ZA200404085B - Inhibitors of factor Xa and other serine poteases involved in the coagulation cascades. - Google Patents
Inhibitors of factor Xa and other serine poteases involved in the coagulation cascades. Download PDFInfo
- Publication number
- ZA200404085B ZA200404085B ZA200404085A ZA200404085A ZA200404085B ZA 200404085 B ZA200404085 B ZA 200404085B ZA 200404085 A ZA200404085 A ZA 200404085A ZA 200404085 A ZA200404085 A ZA 200404085A ZA 200404085 B ZA200404085 B ZA 200404085B
- Authority
- ZA
- South Africa
- Prior art keywords
- amide
- phenyl
- pyrrolidine
- chloro
- dicarboxylic acid
- Prior art date
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- 108010074860 Factor Xa Proteins 0.000 title claims description 19
- 230000015271 coagulation Effects 0.000 title description 8
- 238000005345 coagulation Methods 0.000 title description 8
- 239000003112 inhibitor Substances 0.000 title description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 title 1
- -1 cyano, aminomethyl Chemical group 0.000 claims description 268
- 125000000217 alkyl group Chemical group 0.000 claims description 165
- 125000005843 halogen group Chemical group 0.000 claims description 64
- 125000003118 aryl group Chemical group 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 37
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- 125000001188 haloalkyl group Chemical group 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 18
- 229920006395 saturated elastomer Polymers 0.000 claims description 17
- 208000007536 Thrombosis Diseases 0.000 claims description 14
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 241000124008 Mammalia Species 0.000 claims description 11
- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
- 125000003368 amide group Chemical group 0.000 claims description 11
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 11
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000001475 halogen functional group Chemical group 0.000 claims description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
- 230000001154 acute effect Effects 0.000 claims description 8
- 230000005764 inhibitory process Effects 0.000 claims description 8
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 206010047249 Venous thrombosis Diseases 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 206010003178 Arterial thrombosis Diseases 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 356
- QLEZWYHCXVFRKO-RFZPGFLSSA-N (2r,4r)-4-methoxypyrrolidine-1,2-dicarboxylic acid Chemical compound CO[C@@H]1C[C@H](C(O)=O)N(C(O)=O)C1 QLEZWYHCXVFRKO-RFZPGFLSSA-N 0.000 claims 164
- QLEZWYHCXVFRKO-UHFFFAOYSA-N 4-methoxypyrrolidine-1,2-dicarboxylic acid Chemical compound COC1CC(C(O)=O)N(C(O)=O)C1 QLEZWYHCXVFRKO-UHFFFAOYSA-N 0.000 claims 66
- OAWXZFGKDDFTGS-UHFFFAOYSA-N pyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CCCN1C(O)=O OAWXZFGKDDFTGS-UHFFFAOYSA-N 0.000 claims 52
- HHDQVBSXYDRQGD-QWWZWVQMSA-N (2r,4r)-4-hydroxypyrrolidine-1,2-dicarboxylic acid Chemical compound O[C@@H]1C[C@H](C(O)=O)N(C(O)=O)C1 HHDQVBSXYDRQGD-QWWZWVQMSA-N 0.000 claims 32
- HHDQVBSXYDRQGD-UHFFFAOYSA-N 4-hydroxypyrrolidine-1,2-dicarboxylic acid Chemical compound OC1CC(C(O)=O)N(C(O)=O)C1 HHDQVBSXYDRQGD-UHFFFAOYSA-N 0.000 claims 25
- 150000001408 amides Chemical class 0.000 claims 13
- ZNNRVGZFHOROJG-PHDIDXHHSA-N (2r,4r)-4-ethoxypyrrolidine-1,2-dicarboxylic acid Chemical compound CCO[C@@H]1C[C@H](C(O)=O)N(C(O)=O)C1 ZNNRVGZFHOROJG-PHDIDXHHSA-N 0.000 claims 11
- PSEFWMGUIGBSMX-UHFFFAOYSA-N 3,4-dihydropyrazole-2,3-dicarboxylic acid Chemical compound OC(=O)C1CC=NN1C(O)=O PSEFWMGUIGBSMX-UHFFFAOYSA-N 0.000 claims 11
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 9
- 239000000126 substance Substances 0.000 claims 9
- GXFAYZBQUMULJS-UHFFFAOYSA-N 4-fluoropyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CC(F)CN1C(O)=O GXFAYZBQUMULJS-UHFFFAOYSA-N 0.000 claims 8
- 230000001684 chronic effect Effects 0.000 claims 6
- 239000002253 acid Substances 0.000 claims 5
- 125000001589 carboacyl group Chemical group 0.000 claims 4
- 125000000068 chlorophenyl group Chemical group 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 3
- QUWVWFPFPVLXIW-UHFFFAOYSA-N 5-(hydroxymethyl)-3,4-dihydropyrazole-2,3-dicarboxylic acid Chemical compound OCC1=NN(C(O)=O)C(C(O)=O)C1 QUWVWFPFPVLXIW-UHFFFAOYSA-N 0.000 claims 3
- 206010002383 Angina Pectoris Diseases 0.000 claims 3
- 206010003658 Atrial Fibrillation Diseases 0.000 claims 3
- 206010019280 Heart failures Diseases 0.000 claims 3
- 206010028980 Neoplasm Diseases 0.000 claims 3
- 208000010378 Pulmonary Embolism Diseases 0.000 claims 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- 150000001413 amino acids Chemical class 0.000 claims 3
- 201000011510 cancer Diseases 0.000 claims 3
- 206010008118 cerebral infarction Diseases 0.000 claims 3
- 206010012601 diabetes mellitus Diseases 0.000 claims 3
- 208000010125 myocardial infarction Diseases 0.000 claims 3
- 230000002265 prevention Effects 0.000 claims 3
- 125000006239 protecting group Chemical group 0.000 claims 3
- BXOAORRUHBLISX-UHFFFAOYSA-N pyrrolidine-1,2,4-tricarboxylic acid Chemical compound OC(=O)C1CC(C(O)=O)N(C(O)=O)C1 BXOAORRUHBLISX-UHFFFAOYSA-N 0.000 claims 3
- 208000037803 restenosis Diseases 0.000 claims 3
- GXFAYZBQUMULJS-QWWZWVQMSA-N (2r,4r)-4-fluoropyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@H]1C[C@@H](F)CN1C(O)=O GXFAYZBQUMULJS-QWWZWVQMSA-N 0.000 claims 2
- QLEZWYHCXVFRKO-CRCLSJGQSA-N (2r,4s)-4-methoxypyrrolidine-1,2-dicarboxylic acid Chemical compound CO[C@H]1C[C@H](C(O)=O)N(C(O)=O)C1 QLEZWYHCXVFRKO-CRCLSJGQSA-N 0.000 claims 2
- VLRGXXKFHVJQOL-UHFFFAOYSA-N 3-chloropentane-2,4-dione Chemical compound CC(=O)C(Cl)C(C)=O VLRGXXKFHVJQOL-UHFFFAOYSA-N 0.000 claims 2
- PWRBCZZQRRPXAB-UHFFFAOYSA-N 3-chloropyridine Chemical compound ClC1=CC=CN=C1 PWRBCZZQRRPXAB-UHFFFAOYSA-N 0.000 claims 2
- LXZQZQFUSNSLMQ-UHFFFAOYSA-N 3-oxopyrazolidine-1,5-dicarboxylic acid Chemical compound OC(=O)C1CC(=O)NN1C(O)=O LXZQZQFUSNSLMQ-UHFFFAOYSA-N 0.000 claims 2
- IYOXBCOLEAZKBF-UHFFFAOYSA-N 4,4-difluoropyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CC(F)(F)CN1C(O)=O IYOXBCOLEAZKBF-UHFFFAOYSA-N 0.000 claims 2
- IPQLKFAHUWJGQR-UHFFFAOYSA-N 4-(aminomethyl)pyrrolidine-1,2-dicarboxylic acid Chemical compound NCC1CC(C(O)=O)N(C(O)=O)C1 IPQLKFAHUWJGQR-UHFFFAOYSA-N 0.000 claims 2
- QMZKFOSMBYTKSY-UHFFFAOYSA-N 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylic acid Chemical compound OCC1CC(C(O)=O)N(C(O)=O)C1 QMZKFOSMBYTKSY-UHFFFAOYSA-N 0.000 claims 2
- ZNNRVGZFHOROJG-UHFFFAOYSA-N 4-ethoxypyrrolidine-1,2-dicarboxylic acid Chemical compound CCOC1CC(C(O)=O)N(C(O)=O)C1 ZNNRVGZFHOROJG-UHFFFAOYSA-N 0.000 claims 2
- XFFOVQLJFXBTJC-UHFFFAOYSA-N 4-methylpyrrolidine-1,2-dicarboxylic acid Chemical compound CC1CC(C(O)=O)N(C(O)=O)C1 XFFOVQLJFXBTJC-UHFFFAOYSA-N 0.000 claims 2
- DMFOFFOEZAPORN-UHFFFAOYSA-N 4-oxopyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CC(=O)CN1C(O)=O DMFOFFOEZAPORN-UHFFFAOYSA-N 0.000 claims 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims 2
- FIBYOSWAIMZEKR-UHFFFAOYSA-N 5-(methoxymethyl)-3,4-dihydropyrazole-2,3-dicarboxylic acid Chemical compound COCC1=NN(C(O)=O)C(C(O)=O)C1 FIBYOSWAIMZEKR-UHFFFAOYSA-N 0.000 claims 2
- DTGVTBVHWDTMBC-UHFFFAOYSA-N 5-methyl-4h-pyrazole-1,5-dicarboxylic acid Chemical compound OC(=O)C1(C)CC=NN1C(O)=O DTGVTBVHWDTMBC-UHFFFAOYSA-N 0.000 claims 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 2
- 208000026106 cerebrovascular disease Diseases 0.000 claims 2
- 150000002148 esters Chemical class 0.000 claims 2
- 150000004820 halides Chemical class 0.000 claims 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 2
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 2
- IYOXBCOLEAZKBF-GSVOUGTGSA-N (2r)-4,4-difluoropyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@H]1CC(F)(F)CN1C(O)=O IYOXBCOLEAZKBF-GSVOUGTGSA-N 0.000 claims 1
- DMFOFFOEZAPORN-SCSAIBSYSA-N (2r)-4-oxopyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@H]1CC(=O)CN1C(O)=O DMFOFFOEZAPORN-SCSAIBSYSA-N 0.000 claims 1
- OAWXZFGKDDFTGS-SCSAIBSYSA-N (2r)-pyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@H]1CCCN1C(O)=O OAWXZFGKDDFTGS-SCSAIBSYSA-N 0.000 claims 1
- NHBXKHSRPHSQPL-HZGVNTEJSA-N (2r,4r)-2-ethyl-4-methoxypyrrolidine-1,2-dicarboxylic acid Chemical compound CC[C@]1(C(O)=O)C[C@@H](OC)CN1C(O)=O NHBXKHSRPHSQPL-HZGVNTEJSA-N 0.000 claims 1
- GVZLWFKDTYITCE-QWWZWVQMSA-N (2r,4r)-4-(2h-tetrazol-5-yl)pyrrolidine-1,2-dicarboxylic acid Chemical compound C1N(C(O)=O)[C@@H](C(=O)O)C[C@H]1C1=NN=NN1 GVZLWFKDTYITCE-QWWZWVQMSA-N 0.000 claims 1
- BPMKDLRAYMTVSR-PHDIDXHHSA-N (2r,4r)-4-acetamidopyrrolidine-1,2-dicarboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](C(O)=O)N(C(O)=O)C1 BPMKDLRAYMTVSR-PHDIDXHHSA-N 0.000 claims 1
- JCINQOYGBLWVGB-CRCLSJGQSA-N (2r,4r)-4-cyanopyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@H]1C[C@@H](C#N)CN1C(O)=O JCINQOYGBLWVGB-CRCLSJGQSA-N 0.000 claims 1
- VNGXCFNFIDLEKA-PHDIDXHHSA-N (2r,4r)-4-ethylpyrrolidine-1,2-dicarboxylic acid Chemical compound CC[C@@H]1C[C@H](C(O)=O)N(C(O)=O)C1 VNGXCFNFIDLEKA-PHDIDXHHSA-N 0.000 claims 1
- PLKSHXBKRMGXDC-SVGQVSJJSA-N (2r,4r)-4-methoxy-2-methylpyrrolidine-1,2-dicarboxylic acid Chemical compound CO[C@H]1CN(C(O)=O)[C@@](C)(C(O)=O)C1 PLKSHXBKRMGXDC-SVGQVSJJSA-N 0.000 claims 1
- XFFOVQLJFXBTJC-RFZPGFLSSA-N (2r,4r)-4-methylpyrrolidine-1,2-dicarboxylic acid Chemical compound C[C@@H]1C[C@H](C(O)=O)N(C(O)=O)C1 XFFOVQLJFXBTJC-RFZPGFLSSA-N 0.000 claims 1
- GVZLWFKDTYITCE-IUYQGCFVSA-N (2r,4s)-4-(2h-tetrazol-5-yl)pyrrolidine-1,2-dicarboxylic acid Chemical compound C1N(C(O)=O)[C@@H](C(=O)O)C[C@@H]1C1=NN=NN1 GVZLWFKDTYITCE-IUYQGCFVSA-N 0.000 claims 1
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- OAWXZFGKDDFTGS-BYPYZUCNSA-N (2s)-pyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(O)=O OAWXZFGKDDFTGS-BYPYZUCNSA-N 0.000 claims 1
- PSEFWMGUIGBSMX-GSVOUGTGSA-N (3r)-3,4-dihydropyrazole-2,3-dicarboxylic acid Chemical compound OC(=O)[C@H]1CC=NN1C(O)=O PSEFWMGUIGBSMX-GSVOUGTGSA-N 0.000 claims 1
- KQQMJVJKTXAJRT-UHFFFAOYSA-N 1-[(4-chlorophenyl)carbamoyl]-5-[[2-fluoro-4-(2-oxopiperidin-1-yl)phenyl]carbamoyl]pyrrolidine-3-carboxylic acid Chemical compound C1C(C(=O)O)CC(C(=O)NC=2C(=CC(=CC=2)N2C(CCCC2)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 KQQMJVJKTXAJRT-UHFFFAOYSA-N 0.000 claims 1
- STRUTHDFPCSAAP-DYESRHJHSA-N 1-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxopyridine-3-carboxylic acid Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(C(O)=O)=CC=C1)=O)F)C(=O)NC1=CC=C(Cl)C=C1 STRUTHDFPCSAAP-DYESRHJHSA-N 0.000 claims 1
- XJOYMNODJKLRIS-UHFFFAOYSA-N 1-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxopiperidine-3-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(C(C(O)=O)CCC2)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 XJOYMNODJKLRIS-UHFFFAOYSA-N 0.000 claims 1
- NSIPNUUCWAGVBF-UHFFFAOYSA-N 1-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-5-oxopyrrolidine-2,2-dicarboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(CCC2=O)(C(O)=O)C(O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 NSIPNUUCWAGVBF-UHFFFAOYSA-N 0.000 claims 1
- CPCLIWRBKKYRFS-UHFFFAOYSA-N 1-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-5-oxopyrrolidine-2-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(CCC2C(O)=O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 CPCLIWRBKKYRFS-UHFFFAOYSA-N 0.000 claims 1
- RJRQLNKJVATIAJ-UHFFFAOYSA-N 1-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]imidazole-2-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(=NC=C2)C(O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 RJRQLNKJVATIAJ-UHFFFAOYSA-N 0.000 claims 1
- LYDIFOZLKWKCBD-UHFFFAOYSA-N 1-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]pyrrole-2-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(=CC=C2)C(O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 LYDIFOZLKWKCBD-UHFFFAOYSA-N 0.000 claims 1
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- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 1
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- 230000000004 hemodynamic effect Effects 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000006623 intrinsic pathway Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000009124 positive feedback regulation Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002947 procoagulating effect Effects 0.000 description 1
- 150000003147 proline derivatives Chemical class 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 108010014806 prothrombinase complex Proteins 0.000 description 1
- 238000011555 rabbit model Methods 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 108091006091 regulatory enzymes Proteins 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 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 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 108010065972 tick anticoagulant peptide Proteins 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 201000002282 venous insufficiency Diseases 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
v @ - INHIBITORS OF FACTOR Xa AND OTHER SERINE PROTEASES
INVOLVED IN THE COAGULATION CASCADE
The present invention relates to cyclic amino acid and proline derivatives which display inhibitory effects of the serine protease factor Xa. The invention also discloses pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable compositions comprising the compounds or their salts, and methods of using them as therapeutic agents for treating or preventing disease states in mammals characterized by abnormal thrombosis.
In economically developed countries, cardiovascular disease represents a major cause of mortality. In particular, abnormal coagulation and inappropriate thrombus formation within blood vessels precipitates many acute cardiovascular disease states. While it has long been recognized that a variety of plasma proteins such as fibrinogen, serine proteases, and cellular receptors are involved in hemostasis, it is abnormal regulation that has emerged as important contributing factors to cardiovascular disease.
Thrombin can be considered the key or principal regulatory enzyme in the coagulation cascade; it serves a pluralistic role as both a positive and negative feedback regulator in normal hemostasis. However, in some pathologic conditions, the positive feedback regulation is amplified through catalytic activation of cofactors required for thrombin generation. Such cofactors include ) factor Xa, a serine protease which occupies a pivotal position in the coagulation cascade. Factor X is the zymogen of factor Xa. Factor X can be activated by . either the intrinsic or extrinsic pathways of the coagulation system. Initiation of coagulation by either pathway in response to vascular injury activates factor X to factor Xa. Factor Xa and its cofactor, factor Va, combine on a phospholipid membrane to form the “prothombinase” complex, which activates prothrombin to thrombin. Thrombin cleaves fibrinogen to fibrin, activates platelets, and converts
® v factor XIII to XIIIa which is the principal enzyme involved in thrombus - generation, growth, and stabilization. Accordingly, the location of the ) prothrombinase complex at the convergence of both the intrinsic and extrinsic . coagulation pathways suggests that inhibition of factor Xa, and hence thrombin generation, may be a viable approach to limiting the procoagulant activity of thrombin.
Evidence exists for the role of factor Xa inhibitors as anticoagulants.
Antistasin, a potent inhibitor of blood coagulation factor Xa from the Mexican leech, Haementeria officinalis, displays antithrombotic activity in various models of arterial and venous thrombosis (Lapatto et al., Embo. J, 1997:5151-5161). Other protein or polypeptide factor Xa inhibitors include recombinant tick anticoagulant peptide (rTAP), which is known to accelerate the recombinant tissue plasminogen activator mediated clot lysis and prevent acute reocclusion in the dog, hence indicating factor Xa inhibitors may be useful as an adjunct to thrombolytic therapy (Mellott et al., Fibrinolysis, 1993: 195-202). Furthermore, in a canine coronary artery electrolytic lesion model, rITAP was demonstrated to reduce thrombus mass and time to occlusion in the absence of dramatic hemodynamic or hemostatic changes indicating the primary role for factor Xa in the process of artenial thrombosis (Lynch et al., Thromb. Haemostasis, 1995:640-645; Schaffer et al.,
Circulation, 1991: 1741- 1748). On the venous side, rTAP was also demonstrated to reduce fibrin deposition in a rabbit model of venous thrombosis while having little affect on systemic hemostatic parameters (Fioravanti et al., Thromb. Res., 1993: 317-324). In addition to these relatively high molecular weight proteins that are not suitable as oral antithrombotic agents, there also exist examples of low molecular weight factor Xa inhibitors. In particular DX9065a, a low molecular ] weight synthetic factor Xa inhibitor, has also shown antithrombotic potential in various experimental thrombosis rat models. In both arteriovenous shunt and - venous stasis models, inhibition of thrombus formation was achieved at doses that had litle effect on APTT, indicating that DX9065a is effective in preventing thrombosis and hence has therapeutic antithrombotic potential (Wong et al.,
Thromb. Res., 1996: 117-126).
A
. @
Recently, it has been appreciated that factor Xa inhibition may provide © sustained antithrombotic protection. Specifically, several animal studies show that inhibition of short term exposure to factor Xa produces a sustained antithrombotic. (Leadley, Curr. Top. Med. Chem., 2001: v. 1, 151-159.) Finally, the article by Leadley observes that factor Xa inhibition potentially provides a large therapeutical window between antithrombotic efficacy and bleeding tendency. Consequently, there may exist a range in which factor Xa inhibition is achieved without an concurrent increase in a patients susceptibility to bleeding.
The majority of factor Xa inhibitors known to date have been summarized in two reviews (Edmunds et al., Annual Reports in Medicinal Chemistry, 1996:5) and Kunitada and Nagahara, Curr. Pharm. Des., 1996:531-542). However, it is readily apparent that there still exists a need for more effective agents that regulate factor Xa proteolytic activity.
These and other needs are met by the present invention which is directed to a compound of Formulal w' og
JAS 8 ~ AN
NH le} B d
I
. or a pharmaceutically acceptable salt thereof wherein:
A is aryl or substituted ary} or monocyclic heteroaryl or substituted monocyclic heteroaryl; ? Q
B is -NH —C—(C,-Cg)alkyl, -NH —C— (C3-Cy)cycloalkyl, -
® v 0 - : PY
NH —C— O(C,-Cs alkyl), R' (Ca-Cy)cycloalkyl, (Ca-Co)heterocyclo, (Ce- ,
C)cycloalkenyl, unsaturated (C;-Cy)heterocyclo, aryl, or heteroaryl, any of which may be optionally substituted by halo, (C;-Cs)alkyl, or halo(C,-Ce)alkyl, 0O-(C;-Cs), -CN, haloalkyl, amino, alkylamino, amidino, amido, or sulfonamido;
C is phenyl or heteroaryl, wherein phenyl or heteroaryl is optionally substituted with one or more substituents selected from aryl, heteroaryl, halogen, hydroxy, -CO2R2, -COR2, -CONR2R?’, alkoxy, alkyl, -CN, haloalkyl, amino, alkylamino, amidino, amido, or sulfonamido;
G is H, halo, (C;-Ce)alkyl, halo(C,-Ce)alkyl, hydroxy(C;-Ce)alkyl, -CH,O-(C;-Cg)alkyl, -CH>-CO,(C1-Ce)alkyl, -CH2-NR2R2’, or -CH.-CONH(C;-
Cealkyl;
W1 is a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain having from 2 to 6 atoms, wherein wl connects the nitrogen atom at position 1 to the carbon atom at position 2 to form a four to eight membered ring;
R1 is (C,-Cg)alkoxy, (C3-Cs)cycloalkyl, (C3-Cy)heterocycloalkyl, (Ca-
C-)cycloalkenyl, (Cs-Co)heterocycloalkenyl, aryl, monocyclic heteroaryl, or —
NR3R4;,
R2 and RZ’ are each independently H or (C,-Ce)alkyl; and
R3 and R4 are each independently H, (C;-Cs)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl, aralkoxycarbonyl, -SO»alkyl, or joined ’ together to form a saturated or unsaturated 3 to 7 membered ring.
The invention is also directed to a compound of formula II:
- rR"
N R10 3 G y ‘ XV N
Ny \,
PE il 0
Cc 1 or a pharmaceutically acceptable salt thereof wherein “---7 is a bond or is absent;
X"is CH,, CH, 0, NH or N;
R" and R'! are each independently H, -OH, halo, alkyl, haloalkyl, -
NR8RY, -OR2, -CN, -CH,0H, -CH-NR3R4, aryl, monocyclic heteroaryl, alkylaryl, -CH=0, -CHoOR2, -COR2, -CO7R?, or -CONR3R4 or are taken together to form =0, =NOR2, =C(C;-Cgalkyl)2, or =CR2H, with the proviso that when *---""is a bond, R!! is absent, and X"is CH or N, and R'is H, -OH, halo, alkyl, haloalkyl, -NR8R9, -OR2, -CN, -CH,0H, -CH2-NR3R4, aryl, monocyclic heteroaryl, alkylaryl, -CH=0, -CH,OR?Z, -COR2, -CO,R?2, or -CONR3R4;
A is aryl and substituted aryl or monocyclic heteroaryl or substituted monocyclic heteroaryl, 0 o a.
B is -NH —C— (C,-Cg)alkyl, -NH —C—(C3-C7)cycloalkyl, - 0 0 PR
NH —C— O(C,;-Cs alkyl), R' , (C3-Cy)cycloalkyl, (Cs-Co)heterocyclo, (C,- . C-)cycloalkenyl, unsaturated (C,-Cy)heterocyclo, aryl, or heteroaryl, any of which may be optionally substituted by halo, (C;-Ce)alkyl, or halo(C;-Ce)alkyl,
O~(C)-Ce), -CN, haloalkyl, amino, alkylamino, amidino, amido, or sulfonamido;
C is phenyl or heteroaryl, wherein phenyl or heteroaryl is optionally substituted with one or more substituents selected from halogen, hydroxy, - )
® v
CO-R?, -COR2, -CONR2RZ’, alkoxy, alkyl, -CN, haloalkyl, amino, alkylamino, amidino, amido, or sulfonamido;
G is H, halo, (C,-Ce)alkyl, halo(C,-Cg)alkyl, hydroxy(C,-Cs)alkyl, . -CH,0-(C)-Ce)alkyl, -CHz-CO5(C;-Co)alky), -CH2-NR2R2', or -CH,-CONH(C)- Cealkyl,or -CH;-CONH(C,;-Cg)alkyl;
R1 is (C1-Ce)alkoxy, (C3-Cy)cycloalkyl, (C3-Co)heterocycloalkyl, (C-
Co)cycloalkenyl, (C4-Codheterocycloalkenyl, aryl, monocyclic heteroaryl, or —
NR3R4
R2 and R2’ are each independently H or (C;-Cg)alkyl; and
R3 and R4 are independently H, (C,-Ce)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl, aralkoxycarbonyl, -SOpalkyl, or joined together to form a saturated or unsaturated 5 to 7 membered ring.
The invention is also directed to a compound of Formula III py 3 G
ESO
A I
HN o ~
AY Ji :
NX
R' m . or a pharmaceutically acceptable salt thereof wherein . “---""is a bond or is absent;
Zis C-H, C-halo, C-(C;-Cg)alky!, C-halo(C1-Cs)alkyl, C-(C,-Ce)alkoxy, or
N;
X"is CH,, CH, O, NH or N;
@
R R" and R'' are each independently H, -OH, halo, alkyl, haloalkyl, - . NR8RY, -OR2, -CN, -CH,0H, -CH»-NR3R4, aryl, monocyclic heteroaryl, alkylaryl, -CH=0, -CH2OR?Z, -COR2, -CO2R2, or -CONR3R# or are taken together to form =0, =NORZ2, =C(C;-Cgalkyl)p, or =CRZH, with the proviso that when “---"isabond, R" is absent, and X"is CH or N, and R'® is H, -OH, halo, alkyl, haloalkyl, -NR8RY, -OR2, -CN, -CH,0H, -CH3-NR3R4, aryl, monocyclic heteroaryl, alkylaryl, -CH=0, -CH,ORZ, -COR2, -CO2R2, or -CONR3R4;
A is aryl and substituted aryl or monocyclic heteroaryl or substituted monocyclic heteroaryl; ® ?
B is -NH —C— (C,-Cg)alkyl, -NH —C— (C3-Cy)cycloalkyl, - o) . I
NH —C—0O(C,-Cs alkyl), R', (C3-Cy)cycloalkyl, (C3-Co)heterocyclo, (Cs-
C-)cycloalkenyl, unsaturated (Cs-C7)heterocyclo, aryl, or heteroaryl, any of which may be optionally substituted by halo, (Ci-Ce)alkyl, or halo(C,-Ce)alkyl, 0-(C;-C¢), -CN, haloalkyl, amino, alkylamino, amidino, amido, or sulfonamido;
G is H, halo, (C,-Cg)alkyl, halo(C,;-Ce)alkyl, hydroxy(C,-Ce)alkyl, -CH,0-(C;-Cp)alkyl, -CH2-CO(C;-Cs)alkyl, -CH,-CONH_, or -CH,-CONH(C;-
Ce)alkyl;
R2 and R2 are each independently H or (C;-Ce)alkyl; and
R3 and R4 are independently H, (C;-Ce)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl, aralkoxycarbonyl, -SO»alkyl, or joined together to form a saturated or unsaturated 5 to 7 membered ring; and
R'Z and R" are each independently H, halo, (C;-Ce)alkyl, halo(C;- . Ce)alkyl, or (C,-Ce)alkoxy.
What is also provided is a compound of Formula IV
®
RY _
Rr" A G H . x! N .
Ny X R'
S¢
A © /
HN ro) i A=
B
ZN
R12— J
SeoX
R13
Iv or a pharmaceutically acceptable salt thereof wherein *“---"1s a bond or is absent;
Z is C-H, C-halo, C-(C;-Cg)alkyl, C-halo(C,-Ce)alkyl, C-(C;-Ce)alkoxy, or
N;
X"is CH, CH, 0, NH or N;
R" and R'" are each independently H, -OH, halo, alkyl, haloalkyl, -
NR8RY, -OR2, -CN, -CH,0H, -CH»-NR3R4, aryl, monocyclic heteroaryl, alkylaryl, -CH=0, -CH,OR2, -COR2, -CO5R2, or -CONR3R# or are taken together to form =O, =NORZ2, =C(C-Cgalkyl)s, or =CR2H, with the proviso that when “---" is a bond, R'! is absent, and X"is CH or N, and R'® is H, -OH, halo, alkyl, haloalkyl, -NR8R9, -OR2, -CN, -CH,OH, -CH,-NR3R4, aryl, monocyclic heteroaryl, alkylaryl, -CH=0, -CH,OR2, -COR2, -CO,R2, or -CONR3R%; . 0 o -
Bis -NH —C—(C,-Cg)alkyl, -NH —C— (C3-C;)cycloalkyl, - o : 0 PS
NH —C— O(C,-C; alkyl, R' , (C3-C;)cycloalkyl, (C3-Co)heterocyclo, (Cs-
C;)cycloalkenyl, unsaturated (C4-Co)heterocyclo, aryl, or heteroaryl, any of which may be optionally substituted by halo, (C;-Cg)alkyl, or halo(C;-Ce)alkyl,
@ - 0O-(C;-Cs), -CN, haloalkyl, amino, alkylamino, amidino, amido, or sulfonamido;
G is H, halo, (C;-Ce)alkyl, halo(C,-Ce)alkyl, hydroxy(C,-Ce)alkyl,
S -CH»0-(C;-Ce)alkyl, -CH2-CO,(C,-Ce)alkyl, -CH.-CONH,, or -CH;-CONH(C;-
Ce)alkyl;
R2 and RZ’ are each independently H or (C)-Ce)alkyl; and
R3 and R4 are independently H, (C;-Cs)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl, aralkoxycarbonyl, -SO»alkyl, or joined together to form a saturated or unsaturated 5 to 7 membered ring; rR" and R'? are each independently H, halo, (C;-Ce)alkyl, or halo(C;-
Cgalkyl, or (C;-Ce)alkoxy;
R" and R' are each independently H, halo, alkyl, or haloalkyl, or NR'R’ wherein R® and R? are as defined for R® and RY; ~ X and Y are each C, or one of X and Y is C and the other is N, provided that when one of X or Y is N, R14 or R15 is absent at that position.
What is also provided is a compound of Formula V "
R10 \ 3 G jy " Ny bas ]
A © | ; ™
A i | PY
RY J R'S 7 Ruy oo gS
R13 . \% or a pharmaceutically acceptable salt thereof wherein “.--"jisabondoris absent;
Z is C-H, C-halo, C-(C;-Ca)alkyl, C-halo(C;-Cé)alkyl, C~(C;-Ce)alkoxy, or
N; -
G is H, halo, (C;-Ce)alkyl, halo(C,-Ce)alkyl, hydroxy(C;-Cq)alkyl, -CH10-(C)-C)alkyl, -CH2-CO1(C;-Ce)alkyl, -CH.-CONH,, or -CH>-CONH(C;- .
Co)alkyl;
X"is CH, CH, O, NHor N;
R'® and R"' are each independently H, -OH, halo, alkyl, haloalkyl, -
NR8RY, -OR2, -CN, -CH2OH, -CH,-NR3R4, aryl, monocyclic heteroaryl, alkylaryl, -CH=0, -CH>OR?, -COR2, -CO5R2, or ~CONR3R4 or are taken together to form =0, =NOR?Z, =C(C1-Cgalkyl)a, or =CR2H, with the proviso that when “---"isabond, R'' is absent, and X"is CH or N, and R'® is H, -OH, halo, alkyl, haloalkyl, -NR8RY, -ORZ, -CN, -CH20H, -CH2-NR3R#, aryl, monocyclic heteroaryl, alkylaryl, -CH=0, -CHo0R2, -COR2, -CO2R2, or -CONR3R4;
R2 is H or (C;-Ce)alkyl; and
R3 and R94 are independently H, (C;-Ce)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl, aralkoxycarbonyl, -SO2alkyl, or joined together to form a saturated or unsaturated 5 to 7 membered ring;
Rr" and R?? are each independently H, halo, (C;-Ce)alkyl, or halo(C;-
Ce)alkyl, or (C,;-Ce)alkoxy;
R" and RY are each independently H, halo, alkyl, or haloalkyl, or NR'R’ wherein R® and R® are as defined for R* and R*;
X and Y are each independently C or N, provided that when one of X or Y is N, R14 or R15 is absent at that position.
X’ and Y’ are each independently CH or N;
I is absent or is a fused heterocyclic or fused heteroaryl ring, - provided that when -" is present, Y’ is C; and
R16 and R17 are each independently H, halo, cyano, (C;-Ce)alkoxy
@ - carbonyl, aminomethyl, t-butyl, HINSO>—, Me; NSO,—, (C;-C¢)alkoxy,
MeSO,—, MeSO—, MeS—, NRBRY, or hydroxy
What is also provided is a compound of Formula V1
RM : 10 fi G . R 0 A H
Ny X R" pd
A © / 0
HN o i” A ==
Q z= 7 R! ce
SX
R13
VI or a pharmaceutically acceptable salt thereof wherein ‘“---"is a bond or is absent;
Z is C-H, C-halo, C-(C;-Ce)alkyl, C-halo(C,;-Ce)alkyl, C-(C;-C¢)alkoxy, or
N;
G is H, halo, (C;-Ce)alkyl, halo(C,-Ce)alkyl, bydroxy(C;-Ce)alkyl, -CH,0-(C)-Ce)alkyl, -CH2-CO2(C,-Ce)alkyl, -CH,-CONH, or -CH,-CONH(C,;-
Ce)alkyl;
Q is NH or is absent; :
X"is CH,, CH, O, NH or N;
R' and R" are each independently H, -OH, halo, alkyl, haloalkyl, -
NR8RY, -OR2, -CN, -CH,0H, -CH2-NR3R4, aryl, monocyclic heteroaryl, alkylaryl, -CH=0, -CH,0R2, -COR2, -CO2R2, or -CONR3R# or are taken together to form =O, =NOR2, =C(C;-Cgalkyl)y, or =CR2H, with the proviso that when “---" isa bond, R'! is absent, and X"is CH or N, and R'is H, -OH, halo,
alkyl, haloalkyl, -NR8R9, -OR2, -CN, -CH20H, -CH-NR3R4, aryl, monocyclic ] heteroaryl, alkylaryl, -CH=0, -CH20R2, -CORZ, -CO2R2, or —CONR3R4;
R! is OH, -O-(C;-Ce)alkyl, (C3-Cr)cycloalkyl, (C3-Cr)heterocycloalkyl, (C+-C)cycloalkenyl, (C4+-Co)heterocycloalkenyl, aryl, monocyclic heteroaryl, or — NR3R4, wherein R3 and R#4 are independently H, (C:i-Ce)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl, aralkox ycarbonyl, -SO»alkyl, or joined together to form a saturated or unsaturated 5 to 7 membered ring;
R2 is H or (C;-C)alkyl; and
R3 and R4 are independently H, (C,-Ce)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl, aralkoxycarbonyl, -SOzalkyl, or joined together to form a 5 to 7 membered ring;
R'? and R™ are each independently H, halo, (C;-Ce)alkyl, or halo(C;-
Ce)alkyl, or (C;-Cs)alkoxy;
R" and R' are each independently H, halo, alkyl, or haloalkyl, or NR'R’ wherein R® and R® are as defined for R® and RY
X and Y are each independently C or N, provided that when one of X or Y isN, R14 or
R15 is absent at that position.
What is also provided is a compound of Formula vi
Claims (28)
1. A compound of Formula I: A oy N- N ~ NH S B J 1 or a pharmaceutically acceptable salt thereof wherein: A is aryl or substituted aryl or monocyclic heteroaryl or substituted monocyclic heteroaryl; ? ? B is -NH—C— (C;-Cg)alkyl, -NH —C— (C3-C7)cycloalkyl, - 0 0 PY NH —C— O(C,;-Cs alkyl), R' | (C3-Cy)cycloalkyl, (Cs- Coheterocyclo, (Cs-Cy)cycloalkenyl, unsaturated (Cs-Cq)heterocyclo, aryl, or heteroaryl, any of which may be optionally substituted by halo, (C;-Ce)alkyl, or halo(C;-Cg)alkyl, O-(C;-Cs), -CN, haloalkyl, amino, alkylamino, amidino, amido, or sulfonamido; C is phenyl or heteroaryl, wherein phenyl or heteroaryl is optionally substituted with one or more substituents selected from aryl, heteroaryl, halogen, hydroxy, -COR2, -CORZ2, -CONR2R?2’, alkoxy, alkyl, -CN, haloalkyl, amino, alkylamino, amidino, amido, or sulfonamido; G is H, halo, (C;-Cg)alkyl, halo(C,-C¢)alkyl, hydroxy(C,-C¢)alkyl, -CH,0-(C;-Cg)alkyl, -CH2-CO»(C;-Cg)alkyl, -CH,-NR2R2’, or -CHy- CONH(C,-Cg)alkyl; W1 is a saturated or unsaturated, substituted or unsubstituted hydrocarbon ~ LU chain or hydrocarbon-heteroatom chain having from 2 to 6 atoms, wherein W! . connects the nitrogen atom at position 1 to the carbon atom at position 2 to form a four to eight membered ring; ) Rlis (C,-Ce)alkoxy, (C3-Cy)cycloalkyl, (Cs-Cy)heterocycloalkyl, (Cs- Gycycloalkenyl, (C4-Co)heterocycloalkenyl, aryl, monocyclic heteroaryl, or — NR3R4, R2 and R2’ are each independently H or (C,-Cg)alkyl; and R3 and R4 are each independently H. (C;-Cg)alkyl. aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl, aralkoxycarbonyl, -SO»alkyl, or joined together to form a saturated or unsaturated 3 to 7 membered ring.
2. A compound of formula IV: rR" ’ LY a G H x! N Ny X R15 > A © / HN o i» A= B ZN, RPE SX R13 Iv : or a pharmaceutically acceptable salt thereof wherein “---"is a bond or is absent; Z is C-H, C-halo, C-(C;-Cg)alkyl, C-halo(C,-Cs)alkyl, C-(C;-Cg)alkoxy, or : N; X"is CH,, CH, NH or N; 10 Rand R' are each independently H, -OH, halo, alkyl, haloalkyl, - NR8RY, -OR2, CN, -CH2OH, -CH-NR3R4, aryl, monocyclic heteroaryl, )
-328- ® alkylaryl, -CH=0, -CH,OR?2, -CORZ, -CO2R2, or -CONR3R# or are taken together to form =O, =NOR2, =C(C1-Cgalkyl)s, or =CRZH, with the proviso that when “---" is a bond, R'" is absent, and X"is CH or N, and R'’ is H, -OH. halo, alkyl, haloalkyl, -NR8R?, -ORZ, -CN, -CH,OH, -CHp-NR3R4, aryl, monocyclic heteroaryl, alkylaryl, -CH=0, -CHpOR2, -CORZ, -CO7RZ2, or -CONR3R4: ? ? B is -NH —C—(C,-C¢)alkyl, -NH —C— (C;-C)cycloalkyl -NH(C;- 0 Ce)alkanoyl, PN R' | (C3-Cy)cycloalkyl, (C3-Co)heterocycloalkyl, (Cs- Cy)eycloalkenyl, (Cs-Coheterocycloalkenyl, aryl, or heteroaryl, any of which may be optionally substituted, wherein Rlis (C1-Ce)alkoxy, (C3-Cr)cycloalkyl, (Ca- Cyheterocycloalkyl, (Cs-Co)cycloalkenyl, (C4-Co)heterocycloalkenyl, aryl, monocyclic heteroaryl, or ~NR3R4; G is H, halo, (C;-Cg)alkyl, halo(C;-Cs)alkyl, hydroxy(C;-Cg)alkyl, -CH,0-(C,-Ce)alkyl, -CH>-CO»(C;-Cs)alkyl, -CH,-CONH,, or -CH,-CONH(C;- Coyalkyl; R2 and R?’ are each independently H or (C;-Ce)alkyl; and R3 and R4 are independently H, (C;-Cg)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl, aralkoxycarbonyl, -SO»alkyl, or joined together to form a saturated or unsaturated 5 to 7 membered ring; R” and R" are each independently H, halo, (C;-Cg)alkyl, or halo(C;- Cgalkyl, or (C,;-Ce)alkoxy; rR" and R" are each independently H, halo, alkyl, or haloalkyl, or NR'R’ wherein R® and R® are as defined for R® and RY, X and Y are each C, or one of X and Y is C and the other is N, provided that when one of X or Y is N, R14 or R15 is absent at that position. ‘
3. The compound of claim 2, wherein B is
LL Lr nq R", wherein “~~ " indicates the point of attachment. : Q is NH or is absent; and wherein R' is OH, —0O-(C;-Cg), or NR3'R¥’, wherein R3” and R4’ are independently H, (C,-Cg)alkyl, or are joined together to form a optionally substituted saturated or unsaturated 5 to 7 membered ring;
N red ok , wherein “~~” indicates the point of attachment, or B is optionally substituted phenyl or pyridyl with formyl, H,NSO,, MeSO,, MeSO, Mes, (C1-Cé6)alkoxycarbonyl, cyano, aminomethyl, methoxy, or hydroxy; fo} A J) RY , wherein “~~~” indicates the point of attachment and which is an optionally substituted 4, 5, 6 or 7-membered ring; wherein R* and R” are H, halo, (C;-Cg)alkyl, (C,-Cs)alkoxy, or (C;-Cg)carboxyalkyl, or taken together are O=; X™ is CH, CH-OH, CH-CO,(C;-Cg)alkyl, O, S, NH, or N(C;- Ce)alkyl, provided that when R* and R taken together are O=, XW is CH,. provided that when R* and R” taken together are O=, X'!! is CH; ° : My a J R' or a tautomer thereof, wherein Y" is CH, CH(C,-Cg)alkyl, or N and R'® is H, (C;-Cg)alkyl, hydroxymethyl, CH,0-(C,-Ce)alkyl, CONR?RZ, or CH,NR’R?,
-330- ® a 5-membered heteroaryl ring which contains at least one nitrogen atom, which is selected from imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, any of which may be optionally substituted with halo, (C;-Cs)alkyl, hydroxy(C;-Ce)alkyl, CH,0-(C;- “A Py Cealkyl, or halo(C;-Ce)alkyl, or is R'™ Z| wherein “~~ ” indicates the point of attachment; X® Y?, and Z° are each independently CR® or N, wherein R° is H or (C;-Ce)alkyl; and R'® is H, (C1-Cs)alkyl, hydroxymethyl, CH,0-(C;- Ce)alkyl, or NR3R4; 0 w ro” Ir Le Lo , wherein “~~” indicates the point of attachment; 11, Ia, Ja, and J4 are each C, or any of Jy, Jz, J3, or J4 is N; and RY, RZ, R*, and R* are each independently H, halo, hydroxy, NH, NRZR*, NOs, SH, (C,-Ce)alkyl, halo(C;-Ce)alkyl, (C;-Cs)alkanoyl, (Ci-Cs)alkoxycarbonyl, or (C;-Ce)alkoxy, wherein R23 and R24 are each independently H, (C;-Cg)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl, aralkoxycarbonyl, -SOzalkyl, or joined together to form a saturated or unsaturated 3 to 7 membered ring, or R' and R%, R? and R*, or R* and R*, together with the carbons to which they are attached, form a 5, 6, or seven membered saturated or unsaturated cycloalkyl or heterocycloalkyl ring, or an aryl or heteroaryl ring; provided that when any of J;, J, Js or Jais N, R™, R?, R¥ or R%, respectively, is absent at that position.
4. A compound which is: Pyrrolidine- 1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(3- fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide}; i
° WO 03/045912 PCT/1B02/04757
Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(3- E fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; “ae Pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin-2-yl)-amide] 2-[(3- : flnoro-2'-suifamoyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(2,4-difluoro-phenyl)-amide] 2-[{(3- fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2'-sulfamoyl-bipheny!-4- yl)-amide] 1-p-tolylamide; Pyrrolidine-1,2-dicarboxylic acid 2-{(3-fluoro-2'-sulfamoyl-biphenyl-4- yl)-amide] 1-[(4-methoxy-phenyl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-bromo-phenyl)-amide] 2-[(3- fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2'-sulfamoyl-biphenyl-4- yl)-amide] 1-[(4-isopropyl-phenyl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 2-{(3-fluoro-2'-sulfamoyl-biphenyl-4- yl)-amide] 1-phenylamide; Pyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2'-sulfamoyl-biphenyl-4- yl)-amide] 1-[(4-trifluoromethyl-phenyl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2'-sulfamoyl-biphenyl-4- yl)-amide] 1-[(3-methoxy-phenyl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin-2-yl)-amide] 2-[(3- fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(3- fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-ethyl-phenyl)-amide] 2-[(3-fluoro- 2'-sulfamoyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(3,4-difluoro-phenyl)-amide] 2-[(3- fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; : Pyrrolidine-1,2-dicarboxylic acid 1-[(3-fluoro-4-methyl-phenyl)-amide] 2- [(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[5-(2- sulfamoyl-phenyl)-pyridin-2-yl}-amide};
Pyrrolidine-1,2-dicarboxylic acid 2-[(3-chioro-2"-methanesulfonyl- biphenyl-4-yl)-amide] 1-[(5-chloro-pyridin-2-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyi)-amide] 2-[(3- eo. fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 2-[(3-chloro-2"-methanesulfonyl- biphenyl-4-yl)-amide] 1-[(4-chloro-phenyl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1 -[(5-chloro-pyridin-2-yl)-amide] 2-{[5- (2-sulfamoyl-phenyl)-pyridin-2-yl]-amide} ; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-pheny})-amide] 2-{[4-(1H- tetrazol-5-yl)-phenyl}-amide}; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1- [(4-chloro-phenyl)-amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Methoxy-pyrrolidine- 1 ,2-dicarboxylic acid 1-{(4-chloro-phenyl)-amide] 2-[(3-fluoro-2"-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2- [(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]: 4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(3-fluoro-2"-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2- [(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; 4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(3-fluoro-2-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2- [(3-fluoro-2"-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(3-fluoro-2-methanesulfonyl-biphenyl-4-yl)-amide]; 1 =(4-Chloro-phenylcarbamoyl)-5-(3-fluoro-2'-methanesulfonyl-biphenyl- 4-ylcarbamoyl)-pyrrolidine-3-carboxylic acid; : 1 ~(4-Chloro-phenylcarbamoyl)-5-(3-fluoro-2'-methanesulfonyl-biphenyl- 4-ylcarbamoyl)-pyrrolidine-3-carboxylic acid methyl ester;
A -333- Pyrrolidine-1.2,4-tricarboxylic acid 4-amide 1-[(4-chloro-phenyl)-amide] L 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]); < 4-Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- : amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Methoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2- [(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Methylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Acetylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-{(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Methanesulfonylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- : phenyl)-amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; 5-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2- [(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; Piperidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(3-fluoro- 2'-methanesulfonyl-biphenyl-4-yl)-amide]; Morpholine-3,4-dicarboxylic acid 4-[(4-chloro-phenyl)-amide] 3-((3- fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; Piperazine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(3-fluoro- 2'-methanesulfonyl-biphenyl-4-yl)-amide]; 2,5-Dihydro-pyrrole-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2- [(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2'- methanesulfonyl-3-methyl-biphenyl-4-yl)-amide]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2'-methanesulfonyl-3-methyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2- methanesulfonyl-biphenyl-4-yl)-amide]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2-methanesulfonyl-biphenyl-4-yl)-amide];
-334- ® Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{ [5-(2- methanesulfonyl-phenyl)-pyrimidin-2-yl}-amide}; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] ©. 2-{ [5-(2-methanesulfonyl-phenyl)-pyrimidin-2-yl]-amide }; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{ [5-(2- methanesulfonyl-phenyl)-3-methyl-pyridin-2-yl]-amide 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1 -[(4-chloro-phenyl)-amide] 2-{ [5-(2-methanesulfonyl-phenyl)-3-methyl-pyridin-2-yl]-amide } ; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2'- methanesulfonyl-3-trifluoromethyi-biphenyl-4-yl)-amide]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2'-methanesulfonyl-3-trifluoromethyl-biphenyl-4-yl)-amide}; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{ [5-(2- methanesulfonyl-phenyl)-6-methyl-pyridin-2-yl}-amide}; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1 -[(4-chloro-phenyl)-amide] 2-{[5-(2-methanesulfonyl-phenyl )-6-methyl-pyridin-2-yl]-amide}; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(3-ethyl- 2'-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chioro-phenyl)-amide] 2-[(3-ethyl-2"-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(3,5-difluoro-2'-methanesulfonyl-biphenyl-4-y1)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{(3,5- dichloro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Hydroxy-pyrrolidine-1.2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(3,5-dichloro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2'- methanesulfonyl-3,5-dimethyi-biphenyl-4-yl)-amide]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4~chloro-phenyl)-amide] 2-[(2'-methanesulfonyl-3,5-dimethyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 2-[(3-chloro-2'-methanesulfonyl-5- methyl-biphenyl-4-yl)-amide] 1-[(4-chloro-phenyl)-amide];
4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-[(3-chloro-2'- ' methanesulfonyl-5-methyl-biphenyl-4-yl)-amide] 1-[(4-chloro-phenyl)-amide]; <b Pyrrolidine-1.2-dicarboxylic acid 2-[(2-chloro-2'-methanesulfonyl- : biphenyl-4-yl)-amide] 1-[(4-chloro-phenyl)-amide]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-{(2-chloro-2'- methanesulfonyl-biphenyl-4-yl)-amide] 1-[(4-chloro-phenyl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2'- methanesulfonyl-2-methyl-biphenyl-4-yl)-amide}]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2'-methanesulfonyl-2-methyl-biphenyl-4-yl)-amide}; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2- fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide}; 4-{[1-(4-Chloro-phenylcarbamoyl)-pyrrolidine-2-carbonyl]-amino}-2'- methanesulfonyl-biphenyl-3-carboxylic acid methyl ester; 4-{[1~(4-Chloro-phenylcarbamoyl)-4-hydroxy-pyrrolidine-2-carbonyl]- amino }-2'-methanesulfonyl-biphenyl-3-carboxylic acid methyl ester; Pyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2'-sulfamoyl-biphenyl-4- yl)-amide] 1-[(4-trifluoromethyl-phenyl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2'-sulfamoyl-biphenyl-4- yl)-amide] 1-m-tolylamide; Pyrrolidine-1,2-dicarboxylic acid 1-[(3-acetyl-phenyl)-amide] 2-[(3- fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]); Pyrrolidine-1.2-dicarboxylic acid 1-[(5-chloro-2-methyl-phenyl)-amide] 2- [(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(2-fluoro-phenyl)-amide] 2-((3- fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; ' Pyrrolidine-1,2-dicarboxylic acid 1-[(3-chloro-4-fluoro-phenyl)-amide] 2- [(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(3-chloro-phenyl)-amide] 2-[(3- fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide];
-336- ® Pyrrolidine-1,2-dicarboxylic acid 1-[(4-cyano-phenyl)-amide] 2-[(3- fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-2-methyl-phenyl)-amide] 2- : [(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(3,4-dichloro-phenyl})-amide] 2-[(3- fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2'-sulfamoyl-biphenyl-4- yl)-amide] 1-[(3-trifluoromethyl-phenyl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-dimethylamino-phenyl)-amide] 2- [(3-fluoro-2'-sulfamoyi-biphenyl-4-yl)-amide]; (28)-Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide) 2-[(3- fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide); Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(4- : cyano-phenyl)-amide]; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-|(3-fluoro-2'- methanesulfonyl-biphenyl-4-yl)-amide] 1-[(4-fluoro-phenyl)-amide]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin-2-yl)- amide] 2-[(3-fluoro-2’-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2'- methanesulfonyl-biphenyl-4-yl)-amide] 1-p-tolylamide; 4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2- {(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; and 4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2- [(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; or a pharmaceutically acceptable salt thereof.
5. A compound which is: (R)-Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(3- fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide];
PS WO 03/045912 PCT/IB02/04757
. (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(3- fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; - (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; (2R,4S)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide}; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2" methanesulfonyl-biphenyl-4-yl)-amide] 1-[(4-fluoro-phenyl)-amide]; (2R 4R)-4-Hydroxy-pyrrolidine-1.2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]: (2R ,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-{(3-fluoro-2'- methanesulfonyl-biphenyl-4-yl)-amide] 1-p-tolylamide; (2R)-4-Oxo-pyrrolidine-1.2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; and (2R ,4S)-4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide];or a pharmaceutically acceptable salt thereof.
6. A compound which is: (2R ,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide); (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(2-oxo-piperidin-1-yl)-phenyl]-amide}; (2R 4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- . phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phen yl}-amide}; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1 -yD)-phenyl}-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-([2-fluoro-4-(2-oxo-piperidin-1 -yl)-phenyl}-amide};
-338- ® ) (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin- 2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl}-amide}; (2R 4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl}-amide}; (2R 4R)-4-Propoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl}-amide}; (2R 4R)-4-Propoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin- 2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1 -yl)-phenyl}-amide}; (2R,4R)-4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-{ [2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-azetidin-1-yl)-phenylj-amide}: (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(5-chloro- pyridin-2-yl)-amide] 2~{ [2-fluoro-4-(2-oxo-azetidin-1-yl)-phenyl]-amide }; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide}; (2R ,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chioro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(2-oxo-pyrrolidin-1-yl)-phenyl}-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-azepan-1-yl)-phenylj-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(2-oxo0-azepan-1-yl)-phenyl] -amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [4-(2-oxo0-2H-pyridin-1-yl)-phenyl}-amide (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(2-oxo-2H-pyridin-1 -yl)-phenyl}-amide}; (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin- . 2-yl)-amide] 2-{ [2-fluoro-4-(2-oxo-2H-pyridin-1 -yl)-phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(2-hydroxymethyl-5-oxo-pyrrolidin-1-yl)-phenyl}- amide};
° WO 03/045912 PCT/1B02/04757 ) (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chioro- phenyl)-amide] 2-{ [4-(2,3-dimethyl-5-0x0-2,5-dihydro-pyrazol-1-yl)-phenyl]- . amide}; ' 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[4-(2-hydroxymethyl-pyrrolidin-1-yl)-phenyl]}-amide}; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(4-pyrrolidin-1-yl-phenyl)-amide]; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(4-pyrazol-1-yl-phenyl)-amide]; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(2-fluoro-4-pyrazol-1-yl-phenyl)-amide}; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(4-[1,2,4]triazo}-1-yl-phenyl)-amide]; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(4-[1 ,2,3triazol-2-yl-phenyl)-amide]; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(4-[1,2,3]triazol-1-yl-phenyl)-amide];
(2R.4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-[(4-acetylamino- phenyl)-amide] 1-[(4-chloro-phenyl)-amide}]; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(cyclopentanecarbonyl-amino)-phenyl}-amide}; and 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(4-pyrimidin-5-yi-phenyl)-amide}; or a pharmaceutically acceptable salt thereof.
7. A compound which is: . 1-(4-Chloro-phenylcarbamoyl)-5-[2-fluoro-4-(2-oxo-piperidin-1-yl)- phenylcarbamoyl]-pyrrolidine-3-carboxylic acid; } 1-(4-Chloro-phenylcarbamoyl)-5-[2-fluoro-4-(2-oxo-piperidin-1-yl)- phenylcarbamoyl]-pyrrolidine-3-carboxylic acid methyl ester; 1-(4-Chloro-phenylcarbamoyl)-5-[2-fluoro-4-(2-oxo-piperidin-1-yl)- phenylcarbamoyl]-pyrrolidine-3-carboxylic acid ethyl ester;
-340- ® Pyrrolidine-1,2,4-tricarboxylic acid 4-amide 1-{(4-chloro-phenyl)-amide] R 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl}-amide }; 4-Cyano-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2- { [2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}: ’ 4-(1H-Tetrazol-5-yl)-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}; 4-Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-{[2-fluoro4-(2-oxo-piperidin-1-yl)-phenyl]-amide}; 4-Methylaminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}; 4-Dimethylaminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}; 4-Acetyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2- {[2-fluoro-4-(2-0xo-piperidin-1-yl)-phenyl}-amide}; Pyrrolidine-1,2,4-tricarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2- fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide} 4-methylamide; Pyrrolidine-1,2,4-tricarboxylic acid 1-[(4-chloro-phenyl)-amide] 4- dimethylamide 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}; 4-Trifluoromethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl}-amide}; 4-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2- {[2-fluoro~4-(2-oxo-piperidin-1-yl)-phenyll-amide}; 4-Isopropoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-{{2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}; 4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro-phenyl)-amide] 2- { [2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]l-amide}; 4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- : amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}; 1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl}- amino}-phenyl)-pyrrolidine-2-carboxylic acid; 1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-hydroxy-pyrrolidine-2-carbonyl}- amino }-phenyl)-pyrrolidine-2-carboxylic acid;
® WO 03/045912 PCT/IB02/04757
] 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin-2-yl)- : amide] 2-[(2-0x0-3,4,5,6-tetrahydro-2H-[1 ,3'Ibipyridinyl-6'-yl)-amide]; v 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2-0x0-3,4,5,6-tetrahydro-2H-[1 ,2'1bipyridinyl-5'-yl)-amide], 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin-2-yl)- amide] 2-{[5-(2-oxo-piperidin-1-yl)-pyrimidin-2-yl]-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin-2-yl)- amide] 2-{[2-(2-oxo-piperidin-1-yl)-pyrimidin-5-yl]-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[5-(2-oxo-piperidin-1 -yl)-pyrimidin-2-yl}-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-(2-oxo-piperidin-1-yl)-pyrimidin-5-yl}-amide} 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[2-fluoro-4-(2-oxo- piperidin-1-yl)-phenyl}-amide} 1 -[(5-fluoro-pyridin-2-yl)-amide]; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-fluoro-pyridin-2-yl)- amide] 2-[(2-oxo-3.4,5,6-tetrahydro-2H-[1 ,3'Ibipyridinyl-6'-yl)-amide]; 4-Methoxy-pyrrolidine-1.2-dicarboxylic acid 1-[(5-fluoro-pyridin-2-yl)- amide] 2-[(2-o0x0-3,4,5,6-tetrahydro-2H-[1 .2'Ibipyridinyl-5'-yl)-amide]; 4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2- [(2-0x0-3.4,5,6-tetrahydro-2H-[1,3"]bipyridinyl-6"-yl)-amide]; 4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-{(5-chloro-pyridin-2-yl)- amide] 2-[(2-0x0-3,4,5,6-tetrahydro-2H-[1 ,3'Ibipyridinyl-6'-yl)-amide]; 4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-{(5-fluoro-pyridin-2-yl)- amide] 2-[(2-0x0-3,4,5,6-tetrahydro-2H-[1 ,3'Ibipyridinyl-6'-yl)-amide]; 4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2- [(2-0x0-3 4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-amide); 4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin-2-yl)- amide] 2-[(2-ox0-3,4,5,6-tetrahydro-2H-[1 ,2'Ibipyridinyl-5'-yl)-amide}; 4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(5-fluoro-pyridin-2-yl)- amide] 2-[(2-0x0-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-amide]; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{ [2-fluoro-4-(2-hydroxymethyl-5-oxo-pyrrolidin-1-yl)-phenyl}-amide};
-342- ® 1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]- amino }-3-fluoro-phenyl)-5-oxo-pyrrolidine-2-carboxylic acid; 1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]- Co amino }-3-fluoro-phenyl)-5-oxo-pyrrolidine-2-carboxylic acid, 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[4-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-2-fluoro-phenyl]-amide}; [1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2- carbonyl]-amino }-3-fluoro-phenyl)-2,5-dioxo-imidazolidin-4-yl}-acetic acid, 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[4-(5,5-dimethyl-2,4-dioxo-oxazolidin-3-yl)-2-fluoro-phenyl]-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[4-(2,5-dioxo-pyrrolidin-1-yl)-2-fluoro-phenyl]-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-oxazolidin-3-yl)-phenylJ-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[4-(2,5-dioxo-oxazolidin-3-yl)-2-fluoro-phenyl}-amide } ; 4-Methoxy-pyrmrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-imidazolidin-1-yl)-phenyl]-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[4-(2,5-dioxo-imidazolidin-1-yl)-2-fluoro-phenyl]-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-phenyl}-amide}; 3-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]- amino }-3-fluoro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2,4,5-trioxo-imidazolidin-1-yl)-phenyl]-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[4-(2,5-diox0-2,5-dihydro-pyrrol-1-yl)-2-fluoro-phenyl]-amide }; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(2-aminomethyl-5- oxo-pyrrolidin-1-yl)-2-fluoro-phenyl]-amide} 1-[(4-chloro-phenyl)-amide]; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(2-aminomethyl-5- oxo-pyrrolidin-1-yl)-2-fluoro-phenyl}-amide} 1-[(4-chloro-phenyl)-amide];
A -343- 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(2-carbamoyl-5-0xo- pyrrolidin-1-yl)-2-fluoro-phenylj-amide} 1-[(4-chloro-phenyl)-amide]; . 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(2-carbamoyl-5-oxo- : pyrrolidin-1 _yl)-2-fluoro-phenyl}-amide} 1-{(4-chloro-phenyl)-amide]; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(2,2-bis- hydrox ymethyl-5-oxo-pyrrolidin-1-yl)-2-fluoro-phenyl}-amide} 1-{(4-chioro- phenyl)-amide): 3-(4-{[1-(4-Chiloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]- amino }-3-fluoro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[4-(3,3-dimethyl-2,5-dioxo-pyrrolidin-1-yl)-2-fluoro-phenyl]-amide} ; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(3,3,4-trimethyl-2,5-dioxo-pyrrolidin-1-yl)-phenyl]-amide } ; 1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]- amino}-3-fluoro-phenyl)-5-oxo-pyrrolidine-2,2-dicarboxylic acid; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-methyl-5-oxo-pyrrolidin-1-yl)-phenyl}-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-methyl-6-oxo-piperidin-1-yl)-phenyl}-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{ [2-fluoro-4-(3-hydroxy-2-oxo-piperidin-1-yl)-phenyl]-amide }; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(5-methyl-2,6-dioxo-tetrahydro-pyrimidin-1-yl)-phenyl}-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-tetrahydro-pyrimidin-1-yl)-phenyl]-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{ [2-fluoro-4-(3-methyl-2-oxo-2H-pyridin- 1-yl)-phenyl}-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] : 2-{[4-(2,5-dioxo-piperazin-1-yl)-2-fluoro-phenyl]-amide }; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{ [2-fluoro-4-(3-hydroxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide} ;
4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(3-methoxy-2-oxo-2H-pyridin- I -yl)-phenyl]-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] . 2-{ {2-fluoro-4-(6~methyl-2-oxo0-4-trifluoromethyl-2H-pyridin- 1-yl)-phenyl}- amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro-phenyl)-amide] 2-{[4-(2,6-dioxo-piperidin-1 -yD)-2-fluoro-phenyl}-amide}; 1-(4-{[1 -(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]- amino}-3-fluoro-phenyl)-2-oxo-piperidine-3-carboxylic acid; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid I-[(4-chloro-phenyl)-amide] 2-{ [4-(5,5-dihydroxy-2,4,6-trioxo-tetrahydro-pyrimidin-1 -yD)-2-fluoro-phenyl}- amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide) 2-{[2-fluoro-4-(2,4,6-trioxo-tetrahydro-pyrimidin- 1-yl)-phenyl}-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[4-(4,4-dimethyl-2,6-dioxo-piperidin-1 -yl)-2-fluoro-phenyl]-amide }; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide} 2-{[2-fluoro-4-(2-hydroxy-4-oxo-azetidin-1 -ybD-phenyl]-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{ [4-(acetyl-methyl-amino)- 2-fluoro-phenyl}-amide} 1-[(4-chloro-phenyl)-amide]; 4-(4-{ [1-(4-Chloro-phenylcarbamoy!)-4-methoxy-pyrrolidine-2-carbonyl}- amino }-3-fluoro-phenyl)-1H-pyrrole-3-carboxylic acid; 2-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl}- amino }-3-fluoro-phenyl)-2H-pyrazole-3-carbox ylic acid; 1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]- amino} -3-fluoro-phenyl)-1H-imidazole-2-carboxylic acid; 1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]- amino }-3-fluoro-phenyl)-1H-pyrrole-2-carboxylic acid; 3-(4-{ [1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]- amino}-3-fluoro-phenyl)-1H-pyrrole-2-carboxylic acid; 3-4-{[1 -(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]- amino }-3-fluoro-phenyl)-furan-2-carboxylic acid;
® WO 03/045912 PCT/1B02/04757 3-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]- oo amino } -3-fluoro-phenyl)-thiophene-2-carboxylic acid; . 4-(4-{[1 -(4-Chloro-phenylcarbamoyl)-4-methox y-pyrrolidine-2-carbonyl}- amino }-3-fluoro-phenyl)-furan-3-carboxylic acid; 4-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbon yl]- amino }-3-fluoro-phenyl)-thiophene-3-carboxylic acid;
4.5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4-chloro-phenyl)-amide} 5-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; 3-Oxo-pyrazolidine-1,5-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 5- [(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; 3-Oxo-pyrazolidine-1,5-dicarboxylic acid 1-{(4-chloro-phenyl)-amide] 5- {{2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}; 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] : 5-{[4-(2-oxo-piperidin-1-yl)-phenyl}-amide}; 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(S-chloro-pyridin-2-yl)- amide] 5-{[2-fluoro-4-(2-oxo-piperidin-1 -yl)-phenyl}-amide}; 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(S-chloro-pyridin-2-yl)- amide] 5-{[4-(2-oxo-piperidin-1-yl)-phenyl]-amide}; 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 5-[(2-0x0-3,4,5,6-tetrahydro-2H-{1,3']bipyridinyl-6"-yl)-amide]; 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(5-chloro-pyridin-2-yl)- amide] 5-{(2-ox0-3,4,5,6-tetrahydro-2H-[1 .3'Ibipyridinyl-6'-yl)-amide]; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin-2-yl)- amide) 2-[(3,5-difluoro-2'-sulfamoyl-biphenyl-4-yl)-amide}]; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(5'-fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide}; : 4-Methoxy-pyrrolidine-1.2-dicarboxylic acid 1-[(5-chloro-pyridin-2-y])- amide] 2-[(3,5"-difluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(3,5'-difluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(5'-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide];
-346- ® ) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(3,5'-difluoro-2'-methanesulfonyl-biphenyl-4-yl)-amidel; ) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin-2-yl)- amide] 2-[(3,5'-difluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{(3,5"-difluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide]} 2-[(3,5'-difluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide], or a pharmaceutically acceptable salt thereof.
8. A compound which is: (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(4-pyrazol-1-yl-phenyl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(2-fluoro-4-pyrazol-1-yl-phenyl)-amide]; (2R,4R)-4-Ethoxy-pyrrolidine-1.2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(2-fluoro-4-pyrazol-1-yl-phenyl)-amide]; (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-{(4-pyrazol-1-yl-phenyl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(3-methyl-pyrazol-1-yl)-phenyl}-amide}; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4~(5-methyl-pyrazol-1-yl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(5-methyl-pyrazol-1-yl)-phenyi]-amide}; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-amide }; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(3,5-dimethyl-pyrazol-1-yl)-2-fluoro-phenyl]-amide};
PY WO 03/045912 PCT/IB02/04757 i (2R,4S)-4- Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- : amide) 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide];
*. (2R 4R)-4- Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide} 2-[(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; (2R)-4-Hydroxyimino-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; (2R,4R)-4-Hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(3-fluoro-2'-methylsulfamoyl-biphenyl-4-yl)-amide}; (2R 4R)~4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(2'-dimethylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- : phenyl)-amide} 2-[(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(5-chloro-pyridin- 2-yl)-amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; (2R 4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(3-fluoro-2'-methanesuifonyl-biphenyl-4-yl)-amide]; (2R ,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; (2R,4S)-4-Methoxy-pyrrolidine- 1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{(3-fluoro-2"-methanesulfonyl-biphenyl-4-yl)-amide]: (2R,4R)-4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; (2R)-4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide}; (2R 4R)-4-Methoxy-pyrrolidine- 1,2-dicarboxylic acid 2-[(3-fluoro-2*- methanesulfonyl-biphenyl-4-yl)-amide] 1-[(4-fluoro-phenyl)-amide]; (2R,4R)-4-Acetylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide];
-348- ® (2R 4R)-4-Methanesulfonylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(4- chloro-phenyl)-amide] 2-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]: (2R,45)-4-(1H-Tetrazol-5-yl)-pyrrolidine-1,2-dicarboxylic acid 1-[(4- . chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}; (2R,4S)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2- {[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl}-amide }; (2R,4R)-4-Cyano-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl}-amide}; (2R,4R)-4-(1H-Tetrazol-5-yl)-pyrrolidine-1,2-dicarboxylic acid 1-[(4- chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl}-amide};
(2R.4R)-4-Trifluoromethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- : phenyl)-amide] 2-[(2'-cyano-3-fluoro-biphenyl-4-yl)-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-[(2'-aminomethyl- 3-fluoro-biphenyl-4-yl)-amide] 1-[(4-chloro-phenyl)-amide]; (2R,4R)-4'-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2- carbonyl]-amino }-3'-fluoro-biphenyl-2-carboxylic acid methyl ester; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{[4-(2,5-dihydro-pyrrole-1-carbonyl)-phenyl]}-amide}; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(4-dimethylcarbamoy]-2-fluoro-phenyl)-amide]; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(pyrrolidine-1-carbonyl)-phenyl}-amide}; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[4- (pyrrolidine-1-carbonyl)-phenyl}-amide}: (2R 4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- : phenyl)-amide] 2-{[4-(2-methyl-pyrrolidine-1-carbonyl)-phenyl]-amide}; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- ’ phenyl)-amide] 2-{[4-(ethyl-methyl-carbamoyl)-phenyl]-amide}; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-[(4-dimethylcarbamoyl-phenyl)-amide};
® WO 03/045912 PCT/IB02/04757
. (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- 0 phenyl)-amide] 2-{[4-(2R-methyl-pyrrolidine-1 -carbonyl)-phenyl}-amide} ; » (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[{(4-chloro- phenyl)-amide] 2-{[4-(2S-methyl-pyrrolidine-] -carbonyl)-phenyl}-amide } ; (2R 4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(pyrrolidine-1 -carbonyl)-phenyl}-amide}; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(pyrrolidine-1 -carbonyl)-2-pyrrolidin-1-yl-phenyl]-amide}; (2R,4R)-4-{ [1-(4-Chloro-phenylcarbamoyl)-4-hydroxy-pyrrolidine-2- carbonyl]}-amino}-3-pyrrolidin-1-yl-benzoic acid methyl ester; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(azetidine-1- carbonyl)-phenyl]-amide} 1-[(4-chloro-phenyl)-amide}; (2R 4R)-4-Hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[2-fluoro-4-(pyrrolidine-1 -carbonyl)-phenyl]-amide}; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[4-(pyrrolidine-1 -carbonyl)-phenyl}-amide}; (2R 4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-[(4-dimethylcarbamoyl-phenyl)-amide]; (2R 4R)-4-{[1-(4-Chloro-phenylcarbamoyl)-4-hydroxy-pyrmolidine-2- carbonyl]-amino}-3-dimethylamino-benzoic acid methyl ester; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(pyrrolidine-1 -carbonyl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(4-dimethylcarbamoyl-phenyl)-amide]; (2R 4R)-4-Ethoxy-pyrrolidine-1.2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2- { [4-(pyrrolidine-1-carbonyl)-phenyl]-amide}; (2R 4R)-4-Ethoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(4-dimethylcarbamoyl-phenyl)-amide]; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl}-amide}; (2R 4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-{ [2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl]-amide};
~350- ® (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(4-dimethylcarbamoyl-2-fluoro-phenyl)-amide]; ) (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-([2-methyl-4-(2-oxo-piperidin-1-yl)-phenyl}-amide}; : (ZR 4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-{[2-methyl-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2- fluoro-4-quinolin-8-yl-phenyl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(3,5- difluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2'- methanesulfonyl-2-methyl-biphenyl-4-yl)-amide]; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(2'-methanesulfonyl-biphenyl-4-yl)-amide]; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(2'-methanesulfinyl-biphenyl-4-yl)-amide]; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(3-methyl-2'-methylsulfanyl-biphenyl-4-yl)-amide]; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-[(2-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; (2R ,4R)-4-Hydroxy-pyrrolidine- 1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-[(2'-methanesulfonyl-3-methyl-biphenyl-4-yl)-amide];
(2R.4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-[(2'-methanesulfonyl-3-trifluoromethyl-biphenyl-4-yl)-amide]; 5-Methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 5-[(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; 3-Hydroxymethyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4- chloro-phenyl)-amide] 5-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide]; 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] ’ 5-[(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; (R) 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 5-[(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide];
® WO 03/045912 PCT/1B02/04757
4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] . 5-{ [2-fluoro-4-(2-oxo-piperidin-1 -yl)-phenyl]-amide}; - 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] ’ 5-[(3-fluoro-2'-methanesulfonyl-biphenyl-4-yl)-amide}; 1 -(4-Chloro-phenylcarbamoyl)-5-(3-fluoro-2'-methanesulfonyl -biphenyl- 4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester; (2R ,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-[(2'-methoxy-biphenyl-4-yl)-amide]; (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-[(2'-hydroxy-biphenyl-4-yl)-amide]; : (2R,4R)-4-Methoxy-pyrrolidine- 1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(2-fluoro-4-iodo-phenyl)-amide]; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(3-hydroxy-2-oxo-piperidin-1 -yl)-phenyl}-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-tetrahydro-pyrimidin-1-yl)-phenyl]-amide 1 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-imidazolidin-1 -yl)-phenyl]-amide}; (2R ,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-oxazolidin-3-yl)-phenyl]-amide} ; (2R,4R)-1-(4-{[1 -(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2- carbonyl]-amino }-3-fluoro-phenyl)-2-oxo-piperidine-3-carboxylic acid ethyl ester; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(3-methoxy-2-oxo-2H-pyridin-1 -yl)-phenyl]- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(3-methoxy-2-oxo-2H-pyridin-1-yl)-phenyl}- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(5-chloro- pyridin-2-yl)-amide] 2-{ [4-(3-methyl-2-oxo0-2H-pyridin-1-yl)-phenyl}-amide};
-352- ® ) (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(4-morpholin-4-yl-phenyl)-amide}; ) (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chioro- . phenyl)-amide] 2- { [4-(2-methyl-5-oxo-pyrrolidin-1-yl)-phenyl]-amide}; : (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ {4-(2-methyl-5-oxo-pyrrolidin-1-yl)-phenylj-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(4-methoxy-2-oxo-2H-pyridin-1-yl)-phenyl}- amide}; : (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(4-methoxy-2-oxo-2H-pyridin-1-yl)-phenyl}- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(5-chloro-2- oxo-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide} 1-[(4-chloro-phenyl)-amide}; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-[(4-tert-butyl-phenyl)- amide] 1-[(4-chloro-phenyl)-amide]; 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4~chloro-phenyl)-amide] 2{(3,5'difluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2-0x0-3,4,5,6-tetrahydro-2H-[1,2'Ibipyridinyl-5'-yl)-amide]; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide} 2-[(2-0x0-3,4,5,6-tetrahydro-2H-[1 ,3bipyridinyl-6'-yl)-amide]; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin-2-yl)- amide] 2-{[4-(2,3-dimethyl-5-0x0-2,5-dihydro-pyrazol-1 -yl)-phenyl}-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[4-(2,3-dimethyl-5-0x0-2,5-dihydro-pyrazoil-1 -yl)-phenyl}-amide}; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-[(2-0x0-2H-[1,3'Ibipyridinyl-6'-yl)-amide]; 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(5-chloro-pyridin-2-y})- ’ amide] 2-[(2-0x0-3,4,5,6-tetrahydro-2H-{1,3']bipyridinyl-6'-yl)-amide]-TFA Salt; 4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2- [(2-0x0-3,4,5 6-tetrahydro-2H-[1,3']bipyridinyl-6'-yl)-amide];
® WO 03/045912 PCT/IB02/04757
} 4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2- : [(2-0x0-2H-{1,3"Tbipyridinyl-6'-yl)-amide]; or : 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(6-oxo0-6H-pyridazin-1 -yl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(6-methyl-5-oxo0-SH-[1 2,4]triazin-4-yl)-phenyl]- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 2-{[4-(3-chloro-5- methyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phen yl]-amide} 1-[(4-chloro-phenyl)- amidel; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(3-methyl-5-0x0-4,5-dihydro-pyrazol-1 -yl)-phenyl}-amide}; (2R ,4R)-4-Methoxy-pyrrolidine-1 2-dicarboxylic acid 2-{ {4-(5-chloro-3- methyl-2-oxo-2H-pyridin-1 -yl)-2-fluoro-phenyl}-amide} 1 -[(4-chloro-phenyl)- amide]; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(3,5-dimethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl}- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(5-methoxy-2-oxo-2H-pyridin-1 -y!)-phenyl}- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-3-pyrrol-1-yl-2H-pyridin- 1-yD)-phenyl]- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-ox0-3-phenyl-2H-pyridin-1 -yl)-phenyl}-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(3-methyl-2-oxo-pyrrolidin- 1-yl)-phenyl]-amide}; ) (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(3-methyl-2-oxo-imidazolidin-1-yl)-phenyl}- amide};
-354- ® (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(3,5-dimethyl-2-oxo-imidazolidin-1-yl)-2-fluoro-phenyl]- . amide}; p
(2R.4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- . phenyl)-amide] 2-{ [2-fluoro-4-(3,5,5-trimethyl-2-oxo-imidazolidin-1-y1)-phenyl]- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(3-isopropyl-5,5-dimethyl-2-oxo-imidazolidin-1- yl)-phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(5-methyl-2-oxo-imidazolidin-1-y})-phenyl}- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(5,5-dimethyl-2-oxo-imidazolidin- 1-yl)-2-fluoro-phenyl}- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(3 ,4-dimethyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 2-{ [4-(4-chloro-2- oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]}-amide} 1-[(4-chloro-phenyl)-amide]; (2R 4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(3-methyl-2-oxo-pyrrolidin-1 -yl)-phenyl]- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(3-methyl-2-oxo-imidazolidin-1 -yl)-phenyl]- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(5-chloro- : pyridin-2-yl)-amide] 2-{{4-(3 ,5-dimethyl-2-oxo-imidazolidin-1 -yl)-2-fluoro- phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(3,5,5-trimethyl-2-oxo-imidazolidin-1-y1)- phenylj-amide};
Ps WO 03/045912 PCT/IBO2/04757
. (2R,4R)-4-Methoxy-pyrrolidine-1 .2-dicarboxylic acid 1-[(5-chloro- : pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(3-isopropyl-5,5-dimethyl-2-oxo- : imidazolidin-1-yl)-phenyl}-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(5-methyl-2-oxo-imidazolidin-1-yl)-phenyl]- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1 .2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [4-(5,5-dimethyl-2-0x0-imidazolidin-1-yl)-2-fluoro- phenyl}-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [4-(3,4-dimethyl-2-ox0-2H-pyridin-1-yl)-2-fluoro- phenyl]-amide} ; (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 2-{[4-(4-chloro-2- oxo-2H-pyridin-1 -yl)-2-fluoro-phenyl]-amide} 1-[(5-chioro-pyridin-2-yl)-amide]; or a pharmaceutically acceptable salt thereof.
9. A compound which is: (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-ox0-2H-quinolin- 1-yl)-phenyl}-amide} ; (2R ,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(3-oxo-3H-isoquinolin-2-y})-phenyi}-amide }s (2R ,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(1 -oxo-1H-isoquinolin-2-yl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(5-oxo-SH-[1 ,2,4)triazin-4-yl)-phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- : phenyl)-amide] 2-{ [2-fluoro-4-(6-oxo-6H-pyrimidin-1-yl)-phenyl}-amide : 2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-2H-pyrazin-1 -yl)-phenyi}-amide}; (ZR 4R)- 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-2H-pyrimidin-1 -yl)-phenyl}-amide};
-356- ® ) (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-2H-[1,3,5]triazin-1-yl)-phenyl]-amide}; ) (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- ; phenyl)-amide] 2-[(6-methyl-2-ox0-2H-[1,3']bipyridinyl-6'-yl)-amide]; . (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-phenyl]-amide }; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(1-methyl-1H-pyrrol-2-yl)-phenyl]-amide}; (2R,4R)-5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-[(4-chloro- phenyl)-amide] 6-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridine-1-carbonyl)-phenyl]-amide }; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(3-methyl-3H-imidazol-4-yl)-phenyl}-amide } ; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(2-methyl-2H-pyrazol-3-yl)-phenyl}-amide } ; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{[5-(2,5-dihydro-pyrrole-1-carbonyl)-pyridin-2-yl]-amide }; (2R,4R)- 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(3-methyl-5-0x0-2,5-dihydro-pyrazol-1-yl)- phenyl}-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chioro- phenyl)-amide] 2-{[2-fluoro-4-(5-methoxymethyl-3-methyl-pyrazol-1-yl)- phenyl}-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(3-methoxymethyl-5-methyl-pyrazol-1-yl)- phenylj-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(5-ethyl-3-methyl-pyrazol-1-yl)-phenyl}-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(5-isobutyl-3-methyl-pyrazol-1-yl)-phenyl]- amide}; :
® WO 03/045912 PCT/IB02/04757
. (2R ,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- Lo phenyl)-amide] 2-{ [2-fluoro-4-(5-isopropyl -pyrazol-1-yl)-phenyl]-amide}; s (2R 4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(5-ethyl-pyrazol-1 -yl)-phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(5-isobutyl-pyrazol-1 -yl)-phenyl}-amide}; (2R,4R)-2-(4-{ [1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolodine-2- carbonyl}-amino}-3-fluoro-phenyl)-2H-pyrazole-3-carboxylic acid methyl ester; (2R,4R)-2-(4-{ [1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolodine-2- carbonyl}-amino}-3-fluoro-phenyl)-2H-pyrazole-3-carboxylic acid; (2R 4R)-4-Methoxy-pyrrolidine-1 .2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(5-methoxymethyl-pyrazol-1 -yl)-phenyl]-amide }; (2R,4R)-5-(4-{[1-(4-Chloro-phen ylcarbamoyl)-4-methoxy-pyrrolidine-2- : carbonyl]-amino}-3-fluoro-phenyl)-oxazole-4-carboxylic acid ethyl ester; (2R,4R)-5-(4-{[1-(4-Chloro-phen ylcarbamoyl)-4-hydroxy-pyrrolidine-2- carbonyl]-amino} -3-fluoro-phenyl)-oxazole-4-carboxylic acid ethyl ester; (2R,4R)-5-(4-{ [1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2- carbonyl]-amino }-3-fluoro-phenyl)-oxazole-4-carboxylic acid; (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ (2-fluoro-4-(4-methoxymethyl-oxazol-5-yl)-phenyl]-amide} : (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(4-ethyl-oxazol-5-y])-2-fluoro-phenyl]-amide} ; (2R 4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(4-isopropyl-oxazol-5-yl)-phenyl]-amide) ; (2R,4R)-5-(6-{[1-(4-Chloro-phen ylcarbamoyl)-4-methoxy-pyrrolidine-2- carbonyl]-amino }-pyridin-3-yl)-oxazole-4-carboxylic acid ethyl ester; : (2R,4R)-5-(6-{[1 -(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2- carbonyl]-amino } -pyridin-3-yl)-oxazole-4-carboxylic acid; ) (2R 4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [5-(4-methoxymethyl-oxazol-5-yl)-pyridin-2-yl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [5-(4-ethyl-oxazol-5-yl)-pyridin-2-yl]-amide};
-358- ® ) (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[5-(4-vinyl-oxazol-5-yl)-pyridin-2-yl]-amide}; ] (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[5-(4-isobutyl-oxazol-5-yl)-pyridin-2-yl}-amide}, (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(4-methyl-isoxazol-3-yl)-phenyl]-amide }; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(4-methyl-isoxazol-3-yl)-phenyl}-amide}; (2R,4R)-3-(4-{ [1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2- carbonyl}-amino}-3-fluoro-phenyl)-isoxazole-4-carboxylic acid methyl ester; (2R,4R)-3-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2- carbonyl]-amino }-3-fluoro-phenyl)-isoxazole-4-carboxylic acid, (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(4-methoxymethyl-isoxazol-3-yl)-phenyl]-amide}; (ZR 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(4-isopropyl-isoxazol-3-yl)-phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(4-cyclopropyl-isoxazol-3-yl)-phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(4-cyclopropyl-isoxazol-3-yl)-phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2- { [2-methyl-4-(2-0xo-2H-pyridin-1 -yl)-phenyl]-amide}; (2R 4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-{ [2-methyl-4-(2-ox0-2H-pyridin-1-yl)-phenyl}-amide}; (2R 4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin- 2-yl)-amide] 2-{[2-methyl-4-(2-oxo-2H-pyridin-1-yl)-phenyl}-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-[(4-chloro- : phenyl)-amide] 1-{{2,6-difluoro-4-(2-oxo-2H-pyridin-1 -yl)-phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-[(5-chloro- pyridin-2-yl)-amide] 1-{[2,6-difluoro-4-(2-oxo-2H-pyridin- 1-yl)-phenyl]-amide}; (2R 4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 2-[(4-chloro-phenyl)- amide] 1-{[2,6-difluoro-4-(2-0x0-2H-pyridin-1-yl)-phenyl}-amide};
- ® -359- (2R 4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 2-[(5-chloro-pyridin- ’ ) 2-yl)-amide] 1-{[2,6-difluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl}-amide}; . (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- : phenyl)-amide] 2-[(5'-methyl-2-oxo0-2H-[1,3']bipyridinyl-6'-yl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(5-chloro- pyridin-2-yl)-amide] 2-[(5'-methyl-2-ox0-2H-[1,3")bipyridinyl-6'-yl)-amide]; (2R 4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(5'-methyl-2-ox0-2H-[1,3']bipyridinyl-6'-yl)-amide]; (2R,4R)-4-Ethoxy-pyrrolidine-1.2-dicarboxylic acid 1-[(5-chloro-pyridin- 2-yl)-amide] 2-[(5"-methyl-2-oxo0-2H-[1,3"Jbipyridinyl-6'-yl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{(2'-methyl-2-oxo-2H-[1,3']bipyridinyl-6'-yl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(5-chloro- pyridin-2-yl)-amide] 2-[(2'-methyl-2-ox0-2H-[1,3']bipyridiny}l-6'-yl)-amide]; (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-[(2'-methyl-2-ox0-2H-[1,3']bipyridinyl-6"-yl)-amide]; (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin- 2-yl)-amide] 2-[(2'-methyl-2-oxo-2H-[1 3'Tbipyridinyl-6'-yl)-amide] ; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(ethyl-isopropyl-carbamoyl)-phenyl}-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(ethyl-isopropyl-carbamoyl)-2-fluoro-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(3-ethyl-pyrrolidine-1-carbonyl)-phenyl}-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(3-ethyl-pyrrolidine-1-carbonyl)-2-fluoro-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3R-amino- pyrrolidine-1-carbonyl)-phenyl}-amide} 1-[(4-chloro-phenyl)-amide]; : (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3R-amino- pyrrolidine-1-carbonyl)-2-fluoro-phenyl]-amide} 1-[(4-chloro-phenyl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3S-amino- pyrrolidine-1-carbonyl)-phenyl}-amide} 1-[(4-chloro-phenyl)-amide};
-360- ® (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3S-amino- pyrrolidine- 1-carbonyl)-2-fluoro-phenylj-amide} 1-[(4-chloro-phenyl)-amide]; : ’ (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(3R-methylamino-pyrrolidine-1-carbonyl)-phenyl]-amide}; : (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(3R-methylamino-pyrrolidine-1-carbonyl)-phenyl]- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(3S-methylamino-pyrrolidine-1-carbonyl)-phenyl}-amide }; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(3S-methylamino-pyrrolidine-1-carbonyl)-phenyi}- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- : phenyl)-amide] 2-{ [4-(3R-ethylamino-pyrrolidine-1 -carbonyl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(3R-ethylamino-pyrrolidine- 1-carbonyl)-phenyl}- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(3S-ethylamino-pyrrolidine-1-carbonyl)-phenylj-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(3S-ethy! amino-pyrrolidine-1-carbonyl)-phenyl]- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [4-(2,5-dihydro-pyrrole-1-carbonyl)-phenyl}-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(2,5-dihydro-pyrrole-1 -carbonyl)-2-fluoro-phenyl}-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [4-(2,5-dihydro-pyrrole-1-carbonyl)-2-fluoro-phenyl}- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(pyrrole-1 -carbonyl)-phenyl]-amide};
® WO 03/045912 PCT/IB02/04757 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- Lo phenyl)-amide] 2-{[2-fluoro-4-(pyrrole-1 -carbonyl)-phenyl]-amide}; 1 (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [4-(pyrrole-1-carbonyl)-phenyl]-amide}; S (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(pyrrole-1-carbonyl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(5-fluoro-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}; (2R,4R)-1-(4-{[1-(4-Chloro-phen ylcarbamoyl)-4-methoxy-pyrrolidine-2- carbonyl]}-amino}-3-fluoro-phenyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid; (2R,4R)-4-Methoxy-pyrrolidine- 1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(6-hydroxy-2-oxo-2H-pyridin-1 -yD-phenyl}- amide}; (2R,4R)-1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methox y-pyrrolidine-2- carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid; (2R 4R)-1-(4-{ [1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2- carbonyl]-amino}-3-fluoro-phenyl)-6-oxo-1 ,6-dihydro-pyridine-2-carboxylic acid methyl ester; (2R,4R)-[1-(4-{[1 -(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2- carbonyl]-amino}-phenyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid; (2R,4R)-1-(4-{[1 -(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2- carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1 ,2-dihydro-pyridine-3-carboxylic acid methyl ester; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-3-trifluoromethyl-2H-pyridin-1-yl)- phenyl}-amide};
(2R.4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenyl]}- } amide}; (2R 4R)-1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2- carbonyl}-amino}-3-fluoro-phenyl)-6-0xo0-1,6-dihydro-pyridine-2-carboxylic acid;
-362- ® ) (2R 4R)-4-Methoxy-pyrrolidine- 1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-5-trifluoromethyl-2H-pyridin-1-yl)- phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(6-cyclopropyl-2-oxo-2H-pyridin-1-y1)-2-fluoro-phenyl]- amide}; (2R,4R)-1-(4-{[1 -(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2- carbonyl}-amino }-3-fluoro-phenyl)-6-oxo-1 ,6-dihydro-pyridine-3-carboxylic acid ethyl ester;
(2R.4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(3,3-dimethyl-2-oxo-azetidin-1-yl)-phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)-phenyl]- amide}: (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-0xo-1 -aza-spiro[4.5]dec-1-yl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3-benzoyl-2- oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1-[(4-chloro-phenyl)-amide};
(2R.4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 2-{[4-(3- acetylsulfamoyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide } 1-[(4-chloro- phenyl)-amide]; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-thiazolidin-3-yl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(3-methyl-2-oxo-piperidin-1-yl)-phenyl]-amide }; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-3-sulfamoyl-2H-pyridin- 1-yl)-phenyl]}- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(2,5-diox0-2,5-dihydro-pyrrol-1-yl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3-amino-2- oxo-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide } 1-[(4-chloro-phenyl)-amide};
° WO 03/045912 PCT/IB02/04757 (2R ,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{{2-fluoro-4-(2-oxo-3-phenoxy-2H-pyridin- 1-yl)-phenyl}- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(2,2-dimethyl-5-oxo-pyrrolidin-1 -yl)-2-fluoro-phenyl]- amide};
(2R.,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(3-nitro-2-oxo-2H-pyridin-1 -yl)-phenyl]-amide}; (2R,4R)-1-(4-{[1 -(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2- carbonyl}-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid tert-butyl ester; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(2,5-dioxo-pyrrolidin-1-yl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarbox ylic acid 2-{[4-(3- benzothiazol-2-yl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1-[(4-chloro- phenyl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3-amino-4,6- dimethyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1-[(4-chloro-phenyl)- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(3-diethylaminomethyl-2-oxo-2H-pyridin-1-yl)-2-fluoro- phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine- 1,2-dicarboxylic acid 2-{[4-(3- aminomethyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide} 1-[(4-chloro- phenyl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(3-methyl-5-nitro-2-oxo-2H-pyridin-1-yl)-phenyl}- amide}; (2R,4R)-Acetic acid 1-(4-{[1-(4-chloro-phenylcarbamoyl)-4-methoxy- pyrrolidine-2-carbonyli]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridin-3-yi ester;
-364- ® : (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-( {4-[3-(cyclopentanecarbonyl-amino)-2-oxo-2H-pyridin-1-yl]}- 2-fluoro-phenyl }-amide); (2R ,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(5-amino-3- methyl-2-oxo0-2H-pyridin-1-y!)-2-fluoro-phenyl]-amide} 1-[(4-chloro-phenyl)- amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-({2-fluoro-4- [2-ox0-3-(pyridin-4-ylcarbamoyl)-2H-pyridin-1- yl}-phenyl}-amide); (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(3,5-dichloro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3-amino-5- bromo-2-oxo0-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide} 1-[(4-chloro-phenyl)- amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[4-(3-cyano-2-oxo-2H-pyridin-1 -yl)-2-fluoro-phenyl}-amide }; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(3-cyano-2-ox0-5-phenyl-2H-pyridin-1-yl)-2-fluoro- phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(3-ethyl-6-methyl-2-0x0-2H-pyridin-1-yl)-2-fluoro-phenyl]- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(3-cyano-4-dimethylamino-2-oxo-2H-pyridin-1-yl)-2- fluoro-phenyl}-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1.2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(4-methy] -3-nitro-2-oxo-2H-pyridin-1-yl)-phenyl}- amide}; : (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(5-nitro-2-oxo-3-trifluoromethyl-2H-pyridin-1 -yl)- phenyl}-amide};
® WO 03/045912 PCT/IB02/04757
. (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 2-{[4-(5-amino-6- .o ox0-6H-[3,4'Ibipyridinyl-1 -yl)-2-fluoro-phenyl}-amide} 1-[(4-chloro-phenyl)- ~ amide]; (2R ,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 2-{[4-(5-chloro-3- nitro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1-[(4-chloro-phenyl)- amide]; (2R 4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 2-{[4-(3-carbamoyl- 2-0x0-5-trifluoromethyl-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1 -[(4-chloro- phenyl)-amide]); (2R,4R)-5-Bromo-1-(4-{ [1-(4-chloro-phenylcarbamoyl)-4-methoxy- pyrrolidine-2-carbonyl]-amino}-3-fluoro-pheny!)-2-oxo-1,2-dihydro-pyridine-3- carboxylic acid isobutyl ester; (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 2-{[4-(3-chloro-2- ox0-5-trifluoromethyl-2H-pyridin-1 -yl)-2-fluoro-phenyl]-amide} 1-[(4-chloro- phenyl)-amide];
(2R.4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 2-{[4-(3-bromo-5- chloro-2-oxo0-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide} 1 -[(4-chloro-phenyl)- amide]; (2R ,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 2-{[4-(5-bromo-3- nitro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1-[(4-chloro-phenyl)- amide]; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(3-nitro-2-oxo-5-trifluoromethyl-2H-pyridin-1-yl)- phenyl]-amide};
(2R.4R)-4-Methoxy-pyrrolidine-1 .2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(5-methyl-3-nitro-2-oxo-2H-pyridin-1 -yl)-phenyl}- : amide}; (2R,4R)-5-Chloro-1-(4-{ [1-(4-chloro-phenylcarbamoyl)-4-methoxy- pyrrolidine-2-carbonyl]-amino} -3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3- carboxylic acid methyl ester;
(2R ,4R)-5-Chloro-1-(4-{[1-(4-chloro-phenylcarbamoyl)-4-methoxy- pyrrolidine-2-carbonyl]-amino }-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3- . carboxylic acid; . (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(4-benzyloxy- ’ 2-oxo0-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1-[(4-chloro-phenyl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(4-amino-5- fluoro-2-0xo0-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1-[(4-chloro-phenyl)- amide];
(2R.4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(6-methyl-3-oxo-3H-isoquinolin-2-yl)-phenyl]- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(4-methyl-5-nitro-2-oxo-2H-pyridin-1 ~-yl)-phenyl]- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4~(5- acetylamino-2-oxo-2H-pyridin-1-y1)-2-fluoro-phenyl]-amide} 1-[(4-chloro- phenyl)-amide]; (2R ,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(4-amino-2- . oxo-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide} 1-[(4-chloro-phenyl)-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(6-ox0-6H-[3,4'Ibipyridinyl-1-yl)-phenyl}-amide} ; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{ [4-(4-bromo-2- oxo-2H-pyridin-1-y1)-2-fluoro-phenyl]-amide} 1-[(4-chloro-phenyl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-phenyl}- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- ‘ phenyl)-amide] 2-{ [2-fluoro-4-(1-oxo-1H-[2,6]naphthyridin-2-yl)-phenyl]- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(5-bromo-2- oxo-2H-pyridin-1-y1)-2-fluoro-phenyl]-amide} 1-[(4-chloro-phenyl)-amidel;
® WO 03/045912 PCT/IB02/04757
. (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- -or ‘ phenyl)-amide] 2-{ [2-fluoro-4-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)-phenyl]- . amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(4-ox0-1 ,4-dihydro-imidazo[4,5-c]pyridin-5-yl)- phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 2-{[4-(5-chloro-2- oxo-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide} 1-[(5-chloro-pyridin-2-yl)-amidel; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(3-fluoro-2-oxo-2H-pyridin-1-yl)-phenyl}- amide}; (2R4R)-1-(4-{[1-(5 -Chloro-pyridin-2-ylcarbamoyl)-4-methoxy- pyrrolidine-2-carbonyl]-amino} -3-fluoro-phenyl)-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(6-hydroxy-2-oxo-2H-pyridin-1-yl)-phenyl]- amide}; (2R,4R)-1-(4-{ 1-(5-Chloro-pyridin-2-ylcarbamoyl)-4-methoxy- pyrrolidine-2~carbonyl}-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3- carboxylic acid, (2R,4R)-1-(4-{ [1-(5-Chloro-pyridin-2-ylcarbamoyl)-4-methoxy- pyrrolidine-2-carbonyl]-amino} -3-fluoro-phenyl)-6-oxo-1,6-dihydro-pyridine-2- carboxylic acid methyl ester; (2R,4R)-[1-(4-{[1-(5-Chl oro-pyridin-2-ylcarbamoyl)-4-methoxy- pyrrolidine-2-carbonyl]-amino}-phenyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid; (2R,4R)-1-(4-{[1 -(5-Chloro-pyridin-2-ylcarbamoyl)-4-methoxy- pyrrolidine-2-carbonyl])-amino} -3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3- carboxylic acid methyl] ester; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(2-oxo-3-trifluoromethyl-2H-pyridin-1-yl)- phenyl]-amide};
-368- ® (2R,4R)-4-Methoxy-pyrrolidine-1,2-djcarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide} 2-{[2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenyl]- ) amide}; (2R 4R)-1-(4-{[1-(5-Chloro-pyridin-2-ylcarbamoyl)-4-methoxy- . pyrrolidine-2-carbonyl]-amino} -3-fluoro-phenyl)-6-oxo-1,6-dihydro-pyridine-2- carboxylic acid; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide} 2-{[2-fluoro-4-(2-oxo-5-trifluoromethyl-2H-pyridin-1-y1)- phenyl]-amide} : (2R,4R)-4-Methox y-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [4-(6-cyclopropyl-2-oxo-2H-pyridin-1-yl)-2-fluoro- phenyl]}-amide}; (2R,4R)-1-(4-{ [1-(5-Chloro-pyridin-2-ylcarbamoyl)-4-methoxy- pyrrolidine-2-carbonyl]-amino }-3-fluoro-phenyl)-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid ethyl ester; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[2-fluoro-4-(3-hydroxy-2-oxo-2H-pyridin-1-yl)-phenyl}- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [4-(3,3-dimethyl-2-oxo0-azetidin-1 -yl)-phenyl}-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(7-oxo-7H-thieno[2,3-c]pyridin-6-y1)- : phenylil-amide}; (2R 4R)4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(2-oxo-1-aza-spiro[4.5)dec-1-yl)-phenyl]- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3-benzoyl-2- . oxo-2H-pyridin-1-y1)-2-fluoro-phenyl]-amide } 1-[(5-chloro-pyridin-2-yl)-amide]; (2R .4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(5-chloro- ’ pyridin-2-yl)-amide] 2-{[2-fluoro-4-(2-methyl-5-oxo-pyrrolidin-1-yl)-phenyl}- amide};
® WO 03/045912 PCT/1B02/04757
(2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- Lo pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(2-methyl-6-oxo-piperidin-1-yl)-phenyl]- - amide};
(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3-
acetylsulfamoyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1 -[(5-chloro-
pyridin-2-yl)-amide];
(2R,4R)-4-Methoxy-pyrrolidine- 1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(2-oxo-thiazolidin-3-yl)-phenyl}-amide};
(2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-
pyridin-2-yl)-amide] 2-{[2-fluoro-4-(3-methyl-2-oxo-piperidin-1-yl)-phenyl]-
amide};
(2R4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-3-sulfamoyl-2H-pyridin- 1 -yD)- phenyl]-amide };
(2R,4R)-4-Methoxy-pyrrolidine-1.2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [4-(2,5-diox0-2,5-dihydro-pyrrol-1-yl)-phenyl]-amide} ;
(2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{ [4-(3-amino-2- oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1-[(5-chloro-pyridin-2-yl)-amide];
(2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-
pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(2-oxo-3-phenoxy-2H-pyridin-1-yl)-phenyl]- amide};
(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [4-(2,2-dimethyl-5-0x0-pyrrolidin-1-yl)-2-fluoro-phenyl]- amide};
(2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(3-nitro-2-oxo-2H-pyridin-1-yl)-phenyl}- amide};
(2R 4R)-1-(4-{[1-(5-Chloro-pyridin-2-ylcarbamoyl)-4-methoxy-
’ pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-
carboxylic acid tert-butyl ester;
(2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[4-(2 ,5-dioxo-pyrrolidin-1-yl)-phenyl}-amide};
-370- ® ' (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3- benzothiazol-2-yl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide} 1-[(5-chloro- i pyridin-2-yl)-amide]; ] (2R ,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3-amino-4,6- dimethy}-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1-[(5-chloro-pyridin-2- yl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2- { [4-(3-diethylaminomethyl-2-oxo-2H-pyridin-1-y1)-2- fluoro-phenyl}-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3- aminomethyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1-[(5-chloro- pyridin-2-yl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[2-fluoro-4-(3-methyl-5-nitro-2-oxo-2H-pyridin-1-yl)- phenyl]-amide}; : (2R,4R)-Acetic acid 1-(4-{[1-(5-chloro-pyridin-2-ylcarbamoyl)-4- methoxy-pyrrolidine-2-carbonyl}-amino }-3-fluoro-phenyl)-2-oxo-1,2-dihydro- pyridin-3-yl ester; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-({4-[3-(cyclopentanecarbonyl-amino)-2-oxo-2H-pyridin-1- yl]-2-fluoro-phenyl }-amide); (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{ [4-(5-amino-3- methyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide } 1-[(5-chloro-pyridin-2- yl)-amide};
(2R.4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-({ 2-fluoro-4-[2-oxo-3-(pyridin-4-ylcarbamoyl)-2H- pyridin-1-yl]-phenyl}-amide); (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[4-(3,5-dichloro-2-oxo-2H-pyridin-1-yl)-2-fluoro- ) phenyl]-amide};
) ® WO 03/045912 PCT/IB02/04757
. (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{ [4-(3-amino-5- or bromo-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1-[(5-chloro-pyridin-2- - yl)-amide]; (2R ,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[4-(3-cyano-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl}- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(S-chloro- pyridin-2-yl)-amide] 2-{ [4-(3-cyano-2-oxo-5-phenyl-2H-pyridin-1-yl)-2-fluoro- phenyl}-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [4-(3-ethyl-6-methyl-2-oxo-2H-pyridin-1-yl)-2-fluoro- phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- : pyridin-2-yl)-amide] 2-{ [4-(3-cyano-4-dimethylamino-2-oxo-2H-pyridin-1-yl)-2- fluoro-phenyl]-amide};
(2R.4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(S-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(4-methyl-3-nitro-2-oxo-2H-pyridin-1-yl)- phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(5-nitro-2-oxo-3-trifluoromethyl-2H-pyridin- 1-yD)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 2-{ [4-(5-amino-6- oxo-6H-{3,4'Ibipyridinyl-1-yl)-2-fluoro-phenyl]}-amide} 1-[(5-chloro-pyridin-2- yl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(5-chloro-3- nitro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1-[(5-chloro-pyridin-2-yl)- \ amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3-carbamoy]- 2-0x0-5-trifluoromethyl-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide} 1-[(5-chloro- pyridin-2-yl)-amide]; La BE SE SPEER a L
-372- ® ) (2R,4R)-5-Bromo-1-(4-{[1-(5-chloro-pyridin-2-ylcarbamoyl)-4-methoxy- pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3- i ) carboxylic acid isobutyl ester; .
(2R ,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3-chloro-2- '
oxo-5-trifluoromethyl-2H-pyridin- 1-yl)-2-fluoro-phenylj-amide} 1-[(5-chloro- pyridin-2-yl)-amide];
(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3-bromo-5- chloro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1-[(5-chloro-pyridin-2- yl)-amide];
(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(5-bromo-3- nitro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1-[(5-chloro-pyridin-2-yl)- amide];
(2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(3-nitro-2-oxo-5-trifluoromethyl-2H-pyridin-
1-yl)-phenyl]-amide};
(2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[2-fluoro-4-(5-methyl-3-nitro-2-oxo-2H-pyridin-1-yl)- phenyl]-amide};
(2R,4R)-5-Chloro-1-(4-{ [1-(5-chloro-pyridin-2-ylcarbamoyl)-4-methoxy-
pyrmolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1 ,2-dihydro-pyridine-3- carboxylic acid methyl ester;
(2R,4R)-5-Chloro-1-(4-{ [1-(5-chloro-pyridin-2-ylcarbamoyl)-4-methoxy- pyrrolidine-2-carbonyl]-amino} -3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3- carboxylic acid;
(2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{ [4-(4-benzyloxy- 2-0x0-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide} 1 -[(5-chloro-pyridin-2-yl)- amide]; ’
(2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(4-amino-5-
fluoro-2-ox0-2H-pyridin-1-yl)-2-fluoro-phenylj-amide } 1-[(5-chloro-pyridin-2- yl)-amide];
id -373- (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- . pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(5-nitro-2-oxo-2H-pyridin-1-yl)-phenyl}- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[2-fluoro-4-(6-methyl-3-oxo-3H-isoquinolin-2-yl)- phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(4-methyl-5-nitro-2-oxo-2H-pyridin-1-yl)- phenyl]-amide};
(2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(5- acetylamino-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide} 1-[(5-chloro- pyridin-2-yl)-amide};
(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[2-fluoro-4-(1 -oxo-1H-isoquinolin-2-yl)-phenyl]-amide};
(2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(4-amino-2- oxo-2H-pyridin-1-y1)-2-fluoro-phenyl]-amide} 1-[(5-chloro-pyridin-2-yl)-amide];
(2R 4R)4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[2-fluoro-4-(6-oxo-6H-[3,4'Ibipyridinyl-1-yl)-phenyl}- amide};
(2R 4R)4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(3-ox0-3H-isoquinolin-2-yl)-phenyl}-amide};
(2R 4R)~4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(4-bromo-2- oxo-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide} 1 -[(5-chloro-pyridin-2-yl)-amide]; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(4-oxo-4H-furo[3,2-c]pyridin-3-yl)-phenyl}- amide}; , (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(1-oxo-1H-[2,6]naphthyridin-2-yl)-phenyl]- amide};
(2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{ [4-(5-bromo-2-
oxo-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide} 1-[(S-chloro-pyridin-2-yl)-amide];
-374- ® ) (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[2-fluoro-4-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)- ) : phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[2-fluoro-4-(4-oxo-1,4-dihydro-imidazo[4,5-c]pyridin-5- yl)-phenyl}-amide }; 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 5-{[2-fluoro-4-(2-ox0-2H-pyridin-1-yl)-phenyl]-amide }; 3-Hydroxymethyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4- chloro-phenyl)-amide] 5-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}; 5-Methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 5- { [2-fluoro-4-(2-oxo-2H-pyridin-1 -yl)-phenyl}-amide}; 3-Methoxymethyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4- chloro-phenyl)-amide] 5-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl}-amide}; 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(5-chloro-pyridin-2-yl)- amide] 5-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}; 3-Hydroxymethyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(5- chloro-pyridin-2-yl)-amide] 5-{ [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl}- amide}; 5-Methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(5-chloro-pyridin- 2-yl)-amide) 5-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide }; 3-Methoxymethyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(5- chloro-pyridin-2-yl)-amide] 5-{ [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]- amide}; 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 5-{[4-(2-methyl-thiazol-4-yl)-phenyl}-amide }; (2R,4R)-4-Methoxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4- ’ chloro-phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-piperidin-1 -yl)-phenyl]j-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(3.,4,5,6-tetrahydro-2H-[1,4'Ibipyridinyl-4-ylmethyl)-amide];
} ® WO 03/045912 PCT/IB02/04757
. (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- . phenyl)-amide] 2-{[4-(2-dimethylaminomethyl-imidazol-1 -yl)-2-fluoro-phenyl]- amide}; ) (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[2-chloro-4-(2- oxo-2H-pyridin-1-yl)-phenyl]-amide} 1-[(4-chloro-phenyl)-amide]; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[2-chloro-4-(2- oxo-2H-pyridin-1-yl)-phenyl}-amide} 1 -[(5-chloro-pyridin-2-yl)-amide]; (2R ,4R)-4-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1 -yl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-methylamino-imidazol-1-yl)-phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(2-isopropyl-imidazol-1-yl)-phenyl]-amide }; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(2-ethyl-imidazol-1-yl)-2-fluoro-phenyl]-amide }; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(5-chloro- pyridin-2-yl)-amide] 2-{ [4-(2-ethyl-imidazol-1-yl)-2-fluoro-phenyl]}-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-isopropyl-imidazol-1-yl)-phenyl]-amide}; | (2R,4R)-2-Ethyl-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4- chloro-phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}; 4-Methoxy-2-methoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-{(4- chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1 -yh)-phenyl]-amide}; 2-Hydroxymethyl-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4- chloro-phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-piperidin- 1-yl)-phenyl]-amide}; { 1-(4-Chloro-phenylcarbamoyl)-2-[2-fluoro-4-(2-oxo-piperidin-1-yl)- : phenylcarbamoyl]-4-methoxy-pyrrolidin-2-yl }-acetic acid methyl ester; {1-(4-Chloro-phenylcarbamoyl)-2-[2-fluoro-4-(2-oxo-piperidin-1-yl)- phenylcarbamoyl]-4-methoxy-pyrrolidin-2-yl}-acetic acid; 4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl}-amide}; Ig
-376- ® { 1-(4-Chloro-phenylcarbamoyl)-5-[2-fluoro-4-(2-oxo-piperidin-1-yl)- phenylcarbamoyl]-pyrrolidin-3-yl}-acetic acid; A ) { 1-(4-Chloro-phenylcarbamoyl)-5-[2-fluoro-4-(2-oxo-piperidin-1-yl)- phenylcarbamoyl]-pyrrolidin-3-yl }-acetic acid methyl ester; ’ (2R,4R)-4-Ethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl}-amide} (2R 4R)-4-Isopropyl-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(3-fluoro-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[2-fluoro-4-(3-fluoro-2-oxo-2H-pyridin-1-yl)-phenyl}- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3-chloro-2- oxo-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide } 1-[(5-chloro-pyridin-2-yl)-amide]; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[4-(3-chloro-2- oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide} 1 -[(4-chloro-phenyl)-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1.2-dicarboxylic acid 2-{ [4-(3-bromo-2- oxo-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide } 1-[(4-chloro-phenyl)-amide]; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{ [4-(3-bromo-2- oxo-2H-pyridin-1-yl)-2-fluoro-phenyl}-amide} 1 -[(5-chloro-pyridin-2-yl)-amide]; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(3-iodo-2-ox0-2H-pyridin-1-yl)-phen yl}-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(3-iodo-2-ox0-2H-pyridin-1-yl)-phenyl]- amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- . pyridin-2-yl)-amide] 2-{ [4-(3-ethyl-2-ox0-2H-pyridin-1 -yl)-2-fluoro-phenyl]- amide}; and (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(3-ethyl-2-ox0-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide; a pharmaceutically acceptable salt thereof.
‘ ® WO 03/045912 PCT/IB02/04757
:
10. A compound which is: (2R ,4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl}-amide} : (2R,4R) 4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1 -yl)-phenyl]-amide}; (2R 4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-2H-pyridin-] -yl)-phenyl}-amide}; (2R 4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide} ; (2R 4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(2-oxo-2H-[1 ,3'Ibipyridinyl-6'-yl)-amide]; (2R,4R) 4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(3-methoxy-2-oxo-2H-pyridin-1-yl)-phenyl}- amide}; (2R 4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{ [4-(3-methyl-2-0xo0-2H-pyridin-1 -yl)-phenyl]-amide}; (2R 4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-methyl-imidazol-1 -yl)-phenyl}-amide}; (2R,4R) 4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(4-dimethylcarbamoyl-2-fluoro-phenyl)-amide]; (2R,4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(5-methyl-pyrazol-1 -yl)-phenyl}-amide}; (2R 4R) 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4-chloro-phenyl)- amide] 5-[(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; (2R,4R) 4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- . phenyl)-amide] 2-[(2-fluoro-4-pyrazol-1-yl-phenyl)-amide]; (2R 4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(pyrrolidine-1 -carbonyl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide} :
-378- ® v (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phen yi}-amide}; : (2R ,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl}-amide }; : S (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{[4-(3-methyl-2-0x0-2H-pyridin-1 yl)-phenyl]-amide} ; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(2-methyl-imidazol-1-yl)-phenyl}-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(2-0x0-2H-[1,3'Ibipyridinyl-6'-yl)-amide]; (2R 4R)-4-Ethoxy-pyrrolidine- 1,2-dicarboxylic acid 1-[(4-chioro-phenyl)- amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-[(4-dimethylcarbamoyl-2-fluoro-phenyl)-amide];
(2R.4R)-4-Methoxy-pyrrolidine-1.2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-fluoro-4-(5-methyl-pyrazol-1 -yl)-phenylj-amide}; 5-Methyl-4,5-dihydro-pyrazoie-1,5-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 5-[(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)-amide]; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(4-methyl-2-oxo-2H-pyridin-1 -yl)-phenyl}-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(3-methyl-2-oxo-2H-pyridin-1 -yl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 2-{[2-chloro-4-(2- oxo-2H-pyridin-1-yl)-phenyl]-amide} 1-[(4-chloro-phenyl)-amide]; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{[2-methyl-4-(2-oxo-2H-pyridin-1 -yl)-phenyl}-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2- { [2-fluoro-4-(6-methyl-2-o0x0-2H-pyridin-1-yl)-phenyl]-amide} ; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(3-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-
. © , pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(5-methyl-2-0x0-2H-pyridin-1-yl)-phenyl}- : amide}; (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [2-fluoro-4-(5-methyl-2-oxo-2H-pyridin-1 -yl)-phenyl]-amide}; (2R 4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(5-chloro- pyridin-2-yl)-amide] 2-{ [2-fluoro-4-(4-methyl-2-oxo-2H-pyridin-1-yl)-phenyl}- amide; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1 -[(4-chloro- phenyl)-amide] 2-{ [4-(2,5-dihydrom-pyyrole-1-carbonyl)-2-fluoro-phenyl- amide}; (2R 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(2,5-dihydrom-pyyrole-1-carbonyl)-phenyl-amide} (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-{(4-chloro- phenyl)-amide] 2-{ [4-(2-methyl-5-oxo-pyrrolidin-1-yl)-phenyl]-amide} ; (2R,4R)-4-Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(2,5-dihydro-pyrrole-1-carbonyl)-phenyl]-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4~chloro- phenyl)-amide] 2-{ [2-fluoro-4-(4-methyl-2-oxo-2H-pyridin-1 -yl)-phenyl}-amide}; (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro- phenyl)-amide] 2-{ [4-(2,5-dihydro-pyrrole-1 -carbonyl)-2-fluoro-phenyl]-amide}; or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a compound of formula I 1 AVES: N—= N ACA Ng NH o / I or a pharmaceutically acceptable salt thereof wherein: i, UO OV Fs IO ED FP TS Lo a
-380- ® . Ais aryl or substituted aryl or monocyclic heteroaryl or substituted monocyclic heteroaryl; oF ? ? B is -NH —C— (C;-Cg)alkyl, -NH —C— (C3-Cy)cycloalkyl -NH(C;- . Q . Ce)alkanoyl, PN R' (C3-Cy)cycloalkyl, (C3-Cy)heterocycloalkyl, (Cs- Cy)cycloalkenyl, (Cs-Co)heterocycloalkenyl, aryl, or heteroaryl, any of which may be optionally substituted; C is phenyl or heteroaryl, wherein phenyl or heteroaryl is optionally substituted with one or more substituents selected from halogen, hydroxy, - CO,R2, -COR2, -CONR2R?’, alkoxy, alkyl, -CN, haloalkyl, amino, alkylamino, amidino, amido, or sulfonamido; G is H, halo, (C;-Cg)alkyl, halo(C,-Cg)alkyl, hydroxy(C;-Ce)alkyl, -CH,0-(C;-Cg)alkyl, -CH2-CO2(C;-Ce)alkyl, -CH,-CONHp, or -CH,-CONH(C;- Ce)alkyl; w1 is a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain having from 2 to 6 atoms, wherein W1- connects the nitrogen atom at position 1 to the carbon atom at position 2 to form a four to eight membered ring; Rlis (C;-Ce)alkoxy, (C3-Cy)cycloalkyl, (Ci-Cy)heterocycloalkyl, (Cs- C;)cycloalkenyl, (C4-Co)heterocycloalkenyl, aryl, monocyclic heteroaryl, or — NR3R4; R2 and R?’ are each independently H or (C1-Ce)alkyl; and } R3 and R4 are each independently H, (C;-Ce)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl, aralkoxycarbonyl, -SO»alkyl, or joined together to form a saturated or unsaturated 3 to 7 membered ring; admixed with a carrier, diluent, or excipient. .
SJ -381- PCT/IB02/04757
12. A method for preventing acute, subacute, and chronic thrombotic disorder in a mammal comprising administering to a mammal an effective amount of a compound of claim 1.
13. The method of claim 10, wherein the acute, subacute, and chronic thrombotic disorder is venous thrombosis, arterial thrombosis, pulmonary embolism, myocardial infarction, cerebral infarctions, restenosis, cancer, angina, diabetes, atrial fibrillation, or heart failure.
14. A method for inhibiting Factor Xa in a mammal, comprising administering to 2 mammal a Factor Xa inhibition amount of a compound of claim 1.
15. A process for preparing a compound of Formula I- 1 AN / y oo N AN ‘ oO ~ A a h a : I or a pharmaceutically acceptable salt thereof wherein: ’ : A is aryl or substituted ary] or monocyclic heteroaryl or substituted monocyclic heteroaryl; oR 2 B is -NH —C—(C,;-C¢)alkyl, -NH—C— (G3-Cy)cycloalkyl, -NH(C;-
0 . Ce)alkanoyl, A R' | (C3-Cy)cycloalkyl, (Cs-Cy)heterocycloalkyl, (C,- Cs)cycloalkenyl, (Cs-Crdheterocycloalkenyl, aryl, or heteroaryl, any of which may be optionally substituted by halo, (C,-Cg)alkyl, or halo(C;-Cy)alkyl, (C,- AMENDED SHEET os WO 03/045912 PCT/IBO2/4757
Ce)alkoxy, -CN, haloalkyl. amino, alkylamino, amidino, amido, or sulfonamido; C is phenyl or heteroaryl, wherein phenyl or heteroaryl is optionally substituted with one or more substituents selected from halogen, hydroxy, - CO,R2, -CORZ, -CONR2R?’, alkoxy, alkyl, -CN, haloalkyl, amino, alkylamino. amidino, amido, or sulfonamido; G is H, halo, (C;-Ce)alkyl, halo(C;-Ce)alkyl, hydroxy(C;-Ce)alkyl, -CH,0-(C;-Cg)alkyl, -CH,-CO,(C,-Cg)alkyl, -CH>-NR2R2’, or -CH»- CONH(C,-Cg)alkyl; W! is a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain having from 3 to 6 atoms, wherein W1 connects the nitrogen atom at position 1 to the carbon atom at position 2 to form a four to eight membered ring; R1 is (C,-Cg)alkoxy, (C3-Cy)cycloalkyl, (C3-C)heterocycloalkyl, (Ca- Cy)cycloalkenyl, (C4-Co)heterocycloalkenyl, aryl, monocyclic heteroaryl, or — NR3R%4 R2 and R?’ are each independently H or (C;-Cs)alkyl; and R3 and R4 are each independently H, (C;-Ce)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl, aralkoxycarbonyl, -SO2alkyl, or joined together to form a saturated or unsaturated 3 to 7 membered ring; comprising: (a) reacting an amino acid of formula IA HNL OH © IA with a reagent capable of placing a protecting group P! on the amino group of an amino acid to form a protected amino acid given by formula IB:
*
Pp’ w' VAN ~~ 2 OH 0 Be IB wherein Pl is a protecting group and W1 is the same as defined above; (b) converting the acid moiety in the compound of formula IB to a acid halide; (c) reacting the acid halide with a haloaniline or a haloamino- heterocycle to form a compound having formula IC: P 1 Ww 1 /\_G H 0 N N 12 hil AN Oo 0] Z9 IC : wherein Z; is a halogen and A is as defined above; (d coupling the compound of formula IC with a compound H-B to - give a compound having formula ID:
® -384- PCT/IB02/04757 / H ®) N 1 ir} N 3 I D (e) removing the protecting group from Compound ID and reacting the resulting acid moiety with a C-isocyanate to forma compound of the invention. | :
16. Use of a compound of claim 1 in the manufacture of a preparation for preventing or treating acute, subacute, and chronic thrombotic disorder in a mammal.
17. Use of claim 16, wherein the acute, subacute, and chronic thrombotic disorder is venous thrombosis, arterial thrombosis, pulmonary embolism, myocardial infarction, cerebral infarction, restenosis, cancer, angina, diabetes, : atrial fibrillation, or heart failure.
18. Use of a compound of claim 1 in the manufacture of a preparation for inhibiting Factor Xa in a mammal.
19. A substance or composition for use in a method for preventing or treating acute, subacute, and chronic thrombotic disorder in a mammal, said substance or composition comprising a compound of claim 1, and said method comprising administering to a mammal an effective amount of said substance or composition. ~ AMENDED SHEET
-385- PCT/IB02/04757
20. A substance of composition for use in a method of prevention or treatment of claim 19, wherein the acute, subacute, and chronic thrombotic disorder is venous thrombosis, arterial thrombosis, pulmonary embolism, myocardial infarction, cerebral infarction, restenosis, cancer, angina, diabetes, atrial fibrillation, or heart failure.
21. A substance or composition for use in a method for inhibiting Factor Xa in a mammal, said substance or composition comprising a compound of claim 1, and said method comprising administering to a mammal a Factor Xa inhibition amount of said substance or composition.
22. A compound of any one of claims 1 to 10, substantially as herein described and illustrated.
23. A composition of claim 11, substantially as herein described and illustrated.
24. A method of claim 12 or claim 13 or claim 14, substantially as herein described and illustrated.
25. A process of claim 15, substantially as herein described and illustrated.
26. Use of any one of claims 16 to 18, substantially as herein described and illustrated.
27. A substance or composition for use in a method od prevention or treatment of any one of claims 19 to 21, substantially as herein described and illustrated. AMENDED SHEET
-386- PCT/IB02/04757
28. A new compound, a new composition, a new non-therapeutic method of treatment, a new process for preparing a compound, a new use of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a substance or composition for a new use in a method of prevention or treatment, substantially as herein described. AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33416801P | 2001-11-29 | 2001-11-29 |
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|---|---|
| ZA200404085B true ZA200404085B (en) | 2005-09-05 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200404085A ZA200404085B (en) | 2001-11-29 | 2004-05-25 | Inhibitors of factor Xa and other serine poteases involved in the coagulation cascades. |
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| Country | Link |
|---|---|
| UA (1) | UA77456C2 (en) |
| ZA (1) | ZA200404085B (en) |
-
2002
- 2002-11-14 UA UA20040504094A patent/UA77456C2/en unknown
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- 2004-05-25 ZA ZA200404085A patent/ZA200404085B/en unknown
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| UA77456C2 (en) | 2006-12-15 |
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