US20170253596A2 - Ship1 modulators and methods related thereto - Google Patents
Ship1 modulators and methods related thereto Download PDFInfo
- Publication number
- US20170253596A2 US20170253596A2 US14/772,737 US201414772737A US2017253596A2 US 20170253596 A2 US20170253596 A2 US 20170253596A2 US 201414772737 A US201414772737 A US 201414772737A US 2017253596 A2 US2017253596 A2 US 2017253596A2
- Authority
- US
- United States
- Prior art keywords
- methyl
- inden
- optionally substituted
- hydroxymethyl
- methyleneoctahydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 100
- 101150080778 INPP5D gene Proteins 0.000 title 1
- 101100107199 Mus musculus Znf541 gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 750
- 239000000203 mixture Substances 0.000 claims abstract description 145
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 79
- 201000010099 disease Diseases 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 208000035475 disorder Diseases 0.000 claims abstract description 34
- 101000616502 Homo sapiens Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1 Proteins 0.000 claims abstract description 32
- 102100021797 Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1 Human genes 0.000 claims abstract description 32
- 239000001257 hydrogen Substances 0.000 claims description 295
- 229910052739 hydrogen Inorganic materials 0.000 claims description 295
- -1 2-benzimidazolyl Chemical group 0.000 claims description 222
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 214
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 134
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 134
- 125000000217 alkyl group Chemical group 0.000 claims description 115
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 84
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 81
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 81
- 125000000623 heterocyclic group Chemical group 0.000 claims description 70
- 125000001072 heteroaryl group Chemical group 0.000 claims description 68
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 65
- 125000001188 haloalkyl group Chemical group 0.000 claims description 63
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 59
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 59
- 150000002431 hydrogen Chemical group 0.000 claims description 56
- 125000002947 alkylene group Chemical group 0.000 claims description 53
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 45
- 125000003107 substituted aryl group Chemical group 0.000 claims description 39
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 37
- 241000124008 Mammalia Species 0.000 claims description 27
- 239000012453 solvate Substances 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- 208000027866 inflammatory disease Diseases 0.000 claims description 15
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 208000023275 Autoimmune disease Diseases 0.000 claims description 9
- WIEPZIUQSYFMHZ-FGDWFLNHSA-N (3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-1-methyl-2-(2-morpholin-4-ylethyl)cyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-ol Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2([C@H]([C@@H]1O)CCC2=C)C)CN1CCOCC1 WIEPZIUQSYFMHZ-FGDWFLNHSA-N 0.000 claims description 7
- FTIYHFDBOJTIBX-KSNBFHMFSA-N (3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-1-methyl-2-[2-(4-methylpiperazin-1-yl)ethyl]cyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-ol Chemical compound C1CN(C)CCN1CC[C@@H]1[C@]([C@@H]2[C@H]([C@H]3[C@](C(CC3)=C)(C)CC2)O)(C)CC[C@H](O)C1 FTIYHFDBOJTIBX-KSNBFHMFSA-N 0.000 claims description 7
- JZKHAERGEGFHPR-PTMNFMGBSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[[(3,5-dimethoxyphenyl)methylamino]methyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound COC1=CC(OC)=CC(CNC[C@@H]2[C@H](CC[C@]3(C)C(=C)CC[C@H]32)[C@]2(C)[C@H](C[C@@H](O)CC2)CO)=C1 JZKHAERGEGFHPR-PTMNFMGBSA-N 0.000 claims description 6
- CZOHHJQEEQJPCT-OXTFZXRHSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(2,3-dihydroindol-1-ylmethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CN2C4=CC=CC=C4CC2)CCC3=C)C)CC[C@H](O)C[C@@H]1CO CZOHHJQEEQJPCT-OXTFZXRHSA-N 0.000 claims description 5
- FZMMCZNIASYIKC-XYIAWKELSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(2-aminoethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CCN)CCC3=C)C)CC[C@H](O)C[C@@H]1CO FZMMCZNIASYIKC-XYIAWKELSA-N 0.000 claims description 5
- ZPWFTJKUVLGUGM-BVMLLJBZSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(aminomethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(aminomethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CN)CCC3=C)C)CC[C@H](O)C[C@@H]1CN ZPWFTJKUVLGUGM-BVMLLJBZSA-N 0.000 claims description 5
- IEDQWGVEKPIZFJ-BDJUGDQASA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(benzimidazol-1-ylmethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CN2C4=CC=CC=C4N=C2)CCC3=C)C)CC[C@H](O)C[C@@H]1CO IEDQWGVEKPIZFJ-BDJUGDQASA-N 0.000 claims description 5
- IAQLHWWXUPXBIQ-OXTFZXRHSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(indol-1-ylmethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CN2C4=CC=CC=C4C=C2)CCC3=C)C)CC[C@H](O)C[C@@H]1CO IAQLHWWXUPXBIQ-OXTFZXRHSA-N 0.000 claims description 5
- VLYGPZSJQPEMOE-CQCNWBIYSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[(1h-benzimidazol-2-ylmethylamino)methyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CNCC=2NC4=CC=CC=C4N=2)CCC3=C)C)CC[C@H](O)C[C@@H]1CO VLYGPZSJQPEMOE-CQCNWBIYSA-N 0.000 claims description 5
- CYNKJCNDXTZUQS-RWMUPHSVSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[(6-aminopurin-9-yl)methyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CN2C4=NC=NC(N)=C4N=C2)CCC3=C)C)CC[C@H](O)C[C@@H]1CO CYNKJCNDXTZUQS-RWMUPHSVSA-N 0.000 claims description 5
- DBQDEPPQRFWGTB-BDJUGDQASA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[[(2,2-difluoro-1,3-benzodioxol-5-yl)methylamino]methyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CNCC=2C=C4OC(F)(F)OC4=CC=2)CCC3=C)C)CC[C@H](O)C[C@@H]1CO DBQDEPPQRFWGTB-BDJUGDQASA-N 0.000 claims description 5
- IKAAVRKJMGWOOI-SVKCIREXSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[[(2-fluoro-4-methoxyphenyl)methylamino]methyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound FC1=CC(OC)=CC=C1CNC[C@@H]1[C@@H]([C@]2(C)[C@H](C[C@@H](O)CC2)CO)CC[C@]2(C)C(=C)CC[C@H]21 IKAAVRKJMGWOOI-SVKCIREXSA-N 0.000 claims description 5
- HYWLURVHWUPSHT-OXTFZXRHSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[[(2-fluoro-4-methylphenyl)methylamino]methyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound FC1=CC(C)=CC=C1CNC[C@@H]1[C@@H]([C@]2(C)[C@H](C[C@@H](O)CC2)CO)CC[C@]2(C)C(=C)CC[C@H]21 HYWLURVHWUPSHT-OXTFZXRHSA-N 0.000 claims description 5
- ASFIFFKWWSRPGM-NUYOPYHDSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[[(4-fluoro-2-methoxyphenyl)methylamino]methyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound COC1=CC(F)=CC=C1CNC[C@@H]1[C@@H]([C@]2(C)[C@H](C[C@@H](O)CC2)CO)CC[C@]2(C)C(=C)CC[C@H]21 ASFIFFKWWSRPGM-NUYOPYHDSA-N 0.000 claims description 5
- TYBHPAKMPPZUDN-WVLKTHQZSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[[(4-fluoro-2-methylphenyl)methylamino]methyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound CC1=CC(F)=CC=C1CNC[C@@H]1[C@@H]([C@]2(C)[C@H](C[C@@H](O)CC2)CO)CC[C@]2(C)C(=C)CC[C@H]21 TYBHPAKMPPZUDN-WVLKTHQZSA-N 0.000 claims description 5
- ZYOWCMXFQCAHGE-LZYXPVFYSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[[(4-fluorophenyl)methylamino]methyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NCC1=CC=C(F)C=C1 ZYOWCMXFQCAHGE-LZYXPVFYSA-N 0.000 claims description 5
- GHEFURZIIBXUEB-CRDHRBBASA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[[(4-methoxyphenyl)methylamino]methyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C1=CC(OC)=CC=C1CNC[C@@H]1[C@@H]([C@]2(C)[C@H](C[C@@H](O)CC2)CO)CC[C@]2(C)C(=C)CC[C@H]21 GHEFURZIIBXUEB-CRDHRBBASA-N 0.000 claims description 5
- SGSFNHDJUCXEDD-BHMKJSQQSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-7a-methyl-1-methylidene-4-(1,2,4-triazol-1-ylmethyl)-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)N1C=NC=N1 SGSFNHDJUCXEDD-BHMKJSQQSA-N 0.000 claims description 5
- STNGTNLSBPQTOH-NBXBSOGZSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-7a-methyl-1-methylidene-4-(pyrazol-1-ylmethyl)-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)N1C=CC=N1 STNGTNLSBPQTOH-NBXBSOGZSA-N 0.000 claims description 5
- TZBXVULPVWSROB-HTQRCUPRSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-7a-methyl-1-methylidene-4-[(pyridin-4-ylmethylamino)methyl]-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NCC1=CC=NC=C1 TZBXVULPVWSROB-HTQRCUPRSA-N 0.000 claims description 5
- XVUHLDUHVXSEEH-FXFYXNLOSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-7a-methyl-1-methylidene-4-[[(2-methylphenyl)methylamino]methyl]-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound CC1=CC=CC=C1CNC[C@@H]1[C@@H]([C@]2(C)[C@H](C[C@@H](O)CC2)CO)CC[C@]2(C)C(=C)CC[C@H]21 XVUHLDUHVXSEEH-FXFYXNLOSA-N 0.000 claims description 5
- MRLJJTNRQSVWTQ-FXFYXNLOSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-7a-methyl-1-methylidene-4-[[(3-methylphenyl)methylamino]methyl]-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound CC1=CC=CC(CNC[C@@H]2[C@H](CC[C@]3(C)C(=C)CC[C@H]32)[C@]2(C)[C@H](C[C@@H](O)CC2)CO)=C1 MRLJJTNRQSVWTQ-FXFYXNLOSA-N 0.000 claims description 5
- NUXUPTLOINXZJJ-FXFYXNLOSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-7a-methyl-1-methylidene-4-[[(4-methylphenyl)methylamino]methyl]-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C1=CC(C)=CC=C1CNC[C@@H]1[C@@H]([C@]2(C)[C@H](C[C@@H](O)CC2)CO)CC[C@]2(C)C(=C)CC[C@H]21 NUXUPTLOINXZJJ-FXFYXNLOSA-N 0.000 claims description 5
- WNYFUKYJAVDCJJ-LZYXPVFYSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-7a-methyl-1-methylidene-4-[[(4-nitrophenyl)methylamino]methyl]-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NCC1=CC=C([N+]([O-])=O)C=C1 WNYFUKYJAVDCJJ-LZYXPVFYSA-N 0.000 claims description 5
- OYPQEHTXAKWYGL-GWATUHHTSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-7a-methyl-1-methylidene-4-[[[4-(trifluoromethyl)phenyl]methylamino]methyl]-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NCC1=CC=C(C(F)(F)F)C=C1 OYPQEHTXAKWYGL-GWATUHHTSA-N 0.000 claims description 5
- CDFWYGZTQYHTIW-YEGZKXCGSA-N (1s,3s,4r)-4-[(3as,4s,5s,7as)-4-[2-(1,3-benzodioxol-5-ylmethylamino)ethyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-4-methylcyclohexane-1,3-diol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CCNCC=2C=C4OCOC4=CC=2)CCC3=C)C)CC[C@H](O)C[C@@H]1O CDFWYGZTQYHTIW-YEGZKXCGSA-N 0.000 claims description 5
- HAJVKJRYLSAKEU-MHWSWGBGSA-N (1s,3s,4r)-4-[(3as,4s,5s,7as)-4-[2-[(4-methoxyphenyl)methylamino]ethyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-4-methylcyclohexane-1,3-diol Chemical compound C1=CC(OC)=CC=C1CNCC[C@@H]1[C@@H]([C@]2(C)[C@H](C[C@@H](O)CC2)O)CC[C@]2(C)C(=C)CC[C@H]21 HAJVKJRYLSAKEU-MHWSWGBGSA-N 0.000 claims description 5
- PROMYOWVFQXINJ-FXSSSKFRSA-N (3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-1-methyl-2-[2-(1,2,4-triazol-1-yl)ethyl]cyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-ol Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2([C@H]([C@@H]1O)CCC2=C)C)CN1C=NC=N1 PROMYOWVFQXINJ-FXSSSKFRSA-N 0.000 claims description 5
- FKRFHSUGEUANNC-AHPVPSLJSA-N 2-[[(4r,5s)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-1,1-dimethyl-2,3,4,5,6,7-hexahydroinden-4-yl]methyl]guanidine;hydrochloride Chemical compound Cl.C[C@]1([C@H]2CCC3=C([C@@H]2CN=C(N)N)CCC3(C)C)CC[C@H](O)C[C@@H]1CO FKRFHSUGEUANNC-AHPVPSLJSA-N 0.000 claims description 5
- MPRSZWXXTUMTFU-VNSXJAELSA-N [4-[[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methylamino]methyl]phenyl]-phenylmethanone Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NCC(C=C1)=CC=C1C(=O)C1=CC=CC=C1 MPRSZWXXTUMTFU-VNSXJAELSA-N 0.000 claims description 5
- HHJNDQLSRLQWQZ-XUZFWGHHSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-2,2-dimethylpropanamide Chemical compound C[C@]1([C@H]2CC[C@]3(C)C(=C)CC[C@H]3[C@@H]2CNC(=O)C(C)(C)C)CC[C@H](O)C[C@@H]1CO HHJNDQLSRLQWQZ-XUZFWGHHSA-N 0.000 claims description 5
- JMESYOSSRZSLTG-QTTJWYMNSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-2-methylpropanamide Chemical compound C[C@]1([C@H]2CC[C@]3(C)C(=C)CC[C@H]3[C@@H]2CNC(=O)C(C)C)CC[C@H](O)C[C@@H]1CO JMESYOSSRZSLTG-QTTJWYMNSA-N 0.000 claims description 5
- IOVKJNLMUZINRM-CRUHNJGSSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]benzamide Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)C1=CC=CC=C1 IOVKJNLMUZINRM-CRUHNJGSSA-N 0.000 claims description 5
- FRMKOOYJCQZFIL-QTTJWYMNSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]butanamide Chemical compound C[C@]1([C@H]2CC[C@]3(C)C(=C)CC[C@H]3[C@@H]2CNC(=O)CCC)CC[C@H](O)C[C@@H]1CO FRMKOOYJCQZFIL-QTTJWYMNSA-N 0.000 claims description 5
- ARBKJBPDZVBGPP-MLGCJPHJSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]naphthalene-2-carboxamide Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CNC(=O)C=2C=C4C=CC=CC4=CC=2)CCC3=C)C)CC[C@H](O)C[C@@H]1CO ARBKJBPDZVBGPP-MLGCJPHJSA-N 0.000 claims description 5
- NSBDFOFSVNYSHY-CWOJUHNUSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]pentanamide Chemical compound C[C@]1([C@H]2CC[C@]3(C)C(=C)CC[C@H]3[C@@H]2CNC(=O)CCCC)CC[C@H](O)C[C@@H]1CO NSBDFOFSVNYSHY-CWOJUHNUSA-N 0.000 claims description 5
- QGTMBETVNBTSPB-AJWQKBIASA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]propanamide Chemical compound C[C@]1([C@H]2CC[C@]3(C)C(=C)CC[C@H]3[C@@H]2CNC(=O)CC)CC[C@H](O)C[C@@H]1CO QGTMBETVNBTSPB-AJWQKBIASA-N 0.000 claims description 5
- DHOQXDQAKBCRBZ-KCVUTVIESA-N n-[[(4r,5s)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-1,1-dimethyl-2,3,4,5,6,7-hexahydroinden-4-yl]methyl]acetamide Chemical compound C[C@]1([C@@H]2[C@H](C3=C(C(CC3)(C)C)CC2)CNC(=O)C)CC[C@H](O)C[C@@H]1CO DHOQXDQAKBCRBZ-KCVUTVIESA-N 0.000 claims description 5
- DYELGLMXFUWDGZ-RYCUZSDNSA-N n-[[(4r,5s)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-1,1-dimethyl-2,3,4,5,6,7-hexahydroinden-4-yl]methyl]benzamide Chemical compound C([C@@H]1[C@H](CCC2=C1CCC2(C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)C1=CC=CC=C1 DYELGLMXFUWDGZ-RYCUZSDNSA-N 0.000 claims description 5
- 230000001613 neoplastic effect Effects 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 230000002062 proliferating effect Effects 0.000 claims description 5
- WCMVPMDOSHQETJ-RIGOZCIQSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[[2-(4-methoxyphenyl)ethylamino]methyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C1=CC(OC)=CC=C1CCNC[C@@H]1[C@@H]([C@]2(C)[C@H](C[C@@H](O)CC2)CO)CC[C@]2(C)C(=C)CC[C@H]21 WCMVPMDOSHQETJ-RIGOZCIQSA-N 0.000 claims description 4
- LJZFESIMWARYNF-CTBYUEFUSA-N (1s,3s,4r)-4-[(3as,4s,5s,7as)-4-[2-[bis[(4-methoxyphenyl)methyl]amino]ethyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-4-methylcyclohexane-1,3-diol Chemical compound C1=CC(OC)=CC=C1CN(CC=1C=CC(OC)=CC=1)CC[C@@H]1[C@@H]([C@]2(C)[C@H](C[C@@H](O)CC2)O)CC[C@]2(C)C(=C)CC[C@H]21 LJZFESIMWARYNF-CTBYUEFUSA-N 0.000 claims description 4
- XYJGFRBJQZXGGP-MZANLXKOSA-N (1s,3s,4r)-4-[(4r,5s)-1,1-dimethyl-4-(methylaminomethyl)-2,3,4,5,6,7-hexahydroinden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@@H]2[C@H](C3=C(C(CC3)(C)C)CC2)CNC)CC[C@H](O)C[C@@H]1CO XYJGFRBJQZXGGP-MZANLXKOSA-N 0.000 claims description 4
- TUKLLXZQUDLMOY-WDMROBEHSA-N (1s,3s,4r)-4-[(4r,5s)-1,1-dimethyl-4-[(1h-pyrrol-2-ylmethylamino)methyl]-2,3,4,5,6,7-hexahydroinden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C([C@@H]1[C@H](CCC2=C1CCC2(C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NCC1=CC=CN1 TUKLLXZQUDLMOY-WDMROBEHSA-N 0.000 claims description 4
- XLPKDGOCQUNRKL-FGDWFLNHSA-N (3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-1-methyl-2-(2-pyrrolidin-1-ylethyl)cyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-ol Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2([C@H]([C@@H]1O)CCC2=C)C)CN1CCCC1 XLPKDGOCQUNRKL-FGDWFLNHSA-N 0.000 claims description 4
- KLPIWUZDVWWERA-RSRKLVJMSA-N (3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-2-(2-imidazol-1-ylethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-ol Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2([C@H]([C@@H]1O)CCC2=C)C)CN1C=CN=C1 KLPIWUZDVWWERA-RSRKLVJMSA-N 0.000 claims description 4
- OCOMOUXJGACAJH-NRTRYIRGSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-2,2,2-trifluoroacetamide Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CNC(=O)C(F)(F)F)CCC3=C)C)CC[C@H](O)C[C@@H]1CO OCOMOUXJGACAJH-NRTRYIRGSA-N 0.000 claims description 4
- AHRHVQRKTQHXIP-MZANLXKOSA-N n-[[(4r,5s)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-1,1-dimethyl-2,3,4,5,6,7-hexahydroinden-4-yl]methyl]methanesulfonamide Chemical compound C[C@]1([C@H]2CCC3=C([C@@H]2CNS(C)(=O)=O)CCC3(C)C)CC[C@H](O)C[C@@H]1CO AHRHVQRKTQHXIP-MZANLXKOSA-N 0.000 claims description 4
- RGBSGNXUCAWAAY-PXLZQGEESA-N (1s,3s,4r)-3-(hydroxymethyl)-4-[(4r,5s)-4-(hydroxymethyl)-1,1-dimethyl-4,5,6,7-tetrahydroinden-5-yl]-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@H]2CCC3=C([C@@H]2CO)C=CC3(C)C)CC[C@H](O)C[C@@H]1CO RGBSGNXUCAWAAY-PXLZQGEESA-N 0.000 claims description 3
- IKSYEYYFYKWLFU-BVMLLJBZSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(aminomethyl)-1,7a-dimethyl-3,3a,4,5,6,7-hexahydroinden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@@H]2[C@@H](CN)[C@@H]3CC=C([C@]3(CC2)C)C)CC[C@H](O)C[C@@H]1CO IKSYEYYFYKWLFU-BVMLLJBZSA-N 0.000 claims description 3
- RUJWCQHVLNLVGK-BVMLLJBZSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(hydroxymethyl)-7a-methyl-1-methylidene-4,5,6,7-tetrahydro-3ah-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CO)C=CC3=C)C)CC[C@H](O)C[C@@H]1CO RUJWCQHVLNLVGK-BVMLLJBZSA-N 0.000 claims description 3
- NSHGRCIFCKBYMH-PTMNFMGBSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[(3,5-dimethoxyphenyl)methoxymethyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound COC1=CC(OC)=CC(COC[C@@H]2[C@H](CC[C@]3(C)C(=C)CC[C@H]32)[C@]2(C)[C@H](C[C@@H](O)CC2)CO)=C1 NSHGRCIFCKBYMH-PTMNFMGBSA-N 0.000 claims description 3
- DDQXKBXIVYZCDX-XYIAWKELSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[(methoxyamino)methyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@H]2CC[C@]3(C)C(=C)CC[C@H]3[C@@H]2CNOC)CC[C@H](O)C[C@@H]1CO DDQXKBXIVYZCDX-XYIAWKELSA-N 0.000 claims description 3
- AIRSDKKAGAORTR-GWATUHHTSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-7a-methyl-1-methylidene-4-(phenylmethoxymethyl)-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)OCC1=CC=CC=C1 AIRSDKKAGAORTR-GWATUHHTSA-N 0.000 claims description 3
- KOYOREYUQUIGDU-GAHAAGPZSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-7a-methyl-1-methylidene-4-(pyridin-2-ylmethoxymethyl)-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)OCC1=CC=CC=N1 KOYOREYUQUIGDU-GAHAAGPZSA-N 0.000 claims description 3
- LCSYMDYKBQSMDJ-RYAQRBBLSA-N (1s,3s,4r)-4-[(3as,4s,5s,7as)-4-(2-hydroxyethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-4-methyl-3-pyridin-2-yloxycyclohexan-1-ol Chemical compound O([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2([C@H]([C@@H]1CCO)CCC2=C)C)C1=CC=CC=N1 LCSYMDYKBQSMDJ-RYAQRBBLSA-N 0.000 claims description 3
- HQFVWQWKDRHGLP-ZOWVHQNKSA-N (1s,3s,4r)-4-[(4r,5s)-4-[(cyclopropylmethylamino)methyl]-1,1-dimethyl-2,3,4,5,6,7-hexahydroinden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C([C@@H]1[C@H](CCC2=C1CCC2(C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NCC1CC1 HQFVWQWKDRHGLP-ZOWVHQNKSA-N 0.000 claims description 3
- IYYUZRZBDVXFKM-LZAHKMPMSA-N (2s,3as,6s,7r,7as)-7-(aminomethyl)-6-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-3a-methyl-3-methylidene-2,4,5,6,7,7a-hexahydro-1h-inden-2-ol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CN)C[C@H](O)C3=C)C)CC[C@H](O)C[C@@H]1CO IYYUZRZBDVXFKM-LZAHKMPMSA-N 0.000 claims description 3
- RJVXZYFRGXGCHD-FAMHBGTDSA-N (3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-1-methyl-2-(2-pyrazin-2-yloxyethyl)cyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-ol Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2([C@H]([C@@H]1O)CCC2=C)C)COC1=CN=CC=N1 RJVXZYFRGXGCHD-FAMHBGTDSA-N 0.000 claims description 3
- CCDXPDUETQYKAV-RSRKLVJMSA-N (3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-1-methyl-2-(2-pyrazol-1-ylethyl)cyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-ol Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2([C@H]([C@@H]1O)CCC2=C)C)CN1C=CC=N1 CCDXPDUETQYKAV-RSRKLVJMSA-N 0.000 claims description 3
- NBTHZYBJTYCHLS-RQZQBBPWSA-N (3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-1-methyl-2-(2-pyridin-2-yloxyethyl)cyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-ol Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2([C@H]([C@@H]1O)CCC2=C)C)COC1=CC=CC=N1 NBTHZYBJTYCHLS-RQZQBBPWSA-N 0.000 claims description 3
- JQUDFECKIKMNNV-PEQAPWOXSA-N (3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-1-methyl-2-(2-pyrimidin-2-yloxyethyl)cyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-ol Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2([C@H]([C@@H]1O)CCC2=C)C)COC1=NC=CC=N1 JQUDFECKIKMNNV-PEQAPWOXSA-N 0.000 claims description 3
- RIDSJHUKAJUPCW-FGDWFLNHSA-N (3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-1-methyl-2-(2-pyrrol-1-ylethyl)cyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-ol Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2([C@H]([C@@H]1O)CCC2=C)C)CN1C=CC=C1 RIDSJHUKAJUPCW-FGDWFLNHSA-N 0.000 claims description 3
- JXUYUZCMMDBDBL-OPPBUZLHSA-N (3as,4r,5s,7as)-5-[(1r,2r,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-indene-4-carboxylic acid Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2C(O)=O)CCC3=C)C)CC[C@H](O)C[C@H]1CO JXUYUZCMMDBDBL-OPPBUZLHSA-N 0.000 claims description 3
- PUMMXMNRMREKHH-OXTFZXRHSA-N 1-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-3-benzylurea Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)NCC1=CC=CC=C1 PUMMXMNRMREKHH-OXTFZXRHSA-N 0.000 claims description 3
- MXYXRLQPPHPFKF-AJWQKBIASA-N 1-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-3-ethylurea Chemical compound C[C@]1([C@H]2CC[C@]3(C)C(=C)CC[C@H]3[C@@H]2CNC(=O)NCC)CC[C@H](O)C[C@@H]1CO MXYXRLQPPHPFKF-AJWQKBIASA-N 0.000 claims description 3
- YEPMRKZIUCKWTN-KRDOCUMOSA-N 1-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-3-methylthiourea Chemical compound C[C@]1([C@H]2CC[C@]3(C)C(=C)CC[C@H]3[C@@H]2CNC(=S)NC)CC[C@H](O)C[C@@H]1CO YEPMRKZIUCKWTN-KRDOCUMOSA-N 0.000 claims description 3
- KTTVICJCIKHXQN-RSNXEXBNSA-N 1-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-3-phenylurea Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)NC1=CC=CC=C1 KTTVICJCIKHXQN-RSNXEXBNSA-N 0.000 claims description 3
- PKPHRZFCKMNKTB-VPAFNXHNSA-N 3-[(1r,2s,5s)-2-[(3ar,4r,5r,7as)-4-hydroxy-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-5-hydroxy-2-methylcyclohexyl]propanoic acid Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2O)CCC3=C)C)CC[C@H](O)C[C@H]1CCC(O)=O PKPHRZFCKMNKTB-VPAFNXHNSA-N 0.000 claims description 3
- GNDPDRDRBLUBCN-FPYHTYPQSA-N 3-[(1s,2s,5s)-2-[(3ar,4r,5r,7as)-4-hydroxy-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-5-hydroxy-2-methylcyclohexyl]propanamide Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2O)CCC3=C)C)CC[C@H](O)C[C@@H]1CCC(N)=O GNDPDRDRBLUBCN-FPYHTYPQSA-N 0.000 claims description 3
- DZQUMFLVWMEJTD-BVMLLJBZSA-N [(1s,2r,5s)-2-[(3as,4r,5s,7as)-4-(hydroxymethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-5-amino-2-methylcyclohexyl]methanol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CO)CCC3=C)C)CC[C@H](N)C[C@@H]1CO DZQUMFLVWMEJTD-BVMLLJBZSA-N 0.000 claims description 3
- KJYZQOOJCUOQQB-XYIAWKELSA-N [(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methylcyanamide Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CNC#N)CCC3=C)C)CC[C@H](O)C[C@@H]1CO KJYZQOOJCUOQQB-XYIAWKELSA-N 0.000 claims description 3
- SBAIOEBOLIKUNN-MMRZTJODSA-N n-[2-[(3as,4s,5s,7as)-5-[(1r,2s,4s)-2,4-dihydroxy-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]ethyl]-1,3-benzodioxole-5-carboxamide Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CCNC(=O)C=2C=C4OCOC4=CC=2)CCC3=C)C)CC[C@H](O)C[C@@H]1O SBAIOEBOLIKUNN-MMRZTJODSA-N 0.000 claims description 3
- YSIAGOUKESIBEP-VTMRPTRBSA-N n-[[(1s,2s,5s)-2-[(3ar,4r,5r,7as)-4-hydroxy-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-5-hydroxy-2-methylcyclohexyl]methyl]-1,3-benzodioxole-5-carboxamide Chemical compound C1=C2OCOC2=CC(C(=O)NC[C@H]2C[C@@H](O)CC[C@]2(C)[C@H]2CC[C@]3([C@H]([C@@H]2O)CCC3=C)C)=C1 YSIAGOUKESIBEP-VTMRPTRBSA-N 0.000 claims description 3
- AYJMNHODGWEHHB-JLKNQZHWSA-N n-[[(3as,4r,5s,7ar)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-3,3a,4,5,6,7-hexahydroinden-4-yl]methyl]pentanamide Chemical compound C[C@]1([C@H]2CC[C@]3(C)C=CC[C@H]3[C@@H]2CNC(=O)CCCC)CC[C@H](O)C[C@@H]1CO AYJMNHODGWEHHB-JLKNQZHWSA-N 0.000 claims description 3
- QXOCLLHIYVERPH-CQCNWBIYSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-1,3-benzodioxole-5-carboxamide Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CNC(=O)C=2C=C4OCOC4=CC=2)CCC3=C)C)CC[C@H](O)C[C@@H]1CO QXOCLLHIYVERPH-CQCNWBIYSA-N 0.000 claims description 3
- ARANDTCIHPXOIU-XUZFWGHHSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-1h-pyrrole-2-carboxamide Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)C1=CC=CN1 ARANDTCIHPXOIU-XUZFWGHHSA-N 0.000 claims description 3
- ODHZLJRUQYFFAN-SVKCIREXSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-2-methylbenzamide Chemical compound CC1=CC=CC=C1C(=O)NC[C@@H]1[C@@H]([C@]2(C)[C@H](C[C@@H](O)CC2)CO)CC[C@]2(C)C(=C)CC[C@H]21 ODHZLJRUQYFFAN-SVKCIREXSA-N 0.000 claims description 3
- CWEIKAYRALLUMQ-OXTFZXRHSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-3-methylbenzamide Chemical compound CC1=CC=CC(C(=O)NC[C@@H]2[C@H](CC[C@]3(C)C(=C)CC[C@H]32)[C@]2(C)[C@H](C[C@@H](O)CC2)CO)=C1 CWEIKAYRALLUMQ-OXTFZXRHSA-N 0.000 claims description 3
- ZHTOCEVAWPIQPR-CRUHNJGSSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-4-(trifluoromethyl)benzamide Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)C1=CC=C(C(F)(F)F)C=C1 ZHTOCEVAWPIQPR-CRUHNJGSSA-N 0.000 claims description 3
- ILCTYIJTSGEKJZ-RSNXEXBNSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-4-fluorobenzamide Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)C1=CC=C(F)C=C1 ILCTYIJTSGEKJZ-RSNXEXBNSA-N 0.000 claims description 3
- KXMSQJVTLZISRJ-SVKCIREXSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-4-methoxybenzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NC[C@@H]1[C@@H]([C@]2(C)[C@H](C[C@@H](O)CC2)CO)CC[C@]2(C)C(=C)CC[C@H]21 KXMSQJVTLZISRJ-SVKCIREXSA-N 0.000 claims description 3
- QBYWGLAEOGCYSY-OXTFZXRHSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-4-methylbenzamide Chemical compound C1=CC(C)=CC=C1C(=O)NC[C@@H]1[C@@H]([C@]2(C)[C@H](C[C@@H](O)CC2)CO)CC[C@]2(C)C(=C)CC[C@H]21 QBYWGLAEOGCYSY-OXTFZXRHSA-N 0.000 claims description 3
- SRPMPVXNBKGZQM-CRUHNJGSSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]cyclohexanecarboxamide Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)C1CCCCC1 SRPMPVXNBKGZQM-CRUHNJGSSA-N 0.000 claims description 3
- RNCAHXTVLISQGN-QTTJWYMNSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]cyclopropanecarboxamide Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)C1CC1 RNCAHXTVLISQGN-QTTJWYMNSA-N 0.000 claims description 3
- YTTKKYURUHZQRG-XUZFWGHHSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]furan-2-carboxamide Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)C1=CC=CO1 YTTKKYURUHZQRG-XUZFWGHHSA-N 0.000 claims description 3
- CYUGEIFEVDAQOF-XUZFWGHHSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]pyrazine-2-carboxamide Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)C1=CN=CC=N1 CYUGEIFEVDAQOF-XUZFWGHHSA-N 0.000 claims description 3
- JQJZPQXXRAJIAC-DCMIECQESA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]pyridine-2-carboxamide Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)C1=CC=CC=N1 JQJZPQXXRAJIAC-DCMIECQESA-N 0.000 claims description 3
- JKRZZPGKSBRAFV-RWWDNORZSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]pyridine-3-carboxamide Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)C1=CC=CN=C1 JKRZZPGKSBRAFV-RWWDNORZSA-N 0.000 claims description 3
- XQNNGTXEVOEFKG-RWWDNORZSA-N n-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]pyridine-4-carboxamide Chemical compound C([C@@H]1[C@H](CC[C@]2([C@H]1CCC2=C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)C1=CC=NC=C1 XQNNGTXEVOEFKG-RWWDNORZSA-N 0.000 claims description 3
- GXIBDCOALPCNAF-CWOJUHNUSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(hydroxymethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-4-methyl-3-(pyridin-2-yloxymethyl)cyclohexan-1-ol Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2([C@H]([C@@H]1CO)CCC2=C)C)OC1=CC=CC=N1 GXIBDCOALPCNAF-CWOJUHNUSA-N 0.000 claims description 2
- BGUSTWOQGRIEAB-NRTRYIRGSA-N 2-[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]acetamide Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CC(N)=O)CCC3=C)C)CC[C@H](O)C[C@@H]1CO BGUSTWOQGRIEAB-NRTRYIRGSA-N 0.000 claims description 2
- DXQPEBADTVWSSP-XYIAWKELSA-N 2-[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]acetonitrile Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CC#N)CCC3=C)C)CC[C@H](O)C[C@@H]1CO DXQPEBADTVWSSP-XYIAWKELSA-N 0.000 claims description 2
- IYZMLXNTDRFEAS-YGIASRBBSA-N 3-[(1s,2s,5s)-2-[(3ar,4r,5r,7as)-4-hydroxy-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-5-hydroxy-2-methylcyclohexyl]propanenitrile Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2O)CCC3=C)C)CC[C@H](O)C[C@@H]1CCC#N IYZMLXNTDRFEAS-YGIASRBBSA-N 0.000 claims description 2
- NXEGHKWSVPBXSJ-UGPWVVPWSA-N [(1s,3s,4r)-4-[(1s,3as,4s,5s,7ar)-4-(aminomethyl)-1-ethyl-7a-methyl-1,2,3,3a,4,5,6,7-octahydroinden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexyl] acetate Chemical compound C[C@]1([C@@H]2[C@@H](CN)[C@@H]3CC[C@@H]([C@]3(CC2)C)CC)CC[C@H](OC(C)=O)C[C@@H]1CO NXEGHKWSVPBXSJ-UGPWVVPWSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 8
- 230000008901 benefit Effects 0.000 abstract description 7
- 239000003937 drug carrier Substances 0.000 abstract description 6
- 241001465754 Metazoa Species 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 312
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 268
- 239000000243 solution Substances 0.000 description 211
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 158
- 235000019439 ethyl acetate Nutrition 0.000 description 133
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 122
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 118
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 112
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 110
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 95
- 238000004587 chromatography analysis Methods 0.000 description 81
- 239000000741 silica gel Substances 0.000 description 79
- 229910002027 silica gel Inorganic materials 0.000 description 79
- 238000006243 chemical reaction Methods 0.000 description 72
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 66
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 63
- 229910052786 argon Inorganic materials 0.000 description 59
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 56
- 230000015572 biosynthetic process Effects 0.000 description 56
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 55
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 55
- 238000003786 synthesis reaction Methods 0.000 description 55
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 48
- 238000005160 1H NMR spectroscopy Methods 0.000 description 47
- 239000012267 brine Substances 0.000 description 47
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 47
- 239000007787 solid Substances 0.000 description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- 125000004093 cyano group Chemical group *C#N 0.000 description 38
- 239000006260 foam Substances 0.000 description 38
- 239000000010 aprotic solvent Substances 0.000 description 35
- 239000012044 organic layer Substances 0.000 description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 34
- 125000003118 aryl group Chemical group 0.000 description 32
- 229910052757 nitrogen Inorganic materials 0.000 description 31
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 30
- 125000000753 cycloalkyl group Chemical group 0.000 description 29
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 24
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 24
- 239000012279 sodium borohydride Substances 0.000 description 23
- 229910000033 sodium borohydride Inorganic materials 0.000 description 23
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 21
- 238000002360 preparation method Methods 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- 229920006395 saturated elastomer Polymers 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- 239000003153 chemical reaction reagent Substances 0.000 description 18
- 239000003921 oil Substances 0.000 description 18
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 17
- MDEJTPWQNNMAQF-BVMLLJBZSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(aminomethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CN)CCC3=C)C)CC[C@H](O)C[C@@H]1CO MDEJTPWQNNMAQF-BVMLLJBZSA-N 0.000 description 16
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 229940002612 prodrug Drugs 0.000 description 16
- 239000000651 prodrug Substances 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 15
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- 238000010992 reflux Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 11
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 9
- 150000003254 radicals Chemical group 0.000 description 9
- 238000010561 standard procedure Methods 0.000 description 9
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- RQQIRMLGKSPXSE-WIPMOJCBSA-N [1-acetyloxy-2-[[(2s,3r,5s,6s)-2,6-dihydroxy-3,4,5-triphosphonooxycyclohexyl]oxy-hydroxyphosphoryl]oxyethyl] acetate Chemical compound CC(=O)OC(OC(C)=O)COP(O)(=O)OC1[C@H](O)[C@H](OP(O)(O)=O)C(OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H]1O RQQIRMLGKSPXSE-WIPMOJCBSA-N 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- 239000012458 free base Substances 0.000 description 8
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 239000001301 oxygen Chemical group 0.000 description 8
- 239000003586 protic polar solvent Substances 0.000 description 8
- CQIBMEIJDDUKHP-BAHZVNHDSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(aminomethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol;acetic acid Chemical compound CC(O)=O.C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CN)CCC3=C)C)CC[C@H](O)C[C@@H]1CO CQIBMEIJDDUKHP-BAHZVNHDSA-N 0.000 description 7
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 125000004043 oxo group Chemical group O=* 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- 229910020284 Na2SO4.10H2O Inorganic materials 0.000 description 6
- 108091007960 PI3Ks Proteins 0.000 description 6
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 6
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 6
- 150000005840 aryl radicals Chemical class 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 238000010533 azeotropic distillation Methods 0.000 description 6
- 125000001246 bromo group Chemical group Br* 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000011369 resultant mixture Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 5
- PQPVAYIIVFQSOM-JCODBEKUSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[(1,3-benzodioxol-5-ylmethylamino)methyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CNCC=2C=C4OCOC4=CC=2)CCC3=C)C)CC[C@H](O)C[C@@H]1CO PQPVAYIIVFQSOM-JCODBEKUSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 208000005615 Interstitial Cystitis Diseases 0.000 description 4
- LGDSHSYDSCRFAB-UHFFFAOYSA-N Methyl isothiocyanate Chemical compound CN=C=S LGDSHSYDSCRFAB-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 4
- XDXFTLOKKBDNSK-OQLFRTGZSA-N [(1s,3s,4r)-4-[(3as,4r,5s,7as)-7a-methyl-1-methylidene-4-(1,2,4-triazol-1-ylmethyl)-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methylcyclohexyl] acetate Chemical compound CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](OC(=O)C)CC[C@]1(C)[C@@H]1[C@@H](CN2N=CN=C2)[C@H](CCC2=C)[C@]2(C)CC1 XDXFTLOKKBDNSK-OQLFRTGZSA-N 0.000 description 4
- PSUMEKNAIYSEMY-ILYROKBPSA-N [(1s,3s,4r)-4-[(3as,4r,5s,7as)-7a-methyl-1-methylidene-4-(methylsulfonyloxymethyl)-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methylcyclohexyl] acetate Chemical compound CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](OC(=O)C)CC[C@]1(C)[C@@H]1[C@@H](COS(C)(=O)=O)[C@H](CCC2=C)[C@]2(C)CC1 PSUMEKNAIYSEMY-ILYROKBPSA-N 0.000 description 4
- 150000001540 azides Chemical class 0.000 description 4
- 235000010233 benzoic acid Nutrition 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 235000011167 hydrochloric acid Nutrition 0.000 description 4
- 102000006029 inositol monophosphatase Human genes 0.000 description 4
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 4
- 201000005962 mycosis fungoides Diseases 0.000 description 4
- 108700003805 myo-inositol-1 (or 4)-monophosphatase Proteins 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 4
- 238000006772 olefination reaction Methods 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- INOACIMUKYNFHN-ZYRLFZHTSA-N (1s,3s,4r)-4-[(3as,4s,5s,7as)-4-(2-aminoethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-4-methylcyclohexane-1,3-diol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CCN)CCC3=C)C)CC[C@H](O)C[C@@H]1O INOACIMUKYNFHN-ZYRLFZHTSA-N 0.000 description 3
- NKMHRJAFJSIIKV-PXLZQGEESA-N (1s,3s,4r)-4-[(4r,5s)-4-(aminomethyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydroinden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@H]2CCC3=C([C@@H]2CN)CCC3(C)C)CC[C@H](O)C[C@@H]1CO NKMHRJAFJSIIKV-PXLZQGEESA-N 0.000 description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 3
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 101100189356 Mus musculus Papolb gene Proteins 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 206010047115 Vasculitis Diseases 0.000 description 3
- GBVWHMMUUYTKBB-FGDWFLNHSA-N [(1s,3r,4s)-4-[(3ar,4r,5r,7as)-4-acetyloxy-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-4-methyl-3-(2-oxoethyl)cyclohexyl] acetate Chemical compound O=CC[C@H]1C[C@@H](OC(=O)C)CC[C@]1(C)[C@@H]1[C@@H](OC(C)=O)[C@H](CCC2=C)[C@]2(C)CC1 GBVWHMMUUYTKBB-FGDWFLNHSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 3
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthene Chemical group C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000006268 reductive amination reaction Methods 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 201000005671 spondyloarthropathy Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000011593 sulfur Chemical group 0.000 description 3
- 229910052717 sulfur Chemical group 0.000 description 3
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 3
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 3
- QJTBPOYLABUMPU-CRUHNJGSSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(2-aminoethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methylcyclohexan-1-ol Chemical compound CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H](CCN)[C@H](CCC2=C)[C@]2(C)CC1 QJTBPOYLABUMPU-CRUHNJGSSA-N 0.000 description 2
- IZEMKUVNGMDXLB-ILYROKBPSA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-7a-methyl-1-methylidene-4-(pyrazol-1-ylmethyl)-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methylcyclohexan-1-ol Chemical compound CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H](CN2N=CC=C2)[C@H](CCC2=C)[C@]2(C)CC1 IZEMKUVNGMDXLB-ILYROKBPSA-N 0.000 description 2
- BFUYCRVQVXXIEM-IVQUIZJISA-N (1s,3s,4r)-4-[(3as,4r,5s,7as)-7a-methyl-1-methylidene-4-[[[1-(2-trimethylsilylethoxymethyl)benzimidazol-2-yl]methylamino]methyl]-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@H]2CC[C@]3([C@H]([C@@H]2CNCC=2N(C4=CC=CC=C4N=2)COCC[Si](C)(C)C)CCC3=C)C)CC[C@H](O)C[C@@H]1CO BFUYCRVQVXXIEM-IVQUIZJISA-N 0.000 description 2
- KCSUBYIMPOWBDK-OQWSMYQMSA-N (2r,6s,7r)-6-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7-(hydroxymethyl)-3,3-dimethyl-1,2,4,5,6,7-hexahydroinden-2-ol Chemical compound C[C@]1([C@H]2CCC3=C([C@@H]2CO)C[C@@H](O)C3(C)C)CC[C@H](O)C[C@@H]1CO KCSUBYIMPOWBDK-OQWSMYQMSA-N 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- SCBWKQTVQDJNNV-UHFFFAOYSA-N 1-(2-trimethylsilylethoxymethyl)benzimidazole-2-carbaldehyde Chemical compound C1=CC=C2N(COCC[Si](C)(C)C)C(C=O)=NC2=C1 SCBWKQTVQDJNNV-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical group C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- UGRVYFQFDZRNMQ-UHFFFAOYSA-N 2,4,6-tri(propan-2-yl)benzenesulfonohydrazide Chemical compound CC(C)C1=CC(C(C)C)=C(S(=O)(=O)NN)C(C(C)C)=C1 UGRVYFQFDZRNMQ-UHFFFAOYSA-N 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- AUWDOZOUJWEPBA-UHFFFAOYSA-N 2-(4-methoxyphenyl)ethanol Chemical compound COC1=CC=C(CCO)C=C1 AUWDOZOUJWEPBA-UHFFFAOYSA-N 0.000 description 2
- QCXJEYYXVJIFCE-UHFFFAOYSA-N 4-acetamidobenzoic acid Chemical compound CC(=O)NC1=CC=C(C(O)=O)C=C1 QCXJEYYXVJIFCE-UHFFFAOYSA-N 0.000 description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- KPALKTUTKPPVHQ-IPJWDSEGSA-N 9-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]purin-6-amine Chemical compound CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]1(C)[C@@H]1[C@@H](CN2C3=NC=NC(N)=C3N=C2)[C@H](CCC2=C)[C@]2(C)CC1 KPALKTUTKPPVHQ-IPJWDSEGSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 208000016557 Acute basophilic leukemia Diseases 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 2
- 208000032671 Allergic granulomatous angiitis Diseases 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 208000006344 Churg-Strauss Syndrome Diseases 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 208000019707 Cryoglobulinemic vasculitis Diseases 0.000 description 2
- 206010011796 Cystitis interstitial Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010012438 Dermatitis atopic Diseases 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 2
- 206010013774 Dry eye Diseases 0.000 description 2
- 208000018428 Eosinophilic granulomatosis with polyangiitis Diseases 0.000 description 2
- 208000001640 Fibromyalgia Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 2
- 208000018522 Gastrointestinal disease Diseases 0.000 description 2
- 208000007465 Giant cell arteritis Diseases 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 2
- 206010019668 Hepatic fibrosis Diseases 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 101000688606 Homo sapiens Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 2
- 206010023421 Kidney fibrosis Diseases 0.000 description 2
- 208000032514 Leukocytoclastic vasculitis Diseases 0.000 description 2
- 229910010084 LiAlH4 Inorganic materials 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 2
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 2
- 102100024242 Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 Human genes 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 108091008611 Protein Kinase B Proteins 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 2
- 208000033464 Reiter syndrome Diseases 0.000 description 2
- 206010039085 Rhinitis allergic Diseases 0.000 description 2
- 208000009359 Sezary Syndrome Diseases 0.000 description 2
- 208000021388 Sezary disease Diseases 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- 201000002661 Spondylitis Diseases 0.000 description 2
- 238000003800 Staudinger reaction Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 201000009594 Systemic Scleroderma Diseases 0.000 description 2
- 206010042953 Systemic sclerosis Diseases 0.000 description 2
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 2
- 208000005485 Thrombocytosis Diseases 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 206010046851 Uveitis Diseases 0.000 description 2
- 238000006959 Williamson synthesis reaction Methods 0.000 description 2
- ZENPNRCIFLWSFN-MSFYPIBLSA-N [(1s,2r,5s)-2-[(3as,4r,5s,7as)-4-(benzimidazol-1-ylmethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-5-acetyloxy-2-methylcyclohexyl]methyl acetate Chemical compound CC(=O)OC[C@H]1C[C@@H](OC(C)=O)CC[C@]1(C)[C@@H]1[C@@H](CN2C3=CC=CC=C3N=C2)[C@H](CCC2=C)[C@]2(C)CC1 ZENPNRCIFLWSFN-MSFYPIBLSA-N 0.000 description 2
- POANZZSFEPQESF-LFGFVFIHSA-N [(1s,2r,5s)-2-[(4r,5s)-4-(acetamidomethyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydroinden-5-yl]-5-acetyloxy-2-methylcyclohexyl]methyl acetate Chemical compound C[C@]1([C@@H]2[C@H](C3=C(C(CC3)(C)C)CC2)CNC(=O)C)CC[C@H](OC(C)=O)C[C@@H]1COC(C)=O POANZZSFEPQESF-LFGFVFIHSA-N 0.000 description 2
- ULTHESPOOLEUBY-BHMKJSQQSA-N [(1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(azidomethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(azidomethyl)-4-methylcyclohexyl] acetate Chemical compound [N-]=[N+]=NC[C@H]1C[C@@H](OC(=O)C)CC[C@]1(C)[C@@H]1[C@@H](CN=[N+]=[N-])[C@H](CCC2=C)[C@]2(C)CC1 ULTHESPOOLEUBY-BHMKJSQQSA-N 0.000 description 2
- YFJIIYAOLVOVGO-NBXBSOGZSA-N [(1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(azidomethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-4-methyl-3-(methylsulfonyloxymethyl)cyclohexyl] acetate Chemical compound CS(=O)(=O)OC[C@H]1C[C@@H](OC(=O)C)CC[C@]1(C)[C@@H]1[C@@H](CN=[N+]=[N-])[C@H](CCC2=C)[C@]2(C)CC1 YFJIIYAOLVOVGO-NBXBSOGZSA-N 0.000 description 2
- CBRSSGQCKOGTNW-ILYROKBPSA-N [(1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(cyanomethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methylcyclohexyl] acetate Chemical compound CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](OC(=O)C)CC[C@]1(C)[C@@H]1[C@@H](CC#N)[C@H](CCC2=C)[C@]2(C)CC1 CBRSSGQCKOGTNW-ILYROKBPSA-N 0.000 description 2
- RFUGIVNUIUFZNW-BHMKJSQQSA-N [(1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(hydroxymethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexyl] acetate Chemical compound OC[C@H]1C[C@@H](OC(=O)C)CC[C@]1(C)[C@@H]1[C@@H](CO)[C@H](CCC2=C)[C@]2(C)CC1 RFUGIVNUIUFZNW-BHMKJSQQSA-N 0.000 description 2
- YPVQOFZKVDJMFF-OXTFZXRHSA-N [(1s,3s,4r)-4-[(3as,4r,5s,7as)-4-(hydroxymethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methylcyclohexyl] acetate Chemical compound CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](OC(=O)C)CC[C@]1(C)[C@@H]1[C@@H](CO)[C@H](CCC2=C)[C@]2(C)CC1 YPVQOFZKVDJMFF-OXTFZXRHSA-N 0.000 description 2
- UFPRMORUUKMARA-FGDWFLNHSA-N [(1s,3s,4s)-4-[(3ar,4r,5r,7as)-4-acetyloxy-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(2-hydroxyethyl)-4-methylcyclohexyl] acetate Chemical compound OCC[C@H]1C[C@@H](OC(=O)C)CC[C@]1(C)[C@@H]1[C@@H](OC(C)=O)[C@H](CCC2=C)[C@]2(C)CC1 UFPRMORUUKMARA-FGDWFLNHSA-N 0.000 description 2
- SCOCSGTYUGJOLJ-KOTJOQQYSA-N [(1s,3s,4s)-4-[(3ar,4r,5r,7as)-4-acetyloxy-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-methylcyclohexyl] acetate Chemical compound C([C@@H]1[C@](C)(CC[C@@H](C1)OC(=O)C)[C@@H]1[C@H]([C@H]2[C@](C(CC2)=C)(C)CC1)OC(C)=O)CO[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 SCOCSGTYUGJOLJ-KOTJOQQYSA-N 0.000 description 2
- OBZOXBNLYJTABJ-XPAVSRBOSA-N [(1s,3s,4s)-4-[(3ar,4r,5r,7as)-4-acetyloxy-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-4-methyl-3-(2-morpholin-4-ylethyl)cyclohexyl] acetate Chemical compound C([C@@H]1[C@](C)(CC[C@@H](C1)OC(=O)C)[C@@H]1[C@H]([C@H]2[C@](C(CC2)=C)(C)CC1)OC(C)=O)CN1CCOCC1 OBZOXBNLYJTABJ-XPAVSRBOSA-N 0.000 description 2
- STBAEWMHADNADT-VVYSMVTKSA-N [(1s,3s,4s)-4-[(3ar,4r,5r,7as)-4-acetyloxy-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-4-methyl-3-[2-(4-methylpiperazin-1-yl)ethyl]cyclohexyl] acetate Chemical compound C1CN(C)CCN1CC[C@@H]1[C@]([C@@H]2[C@H]([C@H]3[C@](C(CC3)=C)(C)CC2)OC(C)=O)(C)CC[C@H](OC(C)=O)C1 STBAEWMHADNADT-VVYSMVTKSA-N 0.000 description 2
- RXXYOUIEOHTHCZ-GXQOCQDZSA-N [(3ar,4r,5r,7as)-5-[(1s,2s,4s)-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-hydroxy-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl] acetate Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2(C)C(=C)CC[C@H]2[C@@H]1OC(=O)C)CO[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 RXXYOUIEOHTHCZ-GXQOCQDZSA-N 0.000 description 2
- ZMHRTTOAEWQRFE-LWBXLDEBSA-N [(3ar,4r,5r,7as)-5-[(1s,2s,4s)-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-hydroxy-1-methylcyclohexyl]-7a-methyl-1-oxo-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl] acetate Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2(C)C(=O)CC[C@H]2[C@@H]1OC(=O)C)CO[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 ZMHRTTOAEWQRFE-LWBXLDEBSA-N 0.000 description 2
- RQNCNQHSOXKREV-MDDQDPDHSA-N [(3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-2-(2-methylsulfonyloxyethyl)cyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl] acetate Chemical compound O([C@H]1CC[C@]([C@H](C1)CCOS(C)(=O)=O)(C)[C@H]1CC[C@]2(C)C(=C)CC[C@H]2[C@@H]1OC(=O)C)[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 RQNCNQHSOXKREV-MDDQDPDHSA-N 0.000 description 2
- DFIWSIVUKAHWJR-GXQOCQDZSA-N [(3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-[tert-butyl(diphenyl)silyl]oxy-2-(2-hydroxyethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl] acetate Chemical compound O([C@H]1CC[C@]([C@H](C1)CCO)(C)[C@H]1CC[C@]2(C)C(=C)CC[C@H]2[C@@H]1OC(=O)C)[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 DFIWSIVUKAHWJR-GXQOCQDZSA-N 0.000 description 2
- DYTDIVABHYDRNX-LWBXLDEBSA-N [(3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-[tert-butyl(diphenyl)silyl]oxy-2-(2-hydroxyethyl)-1-methylcyclohexyl]-7a-methyl-1-oxo-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl] acetate Chemical compound O([C@H]1CC[C@]([C@H](C1)CCO)(C)[C@H]1CC[C@]2(C)C(=O)CC[C@H]2[C@@H]1OC(=O)C)[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 DYTDIVABHYDRNX-LWBXLDEBSA-N 0.000 description 2
- WNKWTCCHOVMOOZ-RDELXNOOSA-N [(3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-[tert-butyl(diphenyl)silyl]oxy-2-(2-imidazol-1-ylethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl] acetate Chemical compound C([C@H]1C[C@H](CC[C@]1(C)[C@H]1CC[C@]2(C)C(=C)CC[C@H]2[C@@H]1OC(=O)C)O[Si](C=1C=CC=CC=1)(C=1C=CC=CC=1)C(C)(C)C)CN1C=CN=C1 WNKWTCCHOVMOOZ-RDELXNOOSA-N 0.000 description 2
- WAQAHJRGSOHVQY-KXOHBEHESA-N [(3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-1-methyl-2-(2-morpholin-4-ylethyl)cyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl] acetate Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2(C)C(=C)CC[C@H]2[C@@H]1OC(=O)C)CN1CCOCC1 WAQAHJRGSOHVQY-KXOHBEHESA-N 0.000 description 2
- FJDCSOPLIVYAOH-KXOHBEHESA-N [(3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-1-methyl-2-(2-pyrrolidin-1-ylethyl)cyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl] acetate Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2(C)C(=C)CC[C@H]2[C@@H]1OC(=O)C)CN1CCCC1 FJDCSOPLIVYAOH-KXOHBEHESA-N 0.000 description 2
- JVVPJEJWLRKZIJ-XEYKCJAPSA-N [(3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-1-methyl-2-(2-pyrrolidin-1-ylethyl)cyclohexyl]-7a-methyl-1-oxo-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl] acetate Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2(C)C(=O)CC[C@H]2[C@@H]1OC(=O)C)CN1CCCC1 JVVPJEJWLRKZIJ-XEYKCJAPSA-N 0.000 description 2
- QNWRCZQQNGSFPW-FGDWFLNHSA-N [(3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-1-methyl-2-[2-(1,2,4-triazol-1-yl)ethyl]cyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl] acetate Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2(C)C(=C)CC[C@H]2[C@@H]1OC(=O)C)CN1C=NC=N1 QNWRCZQQNGSFPW-FGDWFLNHSA-N 0.000 description 2
- SCQFTPINMJERAZ-ONCXAFAASA-N [(3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-1-methyl-2-[2-(1,2,4-triazol-1-yl)ethyl]cyclohexyl]-7a-methyl-1-oxo-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl] acetate Chemical compound C([C@H]1C[C@@H](O)CC[C@]1(C)[C@H]1CC[C@]2(C)C(=O)CC[C@H]2[C@@H]1OC(=O)C)CN1C=NC=N1 SCQFTPINMJERAZ-ONCXAFAASA-N 0.000 description 2
- MCHNCHLCYKHXDE-LCNYHSBXSA-N [(3ar,4r,5r,7as)-5-[(1s,2s,4s)-4-hydroxy-1-methyl-2-[2-(4-methylpiperazin-1-yl)ethyl]cyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl] acetate Chemical compound C1CN(C)CCN1CC[C@@H]1[C@]([C@@H]2[C@H]([C@H]3[C@](C(CC3)=C)(C)CC2)OC(C)=O)(C)CC[C@H](O)C1 MCHNCHLCYKHXDE-LCNYHSBXSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 208000002205 allergic conjunctivitis Diseases 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 201000010105 allergic rhinitis Diseases 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical group C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 208000024998 atopic conjunctivitis Diseases 0.000 description 2
- 201000008937 atopic dermatitis Diseases 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical group C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- WDECIBYCCFPHNR-UHFFFAOYSA-N chrysene Chemical group C1=CC=CC2=CC=C3C4=CC=CC=C4C=CC3=C21 WDECIBYCCFPHNR-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 208000010643 digestive system disease Diseases 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 230000002500 effect on skin Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 2
- 208000018685 gastrointestinal system disease Diseases 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical group C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- OVWYEQOVUDKZNU-UHFFFAOYSA-N m-tolualdehyde Chemical compound CC1=CC=CC(C=O)=C1 OVWYEQOVUDKZNU-UHFFFAOYSA-N 0.000 description 2
- GPSDUZXPYCFOSQ-UHFFFAOYSA-N m-toluic acid Chemical compound CC1=CC=CC(C(O)=O)=C1 GPSDUZXPYCFOSQ-UHFFFAOYSA-N 0.000 description 2
- 208000008585 mastocytosis Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- MQWCXKGKQLNYQG-UHFFFAOYSA-N methyl cyclohexan-4-ol Natural products CC1CCC(O)CC1 MQWCXKGKQLNYQG-UHFFFAOYSA-N 0.000 description 2
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 2
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 2
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 2
- FFBLMLRQAKGTJN-VQDLLJBESA-N pelorol Chemical compound CC1(C)CCC[C@]2(C)[C@H]3CC(C(O)=C(O)C=C4C(=O)OC)=C4[C@]3(C)CC[C@H]21 FFBLMLRQAKGTJN-VQDLLJBESA-N 0.000 description 2
- FFBLMLRQAKGTJN-UHFFFAOYSA-N perolol Natural products CC1(C)CCCC2(C)C3CC(C(O)=C(O)C=C4C(=O)OC)=C4C3(C)CCC21 FFBLMLRQAKGTJN-UHFFFAOYSA-N 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical group C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229940081310 piperonal Drugs 0.000 description 2
- 201000006292 polyarteritis nodosa Diseases 0.000 description 2
- 238000012877 positron emission topography Methods 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical group C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 208000002574 reactive arthritis Diseases 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000010410 reperfusion Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
- QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 206010043207 temporal arteritis Diseases 0.000 description 2
- BTEYALZUUDLTLD-MKHRICLXSA-N tert-butyl n-[n'-[[(3as,4r,5s,7as)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-4-yl]methyl]-n-[(2-methylpropan-2-yl)oxycarbonyl]carbamimidoyl]carbamate Chemical compound C[C@]1([C@H]2CC[C@]3(C)C(=C)CC[C@H]3[C@@H]2CN=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC[C@H](O)C[C@@H]1CO BTEYALZUUDLTLD-MKHRICLXSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 2
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- ASZBROXKXBKBJR-LWSMQNBSSA-N (1s,3s,4r)-4-[(1s,3as,4s,5s,7ar)-4-(aminomethyl)-1-ethyl-7a-methyl-1,2,3,3a,4,5,6,7-octahydroinden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@@H]2[C@@H](CN)[C@@H]3CC[C@@H]([C@]3(CC2)C)CC)CC[C@H](O)C[C@@H]1CO ASZBROXKXBKBJR-LWSMQNBSSA-N 0.000 description 1
- AKVJGRFAOYIPJQ-KCVUTVIESA-N (1s,3s,4r)-4-[(4r,5s)-4-[(dimethylamino)methyl]-1,1-dimethyl-2,3,4,5,6,7-hexahydroinden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C[C@]1([C@@H]2[C@H](C3=C(C(CC3)(C)C)CC2)CN(C)C)CC[C@H](O)C[C@@H]1CO AKVJGRFAOYIPJQ-KCVUTVIESA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 125000005988 1,1-dioxo-thiomorpholinyl group Chemical group 0.000 description 1
- HKWJHKSHEWVOSS-OMDJCSNQSA-N 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4-bisphosphate) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCC)COP(O)(=O)O[C@H]1[C@H](O)[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H]1O HKWJHKSHEWVOSS-OMDJCSNQSA-N 0.000 description 1
- 125000005877 1,4-benzodioxanyl group Chemical group 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- BTHIGJGJAPYFSJ-UHFFFAOYSA-N 1-(bromomethyl)-3,5-dimethoxybenzene Chemical compound COC1=CC(CBr)=CC(OC)=C1 BTHIGJGJAPYFSJ-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- 125000005987 1-oxo-thiomorpholinyl group Chemical group 0.000 description 1
- CNWINRVXAYPOMW-FCNJXWMTSA-N 1-stearoyl-2-arachidonoyl-sn-glycero-3-phospho-1D-myo-inositol 4,5-biphosphate Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)O[C@H](COC(=O)CCCCCCCCCCCCCCCCC)COP(O)(=O)O[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H]1O CNWINRVXAYPOMW-FCNJXWMTSA-N 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- GGERGLKEDUUSAP-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbaldehyde Chemical compound C1=C(C=O)C=C2OC(F)(F)OC2=C1 GGERGLKEDUUSAP-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- UNWQNFJBBWXFBG-UHFFFAOYSA-N 2-fluoro-4-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(F)=C1 UNWQNFJBBWXFBG-UHFFFAOYSA-N 0.000 description 1
- MVDRIMBGRZBWPE-UHFFFAOYSA-N 2-fluoro-4-methylbenzaldehyde Chemical compound CC1=CC=C(C=O)C(F)=C1 MVDRIMBGRZBWPE-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- UOBYKYZJUGYBDK-UHFFFAOYSA-N 2-naphthoic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CC=C21 UOBYKYZJUGYBDK-UHFFFAOYSA-N 0.000 description 1
- 125000006088 2-oxoazepinyl group Chemical group 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 1
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- NPAXPTHCUCUHPT-UHFFFAOYSA-N 3,4,7,8-tetramethyl-1,10-phenanthroline Chemical compound CC1=CN=C2C3=NC=C(C)C(C)=C3C=CC2=C1C NPAXPTHCUCUHPT-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- HHUVYTNEKZGITJ-UHFFFAOYSA-N 3-benzoyl-2-methylbenzonitrile Chemical group C(#N)C=1C(=C(C(=O)C2=CC=CC=C2)C=CC1)C HHUVYTNEKZGITJ-UHFFFAOYSA-N 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- BEOBZEOPTQQELP-UHFFFAOYSA-N 4-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=C(C=O)C=C1 BEOBZEOPTQQELP-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- PTKRQIRPNNIORO-UHFFFAOYSA-N 4-fluoro-2-methoxybenzaldehyde Chemical compound COC1=CC(F)=CC=C1C=O PTKRQIRPNNIORO-UHFFFAOYSA-N 0.000 description 1
- ADCFIKGEGWFWEA-UHFFFAOYSA-N 4-fluoro-2-methylbenzaldehyde Chemical compound CC1=CC(F)=CC=C1C=O ADCFIKGEGWFWEA-UHFFFAOYSA-N 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 101710081722 Antitrypsin Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- QIDRDVCOHOEZKI-NKPVOWJYSA-N C(C)(C)(C)[Si](O[C@H]1CC[C@@]2([C@H]3CC[C@@]4(C5(CC[C@H]4[C@@H]3C(C[C@H]2C1)=O)OCCO5)C)C)(C5=CC=CC=C5)C5=CC=CC=C5 Chemical compound C(C)(C)(C)[Si](O[C@H]1CC[C@@]2([C@H]3CC[C@@]4(C5(CC[C@H]4[C@@H]3C(C[C@H]2C1)=O)OCCO5)C)C)(C5=CC=CC=C5)C5=CC=CC=C5 QIDRDVCOHOEZKI-NKPVOWJYSA-N 0.000 description 1
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 241000098128 Dactylospongia elegans Species 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 108010021472 Fc gamma receptor IIB Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000010995 Pleckstrin homology domains Human genes 0.000 description 1
- 108050001185 Pleckstrin homology domains Proteins 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 102000014400 SH2 domains Human genes 0.000 description 1
- 108050003452 SH2 domains Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- SLGBZMMZGDRARJ-UHFFFAOYSA-N Triphenylene Chemical group C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C2=C1 SLGBZMMZGDRARJ-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- VIHMIFUFAPLSTR-KCVUTVIESA-N [(1s,3s,4r)-3-(hydroxymethyl)-4-[(4r,5s)-4-(methanesulfonamidomethyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydroinden-5-yl]-4-methylcyclohexyl] methanesulfonate Chemical compound C[C@]1([C@H]2CCC3=C([C@@H]2CNS(C)(=O)=O)CCC3(C)C)CC[C@H](OS(C)(=O)=O)C[C@@H]1CO VIHMIFUFAPLSTR-KCVUTVIESA-N 0.000 description 1
- KMPDAAOOMONMLD-HTQRCUPRSA-N [(1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[(cyclopropylmethylamino)methyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexyl] acetate Chemical compound OC[C@H]1C[C@@H](OC(=O)C)CC[C@]1(C)[C@@H]1[C@@H](CNCC2CC2)[C@H](CCC2=C)[C@]2(C)CC1 KMPDAAOOMONMLD-HTQRCUPRSA-N 0.000 description 1
- JJQZSDSVLRZOKT-HYLAMMOOSA-N [(1s,3s,4r)-4-[(3as,4r,5s,7as)-4-[(dimethylamino)methyl]-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexyl] acetate Chemical compound C[C@]1([C@H]2CC[C@]3(C)C(=C)CC[C@H]3[C@@H]2CN(C)C)CC[C@H](OC(C)=O)C[C@@H]1CO JJQZSDSVLRZOKT-HYLAMMOOSA-N 0.000 description 1
- WSTFPJHBDGEDLE-LZYXPVFYSA-N [(1s,3s,4r)-4-[(3as,4r,5s,7as)-7a-methyl-1-methylidene-4-[(1h-pyrrol-2-ylmethylamino)methyl]-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexyl] acetate Chemical compound OC[C@H]1C[C@@H](OC(=O)C)CC[C@]1(C)[C@@H]1[C@@H](CNCC=2NC=CC=2)[C@H](CCC2=C)[C@]2(C)CC1 WSTFPJHBDGEDLE-LZYXPVFYSA-N 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- LVKGPFSNRKAXGV-GDLCRWSOSA-N [(3'ar,4'r,5'r,7'as)-5'-[(1s,2s,4s)-4-hydroxy-2-(2-hydroxyethyl)-1-methylcyclohexyl]-7'a-methylspiro[1,3-dioxolane-2,1'-3,3a,4,5,6,7-hexahydro-2h-indene]-4'-yl] acetate Chemical compound C([C@H]1[C@@H]([C@H](CC[C@@]11C)[C@]2(C)[C@H](C[C@@H](O)CC2)CCO)OC(=O)C)CC21OCCO2 LVKGPFSNRKAXGV-GDLCRWSOSA-N 0.000 description 1
- RYULULVJWLRDQH-UHFFFAOYSA-N [4-(bromomethyl)phenyl]-phenylmethanone Chemical compound C1=CC(CBr)=CC=C1C(=O)C1=CC=CC=C1 RYULULVJWLRDQH-UHFFFAOYSA-N 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- KYIKRXIYLAGAKQ-UHFFFAOYSA-N abcn Chemical compound C1CCCCC1(C#N)N=NC1(C#N)CCCCC1 KYIKRXIYLAGAKQ-UHFFFAOYSA-N 0.000 description 1
- 231100000230 acceptable toxicity Toxicity 0.000 description 1
- JDPAVWAQGBGGHD-UHFFFAOYSA-N aceanthrylene Chemical group C1=CC=C2C(C=CC3=CC=C4)=C3C4=CC2=C1 JDPAVWAQGBGGHD-UHFFFAOYSA-N 0.000 description 1
- 125000004054 acenaphthylenyl group Chemical group C1(=CC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- SQFPKRNUGBRTAR-UHFFFAOYSA-N acephenanthrylene Chemical group C1=CC(C=C2)=C3C2=CC2=CC=CC=C2C3=C1 SQFPKRNUGBRTAR-UHFFFAOYSA-N 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- HXGDTGSAIMULJN-UHFFFAOYSA-N acetnaphthylene Chemical group C1=CC(C=C2)=C3C2=CC=CC3=C1 HXGDTGSAIMULJN-UHFFFAOYSA-N 0.000 description 1
- 239000012345 acetylating agent Substances 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 229960000250 adipic acid Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 208000006682 alpha 1-Antitrypsin Deficiency Diseases 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001475 anti-trypsic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- KNNXFYIMEYKHBZ-UHFFFAOYSA-N as-indacene Chemical group C1=CC2=CC=CC2=C2C=CC=C21 KNNXFYIMEYKHBZ-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- GHQPBDDZGPAVJP-UHFFFAOYSA-N azanium;methanol;hydroxide Chemical compound N.O.OC GHQPBDDZGPAVJP-UHFFFAOYSA-N 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005870 benzindolyl group Chemical group 0.000 description 1
- 125000005875 benzo[b][1,4]dioxepinyl group Chemical group 0.000 description 1
- 125000000928 benzodioxinyl group Chemical group O1C(=COC2=C1C=CC=C2)* 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000005878 benzonaphthofuranyl group Chemical group 0.000 description 1
- 125000005872 benzooxazolyl group Chemical group 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- KHAVLLBUVKBTBG-UHFFFAOYSA-N caproleic acid Natural products OC(=O)CCCCCCCC=C KHAVLLBUVKBTBG-UHFFFAOYSA-N 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000010001 cellular homeostasis Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- KLTWJZTUJHGCSJ-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1.OC1CCCCC1 KLTWJZTUJHGCSJ-UHFFFAOYSA-N 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 125000005507 decahydroisoquinolyl group Chemical group 0.000 description 1
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000012351 deprotecting agent Substances 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 125000005509 dibenzothiophenyl group Chemical group 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 125000000597 dioxinyl group Chemical group 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000008846 dynamic interplay Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical group C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000003844 furanonyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000009033 hematopoietic malignancy Effects 0.000 description 1
- 230000002607 hemopoietic effect Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- YDNLNVZZTACNJX-UHFFFAOYSA-N isocyanatomethylbenzene Chemical compound O=C=NCC1=CC=CC=C1 YDNLNVZZTACNJX-UHFFFAOYSA-N 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- SJFNDMHZXCUXSA-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SJFNDMHZXCUXSA-UHFFFAOYSA-M 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 231100000324 minimal toxicity Toxicity 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000002071 myeloproliferative effect Effects 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Chemical group C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 1
- BTFQKIATRPGRBS-UHFFFAOYSA-N o-tolualdehyde Chemical compound CC1=CC=CC=C1C=O BTFQKIATRPGRBS-UHFFFAOYSA-N 0.000 description 1
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960005010 orotic acid Drugs 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940098695 palmitic acid Drugs 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- NQFOGDIWKQWFMN-UHFFFAOYSA-N phenalene Chemical group C1=CC([CH]C=C2)=C3C2=CC=CC3=C1 NQFOGDIWKQWFMN-UHFFFAOYSA-N 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- DIJNSQQKNIVDPV-UHFFFAOYSA-N pleiadene Chemical group C1=C2[CH]C=CC=C2C=C2C=CC=C3[C]2C1=CC=C3 DIJNSQQKNIVDPV-UHFFFAOYSA-N 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- VQGISNOMGHCEPX-UHFFFAOYSA-N propanenitrile Chemical compound C[CH]C#N VQGISNOMGHCEPX-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- WEMQMWWWCBYPOV-UHFFFAOYSA-N s-indacene Chemical group C=1C2=CC=CC2=CC2=CC=CC2=1 WEMQMWWWCBYPOV-UHFFFAOYSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229940116353 sebacic acid Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229930004725 sesquiterpene Natural products 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- QFNFDHNZVTWZED-UHFFFAOYSA-N tert-butyl n-[[(2-methylpropan-2-yl)oxycarbonylamino]-pyrazol-1-ylmethylidene]carbamate Chemical compound CC(C)(C)OC(=O)NC(=NC(=O)OC(C)(C)C)N1C=CC=N1 QFNFDHNZVTWZED-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000005985 thienyl[1,3]dithianyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- NTJPIRDYMVYFNP-UHFFFAOYSA-M trimethylsilylmethanesulfonate Chemical compound C[Si](C)(C)CS([O-])(=O)=O NTJPIRDYMVYFNP-UHFFFAOYSA-M 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
- C07C215/50—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
- C07C215/52—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/04—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
- C07C225/08—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings
- C07C225/10—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings with doubly-bound oxygen atoms bound to carbon atoms not being part of rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/23—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/60—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/74—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/31—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C261/00—Derivatives of cyanic acid
- C07C261/04—Cyanamides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
- C07C275/10—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
- C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
- C07C291/04—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds containing amino-oxide bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C311/04—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
- C07C335/10—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a non-condensed ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
- C07C35/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings
- C07C35/32—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings the condensed ring system being a (4.3.0) system, e.g. indenols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/46—Unsaturated compounds containing hydroxy or O-metal groups containing rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C62/30—Unsaturated compounds
- C07C62/32—Unsaturated compounds containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/14—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/18—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
- C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/14—Benz[f]indenes; Hydrogenated benz[f]indenes
Definitions
- the present invention is generally directed to SHIP1 modulators, as well as to compositions and methods related to the same.
- phosphoinositide 3-kinase In response to extracellular signals, phosphoinositide 3-kinase (PI3K) becomes activated and phosphorylates phosphatidylinositol-4,5-bisphosphate (PI-4,5-P 2 ) within the plasma membrane to generate phosphatidylinositol-3,4,5-trisphosphate (PIP 3 ).
- PIP 3 then initiates a cascade of downstream signaling pathways by interacting with pleckstrin homology (PH) domain-containing proteins, such as protein kinase B (PKB, also known as Akt), that regulate cellular activation, function, proliferation and/or survival, depending on the cell type and stimulus (Deane et al., Annu Rev Immunol 22, 563-598, 2004).
- PH pleckstrin homology
- PIP 3 Cellular levels of PIP 3 are normally tightly regulated by PI3K, the 5′ inositol phosphatases SHIP1 (SH2 domain-containing inositol phosphatase), SHIP2, and by the 3′ inositol phosphatase PTEN.
- SHIP1 and SHIP2 dephosphorylate PIP 3 to phosphatidylinositol-3,4-bisphosphate (PI-3,4-P 2 ), whereas PTEN dephosphorylates PIP 3 to PI-4,5-P 2 (Sly et al., Exp Hematol 31, 1170-1181, 2003; Vivanco et al., Nat Rev Cancer 2, 489-501, 2002).
- SHIP1 is unique in that its expression is restricted primarily to immune and hematopoietic cells (Sly et al., Exp Hematol 31, 1170-1181, 2003;
- SHIP1's role in immune cell homeostasis is shown both by the myeloproliferative syndrome observed in SHIP1 ⁇ / ⁇ mice, as well as the hypersensitivity of SHIP1 ⁇ / ⁇ mice and cells to immune stimulation (Helgason et al., Genes Dev 12, 1610-1620, 1998; Sly et al., Immunity 21, 227-239, 2004).
- SHIP1 has been shown to mediate signaling from the inhibitory Fc ⁇ RIIB receptor (Coggeshall et al., Mol Immunol 39, 521-529, 2002), and is important in terminating signal transduction from activating immune/hematopoietic cell receptor systems (Kalesnikoff et al., Rev Physiol Biochem Pharmacol 149, 87-103, 2003).
- SHIP1 is a particularly ideal target for development of therapeutics for treating immune and hemopoietic disorders because its hematopoietic-restricted expression (Hazen A L, et al. 113, 2924-33, 2009; Rohrschneider L R, Fuller J F, Wolf I, Liu Y, Lucas D M. Structure, function, and biology of SHIP proteins. Genes Dev. 14:505-20, 2000) would limit the effects of a specific SHIP1 agonist to target cells.
- SHIP1 modulators include sesquiterpene compounds such as pelorol.
- Pelorol is a natural product isolated from the topical marine sponge Dactylospongia elegans (Kwak et al., J Nat Prod 63, 1153-1156, 2000; Goclik et al., J Nat Prod 63, 1150-1152, 2000).
- Other reported SHIP1 modulators include the compounds set forth in PCT Published Patent Application Nos. WO 2003/033517, WO 2004/035601, WO 2004/092100 (or U.S. Pat. No. 7,601,874), WO 2007/147251, WO 2007/147252 and WO 2011/069118.
- the present invention is generally directed to compounds which are SHIP1 modulators and pharmaceutical compositions comprising the compounds and methods of using the compounds and the pharmaceutical compositions of the invention for the treatment of diseases, disorders or conditions that would benefit from SHIP1 modulation.
- a SHIP1 modulator can serve as either an agonist or antagonist to SHIP1.
- this invention is directed to compounds of formula (I):
- this invention is directed to compositions comprising a pharmaceutically acceptable excipient, carrier and/or diluent and a compound of formula (I), or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt or solvate thereof.
- this invention is directed to a method for modulating SHIP1 activity in a mammal comprising administering an effective amount of a compound of formula (I), or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt or solvate thereof, or a composition comprising a compound of formula (I), or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt or solvate thereof, to the mammal in need thereof.
- this invention is directed to methods for treating a disease, disorder or condition in a mammal comprising administering an effective amount of a compound of formula (I), or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt or solvate thereof, as set forth above, to the mammal in need thereof, where the disease, disorder or condition is an autoimmune disease, disorder or condition, an inflammatory disease, disorder or condition, or a neoplastic or cell proliferative disease, disorder or condition.
- a disease, disorder or condition is an autoimmune disease, disorder or condition, an inflammatory disease, disorder or condition, or a neoplastic or cell proliferative disease, disorder or condition.
- this invention is directed to methods of treating a disease, disorder or condition in a mammal comprising administering an effective amount of a compound of formula (I), or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt or solvate thereof, typically in the form of a composition, to the mammal in need thereof.
- Methods of this invention include administering an effective amount of a compound of formula (I), or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt or solvate thereof, to the mammal in need thereof (such as a human).
- this invention is directed to methods of preparing compounds of formula (I), or stereoisomers, enantiomers or tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts or solvates thereof.
- Oxo refers to ⁇ O.
- Cyano refers to —CN.
- Niro refers to —NO 2 .
- Haldroxy refers to —OH.
- Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms, more preferably one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.
- an alkyl group may be optionally substituted by one of the following groups: alkyl, halo, haloalkyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR 20 , —OC(O)—R 20 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —N(R 20 )C(O)OR 22 , —N(R 20 )C(O)R 22 , —N(R 20 )S(O) p R 22 (where p is 1 to 2), —S(O) p OR 22 (where p is 1 to 2), —S(O) t R 22 (where t is 0 to 2), and —S(O) p N(R 20 ) 2 (
- Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to twelve carbon atoms, preferably one to eight carbon atoms and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
- an alkenyl group may be optionally substituted by one of the following groups: alkyl, halo, haloalkyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR 20 , —OC(O)—R 20 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —N(R 20 )C(O)OR 22 , —N(R 20 )C(O)R 22 , —N(R 20 )S(O) p R 22 (where p is 1 to 2), —S(O) p OR 22 (where p is 1 to 2), —S(O) t R 22 (where t is 0 to 2), and —S(O) p N(R 20 ) 2
- Alkoxy refers to a radical of the formula —OR a where R a is an alkyl radical as defined above containing one to twelve carbon atoms.
- R a is an alkyl radical as defined above containing one to twelve carbon atoms.
- the alkyl part of the alkoxy radical may be optionally substituted as defined above for an alkyl radical
- Alkylene or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group or linking two parts of the molecule, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, e.g., —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, and the like.
- the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond or is attached to two parts of the molecule through a single bond at each point of attachment.
- an alkylene chain may be optionally substituted by one of the following groups: alkyl, alkenyl, halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR 20 , —OC(O)—R 20 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —N(R 20 )C(O)OR 22 , —N(R 20 )C(O)R 22 , —N(R 20 )S(O) p R 22 (where p is 1 to 2), —S(O) p OR 22 (where p is 1 to 2), —S(O) t R 22 (where t is 0 to 2), and —S(O) p N(R 20 ) 2 (where —OR 20 ,
- Alkylidene refers to a straight or branched hydrocarbon radical group consisting solely of carbon and hydrogen, containing at least one double bond, having from one to seven carbon atoms, and that is attached to the rest of the molecule through a double bond, e.g., methylene, ethylidene, propylidene, and the like.
- an alkylidene radical may be optionally substituted by one of the following groups: alkyl, halo, haloalkyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR 20 , —OC(O)—R 20 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —N(R 20 )C(O)OR 22 , —N(R 20 )C(O)R 22 , —N(R 20 )S(O) p R 22 (where p is 1 to 2), —S(O) p OR 22 (where p is 1 to 2), —S(O) t R 22 (where t is 0 to 2), and —S(O) p N(R 20 )
- Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
- the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may included fused or bridged ring systems.
- Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
- an aryl group may be optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 21 —OR 20 , —R 21 —OC(O)—R 20 , —R 21 —N(R 20 ) 2 , —R 21 —C(O)R 20 , —R 21 —C(O)OR 20 , —R 21 —C(O)N(R 20 ) 2 , —R 21 —N(R 20 )C(O)OR 22 , —R 21 —N(R 20 )C(O)R 22 , —R 21 —N(R 20 )S(O)
- Alkyl refers to a radical of the formula —R b —R c where R b is an alkylene chain as defined above and R c is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like.
- R b is an alkylene chain as defined above
- R c is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like.
- the alkylene chain part of the aralkyl radical may be optionally substituted as described above for an optionally substituted alkylene chain.
- the aryl part of the aralkyl radical may be optionally substituted as described above for an optionally substituted aryl group.
- “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond.
- Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptly, and cyclooctyl.
- Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, and the like.
- a cycloalkyl group may be optionally substituted by one or more substituents independently selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 21 —OR 20 , —R 21 —OC(O)—R 20 , —R 21 —N(R 20 ) 2 , —R 21 —C(O)R 20 , —R 21 —C(O)OR 20 , —R 21 —C(O)N(R 20 ) 2 , —R 21 —N(R 20 )C(O)OR 22 , —R 21 —N(R 20 )C(O)R 22 , —R 21 —N(R 20 )S
- Cycloalkylalkyl refers to a radical of the formula —R b R g where R b is an alkylene chain as defined above and R g is a cycloalkyl radical as defined above.
- R b is an alkylene chain as defined above
- R g is a cycloalkyl radical as defined above.
- the alkylene chain and/or the cycloalkyl radical may be optionally substituted as defined above for optionally substituted alkylene chain and optionally substituted cycloalkyl.
- Halo refers to bromo, chloro, fluoro or iodo.
- Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
- the alkyl part of the haloalkyl radical may be optionally substituted as defined above for an alkyl group.
- Haloalkylidene refers an alkylidene radical, as defined above, that is substituted by one or more halo radicals, as defined above.
- an alkylidene radical may be optionally substituted by one of the following groups: alkyl, haloalkyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR 20 , —OC(O)—R 20 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —N(R 20 )C(O)OR 22 , —N(R 20 )C(O)R 22 , —N(R 20 )S(O) p R 22 (where p is 1 to 2), —S(O) p OR 22 (where p is 1 to 2), —S(
- Heterocyclyl refers to a stable 3- to 18-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
- the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated.
- heterocyclyl radicals include, but are not limited to, dioxolanyl, dioxinyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, 1,2,4-thiadiazol-5(4H)-ylidene, tetrahydrofuryl, trioxanyl, trithianyl, triazinanyl,
- a heterocyclyl group may be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 21 —OR 20 , —R 21 —OC(O)—R 20 , —R 21 —N(R 20 ) 2 , —R 21 —C(O)R 20 , —R 21 —C(O)OR 20 , —R 21 —C(O)N(R 20 ) 2 , —R 21 —N(R 20 )C(O)OR 22 , —R 21 —N(R 20 )C(O)R 22 , —R 21 —N(R 20
- N-heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen. The point of attachment of the N-heterocyclyl to the rest of the molecule can be through a nitrogen atom or a carbon atom in the N-heterocyclyl.
- an N-heterocyclyl radical may be optionally substituted as described above for an optionally substituted heterocyclyl radical.
- Heterocyclylalkyl refers to a radical of the formula —R b R h where R b is an alkylene chain as defined above and R h is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom.
- the alkylene chain of the heterocyclylalkyl radical may be optionally substituted as defined above for an optionally substituted alkyene chain.
- the heterocyclyl part of the heterocyclylalkyl radical may be optionally substituted as defined above for an optionally substituted heterocyclyl group.
- Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
- the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
- Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzo[d]imidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzo[d]isoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinony
- a heteroaryl group may be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, cyano, oxo, thioxo, nitro, thioxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 21 —OR 20 , —R 21 —OC(O)—R 20 , —R 21 —N(R 20 ) 2 , —R 21 —C(O)R 20 , —R 21 —C(O)OR 20 , —R 21 —C(O)N(R 20 ) 2 , —R 21 —N(R 20 )C(O)OR 22 , —R 21 —N(R 20 )C(O)OR 22 , —R 21 —
- N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen. The point of attachment of the N-heteroaryl to the rest of the molecule can be through a nitrogen atom or a carbon atom in the N-heteroaryl.
- an N-heteroaryl radical may be optionally substituted as described above for an optionally substituted heteroaryl radical.
- Heteroarylalkyl refers to a radical of the formula —R b R i where R b is an alkylene chain as defined above and R i is a heteroaryl radical as defined above.
- R b is an alkylene chain as defined above and R i is a heteroaryl radical as defined above.
- the heteroaryl part of the heteroarylalkyl radical may be optionally substituted as defined above for an optionally substituted heteroaryl group.
- the alkylene chain part of the heteroarylalkyl radical may be optionally substituted as defined above for an optionally substituted alkylene chain.
- Prodrugs is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention.
- prodrug refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable.
- a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
- Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood.
- the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)).
- prodrugs are provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
- prodrug is also meant to include any covalently bonded carriers, which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject.
- Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
- Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
- prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amide derivatives of amine functional groups in the compounds of the invention and the like.
- esters may be employed, such as methyl esters, ethyl esters, and the like.
- Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
- “Mammal” includes humans and both domestic animals such as laboratory animals and household pets, (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
- “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
- “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution (“unsubstituted”).
- substitutents on the functional group are also “optionally substituted” and so on, for the purposes of this invention, such iterations are limited to five, preferably such iterations are limited to two.
- “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
- “Pharmaceutically acceptable salt” includes both acid and base addition salts.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic
- “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
- Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
- Particularly preferred organic bases are isoprop
- solvate refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent.
- the solvent may be water, in which case the solvate may be a hydrate.
- the solvent may be an organic solvent.
- the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
- the compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
- some of the crystalline forms of the compounds of formula (I) may exist as polymorphs, which are included in the present invention.
- a “pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans.
- a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
- “Therapeutically effective amount” refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, of a disease or condition alleviated by the modulation of SHIP1 in the mammal, preferably a human.
- the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
- Treating” or “treatment” as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes:
- the terms “disease” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
- the compounds of the invention may contain one or more asymmetric centres and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
- Compounds of formula (I) may also possess axial chirality which may result in atropisomers.
- the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
- Optically active (+) and ( ⁇ ), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallisation.
- Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
- HPLC high pressure liquid chromatography
- a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
- the present invention contemplates various stereoisomers and mixtures thereof and includes enantiomers, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another. See, for example, Smith, M. B. and J. March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th edition (Wiley, 2007), for a detailed description of the structure and properties of enantiomers and stereoisomers.
- a “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
- the present invention includes tautomers of any said compounds.
- cyclopropylethyl comprises an ethyl backbone with cyclopropyl substituent.
- bonds are identified, except for some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.
- One preferred embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R 5 is not a direct bond to C14; C15 is substituted with two hydrogens; R 1 is —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ; R 2 is —R 8 —OR 9 , —R 8 —CN, —R 8 —C(O)OR 9 , —R 8 —C(O)N(R 9 ) 2 , —R 8 —N(R 9 ) 2 , —R 8 —N(R 9 )C(O)R 9 , optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R 4a is hydrogen or alkyl, R 4b is a direct bond to the carbon to which R 7 is attached, and R 3
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —R 8 —OR 9 ; R 2 is —R 8 —OR 9 ; R 4a is hydrogen or alkyl, R 4b is a direct bond to the carbon to which R 7 is attached, and R 3 is —CH 2 NH 2 or —CH 2 N(H)C(O)(CH 2 ) 3 CH 3 ; R 5 is alkyl; R 6 is hydrogen; R 7 is hydrogen; each R 8 is independently a direct bond or a straight or branched alkylene chain; and each R 9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —OH; R 2 is —CH 2 —OH; R 4a is hydrogen or methyl, R 4b is a direct bond to the carbon to which R 7 is attached, and R 3 is —CH 2 NH 2 or —CH 2 N(H)C(O)(CH 2 ) 3 CH 3 ; R 5 is methyl; R 6 is hydrogen; and R 7 is hydrogen.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R 5 is not a direct bond to C14; C15 is substituted with two hydrogens when R 7 is not a direct bond to C15, and one hydrogen when R 7 is a direct bond to C15; R 1 is —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ; R 2 is —R 8 —OR 9 , —R 8 —CN, —R 8 —C(O)OR 9 , —R 8 —C(O)N(R 9 ) 2 , —R 8 —N(R 9 ) 2 , —R 8 —N(R 9 )C(O)R 9 , optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R 4a and R
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R 5 is not a direct bond to C14; C15 is substituted with two hydrogens when R 7 is not a direct bond to C15, and one hydrogen when R 7 is a direct bond to C15; R 1 is —R 8 —OR 9 ; R 2 is —R 8 —OR 9 ; R 4a and R 4b are each independently selected from hydrogen and alkyl and R 3 is —CH 2 OH, —CH 2 NH 2 , —CH 2 N(H)CH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 N(H)CH 2 -cyclopropyl, —CH 2 N(H)CH 2 -pyrrolyl, —CH 2 N(H)C(O)CH 3 , —CH 2 N
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 2 is —CH 2 —OH; R 4a and R 4b are each independently selected from hydrogen, methyl or ethyl and R 3 is —CH 2 OH, —CH 2 NH 2 , —CH 2 N(H)CH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 N(H)CH 2 -cyclopropyl, —CH 2 N(H)CH 2 -pyrrolyl, —CH 2 N(H)C(O)CH 3 , —CH 2 N(H)C(O)-phenyl, —CH 2 N(H)S(O) 2 CH 3 or —CH 2 N(H)C( ⁇ NH)NH 2 ; R 5 is a direct bond to C14; R 6
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens when R 7 is not a direct bond to C15, and one hydrogen when R 7 is a direct bond to C15; R 1 is —R 8 —OR 9 ; R 2 is —R 8 —OR 9 ; R 4a and R 4b are each independently selected from hydrogen and alkyl and R 3 is —CH 2 OH, —CH 2 NH 2 , —CH 2 N(H)CH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 N(H)CH 2 -cyclopropyl, —CH 2 N(H)CH 2 -pyrrolyl, —CH 2 N(H)C(O)CH 3 , —CH 2 N(H)C(O)-phenyl,
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —OH; R 2 is —CH 2 —OH; R 4a and R 4b are each independently selected from hydrogen, methyl or ethyl and R 3 is —CH 2 NH 2 , —CH 2 N(H)CH 3 or —CH 2 N(CH 3 ) 2 ; R 5 is methyl; R 6 is hydrogen; and R 7 is hydrogen.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, which is (1S,3S,4R)-4-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1-ethyl-7a-methyloctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R 5 is not a direct bond to C14; C15 is substituted with two hydrogens when R 7 is not a direct bond to C15, and one hydrogen when R 7 is a direct bond to C15; R 1 is —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ; R 2 is —R 8 —OR 9 , —R 8 —CN, —R 8 —C(O)OR 9 , —R 8 —C(O)N(R 9 ) 2 , —R 8 —N(R 9 ) 2 , —R 8 —N(R 9 )C(O)R 9 , optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R 4a and R
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R 5 is not a direct bond to C14; C15 is substituted with two hydrogens when R 7 is not a direct bond to C15, and one hydrogen when R 7 is a direct bond to C15; R 1 is —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ; R 2 is —R 8 —OR 9 , —R 8 —CN, —R 8 —C(O)OR 9 , —R 8 —C(O)N(R 9 ) 2 , —R 8 —N(R 9 ) 2 , —R 8 —N(R 9 )C(O)R 9 , optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R 4a and R
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens when R 7 is not a direct bond to C15, and one hydrogen when R 7 is a direct bond to C15; R 1 is —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ; R 2 is —R 8 —OR 9 ; R 4a and R 4b together form methylene and R 3 is —OH, —CH 2 —OH, —CH 2 —CH 2 —OH, —CH 2 —O-(3,5-dimethoxy)benzyl, —CH 2 —O-benzyl, —CH 2 —O—CH 2 -pyridinyl, —C(O)OH, —CH 2 —CN, —CH 2 —C(O
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens when R 7 is not a direct bond to C15, and one hydrogen when R 7 is a direct bond to C15; R 1 is —OH or NH 2 ; R 2 is —R 8 —OR 9 ; R 4a and R 4b together form methylene and R 3 is —OH, —CH 2 —OH, —CH 2 —CH 2 —OH, —CH 2 —O-(3,5-dimethoxy)benzyl, —CH 2 —O-benzyl, —CH 2 —O—CH 2 -pyridinyl, —C(O)OH, —CH 2 —CN, —CH 2 —C(O)NH 2 , —CH 2 —NH 2 ,
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —R 8 —OR 9 ; R 2 is —R 8 —CN, —R 8 —C(O)OR 9 , —R 8 —C(O)N(R 9 ) 2 , —R 8 —N(R 9 ) 2 or —R 8 —N(R 9 )C(O)R 9 ; R 4a and R 4b together form methylene and R 3 is —OH or —CH 2 —NH 2 ; R 5 is alkyl; R 6 is hydrogen; R 7 is hydrogen; each R 8 is independently a direct bond or a straight or branched alkylene chain; and each R 9 is independently hydrogen, alkyl, haloalkyl, optionally substituted
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —OH; R 2 is —R 8 —CN, —R 8 —C(O)OH, —R 8 —C(O)NH 2 , —R 8 —NH 2 or —R 8 —N(H)C(O)R 9 ; R 4a and R 4b together form methylene and R 3 is —OH or —CH 2 —NH 2 ; R 5 is alkyl; R 6 is hydrogen; R 7 is hydrogen; and R 9 is benzodioxolyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —R 8 —OR 9 ; R 2 is optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R 4a and R 4b together form methylene and R 3 is —OH; R 5 is alkyl; R 6 is hydrogen; R 7 is hydrogen; R 8 is a direct bond or a straight or branched alkylene chain; and R 9 is hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroary
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —OH; R 2 is optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R 4a and R 4b together form methylene and R 3 is —OH; R 5 is methyl; R 6 is hydrogen; and R 7 is hydrogen.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R 5 is not a direct bond to C14; C15 is substituted with two hydrogens when R 7 is not a direct bond to C15, and one hydrogen when R 7 is a direct bond to C15; R 1 is —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ; R 2 is —R 8 —OR 9 , —R 8 —CN, —R 8 —C(O)OR 9 , —R 8 —C(O)N(R 9 ) 2 , —R 8 —N(R 9 ) 2 , —R 8 —N(R 9 )C(O)R 9 , optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R 4a and R
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —R 8 —OR 9 ; R 2 is —R 8 —OR 9 ; R 4a and R 4b together form methylene and R 3 is —CH 2 —N(H)C(O)-(2-methyl)phenyl, —CH 2 —N(H)C(O)-(3-methyl)phenyl, —CH 2 —N(H)C(O)-(4-fluoro)phenyl, —CH 2 —N(H)C(O)-(4-methoxy)phenyl, —CH 2 —N(H)C(O)-(4-methyl)phenyl, —CH 2 —N(H)C(O)-(4-
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —OH; R 2 is —OH or —CH 2 OH; R 4a and R 4b together form methylene and R 3 is —CH 2 —N(H)C(O)-(2-methyl)phenyl, —CH 2 —N(H)C(O)-(3-methyl)phenyl, —CH 2 —N(H)C(O)-(4-fluoro)phenyl, —CH 2 —N(H)C(O)-(4-methoxy)phenyl, —CH 2 —N(H)C(O)-(4-methyl)phenyl, —CH 2 —N(H)C(O)-(4-trifluoromethyl
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R 5 is not a direct bond to C14; C15 is substituted with two hydrogens when R 7 is not a direct bond to C15, and one hydrogen when R 7 is a direct bond to C15; R 1 is —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ; R 2 is —R 8 —OR 9 , —R 8 —CN, —R 8 —C(O)OR 9 , —R 8 —C(O)N(R 9 ) 2 , —R 8 —N(R 9 ) 2 , —R 8 —N(R 9 )C(O)R 9 , optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R 4a and R
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —R 8 —OR 9 ; R 2 is —R 8 —OR 9 ; R 4a and R 4b together form methylene and R 3 is —CH 2 —N(H)CH 2 -(2,2-difluorobenzodioxolyl), —CH 2 —CH 2 —N(4-methoxybenzyl) 2 , —CH 2 —CH 2 —N(H)-(4-methoxy)benzyl, —CH 2 —N(H)-(2-fluoro-4-methoxy)benzyl, —CH 2 —N(H)-(2-fluoro-4-methyl)benzyl, —CH 2 —N(H)
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —OH; R 2 is —OH or —CH 2 OH; R 4a and R 4b together form methylene and R 3 is —CH 2 —N(H)CH 2 -(2,2-difluorobenzodioxolyl), —CH 2 —CH 2 —N(4-methoxybenzyl) 2 , —CH 2 —CH 2 —N(H)-(4-methoxy)benzyl, —CH 2 —N(H)-(2-fluoro-4-methoxy)benzyl, —CH 2 —N(H)-(2-fluoro-4-methyl)benzyl, —CH 2 —N(H)-(2-meth
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R 5 is not a direct bond to C14; C15 is substituted with two hydrogens when R 7 is not a direct bond to C15, and one hydrogen when R 7 is a direct bond to C15; R 1 is —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ; R 2 is —R 8 —OR 9 , —R 8 —CN, —R 8 —C(O)OR 9 , —R 8 —C(O)N(R 9 ) 2 , —R 8 —N(R 9 ) 2 , —R 8 —N(R 9 )C(O)R 9 , optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R 4a and R
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —R 8 —OR 9 ; R 2 is —R 8 —OR 9 ; R 4a and R 4b together form methylene and R 3 is —CH 2 —N(H)C(O)N(H)-benzyl, —CH 2 —N(H)C(O)N(H)-ethyl, —CH 2 —N(H)C(O)N(H)-phenyl or —CH 2 —N(H)C(S)N(H)CH 3 ; R 5 is alkyl; R 6 is hydrogen; R 7 is hydrogen; each R 8 is independently a direct bond or a straight or branched alkylene chain; and each R 9 is independently hydrogen, alky
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —OH; R 2 is —CH 2 OH; R 4a and R 4b together form methylene and R 3 is —CH 2 —N(H)C(O)N(H)-benzyl, —CH 2 —N(H)C(O)N(H)-ethyl, —CH 2 —N(H)C(O)N(H)-phenyl or —CH 2 —N(H)C(S)N(H)CH 3 ; R 5 is methyl; R 6 is hydrogen; and R 7 is hydrogen.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R 5 is not a direct bond to C14; C15 is substituted with two hydrogens when R 7 is not a direct bond to C15, and one hydrogen when R 7 is a direct bond to C15; R 1 is —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ; R 2 is —R 8 —OR 9 , —R 8 —CN, —R 8 —C(O)OR 9 , —R 8 —C(O)N(R 9 ) 2 , —R 8 —N(R 9 ) 2 , —R 8 —N(R 9 )C(O)R 9 , optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R 4a and R
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —R 8 —OR 9 ; R 2 is —R 8 —OR 9 ; R 4a and R 4b together form methylene and R 3 is —CH 2 -benzimidazolyl, —CH 2 -indolinyl, —CH 2 -indolyl, —CH 2 -purinyl, —CH 2 -pyrazolyl or —CH 2 -triazolyl; R 5 is alkyl; R 6 is hydrogen; R 7 is hydrogen; each R 8 is independently a direct bond or a straight or branched alkylene chain; and each R 9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —OH; R 2 is —CH 2 OH; R 4a and R 4b together form methylene and R 3 is —CH 2 -benzimidazolyl, —CH 2 -indolinyl, —CH 2 -indolyl, —CH 2 -purinyl, —CH 2 -pyrazolyl or —CH 2 -triazolyl; R 5 is methyl; R 6 is hydrogen; and R 7 is hydrogen.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- Another embodiment of the Invention is a compound of formula (Ia):
- C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R 5 is not a direct bond to C14; C15 is substituted with two hydrogens when R 7 is not a direct bond to C15, and one hydrogen when R 7 is a direct bond to C15;
- R 1 is —R 8 —OR 9 or —R 8- N(R 9 ) 2 ;
- R 2 is —R 8 —OR 9 , —R 8 —CN, —R 8 —C(O)OR 9 , —R 8 —C(O)N(R 9 ) 2 , —R 8 —N(R 9 ) 2 , —R 8 —N(R 9 )C(O)R 9 , optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl;
- R 4a is hydrogen or alkyl
- R 4b is a direct bond to the carbon to which
- one embodiment is a compound of formula (Ia) wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R 5 is not a direct bond to C14; C15 is substituted with two hydrogens when R 7 is not a direct bond to C15, and one hydrogen when R 7 is a direct bond to C15; R 1 is —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ; R 2 is —R 8 —OR 9 , —R 8 —CN, —R 8 —C(O)OR 9 , —R 8 —C(O)N(R 9 ) 2 , —R 8 —N(R 9 ) 2 , —R 8 —N(R 9 )C(O)R 9 , optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R 4a and R 4b together form methylene
- another embodiment is a compound of formula (Ia) wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R 5 is not a direct bond to C14; C15 is substituted with two hydrogens when R 7 is not a direct bond to C15, and one hydrogen when R 7 is a direct bond to C15; R 1 is —R 8 —OR 9 or —R 8- N(R 9 ) 2 ; R 2 is —R 8 —OR 9 , —R 8 —CN, —R 8 —C(O)OR 9 , —R 8 —C(O)N(R 9 ) 2 , —R 8 —N(R 9 ) 2 , —R 8 —N(R 9 )C(O)R 9 , optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R 4a and R 4b together form methylene and
- another embodiment is a compound of formula (Ia) wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —R 8 —OR 9 ; R 2 is —R 8 —OR 9 ; R 4a and R 4b together form methylene and R 3 is —CH 2 —N(H)CH 2 -benzodioxolyl; R 5 is alkyl; R 6 is hydrogen; R 7 is hydrogen; each R 8 is independently a direct bond or a straight or branched alkylene chain; and each R 9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally
- another embodiment is a compound of formula (Ia) wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R 1 is —OH; R 2 is —OH or —CH 2 OH; R 4a and R 4b together form methylene and R 3 is —CH 2 —N(H)CH 2 -benzodioxolyl; R 5 is methyl; R 6 is hydrogen; and R 7 is hydrogen.
- another embodiment is a compound of formula (Ia) which is (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((benzo[d][1,3]dioxol-5-ylmethylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol.
- any embodiment of the compounds of the invention, as set forth above, and any specific substituent set forth herein for a particular R group in the compounds of the invention, as set forth above, may be independently combined with other embodiments and/or substituents of compounds of the invention to form embodiments of the inventions not specifically set forth above.
- substituents in the event that a list of substituents is listed for any particular R group in a particular embodiment and/or claim, it is understood that each individual substituent may be deleted from the particular embodiment and/or claim and that the remaining list of substituents will be considered to be within the scope of the invention.
- Another preferred embodiment of the various aspects of the invention is an embodiment of the methods for treating a disease, disorder or condition in a mammal in need thereof is where the disease, disorder or condition is an autoimmune disease, disorder or condition, an inflammatory disease, disorder or condition, or a neoplastic or cell proliferative disease, disorder or condition.
- Another embodiment of the methods for treating a disease, disorder or condition in a mammal in need thereof is where the disease, disorder or condition is an autoimmune disease, disorder or condition selected from idiopathic pulmonary fibrosis, an inflammatory bowel disease, rheumatoid arthritis, Still's Disease, Sjögren's Syndrome, systemic lupus erythematosus, multiple sclerosis, psoriasis and systemic sclerosis.
- an autoimmune disease, disorder or condition selected from idiopathic pulmonary fibrosis, an inflammatory bowel disease, rheumatoid arthritis, Still's Disease, Sjögren's Syndrome, systemic lupus erythematosus, multiple sclerosis, psoriasis and systemic sclerosis.
- Another embodiment of the methods for treating a disease, disorder or condition in a mammal in need thereof is where the disease, disorder or condition is an inflammatory bowel disease selected from Crohn's Disease and ulcerative colitis.
- the disease, disorder or condition is an inflammatory disease, disorder or condition selected from acute respiratory distress syndrome, allergic rhinitis, Alzheimer's Disease, asthma, an ocular inflammatory disease, atopic dermatitis, bladder pain syndrome/interstitial cystitis, chronic obstructive pulmonary disease (COPD) including emphysematous, bronchitic, and alpa 1 anti-trypsin deficiency related COPD; dermal contact hypersensitivy, eczema, eosiniphilic gastrointestinal disorder, fibromyalgia, gout, hepatic fibrosis, irritable bowl syndrome, ischemic reperfusion disease, kidney fibrosis, pancratitis, Parkisons Disease, post operative inflammation, a seronegative spondyloarthropathy, and vasculitis.
- COPD chronic obstructive pulmonary disease
- Another embodiment of the methods for treating a disease, disorder or condition in a mammal in need thereof is where the disease, disorder or condition is an ocular inflammatory disease selected from allergic conjunctivitis, dry eye, and uveitis.
- Another embodiment of the methods for treating a disease, disorder or condition in a mammal in need thereof is where the disease, disorder or condition is a seronegative spondyloarthropathy selected from anklyosing spondylitis, psoriatic arthritis, and Reiter's Syndrome.
- vasculitis selected from Wegener's Granulomatosis, polyarteritis nodosa, leucocytoclastic vasculitis, Churg-Strauss Syndrome, cryoglobulinemic vasculitis, and giant cell arteritis.
- disease, disorder or condition is a neoplastic or cell proliferative disease, disorder or condition selected from acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, basophilic leukemia, cutaneous T-cell lymphoma, Sezary Syndrome, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, hypereosinophilic syndromes, mastocytosis and thrombocythemia.
- a neoplastic or cell proliferative disease, disorder or condition selected from acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, basophilic leukemia, cutaneous T-cell lymphoma, Sezary Syndrome, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma,
- Another embodiment of the invention is a method of using the compounds of formula (I) as standards or controls in in vitro or in vivo assays in determining the efficacy of test compounds in modulating SHIP1 activity.
- the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number.
- isotopically-labeled (i.e., radiolabelled) compounds of formula (I) are considered to be within the scope of this invention.
- isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
- isotopically-labeled compounds would be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action for SHIP1 modulation, or binding affinity to pharmacologically important site of action for SHIP1 modulation.
- isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
- the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
- substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
- Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
- autoimmune diseases such as idiopathic pulmonary fibrosis, inflammatory bowel disease (including Crohn's Disease and ulcerative colitis), rheumatoid arthritis, Still's Disease, Sjögren's Syndrome, systemic lupus erythematosus, multiple sclerosis, psoriasis, and systemic sclerosis; inflammatory diseases such as acute respiratory distress syndrome (ARDS), allergic rhinitis, Alzheimer's Disease, asthma, ocular inflammatory diseases (including allergic conjunctivitis, dry eye, and uveitis), chronic obstructive pulmonary disease (COPD) including emphysematous, brochitic, and COPD due to alpha 1 anti-try
- ARDS acute respiratory distress syndrome
- COPD chronic obstructive pulmonary disease
- the effectiveness of a compound as a SHIP1 modulator may be determined by any number of known techniques, including the assays set forth below in Examples 98-101.
- the compounds of the present invention may be formulated as pharmaceutical compositions.
- Pharmaceutical compositions comprise one or more compounds of this invention in combination with a pharmaceutically acceptable carrier and/or diluent.
- the compound is present in the composition in an amount which is effective to treat a particular disorder, that is, in an amount sufficient to achieve SHIP1 modulation activity, and preferably with acceptable toxicity to the patient.
- the pharmaceutical compositions of the present invention may include a compound in an amount from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more typically from 1 mg to 60 mg. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
- compositions formulated as liquid solutions include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives.
- the compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a compound of this invention, diluents, dispersing and surface active agents, binders, and lubricants.
- diluents dispersing and surface active agents, binders, and lubricants.
- One skilled in this art may further formulate the compounds in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences (Mack Pub. Co., N.J. current edition).
- the present invention provides a method for modulation SHIP1 generally and, more specifically, to treating the diseases, disorders and conditions as discussed above.
- Such methods include administering of a compound of the present invention to a mammal, preferably a human, in an amount sufficient to treat the condition.
- “treat” includes prophylactic administration.
- Such methods include systemic administration of a compound of this invention, preferably in the form of a pharmaceutical composition as discussed above.
- systemic administration includes oral and parenteral methods of administration.
- suitable pharmaceutical compositions include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions.
- compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives.
- flavorants for parenteral administration, the compounds of the present invention can be prepared in aqueous injection solutions which may contain buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.
- the compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples.
- the compounds of formula (I) may be made by the following Reaction Schemes, wherein all substituents are as defined above unless indicated otherwise.
- protecting group strategies may be useful in preparing compounds of formula (I).
- Protecting group methodology is well known to those skilled in the art (see, for example, Greene, T. W. and Wuts, P. G. M. Greene's Protective Groups in Organic Synthesis (2006), 4 th Ed. Wiley).
- starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, e.g., Smith, M. B. and J.
- prodrugs All prodrugs of compounds of this invention are included within the scope of the invention.
- Compounds of formula (I-1) are compounds of formula (I), as defined above in the Summary of the Invention, where R 1 and R 2 are both —R 8 —OH, R 4a and R 4b together form methylene and R 3 is —CH 2 -benzimidazolyl, —CH 2 -indolinyl, —CH 2 -indolyl, —CH 2 -purinyl, —CH 2 -pyrazolyl, —CH 2 -triazolyl, and are prepared as described below in Reaction Scheme 1 where R 5 , R 6 , R 7 and each R 8 are as described above in the Summary of the Invention for compounds of formula (I), R 3a is benzimidazole, imidazole, indoline, indole, purine, pyrazole or triazole, Pg 1 and Pg 2 are each independently selected from an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, ter
- Compounds of formula (A) may be prepared by methods known to one skilled in the art or by the methods disclosed in U.S. Pat. No. 7,601,874.
- Compounds of formula (C) and (E) are commercially available, or can be prepared according to methods known to one skilled in the art.
- compounds of formula (I-1) are prepared, as described above in Reaction Scheme 1, by first protecting a compound of formula (A) under standard oxygen protecting conditions, such as treating the compound of formula (A) with the appropriate oxygen-protecting group under basic conditions in an aprotic solvent. The resulting oxygen-protected compound of formula (B) is then treated with a compound of formula (C) under standard leaving group formation conditions, such as treatment with the appropriate oxygen-activating group under basic conditions in an aprotic solvent, to yield the compound of formula (D).
- standard oxygen protecting conditions such as treating the compound of formula (A) with the appropriate oxygen-protecting group under basic conditions in an aprotic solvent.
- the resulting oxygen-protected compound of formula (B) is then treated with a compound of formula (C) under standard leaving group formation conditions, such as treatment with the appropriate oxygen-activating group under basic conditions in an aprotic solvent, to yield the compound of formula (D).
- the compound of formula (D) is then treated with a compound of formula (E) under standard nucleophilic substitution conditions, such as treatment of the compound of formula (D) with the appropriate nucleophile under basic conditions in an aprotic solvent, to yield the compound of formula (F).
- a compound of formula (E) under standard nucleophilic substitution conditions, such as treatment of the compound of formula (D) with the appropriate nucleophile under basic conditions in an aprotic solvent, to yield the compound of formula (F).
- Deprotection of the oxygens in the compound of formula (F) under standard conditions such as treatment with the appropriate oxygen-deprotecting reagent in a protic solvent, yields the compound of formula (I-1).
- Compounds of formula (D) can be treated with the appropriate cyanating agent, such as potassium cyanide, under standard conditions, such as in the presence of an aprotic solvent, such as DMSO, to yield a compound of formula (F) where R 3a is —CN, which can be deprotected to yield a compound of formula (I-1) wherein R 3a is —CN, or which can then be reduced under standard conditions to yield a compound of formula (I-1) where R 3a is —CH 2 NH 2 .
- the appropriate cyanating agent such as potassium cyanide
- an aprotic solvent such as DMSO
- the compound of formula (I-1) wherein R 3a is —CN can be hydrolyzed in the presence of hydrogen peroxide to yield a compound of formula (I-1) wherein R 3a is —C(O)NH 2 .
- Compounds of formula (I-2) are compounds of formula (I), as defined above in the Summary of the Invention, where R 1 and R 3 are both —R 8 —OH, R 4a and R 4b together form methylene and R 2 is heteroarylalkyl, and are prepared as described below in Reaction Scheme 2A where R 5 , R 6 , R 7 and each R 8 are as described above in the Summary of the Invention for compounds of formula (I), R 2a is heteroaryl, Pg 1 and Pg 2 are each independently selected from an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl, Lg 1 is a functional group which forms a leaving group with the oxygen to which it is attached, such as mesyl or tosyl, and X is bromo or chloro.
- R 1 and R 3 are both —R 8 —OH
- R 4a and R 4b together form
- Compounds of formula (G) may be prepared by methods known to one skilled in the art or by the methods disclosed in U.S. Pat. No. 7,601,874.
- Compounds of formula (C) and (J) are commercially available, or can be prepared according to methods known to one skilled in the art.
- compounds of formula (I-2) are prepared, as described above in Reaction Scheme 2A, by first treating a compound of formula (G) with the compound of formula (C) under standard leaving group formation conditions, such as treating the compound of formula (G) with the appropriate oxygen-activating group under basic conditions in an aprotic solvent, to yield a compound of formula (H).
- the compound of formula (H) is then treated with a compound of formula (J) under standard nucleophilic substitution conditions, such as basic conditions in an aprotic solvent, to form a compound of formula (K).
- Treatment of the compound of formula (K) with acetic acid under standard conditions removes the ketal and Pg 1 to form the compound of formula (L).
- compounds of formula (I-2) can be prepared according the process described below in Reaction Scheme 2B wherein R 5 , R 6 , R 7 , R 8 , R 2a , Pg 1 , Pg 2 , Lg 1 and X are as described above for Reaction Scheme 2A.
- Compounds of formula (N) may be prepared by methods known to one skilled in the art or by the methods disclosed in U.S. Pat. No. 7,601,874.
- Compounds of formula (J) are commercially available, or can be prepared according to methods known to one skilled in the art.
- compounds of formula (I-2) are prepared, as described above in Reaction Scheme 2B, by first treating a compound of formula (N) with a compound of formula (J) under standard nucleophilic substitution conditions, such as basic conditions in an aprotic solvent, to form a compound of formula (O).
- a compound of formula (O) under standard deprotecting conditions, such as treatment with the appropriate oxygen-deprotecting reagent in an aprotic solvent, yields the compound of formula (P), which is further deprotected to yield the compound of formula (I-2).
- compounds of formula (I-2) can be prepared by treating a compound of formula (N), as described above in Reaction Scheme 2B, with a compound of formula (J) under standard conditions, such as under basic conditions in an aprotic solvent, to yield a compound of formula (I-2), as described above.
- compounds of formula (I-2) can be prepared from compounds of formula (V), which can be prepared by the process described below in Reaction Scheme 2C wherein R 5 , R 6 , R 7 , R 8 , Pg 1 and Pg 2 are as described above for Reaction Schemes 2A and 2C, and Pg 3 is acetyl.
- compounds of formula (V) are prepared by the process disclosed in Reaction Scheme 3 by first treating a compound of formula (Q) under standard Baeyer-Villager oxidation conditions, such as using 3-chloroperoxybenzoic acid (MCPBA) in CHCl 3 to yield the lactone compound of formula (R). Reduction of the lactone under standard procedures, such as treating the compound of formula (R) with the appropriate reducing agent in an aprotic solvent, yields the diol compound of formula (S). Sequential protection of the primary hydroxyl groups in the compound of formula (S) under standard procedures yields the compounds of formula (T) and (U), respectively. Treatment of the compound of formula (U) with acetic acid under standard conditions removes the ketal and Pg 2 to yield the compound of formula (V).
- MCPBA 3-chloroperoxybenzoic acid
- the compound of formula (V) can then treated with the appropriate reagent under standard nucleophilic substitution conditions to form the compound of formula (I-2).
- Compounds of formula (I-3) are compounds of formula (I), as defined above in the Summary of the Invention, where R 1 and R 2 are both —R 8 —OH, R 4a and R 4b together form methylene and R 3 is —CH 2 —N(H)—CN, —CH 2 —N(H)-(4-benzoyl)benzyl, and —CH 2 —N(H)-(3,5-dimethoxy)benzyl, and are prepared as described below in Reaction Scheme 3 where R 5 , R 6 , R 7 and each R 8 are as described above in the Summary of the Invention for compounds of formula (I), R 3b is cyano, methylbenzophenone or dimethoxybenzyl, Pg 1 and Pg 2 are each independently selected from an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl, and X is bro
- Compounds of formula (W) are prepared by methods known to one skilled in the art or by methods similar to those described in U.S. Pat. No. 7,601,874 or by methods disclosed herein.
- Compounds of formula (Y) are commercially available or can be prepared by methods known to one skilled in the art.
- compounds of formula (I-3) are prepared, as described above in Reaction Scheme 3, by first treating a compound of formula (Q) under standard reduction conditions, such as Staudinger reaction conditions, to yield a compound of formula (X).
- the compound of formula (X) is then treated with a compound of formula (Y) under standard alkylation conditions, such as under basic conditions in an aprotic solvent, to yield the compound of formula (Z), which is then deprotected under standard deprotecting conditions, such as treating the compound of formula (Z) with the appropriate oxygen-deprotecting reagent in a protic solvent, to yield the compound of formula (I-3).
- Compounds of formula (I-4) are compounds of formula (I), as defined above in the Summary of the Invention, or compounds of formula (Ia), as defined above in the Embodiments, where R 1 and R 2 are both —R 8 —OH, R 4a and R 4b together form methylene and R 3 is —CH 2 —N(H)-(4-fluoro)benzyl, —CH 2 —N(H)—CH 2 -pyridinyl, —CH 2 —N(H)-(4-methyl)benzyl, —CH 2 —N(H)-(3-methyl)benzyl, —CH 2 —N(H)-(2-methyl)benzyl, —CH 2 —N(H)-(4-methoxy)benzyl, —CH 2 CH 2 —N(H)-(4-methoxy)benzyl, —CH 2 —N(H)-(4-trifluoromethyl)benzyl, —CH 2
- Compounds of formula (AA) can be prepared by methods known to one skilled in the art, by methods similar to the methods disclosed in U.S. Pat. No. 7,601,874 or by methods disclosed herein.
- Compounds of formula (BB) are commercially available or can be prepared by methods known to one skilled in the art.
- compounds of formula (I-4) are prepared, as described above in Reaction Scheme 4, by treating a compound of formula (AA) with a compound of formula (BB) under standard reductive amination conditions, such as the appropriate reducing agent in a solvent mixture.
- a compound of formula (AA) may optionally be protected by standard oxygen-protecting procedures known to one skilled in the art prior to the reaction of the compound of formula (AA) with the compound of formula (BB), and the resulting compound may then be deprotected according to methods known to one skilled in the art to arrive at the compound of formula (I-4).
- compounds of formula (AA) can be treated with ethyl isocyanate, phenyl, isocyanate, benzyl isocyanate or methyl isothiocyanate under conditions known to one skilled in the art to yield compounds of formula (I) wherein R 3 is —CH 2 —N(H)C(O)N(H)-benzyl, —CH 2 —N(H)C(O)N(H)-ethyl, —CH 2 —N(H)C(O)N(H)-phenyl or —CH 2 —N(H)C(S)N(H)CH 3 .
- Compounds of formula (I-5) are compounds of formula (I), as defined above in the Summary of the Invention, where R 1 and R 3 are both —R 8 —OH, R 4a and R 4b together form methylene and R 2 is heterocyclylalkyl, and are prepared as described below in Reaction Scheme 5 where R 5 , R 6 , R 7 and each R 8 are as described above in the Summary of the Invention for compounds of formula (I), R 2b is heterocyclyl and Pg 1 and Pg 2 are each independently selected from an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl.
- an oxygen-protecting group such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl.
- Compounds of formula (Ga) are compounds of formula (G) as described above in Reaction Scheme 2A.
- Compounds of formula (DD) can be prepared by methods known to one skilled in the art or by methods disclosed herein.
- compounds of formula (I-5) are prepared, as described above in Reaction Scheme 5, by treating a compound of formula (Ga) with an oxidizing agent, such as TPAP and NMO, to form the ketone compound of formula (CC).
- the compound of formula (CC) is then treated with a compound of formula (DD) under standard reductive amination conditions, such as treatment with the appropriate reducing agent combination in an aprotic solvent, to form the compound of formula (EE).
- Treatment of the compound of formula (EE) with acetic acid under standard conditions removes the ketal and Pg 1 to form the compound of formula (FF).
- the hydroxyl group in the compound of formula (Ga) can first be optionally protected under standard oxygen-protecting procedures and the protected compound can then be treated under similar conditions as the treatment of compounds of formula (EE) and formula (FF) to form the corresponding compound where R 4a and R 4b form methylene, which can then be deprotected, oxidized and treated with a compounds of formula (DD) to produce a compound of formula (GG), which is then treated to deprotecting conditions to form the compound of formula (I-5).
- Compounds of formula (I-6) are compounds of formula (I), as defined above in the Summary of the Invention, where R 1 and R 2 are both —R 8 —OH, R 3 is —CH 2 N(H)C(O)CH 3 , —CH 2 —N(H)C(O)-(2-methyl)phenyl, —CH 2 —N(H)C(O)-(3-methyl)phenyl, —CH 2 —N(H)C(O)-(4-fluoro)phenyl, —CH 2 —N(H)C(O)-(4-methoxy)phenyl, —CH 2 —N(H)C(O)-(4-methyl)phenyl, —CH 2 —N(H)C(O)-(4-trifluoromethyl)phenyl, —CH 2 —N(H)C(O)-2-pyridinyl, —CH 2 —N(H)C(O)-2-pyrroly
- Compounds of (HH) can be prepared according to methods known to one skilled in the art or by methods similar to the methods disclosed in U.S. Pat. No. 7,601,874 or by methods disclosed herein.
- Compounds of formula (JJ) are commercially available or can be prepared by methods known to one skilled in the art.
- compounds of formula (I-6) are prepared, as described above in Reaction Scheme 6, by treating a compound of formula (HH) with a compound of formula (JJ) under suitable conditions, such as treatment with a coupling reagent in an aprotic solvent, to form a compound of formula (I-6).
- suitable conditions such as treatment with a coupling reagent in an aprotic solvent
- the hydroxyls of the compound of formula (HH) may first be optionally protected by treating the compound of formula (HH) under the appropriate oxygen-protecting conditions.
- the resulting protected compound of formula (HH) may then be treated with the compound of formula (JJ) under suitable conditions to form the protected compound of formula (I-6), which can then be deprotected under standard deprotection conditions to form the compound of formula (I-6).
- compounds of formula (HH) where R 4a and R 4b together form methylene can be treated with the appropriate acid, such as p-toulenesulfonic acid, to yield a compound of formula (I) where R 4a is alkyl and R 4b is a direct bond to the carbon to which R 7 is attached.
- the appropriate acid such as p-toulenesulfonic acid
- Compounds of formula (I-7) are compounds of formula (I), as defined above in the Summary of the Invention, where R 1 and R 3 are both —R 8 —OH, R 4a and R 4b together form methylene and R 2 is —R 8 —N(R 9 )C(O)R 9 where R 9 is as defined above in the Summary of the Invention for compounds of formula (I), and are prepared as described below in Reaction Scheme 7 where R 5 , R 6 , R 7 and each R 8 are as described above in the Summary of the Invention for compounds of formula (I), R 2c is R 9 as defined above in the Summary of the Invention for compounds of formula (I), and Pg 1 and Pg 2 are each independently selected from an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl.
- an oxygen-protecting group such as, but not limited to, tert-butyldimethyl
- compounds of formula (I-7) are prepared, as described above in Reaction Scheme 7, by first treating a compound of formula (G) with a suitable azide, such as diphenylphosphoryl azide under standard Mitsunobu reaction conditions in an aprotic solvent, to form the azide compound of formula (KK).
- a suitable azide such as diphenylphosphoryl azide
- the Pg 2 group of the compound of formula (KK) is then removed by standard procedures, such as treatment with the appropriate oxygen-deprotecting reagent in an aprotic solvent, to form the compound of formula (LL), which is then reacted with a compound of formula (MM) under standard amidation conditions, such as treatment with a coupling reagent in an aprotic solvent, to form the compound of formula (I-7).
- Compounds of formula (I-8) are compounds of formula (I), as defined above in the Summary of the Invention, where R 1 and R 2 are both —R 8 —OH, R 4a and R 4b together form methylene and R 3 is —CH 2 —O-(3,5-dimethoxy)benzyl, —CH 2 —O-benzyl, or —CH 2 —O—CH 2 -pyridinyl, and are prepared as described below in Reaction Scheme 8 where R 5 , R 6 , R 7 and each R 8 are as described above in the Summary of the Invention for compounds of formula (I), R 3f is -(3,5-dimethoxy)benzyl, -benzyl, or —CH 2 -pyridinyl, and Pg 1 , Pg 2 and Pg 3 are each independently selected from an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl
- Compounds of formula (MM) may be prepared by methods known to one skilled in the art or by the methods disclosed in U.S. Pat. No. 7,601,874.
- Compounds of formula (TT) are commercially available, or can be prepared according to methods known to one skilled in the art.
- compounds of formula (I-8) are prepared, as described above in Reaction Scheme 8, by first treating a compound of formula (MM) to suitable oxygen-protecting conditions, such as treatment with the appropriate oxygen-protecting group under basic conditions in an aprotic solvent, to form a compound of formula (NN), which is further treated to suitable oxygen-protecting conditions, under basic conditions in an aprotic solvent, to form a compound of formula (OO).
- suitable oxygen-protecting conditions such as treatment with the appropriate oxygen-protecting group under basic conditions in an aprotic solvent
- N suitable oxygen-protecting conditions
- OO treatment of the compound of formula (OO) with acetic acid under standard conditions
- Pg 3 is removed from the compound of formula (QQ) by standard procedures, such as treatment with the appropriate oxygen-deprotecting reagent under basic conditions in an aprotic solvent, to form the compound of formula (RR).
- Olefination of the compound of formula (RR) with the appropriate agent, such as methyl triphenylphosphonium bromide, in the presence of a base, such as KO t Bu provides the compound of formula (SS), which is then treated with a compound of formula (TT) under suitable Williamson ether synthesis conditions, such as treatment with the appropriate alkylating agent under basic conditions in an aprotic solvent, to form the compound of formula (UU).
- the protecting groups on the compound of formula (UU) are then removed by standard procedures to form the compound of formula (I-8).
- Compounds of formula (1-9) are compounds of formula (I), as defined above in the Summary of the Invention, where R 1 and R 3 are both —R 8 —OH, R 4a and R 4b together form methylene and R 2 is —R 8 —OR 9 where R 9 is alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, and are prepared as described below in Reaction Scheme 8 where R 5 , R 6 , R 7 and each R 8 are as described above in the Summary of the Invention for compounds of formula (I), R 2d is alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted ary
- Compounds of formula (VV) may be prepared by methods known to one skilled in the art or by the methods disclosed in U.S. Pat. No. 7,601,874.
- Compounds of formula (WW) are commercially available, or can be prepared according to methods known to one skilled in the art.
- compounds of formula (I-9) are prepared, as described above in Reaction Scheme 9, by first treating a compound of formula (VV) with a compound of formula (WW) under standard Williamson ether synthesis conditions, such as under basic conditions in an aprotic solvent, to form a compound of formula (XX).
- the oxygen-protecting groups on the compound of formula (XX) are removed by standard procedures, such as treating the compound of formula (XX) with the appropriate oxygen-deprotecting reagent in an aprotic solvent, to form the compound of formula (I-9).
- Compounds of formula (I-11) are compounds of formula (I), as defined above in the Summary of the Invention, where R 4a and R 4b are both methyl and R 5 is a direct bond to C14, and are prepared as described below in Reaction Scheme 10 where R 1 , R 2 , R 3 , R 6 and R 7 are as described above in the Summary of the Invention for compounds of formula (I).
- Compounds of formula (I-10) are compounds of formula (I), as defined above in the Summary of the Invention, where R 5 is methyl and R 4a and R 4b together form methlylene, and are prepared as described herein.
- compound of formula (I-11) are prepared, as described above in Reaction Scheme 10, by treating the compound of formula (I-10) with an acid, preferably HCl, to form the compound of formula (I-11).
- Compounds of formula (I-12) are compounds of formula (I), as defined above in the Summary of the Invention, where R 4a and R 4b are both methyl, R 5 is a direct bond to C14 and R 7 is —OH, and are prepared as described below in Reaction Scheme 11 where R 6 and each R 8 are as described above in the Summary of the Invention for compounds of formula (I) and Pg 1 , Pg 2 and Pg 3 are each independently selected from an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl or tert-butyldiphenylsilyl, and Pg 4 is acetyl.
- compounds of formula (I-12) are prepared, as described above in Reaction Scheme 11, by treating a compound of formula (QQa) with methyl lithium under standard conditions, such as treating the compound of formula (QQa) with the appropriate alkyl lithium in an aprotic solvent, to form a compound of formula (YY), which is then subjected to dehydrating conditions, such as treatment with phosphoryl chloride in the presence of an base, to form the compound of formula (ZZ).
- Pg 1 and Pg 2 in the compound of formula (ZZ) are then removed by standard procedures, such as treating the compound of formula (ZZ) with the appropriate oxygen-deprotecting reagent in a protic solvent, to yield the compound of formula (AAA).
- Treatment of the compound of formula (CCC) to acidic conditions yields the compound of formula (DDD), which is then subjected to deprotecting conditions, such as treating the compound of formula (CCC) with deprotecting agent in a protic solvent, to remove each Pg 4 and Pg 3 to yield the compound of formula (I-12).
- Compound of formula (I-13) are compound of formula (I), as described above in the Summary of the Invention, where R 1 is —R 8 —OH, R 2 is —R 8 —NH 2 , R 3 is —CH 2 —NH 2 , and R 4a and R 4b together form methylene, and are prepared as described below in Reaction Scheme 12 where R 5 , R 6 , R 7 and each R 8 are as described above in the Summary of the Invention for compounds of formula (I), Pg 1 is an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl, Lg 1 is a functional group which forms a leaving group with the oxygen to which it is attached, such as mesyl or tosyl, and X is bromo or chloro.
- R 1 is —R 8 —OH
- R 2 is —R 8 —NH 2
- R 3 is —
- compounds of formula (I-13) are prepared, as described above in Reaction Scheme 12, by first treating a compound of formula (A) with a compound of formula (C) under standard leaving group formation conditions, such as under basic conditions in an aprotic solvent, and then treating the resulting mixture with sodium azide under standard conditions, such as treatment with the appropriate nucleophilic azide in an aprotic solvent, to yield the compound of formula (Aa).
- a compound of formula (Aa) under standard leaving group formation conditions, such as under basic conditions in an aprotic solvent
- sodium azide such as treatment with the appropriate nucleophilic azide in an aprotic solvent
- Compound of formula (I-14) are compounds of formula (I), as described above in the Summary of the Invention, where R 1 and R 2 are each —R 8 —OH, R 3 is —CH 2 N(H)C(O)(CH 2 ) 3 CH 3 , and R 7 is hydrogen, and are prepared as described below in Reaction Scheme 13 where R 5 , R 6 , and each R 8 are as described above in the Summary of the Invention for compounds of formula (I), Pg 1 and Pg 2 are each independently an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl, and R 3g is n-butyl.
- Compounds of formula (EEE) may be prepared by methods known to one skilled in the art from compounds disclosed herein or by methods similar to the methods disclosed in U.S. Pat. No. 7,601,874.
- Compounds of formula (FFF) and formula (HHH) are commercially available or can be prepared by methods known to one skilled in the art.
- compounds of formula (I-14) are prepared, as described above in Reaction Scheme 13, by first treating a compound of formula (EEE) with a compound of formula (FFF) under standard conditions, such as in the presence of a drying agent in an aprotic solvent, to yield the compound of formula (GGG). Treatment of the compound of formula (GGG) with a compound of formula (HHH) under standard conditions, in an aprotic solvent, yields the compound of formula (JJJ), with is then deprotected under standard conditions to yield the compound of formula (I-14).
- Compound of formula (I-15) are compounds of formula (I), as described above in the Summary of the Invention, where R 1 and R 2 are each —R 8 —OH, R 3 is —CH 2 NH 2 , R 4a and R 4b together form methylene and R 7 is —R 8 —OR 9 where R 8 is a direct bond and R 9 is hydrogen, and are prepared as described below in Reaction Scheme 14 where R 5 , R 6 , and each R 8 are as described above in the Summary of the Invention for compounds of formula (I), Pg 1 , Pg 2 , Pg 3 and Pg 4 are each independently an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl, Lg 1 is a functional group which forms a leaving group with the oxygen to which it is attached, such as mesyl or tosyl, and X is bromo or chloro.
- Compounds of formula (KKK) may be prepared by methods known to one skilled in the art from compounds disclosed herein or by methods similar to the methods disclosed in U.S. Pat. No. 7,601,874.
- Compounds of formula (C) are commercially available or can be prepared by methods known to one skilled in the art.
- compounds of formula (I-15) are prepared, as described above in Reaction Scheme 14, by first treating a compound of formula (KKK) with a appropriate oxidizing agent, under standard conditions, such as in an aprotic solvent, to yield the compound of formula (LLL). Protection of the hydroxyl on the compound of formula (LLL) under standard conditions, such as treatment with acetic anhydride in pyridine yields the compound of formula (MMM). Removal of the Pg 3 protecting group under standard conditions yields the compound of formula (NNN). Treatment of the compound of formula (NNN) with a compound of formula (C) under standard conditions, such as treatment with the appropriate oxygen-activating group under basic conditions in an aprotic solvent, yields the compound of formula (OOO).
- Compound of formula (I-16) are compounds of formula (I), as described above in the Summary of the Invention, where R 1 is —R 8 —N(R 9 ) 2 where R 8 is a direct bond and each R 9 is hydrogen, R 2 and R 3 are each —CH 2 —OH, R 4a and R 4b together form methylene, and are prepared as described below in Reaction Scheme 15 where R 5 , R 6 and R 7 are as described above in the Summary of the Invention for compounds of formula (I) and Pg 5 is a nitrogen-protecting group, such as trifluoromethylcarbonyl.
- compounds of formula (I-16) are prepared, as described above in Reaction Scheme 15, by first treating a compound of formula (RRR) with an appropriate base, such as sodium hydroxide in a protic solvent, to form the free base compound of formula (SSS).
- SSS free base compound of formula
- the free amino group in the compound of formula (SSS) is then protected by standard nitrogen protecting procedures, such as treatment with trifluoroacetic anhydride under basic conditions in a protic solvent, to yield a compound of formula (TTT).
- TTT Treatment of the compound of formula (TTT) with sodium periodate in THF to oxidatively cleave the diol yields a dialdehyde intermediate, which is then reduced with sodium borohydride in THF to yield the compound of formula (UUU), which is then deprotected under standard conditions, such as treatment with a base in a protic solvent, to yield the compound of formula (I-16).
- Compound of formula (I-17) are compounds of formula (I), as described above in the Summary of the Invention, where R 1 , R 2 and R 3 are each —R 8 —OH, R 4a and R 4b together form methylene and R 7 is a direct bond to C15, and are prepared as described below in Reaction Scheme 16 where R 5 , R 6 and each R 8 are as described above in the Summary of the Invention for compounds of formula (I), and Pg 1 , Pg 2 , and Pg 3 are each independently an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl.
- compounds of formula (I-17) are prepared, as described above in Reaction Scheme 16, by first treating a compound of formula (QQa) with an appropriate silylating reagent under basic conditions in an aprotic solvent followed by oxidation under Saegusa-lto oxidation conditions to yield a compound of formula (QQb). Olefination of the compound of formula (QQb) with the appropriate agent, such as methyl triphenylphosphonium bromide, in the presence of a base, such as KO t Bu, provides the compound of formula (QQc), which is then deprotected under standard deprotecting conditions, such as treatment with the appropriate oxygen-deprotecting reagent in an aprotic solvent, to yield the compound of formula (I-17).
- the appropriate agent such as methyl triphenylphosphonium bromide
- Compound of formula (I-18) are compounds of formula (I), as described above in the Summary of the Invention, where R 1 and R 2 are each —R 8 —OH, R 3 is —CH 2 N(H)OCH 3 , and R 4a and R 4b together form methylene, and are prepared as described below in Reaction Scheme 17 where R 5 , R 6 and each R 8 are as described above in the Summary of the Invention for compounds of formula (I), and Pg 1 and Pg 2 , are each independently an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl.
- compounds of formula (I-18) are prepared, as described above in Reaction Scheme 17, by first oxidizing a compound of formula (B) under standard conditions, such as Swern oxidation conditions, to yield a compound of formula (Ba). Compounds of formula (Ba) are then treated with a compound of formula (VVV) under standard reductive amination conditions, such as the appropriate reducing agent in a solvent mixture, to yield the compound of formula (Bb), which is then deprotected under standard conditions known to one skilled in the art to yield the compound of formula (I-18).
- standard conditions such as Swern oxidation conditions
- All of the compounds described herein as being prepared which may exist in free base or acid form may be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid. Salts of the compounds prepared below may be converted to their free base or acid form by standard techniques. Furthermore, all compounds of the invention which contain an acid or an ester group can be converted to the corresponding ester or acid, respectively, by methods known to one skilled in the art or by methods described herein.
- Representative compounds of the invention which were prepared by the methods disclosed herein include (but are not limited to) the compounds listed below in Table 1.
- the compound (Cpd) numbers in this table correspond to the compound numbers in Examples 98-99 below (but do not correspond with the compound numbers in Examples 1-97 below).
- the mesylate solution from above (1.1 mL) was added and heated to 65° C. for 17 h.
- the mixture was diluted with H 2 O (10 mL) followed by EtOAc (30 mL), and the organic layer was washed with H 2 O (10 mL) and brine (10 mL) then dried (MgSO 4 ) and concentrated.
- the mixture was poured into cold water (80 mL), extracted with Et 2 O (350 mL), washed with brine (40 mL), dried (MgSO 4 ) and concentrated.
- the residue was taken up in AcOH (80 mL) and water (20 mL) and heated at 40° C. for 2 hours, stood at room temperature overnight then heated at 40° C. for 2 hours.
- the mixture was concentrated and the residue was taken up in EtOAc (350 mL), washed successively with saturated NaHCO 3 solution (3 ⁇ 50 mL) and brine (3 ⁇ 30 mL), dried (MgSO 4 ) and concentrated.
- the reaction was fitted with a reflux condenser and was heated in a 50° C. oil bath for 7 hours then was allowed to continue at room temperature overnight.
- the solution was cooled in ice then added saturated NaHCO 3 solution (5 mL). After 10 minutes, the solution was diluted with EtOAc (200 mL), washed with brine (3 ⁇ 30 mL), dried (MgSO 4 ) and concentrated.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Epidemiology (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Furan Compounds (AREA)
- Pyridine Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
Description
- The present invention is generally directed to SHIP1 modulators, as well as to compositions and methods related to the same.
- In response to extracellular signals, phosphoinositide 3-kinase (PI3K) becomes activated and phosphorylates phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) within the plasma membrane to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 then initiates a cascade of downstream signaling pathways by interacting with pleckstrin homology (PH) domain-containing proteins, such as protein kinase B (PKB, also known as Akt), that regulate cellular activation, function, proliferation and/or survival, depending on the cell type and stimulus (Deane et al., Annu Rev Immunol 22, 563-598, 2004). Cellular levels of PIP3 are normally tightly regulated by PI3K, the 5′ inositol phosphatases SHIP1 (SH2 domain-containing inositol phosphatase), SHIP2, and by the 3′ inositol phosphatase PTEN. SHIP1 and SHIP2 dephosphorylate PIP3 to phosphatidylinositol-3,4-bisphosphate (PI-3,4-P2), whereas PTEN dephosphorylates PIP3 to PI-4,5-P2 (Sly et al., Exp Hematol 31, 1170-1181, 2003; Vivanco et al., Nat Rev Cancer 2, 489-501, 2002). Of these three, SHIP1 is unique in that its expression is restricted primarily to immune and hematopoietic cells (Sly et al., Exp Hematol 31, 1170-1181, 2003; Damen et al., Proc Natl Acad Sci USA 93, 1689-1693, 1996).
- SHIP1's role in immune cell homeostasis is shown both by the myeloproliferative syndrome observed in SHIP1−/− mice, as well as the hypersensitivity of SHIP1−/− mice and cells to immune stimulation (Helgason et al., Genes Dev 12, 1610-1620, 1998; Sly et al., Immunity 21, 227-239, 2004). SHIP1 has been shown to mediate signaling from the inhibitory FcγRIIB receptor (Coggeshall et al., Mol Immunol 39, 521-529, 2002), and is important in terminating signal transduction from activating immune/hematopoietic cell receptor systems (Kalesnikoff et al., Rev Physiol Biochem Pharmacol 149, 87-103, 2003).
- Diminished SHIP1 activity or expression has been observed in human inflammatory diseases (Vonakis et al., J Allergy Clin Immunol 108, 822-831, 2001) and hematopoietic malignancies (Liang et al., Proteomics 6, 4554-4564, 2006; Fukuda et al., Proc Natl Acad Sci USA 102, 15213-15218, 2005; Luo et al., Zhongguo Shi Yan Xue Ye Xue Za Zhi 12, 420-426, 2004; Vanderwinden et al., Cell Signal 18, 661-669, 2006; Ong, C. J. et al., Blood (2007), Vol. 110, No. 6, pp. 1942-1949).
- Because dysregulated activation of the PI3K pathway contributes to inflammatory/immune disorders and cancer, intense efforts have been invested into the development of inhibitors of PI3K itself, as well as downstream protein kinases (Workman et al., Nat Biotechnol 24, 794-796, 2006; Simon, Cell 125, 647-649, 2006; Hennessy et al., Nat Rev Drug Discov 4, 988-1004, 2005; Knight et al., Cell 125, 733-747, 2006; Ong, C. J. et al., Blood (2007), Vol. 110, No. 6, pp. 1942-1949). The precedent for discovery and biologic efficacy of kinase inhibitors is well established, and a number of promising new PI3K isoform-specific inhibitors have recently been developed and used in mouse models of inflammatory disease (Camps et al., Nat Med 11, 936-943, 2005; Barber et al., Nat Med 11, 933-935, 2005) and glioma (Fan et al., Cancer Cell 9, 341-349, 2006) with minimal toxicities. However, because of the dynamic interplay between phosphatases and kinases in regulating biologic processes, inositol phosphatase activators represent a complementary, alternative approach to reduce cellular PIP3 levels. Of the phosphoinositol phosphatases that degrade PIP3, SHIP1 is a particularly ideal target for development of therapeutics for treating immune and hemopoietic disorders because its hematopoietic-restricted expression (Hazen A L, et al. 113, 2924-33, 2009; Rohrschneider L R, Fuller J F, Wolf I, Liu Y, Lucas D M. Structure, function, and biology of SHIP proteins. Genes Dev. 14:505-20, 2000) would limit the effects of a specific SHIP1 agonist to target cells.
- To date, a number of small molecule SHIP1 modulators have been disclosed, including sesquiterpene compounds such as pelorol. Pelorol is a natural product isolated from the topical marine sponge Dactylospongia elegans (Kwak et al., J Nat Prod 63, 1153-1156, 2000; Goclik et al., J Nat Prod 63, 1150-1152, 2000). Other reported SHIP1 modulators include the compounds set forth in PCT Published Patent Application Nos. WO 2003/033517, WO 2004/035601, WO 2004/092100 (or U.S. Pat. No. 7,601,874), WO 2007/147251, WO 2007/147252 and WO 2011/069118.
- While significant strides have been made in this field, there remains a need for effective small molecule SHIP1 modulators. There is also a need for pharmaceutical compositions containing such compounds, as well as for methods relating to the use thereof to treat disorders or conditions that would benefit from SHIP1 modulation. The present invention fulfills these needs, and provides other related advantages.
- The present invention is generally directed to compounds which are SHIP1 modulators and pharmaceutical compositions comprising the compounds and methods of using the compounds and the pharmaceutical compositions of the invention for the treatment of diseases, disorders or conditions that would benefit from SHIP1 modulation. As used herein, a SHIP1 modulator can serve as either an agonist or antagonist to SHIP1.
- Accordingly, in one aspect, this invention is directed to compounds of formula (I):
- wherein:
- C1, C4, C11 and C12 are each independently substituted with two hydrogens;
- C9 is substituted with one hydrogen;
- C14 is substituted with one hydrogen when R5 is not a direct bond to C14;
- C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15;
- R1 is —R8—OR9 or —R8—N(R9)2;
- R2 is —R8—OR9, —R8—CN, —R8—C(O)OR9, —R8—C(O)N(R9)2, —R8—N(R9)2, —R8—N(R9)C(O)R9, optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl;
- R4a is hydrogen or alkyl, R4b is a direct bond to the carbon to which R7 is attached, and R3 is —CH2NH2 or —CH2N(H)C(O)(CH2)3CH3;
- or R4a and R4b are each independently selected from hydrogen and alkyl and R3 is —CH2OH, —CH2NH2, —CH2N(H)CH3, —CH2N(CH3)2, —CH2N(H)CH2-cyclopropyl, —CH2N(H)CH2-pyrrolyl, —CH2N(H)C(O)CH3, —CH2N(H)C(O)-phenyl, —CH2N(H)S(O)2CH3 or —CH2N(H)C(═NH)NH2;
- or R4a and R4b together form methylene and R3 is —OH, —CH2—OH, —CH2—CH2—OH, —CH2—O-(3,5-dimethoxy)benzyl, —CH2—O-benzyl, —CH2—O—CH2-pyridinyl, —C(O)OH, —CH2—CN, —CH2—C(O)NH2, —CH2—NH2, —CH2—CH2—NH2, —CH2—N(H)—CN, —CH2—N(H)—OCH3, —CH2—N(H)C(O)-(2-methyl)phenyl, —CH2—N(H)C(O)-(3-methyl)phenyl, —CH2—N(H)C(O)-(4-fluoro)phenyl, —CH2—N(H)C(O)-(4-methoxy)phenyl, —CH2—N(H)C(O)-(4-methyl)phenyl, —CH2—N(H)C(O)-(4-trifluoromethyl)phenyl, —CH2—N(H)C(O)-2-pyridinyl, —CH2—N(H)C(O)-2-pyrrolyl, —CH2—N(H)C(O)-3-pyridinyl, —CH2—N(H)C(O)-4-pyridinyl, —CH2—N(H)C(O)-benzodioxolyl, —CH2—N(H)C(O)-butyl, —CH2—N(H)C(O)CF3, —CH2—N(H)C(O)-cyclohexyl, —CH2—N(H)C(O)-cyclopropyl, —CH2—N(H)C(O)-ethyl, —CH2—N(H)C(O)-furanyl, —CH2—N(H)C(O)-isopropyl, —CH2—N(H)C(O)-naphthyl, —CH2—N(H)C(O)-phenyl, —CH2—N(H)C(O)-propyl, —CH2—N(H)C(O)-pyrazinyl, —CH2—N(H)C(O)-t-butyl, —CH2—CH2—N(H)C(O)benzodioxolyl, —CH2—N(H)CH2-(2,2-difluorobenzodioxolyl), —CH2—CH2—N(4-methoxybenzyl)2, —CH2—CH2—N(H)-(4-methoxy)benzyl, —CH2—N(H)-(2-fluoro-4-methoxy)benzyl, —CH2—N(H)-(2-fluoro-4-methyl)benzyl, —CH2—N(H)-(2-methoxy-4-fluoro)benzyl, —CH2—N(H)-(2-methyl)benzyl, —CH2—N(H)-(2-methyl-4-fluoro)benzyl, —CH2—N(H)-(3,5-dimethoxy)benzyl, —CH2—N(H)-(3-methyl)benzyl, —CH2—N(H)-(4-fluoro)benzyl, —CH2—N(H)-(4-methoxy)benzyl, —CH2—N(H)-(4-methyl)benzyl, —CH2—N(H)-(4-nitro)benzyl, —CH2—N(H)-(4-trifluoromethyl)benzyl, —CH2—N(H)-(4-benzoyl)benzyl, —CH2—N(H)CH2-benzimidazolyl, —CH2—CH2—N(H)CH2-benzodioxolyl, —CH2—N(H)CH2CH2-(4-methoxy)phenyl, —CH2—N(H)CH2-pyridinyl, —CH2—N(H)C(O)N(H)-benzyl, —CH2—N(H)C(O)N(H)-ethyl, —CH2—N(H)C(O)N(H)-phenyl, —CH2—N(H)C(S)N(H)CH3, —CH2-benzimidazolyl, —CH2-indolinyl, —CH2-indolyl, —CH2-purinyl, —CH2-pyrazolyl, or —CH2-triazolyl;
- R5 is alkyl or R5 is a direct bond to C14;
- R6 is hydrogen;
- R7 is hydrogen, —R8—OR9 or a direct bond to C15, provided that when R7 is a direct bond to C15, R4b is not a direct bond to the carbon to which R7 is attached;
- each R8 is independently a direct bond or a straight or branched alkylene chain; and
- each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
- or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof;
- or a pharmaceutically acceptable salt or solvate thereof.
- In another aspect, this invention is directed to compositions comprising a pharmaceutically acceptable excipient, carrier and/or diluent and a compound of formula (I), or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt or solvate thereof.
- In another aspect, this invention is directed to a method for modulating SHIP1 activity in a mammal comprising administering an effective amount of a compound of formula (I), or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt or solvate thereof, or a composition comprising a compound of formula (I), or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt or solvate thereof, to the mammal in need thereof.
- In another aspect, this invention is directed to methods for treating a disease, disorder or condition in a mammal comprising administering an effective amount of a compound of formula (I), or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt or solvate thereof, as set forth above, to the mammal in need thereof, where the disease, disorder or condition is an autoimmune disease, disorder or condition, an inflammatory disease, disorder or condition, or a neoplastic or cell proliferative disease, disorder or condition.
- In another aspect, this invention is directed to methods of treating a disease, disorder or condition in a mammal comprising administering an effective amount of a compound of formula (I), or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt or solvate thereof, typically in the form of a composition, to the mammal in need thereof. Methods of this invention include administering an effective amount of a compound of formula (I), or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt or solvate thereof, to the mammal in need thereof (such as a human).
- In another aspect, this invention is directed to methods of preparing compounds of formula (I), or stereoisomers, enantiomers or tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts or solvates thereof.
- These aspects and embodiments thereof are described in more detail below. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions, and are each hereby incorporated by reference in their entirety.
- As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated:
- “Oxo” refers to ═O.
- “Cyano” refers to —CN.
- “Nitro” refers to —NO2.
- “Hydroxy” refers to —OH.
- “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms, more preferably one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. When specifically stated in the specification, an alkyl group may be optionally substituted by one of the following groups: alkyl, halo, haloalkyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR20, —OC(O)—R20, —N(R20)2, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —N(R20)C(O)OR22, —N(R20)C(O)R22, —N(R20)S(O)pR22 (where p is 1 to 2), —S(O)pOR22 (where p is 1 to 2), —S(O)tR22 (where t is 0 to 2), and —S(O)pN(R20)2 (where p is 1 to 2) where each R20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
- “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to twelve carbon atoms, preferably one to eight carbon atoms and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. When specifically stated in the specification, an alkenyl group may be optionally substituted by one of the following groups: alkyl, halo, haloalkyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR20, —OC(O)—R20, —N(R20)2, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —N(R20)C(O)OR22, —N(R20)C(O)R22, —N(R20)S(O)pR22 (where p is 1 to 2), —S(O)pOR22 (where p is 1 to 2), —S(O)tR22 (where t is 0 to 2), and —S(O)pN(R20)2 (where p is 1 to 2) where each R20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
- “Alkoxy” refers to a radical of the formula —ORa where Ra is an alkyl radical as defined above containing one to twelve carbon atoms. The alkyl part of the alkoxy radical may be optionally substituted as defined above for an alkyl radical
- “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group or linking two parts of the molecule, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, e.g., —CH2—, —CH2—CH2—, —CH2—CH2—CH2—, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond or is attached to two parts of the molecule through a single bond at each point of attachment. When specifically stated in the specification, an alkylene chain may be optionally substituted by one of the following groups: alkyl, alkenyl, halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR20, —OC(O)—R20, —N(R20)2, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —N(R20)C(O)OR22, —N(R20)C(O)R22, —N(R20)S(O)pR22 (where p is 1 to 2), —S(O)pOR22 (where p is 1 to 2), —S(O)tR22 (where t is 0 to 2), and —S(O)pN(R20)2 (where p is 1 to 2) where each R20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
- “Alkylidene” refers to a straight or branched hydrocarbon radical group consisting solely of carbon and hydrogen, containing at least one double bond, having from one to seven carbon atoms, and that is attached to the rest of the molecule through a double bond, e.g., methylene, ethylidene, propylidene, and the like. When specifically stated in the specification, an alkylidene radical may be optionally substituted by one of the following groups: alkyl, halo, haloalkyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR20, —OC(O)—R20, —N(R20)2, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —N(R20)C(O)OR22, —N(R20)C(O)R22, —N(R20)S(O)pR22 (where p is 1 to 2), —S(O)pOR22 (where p is 1 to 2), —S(O)tR22 (where t is 0 to 2), and —S(O)pN(R20)2 (where p is 1 to 2) where each R20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
- “Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may included fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. When specifically stated in the specification, an aryl group may be optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R21—OR20, —R21—OC(O)—R20, —R21—N(R20)2, —R21—C(O)R20, —R21—C(O)OR20, —R21—C(O)N(R20)2, —R21—N(R20)C(O)OR22, —R21—N(R20)C(O)R22, —R21—N(R20)S(O)pR22 (where p is 1 to 2), —R21—N═C(OR20)R20, —R21—S(O)pOR22 (where p is 1 to 2), —R21—S(O)tR22 (where t is 0 to 2), and —R21—S(O)pN(R20)2 (where p is 1 to 2) where each R20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R21 is independently a direct bond or a straight or branched alkylene chain; and each R22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
- “Aralkyl” refers to a radical of the formula —Rb—Rc where Rb is an alkylene chain as defined above and Rc is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. When specifically stated in the specification, the alkylene chain part of the aralkyl radical may be optionally substituted as described above for an optionally substituted alkylene chain. When specifically stated in the specification, the aryl part of the aralkyl radical may be optionally substituted as described above for an optionally substituted aryl group.
- “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptly, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, and the like. When specifically stated in the specification, a cycloalkyl group may be optionally substituted by one or more substituents independently selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R21—OR20, —R21—OC(O)—R20, —R21—N(R20)2, —R21—C(O)R20, —R21—C(O)OR20, —R21—C(O)N(R20)2, —R21—N(R20)C(O)OR22, —R21—N(R20)C(O)R22, —R21—N(R20)S(O)pR22 (where p is 1 to 2), —R21—N═C(OR20)R20, —R21—S(O)pOR22 (where p is 1 to 2), —R21—S(O)tR22 (where t is 0 to 2), and —R21—S(O)pN(R20)2 (where p is 1 to 2) where each R20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R21 is independently a direct bond or a straight or branched alkylene chain; and each R22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
- “Cycloalkylalkyl” refers to a radical of the formula —RbRg where Rb is an alkylene chain as defined above and Rg is a cycloalkyl radical as defined above. When specifically stated in the specification, the alkylene chain and/or the cycloalkyl radical may be optionally substituted as defined above for optionally substituted alkylene chain and optionally substituted cycloalkyl.
- “Halo” refers to bromo, chloro, fluoro or iodo.
- “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. The alkyl part of the haloalkyl radical may be optionally substituted as defined above for an alkyl group.
- “Haloalkylidene” refers an alkylidene radical, as defined above, that is substituted by one or more halo radicals, as defined above. When specifically stated in the specification, an alkylidene radical may be optionally substituted by one of the following groups: alkyl, haloalkyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR20, —OC(O)—R20, —N(R20)2, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —N(R20)C(O)OR22, —N(R20)C(O)R22, —N(R20)S(O)pR22 (where p is 1 to 2), —S(O)pOR22 (where p is 1 to 2), —S(O)tR22 (where t is 0 to 2), and —S(O)pN(R20)2 (where p is 1 to 2) where each R20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
- “Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, dioxinyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, 1,2,4-thiadiazol-5(4H)-ylidene, tetrahydrofuryl, trioxanyl, trithianyl, triazinanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. When specifically stated in the specification, a heterocyclyl group may be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R21—OR20, —R21—OC(O)—R20, —R21—N(R20)2, —R21—C(O)R20, —R21—C(O)OR20, —R21—C(O)N(R20)2, —R21—N(R20)C(O)OR22, —R21—N(R20)C(O)R22, —R21—N(R20)S(O)pR22 (where p is 1 to 2), —R21—N═C(OR20)R20, —R21—S(O)OR22 (where p is 1 to 2), —R21—S(O)tR22 (where t is 0 to 2), and —R21—S(O)pN(R20)2 (where p is 1 to 2) where each R20 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R21 is independently a direct bond or a straight or branched alkylene chain; and each R22 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
- “N-heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen. The point of attachment of the N-heterocyclyl to the rest of the molecule can be through a nitrogen atom or a carbon atom in the N-heterocyclyl. When specifically stated in the specification, an N-heterocyclyl radical may be optionally substituted as described above for an optionally substituted heterocyclyl radical.
- “Heterocyclylalkyl” refers to a radical of the formula —RbRh where Rb is an alkylene chain as defined above and Rh is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. When specifically stated in the specification, the alkylene chain of the heterocyclylalkyl radical may be optionally substituted as defined above for an optionally substituted alkyene chain. When specifically stated in the specification, the heterocyclyl part of the heterocyclylalkyl radical may be optionally substituted as defined above for an optionally substituted heterocyclyl group.
- “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of this invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzo[d]imidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzo[d]isoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinonyl, benzimidazolthionyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,5-a]pyrazinyl, imidazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pryrimidinonyl, pyridazinyl, pyrido[2,3-d]pyrimidinonyl,pyrazolo[1,5-a]pyrimidinyl, quinazolinyl, quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). When specifically stated in the specification, a heteroaryl group may be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, cyano, oxo, thioxo, nitro, thioxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R21—OR20, —R21—OC(O)—R20, —R21—N(R20)2, —R21—C(O)R20, —R21—C(O)OR20, —R21—C(O)N(R20)2, —R21—N(R20)C(O)OR22, —R21—N(R20)C(O)R22, —R21—N(R20)S(O)pR22 (where p is 1 to 2), —R21—N═C(OR20)R20, —R21—S(O)pOR22 (where p is 1 to 2), —R21—S(O)tR22 (where t is 0 to 2), and —R21—S(O)N(R20)2 (where p is 1 to 2) where each R20 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R21 is independently a direct bond or a straight or branched alkylene chain; and each R22 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
- “N-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen. The point of attachment of the N-heteroaryl to the rest of the molecule can be through a nitrogen atom or a carbon atom in the N-heteroaryl. When specifically stated in the specification, an N-heteroaryl radical may be optionally substituted as described above for an optionally substituted heteroaryl radical.
- “Heteroarylalkyl” refers to a radical of the formula —RbRi where Rb is an alkylene chain as defined above and Ri is a heteroaryl radical as defined above. When specifically stated in the specification, the heteroaryl part of the heteroarylalkyl radical may be optionally substituted as defined above for an optionally substituted heteroaryl group. When specifically stated in the specification, the alkylene chain part of the heteroarylalkyl radical may be optionally substituted as defined above for an optionally substituted alkylene chain.
- “Prodrugs” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Thus, the term “prodrug” refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention. Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
- The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention. Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amide derivatives of amine functional groups in the compounds of the invention and the like. Further, in the case of a carboxylic acid (—C(O)OH), esters may be employed, such as methyl esters, ethyl esters, and the like.
- “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
- “Mammal” includes humans and both domestic animals such as laboratory animals and household pets, (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
- “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution (“unsubstituted”). When a functional group is described as “optionally substituted,” and in turn, substitutents on the functional group are also “optionally substituted” and so on, for the purposes of this invention, such iterations are limited to five, preferably such iterations are limited to two.
- “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
- “Pharmaceutically acceptable salt” includes both acid and base addition salts.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.
- “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
- Often crystallizations produce a solvate of the compound of the invention. As used herein, the term “solvate” refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent. Furthermore, some of the crystalline forms of the compounds of formula (I) may exist as polymorphs, which are included in the present invention.
- A “pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
- “Therapeutically effective amount” refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, of a disease or condition alleviated by the modulation of SHIP1 in the mammal, preferably a human. The amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
- “Treating” or “treatment” as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes:
-
- (a) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it;
- (b) inhibiting the disease or condition, i.e., arresting its development;
- (c) relieving (or ameliorating) the disease or condition, i.e., causing regression of the disease or condition; or
- (d) relieving (or ameliorating) the symptoms resulting from the disease or condition, i.e., relieving inflammation without addressing the underlying disease or condition.
- As used herein, the terms “disease” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
- The compounds of the invention, or their pharmaceutically acceptable salts, may contain one or more asymmetric centres and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. Compounds of formula (I) may also possess axial chirality which may result in atropisomers. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallisation. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centres of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
- A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes enantiomers, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another. See, for example, Smith, M. B. and J. March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th edition (Wiley, 2007), for a detailed description of the structure and properties of enantiomers and stereoisomers.
- A “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any said compounds.
- The use of parentheses and brackets in substituent groups is used herein to conserve space. Accordingly, the use of parenthesis in a substituent group indicates that the group enclosed within the parentheses is attached directly to the atom preceding the parenthesis. For example, the following substituent group:
- is represented herein as —CH2—N(H)CH2-(3,5-dimethoxy)phenyl.
- The chemical naming protocol and structure diagrams used herein are a modified form of the I.U.P.A.C. nomenclature system, using ChemBioDraw Ultra Version 12.0 software program, wherein the compounds of the invention are named herein as derivatives of a central core structure. For complex chemical names employed herein, a substituent group is named before the group to which it attaches.
- For example, cyclopropylethyl comprises an ethyl backbone with cyclopropyl substituent. In chemical structure diagrams, all bonds are identified, except for some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.
- Certain carbons are identified by numerals in formula (I) of the compounds of the invention. For purposes herein, the carbon at numeral 1 in formula (I) is indicated herein as C1, and so forth. These numerals may or may not be the same as the locants in the compound names given herein.
- Thus, for example, a compound of formula (I) wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens, C9 is substituted with one hydrogen, C14 is substituted with one hydrogen, C15 is substituted with two hydrogens, R1 is —OH, R2 is —CH2OH, R3 is —CH2—N(H)CH2-(3,5-dimethoxy)phenyl, R4a and R4b together form methylene, R5 is methyl, and R6 and R7 are each hydrogen, i.e., a compound of the following structure:
- is named herein as (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((3,5-dimethoxybenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol.
- Of the various aspects of the invention set forth above in the Summary of the Invention, certain embodiments are preferred.
- One preferred embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R5 is not a direct bond to C14; C15 is substituted with two hydrogens; R1 is —R8—OR9 or —R8—N(R9)2; R2 is —R8—OR9, —R8—CN, —R8—C(O)OR9, —R8—C(O)N(R9)2, —R8—N(R9)2, —R8—N(R9)C(O)R9, optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R4a is hydrogen or alkyl, R4b is a direct bond to the carbon to which R7 is attached, and R3 is —CH2NH2 or —CH2N(H)C(O)(CH2)3CH3; R5 is alkyl or R5 is a direct bond to C14; R6 is hydrogen; R7 is hydrogen or —R8—OR9; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —R8—OR9; R2 is —R8—OR9; R4a is hydrogen or alkyl, R4b is a direct bond to the carbon to which R7 is attached, and R3 is —CH2NH2 or —CH2N(H)C(O)(CH2)3CH3; R5 is alkyl; R6 is hydrogen; R7 is hydrogen; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —OH; R2 is —CH2—OH; R4a is hydrogen or methyl, R4b is a direct bond to the carbon to which R7 is attached, and R3 is —CH2NH2 or —CH2N(H)C(O)(CH2)3CH3; R5 is methyl; R6 is hydrogen; and R7 is hydrogen.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- (1S,3S,4R)-4-((3aS,6S,7R,7aS)-7-(aminomethyl)-3,3a-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-3-(hydroxymethyl)-4-methylcyclohexanol; and
- N-(((3aR,6S,7R,7aS)-6-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl)methyl)pentanamide.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R5 is not a direct bond to C14; C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15; R1 is —R8—OR9 or —R8—N(R9)2; R2 is —R8—OR9, —R8—CN, —R8—C(O)OR9, —R8—C(O)N(R9)2, —R8—N(R9)2, —R8—N(R9)C(O)R9, optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R4a and R4b are each independently selected from hydrogen and alkyl and R3 is —CH2OH, —CH2NH2, —CH2N(H)CH3, —CH2N(CH3)2, —CH2N(H)CH2-cyclopropyl, —CH2N(H)CH2-pyrrolyl, —CH2N(H)C(O)CH3, —CH2N(H)C(O)-phenyl, —CH2N(H)S(O)2CH3 or —CH2N(H)C(═NH)NH2; R5 is alkyl or R5 is a direct bond to C14; R6 is hydrogen; R7 is hydrogen, —R8—OR9 or a direct bond to C15; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R5 is not a direct bond to C14; C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15; R1 is —R8—OR9; R2 is —R8—OR9; R4a and R4b are each independently selected from hydrogen and alkyl and R3 is —CH2OH, —CH2NH2, —CH2N(H)CH3, —CH2N(CH3)2, —CH2N(H)CH2-cyclopropyl, —CH2N(H)CH2-pyrrolyl, —CH2N(H)C(O)CH3, —CH2N(H)C(O)-phenyl, —CH2N(H)S(O)2CH3 or —CH2N(H)C(═NH)NH2; R5 is alkyl or R5 is a direct bond to C14; R6 is hydrogen; R7 is hydrogen, —R8—OR9 or a direct bond to C15; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C15 is substituted with two hydrogens; R2 is —CH2—OH; R4a and R4b are each independently selected from hydrogen, methyl or ethyl and R3 is —CH2OH, —CH2NH2, —CH2N(H)CH3, —CH2N(CH3)2, —CH2N(H)CH2-cyclopropyl, —CH2N(H)CH2-pyrrolyl, —CH2N(H)C(O)CH3, —CH2N(H)C(O)-phenyl, —CH2N(H)S(O)2CH3 or —CH2N(H)C(═NH)NH2; R5 is a direct bond to C14; R6 is hydrogen; and R7 is hydrogen, —OH or a direct bond to C15.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- 1-(((4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-4-yl)methyl)guanidine hydrochloride;
- (1S,3S,4R)-4-((4R,5S)-4-((cyclopropylmethylamino)methyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-4-((4R,5S)-4-((dimethylamino)methyl)-1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- N-(((4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-4-yl)methyl)acetamide;
- (1S,3S,4R)-4-((4R,5S)-1,1-dimethyl-4-((methylamino)methyl)-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-4-((4R,5S)-4-(((1H-pyrrol-2-yl)methylamino)methyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- N-(((4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-4-yl)methyl)methanesulfonamide;
- N-(((4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-4-yl)methyl)benzamide;
- (1S,3S,4R)-3-(hydroxymethyl)-4-((4R,5S)-4-(hydroxymethyl)-1,1-dimethyl-4,5,6,7-tetrahydro-1H-inden-5-yl)-4-methylcyclohexanol; and
- (2R,4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-4-(hydroxymethyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-2-ol.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15; R1 is —R8—OR9; R2 is —R8—OR9; R4a and R4b are each independently selected from hydrogen and alkyl and R3 is —CH2OH, —CH2NH2, —CH2N(H)CH3, —CH2N(CH3)2, —CH2N(H)CH2-cyclopropyl, —CH2N(H)CH2-pyrrolyl, —CH2N(H)C(O)CH3, —CH2N(H)C(O)-phenyl, —CH2N(H)S(O)2CH3 or —CH2N(H)C(═NH)NH2; R5 is alkyl; R6 is hydrogen; R7 is hydrogen, —R8—OR9 or a direct bond to C15; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —OH; R2 is —CH2—OH; R4a and R4b are each independently selected from hydrogen, methyl or ethyl and R3 is —CH2NH2, —CH2N(H)CH3 or —CH2N(CH3)2; R5 is methyl; R6 is hydrogen; and R7 is hydrogen.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, which is (1S,3S,4R)-4-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1-ethyl-7a-methyloctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R5 is not a direct bond to C14; C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15; R1 is —R8—OR9 or —R8—N(R9)2; R2 is —R8—OR9, —R8—CN, —R8—C(O)OR9, —R8—C(O)N(R9)2, —R8—N(R9)2, —R8—N(R9)C(O)R9, optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R4a and R4b together form methylene and R3 is —OH, —CH2—OH, —CH2—CH2—OH, —CH2—O-(3,5-dimethoxy)benzyl, —CH2—O-benzyl, —CH2—O—CH2-pyridinyl, —C(O)OH, —CH2—CN, —CH2—C(O)NH2, —CH2—NH2, —CH2—CH2—NH2, —CH2—N(H)—CN, —CH2—N(H)—OCH3, —CH2—N(H)C(O)-(2-methyl)phenyl, —CH2—N(H)C(O)-(3-methyl)phenyl, —CH2—N(H)C(O)-(4-fluoro)phenyl, —CH2—N(H)C(O)-(4-methoxy)phenyl, —CH2—N(H)C(O)-(4-methyl)phenyl, —CH2—N(H)C(O)-(4-trifluoromethyl)phenyl, —CH2—N(H)C(O)-2-pyridinyl, —CH2—N(H)C(O)-2-pyrrolyl, —CH2—N(H)C(O)-3-pyridinyl, —CH2—N(H)C(O)-4-pyridinyl, —CH2—N(H)C(O)-benzodioxolyl, —CH2—N(H)C(O)-butyl, —CH2—N(H)C(O)CF3, —CH2—N(H)C(O)-cyclohexyl, —CH2—N(H)C(O)-cyclopropyl, —CH2—N(H)C(O)-ethyl, —CH2—N(H)C(O)-furanyl, —CH2—N(H)C(O)-isopropyl, —CH2—N(H)C(O)-naphthyl, —CH2—N(H)C(O)-phenyl, —CH2—N(H)C(O)-propyl, —CH2—N(H)C(O)-pyrazinyl, —CH2—N(H)C(O)-t-butyl, —CH2—CH2—N(H)C(O)benzodioxolyl, —CH2—N(H)CH2-(2,2-difluorobenzodioxolyl), —CH2—CH2—N(4-methoxybenzyl)2, —CH2—CH2—N(H)-(4-methoxy)benzyl, —CH2—N(H)-(2-fluoro-4-methoxy)benzyl, —CH2—N(H)-(2-fluoro-4-methyl)benzyl, —CH2—N(H)-(2-methoxy-4-fluoro)benzyl, —CH2—N(H)-(2-methyl)benzyl, —CH2—N(H)-(2-methyl-4-fluoro)benzyl, —CH2—N(H)-(3,5-dimethoxy)benzyl, —CH2—N(H)-(3-methyl)benzyl, —CH2—N(H)-(4-fluoro)benzyl, —CH2—N(H)-(4-methoxy)benzyl, —CH2—N(H)-(4-methyl)benzyl, —CH2—N(H)-(4-nitro)benzyl, —CH2—N(H)-(4-trifluoromethyl)benzyl, —CH2—N(H)-(4-benzoyl)benzyl, —CH2—N(H)CH2-benzimidazolyl, —CH2—CH2—N(H)CH2-benzodioxolyl, —CH2—N(H)CH2CH2-(4-methoxy)phenyl, —CH2—N(H)CH2-pyridinyl, —CH2—N(H)C(O)N(H)-benzyl, —CH2—N(H)C(O)N(H)-ethyl, —CH2—N(H)C(O)N(H)-phenyl, —CH2—N(H)C(S)N(H)CH3, —CH2-benzimidazolyl, —CH2-indolinyl, —CH2-indolyl, —CH2-purinyl, —CH2-pyrazolyl, or —CH2-triazolyl; R5 is alkyl or R5 is a direct bond to C14; R6 is hydrogen; R7 is hydrogen, —R8—OR9 or a direct bond to C15; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R5 is not a direct bond to C14; C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15; R1 is —R8—OR9 or —R8—N(R9)2; R2 is —R8—OR9, —R8—CN, —R8—C(O)OR9, —R8—C(O)N(R9)2, —R8—N(R9)2, —R8—N(R9)C(O)R9, optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R4a and R4b together form methylene and R3 is —OH, —CH2—OH, —CH2—CH2—OH, —CH2—O-(3,5-dimethoxy)benzyl, —CH2—O-benzyl, —CH2—O—CH2-pyridinyl, —C(O)OH, —CH2—CN, —CH2—C(O)NH2, —CH2—NH2, —CH2—CH2—NH2, —CH2—N(H)—CN or —CH2—N(H)—OCH3; R5 is alkyl or R5 is a direct bond to C14; R6 is hydrogen; R7 is hydrogen, —R8—OR9 or a direct bond to C15; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15; R1 is —R8—OR9 or —R8—N(R9)2; R2 is —R8—OR9; R4a and R4b together form methylene and R3 is —OH, —CH2—OH, —CH2—CH2—OH, —CH2—O-(3,5-dimethoxy)benzyl, —CH2—O-benzyl, —CH2—O—CH2-pyridinyl, —C(O)OH, —CH2—CN, —CH2—C(O)NH2, —CH2—NH2, —CH2—CH2—NH2, —CH2—N(H)—CN or —CH2—N(H)—OCH3; R5 is alkyl; R6 is hydrogen; R7 is hydrogen, —R8—OR9 or a direct bond to C15; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15; R1 is —OH or NH2; R2 is —R8—OR9; R4a and R4b together form methylene and R3 is —OH, —CH2—OH, —CH2—CH2—OH, —CH2—O-(3,5-dimethoxy)benzyl, —CH2—O-benzyl, —CH2—O—CH2-pyridinyl, —C(O)OH, —CH2—CN, —CH2—C(O)NH2, —CH2—NH2, —CH2—CH2—NH2, —CH2—N(H)—CN, or —CH2—N(H)—OCH3; R5 is methyl; R6 is hydrogen; R7 is hydrogen, —OH or a direct bond to C15; R8 is a direct bond, —CH2— or —CH2—CH2—; and R9 is hydrogen, optionally substituted pyridinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(2-aminoethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-hydroxyethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methyl-3-(pyridin-2-yloxy)cyclohexanol;
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methyl-3-((pyridin-2-yloxy)methyl)cyclohexanol;
- (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyrimidin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol;
- (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyrazin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol;
- (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyridin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol;
- (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-((pyridin-2-ylmethoxy)methyl)octahydro-1H-inden-5-yl)cyclohexanol;
- (2S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-2-ol;
- ((1S,2R,5S)-5-amino-2-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methanol;
- (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methylene-3a,4,5,6,7,7a-hexahydro-1H-inden-5-yl)-4-methylcyclohexanol;
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(benzyloxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((3,5-dimethoxybenzyloxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- 2-((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)acetonitrile;
- (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-((methoxyamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexanol;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)cyanamide;
- 2-((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)acetamide; and
- (3aS,4R,5S,7aS)-5-((1R,2R,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-indene-4-carboxylic acid.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —R8—OR9; R2 is —R8—CN, —R8—C(O)OR9, —R8—C(O)N(R9)2, —R8—N(R9)2 or —R8—N(R9)C(O)R9; R4a and R4b together form methylene and R3 is —OH or —CH2—NH2; R5 is alkyl; R6 is hydrogen; R7 is hydrogen; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —OH; R2 is —R8—CN, —R8—C(O)OH, —R8—C(O)NH2, —R8—NH2 or —R8—N(H)C(O)R9; R4a and R4b together form methylene and R3 is —OH or —CH2—NH2; R5 is alkyl; R6 is hydrogen; R7 is hydrogen; and R9 is benzodioxolyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- (1S,3S,4R)-3-(aminomethyl)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexanol;
- 3-((1S,2S,5S)-5-hydroxy-2-((3aR,4R,5R,7aS)-4-hydroxy-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)propanenitrile;
- 3-((1S,2S,5S)-5-hydroxy-2-((3aR,4R,5R,7aS)-4-hydroxy-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)propanamide;
- N-(((1S,2S,5S)-5-hydroxy-2-((3aR,4R,5R,7aS)-4-hydroxy-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl)benzo[d][1,3]dioxole-5-carboxamide; and
- 3-((1R,2S,5S)-5-hydroxy-2-((3aR,4R,5R,7aS)-4-hydroxy-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)propanoic acid.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —R8—OR9; R2 is optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R4a and R4b together form methylene and R3 is —OH; R5 is alkyl; R6 is hydrogen; R7 is hydrogen; R8 is a direct bond or a straight or branched alkylene chain; and R9 is hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —OH; R2 is optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R4a and R4b together form methylene and R3 is —OH; R5 is methyl; R6 is hydrogen; and R7 is hydrogen.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyrrolidin-1-yl)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol;
- (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-morpholinoethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol;
- (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(4-methylpiperazin-1-yl)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol;
- (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol;
- (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-imidazol-1-yl)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol;
- (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-pyrazol-1-yl)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol; and
- (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-pyrrol-1-yl)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R5 is not a direct bond to C14; C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15; R1 is —R8—OR9 or —R8—N(R9)2; R2 is —R8—OR9, —R8—CN, —R8—C(O)OR9, —R8—C(O)N(R9)2, —R8—N(R9)2, —R8—N(R9)C(O)R9, optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R4a and R4b together form methylene and R3 is —CH2—N(H)C(O)-(2-methyl)phenyl, —CH2—N(H)C(O)-(3-methyl)phenyl, —CH2—N(H)C(O)-(4-fluoro)phenyl, —CH2—N(H)C(O)-(4-methoxy)phenyl, —CH2—N(H)C(O)-(4-methyl)phenyl, —CH2—N(H)C(O)-(4-trifluoromethyl)phenyl, —CH2—N(H)C(O)-2-pyridinyl, —CH2—N(H)C(O)-2-pyrrolyl, —CH2—N(H)C(O)-3-pyridinyl, —CH2—N(H)C(O)-4-pyridinyl, —CH2—N(H)C(O)-benzodioxolyl, —CH2—N(H)C(O)-butyl, —CH2—N(H)C(O)CF3, —CH2—N(H)C(O)-cyclohexyl, —CH2—N(H)C(O)-cyclopropyl, —CH2—N(H)C(O)-ethyl, —CH2—N(H)C(O)-furanyl, —CH2—N(H)C(O)-isopropyl, —CH2—N(H)C(O)-naphthyl, —CH2—N(H)C(O)-phenyl, —CH2—N(H)C(O)-propyl, —CH2—N(H)C(O)-pyrazinyl, —CH2—N(H)C(O)-t-butyl or —CH2—CH2—N(H)C(O)benzodioxolyl; R5 is alkyl or R5 is a direct bond to C14; R6 is hydrogen; R7 is hydrogen, —R8—OR9 or a direct bond to C15; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —R8—OR9; R2 is —R8—OR9; R4a and R4b together form methylene and R3 is —CH2—N(H)C(O)-(2-methyl)phenyl, —CH2—N(H)C(O)-(3-methyl)phenyl, —CH2—N(H)C(O)-(4-fluoro)phenyl, —CH2—N(H)C(O)-(4-methoxy)phenyl, —CH2—N(H)C(O)-(4-methyl)phenyl, —CH2—N(H)C(O)-(4-trifluoromethyl)phenyl, —CH2—N(H)C(O)-2-pyridinyl, —CH2—N(H)C(O)-2-pyrrolyl, —CH2—N(H)C(O)-3-pyridinyl, —CH2—N(H)C(O)-4-pyridinyl, —CH2—N(H)C(O)-benzodioxolyl, —CH2—N(H)C(O)-butyl, —CH2—N(H)C(O)CF3, —CH2—N(H)C(O)-cyclohexyl, —CH2—N(H)C(O)-cyclopropyl, —CH2—N(H)C(O)-ethyl, —CH2—N(H)C(O)-furanyl, —CH2—N(H)C(O)-isopropyl, —CH2—N(H)C(O)-naphthyl, —CH2—N(H)C(O)-phenyl, —CH2—N(H)C(O)-propyl, —CH2—N(H)C(O)-pyrazinyl, —CH2—N(H)C(O)-t-butyl or —CH2—CH2—N(H)C(O)benzodioxolyl; R5 is alkyl; R6 is hydrogen; R7 is hydrogen; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —OH; R2 is —OH or —CH2OH; R4a and R4b together form methylene and R3 is —CH2—N(H)C(O)-(2-methyl)phenyl, —CH2—N(H)C(O)-(3-methyl)phenyl, —CH2—N(H)C(O)-(4-fluoro)phenyl, —CH2—N(H)C(O)-(4-methoxy)phenyl, —CH2—N(H)C(O)-(4-methyl)phenyl, —CH2—N(H)C(O)-(4-trifluoromethyl)phenyl, —CH2—N(H)C(O)-2-pyridinyl, —CH2—N(H)C(O)-2-pyrrolyl, —CH2—N(H)C(O)-3-pyridinyl, —CH2—N(H)C(O)-4-pyridinyl, —CH2—N(H)C(O)-benzodioxolyl, —CH2—N(H)C(O)-butyl, —CH2—N(H)C(O)CF3, —CH2—N(H)C(O)-cyclohexyl, —CH2—N(H)C(O)-cyclopropyl, —CH2—N(H)C(O)-ethyl, —CH2—N(H)C(O)-furanyl, —CH2—N(H)C(O)-isopropyl, —CH2—N(H)C(O)-naphthyl, —CH2—N(H)C(O)-phenyl, —CH2—N(H)C(O)-propyl, —CH2—N(H)C(O)-pyrazinyl, —CH2—N(H)C(O)-t-butyl or —CH2—CH2—N(H)C(O)benzodioxolyl; R5 is methyl; R6 is hydrogen; and R7 is hydrogen.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-2-naphthamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)benzamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)pivalamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)isobutyramide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)propionamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)butyramide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)pentanamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)nicotinamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)isonicotinamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)pyrazine-2-carboxamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)picolinamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-4-methoxybenzamide;
- 4-fluoro-N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)benzamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-4-(trifluoromethyl)benzamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methyl cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-4-methylbenzamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-2-methylbenzamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-1H-pyrrole-2-carboxamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-3-methylbenzamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)furan-2-carboxamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)cyclopropanecarboxamide;
- N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)cyclohexanecarboxamide;
- 2,2,2-trifluoro-N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)acetamide; and
- N-(2-((3aS,4S,5S,7aS)-5-((1R,2S,4S)-2,4-dihydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)ethyl)benzo[d][1,3]dioxole-5-carboxamide.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R5 is not a direct bond to C14; C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15; R1 is —R8—OR9 or —R8—N(R9)2; R2 is —R8—OR9, —R8—CN, —R8—C(O)OR9, —R8—C(O)N(R9)2, —R8—N(R9)2, —R8—N(R9)C(O)R9, optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R4a and R4b together form methylene and R3 is —CH2—N(H)CH2-(2,2-difluorobenzodioxolyl), —CH2—CH2—N(4-methoxybenzyl)2, —CH2—CH2—N(H)-(4-methoxy)benzyl, —CH2—N(H)-(2-fluoro-4-methoxy)benzyl, —CH2—N(H)-(2-fluoro-4-methyl)benzyl, —CH2—N(H)-(2-methoxy-4-fluoro)benzyl, —CH2—N(H)-(2-methyl)benzyl, —CH2—N(H)-(2-methyl-4-fluoro)benzyl, —CH2—N(H)-(3,5-dimethoxy)benzyl, —CH2—N(H)-(3-methyl)benzyl, —CH2—N(H)-(4-fluoro)benzyl, —CH2—N(H)-(4-methoxy)benzyl, —CH2—N(H)-(4-methyl)benzyl, —CH2—N(H)-(4-nitro)benzyl, —CH2—N(H)-(4-trifluoromethyl)benzyl, —CH2—N(H)-(4-benzoyl)benzyl, —CH2—N(H)CH2-benzimidazolyl, —CH2—CH2—N(H)CH2-benzodioxolyl, —CH2—N(H)CH2CH2-(4-methoxy)phenyl, or —CH2—N(H)CH2-pyridinyl; R5 is alkyl or R5 is a direct bond to C14; R6 is hydrogen; R7 is hydrogen, —R8—OR9 or a direct bond to C15; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —R8—OR9; R2 is —R8—OR9; R4a and R4b together form methylene and R3 is —CH2—N(H)CH2-(2,2-difluorobenzodioxolyl), —CH2—CH2—N(4-methoxybenzyl)2, —CH2—CH2—N(H)-(4-methoxy)benzyl, —CH2—N(H)-(2-fluoro-4-methoxy)benzyl, —CH2—N(H)-(2-fluoro-4-methyl)benzyl, —CH2—N(H)-(2-methoxy-4-fluoro)benzyl, —CH2—N(H)-(2-methyl)benzyl, —CH2—N(H)-(2-methyl-4-fluoro)benzyl, —CH2—N(H)-(3,5-dimethoxy)benzyl, —CH2—N(H)-(3-methyl)benzyl, —CH2—N(H)-(4-fluoro)benzyl, —CH2—N(H)-(4-methoxy)benzyl, —CH2—N(H)-(4-methyl)benzyl, —CH2—N(H)-(4-nitro)benzyl, —CH2—N(H)-(4-trifluoromethyl)benzyl, —CH2—N(H)-(4-benzoyl)benzyl, —CH2—N(H)CH2-benzimidazolyl, —CH2—CH2—N(H)CH2-benzodioxolyl, —CH2—N(H)CH2CH2-(4-methoxy)phenyl, or —CH2—N(H)CH2-pyridinyl; R5 is alkyl; R6 is hydrogen; R7 is hydrogen; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —OH; R2 is —OH or —CH2OH; R4a and R4b together form methylene and R3 is —CH2—N(H)CH2-(2,2-difluorobenzodioxolyl), —CH2—CH2—N(4-methoxybenzyl)2, —CH2—CH2—N(H)-(4-methoxy)benzyl, —CH2—N(H)-(2-fluoro-4-methoxy)benzyl, —CH2—N(H)-(2-fluoro-4-methyl)benzyl, —CH2—N(H)-(2-methoxy-4-fluoro)benzyl, —CH2—N(H)-(2-methyl)benzyl, —CH2—N(H)-(2-methyl-4-fluoro)benzyl, —CH2—N(H)-(3,5-dimethoxy)benzyl, —CH2—N(H)-(3-methyl)benzyl, —CH2—N(H)-(4-fluoro)benzyl, —CH2—N(H)-(4-methoxy)benzyl, —CH2—N(H)-(4-methyl)benzyl, —CH2—N(H)-(4-nitro)benzyl, —CH2—N(H)-(4-trifluoromethyl)benzyl, —CH2—N(H)-(4-benzoyl)benzyl, —CH2—N(H)CH2-benzimidazolyl, —CH2—CH2—N(H)CH2-benzodioxolyl, —CH2—N(H)CH2CH2-(4-methoxy)phenyl, or —CH2—N(H)CH2-pyridinyl; R5 is methyl; R6 is hydrogen; and R7 is hydrogen.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- (4-((((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methylamino)methyl)phenyl)(phenyl)methanone;
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((4-fluorobenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-((pyridin-4-ylmethylamino)methyl)octahydro-1H-inden-5-yl)cyclohexanol;
- (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-4-((4-methylbenzylamino)methyl)-1-methyleneoctahydro-1H-inden-5-yl)cyclohexanol;
- (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-4-((3-methylbenzylamino)methyl)-1-methyleneoctahydro-1H-inden-5-yl)cyclohexanol;
- (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-4-((2-methylbenzylamino)methyl)-1-methyleneoctahydro-1H-inden-5-yl)cyclohexanol;
- (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-((4-methoxybenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexanol;
- (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-((4-(trifluoromethyl)benzylamino)methyl)octahydro-1H-inden-5-yl)cyclohexanol;
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((3,5-dimethoxybenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(((1H-benzo[d]imidazol-2-yl)methylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-((4-nitrobenzylamino)methyl)octahydro-1H-inden-5-yl)cyclohexanol;
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((4-fluoro-2-methylbenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((2-fluoro-4-methoxybenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((4-fluoro-2-methoxybenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((2-fluoro-4-methylbenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-(bis(4-methoxybenzyl)amino)ethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexane-1,3-diol;
- (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-(4-methoxybenzylamino)ethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexane-1,3-diol;
- (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-((4-methoxyphenethylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexanol; and
- (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-(benzo[d][1,3]dioxol-5-ylmethylamino)ethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexane-1,3-diol.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R5 is not a direct bond to C14; C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15; R1 is —R8—OR9 or —R8—N(R9)2; R2 is —R8—OR9, —R8—CN, —R8—C(O)OR9, —R8—C(O)N(R9)2, —R8—N(R9)2, —R8—N(R9)C(O)R9, optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R4a and R4b together form methylene and R3 is —CH2—N(H)C(O)N(H)-benzyl, —CH2—N(H)C(O)N(H)-ethyl, —CH2—N(H)C(O)N(H)-phenyl or —CH2—N(H)C(S)N(H)CH3; R5 is alkyl or R5 is a direct bond to C14; R6 is hydrogen; R7 is hydrogen, —R8—OR9 or a direct bond to C15; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —R8—OR9; R2 is —R8—OR9; R4a and R4b together form methylene and R3 is —CH2—N(H)C(O)N(H)-benzyl, —CH2—N(H)C(O)N(H)-ethyl, —CH2—N(H)C(O)N(H)-phenyl or —CH2—N(H)C(S)N(H)CH3; R5 is alkyl; R6 is hydrogen; R7 is hydrogen; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —OH; R2 is —CH2OH; R4a and R4b together form methylene and R3 is —CH2—N(H)C(O)N(H)-benzyl, —CH2—N(H)C(O)N(H)-ethyl, —CH2—N(H)C(O)N(H)-phenyl or —CH2—N(H)C(S)N(H)CH3; R5 is methyl; R6 is hydrogen; and R7 is hydrogen.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- 1-ethyl-3-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)urea;
- 1-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-3-methylthiourea;
- 1-benzyl-3-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)urea; and
- 1-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-3-phenylurea.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R5 is not a direct bond to C14; C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15; R1 is —R8—OR9 or —R8—N(R9)2; R2 is —R8—OR9, —R8—CN, —R8—C(O)OR9, —R8—C(O)N(R9)2, —R8—N(R9)2, —R8—N(R9)C(O)R9, optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R4a and R4b together form methylene and R3 is —CH2-benzimidazolyl, —CH2-indolinyl, —CH2-indolyl, —CH2-purinyl, —CH2-pyrazolyl or —CH2-triazolyl; R5 is alkyl or R5 is a direct bond to C14; R6 is hydrogen; R7 is hydrogen, —R8—OR9 or a direct bond to C15; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —R8—OR9; R2 is —R8—OR9; R4a and R4b together form methylene and R3 is —CH2-benzimidazolyl, —CH2-indolinyl, —CH2-indolyl, —CH2-purinyl, —CH2-pyrazolyl or —CH2-triazolyl; R5 is alkyl; R6 is hydrogen; R7 is hydrogen; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —OH; R2 is —CH2OH; R4a and R4b together form methylene and R3 is —CH2-benzimidazolyl, —CH2-indolinyl, —CH2-indolyl, —CH2-purinyl, —CH2-pyrazolyl or —CH2-triazolyl; R5 is methyl; R6 is hydrogen; and R7 is hydrogen.
- Another embodiment is a compound of formula (I), as described above in the Summary of the Invention, selected from:
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-pyrazol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-1,2,4-triazol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-benzo[d]imidazol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((6-amino-9H-purin-9-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
- (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-indol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol; and
- (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-(indolin-1-ylmethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexanol.
- Another embodiment of the Invention is a compound of formula (Ia):
- wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R5 is not a direct bond to C14; C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15; R1 is —R8—OR9 or —R8-N(R9)2; R2 is —R8—OR9, —R8—CN, —R8—C(O)OR9, —R8—C(O)N(R9)2, —R8—N(R9)2, —R8—N(R9)C(O)R9, optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R4a is hydrogen or alkyl, R4b is a direct bond to the carbon to which R7 is attached, and R3 is —CH2NH2 or —CH2N(H)C(O)(CH2)3CH3; or R4a and R4b are each independently selected from hydrogen and alkyl and R3 is —CH2OH, —CH2NH2, —CH2N(H)CH3, —CH2N(CH3)2, —CH2N(H)CH2-cyclopropyl, —CH2N(H)CH2-pyrrolyl, —CH2N(H)C(O)CH3, —CH2N(H)C(O)-phenyl, —CH2N(H)S(O)2CH3 or —CH2N(H)C(═NH)NH2; or R4a and R4b together form methylene and R3 is —CH2—N(H)CH2-benzodioxolyl; R5 is alkyl or R5 is a direct bond to C14; R6 is hydrogen; R7 is hydrogen, —R8—OR9 or a direct bond to C15, provided that when R7 is a direct bond to C15, R4b is not a direct bond to the carbon to which R7 is attached; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt or solvate thereof.
- Of this embodiment, one embodiment is a compound of formula (Ia) wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R5 is not a direct bond to C14; C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15; R1 is —R8—OR9 or —R8—N(R9)2; R2 is —R8—OR9, —R8—CN, —R8—C(O)OR9, —R8—C(O)N(R9)2, —R8—N(R9)2, —R8—N(R9)C(O)R9, optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R4a and R4b together form methylene and R3 is —CH2—N(H)CH2-benzodioxolyl; R5 is alkyl or R5 is a direct bond to C14; R6 is hydrogen; R7 is hydrogen, —R8—OR9 or a direct bond to C15; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Of this embodiment, another embodiment is a compound of formula (Ia) wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R5 is not a direct bond to C14; C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15; R1 is —R8—OR9 or —R8-N(R9)2; R2 is —R8—OR9, —R8—CN, —R8—C(O)OR9, —R8—C(O)N(R9)2, —R8—N(R9)2, —R8—N(R9)C(O)R9, optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R4a and R4b together form methylene and R3 is —CH2—N(H)CH2-benzodioxolyl; R5 is alkyl or R5 is a direct bond to C14; R6 is hydrogen; R7 is hydrogen, —R8—OR9 or a direct bond to C15; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Of this embodiment, another embodiment is a compound of formula (Ia) wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —R8—OR9; R2 is —R8—OR9; R4a and R4b together form methylene and R3 is —CH2—N(H)CH2-benzodioxolyl; R5 is alkyl; R6 is hydrogen; R7 is hydrogen; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
- Of this embodiment, another embodiment is a compound of formula (Ia) wherein C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen; C15 is substituted with two hydrogens; R1 is —OH; R2 is —OH or —CH2OH; R4a and R4b together form methylene and R3 is —CH2—N(H)CH2-benzodioxolyl; R5 is methyl; R6 is hydrogen; and R7 is hydrogen.
- Of this embodiment, another embodiment is a compound of formula (Ia) which is (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((benzo[d][1,3]dioxol-5-ylmethylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol.
- It is understood that any embodiment of the compounds of the invention, as set forth above, and any specific substituent set forth herein for a particular R group in the compounds of the invention, as set forth above, may be independently combined with other embodiments and/or substituents of compounds of the invention to form embodiments of the inventions not specifically set forth above. In addition, in the event that a list of substituents is listed for any particular R group in a particular embodiment and/or claim, it is understood that each individual substituent may be deleted from the particular embodiment and/or claim and that the remaining list of substituents will be considered to be within the scope of the invention.
- Another preferred embodiment of the various aspects of the invention is an embodiment of the methods for treating a disease, disorder or condition in a mammal in need thereof is where the disease, disorder or condition is an autoimmune disease, disorder or condition, an inflammatory disease, disorder or condition, or a neoplastic or cell proliferative disease, disorder or condition.
- Another embodiment of the methods for treating a disease, disorder or condition in a mammal in need thereof is where the disease, disorder or condition is an autoimmune disease, disorder or condition selected from idiopathic pulmonary fibrosis, an inflammatory bowel disease, rheumatoid arthritis, Still's Disease, Sjögren's Syndrome, systemic lupus erythematosus, multiple sclerosis, psoriasis and systemic sclerosis.
- Another embodiment of the methods for treating a disease, disorder or condition in a mammal in need thereof is where the disease, disorder or condition is an inflammatory bowel disease selected from Crohn's Disease and ulcerative colitis.
- Another embodiment of the methods for treating a disease, disorder or condition in a mammal in need thereof is where the disease, disorder or condition is an inflammatory disease, disorder or condition selected from acute respiratory distress syndrome, allergic rhinitis, Alzheimer's Disease, asthma, an ocular inflammatory disease, atopic dermatitis, bladder pain syndrome/interstitial cystitis, chronic obstructive pulmonary disease (COPD) including emphysematous, bronchitic, and alpa 1 anti-trypsin deficiency related COPD; dermal contact hypersensitivy, eczema, eosiniphilic gastrointestinal disorder, fibromyalgia, gout, hepatic fibrosis, irritable bowl syndrome, ischemic reperfusion disease, kidney fibrosis, pancratitis, Parkisons Disease, post operative inflammation, a seronegative spondyloarthropathy, and vasculitis.
- Another embodiment of the methods for treating a disease, disorder or condition in a mammal in need thereof is where the disease, disorder or condition is an ocular inflammatory disease selected from allergic conjunctivitis, dry eye, and uveitis.
- Another embodiment of the methods for treating a disease, disorder or condition in a mammal in need thereof is where the disease, disorder or condition is a seronegative spondyloarthropathy selected from anklyosing spondylitis, psoriatic arthritis, and Reiter's Syndrome.
- Another embodiment of the methods for treating a disease, disorder or condition in a mammal in need thereof is where the disease, disorder or condition is vasculitis selected from Wegener's Granulomatosis, polyarteritis nodosa, leucocytoclastic vasculitis, Churg-Strauss Syndrome, cryoglobulinemic vasculitis, and giant cell arteritis.
- Another embodiment of the methods for treating a disease, disorder or condition in a mammal in need thereof is where the disease, disorder or condition is a neoplastic or cell proliferative disease, disorder or condition selected from acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, basophilic leukemia, cutaneous T-cell lymphoma, Sezary Syndrome, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, hypereosinophilic syndromes, mastocytosis and thrombocythemia.
- Another embodiment of the invention is a method of using the compounds of formula (I) as standards or controls in in vitro or in vivo assays in determining the efficacy of test compounds in modulating SHIP1 activity.
- In another embodiment of the invention, the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabelled) compounds of formula (I) are considered to be within the scope of this invention.
- Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. These isotopically-labeled compounds would be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action for SHIP1 modulation, or binding affinity to pharmacologically important site of action for SHIP1 modulation. Certain isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
- Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
- Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
- In other embodiments, preferred stereochemistry of the compounds of formula (I) is shown below:
- Specific embodiments of the compounds of the invention are described in more detail below in the Preparation of the Compounds of the Invention and in the Examples.
- Compounds of formula (I) above have activity as SHIP1 modulators and utility over a wide range of therapeutic applications, and may be used to treat any of a variety of diseases, disorders or conditions that would benefit from SHIP1 modulation. For example, such diseases, disorders or conditions include (but are not limited to) autoimmune diseases such as idiopathic pulmonary fibrosis, inflammatory bowel disease (including Crohn's Disease and ulcerative colitis), rheumatoid arthritis, Still's Disease, Sjögren's Syndrome, systemic lupus erythematosus, multiple sclerosis, psoriasis, and systemic sclerosis; inflammatory diseases such as acute respiratory distress syndrome (ARDS), allergic rhinitis, Alzheimer's Disease, asthma, ocular inflammatory diseases (including allergic conjunctivitis, dry eye, and uveitis), chronic obstructive pulmonary disease (COPD) including emphysematous, brochitic, and COPD due to alpha 1 anti-trypsin deficiency, atopic dermatitis, dermal contact hypersensitivity, eczema, eosiniphilic gastrointestinal disorder, fibromyalgia, gout, hepatic fibrosis, irritable bowl syndrome, bladder pain syndrome/interstitial cystitis, post operative inflammation, ischemic reperfusion disease, kidney fibrosis, pancreatitis, Parkinsons Disease, seronegative spondyloarthropathies (including anklyosing spondylitis, psoriatic arthritis, and Reiter's Syndrome), and vasculitis (including Wegener's Granulomatosis, polyarteritis nodosa, leucocytoclastic vasculitis, Churg-Strauss Syndrome, cryoglobulinemic vasculitis and giant cell arteritis); and neoplastic diseases or other cell proliferative disorders such as acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, basophilic leukemia, cutaneous T-cell lymphoma, Sezary Syndrome, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, hypereosinophilic syndromes, mastocytosis and thrombocythemia.
- The effectiveness of a compound as a SHIP1 modulator may be determined by any number of known techniques, including the assays set forth below in Examples 98-101.
- For the purposes of administration, the compounds of the present invention may be formulated as pharmaceutical compositions. Pharmaceutical compositions comprise one or more compounds of this invention in combination with a pharmaceutically acceptable carrier and/or diluent. The compound is present in the composition in an amount which is effective to treat a particular disorder, that is, in an amount sufficient to achieve SHIP1 modulation activity, and preferably with acceptable toxicity to the patient. Typically, the pharmaceutical compositions of the present invention may include a compound in an amount from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more typically from 1 mg to 60 mg. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
- Pharmaceutically acceptable carrier and/or diluents are familiar to those skilled in the art. For compositions formulated as liquid solutions, acceptable carriers and/or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. The compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a compound of this invention, diluents, dispersing and surface active agents, binders, and lubricants. One skilled in this art may further formulate the compounds in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences (Mack Pub. Co., N.J. current edition).
- In another embodiment, the present invention provides a method for modulation SHIP1 generally and, more specifically, to treating the diseases, disorders and conditions as discussed above. Such methods include administering of a compound of the present invention to a mammal, preferably a human, in an amount sufficient to treat the condition. In this context, “treat” includes prophylactic administration. Such methods include systemic administration of a compound of this invention, preferably in the form of a pharmaceutical composition as discussed above. As used herein, systemic administration includes oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives. For parenteral administration, the compounds of the present invention can be prepared in aqueous injection solutions which may contain buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.
- The following Reaction Schemes illustrate methods to make compounds of the present invention, i.e., compounds of formula (I), as set forth above in the Summary of the Invention.
- The compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples. In general, the compounds of formula (I) may be made by the following Reaction Schemes, wherein all substituents are as defined above unless indicated otherwise. Although not generally depicted in the following schemes, one skilled in the art will understand that appropriate protecting group strategies may be useful in preparing compounds of formula (I). Protecting group methodology is well known to those skilled in the art (see, for example, Greene, T. W. and Wuts, P. G. M. Greene's Protective Groups in Organic Synthesis (2006), 4th Ed. Wiley).
- It is also understood that one skilled in the art would be able to make the compounds of the invention by similar methods, by methods known to one skilled in the art, or by methods similar to the methods disclosed in U.S. Pat. Nos. 6,635,629 and 7,601,874. It is also understood that one skilled in the art would be able to make in a similar manner as described below other compounds of the invention not specifically illustrated below by using the appropriate starting components and modifying the parameters of the synthesis as needed. In general, starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, e.g., Smith, M. B. and J. March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th edition (Wiley, 2007)) or prepared as described herein. Certain starting materials, or their salts thereof, may be prepared according to the methods disclosed in U.S. Pat. Nos. 6,635,629 and 7,601,874, the relevant disclosures therein are incorporated in reference herein, or by methods known to one skilled in the art.
- It is also understood that in the following description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds.
- It will also be appreciated by those skilled in the art, although protected derivatives of compounds of this invention may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as “prodrugs”. All prodrugs of compounds of this invention are included within the scope of the invention.
- Although depicted without stereochemistry, one skilled in the art will recognize that the compounds depicted in the following general Reaction Schemes can also be prepared in an optically pure form by utilizing methods known to one skilled in the art, such as the use of stereoselective reagents, chiral starting materials and phase transfer catalysts.
- The following abbreviations may be used herein in the following general reaction schemes and the Examples:
- Ac2O for acetic anhydride;
- AcOH for acetic acid;
- AlMe3 for trimethylaluminum;
- Boc for tert-butoxycarbonyl;
- BH3.THF for borane tetrahydrofuran complex;
- BnBr for benzyl bromide;
- Bu3SnH for tributyltin hydride;
- n-BuLi for n-butyl lithium;
- t-BuOOH for tert-butyl hydroperoxide;
- CDI for 1,1′-carbonyldiimidazole;
- d for days;
- DABCO for 1,4-diazalbicyclo[2.2.2]octane;
- DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene;
- DCC for N,N′-dicyclohexylcarbodiimide;
- DCE for dichloroethane;
- DIAD for diisopropyl azodicarboxylate;
- Diglyme for diethylene glycol dimethyl ether;
- DIPEA/DIEA for N,N-diisopropylethylamine;
- DMAP for 4-dimethylaminopyridine;
- DMF for N,N-dimethylformamide;
- DMSO for dimethyl sulfoxide;
- DPPA for diphenylphosphoryl azide;
- Et2O for diethyl ether;
- Et3N for triethylamine;
- EtNCO for ethyl isocyanate;
- EtOAc for ethyl acetate;
- EtOH for ethanol;
- h for hours;
- H2/Pd/C for hydrogen on palladium on charcoal;
- H2NMe.HCl for methylamine hydrochloride;
- HBTU for O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate;
- IBX for 2-iodoxybenzoic acid;
- Imid for imidazole;
- i-PrOH for iso-propanol;
- Imid. for imidazole;
- KOtBu for potassium tert-butoxide;
- LiAlH4/LAH for lithium aluminum hydride;
- LiEt3BH for lithium triethylborohydride (Super hydride);
- m-CPBA/MCPBA for m-chloroperoxybenzoic acid;
- m for minutes;
- MeCN for acetonitrile;
- MeI for methyl iodide;
- MeNCS for methyl isocyanate;
- 2-MePhCO2H for o-toluic acid;
- 3-MePhCO2H for m-toluic acid;
- 4-MePhCO2H for p-toluic acid;
- Me4Phen for 3,4,7,8-tetramethyl-[1,10]-phenanthroline;
- MeOCH2PPh3Cl for methoxymethyl triphenylphosphonium chloride;
- MeOH for methanol;
- MePPh3Br for methyl triphenylphosphonium bromide;
- MeSO3SiMe3 for trimethylsilylmethanesulfonate;
- MsCl for mesyl chloride;
- MW for microwave;
- NaOMe for sodium acetate;
- NaSEt for sodium ethanethiolate;
- NaBH(OAc)3 for sodium triacetoxyborohydride;
- n-BuLi for n-butyllithium;
- NMO for N-methylmorpholine N-oxide;
- NMP for N-methyl-2-pyrrolidone;
- NMR for nuclear magnetic resonance;
- pTsNHNH2 for para-toluenesulfonyl hydrazide;
- PCC for pyridinium chlorochromate;
- Pd/C for palladium metal on charcoal;
- PhCO2H for benzoic acid;
- PPh3 for triphenylphosphine;
- Ph3PMeBr for methyltriphenylphosphonium bromide;
- PhMe for toluene;
- PivCl for trimethylacetyl chloride;
- POCl3 for phosphoryl chloride;
- PTSA/PTSA.H2O for para-toluenesulfonic acid/para-toluenesulfonic acid monohydrate;
- PyBOP for benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate;
- Pyr for pyridine;
- SEMCl for 2-(trimethylsilyl)ethoxymethyl chloride;
- SEM for 2-(trimethylsilyl)ethoxymethyl;
- TBAF for tetrabutylammonium fluoride;
- TBDPS for tert-butyldiphenylsilyl;
- TBDPS for tert-butyldiphenylsilyl;
- TBDPSCI for tert-butyldiphenylsilyl chloride;
- TBS/TBDMS for tert-butyldimethylsilyl;
- TBSCl for tert-butyldimethylsilyl chloride;
- TBTU for O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate;
- TEA for triethylamine;
- TFA for trifluoroacetic acid;
- TFAA for trifluoroacetic anhydride;
- THF for tetrahydrofuran;
- TLC for thin layer chromatography;
- TMSOTf for trimethylsilyl triflate;
- TPAP for tetrapropylammonium perruthenate;
- TPSH for 2,4,6-triisopropylbenzenesulfonyl hydrazide; and
- VAZO® for 1,1′-azobis(cyclohexanecarbonitrile).
- Compounds of formula (I-1) are compounds of formula (I), as defined above in the Summary of the Invention, where R1 and R2 are both —R8—OH, R4a and R4b together form methylene and R3 is —CH2-benzimidazolyl, —CH2-indolinyl, —CH2-indolyl, —CH2-purinyl, —CH2-pyrazolyl, —CH2-triazolyl, and are prepared as described below in Reaction Scheme 1 where R5, R6, R7 and each R8 are as described above in the Summary of the Invention for compounds of formula (I), R3a is benzimidazole, imidazole, indoline, indole, purine, pyrazole or triazole, Pg1 and Pg2 are each independently selected from an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl, Lg1 is a functional group which forms a leaving group with the oxygen to which it is attached, such as mesyl or tosyl, and X is bromo or chloro.
- Compounds of formula (A) may be prepared by methods known to one skilled in the art or by the methods disclosed in U.S. Pat. No. 7,601,874. Compounds of formula (C) and (E) are commercially available, or can be prepared according to methods known to one skilled in the art.
- In general, compounds of formula (I-1) are prepared, as described above in Reaction Scheme 1, by first protecting a compound of formula (A) under standard oxygen protecting conditions, such as treating the compound of formula (A) with the appropriate oxygen-protecting group under basic conditions in an aprotic solvent. The resulting oxygen-protected compound of formula (B) is then treated with a compound of formula (C) under standard leaving group formation conditions, such as treatment with the appropriate oxygen-activating group under basic conditions in an aprotic solvent, to yield the compound of formula (D). The compound of formula (D) is then treated with a compound of formula (E) under standard nucleophilic substitution conditions, such as treatment of the compound of formula (D) with the appropriate nucleophile under basic conditions in an aprotic solvent, to yield the compound of formula (F). Deprotection of the oxygens in the compound of formula (F) under standard conditions, such as treatment with the appropriate oxygen-deprotecting reagent in a protic solvent, yields the compound of formula (I-1).
- Compounds of formula (D) can be treated with the appropriate cyanating agent, such as potassium cyanide, under standard conditions, such as in the presence of an aprotic solvent, such as DMSO, to yield a compound of formula (F) where R3a is —CN, which can be deprotected to yield a compound of formula (I-1) wherein R3a is —CN, or which can then be reduced under standard conditions to yield a compound of formula (I-1) where R3a is —CH2NH2.
- The compound of formula (I-1) wherein R3a is —CN can be hydrolyzed in the presence of hydrogen peroxide to yield a compound of formula (I-1) wherein R3a is —C(O)NH2.
- Compounds of formula (B) can be treated under standard oxidizing conditions to form the corresponding aldehyde, which can then further oxidized to form the corresponding carboxy and then deprotected to form a compound of formula (I) where R3 is —C(O)OH.
- Compounds of formula (I-2) are compounds of formula (I), as defined above in the Summary of the Invention, where R1 and R3 are both —R8—OH, R4a and R4b together form methylene and R2 is heteroarylalkyl, and are prepared as described below in Reaction Scheme 2A where R5, R6, R7 and each R8 are as described above in the Summary of the Invention for compounds of formula (I), R2a is heteroaryl, Pg1 and Pg2 are each independently selected from an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl, Lg1 is a functional group which forms a leaving group with the oxygen to which it is attached, such as mesyl or tosyl, and X is bromo or chloro.
- Compounds of formula (G) may be prepared by methods known to one skilled in the art or by the methods disclosed in U.S. Pat. No. 7,601,874. Compounds of formula (C) and (J) are commercially available, or can be prepared according to methods known to one skilled in the art.
- In general, compounds of formula (I-2) are prepared, as described above in Reaction Scheme 2A, by first treating a compound of formula (G) with the compound of formula (C) under standard leaving group formation conditions, such as treating the compound of formula (G) with the appropriate oxygen-activating group under basic conditions in an aprotic solvent, to yield a compound of formula (H). The compound of formula (H) is then treated with a compound of formula (J) under standard nucleophilic substitution conditions, such as basic conditions in an aprotic solvent, to form a compound of formula (K). Treatment of the compound of formula (K) with acetic acid under standard conditions removes the ketal and Pg1 to form the compound of formula (L). Olefination of the compound of formula (L) with the appropriate agent, such as methyl triphenylphosphonium bromide, in the presence of a base, such as KOtBu, provides the compound of formula (M). Treatment of the compound of formula (M) under standard deprotecting conditions, such as treatment with the appropriate oxygen-deprotecting reagent in an aprotic solvent, yields the compound of formula (I-2).
- Alternatively, compounds of formula (I-2) can be prepared according the process described below in Reaction Scheme 2B wherein R5, R6, R7, R8, R2a, Pg1, Pg2, Lg1 and X are as described above for Reaction Scheme 2A.
- Compounds of formula (N) may be prepared by methods known to one skilled in the art or by the methods disclosed in U.S. Pat. No. 7,601,874. Compounds of formula (J) are commercially available, or can be prepared according to methods known to one skilled in the art.
- In general, compounds of formula (I-2) are prepared, as described above in Reaction Scheme 2B, by first treating a compound of formula (N) with a compound of formula (J) under standard nucleophilic substitution conditions, such as basic conditions in an aprotic solvent, to form a compound of formula (O). Treatment of compound of formula (O) under standard deprotecting conditions, such as treatment with the appropriate oxygen-deprotecting reagent in an aprotic solvent, yields the compound of formula (P), which is further deprotected to yield the compound of formula (I-2).
- Alternatively, compounds of formula (I-2) can be prepared by treating a compound of formula (N), as described above in Reaction Scheme 2B, with a compound of formula (J) under standard conditions, such as under basic conditions in an aprotic solvent, to yield a compound of formula (I-2), as described above.
- Alternatively, compounds of formula (I-2) can be prepared from compounds of formula (V), which can be prepared by the process described below in Reaction Scheme 2C wherein R5, R6, R7, R8, Pg1 and Pg2 are as described above for Reaction Schemes 2A and 2C, and Pg3 is acetyl.
- Compounds of formula (N) can be treated with a cyanating agent, such as potassium cyanide, and then deprotected to form compounds of formula (I-2) where R2a is cyano. Such compounds can be further hydrolyzed to the corresponding amide or carboxylic acid by procedures known to one skilled in the art.
- Compounds of formula (Q) are prepared by methods known to one skilled in the art or by methods disclosed in U.S. Pat. No. 6,635,629 or by methods disclosed herein.
- In general, compounds of formula (V) are prepared by the process disclosed in Reaction Scheme 3 by first treating a compound of formula (Q) under standard Baeyer-Villager oxidation conditions, such as using 3-chloroperoxybenzoic acid (MCPBA) in CHCl3 to yield the lactone compound of formula (R). Reduction of the lactone under standard procedures, such as treating the compound of formula (R) with the appropriate reducing agent in an aprotic solvent, yields the diol compound of formula (S). Sequential protection of the primary hydroxyl groups in the compound of formula (S) under standard procedures yields the compounds of formula (T) and (U), respectively. Treatment of the compound of formula (U) with acetic acid under standard conditions removes the ketal and Pg2 to yield the compound of formula (V).
- The compound of formula (V) can then treated with the appropriate reagent under standard nucleophilic substitution conditions to form the compound of formula (I-2).
- Compounds of formula (I-3) are compounds of formula (I), as defined above in the Summary of the Invention, where R1 and R2 are both —R8—OH, R4a and R4b together form methylene and R3 is —CH2—N(H)—CN, —CH2—N(H)-(4-benzoyl)benzyl, and —CH2—N(H)-(3,5-dimethoxy)benzyl, and are prepared as described below in Reaction Scheme 3 where R5, R6, R7 and each R8 are as described above in the Summary of the Invention for compounds of formula (I), R3b is cyano, methylbenzophenone or dimethoxybenzyl, Pg1 and Pg2 are each independently selected from an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl, and X is bromo or chloro.
- Compounds of formula (W) are prepared by methods known to one skilled in the art or by methods similar to those described in U.S. Pat. No. 7,601,874 or by methods disclosed herein. Compounds of formula (Y) are commercially available or can be prepared by methods known to one skilled in the art.
- In general, compounds of formula (I-3) are prepared, as described above in Reaction Scheme 3, by first treating a compound of formula (Q) under standard reduction conditions, such as Staudinger reaction conditions, to yield a compound of formula (X). The compound of formula (X) is then treated with a compound of formula (Y) under standard alkylation conditions, such as under basic conditions in an aprotic solvent, to yield the compound of formula (Z), which is then deprotected under standard deprotecting conditions, such as treating the compound of formula (Z) with the appropriate oxygen-deprotecting reagent in a protic solvent, to yield the compound of formula (I-3).
- Compounds of formula (I-4) are compounds of formula (I), as defined above in the Summary of the Invention, or compounds of formula (Ia), as defined above in the Embodiments, where R1 and R2 are both —R8—OH, R4a and R4b together form methylene and R3 is —CH2—N(H)-(4-fluoro)benzyl, —CH2—N(H)—CH2-pyridinyl, —CH2—N(H)-(4-methyl)benzyl, —CH2—N(H)-(3-methyl)benzyl, —CH2—N(H)-(2-methyl)benzyl, —CH2—N(H)-(4-methoxy)benzyl, —CH2CH2—N(H)-(4-methoxy)benzyl, —CH2—N(H)-(4-trifluoromethyl)benzyl, —CH2—N(H)—CH2-benzimidazolyl, —CH2—N(H)—CH2-benzodioxolyl, —CH2CH2—N(H)—CH2-benzodioxolyl, —CH2—N(H)-(4-nitro)benzyl, —CH2—N(H)—CH2-(2,2-difluorobenzodioxolyl), —CH2—N(H)-(2-methyl-4-fluoro)benzyl, —CH2—N(H)-(2-fluoro-4-methyl)benzyl, —CH2—N(H)-(2-methoxy-4-fluoro)benzyl, —CH2—N(H)-(2-fluoro-4-methoxy)benzyl, —CH2—N(H)-(4-methoxybenzyl)2, or —CH2—N(H)—CH2CH2-(4-methoxy)phenyl, and are prepared as described below in Reaction Scheme 4 where R5, R6, R7 and each R8 are as described above in the Summary of the Invention for compounds of formula (I), R3d is -(4-fluoro)phenyl, -pyridinyl, -(4-methyl)phenyl, -(3-methyl)phenyl, -(2-methyl)phenyl, -(4-methoxy)phenyl, -(4-trifluoromethyl)phenyl, -benzimidazolyl, -benzodioxolyl, -(4-nitro)phenyl, -(2,2-difluorobenzodioxolyl), -(2-methyl-4-fluoro)phenyl, -(2-fluoro-4-methyl)phenyl, -(2-methoxy-4-fluoro)phenyl, -(2-fluoro-4-methoxy)phenyl, -(4-methoxyphenyl)2, or —CH2-(4-methoxy)phenyl.
- Compounds of formula (AA) can be prepared by methods known to one skilled in the art, by methods similar to the methods disclosed in U.S. Pat. No. 7,601,874 or by methods disclosed herein. Compounds of formula (BB) are commercially available or can be prepared by methods known to one skilled in the art.
- In general, compounds of formula (I-4) are prepared, as described above in Reaction Scheme 4, by treating a compound of formula (AA) with a compound of formula (BB) under standard reductive amination conditions, such as the appropriate reducing agent in a solvent mixture. The hydroxyls of compound (AA) may optionally be protected by standard oxygen-protecting procedures known to one skilled in the art prior to the reaction of the compound of formula (AA) with the compound of formula (BB), and the resulting compound may then be deprotected according to methods known to one skilled in the art to arrive at the compound of formula (I-4).
- Alternatively, compounds of formula (AA) can be treated with ethyl isocyanate, phenyl, isocyanate, benzyl isocyanate or methyl isothiocyanate under conditions known to one skilled in the art to yield compounds of formula (I) wherein R3 is —CH2—N(H)C(O)N(H)-benzyl, —CH2—N(H)C(O)N(H)-ethyl, —CH2—N(H)C(O)N(H)-phenyl or —CH2—N(H)C(S)N(H)CH3.
- Compounds of formula (I-5) are compounds of formula (I), as defined above in the Summary of the Invention, where R1 and R3 are both —R8—OH, R4a and R4b together form methylene and R2 is heterocyclylalkyl, and are prepared as described below in Reaction Scheme 5 where R5, R6, R7 and each R8 are as described above in the Summary of the Invention for compounds of formula (I), R2b is heterocyclyl and Pg1 and Pg2 are each independently selected from an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl.
- Compounds of formula (Ga) are compounds of formula (G) as described above in Reaction Scheme 2A. Compounds of formula (DD) can be prepared by methods known to one skilled in the art or by methods disclosed herein.
- In general, compounds of formula (I-5) are prepared, as described above in Reaction Scheme 5, by treating a compound of formula (Ga) with an oxidizing agent, such as TPAP and NMO, to form the ketone compound of formula (CC). The compound of formula (CC) is then treated with a compound of formula (DD) under standard reductive amination conditions, such as treatment with the appropriate reducing agent combination in an aprotic solvent, to form the compound of formula (EE). Treatment of the compound of formula (EE) with acetic acid under standard conditions removes the ketal and Pg1 to form the compound of formula (FF). Olefination of the compound of formula (FF) with the appropriate agent, such as methyl triphenylphosphonium bromide, in the presence of a base, such as KOtBu, provides the compound of formula (GG). Treatment of the compound of formula (GG) under standard deprotecting conditions, such as treatment with the appropriate oxygen-deprotecting reagent in an aprotic solvent, yields the compound of formula (I-5).
- Alternatively, the hydroxyl group in the compound of formula (Ga) can first be optionally protected under standard oxygen-protecting procedures and the protected compound can then be treated under similar conditions as the treatment of compounds of formula (EE) and formula (FF) to form the corresponding compound where R4a and R4b form methylene, which can then be deprotected, oxidized and treated with a compounds of formula (DD) to produce a compound of formula (GG), which is then treated to deprotecting conditions to form the compound of formula (I-5).
- Compounds of formula (I-6) are compounds of formula (I), as defined above in the Summary of the Invention, where R1 and R2 are both —R8—OH, R3 is —CH2N(H)C(O)CH3, —CH2—N(H)C(O)-(2-methyl)phenyl, —CH2—N(H)C(O)-(3-methyl)phenyl, —CH2—N(H)C(O)-(4-fluoro)phenyl, —CH2—N(H)C(O)-(4-methoxy)phenyl, —CH2—N(H)C(O)-(4-methyl)phenyl, —CH2—N(H)C(O)-(4-trifluoromethyl)phenyl, —CH2—N(H)C(O)-2-pyridinyl, —CH2—N(H)C(O)-2-pyrrolyl, —CH2—N(H)C(O)-3-pyridinyl, —CH2—N(H)C(O)-4-pyridinyl, —CH2—N(H)C(O)-benzodioxolyl, —CH2—N(H)C(O)-butyl, —CH2—N(H)C(O)CF3, —CH2—N(H)C(O)-cyclohexyl, —CH2—N(H)C(O)-cyclopropyl, —CH2—N(H)C(O)-ethyl, —CH2—N(H)C(O)-furanyl, —CH2—N(H)C(O)-isopropyl, —CH2—N(H)C(O)-naphthyl, —CH2—N(H)C(O)-phenyl, —CH2—N(H)C(O)-propyl, —CH2—N(H)C(O)-pyrazinyl, —CH2—N(H)C(O)-t-butyl or —CH2—CH2—N(H)C(O)benzodioxolyl, and are prepared as described below in Reaction Scheme 6 where R4a, R4b, R5, R6, R7 and each R8 are as described above in the Summary of the Invention for compounds of formula (I) and R3e is —CH3, -(2-methyl)phenyl, -(3-methyl)phenyl, -(4-fluoro)phenyl, -(4-methoxy)phenyl, -(4-methyl)phenyl, -(4-trifluoromethyl)phenyl, -2-pyridinyl, -2-pyrrolyl, -3-pyridinyl, -4-pyridinyl, -benzodioxolyl, -butyl, —CF3, -cyclohexyl, -cyclopropyl, -ethyl, -furanyl, -isopropyl, -naphthyl, -phenyl, -propyl, -pyrazinyl, -t-butyl or -benzodioxolyl.
- Compounds of (HH) can be prepared according to methods known to one skilled in the art or by methods similar to the methods disclosed in U.S. Pat. No. 7,601,874 or by methods disclosed herein. Compounds of formula (JJ) are commercially available or can be prepared by methods known to one skilled in the art.
- In general, compounds of formula (I-6) are prepared, as described above in Reaction Scheme 6, by treating a compound of formula (HH) with a compound of formula (JJ) under suitable conditions, such as treatment with a coupling reagent in an aprotic solvent, to form a compound of formula (I-6). The hydroxyls of the compound of formula (HH) may first be optionally protected by treating the compound of formula (HH) under the appropriate oxygen-protecting conditions. The resulting protected compound of formula (HH) may then be treated with the compound of formula (JJ) under suitable conditions to form the protected compound of formula (I-6), which can then be deprotected under standard deprotection conditions to form the compound of formula (I-6).
- Compounds of formula (HH) where R4a and R4b together form ethylidene are prepared by methods disclosed in U.S. Pat. No. 7,601,874 and can be treated to standard reducing conditions to form compounds of formula (HH) where R4a is ethyl and R4b is hydrogen.
- Alternatively, compounds of formula (HH) where R4a and R4b together form methylene can be treated with the appropriate acid, such as p-toulenesulfonic acid, to yield a compound of formula (I) where R4a is alkyl and R4b is a direct bond to the carbon to which R7 is attached.
- Compounds of formula (I-7) are compounds of formula (I), as defined above in the Summary of the Invention, where R1 and R3 are both —R8—OH, R4a and R4b together form methylene and R2 is —R8—N(R9)C(O)R9 where R9 is as defined above in the Summary of the Invention for compounds of formula (I), and are prepared as described below in Reaction Scheme 7 where R5, R6, R7 and each R8 are as described above in the Summary of the Invention for compounds of formula (I), R2c is R9 as defined above in the Summary of the Invention for compounds of formula (I), and Pg1 and Pg2 are each independently selected from an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl.
- Compounds of formula (G) are described above in Reaction Scheme 2A. Compounds of formula (MM) are commercially available or can be prepared by methods known to one skilled in the art.
- In general, compounds of formula (I-7) are prepared, as described above in Reaction Scheme 7, by first treating a compound of formula (G) with a suitable azide, such as diphenylphosphoryl azide under standard Mitsunobu reaction conditions in an aprotic solvent, to form the azide compound of formula (KK). The Pg2 group of the compound of formula (KK) is then removed by standard procedures, such as treatment with the appropriate oxygen-deprotecting reagent in an aprotic solvent, to form the compound of formula (LL), which is then reacted with a compound of formula (MM) under standard amidation conditions, such as treatment with a coupling reagent in an aprotic solvent, to form the compound of formula (I-7).
- Compounds of formula (I-8) are compounds of formula (I), as defined above in the Summary of the Invention, where R1 and R2 are both —R8—OH, R4a and R4b together form methylene and R3 is —CH2—O-(3,5-dimethoxy)benzyl, —CH2—O-benzyl, or —CH2—O—CH2-pyridinyl, and are prepared as described below in Reaction Scheme 8 where R5, R6, R7 and each R8 are as described above in the Summary of the Invention for compounds of formula (I), R3f is -(3,5-dimethoxy)benzyl, -benzyl, or —CH2-pyridinyl, and Pg1, Pg2 and Pg3 are each independently selected from an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl.
- Compounds of formula (MM) may be prepared by methods known to one skilled in the art or by the methods disclosed in U.S. Pat. No. 7,601,874. Compounds of formula (TT) are commercially available, or can be prepared according to methods known to one skilled in the art.
- In general, compounds of formula (I-8) are prepared, as described above in Reaction Scheme 8, by first treating a compound of formula (MM) to suitable oxygen-protecting conditions, such as treatment with the appropriate oxygen-protecting group under basic conditions in an aprotic solvent, to form a compound of formula (NN), which is further treated to suitable oxygen-protecting conditions, under basic conditions in an aprotic solvent, to form a compound of formula (OO). Treatment of the compound of formula (OO) with acetic acid under standard conditions removes the ketal and Pg1 and Pg2 to form the compound of formula (PP), which is then treated with suitable oxygen-protecting conditions to form the compound of formula (QQ). Pg3 is removed from the compound of formula (QQ) by standard procedures, such as treatment with the appropriate oxygen-deprotecting reagent under basic conditions in an aprotic solvent, to form the compound of formula (RR). Olefination of the compound of formula (RR) with the appropriate agent, such as methyl triphenylphosphonium bromide, in the presence of a base, such as KOtBu, provides the compound of formula (SS), which is then treated with a compound of formula (TT) under suitable Williamson ether synthesis conditions, such as treatment with the appropriate alkylating agent under basic conditions in an aprotic solvent, to form the compound of formula (UU). The protecting groups on the compound of formula (UU) are then removed by standard procedures to form the compound of formula (I-8).
- Compounds of formula (1-9) are compounds of formula (I), as defined above in the Summary of the Invention, where R1 and R3 are both —R8—OH, R4a and R4b together form methylene and R2 is —R8—OR9 where R9 is alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, and are prepared as described below in Reaction Scheme 8 where R5, R6, R7 and each R8 are as described above in the Summary of the Invention for compounds of formula (I), R2d is alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, and Pg1 and Pg2 are each independently selected from an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl.
- Compounds of formula (VV) may be prepared by methods known to one skilled in the art or by the methods disclosed in U.S. Pat. No. 7,601,874. Compounds of formula (WW) are commercially available, or can be prepared according to methods known to one skilled in the art.
- In general, compounds of formula (I-9) are prepared, as described above in Reaction Scheme 9, by first treating a compound of formula (VV) with a compound of formula (WW) under standard Williamson ether synthesis conditions, such as under basic conditions in an aprotic solvent, to form a compound of formula (XX). The oxygen-protecting groups on the compound of formula (XX) are removed by standard procedures, such as treating the compound of formula (XX) with the appropriate oxygen-deprotecting reagent in an aprotic solvent, to form the compound of formula (I-9).
- Compounds of formula (I-11) are compounds of formula (I), as defined above in the Summary of the Invention, where R4a and R4b are both methyl and R5 is a direct bond to C14, and are prepared as described below in Reaction Scheme 10 where R1, R2, R3, R6 and R7 are as described above in the Summary of the Invention for compounds of formula (I).
- Compounds of formula (I-10) are compounds of formula (I), as defined above in the Summary of the Invention, where R5 is methyl and R4a and R4b together form methlylene, and are prepared as described herein.
- In general, compound of formula (I-11) are prepared, as described above in Reaction Scheme 10, by treating the compound of formula (I-10) with an acid, preferably HCl, to form the compound of formula (I-11).
- Compounds of formula (I-11) where R3 is —CH2NH2 can be further treated with a sulfonating agent, such as mesyl cloride, under standard conditions to form compounds of formula (I-11) wherein R3 is —CH2N(H)S(O)2CH3.
- Compounds of formula (I-12) are compounds of formula (I), as defined above in the Summary of the Invention, where R4a and R4b are both methyl, R5 is a direct bond to C14 and R7 is —OH, and are prepared as described below in Reaction Scheme 11 where R6 and each R8 are as described above in the Summary of the Invention for compounds of formula (I) and Pg1, Pg2 and Pg3 are each independently selected from an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl or tert-butyldiphenylsilyl, and Pg4 is acetyl.
- Compounds of formula (QQa) are compounds of formula (QQ) as described above in Reaction Scheme 8 where R5 is methyl and R7 is hydrogen and are prepared as described herein.
- In general, compounds of formula (I-12) are prepared, as described above in Reaction Scheme 11, by treating a compound of formula (QQa) with methyl lithium under standard conditions, such as treating the compound of formula (QQa) with the appropriate alkyl lithium in an aprotic solvent, to form a compound of formula (YY), which is then subjected to dehydrating conditions, such as treatment with phosphoryl chloride in the presence of an base, to form the compound of formula (ZZ). Pg1 and Pg2 in the compound of formula (ZZ) are then removed by standard procedures, such as treating the compound of formula (ZZ) with the appropriate oxygen-deprotecting reagent in a protic solvent, to yield the compound of formula (AAA). Treatment of the compound of formula (AAA) with the acetic anhydride under standard conditions, such as treating the compound of formula (ZZ) with the acetylating agent in an aprotic solvent, yields the compound of formula (BBB). Treatment of the compound of formula (BBB) with an appropriate oxidizing agent, such as MCPBA, under standard conditions, such as in an aprotic solvent, yields the compound of formula (CCC). Treatment of the compound of formula (CCC) to acidic conditions yields the compound of formula (DDD), which is then subjected to deprotecting conditions, such as treating the compound of formula (CCC) with deprotecting agent in a protic solvent, to remove each Pg4 and Pg3 to yield the compound of formula (I-12).
- Compound of formula (I-13) are compound of formula (I), as described above in the Summary of the Invention, where R1 is —R8—OH, R2 is —R8—NH2, R3 is —CH2—NH2, and R4a and R4b together form methylene, and are prepared as described below in Reaction Scheme 12 where R5, R6, R7 and each R8 are as described above in the Summary of the Invention for compounds of formula (I), Pg1 is an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl, Lg1 is a functional group which forms a leaving group with the oxygen to which it is attached, such as mesyl or tosyl, and X is bromo or chloro.
- Compounds of formula (A) are described above in Reaction Scheme 1. Compounds of formula (C) and NaN3 are commercially available or can be prepared by methods known to one skilled in the art.
- In general, compounds of formula (I-13) are prepared, as described above in Reaction Scheme 12, by first treating a compound of formula (A) with a compound of formula (C) under standard leaving group formation conditions, such as under basic conditions in an aprotic solvent, and then treating the resulting mixture with sodium azide under standard conditions, such as treatment with the appropriate nucleophilic azide in an aprotic solvent, to yield the compound of formula (Aa). Treatment of the compound of formula (Aa) with sodium azide under standard conditions, such as the above at higher temperatures, yields the compound of formula (Ac), with is then deprotected under standard conditions to yield the compound of formula (I-13).
- Compound of formula (I-14) are compounds of formula (I), as described above in the Summary of the Invention, where R1 and R2 are each —R8—OH, R3 is —CH2N(H)C(O)(CH2)3CH3, and R7 is hydrogen, and are prepared as described below in Reaction Scheme 13 where R5, R6, and each R8 are as described above in the Summary of the Invention for compounds of formula (I), Pg1 and Pg2 are each independently an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl, and R3g is n-butyl.
- Compounds of formula (EEE) may be prepared by methods known to one skilled in the art from compounds disclosed herein or by methods similar to the methods disclosed in U.S. Pat. No. 7,601,874. Compounds of formula (FFF) and formula (HHH) are commercially available or can be prepared by methods known to one skilled in the art.
- In general, compounds of formula (I-14) are prepared, as described above in Reaction Scheme 13, by first treating a compound of formula (EEE) with a compound of formula (FFF) under standard conditions, such as in the presence of a drying agent in an aprotic solvent, to yield the compound of formula (GGG). Treatment of the compound of formula (GGG) with a compound of formula (HHH) under standard conditions, in an aprotic solvent, yields the compound of formula (JJJ), with is then deprotected under standard conditions to yield the compound of formula (I-14).
- Compound of formula (I-15) are compounds of formula (I), as described above in the Summary of the Invention, where R1 and R2 are each —R8—OH, R3 is —CH2NH2, R4a and R4b together form methylene and R7 is —R8—OR9 where R8 is a direct bond and R9 is hydrogen, and are prepared as described below in Reaction Scheme 14 where R5, R6, and each R8 are as described above in the Summary of the Invention for compounds of formula (I), Pg1, Pg2, Pg3 and Pg4 are each independently an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl, Lg1 is a functional group which forms a leaving group with the oxygen to which it is attached, such as mesyl or tosyl, and X is bromo or chloro.
- Compounds of formula (KKK) may be prepared by methods known to one skilled in the art from compounds disclosed herein or by methods similar to the methods disclosed in U.S. Pat. No. 7,601,874. Compounds of formula (C) are commercially available or can be prepared by methods known to one skilled in the art.
- In general, compounds of formula (I-15) are prepared, as described above in Reaction Scheme 14, by first treating a compound of formula (KKK) with a appropriate oxidizing agent, under standard conditions, such as in an aprotic solvent, to yield the compound of formula (LLL). Protection of the hydroxyl on the compound of formula (LLL) under standard conditions, such as treatment with acetic anhydride in pyridine yields the compound of formula (MMM). Removal of the Pg3 protecting group under standard conditions yields the compound of formula (NNN). Treatment of the compound of formula (NNN) with a compound of formula (C) under standard conditions, such as treatment with the appropriate oxygen-activating group under basic conditions in an aprotic solvent, yields the compound of formula (OOO). Azide displacement of the mesylate using sodium azide in DMF gives compound formula (PPP). Reduction of the azide under standard conditions, such as Staudinger reaction conditions, yields the compound of formula (QQQ). Pg1 and Pg2 are removed from the compound of formula (QQQ) by standard techniques, such as treating the compound of formula (QQQ) with the appropriate oxygen-deprotecting reagent in a protic solvent, to yield the compound of formula (I-15).
- Compound of formula (I-16) are compounds of formula (I), as described above in the Summary of the Invention, where R1 is —R8—N(R9)2 where R8 is a direct bond and each R9 is hydrogen, R2 and R3 are each —CH2—OH, R4a and R4b together form methylene, and are prepared as described below in Reaction Scheme 15 where R5, R6 and R7 are as described above in the Summary of the Invention for compounds of formula (I) and Pg5 is a nitrogen-protecting group, such as trifluoromethylcarbonyl.
- Compounds of formula (RRR) may be prepared by methods known to one skilled in the art or by methods similar to the methods disclosed in U.S. Pat. No. 6,635,629.
- In general, compounds of formula (I-16) are prepared, as described above in Reaction Scheme 15, by first treating a compound of formula (RRR) with an appropriate base, such as sodium hydroxide in a protic solvent, to form the free base compound of formula (SSS). The free amino group in the compound of formula (SSS) is then protected by standard nitrogen protecting procedures, such as treatment with trifluoroacetic anhydride under basic conditions in a protic solvent, to yield a compound of formula (TTT). Treatment of the compound of formula (TTT) with sodium periodate in THF to oxidatively cleave the diol yields a dialdehyde intermediate, which is then reduced with sodium borohydride in THF to yield the compound of formula (UUU), which is then deprotected under standard conditions, such as treatment with a base in a protic solvent, to yield the compound of formula (I-16).
- Compound of formula (I-17) are compounds of formula (I), as described above in the Summary of the Invention, where R1, R2 and R3 are each —R8—OH, R4a and R4b together form methylene and R7 is a direct bond to C15, and are prepared as described below in Reaction Scheme 16 where R5, R6 and each R8 are as described above in the Summary of the Invention for compounds of formula (I), and Pg1, Pg2, and Pg3 are each independently an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl.
- Compounds of formula (QQa) are compounds of formula (QQ) as described above in Reaction Scheme 8 where R7 is hydrogen.
- In general, compounds of formula (I-17) are prepared, as described above in Reaction Scheme 16, by first treating a compound of formula (QQa) with an appropriate silylating reagent under basic conditions in an aprotic solvent followed by oxidation under Saegusa-lto oxidation conditions to yield a compound of formula (QQb). Olefination of the compound of formula (QQb) with the appropriate agent, such as methyl triphenylphosphonium bromide, in the presence of a base, such as KOtBu, provides the compound of formula (QQc), which is then deprotected under standard deprotecting conditions, such as treatment with the appropriate oxygen-deprotecting reagent in an aprotic solvent, to yield the compound of formula (I-17).
- Compound of formula (I-18) are compounds of formula (I), as described above in the Summary of the Invention, where R1 and R2 are each —R8—OH, R3 is —CH2N(H)OCH3, and R4a and R4b together form methylene, and are prepared as described below in Reaction Scheme 17 where R5, R6 and each R8 are as described above in the Summary of the Invention for compounds of formula (I), and Pg1 and Pg2, are each independently an oxygen-protecting group, such as, but not limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetyl.
- Compounds of formula (B) are described above in Reaction Scheme 1. Compounds of formula (VVV) are commercially available or can be prepared by methods known to one skilled in the art.
- In general, compounds of formula (I-18) are prepared, as described above in Reaction Scheme 17, by first oxidizing a compound of formula (B) under standard conditions, such as Swern oxidation conditions, to yield a compound of formula (Ba). Compounds of formula (Ba) are then treated with a compound of formula (VVV) under standard reductive amination conditions, such as the appropriate reducing agent in a solvent mixture, to yield the compound of formula (Bb), which is then deprotected under standard conditions known to one skilled in the art to yield the compound of formula (I-18).
- All of the compounds described herein as being prepared which may exist in free base or acid form may be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid. Salts of the compounds prepared below may be converted to their free base or acid form by standard techniques. Furthermore, all compounds of the invention which contain an acid or an ester group can be converted to the corresponding ester or acid, respectively, by methods known to one skilled in the art or by methods described herein.
- Representative compounds of the invention which were prepared by the methods disclosed herein include (but are not limited to) the compounds listed below in Table 1. The compound (Cpd) numbers in this table correspond to the compound numbers in Examples 98-99 below (but do not correspond with the compound numbers in Examples 1-97 below).
-
TABLE 1 Cpd. No. Compound Name Cpd. No. 1 1-(((4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden- 4-yl)methyl)guanidine hydrochloride Cpd. No. 2 (1S,3S,4R)-4-((4R,5S)-4-((cyclopropylmethylamino)methyl)-1,1- dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)- 4-methylcyclohexanol Cpd. No. 3 (1S,3S,4R)-4-((4R,5S)-4-((dimethylamino)methyl)-1,1-dimethyl- 2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4- methylcyclohexanol Cpd. No. 4 N-(((4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden- 4-yl)methyl)acetamide Cpd. No. 5 (1S,3S,4R)-4-((4R,5S)-1,1-dimethyl-4-((methylamino)methyl)- 2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4- methylcyclohexanol Cpd. No. 6 (1S,3S,4R)-4-((4R,5S)-4-(((1H-pyrrol-2-yl)methylamino)methyl)-1,1- dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)- 4-methylcyclohexanol Cpd. No. 7 N-(((4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden- 4-yl)methyl)methanesulfonamide Cpd. No. 8 N-(((4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden- 4-yl)methyl)benzamide Cpd. No. 9 (4-((((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methylamino)methyl)phenyl)(phenyl)methanone Cpd. No. 10 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((4-fluorobenzylamino)methyl)-7a- methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)- 4-methylcyclohexanol Cpd. No. 11 (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyrrolidin- 1-yl)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden- 4-ol Cpd. No. 12 (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a- methyl-1-methylene-4-((pyridin-4- ylmethylamino)methyl)octahydro-1H-inden-5-yl)cyclohexanol Cpd. No. 13 (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a- methyl-4-((4-methylbenzylamino)methyl)-1-methyleneoctahydro- 1H-inden-5-yl)cyclohexanol Cpd. No. 14 (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a- methyl-4-((3-methylbenzylamino)methyl)-1-methyleneoctahydro- 1H-inden-5-yl)cyclohexanol Cpd. No. 15 (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a- methyl-4-((2-methylbenzylamino)methyl)-1-methyleneoctahydro- 1H-inden-5-yl)cyclohexanol Cpd. No. 16 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)-2-naphthamide Cpd. No. 17 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)benzamide Cpd. No. 18 (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-((4- methoxybenzylamino)methyl)-7a-methyl-1-methyleneoctahydro- 1H-inden-5-yl)-4-methylcyclohexanol Cpd. No. 19 (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a- methyl-1-methylene-4-((4- (trifluoromethyl)benzylamino)methyl)octahydro-1H-inden-5- yl)cyclohexanol Cpd. No. 20 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)pivalamide Cpd. No. 21 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)isobutyramide Cpd. No. 22 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)propionamide Cpd. No. 23 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)butyramide Cpd. No. 24 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)pentanamide Cpd. No. 26 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-pyrazol-1-yl)methyl)-7a- methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)- 4-methylcyclohexanol Cpd. No. 27 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-1,2,4-triazol-1-yl)methyl)-7a- methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)- 4-methylcyclohexanol Cpd. No. 28 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-benzo[d]imidazol-1- yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3- (hydroxymethyl)-4-methylcyclohexanol Cpd. No. 29 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(2-aminoethyl)-7a-methyl-1- methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4- methylcyclohexanol Cpd. No. 30 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-indol-1-yl)methyl)-7a-methyl- 1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4- methylcyclohexanol Cpd. No. 31 (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-(indolin-1- ylmethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4- methylcyclohexanol Cpd. No. 32 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((3,5- dimethoxybenzylamino)methyl)-7a-methyl-1-methyleneoctahydro- 1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol Cpd. No. 33 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(((1H-benzo[d]imidazol-2- yl)methylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H- inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol Cpd. No. 34 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((benzo[d][1,3]dioxol-5- ylmethylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H- inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol Cpd. No. 35 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((6-amino-9H-purin-9-yl)methyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3- (hydroxymethyl)-4-methylcyclohexanol Cpd. No. 36 (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a- methyl-1-methylene-4-((4-nitrobenzylamino)methyl)octahydro-1H- inden-5-yl)cyclohexanol Cpd. No. 37 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(((2,2-difluorobenzo[d][1,3]dioxol- 5-yl)methylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H- inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol Cpd. No. 38 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((4-fluoro-2- methylbenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H- inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol Cpd. No. 39 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((2-fluoro-4- methoxybenzylamino)methyl)-7a-methyl-1-methyleneoctahydro- 1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol Cpd. No. 40 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((4-fluoro-2- methoxybenzylamino)methyl)-7a-methyl-1-methyleneoctahydro- 1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol Cpd. No. 41 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((2-fluoro-4- methylbenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H- inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol Cpd. No. 42 (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-((4- methoxyphenethylamino)methyl)-7a-methyl-1- methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexanol Cpd. No. 43 (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-(bis(4- methoxybenzyl)amino)ethyl)-7a-methyl-1-methyleneoctahydro- 1H-inden-5-yl)-4-methylcyclohexane-1,3-diol Cpd. No. 44 (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-(4-methoxybenzylamino)ethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4- methylcyclohexane-1,3-diol Cpd. No. 45 (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-(benzo[d][1,3]dioxol-5- ylmethylamino)ethyl)-7a-methyl-1-methyleneoctahydro-1H-inden- 5-yl)-4-methylcyclohexane-1,3-diol Cpd. No. 46 (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2- morpholinoethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro- 1H-inden-4-ol Cpd. No. 47 (1S,3S,4R)-3-(aminomethyl)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4- methylcyclohexanol Cpd. No. 48 (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(4- methylpiperazin-1-yl)ethyl)cyclohexyl)-7a-methyl-1- methyleneoctahydro-1H-inden-4-ol Cpd. No. 49 (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4- hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro- 1H-inden-4-ol Cpd. No. 50 (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-imidazol-1-yl)ethyl)-4- hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro- 1H-inden-4-ol Cpd. No. 51 (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-pyrazol-1-yl)ethyl)-4- hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro- 1H-inden-4-ol Cpd. No. 52 (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-pyrrol-1-yl)ethyl)-4-hydroxy- 1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden- 4-ol Cpd. No. 53 (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-hydroxyethyl)-7a-methyl-1- methyleneoctahydro-1H-inden-5-yl)-4-methyl-3-(pyridin-2- yloxy)cyclohexanol Cpd. No. 54 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1- methyleneoctahydro-1H-inden-5-yl)-4-methyl-3-((pyridin-2- yloxy)methyl)cyclohexanol Cpd. No. 55 (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyrimidin- 2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H- inden-4-ol Cpd. No. 56 (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyrazin-2- yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H- inden-4-ol Cpd. No. 57 (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyridin-2- yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H- inden-4-ol Cpd. No. 58 (1S,3S,4R)-4-((3aS,6S,7R,7aS)-7-(aminomethyl)-3,3a-dimethyl- 3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-3-(hydroxymethyl)-4- methylcyclohexanol Cpd. No. 59 N-(((3aR,6S,7R,7aS)-6-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden- 7-yl)methyl)pentanamide Cpd. No. 60 (1S,3S,4R)-4-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1-ethyl-7a- methyloctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4- methylcyclohexanol acetate Cpd. No. 61 (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a- methyl-1-methylene-4-((pyridin-2-ylmethoxy)methyl)octahydro- 1H-inden-5-yl)cyclohexanol Cpd. No. 62 (2S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((1R,2S,4S)-4-hydroxy-2- (hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1- methyleneoctahydro-1H-inden-2-ol Cpd. No. 63 ((1S,2R,5S)-5-amino-2-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a- methyl-1-methyleneoctahydro-1H-inden-5-yl)-2- methylcyclohexyl)methanol Cpd. No. 64 (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4- (hydroxymethyl)-7a-methyl-1-methylene-3a,4,5,6,7,7a-hexahydro- 1H-inden-5-yl)-4-methylcyclohexanol Cpd. No. 65 (1S,3S,4R)-3-(hydroxymethyl)-4-((4R,5S)-4-(hydroxymethyl)-1,1- dimethyl-4,5,6,7-tetrahydro-1H-inden-5-yl)-4-methylcyclohexanol Cpd. No. 66 (2R,4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-4-(hydroxymethyl)-1,1-dimethyl-2,3,4,5,6,7- hexahydro-1H-inden-2-ol Cpd. No. 67 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(benzyloxymethyl)-7a-methyl-1- methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4- methylcyclohexanol Cpd. No. 68 (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((3,5-dimethoxybenzyloxy)methyl)- 7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3- (hydroxymethyl)-4-methylcyclohexanol Cpd. No. 69 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)nicotinamide Cpd. No. 70 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)isonicotinamide Cpd. No. 71 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)pyrazine-2-carboxamide Cpd. No. 72 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)picolinamide Cpd. No. 73 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)benzo[d][1,3]dioxole-5-carboxamide Cpd. No. 74 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)-4-methoxybenzamide Cpd. No. 75 4-fluoro-N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2- (hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1- methyleneoctahydro-1H-inden-4-yl)methyl)benzamide Cpd. No. 76 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)-4-(trifluoromethyl)benzamide Cpd. No. 77 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)-4-methylbenzamide Cpd. No. 78 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)-2-methylbenzamide Cpd. No. 79 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)-1H-pyrrole-2-carboxamide Cpd. No. 80 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)-3-methylbenzamide Cpd. No. 81 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)furan-2-carboxamide Cpd. No. 82 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)cyclopropanecarboxamide Cpd. No. 83 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)cyclohexanecarboxamide Cpd. No. 84 1-ethyl-3-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2- (hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1- methyleneoctahydro-1H-inden-4-yl)methyl)urea Cpd. No. 85 1-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)-3-methylthiourea Cpd. No. 86 2,2,2-trifluoro-N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2- (hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1- methyleneoctahydro-1H-inden-4-yl)methyl)acetamide Cpd. No. 87 2-((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)acetonitrile Cpd. No. 88 (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4- ((methoxyamino)methyl)-7a-methyl-1-methyleneoctahydro-1H- inden-5-yl)-4-methylcyclohexanol Cpd. No. 89 N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)cyanamide Cpd. No. 90 2-((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)acetamide Cpd. No. 91 1-benzyl-3-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2- (hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1- methyleneoctahydro-1H-inden-4-yl)methyl)urea Cpd. No. 92 1-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)methyl)-3-phenylurea Cpd. No. 93 N-(2-((3aS,4S,5S,7aS)-5-((1R,2S,4S)-2,4-dihydroxy-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4- yl)ethyl)benzo[d][1,3]dioxole-5-carboxamide Cpd. No. 94 3-((1S,2S,5S)-5-hydroxy-2-((3aR,4R,5R,7aS)-4-hydroxy-7a-methyl-1- methyleneoctahydro-1H-inden-5-yl)-2- methylcyclohexyl)propanenitrile Cpd. No. 95 3-((1S,2S,5S)-5-hydroxy-2-((3aR,4R,5R,7aS)-4-hydroxy-7a-methyl-1- methyleneoctahydro-1H-inden-5-yl)-2- methylcyclohexyl)propanamide Cpd. No. 96 N-(((1S,2S,5S)-5-hydroxy-2-((3aR,4R,5R,7aS)-4-hydroxy-7a-methyl- 1-methyleneoctahydro-1H-inden-5-yl)-2- methylcyclohexyl)methyl)benzo[d][1,3]dioxole-5-carboxamide Cpd. No. 97 3-((1R,2S,5S)-5-hydroxy-2-((3aR,4R,5R,7aS)-4-hydroxy-7a-methyl-1- methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)propanoic acid Cpd. No. 98 (3aS,4R,5S,7aS)-5-((1R,2R,4S)-4-hydroxy-2-(hydroxymethyl)-1- methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-indene-4- carboxylic acid - The following Examples are provided for purposes of illustration, not limitation. In summary, the following Examples disclose the synthesis of representative compounds of this invention and compounds used in the preparation of compounds of the invention, as well as representative assays for the same.
-
- A. A solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate (Compound No. 1, 105 mg, 0.28 mmol), N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (94 mg, 0.30 mmol) and triethylamine (80 μL, 0.57 mmol) in MeOH (1 mL) and THF (5 mL) was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (35 mL), washed with saturated NaHCO3 solution (2×10 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (4% then 6% MeOH/CH2Cl2) to afford (Z)-tert-butyl (tert-butoxycarbonylamino)(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methylamino)methylenecarbamate (Compound No. 2, 142 mg, 90%) as a white solid.
- B. A solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methylamino)methylenecarbamate (Compound No. 2, 142 mg) in 4N HCl/dioxane (2 mL) and MeOH (1 mL) was stirred at room temperature for 3 d. The mixture was concentrated, thrice taken up in MeOH (10 mL) and concentrated and thrice triturated with Et2O (20 mL) to afford 1-(((4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-4-yl)methyl)guanidine hydrochloride (Compound No. 3, 103 mg) as a beige solid. 1H NMR (CDCl3): δ 7.20 (1H), 3.75 (m, 1H), 3.65 (m, 1H), 3.45 (m, 1H), 3.20 (m, 1H), 3.05 (m, 1H), 2.40 (m, 1H), 2.25-1.55 (12H), 1.2 (4H), 1.00 (s, 3H), 0.92 (s, 3H), 0.85 (s, 3H). ES-MS m/z 364 ([M+1]+)
-
- A solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(((cyclopropylmethyl)amino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate (Compound No. 4, 95 mg, 0.22 mmol) in 1 N HCl(aq) (5.5 mL) was stirred at 60° C. overnight. The solution was cooled to 0° C., adjusted to pH 12 using 10 N NaOH(aq), and extracted with EtOAc (30 mL then 2×10 mL). The combined organic layers were dried (MgSO4) and concentrated to give (1S,3S,4R)-4-((4R,5S)-4-((cyclopropylmethylamino)methyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 4a, 55 mg, 67%) as a yellow foam. 1H NMR (CD3OD): δ 3.83 (m, 1H), 3.44 (m, 1H), 3.22 (m, 1H), 2.77 (m, 1H), 2.57 (m, 3H), 2.39 (m, 1H), 1.20-2.22 (m, 17H), 0.99 (s, 3H), 0.93 (s, 3H), 0.91 (s, 3H), 0.54 (m, 2H), 0.19 (m, 2H); 13C NMR (CD3OD): δ 144.5, 135.3, 71.4, 63.4, 55.6, 53.8, 46.7, 43.6, 42.5, 40.2, 38.8, 37.3, 35.7, 34.2, 33.1, 32.2, 27.3, 25.7, 20.9, 20.8, 20.1, 11.2, 4.1, 4.0. ES-MS m/z 376 ([M+1]+).
-
- A solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((dimethylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate (Compound No. 5, 172 mg, 0.420 mmol) in 1 N HCl (aq) (7.5 mL) was stirred at 60° C. overnight. The solution was cooled to 0° C., adjusted to pH 12 using 10 N NaOH(aq), and extracted with EtOAc (20 mL then 2×10 mL). The combined organic layers were dried (MgSO4) and concentrated to give (1S,3S,4R)-4-((4R,5S)-4-((dimethylamino)methyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 6, 114 mg, 78%) as a colourless foam. 1H NMR (CD3OD): δ 3.82 (m, 1H), 3.43 (m, 1H), 3.19 (m, 1H), 2.38 (m, 2H), 1.16-2.25 (m, 23H), 0.98 (s, 3H), 0.92 (s, 3H), 0.90 (s, 3H); 13C NMR (CD3OD): δ 143.5, 136.1, 71.4, 64.9, 63.4, 46.7, 46.3 (2C), 43.6, 41.7, 40.2, 38.7, 35.7, 35.6, 34.6, 33.1, 32.2, 27.4, 25.6, 20.8, 20.4, 20.1. ES-MS m/z 350 ([M+1]+).
-
- A. To a solution of (1S,3S,4R)-4-((4R,5S)-4-(aminomethyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 7, 153 mg, 0.476 mmol), Et3N (0.20 mL, 1.4 mmol) and DMAP (5 mg, 0.04 mmol) in THF (4.8 mL) at 0° C. under argon was added Ac2O (0.14 mL, 1.5 mmol), and the solution was stirred for 5 min at 0° C. then at room temperature for 1 h. The solution was concentrated, and the residue was dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (4×20 mL) and brine (2×20 mL) then dried (MgSO4) and concentrated to give (1S,3S,4R)-4-((4R,5S)-4-(acetamidomethyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(acetoxymethyl)-4-methylcyclohexyl acetate (Compound No. 8, 186 mg) as a colourless foam.
- B. To a solution of (1S,3S,4R)-4-((4R,5S)-4-(acetamidomethyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(acetoxymethyl)-4-methylcyclohexyl acetate (Compound No. 8, 186 mg) in MeOH (4.2 mL) was added 10 N NaOH(aq) (0.42 mL, 4.2 mmol) then stirred vigorously at room temperature for 1 h. The solution was concentrated, and the residue was partitioned between EtOAc (40 mL) and H2O (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (100:10:2 CH2Cl2/MeOH/NH4OH) to give N-(((4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-4-yl)methyl)acetamide (Compound No. 9, 103 mg, 60% over 2 steps) as a colourless foam. 1H NMR (CD3OD): δ 3.79 (dd, J=11, 2.3 Hz, 1H), 3.42 (m, 1H), 3.18 (m, 1H), 2.94 (dd, J=13, 10 Hz, 1H), 2.44 (m, 1H), 1.12-2.21 (m, 20H), 0.99 (s, 3H), 0.92 (s, 3H), 0.81 (s, 3H); 13C NMR (CD3OD): δ 173.0, 144.5, 135.1, 71.3, 63.3, 46.6, 43.6, 43.5, 41.5, 40.2, 38.5, 38.1, 35.6, 33.9, 32.9, 32.2, 27.2, 25.8, 22.7, 20.8, 20.5, 19.7. ES-MS m/z 364 ([M+1]+).
-
- A solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate (Compound No. 10, 112 mg, 0.283 mmol) in 1 N HCl(aq) (7.0 mL) was stirred at 60° C. overnight. The solution was cooled to 0° C., adjusted to pH 12 using 10 N NaOH(aq), and extracted with EtOAc (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated to give (1S,3S,4R)-4-((4R,5S)-1,1-dimethyl-4-((methylamino)methyl)-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 11, 75 mg, 79%) as a yellow foam. 1H NMR (CD3OD): δ 3.82 (m, 1H), 3.43 (m, 1H), 3.21 (m, 1H), 2.67 (dd, J=12, 3.1 Hz, 1H), 2.51 (m, 1H), 2.42 (s, 3H), 1.15-2.21 (m, 17H), 0.99 (s, 3H), 0.92 (s, 3H), 0.90 (s, 3H); 13C NMR (CD3OD): δ 144.3, 135.3, 71.4, 63.4, 56.2, 46.7, 43.6, 42.2, 40.2, 38.7, 37.3, 36.3, 35.7, 34.3, 33.0, 32.2, 27.3, 25.6, 20.8, 20.7, 20.0. ES-MS m/z 336 ([M+1]+).
-
- A suspension of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((((1H-pyrrol-2-yl)methyl)amino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate (Compound No. 12, 49 mg, 0.11 mmol) in 1 N HCl(aq) (5.0 mL) was stirred at 60° C. overnight. The solution was cooled to 0° C., adjusted to pH 12 using 10 N NaOH(aq), and extracted with EtOAc (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated to give (1S,3S,4R)-4-((4R,5S)-4-(((1H-pyrrol-2-yl)methylamino)methyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 13, 41 mg, 95%) as a brown foam. 1H NMR (CD3OD): δ 6.69 (m, 1H), 6.03 (m, 2H), 3.78 (m, 3H), 3.43 (m, 1H), 3.20 (m, 1H), 2.70 (dd, J=12, 3.2 Hz, 1H), 2.51 (dd, J=12, 9.2 Hz, 1H), 1.13-2.32 (m, 17H), 0.98 (s, 3H), 0.91 (s, 3H), 0.89 (s, 3H); 13C NMR (CD3OD): δ 144.6, 135.1, 129.0, 118.8, 108.7, 108.6, 71.4, 63.4, 52.5, 46.7, 46.6, 43.6, 42.3, 40.2, 38.8, 37.2, 35.7, 34.2, 32.9, 32.2, 27.3, 25.6, 20.8, 20.7, 20.0. ES-MS m/z 401 ([M+1]+).
-
- A. To a solution of (1S,3S,4R)-4-((4R,5S)-4-(aminomethyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 7, 101 mg, 0.314 mmol) and Et3N (0.15 mL, 1.1 mmol) in THF (3.2 mL) at 0° C. under argon was added MsCl (0.07 mL, 0.9 mmol), and the solution was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between EtOAc (30 mL) and H2O (10 mL). The organic layer was washed with saturated aqueous NaHCO3 (5×15 mL) and brine (2×15 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (10:90-50:50 EtOAc/CH2Cl2) to give ((1S,2R,5S)-2-((4R,5S)-1,1-dimethyl-4-(methylsulfonamidomethyl)-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-2-methyl-5-((methylsulfonyl)oxy)cyclohexyl)methyl methanesulfonate (Compound No. 14, 24 mg, 14%) as a colourless oil and a by-product, possibly (1S,3S,4R)-4-((4R,5S)-1,1-dimethyl-4-(methylsulfonamidomethyl)-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexyl methanesulfonate, (Compound No. 15, 37 mg, 25%) as a brown oil. Compound No. 14 (24 mg) and Compound No. 15 (37 mg) were combined to use in the next step.
- B. To a solution of the above mixture (61 mg, 0.12 mmol) in MeOH (2.2 mL) was added 10 N NaOH(aq) (0.11 mL, 1.1 mmol) then heated to 60° C. for 22 h.
- The solution was concentrated, and the residue was partitioned between EtOAc (30 mL) and H2O (10 mL). The aqueous layer was extracted with EtOAc (3×15 mL), and the combined the organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (20:80 EtOAc/CH2Cl2) to give N-(((4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-4-yl)methyl)methanesulfonamide (Compound No. 16, 21 mg, 44%) as a colourless foam. 1H NMR (CD3OD): δ 4.24 (m, 1H), 4.05 (d, J=8.1 Hz, 1H), 3.70 (dd, J=4.7, 8.3 Hz, 1H), 3.19 (dd, J=3.5, 13 Hz, 1H), 2.93 (s, 3H), 2.87 (dd, J=9.9, 13 Hz, 1H), 1.29-2.49 (m, 17H), 1.00 (s, 3H), 0.93 (s, 3H), 0.74 (s, 3H); 13C NMR (CD3OD): δ 145.3, 134.3, 76.3, 70.6, 47.1, 46.8, 45.8, 40.2, 39.7, 39.6, 38.4, 35.2, 34.1, 33.0, 30.3, 30.0, 27.3, 25.7, 23.7, 20.4 (2C). ES-MS m/z 400 ([M+1]+).
-
- To a solution of (1S,3S,4R)-4-((4R,5S)-4-(aminomethyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 7, 57 mg, 0.18 mmol), (benzotriazol-1-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate (112 mg, 0.22 mmol), and benzoic acid (27 mg, 0.22 mmol) in DMF (1.8 mL) was added DIEA (0.075 mL, 0.43 mmol), and the solution was stirred under argon for 20 h. The mixture was concentrated, and the residue was dissolved in EtOAc (40 mL). The solution was washed with saturated aqueous NaHCO3 (5×10 mL) and brine (2×10 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (100:10:2 CH2Cl2/MeOH/NH4OH) to give N-(((4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-4-yl)methyl)benzamide (Compound No. 17, 42 mg, 56%) as a colourless foam. 1H NMR (CD3OD): δ 8.63 (m, 1H), 7.79 (d, J=7.2 Hz, 2H), 7.49 (m, 3H), 3.78 (m, 1H), 3.53 (m, 1H), 3.43 (m, 1H), 3.08-3.24 (m, 2H), 2.52 (m, 1H), 2.38 (m, 1H), 1.13-2.20 (m, 15H), 1.02 (s, 3H), 0.94 (s, 3H), 0.76 (s, 3H); 13C NMR (CD3OD): δ 170.3, 144.6, 136.0, 135.2, 132.5, 129.6 (2C), 128.1 (2C), 71.4, 63.3, 46.7, 44.0, 43.5, 41.5, 40.3, 38.6, 38.2, 35.6, 34.0, 33.0, 32.2, 27.3, 25.7, 20.9, 20.6, 19.9. ES-MS m/z 426 ([M+1]+).
-
- A. A mixture of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 18, 283 mg 0.65 mmol), PPh3 (516 mg, 1.95 mmol) and water (0.12 mL, 6.5 mmol) in THF (10 mL) was stirred to room temperature, diluted with saturated NaHCO3 solution (20 mL), extracted with EtOAc (3×5 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (9:1 EtOAc:MeOH) to afford ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-aminoethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 19, 129 mg) as a white foam.
- B. A mixture of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 19, 129 mg), TEA (0.27 mL, 1.9 mmol) and 4-bromomethylbenzophenone (160 mg, 0.59 mmol) in DMF was stirred under argon at room temperature overnight. The resultant mixture was diluted with Et2O (25 mL), washed with water (3×5 mL), dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (4:1 to 2:1 Hexanes:EtOAc) to afford ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(((4-benzoylbenzyl)amino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 20, 140 mg) as a colourless oil.
- C. A mixture of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(((4-benzoylbenzyl)amino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 20, 140 mg) and 1 N NaOH (2.4 mL, 2.4 mmol) in MeOH (3 mL) at room temperature was allowed to stir for 2 d. The resultant mixture was concentrated then suspended in water (15 mL). The pH was adjusted to ˜7 with 1 M aqueous HCl. The mixture was extracted successively with CH2Cl2 (3×20 mL), and EtOAc (20 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (1:1 CH2Cl2:MeOH to load, EtOAc to elute) to afford (4-((((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methylamino)methyl)phenyl)(phenyl)methanone (Compound No. 21, 20 mg, 6% over 3 steps) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.74 (t, J=7.5, 4H), 7.64 (m, 1H), 7.52 (dd, J=7.9, 13.6, 4H), 4.61 (s, 2H), 3.78 (m, 2H), 3.74-3.61 (m, 1H), 3.54-3.36 (m, 1H), 3.13 (m, 1H), 2.82 (d, J=12.4, 1H), 2.62 (d, J=12.1, 1H), 2.53-2.37 (m, 1H), 2.34-2.18 (m, 1H), 2.18-2.03 (m, 1H), 1.93-1.11 (m, 15H), 1.00 (s, 3H), 0.78 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 198.5, 162.9, 147.0, 139.0, 137.5, 133.7, 131.1, 130.9, 129.7, 129.5, 101.5, 71.1, 62.9, 55.0, 52.4, 50.8, 46.4, 44.7, 41.1, 39.3, 38.2, 37.2, 35.2, 32.1, 30.0, 25.8, 21.1, 18.6; MS m/z: 516.5 [M+H]+.
-
- A mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), NaBH(OAc)3 (197 mg, 0.93 mmol), 4A molecular sieves (100 mg) and 4-fluorobenzaldehyde (0.17 mL, 1.55 mmol) in CH2Cl2:MeOH (5:1, 6 mL) under argon was stirred at room temperature for 72 h. The mixture was filtered through Celite using EtOAc and was concentrated to a white solid. A solution of the residue and NaBH4 (15 mg, 0.40 mmol) in MeOH:EtOAc (5:1, 6 mL), was allowed to stir at room temperature for 48 h. The solution was quenched with NH4Cl solution (10 mL), extracted with EtOAc (2×20 mL), washed with NaHCO3 (2×10 mL), and brine (10 mL). The organic layer was dried (Na2SO4), and concentrated to afford a white solid. The residue was purified using a chromatography on silica gel (0%, 10% then 100% MeOH/EtOAc) to afford (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((4-fluorobenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 23, 98 mg, 74%). 1H NMR (300 MHz, CD3OD) δ 7.32 (m, 2H), 7.03 (m, 2H), 4.61 (s, 2H), 3.70 (s, 1H), 3.65 (s, 2H), 3.41 (s, 1H), 3.31 (s, 1H), 3.12 (m, 1H), 2.78 (m, 1H), 2.49 (m, 1H), 2.18 (m, 2H), 1.78 (m, 5H), 1.61 (m, 1H), 1.42 (m, 5H), 1.24 (m, 4H), 0.96 (s, 3H), 0.77 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 162.8, 137.1, 131.6, 131.5, 115.9, 115.7, 101.5, 71.1, 62.8, 54.4, 52.3, 50.5, 46.4, 44.7, 39.2, 38.1, 37.2, 35.1, 31.9, 29.9, 25.8, 24.4, 21.1, 18.6; MS m/z: 430.5 [M+H]+.
-
- A. A mixture of (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 24, 2.00 g, 3.8 mmol), TPAP (200 mg, 0.57 mmol) and NMO (1.33 g, 11.4 mmol) in CH2Cl2 (25 mL) under argon at 0° C. was allowed to warm to room temperature over 1 h. The mixture was filtered through a pad of silica then concentrated. The residue was purified using chromatography on silica gel (2% to 5% to 10% to 20% EtOAc in Hexanes) to afford (3a′R,4′R,5′R,7a'S)-5′-((1S,2R,4S)-4-((tert-butyldimethylsilyl)oxy)-1-methyl-2-(2-oxoethyl)cyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl as the acetate salt (Compound No. 25, 0.66 g, 33%) as a white foam.
- B. A mixture of (3a′R,4′R,5′R,7a'S)-5′-((1S,2R,4S)-4-((tert-butyldimethylsilyl)oxy)-1-methyl-2-(2-oxoethyl)cyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 25, 0.66 g, 1.3 mmol) and pyrrolidine (0.13 mL, 1.6 mmol) in THF (10 mL) under argon at room temperature was allowed to stir for 5 min. To the resultant mixture was added NaBH(OAc)3 (0.40 g, 1.9 mmol) and the solution was stirred for 19 h. To the mixture was added pyrollidine (0.13 mL, 1.6 mmol) and NaBH(OAc)3 (0.40 g, 1.9 mmol) and the solution was stirred for 3 d. The reaction was quenched with saturated NaHCO3 solution (20 mL), extracted with EtOAc (3×20 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (9:1 EtOAc:MeOH+1% NH4Cl) to afford (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-1-methyl-2-(2-(pyrrolidin-1-yl)ethyl)cyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 26, 0.67 g, 89%) as a colourless oil.
- B. A mixture of (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-1-methyl-2-(2-(pyrrolidin-1-yl)ethyl)cyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 26, 0.65 g, 1.1 mmol) and water (8 mL) in AcOH (32 mL) was heated at 50° C. for 2 d. The mixture was concentrated and azeotroped from toluene (2×20 mL). The residue was purified using chromatography on silica gel (9:1 EtOAc:MeOH+2% NH4Cl) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyrrolidin-1-yl)ethyl)cyclohexyl)-7a-methyl-1-oxooctahydro-1H-inden-4-yl acetate (Compound No. 27, 0.36 g, 78%) as a white foam.
- C. To a suspension of Ph3PMeBr (768 mg, 2.15 mmol) in THF (30 mL) under argon at 0° C. was added KOtBu (241 mg, 2.15 mmol). After 20 min a solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyrrolidin-1-yl)ethyl)cyclohexyl)-7a-methyl-1-oxooctahydro-1H-inden-4-yl acetate (Compound No. 27, 0.36 g, 0.86 mmol) in THF (10 mL) was added via cannula and the mixture was stirred at room temperature for 60 h. The reaction was quenched with brine (40 mL), extracted with EtOAc (3×40 mL), dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (9:1 EtOAc:MeOH+1% NH4Cl) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyrrolidin-1-yl)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 28, 0.35 g, 97%) as a white foam.
- D. A mixture of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyrrolidin-1-yl)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 28, 0.35 g, 0.8 mmol) and LiAlH4 (1 mL of a 2 M solution in THF, 2 mmol) in THF (8 mL) under argon at 0° C. was warmed to room temperature over 90 min. The mixture was cooled to 0° C. before the slow addition of water (76 μL), NaOH (2 M, 76 μL) then water (228 μL). The mixture was stirred for 90 min, filtered and concentrated. The residue was purified using chromatography on silica gel (9:1 EtOAc:MeOH+1% NH4Cl) to afford the free base (143 mg, 50%) as a clear film. A mixture of the free base (143 mg, 0.39 mmol) and AcOH (114 μL, 2 mmol) in MeOH (8 mL) was stirred at room temperature for 10 min. The mixture was concentrated and azeotroped from MeOH:toluene (1:3, 2×10 mL). The residue was dissolved in CH2Cl2 (5 mL) and hexanes (10 mL) were added. The mixture was concentrated. The material was dissolved in CH2Cl2 (5 mL) and hexanes (10 mL) were added. The mixture was concentrated to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyrrolidin-1-yl)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 29, 167 mg, 97%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 4.62 (s, 2H), 3.62 (m, 1H), 3.43 (m, 1H), 3.15 (m, 2H), 2.51 (m, 1H), 2.24 (m, 1H), 2.04 (m, 4H), 1.93 (s, 6H), 1.79-1.23 (s, 18H), 1.18 (s, 3H), 0.79 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.7, 161.1, 161.0, 101.1, 71.6, 69.7, 69.7, 56.2, 54.2, 54.1, 53.0, 51.9, 51.8, 45.4, 38.3, 37.5, 35.5, 35.3, 35.3, 31.0, 30.9, 29.2, 25.7, 24.0, 23.5, 23.4, 23.2, 23.1, 22.9, 20.8, 20.7, 18.4; MS m/z: 376.4 [M+H]+ free base.
-
- A mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), NaBH(OAc)3 (197 mg, 0.93 mmol), 4 Å molecular sieves (100 mg) and 4-pyridinecarboxaldehyde (0.15 mL, 1.6 mmol) in CH2Cl2:MeOH (5:1, 6 mL) under argon was stirred at room temperature for 72 h. The mixture was filtered through Celite with EtOAc and was concentrated to a white solid. The residue was purified using chromatography on silica gel (0% to 10% MeOH/EtOAc) to afford an off-white solid. A solution of the solid (70 mg, 0.17 mmol) and NaBH4 (10 mg, 0.26 mmol) in MeOH:THF (2:1, 9 mL) was stirred at room temperature for 24 h. Additional NaBH4 (3 equivalents) was added and the mixture was heated at reflux for 24 h. The reaction was quenched with a solution of NH4Cl (10 mL), extracted with EtOAc (2×10 mL), washed successively with saturated NaHCO3 solution (2×10 mL) and brine (10 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (0% to 100% MeOH/EtOAc) to afford (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-((pyridin-4-ylmethylamino)methyl)octahydro-1H-inden-5-yl)cyclohexanol (Compound No. 30, 39 mg, 30%). 1H NMR (300 MHz, CD3OD) δ 8.44 (d, J=5.6 Hz, 2H), 7.42 (d, J=6.4 Hz, 2H), 4.61 (s, 2H), 3.42 (m, 1H), 3.31 (m, 1H), 3.13 (m, 1H), 2.83 (d, J=11.7 Hz, 1H), 2.58 (m, 1H), 2.45 (m, 1H), 2.19 (m, 2H), 1.77 (m, 5H), 1.62 (m, 1H), 1.44 (m, 5H), 1.27 (m, 4H), 1.02 (s, 3H), 0.78 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 162.9, 152.5, 149.8, 125.2, 101.6, 71.1, 62.9, 54.1, 52.3, 50.9, 46.4, 44.7, 39.3, 38.2, 37.2, 35.2, 32.1, 30.0, 25.8, 24.4, 21.0, 18.6; MS m/z: 413.4 [M+H]+.
-
- A. A mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol) p-tolualdehyde (0.18 mL, 1.55 mmol) and NaBH4 (41 mg, 1.1 mmol) in MeOH:THF (2:1, 9 mL) under argon was allowed to stir at room temperature for 48 h. The solution was concentrated and then dissolved in CH2Cl2 (4 mL). p-Tolualdehyde (0.4 mL, 0.34 mmol) and anhydrous Mg2SO4 (1.1 g, 9.3 mmol) were added and the solution was stirred at room temperature under argon for 24 h then was filtered through Celite with EtOAc, and concentrated. A solution of the residue and NaBH4 (18 mg, 0.46 mmol) in MeOH was stirred at room temperature for 20 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL), extracted with EtOAc (2×10 mL), washed successively with saturated NaHCO3 solution (2×10 mL) and brine (10 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (0% to 100% MeOH/EtOAc) to afford (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-4-((4-methylbenzylamino)methyl)-1-methyleneoctahydro-1H-inden-5-yl)cyclohexanol (Compound No. 31, 69 mg, 63%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.18 (d, J=7.7 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H), 4.61 (s, 2H), 3.69 (m, 1H), 3.63 (m, 2H), 3.39 (m, 1H), 3.11 (m, 1H), 2.78 (m, 1H), 2.55 (m, 1H), 2.44 (m, 1H), 2.31 (s, 3H), 2.18 (m, 2H), 1.81 (m, 5H), 1.60 (m, 1H), 1.41 (m, 5H), 1.25 (m, 4H), 0.96 (s, 3H), 0.77 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 162.8, 137.9, 137.8, 129.9, 129.7, 101.5, 71.0, 62.9, 55.0, 52.5, 50.6, 46.5, 44.7, 39.3, 38.5, 37.2, 35.2, 32.0, 30.0, 25.8, 21.1, 18.6; MS m/z: 426.5 [M+H]+.
-
- A mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), m-tolualdehyde (0.18 mL, 1.55 mmol) and NaBH4 (41 mg, 1.1 mmol) in MeOH:THF (2:1, 9 mL) under argon was allowed to stir at room temperature for 48 h. The solution was concentrated and then dissolved in toluene (4 mL). m-Tolualdehyde (0.4 mL, 0.34 mmol) and anhydrous Mg2SO4 (1.1 g, 9.3 mmol) were added and the solution was stirred at room temperature under argon for 24 h. The solution was filtered through Celite with EtOAc, and concentrated. A solution of the residue and NaBH4 (18 mg, 0.46 mmol) in MeOH, was stirred at room temperature for 20 h. The solution was quenched with saturated aqueous NH4Cl (10 mL), extracted with EtOAc (2×10 mL), washed successively with saturated NaHCO3 solution (2×10 mL) and brine (10 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (0% to 100% MeOH/EtOAc) to afford (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-4-((3-methylbenzylamino)methyl)-1-methyleneoctahydro-1H-inden-5-yl)cyclohexanol (Compound No. 32, 83 mg, 63%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.13 (m, 1H), 7.07 (m, 3H), 4.60 (s, 2H), 3.68 (m, 1H), 3.61 (s, 2H), 3.40 (m, 1H), 3.11 (m, 1H), 2.76 (m, 1H), 2.56 (m, 1H), 2.43 (m, 1H), 2.31 (s, 3H), 2.18 (m, 2H), 1.72 (m, 5H), 1.56 (m, 1H), 1.39 (m, 5H), 1.23 (m, 4H), 0.97 (s, 3H), 0.76 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 161.6, 139.9, 137.7, 129.3, 128.1, 127.6, 125.7, 100.5, 69.9, 61.8, 54.2, 51.3, 49.6, 45.3, 43.6, 38.1, 36.9, 36.0, 34.1, 30.9, 28.9, 24.7, 20.5, 19.9, 17.6; MS m/z: 426.5 [M+H]+.
-
- A mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), o-tolualdehyde (0.04 mL, 0.34 mmol) and anhydrous Mg2SO4 (1.1 g, 9.3 mmol) in CH2Cl2 (4 mL) was stirred at room temperature under argon for 24 h. The solution was filtered through Celite with EtOAc and concentrated. A solution of the residue and NaBH4 (11 mg, 0.29 mmol) in MeOH was stirred at room temperature under argon for 20 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL), extracted with EtOAc (2×10 mL), washed with saturate NaHCO3 solution (2×10 mL) and brine (10 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (0%-100% MeOH/EtOAc) to afford (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-4-((2-methylbenzylamino)methyl)-1-methyleneoctahydro-1H-inden-5-yl)cyclohexanol (Compound No. 33, 56 mg, 42%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.20 (m, 1H), 7.13 (s, 3H), 4.60 (s, 2H), 3.67 (m, 3H), 3.40 (m, 1H), 3.10 (m, 1H), 2.87 (m, 1H), 2.62 (m, 1H), 2.45 (m, 1H), 2.35 (s, 3H), 2.17 (m, 2H), 1.74 (m, 5H), 1.60 (m, 1H), 1.39 (m, 5H), 1.23 (m, 4H), 0.98 (s, 3H), 0.78 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 161.7, 137.9, 136.6, 130.0, 129.3, 127.0, 125.6, 100.4, 69.9, 61.8, 51.9, 51.3, 49.8, 46.9, 45.3, 43.5, 38.1, 36.9, 36.0, 34.0, 30.9, 28.9, 24.6, 19.8, 18.0, 17.5.
-
- To a mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), PyBOP (210 mg, 0.400 mmol), 2-naphthoic acid (69 mg, 0.40 mmol) under argon were added DIEA (0.81 mL, 0.81 mmol) and DMF (3.0 mL). The solution was stirred for 24 h then was diluted with EtOAc (20 mL), washed successively with saturated NaHCO3 solution (2×10 mL) and brine (2×10 mL) then was concentrated. The residue was purified using chromatography on silica gel (0% to 10% MeOH/EtOAc) to afford N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-2-naphthamide (Compound No. 34, 123 mg, 84%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.30 (s, 1H), 7.91 (m 3H), 6.81 (m, 1H), 7.57 (m, 2H), 4.65 (s, 2H), 3.76 (m, 1H), 3.67 (m, 2H), 3.48 (m, 1H), 3.14 (m, 1H), 2.51 (m, 1H), 2.23 (m, 2H), 1.87 (m, 5H), 1.74 (m, 1H), 1.50 (m, 5H), 1.29 (m, 4H), 1.08 (s, 3H), 0.86 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 171.1, 162.6, 136.2, 134.0, 133.3, 129.9, 129.2, 128.8, 127.8, 125.1, 101.8, 71.1, 62.9, 52.9, 47.5, 45.0, 44.8, 43.9, 38.2, 36.9, 35.2, 32.1, 30.2, 26.2, 24.4, 21.7, 18.8; MS m/z: 474.1 [M−H]−.
-
- To a mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), PyBOP (210 mg, 0.400 mmol), benzoic acid (49 mg, 0.40 mmol) under argon were added DIEA (0.81 mL, 0.81 mmol) and DMF (3.0 mL). The solution was stirred for 24 h then was diluted with EtOAc (20 mL), washed successively with saturated NaHCO3 solution (2×10 mL) and brine (2×10 mL) then was concentrated. The residue was purified using chromatography on silica gel (0% to 10% MeOH/EtOAc) to afford N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)benzamide (Compound No. 35, 89 mg, 68%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.74 (d, J=6.93 Hz, 2H), 7.48 (m, 3H), 4.64 (s, 2H), 3.73 (m, 1H), 3.61 (m, 2H), 3.47 (m, 1H), 3.13 (m, 1H), 2.49 (m, 1H), 2.21 (m, 2H), 1.86 (m, 5H), 1.69 (m, 1H), 1.49 (m, 5H), 1.30 (m, 4H), 1.05 (s, 3H), 0.84 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 170.0, 161.3, 134.9, 131.3, 128.3, 127.2, 100.6, 69.9, 61.7, 51.7, 46.9, 46.4, 43.9, 43.7, 42.6, 39.9, 35.8, 34.0, 30.9, 29.0, 24.9, 23.2, 20.5, 17.6; MS m/z: 423.9 [M−H]−.
-
- A mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), 4-methoxybenzaldehyde (0.04 mL, 0.34 mmol) and anhydrous Mg2SO4 (1.1 g, 9.3 mmol) in CH2Cl2 (4 mL) was stirred at room temperature under argon for 18 h. The solution was filtered through Celite with EtOAc and concentrated. A solution of the residue and NaBH4 (35 mg, 0.92 mmol) in MeOH (5 mL) was stirred at room temperature under argon for 48 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL), extracted with EtOAc (2×10 mL), washed successively with saturated NaHCO3 solution (2×10 mL) and brine (10 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (0% to 100% MeOH/EtOAc) to afford (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-((4-methoxybenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexanol (Compound No. 36, 83 mg, 61%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.22 (d, J=8.5, 2H), 6.86 (d, J=8.5, 2H), 4.61 (s, 2H), 3.78 (s, 3H), 3.69 (d, J=10.3, 1H), 3.62 (s, 2H), 3.40 (m, 1H), 3.11 (t, J=10.0, 1H), 2.78 (d, J=11.1, 1H), 2.58 (d, J=11.1, 1H), 2.44 (m, 1H), 2.18 (m, 2H), 1.87-1.04 (m, 15H), 0.96 (s, 3H), 0.78 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 164.5, 162.9 160.4, 131.0, 131.0, 114.7, 101.5, 71.1, 62.9, 55.7, 54.6, 52.5, 50.5, 46.5, 46.4, 44.7, 39.2, 38.1, 37.2, 35.2, 32.0, 30.0, 25.8, 21.1, 18.6.
-
- A mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), 4-trifluoromethylbenzaldehyde (63 mg mL, 0.36 mmol) and anhydrous Mg2SO4 (1.1 g, 9.3 mmol) in CH2Cl2 (3 mL) was stirred at room temperature under argon for 24 h. The solution was filtered through Celite with EtOAc and concentrated. A solution of the residue and NaBH4 (5.3 mg, 0.14 mmol) in MeOH (5 mL) was stirred at room temperature under argon for 24 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL), extracted with EtOAc (2×10 mL), washed successively with saturated NaHCO3 solution (2×10 mL) and brine (10 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (EtOAc) to afford (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-((4-(trifluoromethyl)benzylamino)methyl)octahydro-1H-inden-5-yl)cyclohexanol (Compound No. 37, 20 mg, 13%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=7.7, 2H), 7.42 (d, J=7.5, 2H), 4.63 (m 2H), 3.71 (s, 2H), 3.58 (m, 1H), 3.30 (m, 1H), 2.86 (d, J=12.3, 1H), 2.61 (d, J=12.3, 1H), 2.46 (m, 1H), 2.23 (m, 2H), 1.81-1.19 (m, 15H), 1.04 (s, 3H), 0.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.5, 144.9, 128.6, 125.4, 101.3, 63.2, 63.1, 63.1, 54.3, 51.1, 50.2, 43.8, 38.2, 37.2, 36.1, 34.5, 31.3, 29.2, 24.8, 23.5, 20.6, 18.3.
-
- To a suspension of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate (Compound No. 1, 116 mg, 0.304 mmol) in pyridine (3.0 mL) was added trimethylacetyl chloride (0.11 mL, 0.89 mmol), and the mixture was stirred at room temperature under argon for 24 h then concentrated. Azeotropic removal of remaining pyridine was carried out with toluene (2×4 mL). The residue was dissolved in MeOH (3 mL), and 10 N NaOH(aq) (0.3 mL, 3 mmol) was added then heated to reflux for 2.3 h. The mixture was concentrated, and the residue was partitioned between EtOAc (35 mL) and H2O (10 mL). The organic layer was washed with brine (10 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (4:96-6:94 MeOH/CH2Cl2) to give N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)pivalamide (Compound No. 38, 82 mg, 67% over 2 steps) as a colourless solid. 1H NMR (CD3OD): δ 6.50 (br s, 1H), 4.64 (s, 2H), 3.71 (m, 1H), 3.47 (m, 2H), 3.32 (m, 1H), 3.13 (m, 1H), 2.50 (m, 1H), 2.12-2.26 (m, 2H), 1.18-1.87 (m, 24H), 1.00 (s, 3H), 0.82 (s, 3H). ES-MS m/z 406 ([M+1]+).
-
- To a solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate (Compound No. 1, 104 mg, 0.273 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (96 mg, 0.30 mmol), and isobutyric acid (0.028 mL, 0.30 mmol) in DMF (1.4 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.63 mmol), and the solution was stirred at room temperature for 24 h. The mixture was concentrated, and the residue was partitioned between EtOAc (35 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was washed with brine (5×10 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (7:93 MeOH/CH2Cl2) to give N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)isobutyramide (Compound No. 39, 41 mg, 38%) as a colourless solid. 1H NMR (CD3OD): δ 4.64 (s, 2H), 3.72 (m, 1H), 3.44 (m, 2H), 3.33 (m, 1H), 3.13 (m, 1H), 2.45-2.65 (m, 2H), 2.13-2.28 (m, 2H), 1.20-1.89 (m, 15H), 1.07 (m, 6H), 0.99 (s, 3H), 0.82 (s, 3H). ES-MS m/z 392 ([M+1]+).
-
- To a solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate (Compound No. 1, 97 mg, 0.25 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (90 mg, 0.28 mmol), and propionic acid (0.021 mL, 0.28 mmol) in DMF (1.3 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.63 mmol), and the solution was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between EtOAc (35 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was washed with brine (5×10 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (5:95-7:93 MeOH/CH2Cl2) to give N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)propionamide (Compound No. 40, 38 mg, 40%) as colourless crystals. 1H NMR (CD3OD): δ 7.53 (br s, 1H), 4.63 (s, 2H), 3.72 (m, 1H), 3.46 (m, 2H), 3.33 (m, 1H), 3.13 (m, 1H), 2.50 (m, 1H), 2.13-2.28 (m, 4H), 1.20-1.86 (m, 15H), 1.10 (t, J=7.7 Hz, 3H), 0.98 (s, 3H), 0.82 (s, 3H). ES-MS m/z 378 ([M+1]+).
-
- To a solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate (Compound No. 1, 96 mg, 0.25 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (89 mg, 0.28 mmol), and butyric acid (0.025 mL, 0.27 mmol) in DMF (1.3 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.63 mmol), and the solution was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between EtOAc (35 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was washed with brine (5×10 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (7:93 MeOH/CH2Cl2) to give N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)butyramide (Compound No. 41, 39 mg, 39%) as colourless crystals. 1H NMR (CD3OD): δ 7.55 (br s, 1H), 4.64 (s, 2H), 3.72 (m, 1H), 3.31-3.48 (m, 3H), 3.13 (m, 1H), 2.49 (m, 1H), 2.13-2.28 (m, 4H), 1.20-1.89 (m, 17H), 0.99 (s, 3H), 0.93 (t, J=7.2 Hz, 3H), 0.82 (s, 3H). ES-MS m/z 392 ([M+1]+).
-
- To a solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate (Compound No. 1, 94 mg, 0.25 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (87 mg, 0.27 mmol), and valeric acid (0.054 mL, 0.50 mmol) in DMF (1.2 mL) was added N,N-diisopropylethylamine (0.10 mL, 0.57 mmol), and the solution was stirred at room temperature for 21 h. The mixture was concentrated, and the residue was partitioned between EtOAc (35 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was washed with brine (5×10 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (7:93 MeOH/CH2Cl2) to give N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)pentanamide (Compound No. 42, 41 mg, 41%) as a colourless solid. 1H NMR (CD3OD): δ 7.55 (br s, 1H), 4.64 (s, 2H), 3.72 (m, 1H), 3.31-3.48 (m, 3H), 3.13 (m, 1H), 2.49 (m, 1H), 2.13-2.27 (m, 4H), 1.20-1.86 (m, 19H), 0.99 (s, 3H), 0.93 (t, J=7.2 Hz, 3H), 0.82 (s, 3H). ES-MS m/z 406 ([M+1]+).
-
- A. A solution of (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl acetate (Compound No. 43, 3.60 g, 9.90 mmol), TBSCl (1.64 g, 10.9 mmol), imidazole (1.48 g, 21.8 mmol) in DMF (50 mL) was stirred 5 h at room temperature under nitrogen. The solution was poured into water (90 mL), extracted with Et2O (2×100 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (15% EtOAc/hexanes) to afford (1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl acetate (Compound No. 44, 3.61 g, 76%) as a white foam.
- B. To a solution of (1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl acetate (Compound No. 44, 1.00 g, 2.09 mmol) and DMAP (24 mg, 0.2 mmol) in pyridine (10 mL) at 0° C. under nitrogen was added MsCl (0.50 mL, 6.3 mmol). After 2.5 h saturated NaHCO3 solution (10 mL) was added and the solution was stirred at room temperature for 20 min. The solution was diluted with EtOAc (200 mL), washed with brine, dried (MgSO4) and concentrated to afford (1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-1-methyl ene-4-(((methylsulfonyl)oxy)methyl)octahydro-1H-inden-5-yl)cyclohexyl acetate (Compound No. 45, 1.15 g, 99%) as a white solid.
- C. To a solution of pyrazole (73 mg, 1.1 mmol) in DMF (5 mL) at 0° C. under nitrogen was added NaH (43 mg of a 60% solution in mineral oil, 1.1 mmol). After 45 min, (1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-(((methylsulfonyl)oxy)methyl)octahydro-1H-inden-5-yl)cyclohexyl acetate (Compound No. 45, 200 mg, 0.36 mmol) was added and the reaction was stirred at room temperature for 22 h. The solution was cooled in ice then saturated NaHCO3 solution (3 mL) was added. The solution was diluted with Et2O (100 mL), washed with brine, dried (MgSO4) and concentrated. The resulting colourless oil was purified using chromatography on silica gel (10%, 30% and 40% EtOAc/hexanes) to afford (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-1,2,4-triazol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcyclohexyl acetate (Compound 46, 124 mg, 65%) as a colourless film and (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-pyrazol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcyclohexanol (Compound No. 5, 65 mg, 37%) as a colourless film.
- D. A solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-1,2,4-triazol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcyclohexyl acetate (Compound No. 46, 124 mg, 0.23 mmol) and sodium methoxide (0.4 mL of a 5.4 M solution in methanol, 2.3 mmol) in methanol (5 mL) was stirred at room temperature for 23 h. The solution was cooled in ice then was added (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-pyrazol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcyclohexanol (Compound No. 47, 65 mg, 0.13 mmol) in acetic acid (16 mL) and water (4 mL). The solution was stirred at room temperature for 20 hours then was concentrated and purified by chromatography on silica gel (40% then 80% EtOAc/hexanes) to afford (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-pyrazol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 48, 77 mg, 56%) as a white solid. 1H NMR (CDCl3): δ 7.42 (s, 1H), 7.35 (s, 1H), 6.20 (s, 1H), 4.58 (s, 2H), 4.50 (s, 1H), 3.98 (m, 1H), 3.70 (m, 1H), 3.48 (m, 1H), 3.19 (m, 1H), 2.28 (m, 2H), 2.05 (m, 2H), 1.80 (m, 4H), 1.1-1.4 (9H), 1.02 (s, 3H), 0.85 (m, 1H), 0.70 (s, 3H). ES-MS m/z 373 ([M+1]+).
-
- A. To a solution of 1,2,4-triazole (253 mg, 3.60 mmol) in DMF (5 mL) at 0° C. under nitrogen was added NaH (144 mg of a 60% solution in mineral oil, 3.60 mmol). After 70 min, (1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-(((methylsulfonyl)oxy)methyl)octahydro-1H-inden-5-yl)cyclohexyl acetate (Compound No. 45, 200 mg, 0.36 mmol) was added and the reaction was stirred at room temperature for 25 h then was heated at 50° C. for 18 h then was heated at 80° C. for 4 h. The solution was cooled in ice then saturated NaHCO3 solution (3 mL) was added. The solution was diluted with Et2O (100 mL), washed with brine, dried (MgSO4) and concentrated. The resulting colourless film was purified using chromatography on silica gel (30%, 40% and 50% EtOAc/hexanes) to afford (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-1,2,4-triazol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcyclohexyl acetate (Compound 49, 0.17 g, 89%) as a colourless film.
- B. A solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-1,2,4-triazol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcyclohexyl acetate (Compound No. 49, 0.17 g, 0.32 mmol) and sodium methoxide (0.66 mL of a 5.4 M solution in methanol, 3.6 mmol) in methanol (23 mL) was stirred at room temperature for 4 h. To the solution was added acetic acid (32 mL) and water (8 mL). The solution was stirred at 40° C. for 3 d then was concentrated and purified by chromatography on silica gel (5% then 10% MeOH/EtOAc) to afford (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-1,2,4-triazol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 50, 110 mg, 92%) as a white foam. 1H NMR (CDCl3): δ 8.04 (s, 1H), 7.92 (s, 1H), 4.62 (s, 2H), 4.45 (m, 1H), 4.25 (m, 1H), 3.78 (m, 1H), 3.60 (m, 1H), 3.32 (m, 1H), 2.40 (m, 1H), 2.20 (m, 3H), 1.0-2.0 (15H), 1.18 (s, 3H), 0.85 (m, 1H), 0.80 (s, 3H). ES-MS m/z 374 ([M+1]+).
-
- A. To a solution of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 51, 222 mg, 0.546 mmol) and Et3N (0.099 mL, 0.71 mmol) in CH2Cl2 (5.5 mL) at 0° C. under argon was added MsCl (0.047 mL, 0.61 mmol), and the solution was stirred at room temperature for 1 h. The solution was diluted with CH2Cl2 (15 mL) and washed with saturated aqueous NaHCO3 (15 mL), and the aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried (MgSO4) and concentrated. Azeotropic removal of impurities was carried out with toluene (3×10 mL), and the mesylate residue was dissolved in THF (1.1 mL). A solution of benzimidazole (52 mg, 0.44 mmol) in THF (1.1 mL) was cooled to 0° C. under argon and NaH (35 mg of a 60% solution, 0.88 mmol) was added then stirred at room temperature for 0.5 h. The mesylate solution from above (1.1 mL) was added and heated to 65° C. for 17 h. The mixture was diluted with H2O (10 mL) followed by EtOAc (30 mL), and the organic layer was washed with H2O (10 mL) and brine (10 mL) then dried (MgSO4) and concentrated. The residue was partially purified by chromatography on silica gel (3:97 MeOH/CH2Cl2) to give (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-benzo[d]imidazol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(acetoxymethyl)-4-methylcyclohexyl acetate (Compound No. 52, 74 mg) as a colourless oil.
- B. To a solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-benzo[d]imidazol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(acetoxymethyl)-4-methylcyclohexyl acetate (Compound No. 52, 74 mg) in MeOH (3 mL) was added potassium carbonate (81 mg, 0.59 mmol) and heated to 40° C. for 1 h. The mixture was concentrated, and the residue was purified by chromatography on silica gel (10:90 MeOH/EtOAc) to give (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-benzo[d]imidazol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 53, 16 mg, 9% over 3 steps) as a colourless solid. 1H NMR (CD3OD): δ 8.29 (s, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.26-7.37 (m, 2H), 4.70 (m, 1H), 4.62 (s, 1H), 4.56 (s, 1H), 4.19 (dd, J=14, 9.8 Hz, 1H), 3.76 (m, 1H), 3.52 (m, 1H), 3.18 (m, 1H), 2.53 (m, 1H), 2.19 (m, 2H), 1.23-2.01 (m, 13H), 1.09 (s, 3H), 0.94 (m, 1H), 0.73 (m, 4H). ES-MS m/z 423 ([M+1]+).
-
- A. A solution of (1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-(((methylsulfonyl)oxy)methyl)octahydro-1H-inden-5-yl)cyclohexyl acetate (Compound No. 45, 1.14 g, 2.05 mmol) and KCN (0.42 g, 6.14 mmol) in DMSO (10 mL) was stirred at 60° C. under nitrogen for 16 h. THF (10 mL) was added, then after 1 h the solution was cooled to room temperature, poured into water (40 mL), extracted with Et2O (2×100 mL), washed with brine, dried (MgSO4) and concentrated. The solid residue was purified by chromatography on silica gel (10% then 20% EtOAc/hexanes) to afford (1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((3aS,4R,5S,7aS)-4-(cyanomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl acetate (Compound No. 54, 0.92 g, 92%) as a white solid.
- B. To a solution of (1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((3aS,4R,5S,7aS)-4-(cyanomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl acetate (Compound No. 54, 0.92 g, 1.9 mmol) in THF (10 mL) at 0° C. under nitrogen was added LAH (1.9 mL of a 2 M solution in THF, 3.8 mmol). After 22 h, the solution was cooled in ice then added Na2SO4.10H2O (1.22 g) and stirred the solution at room temperature for 40 min. The solution was filtered through Celite and eluted with EtOAc. The residue was purified using chromatography on silica gel (20% MeOH/EtOAc then 20% MeOH/EtOAc with 5% Et3N) to afford (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(2-aminoethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcyclohexanol (Compound No. 55, 0.48 g, 56%) as a white film.
- C. A solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(2-aminoethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcyclohexanol (Compound No. 55, 0.48 g, 1.1 mmol) in acetic acid (32 mL) and water (8 mL) was stirred at room temperature for 24 h then was concentrated. The residue was purified using chromatography on silica gel (20% MeOH/EtOAc then 20% MeOH/EtOAc with 5% Et3N) to afford (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(2-aminoethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 56, 364 mg, 100%) as a white foam.
-
- To a solution of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 51, 243 mg, 0.598 mmol) and Et3N (0.11 mL, 0.79 mmol) in CH2Cl2 (6.0 mL) at 0° C. under argon was added MsCl (0.051 mL, 0.66 mmol), and the solution was stirred at room temperature for 1 h. The solution was diluted with CH2Cl2 (15 mL) and washed with saturated aqueous NaHCO3 (15 mL), and the aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried (MgSO4) and concentrated. Azeotropic removal of impurities was carried out with toluene (3×10 mL), and the mesylate residue was dissolved in DMF (0.9 mL). To a suspension of KOH (168 mg, 2.99 mmol) in DMF (0.3 mL) was added indole (140 mg, 1.20 mmol), and the mixture was stirred under argon at room temperature for 15 min. The mesylate solution from above (0.9 mL) was added dropwise, and the mixture was stirred at room temperature for 1 h then heated to 50° C. for 20 h. The mixture was diluted with EtOAc (35 mL), and the organic layer was washed with brine (6×15 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (90:10 EtOAc/hexanes) to give (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((1H-indol-1-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 57, 43 mg, 17%) as a colourless solid (. 1H NMR (CDCl3): δ 7.62 (d, J=7.8 Hz, 1H), 7.19-7.32 (m, 3H), 7.09 (m, 1H), 6.52 (d, J=2.7 Hz, 1H), 4.61 (s, 1H), 4.58 (s, 1H), 4.52 (dd, J=14, 3.0 Hz, 1H), 3.93 (dd, J=14, 9.0 Hz, 1H), 3.78 (m, 1H), 3.62 (m, 1H), 3.32 (m, 1H), 2.39 (m, 1H), 2.20 (m, 2H), 1.25-1.99 (m, 13H), 1.03 (m, 4H), 0.83 (m, 4H). ES-MS m/z 480 ([M−1+60]−).
-
- A. To a solution of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 51, 244 mg, 0.600 mmol) and Et3N (0.11 mL, 0.79 mmol) in CH2Cl2 (6.0 mL) at 0° C. under argon was added MsCl (0.051 mL, 0.66 mmol), and the solution was stirred at room temperature for 1.5 h. The solution was diluted with CH2Cl2 (15 mL) and washed with saturated aqueous NaHCO3 (15 mL), and the aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried (MgSO4) and concentrated, and azeotropic removal of impurities was carried out with toluene (3×10 mL). To the mesylate residue was added indoline (143 mg, 1.20 mmol), potassium carbonate (415 mg, 3.00 mmol) and CH3CN (2.0 mL), and the mixture was heated to reflux under argon for 19 h. The mixture was partitioned between CH2Cl2 (15 mL) and H2O (10 mL), and the aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried (MgSO4) and concentrated, and the residue was purified by chromatography on silica gel (12:88 EtOAc/hexanes) to give ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(indolin-1-ylmethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 58, 81 mg, 27% over 2 steps) as a colourless film.
- B. To a solution of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(indolin-1-ylmethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 58, 81 mg, 0.16 mmol) in MeOH (3.2 mL) was added potassium carbonate (88 mg, 0.64 mmol) and heated to 40° C. for 1 h then concentrated. Acetone (20 mL) was added, and the mixture was filtered and concentrated. The residue was purified by chromatography on silica gel (85:15 EtOAc/hexanes) to give (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-(indolin-1-ylmethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexanol (Compound No. 59, 31 mg, 46%) as a colourless solid. 1H NMR (CDCl3): δ 7.06 (m, 2H), 6.64 (m, 1H), 6.41 (d, J=7.8 Hz, 1H), 4.64 (s, 2H), 3.74 (m, 1H), 3.57 (m, 1H), 3.27-3.39 (m, 4H), 2.92 (m, 3H), 2.44 (m, 1H), 2.16 (m, 2H), 1.25-1.92 (m, 15H), 1.07 (s, 3H), 0.83 (s, 3H). ES-MS m/z 424 ([M+1]+).
-
- A. To a solution of 2,2,2-trifluoro-N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)acetamide (Compound No. 60, 3.21 g, 7.69 mmol) and imidazole (1.20 g, 17.6 mmol) in DMF (15 mL) at 0° C. was added TBSCl (2.43 g, 16.1 mmol), and the solution was stirred at room temperature under argon for 3 d. The mixture was diluted with EtOAc (70 mL) and washed with H2O (2×20 mL) and brine (6×20 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (10:90 EtOAc/hexanes) to give N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-2,2,2-trifluoroacetamide (Compound No. 61, 4.60 g, 93%) as a colourless foam.
- B. To a solution of N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-2,2,2-trifluoroacetamide (Compound No. 61, 4.59 g, 7.10 mmol) in 9:1 MeOH/H2O (71 mL) was added potassium carbonate (2.95 g, 21.3 mmol) and heated to 60° C. for 18 h. The mixture was concentrated and H2O (10 mL) was added. The mixture was extracted with CH2Cl2 (40 mL then 2×15 mL), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (5:95 MeOH/CH2Cl2) to give ((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methanamine (Compound No. 62, 3.68 g, 94%) as a colourless foam.
- C. To a mixture of ((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methanamine (Compound No. 62, 167 mg, 0.304 mmol), NaI (6 mg, 0.04 mmol) and DIEA (0.063 mL, 0.36 mmol) in CH3CN (3.0 mL) was added 3,5-dimethoxybenzyl bromide (95%, 74 mg, 0.30 mmol) followed by CH2Cl2 (1 mL). The mixture was stirred at room temperature for 24 h then concentrated. The residue was partitioned between EtOAc (40 mL) and saturated aqueous NaHCO3 (15 mL). The organic layer was washed with brine (4×15 mL) then dried (MgSO4) and concentrated to give 1-((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)-N-(3,5-dimethoxybenzyl)methanamine (Compound No. 63, 216 mg) as a colourless foam.
- D. TBAF (1.2 mL of a 1 M solution in THF, 1.2 mmol) was added to a solution of 1-((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)-N-(3,5-dimethoxybenzyl)methanamine (Compound No 63, 216 mg) in THF (6.0 mL) and stirred at room temperature for 18 h. The solution was concentrated, and the residue was purified by chromatography on silica gel (6:94 MeOH/EtOAc) to give (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((3,5-dimethoxybenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 64 127 mg, 89% over 2 steps) as a colourless solid. 1H NMR (CD3OD): δ 6.48 (s, 2H), 6.36 (s, 1H), 4.61 (s, 2H), 3.55-3.76 (m, 9H), 3.40 (m, 1H), 3.12 (m, 1H), 2.77 (m, 1H), 2.41-2.58 (m, 2H), 2.10-2.29 (m, 2H), 1.18-1.82 (m, 15H), 1.00 (s, 3H), 0.77 (s, 3H). ES-MS m/z 472 ([M+1]+).
-
- A. A solution of 2-(trimethylsilyl)ethoxymethyl chloride (531 mg, 3.18 mmol) in DMF (2.0 mL) was added to a solution of benzimidazole (314 mg, 2.66 mmol) and DIEA (0.69 mL, 4.0 mmol) in DMF (3.3 mL) then heated to 80° C. for 1.5 h. The mixture was diluted with EtOAc (40 mL) and washed with brine (6×18 mL) then dried (MgSO4) and concentrated. Azeotropic removal of impurities was carried out with MeOH (10 mL) then CH2Cl2 (3×10 mL). The residue was dissolved in THF (13 mL) and cooled to −40° C. under argon. n-Butyllithium (1.7 mL of a 1.9 M solution in hexanes, 3.2 mmol) was added and stirred at −40° C. for 20 min then DMF (0.51 mL, 6.6 mmol) was added at −40° C. The mixture was allowed to warm to room temperature over 4 h then stirred at room temperature for 3 d. The mixture was diluted with EtOAc (30 mL) and washed with H2O (10 mL) and brine (3×10 mL). The organic layer was dried (MgSO4) and concentrated, and the residue was partially purified by chromatography on silica gel (1:99 MeOH/CH2Cl2) to give 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbaldehyde (Compound No. 65, 579 mg) as a yellow oil.
- B. A solution of ((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methanamine (Compound No. 62, 164 mg, 0.298 mmol) and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbaldehyde (Compound No. 65, 99 mg) in MeOH (4.3 mL) was heated to reflux under argon for 0.5 h then allowed to cool to room temperature. NaBH4 (14 mg, 0.37 mmol) was added and stirred at room temperature for 17 h. More NaBH4 (14 mg, 0.37 mmol) was added and heated to 60° C. for 1 h. The mixture was diluted with H2O (0.5 mL) and concentrated then 1 N NaOH(aq) (10 mL) was added to the residue. The mixture was extracted with CH2Cl2 (15 mL then 2×10 mL), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (20:80 EtOAc/hexanes) to give 1-((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)methanamine (Compound No. 66, 170 mg, 70%) as a yellow oil.
- C. TBAF (1.0 mL of a 1 M solution in THF, 1.0 mmol) was added to a solution of 1-((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)methanamine (Compound No. 66, 170 mg, 0.210 mmol) in THF (4.2 mL) and heated to 50° C. for 16 h. The solution was concentrated, and the residue was purified by chromatography on silica gel (5:95 MeOH/EtOAc) to give (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-((((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)amino)methyl)octahydro-1H-inden-5-yl)cyclohexanol (Compound No. 67, 85 mg, 70%) as a colourless film.
- D. TBAF (0.44 mL of a 1 M solution in THF, 0.44 mmol) was added to a solution of (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-((((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)amino)methyl)octahydro-1H-inden-5-yl)cyclohexanol (Compound No. 67, 85 mg, 0.15 mmol) in THF (2.9 mL) and heated to 70° C. for 26.5 h. The solution was concentrated, and the residue was purified by chromatography on silica gel (100:5:1 EtOAc/MeOH/NH4OH) to give (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(((1H-benzo[d]imidazol-2-yl)methylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 68, 57 mg, 86%) as a colourless solid. 1H NMR (CD3OD): δ 7.52 (m, 2H), 7.21 (m, 2H), 4.60 (s, 2H), 3.95 (d, J=15 Hz, 1H), 3.88 (d, J=15 Hz, 1H), 3.70 (m, 1H), 3.40 (m, 1H), 3.12 (m, 1H), 2.92 (m, 1H), 2.62 (m, 1H), 2.43 (m, 1H), 2.09-2.28 (m, 2H), 1.20-1.82 (m, 15H), 0.99 (s, 3H), 0.77 (s, 3H). ES-MS m/z 452 ([M+1]+).
-
- A. A solution of ((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methanamine (Compound No. 62, 125 mg, 0.227 mmol) and piperonal (41 mg, 0.27 mmol) in MeOH (4.5 mL) was heated to reflux under argon for 25 min then allowed to cool to room temperature. NaBH4 (17 mg, 0.44 mmol) was added and stirred at room temperature for 1.5 h. The mixture was diluted with H2O (0.5 mL) and concentrated, and the residue was partitioned between 1 N NaOH(aq) (10 mL) and CH2Cl2 (15 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (20:80 EtOAc/hexanes) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)methanamine (Compound No. 69, 137 mg, 88%) as a colourless oil.
- B. TBAF (0.80 mL of a 1 M solution in THF, 0.80 mmol) was added to a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)methanamine (Compound No. 69, 137 mg, 0.200 mmol) in THF (4.0 mL) and stirred at room temperature for 16 h. The solution was concentrated, and the residue was purified by chromatography on silica gel (4:96 MeOH/EtOAc) to give (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((benzo[d][1,3]dioxol-5-ylmethylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 70, 56 mg, 62%) as a colourless solid. 1H NMR (CD3OD): δ 6.82 (s, 1H), 6.74 (s, 2H), 5.91 (s, 2H), 4.61 (s, 2H), 3.69 (m, 1H), 3.59 (m, 2H), 3.40 (m, 1H), 3.12 (m, 1H), 2.77 (m, 1H), 2.42-2.57 (m, 2H), 2.10-2.29 (m, 2H), 1.22-1.82 (m, 15H), 0.98 (s, 3H), 0.78 (s, 3H). ES-MS m/z 456 ([M+1]+).
-
- A. To a solution of ((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methanol (Compound No. 71, 311 mg, 0.56 mmol) and Et3N (0.10 mL, 0.72 mmol) in CH2Cl2 (5.6 mL) at 0° C. under argon was added MsCl (0.048 mL, 0.62 mmol), and the solution was stirred at room temperature for 3 h. The solution was diluted with CH2Cl2 (15 mL) and washed with saturated aqueous NaHCO3 (15 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL), and the combined organic layers were dried (MgSO4) and concentrated. Azeotropic removal of impurities was carried out with toluene (3×10 mL), and the residue was dissolved in DMF (1.9 mL). Adenine (84 mg, 0.62 mmol) and potassium carbonate (234 mg, 1.69 mmol) were added, and the mixture was heated to 80° C. under argon for 17.5 h. The mixture was partitioned between EtOAc (40 mL) and H2O (15 mL), and the organic layer was washed with brine (3×10 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (3:97 MeOH/CH2Cl2) to give 9-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-9H-purin-6-amine (Compound No. 72, 187 mg, 50%) as a pale foam.
- B. TBAF (1.1 mL of a 1 M solution in THF, 1.1 mmol) was added to a solution of 9-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-9H-purin-6-amine (Compound No. 72, 187 mg, 0.280 mmol) in THF (5.6 mL) and heated to 40° C. for 3 d. The solution was concentrated, and the residue was purified by chromatography on silica gel (100:10:2 EtOAc/MeOH/NH4OH) to give (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((6-amino-9H-purin-9-yl)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 73, 104 mg, 85%) as a colourless solid. 1H NMR (CD3OD): δ 8.21 (s, 2H), 4.62 (m, 3H), 4.17 (dd, J=14, 9.6 Hz, 1H), 3.75 (m, 1H), 3.51 (m, 1H), 3.18 (m, 1H), 2.62 (m, 1H), 2.17-2.29 (m, 2H), 1.23-2.08 (m, 13H), 1.07 (m, 4H), 0.72 (m, 4H). ES-MS m/z 440 ([M+1]+).
-
- A solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 109 mg, 0.339 mmol) and 4-nitrobenzaldehyde (61 mg, 0.40 mmol) in MeOH (6.7 mL) was heated to reflux under argon for 35 min then allowed to cool to room temperature. NaBH4 (26 mg, 0.69 mmol) and THF (2.5 mL) were added and stirred at room temperature for 3 d. The mixture was heated to 60° C. for 19 h and more NaBH4 (29 mg, 0.77 mmol) was added. The mixture was heated to 60° C. for 1 h then concentrated. The residue was dissolved in CH2Cl2 (20 mL) and washed with 1 N NaOH(aq) (10 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (0.5:99.5 MeOH/EtOAc) to give (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-((4-nitrobenzylamino)methyl)octahydro-1H-inden-5-yl)cyclohexanol (Compound No. 74, 66 mg, 43%) as a colourless solid. 1H NMR (CD3OD): δ 8.18 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 4.61 (s, 2H), 3.83 (d, J=14 Hz, 1H), 3.76 (d, J=14 Hz, 1H), 3.70 (m, 1H), 3.41 (m, 1H), 3.13 (m, 1H), 2.83 (m, 1H), 2.57 (m, 1H), 2.46 (m, 1H), 2.11-2.29 (m, 2H), 1.18-1.83 (m, 15H), 1.01 (s, 3H), 0.78 (s, 3H). ES-MS m/z 457 ([M+1]+).
-
- A solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 68 mg, 0.21 mmol) and 2,2-difluoro-1,3-benzodioxole-5-carbaldehyde (47 mg, 0.25 mmol) in MeOH (4.2 mL) was heated to reflux under argon for 0.5 h then allowed to cool to room temperature. NaBH4 (16 mg, 0.42 mmol) was added and stirred at room temperature overnight. The mixture was concentrated, and the residue was dissolved in 1:9 MeOH/CH2Cl2 (15 mL) then washed with 1 N NaOH(aq) (10 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (6:94 MeOH/CH2Cl2) to give (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 75, 84 mg, 81%) as a colourless solid (1H NMR (CD3OD): δ 7.21 (s, 1H), 7.11 (s, 2H), 4.61 (s, 2H), 3.69 (m, 3H), 3.42 (m, 1H), 3.13 (m, 1H), 2.80 (m, 1H), 2.42-2.57 (m, 2H), 2.11-2.29 (m, 2H), 1.18-1.83 (m, 15H), 0.99 (s, 3H), 0.78 (s, 3H). ES-MS m/z 492 ([M+1]+).
-
- A solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 93 mg, 0.29 mmol) and 4-fluoro-2-methylbenzaldehyde (48 mg, 0.35 mmol) in MeOH (5.8 mL) was heated to reflux under argon for 0.5 h then allowed to cool to room temperature. NaBH4 (22 mg, 0.58 mmol) was added and stirred at room temperature for 1.75 h. The mixture was concentrated, and the residue was dissolved in CH2Cl2 (15 mL) then washed with 1 N NaOH(aq) (10 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (6:94 MeOH/CH2Cl2) to give (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((4-fluoro-2-methylbenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 76, 113 mg, 88%) as a colourless solid. 1H NMR (CD3OD): δ 7.24 (dd, J=8.4, 6.0 Hz, 1H), 6.87 (m, 2H), 4.61 (s, 2H), 3.67 (m, 3H), 3.41 (m, 1H), 3.11 (m, 1H), 2.89 (m, 1H), 2.64 (m, 1H), 2.37-2.51 (m, 4H), 2.10-2.28 (m, 2H), 1.21-1.82 (m, 15H), 0.97 (s, 3H), 0.79 (s, 3H). ES-MS m/z 444 ([M+1]+).
-
- A solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 60 mg, 0.19 mmol) and 2-fluoro-4-methoxybenzaldehyde (35 mg, 0.23 mmol) in MeOH (3.7 mL) was heated to reflux under argon for 0.5 h then allowed to cool to room temperature. NaBH4 (14 mg, 0.37 mmol) was added and stirred at room temperature for 3 h then THF (1.2 mL) was added. The mixture was stirred at room temperature for 1.25 h then concentrated. The residue was dissolved in 1:9 MeOH/CH2Cl2 (15 mL) and washed with 1 N NaOH(aq) (10 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (8:92 MeOH/CH2Cl2) to give (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((2-fluoro-4-methoxybenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 77, 71 mg, 83%) as a colourless solid. 1H NMR (CD3OD): δ 7.27 (m, 1H), 6.71 (m, 2H), 4.62 (s, 2H), 3.67-3.79 (m, 6H), 3.31 (m, 1H), 3.11 (m, 1H), 2.87 (m, 1H), 2.64 (m, 1H), 2.48 (m, 1H), 2.10-2.30 (m, 2H), 1.17-1.83 (m, 15H), 0.94 (s, 3H), 0.78 (s, 3H). ES-MS m/z 460 ([M+1]+).
-
- A solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 61 mg, 0.19 mmol) and 4-fluoro-2-methoxybenzaldehyde (35 mg, 0.23 mmol) in MeOH (3.8 mL) was heated to reflux under argon for 0.5 h then allowed to cool to room temperature. NaBH4 (14 mg, 0.37 mmol) was added and stirred at room temperature for 5 h. The mixture was concentrated, and the residue was dissolved in 1:9 MeOH/CH2Cl2 (15 mL) then washed with 1 N NaOH(aq) (10 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (10:90 MeOH/CH2Cl2) to give (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((4-fluoro-2-methoxybenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 78, 80 mg, 92%) as a colourless foam. 1H NMR (CD3OD): δ 7.23 (m, 1H), 6.80 (dd, J=11, 2.1 Hz, 1H), 6.65 (m, 1H), 4.63 (s, 2H), 3.85 (s, 3H), 3.73 (m, 3H), 3.41 (m, 1H), 3.12 (m, 1H), 2.87 (m, 1H), 2.64 (m, 1H), 2.49 (m, 1H), 2.10-2.31 (m, 2H), 1.18-1.83 (m, 15H), 0.96 (s, 3H), 0.79 (s, 3H). ES-MS m/z 460 ([M+1]+).
-
- A solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 60 mg, 0.19 mmol) and 2-fluoro-4-methylbenzaldehyde (31 mg, 0.22 mmol) in MeOH (3.7 mL) was heated to reflux under argon for 0.5 h then allowed to cool to room temperature. NaBH4 (14 mg, 0.37 mmol) was added and stirred at room temperature overnight. The mixture was concentrated, and the residue was dissolved in 1:9 MeOH/CH2Cl2 (15 mL) then washed with 1 N NaOH(aq) (10 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (6:94 MeOH/CH2Cl2) to give (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((2-fluoro-4-methylbenzylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 79, 64 mg, 77%) as a colourless solid. 1H NMR (CD3OD): δ 7.23 (m, 1H), 6.93 (m, 2H), 4.61 (s, 2H), 3.67-3.79 (m, 3H), 3.39 (m, 1H), 3.11 (m, 1H), 2.85 (m, 1H), 2.61 (m, 1H), 2.47 (m, 1H), 2.10-2.33 (m, 5H), 1.16-1.82 (m, 15H), 0.94 (s, 3H), 0.78 (s, 3H). ES-MS m/z 444 ([M+1]+).
-
- A. To a solution of 4-methoxyphenethyl alcohol (184 mg, 1.21 mmol) in EtOAc (24 mL) was added 2-iodoxybenzoic acid (1.02 g, 3.64 mmol), and the mixture was heated to 80° C. open to air for 3 h. The mixture was cooled to 0° C. for 10 min then filtered through Celite and concentrated to give Compound No. 80 (185 mg) as a yellow oil.
- B. To a mixture of Compound No. 80 (33 mg) and (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 59 mg, 0.18 mmol) in THF (1.8 mL) was added sodium triacetoxyborohydride (78 mg, 0.37 mmol), and the mixture was stirred at room temperature for 25 h. The mixture was diluted with 1:9 MeOH/CH2Cl2 (15 mL) and washed with 1 N NaOH(aq) (10 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (100:5:1 CH2Cl2/MeOH/NH4OH) to give (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-((4-methoxyphenethylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexanol (Compound No. 81, 49 mg, 58%) as a colourless foam. 1H NMR (CD3OD): δ 7.13 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 4.61 (s, 2H), 3.77 (s, 3H), 3.58 (m, 1H), 3.40 (m, 1H), 2.98 (m, 1H), 2.61-2.75 (m, 6H), 2.44 (m, 1H), 2.09-2.24 (m, 2H), 1.12-1.80 (m, 15H), 0.76 (s, 3H), 0.70 (s, 3H). ES-MS m/z 456 ([M+1]+).
-
- A mixture of (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-aminoethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexane-1,3-diol (Compound No. 82, 68 mg, 0.21 mmol), p-anisaldehyde (51 μL, 0.42 mmol), AcOH (24 μL, 0.42 mmol) and NaBH(OAc)3 (133 mg, 0.63 mmol) in CH2Cl2 (5 mL) under argon was stirred at room temperature for 24 h. A 1 M aqueous solution of NaOH (10 mL) was added and the mixture was extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (1:1 EtOAc:hexanes) to afford (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-(bis(4-methoxybenzyl)amino)ethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexane-1,3-diol (Compound No. 83, 46 mg, 39%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.25 (d, J=7.9, 4H), 6.84 (d, J=7.9, 4H), 4.60 (s, 1H), 4.58 (s 1H), 3.77 (s, 6H), 3.71 (m, 1H), 3.43 (s, 4H and m, 1H), 2.36 (m, 3H), 2.11 (m, 1H), 1.86-1.09 (m, 17H), 0.91 (s, 3H), 0.72 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.9, 158.8, 132.4, 130.1, 113.8, 101.1, 72.2, 68.4, 58.2, 55.5, 52.4, 48.6, 43.8, 40.7, 36.2, 36.1, 30.4, 29.9, 29.7, 29.2, 25.1, 24.0, 19.1, 18.3; MS m/z: 562.6 [M+H]+.
-
- A mixture of (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-aminoethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexane-1,3-diol (Compound No. 22, 40 mg, 0.12 mmol), p-anisaldehyde (21 μL, 0.19 mmol) and anhydrous MgSO4 (0.5 g) in CH2Cl2 (5 mL) at room temperature was stirred for 24 h. The mixture was filtered and concentrated. The residue and NaBH4 (23 mg, 0.61 mmol) in THF (3 mL) and MeOH (1 mL) under argon at room temperature was stirred for 18 h. 80% AcOH (1 mL) was added and the mixture was stirred for 10 min before being concentrated. The residue was taken up in EtOAc (20 mL), washed successively with saturated NaHCO3 solution (3×5 mL) and brine (2×5 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (1:1 EtOAc:MeOH) to afford (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-(4-methoxybenzylamino)ethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexane-1,3-diol (Compound No. 84, 26 mg, 49% over 2 steps) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.26 (d, J=8.4, 2H), 6.89 (d, J=8.4, 2H), 4.60 (s, 2H), 3.93-3.63 (m, 6H), 3.50 (m, 1H), 2.71-2.42 (s, 3H), 2.21 (s, 1H), 1.96-1.12 (m, 19H), 1.06 (s, 3H), 0.77 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 162.8, 160.6, 130.9, 114.9, 101.6, 72.1, 69.5, 55.7, 53.6, 46.5, 44.8, 44.2, 41.3, 40.2, 37.2, 37.0, 31.5, 31.4, 30.0, 29.0, 25.9, 24.6, 19.4, 18.5; MS m/z: 442.4 [M+H]+.
-
- A mixture of (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-aminoethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexane-1,3-diol (Compound No. 82, 38 mg, 0.12 mmol), piperonal (27 mg, 0.18 mmol) and anhydrous MgSO4 (0.5 g) in CH2Cl2 (5 mL) at room temperature was stirred for 20 h. The mixture was filtered and concentrated. The residue and NaBH4 (23 mg, 0.61 mmol) in THF (3 mL) and MeOH (1 mL) under argon at room temperature was stirred for 22 h. 80% AcOH (1 mL) was added and the mixture was stirred for 10 min before being concentrated. The residue was taken up in EtOAc (25 mL), washed with saturated NaHCO3 solution (3×5 mL) and brine (5 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (0% to 25% to 50% MeOH:EtOAc) to afford (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-(benzo[d][1,3]dioxol-5-ylmethylamino)ethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexane-1,3-diol (Compound No. 85, 23 mg, 42% over 2 steps) as a white solid. 1H NMR (300 MHz, CD3OD) δ 6.85 (s, 1H), 6.76 (m, 2H), 5.91 (s, 2H), 4.59 (s, 2H), 3.66 (m, 3H), 3.50 (m, 1H), 2.65 (m, 1H), 2.50 (m, 2H), 2.15 (m, 1H), 1.87-1.16 (m, 18H), 1.06 (s, 3H), 0.77 (s, 3H). 13C NMR (75 MHz, CD3OD) δ 162.8, 149.2, 148.2, 134.4, 122.9, 109.8, 109.0, 102.3, 101.6, 72.1, 69.5, 54.2, 53.6, 46.5, 44.8, 44.0, 41.3, 40.2, 37.2, 37.0, 31.8, 31.4, 30.0, 29.0, 25.9, 24.7, 19.3, 18.5; MS m/z: 456.2 [M+H]+.
-
- A. A mixture of (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-4-hydroxy-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 86, 2.01 g, 3.8 mmol), TBDPSCI (1.2 mL, 4.6 mmol) and imidazole (388 mg, 5.7 mmol) in DMF (8 mL) under argon at room temperature was stirred for 2 h. The reaction was quenched with water (50 mL), extracted with Et2O (3×75 mL), washed successively with water (2×50 mL) and brine (50 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (5% to 10% EtOAc/hexanes) to afford impure (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 87, 2.93 g) as a white foam.
- B. A mixture of (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 87, 2.91 g) in 80% AcOH (150 mL) and THF (50 mL) at 40° C. was stirred for 3.75 h. The reaction was concentrated and azeotroped from toluene (2×75 mL). The residue was purified by chromatography on silica gel (3:2 hexanes:EtOAc) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-oxooctahydro-1H-inden-4-yl acetate (Compound No. 88, 1.87 g, 81% over 2 steps) as a white foam.
- C. To a suspension of Ph3PMeBr (2.77 g, 7.75 mmol) in THF (50 mL) under argon at 0° C. was added KOtBu (870 mg, 7.75 mmol). After 30 min a solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-oxooctahydro-1H-inden-4-yl acetate (Compound No. 88, 1.89 g, 3.1 mmol) in THF (25 mL) was added via cannula and the mixture was stirred at room temperature for 24 h. The reaction was quenched with brine (80 mL), extracted with EtOAc (3×75 mL), dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (2:1 hexanes:EtOAc) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 89, 1.60 g, 85%) as a white foam.
- D. A mixture of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 89, 1.60 g, 2.65 mmol), Ac2O (0.5 mL, 5.3 mmol) and DMAP (32 mg, 0.26 mmol) in pyridine (50 mL) under argon at 0° C. was stirred and warmed to room temperature over 2.5 h. Water (50 mL) and EtOAc (250 mL) were added and separated. The organic layer was washed with brine (3×50 mL), dried (Na2SO4) and concentrated. The material was azeotroped from toluene (2×50 mL) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-1-methyl cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 90, 1.84 g) as a solid white foam.
- E. A mixture of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 90, 1.84 g) and TBAF (4 mL of a 1 M solution in THF, 4 mmol) in THF (60 mL) under argon at room temperature was stirred for 2.5 h. A solution of saturated NaHCO3 solution (50 mL) was added and the mixture was extracted with EtOAc (3×50 mL), washed with brine (50 mL), dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (2:1 hexanes:EtOAc) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 91, 0.99 g, 92% over 2 steps) as a white foam.
- F. A mixture of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 91, 100 mg, 0.25 mmol) and IBX (210 mg, 0.75 mmol) in MeCN (5 mL) under argon was stirred at 65° C. for 75 min. The mixture was cooled to room temperature, filtered through Celite and concentrated to afford (3aR,4R,5R,7aS)-5-((1S,2R,4S)-4-acetoxy-1-methyl-2-(2-oxoethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 92, 125 mg) as a white foam.
- G. A mixture of (3aR,4R,5R,7aS)-5-((1S,2R,4S)-4-acetoxy-1-methyl-2-(2-oxoethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 92, 58 mg, 0.14 mmol) and morpholine (33 μL, 0.35 mmol) in THF (5 mL) under argon at room temperature was allowed to stir for 5 min. To the resultant mixture was added NaBH(OAc)3 (75 mg, 0.35 mmol) and the mixture was stirred for 21 h. The reaction was quenched with saturated NaHCO3 solution (10 mL), extracted with EtOAc (3×10 mL), dried (Na2SO4) and concentrated. The residue was purified by radial chromatography (2:1 EtOAc:hexanes) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-1-methyl-2-(2-morpholinoethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 93, 25 mg, 40%) as a colourless oil.
- H. A mixture of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-1-methyl-2-(2-morpholinoethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 93, 25 mg, 0.05 mmol) and NaOMe (0.1 mL of a 5.4 M solution in MeOH, 54 mmol) in MeOH (2 mL) under argon at room temperature was stirred for 17 h. The reaction was quenched with saturated NaHCO3 solution (10 mL), extracted successively with CH2Cl2 (2×15 mL) and EtOAc (2×15 mL), dried (Na2SO4) and concentrated to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-morpholinoethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 94, 23 mg) as a white foam.
- I. A mixture of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-morpholinoethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 94, 23 mg) and LiALH4 (0.2 mL of a 2 M solution in THF, 0.4 mmol) in THF (8 mL) under argon at 0° C. was stirred and allowed to warm to room temperature over 17 h. The mixture was cooled to 0° C. and powdered Na2SO4.10H2O (excess) was added in portions. The cooling bath was removed and the mixture was stirred for 20 min before being filtered and concentrated. The residue was purified using chromatography on silica gel (0% to 2% to 4% to 6% to 8% to 10% MeOH/EtOAc) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-morpholinoethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 95, 14 mg, 70% over 2 steps) as a colourless oil.
- J. A mixture of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-morpholinoethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 95, 14 mg, 0.04 mmol) and AcOH (20 μL) in MeOH (5 mL) at room temperature was stirred for 10 min before being concentrate. The residue was taken up in CH2Cl2:hexanes (1:1, 10 mL) and concentrated to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-morpholinoethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 96, 16 mg, 93%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 4.64 (s, 1H), 4.61 (s, 1H), 3.75 (m, 4H), 3.68 (m, 1H), 3.49 (m, 1H), 2.58 (m, 4H), 2.49-2.21 (m, 3H), 2.02 (s, 3H), 1.86-1.16 (m, 18H), 1.12 (s, 3H), 0.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 101.5, 72.5, 70.7, 66.4, 57.5, 56.6, 53.5, 52.4, 45.7, 38.5, 37.7, 36.1, 35.4, 31.3, 31.0, 29.5, 25.1, 23.9, 22.9, 21.3, 18.7; MS m/z: 392.4 [M+H]+ free base.
-
- A. To a solution of (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl acetate (Compound No. 43, 519 mg, 1.43 mmol) and DMAP (catalytic amount) in pyridine (2.8 mL) under argon at 0° C. was added MsCl (0.66 mL, 8.5 mmol). The mixture was stirred for 17.5 h at room temperature, then cooled to 0° C. The reaction was quenched with saturated NaHCO3 solution (15 mL), extracted with EtOAc (3×15 mL), washed with brine (3×15 mL), dried (MgSO4) and concentrated to afford a brown oil. To a solution of the oil in DMF (10 mL) under argon was added NaN3 (557 mg, 8.57 mmol) and the mixture was heated to 60° C. for 19 h. The mixture was cooled to room temperature and diluted with water (50 mL) and EtOAc (50 mL), washed with brine (2×50 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (hexanes: EtOAc, 4:1) to afford (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methyl-3-(((methylsulfonyl)oxy)methyl)cyclohexyl acetate (Compound No. 97, 393 mg, 63%) as a colourless oil.
- B. To a solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methyl-3-(((methylsulfonyl)oxy)methyl)cyclohexyl acetate (Compound No. 97, 133 mg, 0.284 mmol) in DMF (2 mL) under argon was added NaN3 (232 mg, 3.57 mmol) and the mixture was heated to 100° C. for 24 h. The yellow suspension was cooled to room temperature, diluted with water (50 mL) and EtOAc (50 mL), washed with brine (2×50 mL), dried (MgSO4), and concentrated. The residue was purified using chromatography on silica gel (hexanes: EtOAc, 19:1 to 9:1) to afford (1S,3S,4R)-3-(azidomethyl)-4-((3aS,4R,5S,7aS)-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl acetate (Compound No. 98, 110 mg, 94%) as a colourless oil.
- C. To a solution of (1S,3S,4R)-3-(azidomethyl)-4-((3aS,4R,5S,7aS)-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl acetate (Compound No. 98, 650 mg, 1.57 mmol) in THF (30 mL) under argon at 0° C. was added LiALH4 (2 M in THF, 5.4 mL, 11 mmol) and the mixture was stirred for 23 h at room temperature. The reaction mixture was cooled to 0° C. and quenched with water (0.42 mL), 2 M NaOH (0.42 mL, 0.84 mmol), followed by water (1.23 mL). The suspension was stirred for 5 min, filtered, and washed with THF (120 mL). The filtrate was concentrated to afford a white solid. The solid was dissolved in MeOH (25 mL) and filtered through Celite to remove excess aluminum salts. The filtrate was concentrated and the residue was dissolved in acetic acid (1 mL), stirred 20 min and concentrated. The residue was dissolved in MeOH (4 mL) and MeCN (25 mL) was added. The mixture was stirred then was added MeCN (75 mL). The mixture was cooled to 0° C. and stirred until the product crashed out of solution. The suspension was filtered to afford (1S,3S,4R)-3-(aminomethyl)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexanol (Compound No. 99, 353 mg, 51%). 1H NMR (CD3OD): δ 4.59 (s, 2H), 3.47-3.38 (m, 1H), 2.97 (d, J=13.8 Hz, 2H), 2.53-2.44 (m, 2H), 2.27-2.19 (m, 1H), 1.96-1.20 (m, 23H), 1.06 (s, 3H), 0.76 (s, 3H). 13C NMR (CD3OD): δ 179.0, 160.5, 101.1, 68.9, 49.8, 43.8, 43.6, 41.2, 39.4, 39.3, 37.5, 36.3, 35.4, 33.3, 30.4, 28.8, 24.3, 23.1, 22.8, 20.3, 17.3, 12.9. MS m/z: 321.3.
-
- A. A mixture of (3aR,4R,5R,7aS)-5-((1S,2R,4S)-4-acetoxy-1-methyl-2-(2-oxoethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 92, 60 mg, 0.15 mmol) and 1-methyl-piperazine (42 μL, 0.37 mmol) in THF (5 mL) under argon at room temperature was allowed to stir for 5 min. To the resultant mixture was added NaBH(OAc)3 (75 mg, 0.35 mmol) and the mixture was stirred for 21 h. The reaction was quenched with saturated NaHCO3 solution (10 mL), extracted with EtOAc (3×10 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (4:1 EtOAc:MeOH) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-1-methyl-2-(2-(4-methylpiperazin-1-yl)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 100, 28 mg, 40%) as a colourless oil.
- B. A mixture of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-1-methyl-2-(2-(4-methylpiperazin-1-yl)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 100, 28 mg, 0.05 mmol) and NaOMe (0.1 mL of a 5.4 M solution in MeOH, 54 mmol) in MeOH (2 mL) under argon at room temperature was stirred for 17 h. The reaction was quenched with saturated NaHCO3 solution(10 mL), extracted successively with CH2Cl2 (2×15 mL) and EtOAc (2×15 mL), dried (Na2SO4) and concentrated to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(4-methylpiperazin-1-yl)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 101, 22 mg) as a white foam.
- C A mixture of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(4-methylpiperazin-1-yl)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 101, 22 mg) and LAH (0.2 mL of a 2 M solution in THF, 0.4 mmol) in THF (4 mL) under argon at 0° C. was stirred and allowed to warm to room temperature over 17 h. The mixture was cooled to 0° C. and powdered Na2SO4.10H2O (excess) was added in portions. The cooling bath was removed and the mixture was stirred for 20 min before being filtered and concentrated. The residue was purified using chromatography on silica gel (0% to 25% to 50% to 50%+1% NH4OH MeOH:EtOAc) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(4-methylpiperazin-1-yl)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 102, 18 mg, 91% over 2 steps) as a colourless oil.
- D. A mixture of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(4-methylpiperazin-1-yl)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 102, 18 mg, 0.04 mmol) and AcOH (40 μL) in MeOH (5 mL) at room temperature was stirred for 10 min then was concentrated. The residue was taken up in CH2Cl2:Hexanes (1:1, 10 mL) and concentrated to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(4-methylpiperazin-1-yl)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 103, 20 mg, 95%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 6.01 (br s, 1H), 4.63 (s, 1H), 4.60 (s, 1H), 3.66 (m, 1H), 3.44 (m, 1H), 2.70 (m, 8H), 2.48 (m, 3H), 2.38 (s, 2H), 2.23 (m, 1H), 2.00 (s, 3H), 1.95-1.16 (m, 18H), 1.11 (s, 3H), 0.76 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 101.4, 72.4, 70.6, 57.0, 56.6, 54.3, 52.6, 52.4, 45.6, 45.4, 38.4, 37.6, 36.1, 35.4, 31.3, 31.0, 29.4, 25.7, 23.9, 22.8, 21.3, 18.7; MS m/z: 405.4 [M+H]+ free base.
-
- A. A solution of (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 24, 389 mg, 0.74 mmol), MsCl (0.18 mL, 2.2 mmol) and DMAP (catalytic amount) in pyridine (4 mL) was stirred at room temperature under nitrogen for 30 min. The solution was cooled in ice, quenched with saturated NaHCO3 solution (5 mL) for 20 min, diluted with EtOAc (100 mL), washed with brine (2×15 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (30% EtOAc/hexanes) to afford (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-1-methyl-2-(2-((methylsulfonyl)oxy)ethyl)cyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 104, 423 mg, 95%) as a white foam.
- B. To a solution of 1,2,4-triazole (465 mg, 6.60 mmol) in DMF (5 mL) at 0° C. under nitrogen was added NaH (264 mg, 6.60 mmol). After 1 h, added (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-1-methyl-2-(2-((methylsulfonyl)oxy)ethyl)cyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 104, 359 mg, 0.60 mmol). After 18 h, the solution was cooled in ice, quenched with saturated NaHCO3 solution (5 mL), diluted with Et2O (100 mL), washed with brine (3×15 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (50% then 65% EtOAc/hexanes) to afford (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-((tert-butyldimethylsilyl)oxy)-1-methyl cyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 105, 0.31 g, 91%) as a white solid.
- C. A solution of (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 105, 0.31 g, 0.54 mmol) in acetic acid (40 mL) and water (10 mL) was stirred at room temperature for 3 d then was concentrated. The residue was 3 times concentrated from toluene (20 mL) then concentrated from CH2Cl2/hexanes to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-oxooctahydro-1H-inden-4-yl acetate (Compound No. 106, 0.25 g, 100%) as a white foam.
- D. A solution of methyl triphenylphosphonium bromide (970 mg, 2.7 mmol) and KOtBu (310 mg, 2.7 mmol) in THF (4 mL) was stirred at room temperature under nitrogen for 1.5 h then added a suspension of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-oxooctahydro-1H-inden-4-yl acetate (Compound No. 106, 0.22 g, 0.54 mmol) in THF (7 mL) and CH2Cl2 (1 mL). After 45 min, the reaction flask was fitted with a reflux condenser and the solution was heated at 50° C. for 18 h. The solution was cooled to room temperature, diluted with saturated NaHCO3 solution (5 mL) then EtOAc (100 mL), washed with brine (3×15 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (5% then 10% MeOH/EtOAc) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 107, 373 mg) as an impure white solid.
- E. To a solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 107, 220 mg, 0.54 mmol) in THF (5 mL) at 0° C. under nitrogen was added LiAH (0.54 mL of a 2 M solution in THF, 1.1 mmol). After 18 h, the solution was cooled in ice, diluted with Et2O (10 mL) then had added to it Na2SO4.10H2O (354 mg). After 1 h, the solution was filtered through Celite, eluted with EtOAc and concentrated. The residue was purified using chromatography on silica gel (EtOAc then 5% MeOH/EtOAc) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 108, 70 mg, 35%) as a white solid. 1H NMR (CDCl3): δ 8.05 (s, 1H), 7.95 (s, 1H), 4.62 (m, 2H), 4.28 (m, 1H), 4.15 (m, 1H), 3.62 (m, 1H), 3.55 (m, 1H), 2.55 (m, 1H), 2.25 (m, 1H), 2.00 (m, 2H), 1.85 (m, 2H), 0.95-1.70 (13H), 1.15 (s, 3H), 0.75 (s, 3H). ES-MS m/z 374 ([M+1]+).
-
- A. A solution of (3S,5R,8R,9S,10S,13S,14S)-3-((tert-butyldiphenylsilyl)oxy)-10,13-dimethyltetradecahydrospiro[cyclopenta[a]phenanthrene-17,2′-[1,3]dioxolan]-7(2H)-one (Compound No. 109, 5.00 g, 8.52 mmol) and MCPBA (3.82 g, 17.0 mmol) in CH2Cl2 (40 mL) was heated at reflux under nitrogen for 3 h. The solution was cooled to room temperature then stirred 1 h with a solution of Na2S2O3.5H2O in water (20 mL). The solution was diluted with CH2Cl2 (200 mL), washed successively with 40% K2CO3 solution (2×20 mL) and brine (2×50 mL), dried (MgSO4) and concentrated to afford (3aR,5S,7aS,7bR,9aS,12aR,12bR)-5-((tert-butyldiphenylsilyl)oxy)-7a,9a-dimethyltetradecahydrospiro[benzo[d]indeno[4,5-b]oxepine-10,2′-[1,3]dioxolan]-2(3H)-one (Compound No. 110, 5.37 g, 100%) as a white foam.
- B. A solution of (3aR,5S,7aS,7bR,9aS,12aR,12bR)-5-((tert-butyldiphenylsilyl)oxy)-7a,9a-dimethyltetradecahydrospiro[benzo[d]indeno[4,5-b]oxepine-10,2′-[1,3]dioxolan]-2(3H)-one (Compound No. 110, 5.14 g, 8.52 mmol), LAH (4.3 mL of a 2 M solution in THF, 8.6 mmol) in THF at 0° C. under nitrogen was stirred for 6 h. The solution was cooled in ice then added Na2SO4.10H2O and stirred 16 h. The solution was filtered through Celite, eluted with EtOAc and concentrated. The residue was purified using chromatography on silica gel (50% EtOAc/hexanes) to afford (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-ol (Compound No. 111, 4.10 g, 79%) as a white solid.
- C. A solution of (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-ol (Compound No. 111, 3.80 g, 6.26 mmol), imidazole (1.27 g, 18.8 mmol) and TBSCl (1.04 g, 6.89 mmol) in DMF (30 mL) at 0° C. under nitrogen was stirred for 1 h. The solution was diluted with Et2O (150 mL), washed with brine (3×30 mL), dried (MgSO4) and concentrated to afford (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-ol (Compound No. 112, 4.54 g, 100%) as a white foam.
- D. A solution of (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-ol (Compound No. 112, 4.51 g, 6.26 mmol), acetic anhydride (1.8 mL, 18.8 mmol) and DMAP (73 mg, 0.6 mmol) in pyridine (30 mL) was stirred at room temperature under nitrogen for 3 h, then at 50° C. for 1 h. The solution was cooled in ice then added saturated NaHCO3 solution (25 mL) and stirred at room temperature for 30 min. The solution was diluted with EtOAc (200 mL), washed with brine (3×30 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (10% then 15% EtOAc/hexanes) to afford (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 113, 4.19 g, 88%) as a white foam.
- E. A solution of (3a′R,4′R,5′R,7a'S)-5′-((1S,2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 113, 4.19 g, 5.49 mmol) in acetic acid (24 mL), water (6 mL) and acetone (40 mL) was stirred at room temperature for 4 days then at 80° C. for 5 h. The solution was cooled to room temperature, concentrated then concentrated 3 times from toluene (30 mL). The residue was purified using chromatography on silica gel (35% then 40% EtOAc/hexanes) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a-methyl-1-oxooctahydro-1H-inden-4-yl acetate (Compound No. 114, 3.06 g, 92%) as a white foam.
- F. A solution of methyl triphenylphosphonium bromide (6.03 g, 16.9 mmol) and KOtBu (1.93 g, 16.9 mmol) in THF (40 mL) was stirred at room temperature under nitrogen for 1 h then added (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a-methyl-1-oxooctahydro-1H-inden-4-yl acetate (Compound No. 114, 3.06 g, 5.06 mmol) in THF (10 mL). After 18 h, added saturated NaHCO3 solution (15 mL), diluted with EtOAc (200 mL), washed with brine (3×30 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (20% EtOAc/hexanes with 1% CH2Cl2) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 115, 2.78 g) as a white foam.
- G. A solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 115, 1.00 g, 1.66 mmol) and MsCl (0.39 mL, 4.98 mmol) in pyridine (8.5 mL) under nitrogen was stirred at 0° C. for 10 min then at room temperature for 80 min. The solution was cooled in ice, quenched with saturated NaHCO3 solution (6 mL) for 20 min, diluted with EtOAc (200 mL), washed with brine (3×30 mL), dried (MgSO4) and concentrated. The residue was concentrated 3 times from toluene (30 mL) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-1-methyl-2-(2-((methylsulfonyl)oxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 116, 1.14 g, 100%) as a white foam.
- H. To a solution of imidazole (306 mg, 4.4 mmol) in DMF (5 mL) at 0° C. under nitrogen was added NaH (176 mg, 4.4 mmol). After 45 min, added (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-1-methyl-2-(2-((methylsulfonyl)oxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 116, 300 mg, 0.44 mmol). After 3 days, the solution was cooled in ice, quenched with saturated NaHCO3 solution (5 mL), diluted with Et2O, washed with brine, dried (MgSO4) and concentrated. The crude white foam (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-imidazol-1-yl)ethyl)-4-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 117, 0.36 g) was used directly in the next step.
- I. A solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-imidazol-1-yl)ethyl)-4-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 117, 288 mg, 0.44 mmol) and LAH (0.66 mL of a 2 M solution in THF, 1.32 mmol) in THF (5 mL) was stirred at 60° C. under nitrogen for 2 h. The solution was cooled in ice, diluted with Et2O (15 mL), quenched with Na2SO4.10H2O for 1.5 h then filtered through Celite, eluted with EtOAc and concentrated. The crude white solid (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-imidazol-1-yl)ethyl)-4-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 118, 318 mg) was used directly in the next step.
- J. To a solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-imidazol-1-yl)ethyl)-4-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 118, 269 mg, 0.44 mmol) and TBAF (0.85 mL of a 1 M solution in THF, 0.88 mmol) in THF was stirred at room temperature under nitrogen for 16 h. The solution was concentrated and the residue purified using chromatography on silica gel (5% then 10% MeOH/EtOAc) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-imidazol-1-yl)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 119, 142 mg, 86% over 3 steps) as a white solid. 1H NMR (CDCl3): δ 7.45 (s, 1H), 7.05 (s, 1H), 6.88 (s, 1H), 4.62 (2H), 4.05 (m, 1H), 3.85 (m, 1H), 3.60 (m, 1H), 3.53 (m, 1H), 2.55 (m, 1H), 2.25 (m, 1H), 1.0-2.0 (16H), 1.15 (s, 3H), 0.80 (m, 1H), 0.75 (s, 3H). ES-MS m/z 373 ([M+1]+).
-
- A. To a solution of pyrazole (300 mg, 4.4 mmol) in DMF (5 mL) at 0° C. under nitrogen was added NaH (176 mg, 4.4 mmol). After 45 min, (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-1-methyl-2-(2-((methylsulfonyl)oxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 116, 300 mg, 0.44 mmol) was added. After 1 day, the solution was cooled in ice, quenched with saturated NaHCO3 solution (5 mL), diluted with EtOAc (100 mL), washed with brine, dried (MgSO4) and concentrated to give (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-pyrazol-1-yl)ethyl)-4-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 120).
- B. A solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-pyrazol-1-yl)ethyl)-4-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 120, 288 mg, 0.44 mmol) and LAH (0.66 mL of a 2 M solution in THF, 1.32 mmol) in THF (5 mL) was stirred at 60° C. under nitrogen for 1 h. The solution was cooled in ice, diluted with Et2O (15 mL), quenched with Na2SO4.10H2O for 1 h then filtered through Celite, eluted with EtOAc (200 mL) and concentrated to give (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-pyrazol-1-yl)ethyl)-4-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 121).
- C. To a solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-pyrazol-1-yl)ethyl)-4-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 121, 269 mg, 0.44 mmol) and TBAF (0.88 mL of a 1 M solution in THF, 0.88 mmol) in THF at 6° C. was stirred under nitrogen for 3 h. The solution was concentrated and the residue purified using chromatography on silica gel (80% EtOAc/hexanes) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-pyrazol-1-yl)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 122, 144 mg, 88% over 3 steps) as a white foam. 1H NMR (CDCl3): δ 7.50 (s, 1H), 7.38 (s, 1H), 6.25 (s, 1H), 4.62 (2H), 4.25 (m, 1H), 4.05 (m, 1H), 3.58 (2H), 2.54 (m, 1H), 2.25 (m, 1H), 2.00 (2H), 1.82 (2H), 1.0-1.7 (12H), 1.15 (s, 3H), 0.90 (m, 1H), 0.75 (s, 3H). ES-MS m/z 373 ([M+1]+).
-
- To a solution of pyrrole (0.31 mL, 4.4 mmol) in DMF (5 mL) at 0° C. under nitrogen was added NaH (176 mg, 4.4 mmol). After 45 min, (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-1-methyl-2-(2-((methylsulfonyl)oxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 116, 300 mg, 0.44 mmol) was added. After 3 days, the solution was cooled in ice, quenched with saturated NaHCO3 solution (5 mL), diluted with Et2O (100 mL), washed with brine, dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (50% then 60% EtOAc/hexanes) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-(1H-pyrrol-1-yl)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 123, 116 mg, 71%) as an off-white foam. 1H NMR (CDCl3): δ 6.62 (m, 2H), 6.15 (m, 2H), 4.62 (2H), 4.00 (m, 1H), 3.98 (m, 1H), 3.58 (2H), 2.54 (m, 1H), 2.25 (m, 1H), 1.90 (4H), 0.9-1.6 (17H), 1.15 (s, 3H), 0.75 (s, 3H). ES-MS m/z 430 ([M+OAc]+).
-
- A mixture of (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-hydroxyethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexane-1,3-diyl diacetate (Compound No. 124, 200 mg, 0.5 mmol), 2-bromo-pyridine (0.14 mL, 1.5 mmol) and NaH (60 mg of a 60% solution, 1.5 mmol) in DMF (5 mL) under argon at 40° C. was stirred overnight. The resultant mixture was cooled to room temperature and partitioned between saturated NaHCO3 solution (5 mL) and Et2O (100 mL). The organic layer was washed successively with water (5×10 mL) and brine (10 mL), dried (Na2SO4) and concentrated. A solution of the residue and NaOMe (1 mL of 5.4 M solution in MeOH, 5.4 mmol) in MeOH (5 mL) was stirred at room temperature for 3 d. Water (10 mL) was added and the MeOH was removed by distillation. The resultant mixture was extracted with EtOAc (3×15 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (EtOAc) to afford (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-hydroxyethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methyl-3-(pyridin-2-yloxy)cyclohexanol (Compound No. 125, 21 mg, 10%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.10 (m, 1H), 7.57 (m, 1H), 6.86 (m, 1H), 6.72 (d, J=8.3, 1H), 5.69 (br s, 1H), 4.59 (d, J=11.5, 2H), 3.90 (m, 1H), 3.84-3.59 (m, 2H), 2.51-2.24 (m, 3H), 1.96 (m, 2H), 1.89-1.18 (m, 15H), 1.18 (s, 3H), 0.70 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.1, 161.5, 146.8, 139.2, 117.0, 112.0, 101.2, 74.5, 67.6, 59.6, 53.1, 43.9, 40.0, 36.1, 35.9, 34.9, 30.1, 29.2, 25.2, 23.8, 19.8, 18.1; MS m/z: 400.4 [M+H]+.
-
- A. To a solution of (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl acetate (Compound No. 43, 1.00 g, 2.74 mmol), imidazole (1.12 g, 16.4 mmol) and TBSCl (1.24 g, 8.23 mmol) in DMF (14 mL) under argon was stirred at room temperature for 18 h. The solution was cooled in ice, quenched with saturated NaHCO3 solution (5 mL), diluted with Et2O (100 mL), wash with brine (3×15 mL), dried (MgSO4) and concentrated to give (1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((3aS,4R,5S,7aS)-4-(((tert-butyldimethylsilyl)oxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl acetate (Compound No. 126).
- B. To a solution of (1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((3aS,4R,5S,7aS)-4-(((tert-butyldimethylsilyl)oxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl acetate (Compound No. 126, 1.63 g, 2.74 mmol) in THF (12 mL) at 0° C. under argon was added LAH (2.7 mL of a 2 M solution in THF, 5.4 mmol). After 1 h, added Et2O (20 mL) and Na2SO4.10H2O (1.74 g) then stirred 45 min. The solution was filtered through Celite, eluted with EtOAc and concentrated to give (1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((3aS,4R,5S,7aS)-4-(((tert-butyldimethylsilyl)oxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexanol (Compound No. 127).
- C. A solution of (1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((3aS,4R,5S,7aS)-4-(((tert-butyldimethylsilyl)oxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexanol (Compound No. 127, 1.51 g, 2.74 mmol), imidazole (560 mg, 8.22 mmol) and TBDPSCI (1.10 mL, 4.11 mmol) in DMF (14 mL) under argon was stirred at room temperature for 4 d. The solution was diluted in Et2O (150 mL), washed successively with saturated NaHCO3 solution (10 mL) and brine (3×15 mL), dried (MgSO4) and concentrated to give tert-butyl(((1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((3aS,4R,5S,7aS)-4-(((tert-butyldimethylsilyl)oxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl)oxy)diphenylsilane (Compound No. 128).
- D. A solution of tert-butyl(((1S,3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((3aS,4R,5S,7aS)-4-(((tert-butyldimethylsilyl)oxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl)oxy)diphenylsilane (Compound No. 128, 2.16 g, 2.74 mmol) in acetic acid (80 mL), water (20 mL), THF (50 mL) and acetone (50 mL) was heated at 40° C. for 1 day then at 50° C. for 1 day then at 60° C. for 1 day. The solution was concentrated and the residue was 3 times taken up in toluene (30 mL) and concentrated. The residue was purified using chromatography on silica gel (5% EtOAc and 5% CH2Cl2 in hexanes) to afford ((1S,2R,5S)-5-((tert-butyldiphenylsilyl)oxy)-2-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methanol (Compound No. 129, 664 mg, 36%) as a white foam.
- E. To a solution of ((1S,2R,5S)-5-((tert-butyldiphenylsilyl)oxy)-2-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methanol (Compound No. 129, 100 mg, 0.18 mmol) and 2-bromopyridine (0.085 mL, 0.89 mmol) in DMF (2 mL) at room temperature under nitrogen was added NaH (36 mg of a 60% solution in mineral oil, 0.89 mmol). The solution was heated at 40° C. for 3 h, cooled in ice, quenched with saturated NaHCO3 solution (3 mL), diluted with Et2O (100 mL), washed with brine (3×15 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (10% then 20% then 30% EtOAc/hexanes) to afford 17 mg of a 2 component mixture. The material was taken up in THF (2 mL) and TBAF (0.5 mL of a 1 M solution in THF, 0.5 mmol) and stirred at room temperature for 3 days then at 55° C. for 3 days. The solution was concentrated and the residue was purified using chromatography on silica gel (50% EtOAc/hexanes) to afford (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methyl-3-((pyridin-2-yloxy)methyl)cyclohexanol (Compound No. 130, 9 mg, 12%) as a white solid. 1H NMR (CDCl3): δ 8.15 (m, 1H), 7.57 (m, 1H), 6.85 (m, 1H), 6.72 (m, 1H), 4.62 (2H), 4.38 (m, 1H), 4.00 (m, 1H), 3.97 (m, 1H), 3.70 (m, 1H), 3.60 (m, 1H), 2.50 (m, 1H), 2.30 (m, 1H), 2.20 (2H), 1.2-2.0 (13H), 1.30 (s, 3H), 0.85 (m, 1H), 0.80 (s, 3H). ES-MS m/z 400 ([M+1]+)
-
- A. To a solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 115, 300 mg, 0.50 mmol) and 2-chloropyrimidine (170 mg, 1.5 mmol) in DMF (5 mL) at room temperature under nitrogen was added NaH (60 mg of a 60% solution in mineral oil, 1.5 mmol). The solution was heated at 40° C. for 5 h, cooled in ice, quenched with saturated NaHCO3 solution (3 mL), diluted with Et2O (100 mL), washed with brine (3×15 mL), dried (MgSO4) and concentrated to give (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-1-methyl-2-(2-(pyrimidin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 131).
- B. A solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-1-methyl-2-(2-(pyrimidin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 131, 339 mg, 0.50 mmol) and LAH (0.50 mL of a 2 M solution in THF, 1.0 mmol) in THF (5 mL) was stirred at 60° C. under nitrogen for 1 h. The solution was cooled in ice, quenched with Na2SO4.10H2O (0.32 g) for 1 h then filtered through paper, eluted with EtOAc and concentrated to give (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-1-methyl-2-(2-(pyrimidin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 132).
- C. To a solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-1-methyl-2-(2-(pyrimidin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 132, 318 mg, 0.50 mmol) and TBAF (1.5 mL of a 1 M solution in THF, 1.5 mmol) in THF (5 mL) was stirred at room temperature under nitrogen for 3 d. The solution was concentrated and the residue purified using chromatography on silica gel (50% then 65% then 80% EtOAc/hexanes) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyrimidin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 133, 41 mg, 20%) as a white solid. 1H NMR (CDCl3): δ 8.50 (m, 2H), 6.95 (m, 1H), 4.62 (2H), 4.50 (m, 1H), 4.35 (m, 1H), 3.72 (m, 1H), 3.55 (m, 1H), 2.55 (m, 1H), 2.25 (m, 1H), 0.85-2.05 (17H), 1.20 (s, 3H), 0.80 (s, 3H). ES-MS m/z 401 ([M+1]+).
-
- A. To a solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 115, 300 mg, 0.50 mmol) and 2-chloropyrazine (0.13 mL, 1.5 mmol) in DMF (5 mL) at room temperature under nitrogen was added NaH (60 mg of a 60% solution in mineral oil, 1.5 mmol). The solution was heated at 40° C. for 5 h, cooled in ice, quenched with saturated NaHCO3 solution (3 mL), diluted with Et2O (100 mL), washed with brine (3×15 mL), dried (MgSO4) and concentrated to give (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-1-methyl-2-(2-(pyrazin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 134).
- B. A solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-1-methyl-2-(2-(pyrazin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 134, 339 mg, 0.50 mmol) and LAH (0.50 mL of a 2 M solution in THF, 1.0 mmol) in THF (5 mL) was stirred at 60° C. under nitrogen for 1 h. The solution was cooled in ice, quenched with Na2SO4.10H2O (0.32 g) for 1 h then filtered through paper, eluted with EtOAc and concentrated to give (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-1-methyl-2-(2-(pyrazin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 135).
- C. To a solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-1-methyl-2-(2-(pyrazin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 135, 318 mg, 0.50 mmol) and TBAF (1.5 mL of a 1 M solution in THF, 1.5 mmol) in THF (5 mL) was stirred at room temperature under nitrogen for 3 d then was heated at 55° C. for 4 h. The solution was concentrated and the residue purified using chromatography on silica gel (50% then 70% EtOAc/hexanes) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyrazin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 136, 81 mg, 40%) as a white solid. 1H NMR (CDCl3): δ 8.20 (s, 1H), 8.12 (m, 1H), 8.07 (m, 1H), 4.62 (2H), 4.40 (m, 1H), 4.33 (m, 1H), 3.72 (m, 1H), 3.54 (m, 1H), 2.55 (m, 1H), 2.25 (m, 1H), 1.82 (2H), 0.95-2.00 (15H), 1.20 (s, 3H), 0.80 (s, 3H). ES-MS m/z 401 ([M+1]+).
-
- A. To a solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 115, 300 mg, 0.50 mmol) and 2-bromopyridine (0.14 mL, 1.5 mmol) in DMF (5 mL) at room temperature under nitrogen was added NaH (60 mg of a 60% solution in mineral oil, 1.5 mmol). The solution was heated at 40° C. for 16 h, cooled in ice, quenched with saturated NaHCO3 solution (5 mL), diluted with Et2O (100 mL), washed with brine (3×15 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (10% EtOAc/hexanes) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-1-methyl-2-(2-(pyridin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 137, 64 mg, 20%) as a white foam.
- B. To a solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-1-methyl-2-(2-(pyridin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 137, 61 mg, 0.10 mmol) and TBAF (0.30 mL of a 1 M solution in THF, 0.30 mmol) in THF was stirred at room temperature under nitrogen for 16 h then was heated at 60° C. for 2 h. More TBAF (0.30 mL, 0.30 mmol) was added and the solution was heated at 60° C. for 7 h. The solution was concentrated and the residue purified using chromatography on silica gel (50% EtOAc/hexanes) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-hydroxy-1-methyl-2-(2-(pyridin-2-yloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 138, 37 mg, 97%) as a white solid. 1H NMR (CDCl3): δ 8.18 (m, 1H), 7.59 (m, 1H), 6.85 (m, 1H), 6.70 (m, 1H), 4.62 (2H), 4.39 (m, 1H), 4.27 (m, 1H), 3.72 (m, 1H), 3.54 (m, 1H), 2.55 (m, 1H), 2.25 (m, 1H), 1.82 (2H), 0.95-2.05 (15H), 1.20 (s, 3H), 0.80 (s, 3H). ES-MS m/z 400 ([M+1]+).
-
- To a solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 523 mg, 1.63 mmol) in 5% MeOH/CH2Cl2 (16 mL) was added PTSA.H2O (371 mg, 1.95 mmol) then stirred at room temperature for 8 d. The solution was diluted with 5% MeOH/CH2Cl2 (10 mL) and washed with 1 N NaOH(aq) (10 mL). The aqueous phase was extracted with 5% MeOH/CH2Cl2 (4×10 mL), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (100:10:1 CH2Cl2/MeOH/NH4OH) to afford (1S,3S,4R)-4-((3aS,6S,7R,7aS)-7-(aminomethyl)-3,3a-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 139, 40 mg, 8%) as a colourless foam. 1H NMR (CD3OD): δ 5.29 (m, 1H), 3.74 (dd, J=11, 2.4 Hz, 1H), 3.45 (m, 1H), 3.14 (m, 1H), 3.07 (dd, J=14, 2.7 Hz, 1H), 2.74 (m, 1H), 2.14 (m, 1H), 1.21-1.93 (m, 18H), 1.09 (s, 3H), 0.78 (s, 3H); 13C NMR (CD3OD): δ 152.4, 123.3, 71.1, 62.9, 54.3, 47.0, 45.5, 44.4, 43.5, 38.7, 38.3, 35.9, 35.2, 32.4, 32.1, 24.2, 21.6, 15.3, 12.5. ES-MS m/z 322 ([M+1]+).
-
- A. To a solution of tert-butyl (((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-oxooctahydro-1H-inden-4-yl)methyl)carbamate (Compound No. 140, 706 mg, 1.08 mmol) in THF (4.3 mL) was added MgSO4 (326 mg, 2.71 mmol) and p-toluenesulfonyl hydrazide (302 mg, 1.62 mmol), and the mixture was stirred at room temperature under argon. After 21 h, the mixture was heated to reflux for 4 h then filtered and concentrated. The residue was purified by chromatography on silica gel (15:85-40:60 EtOAc/hexanes) to tert-butyl (((3aS,4R,5S,7aS,E)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-(2-tosylhydrazono)octahydro-1H-inden-4-yl)methyl)carbamate (Compound No. 141, 715 mg, 81%) as a colourless foam.
- B. To a solution of tert-butyl (((3aS,4R,5S,7aS,E)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-(2-tosylhydrazono)octahydro-1H-inden-4-yl)methyl)carbamate (Compound No. 141, 710 mg, 0.865 mmol) in THF (8.7 mL) was added n-butyllithium (4.80 mL of a 1.8 M solution in hexanes, 8.64 mmol) at room temperature under argon. After stirring for 15 min, the mixture was cooled to 0° C. and saturated aqueous NH4Cl (15 mL) was added followed by EtOAc (15 mL). The organic layer was washed with brine (10 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (5:95 EtOAc/CH2Cl2) to give N-(((3aR,6S,7R,7aS)-6-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl)methyl)pentanamide (Compound No. 142, 164 mg, 31%) as a light yellow foam.
- C. To a solution of N-(((3aR,6S,7R,7aS)-6-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl)methyl)pentanamide (Compound No. 142, 164 mg, 0.264 mmol) in 1,4-dioxane (2 mL) was added 4 M HCl in dioxane (2 mL) followed by H2O (0.5 mL). The mixture was stirred at room temperature for 2 h then cooled to 0° C. and 1 N NaOH(aq) (10 mL) was added. The mixture was extracted with 10% MeOH/CH2Cl2 (2×10 mL) and CH2Cl2 (3×10 mL), and the combined extracts were dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (10:90 MeOH/CH2Cl2) to afford N-(((3aR,6S,7R,7aS)-6-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl)methyl)pentanamide (Compound No. 143, 91 mg, 88%) as a colourless foam. 1H NMR (CDCl3): δ 5.85 (m, 1H), 5.70 (m, 1H), 5.36 (m, 1H), 3.74 (dd, J=11, 2.7 Hz, 1H), 3.58 (m, 1H), 3.49 (m, 2H), 3.30 (m, 1H), 1.26-2.21 (m, 25H), 1.01 (s, 3H), 0.92 (t, J=7.4 Hz, 3H), 0.79 (s, 3H); 13C NMR (CDCl3): δ 173.6, 143.6, 129.1, 69.9, 62.6, 53.7, 46.5, 45.3, 43.0, 42.0, 37.3, 36.6, 36.4, 35.2, 34.3, 32.9, 31.1, 29.8, 28.0, 23.5, 22.5, 21.2, 16.8, 13.9. ES-MS m/z 392 ([M+1]+).
-
- A suspension of (1S,3S,4R)-4-((3aS,4R,5S,7aS,E)-4-(aminomethyl)-1-ethylidene-7a-methyloctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 144, 0.86 g, 2.6 mmol) and 10% Pd/C (86 mg) in EtOAc (55 mL) and MeOH (3 mL) under H2 (balloon) at room temperature was stirred for 3 days. The resultant mixture was filtered through Celite and concentrated. The residue was dissolved in MeOH (20 mL) and AcOH (0.8 mL, 13 mmol) was added. After stirring for 15 min, the mixture was concentrated, reconstituted in MeCN (15 mL) and reconcentrated. The residue was dissolved in MeOH (2 mL) and MeCN (50 mL) was added in a single portion. The mixture was stirred for 20 min at room temperature and the solid was collected by filtration to afford (1S,3S,4R)-4-((1S,3aS,4S,5S,7aR)-4-(aminomethyl)-1-ethyl-7a-methyloctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol as the acetate salt (Compound No. 145, 434 mg, 42%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 3.70 (d, J=8.3, 1H), 3.45 (m, 1H), 3.13 (t, J=10.2, 1H), 2.97 (d, J=11.8, 1H), 2.13 (m, 1H), 1.90 (s, 3H), 1.87-1.74 (m, 11H) 1.64-1.15 (m, 14H), 1.07 (s, 3H), 0.90 (t, J=7.3, 3H), 0.64 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 70.9, 62.6, 54.4, 52.2, 45.5, 44.6, 43.0, 42.6, 38.9, 38.1, 37.4, 35.1, 31.9, 31.8, 28.8, 25.8, 24.2, 24.1, 23.8, 21.8, 13.6, 12.5; MS m/z: 338.1 [M+H]+ free base.
-
- A. To a solution of ((1S,2R,5S)-5-((tert-butyldimethylsilyl)oxy)-2-((3a'S,4′R,5'S,7a'S)-4′-(hydroxymethyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-5′-yl)-2-methylcyclohexyl)methanol (Compound No. 146, 4.75 g, 9.84 mmol) and imidazole (804 mg, 11.8 mmol) in DMF (20 mL) at 0° C. was added TBSCl (1.56 g, 10.4 mmol), and the solution was stirred at room temperature under argon for 19 h. The mixture was diluted with EtOAc (100 mL) and washed with H2O (2×25 mL) and brine (6×20 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (20:80 EtOAc/hexanes) to give ((3a'S,4′R,5'S,7a'S)-5′-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl)methanol (Compound No. 147, 5.41 g, 92%) as a colourless foam.
- B. To a solution of ((3a'S,4′R,5'S,7a'S)-5′-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl)methanol (Compound No. 147, 5.41 g, 9.06 mmol) and DMAP (110 mg, 0.900 mmol) in pyridine (45 mL) at 0° C. under argon was added Ac2O (2.53 g, 24.8 mmol) then stirred at room temperature for 24 h. The mixture was concentrated, and azeotropic removal of remaining pyridine was carried out with toluene (3×50 mL). The pale foam ((3a'S,4′R,5'S,7a'S)-5′-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl)methyl acetate (Compound No. 148, 5.92 g) that was obtained was used in the next step without further purification.
- C. A suspension of ((3a'S,4′R,5'S,7a'S)-5′-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl)methyl acetate (Compound No. 148, 5.92 g) in 80% acetic acid(aq) (90 mL) was stirred at room temperature for 19 h then heated to 40° C. for 2 h. The mixture was concentrated, and azeotropic removal of remaining acetic acid and H2O was carried out with toluene (3×50 mL). The residue was partially purified by chromatography on silica gel (3:97 MeOH/EtOAc) to give a colourless foam (3.28 g). The foam (3.28 g) was dissolved in EtOAc (75 mL) and washed with H2O (20 mL) and brine (5×20 mL) then dried (MgSO4) and concentrated to give ((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-oxooctahydro-1H-inden-4-yl)methyl acetate (Compound No. 149, 3.08 g, 93% over 2 steps) as a colourless foam.
- D. To a solution of ((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-oxooctahydro-1H-inden-4-yl)methyl acetate (Compound No. 149, 3.06 g, 8.35 mmol) and imidazole (1.31 g, 19.2 mmol) in DMF (34 mL) at 0° C. was added TBSCl (2.64 g, 17.5 mmol), and the mixture was stirred at room temperature for 3 d. The mixture was diluted with EtOAc (150 mL) and washed with H2O (2×40 mL) and brine (6×30 mL) then dried (MgSO4) and concentrated. The colourless solid ((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-oxooctahydro-1H-inden-4-yl)methyl acetate (Compound No. 150, 4.50 g) that was obtained was used in the next step without further purification.
- E. A suspension of ((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-oxooctahydro-1H-inden-4-yl)methyl acetate (Compound No. 150, 4.50 g) and potassium carbonate (2.1 g, 15 mmol) in MeOH (76 mL) was heated to 50° C. for 18 h. The mixture was concentrated, and the residue was partitioned between CH2Cl2 (100 mL), H2O (100 mL) and brine (50 mL). The aqueous phase was extracted with CH2Cl2 (2×50 mL), and the combined organic layers were dried (MgSO4) and concentrated to give (3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-4-(hydroxymethyl)-7a-methyloctahydro-1H-inden-1-one (Compound No. 151, 4.21 g) as a pale foam.
- F. Potassium tert-butoxide (2.54 g, 22.6 mmol) was added to a suspension of methyltriphenylphosphonium bromide (8.10 g, 22.7 mmol) in THF (38 mL) at 0° C. under argon and stirred at 0° C. for 1 h. A solution of (3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-4-(hydroxymethyl)-7a-methyloctahydro-1H-inden-1-one (Compound No. 151, 4.21 g) in THF (20 mL) was added then heated to reflux for 1.5 h. The mixture was stirred at room temperature overnight then cooled to 0° C. and brine (20 mL) was added followed by EtOAc (30 mL). The aqueous phase was extracted with EtOAc (2×20 mL), and the combined organic layers were dried (MgSO4) and concentrated. The residue was stirred in 20:80 EtOAc/hexanes (160 mL) for 2.25 h then filtered and concentrated. The residue was purified by chromatography on silica gel (10:90 EtOAc/hexanes) to give ((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methanol (Compound No. 152, 3.85 g, 84% over 3 steps) as a colourless foam.
- G. A solution of 2-(bromomethyl)pyridine in CH2Cl2 was freshly prepared as follows. 2-(Bromomethyl)pyridine hydrobromide (452 mg, 1.79 mmol) was partitioned between CH2Cl2 (20 mL) and saturated aqueous NaHCO3 (15 mL). The aqueous phase was extracted with CH2Cl2 (2×10 mL), and the combined organic layers were dried (MgSO4) and concentrated to approximately 0.3 mL. To a suspension of NaH (18 mg of a 60% solution, 0.45 mmol) in DMF (0.9 mL) at 0° C. under argon was added ((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methanol (Compound No. 152, 101 mg, 0.183 mmol) and stirred at room temperature for 0.5 h. The freshly prepared 2-(bromomethyl)pyridine solution (0.1 mL, ca. 0.6 mmol) was added to the above mixture and stirred at room temperature for 18 h. The mixture was diluted with EtOAc (40 mL) and washed with brine (6×10 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (10:90 EtOAc/hexanes) to give 2-((((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methoxy)methyl)pyridine (Compound No. 153, 64 mg, 54%) as a colourless film.
- H. TBAF (0.40 mL of a 1 M solution in THF, 0.40 mmol) was added to a solution of 2-((((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methoxy)methyl)pyridine (Compound No. 153, 64 mg, 0.10 mmol) in THF (2.0 mL) and heated to 50° C. for 21 h. The solution was concentrated, and the residue was purified by chromatography on silica gel (2:98-5:95 MeOH/EtOAc) to give (1S,3S,4R)-3-(hydroxymethyl)-4-methyl-4-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-((pyridin-2-ylmethoxy)methyl)octahydro-1H-inden-5-yl)cyclohexanol (Compound No. 154, 38 mg, 93%) as colourless crystals. 1H NMR (CDCl3): δ 8.52 (d, J=4.5 Hz, 1H), 7.69 (m, 1H), 7.42 (d, J=7.5 Hz, 1H), 7.18 (m, 1H), 4.63 (br s, 2H), 4.55 (d, J=13 Hz, 1H), 4.47 (d, J=13 Hz, 1H), 3.77 (m, 2H), 3.58 (br s, 1H), 3.49 (m, 1H), 3.30 (br s, 1H), 2.47 (m, 1H), 2.13-2.29 (m, 2H), 1.21-1.82 (m, 15H), 1.03 (s, 3H), 0.77 (s, 3H). ES-MS m/z 414 ([M+1]+).
-
- A. To a solution of SeO2 (70 mg, 0.62 mmol) and tert-butyl hydroperoxide (0.34 mL of a 70% solution in water, 2.5 mmol) in CH2Cl2 (3 mL) was added ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 155, 800 mg, 1.2 mmol) in CH2Cl2 (4 mL). After 5 hours the solution was diluted with EtOAc (75 mL), washed successively with 10% NaOH solution (2×20 mL) and brine (3×15 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (25% EtOAc/hexanes) to afford ((1S,2R,5S)-5-acetoxy-2-((2S,3aS,4R,5S,7aS)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-hydroxy-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 156, 452 mg, 55%) as a white foam.
- B. To a solution of ((1S,2R,5S)-5-acetoxy-2-((2S,3aS,4R,5S,7aS)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-hydroxy-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 156, 146 mg, 0.22 mmol) in pyridine (5 mL) at 0° C. under argon was added Ac2O (0.06 mL, 0.66 mmol). After 2 hours DMAP (catalytic amount) was added then after another 2 hours the reaction was quenched by addition of saturated NaHCO3 solution (3 mL). After 15 minutes the solution was diluted with EtOAc (75 mL), washed with brine (3×15 mL), dried (MgSO4) and concentrated to afford ((1S,2R,5S)-5-acetoxy-2-((2S,3aS,4R,5S,7aS)-2-acetoxy-4-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 157, 160 mg, 100%) as a white foam.
- C. A solution of ((1S,2R,5S)-5-acetoxy-2-((2S,3aS,4R,5S,7aS)-2-acetoxy-4-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 157, 155 mg, 0.22 mmol) and TBAF (0.70 mL of a 1M solution in THF, 0.70 mmol) in THF (10 mL) was heated at reflux under argon for 2 hours. The mixture was concentrated and the residue was purified using chromatography on silica gel (30% then 50% EtOAc/hexanes) to afford ((1S,2R,5S)-5-acetoxy-2-((2S,3aS,4R,5S,7aS)-2-acetoxy-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 158, 66 mg, 66%) as a white foam.
- D. To a solution of ((1S,2R,5S)-5-acetoxy-2-((2S,3aS,4R,5S,7aS)-2-acetoxy-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 158, 66 mg, 0.14 mmol) in pyridine (3 mL) and CH2Cl2 (3 mL) at 0° C. under argon was added MsCl (0.03 mL, 0.43 mmol). After 2.5 hours the solution was cooled in ice then added saturated NaHCO3 solution (3 mL) and stirred 1 hour. The mixture was diluted with EtOAc (40 mL), washed with brine (3×8 mL), dried (MgSO4) and concentrated to afford ((1S,2R,5S)-5-acetoxy-2-((2S,3aS,4R,5S,7aS)-2-acetoxy-7a-methyl-1-methylene-4-(((methylsulfonyl)oxy)methyl)octahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 159, 79 mg, 100%) as a film.
- E. A solution of ((1S,2R,5S)-5-acetoxy-2-((2S,3aS,4R,5S,7aS)-2-acetoxy-7a-methyl-1-methylene-4-(((methylsulfonyl)oxy)methyl)octahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 159, 77 mg, 0.14 mmol) and NaN3 (27 mg, 0.42 mmol) in DMF (5 mL) at 60° C. was stirred under argon for 16 hours. The mixture was diluted with Et2O (40 mL), washed with brine (3×8 mL), dried (MgSO4) and concentrated to afford ((1S,2R,5S)-5-acetoxy-2-((2S,3aS,4R,5S,7aS)-2-acetoxy-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 160, 70 mg, 100%) as a film.
- F. A solution of ((1S,2R,5S)-5-acetoxy-2-((2S,3aS,4R,5S,7aS)-2-acetoxy-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 160, 69 mg, 0.14 mmol), triphenylphosphine (185 mg, 0.70 mmol) and water (0.01 mL, 0.7 mmol) in THF (5 mL) was stirred at room temperature for 2 days. The mixture was concentrated and the residue was purified using chromatography on silica gel (5% MeOH/CH2Cl2 then 10% MeOH/CH2Cl2 with 2% NH4OH) to afford ((1S,2R,5S)-5-acetoxy-2-((2S,3aS,4R,5S,7aS)-2-acetoxy-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 161, 35 mg, 54%) as a film.
- G. A solution of ((1S,2R,5S)-5-acetoxy-2-((2S,3aS,4R,5S,7aS)-2-acetoxy-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 161, 35 mg, 0.075 mmol) and NaOMe (0.21 mL of a 25% solution in MeOH) in MeOH (5 mL) was stirred at room temperature for 18 hours. The mixture was purified using chromatography on silica gel (5% MeOH/EtOAc then 10% MeOH/EtOAc with 2% NH4OH then 20% MeOH/EtOAc with 4% NH4OH) to afford (2S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-2-ol (Compound No. 162, 24 mg, 99%) as a film. 1H NMR (CD3OD): δ 5.05 (1H), 4.85 (1H), 4.62 (m, 1H), 3.72 (m, 1H), 3.45 (m, 1H), 3.12 (2H), 2.75 (m, 1H), 2.15 (m, 1H), 1.9-1.2 (15H), 1.10 (s, 3H), 0.82 (s, 3H). ES-MS m/z 338 ([M+1]+)
-
- A. To a solution of (3S,5S,6R,7R,8R,9S,10R,13S,14S)-3-amino-10,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthrene-6,7-diol acetate (Compound No. 163, 3.86 g, 10.2 mmol) in 1:1 MeOH/H2O (16 mL) was added 1 N NaOH(aq) (20 mL, 20 mmol), giving a colourless precipitate that was collected by filtration and washed with H2O. The precipitate was dissolved in MeOH and concentrated followed by azeotropic removal of remaining H2O using toluene (30 mL). The colourless solid (3S,5S,6R,7R,8R,9S,10R,13S,14S)-3-amino-10,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthrene-6,7-diol (Compound No. 164, 3.30 g) that was obtained was used in the next step without further purification.
- B. To a solution of (3S,5S,6R,7R,8R,9S,10R,13S,14S)-3-amino-10,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthrene-6,7-diol (Compound No. 164, 3.30 g) and Et3N (3.55 mL, 25.5 mmol) in MeOH (10 mL) at 0° C. under argon was added trifluoroacetic anhydride (1.98 mL, 14.2 mmol) dropwise, and the solution was stirred at room temperature for 15 h. More Et3N (1.8 mL, 13 mmol) was added and the mixture was cooled to 0° C. Trifluoroacetic anhydride (1.98 mL, 14.2 mmol) was added dropwise and stirred at room temperature for 2.5 h then concentrated. The residue was dissolved in EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (50 mL then 3×20 mL) and brine (15 mL) then dried (MgSO4) and concentrated to give N-((3S,5S,6R,7R,8R,9S,10R,13S,14S)-6,7-dihydroxy-10,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)-2,2,2-trifluoroacetamide (Compound No. 165, 3.09 g) as a pale foam.
- C. A suspension of sodium periodate (3.18 g, 14.9 mmol) in H2O (7.4 mL) was added to a solution of N-((3S,5S,6R,7R,8R,9S,10R,13S,14S)-6,7-dihydroxy-10,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)-2,2,2-trifluoroacetamide (Compound No. 165, 3.09 g) in THF (74 mL), and the mixture was stirred at room temperature for 1.5 h. The mixture was concentrated, and the residue was partitioned between CH2Cl2 (40 mL) and H2O (30 mL). The aqueous phase was extracted with CH2Cl2 (15 mL), and the combined organic layers were dried (MgSO4) and concentrated. The resulting colourless foam (3.09 g) was dissolved in 1:1 THF/MeOH (74 mL) and cooled to 0° C. under argon. NaBH4 (0.56 g, 15 mmol) was added, and the mixture was stirred at 0° C. for 30 min then at room temperature for 3 h. Acetone (5 mL) was added and the mixture was concentrated. The residue was dissolved in EtOAc (100 mL) and washed with brine (2×25 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (60:40 EtOAc/hexanes) to give 2,2,2-trifluoro-N-((1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl)acetamide (Compound No. 166, 2.40 g, 56% over 4 steps) as a colourless solid.
- D. To a solution of 2,2,2-trifluoro-N-((1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl)acetamide (Compound No. 166, 654 mg, 1.57 mmol) in 9:1 MeOH/H2O (31 mL) was added potassium carbonate (4.3 g, 31 mmol) and heated to 65° C. for 22 h. The mixture was filtered and concentrated, and 1 N NaOH(aq) (3 mL) and H2O (10 mL) were added to the residue. The mixture was stirred and a colourless solid was collected by filtration and washed with H2O. The solid was dissolved in MeOH and concentrated to give ((1S,2R,5S)-5-amino-2-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methanol (Compound No. 167, 405 mg, 80%) as a colourless solid. 1H NMR (CD3OD): δ 4.62 (s, 2H), 3.93 (m, 1H), 3.73 (m, 1H), 3.64 (m, 1H), 3.11 (m, 1H), 2.53 (m, 2H), 2.26 (m, 1H), 2.06 (m, 1H), 1.10-1.94 (m, 18H), 0.80 (s, 3H). ES-MS m/z 322 ([M+1]+).
-
- A. A mixture of (3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-7a-methyloctahydro-1H-inden-1-one (Compound No. 168, 1.28 g, 1.9 mmol), TMSOTf (1.4 mL, 7.7 mmol) and TEA (1.6 mL, 11.5 mmol) in CH2Cl2 (50 mL) under argon at 0° C. was stirred for 90 min. The reaction was quenched with saturated NaHCO3 solution (50 mL), extracted with CH2Cl2 (2×25 mL), dried (Na2SO4) and concentrated. The residue was dissolved in DMSO (30 mL) and CH2Cl2 (20 mL) under argon at room temperature. To this mixture was added Pd(OAc)2 (426 mg, 1.9 mmol) and the resultant mixture was stirred for 18 h. Dilution with Et2O (200 mL) was followed by washing with water (3×50 mL). The aqueous washes were the back extracted with Et2O (3×75 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (9:1 hexanes:EtOAc) to afford (3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-one (Compound No. 169, 1.09 g, 86% over 2 steps).
- B. To a suspension of Ph3PMeBr (3.64 g, 1.02 mmol) in THF (60 mL) under argon at 0° C. was added KOtBu (1.14 g, 10.2 mmol). After 30 min a solution of (3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-1-one (Compound No. 169, 0.68 g, 1.0 mmol) in THF (30 mL) was added via cannula and the mixture was stirred at room temperature for 2.5 h. The reaction was diluted with EtOAc (200 mL), washed successively with saturated NaHCO3 solution (2×50 mL) and brine (50 mL), dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (0% to 5% to 10% EtOAc/hexanes) to afford tert-butyl(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methylene-3a,4,5,6,7,7a-hexahydro-1H-inden-4-yl)methoxy)dimethylsilane (Compound No. 170, 119 mg, 18%) as a colourless oil.
- C. A mixture of tert-butyl(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methylene-3a,4,5,6,7,7a-hexahydro-1H-inden-4-yl)methoxy)dimethylsilane (Compound No. 170, 119 mg, 0.18 mmol) and TBAF (1.8 mL of a 1 M solution in THF, 1.8 mmol) in THF (10 mL) under argon at room temperature was stirred for 24 h.
- TBAF (0.9 mL, 0.9 mmol) was added and the mixture was stirred for 5 h. The solution was diluted with EtOAc (100 mL), washed successively with saturated NaHCO3 solution (2×25 mL) and brine (25 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (0% to 2% to 5% to 10% MeOH/CH2Cl2) to afford (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methylene-3a,4,5,6,7,7a-hexahydro-1H-inden-5-yl)-4-methylcyclohexanol (Compound No. 171, 36 mg, 63%) as a thick colourless oil. 1H NMR (300 MHz, CD3OD) δ 6.28 (d, J=5.8, 1H), 6.10 (m, 1H), 4.74 (s, 1H), 4.60 (s, 1H), 3.97 (d, J=9.4, 1H), 3.86 (d, J=11.1, 1H), 3.73 (d, J=8.8, 1H), 3.45 (m, 1H), 3.13 (m, 1H), 2.51 (m, 1H), 2.15 (m, 1H), 1.83 (m, 7H), 1.58-1.20 (m, 7H), 1.12 (s, 3H), 0.98 (s, 3H). 13C NMR (75 MHz, CD3OD) δ 164.5, 138.2, 133.5, 100.8, 71.2, 63.2, 62.9, 58.1, 46.4, 44.6, 38.3, 35.2, 34.7, 32.1, 24.3, 22.6, 21.7; MS m/z: 379.1 [M+acetate]−.
-
- A mixture of (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methylene-3a,4,5,6,7,7a-hexahydro-1H-inden-5-yl)-4-methylcyclohexanol (Compound No. 171, 17 mg, 0.05 mmol) and concentrated HCl (2 mL) in MeOH (4 mL) at 40° C. was stirred for 20 h. The resultant mixture was cooled to room temperature, concentrated and taken up in EtOAc (25 mL). This mixture was washed successively with saturated NaHCO3 solution (3×5 mL) and brine (5 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (0% to 5% to 10% MeOH/CH2Cl2) to afford (1S,3S,4R)-3-(hydroxymethyl)-4-((4R,5S)-4-(hydroxymethyl)-1,1-dimethyl-4,5,6,7-tetrahydro-1H-inden-5-yl)-4-methylcyclohexanol (Compound No. 172, 14 mg, 82%) as a thick colourless oil. 1H NMR (300 MHz, CD3OD) δ 5.15 (s, 1H), 5.10 (d, J=6.7, 1H), 3.71 (d, J=10.6, 1H), 3.64 (t, J=7.7, 1H), 3.49 (m, 1H), 3.17 (t, J=10.0, 1H), 3.04 (m, 1H), 2.18 (m, 3H), 1.88-1.14 (m, 10H), 1.67 (s, 3H), 1.08 (s, 3H), 0.87 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 156.1, 122.3, 89.5, 73.4, 71.4, 62.8, 50.9, 48.3, 43.1, 41.3, 41.1, 38.7, 35.3, 34.2, 31.8, 30.9, 27.8, 19.3, 18.5, 12.2; MS m/z: 379.3 [M+acetate]−.
-
- A. A solution of ((1S,2R,5S)-5-acetoxy-2-((3a'S,4′R,5'S,7a'S)-4′-(hydroxymethyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-5′-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 173, 5.51 g, 12.2 mmol), TBDPSCI (4.7 mL, 18.6 mmol) and imidazole (2.5 g, 36.6 mmol) in DMF (40 mL) was stirred at room temperature under nitrogen for 21 hours. The mixture was poured into cold water (80 mL), extracted with Et2O (350 mL), washed with brine (40 mL), dried (MgSO4) and concentrated. The residue was taken up in AcOH (80 mL) and water (20 mL) and heated at 40° C. for 2 hours, stood at room temperature overnight then heated at 40° C. for 2 hours. The mixture was concentrated and the residue was taken up in EtOAc (350 mL), washed successively with saturated NaHCO3 solution (3×50 mL) and brine (3×30 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (20% EtOAc/hexanes) to afford ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-methyl-1-oxooctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 174, 4.86 g, 61%) as a white foam.
- B. A solution of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-methyl-1-oxooctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 174, 3.47 g, 5.36 mmol) and NaOMe (7.9 mL of a 5.4M solution in MeOH) in MeOH (30 mL) was stirred at room temperature for 2 days. The solution was cooled in ice then was added AcOH (2.5 mL). The mixture was concentrated and the residue was taken up in EtOAc (200 mL) and water (20 mL). The EtOAc layer was washed with brine (3×15 mL), dried (MgSO4) and concentrated to afford (3aS,4R,5S,7aS)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyloctahydro-1H-inden-1-one (Compound No. 175, 3.55 g) of a white solid.
- C. A solution of (3aS,4R,5S,7aS)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyloctahydro-1H-inden-1-one (Compound No. 175, 3.02 g, 5.36 mmol), TBSCl (1.94 g, 12.9 mmol) and imidazole (1.75 g, 25.7 mmol) in DMF was stirred at room temperature under nitrogen for 1.5 hours. The mixture was diluted with Et2O (300 mL), washed successively with water (40 mL) and brine (2×40 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (5% then 10% EtOAc/hexanes) to afford (3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-methyloctahydro-1H-inden-1-one (Compound No. 176, 3.75 g, 88%) as a white foam.
- D. To a solution of (3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-methyloctahydro-1H-inden-1-one (Compound No. 176, 3.65 g, 4.61 mmol) in THF (20 mL) at −78° C. under nitrogen was added MeLi (12.6 mL of a 1.1M solution in Et2O, 13.8 mmol). After 1 hour the reaction temperature was increased to 0° C. for 4 hours then was added saturated NaHCO3 solution (10 mL).
- The mixture was diluted with EtOAc (350 mL), washed with brine (3×30 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (5% then 15% EtOAc/hexanes) to afford (1S,3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-1,7a-dimethyloctahydro-1H-inden-1-ol (Compound No. 177, 2.54 g, 68%) as a white foam.
- E. To a solution of (1S,3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-1,7a-dimethyloctahydro-1H-inden-1-ol (Compound No. 177, 2.54 g, 3.14 mmol) in pyridine (5 mL) and CH2Cl2 (25 mL) at 0° C. under nitrogen was added POCl3 (0.88 mL, 9.4 mmol). After 24 hours, the solution was cooled in ice then added saturated NaHCO3 solution (15 mL) and EtOAc (350 mL). The EtOAc layer was washed with brine (2×30 mL), dried (MgSO4) and concentrated to afford tert-butyl(((3aS,6S,7R,7aS)-6-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-3,3a-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl)methoxy)diphenylsilane (Compound No. 178, 2.49 g) as a white foam.
- F. A solution of tert-butyl(((3aS,6S,7R,7aS)-6-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-3,3a-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl)methoxy)diphenylsilane (Compound No. 178, 2.48 g, 3.14 mmol) in AcOH (80 mL), water (20 mL) and acetone (200 mL) was stirred at room temperature for 3 days. The mixture was concentrated and the residue was purified using chromatography on silica gel (50% then 70% EtOAc/hexanes) to afford (1S,3S,4R)-4-((3aS,6S,7R,7aS)-7-(((tert-butyldiphenylsilyl)oxy)methyl)-3,3a-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 179, 1.52 g) of a white solid.
- G. To a solution of (1S,3S,4R)-4-((3aS,6S,7R,7aS)-7-(((tert-butyldiphenylsilyl)oxy)methyl)-3,3a-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 179, 1.52 g, 2.71 mmol) in pyridine (5 mL) and CH2Cl2 (25 mL) at 0° C. under nitrogen was added Ac2O (1.5 mL, 16.3 mmol). After 16 hours, the reaction was fitted with a reflux condenser and was heated in a 50° C. oil bath for 7 hours then was allowed to continue at room temperature overnight. The solution was cooled in ice then added saturated NaHCO3 solution (5 mL). After 10 minutes, the solution was diluted with EtOAc (200 mL), washed with brine (3×30 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (10% EtOAc/hexanes) to afford ((1S,2R,5S)-5-acetoxy-2-((3aS,6S,7R,7aS)-7-(((tert-butyldiphenylsilyl)oxy)methyl)-3,3a-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 180, 1.52 g) as a white foam.
- H. A solution of ((1S,2R,5S)-5-acetoxy-2-((3aS,6S,7R,7aS)-7-(((tert-butyldiphenylsilyl)oxy)methyl)-3,3a-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 180, 1.52 g, 2.36 mmol) and MCPBA (1.53 g, 7.09 mmol) in CH2Cl2 (20 mL) at 0° C. under nitrogen was stirred 1.5 hours then was quenched with a 10% Na2SO3 solution (20 mL). After 10 minutes, the solution was diluted with EtOAc (200 mL), washed successively with saturated NaHCO3 solution (3×30 mL) and brine (3×30 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (15% then 20% EtOAc/hexanes) to afford ((1S,2R,5S)-5-acetoxy-2-((1aS,1bS,4S,5R,5aS,6aR)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1a,1b-dimethyloctahydro-1aH-indeno[1,2-b]oxiren-4-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 181, 1.14 g) as a white foam.
- I. A solution of ((1S,2R,5S)-5-acetoxy-2-((1aS,1bS,4S,5R,5aS,6aR)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1a,1b-dimethyloctahydro-1aH-indeno[1,2-b]oxiren-4-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 181, 616 mg, 0.932 mmol) and AcOH (20 mL) was stirred at room temperature for 24 hours then was concentrated. The residue was purified using chromatography on silica gel (25% then 30% EtOAc/hexanes) to afford ((1S,2R,5S)-5-acetoxy-2-((2R,4R,5S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-hydroxy-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 182, 171 mg) as a white foam.
- J. A solution of ((1S,2R,5S)-5-acetoxy-2-((2R,4R,5S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-hydroxy-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 182, 117 mg, 0.18 mmol) and TBAF (1 mL of a 1M solution in THF, 1 mmol) in THF (5 mL) was stirred at room temperature under nitrogen for 16 hours then was concentrated. The residue was purified using chromatography on silica gel (70% then 80% EtOAc/hexanes) to afford ((1S,2R,5S)-5-acetoxy-2-((2R,4R,5S)-2-hydroxy-4-(hydroxymethyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 183, 83 mg) as a white foam.
- K. A solution of ((1S,2R,5S)-5-acetoxy-2-((2R,4R,5S)-2-hydroxy-4-(hydroxymethyl)-1, 1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 183, 83 mg, 0.20 mmol) and NaOMe (0.4 mL of a 5.4M solution in MeOH, 2 mmol) in MeOH (3 mL) was stirred at room temperature for 1 hour then added AcOH (1 mL) and concentrated. The residue was purified using chromatography on silica gel (5% MeOH/EtOAc) to afford (2R,4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-4-(hydroxymethyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-2-ol (Compound No. 184, 64 mg, 97%) as a film. 1H NMR (CD3OD): δ 3.80 (2H), 3.60 (m, 1H), 3.45 (m, 1H), 3.30 (m, 1H), 3.20 (m, 1H), 2.35 (2H), 2.25-1.75 (7H), 1.65 (2H), 1.25 (4H), 0.90 (6H), 0.85 (s, 3H). ES-MS m/z 339 ([M+1]+)
-
- A. To a suspension of NaH (24 mg of a 60% solution, 0.60 mmol) in DMF (1.2 mL) at 0° C. under argon was added ((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methanol (Compound No. 152, 133 mg, 0.241 mmol) and stirred at room temperature for 0.5 h. A solution of benzyl bromide (103 mg, 0.602 mmol) in DMF (1.2 mL) was added and stirred at room temperature for 4 h. The mixture was diluted with EtOAc (40 mL) and washed with H2O (10 mL) and brine (6×10 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (2:98 EtOAc/hexanes) to give (((1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((benzyloxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcyclohexyl)oxy)(tert-butyl)dimethylsilane (Compound No. 185, 142 mg, 92%) as a colourless oil.
- B. TBAF (0.89 mL of a 1 M solution in THF, 0.89 mmol) was added to a solution of (((1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((benzyloxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylcyclohexyl)oxy)(tert-butyl)dimethylsilane (Compound No. 185, 142 mg, 0.221 mmol) in THF (4.4 mL) and heated to 50° C. for 17.5 h. The solution was concentrated, and the residue was purified by chromatography on silica gel (80:20 EtOAc/hexanes) to give (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(benzyloxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 186, 74 mg, 81%) as a colourless solid. 1H NMR (CDCl3): δ 7.31 (m, 5H), 4.62 (m, 2H), 4.43 (d, J=11 Hz, 1H), 4.34 (d, J=12 Hz, 1H), 3.71 (m, 2H), 3.58 (br s, 1H), 3.38 (m, 1H), 3.30 (br s, 1H), 2.46 (m, 1H), 2.13-2.29 (m, 2H), 1.25-1.80 (m, 15H), 1.03 (s, 3H), 0.76 (s, 3H). ES-MS m/z 395 ([M−17]+).
-
- A. To a suspension of NaH (18 mg of a 60% solution, 0.45 mmol) in DMF (0.9 mL) at 0° C. under argon was added ((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methanol (Compound No. 152, 99 mg, 0.18 mmol) and stirred at room temperature for 0.5 h. A solution of 3,5-dimethoxybenzyl bromide (104 mg, 0.450 mmol) in DMF (0.9 mL) was added and stirred at room temperature for 16.5 h. The mixture was diluted with EtOAc (40 mL) and washed with brine (6×10 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (2:98 EtOAc/hexanes) to give tert-butyl(((1S,2R,5S)-5-((tert-butyldimethylsilyl)oxy)-2-((3aS,4R,5S,7aS)-4-(((3,5-dimethoxybenzyl)oxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methoxy)dimethylsilane (Compound No. 187, 87 mg, 69%) as a colourless oil.
- B. TBAF (0.50 mL of a 1 M solution in THF, 0.50 mmol) was added to a solution of tert-butyl(((1S,2R,5S)-5-((tert-butyldimethylsilyl)oxy)-2-((3aS,4R,5S,7aS)-4-(((3,5-dimethoxybenzyl)oxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methoxy)dimethylsilane (Compound No. 187, 87 mg, 0.12 mmol) in THF (2.5 mL) and heated to 50° C. for 16 h. The solution was concentrated, and the residue was purified by chromatography on silica gel (90:10 EtOAc/hexanes) to give (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-((3,5-dimethoxybenzyloxy)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 188, 50 mg, 85%) as a colourless solid. 1H NMR (CDCl3): δ 6.47 (s, 2H), 6.38 (s, 1H), 4.62 (m, 2H), 4.39 (d, J=12 Hz, 1H), 4.27 (d, J=12 Hz, 1H), 3.66-3.78 (m, 8H), 3.58 (br s, 1H), 3.39 (m, 1H), 3.30 (br s, 1H), 2.46 (m, 1H), 2.13-2.27 (m, 2H), 1.20-1.80 (m, 15H), 1.04 (s, 3H), 0.76 (s, 3H). ES-MS m/z 473 ([M+1]+).
-
- A. To a solution of nicotinic acid (34 mg, 0.28 mmol) in DMF (2 mL) was added PyBOP (158 mg, 0.30 mmol). After 10 min (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate (Compound No. 1, 101 mg, 0.26 mmol) was added and DIPEA (0.16 mL, 0.92 mmol). After overnight, the mixture was diluted with EtOAc (50 mL) and brine (15 mL) and stirred 1 h. The EtOAc layer was separated and washed successively with brine (3×10 mL) and water (10 mL), dried (NaS2O4) and concentrated. The residue was purified using chromatography on silica gel (4% then 10% then 15% MeOH/CH2Cl2) to afford N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)nicotinamide (Compound No. 189, 105 mg) as an impure off-white solid.
- B. A solution of N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)nicotinamide (Compound No. 189, 105 mg), triethylamine (150 μL, 1.08 mmol), acetic anhydride (70 μL, 0.74 mmol) and DMAP (2 mg) in DMF (1 mL) and CH2Cl2 (4 mL) was stirred at room temperature for 5 h. The mixture was diluted with EtOAc (25 mL), washed successively with brine (4×10 mL) and water (10 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (3% then 5% MeOH/CH2Cl2) to afford ((1S,2R,5S)-5-acetoxy-2-methyl-2-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-(nicotinamidomethyl)octahydro-1H-inden-5-yl)cyclohexyl)methyl acetate (Compound No. 190, 90 mg) as an oil.
- C. A solution of ((1S,2R,5S)-5-acetoxy-2-methyl-2-((3aS,4R,5S,7aS)-7a-methyl-1-methylene-4-(nicotinamidomethyl)octahydro-1H-inden-5-yl)cyclohexyl)methyl acetate (Compound No. 190, 70 mg, 0.14 mmol) and K2CO3 (375 mg) in MeOH (4.5 mL) and water (0.5 mL) was stirred at room temperature for 2 d. The mixture was concentrated and the residue was taken up in 10% MeOH/CH2Cl2 (40 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×15 mL). The organic layers were combined, dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (4% then 10% MeOH/CH2Cl2) to afford N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)nicotinamide (Compound No. 191, 61 mg) as a white solid. 1H NMR (CDCl3): δ 8.90 (m, 1H), 8.72 (m, 1H), 8.08 (m, 1H), 7.40 (m, 1H), 6.14 (m, 1H), 4.62 (2H), 3.70 (3H), 3.60 (m, 1H), 3.25 (m, 1H), 2.50 (m, 1H), 2.25 (m, 1H), 2.15 (m, 1H), 1.2-2.0 (15H), 1.03 (s, 3H), 0.82 (s, 3H). ES-MS m/z 427 ([M+1]+)
-
- A mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), PyBop (210 mg, 0.400 mmol), isonicotinic acid (50 mg, 0.40 mmol) and DIEA (0.81 mL, 0.81 mmol) in DMF (3.0 mL) at room temperature under argon was stirred for 24 h. The mixture was diluted with EtOAc (20 mL), washed with NaHCO3 solution (2×10 mL) and saturated NaCl solution (2×10 mL) and concentrated. The residue was purified by chromatography on silica gel (9% MeOH/CH2Cl2) to afford N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)isonicotinamide (Compound No. 192, 83 mg, 62%) as a white solid. 1H NMR (300 MHz, CD3OD): δ 8.65 (d, J=6 Hz, 2H), 7.67 (d, J=6 Hz, 2H), 4.64 (s, 2H), 3.7 (m, 1H), 3.63 (s, 2H), 3.47 (m, 1H), 2.48 (m, 1H), 2.15 (m, 2H), 1.85 (m, 9H), 1.69 (m, 3H), 1.48 (m, 6H), 1.28 (m, 3H), 1.04 (s, 3H), 0.83 (s, 3H); 13C NMR (75 MHz, CD3OD): δ 168.8, 162.4, 150.7, 144.4, 123.1, 101.9, 71.1, 62.9, 52.7, 47.5, 45.0, 44.8, 44.0, 41.0, 38.1, 38.0, 36.9, 35.2, 32.1, 30.1, 26.1, 24.4, 21.7, 18.7; MS m/z: 427.2 [M+H]+.
-
- A mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), PyBop (210 mg, 0.400 mmol), 2-pyrazinecarboxylic acid (50 mg, 0.40 mmol) and DIEA (0.81 mL, 0.81 mmol) in DMF (3.0 mL) at room temperature under argon was stirred for 24 h. The mixture was diluted with EtOAc (20 mL), washed with NaHCO3 solution (2×10 mL) and saturated NaCl solution (2×10 mL) and concentrated. The residue was purified by chromatography on silica gel (9% MeOH/CH2Cl2) to afford N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)pyrazine-2-carboxamide (Compound No. 193, 118 mg, 89%) as a white solid. 1H NMR (300 MHz, CD3OD): δ9.23 (s, 1H), 8.80 (m, 1H), 8.68 (m, 1H), 4.62 (s, 2H), 3.71 (m, 2H), 3.60 (m, 1H), 3.46 (m, 1H), 3.12 (m, 1H), 2.48 (m, 1H), 2.18 (m, 2H), 1.87 (m, 5H), 1.68 (m, 1H), 1.45 (m, 5H), 1.26 (m, 4H), 1.06 (s, 3H), 0.85 (s, 3H); MS m/z: 425.9 [M+H]+.
-
- A mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22 100 mg, 0.310 mmol), PyBop (130 mg, 0.400 mmol), picolinic acid (50 mg, 0.40 mmol) and DIEA (0.81 mL, 0.81 mmol) in DMF (3.0 mL) at room temperature under argon was stirred for 24 h. The mixture was diluted with EtOAc (20 mL), washed with NaHCO3 solution (2×10 mL) and saturated NaCl solution (2×10 mL) and concentrated. The residue was purified by chromatography on silica gel (9% MeOH/CH2Cl2) to afford N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)picolinamide (Compound No. 194, 121 mg, 84%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.63 (m, 1H), 8.10 (m, 1H), 7.97 (m, 1H), 7.56 (m, 1H), 4.62 (s, 2H), 3.71 (m, 2H), 3.66 (m, 1H), 3.46 (m, 1H), 3.13 (m, 1H), 2.48 (m, 1H), 2.17 (m, 2H), 1.87 (m, 5H), 1.67 (m, 1H), 1.45 (m, 5H), 1.28 (m, 4H), 1.06 (s, 3H), 0.85 (m, 3H); MS m/z: 426.9 [M+H]+.
-
- To a mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), PyBop (210 mg, 0.400 mmol), piperonylic acid (67 mg, 0.40 mmol) under argon were added DIEA (0.81 mL, 0.81 mmol) and DMF (3.0 mL). After 24 h EtOAc (20 mL) was added to the solution, and the resulting mixture was washed successively with NaHCO3 (2×10 mL) and brine (2×10 mL) and concentrated. The residue was purified using chromatography on silica gel (0 to 10% MeOH/CH2Cl2) to afford N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound No. 195, 156 mg, 68%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.33 (m, 1H), 7.24 (m, 1H), 6.87 (m, 1H), 6.01 (s, 2H), 4.64 (s, 2H), 3.73 (m, 1H), 3.58 (m, 2H), 3.47 (m, 1H), 2.48 (m, 1H), 2.20 (m, 2H), 1.85 (m, 5H), 1.68 (m, 1H), 1.50 (m, 5H), 1.37 (m, 2H), 1.29 (m, 2H), 1.03 (s, 3H), 0.84 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 170.1, 162.5, 151.8, 149.2, 129.9, 123.3, 108.8, 103.1, 101.8, 71.0, 62.8, 52.9, 45.0, 44.8, 43.9, 38.1, 36.9, 35.2, 32.1, 30.2, 27.4, 27.3, 26.1, 24.4, 21.7, 18.8; MS m/z: 468.1 [M+H]+.
-
- To a mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), PyBop (210 mg, 0.400 mmol), 4-methoxybenzoic acid (61 mg, 0.40 mmol) under argon were added DIEA (0.81 mL, 0.81 mmol) and DMF (3.0 mL) and the solution was stirred for 24 h. The solution was diluted with EtOAc (20 mL), washed with saturated NaHCO3 solution (2×10 mL) and brine (2×10 mL) and concentrated. The residue was purified using chromatography on silica gel (0% to 10% MeOH/CH2Cl2) to afford N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-4-methoxybenzamide (Compound No. 196, 125 mg, 65%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.73 (d, J=9.3 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 4.63 (s, 2H), 3.74 (m, 1H), 3.58 (m, 2H), 3.46 (m 1H), 3.13 (m, 1H), 2.48 (m, 1H), 2.19 (m, 2H), 1.85 (m, 5H), 1.68 (m, 1H), 1.47 (m, 5H), 1.29 (m, 5H), 1.04 (s, 3H), 0.84 (m, 3H); 13C NMR (75 MHz, CD3OD) δ 170.6, 163.9, 162.6, 130.2, 128.1, 114.7, 101.8, 71.1, 62.9, 55.9, 52.9, 47.6, 45.0, 44.8, 43.7, 38.2, 38.1, 37.0, 35.2, 32.1, 30.2, 26.1, 24.4, 21.7, 18.7; MS m/z: 454.1 [M−H]−.
-
- To a mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), PyBop (210 mg, 0.400 mmol), 4-fluorobenzoic acid (56 mg, 0.40 mmol) under argon were added DIEA (0.81 mL, 0.81 mmol) and DMF (3.0 mL) and the solution was stirred 24 h. The solution was diluted with EtOAc (20 mL), washed successively with saturated NaHCO3 solution (2×10 mL) and brine (2×10 mL) and then was concentrated. The residue was purified using chromatography on silica gel (0% to 10% MeOH/CH2Cl2) to afford 4-fluoro-N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)benzamide (Compound No. 197, 91 mg, 66%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.80 (m, 2H), 7.18 (m, 2H), 4.64 (s, 2H), 3.72 (m, 1H), 3.60 (m, 2H), 3.46 (m, 1H), 3.14 (m, 1H), 2.48 (m, 1H), 2.19 (m, 2H), 1.83 (m, 5H), 1.68 (m, 1H), 1.46 (m, 5H), 1.28 (m, 4H), 1.04 (s, 3H), 0.85 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 170.0, 167.7, 102.5, 132.4, 131.0, 116.4, 101.8, 71.1, 62.8, 55.9, 52.8, 47.5, 45.0, 43.9, 38.1, 36.9, 35.2, 32.1, 30.1, 27.4, 27.3, 26.1, 24.4, 21.7, 18.7; MS m/z: 442.1 [M−H]−.
-
- To a mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), PyBop (210 mg, 0.400 mmol), 4-trifluoromethylbenzoic acid (77 mg, 0.40 mmol) under argon were added DIEA (0.81 mL, 0.81 mmol) and DMF (3.0 mL). The solution was stirred for 24 h then was diluted with EtOAc (20 mL), washed successively with saturated NaHCO3 solution (2×10 mL) and brine (2×10 mL) and concentrated. The residue was purified using chromatography on silica gel (0% to 10% MeOH/CH2Cl2) to afford N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-4-(trifluoromethyl)benzamide (Compound No. 198, 105 mg, 68%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.89 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H), 4.64 (s, 2H), 3.72 (m, 1H), 3.63 (m, 2H), 3.47 (m, 1H), 3.13 (m, 1H), 2.50 (m, 1H), 2.20 (m, 2H), 1.86 (m, 5H), 1.69 (m, 1H), 1.49 (m, 5H), 1.28 (m, 4H), 1.05 (s, 3H), 0.85 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 169.9, 162.5, 139.9, 134.0, 129.2, 126.4, 119.0, 101.8, 71.1, 62.8, 52.8, 47.4, 45.0, 44.8, 43.9, 38.1, 38.9, 35.2, 30.2, 26.1, 24.4, 21.7, 18.7; MS m/z: 492.1 [M−H]−.
-
- To a mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), PyBop (210 mg, 0.400 mmol), p-toluic acid (55 mg, 0.40 mmol) under argon were added DIEA (0.81 mL, 0.81 mmol) and DMF (3.0 mL). The solution was stirred for 24 then was diluted with EtOAc (20 mL), washed successively with saturated NaHCO3 solution (2×10 mL) and brine (2×10 mL) and concentrated. The residue was purified using chromatography on silica gel (0% to 10% MeOH/EtOAc) to afford N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-4-methylbenzamide (Compound No. 199, 115 mg, 85%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.65 (d, J=8.2 Hz, 2H), 7.26 (d, J=7.6 Hz, 2H), 4.63 (s, 2H), 3.73 (m, 1H), 3.60 (m, 2H), 3.46 (m, 1H), 2.48 (m, 1H), 2.18 (m, 2H), 1.85 (m, 5H), 1.70 (m, 1H), 1.49 (m, 5H), 1.29 (m, 4H), 1.05 (s, 3H), 0.84 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 171.1, 162.5, 143.1, 133.2, 130.1, 128.4, 101.9, 71.1, 62.9, 52.9, 47.6, 47.4, 45.0, 44.8, 43.7, 38.1, 37.0, 35.2, 32.1, 30.2, 27.3, 26.1, 24.4, 21.7, 21.4, 18.8; MS m/z: 438.2 [M+H]+.
-
- To a mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), PyBop (210 mg, 0.400 mmol), o-toluic acid (55 mg, 0.40 mmol) under argon were added DIEA (0.81 mL, 0.81 mmol) and DMF (3.0 mL). The solution was stirred for 24 h then was diluted with EtOAc (20 mL), washed successively with saturated NaHCO3 solution (2×10 mL) and brine (2×10 mL) then was concentrated. The residue was purified using chromatography on silica gel (0% to 10% MeOH/EtOAc) to afford N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-2-methylbenzamide (Compound No. 200, 111 mg, 81%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.30 (m, 1H), 7.23 (m, 3H), 4.63 (s, 2H), 3.69 (m, 1H), 3.61 (m, 2H), 3.45 (m, 1H), 3.10 (m, 1H), 2.52 (m, 1H), 2.21 (m, 2H), 1.83 (m, 5H), 1.66 (m, 1H), 1.47 (m, 5H), 1.29 (m, 4H), 1.07 (s, 3H), 0.85 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.8, 162.5, 138.4, 136.3, 131.5, 130.6, 128.0, 126.6, 101.9, 71.1, 62.8, 52.1, 46.5, 44.9, 44.7, 43.2, 38.1, 37.6, 36.9, 35.1, 32.1, 31.8, 30.1, 25.9, 24.3, 21.3, 21.4, 19.7, 18.7; MS m/z: 438.2 [M−H]−.
-
- To a mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), PyBop (210 mg, 0.400 mmol), 2-pyrrolecarboxylic acid (45 mg, 0.40 mmol) under argon were added DIEA (0.81 mL, 0.81 mmol) and DMF (3.0 mL). The solution was stirred for 24 h then was diluted with EtOAc (20 mL), washed successively with saturated NaHCO3 solution (2×10 mL) and brine (2×10 mL) then was concentrated. The residue was purified using chromatography on silica gel (0% to 10% MeOH/EtOAc) to afford N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-1H-pyrrole-2-carboxamide (Compound No. 201, 69 mg, 54%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 6.88 (m, 2H), 6.16 (m, 1H), 4.64 (s, 2H), 3.73 (m, 1H), 3.57 (m, 2H), 3.47 (m, 1H), 3.13 (m, 1H), 2.48 (m, 1H), 2.21 (m, 2H), 1.86 (m, 5H), 1.67 (m, 1H), 1.47 (m, 5H), 1.31 (m, 4H), 1.03 (s, 3H), 0.84 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 162.9, 161.4, 125.6, 121.8, 111.2, 109.0, 100.6, 69.9, 61.7, 51.6, 46.3, 43.8, 43.6, 41.8, 36.9, 36.9, 35.8, 34.0, 30.9, 28.9, 24.8, 23.2, 20.5, 17.5; MS m/z: 412.9 [M−H]−.
-
- To a mixture of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 100 mg, 0.310 mmol), PyBop (210 mg, 0.400 mmol), m-toluic acid (55 mg, 0.40 mmol) under argon were added DIEA (0.81 mL, 0.81 mmol) and DMF (3.0 mL). The solution was stirred for 24 h then was diluted with EtOAc (20 mL), washed successively with saturated NaHCO3 solution (2×10 mL) and brine (2×10 mL) then was concentrated. The residue was purified using chromatography on silica gel (0% to 10% MeOH/EtOAc) to afford N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-3-methylbenzamide (Compound No. 202, 99 mg, 73%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.67 (s, 1H), 7.53 (m, 1H), 7.34 (m, 2H), 4.64 (s, 2H), 3.73 (m, 1H), 3.60 (m, 2H), 3.46 (m, 1H), 3.13 (m, 1H), 2.47 (m, 1H), 2.20 (m, 2H), 1.87 (m, 5H), 1.69 (m, 1H), 1.49 (m, 5H), 1.30 (m, 4H), 1.05 (s, 3H), 0.84 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 108.2, 161.0, 138.7, 134.8, 132.4, 128.6, 127.7, 123.7, 101.6, 69.9, 62.6, 51.8, 50.6, 46.6, 43.9, 43.3, 41.7, 37.1, 36.9, 35.9, 34.2, 31.1, 29.1, 24.9, 23.5, 21.5, 21.3, 18.4; MS m/z: 438.1 [M−H]−.
-
- To a solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate (Compound No. 1, 111 mg, 0.291 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (103 mg, 0.321 mmol), and 2-furoic acid (36 mg, 0.32 mmol) in DMF (1.5 mL) was added N,N-diisopropylethylamine (0.12 mL, 0.69 mmol), and the solution was stirred at room temperature for 28 h. The mixture was concentrated, and the residue was partitioned between EtOAc (35 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was washed with brine (5×10 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (7:93 MeOH/CH2Cl2) to give N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)furan-2-carboxamide (Compound No. 203, 39 mg, 32%) as a colourless solid. 1H NMR (CD3OD): δ 7.66 (s, 1H), 7.39 (br s, 1H), 7.12 (d, J=3.3 Hz, 1H), 6.58 (m, 1H), 4.63 (s, 2H), 3.70 (m, 2H), 3.43-3.56 (m, 2H), 3.13 (m, 1H), 2.49 (m, 1H), 2.13-2.29 (m, 2H), 1.20-1.88 (m, 15H), 1.05 (s, 3H), 0.84 (s, 3H). ES-MS m/z 416 ([M+1]+).
-
- To a suspension of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate (Compound No. 1, 98 mg, 0.26 mmol) in pyridine (2.6 mL) was added cyclopropanecarbonyl chloride (0.071 mL, 0.78 mmol), and the mixture was stirred at room temperature under argon for 17 h then concentrated. Azeotropic removal of remaining pyridine was carried out with toluene (2×4 mL). The residue was dissolved in MeOH (2.6 mL), and 10N NaOH(aq) (0.26 mL, 2.6 mmol) was added then heated to reflux for 45 min. The mixture was concentrated, and the residue was partitioned between EtOAc (25 mL) and H2O (10 mL). The organic layer was washed with brine (10 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (7:93 MeOH/CH2Cl2) to give N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)cyclopropanecarboxamide (Compound No. 204, 72 mg, 72%) as a colourless solid. 1H NMR (CD3OD): δ7.72 (br s, 1H), 4.64 (s, 2H), 3.73 (m, 1H), 3.47 (m, 2H), 3.33 (m, 1H), 3.14 (m, 1H), 2.50 (m, 1H), 2.13-2.30 (m, 2H), 1.20-1.90 (m, 16H), 0.99 (s, 3H), 0.70-0.83 (m, 7H). ES-MS m/z 390 ([M+1]+).
-
- To a solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate (Compound No. 1, 103 mg, 0.270 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (95 mg, 0.30 mmol), and cyclohexanecarboxylic acid (0.067 mL, 0.54 mmol) in DMF (1.3 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.63 mmol), and the solution was stirred at room temperature for 3 d. The mixture was concentrated, and the residue was partitioned between EtOAc (35 mL), H2O (5 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was washed with brine (5×10 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (6:94 MeOH/CH2Cl2) to give N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)cyclohexanecarboxamide (Compound No. 205, 44 mg, 38%) as a colourless solid. 1H NMR (CD3OD): δ 7.41 (br s, 1H), 4.64 (s, 2H), 3.72 (m, 1H), 3.31-3.45 (m, 3H), 3.13 (m, 1H), 2.49 (m, 1H), 2.13-2.39 (m, 3H), 1.20-1.86 (m, 25H), 0.98 (s, 3H), 0.82 (s, 3H). ES-MS m/z 432 ([M+1]+).
-
- To a solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 49 mg, 0.15 mmol) in THF (3.0 mL) at 0° C. under argon was added ethyl isocyanate (0.024 mL, 0.31 mmol), and the solution was stirred at room temperature for 17 h then concentrated. The residue was purified by chromatography on silica gel (100:10:2 CH2Cl2/MeOH/NH4OH) to give 1-ethyl-3-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)urea (Compound No. 206, 52 mg, 87%) as a colourless solid. 1H NMR (CD3OD): δ5.93 (br s, 1H), 5.67 (br s, 1H), 4.63 (s, 2H), 3.70 (m, 1H), 3.25-3.45 (m, 3H), 3.13 (m, 3H), 2.50 (m, 1H), 2.13-2.26 (m, 2H), 1.21-1.87 (m, 15H), 1.08 (t, J=7.2 Hz, 3H), 1.02 (s, 3H), 0.82 (s, 3H). ES-MS m/z 393 ([M+1]+).
-
- To a solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 50 mg, 0.16 mmol) in THF (3.1 mL) at 0° C. under argon was added methyl isothiocyanate (23 mg, 0.31 mmol), and the solution was stirred at room temperature for 17 h then concentrated. The residue was purified by chromatography on silica gel (100:10:2 CH2Cl2/MeOH/NH4OH) to give 1-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-3-methylthiourea (Compound No. 207, 50 mg, 82%) as a colourless solid. 1H NMR (CD3OD): δ 6.82 (br s, 1H), 4.64 (s, 2H), 3.46-3.72 (m, 4H), 3.13 (m, 1H), 2.98 (s, 3H), 2.50 (m, 1H), 2.13-2.29 (m, 2H), 1.20-1.88 (m, 15H), 0.97 (s, 3H), 0.83 (s, 3H). ES-MS m/z 395 ([M+1]+).
-
- To a suspension of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol acetate (Compound No. 1, 2.31 g, 6.05 mmol) in MeOH (6.1 mL) was added Et3N (2.53 mL, 18.2 mmol), and the mixture was cooled to 0° C. under argon. Trifluoroacetic anhydride (1.18 mL, 8.49 mmol) was added dropwise, and the solution was stirred at room temperature for 2.2 h then concentrated. The residue was dissolved in EtOAc (60 mL) and washed with H2O (20 mL) followed by saturated aqueous NaHCO3 (5×20 mL) and brine (15 mL). The organic layer was dried (MgSO4) and concentrated, and a portion of the residue (306 mg of 2.47 g) was purified by chromatography on silica gel (5:95 MeOH/CH2Cl2) to give 2,2,2-trifluoro-N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-11-methyleneoctahydro-1H-inden-4-yl)methyl)acetamide (Compound No. 208, 303 mg, 97%) as colourless crystals. 1H NMR (CD3OD): δ 4.65 (s, 2H), 3.71 (m, 1H), 3.57 (m, 1H), 3.46 (m, 2H), 3.12 (m, 1H), 2.51 (m, 1H), 2.13-2.30 (m, 2H), 1.20-1.90 (m, 15H), 1.00 (s, 3H), 0.82 (s, 3H). ES-MS m/z 416 ([M−1]−).
-
- A. To a solution of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(cyanomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 51, 660 mg, 1.62 mmol) and Et3N (0.29 mL, 2.1 mmol) in CH2Cl2 (16 mL) at 0° C. under argon was added MsCl (0.14 mL, 1.8 mmol), and the solution was stirred at room temperature for 1 h. The solution was washed with saturated aqueous NaHCO3 (15 mL), and the aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried (MgSO4) and concentrated. Azeotropic removal of impurities was carried out with toluene (3×30 mL), and the resulting yellow solid (1.08 g) was dissolved in DMF (5.4 mL). KCN (317 mg, 4.87 mmol) was added, and the mixture was heated to 80° C. under argon for 18 h. The mixture was partitioned between EtOAc (60 mL) and H2O (10 mL), and the organic layer was washed with brine (5×20 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (1:99-5:95 EtOAc/CH2Cl2) to give ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(cyanomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 209, 534 mg, 79% over 2 steps) as a colourless solid.
- B. To a suspension of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(cyanomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 209, 534 mg, 1.28 mmol) in MeOH (25 mL) was added potassium carbonate (710 mg, 5.14 mmol) and heated to 40° C. for 1 h. The mixture was concentrated, and the residue was partially purified by chromatography on silica gel (5:95 MeOH/CH2Cl2) to give a colourless solid (458 mg). The solid (458 mg) was partitioned between 1:9 MeOH/CH2Cl2 (40 mL) and H2O (10 mL), and the aqueous layer was extracted with 1:9 MeOH/CH2Cl2 (10 mL). The combined organic layers were dried (MgSO4) and concentrated to give 2-((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)acetonitrile (Compound No. 210, 448 mg) as a colourless solid. 1H NMR (CD3OD): δ 4.67 (s, 2H), 3.69 (m, 1H), 3.46 (m, 1H), 3.14 (m, 1H), 2.88 (dd, J=18, 3.5 Hz, 1H), 2.55 (m, 2H), 2.31 (m, 1H), 2.16 (m, 1H), 1.86 (m, 6H), 1.21-1.58 (m, 9H), 1.12 (s, 3H), 0.83 (s, 3H). ES-MS m/z 390 ([M−1+60]−).
-
- A. DMSO (0.078 mL, 1.1 mmol) was added dropwise to a solution of oxalyl chloride (0.048 mL, 0.55 mmol) in CH2Cl2 (1.6 mL) at −78° C. under argon then stirred at −78° C. for 15 min. A solution of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 51, 149 mg, 0.366 mmol) in CH2Cl2 (0.8 mL) was added dropwise and stirred at −78° C. for 1.25 h then Et3N (0.26 mL, 1.9 mmol) was added. The mixture was stirred at −78° C. for 0.5 h then at room temperature for 1.25 h, and H2O (10 mL) was added followed by EtOAc (40 mL). The organic layer was washed with saturated aqueous NaHCO3 (20 mL) and brine (5×20 mL) then dried (MgSO4) and concentrated to give ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-formyl-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 211, 191 mg) as a yellow oil.
- B. To a solution of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-formyl-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 211, 191 mg) in 10:1 MeOH/pyridine (7.7 mL) was added methoxylamine hydrochloride (153 mg, 1.83 mmol), and the mixture was stirred at room temperature under argon for 3 d. The mixture was concentrated followed by azeotropic removal of remaining pyridine with toluene (2×20 mL). The residue was purified by chromatography on silica gel (20:80 EtOAc/hexanes) to give ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-((Z)-(methoxyimino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 212, 85 mg, 53% over 2 steps) as a colourless film.
- C. Sodium cyanoborohydride (49 mg, 0.78 mmol) was added to a solution of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-((Z)-(methoxyimino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 212, 85 mg, 0.20 mmol) in acetic acid (3.9 mL) and stirred at room temperature for 18 h. More sodium cyanoborohydride (70 mg, 1.1 mmol) was added portionwise over 20 min and stirred at room temperature for 5 h. The mixture was concentrated followed by azeotropic removal of remaining acetic acid with toluene (20 mL). The mixture was filtered through silica gel (30:70 EtOAc/hexanes), and the residue was purified by chromatography on silica gel (15:85 EtOAc/hexanes) to give ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-((methoxyamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 213, 18 mg, 21%) as a colourless film.
- D. To a solution of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-((methoxyamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 213, 18 mg, 0.041 mmol) in MeOH (2.1 mL) was added potassium carbonate (23 mg, 0.17 mmol) and heated to 40° C. for 1.5 h. The mixture was concentrated, and the residue was purified by chromatography on silica gel (5:95 MeOH/CH2Cl2) to give (1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,4R,5S,7aS)-4-((methoxyamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexanol (Compound No. 214, 13 mg, 87%) as a colourless solid. 1H NMR (CD3OD): δ 4.62 (s, 2H), 3.69 (m, 1H), 3.48 (m, 4H), 3.02-3.20 (m, 3H), 2.49 (m, 1H), 2.12-2.28 (m, 2H), 1.14-1.92 (m, 18H), 0.79 (s, 3H). ES-MS m/z 352 ([M+1]+).
-
- A solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 96 mg, 0.30 mmol) in MeOH (3.0 mL) was cooled to 0° C. under argon and sodium acetate (73 mg, 0.89 mmol) was added followed by cyanogen bromide (41 mg, 0.39 mmol). The mixture was stirred at 0° C. for 20 min then at room temperature for 18 h. The mixture was concentrated, and the residue was purified by chromatography on silica gel (8:92 MeOH/CH2Cl2) to give N-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)cyanamide (Compound No. 215, 102 mg, 99%) as a colourless solid. 1H NMR (CD3OD): δ 4.65 (s, 2H), 3.70 (m, 1H), 3.48 (m, 2H), 3.22 (m, 1H), 3.13 (m, 1H), 2.51 (m, 1H), 2.14-2.35 (m, 2H), 1.21-1.86 (m, 15H), 1.09 (s, 3H), 0.82 (s, 3H). ES-MS m/z 345 ([M−1]−).
-
- Potassium carbonate (53 mg, 0.38 mmol) was added to a solution of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 210, 255 mg, 0.769 mmol) in DMSO (7.7 mL) and stirred at room temperature while hydrogen peroxide (0.67 mL of a 50% solution in water, 12 mmol) was added dropwise. The mixture was stirred at room temperature for 19.5 h then cooled to 0° C. and ice-H2O (10 mL) was added. The mixture was extracted with EtOAc (2×25 mL), and the combined organic layers were washed with brine (5×10 mL) then dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel (100:10:2 EtOAc/MeOH/NH4OH) to give 2-((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)acetamide (Compound No. 216, 183 mg, 68%) as a colourless solid. 1H NMR (CD3OD): δ 4.61 (s, 2H), 3.69 (m, 1H), 3.45 (m, 1H), 3.10 (m, 1H), 2.65 (m, 1H), 2.46 (m, 1H), 2.05-2.34 (m, 4H), 1.19-1.85 (m, 14H), 1.05 (s, 3H), 0.81 (s, 3H). ES-MS m/z 350 ([M+1]+).
-
- To a suspension of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 56 mg, 0.17 mmol) in THF (3.5 mL) under argon was added benzyl isocyanate (0.043 mL, 0.35 mmol), and the solution was stirred at room temperature for 22 h then concentrated. The residue was purified by chromatography on silica gel (8:92 MeOH/CH2Cl2) to give 1-benzyl-3-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)urea (Compound No. 217, 50 mg, 63%) as a colourless solid. 1H NMR (CD3OD): δ 7.27 (m, 5H), 6.40 (br s, 1H), 5.77 (br s, 1H), 4.63 (s, 2H), 4.30 (m, 2H), 3.69 (m, 1H), 3.31-3.46 (m, 3H), 3.12 (m, 1H), 2.49 (m, 1H), 2.13-2.25 (m, 2H), 1.20-1.86 (m, 15H), 1.02 (s, 3H), 0.82 (s, 3H). ES-MS m/z 455 ([M+1]+).
-
- To a suspension of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol (Compound No. 22, 59 mg, 0.18 mmol) in THF (3.7 mL) at 000° C. under argon was added phenyl isocyanate (0.040 mL, 0.37 mmol), and the solution was stirred at room temperature for 22 h then concentrated. The residue was purified by chromatography on silica gel (100:8:1 CH2Cl2/MeOH/NH4OH) to give 1-(((3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methyl)-3-phenylurea (Compound No. 218, 19 mg, 23%) as a colourless solid. 1H NMR (CD3OD): δ 8.24 (s, 1H), 7.33 (d, J=7.8 Hz, 2H), 7.23 (m, 2H), 6.95 (t, J=7.4 Hz, 1H), 5.97 (br s, 1H), 4.64 (s, 2H), 3.72 (m, 1H), 3.31-3.53 (m, 3H), 3.15 (m, 1H), 2.51 (m, 1H), 2.14-2.28 (m, 2H), 1.22-1.89 (m, 15H), 1.07 (s, 3H), 0.84 (s, 3H). ES-MS m/z 441 ([M+1]+).
-
- A mixture of (1S,3S,4R)-4-((3aS,4S,5S,7aS)-4-(2-aminoethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexane-1,3-diol (Compound No. 82, 40 mg, 0.12 mmol), TBTU (55 mg, 0.17 mmol), DIEA (49 μL, 0.27 mmol) and piperonylic acid (25 mg, 0.15 mmol) in DMF (3 mL) under argon at room temperature was stirred for 2 d. The mixture was diluted with EtOAc (30 mL), washed successively with water (5×3 mL) and brine (2×3 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (EtOAc) to afford N-(2-((3aS,4S,5S,7aS)-5-((1R,2S,4S)-2,4-dihydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)ethyl)benzo[d][1,3]dioxole-5-carboxamide (Compound No. 219, 41 mg, 73%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.38 (d, J=8.1, 1H), 7.29 (s, 1H), 6.86 (d, J=8.2, 1H), 6.02 (s, 2H), 4.62 (s, 2H), 3.81 (m, 1H), 3.51 (s, 1H), 3.42 (s, 2H), 2.81 (s, 1H), 2.49 (m, 1H), 2.29 (m, 1H), 2.12-1.23 (m, 18H), 1.20 (s, 3H), 0.80 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 169.4, 162.9, 151.8, 149.3, 129.8, 123.2, 108.8, 108.4, 103.1, 101.6, 72.2, 69.6, 53.9, 46.7, 44.8, 41.4, 40.3, 37.3, 37.0, 32.0, 31.4, 30.1, 29.1, 26.1, 24.7, 19.7, 18.6; MS m/z: 470.3 [M+H]+.
-
- A solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-2-(2-cyanoethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 220, 49 mg, 0.12 mmol) and NaOMe (0.22 mL of a 5.4 M solution in MeOH, 1.2 mmol) in MeOH (5 mL) was stirred at room temperature overnight then was quenched with AcOH (0.5 mL) and concentrated. The residue was purified using chromatography on silica gel (50% EtOAc/hexanes) to afford 42 mg of a white foam for which 1H NMR indicated only 1 of the acetates had been hydrolysed. A solution of the white foam (42 mg) and NaOMe (0.20 mL, 1.1 mmol) in MeOH at 60° C. under nitrogen was stirred for 6 days then was quenched with AcOH (1 mL) and concentrated. The residue was purified using chromatography on silica gel (50% then 80% EtOAc/hexanes) to afford 3-((1S,2S,5S)-5-hydroxy-2-((3aR,4R,5R,7aS)-4-hydroxy-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)propanenitrile (Compound No. 221, 36 mg, 92%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 4.62 (2H), 3.75 (m, 1H), 3.55 (m, 1H), 2.55 (m, 1H), 2.42 (m, 1H), 2.30 (2H), 1.95-1.20 (16H), 1.15 (s, 3H), 0.88 (m, 1H), 0.80 (s, 3H). MS m/z: 390 [M+AcO]+.
-
- A. A solution of (3aR,4R,5R,7aS)-4-(benzyloxy)-5-((1S,2S,4S)-2-(2-(benzyloxy)ethyl)-4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexyl)-7a-methyloctahydro-1H-inden-1-one (Compound No. 222, 3.00 g, 4.85 mmol) and Pd (52 mg of a 10% solution on carbon, 0.05 mmol) in MeOH (90 mL) under 35 psi hydrogen was agitated for 18 h. The solution was filtered through Celite, eluted with EtOAc and concentrated to afford (3aR,4R,5R,7aS)-4-hydroxy-5-((1S,2S,4S)-4-hydroxy-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a-methyloctahydro-1H-inden-1-one (Compound No. 223, 1.88 g, >100%) as a white foam.
- B. A solution of (3aR,4R,5R,7aS)-4-hydroxy-5-((1S,2S,4S)-4-hydroxy-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a-methyloctahydro-1H-inden-1-one (Compound No. 223, 1.6 g, 4.9 mmol), imidazole (0.74 g, 11 mmol) and TBSCl (0.82 g, 5.4 mmol) in DMF (25 mL) under nitrogen was stirred at 0° C. for 40 min then at room temperature for 4 h. The solution was poured into water (75 mL), extracted with Et2O (200 mL), washed with brine (40 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (50% then 70% EtOAc/hexanes) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-hydroxy-1-methylcyclohexyl)-4-hydroxy-7a-methyloctahydro-1H-inden-1-one (Compound No. 224, 1.33 g, 61%) as a white foam.
- C. A solution of methyl triphenylphosphonium bromide (7.33 g, 20.5 mmol) and KOtBu (2.33 g, 20.2 mmol) in THF (20 mL) was stirred at room temperature under nitrogen for 2 h then added (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-hydroxy-1-methylcyclohexyl)-4-hydroxy-7a-methyloctahydro-1H-inden-1-one (Compound No. 224, 1.45 g, 3.31 mmol) in THF (10 mL). The reaction flask was fitted with a condenser and the solution was heated at reflux for 2 h. The solution was quenched with saturated NaHCO3 solution (10 mL), diluted with EtOAc (200 mL), washed with brine (3×30 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (50% EtOAc/hexanes with 1% CH2Cl2) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 225, 1.25 g, 87%) as a white solid.
- D. A solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-hydroxy-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-ol (Compound No. 225, 1.25 g, 2.87 mmol), acetic anhydride (1.10 mL, 11.5 mmol) and DMAP (35 mg, 0.29 mmol) in pyridine (15 mL) initially at 0° C. under nitrogen was stirred for 1 d. The solution was cooled in ice, quenched with saturated NaHCO3 solution (10 mL) for 15 min, diluted with EtOAc (200 mL), washed with brine (3×30 mL), dried (MgSO4) and concentrated to give (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 226).
- E. A solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 226, 1.49 g, 2.87 mmol) and TBAF (5.7 mL of a 1 M solution in THF, 5.7 mmol) in THF (14 mL) at 50° C. under nitrogen was stirred 1.5 h then was concentrated. The residue was purified using chromatography on silica gel (30% EtOAc/hexanes with 1% CH2Cl2) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 227, 1.137 g, 97%) as a white foam.
- F. A solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-2-(2-hydroxyethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 227, 200 mg, 0.492 mmol), DMAP (6 mg, 0.05 mmol) and TsCl (281 mg, 1.48 mmol) in pyridine (2.5 mL) was maintained at 0° C. under nitrogen for 3.5 h. The solution was quenched with saturated NaHCO3 solution (10 mL) for 25 min, diluted with EtOAc (100 mL), washed with brine (3×15 mL), dried (MgSO4) and concentrated to give (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-1-methyl-2-(2-(tosyloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 228).
- G. A solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-1-methyl-2-(2-(tosyloxy)ethyl)cyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 228, 276 mg, 0.492 mmol) and KCN (100 mg, 1.48 mmol) in DMSO (2.5 mL) under nitrogen was heated at 60° C. for 2 h then at 80° C. for 3.5 h. The room temperature solution was poured into water (20 mL), extracted with Et2O (75 mL), washed with brine (20 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (25% EtOAc/hexanes) to afford (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-2-(2-cyanoethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 220, 161 mg, 78%) as a white foam.
- H. A solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-2-(2-cyanoethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 220, 161 mg, 0.39 mmol) and H2O2(0.20 mL of a 50% solution in water, 3.9 mmol) in NH4OH (2 mL), MeOH (2 mL) and THF (1 mL) was stirred at room temperature for 1 d. The solution was concentrated to give (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-2-(3-amino-3-oxopropyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 229) as a white solid.
- I. A solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-2-(3-amino-3-oxopropyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 229, 168 mg, 0.39 mmol) and NaOMe (0.7 mL of a 5.4 M solution in MeOH, 3.9 mmol) in MeOH (10 mL) at 60° C. under nitrogen was stirred for 4 d. The solution was cooled in ice, quenched with acetic acid (1 mL) and concentrated. The residue was purified using chromatography on silica gel (5% MeOH/EtOAc) to afford 3-((1S,2S,5S)-5-hydroxy-2-((3aR,4R,5R,7aS)-4-hydroxy-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)propanamide (Compound No. 230, 58 mg, 43%) as a white solid. 1H NMR (CD3OD): δ 4.62 (2H), 3.62 (m, 1H), 3.42 (m, 1H), 2.52 (m, 1H), 2.28 (m, 2H), 2.09 (m, 1H), 1.2-2.0 (16H), 1.18 (s, 3H), 0.90 (m, 1H), 0.78 (s, 3H). ES-MS m/z 350 ([M+1]+).
-
- A. A solution of (4′R,7a'S)-5′-((1S,2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 231, 300 mg, 0.587 mmol), triphenylphosphine (339 mg, 1.29 mmol), diphenylphosphoryl azide (0.28 mL, 1.29 mmol) and DIAD (0.25 mL, 1.29 mmol) in THF (6 mL) initially at 0° C. under nitrogen was stirred 18 h. The solution was made basic with saturated NaHCO3 solution (3 mL), diluted with EtOAc (100 mL), washed with brine (3×15 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (10% then 20% then 40% EtOAc/hexanes) to afford (4′R,7a'S)-5′-((1S,2S,4S)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)-1-methyl cyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 232, 220 mg, 70%) as a white foam.
- B. A solution of (4′R,7a'S)-5′-((1S,2S,4S)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-yl acetate (Compound No. 232, 220 mg, 0.41 mmol) and LAH (0.62 mL of a 2 M solution in THF, 1.2 mmol) in THF (6 mL) at 60° C. under nitrogen was stirred 1 h. The solution was cooled in ice, diluted with Et2O (20 mL), quenched with Na2SO4.10H2O (0.4 g) for 2 h, filtered through Celite, eluted with EtOAc and concentrated to give (4′R,7a'S)-5′-((1S,2S,4S)-2-(aminomethyl)-4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-ol (Compound No. 233, 170 mg) as a white foam.
- C. A solution of (4′R,7a'S)-5′-((1S,2S,4S)-2-(aminomethyl)-4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexyl)-7a′-methyloctahydrospiro[[1,3]dioxolane-2,1′-inden]-4′-ol (Compound No. 233, 170 mg, 0.36 mmol), piperonylic acid (72 mg, 0.44 mmol) and DCC (90 mg, 0.44 mmol) in CH2Cl2 at room temperature under nitrogen was stirred for 18 h. More DCC (45 mg, 0.22 mmol) was added and the reaction was allowed to continue for 24 h. The solution was filtered through a plug of silica gel, eluted with EtOAc and concentrated. The residue was purified using chromatography on silica gel (20% then 50% EtOAc/hexanes) to afford 76 mg of a white solid. This material was taken up in acetic acid (16 mL) and water (4 mL) and stirred at room temperature for 4 d then was concentrated. The residue was 3 times taken up in toluene (20 mL) and concentrated. The resulting white solid was purified using chromatography on silica gel (80% then 100% EtOAc/hexanes) to afford N-(((1S,2S,5S)-5-hydroxy-2-((4R,7aS)-4-hydroxy-7a-methyl-1-oxooctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound No. 234, 40 mg, 24%) as a white solid.
- D. A solution of methyl triphenylphosphonium bromide (312 mg, 0.87 mmol) and KOtBu (100 mg, 0.87 mmol) in THF (3 mL) was stirred at room temperature under nitrogen for 1 h then added N-(((1S,2S,5S)-5-hydroxy-2-((4R,7aS)-4-hydroxy-7a-methyl-1-oxooctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound No. 234, 40 mg, 0.087 mmol) in THF (3 mL). After 25 h, the solution was quenched with saturated NaHCO3 solution (3 mL), diluted with EtOAc (100 mL), washed with brine (3×15 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (50% then 80% EtOAc/hexanes) to afford N-(((1S,2S,5S)-5-hydroxy-2-((3aR,4R,5R,7aS)-4-hydroxy-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound No. 235, 26 mg, 65%) as a white solid. 1H NMR (CDCl3): δ 7.30 (m, 1H), 6.82 (m, 1H), 6.05 (m, 1H), 6.02 (s, 2H), 4.65 (2H), 3.75 (m, 1H), 3.63 (m, 1H), 3.58 (m, 1H), 3.00 (m, 1H), 2.55 (m, 1H), 2.30 (m, 1H), 2.09 (m, 1H), 1.25-2.15 (13H), 1.22 (s, 3H), 1.15 (m, 1H), 0.80 (s, 3H). ES-MS m/z 456 ([M+1]+)
-
- A solution of (3aR,4R,5R,7aS)-5-((1S,2S,4S)-4-acetoxy-2-(2-cyanoethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl acetate (Compound No. 220, 100 mg, 0.24 mmol) and KOH (95 mg, 1.7 mmol) in EtOH (5 mL) was heated in an 80° C. oil bath. Water (1 mL and 4 mL) was added after 18 hours and 32 hours, respectively. After a total of 6 days the solution was cooled in ice then added AcOH (1 mL) and concentrated. The residue was taken up in water (40 mL), extracted with CH2Cl2 (5×15 mL), dried (MgSO4) and concentrated. The residue was purified using chromatography on silica gel (1%, then 2%, then 5% then 100% MeOH/EtOAc) to afford 3-((1R,2S,5S)-5-hydroxy-2-((3aR,4R,5R,7aS)-4-hydroxy-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)propanoic acid (Compound No. 236, 44 mg, 52%) as a white solid. 1H NMR (CD3OD): δ 4.62 (2H), 3.60 (m, 1H), 3.40 (m, 1H), 2.50 (m, 1H), 2.25 (2H), 2.03 (m, 1H), 1.90 (2H), 2.85-1.60 (5H), 1.55-1.20 (9H), 1.18 (s, 3H), 0.90 (1H), 0.78 (s, 3H). ES-MS m/z 349 ([M−1]−)
-
- A. A mixture of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 51, 305 mg, 0.75 mmol) and IBX (540 mg, 1.93 mmol) in MeCN (7.5 mL) under argon at 65° C. was stirred for 22 h. The resultant mixture was cooled to room temperature, filtered through Celite and concentrated. The residue was purified using chromatography on silica gel (3:7 EtOAc:hexanes) to afford impure ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-formyl-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 237, 85 mg) which was carried on with no further purification.
- B. A mixture of ((1S,2R,5S)-5-acetoxy-2-((3aS,4R,5S,7aS)-4-formyl-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate (Compound No. 237, 85 mg), NaH2PO4.H2O (174 mg, 1.26 mmol), NaClO2 (57 mg, 0.63 mmol), 2-methyl-2-butene (2 mL) in THF (2 mL), tBuOH (2 mL) and H2O (0.5 mL) at room temperature was stirred for 24 h. Additional NaH2PO4.H2O (87 mg, 0.63 mmol), NaClO2 (29 mg, 0.32 mmol) and 2-methyl-2-butene (1 mL) were added and the mixture was stirred for an additional 24 h. The mixture was diluted with EtOAc (30 mL), washed successively with water (3×10 mL) and brine (10 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (4:1 to 3:2 hexanes:EtOAc then MeOH) to afford impure (3aS,4R,5S,7aS)-5-((1R,2R,4S)-4-acetoxy-2-(acetoxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-indene-4-carboxylic acid (Compound No. 238, 50 mg) which was carried on with no further purification.
- C. A mixture of (3aS,4R,5S,7aS)-5-((1R,2R,4S)-4-acetoxy-2-(acetoxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-indene-4-carboxylic acid (Compound No. 238, 50 mg) and 2 M NaOH (1 mL, 1 mmol) in MeOH (3 mL) at room temperature was stirred for 19 h. The mixture was concentrated and reconstituted in water (10 mL) and AcOH (0.5 mL). This mixture was extracted successively with EtOAc (2×20 mL) and CH2Cl2 (20 mL), dried (Na2SO4) and concentrated. The residue was purified using chromatography on silica gel (9:1 CH2Cl2:MeOH then MeOH) to afford (3aS,4R,5S,7aS)-5-((1R,2R,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-methyleneoctahydro-1H-indene-4-carboxylic acid (Compound No. 239, 33 mg, 13% over 3 steps) as a white solid. 1H NMR (300 MHz, CD3OD) δ 4.64 (s, 2H), 3.76 (d, J=10.9, 1H), 3.44 (m, 1H), 3.11 (m, 1H), 2.44 (m, 1H), 2.29 (m, 3H), 2.02-1.07 (m, 14H), 0.99 (s, 3H), 0.79 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 186.1, 162.3, 102.0, 71.4, 62.7, 53.2, 48.3, 47.0, 44.1, 43.7, 38.8, 36.7, 35.0, 31.9, 31.4, 30.0, 26.2, 22.4, 19.7, 18.4; MS m/z: 335.1 [M−H]−.
- Test compounds are dissolved in 95% ethanol to form stock solutions. Before screening, the stock solutions are diluted with Phosphatase Assay Buffer (20 mM Tris-HCL, 10 mM MgCl2 pH 7.5, 0.02% Tween 20) to form working assay solutions that contain 10% ethanol. The assay is carried out on 96-well microtiter plates using a modified procedure of that reported by Ong et al., Blood 110, 1942-1949, 2007 and Yang et al., Org Lett 7, 1073-1076, 2005, both of which references are incorporated herein by reference in their entirety.
- Data were generated by one of two variant methods. Test compounds are screened by one of two approaches described as follows. In the first approach, each reaction contains 5 μL of His-hSHIP1 enzyme (5-20 ng), 10 μL of the substrate, 1,3,4,5-inositol tetrakisphosphate (IP4; 50 μM final), 5 μL of Phosphatase Assay Buffer, and 5 L of test compound at various concentrations in 10% ethanol (0-300 M final). Control blanks are also prepared by replacing His-hSHIP1 enzyme, IP4, or test compounds with Phosphatase Assay Buffer. After adding the reaction components in a 96-well microtiter plate on ice, the reaction is mixed by briefly shaking the plate vigorously. The reaction is then incubated at 37° C. for 15 min with gentle shaking followed by addition of 100 μL of Biomol Green Reagent (BIOMOL, Pa., USA) to terminate the reaction. The free phosphate released from IP4 by His-hSHIP1 binds to the Biomol Green Reagent, which turns the dye to green color. After incubating the mixture for 20 min at room temperature for color development, the absorbance is read with SpectraMax Plus 96-well plate reader (Molecular Devices, Sunnyvale, Calif., USA) at a wavelength of 650 nm.
- In the second approach, a master mix is prepared that contains 50 μL of His-hSHIP1 enzyme (0.4-1.6 ng/μL final), 25 μL of the substrate, IP4 (25 or 250 μM final), and 50 μL of test compound in 3.3% ethanol (100 μL final). Control blanks are also prepared by replacing His-hSHIP1 enzyme, IP4, or test compounds with Phosphate Assay Buffer. A reference compound that has been shown to activate SHIP1 is also included. Each reaction component is preincubated at 37° C. for 30 min before adding to a 96-well microtiter plate. The master mix is then incubated at 37° C. At time 0, 20, 25 and 30 min, 25 μL of the master mix is removed and transferred to a new 96-well microtiter plate, to which 100 μL of Biomol Green Reagent is added to stop the reaction. After incubating the mixture for 20 min at room temperature for color development, the absorbance is read with SpectraMax Plus 96-well plate reader at a wavelength of 650 nm. Phosphate released is plotted against time to calculate the initial velocities (i.e., slope of the graph) at each IP4 concentration. The initial velocities are baseline corrected and the ratio of initial velocities (IP425/IP4250) is calculated and used to rate the test compounds.
- According to the above assay(s), the representative compounds listed in Table 2 below were found to modulate His-hSHIP1 enzyme at concentrations ≦300 μM. The compound numbers in Table 2 correspond to the compound numbers in Table 1 above. Scoring of the compound is expressed as follows:
-
Approach 1 (% increase relative Approach 2 Scoring to background) (Initial velocity Ratio) +++ x ≧ 65 higher than reference or reference - 15% ++ 50 ≦ x < 65 reference - 16% to reference - 30% + 0 < x < 50 reference - 31% or lower − N/A inhibitor
Data generated by the first method is distinguished by an asterisk. -
TABLE 2 Cpd. No. Scoring 1 ++ 2 + 4 + 5 +++ 6 ++ 7 + 8 + 10 − 11 + 15 ++ 18 + 26 ++ 27 + 29 + 30 ++ 31 − 32 +++ 34 + 35 ++ 37 ++ 38 ++ 43 ++ 44 ++ 45 − 46 ++ 47 + 48 + 50 + 52 − 56 − 57 − 59 ++ 61 ++ 63 ++* 65 ++ 66 + 67 ++ 69 + 91 + 93 ++ - Phosphorylation of AKT has been shown to be modulated by SHIP1 (Helgason et al., J Exp Med 191, 781-794, 2000). Molt-4 (PTEN−/SHIP1+) cells are starved in serum free RPMI for overnight. In a 15 mL conical tube, 2-3 million serum starved cells (1 million cells per mL) are treated with various concentrations of test compound (0.1, 1, or 1 μM final in 0.1% DMSO) for 30 min at 37° C. followed by stimulation with 100 ng/mL of IGF-1 for 1 hour at 37° C. After stimulation, cells are washed once with ice-cold DPBS and lysed with Lysis Buffer (20 mM Tris-HCl, pH 7.5, 140 mM NaCl, 1% NP-40, Complete Mini Protease Inhibitor Cocktail, 10 mM NaF, 1 mM Na3VO4, 1 mM β-glycerolphosphate) on ice for 30 min with vortexing every 10 min. Samples are then centrifuged at 13,000 rpm for 20 min, and supernatants are collected as total cell lysate samples. Protein concentration is determined using bicinchonic acid assay, and about 15 μg of total protein from each sample is loaded and separated on a 4-12% Tris-Glycine gel. After SDS-PAGE, proteins are transferred from the gel to a nitrocellulose membrane. The membrane is blocked in 5% BSA in PBS containing 0.1% Tween-20 (PBS-T) for 1 hour at room temperature before probing with primary antibodies for overnight at 4° C. The following antibodies are used: mouse anti-SHIP1 (1:500 dilution; Santa Cruz, Calif., USA), rabbit anti-phospho-Akt (Ser473) (1:1000 dilution; Cell Signaling Technologies, MA, USA), rabbit anti-Akt (1:1000; Cell Signaling Technologies, MA, USA), and rabbit anti-actin (1:2000; Cell Signaling Technologies, MA, USA). The membrane is then incubated with goat anti-rabbit or anti-mouse secondary antibodies (1:3000) for 1 hour at room temperature. Target proteins on the membrane are detected with ECL solution and exposed on a film.
- According to the above assay, the representative compounds listed in Table 3 below were found to inhibit Akt phosphorylation at ≦30 μM in Molt-4 (SHIP1+). The compound numbers in Table 3 correspond to the compound numbers in Table 1. Scoring in Table 3 is expressed as follows: +(inhibits Akt phosphorylation at 30 μM); −(no effect on Akt phosphorylation at 30 μM).
-
TABLE 3 Cpd. No. Molt-4 (SHIP+) 1 + 3 + 11 + 18 + 20 + 21 + 22 + 23 + 24 + 25 + 27 − 29 + 32 + 34 + 46 + 48 + 50 + 57 + 81 + 82 + 83 + 84 + 85 + 86 + 87 + 88 + 89 + 90 + 94 + 95 + 97 + 98 + - The activity of representative compounds on passive cutaneous anaphylaxis in mice may be evaluated according to the procedures disclosed by Ovary, J Immunol 81, 355-357, 1958 and Halpern et al., Br J Pharmacol Chemother 20, 389-398, 1963, both of which are incorporated herein by reference in their entirety.
- To induce a passive cutaneous anaphylaxis, mice undergo intradermal ear inoculation on their right ear with 25 ng in 20 μL of anti-DNP-IgE. The left ears are untreated and serve as negative controls. Twenty-four hours after inoculation, all mice are administered test compound by oral gavage (PO). Sixty minutes after oral administration, mice are given a tail vein injection of 2% Evan's Blue (0.2 μm filtered, in 200 μL saline) followed by a second tail IV injection of 100 μg DNP-HSA (in 200 μL). Sixty minutes following the DNP-HAS injection, mice are euthanized using CO2 inhalation. Subsequently, ear biopsies are performed by taking four millimeter punches from both ears, which will then undergo Evan's Blue extraction using formamide incubation in 96 well plates. Eighty μL of eluents are transferred to flat-bottom 96-well plates and absorbance read using SpectraMax M5 spectrophotometer (Molecular Devices, Sunnyvale, Calif., USA) at 620 nm. Background readings from all samples are taken at 740 nm and subtracted from the 620 nm readings. Data are reported as OD.
- The activity of representative compounds on carrageenan paw edema in mice may be evaluated according to the procedures disclosed by Winter et al., Proc Soc Exp Biol Med 111, 544-547, 1962 which is incorporated herein by reference in its entirety. To induce edema in the paw, test compounds are administered orally one hour before intraplantar injection of the right hind paw with carrageenan (50 μL of 1% suspension). Hind paw edema, as a measure of inflammation, is recorded using a plethysmometer (Ugo Basile, Italy) 4 hours after λ-carrageenan administration.
- All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification, including U.S. Provisional Patent Application 61/785,860, filed Mar. 14, 2013, are incorporated herein by reference in their entireties.
- Although the foregoing invention has been described in some detail to facilitate understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims. Accordingly, the described embodiments are to be considered as illustrative and not restrictive, and the invention is not to be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims.
Claims (27)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/772,737 US10100056B2 (en) | 2013-03-14 | 2014-02-27 | SHIP1 modulators and methods related thereto |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361785860P | 2013-03-14 | 2013-03-14 | |
PCT/US2014/019125 WO2014143561A1 (en) | 2013-03-14 | 2014-02-27 | Ship1 modulators and methods related thereto |
US14/772,737 US10100056B2 (en) | 2013-03-14 | 2014-02-27 | SHIP1 modulators and methods related thereto |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2014/019125 A-371-Of-International WO2014143561A1 (en) | 2013-03-14 | 2014-02-27 | Ship1 modulators and methods related thereto |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/129,586 Division US20190023709A1 (en) | 2013-03-14 | 2018-09-12 | Ship1 modulators and methods related thereto |
Publications (3)
Publication Number | Publication Date |
---|---|
US20160083387A1 US20160083387A1 (en) | 2016-03-24 |
US20170253596A2 true US20170253596A2 (en) | 2017-09-07 |
US10100056B2 US10100056B2 (en) | 2018-10-16 |
Family
ID=50288306
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/772,737 Active US10100056B2 (en) | 2013-03-14 | 2014-02-27 | SHIP1 modulators and methods related thereto |
US16/129,586 Abandoned US20190023709A1 (en) | 2013-03-14 | 2018-09-12 | Ship1 modulators and methods related thereto |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/129,586 Abandoned US20190023709A1 (en) | 2013-03-14 | 2018-09-12 | Ship1 modulators and methods related thereto |
Country Status (13)
Country | Link |
---|---|
US (2) | US10100056B2 (en) |
EP (1) | EP2970100A1 (en) |
JP (1) | JP6407950B2 (en) |
KR (1) | KR20150130426A (en) |
CN (1) | CN105209429B (en) |
AU (1) | AU2014228574B2 (en) |
BR (1) | BR112015022577A2 (en) |
CA (1) | CA2902764A1 (en) |
HK (2) | HK1218747A1 (en) |
IL (1) | IL241168A0 (en) |
MX (1) | MX2015011280A (en) |
RU (1) | RU2015143675A (en) |
WO (1) | WO2014143561A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10272081B2 (en) | 2013-01-09 | 2019-04-30 | Aquinox Pharmaceuticals (Canada) Inc. | SHIP1 modulators and methods related thereto |
WO2019195692A1 (en) | 2018-04-06 | 2019-10-10 | Aquinox Pharmaceuticals (Canada) Inc. | Hexadecahydro-1h-cyclopenta[a]phenanthrene derivatives useful in treating pain and inflammation |
WO2019195751A1 (en) | 2018-04-06 | 2019-10-10 | Aquinox Pharmaceuticals (Canada) Inc. | Indene derivatives useful in treating pain and inflammation |
WO2019195777A1 (en) | 2018-04-06 | 2019-10-10 | Aquinox Pharmaceuticals (Canada) Inc. | Indene derivatives useful in treating pain and inflammation |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6407951B2 (en) | 2013-03-14 | 2018-10-17 | アクイノックス ファーマシューティカルズ (カナダ) インコーポレイテッド | SHIP 1 Modulators and Related Compositions and Methods-Patent application |
WO2014143561A1 (en) | 2013-03-14 | 2014-09-18 | Aquinox Pharmaceuticals Inc. | Ship1 modulators and methods related thereto |
JP2018518494A (en) | 2015-06-26 | 2018-07-12 | アクイノックス ファーマシューティカルズ (カナダ) インコーポレイテッド | (1S, 3S, 4R) -4-((3aS, 4R, 5S, 7aS) -4- (aminomethyl) -7a-methyl-1-methyleneoctahydro-1H-inden-5-yl) -3- ( Crystalline solid form of acetate of hydroxymethyl) -4-methylcyclohexanol |
US10053415B2 (en) | 2016-01-20 | 2018-08-21 | Aquinox Pharmaceuticals (Canada) Inc. | Synthesis of a substituted indene derivative |
JP2019508424A (en) | 2016-03-02 | 2019-03-28 | パセオン オーストリア ゲーエムベーハー ウント ツェーオー カーゲー | Processes and intermediates for the production of 17 (20) -ene B-secosteroids |
WO2018126040A1 (en) | 2016-12-28 | 2018-07-05 | Aquinox Pharmaceuticals (Canada) Inc. | Crystalline solid forms of (1s,3s,4r)-4-((3as,4r,5s,7as)-4- (aminomethyl)-7a-methyl-1-methyleneoctahydro-1h-inden-5-yl)-3- (hydroxymethyl)-4-methylcyclohexanol |
CN111056962B (en) * | 2019-11-28 | 2022-08-05 | 重庆爱旭龙科技有限公司 | Preparation method of norspeltol and acetate thereof |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1084718B (en) | 1958-07-08 | 1960-07-07 | Bayer Ag | Process for the manufacture of secosteroids |
SE345995B (en) | 1969-01-31 | 1972-06-19 | Bristol Myers Co | |
US3682983A (en) | 1969-11-12 | 1972-08-08 | Klaus Prezewowsky | Preparation of {66 {11 {11 -17 ethinyl steroids |
US3869467A (en) | 1972-06-05 | 1975-03-04 | Hoffmann La Roche | 17-{62 -Hydroxy-17-{60 -methyl-5-{60 -androstano{9 3,2-c{9 or{8 2,3-d{9 isoxazoles |
US3962275A (en) | 1972-06-05 | 1976-06-08 | Hoffmann-La Roche Inc. | 7-oxa steroids |
JPH01290624A (en) | 1988-05-16 | 1989-11-22 | Shiono Chem Kk | Blood serum hypolipemic agent of 5,6-seco-sterol derivative |
AU3417493A (en) | 1991-12-20 | 1993-07-28 | Glaxo Inc. | Inhibitors of 5-alpha-testosterone reductase |
JPH05221924A (en) | 1992-02-17 | 1993-08-31 | Shiono Chem Kk | Secosterol compound |
JPH05221901A (en) | 1992-02-17 | 1993-08-31 | Shiono Chem Kk | Secosterol derivative |
US5464866A (en) | 1992-08-17 | 1995-11-07 | Alcon Laboratories, Inc. | Substituted hydrindanes for the treatment of angiogenesis-dependent diseases |
AP459A (en) | 1992-12-18 | 1996-02-14 | Glaxo Wellcome Inc | Substituted 6-azaandrostenones. |
CN1103755C (en) | 1993-07-09 | 2003-03-26 | 桑拉米克斯实验公司 | Novel structural analogues of vitamin D |
US5541322A (en) | 1994-10-14 | 1996-07-30 | Glaxo Wellcome Inc. | Synthesis of 6-azaandrostenones |
US6046185A (en) | 1996-07-11 | 2000-04-04 | Inflazyme Pharmaceuticals Ltd. | 6,7-oxygenated steroids and uses related thereto |
EP1118654A4 (en) | 1999-04-16 | 2007-03-07 | Nippon Mitsubishi Oil Corp | Fluids for traction drive |
MXPA02010645A (en) | 2000-04-28 | 2004-04-20 | Inflazyme Pharm Ltd | 3 nitrogen 6,7 dioxygen steroids and uses related thereto. |
WO2002094849A2 (en) | 2001-05-22 | 2002-11-28 | Inflazyme Pharmaceuticals Ltd. | Process for the production of 6, 7 - dihydroxy steroid compounds by allylic oxidation of steroid - 5 - ene compounds to steroid - 5 - ene - 7 - one compounds followed by hydroboration and oxidation and intermediates of this process |
CA2463136A1 (en) | 2001-10-17 | 2003-04-24 | Raymond Andersen | Ship 1 modulators |
ES2327829T3 (en) | 2002-10-17 | 2009-11-04 | The University Of British Columbia | SHIP MODULATORS 1. |
DE602004031410D1 (en) | 2003-04-15 | 2011-03-31 | Aquinox Pharmaceuticals Inc | INDIVIDUAL DERIVATIVES AS PHARMACEUTICALS |
JP2009541225A (en) | 2006-06-21 | 2009-11-26 | ザ・ユニバーシティ・オブ・ブリティッシュ・コロンビア | SHIP1 modulator prodrug |
CA2781661A1 (en) | 2009-12-04 | 2011-06-09 | Aquinox Pharmaceuticals Inc. | Ship1 modulators and methods related thereto |
JP6407951B2 (en) | 2013-03-14 | 2018-10-17 | アクイノックス ファーマシューティカルズ (カナダ) インコーポレイテッド | SHIP 1 Modulators and Related Compositions and Methods-Patent application |
WO2014143561A1 (en) | 2013-03-14 | 2014-09-18 | Aquinox Pharmaceuticals Inc. | Ship1 modulators and methods related thereto |
JP2018518494A (en) | 2015-06-26 | 2018-07-12 | アクイノックス ファーマシューティカルズ (カナダ) インコーポレイテッド | (1S, 3S, 4R) -4-((3aS, 4R, 5S, 7aS) -4- (aminomethyl) -7a-methyl-1-methyleneoctahydro-1H-inden-5-yl) -3- ( Crystalline solid form of acetate of hydroxymethyl) -4-methylcyclohexanol |
US10053415B2 (en) | 2016-01-20 | 2018-08-21 | Aquinox Pharmaceuticals (Canada) Inc. | Synthesis of a substituted indene derivative |
-
2014
- 2014-02-27 WO PCT/US2014/019125 patent/WO2014143561A1/en active Application Filing
- 2014-02-27 EP EP14710726.2A patent/EP2970100A1/en not_active Withdrawn
- 2014-02-27 JP JP2016500471A patent/JP6407950B2/en active Active
- 2014-02-27 US US14/772,737 patent/US10100056B2/en active Active
- 2014-02-27 AU AU2014228574A patent/AU2014228574B2/en not_active Ceased
- 2014-02-27 BR BR112015022577A patent/BR112015022577A2/en not_active IP Right Cessation
- 2014-02-27 RU RU2015143675A patent/RU2015143675A/en not_active Application Discontinuation
- 2014-02-27 KR KR1020157028155A patent/KR20150130426A/en not_active Application Discontinuation
- 2014-02-27 CN CN201480026640.8A patent/CN105209429B/en not_active Expired - Fee Related
- 2014-02-27 MX MX2015011280A patent/MX2015011280A/en unknown
- 2014-02-27 CA CA2902764A patent/CA2902764A1/en not_active Abandoned
-
2015
- 2015-09-03 IL IL241168A patent/IL241168A0/en unknown
-
2016
- 2016-06-14 HK HK16106830.3A patent/HK1218747A1/en unknown
- 2016-07-12 HK HK16108135.1A patent/HK1220173A1/en unknown
-
2018
- 2018-09-12 US US16/129,586 patent/US20190023709A1/en not_active Abandoned
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10272081B2 (en) | 2013-01-09 | 2019-04-30 | Aquinox Pharmaceuticals (Canada) Inc. | SHIP1 modulators and methods related thereto |
WO2019195692A1 (en) | 2018-04-06 | 2019-10-10 | Aquinox Pharmaceuticals (Canada) Inc. | Hexadecahydro-1h-cyclopenta[a]phenanthrene derivatives useful in treating pain and inflammation |
WO2019195751A1 (en) | 2018-04-06 | 2019-10-10 | Aquinox Pharmaceuticals (Canada) Inc. | Indene derivatives useful in treating pain and inflammation |
WO2019195777A1 (en) | 2018-04-06 | 2019-10-10 | Aquinox Pharmaceuticals (Canada) Inc. | Indene derivatives useful in treating pain and inflammation |
EP4292655A2 (en) | 2018-04-06 | 2023-12-20 | Taro Pharmaceuticals Inc. | Hexadecahydro-1h-cyclopenta[a]phenanthrene derivatives useful in treating pain and inflammation |
Also Published As
Publication number | Publication date |
---|---|
IL241168A0 (en) | 2015-11-30 |
US10100056B2 (en) | 2018-10-16 |
MX2015011280A (en) | 2016-03-03 |
US20160083387A1 (en) | 2016-03-24 |
CN105209429B (en) | 2018-05-29 |
JP6407950B2 (en) | 2018-10-17 |
JP2016516028A (en) | 2016-06-02 |
US20190023709A1 (en) | 2019-01-24 |
EP2970100A1 (en) | 2016-01-20 |
CA2902764A1 (en) | 2014-09-18 |
KR20150130426A (en) | 2015-11-23 |
AU2014228574A1 (en) | 2015-09-17 |
BR112015022577A2 (en) | 2017-07-18 |
CN105209429A (en) | 2015-12-30 |
HK1218747A1 (en) | 2017-03-10 |
RU2015143675A (en) | 2017-04-27 |
WO2014143561A1 (en) | 2014-09-18 |
HK1220173A1 (en) | 2017-04-28 |
AU2014228574B2 (en) | 2018-07-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10100056B2 (en) | SHIP1 modulators and methods related thereto | |
US10174046B2 (en) | SHIP1 modulators and methods related thereto | |
US10272081B2 (en) | SHIP1 modulators and methods related thereto | |
CN102625808B (en) | Spirocyclic amide derivatives | |
CN107074833A (en) | With β2The Benzocyclodirivative of receptor agonism and M3 receptor antagonist activities and its in purposes pharmaceutically | |
CN107849035A (en) | A kind of phenyl heterocycles derivative and its purposes in medicine |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: AQUINOX PHARMACEUTICALS INC., CANADA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MACKENZIE, LLOYD F.;HARWIG, CURTIS;BOGUCKI, DAVID;AND OTHERS;REEL/FRAME:033873/0107 Effective date: 20140319 |
|
AS | Assignment |
Owner name: AQUINOX PHARMACEUTICALS (CANADA) INC., CANADA Free format text: CHANGE OF NAME;ASSIGNOR:AQUINOX PHARMACEUTICALS INC.;REEL/FRAME:033935/0206 Effective date: 20140521 |
|
AS | Assignment |
Owner name: AQUINOX PHARMACEUTICALS INC., CANADA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MACKENZIE, LLOYD F.;HARWIG, CURTIS;BOGUCKI, DAVID;AND OTHERS;REEL/FRAME:036581/0040 Effective date: 20140319 Owner name: AQUINOX PHARMACEUTICALS (CANADA) INC., CANADA Free format text: CHANGE OF NAME;ASSIGNOR:AQUINOX PHARMACEUTICALS INC.;REEL/FRAME:036619/0679 Effective date: 20140521 |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
FEPP | Fee payment procedure |
Free format text: ENTITY STATUS SET TO UNDISCOUNTED (ORIGINAL EVENT CODE: BIG.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
AS | Assignment |
Owner name: TARO PHARMACEUTICALS INC., CANADA Free format text: MERGER;ASSIGNORS:TARO PHARMACEUTICALS INC.;AQUINOX PHARMACEUTICALS (CANADA) INC.;REEL/FRAME:058371/0661 Effective date: 20200731 |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY Year of fee payment: 4 |