ZA200507751B - Novel hydroxamates as therapeutic agents - Google Patents
Novel hydroxamates as therapeutic agents Download PDFInfo
- Publication number
- ZA200507751B ZA200507751B ZA200507751A ZA200507751A ZA200507751B ZA 200507751 B ZA200507751 B ZA 200507751B ZA 200507751 A ZA200507751 A ZA 200507751A ZA 200507751 A ZA200507751 A ZA 200507751A ZA 200507751 B ZA200507751 B ZA 200507751B
- Authority
- ZA
- South Africa
- Prior art keywords
- hydroxy
- benzamide
- ylcarbonylamino
- ethoxy
- benzofuran
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims description 10
- 229940124597 therapeutic agent Drugs 0.000 title description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 222
- -1 aralkenyl Chemical group 0.000 claims description 186
- 150000001875 compounds Chemical class 0.000 claims description 84
- 125000000217 alkyl group Chemical group 0.000 claims description 74
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 58
- 125000001072 heteroaryl group Chemical group 0.000 claims description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
- 239000001257 hydrogen Substances 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 29
- 125000001188 haloalkyl group Chemical group 0.000 claims description 27
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 23
- 201000010099 disease Diseases 0.000 claims description 22
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 22
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 21
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 15
- 201000011510 cancer Diseases 0.000 claims description 14
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 14
- 241001465754 Metazoa Species 0.000 claims description 13
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 13
- 125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 13
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 208000005176 Hepatitis C Diseases 0.000 claims description 12
- 102000003964 Histone deacetylase Human genes 0.000 claims description 12
- 108090000353 Histone deacetylase Proteins 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000002947 alkylene group Chemical group 0.000 claims description 11
- 125000005326 heteroaryloxy alkyl group Chemical group 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 claims description 9
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 9
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 8
- 125000002431 aminoalkoxy group Chemical group 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000005549 heteroarylene group Chemical group 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- 125000004660 phenylalkylthio group Chemical group 0.000 claims description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 4
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 claims description 3
- 229940126190 DNA methyltransferase inhibitor Drugs 0.000 claims description 3
- 229940122440 HIV protease inhibitor Drugs 0.000 claims description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 3
- 229940123468 Transferase inhibitor Drugs 0.000 claims description 3
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 3
- 229940121369 angiogenesis inhibitor Drugs 0.000 claims description 3
- 230000001028 anti-proliverative effect Effects 0.000 claims description 3
- 239000002254 cytotoxic agent Substances 0.000 claims description 3
- 229940127089 cytotoxic agent Drugs 0.000 claims description 3
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 3
- 239000003968 dna methyltransferase inhibitor Substances 0.000 claims description 3
- 239000002834 estrogen receptor modulator Substances 0.000 claims description 3
- 239000004030 hiv protease inhibitor Substances 0.000 claims description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 229940075993 receptor modulator Drugs 0.000 claims description 3
- 102000027483 retinoid hormone receptors Human genes 0.000 claims description 3
- 108091008679 retinoid hormone receptors Proteins 0.000 claims description 3
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 3
- 239000000849 selective androgen receptor modulator Substances 0.000 claims description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 3
- 239000003558 transferase inhibitor Substances 0.000 claims description 3
- CVYSHGQXOVPJDD-LLVKDONJSA-N (3r)-3-hydroxy-n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]pyrrolidine-1-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)N1C[C@H](O)CC1 CVYSHGQXOVPJDD-LLVKDONJSA-N 0.000 claims description 2
- LWCYLAVASFVIEH-UHFFFAOYSA-N 2,3-dichloro-n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=CC(Cl)=C1Cl LWCYLAVASFVIEH-UHFFFAOYSA-N 0.000 claims description 2
- QDJHIPZZZHXEJS-UHFFFAOYSA-N 3,4-difluoro-n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=C(F)C(F)=C1 QDJHIPZZZHXEJS-UHFFFAOYSA-N 0.000 claims description 2
- GXOFMHYSDHBUFQ-UHFFFAOYSA-N 4-(2-benzamidoethoxy)-n-hydroxybenzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=CC=C1 GXOFMHYSDHBUFQ-UHFFFAOYSA-N 0.000 claims description 2
- XJFDTZOBHUGCRD-UHFFFAOYSA-N 4-[2-[(4-cyclohex-2-en-1-yloxybenzoyl)amino]ethoxy]-n-hydroxybenzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C(C=C1)=CC=C1OC1C=CCCC1 XJFDTZOBHUGCRD-UHFFFAOYSA-N 0.000 claims description 2
- RHAAIIJTUNUHCW-UHFFFAOYSA-N 4-[2-[[2-(3,4,4a,5,6,7,8,8a-octahydro-1h-isoquinolin-2-yl)acetyl]amino]ethoxy]-n-hydroxybenzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)CN1CC2CCCCC2CC1 RHAAIIJTUNUHCW-UHFFFAOYSA-N 0.000 claims description 2
- MKAZJOLBHCXTKM-UHFFFAOYSA-N 4-benzamido-n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C(C=C1)=CC=C1NC(=O)C1=CC=CC=C1 MKAZJOLBHCXTKM-UHFFFAOYSA-N 0.000 claims description 2
- DPFJBMIUUVCKRD-UHFFFAOYSA-N 4-benzyl-n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]piperazine-1-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)N1CCN(CC=2C=CC=CC=2)CC1 DPFJBMIUUVCKRD-UHFFFAOYSA-N 0.000 claims description 2
- KEPFALMJXBYEOQ-UHFFFAOYSA-N 4-tert-butyl-n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]benzamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)NCCOC1=CC=C(C(=O)NO)C=C1 KEPFALMJXBYEOQ-UHFFFAOYSA-N 0.000 claims description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims description 2
- CZHFXUWPKPWKMF-OAQYLSRUSA-N n-[(2r)-1-benzylsulfanyl-3-[4-(hydroxycarbamoyl)phenoxy]propan-2-yl]-1-benzofuran-2-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OC[C@@H](NC(=O)C=1OC2=CC=CC=C2C=1)CSCC1=CC=CC=C1 CZHFXUWPKPWKMF-OAQYLSRUSA-N 0.000 claims description 2
- SZLWUGAPGROVDF-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-1,3-benzodioxole-5-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=C(OCO2)C2=C1 SZLWUGAPGROVDF-UHFFFAOYSA-N 0.000 claims description 2
- RYCCCUXRKBPVMY-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-1,3-benzoxazole-2-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=NC2=CC=CC=C2O1 RYCCCUXRKBPVMY-UHFFFAOYSA-N 0.000 claims description 2
- WTFJXXHTKKNDNE-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-1,3-dihydroisoindole-2-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)N1CC2=CC=CC=C2C1 WTFJXXHTKKNDNE-UHFFFAOYSA-N 0.000 claims description 2
- OYFXBHSLUKBJDP-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-1-methylindole-3-carboxamide Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)NCCOC1=CC=C(C(=O)NO)C=C1 OYFXBHSLUKBJDP-UHFFFAOYSA-N 0.000 claims description 2
- FLCACKUGYDIHGZ-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-1h-benzimidazole-2-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=NC2=CC=CC=C2N1 FLCACKUGYDIHGZ-UHFFFAOYSA-N 0.000 claims description 2
- LBQAEFSQFVTLPT-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-1h-indazole-3-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=NNC2=CC=CC=C12 LBQAEFSQFVTLPT-UHFFFAOYSA-N 0.000 claims description 2
- NJRCBPSTFLVXJQ-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-1h-indole-3-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CNC2=CC=CC=C12 NJRCBPSTFLVXJQ-UHFFFAOYSA-N 0.000 claims description 2
- SJMHHASHIQBWSW-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-1h-pyrrole-2-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=CN1 SJMHHASHIQBWSW-UHFFFAOYSA-N 0.000 claims description 2
- FOKHWUFEZFERTF-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-2,3-dimethylbenzamide Chemical compound CC1=CC=CC(C(=O)NCCOC=2C=CC(=CC=2)C(=O)NO)=C1C FOKHWUFEZFERTF-UHFFFAOYSA-N 0.000 claims description 2
- IRGKHARWUYPFTC-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-2,5-dimethylbenzamide Chemical compound CC1=CC=C(C)C(C(=O)NCCOC=2C=CC(=CC=2)C(=O)NO)=C1 IRGKHARWUYPFTC-UHFFFAOYSA-N 0.000 claims description 2
- DWIUFGMXFGSEKO-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-2-(thiophen-2-ylmethoxy)benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=CC=C1OCC1=CC=CS1 DWIUFGMXFGSEKO-UHFFFAOYSA-N 0.000 claims description 2
- VSXTVMCRTOHQPR-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-2-methyl-2,3-dihydroindole-1-carboxamide Chemical compound CC1CC2=CC=CC=C2N1C(=O)NCCOC1=CC=C(C(=O)NO)C=C1 VSXTVMCRTOHQPR-UHFFFAOYSA-N 0.000 claims description 2
- OKAUZDBFVMIEGD-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-2-phenylbenzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=CC=C1C1=CC=CC=C1 OKAUZDBFVMIEGD-UHFFFAOYSA-N 0.000 claims description 2
- GGLGTBFCFOSCOF-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-2-pyrrol-1-ylbenzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=CC=C1N1C=CC=C1 GGLGTBFCFOSCOF-UHFFFAOYSA-N 0.000 claims description 2
- JNZGWESHFUEKRN-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-2h-benzotriazole-5-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=C(NN=N2)C2=C1 JNZGWESHFUEKRN-UHFFFAOYSA-N 0.000 claims description 2
- CEBMMBJXVCHPHI-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-3,4-dihydro-2h-quinoline-1-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)N1C2=CC=CC=C2CCC1 CEBMMBJXVCHPHI-UHFFFAOYSA-N 0.000 claims description 2
- ZUJZBFQMWRBOSJ-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-3-(thiophen-2-ylmethoxy)benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=CC(OCC=2SC=CC=2)=C1 ZUJZBFQMWRBOSJ-UHFFFAOYSA-N 0.000 claims description 2
- VVDGDUPVQQRPFK-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-3-phenylbenzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=CC(C=2C=CC=CC=2)=C1 VVDGDUPVQQRPFK-UHFFFAOYSA-N 0.000 claims description 2
- JQVVQGXZQRHVFA-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-3h-benzimidazole-5-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=C(NC=N2)C2=C1 JQVVQGXZQRHVFA-UHFFFAOYSA-N 0.000 claims description 2
- ONVRDFZZIJYYPT-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-4-methoxyquinoline-2-carboxamide Chemical compound N=1C2=CC=CC=C2C(OC)=CC=1C(=O)NCCOC1=CC=C(C(=O)NO)C=C1 ONVRDFZZIJYYPT-UHFFFAOYSA-N 0.000 claims description 2
- BXYTWTPTPNNCHZ-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-4-phenyl-1,3-thiazole-2-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=NC(C=2C=CC=CC=2)=CS1 BXYTWTPTPNNCHZ-UHFFFAOYSA-N 0.000 claims description 2
- XPUOZJHAXLVRBN-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-4-phenylbenzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=C(C=2C=CC=CC=2)C=C1 XPUOZJHAXLVRBN-UHFFFAOYSA-N 0.000 claims description 2
- GSJZYVYQKLVZSG-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-4-pyridin-2-ylbenzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=C(C=2N=CC=CC=2)C=C1 GSJZYVYQKLVZSG-UHFFFAOYSA-N 0.000 claims description 2
- CTLBQMCTYDGDKX-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-4-pyridin-3-ylbenzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=C(C=2C=NC=CC=2)C=C1 CTLBQMCTYDGDKX-UHFFFAOYSA-N 0.000 claims description 2
- RQWFHIJXRPVVIP-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-4-pyridin-4-yl-1,3-thiazole-2-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=NC(C=2C=CN=CC=2)=CS1 RQWFHIJXRPVVIP-UHFFFAOYSA-N 0.000 claims description 2
- JRIGNSIQQKUANG-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-5-phenylthiophene-2-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=C(C=2C=CC=CC=2)S1 JRIGNSIQQKUANG-UHFFFAOYSA-N 0.000 claims description 2
- JGLLBLHNIPYTET-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-6-methyl-3,4-dihydro-2h-quinoline-1-carboxamide Chemical compound C1CCC2=CC(C)=CC=C2N1C(=O)NCCOC1=CC=C(C(=O)NO)C=C1 JGLLBLHNIPYTET-UHFFFAOYSA-N 0.000 claims description 2
- TZCIECHOOVXVLZ-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]furan-2-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=CO1 TZCIECHOOVXVLZ-UHFFFAOYSA-N 0.000 claims description 2
- JEHPPLVLBSCHEQ-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]isoquinoline-1-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=NC=CC2=CC=CC=C12 JEHPPLVLBSCHEQ-UHFFFAOYSA-N 0.000 claims description 2
- BUKBTSZBDXYUTQ-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]isoquinoline-3-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC2=CC=CC=C2C=N1 BUKBTSZBDXYUTQ-UHFFFAOYSA-N 0.000 claims description 2
- OPLVVRWFUQXEMS-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]morpholine-4-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)N1CCOCC1 OPLVVRWFUQXEMS-UHFFFAOYSA-N 0.000 claims description 2
- MDSIGQCXHPZMQO-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]naphthalene-1-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=CC2=CC=CC=C12 MDSIGQCXHPZMQO-UHFFFAOYSA-N 0.000 claims description 2
- ZYVUYRKCHDGTET-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]piperidine-1-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)N1CCCCC1 ZYVUYRKCHDGTET-UHFFFAOYSA-N 0.000 claims description 2
- IHZFYYFEOHRXEK-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]quinoline-2-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=C(C=CC=C2)C2=N1 IHZFYYFEOHRXEK-UHFFFAOYSA-N 0.000 claims description 2
- VLYYCJJGRXTMHP-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]quinoline-3-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CN=C(C=CC=C2)C2=C1 VLYYCJJGRXTMHP-UHFFFAOYSA-N 0.000 claims description 2
- SQLBPLFPJINSAH-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]quinoline-8-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=CC2=CC=CN=C12 SQLBPLFPJINSAH-UHFFFAOYSA-N 0.000 claims description 2
- LLDZTGJWTSXAIA-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]thiophene-2-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=CS1 LLDZTGJWTSXAIA-UHFFFAOYSA-N 0.000 claims description 2
- BLQBYQHRXFQFHZ-UHFFFAOYSA-N n-hydroxy-4-[2-[(2-thiophen-2-ylacetyl)amino]ethoxy]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)CC1=CC=CS1 BLQBYQHRXFQFHZ-UHFFFAOYSA-N 0.000 claims description 2
- RPZXKDRIDTWUKH-DHZHZOJOSA-N n-hydroxy-4-[2-[[(e)-3-(2-methylphenyl)prop-2-enoyl]amino]ethoxy]benzamide Chemical compound CC1=CC=CC=C1\C=C\C(=O)NCCOC1=CC=C(C(=O)NO)C=C1 RPZXKDRIDTWUKH-DHZHZOJOSA-N 0.000 claims description 2
- JQWQQGMAQSTBFZ-FPYGCLRLSA-N n-hydroxy-4-[2-[[(e)-3-pyridin-3-ylprop-2-enoyl]amino]ethoxy]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)\C=C\C1=CC=CN=C1 JQWQQGMAQSTBFZ-FPYGCLRLSA-N 0.000 claims description 2
- 238000001959 radiotherapy Methods 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 6
- 150000002431 hydrogen Chemical class 0.000 claims 6
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 5
- AZEIRPAUJXANCS-UHFFFAOYSA-N 4-ethoxybenzamide Chemical compound CCOC1=CC=C(C(N)=O)C=C1 AZEIRPAUJXANCS-UHFFFAOYSA-N 0.000 claims 3
- 125000006345 2,2,2-trifluoroethoxymethyl group Chemical group [H]C([H])(*)OC([H])([H])C(F)(F)F 0.000 claims 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 2
- DSIBSRXKQRYPJP-UHFFFAOYSA-N 1,2-oxazole-5-carboxamide Chemical compound NC(=O)C1=CC=NO1 DSIBSRXKQRYPJP-UHFFFAOYSA-N 0.000 claims 1
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- SPCMUBFTADOPCN-UHFFFAOYSA-N 3-[(2-fluorophenoxy)methyl]-n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-1-benzofuran-2-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=C(COC=2C(=CC=CC=2)F)C2=CC=CC=C2O1 SPCMUBFTADOPCN-UHFFFAOYSA-N 0.000 claims 1
- CBBDSQMDJTUDIZ-UHFFFAOYSA-N 3-[(4-fluorophenoxy)methyl]-n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-1-benzofuran-2-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=C(COC=2C=CC(F)=CC=2)C2=CC=CC=C2O1 CBBDSQMDJTUDIZ-UHFFFAOYSA-N 0.000 claims 1
- CPSKDJNEHCHIIK-UHFFFAOYSA-N 3-[(4-fluorophenyl)sulfinylmethyl]-n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-1-benzofuran-2-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=C(CS(=O)C=2C=CC(F)=CC=2)C2=CC=CC=C2O1 CPSKDJNEHCHIIK-UHFFFAOYSA-N 0.000 claims 1
- MAUCONCHVWBMHK-UHFFFAOYSA-N 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide Chemical compound O1C2=CC=CC=C2C(CN(C)C)=C1C(=O)NCCOC1=CC=C(C(=O)NO)C=C1 MAUCONCHVWBMHK-UHFFFAOYSA-N 0.000 claims 1
- OXUCVIDCYXRHQF-UHFFFAOYSA-N 3-[3-[[4-(2-ethoxyphenyl)benzoyl]amino]propoxy]-n-hydroxy-1,2-oxazole-5-carboxamide Chemical compound CCOC1=CC=CC=C1C1=CC=C(C(=O)NCCCOC2=NOC(=C2)C(=O)NO)C=C1 OXUCVIDCYXRHQF-UHFFFAOYSA-N 0.000 claims 1
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- CTEKFMDNNUZLAZ-UHFFFAOYSA-N 3-ethoxy-n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]benzamide Chemical compound CCOC1=CC=CC(C(=O)NCCOC=2C=CC(=CC=2)C(=O)NO)=C1 CTEKFMDNNUZLAZ-UHFFFAOYSA-N 0.000 claims 1
- QKJUPULAJQGBPV-UHFFFAOYSA-N 3-ethyl-n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-1-benzofuran-2-carboxamide Chemical compound O1C2=CC=CC=C2C(CC)=C1C(=O)NCCOC1=CC=C(C(=O)NO)C=C1 QKJUPULAJQGBPV-UHFFFAOYSA-N 0.000 claims 1
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- DUFWHDWPJFQMTA-UUFSLDAJSA-N 4-[(2r)-3-benzylsulfonyl-2-[[(e)-3-phenylprop-2-enoyl]amino]propoxy]-n-hydroxybenzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OC[C@@H](NC(=O)\C=C\C=1C=CC=CC=1)CS(=O)(=O)CC1=CC=CC=C1 DUFWHDWPJFQMTA-UUFSLDAJSA-N 0.000 claims 1
- BBCNMILSPLMUGY-KRXBUXKQSA-N 4-[2-[[(E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]amino]ethoxy]-N-hydroxybenzamide Chemical compound ONC(C1=CC=C(C=C1)OCCNC(\C=C\C1=CC2=C(C=C1)OCO2)=O)=O BBCNMILSPLMUGY-KRXBUXKQSA-N 0.000 claims 1
- JEILZXMBYAPZON-BQYQJAHWSA-N 4-[2-[[(e)-3-(furan-2-yl)prop-2-enoyl]amino]ethoxy]-n-hydroxybenzamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)\C=C\C1=CC=CO1 JEILZXMBYAPZON-BQYQJAHWSA-N 0.000 claims 1
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- 125000005605 benzo group Chemical group 0.000 claims 1
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- ROULYISZYUUDRL-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-7-methoxy-1-benzofuran-2-carboxamide Chemical compound O1C=2C(OC)=CC=CC=2C=C1C(=O)NCCOC1=CC=C(C(=O)NO)C=C1 ROULYISZYUUDRL-UHFFFAOYSA-N 0.000 claims 1
- SJAGABCRANFIEJ-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]pyridine-2-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=CC=N1 SJAGABCRANFIEJ-UHFFFAOYSA-N 0.000 claims 1
- RBSWWUDUXPAICR-UHFFFAOYSA-N n-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]pyridine-3-carboxamide Chemical compound C1=CC(C(=O)NO)=CC=C1OCCNC(=O)C1=CC=CN=C1 RBSWWUDUXPAICR-UHFFFAOYSA-N 0.000 claims 1
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Description
NOVEL HYDROXAMATES AS THERAPEUTIC AGENTS
The present invention is directed to certain hydroxamate derivatives that are useful in the treatment of hepatitis C. These compounds are also inhibitors of histone deacetylase and are therefore useful in the treatment of diseases associated with histone deacetylase activity.
Pharmaceutical compositions and processes for preparing these compounds are also disclosed.
State of the Art
Hepatitis C:
Chronic hepatitis C is a slowly progressive disease having a significant impact on morbidity and mortality. While many patients who contract hepatitis C will have sub clinical or mild disease, at least 80% of the individuals who contract HCV develop chronic infection and hepatitis. Twenty to fifty percent of these eventually progress to cirrhosis and 1-2% develop liver cancer (Hoofnagle, J. H.; 1997; Hepatology 26: 155-208). There are an estimated 170 million HCV carriers world-wide, and HCV-associated end-stage liver disease is now one of the leading cause of liver transplantation. In the United States alone, hepatitis C is responsible for 8,000 to 10,000 deaths annually.
At the present time, interferon-o2b/ribavirin combination therapy is the only available treatment. Sustained virologic response to IFN -a2b -ribavirin combination therapy occurs in about 40-45% of those treated. For those patients who fail interferon- a2b/ribavirin combination therapy, there is currently no alternative to prevent the progression of liver disease. Thus, a need exists for alternative therapies for the treatment of chronic HCV infection. The present invention fulfills this need.
Histone Deacetylases:
Interest in histone deacetylase enzymes (HDAC:) as targets for pharmaceutical development has centered on the role of HDAC: in regulating genes associated with cell-cycle progression and the development and progression of cancer (reviewed in Kramer et. al. 2001,
Trends Endocrinol. Metab. 12:294-300). Several studies have shown that treatment of various cell lines with HDAC inhibitors leads to hyper acetylation of histone proteins and cell-cycle arrest in late G, phase or at the Go/M transition. Genes involved in the cell cycle that have been shown to be up regulated by HDAC inhibitors include p21, p27, p53 and cyclin E. Cyclin
A and cyclin D have been reported to be down regulated by HDAC inhibitors. In tumor cell lines, several studies have shown that treatment with HDAC inhibitors can lead to growth inhibition, growth arrest, terminal differentiation and/or apoptosis. In vivo studies have . demonstrated growth inhibition of tumors and a reduction in tumor metastasis as a result of treatment with HDAC inhibitors.
The clearest link between abnormal HDAC activity and cancer occurs in acute promyelocytic leukemia. In this condition, a chromosomal translocation leads to the fusion of the retinoic acid receptor RARa with the promyelocytic leukemia (PML) or promyelocytic leukemia zinc-finger (PLZF) proteins. Both PML-RARa and PLZF-RARa promote the progression of leukemia by repressing retinoic acid-regulated genes through the abnormal recruitment of SMRT-mSin3-HDAC complex (Lin et. al., 1998, Nature 391:811-814; Grignani et al., 1998, Nature 391:815-818). Whereas the PML-RARa form of the disease is treatable with retinoic acid, the PLZF-RARa form is resistant to this treatment. For a patient with the retinoic acid-resistant form of the disease, the addition of the HDAC inhibitor sodium butyrate to the dosing regimen led to complete clinical and cytogenic remission (Warrell et al., 1998,
J Natl.Cancer.Inst. 90:1621-1625). HDACs have also been associated with Huntington’s disease (Steffan, et al., Nature 413:739-744, “Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila”).
In summary, an increase in HDAC activity contributes to the pathology and/or symptomatology of a number of diseases. Accordingly, molecules that inhibit the activity of
HDAC are useful as therapeutic agents in the treatment of such diseases.
3 In a first aspect, this invention provides a compound of Formula (I):
T 1 wi—conm ~~) "
I wherein:
R' is hydrogen or alkyl;
X is =O-, -NR2, or -S(O)swhere n is 0-2 and R? is hydrogen or alky!;
Y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy;
Ar' is phenylene or heteroarylene wherein said Ar' is optionally substituted with one or two groups independently selected from alkyl, halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl;
R? is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl; and
Ar is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; or a pharmaceutically acceptable salt thereof.
In a sccond aspect, this invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
In a third aspect, this invention is directed to a method for treating a disease in an animal mediated by HDAC which method comprises administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of
Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Preferably, the disease is a proliferative disorder such as cancer and bipolar disorders and the animal is a human. Preferably, the cancer is prostate cancer, breast cancer, lung melanoma, stomach cancer, neuroblastoma, colon cancer, pancreatic cancer, ovarian cancer, T-cell lymphoma, or leukemia such as myelogenous leukemia (MM) and acute myelogenous leukemia (AML).
In a fourth aspect, this invention is directed to a method for treating cancer in an animal which method comprises administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in combination with radiation therapy and optionally in combination with one or more compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, or a DNA methyl transferase inhibitor.
Applicants have also discovered that the compounds of the present invention are useful in the treatment of hepatitis C. Accordingly, in a fifth aspect, this invention is directed to a method of treating hepatitis C in an animal comprising administering the animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of
Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient optionally in combination with one or more other hepatitis C agent. Preferably, the hepatitis C agents are interferon-a2b, ribavirin, and hcv polymerase inhibitors.
In a sixth aspect, this invention is direct to an intermediate of Formula (II): 0]
Ar? — CONRI—y—x {ay “ors (1 where R¥ is hydrogen or alkyl and Ar', Ar, R®, X and Y are as defined for compounds of
Formula (1) above; or a salt thereof. Preferably, Ar', AP, R®, X and Y are as defined in
Preferred embodiments below.
In a seventh aspect, this invention is directed to a process of preparing a compound of
Formula (I) comprising: (4) reacting a compound of Formula (III): 0)
A= CONRS—Y XA R31 (In where R®' is hydroxy, alkoxy, halo, or succinimido ester with a hydroxylamine of formula
NH,0R” where R” is hydrogen, alkyl, or an oxygen protecting group; or (ii) treating a compound of Formula (IV): oO
A? — CONRS-Y—x—(ay “om av) where M" is an alkali metal with an acid; followed by treatment with NH,OR” where R” is hydrogen, alkyl, or an oxygen protecting group; to give a compound of Formula (V): 0) 2 CONRS—Y x(a NHOR"
Vv) (iii) optionally removing R” group in compound (V) to give a compound of Formula (I) where R' is hydrogen; (iv) optionally forming an acid addition salt of the product formed in Step (i), (ii), or (iii) above; v) optionally forming free base of the product formed in Step (i), (ii), (iii), or (iv) above; or i 5 (vi) optionally modifying any of the X, Y, R',R% R? Ar' and AP groups in the product formed in Step (i), (ii), (iii), (iv), or (v) above.
In a eighth aspect, this invention is directed to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer. 10 In a ninth aspect, this invention is directed to the use of a compound of Formula (I) or (11) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of hepatitis C.
Detailed Description of the Invention : 15 Definitions:
Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning: "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, 20 e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like. "Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, 25 butylene, pentylene, and the like. "Alkenylene" means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing one or two double bonds, e.g., ethenylene, propenylene, 2-propenylene, butenylene (including all isomeric forms), and the like. 30 "Alkylthio" means a -SR radical where R is alkyl as defined above, e.g., methylthio, ethylthio, propylthio (including all isomeric forms), butylthio (including all isomeric forms), and the like. "Alkylsulfiny!" means a —S(O)R radical where R is alkyl as defined above, e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl (including all isomeric forms), and the like. 35 "Alkylsulfonyl" means a —-SO,R radical where R is alkyl as defined above, ¢.g., methylsulfonyl, ethylsulfonyl, and the like. "Amino" means a -NH,; or an N-oxide derivative or a protected derivative thereof e.g, -NH—O, -NHBoc, -NHCbz, and the like. Preferably, -NHa od "Alkylamino" means a ~NHR radical where R is alkyl as defined above; or an N-oxide derivative, or a protected derivative thereof, e.g., methylamino, ethylamino, n-, iso- propylamino, n-, iso-, tert-butylamino, methylamino-N-oxide, -N(Boc)CH;, and the like. "Alkoxy"” means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or fert-butoxy, and the like. "Alkoxycarbonyl" means a -C(O)OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like. "Alkoxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, preferably one or two alkoxy groups, as defined above, e.g., 2- methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like. "Alkoxyalkyloxy" means a -OR radical where R is alkoxyalkyl as defined above, e.g., methoxyethoxy, 2-ethoxyethoxy, and the like. "Alkoxyalkyloxyalkyl" means a —(alkylene)-R radical where R is alkoxyalkyloxy as defined above, e.g., methoxyethoxymethyl, 2-ethoxyethoxymethyl, and the like. "Aminoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, -NRR' where R is hydrogen, alkyl, or -COR* where R* is alkyl, and R' is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or haloalkyl; or an N-oxide derivative or a protected derivative thereof. Preferably, R and R' are independently selected from hydrogen, alkyl, or -
COR? where R? is alkyl, or an N-oxide derivative, or a protected derivative e.g., aminomethyl, methylaminoethyl, 2-ethylamino-2-methylethyl, 1,3-diaminopropyl, dimethylaminomethyl, diethylaminoethyl, acetylaminopropyl, aminomethyl-N-oxide, and the like. "Aminoalkoxy" means a -OR radical where R is aminoalkyl as defined above, e.g., 2- aminoethoxy, 2-dimethylaminopropoxy, and the like. "Aminocarbonyl" means a -CONRR radical where each R is independently hydrogen or alkyl as defined above, e.g., -CONH;, methylaminocarbonyl, 2-dimethylaminocarbonyl, and the like. "Acylamino" means a -NHCOR radical where R is alkyl as defined above, e.g., acetylamino, propionylamino, and the like. "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms e.g., phenyl, naphthyl or anthracenyl. Unless stated otherwise, the ary! ring is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, alkoxyalkyloxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, cycloalkyloxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryloxy, optionally substituted heteroaralkyloxy, aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, haloalkoxyalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyloxyalkyl, optionally substituted ‘ heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkyloxy, -alkylene-S(O),-R* (where n is 0 to 2 and R* is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, optionaily substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl), -alkylene-NHSO»-
R® (where R® is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -alkylene-NHCO-R® (where R° is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), or —(alkylene)n1-CONRUR® (where nl is 0 or 1, R? and R® are independently, hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkylalkyl; or R? and R° together with the nitrogen atom to which they are attached form optionally substituted heterocycloalkyl) wherein the alkyl chain in haloalkoxyalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, or aminoalky! is optionally substituted with one or two fluoro. Preferably, the substituents are independently methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2-(morpholin-4-yl)ethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-(N,N-dimethylamino)-ethoxy, methoxymethyl, phenoxymethyi, 2- morpholino-4-ylethyl, morpholino-4-ylmethyl, N,N-dimethylaminomethyl, i-propoxymethyl, or phenoxymethyl. "Aralkyl" means a —(alkylene)-R radical where R is aryl as defined above. "Aralkenyl" means a —(alkenylene)-R radical where R is ary! as defined above.
"Cycloalkyl" means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl.
The cycloalkyl is optionally substituted with optionally substituted phenyl.
"Cycloalkenyl” means a cyclic unsaturated monovalent hydrocarbon radical of three to six carbon atoms, €.g., cyclopropenyl, cyclobutenyl, cyclohexenyl, and the like.
"Cycloalkylalkyl" means a —(alkylene)-R radical where R is cycloalkyl as defined above; e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl, and the like.
"Cycloalkyloxy" means a -OR radical where R is cycloalkyl as defined above, e.g., cyclopropyloxy, cyclohexyloxy, and the like.
"Cycloalkenyloxy" means a -OR radical where R is cycloalkenyl as defined above, €.g., cyclopropenyloxy, cyclohexenyloxy, and the like.
"Dialkylamino” means a -NRR’ radical where R and R’ are independently alkyl as defined above, e.g., dimethylamino, diethylamino, methylpropylamino, methylethylamino, n-, iso-, or tert-butylamino, and the like.
"Halo" means fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.
"Haloalkyl" means alkyl substituted with one or more halogen atoms, preferably one to five halogen atoms, preferably fluorine or chlorine, including those substituted with different halogens, e.g., -CH,Cl, -CF;, -CHF,, -CF,CF3, -CF(CHs)s, and the like.
"Haloalkoxy" means a -OR radical where R is haloalkyl as defined above e.g., -OCF;,
-OCHF,, and the like.
"Haloalkoxyalkyl” means a —(alkylene)-OR radical where R is haloalkyl as defined above e.g., trifluoromethyloxymethyl, 2,2,2-trifluoroethyloxymethyl, 2-trifluoromethoxyethyl, and the like.
"Hydroxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom.
Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, |-(hydroxymethyl)-2- methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-
(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl)-3-hydroxypropy!, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1- (hydroxymethyl)-2-hydroxyethyl.
oS "Hydroxyalkoxy” or “hydroxyalkyloxy” means a —OR radical where R is hydroxyalkyl as defined above. "Hydroxyalkoxyalkyl" or "hydroxyalkyloxyalkyl"means a —(alkylene)-OR radical where R is hydroxyalkyl as defined above e.g., hydroxymethyloxymethyl, hydroxyethyloxymethyl, and the like. "Heterocycloalkyl" means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C. One or two ring carbon atoms can optionally be replaced by a —CO- group. More specifically the term heterocycloalkyl includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, tetrahydroquinolinyl and thiomorpholino, and the derivatives thereof (formed when the heterocyloalkyl ring is substituted with a substituent listed below); and an N-oxide or a protected derivative thereof. The heterocycloalky! is optionally fused to aryl. Unless stated otherwise, the heterocyloalkyl ring is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, alkoxyalkyloxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, cycloalkyloxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaralkyloxy, aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, haloalkoxyalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkyloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkyloxy, -alkylene-S(O),-R* (where n is 0 to 2 and R* is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl), -alkylene-NHSO,-
R® (where R® is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl), - alkylene-NHCO-R® (where R°® is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl), or —(alkylene)n1-CONR'R® (where nl is 0 or 1, R? and R® are independently, hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally - substituted heteroaralkyl, or optionally substituted heterocycloalkylalkyl, or Rand R® together with the nitrogen atom to which they are attached form optionally substituted heterocycloalkyl) wherein the alkyl chain in haloatkoxyalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, or aminoalkyl is optionally substituted with one or two fluoro. Preferably, the substituents are independently methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2-(morpholin-4-yl)ethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-(N,N-dimethylamino)ethoxy, methoxymethyl, phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-ylmethyl, N,N-dimethylamino- methyl, i-propoxymethyl, or phenoxymethyl. "Heterocycloalkylalkyl” means a —{alkylene)-R radical where R is heterocycloalky! ring as defined above e.g., furanylmethyl, pipcrazinylmethyl, morpholinylethyl, and the like. "Heteroary!" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms where one or more, preferably one, two, or three, ring atoms are heteroatom selected from N, O, or §, the remaining ring atoms being carbon. More specifically the term heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, benzothiophenyl, benzthiazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzopyranyl, and thiazolyl, and the derivatives thereof (formed when the heterocyloalkyl ring is substituted with a substituent listed below); or an N-oxide or a protected derivative thereof. Unless stated otherwise, the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, alkoxyalkyloxyalkyl, optionally substituted phenyl, cycloalkyloxy, cycloaikenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heteroaralkyloxy, aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, haloalkoxyalkyl, optionally substituted phenylalkyl, optionally substituted phenyloxy, optionally substituted phenylalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkyloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkyloxy, -alkylene-
S(0)a-R® (Where n is 0 to 2 and R® is alkyl, hydroxyalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaraikyl), -alkylene-NHSO,-R® (where R® is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -alkylene-
NHCO-R® (where R® is alkyl, haloalkyl, hydroxyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -(alkylene)n1-CONRR' (where nl is 0 or 1, RY is hydrogen or alkyl, and R'is hydrogen, alkyl, hydroxylalkyl, alkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkylalkyl, or R? and R' together with the nitrogen atom to which they are attached form optionally substituted heterocycloalkyl), -alkylene-NR¢-alkyleneCONRR* (where R® is as defined above and R® and R® are independently hydrogen or alkyl), or carboxyalkylaminoalkyl wherein the alkyl chain in haloalkoxyalkyl, optionally substituted phenyloxyalky!, optionally substituted heteroaryloxyalkyl, or aminoalkyl is optionally substituted with one or two fluoro. Preferably, the substituents are independently methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2-(morpholin-4-yl)ethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-(N,N-dimethylamino)ethoxy, methoxymethyl, phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-ylmethyl, N,N-dimethylamino- methyl, i-propoxymethyl, or phenoxymethyl.
When the heteroaryl ring is divalent it has been referred to as heteroarylene in this application. "Heteroarylamino" means a NHR radical where R is heteroaryl as defined above. "Heteroaralkyl" means a —(alkylene)-R radical where R is heteroaryl as defined above. "Heteroaralkenyl" means a —(alkenylene)-R radical where R is heteroaryl as defined above. “Methylenedioxy” means —O-CH;-O-.
The present invention also includes the prodrugs of compounds of Formula (I). The term prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula (I) when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups by routine manipulation or in vivo. Prodrugs of compounds of
Formula (1) include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbony!) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g., trifluoroacetylamino,
i 5 acetylamino, and the like), and the like. Prodrugs of compounds of Formula (I) are also within the scope of this invention.
The present invention also includes N-oxide derivatives and protected derivatives of compounds of Formula (I). For example, when compounds of Formula (I) contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. When compounds of Formula (I) contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable protecting groups. A comprehensive list of suitable protective groups can be found in T.W.
Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981, the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of Formula (I) can be prepared by methods well known in the art. “Phenylene” means a divalent phenyl radical.
A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene- 1 -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference.
oS The compounds of the present invention may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral, diastereomeric, racemic forms are within the scope of this invention, unless the specific stereochemistry or isomeric form is specifically indicated.
Certain compounds of Formula (I) can exist as tautomers and/or geometric isomers.
All possible tautomers and cis and trans isomers, individual and mixtures thereof are within the scope of this invention. Additionally, as used herein the terms alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth.
Furthermore, when the cyclic groups such as aryl, heteroaryl, heterocycloalkyl are substituted, they include all the positional isomers albeit only a few examples are set forth.
Furthermore, all polymorphic forms and hydrates of a compound of Formula (I) are within the scope of this invention. "Optionally substituted phenyl" means a phenyl ring optionally substituted with one, two, or three substituents independently selected from alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkoxy, heteroaryl (that is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino), heterocycloalkyl (that is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino), amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, methylenedioxy, aminocarbonyl, acylamino, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, or carboxy or optionally substituted with five fluorine atoms. "Optionally substituted phenyloxy or phenoxy" means a -OR radical where R is optionally substituted phenyl as defined above e.g., phenoxy, chlorophenoxy, and the like. "Optionally substituted phenylcarbonylamino™ means a -NHCOR radical where R is optionally substituted phenyl as defined above e.g., benzoylamino, and the like. "Optionally substituted phenylalkyl” means a —(alkylene)-R radical where R is optionally substituted phenyl as defined above e.g., benzyl, phenylethyl, and the like. "Optionally substituted phenylalkyloxy" means a —OR radical where R is optionally substituted phenylalkyl as defined above e.g., benzyloxy, phenylethyloxy, and the like. "Optionally substituted phenylalkylthio" means a -S-(alkylene)-R radical where R is optionally substituted phenyl as defined above e.g., benzylthio, phenylethylthio, and the like.
"Optionally substituted phenylalkylsulfonyl" means a -S0O,-(alkylene)-R radical where
R is optionally substituted phenyl as defined above e.g., benzylsulfonyl, phenylethylsulfonyl, and the like. "Optionally substituted phenylalkeny!" means a —(alkenylene)-R radical where R is optionally substituted as defined above e.g., phenylethenyl, phenylpropenyl, and the like. "Optionally substituted phenoxyalkyl" means a ~(alkylene)-OR radical where R is optionally substituted phenyl as defined above e.g., phenoxymethyl, phenoxyethyl, and the like. "Optionally substituted heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms where one or more, preferably one, two, or three, ring atoms are heteroatoms selected from N, O, or S, the remaining ring atoms being carbon that is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, optionally substituted phenyl, optionally substituted phenoxy, carboxy, or heteroaryl that is optionally substituted with alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino, heterocycloalkyl optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, amino, alkylamino or dialkylamino, heterocycloalkylalky! optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, amino, alkylamino or dialkylamino, or heteroarylamino optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, amino, alkylamino or dialkylamino. More specifically the term optionally substituted heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzopyranyl, and thiazolyl, and the derivatives thereof (formed when the heteroaryl ring is substituted with a substituent listed above); or an
N-oxide or a protected derivative thereof. "Optionally substituted heteroaryloxy" means a -OR radical where R is optionally substituted heteroaryl as defined above e.g., furanyloxy, pyridinyloxy, and the like. "Optionally substituted heteroaralkyloxy" means a -OR radical where R is optionally substituted heteroaralkyl ring as defined below. "Optionally substituted heteroaryloxyalkyl" means a —(alkylene)-OR radical where R is optionally substituted heteroaryl ring as defined above.
} 5 ‘Optionally substituted heteroaralkyl" means a ~(alkylene)-R radical where R is optionally substituted heteroaryl ring as defined above. "Optionally substituted heterocycloalkyl" means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or $(O),, where n is an integer from 0 to 2, the remaining ring atoms being C. One or two ring carbon atoms can optionally be replaced by a ~CO- group. More specifically the term heterocycloalky! includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino and the derivatives thereof (formed when the heterocycloaikyl ring is substituted with a substituent listed below); or an
N-oxide or a protected derivative thereof. The heterocycloalkyl is optionally fused to aryl and is optionally substituted with one, two, or three substituents independently selected from alkyl, cycloalkyl, halo, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, optionally substituted phenylalky}, optionally substituted heteroaralkyl aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, or carboxy. "Optionally substituted heterocycloalkyloxy" means a -OR radical where R is optionally substituted heterocycloalkyl ring as defined above. ‘Optionally substituted heterocycloalkylalkyl" means a —(alkylene)-R radical where R is optionally substituted heterocycloalkyl ring as defined above. "Optionally substituted heterocycloalkylalkyloxy" means a -OR radical where R is optionally substituted heterocycloalkylalky! ring as defined above. "Optionally substituted heterocycloalkyloxyalkyl" means a «(alkylene)-OR radical where R is optionally substituted heterocycloalkyl as defined above e.g., piperidinyloxymethyl, pyrrolidinyloxyethyl, and the like. "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "heterocycloalky! group optionally mono- or di-substituted with an alkyl group” means that the alkyl may but need not be present, and the description includes situations where the : heterocycloalkyl group is mono- or disubstituted with an alkyl group and situations where the heterocycloalkyl group is not substituted with the alkyl group.
A "pharmaceutically acceptable carrier or excipient" means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically
_ 5 acceptable carrier/excipient" as used in the specification and claims includes both one and more than one such excipient. "Treating" or "treatment" of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.€., causing regression of the disease or its clinical symptoms.
The term "treating cancer" or "treatment of cancer" refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer.
A "therapeutically effective amount" means the amount of a compound of Formula (I) that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
Representative compounds of Formula (1) are disclosed in Table I-IV below.
Compounds of Formula (I) where R' and R? are hydrogen, Ar' is phenyl and Arfand Y are as defined in Table I below are: lo] wt —Gonr—y-0—{_) NH
Table [
Cpd Ar Y
A EE
I
ME cL LN Nc
I i Nc
R=
Cpd Ar Y
HE
FL E.R
CE —— —
J WA trans pyridin-3-yl-CH=CH-
I oN. 4-(benzoylamino)-phenyl
[cp A Y
HEE
I EV
IE I I s 2-phenylphenyl -CH,-CHa- @ mee] Cm
I LI cic.
IE I TR ic
I Nic
I A Tc.
. Cpd A Y
A
TT |e Shen To CCIE | (CRC 2-yl -C(CH3)=CH- 73 benzofuran-2-yl -(S)-CH(2-phenylethyl)- i yloxy]benzofuran-2-yl 78 benzofuran-2-yl -(R)-CH(benzylSO,-
ME
79 benzofuran-2-yl -(R)-CH(benzylS-methyl)-
ET
I Nec
I cA
WT ween owe
OC ic cc LO
I I ce
I Ic LU
I I rc i: Lo methyl)-CH;-
Cpd Ar Y
FLA
IE cic
I CL ci i : 104 trans phenyl-CH=CH- -(RS)-CH(4-Cl-benzyl)- i I Bi
I I Teco i Chil trans phenyl-CH=CH- a
EC cc I isla
ILL cc I Lac
ER trans phenyl-CH=CH- methyl)-CHa,-
CH;-
TE ee | ook
TE we | oom
. Cpd A Y
HA RE
143 4-[2-(4-methylpiperazin- 1-ylmethyl)thiazol-5- -CH,-CH»-
NC TR i Cpd A Y
NC oe cl 165 3°-(2-hydroxyethyl)biphen-3-yl
IC rc Wc
TO wees | Ge trans thiophen-3-yl-CH=CH-
I Coc cS
. Cpd Ar Y i A
Treo 23] CHC CRC Cr 9 Soest 231 CECE | OCHO Gy
I ic
Dm and are named as:
N-hydroxy-4-(2-benzenecarbonylamino-ethoxy)benzamide;
N-hydroxy-4-(2-trans-cinnamoylaminoethoxy)benzamide;
N-hydroxy-4-(2-trans-2-phenylcyclopropylcarbonylaminoethoxy)benzamide;
N-hydroxy-4-(2-trans-4-methoxycinnamoylaminoethoxy)benzamide;
N-hydroxy-4-[2-(2-phenylethylcarbonylamino)ethoxy Jbenzamide;
N-hydroxy-4-[2-(1 H-indol-3-ylmethylcarbonylamino)ethoxy]benzam ide;
N-hydroxy-4-(2-thiophen-2-ylcarbonylaminoethoxy)benzamide;
N-hydroxy-4-(2-pyridin-3-yicarbonylaminoethoxy)benzamide;
N-hydroxy-4-(2-biphen-4-ylcarbonylaminoethoxy)benzamide;
N-hydroxy-4-(2-biphen-3-ylcarbonylaminoethoxy)benzamide;
N-hydroxy-4-[2-(5-phenylthiophen-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(thiophen-2-ylmethylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(napth-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(quinolin-6-ylcarbonylamino)ethoxy Jbenzamide;
N-hydroxy-4-[2-(4-phenylthiazol-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(4-tert-butylphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(trans-3-pyridin-3-ylacryloylamino)ethoxy]benzamide;
N-hydroxy-4-{2-(4-pyrrol-1 -ylphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(4-cyclohexene-3-oxyphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(benzthiazol-2-ylcarbonylamino)ethoxy |benzamide;
N-hydroxy-4-[2-(benzoxazol-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(octahydroisoquinolin-2-ylmethylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(4-pyridin-4-ylpiperazin-1 -ylmethyicarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(furan-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(4-pyridin-3-ylphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(4-pyridin-2-ylphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(benzimidazol-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(1 H-pyrrol-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(4-benzoylaminophenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(4-pyridin-4-ylthiazol-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(admantan-1-ylcarbonylamino)ethoxy]benzamide; } N-hydroxy-4-[2-(2,4-difluorophenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(3-trans-3 4-methylenedioxyphenylacryloylamino)ethoxy]-benzamide;
N-hydroxy-4-[2-(3,4-methylenedioxyphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(3,4-dimethoxyphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(3,5-dimethoxyphenycarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(3,4-difluorophenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(2,5-dimethylphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(2,3-dichlorophenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(2,3-dimethylphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(4-chloro-2-methoxyphenylcarbonylamino)ethoxylbenzamide;
N-hydroxy-4-[2-(3-ethoxyphenylcarbonylamino)ethoxylbenzamide;
N-hydroxy-4-[2-(4-methoxy-2-methylphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(3-fluoro-4-methoxyphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(2-thiophen-2-ylmethoxyphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(3-thiophen-2-ylmethoxyphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(biphen-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(1 H-indol-5-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(1 H-indol-3-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(quinolin-3-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(quinolin-8-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(1 H-indazol-3-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(1 H-benzotriazol-5-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(isoquinolin-1-ylcarbonylam ino)ethoxy]benzamide;
N-hydroxy-4-[2-(isoquinolin-3-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(quinoxalin-2-ylcarbonylamino)ethoxy}benzamide;
N-hydroxy-4-[2-(naphth-1 -ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(quinolin-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(2-pyrrol-1 -ylphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(4-fluoronapth-1 -ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(1 H-benzimidazol-5-ylcarbonylamino)ethoxy]benzamide;
oS N-hydroxy-4-[2-(1-methylindol-3-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(4-methoxyquinolin-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(3- methoxynapth-2-ylcarbonylamino)ethoxy}benzamide;
N-hydroxy-4-[2-(2-methoxynapth-1 -ylcarbonylamino)ethoxy] benzamide;
N-hydroxy-4-[2-(quinolin-4-ylcarbonylamino)ethoxy ]benzamide;
N-hydroxy-4-[2-(trans-2-methylcinnamoylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(2-N,N-dimethylaminomethylbenzofuran-5-ylcarbonylamino)ethoxy]- benzamide;
N-hydroxy-4-(2-indolin-1-ylcarbonylaminoethoxy)benzamide;,
N-hydroxy-4-[2-(1,2,3,4-tetrahydroquinolin-1-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-{2S-[trans-3-(5-hydroxybenzofuran-2-yl)but-2-enoylamino]butoxy}benzamide;
N-hydroxy-4-{2S-[trans-3-(5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-yl)but-2-enoyl- amino]butoxy}benzamide;
N-hydroxy-4-[2S-(benzofuran-2-ylcarbonylamino)-4-phenylbutoxy)benzamide;
N-hydroxy-4-{2-[5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-ylcarbonylamino}- ethoxy}benzamidc;
N-hydroxy-4-{25-[5-(1-cyclopropy!piperidin-4-yloxy)benzofuran-2-ylcarbonylamino]- butoxy}benzamidc;
N-hydroxy-4-{2-[5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-ylcarbonylamino}-1R- methylethoxy} benzamide; N-hydroxy-4-{2-[5-(1-(2,2,2-trifluoroethyl)piperidin-4-yloxy)benzofuran-2-ylcarbonyl- amino]-ethoxy}benzamide;
N-hydroxy-4-[2R-(benzofuran-2-ylcarbonylamino)-3-benzylsulfonylpropoxy]benzamide;
N-hydroxy-4-[2R-(benzofuran-2-ylcarbonylamino)-3-benzylthiopropoxy]benzamide;
N-hydroxy-4-[2-(trans-3-(5-methoxybenzofuran-2-yl)but-2-enoylcarbonylamino)- ethoxy]benzamide;
N-hydroxy-4-[2-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(isoindolin-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(morpholin-4-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(4-benzylpiperazin-1-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(3(R)-hydroxypyrrolidin-1-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(piperidin- 1 -ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(6-methyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonylamino)ethoxy]-benzamide;
N-hydroxy-4-[2-(2-methylindolin-1-ylcarbonylamino)ethoxy]benzamide;
Claims (41)
1. A compound of Formula (1): ? 1 a= conri—y—x—ar) > no" 1 wherein: R' is hydrogen or alkyl; X is ~O-, -NR?-, or ~S(O)swhere n is 0-2 and R? is hydrogen or alkyl; Y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxyl, or optionally substituted phenoxy; Ar’ is phenylene or heteroarylene wherein said Ar! is optionally substituted with one or two groups independently selected from alkyl, halo, hydroxyl, alkoxy, haloalkoxy, or haloalkyl; R® is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl; and AP is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; or apharmaceutically acceptable salt thereof.
2. The compound of Claim 1 wherein X is -O- and R' and R® are hydrogen.
3. The compound of Claim 1 wherein X is -S(O)rand R' and R? are hydrogen.
4, The compound of Claim 2 or 3 wherein Y is alkylene.
5. The compound of Claim 2 or 3 wherein Y is alkylene substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxyl, or optionally substituted phenoxy.
6. The compound of Claim 1 wherein Ar' is phenylene, X is -O-, R' and R? are hydrogen, and ~-CONHOR' and X groups are at the 1 and 4 position of the phenylene ring.
7. The compound of anyone of the Claims 2-5 wherein Ar' is heteroarylene.
8. The compound of anyone of the Claims 2-5 wherein Ar' is phenylene.
9. The compound of any of the Claims 2-8 wherein Ar? is aryl or aralkenyl.
10. The compound of any one of the Claims 2-5, 7 and 8 wherein Ar is heteroaryl.
11. The compound of Claim 6 wherein Ar’ is heteroaryl.
12. The compound of Claim | wherein AP is heteroaryl optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkyl, alkoxy, alkoxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl,
. 5 aminoalkoxy, haloalkoxy, haloalkoxyalkyl, optionally substituted phenylalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyloxy, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylalkyloxy, -alkylene-S(0).R* (where n is 0 to 2 and R*® is hydroxyalkyl or optionally substituted phenyl), -alkylene-NR°-alkyleneCONR'R® (where RF is hydroxyl and Rr and R® are independently hydrogen or alkyl), or carboxyalkylaminoalkyl.
13. The compound of Claim 10 wherein Afr is heteroaryl optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkyl, aikoxy, alkoxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkoxy, haloalkoxy, haloalkoxyalkyl, optionally substituted phenylalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyloxy, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylalkyloxy, -alkylene-S(0),R® (where n is 0 to 2 and R® is hydroxyalkyl or optionally substituted phenyl), -alkylene-NR°®-alkyleneCON R°R® (where RE is hydroxyl and R* and R° are independently hydrogen or alkyl), or carboxyalkylaminoalkyl.
14. The compound Claim 10 wherein AP is benzofuran-2-yl and is monosubstituted at the 3-position of the benzofuran-2-yl ring wherein the substituent is N,N-dimethylaminomethyl, N,N-diethylaminomethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy- methyl, hydroxyl-4-yloxymethyl, 2,4.6-trifluorophenoxy-methyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxy-methyl, 4-imidazol-1-ylphenoxy-methyl, 4-1 .2.4-triazin-1-yl- phenoxymethyl, 2-phenylethyl, 3-hydroxypropyloxymethyl, 2-methoxyethyloxymethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethylpiperidin-1-ylmethyl, 4- methylpiperazin-1-ylmethyl, 3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl, 4- fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, 2-(3-trifluoromethoxyphenylethyl), N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropyl- thiomethyl, 3-hydroxypropylsulfinyl-methyl, 3-hydroxypropylsulfonylmethyl, N-methyl-N-2- indol-3-ylethylaminomethyl, 2-(4-trifluoromethylphenyl)ethyl, N-hydroxyaminocarbonyl- methylaminomethyl, or 2-carboxyethylaminomethyl.
15. The compound of Claim 11 wherein Ar is heteroaryl optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkyl, alkoxy, alkoxyalky!, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkoxy, haloalkoxy, haloalkoxyalkyl, optionally substituted phenylalkyl, optionally
. 5 substituted phenyloxyalkyl, optionally substituted heteroaryl, optionally substituted ) heteroaralkyloxy, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylalkyloxy, -alkylene-S(O):R* (where nis 0 to 2 and R® is hydroxyalkyl or optionally substituted phenyl), -alkylene-NR°-alkyleneCONR'R® (where R® is hydroxyl and Rr and R® are independently hydrogen or alkyl), or carboxyalkylaminoalkyl.
16. The compound Claim 11 wherein AP is benzofuran-2-yl and is monosubstituted at the 3-position of the benzofuran-2-yl ring wherein the substituent is N,N-dimethylaminomethyl, N,N-diethylaminomethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy- methyl, hydroxyl-4-yloxymethyl, 2,4,6-trifluorophenoxy-methyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxy-methyl, 4-imidazol-1-ylphenoxy-methyl, 4-[1.2.4-triazin-1-yl- phenoxymethyl, 2-phenylethyl, 3-hydroxypropyloxymethyl, 2-methoxyethyloxymethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethylpiperidin-1-ylmethyl, 4- methylpiperazin-1-ylmethyl, 3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl, 4- fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, 2-(3-triflucromethoxyphenylethyl), N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropyl- thiomethyl, 3-hydroxypropylsulfinyl-methyl, 3-hydroxypropylsulfonylmethyl, N-methyl-N-2- indol-3-ylethylaminomethyl, 2-(4-trifluoromethylphenyl)ethyl, N-hydroxyaminocarbonyl- methylaminomethyl, or 2-carboxyethylaminomethyl.
17. The compound of Claim 11 wherein AF is benzofuran-2-yl and is monosubstituted at the S-position of the benzofuran-2-yl ring.
18. The compound of Claim 11 wherein Ar is benzofuran-2-yl and is monosubstituted at the 5-position of the benzofuran-2-yl ring wherein the substituent is cyclopropylpiperidin-4- yloxy, piperidin-4-yloxy, tetrahydropyran-4-yloxy, 2,2,2-trifluoroethoxy, 2-pyrrolidin-1- ylethyloxy, or 1-(2,2,2-trifluoroethyl)piperidin-4-yloxy.
19. The compound of any one of the Claims 15-18 wherein Y is ethylene.
20. The compound of any one of the Claims 2-8 wherein Ar is aralkenyl.
21. The compound of Claim 1 wherein X is -O-, R' and R? are hydrogen, Ar is phenylene, Af is aralkenyl, Y is branched alkylene, and the -CONHOH and X are at the 1 and 4 position of the phenylene ring.
22. The compound of Claim 21 wherein AP is trans phenylCH=CH- wherein the phenyl is optionally substituted with one or two substituents independently selected from alkyl, alkoxy, methylenedioxy, or hydroxyl.
23. A compound selected from the group consisting of:
«35 N-hydroxy-4-(2-benzenecarbonylamino-ethoxy)benzamide; N-hydroxy-4-(2-trans-cinnamoylaminoethoxy)benzamide;
N-hydroxy-4-(2-trans-2-phenyleyclopropylcarbonylaminoethoxy)benzamide;
N-hydroxy-4-(2-trans-4-methoxycinnamoylaminoethoxy)benzamide; N-hydroxy-4-[2-(2-phenylethylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(1 H-indol-3-ylmethylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-(2-thiophen-2-ylcarbonylaminoethoxy)benzamide; N-hydroxy-4-(2-pyridin-3-ylcarbonylaminoethoxy)benzamide; N-hydroxy-4-(2-biphen-4-ylcarbonylaminoethoxy)benzamide; N-hydroxy-4-(2-biphen-3-ylcarbonylaminoethoxy)benzamide;
N-hydroxy-4-[2-(5-phenylthiophen-2-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(thiophen-2-ylmethylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(napth-2-ylcarbonylamino)ethoxy Jbenzamide; N-hydroxy-4-[2-(quinolin-6-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(4-phenylthiazol-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(4-tert-butylphenylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(trans-3-pyridin-3-ylacryloylamino)ethoxy]benzamide; N-hydroxy-4-[2-(4-pyrrol-1 -ylphenylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(4-cyclohexene-3-oxyphenylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(benzthiazol-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(benzoxazol-2-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(octahydroisoquinolin-2-ylmethylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(4-pyridin-4-ylpiperazin-1 -ylmethylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(furan-2-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(4-pyridin-3-ylphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(4-pyridin-2-ylphenylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(benzimidazol-2-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(1 H-pyrrol-2-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(4-benzoylaminophenylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(4-pyridin-4-ylthiazol-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(admantan-1-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(2,4-difluorophenylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(3-trans-3,4-methylenedioxyphenylacryloylamino)ethoxy]-benzamide; N-hydroxy-4-[2-(3,4-methylenedioxyphenylcarbonylamino)ethoxy]benzamide;
. 5 N-hydroxy-4-[2-(3,4-dimethoxyphenylcarbonylamino)ethoxyJbenzamide;
a N-hydroxy-4-[2-(3,5-dimethoxyphenylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(3,4-difluorophenylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(2,5-dimethylphenylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(2,3-dichlorophenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(2,3-dimethylphenylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(4-chloro-2-methoxyphenylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(3-ethoxyphenylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(4-methoxy-2-methylphenylcarbonylamino)ethoxylbenzamide; N-hydroxy-4-{2-(3-fluoro-4-methoxyphenylcarbonylamino)ethoxybenzamide;
N-hydroxy-4-[2-(2-thiophen-2-ylmethoxyphenylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(3-thiophen-2-ylmethoxyphenylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(biphen-2-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(1 H-indol-5-ylcarbonylamino)ethoxy benzamide; N-hydroxy-4-[2-(1H-indol-3-ylcarbonylamino)ethoxy ]benzamide;
N-hydroxy-4-[2-(quinolin-3-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(quinolin-8-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(1 H-indazol-3-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(1 H-benzotriazol-5-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(isoquinolin-1-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(isoquinolin-3-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(quinoxalin-2-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(naphth-1-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(quinolin-2-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(2-pyrrol-1 -ylphenylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(4-fluoronapth-1-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(1H-benzimidazol-5-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(1-methylindol-3-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(4-methoxyquinolin-2-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(3- methoxynapth-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(2-methoxynapth-1-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(quinolin-4-ylcarbonylamino)ethoxy Jbenzamide; N-hydroxy-4-[2-(trans-2-methylcinnamoylamino)ethoxy]benzamide;
- 5 N-hydroxy-4-[2-(2-N,N-dimethylaminomethylbenzofuran-5-ylcarbonylamino)ethoxy]- benzamide; N-hydroxy-4-(2-indolin-1-ylcarbonylam inoethoxy)benzamide; N-hydroxy-4-[2-(1,2,3,4-tetrahydroquinolin- 1-ylcarbonylam ino)ethoxy]benzamide; N-hydroxy-4- {2S-[trans-3-(3-hydroxybenzofuran-2-y})but-2-enoylamino]butoxy} benzamide;
N-hydroxy-4-{2S-|trans-3-(5-(1 _cyclopropylpiperidin-4-yloxy)benzofuran-2-yl)but-2-enoyl- amino]butoxy } benzamide; N-hydroxy-4-[2S-(benzofuran-2-ylcarbonylamino)-4-phenylbutoxy)benzamide; N-hydroxy-4-{2-[5-(1 -cyclopropy!piperidin-4-yloxy)benzofuran-2-ylcarbonylamino]- ethoxy }benzamide;
N-hydroxy-4-{25-[5-(1 -cyclopropylpiperidin-4-yloxy)benzofuran-2-ylcarbonylamino]- butoxy } benzamide;
N-hydroxy-4-{2-[5-(1 —cyclopropylpiperidin-4-yloxy)benzofuran-2-ylcarbonylamino]-1 R- methylethoxy}benzamide; N-hydroxy-4-{2-[5-(1 -(2,2,2-trifluoroethyl)piperidin-4-yloxy)benzofuran-2-yicarbonyl-
amino]-ethoxy}benzamide, N-hydroxy-4-[2R-(benzofuran-2-ylcarbonylamino)-3-benzylsul fonylpropoxy]benzamide; N-hydroxy-4-[2R-(benzofuran-2-ylcarbonylamino)-3-benzylthiopropoxy]benzamide; N-hydroxy-4-[2-(trans-3-(5-methoxybenzofuran-2-yl)but-2-enoylcarbonylamino)- ethoxy]benzamide;
N-hydroxy-4-[2-(1 2.3 4-tetrahydroisoquinolin-2-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(isoindol in-2-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(morpholin-4-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(4-benzylpiperazin-1 -ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(3(R)-hydroxypyrrolidin-1 -ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(piperidin-1-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(6-methyl-1 ,2,3,4-tetrahydroquinolin-1 -ylcarbonylamino)ethoxy]-benzamide; N-hydroxy-4-[2-(2-methylindolin-1 -ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(6-fluoro-2-methyl-1 ,2,3,4-tetrahydroquinolin-1-ylcarbonylamino)- ethoxy]benzamide;
N-hydroxy-4-[2S-(isoindolin-1-ylcarbonylamino)butoxy]benzamide; N-hydroxy-4-[3-(trans-cinnamoylamino)propoxy]benzamide;
N-hydroxy-4-[3-( trans-4-methoxycinnamoylamino)propoxylbenzamide; N-hydroxy-4-[3-(4-phenylthiazol-2-ylcarbonylamino)propoxy]benzamide;
- 5 N-hydroxy-4-[2S ~(trans-cinnamoylamino)propoxy)benzamide; N-hydroxy-4-[2R-(trans-cinnamoylamino)propoxy)benzamide; N-hydroxy-4-[2S-(trans-cinnamoylamino)-4-methylpentoxy]benzamide; N-hydroxy-4-[28-(trans-cinnamoylamino)-3-cyclohexylpropoxy]benzamide; N-hydroxy-4-[2S-(trans-cinnamoylamino)-3-methylbutoxy]benzamide;
N-hydroxy-4-[2S-(trans-cinnamoylamino)-3-pheny Ipropoxy]benzamide; N-hydroxy-4-[2R-(trans-cinnamoylamino)-3-phenylpropoxy]benzamide; N-hydroxy-4-[2R-(trans-cinnamoylamino)-4-methylpentoxy]benzamide; N-hydroxy-4-[2R-(trans-cinnamoylamino)-3-methybutoxy]benzamide; N-hydroxy-4-[2RS -(trans-cinnamoylamino)hexyloxy]benzamide;
N-hydroxy-4-[2RS-(trans-cinnamoylamino)-3-(4-chlorophenyl)propoxy)benzamide; N-hydroxy-4-[2S-(trans-cinnamoylamino)butoxy]benzamide; N-hydroxy-4-[2R-(trans-cinnamoylamino)butoxy]benzamide; N-hydroxy-4-[2S-(trans-cinnamoylamino)-4-methythiobutoxy)benzamide; N-hydroxy-4-[2R-(trans-cinnamoylamino)-4-methylthiobutoxy]benzamide;
N-hydroxy-4-[2S-(trans-cinnamoylamino)-2-phenylethoxy]benzamide; N-hydroxy-4-[2R-(trans-cinnamoylamino)-2-phenylethoxy]benzamide; N-hydroxy-4-[2S-(trans-cinnamoylamino)-4-methylsulfonylbutoxy]benzamide; N-hydroxy-4-[2R-(trans-cinnamoylamino)- 4-methylsulfonylbutoxy]benzamide; N-hydroxy-4-[2R-(trans-cinnamoylamino)-3-benzylsulfonylpropoxy]benzamide;
N-hydroxy-4-[2S-(thiophen-2-ylcarbonylamino)butoxy]benzamide; N-hydroxy-4-[2S-(biphen-4-ylcarbonylamino)butoxy]benzamide; N-hydroxy-4-[2S-(naphth-2-ylcarbonylamino)butoxy]benzamide; N-hydroxy-4-[2R-(trans-cinnamoylamino)-3-benzylthiopropoxy]benzamide; N-hydroxy-4-[2S-(benzenecarbonylamino)butoxy]benzamide;
N-hydroxy-4-[2S-(benzylcarbonylamino)butoxy]benzamide; N-hydroxy-4-[2S-(2-phenylethylcarbonylamino)butoxy]benzamide; N-hydroxy-4-[2S-(trans-cinnamoylamino)-3-hydroxypropoxy]benzamide; N-hydroxy-4-[2S-(4-phenylthiazol-2-ylcarbonylamino)butoxy]benzamide; N-hydroxy-4-[2S-(trans-4-methoxycinnamoylamino)butoxy]benzamide;
N-hydroxy-4-[2S-(2-N,N-dimethylaminomethylbenzofuran-5-ylcarbonylamino)butoxy}- benzamide; N-hydroxy-4-[2-(frans-cinnamoylamino)-1R-methylethoxy]benzamide; N-hydroxy-4-[2-(trans-cinnamoylamino)-1S-methylethoxy)benzam ide;
NE N-hydroxy-4-[2-(4-phenylthiazol-2-ylcarbonylamino)- 1R-methylethoxy]benzamide; N-hydroxy-4-[2-(4-phenylthiazol-2-ylcarbonylamino)- 1S-methylethoxy]benzamide; N-hydroxy-4-[2-(biphen-4-ylcarbonylamino)- 1R-methylethoxylbenzamide; N-hydroxy-4-[2-(trans-4-methoxycinnamoylamino)- 1 R-methylethoxy]benzamide; N-hydroxy-4-{ 2-{4-(2-pyridin-2-ylthiazol-5-yl)phenylcarbonylamino]ethoxy} benzamide;
N-hydroxy-4-[2-(7-chloro-4-methylbenzofuran-2-ylcarbonylamino)ethoxy Jbenzamide; N-hydroxy-4-{2-[4-(2-(4-methylpiperazin-1 -yl)thiazol-5-yl)phenylcarbonylamino}- ethoxy} benzamide;
N-hydroxy-4-{ 2-{4-(2-pyridin-4-ylaminothiazol-5 -yl)phenylcarbonylaminolethoxy}- benzamide;
N-hydroxy-4-{2-[4-(4-methylpiperazin-1-yl)phenylcarbonylamino]ethoxy } benzamide; N-hydroxy-4-{2-[4-(4-hydroxypiperidin-1 -yl)phenylcarbonylamino]ethoxy} benzamide; N-hydroxy-4-{2-[4-(4-morpholin-4-ylmethylthiazol-5 -yhphenylcarbonylaminojethoxy}- benzamide; N-hydroxy-4-[2-(7-fluoro-4-methylbenzofuran-2-ylcarbonylamino)ethoxyJbenzamide;
N-hydroxy-4-{2-{7-fl uoro-4-(2-methoxyethoxymethy)benzofuran-2-ylcarbonylamino)- ethoxy} benzamide; N-hydroxy-4-[2-(4-hydroxyquinolin-2-ylcarbonylamino)ethoxy}benzamide; N-hydroxy-4-[2-(7-fluoro-4-phenoxymethylbenzofuran-2-ylcarbonylamino)ethoxy]- benzamide;
N-hydroxy-4-{2-[4-(2-(4-methylpiperazin-1-ylmethyl)thiazol-2-yl)phenylcarbonyl-amino}- ethoxy} benzamide; N-hydroxy-4-[2-(pyridin-2-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(3-hydroxypyridin-2-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(6-hydroxypyridin-2-ylcarbonylamino)ethoxy Jbenzamide;
N-hydroxy-4-{2-[6-(4-nitrophenoxy)pyridin-2-ylcarbonylamino]ethoxy} benzamide; N-hydroxy-4-{2-[4-(2-methoxyethoxy)quinolin-2-ylcarbonylamino]ethoxy} benzamide; N-hydroxy-4-{ 2-[4-(2-N,N-dimethylaminoethoxy)quinolin-2-ylcarbonylaminojethoxy} - benzamide;
N-hydroxy-4-[2-(6-bromopyridin-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(5-bromopyridin-3-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[25-(4-methoxyquinolin-2-ylcarbonylamino)butoxy]benzamide; N-hydroxy-4-[2-(1 -methoxynaphth-2-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-[2-(4-methoxyquinolin-2-ylcarbonylamino)-1 R-methylethoxy]benzamide;
N-hydroxy-4-[2-(5-phenylpyridin-3 -ylcarbonylamino)ethoxylbenzamide;
N-hydroxy-4-[2-(6-benzyloxypyridin-2-ylcarbonylamino)ethoxy]benzamide;
N-hydroxy-4-{ 2-[6-(2-methylpropyloxy)pyridin-2-ylcarbonylamino]ethoxy} benzamide; N-hydroxy-4-{2-[6-(2-phenylethyloxy)pyridin-2-ylcarbonylamino]ethoxy} benzamide; N-hydroxy-4-{2-[4-(3,3 3-trifluoropropyloxy)quinolin-2-ylcarbonylaminolethoxy} -benzamide;
N-hydroxy-4-{25-[4-(3, 3 3-trifluoropropyloxy)quinolin-2-ylcarbonylamino]butoxy} - benzamide;
N-hydroxy-4- {2-[4-(3,3,3-trifluoropropyloxy)quinolin-2-ylcarbonylamino]-1 R- methylethoxy} benzamide; N-hydroxy-4-[2-(trans-3-hydroxycinnamoylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(trans-4-hydroxycinnamoylamino)ethoxy]benzamide; N-hydroxy-4-{2-[3’<(2-hydroxyethyl)biphen-4-ylcarbonylamino]ethoxy} benzamide; N-hydroxy-4-{2-[3 *(2-hydroxyethyl)biphen-3-ylcarbonylamino]ethoxy} benzamide; N-hydroxy-4-{2-[2’-(2-hydroxyethyl)biphen-4-ylcarbonylamino]ethoxy} benzamide; N-hydroxy-4-[2-(trans-2-benzofuran-2-ylacryloylamino)ethoxy] benzamide;
N-hydroxy-4-{2-[2’-(2-hydroxyethyl)biphen-3-ylcarbonylamino]ethoxy} benzamide; N-hydroxy-4-{ 2-[5-(thiophen-3-yl)pyridin-3-ylcarbonylaminolethoxy} benzamide; N-hydroxy-4-{ 2-[6-(4-acetylaminophenoxy)pyridin-2-ylcarbonylaminolethoxy} -benzamide; N-hydroxy-4- {2-{6-(4-aminophenoxy)pyridin-2-ylcarbonylam inoJethoxy } benzamide; N-hydroxy-4-[2-(trans-2-methoxycinnamoylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(trans-3-methoxycinnamoylamino)ethoxy]benzamide; N-hydroxy-d-{2-[5-(4-dimethylaminophenyl)pyridin-3-ylcarbonylaminoethoxy}-benzamide; N-hydroxy-4-{2-{trans-3-(5-bromothiophen-2-yl)acryloylamino]ethoxy} benzamide; N-hydroxy-4-[2-(trans-3-furan-3-ylacryloylamino)ethoxy]benzam ide; : N-hydroxy-4-[2-(trans-3-thiophen-3-ylacryloylamino)ethoxy]benzamide;
N-hydroxy-4-[2-(trans-thiophen-2-ylacryloylamino)ethoxy]benzamide; N-hydroxy-4-{2-(trans-3 -methylcinnamoylamino]ethoxy} benzamide; N-hydroxy-4-{2-[trans-4-methylcinnamoylamino]ethoxy} benzamide; N-hydroxy-4-{2-[trans-3 -(benzofuran-2-yl)but-2-enoylamino]ethoxy} benzamide; N-hydroxy-4-{ 2-{cis-3-(benzofuran-2-yl)but-2-enoylamino]ethoxy} benzamide;
N-hydroxy-4-[2-(trans-4-dimethylaminocinnamoylamino)ethoxy]benzamide; N-hydroxy-4-[2-(trans-3-indol-3 -ylacryloylamino)ethoxy]benzamide; N-hydroxy-4-{2-[trans-2-methylcinnamoy! amino]ethoxy}benzamide; N-hydroxy-4-[2-(trans-2-hydroxycinnamoylamino)ethoxy]benzamide;
. 3 Nohydroxy-4- {2-[trans-3-(7-methoxybenzofuran-2-yDacryloylaminoJethoxy} benzamide; N-hydroxy-4-{2R-[trans-3-(7-methoxybenzofuran-2-yl)acryloylamino]butoxy} benzamide; N-hydroxy-4-{2S- [trans-3-(5-methoxybenzofuran-2-yl)but-2-enoylamino]butoxy} benzamide; N-hydroxy-4-[2-(trans-3-furan-2-ylacryloylamino)ethoxy]benzamide; N-hydroxy-d- {2-[4-(4-(2-morpholin-4-ylethyl)thiazol-2-yl)phenylcarbonylamino]ethoxy}-
benzamide; N-hydroxy-4-(2-N-trans-cinnamoyl-N-hydroxyethylaminoethoxy)benzamide; N-hydroxy-4-(2-N-trans-cinnamoyl-N-phenylaminoethoxy)benzamide; N-hydroxy-4-(2-N-trans-cinnamoy!-N-methylaminoethoxy)benzamide; N-hydroxy-4-(2-N-benzothiophen-2-yl-N-isopropylaminoethoxy)benzamide;
N-hydroxy-4-(2-N-trans-cinnamoy|-N-isopropylaminoethoxy)benzamide; N-hydroxy-4-(3-N-trans-cinnamoyl-N-methylaminopropoxy)benzamide; N-hydroxy-4-[2-(benzothiophen-2-ylcarbonylamino)ethoxy]-benzamide; N-hydroxy-4-[2-(benzofuran-2-ylcarbonylamino)ethoxy]-benzamide;
N-hydroxy-4-[2-(1 H-indol-2-ylcarbonylamino)ethoxy]-benzamide;
N-hydroxy-4-[2-(1-methylindol-2-ylcarbonylamino)ethoxy]-benzamide; N-hydroxy-4-[3-(benzothiophen-2-ylcarbonylamino)propoxy]-benzamide; N-hydroxy-4-[3-(benzofuran-2-ylcarbonylamino)propoxy)-benzamide; N-hydroxy-4-[25-(benzothiophen-2-ylcarbonylamino)-3-methylbutoxy]-benzamide; N-hydroxy-4-[2S-(benzothiophen-2-ylcarbonylamino)butoxy]-benzamide;
N-hydroxy-4-[2S-(benzothiophen-2-ylcarbonylamino)-propoxy]-benzamide; N-hydroxy-4-[2R-(benzothiophen-2-ylcarbonylamino)-propoxy]-benzamide; N-hydroxy-4-[2S-(benzofuran-2-ylcarbonylamino)butoxy]-benzamide; N-hydroxy-4-[2-(benzothiophen-2-ylcarbonylamino)-1R-methylethoxy]-benzamide; N-hydroxy-4-[2-(benzothiophen-2-ylcarbonylamino)-1S-methylethoxy]-benzamide;
N-hydroxy-4-[2-(benzofuran-2-ylcarbonylamino)-1 R-methylethoxy]-benzamide; N-hydroxy-4-[2-(6-methoxybenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide; N-hydroxy-4-[2-(5-methylbenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide; N-hydroxy-4-[2-(3-chlorobenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide; N-hydroxy-4-[2-(5-methylbenzofuran-2-ylcarbonylamino)ethoxy]-benzamide;
N-hydroxy-4-[2-(6-methylbenzofuran-2-ylcarbonylamino)ethoxy]-benzamide; N-hydroxy-4-[2-(4-trifluoromethylbenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide; N-hydroxy-4-[2-(5-fluorobenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide; N-hydroxy-4-[2-(5-methoxybenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide;
. 5 N-hydroxy-4-[2-(5 —chlorobenzofuran-2-ylcarbonylamino)ethoxy]-benzamide; N-hydroxy-4-[2-(7-methoxybenzofuran-2-ylcarbonylamino)ethoxy] -benzamide; N-hydroxy-4-[2 -(5-methoxybenzofuran-2-ylcarbonylamino)ethoxy] -benzamide; N-hydroxy-4-{2-[5-(2-methoxyethoxy)benzofuran-2-ylcarbonylamino]ethoxy} -benzamide; N-hydroxy-4- {2-[5-(2-morpholin-4-ylethoxy)benzofuran-2-ylcarbonylaminojethoxy} -
benzamide; Nohydroxy-d-{2-[S-(pyridin-3-ylmethoxy)benzofuran-2-ylcarbonylaminojethoxy} -benzamide; N-hydroxy-4-{2-(3 -methylbenzofuran-2-ylcarbonylamino)ethoxy]-benzamide; N-hydroxy-4-[2-(3-methylbenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide; N-hydroxy-4- {2-[5-(2-hydroxyethoxy)benzofuran-2-ylcarbonylaminoJethoxy} -benzamide;
N-hydroxy-4- {2-[5-(2-N,N-dimethylaminoethoxy)benzofuran-2-ylcarbonylam ino]-ethoxy}- benzamide;
N-hydroxy-4- {2-[6-(2-methoxyethoxy)benzofuran-2-ylcarbonylam inoJethoxy }-benzamide; N-hydroxy-4-{ 2-[6-(2-morpholin-4-ylethoxy)benzofuran-2-ylcarbonylaminojethoxy }- benzamide;
N-hydroxy-4-{ 2-[6-(pyridin-3-ylmethoxy)benzofuran-2-ylcarbonylamino]ethoxy} -benzamide;
N-hydroxy-4-[2-(3-ethylbenzofuran-2-ylcarbonylamino)ethoxy]-benzamide; N-hydroxy-4-[2-(5-fluoroindol-2-ylcarbonylamino)ethoxy}-benzamide; N-hydroxy-4-[2-(5-methoxyindol-2-ylcarbonylamino)ethoxy]-benzamide;
N-hydroxy-4- {2-[3-(methoxymethyl)benzofuran-2-ylcarbonylamino]ethoxy} benzamide; N-hydroxy-4-{2-[3-(phenoxymethyl)benzofuran-2-ylcarbonylamino]ethoxy} benzamide; N-hydroxy-4-[2-(5,6-dimethoxyindol-2-ylcarbonylamino)ethoxy]-benzamide; N-hydroxy-4-{2-[3-(morpholin-4-ylmethylbenzofuran-2-ylcarbonylaminolethoxy}- benzamide; N-hydroxy-4-{ 2-[3-(N,N-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy} - benzamide; N-hydroxy-4-{2-{3-(i-propoxymethyl)benzofuran-2-ylcarbonylamino]ethoxy} benzamide; N-hydroxy-4-{ 2-[7-(phenoxymethyl)benzofuran-2-ylcarbonylam ino)ethoxy } benzamide; N-hydroxy-4-{2-[7-(methoxymethyl)benzofuran-2-ylcarbonylamino]ethoxy} benzamide; N-hydroxy-4-{2-[7-(morpholin-4-yimethyl)benzofuran-2-ylcarbonylamino]ethoxy} - benzamide; N-hydroxy-4-{ 2-[7-(N,N-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy}- benzamide; N-hydroxy-4-{ 3-[5-(methyl)benzothiophen-2-ylcarbonylamino]propoxy} -benzamide;
. 5 N-hydroxy-4-{ 3-[6-(methoxy)benzothiophen-2-ylcarbonylamino}propoxy} -benzamide;
) N-hydroxy-4-{3-[7-(methoxymethyl)benzo furan-2-ylcarbonylamino]propoxy} -benzamide; N-hydroxy-4-{ 3-[7-(phenoxymethyl)benzofuran-2-ylcarbonylamino]propoxy } -benzamide; N-hydroxy-4-{2-{5-(2-methoxyethoxy)benzofuran-2-ylcarbonylamino]-1 R-methyl ethoxy}benzamide;
N-hydroxy-4-(2R-benzofuran-2-ylcarbonylamino-3-methylthiopropoxy)benzamide; N-hydroxy-4-(2R-benzofuran-2-ylcarbonylamino-3-methylsulfonylpropoxy)benzamide; N-hydroxy-4-{2-[3 -(2-phenylethyl)benzofuran-2-ylcarbonylamino]ethoxy }benzamide; N-hydroxy-4-{2-{3-(N-methy!-N-benzylam inomethyl)benzofuran-2-ylcarbonylamino]- ethoxy} benzamide;
N-hydroxy-4-{2-[3-(N-methyl-N-2-phenylethylaminomethyl)benzofuran-2-ylcarbonylamino}- ethoxy }benzamide;
N-hydroxy-4-{ 2-[3-(3-hydroxypropylthiomethyl)benzofuran-2-ylcarbonylam ino}- ethoxy} benzamide; N-hydroxy-4-{2-[3-(3-hydroxypropylsulfinylmethyl)benzofuran-2-ylcarbonylamino]-
ethoxy}benzamide;
N-hydroxy-4-{2-[3-(3-hydroxypropylsul fonylmethyl)benzofuran-2-ylcarbonylaminoj- ethoxy} benzamide;
N-hydroxy-4-{2-[3-(N-methyl-N-2-indol-3-ylethylam inomethyl)benzofuran-2- ylcarbonylamino]-ethoxy } benzamide;
N-hydroxy-4-{2-[3-(2-(3-trifluoromethylpheny!)ethyl)benzofuran-2-ylcarbonylamino}- ethoxy} benzamide;
N-hydroxy-4-{2-[3-(2-(3 -trifluoromethoxyphenyl)ethyt)benzofuran-2-ylcarbonylamino}- ethoxy} benzamide; N-hydroxy-4-{ 2-[3-(N-hydroxyaminocarbonylmethylaminomethyl)benzofuran-2-
ylcarbonylaminojethoxy}benzamide; N-hydroxy-4-{2-[3-(2-carboxyethylaminomethy)benzofuran-2-ylcarbonylamino}- ethoxy} benzamide;
N-hydroxy-4-[2-(benzofuran-2-ylcarbonylamino)-1 RS-phenoxymethylethoxy }-benzamide; N-hydroxy-4-{ 2-[3-(3-hydroxypropoxymethyl)benzofuran-2-ylcarbonylamino]ethoxy} -
benzamide;
N-hydroxy-4-{2-[3-(2-fl uorophenoxymethyl)benzofuran-2-ylcarbonylamino]ethoxy}- benzamide,
«5 N-hydroxy-4-{2-[3-(3-fluorophenoxymethyl)benzofuran-2-ylcarbonylaminolethoxy} - benzamide; N-hydroxy-4-{2-[3-(4-fluorophenoxymethyl)benzofuran-2-ylcarbonylamino]ethoxy}- benzamide; N-hydroxy-4-{2-[3-(2 -methoxyethyloxymethyl)benzofuran-2-ylcarbonylamino] ethoxy}-
benzamide; N-hydroxy-4-{2-[3-(pyridin-4-yloxymethyl)benzofuran-2-ylcarbonylaminolethoxy} - benzamide;
N-hydroxy-4- {2-[3-(2.4 6-trifluorophenoxymethyl)benzofuran-2-ylearbonylamino]- ethoxy} benzamide;
N-hydroxy-4-{2-[3-(2-oxopyridin-1 -ylmethyl)benzofuran-2-ylcarbonylamino]ethoxy}- benzamide;
N-hydroxy-4-{ 2-[3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-ylcarbonylam ino}- ethoxy} benzamide; N-hydroxy-4-{2-[3-(4-imidazol-1 -ylphenoxymethyl)benzofuran-2-ylcarbonylamino]- ethoxy}benzamide; N-hydroxy-4-{2-[3-(4-[1.2.4]-triazin-1 -ylphenoxymethyl)benzofuran-2-ylcarbonyl- amino]ethoxy }benzamide; N-hydroxy-4-{2-[3-(pyrrolidin-1 -methy!)benzofuran-2-ylcarbonylamino]ethoxy} -benzamide; N-hydroxy-4-{2-[3-(piperidin-1 -methyl)benzofuran-2-ylcarbonylamino]ethoxy} -benzamide;
N-hydroxy-4-{2-[3-(4-trifluoromethylpiperidin-1-methyl)benzofuran-2-ylcarbonylamino}- ethoxy} benzamide;
N-hydroxy-4-{2-[3-(4-methylpiperazin-1 -methyl)benzofuran-2-ylcarbonylamino]}- ethoxy }benzamide; N-hydroxy-4-{ 2-[3-(3,3,3-trifluoropropyloxymethyl)benzofuran-2-ylcarbonylamino]-
ethoxy}benzamide; N-hydroxy-4-[2-(4-methylbenzofuran-2-ylcarbonylamino)-ethoxyJbenzamide; N-hydroxy-4-{2-[3-(4-fl uorophenylthiomethyl)benzofuran-2-ylcarbonylamino]- ethoxy} benzamide;
N-hydroxy-4-{ 2-[3-(4-fluorophenylsulfinylmethyl)benzofuran-2-ylcarbonylamino]-
ethoxy}benzamide; N-hydroxy-4-{2-[3-(4-fluorophenyisulfonylmethyl)benzofuran-2-ylcarbonylamino]- ethoxy} benzamide;
LS N-hydroxy-4-{25-[3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-ylcarbonylamino]-
) butoxy}benzamide; N-hydroxy-4-[2-(4-hydroxybenzofuran-2-ylcarbonylamino)ethoxybenzamide; N-hydroxy-4-[25-(5-chlorobenzofuran-2-ylcarbonylam ino)butoxy ]benzamide; ‘ N-hydroxy-4-[2-(5-chlorobenzofuran-2-ylcarbonylamino]- 1 R-methylethoxy]benzamide;
N-hydroxy-4-[2-(4-pyridin-3-ylmethyloxymethylbenzofuran-2-ylcarbonylamino)- ethoxy]benzamide; N-hydroxy-4-[2-(4-methoxybenzofuran-2-ylcarbonylamino)ethoxy]benzam ide; N-hydroxy-4-{2-[4-(2-methoxyethyloxy)benzofuran-2-ylcarbonylamino)ethoxy }-benzamide; N-hydroxy-4-[2-(4-pyridin-3-ylmethyloxybenzofuran-2-ylcarbonylamino)-ethoxy]benzamide;
N-hydroxy-4-[2-(4-methoxyindol-2-ylcarbonylamino)ethoxy]benzamide; N-hydroxy-4-{25-[3 -(2-methoxyethyloxymethyl)benzofuran-2-ylcarbonylamino]- butoxy}benzamide;
N-hydroxy-4-{ 2-[3-(2-methoxyethyloxymethyl)benzofuran-2-ylcarbonylamino]- 1R- methylethoxy } benzamide;
N-hydroxy-4-{2-[3-(N,N-diethylaminomethyl)benzofuran-2-ylcarbonylaminolethoxy} - benzamide;
N-hydroxy-4-{ 25-[5-(2-methoxyethyloxy)benzofuran-2-ylcarbonylam ino]butoxy}-benzamide; N-hydroxy-4-{ 2-(5-(tetrahydropyran-4-yloxy)benzofuran-2-ylcarbonylam inojethoxy}- benzamide; N-hydroxy-4-{2S-[5-(tetrahydropyran-4-yloxy)benzo furan-2-yicarbonylamino]butoxy}- benzamide; N-hydroxy-4- {2-[5-(tetrahydropyran-4-yloxy)benzofuran-2-ylcarbonylamino}- 1R- methylethoxy}benzamide; N-hydroxy-4-{2-[5-(2,2,2-trifluoroethyloxy)benzofuran-2-ylcarbonylamino]ethoxy} - benzamide; N-hydroxy-4-{2-[5-(2-pyrrolidin-1 -ylethyloxy)benzofuran-2-ylcarbonylaminolethoxy}- benzamide; N-hydroxy-4-{25-[5-(2-pyrrolidin-1 -ylethyloxy)benzofuran-2-ylcarbonylamino]butoxy}- benzamide; N-hydroxy-4-{2-[S-(2-pyrrolidin-1 _ylethyloxy)benzofuran-2-ylcarbonylamino}- 1R- methylethoxy } benzamide; N-hydroxy-4- {2-[5-(piperidin-4-yloxy)benzofuran-2-ylcarbonylaminolethoxy} -benzamide; N-hydroxy-4-[{2S-(benzofuran-2-ylcarbonylamino)-4-methylthiobutoxy]benzamide;
NE N-hydroxy-4-[28-(benzofuran-2-ylcarbonylamino)-4-methylsulfonylbutoxy]benzamide; N-hydroxy-3-[2-(biphen-ylcarbonylamino)-1R-methylethoxyJisoxazol-5-ylcarboxamide; N-hydroxy-3-[25-(biphen-4-ylcarbonylamino)butoxyJisoxazol-5-ylcarboxamide; N-hydroxy-3-[2-(benzofuran-2-ylcarbonylamino)ethoxylisoxazol-5-ylcarboxamide; N-hydroxy-3-[2-(trans-cinnamoylamino)ethoxyJisoxazol-5-ylcarboxamide;
N-hydroxy-3-[3-(4-(2-ethoxyphenyl)phenylcarbonylamino)propoxy]isoxazol-5-ylcarboxamide; N-hydroxy-3-[3-(biphen-3-yicarbonylamino)propoxylisoxazol-5-ylcarboxamide; N-hydroxy-3-[3-(biphen-4-ylcarbonylamino)propoxyJisoxazol-3-ylcarboxamide; N-hydroxy-3-[2-(naphth-2-ylcarbonylamino)ethoxylisoxazol-5-ylcarboxamide; N-hydroxy-3-[2-(3-methylbiphen-4-ylcarbonylamino)ethoxyJisoxazol-5-ylcarboxamide;
N-hydroxy-3-[2-(2’-ethoxylbiphen-4-ylcarbonylamino)ethoxylisoxazol-5-ylcarboxamide; N-hydroxy-3-[3-(3-methylbiphen-4-ylcarbonylamino)propoxylisoxazol-5-ylcarboxamide; N-hydroxy-3-[3-(4-phenylthiazol-2-ylcarbonylamino)propoxyJisoxazol-5-ylcarboxamide; N-hydroxy-3-[3-(naphth-2-ylcarbonylamino)propoxy]isoxazol-5-ylcarboxamide; N-hydroxy-3-[3-(naphth-1 -ylcarbonylamino)propoxyJisoxazol-5-ylcarboxamide;
N-hydroxy-3-{3-[2-(2-phenylethyl)phenylcarbonylamino]propoxy} isoxazol-5-ylcarboxamide; N-hydroxy-3-[2-(naphth-1 -ylcarbonylamino)ethoxyJisoxazol-5-ylcarboxamide; N-hydroxy-3-[25-(benzofuran-2-ylcarbonylamino)butoxylisoxazol-5-ylcarboxamide; N-hydroxy-3-[25-(biphen-3-ylcarbonylamino)butoxylisoxazol-5-ylcarboxamide; N-hydroxy-3-[2-(benzofuran-2-ylcarbonylamino)- 1 R-methylethoxy]isoxazol-5-yl-
carboxamide;
N-hydroxy-3-[2-(biphen-3-ylcarbonylamino)- 1 R-methylethoxyJisoxazol-5-yl-carboxamide; N-hydroxy-3-[2-(biphen-3-ylcarbonylamino)ethoxy]isoxazol-5-ylcarboxamide; N-hydroxy-3-[2-(biphen-4-ylcarbonylamino)ethoxyJisoxazol-5-ylcarboxamide; N-hydroxy-3-[2-(4-phenylthiazol-2-ylcarbonylamino)ethoxylisoxazol-5-ylcarboxamide;
N-hydroxy-3-{2-[2-(2-phenylethyl)phenylcarbonylamino]ethoxy}isoxazol-5-yl-carboxamide; N-hydroxy-3-[2-(biphen-2-ylcarbonylamino)ethoxyJisoxazol-5-ylcarboxamide; N-hydroxy-3-[3-(biphen-2-ylcarbonylamino)propoxy]isoxazol-5-ylcarboxamide; N-hydroxy-3-[25-(naphth-2-ylcarbonylamino)butoxylisoxazol-5-ylcarboxamide; N-hydroxy-3-[2S-(naphth-1-ylcarbonylamino)butoxyJisoxazol-5-ylcarboxamide;
N-hydroxy-3-[2-(naphth-2-ylcarbonylamino)-1 R-methylethoxyJisoxazol-5-yl-carboxamide; N-hydroxy-3-[2-(naphth-1-ylcarbonylamino)-1 R-methylethoxyJisoxazol-5-yl-carboxamide; N-hydroxy-3-[3-(benzofuran-2-ylcarbonylamino)propoxyJisoxazol-5-ylcarboxamide; N-hydroxy-3-[3-(trans-cinnamoylamino)propoxyJisoxazol-5-ylcarboxamide; and
- N-hydroxy-3-[2-(3-phenoxymethylbenzofuran-2-ylcarbonylamino)ethoxy lisoxazol-3-yl- carboxamide; or a pharmaceutically acceptable salt thereof.
24. A compound having the structure: 0 ~0© Cy TIO 0) H CONHOH or a pharmaceutically acceptable salt thereof.
25. A compound having the structure: (H3C)N 0) N NTC a DAG CONHOH or a pharmaceutically acceptable salt thereof.
26. A compound having the structure: 0 @ OQ H CONHOH or a pharmaceutically acceptable salt thereof.
27. A compound having the structure: \ SO, Cor 0) H CONHOH or a pharmaceutically acceptable salt thereof.
28. A compound having the structure: (0 0 A\ NTC o H CONHOH
: Y WO 2004/092115 PCT/US2004/010549 ’ or a pharmaceutically acceptable salt thereof.
29. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of the Claims 1-28 or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
30. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 24 or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
31. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 25 or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
32. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 26 or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
33. Use of a compound of any of the Claims 1-28 in the preparation of a medicament for treating a disease in an animal mediated by HDAC. :
34. The use of Claim 33 wherein the disease is cancer and the animal is a human.
35. The usec of Claim 34 wherein the cancer is AML or MML.
36. Use of a compound of any of the Claims 1-28 in the preparation of a medicament for treating cancer in an animal in combination with one or more compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, DNA methyltransferase inhibitor, or an angiogenesis inhibitor.
37. Use of a compound of any of the Claims 1-28 in the preparation of a medicament for treating cancer in an animal in combination with radiation therapy and optionally in the presence of one or more compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, DNA methyltransferase inhibitor, or an angiogenesis inhibitor.
38. An intermediate of Formula (II): : 146 RECTIFIED SHEET (RULE 91) ISA/EP Amended sheet: 12 May 2006
0 Ar —CoNRI-y—x—(ar) or® I) wherein: R* is hydrogen or alkyl; X is ~O-, -NR%-, or S(O), where n is 0-2 and R? is hydrogen or alkyl; Y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkyithio, alkylsulfinyl, alkysulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxyl, or optionally substituted phenoxy; Ar' is phenylene or heteroarylene wherein said Ar is optionally substituted with one or two groups independently selected from alkyl, halo, hydroxyl, alkoxy, haloalkoxy, or haloalkyl; R}is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl; and AP is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; or a salt thereof.
39. Use of a compound of any of the Claims 1-28 in the preparation of a medicament for treating hepatitis C in an animal.
40. Use of a compound of Claim 39 in the preparation of a medicament for treating hepatitis C in an animal.
41. A process of preparing a compound of Formula (I) as defined in claim 1 comprising; i) reacting a compound of Formula (III): 0 A CONRI— x(a) “r" (IID where R*! is hydroxy, alkoxy, halo, or succinimido ester with a hydroxylamine of formula NH:>OR™ where R” is hydrogen, alkyl, or an oxygen protecting group and X, Y, Ar', Ar? and R” are as defined in claim I; or (ii) treating a compound of Formula (IV): Q AP —CONR*— x(a om (Iv) where M" is an alkali metal with an acid; followed by treatment with NH,OR” where R” is hydrogen, alkyl, or an oxygen protecting group and X, Y, Ar', Ar and R® are as defined in claim 1; to give a compound of Formula (V): 147 RECTIFIED SHEET (RULE 91) ISA/EP Amended sheet: 12 May 2006
: > WO 2004/092115 PCT/US2004/010549 0] A? CONROY {ar NHOR" v) (ili) optionally removing R™ group in compound (V) to give a compound of Formula (I) as defined in claim 1 where R' is hydrogen and R” is as defined above; (iv) optionally forming an acid addition salt of the product formed in Step (i), (ii), or (iii) above; 0 (v) optionally forming free base of the product formed in Step (i), (ii), (iii), or (iv) above; or (vi) optionally modifying any of the X, Y, RY, R% R? Ar' and Ar? groups in the product formed in Step (i). (ii), (iii), (iv), or (v') above. : 148 RECTIFIED SHEET (RULE 91) ISA/EP Amended sheet: 12 May 2006
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WO2011021209A1 (en) * | 2009-07-07 | 2011-02-24 | Portsmouth Technologies Llc | Histone deacetylase inhibitors |
CN102775368B (en) * | 2011-05-10 | 2016-08-17 | 上海驺虞医药科技有限公司 | One class thiazole compound and its production and use |
SG2014014419A (en) * | 2011-09-13 | 2014-07-30 | Pharmacyclics Inc | Formulations of histone deacetylase inhibitor in combination with bendamustine and uses thereof |
KR20130047623A (en) * | 2011-10-28 | 2013-05-08 | 주식회사종근당 | Hydroxamate derivatives for hdac inhibitor, and the pharmaceutical composition comprising thereof |
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