EP0906099A1 - Verfahren zur behandlung von krebs - Google Patents
Verfahren zur behandlung von krebsInfo
- Publication number
- EP0906099A1 EP0906099A1 EP97921085A EP97921085A EP0906099A1 EP 0906099 A1 EP0906099 A1 EP 0906099A1 EP 97921085 A EP97921085 A EP 97921085A EP 97921085 A EP97921085 A EP 97921085A EP 0906099 A1 EP0906099 A1 EP 0906099A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- substituted
- glycyl
- pyrrolidin
- methionine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 50
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 37
- 201000011510 cancer Diseases 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 127
- 102000004357 Transferases Human genes 0.000 claims abstract description 29
- 108090000992 Transferases Proteins 0.000 claims abstract description 29
- 125000003118 aryl group Chemical group 0.000 claims description 302
- 125000000623 heterocyclic group Chemical group 0.000 claims description 281
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 198
- 125000000217 alkyl group Chemical group 0.000 claims description 186
- 229910052739 hydrogen Inorganic materials 0.000 claims description 164
- 239000001257 hydrogen Substances 0.000 claims description 163
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 133
- -1 1 -imidazolyl Chemical group 0.000 claims description 92
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 83
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 80
- 235000001014 amino acid Nutrition 0.000 claims description 80
- 229910052801 chlorine Inorganic materials 0.000 claims description 76
- 229910052731 fluorine Inorganic materials 0.000 claims description 76
- 150000001413 amino acids Chemical class 0.000 claims description 75
- 229910052794 bromium Inorganic materials 0.000 claims description 75
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 60
- 150000003839 salts Chemical class 0.000 claims description 60
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 50
- 125000001424 substituent group Chemical group 0.000 claims description 48
- 125000001072 heteroaryl group Chemical group 0.000 claims description 46
- 125000003342 alkenyl group Chemical group 0.000 claims description 44
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims description 42
- 125000003107 substituted aryl group Chemical group 0.000 claims description 42
- PFMUCCYYAAFKTH-YFKPBYRVSA-N Gly-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)CN PFMUCCYYAAFKTH-YFKPBYRVSA-N 0.000 claims description 40
- 229910052760 oxygen Inorganic materials 0.000 claims description 36
- 229910052717 sulfur Inorganic materials 0.000 claims description 35
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 33
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 32
- QEFRNWWLZKMPFJ-ZXPFJRLXSA-N L-methionine (R)-S-oxide Chemical compound C[S@@](=O)CC[C@H]([NH3+])C([O-])=O QEFRNWWLZKMPFJ-ZXPFJRLXSA-N 0.000 claims description 30
- UCUNFLYVYCGDHP-BYPYZUCNSA-N L-methionine sulfone Chemical compound CS(=O)(=O)CC[C@H](N)C(O)=O UCUNFLYVYCGDHP-BYPYZUCNSA-N 0.000 claims description 30
- QEFRNWWLZKMPFJ-UHFFFAOYSA-N L-methionine sulphoxide Natural products CS(=O)CCC(N)C(O)=O QEFRNWWLZKMPFJ-UHFFFAOYSA-N 0.000 claims description 30
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 29
- 125000004432 carbon atom Chemical group C* 0.000 claims description 29
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 29
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 28
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 26
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 22
- 235000004279 alanine Nutrition 0.000 claims description 22
- 125000005842 heteroatom Chemical group 0.000 claims description 22
- 229910052720 vanadium Inorganic materials 0.000 claims description 22
- 125000006239 protecting group Chemical group 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 150000002460 imidazoles Chemical class 0.000 claims description 18
- 125000002950 monocyclic group Chemical group 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 17
- DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical compound COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 claims description 16
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 15
- 230000002401 inhibitory effect Effects 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 239000005557 antagonist Substances 0.000 claims description 14
- 229920006395 saturated elastomer Polymers 0.000 claims description 14
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 12
- 229930182817 methionine Natural products 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 239000011593 sulfur Chemical group 0.000 claims description 12
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 11
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 10
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 150000004702 methyl esters Chemical class 0.000 claims description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 6
- 125000006374 C2-C10 alkenyl group Chemical class 0.000 claims description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 6
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 5
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 5
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 5
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 4
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 125000003435 aroyl group Chemical group 0.000 claims description 4
- GCFAUZGWPDYAJN-UHFFFAOYSA-N cyclohexyl 3-phenylprop-2-enoate Chemical compound C=1C=CC=CC=1C=CC(=O)OC1CCCCC1 GCFAUZGWPDYAJN-UHFFFAOYSA-N 0.000 claims description 4
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 3
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 3
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 3
- 125000005002 aryl methyl group Chemical group 0.000 claims description 3
- 210000004556 brain Anatomy 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- 210000000867 larynx Anatomy 0.000 claims description 3
- 210000004072 lung Anatomy 0.000 claims description 3
- 201000005249 lung adenocarcinoma Diseases 0.000 claims description 3
- 210000004324 lymphatic system Anatomy 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 201000006845 reticulosarcoma Diseases 0.000 claims description 3
- 208000029922 reticulum cell sarcoma Diseases 0.000 claims description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 3
- 210000002784 stomach Anatomy 0.000 claims description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 3
- 125000004173 1-benzimidazolyl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N1* 0.000 claims description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- ANPPJNRSHQGSIR-UHFFFAOYSA-N 4-[2-(4-methylsulfanylphenyl)-4-naphthalen-2-yl-1h-imidazol-5-yl]pyridine Chemical compound C1=CC(SC)=CC=C1C1=NC(C=2C=C3C=CC=CC3=CC=2)=C(C=2C=CN=CC=2)N1 ANPPJNRSHQGSIR-UHFFFAOYSA-N 0.000 claims description 2
- MLLJGMFEGRJXLX-UHFFFAOYSA-N 4-[2-(4-methylsulfanylphenyl)-5-naphthalen-1-yl-1h-imidazol-4-yl]pyridine Chemical compound C1=CC(SC)=CC=C1C1=NC(C=2C=CN=CC=2)=C(C=2C3=CC=CC=C3C=CC=2)N1 MLLJGMFEGRJXLX-UHFFFAOYSA-N 0.000 claims description 2
- IJEKVOJHPYSPSL-UHFFFAOYSA-N 4-[2-(4-methylsulfinylphenyl)-4-naphthalen-2-yl-1h-imidazol-5-yl]pyridine Chemical compound C1=CC(S(=O)C)=CC=C1C1=NC(C=2C=C3C=CC=CC3=CC=2)=C(C=2C=CN=CC=2)N1 IJEKVOJHPYSPSL-UHFFFAOYSA-N 0.000 claims description 2
- IJYHRIIXDMNZST-UHFFFAOYSA-N 4-[4-(3,4-dichlorophenyl)-2-piperidin-4-yl-1h-imidazol-5-yl]pyridine Chemical compound C1=C(Cl)C(Cl)=CC=C1C1=C(C=2C=CN=CC=2)N=C(C2CCNCC2)N1 IJYHRIIXDMNZST-UHFFFAOYSA-N 0.000 claims description 2
- WEIMNUYTUJXDSU-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-(2-methylsulfanylphenyl)-1h-imidazol-5-yl]pyridine Chemical compound CSC1=CC=CC=C1C1=NC(C=2C=CC(F)=CC=2)=C(C=2C=CN=CC=2)N1 WEIMNUYTUJXDSU-UHFFFAOYSA-N 0.000 claims description 2
- ITRSTUNWYQNBEQ-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-(2-methylsulfinylphenyl)-1h-imidazol-5-yl]pyridine Chemical compound CS(=O)C1=CC=CC=C1C1=NC(C=2C=CC(F)=CC=2)=C(C=2C=CN=CC=2)N1 ITRSTUNWYQNBEQ-UHFFFAOYSA-N 0.000 claims description 2
- SCVJGNCJNHIZPW-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-(2-methylsulfonylphenyl)-1h-imidazol-5-yl]pyridine Chemical compound CS(=O)(=O)C1=CC=CC=C1C1=NC(C=2C=CC(F)=CC=2)=C(C=2C=CN=CC=2)N1 SCVJGNCJNHIZPW-UHFFFAOYSA-N 0.000 claims description 2
- OJHOIAOSQSNDFE-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-(3-methylsulfanylphenyl)-1h-imidazol-5-yl]pyridine Chemical compound CSC1=CC=CC(C=2NC(=C(N=2)C=2C=CC(F)=CC=2)C=2C=CN=CC=2)=C1 OJHOIAOSQSNDFE-UHFFFAOYSA-N 0.000 claims description 2
- RWCZEVLEBFONQN-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-(3-methylsulfinylphenyl)-1h-imidazol-5-yl]pyridine Chemical compound CS(=O)C1=CC=CC(C=2NC(=C(N=2)C=2C=CC(F)=CC=2)C=2C=CN=CC=2)=C1 RWCZEVLEBFONQN-UHFFFAOYSA-N 0.000 claims description 2
- HBLDNAVQCOHUEH-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-(3-methylsulfonylphenyl)-1h-imidazol-5-yl]pyridine Chemical compound CS(=O)(=O)C1=CC=CC(C=2NC(=C(N=2)C=2C=CC(F)=CC=2)C=2C=CN=CC=2)=C1 HBLDNAVQCOHUEH-UHFFFAOYSA-N 0.000 claims description 2
- XBOAMGVRMOKHNU-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-(4-methoxyphenyl)-1h-imidazol-5-yl]pyridine Chemical compound C1=CC(OC)=CC=C1C1=NC(C=2C=CC(F)=CC=2)=C(C=2C=CN=CC=2)N1 XBOAMGVRMOKHNU-UHFFFAOYSA-N 0.000 claims description 2
- KLRATASOGXHMKV-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-piperidin-3-yl-1h-imidazol-5-yl]pyridine Chemical compound C1=CC(F)=CC=C1C1=C(C=2C=CN=CC=2)N=C(C2CNCCC2)N1 KLRATASOGXHMKV-UHFFFAOYSA-N 0.000 claims description 2
- IXHWMGAFLNPNII-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-piperidin-4-yl-1h-imidazol-5-yl]pyridine Chemical compound C1=CC(F)=CC=C1C1=C(C=2C=CN=CC=2)N=C(C2CCNCC2)N1 IXHWMGAFLNPNII-UHFFFAOYSA-N 0.000 claims description 2
- RMZQNOARFIICNW-DEOSSOPVSA-N 4-[[5-[[(2s)-4-(2,3-dimethylphenyl)-2-(2-methoxyethyl)-5-oxopiperazin-1-yl]methyl]imidazol-1-yl]methyl]benzonitrile Chemical compound C([C@@H]1CCOC)N(C=2C(=C(C)C=CC=2)C)C(=O)CN1CC1=CN=CN1CC1=CC=C(C#N)C=C1 RMZQNOARFIICNW-DEOSSOPVSA-N 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 2
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 2
- UUIQMZJEGPQKFD-UHFFFAOYSA-N Methyl butyrate Chemical compound CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 2
- 201000008275 breast carcinoma Diseases 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 2
- GBDRMPRTNVKBAD-BYPYZUCNSA-N methyl (2s)-2,5-diamino-5-oxopentanoate Chemical compound COC(=O)[C@@H](N)CCC(N)=O GBDRMPRTNVKBAD-BYPYZUCNSA-N 0.000 claims description 2
- AFQQMAICQGFVEI-OVWQWFNUSA-N methyl (2s)-2-[[(2s,3s)-1-[[(2s)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl]-3-ethylpyrrolidine-2-carbonyl]amino]-4-methylsulfanylbutanoate Chemical compound CSCC[C@@H](C(=O)OC)NC(=O)[C@@H]1[C@@H](CC)CCN1C[C@H]1N(C(=O)CN)CCC1 AFQQMAICQGFVEI-OVWQWFNUSA-N 0.000 claims description 2
- MSCWBHRGIUEEMX-ASVWTAOFSA-N methyl (2s)-2-[[2-[[(2s)-1-[(2s)-3-amino-2-(phenylmethoxycarbonylamino)propanoyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound N([C@@H](CN)C(=O)N1CCC[C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=1C2=CC=CC=C2C=CC=1)C(=O)OCC1=CC=CC=C1 MSCWBHRGIUEEMX-ASVWTAOFSA-N 0.000 claims description 2
- HQFUINJGHRJKJL-DPGDXNODSA-N methyl (2s)-2-[[2-[[(2s,3s)-2-[[2-[3-[(4-cyanophenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound N([C@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1CC1=CC=C(C#N)C=C1 HQFUINJGHRJKJL-DPGDXNODSA-N 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 23
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 8
- XNWZWXHDORBTJC-UNMCSNQZSA-N (2s)-2-[[2-[[(2s)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C=1C=CC2=CC=CC=C2C=1CN(CC(=O)N[C@@H](CCSC)C(O)=O)C[C@@H]1CCCN1C(=O)CN XNWZWXHDORBTJC-UNMCSNQZSA-N 0.000 claims 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 3
- BNUFZLNMGFEGNS-ZCYQVOJMSA-N (2s)-2-[[2-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CC1=CNC=N1 BNUFZLNMGFEGNS-ZCYQVOJMSA-N 0.000 claims 2
- JTHYTTAMRPUVFT-BDYUSTAISA-N (2s)-4-methylsulfanyl-2-[[2-[naphthalen-1-ylmethyl-[[(2s)-1-[2-(pyridin-4-ylamino)acetyl]pyrrolidin-2-yl]methyl]amino]acetyl]amino]butanoic acid Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CNC1=CC=NC=C1 JTHYTTAMRPUVFT-BDYUSTAISA-N 0.000 claims 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
- MGIYRDNGCNKGJU-UHFFFAOYSA-N isothiazolinone Chemical compound O=C1C=CSN1 MGIYRDNGCNKGJU-UHFFFAOYSA-N 0.000 claims 2
- KSRIGEDVURVPEB-XCZPVHLTSA-N methyl (2s)-4-methylsulfanyl-2-[[2-[naphthalen-1-ylmethyl-[[(2s)-1-[2-(pyridin-4-ylamino)acetyl]pyrrolidin-2-yl]methyl]amino]acetyl]amino]butanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CNC1=CC=NC=C1 KSRIGEDVURVPEB-XCZPVHLTSA-N 0.000 claims 2
- ZYXVFHLTYWMIHA-ZCYQVOJMSA-N propan-2-yl (2s)-2-[[2-[[(2s)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C=1C=CC2=CC=CC=C2C=1CN(CC(=O)N[C@@H](CCSC)C(=O)OC(C)C)C[C@@H]1CCCN1C(=O)CN ZYXVFHLTYWMIHA-ZCYQVOJMSA-N 0.000 claims 2
- WMLVYMSANAXLFU-QABMSTFYSA-N (2r)-5-amino-2-(dimethylamino)-2-[2-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]-5-oxopentanoic acid Chemical compound C([C@H]1CN(CC(=O)[C@](CCC(N)=O)(C(O)=O)N(C)C)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CC1=CNC=N1 WMLVYMSANAXLFU-QABMSTFYSA-N 0.000 claims 1
- DYFKDTKESTYKPG-DSLXNQLJSA-N (2s)-2-[[(2s)-1-[[(2s,3s)-3-ethyl-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl]pyrrolidine-2-carbonyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C([C@H]1N(CC[C@@H]1CC)C(=O)CC=1N=CNC=1)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(O)=O DYFKDTKESTYKPG-DSLXNQLJSA-N 0.000 claims 1
- QWNMHLWLTMHZOF-JKQORVJESA-N (2s)-2-[[(2s,3s)-1-[[(2s)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl]-3-ethylpyrrolidine-2-carbonyl]amino]-4-methylsulfanylbutanoic acid Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H]1[C@@H](CC)CCN1C[C@H]1N(C(=O)CN)CCC1 QWNMHLWLTMHZOF-JKQORVJESA-N 0.000 claims 1
- CDNYGEBAKLWIHE-GOTSBHOMSA-N (2s)-2-[[2-[(2-cyanophenyl)methyl-[[(2s)-1-[3-(1h-imidazol-5-yl)propanoyl]pyrrolidin-2-yl]methyl]amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=2C(=CC=CC=2)C#N)CCN1C(=O)CCC1=CNC=N1 CDNYGEBAKLWIHE-GOTSBHOMSA-N 0.000 claims 1
- JMEPRQNCQFXREP-VXKWHMMOSA-N (2s)-2-[[2-[(3-cyanophenyl)methyl-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl]amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=2C=C(C=CC=2)C#N)CCN1C(=O)CC1=CN=CN1 JMEPRQNCQFXREP-VXKWHMMOSA-N 0.000 claims 1
- SNJMJAVKVFZWSV-ZCYQVOJMSA-N (2s)-2-[[2-[[(2s)-1-(1h-imidazol-5-ylmethyl)pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=2C3=CC=CC=C3C=CC=2)CCN1CC1=CNC=N1 SNJMJAVKVFZWSV-ZCYQVOJMSA-N 0.000 claims 1
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- KOMHSXFLHLIDMM-ROUUACIJSA-N (2s)-2-[[2-[[(2s)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl-benzylamino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C=1C=CC=CC=1CN(CC(=O)N[C@@H](CCSC)C(O)=O)C[C@@H]1CCCN1C(=O)CN KOMHSXFLHLIDMM-ROUUACIJSA-N 0.000 claims 1
- WGZXCXSLMXNADB-GMAHTHKFSA-N (2s)-2-[[2-[[(2s)-1-(3-aminopropanoyl)pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C=1C=CC2=CC=CC=C2C=1CN(CC(=O)N[C@@H](CCSC)C(O)=O)C[C@@H]1CCCN1C(=O)CCN WGZXCXSLMXNADB-GMAHTHKFSA-N 0.000 claims 1
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- HUBAHCJBIRMDBS-PMVMPFDFSA-N (2s)-2-[[2-[[(2s)-1-[(3s)-3,4-diamino-4-oxobutanoyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C=1C=CC2=CC=CC=C2C=1CN(CC(=O)N[C@@H](CCSC)C(O)=O)C[C@@H]1CCCN1C(=O)C[C@H](N)C(N)=O HUBAHCJBIRMDBS-PMVMPFDFSA-N 0.000 claims 1
- SLZDBRBHGIGMAM-AVRDEDQJSA-N (2s)-2-[[2-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]-(trifluoromethyl)amino]propanoic acid Chemical compound C([C@H]1CN(CC(=O)N([C@@H](C)C(O)=O)C(F)(F)F)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CC1=CNC=N1 SLZDBRBHGIGMAM-AVRDEDQJSA-N 0.000 claims 1
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- SJXPMYBVFKOZTF-UNMCSNQZSA-N (2s)-2-[[2-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl-[(4-methoxyphenyl)methyl]amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C1=CC(OC)=CC=C1CN(CC(=O)N[C@@H](CCSC)C(O)=O)C[C@H]1N(C(=O)CC=2NC=NC=2)CCC1 SJXPMYBVFKOZTF-UNMCSNQZSA-N 0.000 claims 1
- ZSUOHOMDEQTSSS-FPOVZHCZSA-N (2s)-2-[[2-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl-[[2-(trifluoromethyl)phenyl]methyl]amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=2C(=CC=CC=2)C(F)(F)F)CCN1C(=O)CC1=CNC=N1 ZSUOHOMDEQTSSS-FPOVZHCZSA-N 0.000 claims 1
- XQGBKKUAEDGZFI-GMAHTHKFSA-N (2s)-2-[[2-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl-naphthalen-1-ylsulfonylamino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)S(=O)(=O)C=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CC1=CNC=N1 XQGBKKUAEDGZFI-GMAHTHKFSA-N 0.000 claims 1
- NSTOSYAYHNCROE-UPVQGACJSA-N (2s)-2-[[2-[[(2s)-1-[2-(dimethylamino)acetyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C=1C=CC2=CC=CC=C2C=1CN(CC(=O)N[C@@H](CCSC)C(O)=O)C[C@@H]1CCCN1C(=O)CN(C)C NSTOSYAYHNCROE-UPVQGACJSA-N 0.000 claims 1
- XIOHLQQXJBVUKF-GMAHTHKFSA-N (2s)-2-[[2-[[(2s)-1-[2-(methylamino)acetyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound CNCC(=O)N1CCC[C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC1=CC=CC2=CC=CC=C12 XIOHLQQXJBVUKF-GMAHTHKFSA-N 0.000 claims 1
- XVQWFCUFHJJGLS-XCZPVHLTSA-N (2s)-2-[[2-[[(2s)-1-[2-[methyl(pyridin-4-yl)amino]acetyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CN(C)C1=CC=NC=C1 XVQWFCUFHJJGLS-XCZPVHLTSA-N 0.000 claims 1
- LRICZMUKYVXXAT-VXKWHMMOSA-N (2s)-2-[[2-[[(2s)-1-[3-(1h-imidazol-5-yl)propanoyl]pyrrolidin-2-yl]methyl-[(2-methoxyphenyl)methyl]amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound COC1=CC=CC=C1CN(CC(=O)N[C@@H](CCSC)C(O)=O)C[C@H]1N(C(=O)CCC=2N=CNC=2)CCC1 LRICZMUKYVXXAT-VXKWHMMOSA-N 0.000 claims 1
- PJIRHLLXQXEKHG-SFTDATJTSA-N (2s)-2-[[2-[benzyl-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl]amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=2C=CC=CC=2)CCN1C(=O)CC1=CN=CN1 PJIRHLLXQXEKHG-SFTDATJTSA-N 0.000 claims 1
- XGBRPDFOFRPDJH-BDYUSTAISA-N (2s)-4-methylsulfanyl-2-[[2-[naphthalen-1-ylmethyl-[[(2s)-1-(2-pyridin-3-ylacetyl)pyrrolidin-2-yl]methyl]amino]acetyl]amino]butanoic acid Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CC1=CC=CN=C1 XGBRPDFOFRPDJH-BDYUSTAISA-N 0.000 claims 1
- HFABAVNVKIGOQD-MMOCMJAISA-N (2s)-4-methylsulfanyl-2-[[2-[naphthalen-1-ylmethyl-[[(2s)-1-(piperidine-3-carbonyl)pyrrolidin-2-yl]methyl]amino]acetyl]amino]butanoic acid Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)C1CCCNC1 HFABAVNVKIGOQD-MMOCMJAISA-N 0.000 claims 1
- KZMFHSMLMMKVBK-AHWVRZQESA-N (2s)-4-methylsulfanyl-2-[[2-[naphthalen-1-ylmethyl-[[(2s)-1-(piperidine-4-carbonyl)pyrrolidin-2-yl]methyl]amino]acetyl]amino]butanoic acid Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)C1CCNCC1 KZMFHSMLMMKVBK-AHWVRZQESA-N 0.000 claims 1
- ZBBSQXCFADEMLA-XWGVYQGASA-N (2s)-4-methylsulfanyl-2-[[2-[naphthalen-1-ylmethyl-[[(2s)-1-[(2s)-5-oxopyrrolidine-2-carbonyl]pyrrolidin-2-yl]methyl]amino]acetyl]amino]butanoic acid Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)[C@@H]1CCC(=O)N1 ZBBSQXCFADEMLA-XWGVYQGASA-N 0.000 claims 1
- BVVYOFGYTQLBKT-HVCNVCAESA-N (2s)-4-methylsulfanyl-2-[[2-[naphthalen-1-ylmethyl-[[(2s)-1-[(2s)-pyrrolidine-2-carbonyl]pyrrolidin-2-yl]methyl]amino]acetyl]amino]butanoic acid Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)[C@@H]1CCCN1 BVVYOFGYTQLBKT-HVCNVCAESA-N 0.000 claims 1
- YRSFPIMTLHOOHE-AHWVRZQESA-N (2s)-4-methylsulfanyl-2-[[2-[naphthalen-1-ylmethyl-[[(2s)-1-[2-(pyridin-2-ylamino)acetyl]pyrrolidin-2-yl]methyl]amino]acetyl]amino]butanoic acid Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CNC1=CC=CC=N1 YRSFPIMTLHOOHE-AHWVRZQESA-N 0.000 claims 1
- JQTPYILSGRGOOJ-MFXHTCIWSA-N 2,3-dihydroxypropyl (2s)-2-[[2-[[(2s)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C=1C=CC2=CC=CC=C2C=1CN(CC(=O)N[C@@H](CCSC)C(=O)OCC(O)CO)C[C@@H]1CCCN1C(=O)CN JQTPYILSGRGOOJ-MFXHTCIWSA-N 0.000 claims 1
- JFBPYSBUKCGYKB-UHFFFAOYSA-N 2-[4-[4-[4-(3,4-dichlorophenyl)-5-pyridin-4-yl-1h-imidazol-2-yl]piperidin-1-yl]butyl]-1,1-dioxo-1,2-benzothiazol-3-one Chemical compound C1=C(Cl)C(Cl)=CC=C1C1=C(C=2C=CN=CC=2)N=C(C2CCN(CCCCN3S(C4=CC=CC=C4C3=O)(=O)=O)CC2)N1 JFBPYSBUKCGYKB-UHFFFAOYSA-N 0.000 claims 1
- QAQPWEQFMZBSHK-UHFFFAOYSA-N 2-[4-[4-[4-(3,4-dichlorophenyl)-5-pyridin-4-yl-1h-imidazol-2-yl]piperidin-1-yl]butyl]isoindole-1,3-dione Chemical compound C1=C(Cl)C(Cl)=CC=C1C1=C(C=2C=CN=CC=2)N=C(C2CCN(CCCCN3C(C4=CC=CC=C4C3=O)=O)CC2)N1 QAQPWEQFMZBSHK-UHFFFAOYSA-N 0.000 claims 1
- KJIMUXBSMIKVMQ-UHFFFAOYSA-N 2-[5-[4-[4-(3,4-dichlorophenyl)-5-pyridin-4-yl-1h-imidazol-2-yl]piperidin-1-yl]pentyl]-3h-isoindol-1-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.C1=C(Cl)C(Cl)=CC=C1C1=C(C=2C=CN=CC=2)N=C(C2CCN(CCCCCN3C(C4=CC=CC=C4C3)=O)CC2)N1 KJIMUXBSMIKVMQ-UHFFFAOYSA-N 0.000 claims 1
- GYGGXCNUQIYXAV-UHFFFAOYSA-N 2-[6-[4-[4-(3,4-dichlorophenyl)-5-pyridin-4-yl-1h-imidazol-2-yl]piperidin-1-yl]hexyl]-1,1-dioxo-1,2-benzothiazol-3-one Chemical compound C1=C(Cl)C(Cl)=CC=C1C1=C(C=2C=CN=CC=2)N=C(C2CCN(CCCCCCN3S(C4=CC=CC=C4C3=O)(=O)=O)CC2)N1 GYGGXCNUQIYXAV-UHFFFAOYSA-N 0.000 claims 1
- HQRFHWKXJRVSKW-UHFFFAOYSA-N 2-[6-[4-[4-(3,4-dichlorophenyl)-5-pyridin-4-yl-1h-imidazol-2-yl]piperidin-1-yl]hexyl]isoindole-1,3-dione Chemical compound C1=C(Cl)C(Cl)=CC=C1C1=C(C=2C=CN=CC=2)N=C(C2CCN(CCCCCCN3C(C4=CC=CC=C4C3=O)=O)CC2)N1 HQRFHWKXJRVSKW-UHFFFAOYSA-N 0.000 claims 1
- UQQQOQGYMNTYOH-UHFFFAOYSA-N 2-amino-1-[3-[5-(3,4-dichlorophenyl)-5-pyridin-4-yl-1,4-dihydroimidazol-2-yl]piperidin-1-yl]ethanone;dihydrochloride Chemical compound Cl.Cl.C1N(C(=O)CN)CCCC1C1=NC(C=2C=C(Cl)C(Cl)=CC=2)(C=2C=CN=CC=2)CN1 UQQQOQGYMNTYOH-UHFFFAOYSA-N 0.000 claims 1
- UWQNZECDJJWEBU-UHFFFAOYSA-N 4-[2-(1,4-dimethylpiperidin-4-yl)-4-(4-fluorophenyl)-1h-imidazol-5-yl]pyridine Chemical compound C1CN(C)CCC1(C)C1=NC(C=2C=CN=CC=2)=C(C=2C=CC(F)=CC=2)N1 UWQNZECDJJWEBU-UHFFFAOYSA-N 0.000 claims 1
- GERIIDXVWNXOOS-UHFFFAOYSA-N 4-[2-(1-benzylpiperidin-4-yl)-4-(3,4-dichlorophenyl)-1h-imidazol-5-yl]pyridine Chemical compound C1=C(Cl)C(Cl)=CC=C1C1=C(C=2C=CN=CC=2)N=C(C2CCN(CC=3C=CC=CC=3)CC2)N1 GERIIDXVWNXOOS-UHFFFAOYSA-N 0.000 claims 1
- COOLOZPVKKTIEA-UHFFFAOYSA-N 4-[2-(1-benzylpiperidin-4-yl)-4-(4-fluorophenyl)-1h-imidazol-5-yl]pyridine Chemical compound C1=CC(F)=CC=C1C1=C(C=2C=CN=CC=2)N=C(C2CCN(CC=3C=CC=CC=3)CC2)N1 COOLOZPVKKTIEA-UHFFFAOYSA-N 0.000 claims 1
- IAOJVAYDEVIOKV-UHFFFAOYSA-N 4-[2-(4-methylsulfinylphenyl)-5-naphthalen-1-yl-1h-imidazol-4-yl]pyridine Chemical compound C1=CC(S(=O)C)=CC=C1C1=NC(C=2C3=CC=CC=C3C=CC=2)=C(C=2C=CN=CC=2)N1 IAOJVAYDEVIOKV-UHFFFAOYSA-N 0.000 claims 1
- IWRRFNAWLGECQE-UHFFFAOYSA-N 4-[4-(3,4-dichlorophenyl)-2-(1-methylpiperidin-4-yl)-1h-imidazol-5-yl]pyridine Chemical compound C1CN(C)CCC1C1=NC(C=2C=CN=CC=2)=C(C=2C=C(Cl)C(Cl)=CC=2)N1 IWRRFNAWLGECQE-UHFFFAOYSA-N 0.000 claims 1
- BTDUYFSSFLWEDE-UHFFFAOYSA-N 4-[4-(3,4-dichlorophenyl)-2-[1-(2-phenylethyl)piperidin-4-yl]-1h-imidazol-5-yl]pyridine Chemical compound C1=C(Cl)C(Cl)=CC=C1C1=C(C=2C=CN=CC=2)N=C(C2CCN(CCC=3C=CC=CC=3)CC2)N1 BTDUYFSSFLWEDE-UHFFFAOYSA-N 0.000 claims 1
- POUDZVWQMHMTCJ-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-(1-methylpiperidin-3-yl)-1h-imidazol-5-yl]pyridine Chemical compound C1N(C)CCCC1C1=NC(C=2C=CN=CC=2)=C(C=2C=CC(F)=CC=2)N1 POUDZVWQMHMTCJ-UHFFFAOYSA-N 0.000 claims 1
- XIRXPGXOBQGWNW-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-(1-methylpiperidin-4-yl)-1h-imidazol-5-yl]pyridine Chemical compound C1CN(C)CCC1C1=NC(C=2C=CN=CC=2)=C(C=2C=CC(F)=CC=2)N1 XIRXPGXOBQGWNW-UHFFFAOYSA-N 0.000 claims 1
- LBHNZGNSUMLAQN-IFUPQEAVSA-N 4-[[2-[[(2s)-4-(3-chlorophenyl)-2-(2-methylsulfonylethyl)-5-oxopiperazin-1-yl]methyl]imidazol-1-yl]methyl]benzonitrile;dihydrochloride Chemical compound Cl.Cl.C([C@@H]1CCS(=O)(=O)C)N(C=2C=C(Cl)C=CC=2)C(=O)CN1CC1=NC=CN1CC1=CC=C(C#N)C=C1 LBHNZGNSUMLAQN-IFUPQEAVSA-N 0.000 claims 1
- VHYIMLUJJQTCQU-UHFFFAOYSA-N 4-[[2-[[4-(3-chlorophenyl)-3-oxopiperazin-1-yl]methyl]imidazol-1-yl]methyl]benzonitrile;dihydrochloride Chemical compound Cl.Cl.ClC1=CC=CC(N2C(CN(CC=3N(C=CN=3)CC=3C=CC(=CC=3)C#N)CC2)=O)=C1 VHYIMLUJJQTCQU-UHFFFAOYSA-N 0.000 claims 1
- NOMMEZMKFQOQSL-AVLXHCLOSA-N N([C@@H]([C@H](CSC)C(=O)C1C2=CC=CC=C2CCN1)C(=O)OC)C([C@@H](N)[C@@H](C)CC)C(=O)[C@@H]1CCC(=O)N1 Chemical compound N([C@@H]([C@H](CSC)C(=O)C1C2=CC=CC=C2CCN1)C(=O)OC)C([C@@H](N)[C@@H](C)CC)C(=O)[C@@H]1CCC(=O)N1 NOMMEZMKFQOQSL-AVLXHCLOSA-N 0.000 claims 1
- OJTJXQYWGCVNPP-SJCKSWINSA-N N([C@@H]([C@H](CSC)C(=O)C1C2=CC=CC=C2CCN1)C(O)=O)C([C@@H](N)[C@@H](C)CC)C(=O)[C@@H]1CCC(=O)N1 Chemical compound N([C@@H]([C@H](CSC)C(=O)C1C2=CC=CC=C2CCN1)C(O)=O)C([C@@H](N)[C@@H](C)CC)C(=O)[C@@H]1CCC(=O)N1 OJTJXQYWGCVNPP-SJCKSWINSA-N 0.000 claims 1
- OITGWZQOTKBNHC-MHAHJAEUSA-N [(3s)-4-[(2r)-2-amino-3-hydroxyheptadecyl]-3-butylpiperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound C1[C@H](CCCC)N(C[C@@H](N)C(O)CCCCCCCCCCCCCC)CCN1C(=O)C1=CC=CC2=CC=CC=C12 OITGWZQOTKBNHC-MHAHJAEUSA-N 0.000 claims 1
- DSPPCOUSGYJEON-UXHICEINSA-N [(3s)-4-[(2r)-2-amino-4-hydroxybutyl]-3-butylpiperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound C1CN(C[C@H](N)CCO)[C@@H](CCCC)CN1C(=O)C1=CC=CC2=CC=CC=C12 DSPPCOUSGYJEON-UXHICEINSA-N 0.000 claims 1
- SFMJVGMTFJODNJ-CGAIIQECSA-N [(3s)-4-[2-amino-3-(2-hydroxyphenyl)propyl]-3-butylpiperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound C([C@@H]1CCCC)N(C(=O)C=2C3=CC=CC=C3C=CC=2)CCN1CC(N)CC1=CC=CC=C1O SFMJVGMTFJODNJ-CGAIIQECSA-N 0.000 claims 1
- AVXFQBJAVCGIFW-FLDQDSGZSA-N [(3s)-4-[2-amino-3-(2-phenylmethoxyphenyl)propyl]-3-butylpiperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound C([C@@H]1CCCC)N(C(=O)C=2C3=CC=CC=C3C=CC=2)CCN1CC(N)CC1=CC=CC=C1OCC1=CC=CC=C1 AVXFQBJAVCGIFW-FLDQDSGZSA-N 0.000 claims 1
- QDVKETOAAQPNNT-ZSXSBBPPSA-N [(3s)-4-[3-amino-2-(naphthalen-2-ylmethylamino)propyl]-3-butylpiperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound C1=CC=C2C(C(=O)N3C[C@@H](N(CC3)CC(CN)NCC=3C=C4C=CC=CC4=CC=3)CCCC)=CC=CC2=C1 QDVKETOAAQPNNT-ZSXSBBPPSA-N 0.000 claims 1
- BYLXOJATODGOPS-SANMLTNESA-N [(3s)-4-[[3-[(4-bromophenyl)methyl]imidazol-4-yl]methyl]-3-butylpiperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound C([C@@H]1CCCC)N(C(=O)C=2C3=CC=CC=C3C=CC=2)CCN1CC1=CN=CN1CC1=CC=C(Br)C=C1 BYLXOJATODGOPS-SANMLTNESA-N 0.000 claims 1
- XSAJRSTXUWYGPC-KGLYDCNGSA-N [(3s)-4-butan-2-yl-3-[(2r)-3-hydroxy-2-[(4-nitrophenyl)methylamino]propyl]piperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound N([C@@H](CO)C[C@H]1CN(CCN1C(C)CC)C(=O)C=1C2=CC=CC=C2C=CC=1)CC1=CC=C([N+]([O-])=O)C=C1 XSAJRSTXUWYGPC-KGLYDCNGSA-N 0.000 claims 1
- MXOQNVMDKHLYCZ-UHFFFAOYSA-N benzamidoxime Chemical compound ON=C(N)C1=CC=CC=C1 MXOQNVMDKHLYCZ-UHFFFAOYSA-N 0.000 claims 1
- ULHMCEYWNWSATD-YTMVLYRLSA-N benzyl (2s)-2-[[2-[[(2s)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound N([C@@H](CCSC)C(=O)OCC=1C=CC=CC=1)C(=O)CN(CC=1C2=CC=CC=C2C=CC=1)C[C@@H]1CCCN1C(=O)CN ULHMCEYWNWSATD-YTMVLYRLSA-N 0.000 claims 1
- YUONEWNPBFBBSG-LSYYVWMOSA-N cyclohexyl (2s)-2-[[2-[[(2s)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound N([C@@H](CCSC)C(=O)OC1CCCCC1)C(=O)CN(CC=1C2=CC=CC=C2C=CC=1)C[C@@H]1CCCN1C(=O)CN YUONEWNPBFBBSG-LSYYVWMOSA-N 0.000 claims 1
- GKUBDIRGMHVTLT-UPVQGACJSA-N ethyl (2s)-2-[[2-[[(2s)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C=1C=CC2=CC=CC=C2C=1CN(CC(=O)N[C@@H](CCSC)C(=O)OCC)C[C@@H]1CCCN1C(=O)CN GKUBDIRGMHVTLT-UPVQGACJSA-N 0.000 claims 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims 1
- VVYNQTLYCFOOIU-GOTSBHOMSA-N methyl (2s)-2-[[2-[(2-cyanophenyl)methyl-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl]amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C(=CC=CC=2)C#N)CCN1C(=O)CC1=CN=CN1 VVYNQTLYCFOOIU-GOTSBHOMSA-N 0.000 claims 1
- XTEQPZARJCTXPJ-ZEQRLZLVSA-N methyl (2s)-2-[[2-[(2-cyanophenyl)methyl-[[(2s)-1-[3-(1h-imidazol-5-yl)propanoyl]pyrrolidin-2-yl]methyl]amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C(=CC=CC=2)C#N)CCN1C(=O)CCC1=CNC=N1 XTEQPZARJCTXPJ-ZEQRLZLVSA-N 0.000 claims 1
- ULRBQPQVNVQOSF-GOTSBHOMSA-N methyl (2s)-2-[[2-[(3-cyanophenyl)methyl-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl]amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C=C(C=CC=2)C#N)CCN1C(=O)CC1=CN=CN1 ULRBQPQVNVQOSF-GOTSBHOMSA-N 0.000 claims 1
- XBHIDWKJAGFKQB-UPVQGACJSA-N methyl (2s)-2-[[2-[[(2s)-1-(1h-imidazole-5-carbonyl)pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)C1=CNC=N1 XBHIDWKJAGFKQB-UPVQGACJSA-N 0.000 claims 1
- NZWWGJWSMAITAX-REWPJTCUSA-N methyl (2s)-2-[[2-[[(2s)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]-thiophen-2-ylamino]propanoate Chemical compound C=1C=CSC=1N([C@@H](C)C(=O)OC)C(=O)CN(CC=1C2=CC=CC=C2C=CC=1)C[C@@H]1CCCN1C(=O)CN NZWWGJWSMAITAX-REWPJTCUSA-N 0.000 claims 1
- LAHFLOMTYJVEHX-PMACEKPBSA-N methyl (2s)-2-[[2-[[(2s)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl-[(2-cyanophenyl)methyl]amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C=1C=CC=C(C#N)C=1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)C[C@@H]1CCCN1C(=O)CN LAHFLOMTYJVEHX-PMACEKPBSA-N 0.000 claims 1
- QXEVYVICZGRUKQ-OALUTQOASA-N methyl (2s)-2-[[2-[[(2s)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl-[(2-methoxyphenyl)methyl]amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C=1C=CC=C(OC)C=1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)C[C@@H]1CCCN1C(=O)CN QXEVYVICZGRUKQ-OALUTQOASA-N 0.000 claims 1
- JFYFNPZTRVRKGS-ICSRJNTNSA-N methyl (2s)-2-[[2-[[(2s)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl-[(3-methoxyphenyl)methyl]amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C=1C=CC(OC)=CC=1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)C[C@@H]1CCCN1C(=O)CN JFYFNPZTRVRKGS-ICSRJNTNSA-N 0.000 claims 1
- WZYNXYYGPAHRAE-OALUTQOASA-N methyl (2s)-2-[[2-[[(2s)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl-benzylamino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C=1C=CC=CC=1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)C[C@@H]1CCCN1C(=O)CN WZYNXYYGPAHRAE-OALUTQOASA-N 0.000 claims 1
- OMJJXOGARPFMJT-UPVQGACJSA-N methyl (2s)-2-[[2-[[(2s)-1-(3-aminopropanoyl)pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C=1C=CC2=CC=CC=C2C=1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)C[C@@H]1CCCN1C(=O)CCN OMJJXOGARPFMJT-UPVQGACJSA-N 0.000 claims 1
- KKHKWUHYSPSTGC-OIKPOIBNSA-N methyl (2s)-2-[[2-[[(2s)-1-[(2r)-2-amino-3-(1h-imidazol-5-yl)propanoyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C([C@@H](N)C(=O)N1CCC[C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=1C2=CC=CC=C2C=CC=1)C1=CN=CN1 KKHKWUHYSPSTGC-OIKPOIBNSA-N 0.000 claims 1
- NGXKPLLTHVOWOD-UCFCWBNQSA-N methyl (2s)-2-[[2-[[(2s)-1-[(2r)-2-aminopropanoyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C=1C=CC2=CC=CC=C2C=1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)C[C@@H]1CCCN1C(=O)[C@@H](C)N NGXKPLLTHVOWOD-UCFCWBNQSA-N 0.000 claims 1
- MVEXQFGXLMPEIZ-HVCNVCAESA-N methyl (2s)-2-[[2-[[(2s)-1-[(2s)-2,5-diamino-5-oxopentanoyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C=1C=CC2=CC=CC=C2C=1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)C[C@@H]1CCCN1C(=O)[C@@H](N)CCC(N)=O MVEXQFGXLMPEIZ-HVCNVCAESA-N 0.000 claims 1
- KKHKWUHYSPSTGC-URORMMCBSA-N methyl (2s)-2-[[2-[[(2s)-1-[(2s)-2-amino-3-(1h-imidazol-5-yl)propanoyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C([C@H](N)C(=O)N1CCC[C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=1C2=CC=CC=C2C=CC=1)C1=CN=CN1 KKHKWUHYSPSTGC-URORMMCBSA-N 0.000 claims 1
- XKCYHPWIWUBOPM-XWGVYQGASA-N methyl (2s)-2-[[2-[[(2s)-1-[(2s)-2-amino-3-hydroxypropanoyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C=1C=CC2=CC=CC=C2C=1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)C[C@@H]1CCCN1C(=O)[C@@H](N)CO XKCYHPWIWUBOPM-XWGVYQGASA-N 0.000 claims 1
- RJXFHHSCMXXBLC-CVDCTZTESA-N methyl (2s)-2-[[2-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]-(trifluoromethyl)amino]propanoate Chemical compound C([C@H]1CN(CC(=O)N([C@@H](C)C(=O)OC)C(F)(F)F)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CC1=CNC=N1 RJXFHHSCMXXBLC-CVDCTZTESA-N 0.000 claims 1
- GVYRRSIDCKETTR-GOTSBHOMSA-N methyl (2s)-2-[[2-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl-[(2-methylphenyl)methyl]amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C(=CC=CC=2)C)CCN1C(=O)CC1=CN=CN1 GVYRRSIDCKETTR-GOTSBHOMSA-N 0.000 claims 1
- CBMLEDWACNYBEU-UNMCSNQZSA-N methyl (2s)-2-[[2-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl-[[2-(trifluoromethyl)phenyl]methyl]amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C(=CC=CC=2)C(F)(F)F)CCN1C(=O)CC1=CNC=N1 CBMLEDWACNYBEU-UNMCSNQZSA-N 0.000 claims 1
- ONYWHQGMJJQBFA-UPVQGACJSA-N methyl (2s)-2-[[2-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl-naphthalen-1-ylsulfonylamino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)S(=O)(=O)C=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CC1=CNC=N1 ONYWHQGMJJQBFA-UPVQGACJSA-N 0.000 claims 1
- MBPQSJQKBMFGNV-ZCYQVOJMSA-N methyl (2s)-2-[[2-[[(2s)-1-[2-(dimethylamino)acetyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C=1C=CC2=CC=CC=C2C=1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)C[C@@H]1CCCN1C(=O)CN(C)C MBPQSJQKBMFGNV-ZCYQVOJMSA-N 0.000 claims 1
- FEQRRGQGHNRALO-UPVQGACJSA-N methyl (2s)-2-[[2-[[(2s)-1-[2-(methylamino)acetyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound CNCC(=O)N1CCC[C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=CC2=CC=CC=C12 FEQRRGQGHNRALO-UPVQGACJSA-N 0.000 claims 1
- YOXZXGNNGZYPKQ-YTMVLYRLSA-N methyl (2s)-2-[[2-[[(2s)-1-[2-[methyl(pyridin-4-yl)amino]acetyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CN(C)C1=CC=NC=C1 YOXZXGNNGZYPKQ-YTMVLYRLSA-N 0.000 claims 1
- RJEDCSBFWPXDQX-GOTSBHOMSA-N methyl (2s)-2-[[2-[[(2s)-1-[3-(1h-imidazol-5-yl)propanoyl]pyrrolidin-2-yl]methyl-[(2-methoxyphenyl)methyl]amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C(=CC=CC=2)OC)CCN1C(=O)CCC1=CNC=N1 RJEDCSBFWPXDQX-GOTSBHOMSA-N 0.000 claims 1
- IDOPLSXAMKHPEG-VXKWHMMOSA-N methyl (2s)-2-[[2-[benzyl-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl]amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C=CC=CC=2)CCN1C(=O)CC1=CN=CN1 IDOPLSXAMKHPEG-VXKWHMMOSA-N 0.000 claims 1
- LMWZXKDVEIHYSV-XCZPVHLTSA-N methyl (2s)-4-methylsulfanyl-2-[[2-[naphthalen-1-ylmethyl-[[(2s)-1-(2-pyridin-2-ylacetyl)pyrrolidin-2-yl]methyl]amino]acetyl]amino]butanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CC1=CC=CC=N1 LMWZXKDVEIHYSV-XCZPVHLTSA-N 0.000 claims 1
- NKHUVKYFYROPGF-XCZPVHLTSA-N methyl (2s)-4-methylsulfanyl-2-[[2-[naphthalen-1-ylmethyl-[[(2s)-1-(2-pyridin-3-ylacetyl)pyrrolidin-2-yl]methyl]amino]acetyl]amino]butanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CC1=CC=CN=C1 NKHUVKYFYROPGF-XCZPVHLTSA-N 0.000 claims 1
- PQHPNFNTLZVBKS-ZVNMQXQGSA-N methyl (2s)-4-methylsulfanyl-2-[[2-[naphthalen-1-ylmethyl-[[(2s)-1-(piperidine-3-carbonyl)pyrrolidin-2-yl]methyl]amino]acetyl]amino]butanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)C1CCCNC1 PQHPNFNTLZVBKS-ZVNMQXQGSA-N 0.000 claims 1
- SBVVZLWMKBDEEF-BDYUSTAISA-N methyl (2s)-4-methylsulfanyl-2-[[2-[naphthalen-1-ylmethyl-[[(2s)-1-(piperidine-4-carbonyl)pyrrolidin-2-yl]methyl]amino]acetyl]amino]butanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)C1CCNCC1 SBVVZLWMKBDEEF-BDYUSTAISA-N 0.000 claims 1
- ZPSOILKVHRWGCY-HVCNVCAESA-N methyl (2s)-4-methylsulfanyl-2-[[2-[naphthalen-1-ylmethyl-[[(2s)-1-[(2s)-5-oxopyrrolidine-2-carbonyl]pyrrolidin-2-yl]methyl]amino]acetyl]amino]butanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)[C@@H]1CCC(=O)N1 ZPSOILKVHRWGCY-HVCNVCAESA-N 0.000 claims 1
- PYEKJLQAZSGDMI-RNXOBYDBSA-N methyl (2s)-4-methylsulfanyl-2-[[2-[naphthalen-1-ylmethyl-[[(2s)-1-[(2s)-pyrrolidine-2-carbonyl]pyrrolidin-2-yl]methyl]amino]acetyl]amino]butanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)[C@@H]1CCCN1 PYEKJLQAZSGDMI-RNXOBYDBSA-N 0.000 claims 1
- XPBXPNCQVAZGSR-AHWVRZQESA-N methyl (2s)-5-amino-2-[[2-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]-methylamino]-5-oxopentanoate Chemical compound C([C@H]1CN(CC(=O)N(C)[C@@H](CCC(N)=O)C(=O)OC)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CC1=CNC=N1 XPBXPNCQVAZGSR-AHWVRZQESA-N 0.000 claims 1
- STTPMEVACJNPEF-YADHBBJMSA-N n-[[(2r)-2-amino-3-[(2s)-2-butyl-4-(naphthalene-1-carbonyl)piperazin-1-yl]propyl]sulfanylmethyl]acetamide Chemical compound C1CN(C[C@@H](N)CSCNC(C)=O)[C@@H](CCCC)CN1C(=O)C1=CC=CC2=CC=CC=C12 STTPMEVACJNPEF-YADHBBJMSA-N 0.000 claims 1
- YACFKQLKKNHPDA-IGKIAQTJSA-N pentan-3-yl (2s)-2-[[2-[[(2s)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C=1C=CC2=CC=CC=C2C=1CN(CC(=O)N[C@@H](CCSC)C(=O)OC(CC)CC)C[C@@H]1CCCN1C(=O)CN YACFKQLKKNHPDA-IGKIAQTJSA-N 0.000 claims 1
- JLXIOVDVKLIIOJ-XCZPVHLTSA-N propan-2-yl (2s)-2-[[2-[[(2s)-1-[2-(1h-imidazol-5-yl)acetyl]pyrrolidin-2-yl]methyl-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound C([C@H]1CN(CC(=O)N[C@@H](CCSC)C(=O)OC(C)C)CC=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CC1=CNC=N1 JLXIOVDVKLIIOJ-XCZPVHLTSA-N 0.000 claims 1
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- UAEBCZDITCOVNB-WMCAAGNKSA-N tert-butyl n-[(2s)-1-oxo-5-phenylmethoxyhexan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C=O)CCC(C)OCC1=CC=CC=C1 UAEBCZDITCOVNB-WMCAAGNKSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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- 125000004587 thienothienyl group Chemical group S1C(=CC2=C1C=CS2)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
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- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
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- 229960004072 thrombin Drugs 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 125000000169 tricyclic heterocycle group Chemical group 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
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- 235000005074 zinc chloride Nutrition 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to a method of treating cancer using a combination of a compound which has Raf antagonist activity and a compound which has famesyl transferase inhibiting activity.
- the Raf antagonist compounds used in the present invention demonstrate anti-cancer activity through antagonism of the kinase, Raf .
- the raf genes code for a family of proteins which can be oncogenically activated through N-terminal fusion, truncation or point mutations.
- Raf is a member of the MAP Kinase cascade, which also includes MEK's and MAP Kinase (ERK).
- Raf can be activated and undergoes rapid phosphorylation in response to treatment of cells with PDGF, EGF, insulin, thrombin, endothelin, acidic FGF, CSF1 or TPA, as well as in response to oncoproteins v-fms, v-src, v-sis, Hras and polyoma middle T antigen.
- Antisense constructs which reduce cellular levels of c-Raf, and hence Raf activity, inhibit the growth of oncogene-transformed rodent fibroblasts in soft agar, while exhibiting little or no general cytotoxicity. Since inhibition of growth in soft agar is highly predictive of tumor responsiveness in whole animals, these studies suggest that the antagonism of Raf is an effective means by which to treat cancers in which Raf plays a role.
- Examples of cancers where Raf is implicated through overexpression include cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. More particularly, such examples include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes (e.g., K-ras, erb-B) is observed. More particularly, such cancers include pancreatic and breast carcinoma.
- Raf-activating oncogenes e.g., K-ras, erb-B
- the Ras protein is part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation, Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP -bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen,
- Ras Activation of Ras leads to activation of multiple intracellular signal transduction pathways, including the MAP Kinase pathway and the Rho/Rac pathway (Joneson et al, Science 271.-810-812).
- Mutated ras genes are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.
- the protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
- the Ras protein is one of several proteins that are known to undergo post-translational modification.
- Famesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group (Reiss et al, Cell, 62:81 -88 (1990): Schaber et al, J. Biol. Chem., 265: 14701 - 14704 ( 1990); Schafer et al, Science, 249: ⁇ 133-1 139 ( 1990); Marine et al, Proc. Natl Acad. Sci USA, 57:7541 -7545 (1990)).
- Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras.
- the Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa ⁇ -Aaa ⁇ -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al, Nature 370:583-586 (1984)).
- this motif serves as a signal sequence for the enzymes famesyl-protein transferase or geranylgeranyl -protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively.
- famesyl-protein transferase or geranylgeranyl -protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively.
- farnesylated proteins include the Ras-related GTP- binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
- FPTase famesyl-protein transferase
- the first class includes analogs of famesyl diphosphate (FPP), while the second is related to protein substrates (e.g., Ras) for the enzyme.
- FPP famesyl diphosphate
- the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al, ibid; Reiss et. al, ibid; Reiss et al, PNAS, 88:132-136 (1991 )).
- Such inhibitors may inhibit protein prenylation while serving as altemate substrates for the famesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141 ,851 , University of Texas; N.E. Kohl et al, Science, 260:1934-1931 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
- Inhibition of famesyl-protein transferase has been shown to block the growth of ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of famesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly (N.E.
- a Raf antagonist compound and a famesyl protein transferase inhibitor are used in the present invention to treat cancer, such as in tumor cells which are not particularly Raf or FPTase dependent.
- the Raf antagonist compound and a famesyl protein transferase inhibiting compound are used in combination.
- a method of treating cancer is disclosed which is comprised of administering to a mammalian patient in need of such treatment an effective amount of a Raf antagonist compound and an effective amount of a famesyl protein transferase inhibiting compound.
- the present invention relates to a method of treating cancer which is comprised of admininstering to a mammalian patient in need of such treatment an effective amount of a Raf antagonist compound and an effective amount of a famesyl protein transferase inhibiting compound. Any compound which antagonizes Raf and any compound which inhibits famesyl protein transferase can be used.
- Raf antagonist is used in the general sense to relate to compounds which antagonize, inhibit or counteract the activity of the ra/ ' gene or the protein produced in response thereto.
- famesyl protein transferase inhibiting compound is likewise used in the general sense and refers to compounds which antagonize, inhibit or counteract the activity of the gene coding famesyl protein transferase or the protein produced in response thereto.
- Cancers which are treatable in accordance with the inven ⁇ tion described herein include cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx, liver and lung. More particularly, such cancers include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes (e.g., K-ras, erb-B) is observed. More particularly, such cancers include pancreatic, mammary and salivary carcinomas, colorectal carcinoma, exocrine pancreatic carcinoma and myeloid leukemias.
- Raf-activating oncogenes e.g., K-ras, erb-B
- AR represents an aromatic group containing 6-10 atoms
- X and X' each independently represent -(CH2)m-Y-(CH2)n -, wherein m and n represent integers within the range of from 0 - 4, such that the sum of m and n is from 0 - 6;
- Y represents a member selected from the group consisting of: a direct bond: O; S(0)y, with y equal to 0, 1 or 2; NRq ' , with Rq ' as defined below; C(O); OC(O); C(0)0; SO ⁇ NRq ' with x equal to 1 or 2 and Rq ' as defined below; NRq ' SO x ; C(0)NRq ' and NRq'C(O) ;
- — represents a 4 to 10 membered non-aromatic heterocycle containing at least one N atom, and optionally containing 1-2 additional N atoms and 0-1 O or S atom;
- Rx represents H, Ci- alkyl(R q ) , OCi-6 alkyl(Rq) 3 or
- each R and R" independently represents a member selected from the group consisting of: halo; hydroxy; Ci-6 alkyl(Rq)3; OCi-6 alkyl(Rq)3; C3-8 cycloalkyl(Rq)3; CN; CONH 2 ; CONHCi-6 alkyl(R q ) 3 ; CON(Ci- 6 alkyl(Rq)3)2; NH ; NHCi-6 alkyl(Rq) ; N(Ci- 6 alkyl(Rq)3)2; C0 2 H; C0 2 Ci- 6 alkyl(Rq) 3 ; C(0)Ci- 6 alkyl(Rq) 3 ; aryl(Rq)3; heteroaryl(Rq) 3 ; CF3; SH; NO2; SO y C ⁇ _6 alkyl(Rq)3, with y as defined above; SO2NH2; SO2NHC1- 6 alkyl(Rq)3; S ⁇ 2N(C ⁇ .
- each R' independently represents a member selected from the group consisting of: CONH2; CONHCi-6 alkyl(Rq)3;
- each R 5 and R 6 independently represents H, aryl, Cj-6 alkyl(Rq)3, or each CR 5 R 6 taken in combination represents a 3, 4, 5 or 6 membered cycloalkyl or heterocyclyl group, an aryl group or a heteroaryl group, wherein when p equals 1 , at least one of j and k is 1 , 2 or 3;
- each R 7 and R x independently represents H, alkyl or aryl
- Rq represents a member selected from the group consisting of: R q' ; CN; CO2H; CO2C1-4 alkyl; C(0)Ci- 4 alkyl ; aryl(Ra) 3 ; NH2; NHCl -6 alkyl(Ra)3; N(Ci -6 alkyl(Ra)3)2; heteroaryl(Ra) 3 ; CONH 2 ; SH ; S(0) y C ⁇ -6 alkyl(R ⁇ '9 3 ; C(0)NHC ⁇ -6 alkyl(R ⁇ ' >) 3 ; C(0)N(C ⁇ - 6 aLkyl(R a ) 3 ) 2 ; -heteroalkyl(R") 3; -NHC(0)NH 2 ; -NHC(NH)NH 2 ;
- each R a independently represents a member selected from the group consisting of: H, Cj-6 alkyl, OCj-6 alkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, aralkoxy, substituted aralkoxy , halo, hydroxy, CN, CONH 2 , CONHC ] - ⁇ alkyl, CON(C 1.
- Rq ' represents H, OH, C 1 . 4 alkyl, -OC 1 -4 alkyl, aryl or C(0)C 1 - 4 alkyl;
- each R' independently represents a member selected from the group consisting of: hydroxy; Ci-6 alkyl(Rq)3; C3-8 cycloalkyl(Rq)3; OC1-6 alkyl(Rq)3; OC3-8 cycloalkyl(Rq) 3 ; heterocyclyl(Rq) 3 ; CN; NH(Rq”); NHC ⁇ _ 6 alkyl(Rq) 3 ; N(Ci-6 alkyl(Rq) 3 ) 2 ; NHC3-8 cycloalkyl(Rq)3; N(C _8 cycloalkyl(Rq) 3 ) 2 ; CF3; SH; NO2; C2-4 alkenyl(Rq)2-3 , aryl(Rq)3 , heteroaryl(Rq) 3 ; C2-4 alkynyl(Rq)i-3 -OC(O) C3-8 cycloalkyI(Rq) 3
- R 5 and R 6 are independently H, aryl, Ci- f i alkyl(Rq)3, or CR 5 R 6 in combination represents a 3, 4, 5 or 6 membered cycloalkyl or heterocyclyl group, an aryl group or a heteroaryl group;
- p represents 1 , 2 or 3, with the proviso that when p represents 1 , CR 5 R 6 represents a 3, 4, 5 or 6 membered cycloalkyl group or a heterocyclyl group, an aryl group or a heteroaryl group, and at least one of j and k is 1 , 2 or 3;
- R 9 represents H, a negative charge balanced by a positively charged group or a protecting group
- Rq represents a member selected from the group consisting of: Rq ' ; CN; C0 2 H; CO2C1 -4 alkyl; C(0)Ci- alkyl ; NH(Rq " ) ; aryl(Ra) 3; heteroaryl(Ra) 3 ; NHC 1 -4 alkyl ; N(C]. 4 alkyl) 2 ; CONH 2 ; SH; S(0) y Ci -6 alkyl(R C(0)NHC 1-6 alkyl(R") 3 ; C(0)N(C ⁇ -6 alkyl(Ra) 3 ) 2 ; NHC(NH)NH 2 ; -heteroalkyl(R ⁇ 3 . -NHC(0)NH 2 ;
- Rq represents H, OH or OC1-4 alkyl
- R l is 4-pyridyl, pyrimidinyl, quinazolin-4-yl, quinolyl, isoquinolinyl, 1 -imidazolyl or 1 -benzimidazolyl which is optionally substituted with one or two substituents each of which is independently selected from C l-4 alkyl, halogen, Cl -4 alkoxy, Cl -4 alkylthio, NR 10R20, or N- heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR22;
- R2 is hydrogen, -(CRioR20)n OR 12, heterocyclyl, heterocyclyl Ci -io alkyl, Cl - 10 alkyl, halo-substituted Cl -10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl.
- 0 is an aryl or heteroaryl group; t is a number having a value of 1 , 2 or 3; Z is oxygen or sulfur; n is 0 or an integer from 1 to 10; Y ] is independently selected from hydrogen, Cl -5 alkyl, halo- substituted Cl -5 alkyl, halogen, or -(CRl ⁇ R2 ⁇ )nY2; Y2 is -OR8, -N02, -S(0) m 'Rl l , -SR8, -S(0)) m 'OR8, -S(0)mNR 8 R9, -NR8R9, -O(CRi0R20)nNR8R9, -C(0)R8, -CO2R8, -C ⁇ 2(CRl ⁇ R20)n * CONR8R9, -ZC(0)R8, -CN, -C(Z)NR8R9, NR-NRioC(Z)R8, -C(Z)NR8 ⁇ R9, -
- m' is a number having a value of 1 or 2;
- R4 is phenyl, naphth-1 -yl or naphth-2-yl which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-l -yl or 5-naphth-l -yl substituent, is halo, cyano,-C(Z)NR7Ri7, -C(Z)OR23, -(CRj ⁇ R20)m"'COR36, SR5, -SOR5, OR36
- R5 is hydrogen, Cl -4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties -SR5 being -SNR7R17 and -SOR5 being -SOH;
- R6 is Cl -4 alkyl, halo-substituted-Ci -4 alkyl, Cl -4 alkenyl, C2-4 alkynyl or C3-5 cycloalkyl
- R7 and R17 are each independently selected from hydrogen or Cl-4 alkyl, or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR22
- R8 is hydrogen, heterocyclyl, heterocyclylalkyl or Rn
- R9 is hydrogen, Cl -10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or Rg and R9 may together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from
- R l3 is hydrogen, Cl - 10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl Cl -10 alkyl, aryl, aryl Cl - 10 alkyl, heteroaryl or heteroaryl Cl - 10 alkyl;
- R l4 and R24 is each independently selected from hydrogen, alkyl, nitro or cyano;
- R l5 is hydrogen, cyano, Cl -4 alkyl, C3-7 cycloalkyl or aryl;
- R 16 and R26 is each independently selected from hydrogen or optionally substituted Cl -4 alkyl, optionally substituted aryl or optionally substituted aryl-Cl -4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen,
- R21 is hydrogen, a pharmaceutically acceptable cation, Cl -10 alkyl, C3-7 cycloalkyl, aryl, aryl Cl -4 alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or Cl -10 alkanoyl;
- R23 is Cl -4 alkyl, halo-substituted-Cl -4 alkyl or C3-5 cycloalkyl;
- R36 is hydrogen or R23;
- R25 is Cl -10 alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-Cl -10 alkyl, heteroaryl or heteroarylalkyl;
- R27 is hydrogen, cyano, Cl -4 alkyl, C3-7 cycloalkyl or aryl; or a pharmaceutically acceptable salt thereof.
- famesyl protein transferase inhibiting compounds include the following:
- Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, R 1 ⁇ (O) -, R!0C(O)NR10-, CN, N02, (R 10 )2N-C(NRlO)_, RlOc(O)-, R ] 0 ⁇ C(O)-, N3,
- R2 and R3 are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle,
- substituted group is substituted with one or more of:
- R2 and R ⁇ are attached to the same C atom and are combined to form (CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(CORIO)- ; R4 and R5 are independently selected from H and CH3;
- R2, R , R4 anf j R5 are optionally attached to the same carbon atom;
- R6, R7 and R 7a are independently selected from: H; Cl -4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
- R6 and R? may be joined in a ring;
- R7 and R ⁇ may be joined in a ring;
- R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R ⁇ 0 ⁇ -, Rl ls(0)m-, R 10 C(O)NRl ., CN, N ⁇ 2, R 1 °2N-C(NR 10)-,
- R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0)m-, R 10 C(O)NRl0-, CN, N ⁇ 2, (RlO)2N-C-(NRlO)-,RlOC(0)-, RlO ⁇ C(O)-, N3, -N(RlO)2, or Rl l ⁇ C(O)NRl0-, and c) Cl-C alkyl unsubstituted or substituted by perfluoroalkyl,
- RlO is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;
- Rl 1 is independently selected from Cj-C6 alkyl and aryl
- V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A2 is S(0) m ; W is a heterocycle;
- Rla, Rib , RlO, Rl 1, m , R2, R3, R6, R7 ? p , R7a, u , R8, Al, A2, V, W, X , n, p, r, s, t and u are as defined above with respect to formula (Il-a);
- R4 is selected from H and CH3;
- R2, R3 and R ⁇ are optionally attached to the same carbon atom;
- R9 is selected from: a) hydrogen, b) alkenyl. alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) ⁇ r, R!0C(O)NR10-, CN, NO2,
- G is H2 or O
- - Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1 ) Cl-4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy,
- R la, Rib, RlO, RU , m, R2, R3 ? R6 ? R7, p , u , R 7a ? R 8, A l , A , V, W, X, n, r and t are as defined above with respect to formula (Il-a);
- - R4 is selected from H and CH3;
- R2, R3 and R ⁇ are optionally attached to the same carbon atom;
- G is O;
- Rl 1 , V, W, m, n, p and r are as defined above with respect to formula (Il-a);
- Rl and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl,
- R2a and R2b are independently selected from: a) hydrogen, b) Cl -C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, RlOO-, Rl lS(0) m -, R10C(0)NR10-, CN, N3, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, -N(RlO)2, or
- R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cj -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R l0)2, N02, Rl°0-, R l ! S(0)m-, R 10C(0)NR 10-,
- R3 and R4 are combined to form - (CH2)s - ;
- R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br.
- R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and-N(CORlO)-;
- R7a i selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C 10 cycloalkyl;
- R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, e) Cl -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and
- C3-C10 cycloalkyl f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;
- R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C alkenyl,
- R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RllS(0) m -, R!0C(O)NR10-, CN, NO2,
- RlO is independently selected from H, C1-C6 alkyl, benzyl, substituted aryl and C1-C alkyl substituted with substituted aryl;
- Z is independently H2 or O
- R 11 , W, m, n, p and r are as defined above with respect to formula (II- a);
- Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3- 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, Rl lS(0) m -, R10C(0)NR10-, CN,
- R2a and R2b are independently selected from: a) hydrogen, b) Cl -C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, RlOO-, RllS(0) m -, R10C(O) R10-, CN, N3, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlO ⁇ C(O)-, -N(RlO)2, or RllOC(O)NRl0-, c) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, RlOO,
- R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N ⁇ 2, Rl°0-, Rl lS(0) m -, R 10 C(O)NRl0-, CN, (R10)2N-C(NR10)-, Rl0 (O)-, RlO ⁇ C(O)-,
- R3 and R are combined to form - (CH2)s - ;
- R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C2O alkyl, C2-C20 alkenyl,
- R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0)m, -NC(O)-, and -N(CORlO)- ;
- R6 is a) substituted or unsubstituted C1 -C8 alkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from:
- R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C l -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and
- R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C 10 cycloalkyl.
- R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl F, Cl, Br, RlOO-, RUsiO -, Rl0c(O)NRl0-, CN, N ⁇ 2, R1°2N-C(NR10)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(Rl0)2, or
- Rll ⁇ C(O)NRl0- and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R J 0 ⁇ -, Rl lS(0) m -, Rl0C(O)NH-, CN, H2N-C(NH)-, RlOc(O)-, RlO ⁇ C(O)-,
- R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl,
- RlO is independently selected from H, C1-C6 alkyl, benzyl, substituted aryl and C 1 -C6 alkyl substituted with substituted aryl;
- Rl2 is hydrogen or C1-C6 alkyl
- Rl3 is C1-C6 alkyl
- Z is independently H2 or O
- Rl 1 V, W, m, n, p and r are as defined above with respect to formula (Il-a);
- Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, Rl lS(0) m -, R!0C(O)NR10-, CN, N02, (RlO)2N-C(NRl )-, Rl c(O)-, Rl ⁇ C(O)-, N3,
- R2a and R2b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C alkenyl, RlOO-, Rl ] S(0) m -, R!0C(O)NR10-, CN, N3, (Rl0)2N-C(NRl0)-, RlOc(O)-, RlO ⁇ C(O)-, -N(RlO)2, or Rll ⁇ C(O)NRl0-, c) aryl, heterocycle, C3-C10 cycloalkyl, C2-C alkenyl, R J 0 ⁇ -, RHS(0) m -, R! C(O) R1 -, CN, NO2,
- R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C2O alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N02, R 10 O-, Rl lS(0) m -, R1°C(0)NR10-, CN, (Rl0) 2 N-C(NRl0)-,Rl0 (O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, Rl l ⁇ C(O)NRl0- and C1-C2O alkyl, and d)
- R3 and R4 are combined to form - (CH2)s - ;
- R7a i selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and
- R7b i selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, e) C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycl
- R is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R l OO-,
- R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R!0C(O)NR1 -, CN, N02,
- RlO is independently selected from H, C1-C alkyl, benzyl, substituted aryl and C1-C6 alkyl substituted with substituted aryl;
- Rl2 is hydrogen or C1-C6 alkyl
- Rl3 is C1-C6 alkyl
- Z is independently H2 or O
- Rl 1, V, W, m, n, p and r are as previously defined with respect to formula (Il-a);
- Rl and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
- R2a and R2b are independently selected from: a) hydrogen, b) Cl -C6 alkyl unsubstituted or substituted by C2-C alkenyl, RlOO-, RllS(0) m -, R!0C(O)NR10., CN, N3, (Rl ) 2 N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, -N(RlO)2, or
- R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N ⁇ 2, RlOO-, Rl lS(0) m -, R10C(O)NR10-, CN, (RlO) 2 N-C(NRlO)-,RlOc(0)-, RlO ⁇ C(O)-, N3, -N(RlO)2, Rl l ⁇ C(O)NRl0- and C1-C2O alkyl, and d) C1-C
- R3 and R4 are combined to form - (CH2)s - ;
- R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;
- R7b i selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, e) C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycl
- R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, Rl OO-, Rl lS(0) m -, R 10C(O)NR 10-, CN, N02, R1°2N-C(NR 10)-,
- R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl l S(0) m -, R 10 C(O)NR l0-, CN, N ⁇ 2, (R 10) N-C-(NR 10)-, R lOc(O)-, R lO ⁇ C(O)-, N3, -N(R 10)2, or R 1 1 OC(0)NR 10-, and c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl'S(0) m -, R10C(O)NR10-, CN, (R10) 2 N-C(NR10)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(Rl0)2,orRllOC(O)NRl0- ;
- RlO is independently selected from H, Cl-C6 alkyl, benzyl, substituted aryl and -C6 alkyl substituted with substituted aryl;
- Rl2 is hydrogen or C1-C6 alkyl
- Rl3 is C1-C6 alkyl
- Z is independently H2 or O
- R la, Rib, RX, R 5 RIO, R1 1 , A » , A2, V, W, m, n, p and r are as previously defined with respect to formula (Il-a);
- R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N02, R lOO-, R l lS(0) m -, R ! 0C(O)NR 10-, CN, (R 10) N-C(NR 1 )-, R 10c(O)-, R 10 ⁇ C(O)-,
- R2 and R3 are combined to form - (CH2)s - ;
- R2 or R3 are combined with R6 to form a ring such that
- R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C l -C6 alkyl unsubstituted or substituted by alkenyl, R 10 ⁇ -, R ⁇ S(0)m-, R l °C(O)NR l0-, CN, N3, (R 10)2N-C(NR 10)-, RlOC(O)-, RlO ⁇ C(O)-, -N(RlO)2, or Rl l ⁇ C(O)NR l0-, c) aryl, heterocycle, cycloalkyl, alkenyl, R lOO-, Rl lS(0)m-, Rl°C(O)NR l0-, CN, N02,
- R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted -C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br,
- R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(COR lO)- ;
- R6 is independently selected from hydrogen or C1 -C6 alkyl; 0 is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
- X, Y and Z are independently H2 or O;
- R la, R i b, R8, R9 ? R lO, R l 1 , A l , A2, V, W, m, n, p and r are as previously defined with respect to formula (Il-a);
- R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1 -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N ⁇ 2, Rl°0-, Rl lS(0) m -, R!0C(O)NR10-, CN, (R10) 2 N-C(NR10)-, RlOc(O)-, RlO ⁇ C(O)-, N3, -N(Rl )2, Rl lOC(O)NRl0- and C1-C2O alkyl, and d) Cl
- R and R3 are combined to form - (CH2)s - ;
- R2 or R are combined with R6 to form a ring such that
- R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) Cl -C6 alkyl unsubstituted or substituted by alkenyl, Rl O-, R ⁇ s m-, Rl°C(O)NRl0-, CN, N3, (R 10 )2N-C(NR 1 0)-, R 10c(O)-, R 10 ⁇ C(O)-, -N(R 1 ) 2 , or R 11 OC(0)NR 10- , c) aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, Rl lS(0)m-, R 10 C(O)NRl0-, N, NO2, (R10) N-C(NR10)-, RlOc(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2 or Rl 10C(0)NR10-, and d) C1-C6 alkyl substituted with an unsubsti
- R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl -C20 alkyl, C2-C20 alkenyl,
- C3-C10 cycloalkyl, aryl or heterocycle group wherein the substituent is selected from F, Cl, Br, N(RlO)2, N02, Rl°0-, Rl l S(0)m-, R1 °C(0)NR 10-, CN, (R10) 2 N-C(NR10)-, R 10C(O)-, R lO ⁇ C(O)-, N3, -N(Rl0)2, R l 1 OC(O)NR 10- and C1 -C20 alkyl, d) C1 -C alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or
- R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(COR lO)- ;
- R6 is independently selected from hydrogen or C1 -C6 alkyl
- R l 2 is a) substituted or unsubstituted Cl -C8 alkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the alkyl or cycloalkyl is selected from: 1) aryl,
- R is independently selected from hydrogen and -C ⁇ alkyl;
- Rl4 is independently selected from C1 -C6 alkyl;
- Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
- X, Y and Z are independently H2 or O;
- R la, Rib, R , R9 ? R 10 ? Rl 1 , A l , A 2 , V, W, m, n, p and r are as previously defined with respect to formula (Il-a);
- R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl -C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N ⁇ 2, Rl°0-, Rl lS(0) m -, R!0C(O)NR1 -, CN, (RlO) 2 N-C(NRlO)-, R10C(O)-, RlO ⁇ C(O)-,
- R2 and R3 are combined to form - (CH2 ⁇ s - ; or
- R2 or R3 are combined with R6 to form a ring such that
- R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, Rl O-,
- R6 is independently selected from hydrogen or C1-C6 alkyl;
- Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
- X, Y and Z are independently H2 or O;
- Rla, R ib, RX, R9, R lO, Rl 1, A* , A2, V, W, m, n, p, and r are as defined above with respect to formula (Il-a);
- R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C 1 -C20 alkyl, C2-C2O alkenyl, C3-C 10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N ⁇ 2, Rl°0-, Rl lS(0) m -, R1°C(0)NR10-, CN, (R 10) 2 N-C(NR 10)-, R 10c(O)-, R 1 O ⁇ C(O)-, N3, -N(RlO)2, R110C(0)NR10- and C1-C2O alkyl, and d) Cl -C6 al
- R2 and R3 are combined to form - (CH2)s - ;
- R2 or R3 are combined with R ⁇ to form a ring such that
- R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) Cl -C6 alkyl unsubstituted or substituted by alkenyl, R 1°0-, Rl lS(0) m -, RlOC(0)NRlO-, CN, N3, (R10) 2 N-C(NR10)-, RlOC(O)-, RlO ⁇ C(O)-, -N(Rl0)2, or Rl 10C(0)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, R J lS(0) m -, Rl°C(O)NRl0-, CN, N02,
- R6 is independently selected from hydrogen or C1-C6 alkyl;
- Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
- X, Y and Z are independently H2 or O;
- R la, Ri b, R8, R9, R 10, R 1 1 , A l , A 2 , V, W, m, n, p and r are as defined above with respect to formula (Il-a);
- R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl-C20 alkyl, C2-C2O alkenyl,
- R2 and R3 are combined to form - (CH2)s - ;
- R2 or R3 are combined with R ⁇ to form a ring such that
- R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C l -C6 alkyl unsubstituted or substituted by alkenyl, R 1 °0-, Rl lS(0) m -, R!0C(O)NR10-, CN, N3, (R 10 )2N-C(NRlO)-,
- R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl -C20 alkyl, C2-C20 alkenyl, C3-C 10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R l0)2, NO2, Rl°0-, Rl !S(0)m-, R 10 C(O)NR l0-, CN, (R 1 °)2N-C(NR 10)-, R 10c(O)-, R 10 ⁇ C(O)-,
- R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0)m, -NC(O)-, and -N(COR l O)- ;
- R6 is independently selected from hydrogen or C1 -C6 alkyl
- 0 is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
- X, Y and Z are independently H2 or O;
- R l a, R ib, R8, R9, RlO, Rl l , A' , A 2 , V, W, m, n, p and r are as defined above with respect to formula (Il-a);
- R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C2O alkyl, C2-C20 alkenyl, C3-C 10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(RlO) 2 , NO2, RlOO-, R l lS(0)m-, R 10 C(O)NR l0_, CN, (R lO) 2 N-C(NRlO)-, Rl0c(O)-, RlO ⁇ C(O)-,
- R2 and R3 are combined to form - (CH2)s - ; or R2 or R3 are combined with R6 to form a ring such that
- R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C 1 -C6 alkyl unsubstituted or substituted by alkenyl, R 10 ⁇ -, Rl lS(0) m -, RlOC(0)NRl -, CN, N3, (Rl°)2N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, -N(RlO)2, orRllOC(O)NRl0-, c) aryl, heterocycle, cycloalkyl, alkenyl, RlOO-,
- R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C] -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N02, Rl°0-, Rl IS(0) m -, R10C(O)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlO ⁇ C(O)-, N3, -N(Rl0)2, Rl lOC(O)NRl0- and C1-C20 alkyl, d) C1 -
- R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(CORlO)- ;
- R6 is independently selected from hydrogen or C 1 -C6 alkyl
- R l2 is a)
- R 3 is independently selected from hydrogen and C1-C6 alkyl
- Rl4 is independently selected from C1-C6 alkyl
- 0 is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
- X, Y and Z are independently H2 or O;
- t lS 3, 4 or 5; and u is O or 1 ;
- R la, Rib, R8, R9, RlO, Rl l , Al , A 2 , V, W, m, n, p and r are as defined above with respect to formula (Il-a);
- R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cj-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br,
- R2 or R3 are combined with R6 to form a ring such that
- R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) Cl -C6 alkyl unsubstituted or substituted by alkenyl, R 1 ° ⁇ -, Rl lS(0) m -, R!0C(O)NR10-, CN, N3, (R1°)2N-C(NR10)-,
- R6 is independently selected from hydrogen or Cl -C6 alkyl
- Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
- X, Y and Z are independently H2 or O;
- R la, R i b, R8, R9, Rl O, R l l , Al , A 2 , V, W, m, n, p and r are as defined above with respect to formula (Il-a);
- R and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl -C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R lO) 2 , N02, RlOO-, R l lS(0)m-, R 1°C(0)NR 10-, CN, (R 10) 2 N-C(NR 10)-, R 10c(O)-, R 1 ⁇ C(O)-,
- R2 and R3 are combined to form - (CH2)s - ;
- R2 or R3 are combined with R6 to form a ring such that
- R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) Cl -C6 alkyl unsubstituted or substituted by alkenyl, R 1°0-, R 1 ⁇ (O ⁇ m-, Rl0C(O)NRl0-, CN, N3, (R 10 )2N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, -N(RlO)2, orRH ⁇ C(O)NRl0-, c) aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, Rl lS(0)m-, R!0C(O)NR10-, CN, N ⁇ 2,
- R6 is independently selected from hydrogen or C1-C6 alkyl
- Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
- X, Y and Z are independently H2 or O;
- Raf Specific compounds which antagonize Raf include the following: 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-l H-imidazol-2-yl]-piperidine-l - carboxylic acid tert-butyl ester;
- Examples of compounds which antagonize or inhibit famesyl protein transferase include the following: 2(S)-Butyl-l -(2,3-diaminoprop-l -yl)- l -(l -naphthoyl)piperazine;
- Raf antagonists are described herein using the terms defined below unless otherwise specified.
- alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.
- the alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.
- substituted alkyl when substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups as defined with respect to each variable.
- Heteroalkyl refers to an alkyl group having from 2-15 carbon atoms, and interrupted by from 1 -4 heteroatoms selected from O, S and N.
- alkenyl refers to a hydrocarbon radical straight, branched or cyclic " containing from 2 to 15 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non- aromatic (non-resonating) carbon-carbon double bonds may be present.
- alkenyl groups examples include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1 -propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, famesyl, geranyl, geranylgeranyl and the like.
- Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted when a substituted alkenyl group is provided.
- alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 15 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon- carbon triple bonds may be present.
- Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted when a substituted alkynyl group is provided.
- Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like.
- Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
- the preferred aryl groups are phenyl and naphthyl.
- Aryl groups may likewise be substituted as defined below.
- Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
- aryl is intended to include any stable monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic.
- aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.
- heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms.
- the heteroaryl group is optionally substituted with up to three groups. Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms.
- Examples of this type are thiophene, purine, imidazopyridine, pyridine, oxazole, thiazole, oxazine, pyrazole, tetrazole, imidazole, pyridine, pyrimidine, pyrazine and triazine.
- Examples of partially aromatic groups are tetrahydro- imidazof4,5-c]pyridine, phthalidyl and saccharinyl, as defined below.
- heterocycle or heterocyclic represents a stable 5- to 7- membered monocyclic or stable 8- to 1 1 -membered bicyclic or stable 1 1 -15 membered tricyclic heterocycle ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined hetero ⁇ cyclic rings is fused to a benzene ring.
- the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
- heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro-benzothienyl.
- heterocycle is selected from imidazolyl, 2-oxopyrrolidinyl, piperidyl, pyridyl and pyrrolidinyl.
- Substituted alkyl, aryl and heteroaryl, and the substituted portions of aralkyl, aralkoxy, heteroaralkyl, heteroaralkoxy and like groups are substituted with from 1 -3 groups selected from the group consisting of: halo, hydroxy, cyano, acyl, acylamino, aralkoxy, alkylsulfonyl, arylsulfonyl, alkylsulfonyla ino, arylsulfonylamino, alkylaminocarbonyl, alkyl, alkoxy, aryl, aryloxy, aralkoxy, amino, alkylamino, dialkylamino, and sulfonylamino.
- substituted aryl substituted heterocycle
- substituted cycloalkyl are intended to include the cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N( -C6 alkyl)2, N ⁇ 2, CN, (Cl -C6 alkyl)0-, -OH, (C1 -C6 alkyl)S(0) m -, (Cl -C6 alkyl)C(0)NH-, H2N-C(NH)-, (C1 -C6 alkyl)C(O)-, (Cl -C6 alkyl)OC(O)-, N3,(Cl -C6 alkyl)OC(0)NH- and C1-C20 alkyl.
- heterocycloalkyl and “heterocyclyl” refer to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S(0) y or N, and in which up to three additional carbon atoms may be replaced by said heteroatoms. When three heteroatoms are present in the heterocycle, they are not all linked together.
- heterocyclyls are piperidinyl, mo ⁇ holinyl, pyrrohdinyl, tetrahydrofuranyl, imidazolinyl, piperazinyl, pyrolidine- 2-one, piperidine-2-one and the like.
- Acyl as used herein refers to -C(0)Ci-6 alkyl and -C(O)- aryl.
- Acylamino refers to the group -NHC(0)C]-6 alkyl and -NHC(0)aryl.
- Aralkoxy refers to the group -OCi-6 alkylaryl.
- Alkylsulfonyl refers to the group -SO2C 1 -6 alkyl.
- Alkylsulfonylamino refers to the group -NHS02Ci-6alkyl.
- Arylsulfonylamino refers to the group -NHS ⁇ 2aryl.
- Alkylaminocarbonyl refers to the group -C(0)NHCi-6 alkyl.
- Aryloxy refers to the group -O-aryl.
- Aralkoxy refers to the group -O-C1-6 alkylaryl.
- Sulfonylamino refers to the group -NHSO3H.
- Halo means Cl, F, Br and I selected on an independent basis.
- -[C(0)(CH 2 )j-CR5R6-(CH 2 )k-NR7]p-R X there may be from 1 to 3 groups -[C(0)(CH 2 )j-CR5R6-(CH 2 )k-NR7]-.
- -[C(0)(CH 2 )j-CR 5 R6-(CH2)k-NR 7 ]p-RK with p equal to 1 , 2 or 3 means the following: -C(0)(CH 2 )j-CR5R6-(CH 2 )k-NR7-RX;
- cycloalkylene attachment is as follows:
- the ring may also be heterocyclic as defined above.
- these ring systems can be heteroaryl or heterocyclic as defined above.
- HETCy is linked to HETCy through a nitrogen atom contained in the ring system, either directly or through a linking group which is part of R'.
- R' a linking group which is part of R'. Examples include phthalidyl and saccharinyl, as further defined below.
- phthalidyl refers to the heteroaryl group:
- heteroaryl group is a group having the term heteroaryl group:
- amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below:
- the compounds used in the present method may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
- named amino acids are understood to have the natural "L" stereoconfiguration
- cyclic amine moiety having 5 or 6 members in the ring, such a cyclic amine which may be optionally fused to a phenyl or cyclohexyl ring.
- a cyclic amine moiety include, but are not limited to, the following specific structures:
- substitution on the cyclic amine moiety by R2a and R2b m ay be on different carbon atoms or on the same carbon atom.
- cyclic moieties are formed.
- examples of such cyclic moieties include, but are not limited to:
- cyclic moieties as described hereinabove for R ⁇ and R ⁇ are formed.
- cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to:
- the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
- such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanihc, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
- any substituent or variable e.g., Rl O, Z, n, etc.
- -N(R lO)2 represents -NHH, -NHCH3, -NHC2H5, etc.
- substituents and substitution pattems on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below.
- the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base with stoichiometric amounts or with an excess of the desired salt- I n ⁇
- the compounds of formulas (ITa) through (Il-k) can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below. Standard methods of peptide synthesis are disclosed, for example, in the following works: Schroeder et al, "The Peptides", Vol. I, Academic Press 1965, or Bodanszky et al, “Peptide Synthesis”, Interscience Publishers, 1966, or McOmie (ed.) "Protective Groups in Organic Chemistry", Plenum Press, 1973, or Barany et al, "The Peptides: Analysis, Synthesis, Biology” 2, Chapter 1 , Academic Press, 1980, or Stewart et al, "Solid Phase Peptide Synthesis", Second Edition, Pierce Chemical Company, 1984. Also useful in exemplifying syntheses of specific unnatural amino acid residues are European Pat. Appl. No. 0 350 163 A2 (particularly page 51 -52) and J. E. Baldwin et al
- the compounds of formula (I-a) and (I-b) are prepared in accordance with U. S. Application No. 60/005,059 filed on October 6, 1995 and 60/005,063 filed on October 6, 1995.
- Two general methods for preparation of the imidazole nucleus are outlined.
- a suitably protected picolyl alcohol is deprotonated with a strong base such as n-butyl lithium or lithium diisopropyl amide and the resulting anion is reacted with an appropriate N,0-dimethylhydrox- amide to give a protected alpha hydroxy ketone.
- the protected alpha hydroxy ketone is then condensed with a suitably functionalized and protected aminoaldehyde in the presence of ammonium acetate, acetic acid and copper acetate.
- the aldehydes typically used contain a suitably protected nitrogen atom. After the imidazole nucleus has been formed, the nitrogen is deprotected and then reacted with an appropriate electrophilic reagent to provide the final compounds.
- a suitably protected picolyl alcohol is deprotonated with a strong base such as n-butyl lithium or lithium diisopropyl amide and the resulting anion is reacted with an appropriate aryl or alkyl aldehyde to give a mono-protected diol.
- the protecting group is removed and the resulting diol is oxidized (by the method of Swem or Moffat) to a dione.
- the dione is then condensed with a suitably functionalized and protected aminoaldehyde in the presence of ammonium acetate in acetic acid to give the imidazole.
- TBDMSO refers to t-butyldimethylsilyloxy
- TFAA refers to trifluoroacetic anhydride
- TBDMS refers to t-butyldimethylsilyl
- TBAF refers to tetrabutyl ammonium fluoride
- Cbz refers to carboxyl- benzyl
- Ac refers to acetyl
- LDA refers to lithium diisopropyl amide.
- E represents an electrophile attached to the heterocyclic ring nitrogen atom.
- suitable electrophiles include alkyl halides, alkyl triflates, alkyl mesylates, benzyl halides, vinyl pyridine and the like.
- E represents alkyl, benzyl, vinyl and the like.
- the compounds are useful in various pharmaceutically acceptable salt forms.
- pharmaceutically acceptable salt refers to those salt forms which would be apparent to the pharma ⁇ ceutical chemist, i.e., those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, ⁇ re ⁇
- compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
- Non-toxic salts include conventional non-toxic salts or quarternary ammonium salts formed, e.g., from non-toxic inorganic or organic acids.
- Non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, sulfanihc, 2-acetoxybenzoic, fumaric, toluenesulfonic, methane- sulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
- the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt- forming inorganic or organic acid or base, in a suitable solvent or solvent combination.
- Raf antagonists described herein are useful in various pharmaceutically acceptable salt forms.
- pharmaceutically acceptable salt refers to those salt forms which would be apparent to the pharmaceutical chemist, i.e., those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatabihty, absorption, distribution, metabolism or excretion.
- compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
- Non-toxic salts include conventional non-toxic salts or quartemary ammonium salts formed, e.g., from non-toxic inorganic or organic acids.
- Non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, sulfanihc, 2-acetoxybenzoic, fumaric, toluenesulfonic, methane- sulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
- the pharmaceutically acceptable salts can be synthesized by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base, in a suitable solvent or solvent combination.
- the famesyl transferase inhibitors of formula (Il-a) through (II-c) can be synthesized in accordance with reaction schemes 1-16, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
- Substituents R a and R D as shown in the Schemes, represent the substituents R2, R 5 R 4 , and R ⁇ ; however their point of attachment to the ring is illustrative only and is not meant to be limiting.
- These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Reaction Schemes.
- Boc -protected amino acids I available commercially or by procedures known to those skilled in the art, can be coupled to N-benzyl amino acid esters using a variety of dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDC HC1 (1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride , chloroform, dichloroethane, or in dimethylformamide.
- dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDC HC1 (1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride , chloroform, dichloroethane, or in dimethylformamide.
- the product II is then deprotected with acid, for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride, and cyclized under weakly basic conditions to give the diketopiperazine III.
- acid for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride
- Reduction of III with lithium aluminum hydride in refluxing ether gives the piperazine IV, which is protected as the Boc derivative V.
- the N-benzyl group can be cleaved under standard conditions of hydrogenation, e.g., 10% palladium on carbon at 60 psi hydrogen on a Parr apparatus for 24-48 h.
- the product VI can be treated with an acid chloride, or a carboxylic acid under standard dehydrating conditions to furnish the carboxamides VII.
- intermediate VIII (Scheme 2).
- Intermediate VIII can be reductively alkylated with a variety of aldehydes, such as IX, prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988, 67, 69-75, from the appropriate amino acid (Scheme 3).
- the reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent such as dichloroethane, methanol or dimethylformamide.
- the product X can be deprotected to give the final compounds XI with trifluoroacetic acid in methylene chloride.
- the final product XI is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
- the product diamine XI can further be selectively protected to obtain XII, which can subsequently be reductively alkylated with a second aldehyde to obtain XIII. Removal of the protecting group, and conversion to the cyclized product such as the dihydroimidazole XV, can be accomplished by literature procedures.
- the trityl protecting group can be removed from XVI to give XVII, or alternatively, XVI can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole XVIII.
- the intermediate VIII can be acylated or sulfonylated by standard techniques.
- the imidazole acetic acid XIX can be converted to the acetate XXI by standard procedures, and XXI can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XXII.
- Hydrolysis and reaction with piperazine VIJ in the presence of condensing reagents such as l -(3-dimethylaminopropyl)- 3-ethylcarbodiimide (EDC) leads to acylated products such as XXIV.
- the piperazine VIII is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XXV in Scheme 6, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 6, 7).
- the alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometalhc reagents such as Grignard reagents, to obtain secondary alcohols such as XXIX.
- the fully deprotected amino alcohol XXX can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXI (Scheme 7), or tertiary amines.
- the protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXXII (Scheme 8).
- Treating XXVII with l ,l '-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide leads to the formation of aziridine XXXII.
- the aziridine reacts in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXXIII.
- Piperazine VIII can be reacted with an aldehyde derived from an amino acid, such as an O-alkylated tyrosine, to obtain compounds such as XXXIX.
- R' is an aryl group
- XXXIX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XL.
- the amine protecting group in XXXIX can be removed, and O-alkylated phenolic amines such as XLI produced.
- N-Aryl piperazines can be prepared as described in Scheme 1 1.
- An aryl amine XLV is reacted with bis -chloroethyl amine hydro ⁇ chloride (XLVI) in refluxing n -butanol to furnish compounds XLVII.
- the resulting piperazines XLVII can then be carried on to final products as described in Schemes 3-9.
- Piperazin-5-ones can be prepared as shown in Scheme 12. Reductive amination of protected amino aldehydes XLIX (prepared from I as described previously) gives rise to compound L. This is then reacted with bromoacetyl bromide under Schotten-Baumann conditions. Ring closure is effected with a base, such as sodium hydride, in a polar aprotic solvent, such as dimethylformamide, to give LI. The carbamate protecting group is removed under acidic conditions, such as trifluoro ⁇ acetic acid in methylene chloride or hydrogen chloride gas in methanol or ethyl acetate, and the resulting piperazine can then be carried on to final products as described in Schemes 3-9.
- a base such as sodium hydride
- a polar aprotic solvent such as dimethylformamide
- the isomeric piperazin-3-ones can be prepared as described in Scheme 13.
- the imine formed from arylcarboxamides LII and 2- aminoglycinal diethyl acetal (LIII) can be reduced under a variety of conditions, including sodium triacetoxyborohydride in dichloroethane, to give the amine LIV.
- Amino acids I can be coupled to amines LIV under standard conditions, and the resulting amide LV when treated with aqueous acid in tetrahydrofuran can cyclize to the unsaturated LVI.
- Catalytic hydrogenation under standard conditions gives the requisite intermediate LVD, which is elaborated to final products as described in Schemes 3-9.
- N-benzyl piperazine V can be acylated with an aryl carboxylic acid.
- the resulting N-benzyl aryl carboxamide LIX can be hydrogenated in the presence of a catalyst to give the piperazine carboxamide LX which can then be carried on to final products as described in Schemes 3-9.
- Reaction Scheme 15 provides an example of the synthesis of compounds wherein the substituents R and R ⁇ are combined to form - (CH2)u - ⁇
- 1-aminocyclohexane-l -carboxylic acid LXI can be converted to the spiropiperazine LXVI essentially according to the procedures outlined in Schemes 1 and 2.
- the piperazine inter ⁇ mediate LXIX can be deprotected as before, and carried on to final products as described in Schemes 3-9.
- the aldehyde XLIX from Scheme 12 can also be reductively alkylated with an aniline as shown in Scheme 16.
- the product LXX1 can be converted to a piperazinone by acylation with chloroacetyl chloride to give LXXII, followed by base-induced cyclization to LXXIII.
- Deprotection, followed by reductive alkylation with a protected imidazole carboxaldehyde leads to LXXV, which can be alkylation with an arylmethylhalide to give the imidazolium salt LXXVI.
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- 1997-03-31 CA CA002250232A patent/CA2250232A1/en not_active Abandoned
- 1997-03-31 WO PCT/US1997/005328 patent/WO1997036587A1/en not_active Application Discontinuation
- 1997-03-31 EP EP97921085A patent/EP0906099A4/de not_active Withdrawn
- 1997-03-31 AU AU27221/97A patent/AU727939B2/en not_active Ceased
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Also Published As
Publication number | Publication date |
---|---|
AU2722197A (en) | 1997-10-22 |
JP2000504023A (ja) | 2000-04-04 |
WO1997036587A1 (en) | 1997-10-09 |
EP0906099A4 (de) | 2001-02-07 |
CA2250232A1 (en) | 1997-10-09 |
AU727939B2 (en) | 2001-01-04 |
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