NO337361B1 - Bicykliske[3.1.0] derivater som glysintransportørinhibitorer, og farmasøytiske sammensetninger inneholdende slike. - Google Patents
Bicykliske[3.1.0] derivater som glysintransportørinhibitorer, og farmasøytiske sammensetninger inneholdende slike. Download PDFInfo
- Publication number
- NO337361B1 NO337361B1 NO20062193A NO20062193A NO337361B1 NO 337361 B1 NO337361 B1 NO 337361B1 NO 20062193 A NO20062193 A NO 20062193A NO 20062193 A NO20062193 A NO 20062193A NO 337361 B1 NO337361 B1 NO 337361B1
- Authority
- NO
- Norway
- Prior art keywords
- ylmethyl
- bicyclo
- aza
- hex
- amide
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
- 239000003112 inhibitor Substances 0.000 title description 5
- 125000002619 bicyclic group Chemical group 0.000 title description 4
- 102000010726 Glycine Plasma Membrane Transport Proteins Human genes 0.000 title 1
- 108010063380 Glycine Plasma Membrane Transport Proteins Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 92
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 31
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 27
- -1 dihydroquinolyl Chemical group 0.000 claims description 22
- 238000011282 treatment Methods 0.000 claims description 21
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 claims description 18
- 208000028017 Psychotic disease Diseases 0.000 claims description 17
- 201000000980 schizophrenia Diseases 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 208000027691 Conduct disease Diseases 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 229910052720 vanadium Inorganic materials 0.000 claims description 9
- 208000019901 Anxiety disease Diseases 0.000 claims description 8
- 208000020925 Bipolar disease Diseases 0.000 claims description 8
- 208000019022 Mood disease Diseases 0.000 claims description 8
- 208000016285 Movement disease Diseases 0.000 claims description 8
- 230000036506 anxiety Effects 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 206010012289 Dementia Diseases 0.000 claims description 6
- 208000012661 Dyskinesia Diseases 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- 208000010877 cognitive disease Diseases 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 4
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 4
- 208000020706 Autistic disease Diseases 0.000 claims description 4
- 206010026749 Mania Diseases 0.000 claims description 4
- 208000036626 Mental retardation Diseases 0.000 claims description 4
- 208000018737 Parkinson disease Diseases 0.000 claims description 4
- 208000027465 Psychotic Affective disease Diseases 0.000 claims description 4
- 208000000323 Tourette Syndrome Diseases 0.000 claims description 4
- 208000016620 Tourette disease Diseases 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 4
- 230000003542 behavioural effect Effects 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 208000024714 major depressive disease Diseases 0.000 claims description 4
- 230000004770 neurodegeneration Effects 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 3
- 208000026139 Memory disease Diseases 0.000 claims description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 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 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000003838 furazanyl group Chemical group 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 3
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000005493 quinolyl group Chemical group 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000004306 triazinyl group Chemical group 0.000 claims description 3
- 125000001425 triazolyl group Chemical group 0.000 claims description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 2
- CLHRIGBQIKLOIF-UHFFFAOYSA-N O(C1=CC=CC=C1)C1N(CCOC1)F Chemical compound O(C1=CC=CC=C1)C1N(CCOC1)F CLHRIGBQIKLOIF-UHFFFAOYSA-N 0.000 claims description 2
- 240000001987 Pyrus communis Species 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 claims description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 125000006267 biphenyl group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000004612 furopyridinyl group Chemical group O1C(=CC2=C1C=CC=N2)* 0.000 claims description 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- COVQNCWUYFBSRV-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(6-chloropyridin-3-yl)thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=NC(Cl)=CC=3)C2C1 COVQNCWUYFBSRV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 2
- KRFOMGKWNXKKOI-UHFFFAOYSA-N n-[[3-(4-bromophenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=CC(Br)=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 KRFOMGKWNXKKOI-UHFFFAOYSA-N 0.000 claims 2
- UDKFRASYMGTWMR-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(4-morpholin-4-ylcyclohexyl)thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C3CCC(CC3)N3CCOCC3)C(=O)C=3SC=CC=3)C2C1 UDKFRASYMGTWMR-UHFFFAOYSA-N 0.000 claims 2
- PIBCMCBHLFKQDZ-UHFFFAOYSA-N 1-acetyl-n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)pyrrolidine-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C3N(CCC3)C(C)=O)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 PIBCMCBHLFKQDZ-UHFFFAOYSA-N 0.000 claims 1
- FKDVUMKDBNGBIS-UHFFFAOYSA-N 3-bromo-n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C3=C(C=CS3)Br)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 FKDVUMKDBNGBIS-UHFFFAOYSA-N 0.000 claims 1
- ZRKYIJZBEZBTLV-UHFFFAOYSA-N 3-chloro-n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C3=C(C=CS3)Cl)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 ZRKYIJZBEZBTLV-UHFFFAOYSA-N 0.000 claims 1
- IEJLQHZRMFPCRX-UHFFFAOYSA-N 3-ethoxy-n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CSC(C(=O)N(CC2C3CN(CC=4C=CC(CC)=CC=4)CC32)C=2C=C(F)C(N3CCOCC3)=CC=2)=C1OCC IEJLQHZRMFPCRX-UHFFFAOYSA-N 0.000 claims 1
- DTHZZEDXBYEOCD-UHFFFAOYSA-N 4-[[6-[[3-fluoro-4-morpholin-4-yl-n-(thiophene-2-carbonyl)anilino]methyl]-3-azabicyclo[3.1.0]hexan-3-yl]sulfonyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 DTHZZEDXBYEOCD-UHFFFAOYSA-N 0.000 claims 1
- YKVUVPWFXSVLSC-UHFFFAOYSA-N 5-bromo-n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3SC(Br)=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 YKVUVPWFXSVLSC-UHFFFAOYSA-N 0.000 claims 1
- BWYREGQRGGGSMB-UHFFFAOYSA-N 5-tert-butyl-n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-2-methylpyrazole-3-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3N(N=C(C=3)C(C)(C)C)C)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 BWYREGQRGGGSMB-UHFFFAOYSA-N 0.000 claims 1
- 241000272525 Anas platyrhynchos Species 0.000 claims 1
- 201000004311 Gilles de la Tourette syndrome Diseases 0.000 claims 1
- DAVZSZZFCOFKKX-UHFFFAOYSA-N methyl 3-[4-[[6-[[3-fluoro-4-morpholin-4-yl-n-(thiophene-2-carbonyl)anilino]methyl]-3-azabicyclo[3.1.0]hexan-3-yl]sulfonyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 DAVZSZZFCOFKKX-UHFFFAOYSA-N 0.000 claims 1
- LFKJGXJNZULMIB-UHFFFAOYSA-N methyl 4-[[6-[[3-fluoro-4-morpholin-4-yl-n-(thiophene-2-carbonyl)anilino]methyl]-3-azabicyclo[3.1.0]hexan-3-yl]methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 LFKJGXJNZULMIB-UHFFFAOYSA-N 0.000 claims 1
- ZWFRJNXIWQSNQJ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[(3-hexyl-3-azabicyclo[3.1.0]hexan-6-yl)methyl]thiophene-2-carboxamide Chemical compound C12CN(CCCCCC)CC2C1CN(C=1C=C(F)C(N2CCOCC2)=CC=1)C(=O)C1=CC=CS1 ZWFRJNXIWQSNQJ-UHFFFAOYSA-N 0.000 claims 1
- BXEOFMYVKOLHRS-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[(3-isoquinolin-5-ylsulfonyl-3-azabicyclo[3.1.0]hexan-6-yl)methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C3=CC=NC=C3C=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 BXEOFMYVKOLHRS-UHFFFAOYSA-N 0.000 claims 1
- VFGBNNGZEMTRND-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[(3-naphthalen-2-ylsulfonyl-3-azabicyclo[3.1.0]hexan-6-yl)methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=C3C=CC=CC3=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 VFGBNNGZEMTRND-UHFFFAOYSA-N 0.000 claims 1
- XACJZVCSXRMNTA-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[(3-quinolin-8-ylsulfonyl-3-azabicyclo[3.1.0]hexan-6-yl)methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C3=NC=CC=C3C=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 XACJZVCSXRMNTA-UHFFFAOYSA-N 0.000 claims 1
- RFRUHVOPRFDXJV-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(1-methylimidazol-4-yl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound CN1C=NC(S(=O)(=O)N2CC3C(CN(C(=O)C=4SC=CC=4)C=4C=C(F)C(N5CCOCC5)=CC=4)C3C2)=C1 RFRUHVOPRFDXJV-UHFFFAOYSA-N 0.000 claims 1
- FNZFXJGVLHNFND-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(1h-indol-3-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C5=CC=CC=C5NC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 FNZFXJGVLHNFND-UHFFFAOYSA-N 0.000 claims 1
- YZWYLLPEWFZVQC-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(2-methoxy-4-methylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound COC1=CC(C)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 YZWYLLPEWFZVQC-UHFFFAOYSA-N 0.000 claims 1
- VKHCKXPAUZVMON-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(2-oxochromen-6-yl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=C3C=CC(=O)OC3=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 VKHCKXPAUZVMON-UHFFFAOYSA-N 0.000 claims 1
- BHDDSZDEWGXCCU-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(2-phenylethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CCC=4C=CC=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 BHDDSZDEWGXCCU-UHFFFAOYSA-N 0.000 claims 1
- NQEXGCYYWHAZJI-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(3-phenylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=C(C=CC=2)C=2C=CC=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 NQEXGCYYWHAZJI-UHFFFAOYSA-N 0.000 claims 1
- AXNHPOVOPSGNIM-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CCCC=4C=CC=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 AXNHPOVOPSGNIM-UHFFFAOYSA-N 0.000 claims 1
- GXIQQQWWVJDMLU-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(4-fluorophenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(F)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 GXIQQQWWVJDMLU-UHFFFAOYSA-N 0.000 claims 1
- PQDIXHXSDKWZGL-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(4-methoxyphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 PQDIXHXSDKWZGL-UHFFFAOYSA-N 0.000 claims 1
- LUUZWZINBVVSSM-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(4-methylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 LUUZWZINBVVSSM-UHFFFAOYSA-N 0.000 claims 1
- MOQKBWYBNUAXDP-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(4-methylthiophen-2-yl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound CC1=CSC(S(=O)(=O)N2CC3C(CN(C(=O)C=4SC=CC=4)C=4C=C(F)C(N5CCOCC5)=CC=4)C3C2)=C1 MOQKBWYBNUAXDP-UHFFFAOYSA-N 0.000 claims 1
- HXKUFDANJZKLDH-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(4-nitrophenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 HXKUFDANJZKLDH-UHFFFAOYSA-N 0.000 claims 1
- IQHGXIPYFFPQAK-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(4-pentylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(CCCCC)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 IQHGXIPYFFPQAK-UHFFFAOYSA-N 0.000 claims 1
- PNQNZKUJJOEHBO-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(4-phenoxyphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=CC(OC=3C=CC=CC=3)=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 PNQNZKUJJOEHBO-UHFFFAOYSA-N 0.000 claims 1
- BIYCDDNXMVIQDS-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(4-phenylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=CC(=CC=2)C=2C=CC=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 BIYCDDNXMVIQDS-UHFFFAOYSA-N 0.000 claims 1
- XFAUGMWOFRWKHJ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(4-propan-2-ylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)C)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 XFAUGMWOFRWKHJ-UHFFFAOYSA-N 0.000 claims 1
- YGOOSQAQIQIPRD-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(4-propylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(CCC)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 YGOOSQAQIQIPRD-UHFFFAOYSA-N 0.000 claims 1
- LVYMTKLDSUHFJJ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(4-pyridin-2-yloxyphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=CC(OC=3N=CC=CC=3)=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 LVYMTKLDSUHFJJ-UHFFFAOYSA-N 0.000 claims 1
- YNXROAUTCOVBJQ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(4-pyridin-3-yloxyphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=CC(OC=3C=NC=CC=3)=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 YNXROAUTCOVBJQ-UHFFFAOYSA-N 0.000 claims 1
- FHVYXINMHABJKJ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(4-pyridin-4-yloxyphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=CC(OC=3C=CN=CC=3)=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 FHVYXINMHABJKJ-UHFFFAOYSA-N 0.000 claims 1
- MWUSLQYFVVKXRL-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(furan-3-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC4=COC=C4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 MWUSLQYFVVKXRL-UHFFFAOYSA-N 0.000 claims 1
- HESDGZFODLODBS-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(naphthalen-1-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C5=CC=CC=C5C=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 HESDGZFODLODBS-UHFFFAOYSA-N 0.000 claims 1
- WPEOGYDJZJUMKE-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(naphthalen-2-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=C5C=CC=CC5=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 WPEOGYDJZJUMKE-UHFFFAOYSA-N 0.000 claims 1
- SAEBZPKSDWYVMX-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(pyridin-2-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4N=CC=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 SAEBZPKSDWYVMX-UHFFFAOYSA-N 0.000 claims 1
- NOMRWXCJWDFVLS-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(pyridin-3-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=NC=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 NOMRWXCJWDFVLS-UHFFFAOYSA-N 0.000 claims 1
- YVHDWRQVXDCCKK-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(pyridin-4-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=CN=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 YVHDWRQVXDCCKK-UHFFFAOYSA-N 0.000 claims 1
- HTELZKSDQDJZKU-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(quinolin-2-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4N=C5C=CC=CC5=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 HTELZKSDQDJZKU-UHFFFAOYSA-N 0.000 claims 1
- XZPVUZBAYFYAIF-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(quinolin-3-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=C5C=CC=CC5=NC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 XZPVUZBAYFYAIF-UHFFFAOYSA-N 0.000 claims 1
- NQRAOFGNXVCZEJ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(quinolin-4-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C5=CC=CC=C5N=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 NQRAOFGNXVCZEJ-UHFFFAOYSA-N 0.000 claims 1
- NLXLSZJGLYFLTP-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(quinoxalin-6-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=C5N=CC=NC5=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 NLXLSZJGLYFLTP-UHFFFAOYSA-N 0.000 claims 1
- HHGINYZXQXQTJA-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(thiophen-2-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4SC=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 HHGINYZXQXQTJA-UHFFFAOYSA-N 0.000 claims 1
- JBUGVLWRPHDFGI-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-(thiophen-3-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC4=CSC=C4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 JBUGVLWRPHDFGI-UHFFFAOYSA-N 0.000 claims 1
- PENOUBRYMQDFLG-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(1-hydroxycyclohexyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1C2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2CN1CC1(O)CCCCC1 PENOUBRYMQDFLG-UHFFFAOYSA-N 0.000 claims 1
- BMSGRSMZSGPTKW-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(1-methylpyrrol-2-yl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound CN1C=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 BMSGRSMZSGPTKW-UHFFFAOYSA-N 0.000 claims 1
- VCPVLUJMNGQKOV-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(2-hydroxy-1,3-dihydroinden-2-yl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1C2=CC=CC=C2CC1(O)CN(CC12)CC1C2CN(C=1C=C(F)C(N2CCOCC2)=CC=1)C(=O)C1=CC=CS1 VCPVLUJMNGQKOV-UHFFFAOYSA-N 0.000 claims 1
- KYUKOOYKPQKLDY-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(2-methylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound CC1=CC=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 KYUKOOYKPQKLDY-UHFFFAOYSA-N 0.000 claims 1
- GKKYLKKTIHOWNA-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(3,4,5-trimethoxyphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound COC1=C(OC)C(OC)=CC(CN2CC3C(CN(C(=O)C=4SC=CC=4)C=4C=C(F)C(N5CCOCC5)=CC=4)C3C2)=C1 GKKYLKKTIHOWNA-UHFFFAOYSA-N 0.000 claims 1
- WRSAMJHXXLFYHY-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(3-methoxyphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound COC1=CC=CC(CN2CC3C(CN(C(=O)C=4SC=CC=4)C=4C=C(F)C(N5CCOCC5)=CC=4)C3C2)=C1 WRSAMJHXXLFYHY-UHFFFAOYSA-N 0.000 claims 1
- ZZCNBLWHLIVKJG-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(3-methyl-1-benzothiophen-2-yl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound S1C2=CC=CC=C2C(C)=C1CN(CC12)CC1C2CN(C=1C=C(F)C(N2CCOCC2)=CC=1)C(=O)C1=CC=CS1 ZZCNBLWHLIVKJG-UHFFFAOYSA-N 0.000 claims 1
- SFPPPSOMHAPZDS-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(3-methylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound CC1=CC=CC(CN2CC3C(CN(C(=O)C=4SC=CC=4)C=4C=C(F)C(N5CCOCC5)=CC=4)C3C2)=C1 SFPPPSOMHAPZDS-UHFFFAOYSA-N 0.000 claims 1
- YJHZDQUDAZAGTJ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(3-phenoxyphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=C(OC=5C=CC=CC=5)C=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 YJHZDQUDAZAGTJ-UHFFFAOYSA-N 0.000 claims 1
- AFACQAWFNBCFSB-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(3-propoxyphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound CCCOC1=CC=CC(CN2CC3C(CN(C(=O)C=4SC=CC=4)C=4C=C(F)C(N5CCOCC5)=CC=4)C3C2)=C1 AFACQAWFNBCFSB-UHFFFAOYSA-N 0.000 claims 1
- GDDRCQQBQYEDCJ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-fluorophenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(F)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 GDDRCQQBQYEDCJ-UHFFFAOYSA-N 0.000 claims 1
- APHYRXHKPNQBJP-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-fluorophenyl)methylsulfonyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(F)=CC=C1CS(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 APHYRXHKPNQBJP-UHFFFAOYSA-N 0.000 claims 1
- FBRSMUOMYVJYOA-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-hydroxyphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(O)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 FBRSMUOMYVJYOA-UHFFFAOYSA-N 0.000 claims 1
- PVTARHLZFJQYHD-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-imidazol-1-ylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=CC(=CC=4)N4C=NC=C4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 PVTARHLZFJQYHD-UHFFFAOYSA-N 0.000 claims 1
- GGIFDAOMMFSCOL-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-methoxyphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(OC)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 GGIFDAOMMFSCOL-UHFFFAOYSA-N 0.000 claims 1
- UBQKBZUKINQRHY-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-methylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(C)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 UBQKBZUKINQRHY-UHFFFAOYSA-N 0.000 claims 1
- GQSQQANJZKNEGE-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-methylsulfanylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(SC)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 GQSQQANJZKNEGE-UHFFFAOYSA-N 0.000 claims 1
- BOBKROQAJIYUII-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-methylsulfonylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(S(=O)(=O)C)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 BOBKROQAJIYUII-UHFFFAOYSA-N 0.000 claims 1
- TWUZTMYDYMCJJV-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-morpholin-4-ylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=CC(=CC=4)N4CCOCC4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 TWUZTMYDYMCJJV-UHFFFAOYSA-N 0.000 claims 1
- DVXAUTWKUHEGFL-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-nitrophenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 DVXAUTWKUHEGFL-UHFFFAOYSA-N 0.000 claims 1
- BRKFSFDLJHCOAQ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-phenoxyphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=CC(OC=5C=CC=CC=5)=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 BRKFSFDLJHCOAQ-UHFFFAOYSA-N 0.000 claims 1
- GZICFABLXOJCTJ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-phenylmethoxyphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=CC(OCC=5C=CC=CC=5)=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 GZICFABLXOJCTJ-UHFFFAOYSA-N 0.000 claims 1
- VFFFMQCREXTDPH-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-phenylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=CC(=CC=4)C=4C=CC=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 VFFFMQCREXTDPH-UHFFFAOYSA-N 0.000 claims 1
- JJQOVSIPFHBMPQ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-propan-2-ylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)C)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 JJQOVSIPFHBMPQ-UHFFFAOYSA-N 0.000 claims 1
- PHPGPGDOELROGZ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-propoxyphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(OCCC)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 PHPGPGDOELROGZ-UHFFFAOYSA-N 0.000 claims 1
- ZCCSRUXURMTMFW-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-pyridin-2-ylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=CC(=CC=4)C=4N=CC=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 ZCCSRUXURMTMFW-UHFFFAOYSA-N 0.000 claims 1
- TWTGMUJHRVHZMZ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[(4-pyrimidin-5-ylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=CC(=CC=4)C=4C=NC=NC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 TWTGMUJHRVHZMZ-UHFFFAOYSA-N 0.000 claims 1
- UUKXJXZKXDRJNJ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[2-(4-methylphenyl)ethyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(C)=CC=C1CCN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 UUKXJXZKXDRJNJ-UHFFFAOYSA-N 0.000 claims 1
- NEVFLHRISPAWDT-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[4-(2-methylbutan-2-yl)phenyl]sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)CC)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 NEVFLHRISPAWDT-UHFFFAOYSA-N 0.000 claims 1
- AOUYDQHVLVFREK-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[4-(4-fluorophenyl)phenyl]sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(F)=CC=C1C1=CC=C(S(=O)(=O)N2CC3C(CN(C(=O)C=4SC=CC=4)C=4C=C(F)C(N5CCOCC5)=CC=4)C3C2)C=C1 AOUYDQHVLVFREK-UHFFFAOYSA-N 0.000 claims 1
- IJPWZILIXDTMIQ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[4-(trifluoromethoxy)phenyl]sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=CC(OC(F)(F)F)=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 IJPWZILIXDTMIQ-UHFFFAOYSA-N 0.000 claims 1
- SKCWXZXUZVJECD-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[4-(trifluoromethyl)phenyl]sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=CC(=CC=2)C(F)(F)F)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 SKCWXZXUZVJECD-UHFFFAOYSA-N 0.000 claims 1
- DKKSQHNUAZGOTH-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC=C(C(F)(F)F)C=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 DKKSQHNUAZGOTH-UHFFFAOYSA-N 0.000 claims 1
- FXHGEIYIQPEDJU-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[[3-(trifluoromethoxy)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=C(OC(F)(F)F)C=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 FXHGEIYIQPEDJU-UHFFFAOYSA-N 0.000 claims 1
- YCONVXWIFUVQEM-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[[3-(trifluoromethyl)phenyl]methylsulfonyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)CC=2C=C(C=CC=2)C(F)(F)F)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 YCONVXWIFUVQEM-UHFFFAOYSA-N 0.000 claims 1
- JKVHQHBUZDEYIZ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[[4-(2-hydroxyethoxy)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(OCCO)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 JKVHQHBUZDEYIZ-UHFFFAOYSA-N 0.000 claims 1
- PAHUNXRWSVNIED-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[[4-(2-methylpropyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(CC(C)C)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 PAHUNXRWSVNIED-UHFFFAOYSA-N 0.000 claims 1
- SQBVTSFPCLVIQQ-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[[4-(trifluoromethoxy)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=CC(OC(F)(F)F)=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 SQBVTSFPCLVIQQ-UHFFFAOYSA-N 0.000 claims 1
- MFIOZUCEHMHLDR-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[[4-(trifluoromethyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=CC(=CC=4)C(F)(F)F)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 MFIOZUCEHMHLDR-UHFFFAOYSA-N 0.000 claims 1
- VOHWXYKPFGKNQE-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[[4-(trifluoromethyl)phenyl]methylsulfonyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)CC=2C=CC(=CC=2)C(F)(F)F)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 VOHWXYKPFGKNQE-UHFFFAOYSA-N 0.000 claims 1
- GJUMYZFOEQSFLD-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[[4-[(2-methylpropan-2-yl)oxy]phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(OC(C)(C)C)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 GJUMYZFOEQSFLD-UHFFFAOYSA-N 0.000 claims 1
- NVEWZDMCWMKIIG-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[[5-(hydroxymethyl)furan-2-yl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound O1C(CO)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 NVEWZDMCWMKIIG-UHFFFAOYSA-N 0.000 claims 1
- VMTZPVQDTAKMJI-UHFFFAOYSA-N n-(3-fluoro-4-morpholin-4-ylphenyl)-n-[[3-[[6-(4-methylphenoxy)pyridin-3-yl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(C)=CC=C1OC(N=C1)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 VMTZPVQDTAKMJI-UHFFFAOYSA-N 0.000 claims 1
- LBIIYTPEDMOVCG-UHFFFAOYSA-N n-(4-benzylphenyl)-n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=CC(CC=4C=CC=CC=4)=CC=3)C2C1 LBIIYTPEDMOVCG-UHFFFAOYSA-N 0.000 claims 1
- YXUHDCMYTZZMQY-UHFFFAOYSA-N n-(4-tert-butylphenyl)-n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=CC(=CC=3)C(C)(C)C)C2C1 YXUHDCMYTZZMQY-UHFFFAOYSA-N 0.000 claims 1
- ZCTLXYJLJIRBMU-UHFFFAOYSA-N n-[(3-benzylsulfonyl-3-azabicyclo[3.1.0]hexan-6-yl)methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)CC=2C=CC=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 ZCTLXYJLJIRBMU-UHFFFAOYSA-N 0.000 claims 1
- LHEBJLFTCXWMFC-UHFFFAOYSA-N n-[1-[n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-3-fluoro-4-morpholin-4-ylanilino]-1-oxopropan-2-yl]benzamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C(C)NC(=O)C=3C=CC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 LHEBJLFTCXWMFC-UHFFFAOYSA-N 0.000 claims 1
- BJMXHJMXEYBCKX-UHFFFAOYSA-N n-[4-(4-ethyl-2,6-dioxopiperidin-4-yl)phenyl]-n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=CC(=CC=3)C3(CC)CC(=O)NC(=O)C3)C2C1 BJMXHJMXEYBCKX-UHFFFAOYSA-N 0.000 claims 1
- OFTZYGYISRXYBM-UHFFFAOYSA-N n-[4-(diethylamino)phenyl]-n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1=CC(N(CC)CC)=CC=C1N(C(=O)C=1SC=CC=1)CC1C2CN(CC=3C=CC(CC)=CC=3)CC21 OFTZYGYISRXYBM-UHFFFAOYSA-N 0.000 claims 1
- RWGGMRGRDXZJEK-UHFFFAOYSA-N n-[6-(4-acetylpiperazin-1-yl)pyridin-3-yl]-n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]thiophene-2-carboxamide Chemical compound C1CN(C(=O)C)CCN1C1=CC=C(N(CC2C3CN(CC32)C(=O)C=2C=CC(=CC=2)C(C)(C)C)C(=O)C=2SC=CC=2)C=N1 RWGGMRGRDXZJEK-UHFFFAOYSA-N 0.000 claims 1
- OSDBVJVXCUCWTR-UHFFFAOYSA-N n-[[3-(1,3-benzodioxol-5-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=C5OCOC5=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 OSDBVJVXCUCWTR-UHFFFAOYSA-N 0.000 claims 1
- GJERGRGRBJJXJM-UHFFFAOYSA-N n-[[3-(1-benzofuran-2-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4OC5=CC=CC=C5C=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 GJERGRGRBJJXJM-UHFFFAOYSA-N 0.000 claims 1
- RYVAKAJXNHKICK-UHFFFAOYSA-N n-[[3-(1-benzothiophen-2-ylsulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2SC3=CC=CC=C3C=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 RYVAKAJXNHKICK-UHFFFAOYSA-N 0.000 claims 1
- TUKOTROLXKELCU-UHFFFAOYSA-N n-[[3-(2,2-diphenylethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC(C=4C=CC=CC=4)C=4C=CC=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 TUKOTROLXKELCU-UHFFFAOYSA-N 0.000 claims 1
- QYSHUFSIOBDLQQ-UHFFFAOYSA-N n-[[3-(4-acetamidophenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(NC(=O)C)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 QYSHUFSIOBDLQQ-UHFFFAOYSA-N 0.000 claims 1
- VHKITRSKNIOCLJ-UHFFFAOYSA-N n-[[3-(4-acetylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 VHKITRSKNIOCLJ-UHFFFAOYSA-N 0.000 claims 1
- ZNWCTYFAWXVIBT-UHFFFAOYSA-N n-[[3-(4-butoxyphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(OCCCC)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 ZNWCTYFAWXVIBT-UHFFFAOYSA-N 0.000 claims 1
- OFLYTVGNWHFTCV-UHFFFAOYSA-N n-[[3-(4-butylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(CCCC)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 OFLYTVGNWHFTCV-UHFFFAOYSA-N 0.000 claims 1
- QZACQFBJMXGBJU-UHFFFAOYSA-N n-[[3-(4-chlorophenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=CC(Cl)=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 QZACQFBJMXGBJU-UHFFFAOYSA-N 0.000 claims 1
- RDJSQPMUYGTAKS-UHFFFAOYSA-N n-[[3-(4-cyanophenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=CC(=CC=2)C#N)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 RDJSQPMUYGTAKS-UHFFFAOYSA-N 0.000 claims 1
- NHBOWMCJRLROHH-UHFFFAOYSA-N n-[[3-(4-ethylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(CC)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 NHBOWMCJRLROHH-UHFFFAOYSA-N 0.000 claims 1
- ZRCBZJPLECPYPM-UHFFFAOYSA-N n-[[3-(4-ethylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(CC)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 ZRCBZJPLECPYPM-UHFFFAOYSA-N 0.000 claims 1
- NBWFMIHFXAUISX-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-1-methyl-n-(6-morpholin-4-ylpyridin-3-yl)pyrrole-2-carboxamide Chemical compound CN1C=CC=C1C(=O)N(C=1C=NC(=CC=1)N1CCOCC1)CC1C2CN(C(=O)C=3C=CC(=CC=3)C(C)(C)C)CC21 NBWFMIHFXAUISX-UHFFFAOYSA-N 0.000 claims 1
- APVRSQOQSOHXPY-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-2-methyl-n-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxamide Chemical compound S1C(C)=NC(C(=O)N(CC2C3CN(CC32)C(=O)C=2C=CC(=CC=2)C(C)(C)C)C=2C=NC(=CC=2)N2CCOCC2)=C1 APVRSQOQSOHXPY-UHFFFAOYSA-N 0.000 claims 1
- ULBGNEIPSPVXFN-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-3-chloro-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C3=C(C=CS3)Cl)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 ULBGNEIPSPVXFN-UHFFFAOYSA-N 0.000 claims 1
- XKGQCVGSSBSDSH-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-3-chloro-n-(6-morpholin-4-ylpyridin-3-yl)thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C3=C(C=CS3)Cl)C=3C=NC(=CC=3)N3CCOCC3)C2C1 XKGQCVGSSBSDSH-UHFFFAOYSA-N 0.000 claims 1
- QXUBQLUGOQMKCL-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-4-methyl-n-(6-morpholin-4-ylpyridin-3-yl)benzamide Chemical compound C1=CC(C)=CC=C1C(=O)N(C=1C=NC(=CC=1)N1CCOCC1)CC1C2CN(C(=O)C=3C=CC(=CC=3)C(C)(C)C)CC21 QXUBQLUGOQMKCL-UHFFFAOYSA-N 0.000 claims 1
- UAIQKLFHRGMPSV-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-4-methyl-n-(6-morpholin-4-ylpyridin-3-yl)thiadiazole-5-carboxamide Chemical compound N1=NSC(C(=O)N(CC2C3CN(CC32)C(=O)C=2C=CC(=CC=2)C(C)(C)C)C=2C=NC(=CC=2)N2CCOCC2)=C1C UAIQKLFHRGMPSV-UHFFFAOYSA-N 0.000 claims 1
- PHEWFLQKKGWSDS-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-5-fluoro-n-(6-morpholin-4-ylpyridin-3-yl)thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC(F)=CC=3)C=3C=NC(=CC=3)N3CCOCC3)C2C1 PHEWFLQKKGWSDS-UHFFFAOYSA-N 0.000 claims 1
- SKRXIDNXYYFZNK-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-5-methyl-n-(6-morpholin-4-ylpyridin-3-yl)thiophene-2-carboxamide Chemical compound S1C(C)=CC=C1C(=O)N(C=1C=NC(=CC=1)N1CCOCC1)CC1C2CN(C(=O)C=3C=CC(=CC=3)C(C)(C)C)CC21 SKRXIDNXYYFZNK-UHFFFAOYSA-N 0.000 claims 1
- UGXJBRDZLCPEOS-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-6-morpholin-4-yl-n-(thiophen-2-ylmethyl)pyridine-3-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(CC=3SC=CC=3)C(=O)C=3C=NC(=CC=3)N3CCOCC3)C2C1 UGXJBRDZLCPEOS-UHFFFAOYSA-N 0.000 claims 1
- WAJXUCSXBUMKFM-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 WAJXUCSXBUMKFM-UHFFFAOYSA-N 0.000 claims 1
- BBVDZQMEDIMQHN-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(6-morpholin-4-ylpyridin-3-yl)-1-benzofuran-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3OC4=CC=CC=C4C=3)C=3C=NC(=CC=3)N3CCOCC3)C2C1 BBVDZQMEDIMQHN-UHFFFAOYSA-N 0.000 claims 1
- MOECKDZDZKYQNI-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(6-morpholin-4-ylpyridin-3-yl)furan-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3OC=CC=3)C=3C=NC(=CC=3)N3CCOCC3)C2C1 MOECKDZDZKYQNI-UHFFFAOYSA-N 0.000 claims 1
- WGRZJVTYFJGAJS-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(6-morpholin-4-ylpyridin-3-yl)pyridine-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3N=CC=CC=3)C=3C=NC(=CC=3)N3CCOCC3)C2C1 WGRZJVTYFJGAJS-UHFFFAOYSA-N 0.000 claims 1
- LXTPZEPOSXWEPP-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(6-morpholin-4-ylpyridin-3-yl)thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=NC(=CC=3)N3CCOCC3)C2C1 LXTPZEPOSXWEPP-UHFFFAOYSA-N 0.000 claims 1
- PZYJBHHIDIZNNJ-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(6-thiomorpholin-4-ylpyridin-3-yl)thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=NC(=CC=3)N3CCSCC3)C2C1 PZYJBHHIDIZNNJ-UHFFFAOYSA-N 0.000 claims 1
- PNNVWZLJOCAJDB-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[1-(oxan-4-yl)piperidin-4-yl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C3CCN(CC3)C3CCOCC3)C(=O)C=3SC=CC=3)C2C1 PNNVWZLJOCAJDB-UHFFFAOYSA-N 0.000 claims 1
- ACJGLBDBRYNJMQ-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[1-(oxan-4-yl)pyrrolidin-3-yl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C3CN(CC3)C3CCOCC3)C(=O)C=3SC=CC=3)C2C1 ACJGLBDBRYNJMQ-UHFFFAOYSA-N 0.000 claims 1
- BKUFZFWRPCRHOO-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[2-(2-ethoxyethyl)-3,4-dihydro-1h-isoquinolin-7-yl]thiophene-2-carboxamide Chemical compound C1=C2CN(CCOCC)CCC2=CC=C1N(C(=O)C=1SC=CC=1)CC(C1C2)C1CN2C(=O)C1=CC=C(C(C)(C)C)C=C1 BKUFZFWRPCRHOO-UHFFFAOYSA-N 0.000 claims 1
- GPDDJGWHXRPIFC-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[3-(oxan-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C3C4CN(CC43)C3CCOCC3)C(=O)C=3SC=CC=3)C2C1 GPDDJGWHXRPIFC-UHFFFAOYSA-N 0.000 claims 1
- HELHJTWSJCAQOT-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[4-(2-oxopyrrolidin-1-yl)phenyl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=CC(=CC=3)N3C(CCC3)=O)C2C1 HELHJTWSJCAQOT-UHFFFAOYSA-N 0.000 claims 1
- XLDVCNCMJDOPNG-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[4-(diethylcarbamoyl)phenyl]thiophene-2-carboxamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1N(C(=O)C=1SC=CC=1)CC1C2CN(C(=O)C=3C=CC(=CC=3)C(C)(C)C)CC21 XLDVCNCMJDOPNG-UHFFFAOYSA-N 0.000 claims 1
- ZZAZIQFNYDSDNK-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[4-(morpholin-4-ylmethyl)phenyl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=CC(CN4CCOCC4)=CC=3)C2C1 ZZAZIQFNYDSDNK-UHFFFAOYSA-N 0.000 claims 1
- HTYKLTQJNCVYPE-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[4-(morpholine-4-carbonyl)phenyl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=CC(=CC=3)C(=O)N3CCOCC3)C2C1 HTYKLTQJNCVYPE-UHFFFAOYSA-N 0.000 claims 1
- INMQGCUMQZPISQ-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[4-(oxan-4-yl)phenyl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=CC(=CC=3)C3CCOCC3)C2C1 INMQGCUMQZPISQ-UHFFFAOYSA-N 0.000 claims 1
- CPHOJYXGBCYBEA-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-(3,5-dihydro-2h-1,4-benzoxazepin-4-yl)pyridin-3-yl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=NC(=CC=3)N3CC4=CC=CC=C4OCC3)C2C1 CPHOJYXGBCYBEA-UHFFFAOYSA-N 0.000 claims 1
- INEDCOJOUAYSHB-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-(3,6-dihydro-2h-pyran-4-yl)pyridin-3-yl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=NC(=CC=3)C=3CCOCC=3)C2C1 INEDCOJOUAYSHB-UHFFFAOYSA-N 0.000 claims 1
- RJNYTWONLVZSFY-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-(3-morpholin-4-ylazetidin-1-yl)pyridin-3-yl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=NC(=CC=3)N3CC(C3)N3CCOCC3)C2C1 RJNYTWONLVZSFY-UHFFFAOYSA-N 0.000 claims 1
- JVQSZPPZZKMSQZ-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-(3-morpholin-4-ylpyrrolidin-1-yl)pyridin-3-yl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=NC(=CC=3)N3CC(CC3)N3CCOCC3)C2C1 JVQSZPPZZKMSQZ-UHFFFAOYSA-N 0.000 claims 1
- WLZSFJKGSBIWBD-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-(3-oxopiperazin-1-yl)pyridin-3-yl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=NC(=CC=3)N3CC(=O)NCC3)C2C1 WLZSFJKGSBIWBD-UHFFFAOYSA-N 0.000 claims 1
- SBOVRSOHCNAWAQ-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl]thiophene-2-carboxamide Chemical compound C1CN(C)CCCN1C1=CC=C(N(CC2C3CN(CC32)C(=O)C=2C=CC(=CC=2)C(C)(C)C)C(=O)C=2SC=CC=2)C=N1 SBOVRSOHCNAWAQ-UHFFFAOYSA-N 0.000 claims 1
- XMWZQESQIVHZKU-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]thiophene-2-carboxamide Chemical compound C1CN(C)CCN1C1=CC=C(N(CC2C3CN(CC32)C(=O)C=2C=CC(=CC=2)C(C)(C)C)C(=O)C=2SC=CC=2)C=N1 XMWZQESQIVHZKU-UHFFFAOYSA-N 0.000 claims 1
- JMUSTUZRYWUOKS-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl]thiophene-2-carboxamide Chemical compound CN1CC2CC1CN2C(N=C1)=CC=C1N(C(=O)C=1SC=CC=1)CC(C1C2)C1CN2C(=O)C1=CC=C(C(C)(C)C)C=C1 JMUSTUZRYWUOKS-UHFFFAOYSA-N 0.000 claims 1
- ZUSCUARAOIQFFJ-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl]thiophene-2-carboxamide Chemical compound CN1C(C2)CCC1CN2C(N=C1)=CC=C1N(C(=O)C=1SC=CC=1)CC(C1C2)C1CN2C(=O)C1=CC=C(C(C)(C)C)C=C1 ZUSCUARAOIQFFJ-UHFFFAOYSA-N 0.000 claims 1
- SLCHLYGZILGZPK-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-(morpholin-4-ylmethyl)pyridin-3-yl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=NC(CN4CCOCC4)=CC=3)C2C1 SLCHLYGZILGZPK-UHFFFAOYSA-N 0.000 claims 1
- WHQBPTUZLFNPEI-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-(oxan-4-yl)pyridin-3-yl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=NC(=CC=3)C3CCOCC3)C2C1 WHQBPTUZLFNPEI-UHFFFAOYSA-N 0.000 claims 1
- RKJVXHIMPSBCAZ-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-[1h-imidazol-2-ylmethyl(methyl)amino]pyridin-3-yl]thiophene-2-carboxamide Chemical compound C=1C=C(N(CC2C3CN(CC32)C(=O)C=2C=CC(=CC=2)C(C)(C)C)C(=O)C=2SC=CC=2)C=NC=1N(C)CC1=NC=CN1 RKJVXHIMPSBCAZ-UHFFFAOYSA-N 0.000 claims 1
- ZLECDXRDBRUWIA-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-[2-methoxyethyl(methyl)amino]pyridin-3-yl]thiophene-2-carboxamide Chemical compound C1=NC(N(C)CCOC)=CC=C1N(C(=O)C=1SC=CC=1)CC1C2CN(C(=O)C=3C=CC(=CC=3)C(C)(C)C)CC21 ZLECDXRDBRUWIA-UHFFFAOYSA-N 0.000 claims 1
- NWGJLBZONMFETH-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-[3-(diethylamino)pyrrolidin-1-yl]pyridin-3-yl]thiophene-2-carboxamide Chemical compound C1C(N(CC)CC)CCN1C1=CC=C(N(CC2C3CN(CC32)C(=O)C=2C=CC(=CC=2)C(C)(C)C)C(=O)C=2SC=CC=2)C=N1 NWGJLBZONMFETH-UHFFFAOYSA-N 0.000 claims 1
- KQJFANKLPQYSMH-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-[3-(dimethylamino)pyrrolidin-1-yl]pyridin-3-yl]thiophene-2-carboxamide Chemical compound C1C(N(C)C)CCN1C1=CC=C(N(CC2C3CN(CC32)C(=O)C=2C=CC(=CC=2)C(C)(C)C)C(=O)C=2SC=CC=2)C=N1 KQJFANKLPQYSMH-UHFFFAOYSA-N 0.000 claims 1
- APTKRKVLXXIJBL-UHFFFAOYSA-N n-[[3-(4-tert-butylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[6-[ethyl(2-methoxyethyl)amino]pyridin-3-yl]thiophene-2-carboxamide Chemical compound C1=NC(N(CCOC)CC)=CC=C1N(C(=O)C=1SC=CC=1)CC1C2CN(C(=O)C=3C=CC(=CC=3)C(C)(C)C)CC21 APTKRKVLXXIJBL-UHFFFAOYSA-N 0.000 claims 1
- ARPIUUVNGCIEEK-UHFFFAOYSA-N n-[[3-(4-tert-butylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-1-methyl-n-(6-morpholin-4-ylpyridin-3-yl)pyrrole-2-carboxamide Chemical compound CN1C=CC=C1C(=O)N(C=1C=NC(=CC=1)N1CCOCC1)CC1C2CN(S(=O)(=O)C=3C=CC(=CC=3)C(C)(C)C)CC21 ARPIUUVNGCIEEK-UHFFFAOYSA-N 0.000 claims 1
- GEPOYZBQGRNHQV-UHFFFAOYSA-N n-[[3-(4-tert-butylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-3-chloro-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C3=C(C=CS3)Cl)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 GEPOYZBQGRNHQV-UHFFFAOYSA-N 0.000 claims 1
- MNUXZVJENSZMHD-UHFFFAOYSA-N n-[[3-(4-tert-butylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-3-chloro-n-(6-morpholin-4-ylpyridin-3-yl)thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C3=C(C=CS3)Cl)C=3C=NC(=CC=3)N3CCOCC3)C2C1 MNUXZVJENSZMHD-UHFFFAOYSA-N 0.000 claims 1
- HBOOJDDORLHDJT-UHFFFAOYSA-N n-[[3-(4-tert-butylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-4-methyl-n-(6-morpholin-4-ylpyridin-3-yl)benzamide Chemical compound C1=CC(C)=CC=C1C(=O)N(C=1C=NC(=CC=1)N1CCOCC1)CC1C2CN(S(=O)(=O)C=3C=CC(=CC=3)C(C)(C)C)CC21 HBOOJDDORLHDJT-UHFFFAOYSA-N 0.000 claims 1
- NWWPXGMLXVHCKW-UHFFFAOYSA-N n-[[3-(4-tert-butylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-4-methyl-n-(6-morpholin-4-ylpyridin-3-yl)thiadiazole-5-carboxamide Chemical compound N1=NSC(C(=O)N(CC2C3CN(CC32)S(=O)(=O)C=2C=CC(=CC=2)C(C)(C)C)C=2C=NC(=CC=2)N2CCOCC2)=C1C NWWPXGMLXVHCKW-UHFFFAOYSA-N 0.000 claims 1
- XXJDFJNLDRXJKX-UHFFFAOYSA-N n-[[3-(4-tert-butylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-5-fluoro-n-(6-morpholin-4-ylpyridin-3-yl)thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC(F)=CC=3)C=3C=NC(=CC=3)N3CCOCC3)C2C1 XXJDFJNLDRXJKX-UHFFFAOYSA-N 0.000 claims 1
- CWZHWZMNOGTNQN-UHFFFAOYSA-N n-[[3-(4-tert-butylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(6-morpholin-4-ylpyridin-3-yl)cyclobutanecarboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C3CCC3)C=3C=NC(=CC=3)N3CCOCC3)C2C1 CWZHWZMNOGTNQN-UHFFFAOYSA-N 0.000 claims 1
- YUISVONRFOZIEL-UHFFFAOYSA-N n-[[3-(4-tert-butylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(6-morpholin-4-ylpyridin-3-yl)cyclopentanecarboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C3CCCC3)C=3C=NC(=CC=3)N3CCOCC3)C2C1 YUISVONRFOZIEL-UHFFFAOYSA-N 0.000 claims 1
- IFNBQQXBBSXAFE-UHFFFAOYSA-N n-[[3-(4-tert-butylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(6-morpholin-4-ylpyridin-3-yl)cyclopropanecarboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C3CC3)C=3C=NC(=CC=3)N3CCOCC3)C2C1 IFNBQQXBBSXAFE-UHFFFAOYSA-N 0.000 claims 1
- SIOMMOADPROREX-UHFFFAOYSA-N n-[[3-(4-tert-butylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(6-morpholin-4-ylpyridin-3-yl)thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=NC(=CC=3)N3CCOCC3)C2C1 SIOMMOADPROREX-UHFFFAOYSA-N 0.000 claims 1
- VENNRCPDDWOXJT-UHFFFAOYSA-N n-[[3-(4-tert-butylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[2-(2-ethoxyethyl)-3,4-dihydro-1h-isoquinolin-7-yl]thiophene-2-carboxamide Chemical compound C1=C2CN(CCOCC)CCC2=CC=C1N(C(=O)C=1SC=CC=1)CC(C1C2)C1CN2S(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 VENNRCPDDWOXJT-UHFFFAOYSA-N 0.000 claims 1
- IBJZHSWXMQLUER-UHFFFAOYSA-N n-[[3-(4-tert-butylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[4-(2-oxopyrrolidin-1-yl)phenyl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=CC(=CC=3)N3C(CCC3)=O)C2C1 IBJZHSWXMQLUER-UHFFFAOYSA-N 0.000 claims 1
- IMMOLJFZPKERPY-UHFFFAOYSA-N n-[[3-(4-tert-butylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[4-(diethylcarbamoyl)phenyl]thiophene-2-carboxamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1N(C(=O)C=1SC=CC=1)CC1C2CN(S(=O)(=O)C=3C=CC(=CC=3)C(C)(C)C)CC21 IMMOLJFZPKERPY-UHFFFAOYSA-N 0.000 claims 1
- SWYMCYKZPQSFLH-UHFFFAOYSA-N n-[[3-(4-tert-butylphenyl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[4-(morpholine-4-carbonyl)phenyl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=CC(=CC=3)C(=O)N3CCOCC3)C2C1 SWYMCYKZPQSFLH-UHFFFAOYSA-N 0.000 claims 1
- XPSQEMXGJUJQSR-UHFFFAOYSA-N n-[[3-(5-bromo-6-chloropyridin-3-yl)sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=C(Br)C(Cl)=NC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 XPSQEMXGJUJQSR-UHFFFAOYSA-N 0.000 claims 1
- RLMBTRLYMACNGN-UHFFFAOYSA-N n-[[3-(5-butylpyridine-2-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound N1=CC(CCCC)=CC=C1C(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 RLMBTRLYMACNGN-UHFFFAOYSA-N 0.000 claims 1
- ZLNJTOQZBFVWCY-UHFFFAOYSA-N n-[[3-(cyclohexylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC4CCCCC4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 ZLNJTOQZBFVWCY-UHFFFAOYSA-N 0.000 claims 1
- VIHKJHIYMCGCBB-UHFFFAOYSA-N n-[[3-[(2-acetamido-4-methyl-1,3-thiazol-5-yl)sulfonyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound S1C(NC(=O)C)=NC(C)=C1S(=O)(=O)N1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 VIHKJHIYMCGCBB-UHFFFAOYSA-N 0.000 claims 1
- ADCWNLLJDONINO-UHFFFAOYSA-N n-[[3-[(2-ethyl-5-methyl-1h-imidazol-4-yl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound N1C(CC)=NC(C)=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 ADCWNLLJDONINO-UHFFFAOYSA-N 0.000 claims 1
- DPVFIVOZYIXCCH-UHFFFAOYSA-N n-[[3-[(3,4-dichlorophenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=C(Cl)C(Cl)=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 DPVFIVOZYIXCCH-UHFFFAOYSA-N 0.000 claims 1
- YGEHJCNWZADWGK-UHFFFAOYSA-N n-[[3-[(3-ethoxyphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound CCOC1=CC=CC(CN2CC3C(CN(C(=O)C=4SC=CC=4)C=4C=C(F)C(N5CCOCC5)=CC=4)C3C2)=C1 YGEHJCNWZADWGK-UHFFFAOYSA-N 0.000 claims 1
- RGAPBHICVFRLPV-UHFFFAOYSA-N n-[[3-[(4-acetamidophenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(NC(=O)C)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 RGAPBHICVFRLPV-UHFFFAOYSA-N 0.000 claims 1
- BEGICTOEHFNFDK-UHFFFAOYSA-N n-[[3-[(4-bromophenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=CC(Br)=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 BEGICTOEHFNFDK-UHFFFAOYSA-N 0.000 claims 1
- NQXRTFWKMHGADS-UHFFFAOYSA-N n-[[3-[(4-butylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(CCCC)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 NQXRTFWKMHGADS-UHFFFAOYSA-N 0.000 claims 1
- PMFNFJCQRWUBSX-UHFFFAOYSA-N n-[[3-[(4-chlorophenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=CC(Cl)=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 PMFNFJCQRWUBSX-UHFFFAOYSA-N 0.000 claims 1
- VDGBGMYHXSPWDA-UHFFFAOYSA-N n-[[3-[(4-cyanophenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4C=CC(=CC=4)C#N)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 VDGBGMYHXSPWDA-UHFFFAOYSA-N 0.000 claims 1
- HHKNRORDYIFADO-UHFFFAOYSA-N n-[[3-[(4-ethoxyphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(OCC)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 HHKNRORDYIFADO-UHFFFAOYSA-N 0.000 claims 1
- RLVDUOMRTBQAJN-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-2,4-difluoro-n-(3-fluoro-4-morpholin-4-ylphenyl)benzamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3C(=CC(F)=CC=3)F)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 RLVDUOMRTBQAJN-UHFFFAOYSA-N 0.000 claims 1
- YCJZXLKCBWJZHU-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-1,2-oxazole-5-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3ON=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 YCJZXLKCBWJZHU-UHFFFAOYSA-N 0.000 claims 1
- UEMVAEXGQDDBLB-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-1,5-dimethylpyrazole-3-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C3=NN(C)C(C)=C3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 UEMVAEXGQDDBLB-UHFFFAOYSA-N 0.000 claims 1
- RDQPWGRDUKSNAL-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-1-benzofuran-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3OC4=CC=CC=C4C=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 RDQPWGRDUKSNAL-UHFFFAOYSA-N 0.000 claims 1
- QOQMKSUWSLTHDS-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-1-benzothiophene-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3SC4=CC=CC=C4C=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 QOQMKSUWSLTHDS-UHFFFAOYSA-N 0.000 claims 1
- JTAXUFCNFBPNCY-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-1-methylimidazole-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3N(C=CN=3)C)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 JTAXUFCNFBPNCY-UHFFFAOYSA-N 0.000 claims 1
- KZZWGCWUNXPRLW-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-1-methylpyrazole-3-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C3=NN(C)C=C3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 KZZWGCWUNXPRLW-UHFFFAOYSA-N 0.000 claims 1
- PJVZFMPIMYBDTA-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-1-methylpyrrole-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3N(C=CC=3)C)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 PJVZFMPIMYBDTA-UHFFFAOYSA-N 0.000 claims 1
- IQZGZUVZNCWEHF-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-2,5-dimethylfuran-3-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C3=C(OC(C)=C3)C)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 IQZGZUVZNCWEHF-UHFFFAOYSA-N 0.000 claims 1
- VCCANXRQOZCCSW-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-2-(2-fluorophenyl)acetamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)CC=3C(=CC=CC=3)F)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 VCCANXRQOZCCSW-UHFFFAOYSA-N 0.000 claims 1
- SHMDSDDUTANZAN-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-2-(2-methoxyphenyl)acetamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)CC=3C(=CC=CC=3)OC)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 SHMDSDDUTANZAN-UHFFFAOYSA-N 0.000 claims 1
- NCSCOQIYWQOYJF-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-2-methoxybenzamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3C(=CC=CC=3)OC)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 NCSCOQIYWQOYJF-UHFFFAOYSA-N 0.000 claims 1
- ZOSVATWYUJVXEN-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-2-methyl-1,3-thiazole-4-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3N=C(C)SC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 ZOSVATWYUJVXEN-UHFFFAOYSA-N 0.000 claims 1
- CGRYSESMMLXTBF-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-2-methylsulfanylpyridine-3-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3C(=NC=CC=3)SC)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 CGRYSESMMLXTBF-UHFFFAOYSA-N 0.000 claims 1
- OTIHOMHPRAZJRU-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-2-pyridin-3-ylacetamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)CC=3C=NC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 OTIHOMHPRAZJRU-UHFFFAOYSA-N 0.000 claims 1
- JCRIBNKYCHLIDW-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-3,5-dimethoxybenzamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3C=C(OC)C=C(OC)C=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 JCRIBNKYCHLIDW-UHFFFAOYSA-N 0.000 claims 1
- IGDUNJYHENUXCJ-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-3,5-dimethyl-1h-pyrrole-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C3=C(C=C(C)N3)C)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 IGDUNJYHENUXCJ-UHFFFAOYSA-N 0.000 claims 1
- HBHFQBTXMRMCPP-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-3-methoxybenzamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3C=C(OC)C=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 HBHFQBTXMRMCPP-UHFFFAOYSA-N 0.000 claims 1
- GUQPWYSBEYHBFA-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-3-methylfuran-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C3=C(C=CO3)C)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 GUQPWYSBEYHBFA-UHFFFAOYSA-N 0.000 claims 1
- FNKFIRDQORCATR-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-3-methylthiophene-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C3=C(C=CS3)C)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 FNKFIRDQORCATR-UHFFFAOYSA-N 0.000 claims 1
- AMHQQVUYQHUOHX-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-4-methoxybenzamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3C=CC(OC)=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 AMHQQVUYQHUOHX-UHFFFAOYSA-N 0.000 claims 1
- VGFLWRCSAGOBDN-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-5-methyl-1,2-oxazole-3-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C3=NOC(C)=C3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 VGFLWRCSAGOBDN-UHFFFAOYSA-N 0.000 claims 1
- HPLRJVWAESELDA-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-5-methylthiophene-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3SC(C)=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 HPLRJVWAESELDA-UHFFFAOYSA-N 0.000 claims 1
- FFPPZTOPCHTTFV-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)-5-oxopyrrolidine-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C3NC(=O)CC3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 FFPPZTOPCHTTFV-UHFFFAOYSA-N 0.000 claims 1
- VPCJPUKUZMVPAJ-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)furan-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3OC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 VPCJPUKUZMVPAJ-UHFFFAOYSA-N 0.000 claims 1
- MNNXTQNBJHWESE-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)furan-3-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C3=COC=C3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 MNNXTQNBJHWESE-UHFFFAOYSA-N 0.000 claims 1
- RWENJIZXJXROBC-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)pyridine-3-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3C=NC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 RWENJIZXJXROBC-UHFFFAOYSA-N 0.000 claims 1
- LNJDNZRJMUKAIF-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)pyridine-4-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3C=CN=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 LNJDNZRJMUKAIF-UHFFFAOYSA-N 0.000 claims 1
- SNOXBIISFFXTFL-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-3-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C3=CSC=C3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 SNOXBIISFFXTFL-UHFFFAOYSA-N 0.000 claims 1
- JSHDYIVUBCPHIW-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(4-piperidin-1-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=CC(=CC=3)N3CCCCC3)C2C1 JSHDYIVUBCPHIW-UHFFFAOYSA-N 0.000 claims 1
- AAEOJUSYIGSQAG-UHFFFAOYSA-N n-[[3-[(4-tert-butylcyclohexyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1CC(C(C)(C)C)CCC1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 AAEOJUSYIGSQAG-UHFFFAOYSA-N 0.000 claims 1
- RWTBLBRVXKUAQH-UHFFFAOYSA-N n-[[3-[(4-tert-butylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 RWTBLBRVXKUAQH-UHFFFAOYSA-N 0.000 claims 1
- GCKLHLQDUWVIBP-UHFFFAOYSA-N n-[[3-[(4-tert-butylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(6-morpholin-4-ylpyridin-3-yl)thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=NC(=CC=3)N3CCOCC3)C2C1 GCKLHLQDUWVIBP-UHFFFAOYSA-N 0.000 claims 1
- OUKOEFBSBQSMPZ-UHFFFAOYSA-N n-[[3-[(4-tert-butylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[(4-morpholin-4-ylphenyl)methyl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1CN1CC2C(CN(CC=3C=CC(=CC=3)N3CCOCC3)C(=O)C=3SC=CC=3)C2C1 OUKOEFBSBQSMPZ-UHFFFAOYSA-N 0.000 claims 1
- UHPNHTQPAXRDIB-UHFFFAOYSA-N n-[[3-[(4-tert-butylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[2-(2-ethoxyethyl)-3,4-dihydro-1h-isoquinolin-7-yl]thiophene-2-carboxamide Chemical compound C1=C2CN(CCOCC)CCC2=CC=C1N(C(=O)C=1SC=CC=1)CC(C1C2)C1CN2CC1=CC=C(C(C)(C)C)C=C1 UHPNHTQPAXRDIB-UHFFFAOYSA-N 0.000 claims 1
- UTZUFHBLOVLEAK-UHFFFAOYSA-N n-[[3-[(4-tert-butylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[4-(2-oxopyrrolidin-1-yl)phenyl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=CC(=CC=3)N3C(CCC3)=O)C2C1 UTZUFHBLOVLEAK-UHFFFAOYSA-N 0.000 claims 1
- PJTBDEJOIVVJGR-UHFFFAOYSA-N n-[[3-[(4-tert-butylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[4-(morpholine-4-carbonyl)phenyl]thiophene-2-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=CC(=CC=3)C(=O)N3CCOCC3)C2C1 PJTBDEJOIVVJGR-UHFFFAOYSA-N 0.000 claims 1
- NJKULANMQFGCMF-UHFFFAOYSA-N n-[[3-[(4-tert-butylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-[4-[ethyl(2-hydroxyethyl)amino]phenyl]thiophene-2-carboxamide Chemical compound C1=CC(N(CCO)CC)=CC=C1N(C(=O)C=1SC=CC=1)CC1C2CN(CC=3C=CC(=CC=3)C(C)(C)C)CC21 NJKULANMQFGCMF-UHFFFAOYSA-N 0.000 claims 1
- BRRWLFJUYQXOIM-UHFFFAOYSA-N n-[[3-[(5-benzylpyridin-2-yl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC=4N=CC(CC=5C=CC=CC=5)=CC=4)CC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 BRRWLFJUYQXOIM-UHFFFAOYSA-N 0.000 claims 1
- GCDBXZWYATXJQI-UHFFFAOYSA-N n-[[3-[(5-ethylthiophen-2-yl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound S1C(CC)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 GCDBXZWYATXJQI-UHFFFAOYSA-N 0.000 claims 1
- INSBKDFGLGDBNL-UHFFFAOYSA-N n-[[3-[3-(4-chlorophenoxy)phenyl]sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=C(OC=3C=CC(Cl)=CC=3)C=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 INSBKDFGLGDBNL-UHFFFAOYSA-N 0.000 claims 1
- UQPRGYGIFWHZOU-UHFFFAOYSA-N n-[[3-[3-(4-chlorophenyl)phenyl]sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=C(C=CC=2)C=2C=CC(Cl)=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 UQPRGYGIFWHZOU-UHFFFAOYSA-N 0.000 claims 1
- JXMUSNWVHHQNBH-UHFFFAOYSA-N n-[[3-[4-(4-chlorophenoxy)phenyl]sulfonyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CN(CC32)S(=O)(=O)C=2C=CC(OC=3C=CC(Cl)=CC=3)=CC=2)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 JXMUSNWVHHQNBH-UHFFFAOYSA-N 0.000 claims 1
- WQYZLAIJBWDKEB-UHFFFAOYSA-N n-[[3-[[2-fluoro-4-(2-hydroxypropan-2-yl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(C(C)(O)C)=CC=C1CN1CC2C(CN(C(=O)C=3SC=CC=3)C=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 WQYZLAIJBWDKEB-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 67
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 38
- 239000000460 chlorine Substances 0.000 description 32
- 239000000203 mixture Substances 0.000 description 31
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 230000002829 reductive effect Effects 0.000 description 27
- 239000002904 solvent Substances 0.000 description 25
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
- 238000000034 method Methods 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 22
- 150000001412 amines Chemical class 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- 239000003153 chemical reaction reagent Substances 0.000 description 19
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- 239000004471 Glycine Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 239000013058 crude material Substances 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 150000001299 aldehydes Chemical class 0.000 description 12
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- 238000003818 flash chromatography Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 8
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 6
- 229940092714 benzenesulfonic acid Drugs 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 229940098779 methanesulfonic acid Drugs 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 229930195712 glutamate Natural products 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229930006000 Sucrose Natural products 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 210000003568 synaptosome Anatomy 0.000 description 4
- FDORQEIHOKEJNX-UHFFFAOYSA-N 2-[[3-(4-fluorophenyl)-3-(4-phenylphenoxy)propyl]-methylamino]acetic acid Chemical compound C=1C=C(F)C=CC=1C(CCN(C)CC(O)=O)OC(C=C1)=CC=C1C1=CC=CC=C1 FDORQEIHOKEJNX-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 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 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 3
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000024587 synaptic transmission, glutamatergic Effects 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- FQGIBHQUVCGEAC-UHFFFAOYSA-N 3-Fluoro-4-morpholinoaniline Chemical compound FC1=CC(N)=CC=C1N1CCOCC1 FQGIBHQUVCGEAC-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 206010043118 Tardive Dyskinesia Diseases 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000000969 carrier Substances 0.000 description 2
- 208000015114 central nervous system disease Diseases 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 230000001149 cognitive effect Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000007788 liquid Substances 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
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- XZBIOMPCWMJBLA-UHFFFAOYSA-N n-(3-azabicyclo[3.1.0]hexan-6-ylmethyl)-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide Chemical compound FC1=CC(N(CC2C3CNCC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 XZBIOMPCWMJBLA-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000001242 postsynaptic effect Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 210000000225 synapse Anatomy 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- DNGLRCHMGDDHNC-UHFFFAOYSA-N 1-benzothiophene-2-carbonyl chloride Chemical compound C1=CC=C2SC(C(=O)Cl)=CC2=C1 DNGLRCHMGDDHNC-UHFFFAOYSA-N 0.000 description 1
- DYSJMQABFPKAQM-UHFFFAOYSA-N 1-benzothiophene-2-carboxylic acid Chemical compound C1=CC=C2SC(C(=O)O)=CC2=C1 DYSJMQABFPKAQM-UHFFFAOYSA-N 0.000 description 1
- YGYOQZPGFXHQMW-UHFFFAOYSA-N 3-azabicyclo[3.1.0]hexan-6-ylmethanol Chemical compound C1NCC2C(CO)C21 YGYOQZPGFXHQMW-UHFFFAOYSA-N 0.000 description 1
- KYSZLSYGLCGLOS-UHFFFAOYSA-N 3-azabicyclo[3.1.0]hexan-6-ylmethanol;hydrochloride Chemical compound Cl.C1NCC2C(CO)C21 KYSZLSYGLCGLOS-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- ULHICZRVKSZTTF-UHFFFAOYSA-N 4-bromo-n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-3-fluoroaniline Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CNC=3C=C(F)C(Br)=CC=3)C2C1 ULHICZRVKSZTTF-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- AVTLLLZVYYPGFX-UHFFFAOYSA-N 4-ethylbenzoyl chloride Chemical compound CCC1=CC=C(C(Cl)=O)C=C1 AVTLLLZVYYPGFX-UHFFFAOYSA-N 0.000 description 1
- YEZADZMMVHWFIY-UHFFFAOYSA-N 4-tert-butylbenzenesulfonyl chloride Chemical compound CC(C)(C)C1=CC=C(S(Cl)(=O)=O)C=C1 YEZADZMMVHWFIY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000007415 Anhedonia Diseases 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical class NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 101100189356 Mus musculus Papolb gene Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000009668 Neurobehavioral Manifestations Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 206010041243 Social avoidant behaviour Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 102100023145 Sodium- and chloride-dependent glycine transporter 1 Human genes 0.000 description 1
- 101710083171 Sodium- and chloride-dependent glycine transporter 1 Proteins 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- ARHITBSWNIGGQI-UHFFFAOYSA-N [3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methanol Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CO)C2C1 ARHITBSWNIGGQI-UHFFFAOYSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940003380 geodon Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 230000000575 glycinergic effect Effects 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- JFQICQDBJKKSHZ-UHFFFAOYSA-N n-(3-azabicyclo[3.1.0]hexan-6-ylmethyl)-n-(3-fluoro-4-morpholin-4-ylphenyl)thiophene-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.FC1=CC(N(CC2C3CNCC32)C(=O)C=2SC=CC=2)=CC=C1N1CCOCC1 JFQICQDBJKKSHZ-UHFFFAOYSA-N 0.000 description 1
- UMFJAHHVKNCGLG-UHFFFAOYSA-N n-Nitrosodimethylamine Chemical compound CN(C)N=O UMFJAHHVKNCGLG-UHFFFAOYSA-N 0.000 description 1
- CNROJCRHSSUUTP-UHFFFAOYSA-N n-[[3-[(4-ethylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-3-fluoro-4-morpholin-4-ylaniline Chemical compound C1=CC(CC)=CC=C1CN1CC2C(CNC=3C=C(F)C(N4CCOCC4)=CC=3)C2C1 CNROJCRHSSUUTP-UHFFFAOYSA-N 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000001561 neurotransmitter reuptake Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 230000000698 schizophrenic effect Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- JVIDPFGQYMFQDZ-UHFFFAOYSA-N tert-butyl 6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC2C(CO)C21 JVIDPFGQYMFQDZ-UHFFFAOYSA-N 0.000 description 1
- DEHGQGNTPSFFGJ-UHFFFAOYSA-N tert-butyl 6-[(3-fluoro-4-morpholin-4-ylanilino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate Chemical compound C12CN(C(=O)OC(C)(C)C)CC2C1CNC(C=C1F)=CC=C1N1CCOCC1 DEHGQGNTPSFFGJ-UHFFFAOYSA-N 0.000 description 1
- WZGVNWBQFRQOCH-UHFFFAOYSA-N tert-butyl 6-[[3-fluoro-4-morpholin-4-yl-n-(thiophene-2-carbonyl)anilino]methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate Chemical compound C12CN(C(=O)OC(C)(C)C)CC2C1CN(C=1C=C(F)C(N2CCOCC2)=CC=1)C(=O)C1=CC=CS1 WZGVNWBQFRQOCH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- WLQZEFFFIUHSJB-UHFFFAOYSA-N ziprasidone mesylate trihydrate Chemical compound O.O.O.CS(O)(=O)=O.C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 WLQZEFFFIUHSJB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Indole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
Foreliggende oppfinnelse angår bicykliske[3.1.0]aminer og farmasøytiske sammensetninger som inneholder dem og deres anvendelse ved behandling av sentralnerve-systemforstyrrelser, kognitive forstyrrelser, schizofreni, demens og andre forstyrrelser hos pattedyr, som inkluderer mennesker. Disse sammensetningene fremviser aktivitet som inhibitorer av glysin type-1 transporteren.
Schizofreni, en progressiv neurologisk sykdom, manifesteres i tidlig stadier som tanke-forstyrrelser slike som hallusinasjoner, paranoide vrangforestillinger og bisarre tenke-mønstre, kollektivt kjent som positive symptomer. Disse tidlige oppdagbare symptomene ga sykdommen historisk navnet "sinnsyke". Idet sykdommen skrider frem blir negative symptomer, slik som sosial tilbaketrekning og anhedoni og kognitive symptomer slik som demens mer fremtredende. Kun ca. en tredjedel av schizofrene pasienter kan behandles vellykket og returnerer til samfunnet, mens resten blir generelt institusjonalisert. Byrden på samfunnet når det gjelder denne ødeleggende sykdommen og belastningen den fører til for familiemedlemmer til berørte pasienter gjør den til den mest kostbare av alle CNS forstyrrelser.
Farmakologisk behandling for schizofreni har tradisjonelt involvert blokkering av dopaminsystemet, som antas å være ansvarlig for de positive symptomene. Slik behandling ignorerer imidlertid de negative og kognitive aspektene ved sykdommen. Et annet neurotransmittersystem som antas å spille en rolle ved schizofreni er glutamatsystemet, det viktige eksitatoriske transmittersystemet i hjernen. Denne hypotesen er basert på observasjonen om at blokkering av glutamatsystemet ved forbindelser slik som PCP ("englestøv") kan reprodusere mange av symptomene ved schizofreni, som inkluderer dens positive, negative og kognitive aspekter. Hvis schizofreni involverer en svekkelse ved glutamatergisk transmisjon kan forsterkning av glutamatsystemet og særlig NDMA reseptoren være fordelaktig. Mens glutamat er den viktigste agonisten ved NMDA reseptorer kreves glysin som en koagonist for å fremsette "tonen" til reseptoren for dens respons på glutamat. Ved å forsterke denne "tonen" ved å øke effekten av glysin vil dette forsterke NDMA neurotransmisjon og gi potensiell fordel ved behandling av schizofreni.
En spesifikk forsterkningsmekanisme for den glysinergiske "tonen" til NMDA reseptoren ble nylig beskrevet av Bergeron, et al. ( Proe. Nati. Acad. Sei. USA, 95, 15730, (1998)), som er innbefattet her med referanse. Denne gruppen viste at en spesifikk og potent inhibitor av glysin type-1 transporteren (GlyTl) ansvarlig for å fjerne glysin fra synapsen ved NMDA reseptoren, navngitt NFPS (WO 97/45115), kan øke NMDA reseptorfunksjonen. For eksempel øker NFPS den postsynaptiske strømmen drevet av NMDA reseptoren, en effekt blokkert av både en spesifikk NMDA seteantagonist og en glysinseteantagonist. Til tross for dette er glysinnivåene i hjernen høye relativt til mengden reseptorfunksjon. For eksempel øker NFPS den postsynaptiske strømmen drevet av NMDA reseptoren, en effekt blokkert av både en spesifikk NMDA seteantagonist og en glysinseteantagonist. Selv om glysinnivåene i hjernen er høye relativt til mengden som kreves for å virke som en NMDA reseptorkoagonist viser dette arbeidet at GlyTl fjerner glysin effektivt ved synapsen, og at inhibering av GlyTl kan forsterke NMDA reseptorfunksjonen. Foreliggende oppfinnelse tilveiebringer GlyTl inhibitorer som en behandling for forstyrrelser eller tilstander slike som schizofreni ved dens forsterkning av glutamatergisk neutrotransmisjon.
Foreliggende oppfinnelse angår forbindelser med formel I,
hvori Yer(R<100>)k-R<1->(R<6>)m; k er 0 eller 1; 1 = 0, 1,2 eller 3;
m = 1, 2 eller 3; n er 0, 1,2, 3 eller 4;
o er 0 eller 1;
perO, 1,2, eller 3;
q er 0, 1,2, 3 eller 4;
r er 1 eller 2;
serO, 1,2, 3 eller 4;
t er 0 eller 1;
u er 1, 2, eller 3;
v er 1, 2, eller 3;R1<00>er -CH2-, -CH(Ci-C3)alkyl-, -C(=0)- eller -S02-; R<1>er -(Ci-C6)alkyl, -(C3-C8)cykloalkyl, -(4 til 7 leddet) heterocykloalkyl som inneholder 1-3 heteroatomer valgt fra N, O, S og eventuelt en 2 C=0 gruppe, -(CH2)i-(C6-C10aryl) der aryl gruppen er valgt blant fenyl, indenyl, indanyl og naftyl eller -(5 til 10 leddet) heteroaryl der heteroarylgruppen er valgt blant pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, kinolyl, isokinolyl, tetrazolyl, furyl, thienyl, isoksazolyl, tiazolyl, oksazolyl, isotiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oksadiazolyl, tiadiazolyl, furazanyl, benzofurazanyl, benzothiofenyl, benzotriazolyl, benzotiazolyl, benzoksazolyl, kinazolinyl, kinoksalinyl, naphthyridinyl, dihydrokinolyl, tetrahydrokinolyl, dihydroisokinolyl, tetrahydroisokinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, og azaindolyl, hver R<6>kan være like eller forskjellige og er uavhengig valgt fra H, halo, -(Ci-Ce)alkyl-B, (C1-C7) alkoksy-D, (C2-C4)alkenoksy, (Ci-C6)alkyl-OH, -OH, CN, -N02, -CR^V, -NR<20>R<21>, -NHCOalkyl(Ci-C3), NHS02alkyl(Ci-C3), C(=0)OR<22>, -R23-C(=0)OR22, - C(=0)NH2, fenyl-E, fenoksy-F, morfolin, -NR<20>R<21>, ar<y>l som definert for R1, heteroaryl som definert for R<1>, -S-R<24>, og -S02-<R25;>B og D er hver uavhengig H, OH, fenyl, difenyl eller trifluro; E og F er hver uavhengig H, alkyl valgt fra gruppen bestående av metyl, etyl, propyl, isopropyl, butyl, iso-butyl, sek-butyl, tert-butyl, pentyl, heksyl, heptyl, 3-etylbutyl, cyklopropyl, cyklobutyl, cyklopentyl, cykloheksyl, cykloheptyl og norbornyl, eller halo; R<7>, R<8>og R<9>er hver uavhengig H, (C1-C4) alkyl, -OH, -0-(Ci-C4)alkyl, -CN, -NR 26 R 27 og -NHC(=0) (Ci-C3)alkyl, hvori nevnte alkylgrupper eventuelt er substituert med OH, OCH3, NH2, NHC(=0)(Ci-C3)alkyl, eller R<7>og R8 sammen med karbonatomet til hvilket de er bundet eventuelt danner en (C3-C7)cykloalkyl ring, eller en (4 til 7 leddet)heterocykloalkyl ring som inneholder 1-3 heteroatomer valgt fra N, O, S og inneholder eventuelt en C=0 gruppe;
R<20>og R<21>er hver uavhengig H eller (Ci-C6) alkyl;
or R'2u 0 og R 21 kan bindes sammen med 4 til 7 karbonatomer hvori fra en til tre av nevnte karbonatomer eventuelt kan være erstattet med O, N eller S, for å danne en heterocykloalkylring;
eller R<20>og R<21>kan bindes sammen med 3 til 7 atomer valgt fra C, N, O eller S for å danne en 5 til 10 leddet heteroarylring;
R22,R2<3>og R<24>er hver uavhengig H, eller (Ci-C5)alkyl;
R<25>er (Ci-Cs)alkyl;
R<26>og R<27>er hver uavhengig H eller (Ci-C3)alkyl;
eller R<26>og R<27>kan bindes sammen med 4 til 7 karbonatomer for å danne en heterocykloalkyl ring;
R<2>og R<3>er hver H;
R<4>og R<5>er hver H;
AerH;
R<28>er uavhengig (Ci-C3)alkoksy, -OH, -NR<12>R<13>eller -NHC(=0)(Ci-C4)alkyl;
R 12 og R 13 er hver uavhengig H eller -(C1-C4 )alkyl; eller
R<12>og R13 kan bindes sammen med 4 til 7 karbonatomer for å danne en heterocykloalkyl ring;
X er en binding, -CH2-(R<29>)P, -C(=0) eller -S02;
R<29>er-(Ci-C3)alkyl;
W er (Ci-Cg)alkyl, -(C3-C6)cykloalkyl, -(3 til 7 leddet) heterocyclkoalkyl som inneholder 1-3 heteroatomer valgt fra N, O, S og eventuelt 1 eller 2 C=0 grupper, fenyl, eller -(5 til 7 leddet) heteroaryl som definert for R1 eller heterocyklisk gruppe som definert for R<1>;
R<30>er-(Ci-C4)alkyl, -(Ci-C3)alkoksy, CN, -F, -Cl, -Br, -I, -NR<18>R<19>, -NHC(=0)<R18>, -SCH»eller -C(=0)CH3;
R<18>og R<19>er hver uavhengig H eller -(Ci-C3 )alkyl;
Q er en binding, -CH-(R<31>)r, -C(=0) eller -S02;
R<31>er uavhengig H eller -(Ci-C3)alkyl;
Z er -(Ci-Cg)alkyl, -(C3-C8)cykloalkyl, -(4 til 8 leddet) heterocykloalkyl, fenyl eller -(5 til 7 leddet) heteroaryl som definert for R1 eller heterocyklisk gruppe som definert forR<1>;
R<14>er F, Cl, Br, I, V, H, -NR<16>R<17>, -OR<16>, -C(=0)NR<16>R<17>,
-(S02)NR<16>R<17>, eller -NR<32->C=0-R<33>;
R<15>er -(Ci-C3)alkyl, -(Ci-C3)alkoksy, -F, -Br, -Cl, -I -OH eller-CN;
V er -(C3-C8)cykloalkyl, -(Ci-Cs)alkyl, (5 til 7 leddet) heterocykloalkyl som definert for R<1>, (5 til 7 leddet)heterocykloalkyl substituert med 1 eller 2 C=0 grupper eller 1, 2, eller 3 (Ci-Cs)alkyl grupper;
R16og R<17>er hver uavhengig H, -(Ci-C6)alkyl-(R<34>)U, eller (C3-C8)cykloalkyl-(R<35>)v; eller R 16 og R 17 sammen med nitrogenatomet til hvilket de er bundet danner en 4 til 7 leddet heterocykloalkyl ring som eventuelt inneholder fra 1 til 3 ytterligere heteroatomer uavhengig valgt fra N, S og O, og inneholder C=0, hvori nevnte heterocykloalkylring eventuelt og uavhengig er substituert med 1 til 3 substituenter uavhengig valgt fra (Ci-C4)alkyl, OH, (Ci-C4)alkoksy, NH2,
-NH(C=0)(Ci-C8)alkyl, -N(Ci-C3)alkyl)2, -C(=0)CH3, CONH2, C02H, CH2OH, CH20alkyl(C2-C4), og (5 til 7 leddet) heterocykloalkyl som definert for R<1>;R3<2>og R33 er hver uavhengig H eller (d-C5)alkyl; 32 33
eller R~ ogR<JJ>kan sammen danne en 3-7 leddet cykloalkylring, en 3-7 leddet heterocykloalkyl ring med 1 til 3 heteroatomer, eller en 5-7 leddet heteroaryl ring med 1 til 3 heteroatomer;R<34>og R35 er hver uavhengig H, OH, (d-C5)alkyl, (C2-C4)alkoksy, NH2, NH(C=0)(Ci-C3)alkyl, eller en 5 til 7 leddet heterocykloalkyl;
eller R<34>og R<35>kan sammen danne en bro som inneholder 1-2 karbonatomer; der stereokjemien er som i formel II;
eller et farmasøytisk akseptabelt salt derav.
Foreliggende oppfinnelse angår en forbindelse med formel I som definert over, eller et farmasøytisk akseptabelt salt derav for anvendelse ved behandling av en forstyrrelse eller tilstand valgt fra psykoser, schizofreni, adferdsforstyrrelser, urolig oppførselforstyrrelse, bipolare forstyrrelser, psykotiske episoder av angst, angst assosiert med psykoser, psykotiske humørforstyrrelser, alvorlig viktig depressiv forstyrrelse, humørforstyrrelse assosiert med psykotisk forstyrrelse, akutt mani, depresjon assosiert med bipolare forstyrrelser, humørforstyrrelser assosiert med schizofreni, oppførselsmanifestasjoner med mental retardasjon, oppførselsforstyrrelse, autistisk forstyrrelse, bevegelsesforstyrrelser, Tourettes syndrom, akinetisk stivehetssyndrom, bevegelsesforstyrrelser assosiert med Parkinsons sykdom, tartiv dyskinesi, andre legemiddelinduserte og neurodegenerasjonsbaserte dyskinesier, oppmerksomhetssvikt hyperaktivitetsforstyrrelse, kognitive forstyrrelser, demenser og hukommelsesforstyrrelser.
Foreliggende oppfinnelse angår en farmasøytisk sammensetning omfattende en forbindelse med formel I som definert over, eller et farmasøytisk akseptabelt salt derav, for anvendelse i behandling av en forstyrrelse eller tilstand valgt fra psykoser, schizofreni, adferdsforstyrrelser, urolig oppførselforstyrrelse, bipolare forstyrrelser, psykotiske episoder av angst, angst assosiert med psykoser, psykotiske humørforstyrrelser, alvorlig viktig depressiv forstyrrelse, humørforstyrrelse assosiert med psykotisk forstyrrelse, akutt mani, depresjon assosiert med bipolare forstyrrelser, humørforstyrrelser assosiert med schizofreni, oppførselsmanifestasjoner med mental retardasjon, oppførselsforstyrrelse, autistisk forstyrrelse, bevegelsesforstyrrelser, Tourettes syndrom, akinetisk stivehetssyndrom, bevegelsesforstyrrelser assosiert med Parkinsons sykdom, tartiv dyskinesi, andre legemiddelinduserte og neurodegenerasjonsbaserte dyskinesier, oppmerksomhetssvikt hyperaktivitetsforstyrrelse, kognitive forstyrrelser, demenser og hukommelsesforstyrrelser.
Det beskrives også isotopisk merkede forbindelser, som er identiske med de som er angitt i formel I, unntatt for det faktum at et eller flere atomer er erstattet med et atom som har en atommasse eller massetall forskjellig fra atommassen eller massetallet som vanligvis finnes i naturen. Eksempler på isotoper som kan inkorporeres i forbindelsen ifølge oppfinnelsen inkluderer isotoper av hydrogen, karbon, nitrogen, oksygen, fosfor, svovel, fluor og klor, slike som<2>H,<3>H,<13>C, nC,<14>C,<15>N,<18>0,<17>0,<31>P,<32>P,<35>S,<18>F, og<36>Cl, respektivt. Forbindelser ifølge oppfinnelsen, prodrug derav og farmasøytisk akseptable salter av nevnte forbindelse eller nevnte prodrug som inneholder tidligere nevnte isotoper og/eller andre isotoper av andre atomer er innenfor omfanget av foreliggende oppfinnelse. Visse isotopisk merkede forbindelser ifølge oppfinnelsen, f. eks. de hvori radioaktive isotoper slike som<3>H og<14>C er inkorporert, er anvendelige i legemiddel og/eller substratvev fordelingsundersøkelser. Tritium og<14>C isotoper er særlig foretrukket for deres enkle fremstilling og detekterbarhet. Videre kan substitusjon med tyngre isotoper slik som deuterium vise terapeutiske fordeler som resultat av større metabolitisk stabilitet, f.eks. økt in vivo halveringstid eller reduserte dosekrav og, kan således være foretrukket under noen omstendigheter. Isotopisk merkede forbindelser med formel I ifølge oppfinnelsen og prodrug derav kan generelt fremstilles ved utføring av fremgangsmåtene beskrevet i skjema og/eller eksemplene og fremstillingene nedenfor, ved å anvende et lett tilgjengelig isotopisk merket reagens istedenfor et ikke-isotopisk merket reagens.
Uttrykket "alkyl", slik det anvendes heri, med mindre annet er indikert, inkluderer mettede monovalente hydrokarbonradikaler som har rette, forgrenede eller cykliske bestanddeler eller kombinasjoner derav. Eksempler på "alkyl" grupper inkluderer, men er ikke begrenset til, metyl, etyl, propyl, isopropyl, butyl, iso-butyl, sek-butyl, tert-butyl, pentyl, heksyl, heptyl, 3-etylbutyl, cyklopropyl, cyklobutyl, cyklopentyl, cykloheksyl, cykloheptyl, norbornyl, og lignende.
Begrepet "halo", slik det anvendes heri, betyr klor, fluor, jod eller brom.
Begrepet "alkoksy", slik det anvendes heri, betyr "alkyl-O-", hvori "alkyl" er som definert ovenfor.
Begrepet "behandle", slik det anvendes heri, refererer til reversering, lindring, inhibering og fremskritt av eller hindring av forstyrrelsen eller tilstanden som begrepet gjelder for, eller et eller flere symptomer på tilstanden eller forstyrrelsen. Begrepet "behandling", slik det anvendes heri, refererer til handlingen med å "behandle" som definert umiddelbart ovenfor.
Begrepet "bro", slik det anvendes heri, refererer til en bro, som inneholder 1 eller 2 karboner, som binder to brohoder i et cyklisk system for å danne en bicyklisk forbindelse.
Slik det anvendes heri refererer uttrykket "reaksjonsinert løsemiddel" til et løsemiddel-system hvori komponentene ikke reagerer innbyrdes med utgangsmaterialene som reagensene eller intermediatene til produktene på en måte som på en uheldig måte berører utbyttet av det ønskede produktet.
Forbindelsene med formel I kan ha optiske sentre og kan derfor eksistere i forskjellige enantiomere konfigurasjoner. Formel I, som angitt ovenfor, inkluderer alle enantiomerer, diastereomerer og andre stereoisomerer av forbindelsene angitt med strukturformel I, så vel som racemiske og andre blandinger derav. Individuelle isomerer kan oppnås ved kjente fremgangsmåter, slik som optisk oppløsning, optisk selektiv reaksjon eller kromatografisk separasjon ved fremstilling av det endelige produktet eller dets intermediater.
Ytterligere annen utførelsesform ifølge oppfinnelsen angår forbindelser med formel I, hvori eksempler på C6-C10aryl inkluderer substiuerte og usubstituerte fenyl, indenyl, indanyl og naftyl; hvor eksempler heterocykloalkyl inkluderer heterocyklisk bestanddel og den heterocykliske bestanddelen til nevnte heterocykliske-(Ci-C8)alkyl- er valgt fra mettede eller umettede ikke-aromatiske monocykliske eller bicykliske ringsystemer, hvori nevnte monocykliske ringsystemer inneholder fra fire til syv ring karbonatomer, fra en til tre av disse kan eventuelt erstattes med O, N, C=0 eller S; eksempler på heteroaryl inkluderer pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, kinolyl, isokinolyl, tetrazolyl, furyl, thienyl, isoksazolyl, tiazolyl, oksazolyl, isotiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oksadiazolyl, tiadiazolyl, furazanyl, benzofurazanyl, benzothiofenyl, benzotriazolyl, benzotiazolyl, benzoksazolyl, kinazolinyl, kinoksalinyl, naphthyridinyl, dihydrokinolyl, tetrahydrokinolyl, dihydroisokinolyl, tetrahydroisokinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, og azaindolyl.
100 1 6
I definisjonene ovenfor kan Y enten være H eller (R,<uu>)k-R'-(R<0>)m, hvori k er lik med 0 eller 1. Det er å forstå at når k er 0, R 100 er en binding slik at R 1 er bundet direkte til nitrogenatomet til den bicykliske ringen. Som definert heri er R er en brodannende gruppe som forbinder N atomet til den bicykliske ringen med R 6 . Delen av R 1 som er bundet direkte til R kan være mono, di eller trisubstiuert med R avhengig av om m er 1, 2 eller 3, respektivt. For eksempel, når m er lik med 2, Y er (R<100>)k- R<1>- (R6 )2- Forbindelser med formel I, ovenfor, og deres farmasøytisk akseptable salter kan fremstilles i henhold til følgende reaksjonsskjema I til og med VIII som diskutert heri nedenfor. Med mindre annet er indikert er A, B, D, Q, V, W, X, Y, Z, R^-R35 og R<100>som definert ovenfor. Isolering og rensing av produktene utføres ved standard fremgangsmåter, som er kjente for fagmannen.
Forbindelser med formel I, ovenfor, og intermediatene vist i følgende reaksjons-skjemaer kan isoleres og renses ved vanlige fremgangsmåter, slik som rekrystallisasjon eller kromatografisk separasjon.
For så vidt som forbindelsene med formel I ifølge oppfinnelsen kan inneholde basiske substituenter, er de i stand til å danne et bredt spekter av forskjellige salter med forskjellige uorganiske og organiske syrer. Selv som slike salter på være farmasøytisk akseptable for administrasjon til dyr, er det ofte ønskelig å praktisere og isolere basisforbindelsen fra reaksjonsblandingen som et farmasøytisk uakseptabelt salt og deretter omdanne den til fri base forbindelsen ved behandling med en alkalisk reagens og deretter omdanne den frie basen til et farmasøytisk akseptabelt syreaddisjonssalt. Syre-addisjonssaltene av basisforbindelsen ifølge oppfinnelsen blir enkelt fremstilt ved behandling av basisforbindelsen med en i det vesentlige ekvivalent mengde av den valgte mineral eller organiske syren i et vandig løsemiddel eller i et egnet organisk løse-middel, slik som metanol eller etanol. Etter forsiktig fordamping av løsemidlet blir det ønskede faste saltet lett oppnådd.
Syrene som anvendes for fremstilling av de farmasøytisk akseptable syreaddisjons-saltene av de tidligere nevnte basisforbindelsene ifølge oppfinnelsen er de som danner ikke-toksiske syreaddisjonssalter, dvs. salter som inneholder farmasøytisk akseptable anioner, slik som hydroklorid, hydrobromid, hydrojodid, nitrat, sulfat eller bisulfat, fosfat eller syrefosfat, acetat, laktat, citrat eller syrecitrat, tartrat eller bi-tartrat, suksinat, maleat, fumarat, glukonat, sakkarat, benzoat, metansulfonat, etansulfonat, benzensulfonat, ptoluensulfonat og pamoat ( dvs., l,r-metylen-bis-(2-hydroksy-3-naftoat))salter.
Forbindelsene ifølge oppfinnelsen fremviser signifikant glysintransport inhiberende aktivitet og har derfor verdi ved behandling av et bredt spekter av kliniske tilstander som er kjennetegnet ved underskudd i glutamaterisk neurotransmisjon hos pattedyrsubjekter, særlig mennesker. Slike tilstander inkluderer positive og negative symptomer for schizofreni og andre psykoser, og kognitive underskudd.
Forbindelsene ifølge oppfinnelsen kan administreres enten via oral, parenteral (slik som subkutan, intravenøs, intramuskulær, intrasternal og infusjonsteknikker), rektal, intranasal eller topiske ruter til pattedyr. Generelt blir disse forbindelsene mest ønskelig administrert til mennesker i doser som varierer fra ca. 1 mg til ca. 2000 mg per dag, selv om variasjoner vil være nødvendig avhengig av vekt og tilstand til subjektet som behandles og den bestemte administrasjonsruten som velges. Imidlertid blir et doseringsnivå som er i området fra ca. 0,1 mg til ca. 20 mg per kg kroppsvekt per dag mest ønsket anvendt. Uansett kan variasjoner fremdeles opptre avhengig av arten av dyr som behandles og den individuelle responsen til nevnte medikament, så vel som type farmasøytisk formulering som velges og tidsperiode og intervall hvorved slik administrasjon utføres. I noen tilfeller kan doseringsnivåer under den lavere grensen til det nevnte området være mer enn adekvat, mens i andre tilfeller kan enda høyere doser anvendes uten å forårsake skadelige bivirkninger forutsatt at slike høyere doseringsnivåer først deles i flere små doser for administrasjon i løpet av dagen.
I en utførelsesform blir forbindelsene ifølge oppfinnelsen administrert som tilleggs-behandling med kjente antipsykotiske midler slik som Geodon.
Forbindelsene ifølge oppfinnelsen kan administreres alene eller i kombinasjon med farmasøytisk akseptable bærere eller fortynningsmidler ved en av de ovenfor angitte rutene, og slik administrasjon kan utføres i enkle eller multiple doser. Spesielt kan de nye terapeutiske midlene ifølge oppfinnelsen administreres med et bredt spekter av forskjellige doseringsformer, dvs. de kan kombineres med forskjellige farmasøytisk akseptable inerte bærere i form av tabletter, kapsler, lozenger, trocheer, harde sukkertøy, pulvere, sprayer, kremer, salver, stikkpiller, geleer, geler, pastaer, lotioner, kremer, vandige suspensjoner, injuserbare løsninger, eliksirer, siruper og lignende. Slike bærere inkluderer faste fortynningsmidler eller fyllstoffer, sterilt vandig media og forskjellige ikke-toksiske løsemidler etc. Videre kan orale farmasøytiske sammensetninger bli passende søtgjort og/eller smakstilsatt. Generelt er de terapeutisk effektive forbindelsene ifølge oppfinnelsen tilstede i slike doseringsformer i konsentrasjonsområder varierende fra ca. 5,0 % til ca. 70 % i forhold til vekt.
For oral administrasjon kan tabletter som inneholder forskjellige eksipienter slike som mikrokrystallinsk cellulose, natriumcitrat, kalsiumkarbonat, dikalsiumfosfat og glysin anvendes sammen med forskjellige desintegreringsmidler slike som stivelse og foretrukket mais, potet eller tapiokastivelse, algininsyre og visse komplekse silikater, sammen med granuleringsbindemidler som polyvinylpyrrolidon, sukrose, gelatin og acacia. I tillegg blir smøremidler slike som magnesiumstearat, natriumlaurylsulfat og talkum svært ofte anvendt for tabletteringsformål. Faste sammensetninger av tilsvarende type kan også anvendes som fyllstoffer i gelatinkapsler; hvor foretrukne materialer i denne forbindelse også inkluderer laktose eller melkesukker så vel som høymolekylvekt polyetylenglykoler. Når vandige suspensjoner og/eller eliksirer er ønskelig for oral administrasjon kan den aktive ingrediensen kombineres med forskjellige søtnings eller smaksstoffer, fargestoffer og, hvis ønskelig, emulgerings og/eller suspenderingsmidler i tillegg, sammen med fortynningsmidler slike som vann, etanol, propylenglykol, glyserin og forskjellige liknende kombinasjoner derav.
For parenteral administrasjon kan løsninger av en forbindelse ifølge oppfinnelsen enten i sesam eller peanøttolje eller i vandig propylenglykol anvendes. De vandige løsningene bør være hensiktsmessig bufret (foretrukket pH>8) hvis nødvendig og det flytende for-tynningsmidlet først gjøres isotonisk. Disse vandige løsningene er egnet for intravenøse injeksjonsformål. Oljeløsninger er egnet for intraartikulær, intramuskulær og subkutant injeksjonsformål. Fremstilling av alle disse løsningene under sterile betingelser kan lett utføres ved standard farmasøytiske teknikker godt kjente for fagmannen. I tillegg er det også mulig å administrere forbindelsen ifølge oppfinnelsen topisk ved behandling av inflammasjonstilstander på huden og dette kan foretrukket gjøres med kremer, geleer, geler, pastaer, salver og lignende i henhold til standard farmasøytisk praksis.
Forbindelsen ifølge oppfinnelsen blir undersøkt for deres aktivitet når det gjelder å inhibere glysingjenopptak i synaptosomer ved først å fremstilles synaptosomer og deretter måle neurotransmitter gjenopptakningsaktivitet som følger: Hann Sprague Dawley rotter ble dekapittert og hjernen fjernet. Hele hjernen ble dissekert ut og plassert i iskald sukrosebuffer; 1 gram i 20 ml (320 mM sukrose som inneholder 1 mg/ml glukose, 0. ImM EDTA og bragt til pH 7.4 med Tris base). Vevet homogeniseres i et glasshomogeniseringsrør med en teflonmorter ved 350 RPMS ved anvendelse av et Potters homogeniseringsapparat. Homogenatet sentrifugeres ved 1000 x g i 10 min ved 4°C. Den resulterende supernatanten resentrifugeres ved 17,000 x g i 20 min ved 4 °C. De endelige pelletene resuspenderes i et passende volum sukrosebuffer som inneholder 5 mM alanin, for å gi mindre enn 10 % opptak.
Opptaksundersøkelsen ble utført i 96 brønns matriksplater. Hver brønn inneholder 25 uL løsemiddel, inhibitor eller 10 mM glysin for ikke-spesifikt opptak, 200 uL [ H]-glysin (40 nM til slutt), tilsettes modifisert Krebs som inneholder 5 mM alanin og glukose (1 mg/ml) og 25 uL synaptosomer. Pelettene blir deretter inkubert ved romtemperatur i 15 min. Inkuberingen termineres ved filtrering gjennom GF/B filtere ved anvendelse av en 96 brønns Brandel Cell Harvester. Filtrene vaskes med modifisert Krebs buffer og telles i en flytende scintillasjonteller eller i en LKB Beta Plate teller. Forbindelsene ifølge oppfinnelsen analysert ved denne undersøkelsen ble funnet å ha signifikant aktivitet i å inhibere glysingjenopptak i synaptosomer, som har IC50verdier mer potent enn 10 uM.
Foreliggende oppfinnelse er illustrert ved eksemplene og fremstillingene nedenfor. Imidlertid er det å forstå at oppfinnelsen ikke er begrenset til de spesifikke detaljene i disse eksemplene. Smeltepunktene ble tatt med en Buchi mikro smeltepunktapparatur og er ukorrigerte. Infrarød adsopsjonsspektra (TR) ble målt med et Shimazu infrarødt spektrometer (IR-470).<*>H og<13>C kjernemagnetiske resonansespektre (NMR) ble målt i CDCI3med et Varian NMR spektrometer (Unity, 400MHz for<1>H, 100MHz for 13C)med mindre annet er indikert og topp posisjoner er uttrykt som deler per million (ppm) nedfelts fra tetrametylsilan (5). Toppformene er betegnet som følger: s, singlett; d, dublett; t, triplett; m, multiplett; br, bred.
I løpet av en hvilken som helst av følgende syntesesekvenser kan det være nødvendig og/eller ønskelig å beskytte sensitive eller reaktive grupper på et hvilket som helst av molekylene som angås. Dette kan oppnås ved hjelp av vanlige beskyttende grupper, slik som de som er beskrevet i T. W. Greene, Protective Grupper in Organic Chemistry, John Wiley & Sons, 1981; og T. W. Greene og P. G. M. Wuts, Protective Grupper in Organic Chemistry, John Wiley & Sons, 1991, som er innbefattet her ved referanse.
Forbindelsene med formel I, ovenfor, og deres farmasøytisk akseptable salter, kan fremstilles i henhold til følgende reaksjonsskjema I til og med VII som diskutert heri nedenfor. Med mindre annet er indikert er A, B, D, Q, V, W, X, Y, Z, R^R<35>og R<100>definert som ovenfor. Isolering og rensing av produktene utføres ved standard fremgangsmåter, som er kjente for fagmannen.
Følgende skjemaer er eksempler på fremgangsmåter for fremstilling av forbindelsene med formel I
Skjema I illustrerer en fremgangsmåte for fremstilling av forbindelser som har den grunnleggende strukturen med formel I, hvori A er hydrogen, X er C=0 eller SO2, W er 2-tiofen, Q er en enkelt binding eller en metylengruppe, Y er H, R 2 og R 3 er H, og Z,R14, R15 , og V er beskrevet som ovenfor.
Med referanse til skjema I kan en forbindelse med (I) [ SynLett, 1996,1097] behandles med (BOQ2O under nærvær av en passende base slik som trietylamin, i løsemidler slike som CH2CI2, for å gi det ønskede karbamatet med formel (II). Oksidering av den primære alkoholen under Swern betingelser med DMSO og oksaylklorid, under nærvær av en passende base slik som trietylamin (TEA) eller diisopropyletylamin (DIEA), i løsemidler slike som CH2CI2eller 1,2-dikloretan (DCE), ved temperaturer varierende fra -78 °C til romtemperatur, foretrukket ved ca. romtemperatur, for å gi det korresponderende aldehydet (ikke angitt). Andre egnede oksidasjonsreagenser for denne omdanningen inkluderer TPAP/NMO eller PCC.
Behandling av aldehydet med et passende substituert amin eller anilinreagens med formel (III) og et passende reduksjonsmiddel slik som NaCNBH?, i et løsemiddel slik som MeOH, ved temperaturer varierende fra -5 °C til romtemperatur, foretrukket ved ca. romtemperatur, gir det ønskede aminet med formel (IV). Andre egnede reduksjons-midler for denne reaksjon inkluderer NaBHj eller NaHB(OAc)3, i løsemidler slike som MeOH, CH2CI2eller DCE. Andre egnede betingelser for denne omdanningen inkluderer behandling av det korresponderende aldehydet med et aminereagens (Ul) i CH2CI2eller DCE under nærvær av 4 Å molekylsikt og en base slik som TEA ved romtemperatur, fulgt av behandling med NaHB(OAc)3.
Forbindelser med formel (VI) kan fremstilles ved behandling av et amin med formel (IV) med et passende substituert syreklorid eller sulfonylkloridreagens med formel (V) under nærvær av en passende base slik som DIEA, pyridin eller TEA, i løsemidler slike som DCE eller CH2CI2, ved temperaturer som varierer fra romtemperatur til ca. reflukstemperatur, foretrukket ved ca. romtemperatur, for å gi den korresponderende forbindelse med formel (VI). Til slutt kan forbindelser med formel (VU) fremstilles ved behandling av et karbamat med formel (VI) med TF A, i løsemidler slik som CH2CI2eller DCE, ved temperaturer varierende fra 0 °C til ca. romtemperatur, foretrukket ved ca. romtemperatur, for å gi det korresponderende aminet med formel (VII).
Skjema II illustrerer en fremgangsmåte for fremstilling av forbindelser som har den grunnleggende strukturen med formel I, hvori A er hydrogen, X er C=0 eller SO2, W er 2-tiofen, Q er en enkelt binding eller en metylengruppe, R<100>er a metylen (CH2) eller substituert metylen, R<2>og R<3>er H, og Z, R14,R1<5>, R1,R6, m, V og Y er som beskrevet ovenfor.
Med referanse til skjema II nedenfor kan forbindelser med formel (VIII) fremstilles ved behandling av et amin med formel (VU) med et passende substituert aldehyd eller keton og et reduksjonsmiddel slik som NaHB(OAc)3, i løsemidler slike som CH2CI2eller DCE, ved temperaturer varierende fra 0 °C til ca. romtemperatur, foretrukket ved ca. romtemperatur, for å gi det korresponderende aminet med formel (VIII). Andre egnede betingelser for denne fremgangsmåten inkluderer behandling av aminet med formel (VU) med et aldehyd i toluen, ved ca. reflukstemperatur; fulgt av behandling med NaBH4, i løsemidler slik som MeOH, for å gi det korresponderende aminet med formel (VIII). I tillegg gir behandling av et amin med formel (VU) med et aldehyd og NaCNBH3i et løsemiddel slik som MeOH det korresponderende aminet med formel ( ymy
Skjema III illustrerer en fremgangsmåte for fremstilling av forbindelser som har den grunnleggende strukturen med formel I, hvor A er hydrogen, X er C=0 eller SO2, W er 2-tiofen, Q er en enkeltbinding eller en metylengruppe, R 100 er C=0 eller SO2, R 2 og R<3>er H, og Z, R<1>4,R15,R1,R6, V og Y er som beskrevet ovenfor.
Med referanse til skjema Ul nedenfor kan forbindelser med formel (VIII), hvori R<100>= C=0, fremstilles ved behandling av forbindelser med formel (VU) med et passende substituert syreklorid (R<100>= C=0) reagens med formel (IX) under nærvær av en passende base slik som DIEA, i løsemidler slike som CH2CI2eller DCE, ved en temperatur som varierer fra 0 °C til ca. romtemperatur, foretrukket ved ca. romtemperatur, for å gi de korresponderende forbindelsene med formel (VIII). Videre kan forbindelser med formel (VIII), hvor R<100>= SO2, fremstilles ved behandling av forbindelser med formel (VII) med et passende substituert sulfonylklorid (R<100>= SO2) reagens med formel (IX), under nærvær av en passende base slik som DIEA eller TEA, i løsemidler slike som CH2CI2eller DCE, ved temperaturer varierende fra romtemperatur til ca. reflukstemperatur, foretrukket ved ca. reflukstemperatur, for å gi forbindelser med formel (VIII).
Skjema IV illustrerer en fremgangsmåte for fremstilling av forbindelser som har den grunnleggende strukturen med formel I, hvori A er hydrogen, X er C=0, Q er enkelt binding eller en metylengruppe, R 100 er C=0, CH2eller SO2, R 2 og R 3 er H, og W, q, R<3>0, Z,R14, R<15>, R<1>, R<6>, V og Y er som beskrevet ovenfor.
Med referanse til skjema IV nedenfor kan forbindelser med formel (XII) fremstilles ved behandling av forbindelser med formel (X) med et passende substituert syrekloridreagens med formel (XI) under nærvær av en passende base slik som pyridin, DIEA eller TEA, i løsemidler slike som CH2CI2eller DCE, ved en temperatur som varierer fra 0 °C til ca. romtemperatur, foretrukket til ca. romtemperatur, for å gi de korresponderende forbindelsene med formel (XII).
Skjema V illustrerer en fremgangsmåte for fremstilling av forbindelser som har den grunnleggende strukturen med formel I, hvori A er hydrogen, X er metylen (CH2), Q er en enkelt binding eller en metylengruppe, R 100 er C=0 eller SO2, R 2 og R 3 er H, og W, o, q,R30, Z,R14, R15, R1, R<6>, V og Y er som beskrevet ovenfor.
Med referanse til skjema V nedenfor kan forbindelser med formel (X) behandles med en passende base slik som NaH eller KH, og et passende substituert alkyleringsmiddel med formel (XIII), hvori L er passende utgående gruppe slik som Cl, Br, I, OMs, OTs, i løsemidler slike som THF eller eter, ved temperaturer som varierer fra 0 °C til ca. romtemperatur, foretrukket ved ca. romtemperatur, for å gi forbindelsene med formel
(XIV).
Skjema VI en fremgangsmåte for fremstilling av forbindelser som har den grunnleggende strukturen med formel I, hvor A er hydrogen, Q er en enkelt binding eller en metylengruppe, R<100>er C=0, CH2eller S02, R<2>og R<3>er H, og X, W, q, R<30>, Z, R<14>, R<15>, R<1>, R<6>, V og Y er som beskrevet ovenfor.
Med referanse til skjema VI nedenfor gir behandling av en forbindelse med formel (XV) med et passende substituert primært eller sekundært amin (HNR 16 R 17), en passende katalysator slik som palladium (II) acetat og BINAP, og en base, slik som natrium tert-butoksid, i løsemidler slik som toluen, ved temperaturer varierende fra romtemperatur til ca. reflukstemperatur, foretrukket ved reflukstemperatur, den ønskede forbindelsen med formel (XVI).
Alternativt kan forbindelser med formel (XVI), hvori Z gruppen er en heteroaryl bestanddel, slik som pyridingruppe, fremstilles ved den alternative fremgangsmåten beskrevet ovenfor. Med referanse til skjema VU nedenfor gir behandling av en forbindelse med formel (XVII), hvori halogen er brom eller klor, rent i et passende subsituert primært eller sekundært aminreagens (HNR i g k. 17), ved temperaturer varierende fra 50 °C til ca. 180 °C, foretrukket ved ca. 150 °C, den ønskede forbindelsen med formel (XVI). Alternativt kan betingelsene for denne reaksjonen inkludere behandling av forbindelsen med formel (XVII) med et aminreagens (HNR i g 17) i løsemidler slik som DMF eller DMP, ved temperaturer varierende fra romtemperatur til ca. reflukstemperatur for å gi de korresponderende forbindelsene med formel (XVI)-
I skjemaene ovenfor er R lik H. Imidlertid omfatter foreliggende oppfinnelse skjemaer når R er forskjellig fra H, som definert heri. Kjemien vist i skjemaene ovenfor kan anvendes i de tilfeller hvor R er forskjellig fra hydrogen. Imidlertid, hvis noen av substituentene for R 6 er reaktive med reaktanter eller intermediater da kan R 6 beskyttes med en beskyttende gruppe ved anvendelse av kjente teknikker slik som de som er beskrevet ovenfor.
Følgende eksempler illustrerer foreliggende oppfinnelse. Det er imidlertid å forstå at oppfinnelsen, slik den er beskrevet heri og angitt i kravene, ikke er begrenset til detaljene i følgende eksempler.
EKSEMPLER
FREMSTILLING 1
6- hvdroksvmetvl- 3- aza- bicvklor3. 1 . Olheksan- 3- karboksvlsyre tert- butvlester
Til en løsning av (3-aza-bicyklo[3.1.0]heks-6-yl)-metanol-HCl (11.8gm, 78.7 mmol) i 350 ml vannfri CH2CI2ble det ved romtemperatur tilsatt Et?N (32.9 ml, 236 mmol), fulgt av (BOQ2O (18.9 gm, 86.6 mmol) i porsjoner. Reaksjonsblandingen ble rørt ved romtemperatur i 18 timer. Blandingen ble vasket med mettet NaHC03, vann, saltvann og tørket over vannfri MgSC>4. Blandingen ble filtrert og konsentrert under redusert trykk som ga det urene materialet, som ble renset med flashkromatografi med 10 % MeOH/EtOAc. De produktinneholdende fraksjonene ble samlet opp og konsentrert som ga det ønskede produktet (15.6 g).
400 MHz<*>H NMR (CDCI3) 5 3.42-3.56 (m, 4H), 3.24-3.37 (m, 2H), 1.72 (brs, 1H), 1.37-1.41 (m, 10 H), 0.87-0.93 (m, 1H); MS (M+l) 213.2.
FREMSTILLING 2
6-[( 3 - fluor- 4- morfolin- 4- vl- fenylamino)- metvll - 3 - aza- bicyklo [ 3. 1. 01heksan- 3 - karboksylsyre tert- butyl ester
Til en rørt løsning av oksalylklorid (0.49 ml, 5.63 mmol) i 30 ml vannfri CH2CI2ble det ved-78 °C tilsatt DMSO (0.87 ml, 12.2 mmol) dråpevis. Etter 10 minutter ble 6-hydroksymetyl-3-aza-bicyklo[3.1.0]heksan-3-karboksylsyre tert-butyl ester (1.0 g, 4.69 mmol) i 10 ml vannfri CH2CI2tilsatt. Etter røring av blandingen i 30 minutter ble trietylamin (3.24 ml, 23.4 mmol) tilsatt og blandingen ble sakte varmet opp til 0 °C i løpet av 1 time. Blandingen ble konsentrert og det resulterende faste stoffet tatt opp i mettet NaHCC>3 og EtOAc, sjiktene ble separert og det vandige sjiktet ble ekstrahert med EtOAc. De kombinerte organiske sjiktene ble tørket, filtrert og konsentrert som ga det urene aldehydet, som ble anvendt i neste trinn uten rensing.
Til en rørt løsning av aldehydet fremstilt ovenfor (991 mg, 4.69 mmol) i 30 ml MeOH ble det tilsatt 3-fluor-4-morfolinanilin (920 mg, 4.69 mmol), AcOH (0.38 ml, 6.56 mmol) og NaCNBH?(295 mg, 4.69 mmol). Reaksjonsblandingen ble rørt ved romtemperatur i 90 minutter. Blandingen ble konsentrert under redusert trykk og det resulterende materialet ble tatt opp i mettet NaHC03og ekstrahert med CH2CI2. De kombinerte organiske sjiktene ble tørket over vannfri MgS04, filtrert og konsentrert under redusert trykk. Det urene materialet ble renset ved flashkromatografi ved 50 % EtOAc/heksan. Produktinneholdende fraksjoner ble samlet opp og konsentrert som ga 1.3 g av det ønskede aminet.
400 MHz<*>H NMR (CDCI3) 6 6.74-6.81 (m, 1H), 6.30-6.42 (m, 2H), 3.81-3.83 (m, 4H), 3.61 (brs, 1H), 3.59 (d, J= 10.8 Hz, 1H), 3.51 (d, J= 10.8 Hz, 1H), 3.32 (t, J= 9.5 Hz, 2H), 2.93 (brs, 6H), 1.40 (s, 11H), 0.87-0.92 (m, 1H); MS (M+l) 392.2.
FREMSTILLING 3
6-{ r( 3- lfuor- 4- morfolin- 4- vl- fenv^^ bicyklo[ 3. 1. 01heksan- 3- karboksvlsyre tert- butyl ester
Til en rørt løsning av 6-[(3-fluor-4-morfolin-4-yl-fenylamino)-metyl]-3-aza-bicyklo[3.1.0]heksan-3-karboksylsyre tert-butyl ester fremstilt ovenfor (500 mg, 1.28 mmol) i 10 ml DCE ble det ved romtemperatur tilsatt DIEA (0.33 ml, 1.92 mmol) og 2-tiofenkarbonylklorid (0.21 ml, 1.92 mmol). Etter 2 timer ble NaHC03tilsatt og blandingen ble ekstrahert med CH2CI2. De kombinerte ekstraktene ble tørket over vannfri MgSC>4, filtrert og konsentrert under redusert trykk. Det resulterende urene materialet ble tatt opp i 50 % EtOAc/heksan og det hvite faste stoffet ble filtrert fra. Det gjenværende filtratet ble konsentrert under redusert trykk som ga 640 mg av ønsket produkt.
400 MHz<*>H NMR (CDC13) 5 7.26-7.28 (m, 1H), 6.83-7.15 (m, 4H), 6.76-6.78 (m, 1H), 3.79-3.85 (m, 5H), 3.54-3.59 (m, 1H), 3.44 (d, J= 11.0 Hz, 1H), 3.39 (d, J= 11.0 Hz, 1H), 3.21-3.26 (m, 2H), 3.08-3.10 (m, 4H), 1.36-1.38 (m, 11H), 0.81-0.86 (m, 1H); MS
(M+l)
FREMSTILLING 4
Tiofen- 2- karboksylsyre ( 3- aza- bicyklo[ 3. 1 ■ 01heks- 6- vlmetyl)-( 3- fluor- 4- morfolin- 4- yl-fenvP- amid trifluoreddiksvre salt
Til en rørt løsning av 6-{[(3-fluor-4-morfolin-4-yl-fenyl)-(tiofen-2-karbonyl)-amino]metyl}-3-aza-bicyklo[3.1.0]heksan-3-karboksylsyre tert-butyl ester fremstilt ovenfor (640 mg, 1.28 mmol) i 6 ml CH2CI2ble det ved romtemperatur tilsatt 6 ml TF A. Reaksjonsblandingen ble rørt ved romtemperatur i 1 time. Blandingen ble konsentrert under redusert trykk, tatt opp i toluen og konsentrert igjen som ga 854 mg av ønsket produkt.
400 MHz<*>H NMR (CDCI3) 5 9.06 (brs, 1H), 8.62 (brs, 1H), 7.33-7.35 (m, 1H), 7.21-7.25 (m, 1H), 6.94-7.11 (m, 2H), 6.88-6.92 (m, 1H), 6.81-6.84 (m, 1H), 3.89-3.91 (m, 4H), 3.72 (d, J= 7.05 Hz, 2H), 3.39-3.46 (m, 4H), 3.16-3.18 (m, 4H), 1.77 (brs, 2H), 1.35-1.37 (m, 1H); MS (M+l) 402.1
EKSEMPEL 1
Tiofen- 2- karboksvlsvre ( 3- benzyl- 3- aza- bicyklo[ 3. 1 ■ 01heks- 6- vlmetvlW3- fluor- 4-morfolin- 4- vl- fenvl)- amid
Til en rørt løsning av tiofen-2-karboksylsyre (3-aza-bicyklo[3.1.0]heks-6-ylmetyl)-(3-fluor-4-morfolin-4-yl-fenyl)-amid trifluoreddiksyre salt fremstilt ovenfor (100 mg, 0.16 mmol) i 4 ml CH2CI2ble det ved romtemperatur tilsatt benzaldehyd (0.02 ml, 0.24 mmol) og NaHB(OAc)3(50 mg, 0.24 mmol). Reaksjonsblandingen ble rørt ved romtemperatur i 2 timer. Reaksjonen ble stoppet ved tilsetning av mettet NaHCC>3, sjiktene ble separert og vannsjiktet ble ekstrahert med CH2CI2. De kombinerte organiske sjiktene ble tørket over vannfri MgSC>4, filtrert og konsentrert under redusert trykk. Det resulterende urene materialet ble renset med flashkromatografi med 75% EtOAc/heksan. De produktinneholdende fraksjonene ble samlet opp og konsentret som ga 32 mg av ønsket produkt.
400 MHz<*>H NMR (CDCI3) 6 7.17-7.29 (m, 6H), 6.94-6.98 (m, 4H), 6.78-6.80 (m, 1H), 3.86-3.88 (m, 4H), 3.65 (d, J= 1 Al Hz, 2H), 3.52 (brs, 2H), 3.09-3.12 (m, 4H), 2.86-2.88 (m, 2H), 2.26-2.28 (m, 2H), 1.63 (brs, 1H), 1.47 (brs, 1H), 1.21-1.25 (m, 1H); MS (M+l) 492.2.
Generell fremgangsmåte for reduktiv alkyleringsfremstilling av forbindelser med formel vin
Til en rørt løsning av 1.0 ekviv. av en forbindelse med formel (VU) i metylenklorid (0.2 M) ble det ved romtemperatur tilsatt det passende substituerte aldehydreagenset (2.0 ekviv.), eddiksyre (2.0 ekviv.) og natriumtriacetoksyborhydrid (2.0 ekviv.). Reaksjonsblandingene ble rørt ved romtemperatur i opp til 24 timer. Reaksjonene ble deretter stoppet ved tilsetning av mettet natriumbikarbonatløsning og blandingene ble ekstrahert med metylenklorid. De kombinerte organiske sjiktene ble tørket over vannfri MgSC>4 og konsentrert under redusert trykk. Det resulterende urene materialet ble renset med flashkromatografi som ga ønskede tertinære aminer i 40-95 % utbytte.
Følgende forbindelser ble fremstilt ved anvendelse av fremgangsmåten ovenfor i eksempel 1, med utgangspunkt i passende utgangsamin med formel (VII) og passende aldehydreagenser. Videre kan de farmasøytisk akseptable saltene av forbindelsene listet nedenfor fremstilles som følger. Til en rørt løsning av forbindelsene med generell formel (VTH) (fremstilt som beskrevet ovenfor i eksempel 1,1.0 ekviv.) i et passende løsemiddel slik som metyletylketon, metylenklorid/metanol (1:1) eller metanol (0.1 M) ved romtemperatur ble det tilsatt passende syre, slik som saltsyre, sitronsyre, p-toluensulfonsyre, metansulfonsyre eller benzensulfonsyre (2-3 ekviv) i en porsjon. Den resulterende blandingen ble rørt ved romtemperatur i opp til 18 timer, hvorved et presipitat ble dannet. Filtrert av det faste stoffet og tørking under redusert trykk ga de ønskede saltene.
Tiofen- 2- karboksylsvre [ 3-( 4- etvl- benzyl)- 3- aza- bicyklor3. 1. 01heks- 6- vlmetyll-( 3-fluor- 4- morfolin- 4- vl- fenvD- amid
400 MHz<*>H NMR (CDC13) 8 7.27-7.29 (m, 1H), 7.07-7.13 (m, 4H), 6.90-6.98 (m, 2H), 6.84-6.89 (m, 2H), 6.78-6.80 (m, 1H), 3.86-3.88 (m, 4H), 3.65 (d, J= 1Å1 Hz, 2H), 3.50 (brs, 2H), 3.09-3.11 (m, 4H), 2.86-2.89 (m, 2H), 2.59 (q, 2H), 2.28-2.29 (m, 2H), 1.47 (brs, 1H), 1.17-1.27 (m, 5H); MS (M+l) 520.2.
EKSEMPEL 2
Tiofen- 2- karboksvlsvre [ 3-( 4- etvl- benzovn- 3- aza- bicyklo[ 3. 1. 01heks- 6- vlmetvll-( 3-fluor- 4- morfolin- 4- vl- fenv0- amid
Til en rørt løsning av tiofen-2-karboksylsyre (3-aza-bicyklo[3.1.0]heks-6-ylmetyl)-(3-fluor-4-morfolin-4-yl-fenyl)-amid (50 mg, 0.13 mmol) i 3 ml vannfri CH2CI2, ble det tilsatt DIEA (0.065 ml, 0.37 mmol), fulgt av 4-etylbenzoylklorid (0.02 ml, 0.14 mmol). Reaksjonsblandingen ble rørt ved romtemperatur i 1 time, reaksjonen stoppet med mettet NaHCC>3, og blandingen ekstrahert med CH2CI2. De kombinerte ekstraktene ble tørket over vannfri MgSC>4, filtrert og konsentrert. Det resulterende urene materialet ble renset med flashkromatografi med 75% EtOAc/heksan. Produktinneholdende fraksjoner ble samlet opp og konsentrert som ga 50 mg av en klar fargeløs olje.
400 MHz<*>H NMR (CDC13) 6 7.25-7.28 (m, 3H), 7.14-7.16 (m, 2H), 6.82-6.92 (m, 4H), 6.76-6.78 (m, 1H), 4.02-4.09 (m, 1H), 3.84-3.91 (m, 5H), 3.48-3.54 (m, 2H), 3.37-3.44
(m, 2H), 3.08-3.11 (m, 4H), 2.60 (q, 2H), 1.45 (s, 2H), 1.16-1.19 (m, 3H), 0.82-0.85 (m, 1H); MS (M+l) 534.2.
Generell fremgangsmåte for syrekloridfremstilling av forbindelser med ( VIII), hvorR<100>=C=O
Til en rørt løsning av 1.0 ekviv. av en forbindelse med (VII) i metylenklorid (0.2 M) ble det ved romtemperatur tilsatt DIEA (2.8 ekviv.), fulgt av syrekloridreagenset med formel (DC) (1.1 ekviv.). Reaksjonsblandingene ble rørt ved romtemperatur i opp til 24 timer. Reaksjonen ble deretter stoppet ved tilsetning av mettet natriumbikarbonat-løsning og blandingen ble ekstrahert med metylenklorid. De kombinerte organiske sjiktene ble tørket over vannfri MgSC>4 og konsentrert under redusert trykk. Det resulterende urene materialet ble renset med flashkromatografi som ga de ønskede tertiære aminene i 35-95 % utbytte.
Følgende forbindelser ble fremstilt ved anvendelse av fremgangsmåten ovenfor i eksempel 2, med utgangspunkt i passende utgangsamin med formel (VII) og passende syrekloridreagens med formel (EX).
Videre kan farmasøytisk akseptable salter av forbindelsene listet nedenfor fremstilles som følger. Til en rørt løsning av forbindelser med generell formel (VIII) (fremstilt som beskrevet ovenfor i eksempel 2, 1,0 ekviv) i et passende løsemiddel slik som metyletyl keton, metylenklorid/metanol (1:1) eller metanol (0.1 M) ble det ved romtemperatur tilsatt passende syre, slik som saltsyre, sitronsyre, p-toluensulfonsyre, metansulfonsyre eller benzensulfonsyre (1.0 ekviv) i en porsjon. Den resulterende blandingen ble rørt ved romtemperatur i opptil 18 timer, hvorved presipitatet ble dannet. Filtrering av det faste stoffet og tørking under redusert trykk ga de ønskede saltene.
EKSEMPEL 3
Tiofen- 2- karboksvlsyre [ 3-( 4- tert- butvl- benzensulfonyl)- 3- aza- bicvklo[ 3. 1 . Olheks- 6-vlmetv 11 -( 3 - fluor- 4- mofrolin- 4- vl- fenyl)- amid
Til en rørt løsning av tiofen-2-karboksylsyre (3-aza-bicyklo[3.1.0]heks-6-ylmetyl)-(3-fluor-4-morfolin-4-yl-fenyl)-amid (60 mg, 0.15 mmol) i 3 ml DCE ble det tilsatt DIEA (0.026 ml, 0.45 mmol), DMAP (eat.) og 4-tert-butylbenzensulfonyl klorid (0.10 ml, 0.45 mmol). Den resulterende blandingen ble varmet opp til 80 °C i 1.5 timer, avkjølt til romtemperatur og reaksjonen stoppet med mettet NaHCC>3. Sjiktene ble separert, vannsjiktet ekstrahert med CH2CI2, og de kombinerte organiske sjiktene tørket og konsentrert. Det resulterende urene materialet ble renset med flashkromatografi med 40% EtOAc/heksaner. Produktinneholdende fraksjoner ble samlet opp og konsentrert som ga 70 mg av et hvitt skum.
400 MHz *H NMR (CDCI3) 6 7.62-7.66 (m, 2H), 7.47-7.50 (m, 2H), 7.29-7.31 (m, 1H), 6.79-6.95 (m, 5H), 3.87-3.89 (m, 4H), 3.68 (d, J= 7.47 Hz, 2H), 3.46 (d, J= 9.13 Hz, 2H), 3.13-3.15 (m, 4H), 2.94-2.96 (m, 2H), 1.64 (s, 2H), 1.31 (s, 9H), 1.12-1.14 (m, 1H); MS (M+l) 598.2.
General fremgangsmåte for sulfonvlklorid fremstillingene av forbindelser med formel ( VTjq hvor R100 = SO,
Til en rørt løsning av 1.0 ekviv. av en forbindelse med formel (VU) i DCE (0.2 M) ble ved romtemperatur tilsatt DIEA (3.0 ekviv.), fulgt av sulfonylklorid reagenset med formel (DC) (3.0 ekviv.). Reaksjonsblandingen ble varmet opp til 80 °C i 18 timer. Blandingen ble deretter avkjølt til romtemperatur, reaksjonen ble stoppet ved tilsetning av mettet natriumbikarbonatløsning og blandingen ble ekstrahert med metylenklorid. De kombinerte organiske sjiktene ble tørket over vannfri MgS04og konsentrert under redusert trykk. Det resulterende urene materialet ble renset med flashkromatografi som ga ønskede tertiære aminer i 55-95 % utbytte.
Følgende forbindelser ble fremstilt ved anvendelse av fremgangsmåten ovenfor i eksempel 3, med utgangspunkt i passende utgangsamin med (VII) og passende sulfonylkloridreagens med formel (DC).
Videre kan farmasøytisk akseptable salter av forbindelsene listet nedenfor fremstilles som følger. Til en rørt løsning av forbindelsene med generell formel (VIII) (fremstilt som beskrevet ovenfor i eksempel 3, 1.0 ekviv.) i et passende løsemiddel slik som metyl etyl keton, metylenklorid/metanol (1:1) eller metanol (0.1 M) ved romtemperatur ble det tilsatt passende syre, slik som saltsyre, sitronsyre, p-toluensulfonsyre, metansulfonsyre eller benzensulfonsyre (1.0 ekviv) i en porsjon. Den resulterende blandingen ble rørt ved romtemperatur i opptil 18 timer, hvorved et presipitat ble dannet. Filtrering av det faste stoffet og tørking under redusert trykk ga de ønskede saltene.
FREMSTILLING 5
[ 3-( 4- Etvl- benzyl)- 3- aza- bicvklo[ 3. 1 . Olheks- 6- yll- metanol
Til en rørt løsning av (3-Aza-bicyklo[3.1.0]heks-6-yl)-metanol (18.4 gm, 123 mmol) i 450 ml MeOH ble det ved romtemperatur tilsatt 4-etylbenzaldehyd (18.5 ml, 135 mmol) og NaCNBH?(8.5 gm, 135 mmol). Etter røring i 3 timer ble reaksjonsblandingen konsentrert under redusert trykk, tatt opp i vann, behandlet med 1 M NaOH, og fortynnet med CH2CI2. Sjiktene ble separert, vannsjiktet ekstrahert med CH2CI2og de kombinerte organiske sjiktene tørket og konsentrert under redusert trykk. Det urene materialet ble løst i CH2CI2, behandlet med 1 M HC1 og konsentrert. Dette materialet ble tatt opp i vann og ekstrahert med Et20, vannsjiktet gjort basisk med NH4OH og blandingen ble ekstrahert med CH2CI2. De kombinerte ekstraktene ble tørket, filtrert og konsentrert under redusert trykk som ga 22.4 g av ønsket amin.
400 MHz<*>H NMR (CDC13) 5 7.14-7.16 (m, 2H), 7.08-7.10 (m, 2H), 3.54 (s, 2H), 3.38-3.40 (m, 2H), 2.95 (d, J= 8.7 Hz, 2H), 2.59 (q, 2H), 2.33 (d, J= 8.7 Hz, 2H), 1.55-1.59 (m, 1H), 1.42 (brs, 1H), 1.25-1.26 (m, 2H), 1.18-1.23 (m, 3H); MS (M+l) 232.2.
FREMSTILLING 6
[ 3-( 4- Etyl- benzvl)- 3- aza- bicvklo[ 3. 1. 01heks- 6- vlmetvll-( 3- fluor- 4- morfolin- 4- vl- fenyl)-amin
Til en rørt løsning av oksalylklorid (0.45 ml, 5.19 mmol) i 25 ml vannfri CH2CI2ble det ved -78 °C tilsatt DMSO (0.79 ml, 11.2 mmol) dråpevis. Etter 10 minutter ble [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-yl]-metanol (1.0 g, 4.32 mmol) i 10 ml vannfri CH2CI2tilsatt. Etter røring av reaksjonsblandingen i 30 minutter ble trietylamin (3.01 ml, 21.6 mmol) tilsatt og blandingen ble sakte varmet opp til 0 °C i løpet av 1 time. Blandingen ble konsentrert, det resulterende faste stoffet tatt opp i mettet NaHC03og EtOAc, sjiktene separert og vannsjiktet ekstrahert med EtOAc. De kombinerte organiske sjiktene ble tørket, filtrert og konsentrert som ga det urene aldehydet, som ble anvendt i neste trinn uten rensing.
Til en rørt løsning av det urene aldehydet (1.32 gm, 5.75 mmol) i 40 ml MeOH ble det tilsatt 3-fluor-4-morfolinoanilin (1.1 g, 5.75 mmol), AcOH (0.46 ml, 8.05 mmol) og NaCNBH3(361 mg, 5.75 mmol). Reaksjonsblandingen ble rørt ved romtemperatur i 60 minutter. Blandingen ble konsentrert under redusert trykk og det resulterende materialet samlet opp i mettet NaHCC>3 og ekstrahert med CH2CI2. De kombinerte organiske sjiktene ble tørket over vannfri MgSC>4, filtrert og konsentrert under redusert trykk. Det resulterende urene materialet ble renset ved flashkromatografi med 10-25% iso-propanol/heksangradient. Produktet inneholdende fraksjoner ble samlet opp og konsentrert som ga 1.55 g av det ønskede aminet.
400 MHz<*>H NMR (CDC13) 5 7.18-7.20 (m, 2H), 7.12-7.14 (m, 2H), 6.80-6.84 (m, 1H), 6.29-6.35 (m, 2H), 3.84-3.86 (m, 4H), 3.62 (brs, 1H), 3.53-3.57 (m, 2H), 3.00 (d, J = 8.70 Hz, 2H), 2.95-2.97 (m, 4H), 2.85 (d, J= 7.05 Hz, 2H), 2.63 (q, 2H), 2.38 (d, J= 8.40 Hz, 2H), 1.59 (s, 1H), 1.26-1.30 (m, 2H), 1.23 (t, 3H); MS (M+l) 410.2.
Følgende forbindelser ble fremstilt ved anvendelse av fremgangsmåten ovenfor for fremstilling 6.
( 4- brom- 3 - fluor- fenyl)-[ 3 -( 4- etyl- benzvl)- 3 - aza- bicyklo[ 3. 1. 01heks- 6- ylmetyll - amin
400 MHz<*>H NMR (CDCI3) 6 7.13-7.23 (m, 4H), 6.27-6.38 (m, 2H), 6.20-6.22 (m, 1H), 3.58 (s, 2H), 3.01 (d, J= 8.70 Hz, 2H), 2.82 (d, J= 7.05 Hz, 2H), 2.62 (q, 2H), 2.39 (d, J= 8.70 Hz, 2H), 1.53-1.57 (m, 1H), 1.29 (s, 2H), 1.23 (t, 3H); MS (M+l) 405.0.
EKSEMPEL 4
Benzo[b]tiofen-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmety 1] -(3 -fluor-4-morfolin-4-y l-fenyl)-amid
Til en rørt løsning av [3-(4-Etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amin fremstilt ovenfor (50 mg, 0.12 mmol) i 2 ml DCE ble det ved romtemperatur tilsatt DIEA (0.03 ml, 0.18 mmol) og 2-benztiofenkarbonylklorid (0.02 ml, 0.18 mmol). Etter 1 time ble mettet NaHCC>3 tilsatt og blandingen ble ekstrahert med CH2CI2. De kombinerte ekstraktene ble tørket over vannfri MgSC>4, filtrert og konsentrert under redusert trykk. Det resulterende urene materialet ble tatt opp i 50 % EtOAc/heksan og det hvite faste stoffet ble filtrert fra. Det gjenværende filtratet ble konsentrert under redusert trykk som ga 58 mg av ønsket produkt.
400 MHz<*>H NMR (CDCI3) 6 7.60-7.68 (m, 2H), 7.24-7.31 (m, 2H), 7.08-7.18 (m, 5H), 6.99-7.02 (m, 2H), 6.86-6.91 (m, 1H), 3.82-3.88 (m, 4H), 3.68 (d, J= 7. 47 Hz, 2H), 3.50 (brs, 2H), 3.10-3.12 (m, 4H), 2.88 (brd, J= 7. 47 Hz, 2H), 2.49 (q, 2H), 2.28, (brs, 2H), 1.49 (brs, 1H), 1.22-1.24 (m, 2H), 1.19 (t, 3H); MS (M+l) 570.2.
Følgende forbindelser ble fremstilt ved anvendelse av fremgangsmåten ovenfor i eksempel 4, med utgangspunkt i passende utgangsamin med formel (X) og syrekloridreagens med formel (XI).
Videre kan farmasøytisk akseptable salter av forbindelse listet nedenfor fremstilles som følger. Til en rørt løsning av forbindelsen med generell formel (XII) (fremstilt som beskrevet ovenfor i eksempel 4, 1.0 ekviv.) i et passende løsemiddel slik som metyletyl keton, metylenklorid/metanol (1:1) eller metanol (0.1 M) ved romtemperatur ble det tilsatt passende syre, slik som saltsyre, sitronsyre, p-toluensulfonsyre, metansulfonsyre eller benzensulfonsyre (1.0 ekviv) i porsjon. Den resulterende blandingen ble rørt ved romtemperatur i opptil 18 timer, hvorved et presipitat ble dannet. Filtrering av det faste stoffet og tørking under redusert trykk ga de ønskede saltene.
Tiofen- 2- karboksvlsyre ( 4- brom- 3- fluor- fenyl)-[ 3-( 4- etyl- benzyl)- 3- aza-bicyklo[ 3. 1 . Olheks- 6- vlmetvll- amid
400 MHz<*>H NMR (CDCI3) 5 7.54 (t, 1H), 7.31-7.32 (m, 1H), 7.04-7.12 (m, 5H), 6.93-6.95 (m, 1H), 6.80-6.84 (m, 2H), 3.67 (d, J= 7. 47 Hz, 2H), 3.49 (s, 2H), 2.85 (d, J =
8.71 Hz, 2H), 2.59 (q, 2H), 2.25 (d, J= 8.31 Hz, 2H), 1.46 (brs, 1H), 1.18-1.24 (m, 5H); MS (M+l) 513.0, 514.8.
EKSEMPEL 5
Tiofen- 2- karboksvlsyre [ 3-( 4- etvl- benzvl)- 3- aza- bicvklor3. 1. 01heks- 6- vlmetyll-[ 3-fluor- 4-( 4- metyl- piperazin- 1 - vlVfenyll - amid
Til en rørt løsning av (4-bromo-3-fluor-fenyl)-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amin fremstilt ovenfor (100 mg, 0.20 mmol) i 3 ml vannfri toluen ble det ved romtemperatur tilsatt N-metylpiperazin (0.03 ml, 0.23 mmol), BINAP (9.1 mg, 0.015 mmol), NaOtBu (26 mg, 0.27 mmol) og palladium (II) acetat (2.2 mg, 0.009 mmol). Blandingen ble evakuert under redusert trykk og overstrømmet med N2. Reaksjonsblandingen ble varmet opp til 100 °C i 18 timer. Blandingen ble avkjølt til romtemperatur, reaksjonen stoppet med mettet NaHCC>3, og blandingen ble ekstrahert med CH2CI2. De kombinerte organiske sjiktene ble tørket og konsentrert under redusert trykk. Rensing av det urene materialet med flashkromatografi med 5% MeOH/ CH2CI2ga det ønskede produktet (24 mg) som et hvitt skum.
400 MHz<*>H NMR (CDCI3) 5 7.27-7.29 (m, 1H), 7.08-7.15 (m, 4H), 6.89-6.98 (m, 3H), 6.77-6.84 (m, 2H), 3.64 (d, J= 7.05 Hz, 2H), 3.53 (s, 2H), 3.15-3.17 (m, 4H), 2.90 (brs, 2H), 2.57-2.62 (m, 6H), 2.29-2.40 (m, 5H), 1.39 (brs, 1H), 1.27 (brs, 2H), 1.19 (t, 3H); MS (M+l) 533.2.
Følgende forbindelser ble fremstilt ved anvendelse av fremgangsmåten ovenfor i eksempel 5, med utgangspunkt i passende bromid med formel (XV) og korresponderende aminet (R i fr R i *rNH).
Videre kan farmasøytisk akseptable salter av forbindelsene listet nedenfor fremstilles som følger. Til en rørt løsning av forbindelser med generell formel (XVI) (fremstilt som beskrevet ovenfor i eksempel 5, 1.0 ekviv.) i et passende løsemiddel slik som metyletyl keton, metylenklorid/metanol (1:1) eller metanol (0.1 M) ble det ved romtemperatur tilsatt passende syre, slik som saltsyre, sitronsyre, p-toluensulfonsyre, metansulfonsyre eller benzensulfonsyre (1.0 ekviv) i en porsjon. Den resulterende blandingen ble rørt ved romtemperatur i opptil 18 timer, hvorved et presipitat ble dannet. Filtrering av det faste stoffet og tørking under redusert trykk ga de ønskede saltene.
Tiofen- 2- karboksylsvre [ 4-( 4- acetyl- piperazin- 1 - yl)- 3 - lfuor- fenyll-[ 3-( 4- etyl- benzyl)- 3-aza- bicykloP. 1 . Olheks- 6- ylmetvll- amid
400 MHz<*>H NMR (CDC13) 6 7.27-7.29 (m, 1H), 6.95-7.09 (m, 4H), 6.88-6.91 (m, 2H), 6.85-6.87 (m, 2H), 6.78-6.80 (m, 1H), 3.77-3.80 (m, 2H), 3.62-3.66 (m, 4H), 3.50 (brs, 2H), 3.06-3.12 (m, 4H), 2.82-2.88 (m, 2H), 2.59 (q, 2H), 2.29 (brs, 2H), 2.13 (s, 3H), 1.44-1.47 (m, 1H), 1.17-1.25 (m, 5H); MS (M+l) 561.2.
EKSEMPEL 6
Tiofen- 2- karboksylsyre [ 3-( 4- tert- butvl- benzoyl)- 3- aza- bicvklo[ 3. 1 . Olheks- 6- vlmetyll-(3A5. 6- tetrahvdro- 2H- r<i>. 2Hbi<py>ridinvl-5WlVamid
En rørt løsning av tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(6-klor-pyridin-3-yl)-amid fremstilt ovenfor (50 mg, 0.10 mmol) i 1 ml vannfri piperidin ble varmet opp til 150 °C i 18 timer. Blandingen ble avkjølt til romtemperatur, reaksjonen stoppet med vann og blandingen ekstrahert med Et20. De kombinerte organiske sjiktene ble tørket over vannfri MgSC>4 og konsentrert under redusert trykk som ga ønsket forbindelse (40 mg, 73%).
Følgende forbindelser ble fremstilt ved anvendelse av fremgangsmåten ovenfor i eksempel 6, med utgangspunkt i passende utgangsbrom eller klorforbindelse med formel (XVII) og det korresponderende aminet (R 16 R 17NH). Videre kan farmasøytisk akseptable salter av forbindelsene listet nedenfor fremstilles som følger. Til en rørt løsning av forbindelsene med generell formel (XVI) (fremstilt som beskrevet ovenfor i eksempel 6, 1.0 ekviv.) i et passende løsningsmiddel slik som metyletylketon, metylen klorid/metanol (1:1) eller metanol (0.1 M) ble det ved romtemperatur tilsatt passende syre, slik som saltsyre, sitronsyre, p-toluensulfonsyre, metansulfonsyre eller benzen sulfonsyre (1.0 ekviv) i en porsjon. Den resulterende blandingen ble rørt ved romtemperatur i opptil 18 timer, hvorved det ble dannet et presipitat. Filtrering av det faste stoffet og tørking under redusert trykk ga de ønskede saltene.
Claims (4)
1.
En forbindelse,karakterisert vedformell,
hvori Yer(R<100>)k-R<1->(<R6>)<m;>k er 0 eller 1;
1 = 0,1,2 eller 3;
m = 1, 2 eller 3; n er 0, 1,2, 3 eller 4; o er 0 eller 1;
perO, 1,2, eller 3; q er 0, 1,2, 3 eller 4; r er 1 eller 2;
serO, 1,2, 3 eller 4;
t er 0 eller 1;
u er 1, 2, eller 3;
v er 1, 2, eller 3;R<100>er -CH2-, -CH(Ci-C3)alkyl-, -C(=0)- eller -S02-;
R1 er -(Ci-C6)alkyl, -(C3-C8)cykloalkyl, -(4 til 7 leddet) heterocykloalkyl som inneholder 1-3 heteroatomer valgt fra N, O, S og eventuelt en 2 C=0 gruppe, -(CH2)i-(C6-C10aryl) der aryl gruppen er valgt blant fenyl, indenyl, indanyl og naftyl eller -(5 til 10 leddet) heteroaryl der heteroarylgruppen er valgt blant pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, kinolyl, isokinolyl, tetrazolyl, furyl, thienyl, isoksazolyl, tiazolyl, oksazolyl, isotiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oksadiazolyl, tiadiazolyl, furazanyl, benzofurazanyl, benzothiofenyl, benzotriazolyl, benzotiazolyl, benzoksazolyl, kinazolinyl, kinoksalinyl, naphthyridinyl, dihydrokinolyl, tetrahydrokinolyl, dihydroisokinolyl, tetrahydroisokinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, og azaindolyl, hver R<6>kan være like eller forskjellige og er uavhengig valgt fra H, halo, -(Ci-Ce)alkyl-B, (C1-C7) alkoksy-D, (C2-C4)alkenoksy, (Ci-C6)alkyl-OH, -OH, CN, -N02, -CR<7>RV, -NR<20>R<21>, -NHCOalkyl(Ci-C3), NHS02alkyl(Ci-C3), C(=0)OR<22>, -R23-C(=0)OR22, - C(=0)NH2, fenyl-E, fenoksy-F, morfolin, -NR<20>R<21>, ar<y>l som definert for R<1>, heteroaryl som definert for R<1>, -S-R<24>, og -S02-R<25>;
B og D er hver uavhengig H, OH, fenyl, difenyl eller trifluro;
E og F er hver uavhengig H, alkyl valgt fra gruppen bestående av metyl, etyl, propyl, isopropyl, butyl, iso-butyl, sek-butyl, tert-butyl, pentyl, heksyl, heptyl, 3-etylbutyl, cyklopropyl, cyklobutyl, cyklopentyl, cykloheksyl, cykloheptyl og norbornyl, eller halo; R7, R8 og R<9>er hver uavhengig H, (C1-C4) alkyl, -OH, -0-(Ci-C4)alkyl, -CN, -NR 26 R 27 og -NHC(=0) (Ci-C3)alkyl, hvori nevnte alkylgrupper eventuelt er substituert med OH, OCH3, NH2, NHC(=0)(Ci-C3)alkyl, eller R<7>og R8 sammen med karbonatomet til hvilket de er bundet eventuelt danner en (C3-C7)cykloalkyl ring, eller en (4 til 7 leddet)heterocykloalkyl ring som inneholder 1-3 heteroatomer valgt fra N, O,
S og inneholder eventuelt en C=0 gruppe;
R<20>og R<21>er hver uavhengig H eller (Ci-C6) alkyl;
or R<20>og R<21>kan bindes sammen med 4 til 7 karbonatomer hvori fra en til tre av nevnte karbonatomer eventuelt kan være erstattet med O, N eller S, for å danne en heterocykloalkylring;
eller R<20>og R<21>kan bindes sammen med 3 til 7 atomer valgt fra C, N, O eller S for å danne en 5 til 10 leddet heteroarylring;
R22,R2<3>og R<24>er hver uavhengig H, eller (Ci-C5)alkyl;
R<25>er (Ci-Cs)alkyl;
R<26>og R<27>er hver uavhengig H eller (Ci-C3)alkyl;
eller R<26>og R<27>kan bindes sammen med 4 til 7 karbonatomer for å danne en heterocykloalkyl ring;
R<2>og R<3>er hver H;
R<4>og R<5>er hver H;
AerH;
R<28>er uavhengig (Ci-C3)alkoksy, -OH, -NR<12>R<13>eller -NHC(=0)(Ci-C4)alkyl;
R<12>og R<13>er hver uavhengig H eller -(d-C4)alkyl; eller
R<12>og R13 kan bindes sammen med 4 til 7 karbonatomer for å danne en heterocykloalkyl ring;
X er en binding, -CH2-(R<29>)P, -C(=0) eller -S02;
R<29>er-(Ci-C3)alkyl;
W er (Ci-Cg)alkyl, -(C3-C6)cykloalkyl, -(3 til 7 leddet) heterocyclkoalkyl som inneholder 1-3 heteroatomer valgt fra N, O, S og eventuelt 1 eller 2 C=0 grupper, fenyl, eller -(5 til 7 leddet) heteroaryl som definert for R1 eller heterocyklisk gruppe som definert for R<1>;
R<30>er-(Ci-C4)alkyl, -(Ci-C3)alkoksy, CN, -F, -Cl, -Br, -I, -NR<18>R<19>, -NHC(=0)<R18>, -SCH3eller -C(=0)CH3;
R<18>og R<19>er hver uavhengig H eller -(Ci-C3 )alkyl;
Q er en binding, -CH-(R<31>)r, -C(=0) eller -S02;
R<31>er uavhengig H eller -(Ci-C3)alkyl;
Z er -(Ci-Cg)alkyl, -(C3-C8)cykloalkyl, -(4 til 8 leddet) heterocykloalkyl, fenyl eller -(5 til 7 leddet) heteroaryl som definert for R1 eller heterocyklisk gruppe som definert forR<1>;
R<14>er F, Cl, Br, I, V, H, -NR<16>R<17>, -OR<16>, -C(=0)NR<16>R<17>, -(S02)NR<16>R<17>, eller -NR<32->C=0-R<33>;
R<15>er -(Ci-C3)alkyl, -(Ci-C3)alkoksy, -F, -Br, -Cl, -I -OH eller-CN;
V er -(C3-C8)cykloalkyl, -(Ci-C5)alkyl, (5 til 7 leddet) heterocykloalkyl som definert for R<1>, (5 til 7 leddet)heterocykloalkyl substituert med 1 eller 2 C=0 grupper eller 1, 2, eller 3 (Ci-Cs)alkyl grupper;
R<16>og R<17>er hver uavhengig H, -(Ci-C6)alkyl-(R<34>)U, eller (C3-C8)cykloalkyl-(R<35>)v; eller R 16 og R 17 sammen med nitrogenatomet til hvilket de er bundet danner en 4 til 7 leddet heterocykloalkyl ring som eventuelt inneholder fra 1 til 3 ytterligere heteroatomer uavhengig valgt fra N, S og O, og inneholder C=0, hvori nevnte heterocykloalkylring eventuelt og uavhengig er substituert med 1 til 3 substituenter uavhengig valgt fra (Ci-C4)alkyl, OH, (Ci-C4)alkoksy, NH2, -NH(C=0)(Ci-C8)aikyl, -N(Ci-C3)alkyl)2, -C(=0)CH3, CONH2, C02H, CH2OH, CH20alkyl(C2-C4), og (5 til 7 leddet) heterocykloalkyl som definert for R<1>;
R3<2>og R33 er hver uavhengig H eller (d-C5)alkyl;
eller R 32 og R 33 kan sammen danne en 3-7 leddet cykloalkylring, en 3-7 leddet heterocykloalkyl ring med 1 til 3 heteroatomer, eller en 5-7 leddet heteroaryl ring med 1 til 3 heteroatomer;
R<34>og R35 er hver uavhengig H, OH, (Ci-C5)alkyl, (C2-C4)alkoksy, NH2, NH(C=0)(Ci-C3)alkyl, eller en 5 til 7 leddet heterocykloalkyl;
eller R<34>og R<35>kan sammen danne en bro som inneholder 1-2 karbonatomer; der stereokjemien er som i formel II;
eller et farmasøytisk akseptabelt salt derav.
2.
Farmasøytisk sammensetning omfattende forbindelsen ifølge krav 1, eller et farmasøytisk akseptabelt salt derav, for anvendelse i behandling av en forstyrrelse eller tilstand valgt fra psykoser, schizofreni, adferdsforstyrrelser, urolig oppførselforstyrrelse, bipolare forstyrrelser, psykotiske episoder av angst, angst assosiert med psykoser, psykotiske humørforstyrrelser, alvorlig viktig depressiv forstyrrelse, humørforstyrrelse assosiert med psykotisk forstyrrelse, akutt mani, depresjon assosiert med bipolare forstyrrelser, humørforstyrrelser assosiert med schizofreni, oppførselsmanifestasjoner med mental retardasjon, oppførselsforstyrrelse, autistisk forstyrrelse, bevegelsesforstyrrelser, Tourettes syndrom, akinetisk stivehetssyndrom, bevegelsesforstyrrelser assosiert med Parkinsons sykdom, tartiv dyskinesi, andre legemiddelinduserte og neurodegenerasjonsbaserte dyskinesier, oppmerksomhetssvikt hyperaktivitetsforstyrrelse, kognitive forstyrrelser, demenser og hukommelsesforstyrrelser.
3.
Forbindelse ifølge krav 1, eller et farmasøytisk akseptabelt salt derav for anvendelse ved behandling av en forstyrrelse eller tilstand valgt fra psykoser, schizofreni, adferdsforstyrrelser, urolig oppførselforstyrrelse, bipolare forstyrrelser, psykotiske episoder av angst, angst assosiert med psykoser, psykotiske humørforstyrrelser, alvorlig viktig depressiv forstyrrelse, humørforstyrrelse assosiert med psykotisk forstyrrelse, akutt mani, depresjon assosiert med bipolare forstyrrelser, humørforstyrrelser assosiert med schizofreni, oppførselsmanifestasjoner med mental retardasjon, oppførselsforstyrrelse, autistisk forstyrrelse, bevegelsesforstyrrelser, Tourettes syndrom, akinetisk stivehetssyndrom, bevegelsesforstyrrelser assosiert med Parkinsons sykdom, tartiv dyskinesi, andre legemiddelinduserte og neurodegenerasjonsbaserte dyskinesier, oppmerksomhetssvikt hyperaktivitetsforstyrrelse, kognitive forstyrrelser, demenser og hukommelsesforstyrrelser.
4.
Forbindelse ifølge krav 1,karakterisert vedat den er valgt fra gruppen som består av: tiofen-2-karboksylsyre (3-cykloheksylmetyl-3-aza-bicyklo[3.1.0]heks-6-ylmetyl)-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-metyl-benzyl)-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-metoksy-benzyl)-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(2-hydroksy-indan-2-ylmetyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(l-hydroksy-cykloheksylmetyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre [3-(4-butyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-(3-pyridin-3 -ylmetyl-3-aza-bicyklo[3.1.0]heks-6-ylmetyl)-amid; tiofen-2-karboksylsyre [3-(4-klor-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre [3-(4-fluor-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre [3-(2-etyl-5-metyl-3H-imidazol-4-ylmetyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-lfuor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(2-p-tolyl-etyl)-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-(3-thiofen-2-ylmetyl-3-aza-bicyklo[3.1.0]heks-6-ylmetyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)-(3 -kinolin-2-ylmetyl-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl)-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(4-nitro-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(3 -metyl-benzyl)-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(3,4,5-trimetoksy-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-(3-pyridin-2-ylmetyl-3-aza-bicyklo[3.1.0]heks-6-ylmetyl)-amid; tiofen-2-karboksylsyre [3-(3,4-diklor-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(3 -metoksy-benzyl)-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(5-hydroksymetyl-furan-2-ylmetyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(lH-indol-3-ylmetyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)-(3 -pyridin-4-ylmetyl-3-aza-bicyklo[3.1.0]heks-6-ylmetyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(2-metyl-benzyl)-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-feny 1)- [3 -(3 -fenoksy-benzyl) -3 -aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)-(3 -naphthalen-1 -ylmetyl-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)-(3 -fenetyl-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl)-amid; tiofen-2-karboksylsyre (3-benzo[l,3]dioksol-5-ylmetyl-3-aza-bicyklo[3.1.0]heks-6-ylmetyl)-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)-(3 -naphthalen-2-ylmetyl-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl)-amid; tiofen-2-karboksylsyre [3-(2,2-difenyl-etyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)-(3 -kinolin-4-ylmetyl-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)-(3 -kinolin-3 -ylmetyl-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(3 -trifluormetoksy-benzyl)-3 - aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(3-metyl-benzo[b]thiofen-2-ylmetyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3-benzofuran-2-ylmetyl-3-aza-bicyklo[3.1.0]heks-6-ylmetyl)-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)-(3 -kinoksalin-6-ylmetyl-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(2-fluor-5 -trifluormetyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-{3-[4-(2-hydroksy-etoksy)-benzyl] -3 -aza-bicyklo [3.1.0]heks-6-ylmetyl} -amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-metansulfonyl-benzyl)-3 - aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(1 -metyl-1 H-pyrrol-2-ylmetyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)-(3 -furan-3 -ylmetyl-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl)-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-(3-thiofen-3-ylmetyl-3-aza-bicyklo[3.1.0]heks-6-ylmetyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-trifluormetoksy-benzyl)-3 - aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre [3-(4-tert-butoksy-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre [3-(4-bromo-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(4-isopropyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3-bifenyl-4-ylmetyl-3-aza-bicyklo[3.1.0]heks-6-ylmetyl)-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre [3-(4-cyano-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-hydroksy-benzyl)-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-trifluormetyl-benzyl)-3 - aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre [3-(4-etoksy-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-metylsulfanyl-benzyl)-3 - aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(4-fenoksy-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; 4-(6-{[(3-fluor-4-morfolin-4-yl-fenyl)-(tiofen-2-karbonyl)-amino]-metyl}-3-aza-bicyklo[3.1.0]heks-3-ylmetyl)-benzoic acid metyl ester; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(4-isobutyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre [3-(4-acetylamino-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(4-imidazol-l-yl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre [3-(4-benzyloksy-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-pyridin-2-yl-benzyl)-3 - aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(4-morfolin-4-yl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(4-pyrimidin-5-yl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(4,5,6,7-tetrahydro-benzotiazol-2-ylmetyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(3 -propoksy-benzyl)-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(3 -fenyl-propyl)-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre [3-(5-etyl-thiofen-2-ylmetyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre [3-(3-etoksy-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-propoksy-benzyl)-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre [3-(4-allyloksy-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)-(3 -heksyl-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl)-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(4-morfolin-4-yl-benzyl)-amid; tiofen-2-karboksylsyre (4-tert-butyl-fenyl)-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(4-piperidin-1 -yl-fenyl)-amid; tiofen-2-karboksylsyre (4-dietylamino-fenyl)-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[4-(4-etyl-2,6-diokso-piperidin-4-yl)-fenyl]-amid; tiofen-2-karboksylsyre (4-benzyl-fenyl)-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre [3-(5-benzyl-pyridin-2-ylmetyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(6-p-tolyloksy-pyridin-3 - ylmetyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-cykloheksylmetyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre {3-[2-fluor-4-(l -hydroksy-1 -metyl-etyl)-benzyl]-3-aza-bicyklo[3.1.0]heks-6-ylmetyl}-(3-lfuor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(6-morfolin-4-yl-pyridin-3-yl)-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-{4-[etyl-(2-hydroksy-etyl)-amino]-fenyl}-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[4-(2-okso-pyrrolidin-1 -yl)-fenyl] -amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[2-(2-etoksy-etyl)-l,2,3,4-tetrahydro-isokinolin-7-yl]-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[4-(morfolin-4-karbonyl)-fenyl]-amid; tiofen-2-karboksylsyre {3-[4-(cyano-dimetyl-metyl)-benzoyl]-3-aza-bicyklo[3.1 .OJheks-6-ylmetyl}-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre {3-[4-(cyano-dimetyl-metyl)-benzoyl]-3-aza-bicyklo[3.1.0]heks-6-ylmetyl} -(6-morfolin-4-y 1-pyridin- 3 -yl)-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[4-(tetrahydro-pyran-4-yl)-fenyl]-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[4-(2-okso-pyrrolidin-1 -yl)-fenyl] -amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[2-(2-etoksy-etyl)-l,2,3,4-tetrahydro-isokinolin-7-yl]-amid; 3-klor-tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl] -(6-morfolin-4-yl-pyridin-3 -yl)-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[4-(morfolin-4-karbonyl)-fenyl]-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(4-morfolin-4-ylmetyl-fenyl)-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(6-tiomorfolin-4-yl-pyridin-3-yl)-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(6-klor-pyridin-3 -yl)-amid; 5-fluor-tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl] -(6-morfolin-4-yl-pyridin-3 -yl)-amid; 5-metyl-tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl] -(6-morfolin-4-yl-pyridin-3 -yl)-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[l-(tetrahydro-pyran-4-yl)-pyrrolidin-3-yl]-amid; N-[3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-4-metyl-N-(6-morfolin-4-yl-pyridin-3-yl)-benzamid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[6-(3,6-dihydro-2H-pyran-4-yl)-pyridin-3-yl]-amid; tiofen-2-karboksylsyre [3-(4-etyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[6-(tetrahydro-pyran-4-yl)-pyridin-3-yl]-amid; furan-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(6-morfolin-4-yl-pyridin-3-yl)-amid;
1 -metyl-1 H-pyrrol-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl] -(6-morfolin-4-yl-pyridin-3 -yl)-amid; 4-metyl-[ 1,2,3]tiadiazole-5-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(6-morfolin-4-yl-pyridin-3-yl)-amid; pyridin-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(6-morfolin-4-yl-pyridin-3-yl)-amid;
benzofuran-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl] -(6-morfolin-4-yl-pyridin-3 -yl)-amid;
2-metyl-tiazol-4-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl] -(6-morfolin-4-yl-pyridin-3 -yl)-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(4-morfolin-4-yl-cykloheksyl)-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(4-morfolin-4-yl-cykloheksyl)-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(6-morfolin-4-ylmetyl-pyridin-3-yl)-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre [3-(5-butyl-pyridin-2-karbonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-cykloheksankarbonyl)-3-aza-bicyklo[3.1 .OJheks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre {3-[2-(4-tert-butyl-fenyl)-acetyl]-3-aza-bicyklo[3.1.0]heks-6-ylmetyl} -(3 -fluor-4-morfolin-4-y 1-fenyl)-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(6-morfolin-4-yl-pyridin-3-yl)-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(4-dietylkarbamoyl-fenyl)-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[ 1 -(tetrahydro-pyran-4-yl)-piperidin-4-yl] -amid;
3-klor-tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[3-(tetrahydro-pyran-4-yl)-3-aza-bicyklo[3.1.0]heks-6-yl]-amid; N-[3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-6-morfolin-4-yl-N-thiofen-2-ylmetyl-nikotinamid;
tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(3 -trifluormetyl-fenylmetansulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre {3 -[3 -(4-klor-fenoksy)-benzensulfonyl] -3 -aza-bicyklo[3.1.0]heks-6-ylmetyl}-(3-lfuor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-trifluormetoksy-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre [3-(4-cyano-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-{3-[4-(pyridin-2-yloksy)-benzensulfonyl] -3 -aza-bicyklo[3.1.0] heks-6-ylmetyl} -amid;
tiofen-2-karboksylsyre [3-(4-butyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-{3-[4-(pyridin-3-yloksy)-benzensulfonyl] -3 -aza-bicyklo[3.1.0] heks-6-ylmetyl} -amid;
tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(toluen-4-sulfonyl)-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre { 3 - [4-(4-klor-fenoksy)-benzensulfonyl] -3 -aza-bicyklo[3.1.0]heks-6-ylmetyl}-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre [3-(4'-fluor-bifenyl-4-sulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(1 -metyl-1 H-imidazole-4-sulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre [3-(4-bromo-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre [3-(4-bromo-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre [3-(2-acetylamino-4-metyl-tiazole-5-sulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-lfuor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(4-dietylkarbamoyl-fenyl)-amid;
tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-metyl-tiofen-2-sulfonyl)-3 - aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre [3-(4-klor-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
3-klor-tiofen-2-karboksylsyre [3-(4-tert-butyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-lfuor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre [3-(4-fluor-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[4-(2-okso-pyrrolidin-l-yl)-fenyl]-amid;
tiofen-2-karboksylsyre [3-(benzo[b]tiofen-2-sulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre [3-(bifenyl-3-sulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[2-(2-etoksy-etyl)-l,2,3,4-tetrahydro-isokinolin-7-yl]-amid; tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)-(3 -fenylmetansulfonyl-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl)-amid;
3- klor-tiofen-2-karboksylsyre [3-(4-tert-butyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(6-morfolin-4-yl-pyridin-3-yl)-amid; Ttofen-2-karboksylsyre [3-(4-klor-fenylmetansulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
5-fluor-tiofen-2-karboksylsyre [3-(4-tert-butyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(6-morfolin-4-yl-pyridin-3-yl)-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[4-(morfolin-4-karbonyl)-fenyl]-amid;
4- metyl-[l,2,3]tiadiazole-5-karboksylsyre [3-(4-tert-butyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(6-morfolin-4-yl-pyridin-3-yl)-amid; 1-metyl-lH-pyrrol-2-karboksylsyre [3-(4-tert-butyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(6-morfolin-4-yl-pyridin-3-yl)-amid;
tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(kinoline-8-sulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-propyl-benzensulfonyl)-3 - aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-metoksy-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(2-metoksy-4-metyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-trifluormetyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(isokinolin-5-sulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(4-isopropyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre [3-(5-bromo-6-klor-pyridin-3-sulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-lfuor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre [3-(4-etyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(2-okso-2H-chromene-6-sulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-fluor-fenylmetansulfonyl)-3- aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(4-nitro-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-trifluormetyl-fenylmetansulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-{3-[4-(pyridin-4-yloksy)-benzensulfonyl] -3 -aza-bicyklo[3.1.0] heks-6-ylmetyl} -amid;
4- (6-{[(3-fluor-4-morfolin-4-yl-fenyl)-(tiofen-2-karbonyl)-amino]-metyl}-3-aza-bicyklo[3.1.0]heksan-3-sulfonyl)-benzoic acid;
tiofen-2-karboksylsyre [3-(bifenyl-4-sulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre [3-(4-butoksy-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre [3-(4'-klor-bifenyl-3-sulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-2-karboksylsyre [3-(4-acetyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
cyklopropankarboksylsyre [3-(4-tert-butyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl] -(6-morfolin-4-yl-pyridin-3 -yl)-amid;
tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-pentyl-benzensulfonyl)-3 - aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
cyklopentankarboksylsyre [3-(4-tert-butyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl] -(6-morfolin-4-yl-pyridin-3 -yl)-amid;
tiofen-2-karboksylsyre (3 -fluor-4-morfolin-4-yl-fenyl)- [3 -(4-fenoksy-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
cyklobutankarboksylsyre [3-(4-tert-butyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl] -(6-morfolin-4-yl-pyridin-3 -yl)-amid;
3- [4-(6-{[(3-fluor-4-morfolin-4-yl-fenyl)-(tiofen-2-karbonyl)-amino]-metyl}-3-aza-bicyklo[3.1.0]heksan-3-sulfonyl)-fenyl]-propionic acid metyl ester; tiofen-2-karboksylsyre [3-(4-acetylamino-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; N-[3-(4-tert-butyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-4-metyl-N-(6-morfolin-4-yl-pyridin-3-yl)-benzamid;
tiofen-2-karboksylsyre {3-[4-(l,l-dimetyl-propyl)-benzensulfonyl]-3-aza-bicyklo[3.1.0]heks-6-ylmetyl}-(3-fluor-4-morfolin-4-yl-fenyl)-amid; tiofen-2-karboksylsyre (3-fluor-4-morfolin-4-yl-fenyl)-[3-(naftalen-2-sulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzensulfonyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl] -(6-morfolin-4-yl-pyridin-3 -yl)-amid; N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-N-(3-fluor-4-morfolin-4-yl-fenyl)- isonikotinamid;
benzofuran-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
furan-3 -karboksylsyre [3 -(4-etyl-benzyl)-3 -aza-bicyklo[3.1.0]heks-6-ylmetyl] -(3 -fluor-4- morfolin-4-yl-fenyl)-amid; N-{l-[[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-karbamoyl]-etyl} -benzamid;
3-brom-tiofen-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
3-metyl-furan-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
5-metyl-isoksazol-3-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-N-(3-lfuor-4-morfolin-4-yl-fenyl)-2-metoksy-benzamid;
3-metyl-tiofen-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-N-(3-lfuor-4-morfolin-4-yl-fenyl)-4-metoksy-benzamid;
2,5-dimetyl-furan-3-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-N-(3-lfuor-4-morfolin-4-yl-fenyl)-4-metyl-benzamid;
5-metyl-tiofen-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; 5-tert-butyl-2-metyl-2H-pyrazole-3-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-lfuor-4-morfolin-4-yl-fenyl)-amid; N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-N-(3-lfuor-4-morfolin-4-yl-fenyl)- 3,5 -dimetoksy-benzamid; N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-N-(3-lfuor-4-morfolin-4-yl-fenyl)- 3 -metoksy-benzamid;
1,5-dimetyl-1 H-pyrazol-3-karboksylsyre [3 -(4-etyl-benzyl)-3 -aza-bicyklo [3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
3- etoksy-tiofen-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
isoksazol-5-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
1 -metyl-lH-imidazol-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
furan-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4- morfolin-4-yl-fenyl)-amid; N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-N-(3-lfuor-4-morfolin-4-yl-fenyl)-2-metyl-benzamid;
benzo[b]tiofen-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; 4-cyano-N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-N-(3-fluor-4-morfolin-4-yl-fenyl)-benzamid;
4-etyl-N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-yl^ 4-yl-fenyl)-benzamid;
3- klor-tiofen-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-N-(3-lfuor-4-morfolin-4-yl-fenyl)-2-metylsulfanyl-nikotinamid;
1 -metyl-1 H-pyrazol-3-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-2,4-difluor-N-(3-fluor-4-morfolin-4-yl-fenyl)-benzamid; N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-N-(3-lfuor-4-morfolin-4-yl-fenyl)-nikotinamid;
3,5-dimetyl-lH-pyrrol-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
1 -metyl-1 H-pyrrol-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
2-metyl-tiazol-4-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
4- brom-N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-N-(3-fluor-4-morfolin-4-yl-fenyl)-benzamid;
5- okso-pyrrolidin-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-N-(3-lfuor-4-morfolin-4-yl-fenyl)-2-(2-metoksy-fenyl)-acetamid; N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-N-(3-lfuor-4-morfolin-4-yl-fenyl)-2-(2-fluor-fenyl)-acetamid; l-acetyl-pyrrolidin-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid;
tiofen-3-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4- morfolin-4-yl-fenyl)-amid; N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-N-(3-lfuor-4-morfolin-4-yl-fenyl)-2-pyridin-3 -yl-acetamid;
5- brom-tiofen-2-karboksylsyre [3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3-fluor-4-morfolin-4-yl-fenyl)-amid; N-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-N-(3-lfuor-4-morfolin-4-yl-fenyl)-2-o-tolyl-acetamid;
tiofen-2-karboksylsyre [4-(4-acetyl-[l,4]diazepan-l-yl)-3-Tfluor-fenyl]-[3-(4-etyl-benzyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre [6-(4-acetyl-piperazin-1 -yl)-pyridin-3-yl]-[3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-(3,4,5,6-tetrahydro-2H-[l,2']bipyridinyl-5'-yl)-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[6-(5-metyl-2,5-diaza-bicyklo[2.2.1]hept-2-yl)-pyridin-3-yl]-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[6-(4-metyl-piperazin-l-yl)-pyridin-3-yl]-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-{6-[etyl-(2-metoksy-etyl)-amino]-pyridin-3-yl}-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-{ 6- [(1 H-imidazol-2-ylmety l)-metyl-amino] -pyridin- 3 -yl} -amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[6-(3-okso-piperazin-1 -yl)-pyridin-3 -yl] -amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-{ 6- [(2-metoksy-etyl)-metyl-amino] -pyridin-3 -yl} -amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[6-(3 -dimetylamino-pyrrolidin-1 -yl)-pyridin-3-yl] -amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[6-(4-metyl-[ 1,4] diazepan-1 -yl)-pyridin-3 -yl] -amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[6-(3 -dietylamino-pyrrolidin-1 -yl)-pyridin-3 -yl]-amid;
tiofen-2-karboksylsyre (6-[l,3']bipyrrolidinyl-r-yl-pyridin-3-yl)-[3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[6-(3-morfolin-4-yl-azetidin-l-yl)-pyridin-3-yl]-amid;
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[6-(8-metyl-3,8-diaza-bicyklo[3.2.1]oct-3-yl)-pyridin-3-yl]-amid; tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[6-(3-morfolin-4-yl-pyrrolidin-l-yl)-pyridin-3-yl]-amid; and
tiofen-2-karboksylsyre [3-(4-tert-butyl-benzoyl)-3-aza-bicyklo[3.1.0]heks-6-ylmetyl]-[6-(2,3-dihydro-5H-benzo[f][ 1,4]oksazepin-4-yl)-pyridin-3-yl]-amid, eller et farmasøytisk akseptabelt salt derav.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US51084603P | 2003-10-14 | 2003-10-14 | |
PCT/US2004/034083 WO2005037216A2 (en) | 2003-10-14 | 2004-10-14 | Bicyclic [3.1.0] derivatives as glycine transporter inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
NO20062193L NO20062193L (no) | 2006-05-15 |
NO337361B1 true NO337361B1 (no) | 2016-03-29 |
Family
ID=34465157
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO20062193A NO337361B1 (no) | 2003-10-14 | 2006-05-15 | Bicykliske[3.1.0] derivater som glysintransportørinhibitorer, og farmasøytiske sammensetninger inneholdende slike. |
Country Status (26)
Country | Link |
---|---|
US (1) | US7473787B2 (no) |
EP (1) | EP1680124B1 (no) |
JP (2) | JP4732354B2 (no) |
KR (1) | KR20060095865A (no) |
CN (2) | CN1867338A (no) |
AP (1) | AP2006003592A0 (no) |
AU (1) | AU2004281794B2 (no) |
BR (1) | BRPI0415356A (no) |
CA (1) | CA2542279C (no) |
CR (2) | CR8333A (no) |
DK (1) | DK1680124T3 (no) |
EA (1) | EA009903B1 (no) |
EC (1) | ECSP066504A (no) |
ES (1) | ES2634841T3 (no) |
GE (1) | GEP20104959B (no) |
IL (1) | IL174299A (no) |
IS (1) | IS8355A (no) |
MA (1) | MA28094A1 (no) |
MX (1) | MXPA06004279A (no) |
NO (1) | NO337361B1 (no) |
NZ (1) | NZ546012A (no) |
RS (1) | RS20060190A (no) |
TN (1) | TNSN06109A1 (no) |
UA (1) | UA86037C2 (no) |
WO (1) | WO2005037216A2 (no) |
ZA (1) | ZA200602174B (no) |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK1680124T3 (en) * | 2003-10-14 | 2017-08-21 | Pfizer Prod Inc | Bicyclic [3.1.0] derivatives as glycine transporter inhibitors |
GB0408772D0 (en) * | 2004-04-20 | 2004-05-26 | Glaxo Group Ltd | Compounds |
GB0408774D0 (en) * | 2004-04-20 | 2004-05-26 | Glaxo Group Ltd | Compounds |
CN101005838A (zh) * | 2004-06-22 | 2007-07-25 | 先灵公司 | 大麻素受体配体 |
CN101189228A (zh) * | 2005-04-08 | 2008-05-28 | 辉瑞产品有限公司 | 用作i型甘氨酸转运抑制剂的二环[3.1.0]杂芳酰胺 |
US8067415B2 (en) | 2005-11-01 | 2011-11-29 | Millennium Pharmaceuticals, Inc. | Compounds useful as antagonists of CCR2 |
WO2007053498A1 (en) | 2005-11-01 | 2007-05-10 | Millennium Pharmaceuticals, Inc. | Compounds useful as antagonists of ccr2 |
WO2007135527A2 (en) * | 2006-05-23 | 2007-11-29 | Pfizer Products Inc. | Benzimidazolyl compounds |
WO2008065500A2 (en) * | 2006-11-30 | 2008-06-05 | Pfizer Products Inc. | Heteroaryl amides as type i glycine transport inhibitors |
SI2247589T1 (sl) * | 2007-11-05 | 2013-03-29 | Merck Patent Gmbh | Derivati 7-azaindola kot selektivni inhibitorji 11-beta-hidroksisteroidne dehidrogenaze tipa 1 |
AU2009324479A1 (en) * | 2008-12-12 | 2011-06-30 | Vanderbilt Universtiy | 3.3.0 bicyclic GlyT1 inhibitors and methods of making and using same |
JP2012514006A (ja) * | 2008-12-29 | 2012-06-21 | バンダービルト ユニバーシティ | 3.1.0二環式GlyT1阻害剤ならびにその作製および使用の方法 |
FR2944283B1 (fr) * | 2009-04-14 | 2011-05-06 | Sanofi Aventis | Derives de n-°(2-aza-bicyclo°2.1.1!hex-1-yl)-aryl-methyl!- heterobenzamide, leur preparation et leur application en therapeutique |
JPWO2010107115A1 (ja) * | 2009-03-19 | 2012-09-20 | 大正製薬株式会社 | グリシントランスポーター阻害物質 |
EP2617715A4 (en) | 2010-09-17 | 2014-02-26 | Taisho Pharmaceutical Co Ltd | GLYCINE TRANSPORTER INHIBITOR |
WO2012042539A2 (en) | 2010-09-28 | 2012-04-05 | Panacea Biotec Ltd | Novel bicyclic compounds |
US9012489B2 (en) * | 2011-08-03 | 2015-04-21 | Boehringer Ingelheim International Gmbh | Phenyl-3-aza-bicyclo[3.1.0]hex-3-yl-methanones and the use thereof as medicament |
US9371282B2 (en) | 2013-05-17 | 2016-06-21 | Centrexion Therapeutics Corporation | Somatostatin receptor subtype 4 (SSTR4) agonists |
CN103319645B (zh) * | 2013-05-31 | 2016-08-10 | 南京洁雅新材料有限公司 | 一种水性金属保护剂及其生产工艺 |
WO2015165341A1 (zh) * | 2014-04-28 | 2015-11-05 | 南京明德新药研发股份有限公司 | 作为rho激酶抑制剂的异喹啉磺酰衍生物 |
CA2998493A1 (en) | 2015-09-16 | 2017-03-23 | Metacrine, Inc. | Farnesoid x receptor agonists and uses thereof |
JP2018532772A (ja) | 2015-09-16 | 2018-11-08 | メタクリン,インク. | ファルネソイドx受容体アゴニストおよびそれらの使用 |
WO2017049176A1 (en) * | 2015-09-16 | 2017-03-23 | Metacrine, Inc. | Farnesoid x receptor agonists and uses thereof |
EP3350158A4 (en) | 2015-09-16 | 2019-05-08 | Metacrine, Inc. | X FARNESOID RECEPTOR AGONISTS AND USES THEREOF |
CN113784966B (zh) * | 2019-05-01 | 2024-07-19 | 勃林格殷格翰国际有限公司 | Glyt1抑制剂的固体形式 |
MX2021014441A (es) | 2019-05-31 | 2022-01-06 | Ikena Oncology Inc | Inhibidores del dominio asociado mejorador de la transcripcion (tead) y usos de los mismos. |
CA3142351A1 (en) | 2019-05-31 | 2020-12-03 | Ikena Oncology, Inc. | Tead inhibitors and uses thereof |
JP2023537963A (ja) | 2020-08-13 | 2023-09-06 | 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 | 統合失調症に伴う認知機能障害に対する処置法 |
TWI822326B (zh) | 2021-09-14 | 2023-11-11 | 美商美國禮來大藥廠 | Sstr4促效劑鹽 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997045115A1 (en) * | 1996-05-31 | 1997-12-04 | Trophix Pharmaceuticals, Inc. | Pharmaceutical for treatment of neurological and neuropsychiatric disorders |
WO2003055478A1 (en) * | 2001-12-21 | 2003-07-10 | Smithkline Beecham P.L.C. | Glyt1 transporter inhibitors and uses thereof in treatment of neurological and neuropsychiatric disorders |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UA49006C2 (uk) * | 1996-03-29 | 2002-09-16 | Файзер Інк. | Похідні 6-фенілпіридил-2-аміну, фармацевтична композиція, спосіб інгібування синтази оксиду нітрогену у ссавців та спосіб лікування |
EP1385834B1 (en) * | 2001-04-17 | 2005-09-14 | Merck & Co., Inc. | Bicyclo[3,1,0]hexane containing oxazolidinone antibiotic and derivatives thereof |
IL161157A0 (en) * | 2001-10-22 | 2004-08-31 | Pfizer Prod Inc | 3-azabicyclo (3.1.0) hexane derivatives as opioid receptor antagonists |
WO2003037865A1 (en) | 2001-10-31 | 2003-05-08 | Morphochem Aktiengesellschaft für kombinatorische Chemie | Novel anticancer compounds |
CN1668585A (zh) * | 2002-07-08 | 2005-09-14 | 兰贝克赛实验室有限公司 | 用作蝇蕈碱受体拮抗剂的3,6-二取代氮杂双环[3.1.0]己烷衍生物 |
US7288562B2 (en) * | 2002-08-23 | 2007-10-30 | Ranbaxy Laboratories Limited | Fluoro and sulphonylamino containing 3,6-disubstituted azabicyclo (3.1.0) hexane derivatives as muscarinic receptor antagonists |
WO2004089900A1 (en) * | 2003-04-11 | 2004-10-21 | Ranbaxy Laboratories Limited | Azabicyclo derivatives as muscarinic receptor antagonists |
DK1680124T3 (en) * | 2003-10-14 | 2017-08-21 | Pfizer Prod Inc | Bicyclic [3.1.0] derivatives as glycine transporter inhibitors |
BRPI0415459A (pt) * | 2003-10-16 | 2006-12-19 | Pfizer Prod Inc | preparação de derivados de 3-azabiciclo[3.1.0]hexano |
DK2447252T3 (da) | 2004-05-23 | 2020-03-16 | Hmi Medical Innovations Llc | Theramuteinmodulatorer |
-
2004
- 2004-10-14 DK DK04795270.0T patent/DK1680124T3/en active
- 2004-10-14 WO PCT/US2004/034083 patent/WO2005037216A2/en active Application Filing
- 2004-10-14 BR BRPI0415356-1A patent/BRPI0415356A/pt not_active IP Right Cessation
- 2004-10-14 KR KR1020067007132A patent/KR20060095865A/ko active IP Right Grant
- 2004-10-14 EA EA200600513A patent/EA009903B1/ru not_active IP Right Cessation
- 2004-10-14 GE GEAP20049350A patent/GEP20104959B/en unknown
- 2004-10-14 CA CA2542279A patent/CA2542279C/en not_active Expired - Fee Related
- 2004-10-14 JP JP2006535348A patent/JP4732354B2/ja not_active Expired - Fee Related
- 2004-10-14 AU AU2004281794A patent/AU2004281794B2/en not_active Ceased
- 2004-10-14 UA UAA200604173A patent/UA86037C2/ru unknown
- 2004-10-14 NZ NZ546012A patent/NZ546012A/en not_active IP Right Cessation
- 2004-10-14 ES ES04795270.0T patent/ES2634841T3/es active Active
- 2004-10-14 CN CNA2004800300443A patent/CN1867338A/zh active Pending
- 2004-10-14 US US10/964,931 patent/US7473787B2/en active Active
- 2004-10-14 RS YUP-2006/0190A patent/RS20060190A/sr unknown
- 2004-10-14 AP AP2006003592A patent/AP2006003592A0/xx unknown
- 2004-10-14 EP EP04795270.0A patent/EP1680124B1/en active Active
- 2004-10-14 CN CN201010128454A patent/CN101838271A/zh active Pending
- 2004-10-14 MX MXPA06004279A patent/MXPA06004279A/es active IP Right Grant
-
2006
- 2006-03-13 IL IL174299A patent/IL174299A/en active IP Right Grant
- 2006-03-15 ZA ZA2006/02174A patent/ZA200602174B/en unknown
- 2006-03-16 IS IS8355A patent/IS8355A/is unknown
- 2006-04-06 CR CR8333A patent/CR8333A/es unknown
- 2006-04-12 EC EC2006006504A patent/ECSP066504A/es unknown
- 2006-04-14 TN TNP2006000109A patent/TNSN06109A1/fr unknown
- 2006-04-14 MA MA28935A patent/MA28094A1/fr unknown
- 2006-05-15 NO NO20062193A patent/NO337361B1/no not_active IP Right Cessation
-
2011
- 2011-01-28 JP JP2011016751A patent/JP2011157358A/ja active Pending
- 2011-02-17 CR CR20110095A patent/CR20110095A/es not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997045115A1 (en) * | 1996-05-31 | 1997-12-04 | Trophix Pharmaceuticals, Inc. | Pharmaceutical for treatment of neurological and neuropsychiatric disorders |
WO2003055478A1 (en) * | 2001-12-21 | 2003-07-10 | Smithkline Beecham P.L.C. | Glyt1 transporter inhibitors and uses thereof in treatment of neurological and neuropsychiatric disorders |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
NO337361B1 (no) | Bicykliske[3.1.0] derivater som glysintransportørinhibitorer, og farmasøytiske sammensetninger inneholdende slike. | |
TWI353983B (en) | Aromatic compound and pharmaceutical composition c | |
US20110124626A1 (en) | Benzazepine derivatives and their use as histamine h3 antagonists | |
TWI332838B (en) | Antitumor agent comprising an aromatic compound or a salt thereof and use of the aromatic compound or a salt thereof for manufacturing an antitumor agent | |
TWI796205B (zh) | 新穎cyp11a1抑制劑 | |
KR101721025B1 (ko) | 테트라하이드로벤조티오펜 화합물 | |
CN104352492A (zh) | 以芳基磺酰基衍生物作为有效成分的长链脂肪酸延长酶抑制剂 | |
WO2006022442A1 (ja) | ジヒドロオロテートデヒドロゲナーゼ阻害活性を有する新規複素環アミド誘導体 | |
SK17222002A3 (sk) | Inhibítory serínových proteáz | |
JP5411867B2 (ja) | 新規sEH阻害剤およびそれらの使用 | |
TW201406736A (zh) | 新穎的醯胺衍生物或其鹽 | |
CA3208103A1 (en) | Anti-viral compounds | |
CA2808246A1 (en) | Arylosulfonamides for the treatment of cns diseases | |
SK286687B6 (sk) | Sulfónamidy, spôsob ich výroby, medziprodukty, liečivo a farmaceutická kompozícia s ich obsahom | |
KR20170117024A (ko) | 생체 아민 수송 조절인자로서 신규한 퀴나졸린 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
CHAD | Change of the owner's name or address (par. 44 patent law, par. patentforskriften) |
Owner name: PFIZER PRODUCTS INC, US |
|
MM1K | Lapsed by not paying the annual fees |