CA2694955A1 - 3,4-disubstituted coumarin and quinolone compounds - Google Patents
3,4-disubstituted coumarin and quinolone compounds Download PDFInfo
- Publication number
- CA2694955A1 CA2694955A1 CA2694955A CA2694955A CA2694955A1 CA 2694955 A1 CA2694955 A1 CA 2694955A1 CA 2694955 A CA2694955 A CA 2694955A CA 2694955 A CA2694955 A CA 2694955A CA 2694955 A1 CA2694955 A1 CA 2694955A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- aryl
- heteroaryl
- cycloalkyl
- aralkyl
- 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.)
- Abandoned
Links
- 150000007660 quinolones Chemical class 0.000 title abstract description 14
- 125000000332 coumarinyl group Chemical class O1C(=O)C(=CC2=CC=CC=C12)* 0.000 title abstract 3
- 238000000034 method Methods 0.000 claims abstract description 79
- 208000015181 infectious disease Diseases 0.000 claims abstract description 10
- 125000003118 aryl group Chemical group 0.000 claims description 705
- 125000001072 heteroaryl group Chemical group 0.000 claims description 700
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 656
- 125000000217 alkyl group Chemical group 0.000 claims description 632
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 613
- 125000000304 alkynyl group Chemical group 0.000 claims description 591
- 125000003342 alkenyl group Chemical group 0.000 claims description 589
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 563
- 125000005842 heteroatom Chemical group 0.000 claims description 262
- 150000001875 compounds Chemical class 0.000 claims description 209
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 203
- 229910052757 nitrogen Inorganic materials 0.000 claims description 201
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 199
- 125000001424 substituent group Chemical group 0.000 claims description 130
- 125000005843 halogen group Chemical group 0.000 claims description 106
- 150000003839 salts Chemical class 0.000 claims description 87
- 229910019142 PO4 Inorganic materials 0.000 claims description 67
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 67
- 239000010452 phosphate Substances 0.000 claims description 67
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 67
- 125000006413 ring segment Chemical group 0.000 claims description 59
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 239000003112 inhibitor Substances 0.000 claims description 14
- 229940079322 interferon Drugs 0.000 claims description 10
- 102000014150 Interferons Human genes 0.000 claims description 6
- 108010050904 Interferons Proteins 0.000 claims description 6
- 108060004795 Methyltransferase Proteins 0.000 claims description 6
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 6
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 6
- 229960000329 ribavirin Drugs 0.000 claims description 6
- 101800001014 Non-structural protein 5A Proteins 0.000 claims description 4
- 230000026731 phosphorylation Effects 0.000 claims description 4
- 238000006366 phosphorylation reaction Methods 0.000 claims description 4
- 229940121819 ATPase inhibitor Drugs 0.000 claims description 2
- 229940124683 HCV polymerase inhibitor Drugs 0.000 claims description 2
- 229940122604 HCV protease inhibitor Drugs 0.000 claims description 2
- 239000000362 adenosine triphosphatase inhibitor Substances 0.000 claims description 2
- OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-D Chemical compound OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-UHFFFAOYSA-N 0.000 claims 1
- 241000711549 Hepacivirus C Species 0.000 abstract description 52
- 230000008569 process Effects 0.000 abstract description 12
- 238000002360 preparation method Methods 0.000 abstract description 9
- -1 alkyl radicals Chemical class 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- 101150041968 CDC13 gene Proteins 0.000 description 16
- 238000003556 assay Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 15
- 239000002585 base Substances 0.000 description 14
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 230000005764 inhibitory process Effects 0.000 description 13
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 150000004775 coumarins Chemical class 0.000 description 11
- 230000010076 replication Effects 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical class C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000126 substance Substances 0.000 description 8
- 231100000419 toxicity Toxicity 0.000 description 8
- 230000001988 toxicity Effects 0.000 description 8
- 108060001084 Luciferase Proteins 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000005089 Luciferase Substances 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 150000004679 hydroxides Chemical class 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 235000001671 coumarin Nutrition 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000003863 ammonium salts Chemical class 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000003570 cell viability assay Methods 0.000 description 4
- 229960000956 coumarin Drugs 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 108091006112 ATPases Proteins 0.000 description 3
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 3
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 3
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000005362 aryl sulfone group Chemical group 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000005323 carbonate salts Chemical class 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 238000012054 celltiter-glo Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 3
- 150000004678 hydrides Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 238000010899 nucleation Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 3
- 238000003753 real-time PCR Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 101710172711 Structural protein Proteins 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 230000006037 cell lysis Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 229960002887 deanol Drugs 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
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Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
- C07D311/56—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 without hydrogen atoms in position 3
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Abstract
The present invention relates to 3,4-disubstituted coumarin and quinolone derivatives and processes for their preparation. The invention also related to methods for treating infection of Hepatitis C virus by administering a 3,4-disubstituted coumarin or quinolone derivative.
Description
3,4-DISUBSTITUTED COUMARIN AND QUINOLONE COMPOUNDS
FIELD OF THE INVENTION
[0001] The present invention relates to 3,4-disubstituted coumarin and quinolone derivatives and processes for their preparation. The invention also related to methods for treating infection of Hepatitis C virus by administering a 3,4-disubstituted coumarin or quinolone derivative. The invention provides a synthetic process for the preparation of 3,4-disubstituted coumarin and quinolone derivatives using mild reaction conditions, which provides a high substituent tolerance and is appropriate for use in solid phase syntheses for producing a library of 3,4-disubstituted coumarin and quinolone derivatives for biological screening.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
[0001] The present invention relates to 3,4-disubstituted coumarin and quinolone derivatives and processes for their preparation. The invention also related to methods for treating infection of Hepatitis C virus by administering a 3,4-disubstituted coumarin or quinolone derivative. The invention provides a synthetic process for the preparation of 3,4-disubstituted coumarin and quinolone derivatives using mild reaction conditions, which provides a high substituent tolerance and is appropriate for use in solid phase syntheses for producing a library of 3,4-disubstituted coumarin and quinolone derivatives for biological screening.
BACKGROUND OF THE INVENTION
[0002] Strategies in new drug discovery often look to natural products for leads in finding new chemical compounds with therapeutic properties. One of the recurring problems in drug discovery is the availability of organic compounds derived from natural sources.
Techniques employing combinatorial chemistry attempt to overcome this problem by allowing the high throughput synthesis and testing of hundreds or thousands of related synthetic compounds, called a chemical library. In designing the synthesis of a prospective therapeutic compound or a chemical library, one often looks to natural chemical motifs which are known to have broad biological activity. Coumarin and Quinolone derivatives are of particular interest due to their frequent occurrence in nature and range of biological activities.
Techniques employing combinatorial chemistry attempt to overcome this problem by allowing the high throughput synthesis and testing of hundreds or thousands of related synthetic compounds, called a chemical library. In designing the synthesis of a prospective therapeutic compound or a chemical library, one often looks to natural chemical motifs which are known to have broad biological activity. Coumarin and Quinolone derivatives are of particular interest due to their frequent occurrence in nature and range of biological activities.
[0003] Coumarins are widely distributed in the plant kingdom. Approximately 50 naturally occurring coumarin derivatives have been identified. Derivatives of both coumarin and quinolone posses a range of biological activities. To avoid confusion, the coumarin and quinolone derivatives described herein are nunlbered according to the following convention:
4
5 4 6 / \ 3
6 / \ 3 I ZZZ, 1
7\ 2 O 7 6 ' 2 O
[0004] Infection with the Hepatitis C virus (HCV) represents a serious world-wide health crisis. In more than 70% of infected individuals, the virus evades clearance by the immune system leading to a persistent HCV infection. The long term effects of persistent HCV infection range from an apparently healthy carrier state to chronic hepatitis, liver fibrosis, cirrhosis, and eventually hepatocellular carcinoma. HCV is a leading cause of chronic liver disease. The best therapy currently available for treatment of HCV infection uses a combination of pegylated a-interferon and ribavirin. However, many of the patients treated with this therapy fail to show a sufficient antiviral response. Additionally, interferon treatment also induces severe side-effects (i.e. retinopathy, thyroiditis, acute pancreatitis, depression) that diminish the quality of life of treated patients. Thus, it is vital that more effective treatments be identified.
SUMMARY OF THE INVENTION
[0005] The present invention provides 3,4-disubstituted coumarin and quinolone derivatives having the formula I
X'IR2 ~R~)n Y o (I) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(Rl2)(R13), -N(Rll)C(O)R11, -N(Rl)SO2R11, -SRII, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR", -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R' substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, allcenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nisOto4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)aC(O)N(R32)(R3), (CH2),C(O)OR31, -(CH2)aC(O)N(R32)(R3s), -(CH2)aN(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
X is selected from 0 and N-R4;
R~ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R¾2)(R4'), -(CH2)bC(O)OR¾1, and -(CH2)bC(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R4' and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
Y is selected from 0 and N-R5;
RS is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R 51, -(CH2)bC(0)N(R52)(R53), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R 53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
[0006] The invention also provides a synthetic process for the preparation of compounds of the formula I. The process uses mild reaction conditions, which provides a high substituent tolerance. Thus, the process is applicable to the preparation of a wide variety of 3,4-disubstituted coumarin and quinolone derivatives with diverse substitution patterns.
Additionally, the process is appropriate for use with combinatorial synthesis techniques. Thus, the process provides a method for producing a library of 3,4-disubstituted coumarin and quinolone derivatives for biological screening.
[0007] The invention also provides compositions and methods for the treatment of HCV
by administering a compound of the present invention in a therapeutically effective amount.
DETAILED DESCRIPTION OF THE INVENTION
[0004] Infection with the Hepatitis C virus (HCV) represents a serious world-wide health crisis. In more than 70% of infected individuals, the virus evades clearance by the immune system leading to a persistent HCV infection. The long term effects of persistent HCV infection range from an apparently healthy carrier state to chronic hepatitis, liver fibrosis, cirrhosis, and eventually hepatocellular carcinoma. HCV is a leading cause of chronic liver disease. The best therapy currently available for treatment of HCV infection uses a combination of pegylated a-interferon and ribavirin. However, many of the patients treated with this therapy fail to show a sufficient antiviral response. Additionally, interferon treatment also induces severe side-effects (i.e. retinopathy, thyroiditis, acute pancreatitis, depression) that diminish the quality of life of treated patients. Thus, it is vital that more effective treatments be identified.
SUMMARY OF THE INVENTION
[0005] The present invention provides 3,4-disubstituted coumarin and quinolone derivatives having the formula I
X'IR2 ~R~)n Y o (I) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(Rl2)(R13), -N(Rll)C(O)R11, -N(Rl)SO2R11, -SRII, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR", -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R' substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, allcenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nisOto4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)aC(O)N(R32)(R3), (CH2),C(O)OR31, -(CH2)aC(O)N(R32)(R3s), -(CH2)aN(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
X is selected from 0 and N-R4;
R~ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R¾2)(R4'), -(CH2)bC(O)OR¾1, and -(CH2)bC(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R4' and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
Y is selected from 0 and N-R5;
RS is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R 51, -(CH2)bC(0)N(R52)(R53), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R 53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
[0006] The invention also provides a synthetic process for the preparation of compounds of the formula I. The process uses mild reaction conditions, which provides a high substituent tolerance. Thus, the process is applicable to the preparation of a wide variety of 3,4-disubstituted coumarin and quinolone derivatives with diverse substitution patterns.
Additionally, the process is appropriate for use with combinatorial synthesis techniques. Thus, the process provides a method for producing a library of 3,4-disubstituted coumarin and quinolone derivatives for biological screening.
[0007] The invention also provides compositions and methods for the treatment of HCV
by administering a compound of the present invention in a therapeutically effective amount.
DETAILED DESCRIPTION OF THE INVENTION
[0008] The term "halo" or "halogen" as used herein includes fluorine, chlorine, bromine and iodine.
[0009] The term "alkyl" as used herein contemplates substituted or unsubstituted, straight and branched chain alkyl radicals containing from one to fifteen carbon atoms.
The term "lower alkyl" as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like. The alkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO2, CO2R, C(O)R, -O-R, -N(R')(R"), -N(R)C(O)R, -N(R)SO2R, -SR, -C(O)N(R')(R"), -OC(O)R, -OC(O)N(R')(R"), SO2, -SOR, -SO3R, -SO2N(R')(R"), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
The term "lower alkyl" as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like. The alkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO2, CO2R, C(O)R, -O-R, -N(R')(R"), -N(R)C(O)R, -N(R)SO2R, -SR, -C(O)N(R')(R"), -OC(O)R, -OC(O)N(R')(R"), SO2, -SOR, -SO3R, -SO2N(R')(R"), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0010] The term "alkenyl" as used herein contemplates substituted or unsubstituted, straight and branched chain alkene radicals containing from two to 8 carbon atoms. The alkenyl group may be optionally substituted with one or more substituents selected from halo, CN, NO2, CO2R, C(O)R, -O-R, -N(R')(R"), -N(R)C(O)R, -N(R)SOaR, -SR, -C(O)N(R')(R"), -OC(O)R, -OC(O)N(R')(R"), SO2, -SOR, -SO3R, -SO2N(R')(R"), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0011] The term "alkynyl" as used herein contemplates substituted or unsubstituted, straight and branched carbon chain containing from two to 8 carbon atoms and having at least one carbon-carbon triple bond. The term alkynyl includes, for example ethynyl, 1 -propynyl, 2-propynyl, 1-butynyl, 3-methyl-l-butynyl, and the like. The alkynyl group may be optionally substituted with one or more substituents selected from halo, CN, NO2, CO2R, C(O)R, -O-R, -N(R')(R"), -N(R)C(O)R, -N(R)SO2R, -SR, -C(O)N(R')(R"), -OC(O)R, -OC(O)N(R')(R"), SO2, -SOR, -SO3R, -SO2N(R')(R"), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0012] The term "cycloalkyl" as used herein contemplates substituted or unsubstituted cyclic alkyl radicals containing form 3 to 7 carbon atoms and includes cyclopropyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO2, CO2R, C(O)R, -O-R, -N(R')(R"), -N(R)C(O)R, -N(R)SO2R, -SR, -C(O)N(R')(R"), -OC(O)R, -OC(O)N(R')(R"), SOa, -SOR, -SO3R, -SO2N(R')(R"), phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl.
[0013] The term "cycloalkenyl" as used herein contemplates substituted or unsubstituted cyclic alkenyl radicals containing form 5 to 7 carbon atoms in which has a double bond between two of the ring carbons and includes cyclopentenyl, cyclohexenyl, and the like. The cycloalkenyl group may be optionally substituted with one or more substituents selected from halo, CN, NO2, CO2R, C(O)R, -O-R, -N(R')(R"), -N(R)C(O)R, -N(R)SO2R, -SR, -C(O)N(R')(R"), -OC(O)R, -OC(O)N(R')(R"), SOa, -SOR, -SO3R, -SO2N(R')(R"), phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl.
[0014] The term "aralkyl" as used herein contemplates a lower alkyl group which has as a substituent an aromatic group, which aromatic group may be substituted or unsubstituted. The aralkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO2, CO2R, C(O)R, -O-R, -N(R')(R"), -N(R)C(O)R, -N(R)SO2R, -SR, -C(O)N(R')(R"), -OC(O)R, -OC(O)N(R')(R"), SO2, -SOR, -SO3R, -SO2N(R')(R"), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0015] The terms phosphate and phosphonate as used herein refer to the moieties having the following structures, respectively:
-OJ-OR -p-OR
6R ~R
-OJ-OR -p-OR
6R ~R
[0016] The term "heterocyclic group" or "heterocyclic ring" as used herein contemplates substituted or unsubstituted aromatic and non-aromatic cyclic radicals having at least one heteroatom as a ring member. Preferred heterocyclic groups are those containing 5 or 6 ring atoms which includes at least one hetero atom, and includes cyclic amines such as morpholino, piperidino, pyrrolidino, and the like, and cyclic ethers, such as tetrahydrofuran, tetrahydropyran, and the like. Aromatic heterocyclic groups, also termed "heteroaryl" groups contemplates single-ring hetero-aromatic groups that may include from one to three heteroatoms, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. The term heteroaryl also includes polycyclic hetero-aromatic systems having two or more rings in which two atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is a heteroaryl, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls.
Examples of polycyclic heteroaroinatic systems include quinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, quinaxoline, benzimidazole, benzofuran, purine, imidazopyridine, benzotriazole, and the like.
The heterocyclic group may be optionally substituted with one or more substituents selected from halo, alkyl, CN, NO2, CO2R, C(O)R, -O-R, -N(R')(R"), -N(R)C(O)R, -N(R)SO2R, -SR, -C(O)N(R')(R"), -OC(O)R, -OC(O)N(R')(R"), SO2, -SOR, -SO3R, -SO2N(R')(R"), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
Examples of polycyclic heteroaroinatic systems include quinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, quinaxoline, benzimidazole, benzofuran, purine, imidazopyridine, benzotriazole, and the like.
The heterocyclic group may be optionally substituted with one or more substituents selected from halo, alkyl, CN, NO2, CO2R, C(O)R, -O-R, -N(R')(R"), -N(R)C(O)R, -N(R)SO2R, -SR, -C(O)N(R')(R"), -OC(O)R, -OC(O)N(R')(R"), SO2, -SOR, -SO3R, -SO2N(R')(R"), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0017] The terms "aryl", "aromatic group", or "aromatic ring" as used herein contemplates substituted or unsubstituted single-ring aromatic groups (for example, phenyl, pyridyl, pyrazole, etc.) and polycyclic ring systems (naphthyl, quinoline, etc.). The polycyclic rings may have two or more rings in which two atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is aromatic, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls. The aryl group may be optionally substituted with one or more substituents selected from halo, alkyl, CN, NO2, CO2R, C(O)R, -O-R, -N(R')(R"), -N(R)C(O)R, -N(R)SO2R, -SR, -C(O)N(R')(R"), -OC(O)R, -OC(O)N(R')(R"), SO2, -SOR, -SO3R, -SO2N(R')(R"), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0018] Each R is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl. Each R' and R" are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R' and R" may be taken together with the nitrogen to wliich they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom.
[0019] The term "heteroatom", particularly as a ring heteroatom, refers to N, 0, and S.
[0020] All value ranges, for example those given for n and m, are inclusive over the entire range. Thus, a range of 0 to 4 would include the values 0, 1, 2, 3 and 4.
[0021] The present invention provides compounds of the fonnula I:
X" R2 \
~R~ )n ~ Y O
(I) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R12)(R13), -N(Rll)C(O)Rll, -N(Rll)SO2RII, -SRII, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR", -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R' substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each R" is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nis0to4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)aC(O)N(R32)(R33), (CH2)aC(O)OR31, -(CH2)aC(O)N(R32)(R33)' -(CH2)QN(R32)(Rs3), -CH=N-R3¾, R31 selected from H, alkyl, cycloalkyl, cycloalkeinyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl aisOto6;
X is selected from 0 and N-R4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CHa)bC(O)N(Wz)(W), -(CH2)bC(O)OR41, and -(CH2)bC(O)N(Ra2)(Ra), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R¾Z and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
Y is selected from 0 and N-R5;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(R52)(R53), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is O to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
X" R2 \
~R~ )n ~ Y O
(I) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R12)(R13), -N(Rll)C(O)Rll, -N(Rll)SO2RII, -SRII, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR", -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R' substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each R" is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nis0to4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)aC(O)N(R32)(R33), (CH2)aC(O)OR31, -(CH2)aC(O)N(R32)(R33)' -(CH2)QN(R32)(Rs3), -CH=N-R3¾, R31 selected from H, alkyl, cycloalkyl, cycloalkeinyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl aisOto6;
X is selected from 0 and N-R4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CHa)bC(O)N(Wz)(W), -(CH2)bC(O)OR41, and -(CH2)bC(O)N(Ra2)(Ra), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R¾Z and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
Y is selected from 0 and N-R5;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(R52)(R53), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is O to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
[0022] The substances according to the invention may be present as salts. In the context of the invention, preference is given to pharmaceutically acceptable salts.
Pharmaceutically acceptable salts refers to an acid addition salt or a basic addition salt of a compound of the invention in which the resulting counter ion is understood in the art to be generally acceptable for pharmaceutical uses. Pharmaceutically acceptable salts can be salts of the coinpounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or to salts with organic carboxylic or sulfonic acids, 'such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid. Pharmaceutically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Particular preference is given to, for exainple, sodium, potassium, magnesium or calcium salts, and also to ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or phenylethylamine. (see, Berge et al. J. Pharm. Sci. 1977, 66, 1-19.)
Pharmaceutically acceptable salts refers to an acid addition salt or a basic addition salt of a compound of the invention in which the resulting counter ion is understood in the art to be generally acceptable for pharmaceutical uses. Pharmaceutically acceptable salts can be salts of the coinpounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or to salts with organic carboxylic or sulfonic acids, 'such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid. Pharmaceutically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Particular preference is given to, for exainple, sodium, potassium, magnesium or calcium salts, and also to ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or phenylethylamine. (see, Berge et al. J. Pharm. Sci. 1977, 66, 1-19.)
[0023] When one or more chiral centers are present in the compounds of the present invention, the individual isomers and mixtures thereof (e.g., racemates, etc.) are intended to be encompassed by the formulae depicted herein. In certain embodiments, compounds of the invention may exist in several tautomeric forms. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.
Compounds of the invention may exist in various hydrated forms.
Compounds of the invention may exist in various hydrated forms.
[0024] It is understood that when n is a value greater than 1, each Ri group may be selected independently. Thus, when more than one Rl group is present, the R' groups may be selected from any of the stated groups so as to be the same or different. This also holds true for any other group or substituent which may be selected independently from among various groups or values.
[0025] In preferred embodiments of the invention, R2 is selected from aryl and aralkyl.
[0026] In one embodiment of the invention, Y is selected to be a 0 to give a compound of the formula II:
X"R 2 (R')n O
(II) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, (R 12)(R 13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11 -N, -C(O)N(R12)(R13), -OC(O)R", -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -S03R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)QC(O)N(R32)(R33), (CH2)QC(O)OR31, -(CH2)aC(O)N(R32)(R33), -(CH2)aN(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R 32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
a is 0 to 6;
X is selected from 0 and N-R4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R¾l, -(CH2)bC(O)N(W2)(R4), -(CH2)bC(O)OR41, and -(CH2)bC(O)N(Ra2)(Ra3)' each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- inembered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
X"R 2 (R')n O
(II) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, (R 12)(R 13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11 -N, -C(O)N(R12)(R13), -OC(O)R", -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -S03R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)QC(O)N(R32)(R33), (CH2)QC(O)OR31, -(CH2)aC(O)N(R32)(R33), -(CH2)aN(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R 32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
a is 0 to 6;
X is selected from 0 and N-R4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R¾l, -(CH2)bC(O)N(W2)(R4), -(CH2)bC(O)OR41, and -(CH2)bC(O)N(Ra2)(Ra3)' each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- inembered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
[0027] In a further embodiment of the invention, X of a compound according to formula II is selected to be a 0 to give a compound of the formula III:
~R~)n O
(III) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(Rll)C(O)Rll, -N(Rll)SOaRII, -SRII, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)Rl l, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SORII, -S03R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R' substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R3r, =(CH2)aC(O)N(R32)(R33), (CH2)aC(O)OR31, -(CH2)aC(O)N(R32)(R13), -(CH2)aN(R32)(R31), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and aisOto6;
or a pharmaceutically acceptable salt or hydrate thereof.
~R~)n O
(III) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(Rll)C(O)Rll, -N(Rll)SOaRII, -SRII, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)Rl l, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SORII, -S03R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R' substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R3r, =(CH2)aC(O)N(R32)(R33), (CH2)aC(O)OR31, -(CH2)aC(O)N(R32)(R13), -(CH2)aN(R32)(R31), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and aisOto6;
or a pharmaceutically acceptable salt or hydrate thereof.
[0028] In further preferred embodiment of the invention, R2 and R3 of a compound according to formula III are selected to be a-CH2-R6 and -CH2-R7 , respectively, to give a compound of the formula IV:
0~
~~' 1)n (IV) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RIt, -N(R1a)(R13), -N(R11)C(O)R11, -N(Rll)SO2R11, -SR11, -C(O)Rll, -C(O)ORI1, -C(O)N(R12)(R13), -OC(O)Rrl, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SORII, -S03R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nisOto4;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R3), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R 32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
0~
~~' 1)n (IV) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RIt, -N(R1a)(R13), -N(R11)C(O)R11, -N(Rll)SO2R11, -SR11, -C(O)Rll, -C(O)ORI1, -C(O)N(R12)(R13), -OC(O)Rrl, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SORII, -S03R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nisOto4;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R3), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R 32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
[0029] In a preferred embodiment for compounds of the formula IV, R7 is selected to be an aryl or heteroaryl groups.
[0030] In another einbodiment of the invention, RZ of a coinpound according to formula III is selected to be a benzyl group to give a compound of the formula V:
(RB)m Q
(V) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-Rl1, -N(R 12)(R13), -N(R1)C(O)Rli, -N(Rii)S02Rli, -SRil, -C(O)Rii, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SOZ, -SORII, -S03R11, -SO2N(R12)(R13), -alkyl-O-RlI, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adj acent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each Rll is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and Rl3 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further lieteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)aC(O)N(R3)(R33), (CH2)aC(O)OR31, -(CH2)QC(O)N(R32)(R33), -(CH2)aN(R32)(R3s), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02R81, C(O)R81, -O-R81, -N(Rs2)(Rs3), -N(Rsi)C(O)Rsi, -N(Rsi)S02Rsi, -SRsi, -C(O)N(R
82)(R$3), -OC(O)Rgl, -OC(O)N(R82')(R$3), SO2, -SOR81, -S03R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
(RB)m Q
(V) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-Rl1, -N(R 12)(R13), -N(R1)C(O)Rli, -N(Rii)S02Rli, -SRil, -C(O)Rii, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SOZ, -SORII, -S03R11, -SO2N(R12)(R13), -alkyl-O-RlI, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adj acent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each Rll is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and Rl3 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further lieteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)aC(O)N(R3)(R33), (CH2)aC(O)OR31, -(CH2)QC(O)N(R32)(R33), -(CH2)aN(R32)(R3s), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02R81, C(O)R81, -O-R81, -N(Rs2)(Rs3), -N(Rsi)C(O)Rsi, -N(Rsi)S02Rsi, -SRsi, -C(O)N(R
82)(R$3), -OC(O)Rgl, -OC(O)N(R82')(R$3), SO2, -SOR81, -S03R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
[0031] In further preferred embodiment of the invention, R6 and R7 of a compound according to formula IV are selected to be phenyl groups, to give a compound of the formula VI:
/
(R8)m I
\
\ \ /
(R')n (R9)p O
(VI) wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RI
l, -N(Ri2)(Ris), -N(Rii)C(O)Rii, -N(R1 )SO2Ri1, -SRii, -C(O)Rii, _C(O)ORii, -C(O)N(R12)(R13), -OC(O)Rl l, -OC(O)N(Rl2)(R13), CN, CF3, NO2, SO2, -SOR", -SO3R11, -SO2N(R12)(R13), -alkyl-O-R", cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R' substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Ri;
each R" is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO22, CO2R81, C(O)R81, -O-R", -N(R82)(R83), -N(R81)C(O)R81, -N(Rxl)S02R81, -SR81, -C(O)N(Rsz)(Ra3), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
na is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, COzRgI, C(O)R91, -O-R91, -N(R92)(R9s), -N(R91)C(O)R91, -N(R91)SOZR?1, -SR91, -C(O)N(R9)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -S03R91, -SO2N(R92 )(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a fizrther heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
/
(R8)m I
\
\ \ /
(R')n (R9)p O
(VI) wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RI
l, -N(Ri2)(Ris), -N(Rii)C(O)Rii, -N(R1 )SO2Ri1, -SRii, -C(O)Rii, _C(O)ORii, -C(O)N(R12)(R13), -OC(O)Rl l, -OC(O)N(Rl2)(R13), CN, CF3, NO2, SO2, -SOR", -SO3R11, -SO2N(R12)(R13), -alkyl-O-R", cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R' substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Ri;
each R" is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO22, CO2R81, C(O)R81, -O-R", -N(R82)(R83), -N(R81)C(O)R81, -N(Rxl)S02R81, -SR81, -C(O)N(Rsz)(Ra3), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
na is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, COzRgI, C(O)R91, -O-R91, -N(R92)(R9s), -N(R91)C(O)R91, -N(R91)SOZR?1, -SR91, -C(O)N(R9)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -S03R91, -SO2N(R92 )(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a fizrther heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
[0032] Exemplary compounds of the formula VI include the following structures:
,CH3 Gi CF3 \ \ ~ \ ( \ `. / CH3 \ \ ~ CI \ \ ~ CF3 I. I 1 1 I I
CH3 ~ 0 CH3 0 0 F
\ I \ ~ \ I
I\ \ / I I\ F I\ \ /= I CF3 CH3 0 \ CH3 / O \ F CH3 f/ 0 CF3 CH3 CF3 I \ \ / I I \ \ a a F F
F F
a a I \ / I \ O CH3 CH3O / O ~ F CH3 / 0 F
,CH3 Gi CF3 \ \ ~ \ ( \ `. / CH3 \ \ ~ CI \ \ ~ CF3 I. I 1 1 I I
CH3 ~ 0 CH3 0 0 F
\ I \ ~ \ I
I\ \ / I I\ F I\ \ /= I CF3 CH3 0 \ CH3 / O \ F CH3 f/ 0 CF3 CH3 CF3 I \ \ / I I \ \ a a F F
F F
a a I \ / I \ O CH3 CH3O / O ~ F CH3 / 0 F
[0033] In a another embodiment of the invention, X of a compound according to fonnula II is selected to be a N-R4 to give a compound of the formula VII:
R4 \N-" R2 (Rl )n (VII) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -0-Rll, -N(R12)(R13), -N(R1)C(O)R11, -N(R11)SO2R11, -SRiI, -C(O)Rli, -C(O)OR", -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(Rl2)(.R.13), CN, CF3, NO2, SO2a -SOR", -S03R11, -SO2N(R12)(R13), -alkyl-O-Rz1, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R' substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)QC(O)R31, -(CH2)aC(O)N(R32)(R33), (CH2)aC(O)OR31, -(CH2)aC(O)N(R3)(R33), -(CH2)aN(R3)(R33), -CH=N-R3¾, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(e)(R43), -(CH2)bC(O)OR41, and -(CH2)bC(O)N(Ra2)(R43)' each R4' is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to whicli they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
R4 \N-" R2 (Rl )n (VII) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -0-Rll, -N(R12)(R13), -N(R1)C(O)R11, -N(R11)SO2R11, -SRiI, -C(O)Rli, -C(O)OR", -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(Rl2)(.R.13), CN, CF3, NO2, SO2a -SOR", -S03R11, -SO2N(R12)(R13), -alkyl-O-Rz1, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R' substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)QC(O)R31, -(CH2)aC(O)N(R32)(R33), (CH2)aC(O)OR31, -(CH2)aC(O)N(R3)(R33), -(CH2)aN(R3)(R33), -CH=N-R3¾, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(e)(R43), -(CH2)bC(O)OR41, and -(CH2)bC(O)N(Ra2)(R43)' each R4' is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to whicli they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
[0034] In a preferred embodiment for compounds of the formula VII, R3 is selected to be -CH=N-R34, to give a compound of the formula VIIa R4 \N-~ R2 \ \ ~(~
O
wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R12)(R13), -N(Rl l)C(O)Ri 1, -N(Rll)SO2R11, -SRl l, -C(O)R11, -C(O)OR", -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NOa, SO2, -SORII, -S03R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms iny be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R42)(R4)' -(CH2)bC(O)OR41, and -(CH2)bC(O)N(R42)(R43), each R41 is==independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6; and R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or a pharmaceutically acceptable salt or hydrate thereof.
O
wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R12)(R13), -N(Rl l)C(O)Ri 1, -N(Rll)SO2R11, -SRl l, -C(O)R11, -C(O)OR", -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NOa, SO2, -SORII, -S03R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms iny be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R42)(R4)' -(CH2)bC(O)OR41, and -(CH2)bC(O)N(R42)(R43), each R41 is==independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6; and R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or a pharmaceutically acceptable salt or hydrate thereof.
[0035] In a preferred embodiment for compounds of the formula VII and VIIa, R2 is selected to be an aryl or heteroaryl groups. I further preferred embodiments, R4 is H.
[0036] Exemplary compounds of the formula VIIa include the following structures:
OC
OCH3 OCH3 a I \ I \ H ~ H ~ H
co- (~ O I/ O
\ OCH3 \ OCH3 \ OCH3 I \ \ ~ I \ \ ~ ccHX
OC
OCH3 OCH3 a I \ I \ H ~ H ~ H
co- (~ O I/ O
\ OCH3 \ OCH3 \ OCH3 I \ \ ~ I \ \ ~ ccHX
[0037] In further preferred embodiment of the invention, Ra and R3 of a compound according to forinula VII are selected to be a-CHa-R6 and -CH2-R7, respectively, to give a compound of the formula VIII:
Rs R4 \W
(Ri)n (VIII) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R12)(Rr3), -N(R1)C(O)Rl1, -N(Rl1)S02RII, -SRII, -C(O)Rli, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)Rli, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SORIi, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to forni a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each Rll is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nisOto4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R12)(R43), -(CH2)bC(O)OR41, and -(CH2)bC(O)N(R42)(R43), each R4' is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R`43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
Rs R4 \W
(Ri)n (VIII) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R12)(Rr3), -N(R1)C(O)Rl1, -N(Rl1)S02RII, -SRII, -C(O)Rli, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)Rli, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SORIi, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to forni a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each Rll is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nisOto4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R12)(R43), -(CH2)bC(O)OR41, and -(CH2)bC(O)N(R42)(R43), each R4' is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R`43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
[0038] In a preferred embodiment for compounds of the formula VIII, R7 is selected to be an aryl or heteroaryl groups.
[0039] In another embodiment of the invention, R2 of a compound according to formula VII is selected to be a benzyl group to give a compound of the formula IX:
(R8 )m I
\
~
(R~)n Q
(IX) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RI
l, -N(R1z)(Ri3), -N(R11)C(O)R11, -N(R1 1)SO2R1 1, -SR11, -C(O)Rll, -C(O)ORi1, -C(O)N(R12)(R13), -OC(O)Rl l, -OC(O)N(R12)(R13), CN, CF3a NO2, SO2, -SORII, -S03R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, phosphate, phosphonate, halo, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)aC(O)N(R32)(R33), (CH2)aC(O)OR31, -(CH2)aC(O)N(Rs2)(R33), -(CH2)'N(R32)(R33), -CH N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CHa)bC(O)N(R42)(R43), -(CH2)bC(O)OR41, and -(CH2)bC(O)N(R42)(R43)' each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R¾2 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02Rg1, C(O)R81, -O-Rsi, -N(Rs2)(Rs3), -N(Rsi)C(O)Rst, -N(Rai)S02Rsi, -SRsl, -C(O)N(R
82)(R 83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SORg1, -S03R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
(R8 )m I
\
~
(R~)n Q
(IX) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RI
l, -N(R1z)(Ri3), -N(R11)C(O)R11, -N(R1 1)SO2R1 1, -SR11, -C(O)Rll, -C(O)ORi1, -C(O)N(R12)(R13), -OC(O)Rl l, -OC(O)N(R12)(R13), CN, CF3a NO2, SO2, -SORII, -S03R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, phosphate, phosphonate, halo, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)aC(O)N(R32)(R33), (CH2)aC(O)OR31, -(CH2)aC(O)N(Rs2)(R33), -(CH2)'N(R32)(R33), -CH N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CHa)bC(O)N(R42)(R43), -(CH2)bC(O)OR41, and -(CH2)bC(O)N(R42)(R43)' each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R¾2 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02Rg1, C(O)R81, -O-Rsi, -N(Rs2)(Rs3), -N(Rsi)C(O)Rst, -N(Rai)S02Rsi, -SRsl, -C(O)N(R
82)(R 83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SORg1, -S03R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
[0040] In further preferred embodiment of the invention, R6 and R7 of a compound according to formula VIII are selected to be phenyl groups, to give a compound of the formula X:
(R8)m I
~
\ \ /
(R')n (R9)P
O
(X) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R 12)(R 13), -N(R11)C(O)R11, -N(R11)S02R11, -SR11, -C(O)R", -C(O)OR11 , -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(Rla)(R13), CN, CF3, NO2, SO2, -SORiI, -S03R11, -SO2N(R12)(R13), -alkyl-O-RlI, cycloalkyl, cycloalkenyl, phosphate, phosphonate, halo, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be coinbined to form a fused 5 or 6- meinbered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each RI 1 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R¾2)(R43), -(CH2)bC(O)OR41, and -(CH2)bC(O)N(I42)(R43)' each R¾1 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R 42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R¾a and W3 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02R8r, C(O)R81, -O-R81, -N(R12)(R13), -N(R81)C(O)Rsl, -N(R81)S02R$1, -SR81, -C(O)N(Ra2)(Rss), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -S03R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R 83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a fiurther heteroatom;
mis0to5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)S02R91, -SR9i, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -S03R91, -SOZN(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
(R8)m I
~
\ \ /
(R')n (R9)P
O
(X) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R 12)(R 13), -N(R11)C(O)R11, -N(R11)S02R11, -SR11, -C(O)R", -C(O)OR11 , -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(Rla)(R13), CN, CF3, NO2, SO2, -SORiI, -S03R11, -SO2N(R12)(R13), -alkyl-O-RlI, cycloalkyl, cycloalkenyl, phosphate, phosphonate, halo, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be coinbined to form a fused 5 or 6- meinbered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each RI 1 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R¾2)(R43), -(CH2)bC(O)OR41, and -(CH2)bC(O)N(I42)(R43)' each R¾1 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R 42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R¾a and W3 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02R8r, C(O)R81, -O-R81, -N(R12)(R13), -N(R81)C(O)Rsl, -N(R81)S02R$1, -SR81, -C(O)N(Ra2)(Rss), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -S03R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R 83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a fiurther heteroatom;
mis0to5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)S02R91, -SR9i, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -S03R91, -SOZN(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
[0041] In another embodiment of the invention, Y is selected to be a N-R5 to give a compound of the formula XI:
X" R2 ~R~ )n O
(XI) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-Ri 1, -N(R12)(R13), -N(Rll)C(O)Rll, -N(Rll)SO2R11, -SRII, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)R", -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-RlI, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted witll on or more substituents selected from Rl;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nisOto4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)aC(O)N(R32)(R33), (CH2)aC(O)OR31, -(CH2)aC(O)N(R32)(R33), -(CH2)aN(R32)(R33), -CH N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
X is selected from 0 and N-R4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R42)(R43), -(CHa)bC(O)OR41, and -(CH2)bC(O)N(R42)(Ra3)' each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(R52)(R53), and -(CH2)bC(O)OR51;
each R51 is independently selected froin H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R 52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
X" R2 ~R~ )n O
(XI) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-Ri 1, -N(R12)(R13), -N(Rll)C(O)Rll, -N(Rll)SO2R11, -SRII, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)R", -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-RlI, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted witll on or more substituents selected from Rl;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nisOto4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)aC(O)N(R32)(R33), (CH2)aC(O)OR31, -(CH2)aC(O)N(R32)(R33), -(CH2)aN(R32)(R33), -CH N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
X is selected from 0 and N-R4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R42)(R43), -(CHa)bC(O)OR41, and -(CH2)bC(O)N(R42)(Ra3)' each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(R52)(R53), and -(CH2)bC(O)OR51;
each R51 is independently selected froin H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R 52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
[0042] In a further embodiment of the invention, X of a compound according to formula XI is selected to be a 0 to give a compound of the formula XII:
(R' )~
(XII) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R12)(RI3), -N(Rll)C(O)Rll, -N(Rll)SO2R11, -SR11, -C(O)Rll, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(R12)(RI3), CN, CF3, NO2, SOZ, -SOR", -S03R11, -SO2N(R12)(R13), -alkyl-O-RlI, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R' substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; -each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nisOto4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)aC(O)N(R32)(R33), (CH2)aC(O)OR31, -(CH2)aC(O)N(R32)(R33), -(CH2)aN(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected fiom H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)Rsl, -(CHa)bC(O)N(Rs2)(Rs3), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
(R' )~
(XII) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R12)(RI3), -N(Rll)C(O)Rll, -N(Rll)SO2R11, -SR11, -C(O)Rll, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(R12)(RI3), CN, CF3, NO2, SOZ, -SOR", -S03R11, -SO2N(R12)(R13), -alkyl-O-RlI, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R' substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; -each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nisOto4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)aC(O)N(R32)(R33), (CH2)aC(O)OR31, -(CH2)aC(O)N(R32)(R33), -(CH2)aN(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected fiom H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)Rsl, -(CHa)bC(O)N(Rs2)(Rs3), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
[0043] In further preferred einbodiment of the invention, Ra and R3 of a compound according to formula XII are selected to be a-CH2-R6 and -CH2-R7, respectively, to give a compound of the formula XIII:
o) ~R~ )n (XIII) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RI
l, -N(R12)(R13), -N(Rll)C(O)Rll, -N(R11)S02R11, -SRII, -C(O)Rll, -C(O)ORiI, -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-RiI, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R' substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R 13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(R52)(R5), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl;
alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
o) ~R~ )n (XIII) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RI
l, -N(R12)(R13), -N(Rll)C(O)Rll, -N(R11)S02R11, -SRII, -C(O)Rll, -C(O)ORiI, -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-RiI, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R' substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R 13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(R52)(R5), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl;
alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
[0044] In a preferred embodiment for compounds of the formula XIII, R6 is selected to be an aryl or heteroaryl groups.
[0045] In another embodiment of the invention, R2 of a compound according to formula XII is selected to be a benzyl group to give a compound of the formula XIV:
i (R8)m ~
\
\
(R1)n ~ O
RS
(XIV) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RI
l, -N(Rla)(R13), -N(R11)C(O)Rll, -N(R11)SO2R11, -SR11, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(Rla)(R13), CN, CF3, NO2, SO2, -SORII, -S03R11, -SO2N(R12)(R13), -alkyl-O-RlI, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nis0to4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2),,C(O)R31, -(CH2),C(O)N(R12)(R33), (CH2)aC(O)OR31, -(CH2)aC(O)N(R32)(R33)' -(CH2)aN(Rs2)(Rs)' -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(R52)(R53), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R 52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02R81, C(O)R81, -O-R81, -N(Rs2)(R83), -N(R 81)C(O)R81' _N(Rs1)SO2R81, -SR81, -C(O)N(R
82)(R83), -OC(O)R81, -OC(O)N(R82i)(R8), SO2, -SOR", -S03R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R 82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further-heteroatom; and rnis0to5;
or a pharmaceutically acceptable salt or hydrate thereof.
i (R8)m ~
\
\
(R1)n ~ O
RS
(XIV) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RI
l, -N(Rla)(R13), -N(R11)C(O)Rll, -N(R11)SO2R11, -SR11, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(Rla)(R13), CN, CF3, NO2, SO2, -SORII, -S03R11, -SO2N(R12)(R13), -alkyl-O-RlI, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nis0to4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2),,C(O)R31, -(CH2),C(O)N(R12)(R33), (CH2)aC(O)OR31, -(CH2)aC(O)N(R32)(R33)' -(CH2)aN(Rs2)(Rs)' -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(R52)(R53), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R 52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02R81, C(O)R81, -O-R81, -N(Rs2)(R83), -N(R 81)C(O)R81' _N(Rs1)SO2R81, -SR81, -C(O)N(R
82)(R83), -OC(O)R81, -OC(O)N(R82i)(R8), SO2, -SOR", -S03R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R 82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further-heteroatom; and rnis0to5;
or a pharmaceutically acceptable salt or hydrate thereof.
[0046] In further preferred embodiment of the invention, R6 and R7 of a compound according to formula XIII are selected to be phenyl groups, to give a compound of the formula XV:
/
(R8)M I
\
\ \ /
(R')n (R9)P
0 \
l~J1 R5 (XV) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R 12)(R13), -N(R11)C(O)R11, -N(R11)S02R11, -SR11, -C(O)R11, -C(O)OR11 , -C(O)N(R12)(R13), -OC(O)R", -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SORII, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nisOto4;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(R52)(R53), and -(CHa)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R 52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
bis0to6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02R", C(O)R81, -O-R81, -N(Rs2)(Rs3), -N(Ral)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(Rs2)(Rss), -OC(O)R81, -OC(O)N(R82')(R$3), SO2, -SOR$1, -S03R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl,-aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R 82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
rnisOto5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NOZ, C02R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
/
(R8)M I
\
\ \ /
(R')n (R9)P
0 \
l~J1 R5 (XV) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R 12)(R13), -N(R11)C(O)R11, -N(R11)S02R11, -SR11, -C(O)R11, -C(O)OR11 , -C(O)N(R12)(R13), -OC(O)R", -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SORII, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, nisOto4;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(R52)(R53), and -(CHa)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R 52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
bis0to6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02R", C(O)R81, -O-R81, -N(Rs2)(Rs3), -N(Ral)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(Rs2)(Rss), -OC(O)R81, -OC(O)N(R82')(R$3), SO2, -SOR$1, -S03R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl,-aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R 82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
rnisOto5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NOZ, C02R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
[0047] Exemplary compounds of the formula XV include the following structures:
CH3 Cil c~,l \ I \ I
CI
I \ \
/ I &XO C)a 1 o \ CH3 CI 1:1~3 C H3
CH3 Cil c~,l \ I \ I
CI
I \ \
/ I &XO C)a 1 o \ CH3 CI 1:1~3 C H3
[0048] In a another embodiment of the invention, Xof a compound according to fonnula XI is selected to be a N-R4 to give a compound of the formula XVI:
N-~
(R,)n O
(XVI) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RiI, -N(R12)(R13), -N(R11)C(O)Rll, -N(Rll)S02R11, -SRII, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R1), -OC(O)Rll, -OC(O)N(R1a)(R13), CN, CF3, NO2, SO2, -SORIi, -SO3R11, -SO2N(R12)(R13), -alkyl-O-RlI, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- meinbered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Ri;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)aC(O)N(R32)(R33), (CH2,)aC(O)OR31, -(CH2)aC(O)N(R32)(R3s), -(CH2)aN(R32)(R33), -CH=N-R3¾, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R 34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R42)(R43), -(CH2)bC(O)OR¾l, and -(CH2)bC(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or W2 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)6C(O)Rsi, -(CH2)bC(O)N(R12)(Rss), and -(CHa)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R 52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and bisOto6;
or a pharmaceutically acceptable salt or hydrate thereof.
N-~
(R,)n O
(XVI) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RiI, -N(R12)(R13), -N(R11)C(O)Rll, -N(Rll)S02R11, -SRII, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R1), -OC(O)Rll, -OC(O)N(R1a)(R13), CN, CF3, NO2, SO2, -SORIi, -SO3R11, -SO2N(R12)(R13), -alkyl-O-RlI, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- meinbered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Ri;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)aC(O)R31, -(CH2)aC(O)N(R32)(R33), (CH2,)aC(O)OR31, -(CH2)aC(O)N(R32)(R3s), -(CH2)aN(R32)(R33), -CH=N-R3¾, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R 34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R42)(R43), -(CH2)bC(O)OR¾l, and -(CH2)bC(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or W2 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)6C(O)Rsi, -(CH2)bC(O)N(R12)(Rss), and -(CHa)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R 52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and bisOto6;
or a pharmaceutically acceptable salt or hydrate thereof.
[0049] In further preferred embodiment of the invention, R2 and R3 of a compound according to formula XVI are selected to be a-CH2-R6 and -CH2-R7, respectively, to give a compound of the formula XVII:
R4 \N' ~R~)n R (XVII) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R12)(R13), -N(R1)C(O)R11, -N(R1)SO2R11, -SR", -C(O)R11, -C(O)OR11, -C(O)N(Rla)(R13), -OC(O)Rll, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SORII, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 a.nd R 13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R42)(R43), -(CH2)IC(O)OR¾l, and -(CH2)bC(O)N(Ra2)(R43), each R4' is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R 42 and R43 are independentlY selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- meinbered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(R52)(R53), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7-lnembered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
R4 \N' ~R~)n R (XVII) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R12)(R13), -N(R1)C(O)R11, -N(R1)SO2R11, -SR", -C(O)R11, -C(O)OR11, -C(O)N(Rla)(R13), -OC(O)Rll, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SORII, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each Rl l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 a.nd R 13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R42)(R43), -(CH2)IC(O)OR¾l, and -(CH2)bC(O)N(Ra2)(R43), each R4' is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R 42 and R43 are independentlY selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- meinbered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(R52)(R53), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7-lnembered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
[0050] In a preferred einbodiinent for compounds of the formula XVII, R6 is selected to be an aryl or heteroaryl groups.
[0051] In another embodiment of the invention, R2 of a compound according to formula XVI is selected to be a benzyl group to give a compound of the formula XVIII:
(R8)m O
(XVIII) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R12)(R13), -N(R11)C(O)R11, -N(R1)S02R11, -SR11, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SORII, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each Rll is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2),,C(O)R31, -(CH2)aC(O)N(R32)(R33), (CHa)QC(O)OR31, -(CH2). C(O)N(R32)(R31), -(CH2) "N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R42)(R43), -(CH2)bC(O)OR41, and -(CH2)bC(O)N(R4a)(R4), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- meinbered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(R52)(R53), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R 52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02R81, C(O)R81, -O-R$1, -N(R82)(R 83), -N(R81)C(O)R81, -N(R81)S02R81, -SR81, -C(O)N(Ra2)(Rs3)~
-OC(O)R81, -OC(O)N(R$2')(R83), SO2, -SOR81, -S03R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
(R8)m O
(XVIII) wherein:
each Rl is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-RII, -N(R12)(R13), -N(R11)C(O)R11, -N(R1)S02R11, -SR11, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SORII, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each Rll is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2),,C(O)R31, -(CH2)aC(O)N(R32)(R33), (CHa)QC(O)OR31, -(CH2). C(O)N(R32)(R31), -(CH2) "N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R41, -(CH2)bC(O)N(R42)(R43), -(CH2)bC(O)OR41, and -(CH2)bC(O)N(R4a)(R4), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- meinbered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(R52)(R53), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R 52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02R81, C(O)R81, -O-R$1, -N(R82)(R 83), -N(R81)C(O)R81, -N(R81)S02R81, -SR81, -C(O)N(Ra2)(Rs3)~
-OC(O)R81, -OC(O)N(R$2')(R83), SO2, -SOR81, -S03R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
[0052] In further preferred embodiment of the invention, R6 and R7 of a compound according to formula XVII are selected to be phenyl groups, to give a compound of the formula XIX:
~R$
)m I
\ \
\ \ /
~R~ )n (R9)P
O \
RS
(XIX) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R", -N(R1z)(Ri3), -N(R1)C(O)R11, -N(Ri)SO2R11, -SRII, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SORII, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each R" l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R¾1, -(CH2)bC(O)N(R42)(R4), -(CHa)bC(O)OR41, and -(CH2)6C(O)N(Ra2)(R43), each R¾I is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
RS is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(Rs)(R53), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is O to 6;
each R8 is independently selected from the grqup consisting of halo, alkyl, CN, NO2, COaRsI, C(O)Rsl, -O-R", -N(Rsa)(Rg3), -N(R81)C(O)R81, -N(R81)S02R81, -SR81, -C(O)N(Rs2)(R83 -OC(O)R81, -OC(O)N(R$2')(R83), SO2, -SOR81, -S03R$1, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
nais0to5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02R91, C(O)R91, -O-R91, -N(R12)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R
92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is O to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
~R$
)m I
\ \
\ \ /
~R~ )n (R9)P
O \
RS
(XIX) wherein:
each R' is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R", -N(R1z)(Ri3), -N(R1)C(O)R11, -N(Ri)SO2R11, -SRII, -C(O)Rll, -C(O)ORII, -C(O)N(R12)(R13), -OC(O)Rll, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SORII, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two Rl substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from Rl;
each R" l is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R¾1, -(CH2)bC(O)N(R42)(R4), -(CHa)bC(O)OR41, and -(CH2)6C(O)N(Ra2)(R43), each R¾I is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
RS is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)bC(O)R51, -(CH2)bC(O)N(Rs)(R53), and -(CH2)bC(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is O to 6;
each R8 is independently selected from the grqup consisting of halo, alkyl, CN, NO2, COaRsI, C(O)Rsl, -O-R", -N(Rsa)(Rg3), -N(R81)C(O)R81, -N(R81)S02R81, -SR81, -C(O)N(Rs2)(R83 -OC(O)R81, -OC(O)N(R$2')(R83), SO2, -SOR81, -S03R$1, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
nais0to5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, C02R91, C(O)R91, -O-R91, -N(R12)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R
92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is O to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
[0053] The substances according to the invention may also be present as salts.
In the context of the invention, preference is given to pharmaceutically acceptable salts.
Pharmaceutically acceptable salts refers to an acid addition salt or a basic addition salt of a compound of the invention in which the resulting counter ion is understood in tlie art to be generally acceptable for pharmaceutical uses. Pharmaceutically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids.
Preference is given to salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or to salts with organic carboxylic or sulfonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid. Pharmaceutically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Particular preference is given to, for example, sodium, potassium, magnesium or calcium salts, and also to ammonium salts which are derived from annnonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine. (see, Berge et al. J. PhaYm. Sci. 1977, 66, 1-19.)
In the context of the invention, preference is given to pharmaceutically acceptable salts.
Pharmaceutically acceptable salts refers to an acid addition salt or a basic addition salt of a compound of the invention in which the resulting counter ion is understood in tlie art to be generally acceptable for pharmaceutical uses. Pharmaceutically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids.
Preference is given to salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or to salts with organic carboxylic or sulfonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid. Pharmaceutically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Particular preference is given to, for example, sodium, potassium, magnesium or calcium salts, and also to ammonium salts which are derived from annnonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine. (see, Berge et al. J. PhaYm. Sci. 1977, 66, 1-19.)
[0054] When one or more chiral centers are present in the compounds of the present invention,the individual isomers and mixtures thereof (e.g., racemates, etc.) are intended to be encompassed by the formulae depicted herein. In certain embodiments, compounds of the invention may exist in several tautomeric forms. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.
Compounds of the invention may exist in various hydrated forms.
Compounds of the invention may exist in various hydrated forms.
[0055] It is understood that when n is a value greater than 1, each RI group may be selected independently. Thus, when more than one R1 group is present, the Rl groups may be selected from any of the stated groups so as to be the same or different. This also holds true for any other group or substituent which may be selected independently from among various groups or values.
[0056] In another aspect of the invention, a synthetic process for the preparation of compounds of the inventiop is provided. The inventive process uses mild reaction conditions, which provides a high substituent tolerance. The product is obtained in high yield and high purity. A process of the present invention is illustrated by Scheme I:
Sclieme I
\ R3 HO-Rz R3 (R')n / Y base ~ (R1)n / Y O
LG HN' R2 R3 H2N-R2 \ R3 (R~n ~RI)n Y 0 base / Y 0
Sclieme I
\ R3 HO-Rz R3 (R')n / Y base ~ (R1)n / Y O
LG HN' R2 R3 H2N-R2 \ R3 (R~n ~RI)n Y 0 base / Y 0
[0057] AI and A2 may be treated with an alcohol (HO-R2) or amine (H2N-R2) in the presence of an appropriate base. LG represents a leaving group, such as halo, aryl sulfones (tosyl, etc.), triflate or other appropriate leaving group as would be recognized by the ordinarily skilled practitioner. The base may be selected from amine bases, hydroxide salts (non-limiting examples include sodium hydroxide and tetraalkylamonium hydroxides), carbonate salts, hydrides, alkoxide salts (non-limiting examples include sodium methoxide and potassium t-butoxide) and the like.
[0058] In other embodiments, compounds of the invention may be prepared according the reactions provided in Scheme 2:
Scheme 2 ~
\
Rs ~ ~ \ \ R3 (RI)n base (R%
/
\ I
OH LG
R3 \ / \ Rs (R~)n -~ (R~)n / Y O base / Y
A4 $4
Scheme 2 ~
\
Rs ~ ~ \ \ R3 (RI)n base (R%
/
\ I
OH LG
R3 \ / \ Rs (R~)n -~ (R~)n / Y O base / Y
A4 $4
[0059] A3 and A4 may be treated with an activated benzyl group in the presence of an appropriate base. LG represents a leaving group, such as halo, aryl sulfones (tosyl, etc.), triflate or other appropriate leaving group as would be recognized by the ordinarily skilled practitioner.
The base may be selected from amine bases, hydroxide salts (non-limiting examples include sodium hydroxide and tetraalkylamonium hydroxides), carbonate salts, hydrides, alkoxide salts (non-limiting examples include sodium methoxide and potassium t-butoxide) and the like.
The base may be selected from amine bases, hydroxide salts (non-limiting examples include sodium hydroxide and tetraalkylamonium hydroxides), carbonate salts, hydrides, alkoxide salts (non-limiting examples include sodium methoxide and potassium t-butoxide) and the like.
[0060] In other embodiments, compounds of the invention may be prepared in the manner described in Scheme 3:
Scheme 3 (R8)m OH (R8)m LG (R8)m \ \ /
(R1)n (R~)n \
/ base /
Y\O Y p
Scheme 3 (R8)m OH (R8)m LG (R8)m \ \ /
(R1)n (R~)n \
/ base /
Y\O Y p
[0061] A4 may be treated with an activated benzyl group in the presence of an appropriate base. LG represents a leaving group, such as halo, aryl sulfones (tosyl, etc.), triflate or other appropriate leaving group as would be recognized by the ordinarily skilled practitioner. The base may be selected from amine bases, hydroxide salts (non-limiting examples include sodium hydroxide and tetraalkylamonium hydroxides), carbonate salts, hydrides, alkoxide salts (non-limiting examples include sodium methoxide and potassium t-butoxide) and the like.
[0062] It may be advantageous to employ a temporary protecting group in achieving the final product. The phrase "protecting group" as used herein means temporary modifications of a potentially reactive functional group which protect it from undesired chemical transformations.
Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2"d ed.; Wiley: New York, 1991).
Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2"d ed.; Wiley: New York, 1991).
[0063] The compounds and processes disclosed herein are useful in the production of a library of 3,4-disubstituted coumarin and quinolone derivatives for biological screening.
Derivatives of coumarin and quinolone posses a range of biological activities.
Coumarin-based and quinolone-based compounds have shown efficacy, for example, as antivirals.
Particularly, the compounds of the present invention may be used to prevent or treat infection with HCV.
Derivatives of coumarin and quinolone posses a range of biological activities.
Coumarin-based and quinolone-based compounds have shown efficacy, for example, as antivirals.
Particularly, the compounds of the present invention may be used to prevent or treat infection with HCV.
[0064] The identification of inhibitors of HCV replication and/or proliferation has been facilitated by the development ofa cell based system to study HCV replication and assay for HCV inhibitors. Inhibition of HCV replication may be performed using the HCV
Replicon Assay developed in the laboratories of Bartenschlager (Lobman et al, Science 285, 110-113, 1999) and Rice (Blight et al, Science 290, 1972-1974, 2000). The assay is performed using the Huh-Luc- Neo cell line (Lohman et al, Science 285, 110-113, 1999). Huh-Luc-Neo cells are a human hepatoma cell line (Huh-7) stably expressing a bi-cistronic subgenomic replicon containing the HCV IRES in which the structural proteins of HCV had been deleted and replaced by a construct containing sequences coding for the firefly luciferase reporter gene, the neomycin selectable marker and the EMCV IRES to direct expression of a truncated HCV
genome expressing the structural proteins NS3, NS4A, NS4B, NS5A, and NS5B. HCV
targets through which inhibitors could act to inhibit replication include the NS3 protease, the helicase/ATPase, NS5A, the NS5B- RNA dependent RNA polymerase, and the HCV IRES.
Replicon Assay developed in the laboratories of Bartenschlager (Lobman et al, Science 285, 110-113, 1999) and Rice (Blight et al, Science 290, 1972-1974, 2000). The assay is performed using the Huh-Luc- Neo cell line (Lohman et al, Science 285, 110-113, 1999). Huh-Luc-Neo cells are a human hepatoma cell line (Huh-7) stably expressing a bi-cistronic subgenomic replicon containing the HCV IRES in which the structural proteins of HCV had been deleted and replaced by a construct containing sequences coding for the firefly luciferase reporter gene, the neomycin selectable marker and the EMCV IRES to direct expression of a truncated HCV
genome expressing the structural proteins NS3, NS4A, NS4B, NS5A, and NS5B. HCV
targets through which inhibitors could act to inhibit replication include the NS3 protease, the helicase/ATPase, NS5A, the NS5B- RNA dependent RNA polymerase, and the HCV IRES.
[0065] Expression of HCV IRES driven luciferase reporter activity arid HCV RNA
is measured to obtain indirect and direct measures of replication of HCV RNA
respectively.
Inhibitors of HCV replication and/or proliferation are determined by initially identifying molecules that inhibit expression of the HCV IRES driven luciferase reporter in this HCV
Replicon Luciferase Assay. Cell viability assays and control cell based luciferase assays are then run on hits identified in the HCV Replicon Luciferase Assay to eliminate cytoxic compounds and non-specific compounds which act by inhibiting the luciferase enzyme.
Validated inhibitors of HCV replication and/or proliferation are identified by evaluating HCV Replicon Luciferase hits that are specific and non-cytoxic and demonstrating that these compounds inhibit expression of HCV RNA using a quantitative PCR based approach (Taqman) using primers and probes specific for HCV RNA (HCV Replicon RNA Assay).
is measured to obtain indirect and direct measures of replication of HCV RNA
respectively.
Inhibitors of HCV replication and/or proliferation are determined by initially identifying molecules that inhibit expression of the HCV IRES driven luciferase reporter in this HCV
Replicon Luciferase Assay. Cell viability assays and control cell based luciferase assays are then run on hits identified in the HCV Replicon Luciferase Assay to eliminate cytoxic compounds and non-specific compounds which act by inhibiting the luciferase enzyme.
Validated inhibitors of HCV replication and/or proliferation are identified by evaluating HCV Replicon Luciferase hits that are specific and non-cytoxic and demonstrating that these compounds inhibit expression of HCV RNA using a quantitative PCR based approach (Taqman) using primers and probes specific for HCV RNA (HCV Replicon RNA Assay).
[0066] The HCV Replicon Assay may be used to predict compound efficacy in treatment and/or prevention of HCV infection as well as inhibition of HCV replication and/or proliferation.
The HCV Replicon encompasses a multiplicity of viral and host targets through which an inhibitor could work to inhibit HCV Replication. Viral targets expressed in the HCV Replicon include the HCV IRES (for translation), NS3 Protease, the HCV Helicase/ATPase, phosphorylation, and the NS5B polymerase. Without being limited to theory, it is believed that the compounds of the present invention inhibit HCV replication. The compounds of the invention may inhibit replication as by acting on the IRES, NS3 protease, NS5B
polymerase, Helicase/ATPase, or NS5A phosphorylation.
The HCV Replicon encompasses a multiplicity of viral and host targets through which an inhibitor could work to inhibit HCV Replication. Viral targets expressed in the HCV Replicon include the HCV IRES (for translation), NS3 Protease, the HCV Helicase/ATPase, phosphorylation, and the NS5B polymerase. Without being limited to theory, it is believed that the compounds of the present invention inhibit HCV replication. The compounds of the invention may inhibit replication as by acting on the IRES, NS3 protease, NS5B
polymerase, Helicase/ATPase, or NS5A phosphorylation.
[0067] Thus, in another embodiment, the present invention provides pharmaceutical compositions comprising an anti-HCV effective amount of a compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof, in combination with a pharmaceutically acceptable carrier or auxiliary agent. As used herein, the terms "pharmaceutically acceptable salts" and "hydrates" refer to those salts and hydrated forms of the compound that would favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which those skilled in the art may take into account in the selection include the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.
[0068] The invention also provides a method of treating HCV infection in a mammal, preferable a human, by administering to the mammal an effective amount of a compound of the present invention, a pharmaceutically acceptable salt or hydrate thereof, or a composition as described above. The compounds of the invention may be administered alone or may be administered in combination with other approved therapeutics, such as: an interferon (pegylated or not), preferably a-interferon, ribavirin, or interferon and ribavirin, or one or more other anti-HCV agent, such as an HCV protease inhibitor, HCV polymerase inhibitor, HCV IRES
inhibitor, HCV Helicase and/or ATPase inhibitor, NSSA phosphorylation inhibitor, HCV NS2 inhibitor, or other HCV life cycle inhibitor. Combination therapies with may include a compound of the invention with multiple different inhibitors of HCV life cycle (immunomodulatory agents, Toll Like Receptor modulators, antisense therapeutics etc.). The agents that comprise a combination therapy may be administered together or separately, e.g., prior to, concurrently with or following the administration of the compound of the invention or pharmaceutically acceptable salt thereof. These additional agents may be combined with the compounds of this invention to create a single pharmaceutical dosage form.
Alternatively these additional agents may be separately adniinistered to the patient as part of a multiple dosage forin, for example, using a kit. Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof.
inhibitor, HCV Helicase and/or ATPase inhibitor, NSSA phosphorylation inhibitor, HCV NS2 inhibitor, or other HCV life cycle inhibitor. Combination therapies with may include a compound of the invention with multiple different inhibitors of HCV life cycle (immunomodulatory agents, Toll Like Receptor modulators, antisense therapeutics etc.). The agents that comprise a combination therapy may be administered together or separately, e.g., prior to, concurrently with or following the administration of the compound of the invention or pharmaceutically acceptable salt thereof. These additional agents may be combined with the compounds of this invention to create a single pharmaceutical dosage form.
Alternatively these additional agents may be separately adniinistered to the patient as part of a multiple dosage forin, for example, using a kit. Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof.
[0069] The compounds of the present invention may be employed in solid or liquid form includiiig, for example, amorphous powder or crystalline form, in solution or in suspension.
They may be administered in numerous different ways, such as orally, parenterally, topically, transdermally or by inhalation. Oral administration or administration by injection is preferred.
The choice of carrier and the content of active compound in the carrier are generally determined in accordance with the solubility and chemical properties of the desired product, the particular mode of administration and well established pharmaceutical practice. The pharmaceutical composition of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, and intralesional injection or infusion techniques.
They may be administered in numerous different ways, such as orally, parenterally, topically, transdermally or by inhalation. Oral administration or administration by injection is preferred.
The choice of carrier and the content of active compound in the carrier are generally determined in accordance with the solubility and chemical properties of the desired product, the particular mode of administration and well established pharmaceutical practice. The pharmaceutical composition of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, and intralesional injection or infusion techniques.
[0070] Examples of liquid carriers include syrups, peanut oil, olive oil, water, saline and the like. For parenteral administration, emulsions, suspensions or solutions of the compounds according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, may be used. Injectable forms must be fluid to the extent they can be easily syringed, and proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of the injectable compositions can be brought about by use of agents delaying absorption, for example, aluminum monostearate and gelatin. The pharmaceutical composition may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example Tween 80) and suspending agents.
[0071] The pharmaceutical composition of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. Compounds of the invention may be enclosed in hard or soft shell gelatin capsules, or compressed into tablets. Examples of oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like.
Carriers for oral use (solid or liquid) may include time delay materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax. To prepare a capsule, it may be advantageous to use lactose and a liquid carrier, such as high molecular weight polyethylene glycols.
Carriers for oral use (solid or liquid) may include time delay materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax. To prepare a capsule, it may be advantageous to use lactose and a liquid carrier, such as high molecular weight polyethylene glycols.
[0072] Compositions and dosage forms prepared in accordance with the present invention optionally may contain lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silica gels combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets, capsules and the like. Various other materials may be present as coatings or to otherwise modify the physical fonn of the dosage unit. For instance, tablets, and capsules may be coated with shellac, sugar or both. When aqueous suspensions are used they may contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and mixtures thereof also may be used. In addition, the active compound may be incorporated into sustained-release preparations and formulations. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. Other suitable vehicles or carriers for the above noted formulations and compositions can be found in standard phamiaceutical texts, e.g. in "Remington's Pharmaceutical Sciences", The Science and Practice of Pharmacy, 19th Ed. Mack Publishing Company, Easton, Pa., (1995).
[0073] When these compounds or their pharmaceutically acceptable salts are formulated together with a pharmaceutically acceptable carrier, the resulting composition may be administered in vivo to mammals, such as man, to treat or prevent HCV virus infection. Such treatment may also be achieved using a compound of this invention in combination with other anti-viral agents which include, but are not limited to a-interferon and ribavirin. The additional agents may be combined with compounds of this invention to create a single dosage form.
Alternatively these additional agents may be separately administered to a mammal as part of a multiple dosage form.
EXAMPLES
Genet=al Methods
Alternatively these additional agents may be separately administered to a mammal as part of a multiple dosage form.
EXAMPLES
Genet=al Methods
[0074] Reaction solvents were commercially purchased from Acros and Aldrich without further purification and reagents were used as received. Reactions for the synthesis of the starting material were monitored by thin-layer chromatography (TLC) on 0.25 mm precoated Merck Silica Gel 60 F254, visualizing with ultraviolet light or phosphomolybdic acid stain. Flash column chromatography was performed on Merck Silica Gel 60 (230-400 mesh) using reagent grade hexanes, dichioromethane, methanol and ethyl acetate.
[0075] Reaction reagents were commercially purchased from Alrich and used as received. 1H and 13C NMR spectra were recorded on a Varian 500 MHz spectrometer and are referenced to residual solvent peaks or to an internal reference of tetramethylsilane in CDC13.
LC-MS were obtained on a Micromass ZQ mass spectrameter in ES+ mode with a Water 2790 HPLC system. HPLC condition: C18 column (3.5 m, 2.1 X 50 mm, W93491F 26) using a flow rate of 0.4 mL/min in a gradient of 15-100% CH3CN in H20 in 9 min with 1 min wash.
Example 1 OH Br \ K2C03 O
O O + Acetone \ 65 C 1 2
LC-MS were obtained on a Micromass ZQ mass spectrameter in ES+ mode with a Water 2790 HPLC system. HPLC condition: C18 column (3.5 m, 2.1 X 50 mm, W93491F 26) using a flow rate of 0.4 mL/min in a gradient of 15-100% CH3CN in H20 in 9 min with 1 min wash.
Example 1 OH Br \ K2C03 O
O O + Acetone \ 65 C 1 2
[0076] To the mixture of 1 (60 mg, 0.37 mmol) and K2C03 (100 mg, 0.73 mmol) in acetone (3 mL), 2 (103 mg, 0.56 mmol) was added slowly. Then the reaction was stirred at 65 C
overnight. After cooled down, and filtered, the solvent was removed, the given residue was purified using PTLC (eluent: EtOAc/Petroleum ether = 1:3) to give 3 (13.9 mg, 10%) as solid.
I \ CF3 VQ_31711 LC-MS (6.77 min, ES): calcd: 478.10; Found: 479.48. 1H NMR (CDCl3): 7.72-7.63 (m, 2H), 7.62-7.52 (m, 3H), 7.52-7.43 (m, 2H), 7.43-7.34 (m, 3H), 7.314 (t, J= 7.5 Hz, 1H), 5.13 (s, 2H), 3.977 (s, 2H).
O
a \ / CF3 o o VQ_31712 LC-MS (6.81 min, ES+): calcd: 478.10; Found: 479.41. 1H NMR (CDC13): 7.656 (d, J= 8 Hz, 1H), 7.627 (AABB, J = 80.5, 8.5 Hz, 4H), 7.57 (t, J = 7.5 Hz, 1H), 7.455 (AABB, J = 52, 8 Hz, 4H), 7.403 (d, J = 8 Hz, 1 H), 7.3 09 (t, J= 7.5 Hz, 1 H), 5.13 8 (s, 2H), 3.97 8 (s, 2H).
I\
0 ~VQ_31715 LC-MS (6.65 min, ES+): calcd: 370.16; Found: 371.45. 1H NMR (CDC13): 7.72 (d, J = 8.5 Hz, 1H), 7.523 (t, J = 8.5 Hz, 1H), 7.376 (d, J = 8 Hz, 1H), 7.297 (t, J = 8 Hz, 1H), 7.31 (AABB, J =
45.5, 9.5 Hz, 4H), 7.175 (AABB, J = 81.5, 8 Hz, 4H), 5.072 (s, 2H), 3.913 (s, 2H), 2.421 (s, 3H), 2.314 (s, 3H).
O
I \ \ \ /
MeO o O VQ_31729 LC-MS (6.68 min, ES+): calcd: 400.17; Found: 401.47. 'H NMR (CDC13): 7.589 (d, J= 8.5 Hz, 1H), 7.325 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.224 (s, 1H), 7.216 (d, J= 8.0 Hz, 1H), 7.171-7.115 (m, 3H), 6.999 (d, J = 7.5 Hz, 1H), 6.857-6.835 (m, 2H), 5.006 (s, 2H), 3.890 (s, 2H), 3.874 (s, 3H), 2.4 (s, 3H), 2.298 (s, 3H).
O
Meo o O VQ_31734 LC-MS (6.71 min, ES): calcd: 440.06; Found: 441.38. 1H NMR (CDC13): 7.542 (d, J = 9.5 Hz, 1 H), 7.412 (s, 1 H), 7.371 (s, 1H), 7.4 N 7.3 5(m, 1H), 7.3-7.24 (m, 2H), 7.2-7.15 (m, 3H), 6.9-6.85 (m, 2H), 5.002 (s, 2H), 3.879 (s, 3H), 3.861 (s, 2H). -y Me Me O
Meo O o VQ_31738 LC-MS (6.64 min, ES+): calcd: 400.17; Found: 401.47. 1H NMR (CDC13): 7.595 (d, J = 9.0 Hz, 1H), 7.4-7.25 (m, 3H), 7.25-7.15 (m, 2H), 7.15~7.05 (m, 3H), 6.95-6.85 (m, 2H), 5.01 (s, 2H), 3.886 (s, 3H), 3.872 (s, 2H), 2.33 (s, 3H), 2.207 (s, 3H).
F
F
F
O
F
MeO O O VQ_31744 LC-MS (6.33 min, ES+): calcd: 444.10; Found: 445.46. 'H NMR (CDC13): 7.576 (d, J = 9 Hz, 1H), 7.428 (q, J= 15.5, 8 Hz, IH), 7.223 (q, J = 15, 8 Hz, 1H), 6.937 (t, J=
7.5 Hz, 1H), 6.9-6.82 (m, 3H), 6.763 (tt, J = 8.5, 2H), 5.078 (s, 2H), 3.825 (s, 5H).
F
F
F
O
F
Meo o o VQ_31748 LC-MS (6.51 min, ES+): calcd: 444.10; Found: 445.41. 1H NMR (CDC13): 7.516 (d, J= 9.5 Hz, 1H), 7.3-7.16 (m, 2H), 7.15-6.94 (m, 4H), 6.9-6.83 (m, 2H), 5.009 (s, 2H), 3.884 (s, 3H), 3.808 (s, 2H).
MeO 0 0 VQ_31754 LC-MS (6.78 min, ES}): calcd: 508.11; Found: 509.46. 'H NMR (CDC13): 7.7-7.63 (m, 2H), 7.6-7.5 (m, 4H), 7.5-7.42 (2H), 7.4-7.33 (m, 1H), 6.85-6.82 (m, 2H), 5.097 (s, 2H), 3.939 (s, 2H), 3.885 (s, 3H).
.
\ / CF3 MeO O o VQ_31758 LC-MS (6.84 min, ES+): caled: 508.11; Found: 509.45. 1H NMR (CDC13): 7.614 (AABB, J
85.5, 8.5 Hz, 4H), 7.53 (d, J = 8 Hz, 1H), 7.446 (AABB, J = 55, 8 Hz, 4H), 6.875 (s, 1H), 6.866 (d, J = 8 Hz, 1H), 5.106 (s, 2H), 3.94 (s, 2H), 3.884 (s, 3H).
Meo 0 0 VQ_31763 LC-MS (6.68 min, ES+): calcd: 400.17; Found: 401.47. 1H NMR (CDC13): 7.576 (d, J = 8 Hz, 1H), 7.226 (AABB, J= 8, 4 Hz, 4H), 7.19 (AABB, J=121, 8 Hz, 4H), 6.845 (s, 1H), 6.837 (d, J
= 8 Hz, 1H), 5.028 (s, 2H), 3.869 (s, 3H), 3.859 (s, 2H), 2.40 (s, 3H), 2.294 (s, 3H).
F
F
O
~ \ / F
o o F VQ_32806 LC-MS (6.64 min, ES+): calcd: 442.12; Found: 443.40. 1H NMR (CDC13): 7.438 (q, J= 14.5, 8 Hz, 1 H), 7.41 (s, 1 H), 7.21 (q, J = 15.5, 8.5 Hz, 1 H), 7.16 (s, 1 H), 6.942 (t, J = 8 Hz, 1 H), 6.881 (t, J= 8 Hz, 1H), 6.81-6.7 (m, 2H), 5.081 (s, 2H), 3.882 (s, 2H), 2.36 (s, 3H), 2.306 (s, 311).
Example 2 r I
OH CI NH
C~O POCI3 C ~ CHO NH2 CC101 CHO
O DMF O O Et3N,MeOH O
/I
H2N^CO2Me NaBH4 NH
THF THF CIO H N CO2Me
overnight. After cooled down, and filtered, the solvent was removed, the given residue was purified using PTLC (eluent: EtOAc/Petroleum ether = 1:3) to give 3 (13.9 mg, 10%) as solid.
I \ CF3 VQ_31711 LC-MS (6.77 min, ES): calcd: 478.10; Found: 479.48. 1H NMR (CDCl3): 7.72-7.63 (m, 2H), 7.62-7.52 (m, 3H), 7.52-7.43 (m, 2H), 7.43-7.34 (m, 3H), 7.314 (t, J= 7.5 Hz, 1H), 5.13 (s, 2H), 3.977 (s, 2H).
O
a \ / CF3 o o VQ_31712 LC-MS (6.81 min, ES+): calcd: 478.10; Found: 479.41. 1H NMR (CDC13): 7.656 (d, J= 8 Hz, 1H), 7.627 (AABB, J = 80.5, 8.5 Hz, 4H), 7.57 (t, J = 7.5 Hz, 1H), 7.455 (AABB, J = 52, 8 Hz, 4H), 7.403 (d, J = 8 Hz, 1 H), 7.3 09 (t, J= 7.5 Hz, 1 H), 5.13 8 (s, 2H), 3.97 8 (s, 2H).
I\
0 ~VQ_31715 LC-MS (6.65 min, ES+): calcd: 370.16; Found: 371.45. 1H NMR (CDC13): 7.72 (d, J = 8.5 Hz, 1H), 7.523 (t, J = 8.5 Hz, 1H), 7.376 (d, J = 8 Hz, 1H), 7.297 (t, J = 8 Hz, 1H), 7.31 (AABB, J =
45.5, 9.5 Hz, 4H), 7.175 (AABB, J = 81.5, 8 Hz, 4H), 5.072 (s, 2H), 3.913 (s, 2H), 2.421 (s, 3H), 2.314 (s, 3H).
O
I \ \ \ /
MeO o O VQ_31729 LC-MS (6.68 min, ES+): calcd: 400.17; Found: 401.47. 'H NMR (CDC13): 7.589 (d, J= 8.5 Hz, 1H), 7.325 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.224 (s, 1H), 7.216 (d, J= 8.0 Hz, 1H), 7.171-7.115 (m, 3H), 6.999 (d, J = 7.5 Hz, 1H), 6.857-6.835 (m, 2H), 5.006 (s, 2H), 3.890 (s, 2H), 3.874 (s, 3H), 2.4 (s, 3H), 2.298 (s, 3H).
O
Meo o O VQ_31734 LC-MS (6.71 min, ES): calcd: 440.06; Found: 441.38. 1H NMR (CDC13): 7.542 (d, J = 9.5 Hz, 1 H), 7.412 (s, 1 H), 7.371 (s, 1H), 7.4 N 7.3 5(m, 1H), 7.3-7.24 (m, 2H), 7.2-7.15 (m, 3H), 6.9-6.85 (m, 2H), 5.002 (s, 2H), 3.879 (s, 3H), 3.861 (s, 2H). -y Me Me O
Meo O o VQ_31738 LC-MS (6.64 min, ES+): calcd: 400.17; Found: 401.47. 1H NMR (CDC13): 7.595 (d, J = 9.0 Hz, 1H), 7.4-7.25 (m, 3H), 7.25-7.15 (m, 2H), 7.15~7.05 (m, 3H), 6.95-6.85 (m, 2H), 5.01 (s, 2H), 3.886 (s, 3H), 3.872 (s, 2H), 2.33 (s, 3H), 2.207 (s, 3H).
F
F
F
O
F
MeO O O VQ_31744 LC-MS (6.33 min, ES+): calcd: 444.10; Found: 445.46. 'H NMR (CDC13): 7.576 (d, J = 9 Hz, 1H), 7.428 (q, J= 15.5, 8 Hz, IH), 7.223 (q, J = 15, 8 Hz, 1H), 6.937 (t, J=
7.5 Hz, 1H), 6.9-6.82 (m, 3H), 6.763 (tt, J = 8.5, 2H), 5.078 (s, 2H), 3.825 (s, 5H).
F
F
F
O
F
Meo o o VQ_31748 LC-MS (6.51 min, ES+): calcd: 444.10; Found: 445.41. 1H NMR (CDC13): 7.516 (d, J= 9.5 Hz, 1H), 7.3-7.16 (m, 2H), 7.15-6.94 (m, 4H), 6.9-6.83 (m, 2H), 5.009 (s, 2H), 3.884 (s, 3H), 3.808 (s, 2H).
MeO 0 0 VQ_31754 LC-MS (6.78 min, ES}): calcd: 508.11; Found: 509.46. 'H NMR (CDC13): 7.7-7.63 (m, 2H), 7.6-7.5 (m, 4H), 7.5-7.42 (2H), 7.4-7.33 (m, 1H), 6.85-6.82 (m, 2H), 5.097 (s, 2H), 3.939 (s, 2H), 3.885 (s, 3H).
.
\ / CF3 MeO O o VQ_31758 LC-MS (6.84 min, ES+): caled: 508.11; Found: 509.45. 1H NMR (CDC13): 7.614 (AABB, J
85.5, 8.5 Hz, 4H), 7.53 (d, J = 8 Hz, 1H), 7.446 (AABB, J = 55, 8 Hz, 4H), 6.875 (s, 1H), 6.866 (d, J = 8 Hz, 1H), 5.106 (s, 2H), 3.94 (s, 2H), 3.884 (s, 3H).
Meo 0 0 VQ_31763 LC-MS (6.68 min, ES+): calcd: 400.17; Found: 401.47. 1H NMR (CDC13): 7.576 (d, J = 8 Hz, 1H), 7.226 (AABB, J= 8, 4 Hz, 4H), 7.19 (AABB, J=121, 8 Hz, 4H), 6.845 (s, 1H), 6.837 (d, J
= 8 Hz, 1H), 5.028 (s, 2H), 3.869 (s, 3H), 3.859 (s, 2H), 2.40 (s, 3H), 2.294 (s, 3H).
F
F
O
~ \ / F
o o F VQ_32806 LC-MS (6.64 min, ES+): calcd: 442.12; Found: 443.40. 1H NMR (CDC13): 7.438 (q, J= 14.5, 8 Hz, 1 H), 7.41 (s, 1 H), 7.21 (q, J = 15.5, 8.5 Hz, 1 H), 7.16 (s, 1 H), 6.942 (t, J = 8 Hz, 1 H), 6.881 (t, J= 8 Hz, 1H), 6.81-6.7 (m, 2H), 5.081 (s, 2H), 3.882 (s, 2H), 2.36 (s, 3H), 2.306 (s, 311).
Example 2 r I
OH CI NH
C~O POCI3 C ~ CHO NH2 CC101 CHO
O DMF O O Et3N,MeOH O
/I
H2N^CO2Me NaBH4 NH
THF THF CIO H N CO2Me
[0077] POC13 was added slowly to the solution of 1 in DMF at -5--10 C (ice bath). Then the mixture stirred for 1 hr at r.t. and for another 2 hrs at 60 C. After cooling down, the mixture was poured to the crushed ice in the flask and stored at 0 C overnight. Then filtered, and washed down with 5% Na2CO3 solution and water followed by drying in vacuum to give 2.
[0078] 4-Methyl aniline was dissolved in MeOH and added slowly to the mixture of 2 and Et3N in MeOH and in a couple minutes the precipitation of 3 formed. After filtration, washing down with MeOH, and drying in vacuum amine was added to the solution 3 in THF and the mixture stirred overnight followed adding NaBH4 to acquired 4. And VQ_36344 is the result of the direct reduction of 3.
N \ NH
H^COOMe 0 0 VQ_36341 'H NMR (CDC13): 7.581 (br, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.351 (d, J = 7.5 Hz, 1H), 7.301 (d, J = 7.5 Hz, 1H), 7.023 (t, J = 7.5 Hz, 1H), 7.017 (AABB, J = 93, 7.5 Hz, 4H), 4.733 (s, 2H), 4.2 (br, 1H), 3.818 (s, 3H), 3.614 (d, J 7.5 Hz, 1H), 3.60 (d, J = 6.5 Hz, 1H), 2.339 (s, 3H).
NH
~ \ \ N
H
~ 0 0 VQ_36343 'H NMR (CDC13): 8.471 (s, 1H), 8.394 (d, J 4.5 Hz, 1H), 7.579 (br, 1H), 7.437 (t, J
7.5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.022 (t, J =
7.0 Hz, 1H), 7.014 (AABB, J = 93.5, 8.0 Hz, 4H), 6.725 (t, J = 6.0 Hz, 1H), 4.737 (s, 2H), 2.338 (s, 3H).
~/\/ I
NH
CCOI\co VQ_36344 1H NMR (CDC13): 7.456 (t, J = 8.0 Hz, 1H), 7.411 (d, J = 8.0 Hz, 1H), 7.355 (d, J = 8.0 Hz, 1H), 7.124 (t, J = 8.0 Hz, 1H), 6.975 (AABB, J = 132.5, 7.5 Hz, 4H), 6.064 (br, 1H), 2.333 (s, 3H), 2.031 (s, 3H).
Example 3 OH Br O
K2CO3 I ~ - O
+
I~ N O I Acetone ~ N O\/ ~
N \ NH
H^COOMe 0 0 VQ_36341 'H NMR (CDC13): 7.581 (br, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.351 (d, J = 7.5 Hz, 1H), 7.301 (d, J = 7.5 Hz, 1H), 7.023 (t, J = 7.5 Hz, 1H), 7.017 (AABB, J = 93, 7.5 Hz, 4H), 4.733 (s, 2H), 4.2 (br, 1H), 3.818 (s, 3H), 3.614 (d, J 7.5 Hz, 1H), 3.60 (d, J = 6.5 Hz, 1H), 2.339 (s, 3H).
NH
~ \ \ N
H
~ 0 0 VQ_36343 'H NMR (CDC13): 8.471 (s, 1H), 8.394 (d, J 4.5 Hz, 1H), 7.579 (br, 1H), 7.437 (t, J
7.5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.022 (t, J =
7.0 Hz, 1H), 7.014 (AABB, J = 93.5, 8.0 Hz, 4H), 6.725 (t, J = 6.0 Hz, 1H), 4.737 (s, 2H), 2.338 (s, 3H).
~/\/ I
NH
CCOI\co VQ_36344 1H NMR (CDC13): 7.456 (t, J = 8.0 Hz, 1H), 7.411 (d, J = 8.0 Hz, 1H), 7.355 (d, J = 8.0 Hz, 1H), 7.124 (t, J = 8.0 Hz, 1H), 6.975 (AABB, J = 132.5, 7.5 Hz, 4H), 6.064 (br, 1H), 2.333 (s, 3H), 2.031 (s, 3H).
Example 3 OH Br O
K2CO3 I ~ - O
+
I~ N O I Acetone ~ N O\/ ~
[0079] To the mixture of 1 (50 mg, 0.285 mmol) and K2C03 (197 mg, 1.43 mmol) in acetone (3 mL), 2 (158 mg, 0.854 mmol) was added slowly. Then the reaction was stirred at 65 C overnight. After cooled down, and filtered, the solvent was removed, the given residue was purified using PTLC (eluent: EtOAc/Petroleum ether =1:3) to give 3 (81.3 mg, 74.3%) and 4 (23.2 mg, 21.2%) as solids.
O
ayN~(O
CH3 VQ_32833 LC-MS (6.42 min, ES+): caled: 383.48; Found: 384.39. 1H NMR (CDCl3): 7.85 (dd, J= 8.0, 2.0 Hz, 1 H), 7.326 (dt, J= 9.0, 2.0 Hz, 1 H), 6.961 (t, J= 7.5 Hz, 1 H), 6.8 8(AABB, J= 46, 8.5 Hz, 8H), 6.66 (d, J = 8.5 Hz, 1H), 3.42 (s, 2H), 3.188 (s, 2H), 2.146 (s, 6H).
Example 4 OH CHaBr O
O
aceton N 0 \
I / ~\1 O + + +
o N 0 I /
ry 65 C \ N O
~ 2 lo ~\ \
~ ~o To the mixture of 1 (50 mg, 0.31 mmol) and K2C03 (429 mg, 3.1 mmol) in acetone (3 mL), 2 (345 mg, 1.86 mmol) was added slowly. Then the reaction was stirred at 65 C
overnight. After cooled down, and filtered, the solvent was removed, the given residue was purified using PTLC
(eluent: EtOAc/Petroleum ether = 1:3) to give 3 (61.3 mg, 25.6%), 4 (43.9 mg, 38.3 1 ) and 5 (12.6 mg, 8.6%) as solids.
O a I \ t \
~ N O I ~
/ ~
~ VQ_33645 LC-MS (6.90 min, ES+): calcd: 473.60; Found: 474.48. 1H NMR (CDC13): 7.92 (d, J = 8.5 Hz, 1H), 7.165 (t, J = 8.5 Hz, 1H), 6.947 (AABB, J = 33.5, 8.5 Hz, 4H), 6.931 (AABB, J = 49, 8.5 Hz, 4H), 6.922 (t, J = 8.5 Hz, 1H), 6.71 (AABB, J = 189, 8.5 Hz, 4H), 6.52 (d, J = 8.5 Hz, 1H), 5.0 (br, 2H), 3.583 (s, 1H), 3.557 (s, 1H), 3.452 (s, 1H), 3.427 (s, 1H), 2.273 (s, 3H), 2.21 (s, 6H).
Example 5 HCVReplicon Luciferase Assay
O
ayN~(O
CH3 VQ_32833 LC-MS (6.42 min, ES+): caled: 383.48; Found: 384.39. 1H NMR (CDCl3): 7.85 (dd, J= 8.0, 2.0 Hz, 1 H), 7.326 (dt, J= 9.0, 2.0 Hz, 1 H), 6.961 (t, J= 7.5 Hz, 1 H), 6.8 8(AABB, J= 46, 8.5 Hz, 8H), 6.66 (d, J = 8.5 Hz, 1H), 3.42 (s, 2H), 3.188 (s, 2H), 2.146 (s, 6H).
Example 4 OH CHaBr O
O
aceton N 0 \
I / ~\1 O + + +
o N 0 I /
ry 65 C \ N O
~ 2 lo ~\ \
~ ~o To the mixture of 1 (50 mg, 0.31 mmol) and K2C03 (429 mg, 3.1 mmol) in acetone (3 mL), 2 (345 mg, 1.86 mmol) was added slowly. Then the reaction was stirred at 65 C
overnight. After cooled down, and filtered, the solvent was removed, the given residue was purified using PTLC
(eluent: EtOAc/Petroleum ether = 1:3) to give 3 (61.3 mg, 25.6%), 4 (43.9 mg, 38.3 1 ) and 5 (12.6 mg, 8.6%) as solids.
O a I \ t \
~ N O I ~
/ ~
~ VQ_33645 LC-MS (6.90 min, ES+): calcd: 473.60; Found: 474.48. 1H NMR (CDC13): 7.92 (d, J = 8.5 Hz, 1H), 7.165 (t, J = 8.5 Hz, 1H), 6.947 (AABB, J = 33.5, 8.5 Hz, 4H), 6.931 (AABB, J = 49, 8.5 Hz, 4H), 6.922 (t, J = 8.5 Hz, 1H), 6.71 (AABB, J = 189, 8.5 Hz, 4H), 6.52 (d, J = 8.5 Hz, 1H), 5.0 (br, 2H), 3.583 (s, 1H), 3.557 (s, 1H), 3.452 (s, 1H), 3.427 (s, 1H), 2.273 (s, 3H), 2.21 (s, 6H).
Example 5 HCVReplicon Luciferase Assay
[0080] Day 0, Cell Seeding and Compound Treatment: Huh-Luc-Neo Cells are seeded at 25,000/well in an opaque-walled 96 plate with Growth Medium (DMEM phenol red free + PS
+ 2mM glutamine; 100 l/well). The compounds to be tested are added to the experimental wells (10 l/well at lOX assay concentration) and the cells are then incubated (5% C02, 37 C) for 48h.
+ 2mM glutamine; 100 l/well). The compounds to be tested are added to the experimental wells (10 l/well at lOX assay concentration) and the cells are then incubated (5% C02, 37 C) for 48h.
[0081] Day 2, Rea eng t Preparation and Luciferase Assay: The Bright-Glo Luciferase Assay Buffer (Promega) is thawed and equilibrated to room temperature prior to use. The lyophilized Bright-Glo Luciferase Assay Substrate is equilibrated to room temperature prior to use. 10 ml of Bright-Glo Luciferase Assay Buffer is transferred to 1 vial of Bright-Glo Luciferase Assay Substrate bottle and mixed by gently with a Vortex. 100 ul of Bright-Glo Luciferase Assay reagent (Bright-Glo Luciferase Assay Buffer + Bright-Glo Luciferase Assay Substrate Mixture) is added to each well. The well contents are mixed for 5 min. on an orbital shaker at room temperature to induce cell lysis and the luminescence is then measured using a luminometer. The data is analyzed and IC50s are determined using GraphPad Prism 4 software.
Hits validated in the Replicon Luciferase assay have IC50s < 8.0 M and show <
30% inhibition of Cell Viability at a compound concentration of 100 M (Cell Titer Glow Assay, cell viability assay conditions identical to HCV Replicon Luciferase Assay conditions).
Example 6 HCVReplicon RNA Assay
Hits validated in the Replicon Luciferase assay have IC50s < 8.0 M and show <
30% inhibition of Cell Viability at a compound concentration of 100 M (Cell Titer Glow Assay, cell viability assay conditions identical to HCV Replicon Luciferase Assay conditions).
Example 6 HCVReplicon RNA Assay
[0082] Day 0, Cell Seeding and Compound Treatment: Huh-Luc-Neo Cells are seeded at 25,000/well in an opaque-walled 96 plate with Growth Medium (DMEM phenol red free + PS +
2mM glutamine; 100 l/well). The compounds to be tested are added to the experimental wells (10 l/well at 10X assay concentration) and the cells are then incubated (5%
C02, 37 C).
2mM glutamine; 100 l/well). The compounds to be tested are added to the experimental wells (10 l/well at 10X assay concentration) and the cells are then incubated (5%
C02, 37 C).
[0083] Day 1, Media Change and Compound Treatment: 24 hours after the initial compound treatment the cell culture media is aspirated from the wells and fresh Growth Medium is added (DMEM phenol red free + PS + 2mM glutamine; 100 l/well). The compounds to be tested are then added to the appropriate experimental wells (10 l/well at l OX assay concentration) and the cells are then incubated (5% C02, 37 C) for an additional 24 hrs.
[0084] Day 2, RNA Isolation and cDNA Synthesis: The cells are washed with 1X
Phosphate Buffered Saline (PBS) once. Cells are then lysed and RNA is isolated in 96 well format using a vacuum manifold and the RNAeasy 96 kit (Qiagen) according to the manufacturer's suggested protocol. cDNA is then synthesized from RNA isolated from each well using the Taqman Reverse Transcription Reagents kit (Applied Biosystems) according to manufacturer's suggested protocol.
Phosphate Buffered Saline (PBS) once. Cells are then lysed and RNA is isolated in 96 well format using a vacuum manifold and the RNAeasy 96 kit (Qiagen) according to the manufacturer's suggested protocol. cDNA is then synthesized from RNA isolated from each well using the Taqman Reverse Transcription Reagents kit (Applied Biosystems) according to manufacturer's suggested protocol.
[0085] Day 3, Quantitative PCR Based Measurement of HCV RNA (Taqman Assayl:
Quantitative PCR analysis to measure HCV RNA expression from cDNA synthesized on Day 2 is performed using the ABI 9700 HT Sequence Detection System (Applied Biosystems) as previously described (Lohman et al, Science 285, 110-113, 1999). The data is analyzed and IC50s are determined using GraphPad Prism 4 software. Hits validated in the Replicon RNA
Assay have IC50s < 8.0 M and show < 30% inhibition of Cell Viability at a compound concentration of 50 M (Cell Titer Glow Assay, cell viability assay conditions identical to HCV
Replicon RNA Assay conditions).
Example 7 CellTiter-Glo Cell Viability Assay (Promega)
Quantitative PCR analysis to measure HCV RNA expression from cDNA synthesized on Day 2 is performed using the ABI 9700 HT Sequence Detection System (Applied Biosystems) as previously described (Lohman et al, Science 285, 110-113, 1999). The data is analyzed and IC50s are determined using GraphPad Prism 4 software. Hits validated in the Replicon RNA
Assay have IC50s < 8.0 M and show < 30% inhibition of Cell Viability at a compound concentration of 50 M (Cell Titer Glow Assay, cell viability assay conditions identical to HCV
Replicon RNA Assay conditions).
Example 7 CellTiter-Glo Cell Viability Assay (Promega)
[0086] Day 0, Cell Seeding and Compound Treatment: Huh-Luc-Neo Cells are seeded at 25,000/well in an opaque-walled 96 plate with Growth Medium (DMEM phenol red free + PS
+ 2mM glutamine; 100u1/well). The compounds to be tested for inhibition of cell viability are added to the experimental wells (10 l/well at lOX assay concentration) and the cells are then incubated (5% C02, 37 C) for 48h.
+ 2mM glutamine; 100u1/well). The compounds to be tested for inhibition of cell viability are added to the experimental wells (10 l/well at lOX assay concentration) and the cells are then incubated (5% C02, 37 C) for 48h.
[0087] Day 2, Rea eng t Preparation and Assay: The CeIlTiter-Glo Buffer is thawed and equilibrated to room temperature prior to use. The lyophilized CeIlTiter-Glo Substrate is equilibrated to room temperature prior to use. 10 ml of CeIlTiter-Glo Buffer is transferred to 1 vial of CellTiter-Glo Substrate and mixed by gently with a Vortex. 100 l of CellTiter-Glo Assay reagent (Ce1lTiter-Glo Buffer + CeIlTiter-Glo Substrate Mixture) is added to each well.
The well contents are mixed for 5 min. on an orbital shaker at room temperature to induce cell lysis and the luminescence is then measured using a luminometer.
Table 1 comp. # Structure Luciferase Toxicity TaqMan Toxicity % Inhibition % Inhibition IC50 at 100uM IC50 at 5OuM
1 dose) 2 doses) I % CH3 ~
VQ_31729 CH3 3 3.53 3.0 0.36 5.1 ~.. \/
ei VQ_31734 0 c 3.84 4.3 0.67 0.7 MeO
VQ_31711 0 _ CF3 5.16 4.6 0.12 4.3 1 . \!
~ Me VQ_31738 "~e 5.44 23.6 0.21 6.1 L96~~
F
F
VQ_31748 o F 5.38 10.0 1.97 4.9 F
O o hieo CF3 VQ_31754 o cF 5.45 2.5 5.35 1.9 VQ_31758 0 6.16 14.7 5.24 2.6 1~ \! CF3 O
comp. # Structure Luciferase Toxicity TaqMan Toxicity % Inhibition % Inhibition IC50 at 100uM IC50 at 50uM
1 dose) 2 doses) VQ_31763 0 8.29 4.6 0.43 6.5 ~. . ~ /
meo VQ_31712 &'o 4.92 16.6 >30 10.0 \ / CF3 VQ_31715 0 2.80 53.4 0.55 13.4 ~. . ~/
r VQ_31744 o F F 4.50 10.9 0.28 7.0 \/ r M O O
F
VQ_32806 F 0 5.57 16.5 1.40 8.3 .
CFy 3.06 5.0 0.89 40.8 i..
/I
~
VQ_36341 HN 0.28 14.6 0.40 31.2 N COZMe 0~0 H
/ I HN~N
VQ_36343 0~-O ~ NN 0.13 21.1 0.16 37.9 x comp. # Structure Luciferase Toxicity TaqMan Toxicity % Inhibition % Inhibition IC50 at 100uM IC50 at 50uM
(1 dose) 2 doses MO
VQ 36467 NH O 51.13 22.8 0.46 13.9 \ N
/ O
Me0 /
VQ 36468 NH "43.30 40.7 0.71 16.3 N
MeO
VQ_36469 \ Nn , ~ 53.64 14.7 4.16 3.3 \ \ N N
/ O O
O
VQ_36470 MeO \ NH ~ 59.94 12.5 4.08 -2.7 ~ \ N N
VQ_36471 MeO \ NH c' 0.04 9.8 1.78 15.2 \
e0~
VQ_36472 Nx N:Y 0.03 5.9 0.85 6.5 ~\ \
~
VQ_36473 e0~ r_5:N,b30M1 0.02 4.3 1.71 10.7 e0 / I CI
, VQ_36594 1 0.74 9.1 >30 13.7 comp. # Structure Lnciferase Toxicity TaqMan Toxicity % Inhibition % Inhibition IC50 at 100uM IC50 at 5OuM
1 dose) 2 doses) VQ 32833 0 2.89 34.6 0.58 20.7 ~. . ~i N O
CiI
VQ_33645 " 02.33 21.5 >30 17.2 cl CI
VQ_34453 0 8.5 24.6 1.97 12.2 ~ ~ el N O I~ CI
~ \
/
VQ_35027 o 2.1 4.6 Inactive 12.5 H
F
~ \
VQ_35018 0 1.0 10.0 Inactive 12.3 ~~ ~~
N O F
The well contents are mixed for 5 min. on an orbital shaker at room temperature to induce cell lysis and the luminescence is then measured using a luminometer.
Table 1 comp. # Structure Luciferase Toxicity TaqMan Toxicity % Inhibition % Inhibition IC50 at 100uM IC50 at 5OuM
1 dose) 2 doses) I % CH3 ~
VQ_31729 CH3 3 3.53 3.0 0.36 5.1 ~.. \/
ei VQ_31734 0 c 3.84 4.3 0.67 0.7 MeO
VQ_31711 0 _ CF3 5.16 4.6 0.12 4.3 1 . \!
~ Me VQ_31738 "~e 5.44 23.6 0.21 6.1 L96~~
F
F
VQ_31748 o F 5.38 10.0 1.97 4.9 F
O o hieo CF3 VQ_31754 o cF 5.45 2.5 5.35 1.9 VQ_31758 0 6.16 14.7 5.24 2.6 1~ \! CF3 O
comp. # Structure Luciferase Toxicity TaqMan Toxicity % Inhibition % Inhibition IC50 at 100uM IC50 at 50uM
1 dose) 2 doses) VQ_31763 0 8.29 4.6 0.43 6.5 ~. . ~ /
meo VQ_31712 &'o 4.92 16.6 >30 10.0 \ / CF3 VQ_31715 0 2.80 53.4 0.55 13.4 ~. . ~/
r VQ_31744 o F F 4.50 10.9 0.28 7.0 \/ r M O O
F
VQ_32806 F 0 5.57 16.5 1.40 8.3 .
CFy 3.06 5.0 0.89 40.8 i..
/I
~
VQ_36341 HN 0.28 14.6 0.40 31.2 N COZMe 0~0 H
/ I HN~N
VQ_36343 0~-O ~ NN 0.13 21.1 0.16 37.9 x comp. # Structure Luciferase Toxicity TaqMan Toxicity % Inhibition % Inhibition IC50 at 100uM IC50 at 50uM
(1 dose) 2 doses MO
VQ 36467 NH O 51.13 22.8 0.46 13.9 \ N
/ O
Me0 /
VQ 36468 NH "43.30 40.7 0.71 16.3 N
MeO
VQ_36469 \ Nn , ~ 53.64 14.7 4.16 3.3 \ \ N N
/ O O
O
VQ_36470 MeO \ NH ~ 59.94 12.5 4.08 -2.7 ~ \ N N
VQ_36471 MeO \ NH c' 0.04 9.8 1.78 15.2 \
e0~
VQ_36472 Nx N:Y 0.03 5.9 0.85 6.5 ~\ \
~
VQ_36473 e0~ r_5:N,b30M1 0.02 4.3 1.71 10.7 e0 / I CI
, VQ_36594 1 0.74 9.1 >30 13.7 comp. # Structure Lnciferase Toxicity TaqMan Toxicity % Inhibition % Inhibition IC50 at 100uM IC50 at 5OuM
1 dose) 2 doses) VQ 32833 0 2.89 34.6 0.58 20.7 ~. . ~i N O
CiI
VQ_33645 " 02.33 21.5 >30 17.2 cl CI
VQ_34453 0 8.5 24.6 1.97 12.2 ~ ~ el N O I~ CI
~ \
/
VQ_35027 o 2.1 4.6 Inactive 12.5 H
F
~ \
VQ_35018 0 1.0 10.0 Inactive 12.3 ~~ ~~
N O F
Claims (109)
1. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of Formula I:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R3)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R3), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
X is selected from O and N-R4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R4), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
Y is selected from O and N-R5;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R3)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R3), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
X is selected from O and N-R4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R4), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
Y is selected from O and N-R5;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
2. The method of claim 1, comprising administering a compound of the formula II:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R1)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, phosphate, phosphonate, halo, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH7)a C(O)R31, -(CH2)a C(O)N(R32)(R3), (CH2)a C(O)OR31, -(CH2)a C(O)N(R3)(R33), -(CH2)a N(R3)(R31), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
a is 0 to 6;
X is selected from O and N-R4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R1)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, phosphate, phosphonate, halo, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH7)a C(O)R31, -(CH2)a C(O)N(R32)(R3), (CH2)a C(O)OR31, -(CH2)a C(O)N(R3)(R33), -(CH2)a N(R3)(R31), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
a is 0 to 6;
X is selected from O and N-R4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
3. The method of claim 2, comprising administering a compound of the formula III:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R3), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and a is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R3), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and a is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
4. The method of claim 3, comprising administering a compound of the formula IV:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
5. The method of claim 4, comprising administering a compound of the formula IV, wherein R7 is selected to be an aryl or heteroaryl group.
6. The method of claim 3, comprising administering a compound of the formula V:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R3), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R8)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82,)(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R 83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R3), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R8)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82,)(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R 83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
7. The method of claim 4, comprising administering a compound of the formula VI:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82,)(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82,)(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
8. The method of claim 2, comprising administering a compound of the formula VII:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2).alpha. C(O)R31, -(CH2).alpha. C(O)N(R32)(R33), (CH2).alpha.
C(O)OR31, -(CH2).alpha. C(O)N(R32)(R33), -(CH2).alpha. N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl .alpha. is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2).alpha. C(O)R31, -(CH2).alpha. C(O)N(R32)(R33), (CH2).alpha.
C(O)OR31, -(CH2).alpha. C(O)N(R32)(R33), -(CH2).alpha. N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl .alpha. is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
9. The method of claim 8, comprising administering a compound of the formula VIIa:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6; and R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6; and R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or a pharmaceutically acceptable salt or hydrate thereof.
10. The method of claim 9, comprising administering a compound of the formula VIIa wherein R2 is selected from the group consisting of aryl and heteroaryl.
11. The method of claim 10, comprising administering a compound of the formula VIIa wherein R2 is selected from the group consisting of aryl and heteroaryl, and R4 is H.
12. The method of claim 8, comprising administering a compound of the formula VIII:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl; aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl; aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
13. The method of claim 12, comprising administering a compound of the formula VIII wherein R7 is selected from the group consisting of aryl and heteroaryl groups.
14. The method of claim 8, comprising administering a compound of the formula IX:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2).alpha.C(O)R31, -(CH2).alpha.C(O)N(R32)(R33), (CH2).alpha.C(O)OR31, -(CH2).alpha.C(O)N(R32)(R33), -(CH2).alpha.N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl .alpha. is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2).alpha.C(O)R31, -(CH2).alpha.C(O)N(R32)(R33), (CH2).alpha.C(O)OR31, -(CH2).alpha.C(O)N(R32)(R33), -(CH2).alpha.N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl .alpha. is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
15. The method of claim 12, comprising administering a compound of the formula X:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2-)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82,)(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2-)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82,)(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
16. The method of claim 1, comprising administering a compound of the formula XI:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2).alpha.C(O)R31, -(CH2).alpha.C(O)N(R32)(R33), (CH2).alpha.C(O)OR31, -(CH2).alpha.C(O)N(R32)(R33), -(CH2).alpha.N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl .alpha. is 0 to 6;
X is selected from O and N-R4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R4)(R4), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R5), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2).alpha.C(O)R31, -(CH2).alpha.C(O)N(R32)(R33), (CH2).alpha.C(O)OR31, -(CH2).alpha.C(O)N(R32)(R33), -(CH2).alpha.N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl .alpha. is 0 to 6;
X is selected from O and N-R4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R4)(R4), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R5), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
17. The method of claim 16, comprising administering a compound of the formula XII:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13),-N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13),-N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
8. The method of claim 17, comprising administering a compound of the formula XIII:
therein:
ach R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, is 0 to 4;
is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
therein:
ach R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, is 0 to 4;
is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
19. The method of claim 18, comprising administering a compound of the formula XIII wherein R6 is selected from the group consisting of aryl and heteroaryl groups.
20. The method of claim 17, comprising administering a compound of the formula XIV:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2).alpha.C(O)R31, -(CH2).alpha.C(O)N(R32)(R33), (CH2).alpha.C(O)OR31, -(CH2).alpha.C(O)N(R32)(R33), -(CH2).alpha.N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 maybe taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2).alpha.C(O)R31, -(CH2).alpha.C(O)N(R32)(R33), (CH2).alpha.C(O)OR31, -(CH2).alpha.C(O)N(R32)(R33), -(CH2).alpha.N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 maybe taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
21. The method of claim 18, comprising administering a compound of the formula XV:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
22. The method of claim 16, comprising administering a compound of the formula XVI:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
23. The method of claim 22, comprising administering a compound of the formula XVII:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof:
24. The method of claim 23, comprising administering a compound of the formula XVII wherein R6 is selected from the group consisting of aryl or heteroaryl groups.
25. The method of claim 22, comprising administering a compound of the formula XVIII:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
26. The method of claim 17, comprising administering a compound of the formula XIX:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2,R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each W is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2,R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each W is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
27. The method of claim 7, comprising administering a compound of the formula
28. The method of claim 7, comprising administering a compound of the formula
29. The method of claim 7, comprising administering a compound of the formula
30. The method of claim7, comprising administering a compound of the formula
31. The method of claim 7, comprising administering a compound of the formula
32. The method of claim 7, comprising administering a compound of the formula
33. The method of claim 7, comprising administering a compound of the formula
34. The method of claim 7, comprising administering a compound of the formula
35. The method of claim 7, comprising administering a compound of the formula
36. The method of claim 7, comprising administering a compound of the formula
37. The method of claim 7, comprising administering a compound of the formula
38. The method of claim 7, comprising administering a compound of the formula
39. The method of claim 6, comprising administering a compound of the formula
40. The method of claim 8, comprising administering a compound of the formula
41. The method of claim 8, comprising administering a compound of the formula
42. The method of claim 9, comprising administering a compound of the formula
43. The method of claim 9, comprising administering a compound of the formula
44. The method of claim 9, comprising administering a compound of the formula
45. The method of claim 9, comprising administering a compound of the formula
46. The method of claim 9, comprising administering a compound of the formula
47. The method of claim 9, comprising administering a compound of the formula
48. The method of claim 9, comprising administering a compound of the formula
49. The method of claim 21, comprising administering a compound of the formula
50. The method of claim 21, comprising administering a compound of the formula
51. The method of claim 21, comprising administering a compound of the formula
52. The method of claim 21, comprising administering a compound of the formula
53. The method of claim 21, comprising administering a compound of the formula
54. The method of claim 21, comprising administering a compound of the formula
55. The method of claim 1, comprising administering a therapeutically effective amount of a combination of the compound having the formula I, or a therapeutically acceptable salt or hydrate thereof, and at least one additional agent selected from an interferon, ribavirin, an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV IRES inhibitor, an HCV
Helicase, an HCV ATPase inhibitor, an NS5A phosphorylation inhibitor, and an inhibitor.
Helicase, an HCV ATPase inhibitor, an NS5A phosphorylation inhibitor, and an inhibitor.
56. The method of claim 55, wherein the at least one additional agent is an interferon.
57. The method of claim 56, wherein the at least one additional agent is .alpha.-interferon.
58. The method of claim 55, wherein the at least one additional agent is an interferon and ribavirin.
59. A compound having the formula II:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO,R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, phosphate, phosphonate, halo, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
a is 0 to 6;
X is selected from 0 and N-R4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO,R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, phosphate, phosphonate, halo, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
a is 0 to 6;
X is selected from 0 and N-R4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
60. The compound of claim 59, having the formula III:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and a is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and a is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
61. The compound of claim 60, having the formula IV:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)S02R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -S03R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)S02R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -S03R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
62. The compound of claim 61, wherein R7 is selected to be an aryl or heteroaryl group.
63. The compound of claim 60, having the formula V:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13); CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82,)(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13); CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82,)(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
64. The compound of claim 61, having the formula VI:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82,)(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -S03R91, -SO2N(R92)(R43), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82,)(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -S03R91, -SO2N(R92)(R43), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
65. The compound of claim 59, having the formula VII:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
66. The compound of claim 65, having the formula VII a:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R", -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6; and R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R", -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6; and R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or a pharmaceutically acceptable salt or hydrate thereof.
67. The compound of claim 66, wherein R2 is selected from the group consisting of aryl and heteroaryl.
68. The compound of claim 67, wherein R4 is H.
69. The compound of claim 65, having the formula VIII:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
70. The compound of claim 69, wherein, R7 is selected from the group consisting of aryl and heteroaryl groups.
71. The compound of claim 65, having the formula IX:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R3), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH,)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R142)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82,)(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R3), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH,)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R142)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82,)(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
72. The compound of claim 69, having the formula X:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82,)(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82,)(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
73. A compound having the formula XIII:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R12)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R12)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
74. The compound of claim 73, wherein R6 is selected from the group consisting of aryl and heteroaryl groups.
75. The compound of claim 73, having the formula XV:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R9)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R9)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
76. A compound having the formula XIV:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
77. A compound having the formula XVI:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
and b is 0 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
78. The compound of claim 77, having the formula XVII:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R6 is selected from the group consisting of aryl and heteroaryl;
R7 is selected from the group consisting of aryl, heteroaryl, -C(O)R31, -C(O)N(R32)(R33), -C(O)OR31, -C(O)N(R32)(R33), and -N(R32)(R33), R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; and R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
or a pharmaceutically acceptable salt or hydrate thereof.
79. The compound of claim 78, wherein R6 is selected from the group consisting of aryl or heteroaryl groups.
80. The compound of claim 77, having the formula XVIII:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharinaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)a C(O)R31, -(CH2)a C(O)N(R32)(R33), (CH2)a C(O)OR31, -(CH2)a C(O)N(R32)(R33), -(CH2)a N(R32)(R33), -CH=N-R34, R31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl a is 0 to 6;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and m is 0 to 5;
or a pharinaceutically acceptable salt or hydrate thereof.
81. The compound of claim 78, having the formula XIX:
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R1, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken,together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
wherein:
each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11)C(O)R11, -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R1, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl;
additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1;
each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R41, -(CH2)b C(O)N(R42)(R43), -(CH2)b C(O)OR41, and -(CH2)b C(O)N(R42)(R43), each R41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R42 and R43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R42 and R43 may be taken,together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -(CH2)b C(O)R51, -(CH2)b C(O)N(R52)(R53), and -(CH2)b C(O)OR51;
each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R81, C(O)R81, -O-R81, -N(R82)(R83), -N(R81)C(O)R81, -N(R81)SO2R81, -SR81, -C(O)N(R82)(R83), -OC(O)R81, -OC(O)N(R82')(R83), SO2, -SOR81, -SO3R81, -SO2N(R82)(R83), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R82 and R83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R82 and R83 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
m is 0 to 5;
each R9 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R91, C(O)R91, -O-R91, -N(R92)(R93), -N(R91)C(O)R91, -N(R91)SO2R91, -SR91, -C(O)N(R92)(R93), -OC(O)R91, -OC(O)N(R92)(R93), SO2, -SOR91, -SO3R91, -SO2N(R92)(R93), cycloalkyl, cycloalkenyl, aryl and heteroaryl;
each R91 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
each R92 and R93 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R92 and R93 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and p is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
82. The compound of claim 64, having the formula
83. The compound of claim 64, having the formula
84. The compound of claim 64, having the formula
85. The compound of claim 64, having the formula
86. The compound of claim 64, having the formula
87. The compound of claim 64, having the formula
88. The compound of claim 64, having the formula
89. The compound of claim 64, having the formula
90. The compound of claim 64, having the formula
91. The compound of claim 64, having the formula
92. The compound of claim 64, having the formula
93. The compound of claim 64, having the formula
94. The compound of claim 63, having the formula
95. The compound of claim 65, having the formula
96. The compound of claim 65, having the formula
97. The compound of claim 66, having the formula
98. The compound of claim 66, having the formula
99. The compound of claim 66, having the formula
100. The compound of claim 66, having the formula
101. The compound of claim 66, having the formula
102. The compound of claim 66, having the formula
103. The compound of claim 66, having the formula
104. The compound of claim 75, having the formula
105. The compound of claim 75, having the formula
106. The compound of claim 75, having the formula
107. The compound of claim 75, having the formula
108. The compound of claim 75, having the formula
109. The compound of claim 75, having the formula
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PCT/US2006/018857 WO2007133211A1 (en) | 2006-05-15 | 2006-05-15 | 3,4-disubstituted coumarin and quinolone compounds |
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EP (1) | EP2028938A4 (en) |
JP (1) | JP2009537518A (en) |
AU (1) | AU2006343604A1 (en) |
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WO (1) | WO2007133211A1 (en) |
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US20090312406A1 (en) * | 2008-06-12 | 2009-12-17 | Hsing-Pang Hsieh | Coumarin compounds and their use for treating viral infection |
JP6669499B2 (en) | 2013-02-15 | 2020-03-18 | カラ ファーマシューティカルズ インコーポレイテッド | Therapeutic compounds |
US9688688B2 (en) | 2013-02-20 | 2017-06-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof |
US9353123B2 (en) | 2013-02-20 | 2016-05-31 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
CN106061261B (en) | 2013-11-01 | 2018-04-24 | 卡拉制药公司 | Crystal form of therapeutic compounds and application thereof |
US9890173B2 (en) | 2013-11-01 | 2018-02-13 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
AU2017324716B2 (en) | 2016-09-08 | 2020-08-13 | KALA BIO, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
US10253036B2 (en) | 2016-09-08 | 2019-04-09 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
EP3509421A4 (en) | 2016-09-08 | 2020-05-20 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
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US5430153A (en) * | 1991-04-03 | 1995-07-04 | Korea Research Institute Of Chemical Technology | 2-quinolinone derivatives |
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FR2749585B1 (en) * | 1996-06-11 | 1998-08-14 | Hoechst Marion Roussel Inc | NOVEL AROMATIC DERIVATIVES SUBSTITUTED BY RIBOSIS, PROCESS FOR THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS |
US7148253B2 (en) * | 2002-05-14 | 2006-12-12 | Xtl Biopharmaceuticals Ltd. | 4-thio coumarins |
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JP2009537518A (en) | 2009-10-29 |
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