JP4805916B2 - 化合物、組成物、および方法 - Google Patents
化合物、組成物、および方法 Download PDFInfo
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- JP4805916B2 JP4805916B2 JP2007511593A JP2007511593A JP4805916B2 JP 4805916 B2 JP4805916 B2 JP 4805916B2 JP 2007511593 A JP2007511593 A JP 2007511593A JP 2007511593 A JP2007511593 A JP 2007511593A JP 4805916 B2 JP4805916 B2 JP 4805916B2
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- JP
- Japan
- Prior art keywords
- mmol
- solution
- alkyl
- phenyl
- optionally substituted
- 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.)
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- 150000001875 compounds Chemical class 0.000 title claims description 255
- 239000000203 mixture Substances 0.000 title description 160
- 238000000034 method Methods 0.000 title description 49
- -1 8- (1-hydroxy-ethyl) -imidazo [1,2-a] pyridin-2-yl Chemical group 0.000 claims description 192
- 150000003839 salts Chemical class 0.000 claims description 49
- BTHLVVULQLRTBK-UHFFFAOYSA-N 2-propan-2-yloxybenzamide Chemical compound CC(C)OC1=CC=CC=C1C(N)=O BTHLVVULQLRTBK-UHFFFAOYSA-N 0.000 claims 1
- WHMXDBPHBVLYRC-UHFFFAOYSA-N 3-chloro-N-[1-[[2-(dimethylamino)-1-oxoethyl]amino]-3-[4-[8-(1-hydroxyethyl)-2-imidazo[1,2-a]pyridinyl]phenyl]propan-2-yl]-4-propan-2-yloxybenzamide Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C(=O)NC(CNC(=O)CN(C)C)CC1=CC=C(C=2N=C3C(C(C)O)=CC=CN3C=2)C=C1 WHMXDBPHBVLYRC-UHFFFAOYSA-N 0.000 claims 1
- KNPXSKDHWOISGC-UHFFFAOYSA-N 3-chloro-n-[1-[4-[1-ethyl-2-(2-hydroxypropan-2-yl)imidazol-4-yl]phenyl]-4-hydroxybutan-2-yl]-4-(1,1,1-trifluoropropan-2-yloxy)benzamide Chemical compound N1=C(C(C)(C)O)N(CC)C=C1C(C=C1)=CC=C1CC(CCO)NC(=O)C1=CC=C(OC(C)C(F)(F)F)C(Cl)=C1 KNPXSKDHWOISGC-UHFFFAOYSA-N 0.000 claims 1
- RPQCVJGKIRUYDA-UHFFFAOYSA-N 3-chloro-n-[1-[[2-(dimethylamino)acetyl]amino]-3-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]propan-2-yl]-4-propan-2-yloxybenzamide Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C(=O)NC(CNC(=O)CN(C)C)CC1=CC=C(C=2N=C3C(C)=CC=CN3C=2)C=C1 RPQCVJGKIRUYDA-UHFFFAOYSA-N 0.000 claims 1
- QPNFZTVDKLCKAN-UHFFFAOYSA-N 3-chloro-n-[4-hydroxy-1-[4-[2-(2-hydroxypropan-2-yl)-1-methylimidazol-4-yl]phenyl]butan-2-yl]-4-(1,1,1-trifluoropropan-2-yloxy)benzamide Chemical compound C1=C(Cl)C(OC(C)C(F)(F)F)=CC=C1C(=O)NC(CCO)CC1=CC=C(C=2N=C(N(C)C=2)C(C)(C)O)C=C1 QPNFZTVDKLCKAN-UHFFFAOYSA-N 0.000 claims 1
- LYTDVIWQYRFTRA-UHFFFAOYSA-N n-[1-[(2-amino-2-methylpropanoyl)amino]-3-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]propan-2-yl]-3-chloro-4-propan-2-yloxybenzamide Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C(=O)NC(CNC(=O)C(C)(C)N)CC1=CC=C(C=2N=C3C(C)=CC=CN3C=2)C=C1 LYTDVIWQYRFTRA-UHFFFAOYSA-N 0.000 claims 1
- MYRHWJOHCWMERK-UHFFFAOYSA-N n-[1-[4-[2-(1-acetamidoethyl)-1-ethylimidazol-4-yl]phenyl]-4-hydroxybutan-2-yl]-3-chloro-4-(1,1,1-trifluoropropan-2-yloxy)benzamide Chemical compound N1=C(C(C)NC(C)=O)N(CC)C=C1C(C=C1)=CC=C1CC(CCO)NC(=O)C1=CC=C(OC(C)C(F)(F)F)C(Cl)=C1 MYRHWJOHCWMERK-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 425
- 239000000243 solution Substances 0.000 description 330
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 228
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 187
- 230000002829 reductive effect Effects 0.000 description 179
- 235000019439 ethyl acetate Nutrition 0.000 description 178
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 177
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 177
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 164
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 158
- 239000011541 reaction mixture Substances 0.000 description 142
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 140
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 126
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 113
- 238000006243 chemical reaction Methods 0.000 description 111
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 102
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 79
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 73
- 239000000741 silica gel Substances 0.000 description 70
- 229910002027 silica gel Inorganic materials 0.000 description 70
- 239000012044 organic layer Substances 0.000 description 69
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 68
- 238000004007 reversed phase HPLC Methods 0.000 description 67
- 125000000217 alkyl group Chemical group 0.000 description 65
- 102000010638 Kinesin Human genes 0.000 description 63
- 108010063296 Kinesin Proteins 0.000 description 63
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
- 239000002904 solvent Substances 0.000 description 61
- 238000003818 flash chromatography Methods 0.000 description 59
- 230000000394 mitotic effect Effects 0.000 description 56
- 239000012267 brine Substances 0.000 description 55
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 55
- 125000001072 heteroaryl group Chemical group 0.000 description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 52
- 230000000694 effects Effects 0.000 description 49
- 239000007787 solid Substances 0.000 description 45
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 43
- 239000001257 hydrogen Substances 0.000 description 43
- 229910052739 hydrogen Inorganic materials 0.000 description 43
- 125000003118 aryl group Chemical group 0.000 description 42
- 239000000706 filtrate Substances 0.000 description 41
- 239000010410 layer Substances 0.000 description 38
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 38
- 210000004027 cell Anatomy 0.000 description 37
- 238000003756 stirring Methods 0.000 description 37
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 36
- 229910052938 sodium sulfate Inorganic materials 0.000 description 36
- 235000011152 sodium sulphate Nutrition 0.000 description 36
- 239000000047 product Substances 0.000 description 34
- 238000000746 purification Methods 0.000 description 33
- 102100025832 Centromere-associated protein E Human genes 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- 239000000651 prodrug Substances 0.000 description 31
- 229940002612 prodrug Drugs 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000003795 chemical substances by application Substances 0.000 description 30
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 29
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 29
- 239000000543 intermediate Substances 0.000 description 29
- 150000001412 amines Chemical class 0.000 description 28
- 230000027455 binding Effects 0.000 description 28
- 108010031379 centromere protein E Proteins 0.000 description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 28
- 229920006395 saturated elastomer Polymers 0.000 description 28
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 28
- 125000005843 halogen group Chemical group 0.000 description 27
- 239000012453 solvate Substances 0.000 description 27
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 26
- 206010028980 Neoplasm Diseases 0.000 description 26
- 125000000623 heterocyclic group Chemical group 0.000 description 26
- 239000003814 drug Substances 0.000 description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 25
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 125000000547 substituted alkyl group Chemical group 0.000 description 24
- 238000011282 treatment Methods 0.000 description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 23
- 125000004093 cyano group Chemical group *C#N 0.000 description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 23
- 125000003107 substituted aryl group Chemical group 0.000 description 23
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 22
- 201000010099 disease Diseases 0.000 description 22
- 102000029749 Microtubule Human genes 0.000 description 21
- 108091022875 Microtubule Proteins 0.000 description 21
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 21
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 21
- 210000004688 microtubule Anatomy 0.000 description 21
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- 125000001424 substituent group Chemical group 0.000 description 20
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 19
- 239000012299 nitrogen atmosphere Substances 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
- 235000018102 proteins Nutrition 0.000 description 18
- 102000004169 proteins and genes Human genes 0.000 description 18
- 125000005415 substituted alkoxy group Chemical group 0.000 description 18
- 238000003556 assay Methods 0.000 description 17
- 201000011510 cancer Diseases 0.000 description 17
- 229940079593 drug Drugs 0.000 description 17
- 108090000623 proteins and genes Proteins 0.000 description 17
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 17
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 16
- 125000004429 atom Chemical group 0.000 description 16
- 150000002431 hydrogen Chemical class 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 125000005842 heteroatom Chemical group 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 150000001408 amides Chemical class 0.000 description 14
- 239000000546 pharmaceutical excipient Substances 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- 229960000583 acetic acid Drugs 0.000 description 13
- 125000000753 cycloalkyl group Chemical group 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- 229940124531 pharmaceutical excipient Drugs 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 12
- 125000003545 alkoxy group Chemical group 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 239000012442 inert solvent Substances 0.000 description 12
- 125000002252 acyl group Chemical group 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 230000002062 proliferating effect Effects 0.000 description 11
- 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 10
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 10
- 125000002837 carbocyclic group Chemical group 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 230000011278 mitosis Effects 0.000 description 10
- 229910052760 oxygen Inorganic materials 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 208000009956 adenocarcinoma Diseases 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 229940000406 drug candidate Drugs 0.000 description 9
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 8
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 7
- 206010025323 Lymphomas Diseases 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 206010039491 Sarcoma Diseases 0.000 description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 7
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 125000004104 aryloxy group Chemical group 0.000 description 7
- HGXJOXHYPGNVNK-UHFFFAOYSA-N butane;ethenoxyethane;tin Chemical compound CCCC[Sn](CCCC)(CCCC)C(=C)OCC HGXJOXHYPGNVNK-UHFFFAOYSA-N 0.000 description 7
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical compound BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 7
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- 238000000926 separation method Methods 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
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- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
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- 238000001802 infusion Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 239000003880 polar aprotic solvent Substances 0.000 description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 230000020347 spindle assembly Effects 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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Description
Xは−COまたは−SO2−であり;
R2は水素または置換されていてもよい低級アルキルであり;
Wは−CR4−、−CH2CR4−、またはNであり;
R3は−CO−R7、水素、置換されていてもよいアルキル、置換されていてもよいヘテロシクリル、シアノ、置換されていてもよいスルホニル、または置換されていてもよいアリールであり;
R4は水素または置換されていてもよいアルキルであり;
R5は水素、ヒドロキシル、置換されていてもよいアミノ、置換されていてもよいヘテロシクリル;または置換されていてもよい低級アルキルであり;
R6は水素、置換されていてもよいアルキル、置換されていてもよいアルコキシ、置換されていてもよいアリールオキシ、置換されていてもよいヘテロアリールオキシ、置換されていてもよいアルコキシカルボニル−、置換されていてもよいアミノカルボニル−、置換されていてもよいアリール、置換されていてもよいヘテロアリール、置換されていてもよいヘテロシクリル、または置換されていてもよいアラルキルであり;そして
R7は置換されていてもよい低級アルキル、置換されていてもよいアリール、ヒドロキシル、置換されていてもよいアミノ、置換されていてもよいアラルコキシ、または置換されていてもよいアルコキシである)ならびにその薬学的に許容される塩、溶媒和物、キレート、非共有結合錯体、プロドラッグ、および混合物から選択される少なくとも1つの化合物が提供される。
R11は置換されていてもよいヘテロシクリル、置換されていてもよい低級アルキル、ニトロ、シアノ、水素、スルホニル、またはハロであり;
R12は水素、ハロ、置換されていてもよいアルキル、置換されていてもよいアミノ、置換されていてもよいスルファニル、置換されていてもよいアルコキシ、置換されていてもよいアリールオキシ、置換されていてもよいヘテロシクリル、または置換されていてもよいヘテロアリールオキシであり;そして
R13は水素、アシル、置換されていてもよいアルキル−、置換されていてもよいアルコキシ、ハロ、ヒドロキシル、ニトロ、シアノ、置換されていてもよいアミノ、アルキルスルホニル−、アルキルスルホンアミド−、アルキルスルホニル−、カルボキシアルキル−、アミノカルボニル−、置換されていてもよいアリールまたは置換されていてもよいヘテロアリール−である)ならびにその薬学的に許容される塩、溶媒和物、キレート、非共有結合錯体、プロドラッグ、および混合物から選択される少なくとも1つの化合物もまた提供される。
本明細書において、1つの化学式に2以上の可変体が存在する場合、それぞれの存在に対する定義は、他の存在のそれぞれに対する定義とは独立したものである。
Ac=アセチル
Boc=t−ブチルオキシカルボニル
Bu=ブチル
c−=シクロ
CBZ=カルボベンゾキシ=ベンジルオキシカルボニル
DCM=ジクロロメタン=塩化メチレン=CH2Cl2
DCE=ジクロロエタン
DEAD=アゾジカルボン酸ジエチル
DIC=ジイソプロピルカルボジイミド
DIEA=N,N−ジイソプロピルエチルアミン
DMAP=4−N,N−ジメチルアミノピリジン
DMF=N,N−ジメチルホルムアミド
DMSO=ジメチルスルホキシド
Et=エチル
Fmoc=9−フルオレニルメトキシカルボニル
GC=ガスクロマトグラフィー
HATU=ヘキサフルオロリン酸O−(7−アザベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウム
HOAc=酢酸
HOBt=ヒドロキシベンゾトリアゾール
LAH=水素化アルミニウムリチウム
Me=メチル
mesyl=メタンスルホニル
NCS=N−クロロコハク酸イミド
Ph=フェニル
Py=ピリジン
rt=室温
sat’d=飽和
s−=二級
t−=三級
TES=トリエチルシリル
TFA=トリフルオロ酢酸
THF=テトラヒドロフラン
TMS=トリメチルシリル
tosyl=p−トルエンスルホニル
2つの文字または記号の間に存在しないダッシュ(”−”)は、置換基の結合個所を示すために用いられる。例えば、−CONH2は炭素原子を介して結合している。
a)疾患を予防すること、すなわち、疾患の臨床症状が発症しないようにすること;
b)疾患を抑制すること;
c)臨床症状の発症を遅延または抑止すること;および/または
d)疾患を緩和すること、すなわち、臨床症状を退縮させること;
を含む、患者の疾患のいずれの治療をも意味する。
Xは−COまたは−SO2−であり;
R2は水素または置換されていてもよい低級アルキルであり;
Wは−CR4−、−CH2CR4−、またはNであり;
R3は−CO−R7、水素、置換されていてもよいアルキル、置換されていてもよいヘテロシクリル、シアノ、置換されていてもよいスルホニル、または置換されていてもよいアリールであり;
R4は水素または置換されていてもよいアルキルであり;
R5は水素、ヒドロキシル、置換されていてもよいアミノ、置換されていてもよいヘテロシクリル;または置換されていてもよい低級アルキルであり;
R6は水素、置換されていてもよいアルキル、置換されていてもよいアルコキシ、置換されていてもよいアリールオキシ、置換されていてもよいヘテロアリールオキシ、置換されていてもよいアルコキシカルボニル−、置換されていてもよいアミノカルボニル−、置換されていてもよいアリール、置換されていてもよいヘテロアリール、置換されていてもよいヘテロシクリル、または置換されていてもよいアラルキルであり;そして
R7は置換されていてもよい低級アルキル、置換されていてもよいアリール、ヒドロキシル、置換されていてもよいアミノ、置換されていてもよいアラルコキシ、または置換されていてもよいアルコキシであり;ただしWがNであるとき、R5はヒドロキシルまたは置換されていてもよいアミノではなく、R6は置換されていてもよいアルコキシ、置換されていてもよいアラルコキシ、置換されていてもよいヘテロアラルコキシ、または置換されていてもよいアミノではない)ならびにその薬学的に許容される塩、溶媒和物、キレート、非共有結合錯体、プロドラッグ、および混合物から選択される少なくとも1つの化合物を提供する。
R11は置換されていてもよいヘテロシクリル、置換されていてもよい低級アルキル、ニトロ、シアノ、水素、スルホニル、またはハロであり;
R12は水素、ハロ、置換されていてもよいアルキル、置換されていてもよいアミノ、置換されていてもよいスルファニル、置換されていてもよいアルコキシ、置換されていてもよいアリールオキシ、置換されていてもよいヘテロシクリル、または置換されていてもよいヘテロアリールオキシであり;そして
R13は水素、アシル、置換されていてもよいアルキル−、置換されていてもよいアルコキシ、ハロ、ヒドロキシル、ニトロ、シアノ、置換されていてもよいアミノ、アルキルスルホニル−、アルキルスルホンアミド−、アルキルスルホニル−、カルボキシアルキル−、アミノカルボニル−、置換されていてもよいアリールまたは置換されていてもよいヘテロアリール−である)ならびにその薬学的に許容される塩、溶媒和物、キレート、非共有結合錯体、プロドラッグ、および混合物から選択される少なくとも1つの化合物もまた提供される。
(S)−N−(1−(4−(2−アセチル−1−エチル−1H−イミダゾール−4−イル)フェニル)−4−ヒドロキシブタン−2−イル)−3−クロロ−4−イソプロポキシベンズアミド
N−((S)−1−(4−(2−(1−アセトアミドエチル)−1−エチル−1H−イミダゾール−4−イル)フェニル)−4−ヒドロキシブタン−2−イル)−3−クロロ−4−イソプロポキシベンズアミド
3−クロロ−N−((S)−1−(4−(1−エチル−2−(2−ヒドロキシプロパン−2−イル)−1H−イミダゾール−4−イル)フェニル)−4−ヒドロキシブタン−2−イル)−4−(1,1,1−トリフルオロプロパン−2−イルオキシ)ベンズアミド
N−((S)−1−(4−(2−(1−アセトアミドエチル)−1−エチル−1H−イミダゾール−4−イル)フェニル)−4−ヒドロキシブタン−2−イル)−3−クロロ−4−(1,1,1−トリフルオロプロパン−2−イルオキシ)ベンズアミド
(S)−N−(1−(4−(2−アセチル−1−(2,2,2−トリフルオロエチル)−1H−イミダゾール−4−イル)フェニル)−4−ヒドロキシブタン−2−イル)−3−クロロ−4−イソプロポキシベンズアミド
3−クロロ−N−((S)−4−ヒドロキシ−1−(4−(8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル)フェニル)ブタン−2−イル)−4−イソプロポキシベンズアミド
(S)−3−クロロ−N−(1−(2−(ジメチルアミノ)アセトアミド)−3−(4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル)プロパン−2−イル)−4−イソプロポキシベンズアミド
3−クロロ−N−((S)−1−(2−(ジメチルアミノ)アセトアミド)−3−(4−(8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル)フェニル)プロパン−2−イル)−4−イソプロポキシベンズアミド
3−シアノ−N−((1S)−3−ヒドロキシ−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド;
3−クロロ−N−[(1S)−3−ヒドロキシ−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−2−[(N,N−ジメチルグリシル)アミノ]−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)エチル]−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−2−(D−アラニルアミノ)−1−{[4−(8−ブロモイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−2−[(2−メチルアラニル)アミノ]−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−2−[(N,N−ジメチルグリシル)アミノ]−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1R)−4−アミノ−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−4−オキソブチル)−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1R)−1−{[4−(2−アセチル−1−メチル−1H−イミダゾール−4−イル)フェニル]メチル}−4−アミノ−4−オキソブチル)−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−[(1S)−3−ヒドロキシ−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−3−ヒドロキシ−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−[(1S)−2−[(N,N−ジメチルグリシル)アミノ]−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)エチル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−((1S)−2−[(N,N−ジメチルグリシル)アミノ]−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド;
N−((1R)−1−{[4−(2−アセチル−1−メチル−1H−イミダゾール−4−イル)フェニル]メチル}−4−アミノ−4−オキソブチル)−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−[(1R)−4−アミノ−1−({4−[2−(1−ヒドロキシ−1−メチルエチル)−1−メチル−1H−イミダゾール−4−イル]フェニル}メチル)−4−オキソブチル]−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−[(1S)−2−(D−アラニルアミノ)−1−({4−[1−(2−アミノエチル)−2−(1,1−ジメチルエチル)−1H−イミダゾール−4−イル]フェニル}メチル)エチル]−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−2−{4−[1−(2−アミノエチル)−2−(1,1−ジメチルエチル)−1H−イミダゾール−4−イル]フェニル}−1−{[(2−メチルアラニル)アミノ]メチル}エチル)−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−[(1S)−2−(D−アラニルアミノ)−1−({4−[1−(2−アミノエチル)−2−(1,1−ジメチルエチル)−1H−イミダゾール−4−イル]フェニル}メチル)エチル]−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−2−{4−[1−(2−アミノエチル)−2−(1,1−ジメチルエチル)−1H−イミダゾール−4−イル]フェニル}−1−{[(ヒドロキシアセチル)アミノ]メチル}エチル)−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−2−{4−[1−(2−アミノエチル)−2−(1,1−ジメチルエチル)−1H−イミダゾール−4−イル]フェニル}−1−{[(2−メチルアラニル)アミノ]メチル}エチル)−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−2−{4−[1−(2−アミノエチル)−2−(1,1−ジメチルエチル)−1H−イミダゾール−4−イル]フェニル}−1−{[(N,N−ジメチルグリシル)アミノ]メチル}エチル)−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−2−{4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}−1−({[(2R)−2−ヒドロキシプロパノイル]アミノ}メチル)エチル]−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−2−[(アミノカルボニル)アミノ]−1−{[4−(8−ブロモイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−{(1S)−2−[4−(8−ブロモイミダゾ[1,2−a]ピリジン−2−イル)フェニル]−1−[(2−オキソテトラヒドロ−1(2H)−ピリミジニル)メチル]エチル}−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−{(1S)−2−[4−(8−ブロモイミダゾ[1,2−a]ピリジン−2−イル)フェニル]−1−[(2−オキソヘキサヒドロ−1H−1,3−ジアゼピン−1−イル)メチル]エチル}−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−2−[(アミノカルボニルチオイル)アミノ]−1−{[4−(8−ブロモイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
2−(4−{(2S)−2−[({3−シアノ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−3−[(1,2,3−チアジアゾール−4−イルカルボニル)アミノ]プロピル}フェニル)イミダゾ[1,2−a]ピリジン−8−カルボキサミド
N−((1S)−2−[(アミノスルホニル)アミノ]−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
(3S)−3−[({3−クロロ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−4−{4−[2−(1,1−ジメチルエチル)−1−メチル−1H−イミダゾール−4−イル]フェニル}ブタン酸
N−[(1S)−2−[(アミノスルホニル)アミノ]−1−({4−[2−(1,1−ジメチルエチル)−1−メチル−1H−イミダゾール−4−イル]フェニル}メチル)エチル]−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−1−{[4−(1H−ベンゾイミダゾール−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−3−ヒドロキシ−1−({4−[5−(トリフルオロメチル)−1H−ベンゾイミダゾール−2−イル]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−1−{[4−(5,6−ジメチル−1H−ベンゾイミダゾール−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−3−ヒドロキシ−1−({4−[5−(メチルオキシ)−1H−ベンゾイミダゾール−2−イル]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−1−{[4−(5−クロロ−1H−ベンゾイミダゾール−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−3−ヒドロキシ−1−{[4−(4−メチル−1H−ベンゾイミダゾール−2−イル)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−1−{[4−(6−クロロ−1H−イミダゾ[4,5−b]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
2−(4−{(2S)−2−[({3−クロロ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−4−ヒドロキシブチル}フェニル)−1H−ベンゾイミダゾール−5−カルボン酸エチル
2−(4−{(2S)−2−[({3−クロロ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−4−ヒドロキシブチル}フェニル)−1H−ベンゾイミダゾール−5−カルボン酸
N−((1S)−3−アミノ−1−{[4−(1H−ベンゾイミダゾール−2−イル)フェニル]メチル}プロピル)−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−((1S)−1−{[4−(8−シアノイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−1−{[4−(8−クロロイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−[(1S)−3−ヒドロキシ−1−({4−[8−(トリフルオロメチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−((1S)−3−ヒドロキシ−1−{[4−(8−ヒドロキシイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
2−(4−{(2S)−2−[({3−シアノ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−4−ヒドロキシブチル}フェニル)イミダゾ[1,2−a]ピリジン−7−カルボキサミド
2−(4−{(2S)−2−[({3−シアノ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−4−ヒドロキシブチル}フェニル)イミダゾ[1,2−a]ピリジン−7−カルボン酸エチル
3−シアノ−N−((1S)−3−ヒドロキシ−1−{[4−(8−ニトロイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−1−{[4−(8−アミノイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
2−(4−{(2S)−2−[({3−シアノ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−4−ヒドロキシブチル}フェニル)イミダゾ[1,2−a]ピリジン−8−カルボキサミド
3−シアノ−N−[(1S)−3−ヒドロキシ−1−({4−[8−(ヒドロキシメチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
N−[(1S)−1−({4−[8−(アミノメチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)−3−ヒドロキシプロピル]−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−1−{[4−(8−アセチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−[(1S)−3−ヒドロキシ−1−({4−[8−(1−ヒドロキシ−1−メチルエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−[(1S)−3−ヒドロキシ−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−((1S)−3−ヒドロキシ−1−{[4−(8−メチル−5,6,7,8−テトラヒドロイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−[(1S)−1−({4−[2−(1,1−ジメチルエチル)−1−(2−ヒドロキシエチル)−1H−イミダゾール−4−イル]フェニル}メチル)−3−ヒドロキシプロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
N−[(1S)−1−({4−[1−[2−(アセチルアミノ)エチル]−2−(1,1−ジメチルエチル)−1H−イミダゾール−4−イル]フェニル}メチル)−3−ヒドロキシプロピル]−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−{(1S)−3−ヒドロキシ−1−[(4−{8−[(1R)−1−ヒドロキシエチル]イミダゾ[1,2−a]ピリジン−2−イル}フェニル)メチル]プロピル}−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−{(1S)−3−ヒドロキシ−1−[(4−{8−[(1S)−1−ヒドロキシエチル]イミダゾ[1,2−a]ピリジン−2−イル}フェニル)メチル]プロピル}−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−3−ヒドロキシ−1−({4−[8−(1−ヒドロキシプロピル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−1−{[4−(8−ブロモイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−1−{[4−(8−クロロイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−3−ヒドロキシ−1−({4−[8−(1−ヒドロキシ−2−メチルプロピル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
N−[(1R)−4−アミノ−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)−4−オキソブチル]−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−[(1R)−4−アミノ−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)−4−オキソブチル]−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−1−{[4−(3−フルオロ−8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−((1S)−1−{[4−(3−フルオロ−8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−2−ヒドロキシ−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−4−[(1−メチルエチル)オキシ]−N−[(1S)−2−[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]−1−(4−モルホリニルメチル)エチル]ベンズアミド
3−クロロ−N−((1S)−2−(4−ヒドロキシ−1−ピペリジニル)−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−2−(3−ヒドロキシ−1−ピロリジニル)−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−2−[(2S)−2−(ヒドロキシメチル)−1−ピロリジニル]−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−2−[(2R)−2−(ヒドロキシメチル)−1−ピロリジニル]−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−4−[(1−メチルエチル)オキシ]−N−((1S)−2−[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]−1−{[(2,2,2−トリフルオロエチル)アミノ]メチル}エチル)ベンズアミド
3−クロロ−N−((1S)−2−[(2−ヒドロキシエチル)アミノ]−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−((1S)−1−{[4−(8−エチル−5−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
(3S)−3−[({3−クロロ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−4−{4−[(フェニルカルボニル)アミノ]フェニル}ブタン酸メチル
3−クロロ−N−[(1S)−3−ヒドロキシ−1−({4−[(フェニルカルボニル)アミノ]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−{(1S)−1−[(4−{[(4−クロロフェニル)カルボニル]アミノ}フェニル)メチル]−3−ヒドロキシプロピル}−4−[(1−メチルエチル)オキシ]ベンズアミド
(4−{(2S)−2−[({3−クロロ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−4−ヒドロキシブチル}フェニル)カルバミン酸フェニルメチル
3−クロロ−N−((1S)−3−ヒドロキシ−1−{[4−({[2−(メチルアミノ)フェニル]カルボニル}アミノ)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
N−(4−{(2S)−2−[({3−クロロ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−4−ヒドロキシブチル}フェニル)−4−ピリジンカルボキサミド
3−クロロ−N−[(1S)−1−({4−[(シクロヘキシルカルボニル)アミノ]フェニル}メチル)−3−ヒドロキシプロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−1−({4−[(3,3−ジメチルブタノイル)アミノ]フェニル}メチル)−3−ヒドロキシプロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−3−ヒドロキシ−1−({4−[(フェニルアセチル)アミノ]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−{(1S)−3−ヒドロキシ−1−[(4−{[(フェニルアミノ)カルボニル]アミノ}フェニル)メチル]プロピル}−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−((1S)−3−ヒドロキシ−1−{[4−(8−メチル−5−オキソ−5,6−ジヒドロイミダゾ[1,2−c]ピリミジン−2−イル)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−((1S)−3−ヒドロキシ−1−{[4−(1−メチル−3−オキソ−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−6−イル)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−((1S)−3−ヒドロキシ−1−{[4−(8−オキソ−7,8−ジヒドロイミダゾ[1,2−a]ピラジン−2−イル)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
2,3−ジクロロ−N−((1S)−3−ヒドロキシ−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−3−ヒドロキシ−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]−3−ニトロベンズアミド
3−クロロ−N−[(1S)−2−[(ヒドロキシアセチル)アミノ]−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)エチル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−2−{4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}−1−({[(2R)−2−ヒドロキシプロパノイル]アミノ}メチル)エチル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−2−{4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}−1−({[(2S)−2−ヒドロキシプロパノイル]アミノ}メチル)エチル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−2−[(N,N−ジメチルグリシル)アミノ]−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)エチル]−4−[(1−メチルエチル)オキシ]ベンズアミド
N−[(1S)−2−(D−アラニルアミノ)−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)エチル]−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−3−ヒドロキシ−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−2−{4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}−1−{[(2−メチルアラニル)アミノ]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
(3S)−3−[({3−クロロ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−4−{4−[(フェニルカルボニル)アミノ]フェニル}ブタン酸
3−クロロ−N−{(1S)−3−ヒドロキシ−1−[(4−イミダゾ[1,2−a]ピリジン−6−イルフェニル)メチル]プロピル}−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−1−({4−[2−(1,1−ジメチルエチル)イミダゾ[1,2−a]ピリジン−6−イル]フェニル}メチル)−3−ヒドロキシプロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−{(1S)−3−ヒドロキシ−1−[(4−イミダゾ[1,2−a]ピリジン−2−イルフェニル)メチル]プロピル}−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−{(1S)−3−ヒドロキシ−1−[(4−イミダゾ[1,2−a]ピリミジン−2−イルフェニル)メチル]プロピル}−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−3−ヒドロキシ−1−{[4−(5−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−3−ヒドロキシ−1−{[4−(7−メチルイミダゾ[1,2−a]ピリミジン−2−イル)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−{(1S)−3−ヒドロキシ−1−[(4−イミダゾ[2,1−b][1,3]チアゾール−6−イルフェニル)メチル]ブチル}−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−((1S)−3−ヒドロキシ−1−{[4−(3−メチルイミダゾ[2,1−b][1,3]チアゾール−6−イル)フェニル]メチル}ブチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−((1S)−1−{[4−(2,3−ジヒドロイミダゾ[2,1−b][1,3]チアゾール−6−イル)フェニル]メチル}−3−ヒドロキシブチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−((1S)−1−{[4−(1,1−ジオキシド−2,3−ジヒドロイミダゾ[2,1−b][1,3]チアゾール−6−イル)フェニル]メチル}−3−ヒドロキシブチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
N−[(1S)−1−({4−[1−(3−アミノプロピル)−2−(1,1−ジメチルエチル)−1H−イミダゾール−4−イル]フェニル}メチル)−3−ヒドロキシプロピル]−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−4−[(1−メチルエチル)オキシ]−N−[(1S)−2−[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]−1−(5−メチル−1,2,4−オキサジアゾール−3−イル)エチル]ベンズアミド
3−シアノ−N−[(1S)−1−({4−[8−(3,5−ジメチル−4−イソオキサゾリル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)−3−ヒドロキシプロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−((1S)−3−ヒドロキシ−1−{[4−(8−フェニルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−[(1S)−3−ヒドロキシ−1−({4−[8−(1H−ピラゾール−4−イル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−[(1S)−3−ヒドロキシ−1−({4−[8−(4−イソオキサゾリル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−1−{[4−(8−アセチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
(2E)−3−[2−(4−{(2S)−2−[({3−シアノ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−4−ヒドロキシブチル}フェニル)イミダゾ[1,2−a]ピリジン−8−イル]−2−プロペン酸エチル
(2E)−3−[2−(4−{(2S)−2−[({3−シアノ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−4−ヒドロキシブチル}フェニル)イミダゾ[1,2−a]ピリジン−8−イル]−2−プロペン酸
N−{(1S)−1−[(4−{8−[(1E)−3−アミノ−3−オキソ−1−プロペン−1−イル]イミダゾ[1,2−a]ピリジン−2−イル}フェニル)メチル]−3−ヒドロキシプロピル}−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−[(1S)−1−({4−[8−(3−アミノ−3−オキソプロピル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)−3−ヒドロキシプロピル]−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−1−{[4−(3−クロロ−8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−1−{[4−(3−クロロ−8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−[(1S)−1−({3−フルオロ−4−[2−(1−ヒドロキシ−1−メチルエチル)−1−メチル−1H−イミダゾール−4−イル]フェニル}メチル)−3−ヒドロキシプロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−2−ヒドロキシ−1−{[5−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)−2−ピリジニル]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−2−ヒドロキシ−1−{[5−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)−2−チエニル]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−1−({4−[2−(1,1−ジメチルエチル)−1−メチル−1H−イミダゾール−4−イル]−2−フルオロフェニル}メチル)−3−ヒドロキシプロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−1−({4−[2−(1,1−ジメチルエチル)−1−メチル−1H−イミダゾール−4−イル]−2,6−ジフルオロフェニル}メチル)−3−ヒドロキシプロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−1−({2−クロロ−4−[2−(1,1−ジメチルエチル)−1−メチル−1H−イミダゾール−4−イル]フェニル}メチル)−3−ヒドロキシプロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−1−({5−[2−(1,1−ジメチルエチル)−1−メチル−1H−イミダゾール−4−イル]−2−ピリジニル}メチル)−3−ヒドロキシプロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−1−{[2−クロロ−4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−1−{[2−クロロ−4−(8−クロロイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−1−{[2,5−ジフルオロ−4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−1−{[3−クロロ−4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−3−ヒドロキシプロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−1−({4−[2−(1,1−ジメチルエチル)−1−メチル−1H−イミダゾール−4−イル]フェニル}メチル)−3−(メチルアミノ)−3−オキソプロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−[(1S)−2−{4−[2−(1,1−ジメチルエチル)−1−メチル−1H−イミダゾール−4−イル]フェニル}−1−({[(フェニルアミノ)カルボニル]アミノ}メチル)エチル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−[(1S)−2−{4−[2−(1,1−ジメチルエチル)−1−メチル−1H−イミダゾール−4−イル]フェニル}−1−({[(エチルアミノ)カルボニル]アミノ}メチル)エチル]−4−[(1−メチルエチル)オキシ]ベンズアミド
N−[(1S)−2−(アミノスルホニル)−1−({4−[2−(1,1−ジメチルエチル)−1−メチル−1H−イミダゾール−4−イル]フェニル}メチル)エチル]−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−((1S)−2−{4−[2−(1,1−ジメチルエチル)−1−メチル−1H−イミダゾール−4−イル]フェニル}−1−{[(メチルスルホニル)アミノ]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−{(1S)−2−{4−[2−(1,1−ジメチルエチル)−1−メチル−1H−イミダゾール−4−イル]フェニル}−1−[({[(2−ヒドロキシエチル)アミノ]カルボニル}アミノ)メチル]エチル}−4−[(1−メチルエチル)オキシ]ベンズアミド
N−[(S)−1−[4−(2−tert−ブチル−1−メチル−1H−イミダゾール−4−イル)−ベンジル]−2−(2−メトキシ−エタノイルアミノ)−エチル]−3−シアノ−4−イソプロポキシ−ベンズアミド
(4R)−4−[({3−シアノ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−5−{4−[2−(1,1−ジメチルエチル)−1−メチル−1H−イミダゾール−4−イル]フェニル}ペンタン酸
3−シアノ−N−{(1S)−2−{4−[2−(1,1−ジメチルエチル)−1−メチル−1H−イミダゾール−4−イル]フェニル}−1−[(2−オキソ−1−イミダゾリジニル)メチル]エチル}−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−2−アミノ−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−2−(アセチルアミノ)−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((1S)−2−{[(2R)−2−ヒドロキシプロパノイル]アミノ}−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−[(1S)−2−[(N,N−ジメチルグリシル)アミノ]−1−({4−[2−(1−ヒドロキシ−1−メチルエチル)−1−メチル−1H−イミダゾール−4−イル]フェニル}メチル)エチル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−[(1S)−2−[(N,N−ジメチルグリシル)アミノ]−1−({4−[2−(1−ヒドロキシ−1−メチルエチル)−1−メチル−1H−イミダゾール−4−イル]フェニル}メチル)エチル]−4−[(1−メチルエチル)オキシ]ベンズアミド
3−クロロ−N−((S)−4−ヒドロキシ−1−(4−(1−メチル−2−((R)−1−(2−オキソピロリジン−1−イル)エチル)−1H−イミダゾール−4−イル)フェニル)ブタン−2−イル)−4−イソプロポキシベンズアミド
3−クロロ−N−((S)−4−ヒドロキシ−1−(4−(1−メチル−2−((R)−1−(2−オキソピロリジン−1−イル)エチル)−1H−イミダゾール−4−イル)フェニル)ブタン−2−イル)−4−(1,1,1−トリフルオロプロパン−2−イルオキシ)ベンズアミド
3−クロロ−N−((S)−4−ヒドロキシ−1−(4−(1−メチル−2−((R)−1−(2−オキソオキサゾリジン−3−イル)エチル)−1H−イミダゾール−4−イル)フェニル)ブタン−2−イル)−4−イソプロポキシベンズアミド
3−クロロ−N−((S)−4−ヒドロキシ−1−(4−(1−メチル−2−((R)−1−(2−オキソオキサゾリジン−3−イル)エチル)−1H−イミダゾール−4−イル)フェニル)ブタン−2−イル)−4−(1,1,1−トリフルオロプロパン−2−イルオキシ)ベンズアミド。
噴門:肉腫(血管肉腫、線維肉腫、横紋筋肉腫、脂肪肉腫)、粘液腫、横紋筋腫、線維腫、脂肪腫および奇形腫;
肺:気管支原性癌(扁平上皮細胞、未分化小細胞、未分化大細胞、腺癌)、胞巣状癌(気管支肺胞癌)、気管支腺腫、肉腫、リンパ腫、軟骨性過誤腫、中皮腫;
消化器:食道(扁平上皮細胞癌、腺癌、子宮平滑筋肉腫、リンパ腫)、胃(癌、リンパ腫、子宮平滑筋肉腫)、膵臓(管状腺癌、インスリノーマ、グルカゴノーマ、ガストリノーマ、カルチノイド腫瘍、VIP分泌腫瘍)、小腸(腺癌、リンパ腫、カルチノイド腫瘍、カポジ肉腫、平滑筋腫、血管腫、脂肪腫、神経線維腫、線維腫)、大腸(腺癌、管状腺腫、絨毛腺腫、過誤腫、平滑筋腫);
泌尿生殖路:腎臓(腺癌、ウイルムス腫瘍[腎芽細胞腫]、リンパ腫、白血病)、膀胱および尿道(扁平上皮細胞癌、移行上皮癌、腺癌)、前立腺(腺癌、肉腫)、睾丸(精上皮腫、奇形腫、胎児性癌、奇形癌、絨毛癌、肉腫、間質細胞癌、線維腫、線維腺腫、腺腫様腫瘍、脂肪腫);
肝臓:肝癌(肝細胞癌)、胆管癌、肝芽腫、血管肉腫、肝細胞腺腫、血管腫;
骨:骨肉腫(骨肉腫)、線維肉腫、悪性線維性組織球腫、軟骨肉腫、ユーイング肉腫、悪性リンパ腫(細網細胞肉腫)、多発性骨髄腫、悪性巨細胞性脊索腫、骨軟骨腫(骨軟骨性外骨腫)、良性軟骨腫、軟骨芽細胞腫、軟骨粘液線維腫、類骨骨腫および巨細胞腫;
神経系:頭蓋骨(骨腫、血管腫、肉芽腫、黄色腫、変形性骨炎)、髄膜(髄膜腫、髄膜肉腫、神経膠腫症)、脳(星状細胞腫、髄芽腫、神経膠腫、上衣腫、胚細胞腫[松果体腫]、多型膠芽腫、乏突起膠腫、神経鞘腫、網膜芽細胞腫、先天性腫瘍)、脊髄神経線維腫、髄膜腫、神経膠腫、肉腫);
婦人科:子宮(子宮内膜癌)、子宮頚(子宮頸癌、前癌頚管異形成)、卵巣(卵巣癌[漿液性嚢胞腺癌、粘液性膵嚢胞腺腫、分類不能癌]、顆粒膜細胞癌、Sertoli-Leydig細胞腫、未分化胚細胞腫、悪性奇形腫)、外陰(扁平上皮細胞癌、上皮内癌、腺癌、線維肉腫、メラノーマ)、膣(明細胞癌、扁平上皮細胞癌、ブドウ状肉腫(胎児性横紋筋肉腫]、卵管(癌);
血液:血液(骨髄性白血病[急性および慢性の]、急性リンパ性白血病、慢性リンパ性白血病、脊髄増殖性疾患、多発性骨髄腫、骨髄異形成症候群)、ホジキン病、非ホジキンリンパ腫[悪性リンパ腫];
皮膚:悪性メラノーマ、基底細胞癌、扁平上皮細胞癌、カポジ肉腫、モル異型性母斑、脂肪腫、血管腫、皮膚線維腫、ケロイド、乾癬;ならびに
副腎:神経芽細胞腫;を含む。本明細書において、癌の治療は、上記の疾患のいずれか1つにかかっている細胞を含む、癌細胞の治療を含む。従って、”癌細胞”という用語は、上記の疾患のいずれか1つにかかっている細胞を含む。
アルコール(例えば5%アルコール)(例えば、5%デキストロースおよび水(”D5/W”)、またはNSS中D5/W中を含む、デキストロースおよび水(”D/W”)または生理食塩水(”NSS”)中D/W中で);
Aminosyn、FreAmine、Travasolなどの合成アミノ酸(例えばそれぞれ3.5または7;8.5;3.5、5.5または8.5%);
塩化アンモニウム(例えば2.14%);
デキストラン40(NSS中例えば10%、またはD5/W中例えば10%);
デキストラン70(NSS中例えば6%、またはD5/W中例えば6%);
デキストロース(グルコース、D5/W)(例えば2.5〜50%);
デキストロースおよび塩化ナトリウム(例えば5〜20%デキストロースおよび0.22〜0.9%NaCl);
乳酸リンゲル液(ハルトマン)(例えば、NaCl 0.6%、KCl 0.03%、CaCl2 0.02%;
乳酸0.3%);
マンニトール(例えば5%、所望によりデキストロース、例えば、10%またはNaCl、例えば、15または20%と組み合わせて);
種々の組み合わせの電解質を有する多電解質液、デキストロース、フルクトース、転化糖リンゲル液(例えば、NaCl 0.86%、KCl 0.03%、CaCl2 0.033%);
炭酸水素ナトリウム(例えば5%);
塩化ナトリウム(例えば0.45、0.9、3、または5%);
乳酸ナトリウム(例えば1/6M);および
注射用滅菌水。
2(20g,93mmol)のDCM溶液に、0℃でペンタフルオロトリフルオロアセテート(20mL,112mmol)およびトリエチルアミン(17mL,112mmol)を加えた。反応混合物を1時間撹拌した。溶液を濃縮し、混合物をフラッシュカラムクロマトグラフィー(100%DCM)で精製して、白色固体で3(35g,定量的収率)を得た。
4(71mg,0.16mmol)のジオキサン(1mL)懸濁液に、ピペラジン(16mg,0.19mmol)、酢酸パラジウム(II)(4mg,0.016mmol)、ジシクロヘキシルホスフィノ−2’−(N,N’−ジメチルアミノ)−ビフェニル(6mg,0.016mmol)、および炭酸セシウム(104mg,0.32mmol)を加えた。得られた混合物を110℃で36時間撹拌した。反応混合物をEtOAcで希釈した。有機層を飽和NaHCO3(20mL)およびブラインで洗浄し、Na2SO4で乾燥し、濃縮した。残渣をアセトニトリルおよびH2Oの混合物を用いるRP−HPLCで精製して1a(6mg,8%)を得た。LRMS (M+H+) m/z 459.2.
実施例3
4(50mg,0.13mmol)のDMF(1mL)溶液に、(s)−(+)−3−ブロモ−2−メチル−1−プロパノール(0.083mL,0.8mmol)および炭酸カリウム(110mg,0.8mmol)を加えた。得られた混合物を50℃で15時間撹拌した。混合物を濾過し、アセトニトリルおよびH2Oの混合物を用いるRP−HPLCで濾液を精製して1b(30mg,51%)を得た。LRMS (M+H+) m/z 449.1.
実施例4
4(3.1g,8mmol)のDMF(25mL)溶液にグリシンアミド塩酸塩(1.1g,9.6mmol)、ジイソプロピルエチルアミン(7mL,40mmol)、およびHBTU(3.6g,9.6mmol)を加えた。反応混合物を15時間撹拌し、ついで溶液を酢酸エチルで希釈し、飽和NaHCO3で洗浄した。有機層を分離し、ブラインで洗浄し、Na2SO4で乾燥し、濃縮した。得られた粗製物を、アセトニトリルおよびH2Oの混合物をRP−HPLCで精製して5(38mg,35%)を得た。LRMS (M+H+) m/z 434.1.
5(100mg,0.23mmol)のDMF(1mL)溶液に臭化シクロプロピルメチル(0.18mL,1.84mmol)および炭酸カリウム(317mg,2.3mmol)を加えた。得られた混合物を80℃で10時間撹拌した。混合物を濾過し、アセトニトリルおよびH2Oの混合物を用いるRP−HPLCで濾液を精製して1c(36mg,34%)を得た。LRMS (M+H+) m/z 488.1.
実施例5
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実施例8
実施例9
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実施例11
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実施例13
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実施例15
粗製物3のDMF(6mL,〜2mmol)溶液にグリシンアミドHCl(330mg,3mmol)、HBTU(1.14g,3mmol)およびN,N−ジイソプロピルエチルアミン(522μL,3mmol)を加えた。反応物を終夜撹拌した。アセトニトリルおよびH2Oの混合物を用いるRP−HPLCで得られた粗生成物を精製して4(600mg,2から69%)を得た。LRMS (M+H+) m/z 433.1.
実施例16
粗製物5(75mg,〜0.2mmol)のDCM(2mL)溶液に塩化ベンゾイル(23μL,0.2mmol)およびN,N−ジイソプロピルエチルアミン(35μL,0.2mmol)を加えた。反応混合物を終夜撹拌した。溶液を濃縮し、アセトニトリルおよびH2Oの混合物を用いるRP−HPLCで精製して6(36mg,2から40%)を得た。LRMS (M+H+) m/z 494.1
実施例17
実施例18
実施例19
実施例20
2(6.9g,18mmol)のDMF(30mL)溶液に3(5.9g,21.8mmol)およびN,N−ジイソプロピルエチルアミン(9.5mL,54.3mmol)を加えた。反応物をLC/MSでモニターした。終了後、反応溶液に2Mメチルアミン/THF(13.6mL,27mmol)、HOBt(4g,27mmol)、およびHBTU(10g,27mmol)を加えた。反応物を4時間撹拌した。混合物を酢酸エチル(60mL)で希釈し、飽和NaHCO3(20mL)で洗浄した。有機層を分離し、水層を酢酸エチル(2x50mL)で抽出した。合わせた有機層をブラインで洗浄し、硫酸ナトリウムで乾燥し、濃縮した。酢酸エチルおよびヘキサンの混合物を溶離液としてとして用いるフラッシュカラムクロマトグラフィーで得られた粗生成物を精製して4(シス異性体808mg,1.68mmol,トランス異性体300mg,0.63mmol)を得た。LRMS (M+H+) m/z 481.1.
4(290mg,0.6mmol)のジクロロメタン(20mL)溶液にトリフルオロ酢酸(5mL)を加えた。得られた溶液を室温で1時間撹拌し、ついで減圧下で濃縮した。99%酢酸エチルおよび1%酢酸の混合物を溶離液として用いるフラッシュカラムクロマトグラフィーで残渣を精製して、5を白色固体(140mg,55%)で得た。LRMS (M+H+) m/z 425.1.
5(330mg,0.7mmol)のDMSO(5mL)溶液に塩化アンモニウム(83mg,1.5mmol)、ジイソプロピルエチルアミン(0.27mL,1.5mmol)、およびHBTU(580mg,1.5mmol)を加えた。得られた溶液を室温で15時間撹拌した。塩化アンモニウム(37mg,0.7mmol)、ジイソプロピルエチルアミン(0.12mL,0.7mmol)、およびHBTU(266mg,0.7mmol)をさらに加えた。撹拌をさらに5時間続け、混合物を酢酸エチル(50mL)で希釈し、飽和NaHCO3(20mL)で洗浄した。有機層を分離し、水層を酢酸エチル(2x50mL)で抽出した。合わせた有機層をブラインで洗浄し、硫酸ナトリウムで乾燥し、濃縮して微黄色粗製物を得た。アセトニトリルおよびH2Oの混合物を用いるRP−HPLCで残渣を精製して、6(128mg,30%)を得た。LRMS (M+H+) m/z 424.1.
6(94mg,0.2mmol)のDMF(2mL)溶液に0℃で塩化シアヌル(45mg,0.2mmol)を加え、反応混合物を窒素雰囲気下で撹拌した。1時間後、反応溶液を濃縮して7(79mg)を得、これをさらに精製せずに次の工程に用いた。LRMS (M+H+) m/z 406.1.
7(17mg,0.04mmol)のメタノール(2mL)溶液をHCl気流下15分間撹拌した。ついで反応混合物に窒素気流をバブリングした。1時間後、反応溶液を濃縮して8を得、これをさらに精製せずに次の工程に用いた。LRMS (M+H+) m/z 438.1.
粗製物8(17mg,〜0.04mmol)の酢酸(2mL)溶液にo−フェニレンジアミン(50mg,0.46mmol)を加え、得られた溶液を80℃で1時間撹拌した。反応混合物を濃縮し、溶離液として5%メタノール/ジクロロメタンを用いる分取薄層クロマトグラフィーで精製して白色固体を得た。アセトニトリルおよびH2Oの混合物を用いるRP−HPLCで固体を精製して9(9mg,45%)を得た。LRMS (M+H+) m/z 497.1.
実施例21
実施例22〜24
粗製物2(3.2g,11.2mmol)のDMF(20mL)溶液に3(3.8g,10mmol)およびN,N−ジイソプロピルエチルアミン(5.2mL,30mmol)を加えた。反応物をLC/MSでモニターした。終了後、反応溶液にメチルアミン(2M THF溶液,7.5mL,15mmol)、およびHBTU(5.7g,15mmol)を加えた。反応物を終夜撹拌した。混合物を酢酸エチル(60mL)で希釈し、飽和NaHCO3(20mL)で洗浄した。有機層を分離し、水層を酢酸エチル(2x50mL)で抽出した。合わせた有機層をブラインで洗浄し、硫酸ナトリウムで乾燥し、濃縮した。得られた粗製物をアセトニトリルおよびH2Oの混合物を用いるRP−HPLCで精製して4(1.0g,1から18%)を得た。LRMS (M+H+) m/z 496.1.
4(1.0g,2.0mmol)のジクロロメタン(25mL)溶液にトリフルオロ酢酸(8mL)を加えた。得られた溶液を室温で4時間撹拌し、ついで減圧下で濃縮した。アセトニトリルおよびH2Oの混合物を用いるRP−HPLCで残渣を精製して5(820mg,79%)を得た。LRMS (M+H+) m/z 396.1.
5(75mg,0.16mmol)のTHF(3mL)溶液に塩化4−フルオロベンゾイル(28μL,0.23mmol)およびN,N−ジイソプロピルエチルアミン(100μL,0.57mmol)を加えた。反応混合物を終夜撹拌した。得られた溶液を濃縮し、アセトニトリルおよびH2Oの混合物を用いるRP−HPLCで精製して6(65mg,78%)を得た。LRMS (M+H+) m/z 518.1.
実施例25
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実施例31
アルコール5(50mg,0.12mmol)、デス・マーチン・ペルヨージナン(90mg,0.21mmol)、およびCH2Cl2(3mL)の溶液を23℃で2時間撹拌した。反応混合物をEtOAc(20mL)で希釈し、飽和NaHCO3水溶液(10mL)およびブライン(20mL)で洗浄した。有機層を乾燥(MgSO4)し、濾過し、減圧下で濃縮した。得られた残渣を直接に用いた。
実施例32
エステル10(165mg,0.31mmol)、水酸化カリウム(35mg,0.62mmol)、H2O(1mL)、MeOH(1mL)、およびTHF(2mL)の溶液を50℃で2時間撹拌した。ついで反応混合物をEtOAc(20mL)で希釈し、1N HCl(5mL)およびブライン(10mL)で洗浄した。有機層を乾燥(MgSO4)し、濾過し、減圧下で濃縮し、得られた残渣を直接に用いた。
実施例33
アミジン17(50mg,0.12mmol)、イソブチリル酢酸メチル(17μL,0.12mmol)、およびNaOMe(0.5M MeOH溶液,0.72mL)の溶液を120℃で1時間撹拌した。ついで反応混合物を減圧下で濃縮し、得られた残渣を逆相HPLC(C18,アセトニトリル/水)で精製して10mg(16%)のピリミジン18を得た。LRMS (M+H+) t/z 511.2.
実施例34
化合物19(540mg,1.21.mmol)、THF:H2O(3:1,12mL)、およびN−ブロモコハク酸イミド(216mg,1.21mmol)の溶液を23℃で15分間撹拌した。ついで反応混合物を減圧下で濃縮し、粗残渣をEtOAc(30mL)で希釈し、ブライン(10mL)で洗浄し、減圧下で濃縮した。得られた残渣をフラッシュカラムクロマトグラフィー(シリカゲル,1:1 EtOAc:ヘキサン)で精製して210mg(35%)のブロモケトン20を得た。LRMS (M+H+) m/z 495.1.
ブロモケトン20(210mg,0.42mmol)、K2CO3(174mg1.26mmol),tert−ブチルカルバミジン塩酸塩(115mg,0.84mmol)、およびDMF(4mL)の溶液を、23℃、N2下で18時間撹拌した。反応混合物を高真空下(0.1mmHg)で濃縮し、得られた残渣をカラムクロマトグラフィー(シリカゲル,4:1 EtOAc:ヘキサン)で精製して50mg(24%)のイミダゾール21を得た。LRMS (M+H+) m/z 497.2.
実施例35
実施例36
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実施例38
実施例39
エステル66(3.5g,7.36mmol)、TFA:H2O(97.5:2.5,10mL)、およびCH2Cl2(10mL)の溶液を23℃で3時間撹拌した。反応溶液を減圧下で濃縮し、得られた残渣を高真空下に2時間おき、ついでさらに精製せずに用いた。
実施例40
実施例41
アミン72(10mg,0.02mmol)、塩化ベンゾイル(3.2μL,0.03mmol)、トリエチルアミン(50μL,0.36mmol)、およびCH2Cl2(0.5mL)の溶液を23℃で2時間撹拌した。ついで反応混合物をEtOAc(15mL)で希釈し、1N HCl(2mL)、飽和NaHCO3水溶液(2mL)およびブライン(5mL)で洗浄した。有機層を乾燥(MgSO4)し、濾過し、減圧下で濃縮した。得られた残渣をフラッシュカラムクロマトグラフィー(シリカゲル,2:1 ヘキサン:EtOAc)で精製して5mg(49%)のアミド73を得た。LRMS (M+H+) m/z 508.2.
実施例42
ヒドロキシアミジン74(20mg,0.05mmol)、カルボニルジイミダゾール(CDI,15mg,0.09mmol)、トリエチルアミン(13μL,0.09mmol)、およびDMF(1mL)の溶液を100℃で2時間撹拌した。得られた残渣をEtOAc(15mL)で希釈し、ブライン(3x5mL)で洗浄した。有機層を乾燥(MgSO4)し、濾過し、濾液を減圧下で濃縮した。得られた残渣をフラッシュカラムクロマトグラフィー(シリカゲル,1:20 MeOH:EtOAc)で精製して10mg(44%)のオキサジアゾロン75を得た。LRMS (M+H+) m/z 459.2.
実施例43
実施例44
実施例45
69(400mg,0.775mmol)をHBr/HOAc溶液(10mL)に溶解した。10分間撹拌後、溶媒を除去した。残渣を炭酸水素ナトリウム溶液(50mL)に溶解し、DCM(50mL)で3回抽出した。合わせたDCM層を硫酸ナトリウムで乾燥し、濾過し、濾液を減圧下で濃縮して70(285mg,96%)を得た。
71(128mg,0.271mmol)の水(1mL)およびメタノール(1mL)溶液に、EDTAナトリウム(273mg,0.814mmol)、HOAc(20uL)およびHg(OAc)2(259mg,0.814mmol)を加えた。反応混合物を100℃で8時間撹拌し、ついで溶媒を減圧下で留去した。残渣をDMF(2mL)に再溶解し、濾過し、濾液をアセトニトリルおよびH2Oの混合物を用いる逆相HPLC(C18)で精製して72(37.6mg,28.5%)を得た。LCMS (M+H+) m/z 486.1.
実施例46
47に適用した方法と同じ方法を50(58.3mg)の製造に用いた。LCMS (M+H+) m/z 441.4.
実施例47
14(1.5g,2.71mmol)のメタノール(20mL)溶液にヒドラジン水和物(0.845mL,27.1mmol)を加えた。反応混合物を50℃で5時間撹拌し、ついで室温に冷却した。固形物を濾去し、濾液を減圧下で濃縮して15(1.0g,87.2%)を得た。LCMS (M+H+) m/z 423.1.
実施例48
15(60.0mg,0.142mmol)のDCM(2mL)溶液にジイソプロピルエチルアミン(49.5uL,0.282mmol)、17(32.2mg,0.170mmol)およびHBTU(80.8mg,0.213mmol)を加えた。反応混合物を10分間撹拌し、ついで減圧下で濃縮した。得られた残渣をDCM(1mL)およびTFA(1mL)に溶解し、10分間撹拌し、減圧下で濃縮し、生成物をアセトニトリルおよびH2Oの混合物を用いる逆相HPLC(C18)で精製して19(25.0mg,35.6%)を得た。LCMS (M+H+) m/z 494.2.
15(35.0mg,0.0828mmol)のDCM(2mL)溶液にジイソプロピルエチルアミン(28.8uL,0.166mmol)および塩化メタノスルホニル(9.64uL,0.124mmol)を加えた。反応混合物を10分間撹拌し、ついで減圧下で濃縮し、アセトニトリルおよびH2Oの混合物を用いる逆相HPLC(C18)で生成物を精製して20(25.0mg,60.3%)を得た。LCMS (M+H+) m/z 501.2.
15(60.0mg,0.142mmol)のDCM(2mL)溶液にジイソプロピルエチルアミン(49.5uL,0.282mmol)およびトリメチルシリルイソシアニド(19.6mg,0.170mmol)を加えた。反応混合物を10分間撹拌し、ついで減圧下で濃縮し、アセトニトリルおよびH2Oの混合物を用いる逆相HPLC(C18)で生成物を精製して21(20.6mg,31.1%)を得た。LCMS (M+H+) m/z 466.1.
15(60.0mg,0.142mmol)のDCM(2mL)溶液にジイソプロピルエチルアミン(49.5uL,0.282mmol)およびクロロギ酸メチル(13.1uL,0.170mmol)を加えた。反応混合物を10分間撹拌し、ついで減圧下で濃縮し、残渣をアセトニトリルおよびH2Oの混合物を用いる逆相HPLC(C18)で精製して22(19.9mg,29.1%)を得た。LCMS (M+H+) m/z 481.1.
実施例49
水素化ホウ素ナトリウム(4.6g,124mmol)のテトラヒドロフラン(100mL)溶液に、0℃でボラン−テトラヒドロフラン錯体(150mL,150mmol,1.0M)を加えた。ついで得られた溶液をさらに15分間室温で撹拌し、中間体2(6.5g,27mmol)のテトラヒドロフラン(30mL)溶液を滴下し、得られた溶液を4時間還流した。これを室温に冷却し、反応物を水でクエンチし、ジクロロメタン(3x80mL)で抽出した。合わせた有機層を硫酸ナトリウムで乾燥し、減圧下で濃縮し、フラッシュクロマトグラフィー(シリカゲル,ヘキサン/酢酸エチル)で残渣を精製して中間体3(5.2g,90%)を得、これをLC/MS (LRMS (M+H+) m/z: 213.02) で構造決定した。
臭化物6(212mg,0.53mmol)のジオキサン(10mL)溶液に、室温でトランス−ジクロロビス(トリフェニルホスフィン)パラジウム(II)(37mg,10mol%)および1−エトキシビニルトリ−n−ブチルスズ(481mg,1.33mmol)を順次加えた。得られた溶液を100℃で4時間加熱した。これを室温に冷却し、減圧下で溶媒を除去した。ついで残渣をフラッシュクロマトグラフィー(シリカゲル,酢酸エチル+5%トリエチルアミン)で精製して中間体7(250mg)を得たが、これは不安定であり、次の変換に使用するために十分な純度であることが確認された。LC/MS (LRMS (M+H+) m/z: 402.8).
中間体7のテトラヒドロフラン(10mL)および水(3mL)溶液を、N−ブロモコハク酸イミド(190mg,1.1mmol)と共に50℃で2時間撹拌した。減圧下で溶媒を除去し、得られた残渣を水(10mL)と分配し、酢酸エチル(3x50mL)で抽出した。合わせた有機層を硫酸ナトリウムで乾燥し、減圧下で濃縮した。ついで残渣をフラッシュクロマトグラフィー(シリカゲル,ヘキサン/酢酸エチル)で精製して中間体8(55mg,23%)を得、これをLC/MS (LRMS (M+H+) m/z: 452.1)で構造決定した。
アニリン3(2.47g,8.0mmol)のジクロロメタン(20mL)溶液に、室温でトリフルオロ酢酸(20mL)を加えた。得られた溶液を45分間撹拌し、減圧下で溶媒を除去した。残渣をジクロロメタン(75mL)および飽和炭酸水素ナトリウム水溶液(25mL)間で分配し、2層を分離した。水層を塩化ナトリウムで飽和し、ジクロロメタン(3x75mL)およびテトラヒドロフラン(2x50mL)で抽出した。合わせた有機層を硫酸ナトリウムで乾燥し、減圧下で濃縮して4(1.30g,6.3mmol)を粘性のあるオイルで得、これをLC/MS (LRMS (MH) m/z: 209.30)で構造決定した。
カルバミン酸エステル7(139mg,0.28mmol)のメタノール(2mL)およびテトラヒドロフラン(2mL)溶液に、室温で水素化ホウ素ナトリウム(261mg,6.9mmol)を加えた。得られた混合物を2時間撹拌し、ついで減圧下で溶媒を除去した。残渣を酢酸エチル(15mL)および水(15mL)間で分配し、2層を分離し、水層を酢酸エチル(3x15mL)で抽出した。合わせた有機層を硫酸ナトリウムで乾燥し、減圧下で濃縮した。残渣をアセトニトリルおよび水からなる移動層勾配を用いる逆相HPLCで精製した。純粋な生成物8(47mg,36%)を単離し、1H-NMRおよび LC/MS (LRMS (M+H+) m/z: 477.20) により構造決定した。
尿素9(150mg,0.29mmol)のメタノール(2mL)およびテトラヒドロフラン(2mL)溶液に室温で水素化ホウ素ナトリウム(260mg,6.90mmol)を加えた。得られた混合物を窒素雰囲気下、室温で2時間撹拌した。溶媒を除去し、残渣を酢酸エチル(15mL)および水(15mL)間で分配した。2層を分離し、水層を酢酸エチル(3x15mL)で抽出した。合わせた有機層を硫酸ナトリウムで乾燥し、減圧下で濃縮した。アセトニトリルおよび水からなる移動層勾配を用いる逆相HPLCで残渣を精製した。純粋な生成物10(4mg,28%)を単離し、1H-NMR およびLC/MS (LRMS (M+H+) m/z: 490.1) で構造決定した。
粗アミン5(72mg,0.26mmol)をジイソプロピルエチルアミン(197μl,1.1mmol)と共にジメチルホルムアミド(3mL)中室温で5分間撹拌し、ついで中間体6(100mg,0.26mmol)を加えた。得られた混合物をさらに30分間撹拌し、溶媒を減圧下で除去した。粗残渣をアセトニトリルおよび水からなる移動層勾配を用いる逆相HPLCで精製して化合物7(10mg,8%)をガラス状固体で得、これを1H NMRおよびLC/MS (LRMS (M+H+) m/z: 470.2) で構造決定した。
2(5.5g,13.76mmol)のTHF(100mL)溶液に0℃でLAH(1M THF溶液,13.7mL,13.7mmol)を加えた。得られた溶液を2時間撹拌し、メタノール(〜20mL)を加えて反応物をクエンチした。ついで溶媒を留去して黄色がかった固体を得、これを酢酸エチルで希釈し、飽和NaHCO3で洗浄した。有機層をブラインで洗浄し、Na2SO4で乾燥し、減圧下で濃縮した。溶離液として酢酸エチルおよびヘキサンの混合物を用いるフラッシュカラムクロマトグラフィーで残渣を精製して3を白色固体(3.5g,70%)で得た。LRMS (M+H+) m/z 394.4.
3(1.9g,5mmol)のMeOH(40mL)溶液をH2(50psi)気流下、10%Pd/C(200mg)の存在下で30時間撹拌した。触媒をPTFE(0.45μm)フィルターによる濾過で除去し、溶媒を留去して白色固体(1.5g)を得、これをTFA(1mL)およびDCM(9mL)の混合物中2時間撹拌した。得られた溶液を濃縮し、さらに精製せずに次の工程に用いた。LRMS (M+H+) m/z 182.3.
4(926mg,5mmol)のTHF(10mL)溶液に5(950mg,2.6mmol)およびN,N−ジイソプロピルエチルアミン(4.5mL,25.5mmol)を加えた。反応物を室温で10時間撹拌した。混合物を濃縮し高真空で乾燥した。得られた粗生成物を、溶離液として酢酸エチルを用いるフラッシュカラムクロマトグラフィーで精製して6(710mg,74%)を得た。LRMS (M+H+) m/z 370.4.
6(70mg,0.2mmol)のDMF(1mL)溶液に臭化4−フルオロベンジル(0.15mL,1.2mmol)および炭酸カリウム(166mg,1.2mmol)を加えた。得られた混合物を室温で12時間撹拌した。混合物を濾過し、アセトニトリルおよびH2Oの混合物を用いるRP−HPLCで濾液を精製して1e(35mg,37%)を得た。LRMS (M+H+) m/z 477.5.
実施例56
実施例57
臭化物30(200mg,0.51mol)、ジクロロビス(トリフェニルホスフィン)パラジウム(II)(35mg,0.05mol)、トリブチル(1−エトキシビニル)スズ(0.34ml,1.0mmol)、およびトルエン(2mL)の溶液をN2下100℃で4時間撹拌した。LCMSでモニターして反応が完結したとき、反応混合物を冷却し、綿で濾過し、減圧下で濃縮した。得られた残渣をフラッシュカラムクロマトグラフィー(シリカゲル,1:4:0.1 EtOAc:ヘキサン:トリエチルアミン)で精製して100mg(52%)のスチレン31を得た。LRMS (M+H+) m/z 388.2.
化合物31(100mg,0.25.mmol)、THF:H2O(3:1,4mL)、およびN−ブロモコハク酸イミド(46mg,0.25mmol)の溶液を23℃で15分間撹拌した。ついで反応混合物を減圧下で濃縮し、粗残渣をEtOAc(30mL)で希釈し、ブライン(10mL)で洗浄し、減圧下で濃縮した。得られた残渣をフラッシュカラムクロマトグラフィー(シリカゲル,4:1 EtOAc:ヘキサン)で精製して50mg(46%)のブロモケトン32を得た。LRMS (M+H+) m/z 438.1.
ブロモケトン32(50mg,0.11mmol)、K2CO3(47mg0.34mmol)、tert−ブチルカルバミジン塩酸塩(21mg,0.23mmol)、およびDMF(2mL)の溶液を23℃、N2下で18時間撹拌した。反応混合物を高真空下(0.1mmHg)で濃縮し、得られた残渣をカラムクロマトグラフィー(シリカゲル,2:1 EtOAc:ヘキサン)で精製して35mg(72%)のイミダゾール34を得た。LRMS (M+H+) m/z 440.2.
実施例58
アルデヒド36(570mg,1.16mmol)、KMnO4(368mg,2.32mmol)、ジオキサン(3mL)、およびH2O(1mL)の溶液を23℃で3時間撹拌した。反応混合物を減圧下で濃縮し、得られた残渣をカラムクロマトグラフィー(シリカゲル,1:1 EtOAc:ヘキサン)で精製して350mg(60%)の酸37を得た。LRMS (M+H+) m/z 506.2.
酸37(115mg,0.23mmol)、ジメチルアミン(0.23mL,2.0M THF溶液)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩(65mg,0.34mmol)、ジイソプロピルエチルアミン(0.12mL,0.68mmol)、およびCH2Cl2(1mL)の溶液を23℃で4時間撹拌した。ついで反応混合物をEtOAc(10mL)で希釈し、1N HCl(5mL)およびブライン(5mL)で洗浄した。有機層を乾燥(MgSO4)し、濾過し、減圧下で濃縮した。得られた残渣をフラッシュカラムクロマトグラフィー(シリカゲル,1:1 ヘキサン:EtOAc)で精製して60mg(49%)のアミド38を得た。LRMS (M+H+) m/z 533.3.
アミド38(60mg,0.11mmol)、TFA:H2O(97.5:2.5,1mL)およびCH2Cl2(1mL)の溶液を23℃で30分間撹拌した。反応溶液を減圧下で濃縮し、得られた残渣を高真空下に2時間置き、ついでさらに精製せずに用いた。
エステル41(50mg,0.08mmol)、NaBH4(30mg,0.81mmol)、THF(0.5mL)、およびMeOH(0.5mL)の溶液を23℃で2時間撹拌した。ついで反応混合物をEtOAc(10mL)で希釈し、1N HCl(5mL)およびブライン(5mL)で洗浄した。有機層を乾燥(MgSO4)し、濾過し、減圧下で濃縮した。得られた残渣をフラッシュカラムクロマトグラフィー(シリカゲル,1:50 MeOH:EtOAc)で精製して31mg(75%)のアルコール42を得た。LRMS (M+H+) m/z 516.3.
実施例59
エステル44(100mg,0.21mmol)、NaBH4(24mg,0.63mmol)、THF(1mL)、およびMeOH(1mL)の溶液を23℃で18時間撹拌した。ついで反応混合物をEtOAc(10mL)で希釈し、1N HCl(5mL)、およびブライン(5mL)で洗浄した。有機層を乾燥(MgSO4)し、濾過し、減圧下で濃縮した。得られた残渣をさらに精製せずに用いた。
実施例60
ニトリル49(60mg,0.27mmol)およびTFA:H2O(97.5:2.5,2mL)の溶液を23℃で30分間撹拌した。反応溶液を減圧下で濃縮し、得られた残渣を高真空下に2時間置き、ついでさらに精製せずに用いた。
エステル51(60mg,0.1mmol)、NaBH4(12mg,0.3mmol)、THF(1mL)、およびMeOH(1mL)の溶液を23℃で18時間保った。ついで反応混合物をEtOAc(10mL)で希釈し、1N HCl(5mL)、およびブライン(5mL)で洗浄した。有機層を乾燥(MgSO4)し、濾過し、減圧下で濃縮した。得られた残渣をフラッシュカラムクロマトグラフィー(シリカゲル,1:2 ヘキサン:EtOAc)で精製して30mg(64%)のアルコール52を得た。LRMS (M+H+) m/z 470.2.
実施例61
フェノール56(700mg,1.92mmol)、Cs2CO3(1.25mg,3.84mmol)、臭化ベンジル(0.46mL,3.84mmol)、およびDMF(10mL)の溶液を50℃で2時間保った。反応混合物をEtOAc(30mL)で希釈し、1N HCL(20mL)およびブライン(3x30mL)で洗浄した。有機層を乾燥(MgSO4)し、濾過し、濾液を減圧下で濃縮した。得られた残渣をフラッシュカラムクロマトグラフィー(シリカゲル,1:3 EtOAc:ヘキサン)で精製して500mg(57%)のアミド57を得た。LRMS (M+H+) m/z 455.2.
アミド57(150mg,0.33mmol)、四酸化オスミウム(8mg,0.03mmol)、N−メチルモルホリン−N−オキシド(182mg,1.55mmol)、ピリジン(2.4μL,0.03mmol)、THF(2mL)およびH2O(2mL)の溶液を23℃に保った。2時間後、セライト(1g)、NaHSO3(1g)およびEtOAc(20mL)を加え、得られた混合物を撹拌した。30分後、反応混合物を濾過し、得られた濾液を減圧下で濃縮した。得られた残渣をフラッシュカラムクロマトグラフィー(シリカゲル,3:1 EtOAc:ヘキサン)で精製して100mg(62%)のジオール58を得た。LRMS (M+H+) m/z 489.2.
ジオール58(52mg,0.11mmol)、Pb(OAc)4、およびCH2Cl2(2mL)の溶液を23℃で30分間保った。ついで反応混合物をセライトプラグで濾過し、濾液を濃縮してアルデヒドを無色オイルで得た。
実施例62
アルコール61(120mg,0.32mmol)、TFA:H2O(97.5:2.5,4mL)の溶液を23℃で30分間保った。反応溶液を減圧下で濃縮し得られた残渣を高真空下に2時間置き、ついでさらに精製せずに用いた。
実施例63
23(50.0mg,0.119mmol)のメタノール(2mL)溶液にジイソプロピルエチルアミン(62.0uL,0.356mmol)、26(31.1uL,0.356mmol)およびシアノ水素化ホウ素ナトリウム(22.4mg,0.356mmol)を加えた。反応混合物を終夜撹拌し、ついで減圧下で濃縮し、残渣をアセトニトリルおよびH2Oの混合物を用いる逆相HPLC(C18)で精製して27(31.0mg,22.9%)を得た。LRMS (M+H+) m/z 518.5.
実施例64
7(50mg,0.119mmol)のDMF(2mL)溶液にアジ化ナトリウム(15.5mg,0.239mmol)および塩化アンモニウム(12.8mg,0.238mmol)を加えた。混合物を80℃で終夜撹拌し、ついで濾過した。アセトニトリルおよびH2Oの混合物を用いる逆相HPLC(C18)で濾液を精製して8(6.40mg,11.6%)を得た。LCMS (M+H+) m/z 462.4.
実施例66
スキームA:
N−{(1S)−1−[(4−ブロモフェニル)メチル]−3−ヒドロキシプロピル)}−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
N−((1S)−1−{[4−(ブロモアセチル)フェニル]メチル−}3−ヒドロキシプロピル)−3−シアノ−4−[(1−メチルエチル)オキシ]ベンズアミド
3−シアノ−N−((1S)−3−ヒドロキシ−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}プロピル)−4−[(1−メチルエチル)オキシ]ベンズアミド
スキームC:
[(1S)−3−ヒドロキシ−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)プロピル]カルバミン酸1,1−ジメチルエチル
3−クロロ−N−[(1S)−3−ヒドロキシ−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)プロピル]−4−[(1−メチルエチル)オキシ]ベンズアミド
スキームE:
{(1S)−2−(4−ブロモフェニル)−1−[(1,3−ジオキソ−1,3−ジヒドロ−2H−イソインドール−2−イル)メチル]エチル}カルバミン酸1,1−ジメチルエチル:
{(1S)−2−[4−(ブロモアセチル)フェニル]−1−[(1,3−ジオキソ−1,3−ジヒドロ−2H−イソインドール−2−イル)メチル]エチル}カルバミン酸1,1−ジメチルエチル:
[(1S)−2−(1,3−ジオキソ−1,3−ジヒドロ−2H−イソインドール−2−イル)−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)エチル]カルバミン酸1,1−ジメチルエチル:
3−クロロ−N−[(1S)−2−(1,3−ジオキソ−1,3−ジヒドロ−2H−イソインドール−2−イル)−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)エチル]−4−[(1−メチルエチル)オキシ]ベンズアミド:
N−[(1S)−2−アミノ−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)エチル]−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド:
3−クロロ−N−[(1S)−2−[(N,N−ジメチルグリシル)アミノ]−1−({4−[8−(1−ヒドロキシエチル)イミダゾ[1,2−a]ピリジン−2−イル]フェニル}メチル)エチル]−4−[(1−メチルエチル)オキシ]ベンズアミド:
{(1S)−2−[4−(8−ブロモイミダゾ[1,2−a]ピリジン−2−イル)フェニル]−1−[(1,3−ジオキソ−1,3−ジヒドロ−2H−イソインドール−2イル)メチル]エチル}カルバミン酸1,1−ジメチルエチル:
((1S)−2−(1,3−ジオキソ−1,3−ジヒドロ−2H−イソインドール−2−イル)−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)カルバミン酸1,1−ジメチルエチル:
N−{(1S)−2−[4−(8−ブロモイミダゾ[1,2−a]ピリジン−2−イル)フェニル]−1−[(1,3−ジオキソ−1,3−ジヒドロ−2H−イソインドール−2−イル)メチル]エチル}−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド:
3−クロロ−N−((1S)−2−(1,3−ジオキソ−1,3−ジヒドロ−2H−イソインドール−2−イル)−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド:
N−((1S)−2−アミノ−1−{[4−(8−ブロモイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド:
N−((1S)−2−アミノ−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド:
N−((1S)−2−(D−アラニルアミノ)−1−{[4−(8−ブロモイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド:
3−クロロ−N−((1S)−2−[(2−メチルアラニル)アミノ]−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド:
3−クロロ−N−((1S)−2−[(N,N−ジメチルグリシル)アミノ]−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}エチル)−4−[(1−メチルエチル)オキシ]ベンズアミド:
スキームF:
スキームG:
スキームH:
(4R)−4−({[(1,1−ジメチルエチル)オキシ]カルボニル}アミノ)−5−[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]ペンタン酸1,1−ジメチルエチル:
(4R)−4−({[(1,1−ジメチルエチル)オキシ]カルボニル}アミノ)−5−[4−(1−メチル−2−{[メチル(メチルオキシ)アミノ]カルボニル}−1H−イミダゾール−4−イル)フェニル]ペンタン酸1,1−ジメチルエチル:
(4R)−4−[({3−クロロ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−5−[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]ペンタン酸:
(4R)−4−[({3−クロロ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−5−[4−(1−メチル−2−{[メチル(メチルオキシ)アミノ]カルボニル}−1H−イミダゾール−4−イル)フェニル]ペンタン酸:
(4R)−5−[4−(2−アセチル−1−メチル−1H−イミダゾール−4−イル)フェニル]−4−[({3−クロロ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]ペンタン酸:
N−((1R)−4−アミノ−1−{[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]メチル}−4−オキソブチル)−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド:
N−((1R)−1−{[4−(2−アセチル−1−メチル−1H−イミダゾール−4−イル)フェニル]メチル}−4−アミノ−4−オキソブチル)−3−クロロ−4−[(1−メチルエチル)オキシ]ベンズアミド:
スキームI:
リン酸二水素(3S)−3−[({3−クロロ−4−[(1−メチルエチル)オキシ]フェニル}カルボニル)アミノ]−4−[4−(8−メチルイミダゾ[1,2−a]ピリジン−2−イル)フェニル]ブチル:
スキームJ:
スキームK:
前述の方法を用いて以下の化合物を製造した:
構造
名称
(M + H)+
502.4
518.4
583.6
597.6
574.4
561.4
588.2
588.4
569.4
584.2
625.1
639.2
601.2
547.2
512.4
553.2
546.2
506.2
508.2
513.2
550.2
537.2
485.2
512.2
512.2
499.4
498.4
511.2
527.4
513.4
487.2
519.4
560.4
513.4
513.4
536.2
550.4
549.2
540.6
510.2
501.2
547.2
561.2
547.2
561.2
561.2
559.2
521.2
511.2
500
488
486
526
565
579
579
592
578
522
592
534.2
494.2
503.2
491.2
523.2
532.4
521.4
564.2
545.4
535.4
536.2
520.2
567.6
539.4
538.4
540.4
526.2
517.2
509.2
479
516
534
532
499
526
546
528
525.4
593.2
545.2
548.2
552.4
561.2
546.2
517.4
543.4
510.4
549.2
570.4
561.4
実施例67
3−シアノ−4−ヒドロキシ安息香酸メチル3:100mLのDMFに溶解した28g(0.1mol)の4−ヒドロキシ−3−ヨード安息香酸メチル2を9.92g(0.11mol)のCuCNおよび0.49g(0.11mol)のNaCNで処理した。この系を窒素でフラッシュし、ついで混合物を105℃に加熱し、18時間撹拌した。混合物を室温まで放冷し、沈殿物を濾過で除去し、EtOAcで洗浄した。合わせた有機物を200mLの水で希釈し、ついでEtOAc(2x200mL)で抽出した。合わせた層を硫酸ナトリウムで乾燥し、濾過し、蒸発乾固した。減圧下で乾燥後、得られた18g(収率100%)の3をLCMSおよびHNMRで構造決定した。
実施例70
実施例71
実施例73
実施例74
実施例75
2(9.6g,〜36.8mmol)のEt2O(100mL)溶液に0℃でMeMgBr(3M Et2O溶液,27ml)を加えた。得られた混合物を4時間撹拌し、この間に室温まで加温した。反応混合物を飽和NH4Cl(100mL)でクエンチした。有機層をH2O、ブラインで洗浄し、Na2SO4で乾燥し、濃縮して3(7g,1から71%)を得、これをNMRで構造決定した。
粗製物5(〜16.9mmol)のジオキサン(50mL)溶液にNaOAc(6.93g,84.5mmol)、HOAc(4.8mL,84.5mmol)、および5.1.(5.93g,84.5mmol)を加えた。1時間後、反応混合物を80℃まで加熱し、3時間撹拌した。反応混合物をEtOAc(500mL)および飽和NaHCO3(200mL)間で分配した。水層をEtOAc(300mLx2)で抽出した。合わせた有機層をブラインで洗浄し、Na2SO4で乾燥し、濃縮した。得られた残渣をシリカゲル(ヘキサン/EtOAc,1:0,1:2,1:1,0:1)で精製して6(1.2g,4から23%)を得た。LRMS (M+H+) m/z 312.9.
実施例76
実施例78
p−ヨードアセトフェノン1(30.0g,122mmol)のジオキサン(200mL)溶液に、氷浴上、撹拌しながら臭素(6.56mL,128mmol)を滴下した。反応混合物を室温で撹拌し、LC/MSでモニターした。終了後(約1時間)、溶媒をロータリーエバポレーターで留去し、残渣を減圧下で乾燥して固体の2(40g,100%)を得た。
2(〜0.5mmol)のDCM(5mL)溶液にKH2PO4水溶液(2M,1ml)およびMCPBA(77%,135mg,0.6mmol)を加えた。得られた混合物を6時間撹拌した。反応混合物を飽和Na2S2O3(10mL)でクエンチした。有機層を飽和NaHCO3、H2O、ブラインで洗浄し、Na2SO4で乾燥し、濃縮した。アセトニトリルおよびH2Oの混合物を用いるRP−HPLCで残渣を精製して3(150mg,1から65%)を得た。LRMS (M+H+) m/z 384.2.
3(150mg,0.39mmol)のDCM(8mL)溶液にTFA(1mL)を加えた。反応混合物を4時間撹拌した。混合物を濃縮し、高真空下で乾燥した。得られた残渣(90mg,0.32mmol)のTHF(4mL)溶液にDIEA(165uL,0.95mmol)および4(140mg,0.38mmol)を加えた。得られた混合物を14時間撹拌した。反応混合物を濃縮したアセトニトリルおよびH2Oの混合物を用いるRP−HPLCで残渣を精製して5(120mg,65%)を得た。LRMS (M+H+) m/z 471.2.
5(90mg,0.19mmol)のTHF/H2O(2mL/2mL)溶液にOsO4(4.8mg,0.019mmol)、NMO(117mg,0.95mmol)およびピリジン(1.5uL,0.019mmol)を加えた。得られた混合物を6時間撹拌し、NaHSO3(300mg)を加えた。反応混合物を濃縮した。得られた固体をEtOAc(100mLx3)で洗浄した。濾液を濃縮した。得られた残渣を分取TLCプレート(シリカゲル,5:1 EtOAc/MeOH)で精製してジアステレオ異性体6a(23mg,24%)および6b(2mg,2%)を得た。LRMS (M+H+) m/z 505.2.
実施例87
実施例88
実施例89
実施例90
実施例91
(S)−N−(1−(4−(2−アセチル−1−メチル−1H−イミダゾール−4−イル)フェニル)−4−ヒドロキシブタン−2−イル)−3−クロロ−4−イソプロポキシベンズアミド(80mg(0.031mmol))のピリジン(2mL)溶液をヒドロキシルアミンメチルエーテル塩酸塩(27.6mg(0.033mmol))で処理した。反応物を終夜撹拌し、ついで溶媒を留去し、逆相HPLC(アセトニトリル/水)で残渣を精製して11.2mg(収率70%)の2を得、LCMSおよびHNMRで構造決定した。
(S)−N−(1−(4−(2−アセチル−1−メチル−1H−イミダゾール−4−イル)フェニル)−4−ヒドロキシブタン−2−イル)−3−クロロ−4−イソプロポキシベンズアミド(100mg(0.21mmol))のピリジン(2mL)溶液をヒドロキシルアミン塩酸塩(71.8mg(1.0mmol))で処理した。反応物を終夜撹拌し、ついで溶媒を留去し、逆相HPLC(アセトニトリル/水)で残渣を精製して69.7mg(収率67%)の3を得、LCMSおよびHNMRで構造決定した。
(S)−N−(1−(4−(2−アセチル−1−メチル−1H−イミダゾール−4−イル)フェニル)−4−ヒドロキシブタン−2−イル)−3−クロロ−4−イソプロポキシベンズアミド(150mg(0.31mmol))のベンゼン(2mL)溶液をエタン−1,2−ジオール(34.6uL(0.62mmol))およびp−トルエンスルホン酸一水和物(59mg(0.31mmol))で処理した。反応物を70℃で2時間撹拌し、ついで溶媒を留去し、残渣を逆相HPLC(アセトニトリル/水)で精製した。25.5mg(収率16%)の4を得、LCMSおよびHNMRで構造決定した。
実施例96
実施例98
前述の手順を用いて以下の化合物を製造した。
有糸分裂キネシン阻害剤で処理した腫瘍細胞系における細胞生存率の抑制
物質および溶液:
細胞:SKOV3(ヒト卵巣癌)。
付着SKOV3細胞を10mLのPBSで洗浄し、ついで2mLの0.25%トリプシンを加え、37℃で5分間インキュベートする。8mLの培地(フェノールレッド不含RPMI+5%FBS)でフラスコから細胞をすすぎだし、新しいフラスコに移す。コールターカウンターを用いて細胞濃度を測定し、1000細胞/100μLになるように、適切な細胞容量を算出する。96−ウェルプレートの全てのウェルに100μLの細胞浮遊培地(1000細胞/100mLに調節)を加え、ついで37℃で18〜24時間インキュベートする。湿度100%、5%CO2で細胞をプレートに付着させる。
オートクレーブしたアッセイブロックのウェルの1列に、最初の2.5μLの試験化合物(単数または複数)を400Xの最大所望濃度で加える。1.25μLの400X(400μM)トポテカンを他のウェルに加える(このウェルからの吸光度は、死細胞およびビヒクルのバックグラウンド吸光度を差し引くために用いる)。試験化合物を含有するウェルには、DMSOを含まない500μLの培地を加え、トポテカンのウェルには250μLを加える。残る全てのウェルに250μLの培地+0.5%DMSOを加え、これに試験化合物(単数または複数)を連続希釈する。アッセイブロックから対応する細胞プレートに、列ごとに化合物含有培地を2連でプレーティングする。37℃、湿度100%、5%CO2で72時間細胞プレートをインキュベートする。
インキュベーターからプレートを除き、40μlのMTS/PMSを各ウェルに加える。ついでプレートを37℃、湿度100%、5%CO2で120分間インキュベートし、ついで96ウェル分光光度計における5秒振盪サイクルを行った後、490nmでの吸光度を読み取る。
対照(吸光度−バックグラウンド)の正規化%を算出し、生存率を50%抑制するために必要な化合物の濃度を決定するための用量反応曲線を作成するためにXLfitを用いる。本発明の化合物はこの方法で試験するとき活性を示す。
有糸分裂キネシン阻害剤の適用
ヒト腫瘍細胞Skov−3(卵巣)を、4,000細胞/ウェルの密度で96−ウェルプレートにプレーティングし、24時間付着させ、種々の濃度の試験化合物で24時間処理した。4%ホルムアルデヒドで細胞を固定し、抗チューブリン抗体(続いて蛍光標識された二次抗体を用いて認識する)およびヘキスト染料(DNAを染色する)で染色した。
有糸分裂キネシン阻害剤で処理した腫瘍細胞系における細胞増殖阻害
96−ウェルプレートに1000〜2500細胞/ウェルの密度で細胞をプレーティングし、24時間付着/増殖させた。ついでこれらを種々の濃度の薬剤で48時間処理した。化合物を添加する時点をT0とみなす。T0における生存細胞数および化合物暴露の48時間後に生き残っている細胞数を決定するために、試薬3−(4,5−ジメチルチアゾール−2−イル)−5−(3−カルボキシメトキシフェニル)−2−(4−スルホフェニル)−2H−テトラゾリウム(MTS)(I.S>米国特許第5,185,450号)(Promega製品カタログ#G3580,CellTiter 96(登録商標) AQueous One Solution Cell Proliferation Assayを参照のこと)を用いるテトラゾリウムベースアッセイを用いた。48時間後に生き残った細胞数を、薬剤添加時における生存細胞数と比較することにより増殖阻害を算出することが可能となった。
100 x [(Treated48 - T0) / (Control48 - T0)] = 50.
化合物の全ての濃度について2連で試験し、対照は12ウェルについて平均化する。米国立癌研究所では、よく似ている96−ウェルプレートレイアウトとGi50算出スキームが用いられている(Monks, et al., J. Natl. Cancer Inst. 83:757-766 (1991)を参照のこと)。しかしながら、米国立癌研究所による方法においては、細胞数の定量にはMTSを用いず、代わりに代替法を用いている。
IC50の算出:
組成物のIC50の測定にはATPアーゼアッセイを用いる。以下の溶液を用いる:溶液1は、3mMホスホエノールピルビン酸カリウム塩(Sigma P−7127)、2mM ATP(Sigma A−3377)、1mM IDTT(Sigma D−9779)、5μMパクリタキセル(Sigma T−7402)、10ppmアンチフォーム289(Sigma A−8436)、25mM Pipes/KOH pH6.8(Sigma P6757)、2mM MgCl2(VWR JT400301)、および1mM EGTA(Sigma E3889)からなる。溶液2は、1mM NADH(Sigma N8129)、0.2mg/ml BSA(Sigma A7906)、ピルビン酸キナーゼ7U/ml、L−乳酸脱水素酵素10U/ml(Sigma P0294)、100nM有糸分裂キネシンモータードメイン、50μg/ml微小管、1mM DTT(Sigma D9779)、5μMパクリタキセル(Sigma T−7402)、10ppmアンチフォーム289(Sigma A−8436)、25mM Pipes/KOH pH6.8(Sigma P6757)、2mM MgCl2(VWR JT4003−01)、および1mM EGTA(Sigma E3889)からなる。溶液1を用いて96ウェルマイクロタイタープレート(Corning Costar3695)において組成物の連続希釈液(8〜12 2倍希釈液)を作成する。連続希釈に続き、各ウェルに溶液1を50μl加える。各ウェルに溶液2を50μl加えて反応を開始する。これを手動か、自動液体処理装置のいずれかにより多チャンネルピペットを用いて行う。ついでマイクロタイタープレートをマイクロプレート吸光度記録装置に移し、各ウェルに関して反応速度論的に340nmでの複数の吸光度を記録する。ついで、ATPアーゼの反応速度と比例している変化の実測速度を化合物濃度の関数としてプロットする。標準的なIC50測定に関しては、非線形フィッティングプログラム(例えば、Grafit4):
Claims (2)
- 以下:
N-(1-{4-[2-(1-アセチルアミノ-エチル)-1-エチル-1H-イミダゾール-4-イル]-ベンジル}-3-ヒドロキシプロピル)-3-クロロ-4-(2,2,2-トリフルオロ-1-メチル-エトキシ)-ベンズアミド、
N-(2-(2-ジメチルアミノ-アセチルアミノ)-1-{4-[8-(1-ヒドロキシ-エチル)-イミダゾ[1,2-a]ピリジン-2-イル]-ベンジル}-エチル)-3-クロロ-4-イソプロポキシ-ベンズアミド、
N-(1-{4-[2-(1-メチル-1-ヒドロキシ-エチル)-1-エチル-1H-イミダゾール-4-イル]-ベンジル}-3-ヒドロキシ-プロピル)-3-クロロ-4-(2,2,2-トリフルオロ-1-メチル-エトキシ)-ベンズアミド、
N-(2-(2-ジメチルアミノ-アセチルアミノ)-1-{4-[8-メチル-イミダゾ[1,2-a]ピリジン-2-イル]-ベンジル}-エチル)-3-クロロ-4-イソプロポキシ-ベンズアミド、
N-(1-{4-[2-(1-ヒドロキシ-1-メチル-エチル)-1-メチル-1H-イミダゾール-4-イル]-ベンジル}-3-ヒドロキシ-プロピル)-3-クロロ-4-(2,2,2-トリフルオロ-1-メチル-エトキシ)-ベンズアミド、
N-(2-(2-アミノ-2-メチル-プロピオニルアミノ)-1-{4-[8-メチル-イミダゾ[1,2-a]ピリジン-2-イル]-ベンジル}-エチル)-3-クロロ-4-イソプロポキシ-ベンズアミド、および
N-{1-[4-(8-(1-ヒドロキシ-エチル)-イミダゾ[1,2-a]ピリジン-2-イル)-ベンジル]-3-ヒドロキシ-プロピル}-3-クロロ-4-イソプロポキシ-ベンズアミド
から選択される化合物またはその薬学的に許容される塩。
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PE20060361A1 (es) | 2006-05-05 |
KR101026861B1 (ko) | 2011-04-06 |
EP1742907A4 (en) | 2008-01-02 |
BRPI0510663A (pt) | 2007-12-04 |
CA2565695C (en) | 2013-01-22 |
MA28646B1 (fr) | 2007-06-01 |
CN102557982A (zh) | 2012-07-11 |
JP2007537163A (ja) | 2007-12-20 |
PL212494B1 (pl) | 2012-10-31 |
PL381704A1 (pl) | 2007-06-25 |
AU2005240178A1 (en) | 2005-11-17 |
US20060094708A1 (en) | 2006-05-04 |
RU2413720C2 (ru) | 2011-03-10 |
KR20070057708A (ko) | 2007-06-07 |
TW200607513A (en) | 2006-03-01 |
AR053748A1 (es) | 2007-05-23 |
IL178860A (en) | 2013-04-30 |
US7618981B2 (en) | 2009-11-17 |
WO2005107762A3 (en) | 2006-08-17 |
NZ550811A (en) | 2010-07-30 |
NO20065504L (no) | 2007-01-30 |
AU2005240178B2 (en) | 2011-03-17 |
IL178860A0 (en) | 2007-03-08 |
RU2006137794A (ru) | 2008-05-10 |
MY146548A (en) | 2012-08-15 |
MXPA06012796A (es) | 2007-05-09 |
CA2565695A1 (en) | 2005-11-17 |
EP1742907A2 (en) | 2007-01-17 |
WO2005107762A2 (en) | 2005-11-17 |
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