21 )q is C and there are no valences to fili with a H atom), (b) -CH- (i.e., q is 0 and there is a valence to fill with a H), (c) -C(R 21 ) q wherein q is 1, and (d) -N(R 2 ) d wherein d is 0 (and there is no H on the N due to the double bond between G 3 and G 4 ); and with the proviso that: when moiety G is bound to G 4 , then G 4 is carbon (i.e., the group G 4 is the group -C(R 21 ) ⁇ wherein q is 0 there is no valence to fill with a H atom); and provided that 0 to 2 of the G 1 , G 2 , G 3 , and G
- R 1A is selected from the group consisting of: alky!-, alkenyh afkynyh aryl-, arylalkyh alkylary!-, cydoa ⁇ kyi, cydoaikenyl, cycloaikylalkyh fused benzocycloalkyl- (Le., benzofusedcycloalkyl-), fused benzoheterocycloalkyl- (i.e., benzofused ⁇ eterocycioalkyl-), fused heteroarylcycloalkyl- (i.e., heteroarylfusedcycloatkyl-), fused heteroaryfheterocycloalkyt- (i.e., heteroaryifusedheterocycloafkyf-), fused cycioalkylaryt (i.e., cycjoalkyfusediaryi-), fused heterocycloalkylaryf- (i.e., hetero
- -O ⁇ alkyl i.e., alkoxy), -O-(ha!o substituted alky) (such as, for example, -O-fluoroalkyl
- -NH(R 4 ), -N(R 4 ⁇ 2 wherein each R 4 is independently selected), -NH 2 , -S(O)R 4 , -S(O)(OR 4 ), -S(O) 2 R 4 , -S(O) 2 (OR 4 ), -S(O)NHR 4 , ⁇ S(O)N(R 4 ⁇ 2 , -S(O)NH 2 , -S(O) 2 NHR 4 , -S(O) 2 N(R 4 J 2 , -S(O) 2 NH 2 , -CN, -C(O) 2 R 4 , -C(O)NHR 4 , -C(O)N(R 4 ) 2 , -C(O)NH 2 , -C
- R 3 is selected from the group consisting of: H, -OH, halo, -O-alkyl (i.e., alkoxy), -O-(halo substituted alky) (such as, for example, -O-fluoroalkyl), -NH(R 4 ), -N(R 4 ) 2 (wherein each R 4 is independently selected), -NH 2 , -S(R 4 ), -S(O)R 4 , -S(O)(OR 4 ), -S(O) 2 R 4 , -S(O) 2 (OR 4 ), -S(O)NHR 4 , -S(O)N(R 4 ) 2> -S(O)NH 2 , -S(O) 2 NHR 4 , -S(O) 2 N(R 4 J 2 , -S(O) 2 NH 2 , -CN 1 -C(O) 2 R 4 , -C(O)NHR 4 ,
- substituted groups are substituted with one or more (e.g., 1 to 5) substttuents independently selected from: R 2 ;
- R 9 is selected from the group consisting of: arylalkoxy-, heteroaryialkoxy-, arylalkylamino-, heteroarylalkylamino-, aryl, aryiaikyh heteroary!, heteroarylalkyl-, heterocycfyi, heterocyclenyl, and heterocyclyafkyh wherein each of said R 9 arylalkoxy-, heteroarylaSkoxy-, arylalkylamino-, heteroarylalkylamino-, aryl, arylalky!-, heteroaryl, heteroarylalkyl-, heterocyclyl, heterocyclenyl, and heterocyclyalkyl- is optionally substituted with 1-5 independently selected R 21 groups;
- R 1G is selected from the group consisting of: aryi- (e.g., phenyl), heteroaryl- (e.g., pyridyl), cycloalkyl-, cycloalkenyl, cycloalkylalkyl-, heterocyclyl-, heterocyclenyl-, heterocyclylalkyl-, heterocyclyalkenyi-, fused benzocycloalkyl- (i.e., benzofusedcycloalkyl-), fused benzoheterocycloalkyl- (i.e., benzofusedheterocycioalkyl-), fused heteroarylcycloalkyi- (i.e., heteroarylfusedcycloalkyl-), fused heteroarylheterocycloalkyl- (i.e., heteroaryifusedheterocycloalkyl-), fused cycloalkylaryl (i.e., cycloalkyfusedlaryl-),
- X is selected from the group consisting of: 0, -N(R 14 )- and -S-; and wherein each of said R 10 moieties is optionally substituted with 1-5 independently selected R 21 groups; or
- R 9 and R 10 are linked together to form a fused tricyclic ring system wherein R 9 and R 10 are as defined above and the ring linking R 9 and R 10 is an aikyl ring, or a heteroalkyi ring, or an aryl ring, or a heteroaryl ring, or an alkenyi ring, or a heteroalkenyl ring (for example, the tricyclic ring system is formed by linking the atoms adjacent to the atoms by which R 9 and R 10 are bound together);
- R 14 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycioalkylalkyl, cycloalkenyi, heterocyciyl, heterocyclenyl, heterocyclylalkyl, heterocyclyalkenyh aryl, arylalkyl, heteroaryl, heteroarylalkyl, -CN, -C(O)R 15 -C(O)OR ,1 5 5 0 , and -P(O)(OR 15 XOR 16 );
- R 15A and R 16A are independently selected from the group consisting of aikyl, alkenyl, alkynyl, cycloalkyf, cycloalkytalkyl, heterocyciyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocyciyl, (R 18 ) ⁇ -aikyl, 8 V (R v1 l 8 ⁇ ) n -cycloa!kylalkyl, ⁇ R 1 l S o )v n -heterocyc!yl t (R J 1 'Vheterocyclylalkyl, (R >1 ! ⁇ 0 )v n -arylalkyl, (R ,1'8°) n -heteroaryi and (R 1'8V, heteroarylalkyl; or
- R 15 , R st 1 e D and R i1"7 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycioaJkylalkyl, heterocyciyl, heterocyciylalkyS, aryl, arylalkyf, heteroaryi, heteroarylalkyi, arylcycloalkyi, arylheterocyciyl, (R 18 ) n -alkyl, (R 1 Vcycloalkyf, (R ⁇ -cycloalkylalkyl, (R 18 ) n -heterocyclyl, (R 18 ) n -heterocyciylaikyi, (R 1 Varyt ⁇ tkyl, (R ' Vheteroaryl and (R 18 ) n -heteroarylalkyi; each R 18 is independently selected from the group consisting
- R 19 is selected from the group consisting of: alky!, cydoalkyl, aryl, arylalkyl and heteroaryialky!;
- the compounds of this invention are useful for treating central nervous system disorders such as, for example, neurodegenerative diseases such as Alzheimer's disease and other diseases relating to the deposition of amyloid protein. They are especially useful for reducing Amyloid beta (hereinafter referred to as A ⁇ ) production which is effective in the treatment of diseases caused by A ⁇ such as, for example, Alzheimers and Down Syndrome.
- a ⁇ Amyloid beta
- the compounds of this invention can be used to treat the following diseases or conditions: Alzheimers disease, mild cognitive impairment (MCI), Downs Syndrome, Glaucoma (Guo et.al., Proc. Natl. Acad. Sci. USA 104, 13444- 13449 (2007)), Cerebral amyloid angiopathy, stroke or dementia (Frangione et al., Amyloid: J. Protein folding Disord. 8, suppl. 1 , 36-42 (2001), Mtcrogliosis and brain inflammation (M P Lamber, Proc, Natl. Acad. Sci. USA 95, 6448-53 (1998)), and Olfactory function loss (Getchell, et.al.
- MCI mild cognitive impairment
- Glaucoma Glaucoma
- Cerebral amyloid angiopathy Cerebral amyloid angiopathy
- stroke or dementia Flrangione et al., Amyloid: J. Protein folding Disord. 8, suppl. 1 , 36-42 (
- R 1A is selected from the group consisting of: alky!-, alkenyh alkynyh aryh arylaikyh alkylaryl-, cycioaikyh cycloafkenyl, cycloalkylalkyl-, fused benzocycloalkyS (i.e., benzofusedcycloafkyl), fused benzoheterocycloalkyl (i.e., benzofusedhetero-cycloalkyi), fused heteroarylcycloaikyl (i.e., heteroarylfusedcycloalky!), fused heteroaryiheterocycloafky) (i.e., heteroarylfusedheterocycloalkyl), heteroaryh heteroaryfalkyl-, heterocyciyl-, heterocyclenyl, -and heterocyclyalkyl-; wherein each of said alky!-, alkenyh alkynyh aryh arylai
- moieties formed when R 10 and R 9 are linked together to form a fused tricyclic ring system include., but are not limited to:
- Ring C is the ring linking R 10 and R 9 , that is Ring C is an aikyt ring, or a heteroalkyl ring, or an aryl ring, or a heteroaryl ring, or an alkenyl ring, or a heteroalkenyl ring.
- moieties formed when R 10 and R 9 are linked together to form a fused tricyclic ring system include, but are not limited to:
- Ring C is the ring linking R aanndd R 9 , that is Ring C is a heteroalkyl ring, or a heteroaryi ring, or a heteroalkenyl ring.
- the fused tricyclic ring system formed when R 1Q and R 9 are linked together is
- Ring C is a heteroalkyi ring, or a heteroaryi ring, or a heteroalkenyl ring, thus, for example, the tricyclic ring system is formed by linking the atoms adjacent to the atoms by which R 10 and R 9 are bound together), and wherein said fused tricyclic ring system is optionally substituted with 1 to 5 independently selected R 21 groups.
- moieties formed when R 10 and R 9 are linked together to form a fused tricyclic ring system include, but are not limited to:
- Another embodiment of this is directed to compounds of formula (0 wherein at least one (e.g., 1 to 3, or 1-2, or 1) group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present, and wherein each R 15A is independently selected, an ⁇ wherein when there is more than one group, each group is independently selected.
- at least one (e.g., 1 to 3, or 1-2, or 1) group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present, and wherein each R 15A is independently selected, an ⁇ wherein when there is more than one group, each group is independently selected.
- Another embodiment of this is directed to compounds of formula (I) wherein at ieast one (e.g., 1 to 3, or 1-2, or 1) group selected from the group consisting of: -SF 5 and -OSF 5 is present, and wherein when there is more than one group, each group is independently selected.
- one group selected from the group consisting of: -SF 5 , -OSFs, and -Si(R 15A ) 3 (wherein each R 15A is independently selected ⁇ is present in the compounds of formula (( ⁇ .
- two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
- two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A ) 3 .
- three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (J), wherein at least one group is other than -Si(R 15A ) 3 .
- one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present in the compounds of formula (I).
- two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
- each R 15A is independently selected from the group consisting of aikyl (e.g., methyl and ethyl) and aryi (e.g., phenyl)) are present in the compounds of formula (I).
- two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A )s are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A ) 3 .
- three groups selected from the group consisting of: -SF 5 .. -OSF 5 ., and -Si(R 15A ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A ) 3 .
- one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si ⁇ R 1SA ⁇ 3 (wherein each R 15A is independently selected from the group consisting of rnethyf, ethyl and phenyl) is present in the compounds of formula (I).
- two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 wherein each R 15A is independently selected from the group consisting of methyl, ethyl and phenyl are present in the compounds of formula (I).
- three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
- two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 1SA ) 3 are present in the compounds of formula (i), wherein at least one group is other than -Si(R 1SA ) 3 .
- Jn another embodiment of this invention three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected from the group consisting of methyl, ethyl and phenyl) are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A ) 3 .
- one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (I).
- two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
- three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
- two groups selected from the group consisting of: -SF 5 , -OSF 5 , an ⁇ -Si ⁇ R 15A ) 3 are present in the compounds of formula (i), wherein at least one group is other than -Si(R 1SA ⁇ 3 .
- three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A ) 3 .
- one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present in the compounds of formula (I), and said -Si(R 15A ) 3 group is selected from the group consisting of. -Si(CHa) 3 , -Si(CH 3 ) 2 phenyl, and -Si(CH 2 CHa) 2 CH 3 ,
- two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), and said -Si(R 1SA ) 3 group is selected from the group consisting of: -Si(CHs) 3 , -Si(CH 3 ) 2 phenyl, and -Si(CH 2 CHg) 2 CH 3 .
- three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), and said -Si(R 16A ) 3 group is selected from the group consisting of: -Si(CHs) 3 , - Si(CH 3 ) 2 ⁇ henyi, and ⁇ Si(CH 2 CH 3 ) 2 CH 3 .
- two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A )3, and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3 , ⁇ Si(CH 3 ) 2 phenyl, and -Si(CH 2 CH 3 ) 2 CH 3 .
- three groups selected from the group consisting of: -SF 5 , -OSFg, and -Si(R 15 ⁇ ) 3 are present in the compounds of formula (!), wherein at least one group is other than -Si(R 1SA ) 3 , and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyl, and -Si(CH 2 CHs) 2 CH 3 ,
- one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 1SA ) 3 is present in the compounds of formula (I) 1 and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CHs) 3 and -Si(CH 2 CHa) 2 CH 3 ,
- two groups selected from the group consisting of: -SF 5 , -OSF 5 , and ⁇ Si(R 15A ) 3 are present in the compounds of formuia (! ⁇ , and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3 and -Si(CH 2 CHs) 2 CH 3
- three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I)
- two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A )s, and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CHs) 3 and -Si(CH 2 CH 3 ) 2 CH 3 ,
- three groups selected from the group consisting of: -SF 5 , -OSFg, and -Si(R 15A ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A ) 3 , and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 J 3 , -S ⁇ (CH 3 ) 2 phenyl, and -Si(CH 2 CHs) 2 CH 3.
- one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(CH 3 ) 3 is present.
- two groups selected from the group consisting of: -SFs, -OSFs, and -Si(CH 3 ) 3 are present in the compounds of formuia (I)..
- three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(CH 3 ) 3 are present in the compounds of formula (I).
- two groups selected from the group consisting of: -SF 5 , -OSFs, and -Si(CH 3 ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(CHa) 3 ,
- three groups selected from the group consisting of: -SF 5 , -OSF 5 , and ⁇ Si(R 24 ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(CH 3 ) 3 .
- one group selected from the group consisting of: -SF 5 and -OSF 5 is present in the compounds of formula (I).
- two groups selected from the group consisting of: -SF 5 and -OSF 5 are present in the compounds of formula (I).
- three groups selected from the group consisting of: -SF 5 and -OSF 5 are present in the compounds of formula (I)
- one -SF 5 group is present in the compounds of formula (I).
- two -SFg groups are present in the compounds of formula (I).
- one -OSF 5 group is present in the compounds of formula (I).
- two -OSF 5 groups are present in the compounds of formula (I).
- three -OSF 5 groups are present in the compounds of formula (f).
- one -Si(R 15a ) 3 (wherein each R 15A is independently selected) group is present in the compounds of formula (!).
- two -Si(R 15A ⁇ 3 (wherein each R 15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and ary! (e.g., phenyl)) is present in the compounds of formula (I).
- one -Si(R 15A ) 3 (wherein each R 15A is independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (f).
- two -Si(R 15A ) 3 (wherein each R 15A is independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (I).
- one -Si(R 15A ) 3 group is present m the compounds of formula (I), and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CHa) 3 , -Si(CH 3 ) 2 phenyl, and ⁇ Si(CH 2 CH 3 ) 2 CH 3 .
- two -Si(R 15A ) 3 groups are present in the compounds of formula (I), and said -Si(R 15A ) 3 groups are independently selected from the group consisting of: -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyf, and -Si(CH 2 CH 3 ) 2 CH 3 ,.
- three -Si(R 15 ⁇ ) 3 groups are present in the compounds of formula (i), and said -Si(R i5A ) 3 groups are independently selected from the group consisting of: -Si(CH 3 ) 3 , -Si(CH 3 ) 2 pheny!, and ⁇ -Si(CH 2 CH 3 ) 2 CH 3 .
- one -Si(R 15A ) 3 group is present in the compounds of formula (I), and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3 and -Si(CH 2 CHs) 2 CH 3.
- two -St(R 15A ) 3 groups are present in the compounds of formula (I), and said -Si(R 15A ) 3 groups are independently selected from the group consisting of: -Si(CH 3 ) 3 and
- three -Si(R 15A ) 3 groups are present in the compounds of formula (I), and said -Si(R 15A ) 3 groups are independently selected from the group consisting of: -Si(CHa) 3 and -Si(CH 2 CH 3 ) 2 CH 3. .
- one -S!(R 15A )s group is present in the compounds of formula (I), and said -Si(R 1SA ) 3 group is -Si(CH 3 ) 3 .
- two -Si(R 15A )3 groups are present in the compounds of formula (!), and said -Si(R 15 ⁇ ) 3 groups are -Si(CHs) 3 ,. fn another embodiment of this invention three -Si(R 15A ) 3 groups are present in the compounds of formula (i), and said -Si(R 15A )3 groups are -Si(CH 3 J 3 ,.
- one group selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyi, and -Si(CH 2 CHs) 2 CH 3 ) is present in the compounds of formula (I).
- one group selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3 , and ⁇ Si(CH 2 CH 3 ) 2 CH 3 ) is present in the compounds of formula (I).
- one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(CHa) 3 is present in the compounds of formula (I).
- one -SF 5 group is present in the compounds of formula (I)
- one or two additional groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected) are also present in the compounds of formula (I).
- one -SF 5 group is present in the compounds of formula (I) 1 and one or two additional groups selected from the group consisting of: -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected) are also present in the compounds of formula (I).
- one -OSF 5 group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected) are also present in the compounds of formula (I).
- one -OSF 5 group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: -SF 5 and -Si(R 15A ) 3 (wherein each R 15A is independently selected) are also present in the compounds of formula (I).
- one -SF 5 group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: -SF 5 and -OSF 5 are also present in the compounds of formula (I).
- one -OSF 5 group is present in the compounds of formula (f ), and one or two additional groups selected from the group consisting of: -SF 5 and -OSF 5 are also present in the compounds of formula (I).
- one -Si(R 15A )a (wherein each R 15A is independentfy selected) group is present in the compounds of formula (i), and one or two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected) are also present in the compounds of formula (I).
- one ⁇ Si(R 15A )3 (wherein each R 15A is independently selected) group is present in the compounds of formula (I), and one or two groups selected from the group consisting of: -SF 5 and -OSF 5 are also present in the compounds of formula (I).
- At least one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present in the compounds of formula (I).
- At least one group selected from the group consisting of: -SF 5 , -OSF 5 , and ⁇ S ⁇ (R 15A ) 3 is present in the compounds of formuia (I).
- at least one group selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyi, and -Si(CH 2 CH 3 ) 2 CH 3 ) is present in the compounds of formula (I).
- At least one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(CH 3 ) 3 is present in the compounds of formula (I).
- one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently seiected) Is present in the compounds of formula (I).
- one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15 ⁇ ) 3 (wherein each R 15A is independently selected from the group consisting of aikyi (e.g., methyl and ethyi) and aryl (e.g., phenyl)) is present in the compounds of formula (I).
- Sn another embodiment of this invention one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and phenyl) is present in the compounds of formula (I).
- R 15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and phenyl) is present in the compounds of formula (I).
- one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected from the group consisting of methyl, ethyl and phenyl) is present in the compounds of formula (I).
- one group selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyl, and -Si(CH 2 CHs) 2 CH 3 ) is present in the compounds of formula (I).
- one group selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3> and -Si(CH 2 CH 3 ) 2 CH 3 ) is present in the compounds of formula (I).
- one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(CHa) 3 is present in the compounds of formula (I).
- two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
- two groups independently selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
- two groups independently selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 1SA ) 3 are present in the compounds of formula (I).
- two groups selected from the group consisting of: -SF 6 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
- two groups independently selected from the group consisting of: -SF 5 , -OSFs, -Si(CHa) 3 , -Si(CH 3 ) 2 phenyl, and -S ⁇ (CH 2 CHb) 2 CH 3 ) is present in the compounds of formula (I).
- two groups independently selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3 , and -Si(CH 2 CHa) 2 CH 3 ) are present in the compounds of formula (i).
- two groups independently selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(CH 3 ) S are present in the compounds of formula (I).
- three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (i)i.
- three groups independently selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (i)i.
- three groups independently selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
- each R 15A is independently selected from the group consisting of aikyl (e.g., methyl and ethyl) and phenyl) are present in the compounds of formula (I).
- three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -S ⁇ (R 1SA ) 3 are present in the compounds of formula (I)
- three groups independently selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3 , ⁇ Si(CH 3 )2phenyl, and -Si(CH 2 CHs) 2 CH 3 ) is present in the compounds of formula (f).
- three groups independently selected from the group consisting of: -SF 5s -OSF 5 , -Si(CH 3 ) 3 , and "Si(CH 2 CHs) 2 CH 3 ) are present in the compounds of formula (I).
- three groups independently selected from the group consisting of; -SF 5 , -OSF 51 and -Si(CH 3 )3 are present in the compounds of formula (I).
- at (east one group selected from the group consisting of: -SFs, -OSF 5 , and -S ⁇ R 15A ) 3 (wherein each R 15A is the same or different alkyi group) is present in the compounds of formula (I).
- At least one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A )3 is present in the compounds of formula (I).
- one -SF 5 group is present in the compounds of formula (I) 1 and one or two groups selected from the group consisting of: -SF 5 and -OSF5 are also present In the compounds of formula (I).
- one -OSF 5 group is present in the compounds of formula (I), and one or two groups selected from the group consisting of: -SFs and -OSF5 are also present in the compounds of formula (I).
- the cycloaikyl G moiety is unsubstitued In another embodiment of this invention, the cycloaikyl G moiety is substituted with 1 to 6 independently seiected R 21 groups.
- the cycloaikyl G moiety is a C3 to C10 cycloaikyl substituted with 1 to 6 independently selected R 21 groups.
- G is a cyclobutanone ring.
- the cycloalky! G moiety is a C3 to C-io cycloalkyi.
- said cycloalky! is selected from the group consisting of: cyclopropyj, cyciobuty ⁇ , cyclopentyl and cyclohexyl.
- said cycloaSkyl G moiety the cycloaikyi ring carbon by which said cycioalkyl moiety is bound to position (1 ) or (2) is different from the cycfoafkyl ring carbon by which said cycloalky! moiety is bound to moiety R 10 .
- cycloalkyl G moiety In another example of said cycloalkyl G moiety the cycloalky! ring is bound to position (1 ) or (2) and the R 10 moiety by the same cycloalkyl ring carbon. in another embodiment of this invention, the heterocycloalkyl G moiety is unsubstitued.
- the heterocycloalkyl G moiety is unsubstitued and said heterocycioalkyi G moiety comprises 1 to 4 heteroatoms independently setected from the group consisting of: -O-, -NR 2 -, -S-, -S(O)-, and -S(O) 2 .
- the heterocycioaikyi G moiety is substituted with 1 to 6 independently selected R 21 groups, and said heterocycloalkyl G moiety comprises 1 to 4 ring heteroatoms independently selected from the group consisting of: -O-, -NR 2 -, -S-, -S(Oh and -S(O) 2 .
- the heterocycioaikyi G moiety comprises 1 to 4 heteroatoms. In one example, said heterocycloalkyl G moiety comprises 1 to 4 heteroatoms. In another example, said heterocycloalkyl G moiety comprises 1 to 3 heteoatoms. In another example, said heterocycioaikyi G moiety comprises 1 to 2 heteroatoms. In another example, said heterocycloalkyl G moiety comprises 1 heteroatom.
- the heteroatoms in said heterocycloalkyl G moiety are independently selected from the group consisting of -O- , -NR 2 -, -S-, -S(O)-, and
- said heterocycloalkyl G moiety is bound to the R 10 moiety and position (1 ) or (2) by the same heterocycfoalky! ring atom.
- said heterocycloalkyl moiety is bound to the R 10 moiety and position (1 ) or (2) by different heterocycioaikyi ring atoms, and wherein the heterocycloalkyl ring atoms that bind the heterocycloalkyl moiety to R 10 and position (1 ) or (2) are selected from the group consisting of carbon and nitrogen.
- alkynyf G moiety is:
- the -S(O)- moiety can be: or the -S(O)- moiety can be;
- the compounds of formufa (I) do not have three consecutive nitrogen atoms in the ring.
- there are 0 to 2 additional nitrogens in the ring i.e., 0 to 2 -N(R 2 ) d - groups in the ring) provided that the nitrogens are not in consecutive ring positions.
- Ring (A) in formula (I) comprises a total of 1 to 3 nitrogen atoms (the N at position (5) and 0 to 2 -N(R 2 Jd- moieties) in the ring such that the Ring (A) does not comprise three consecutive ring nitrogens, and each d and each R 2 is independently selected.
- the moiety -G-R 10 -R 9 is bound through G to position (1).
- the moiety — G-R 10 -R 9 is bound through G to position (2).
- G is selected from the group consisting of: G is selected from the group consisting of: a direct bond (i.e., R 10 is bound directly to either G 3 or G 4 ), cycloaikyl (e.g., C 3 to Cto, and also for example, cyclopropyl, cyclobutyl, cyclopentyi and cyclohexyl, and wherein in one example the cycloalkyi ring carbon by which said cycloaikyl moiety is bound to positions (1) or (2) is different from the cycfoafky!
- a direct bond i.e., R 10 is bound directly to either G 3 or G 4
- cycloaikyl e.g., C 3 to Cto, and also for example, cyclopropyl, cyclobutyl, cyclopentyi and cyclohexyl, and wherein in one example the cycloalkyi ring carbon by which said cycloaikyl moiety is
- heterocycloalkyl (wherein said heterocycloalkyl comprises 1 to 4 heteroatoms, and in one example, 1 to 4 heteroatoms, and in another example 1 to 3 heteoatoms, and in another example 1 to 2 heteroatoms, and in another example 1 heteroatom, and wherein said heteroatoms are selected from the group consisting of -O-, -NR 2 -, -S-, -S(O)-, and -S(O)z, and wherein in one example said heterocycloalky!
- the moiety -G-R 10 -R 9 is bound through G to position (2).
- t is 1.
- t is 2.
- r is 1.
- r is 2. In another embodiment of this invention r is 3.
- G is selected from the group consisting of: a direct bond, and -N(R 2 )- (e.g., -NH-).
- G is a direct bond
- G is -N(R 2 )- (e.g., -NH-). In another embodiment of this invention G is a cycloalkyl.
- G is a heterocycloalkyl
- G is -CF 2 -. in another embodiment of this invention G is alkynyt In another embodiment of this invention G is -O-.
- G is -CR 4 (OH)-. fn another embodiment of this invention G is -CR 4 (OR 4 )-.
- G is -(CH 2 ) r N(R )-. In another embodiment of this invention G is -N(R 2 )(CH 2 )r -. in another embodiment of this invention G is - ⁇ CH 2 )2-5 -. in another embodiment of this invention G is -(C(R 4 )z) r ⁇ (wherein each R 4 is independently selected). In another embodiment of this invention G is ⁇ (CHR 4 ) 2 .5 - (wherein each R 4 is independent ⁇ selected).
- G is -S-.
- G is -S(O)-.
- G is -S(O) 2 . In another embodiment of this invention G is -C(O)-.
- G is -(CHR 3 )-. in another embodiment of this invention G 1 is -C(R 21 ) q -. in another embodiment of this invention G 1 is -N(R 2 ) d ⁇ . in another embodiment of this invention G 2 is a direct bond.
- G 2 is -C(R 21 ) q -.
- G 2 is -N(R 2 ) d -.
- G 2 is -S(O) 2 .
- G 2 is-S(O)-.
- G 2 is -C(N(R 2 )a)-.
- G 3 is -C(R 21 ) q -. In another embodiment of this invention G 3 is -N(R 2 ) d -.
- W is -C(O)-. in another embodiment of this invention W is -S(O)-.
- W is -S(O) 2 -.
- G is -C(O)-, and W is -C(O)-.
- G is --(C-G(R 6 ⁇ )- wherein each R 6 is independently selected, and W is -C(O)-.
- G is -(CHR 3 )-, and W is -C(O)-.
- G is -(CHR )-. and R is H (i.e., G is -CH 2 -), and W is -C(O)-.
- G is -(CHR 3 )-. and R 3 is -OH (i.e., G is -(CHOH)-), and W is -C(O)-.
- G is -(CHR 3 )-. and R 3 is -O-a!kyl (i.e., aikoxy, such as, for example, -OCH 3 ), and W is -C(O)-.
- G 1 is -C(R 21 Jq-, and W is -C(O)-.
- G 1 is -N(R 2 Jd-, and W is -C(O)-.
- G 2 is -C(R 21 ) q -, and W is -C(O)-.
- G is -N(R ) ⁇ j-, and W is -C(O)-.
- G 2 is -C(O)-, and W is -C(O)-.
- G 2 is -S(O)- ,and W is -C(O)-.
- G 2 is -S(O) 2 -, and W is -C(O)-.
- iInn aannootthheerr eemmbbooddiimmeenntt ooff tthhiiss iinnvveention G 2 is -C(N(R 2 J 2 )- wherein each R 2 is independently selected, and W is -C(O)-.
- G 3 is -C(R 21 ) q ⁇ , and W is -C(O)-.
- G 3 is -N(R 2 ) d -, and W is -C(O)-.
- R 21 is selected from the group consisting of: atkyf, -OR 15 , -C(O)OR 15 , -C(O)NR 15 R 16 , and alky! substituted with 1 to 5 independently selected R 22 groups (e.g., haio, such as, for example, F, Cl, and Br).
- R is selected from the group consisting of: aikyl, -OR 15 , -C(O)OR 15 , -C(O)NR 15 R 16 , and alkyf substituted with t to 5 independently selected R 22 groups (e.g., halo, such as, for example, F, CJ, and Br 5 and wherein in one example the alkyl substituted R 21 group is -CF 3 ), wherein R 15 and R 16 are independently selected from the group consisting of: H, alkyl, (R 1s ) n -arylafkyl- (wherein, for example, n is 1 , and R 1S is -OR 20 , and R 20 is alkyl (e.g., methyl), cycloalkyl (e.g., cyclobutyl), and (R 18 ) ⁇ -alkyi (e.g, n is 1, R 18 is -OR 20 , and R 20 is alkyl (e.g., halo, such as
- R 21 is selected from the group consisting of: (a) alkyl, -OR 1S (wherein R 15 is alkyl, e.g., methyl and ethyl), (b) -C(O)OR 15 (wherein R 15 is aikyi.e.g., methyl), (c) -C(O)NR 15 R 16 (wherein R 15 and R 16 are independently selected from the group consisting of: H, alkyl, (R 18 ) n -aryla!kyl- (wherein, for example, ⁇ is 1 , and R 1 ⁇ is -OR 20 , and R 20 is alkyl (e.g., methyl), cycioaikyi (e.g., cyciobutyi), and (R 18 ) n -alkyf (e.g.
- n 1
- R 18 is ⁇ OR 20 S and R 20 is alky! (e.g., methyt), and in one example, only one of R 15 and R 16 is H), and (d) atkyl substituted with 1 to 5 independently selected R 22 groups (e.g., halo, such as, for example, F, Cf, and Br, and wherein in one example the afkyl substituted R 21 group is -CF 3 ).
- R 22 groups e.g., halo, such as, for example, F, Cf, and Br, and wherein in one example the afkyl substituted R 21 group is -CF 3 ).
- R 10 is selected from the group consisting of: aryl- (e.g., phenyl), heteroaryl- (e.g., pyridyl), cycloafkyl-, cycloalkenyl, cycloalkylalkyh heterocyclyh heterocyclenyh heterocyclylalkyl-, heterocyciyalkeny!-, fused benzocycloalkyl- (i.e., benzofusedcycioaikyl-), fused benzoheterocycloalkyi- (i.e., benzofusedheterocycioaikyi-), fused heteroarylcycioalkyl- (i.e., heteroaryifusedcycloaikyl-), fused heteroarylheterocycloalkyl- (i.e., heteroarylfusedheterocycloalkyl-), fused cycloalkylaryl (i.e.,
- R 10 is selected from the group consisting of:
- X is selected from the group consisting of: O, -N(R 14 )- and -S-; and wherein each of said R 10 moieties is optionally substituted with 1-5 independently selected R 21 groups.
- R 10 is selected from the group consisting of:
- each of said R ,10 moieties is optionally substituted with 1-5 independently selected R 21 groups.
- R 10 in formula (!) is selected from the group consisting of:
- R 10 ⁇ is group 1AA, In another embodiment of this invention R 10 is group 2AA. in another embodiment of this invention R 10 is group 3AA. In another embodiment of this invention R 10 is group 4AA. In another embodiment of this invention R 10 is group 5AA, In another embodiment of this invention R 10 is group 6AA. In another embodiment of this invention R 10 is group 7AA. !n another embodiment of this invention R 10 is group 8AA. In another embodiment of this invention R 10 is group 9AA. in another embodiment of this invention R 10 is group 10AA. In another embodiment of this invention R 10 is group 11AA. In another embodiment of this invention R 10 is group 12AA. in another embodiment of this invention R 10 is group 13AA. Sn another embodiment of this invention R 10 is group 14AA.
- R 10 is group 15AA. in another embodiment of this invention R 10 is group 16AA. tn another embodiment of this invention R 10 is group 17AA. tn another embodiment of this invention R 10 is group 1 SAA. In another embodiment of this invention R 10 is group 19AA. Sn another embodiment of this invention R * ' 0 is group 20AA. in another embodiment of this invention R 10 is group 21 AA. In another embodiment of this invention R 10 is group 22AA. In another embodiment of this invention R 10 is group 23AA. tn another embodiment of this invention R 10 is group 24AA. In another embodiment of this invention R 1 ⁇ is group 25AA. in another embodiment of this invention R 10 is group 26AA. In another embodiment of this invention R 1G is group 27AA.
- R 10 is group 28AA. in another embodiment of this invention R s0 is group 29AA. in another embodiment of this invention R 10 is group 30AA. in another embodiment of this invention R 10 is group 31AA. in another embodiment of this invention R 10 is group 32AA. In another embodiment of this invention R 10 is group 33AA. in another embodiment of this invention R 10 is group 34AA. !n another embodiment of this invention R 10 is group 35AA. fn another embodiment of this invention R 10 is group 36AA. In another embodiment of this invention R 10 is group 37AA. In another embodiment of this invention R' 0 is group 38AA. In another embodiment of this invention R 10 is group 39A. in another embodiment of this invention R 10 is group 40AA. in another embodiment of this invention R 10 is group 41 AA. fn another embodiment of this invention R 10 is group 42AA. in another embodiment of this invention R 10 is aryi. in another embodiment of this invention R 10 ary! is aryl and said aryi is phenyl.
- R 10 is aryl substituted with one or more R 21 groups.
- R 10 is aryl substituted with one or more R 21 groups, and said aryi is phenyl, i.e., said R 10 group is phenyl substituted with one or more R 21 groups.
- R 10 is phenyl substituted with one or more R 21 groups, and each R 21 group is the same or different -OR 15 group.
- R 10 is phenyl substituted with one or more R 21 groups, and each R 21 group is the same or different -OR 15 group, and said R 15 is alky], and each alky! is independently seiected.
- R 10 is phenyl substituted with one R 21 group, and said R 21 group is -OR 15 , and said R 15 is alky!.
- R 10 is phenyl substituted with one R 21 group, and said R 21 group is -OR 15 , and said R 15 is alkyl, and said alkyi is methyl.
- R 10 is phenyl substituted with one or more (e.g., one or two, or one) independently selected R 21 halo groups.
- R 10 is phenyl substituted with one R 21 group, and said R 21 group is halo.
- R 10 is phenyl substituted with one R 21 group, and said R 21 group is F.
- R 10 is phenyl substituted with one R 21 group and said R 21 is an -OR 15 group, and R 15 is an ⁇ R 18 ) n aiky! group, and R 1S is halo, and n is 1 to 3, and each ha ⁇ o is independently selected.
- R 10 is phenyl substituted with one R 21 group and said R 21 is an -OR 15 group, and R 15 is an (R 1 ⁇ ) n alkyl group, and R 18 is F, and n is 3.
- R 10 is phenyl substituted with one R 21 group and said R 21 is an -OR 15 group, and R 15 is an (R 18 ) n alkyl group, and R 18 is F, and n is 3, and the alkyl is methyl (i.e., the R 21 substituent is -OCF 3 ). in another embodiment of this invention R 10 is heteroaryi.
- R 10 is heteroaryi substituted with one or more R 21 groups.
- R 9 is selected from the group consisting of:
- R 10 is selected from the group consisting of 1AA to 42AA 1 and R 9 is selected from the group consiting of 1gg to
- R 10 is selected from the group consisting of 1AA to 42AA, and R 9 is 2gg.
- R 9 -R 10 - moiety include, but are not limited to:
- R -R ⁇ 10 - moiety is 1 bb. in another embodiment the R 9 -R 10 - moiety is 2bb. ⁇ n another embodiment the R 9 -R 10 - moiety is 3bb. Jn another embodiment the R -R ⁇ »10 - moiety is 4bb. In another embodiment the R -R 10 - moiety is
- R -R j10 - moiety is 6bb. In another embodiment the R 9 -R 10 - moiety is 7bb. in another embodiment the R 9 -R 10 - moiety is 8bb. in another embodiment the R 9 -R 10 - moiety is 9bb. In another embodiment the R 9 -R 10 - moiety is tObb. In another embodiment the R j9- aRlO- moiety is 11 bb. In another embodiment the R -.9 - »R10 - moiety is 12bb. In another embodiment the R ,9 - rRjtO- moiety is 13bb. In another embodiment the R -R ,10 - moiety is 14bb. In another embodiment the R -R 10-
- R -R - moiety is 16bb.
- R >9- cR-v 10- moiety is 17bb.
- R 9- O R1 ⁇ - moiety is
- R -R »10 - moiety is 19bb.
- the R 9 -R 10 - moiety is 20bb.
- the R 9 -R 10 - moiety is 21 bb.
- the R 9 -R 10 - moiety is 22bb.
- the R 9 ⁇ R 10 - moiety is 23bb.
- the R 9 -R 10 - moiety is 24bb.
- the R 9 -R 10 - moiety is 25bb.
- the R 9 -R 10 - moiety is 26bb. in another embodiment the R 9 -R 10 - moiety is 27bb.
- the R 9 -R 10 - moiety is 28bb, In another embodiment the R 9 -R 10 - moiety is 29bb. In another embodiment the R 3 -R t0 - moiety is 30bb. In another embodiment the R 9 -R 1G - moiety is 31 bb. In another embodiment the R 9 -R 10 - moiety is 32bb. In another embodiment the R 9 -R 10 - moiety is 33bb. In another embodiment the R 9 -R 10 - moiety is 34bb. in another embodiment the R 9 -R 10 - moiety is 35bb. fn another embodiment the R 9 -R 10 - moiety is 36bb.
- R 9 -R 10 - moiety is 37bb. In another embodiment the R 9 -R 10 - moiety is 38bb. In another embodiment the R 9 -R 10 - moiety is 39bb. in another embodiment the R 9 -R 1Q - moiety is 40bb.
- R 9 is heteroaryl. In another embodiment of this invention R 9 is heteroaryl substituted with one or more R groups.
- R 9 is heteroaryl substituted with one or more R 21 groups, and said R 21 groups are the same or different alkyl.
- R 9 is heteroaryl substituted with one R 21 group, and said R 21 is aikyl.
- R 9 is heteroaryl substituted with one R 21 group, and said R 21 is alkyi, and said alkyl is methyl.
- R 9 is and said heteroaryl is imidazoyl.
- R a is imidaz ⁇ ly! substituted with one or more R 21 groups.
- R 9 is tmidazolyl substituted with one or more R 21 groups, and said R 21 groups are the same or different alkyl.
- R 9 is imidazolyl substituted with one R 21 group, and said R Z1 is alkyl. Jn another embodiment of this invention R 9 is imidazolyl substituted with one
- R 21 group and said R 21 is alkyl, and said aikyl is methyi.
- R 10 is selected from the group consisting of aryl and aryl substituted with one or more R 2 ⁇ groups, and said R 9 group is selected from the group consisting of heteroaryl and heteroaryi substituted with one or more R z1 groups, wherein each R 21 is independently setected.
- R 10 is phenyl substituted with one or more R 21 groups, and said R 9 is imidazoiy! substituted with one or more R 21 groups, wherein each R 21 is independently selected.
- R 10 is phenyi substituted with one R 21 group, and said R 9 is imidazolyi substituted with one R 21 group, wherein each R 21 is independently selected.
- R 10 Is phenyi substituted with one or more independently selected -OR 15 groups, and said R 9 is imidazolyl substituted with one or more independently selected alky! groups.
- R 10 is phenyl substituted with one or more independently selected -OR 15 groups, and said R 9 is imidazolyi substituted with oonnee oorr mmoorree iinnddeeppeenndently selected alkyl groups, and each R 15 is the same or different alky! group.
- R 10 is phenyi substituted with one -OR 15 group, and said R 9 is imidazoiy! substituted with one alky! group.
- R 10 Ss phenyl substituted with one -OR 15 group, and said R 9 is imidazolyt substituted with one alkyl group, and R 15 is alkyi, and wherein the R 15 alkyl group, and the alkyl group on said imidazolyl are independently selected.
- R 10 J s phenyi substituted with one -OR 15 group, and said R 9 is imidazolyt substituted with one methyl group, and R 15 is methyl, and wherein the R 15 aikyl group, and the afkyl group on said imidazoiy! are independently selected.
- R 9 -R 10 - moiety is:
- the R 9 ⁇ R 10 - moiety is: in another embodiment of this invention the R y -R »1 ⁇ 0 u - moiety is in another embodiment of this invention the R 9- rRj 10- moiety is in another embodiment of this invention the R ,9 s -R »1'0 ⁇ - moiety is
- R 1A is an unsubstituted or substituted aryl (e.g., phenyl) group.
- R 1A is an unsubstituted aryl (e.g., phenyl) or aryl (e.g., phenyl) substituted with one or more independently selected R 21 groups.
- R 1 ⁇ is an aryi group.
- R 1A is an aryl group, and said aryl group is substituted with one or more independently selected R 21 groups.
- R 1 ⁇ is an aryl group, and said aryl group is substituted with 1 to 3 independently selected R 21 groups.
- R 1A is an aryl group, and said aryl group is substituted with one or more R 21 groups, and each R 21 group is the same or different haio.
- R 1A is an aryl group, and said aryl group is substituted with 1 to 3 R 21 groups, and each R 21 group is the same or different halo.
- R 1A is an aryl group, and said aryl group is substituted with three R 21 hafo groups, and each R 21 group is the same or different haio.
- R 1A is an aryl group, and said aryl group is substituted with two R 21 haio groups, and each R 21 group is the same or different halo.
- R 1A is an aryl group, and said aryl group is substituted with one R 21 halo group.
- R 1A is an aryl group, and said aryl group is substituted with one R 21 halo groups, and each R 21 group is the same or different halo.
- R 1 ⁇ is an aryl group, and said aryl group is substituted with one F (i.e., said aryl is substituted with one R 21 group, and said R 21 group is halo, and said halo is F).
- R 1A is an aryl group, and said aryl group is substituted with two F atoms (i.e., said aryl is substituted with two R 21 groups, and said R 21 groups are halo, and said halo is F).
- R 1A is an aryS group, and said aryl group is substituted with three F atoms (i.e., said aryl is substituted with three R 21 groups, and said R 21 groups are halo, and said halo is F).
- R 1A is phenyl.
- R 1 ⁇ is phenyl, and said phenyl is substituted with one or more independently selected R 21 groups.
- R 1A is phenyl, and said phenyl is substituted with 1 to 3 independently selected R 21 groups.
- R 1A is a phenyl, and said phenyl is substituted with one or more R 21 groups, and each R 21 group is the same or different halo.
- R 1A is phenyl, and said phenyl is substituted with 1 to 3 R 21 groups, and each R 21 group is the same or different halo.
- R 1A is phenyl, and said phenyl is substituted with three R 21 halo groups, and each R 21 group is the same or different halo.
- R 1A is phenyl, and said phenyl is substituted with two R 21 halo groups, and each R 21 group is the same or different halo.
- R 1A is phenyl, and said phenyl is substituted with one R 21 halo group. fn another embodiment of this invention R 1A is phenyl, and said phenyl is substituted with one R 21 halo group. In another embodiment of this invention R 1A is phenyl, and said phenyl is substituted with one F (i.e., said aryl is substituted with one R group, and said R group is halo, and said halo is F).
- R ,1A i ⁇ s phenyl and said phenyl is substituted with two F atoms (i.e., said ary! is substituted with two R 21 groups, and said R 21 groups are halo, and said halo is F).
- R 1A is phenyl, and said phenyl is substituted with three F atoms (i.e,, said aryl is substituted with three R 21 groups, and said R 21 groups are halo, and said halo is F).
- R 1A is selected from the group consisting of:
- R 4 1A is, selected from the group consisting of: in another embodiment of this invention R >1A i ⁇ s selected from the group consisting of:
- R 1A is:
- R 1A is
- R 1A ⁇ is:
- R 1A is:
- R i1A is:
- R 1A • is , in another embodiment of this invention R 1A is: .
- R 1A is: in another embodiment of this invention R 1A is:
- R 1A • is: _
- R IA is in another embodiment of this invention R ,1A i .s:
- R 1A is:
- R 1A is
- R 1A i ;s, : !n another embodiment of this invention R IA - is:
- R 1A is:
- R 1A is:
- R is phenyl substituted with 1-3 halos independently selected from the group consisting of F and Ct. In one example said phenyl is substituted with one F and one Cl.
- R 1A is aryl (e.g., phenyl) substituted with 1 to 3 independent ⁇ y selected R 21 moieties wherein at (east one R 21 moiety is selected from the group consisting of -SF 5 , -OSF 5 and -Si(R 15A ) 3 (and in one example each R 1SA is the same or different alkyl, and in another example the -Si(R 24 ) 3 group is -Si(CH 3 ) 3 or -Si(CH 2 CH 3 ⁇ CH 3 , and in another example the -Si(R 24 ) 3 group is -Si(CH 3 )S).
- R 1A is aryl (e.g., phenyl) substituted with 1 to 3 independently selected R 21 moieties wherein at least one R 21 moiety is selected from the group consisting of -SF 5 and -OSF 5 .
- R 1A is aryi (e.g., phenyl) substituted with 1 to 3 R 21 moieties independently selected from the group consisting of: halo (e.g., F), -SF 5 , -OSF 5 and -Si(R 15A ) 3 (and in one example each R 15A is the same or different alkyl, and in another example the -Si(R 1SA ) 3 group is -Si(CH 3 ) 3 or -Si(CH2CH 3 )2CH 3 , and in another example the -Si(R t5A ) 3 group is -Si(CH 3 )S), and wherein at least one R 21 moiety is selected from the group consisting of -SF 5 , -OSFg and -Si(R 15A )s (and in one example each R 15A is the same or different alkyl, and in another example the -Si(R 15A ) 3 group is -Si(CH 3 )
- R 1A is aryl (e.g., phenyl) substituted with 1 to 3 R 21 moieties independently selected from the group consisting of: halo (e.g., F), -SF 5 and -OSF 5 , and wherein at least one R 21 moiety is selected from the group consisting of -SF 5 and -OSF 5 ,
- R 1A is aryl (e.g., phenyl) substituted with 1 to 3 independently selected R 21 moieties wherein at least one R 21 moiety is selected from the group consisting of -SF 5 , -OSF 5 and -Si(R 15A ) 3 (and in one example each R 15A is the same or different alky), and in another example the ⁇ Si(R 15A ) 3 group is -Si(CH 3 ) 3 or -Si(CH 2 CHa) 2 CH 3 , and in another example the -Si(R 15A ) 3 group is -Si(CH 3
- R 1A is phenyl substituted with 1-3 R 2t groups independently selected from the group consisting of hafos, -SF 5 and -OSF 5 , wherein at least one R 21 group is -SF 5 Or-OSF 5 .
- H 1A is phenyl substituted with 1-3 R 21 groups independently selected from the group consisting of halos, -SF 5 and -OSF 5 , wherein at least one R 21 group is -SF 5 or -OSF 5 .
- R 1A is phenyl substituted with 1-3 R 21 groups independently selected from the group consisting of F, Cl 1 -SFs and -OSF 5 .
- R 1A is phenyl substituted with 1-3 R 21 groups independently selected from the group consisting of -SF 5 and -OSFs. In another embodiment, R 1A is phenyl substituted with 1-3 R 21 groups independently selected from the group consisting of F, -SF 5 and -OSF 5 , wherein at least one R 21 group is -SF 5 or -OSF 5 . in another embodiment, R 1A is phenyl substituted with one -SFs group.
- R fA is phenyl substituted with two -SF 5 groups
- R 1A is phenyl substituted with three -SF 5 groups.
- R 1A is phenyl substituted with one -OSF 5 group. in another embodiment, R 1A is phenyl substituted with two -OSF 5 groups.
- R 1A is phenyl substituted with three -OSF 5 groups.
- R 1A is phenyl substituted with 1 F
- R 1A is phenyl substituted with 1 F, and also substituted with 1 to 2 groups independently selected from the group consisting of -SF 5 and -OSF 5 .
- R 1A is phenyl substituted with 2 F.
- R 1A is phenyl substituted with 3F.
- R 10 is selected from the group consisting of aryl and aryl substituted with one or more R 21 groups, and said R ⁇ group is selected from the group consisting of heteroaryl and heteroaryl substituted with one or more R 21 groups, and wherein each R 21 is independently selected,
- R 1A is an aryl group, or R 1A is an aryl group substituted with 1 to 3 independently selected R 21 groups
- R 10 is selected from the group consisting of aryl and aryf substituted with one or more independently selected R 21 groups
- R 9 is selected from the group consisting of heteroaryl and heteroaryl substituted with one or more independently selected R 21 groups.
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 independently selected R 21 groups
- R 10 is selected from the group consisting of aryi and aryi substituted with one or more independently selected R 21 groups
- R 9 is selected from the group consisting of heteroaryl and heteroaryl substituted with one or more independently selected R 21 groups.
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 independently selected R 21 groups
- R 10 is selected from the group consisting of phenyl and phenyl substituted with one or more independently selected R 21 groups
- R 9 is selected from the group consisting of imidazolyl and imidazolyl substituted with one or more independently selected R 21 groups.
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 independently selected R 21 halo groups
- R 10 is selected from the group consisting of phenyl and phenyl substituted with one or more independently selected -OR 15 groups
- R 9 is selected from the group consisting of imidazolyl and imidazolyl substituted with one or more independently selected alkyf groups groups.
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 2 independently selected R 21 halo groups
- R 10 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR 15 groups, wherein R 15 is alkyl
- R 9 is selected from the group consisting of imidazofyl and tm ⁇ dazolyl substituted with one or two independently selected alky! groups groups.
- R 1A is phenyl, or R 1A is phenyl substituted with 1 R 21 halo group, and (5) R m is seiected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR 15 groups, wherein R 15 is alkyl, and (c) R 9 is selected from the group consisting of imidazoiyl and imidazolyi substituted with one or two independently selected alkyl groups groups.
- R 1 ⁇ is phenyl, or R 1A is phenyl, substituted with 1 to 3 F (i.e., R 1A is phenyl substituted with 1 to 3 R 21 groups, and said R 21 groups are halo, and said halo is F), and
- R 1 ⁇ is seiected from the group consisting of phenyl and phenyl substituted with one or two independently selected - OR 15 groups, wherein R 15 is methyl
- R 9 is selected from the group consisting of imidazolyJ and smidazoiy! substituted with one or two independently selected methyl groups groups.
- R 1A is phenyl, or R 1A is phenyl, substituted with 1 to 2 F (i.e., R 1A is phenyl substituted with 1 to 2 R 21 groups, and said R 21 groups are halo, and said halo is F) 1 and
- R 10 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected - OR 15 groups, wherein R 15 is methyl
- R 9 is selected from the group consisting of imidazolyi and imidazolyi substituted with one or two independently selected methyl groups groups.
- R 1A is phenyl, or R 1A is phenyl, substituted with 1 F (i.e., R 1A is phenyl substituted with 1 R 21 group, and said R 21 group is halo, and said halo is F), and
- R 10 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR 15 groups, wherein R 15 is methyl, and
- R 9 is seiected from the group consisting of imidazolyi and imidazolyi substituted with one or two independently selected methyl groups groups.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 5 1A i .s selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R i1A is selected from the group consisting of:
- R *1A i -s selected from the group consisting of:
- R >1A i ⁇ s selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is phenyl, or R ,1A is phenyl substituted with 1 to 3 independently selected R 21 halo groups
- R ⁇ 0 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR 15 groups, wherein R 15 is alkyl
- R 9 is selected from the group consisting of imidazolyi and imidazofy! substituted with one or two independently selected alkyi groups groups.
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 independently selected R 21 hafo groups
- R 10 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR 15 groups, wherein R 15 is aikyl
- R ⁇ is selected from the group consisting of imidazolyl and imidazofyl substituted with one or two independently selected alkyl groups groups
- G is -C(O)-
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 independently selected R 21 halo groups
- R 10 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR 15 groups, wherein R 15 is alkyl
- R 9 is sefected from the group consisting of imidazolyl and irnidazolyt substituted with one or two independently selected alkyl groups groups
- R 1A is phenyi, or R 1A is phenyl substituted with 1 to 3 independently selected R 21 halo groups
- R 10 is selected from the group consisting of phenyl and phenyl substituted with one or two independent ⁇ selected -OR 15 groups, wherein R 15 is afkyl
- R 9 is selected from the group consisting of imidazolyl and imidazoly! substituted with one or two independently selected alkyl groups groups
- R 1A is pheny
- R 1A is phenyl substituted with 1 to 3 independently selected R 21 halo groups
- R 10 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR 15 groups, wherein R 15 is alkyl
- R 9 is selected from the group consisting of imidazolyt and imidazoiyl substituted with one or two independently selected aikyl groups groups
- G is -CHR 3 -;
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 independently selected R 21 halo groups
- R 10 is selected from the group consisting of phenyi and phenyl substituted with one or two independently selected -OR 15 groups, wherein R 15 is alky!
- R 9 is selected from the group consisting of imidazolyl and imidazolyl substituted with one or two independently selected alky ⁇ groups groups
- G is -CHz-.
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 Independently selected R 21 halo groups
- R 10 is selected from the group consisting of phenyl and pheny! substituted with one or two independently selected -OR 15 groups, wherein R 15 is alkyl
- R 9 is selected from the group consisting of imidazolyl and imidazolyi substituted with one or two independently seiected alkyt groups groups
- G is -(CHOH)-.
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 F atoms, and (b) R 10 is phenyl substituted with one-OR 15 group, wherein R 15 is methyl, and (c) R 9 is selected from the group consisting of imidazolyl and imidazolyi substituted with one methyl group.
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 F atoms, and (b) R 10 is phenyl substituted with one-OR 15 group, wherein R 16 is methyl, and (c) R 9 is seiected from the group consisting of imidazoiyl and imidazolyl substituted with one methyl group, and (d) G is -C(O)-.
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 F atoms
- R 10 is phenyl substituted with one-OR 15 group, wherein R 15 is methyl
- R 9 is selected from the group consisting of im/dazoJyJ and imidazolyl substituted with one methyl group
- G is -CHR 3 -.
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 F atoms, and (b) R f0 is phenyl substituted with one-OR 15 group, wherein R 15 is methyl, and (c) R 9 is selected from the group consisting of imidazolyl and imidazolyl substituted with one methyl group, and (d) G is -CH 2 -.
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 F atoms, and (b) R 10 is phenyl substituted with one-OR 15 group, wherein R 15 is methyl, and (c) R 9 is selected from the group consisting of imidazolyf and imidazofyi substituted with one methyl group, and (d) G is -(CHOH)-.
- R 1A is selected from the group consisting of: wherein the R 9 -R 10 - moiety is:
- R *1 1 A A - is selected from the group consisting of:
- R 9 9 -R ⁇ VI ⁇ O ⁇ - moiety is:
- G is -C(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R ,1 i A / ⁇ - is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -NHC(O ⁇ .
- R 1A is selected from the group consisting of.
- R 9 -R 10 - moiety is:
- R > 1' ⁇ A i ⁇ s selected from the group consisting of;
- R 9 -R t0 - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1 ⁇ is selected from the group consisting of: q in wherein the R -R - moiety is;
- R »1A i.s selected from the group consisting of:
- R 9 -R 10 ⁇ moiety is:
- G is -C(O)-.
- R 1A is selected from the group consisting of:
- R 9 ⁇ R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -NHC(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R ⁇ -R 10 - moiety is
- R i1A is selected from the group consisting of:
- R 1A is selected from the group consisting of:
- R 9 ⁇ R 10 - moiety is:
- G is -C(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R ⁇ -R 10 - moiety is:
- G is -CHR'-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 1A is selected from the group consisting of:
- R 9 ⁇ R 10 - moiety is:
- G is -C(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -(C ⁇ NR 2 >.
- R 1A is selected from the group consisting of:
- G is -NHC(Oh-
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R ,1A i .s selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R ⁇ -R 10 - moiety is:
- R -R ,10- moiety is:
- G is -C(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -(C-NR 2 )-.
- R 1A is selected from the group consisting of:
- R' is selected from the group consisting of:
- R ⁇ -R 1G - moiety is:
- G is -CHR 3 -.
- R 1A is selected from the group consisting of:
- R 9-R D 10 - moiety is:
- R ,1A is selected from the group consisting of: wherein the R 9 -R 10 - moiety is:
- R 1A i s, phenyl, or R j1A is phenyl substituted with 1 to 3 independently selected R 21 halo groups
- R 10 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR 15 groups, wherein R 15 is alky!
- R 9 is selected from the group consisting of imidazoiyl and imidazolyl substituted with one or two independently selected alkyi groups groups
- G is selected from the group consisting of-NH-, -O-, -S-, -S(O)-, -S(O) 2 - and a direct bond
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 F atoms
- R 10 is phenyl substituted with one-OR 15 group, wherein R 15 is methyl
- R 9 is selected from the group consisting of imidazolyl and imidazolyl substituted with one methyl group
- G is selected from the group consisting of-NH-, -O-, -S-, -S(O)-, -S(O) 2 - and a direct bond.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -O-, -S-, -S(Oy, -S(O ⁇ 2 - and a direct bond.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -O ⁇ , -S-, -S(O)-, -S(O) 2 - and a direct bond.
- G is selected from the group consisting of -NH-, -O-, -S-, -S(O)-, -S(O) 2 - and a direct bond.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -O- , -S-, -S(O)-, -S(O) 2 - and a direct bond.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -O-, -S-, -S(O)-, -S(O) 2 - and a direct bond.
- R 1A • is phenyt, or R i1A ; i,s phenyl substituted with 1 to 3 F atoms
- R 10 is phenyl substituted with one-OR 15 group, wherein R 15 is methyl
- R 9 is selected from the group consisting of imidazolyl and imidazolyl substituted with one methyl group
- G is selected from the group consisting Of -NH-, -O- , -S-, -S(O) ⁇ , -S(O) 2 - and a direct bond
- W is -C(O)-.
- R 1 ⁇ is selected from the group consisting of:
- R -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -O- , -S-, -S(O)-, -S(O ⁇ - and a direct bond, and W is -C(O)-.
- R 1 ⁇ is selected from the group consisting of: wherein the R 9 -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -Cs -S-, -S(O)-, -S(O) 2 - and a direct bond, and W is -C(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -O- , -S-, -S(O)-, -S(O) 2 - and a direct bond, and W is -C(O)-.
- R 1A is selected from the group consisting of: wherein the R 9 -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -O-, -S-, -S(O)-, -S(O) 2 ⁇ and a direct bond, and W is -C(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -O- , -S-, -S(O)-, -3(0) 2 - and a direct bond, and W is -C(O)-.
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 F atoms, and
- R 10 is phenyl substituted with one-OR 15 group, wherein R 15 is methyl
- R 9 is selected from the group consisting of imidazoly!
- G is selected from the group consisting of -NH-, -O-, -S-, -S(O)-, -S(O) 2 - and a direct bond, and (e) W is -S(O)».
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -0-, -S-, -S(O)-, -S(O) 2 - and a direct bond, and W is -S(O)-.
- R 1A is selected from the group consisting of:
- G is selected from the group consisting of -NH-, -O- , -S-, -S(O)-, -S(O) 2 - and a direct bond, and W is -S(O)-.
- R 1A is selected from the group consisting of: , and wherein the R -R - moiety is:
- G is selected from the group consisting of -NH-, -O-, -S-, -S(O)-, -S(O)2 ⁇ and a direct bond, and W is -S(O)-.
- R 1A is selected from the group consisting of:
- R ⁇ -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -O-, -S-, -S(O)-, -S(O ⁇ 2 ⁇ and a direct bond, and W is -S(O)-.
- R 1 ⁇ is selected from the group consisting of: , and wherein the R 9 -R t0 - moiety is:
- G is selected from the group consisting of -NH-, -O-, -S-, -S(O)-, -S ⁇ 0)2- and a direct bond, and W is -S(O)-.
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 F atoms
- R 10 is phenyl substituted with one-OR ,15 group, wherein R 15 is methyl
- R 9 is selected from the group consisting of Imidazolyl and imidazoiyl substituted with on® methyl group
- G is selected from the group consisting of -NH-, -O-, -S-, -S(O)-, -S(O) 2 - and a direct bond
- W is -S(O) 2 -.
- R 1A is selected from the group consisting of:
- R a -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -O-, -S-, -S(O)-, -S(OV and a direct bond, and W is -S(O) 2 -.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -O-, -S-, -S(O)-, -S(OV and a direct bond, and W is -S(O) 2 -.
- R 1A is selected from the group consisting of:
- R ⁇ -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -0-, -S-, -S(O)-, -S(OV and a direct bond, and W is -S(O) 2 -,
- R 9 -R 10 - moiety is:
- G is seJected from the group consisting of -NH-, -O-, -S-, -S(O)-, -S ⁇ 0> 2 - and a direct bond, and W iS -S(O) 2 -.
- R 1A is selected from the group consisting of:
- R ⁇ -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -O-, -S-, -S(O)-, -S(O) 2 - and a direct bond, and W is -S(O) 2 -.
- R 1A is selected from the group consisting of:
- R -R - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is selected from the group consisting of -NH-, -0-, -S-, -S(O)-, -S(Q) 2 - and a direct bond, and W is -C( ⁇ NR 2 )-. ,1A .
- R 1A is selected from the group consisting of:
- R ⁇ -R 10 - moiety is:
- R 1A is selected from the group consisting of: wherein the R ⁇ -R tQ - moiety is:
- R IA i is phenyl substituted with 1 to 3 F atoms
- R 10 is phenyl substituted with one-OR 15 group, wherein R t5 is methyl
- R 9 is selected from the group consisting of imidazolyl and imidazolyl substituted with one methyl group
- G is -C(O)-
- W is -C(O)-.
- R 9 -R 10 - moiety is:
- R »1A is selected from the group consisting of:
- G is -C(O)-
- W is -C(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R t0 - moiety is:
- G is -C(O)-
- W is -C(O)-.
- R 1A is selected from the group consisting of: wherein the R 9 -R 10 - moiety is:
- G is -C(O)-
- W is -C(O)-.
- R 1A is selected from the group consisting of:
- G is -C(O)-
- W is -C(O)-.
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 F atoms, and (b) R 10 is phenyl substituted with one ⁇ OR 15 group, wherein R 15 is methyt, and (c) R 9 is selected from the group consisting of imidazoiy! and imidazoiyi substituted with one methyl group, and (d) G is -C(O)-, and (e) W is -S(OK
- R is selected from the group consisting of: wherein the R ,9 - D R1 1 G - moiety is:
- G is -C(O)-, and W is -S(O)-.
- R 1A is selected from the group consisting of:
- R s -R 10 - moiety is
- R 1A is selected from the group consisting of:
- R v -R 10 - moiety is:
- G is -C(Oh and W is -S(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -C(O)-, and W is -S(O)-.
- R ⁇ -R 10 - moiety is:
- G is -C(O)-, and W is -S(O)-.
- R 1A is phenyl, or R tA is phenyl substituted with 1 to 3 F atoms
- R 10 is phenyl substituted with one- ⁇ OR 15 group, wherein R 15 is methyl
- R 9 is selected from the group consisting of imidazoiyi and imidazolyl substituted with one methyl group
- G is -C(O)-
- W is -S(O) 2 -.
- R 1A is sefected from the group consisting of:
- G is -C(O)-, and W is -S(O) 2 -.
- R 1A is sefected from the group consisting of:
- G is -C(Oh and W is -S(O) 2 -.
- R 1A is selected from the group consisting of:
- R 9- rR 10- moiety
- G is -C(O)-, and W is -S(O) 2 -.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -C(O)-, and W is -S(O) 2 -,
- R j1 ⁇ n A i -s selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -C(O)-, and W is -S(O) 2 -.
- R 1A is phenyi, or R 1A is phenyl substituted with 1 to 3 F atoms
- R 10 is phenyl substituted with one-OR 15 group, wherein R 15 is methyl
- R 9 is selected from the group consisting of imidazoiyl and fmidazoiyl substituted with one methyl group
- G is -C(O)-
- W is -C( ⁇ NR 2 )-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is: ⁇ and
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -C(O)-
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -C(O)-
- W is -C( ⁇ NR 2 ⁇ -.
- R 9 -R 1Q - moiety is:
- G is -C(O)-
- R i1 I ⁇ A i ⁇ s selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is phenyl, or R i1A . is phenyl substituted with 1 to 3 F atoms
- R 10 is phenyl substituted with one-OR 15 group, wherein R" is methyl
- R ⁇ 9 is, selected from the group consisting of imidazoiyi and imidazoiyl substituted with one methyl group
- W is -C(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of: wherein the R s -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 F atoms
- R 10 is phenyl substituted with one-OR 15 group, wherein R 15 is methyl
- R 9 is selected from the group consisting of imidazoiyf and imidazoiyl substituted with one methyl group
- W is -S(O)-.
- R 1 ⁇ is selected from the group consisting of:
- R 9- rR-,10- moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 1Q - moiety is:
- R 1 ⁇ is selected from the group consisting of:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -(C-NR 2 )-, and W is -S(O) 2 -.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- W is -S(O) 2 -.
- R 1A is selected from the group consisting of:
- R -R - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 F atoms
- R 10 is phenyl substituted with one-OR 15 group, wherein R 15 is methyl
- R 9 is selected from the group consisting of imidazolyi and tmidazotyi substituted with one methyl group
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of: wherein the R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of;
- R -R - moiety is:
- R 1A is selected from the group consisting of;
- R 1A is phenyl, or R >1A is phenyl substituted with 1 to 3 F atoms
- R 10 is phenyl substituted with one-OR 15 group, wherein R 15 is methyi
- R 9 is selected from the group consisting of imJdazolyl and imidazolyl substituted with one methyl group
- G is -NHC(OH and (e) W is -C(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 ⁇ moiety is:
- G is -NHC(Oy 1 and W is -C(O ⁇ .
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -NHC(OK and W is -C(O)-.
- R 1A is selected from the group consisting of:
- R 9 ⁇ R 10 - moiety is:
- G is -NHC(OK and W is -C(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 ⁇ moiety is:
- G is -NHC(Oh, and W is -C(O)-.
- R tA is phenyl, or R 1A is phenyl substituted with 1 to 3 F atoms, and (b) R 10 is phenyf substituted with one-OR 15 group, wherein R 15 is methyl, and (c) R 9 is selected from the group consisting of imidazofyl and imtdazofy! substituted with one methyl group, and (d) G is -NHC(O)-, and (e) W is -S(O)-,
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -NHC(OH and W is -S(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -NHC(OH and W is -S(O)-.
- R 1A is selected from the group consisting of;
- R 9 -R 10 - moiety is: , and wherein the R 9 -R 10 - moiety is: , and G is -NHC(OK and W is -S(O)-.
- G is -NHC(OK and W is -S(O)-.
- R 1A is selected from the group consisting of:
- R 9- a RW- moiety is:
- G is -NHC(OK. and W is -S(O)-.
- R 1A i .s, phenyl, or R »1A is phenyl substituted with 1 to 3 F atoms
- R 10 is phenyl substituted with one-OR 15 group, wherein R 15 is methyl
- R 9 is selected from the group consisting of imidazolyl and imidazolyi substituted with one methyl group
- W is -S(O) 2 -.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -NHC(Oh, and W is -S(O) 2 -.
- a ⁇ - is. selected from the group consisting of: wherein the R 9 -R 10 - moiety is:
- G is -NHC(O)-, and W is -S(O) 2 -.
- R 1A is selected from the group consisting of;
- R 9 -R 10 - moiety is:
- G is -NHC(O)-, and W is -S(O) 2 -.
- R 1A is selected from the group consisting of:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -NHC(OK and W is -C(-NFr)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R ,1 i A ⁇ - is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is phenyl, or R 1A is phenyl substituted with 1 to 3 F atoms
- R 10 is phenyl substituted with one-OR 15 group, wherein R 15 is methyf
- R 9 is selected from the group consisting of imtdazolyl and imidazoly! substituted with one methyf group
- G is -CHR 3 - (e.g. -CHOH) 1 and (e) W is -C(O)-.
- R 1A is selected from the group consisting of:
- R ' -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 1A is selected from the group consisting of:
- R -R ⁇ > ⁇ o - moiety is:
- G is -CHR 3 - (e.g., -CHOH) 1 and W is -C(O)-.
- R 1A is selected from the group consisting of:
- R -R - moiety is:
- G is -CHR 3 - (e.g., -CHOH), and W is -C(O)-.
- R 1A is selected from the group consisting of.
- R 9 -R 10 - moiety is:
- G is -CHR J - (e.g., -CHOH), and W is -C(O)-.
- R 1A is phenyl, or R 1 ⁇ is phenyl
- R is phenyl substituted with one-OR group, wherein R 15 is methyt
- R 9 is selected from the group consisting of imidazolyl and imidazofyl substituted with one methyl group
- G is -CHR 3 - (e.g., -CHOH)
- W is -S(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -CHR 3 - (e.g., -CHOH) 1 and W is -S(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -CHR 3 - (e.g., -CHOH), and W is -S(O)-.
- G is -CHR 3 - (e.g., -CHOH), and W is -S(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -CHR 3 - (e.g., -CHOH), and W is -S(O)-.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -CHR 3 - (e.g., -CHOH), and W is -S(O)-.
- R 1A is phenyl, or R ⁇ 1 A ⁇ is phenyl substituted with 1 to 3 F atoms
- R 10 is phenyl substituted with one-OR 15 group, wherein R 15 is methyl
- R 9 is selected from the group consisting of ⁇ midazotyi and imidazolyt substituted with one methyl group
- G is -CHR 3 - (e.g., -CHOH)
- W is -S(O) 2 -.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R -R - moiety is:
- G is -CHR 3 - (e.g., -CHOH) 1 and W is -S(O) 2 -.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -CHR - (e.g., -CHOH), and W is -S(O) 2 -.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -CHR 3 - (e.g., -CHOH), and W is -S(O) 2 --
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -CHR 3 - (e.g., -CHOH) 1 and W is -S(O) 2 -.
- R 1A is, phenyf, or R »1A is phenyl substituted with 1 to 3 F atoms
- R 10 is phenyl substituted with one-OR ,15 group, wherein R 15 is methyl
- R 9 is selected from the group consisting of imidazolyi and imidazoiyf substituted with one methyl group
- G is -CHR 3 - (e.g., -CHOH)
- R 1A is selected from the group consisting of:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- G is -CHR - (e.g., -CHOH), and W is -C(-NR>.
- R 1A is selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R >1A is vibration selected from the group consisting of:
- R 9 -R 10 - moiety is:
- R 1A is selected from the group consisting of: benzofusedcycfoa ⁇ kyl (i.e., fused benzocycloatkyl), fused benzoheterocycloalkyi, fused heteroaryicycioaikyi, fused heteroaryfheterocycSoalkyi, and wherein said R 1A groups are optionally substituted with 1-5 independently selected R 21 groups.
- the R 21 groups are halo
- fused ring R ,1A groups examples include, but are not limited to:
- each Y is independently selected from the group consisting of: -O-, -NR 14 - and TMC(R 21 ) q -, wherein q is as defined above (i.e., 0, 1 or 2 and each R 21 is independently selected), and wherein R 14 and R 21 are as defined for formula (I).
- R ⁇ 1A groups examples include, for example:
- Compounds of formula (!) also include compounds wherein R 1A is an aikyl group (e.g., ethyl) substituted with one R 21 group.
- R 1A groups include alkyl (e.g., methy! or ethyl) substituted with the R 21 moiety aryi (e.g., phenyl or naphthyl).
- R 1A groups also include alkyf (e.g., methyl or ethyl) substituted with the R 21 moiety aryt (e.g., phenyl or naphthyl), which in turn is substituted with one or more (e.g., one or two) independently selected R 22 groups (e.g., R 22 is haio, such as, for example, F).
- alkyf e.g., methyl or ethyl
- aryt e.g., phenyl or naphthyl
- R 22 groups e.g., R 22 is haio, such as, for example, F.
- substituted R 1 ⁇ alkyi groups examples include, but are not limited to:
- R >1A i s a cycloalky! group (e.g., cyciopropyl or cyclobutyl) substituted with one R 21 group (e.g., ary!, such as, for example, phenyl), or a cycloalkyi group (e.g., cyclopentyl or cyclohexyl) substituted with one R 21 group (e.g., aryl, such as, for example, phenyl) which in turn is substituted with one or more (e.g., one or two) independently selected R 22 groups (e.g., hato, such as, for example, F).
- R 21 group is bound to the same carbon of the R 1A group that binds the R 1A group to the rest of the molecule.
- cycloalkyi R 1A groups examples include, but are not limited to:
- R 1A groups include, but are not limited to:
- s is 0 (i.e., the ring is cyciopropyl), or 1 (Le., the ring is cyclobutyl).
- Z is selected from the group consisting of: (1) -O 1 (2) -NR 14 -, (3) -C(R 21 X,- wherein q is 0, 1 or 2, and each R ,21 is independently selected, (4) -C(R 21 ) ⁇ q -C(R i21 ) ⁇ q - wherein each q is independently 0, 1 or 2 and each R 21 is indepenendently selected, (5) -(C ⁇ R 21 )q) q -O-(C(R 21 )c,) q - wherein each q is independently 0, 1 or 2, and each R 21 is independently selected, and (6) -(C(R 21 ) q ) q -N(R 14 )-(C ⁇ R 2i ) q )c,- wherein each q is independently 0, 1 or 2, and each R 21 is independently selected.
- R 21 examples include, but are not limited to, aryl (e.g., phenyl) and ary! (e.g., phenyl) substituted with one or more (e.g., one or two, or one) independently selected R 22 groups (e.g., halo, such as, for example, F).
- R 22 groups e.g., halo, such as, for example, F.
- R 1A examples include, but are not limited to:
- examples of this R ,1A group include, but are not limited to:
- R >1A also include, but are not limited to:
- R 1A group examples include, but are not limited to: such as, for example,
- R 10 is aryi (e.g., phenyl) or ary! (e.g., phenyl) substituted with one or more (e.g., one or two, or one) R 21 groups (e.g., -OR 15 , wherein, for example, R 15 is alkyl, such as, for example, methyl), and R 9 is heteroaryl (e.g., imidazoly! or heteroaryl (e.g., ⁇ midazolyl) substituted with one or more (e.g., one or two, or one) R 21 groups (e.g., alkyi, such as, for example, methyl).
- R 10 is aryi (e.g., phenyl) or ary! (e.g., phenyl) substituted with one or more (e.g., one or two, or one) R 21 groups (e.g., -OR 15 , wherein, for example, R 15 is alkyl, such as, for example, methyl),
- R 15 is alky! (e.g., methyl), such as, for example,
- R 15 is alkyl (e.g., methyl), such as, for example,
- R 15 is alkyl (e.g., methyl), such as, for example,
- R 10 is heteroaryf or heteroaryl substituted with one or more R 21 groups
- R 9 is heteroaryl (e.g., ⁇ midazoiy! or heteroaryi (e.g., ⁇ midaz ⁇ iyi) substituted with one or more (e.g., one or two, or one) R 21 groups (e.g., alky!, such as, for example, methyl).
- R 10 is aryl substituted with one R 21 group, wherein said R 21 group is -OR 10 , in one example, R 15 is alkyl. In another exampie R w is methyl.
- R TO is phenyl substituted with one R 21 group, wherein said R 21 group is -OR T5 .
- R 15 is alky!. In another example R 15 is methyl.
- R 10 is heteroaryl.
- R 9 is heteroaryl
- R 9 is heteroaryl substituted with one or more (e.g., one) independently selected R 21 groups. fn another embodiment of the compounds of formula (i) R 9 is heteroaryl substituted with one or more (e.g., one) independently selected R 21 groups, wherein each R 21 group is the same or different alkyl group (e.g., methyl).
- R 9 is heteroaryi substituted with one R 21 group.
- R 9 is heteroaryl substituted with one R 21 group, wherein R 21 is an alkyl group (e.g., methyl). In another embodiment of the compounds of formula (I) R 9 is imidazolyl.
- R 9 is imidazolyl substituted with one or more (e.g., one) independently selected R 21 groups.
- R 9 is imidazolyf substituted with one or more (e.g., one) independently selected R 21 groups, wherein each R 21 group is the same or different aikyl group (e.g., methyl).
- R 9 is irnidazoiy! substituted with one R 21 group.
- R 9 is imidazolyl substituted with one R 21 group, wherein R 21 is an alkyl group (e.g., methyl).
- R 21 is an alkyl group (e.g., methyl).
- R 9 is heteroaryl, optionally substituted with one R 21 group, and R 10 is aryl optionally substituted with one R 21 group.
- R 9 is heteroaryJ, optionally substituted with one or more R 21 groups, and R 10 is phenyl optionaily substituted with one or more (e.g., one) R 21 groups.
- R 9 is heteroaryf, optionally substituted with one R 21 group, and R 10 is phenyl optionally substituted with one R 21 group, in another embodiment of the compounds of formula (I) R & is imidazoiyf, optionally substituted with one or more R 21 groups, and R 10 is aryl optionally substituted with one or more (e.g., one) R 21 groups.
- R 9 is imidazolyl, optionaily substituted with one R 21 group, and R 10 is aryl optionally substituted with one R 21 group.
- R ⁇ is imidazolyl, optionally substituted with one or more R 21 groups, and R 10 is phenyl optionally substituted with one or more (e.g., one) R 21 groups.
- R 9 is imidazolyl, optionally substituted with one R 21 group, and R 10 is phenyl optionally substituted with one R 21 group.
- R 1A is benzofusedcycioalkyl. In another embodiment of the compounds of formula (I) R 1A is:
- R 1 1 A A is:
- R 1 m A j is, in another embodiment of the compounds of formula (I) R I 1 A M is atkyl substituted with one R 2'1 ! group. in another embodiment of the compounds of formula (I) R is alkyf substituted with one R 21 group, and said alkyl is
- R J'A rt i s spiral aikyl (e.g., (a),
- R 1A is afkyl (e.g., (a), (b) or (c) described above) substituted with one R 21 group wherein said R 21 group is phenyl.
- R 1A is alkyl (e.g., (a),
- R 1A is alky! substituted with one R group, and said R group is substituted with two independently selected R 22 groups.
- R 1A is alky! substituted with one R 21 group, and said R 21 group is substituted with one R 22 group.
- R 1 ⁇ is alkyl substituted with one R 21 group, wherein said alkyf group is (a) (e.g., (b) or (c)), as described above, and said R group is substituted with two independently selected R groups,.
- R 1A is alkyl substituted with one R 21 group, wherein said alkyl group is (a) (e.g., (b) or (c)), as described above, and said R 21 group is substituted with one R 22 group.
- R 1A is atkyl substituted with one R 21 group, wherein said R 21 group is aryl, and said R 21 group is substituted with two independently selected R 22 groups.
- R 1A is alkyl substituted with one R 21 group, wherein said R 21 group is aryl, and said R 21 group is substituted with one R 22 group.
- R 1A is atkyl substituted with one R 21 group, wherein said R 21 group is aryf, said alkyl group Is (a) (e.g., (b) or (c)), as described above, and said R 21 group is substituted with two independently selected R 22 groups.
- R 1A is alkyl substituted with one R 21 group, wherein said R 21 group is aryl ; wherein said alkyl group is (a) (e.g., (b) or (c)) s as described above, and said R 21 group is substituted with one R 22 group.
- R 1A is alkyl substituted with one R 21 group, wherein said R 21 group is aryl, said R 21 group is substituted with two independently selected R 2 groups, and each R 22 is halo.
- R 1A i alkyl substituted with one R 21 group, wherein said R 21 group is aryl, and said R 21 group is substituted with one R 22 group, and said R 22 is halo.
- R 1A is alkyl substituted with one R 21 group, wherein said R 2i group is aryf, said alkyl group is (a) (e.g., (b) or (c)), as described above, and said R 21 group is substituted with two independently selected R 22 groups, and each R 22 is halo.
- R 1A is alkyl substituted with one R 21 group, wherein said R 21 group is aryl, wherein said aikyl group is (a) (e.g., (b) or (c)), as described above, and said R 21 group is substituted with one R 22 group, and said R 22 is halo.
- R 1A is aikyl substituted with one R 21 group, wherein said R 21 group is aryl, said R 21 group is substituted with two independently selected R 22 groups, and each R 22 is F.
- R 1A is alkyl substituted with one R 21 group, wherein said R 21 group is aryl, and said R 21 group is substituted with one R 22 group, and said R 22 is F.
- R 1A is alkyl substituted with one R 21 group, wherein said R 21 group is aryi, said alkyl group is (a) (e.g., (b) or (c)), as described above, and said R 21 group is substituted with two independently selected R 22 groups, and each R 22 is F,
- R 1A is afkyl substituted with one R 21 group, wherein said R 21 group is aryl, wherein said alkyl group is (a) (e.g., (b) or (c)), as described above, and said R group is substituted with one R ⁇ group, and said R 22 is F.
- R 1A is:
- R 1A is:
- R 1A is:
- R 1A is:
- R 21 groups include -OR 15 wherein, for example, R 15 is alkyl (such as methyl or ethyl), or R 15 is cycloalkyiafkyi (such as, for example, -CH ⁇ -cyclopropyl), or R 15 is -a!kyl-(R 18 )r, (wherein, for example, said R 18 is -OR 20 , and said R 20 is aikyi, and wherein examples of said -alkyJ-(R ia ) n moiety is -(CH 2 ⁇ OCHs).
- R 21 also include -C(O)OR 15 wherein, for example, R 15 is alkyl, such as, for example, methyl).
- R 21 also include -C(O)NR 15 R 16 , wherein, for example, one of R 15 or R 1 ⁇ is H 1 and the other is selected from the group consisting of: (R 1s ) n -ary!alkyi-, (R 1 Vafkyh and cycloa ⁇ kyl.
- this -C(O)NR 15 R 18 moiety the R 18 is -OR 20 , n is 1, R 20 is aikyi, said cycloalkyl is cyclobutyl, and said aryialkyl- is benzyl.
- R 21 also include halo (e.g., Br 5 Cl or F).
- R 21 also include aryialkyl, such as r for example, benzyl.
- the dashed line between G 1 and the C that R 1A is bound to in the formulas below represents the presence of Ring B (i.e., Ring B is present in the formulas with the dashed line between G 1 and the C that R 1A is bound to).
- Ring B is present in formulas IA to IH, 6.2, 10,2, 10.3, 20.2 21.2, and 23.2.
- the compound of formula (i) is a compound of formula (IA):
- the compound of formula (I) in another embodiment of this invention, is a compound of formula (IB):
- the optional bond between G 1 and G 2 is present in formula (I).
- the compound of formula (i) is a compound of formula (IC):
- the compound of formula (I) is a compound of formula (ID):
- the compound of formuia (i) is a compound of formuia (IE):
- the compound of formula (J) is a compound of formula (IF):
- the compound of formula (I) is a compound of formula (IG):
- the compound of formula (I) is a compound of formula (IH):
- the compound of formula (I) is a compound of formula (6.2):
- the compound of formula (J) is a compound of formula (10.2):
- the compound of formula (I) is a compound of formula (10.3):
- the compound of formula (!) is a compound of formula (20.2):
- the compound of formula (I) is a compound of formula (21.2):
- the compound of formula (I) is a compound of formuta (23.2):
- Ring (B) is a 6 membered (including the atoms common to Rings (A) and (B)) heterocycloaikyi ring, optionally comprising one additional heteroatom (e.g., -NR 2 - or -O-),
- Ring (B) is a 5 membered (including the atoms common to Rings (A) and (B)) heterocycloaikyi ring, optionally comprising one additional heteroatom (e.g., -NR 2 - or -O-).
- Ring (B) is a 6 membered (including the atoms common to Rings (A) and (B)) heteroary! ring, optionally comprising one or two additional heteroatoms (e.g., each independently selected from -NR 2 - or -O-).
- Ring (B) is a 5 membered (including the atoms common to Rings (A) and (B)) heterocycloaikyi ring, optionally comprising one or two additional heteroatom (e.g., each independently selected from -NR 2 - or -O-).
- Another embodiment of this invention is directed to compounds of formula (I) having the formula:
- R 1A in compound 2A is aryl or substituted aryl
- R 1A in compound 2A is phenyl or substituted phenyl
- R 1A in compound 2A is phenyl substituted with 1 to 3 independently selected R 21 groups.
- R 1A in compound 2A is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) independently selected halos.
- R 1A in compound 2A is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms.
- R 1A in compound 2A is phenyl substituted with 1 F atom.
- Another embodiment of this invention is directed to compounds of formuta (f) having the formula:
- Another embodiment of this invention is directed to compounds of formula (I) having the formula:
- R OA in compound 2C is aryl or substituted aryi. In another embodiment R OA in compound 2C is phenyl or substituted phenyl. In another embodiment R 1A in compound 2C is phenyl substituted with 1 to 3 independently selected R 21 groups. In another embodiment of this invention R 1A in compound 2C is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) independently selected halos. In another embodiment of this invention R 1A in compound 2C is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In another embodiment of this invention R 1A in compound 2C is phenyl substituted with 1 F atom.
- Another embodiment of this invention is directed to compounds of formula (I) having the formufa:
- Another embodiment of this invention is directed to compounds of formula (I) having the formula:
- R »1A in compound 3A is aryl or substituted aryl.
- R ⁇ 1A i ⁇ n compound 3A is phenyl or substituted phenyl.
- R 1A in compound 3A is phenyl substituted with 1 to 3 independently selected R 21 groups.
- R 1A in compound 3A is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) independently selected halos.
- R 1A in compound 3A is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms.
- R 1A in compound 3A is phenyl substituted with 1 F atom.
- Another embodiment of this invention is directed to compounds of formula ( ⁇ ) having the formula:
- Another embodiment of this invention is directed to compounds of formula (I) having the formula:
- R 1A in compound 3C is aryl or substituted aryl.
- R 1 ⁇ in compound 3C is phenyl or substituted phenyl
- R 1A in compound 3C is phenyl substituted with 1 to 3 independently selected R 21 groups.
- R 1A in compound 3C is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1 ⁇ independently selected halos.
- R 1A in compound 3C is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms.
- R 1A in compound 3C is phenyf substituted with 1 F atom.
- Another embodiment of this invention is directed to compounds of formula (I) having the formula:
- Another embodiment of this invention is directed to compounds of formufa (I) having the formula:
- R 1A in compound 4A is aryl or substituted aryl. In another embodiment R 1A in compound 4A is phenyl or substituted phenyl, in another embodiment R 1A in compound 4A is phenyl substituted with 1 to 3 independently selected R 21 groups. In another embodiment of this invention R 1A ⁇ n compound 4A is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) independently selected halos. In another embodiment of this invention R 1A in compound 4A is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In another embodiment of this invention R 1A in compound 4A is phenyl substituted with 1 F atom.
- Another embodiment of this invention is directed to compounds of formula (I) having the formula:
- Another embodiment of this invention is directed to compounds of formula (!) having the formula:
- R 1A in compound 4C is aryl or substituted aryi. in another embodiment R 1A in compound AC is phenyl or substituted phenyl. In another embodiment R 1A in compound 4C is phenyl substituted with 1 to 3 independently selected R 21 groups, in another embodiment of this invention R IA in compound 4C is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) independently selected halos. In another embodiment of this invention R 1A in compound 4C is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1 ) F atoms. In another embodiment of this invention R 1A in compound 4C is phenyl substituted with 1 F atom.
- Another embodiment of this invention is directed to compounds of formula (I) having the formula:
- Another embodiment of this invention is directed to compounds of formula (f) having the formula:
- R 1 ⁇ in compound 5A is aryl or substituted aryl.
- R 1A in compound 5A is phenyl or substituted phenyl.
- R 1A in compound 5A is phenyl substituted with 1 to 3 independently selected R 21 groups, fn another embodiment of this invention R 1A in compound 5A is phenyl substituted with 1 to 3 (e.g., 1 to 3 » or 1 to 2, or 1) independently selected halos,
- R 1A m " compound 5A is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms.
- R 1A in compound 5A is phenyl substituted with 1 F atom.
- Another embodiment of this invention is directed to compounds of formula (I) having the formula:
- Another embodiment of this invention is directed to compounds of formula (I) having the formula
- R ,1A - in compound 5C is aryl or substituted aryl.
- R >1A i n compound 5C is phenyf or substituted phenyl, in another embodiment R 1A in compound 5C is phenyl substituted with 1 to 3 independently selected R 21 groups. Jn another embodiment of this invention R 1A in compound 5C is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) independently selected halos. In another embodiment of this invention R 1A in compound 5Cis phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In another embodiment of this invention R tA in compound SC is phenyl substituted with 1 F atom.
- Another embodiment of this invention is directed to compounds of formula (I) having the formufa:
- Another embodiment of this invention is directed to compounds of formula (() having the formula:
- R > 1A in compound 6A is ary! or substituted aryf.
- R in compound 6A is phenyl or substituted phenyl.
- R ,1A in compound 6A is phenyl substituted with 1 to 3 independently selected R ⁇ 2"1 ' groups.
- R 1A - in compound 6A is phenyl substituted with 1 to 3 (e.g., 1 to 3. or 1 to 2, or 1 ) independently selected haios.
- R 1A in compound 6A is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms.
- R 1 ⁇ in compound 5A is phenyl substituted with 1 F atom.
- Another embodiment of this invention is directed to compounds of formula (I) having the formula:
- Another embodiment of this invention is directed to compounds of formula (I) having the formula:
- R 1A in compound 6C is aryl or substituted aryi. in another embodiment R 1 ⁇ in compound 6C is phenyl or substituted phenyl. In another embodiment R 1A in compound 6C is phenyl substituted with 1 to 3 independently selected R 21 groups, in another embodiment of this invention R 1A in compound 6C is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) independently selected halos. In another embodiment of this invention R 1A in compound 6C is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In another embodiment of this invention R 1A in compound 6C is phenyl substituted with 1 F atom.
- Another embodiment of this invention is directed to compounds of formula (I) having the formula:
- Another embodiment of this invention is directed to compounds of formula (I) having the formula:
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2010006379A MX2010006379A (en) | 2007-12-11 | 2008-12-09 | Gamma secretase modulators. |
EP08858841A EP2268636A1 (en) | 2007-12-11 | 2008-12-09 | Gamma secretase modulators |
CN2008801265657A CN101970433A (en) | 2007-12-11 | 2008-12-09 | Gamma secretase modulators |
JP2010538088A JP2011506460A (en) | 2007-12-11 | 2008-12-09 | γ-secretase modulator |
US12/747,001 US20100298372A1 (en) | 2007-12-11 | 2008-12-09 | Gamma secretase modulators |
CA2708151A CA2708151A1 (en) | 2007-12-11 | 2008-12-09 | Gamma secretase modulators |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US1286307P | 2007-12-11 | 2007-12-11 | |
US61/012,863 | 2007-12-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2009076337A1 true WO2009076337A1 (en) | 2009-06-18 |
Family
ID=40409932
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2008/086030 WO2009076337A1 (en) | 2007-12-11 | 2008-12-09 | Gamma secretase modulators |
Country Status (7)
Country | Link |
---|---|
US (1) | US20100298372A1 (en) |
EP (1) | EP2268636A1 (en) |
JP (1) | JP2011506460A (en) |
CN (1) | CN101970433A (en) |
CA (1) | CA2708151A1 (en) |
MX (1) | MX2010006379A (en) |
WO (1) | WO2009076337A1 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011007819A1 (en) | 2009-07-17 | 2011-01-20 | 塩野義製薬株式会社 | Pharmaceutical product containing lactam or benzene sulfonamide compound |
WO2011092272A1 (en) * | 2010-02-01 | 2011-08-04 | F. Hoffmann-La Roche Ag | Gamma secretase modulaters |
US8188101B2 (en) | 2008-11-06 | 2012-05-29 | Astrazeneca Ab | Dihydropyridopyrimidines for the treatment of AB-related pathologies |
US8252829B2 (en) | 2009-06-05 | 2012-08-28 | Link Medicine Corporation | Aminopyrrolidinone derivatives and uses thereof |
US8288403B2 (en) | 2008-11-10 | 2012-10-16 | Hoffmann-La Roche Inc. | Heterocyclic gamma secretase modulators |
US8389717B2 (en) | 2008-10-09 | 2013-03-05 | Hoffmann-La Roche Inc. | Modulators for amyloid beta |
WO2013093484A1 (en) | 2011-12-21 | 2013-06-27 | Ono Pharmaceutical Co., Ltd. | Pyridinone and pyrimidinone derivatives as factor xia inhibitors |
US8486967B2 (en) | 2010-02-17 | 2013-07-16 | Hoffmann-La Roche Inc. | Heteroaryl substituted piperidines |
US8962834B2 (en) | 2008-02-22 | 2015-02-24 | Hoffmann-La Roche Inc. | Modulators of amyloid beta |
KR20170095845A (en) | 2014-12-10 | 2017-08-23 | 오노 야꾸힝 고교 가부시키가이샤 | Dihydroindolizinone derivative |
WO2018007331A1 (en) * | 2016-07-08 | 2018-01-11 | F. Hoffmann-La Roche Ag | Fused pyrimidine derivatives |
US10647721B2 (en) | 2016-10-04 | 2020-05-12 | Hoffmann-La Roche Inc. | Bicyclic heteroaryl derivatives |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8637525B2 (en) | 2009-07-31 | 2014-01-28 | Bristol-Myers Squibb Company | Compounds for the reduction of beta-amyloid production |
TWI468402B (en) * | 2009-07-31 | 2015-01-11 | 必治妥美雅史谷比公司 | Compounds for the reduction of β-amyloid production |
CA2830027C (en) | 2011-03-31 | 2016-04-26 | Pfizer Inc. | Novel bicyclic pyridinones |
TW201247631A (en) | 2011-04-28 | 2012-12-01 | Du Pont | Herbicidal pyrazinones |
UA110688C2 (en) | 2012-09-21 | 2016-01-25 | Пфайзер Інк. | Bicyclic pirydynony |
WO2015011087A1 (en) * | 2013-07-23 | 2015-01-29 | Bayer Pharma Aktiengesellschaft | Substituted oxopyridine derivatives and use thereof as factor xia/plasma |
MX368391B (en) | 2015-02-03 | 2019-09-30 | Pfizer | Novel cyclopropabenzofuranyl pyridopyrazinediones. |
WO2018214866A1 (en) * | 2017-05-24 | 2018-11-29 | 上海和誉生物医药科技有限公司 | Azaaryl derivative, preparation method therefor, and application thereof for use in pharmacy |
JP6903825B2 (en) * | 2017-12-19 | 2021-07-14 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Triazolopyridine as a modulator of γ-secretase |
CN112028877B (en) * | 2019-06-04 | 2021-11-26 | 江西济民可信集团有限公司 | Alkoxy pyridone compound and preparation method and application thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998025930A2 (en) * | 1996-12-13 | 1998-06-18 | F. Hoffmann-La Roche Ag | Use of bi- and tricyclic pyridone derivatives against alzheimer's disease |
WO2003055856A2 (en) * | 2001-10-17 | 2003-07-10 | Bristol-Myers Squibb Company | BICYCLIC LACTAM DERIVATIVES AS INHIBITORS OF MATRIX METALLOPROTEINASES AND/OR TNF-α CONVERTING ENZYME (TACE) |
US20070117839A1 (en) * | 2005-11-24 | 2007-05-24 | Eisai R&D Management Co., Ltd. | Two cyclic cinnamide compound |
US20070117798A1 (en) * | 2005-11-24 | 2007-05-24 | Eisai R&D Management Co., Ltd. | Morpholine type cinnamide compound |
WO2007102580A1 (en) * | 2006-03-09 | 2007-09-13 | Eisai R & D Management Co., Ltd. | Polycyclic cinnamide derivative |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050042284A1 (en) * | 2003-07-11 | 2005-02-24 | Myriad Genetics, Incorporated | Pharmaceutical methods, dosing regimes and dosage forms for the treatment of Alzheimer's disease |
JP4101852B2 (en) * | 2004-05-26 | 2008-06-18 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Cinnamide compounds |
-
2008
- 2008-12-09 CA CA2708151A patent/CA2708151A1/en not_active Abandoned
- 2008-12-09 JP JP2010538088A patent/JP2011506460A/en not_active Withdrawn
- 2008-12-09 CN CN2008801265657A patent/CN101970433A/en active Pending
- 2008-12-09 US US12/747,001 patent/US20100298372A1/en not_active Abandoned
- 2008-12-09 MX MX2010006379A patent/MX2010006379A/en not_active Application Discontinuation
- 2008-12-09 WO PCT/US2008/086030 patent/WO2009076337A1/en active Application Filing
- 2008-12-09 EP EP08858841A patent/EP2268636A1/en not_active Withdrawn
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998025930A2 (en) * | 1996-12-13 | 1998-06-18 | F. Hoffmann-La Roche Ag | Use of bi- and tricyclic pyridone derivatives against alzheimer's disease |
WO2003055856A2 (en) * | 2001-10-17 | 2003-07-10 | Bristol-Myers Squibb Company | BICYCLIC LACTAM DERIVATIVES AS INHIBITORS OF MATRIX METALLOPROTEINASES AND/OR TNF-α CONVERTING ENZYME (TACE) |
US20070117839A1 (en) * | 2005-11-24 | 2007-05-24 | Eisai R&D Management Co., Ltd. | Two cyclic cinnamide compound |
US20070117798A1 (en) * | 2005-11-24 | 2007-05-24 | Eisai R&D Management Co., Ltd. | Morpholine type cinnamide compound |
WO2007102580A1 (en) * | 2006-03-09 | 2007-09-13 | Eisai R & D Management Co., Ltd. | Polycyclic cinnamide derivative |
EP1992618A1 (en) * | 2006-03-09 | 2008-11-19 | Eisai R&D Management Co., Ltd. | Polycyclic cinnamide derivative |
Cited By (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8962834B2 (en) | 2008-02-22 | 2015-02-24 | Hoffmann-La Roche Inc. | Modulators of amyloid beta |
US8389717B2 (en) | 2008-10-09 | 2013-03-05 | Hoffmann-La Roche Inc. | Modulators for amyloid beta |
US8188101B2 (en) | 2008-11-06 | 2012-05-29 | Astrazeneca Ab | Dihydropyridopyrimidines for the treatment of AB-related pathologies |
US8288403B2 (en) | 2008-11-10 | 2012-10-16 | Hoffmann-La Roche Inc. | Heterocyclic gamma secretase modulators |
US8252829B2 (en) | 2009-06-05 | 2012-08-28 | Link Medicine Corporation | Aminopyrrolidinone derivatives and uses thereof |
WO2011007819A1 (en) | 2009-07-17 | 2011-01-20 | 塩野義製薬株式会社 | Pharmaceutical product containing lactam or benzene sulfonamide compound |
WO2011092272A1 (en) * | 2010-02-01 | 2011-08-04 | F. Hoffmann-La Roche Ag | Gamma secretase modulaters |
US8486967B2 (en) | 2010-02-17 | 2013-07-16 | Hoffmann-La Roche Inc. | Heteroaryl substituted piperidines |
EP3290413A1 (en) | 2011-12-21 | 2018-03-07 | ONO Pharmaceutical Co., Ltd. | Pyridinone and pyrimidinone derivatives as factor xia inhibitors |
WO2013093484A1 (en) | 2011-12-21 | 2013-06-27 | Ono Pharmaceutical Co., Ltd. | Pyridinone and pyrimidinone derivatives as factor xia inhibitors |
US9732085B2 (en) | 2011-12-21 | 2017-08-15 | Ono Pharmaceutical Co., Ltd. | Pyridinone and pyrimidinone derivatives as factor Xia |
US10717738B2 (en) | 2011-12-21 | 2020-07-21 | Ono Pharmaceutical Co., Ltd. | Pyrimidinone and its derivatives inhibiting factor XIa |
KR20170095845A (en) | 2014-12-10 | 2017-08-23 | 오노 야꾸힝 고교 가부시키가이샤 | Dihydroindolizinone derivative |
US10065955B2 (en) | 2014-12-10 | 2018-09-04 | Ono Pharmaceutical Co., Ltd. | Dihydroindolizinone derivative |
US10407426B2 (en) | 2014-12-10 | 2019-09-10 | Ono Pharmaceutical Co., Ltd. | Dihydroindolizinone derivative |
US10550119B2 (en) | 2014-12-10 | 2020-02-04 | Ono Pharmaceutical Co., Ltd. | Dihydroindolizinone derivative |
EP3702357A1 (en) | 2014-12-10 | 2020-09-02 | ONO Pharmaceutical Co., Ltd. | Dihydroindolizinone derivative |
US10815233B2 (en) | 2014-12-10 | 2020-10-27 | Ono Pharmaceutical Co., Ltd. | Dihydroindolizinone derivative |
US11566027B2 (en) | 2014-12-10 | 2023-01-31 | Ono Pharmaceutical Co., Ltd. | Dihydroindolizinone derivative |
CN109415369A (en) * | 2016-07-08 | 2019-03-01 | 豪夫迈·罗氏有限公司 | Fused pyrimidine derivative |
US10669276B2 (en) | 2016-07-08 | 2020-06-02 | Hoffmann-La Roche Inc. | Fused pyrimidine derivatives |
WO2018007331A1 (en) * | 2016-07-08 | 2018-01-11 | F. Hoffmann-La Roche Ag | Fused pyrimidine derivatives |
US10647721B2 (en) | 2016-10-04 | 2020-05-12 | Hoffmann-La Roche Inc. | Bicyclic heteroaryl derivatives |
Also Published As
Publication number | Publication date |
---|---|
MX2010006379A (en) | 2010-09-07 |
CN101970433A (en) | 2011-02-09 |
CA2708151A1 (en) | 2009-06-18 |
EP2268636A1 (en) | 2011-01-05 |
JP2011506460A (en) | 2011-03-03 |
US20100298372A1 (en) | 2010-11-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2009076337A1 (en) | Gamma secretase modulators | |
EP2227471A1 (en) | Gamma secretase modulators | |
EP2155737A1 (en) | Gamma secretase modulators | |
EP2356115A1 (en) | Gamma secretase modulators | |
EP2229375A1 (en) | Gamma secretase modulators | |
WO2009061699A1 (en) | Gamma secretase modulators | |
EP2152695A2 (en) | Gamma secretase modulators | |
EP2257542A1 (en) | Gamma secretase modulators for the treatment of alzheimer ' s disease | |
EP2379563A1 (en) | Gamma secretase modulators | |
WO2010075204A2 (en) | Gamma secretase modulators | |
WO2009020579A1 (en) | Gamma secretase modulators | |
WO2008153792A2 (en) | Gamma secretase modulators | |
WO2010056722A1 (en) | Gamma secretase modulators | |
EP2443119A1 (en) | Gamma secretase modulators | |
EP2443121A2 (en) | Gamma secretase modulators | |
EP2356124A1 (en) | Gamma secretase modulators | |
WO2010147973A1 (en) | Gamma secretase modulators |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200880126565.7 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 08858841 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2708151 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010538088 Country of ref document: JP Ref document number: MX/A/2010/006379 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2008858841 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12747001 Country of ref document: US |