ZA200506215B - Biphenyl derivatives having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity - Google Patents
Biphenyl derivatives having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity Download PDFInfo
- Publication number
- ZA200506215B ZA200506215B ZA200506215A ZA200506215A ZA200506215B ZA 200506215 B ZA200506215 B ZA 200506215B ZA 200506215 A ZA200506215 A ZA 200506215A ZA 200506215 A ZA200506215 A ZA 200506215A ZA 200506215 B ZA200506215 B ZA 200506215B
- Authority
- ZA
- South Africa
- Prior art keywords
- hydroxy
- piperidin
- ylene
- biphenyl
- ester
- Prior art date
Links
- 230000000694 effects Effects 0.000 title claims description 14
- 239000000048 adrenergic agonist Substances 0.000 title claims description 12
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 title claims description 11
- 229940126157 adrenergic receptor agonist Drugs 0.000 title claims description 10
- 239000003149 muscarinic antagonist Substances 0.000 title claims description 10
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title description 9
- 102100039705 Beta-2 adrenergic receptor Human genes 0.000 title 1
- 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims description 229
- 150000001875 compounds Chemical class 0.000 claims description 142
- 229910052739 hydrogen Inorganic materials 0.000 claims description 102
- 239000001257 hydrogen Substances 0.000 claims description 102
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 97
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 83
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 69
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 65
- 125000001424 substituent group Chemical group 0.000 claims description 54
- 125000005843 halogen group Chemical group 0.000 claims description 47
- 125000002947 alkylene group Chemical group 0.000 claims description 43
- -1 oxiran- 2,3-diyl Chemical group 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 40
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 39
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 36
- 239000012453 solvate Substances 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 33
- 125000000732 arylene group Chemical group 0.000 claims description 32
- 125000005549 heteroarylene group Chemical group 0.000 claims description 32
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- 125000003386 piperidinyl group Chemical group 0.000 claims description 27
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 26
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 26
- 125000004450 alkenylene group Chemical group 0.000 claims description 24
- 125000001153 fluoro group Chemical group F* 0.000 claims description 23
- 125000004429 atom Chemical group 0.000 claims description 22
- 125000004419 alkynylene group Chemical group 0.000 claims description 20
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 125000000304 alkynyl group Chemical group 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 150000002431 hydrogen Chemical group 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 208000019693 Lung disease Diseases 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 108060003345 Adrenergic Receptor Proteins 0.000 claims description 6
- 102000017910 Adrenergic receptor Human genes 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- 230000007883 bronchodilation Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 claims description 4
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 claims description 4
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 239000002294 steroidal antiinflammatory agent Substances 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- QMOVGVNKXUTCQU-UHFFFAOYSA-N (2-phenylphenyl)carbamic acid Chemical compound OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 QMOVGVNKXUTCQU-UHFFFAOYSA-N 0.000 claims 118
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 102
- 239000000126 substance Substances 0.000 claims 16
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 8
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims 6
- 150000002148 esters Chemical class 0.000 claims 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 6
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 6
- 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 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 5
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 3
- REUZFCAPUWZSMB-GTIIJGOXSA-N [1-[3-[[4-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]cyclohexyl]amino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCC(CC1)CCC1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 REUZFCAPUWZSMB-GTIIJGOXSA-N 0.000 claims 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 claims 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 2
- 125000006534 ethyl amino methyl group Chemical group [H]N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims 2
- 229910052698 phosphorus Inorganic materials 0.000 claims 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims 2
- 229940080818 propionamide Drugs 0.000 claims 2
- XJRIDJAGAYGJCK-UHFFFAOYSA-N (1-acetyl-5-bromoindol-3-yl) acetate Chemical compound C1=C(Br)C=C2C(OC(=O)C)=CN(C(C)=O)C2=C1 XJRIDJAGAYGJCK-UHFFFAOYSA-N 0.000 claims 1
- CGAQTOMYVNCBLR-UHFFFAOYSA-N (4-bromo-2-phenylphenyl)carbamic acid Chemical compound OC(=O)NC1=CC=C(Br)C=C1C1=CC=CC=C1 CGAQTOMYVNCBLR-UHFFFAOYSA-N 0.000 claims 1
- LKXSTUSHJUFQQM-DHUJRADRSA-N 1-[1-[3-[4-[2-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]ethyl]piperidin-1-yl]-3-oxopropyl]piperidin-4-yl]-3-(2-phenylphenyl)urea Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCC(CC1)CCN1C(=O)CCN(CC1)CCC1NC(=O)NC1=CC=CC=C1C1=CC=CC=C1 LKXSTUSHJUFQQM-DHUJRADRSA-N 0.000 claims 1
- XNOIKAXDDGFZLM-UHFFFAOYSA-N 1-[1-[9-[[2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]nonyl]piperidin-4-yl]-3-(2-phenylphenyl)urea Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCCCCN2CCC(CC2)NC(=O)NC=2C(=CC=CC=2)C=2C=CC=CC=2)=C1 XNOIKAXDDGFZLM-UHFFFAOYSA-N 0.000 claims 1
- 102100033668 Cartilage matrix protein Human genes 0.000 claims 1
- 101001018382 Homo sapiens Cartilage matrix protein Proteins 0.000 claims 1
- 241001499740 Plantago alpina Species 0.000 claims 1
- 240000005809 Prunus persica Species 0.000 claims 1
- 235000006040 Prunus persica var persica Nutrition 0.000 claims 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 1
- MLUNUIAQNHKEJW-LHEWISCISA-N [1-[2-[1-[6-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]hexanoyl]piperidin-4-yl]ethyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCCCCC(=O)N(CC1)CCC1CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 MLUNUIAQNHKEJW-LHEWISCISA-N 0.000 claims 1
- LWEUXTMXEIZXKV-BEAQJDPXSA-N [1-[2-[4-[3-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]propanoylamino]cyclohexyl]ethyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCC(=O)NC(CC1)CCC1CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 LWEUXTMXEIZXKV-BEAQJDPXSA-N 0.000 claims 1
- HMMXOSCEYWJOSV-DGZUKHSISA-N [1-[2-[4-[5-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]pentanoylamino]cyclohexyl]ethyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCCCC(=O)NC(CC1)CCC1CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 HMMXOSCEYWJOSV-DGZUKHSISA-N 0.000 claims 1
- VMPYFGWTRPJMGP-YVTQSTKTSA-N [1-[2-[4-[[2-[3-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]phenoxy]acetyl]amino]cyclohexyl]ethyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCC(C=1)=CC=CC=1OCC(=O)NC(CC1)CCC1CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 VMPYFGWTRPJMGP-YVTQSTKTSA-N 0.000 claims 1
- QDKBBPFMZFQKBA-WBCKFURZSA-N [1-[2-[4-[[2-[3-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]phenoxy]acetyl]amino]phenyl]ethyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCC(C=1)=CC=CC=1OCC(=O)NC(C=C1)=CC=C1CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 QDKBBPFMZFQKBA-WBCKFURZSA-N 0.000 claims 1
- XDLNTCZFKOLMEA-XIFFEERXSA-N [1-[2-[6-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]hexanoylamino]ethyl]-4-methylpiperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C1CN(CCNC(=O)CCCCCNC[C@H](O)C=2C=3C=CC(=O)NC=3C(O)=CC=2)CCC1(C)OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 XDLNTCZFKOLMEA-XIFFEERXSA-N 0.000 claims 1
- HCOFWPMPGQOCOZ-LIUDWSNTSA-N [1-[2-[[(1r,3s)-3-[[(2r)-2-(3-formamido-4-hydroxyphenyl)-2-hydroxyethyl]amino]cyclopentanecarbonyl]amino]ethyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound O=C([C@@H]1CC[C@@H](C1)NC[C@H](O)C=1C=C(NC=O)C(O)=CC=1)NCCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 HCOFWPMPGQOCOZ-LIUDWSNTSA-N 0.000 claims 1
- UASWHSALGKZFSI-GJCZEXATSA-N [1-[2-[[(1r,3s)-3-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]cyclopentanecarbonyl]amino]ethyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound O=C([C@@H]1CC[C@@H](C1)NC[C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 UASWHSALGKZFSI-GJCZEXATSA-N 0.000 claims 1
- QFMIBULTNOEUEO-DHUJRADRSA-N [1-[2-[[4-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]benzoyl]amino]ethyl]-4-methylpiperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C1CN(CCNC(=O)C=2C=CC(CNC[C@H](O)C=3C=4C=CC(=O)NC=4C(O)=CC=3)=CC=2)CCC1(C)OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 QFMIBULTNOEUEO-DHUJRADRSA-N 0.000 claims 1
- XZLOIELNTMFOFW-UMSFTDKQSA-N [1-[3-[2,6-dichloro-4-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]anilino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCC(C=C1Cl)=CC(Cl)=C1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 XZLOIELNTMFOFW-UMSFTDKQSA-N 0.000 claims 1
- ZGFIYBVOSWLSNO-DHUJRADRSA-N [1-[3-[2-bromo-4-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]anilino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCC(C=C1Br)=CC=C1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 ZGFIYBVOSWLSNO-DHUJRADRSA-N 0.000 claims 1
- URWYQGVSPQJGGB-DHUJRADRSA-N [1-[3-[2-chloro-4-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]-5-methoxyanilino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound ClC=1C=C(CNC[C@H](O)C=2C=3C=CC(=O)NC=3C(O)=CC=2)C(OC)=CC=1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 URWYQGVSPQJGGB-DHUJRADRSA-N 0.000 claims 1
- NMVBCIFXOKUEQA-DHUJRADRSA-N [1-[3-[2-chloro-4-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]-6-methylanilino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound CC1=CC(CNC[C@H](O)C=2C=3C=CC(=O)NC=3C(O)=CC=2)=CC(Cl)=C1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 NMVBCIFXOKUEQA-DHUJRADRSA-N 0.000 claims 1
- LOCRWCHVWSBTGW-DHUJRADRSA-N [1-[3-[2-chloro-4-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]anilino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCC(C=C1Cl)=CC=C1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 LOCRWCHVWSBTGW-DHUJRADRSA-N 0.000 claims 1
- DXUNSJAGXSTYLQ-DHUJRADRSA-N [1-[3-[2-chloro-5-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]anilino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCC(C=1)=CC=C(Cl)C=1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 DXUNSJAGXSTYLQ-DHUJRADRSA-N 0.000 claims 1
- ZEXVCGLFPNYNMH-BHVANESWSA-N [1-[3-[3-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]-4-methylanilino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C1=C(CNC[C@H](O)C=2C=3C=CC(=O)NC=3C(O)=CC=2)C(C)=CC=C1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 ZEXVCGLFPNYNMH-BHVANESWSA-N 0.000 claims 1
- NUZGHPRAJRDAHI-DHUJRADRSA-N [1-[3-[3-chloro-4-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]anilino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCC(C(=C1)Cl)=CC=C1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 NUZGHPRAJRDAHI-DHUJRADRSA-N 0.000 claims 1
- FSXKCWFRVBPZOU-MJVKXCJRSA-N [1-[3-[4-[(1r)-1-[[(2r)-2-(3-formamido-4-hydroxyphenyl)-2-hydroxyethyl]amino]ethyl]anilino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C1([C@@H](O)CN[C@H](C)C=2C=CC(NC(=O)CCN3CCC(CC3)OC(=O)NC=3C(=CC=CC=3)C=3C=CC=CC=3)=CC=2)=CC=C(O)C(NC=O)=C1 FSXKCWFRVBPZOU-MJVKXCJRSA-N 0.000 claims 1
- MSPQQLHGSZGDCM-BHVANESWSA-N [1-[3-[4-[2-[[(2r)-2-(3-formamido-4-hydroxyphenyl)-2-hydroxyethyl]amino]ethyl]anilino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=C(NC=O)C(O)=CC=1)NCCC(C=C1)=CC=C1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 MSPQQLHGSZGDCM-BHVANESWSA-N 0.000 claims 1
- TZPZIWQUGYSTDR-XIFFEERXSA-N [1-[3-[4-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]piperidin-1-yl]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NC(CC1)CCN1C(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 TZPZIWQUGYSTDR-XIFFEERXSA-N 0.000 claims 1
- OHKFCGHWURDQLH-DHUJRADRSA-N [1-[3-[4-[[[(2r)-2-(3-formamido-4-hydroxyphenyl)-2-hydroxyethyl]amino]methyl]anilino]-3-oxopropyl]-4-methylpiperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C1([C@@H](O)CNCC2=CC=C(C=C2)NC(=O)CCN2CCC(CC2)(C)OC(=O)NC=2C(=CC=CC=2)C=2C=CC=CC=2)=CC=C(O)C(NC=O)=C1 OHKFCGHWURDQLH-DHUJRADRSA-N 0.000 claims 1
- IYLGFGHRVXEGOR-DHUJRADRSA-N [1-[3-[4-[[[(2r)-2-(3-formamido-4-hydroxyphenyl)-2-hydroxyethyl]amino]methyl]anilino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=C(NC=O)C(O)=CC=1)NCC(C=C1)=CC=C1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 IYLGFGHRVXEGOR-DHUJRADRSA-N 0.000 claims 1
- GDJRFZAXEHZNNO-BHVANESWSA-N [1-[3-[4-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]-2-methylanilino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound CC1=CC(CNC[C@H](O)C=2C=3C=CC(=O)NC=3C(O)=CC=2)=CC=C1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 GDJRFZAXEHZNNO-BHVANESWSA-N 0.000 claims 1
- LWQOWJRRXSOCHS-DHUJRADRSA-N [1-[3-[4-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]anilino]-3-oxopropyl]-4-methylpiperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C1CN(CCC(=O)NC=2C=CC(CNC[C@H](O)C=3C=4C=CC(=O)NC=4C(O)=CC=3)=CC=2)CCC1(C)OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 LWQOWJRRXSOCHS-DHUJRADRSA-N 0.000 claims 1
- SBRNHWWXPRISTF-UHFFFAOYSA-N [1-[3-[4-[[[2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]anilino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C=1C=C(O)C=2NC(=O)C=CC=2C=1C(O)CNCC(C=C1)=CC=C1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 SBRNHWWXPRISTF-UHFFFAOYSA-N 0.000 claims 1
- IGDBHNOEFDQHKO-DHUJRADRSA-N [1-[3-[4-chloro-3-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]anilino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCC(C(=CC=1)Cl)=CC=1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 IGDBHNOEFDQHKO-DHUJRADRSA-N 0.000 claims 1
- IIOPPCULJBJUTN-BHVANESWSA-N [1-[3-[5-[3-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]propyl]furan-2-yl]propyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCCC(O1)=CC=C1CCCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 IIOPPCULJBJUTN-BHVANESWSA-N 0.000 claims 1
- QPDBPFXKTXZWRX-DHMSSXBRSA-N [1-[3-[5-[3-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]propyl]oxolan-2-yl]propyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCCC(O1)CCC1CCCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 QPDBPFXKTXZWRX-DHMSSXBRSA-N 0.000 claims 1
- ISFVODBRKNPBCZ-BHVANESWSA-N [1-[3-[5-[3-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]propyl]thiophen-2-yl]propyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCCC(S1)=CC=C1CCCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 ISFVODBRKNPBCZ-BHVANESWSA-N 0.000 claims 1
- METNKBRCZWBELQ-XIFFEERXSA-N [1-[3-[5-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]pentylamino]-3-oxopropyl]-4-methylpiperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C1CN(CCC(=O)NCCCCCNC[C@H](O)C=2C=3C=CC(=O)NC=3C(O)=CC=2)CCC1(C)OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 METNKBRCZWBELQ-XIFFEERXSA-N 0.000 claims 1
- LCPPPDOBUBUKNL-UHFFFAOYSA-N [1-[3-[5-[[2-(3-formamido-4-hydroxyphenyl)-2-hydroxyethyl]amino]pentylcarbamoylamino]propyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C=1C=C(O)C(NC=O)=CC=1C(O)CNCCCCCNC(=O)NCCCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 LCPPPDOBUBUKNL-UHFFFAOYSA-N 0.000 claims 1
- FUIVIZCFQUCDAW-UHFFFAOYSA-N [1-[3-[5-[[2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]pentylamino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C=1C=C(O)C=2NC(=O)C=CC=2C=1C(O)CNCCCCCNC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 FUIVIZCFQUCDAW-UHFFFAOYSA-N 0.000 claims 1
- LSEUVMGTMCVQLV-FAIXQHPJSA-N [1-[3-[[4-[2-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]ethyl]naphthalen-1-yl]amino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCC(C1=CC=CC=C11)=CC=C1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 LSEUVMGTMCVQLV-FAIXQHPJSA-N 0.000 claims 1
- XNSGYJQAHZYKSI-KUHMYPHZSA-N [1-[3-[[4-[[[(2r)-2-(3-formamido-4-hydroxyphenyl)-2-hydroxyethyl]amino]methyl]cyclohexyl]amino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=C(NC=O)C(O)=CC=1)NCC(CC1)CCC1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 XNSGYJQAHZYKSI-KUHMYPHZSA-N 0.000 claims 1
- QGJUVLUNRBYBCM-BHVANESWSA-N [1-[3-[[4-[[[(2r)-2-(3-formamido-4-hydroxyphenyl)-2-hydroxyethyl]amino]methyl]phenyl]methylamino]-3-oxopropyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=C(NC=O)C(O)=CC=1)NCC(C=C1)=CC=C1CNC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 QGJUVLUNRBYBCM-BHVANESWSA-N 0.000 claims 1
- CBEUSZUIZZCTSR-DHUJRADRSA-N [1-[9-[[(2r)-2-(3-formamido-4-hydroxyphenyl)-2-hydroxyethyl]amino]nonyl]-4-methylpiperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C1([C@@H](O)CNCCCCCCCCCN2CCC(CC2)(C)OC(=O)NC=2C(=CC=CC=2)C=2C=CC=CC=2)=CC=C(O)C(NC=O)=C1 CBEUSZUIZZCTSR-DHUJRADRSA-N 0.000 claims 1
- VOVDJOWNTGDCTE-CFZODSDCSA-O [1-[9-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]nonyl]-1-azoniabicyclo[2.2.2]octan-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCCCCCCCC[N+](CC1)(CC2)CCC12OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 VOVDJOWNTGDCTE-CFZODSDCSA-O 0.000 claims 1
- NVEMUJANQDPDSC-DHUJRADRSA-N [1-[9-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]nonyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCCCCCCCCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 NVEMUJANQDPDSC-DHUJRADRSA-N 0.000 claims 1
- BKEXYNSNJJMFTH-DHUJRADRSA-N [1-[9-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]nonyl]piperidin-4-yl] n-[2-(2-fluorophenyl)phenyl]carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCCCCCCCCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1F BKEXYNSNJJMFTH-DHUJRADRSA-N 0.000 claims 1
- ZABUDLNHBIMCGV-WJVKJDHCSA-N [1-[[(2s)-1-[5-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]pentanoyl]pyrrolidin-2-yl]methyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@@H]1CCCN1C(=O)CCCCNC[C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)N(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 ZABUDLNHBIMCGV-WJVKJDHCSA-N 0.000 claims 1
- DUSCBHGQHYJODS-FAIXQHPJSA-N [1-[[2-fluoro-3-[[4-[2-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]ethyl]piperidin-1-yl]methyl]phenyl]methyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCC(CC1)CCN1CC(C=1F)=CC=CC=1CN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 DUSCBHGQHYJODS-FAIXQHPJSA-N 0.000 claims 1
- YXEMCZDGFMKPBJ-RWYGWLOXSA-N [1-[[2-fluoro-3-[[4-[3-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]propyl]piperidin-1-yl]methyl]phenyl]methyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCCC(CC1)CCN1CC(C=1F)=CC=CC=1CN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 YXEMCZDGFMKPBJ-RWYGWLOXSA-N 0.000 claims 1
- XKZDSHGNWRJIQS-LHEWISCISA-N [1-[[2-fluoro-3-[[4-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]piperidin-1-yl]methyl]phenyl]methyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NC(CC1)CCN1CC(C=1F)=CC=CC=1CN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 XKZDSHGNWRJIQS-LHEWISCISA-N 0.000 claims 1
- CTACTEVAZZLKFR-XIFFEERXSA-N [1-[[2-fluoro-3-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]phenyl]methyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCC(C=1F)=CC=CC=1CN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 CTACTEVAZZLKFR-XIFFEERXSA-N 0.000 claims 1
- NGEHAFVJXGDARK-UHFFFAOYSA-N [2-(3-chlorophenyl)-4,6-difluorophenyl]carbamic acid Chemical compound OC(=O)NC1=C(F)C=C(F)C=C1C1=CC=CC(Cl)=C1 NGEHAFVJXGDARK-UHFFFAOYSA-N 0.000 claims 1
- 239000004202 carbamide Substances 0.000 claims 1
- NKLCHDQGUHMCGL-UHFFFAOYSA-N cyclohexylidenemethanone Chemical group O=C=C1CCCCC1 NKLCHDQGUHMCGL-UHFFFAOYSA-N 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 claims 1
- 229940015043 glyoxal Drugs 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 claims 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 230000002685 pulmonary effect Effects 0.000 claims 1
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 150000001721 carbon Chemical group 0.000 description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 8
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 8
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 125000004956 cyclohexylene group Chemical group 0.000 description 6
- 125000004979 cyclopentylene group Chemical group 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 125000005556 thienylene group Chemical group 0.000 description 5
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical group C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 4
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 description 3
- 229940124630 bronchodilator Drugs 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000004539 5-benzimidazolyl group Chemical group N1=CNC2=C1C=CC(=C2)* 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000004957 naphthylene group Chemical group 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 125000005551 pyridylene group Chemical group 0.000 description 2
- OBRNDARFFFHCGE-PERKLWIXSA-N (S,S)-formoterol fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1=CC(OC)=CC=C1C[C@H](C)NC[C@@H](O)C1=CC=C(O)C(NC=O)=C1.C1=CC(OC)=CC=C1C[C@H](C)NC[C@@H](O)C1=CC=C(O)C(NC=O)=C1 OBRNDARFFFHCGE-PERKLWIXSA-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
- DGGKXQQCVPAUEA-UHFFFAOYSA-N 8-azabicyclo[3.2.1]octane Chemical group C1CCC2CCC1N2 DGGKXQQCVPAUEA-UHFFFAOYSA-N 0.000 description 1
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 description 1
- 102100025191 Cyclin-A2 Human genes 0.000 description 1
- 101000934320 Homo sapiens Cyclin-A2 Proteins 0.000 description 1
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960002848 formoterol Drugs 0.000 description 1
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 1
- 229960000193 formoterol fumarate Drugs 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- OEXHQOGQTVQTAT-JRNQLAHRSA-N ipratropium Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 OEXHQOGQTVQTAT-JRNQLAHRSA-N 0.000 description 1
- 229960001888 ipratropium Drugs 0.000 description 1
- 230000003551 muscarinic effect Effects 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical group C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical compound O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
- 229940110309 tiotropium Drugs 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
BIPHENYL DERIVATIVES
The present invention relates to novel biphenyl derivatives that are useful for treating pulmonary disorders. This invention also relates to pharmaceutical compositions comprising such biphenyl derivatives, processes and intermediates for preparing such biphenyl derivatives and methods of using such biphenyl derivatives to treat pulmonary disorders.
State of the Art
Pulmonary disorders, such as asthma and chronic obstructive pulmonary disease (COPD), are commonly treated with bronchodilators. One class of bronchodilator in widespread use consists of B, adrenergic receptor (adrenoceptor) agonists, such as albuterol, formoterol and salmeterol. These compounds are generally administered by inhalation. Another class of bronchodilator consists of muscarinic receptor antagonists (anticholinergic compounds), such as ipratropium and tiotropium. These compounds are also typically administered by inhalation.
Pharmaceutical compositions containing both a 3; adrenergic receptor agonist and a muscarinic receptor antagonist are also known in the art for use in treating pulmonary disorders. For example, U.S. Patent No. 6,433,027 discloses medicament compositions containing a muscarinic receptor antagonist, such as tiotropium bromide, and a f3, ” adrenergic receptor agonist, such as formoterol fumarate.
Although compounds having either , adrenergic receptor agonist or muscarinic receptor antagonist activity are known, no compound having both 3, adrenergic receptor agonist and muscarinic receptor antagonist activity has been previously disclosed.
Compounds possessing both B, adrenergic receptor agonist and muscarinic receptor . antagonist activity are highly desirable since such bifunctional compounds would provide . bronchodilation through two independent modes of action while having single molecule ' 5 pharmacokinetics.
The present invention provides novel biphenyl derivatives that are useful for treating pulmonary disorders. Among other properties, compounds of this invention have been found to possess both 3; adrenergic receptor agonist and muscarinic receptor antagonist activity.
Accordingly, in one of its composition aspects, the present invention is directed to a compound of formula I: 1 ws fo (R),
R RF OH
R®
I wherein: a is 0 or an integer of from 1 to 3; cach R! is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR'?, -C(O)OR"®, -SR", -S(O)R, -S(O);R'® and -NR'R'S; . each of R'?, R'® R'°, R! R'®, R'f and R'8 is independently hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl; -- . b is 0 or an integer of from 1 to 3; each R? is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR™, -.C(O)OR®, -SR”, -S(0)R*, -S(O),R** and —NR*R’%; oe each of RZ, R?, R%, R®, R%, R¥ and R? is independently hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl;
W is attached to the 3- or 4-position with respect to the nitrogen atom in the piperidine ring and represents O or NW";
W? is hydrogen or (1-4C)alkyl; c is O or an integer of from 1 to 4; each R’ is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR™, -C(O)OR™, -SR*, -S(O)R*, -S(0),R** and ~NR3R?8; or two R® groups are joined to form (1-3C)alkylene, (2-3C)alkenylene or oxiran- 2,3-diyl; each of R*, R*®, R®*, R* R*, R*' and R38 is independently hydrogen or (1- 4C)alkyl;
R* is a divalent group of the formula: ~(R*)~(Ae(R™)-Q-(R*)g~(AD~(R*)i- wherein d, ¢, f, g, h and i are each independently selected from 0 and 1;
R* R* R* and R* are each independently selected from (1-10C)alkylene, (2- 10C)alkenylene and (2-10C)alkynylene, wherein each alkylene, alkenylene or alkynylene group is unsubstituted or substituted with from 1 to 5 substituents independently selected from (1-4C)alkyl, fluoro, hydroxy, phenyl and phenyl-(1-4C)alkyl;
A! and A? are each independently selected from (3-7C)cycloalkylene, (6- 10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene, -O-(2- 9C)heteroarylene, (2-9C)heteroarylene-O- and (3-6C)heterocyclene, wherein each cycloalkylene is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, —S-(1-4C)alkyl, -S(0)-(1-4C)alkyl, -S(0),-(1-4C)alkyl, - - -C(0)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy;
Q is selected from a bond, -0-, -C(0)O-, -OC(O)-, -S-, -S(0)-, -S(O)2-,
N(Q)C(O)-, -CONQ")-, -N(Q)S(O)z-, -S(0)2N(Q)-, NQICON(Q)-
N(Q9)S(0)2N(Q")-, -OC(OIN(Q)-, -N(Q)C(0)O- and ~N(Q");
Q4,Q% Q°, Q% Q° Qf, 8 QN, Q', @ and Q are each independently selected from hydrogen, (1-6C)alkyl, A* and (1-4C)alkylene-A*, wherein the alkyl group is unsubstituted or substituted with from 1 to 3 substituents independently selected from fluoro, hydroxy and (1-4C)alkoxy; or together with the nitrogen atom and the group R* or R* to which they are attached, form a 4-6 membered azacycloalkylene group;
A® and A* are each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl, wherein each cycloalkyl is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl and (1-4C)alkoxy; provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R* is attached is in the range of from 4 to 16;
R’ represents hydrogen or (1-4C)alkyl;
RS is -NR®CR®(0) or -CR®R®OR® and R’ is hydrogen; or R® and R” together form -NR7*C(O)-CR™=CR"-, -CR™=CR’*-C(0)-NR""-, -NR"8C(0)-CR™R""-CR"R"*- or - CR"R™.CR™R°- C(O) -NR"-; each of R%, R®, R®, R% and R® is independently hydrogen or (1-4C)alkyl; and each of R™ R™®, R™, R74 R’¢, R”", R%, R™ R” RY RR”, R’™ R™ R” and R” is independently hydrogen or (1-4C)alkyl; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
In another of its composition aspects, this invention is directed to a compound of formula II:
No _W
Cat
Oo N RY N
OH
“& 0
II
-b-
wherein
R* is as defined herein (including any specific or preferred embodiments);
W represents O or NH; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
In yet another of its composition aspects, this invention is directed to a compound of formula III:
H
No W
ORAS WED: oO N— gse—N
OH
~ oO 111 wherein
R* is as defined herein (including any specific or preferred embodiments);
W represents O or NH; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
In still another of its composition aspects, this invention is directed to a compound of formula IV:
H
N_ _W
Oo N- Ri N ~SOH .
OH
Iv wherein
R* is as defined herein (including any specific or preferred embodiments);
W represents O or NH; . or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
In another of its composition aspects, this invention is directed to a pharmaceutical v 5 composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. Such pharmaceutical compositions may optionally contain other therapeutic agents. Accordingly, in one embodiment, this invention is directed to such a pharmaceutical composition wherein the composition further comprises a therapeutically effective amount of a steroidal anti-inflammatory agent, such as a corticosteroid.
Compounds of this invention possess both B, adrenergic receptor agonist activity and muscarinic receptor antagonist activity. Accordingly, the compounds of formula I are useful for treating pulmonary disorders, such as asthma and chronic obstructive pulmonary disease.
Accordingly, in one of its method aspects, this invention is directed to a method for treating a pulmonary disorder, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula l or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
Additionally, in another of its method aspects, this invention is directed to a method of providing bronchodilation in a patient, the method comprising administering to a patient requiring bronchodilation a therapeutically effective amount of a compound of formula or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
This invention is also directed to a method of treating chronic obstructive pulmonary disease or asthma, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. : Since compounds of this invention possess both 8; adrenergic receptor agonist activity and muscarinic receptor antagonist activity, such compounds are also useful as : 30 research tools. Accordingly, in yet another of its method aspects, this invention is directed to a method for using a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof as a research tool for studying a biological system or sample, or for discovering new chemical compounds having both 3, adrenergic agonist activity and muscarinic receptor antagonist activity. . This invention is also directed to processes and novel intermediates useful for preparing compounds of formula I or a pharmaceutically acceptable salt or solvate or : 5 stereoisomer thereof. Accordingly, in another of its method aspects, this invention is directed to a process of preparing a compound of formula I, the process comprising: (a) reacting a compound of formula 1 or a salt thereof, with a compound of formula 2; (b) reacting a compound of formula 3 or a salt thereof, with a compound of formula 4; (c) coupling a compound of formula 5 with a compound of formula 6; (d) for a compound of formula I wherein R’ represents a hydrogen atom, reacting a compound of formula 3 with a compound of formula 7 or a hydrate thereof, in the presence of a reducing agent; (e) reacting a compound of formula 1 with a compound of formula 8 or a hydrate thereof, in the presence of a reducing agent, f) reacting a compound of formula 9, with a compound of formula 10; or (8) reacting a compound of formula 11 or a hydrate thereof, with a compound of formula 10, in the presence of a reducing agent; and then removing any protecting groups to form a compound of formula I; wherein the compounds of formula 1-11 are as defined therein.
In one embodiment, the above process further comprises the step of forming a pharmaceutically acceptable salt of a compound of formula I. In other embodiments, this invention is directed to the other processes described herein; and to the product prepared by any of the processes described herein.
This invention is also directed to a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof, for use in therapy or as a medicament. . Additionally, this invention is directed to the use of a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof, for the manufacture of - - 30 a medicament; especially for the manufacture of a medicament for the treatment of a pulmonary disorder.
In one of its composition aspects, this invention is directed to novel biphenyl derivatives of formula I or pharmaceutically acceptable salts or solvates or stereoisomers thereof. These compounds contain one or more chiral centers and therefore, this invention is directed to racemic mixtures; pure stereoisomers (i.e., enantiomers or diastereomers); stereoisomer-enriched mixtures and the like unless otherwise indicated. When a particular stereoisomer is shown or named herein, it will be understood by those skilled in the art that minor amounts of other stereoisomers may be present in the compositions of this invention unless otherwise indicated, provided that the utility of the composition as a whole is not eliminated by the presence of such other isomers.
In particular, compounds of formula I contain a chiral center at the carbon atom indicated by the symbol * in the following formula:
OH
J * 5
R®
In one embodiment of this invention, the carbon atom identified by the symbol * has the (R) configuration. In this embodiment, it is preferred for compounds of formula I to have the (R) configuration at the carbon atom identified by the symbol * or to be enriched in a stereoisomeric form having the (R) configuration at this carbon atom. In another embodiment of this invention, the carbon atom identified by the symbol * has the (S) configuration. In this embodiment, it is preferred for compounds of formula I to have the (S) configuration at the carbon atom identified by the symbol * or to be enriched in a stereoisomeric form having the (S) configuration at this carbon atom. In some cases, in order to optimize the 3, adrenergic agonist activity of the compounds of this invention, it is preferred that the carbon atom identified by the symbol * has the (R) configuration.
The compounds of formula I also contain several basic groups (e.g., amino groups) and therefore, the compounds of formula I can exist as the free base or in various salt forms. All such salt forms are included within the scope of this invention. Furthermore, --§--
solvates of compounds of formula I or salts thereof are included within the scope of this invention. } Additionally, where applicable, all cis-trans or E/Z isomers (geometric isomers), tautomeric forms and topoisomeric forms of the compounds of formula I are included ‘ 5 within the scope of this invention unless otherwise specified.
The nomenclature used herein to name the compounds of this invention and intermediates thereof has generally been derived using the commercially-available
AutoNom software (MDL, San Leandro, California). Typically, compounds of formula I wherein W is O have been named as ester derivatives of biphenyl-2-ylcarbamic acid; and compounds of formula I wherein W is NW? have been named as urea derivatives.
Representative Embodiments
The following substituents and values are intended to provide representative examples of various aspects and embodiments of this invention. These representative values are intended to further define and illustrate such aspects and embodiments and are not intended to exclude other embodiments or to limit the scope of this invention. In this regard, the representation that a particular value or substituent is preferred is not intended in any way to exclude other values or substituents from this invention unless specifically indicated.
In particular embodiments of the compounds of formula I, a and b are independently 0, 1 or 2; including O or 1. In one embodiment, both a and b are 0.
When present, each R! may beat the 2, 3,4, Sor 6-position of the phenyl ring to which it is attached. In one embodiment, each R! is independently selected from (1- 4C)alkyl, halo, -OR' and -NR"R!&; such as methyl, fluoro, chloro, bromo, hydroxy, methoxy, amino, methylamino, dimethylamino and the like. Particular values for R! are fluoro or chloro.
When present, each R? may be at the 3, 4, 5 or 6-position on the phenylene ring to . which it is attached (where the carbon atom on the phenylene ring attached to the nitrogen atom is position 1). In one embodiment, each R? is independently selected from (1- : 30 4C)alkyl, halo, -OR* and -NR*R?, such as methyl, fluoro, chloro, bromo, hydroxy, methoxy, amino, methylamino, dimethylamino and the like. Particular values for R? are fluoro or chloro.
Each R'® R'® R'®, R' R'*, R'f and R'® and R®, R®, R*, R*, R*, R* and R*® as used in R' and R?, respectively, is independently hydrogen, (1-4C)alkyl or phenyl-(1- . 4C)alkyl; such as hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl or benzyl. In one embodiment, these groups are independently hydrogen or (1- : 5 3Q)alkyl. In another embodiment, these groups are independently hydrogen, methyl or ethyl.
In one embodiment of this invention, W is O. In another embodiment, W is NW?
Generally, it has been found that compounds in which W represents O exhibit particularly high affinity for muscarinic and 3; adrenergic receptors. Accordingly, ina particular embodiment of this invention, W preferably represents O.
When referring to W, particular mention may be made of compounds wherein W is attached to the piperidine ring at the 4-position with respect to the nitrogen atom of the piperidine ring.
When W is NW?, W? is hydrogen or (1-4C)alkyl; such as hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In one embodiment, W* is hydrogen or (1-3C)alkyl. In another embodiment, W? is hydrogen, methyl or ethyl; such as hydrogen or methyl. In yet another embodiment, W? is hydrogen and NW? is NH.
In a particular embodiment of the compounds of formula I, ¢ is 0, I or 2; including 0 or 1. In one embodiment, c is 0.
In one embodiment, each R® is at the 3, 4 or 5-position on the piperidine ring (where the nitrogen atom of the piperidine ring is position 1). In another embodiment, R’ is at 4-position on the piperidine ring. In a particular aspect of these embodiments, each R® is independently selected from (1-4C)alkyl; such as methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl and tert-butyl. In another aspect, each R? is independently methyl or ethyl.
In another embodiment, R? is at the 1-position of the piperidine ring, i.e., on the nitrogen atom of the piperidine ring thus forming a quaternary amine salt. In a particular . aspect of this embodiment, each R? is independently selected from (1-4C)alkyl; such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In another - ’ 30 aspect, each R’ is independently methyl or ethyl.
In yet another embodiment, two R* groups are joined to form a (1-3C)alkylene or (2-3C)alkenylene group. For example, two R? groups at the 2 and 6-positions on the piperidine ring can be joined to form an ethylene bridge (i.e., the piperidine ring and the R3 groups form an 8-azabicyclo[3.2.1]octane ring); or two R? groups at the 1 and 4-positions on the piperidine ring can be joined to form an ethylene bridge (i.e., the piperidine ring and . the R® groups form an 1-azabicyclo[2.2.2]octane ring). In this embodiment, other R? groups as defined herein may also be present. ) 5 In still another embodiment, two R? groups are joined to form a oxiran-2,3-diyl group. For example, two R® groups at the 2 and 6-positions on the piperidine ring can be joined to form a 3-oxatricyclo[3.3.1.0>*]nonane ring). In this embodiment, other R? groups as defined herein may also be present.
Bach R®, R®, R*, R*, R*, R*" and R*® as used in R® is independently hydrogen or (1-4C)alkyl; such as hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In one embodiment, these groups are independently hydrogen or (1-3C)alkyl. In another embodiment, these groups are independently hydrogen, methyl or ethyl.
In one embodiment of the compounds of formula J, R® is hydrogen or (1-4C)alkyl; such as hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and fert- butyl. In another embodiment, each R’ is independently hydrogen, methyl or ethyl. Ina particular embodiment, R’ is hydrogen.
In one embodiment of this invention, R® is -NR®CR®*(0) and R’ is hydrogen, where each of R® and R® is independently hydrogen or (1-4C)alkyl, such as hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In one embodiment, these groups are independently hydrogen or (1-3C)alkyl. In another embodiment, these groups are independently hydrogen, methyl or ethyl. A particular value for R® in this embodiment is -NHCHO.
In another embodiment, R® and R together form “NR7*C(0)-CR”=CR"*-, 25 .CRM=CR™-C(0)-NR"-, -NR7*C(0)-CR"™R"-CRR™- or - CR"R""-CR""R™- C(O)
NR: where each of R™ R”", R”®, R™%, R”, R”, R"8, R"", R", R", R”", R”, R"™, R"", R"® and R"? is independently hydrogen or (1-4C)alkyl; such as hydrogen, methyl, ethyl, »n- : propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In one embodiment, these groups are independently hydrogen or (1 -3C)alkyl. In another embodiment, these groups ’ 30 are independently hydrogen, methyl or ethyl. Particular values for R® and R’ in this embodiment are R® and R’ together form -NHC(O)-CH=CH-, -CH=CH-C(O)-NH-, -CH,-
CH,-C(O)NH- or -NHC(0)-CH,-CH>-; including where R® and R’ together form -NHC(0)-CH=CH- or -CH=CH-C(O)-NH-; and in particular, where R® and R’ together form -NHC(O)-CH=CH- (i.e., the nitrogen atom is attached at R® and the carbon atom is attached at R to form, together with the hydroxyphenyl ring to which R® and R’ are attached, a 8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl group).
In the compounds of formula I, R* is a divalent group of the formula: - 5 ~R*)a~(ADe-(R®)-Q-R*) (A(R )i- wherein R*, Al R®, Q, R¥, A% R* d, ef, ghandi are as defined herein. In the compound of this invention, the values of each of the components R*, A", R¥®, Q, R¥, A’ and R* are selected such that the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R” is attached is in the range of from 4 to 16, (specifically, 4,5, 6,7, 8,9, 10, 11, 12, 13, 14, 15 or 16); including 8, 9, 10, 11, 12, 13 or 14; such as 8,9, 10 or 11; or 9 or 10. When selecting values for each variable in RY, it will be appreciated by those skilled in the art that values should be selected such that a chemically stable group is formed.
When determining the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R? is attached, each contiguous atom of the chain is counted consecutively starting from the first atom in the R* group adjacent to the nitrogen of the piperidine ring ending with the last atom in the R* group adjacent to the nitrogen of the aminohydroxyethyl group. Where two or more chains are possible, the shortest chain is used to determine the number of contiguous atoms. As shown below, for example, when
R* is -(CH,),-NHC(0)-CH,-(phen-1,4-ylene)-CH,-, there are 10 contiguous atoms in the shortest chain counted consecutively starting from the first atom in the R* group adjacent to the nitrogen of the piperidine ring ending with the last atom in the R* group adjacent to the nitrogen of the aminohydroxyethyl group as shown below: 10 '
N 2 4 H N
ONT TE
. 1 H 5 7
In one embodiment of R*, R*® is selected from (1-10C)alkylene, (2-10C)alkenylene and (2-10C)alkynylene wherein the alkylene group is unsubstituted or substituted with 1 or 2 substituents independently selected from (1-4C)alkyl, hydroxy and phenyl.
Representative examples of particular values for R* are -(CHy)z-, -(CH2)s-, -(CH2)4-, ’ 5 -(CH)s-, (CH, -(CHa)-, -(CHa)g-, -(CHz)s-, -(CHz)io-, -(CH2)CH(CH)-, -(CH,)C(CHs),-, and -(CH2);C(phenyl)>-. In another aspect, R* is -(CH,)C(=CHa)-.
In one embodiment, d is 1.
In one embodiment, A! is an optionally substituted (3-7C)cycloalkylene group; including a cyclohexylene group, such as cyclohex-1,4-ylene and cyclohex-1,3-ylene; and a cyclopentylene group, such as cyclopent-1,3-ylene.
In another embodiment, A' is an optionally substituted (6-10C)arylene group, including a phenylene group, such as phen-1,4-ylene, phen-1,3-ylene and phen-1,2-ylene; and a naphthylene group, such as naphth-1,4-ylene and napth-1,5-ylene.
In yet another embodiment, A! is an optionally substituted (2-9C)heteroarylene group, including a pyridylene group, such as pyrid-1,4-ylene; a furylene group, such as fur- 2,5-ylene and fur-2,4-ylene; a thienylene group, such as thien-2,5-ylene and thien-2,4- ylene; and a pyrrolylene, such as pyrrol-2,5-ylene and pyrrol-2,4-ylene.
In still another embodiment, A' is an optionally substituted (3-6C)heterocyclene group, including a piperidinylene group, such as piperidin-1,4-ylene; and a pyrrolidinylenc group, such as pyrrolidin-2,5-ylene.
In a particular embodiment, A! is an optionally substituted phenylene, thienylene, cyclopentylene, cyclohexylene or piperidinylene.
In one embodiment, ¢ is 0.
In a particular embodiment, R* is (1-5C)alkylene. Representative examples of particular values for R* are -CHa-, -(CHz)z-, (CHa)s-, -(CHa)s-, -(CHy)s-; including methylene, ethylene and propylene.
In one embodiment, fis 0. - In a particular embodiment, Q is selected from a bond, -N(Q*)C(O)-, -C(OIN(QY)-,
N(Q)S(O)z-, -S(O)N(QY-, -N(QIC(OIN(Q)-, -OC(OIN(Q))-, -N(Q)C(O)O- or -N(Q); such as where Q is a bond, -N(Q*)C(O)- or -C(O)N(QY)-. Representative examples of particular values for Q are a bond, O, NH, -C(O)NH-, -C(O)N(CH3)-, -NHC(O)-, -N(CH3)C(O)-, -S(O):NH-, -8(0).N(CHj3)-, -NHS(O),-, -N(CH;)S(0);- and
~NHC(O)NH-. Another example of a value for Q, together with R*, is -C(O)(piperidin- 1,4-ylene). } In one embodiment, Q%, Q°, Q%, Q¢, Q%, Qf, Q&, Q", Q, Q' and Q are each independently selected from hydrogen and (1-6C)alkyl, wherein the alkyl group is - 5 unsubstituted or substituted with from 1 to 3 substituents independently selected from fluoro, hydroxy and (1-4C)alkoxy. For example, Q%, Q°, Q°, Q% Q° Qf, Q% Q", Q, Q and
Q are each independently selected from hydrogen, and (1-3C)alkyl, including hydrogen, methyl, ethyl, n-propyl and isopropyl. An example of a value for each of Q°, Q°, Q°, QY,
Q%, Qf, Q8 Q", Q', Q and Q is hydrogen.
In another embodiment, Q%, Q°, Q°, Q%, Q°, QF, Q& Q", Q', Q and Q* together with the nitrogen atom and the group R* or R* to which they are attached, form a 4-6 membered azacycloalkylene group. For example, Q” and Q" together with the nitrogen atom and the group R* or R* to which they are attached, form a piperidin-4-ylene group.
By way of illustration, when Q represents -N(Q*)C(O)- and Q° together with the nitrogen atom and the group R* to which it is attached, forms a piperidin-4-ylene group, Risa group of formula: — Ren Ne C(O)-(RH*)g-(A2)~(R4), —
Similarly, when Q represents -C(O)N(QP)- and Q" together with the nitrogen atom and the group R* to which it is attached, forms a piperidin-4-ylene group, R* is a group of formula: — (R#2)4-(A")~(R*)-C(O) — Nad Rd), — . 25
In a particular embodiment, R* is (1-5C)alkylene. Representative examples of a. ’ particular values for R* are -CH,-, -(CHa)-, -(CH2)3-, -(CHz)s-, -(CHy)s-; including methylene, ethylene and propylene.
In one embodiment, A? is an optionally substituted (3-7C)cycloalkylene group; including a cyclohexylene group, such as cyclohex-1,4-ylene and cyclohex-1,3-ylene; and . a cyclopentylene group, such as cyclopent-1,3-ylene.
In another embodiment, A? is an optionally substituted (6-10C)arylene group, i 5 including a phenylene group, such as phen-1,4-ylene, phen-1,3-ylene and phen-1,2-ylene; and a naphthylene group, such as naphth-1,4-ylene and napth-1,5-ylene.
In yet another embodiment, A? is an optionally substituted (2-9C)heteroarylene group, including a pyridylene group, such as pyrid-1,4-ylene; a furylene group, such as fur- 2,5-ylene and fur-2,4-ylene; a thienylene group, such as thien-2,5-ylene and thien-2,4- ylene; and a pyrrolylene, such as pyrrol-2,5-ylene and pyrrol-2,4-ylene.
In still another embodiment, A’ is an optionally substituted (3-6C)heterocyclene group, including a piperidinylene group, such as piperidin-1,4-ylene; and a pyrrolidinylene group, such as pyrrolidin-2,5-ylene.
In a particular embodiment, A? is optionally substituted phenylene, thienylene, cyclopentylene, cyclohexylene or piperidinylene.
By way of illustration, either A! or A? or both can be phenylene, such as phen-1,4- ylene or phen-1,3-ylene, where the phenylene group is unsubstituted or substituted with from 1 to 4 substituents independently selected {rom halo, (1-4C)alkyl, (1-4C)alkoxy, -S-(1-4C)alkyl, -S(O)-(1-4C)alkyl, -S(O).-(1-4C)alkyl, -C(0)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy. Representative examples include phen-1,3-ylene, phen-1,4-ylene, 4-chlorophen-1,3-ylene, 6-chlorophen-1,3-ylene, 4-methylphen-1,3-ylene, 2-fluorophen-1,4-ylene, 2-chlorophen-1 ,4-ylene, 2-bromophen- 1,4-ylene, 2-iodophen-1,4-ylene, 2-methylphen-1,4-ylene, 2-methoxyphen-1 4-ylene, 2- trifluoromethoxyphen-1,4-ylene, 3-nitrophen-1,4-ylene, 3-chlorophen-1,4-ylene, 2,5- difluorophen-1,4-ylene, 2,6-dichlorophen-1,4-ylene, 2,6-diiodophen-1,4-ylene, 2-chloro-6- methylphen-1,4-ylene, 2-chloro-5-methoxyphen-1,4-ylene, 2,3 ,5,6-tetrafluorophen-1,4- ylene. . Alternatively, A' or A? or both can be cyclopentylene or cyclohexylene; wherein the cyclopentylene or cyclohexylene group is unsubstituted or substituted with (1-4C)alkyl. ; 30 Representative examples include cis-cyclopent-1,3-ylene, trans-cyclopent-1,3-ylene, cis- cyclohex-1,4-ylene and trans-cyclohex-1,4-ylene. A! or A? or both can also be optionally substituted thienylene or piperidinylene, for example, thien-2,5-ylene or piperidin-1 ,4- ylene.
In one embodiment, R*? is selected from (1-10C)alkylene, (2-10C)alkenylene and (2-10C)alkynylene wherein the alkylene is unsubstituted or substituted with 1 or 2 . substituents independently selected from (1-4C)alkyl, hydroxy and phenyl. Representative examples of particular values for R** are -(CHz)-, -(CHa)2-, -(CHa)3-, -(CHa)s-, -(CH,)s-, : 5 ~(CHy)s-, -(CHz)s-, -(CHz)s-, -(CH2)s-, -(CHz)10- and -(CH2)CH(CH;)-(CH,)-C(CHs)2- (CHy),-.
In a particular embodiment, R* is a divalent group of the formula: -(R*)4- where
R* is (4-10C)alkylene. In one aspect of this embodiment, R* is a divalent group of the formula: -(CH,);- where j is 8, 9 or 10. Examples of particular values for R* in this embodiment are -(CH;)4-, -(CH3)s-, -(CH3)s-, -(CH2)7-, -(CH2)s-, -(CH2)s, and -(CHz)10-; including -(CH,)s-, -(CHz)s, and -(CH2),¢-.
In another particular embodiment, R* is a divalent group of the formula: “(Ra (AD)n-(RY);- where R* is (1-10C)alkylene, such as ~(CHa)-, (CHa),-, -(CHa)s-; A’ is (6- 10C)arylene, such as phen-1,4-ylene or phen-1,3-ylene, or (2-9C)heteroarylene, such as thien-2,5-ylene or thien-2,4-ylene; and R* is (1-10C)alkylene, such as -(CH,)-, -(CHa),-, -(CHa);-. Examples of particular values for R* in this embodiment are (CH,)-(phen-1,4- ylene)-(CH,)-; |(CH,)-(phen-1,4-ylene)-(CHz),-; -(CH:)-(phen-1,4-ylene)-(CHa)s-; — (CH,),-(phen-1,4-ylene)-(CHa)-; -(CHa).-(phen-1,4-ylene)-(CHy,),-; —(CH,),-(phen-1,4- ylene)-(CH,)3-; —(CH,);-(phen-1,4-ylene)-(CHz)-; (CH,)3-(phen-1,4-ylene)-(CHz),-, — (CH5)3-(phen-1,4-ylene)-(CH,);-, |(CH,)4-(phen-1,4-ylene)-(CH,)-; -(CHz)s-(phen-1,4- ylene)-(CHz)2- and —(CHz)4-(phen-1,4-ylene)-(CHy)s-.
In yet another particular embodiment, R* is a divalent group of the formula: -(R*)e-Q-(A)-(R™)- where Q is -O- or -N(Q¥)-; Q* is hydrogen or (1-3C)alkyl, such as methyl or ethyl; o : 30 R*is (1-10C)alkylene, such as -(CHj)-, ~(CHz),~, -(CH2)3-; A? is (6-10C)arylene, such as phen-1,4-ylene or phen-1,3-ylene, or (2-9C)heteroarylene, such as thien-2,5-ylene or thien- 2 4-ylene; and R* is (1-10C)alkylene, such as -(CHy)-, -(CHz)-, -(CHz)3-. Examples of particular values for R* in this embodiment are —(CHa),-O-(phen-1,4-ylene)-(CH,)-;
~(CH2)2-O-(phen-1,4-ylene)-(CH,),-; —(CH2),-O-(phen-1,4-ylene)-(CH,);-; (CH,)s-O- (phen-1,4-ylene)-(CHz)-; {CH;);-O-(phen-1,4-ylene)-(CH,),-; —(CH,)3-O-(phen-1,4- ylene)-(CHz)s-; —(CHz),-NH-(phen-1,4-ylene)-(CHz)-; —(CH,),-NH-(phen-1,4-ylene)- (CHa)z-; «(CHz)2-NH-(phen-1,4-ylene)-(CH>);-; —(CHz);-NH-(phen-1,4-ylene)-(CHa)-; . 5 ~(CH,);-NH-(phen-1,4-ylene)-(CH;),- and «(CHz);-NH-(phen-1,4-ylene)-(CH,);-.
In yet another particular embodiment, R* is a divalent group of the formula: ~R*)~(ADe-R*)-Q-(R*)—(AM(R*)i where Q is -N(Q%)C(0)- or —-C(O)N(Q%-. A particular value for R* in this embodiment is the formula:
Q
— (Chg —C—N—(CHy),— where m is an integer from 2 to 10; and n is an integer from 2 to 10; provided that m + n is an integer from 4 to 12. In this formula for R* d and gare 1 and e, f, h and i are 0; and R* is -(CHy)n-, R* is =(CH,),- and Q is —C(O)NH-. Particular values for m are 2 or 3; and for n, 4, 5 or 6.
Another particular value for R* is the formula: i
SP Se where o is an integer from 2 to 7; and p is an integer from 1 to 6; provided that o + p is an integer from 3 to 8. In this formula for R*, d, h and i are 1 and e, f and g are 0; and
R*is -(CH,)-, A’ is phen-1,4-ylene, R* is —(CH,),- and Q is -C(O)NH-. Particular values for 0 are 2 or 3; and for p, 1 or 2. In this embodiment, the phen-1,4-ylene group Co . may be optionally substituted as defined herein for A%. w17--
Another particular value for R* is the formula: —(CH,), —E-y—oh)—( (oH — where q is an integer from 2 to 6; r is an integer from 1 to 5; and s is an integer from 1 to 5; provided that q + r + s is an integer from 4 to 8. In this formula for R*, d, gh and i are 1 and e and fare 0; and R** is -(CHy)q-, R*® is -(CH,),-, A? is 1,4-phenylene, R*! is —(CHy)s- and Q is —C(O)NH-. Particular values for q are 2 or 3; forr, 1 or 2; and fors, 1 or 2. In this embodiment, the phen-1,4-ylene group may be optionally substituted as defined herein for AZ.
Another particular value for R? is the formula: i
TT (CH) —N~C— (CHy), — where t is an integer from 2 to 10; and u is an integer from 2 to 10; provided that t + u is an integer from 4 to 12. In this formula for R* d and gare l and e, f, h and i are 0; and
R* is -(CHy),-, R* is —(CHy)u- and Q is -NHC(O)-. Particular values for t are 2 or 3; and foru, 4, 5 or 6.
Another particular value for R* is the formula: i — ert) (CHa —
H where v is an integer from 2 to 7; and w is an integer from 1 to 6; provided that v + : w is an integer from 3 to 8. In this formula for R*, d, h and i are 1 and e, fand g are 0; and
R*is -(CHy).-, A’ is 1,4-phenylene, R* is <(CH,)y- and Q is ~NHC(O)-. Particular values for v are 2 or 3; and for w, 1 or 2. In this embodiment, the phen-1,4-ylene group may be optionally substituted as defined herein for A”.
Another particular value for R* is the formula: 0 — (CH), —N—C— ory —(_)—tcr— where x is an integer from 2 to 6; y is an integer from 1 to 5; and z is an integer from 1 to 5; provided that x + y + z is an integer from 4 to 8. In this formula for R% d, gh and i are 1 and e and f are 0; and R* is -(CHa),-, R* is -(CH,),-, A? is 1,4-phenylene, RY is -(CHa),- and Q is -NHC(O)-. Particular values for x are 2 or 3; for y, 1 or 2; and for z, 1 or 2. In this embodiment, the phen-1,4-ylene group may be optionally substituted as defined herein for A%
By way of further illustration, R* can be selected from: ~(CHz)r-; -(CH2)s-; -(CHz)o-; «(CH2)io-; (CHa) 11; -(CH2)2C(O)NH(CH2)s-; -(CH2):N(CH3)C(O)(CH2)s-; -(CH;),C(O)NH(phen-1,4-ylene)CHo-; -(CH;);NHC(O)(phen-1,4-ylene)CHa-; -(CH3),NHC(O)NH(CHo)s~; -(CH,);NHC(O)NH(CHz)s-; -(CH,),C(O)NHCH;(cyclohex-1,3-ylene)CH,-; -(CH;):NHC(O)(cyclopent-1,3-ylene)-; -(CH,);NHC(O)NH(phen-1,4-ylene)(CHz);-; 1-[-(CH2),C(O)}(piperidin-4-yl)(CHz2)2-; ' -(CH2);NHC(O)(trans-cyclohex-1,4-ylene)CH>-; -(CH;);NHC(O)(cis-cyclopent-1,3-ylene)-; - -(CH,):NH(phen-1,4-ylene)(CHz),-; 1-[-(CH,),NHC(O))(piperidin-4-yl)(CHz),-; -CH2(phen-1,4-ylene)NH(phen-1,4-ylene)CHa-; -(CH,),C(O)NHCH,(phen-1,3-ylene)CH,-;
-(CH,),C(O)NHCH,(pyrid-2,6-ylene)CH-; -(CH,),C(O)NH(cis-cyclohex-1,4-ylene)CHa-;
: -(CH,),C(O)NH(trans-cyclohex-1,4-ylene)CHa-; -(CH,),NHC(O)(cis-cyclopent-1,3-ylene)CHo-;
) 5 -(CH;,);N(CH;3)C(O)(phen-1,3-ylene)CH,-; -(CH,);N(CH;)C(O)(trans-cyclohex-1,4-ylene)CHz-; «(CH,),C(O)NH(phen-1,4-ylene)CHa-; -(CH,),C(O)NH(phen-1,4-ylene)C*H(CH;)- ((S)-isomer); -(CH,),C(O)NH(phen-1,4-ylene)C*H(CHj;)- ((R)-isomer);
2-[(S)~(-CHy-)(pyrrolidin-1-y)C(O)(CHa)4-; 2-[(S)-(-CHz-])(pyrrolidin-1-y1)C(O)(phen-1,4-ylene) CHz-; -(CH,),C(O)NH(4-chlorophen-1,3-ylene)CHa-; -CH,(2-fluorophen-1,3-ylene)CHz-; -(CH,),C(O)NH(4-methylphen-1,3-ylene)CHa-;
-(CH,)>C(O)NH(6-chlorophen-1,3-ylene)CHz-; -(CH;),C(O)NH(2-chlorophen-1,4-ylene)CH,-; -(CH,),C(O)NH(2,6-dichlorophen-1,4-ylene)CH,-; -(CH,),NHC(O)NHCH,(phen-1,3-ylene)CH,-; 4-[-CH,-](piperidin-1-yl)C(O)(phen-1,4-ylene)CH,-;
-(CH,),C(O)N(CH,CHjs)(phen-1,4-ylene)CH,-; 1-[-(CH,),NHC(O)](piperidin-4-yl)-; -(CH,),C(O)NH(phen-1,4-ylene)(CHz).-; -(CH;),NHC(O)(thien-2,5-ylene)CH,-; -(CH,);N(CH;)C(O)(3-nitrophen-1,4-ylene)CH-;
-(CH,)2N(CH;)C(O)(trans-cyclohex-1,4-ylene)-; 1-[-CH2(2-fluorophen-1,3-ylene)CH,](piperidin-4-yl)-; 5-[-(CH2);NHC(O)](pyrid-2-yl)CHa-;
. -(CH»)a(phen-1,4-ylene)(CHz)2-;
-(CH,)s(thien-2,5-ylene)(CHa)3-; BN
-(CHy)x(phen-1,4-ylene)NH(phen-1,4-ylene)(CHa),-;
-CH.(phen-1,2-ylene)NH(phen-1,4-ylene)(CHz)2-;
1-[-CH,(2-fluorophen-1 ,3-ylene)CH,](piperidin-4-y1)(CHz)2-;
1-[-CHa(2-fluorophen-1,3-ylene)CH.](piperidin-4-yl)CHz-;
-(CH,),C(O)NH(3-chlorophen-1,4-ylene)CH-; -(CH,),C(O)NH(2-(CF30-)phen-1,4-ylene)CH>-;
-(CH,)s(phen-1,3-ylene)NH(phen-1,4-ylene)(CHa),-; -(CH3),S(0):NH(CH>)s-;
) 5 -CHa(phen-1,3-ylene)NH(phen-1,4-ylene)(CHz)z-; -(CH,),C(O)NH(2-iodophen-1,4-ylene)CHz-; -(CH,),C(O)NH(2-chloro-5-methoxyphen-1,4-ylene)CHz-; -(CH,),C(O)NH(2-chloro-6-methylphen-1,4-ylene)CHz-; -(CH,),C(O)NH(CH>)s-;
-(CH,),N(CH;)S(O)(phen-1,4-ylene)CH;-; -(CH,),C(O)NH(2-bromophen-1,4-ylenc)CH,-; -(CH,)3(phen-1,4-ylene)NH(phen-1,4-ylene)(CHz)-; -(CH,)s(phen-1,2-ylene)NH(phen-1,4-ylene)(CHz)-;
1 -[-CHa(2-fluorophen-1,3-ylene)CH,](piperidin-4-y1)(CHa)-;
-(CH,),C(O)NH(2-methoxyphen-1,4-ylene)CHz-; -(CH,)sNH(phen-1,4-ylene)(CHy),-; 4-[-(CHa,),-](piperidin-1-yl)(phen-1,4-ylene)(CHz):-; -(CH,),C(O)NH(phen-1,4-ylene)CH(CH3)CH,-; -(CH,),-(trans-cyclohex-1,4-ylene)NH(phen-1 ,4-ylene)(CHz)2-;
-(CH,);C(O)NH(2-fluorophen-1,4-ylene)CH>-; -(CHy)(phen-1,3-ylene)NH(phen-1 ,4-ylene)(CH3)»-; -(CH,),C(O)NH(2,5-difluorophen-1 ,4-ylene)CH-; -(CH,),NHC(O)(phen-1,4-ylene)(CHz)z-;
1-[-CHx(pyrid-2,6-ylene)CH;](piperidin-4-yl)CH,-;
-(CH;);sNH(phen-1,4-ylene)(CHz)z-; -(CH3);NH(naphth-1,4-ylene)(CHz)>-; -(CH,);O(phen-1,4-ylene)CHy-;
. 1-[-(CH,);)(piperidin-4-yl)CH,-; 4-[-(CHa)2](piperidin-1-yl)C(O)(phen-1,4-ylene)CHa-; - -(CH,)s(phen-1,4-ylene)NHC(O)(CHa)z-; ~(CH,);O(phen-1,4-ylene)(CHz)2-; 2-[-(CHy)](benzimidazol-5-yl)CHz-; -(CHa),~(trans-cyclohex-1,4-ylene)NHC(O)(CHz).-;
-(CHa),-(trans-cyclohex-1,4-ylene)NHC(O)(CHz)4-; : ~(CH,),-(trans-cyclohex-1,4-ylene)NHC(O)}CH)s-; : 4-[-(CHy)2](piperidin-1-yl)C(O)(CHz)2-; - -(CH,),NHC(O)NH(phen-1,4-ylene)CH,-; ‘ 5 -(CH,):N(CH3)(CH,),(cis-cyclohex-1,4-ylene)-; -(CH,),C(O)NH(2,3,5,6-tetrafluorophen-1,4-ylene) CHo-; -(CH,),C(O)NH(2,6-diiodophen-1,4-ylene)CH;-; 4-[-(CHa),](piperidin-1-y)C(O)(CHz)3-; 4-[-(CHz),)(piperidin-1-yl)C(O)(CHa)4-; 4-[-(CHa))(piperidin-1-y))C(O)(CHy)s-; -(CH,)>C(O)NHCH;(phen-1,4-ylene)CH;-; -(CH;);NHC(O)NHCH,(phen-1,4-ylene)CH>-; -(CH3),C(O)NH(2-methylphen-1,4-ylene)CH,-; 1-[-(CH3):O(phen-1,4-ylenc)(CH,).](piperidin-4-yl)CH-; -(CH,),C(O)NHCH,(phen-1,3-ylene)(CHz),-; -(CH;),O(phen-1,3-ylene)CH-; -(CH,)2N(CH3)C(O)CH,O(phen-1,4-ylene)CH,-; -(CH,)>N(CH3)C(O)CH20(phen-1,3-ylene)CHz-; : -(CH,),N(CH3)C(O)(fur-2,5-ylene)CHa-; -(CH,)>N(CH3)C(O)(thien-2,5-ylene)CHy-; -(CH,)20(phen-1 ,4-ylene)O(CHz)2-; -(CH,)a(trans-cyclohex-1,4-ylene)NHC(O)(phen-1 ,4-ylene)CH;-; -(CH,)x(trans-cyclohex-1,4-ylene)NHC(O)CH,O(phen-1 ,2-ylene)CHa,-; -(CHa)x(trans-cyclohex-1,4-ylene)NHC(O)CH,O(phen-1 ,3-ylene)CH;-; -(CHy)y(trans-cyclohex-1,4-ylene)NHC(O)CH,O(phen-1 ,4-ylene)CH;-; -(CHa)(trans-cyclohex-1,4-ylene)NHC(O)(fur-2,5 -ylene)CH,-; -(CH,)x(trans-cyclohex-1,4-yl ene)NHC(O)(thien-2,5-ylene)CH,-; . 4-[-(CHz)2](piperidin-1 -yl)C(O)CH,O(phen-1,2-ylene)CHa-; 4-[-(CHy),](piperidin-1-yl)C(O)CH,O(phen-1 ,3-ylene)CH3-; oe 4-[-(CHy).](piperidin-1-yl)C(O)CH,O(phen-1,4-ylene)CHa-; 4-[-(CH,);](piperidin-1-y[)C(O)(fur-2,5-ylene)CHz-; 4-[-(CH,);](piperidin-1-yl)C(O)(thien-2,5-ylene)CH-; -(CH,)2(phen-1,4-ylene)NHC(O)(phen-1 ,3-ylene)CHy-;
Jo
-(CH,),(phen-1,4-ylene)NHC(O)(phen-1,4-ylene)CH,-; -(CHy),(phen-1,4-ylene)NHC(O)CH,O(phen-1,2-ylene)CH,-;
-(CH,)2(phen-1,4-ylene)NHC(O)CH,O(phen-1,3-ylene)CH,-; -(CHa),(phen-1,4-ylene)NHC(O)CH,O(phen-1,4-ylene)CH,-;
: 5 -(CH,)x(phen-1,4-ylene)NHC(O)(fur-2,5-ylene)CH-; -(CH,)2(phen-1,4-ylene)NHC(O)(thien-2,5-ylene) CH,-; -(CH,)(trans-cyclohex-1,4-ylene)NHC(O)(phen-1,3-ylenc)CH-; -(CH;);0(phen-1,3-ylene)CH,-;
-CH,CH(OH)CH,NH(phen-1,4-ylene)(CH),-;
-(CH,)4NH(phen-1,4-ylene)(CH,),-; -(CH3)2C(O)NH(phen-1,4-ylene) CH,NHC(O)CH,-; -(CH;),C(O)NH(phen-1,4-ylene)(CH,),NHC(O)CH,-; -(CH;),C(O)NHCH;(trans-cyclohex-1,4-ylene)CH,-; ~(CH,);NHC(O)(CH,)s-;
-(CH;);0(phen-1,3-ylene)O(CH,);-; -(CH2)20(phen-1,2-ylene)O(CH_),-; -CH,(phen-1,2-ylene)O(phen-1,2-ylene)CH,-; -(CH2)2,C(O)NH(CHa)s-;
-(CH,);(phen-1,4-ylene)(CH,)3-;
-(CH,)s(phen-1,4-ylene)(CH;),-; -(CH,)4(phen-1,4-ylene)(CH;),-; -(CH,);(furan-2,5-ylene)(CHj;)s-; -(CH;),N(CH3)C(O)NH(phen-1,4-ylene)(CH,),-; 4-[-(CH,),](piperidin-1-yl)C(O)NH(phen-1,4-ylene)(CH,)-;
-(CHy)s(phen-1,3-ylene)(CH,);-; -(CH,)s(tetrahydrofuran-2,5-ylene)(CH;)s-; and -(CH,),O(phen-1,4-ylene)C(O)(CH,),-.
: 30
Representative Subgeneric Groupings
The following subgeneric formulae and groupings are intended to provide representative examples of various aspects and embodiments of this invention and as such, they are not intended to exclude other embodiments or to limit the scope of this invention unless otherwise indicated.
A particular group of compounds of formula I are those disclosed in U.S.
Provisional Application No. 60/447,843, filed on February 14, 2003. This group includes compounds of formula I, wherein: a 1s 0 or an integer of from 1 to 3; each R' is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR'?, -C(O)OR'®, SR'®, -S(O)R'Y, -S(O),R'® and _NR'R'& each of R'*, R'® R', R'Y R' R'f and R'€ is independently hydrogen or (1- 4C)alkyl; b is 0 or an integer of from 1 to 3; each R? is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR?, -C(O)OR?®, SR*, -S(O)R*, -S(0),R* and ~NR*R%, each of R*, R*™®, R*, R**, R*®, R*' and R?® is independently hydrogen or (1- 4C)alkyl;
W is attached to the 3- or 4-position with respect to the nitrogen atom in the piperidine ring, and represents O or NW?
W? is hydrogen or (1-4C)alkyl; c is 0 or an integer of from 1 to 4; each R? is a substituent on carbon independently selected from (1-4C)alkyl, (2- 4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR*, -C(O)OR?®, SR*, -S(O)R%, -S(0),R*® and -NR*R’¢; each of R*®, R*® R* R*! R3 R¥ and Ris independently hydrogen or (1- 4C)alkyl; -
R* is a divalent group of the formula: “R*)a-(ADe-R™)-Q-(R*)e-(A”)n-(R“):- wherein
IY.
d, e, f, g, hand i are each independently selected from 0 and 1;
R* R*, R* and R* are each independently selected from (1-10C)alkylene, (2- : 10C)alkenylene and (2-10C)alkynylene wherein each alkylene, alkenylene or alkynylene group is unsubstituted or substituted with from 1 to 5 substituents independently selected from (1-4C)alkyl, fluoro, hydroxy, phenyl and phenyl(1-4C)-alkyl;
A! and A? are each independently selected from (3-7C)cycloalkylene, (6- 10C)arylene, (2-9C)heteroarylene and (3-6C)heterocyclene; wherein each cycloalkylene is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1- 4C)alkyl and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl and (1-4C)alkoxy;
Q is selected from a bond, -O-, -C(0)0-, -OC(O)-, -S-, -S(0)-, -S(0)2-,
N(Q)C(O)-, -CON@Q), N(Q)S(O)r, -S(0)2N(QY)-, NQICOINQ)-
NQIS(0):N(QY-, -OC(OIN(Q)- and -N(Q)C(0)O-;
QQ Q% Q4% QS Qf, Q%, Q", Q' and Q are each independently selected from hydrogen, (1-6C)alkyl, A’ and (1-4C)alkylene-A*; wherein the alkyl group is unsubstituted or substituted with from 1 to 3 substituents independently selected from fluoro, hydroxy and (1-4C)alkoxy; or together with the nitrogen atorn and the group R* or R* to which they are attached, form a 4-6 membered azacycloalkylene group;
A and A* are each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl; wherein each cycloalkyl is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl and (1-4C)alkoxy; provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R* is attached is in the range of from 8 to 14;
R® represents hydrogen or (1-4C)alkyl; : RS is -NR®2CR®®(0) and R’ is hydrogen, or R® and R’ together form _NR™C(0)-CR™=CR™-, -CR"=CR™-C(0)-NR", _NR5C(0)-CR™™R"-CR"R™- or -CR'R”-CR™R7-C(O)-NR'P-; each of R® and R® is independently hydrogen or (1-4C)alkyl; and each of R”, R”®, R™, R™, R”, R” R'E R™ RT, RRR", R™, R™ R’ and RP is independently hydrogen or (1-4C)alkyl;
or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
Another particular group of compounds of formula I are those disclosed in U.S. . Provisional Application No. 60/467,035, filed on May 1, 2003. This group of compounds includes compounds of formula I; wherein: ais 0 or an integer of from 1 to 3; each R' is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR'?, -C(O)OR'®, SR’, -S(O)R'“, -S(O)R*, and _NR'RIE: each of R'* R'®, R", R'Y R'®, R'f and R'¢ is independently hydrogen or (1- 4C)alkyl; b is 0 or an integer of from 1 to 3; each R? is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR%, -C(O)OR?, SR%, -S(O)R*, -S(0),R*, and _NR¥R%: each of R%, R®, R*, R%, R?, R¥ and R* is independently hydrogen or (1- 4C)alkyl;
W is attached to the 3- or 4-position with respect to the nitrogen atom in the piperidine ring, and represents O or NW?
W? is hydrogen or (1-4C)alkyl; cis 0 or an integer of from 1 to 4; each R° is a substituent on carbon independently selected from (1-4C)alkyl, (2- 4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR™, -C(O)OR™, SR*°, -S(0)R*, -S(0),R*, and -NR*'R’; each of R*, R*®, R*, R¥, R* R*f and R* is independently hydrogen or (1- 4QC)alkyl;
R* is a divalent group of the formula: “R*)a-(AD)e-R*)eQ-R)e( AMR) wherein ” d, e, f, g, hand i are each independently selected from 0 and 1;
R* R* R* and R* are each independently selected from (1-10C)alkylene, (2- 10C)alkenylene and (2-10C)alkynylene wherein each alkylene, alkenylene or alkynylene group is unsubstituted or substituted with from 1 to 5 substituents independently selected from (1-4C)alkyl, fluoro, hydroxy, phenyl and phenyl(1-4C)-alkyl;
A' and A? are each independently selected from (3-7C)cycloalkylene, (6- 10C)arylene, (2-9C)heteroarylene and (3-6C)heterocyclene; wherein each cycloalkylene is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1- 4C)alkyl and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl and (1-4C)alkoxy;
Q is selected from a bond, -O-, -C(0)0O-, -OC(0)-, -S-, -S(O)-, -S(0),-, -N(Q)C(0)-, -COIN(QY)-, -N(QI)S(0)z-, -S(0):N(QY)-, -N(QIC(ON(Q')-
N(Q®)S(0):N(Q")-, -OC(O)N(Q)- and -N(Q)C(0)O-;
Q*, Q% Q°%, QY, Q°, QF, Q% Q", Q'and Q are each independently selected from hydrogen, (1-6C)alkyl, A’ and (1-4C)alkylene-A*; wherein the alkyl group is unsubstituted or substituted with from 1 to 3 substituents independently selected from fluoro, hydroxy and (1-4C)alkoxy; or together with the nitrogen atom and the group R* or R* to which they are attached, form a 4-6 membered azacycloalkylene group;
A’ and A* are each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl; wherein each cycloalkyl is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl and (1-4C)alkoxy; provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R? is attached is in the range of from 4 to 14;
R’ represents hydrogen or (1-4C)alkyl;
R® is -NR®CR®(0) or CR*R¥OR® and R’ is hydrogen, or R® and R together form -NR7*C(0)-CR™=CR’°-, -CR"*=CR"°-C(0)-NR"", -NR"6C(0)-CR""R"-CR"R"*- or - CR"R"™.CR™R°-C(0)-NRP-; . each of R%, R%, R®, R% and R® is independently hydrogen or (1-4C)alkyl; and each of R”®, R™ RR” R’® Rf R78 R™ R" R% R™ R”,R"™ R™, Rand R” -- is independently hydrogen or (1-4C)alkyl; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
Another particular group of compounds of formula I are those where: a is 0; b is 0; cis 0; Wis O; W is attached at the 4-position of the piperidinyl ring; R? is hydrogen; and wT
R*, R® and R’ are as defined herein; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
Still another particular group of compounds of formula I are those wherein: a is 0; b is 0; c is 0; W is NH; W is attached at the 4-position of the piperidinyl ring; R’is . 5 hydrogen; and R?, R® and R’ are as defined herein; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
Yet another particular group of compounds of formula I are those wherein: a is 0; b is 0; ¢ is 0; W is O; W is attached at the 4-position of the piperidinyl ring; R* is -(CHy);- where j is 8, 9 or 10; R® is hydrogen; and R® and R’ are as defined herein; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof,
Another particular group of compounds of formula I are those wherein: a is 0; b is 0; cis 0; W is NH; W is attached at the 4-position of the piperidinyl ring; R* is -(CHy)- where j 1s 8, 9 or 10; R’ is hydrogen; and R® and R’ are as defined herein; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
Yet another particular group of compounds of formula I are those wherein: a is 0; b is 0; cis 0; W is O; W is attached at the 4-position of the piperidiny! ring; R* is —(CHy),-
C(O)NH-(CH,)s-; R® is hydrogen; and R® and R’ are as defined herein; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
Another particular group of compounds of formula I are those wherein: a is 0; b is 0; cis 0; Wis NH; W is attached at the 4-position of the piperidinyl ring; R* is <(CH,)-
C(O)NH-(CH,)s-; R’ is hydrogen; and R® and R’ are as defined herein; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
Another particular group of compounds of formula I are those of formula II as defined herein; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
Another particular group of compounds of formula I are those of formula III as defined herein; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
Another particular group of compounds of formula I are those of formula IV as defined herein; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
Another particular group of compounds of formula I are those of formula II, HI or -
IV as defined herein, wherein the piperidinyl! ring is substitued at the 4-position with a methyl group; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. -D8--
ot > 3 PCT/US2004/(04449 »
Another particular group of compounds of formula I are compounds of formula V: su uc WEIN
Oo Na ge—N :
TAC,
R® \% wherein W, R*, R® and R” are as defined in Table I; or a pharmacentically acceptable salt or solvate thereof. g
Table I :
EE 0 NA
Frc
El
To [o [EmeeRy, [woe]
Il GC Gc
TO [COG ec NAOCRCR
Bl Ol Be
NOCHE
I le CO Oc ll T E-. Sn -(CHa)s~ | -CH,OH |H
TO CTO Sec | NRCC --29--
RAMIENDED SHEET hy PCT/US2004/004449 [0 [CHSONIGy [wooo [FO CONCERN ae: | HCO [00 Rhee 41 CF NECOCH-CE-_ 21 1-[-CH,(2-fluorophen-1,3-ylene)CH,](piperidin-4- -NHC(O)CH=CH- fe
IE EC a csciall
IE al EC CN Bc lcnciall
I al EC CT Bic niall -(CH2),C(O)NH(2-chloro-5-methoxyphen-1,4- -NHC(O)CH=CH- a hii
IE coin
TE EC icc
TO CRNA ope ney | NACORHCH
FO CRNICONACHY | NAGOH [A [0 [CRG ae CR SHeoren 0 [CHINFCONRCE)- | NHCOH JH
I [0 [CECRINRCON pein NCA: | NECOCHCH: -(CH3),C(O)NHCH,(phen-1,3-ylene)CH,- -NHC(O)CH=CH- [0 | CRCONACHGrR 26H | NRCORH=C [© CRRCON ee Len CF | NHCOCH-CEE 0 | CHOON any eC; | NHOOICH=CH
ERE -(CH;):NHC(O)(cis-cyclopent-1,3-ylene)CH,- -NHC(O)CH=CH-
OOO Cy faces | NCORHCH -30--
AMENDED SHEET
. Oo Coa . wl PCT/US2004/004449 46 -(CH,),C(O)NH(phen-1,4-ylene)C*H(CH;)- -NHC(O)CH=CH-
Re 47 -(CHz),C(O)NH(phen-1,4-ylene)C*H(CHj3)- -NHC(O)CH=CH-
MN
[EO ER CCH TOONS: | WHOOCR-CR- _ 49 2-[(S)-(-CHx-1(pyrrolidin-1-yl)C(O)(phen-1,4- -NHC(O)CH=CH-
UL fre ROR
TO ORRON The ew | NCO 51 -(CH2):C(O)NH(phen-1,4-ylene)C*H(CHa)- -NHC(O)H |H
RN hl
NA TORO IC): | NACOCH=CR
RHCOICH-CE:
NHCOCH-C.
FHC: [0 [0 [ETT 5ONehn Alen CHr_| NACOUH-CE:
HCH]
NACOJ-CE: © JO [TECENCON gpa) | NRCOCR-CH: 64 | O | -(CH2),C(O)NH(phen-1,4-ylene)(CHy),- -NHC(O)CH=CH- ll CE ec RE OC
G6 [© CHRO CON oper [iow CHr__| NHCOCH-CH: 7 | © | CHRON Hrs ylohec aieodHr | NECOR_[H [0 | CHRO ar eer ene: | NRCOUR-CE: 1-[-CHa(2-fluorophen-1,3-ylene)CH,](piperidin-4- -NHC(O)CH=CH- )
MN
70 | O | 5-[-(CH;);NHC(O)](pyrid-2-y1)CH,- -NHC(O)CH=CH-
A cE i -31--
AMENDED SHEET
E. vy PCT/US2004/004449
A ES EL NL
I el Re i BCL
I Il eC Bi 74 1-[-CH;(2-fluorophen-1,3-ylene)CH,](piperidin-4- -NHC(O)CH=CH-
TC
IE Ea Rac 76 [0 [CCNA gies eis | WOE 77 OC ONAT CE op: | NCO
TO CG Ses CR _| NRO 0 [0 | CH CON ogi dio | WECOGCE 81 -(CH2),C(O)NH(2-chloro-6-methylphen-1,4- -NHC(O)CH=CH- 57 [0 [CONC ey [NACOGCE
NCO
Il Rl RC CR i RL Cl 85 1-[-CH;(2-flucrophen-1,3-ylene)CH, }(piperidin-4- -NHC(O)CH=CH- fo EE 0 [CONE ep | NCO
Tl el RC Ca oc icc
Tl lo Ces Gl ca 50 [CRON Syme: | SEO -(CHy)z~(trans-cyclohex-1,4-ylene)NH(phen-1,4- -NHC(O)CH=CH- 7 fm
OT [0 | CORRE Bogie yes SEOCRCE [CHGS NAG a CH NEOCHCE 1-[-CHa(pyrid-2,6-ylene)CH,](piperidin-4-yl)CHz- | -NHC(O)CH=CH- -- [OC SyteCg_| NHOORCH 97 | O [4-[-(CHa):l(piperidin-1-yl)C(O)(phen-1,4- -NHC(O)CH=CH- : er ha
AMENDED SHEET
[= ! . » “4 : PCT/US2004/004449
EE -(CH,)3(phen-1,4-ylene)NHC(O)(CH,),- -NHC(0O)CH=CH-
ERER -(CH,);0(phen-1,4-ylene)CH,- -NHC(O)CH=CH- 100] 0 | 2-[-(CH,),](benzimidazol-5-yl)CHa- -NHC(0O)CH=CH- 1011-0 | -(CH,),~(trans-cyclohex-1,4-ylene)NHC(O)(CH,),- | -NHC(O)CH=CH- 102] 0 | -(CH,),-(trans-cyclohex-1,4-ylene)NHC(O)(CHy)s- | -NHC(O)CH=CH- 103 | O | -(CHa)a~(trans-cyclohex-1,4-ylene)NHC(O)(CH,)s- | -NHC(O)CH=CH-
O | 4-[-(CH>);)(piperidin-1-yl)C(O)(CHz).- -NHC(0O)CH=CH- 105 | O | -(CH,),NHC(O)NH(phen-1,4-ylene)CH,- -NHC(O)CH=CH-
O | -(CH):N(CH;)(CH,),(cis-cyclohex- 1,4-ylene)- -NHC(O)CH=CH- 107 -(CH,),C(O)NH(2,3,5,6-tetrafluorophen-1,4- -NHC(O)CH=CH- ylene)CH;- 108 | O | -(CH,),C(O)NH(2,6-diiodophen-1,4-ylene)CH,- -NHC(O)CH=CH- 109] 0 4-[-(CHy),}(piperidin-1-yl)C(O}CH)s- -NHC(O)CH=CH- 110] O | 4-[-(CHa),](piperidin- 1 -y)C(O)(CH3)s- -NHC(O)CH=CH-
BEE 4-[-(CH2):}(piperidin-1-yl)C(O)(CH2)s- -NHC(O)CH=CH-
O | -(CH,),C(O)NHCH;(phen-1,4-ylene)CH;- -NHC(O)CH=CH- 113] O | -(CH,)2C(O)NHCH,(phen-1,4-ylene)CH,- -NHC(O)H | H 114] 0 | -(CH;),NHC(O)NHCH(phen-1,4-ylene)CHa- -NHC(O)CH=CH- 0 | -(CH2);NHC(O)NHCH,(phen-1,4-ylene)CH- -NHC(O)H |H 116 | O | -(CH,),C(O)NH(2-methylphen-1,4-ylene)CH,- -NHC(0O)CH=CH- 117 | O | 1-[-(CH,);O(phen-1,4-ylene)(CH>),}(piperidin-4- | -NHC(O)CH=CH- yl)CHo- "118 | O | -(CH,),C(O)NHCHa(phen-1,3-ylene)(CH,)2- -NHC(O)CH=CH- 119] O | -(CH,),O(phen-1,3-ylene)CH,- -NHC(O)CH=CH- (120 | O -(CH,),N(CH;)C(O)CH,O(phen-1,4-ylene)CH,- | -NHC(O)CH=CH- 8) | -(CH2):2N(CH3)C(0)CH,0(phen-1,3-ylene)CHy- -NHC(0)CH=CH- 122 | O | -(CH,).N(CH;)C(O)(fur-2,5-ylene)CH,- -NHC(O)CH=CH- 123 | O | -(CH2).N(CH;3)C(O)(thien-2,5-ylene)CH»- | -NHC(O)CH=CH- - 124 | O | -(CH2),O(phen-1,4-ylene)O(CH,)2- -NHC(O)CH=CH- 125 | O | -(CHj)y(trans-cyclohex-1,4-ylene)NHC(O)(phen-1,4- | -NHC(O)CH=CH- ylene)CHy- 33.
AMENDED SHEET
EE IL RL
126 -(CHy) (trans-cyclohex-1,4- -NHC(O)CH=CH-
SN sr 127 -(CHy)a(trans-cyclohex-1,4- -NHC(O)CH=CH-
CL encomomsn, : 128 -(CHy),(trans-cyclohex-1,4- -NHC(O)CH=CH- 1 encom mns 129 -(CH,)y(trans-cyclohex-1,4-ylene)NHC(O)(fur-2,5- -NHC(O)CH=CH- 7 130 -(CH,;),(trans-cyclohex-1,4-ylene)NHC(O)(thien- -NHC(O)CH=CH-
Re ha 131 4-[-(CH,),)(piperidin-1-y1)C(O)CH,O(phen-1,2- -NHC(O)CH=CH-
EE RE
132 4-[-(CH;),](piperidin-1-yl)C(O)CH,O(phen-1,3- ~-NHC(O)CH=CH- 1 133 4-[-(CH,),](piperidin-1-yl)C(O)CH,O(phen-1,4- -NHC(O)CH=CH-
BE
OSC pe CO 2S | SHORE 135 4-[-(CHa):)(piperidin-1-yl)C(O)(thien-2,5- -NHC(O)CH=CH-
RE hi 136 -(CH2)2(phen-1,4-ylene)NHC(O)(phen-1,3- -NHC(O)CH=CH- 7 fe 137 -(CH,)2(phen-1,4-ylene)NHC(O)(phen- 1 ,4- -NHC(O)CH=CH-
RE
138 -(CH>)»(phen-1,4-ylene)NHC(O)CH,O(phen-1,2- -NHC(O)CH=CH- pe 139 -(CH;)2(phen-1,4-ylene) NHC(O)CH,O(phen-1,3- -NHC(O)CH=CH-
I a hl 140 -(CH2)2(phen-1,4-ylene) NHC(O)CH,O(phen-1,4- -NHC(O)CH=CH- =
TO [Cote SCOR 5 ri | SHOCHCH
Claims (59)
1. A compound of formula I: 1 wo £ (RY), Oo R° R OH R® I wherein: a is 0 or an integer of from 1 to 3; each R! is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR'?, -C(O)OR'®, -SR', -S(O)R'Y, -S(0),R'® and _NR'RE; each of R™ R'®, R'®, R' R'® RT and R'® is independently hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl; b is O or an integer of from | to 3; each R? is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR*, -C(O)OR™, -SR?, -S(O)R?, -S(0),R* and ~NR*R?; each of R?, R?, R®, R®, R*, R* and R*® is independently hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl; W is attached to the 3- or 4-position with respect to the nitrogen atom in the piperidine ring and represents O or NW? W? is hydrogen or (1-4C)alkyl; cis 0 or an integer of from 1 to 4; each R® is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, RN (3-6C)cycloalkyl, cyano, halo, -OR*, -C(O)OR™, -SR*, -S(O)R*, -S(0)zR* and _NR3*R’; or two R? groups are joined to form (1-3C)alkylene, (2-3C)alkenylene or oxiran- 2,3-diyl;
each of R¥, R*®, R*, R* R3 Rand R’® is independently hydrogen or (1- 4C)alkyl; R* is a divalent group of the formula: ~(R*)~ ADR) Q-(R* (AR )~ } wherein d, e, f, g, h and i are each independently selected from 0 and 1; R* R® R* and R* are each independently selected from (1-10C)alkylene, (2-
10C)alkenylene and (2-10C)alkynylene, wherein each alkylene, alkenylene or alkynylene group is unsubstituted or substituted with from 1 to 5 substituents independently selected from (1-4C)alkyl, fluoro, hydroxy, phenyl and phenyl-(1-4C)alkyl;
A' and A? are each independently selected from (3-7C)cycloalkylene, (6- 10C)arylene, -0-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene, -O-(2- 9C)heteroarylene, (2-9C)heteroarylene-O- and (3-6C)heterocyclene, wherein each ~ cycloalkylene is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted with from 1 to 4 substituents independently sclected from halo, (1-4C)alkyl, (1-4C)alkoxy, —S-(1-4C)alkyl, -S(O)-(1-4C)alkyl, -S(0);-(1-4C)alkyl, -C(0)O(1-4C)alkyl, carboxy, cyano, Lydroxy, nitro, trifluoromethyl and trifluoromethoxy; Q is selected from a bond, -O-, -C(0)O-, -OC(O)-, -S-, -S(0)-, -S(0);-, N(Q")C(0)-, “CLOIN(Q)-, -N(Q)S(O):-, -8(0)2N(Q")-, -N(QICOIN(Q)-, N(QS(0)N(Q")-, -OCON(Q)-, -N(Q)C(0)O- and -N(Q"); Q% Q% Q% Q4 Q% QL Q5 Qh, Q', Q and Q" are each independently selected from hydrogen, (1-6C)alkyl, A’ and (1-4C)alkylene-A*, wherein the alkyl group is unsubstituted or substituted with from 1 to 3 substituents independently selected from fluoro, hydroxy and (1-4C)alkoxy; or together with the nitrogen atom and the group R* or R* to which they are attached, form a 4-6 membered azacycloalkylene group;
A> and A* are each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, —
(2-9C)heteroaryl and (3-6C)heterocyclyl, wherein each cycloalkyl is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl and (1-4C)alkoxy;
provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R* is attached is in the range of from 4 to 16; . R’ represents hydrogen or (1-4C)alkyl; R® is -NR®CR®(0) or -CR*R*OR®® and R” is hydrogen; or R® and R’ together ’ 5 form -NR™C(0)-CR™=CR”-, -CR™=CR"-C(0)-NR’"-, -NR"*C(0)-CR”"R"-CR"R"- or - CR"R"™.CR™R"°- C(O) -NR'"-; each of R®, R®, R%, R% and R® is independently hydrogen or (1-4C)alkyl; and each of R’® rR", rR’, RY R’¢, Rf R’® R™, Rr R7, R¥ rR" R’™ rR" R® and RP is independently hydrogen or (1-4C)alkyl; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
2. The compound of Claim 1, wherein the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R* is attached is in the range of from 8 to 14.
3. The compound of Claim 2, wherein the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R* is attached is 8, 9, 10 or 11.
4. The compound of any one of Claims 1 to 3, wherein W is attached to the piperidine ring at the 4-position with respect to the nitrogen atom.
S. The compound of any one of Claims 1 to 4, wherein a, b, and c are each 0, and W* and R’ are both hydrogen.
6. The compound of any one of Claims 1 to 5, wherein W represents O.
7. The compound of any one of Claims 1 to 6, wherein RS is -NHCHO or - . CH,OH and R’ is hydrogen; or R® and R” together form -NHC(O)-CH=CH-, -CH=CH- C(0)-NH-, -CH,-CH,-C(O)NH- or —-NHC(0)-CH,-CH,-. — . 30
8. The compound of any one of Claims 1 to 7, wherein R* is a divalent group of the formula: -(R**)¢- where R* is (4-10C)alkylene.
9, The compound of Claim 8, wherein R* is -(CH,)s-, -(CH3)o, and -(CHjy)o-- .
10. The compound of any one of Claims 1 to 7, wherein R* is a divalent group of the formula: ’ 5 -(R*)a-(A)-(R*;- wherein R* is (1-10C)alkylene; A? is (6-10C)arylene or (2-9C)heteroarylene; and R* is (1-10C)alkylene.
11. The compound of any one of Claims 1 to 7, wherein R* is a divalent group of the formula: “(R*)g-Q-(A-(R*):- wherein Q is -O- or —-N(Q¥)-; Q is hydrogen or (1-3C)alkyl; R* is (1- 10C)alkylene; A? is (6-10C)arylene or (2-9C)heteroarylene; and R* is (1-10C)alkylene.
12. The compound of any one of Claims 1 to 7, wherein Q is —-N(Q*)C(O)- or —C(O)N(Q"-.
13. The compound of Claim 12, wherein R* is selected from: i ~—(CH)p —C—N—(CH,),— wherein m is an integer from 2 to 10; and n is an integer from 2 to 10; provided that : m + n is an integer from 4 to 12; i — (ery) —
wherein o is an integer from 2 to 7; and p is an integer from 1 to 6; provided that 0
. + p is an integer from 3 to 8; and wherein the phen-1,4-ylene group is optionally substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl, : 5 (1-4C)alkoxy, —S-(1-4C)alkyl, -S(0)-(1-4C)alkyl, -S(0)2-(1-4C)alkyl, -C(0)0O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy; 9 — (ea — Eyer —( por — wherein q is an integer from 2 to 6; r is an integer from 1 to 5; and s is an integer from 1 to 5; provided that q + r + s is an integer from 4 to 8; and wherein the phen-1,4- ylene group is optionally substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, —S-(1-4C)alkyl, -S(0)-(1-4C)alkyl, -S(O)2~(1- 4C)alkyl, -C(0)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy; 9 (CH,), —N-C— (CH,), wherein t is an integer from 2 to 10; and u is an integer from 2 to 10; provided that t + uis an integer from 4 to 12; 9 wherein v is an integer from 2 to 7; and w is an integer from [ to 6; provided that v B + wis an integer from 3 to 8; and wherein the phen-1,4-ylene group is optionally substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, —S-(1-4C)alkyl, -S(O)-(1-4C)alkyl, -S(0)-(1-4C)alkyl, -C(O)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy; and
0 (CH, —N—C— or, —()—(CH— wherein x is an integer from 2 to 6; y is an integer from 1 to 5; and z is an integer from 1 to 5; provided that x + y + z is an integer from 4 to 8; and wherein the phen-1,4~ ylene group is optionally substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, —S-(1-4C)alkyl, -S(O)-(1-4C)alkyl, -S(O),~(1- 4C)alkyl, -C(0)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy.
14, A compound of formula II: H N Ww g oT 1@ gy 0) N\ge— N OH NH 0] II wherein W represents O or NW? W? is hydrogen or (1-4C)alkyl; R* is a divalent group of the formula: : ~R*)e(ADe(R*)-Q-(R* YAIR) 3
) wherein d, e, f, g, h and i are each independently selected from 0 and 1; R* R* R* and R* are each independently selected from (1-10C)alkylene, (2- 10C)alkenylene and (2-10C)alkynylene, wherein each alkylene, alkenylene or alkynylene group is unsubstituted or substituted with from 1 to 5 substituents independently selected from (1-4C)alkyl, fluoro, hydroxy, phenyl and phenyl-(1-4C)alkyl;
. A' and A? are each independently selected from (3-7C)cycloalkylene, (6- 10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene, -O-(2- : 5 9C)heteroarylene, (2-9C)heteroarylene-O- and (3-6C)heterocyclene, wherein each cycloalkylene is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, —S-(1-4C)alkyl, -S(0)-(1-4C)alkyl, -S(0)2~(1-4C)alkyl, -C(0)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy; Q is selected from a bond, -O-, -C(O)O-, -OC(0)-, -S-, -S(0)-, -S(0).-, N(QY)C(0)-, -CON(Q)-, N(Q)S(O)z-, -S(0:N(Q)-, -NQICON(Q)-, N(QS(0):N(Q")-, -OC(O)N(Q)-, -N(Q)C(0)O- and -N(Q¥); Q% Q% Q%, Q% Q° Qf, Q%, Q", Q, Q and Q are each independently selected from hydrogen, (1-6C)alkyl, A® and (1-4C)alkylene-A*, wherein the alkyl group is unsubstituted or substituted with from 1 to 3 substituents independently selected from fluoro, hydroxy and (1-4C)alkoxy; or together with the nitrogen atom and the group R** or R* to which they are attached, form a 4-6 membered azacycloalkylene group; A> and A* are each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyciyl, wherein each cycloalkyl is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl and (1-4C)alkoxy; provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R* is attached is in the range of from 4 to 14; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. : 30
1S.
A compound of formula III: No WwW T \@ , OH 0 OH H NH T ! II wherein W represents O or NW? W? is hydrogen or (1-4C)alkyl; R* is a divalent group of the formula:
—R*e—A)eR™)-Q-R* (A(R) wherein d, e, f, g, h and i are each independently selected from 0 and [;
R* R® R* and R* are each independently selected from (1-10C)alkylene, (2- 10C)alkenylene and (2-10C)alkynylene, wherein each alkylene, alkenylene or alkynylene group is unsubstituted or substituted with from 1 to 5 substituents independently selected from (1-4C)alkyl, fluoro, hydroxy, phenyl and phenyl-(1-4C)alkyl;
A' and A? are each independently selected from (3-7C)cycloalkylene, (6- 10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene, -O-(2- 9C)heteroarylene, (2-9C)heteroarylene-O- and (3-6C)heterocyclene, wherein each - : cycloalkylene is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, —S-(1-4C)alkyl, -S(O)-(1-4C)alkyl, -S(0)~(1-4C)alkyl,
-C(0)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy; Q is selected from a bond, -O-, -C(0)O-, -OC(0O)-, -S-, -S(O)-, -S(0)-, N(QY)C(0)-, -COIN(QY)-, -N(Q)S(0)z-, -S(0):N(Q%)-, -N(Q)C(OIN(Q)-, “N(Q9)S(0)N(Q")-, ~-OC(ON(Q)-, -N(Q)C(0)O- and -N(Q"); ’ 5 Q* QQ, Q4, Q°, Qf, 8, Q", Q', Q’ and Q* are each independently selected from hydrogen, (1-6C)alkyl, A’ and (1-4C)alkylene-A*, wherein the alkyl group is unsubstituted or substituted with from 1 to 3 substituents independently selected from fluoro, hydroxy and (1-4C)alkoxy; or together with the nitrogen atom and the group R* or R* to which they are attached, form a 4-6 membered azacycloalkylene group; A® and A* are each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl, wherein each cycloalkyl is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl and (1-4C)alkoxy; provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R* is attached is in the range of from 4 to 14; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
16. A compound of formula IV: A Aw ~ “N- ri—N SN OH Iv wherein W represents O or NW? W? is hydrogen or (1-4C)alkyl;
R* is a divalent group of the formula: : ~R)(A)eR)-Q-R*) (AR) ‘ 5 wherein d, e, f, g, h and i are each independently selected from 0 and 1; R* R* R* and R* are each independently selected from (1-10C)alkylene, (2- 10C)alkenylene and (2-10C)alkynylene, wherein each alkylene, alkenylene or alkynylene group is unsubstituted or substituted with from 1 to 5 substituents independently selected from (1-4C)alkyl, fluoro, hydroxy, phenyl and phenyl-(1-4C)alkyl;
A! and A? are each independently selected from (3-7C)cycloalkylene, (6- 10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene, -O-(2- 9C)heteroarylene, (2-9C)heteroarylene-O- and (3-6C)heterocyclene, wherein each cycloalkylene is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, —S-(1-4C)alkyl, -S(0)-(1 -4C)alkyl,
-$(0),-(1-4C)alkyl, -C(O)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy;
Q is selected from a bond, -O-, -C(0)O-, -0OC(0)-, -S-, -S(0)-, -S(0)z-, N(QY)C(O)-, -COIN(QY)-, -N(Q)S(O):-, -S(0)2N(Q")-, -N(Q)CON(Q)-, N(Q9S(0);N(Q")-, -OC(OIN(Q)-, -N(Q)C(O)O- and -N(Q);
Q, Q° Q°, Q4, Q°, QF, 8, Q", Q, Q and QX are each independently selected from hydrogen, (1-6C)alkyl, A® and (1-4C)alkylene-A®, wherein the alkyl group is unsubstituted
75 or substituted with from 1 to 3 substituents independently selected from fluoro, hydroxy and (1-4C)alkoxyj; or together with the nitrogen atom and the group R* or R* to which they are attached, form a 4-6 membered azacycloalkylene group;
: A’ and A? are each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl, wherein each cycloalkyl is unsubstituted or -- : 30 substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl and (1-4C)alkoxy;
provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R* is attached is in the range of from 4 to 14; X or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
17. The compound of any one of Claims 14, 15 or 16, wherein the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R* is attached is in the range of from 8 to 14.
18. The compound of any one of Claims 14, 15 or 16, wherein the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R*is attached is 8,9, 10 or 11.
19. The compound of any one of Claims 14, 15 or 16, wherein W represents O.
20. The compound of any one of Claims 14, 15 or 16, wherein R* is a divalent group of the formula: -(R**)¢- where R* is (4-10C)alkylene.
21. The compound of Claim 20, wherein R* is ~(CH,)s-, -(CH>)s, and -(CHy)jo-.
22. The compound of any one of Claims 14, 15 or 16, wherein R* is a divalent group of the formula: -R*)a-(ADn-R*):- wherein R* is (1-10C)alkylene; A? is (6-10C)arylene or (2-9C)heteroarylene; and R* is (1-10C)alkylene. . 23. The compound of any one of Claims 14, 15 or 16, wherein R* is a divalent group of the formula: a. : 30 -(R™)a-Q-(AM-(R™):-
wherein Q is -O- or -N(QY)-; Q* is hydrogen or (1-3C)alkyl; R** is (1- 10C)alkylene; A?is (6-10C)arylene or (2-9C)heteroarylene; and R* is (1-10C)alkylene.
24. The compound of any one of Claims 14, 15 or 16, wherein Q is C5 N@)C(0)- or ~CONQ)-
25. The compound of Claim 24 wherein R* is selected from: i (CHa) —C— N(CH), — wherein m is an integer from 2 to 10; and n is an integer from 2 to 10; provided that m + n is an integer from 4 to 12; i — or), —Ep—( (cr — H wherein o is an integer from 2 to 7; and p is an integer from 1 to 6; provided that 0 + p is an integer from 3 to 8; and wherein the phen-1,4-ylene group is optionally substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, —S-(1-4C)alkyl, -S(0)-(1-4C)alkyl, -S(0),-(1-4C)alkyl, -C(0)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy; i a a wherein q is an integer from 2 to 6; 1 is an integer from 1 to 5; and s is an integer from 1 to 5; provided that q + r + s is an integer from 4 to 8; and wherein the phen-1,4- ylene group is optionally substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, —S-(1-4C)alkyl, -S(0)-(1-4C)alkyl, -S(0)~(1-
4QC)alkyl, -C(0)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy; Q — (CH) —N-C— (CH),
wherein t is an integer from 2 to 10; and u is an integer from 2 to 10; provided that t + u is an integer from 4 to 12; Q - (OH —p-E— (CHa —
wherein v is an integer from 2 to 7; and w is an integer from 1 to 6; provided that v + w is an integer from 3 to 8; and wherein the phen-1,4-ylene group is optionally substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, —S-(1-4C)alkyl, -S(0)-(1-4C)alkyl, -S(0).-(1-4C)alkyl, -C(O)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy; and Q — (CH) —N—C— ory y—ora— wherein x is an integer from 2 to 6; y is an integer from 1 to 5; and z is an integer from | to 5; provided that x + y + z is an integer from 4 to 8; and wherein the phen-1,4- ylene group is optionally substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, —S-(1-4C)alkyl, -S(0)-(1-4C)alkyl, -S(O)2-(1- 4C)alkyl, -C(0)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and : trifluoromethoxy.
N
26. The compound of any one of Claims 14, 15 or 16, wherein R* is selected from: ~~ «CHa; «(CHy)s-; «(CHy)s-; . ~(CH2)10-; «(CH2)11-; «(CH,),C(O)NH(CHz)s-; ~(CH;)2N(CH;)C(O)(CHo)s-; -(CH,),C(O)NH(phen-1,4-ylene)CH,-; -(CH,),NHC(O)(phen-1,4-ylene)CH,-; -(CH,),NHC(O)NH(CH,)s-; -(CH2)sNHC(O)NH(CHz)s-; -(CH,),C(O)NHCH,(cyclohex-1,3-ylene)CHa-;
-(CH;);NHC(O)(cis-cyclopent-1,3-ylene)-; -(CH,),NHC(O)NH(phen-1,4-ylene)(CH3),-; 1-[-(CH2)2C(O)](piperidin-4-yl)(CHa),-; -(CH,),NHC(O)(¢rans-cyclohex-1,4-ylene)CH,-; -(CH,),NHC(O)(cis-cyclopent-1,3-ylene)-;
-(CH,);NH(phen-1,4-ylene)(CH,),-; 1-[-(CH3),NHC(O)](piperidin-4-y1)(CHa)z-; -CHj(phen-1,4-ylene)NH(phen-1,4-ylene)CH,-; -(CH,),C(O)NHCH,(phen-1,3-ylene)CH,-;
-(CH,),C(O)NHCH (pyrid-2,6-ylene)CH,-;
-(CH,),C(O)NH(cis-cyclohex-1,4-ylene)CH,-; -(CH,);C(O)NH(trans-cyclohex-1,4-ylene)CH»-; -(CH,),NHC(O)(cis-cyclopent-1,3-ylene)CH,-;
} -(CH,),N(CH3)C(O)(phen-1,3-ylene)CH,-; -(CH,),N(CH;)C(O)(trans-cyclohex-1,4-ylene)CH-; a. : 30 -(CH;),C(O)NH(phen-1,4-ylene)CH;-; -(CH,)>,C(O)NH(phen-1,4-ylene) C¥*H(CH3)- ((S)-isomer); -(CH,)>,C(O)NH(phen-1,4-ylene)C*H(CH3)- ((R)-isomer); 2-[(S)-(-CHa-](pyrrolidin-1-y)C(O)(CHz)4-;
2-[(S)~(-CHa-](pyrrolidin-1-y1)C(O)(phen-1,4-ylene)CH,-; -(CH,),C(O)NH(4-chlorophen-1,3-ylene)CH-;
. -CH,(2-fluorophen-1,3-ylene)CH,-; -(CH,),C(O)NH(4-methylphen-1,3-ylene)CH,-; -(CH,),C(O)NH(6-chlorophen-1,3-ylene)CHz-; -(CHa),C(O)NH(2-chlorophen-1,4-ylene)CH-; -(CH,),C(O)NH(2,6-dichlorophen-1,4-ylene)CHz-; -(CH,),NHC(O)NHCH;(phen-1,3-ylene)CH,-; 4-[-CH,-](piperidin-1-yl)C(O)(phen-1,4-ylene)CH2-; -(CH2),C(O)N(CH,CH3)(phen-1,4-ylene)CH,-; 1-[-(CH,),NHC(O)](piperidin-4-yl)-; -(CH,).C(O)NH(phen-1,4-ylene)(CHz)-; -(CH;);NHC(O)(thien-2,5-ylene)CH,-; -(CH_),N(CH3;)C(O)(3-nitrophen-1,4-ylene)CH»-; -(CH,);N(CH3)C(O)(trans-cyclohex-1,4-ylene)-; 1-[-CH2(2-fluorophen-1,3-ylene)CH,](piperidin-4-yl)-; 5-[-(CH)2NHC(0)}(pyrid-2-yl)CHz-; -(CH3)2(phen-1,4-ylene)(CHz)2-; -(CH_)s(thien-2,5-ylene)(CHz)s3-; -(CH)a(phen-1,4-ylene)NH(phen-1,4-ylene)(CHz)2-; -CH,(phen-1,2-ylene)NH(phen-1,4-ylene)(CHz)-; 1-[-CH,(2-fluorophen-1,3-ylene)CHa](piperidin-4-yl)(CHz),-; 1-[-CH(2-fluorophen-1,3-ylene)CH,](piperidin-4-yl)CH-; -(CH,),C(O)NH(3-chlorophen-1,4-ylene)CHa-; -(CH,),C(O)NH(2-(CF30-)phen-1,4-ylene)CHy-; -(CHy)3(phen-1,3-ylene)NH(phen-1,4-ylene)(CHa)2-; -(CH2)2S(0):NH(CH,)s-; : -CHa(phen-1,3-ylene)NH(phen-1,4-ylene)(CHz),-; -(CH,),C(O)NH(2-iodophen-1,4-ylene)CH>-; = : 30 -(CH1)2,C(O)NH(2-chloro-5-methoxyphen-1,4-ylene)CHs-; -(CH,)>C(O)NH(2-chloro-6-methylphen-1,4-ylene)CHa-; -(CH2),C(O)NH(CH>)s-; -(CH,),N(CHj3)S(O)2(phen-1,4-ylene)CH,-;
-(CH,),C(O)NH(2-bromophen-1,4-ylene)CHa-; ~(CH,)3(phen-1,4-ylene)NH(phen-1,4-ylene)(CHz)2-; X -(CH,)s(phen-1,2-ylene)NH(phen-1,4-ylene)(CH2),-; 1-[-CH,(2-fluorophen-1,3-ylene)CH,](piperidin-4-yl)(CHz)s-; ‘ 5 -(CH,),C(O)NH(2-methoxyphen-1,4-ylene)CH,-; -(CH,)sNH(phen-1,4-ylene)(CHz)2-; 4-[-(CH,),-](piperidin-1-yl)(phen-1,4-ylene)(CHz)2-; -(CH,),C(O)NH(phen-1,4-ylene)CH(CH;)CH-; -(CHa)s-(trans-cyclohex-1,4-ylene)NH(phen-1,4-ylene)(CHz),-; -(CH,),C(O)NH(2-fluorophen-1,4-ylene)CH>-; -(CHa)a(phen-1,3-ylene)NH(phen-1,4-ylene)(CHz),-; -(CH,),C(O)NH(2,5-difluorophen-1,4-ylene)CH-; -(CH,),NHC(O)(phen-1,4-ylene)}(CHz)z-; 1-[-CHy(pyrid-2,6-ylene)CH,](piperidin-4-yl)CH,-; -(CH,);NH(phen-1,4-ylene)(CHz)2-: -(CH;),NH(naphth-1,4-ylene)(CHz)2-; -(CH,);0(phen-1,4-ylene)CH,-; 1-[-(CHy)s](piperidin-4-yl)CHa-; 4-[-(CHy),](piperidin-1-yl)C(O)(phen-1,4-ylene)CH,-; -(CH,)s(phen-1,4-ylene)NHC(O)(CHz),-; -(CH,);O(phen-1,4-ylene)}(CHz)2~; 2-[-(CHy),](benzimidazol-5-y)CH,-; -(CHay).~(trans-cyclohex-1,4-ylene)NHC(O)(CHz),-; -(CHa)p-(trans-cyclohex-1,4-ylene)NHC(O)(CHz)4-; -(CHy),-(trans-cyclohex-1,4-ylene)NHC(O)(CHz)s-; 4-[-(CH)2](piperidin-1-y)C(O)(CHa)z-; -(CH;),NHC(O)NH(phen-1,4-ylene)CHp-;
. -(CH,)>N(CH3)(CHa)2(cis-cyclohex-1,4-ylene)-; -(CH,),C(O)NH(2,3,5,6-tetrafluorophen-1,4-ylene) CH,-; - : 30 -(CH,),C(O)NH(2,6-diiodophen-1,4-ylene)CHz-; 4-[-(CHy);)(piperidin-1-y)C(O)(CHa)s 4-[-(CHa),](piperidin-1-yDC(O)(CHa)a-; 4-[-(CH,)s)(piperidin-1-y)C(O)(CHa)s
-(CH,),C(O)NHCH(phen-1,4-ylene)CH,-; -(CH3);NHC(O)NHCH,(phen-1,4-ylene)CH>-;
-(CH;),C(O)NH(2-methylphen-1,4-ylene)CH,-; 1-[-(CH,);0(phen-1,4-ylene)(CH,),](piperidin-4-yl)CH>-;
-(CH,);C(O)NHCH,(phen-1,3-ylene)(CH)-; -(CH,).0O(phen-1,3-ylene)CH>-; -(CH;),N(CH;3)C(O)CH,0O(phen-1,4-ylene)CH,-; -(CH,)2N(CH3)C(O)CH,0(phen-1,3-ylene)CH,-; -(CH;).N(CH3)C(O)(fur-2,5-ylene)CH,-;
-(CH3),N(CH3)C(O)(thien-2,5-ylene)CH,-; -(CH,)20(phen-1,4-ylene)O(CH,),-; -(CHy)a(trans-cyclohex-1,4-ylene)NHC(O)(phen-1,4-ylene)CH,-; -(CHy),(trans-cyclohex-1,4-ylene)NHC(O)CH,O(phen-1,2-ylene)CH>-; -(CH,)a(trans-cyclohex-1,4-ylene) NHC(O)CH,O(phen-1,3-ylene)CH,-;
-(CHj),(trans-cyclohex-1,4-ylene)NHC(O)CH,O(phen-1,4-ylene)CH-; -(CH,)2(trans-cyclohex-1,4-ylene)NHC(O)(fur-2,5-ylene)CH,-; -(CH,)y(trans-cyclohex-1,4-ylene)NHC(O)(thien-2,5-ylene)CH,-; 4-[-(CHj);](piperidin-1-yl)C(O)CH,O(phen-1,2-ylene)CH,-; 4-[-(CH;):)(piperidin-1-yl)C(O)CH,O(phen-1,3-ylene)CH;-;
4-[-(CH;),](piperidin-1-yl)C(O)CH;O(phen-1,4-ylene)CH,-; 4-[-(CH,),](piperidin-1-yl)C(O)(fur-2,5-ylene)CH-; 4-[-(CH,),](piperidin-1-yl)C(O)(thien-2,5-ylene)CH,-; -(CH,)x(phen-1,4-ylene)NHC(O)(phen-1,3-ylene)CH,-; -(CH;)2(phen-1,4-ylene)NHC(O)(phen-1,4-ylene)CH,-;
-(CHy)z(phen-1,4-ylene)NHC(O)CH,O(phen-1,2-ylene)CH,-; -(CH,)2(phen-1,4-ylene)NHC(O)CH,O(phen-1,3-ylene)CH;-; -(CH,)2(phen-1,4-ylene) NHC(O)CH,O(phen-1,4-ylene)CH,-; -(CH,),(phen-1,4-ylene)NHC(O)(fur-2,5-ylene)CH,-; -(CH,),(phen-1,4-ylene)NHC(O)(thien-2,5-ylene)CH,-; nC
: 30 -(CHy)a(trans-cyclohex-1,4-ylene)NHC(O)(phen-1,3-ylene)CH,-; -(CH,);O0(phen-1,3-ylene)CH>-; -CH,CH(OH)CH,NH(phen-1,4-ylene)(CH,),-; -(CH,)4sNH(phen-1,4-ylene)(CHy),-;
-(CH,),C(O)NH(phen-1,4-ylene)CH,NHC(O)CH>-; -(CH,),C(O)NH(phen-1,4-ylene)(CH,),NHC(O)CH-; -(CH,),C(O)NHCH,(trans-cyclohex-1,4-ylene)CH,-; -(CH,),NHC(O)(CH2)s-; : 5 -(CH;);O(phen-1,3-ylene)O(CHz),-; -(CH,),0(phen-1,2-ylene)O(CH>),-; -CH,(phen-1,2-ylene)O(phen-1,2-ylene)CH>-; -(CH2):C(O)NH(CHz)s-; -(CH,)s(phen-1,4-ylene)(CHz)3-; -(CHy)s(phen-1,4-ylene)(CHaz),-; -(CHz)a(phen-1,4-ylene)(CHz)x-; -(CH,);(furan-2,5-ylene)(CH3)s-; -(CH,),N(CH3)C(O)NH(phen- 1,4-ylene)(CHa)2-; 4-[-(CH,);](piperidin-1-yl)C(O)NH(phen-1,4-ylene)(CHz)2-; -(CHy)s(phen-1,3-ylene)(CH,)s-; -(CH,)s(tetrahydrofuran-2,5-ylene)(CHy);-; and -(CH;),0(phen-1,4-ylene)C(O)(CHz)2-.
27. A compound of formula I: 1 (R pe (RY). (RY); C] T Ngo O 5 R® I wherein: Ll a is 0 or an integer of from 1 to 3; each R' is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR'?, -C(O)OR'®, SR'°, -S(O)R'?, -S(O);R'", and _NR'RS:
each of R'*, R'®, R'°, R' R!®, R'T and R'2 is independently hydrogen or (1- 4Cjalkyl; . b is 0 or an integer of from 1 to 3; each R? is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR?, -C(O)OR?, SR*, -S(O)R*, -S(0),R*, and _NRR2: each of R%, R%, R*, R*, R**, R*' and R* is independently hydrogen or (1- 4Cjalkyl; W is attached to the 3- or 4-position with respect to the nitrogen atom in the piperidine ring, and represents O or NW? W? is hydrogen or (1-4C)alkyl; cis 0 or an integer of from 1 to 4; each R? is a substituent on carbon independently selected from (1-4C)alkyl, (2- 4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR*, -C(O)OR™, SR, -S(O)R%*, -S(0);R*, and —-NR*R>%; each of R*®, R*® R* R%* R3¢ R* and R® is independently hydrogen or (1- 4C)alkyl; R* is a divalent group of the formula: : -R*)a(AN)e(R*)EQ-(R™)g-(AI-(R™):- wherein d, e, f, g, h and i are each independently selected from O and 1; R* R*, R* and R* are each independently selected from (1-10C)alkylene, (2- 10C)alkenylene and (2-10C)alkynylene wherein each alkylene, alkenylene or alkynylene group is unsubstituted or substituted with from I to 5 substituents independently selected from (1-4C)alkyl, fluoro, hydroxy, phenyl and phenyl(1-4C)-alkyl, A! and A? are each independently selected from (3-7C)cycloalkylene, (6- 10C)arylene, (2-9C)heteroarylene and (3-6C)heterocyclene; wherein each cycloalkylene is ) : 30 unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1- 4C)alkyl and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl and (1-4C)alkoxy; :
Q is selected from a bond, -O-, -C(0)O-, -OC(O)-, -S-, -S(0)-, -S(0)2-, -N(Q)C(0)-, -C(ON(Q")-, -N(Q)S(0)z-, -8(0)2N(Q%)-, N(QICONQ)-, -N(Q¥)S(0);N(Q"-, -OC(O)N(Q)- and -N(Q)C(0)O-; Q° Q% Q%, Q% Q°, Q', QQ", Q' and Q’ are each independently selected from : 5 hydrogen, (1-6C)alkyl, A’ and (1-4C)alkylene-A*; wherein the alkyl group is unsubstituted or substituted with from 1 to 3 substituents independently selected from fluoro, hydroxy and (1-4C)alkoxy; or together with the nitrogen atom and the group R* or R* to which they are attached, form a 4-6 membered azacycloalkylene group; A’ and A* are each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl; wherein each cycloalkyl is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl and (1-4C)alkoxy; provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R* is attached is in the range of from 8 to 14; R® represents hydrogen or (1-4C)alkyl; R® is -NR®*CR®*(0) and R’ is hydrogen, or R® and R’ together form _NR"*C(0)-CR™=CR’®-, -CR"=CR*-C(0)-NR'"-, -NR72C(0)-CR™R"-CR"R"*- or - CR"R’™.CR""R"°-C(O)-NR*-; each of R®® and R®® is independently hydrogen or (1-4C)alkyl; and each of rR, rR, R”, RY, R™, rR" RE, R™ Rr”, RY, R%, rR” R™ R™, R’° and RP is independently hydrogen or (1-4C)alkyl; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
28. A compound selected from: 1-biphenyl-2-yl-3-(1- {9-[2-hydroxy-2-(8-hydroxy-2-o0xo-1,2-dihydroquinolin-5- yl)ethylamino]nonyl} piperidin-4-yl)urea; biphenyl-2-ylcarbamic acid 1- {9-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]nonyl} piperidin-4-yl ester; biphenyl-2-yl carbamic acid 1- {9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]nonyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-(3-formylamino-4-hydroxy-phenyl)-2- hydroxyethylamino]nonyl} piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-0xo0-1,2,3,4- tetrahydroquinolin-5-yl)ethylamino]nonyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]pentylcarbamoyl} ethyl)piperidin-4-yl ester; : biphenyl-2-ylcarbamic acid 1-[2-({6-[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylaminoJhexanoyl } methylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]methyl} phenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4- {[(R)-2-hydroxy-2-(8-hydroxy-2-o0xo0-1,2- dihydroquinolin-5-yl)ethylamino]methyl} -benzoylamino)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(3-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-0xo-1,2- dihydroquinolin-5-yl)ethylamino]pentyl } -ureido)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[3-(3-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]pentyl}-ureido)propyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(4-hydroxy-3- hydroxymethylphenyl)ethylamino]nonyl} piperidin-4-yl ester; 1-biphenyl-2-yl-3-(1-{9-[2-hydroxy-2-(4-hydroxy-3- hydroxymethylphenyl)ethylamino]nonyl} piperidin-4-yl)urea; biphenyl-2-ylcarbamic acid 1-{2-[(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]methyl} -cyclohexylmethyl)carbamoyl]ethyl} piperidin-4- yl ester; biphenyl-2-ylcarbamic acid 1-[2-({(1R,3S5)-3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2,3,4-tetrahydroquinolin-5-yl)ethylamino]cyclopentanecarbonyl } amino)ethyl]piperidin- 4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]methyl } phenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- 40 dihydroquinolin-5-yl)ethylamino]pentylsulfamoyl} -ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-0xo0-1,2- dihydroquinolin-5-yl)ethylamino]methyl} -benzenesulfonyl)methylamino]ethyl} piperidin- ” 4-yl ester; 45 biphenyl-2-ylcarbamic acid 1-{2-[3-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-o0xo-1,2- dihydroquinolin-5-yl)ethylamino]methyl} benzyl )ureido}ethyl } piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{3-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} phenylamino)phenyl]propyl} piperidin-4-yl ester; } biphenyl-2-ylcarbamic acid 1-[2-fluoro-3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-0x0- 1,2-dihydroquinolin-5-yl)ethylamino}methyl} piperidin-1-ylmethyl)benzyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} phenoxy)propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino}ethyl} phenyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[3-(4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]methyl} piperidin-1-yl)-propyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]methyl } -5-methoxyphenylcarbamoyl)ethyl]- piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{7-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylaminolheptyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{8-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]octyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]ethyl } phenyl)ureido]ethyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} piperidin-1-yl)-3-oxopropyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]methyl}-cyclohexanecarbonyl)amino]ethyl } piperidin-4- yl ester; biphenyl-2-ylcarbamic acid 1-[2-({(1R,35)-3-[(R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylamino]-cyclopentanecarbonyl } amino)ethyl]piperidin-4-yl ester; 40 biphenyl-2-ylcarbamic acid 1-[2-(3-{5-[(R)-2-(3-formylamino-4-hydroxypheny!)- : 2-hydroxyethylamino]pentyl } ureido)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- 45 dihydroquinolin-5-yl)ethylaminoJethyl} phenylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[3-(3-{5-[2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]pentyl }ureido)propyl]piperidin-4-yl ester; :
biphenyl-2-ylcarbamic acid 1-{2-[(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} piperidine-1-carbonyl)amino]ethyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-ox0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} -phenylamino)benzyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- ) dihydroquinolin-5-yl)ethylamino]methyl} -benzylcarbamoyl)ethyl]piperidin-4-yl ester;
3-[4-(3-biphenyl-2-yl-ureido)piperidin-1-y1]-N-(4- {[(R)-2-hydroxy-2-(8-hydroxy- 2-0x0-1,2-dihydroquinolin-5-yl)ethylamino]methyl } phenyl)propionamide; biphenyl-2-ylcarbamic acid 1-{2-[(6-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-l)ethylamino]methyl} pyridin-2-ylmethyl)carbamoyl]ethyl} piperidin-4- yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]methyl}-cyclohexylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]methyl} -cyclohexylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-({(1R,3S5)-3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]-cyclopentanecarbonyl} amino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-0xo0-1,2- dihydroquinolin-5-yl)ethylamino]methyl} -benzoyl)methylamino]ethyl } piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]methyl} -cyclohexanecarbonyl)methylamino}- ethyl} piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4- {[2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]methyl} phenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4- {(S)-1-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 40 1,2-dihydroquinolin-5-yl)ethylamino]ethyl} phenylcarbamoyl)ethyl]piperidin-4-yl ester, : biphenyl-2-ylcarbamic acid 1-[2-(4-{(R)-1-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- ],2-dihydroquinolin-5-yl)ethylamino]ethyl} phenylcarbamoyl)ethyl]piperidin-4-y1 ester; 45 biphenyl-2-ylcarbamic acid 1-((S)-1-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]pentanoyl} pyrrolidin-2-ylmethyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[(S)-1-(4- {{(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino Jmethyl}-benzoyl)pyrrolidin-2-ylmethylpiperidin-4-yl ester; ) 5 biphenyl-2-ylcarbamic acid 1-[2-(4- {[(R)-2-(3-formylamino-4-hydroxy-phenyl)-2- hydroxy-ethylamino]methyl} phenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{(R)-1-[(R)-2-(3-formylamino-4-hydroxy- phenyl)-2-hydroxy-ethylamino]ethyl} phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-chloro-3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]methyl} phenylcarbamoyl)ethyl]piperidin-4-yl ester; N-{2-[4-(3-biphenyl-2-yl-ureido)-piperidin-1-yl]ethyl}-4- {[(R)-2-hydroxy-2-(8- hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl } benzamide; 1-biphenyl-2-yl-3-{1-[3-(4- {2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} piperidin-1-yl)-3-oxo-propyl]piperidin-4-yl } urea; 3-[4-(3-biphenyl-2-yl-ureido)piperidin- 1-yl]-N-(3- {[(R)-2-hydroxy-2-(S-hydroxy- 2-0x0-1,2-dthydroquinolin-5-yl)ethylamino]methyl} -benzyl)propionamide; biphenyl-2-ylcarbamic acid 1-(2-fluoro-3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]methyl} -benzyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]methyl} -4-methyl-phenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]methyl} phenylcarbamoyl)ethyl ]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(2,6-dichloro-4- {[(R)-2-hydroxy-2-(8-hydroxy-2- oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl} phenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[1-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]methyl} benzoyl)-piperidin-4-ylmethyl]piperidin-4-yl ester; 40 biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxy-phenyl)-2- : hydroxyethylamino]methyl}-benzoylamino)ethyl]piperidin-4-yl ester; B biphenyl-2-ylcarbamic acid 1-{2-[ethyl-(4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- : 45 1,2-dihydroquinolin-5-yl)ethylamino]methyl} phenyl)carbamoyl]ethyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(3-{4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]piperidin-1-yl}-3-oxo-propyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4- {2-[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} phenylcarbamoyl)ethyl]piperidin-4-yl ester;
. biphenyl-2-ylcarbamic acid 1-{2-[(5- {[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]methyl}-thiophene-2-carbonyl)amino]ethy!} piperidin-4- yl ester; biphenyl-2-ylcarbamic acid 1- {2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-ox0-1,2- i dihydroquinolin-5-yl)ethylaminojmethyl} -3-nitro-benzoyl)methylamino]ethyl} piperidin-4- yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]methyl} -cyclohexylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-({4-[(R)-2-hydroxy-2-(8-hydroxy-2-ox0-1,2- dihydroquinolin-5-yl)ethylamino]cyclohexanecarbonyl} -methylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-fluoro-3- {4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]piperidin-1-ylmethyl} benzyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(6- {[(R)-2-hydroxy-2-(8-hydroxy-2-0xo0-1,2- dihydroquinolin-5-yl)ethylamino]methyl} pyridine-3-carbonyl)aminojethyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[3-(5-{ 3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]propyl} -thiophen-2-yl)propyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-(3-formylamino-4-hydroxyphenyl)- 2-hydroxy-ethylamino]ethyl} phenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4- {2-[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino] ethyl} phenylamino)benzyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-fluoro-3-(4- {2-[(R)-2-hydroxy-2-(8-hydroxy-2- oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl} piperidin-1 -ylmethyl)benzyl]piperidin-4- yl ester; : biphenyl-2-ylcarbamic acid 1-[3-(4- {2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- 40 dihydroquinolin-5-yl)ethylamino]ethyl} phenylamino)propyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(3-chloro-4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]methyl} phenylcarbamoyl)ethyl]piperidin-4-yl ester; 45 biphenyl-2-ylcarbamic acid 1-[2-(4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]methyl}-2-trifluoromethoxy- phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{3-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} phenylamino)phenyl]propyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[3-(4-{2-[(S)-2-hydroxy-2-(8-hydroxy-2-o0xo0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} phenylamino)benzyl]piperidin-4-yl ester;
: biphenyl-2-ylcarbamic acid 1-[2-(4- {[(R)-2-hydroxy-2-(8-hydroxy-2-0xo0-1,2- dihydroquinolin-5-yl)ethylamino]methyl}-2-iodo-phenylcarbamoyl)ethyljpiperidin-4-yl B ester;
biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]methyl } -6-methylphenylcarbamoyl)ethyl]piperidin- 4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{5-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]pentylcarbamoyl} ethyl)-piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(2-bromo-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]methyl } phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{3-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-o0xo-1,2- dihydroquinolin-S-yl)ethylamino]ethyl} phenylamino)-phenyl]propyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-fluoro-3-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2- oxo-1,2-dihydroquinolin-5-yl)ethylamino]propyl} piperidin-1-ylmethyl)benzyl]piperidin-4- yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2~ dihydroquinolin-5-yl)ethylamino]methyl}-2-methoxy-phenylcarbamoyl)ethyl]piperidin-4- yl ester; biphenyl-2-ylcarbamic acid 1-[5-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} phenylamino)pentyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[1-(4- {2-[(R)-2-hydroxy-2-(8-hydroxy-2-o0xo0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} phenyl)-piperidin-4-yl]ethyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]-1-methyl-ethyl} phenylcarbamoyl)ethyl]jpiperidin-4-yl 40 ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(4- {2-[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} phenylamino)cyclohexyl]ethyl} piperidin-4-yl ester; 45 biphenyl-2-ylcarbamic acid 1-[2-(2-fluoro-4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino Jmethyl } phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]ethyl } phenylamino)phenyl]ethyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(2,5-difluoro-4- {[(R)-2-hydroxy-2-(8-hydroxy-2- oxo0-1,2-dihydroquinolin-5-yl)ethylamino]methyl} phenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl }-benzoylamino)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[6-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]methyl} piperidin- 1-ylmethyl)pyridin-2- ylmethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} -naphthalen- 1-ylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[1-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-
dihydroquinolin-5-yl)ethylaminolmethyl}-benzoyl)piperidin-4-yljethyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[3-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2~ dihydroquinolin-5-yl)ethylamino]propionylamino } phenyl)propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-0xo0-1,2- dihydroquinolin-5-yl)cthylaminojmethyl} phenoxy)propyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-0xo-1,2-
dihydroquinolin-5-yl)ethylamino]methyl}-1H-benzoimidazol-2-yl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]propionylamino } cyclohexyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]pentanoylamino} cyclohexyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-
40 dihydroquinolin-5-yl)ethylamino]-hexanoylamino} cyclohexyl)ethyl]piperidin-4-yl ester;
: biphenyl-2-ylcarbamic acid 1-[2-(1-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-ox0-1,2- dihydroquinolin-5-yl)ethylamino]propionyl} piperidin-4-yl)ethyl]piperidin-4-yl ester; 45 biphenyl-2-ylcarbamic acid 1-{2-[3-(4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]methyl} phenyl)ureido]ethyl} piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[(2-{4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]cyclohexyl}-ethyl)methylamino]ethyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(2,3,5,6-tetrafluoro-4- {[(R)-2-hydroxy-2-(8- hydroxy-2-0x0-1,2-dihydroquinolin-5-yl)ethylamino]methyl } phenylcarbamoyl)- : ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]methyl}-2,6-diiodo-phenylcarbamoyl)ethyl]piperidin-4- yl ester; biphenyl-2-ylcarbamic acid 1-[2-(1-{4-[(R)-2-hydroxy-2-(8-hydroxy-2-o0xo0-1,2- dihydroquinolin-5-yl)ethylamino]-butyryl} piperidin-4-yl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(1-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-ox0-1,2- dihydroquinolin-5-yl)ethylamino]pentanoyl} piperidin-4-yl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(1-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]-hexanoyl} piperidin-4-yl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4- {[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]methyl}-benzylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4- {[(R)-2-(3-formylamino-4-hydroxy-phenyl)-2- hydroxyethylamino]methyl } -benzylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-o0xo0-1,2- dihydroquinolin-5-yl)ethylamino methyl} -benzyl)ureido]ethyl} piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[3-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)- 2-hydroxyethylamino]methyl} benzyl)-ureidojethyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]methyl}-2-methyl-phenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(3-{4-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0- 1,2-dihydroquinolin-5-yl)ethylamino]methyl} piperidin-1-yl)ethyl phenoxy} propyl)- 40 piperidin-4-yl ester; : biphenyl-2-ylcarbamic acid [-[2-(3-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl}-benzylcarbamoyl)ethyl]piperidin-4-yl ester; 45 biphenyl-2-ylcarbamic acid 1-[2-(3- {[(R)-2-hydroxy-2-(8-hydroxy-2-ox0-1,2- dihydroquinolin-5-yl)ethylamino]methyl } phenoxy)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]methyl} phenoxy)acetyl)methylamino} ethyl)piperidin-4- yl ester; : 5 biphenyl-2-ylcarbamic acid 1-(2-{[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]methyl} phenoxy)acetylJmethylamino } ethyl)-piperidin-4- . yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(5- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]methyl} furan-2-carbonyl) methylamino]ethyl} piperidin- 4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]methyl}-thiophene-2-carbonyl)methylaminoJethyl } - piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-o0xo-1,2- dihydroquinolin-5-yl)ethylamino]ethoxy} phenoxy)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]methyl} -benzoylamino)cyclohexyl]ethyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{4-[2-(2- {[(R)-2-hydroxy-2-(8-hydroxy-2-0xo0- 1,2-dihydroquinolin-5-yl)ethylamino]methyl} phenoxy)acetylamino]cyclohexyl } ethyl)- piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{4-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]methyl} phenoxy)acetylamino]cyclohexyl} ethyl)- piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{4-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-o0xo- 1,2-dihydroquinolin-5-yl)ethylamino]Jmethyl} phenoxy)acetylamino]cyclohexyl } ethyl)- piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2- {4-[(5- {[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]methyl} furan-2-carbonyl)amino}cyclohexyl} - ethyl)piperidin-4-yl ester; 40 biphenyl-2-ylcarbamic acid 1-(2- {4-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]methyl}-thiophene-2-carbonyl)amino]cyclohexyl }-
. ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{1-[2-(2-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- : 45 1,2-dihydroquinolin-5-yl)ethylamino]methyl } phenoxy)acetyl]piperidin-4-yl} ethyl)- piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{1-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino methyl} phenoxy)acetyl]piperidin-4-yl} ethyl)- piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]methyl} phenoxy)acetyl]piperidin-4-yl} ethyl)- piperidin-4-y] ester; ] biphenyl-2-ylcarbamic acid 1-{2-[1-(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-o0xo0-1,2- dihydroquinolin-5-yl)ethylamino]methy!} furan-2-carbonyl) piperidin-4-yl]ethyl} piperidin- 4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[1-(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-0xo0-1,2- dihydroquinolin-5-yl)ethylamino]methyl} -thiophene-2-carbonyl)piperidin-4- yllethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]methyl} -benzoylamino)phenyljethyl} piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[4-(4- {[(R)-2-hydroxy-2-(8-hydroxy-2-o0x0-1,2- dihydroquinolin-5-yl)ethylamino]methyl}-benzoylamino)phenyl]ethyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2- {4-[2-(2-{[(R)-2-hydroxy-2-(§8-hydroxy-2-0xo- 1,2-dihydroquinolin-5-yl)ethylamino]methyl} phenoxy)acetylamino]phenyl} ethyl)- piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2- {4-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]methyl} phenoxy)acetylamino]phenyl} ethyl)- piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{4-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-0xo- 1,2-dihydroquinolin-5-yl)ethylamino]methyl} phenoxy)acetylamino]phenyl } ethyl)- piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2- {4-[(5- {[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]methyl} furan-2-carbonyl)amino]phenyl} ethyl )piperidin- 4-yl ester; 40 biphenyl-2-ylcarbamic acid 1-(2-{4-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- . dihydroquinolin-5-yl)ethylaminojmethyl } -thiophene-2-carbonyl)amino phenyl} - ethyl)piperidin-4-yl ester; B ‘ 45 biphenyl-2-ylcarbamic acid 1-{2-[4-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]methyl}-benzoylamino)cyclohexyljethyl } piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]methyl} phenoxy)-propyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-hydroxy-3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2- ’ 5 o0xo0-1,2-dihydroquinolin-5-yl)ethylamino]ethyl} phenylamino)propyl]piperidin-4-y] ester; : biphenyl-2-ylcarbamic acid 1-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino)ethyl } phenylamino)butyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-({2-[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino)acetylamino} -methyl)phenylcarbamoyl}ethyl} piperidin- 4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(2-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-0xo0-1,2- dihydroquinolin-5-yl)ethylamino]acetylamino} ethyl)phenylcarbamoyllethyl} piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]methyl} -cyclohex ylmethyl)carbamoyl]ethyl} piperidin-4- yl ester; biphenyl-2-ylcarbamic acid 1-(2-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino}hexanoylamino }-ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(3-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]ethoxy} phenoxy)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(2-{2-[(S)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylaminoJethoxy} phenoxy)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(2-{[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]methyl } phenoxy)benzyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino}hexylcarbamoyl} ethyl) piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-({(1R,35)-3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]cyclopentanecarbonyl } amino)ethyl]piperidin-4-yl ester; 40 biphenyl-2-ylcarbamic acid 1-[3-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]propyl} phenyl)propyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-ox0-1,2- 45 dihydroquinolin-5-yl)ethylamino]ethyl} phenyl)propyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-ox0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} phenyl)butyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(5-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]propyl} furan-2-yl)propyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} phenyl)-1-methylureido]ethyl} piperidin-4-yl ester; : biphenyl-2-ylcarbamic acid 1-{2-[1-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} phenylcarbamoy!)piperidin-4-yl]ethyl} piperidin-4- - yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(3-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)ethylamino]propyl} phenyl)propyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[3-(5-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]propyl} tetrahydrofuran-2-yl)propyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-0x0-1,2- dihydroquinolin-5-yl)ethylamino]ethylcarbamoyl} phenoxy)ethyl]piperidin-4-yl ester; (5-bromobiphenyl-2-yl)carbamic acid 1-{9-[2-hydroxy-2-(8-hydroxy-2-o0x0-1,2- dihydroquinolin-5-yl)ethylamino]nonyl} -piperidin-4-yl ester; (2'-fluorobiphenyl-2-yl)carbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]nonyl} -piperidin-4-yl ester;
(3'-chloro-3,5-difluorobiphenyl-2-yl)carbamic acid 1-{9-[(R)-2-hydroxy-2-(8- hydroxy-2-oxo0-1,2-dihydroquinolin-5-yl)-ethylamino]nonyl} piperidin-4-yl ester; (3',5'-dichloro-3,5-difluorobiphenyl-2-yl)carbamic acid 1-{9-[(R)-2- hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)-ethylamino]nonyl} piperidin-4-yl ester; (3,5-difluorobiphenyl-2-yl)carbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2- oxo-1,2-dihydroquinolin-5-yl)ethylamino]nonyl} piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]methyl}-phenylcarbamoyl)ethyl]-4-methylpiperidin-4-yl ester; 40 biphenyl-2-ylcarbamic acid 1-[2-(4- {[(R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]methyl} phenylcarbamoyl)-ethyl]-4-methylpiperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-ox0-1,2- a. dihydroquinolin-5-yl)ethylamino]nonyl} -4-methylpiperidin-4-yl ester; 45 biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-(3-formylamino-4-hydroxy-phenyl)-2- hydroxyethylamino]nonyl}-4-methylpiperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]pentylcarbamoyl} -ethyl)-4-methylpiperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{5-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylaminoJpentylcarbamoyl}ethyl)-4-methylpiperidin-4-yl ester; . biphenyl-2-ylcarbamic acid 1-(2- {6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]hexanoylamino } ethyl)-4-methylpiperidin-4-yl ester; N biphenyl-2-ylcarbamic acid 1-(2-{6-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino}hexanoylamino} ethyl)-4-methylpiperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]methyl} benzoylamino)ethyl]-4-methylpiperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino methyl } benzoylamino)ethyl]-4-methylpiperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{3-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-ox0-1,2- dihydroquinolin-5-yl)ethylamino]ethyl} phenylamino)phenyl]propyl} -4-methylpiperidin-4- yl ester; biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-0xo- 1,2-dihydroquinolin-5-yl)ethylamino}methyl} phenylcarbamoyl)ethyl]-4-methylpiperidin- 4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4- {[(R)-2-hydroxy-2-(8-hydroxy-2-o0xo- 1,2-dihydroquinolin-5-yl)ethylamino]methyl} -5-methoxyphenylcarbamoyl)ethyl]-4- methylpiperidin-4-yl ester; 4-(biphenyl-2-ylcarbamoyloxy)-1- {9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)-ethylamino]nonyl} - 1-azoniabicyclo[2.2.2]octane; | biphenyl-2-ylcarbamic acid 8-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]nonyl}-8-azabicyclo[3.2.1]oct-3-y] ester; 7-(biphenyl-2-ylcarbamoyloxy)-9- {9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo0-1,2- dihydroquinolin-5-yl)-ethylamino]nonyl}-9-methyl-3-oxa-9- 40 azoniatricyclo[3.3.1.0%¥2,4*nonane; and
. biphenyl-2-ylcarbamic acid 9-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl)ethylamino]nonyl}-3-oxa-9-aza-tricyclo[3.3.1.0¥2,4¥]non-7-yl ester; “ 45 or a pharmaceutically acceptable salt or solvate thereof.
® PCT/US2004/004449
29. Biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydro-quinolin-5-yl)ethylamino]nonyl} piperidin-4-yl ester or a pharmaceutically acceptable salt or solvate thereof,
30. Biphenyl-2-ylcarbamic acid 1-(2-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1,2-dihydroquinolin-5-yl)ethylamino]pentylcarbamoy!} ethyl)piperidin-4-yl ester or a pharmaceutically acceptable salt or solvate thereof,
31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of Claims 1 to 30.
32. The pharmaceutical composition of Claim 31, wherein the composition further comprises a therapeutically effective amount of a steroidal anti-inflammatory agent.
33. The pharmaceutical composition of Claim 31, wherein the composition further comprises a therapeutically effective amount of a PDE, inhibitor.
34. A substance or composition for use in a method for treating a pulmonary disorder, said substance or composition comprising a compound of any one of Claims 1 to 30, and said method comprising administering to a patient in need of treatment a therapeutically effective amount of said substance or composition.
35. A substance or composition for use in a method of providing bronchodilation in a patient, said substance or composition comprising a compound of any one of Claims I to 30, and said method comprising administering to a patient requiring bronchodilation a therapeutically effective amount of said substance or composition.
36. A substance or composition for use in a method of treating chronic - obstructive pulmonary disease or asthma, said substance or composition comprising a compound of any one of Claims 1 to 30, and said method comprising administering to a patient in need of treatment a therapeutically effective amount of said substance or composition. --208-- AMENDED SHEET
PCT/US2004/004449
37. A substance or composition for use in a method for treating a pulmonary ® disorder, said substance or composition comprising a compound having both muscarinic receptor antagonist and f;-adrenergic receptor agonist activity, and said method comprising administering said substance or composition.
38. A substance or composition for use in a method of treatment of Claim 37, wherein the compound has a K; for the M; muscarinic receptor of less than about 100 nM and an EC, for the §, adrenergic receptor of less than about 100nM. -
39. A substance or composition for use in a method of treatment of Claim 37 or Claim 38, wherein the compound has a ratio of the K; for the M, muscarinic receptor to the EC, for the B, adrenergic receptor is from about 30:1 to about 1:30.
40. A method of studying a biological system or sample comprising a muscarinic receptor or a f3; adrenergic receptor, the method comprising: (a) contacting the biological system or sample with a compound of any one of Claims 1 to 30; and (b) determining the effects caused by the compound on the biological system or sample.
41, A process for preparing a compound of formula I: 1 "os ® (R%), Ras Sel Oo ks R OH R® I wherein: ais 0 or an integer of from 1 to 3; each R! is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR'?, -C(O)OR'®, -SR'®, -S(O)R'Y, -S(0),R'® and _NR'R'2 each of R'*, R'®, R'®, R'"Y, R'®, R!f and R'® is independently hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl; --209-- AMENDED SHEET b is 0 or an integer of from 1 to 3; each R? is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR?, -C(O)OR?®, -SR*, -S(O)R?**, -S(O),R* and — NRR2 : 5 each of R®, R®®, R*, R*, R?®, R* and R? is independently hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl; W is attached to the 3- or 4-position with respect to the nitrogen atom in the piperidine ring and represents O or NW?; W? is hydrogen or (1-4C)alkyl; cis 0 or an integer of from 1 to 4; each R? is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, -OR*, -C(O)OR™®, -SR™, -S(O)R*?, -S(0),R*® and -NR*R%; or two R® groups are joined to form (1-3C)alkylene, (2-3C)alkenylene or oxiran- 2,3-diyl; each of R*, R*®, R*, R*, R*®, R*" and R® is independently hydrogen or (1- 4Cjalkyl; R* is a divalent group of the formula: ~R*)e~(AD-RT)-Q-R™) (AR)
wherein d, e, f, g, h and i are each independently selected from 0 and 1; R* R*, R* and R*? are each independently selected from (1-10C)alkylene, (2- 10C)alkenylene and (2-10C)alkynylene, wherein each alkylene, alkenylene or alkynylene group is unsubstituted or substituted with from 1 to 5 substituents independently selected from (1-4C)alkyl, fluoro, hydroxy, phenyl and phenyl-(1-4C)alkyl; A' and A? are each independently selected from (3-7C)cycloalkylene, (6- 10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene, -O-(2- 9C)heteroarylene, (2-9C)heteroarylene-O- and (3-6C)heterocyclene, wherein each ” cycloalkylene is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted with from | to 4 substituents independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, —S-(1-4C)alkyl, -S(0)-(1-4C)alkyl, -S(0)-(1-4C)alkyl,
-C(0)0O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy; Q is selected from a bond, -O-, -C(O0)O-, -OC(O)-, -S-, -S(0)-, -S(O),-, -N(Q*)C(0)-, -C(OIN(Q)-, -N(Q)S(O)2-, -S(0)2N(Q)-, -N(Q)C(O)N(Q')-, -N(Q%)S(0):N(Q")-, -OC(OIN(Q))-, -N(Q)C(0)O- and -N(Q");
Q* Q°, Q5, Q°, Q°, Qf, Q8, Q, Ql, Q and QF are each independently selected from hydrogen, (1-6C)alkyl, A’ and (1-4C)alkylene-A*, wherein the alkyl group is unsubstituted ) or substituted with from 1 to 3 substituents independently selected from fluoro, hydroxy and (1-4C)alkoxy; or together with the nitrogen atom and the group R*® or R* to which they are attached, form a 4-6 membered azacycloalkylene group;
A’ and A* are each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl, wherein each cycloalkyl is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl and (1-4C)alkoxy;
provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R* is attached is in the range of from 4 to 14;
R’ represents hydrogen or (1-4C)alkyl; R® is -NR%CR®(0) or -CR®R*OR®® and R’ is hydrogen; or R® and R’ together form -NR7*C(0)-CR™®=CR™. | -CR"=CR’°-C(0)-NR'"-, -NR"8C(0)-CR""R":-CR"R*- or
-CR"R™-CR™R’°- C(O) -NR"-;
each of R®, R®, R® R® and R® is independently hydrogen or (1-4C)alkyl; and each of R™%, R™, R”, R™, R”*, R" R’¢, R”* R” R%, R” R" R™™ R™ R’® and R”® is independently hydrogen or (1-4C)alkyl; or a stereoisomer thereof; the process comprising: (a) reacting a compound of formula 1: (R'); ® : (R) § wf) - hi NH 0 1 or a salt thereof; with a compound of formula 2: : y oP" X—R&-N : 1s R OP? RO 2 wherein X' represents a leaving group, and P' and P? each independently represent a hydrogen atom or a hydroxyl-protecting group; (b) reacting a compound of formula 3: (R"); (RY), = No _4NH R= | T RY? NN Oo
3 or salt thereof; with a compound of formula 4: OP’ Ve R® 7 4 R oP R®
: 4 wherein X° represents a leaving group, and P? and P* each independently represent a hydrogen atom or a hydroxyl-protecting group; (c) coupling a compound of formula 3:
(RY); $ . (Re N a a (R%); 2 T S(R®) HA) -R™)XE 3 with a compound of formula 6: p52 0 pse Xab-(R)-(A2),-(R49)—N R R’ OP° 6 5 R 6 wherein X% and X® each independently represent functional groups that couple to form a group Q, P* represents a hydrogen atom or an amino-protecting group; and P*® and Peach independently represent a hydrogen atom or a hydroxyl-protecting group; (d) for a compound of formula I wherein R® represents a hydrogen atom, reacting a compound of formula 3 with a compound of formula 7: Oo OHC R’ oP’ RS
7 . or a hydrate thereof (e.g., a glyoxal), in the presence of a reducing agent, wherein P’ represents a hydrogen atom or a hydroxyl-protecting group;
(e) reacting a compound of formula 1 with a compound of formula 8: } le) - opP® Joh
HR . R® } R oP’ R® 8 or a hydrate thereof, in the presence of a reducing agent, wherein P? and P° each independently represent a hydrogen atom or a hydroxyl-protecting group, P' represents a hydrogen atom or an amino-protecting group, and R* represents a residue that, together with the carbon to which it is attached, affords a group R* upon completion of the reaction; H reacting a compound of formula 9: (RY); ; all No 4X R? hig “RY (RITZ J R 2 wherein X’ represents a leaving group, with a compound of formula 10: op" PHN 5 R rR’ op™ R® 10 _ : wherein P'' and P'? each independently represent a hydrogen atom or a hydroxyl- protecting group, and p'3 represents a hydrogen atom or an amino-protecting group; or (2) reacting a compound of formula 11:
R"); Fl (RY), Let ’ N Ww RN GL 0) 11 or a hydrate thereof; wherein R* represents a residue that, together with the carbon to which it is attached, affords a group R* upon completion of the reaction; with a compound of formula 10 in the presence of a reducing agent; and then . I p2 p3 p4 psa pb p6 p7 pd pd plo pil pi2 removing any protecting group P°, P*, P°, P*, P>*, P°°, P°, P', P*, P,P", P,P“ or P" to provide a compound of formula I.
42. The process of Claim 41, wherein the process further comprises forming a pharmaceutically acceptable salt of the compound of formula I.
43. The product prepared by the process of Claim 41 or 42.
44, A compound of any one of Claims 1 to 30 for use in therapy or as a medicament.
45. A compound of any one of Claims 1 to 30 for treatment of a pulmonary disorder.
46. Medicament containing a compound of any one of Claims 1 to 30.
47. Use of a compound of any one of Claims 1 to 30 for the manufacture of a medicament. N
48. The use of Claim 45, wherein the medicament is for the treatment of a pulmonary disorder.
PCT/US2004/004449
49. Use of a compound of any one of Claims 1 to 30 for treatment of a pulmonary disorder.
50. The use of Claim 48 or 49, wherein the pulmonary disorder is chronic obstructive pulmonary disease or asthma.
51. A compound of any one of claims 1 to 30, 44 or 45, substantially as herein described and illustrated.
52. A composition of any one of claims 31 to 33, substantially as herein described and illustrated.
53. Use of any one of claims 47 to 50, substantially as herein described and illustrated.
54. A method of claim 40, substantially as herein described and illustrated.
55. A process of claim 41 or claim 42, substantially as herein described and illustrated.
56. A product of claim 43, substantially as herein described and illustrated.
57. A medicament of claim 46, substantially as herein described and illustrated.
58. A substance or composition for use in a method of treatment of any one of claims 34 to 39, substantially as herein described and illustrated.
59. A new compound, a new composition, a new use of a compound of any one of claims 1 to 30, a new method of studying a biological system, a new process for preparing a compound, a new product, a new medicament, or a substance or composition for a new use in a method of treatment, substantially as herein described. TC --216-- AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US44784303P | 2003-02-14 | 2003-02-14 |
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| ZA200506215B true ZA200506215B (en) | 2006-06-28 |
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| AR (1) | AR098785A2 (en) |
| ES (1) | ES2351392T3 (en) |
| ZA (1) | ZA200506215B (en) |
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| US8263623B2 (en) * | 2008-07-11 | 2012-09-11 | Pfizer Inc. | Triazol derivatives useful for the treatment of diseases |
| EP2419409B1 (en) * | 2009-04-14 | 2015-01-28 | Glaxo Group Limited | Process for the preparation of a biphenyl-2-ylcarbamic acid ester |
| TR201903556T4 (en) * | 2009-04-23 | 2019-04-22 | Theravance Respiratory Co Llc | Diamide compounds with muscarinic receptor antagonist and beta 2 adrenergic receptor agonist activity. |
| MX2011011446A (en) * | 2009-04-30 | 2011-11-18 | Teijin Pharma Ltd | Quaternary ammonium salt compound. |
| CN104876854B (en) * | 2015-04-16 | 2017-03-01 | 御盛隆堂药业有限责任公司 | Hydroxy acetate derivative and application thereof |
| TW201704211A (en) * | 2015-05-14 | 2017-02-01 | Sichuan Haisco Pharmaceutical Co Ltd | Biphenyl derivative having beta2 receptor excitement and m receptor antagonistic activities and application therefof in medicament |
| US20190185461A1 (en) * | 2015-07-21 | 2019-06-20 | Sichuan Haisco Pharmaceutical Co., Ltd. | Benzocyclic derivative having b2-receptor agonist activity and m3-receptor antagonist activity and medical use thereof |
| KR20180100106A (en) * | 2016-01-22 | 2018-09-07 | 스촨 하이스코 파마수티컬 씨오., 엘티디 | Nitrogen-containing heterocyclic amide derivatives and their preparation and pharmaceutical uses |
| WO2019015640A1 (en) * | 2017-07-21 | 2019-01-24 | 四川海思科制药有限公司 | Salt of azacyclic amide derivative, crystal form thereof and preparation method therefor and use thereof |
| WO2019015639A1 (en) * | 2017-07-21 | 2019-01-24 | 四川海思科制药有限公司 | Azacyclic amide derivative composition and preparation thereof |
| CN108794395B (en) * | 2018-07-06 | 2021-04-20 | 大连理工大学 | Preparation method of 2-quinolinone compounds |
| CN111423434A (en) * | 2019-01-09 | 2020-07-17 | 四川海思科制药有限公司 | Carbonamide derivative and preparation method thereof |
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| US6362371B1 (en) * | 1998-06-08 | 2002-03-26 | Advanced Medicine, Inc. | β2- adrenergic receptor agonists |
| US7238709B2 (en) * | 1999-12-07 | 2007-07-03 | Theravance, Inc. | Therapeutic carbamates |
| UA73543C2 (en) * | 1999-12-07 | 2005-08-15 | Тераванс, Інк. | Urea derivatives, a pharmaceutical composition and use of derivative in the preparation of medicament for the treatment of disease being mediated by muscarine receptor |
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2004
- 2004-02-13 CN CNB2004800065284A patent/CN100378092C/en not_active Expired - Lifetime
- 2004-02-13 CN CN2008100741569A patent/CN101239968B/en not_active Expired - Lifetime
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- 2004-02-13 CN CN2008100741573A patent/CN101239969B/en not_active Expired - Lifetime
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| CN101239969A (en) | 2008-08-13 |
| CN100378092C (en) | 2008-04-02 |
| ES2351392T3 (en) | 2011-02-03 |
| CN101239970B (en) | 2011-07-20 |
| CN1759108A (en) | 2006-04-12 |
| CN101239971A (en) | 2008-08-13 |
| CN101239971B (en) | 2011-07-20 |
| CN101239970A (en) | 2008-08-13 |
| CN101239969B (en) | 2011-07-20 |
| CN101239968B (en) | 2011-07-20 |
| AR098785A2 (en) | 2016-06-15 |
| CN101239968A (en) | 2008-08-13 |
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