NZ623918B2 - Azole derivative - Google Patents
Azole derivative Download PDFInfo
- Publication number
- NZ623918B2 NZ623918B2 NZ623918A NZ62391812A NZ623918B2 NZ 623918 B2 NZ623918 B2 NZ 623918B2 NZ 623918 A NZ623918 A NZ 623918A NZ 62391812 A NZ62391812 A NZ 62391812A NZ 623918 B2 NZ623918 B2 NZ 623918B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- acetamide
- ethyl
- propan
- compound
- phenyl
- Prior art date
Links
- 150000007980 azole derivatives Chemical class 0.000 title claims abstract description 23
- -1 2-oxa-6-azaspiro[3.3]hept-6-yl Chemical group 0.000 claims abstract description 162
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 61
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 53
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 53
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 47
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 42
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 21
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000001301 oxygen Substances 0.000 claims abstract description 17
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 17
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 125000005843 halogen group Chemical group 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 10
- 125000001589 carboacyl group Chemical group 0.000 claims description 8
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 7
- 238000004132 cross linking Methods 0.000 claims description 7
- 125000004043 oxo group Chemical group O=* 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 3
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 738
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 179
- 206010008118 cerebral infarction Diseases 0.000 abstract description 10
- 201000010099 disease Diseases 0.000 abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 10
- 208000019901 Anxiety disease Diseases 0.000 abstract description 7
- 208000019022 Mood disease Diseases 0.000 abstract description 7
- 125000001424 substituent group Chemical group 0.000 abstract description 7
- 206010048962 Brain oedema Diseases 0.000 abstract description 6
- 208000030814 Eating disease Diseases 0.000 abstract description 6
- 208000019454 Feeding and Eating disease Diseases 0.000 abstract description 6
- 206010019196 Head injury Diseases 0.000 abstract description 6
- 206010020772 Hypertension Diseases 0.000 abstract description 6
- 206010061218 Inflammation Diseases 0.000 abstract description 6
- 208000018737 Parkinson disease Diseases 0.000 abstract description 6
- 208000006752 brain edema Diseases 0.000 abstract description 6
- 208000026106 cerebrovascular disease Diseases 0.000 abstract description 6
- 235000014632 disordered eating Nutrition 0.000 abstract description 6
- 206010013663 drug dependence Diseases 0.000 abstract description 6
- 206010015037 epilepsy Diseases 0.000 abstract description 6
- 230000004054 inflammatory process Effects 0.000 abstract description 6
- 208000011117 substance-related disease Diseases 0.000 abstract description 6
- 201000004384 Alopecia Diseases 0.000 abstract description 5
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 5
- 208000018522 Gastrointestinal disease Diseases 0.000 abstract description 5
- 208000023105 Huntington disease Diseases 0.000 abstract description 5
- 231100000360 alopecia Toxicity 0.000 abstract description 5
- 208000010643 digestive system disease Diseases 0.000 abstract description 5
- 208000018685 gastrointestinal system disease Diseases 0.000 abstract description 5
- 201000000980 schizophrenia Diseases 0.000 abstract description 5
- 201000006474 Brain Ischemia Diseases 0.000 abstract description 4
- 206010008120 Cerebral ischaemia Diseases 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract description 4
- 150000001924 cycloalkanes Chemical class 0.000 abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 4
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 4
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 3
- ACHHEMNDFQPOMY-UHFFFAOYSA-N 2-[2-(3-chlorophenyl)-4-[4-(2-morpholin-4-ylethyl)phenyl]imidazol-1-yl]-n-propan-2-ylacetamide Chemical compound CC(C)NC(=O)CN1C=C(C=2C=CC(CCN3CCOCC3)=CC=2)N=C1C1=CC=CC(Cl)=C1 ACHHEMNDFQPOMY-UHFFFAOYSA-N 0.000 abstract 2
- ICCSWFSDTPHMAK-UHFFFAOYSA-N 2-[2-(3-chlorophenyl)-4-[4-(2-piperidin-1-ylethyl)phenyl]imidazol-1-yl]-n-propan-2-ylacetamide Chemical compound CC(C)NC(=O)CN1C=C(C=2C=CC(CCN3CCCCC3)=CC=2)N=C1C1=CC=CC(Cl)=C1 ICCSWFSDTPHMAK-UHFFFAOYSA-N 0.000 abstract 2
- UTPISOSJNFMUCF-UHFFFAOYSA-N 2-[2-(3-chlorophenyl)-4-[4-[2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl]phenyl]imidazol-1-yl]-n-propan-2-ylacetamide Chemical compound CC(C)NC(=O)CN1C=C(C=2C=CC(CCN3CC4(COC4)C3)=CC=2)N=C1C1=CC=CC(Cl)=C1 UTPISOSJNFMUCF-UHFFFAOYSA-N 0.000 abstract 2
- WQXAPHFLCGDCDW-UHFFFAOYSA-N 2-[2-(3-chlorophenyl)-4-[4-[2-[3-(hydroxymethyl)pyrrolidin-1-yl]ethyl]phenyl]imidazol-1-yl]-n-propan-2-ylacetamide Chemical compound CC(C)NC(=O)CN1C=C(C=2C=CC(CCN3CC(CO)CC3)=CC=2)N=C1C1=CC=CC(Cl)=C1 WQXAPHFLCGDCDW-UHFFFAOYSA-N 0.000 abstract 2
- PRGLVTYMUBVODA-UHFFFAOYSA-N 2-[2-(4-fluoro-3-methoxyphenyl)-4-[4-[2-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)ethyl]phenyl]imidazol-1-yl]-n-propan-2-ylacetamide Chemical compound C1=C(F)C(OC)=CC(C=2N(C=C(N=2)C=2C=CC(CCN3C4CCC3CC(O)C4)=CC=2)CC(=O)NC(C)C)=C1 PRGLVTYMUBVODA-UHFFFAOYSA-N 0.000 abstract 2
- HHRJHJLTVNCGJV-UHFFFAOYSA-N 2-[3-(3-chlorophenyl)-1-[4-(2-piperidin-1-ylethyl)phenyl]pyrazol-4-yl]-n-propan-2-ylacetamide Chemical compound CC(C)NC(=O)CC1=CN(C=2C=CC(CCN3CCCCC3)=CC=2)N=C1C1=CC=CC(Cl)=C1 HHRJHJLTVNCGJV-UHFFFAOYSA-N 0.000 abstract 2
- HXWRUWZVLJDFJH-UHFFFAOYSA-N 2-[4-(3-chlorophenyl)-1-[4-(2-morpholin-4-ylethyl)phenyl]-2,5-dioxopyrrol-3-yl]-n-propan-2-ylacetamide Chemical compound O=C1C(CC(=O)NC(C)C)=C(C=2C=C(Cl)C=CC=2)C(=O)N1C(C=C1)=CC=C1CCN1CCOCC1 HXWRUWZVLJDFJH-UHFFFAOYSA-N 0.000 abstract 2
- NOLNSOPAPSDXMA-UHFFFAOYSA-N 2-[4-(3-chlorophenyl)-2-[4-(2-piperidin-1-ylethyl)phenyl]-1,3-oxazol-5-yl]-n-propan-2-ylacetamide Chemical compound CC(C)NC(=O)CC=1OC(C=2C=CC(CCN3CCCCC3)=CC=2)=NC=1C1=CC=CC(Cl)=C1 NOLNSOPAPSDXMA-UHFFFAOYSA-N 0.000 abstract 2
- SVIFIUWMIJSEAF-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-2-[4-(2-piperidin-1-ylethyl)phenyl]-1,3-thiazol-4-yl]-n-propan-2-ylacetamide Chemical compound CC(C)NC(=O)CC=1N=C(C=2C=CC(CCN3CCCCC3)=CC=2)SC=1C1=CC=CC(Cl)=C1 SVIFIUWMIJSEAF-UHFFFAOYSA-N 0.000 abstract 2
- PWDBSKFUCRAPKO-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-3-[4-(2-morpholin-4-ylethyl)phenyl]-1,2,4-triazol-1-yl]-n-propan-2-ylacetamide Chemical compound CC(C)NC(=O)CN1N=C(C=2C=CC(CCN3CCOCC3)=CC=2)N=C1C1=CC=CC(Cl)=C1 PWDBSKFUCRAPKO-UHFFFAOYSA-N 0.000 abstract 2
- BITVWYSHSJOCGC-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-3-[4-(2-morpholin-4-ylethyl)phenyl]-2-oxoimidazol-1-yl]-n-propan-2-ylacetamide Chemical compound O=C1N(CC(=O)NC(C)C)C(C=2C=C(Cl)C=CC=2)=CN1C(C=C1)=CC=C1CCN1CCOCC1 BITVWYSHSJOCGC-UHFFFAOYSA-N 0.000 abstract 2
- AXMBUGATQYFCJJ-UHFFFAOYSA-N n-tert-butyl-2-[4-(3-methoxyphenyl)-1-[4-[2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)ethyl]phenyl]-5-oxo-1,2,4-triazol-3-yl]acetamide Chemical compound COC1=CC=CC(N2C(N(C=3C=CC(CCN4C5CCC4COC5)=CC=3)N=C2CC(=O)NC(C)(C)C)=O)=C1 AXMBUGATQYFCJJ-UHFFFAOYSA-N 0.000 abstract 2
- PMQMWNGJQFXWLW-UHFFFAOYSA-N n-tert-butyl-2-[5-(3-methoxyphenyl)-3-[5-[2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)ethyl]pyridin-2-yl]-1,2,4-triazol-1-yl]acetamide Chemical compound COC1=CC=CC(C=2N(N=C(N=2)C=2N=CC(CCN3C4CCC3COC4)=CC=2)CC(=O)NC(C)(C)C)=C1 PMQMWNGJQFXWLW-UHFFFAOYSA-N 0.000 abstract 2
- 125000003107 substituted aryl group Chemical group 0.000 abstract 2
- 229910052739 hydrogen Inorganic materials 0.000 description 746
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 528
- 238000003786 synthesis reaction Methods 0.000 description 213
- 238000000034 method Methods 0.000 description 207
- 230000015572 biosynthetic process Effects 0.000 description 179
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 170
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 157
- 239000007787 solid Substances 0.000 description 151
- 239000000203 mixture Substances 0.000 description 142
- 238000005160 1H NMR spectroscopy Methods 0.000 description 135
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 118
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 96
- 239000000243 solution Substances 0.000 description 94
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 85
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 80
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 79
- 235000019439 ethyl acetate Nutrition 0.000 description 76
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 75
- 230000002829 reductive effect Effects 0.000 description 75
- 238000006243 chemical reaction Methods 0.000 description 64
- 239000002904 solvent Substances 0.000 description 63
- 239000012044 organic layer Substances 0.000 description 60
- 239000011541 reaction mixture Substances 0.000 description 57
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 56
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 55
- 101150041968 CDC13 gene Proteins 0.000 description 55
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 55
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 239000002274 desiccant Substances 0.000 description 38
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 37
- 235000019341 magnesium sulphate Nutrition 0.000 description 37
- 239000000706 filtrate Substances 0.000 description 36
- 239000003921 oil Substances 0.000 description 36
- 235000019198 oils Nutrition 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 239000012267 brine Substances 0.000 description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- 238000010898 silica gel chromatography Methods 0.000 description 30
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
- 230000008569 process Effects 0.000 description 29
- 239000002585 base Substances 0.000 description 28
- 239000012442 inert solvent Substances 0.000 description 27
- 238000001816 cooling Methods 0.000 description 26
- 238000001914 filtration Methods 0.000 description 26
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 25
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- 239000012046 mixed solvent Substances 0.000 description 24
- 238000001035 drying Methods 0.000 description 23
- 239000000460 chlorine Substances 0.000 description 22
- 238000000605 extraction Methods 0.000 description 21
- 238000012552 review Methods 0.000 description 21
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- 239000003795 chemical substances by application Substances 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 20
- 125000006239 protecting group Chemical group 0.000 description 20
- 125000004076 pyridyl group Chemical group 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- 235000011054 acetic acid Nutrition 0.000 description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 150000001412 amines Chemical class 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- 239000002253 acid Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 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 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].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.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 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 15
- 150000002500 ions Chemical class 0.000 description 15
- 108020003175 receptors Proteins 0.000 description 15
- 102000005962 receptors Human genes 0.000 description 15
- 101800001144 Arg-vasopressin Proteins 0.000 description 14
- 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 description 14
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- 238000005259 measurement Methods 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 13
- 229910052738 indium Inorganic materials 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- 230000009466 transformation Effects 0.000 description 11
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 10
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 238000009835 boiling Methods 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- 239000012264 purified product Substances 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- 238000000844 transformation Methods 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 125000001309 chloro group Chemical group Cl* 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 229910052783 alkali metal Inorganic materials 0.000 description 8
- 150000001340 alkali metals Chemical class 0.000 description 8
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 8
- 150000001342 alkaline earth metals Chemical class 0.000 description 8
- 238000007112 amidation reaction Methods 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 239000007810 chemical reaction solvent Substances 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- PDUSWJORWQPNRP-UHFFFAOYSA-N n-propan-2-ylacetamide Chemical compound CC(C)NC(C)=O PDUSWJORWQPNRP-UHFFFAOYSA-N 0.000 description 8
- 235000011181 potassium carbonates Nutrition 0.000 description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 7
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- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 1
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 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
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- 239000011736 potassium bicarbonate Substances 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
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- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
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- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
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- IBDSNZLUHYKHQP-UHFFFAOYSA-N sodium;3-oxidodioxaborirane;tetrahydrate Chemical compound O.O.O.O.[Na+].[O-]B1OO1 IBDSNZLUHYKHQP-UHFFFAOYSA-N 0.000 description 1
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- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
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- UIUJIQZEACWQSV-UHFFFAOYSA-N succinic semialdehyde Chemical compound OC(=O)CCC=O UIUJIQZEACWQSV-UHFFFAOYSA-N 0.000 description 1
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- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- FCMLWBBLOASUSO-UHFFFAOYSA-N tert-butyl 3-oxopiperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNC(=O)C1 FCMLWBBLOASUSO-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 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
- 125000005922 tert-pentoxy group Chemical group 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
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- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
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- PLLAKAFNKUYEMM-UHFFFAOYSA-N tributyl-(3-chlorophenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC(Cl)=C1 PLLAKAFNKUYEMM-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 1
- AVCVDUDESCZFHJ-UHFFFAOYSA-N triphenylphosphane;hydrochloride Chemical compound [Cl-].C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 AVCVDUDESCZFHJ-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
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Abstract
Disclosed are 2-(imidazolyl/1H-1,2,4-triazolyl/1,3-oxazolyl/1,3-thiazolyl/1H-pyrazolyl/2,5-dioxo-2,5-dihydro-1H-pyrrolyl)acetamide derivatives and analogues as represented by the general formula (I), or a pharmaceutically acceptable salt thereof, wherein: R1 represents a hydrogen atom, optionally substituted alkyl, cycloalkyl, or 4- to 8-membered saturated heterocycle; R2 represents a hydrogen atom or alkyl; R3 represents optionally substituted aryl or heteroaryl; R4 and R5 which may be the same or different each represent a hydrogen atom, optionally substituted alkyl, cycloalkyl, or an optionally substituted 4- to 8-membered saturated or unsaturated heterocycle containing one or more nitrogen, oxygen or sulfur atoms in the ring; or R4 and R5 together with the adjoining nitrogen atom, form a 4- to 8-membered saturated or unsaturated heterocycle optionally containing one or more nitrogen, oxygen or sulfur atoms in the ring in addition to the adjoining nitrogen atom, 2-oxa-6-azaspiro[3.3]hept-6-yl or 7-oxa-2-azaspiro[3.5]non-2-yl, wherein the 4- to 8-membered saturated or unsaturated heterocycle is optionally substituted; X1 is a single bond, -CO-, or -CONRx1; X2 is a single bond, alkylene -O-alkylene-; wherein iii) when X1 is a single bond or -CO-, X2 represents alkylene- or -O-alkylene-; and iv) when X1 is -CONRx1-, X2 represents a single bond; the ring A represents a benzene ring, a 6-membered aromatic heterocycle, a 4- to 8-membered saturated or partially unsaturated heterocycle containing one or two nitrogen atoms, or a cycloalkane, wherein the benzene ring, the 6-membered aromatic heterocycle and the 4- to 8-membered saturated or unsaturated heterocycle is optionally substituted, and wherein the remaining substituents are as defined herein. Representative compounds include 2-[2-(3-chlorophenyl)-4-{4-[2-(piperidin-1-yl)ethyl]phenyl}-1H-imidazol-1-yl]-N-(propan-2-yl)acetamide; 2-[2-(3-chlorophenyl)-4-{4-[2-(morpholin-4-yl)ethyl]phenyl}-1H-imidazol-1-yl]-N-(propan-2-yl)acetamide; 2-[2-(3-chlorophenyl)-4-(4-{2-[3-(hydroxymethyl)pyrrolidin-1-yl]ethyl}phenyl)-1H-imidazol-1-yl]-N-(propan-2-yl)acetamide; 2-[2-(4-fluoro-3-methoxyphenyl)-4-{4-[2-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)ethyl]phenyl}-1H-imidazol-1-yl]-N-(propan-2-yl)acetamide; 2-[5-(3-chlorophenyl)-3-{4-[2-(morpholin-4-yl)ethyl]phenyl }-1H-1,2,4-triazol-1-yl]-N-(propan-2-yl)acetamide; N-tert-butyl-2-[5-(3-methoxyphenyl)-3-{5-[2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)ethyl]pyridin-2-yl}-1H-1,2,4-triazol-1-yl]acetamide; 2-[5-(3-chlorophenyl)-3-{4-[2-(morpholin-4-yl)ethyl]phenyl}-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-N-(propan-2-yl)acetamide; 2-[4-(3-chlorophenyl)-2-{4-[2-(piperidin-1-yl)ethyl]phenyl}-1,3-oxazol-5-yl]-N-(propan-2-yl)acetamide; 2-[5-(3-chlorophenyl)-2-{4-[2-(piperidin-1-yl)ethyl]phenyl}-1,3-thiazol-4-yl]-N-(propan-2-yl)acetamide; 2-[3-(3-chlorophenyl)-1-{4-[2-(piperidin-1-yl)ethyl]phenyl}-1H-pyrazol-4-yl]-N-(propan-2-yl)acetamide; 2-[4-(3-chlorophenyl)-1-{4-[2-(morpholin-4-yl)ethyl]phenyl}-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-N-(propan-2-yl)acetamide; N-tert-butyl-2-[4-(3-methoxyphenyl)-1-{4-[2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)ethyl]phenyl}-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]acetamide; and 2-[2-(3-chlorophenyl)-4-{4-[2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl]phenyl}-1H-imidazol-1-yl]-N-(propan-2-yl)acetamide. Also disclosed is a pharmaceutical composition comprising the azole derivative or pharmaceutically acceptable salt thereof as defined above as an active ingredient, for treating or preventing mood disorder, anxiety disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal disease, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, immune-related disease, or alopecia. bstituted alkyl, cycloalkyl, or 4- to 8-membered saturated heterocycle; R2 represents a hydrogen atom or alkyl; R3 represents optionally substituted aryl or heteroaryl; R4 and R5 which may be the same or different each represent a hydrogen atom, optionally substituted alkyl, cycloalkyl, or an optionally substituted 4- to 8-membered saturated or unsaturated heterocycle containing one or more nitrogen, oxygen or sulfur atoms in the ring; or R4 and R5 together with the adjoining nitrogen atom, form a 4- to 8-membered saturated or unsaturated heterocycle optionally containing one or more nitrogen, oxygen or sulfur atoms in the ring in addition to the adjoining nitrogen atom, 2-oxa-6-azaspiro[3.3]hept-6-yl or 7-oxa-2-azaspiro[3.5]non-2-yl, wherein the 4- to 8-membered saturated or unsaturated heterocycle is optionally substituted; X1 is a single bond, -CO-, or -CONRx1; X2 is a single bond, alkylene -O-alkylene-; wherein iii) when X1 is a single bond or -CO-, X2 represents alkylene- or -O-alkylene-; and iv) when X1 is -CONRx1-, X2 represents a single bond; the ring A represents a benzene ring, a 6-membered aromatic heterocycle, a 4- to 8-membered saturated or partially unsaturated heterocycle containing one or two nitrogen atoms, or a cycloalkane, wherein the benzene ring, the 6-membered aromatic heterocycle and the 4- to 8-membered saturated or unsaturated heterocycle is optionally substituted, and wherein the remaining substituents are as defined herein. Representative compounds include 2-[2-(3-chlorophenyl)-4-{4-[2-(piperidin-1-yl)ethyl]phenyl}-1H-imidazol-1-yl]-N-(propan-2-yl)acetamide; 2-[2-(3-chlorophenyl)-4-{4-[2-(morpholin-4-yl)ethyl]phenyl}-1H-imidazol-1-yl]-N-(propan-2-yl)acetamide; 2-[2-(3-chlorophenyl)-4-(4-{2-[3-(hydroxymethyl)pyrrolidin-1-yl]ethyl}phenyl)-1H-imidazol-1-yl]-N-(propan-2-yl)acetamide; 2-[2-(4-fluoro-3-methoxyphenyl)-4-{4-[2-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)ethyl]phenyl}-1H-imidazol-1-yl]-N-(propan-2-yl)acetamide; 2-[5-(3-chlorophenyl)-3-{4-[2-(morpholin-4-yl)ethyl]phenyl }-1H-1,2,4-triazol-1-yl]-N-(propan-2-yl)acetamide; N-tert-butyl-2-[5-(3-methoxyphenyl)-3-{5-[2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)ethyl]pyridin-2-yl}-1H-1,2,4-triazol-1-yl]acetamide; 2-[5-(3-chlorophenyl)-3-{4-[2-(morpholin-4-yl)ethyl]phenyl}-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-N-(propan-2-yl)acetamide; 2-[4-(3-chlorophenyl)-2-{4-[2-(piperidin-1-yl)ethyl]phenyl}-1,3-oxazol-5-yl]-N-(propan-2-yl)acetamide; 2-[5-(3-chlorophenyl)-2-{4-[2-(piperidin-1-yl)ethyl]phenyl}-1,3-thiazol-4-yl]-N-(propan-2-yl)acetamide; 2-[3-(3-chlorophenyl)-1-{4-[2-(piperidin-1-yl)ethyl]phenyl}-1H-pyrazol-4-yl]-N-(propan-2-yl)acetamide; 2-[4-(3-chlorophenyl)-1-{4-[2-(morpholin-4-yl)ethyl]phenyl}-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-N-(propan-2-yl)acetamide; N-tert-butyl-2-[4-(3-methoxyphenyl)-1-{4-[2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)ethyl]phenyl}-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]acetamide; and 2-[2-(3-chlorophenyl)-4-{4-[2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl]phenyl}-1H-imidazol-1-yl]-N-(propan-2-yl)acetamide. Also disclosed is a pharmaceutical composition comprising the azole derivative or pharmaceutically acceptable salt thereof as defined above as an active ingredient, for treating or preventing mood disorder, anxiety disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal disease, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, immune-related disease, or alopecia.
Description
DESCRIPTION
AZOLE DERIVATIVE
TECHNICAL FIELD
The present invention s to a nd with an azole skeleton that has an
antagonistic action against the ne—vasopressin (AVP) Vlb receptor and to
pharmaceutical compositions comprising the compound as an active ient, in particular,
to agents for treating or preventing diseases such as mood disorder (including depression),
anxiety disorder, schizophrenia, mer's disease, Parkinson's disease, Huntington's
chorea, eating disorder, hypertension, gastrointestinal disease, drug addiction, epilepsy,
cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, immune—
related disease, and alopecia.
BACKGROUND ART
The arginine-vasopressin (AVP) is a peptide composed of nine amino acids that is
biosynthesized mainly in the hypothalamus and closely involved as a posterior pituitary
hormone in the regulation of plasma osmolality, blood pressure, and body fluid volume.
The AVP receptors have so far been cloned in three subtypes, Vla, Vlb, and V2
receptors, all of which are known to be seven—transmembrane receptors. The V2 receptor is
coupled to Gs to increase the CAMP level. The Vla receptor is coupled to Gq/ 11 to facilitate
PI response and increase the ellular Ca level. The Vla receptor is expressed in the
brain, liver, adrenal gland, and vascular smooth muscle, for example, and is ed in the
vasoconstrictive . As is the Vla receptor, the Vlb receptor is also coupled to Gq/ 11 to
facilitate PI response (see Non-Patent Documents 1 and 2). The Vlb or is found most
commonly in the pituitary gland (expressed in 90% or more of ACTH secreting cells of the
or lobe) and is estimated to participate in the AVP-mediated secretion ofACTH from
the or pituitary. Other than in the pituitary gland, the Vlb receptor is widely distributed
in the brain and occurs in large amounts not only in the limbic cortex system including the
hippocampus, amygdala and entorhinal cortex but also in the cerebral cortex, the olfactory
bulb, and the raphe nuclei which are the nuclei of origin of the serotonin nervous system (see
Non-Patent Documents 3 and 4).
In recent years, involvement of the Vlb receptor in mood disorder or anxiety
disorder has been suggested, and usefulness of Vlb receptor antagonists is being studied.
The Vlb receptor KO mice exhibit reduced aggressive behavior (see tent Document
). In addition, injection of a Vlb receptor antagonist into the septal area prolonged the time
spent in the open arms (anxiolytic—like action) in an elevated plus-maze test (see Non—Patent
Document 6). In recent years, a peripherally administrable l,3~dihydro-2H—indol—2-one
compound has been d as a Vlb receptor specific antagonist (see Patent Documents 1 to
3). Furthermore, the l,3-dihydro-2H—indol—2-one nd has been reported to show
antidepressant and anxiolytic actions in a variety of animal models (see Non—Patent
Documents 7 and 8). The compound disclosed in Patent Document 1 has high affinity for the
Vlb receptor (1 x 10‘9 mol/L to 4><10'9 mol/L) on which it selectively acts; this nd,
however, antagonizes AVP, AVP + CRF, and restraint stress-induced ACTH increases.
Recently, Vlb receptor antagonists having different structures from the 1,3-dihydro-
2H—indolone compound have been reported and they are quinazolinone tives (see
Patent Documents 4 and 10), B-lactam derivatives (see Patent Documents 5 and 7),
azinon/diazinon tives (see Patent nt 6), benzimidazolone derivatives (Patent
Document 8), isoquinolinone derivatives (see Patent nts 9 and 10), pyridopyrimidin-
4—one derivatives (see Patent Document 11), pyrrolo[l,2~a]pyrazine derivatives (see Patent
Document 12), pyrazolo[l,2-a]pyrazine derivatives (see Patent document 13), quinoline
derivatives (see Patent nt 14), tetrahydroquinoline sulfonamide tives (see
Non-Patent Document 9), thiazole tives (see Non—Patent Document 10), and
sulfonamide derivatives (see Non-Patent Document 1 1). However, no report has been made
of the compounds disclosed in the present ion that have an azole skeleton.
CITATION LIST
PATENT DOCUMENTS
Patent Document 1: W02001/055130
Patent Document 2: /021534
Patent nt 3: WO2005/030755
Patent Document 4: WO2006/095014
Patent Document 5: W02006/102308
Patent Document 6: WO2006/133242
Patent Document 7: W02007/109098
Patent Document 8: W02008/025736
Patent Document 9: W02008/033757
Patent Document 10: W02008/033764
Patent Document 11: W02009/017236
Patent Document 12: W02009/130231
Patent Document 13: WO2009/130232
Patent Document 14: WO2011/O96461
NON-PATENT DOCUMENTS
Non—Patent Document 1: Sugimoto T, Kawashima G, J. Biol. Chem, 269, 27088—
27092, 1994
Non—Patent Document 2: Lolait S, Brownstein M, PNAS, 92, 6783-6787, 1995
Non—Patent Document 3: Vaccari C, Ostrowski N, Endocrinology, 139, 5015-5033,
1998
Non—Patent Document 4: Hernando F, Burbach J, Endocrinology, 142, 1659—1668,
2001
tent Document 5: Wersinger SR, Toung WS, M01. Psychiatry, 7, 975—984,
2002
Non-Patent nt 6: Liebsch G, ann M, ci. Lett., 217, 101-104,
1996
Non-Patent Document 7: Gal CS, Le Fur G, 300, JPET, 1122-1130, 2002
Non—Patent Document 8: Griebel G, Soubrie P, PNAS, 99, 6370-6375, 2002
tent Document 9: Jack D. Scott, et al., Bioorganic & Medicinal Chemistry
Letters, 19, 21, 6018—6022, 2009
Non-Patent nt 10: Chris A S, et. al., Bioorganic & nal Chemistry
Letters, 21, 92—96, 2011
Non—Patent Document 11: James B, et. a1., Bioorganic & Medicinal Chemistry
Letters, 21, 3603-3607, 2011.
SUMMARY OF INVENTION
CAL PROBLEM
It is an object of the present invention to find novel compounds having a Vlb
receptor antagonistic action and to provide agents for treating or preventing diseases such as
mood disorder (including depression), anxiety disorder, schizophrenia, Alzheimer's disease,
Parkinson's disease, Huntington’s chorea, eating disorder, hypertension, gastrointestinal
disease, drug addiction, epilepsy, cerebral infarction, al ischemia, cerebral edema, head
injury, inflammation, immune—related disease, and ia, or which at least provide a useful
ative.
SOLUTION TO PROBLEM
As a result of diligent studies, the present inventors have found novel compounds
with a novel azole skeleton that have a Vlb receptor antagonistic action (the compounds are
after referred to as "azole derivatives") and this has led to the accomplishment of the
present invention.
Thus, the present invention es the following embodiments:
(1) An azole derivative represented by Formula (I):
[Chem 1]
ti 0
R2’ T
1/Y2 \N—RS
\ I
or a pharmaceutically acceptable salt of the azole derivative,
wherein in the above Formula (I),
R1 represents a en atom, C1_5 alkyl, C3-7 cycloalkyl, or 4- to 8—membered saturated
heterocycle, wherein the C15 alkyl is optionally substituted by one to three groups selected
from the group consisting of y, halogen atoms, cyano, C3-7 cycloalkyl, and C1-5
alkoxy;
R2 represents a hydrogen atom or C1-5 alkyl;
R3 represents aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted by
one or two groups selected from the group consisting of C1-5 alkoxy, C1_5 alkyl, halogen
atoms, romethyl, trifluoromethoxy, cyano, hydroxy, difluoromethoxy, and C1_5
alkylsulfonyl;
R4 and R5 which may be the same or different each represent a en atom, C1_5 alkyl, C3_
7 cycloalkyl, or a 4- to ered saturated or unsaturated heterocycle containing one or
more nitrogen, oxygen or sulfur atoms in the ring, wherein the C1_5 alkyl is optionally
substituted by one to three groups selected from the group consisting of hydroxy, n
atoms, cyano, C3_7 cycloalkyl, and C1_5 alkoxy, and the 4- to ered saturated or
rated heterocycle is optionally substituted by one or two groups selected from the
group consisting ofhydroxy, C1_5 alkyl, C1_5 alkoxy, halogen atoms, cyano, C2_5 alkanoyl, and
trifluoromethyl, or
R4 and R5, er with the adjoining nitrogen atom, form a 4— to 8—membered ted or
unsaturated heterocycle optionally containing one or more nitrogen, oxygen or sulfur atoms
in the ring in addition to the adjoining nitrogen atom, 2-oxa—6—azaspiro[3.3]11eptyl or 7-
oxa—2-azaspiro[3.5]non-2—y1, wherein the 4- to 8-membered saturated or unsaturated
heterocycle is ally substituted by one or two groups selected from the group consisting
of hydroxy, C1_5 alkoxy, halogen atoms, cyano, C2_5 alkanoyl, oxo, aminocarbonyl, mono-C1_5
alkylaminocarbonyl, di—C1_5 alkylaminocarbonyl, trifluoromethyl, amino, mono-C15
alkylamino, di-C1-5 alkylamino, C2-5 alkanoylamino, and C1_5 alkyl optionally substituted by
one or two yl groups, and the 4— to 8-mernbered saturated or unsaturated heterocycle
optionally has a C]_5 alkylene group crosslinking two different carbon atoms in the ring;
the optionally substituted azole ring which is represented by the following formula (0t):
(Followed by page 5a)
has any one of the structrures in the following formula group (II):
[Chem 3]
0 RV 0 (II)
where
Ry represents a hydrogen atom or C1-5 alkyl;X1 is a single bond, the formula ~CO—, or the
formula -CONRX1~;
X2 is a single bond, —C1_5 alkylene- or 5 alkylene-;
wherein
i) when X1 is a single bond or the formula -CO-, X2 represents —C1_5 alkylene- or ~0—
C1_5 alkylene-; and
ii) when X1 is the formula -CONRX1—, X2 represents a single bond;
RXI represents a hydrogen atom or C1-5 alkyl; and
the ring A represents a benzene ring, a 6—membered aromatic heterocycle, a 4- to 8-
membered saturated or lly rated heterocycle ning one or two nitrogen
atoms, or C3_7 cycloalkane, wherein the benzene ring and the 6-rnembered aromatic
(Followed by page 5b)
heterocycle are ally substituted by one or two groups selected from the group
consisting of halogen atoms and C1-5 alkoxy, and wherein the 4- to 8-membered saturated or
unsaturated heterocycle is optionally substituted by one 0x0.
(Followed by page 6)
has any one of the structrures in the following formula group (II):
[Chem 3]
Ry o ( u )
where
Ry ents a hydrogen atom or C1_5 alkyl;
X1 and X2 are such that
i) when X1 is a single bond or the a -CO-, X2 represents —C1-5 alkylene— or ~0—
C1_5 alkylene-; and
ii) when X1 is the formula -CONRX1-, X2 represents a single bond;
RX1 represents a hydrogen atom or C1_5 alkyl; and
the ring A represents a benzene ring, a 6-membered aromatic heterocycle (the benzene ring
and the 6-membered aromatic heterocycle are optionally substituted by one dr two groups
selected from the group consisting of halogen atoms and C1_5 alkoxy), a 4- to 8—membered
saturated or lly unsaturated heterocycle containing one or two nitrogen atoms (the 4- to
8-membered saturated or unsaturated heterocycle is optionally substituted by one oxo) or C3_7
cycloalkane] or a pharmaceutically acceptable salt of the azole derivative.
(2) The azole derivative or pharmaceutically acceptable salt thereof according to embodiment
(1), wherein in the above a (I),
R4 and R5 which may be the same or different each represent a hydrogen atom, C1_5 alkyl (the
C1_5 alkyl is optionally tuted by one to three groups selected from the group consisting
of hydroxy, halogen atoms, cyano, C3_7 cycloalkyl, and C1_5 alkoxy), C3-7 cycloalkyl, or a 4-
to 8-membered saturated or rated cycle ning one or more en, oxygen
or sulfur atoms in the ring (the 4- to 8-membered saturated or unsaturated heterocycle is
optionally substituted by one or two groups selected from the group consisting of y,
C1_5 alkyl, C1_5 alkoxy, halogen atoms, cyano, C25 alkanoyl, and trifluoromethyl), or
R4 and R5, together with the adjoining nitrogen atom, form a 4- to 8-membered saturated or
rated heterocycle optionally containing one or more nitrogen, oxygen or sulfur atoms
in the ring in addition to the adjoining nitrogen atom (the 4- to 8-membered saturated or
unsaturated heterocycle is ally substituted by one or two groups selected from the
group ting of hydroxy, C1-5 alkyl (the C1_5 alkyl is optionally substituted by one or two
hydroxyl groups), C1_5 alkoxy, halogen atoms, cyano, C2_5 alkanoyl, oxo, aminocarbonyl,
mono-CM alkylaminocarbonyl, di—C1_5 alkylaminocarbonyl and trifluoromethyl, and the 4— to
8-membered saturated or unsaturated heterocycle optionally has a C1_5 alkylene group
crosslinking two different carbon atoms in the ring) or form 2-oxa-6—azaspiro[3.3]hept—6-yl
or 7—oxa-2—azaspiro[3.5]nonyl.
(3) The azole derivative or pharmaceutically acceptable salt thereof according to embodiment
(1) or (2), wherein in the above Formula (I),
X1 represents a single bond;
X2 represents -C1.5 ne- or 5 a1ky1ene-; and
the ring A represents a benzene ring, a 6-membered aromatic heterocycle (the benzene ring
and the 6—membered aromatic heterocycle are optionally substituted by one or two groups
selected from the group consisting of halogen atoms and C1_5 alkoxy) or a 4- to 8-membered
saturated or unsaturated heterocycle containing one or two nitrogen atoms (the 4- to 8—
ed ted or unsaturated heterocycle is optionally substituted by one 0x0).
(4) The azole derivative or ceutically able salt thereof according to any one of
embodiments (l) to (3), wherein in the above a (I),
the ring A represents a benzene ring or a 6-membered aromatic heterocycle (the benzene ring
and the 6-membered aromatic heterocycle are ally substituted by one or two groups
selected from the group consisting of halogen atoms and C1_5 alkoxy).
(5) The azole derivative or pharmaceutically acceptable salt thereof according to any one of
embodiments (1) to (4), wherein in the above a (I),
the ring A represents a benzene ring or a pyridine ring (the benzene ring and the pyridine ring
are ally substituted by one or two groups selected from the group consisting of halogen
atoms and C1_5 alkoxy).
(6) The azole derivative or pharmaceutically acceptable salt thereof according to any one of
embodiments (l) to (5), wherein in the above Formula (I),
R1 is a C1_5 alkyl;
R2 is a hydrogen atom; and
R3 is phenyl or pyridyl (the phenyl and pyridyl are optionally substituted by one or two
groups selected from the group consisting of C1-5 alkyl, C1_5 alkoxy, halogen atoms, cyano,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, and C1_5 ulfonyl).
(7) The azole derivative or pharmaceutically acceptable salt thereof according to any one of
embodiments (1) to (6), wherein in the above Formula (I),
the optionally substituted azole ring which is represented by the following formula (0c):
[Chem 4]
has any one of the structrures in the following formula group (III):
[Chem 5]
:NW +
.... 3‘
‘N a; fig (Ill)
where
Ry represents a hydrogen atom or a methyl group.
(8) The azole derivative or pharmaceutically acceptable salt thereof according to any one of
embodiments (l) to (7), wherein in the above Formula (I),
X1 is a single bond;
X2 is ethylene or methylethylene; and
R4 and R5, together with the adjoining nitrogen atom, form a 4— to ered saturated or
unsaturated heterocycle optionally containing one or more nitrogen, oxygen or sulfur atoms
in the ring in on to the adjoining nitrogen atom (the 4- to 8-membered saturated or
unsaturated heterocycle is ally tuted by one or two groups selected from the
group ting of hydroxy, C1_5 alkyl (the C1-5 alkyl is optionally substituted by one or two
hydroxyl groups), C1_5 alkoxy, halogen atoms, cyano, C2_5 alkanoyl and trifluoromethyl, and
the 4- to 8-membered saturated or unsaturated heterocycle optionally has a C1_5 alkylene
group crosslinking two different carbon atoms in the ring) or form 2—oxa-6—azaspiro[3.3]hept-
6—yl.
(9) The azole derivative or pharmaceutically acceptable salt thereof according to any one of
embodiments (l) to (8), wherein in the above Formula (I),
R4 and R5, together with the adjoining nitrogen atom, form a 5— or 6-membered saturated
heterocycle optionally ning one or more oxygen atoms in the ring in addition to the
adjoining nitrogen atom (the 6—membered saturated heterocycle is optionally substituted by
one or two groups selected from the group consisting of yl and C1-5 alkyl, and the 6-
membered saturated heterocycle optionally has a C1_5 alkylene group crosslinking two
different carbon atoms in the ring) or form 2-oxaazaspiro[3.3]hept—6—yl.
(10) A pharmaceutical compositiOn sing the azole derivative or pharmaceutically
acceptable salt thereof according to any one of embodiments (1) to (9) as an active
ingredient.
(11) An agent for treating or preventing mood disorder, anxiety disorder, schizophrenia,
Alzheimer's disease, Parkinson‘s disease, Huntington's chorea, eating disorder, hypertension,
gastrointestinal disease, drug addiction, epilepsy, cerebral infarction, cerebral ia,
cerebral edema, head injury, inflammation, immune—related disease, or alopecia, comprising
the azole derivative or pharmaceutically acceptable salt thereof according to any one of
embodiments (1) to (9) as an active ingredient.
AGEOUS EFFECTS OF INVENTION
It has now become clear that the novel azole derivatives of the present invention not
only show an affinity for the Vlb or but also exhibit an antagonistic action against a
stimulus to the receptor by a physiological ligand.
DESCRIPTION OF EMBODIMENTS
The terms used in the specification have the following gs.
The term "halogen atom" refers to a fluorine atom, a chlorine atom, a e atom,
or an iodine atom.
The term "C1_5 alkyl" refers to a linear or branched alkyl group having 1 to 5 carbon
atoms, and examples thereof include methyl, ethyl, n—propyl, isopropyl, n—butyl, isobutyl,
sec—butyl, tert—butyl, n—pentyl, isopentyl, neopentyl, and tert-pentyl.
The term "C34 cycloalkyl" may be exemplified by a ropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl group.
The term "C1_5 alkoxy" refers to a linear or ed alkoxy group having 1 to 5
carbon atoms, and es thereof include methoxy, ethoxy, n—propoxy, isopropoxy, n-
butoxy, isobutoxy, sec—butoxy, tert-butoxy, n—pentyloxy, isopentyloxy, tyloxy, and
tert-pentyloxy.
The term "C1-5 alkylsulfonyl" refers to a yl group substituted by the "C1-5
alkyl" defined above, and examples thereof include methylsulfonyl, ethylsulfonyl, n—
sulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-
butylsulfonyl, n-pentylsulfonyl, tylsulfonyl, neopentylsulfonyl, and tert-pentylsulfonyl.
The term "C25 alkanoyl" refers to a linear or ed alkanoyl group having 2 to 5
carbon atoms, and examples thereof include acetyl, nyl, butyryl, isobutyryl, valeryl,
isovaleryl, and pivaloyl.
The term "C2_5 alkanoylamino”refers to an amino group having one "C2_5 alkanoyl"
defined above as a substituent and examples thereof include acetylamino, propionylamino,
butyrylamino, isobutyrylamino, valerylamino, isovalerlylamino, and pivaloylamino.
The term “mono-C15 alkylaminocarbony " refers to a carbonyl group substituted by
an amino having one "C1_5 alkyl" group defined above as a substituent, and examples thereof
include methylaminocarbonyl, ethylaminocarbonyl, n—propylaminocarbonyl,
isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, sec-
butylaminocarbonyl, tert-butylaminocarbonyl, n—pentylaminocarbonyl,
isopentylaminocarbonyl, and neopentylaminocarbonyl.
The term “mono—Cm alkylamino" refers to an amino group having one "(31-5 alkyl"
group defined above as a substituent, and examples thereof e methylamino,
ethylamino, n—propylamino, isopropylamino, n—butylamino, isobutylamino, tylamino,
tert-butyamino, n—pentylamino, isopentylamino, and neopentylamino.
The term "di—C1_5 alkylaminocarbonyl" refers to a carbonyl group tuted by an
amino having two cal or ent "C1_5 alkyl" groups defined above as substituents, and
examples thereof include dimethylaminocarbonyl, diethylaminocarbonyl, di(n-
propyl)aminocarbonyl, di(isopropyl)aminocarbonyl, ethylmethylaminocarbonyl, methy1(n-
propyl)aminocarbonyl, and isopropyl(methyl)aminocarbonyl.
The term “di-C1-5 alkylamino" refers to an amino group having two identical or
different "C15 alkyl" groups defined above as substituents, and examples thereof include
dimethylamino, diethylamino, di(n—propyl)amino, di(isopropyl)amino, ethylamino,
methyl(n-propyl)amino, and isopropyl(methyl)amino.
The term "aryl" refers to a monocyclic or bicyclic aromatic carbocycle, and
examples thereof include phenyl, l-naphthyl, and 2—naphthyl.
The term "heteroaryl" refers to a mono- or bi-cyclic aromatic group having 1 to 9
carbon atoms and also having at least one hetero atom selected from the group consisting of
oxygen, nitrogen, and sulfur atoms, and examples f include thienyl, furyl, pyrazolyl,
imidazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, pyridyl, pyrimidinyl, quinolyl, indolyl, and benzofuranyl.
[003 0] The term ”4— to 8-membered saturated heterocycle" may be exemplified by oxetan-
3—yl, azetidin—l-yl, 1—pyrrolidiny1, piperidino, 2-piperidyl, 3—piperidyl, 1—piperazinyl,
morpholin—4-yl, morpholin-3—yl, rpholinyl, thiomorpholin—3—yl, azepan-l-yl, 1,4-
oxazepanyl, and azocan- 1 —yl.
The term "4- to 8-membered saturated or unsaturated cycle containing one or
more nitrogen, oxygen or sulfur atoms in the ring" may be exemplified by oxetan—3 —yl,
in-l—yl, l—pyrrolidinyl, piperidino, 2—piperidyl, 3-piperidyl, razinyl, morpholin
yl, morpholinyl, thiomorpholinyl, thiomorpholin—3-yl, azepan-l-yl, 1,4-oxazepanyl,
and azocan— 1 —y1.
The term "a 4— to 8-membered saturated or unsaturated heterocycle formed together
with the adjoining nitrogen atom and ally containing one or more nitrogen, oxygen or
sulfur atoms in the ring in addition to the adjoining nitrogen atom" may be exemplified by
azetidin-l-yl, l—pyrrolidinyl, piperidino, razinyl,morpholin—4-yl,thiomorpholin-4—yl,
azepan—l—yl, 1, epan—4—yl, azocan—l—yl, hydropyridin— l (2H)—yl, l,4~diazepan-l-
yl, and l,2,3,6—tetrahydropyridin-l—yl. The cycle under consideration is preferably a 5—
or 6-membered ted heterocycle that is formed together with the adjoining nitrogen atom
and which may optionally contain one or more oxygen atoms in the ring in addition to the
adjoining nitrogen atom, and examples thereof include 1—pyrrolidinyl, piperidino, morpholin-
4-yl, 5,6-dihydropyridin- l (2H)-yl, and 1,2,3,6-tetrahydropyridin-l-yl.
The term "C15 alkylene" refers to a divalent group having one hydrogen atom
removed from the "C15 alkyl" defined above, and examples thereof include methylene,
ne, methylmethylene, trimethylene, methylethylene, propylene, tetramethylene,
ethylethylene, and pentamethylene.
The term "4- to 8-membered saturated or unsaturated heterocycle having a C1-5
alkylene group crosslinking two different carbon atoms in the ring" as referred to in
connection with the "4- to 8-membered saturated or unsaturated heterocycle formed together
with the ing nitrogen atom and optionally containing one or more nitrogen, oxygen or
sulfur atoms in the ring in addition to the adjoining nitrogen atom" defined above, may be
exemplified by 8-azabicyclo[3.2.l]octyl (tropinyl), 8-oxa—3—azabicyclo[3.2.1]octyl, 3—
oxa-S—azabicyclo[3.2.l]octyl, and octahydroisoquinolin—2(lH)—yl. Preferred are 8-
azabicyclo[3.2.l]oct—8—yl (tropinyl), 8-oxa—3—azabicyclo[3.2.l]oct—3-y1, and 3-oxa—8—
azabicyclo[3.2.1]oct—8-yl. Examples of the 8—azabicyclo[3.2. l]oct-8—yl that is substituted by
hydroxy include 3—hydroxy—8—azabicyclo[3 .2. 1]oct—8—yl.
The term “6-membered aromatic heterocycle” may be ified by pyridine and
pyrimidine rings
[003 6] The term "4- to 8-membered saturated or partially unsaturated heterocycle
containing one or two en atoms” may be ified by azetidine, pyrrolidine,
piperidine, piperazine, azepane, l, 4—diazepane, 1,2-dihydropyridine, and l,2,3,6-
tetrahydropyridine rings.
The term “C3_7 lkane” may be exemplified by cyclopropane, utane,
cyclopentane, cyclohexane, and eptane rings.
In the present invention, R1 is preferably C1_5 alkyl and more preferably isopropyl or
tert—butyl.
In the present invention, R2 is preferably a hydrogen atom.
In the present ion, R3 is preferably phenyl or pyridyl (the phenyl and pyridyl
are optionally substituted by one or two groups selected from the group ting of C1_5
alkyl, C1.5 alkoxy, halogen atoms, cyano, hydroxy, romethyl, difluoromethoxy,
trifluoromethoxy, and C1_5 alkylsulfonyl).
More preferably, R3 is phenyl (the phenyl is optionally substituted by one or two
groups selected from the group consisting of C1_5 alkyl, C1_5 alkoxy, halogen atoms, cyano,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, and C1_5 alkylsulfonyl) or pyridyl (the
pyridyl is optionally substituted by one or two groups selected from the group consisting of
C1_5 alkyl, C1_5 alkoxy, halogen atoms, cyano, hydroxy, trifluoromethyl, difluoromethoxy,
and trifluoromethoxy).
Still more preferably, R3 is phenyl (the phenyl is optionally substituted by one or
two groups selected from the group consisting of C1_5 alkoxy, chlorine atom, fluorine atom,
cyano, and C1-5 alkylsulfonyl) or pyridyl (the pyridyl is ally substituted by C1_5
alkoxy).
In a particularly preferred case, R3 is a group represented by any one of the
structures in the following formula group (IV).
[Chem 6]
U“ ”U" U‘ ”I?" ”°Uf
In a preferred embodiment of the present invention, the optionally tuted azole
ring represented by the following a (on)
[Chem 7]
is a ring that is ented by any one of the structures in the following formula group (V).
0 RV o ( V )
In a further preferred ment, the optionally substituted azole ring represented
by the above a (0t) is a ring that is represented by any one of the structures in the
following formula group (VI).
[Chem 9]
:LN/gi- :“::%"% :1}? (VI)
In the present invention, Ry is preferably a hydrogen atom or a methyl group.
In the present ion, X1 is preferably a single bond.
In the present invention, X2 is preferably -C1_5 alkylene- or -O- C1_5 alkylene—.
More preferably, X2 is -C1_5 alkylenem
Still more preferably, X2 is ethylene or methylethylene.
In the present invention, the ring A is preferably benzene or pyridine (the benzene
ring and the pyridine are optionally tuted by one or two groups selected from the group
consisting of halogen atoms and C1_5 alkoxy) or a 4— to S-membered saturated or partially
—16—
unsaturated heterocycle having one or two nitrogen atoms (the 4- to 8—membered saturated or
unsaturated heterocycle is optionally substituted by one 0x0).
More preferably, the ring A is a ring represented by any one of the structures in the
following formula group (V11).
[Chem 10]
Me-O O-Me -E©§- -§F s- —§©- 5%}— -©s—
_/>§-N— -§@§ $N_ é- --\__/NNi- (VII)
[005 8] Still more preferably, the ring A is a ring represented by any one of the structures in
the following formula group .
[Chem 11]
_§©é' 'igi (VIII)
In the present invention, R4 and R5 preferably, together with the adjoining nitrogen
atom, form a 4- to 8—membered saturated or unsaturated heterocycle ally containing
one or more nitrogen, oxygen or sulfur atoms in the ring in addition to the adjoining en
atom (the 4- to 8—membered saturated or rated heterocycle is ally substituted by
one or two groups selected from the group consisting of hydroxy, C1_5 alkyl (the C1_5 alkyl is
optionally substituted by one or two hydroxyl groups), C15 alkoxy, halogen atoms, cyano,
C2_5 alkanoyl and trifluoromethyl, and the 4- to 8—membered saturated or unsaturated
heterocycle optionally has a C1-5 ne group crosslinking two different carbon atoms in
the ring) or form 2—oxaazaspiro[3.3]heptyl.
More preferably, R4 and R5, together with the adjoining nitrogen atom, form a 5- or
6-membered saturated heterocycle optionally containing one or more oxygen atoms in the
ring in addition to the adjoining nitrogen atom (the 6-membered saturated heterocycle is
optionally substituted by one or two groups selected from the group consisting of hydroxyl
and C1_5 alkyl, and the 6-membered saturated heterocycle optionally has a C1_5 alkylene group
inking two different carbon atoms in the ring) or form 6-azaspiro[3.3]heptyl.
Particularly preferred examples of the ring which R4 and R5 form together with the ing
nitrogen atom are l-pyrrolidinyl, piperidino (where the 1-pyrrolidiny1 and piperidino are
optionally substituted by one or two hydroxyl groups), morpholinyl (where morpholine is
optionally substituted by one or two C1_5 alkyl , as in 3-methyl—morpholin~4—yl), 1,4-
oxazepan—4-yl, thiomorpholin-4—yl, 8—azabicyclo[3.2.l]oct—8-y1 (tropinyl), 3-hydroxy—8-
yclo[3.2.1]oct—8—yl, 8—oxa~3—azabicyclo[3.2. l ]oct-3 -yl, 3-oxa—8-azabicyclo[3.2.1]oct
yl, 2-oxaazaspiro[3.3]hept—6—yl, and 7—oxa—2—azaspiro[3.5]non-1—yl.
Among the compounds of the present invention, the following may be listed as
preferred examples:
2—[2—(3 —ch10rophenyl) {4-[2—(piperidin— l-y1)ethyl]phenyl} - lH-imidazol- l-yl]-N-(propan-2—
y1)acetamide;
2— [2—(3 -chlorophenyl)—4- {4-[2-(morpholin—4-yl)ethyl]phenyl}-lH—imidazol—1-yl]-N-(propan—
2—y1)acetamide;
2— [2—(3 —chlorophenyl)—4-(4— {2— [3 -(hydroxyrnethyl)pyrrolidin— 1 —yl] ethyl } phenyl)- 1 H-
imidazolyl]-N-(propanyl)acetamide;
2-[2-(3-chlorophenyl)—4—{4—[2—(3—oxaazabicyclo[3.2.1]octyl)ethyl]phenyl}-lH-
imidazol-l-y1]—N—(propan—2—y1)acetamide;
2-[2—(4-fluoromethoxyphenyl)—4— {4-[2~(piperidin—1—y1)ethyl]phenyl}-lH—imidazol—l-yl]-
N~(propan—2—yl)acetamide;
2—[2-(4-flu0romethoxyphenyl)~4~{4—[2-(morpholinyl)ethyl]phenyl}-1H-imidazol—l-yl]—
N-(propan-Z-y1)acetamide;
2-[2-(4-fluoromethoxyphenyl) {4-[2-(pyrrolidin-l-yl)ethy1]phenyl}-lH-imidazol-l-yl]-
N-(propan-Z-yl)acetamide;
2—[2-(4-fluoromethoxyphenyl)-4—(4— R)—2-methylpyrrolidin— l -yl] ethyl } phenyl)- l H-
imidazolyl]—N—(propan—Z—yl)acetamide;
2-[2-(4—fluoromethoxypheny1) {4-[2-(3-hydroxy—8-azabicyclo [3 .2. 1]oct-8—
yl)ethy1]pheny1}-1H—imidazoly1]—N-(propan-2—y1)acetamide;
2-[2-(4-fluoro—3-methoxyphenyl)—4— {4— methoxypiperidiny1)ethy1]phenyl}-1H-
imidazoly1]-N-(propan—Z—y1)acetamide;
2-[4— {4-[2-(2,6—dimethy1morph01in-4—y1)ethy1]phenyl } -2—(4~fluor0methoxypheny1)-1H-
imidazolyl] —N-(propan—Z-y1)acetamide;
2—[2—(4-fluor0-3~meth0xypheny1)—4- {4—[2-(3-methy1pyrrolidin—1—yl)ethyl]pheny1}—1H—
imidazol- 1 —y1]~N—(propan-Z—yl)acetamide;
2-[2-(4—fluoro-3~methoxypheny1)~4—{4—[2-(3-oxa~8—azabicyc10[3 .2. 8-y1)ethyl]phenyl}-
lH—imidazol— 1 -y1] -N—(propanyl)acetamide;
2- [2-(4-fluor0methoxypheny1)—4—{4-[2—(1,4-oxazepan-4—y1)ethy1]phenyl}~1H-imidazol
yl] ~N-(propan-2—yl)acetamide;
2-[4- {4-[2-(3 ,5—dimethy1morpholin—4-yl)ethy1]pheny1}~2-(4-flu0r0-3—methoxyphenyl)—1H—
imidazolyl]-N-(propany1)acetamide;
2-[2-(3 -chlorophenyl){5—[2—(morpho1iny1)ethy1]pyridinyl}-1H-imidazol—1—y1]—N-
(propan—Z—yl)acetamide;
2~[2—(3 —chlorophenyl)—4- {5—[2-(3-oxa-8—azabicyclo[3 .2. 8-y1)ethy1]pyridin—2-y1} — 1 H—
imidazolyl]-N—(propan—Z-y1)acetamide;
2- [2—(3 -chloropheny1) {6— [2—(morph01in-4—y1)ethyl]pyridiny1}—1H—imidazol-1 -y1]-N-
(propan-Z—y1)acetamide;
2— [2-(3 —methoxyphenyl)~5-methy1-4— {4-[2-(morpholin—4-y1)ethyl]pheny1}—1H-imidazol—1-
yl] -N-(propan—Z—y1)acetamide;
3-meth0xyphenyl) {4—[2—(morpholin—4—y1)ethy1]phenyl} —1H~imidazolyl]-N—
n—2—yl)acetamide;
2-[2-(3-ch10rofluoropheny1) {4-[2—(morpholiny1)ethy1]pheny1}-1H-imidazoly1]-N-
(propan—Z-yl)acetamide;
2—[2—(3—methoxypheny1)—4—{4—[2—(3—0xa—8—azabicyclo [3 .2. 1 ]oct—8—y1)ethyl]phenyl } - 1 H-
imidazol-l-yl]-N-(propan—Z-y1)acetamide;
2-[2-(3 —ch10rophenyl) {2-fluoro—4-[2-(morpholin-4—y1)ethy1]pheny1}—1H—imidazoly1]—N—
(propany1)acetamide;
2-[2-(3 —chloropheny1) {4-[2-(morpholin-4—y1)propy1]phenyl} - 1 H—imidazol— 1 —y1]—N—
(propan-Z—yl)acetamide;
2-[5-(3—ch10ropheny1){4—[2-(3-0xa-8—azabicy010[3.2. 1]octy1)ethyl]phenyl}~1H—1,2,4-
triazol—1~yl]—N—(propan-2—yl)acetamide;
2—[5-(3—chlorophenyl)—3- {4-[2-(morpholin-4—y1)ethy1]phenyl}-1H—1,2,4~triazol~1—y1]-N—
(propan—2-yl)acetamide;
2-[5—(3 —ch10rophenyl)-3— {5-[2—(3 -oxa—8—azabicyclo[3 .2. 1]oct—8—y1)ethy1]pyridin-2—yl } — 1H-
1 ,2,4~triazol—1—y1]-N-(pr0pan-2—y1)acetamide;
2—[5—(3-methoxypheny1) {5-[2-(3-0xaazabicyclo[3.2. 1]octyl)ethy1]pyridin—2—y1}—1H—
1 riazol—1-y1]—N—(propan—2-y1)acetamide;
4-flu0ro-3—methoxypheny1) (3 —oxaazabicyclo[3 .2. 1]octy1)ethy1]pyridin—
2-y1}-1H—1,2,4-triazoly1]—N-(propany1)acetamide;
N—tert-butyl—Z—[S—(3 —methoxypheny1)—3- {5-[2-(3 -oxa—8-azabicyclo[3.2.1]oct—8-
y1)ethy1]pyridin—2—y1}—1H—1,2,4—triazol-1—yl]acetamide;
2-[5-(3—chloro-4—fluoropheny1)—3-{5-[2-(3—0xa—8—azabicyclo[3.2.1]oct—8-yl)ethyl]pyridin-2—
y1}—1H-1,2,4—triazol—1-y1]-N-(propan—2—y1)acetamide;
N—tert-butyl-2—[5—(3 opheny1)—3— {5—[2—(3 —0xa—8—azabicy010[3 .2. 8—yl)ethy1]pyridin-
2-yl}—1H~1,2,4-triazol—1~y1]acetamide;
3 —ch10r0pheny1)—3- {5-[2-(morpholin-4~y1)ethy1]pyridin~2—y1} — 1 H- 1 ,2,4-triazol— 1 —y1]-N-
(propan-2~yl)acetamide;
N—tert-butyl-Z-[S-(3-ch10ropheny1) {5—[2-(morpholiny1)ethy1]pyridinyl}-1H—1 ,2,4-
triazol— 1—y1]acetamide; ‘
2-[5-(3-chlorofluoropheny1){5-[2-(morpholin—4-y1)ethy1]pyridinyl}-1H-1,2,4-
triazoly1]-N—(propan—2-y1)acetamide;
2—[5—(4-flu0r0meth0xyphenyI) {5-[2-(morpholin—4~y1)ethy1]pyridin—2-yl } - 1 H- 1 ,2,4—
triazol— 1 —y1]—N—(propan-2—y1)acetamide;
N—tert—butyl-Z-[S—(3—methoxypheny1)—3- {5-[2-(m0rpholin—4-y1)ethy1]pyridin-Z-y1 } - 1 H— 1 ,2,4—
l- 1 etamide;
2—[5—(3—meth0xypheny1){4—[2-(morpholiny1)ethy1]phenyl} 2,4—triazoly1]-N-
(propan—Z—yl)acetamide;
2-[5-(3-methoxyphenyl)—3~ {4—[2-(3—oxa—8-azabicyclo[3.2. 1]oct—8—y1)ethyl]pheny1}-1H-1,2,4-
triazol— 1 ~y1]—N-(propan—2~y1)acetamide;
2-[3- {2~fluoro—4—[2—(morpholin—4-yl)ethyl]phenyl } —5-(3-methoxyphenyl)—1H—1,2,4-triazol—1 —
yl] -N—(propan—2-yl)acetamide;
2—[3- {3-fluoro-4—[2-(morpholin-4—y1)ethy1]pheny1}-5—(3~methoxypheny1)—1H-1,2,4—triazol—1—
yl]~N—(pr0pany1)acetamide;
2-[5-(3-methoxyphenyl){4-[2-(3-oxa-8—azabicyc1o[3.2. 1]oct—8—y1)pr0pyl]pheny1}-1H-
1,2,4-triazoly1]-N—(propan—Z—y1)acetamide;
2—[5—(3—methoxyphenyl)—3— {4-[2-(7-oxaazaspiro[3.5]n0n—2-y1)ethy1]pheny1} - 1H— 1 ,2,4-
triazoly1]-N-(propany1)acetamide;
2-[5—(3—methoxypheny1)-3— {4-[2—(2—oxa—6~azaspiro[3 .3]hepty1)ethy1]pheny1}-1H— 1 ,2,4—
l— 1 -yl]-N—(propanyl)acetamide;
2-[1-(3-chloropheny1)-3 — {4-[2—(morpholiny1)ethy1]pheny1}~1H—1,2,4-triazol-5—y1]—N—
(propan-Z—yl)acetamide;
2-[1—(3—chloropheny1)-3— {4-[2-(3-oxa—8~azabicyc10[3.2. 1]oct—8—y1)ethy1]pheny1}—1H—1,2,4—
triazol~5~yl] —N—(propan-2—y1)acetamide;
2—[5-(3 ophenyl)-3 - {4-[2-(morpholiny1)ethy1]pheny1} —2—oxo-2,3—dihydr0- 1H—
imidazo1y1]-N-(propan-Z-yl)acetamide;
2- [4-(3-chloropheny1)~2- {4-[2-(piperidin- 1 ~y1)ethy1]pheny1} - 1 ,3-oxazoly1]-N-(propan—2-
yl)acetamide;
2-[4-(3-chlorophenyl)-2—{4-[2-(morph01iny1)ethyl]pheny1}-1,3-oxazol-5—y1]-N-(propan
y1)acetamide;
2—[4-(3-chloropheny1)—2- {4—[2—(2—0xa—6-azaspir0[3.3]hept—6-y1)ethy1]phenyl}-1,3—0xazol
y1]—N-(pr0pany1)acetamide;
2-[5-(3-ch10ropheny1)-2—{4—[2-(piperidin—1-yl)ethyl]pheny1}-1,3—thiazolyl]-N-(propan—2—
y1)acetamide;
2—[5—(3-Chloropheny1)-2—{4-[2—(morpholiny1)ethy1]pheny1}—1,3-thiazol-4—yl]-N—(propan
y1)acetamide;
2- [3 -(3 -chloropheny1)—1~{4—[2-(piperidinyl)ethyl]pheny1}-1H—pyrazol—4—y1]-N-(propan
tamide;
2-[3-(3-chloropheny1)—1-{4—[2-(m0rpho1iny1)ethy1]pheny1}-1H-pyrazol—4—y1]—N—(pr0pan-2—
y1)acetamide;
3 -chlorophenyl)-3 — {4—[2—(morpholinyl)ethyl]phenyl} razoly1]-N—(pr0pan—2-
y1)acetamide;
2- [4-(3 -chloropheny1) {4~[2-(m0rph01in—4—y1)ethyl]phenyl}~2,5~dioxo—2,5—dihydro— 1 H-
pyrr01yl] -N-(propan—2—y1)acetamide;
2-[4-(3-chlorophenyl)—1—{4—[2-(morpholin-4—yl)ethy1]pheny1}—5-oxo—4,5-dihydro~1H—1,2,4-
triazoIy1]-N-(propanyl)acetamide;
2-[4-(3-chlorophenyl){4—[2-(3—oxa~8—azabicyc10[3.2.1]oct—8—yl)ethyl]phenyl}oxo—4,5—
dihydro- 1 H- 1 ,2,4-triazol-3 -y1]-N-(propan—Z—y1)acetamide;
N—tert—butyl—Z-[4-(4—fluoro-3~methoxyphenyl) {4-[2-(morpholiny1)ethy1]pheny1} -5—0x0—
4,5-dihydro-1H—l ,2,4»triazol-3~y1]acetamide;
N-tert—butyl-Z-[4—(3~methoxypheny1)— 1— {4-[2-(morpholinyl)ethy1]phenyl } —5—0x0-4,5-
dihydro—1H—1,2,4-triazoI—3 ~y1]acetamide;
N~tert~butyl~2~[4~(3—methoxypheny1)—1-{4-[2—(3-oxaazabicyclo [3 .2. 1]oct—8—
yl)ethyl]phenyl}0xo-4,5—dihydro—1H-1,2,4-triazol-3—y1]acetamide;
N-tert-butyl-Z-[4-(4-flu0romethoxypheny1) {4-[2-(3-oxaazabicyclo [3 .2. Hoot
yl)ethy1]phenyl}0xo—4,5—dihydro-1H~1,2,4—triazoly1]acetamide;
N-tert—butyl-Z-[4-(4-fluoromethoxyphenyl){5—[2-(3-0xaazabicyclo[3.2.1]oct
y1)ethy1]pyridinyl}—5-oxo-4,5-dihydro-1H-1,2,4-triazol—3-y1]acetamide;
N-tert-butyl—Z-[4—(3 opheny1) {4- [2—(morpholinyl)ethy1]phenyl } ~5—0x0—4,5-
dihydro- 1 H— 1 ,2,4-triazol—3 -yl] acetamide;
—buty1[4-(3-chloropheny1)—1-{4-[2-(3—0xa—8—azabicyc10[3.2.1]oct-8—
y1)ethy1]phenyl}oxo-4,5-dihydro-1H-1,2,4-triazoly1]acetamide;
2-[4-(3—ch10ropheny1){4-[2-(morpholin—4-y1)propy1]pheny1}ox0—4,5—dihydro-1H-1,2,4—
triazolyl]-N—(propan—2—y1)acetamide;
2-[4-(3-chlorophenyl)—1—{4—[2—(3—oxa—8-azabicyclo[3.2.1]oct~8~y1)pr0pyl]pheny1}—5-0xo—4,5-
dihydro- 1 H- 1 ,2,4~triazol-3—yl] -N-(propan—2-y1)acetamide;
2-[4-(3-chloropheny1)-1— {3-fluor0—4-[2-(morpholin-4—y1)ethy1]pheny1}0X0—4,5—dihydro-
1H-1,2,4—triazol—3-y1]-N-(propan—Z-y1)acetamide;
2-[4-(3—chloropheny1)-1—{3—fluoro[2-(3-0xaazabicyclo[3.2.1]oct-8—y1)ethy1]pheny1}
0x0—4,5—dihydr0-1H—1,2,4-triazol-3—y1]-N-(propan—Z—y1)acetamide;
2-[4—(3 ~chlor0phenyl)— 1 - hoxy[2—(morpholin-4—y1)ethy1]phenyl } 0xo-4,5—dihydro—
1H-1,2,4-triazol-3—y1]—N—(propan-2—y1)acetamide;
2-[4-(3-ch10ropheny1){3-methoxy—4-[2-(3-oxaazabicyclo[3.2.1]0ct—8—y1)ethy1]phenyl}-
-oxo-4,5-dihydro-1H-1,2,4-triazoly1]-N-(propan-Z-y1)acetamide;
2-[4-(3—chloro—4—flu0r0pheny1)—1—{4—[2—(m0rpholin—4—y1)ethy1]pheny1}—5-oxo—4,5-dihydro—
1H-1 ,2,4—triazol-3 -y1] ~N—(propan—2-y1)acetamide;
2—[4—(3~chlor0fluorophenyl)-1—{4-[2-(3~oxaazabicyclo[3.2.1]octyl)ethy1]pheny1}-5—
-dihydro—1H—1,2,4—triazol-3—y1]~N—(propan-Z-yl)acetamide;
N—tert—butyl—Z—[4—(3-chlor0—4—fluoropheny1)- 1— {4-[2-(m0rpholin—4-y1)ethy1]pheny1}—5-0X0—
4,5-dihydro—1H~1,2,4-triazol—3—y1]acetamide;
N—tert-butyl-Z—[4-(3-chloro-4—fluorophenyl) {4-[2—(3—oxa-8—azabicyclo[3.2.1]oct—8—
y1)ethyl]phenyl}—5-0xo-4,5—dihydro—1H—1,2,4-triazol—3-yl]acetamide;
N-tert—buty1—2-[4-(3-ch10r0fluorophenyl)- 1 — {5-[2~(morpholin—4-y1)ethyl]pyridin-2—y1} ~5-
—dihydro-1H-1,2,4-triazoly1]acetamide;
N-tex’c-butyl-Z-[4-(3 -chlorofluoropheny1){5-[2-(3-oxaazabicyclo[3.2. 1]oct
y1)ethy1]pyridiny1} —5 -oxo-4,5-dihydro-1H—1,2,4-triazolyl]acetamide;
2—[4—(3—chlorophenyl)-1—{5~[2—(3—oxa-8—azabicyclo[3.2.1]oct—8—y1)propy1]pyridin—2-yl}-5—
oxo-4,5-dihydro— 1 H— 1 ,2,4—triazol—3—y1]~N-(pr0pany1)acetamide;
2-(1-{4-[2-(morpholin—4-yl)ethyl]phenyl}oxo-4— ifluoromethyl)phenyl]-4,5-dihydro-
lH-l,2,4—triazoly1)-N-(propan-Z-yl)acetarnide;
2-[4—(3-chloro—4-fluorophenyl){4-[2—(3—0xa—8—azabicyclo[3.2.1]oct—8-yl)pr0pyl]phenyl}-5—
oxo—4,5—dihydr0— lH-l riazol-3 -yl] »N—(propan-Z-yl)acetamide;
2—[4-(4—fluoro—3-methoxyphenyl)— l - {4—[2—(3-oxaazabicyclo [3 .2. l]oct—8—yl)ethyl]phenyl } —
—0xo—4,5—dihydro—1H—1,2,4-triazol-3—yl]—N—(propanyl)acetamide;
2—[4-(4-fluoro—3-methoxyphenyl)— l — {3-methoxy—4-[2-(3-oxa—8-azabicyclo [3 .2. 1 ]oct—8-
yl)ethyl]phenyl } oxo-4,5 —dihydro-1H—l,2,4—triazolyl]-N—(propan—Z-yl)acetamide;
2—[1—{3—methoxy-4—[2—(3-oxa-8—azabicyclo[3.2. l]oct—8—yl)ethyl]phenyl}—4—(3—
methoxyphenyl)oxo-4,5-dihydro-lH-l ,2,4-triazol—3—yl]-N-(propan-Z—yl)acetamide;
2—[4-(3-chloro-4—fluorophenyl)oxo {4-[2—(pyrrolidin— l -yl)ethyl]phenyl } -4,5-dihydro—
1H-1,2,4-triazolyl]-N—(propanyl)acetamide;
2-[4—(3 —chloro—4-fluorophenyl)oxo{4-[2—(piperidiny1)ethyl]phenyl}-4,5-dihydro-1H—
1,2,4-triazol—3-y1]-N-(propanyl)acetamide;
or pharmaceutically acceptable salts of these compounds.
Examples of the "pharmaceutically acceptable salt" include salts with inorganic
acids, such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, and nitric
acid; salts With organic acids such as formic acid, trifluoroacetic acid, acetic acid, oxalic acid,
lactic acid, ic acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid,
methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid,
ethanesulfonic acid, glucoheptcnic acid, gluconic acid, glutamic acid, glycolic acid, malic
acid, malonic acid, ic acid, galactaric acid, and naphthalene-Z—sulfonic acid; salts with
one or more metal ions such as lithium, sodium, ium, calcium, ium, zinc, and
aluminum ions; and salts with amines such as a, arginine, lysine, piperazine, choline,
diethylamine, 4-phenylcyclohexylamine, oethanol, and benzathine.
The compounds of the present invention can also occur in the form of various
solvates. From the aspect of applicability as medicines, the compounds may also occur in the
form of hydrates.
The compounds of the present invention encompass all possible forms including
their enantiomers, diastereomers, equilibrium compounds, mixtures thereof at any
proportions, and racemates.
The compounds of the present invention can be formulated into ceutical
preparations together with one or more pharmaceutically acceptable carriers, excipients, or
diluents. es of the carrier, excipient, and diluent include water, lactose, dextrose,
se, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, , gum,
gelatin, alginate, calcium te, calcium phosphate, cellulose, water syrup, methylcellulose,
polyvinylpyrrolidone, alkyl parahydroxybenzosorbate, talc, magnesium te, stearic acid,
in, and various oils such as sesame oil, olive oil, and n oil.
The above-mentioned carrier, excipient, or diluent is optionally mixed with
commonly used additives, such as a bulking agent, a binder, a disintegrant, a pH adjuster, or
a solubilizer, and can be prepared in the form of oral or parenteral medicines, such as tablet,
pill, capsule, granule, powder, liquid, emulsion, suspension, ointment, injection, or skin
plasters and pressure—sensitive adhesives tapes, by common preparation technology. The
compounds of the present invention can be orally or parenterally administered to adult
patients in a unit dosage of 0.001 to 500 mg once or several times per day. The dosage can
be riately ed depending on, for example, the type of the disease to be treated and
the age, weight, and symptoms of the patient.
The nds of the present invention may include those in which one or more of
the hydrogen, fluorine, carbon, nitrogen, oxygen, and sulfur atoms are replaced with
radioisotopes or stable es thereof. These labeled compounds are useful, for example,
for metabolic or pharmacokinetic study or as ligands of receptors in biological is.
The compounds of the present invention can, for example, be produced in
accordance with the methods shown below.
The compounds represented by Formula (I) and pharmaceutically able salts
thereof can be produced by various organic synthesis techniques known to those skilled in the
art. For e, they can be produced by the following synthetic processes to which the
-25..
present invention is by no means limited.
The term “inert solvents” as used herein covers, for example, aromatic solvents such
as e, toluene, xylene, and pyridine; arbon solvents such as , pentane, and
cyclohexane; halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-
dichloroethane, and carbon tetrachloride; ether solvents such as tetrahydrofuran, diethyl
ether, 1,2-dimethoxyethane, and l,4—dioxane; ester solvents such as ethyl acetate and ethyl
formate; alcoholic solvents such as methanol, ethanol, isopropyl alcohol, tert—butyl alcohol,
and ethylene glycol; ketonic ts such as acetone and methyl ethyl ketone; amide
solvents such as N,N—dimethylformamide, N—methylpyrrolidone, and N,N—dimethylactamide;
sulfoxide solvents such as dimethyl sulfoxide; nitrile solvents such as acetonitrile and
nitrile; water; as well as homogeneous and heterogeneous mixed ts thereof.
These inert ts may be chosen as appropriate depending on various reaction conditions
known to those skilled in the art.
The term “bases” as used herein covers, for example, es of alkali metals or
alkaline earth metals such as lithium hydride, sodium hydride, potassium hydride, and
calcium hydride; amides of alkali metals or alkaline earth metals such as lithium amide,
sodium amide, lithium diisoproylamide, lithium dicyclohexylamide, lithium
hexamethyldisilazide, sodium thyldisilazide, and potassium hexamethyldisilazide;
lower alkoxides of alkali metals or alkaline earth metals such as sodium methoxide, sodium
ethoxide, and potassium tert-butoxide; alkyl m compounds such as butyl m, sec—
butyl lithium, tert~butyl lithium, and methyl lithium; hydroxides of alkali metals or alkaline
earth metals such as sodium hydroxide, ium hydroxide, lithium hydroxide, and barium
hydroxide; carbonates of alkali metals or alkaline earth metals such as sodium carbonate,
potassium carbonate, and cesium carbonate; hydrogencarbonates of alkali metals or alkaline
earth metals such as sodium hydrogencarbonate and potassium hydrogencarbonate; amines
such as triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, 1,8-
diazabicyclo[5.4.0]undec—7—ene (DBU), l,5—diazabicyclo[4.3.0]non—5—ene (DBN), and N,N—
dimethylaniline; and basic heterocyclic compounds such as pyridine, imidazole, and 2,6-
-26~
lutidine. These bases may be chosen as appropriate depending on various on conditions
known to those skilled in the art.
The term “acids” as used herein covers, for example, inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and
organic acids such as p—toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid,
formic acid, and acetic acid. These acids may be chosen as appropriate depending on s
on conditions known to those skilled in the art.
The compounds of the present invention can, for example, be ed in
accordance with the methods shown below.
The compound represented by Formula (I) can be produced by
the synthetic process shown in Scheme 1:
[Chem 12]
R1 R1
3 l
Rz‘NTO 1-1 R2"" 0
_.____—>
Y1'Y\2 ’OH y‘le‘2 1L1
x2 Y.p y3_x1 x2
+9 y3_x1~
Y4 , 4
R3 Y
(1'3) (140)
1-2 HN,
51 (1'0)
N O
R f2, R?
iowlxt®ixz1aY2 ,N_R5
R3, ~Y4
( I)
Scheme 1
(wherein, R1, R2, R3, R4, R5, X1, X2, Y1, Y2, Y3, Y4, Y5 and A are the same as above, and L1
represents a leaving group; the term “leaving group” means a p-toluenesulfonyloxy group, a
methanesulfonyloxy group, a halogen atom, etc.)
The compound represented by Formula (I) can be obtained by conversion of the
yl group of a compound represented by Formula (l—a) into a common leaving group so
as to give a compound represented by Formula (l-b) (Step 1—1), which is then reacted with a
corresponding amine (l-c) (Step 1-2). The reaction in Step 1-1 (conversion to a leaving
group) is performed by, for example, chlorination, bromination, iodination,
methanesulfonylation, or p-toluenesulfonylation.
Examples of the chlorination include a method of using carbon tetrachloride and
nylphosphine, a method of using thionyl chloride or phosphorus oxychloride, and a
method of introducing a leaving group using p—toluenesulfonyl chloride or the like and then
performing substitution using lithium chloride or the like. These reactions can be performed
using a solvent such as ydrofuran, dioxane, dichlorornethane7 chloroform, N,N-
dimethylformamide, or mixed solvents thereof. These reactions can be med at -50 to
1 00°C.
Examples of the bromination e a method of using carbon tetrabromide and
triphenylphosphine. This reaction can be performed in a solvent such as tetrahydrofuran,
dioxane, dichloromethane, chloroform, methylformamide, or mixed solvents thereof at
-50 to 50°C.
Examples of the iodination include a method of using iodine, triphenylphosphine,
and imidazole. This reaction can be performed using a solvent such as tetrahydrofuran,
dioxane, romethane, chloroform, N,N-dimethylformamide, or mixed solvents thereof
under the temperature condition of ~50 to 100°C.
The methanesulfonylation and the p-toluenesulfonylation can be performed using,
for example, methanesulfonyl chloride and p-toluenesulfonyl chloride, respectively. These
reactions may be performed in the presence of an appropriate added base. Examples of the
base to be added include organic amines such as triethylamine and diisopropylethylamine;
and inorganic bases such as potassium carbonate. The ons can be performed in a
reaction t such as N,N-dimethylformamide, tetrahydrofuran, dioxane,
dichloromethane, chloroform, 1,2-dichloroethane, or mixed solvents f under the
temperature condition of -50 to 50°C.
The on in Step 1-2 proceeds in the absence of a solvent, or in a solvent such as
tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, ethanol, isopropyl
alcohol, or mixed ts thereof under the temperature ion of from room temperature
to near the boiling point of the solvent. The reaction will proceed more smoothly in the
presence of sodium iodide or potassium iodide if this is added in addition to an inorganic
base such as potassium carbonate or cesium carbonate, or an organic base such as
triethylamine or ropylethylamine.
Among the compounds represented by the above Formula (l-a), a compound
represented by Formula (2—g) can be produced by the synthetic s shown in Scheme 2:
[Chem 13]
R60 0 HO 0 R2 (2-c)
\f 2-1 T 2-2
+9f-Q‘}”Y1—Y3 ——> Y1’Y\ ———>
+92”— L2
R3! ‘Y R3
(Z-a) (240)
R1 R1
I l
R2.N\Eo 2_3 R2 Nfo
._.__.____>
Y1—Y3 Y1—Y\2
Yer- L2 3 /
+0: {94
R3 ‘Y R3, ‘Y
(2-d) (2-e)
'31 i '31 lz-s
RZ.N 0 2'6 R2“ 0
\fwyg ’
/ 0R5 Yl’sz OH
+04”- +04”-
R31 ‘Y R3, FY
(2-f) (2-9)
Scheme 2
(wherein, R1, R2, R3, Y1, Y2, Y3, Y4, Y5 and A are the same as above; R6 represents a C1_5
alkyl; L2 represents a chlorine atom, a bromine atom, an iodine atom, or a
trifluoromethanesulfonyloxy group).
The compound represented by Formula (2-b) can be prepared by hydrolyzing the
compound represented by Formula (2—a) (Step 2-1). The reaction in Step 2—1 proceeds in a
solvent such as water, methanol, ethanol, or a mixed solvent thereof in the presence of a base
such as sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide
under the ature condition of from near 0°C to near the boiling point of the solvent.
The compound represented by Formula (2-d) can be prepared by subjecting the
compound ented by Formula (2—b) to amidation reaction with the compound
represented by Formula (2—c) (Step 22). Here the amidation reaction may, for example, be
performed by a method using a dehydration-condensation agent. Examples of the
dehydration-condensation agent include l~ethyl(3—dimethylaminopropyl)carbodiimide
hydrochlroride, dicyclohexylcarbodiimide, diphenylphophonylazide, and
carbonyldiimidazole; if necessary, activators may be used as exemplified by 1-
ybenzotriazole and hydroxysuccinimide. Exemplary reaction solvents include
dichloromethane, chloroform, 1,2-dichloroethane, N,N—dimethylformamide, tetrahydrofuran,
dioxane, toluene, ethyl acetate, and mixed solvents thereof. The reaction may be performed
using a base and examples of the base include c amines such as triethylamine and
diisopropylethylamine, organic acid salts such as sodium 2—ethylhexanoate and potassium 2-
ethylhexanoate, and inorganic bases such as potassium carbonate. The reaction can be
performed at from -50°C to near the g point of the reaction solvent.
The compound represented by a (2-e) can be obtained from the compound
represented by Formula (2—d) by means of introducing Vinyl through the Migita-Kosugi-Stille
cross coupling reaction or the Suzuki-Miyaura cross coupling on (Step 2—3). The
comprehensive review of the Migita—Kosugi—Stille cross coupling reaction is found in
Angew. Chem. Int, Ed. 2004, 43, 4704-4734. The comprehensive review of the Suzuki—
Miyaura cross coupling reaction is found in Chem. Rev., 1995, 95, 2457-2483.
The compound represented by Formula (2-g) can be obtained from the compound
represented by Formula (2-e) by means of common hydroboration and uent ion
on (Step 2-5). The on in Step 2-5 proceeds in two stages, where the alkene moiety
of the compound represented by Formula (2—e) is orated with, for example, a borane-
tetrahydrofuran complex, 9—borabicyclo[3.3. l]nonane, disiamylborane, or thexylborane in a
solvent such as tetrahydrofilran, e, acetonitrile, or mixed solvents thereof under the
temperature condition of -10°C to near room temperature and subsequently hydrogen
peroxide or the like is used in the presence of a base such as sodium peroxoborate
(monohydrate or tetrahydrate) or sodium hydroxide. The comprehensive review of the
hydroboration is found in J. Am. Chem. Soc, 1956, 78, 5694-5695 and J. Org. Chem, 1986,
51, 43 9-445.
The compound represented by Formula (2-D can be ed from the compound
represented by Formula (2—d) by means of introducing alkoxyvinyl through the Migita-
Kosugi~Stille cross coupling reaction or the -Miyaura cross coupling reaction (Step 2-
4). Step 2-4 proceeds under the same reaction conditions as those in Step 2-3.
The compound represented by Formula (2-g) can be obtained from the compound
represented by Formula (2-f) by means of converting it to a formyl compound through
hydrolysis reaction in a hydrous solvent in the ce of an acid catalyst and then
subjecting the ing formyl compound to reduction reaction with a reducing agent. The
comprehensive review of the hydrolysis reaction is found in Protective Groups in Organic
Synthesis, Fourth Edition, John Wiley & Sons, INC. The comprehensive review of the
reduction reaction is found in Comprehensive Organic Transformations, Second Edition,
1999, John Wiley & Sons, INC. The ng agent is a reagent that is capable of ting
a formyl compound to an alcoholic compound through reduction and may be exemplified by
lithium borohydride, sodium borohydride, calcium borohydride, zinc borohydride, lithium
aluminum hydride, sodium aluminum hydride, utylaluminum hydride, etc.
Among the nds represented by the above Formula (Z-a), a compound
ented by Formula (3—h) can be produced by the synthetic process shown in Scheme 3:
[Chem. 14]
9:0 + HN— L2 L PIN—GL2 —3:———>
R3 HZN R>2N N—Q'
(3'3) (343) (3'0) (3d)
0H 1
3-3 5? 3-4 LS: 3-5
————> /w» ———>
/ ~-®v —————>
R3 N
R3 \N
(3-9) (34)
CN HO 0
R3 any —> W}N R3 \N
CH!) (3-h)
Scheme 3
(wherein, R3, L1, L2, and A are the same as above).
The compound represented by Formula (3-c) can be obtained by reacting a ketone
nd represented by Formula (3 ~a) with a hydrazine compound ented by Formula
(3-b) in the presence or absence of an acid catalyst (Step 3-1). Here, the ketone compound
(3-a) and the hydrazine compound (3-b) are available as commercial compounds or known
nds; alternatively, they may be compounds that are synthesized from commercial
compounds or known compounds using various organic synthesis techniques known to those
skilled in the art.
The compound represented by Formula (3-d) can be obtained by reacting the
compound represented by Formula (3 —c) with phosphoryl chloride either in an inert solvent or
in a solventless manner (Step 2—3).
The compound represented by Formula (3—e) can be obtained from the compound
represented by Formula (3-d) by means of reacting it with a ng agent in an inert solvent
(Step 3-3). The hensive review of the reduction reaction is found in Comprehensive
c Transformations, Second Edition, 1999, John Wiley & Sons, INC. The reducing
agent is a reagent that is capable of converting a formyl compound to an alcoholic compound
through reduction and may be exemplified by m borohydride, sodium borohydride,
calcium dride, zinc borohydride, lithium aluminum hydride, sodium aluminum
hydride, diisobutylaluminum hydride, etc.
The alcoholic compound (3-e) can be converted to a compound (3—f) by the same
technique as in Step 1—1 of Scheme 1 (Step 3—4).
The nd represented by Formula (3-g) can be obtained from the nd
represented by Formula (34) by means of reacting it with a cyanation agent in an inert
solvent (Step 3—5). Examples of the cyanation agent include potassium cyanide and sodium
cyanide. The comprehensive review of the cyanation reaction is found in Comprehensive
Organic Transformations, Second Edition, 1999, John Wiley & Sons, INC.
The compound represented by Formula (3-h) can be obtained by hydrolyzing a
nd represented by a (3-g) (Step 3-6). The hydrolysis reaction in this step
proceeds in a solvent such as water, methanol, ethanol or mixed solvents thereof in the
presence of a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide or
barium hydroxide under the ature condition of from near 0°C to near the boiling point
of the solvent. Alternatively, the hydrolysis reaction proceeds in a solvent such as methanol,
or ethanol, or mixed solvents f in the presence of an acid such as hydrochloric acid or
sulfuric acid, under the temperature condition of from near 0°C to near the boiling point of
the solvent. The comprehensive review of the hydrolysis reaction is found in Comprehensive
c ormations, Second Edition, 1999, John Wiley & Sons, INC.
Among the compounds represented by the above Formula (2-6), a compound
represented by Formula (4-1) can be produced by the synthetic process shown in Scheme 4:
[Chem 15]
\E/‘NHN 4.1 ,N\ 4—2 /N\
N OH N CH
+ H \ _>
\ L4
(4-a) (4-b) (4-c) (4—d)
—> —>
\ NVQOH \ N®Ls
R3-Mt R3 R3
(4'9)
(44) (4-9)
L4 CN CN
be: M» bow % my4-6 4-7
N N N
\ \ \
R3 R3 R3
(4-h) (44) (4-1)
:N‘N‘QJ/fl:‘ E“”@J
(4k) (2-c) (44)
Scheme 4
(wherein, R1, R2, R3, and A are the same as above; L3 represents a bromine atom or an iodine
atom; L4 represents a halogen atom such as a chlorine atom, a bromine atom or an iodine
atom; L5 represents a chlorine atom, a bromine atom, an iodine atom, or a
trifluoromethanesulfonyloxy group; Mt represents a metal atom or a metal atomic group that
are used in a coupling reaction; examples of the compound (4—e) include a magnesium
reactant, a zinc reactant, or a boron reactant having boric acid or a boric acid ester attached
thereto, and a tin reactant).
The compound represented by Formula (4—c) can be obtained by the Ullmann
reaction between the compound represented by a (4—a) and the compound represented
by formula (4—b) (Step 4—1). Here the compound represented by Formula (4-b) is ble as
a commercial compound or a known nd; alternatively, it may be a compound that is
sized from commercial compounds or known nds using various organic
synthesis techniques known to those skilled in the art. The comprehensive review of the
Ullmann reaction is found in Ley, S. V.; Thomas, A. W. Angew. Chem, Int. Ed. 2003, 42,
5400-5449.
The compound represented by Formula (4-d) can be obtained by subjecting the
compound (4—c) to an electrophilic substitution reaction with a halogenating agent. Here the
electrophilic substitution reaction proceeds in an inert solvent or in a solventless manner in
the presence or absence of an acid and in the presence of a halogenating agent such as
chlorine, bromine, iodine or N-chlorosuccinimide, osuccinimide or N—
iodosuccinimide under the temperature condition of from near 0°C to near the g point
of the t (Step 4-2). The comprehensive review of the electrophilic substitution reaction
is found in hensive Organic Transformations, Second Edition, 1999, John Wiley &
Sons, INC.
The compound represented by Formula (4-t) can be obtained from the compound
represented by Formula (4-d) and the compound represented by Formula (4-e) through the
Migita—Kosugi—Stille cross coupling reaction or the Suzuki-Miyaura cross coupling reaction
(Step 4-3). The comprehensive review of the Migita-Kosugi-Stille cross coupling on is
found in Angew. Chem. Int, Ed. 2004, 43, 734. The comprehensive review of the
Suzuki—Miyaura cross coupling reaction is found in Chem. Rev., 1995, 95, 2457-2483.
The compound represented by Forrnula (4—g) can be obtained from the compound
ented by Formula (4-f) by means of halogenating or trifluoromethanesulfonylating the
hydroxyl group of the latter compound (Step 4-4). The comprehensive review of the
halogenation or trifluoromethanesulfonylation reaction can be found in Comprehensive
c Transformations, Second Edition, 1999, John Wiley & Sons, INC.
The compound represented by Formula (4—h) can be obtained from the compound
represented by Formula (4—g) by means of subjecting it to halogenation reaction with a
halogenating agent either in the ce of an initiator of radical reaction or under
irradiation with light (Step 4-5). Here the initiator of l reaction may be exemplified by
azobisisobutyronitrile, benzoyl peroxide or the like. Examples of the halogenating agent
include chlorine, e, or N—chlorosuccinirnide and N—bromosuccinimide. The
comprehensive review of the halogenation reaction can be found in Comprehensive Organic
Transformations, Second Edition, 1999, John Wiley & Sons, INC.
The halogen compound (4-h) can be converted to a cyano compound (4-i) by the
same technique as in Step 3-5 of Scheme 3 (Step 4-6). The compound (4—i) can be converted
to a compound (4-j) by the same technique as in Step 2-3 of Scheme 2 (Step 4—7). The
compound (4-j) can be converted to a compound (4-k) by the same technique as in Step 3-6
of Scheme 3 (Step 4~8). The compound (4-k) can be converted to an amide compound (4-1)
by the same technique as in Step 2-2 of Scheme 2 (Step 4-9).
Among the compounds represented by the above Formula (2—d), a compound
represented by a (5—1) can be produced by the synthetic process shown in Scheme 5.
[Chem 16]
o b)
(5-a) (5--c) (5-d) (5-e)
R3-NHNH2 (5-f)
—>5'4 // OP“_—>
Rs-Nw 0P1—>
(5-9) N-(5h) N-(5i)
2NH (2_0)
R5-7 $1
”wR2 w1%
(5-1') (5-k) (5-l)
Scheme 5
(wherein, R1, R2, R3, L5 and A are the same as above; P1 represents a protecting group for
phenolic hydroxyl groups, such as a methyl group, a methoxymethyl group, an allyl group, an
acetyl group, a methyl carbonate ester group or a benzyl group [see Protective Groups in
Organic Synthesis, Fourth n, John Wiley & Sons, INC]; P2 represents a protecting
group for terminal alkyne groups, such as a trimethylsilyl group, a triethylsilyl group, or a
triisopropylsilyl group [see Protective Groups in Organic Synthesis, Fourth Edition, John
Wiley & Sons, INC]
The nd represented by Formula (5-c) can be obtained from the compound
-36—
ented by Formula (5-a) and the compound represented by Formula (S-b) through
alkynylation reaction in an inert solvent in the ce of a base (Step 5-1). Here, the
compound (5—a) and the compound (5-b) are available as commercial compounds or known
compounds; alternatively, they may be compounds that are synthesized from commercial
compounds or known compounds using various organic synthesis techniques known to those
d in the art. The base as ed to above may be exemplified by amides of alkali
metals or alkaline earth metals such as lithium diisoproylamide and lithium
dicyclohexylamide; lower alkoxides of alkali metals or alkaline earth metals such as sodium
methoxide, sodium ethoxide, and potassium tert—butoxide; alkyl lithium compounds such as
butyl lithium, sec-butyl lithium, utyl lithium, and methyl lithium; and Grignard reagents
such as ethylmagnesium bromide.
The compound represented by Formula (S—d) can be obtained by removing the
protective group P2 on the al alkyne of the compound (5-c) using various organic
synthesis techniques known to those skilled in the art [see Protective Groups in Organic
Synthesis, Fourth Edition, John Wiley & Sons, INC] (Step 5—2).
The compound represented by Formula (5—e) can be obtained from the compound
represented by a (S—d) by means of ting it to oxidation reaction (Step 5-3). The
oxidizing agent for use in the oxidation reaction may be exemplified by manganese dioxide,
chromic acid compounds such as pyridinium chlorochromate or pyridinium dichromate, and
a Dess—Martin reagent (1,1, 1—triacetoxy—l,1—dihydro~1 ,2-benziodoxol-3(1H)—one). The
reaction solvent may be exemplified by dichloromethane and chloroform, with the reaction
temperature ranging from 0°C to near the boiling point of the on solvent. In another
case, the reaction may be performed using IBX (l-hydroxy— l ,2-benziodoxol-3(lH)—one l-
oxide), for example. yl sulfoxide, for example, may be used as the reaction solvent
and reaction can be performed by further diluting it with a solvent that does not ipate in
the reaction, such as tetrahydrofuran, dichloromethane, or chloroform. The reaction
temperature may range from 0°C to 40°C. This oxidation reaction is not particularly limited
and aside from the described methods, it may be performed by any method that can
oxidize alcohol into de. Examples include a reaction of dimethyl sulfoxide with an
activating agent (e. g., oxalyl chloride, N—chlorosuccinimide, or dicyclohexyl carbodiimide) or
an oxidation method using tetra—n-propylammonium perruthenate(VII) and N-
methylmorpholine oxide. The comprehensive review of the oxidation reaction under
eration can be found in Richard C. Larock, Comprehensive Organic Transformation,
WILEY-VCH, 1999, 604.
The compound represented by Formula (S—g) can be obtained from the compound
represented by Formula (5—e) by means of subjecting it to a pyrazole ring formation reaction
h the reaction with a hydrazine compound (5-t) (Step 5—4). Here the ine
compound (5—f) is available as a commercial compound or a known compound; alternatively,
it may be a compound that is synthesized from commercial compounds or known compounds
using various organic synthesis techniques known to those skilled in the art.
The compound represented by Formula (5-h) can be obtained from the compound
represented by Formula (5-g) through a homologation reaction with carbon dioxide in an
inert solvent in the presence of a base such as m
diisopropylamide (Step 5~5).
The compound represented by Formula (5-i) can be obtained from the compound
represented by la (5 —h) through homologation by the Arndt-Eistert reaction (Step 5—6).
The hensive review of the Arndt-Eistert reaction can be found in Chem. Ber., 1927,
60, 1364.
The compound (S-i) can be converted to an amide compound (5-j) by the same
technique as in Step 2-2 of Scheme 2 (Step 5—7).
The tive group P1 in the compound represented by Formula (5-j) is then
removed by various organic sis techniques known to those skilled in the art (see
Protective Groups in c sis, Fourth Edition, John Wiley & Sons, INC), to give a
compound represented by Formula (5—k) can be obtained (Step 5-8).
The compound represented by Formula (S-k) can be converted to a compound
represented by Formula (5—1) by the same technique as in Step 4-4 of Scheme 4 (Step 5—9).
—38—
Among the compounds represented by the above Formula (2-a), a compound
represented by Formula (6—f) can be produced by the synthetic process shown in Scheme 6.
[Chem 17]
RGOJK/NHNH2
o °
0 6-1 6-2 (64’)
J + m —————-——>» mm ——————>
L?- L2
(6-a) (6-b) (6-c)
R60 0 R60 0
t N ———~> r -N
N , N
\ L2 \ L2
R3 R3
(5-6) (6-f)
Scheme 6
(wherein, R3, R6, L2 and A are the same as above.)
The compound represented by a (6-c) can be ed by the aldol reaction
between the nd ented by Formula (6-a) and the compound represented by
Formula (6—b) (Step 6-1). The comprehensive review of the aldol reaction can be found in
Comprehensive Organic Transformations, Second Edition, 1999, John Wiley & Sons, INC.
Here the nd represented by Formula (6-a) and the compound represented by Formula
(6-b) are available as commercial nds or known compounds; alternatively, they may
be compounds that are synthesized from commercial compounds or known compounds using
various organic synthesis ques known to those skilled in the art.
The compound represented by Formula (6-e) can be obtained from the compound
represented by Formula (6—c) and the hydrazine compound represented by Formula (6-d)
through a dihydropyrazole ring forming reaction based on the reaction between the two
compounds in an inert solvent in the presence or absence of an acid catalyst (Step 6-2). Here
the hydrazine nd (6-d) is available as a commercial compound or a known
compound; alternatively, it may be a compound that is synthesized from commercial
compounds or known compounds using various organic synthesis techniques known to those
skilled in the art.
The compound represented by Formula (6—f) can be obtained from the compound
represented by Formula (6-6) through oxidation on with an oxidizing agent (Step 6—3).
The oxidizing agent that may be used is 2,3-dichloro-5,6-dicyano—p-benzoquinone,
manganese dioxide or potassium permanganate, for example. Exemplary reaction solvents
include e, dichloromethane, and form, with the reaction temperature ranging
from 0°C to near the boiling point of the reaction solvent.
Among the compounds represented by the above Formula (2—a), a compound
represented by Formula (7-t) can be produced by the synthetic process shown in Scheme 7.
[Chem 18]
(7-b) (7-d)
NH2 7-1 NH 7-2
R3 —-———> R3~<_ L2 ———-—>
o o o
(7-a)
(7_c)
R60 0 R60 0
3 L2 1 N\>_®'Lz
0 0>— R3 0
(7-f)
(7-e)
Scheme 7
(wherein, R3, R6, L2 and A are the same as above; L6 represents a chlorine atom, a bromine
atom or a hydroxyl group; L7 represents a chlorine atom or a bromine atom).
The compound ented by Formula (7-c) can be produced from the compound
represented by Forrnula (7-a) and a compound represented by Formula (”l-b) in which L6 is a
halogen atom h ion reaction between the two nds in an inert solvent in
the ce or absence of a base; alternatively, the compound represented by Formula (7-c)
can be produced from the compound represented by Formula (7-a) and a compound
represented by Formula (7-b) in which L6 is a hydroxyl group through various amidation
reactions known to those skilled in the art (Step 7-1). The compound ented by Formula
(7-a) and the nd represented by a (7-b) are available as commercial
compounds or known compounds; alternatively, they may be compounds that are synthesized
from commercial compounds or known compounds using various organic synthesis
techniques known to those skilled in the art. The amidation reaction of the compound (7—b)
wherein L6 is a hydroxyl group may be ified by a condensation reaction in an inert
solvent in the ce or absence of a base using a condensation agent such as O-(7-
azabenzotriazolyl)~N,N,N’,N’-tetramethyl uronium hexafluorophosphate (HATU), O—
(benzotriazol—l-yl)—N,N,N’,N’—tetramethyl uronium hexafluorophosphate (HBTU), N,N’—
dicyclohexylcarbodiimide (DCC), l(3~dimethylaminopropyl)carbodiimide
hydrochloride (EDC ' HCl), diphenylphosphoryl azide (DPPA) or carbonyldiimidazole (CD1),
or by a condensation reaction again in an inert solvent in the presence or absence of a base
but via a mixed acid anhydride using ethyl chloroformate, isobutyl chloroformate,
trimethylacetyl chloride, or the like. In the case of amidation reaction using a condensation
agent, an additive such as oxybenzotriazole (HOBt) or hydroxysuccinimide (HOSu)
may be used depending on the need.
The compound represented by Formula (7-e) can be obtained from the nd
represented by Formula (7-c) and the compound represented by Formula (7-d) through
alkylation reaction in an inert solvent in the ce of a base (Step 7—2).
The compound represented by (7—i) can be obtained from the compound represented
by Formula (7-e) through intramolecular ring closing reaction in an inert solvent in the
presence of oryl chloride (Step 7—3).
Among the compounds represented by Formula (2—a), a compound represented by
Formula (8-0) can be produced by the synthetic process shown in Scheme 8.
[Chem. 19]
NC‘GLZ
0H (8-b) R60 0
R3 %
0R6 ——'—'> O
0 R3 N
(8-a) (8-C)
Scheme 8
(wherein, R3, R6, L2 and A are the same as above.)
The compound represented by (8—c) can be obtained from the compound represented
by Formula (8-a) and the compound represented by Formula (8-b) through an oxazole ring
forming reaction in the ce of an acid (Step 8-1). Here the acid may be exemplified by
conc. sulfiu‘ic acid. Here the nd represented by Formula (8—a) and the compound
represented by Formula (8-b) are available as commercial compounds or known compounds;
alternatively, they may be compounds that are synthesized from commercial compounds or
known compounds using s organic synthesis techniques known to those d in the
art.
Among the compounds represented by the above Formula (2—b), a compound
represented by Formula (9-6) can be produced by the synthetic process shown in Scheme 9.
[Chem. 20]
HZN C
(94°) 0
0I o 9-1
R3jfiHkOR5 R 0%s N
> >— L2
0 R3
(9-c)
(9-a)
H0 0
9-2 HO/UjI \>—N 9-3 N
L2 ________________> I \>__®_L2
R3 S R3 3
(9-d) (9-6)
Scheme 9
in, R3, R6, L2 and A are the same as above.)
The compound represented by (9—0) can be obtained from the compound represented
by Formula (9-a) and the compound represented by Formula (9-b) through a thiazole ring
forming on in an inert solvent (Step 9—1). Here the compound represented by Formula
(9—a) and the compound represented by Formula (9-b) may be available as commercial
compounds or known compounds; alternatively, they may be compounds that are synthesized
from commercial compounds or known compounds using various organic synthesis
techniques known to those skilled in the art. The compound represented by a (9—d)
can be obtained from the compound represented by Formula (9-0) by means of the same
technique as that in Step 2—1 shown in Scheme 2. The nd represented by a (9—
e) can be obtained from the compound represented by Formula (9—d) by means of the same
technique as that in Step 5-6 shown in Scheme 5.
Among the compounds represented by the above Formula (2-d), a compound
represented by Formula (lO—e) can be produced by the synthetic process shown in Scheme
1 O.
[0 l 3 5]
[Chem.21]
L7szo 0
R1‘I~i/U\/L7 '31
. .N 0
(10-b) R2 (10-d) R2
NH 10-1
R3’U\NH2 —> HL\ -
L2 _~_1_9__2__’ \fN \ L2
R3 N k
R3 N
(”'3’
(10-c) (10-e)
Scheme 10
(wherein, R1, R2, R3, L2, L7 and A are the same as above.)
The compound represented by (10—0) can be obtained from the compound
represented by Formula (lO-a) and the compound represented by Formula (IO—b) through an
imidiazole ring g reaction in an inert solvent in the presence of a base (Step 10—1).
Here the compound represented by Formula (IO-a) and the compound represented by
Formula (lO-b) are ble as commercial compounds or known nds; alternatively,
they may be compounds that are sized from commercial nds or known
compounds using various organic synthesis techniques known to those skilled in the art.
The compound represented by Formula (10~e) can be obtained from the compound
represented by Formula (10-0) and the compound represented by Formula (IO-d) through an
alkylation reaction in an inert solvent in the presence of a base (Step 10-2).
Among the compounds represented by the above a (l-a), a compound
represented by Formula (1 H) can be produced by the synthetic process shown in Scheme 11.
[Chem. 22]
I o
L4 R3-Mt
0(1143) o (4-9) 0
opz 11-1 OF2 11-2 0P2
HZN —-—> [ N -——--—> 1 “GI
L4 R3
o o
(11-a) (11-c) (11-d)
o o
RGOMORG R60 0
11-3 L6 11-4 ‘1”) R60 0P2
-——————)- I N -———-——~—-)-
I N
R3 {9—for-2 0
o R3
(116) R1 (“-9)
H0 0 RZ'NH(2-c) E1 0
11-5 0 11-6 R2.
I 0H
0 R3
(11-h)
(11-1)
Scheme 11
(wherein, R1, R2, R3, R6, L4, Mt and A are the same as above; P2 represents a protecting
group for a hydroxyl group, such as a methoxymethyl group, a tert-butyldimethylsilyl group,
an acetyl group, a benzyl group, a tetrahydropyranyl group, or a 2-
thylsilyl)ethoxymethyl group [see Protective Groups in Organic Synthesis, Fourth
Edition, John Wiley & Sons, INC.] or a hydrogen atom).
The compound represented by Formula (1 1—c) can be obtained from the compound
represented by Formula (1 l—a) and the compound represented by Formula (1 1—b) through a
cyclization on in an inert solvent or without a solvent in the presence or absence of an
acid (Step 11-1). Here the compound represented by Formula (1 l-a) and the compound
represented by Formula (1 1-b) are available as commercial compounds or known
compounds; atively, they may be compounds that are synthesized from commercial
compounds or known compounds using various organic synthesis techniques known to those
d in the art.
The compound (1 l—c) can be converted to the compound ented by Formula
(11-d) by means of the same technique as that in Step 4—3 of Scheme 4 (Step 11-2).
The compound (1 l-d) is then subjected to a halogenation on with chlorine,
bromine, iodine or N—chlorosuccinimide, N—bromosuccinimide, N—iodosuccinimide, thionyl
chloride or the like, to convert it to the nd (1 l-e) having a n atom introduced
thereinto (Step 11—3).
The compound represented by Formula (1 lg) can be obtained from the compound
represented by Formula (1 l-e) and the compound ented by Formula (1 l—t) through a
nucleophilic substitution reaction in an inert solvent in the presence of a base (Step 11-4).
Here the compound represented by Formula (1 l-f) is available as a commercial compound or
a known compound; alternatively, it may be a compound as synthesized from commercial
compounds or known compounds using various c synthesis techniques known to those
skilled in the art.
The compound represented by Formula (1 l—h) can be obtained from the compound
represented by Formula (l l-g) through hydrolysis of the ester in an inert solvent in the
presence of an acid, followed by uent decarboxylation on and the removal of the
protective group P2 (Step 11-5).
The compound (11—h) can be converted to the amide compound (1 H) by the same
technique as in Step 2—2 of Scheme 2 (Step 11—6).
Among the compounds represented by the above Formula (2—d), a nd
represented by Formula (12-6) can be produced by the synthetic process shown in Scheme
—46-
[Chem 23]
Lflflteea RLNH- .
L 2
(12-a) (12-b) (12-c)
RLNJK/U
R2 (10-d) $1
J< 12-3 R2“ 0
-—*-> 4
R3“LG
R3new
(1241) (12-e)
Scheme 12
(wherein, R], R2, R3, L2, L7 and A are the same as above).
The nd represented by (12-c) can be obtained from the compound
represented by Formula (12—a) and the compound represented by Formula (12-b) through an
tion reaction in an inert solvent or in a solventless manner in the ce of a base
(Step 12-1). Here the compound represented by Formula (12-a) and the compound
represented by Formula (12-b) are available as commercial compounds or known
compounds; alternatively, they may be compounds as synthesized from cial
compounds or known compounds using various organic synthesis techniques known to those
skilled in the art.
The compound represented by Formula (12—d) can be obtained from the compound
represented by Formula (12—c) and potassium cyanate, sodium cyanate or the like through a
ring closing reaction either Within or in the absence of an inert solvent in the ce or
absence of an acid (Step 12-2).
The compound (12—d) can be ted to an amide compound (12-e) by the same
technique as in Step 10-2 of Scheme 10 (Step 12-3).
Among the compounds represented by the above Formula (2-d), a compound
ented by Formula (13-d) can be produced by the synthetic process shown in Scheme
[Chem 24]
NOH 13-1
N R3fl\n/ 0
Ni}. 0 R1NJVL7
0 (a. R2
L L .:10 HNjNUw1§i> R2 0
(13-a) 3J\<N "’4 G.
R \N L2
(13-c) (13-d)
Scheme 13
(wherein, R1, R2, R3, L2, L7 and A are the same as above).
The compound represented by Formula (13—c) can be obtained from the compound
represented by Formula (13-a) and the compound represented by Formula (13-b) through
reaction in an inert solvent (Step 13-1). Here the compound represented by Formula (l3-a)
and the compound ented by Forrnula (l3-b) are available as commercial compounds or
known compounds; alternatively, they may be compounds as synthesized from commercial
compounds or known compounds using s organic synthesis ques known to those
d in the art.
The compound (13-c) can be converted to the compound (l3—d) by the same
technique as in Step 10-2 of Scheme 10 (Step 13-2).
Among the compounds represented by the above a (2-a), a compound
represented by Formula (144) can be produced by the synthetic process shown in Scheme 14.
—48—
[Chem 25
W+ *6) -——-> “3“le
(14-a) (14-b) (14-c)
14-2 RnNfimLz 14-3 E”:>‘®L2
(14-d) (144)
Scheme 14
(wherein, R3, R6, L2, L7 and A are the same as .
The compound ented by Formula (l4-c) can be obtained by reacting the
compound represented by Formula (14—a) with an acid halide represented by Formula (l4—b)
(Step l4-1). The reaction in Step 14-1 proceeds in a solvent such as chloroform, toluene,
tetrahydrofuran, itrile or mixed ts thereof in the presence of a base such as
triethylamine or diisopropylethylamine under the temperature condition of from near 0°C to
near room temperature. Here the compound represented by Formula (l4—a) and the
compound represented by Formula (l4-b) are available as commercial nds or known
compounds; alternatively, they may be compounds that are synthesized from commercial
compounds or known compounds using various organic synthesis techniques known to those
skilled in the art.
The compound represented by Formula (l4—d) can be obtained by a nation
reaction of the compound represented by Formula (l4—c) (Step 14-2). Examples of the
halogenation reaction e a method using carbon tetrachloride and triphenylphosphine,
and a method using thionyl chloride or phosphorus oxychloride. These reactions may
employ solvents such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N-
dimethylforamide, or mixed ts thereof. These reactions can be performed at -50 to
100°C.
The compound represented by a (14-1) can be obtained from the compound
represented by Formula (14-d) and the amine nd represented by Formula (l4—e)
through reaction in the presence of an oxidizing agent (Step 14-3). Examples of the
oxidizing agent e silver carbonate, hydrogen peroxide, sodium hypochlorite, Dess—
Martin reagent (1,1,l-triacetoxy-l,l~dihydro-1,2-benziodoxol—3(1H)-one), etc.
Among the nds ented by the above Formula (1-a), a compound
ented by Formula (15—g) can be ed by the synthetic process shown in Scheme
1 5.
[Chem.26]
-1 0 0
0 o H H 15-2
R3—Nco + N N M
————> R3- jg” s u 0R6 ————>
HZNHNMORE
(15-a) (15-b) (154;)
$1 OH
.NH 1 1
HO 0 R2 (2-c) 'T L3‘®—/7 3
2,N o (15-f) o
-3 R RZN
-4
/ _‘“ ’
NH /N i /N\ @JOH
N «o NH N
R3 N
R3 K R3 K
o o
(15-d) (15-e) (15-9)
Scheme 15
(wherein, R1, R2, R3, R6, L3 and A are the same as above).
The compound represented by Formula (1 S-c) can be obtained from the isocyanate
derivative represented by Formula (15-a) and the compound represented by Formula (15-b)
by means of allowing the latter to act on the former (Step 15-1). The reaction in Step 15—1
proceeds in a solvent such as chloroform, toluene, tetrahydrofuran, acetonitrile or mixed
solvents thereof under the temperature condition of from a temperature near room
temperature to near the boiling point of the solvent. Here the compound represented by
Formula (1 5-a) and the compound represented by a (15-b) are available as
commercial compounds or known compounds; alternatively, they may be compounds that are
synthesized from commercial compounds or known compounds using various organic
synthesis techniques known to those d in the art. The compound represented by
Formula (IS-d) can be obtained from the compound represented by Formula (15-0) through
reaction under a basic ion (Step 15-2). The reaction in Step 15-2 proceeds in a solvent
such as water, tetrahydrofuran, l,4-dioxane, N,N-dimethylforamide, or mixed solvents
thereof in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide,
lithium hydroxide or barium hydroxide under the ature condition of from near room
temperature to near the boiling point of the solvent. The compound ented by Formula
(lS-e) can be obtained by an amidation reaction of the compound represented by Formula
(lS-d) with an amine (2-c) (Step 15—3). es of the amidation reaction that can be used
in Step 15—3 include a method using a dehydration—condensation agent. Examples of the
dehydration—condensation agent include l-ethyl-3—(3-dimethylaminopropyl)carbodiimide
hydrochloride, dicyclohexyl carbodiimide, diphenylphosphonyl azide, and
carbonyldiimidazole; if necessary, an activating agent, such as l-hydroxybenzotriazole or
hydroxysuccinimide may be used. Examples of the reaction solvent include
dichloromethane, chloroform, l,2—dichloroethane, N,N—dimethylformamide, ydrofuran,
dioxane, toluene, ethyl acetate, and mixed solvents thereof. The process can be performed
using a base, examples of which include c amines such as triethylamine and
diisopropylethylamine; organic acid salts such as sodium 2—ethylhexanoate and potassium 2—
ethylhexanoate; and nic bases such as potassium carbonate. The on can be
performed at a temperature ranging from ~50°C to near the boiling point of the reaction
solvent. Conversion to the compound (IS-g) can be achieved through the Ullmann reaction
between the compound (lS—e) and the compound (1 5-D by the same technique as in Step 4-1
‘of Scheme 4.
Among the compounds ented by the above Formula (l-a), a compound
represented by Fonnula (l6-e) can be prepared by the synthetic process shown in Scheme 16.
,N 2N o
L>— _ R f
+ wen 161,
n \>_L4
L4 N
(16-a) (10-d) (16-b)
2‘2“”; 31 0 “MW 3‘
'9 R2” (16-d) 2N 0
16-2 f R f
,N 16-3
, N
\>_L4 Wu CH
R3k}:
(16-6) (16-e)
Scheme 16
(wherein, R1, R2, R3, L4, L7, Mt and A are the same as above).
The compound represented by Formula (l6-b) can be obtained from the nd
ented by Formula (16-a) and the compound represented by Formula (IO-d) h
alkylation reaction by means of the same technique as that in Step 10-2 of Scheme 10. Here
the compound represented by Formula (16-a) and the compound ented by Formula (10—
d) are available as commercial compounds or known compounds; alternatively, they may be
compounds as synthesized from commercial compounds or known compounds using various
organic synthesis techniques known to those skilled in the art.
The compound (16-h) can be converted to the compound represented by Formula
(16—0) by means of the same technique as that in Step 4-3 of Scheme 4 (Step 16—2). The
nd represented by Formula (16-6) can be ed from the compound represented by
Formula (16-c) and the compound represented by Formula (l6—d) through coupling reaction
by the same technique as in Step 4—3 of Scheme 4 (Step 16-3).
Among the compounds represented by the above Formula (I), a compound
represented by Formula (17-b) can be prepared by the synthetic process shown in Scheme 17.
[Chem. 28]
R1 R1
1 l
Rz'Nfo 17-1
96)”Y1,Y\2 / 0R6 RZ‘NfO
newY1N3 —o
R R
(17-a)
17-2 HN\
(1-0)
(17-b)
Scheme 17
(wherein, R1, R2, R3, R4, R5, R6, Y1, Y2, Y3, Y4, Y5 and A are the same as above).
The compound represented by Formula (17-a) can be obtained from the compound
represented by a (Z-i) through hydrolysis on in a hydrous solvent in the presence
of an acid catalyst. The hensive review of the ysis reaction is found in
Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, INC. (Step 17-
The compound represented by Formula (l7—b) can be obtained from the compound
represented by Formula (l7—a) and the compound represented by Formula (l—c) through
reductive amination reaction (Step 17-2). The reductive amination reaction is accomplished
by reacting the aldehyde (l7—a) with a corresponding amine (l-c) to generate an imine
derivative, which is then reduced with a reducing agent such as, for example, sodium
triacetoxyborohydride. This reaction proceeds in an inert solvent such as methanol, ethanol,
tetrahydrofuran, dichloromethane, chloroform, or mixed solvents thereof in the presence or
absence of an acid st under the temperature ion of from -70°C to room
temperature. Alternatively, the reaction may employ en gas with palladium-on—carbon
or the like being used as a catalyst; alternatively, the reaction may be performed using other
boron reagents such as borohydride, sodium borohydride, and sodium cyanoborohydride.
Among the compounds ented by the above Formula (I), a nd
represented by Formula (18—l) can be prepared by the synthetic s shown in Scheme 18.
[Chem 29]
R1\NJIVL1
{22 (10-6) R151 (4e)
L4 0 21 0
18-1 R2 L4 18-2 R2.
HN \ —> —>
L4J§N L4 ixL4 1\ L4
4 \N R3 \N
(13-a) (18-b) (18-c)
0 l 18-3 RlNJK/U R3-Mt
R2 (10-e) 31 (4-e) I31 I31
HN 18-4 R2“ 0 18-5 0 R2“ 0
L3 R2 18-6
, r _. r _.
L4 N
N \ N \
L4J§N L4 L4 NV
R3JQN RSJQN OR6
(18-d) (18-e) (18 f) (18-g)
R3 N OH R3 0R8
(18-h) HNB“ (18-1)
31 \Rs 1
(1-c) 'i
N 0
. °
18-9 R2” 18-10 R2 f
—--—> 1M0 ——-—>
R3 \N 1M0
N—<:>=O R3 \N
R7 R7N—<:>—N:R5
(18-k) (18-l)
Scheme 18
(wherein, R1, R2, R3, R4, R5, L4, L7 and A are the same as above; R7 represents a hydrogen
atom or a C1_5 alkyl group; R8 represents a protecting group for a carbonyl group, such as a
methyl group or an ethyl group; alternatively, adjacent R8 groups may combine to form a ring
[see Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, ]NC.])
The compound (18-a) can be converted to the compound represented by Formula
(18-b) by means of the same technique as that in Step 10-2 of Scheme 10 (Step 18—1). Here
the compound (18—a) is available as a commercial compound or a known compound;
atively, it may be a compound as sized from commercial compounds or known
compounds using various organic synthesis techniques known to those skilled in the art.
The compound represented by Formula (lS-b) can be converted to the compound
represented by Formula (1 8—0) by means of the same technique as that in Step 4-2 of Scheme
4 (Step 18—2).
The compound represented by Formula (1 8-D can be obtained from the nd
represented by a (18—c) through dehalogenation reaction in an inert solvent in the
presence of a base (Step 18—3).
The compound represented by Formula (1 8—d) can be converted to the compound
represented by Formula (1 8-6) by means of the same technique as that in Step 10—2 of
Scheme 10 (Step 18-4). Here the compound represented by a (18-d) is available as a
commercial nd or a known compound; alternatively, it may be a compound as
sized from commercial compounds or known compounds using various organic
synthesis techniques known to those skilled in the art.
The compound represented by Formula (1 8-e) can be converted to the compound
represented by Formula (1 8—D by means of the same technique as that in Step 4—2 of Scheme
4 (Step 18-5).
The compound represented by Formula (18-g) can be ed by reacting the
compound represented by Formula (18%) with carbon monoxide and R6OH in an inert
solvent in the presence or absence of a base and in the presence of a palladium catalyst,
optionally using a ligand for the palladium catalyst (Step 18-6) (see Comprehensive Organic
Transformations, Second Edition, 1999, John Wiley & Sons, INC.) Examples of the
palladium catalyst here mentioned include palladium(II) acetate,
dichlorobis(triphenylphosphine)palladium(11), dichlorobisacetonitrilepalladium(II), and
tetraquistriphenylphosphine palladium(0). Examples of the ligand include
triphenylphosphine, tributylphosphine, 2,2-bis(dipheny1phosphino)- l , 1 hthy1 ),
2—(di—tert-butylph0sphino)biphenyl, 1,1’-bis(diphenylphosphino)ferrocene (dppi), and 1,3-
bis(diphenylphosphino)propane (dppp).
The compound represented by Formula (18-g) can be converted to the compound
represented by Formula (18-h) by means of the same technique as that in Step 2—1 of Scheme
2 (Step 18—7). The compound represented by Formula (18—j) can be obtained from the
compound represented by Formula (18—h) and the compound represented by Formula (18—i)
through amidation reaction by the same technique as in Step 2-2 of Scheme 2 (Step 18—8).
The compound (18-k) can be produced from the nd (1 8-j) by removing the
protecting groups R8 for a yl group, using various organic synthesis techniques known
to those skilled in the art [see Protective Groups in Organic Synthesis, Fourth Edition, John
Wiley & Sons, INC] (Step 18-9).
The compound (1 8-k) can be converted to the compound ented by Formula
(18—1) by means of the same technique as that in Step 17—2 of Scheme 17 (Step 18-10).
Among the compounds ented by the above Formula (I), a compound
represented by Formula (19-c) can be prepared by the synthetic process shown in Scheme 19.
[men filmn3m
HO R5
I31 (19-b) I31
RZ'NTO 19-1 RZ'NTO R4
_‘_“‘_—‘_—> /
11v? lgf-flG—o1an WM
:3 X‘G’OH R5
R3 \Y R31 ~Y
(19-a) (19-c)
19-2 ,5 O
R T2.
L1 L1\\ 19-3/v ,R4
(V) L1
Y5\Y3_X12, HN\ (1-c)
(1 9-3) o/flfi( R5
3,Y ‘Y4
(19-e)
Scheme 19
in, R1, R2, R3, R4, R5, Y1, Y2, Y3, Y4, Y5, Ll, X1 and A are the same as above; n is an
integer of 1 to 5).
The nd represented by Formula (19—c) can be obtained from the compound
represented by Formula (19-a) and the compound represented by Formula (19-b) through
reaction under the conditions of the obu reaction (Step 19-1). The comprehensive
review of the Mitsunobu reaction is found in Synthesis. 1981, 1-28.; Chem. Asian J. 2007, 2,
1340-1355.; Chem. . Bull. 2003, 51(4), 474—476.
The compound represented by Formula (19—e) can be obtained from the compound
represented by Formula (19-a) and the compound represented by Formula (19-d) h
reaction under a basic condition (Step 19—2). The reaction in Step 19-2 proceeds in a solvent
such as N,N—dimethylformamide, yl sulfoxide, tetrahydrofuran, acetonitrile, ethanol,
isopropyl alcohol or mixed solvents thereof in the presence of an inorganic base such as
potassium carbonate or cesium carbonate or an organic base such as triethylamine or
diisopropylethylamine under the temperature condition of from near 0°C to near the boiling
point of the solvent.
The compound represented by Formula (19—c) can be obtained by reacting the
compound represented by Formula (19-e) with a nd in the class of amines which is
represented by Formula (1-c) (Step 19—3). The reaction in Step 19-3 proceeds under the same
conditions as those in Step 1-2.
Among the compounds ented by the above Formula (19-a), a nd
represented by Formula (20-d) can be prepared by the synthetic process shown in Scheme 20.
[Chem 31]
L7} 0P1
(20-a)
-2
JNLH 20-1 HN \ 0P1
R3 NH2 RakN
(10-a) (20-b)
R1 R1
I [
R2“ 0 N
f 20-3 0
——-—>
N>—®i~\ « ~\ 6}
OF R3L\/N>. DH
(20-c) (20-d)
Scheme 20
(wherein, R1, R2, R3, L7, P1 and A are the same as above).
The compound represented by Formula (IO-a) can be converted to the compound
represented by Formula (20—b) by means of the same que as that in Step 10-1 of
Scheme 10 (Step 20—1). The compound represented by Formula (20-h) can be converted to
the compound represented by Formula (20-0) by means of the same technique as that in Step
—2 of Scheme 10 (Step 20-2). The nd represented by Formula (20-0) can be
converted to the compound represented by Forrnula (20—d) by means of the same technique as
that in Step 5-8 of Scheme 5 (Step 20-3).
Among the compounds represented by the above Formula (19-a), a compound
ented by Formula (21—a) can be prepared by the synthetic process shown in Scheme 21.
[Chem 32]
R1 R1
| l
RZ‘NfO 21_1 —> R2.N\f0
RSJQN L RSJQN OH
(10-e) (21-a)
Scheme 21
in, R', R2, R3, L2 and A are the same as above).
The compound represented by Formula (21-a) can be obtained by first preparing a
boronic acid derivative from the compound represented by Formula (IO-e) and then
hydroxylating the derivative with a peracid (Step 21—1). This step can be carried out in
accordance with the method described in .
Among the compounds represented by the above Formula (I), a compound
represented by a (22-h) can be prepared by the synthetic process shown in Scheme 22.
—58-
[Chem 33]
'31 I31
.N O 4 {N 0
R2 R\N_R5 22-1 R2 as
-——>
N N ’N-‘Rs
/ \ + L4 X2 / \
N N NGX
R3 r R: r
O 0
(15-9) (22-a) (22-b)
Scheme 22
(wherein, R1, R2, R3, R4, R5, L4, X2 and A are the same as above).
The Compound represented by Formula (22-b) can be obtained by reacting the
compound represented by Formula (15—e) with the compound represented by Formula (22-a)
(Step 22-1). The reaction in Step 22—1 proceeds under the same conditions as those 'in Step
1 5—4.
Among the compounds represented by the above Formula (I), a compound
represented by Formula (23-c) can be prepared by the synthetic process shown in Scheme 23.
[Chem 34]
$1 +31
R\N_R54 RZ'NTO 23-1 R2 Nfo R3
+ ’ 5
[rpm Mt x2 {#6}?
R3 \N R3 \N
(23-a) (23-b) (23-c)
Scheme 23
(wherein, R1, R2, R3, R4, R5, L4, X2, Y2, Mt and A are the same as above).
The compound represented by Formula (23 -c) can be obtained by reacting the
compound represented by Formula (23-a) with the compound represented by Formula (23—b)
(Step 23-1). The on in Step 23-1 ds under the same ions as those in Step 4—
Among the compounds ented by the above Formula (23-a), a compound
represented by Formula (24-a) can be prepared by the synthetic process shown in Scheme 24.
R1 R1
l l
Rz.N\f0 24_1
_._______._> RleTo
N/\S_ N
4 \ 4
R3J§N L RSJQN L
(18-c) (24-a)
Scheme 24
(wherein, R1, R2, R3 and L4 A are the same as above).
The compound ented by Formula (24—a) can be obtained by reacting the
compound represented by Formula (18-0) with a methylating agent such as methyl iodide in
the presence of a base (Step 24—1).
Among the compounds represented by the above Formula (I), a compound
represented by Formula (25—b) can be prepared by the synthetic process shown in Scheme 25.
[Chem 36]
R1 R1
l |
N o
2 0 R3 2N o
R T 251_ R
HN>\:\>‘ éN_R5 RTN‘R5
3;\ X
L4 — LXNb‘XZ
R3 N —
R3 N
(18—f) (25-a) (25-b)
Scheme 25
in, R1, R2, R3, R4, R5, L4 and X2 are the same as above).
The compound represented by Formula (25-b) can be obtained by reacting the
nd represented by Formula (18—0 with the compound ented by Formula (25-a)
(Step 25-1). The reaction in Step 25—1 proceeds under the same conditions as those in Step 4-
Among the compounds represented by the above Formula (I), a compound
represented by Formula (26-f) can be prepared by the synthetic process shown in Scheme 26.
[Chem 37]
R1 R1
| |
Rz-NTO 0 26-1 R2“ 0 26-2
* a»? w “9
N N >\—\ —’
RSJQN L3 \—/ \
RSJQN N N—P3
\--/
(26-a) (ZS-b) (26-c)
‘N—R5
:1 L ~X2
(we)
o :11 0
R2. \f 26-3 R2.
0 0 R4
—-—————> \
N 3
Rak} \._/\ \ N \ 2N—R
N NH R3J§/N>— \_JN N—x
(26-d) (26-f)
Scheme 26
(wherein, R1, R2, R3, R4, R5, L4 and X2 are the same as above; P3 represents a protecting
group for amino groups, such as a benzyloxycarbonyl group, an allyloxycarbonyl group, a
tert-butylcarbonyl group or a p-toluenesulfonyl group [see Protective Groups in Organic
Synthesis, Fourth Edition, John Wiley & Sons, INC.])
The nd ented by Formula (26—c) can be obtained by reacting the
compound represented by Formula (26—a) with the compound represented by Formula (26-b)
(Step 26—1). The reaction in Step 26-1 proceeds under the same conditions as those in Step 4-
1. Here the compound represented by Formula (26-b) is available as a commercial
compound or a known compound; alternatively, it may be a compound as synthesized from
commercial compounds or known nds using various organic synthesis techniques
known to those skilled in the art.
The compound represented by Formula (26—d) can be obtained from the compound
ented by Formula (26-c) by means of removing the protective group P3 using various
organic synthesis techniques known to those skilled in the art [see Protective Groups in
Organic Synthesis, Fourth Edition, John Wiley & Sons, INC] (Step 26-2).
The compound represented by Formula (26-f) can be obtained by reacting the
nd represented by a (26-d) with the compound represented by Forrnula (26»e)
(Step 26—3). The reaction in Step 26-3 proceeds under the same conditions as those in Step 1—
Among the compounds represented by Formula (22-a), compounds represented by
a (27-e) and a (27-j) can be prepared by the synthetic process shown in
Scheme 27.
[Chem. 38]
”G40” 27-1 ”We“ 27-2 L4‘®JOH
(27-a) (27-b) (27-c)
27-3 L 27-5
0 0— 21/ 0
/ L1
(27-g) (27-d) (274-)
27-8 "(2'33 274 27-6
R4 4
0 \R5 R5
Ra 27-9 (1-c) (1-c)
L4 R\4‘ Ra R4 R4
N: N:
(27-i) NH’ L4 R5 UQJR5 \R5
“-6) (27-1') (27-e)
Scheme 27
(wherein, R4, R5, R7, L1, L4 and A are the same as above; Met represents a metal such as -
MgBr, MgCl, or—Li; and Ra represents a methyl or ethyl group).
The compound represented by Formula (27-b) can be obtained from the nd
represented by Formula (27—a) through homologation by the Arndt- Eistert reaction (Step 27-
1). The comprehensive review of the Arndt-Eistert reaction can be found in Chem. Ber.,
1927, 60, 1364. Here the compound (27-a) is available as a commercial compound or a
known compound; alternatively, it may be a compound as synthesized from commercial
compounds or known compounds using s organic synthesis techniques known to those
skilled in the art. The compound represented by Formula (27-0) can be obtained by reducing
the compound represented by Formula (27-h) (Step 27-2). The reduction reaction in Step 27-
2 proceeds in a solvent such as tetrahydrofuran, 1,4—dioxane, diethyl ether, diisopropyl ether,
or mixed solvents thereof in the presence of a reducing agent such as a borane-THF complex
or lithium aluminum hydride under the temperature condition of from —78°C to near room
temperature. The compound represented by Formula (27—e) can be prepared from the
compound represented by Formula (27-c) by means of converting the hydroxyl group to a
leaving group (Step 27—3) and then allowing an amine (1—0) to act on the resulting compound
(Step 27-4). The compound represented by a (27—e) can also be obtained by oxidizing
the hydroxyl group of the compound ented by Formula (27—0) into an aldehyde group
h a common oxidation reaction (Step 27—5) and then performing a reductive amination
reaction with the amine (l-c) (Step 27-6). Step 27-3, Step 27—4 and Step 27—6 d under
the same reaction conditions as those for Step 1—1, Step 1-2 and Step 17—2, respectively. The
compound represented by a (27—j) can be obtained by ting the compound
represented by Formula (27-h) into a Weinreb amide (Step 27-7), then allowing a
corresponding organometallic reagent (e.g., a Grignard reagent or an organolithium reagent)
to act on the amide so that it is converted into a ketonic form (27-i) (Step 27—8), and
thereafter subjecting the ketonic form to a reductive amination reaction with the amine (l-c)
(Step 27-9). The reaction in Step 27—7 ds in the presence of N,O~
dimethylhydroxylamine under the same ion conditions as those in Step 2-2. The
reaction in Step 27-8 is one in which the compound represented by Forrnula (27—h) (a
metallic reagent such as a Grignard reagent or an organioithium reagent) is d to act in a
solvent such as ydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether, or mixed
solvents f under the temperature condition of from —78°C to near room temperature.
The compound represented by Formula (23—h) can be prepared by the synthetic
process shown in Scheme 28.
[Chem 39]
R‘N—RE’4 4
28'1 R\N-R5
, —> ,
L4 x2 Mt x2
(22-a) (23-b)
Scheme 28
(wherein, R4, R5, L4, X2, Mt and A are the same as above).
The compound represented by the above Formula (23-b) can be synthesized from
the compound represented by Formula (22-a) through a metal exchange reaction in the
presence or e of a transition metal catalyst and in the presence or absence of a base
(Step 28—1). Here the “metal exchange on” may be exemplified by such a reaction that
(22—a) is treated with lato borane or bispinacol diborane in an inert solvent in the
ce of a palladium catalyst, optionally using a ligand for the palladium catalyst, in the
presence of a base such as potassium acetate or triethylamine (see Comprehensive Organic
Transformations, Second Edition, 1999, John Wiley & Sons, INC.) Examples of the
palladium catalyst here mentioned include palladium(ll) acetate,
dichlorobis(triphenylphosphine)palladium(ll), dichlorobisacetonitrilepalladium(11), and
tetraquistriphenylphosphine ium(0). Examples of the ligand include
triphenylphosphine, tributylphosphine, 2,2—bis(diphenylphosphino)— 1 , 1 ~binaphthyl (BINAP),
2—(di~tert-butylphosphino)biphenyl, 1,1 ’-bis(diphenylphosphino)ferrocene (dppf), and 1,3—
bis(diphenylphosphino)propane (dppp). Another example of the metal exchange on
that may be given is one in which (22-a) is converted to a Grignard reagent, an organolithium
reagent or the like in an inert solvent using various organic sis techniques known to
those skilled in the art and thereafter the reagent is treated with trimethyl , triethyl
borate, triisopropyl borate or the like.
The compound represented by Formula (27-c) can be prepared by the synthetic
process shown in Scheme 29.
-64—
[Chem 40]
L4—®—//0 ——9—> / OR6 29.2 CH
L4 ——> L4n®f
(29-a) (29-h) (27-c)
Scheme 29
(wherein, R6, L4and A are the same as above).
The compound represented by Formula (29-b) can be obtained from the compound
represented by Formula (29-a) through gation by the Wittig reaction (Step 29-1). The
comprehensive review of the Wittig reaction can be found in Comprehensive Organic
Transformations, Second Edition, 1999, John Wiley & Sons, Inc.
The compound (29—b) can be converted to the compound represented by Formula
(27-c) by means of the same technique as that in Step 2-6 of Scheme 2 (Step 29-2).
EXAMPLES
The t invention will now be described in more detail by Reference Examples,
Examples, and Test Examples, which are by no means intended to limit the present invention
and may be d without departing from the scope of the present invention.
In Reference Examples and Examples, the "phase separator" in post-treatment is an
ISOLUTE (registered trademark) Phase tor of Biotage Inc. In purification by column
chromatography, for "SNAP Cartridge , SNAP Cartridge KP—NH of Biotage Inc.
was used, for "SNAP Cartridge KP-Sil", SNAP Cartridge KP-Sil of Biotage Inc. was used,
for "SNAP Cartridge HP-Sil" SNAP Cartridge HP—Sil of Biotage Inc, and for "Chromatorex
(registered trademark) NH" Chromatorex (registered trademark) NH of Fuji Silysia Chemical
Ltd. was used. In purification by preparative thin-layer chromatography (PTLC), Silica Gel
, 20 cm x 20 cm, of Merck was used. In ation by "reverse-phase column
Chromatography", Waters SunFire prep C18 OBD, 5.0 pm, (1) 30 x 50 mm or YMC-Actus
Triart C18, 5.0 um, (i) 30 x 50 mm was used.
The data described in the Reference Examples and Examples below were ed
by measurement with the ing instruments:
NMR spectrometer: JNM-ECA 600 (600 MHZ, JEOL Ltd), INM—ECA 500
(500 MHz, JEOL Ltd), UNITY NOVA 300 (300 MHZ, Varian, Inc.), or GEMINI 00
(200 MHz, Varian, Inc);
MS spectrometer: LCMS-2010EV (Shimadzu Corporation) or Platform LC
(Micromass, Ltd).
In the Reference Examples and Examples below, high-performance liquid
chromatography-mass spectrometry (LCMS) was performed under the following conditions
of measurement:
Condition 1
Instrument: Platform LC mass, Ltd.) and Agilent 1100 (Agilent
logies, Inc);
: SunFire C18, 2.5 pm, (1) 4.6 X 50 mm (Waters Corporation);
Solvent: Solution A, water containing 0. 1% trifluoroacetic acid; Solution B,
acetonitrile containing 0.1% trifluoroacetic acid;
Gradient: 0 min (Solution A/Solution B = 90/10), 0.5 min (Solution A/Solution B =
90/10), 5.5 min (Solution A/Solution B = 20/80), 6.0 min (Solution A/Solution B = 1/99),
and 6.3 min (Solution A/Solution B = 1/99);
Flow rate: 1 mL/min, ion: 254 nm; and
Ionization: electron spray ionization (ESI).
ion 2-1
Instrument: Agilent 2900 and Agilent 6150;
Column: Waters Acquity CSH C18, 1.7 rim, (1) 2.1 X 50 mm;
Solvent: Solution A, water containing 0.1% formic acid; on B, acetonitrile
containing 0.1% formic acid;
Gradient: 0 min (Solution A/Solution B = 80/20), 1.2 to 1.4 min (Solution
tion B = 1/99); and
Flow rate: 0.8 mL/min, Detection: 254 nm.
Condition 2-2
Instrument, column, and solvent are the same as those in ion 2-1;
Gradient and flow rate: 0.8 mL/min for 0 min (Solution A/Solution B = 95/5),
120 min (Solution A/Solution B = 50/50), and 1.0 mL/min for 1.38 min (Solution A/Solution
B = 3/97); and
Detection: 254 nm.
In the Reference Examples and Examples below, compounds were named using
ACD/Name (ACD/Labs 12.01, ed Chemistry Development Inc.)
Terms and reagent names in the es are denoted by the following
abbreviations:
Brine (saturated brine), MeOH nol), MgSO4 (anhydrous magnesium sulfate),
K2C03 (potassium carbonate), Na2C03 (sodium carbonate), Na2S04 (anhydrous sodium
sulfate), NaHC03 (sodium hydrogencarbonate), NaOH (sodium hydroxide), KOH (potassium
ide), HCl (hydrogen chloride), IPE (diisopropyl ether), THF (tetrahydrofuran), DMF
imethylformamide), EtZO (diethyl ether), EtOH (ethanol), NH4OH (25 to 28%
aqueous ammonia), EtOAc (ethyl acetate), CHC13 (chloroform), DMSO (dimethyl sulfoxide),
MeCN (acetonitrile), n—Hexane (n-hexane), Et3N (triethylamine), iPrZNEt
(diisopropylethylamine), Pd(PPh3)4 [tetrakistriphenylphosphine palladium(0)], HATU [0—(7-
azabenzotriazol-l-yl)—N,N,N',N'—tetramethyluronium hexafluorophosphate], DPPA
(diphenylphosphoryl azide), BH3'THF e—tetrahydrofuran complex), NaBOg-4H20
(sodium perborate tetrahydrate), 9-BBN (9-borabicyclo[3.3.1]nonane), IBX (l-hydroxy-1,2-
doxol-3(1H)—one l—oxide), BBr3 (boron tribromide), MsCl (methanesulfonyl chloride),
TMSCH2N2 (trimethylsilyl diazomethane), n-BuLi (n-butyllithium), EDC-HCl [l—ethyl-3—(3-
dimethylaminopropyl)carbodiimide hydrochloride], HOBt-HZO roxybenzotriazole
monohydrate), CszC03 (cesium carbonate), PPh3)2
[bis(triphenylphosphine)palladium(II) dichloride], NaBI-I4 (sodium borohydride), Na2S03
(sodium sulfite), dppt)-CH2C12 {[1,1’-bis(dipheny1phosphino)ferrocene]palladium(II)
dichloride/dichloromethane complex (1 : 1)}, ACOK (potassium acetate), Boc (tert-
butoxycarbonyl), NBS (N-bromosuccinimide), NIS (N-idodosuccinimide), ngO
(trifluoromethanesulfonic acid anhydride), NH4C1 (ammonium chloride), and TBDPS (tert-
butyldiphenylsilyl).
-Reference Example P—A01: Synthesis of 4-(4-bromophenyl)—2-(3 —chlorophenyl)-1H-
imidazole
[Chem.41]
Cl Bf
A mixture of 3-chloro-benzamidine (3.53 g), NaHCO3 (7.67 g), THF (35 mL) and
water (14 mL) was refluxed. Under continued refluxing, a on of 2,4’—
dibromoacetophenone (5.23 g) in THF (14 mL) was added and the resulting mixture was
refluxed for 2 hours. After leaving the mixture to cool, the solvent was led off under
reduced pressure and water was added for extraction with CHC13. After drying the organic
layer with Nazso4, the desiccant was filtered off and the solvent distilled off under reduced
pressure. The resulting residue was purified by silica gel column chromatography
(Chromatorex NH; mobile phase: EtOAc/n—Hexane = 0/100 - 50/50; v/v) to give the titled
compound (4.18 g as a yellow solid).
MS (ESI pos.) m/Z : 333, 335 ([M+H]+).
'Reference Example P—A02: Synthesis of 2—[4-(4—bromophenyl)(3-chlorophenyl)-1H—
ol-l-yl]-N-(propan-2—yl)acetamide
[Chem 42]
A mixture of the nd (4.18 g) obtained in Reference Example P—AOl, 2-
bromo-N~isopropylacetamide (3.39 g), K2C03 (3.46 g), and DMF (84 mL) was stirred
~68-
overnight at room temperature. Water was added and the solid precipitating upon addition of
IPE was recovered by filtration to give the titled compound (4.14 g as a pale brown solid).
MS (ESI p05.) m/z : 432, 434 ([M+H]+).
'Reference e P—A03: Synthesis of 2-[2-(3—chloropheny1)-4—(4—ethenylphenyl)-1H-
imidazol-l—yl]-N—(propan—2~yl)acetamide
[Chem 43]
7’“:
A e of the compound (1.03 g) obtained in Reference e P-A02,
tributyl(vinyl)tin (0.76 mL), Pd(PPh3)4 (274 mg) and toluene (20 mL) was stirred at an
external temperature of 100°C. Tributyl(vinyl)tin (0.76 mL) and Pd(PPh3)4 (274 mg) were
further added and the mixture was stirred at an external temperature of 100°C for 7 hours.
After allowing the mixture to cool, the solvent was distilled off under reduced re and
the resulting residue was purified by column chromatography (Chromatorex NH; mobile
phase: n-Hexane/CHC13 = 90/10 — 50/50; v/v) to give the titled compound (660 mg as a
ess solid).
MS (ESI pos.) m/z : 380 ([M+H]+).
'Reference Example P-A04: Synthesis of 2—{2—(3-chlorophenyl)[4-(2-
hydroxyethyl)phenyl]—1H—imidazol—l-yl} —N—(propan-2—yl)acetamide
[Chem 44]
\erO
Cl \N
To a THF solution (20 mL) of the compound (658 mg) obtained in Reference
Example P—A03, 1.09 mol/L BH3 - THF—THF solution (2.38 mL) was added dropwise under
an ice bath and after stirring the mixture for an hour under cooling with ice, water (26 mL)
and NaBO3 '4H20 (1.20 g) were added and the mixture was stirred for 6 hours under cooling
with ice. After adding Na2S03, the organic solvent was distilled off under reduced pressure
and extraction was conducted with CHC13. The t was distilled off under reduced
pressure and the residue was washed with a mixed solvent (EtOAc/n-Hexane = 1/6; v/v); the
solid was recovered by filtration to give the titled compound (536 mg as a colorless solid).
MS (ESI pos.) m/z : 398 ([M+H]+).
' Reference Example P—AOS: Synthesis of 4—(4—bromophenyl)~2—(4-fluoromethoxyphenyl)—
lH—imidazole
[Chem 45]
HN \
,0 \N Br
Starting from romethoxybenzamidine (8.00 g) and 2,4’-
dibromoacetophenone (10.8 g), the same procedure as in Reference e P-AOI was
applied to give the titled compound (13.3 g as a pale yellow amorphous product).
Ms (ESI pos.) m/z : 347, 349 ([M+H]+).
ence Example P—A06: Synthesis of 2-[4—(4—bromophenyl)~2-(4—fluoro-3~
methoxyphenyl)-1H—imidazol- l -y1]—N-(propan-2—yl)acetamide
[Chem 46]
t“I:
Starting from the compound (13.3 g) obtained in Reference Example P-A05, the
same procedure as in Reference e P-A02 was applied to give the titled compound
(14.7 g as a pale red solid).
MS (ESI pos.) m/z : 446, 448 ([M+H]+).
'Reference Example P-A07: Synthesis of 2-[4-(4-ethenylphenyl)(4-fluoro
methoxyphenyl)— lH—imidazol- l -yl]~N—(propany1)acetamide
[Chem 47]
7” f0H
,0 W
Starting from the compound (5.00 g) obtained in Reference Example P-A06, the
same procedure as in Reference Example P—A03 was applied to give the titled nd
(3.06 g as a pale yellow amorphous product).
MS (ESI pos.) m/z : 394 ([M+H]+).
'Reference Example P-A08: Synthesis of 2- {2—(4-fluoromethoxyphenyl)[4-(2-
hydroxyethyl)phenyl]- l H—imidazol— 1 —yl } ~N-(propanyl)acetamide
] [Chem 48]
V”i:
/0:©/LWOHF
Starting from the compound (3.06 g) obtained in Reference Example P—A07, the
same procedure as in Reference P-A04 was applied to give the titled nd (3.20 g as a
pale yellow solid).
MS (ESI pos.) m/z : 412 +).
Reference Example P-AO9: Synthesis of 5-bromo-2—[2-(3-chlorophenyl)-1H-imidazol—4-
yl]pyridine
[023 9]
-71_
[Chem. 49]
CI \N \ / Br
Starting from 3-chloro—benzamidine (1.65 g) and 2—bromo—l—(5—bromopyridin—2—
yl)ethanone (2.97 g), the same procedure as in Reference Example P-AOl was applied to give
the titled compound (2.65 g as a reddish brown amorphous product).
M3 (E81 pos.) m/z : 334, 336 ([M+H]+).
- Reference Example P-A10: Synthesis of 2-[4—(5-bromopyridin—2—yl)-2—(3—chlorophenyl)—
1H—imidazolyl]—N—(propan—2-yl)acetamide
H.[Chem 50]
\Ft:
Starting from the compound (2.64 g) ed in nce Example P—A09, the
same ure as in Reference Example P-A02 was applied to give the titled compound
(2.54 g as a pale reddish brown solid).
MS (ESI pos.) m/z : 433, 435 ([M+H]+).
- Reference Example P-A11: 2-[2—(3-chlorophenyl)(5-ethenylpyridin—2-yl)—1H—imidazol—l-
(propan~2-yl)acetamide
[Chem 51]
[MTG
N N
\ »
~-—.
Starting from the compound (1.50 g) obtained in Reference Example P-AlO, the
same procedure as in Reference Example P—A03 was applied to give the titled compound
(768 mg as an orange-colored solid).
MS (Es1 pos.) m/z : 381 ([M+H]+).
' nce Example P-A12: Synthesis of 2-{2—(3-chlorophenyl)[5-(2-
hydroxyethyl)pyridin-Z-yl]-1H—imidazol-l-yl} -N—(propanyl)acetamide
[Chem 52]
\F1:,
c.©/LWOH
Starting from the compound (760 mg) obtained in Reference Example P—Al l, the
same procedure as in Reference Example P-A04 was applied to give the titled compound
(362 mg as a pale brown solid).
MS (ESI pos.) m/z : 399 ([M+H]+).
- Reference e P—Al3: Synthesis of 2-[4-(4—bromophenyl)—lH—imidazol-Z—yl]—6—
methoxypyridine
[Chem 53]
{,0 N\ KN Br
Starting from 6—methoxypicolinimidamide hydrochloride (3.00 g) and 2,4’-
dibromoacetophenone (4.45 g), the same procedure as in Reference Example P—AOl was
applied to give the titled nd (2.23 g as a colorless solid).
MS (ESI pos.) m/z : 330, 332 ([M+H]+).
' Reference Example P—Al4: Synthesis of 2—[4-(4-bromophenyl—2-(6—methoxypyridinyl)-
lH—imidazol-l-yl]-N-(propanyl)acetamide
[Chem 54]
Starting from the compound (2.23 g) obtained in Reference Example P—Al3, the
same procedure as in Reference Example P-A02 was applied to give the titled compound
(2.85 g as a pale pink solid).
MS (ESI pos.) m/z : 429, 431([M+H]+).
' Reference Example P-A15: Synthesis of 2-[4— )—2-ethoxyethenyl]phenyl}—2—(6—
methoxypyridin—Z-yl)—1H—imidazol~l—yl]~N-(propanyl)acetamide
[Chem 55]
Y“? >
/O N\ NW
Starting from the compound (500 mg) obtained in Reference Example P-Al4 and
(Z)-l—ethoxy—2—(tributylstannyl)ethane (0.47 mL), the same procedure as in Reference
Example P-AO3 was d to give the titled compound (180 mg as a pale yellow solid).
MS (ESI pos.) m/z : 421 ([M+H]+).
- Reference Example P—A16: Synthesis of 2- {2-(6-methoxypyridinyl)—4—[4—(2—
oxoethyl)phenyl]—lH—imidazol—l-yl}-N-(propan—2-yl)acetamide
[Chem 56]
0“)"t
A mixture of the compound (180 mg) obtained in Reference Example P-A15, a l M
HCl aqueous solution (2 m L) and THF (10 mL) was refluxed overnight at an external
temperature of 80°C. After leaving the mixture to cool, a 1 M HCl aqueous on (2 mL)
was further added and the mixture was refluxed for 6 hours at an al temperature of
80°C. After leaving the mixture to cool, the solvent was distilled off under reduced pressure;
uently, the residue was neutralized with a saturated aqueous NaHCO3 solution,
followed by extraction with CHClg. The organic layer was filtered with Phase Separator and
the solvent was distilled off under reduced pressure to give the titled compound (180 mg as a
pale yellow solid).
MS (ESI pos.) m/z : 393 ([M+H]+).
-Reference Example P—Al7: Synthesis of 2-bromo[2-(3—chlorophenyl)—1H—imidazol-4—
yl]pyridine
[Chem 57]
Cl HNWKN \ / Br
Starting from 3-chlorobenzamidine (4.00 g) and 2-bromo-l-(6—bromopyrid—3-
yl)ethanone (7.29 g), the same procedure as in Reference e P-AOl was applied to give
the titled compound (4.02 g as a powder).
MS (ESI pos.) m/z : 334, 336 ([M+H]+).
'Reference e P—A18: Synthesis of 2—[4—(6—bromonopyridin—3~y1)(3-chlorophenyl)—
lH—imidazol- l -yl] opan-2—yl)acetarnide
[Chem 58]
CI\[:r&LN\ \/ Br
ng from the compound (3.52 g) obtained in Reference Example P—A17, the
same procedure as in Reference Example P-A02 was applied to give the titled compound
(4.11 g as a powder).
MS (ESI pos.) m/z : 433, 435 ([M+H]+).
~Reference Example P-A19: sis of 2—[2-(3-chlorophenyl)—4- {6-[(Z)
ethoxyethenyl]pyridin-3—yl}-1H—imidazol-1—yl]-N—(propanyl)acetamide
[Chem 59]
Y“f0 O>
C'\©/Lm \/
Starting from the compound (2.04 g) obtained in Reference Example P-A18, the
same procedure as in Reference Example P-A15 was applied to give the titled compound
(863 mg as a colorless solid).
MS (ESI pos.) m/z : 425 ([M+H]+).
- Reference Example P-A20: Synthesis of 2-{2-(3—chlorophenyl)—4—[6-(2—oxoethyl)pyridin—3-
y1]—lH—imidazol—l-yl}—N—(propan—2-yl)acetamide
H.[Chem 60]
Starting from the compound (211 mg) obtained in nce Example P—A19, the
same ure as in Reference Example P—A16 was applied to give the titled compound
(290 mg as a red oil).
MS (ESI pos.) m/z : 397 ([M+H]+).
- Reference Example P—A21: Synthesis of 2—[4— {4—[(Z)—2—ethoxyethenyl]phenyl}—2-(4-fluoro-
3~methoxyphenyl)— l H-imidazol- l ~yl]-N-(propan-Z-yl)acetamide
[Chem 61]
“f o>
,0 W
—76-
Starting from the compound (2.00 g) obtained in Reference Example P-A06, the
same procedure as in Reference Example P-AlS was applied to give the titled compound
(1.12 g as a colorless solid.)
MS (ESI pos.) m/z : 438 ([M+H]+).
'Reference Example P—A22: Synthesis of 2~{2—(4-fluoro-3—methoxyphenyl)—4-[4—(2-
oxoethyl)phenyl]—1H-imidazoly1}-N—(propan-2—y1)acetamide
[Chem 62]
[0:66] Starting from the compound (1.12 g) obtainedin nce Example P-A21, the
same procedure as in Reference Example P-A16 was applied to give the titled compound
(1.00 g as a yellow solid).
MS (ESI pos.) m/z : 410 ([M+H]+).
'Reference Example P—A23: Synthesis of 2-{2—(3~chlorophenyl)-4—[4—(4,4,5,5-tetramethyl-
1,3 ,2~dioxaborolan—2~y1)pheny1]- 1 H-imidazol— 1 ~y1} opan—2-yl)acetamide
O[267] [HChem 63]
new???
A mixture of the compound (500 mg) obtained1n Reference Example P-A02,
4,4,4’,4’,5,5,5’,5’—octamethyl-2,2’—bi-1,3,2-dioxaborolane (381 mg), PdC12(dppf) - CH2C12
(95 mg), AcOK (342 mg) and DMSO (8 mL) was stirred at an external temperature of 100°C
for 1.5 hours under a nitrogen atmosphere. After leaving the e to cool, water and IPE
were added and after continuing the ng for a While, the precipitating solid was recovered
by filtration to give the titled compound (610 mg as a dark gray solid).
MS (ESI pos.) m/z : 480 ([M+H]+).
' Reference Example P-A24: Synthesis of 2—[2-(3-chlorophenyl)(4—hydroxyphenyl)-1H-
imidazol-l-yl]-N-(propan-2—yl)acetamide
[Chem 64]
\rz:
CKQ/‘Q‘QOH
To an EtOH (2 mL) solution of the compound (255 mg) obtained in nce
Example P-A23, a 30% aqueous H202 solution (2 mL) was added and the mixture was d
at room temperature for one day. Water was added for extraction with CHClg. The organic
layer was washed with Brine and dried over Na2804; subsequently, the desiccant was filtered
off and the solvent was distilled off under reduced pressure. The resulting residue was
d by silica gel column chromatography (SNAP Cartridge KP—Sil 25g; mobile phase:
CHClg/MeOH = 99/1 - 95/5; v/v). The purified product was washed with 320 to give the
titled compound (123 mg as a ess solid).
MS (ESI pos.) m/z : 370 ([M+H]+).
ence Example P-A25: Synthesis of 2—(3-chlorophenyl)—4-(3-methoxyphenyl)»lH-
imidazole
[Chem 65]
CI \N
Starting from 3-chloro-benzamidine (943 mg) and 3’-methoxyphenacyl bromide
(1.03 g), the same procedure as in Reference Example P-AOl was applied to give the titled
compound (760 mg as a pale pink solid).
MS (ESI pos.) m/z : 285 ([M+H]+).
~Reference Example P—A26: Synthesis of 2-[2-(3-chlorophenyl)(3—meth0xypheny1)—1H-
imidazolyl]-N-(propan—Z-yl)acetamide
[Chem 66]
7% \O
Starting from the compound (760 mg) obtained in Reference Example P—A25, the
same procedure as in Reference Example P-A02 was applied to give the titled compound
(910 mg as a ess solid).
MS (ESI pos.) m/z : 384 ([M+H]+).
Reference Example P-A27: Synthesis of 2—[2-(3-chloropheny1)-4—(3-hydroxypheny1)—1H-
imidazol-l-yl]-N-(propan—2-yl)acetamide
[Chem 67]
7"?N c...
To a CHC13 (10 mL) on of the compound (910 mg) obtained in Reference
Example P—A26, l M BBr3/n-Hexane (6.0 mL) was added dropwise in an ice bath under a
nitrogen atmosphere and the mixture was stirred at room temperature for one day. In a salt
ice bath, a saturated aqueous NaHC03 solution was gradually added. After adding EtOAc
and IPE, the mixture was stirred for a while at room ature. The precipitating solid was
recovered by filtration to give the titled compound (658 mg as a colorless solid).
MS (ESI pos.) m/z : 370 +).
'Reference Example P—A28: Synthesis of N—(propan—2-yl)(2,4,5-tribrom0—lH-imidazol—l—
yl)acetamide
[0277H [Chem 68]
7’“3:8
B r.N
Starting from 2,4,5-tribromoimidazole (3.00 g), the same procedure as in Reference
e P—A02 was applied to give the titled compound (2.65 g as a pale red solid).
MS (ESI pos.) m/z : 402 ([M+H]+).
'Reference Example P—A29: Synthesis of 2-[4,5~dibromo(3—methoxyphenyl)-1H—
imidazol—l~y1]-N—(propan-Z-yl)acetamide
[Chem 69]
YNfOB.
L’S‘Br
A mixture of the nd (2.00 g) obtained in Reference Example P-A28, 3-
methoxyphenylboronic acid (790 mg), Pd(PPh3)4 (572 mg), a 2 M Na2C03 aqueous solution
(4.95 mL) and a mixed solvent (50 mL, toluene/MeOI-l = 5/1; v/v) was stirred at an external
temperature of 60°C for 4 hours. After being left to cool, the mixture was diluted with
CHC13 and washed with water. After being dried over MgSO4, the organic layer was
concentrated under reduced pressure. The resulting residue was purified by silica gel (neutral
OH form) column chromatography (mobile phase: CHClg/EtOAc = 95/5 -70/30; V/v) to give
the titled compound (1.05 g as a colorless oil).
MS (ESI pos.) m/z : 430 +).
'Reference Example P-A30: Synthesis of 2-[4-bromo(3-methoxyphenyl)methyl—1H-
imidazol— 1 —yl]—N—(propan—2-yl)acetamide
with.
.f N
To a THF (7.0 mL) solution of the nd (300 mg) obtained in Reference
e P—A29, 2.66 M nBuLi/n-Hexane (0.37 mL) was added at -78°C and the mixture was
stirred for 10 minutes. After adding methyl iodide (0.087 mL), the mixture was stirred for an
additional 30 minutes. The reaction was quenched with MeOH and after dilution with
EtOAc, the reaction mixture was washed with water and Brine. After being dried over
MgSO4, the organic layer was concentrated under d pressure. The resulting residue
was purified by silica gel (OH form) column chromatography (mobile phase: EtOAc
= 97/3 - 90/10; v/v) to give the titled compound (86 mg as a pale yellow oil).
MS (ESI pos.) m/z : 366 ([M+H]+).
-Reference Example P-A3 1: Synthesis of 2—(2,4-dibromo-lH—imidazol—l—yl)-N-(propan—2—
yl)acetamide
[Chem 71]
7’”?
AXBFN
Br N
Starting from bromo—1H—imidazole (2.36 g), the same procedure as in
Reference Example P-A02 was applied to give the titled compound (2.65 g as a colorless
solid).
MS (1381 pos.) m/z : 324 ([M+H]+).
Starting from the compound obtained in Reference Example P-A31, the same procedure as in
Reference Example P—A29 was applied to give the following compounds.
' Reference Example P-A32: romo—2—(3—meth0xyphenyl)- lH-imidazol-l-yl]—N-
~81-
(propanyl)acetamide
[Chem 72]
Mgll
MS (ESI pos.) m/z : 352 ([M+H]+).
- Reference Example P—A33: 2—[4—brom0—2-(3-chlorofluor0phenyl)—lH—imidazol— 1-yl]-N—
(propan—Z-yl)acetamide
[Chem 73]
0. film
MS (ESI pos.) m/z : 374 ([M+H]+).
'Reference Example P—A34: 2—[4—br0mo—2-(5—methoxypyridin—3-yl)-lH-imidazol-l-y1]-N—
nyl)acetamide
[Chem 74]
12* Br
MS (ESI pos.) m/z : 353 ([M+H]+).
'Reference Example P-A35: 2-[4—bromo(2-meth0xypyridin-4—yl)-1H—imidazol-l-y1]-N-
—82-
(propan—2-yl)acetamide
[Chem 75]
O \N’XBF
MS (ESI pos.) m/z : 353 ([M+H]+).
- nce Example P-A36: 2—[4—bromo—2-(3~chloropheny1)-1H—imidazol—1-y1]-N-(propan-
2—y1)acetamide
[Chem. 76]
c. :15
MS (ESI pos.) m/z ; 356 ([M+H]+).
' Reference Example P-A37: Synthesis of 2-[2—(3-ch1oropheny1)—4-(2~oxopiperazin—1—y1)—1H-
imidazoly1]-N—(propan-2—y1)acetamide
[Chem 77]
72:9
0][296 A mixture in 1,-4dioxane (6.0 mL) of the compound (300 mg) obtained1n Reference
Example P—A36, 1—Boc—3— oxopiperazine (177 mg), copper iodide (160 mg), tripotassium
—83-
phosphate (357 mg) and trans—N,N’-bismethyl—l,2-cyclohexanediamine (0.13 mL) was
stirred overnight at an al temperature of 90°C under a nitrogen stream. After leaving
the mixture to cool, 20% aqueous ammonia was added and extraction was conducted with
toluene (containing 10% EtOAc); after drying over NaZSO4, the desiccant was filtered off and
the e was concentrated under reduced pressure. The resulting residue was purified by
silica gel column chromatography (SNAP dge KP-NH 28g; mobile phase: n—
Hexane/CHC13 : 80/20 - 0/100; v/v) to give a purified t (206 mg as a colorless solid).
To a solution of this purified product (192 mg) in 1,4-dioxane (6.0 mL), 4 M
HCl/EtOAc (0.5 mL) was added and the mixture was stirred at room temperature for two
days. After the solvent was distilled off under d pressure, the residue was neutralized
with a saturated aqueous NaHCO3 solution in an ice bath and the precipitating solid was
recovered by filtration to give the titled compound (100 mg as a colorless solid).
MS (ESI pos.) m/z : 376 ([M+H]+).
-Reference Example P-A38: Synthesis of sodium 2-(3-chloropheny1)-l-[2-oxo(propan
ylamino)ethyl]-1H—imidazole—4—carboxylate
[Chem 78]
c. TM“;(a
A mixture of the nd (2.52 g) obtained in Reference Example P-A36,
Pd(PPh3)4 (816 mg), K2C03 (1.47 g) and a mixed solvent (35 mL, DMF/EtOH = 2/1; v/v)
was stirred at an external temperature of 100°C for 17 hours under a carbon monoxide
atmosphere. The reaction mixture was filtered through Celite tered trademark) and the
filtrate was extracted with EtOAc; after being dried over MgSO4, the organic layer was
trated under reduced pressure. The resulting e was purified by silica gel (OH
form) column chromatography (mobile phase: CHClg/EtOAc = 90/10 - 50/50; v/v) to give a
—84-
purified product (435 mg as a pale yellow solid).
To a suspension of this purified product (300 mg) in THF (4.5 mL), a 1M NaOH aqueous
solution (0.9 mL) was added and the mixture was heated under reflux for 5 hours.
Subsequent concentration under reduced re gave the titled compound (307 mg as a
colorless solid).
1H-NMR (600 MHz, DMSO—d6) 5 (ppm) ; 1.06 (6 H, d, J=6.6 Hz), 3.79 — 3.88 (l H, m), 4.62
(2 H, s), 7.31 (l H, s), 7.42 - 7.47 (2 H, m), 7.59 - 7.64 (l H, m),
7.69 ~ 7.72 (1 H, m), 8.22 (l H, d, J=7.4 Hz).
'Reference Example P-A39: Synthesis of 2-(3-chlorophenyl)—N-(4—oxocyclohexyl)—l—[2—oxo-
2-(propanylamino)ethyl]—lH-imidazolcarboxamide
[Chem 79]
Ynfo
To a CHC13 (4.0 mL) solution of the compound (201 mg) obtained in Reference
Example P-A38 and oxa-spiro[4.5]dec—8-ylamine (92 mg) in, zO (108 mg) and
EDC ' HCl (135 mg) were added and the mixture was stirred overnight. After adding water
and performing extraction with CHC13, the extract was purified by silica gel (OH form)
column chromatography (mobile phase: CHCl3/MeOH = 100/0 — 95/5; v/v) to give a d
t (237 mg as a colorless solid).
A mixture of this purified product (237 mg), THF (3.5 mL) and a 2 M HCl aqueous
on (3.5 mL) was refluxed overnight. After adding a saturated aqueous NaHCO3
solution, the solvent was distilled off under reduced pressure and water was added for
extraction with CHCI3. The solvent was then distilled off under reduced pressure to give the
titled compound (194 mg as a colorless ous product).
MS (ESI pos.) m/z : 417 ([M+H]+).
'Reference Example P-A40: Synthesis of 2—(3—chlorophenyl)—N-methyl—N-(4-
—85-
oxocyclohexyl)-l—[2—oxo—2—(propanylamino)ethyl]—1H-imidazole-4—carboxamide
[Chem 80]
Starting from the compound (206 mg) obtained in Reference Example P—A38 and 4-
(methylamino)cyclohexanone 2,2—dimethyltrimethylene ketal (165 mg), the same procedure
as in Reference e P—A39 was applied to give the titled compound (213 mg as a pale
yellow oil).
MS (ESI pos.) m/z : 431 ([M+H]+).
- Reference Example P-A4l: Synthesis 3—chlorophenyl)—4— {[3-(2-
hydroxyethyl)pyrrolidinyl]carbonyl}-lH-imidazolyl]-N—(propan-Z—yl)acetamide
H.[Chem 81]
\F1:
WWW.)
To a CHC13 (4.0 mL) solution of the compound (206 mg) obtained in Reference
Example P-A38 and 3-pyrrolidine ethanol (0.08 mL) in, ZO (l 10 mg) and EDC ' HCl
(138 mg) were added and the mixture was stirred overnight. After adding water for
extraction with CHCl3, the extract was purified by silica gel (OH form) column
chromatography (mobile phase: CHClg/MeOH = 100/0 - 95/5; v/V) to give the titled
compound (156 mg as a colorless amorphous product).
MS (ESI pos.) m/z : 419 +).
'Reference Example P-A42: Synthesis of 8-[2-(4-bromopheny1)ethyl]oxa
azabicyclo[3.2.1]0ctane
-86—
[Chem. 82]
To a solution of 2-(4-bromophenyl)ethanol (1.50 g) in CHC13 (10 mL), Eth
(1.30 mL) and MsCl (0.64 mL) were added sequentially under cooling with ice and the
mixture was stirred at room temperature for 2 hours. After adding water under cooling with
ice, extraction with CHCl3 was conducted. The c layer was filtered with Phase
Separator and the filtrate was concentrated under d pressure.
A mixture of the resulting e (2.40 g as a pale yellow oil), 3—oxa
azabicyclo[3.2.1]octane (904 mg), 2,2,6,6-tetramethylpiperidine (2.0 mL) and MeCN
(10 mL) was stirred at an external temperature of 95°C for 4 days. After leaving the e
to cool, water was added for extraction with CHC13. The organic layer was filtered with
Phase Separator and the solvent was distilled off under reduced pressure. The resulting
residue was purified by silica gel column chromatography (SNAP Cartridge HP-Sil 50 g;
mobile phase: EtOAc/MeOH = 99/1 - 90/10; v/v) to give the titled nd (1.47 g as a
pale brown solid).
MS (ESI pos.) m/z : 296,298 ([M+H]+).
'Reference Example P-A43: Synthesis of {4-[2—(3-oxaazabicyclo[3.2.Hoot—8-
yl)ethy1]phenyl}boronic acid
[Chem. 83]
To a THF (8.0 mL) solution of the compound (800 mg) obtained in Reference
Example P-A42, 2.64 M nBuLi/n-Hexane (1.2 mL) was added at -78°C under a nitrogen
atmosphere and the mixture was stirred for 30 minutes. After adding triisopropyl borate
(0.74 mL), the mixture was stirred for 2 hours in an ice bath. After neutralization with a
saturated aqueous NaHC03 on, the mixture was extracted with EtOAc. After drying the
organic layer over NazSO4, the desiccant was d off and the solvent was distilled off
under reduced pressure. The ing residue was washed with IPE (containing 10% AcOEt)
to give the titled compound (190 mg as a colorless solid).
MS (ESI pos.) m/z : 262 ([M+H]+).
'Reference Example P-A44: Synthesis of 2—(4-bromo—3—fluorophenyl)ethanol
[Chem 84]
To a solution of 4-bromofluorophenylacetic acid (3.45 g) in THF (70 mL),
1.08 M BH3 ' THF (20.5 mL) was added under cooling with ice and the mixture was d
for 1.5 hours. Under cooling with ice, MeOH was added until there was no foaming in the
system and the solvent was distilled off under reduced pressure; to the resulting e,
water was added for extraction with CHC13 and the solvent was distilled off under reduced
pressure. The resulting residue was purified by silica gel (OH form) column chromatography
(mobile phase: CHClg/EtOAc = 95/5; V/V) to give the titled compound (2.74 g as a yellow
oil).
MS (ESI pos.) rn/z : 218, 220 (M+).
'Reference e P-A45: Synthesis of 4-[2—(4-bromo—3-fluorophenyl)ethyl]morpholine
[Chem 85]
Br NCO
Starting from the compound (500 mg) obtained in Reference e P—A44 and
morpholine (0.6 mL), the same procedure as in Reference Example P-A42 was applied to
give the titled compound (564 mg as a pale brown oil).
MS (ESI pos.) m/z : 288, 290 ([M+H]+).
°Reference Example P-A46: Synthesis of {2-fluoro[2-(morpholin
yl)ethyl]phenyl}boronic acid
-88—
[Chem. 86]
HO‘B N/fi\o
HO/ \~_/
Starting from the compound (785mg) obtained in Reference Example P-A45, the
same procedure as in Reference Example P-A43 was applied to give the titled compound
(493 mg as a yellow solid).
MS (ESI pos.) m/z : 254 +).
' Reference Example P—A47: Synthesis of 8-[2—(4-bromo—3-fluorophenyl)ethyl]—3~oxa
azabicyclo[3.2.1]octane
[Chem 87]
Br 12”
Starting from the compound (543 mg) obtained in Reference e P-A44 and 3—
oxa—8-azabicyclo[3.2.1]octane (421 mg), the same procedure as in Reference Example P-A42
was applied to give the titled compound (207 mg as a pale yellow solid).
MS (ESI pos.) m/z : 314, 316 +).
- Reference Example P—A48: Synthesis of romo-2—fluoropheny1)ethanol
[Chem 88]
Br OH
Starting from 4—bromofluorophenylacetic acid (2.46 g), the same procedure as in
Reference Example P-A44 was applied to give the titled compound (1.93 g as a colorless oil).
MS (ESI pos.) m/z : 218, 220 (M+).
-Reference Example P-A49: Synthesis of 4-[2-(4-bromofluorophenyl)ethyl]morpholine
—89-
[Chem 89]
BrQflCo
Starting from the compound (500 mg) obtained in Reference Example P-A48 and
morpholine (0.20 mL), the same procedure as in Reference Example P-A42 was applied to
give the titled compound (315 mg as a pale brown oil).
MS (ESI pos.) m/z : 288, 290 ([M+H]+).
' Reference Example P-ASO: Synthesis of 4-bromo-2—fluorophenyl)ethyl]oxa-8—
azabicyclo[3.2.1]octane
[Chem 90]
3.. pie/‘0r
ng from the compound (500 mg) obtained in nce e P-A48 and 3—
oxaazabicyclo[3.2.l]octane (194 mg), the same procedure as in Reference Example P-A42
was applied to give the titled compound (330 mg as a colorless solid).
MS (ESI pos.) m/z : 314, 316 ([M+H]+).
' Reference Example P—ASl: Synthesis of 2—(4-bromo—3-methoxyphenyl)ethanol
[Chem 91]
Starting from 4-bromo-3—methoxyphenylacetic acid (1.20 g), the same procedure as
in nce Example P-A44 was applied to give the titled compound (941 mg as a yellow
oil).
MS (ESI pos.) m/z : 227, 229 ([M-H]').
'Reference Example P-A52: Synthesis of 8-[2-(4—bromo-3—methoxyphenyl)ethyl]~3—oxa
azabicyclo[3 .2. l]octane
[Chem 92]
Br 1%
Starting from the compound (308 mg) obtained in Reference Example P—A51 and 3—
oxa—8-azabicyclo[3.2.1]octane (226 mg), the same procedure as in Reference Example P-A42
was applied to give the titled compound (401 mg as a pale yellow oil).
MS (ESI pos.) m/z : 326, 328 ([M+H]+).
- nce Example P-A53: Synthesis of 2-(4~bromomethoxyphenyl)ethanol
[Chem 93]
Starting from 2—(4-bromomethoxypheny1)acetic acid (1.02 g), the same procedure
as in Reference e P-A44 was applied to give the titled compound (828 mg as a yellow
oil).
MS (ESI pos.) m/z : 231 ([M+H]+).
' Reference Example P—A54: Synthesis of 4—[2—(4—bromo-2—methoxyphenyl)ethyl]morpholine
[Chem 94]
ergfo
Starting from the nd (500 mg) obtained in Reference Example P-A53 and
morpholine (0.6 mL), the same procedure as in Reference Example P-A42 was applied to
give the titled compound (586 mg as a pale yellow oil).
MS (ESI pos.) m/z : 300, 302 ([M+H]+).
ence Example P-ASS: Synthesis of 8-[2-(4—bromomethoxyphenyl)ethyl]oxa—8—
azabicyclo[3.2. 1]octane
_ 9] _
[Chem 95]
Br “1%
Starting from the compound (100 mg) obtained in nce Example P-A53 and 3-
oxa~8—azabicyclo[3.2.l]octane (146 mg), the same procedure as in Reference e P—A42
was applied to give the titled compound (147 mg as a pale brown oil).
MS (ESI pos.) m/z : 326, 328 +).
° Reference Example P-A56: Synthesis of 4-[2—(6—chloropyridin-3~yl)ethyl]morpholine
[Chem 96]
N...__ /“'\
\ / ”V0
Starting from 2—(6—chloropyridin—3-yl)ethanol (900 mg) and morpholine (0.32 mL),
the same procedure as in Reference Example P-A42 was applied to give the titled compound
(518 mg as a dark orange—colored amorphous product).
MS (ESI pos.) rn/z : 227 ([M+H]+).
'Reference Example P—A57: Synthesis of 8-[2-(6-chloropyridinyl)ethyl]—3-oxa-8—
azabicyclo[3 .2. l]octane
[Chem 97]
W{N...
Starting from hloropyridin—3-yl)ethanol (400 mg) and 3-oxa-8~
azabicyclo[3.2. l]octane (310 mg), the same procedure as in Reference Example P-A42 was
applied to give the titled nd (280 mg as a pale brown solid).
MS (ESI pos.) m/z : 253 ([M+H]+).
-Reference Example P—A58: Synthesis of 2—(6-bromopyridin—3-y1)ethanol
[Chem. 98]
Br~&>_§/~N.“ OH
To a suspension of (Inethoxymethyl)triphenylphosphonium chloride (6.63 g) in THF
(25 mL), 2.66 M nBuLi/n—Hexane (7.28 mL) was added dropwise under cooling with ice and
the mixture was stirred for an hour. To the stirred mixture, a suspension of 6—
bromonicotinaldehyde (3.00 g) in THF (10 mL) was added and the mixture was stirred for an
hour. To the reaction mixture, water was added for extraction with EtOAc and thereafter the
organic layer was washed with Brine. After drying the organic layer over MgSO4, the
desiccant was filtered off and the solvent was distilled off under reduced pressure. The
resulting residue was purified by silica gel (OH form) column chromatography (mobile
phase: n-Hexane/EtOAc = 90/ 10 ~ 70/30; v/v) to give a purified product (1.98 g as a pale
yellow oil).
To 4 M HCl/1,4-dioxane, a solution of the resulting purified product (2.28 g) in
MeCN-HZO (10: 1) was added dropwise and the e was stirred at room temperature for 2
hours. After being concentrated, the reaction mixture was diluted with CHC13 and washed
with water. After drying the organic layer over MgSO4, the desiccant was filtered off and the
t was distilled off under reduced re.
After adding MeOH (35 mL) to the resulting residue, NaBH4 (636 mg) was added
under cooling with ice and the mixture was stirred for an hour. After being concentrated, the
reaction mixture was d with CHC13 and washed with water. After drying the c
layer over MgSO4, the desiccant was filtered off and the solvent was distilled off under
reduced pressure. The resulting residue was purified by silica gel (OH form) column
chromatography e phase: CHClg/MeOH = 97/3 — 93/7; V/v) to give the titled compound
(1.25 g as a pale yellow solid).
MS (1381 pos.) m/z : 202 +).
-Reference Example P-A59: sis of 4—[2-(6-bromopyridin—3—yl)ethyl]morpholine
'[0343]
[Chem. 99]
Starting from the compound (1.00 g) ed in Reference Example P—A58 and
morpholine (0.25 mL), the same procedure as in nce Example P-A42 was applied to
give the titled compound (537 mg as a pale yellow solid).
MS (ESI pos.) m/z : 271, 273 ([M+H]+).
'Reference Example P-A60: Synthesis of 4- {2-[6-(tributylstannyl)pyridin
yl]ethyl}morpholine
[Chem 100]
N...
N m
s WNLJOn
To a THF (12 mL) solution of the compound (600 mg) obtained in Reference
Example P-A58, 2.6 M n-BuLi/n—Hexane (1.05 mL) was added se at -78°C and the
mixture was immediately stirred for an hour. To the d mixture, tributyltin chloride
(0.74 mL) was added dropwise and the mixture was stirred as its temperature was raised to
room temperature. Water was added for extraction with EtOAc. After washing the organic
layer with Brine and drying the same over Na2804, the desiccant was filtered off and the
solvent was distilled off under reduced pressure to give the titled compound (766 mg as a
pale orange-colored amorphous product).
MS (ESI pos.) In/z : 481 ([M+H]+).
‘Reference Example P-A6l: sis of 8-[2-(6—bromopyridin—3-yl)ethyl]oxa
azabicyclo[3 .2. l]octane
[Chem 101]
Br \N‘} I‘d/$0
Starting from the nd (1.00 g) obtained in Reference Example P-A58 and 3-
oxa-8—azabicyclo[3.2.1]octane (490 mg), the same procedure as in Reference Example P—A42
was applied to give the titled compound (838 mg as a pale yellow solid).
MS (ESI pos.) m/z : 297, 299 ([M+H]+).
'Reference Example P—A62: Synthesis of 8— {2-[6-(tributylstannyl)pyridiny1]ethyl}-3—oxa—
8—azabicyclo[3.2.1]octane
[Chem 102]
Starting from the compound (200 mg) obtained in Reference Example P—A61 , the
same procedure as in Reference Example P-A60 was applied to give the titled compound
(245 mg as a pale brown oil).
MS (ESI pos.) m/z : 509 +).
- nce Example P—A63: Synthesis of 8-[l-(4-bromophenyl)propan—2-yl]0xa-8—
azabicyclo[3.2.1]octane
[Chem 103]
.2 v”
A solution of 4—bromophenyl acetone (1.00 g) and 3—oxaazabicyclo[3.2.1]octane
(560 mg) in MeOH/ACOH (10:1, 15 mL) was stirred at room temperature for 30 minutes and,
thereafter, line borane complex (1 .00 g) was added and the mixture was stirred at an
external temperature of 60°C for 8 hours. After leaving the reaction mixture to cool, it was
added to a saturated aqueous NaHCO3 solution for neutralization under cooling with ice and
tion with CHC13 was conducted. The organic layer was d with Phase Separator
and the solvent was distilled off under reduced pressure. The resulting e was purified
by silica gel column chromatography (SNAP Cartridge HP-Sil 25 g; mobile phase:
CHCl3/MeOH = 99/1 - 90/10; v/v) to give the titled nd (418 mg as a pale yellow oil).
MS (ESI pos.) m/z : 310, 312 +).
' Reference Example P-A64: Synthesis of 4—[1-(4—bromophenyl)propanyl]morpholine
[Chem 104]
Br NLJO
Starting from 4-bromophenyl acetone (2.00 g) and morpholine (1.64 mL), the same
procedure as in Reference Example P-A63 was applied to give the titled compound (755 mg
as a ess oil).
MS (ESI posr) m/z : 284, 286 ([M+H]+).
- Reference Example P-A65: Synthesis of {4-[2-(morpholine—4-yl)propyl]phenyl}boronic
acid
[Chem 105]
Starting from the compound (1.61 g) obtainedin Reference Example P-A64, the
same procedure as in Reference e P-A43 was applied to give the titled compound
(1.09 g as a colorless solid).
MS (ESI pos.) m/z : 250 ([M+H]+).
' Reference Example P—A66: Synthesis of 8-[1-(6—chloropyridin-3—yl)propan—2-yl]—3-oxa
azabicyclo[3.2.1]octane
[Chem 106]
N...»
\/ “ifO
Starting from (6-chloropyridiny1)propan—2-0ne (235 mg) and 3-oxa
azabicyclo[3.2.1]octane (165 mg), the same procedure as in
Reference Example P-A63 was applied to give the titled compound (166 mg as a pale yellow
()il).
—96-
MS (ESI pos.) m/z : 267 ([M+H]+).
'Reference Example P-A67: Synthesis of 4-[1-(6-chloropyridiny1)propanyl]morpholine
[Chem 107]
N... NH
\ / U0
Starting from (6—chloro—pyridiny1)propan-2—one (200 mg) and morpholine
(0.21 mL), the same procedure as in Reference Example P-A63 was applied to give the titled
nd (216 mg as a pale yellow oil).
MS (ESI pos.) m/z ; 241 ([M+H]+).
- Reference Example P—A68: Synthesis of 4-[2-(2-methoxypyridiny1)ethyl]morpholine
[Chem 108]
N I‘*/~\o
\ / \4
ng from 2-(2-methoxypyridinyl)ethanol (1.30 g) and morpholine (1.3 mL),
the same procedure as in Reference Example P—A42 was d to give the titled compound
(1.39 g as a colorless solid).
1H—NMR (600 MHz, CDC13) 5 (ppm) ; 2.47 — 2.54 (4 H, In), 2.58 — 2.63 (2 H, m), 2.73 - 2.77
(2 H, m), 3.71 ~ 3.75 (4 H, m), 3.93 (3 H, s), 6.60 (1 H, s), 6.72 -6.76 (1 H, m), 8.06 (1 H, d,
J=5.4 Hz).
'Reference Example P-A69: Synthesis of 4-[2—(morpholin-4—y1)ethy1]pyridin-2(1H)—one
[Chem 109]
HM \ ”we
To a THF (2.8 mL) of the nd (300 mg) obtained in Reference Example P-
A68, a 6 M HCl aqueous solution (5.6 mL) was added dropwise. The mixture was stirred at
60°C for 6 hours. After distilling off the solvent under reduced pressure, azeotropic
distillation with e was conducted twice. The resulting residue was washed with EtOAc
and the solids were recovered by filtration to give the titled compound (375 mg as a colorless
solid).
1H-NMR (600 MHz, DMSO-d6) 5 (ppm) ; 3.00 - 3.14 (4 H, m), 3.30 - 3.39 (2 H, m), 3.45
(2 H, d, J=12.4 Hz), 3.76 — 3.83 (2 H, m), 3.97 (2 H, d, J=12.4 Hz),6.77 (1 H, s), 6.89 - 6.96
(1 H, m), 8.13 (1 H, d, J=5.4 Hz), 11.24 - 11.37 (1 H, m).
'Reference Example P-B01: Synthesis of 2—(3,5-dibromo-lH-l,2,4-triazolyl)-N~(propan-
2—yl)acetamide
[0365H [Chem 110]
N..N
BrANyBr
[03 66] Starting from 3,5-dibromo-1H-1,2,4—triazole (1.00 g), the same procedure as in
Reference Example P-A02 was applied to give the titled compound (1.06 g as a pale yellow
solid).
MS (ESI pos.) rn/z : 325, 327([M+H]+).
Starting from the compound obtained in nce Example P-BOl , the same
procedure as in Reference Example P—A29 was applied to synthesize the following
compounds.
' nce Example P-B02: romo—5—(3—chlorophenyl)—1H-1,2,4-triazolyl]-N—
(propan—2—yl)acetamide
[Chem 111]
CI my”
.98_
MS (ESI pos.) m/z : 357, 359([M+H]+).
' Reference Example P—BO3: 2-[3-bromo(4-fluoromethoxyphenyl)- l H- 1 ,2,4-triazol
yl]—N-(propan—2-yl)acetamide
[Chem 112]
N-vN
/O r
MS (ESI pos.) m/z : 371([M+H]+).
' Reference Example P—B04: 2-[3-bromo~5—(3-meth0xyphenyl)-1H—1,2,4-triazol—l-yl]—N-
(propan—Z-yl)acetamide
[Chem 113]
11::
/O \:\>‘Br
MS (ESI pos.) m/z : 353, 355([M+H]+).
' Reference Example P—BOS: 2-[3-bromo-5—(3—chlor0fluorophenyl)-1H—l,2,4—triazol~1—yl]-
N-(propan—Z-yl)acetamide
[Chem 114]
\>‘Br
CI: :NAN
1H-NMR (600 MHz, CDC13)5 (ppm) ; 1.18 - 1.23 (6 H, m), 4.10 - 4.17 (1 H, m),
4.76 (2 H, s), 5.86 — 5.93 (l H, m), 7.31 (l H, t, J=8.7 Hz), 7.63 - 7.67 (l H,m), 7.90 (1 H, dd,
J=6.6, 2.1 Hz).
' Reference Example P-B06: Synthesis of N—tert—butyl-Z-(3,5-dibromo-1H-1,2,4-triazol
yl)acetamide
H [Chem 115]
ANyBr
Starting from 3,5—dihromo-1H-1,2,4—triazole (5.0 g) and 2~bromo—N-tert-
butylacetamide (5.14 g), the same procedure as in Reference e P—A02 was applied to
give the titled compound (5.4 g as a colorless solid).
1H-NMR (600 MHz, DMSO-d6) 5 (ppm) ; 1.27 (9 H, s), 4.81 (2 H, s), 8.03 (1 H, s).
Starting from the nd obtained in Reference Example P-B06, the same procedure as in
Reference Example P-A29 was applied to synthesize the following compounds.
- Reference e P—B07: 2-[3-bromo(3-chlorophenyl)-1H-1,2,4-triazolyl]-N-tert-
butylacetamide
[Chem 116]
1H-NMR (600 MHZ, CDCl3) 5 (ppm) ; 1.36 — 1.39 (9 H, m), 4.73 (2 H, s), 5.88 —
.95 (1 H, m), 7.45 - 7.49 (l H, m), 7.51 — 7.55 (1 H, m), 7.58 — 7.62 (1 H, m),7.74 — 7.77
(1 H, m).
'Reference Example P—B08: 2-[3—bromo-5—(3—methoxyphenyl)-1H-1,2,4-triazolyl]-N-tert—
butylacetamide
[Chem 1 17]
1NWBr
1H-NMR (600 MHz, CDCl3) 5 (ppm) ; 1.32 - 1.40 (9 H, m), 3.86 (3 H, s), 4.74 (2 H,
s), 5.97 — 6.06 (1 H, m), 7.06 - 7.11 (1 H, m), 7.22 —
— 7.25 (1 H, m), 7.39 -7.44 (1 H, m), 7.52
7.58 (1 H, m).
Staiting from the compound obtained in Reference Example P-B04, the same procedure as in
Reference e P~A29 was applied to synthesize the following nd.
'Reference Example P—B09: 2—{3~[4-(2-hydroxyethyl)phenyl](3-methoxyphenyl)-1H—
1,2,4—triazolyl}-N—(propan-2—y1)acetamide
[Chem 118]
MS (ESI pos.) m/z: 395 ([M—tH]+).
- Reference Example P—C01: Synthesis of 4—(3-methyl-1H—pyrazol-l—y1)phenol
[Chem 119]
A suspension of 3—methylpyrazole (30 g), 4-iodophenol (6. 3 g), copper iodide
(350 mg), potassium carbonate (2.1 g) and trans—N,N’-bismethyl-1,2-cyclohexanediamine
(1.0 g) in e (18 mL) was stirred at an external temperature of 100°C for 60 hours under
a nitrogen stream. After leaving the reaction mixture to cool, EtOAc was added and after
filtering off the insoluble matter, the organic layer was washed with water and Brine. After
drying the organic layer over MgSO4, the desiccant was filtered off and the filtrate was
-lOl—
concentrated under reduced pressure. The resulting residue was purified by silica gel column
chromatography (SNAP Cartridge KP—Sil; mobile phase: ne/EtOAc = 80/20 - 40/60;
v/v); after washing the resulting compound with IPE, the solids were recovered by filtration
to give the titled compound (2.7 g as a pale red solid).
MS (ESI pos.) m/z : 175 ([M+H]+).
'Reference Example P-C02: Synthesis of 4-(4-iodomethyl—1H-pyrazol—1—y1)phenol
[Chem 120]
* wow
To a DMF solution of the compound (2.7 g) obtained in Reference Example P-COl,
NIS (5.9 g) was added and the mixture was stirred at room temperature for 4 hours. To the
reaction mixture, EtOAc was added and after washing with a Na2803 s solution,
water, and Brine, the organic layer was dried over MgSO4; subsequently, the desiccant was
filtered off and the e was concentrated under d pressure. The resulting residue
was purified by silica gel column chromatography (SNAP Cartridge KP—Sil; mobile phase: n-
Hexane/EtOAc = 90/10 - 60/40; v/v) to give the titled compound (2.1 g as a pale yellow
solid).
MS (ESI pos.) m/z : 301 ([M+H]+).
° Reference Example P—C03: sis of 4—[4—(3-chloropheny1)~3~methyl-lH-pyrazol-l—
yl]phenol
[Chem 121]
I’Nc
A mixture of the compound (2.1 g) obtained in Reference Example P-C02, (3—
chlorophenyl)boronic acid (l .6 g), Pd(PPh3)4 (800 mg), NaHCO3 aqueous solution (2 M,
34 mL) and EtOH (70 mL) was heated under reflux for 2 hours under a nitrogen atmosphere.
After g the mixture to cool, EtOH was distilled off under d pressure and the
—102—
resulting residue was subjected to extraction with CHC13. The organic layer was washed
with water and Brine and dried over MgSO4; subsequently, the desiccant was filtered off and
the filtrate was trated under d pressure. The resulting residue was purified by
column chromatography (SNAP Cartridge KP—NH; mobile phase: CHCl3/MeOH = 98/2 —
90/ 10; V/V) to give the titled compound (2.0 g as a pale brown solid).
MS (ESI pos.) m/z : 285 ([M+H]+).
° Reference Example P-C04: Synthesis of 4—[4—(3-chlorophenyl)~3-methyl~lH—pyrazol—l—
yl]phenyl trifluoromethanesulfonate
[Chem 122]
N 0
j; —g-CFg
c: 3
To a CHC13 solution (16 mL) of the compound (900 mg) obtained in Reference
Example P-C03, Et3N (0.80 mL) and szO (0.67 mL) were added under an ice bath and the
mixture was stirred at room temperature for 17 hours. The reaction mixture was washed with
hydrochloric acid (1 M), a NaHC03 aqueous solution (1 M) and Brine; after drying over
MgSO4, the desiccant was filtered off and the filtrate was concentrated under reduced
pressure. The organic layer was filtered with Phase tor and the solvent was
subsequently distilled off under reduced re. The resulting residue was purified by
column chromatography (SNAP Cartridge HP-Sil; mobile phase: n-Hexane/EtOAc = 90/10 -
70/30; V/V) to give the titled nd (1.1 g as a pale yellow oil).
MS (ESI pos.) m/z : 417 ([M+H]+).
'Reference Example P-C05: Synthesis of 4-[3—(bromomethyl)(3-chlorophenyl)-1H-
pyrazol— 1 —y1]phenyl trifluoromethanesulfonate
—103—
[Chem 123]
N O
: ‘NQ—o-g—CF3
c: 3
To a CHC13 on of the compound (1.1 g) ed in Reference Example P—
C04, NBS (530 mg) and benzoyl peroxide (87 mg) were added and the mixture was heated
under reflux for 60 hours. The reaction mixture was washed with water and Brine and dried
over MgSO4; thereafter, the desiccant was filtered off and the filtrate was concentrated under
d pressure to give the titled compound (1.3 g as a pale yellow oil).
MS (ESI pos.) m/z : 495 ([M+H]+).
'Reference Example P—C06: Synthesis of 4-[4—(3—chlorophenyl)(cyanomethyl)-1H—
l— 1 enyl tfifluoromethanesulfonate
[Chem 124]
a”:0»
To a DMSO solution (13 mL) of the compound (1.3 g) obtained1n Reference
Example P-COS, sodium cyanide (200 mg) was added and the mixture was stirred at room
temperature for 3 hours. After adding EtOAc to the reaction mixture, it was washed with
water and Brine and dried over MgSO4; subsequently, the desiccant was filtered off and the
filtrate was concentrated under reduced pressure. The resulting residue was purified by
column chromatography (SNAP Cartridge HP-Sil; mobile phase: n-Hexane/EtOAc = 90/10 —
60/40; V/V) to give the titled compound (460 mg as a pale yellow oil).
MS (ESI pos.) m/z : 442 ([M+H]+).
'Reference Example P-C07: Synthesis of [4-(3~chlorophenyl)-l-(4-ethenylphenyl)-1H—
pyrazol—3—yl]acetonitrile
-104—
[Chem 125]
83434
Starting from nce Example PC06 (460 mg), the same procedure as in
Reference Example P-A03 was applied to give the titled compound (140 mg as a pale yellow
solid).
MS (ESI pos.) m/z : 320([M+H]+).
-Reference Example P—C08: Synthesis of [4—(3-chloropheny1)—1-(4—etheny1phenyl)-1H—
pyrazol—3-yl]acetic acid
0[Cheom. 126]
036/
To an EtOH solution (4 mL) of the compound (140 mg) obtainedin Reference
Example P—C07, a NaOH aqueous solution (2.5 M, 4 mL) was added and the e was
heated under reflux for 3 hours. After leaving the reaction mixture to cool, hydrochloric acid
(1 M) was added and following an adjustment to pH 4, EtOAc was added to separate the
organic layer. The resulting c layer was washed with Brine and dried over MgSO4;
subsequently, the desiccant was d off and the filtrate was concentrated under reduced
pressure to give the titled compound (148 mg as a pale yellow solid).
MS (ESI pos.) m/z : 339 ([M+H]+).
'Reference Example P—C09: Synthesis of 2-[4-(3-chloropheny1)-l-(4-etheny1phenyl)—1H—
pyrazolyl]-N-(propanyl)acetamide
[O3 99]
—105—
[Chem. 127]
c. 41%?”
To a THF (4 mL) solution of the compound (148 mg) obtained in Reference
Example P-C08, HOBt'HzO (100 mg) and isopropylamine (0.06 mL), EDC - HCl (130 mg)
was added under a nitrogen stream and the mixture was stirred at room temperature for 17
hours. After adding CHCl3 to the reaction mixture, it was washed with a saturated aqueous
NH4Cl on, water and Brine and dried over MgSO4; subsequently, the desiccant was
filtered off and the filtrate was concentrated under reduced pressure. The ing residue
was d by silica gel column tography (SNAP Cartridge HP—Sil 50g; mobile
phase: n—Hexane/EtOAc = 50/50 - 20/80; v/V) to give the titled compound (130 mg as a
colorless solid).
MS (ESI pos.) m/z : 380 ([M+H]+).
- Reference Example P—ClO: Synthesis of 2-{4-(3-chlorophenyl)—1—[4-(2—
hydroxyethyl)phenyl] — 1H-pyrazol-3 -yl } opan—2~yl)acetamide
[Chem 128]
IN ,v—OH
Cl :
Starting from Reference Example P-CO9 (130 mg), the same procedure as in
Reference Example P-A04 was applied to give the titled compound (120 mg as a pale yellow
solid).
MS (ESI pos.) m/z : 398 ([M+H]+).
' Reference Example P—Cl 1: Synthesis of (2E)(4-bromophenyl)[l—(3-
chlorophenyl)ethy1idene]hydrazine
~106-
[Chem 129]
CI \N,NO
To an EtOH suspension (18 mL) of 1-(3-chlorophenyl)ethanone (1.0 g) and (4-
bromophenyl)hydrazine hydrochloride (1.6 g), acetic acid (0.36 mL) was added and the
mixture was stirred at an external temperature of 100°C for 3 hours. After adding EtOAc to
the reaction mixture, it was neutralizedrwith a NaHC03 aqueous solution and the organic
layer was subsequently separated. The resulting organic layer was neutralized with a
ted aqueous NaHC03 on and the organic layer was separated. After drying the
resulting organic layer over MgSO4, the desiccant was filtered off and the filtrate was
trated under reduced pressure to give the titled compound (3.0 g as a pale brown oil).
MS (ESI neg.) m/z : 323 ([M]+).
ence Example P—C12: Synthesis of 1-(4-bromophenyl)-3—(3 -chloropheny1)-1H-
pyrazolecarbaldehyde
[Chem 130]
f. Gar
c: N
To a DMF (3 mL) solution of phosphorus oxychloride (l .8 mL), a DMF solution
(6 mL) of the compound (2.1 g) ed in nce Example P-Cll was added under
cooling with ice and the mixture was stirred at an external temperature of 80°C for 3 hours.
After cooling with ice, the reaction mixture was added dropwise to a saturated aqueous
NaHC03 solution and the precipitating solid was recovered by filtration and dried to give the
titled compound (2.3 g as a pale brown .
1H-NMR (600 MHz, CDC13) 8 (ppm) ; 7.42 - 7.48 (2 H, m), 7.63 - 7.67 (2 H, m), 7.67 - 7.71
(2 H, m), 7.72 — 7.77 (1 H, m), 7.85 — 7.89 (1 H, m), 8.52 (l H, 5), 10.05 (1 H, s).
' Reference Example P—C13: Synthesis of [l-(4-bromophenyl)-3 -(3 -chlorophenyl)-1H—
—lO7-
pyrazol—4—y1]methanol
[Chem 131]
:2 oar
Cl N
To a MeOH solution (32 mL) of the compound (2.3 g) obtained in Reference
Example P—C12, NaBH4 (540 mg) was added in small portions under cooling with ice and the
mixture was subsequently stirred at room temperature for an hour. After adding hloric
acid (2 M, 60 mL) to the reaction mixture, MeOH was distilled off under reduced pressure.
After extracting the aqueous layer with EtOAc, the resulting organic layer was washed with
Brine and dried over MgSO4; subsequently, the desiccant was d off and the filtrate was
concentrated under d pressure to give the titled compound (2.4 g as a brown
amorphous product).
MS (ESI pos.) m/z : 363 ([M+H]+).
'Reference Example P-C14: Synthesis of l-(4-bromophenyl)~4-(chlorornethy1)—3—(3—
phenyl)— l H—pyrazole
[Chem 132]
CI rye—er
_ N
To a CHC13 solution (32 mL) of the compound (2.4 g) obtained in Reference
Example P—C13, thionyl chloride (0.92 mL) was added and the mixture was heated under
reflux for 3 hours. The reaction mixture was concentrated under reduced pressure to give the
titled compound (2.5 g as a brown amorphous product).
MS (ESI pos.) m/z : 381 +).
'Reference e P—C15: Synthesis of [1~(4—bromophenyl)(3-chlorophenyl)—1H-
-108—
pyrazolyl]acetonitrile
[Chem 133]
CI momN
Starting from the compound (2.5 g) obtained in nce Example P—C14, the same
procedure as in Reference Example P-C06 was applied to give the titled compound (15 g as
a pale yellow solid).
MS (ESI pos.) m/z : 372 ([M+H]+).
' nce Example P-C16: Synthesis of bromophenyl)-3—(3—chlorophenyl)- 1 H—
pyrazolyl]acetic acid
[Chem 134]
Ho 0
:2 oar
CI N
To a e solution (16 mL) of the compound (1.5 g) obtained in Reference
Example P—C15, hydrochloric acid (6 M, 8 mL) was added and the mixture was heated under
reflux for 48 hours. After additional supply of a HCl-dioxane solution (4 M, 8 mL), the
mixture was heated under reflulx for 72 hours. To the reaction mixture, EtOAc was added
and the organic layer was ted; subsequently, the organic layer was washed with water
and Brine and dried over MgSO4; thereafter, the desiccant was filtered off and the filtrate was
concentrated under reduced pressure to give the titled compound (1.6 g as a pale brown
solid).
MS (ESI neg.) m/z : 389 ([M-HD.
~Reference Example P-C17: Synthesis of 2-[1-(4-bromophenyl)(3—chloropheny1)—1H-
pyrazol—4-yl]-N-(propan—2-yl)acetamide
-109—
[Chem 135]
\l," 0
17 Q”
Cl N
ng from the compound (1.4 g) obtained in Reference e P—C16, the same
procedure as in Reference Example P-C09 was applied to give the titled compound (1.1 g as
a pale brown solid).
MS (ESI pos.) m/z : 432 ([M+H]+).
'Reference Example P—C18: Synthesis of 2—[3-(3—chlorophenyl)(4-ethenylphenyl)—1H-
pyrazolyl]-N-(propan—2-y1)acetamide
[Chem 136]
1"”W
Cl N
Starting from the nd (1.6 g) obtained in Reference Example P-C17, the same
procedure as in Reference Example P—A03 was applied to give the titled compound (1.4 g as
a pale yellow solid).
MS (ESI pos.) m/z : 380 ([M+H]+).
- Reference Example PC 1 9: Synthesis of 2-{3-(3-chlorophenyl)[4-(2-
hydroxyethyl)phenyl] - 1H-pyrazolyl} -N-(propanyl)acetamide
[Chem 137]
\rN O
on ‘N,N_©_F°
ng from the compound (1.1 g) obtained in Reference Example P-Cl 8, the same
procedure as in Reference Example P-A04 was applied to give the titled compound (1.1 g as
a pale brown amorphous product).
MS (ESI pos.) m/z : 420 ]+).
ence Example P-C20: Synthesis of l—(4—methoxyphenyl)propyn—l—one
[Chem 138]
o f
To a CHCl3 solution (160 m L) of 1—(4-methoxyphenyl)prop—2-ynol (12 g),
manganese e (85 g) was added and the mixture was stirred at room temperature for 2
hours. The insoluble matter was removed by filtration through Celite (registered trademark)
and the filtrate was concentrated under reduced pressure; thereafter, the resulting residue was
washed with n-Hexane under stirring to give the titled compound (7.8 g as a yellow solid).
MS (ESI pos.) m/z : 161 ([M+H]+).
' Reference Example P—C21: Synthesis of 1-(3-chlorophenyl)—3-(4-methoxyphenyl)-1H—
pyrazole
[Chem 139]
av" /
CI ”"
To a MeOH suspension (120 mL) of the nd (3.0 g) obtained in Reference
Example P~C19 and orophenyl)hydrazine hydrochloride (3.4 g), conc. hydrochloric
acid (1.8 mL) was added and the mixture was stirred at room temperature for 26 hours, then
stirred at an external temperature of 60°C for 2 hours. After concentrating the reaction
mixture under reduced pressure, EtOAc was added to the ing residue and the mixture
was washed with weater and Brine. After drying the organic layer over MgSO4, the
desiccant was filtered off and the filtrate was concentrated under reduced pressure; thereafter,
-lll—
the resulting residue was purified by silica gel column chromatography (SNAP Cartridge HP—
Sil 50g; mobile phase: n-Hexane/EtOAc = 100/0 - 85/15; v/v) to give the titled compound
(28 g as a pale yellow solid).
Ms (ESI pos.) m/z : 285 ([M+H]+).
'Reference Example P-C22: Synthesis of 1-(3—chlorophenyl)-3~(4-methoxyphenyl)—1H-
pyrazole—S-carboxylic acid
[Chem 140]
.--' f
To a THF solution (40 mL) of diisopropylamine (870 mg), 2.6 M n-BuLi (3.3 mL)
in hexane was added dropwise under cooling with ice and the mixture was stirred for 10
minutes. After cooling the reaction mixture to -60°C, a THF solution (10 mL) of the
nd (2.2 g) obtained in nce Example P-C21 was added and the mixture was
stirred for 30 minutes. To a mixture of Dry Ice with EtZO, the reaction mixture was added
dropwise through a cannula and the mixture was stirred overnight. After adding water and
EtOAc to the reaction mixture, it was subjected to extradition with a 1 M NaOH aqueous
solution. The resulting aqueous layer was ed to pH = 4 with 1 M hydrochloric acid and
subjected to extraction with EtOAc. After drying the organic layer over MgSO4, the
desiccant was filtered off and the filtrate was trated under d pressure to give the
titled compound (1.2 g as a pale yellow solid).
MS (ESI pos.) m/z : 329 ([M+H]+).
-Reference Example P-C23: sis of [l-(3—chlorophenyl)(4-methoxyphenyl)—1H-
pyrazol-S-yl]acetic acid
[Chem. 141]
HO 0
CI "'
To a CHCl3 (45 mL) suspension of the compound (1.5 g) obtained in nce
Example P—C22, oxalyl chloride (0.78 mL) and DMF (one drop) were added in an ice bath
and the mixture was stirred for an hour. After trating the reaction mixture, a
THF/MeCN liquid mixture (l/l; WV, 45 mL) was added to the resulting residue and at 0°C,
TMSCH2N2 (2 mol/L EtzO solution, 4.5 mL) was also added and the mixture was stirred for
an hour. After concentrating the stirred mixture, a 1,4-dioxane/water liquid mixture (1/ l; V/V,
45 mL) was added and following the addition of silver acetate (230 mg), the mixture was
stirred at 60°C for an hour. After concentrating the stirred mixture, a saturated NaHC03
s solution was added and the mixture was stirred at room temperature for an hour.
After filtering the reaction mixture through Celite (registered trademark), the filtrate was
diluted with added EtOAc; thereafter, the organic layer was washed with water and Brine and
dried over MgSO4; subsequently, the desiccant was filtered off and the filtrate was
trated under reduced pressure to give the titled compound (1.6 g as a pale brown
MS (ESI pos.) m/z : 343 ([M+H]+).
'Reference Example P—C24: Synthesis of 2—[l—(3-chlorophenyl)-3—(4-methoxyphenyl)-1H—
pyrazol—S-yl]—N-(propanyl)acetamide
[Chem 142]
\[fi 0
.3 0/
00“‘N
—ll3-
Starting from the compound (1.6 g) obtained in Reference Example P-C23, the same
procedure as in Reference Example P-CO9 was d to give the titled nd (780 mg
as a pale yellow solid).
MS (ESI pos.) m/z : 384([M+H]+).
- Reference Example P—C25: Synthesis of 2—[l-(3—chlorophenyl)(4-hydroxyphenyl)—1H-
pyrazol-S-yl]-N-(propan~2~yl)acetamide
[Chem 143]
Y” ‘1
, H
Starting from the compound (780 mg) obtained in Reference Example P-C24, the
same procedure as in Reference Example P—A27 was applied to give the titled compound
(750 mg as a pale brown solid).
MS (ESI pos.) m/z : 370 ([M+H]+).
'Reference Example P-C26: Synthesis of 4-{1-(3~chlorophenyl)[2-oxo—2—(propan-2—
ylamino)ethyl] - l zol—3—yl l trifluoromethanesulfonate
[Chem 144]
w" °
“C -g-CF3
“0”“ 8
Starting from the compound (750 mg) obtained in Reference Example P-C25, the
same procedure as in Reference Example P-C04 was applied to give the titled compound
(270 mg as a pale yellow oil).
MS (1381 pos.) m/z : 502 ([M+H]+).
'Reference Example P-C27: Synthesis of 2-[1—(3-chlorophenyl)(4—ethenylphenyl)-lH-
pyrazol-S—yl]~N-(propan—2—yl)acetamide
~114—
[Chem 145]
Starting from the compound (270 mg) obtained in Reference Example P-C26, the
same procedure as in Reference Example P-A03 was d to give the titled compound
(75 mg as a pale yellow solid).
MS (ESI pos.) m/z : 380 ([M+H]+).
'Reference e P-C28: Synthesis of 2-{ l—(3-chlorophenyl)—3-[4-(2-
hydroxyethyl)phenyl] - lH—pyrazol—S -yl} -N—(propanc2-yl)acetamide
[Chem 146]
\r” °
Starting from the compound (75 mg) obtained in Reference Example P—C27, the
same procedure as in Reference Example P—A04 was applied to give the titled compound
(79 mg as a pale yellow solid).
MS (ESI pos.) m/z : 398 ([M+H]+).
'Reference Example P-C29: Synthesis of (2E)-l-(4—bromophenyl)—3—(3—chlorophenyl)prop-
2—en—1—one
[Chem 147]
C \ i Br
To a MeOH solution (125 mL) of 3-chlorobenzaldehyde (3.0 g) and 1—(4-
henyl)ethanone (4.5 g), sodium methoxide (1.2 g) was added and the mixture was
—115—
stirred at room temperature for 60 hours. To the reaction mixture, dilute hydrochloric acid
(0.5 M, 125 mL) was added and the precipitating solid was recovered by filtration and dried
to give the titled compound (6.8 g as a pale yellow solid).
MS (ESI pos.) m/z : 321([M+H]+).
- Reference Example P—C30: Synthesis of ethyl [3-(4—bromophenyl)-5—(3-chlorophenyl)~4,5~
dihydro— 1 zol- l —y1] acetate
[Chem 148]
\x" 0
An EtOI—I solution (70 mL) of the compound (4.4 g) obtained in Reference e
P-C29 and ethyl 2-hydraziny1 acetate hydrochloride (2.2 g) was heated under reflux for 4
hours. After concentrating the reaction mixture under d pressure, it was stirred at an
external temperature of 60°C for 2 hours. After concentrating the reaction mixture under
reduced pressure, EtOAc was added to the resulting residue and the mixture was washed with
water and Brine. After drying the organic layer over MgSO4, the ant was filtered off
and the filtrate was concentrated under reduced pressure to give the titled compound (5.7 g as
a pale yellow oil).
MS (ESIpos.) m/z : 421 ([M+H]+).
- Reference Example P-C3 1: Synthesis of ethyl [3~(4—bromophenyl)(3-chlorophenyl)-1H-
pyrazol— l etate
[Chem 149]
To a toluene solution (130 mL) of the compound (5.7 g) obtained in Reference
Example P-C30, 2,3-dichloro-5,6-dicyano-p-benzoquinone (5.2 g) was added and the mixture
—ll6—
was stirred at an external temperature of 100°C for an hour. After filtering the reaction
mixture, the filtrate was diluted with added EtOAc and washed with water and Brine. After
drying the organic layer over MgSO4, the desiccant was filtered off and the filtrate was
concentrated under reduced pressure; thereafter, the resulting residue was purified by silica
gel column chromatography in sequential stages (SNAP Cartridge KP-NH; mobile phase: n-
Hexane/EtOAc = 90/10 — 70/30; V/V, and SNAP Cartridge HP-Sil 50 g; mobile phase: n—
/EtOAc = 80/20 - 70/30; V/V) to give the titled compound (3.6 g as a pale yellow
solid).
MS (ESI pos.) m/z : 419 ([M+H]+).
' Reference Example P-C32: Synthesis of [3-(4—bromophenyl)(3 -chlorophenyl)-1H—
pyrazol-l -yl] acetic acid
[Chem 150]
Ho 0
To a THF solution (40 mL) of the compound (3.6 g) obtained in Reference e
P—C3 l, a NaOH aqueous solution (2.5 M, 8 mL) was added and the mixture was d at
room temperature for 2 hours. To the reaction mixture, hydrochloric acid (2.0 M) was added
for adjustment to pH 4 and extraction was conducted with EtOAc. After drying the organic
layer over MgSO4, the desiccant was filtered off and the e was concentrated under
reduced pressure to give the titled compound (3.3 g as a pale yellow solid).
MS (ESI pos.) m/z : 391 +).
ence Example P—C33: Synthesis of 2-[3-(4-bromophenyl)(3—chlorophenyl)-1H-
pyrazol-l—yl]—N—(propanyl)acetamide
-ll7-
[Chem. 151]
Starting from the compound (3.3 g) obtained in Reference Example P—C32, the same
procedure as in Reference Example P—C09 was applied to give the titled compound (3.1 g as
a colorless solid).
MS (ESI pos.) m/z : 432 ([M+H]+).
'Reference Example P-C34: Synthesis of 2—[5-(3-chlorophenyl)—3—(4—ethenylphenyl)—1H-
pyrazol- 1-yl]-N-(propanyl)acetamide
[Chem 152]
N O/
ng from the compound (3.1 g) obtained in Reference e P—C33, the same
procedure as in Reference Example P-A03 was applied to give the titled compound (1.3 g as
a pale brown solid).
MS (ESI pos.) m/z : 380 ([M+H]+).
ence Example P-C35: Synthesis of 2- {5-(3—chlorophenyl)-3—[4-(2-
hydroxyethyl)phenyl]— 1 H—pyrazolyl } -N-(propan-Z-yl)acetamide
H.[Chem 153]
—118~
Starting from the compound (1.3 g) obtained in Reference Example P-C34, the same
ure as in Reference Example P-A04 was d to give the titled compound (1.4 g as
a pale yellow solid).
MS (ESI pos.) m/z : 398 ([M+H]+).
- nce Example P-C36: Synthesis of 4-bromo—N—[2-(3-chlorophenyl)—2-
oxoethyl]benzamide
ooio[0453] [Chem 154]
To a CHCl3 solution (24 mL) of 2-amino1-(3-chlorophenyl)ethanone hydrochloride
(2.0 g), a saturated aqueous NaHC03 solution (48 mL) and 4-bromobenzoyl chloride (3.2 g)
were added under cooling with ice and the mixture was stirred for 2 hours. The organic layer
was separated and dried over MgSO4; uently, the desiccant was filtered off and the
filtrate was concentrated under reduced pressure to give the titled nd (3.2 g as a
colorless solid).
MS (ESI pos.) m/z : 352 ([M+H]+).
'Reference Example P-C37: sis of ethyl 3-[(4—bromobenzoyl)amino](3-
chlorophenyl)«4—oxobutanoate
[Chem. 155]
\VO 0
To a DMF solution (10 mL) of the compound (1.1 g) obtained in Reference
Example P—C36, sodium hydride (160 mg) was added at -50°C and the mixture was stirred
for 30 minutes; subsequently, 2-bromoacetic acid ethyl ester (0.39 mL) was added and the
mixture was stirred for 30 minutes under cooling with ice. After adding water to the reaction
mixture, it was diluted with added EtOAc. The organic layer was separated and subsequently
-ll9—
washed with Brine. After drying the organic layer over MgSO4, the desiccant was filtered off
and the filtrate was trated under reduced pressure; the resulting residue was purified
by silica gel column chromatography in sequential stages (SNAP Cartridge HP-Sil; mobile
phase: n-Hexane/EtOAc/CHC13 = 80/20/3 — 70/30/3; V/V/V) to give the titled compound
(460 mg as a pale yellow oil).
MS (ESI pos.) m/z : 438 ([M+H]+).
'Reference Example P-C38: Synthesis of ethyl [2-(4-bromophenyl)(3-chlorophenyl)~1,3-
oxazol—4-yl]acetate
[Chem 156]
V0 0
To a DMF solution (10 mL) of the compound (460 mg) obtained in Reference
Example P-C37, phosphorus oxychloride (0.39 mL) was added under g with ice and
the mixture was d for 4 hours. The reaction mixture was added to a mixture of EtOAc
and ice water. The organic layer was separated and uently washed with Brine. After
drying the organic layer over MgSO4, the desiccant was filtered off and the filtrate was
concentrated under reduced pressure to give the titled compound (441 mg as a pale yellow
solid).
MS (ESI pos.) m/z ; 420 ([M+H]+).
- Reference Example P-C39: Synthesis of [2-(4-bromophenyl)—5—(3—chlorophenyl)~l,3-
oxazolyl]acetic acid
[Chem 157]
HO 0
—120-
Starting from the compound (3.2 g) obtained in Reference Example P~C3 8, the same
procedure as in nce Example P—C32 was applied to give the titled compound (3.0 g as
a pale yellow solid).
MS (ESI pos.) m/z : 392 ([M+H]+).
- Reference Example P-C40: Synthesis of 2-[2-(4—bromophenyl)—5—(3—chlorophenyl)—1,3—
yl]—N~(propan—2—y1)acetamide
[Chem 158]
| ‘9—Q—Br
Starting from the compound (3.0 g) ed in Reference Example P-C39, the same
procedure as in Reference Example P-CO9 was applied to give the titled compound (2.3 g as
a colorless solid).
MS (ESI pos.) m/z : 433 ([M+H]+).
- nce Example P-C4l: Synthesis of 2—[5—(3-chlorophenyl)—2-(4—ethenylphenyl)—1,3—
oxazol—4-yl]—N-(propan—2-yl)acetamide
[Chem 159]
C. 'W
Starting from the compound (2.3 g) obtained in Reference Example P—C40, the same
procedure as in Reference Example P-A03 was applied to give the titled nd (1.3 g as
a pale brown solid).
MS (ESI pos.) m/z : 381 ([M+H]+).
' Reference Example P—C42: Synthesis of 2—{5—(3-chlorophenyl)—2—[4-(2-
hydroxyethyl)phenyl]-l ,3 -oxazol—4—yl} —N-(propan—2-yl)acetamide
—121—
[Chem 160]
Y“ o
c. 'EW"
Starting from the compound (1.3 g) obtained in Reference Example P-C41, the same
procedure as in Reference Example P—A04 was applied to give the titled compound (1.3 g as
a pale yellow solid).
MS (ESI pos.) m/z : 399 ([M+H]+).
'Reference Example P-C43: Synthesis of methyl hlorophenyl)—4—hydroxybutynoate
[Chem 161]
To a THF solution (100 mL) of methyl gylate (3.6 g),-n-BuLi (2.7 M, 16 mL)
was added at —78°C and after stirring the mixture for 30 minutes, a THF solution (20 mL) of
robenzaldehyde (4.0 g) was added dropwise. After 1-hour stirring, acetic acid (20 mL)
was added and the reaction mixture was subsequently washed with water. After extracting
the aqueous layer with EtOAc, the combined organic layer was washed with a saturated
s NaHCO3 solution and Brine. After drying the organic layer over MgSO4, the
desiccant was filtered off and the filtrate was concentrated under reduced pressure; the
resulting residue was purified by silica gel column chromatography (SNAP Cartridge HP-Sil;
mobile phase: n-Hexane/EtOAc = 90/10 - 70/30; V/V) to give the titled compound (4.6 g as a
pale red oil).
1H NMR (600 MHz, CHLOROFORM—d) 5 (ppm) ; 2.43 — 2.52 (1 H, m) 3.79 (3 H, s) 5.55
(1 H, d, J=6.4 Hz) 7.29 - 7.35 (2 H, m) 7.36 - 7.42 (1 H, m) 7.47 - 7.57 (1 H, m).
' Reference Example P-C44: Synthesis of methyl [4—(3—chloropheny1)—2-(4-iodophenyl)-1,3—
oxazol—S—yl]acetate
—122-
[Chem 162]
O O
c. 'H}
To a mixture of the compound (4.4 g) obtained in Reference Example P~C43 and 4-
iodobenzonitrile (4.5 g), conc. ic acid (2.1 mL) was added under cooling with ice and
the e was stirred at room ature for 3 hours. After adding CHC13 to the reaction
mixture, it was washed with water and Brine. After drying the organic layer over MgSO4,
the desiccant was filtered off and the filtrate was concentrated under reduced pressure; the
resulting e was purified by silica gel column chromatography (SNAP Cartridge HP-Sil;
mobile phase: n—Hexane/EtOAc = 95/5 - 80/20; V/V) to give the titled compound (2.3 g as a
pale red oil).
MS (E81 [308.) m/z : 454 ([M+H]+).
' Reference Example P-C45: Synthesis of [4-(3-chlorophenyl)(4-iodophenyl)-1,3-oxazol-
—yl] acetic acid
[Chem 163]
HO O
c. 'NIFQH
Starting from the compound (3.5 g) obtained in nce Example P-C44, the same
procedure as in Reference Example P-C32 was applied to give the titled compound (3.3 g as
a pale yellow solid).
MS (ESI pos.) m/z : 440 ([M+H]+).
'Reference Example P-C46: Synthesis of 3-chlorophenyl)(4-iodophenyl)-1,3-oxazol-5—
yl]-N-(propany1)acetamide
~123-
[Chem 164]
Y” O
c. 'W'
Starting from the compound (3.3 g) obtained in Reference Example P-C45, the same
procedure as in Reference Example P-C09 was applied to give the titled compound (3.1 g as
a colorless .
MS (ESI pos.) m/z : 481 ([M+H]+).
' Reference Example P-C47: Synthesis of 2-[4—(3~chlorophenyl)~2—(4-ethenylphenyl)-1,3—
oxazol-S-yl]-N-(propan—Z-yl)acetamide
[Chem 165]
c. 1W
Starting from the compound (3.1 g) obtained in Reference Example P—C46, the same
procedure as in nce Example P-A03 was applied to give the titled compound (1.6 g as
a pale brown solid).
MS (ESI pos.) m/z : 381 ([M+H]+).
- Reference Example P—C48: Synthesis of 2- {4-(3-chlorophenyl)[4-(2-
hydroxyethyl)phenyl] - 1 ,3 —oxazol—5-yl} -N—(propan-Z-yl)acetamide
[Chem 166]
Yrs: 0
. A?
Starting from the compound (1.6 g) obtained in Reference e P-C47, the same
ure as in Reference Example P-A04 was applied to give the titled compound (1 .7 g as
a pale yellow solid).
—124-
MS (ESI pos.) m/z : 399 ([M+H]+).
ence e P-C49: Synthesis of methyl 3-chloro3-(3-chlorophenyl)
oxopropanoate
[Chem 167]
c1 0
Cl /
To a tert—butyl methyl ether solution (70 mL) of 3-chlorobenzaldehyde (10 g) and
methyl 3,3-dichloro~2—oxopropanoate (9.6 mL), sodium methoxide (4.8 g) was added under
cooling with ice and the mixture was stirred at 70°C for 17 hours. After adding EtOAc to the
reaction mixture, it was washed with water and Brine. After drying the organic layer over
MgSO4, the desiccant was filtered off and the filtrate was concentrated under reduced
pressure to give the titled compound (18 g as a brown oil).
MS (ESI neg.) m/z : 245 ([M-H]').
Reference e P-C50: Synthesis of methyl 2-(4-bromophenyl)-5—(3-chlorophenyl)-1,3-
thiazole-4—carboxylate
[Chem 168]
\o N
CI 8
To a MeOH solution (150 mL) of the compound (7.0 g) obtained in Reference
Example P—C49, 4-bromobenzothioamide (6.1 g) was added and the mixture was stirred at
70°C for 2 hours. After leaving the mixture to cool, the precipitating solid was red by
ion to give the titled compound (49 g as a colorless solid).
MS (ESI pos.) m/z : 408 ([M+H]+).
-Reference Example P-CS 1: Synthesis of 2-(4-bromophenyl)(3-chlorophenyl)-l,3-
thiazolecarboxylic acid
—125—
[Chem 169]
Ho N
C! s
Starting from the compound (4.9 g) obtained in Reference Example P—CSO, the same
procedure as in Reference Example P-C32 was applied to give the titled compound (4.7 g as
a pale yellow solid).
MS (ESI pos.) m/z : 394 +).
- Reference Example P—CSZ: Synthesis of [2—(4—bromophenyl)—5-(3—chlorophenyl)-l ,3—
thiazolyl]acetic acid
[Chem 170]
HO O
Cl S
Starting from the compound (210 mg) obtained in Reference Example P-CSl, the
same procedure as in Reference Example P—C23 was applied to give the titled compound
(220 mg as a pale brown solid).
MS (ESI pos.) m/z : 408 ([M+H]+).
' nce Example P-C53: Synthesis of 2—[2—(4—bromophenyl)—5~(3-chlorophenyl)-1,3-
thiazoly1]-N-(propan—2—yl)acetamide
[Chem 171]
Y” °
CI 8
Starting from the nd (220 mg) obtained in Reference Example P-C52, the
same procedure as in Reference Example P—C09 was applied to give the titled compound
(85 mg as a pale yellow solid).
-l26-
MS (ESI pos.) m/z ; 449 ([M+H]+).
-Reference Example P-C54: Synthesis of 2-[5—(3-chlorophenyl)(4-ethenylphenyl)-l,3-
thiazolyl]—N-(propan—2—yl)acetamide
] [Chem 172]
I :W
Starting from the compound (1 .9 g) obtained in Reference e P—C53, the same
procedure as in nce Example P-A03 was applied to give the titled compound (820 mg
as a pale yellow solid).
MS (ESI pos.) m/z : 397 ([M+H]+).
'Reference Example P-C55: Synthesis of 3—chlorophenyl)-2—[4-(2-
hydroxyethyl)phenyl] -1 ,3 -thiazolyl } -N-(propanyl)acetamide
[Chem 173]
N H
| \
Cl S
Starting from the compound (820 mg) obtained in Reference Example P-C54, the
same procedure as in Reference Example P-A04 was applied to give the titled compound
(830 mg as a pale yellow solid).
MS (ESI pos.) m/z : 415 ([M+H]+).
'Reference Example P—C56: Synthesis of methyl 2—(3-bromophenyl)(3-
chlorophenyl)thiazole—4~carboxylate
[Chem 174]
0 N
I \
Cl 8
Starting from the compound (7.0 g) obtained in Reference Example P-C49 and 3-
—127—
bromobenzothioamide (4.9 g), the same procedure as in Reference Example P—C50 was
applied to give the titled compound (4.1 g as a colorless solid).
MS (ESI pos.) m/z : 408 ([M+H]+).
'Reference Example P~C57z Synthesis of 2-(3-bromophenyl)(3 -chlorophenyl)thiazole—4—
carboxylic acid
[Chem 175]
H0 N
I \
c: s
Starting from the compound (4.1 g) obtained in Reference Example P-C56, the same
procedure as in Reference Example P-C32 was d to give the titled compound (3.9 g as
a pale yellow solid).
MS (ESI pos.) m/z : 394 +).
'Reference Example P-C58: Synthesis of 2-(2-(3-bromophenyl)(3-chlorophenyl)thiazol
yl)acetic acid
[Chem 176]
HO O
I \
CI S
Starting from the compound (3.9 g) obtained in Reference Example P—C57, the same
procedure as in Reference Example P—C23 was applied to give the titled nd (4.1 g as
a pale brown .
MS (ESI pos.) m/z : 408 ([M+H]+).
'Reference Example P—C59: Synthesis of 2—(2-(3-bromophenyl)—5—(3-chlorophenyl)thiazol—4~
yl)-N-isopropylacetamide
—128—
[Chem. 177]
I \
Cl S
ng from the compound (4.1 g) obtained in nce Example P—C58, the same
procedure as in Reference Example P-C09 was d to give the titled compound (2.3 g as
a pale yellow solid).
MS (ESI pos.) m/z : 449 ([M+H]+).
- Reference Example P—C60: Synthesis of 2—(5-(3—chlorophenyl)—2-(3-vinylpheny1)thiazol—4—
yl)-N—isopropylacetamide
[Chem 178]
\K“ 0
. "*6
Cl 5
Starting from the compound (2.3 g) obtained in Reference Example P—C59, the same
procedure as in Reference Example P-A03 was applied to give the titled compound (650 mg
as a pale yellow solid).
M3 (E81 pos.) m/z : 397 ([M+H]+).
'Reference Example P-C61: Synthesis of 2—(5-(3-chlorophenyl)—2-(3—(2—
hydroxyethyl)phenyl)thiazol—4-yl)-N—isopropylacetamide
[Chem 179]
\rN °
N OH
Cl 3
Starting from the compound (650 mg) obtained in Reference Example P-C60, the
same procedure as in Reference e P—A04 was applied to give the titled compound
-129~
(660 mg as a pale yellow solid).
MS (ESI pos.) m/z : 415 ([M+H]+).
'Reference Example P-C62: Synthesis of 4—(2—{[tert-butyl(diphenyl)silyl]oxy} ethyl)aniline
[Chem 180]
OTBDPS
To a DMF solution (15 mL) of 2-(4-aminophenyl)ethanol (1.0 g) and iPr2NEt
(1.5 mL), utyl(chloro)diphenylsilane (2.1 mL) was added and the mixture was stirred at
room temperature for 17 hours. After adding EtOAc to the reaction mixture, it was washed
with water and Brine. After drying the organic layer over MgSO4, the desiccant was filtered
off and the filtrate was concentrated under d pressure; the resulting residue was
purified by silica gel column chromatography (SNAP Cartridge HP-Sil; mobile phase: n-
Hexane/EtOAc = 90/10 — 70/30; V/V) to give the titled compound (2.1 g as a pale yellow oil).
MS (ESI pos.) m/z : 376 ([M+H]+).
~Reference e P-C63: Synthesis of 3—bromol-[4-(2-{[tert-
butyl(diphenyl)silyl]oxy} ethyl)phenyl] — l H-pyrrole-2,5-dione
Cll.[Chem 181]
To an acetic acid solution (45 mL) of the nd (50 g) ed1n Reference
Example P—C62, 3—bromofi1ran—2,5-dione (2.6 g) was added and the mixture was stirred at
80°C for 4 hours. The reaction e was concentrated under reduced pressure and the
resulting residue was purified by silica gel column chromatography (SNAP Cartridge HP-Sil;
mobile phase: n-Hexane/EtOAc = 95/5 - 85/15; V/V) to give the titled compound (4.5 g as a
pale brown oil).
MS (ESI pos.) m/z : 534, 536 ([M+H]+).
'Reference Example P—C64: Synthesis of tributyl(3-chlorophenyl)stannane
~130—
[Chem. 182]
(”08an
To a THF solution (0.5 M, 30 mL) of (3—chlorophenyl)magnesium e,
tributyltin chloride (4.3 mL) was added under cooling with ice and the mixture was stirred at
room temperature for 5 hours. To the reaction mixture, a saturated aqueous ammonium
chloride solution and EtOAc were added and the organic layer was separated. After drying
the resulting organic layer over MgSO4, the desiccant was filtered off and the filtrate was
concentrated under d pressure; the resulting residue was purified by silica gel column
chromatography (SNAP Cartridge HP-Sil; mobile phase: n—Hexane) to give the titled
compound (5.6 g as a colorless oil).
1H NMR (600 MHz, CHLOROFORM—d) 5 (ppm) ;0.82 - 0.92 (34 H, m); 0.97 - 1.13 (24 H,
m), 1.32 (24 H, dq, J=14.7, 7.4 Hz), 1.43 - 1.63 (27 H, m), 7.20 - 7.27 (12 H, m), 7.28 — 7.32
(3 H, m), 7.39 (3 H, d, J=2.1 Hz)
'Reference Example P-C65: Synthesis of l-[4—(2-{[tert-
butyl(diphenyl)silyl]oxy} ethyl)phenyl] -3 -(3-chlorophenyl)- l ole-2,5-dione
[Chem 183]
TBDPS
To a dioxane solution (18 mL) of the nd (2.0 g) obtained in Reference
e P-C63 and the compound (2.3 g) obtained in Reference Example P-C64, Pd(PPh3)4
(430 mg) was added and the mixture was stirred at 100°C for 17 hours. After filtering the
reaction mixture through Celite tered trademark), the filtrate was diluted with added
tEtOAc; subsequently, the organic layer was washed with water and Brine and dried over
MgSO4; the desiccant was then filtered off and the filtrate was concentrated under reduced
re. The resulting residue was purified by silica gel column chromatography (SNAP
Cartridge HP—Sil; mobile phase: n—Hexane/EtOAc = 90/10 ~ 70/30; V/V) to give the titled
—13l-
compound (1.0 g as a pale red oil).
Ms (ESI pos.) m/z : 588 ([M+Na]+).
' nce Example P-C66: Synthesis of 1-[4-(2—{[tert-
butyl(diphenyl)silyl]oxy}ethyl)phenyl]—3~chloro—4—(3~chlorophenyl)-1H-pyrrole-2,5—dione
[Chem 184]
To a thionyl chloride solution (8.0 mL) of the compound (900 mg)
obtained in Reference Example P-C65, pyridine (0.26 mL) was added and the mixture was
stirred at 60°C for an hour. After concentrating the reaction mixture under reduced pressure,
toluene was added and the insoluble matter was filtered off, with the resulting filtrate being
concentrated under reduced pressure. The ing residue was purified by silica gel column
chromatography (SNAP Cartridge HP-Sil; mobile phase: n-Hexane/EtOAc = 90/10 - 80/20;
V/V) to give the titled compound (630 mg as a pale yellow amorphous product).
MS (ESI pos.) m/z : 622 ([M+Na]+).
ence Example P-C67: Synthesis of di-tert—butyl {1-[4-(2—{[tert-
butyl(diphenyl)silyl]oxy} ethyl)phenyl] chlorophenyl)—2,5~dioxo—2,5—dihydro- 1 H—pyrrol-
3-y1}propanedioate
[Chem 185]
To a THF solution (5.0 mL) of di-tert-butyl te (480 mg), sodium hydride
(88 mg) was added under cooling with ice and the mixture was stirred for 30 minutes;
subsequently, a THF solution (5.0 mL) of the nd (630 mg) obtained in Reference
~132-
Example P-C66 was added dropwise. After l-hr ng at room temperature, CHC13 and
water were added to the reaction mixture. The organic layer was ted and dried over
MgSO4; subsequently, the desiccant was filtered off and the filtrate was concentrated under
reduced pressure. The resulting residue was purified by silica gel column chromatography
(SNAP Cartridge HP-Sil; mobile phase: n—Hexane/EtOAc = 90/10 — 80/20; V/V) to give the
titled nd (770 mg as a pale yellow oil).
MS (ESI neg.) m/z : 778([M-H]').
'Reference Example P-C68: Synthesis of {4—(3-chlorophenyl)~l~[4~(2-hydroxyethyl)phenyl]-
2,5-dioxo—2,5-dihydro-lH—pyrrol-3 -yl} acetic acid
[Chem 186]
6. 'Of’"
To a CHC13 solution (4.50 rnL) of the compound (669 mg) ed in Reference
e P-C6’7, trifluoroacetic acid (4.50 mL) was added and the mixture was stirred at
room temperature for 17 hours. The reaction mixture was concentrated to give the titled
compound as a crude product (535 mg as a pale yellow oil).
MS (ESIpos.) m/z : 386 ([M+H]+).
'Reference Example P—C69: Synthesis of 2- {4-(3-chlorophenyl)-l-[4—(2~
hydroxyethyl)phenyl] —2 xo-2,5~dihydro— l H-pyrrol—3 —yl } ~N—(propan—2—yl)acetamide
[Chem 187]
Starting from the compound (49 mg) obtained in Reference ExampleP-C68, the
same procedure as in Reference Example P-C09 was applied to give the titled compound
(16 mg as a pale yellow oil).
MS (ESI pos.) m/z : 427([M+H]+).
—l33-
‘ Reference Example P-C70: Synthesis of 2—[(4—bromophenyl)amino](3-
chlorophenyl)ethanone
[Chem. 188]
A MeCN (30 mL) suspension of 3—chlorophenacyl bromide (3.0 g),
4-bromoani1ine (2.2 g) and NaHCO3 (1.1 g) was stirred first at room temperature for 14
hours, then at an external temperature of 60°C for 4 hours. After leaving the reaction mixture
to cool, water and EtOAc were added for phase separation, followed by g with Brine.
The s layer was ted with EtOAc twice and the organic layer was dried over
Na2804; subsequently, the desiccant was filtered off and the e was concentrated under
reduced pressure. To the resulting solids, n—Hexane was added and the mixture was stirred at
an external temperature of 60°C for an hour. After leaving the mixture to cool, the solids
were recovered by filtration and dried to give the titled the nd (3.5 g as a pale brown
solid).
MS (ESI pos.) m/z : 324, 326 ([M+H]+).
- Reference e P~C71: Synthesis of 1—(4-bromophenyl)(3—chlorophenyl)-1,3-
dihydro~2H—imidazol—2-one
[Chem 189]
HmdliN Br
Cl 5-
To the compound (4.1 g) obtained in Reference ExampleP-C70 and potassium
cyanide (17 g), acetic acid (115 mL) was added and the mixture was stirred at an external
temperature of 60°C for 2 hours. After leaving the reaction mixture to cool, water was added
and the resulting solids were recovered by filtration and dried to give the titled the compound
—134—
(4.8 g as a colorless solid).
MS (ESI pos.) m/z : 351 ([M+H]+).
'Reference Example P-C72: Synthesis of 2-[3—(4-bromophenyl)—5-(3-chlorophenyl)oxo—
2,3-dihydr0—1H—imidazol—1~y1]—N~(propan—2-yl)acetamide
[Chem 190]
CWHQ®Br
Starting from the compound (1.7 g) obtained in Reference e P—C71, the same
procedure as in nce Example P-A02 was applied to give the titled the compound (1.7 g
as a pale brown solid).
MS (ESI pos.) m/z : 448, 450 +).
'Reference Example P-C73: Synthesis of 2-[5-(3-chlorophenyl)(4-ethenylpheny1)oxo—
2,3-dihydro-lH—imidazol—l-yl]-N-(propanyl)acetamide
H [Chem 191]
CIUVN—Q'JY"‘f°4@_/
Starting from the nd (1.7 g) obtainedin Reference Example PC72, the same
procedure as in Reference Example P-A03 was applied to give the titled the compound
(0.69 g as a pale brown solid).
MS (ESI pos.) m/z : 396 ([M+H]+).
Reference Example P-C74: Synthesis of 2-{5-(3-chlorophenyl)[4-(2—
hydroxyethyl)phenyl]oxo-2,3-dihydro-lH-imidazol—1-yl}-N-(propan—2-yl)acetamide
—135-
[ChemH192]
\rNfoo
c\©)\/N_©fNAN—0J—0H
Starting from the nd (0.69 g) edin Reference Example P-C73, the
same procedure as in nce Example P—A04 was applied to give the titled the compound
(0.24 g as a pale brown solid).
MS (ESI pos.) m/z : 414 ([M+H]+).
- Reference Example P—C75: Synthesis of (1E)—l—(3-chlorophenyl)—1-(hydroxyimino)propan—
2-one
[Chem 193]
HO.._N
To a solution of 3—chlorophenylacetone (5.0 g) in EtOH (100 mL), a 20% sodium
ethoxide—EtOH on (14 mL) was added and under cooling with ice, isoamyl nitrite
(5.9 mL) was gradually added and the mixture was stirred for 2 hours under cooling with ice.
To the reaction mixture, diethyl ether and water were added for phase separation. After
adjusting the aqueous layer to about pH 3 with l M aqueous hydrochloric acid, extraction
was conducted with EtOAc, followed by washing with Brine. After drying the organic layer
over NaZSO4, the ant was filtered off and the filtrate was concentrated under reduced
pressure. The resulting residue was purified by column chromatography (SNAP dge
KP—NH 55 g; mobile phase: CHCl3/MeOH = 100/0 — 95/5; V/V) to give the titled compound
(4.2 g as a colorless solid).
MS (ESI neg.) m/z : 196 ([M—H]').
' Reference Example P-C76: Synthesis of 1,3,5-tris(4-bromophenyl)—1,3,5-triazinane
—l36-
[Chem 194]
To 4-brom0ani1ine (5.0 g) and paraformaldehyde (1.2 g), toluene (50 mL) was
added and the mixture was stirred at an external temperature of 110°C for 2 hours. After
g the reaction mixture to cool, it was concentrated under reduced pressure. After
adding EtOAc and heating under reflux for 30 minutes, the on mixture was left to cool
and the resulting solids were recovered by filtration and dried to give the titled nd
(1.8 g as a colorless solid). The mother liquor was concentrated under reduced pressure and
following the addition of a hexane/EtOAc mixed solvent (6/ 1; v/V), the mixture was stirred at
60°C for 30 s; thereafter, the reaction mixture was left to cool and stirred at room
temperature for 16 hours. The resulting solids were recovered by filtration and dried to give
the titled compound (2.2 g as a colorless .
MS (ESI pos.) m/z : 550, 552 ([M+H]+).
'Reference Example P—C77: Synthesis of 1—(4~bromophenyl)—4-(3—chloropheny1)-5—methy1~
1,3 —dihydro-2H—imidazol—2—one
[Chem 195]
HN’qN B r
CI \
To the compound (2.0 g) obtained in Reference Example P-C75 as well as the
compound (1.9 g) obtained in Reference Example P-C76, EtOH (60 mL) was added and the
mixture was d at an external temperature of 100°C for 16 hours. After leaving the
mixture to cool, it was trated under reduced pressure and EtOH (15 mL) was added,
followed by stirring the mixture at an external temperature of 100°C for 30 hours. After
~137—
leaving the mixture to cool, the resulting solids were recovered by filtration, washed with
cold EtOH, and dried to give the titled compound (1.4 g as a colorless solid).
MS (ESI pos.) m/z : 363 ([M+H]+).
'Reference Example P-C78: Synthesis of 2-[3-(4-bromopheny1)(3-chlorophenyl)
methyl0xo-2,3-dihydro-lH-imidazolyl]-N-(propan—2-yl)acetamide
H.[Chem 196]
U530W44}
Starting from the compound (0.70 g) obtainedin Reference e P-C77, the
same procedure as in nce Example P—AO2 was applied to give the titled compound
(0.94 g as a pale brown solid).
MS (ESI pos.) m/z : 462, 464 ([M+H]+).
'Reference Example P-C79: sis of 2-[5—(3-chlorophenyl)(4-ethenylphenyl)
methyl—2—oxo-2,3—dihydro- l H-imidazol— l -yl]-N-(propanyl)acetamide
H.[Chem 197]
#341494
Starting from the compound (042 g) obtainedin Reference Example PC78, the
same ure as in Reference Example P-A03 was applied to give the titled compound
(0.29 g as a pale brown solid).
MS (ESI pos.) m/z : 410 +).
'Reference Example P-C80: Synthesis of 2-{5-(3-chlorophenyl)[4—(2-
hydroxyethyl)pheny1]methyl-2—oxo—2,3~dihydro-lH-imidazolyl}-N-(propan—2—
y1)acetamide
—l38-
H.[Chem 198]
mnYt‘EEN_@_/—OH
Starting from the compound (0.29 g) obtained1n Reference Example P-C79, the
same procedure as in Reference Example P-A04 was applied to give the titled compound
(0.11 g as a ess solid).
MS (1381 pos.) m/z : 428 ([M+H]+).
- Reference e P—C8 1: Synthesis of 4—bromo—N‘~(3-chlorophenyl)benzohydrazide
[Chem 199]
an N
‘1»:
To a CHC13 solution (80 mL) of orophenyl)hydrazine hydrochloride (5.0 g)
and Et3N (8.6 mL), a CHCl3 suspension (40 mL) of obenzoyl chloride (6.1 g) was
added under an ice bath and the mixture was stirred overnight at room temperature. To the
reaction mixture, water (100 mL) and a saturated aqueous NaHC03 on (30 mL) were
added in an ice bath and after separating the organic layer, the aqueous layer was extracted
with CHC13' twice. The organic layers were combined and concentrated under reduced
pressure. The resulting residue was washed with IPE (80 mL) under stirring and recovered
by filtration to give the titled compound (6.3 g as a pale pink solid).
MS (ESI pos.) m/z : 327 ([M+H]+).
‘Reference Example P-C82: Synthesis of 4-bromo-N—(3-
chlorophenyl)benzenecarbohydrazonoyl chloride
[Chem 200]
Cl N
To a MeCN sion (40 mL) of the compound (2.0 g) obtained in Reference
Example P-C81, triphenylphosphine (1.9 g) and carbon tetrachloride (1.1 g) were added and
the mixture was stirred overnight at room temperature. After heating the reaction mixture to
40°C, it was left to cool and following the addition of triphenylphosphine (1.6 g) and carbon
tetrachloride (0.6 mL), the mixture was stirred at room ature for 24 hours. The
reaction mixture was trated under reduced pressure and the resulting e was
purified by silica gel column chromatography (SNAP Cartridge HP—Sil 50g; mobile phase: n-
Hexane/EtOAc = 95/5 - 80/20; v/v) to give the titled compound (1.9 g as a colorless solid).
MS (ESI neg.) rn/z : 341, 343 ([M-H]').
'Reference Example P—C83: Synthesis of 2-[3-(4—bromophenyl)(3—chlorophenyl)-1H-
triazol—5—yl]-N-(propanyl)acetamide
[Chem 201]
\I/N
”80*1 r
Gig "N
To a MeCN suspension (55 mL) of the compound (1.1 g) obtained in Reference
Example P-C82, Et3N (1.1 mL) and 3—amino-N-(propan—2-yl)propanamide hydrochloride
(0.64 g) were added and the mixture was stirred at room temperature for 3 hours. The
reaction mixture was concentrated under d pressure and after adding MeCN (50 mL)
and silver carbonate (1.3 g) to the resulting residue, the mixture was stirred with light
shielded, first at 50°C for 4 hours, then at 60°C for 4 hours. After leaving the mixture to
cool, silver carbonate (0.44 g) was added and the mixture was stirred at 60°C for 4 hours.
After leaving the reaction mixture to cool, it was concentrated under reduced pressure;
uently, the resulting residue was purified by silica gel column chromatography (SNAP
Cartridge HP-Sil 25 g; mobile phase: n-Hexane/EtOAc = 88/12 - 0/100; V/V) and the resulting
compound was washed With IPE; the solids were recovered by filtration to give the titled
nd (990 mg as a colorless solid).
—l40-
MS (ESI pos.) m/z : 433 +).
' Reference Example P-C84: Synthesis of 2-[1-(3-chlorophenyl)(4-ethenylpheny1)-1H-
l,2,4-triazol-5—yl] —N-(propan—Z-yl)acetamide
[Chem 202]
\l/N
’">-©J’/
(Hg“'N
Starting from the compound (282 mg) obtained in Reference Example P-C83, the
same procedure as in nce Example P—A03 was applied to give the titled compound
(65 mg as a colorless solid).
MS (ESI pos.) m/z : 381 ([M+H]+).
-Reference Example P—C85: Synthesis of 2-{ l—(3—chlorophenyl)—3-[4—(2—
hydroxyethyl)phenyl] - l H- l ,2,4—triazol—5-yl } opan-2—y1)acetamide
[Chem 203]
Y“:NFO—rorl
Cl\©N“N
Starting from the compound (65 mg) obtained in Reference Example P-C84, the
same ure as in Reference Example P-A04 was applied to give the titled compound
(57 mg as a colorless solid).
MS (ESI pos.) m/z : 399 ([M+H]+).
- Reference Example P-D01: Synthesis of l—fluoro—4-isocyanatomethoxybenzene
[Chem 204]
/0FDN’
To a toluene solution (60 mL) of 4—fluoro3-methoxyaniline (3.0 g), triphosgene
-l41—
(4.5 g) was added under cooling with ice and the mixture was stirred overnight at 110°C.
The reaction mixture was concentrated to give the titled the compound as a crude t
(dark purple oil).
'Reference Example P—D02: Synthesis of ethyl 3-{2—[(4—fluoro—3—
methoxyphenyl)carbamoyl]hydrazinyl}oxopropanoate
[Chem 205]
To a THF solution (80 mL) of ethyl 3— hydrazinyl—3—oxopropanoate (3.2 g), the
crude product (3.7 g) obtained in Reference Example P-D01 was added under g with
ice and the mixture was d overnight at room temperature. The reaction mixture was
concentrated and the resulting residue was d by silica gel column chromatography
(SNAP Cartridge HP-Sil 100g; mobile phase: CHCl3/MeOH = 99/1 - 80/20; v/v) to give the
titled compound (3.8 g as a pale purple solid).
1H NMR (600 MHz, DMSO-d6) 5 (ppm) ;1.12 - 1.22 (3 H, m) 3.27 - 3.32 (4 H, m) 3.75
(3 H, s) 4.02 - 4.14 (2 H, m) 6.82 — 6.95 (l H, m) 7.05 (1 H, dd, J=1l.4, 8.9 Hz) 7.30 (1 H,
dd, J=8.1, 2.3 Hz) 8.22 (1 H, br. s.) 8.64 (l H, br. s.) 9.87 (1 H, br. s.)
° Reference Example P-D03: Synthesis of [4—(4—fluoro3-methoxyphenyl)oxo-4,5—dihydro-
1H— 1 ,2,4—triazol—3—yl]acetic acid
[Chem 206]
HO O
A 3.0 M NaOH aqueous solution (30 mL) of the nd (3.7 g) obtained1n
Reference Example P-D02 was stirred at 120°C for 3 days. After leaving the reaction
mixture to cool, conc. hydrochloric acid was added for an adjustment to pH = l and the
e was stirred at 0°C for an hour. The resulting solids were recovered by filtration,
—l42-
washed with water and subsequently dried to give the titled compound (2.9 g as a pale yellow
solid).
MS (ESI pos.) m/z : 268 ([M+H]+).
' Reference Example P—D04: Synthesis of 2—[4—(4~fluoromethoxyphenyl)-5—oxo—4,5-
dihydro-l H— 1,2,4—triazol—3 —yl] ~N-(propan—Z-yl)acetamide
H.[Chem 207]
YQH0Pg
To a DMF suspension (8 mL) of the compound (800 mg) obtained in Reference
Example P-D03, HOBt-HZO (590 mg) and EDC ‘ HCl (740 mg) were added at room
temperature and the mixture was stirred for 15 minutes. After adding pylamine
(0.60 mL) to it, the reaction mixture was stirred at 50°C for 3 hours. After leaving the
reaction mixture to cool, water and CHCl3 were added under cooling with ice and the organic
layer was subsequently separated. The ing organic layer was d with Phase
Separator and the filtrate was concentrated under reduced pressure. The ing residue
was purified by silica gel column chromatography (SNAP dge HP-Sil 25g; mobile
phase: CHClg/MeOH = 99/1 - 85/15; V/v) to give the titled compound (400 mg as a colorless
solid).
MS (ESI pos.) m/z ; 309 ([M+H]+).
'Reference ExampleP—DOS: Synthesis of N—tert-butyl—Z—[4—(4-fluoromethoxyphenyl)-5—
oxo-4,5-dihydro—lH—l,2,4-triazol—3—yl]acetamide
[Chem 208]
wfiwfim
—143—
A mixture of the compound (100 mg) obtained in Reference Example P-D03, tert-
butylamine (0.08 mL), HATU (210 mg), iPerEt (0.13 mL) and THF (1.5 mL) was stirred at
room temperature for 5 hours. To the reaction mixture, a saturated aqueous um
chloride solution (20 mL) and CHC13 were added for phase separation; uently, the
aqueous layer was extracted with CHCl3 (20 mL x 3 times). The combined organic layer was
dried over MgSO4 and, subsequently, the desiccant was filtered off and the e was
concentrated under reduced pressure. The ing residue was purified by silica gel column
chromatography (SNAP Cartridge KP-Sil; mobile phase: CHClg/MeOH/NH4OH = 99/1/01 —
95/5/05; v/v/v) to give the titled compound (65 mg as a pale purple amorphous product).
MS (ESI pos.) m/z : 323 ([M+H]+).
-Reference Example P-D06: Synthesis of ethyl (3-
chlorophenyl)carbamoyl]hydrazinyl} oxopropanoate
[Chem 209]
O O
C'UNY"BU°’\H H
Starting from 1-chloroisocyanatobenzene (5.0 mL) and ethyl 3- hydraziny1-3—
oxopropanoate (6.0 g), the same procedure as in Reference Example P-DOZ was applied to
give the titled compound (12 g as a pale brown solid).
MS (1381 pos.) m/z : 300 ([M+H]+).
- Reference Example P-D07: Synthesis of [4-(3-chlorophenyl)oxo-4,5-dihydro-lH-l,2,4-
triazol—3-yl]acetic acid
[Chem 210]
HO 0
(14%
Cl\U‘Vg
Starting from the compound (3.0 g) obtained in Reference e P-D06, the same
procedure as in Reference Example P-D03 was applied to give the titled compound (1.2 g as
a colorless solid).
MS (ESI pos.) m/z : 254([M+H]+).
- Reference e P-D08: Synthesis of 2-[4-(3-chlorophenyl)oxo—4,5-dihydro-1H-
l,2,4—triazol-3—yl]-N—(p1‘opan-2—yl)acetamide
H [Chem. 211]
Yam.“0
Starting from the compound (1.0 g) ed in Reference Example P—D07, the same
procedure as in Reference Example P-D04 was applied to give the titled compound (960 mg
as a colorless solid).
M5 (E31 pos.) m/z : 295 ([M+H]+).
'Reference Example P-D09: Synthesis of N-tert-butyl-Z-[4-(3-chloropheny1)oxo-4,5—
dihydro—1H—1,2,4-triazol—3—yl]acetamide
H [Chem. 212]
XflfiN‘N
Clfi o
A e of the compound (400 mg) obtained in Reference Example P—D07, tert—
butylamine (0.26 mL), HATU (900 mg), iPerEt (0.81 mL) and DMF (10 mL) was stirred
overnight at room temperature and left to stand at room temperature for 5 days. After adding
1 M hydrochloric acid (40 mL) and EtOAc (20 mL) for phase separation, the aqueous layer
was ted with EtOAc (20 mL x 5 times). The combined organic layer was washed with
1 M hydrochloric acid (30 mL), water (30 mL) and Brine, followed by concentrating under
reduced re. The resulting residue was purified by silica gel column chromatography
(SNAP Cartridge HP~Sil 25g; mobile phase: CHClg/MeOH = 99/1 ~ 90/10; v/V) and the
—l45—
resulting solids were washed with a mixed t of EtOAc and n-Hexane (EtOAc/n-
Hexane = 1/ 1; V/V) under stirring and recovered by filtration to give the titled compound
(310 mg as a colorless solid).
MS (ESI pos.) m/z : 309 ([M+H]+).
'Reference e P-DlO: Synthesis of ethyl 3-{2-[(3-chloro
fluorophenyl)carbamoyl]hydrazinyl}-3~oxopropanoate
[Chem 213]
O O
H H
C! N‘II’N‘“Mo“H
Starting from 2—chloro—l—fluoro—4~isocyanatobenzene (11 g) and ethyl 3- hydrazinyl-
3-oxopropanoate (9.4 g), the same procedure as in Reference Example P-D02 was applied to
give the titled compound (15 g as a colorless solid).
1H NMR (600 MHz, 6) 5 (ppm) ;1.16 (3 H, t, J=7.0 Hz), 3.26 (2 H, s), 4.07 (2 H, q,
J=7.0 Hz), 7.17 - 7.46 (2 H, m), 7.63 - 7.84 (1 H, m), 8.39 (1 H, br. s), 8.84 (1 H, br. s), 9.90
(l H, br. s)
- Reference Example P-Dl 1: Synthesis of [4—(3-chloro-4—fluorophenyl)—5—oxo—4,5—dihydro-
1H— 1 riazol—3—yl]acetic acid
[Chem 214]
Ho 0
mg“:"N
A 3.0 M NaOH aqueous solution (14 mL) of the compound (650 mg) obtainedin
Reference Example P-D10 was stirred at 120°C for 2 hours. After leaving the on
mixture to cool, it was washed with Et20. To the aqueous layer, conc. hydrochloric acid was
added for an adjustment to pH = 1 and the mixture was subsequently stirred at 0°C for 30
minutes. The resulting solids were recovered by filtration, washed with water and
subsequently dried to give the titled compound (400 mg as a pale orange—colored solid).
1H NMR (600 MHZ, DMSO-d6) 5 (ppm) ;3.60 (2 H, s), 7.36 - 7.45 (1 H, m), 7.56 (l H, t,
J=8.9 Hz), 7.67 (1 H, dd, J=6.6, 2.9 Hz), 11.87 (1 H, 3), 12.52 - 12.89 (1 H, m)
'Reference Example P-D12: Synthesis of 3-chlorof1uorophenyl)—5-0x0—4,5—dihydro—
lH-1,2,4-triazol-3 —yl] «N-(propan—2-yl)acetamide
H [Chem 215]
Y???F
Starting from the compound (3.0 g) obtained in Reference Example P-D07, the same
procedure as in nce e P-D04 was applied to give the titled compound (2.5 g as
a colorless solid).
MS (ESI pos.) m/z : 313 ([M+H]+).
'Reference Example P-D13: Synthesis of N-tert-buty1[4-(3-chloro—4-flu0rophenyl)oxo-
4,5 -dihydro-1H-1,2,4-triazol—3 —yl]acetamide
H.[Chem 216]
Starting from the compound (1.8 g) obtained in Reference Example P-D07, the same
procedure as in Reference Example P-D05 was applied to give the titled compound (1.3 g as
a colorless solid).
MS (ESI pos.) m/z : 327 ([M+H]+).
'Reference e P-Dl4: Synthesis of ethyl 3-{2-[(3-
methoxyphenyl)carbamoyl]hydrazinyl} —3-oxopropanoate
[Chem 217]
H H
””0”“1““H
Starting from l—isocyanato—3—methoxybenzene (5.0 g) and ethyl 3- hydrazinyl-3—
oxopropanoate (4.4 g), the same procedure as in Reference Example P-D02 was applied to
give the titled compound (8.5 g as a colorless amorphous product).
MS (ESI pos.) m/z : 296 +).
- Reference Example P-DlS: Synthesis of [44(3-methoxyphenyl)0xo-4,5-dihydro-1H-
1,2,4-triazolyl]acetic acid
[Chem 218]
H0 0
.n x“
26°“
ng from the compound (8.4 g) obtained in Reference Example P-Dl4, the same
procedure as in nce Example P—D03 was applied to give the titled compound (3.8 g as
a pale yellow solid).
MS (ESI pos.) m/z : 250 ([M+H]+).
'Reference Example P-D16: Synthesis of 2—[4»(3-methoxyphenyl)—5~0xo-4,5-dihydr0-1H—
1,2,4—triazol—3-yl]~N—Q3r0pan—2—yl)acetamide
H.[Chem 219]
K"?x
[0584 Starting from the compound (800 mg) obtainedin Reference e P—D15, the
same procedure as in Reference Example P-D04 was applied to give the titled compound
(720 mg as a colorless .
MS (ESI pos.) m/z : 291 ([M+H]+).
' Reference Example P-D17: Synthesis of N-tert-butyl—Z—[4-(3—meth0xyphenyl)oxo—4,5—
dihydro- 1 H- 1 ,2,4—triazol-3 —y1]acetamide
H.[Chem 220]
:3?“0
Starting from the compound (400 mg) obtained in Reference Example P—DlS, the
same procedure as in Reference Example P—D09 was d to give the titled compound
(370 mg as a colorless amorphous product).
MS (ESI pos.) m/z ; 305 +).
Reference Example P-D18: Synthesis of ethyl 3-oxo(2-{[3-
(trifluoromethyl)phenyl]carbamoyl}hydrazinyl)propanoate
[Chem 221]
F o o
F H H
Starting from 1~isocyanato(trifluoromethyl)benzene (5.0 g) and ethyl 3-
hydrazinyl—3-oxopropanoate (3.9 g), the same procedure as in Reference Example P-D02 was
applied to give the titled compound (7.0 g as a colorless amorphous product).
'Reference Example P—Dl9: Synthesis of {5-oxo—4—[3—(trifluoromethyl)phenyl]-4,5-dihydro~
1H- 1 riazol-3 —yl}acetic acid
[Chem 222]
Ho 0
-l49—
Starting from the compound (6.8 g) obtained in Reference Example P—DO6, the same
procedure as in Reference Example P-D03 was applied to give the titled compound (1.5 g as
a colorless .
MS (ESI pos.) m/z : 288 ([M+H]+).
'Reference Example P-D20: Synthesis of xo[3-(trifluoromethyl)phenyl]—4,5—
dihydro-1H-1,2,4—triazol-3~y1}—N—(propanyl)acetamide
[Chem 223]
FW’NN
Starting from the compound (800 mg) obtained in Reference Example P-D07, the
same procedure as in Reference Example P—D04 was applied to give the titled nd
(520 mg as a ess .
MS (1381 pos.) m/z : 329 ([M+H]+).
- Reference Example P-D21: Synthesis of 2- {4—(3-chlorophenyl)[4-(2-
hydroxyethyl)phenyl] —5-oxo—4,5~dihydro— 1 H- 1 ,2,4-triazol-3 —yl } -N-(propan-2—yl)acetamide
H [Chem 224]
\F" °
avatarN c...
A 1,4-dioxane (70 mL) suspension of the compound (2.8 g) obtained in Reference
Example P-D08, 2-(4-bromophenyl)ethanol (1.4 mL), copper iodide (1.8 g), tripotassium
phosphate (4.0 g) and trans-N,N’-bismethyl-1,2- cyclohexanediamine (1.5 mL) was stirred at
an external temperature of 100°C for 4 hours under a nitrogen . After leaving the
mixture to cool, 20% aqueous ammonia and CHCl3 were added to separate the organic layer,
with the aqueous layer being subsequently extracted with CHC13 twice. The combined
—150-
organic layer was washed with water and 20% aqueous ammonia and subsequently dried
over MgSO4; thereafter, the desiccant was filtered off and the filtrate was concentrated under
reduced pressure. The resulting residue was purified by silica gel column chromatography
(REVELERIS 80g Silica Cartridge; mobile phase: n-Hexane/CHCl3/MeOH = 50/50/0 —
0/ 100/0 - 0/90/10; v/v/v). The resulting crudely purified product was washed with a mixed
solvent of EtOAC and n—Hexane (EtOAc/n-Hexane = 1/1; v/v) under stirring to give the titled
compound (2.5 g as a pale gray solid).
MS (ESI pos.) m/Z : 415 ([M+H]+).
-Reference Example P-D22: Synthesis of 2-(4—(3-chlorofluorophenyl)—l—(4-(2—
hydroxyethyl)phenyl)—5-oxo-4,5-dihydro— lH— l ,2,4—triazol-3 ~y1)—N~isopropylacetarnide
[Chem 225]
law0HF
Starting from the nd (500 mg) obtained in Reference Example P-D12, the
same procedure as in Reference Example P-D21 was applied to give the titled compound
(430 mg as a colorless solid).
MS (ESI pos.) m/z : 433([M+H]+).
'Example A—01: Synthesis of 2—[2—(3-chlorophenyl)-4— (piperidin—1-yl)ethyl]phenyl}—
lH—imidazol-1—yl]-N-(propanyl)acetamide
N[Chem 226]
To a CHC13 (1 1 mL) on of the nd (533 mg) obtained1n nce
Example P—A04, Et3N (0.28 mL) was added and after adding MsCl (0.12 mL) under cooling
~151-
with ice, the mixture was stirred at room ature for 2 hours and a half. Under cooling
with ice, water was added, extraction was conducted with CHC13, and the e was
concentrated under reduced pressure. The resulting residue was purified by silica gel (OH)
column chromatography (mobile phase: CHCl3/EtOAc = 70/30; v/V) to yield a mesyl form
(414 mg as a colorless solid).
A mixture of the obtained mesyl form (102 mg), piperidine (0.042 mL), iPerEt
(0.073 mL) and MeCN (2.0 mL) was subjected to microwave for a reaction (100°C x 1.5 hr).
The reaction e was purified by reverse-phase column chromatography (mobile phase:
0.1% TFA MeCN/H20 = 10/90 - 90/10; V/V). The fractions were neutralized with a saturated
aqueous NaHCO3 solution, extracted with CHC13, and filtered with Phase Separator. The
solvent was distilled off under d pressure to give the titled compound (65 mg as a
colorless solid).
M3 (E81 pos.) m/z : 465 +).
1H-NMR (600 MHz, CDC13) 5 (ppm) ; 1.12 (6 H, d, J=6.4 Hz), 1.43 - 1.51 (2 H, m), 1.60 -
1.67 (4 H, m), 2.48 (4 H, br. s.), 2.55 - 2.62 (2 H, m), 2.80 - 2.87 (2 H, m), 4.09 - 4.19 (1 H,
m), 4.65 (2 H, s), 5.33 — 5.40 (1 H, m), 7.23 - 7.26 (2 H, m), 7.28 (1 H, s), 7.38 - 7.47 (3 H,
m), 7.67 (1 H, s), 7.74 - 7.78 (2 H, m).
Starting from nce Example P—A04, Reference Example P-A08 and Reference
Example P-A12, the same procedure as in Example A—Ol was applied to synthesize the
following compounds:
- Example A—02: 2-[2-(3—chlorophenyl)—4- {4—[2—(morpho1in-4—yl)ethy1]phenyl}- lH-imidazolyl] -N-(propan—2-yl)acetamide
H.[Chem 227]
C.\©)WNCO
MS (ESI pos.) m/z: 467 ([M+H]).
~152—
1H-NMR (600 MHz, CDC13) 5 (ppm) ; 1.12 (6 H, d, J=6.9 Hz), 2.54 (4 H, br. s.), 2.59 - 2.67
(2 H, m), 2.79 - 2.87 (2 H, m), 3.75 (4 H, br. s.), 4.15 (1 H, dt, J=7.9, 6.8 Hz), 4.65 (2 H, s),
.37 (1 H, d, J=7.8 Hz), 7.24 — 7.26 (2 H, m), 7.28 (1 H, s), 7.38 — 7.68
- 7.48 (3 H, m), 7.65
(1 H, m), 7.75 — 7.79 (2 H, m).
- Example A—03: 2-[2—(3—ch10ropheny1)—4-{4-[2-(2-0xa—6-azaspiro[3.3]hept
y1)ethy1]pheny1}-1H-imidazol—1~y1]~N-(propany1)acetamide
H [Chem. 228]
MS (ESI pos.) m/z: 479 ([M+H]).
1H-NMR (600 MHZ, CDC13) 5 (ppm) ; 1.12 (6 H, d, J=6.4 Hz), 2.63 - 2.66 (4 H, m), 3.34
(4 H, s), 4.11 - 7.23
- 4.18 (1 H, m), 4.64 (2 H, s), 4.73 (4 H, s), 5.38 (1 H, d, J=7.8 Hz), 7.20
(2 H, m), 7.28 (1 H, s), 7.38 - 7.47 (3 H, m), 7.66 - 7.68 (1 H, m), 7.74 - 7.78 (2 H, m).
- Example A-04: 2—[2—(3-chloropheny1)—4- {4-[2-(4-hydroxypiperidin-1 hy1]pheny1}—1H—
imidazol— 1 —y1]-N—(pr0pan-2—yl)acetamide
[Chem 229]
QVW”OOH
MS (ESI pos.) m/z : 481 ([M+H]+).
1H-NMR (600 MHz, CDC13) 6 (ppm) ; 1.12 (6 H, d, J=6.9 Hz), 1.61 - 1.67 (2 H, m), 1.90 —
1.97 (2 H, m), 2.19 — 2.27 (2 H, m), 2.58 - 2.64 (2 H, m), 2.80 - 2.91 (4 H, m), 3.72 (1 H, br.
s.), 4.11 - 7.26 (2 H, m), 7.28
- 4.19 (1 H, m), 4.64 (2 H, s), 5.39 (1 H, d, J=8.3 Hz), 7.23
(1 H, s), 7.38 — 7.47 (3 H, m), 7.66 (1 H, s), 7.74 - 7.78 (2 H, m).
‘ Example A-05: 2-[2-(3-ch10r0pheny1) {4-[2-(3—hydroxypiperidin- 1 —yl)ethyl]pheny1}- 1H—
imidazoly1]-N—(pr0pan-2—y1)acetamide
—153—
[Chem 230]
YNfNo
MS (ESI pos.) m/z: 481 ([M+H]).
1H-NMR (600 MHz, CDC13) 5 (ppm); 1.12 (6 H, d, J=6.9 Hz), 1.50 - 1.59 (3 H, m), 1.77 —
1.86 (1 H, m), 2.30 - 2.39 (1 H, m), 2.50 — 2.67 (5 H, m), 2.78 - 2.84 (2 H, m), 3.84 (1 H, br.
3.), 4.11 — 4.19 (1 H, m), 4.65 (2 H, s), 5.39 (1 H, d, J=7.8 Hz), 7.22 ~ 7.25 (2 H, In), 7.28
(1 H, s), 7.38 — 7.47 (3 H, m), 7.66 — 7.68 (1 H, m), 7.75 - 7.79 (2 H, m).
' Example A-06: 2—[2-(3-chlorophenyl)—4— {4—[2-(3-hydroxypyrrolidin—1-yl)ethyl]phenyl}-1H-
imidazolyl]-N-(propan—2—y1)acetamide
H [Ch.em 231]
“WWW
MS (ESI pos) m/z 467 ([M+H])
1H-NMR (600 MHz, CDC13) 5 (ppm) ; 1.12 (6 H, d, J=6.4 Hz), 1.73 - 1.80 (1 H, m), 2.16 —
2.24 (1 H, m), 2.32 _ 2.38 (1 H, m), 2.57 (1 H, dd, 1:101, 50 Hz), 2.71 - 2.79 (3 H, m), 2.82
— 2.88 (2 H, m), 2.94 — 2.99 (1 H, m), 4.11 — 4.19 (1 H, m), 4.33 — 4.37 (1 H, m), 4.65 (2 H, s),
.39 (1 H, d, J=7.8 Hz), 7.24 - 7.26 (2 H, m), 7.28 (1 H, s), 7.38 — 7.47 (3 H, m), 7.65 — 7.68
(1 H, m), 7.75 . 7.79 (2 H, m).
- Example A-O7: 2-[2-(3—chloropheny1)—4—(4— {2—[3~(hydr0xymethyl)pyrrolidin— 1
yl] ethyl } )— 1 H—imidazol- 1 —yl] -N—(propanyl)acetamide
[Chem 232]
GIULNWNQ/‘OH
MS (ESI pos.) m/z : 481 ([M+H]+).
—154—
1H—NMR (600 MHz, CDClg) 5 (ppm) ; 1.12 (6 H, d, J=6.9 Hz), 1.67 — 1.75 (1 H, m), 1.98 -
2.05 (1 H, m), 2.32 - 2.38 (2 H, m), 2.53 - 2.86 (2
- 2.58 (1 H, m), 2.67 - 2.75 (3 H, m), 2.81
H, m), 2.89 — 2.95 (1 H, m), 3.53 (1 H, dd, J=9.9, 4.8 Hz), 3.69 (1 H, dd, J=10.1, 4.1 Hz),
4.10 - 4.19 (1 H, m), 4.64 (2 H, s), 5.42 (1 H, d, J=7.8 Hz), 7.23 - 7.26 (2 H, m), 7.27 (1 H,
s), 7.38 - 7.79 (2 H, m).
- 7.46 (3 H, m), 7.65 — 7.67 (1 H, m), 7.75
- Example A—08: 2-[2—(3-chlorophenyl)~4— {4—[2—(3-oxa—8—azabicyclo[3.2. 8-
yl)ethyl]phenyl}-lH—imidazolyl]—N-(propanyl)acetamide
H [Chem 233]
\r1:
(”WWW
MS (ESI pos.) m/z : 493 ([M+H]+).
1H-NMR (600 MHz, CDC13) 5 (ppm) ; 1.12 (6 H, d, J=6.6 Hz), 1.85 - 1.95 (4 H, m), 2.51 -
2.57 (2 H, m), 2.78 - 2.84 (2 H, m), 3.10 (2 H, br. s.), 3.53 (2 H, dd, J=10.3, 1.7 Hz), 3.74 (2
H, d, J=10.3 Hz), 4.11 — 7.28 (2
- 4.20 (1 H, m), 4.65 (2 H, s), 5.37 (1 H, d, J=7.8 Hz), 7.25
H, m), 7.29 (1 H, s), 7.38 - 7.79 (2 H, m).
- 7.47 (3 H, m), 7.67 (1 H, t, J=1.7 Hz), 7.75
- Example A—09: 2—[2—(4-fluoromethoxyphenyl)—4- {4-[2—(piperidinyl)ethyl]phenyl } - 1 H-
imidazol-1—yl]—N-(propan—Z-yl)acetamide
H.[Chem 234]
MS (ESI pos) m/z: 479 ([M+H])
1H-NMR (600 MHz, CDC13) 5 (ppm) ; 1.04 - 1.17 (6 H, m), 1.39 - 1.72 (7 H, m), 2.39 — 2.94
(7 H, m), 3.93 (3 H, s), 4.07 - 4.21 (1 H, m), 4.64 (2 H,s), 5.35 - 5.46 (1 H, m), 7.01 - 7.10
(1 H, m), 7.12 - 7.19 (1 H, m), 7.21 — 7.35 (4 H, m), 7.69 - 7.82 (2 H, m).
- Example A-10: 2-[2—(4vfluoro—3-methoxyphenyl) {4-[2~(morpholin-4—yl)ethyl]phenyl} -
-155—
lH-imidazol-1~y1]—N-(propany1)acetamide
H [Chem 235]
:D/LWNCO
MS (ESI pos.) m/z: 481 ([M+H]).
1H-NMR (600 MHz, CDC13) 8 (ppm) ; 1.11 (6 H, d, J=6.4 Hz), 2.47 - 2.57 (4 H, m), 2.58 —
2.67 (2 H, m), 2.75 — 2.89 (2 H, m), 3.68 — 3.83 (4 H, m),3.93 (3 H, s), 4.08 - 4.21 (1 H, m),
4.64 (2 H, s), 5.40 (1 H, d, J=7.8 Hz), 7.03 - 7.10 (1 H, m), 7.12 - 7.20 (1 H, m), 7.20 — 7.34
(4 H, m), 7.73 - 7.82 (2 H, m).
- Example A-l 1 : 2-[2—(4-fluoromethoxypheny1)-4—{4-[2—(pyrrolidiny1)ethy1]phenyl}—
lH—imidazol—1-y1]-N—(propan—2-yl)acetamide
[C.hem 236]
08:;
[0F618] MS (ESI pos.) m/z: 465 ([M+H]).
1H-NMR (600 MHz, CDC13) 5 (ppm) ; 1.12 (6 H, d, J=6.9 Hz), 1.92 (4 H, br. s.), 2.46 - 3.21
(8 H, m), 3.94 (3 H, s), 4.07 - 4.21 (1 H, m), 4.64 (2 H, s), 5.41 (1 H, d, J=7.8 Hz), 7.00 —
7.10 (1 H, m), 7.16 (1 H, dd, J=11.0, 8.3 Hz), 7.22 - 7.31 (4 H, m), 7.78 (2 H, d, J=8.3 Hz).
- Example A- 12: 2-[2-(4-flu0r0methoxypheny1)—4—(4- {2—[(2R)—2-methy1pyrrolidin— 1
y1]ethy1}pheny1)—lH-imidazol—1—y1]-N—(propan—2-yl)acetamide
H[.Chem 237]
MS (ESI pos.) m/z : 479 ([M+H]+).
1H—NMR (600 MHz, CDC13) 5 (ppm) ; 1.11 (9 H, d, J=6.4 Hz), 1.45 (1 H, br. s.), 1.66 — 1.87
(2 H, m), 1.89 - 2.00 (1 H, m), 2.13 - 2.25 (1 H, m), 2.27 - 2.40 (2 H, m), 2.79 - 2.94 (2 H,
m), 2.98 — 3.10 (1 H, m), 3.19 — 3.32 (1 H, m), 3.94 (3 H, s), 4.09 - 4.20 (1 H, m), 4.65 (2 H,
s), 5.40 (1 H, d, J=8.3 Hz), 7.02 — 7.10 (2 H, m), 7.16 (2 H, dd, J=10.8, 8.5 Hz), 7.21 - 7.34
(4 H, m), 7.78 (2 H, d, J=8.3 Hz).
- Example A— 13 : 2-[4- {4-[2—(3 ~cyanopiperidiny1)ethy1]pheny1}(4-fluor0
methoxyphenyl)— 1 H-imidazol- 1 ~y1]—N—(propany1)acetamide
[Chem 238]
6::W63WN
MS (ESI pos.) m/z: 504 ([[M+H]).
1H-NMR (600 MHz, CDC13) 5 (ppm) ; 1.12 (6 H, d, J=6.9 Hz), 1.56 - 1.76 (2 H, m), 1.78 -
1.96 (2 H, m), 2.38 (1 H, br. s.), 2.56 (1 H, br. s.), 2.61 - 2.69 (3 H, m), 2.74 - 2.90 (4 H, m),
3.94 (3 H, s), 4.07 — 7.10 (1 H,
— 4.20 (1 H, m), 4.64 (2 H, s), 5.40 (1 H, d, J=8.3 Hz), 7.02
m), 7.16 (1 H, dd, J=10.8, 8.5 Hz), 7.22 — 7.33 (4 H, m), 7.78 (2 H, d, J=8.3 Hz).
- Example A-14: 2—[4~ {4—[2-(4—cyanopiperidin—1—yl)ethyl]phenyl}—2-(4—fluor0-3—
yphenyl)—1H—imidazol—1-y1]-N-(propan—2—y1)acetamide
[Chem 239]
MS (ESI pos.) m/z : 504 ([M+H]+).
1H—NMR (600 MHz, CDClg) 5 (ppm) , 1.12 (6 H, d, J=6.9 Hz), 1.84 - 2.02 (4 H, m), 2.42
(2 H, br. 3.), 2.58 — 2.78 (5 H, m), 2.78 - 2.86 (2 H, m), 3.94 (3 H, s), 4.08 - 4.20 (1 H, m),
4.64 (2 H, s), 5.40 (1 H, d, J=7.8 Hz), 6.99 - 7.10 (1 H, m), 7.16 (1 H, dd, J=11.0, 8.3 Hz),
7.22 - 7.34 (4 H, m), 7.77 (2 H, d, J=7.8 Hz).
—157—
- Example A-15: 2—[2—(4—flu0r0-3—methoxyphenyl)—4- {4-[2—(3-hydroxy
azabicyclo[3.2.1]octyl)ethyl]pheny1}-1H-imidazoly1]-N-(propanyl)acetamide
[Chem 240]
:BiWfi
MS (ESI pos.) m/z: 521 ([M+H]).
1H-NMR (500 MHz, CDC13) 5 (ppm) ; 1.12 (6 H, d, J=6.5 Hz), 1.18 - 1.33 (1 H, m), 1.63 -
1.74 (2 H, m), 1.89 - 2.01 (2 H, m), 2.03 - 2.20 (4 H, m), 2.54 ~ 2.68 (2 H, m), 2.78 - 2.89
(2 H, m), 3.22 - 3.31 (2 H, m), 3.94 (3 H, s), 4.05 — 4.10 (1 H, m), 4.10 - 4.20 (1 H, m), 4.65
(2 H, s), 5.35 - 5.46 (1 H, m), 7.02 — 7.09 (1 H, m), 7.17 (1 H, dd, J=10.9, 8.2 Hz), 7.23 - 7.33
(4 H, m), 7.78 (2 H, d, J=8.4 Hz).
- Example A-16: 2-[4-{4-[2-(3—cyanoazetidiny1)ethyl]pheny1}—2—(4—fluoro—3—
methoxyphenyl)-1H-imidazol—1-yl]—N-(propany1)acetamide
[Chem 241]
VH7?
MS (ESI pos.) m/z : 476 ([M+H]+).
1H-NMR (500 MHz, CDC13) 5 (ppm) ; 1.13 (6 H, d, J=6.5 Hz), 2.63 - 2.79 (4 H, m), 3.21 —
3.32 (3 H, m), 3.55 - 3.63 (2 H, m), 3.94 (3 H, s), 4.09 - 4.22 (1 H, m), 4.65 (2 H, s), 5.37 -
.45 (1 H, m), 7.04 — 7.10 (1 H, m), 7.17 (1 H, dd, J=10.7, 8.4 Hz), 7.20 — 7.33 (4 H, m), 7.79
(2 H, d, J=8.0 Hz).
- Example A—17: 2—[2—(4-flu0ro-3~methoxypheny1)—4-{4—[2—(3-methoxypyrrolidin—1—
y1)ethy1]phenyl}- lH-imidazol- 1-yl]-N-(propany1)acetamide
—158-
[ChemH242]
O“?1:;
MS (ESI pos.) m/z: 495 ([M+H]).
1H—NMR (600 MHz, CDC13) 6 (ppm) ; 1.11 (6 H, d, J=6.6 Hz), 1.27 - 1.37 (1 H, m), 1.73 -
1.85 (1 H, m), 1.94 (1 H, d, J=9.5 Hz), 2.08 — 2.25 (2 H, m), 2.55 - 2.67 (2 H, m), 2.68 - 2.77
(1 H, m), 2.78 - 2.89 (2 H, m), 2.97 (1 H, d, J=8.3 Hz), 3.29 — 3.42 (3 H, m), 3.93 (3 H, s),
4.09 - 4.19 (1 H, m), 4.64 (2 H, s), 5.41 (1 H, d, J=7.8 Hz), 7.03 - 7.10 (1 H, m), 7.16 (1 H,
dd, J=10.7, 8.3 Hz), 7.24 (2 H, s), 7.28 — 7.32 (2 H, m), 7.77 (2 H, d, J=8.3 Hz).
' Example A—18: 2-[2-(4-fluoro—3—methoxypheny1)—4-{4-[2-(3-meth0xypiperidin
yl)ethy1]phenyl}-1H-imidazoly1]-N—(propan-Z—y1)acetamide
[Chem 243]
0“?‘q
[0F632] MS (ESI pos.) m/z: 509 ([M+H]).
1H-NMR (600 MHz, CDC13) 5 (ppm) ; 1.12 (6 H, d, J=6.6 Hz), 1.85 (2 H, br. s.), 2.04 - 2.15
(1 H, m), 2.46 - 2.57 (1 H, m), 2.63 — 2.81 (5 H, m), 2.82 — 2.92 (2 H, m), 3.30 (3 H, s), 3.94
(5 H, s), 4.10 — 4.19 (1 H, m), 4.64 (2 H, s), 5.40 (1 H, d, J=7.8 Hz), 7.03 - 7.10 (1 H, m),
7.16 (2 H, dd, , 8.3 Hz), 7.25 (2 H, br. 3.), 7.29 (1 H, dd, J=8.3, 2.1 Hz), 7.77 (2 H, d,
J=8.3 Hz).
- Example A-19: 2-[4- {4- [2—(3 -fluoroazetidin~1—y1)ethy1]pheny1}-2—(4—fluoro
methoxyphenyl)—lH-imidazoly1]-N-(propan—2—y1)acetamide
-159—
[ChemH244]
\Ff."
MS (ESI pos) m/z: 469 ([M+H]).
1H—NMR (600 MHz, CDC13) 8 (ppm) ; 1.12 (6 H, d, J=6.6 Hz), 2.60 - 2.81 (4 H, m), 3.06 —
3.19 (2 H, m), 3.60 — 3.74 (2 H, m), 3.94 (3 H, s), 4.09 - 4.20 (1 H, m), 4.64 (2 H, s), 5.02 -
.20 (1 H, m), 5.40 (1 H, d, J=8.3 Hz), 7.02 — 7.10 (1 H, m), 7.16 (1 H, dd, J=10.7, 8.3 Hz),
7.20 - 7.33 (4 H, m), 7.77 (2 H, d, J=8.3 Hz).
° Example A-20: 2-[4- {4-[2—(2,6—dimethylmorpholin—4-y1)ethy1]pheny1}—2-(4-flu0ro
methoxypheny1)-1H-imidazol-1—y1]-N—(propan-Z-y1)acetamide
[063 5] H.[Chem 245]
MS (ESI pos.) m/z: 509 ([M+H])
1H-NMR (600 MHz, CDC13) 5 (ppm); 1.12 (6 H, d, J=6.6 Hz), 1.18 (6 H, d, J=6.6 Hz), 1.81
(2 H, t, J=10.7 Hz), 2.55 - 2.65 (2 H, m), 2.83 (4 H, d, J=10.3 Hz), 3.66 - 3.77 (2 H, m), 3.94
(3 H, s), 4.10 - 4.20 (1 H, m), 4.64 (2 H, s), 5.40 (1 H, d, J=7.8 Hz), 7.02 — 7.09 (1 H, m),
7.16 (1 H, dd, J=10.7, 8.3 Hz), 7.22 - 7.27 (3 H, m), 7.28 - 7.32 (1 H, m), 7.77 (2 H, d,
J=7.8 Hz).
' Example A-21 : 2-[2-(4-flu0ro—3-methoxypheny1) {4-[2-(3—methylpyrrolidin
y1)ethy1]pheny1}-1H—imidazol—l—y1]—N~(propany1)acetamide
H [Chem 246]
:35“qu
—160-
MS (ESI pos.) m/z : 479 ([M+H]+).
1H-NMR (600 MHz, CDC13) 5 (ppm) ; 1.11 (6 H, d, J=6.6 Hz), 1.94 (2 H, d, J=10.3 Hz), 2.24
(2 H, br. s.), 2.56 - 2.67 (2 H, m), 2.79 - 2.90 (4 H, m), 3.24 (1 H, br. s.), 3.35 (3 H, s), 3.93
(3 H, s), 4.08 - 4.22 (1 H, m), 4.64 (2 H, s), 5.40 (1 H, d, J=7.8 Hz), 7.02 - 7.07 (1 H, m),
7.16 (1 H, dd, J=10.7, 8.3 Hz), 7.22 - 7.31 (4 H, m), 7.77 (2 H, d, J=8.3 Hz).
- Example A-22: 2-[2—(4—fluoro—3—methoxypheny1)-4— {4—[2-(3—oxa-8—azabicyclo[3 .2. 1]oct
y1]phenyl}-1H-imidazol— 1 —y1]-N—(propan—2—y1)acetamide
H [Chem 247]
”30*W”
MS (ESI pos.) m/z : 507 ([M+H]+).
1H—NMR (600 MHz, CDC13) 5 (ppm) ; 1.12 (6 H, d, J=6.4 Hz), 1.82 - 2.00 (4 H, m), 2.49 -
2.60 (2 H, m), 2.77 - 2.88 (2 H, m), 3.06 - 3.17 (2 H, m), 3.49 - 3.58 (2 H, In), 3.69 — 3.81
(2 H, m), 3.94 (3 H, s), 4.07 — 4.24 (1 H, m), 4.65 (2 H, s), 5.36 — 5.48 (1 H, m), 7.01 - 7.11
(1 H, m), 7.17 (1 H, dd, J=11.0, 8.3 Hz), 7.24 - 7.29 (3 H, m), 7.30 (1 H, dd, J=8.0, 2.1 Hz),
7.78 (2 H, d, J=8.3 Hz).
- Example A-23: 2—[2—(4—flu0ro—3~methoxypheny1)—4-{4—[2-(1,4—oxazepan-4—
y1)ethy1]pheny1}- 1H—imidazol- 1-y1]-N-(pr0pan—2—y1)acetamide
H [Chem 248]
MS (ESI pos.) m/z : 495 ([M+H]+).
1H—NMR (600 MHz, CDC13) 5 (ppm) ; 1.12 (6 H, d, J=6.6 Hz), 1.92 (2 H, quin, J=5.8 Hz),
2.73 - 2.87 (8 H, m), 3.72 - 3.78 (2 H, m), 3.82 (2 H, t, J=6.0 Hz), 3.94 (3 H, s), 4.08 — 4.19
(1 H, m), 4.64 (2 H, s), 5.40 (1 H, d, J=8.3 Hz), 7.01 - 7.10 (1 H, m), 7.16(1 H, dd, J=10.7,
8.3 Hz), 7.21 - 7.34 (4 H, m), 7.77 (2 H, d, J=8.3 Hz).
—161-
' Example A—24: 2-[2-(4-flu0r0methoxyphenyl)-4— {4—[2—(4-methoxypiperidin— 1
y1)ethy1]phenyl}-lH-imidazoly1]-N-(propanyl)acetamide
[Chem 249]
[0F644] MS (ESI pos.) m/z: 509 ([M+H]).
1H-NMR (600 MHz, CDCl3) 5 (ppm) ; 1.04 (3 H, s), 1.11 (6 H, d, J=6.6 Hz), 1.37 (1 H, td,
J=12.5, 6.0 Hz), 1.97 — 2.14 (2 H, m), 2.23 - 2.35 (1 H, m), 2.52 (1 H, br. 5.), 2.61 - 2.98 (8 H,
m), 3.93 (3 H, s), 4.08 - 4.20 (1 H, m), 4.64 (2 H, s), 5.41 (1 H, d, J=7.8 Hz), 7.02 - 7.11
(1 H, m), 7.16 (1 H, dd, J=10.7, 8.3 Hz), 7.21 « 7.33 (4 H, m), 7.77 (2 H, d, J=7.8 Hz).
' Example A-25: 2-[4- {4—[2—(3,5—dimethylmorpholin—4-yl)ethyl]pheny1}(4—fluoro—3-
methoxyphenyl)-1H-imidazolyl]-N-(propany1)acetamide
[Chem. 250]
:DZWQD"
MS (ESI pos.) m/z: 509 ([M+H])
1H-NMR (600 MHz, CDClg) 5 (ppm) ; 1.02 — 1.10 (6 H, m), 1.13 (6 H, d, J=6.6 Hz), 2.50 -
2.58 (1 H, m), 2.65 — 2.75 (1 H, m), 2.80 - 2.99 (4 H, m), 3.40 — 3.46 (2 H, m), 3.68 - 3.75
(2 H, m), 3.95 (3 H, s), 4.11 - 4.20 (1 H, m), 4.66 (2 H, s), 5.37 - 5.44 (1 H, m), 7.05 - 7.10
(1 H, m), 7.14 - 7.20 (1 H, m), 7.21 - 7.33 (4 H, m), 7.79 (2 H, d, J=8.3 Hz).
- e A-26: 2—[2-(3-chlor0pheny1) {5-[2-(morpholin—4-y1)ethyl]pyridinyl}
- 1 H-
imidazoly1]-N—(propanyl)acetamide
[Chem 251]
\ NH Nmo
CREE/LN \ / L4
~162-
MS (ESI pos.) m/z : 468 +).
1H-NMR (600 MHz, DMSO-d6) 5 (ppm) ; 1.04 - 1.07 (6 H, m), 3.07 - 3.20 (4 H, m), 3.39 -
3.46 (2 H, m), 3.47 — 3.53 (2 H, m), 3.77 - 3.87 (3 H, m), 3.97 - 4.03 (2 H, m), 4.82 (2 H, s),
7.55 - 7.71 (1 H, m), 7.91 —
— 7.66 (1 H, m), 7.69
— 7.59 (1 H, m), 7.59 — 7.63 (l H, m), 7.63
8.22 (3 H, m), 8.26 - 8.35 (l H, m), 8.50 - 8.61 (1 H, m).
'Example A—27: 3—chlorophenyl){5-[2—(3—oxa~8-azabicyclo[3.2.1]oct—8—
y1]py1'idinyl}~1H—imidazolyl]-N-(propan—2—yl)acetamide
[Chem. 252]
121°
WW”?
MS (ESI pos.) m/z: 494 ([M+H]).
1H-NMR (600 MHz, DMSO-d6) 5 (ppm) ; 1.05 (6 H, d, J=6.6 Hz), 2.02 - 2.06 (2 H, m), 2.18
- 3.86 (1 H, m), 4.01 - 4.06 (2 H,
- 2.23 (2 H, m), 3.27 (4 H, s), 3.71 (2 H, d, J=11.1 Hz), 3.79
m), 4.13 — 7.62 (l H, m), 7.62 - 7.68 (2 H, m), 7.72 (1 H,
- 4.19 (2 H, m), 4.85 (2 H, s), 7.57
s), 8.10 - 8.24 (2 H, m), 8.29 - 8.37 (1 H, m), 8.58 - 8.65 (1 H, m).
'Example A—28: Synthesis of 2-[2—(6—methoxypyridin—2-yl)~4~{4—[2-(piperidin~1—
y1)ethyl]phenyl}—lH-imidazol—1—yl]~N—(propan-2—yl)acetamide
[0651N[Chem 253]
To a CHC13 (4 mL) solution of the compound (90 mg) obtained in Reference
Example P-A16, piperidine (0.06 mL) and acetic acid (0.06 mL) were added and the mixture
was stirred for a while at room temperature; subsequently, sodium triacetoxyborohydride
(136 mg) was added and the mixture was immediately subjected to stirring which continued
overnight. The mixture in an ice bath was then neutralized with a saturated aqueous NaHC03
-l63-
solution and extracted with CHC13. The organic layer was filtered with Phase Separator and
the solvent was distilled off under d pressure. The resulting e was purified by
silica gel column chromatography (SNAP Cartridge HP—Sil 10g; mobile phase:
CHClg/MeOH = 99/1 - 90/10; v/v). The purified product was washed with a mixed solvent
(EtOAc/n—Hexane = 1/6; WW and the solids were recovered by ion to give the titled
compound (20 mg as a colorless solid).
MS (ESI pos.) m/z : 462 ([M+H]+).
1H-NMR (600 MHz, CDCl3) 6 (ppm) ; 0.99 (6 H, d, J=6.4 Hz), 1.42 - 1.51 (2 H, m), 1.61 -
1.68 (4 H, m), 2.44 - 2.54 (4 H, m), 2.56 - 2.63 (2 H, m), 2.82 - 2.88 (2 H, m), 3.95 (3 H, s),
4.03 — 4.11 (1 H, m), 5.28 (2 H, s), 5.57 - 5.64 (1 H, m), 6.72 - 6.78 (1 H, m), 7.24 - 7.28 (3
H, m), 7.68 - 7.73 (1 H, m), 7.79 (2 H, d, J=8.3 Hz), 7.95 — 7.99 (l H, m).
Starting from the compounds obtained in Reference Example P-A16, Reference
Example P-A20 and Reference Example P-A22, the same ure as in Example A—28 was
applied to give the following compounds:
'Example A—29: 2-[2-(6-methoxypyridin—2—yl) {4—[2-(morpholin—4-y1)ethy1]phenyl}-1H-
imidazoly1]-N-(propany1)acetamide
[0653 l [Chem 254]
\ Nmo
/O N\ \N \~_/
MS (ESI pos.) m/z : 464 +).
1H—NMR (600 MHz, CDC13) 6 (ppm) ; 0.99 (6 H, d, J=6.4 Hz), 2.51 - 2.58 (4 H, m), 2.61 —
2.66 (2 H, m), 2.82 — 2.87 (2 H, m), 3.73 — 3.79 (4 H, m), 3.95 (3 H, s), 4.03 - 4.11 (1 H, m),
.28 (2 H, s), 5.60 - 5.65 (1 H, m), 6.75 (1 H, d, J=8.3 Hz), 7.25 - 7.29 (3 H, m), 7.68 - 7.74
(l H, m), 7.80 (2 H, d, J=8.3 Hz), 7.95 - 7.99 (1 H, m).
° Example A-30: 2-[2—(3-chlorophenyl) {6—[2—(morpholiny1)ethy1] pyridinyl} -1H-
imidazol- l —y1]~N—(propan—2—yl)acetamide
~164-
[Chem 255]
MS (ESI pos.) m/z: 468 ([M+H]).
1H-NMR (600 MHz, CDC13) 5 (ppm) ; 1.14 (6 H, d, J=6.4 Hz), 2.55 (4 H, br. s.), 2.77 — 2.82
(2 H, m), 3.00 — 3.04 (2 H, m), 3.73 (4 H, t, J=4.6 Hz), 4.11 - 4.20 (1 H, m), 4.65 (2 H, s),
.36 (1 H, d, J=7.8 Hz), 7.24 (1 H, d, J=8.3 Hz), 7.37 (1 H, s), 7.40 — 7.49 (3 H, m), 7.65
(1 H, s), 8.11 (1 H, dd, J=8.0, 2.1 Hz), 8.92 (1 H, d, J=2.3 Hz).
‘ Example A-31 : 2-[4- {4-[2-(diethy1amino)ethyl]pheny1} -2—(4—fluoro—3—methoxyphenyl)— 1 H—
imidazoly1]—N—(propan-Z-yl)acetamide
H [Chem 256]
:D/LWNC
MS (ESI pos.) m/z: 467 ([M+H]+).
1H-NMR (600 MHz, CDC13) 5 (ppm) ; 1.09 (6 H, t, J=7.0 Hz), 1.12 (6 H, d, J=6.2 Hz), 2.59 -
2.67 (4 H, m), 2.70 - 2.83 (4 H, m), 3.94 (3 H, s), 4.11 —
— 4.20 (1 H, m), 4.65 (2 H, s), 5.38
.45 (1 H, m), 7.04 - 7.09 (1 H, m), 7.17 (1 H, dd, J=11.1, 8.3 Hz), 7.22 - 7.34 (4 H, m), 7.78
(2 H, d, J=8.3 Hz).
- Example A-32: 2-[4—(4— {2—[ethy1(2—meth0xyethy1)amino]ethyl}phenyl)—2-(4—fluoro~3-
methoxyphenyl)- 1 azoly1]-N-(propan~2—y1)acetamide
H [Chem 257]
OD/LWNH0
MS (ESI pos) m/z 497 ([M+H])
1H—NMR (600 MHz, CDC13) 5 (ppm) ; 1.08 (3 H, t, J=7.0 Hz), 1.12 (6 H, d, J=6.6 Hz), 2.64 —
—l65—
2.83 (8 H, m), 3.38 (3 H, s), 3.47 - 3.54 (2 H, m), 3.94 (3 H, s), 4.11- 4.21 (1 H, m), 4.65
(2 H, s), 5.39 - 5.44 (1 H, m), 7.04 - 7.10 (1 H, m), 7.13 - 7.19 (1 H, m), 7.23 - 7.28 (3 H, m),
7.28 - 7.33 (l H, m), 7.78 (2 H, d, J=8.3 Hz).
- Example A-33: Synthesis of 2—[2—(3—chlorophenyl) {4-[2-(piperidin-l-y1) ethoxy]phenyl}—
dazol- l ~yl]—N—(propan—2-yl)acetamide
[Chem 258]
“@895
A mixture of the nd (60 mg) ed in Reference Example P-A24, l-
piperidineethanol (0.06 mL), cyanomethylenetributylphosphorane (94 mg) and toluene
(2.0 mL) was stirred at an external temperature of 90°C for 4 hours under a nitrogen
atmosphere. After leaving the mixture to cool, l—piperidineethanol (0.03 mL) and
cyanomethylenetributylphosphorane (47 mg) were further added and the mixture was stirred
at an al temperature of 90°C for 6 hours. After leaving the mixture to cool, the t
was distilled off under reduced pressure and the resulting residue was purified by column
chromatography (SNAP Cartridge KP—Sil 25g: mobile phase: CHCl3/MeOH = 98/2 — 90/ 10;
V/v). The resulting crudely refined product was washed With EtzO to give the titled
compound (39 mg as a colorless solid).
MS (ESI pos.) m/z : 481 ([M+H]+).
1H-NMR (600 MHz, CDCl3) 5 (ppm) ; 1.13 (6 H, d, J=6.4 Hz), 1.44 - 1.50 (2 H, m), 1.60 -
1.67 (4 H, m), 2.48 — 2.59 (4 H, m), 2.76 - 2.83 (2 H, m), 4.11 - 4.20 (3 H, m), 4.65 (2 H, s),
.36 — 5.42 (1 H, m), 6.94 — 6.99 (2 H, m), 7.22 (1 H, s), 7.38 — 7.47 (3 H, m), 7.66 — 7.69
(1 H, m), 7.75 - 7.80 (2 H, m).
Starting from Reference Example P—A27, the same procedure as in Example A-33
was applied to synthesize the following compounds.
- Example A-34: 3-chlorophenyl)—4—{3—[2—(piperidin—1—yl)ethoxy]phenyl}—1H-imidazol—
1-y1]—N-(propan-2—yl)acetamide
0[663] [Chem 259]
\[f° m3
MS (ESI pos.) m/z : 481 ([M+H]+).
1H—NMR (600 MHZ, CDC13) 5 (ppm); 1.13 (6 H, d, J=6.4 Hz), 1.41 - 1.50 (2 H, m), 1.61 —
1.67 (4 H, m), 2.37 — 2.61 (4 H, m), 2.79 - 2.85 (2 H, m), 4.12 - 4.23 (3 H, m), 4.66 (2 H, s),
.37 - 5.42 (1 H, m), 6.84 — 6.88 (1 H, m), 7.29 — 7.34 (2 H, m), 7.40 - 7.48 (5 H, m), 7.67 —
7.70 (1 H, m).
- e A—35: 2-[2-(3-ch10ropheny1)—4- {3—[3—(piperidin- 1 —y1)propoxy]phenyl}- 1 H-
imidazol-1~y1]-N-(propan~2-y1)acetamide
[Chem 260]
MS (ESI pos.) m/z : 495 ([M+H]+).
1H-NMR (600 MHz, CDC13) 5 (ppm) ; 1.13 (6 H, d, J=6.4 Hz), 1.43 - 1.50 (2 H, m), 1.63 —
1.71 (4 H, m), 2.00 — 2.10 (2 H, m), 2.35 — 2.63 (6 H, m), 4.08 - 4.12 (2 H, m), 4.13 - 4.21
(1 H, m), 4.66 (2 H, s), 5.37 — 5.42 (1 H, m), 6.83 —
- 6.87 (1 H, m), 7.29 - 7.34 (2 H, m), 7.38
7.49 (5 H, m), 7.67 — 7.70 (1 H, m).
le A-36: Synthesis of 2—[2—(3-methoxyphenyl)—5-methy1-4—{4-[2-(morpholin—4-
yl)ethyl]phenyl}-1H-imidazol—1—yl]-N—(propany1)acetamide
[Chem 261]
@123\7/N[40
668 A mixture of the compound (86 mg) obtained1n Reference Example P-A30, 4--(2—
morpholinoethy1)phenylboronic acid (166 mg), Pd(PPh3)4 (54 mg), 2 M NazCO3 aqueous
~167-
solution (0.24 mL) and a mixed t (2.5 mL; toluene /MeOH = 5/3; V/v) was stirred at an
external temperature of 100°C for 17 hours. After leaving the e to cool, 4—(2-
morpholinoethyl)phenylboronic acid (83 mg) and Pd(PPh3)4 (27 mg) were further added and
the mixture was stirred at an external temperature of 100°C for 5 hours. After leaving the
mixture to cool, it was diluted with CHC13 and washed with water. The organic layer was
dried over MgSO4 and subsequently concentrated under reduced pressure. The resulting
residue was d by silica gel (neutral OH form) column chromatography e phase:
CHCl3/MeOH = 97/3 - 90/10; V/V) and washed with IPE to give the titled compound (12 mg
as a colorless solid).
MS (ESI pos.) m/z : 477 ([M+H]+).
1H—NMR (600 MHz, CDC13) 5 (ppm) ; 1.13 (6 H, d, J=6.0 Hz), 2.43 (3 H, s), 248 ~ 2.58
(4 H, m), 2.59 - 2.69 (2 H, m), 2.79 - 2.90 (2 H, m), 3.69 —3.77 (4 H, m), 3.83 (3 H, s), 4.13 -
4.23 (1 H, m), 4.60 (2 H, s), 5.32 - 5.41 (l H, m), 6.92 - 7.16 (3 H, m), 7.21 - 7.30 (2 H, m),
7.31 - 7.41 (1 H, m), 7.59 -7.71 (2 H, m).
Starting from the compounds obtained in Reference Example P—A32, Reference
Example P-A33, Reference Example P-A34, Reference Example P—A35, Reference Example
P—A36, Reference Example P-A43, Reference Example P—A46 and Reference Example P—
A65, the same procedure as in e A—36 was applied to synthesize the following
nds:
- Example A—37: 2-[2-(3-methoxyphenyl) {4—[2—(piperidin— l-yl)ethyl]phenyl}
- 1H-
imidazol-l-yl]~N-(propan-2—yl)acetamide
N[Chem 262]
MS (ESI pos) m/z 461 ([M+H]).
1H—NMR (600 MHz, CDC13) 6 (ppm) ; 1.09 (6 H, d, J=6.4 Hz), 1.45 (1 H, br. s.), 1.53 - 1.67
(5 H, m), 2.39 - 2.53 (4 H, m), 2.52 — 2.62 (2 H, m),2.73 - 2.90 (2 H, m), 3.71 - 3.89 (3 H, m),
4.04 - 4.20 (1 H, m), 4.66 (2 H, s), 5.40 (1 H, d, J=7.8 Hz), 6.95 — 7.02 (1 H, m), 7.07 - 7.20
(2 H, m), 7.18 - 7.29 (3H, m), 7.32 - 7.41 (1 H, m), 7.67 - 7.84 (2 H, m).
' e A-3 8: 2-[2-(3—methoxyphenyl)—4- {4—[2-(morpholinyl)ethyl]phenyl} - 1 H-
imidazolyl]-N-(propan~2~yl)acetamide
[Chem 263]
figiwhlsoYN
MS (ESI pos.) m/z : 463 ([M+H]+).
1H—NMR (600 MHz, .5 (ppm) ; 1.11 (6 H, s), 2.54 (4 H, br. 5.), 2.58 - 2.67 (2 H, m),
2.75 — 2.90 (2 H, m), 3.70 — 3.79 (4 H, m), 3.85 (3 H, s),4.06 — 4.20 (1 H, m), 4.67 (2 H, s),
.40 (l H, d, J=7.8 Hz), 6.93 — 7.03 (1 H, m), 7.09 - 7.19 (2 H, m), 7.22 — 7.29 (3 H, m), 7.32
- 7.42 (1 H, m), 7.71 - 7.87 (2H, m).
- Example A-39: 2—[2—(3—chlor0—4-fluorophenyl)—4— {4-[2-(m0rpholin-4—yl)ethyl]phenyl}
- 1 H—
imidazol-1—y1]—N—(propanyl)acetamide
[Chem 264]
CFDEWNMYNF) \~—/0
MS (ESI pos.) m/z: 485 ([M+H]+.)
1H—NMR (600 MHz, CDC13) 5 (ppm) ; 1.13 (6 H, d, J=6.4 Hz), 2.54 (4 H, br. s.), 2.59 — 2.68
(2 H, m), 2.76 - 2.89 (2 H, m), 3.67 - 3.81 (4 H, m),4.09 — 4.22 (1 H, m), 4.62 (2 H, s), 5.37
(1 H, d, J=7.8 Hz), 7.14 - 7.34 (4 H, m), 7.40 - 7.51 (1 H, m), 7.63 - 7.84 (3 H, m).
- Example A—40: 2—[2—(5—meth0xypyridin-3—y1)—4- {4—[2-(m0rpholin—4—y1)ethy1]phenyl}
— 1H—
imidazol-l-yl]-N—(propany1)acetamide
—169-
[ChemH 265]
Y:j’
(DU/”(WWL40
MS (ESI pos.) m/z: 464 ([M+H]).
1H—NMR (600 MHz, CDC13) 5 (ppm) ; 1.12 (6 H, d, J=6.4 Hz), 2.54 (4 H, br. s.), 2.58 — 2.66
(2 H, m), 2.78 — 2.90 (2 H, m), 3.71 - 3.78 (4 H, m),3.91 (3 H, s), 4.08 - 4.20 (1 H, m), 4.66
(2 H, s), 5.39 (1 H, d, J=7.8 Hz), 7.21 — 7.29 (2 H, m), 7.32 (1 H, s), 7.47 — 7.52 (1 H, m),
7.74 — 7.80 (2 H, m), 8.36 —8.45 (2 H, m).
- Example A-41 : 2-[2—(2-methoxypyridiny1) {4-[2-(morpholiny1)ethyl]pheny1} - 1H—
imidazolyl]—N-(propany1)acetamide
[Chem 266]
\rnfo
/o \ NWNCO
MS (ESI pos.) m/z : 464 ([M+H]+).
1H—NMR (600 MHz, CDCng 5 (ppm) ; 1.11 (6 H, d, J=6.4 Hz), 2.54 (4 H, br. s.), 2.59 — 2.65
(2 H, m), 2.80 — 2.89 (2 H, m), 3.71 — 3.78 (4 H, m),3.98 (3 H, s), 4.10 - 4.20 (1 H, m), 4.70
(2 H, s), 5.35 (1 H, d, J=8.3 Hz), 6.98 (1 H, s), 7.12 - 7.17 (1 H, m), 7.23 - 7.28 (2 H, m),
7.31 (1 H, s), 7.77 (2 H, d, J=8.3 Hz), 8.26 (1 H, d, J=5.0 Hz).
- e A-42: 2-[2-(3~methoxypheny1)-4~ {4—[2—(3~0xa—8—azabicyclo[3.2. 1]oct-8—
yl)ethy1]pheny1}-1H-imidazol-1~y1]~N—(propany1)acetamide
N [Chem 267]
MS (ESI pos.) m/z: 489 ([M+H])
lH-NMR (600 MHz, CDC13) 8 (ppm) ; 1.11 (6 H, d, J=6.6 Hz), 1.84 — 1.97 (4 H, m), 2.51 —
-170—
2.59 (2 H, m), 2.79 - 2.85 (2 H, m), 3.11 (2 H, br. 3.), 3.53 (2 H, d, J=9.1 Hz), 3.75 (2 H, d,
J=10.3 Hz), 3.86 (3 H, s), 4.10 - 4.20 (1 H, m), 4.68 (2 H, s), 5.36 - 5.43 (1 H, m), 6.97 - 7.04
(1 H, m), 7.13 (1 H, d, J=7.4 Hz), 7.16 - 7.20 (1 H, m), 7.23 - 7.30 (3 H, m), 7.38 (1 H, t,
J=8.1 Hz), 7.79 (2 H, d, J=7.8 Hz).
- Example A-43: 2-[2—(3~chloropheny1) {2-fluoro—4—[2-(morpholin-4—yl)ethyl]pheny1}— 1H—
imidazol-l-yl]—N-(propan-2—y1)acetamide
[Chem 268]
13:Y”To N/“WO
MS (ESI pos.) m/z: 485 ([M+H]+).
1H-NMR (600 MHz, CDC13) 8 (ppm) ; 1.12 (6 H, d, J=6.6 Hz), 2.53 (4 H, br. s.), 2.60 - 2.65
(2 H, m), 2.80 - 2.85 (2 H, m), 3.74 (4 H, t, J=4.5 Hz), 4.10 - 4.19 (1 H, m), 4.65 (2 H, s),
.42 (1 H, d, J=7.8 Hz), 6.99 (1 H, dd, J=12.2, 1.4 Hz), 7.07 (1 H, dd, J=8.1, 1.4 Hz), 7.38 —
7.50 (4 H, m), 7.66 — 7.69 (1 H, m), 8.15 (1 H, t, J=8.1Hz).
' Example A-44: 3~chlorophenyl)-4— {4-[2-(morpholiny1)propy1]pheny1}— 1H—
imidazol-l-yl]-N—(propan—Z—y1)acetamide
[Chem 269]
‘7’”f0
QUE}? N/“xo
[]0684 MS (ESI pos) m/z: 481 ([M+H])
1H-NMR (600 MHz, CD013) 5 (ppm) ; 0.98 (3 H, d, J=6.6 Hz), 1.12 (6 H, d, J=6.6 Hz), 2.42
- 3.05 (1 H, m), 3.71 - 3.77
- 2.48 (1 H, m), 2.59 - 2.65 (4 H, In), 2.76 - 2.83 (1 H, m), 2.99
(4 H, m), 4.10 — 4.20 (1 H, m), 4.65 (2 H, s), 5.38 (1 H, d, J=7.8 Hz), 7.22 (2 H, d, J=8.3 Hz),
7.29 (1 H, s), 7.38 - 7.47 (3 H, m), 7.67 (1 H, t, 1=1.7 Hz), 7.75 - 7.79 (2 H, m).
-171—
'Example A-45: Synthesis of 2—[2-(3—chlorophenyl) {4-[2-(morpholinyl)ethy1]
oxopyridin-l (2H)-yl}—1H—imidazolyl]-N—(propanyl)acetamide
H [Chem 270]
c\[7303:A~;\>‘
\ NL/0
A mixture in DMF (8.0 mL) of the compound (481 mg) obtained in Reference
Example P—A36, the compound obtained in nce Example P-A69, copper iodide
(52 mg), tripotassium phosphate (516 mg) and 4,7—dimethoxy—1,10-phenanthroline (98 mg)
was stirred at an external temperature of 100°C for 2 days. After leaving the mixture to cool,
it was purified by reverse—phase column chromatography (mobile phase: 0.1% TFA
MeCN/H20 = 10/90 - 90/10; v/V). The fractions were neutralized with a saturated aqueous
NaHC03 solution, extracted with CHCl3 and filtered with Phase Separator. The solvent was
distilled off under reduced pressure to give the titled compound (155 mg as a colorless solid).
MS (ESI pos.) m/z : 484 ([M+H]+).
1H—NMR (600 MHz, CDC13) 5 (ppm) ; 1.13 (6 H, d, J=6.6 Hz), 2.32 - 2.90 (8 H, m), 3.73
(4 H, br. s.), 4.05 - 4.22 (1 H, m), 4.65 (2 H, s), 5.49 (1 H, d, J=7.4 Hz), 6.25 (1 H, d, J=7.4
Hz), 6.49 (1 H, s), 7.36 — 7.51 (3 H, m), 7.66 (1 H, t, J=1.7 Hz), 8.03 (1 H, s), 8.54 (1 H, d,
J=7.0 Hz).
- Example A-46: Synthesis of 2—[2-(3-chlorophenyl)—4- {4—[2-(morpholin—4—yl)ethyl]~2-
oxopiperazin- 1 ~yl} — l H-imidazol- 1 —yl] —N-(propan—2-yl)acetamide
[Chem 271]
\r” o
or\Q/LQ‘NEDNfNL/O
A mixture of the nd (100 mg) obtained in nce Example P-A3 7, 4-(2-
chloroethyl)morpholine hydrochloride (52 mg), t (0.14 mL) and MeCN (2.0 mL) was
stirred overnight at an al ature of 100°C. After leaving’the mixture to cool, the
—172-
solvent was distilled off under reduced pressure. The resulting e was purified by silica
gel column chromatography (SNAP Cartridge HP-Sil 10g; mobile phase: CHClg/MeOH =
98/2 - 90/10; v/v); and after washing with a mixed t (EtOAc/n-Hexane = 1/6; V/V), the
solids were recovered by filtration to give the titled compound (25 mg as a colorless solid).
MS (ESI pos.) m/z : 489 ([M+H]+).
1H-NMR (600 MHz, CDC13) 5 (ppm) ; 1.13 (6 H, d, J=6.6 Hz), 2.52 (4 H, br. 3.), 2.55 - 2.60
(2 H, m), 2.63 - 2.68 (2 H, m), 2.87 - 2.92 (2 H, m), 3.40 (2 H, s), 3.69 - 3.77 (4 H, m), 4.07 -
4.18 (3 H, m), 4.61 (2 H, s), 5.37 — 5.43 (1 H, m), 7.37 — 7.43 (3 H, m), 7.59 — 7.63 (1 H, m),
7.69 (1 H, s).
' Example A—47: Synthesis of 2-(3-chlorophenyl)-N-[4—(morpholin—4-yl)cyclohexy1]-1—[2-
oxo—2—(propanylamino)ethyl]-1H—imidazolecarboxamide
[Chem 272]
\rme
ULN H NQNCO
Starting from the compound (61 mg) obtained in Reference Example P—A3 9, the
same procedure as in Example A—28 was applied to give the titled nd (45 mg as a
colorless solid).
MS (ESI pos.) m/z : 488 ([M+H]+).
1H-NMR (600 MHz, CDClg) 6 (ppm) ; 1.14 (6 H, d, J=6.6 Hz), 1.23 — 1.61 (3 H, m), 1.64 —
1.77 (4 H, m), 1.85 — 2.03 (2 H, m), 2.12 - 2.21 (1 H, m), 2.47 — 2.61 (4 H, m), 3.73 (4 H, br.
s.), 4.09 ~ 4.22 (2 H, m), 4.56 — 4.62 (2 H, m), 5.27 - 5.35 (1 H, m), 7.39 - 7.50 (3 H, m), 7.59
- 7.66 (2 H, m).
' Example A-48: Synthesis of 2-(3-chlorophenyl)-N—methyl-N—[4-(morpholin
yl)cyclohexyl][2-ox0(propanylamino)ethyl]—1H-imidazole—4-carboxamide
~173—
[Chem 273]
CifiMO‘NC/oN \ o
Starting from the compound (105 mg) obtained in nce Example P-A40, the
same ure as in Example A—28 was applied to give the titled compound (56 mg as a
colorless solid).
MS (ESI pos.) m/Z ; 502 ([M+H]+).
1H-NMR (600 MHz, CDCl3) 5 (ppm) ; 1.14 (6 H, d, J=6.6 Hz), 1.36 — 1.69 (6 H, m), 1.84 -
2.19 (4 H, m), 2.45 (2 H, br. s.), 2.57 (2 H, br. s.), 2.93 - 3.05 (1 H, m), 3.36 (1 H, br. s.), 3.67
- 3.79 (4 H, m), 4.08 - 4.18 (1 H, m), 4.63 (2 H, d, J=12.0 Hz), 7.37 - 7.49 (3 H, m), 7.58 -
7.66 (2 H, m).
- Example A—49: Synthesis of 2-[2-(3-chloropheny1)—4-( {3-[2-(morpholin
y1)ethyl]pyrrolidinyl } carbonyl)- 1 H—imidazol— 1 -yl] -N-(propanyl)acetamide
[Chem 274]
Starting from the compound (98 mg) obtained in Reference Example P-A4l, the
same procedure as in Example A~01 was d to give the titled compound (50 mg as a
ess amorphous product).
MS (1331 pos.) m/z 2 488 ([M+H]+).
1H-NMR (600 MHz, CDCl3) 5 (ppm) ; 1.13 (6 H, d, J=6.6 Hz), 1.50 - 1.72 (5 H, m), 2.04 -
2.30 (2 H, m), 2.35 - 2.52 (4 H, m), 3.19 - 3.63 (1 H, m), 3.66 - 3.84 (5 H, m), 3.86 - 4.00
(1 H, m), 4.08 - 4.17 (1 H, m), 4.30 - 4.46 (1 H, m), 4.63 (2 H, s), 5.65 - 5.78 (1 H, In), 7.37 -
7.50 (3 H, m), 7.64 (1 H, s), 7.71 (1 H, 8).
Starting from the compound obtained in Reference Example P-B02, together with
-l74-
the compound obtained in nce Example P—A43, 4~(2—m01pholinoethyl)phenylboronic
acid, and 4-(4-methy1piperaziny1methyl)benzeneboronic acid l ester, the same
procedure as in Example A-36 was applied to synthesize the following compounds:
- Example B—Ol: 2-[5—(3—chlorophenyl)—3— {4-[2—(3—oxaazabicyclo[3 .2. 1]oct
yl)ethyl]phenyl}—1H-l,2,4—triazol—1-yl]-N—(propan—2—yl)acetamide
[Chem 275]
MS (ESI pos.) m/z : 494 ([M+H]+).
1H-NMR (600 MHz, CDCl3) 5 (ppm) ; 1.17 (6 H, d, J=6.6 Hz), 1.85 - 1.97 (4 H, m), 2.54 -
2.60 (2 H, m), 2.83 - 2.88 (2 H, m), 3.11 (2 H, br. s.), 3.54 (2 H, d, J=9.1 Hz), 3.75 (2 H, d,
J=10.3 Hz), 4.11 - 4.18 (1 H, m), 4.85 (2 H, s), 6.15 - 6.20 (1 H, m), 7.34 (2 H, d, J=7.8 Hz),
7.46 - 7.50 (1 H, m), 7.51 — 7.55 (1 H, m), 7.55 - 7.58 (1 H, m), 7.78 - 7.80 (1 H, m), 8.09
(2 H, d, J=8.3 Hz).
'Example B-02: 2-[5-(3-chlorophenyl)—3—{4~[2-(morpholin—4-yl)ethyl]phenyl}—1H-1,2,4-
triazol—1-yl]-N-(propan—2—yl)acetamide
[Chem 276]
MS (ESl pos.) m/z : 468 ([M+H]+).
1H—NMR (600 MHz, CDC13) 5 (ppm) ; 1.16 (6 H, d, J=6.6 Hz), 2.52 — 2.57 (4 H, m), 2.62 -
2.68 (2 H, m), 2.85 — 2.90 (2 H, m), 3.75 (4 H, t, J=4.5 Hz), 4.11 — 4.17 (1 H, m), 4.85 (2 H,
s), 6.14 - 6.19 (1 H, m), 7.31 - 7.34 (2 H, m), 7.46 - 7.50 (1 H, m), 7.51 - 7.53 (1 H, m), 7.54 -
7.57 (1 H, m), 7.77 - 7.79 (1 H, m), 8.08 (2 H, d, J=8.3 Hz).
- Example B—03: 2-[5—(3-chlorophenyl)~3
- {4-[(4—methylpiperazin- 1—y1)methyl]pheny1}-1H-
-l75—
1 ,2,4-triazol—1 ~yl]—N—(propanyl)acetamide
[Chem 277]
Y”To /
MS (ESI pos.) m/z: 467 ([M+H]+).
1H-NMR (600 MHz, DMSO-d6) 5 (ppm) ; 1.08 (6 H, d, J=6.6 Hz), 2.15 (3 H, s), 3.50 (2 H,
s), 3.81 — 3.88 (l H, m), 4.93 (2 H, s), 7.40 (2 H, d, J=8.3 Hz), 7.58 — 7.62 (1 H, m), 7.63 —
7.66 (l H, m), 7.76 - 7.79 (1 H, m), 7.83 - 7.85 (l H, m), 7.98 (2 H, d, J=8.3 Hz), 8.34 (1 H,
d, J=7.4 Hz).
- Example B-04: Synthesis of 2—[5-(3-chlorophenyl)-3—{5-[2—(3-oxa-8—azabicyclo[3.2. 1]oct
yl)ethyl]pyridin—2—yl}—1H—1,2,4-triazol-l-yl]-N-(propan—2-yl)acetamide
[Chem. 278]
A mixture of the compound (99 mg) obtained in Reference Example P-A62, the
compound (70 mg) obtained in Reference Example P-B04, Pd(PPh3)4 (23 mg) and DMF
(3.0 mL) was stirred at an al ature of 95°C for 3 hours under a nitrogen
atmosphere. After leaving the mixture to cool, Pd(PPh3)4 (23 mg) was r added and the
mixture was stirred at an external temperature of 95°C for 4 hours. After g the mixture
to cool, Pd(PPh3)4 (23 mg) was further added and the mixture was stirred at an external
temperature of 95°C for 2 days. After leaving the mixture to cool, water and a saturated
aqueous NaHC03 solution were added and extraction was conducted with CHC13. The
organic layer was filtered with Phase Separator and the t was distilled off under
reduced pressure. The resulting e was purified by silica gel column chromatography
(SNAP Cartridge HP-Sil 50g; mobile phase: CHClg/MeOH = 98/2 - 85/15; v/V). The purified
product was washed with EtzO to give the titled compound (27 mg as a colorless solid).
—176-
MS (ESI pos.) m/z : 495 +).
1H-NMR (600 MHz, CDC13)5 (ppm) ; 1.16 (6 H, d, J=6.6 Hz), 1.86 - 1.94 (4 H, m), 2.55 -
2.60 (2 H, m), 2.82 - 2.87 (2 H, m), 3.08 (2 H, br. s.), 3.53 (2 H, d, J=9.1 Hz), 3.72 (2 H, d,
J=10.3 Hz), 4.11 - 6.02 (1 H, In), 7.46 - 7.51
- 4.18 (1 H, m), 4.92 (2 H, s), 5.96 (1 H, m),
7.52 - 7.55 (1 H, m), 7.62 — 7.66 (1 H, m), 7.70 - 7.74 (1 H, m), 7.86 — 7.89 (1 H, m), 8.15
(1 H, d, J=7.8 Hz), 8.66 (1 H, d, J=l.7 Hz).
Starting from the compounds obtained in Reference Example P-A60, Reference
Example P-A62, Reference Example P—B02, Reference Example P-BO3, Reference Example
P-B04, Reference Example P-B05, Reference Example P—B07 and nce Example P-
308, the same procedure as in e B-04 was applied to synthesize the following
compounds .
- Example B-05: 2-[5—(3—methoxyphenyl)-3—{5-[2-(3-0xaazabicyclo[3.2.1]0ct—8—
yl)ethy1]pyridin-2—y1}-1H-1,2,4-triazol—1—yl]—N—(propany1)acetamide
[Chem 279]
1:5 :7. me
MS (ESI pos.) m/z : 491 ([M+H]+).
1H-NMR (600 MHz, CDCl3) 5 (ppm) ; 1.14 (6 H, d, J=6.6 Hz), 1.91 (4 H, br. s.), 2.49 — 2.61
(2 H, m), 2.84 (2 H, t, J=7.4 Hz), 3.08 (2 H, br. s.), 3.52 (2 H, d, J=10.7 Hz), 3.71 (2 H, d,
J=9.9 Hz), 3.88 (3 H, s), 4.07 — 4.19 (1 H, m), 4.93 (2 H, s), 6.03 (1 H, d, J=9.5 Hz), 7.02 —
7.12 (1 H, m), 7.28 — 7.35 (2 H, m), 7.39 - 7.49 (1 H, m), 7.71 (1 H, d, J=9.9 Hz), 8.16 (1 H,
d, J=8.3 Hz), 8.66 (1 H, s).
- Example B-06: 2—[5-(4-fluoro-3~methoxyphenyl)—3— {5-[2—(3~oxaazabicyclo[3 .2. 1]oct
y1)ethyl]pyridinyl}-1H-1,2,4-triazoly1]-N-(propanyl)acetamide
-177~
611::
MS (ESI pos.) m/z: 509 ([M+H]).
1H-NMR (600 MHz, CDC13) 8 (ppm) ; 1.16 (6 H, d, J=6.2 Hz), 1.83 — 1.97 (4 H, m), 2.51 -
2.61 (2 H, m), 2.81 — 2.88 (2 H, m), 3.08 (2 H, br. 3.), 3.53 (2 H, d, J=9.9 Hz), 3.71 (2 H, d,
J=10.3 Hz), 3.98 (3 H, s), 4.09 - 4.18 (1 H, m), 4.91 (2 H, s), 6.02 - 6.12 (1 H, m), 7.23 (1 H,
dd, J=10.7, 8.3 Hz), 7.29 — 7.33 (1 H, m), 7.48 (1 H, dd, J=7.8, 2.1 Hz), 7.69 - 7.75 (1 H, m),
8.15 (1 H, d, J=7.8 Hz), 8.66 (1 H, d, J=2.1 Hz).
' Example B-07: N-tert-buty1[5—(3—methoxypheny1)—3-{5-[2—(3—oxa
yclo[3.2.1]cot—8—y1)ethy1]pyridiny1}-1H—1,2,4-triazoly1]acetamide
H.[Chem 281]
11::
01’H51W
MS (ESI pos.) m/z: 505 ([M+H])
1H—NMR (600 MHz, CDC13) 5 (ppm) ; 1.34 (9 H, s), 1.90 (4 H, br. s.), 2.56 (2 H, t,
J=7.6 Hz), 2.84 (2 H, t, J=7.4 Hz), 3.07 (2 H, br. 3.), 3.52 (2 H, d, J=9.1 Hz), 3.71 (2 H, d,
J=10.3 Hz), 3.88 (3 H, s), 4.87 (2 H, s), 6.05 (1 H, s), 7.08 (1 H, dd, J=8.3, 2.5 Hz), 7.28 -
7.34 (2 H, m), 7.44 (1 H, t, J=7.8 Hz), 7.70 (1 H, dd, J=8.1, 1.9 Hz), 8.16 (1 H, d, J=8.3 Hz),
8.65 (1 H, d, J=2.1 Hz).
- Example B-O8: 2-[5-(3-ch10ro-4—fluoropheny1)—3—{5-[2-(3-oxa—8-azabicyclo[3.2. 1]0ct—8-
yl)ethy1]pyridin—2—y1}-1H—1,2,4-triazoly1]—N-(propanyl)acetamide
—178-
[Chem 282]
0:01;-N {k/ Nfo
MS (ESI pos.) m/z : 513 ([M+H]“).
1H-NMR (600 MHz, CDC13) 8 (ppm) ; 1.16 (6 H, d, J=6.6 Hz), 1.90 (4 H, s), 2.56 (2 H, t,
J=7.4 Hz), 2.84 (2 H, t, J=7.6 Hz), 3.07 (2 H, br. s.), 3.52 (2 H, dd, J=10.5, 1.9 Hz), 3.70
(2 H, d, J=10.3 Hz), 4.05 - 4.18 (1 H, m), 4.89 (2 H, s), 6.03 (1 H, d, J=7.8 Hz), 7.31 (1 H, t,
J=8.5 Hz), 7.64 — 7.74 (2 H, m), 7.98 (1 H, dd, J=7.0, 2.1 Hz), 8.13 (1 H, d, J=7.8 Hz), 8.65
(1 H, d, J=1.7 Hz).
- Example B-09: N—tert—butyl—2—[5-(3-ch10r0pheny1)~3-{5-[2—(3-oxaazabicyclo[3.2.1]oct
y1)ethyl]pyridin—2—y1}—1H-1,2,4-triazoly1]acetamide
[Chem 283]
>FNf°
MS (ESI pos.) m/z: 509 ([M+H])
1H-NMR (600 MHz, CDC13) 8 (ppm) ; 1.35 (9 H, s), 1.91 (4 H, br. s.), 2.57 (2 H, t,
J=7.6 Hz), 2.84 (2 H, t, J=7.2 Hz), 3.08 (2 H, br. s.), 3.53 (2 H, d, J=10.7 Hz), 3.71 (2 H, d,
J=9.9 Hz), 4.86 (2 H, s), 6.00 (1 H, br. s.), 7.40 - 7.58 (2 H, m), 7.60 — 7.76 (2 H, m), 7.86
(1 H, s), 8.14 (1 H, d, J=8.3 Hz), 8.65 (1 H, s).
- Example B-10: 2-[5—(3-ch10r0phenyl)-3
- {5—[2-(morpholin-4—y1)ethy1]pyridin- ~2-y1} ~1H—
1,2,4-triazoly1]-N—(propany1)acetamide
H [Chem 284]
V“f0
CED/NS N/jo
—179—
MS (ESI pos.) m/z : 469 ([M+H]+).
1H-NMR (600 MHz, CDC13) 8 (ppm) ; 1.16 (6 H, d, J=6.6 Hz), 2.95 (2 H, br. s.), 3.20 - 3.29
(2 H, m), 3.35 - 3.46 (2 H, m), 3.56 (2 H, br. s.), 3.93 - 4.18 (3 H, m), 4.26 (2 H, br. s.), 4.92
(2 H, s), 6.07 (1 H, d, J=7.0 Hz), 7.45 - 7.58 (2 H, m), 7.65 (1 H, d, J=7.8 Hz), 7.77 - 7.90
(2 H, m), 8.21 (1 H, d, J=8.3 Hz), 8.64 (1 H, s).
- Example B-1 1 : N—tert-buty1—2-[5-(3-ch10ropheny1)—3- {5—[2-(morpholin—4-yl)ethy1]pyridin
y1}—1H-1,2,4-triazolyl]acetamide
[Chem 285]
C©1WLJO#NToWNW
MS (ESI pos.) m/z: 483 ([M+H])
1H-NMR (600 MHz, CDC13) 8 (ppm) ; 1.33 (9 H, s), 2.52 (4 H, br. s.), 2.58 - 2.69 (2 H, m),
2.81 - 2.90 (2 H, m), 3.72 (4 H, t, J=4.7 Hz), 4.84 (2 H, s), 5.97 (1 H, s), 7.44 - 7.53 (2 H, m),
7.59 - 7.70 (2 H, m), 7.84 (1 H, t, J=1.9 Hz), 8.13 (1 H, d, J=7.8 Hz), 8.61 (1 H, d, J=2.1 Hz).
- e B-12: 2-[5-(3—chloro—4-fluoropheny1){5-[2—(morpholinyl)ethy1]pyridin—2-
y1}—1H-1,2,4-triazol—1~y1]~N—(propan-2—y1)acetamide
[Chem 286]
Y”f0N»N
‘11:“ Nffio
MS (ESI pos.) m/z: 487 ([M+H]).
1H-NMR (600 MHZ, CDC13) 5 (ppm) ; 1.16 (6 H, d, J=6.6 Hz), 2.53 (4 H, br. s.), 2.65 (2 H, t,
J=7.6 Hz), 2.87 (2 H, t, J=7.6 Hz), 3.73 (4 H, t, J=4.3 Hz), 4.07 - 4.17 (1 H, m), 4.89 (2 H, s),
6.01 (1 H, d, J=8.7 Hz), 7.31 (1 H, t, J=8.7 Hz), 7.64 - 7.73 (2 H, m), 7.98 (1 H, dd, J=6.8,
2.3 Hz), 8.13 (1 H, d, J=7.8 Hz), 8.63 (1 H, d, J=1.7 Hz).
- Example B-13: 2-[5-(4—flu0ro—3-rneth0xypheny1)-3—{5—[2-(morph01in-4—y1)ethyl]pyridin- 2—
~180-
yl}-1H-1,2,4-triazol—1~y1]—N—(propan—2—yl)acetamide
[Chem 287]
MS (ESI pos.) m/z : 483 ([M+H]+).
1H—NMR (600 MHz, CDC13) 8 (ppm) ; 1.15 (6 H, d, J=6.6 Hz), 2.53 (4 H, br. s.), 2.65 (2 H, t,
J=7.6 Hz), 2.88 (2 H, t, J=7.6 Hz), 3.74 (4 H, t, J=4.5 Hz), 3.97 (3 H, s), 4.12 (1 H, dq,
J=13.5, 6.6 Hz), 4.91 (2 H, s), 6.01 -
- 6.13 (1 H, m), 7.23 (1 H, dd, J=10.5, 8.5 Hz), 7.28
7.35 (1 H, m), 7.47 (1 H, dd, J=7.8, 1.7 Hz), 7.69 (1 H, dd, J=8.1, 1.9 Hz), 8.15 (1 H, d,
J=8.3 Hz), 8.63 (1 H, d, J=2.1 Hz).
- e B-14: N—tert-butyl-Z-[S-(3~methoxyphenyl)-3— {5—[2-(morpholin
yl)ethy1]pyridin— 2—y1}-1H-1,2,4—triazoly1]acetamide
H [Chem 288]
MS (ESI pos.) m/z : 479 ([M+H]+).
1H-NMR (600 MHz, CDC13) 8 (ppm) ; 1.34 (9 H, s), 2.54 (4 H, br. s.), 2.61 — 2.69 (2 H, m),
2.84 — 2.90 (2 H, m), 3.74 (4 H, t, J=4.7 Hz), 3.87 (3 H, s), 4.87 (2 H, s), 6.04 (1 H, s), 7.08
(1 H, dd, J=8.9, 3.1 Hz), 7.28 - 7.35 (2 H, m), 7.40 - 7.47 (1 H, m), 7.68 (1 H, dd, J=8.1,
2.3 Hz), 8.16 (1 H, d, J=8.3 Hz), 8.63 (1 H, d, J=2.1 Hz).
'Example B—15: Synthesis of 2-[5—(3~methoxypheny1)—3—{5-[2-(morpholin
y1)ethy1]pyridiny1}—1H—1,2,4-triazol—1—y1]-N-(propan-2—yl)acetamide
[Chem 289]
°©*W'C"
~181—
A mixture of the compound (100 mg) obtained in Reference ExampleP-B04,
hexamethylditin (370 mg), Pd(PPh3)4 (33 mg) and toluene (3.0 mL) was stirred at an external
temperature of 100°C for 3 days. After leaving the mixture to cool, water was added and
extraction was conducted with EtOAc. The organic layer was washed with Brine and dried
over NaZSO4; subsequently, the desiccant was filtered off and the solvent was distilled off
under reduced pressure.
A mixture of the resulting residue, the compound (95 mg) obtained in Reference
Example P-A59, Pd(PPh3)4 (80 mg) and DMF (2.5 mL) was stirred at an al temperature
of 95°C for 2 days. After leaving the mixture to cool, water and a saturated aqueous
NaHCO3 solution were added and extraction was conducted with CHCl3. The c layer
was washed with Brine and d with Phase Separator; subsequently, the solvent was
led off under reduced re. The resulting residue was purified by silica gelcolumn
chromatography (SNAP Cartridge HP-Sil; mobile phase: CHClg/MeOH = 98/2 — 85/ 15; v/v).
The d t was washed with a mixed solvent (EtOAc/n-Hexane = 1/4; v/v) to give
the titled compound (68 mg as a colorless solid).
MS (ESI pos.) m/z : 465 ([M+H]+).
1H—NMR (600 MHz, CDC13) 6 (ppm) ; 1.14 (6 H, d, J=6.6 Hz), 2.53 (4 H, br. s.), 2.60 — 2.70
(2 H, m), 2.82 — 2.91 (2 H, m), 3.74 (4 H, t, J=4.5 Hz), 3.87 (3 H, s), 4.07 — 4.19 (1 H, m),
4.93 (2 H, s), 6.04 (1 H, d, J=7.4 Hz), 7.04 - 7.11 (1 H, m), 7.27 — 7.35 (2 H, m), 7.44 (1 H, t,
J=7.8 Hz), 7.68 (1 H, dd, J=8.3, 2.1 Hz), 8.16 (1 H, d, J=8.3 Hz), 8.63 (1 H, d, J=1.7 Hz).
ng from the compound obtained in Reference Example P~B04, together with 4-
(4—bromophenethyl)morpholine, Reference Example P-A42, Reference Example P-A45,
Reference Example P-A49 and Reference Example P—A64, the same procedure as in
Example B—15 was d to synthesize the following compounds.
' Example B-16: 2-[5-(3-methoxyphenyl)—3—{4—[2-(morpholinyl)ethyl]pheny1}-1H-1,2,4-
triazoly1]-N-(propan-Z-yl)acetamide
—182—
[Chem 290]
MS (ESI pos.) m/z : 464 +).
1H—NMR (600 MHz, CDC13) 5 (ppm) ; 1.10 — 1.18 (6 H, m), 2.55 (4 H, br. s.), 2.62 — 2.68
(2 H, m), 2.83 - 2.91 (2 H, m), 3.75 (4 H, t, J=4.5 Hz), 3.81 - 4.18 (1 H,
— 3.90 (3 H, m), 4.07
m), 4.76 (2 H, s), 6.19 (1 H, d, J=7.0 Hz), 7.00 - 7.10 (1 H, m), 7.14 - 7.25 (2 H, m), 7.32
(1 H, d, J=7.8 Hz), 7.42 - 7.47 (1 H, m), 8.06 (1 H, s), 8.10 (2 H, d, J=8.3 Hz).
' Example B~17: 2—[5-(3-methoxypheny1)-3— {4—[2—(3—oxa—8—azabicyclo[3.2.1]oct—8—
y1)ethyl]pheny1}—1H-1,2,4-triazol—1—yl]-N-(propan—Z—y1)acetamide
[Chem 291]
MS (ESI pos.) m/z : 490 ([M+H]+).
1H—NMR (600 MHz, CDC13) 5 (ppm); 1.17 (1 H, d, J=6.6 Hz), 1.83 — 1.98 (4 H, m), 2.54 —
2.61 (2 H, m), 2.82 — 3.78
- 2.89 (2 H, m), 3.08 - 3.15 (2 H, m), 3.52 - 3.57 (2 H, m), 3.72
(2 H, m), 3.88 (3 H, s), 4.11 - 7.11
— 4.18 (1 H, m), 4.87 (2 H, s), 6.17 — 6.23 (1 H, m), 7.06
(1 H, m), 7.22 - 7.26 (2 H, m), 7.31 - 8.13 (2 H,
- 7.36 (2 H, m), 7.42 - 7.46 (1 H, m), 8.08
- Example B—18: 2-[3- {2—fluoro-4—[2-(morpholin-4—yl)ethyl]pheny1}(3-methoxypheny1)—
1H-1,2,4-triazoly1]-N—(propan—Z-y1)acetamide
[Chem 292]
\erO F
\ O
,0 \N LJ
MS (ESI pos.) m/z : 482 +).
1H-NMR (600 MHz, CDC13) 8 (ppm) ; 1.10 - 1.21 (6 H, m), 2.53 (4 H, br. S.), 2.60 - 2.70
(2 H, m), 2.80 - 2.92 (2 H, m), 3.74 (4 H, t, J=4.7 Hz), 3.81 - 3.91 (3 H, m), 4.04 — 4.18 (1 H,
m), 4.90 (2 H, s), 6.54 (1 H, d, J=7.4 Hz), 7.01 - 7.25 (4 H, m), 7.34 - 7.48 (2 H, In), 7.97 —
8.11 (1 H, m).
' Example B-19: 2-[3- {3—fluoro[2—(morph0lin—4—yl)ethyl]pheny1} (3-meth0xypheny1)—
1H-1 ,2,4-triazol-1—y1]—N-(propan—2~yl)acetamide
[Chem 293]
MS (ESI pos.) m/z : 482 ([M+H]+).
1H—NMR (600 MHz, CDC13) 5 (ppm) ; 1.10 - 1.20 (6 H, m), 2.55 (4 H, br. 3.), 2.60 — 2.68
(2 H, m), 2.84 - 2.94 (2 H, m), 3.74 (2 H, t, J=4.5 Hz), 3.82 - 3.90 (5 H, m), 4.14 (1 H, d,
J=7.4 Hz), 4.86 (2 H, d, J=5.0 Hz), 6.12 (1 H, d, J=7.4 Hz), 7.00 - 7.11 (1 H, m), 7.17 - 7.21
(1 H, m), 7.32 (1 H, t, J=7.6 Hz), 7.43 (1 H, q, J=8.1 Hz), 7.75 - 7.93 (2 H, m), 8.06 (1 H, s).
- Example B-20: 2-[5-(3-methoxypheny1)—3- {4—[2-(3—oxa—8—azabicyclo[3.2. 1]oct-8—
y1)propy1]pheny1}-1H—1,2,4-triazol~1—y1]-N-(propan—2—y1)acetamide
[Chem 294]
0059}7’”f0Wwfo
MS (ESI pos) m/z: 504 ([M+H])
lH—NMR (600 MHz, 013013) 8 (ppm) ; 1.17 (6 H, d, J=6.6 Hz), 2.42 — 2.51 (2 H, m), 2.55 —
2.62 (2 H, m), 3.04 (2 H, dd, J=12.6, 2.3 Hz), 3.36 (2 H, d, J=7.0 Hz), 3.47 (2 H, d,
J=5.0 Hz), 3.57 (2 H, dd, J=8.1, 2.3 Hz), 3.68 — 3.83 (3 H, m), 3.88 (3 H, s), 4.06 — 4.21 (2 H,
m), 4.87 (2 H, s), 6.20 (1 H, d, J=7.4 Hz), 7.00 — 7.12 (2 H, m), 7.19 - 7.26 (3 H, m), 7.39 —
~184-
7.49 (1 H, m), 8.09 (2 H, d, J=8.3 Hz).
Starting from the compound obtained in Reference Example P-B09, the same
procedure as in Example A—Ol was applied to synthesize the following compounds:
- Example B—21 : 2—[5—(3 —methoxyphenyl)—3- {4— [2—(pyrrolidin- l —yl)ethyl]phenyl} — l H- 1 ,2,4-
triazoly1]-N-(propan-2—yl)acetamide;
- Example B-22: 2—[3—{4-[2-(3,6-dihydropyridin—1(2H)-yl)ethyl]phenyl}—5-(3—
yphenyl)—1H—1,2,4-triazol-1—yl]—N—(propan-Z-yl)acetamide;
- Example B-23: 2—[5-(3—methoxyphenyl)~3- {4-[2-(4-methylpiperidinyl)ethyl]phenyl}-1H~
1,2,4-triazoly1]-N—(propanyl)acetamide;
' Example B—24: 2—[3- {4— [2—(4~cyanopiperidin- 1 ~y1)ethyl]phenyl } -5—(3—methoxyphenyl)— 1 H-
1,2,4—triazol-1—yl]-N-(propan—2-yl)acetamide;
- Example B-25: 2-[5~(3—methoxyphenyl)-3— {4—[2-(3—methoxypiperidin—1-yl)ethyl]phenyl}-
,4-triazol-1~yl]—N-(propan-Z—y1)acetamide;
- Example B-26: 2-[3 —(4— {2-[4-(dimethylamino)piperidinyl] ethyl } phenyl)(3 -
methoxyphenyl)—lH—1 ,2,4-triazol-1—yl]~N—(propan-Z-yl)acetamide;
- Example B—27: 2—[5-(3-methoxyphenyl)—3— {4-[2-(octahydroisoquinolin—2( l H)-
yl]phenyl}-1H—1,2,4—triazolyl]-N-(propan—Z—yl)acetamide;
' e B-28: 2— [5—(3—methoxyphenyl) {4~[2-(thlomorpholinyl)ethyl]phenyl} — 1H-
1 ,2,4~triazolyl]-N—(propanyl)acetamide;
- Example B-29: 2-[3—(4— {2-[(2R,6S)-2,6—dimethylmorpholin—4—yl]ethy1}phenyl)—5-(3-
methoxyphenyl)-1H~1,2,4—triazol—1-y1]~N—(propan-Z-y1)acetamide;
- Example B-30: 2-[5-(3—methoxyphenyl)~3 ~
— {4-[2—(3 lmorpholiny1)ethyl]phenyl}
1H- 1 ,2,4-triazolyl]—N—(propan-Z-yl)acetamide;
- Example B-3 1 : 2—[3— {4-[2-(3 -ethylmorpholin—4-y1)ethyl]phenyl} methoxyphenyl)— 1 H—
1 ,2,4-triazolyl]-N—(propanyl)acetamide;
- Example B-32: 2-[5-(3-methoxyphenyl)—3- (4-methylpiperazin—1—y1)ethy1]phenyl}-
1H- 1 ,2,4—triazol— 1 —y1]-N-(propan-Z—yl)acetamide;
- Example B—33: 2-[3
- {4-[2—(4—acetylpiperazin— l -yl)ethyl]phenyl} -5 -(3-methoxyphenyl)— 1 H—
~185-
1 ,2,4-triazol-1—y1]—N—(propan—Z—yl)acetamide;
- Example B-34: 1- [2-(4- {5-(3 -methoxyphenyl)-l-[2-0x0(propanylamino)ethyl]-1H-
1 ,2,4—triazol—3—yl}phenyl)ethyl]piperidinecarboxamide;
' Example B—3 5: 2— [3-(4- {2- [4-(acetylamino)piperidin— l -y1] phenyl)-5 -(3-
methoxyphenyl)-1H—1,2,4—triazol—l-yl]-N—(propan—Z-yl)acetamide;
' Example B-36: 2—[3- {4-[2-(4—hydroxy—4—methylpiperidin~ l -yl)ethyl]phenyl}(3-
methoxypheny1)-1 H-l ,2,4-triazol— l -yl]—N—(propan—Z-yl)acetamide;
- Example B-37: 3~methoxyphenyl)~3— {4—[2—(7-oxa-2—azaspiro[3 .5]non—2-
yl)ethyl]phenyl}-1H~1 ,2,4—triazol—1—yl]—N-(propanyl)acetamide;
- Example B-38: 2—[5-(3~methoxyphenyl)-3—(4~ {2—[4-(trifluoromethyl)piperidin— l
y1]ethyl}phenyl)- 1 H—l ,2,4-triazol- 1 ~yl]-N-(propan-Z-yl)acetamide;
- Example B-39: 2-[3
— {4— [2—(4-fluoropiperidin— l —yl)ethyl]phenyl } -5—(3-methoxyphenyl)— 1 H-
1 ,2,4-triazolyl]-N—(propan—Z—yl)acetamide;
' Example 3-40: 2- [3- {4— 4—difluoropiperidinyl)ethy1]phenyl} (3-methoxyphenyl)-
1H— 1 ,2,4-triazol- l —yl] -N-(propanyl)acetamide;
- Example B-4l : 2—[3- {4-[2-(3 ,5-dimethylmorpholinyl)ethyl]phenyl } -5 -(3 -
methoxyphenyl)-1H—l ,2,4-triazol»1-yl]-N—(propan-2—yl)acetamide;
' Example B—42: 2~[5—(3-methoxyphenyl) {4—[2—(2~oxa—6—azaspiro [3 t-6—
y1)ethyl]phenyl}-1H-1,2,4—triazol-l-yl]-N-(propan-Z-yl)acetamide.
Tables 1—1 to 1-4 show the results of measurements of the retention time (hereinafter RT) and
MS in LCMS as med in Examples B-21 to B—42.
—186-
[Table 1—1]
Table 1-1
Conditions for LC-MS MS (ESl pos.)
Structure
measurement RT (min)
+H]*)
13—24 \ 3—3
/O\d§\l 2 — 1 0.47 487
\l/n 0 O
13—25 C3 2 — 1 0.49 492
\N\>_<;>_/—N
/N N
8—26 W \ 2 — 2 0.60 505
~187-
[Table 1—2]
Table 1-2
Conditions for LC-MS M5 (E81 pos.)
e Structure
measurement m/z( M+H +)
/o\(::j}§N 2 — 1 0.63 516
B-28 \ \_—/
/0\6§V 2 — 1 0.48 480
YNfN/NO 0
13—30 /o\@\N\>—©—/—N>—/ 2 — 1 0.46 478
$13O no
13—31 /0\6§VW34 2 — 1 0.50 492
-188—
[Table 1-3]
Table 1-3
Conditions for LC-MS MS (1351 pos.)
Example Structure
measurement m/z( M+H +)
A“ 0%
/0\<::j)§w 2-1 Q42 505
B-35 \ CH 2 -] 0.43 519
/ )§N
W 2 —1 046 492
B“37 <><:o
/0\©‘§V 048 504
/~ 0+F
/fi 2 -1 Q56 530
-189—
[Table 1-4]
Table 1-4
Conditions for LC-MS M5 (E51 pos.)
Example Structure ,
measurement RT (mm)
m/z([M+H]+)
Y“ 0
B-39 \ 0*
/O\d§\l 2 — l 0.49 480
B—40 O<
\d§: 2 — 1 0.51 498
13—41 WW 2 — 1 0.49 492
/ 6W
YN 0
\fiv/ 0
13—42 2 — 1 0.43 476
0 .
Starting from the compounds obtained in Reference Examples P-CIO, P-Cl9, P-
C28, P-C35, P-C42, P—C48, P—CSS, P—C6l, P—C69, P-C74, P-C80 and P-C85, the same
procedure as in Example A-Ol was applied to size the following compounds of
Examples C-Ol to C-22:
- e C~01 : 2—[4-(3-chlorophenyl)— l — {4-[2-(piperidin- l —yl)ethyl]phenyl}-lH—pyrazol
yl]—N—(propan—2-yl)acetamide;
- Example C-02: 2—[3—(3—chlorophenyl)-1~{4-[2-(piperidin-l—yl)ethyl]pheny1}-lH—pyrazol
yl]-N-(propan—2-yl)acetamide;
° Example 003: 2—[3-(3-chloropheny1)—1
— (morpholinyl)ethyl]pheny1}-lH—pyrazol—
4-y1]-N—(propan-Z-yl)acetamide;
-190—
' Example C-04: 3—chlor0phenyl)-l—{4-[2-(2-0xaazaspir0[3.3]hept—6-
yl)ethy1]pheny1}-1H-pyrazolyl]-N-(propan-2—y1)acetamide;
' Example C-OS: 2-[1-(3-chlorophenyl)—3-{4-[2-(m0rpholin—4-yl)ethyl]phenyl}—lH-pyrazol-
-yl]-N-(propan-Z-yl)acetamide;
- Example 006: 3—chlorophenyl)-3— {4—[2—(piperidiny1)ethyl]phenyl}-1H—pyrazol- 1 —
yl] —N-(propan-Z—yl)acetamide;
- Example 007: 2—[5-(3-chlorophenyl)—3- {4-[2-(morpholin—4-yl)ethyl]phenyl}~1H—pyrazol-
1—yl]-N—(propan-2—yl)acetamide;
- Example C-08: 2-[5-(3—chlorophenyl)—2— (piperidinyl)ethyl]phenyl} ~ 1 ,3-oxazol
yl] —N-(propanyl)acetamide;
- Example C-09: 2— [5-(3 —ch10ropheny1)—2~ {4- [2-(morpholinyl)ethyl]phenyl }
- 1 ,3 -oxazol-4—
yl] -N-(propan—2—yl)acetamide;
- Example C-10: 2-[4-(3-chlorophenyl) (piperidin— 1 —yl)ethyl]phenyl }
— l ,3-oxazol
yl] -N-(propany1)acetamide;
- Example C-1 1: 2-[4-(3-chlorophenyl)-2—{4-[2-(morpholin—4—yl)ethyl]phenyl}—1,3—0xazol—5—
yl] —N—(propanyl)acetamide;
- Example C- 12: 2—[4-(3 -chlorophenyl)-2— {4-[2—(2—oxa-6—azaspiro[3.3]hept
yl)ethyl]phenyl}-1,3-oxazol—5-yl]—N—(propan-Z-yl)acetamide;
' Example 0 l 3: 2-[5-(3 0phenyl)—2— {4-[2—(piperidin-1—yl)ethyl]phenyl}-1,3—thiazol
yl] -N—(propan—2-yl)acetamide;
- Example 0 14: 2—[5-(3—ch10r0phenyl) {4-[2-(morpholin-4—yl)ethyl]phenyl}-1,3~thiazol-4—
yl] -N-(propan—2—yl)acetamide;
- Example C—15: 2—[5-(3-chlorophenyl)—2- {4-[2-(2-0xa—6—azaspiro[3 .3]hept—6-
yl)ethyl]phenyl} —l ,3 -thiazolyl]—N-(pr0panyl)acetamide;
~ Example C- l 6: 2-[5-(3-chlorophenyl) {3-[2-(piperidiny1)ethyl]phenyl}-l,3-thiazol-4—
yl]-N—(propanyl)acetamide;
' Example C-17: 2-[5—(3—chlorophenyl)—2- {3-[2—(morpholin—4—yl)ethyl]phenyl}-1,3-thiazol—4-
yl]-N-(propan-2—y1)acetamide;
-l91-
- Example C-18: 2— [4-(3 -chlorophenyl)- l
- {4-[2-(morpholin-4—yl)ethyl]phenyl } -2,5 -dioxo-
2,5-dihydr0- l H-pyrrolyl]-N-(propan-Z-yl)acetamide;
' Example C-19: 2—[5-(3-Chlor0phenyl)—3- {4-[2-(m0rpholin—4—yl)ethyl]phenyl } 0x0-2,3-
dihydro- 1 H-imidazol- l -yl] -N—(propanyl)acetamide;
- Example C—20: 2—[5-(3-chlorophenyl)methyl {4—[2-(morpholinyl)ethyl]phenyl} -2—
oxo—2,3-dihydro—1H-imidazol- l —yl]—N—(propanyl)acetamide;
' Example C-21: 2—[1-(3-chlorophenyl) {4—[2-(m0rpholinyl)ethyl]pheny1}-1H—1,2,4—
triazol-S~yl]—N~(propan~2—yl)acetamide;
' Example C-22: 2—[1—(3—chlorophenyl) {4-[2-(3—0xa—8—azabicyclo[3.2. 1]oct-8—
yl]pheny1}- 1 H-l riazolyl]~N—(propan-Z-yl)acetamide
Tables 2—1 to 2—4 show the results of 1H—NMR and MS measurements in Examples C-Ol to
C-22.
~192—
[Table 2— 1]
Table 2-1
1H NMR (600 MHz, CHLOROFORM—d) 6 ppm ; 1.10
(6 H, d, 1:6.4 Hz), 1.43 — 1.50 (2 H, m), 1.59 — 1.68 (4
H, m), 2.42 — 2.53 (4 H, m), 2.54 — 2.63 (2 H, m), 2.80
C-01
~ 2.91 (2 H, m), 3.74 (2 H, s), 3.97 — 4.15 (1 H, m),
6.36 (1 H, br. 8.), 7.27 — 7.38 (5 H, m), 7.42 (1 H, s),
7.55 — 7,63 (2 H, m), 7.99 (1 H, s)
1H NMR (600 MHz, FORM~d) 5 ppm ; 1.04
(6 H, d, 1:6.9 Hz), 1.42 - 1.72 (7 H, m), 2.38 — 2.69 (5
H, m), 2.81 — 2.93 (2 H, m), 3.59 (2 H, s), 4.01 — 4.11
C~02
(1 H, m), 5.35 (1 H, br. 3.), 7.29 — 7.33 (2 H, m), 7.33 —
7.40 (2 H, m), 7.49 — 7.56 (1 H, m), 7.63 — 7.69 (2 H,
m), 7.71 ~ 7.75 (1 H, m), 7.96 (1 H, s)
‘H NMR (600 MHz, CHLOROFORM—d) 6 ppm ; 1.04
(6 H, d, J=6.9 Hz), 2.46 - 2.58 (4 H, m), 2.59 — 2.66 (2
H, m), 2.80 — 2.90 (2 H, m), 3.59 (2 H, s), 3.71 — 3.80
6'03 (4 H, m), 3.98 - 4.15 (1 H, m), 5.36 (1 H, m, J=6.9 Hz), 467
7.29 - 7.33 (2 H, m), 7.33 — 7.40 (2 H, m), 7.50 — 7.57
(1 H, s), 7.97
S(1 H, m), 7.63 - 7.69 (2 H, m), 7.73 (1 H,
xH NMR (600 MHz, CHLOROFORM-d) 6 ppm ; 1.07
(6 H, d, J=6.4 Hz), 3.07 - 3.22 (4 H, m), 3.27 - 3.41 (4
C-04 H, m), 3.57 (2 H, s), 3.98 ~— 4.16(1H, m), 4.69 (4H, s), 479
.20 - 5.44 (1 H, m), 7.38 (4 H, d, J=6.9 Hz), 7.54 (1 H,
s), 7.62 — 7.83 (3 H, m), 8.02 (1 H, s)
1H NMR (600 MHz, CHLOROFORM—d) 6 ppm ; 1.10
(6 H, d, 1:6.9 Hz), 2.54 (4 H, br. s.), 2.60 — 2.65 (2 H,
m), 2.80 ~ 2.88 (2 H, m), 3.64 (2 H, s), 3.75 (4 H, br.
C'OS
s), 4.00 ~ 4.13 (1 H, m), 5.33 (1 H, d, 1:5.0 Hz), 6.69
(1 H, s), 7.23 — 7.29 (2 H, m), 7.34 — 7.45 (3 H, m),
7.56 (1 H, s), 7.76 ~ 7.81 (2 H, m)
[Table 2-2]
Table 2-2
1H NMR (600 MHZ, CHLOROFORM-d) 5 ppm ; 1.12
(6 H, d, J=6.4 Hz), 1.34 - 1.74 (6 H, m), 2.50 (4 H, br.
C-06 8.), 2.61 (2 H, br. 8.), 2.87 (2 H, br. 5.), 3.92 — 4.23 (1 465
H, m), 4.75 (2 H, s), 6.20 (1 H, d, J=6.4 Hz), 6.67 (1 H,
s), 7.21 - 7.32 (3 H, m), 7.37 - 7.45 (3 H, m), 7.69 —
7.79 (2 H, m)
‘H NMR (600 MHz, CHLOROFORM-d) 6 ppm ; 1.13
(6 H, d, J=6.4 Hz), 2.55 (4 H, br. 5.), 2.64 (2 H, br. 5.),
2.78 — 2.94 (2 H, m), 3.76 (4 H, br.
c—07 5.), 4.03 — 4.14 (1 467
H, m), 4.76 (2 H, s), 6.19 (1 H, d, J=7.3 Hz), 6.67 (1 H,
s), 7.26 — 7.33 (3 H, m), 7.37 — 7.46 (3 H, m), 7.72 —
7.81 (2 H, m)
1H NMR (600 MHz, FORM-d) 6 ppm ; 1.15
(6 H, d, J=6.4 Hz), 1.43 — 1.51 (2 H, m), 1.53 — 1.69 (6
H, m), 2.44 — 254(3 H, m), 2.56 — 2.67 (2 H, m), 2.82
C-08 — 2.96 (2 H, m), 3.70 (2 H, s), 3.99 — 4.16 (1 H, m). 466
6.56 (1 H, br. s.), 7.31 — 7.37 (3 H, m), 7.38 — 7.43 (1
H, m), 7.61 (1 H, d, J=7.8 Hz), 7.68 — 7.75 (1 H, m),
7.96 — 8.03 (2 H, m)
1H NMR (600 MHz, CHLOROFORM-d) 6 ppm ; 1.15
(6 H, d, J=6.9 Hz), 2.48 - 2.57 (4 H, m), 2.60 — 2.68 (2
H, m), 2.84 - 2.91 (2 H, m), 3.70 (2 H, s), 3.72 — 3.78
c—09 (4 H, m), 4.10 (1 H, dd, J=14.0, 6.6 Hz), 6.53 (1 H, br. 468
.), 7.32 ~ 7.37 (3 H, m), 7.38 — 7.44 (1 H, m), 7.58 —
7.65 (1 H, m), 7.69 ~ 7.75 (1 H, m), 7.96 - 8.04 (2 H,
111)
‘H NMR (600 MHz, CHLOROFORM—d) 6 ppm ; 1.11
(6 H, d, J=6.4 Hz), 1.42 — 1.52 (2 H, m), 1.54 — 1.71 (4
H, m), 2.45 — 2.66 (6 H, m), 2.85 - 2.94 (2 H, m), 3.85
0-10 (2 H, s), 4.12 (1 H, m, J=7.8, 6.6, 6.6 Hz). 5.45 (1 H, 1:1. 466
J=7.3 Hz), 7.30 - 7.36 (3 H, m), 7.36 ~ 7.41 (1 H, m),
7.59 — 7.64 (1 H, m), 7.81 (1 H, 1, J=1.8Hz), 7.96 — 8.02
(2 H, m)
1H NMR (600 M312, CHLOROFORM-fi) 5 ppm ; 1.12
(6 H, d, j=6.9 Hz), 2.48 - 2.58 (4 H, m), 2.60 ~ 2.67 (2
H, m), 2.83 - 2.91 (2 H, m), 3.71 - 3.77 (4 H, m), 3.85
c—11 (2 H, s), 4.05 - 4.18 (1 H, m), 5.45 (1 H, m, J=7.8 Hz), 468
7.30 ' 7.36 (3 E, m), 7.36 — 7.41(1H,m), 7.58 - 7.65
(1H,m),7.81(- H, m, j=1.6, 1.6 Hz), 7.98 — 8.03 (2 H,
—194—
[Table 2—3]
Table 2—3
Examp'e 43:55:38
1H NMR (600 MHz, FORM—d) 6 ppm ; 1.12
(6 H, d, J=6.9 Hz), 2.70 (4 H, br. 5.), 3.37 (4 H, br. s.),
C—IZ 8.85 (2 H, s), 4.07 — 4.16 (1 H, m), 4.73 (4 H, s), 5.38 — 480
.48 (1 H, m), 7.27 — 7.41 (4 H, m), 7.59 — 7.64 (1 H,
m), 7.79 — 7.83 (1 H, m), 7.98 - 8.03 (2 H, m)
1H NMR (600 MHz, CHLOROFORM-d) 6 ppm ; 1.17
(6 H, d, J=6.4 Hz), 1.44 ~ 1.51 (2 H, m), 1.61 — 1.70 (4
H, m), 2.40 — 2.55 (4 H, m), 2.57 — 2.66 (2 H, m), 2.82
C"13 482
— 2.94 (2 H, m), 3.70 (2 H, s), 4.02 — 4.16 (1 H, m),
6.86 (1 H, br. s), 7.29 - 7.34 (2 H, m), 7.35 — 7.45 (3
H, m), 7.48 — 7.53 (1 H, m), 7.81 — 7.87 (2 H, m)
’H NMR (600 MHz, CHLOROFORM—d) 6 ppm ; 1.17
(6 H, d, j=6.4 Hz), 2.47 ~ 2.58 (4 H, m), 2.60 — 2.69 (2
H, m), 2.81 — 2.92 (2 H, m), 3.70 (2 H, s), 3.73 — 3.77
C—14 484
(4 H, m), 4.03 - 4.15 (1 H, m), 6.83 (1 H, hr. 5.), 7.30 —
7.34 (2 H, m), 7.35 — 7.41 (2 H, m), 7.42 — 7.46 (1 H,
m), 7.49 — 7.53 (1 H, m), 7.83 — 7.88 (2 H, m)
lH NMR (600 MHz, CHLOROFORM-d) 6 ppm ; 1.17
(6 H, d, J=6.9 Hz), 2.70 (4 H, br. 5.), 3.40 (4 H, s), 3.70
C-15 (2 H, s), 4.03 — 4.13 (1 H, m), 4.74 (4 H, s), 6.81 (1 H, 496
br. 5.), 7.29 (2 H, s), 7.35 - 7.46 (3 H, m), 7.51 (1 H, 1,
J=1.6 Hz), 7.82 — 7.87 (2 H, m)
1H NMR (600 MHz, CHLOROFORM-d) 5 ppm ; 1.18
(6 H, d, J=6.4 Hz), 1.44 — 1.52 (2 H, m), 1.60 - 1.68 (4
H, m), 2.42 - 2.55 (4 H, m), 2.57 - 2.67 (2 H, m), 2.83
C-16 - 2.96 (2 H, m), 3.71 (2 H, s), 4.01 - 4.14 (1 H, m), 482
6.85 (1 H, 131‘. 5.), 7.29 - 7.33 (1 H, m), 7.35 — 7.42 (3
H, m), 7.42 - 7.47 (1 H, In), 7.50 - 7.54 (1 H, m), 7.73
- 7.77 (1 H, m), 7.79 (1 H, s)
1H NMR (600 MHZ, CHLOROFORM-d) 6 ppm ; 1.18
(6 H, d, J=6.9 Hz), 2.49 — 2.59 (4 H, m), 2.62 - 2.71 (2
H, m), 2.85 - 2.94 (2 H, m), 3.71 (2 H, s), 3.73 - 3.78
C-17 (4 H, m), 3.98 - 4.19 (1 H, m), 6.80 (1 H, hr. 3.), 7.32 484
(1 H, d, J=7.8 Hz), 7.35 - 7.42 (3 H, m), 7.43 - 7.46 (1
H, m), 7.50 - 7.54 (1 H, m), 7.75 - 7.78 (1 H, m), 7.78
— 7.81 (1 H, m)
~195-
[Table 2—4]
Table 2-4
1355:1255)
1H NMR (600 MHz, CHLOROFORM—d) 5 ppm ; 1.18
(6 H, d, 1:6.6 Hz), 2.54 (4 H, br. 3.), 2.58 — 2.66 (2 H,
m), 2.81- 2.90 (2 H, m), 3.49 (2 H, s), 3.71 — 3.77 (4 496
H, m), 4.00 — 4.13 (1 H, m), 6.09 (1 H, d, J=7.8 Hz),
7.28 - 7.37 (4 H, m), 7.42 ~ 7.50 (2 H, m), 7.84 — 7.91
(1 H, m), 7.95 (1 H, s)
1H NMR (600 MHz, DMSO-dG) 6 ppm ; 1.01 (6 H, d,
j=6.6 Hz), 2.43 (4 H, br. s.), 2.73 - 2.79 (2 H, m), 3.28
(2 H, s), 3.55 — 3.61 (4 H, m). 3.76 — 3.83 (1 H, m), 483
4.27 (2 H, s), 7.33 (2 H, d, J=8.7 Hz), 7.37 (1 H, s),
7.40 — 7.49 (3 H, m), 7.52 — 7.55 (1 H, m). 7.69 (2 H, d,
1:8.7 Hz), 8.04 (1 H, d, J=7.4 Hz)
1H NMR (600 MHz, DMSO-dfi) 6 ppm ; 1.08 (6 H, d,
J=6.6 Hz), 2.15 (3 H, s), 3.50 (2 H, s), 3.81 - 3.88 (1 H,
m), 4.93 (2 H, s), 7.40 (2 H, d, J=8.3 Hz), 7.58 - 7.62 (1 497
H, m), 7.63 _ 7.66 (l H, m), 7.76 — 7.79 (1 H, m), 7.83
“ 7.85 (1 H, m), 7.98 (2 H, d, J=8.3 Hz), 8.34 (l H, d,
J=7.4 Hz)
IH NMR (600 MHZ, CHLOROFORM-d) 6 ppm ; 1.22
(6 H, d, J=6.6 Hz), 2.55 (4 H, br. 3.), 2.63 - 2.69 (2 H,
m), 2.85 - 2.91 (2 H, m), 3.73 - 3.80 (6 H, m), 4.07 - 468
4.14 (1 H, m), 7.33 (2 H, d, J=8.3 Hz), 7.39 - 7.50 (4 H,
m), 7.61 ~ 7.63 (1 H, m), 8.06 (2 H, d, J=8.3 Hz).
1H NMR (600 MHz, CHLOROFORM~d) 6 ppm ; 1.22
(6 H, d, J=6.6 Hz), 1.85 — 1.97 (4 H, m), 2.53 — 2.62 (2
H, m), 2.82 — 2.90 (2 H, m), 3.08 ~ 3.15 (2 H, m), 3.51
— 3.57 (2 H, m), 3.72 ~ 3.77 (2 H, m), 3.79 (2 H, s), 494
4.07 — 4.14 (1 H, m), 7.34 (2 H, d, J=8.3 Hz), 7.39 —
7.5)1 (4 H, m), 7.60 ~ 7.63 (1 H, m). 8.06 (2 H, d, J=7.8Hz.
'Example D—Ol: Synthesis of 2—[4—(3-chlorophenyl)—l- {4—[2—(morpholin-4—
yl)ethyl]phenyl } —5-oxo-4,5—dihydro- l H- l ,2,4-triazol~3~yl]—N—(propan—Z—yl)acetamide
[Chem 295]
A oxane (1.8 mL) suspension of the compound (90 mg) obtained in Reference
Example P-DOS, 4-(4—bromophenethyl)morpholine (91 mg), copper iodide (64 mg),
tripotassium phosphate (130 mg) and N,N’—bismethyl-l,2-cyclohexanediamine
(0.055 mL) was stirred overnight at an external temperature of 100°C under a nitrogen
-l96—
stream. After leaving the reaction mixture to cool, it was filtered through Celite (registered
trademark) and the remaining solids were washed with CHC13. The filtrate was concentrated
and the resulting residue was d by silica gel column chromatography (SNAP Cartridge
KP-NH 28g; mobile phase: n—Hexane/CHC13 = 25/75; V/V) and the resulting compound was
washed in a mixed solvent (n-Hexane/EtOAc = 6/1; V/V); subsequently, the solids were
recovered by filtration to give the titled nd (77 mg as a colorless .
1H-NMR (600 MHz, CDC13)5 (ppm) ; 1.14 (6 H, d, J=6.6 Hz), 2.53 (4 H, br. s.), 2.58 - 2.64
(2 H, m), 2.78 — 2.87 (2 H, m), 3.47 (2 H, s), 3.75 (4 H, t, J=4.5 Hz), 3.96 — 4.09 (1 H, m),
.92 (1 H, d, J=6.6 Hz), 7.27 - 7.33 (3 H, m), 7.37 - 7.50 (3 H, m), 7.81 - 7.93 (2 H, m).
MS (ESI pos.) m/z : 484 ([M+H]+).
Starting from the compounds obtained in Reference Example P-DO4, Reference
Example P-D05, Reference Example P-DOS, Reference Example P-D09, Reference Example
P-D 12, Reference Example P-Dl3, Reference Example P—D16, Reference Example P-D17,
nce Example P—D20, Reference Example P-A42, Reference Example P-A47,
Reference Example P-A49, Reference e P-A50, Reference Example P-A52,
Reference Example P-A54, Reference Example P-A55, Reference e P-A56,
Reference Example P—A5 7, Reference Example P-A59, Reference e P-A61,
Reference Example P-A63, Reference Example P—A64, Reference Example P—A66 and
Reference Example P—A67, as well as from 4-(4—bromophenethyl)morpholine, the same
procedure as in Example D—01 was applied to synthesize the following compounds:
- Example D-02: 3-chlorophenyl)-1—{5—[2—(3—oxaazabicyclo[3.2. l]oct-—8-
yl)ethyl]pyridin—2-yl} oxo-4,5 -dihydro—1H-l,2,4—triazol-3 -yl] —N—(propan-2—yl)acetamide;
‘ Example D—03: 2-[4-(3-chlorophenyl)~1-{4—[2-(3~oxa-8—azabicyclo[3.2. l]oct~8-
yl)ethyl]phenyl}—5-oxo-4,5-dihydro-1H—1,2,4-triazol-3—y1]—N-(propanyl)acetamide;
' Example D-04: 2-[4-(3-chlorophenyl) {5-[2-(morpholinyl)ethyl]pyridinyl } -
4,5-dihydro-lH-l,2,4-triazolyl]-N-(propanyl)acetamide;
' Example D-05: N-tert-butyl-Z—[4-(4—fluoro—3—methoxyphenyl)— l
- {4—[2-(morpholin—4—
yl)ethy1]phenyl}—5-oxo-4,5—dihydro-1H-1,2,4~triazolyl]acetamide;
—l97-
' Example D-O6: N-tert—butyl-Z—[4—(3-methoxyphenyl)-1—{4-[2-(morpholin—4-
y1)ethyl]phenyl}oxo-4,5-dihydro-1H-1,2,4-triazolyl]acetamide;
- Example D-07: N-tert-butyl-Z—[4-(3-meth0xyphenyl){4-[2—(3—oxa—8—
azabicyclo[3.2.1]octyl)ethyl]phenyl}oxo—4,5-dihydro-lH—1,2,4-triazolyl]acetamide;
- e D-08: N—tert—butyl—Z—[4—(3—methoxyphenyl)- 1
— {5 — [2-(morpholin-4—
yl)ethyl]pyridin-2—yl}~5-oxo—4,5—dihydro—1H-1,2,4-triazol-3~yl]acetamide;
- Example D-09: N—tert—butyl-Z-[4-(3—methoxyphenyl)- l
- {5-[2—(3 -oxa
azabicyclo[3 .2. 1]oct—8~yl)ethyl]pyridin~2—yl}~5-oxo-4,5-dihydro- l H- 1 ,2,4—triazol-3~
y1]acetamide;
- e D— l O: N-tert-butyl—2~[4—(4—fluoromethoxyphenyl)-1—{4-[2-(3-0xa-8—
azabicyclo[3.2.1]octyl)ethyl]phenyl}—5—0X0—4,5—dihydro-lH—1,2,4—triazol-3 -yl]acetamide;
~ Example D—l 1 : N—tert-butyl—Z-[4—(4-fluoro-3—methoxyphenyl)- l - {5-[2-(morpholin—4-
y1)ethyl] pyridin—Z—yl}—5—oxo—4,5-dihydro—1H-1,2,4-triazolyl]acetamide;
- e D— 12: N-tert—butyl-Z-[4-(4-fluor0methoxyphenyl) {5-[2-(3-oxa—8-
azabicyclo[3.2.1]oct-8—yl)ethyl] pyridin-Z-yl}oxo-4,5-dihydro—1H—1,2,4-triazol-3—
yl] acetamide;
- Example D— 1 3: -butyl-Z—[4-(3-chlorophenyl){4—[2-(morpholin—4—yl)ethyl]phenyl}-
—0x0-4,5-dihydro-1H—1,2,4—triazolyl]acetamide;
- Example D- 14: N—tert-butyl-Z—[4-(3-chlorophenyl){4—[2-(3-oxaazabicyclo[3.2.1]oct-8—
yl)ethyl]phenyl}-5—ox0-4,5-dihydro—1H-l,2,4-triazolyl]acetamide;
‘ Example D—15: N—tert—butyl-Z-[4—(3-chlorophenyl)-1—{5-[2—(morpholin-4—yl)ethyl]pyridin—
2-yl}oxo-4,5-dihydro-1H—l,2,4~triazol-3—yl]acetamide;
- Example D-16: N—tert-butyl-Z-[4-(3—chlorophenyl)— 1- {5—[2-(3—oxaazabicyclo[3.2. 1]oct
yl)ethyl]pyridinyl}oxo-4,5-dihydro~lH—1,2,4-triazol—3-yl]acetamide;
- Example D- l 7: 2-[4-(3 -chlorophenyl)- l
- (morpholin—4-yl)propyl]phenyl } 0xo-4,5-
dihydro- l H- 1 ,2,4-triazol-3—yl] -N—(propanyl)acetamide;
' Example D—18: 2—[4-(3-chlorophenyl){4-[2-(3—0xa—8-azabicyclo[3.2.1]oct
yl)propyl]phenyl } —4 ,5~dihydro- l H—1 ,2,4-triazol-3 —yl] -N-(pr0pan—2—yl)acetamide;
- Example D- l 9: 2-[4—(3—chlorophenyl)- l
- {5- [2-(morpholinyl)propyl]pyridin—Z—yl } oxo-
4,5-dihydro-1H-l,2,4-triazolyl]-N-(propan-Z-yl)acetamide;
- Example D—ZO: 2-[4-(3—ch10ropheny1) {3-fluoro[2-(morpholinyl)ethyl]phenyl}-5—
oxo—4,5—dihydro—1H-l,2,4—triazol—3—yl]~N~(propan-Z-yl)acetamide;
- Example D—21: 3-chlorophenyl){3~fluoro[2-(3-oxa—8-azabicyclo[3.2. l]oct-8—
yl)ethyl]phenyl}-5—oxo-4,5-dihydro—1H—1,2,4-triazol—3-yl]-N—(propan—Z-yl)acetamide;
- Example D—22: 2—[4-(3-chlorophenyl)— l
— {3—methoxy—4-[2—(morpholin—4-yl)ethyl]phenyl} ~5-
0x0—4,5-dihydro— l H—l ,2,4-triazolyl]-N—(propan-Z-yl)acetamide;
- Example D—23: 2-[4-(3-chlorophenyl) {3—methoxy—4—[2—(3-0xa—8-azabicyclo[3 .2. l ]oct
yl)ethy1]phenyl}oxo—4,5-dihydro-1H-1,2,4-triazol-3—yl]~N—(p1‘opanyl)acetamide;
- Example D-24: 3—chlorophenyl)~ 1
— {2~flu0r0-4—[2—(3-oxa—8-azabicyclo[3.2. 1]oct—8—
yl)ethyl]phenyl}—5—oxo—4,5-dihydro-1H—l,2,4—triazolyl]-N—(propan—2—yl)acetamide;
- Example D—25: 2-[4-(3-chlorophenyl)— l
- {2—methoxy—4-[2-(3—oxa—8—azabicyclo[3 .2. l]oct
yl)ethyl]phenyl}oxo-4,5-dihydro-1H-1,2,4-triazol-3—yl]-N-(propan-Z-yl)acetamide;
' Example D—26: 2—[4-(3-chlor0—4~fluorophenyl){4-[2—(morpholinyl)ethyl]phenyl}-5 -
oxo—4,5-dihydr0-1H-1,2,4—triazol—3-yl]-N-(propan-Z-yl)acetamide;
- Example D—27: 2— [4—(3-chloro—4-fluor0phenyl)-1—{4-[2-(3-0xa—8—azabicyclo[3.2.1]oct—8—
yl)ethyl]phenyl}-5—ox0-4,5-dihydro-1H-1,2,4-triazol-3—yl]-N—(propan~2-yl)acetamide;
- e D—28: 2— [4—(3 -chloro-4—flu0rophenyl)—1—{5—[2-(morpholin~4-yl)ethyl]pyridin~2~
yl}—5—oxo-4,5~dihydro-1H—1,2,4—triazol—3—yl]-N-(propanyl)acetamide;
- Example D—29: 2—[4-(3-chlor0—4—fluorophenyl){5-[2-(3—oxa—8—azabicyclo[3.2. 1]oct
yl)ethyl]pyridin—2—yl}oxo-4,5-dihydro—1H-1,2,4-triazol—3-yl]-N-(propan-Z-yl)acetamide;
' Example D—30: —butyl-Z-[4~(3~chloro—4—fluorophenyl)-1—{4—[2-(m0rpholin—4-
yl)ethyl]phenyl}oxo-4,5-dihydro-1H-l,2,4-triazol—3-yl]acetamide;
' Example D-31: N-tert-butyl-Z-[4-(3-chlorofluorophenyl){4-[2-(3-0xa
azabicyclo[3 .2. l ]oct-8—yl)ethyl]phenyl}oxo-4,5-dihydro- 1 H-l ,2,4-triazolyl] acetamide;
' Example D-32: N—tert—butyl—Z-[4—(3—chlor0—4-fluorophenyl)-1—{5-[2-(morpholin
yl)ethyl]pyridin-2—yl}0x0-4,5—dihydro-1H-1,2,4—triazol-3~yl]acetamide;
—l99-
' Example D—33: N—tert-butyl[4-(3-chlorofluorophenyl)- l
— {5 -[2-(3-oxa
azabicyclo[3.2. 1]octyl)ethy1]pyridin—2-yl}oxo-4,5-dihydr0-1H-1,2,4-triazol
y1]acetamide;
' Example D-34: 2-[4-(3—chlor0phenyl){5-[2—(3—0xaazabicyclo[3.2.1]oct—8-
yl)propyl]pyridinyl } ox0—4,5 -dlhydro- l H— l ,2,4-triazol—3 —yl]-N—(propan-Z-yl)acetamide;
- Example D-3 5: 2-(1— {4-[2—(morpholin—4-yl)ethyl]phenyl}—5~0x0-4— [3~
(trifluoromethyl)phenyl]-4,5—dihydro- l H— l ,2,4-triazolyl)-N-(propan—2-yl)acetamide;
- e D-36: 2-[4—(3-chloro—4—fluorophenyl)- l
- {4-[2-(3 -oxaazabicyclo[3 .2. l]oct-8~
pyl]phenyl}~5-oxo-4,5-dihydro-1H—1,2,4-triazol-3—yl]—N—(propan—2~yl)acetamide;
- e D-37: 2—[4—(4—fluoro-3—methoxyphenyl)- l
- {4-[2—(3-oxa—8-azabicyclo[3 .2. l ]oct—8—
yl)ethyl]phenyl}-5—oxo—4,5-dihydro—1H-l,2,4-triazol—3—yl]—N—(pr0panyl)acetamide;
- Example D-3 8: 2-[4—(4—fluoro—3—methoxyphenyl)-l- (3-0xa-8—azabicyclo[3.2. 1]oct—8-
y1)ethy1]pyridinyl } oxo-4,5-dihydro- l H- l ,2,4-triazolyl]-N-(propan—Z—yl)acetamide;
' e D-39: 2-[4-(3-methoxyphenyl)—1-{4-[2-(3-oxa-8—azabicyclo[3.2. l]oct
y1)ethyl]phenyl}—5-0x0-4,5—dihydr0-lH—1,2,4-triazol—3—yl]—N—(propan—2—yl)acetamide;
- Example D-40: 2-[4-(3-methoxyphenyl)—l— {5—[2-(3—0xa—8—azabicyclo[3.2. 1]oct-8—
y1)ethyl]pyridin—2—yl} —5—oxo-4,5—dihydro— l H—l ,2,4-triazolyl]-N~(pr0pan-2—yl)acetamide;
- Example D—41 : 2— [4-(4—fluoro—3-methoxyphenyl)— l - {3-meth0xy—4- [2-(3-0xa—8—
azabicyclo[3.2.l]oct—8—yl)ethyl]phenyl}ox0—4,5—dihydro-lH-1,2,4—triazolyl]-N-(pr0pan-
2—y1)acetamide;
- Example D—42: 2-[1-{3-meth0xy—4—[2—(3-oxa-8—azabicyclo[3.2.1]octy1)ethyl]phenyl}~4—
(3-methoxyphenyl)~5~0xo—4,5-dihydro-1H-l,2,4—triazol—3-yl]—N—(propan—2-yl)acetamide.
Tables 3-1 to 3-7 Show the results of 1H—NMR and MS measurements in Examples D—O2 to
D-42.
—200«
[1550:3—u
Table 3-1
Structure MS (ESI pos.)
1“ NMR
m/z([M+H]+)
1'! 1H NMR (600 MHZ, CHLOROFORM—d) 5 ppm ; 1.11
(6 H, d, 1:6.6 Hz), 1.89 (4 H, s), 2.53 (2 H, t, J=7.4
Hz), 2.80 (2 H, t, J=7.2 HZ), 3.06 (2 H, br. 5.), 3.45 -
D-OZ 3.59 (4 H, m), 3.70 (2 H, d, J=10.3 Hz), 3.93 — 4.05 (l 511
H, m), 5.70 (1 H, d, J=7.4 HZ), 7.30 ~ 7.39 (1 H, m).
7.41 - 7.54 (3 H, m), 7.72 (1 H, dd, J=8.3, 2.5 Hz), 8.12
(1 H, d, J=8.7 HZ), 8.45 (1 H, d, J=1.7 Hz)
\r;\' O
1H NMR (600 MHZ, CHLOROFORM—d) 5 ppm ; 1.14
(6 H, d, J=6.6 Hz), 1.80 — 1.97 (4 H, m), 2.48 — 2.59 (2
, “
H, m), 2.74 — 2.85 (2 H, m), 3.09 (2 H, br. 5.), 3.43 —
D—03 /\,
‘\ O 510
N 3.57 (4 H, m), 3.73 (2 H, d, 1:103 Hz), 3.94 — 4.10 (1
c, \( H, m), 5.91 (1 H, d, J=9.1 Hz), 7.27 — 7.35 (3 H, m).
0 7.37 — 7.53 (3 H, m), 7.87 (2 H, d, J=8.7 Hz)
\r‘ 0
1H NMR (500 MHz, CHLOROFORM—d) 8 ppm ; 1.12
(5 H, d, J=5.5 Hz), 2.53 (4 H, br. 5.), 2.57 — 2.66 (2 H,
1 \ (“\O
w / m), 2.84 (2 H, t, J=7.6 Hz), 3.54 (2 H, s), 3.74 (4 H, t,
13-04 /\\, ; \ 485
\ J=4.5 Hz), 3.93 — 4.06 (1 H, m), 5.52 — 5.75 (1 H, m),
C, \( 7.32 — 7.54 (4 H, m), 7.70 (1 H, dd, 1:85, 2.3 Hz), 8.13
0 (1 H, d, J=8.7 Hz), 8.43 (1 H, d, J=2.1 Hz).
1H NMR (600 MHZ, CHLOROFORM—D) 6 ppm ; 1.34
(9 H, s), 2.51 ~ 2.57 (4 H, m), 2.60 - 2.65 (2 H, m),
2.81 ~ 2.87 (2 H, m), 3.43 (2 H, s), 3.73 - 3.78 (4 H.
m), 3.92 (3 H, s), 5.89 - 5.94 (1 H, m), 6.90 - 6.95 (1
H, m), 7.03 - 7.07 (1 H, m), 7.18 - 7.23 (1 H, m), 7.28
- 7.31 (2 H, m), 7.87 - 7.91 (2 H, m).
1H NMR (600 MHZ, FORM—D) (3 ppm ; 1.33
(9 H, s), 2.47 ' 2.58 (4 H, m), 2.58 — 2.66 (2 H, m),
2.80 — 2.89 (2 H, m), 3.44 (2 H, s), 3.72 - 3.79 (4 H,
m), 3.84 (3 H, s), 5.98 - 6.07 (1 H, m), 6.89 — 6.93 (1
H, In), 6.93 - 6.96 (1 H, m), 7.01 - 7.05 (l H, m), 7.28
” 7.32 (2 H, m), 7.39 — 7.45 (1 H, m), 7.87 — 7.94 (2 H,
1H NMR (600 MHz, CHLOROFORM—D) 6 ppm ; 1.33
(9 H, s), 1.84 — 1.97 (4 H, m), 2.50 — 2.57 (2 H, m).
2.78 — 2.84 (2 H, m), 3.06 - 3.13 (2 H, m), 3.44 (2 H,
s), 3.50 — 3.56 (2 H, m). 3.71 — 3.77 (2 H, m), 3.84 (3
H, s), 5.99 — 6.06 (1 H, m), 6.90 — 6.93 (1 H, m). 6.93 -
.95 (1 H, m), 5.99 — 7.05 (1 H, m), 7.28 — 7.32 (2 H,
m), 7.40 — 7.45 (1 H, m), 7.88 — 7.93 (2 H, m).
~201-
[Table 3-2]
Table 3-2
MS (551 pos.)
m/z([M+H]*)
1H NMR (600 MHz, CHLOROFORM—D) 5 ppm ; 1.30
(9 H, s), 2.49 ~ 2.57 (4 H, m), 2.59 — 2.65 (2 H, m),
2.81— 2.87 (2 H, m), 3.51 (2 H, s), 3.71 — 3.77 (4 H,
D‘08 m), 3.84 (3 H, s), 5.69 — 5.77 (1 H, m), 6.94 — 7.00 (2
H, m), 7.01 - 7.05 (1 H, m), 7.40 — 7.46 (1 H, m), 7.66
~)7.72 (1 H, m), 8.12 — 8.18 (1 H, m), 8.40 — 8.46 (1 H,m .
1H NMR (600 MHz, CHLOROFORM-D) 5 ppm ; 1.30
(9 H, s), 1.86 - 1.96 (4 H, m), 2.48 - 2.58 (2 H, m),
2.76 — 2.85 (2 H, m), 3.03 - 3.10 (2 H, m), 3.48 - 3.75
D-OQ (6 H, m), 3.84 (3 H, s), 5.68 - 5.78 (1 H, m), 6.93 - 521
7.00 (2 H, m), 7.01 - 7.05 (1 H, m), 7.40 - 7.45 (1 H,
m), 7.69 — 7.75 (1 H, m), 8.11 - 8.18 (1 H, m), 8.41 -
8.47 (1 H, m).
‘H NMR (600 MHz, CHLOROFORM-D) 5 ppm ; 1.34
(9 H, s), 1.85 — 1.95 (4 H, m), 2.51 — 2.57 (2 H, m),
2.78 — 2.84 (2 H, m), 3.08 — 3.12 (2 H, m). 3.43 (2 H,
D-IO s), 3.51 — 3.56 (2 H, m), 3.72 — 3.76 (2 H, m), 3.92 (3 538
H, s), 5.90 — 5.95 (1 H, m), 6.89 — 6.95 (1 H, m), 7.03 —
7.07 (1 H, m), 7.18 — 7.23 (1 H, m), 7.29 - 7.33 (2 H,
m), 7.85 — 7.91 (2 H, m).
‘H NMR (600 MHz, CHLOROFORM-D) 5 ppm ; 1.31
(9 H, s), 2.48 ~ 2.56 (4 H, m), 2.59 — 2.66 (2 H, m),
2.81 - 2.87 (2 H, m), 3.49 (2 H, s), 3.70 — 3.77 (4 H,
D—11 m), 3.92 (3 H, s), 5.65 — 5.71 (1 H, m), 6.94 — 6.98 (1 513
H, m), 7.09 — 7.13 (1 H, m), 7.18 — 7.24 (1 H, m), 7.67
—)7.73 (1 H, m), 8.10 - 8.15 (1 H, m), 8.41 — 8.45 (1 H,m .
‘H NMR (600 MHz, CHLOROFORM—D) 5 ppm ; 1.25
- 1.34 (9 H, m), 1.90 (4 H, br. s.), 2.47 — 2.58 (2 H, m),
2.75 — 2.84 (2 H, m), 3.02 ~ 3.11 (2 H, m), 3.49 (4 H,
D-12 s), 3.67 - 3.73 (2 H, m). 3.92 (3 H, s), 5.64 — 5.72 (1 H, 539
1- 7.00 (1 H, m), 7.07 — 7.13 (1 H, m). 7.18 -
7.23 (1 H, m), 7.59 - 7.75 (1 H, m), 8.09 — 8.15 (1 H.
m). 8.42 — 8.47 (1 H, m).
1H NMR (600 MHz, CHLOROFORM'D) 5 ppm ; 1.33
(9 H, s), 2.49 - 2.58 (4 H, m), 2.59 ~ 2.65 (2 H, m),
D-13 I X 2.80 - 2.87 (2 H, m), 3.44 (2 H, s). 3.70 - 3.80 (4 H. 498
m), 5.86 - 5.92 (1 H, m), 7.28 - 7.34 (3 H, m), 7.40 -
7.50 (3 H, m), 7.85 — 7.93 (2 H.111).
[Table 3—3]
Table 3—3
mm“? 45:53.51?
1H NMR (600 MHz, CHLOROFORM—D) 5 ppm ; 1.33
(9 H, s), 1.85 — 1.99 (4 H, m), 2.50 - 2.63 (2 H, m),
2.77 - 2.89 (2 H, m), 3.07 ~ 3.19 (2 H, m), 3.44 (2 H,
s), 3.51 — 3.57 (2 H, m),3.71— 3.83 (2 H, m), 5.86 —
.92 (1 H, m), 7.28 — 7.34 (3 H, m), 7.42 — 7.50 (3 H,
m), 7.89 (2 H, d, J=8.7 Hz).
1H NMR (600 MHz, CHLOROFORM-D) 5 ppm ; 1.30
(9 H, s), 2.49 ~ 2.57 (4 H, m), 2.59 — 2.66 (2 H, m),
2.80 - 2.87 (2 H, m), 3.51 (2 H, s), 3.69 — 3.78 (4 H,
m), 559 ~ 5.68 (1 H, m), 7.34 — 7.38 (1 H, m), 7.44 —
7.51 (3 H, m), 7.70 (1 H, dd, 1:83, 2.5 Hz), 8.12 (1 H,
d, J=8.3 Hz), 8.41 — 8.45 (1 H, m).
1H NMR (600 MHz, CHLOROFORM-D) 5 ppm ; 1.30
(9 H, s), 1.86 - 1.95 (4 H, m), 2.54 (2 H, t, J=7.4 Hz),
2.80 (2 H, t, J=7.4 Hz), 3.07 (2 H, br. 8.), 3.48 - 3.56 (4
H, m), 3.71(2 H, d, J=10.3 Hz), 5.59 — 5.68 (1 H, m),
7.33 - 7.39 (1 H m), 7.43 - 7.51 (3 H, m), 7.72 (1 H,
dd, J=8.3, 2.5 H ), 8.12 (1 H, d, J=8.3 Hz), 8.45 (1 H,
d, J=2.5 Hz).
1H NMR (600 MHz, FORM-D) 5 ppm ; 0.98
(3 H, d, J=6.6 Hz), 1.15 (6 H, d, J=6.6 Hz), 2.46 (1 H,
dd, J=13.0, 9.3 Hz), 2.61 — 2.65 (4 H, m), 2.76 — 2.83 (1
H, m), 2.99 - 3.05 (1 H, m), 3.48 (2 H, s), 3.71 — 3.77
(4 H, m), 4.05 (1 H, d, J=7.4 Hz), 5.89 — 5.95 (1 H, m),
7.25 — 7.28 (2 H, m), 7.30 ~ 7.33 (1 H, m), 7.42 — 7.44
(1 H, m), 7.47 ~ 7.50 (2 H, m), 7.88 (2 H, d, J=8.3 Hz).
1H NMR (600 MHz, CHLOROFORM—D) 5 ppm ; 0.94
(3 H, d, J=6.2 Hz), 1.15 (6 H, d, J=6.6 Hz), 1.76 — 2.01
(4 H, m), 2.45 (1 H, dd, 1:132, 9.1 Hz), 2.52 — 2.59 (1
H, m), 3.01 (1 H, dd, J=13.4, 3.5 Hz), 3.33 — 3.37 (1 H,
m), 3.44 — 3.47 (1 H, m), 3.47 — 3.50 (2 H, m), 3.54 —
3.59 (2 H, m), 3.78 (2 H, dd, 1:103, 3.7 Hz), 4.01 —
4.09 (1 H, m), 5.90 - 5.96 (1 H, m), 7.26 (2 H, d, J=8.3
Hz), 7.30 — 7.34 (1 H, m), 7.42 — 7.44 (1 H, m), 7.46 —
7.49 (2 H, m), 7.89 (2 H, d, J=8.7 Hz).
1H NMR (600 MHZ, CHLOROFORM~D) 5 ppm ; 0.98
— 1.07 (3 H, m), 1.08 - 1.14 (6 H, m), 2.48 - 3.06 (7 H,
m), 3.55 (2 H, s), 3.64 - 3.82 (4 H, m), 3.96 - 4.05 (1
H, m), 5.69 - 5.77 (1 H, m), 7.33 - 7.39 (1 H, m). 7.44
- 7.51 (3 H, m), 7.65 - 7.72 (1 H, m), 8.13 (1 H, d,
J=8.3 HZ), 8.37 - 8.41 (1 H, m).
-203—
[Table 3-4]
Table 3-4
“$523?
1H NMR (600 MHz, FORM——D) 6 ppm ; 1.15
(6H,,=.,.-d]66Hz)250 2.58(4H,,.m)259— 254(2
‘ . H, m), 2.83 — 2.89 (2 H, m), 3.47 (2 H, s), 3.72 — 3.78 11—20 502
« (4 H, m), 4.01 — 4.08 (1 H, m), 5.78 - 5.84 (1 H, m),
7.27 — 7.34 (2 H, m), 7.41 — 7.44 (1 H, m), 7.47 — 7.50
(2 H, m), 7.71 ~ 7.76 (2 H, m).
1H NMR (600 MHz, CHLOROFORM—D) 6 ppm ; 1.15
(6 H, d, J=6.6 Hz), 1.85 — 1.96 (4 H, m), 2.47 — 2.55 (2
D_21 H, m), 2.80 — 2.86 (2 H, m), 3.10 (2 H, br. 5.), 3.48 (2
, 528
.1 H, s), 3.53 (2 H, d, J=9.1 Hz), 3.72 (2 H, d, 1:103 Hz),
4.01 — 4.08 (1 H, m), 5.77 — 5.86 (1 H, m), 7.28 — 7.34
(2 H, m), 7.41 — 7.51 (3 H, m), 7.70 — 7.76 (2 H, m).
‘H NMR (600 MHz, CHLOROFORM-D) 5 ppm ; 1.15
(6 H, d, J=6.6 Hz), 2.50 — 2.61 (6 H, m), 2.80 — 2.88 (2
D-22 H, m), 3.49 (2 H, s), 3.73 — 3.79 (4 H, m), 3.88 (3 H, 514
‘ 4.01 — 4.09 (1 H, m), 5.89 — 5.97 (1 H, m), 7.21 (1 H, d,
J=8.3 Hz), 7.29 — 7.34 (1 H, m), 7.41 - 7.51 (4 H, m),
7.60 — 7.65 (1 H, m).
1H NMR (600 MHz, CHLOROFORM—D) 5 ppm ; 1.15
(6 H, d, J=6.6 Hz), 1.85 - 1.95 (4 H, m), 2.46 — 2.51 (2
, H, m), 2.78 — 2.84 (2 H, m), 3.12 — 3.17 (2 H, m), 3.49
1 (2 H,
13—23 , s), 3.51 — 3.56 (2 H, m), 3.76 (2 H, d, 1:103 Hz), 540
= 3.87 (3 H, s), 4.02 - 4.09 H, m), 5.90 — 5.97 (1 H,
m), 7.22 (1 H, d, J=8.3 Hz 7.30 — 7.33 (1 H, m), 7.42 —
7.44 (1 H, m), 7.45 (1 H =8.3, 2.1 Hz), 7.47 — 7.49
(2 H, m), 7.62 (1 H, 11,] .
1H NMR (600 MHz, CHLOROFORM—D) 5 ppm ; 1.15
‘ 0 (6 H, d, J=6.2 Hz), 1.87 - 1.95 (4 H, m), 2.51 — 2.57 (2
. V>
/ y H, m), 2.79 H 2.85 (2 H, m), 3.07 — 3.11 (2 H, m), 3.47
0-24 * 528
.\ (2 H, s), 3.51 _ 3.56 (2 H, m), 3.70 — 3.75 (2 H, m),
QC \\< 4.00 — 4.09 (1 H, m), 6.08 — 6.14 (1 H. m), 7.10 - 7.17
O (2 H, m), 7.30 - 7.35 (1 H, m), 7.43 - 7.54 (4 H, m).
\r \1:Q\4©_fx<€x: 0 ‘H NMR (600 MHz, CHLOROFORM—D) 6 ppm 1.14
0/ ;
0 (6 H, d, J=6.6 Hz), 1.87 — 1.98 (4 H, m), 2.52 — 2.58 (2
H, m), 2.80 — 2.86 (2 H, m), 3.09 — 3.14 (2 H, m), 3.47
13—25 (2 H, s), 3.53 — 3.57 (2 H, m), 3.72 — 3.77 (2 H, m), 540
3.88 (3 H, s), 4.02 — 4.09 (1 H, m), 6.10 — 6.16 (1 H,
Cl m), 6.90 — 6.93 (1 H, m), 6.94 ~ 6.98 (1 H, m), 7.31 —
7.36 (2 H, m), 7.43 - 7.49 (3 H, m).
—204-
[Table 3-5]
Table 3—5
Examp'e 3:53.55)
1H NMR (600 MHz, DMSO-dfi) 6 ppm ; 0.89 (6 H, d,
J=6.6 Hz), 2.42 (4 H, br. s.), 2.51 — 2.57 (2 H, m), 2.70
— 2.81 (2 H, m), 3.53 (2 H, s), 3.55 — 3.60 (4 H, m),
D~26
3.61 - 3.70 (1 H, m), 7.34 (2 H, d, J=8.3 Hz), 7.48 —
7.56 (1 H, m), 7.58 — 7.67 (1 H, m), 7.72 — 7.83 (3 H,
m), 7.89 (1 H, d, J=7.4 Hz)
1H NMR (600 MHz, DMSO-d6) 6 ppm ; 0.89 (6 H, d,
J=6.6 Hz), 1.62 — 1.72 (2 H, m), 1.84 (2 H, dd, J=7.6,
3.08 (2 H, br. 8.), 3.40 (2 H, dd, J=10.1, 1.9 Hz), 3.47 -
3.55 (4 H, m), 3.65 (1 H, dq, , 6.8 Hz), 7.36 (2 H,
d, J=8.7 Hz), 7.50 - 7.56 (1 H, m), 7.58 - 7.65 (1 H, m),
7.75 — 7.82 (3 H, m), 7.88 (1 H, d, J=7.4 Hz)
NMR (600 MHZ, DMSO-dfi) 5 ppm ; 0.90 (6 H, d,
J=6.6 Hz), 2.36 — 2.40 (1 H, m), 2.41 - 2.46 (2 H, m),
51 — 2. 7 (2 H, m), 2.61 (1 H, dt, J=3.7, 1.9 Hz), 2.79
D-28 2 H, t, J=7.2 Hz), 3.53 (2 H, s), 3.57 (4 H, t, J=4.7
3.61 - 3.69 (1 H, m), 7.52 - 7.56 (1 H, m), 7.59 —
( H, m), 7.79 (1 H, dd, j=6.6, 2.5 Hz), 7.83 (2 H,
( H, d, j=7.8 Hz), 8.36 - 8.40 (1 H, m)
1H NMR (600 MHz, DMso—ds) 6 ppm ; 0.86 — 0.92 (6
H, m), 1.66 — 1.73 (2 H, m), 1.81 — 1.88 (2 H, m), 2.44
— 2.48 (2 H, m), 2.75 (2 H, t, 1:7.4 Hz), 3.09 (2 H, br.
D-29 5.), 3.40 (2 H, dd, 1:99, 17 Hz), 3.49 (2 H, d, 1:99
Hz), 3.53 (2 H, s), 3.61 — 3.69 (1 H, m), 7.52 — 7.56 (1
H, m), 7.59 - 7.66 (1 H, 111), 7.80 (1 H, dd, J=6.6, 2.5
Hz), 7.82 — 7.92 (3 H, ), .40 (1 H, d, J=1.7 Hz)
1H NMR (600 MHz, DMso—de) 6 ppm ; 1.09 (9 H, s),
2.43 (4 H, br. s.), 2.51 — 2.55 (2 H, m), 2.72 — 2.79 (2
D-30 H, m), 3.54 (2 H, s), 3.57 (4 H, t, J=4.7 Hz), 7.34 (2 H, 516
d, J=8.7 Hz), 7.49 — 7.56 (1 H, m), 7.59 ~ 7.67 (2 H, m),
7.7 (1 H, dd, J=6.6, 2.5 Hz), 7.79 ~ 7.83 (2 H, m)
1H NMR (600 MHz, DMSO—d6) 5 ppm ; 1.09 (9 H, s),
1.66 — 1.72 (2 H, m), 1.81 — 1.87 (2 H, m), 2.42 — 2.47
(2 H, m), 2.68 — 2.76 (2 H, m), 3.08 (2 H, br. 5.), 3.40
D-3l 542
(2 H, dd, 1:99, 1.7 Hz), 3.47 — 3.57 (4 H, m), 7.36 (2
H, d, J=8.7 Hz), 7.48 - 7.57 (1 H, m), 7.59 — 7.67 (2 H,
m), 7.76 (1 H, dd, J=6.6, 2.5 Hz), 7.78 — 7.83 (2 H, m)
[Table 3-6]
Table 3-6
MS (581 pos.)
Structure
8.67.65
1H NMR (600 MHz, CHLOROFORM—d) 6 ppm ; 1.30
(9 H, s), 2.52 (4 H, br. 5.), 2.57 - 2.65 (2 H, m), 2.83 (2
H, t, J=7.6 Hz), 3.48 (2 H, s), 3.73 (4 H, t, J=4.5 Hz),
D'32 517
.60 (1 H, br. 5.), 7.31 (1 H, d, J=8.7 Hz), 7.34 - 7.41
(1 H, m), 7.51 — 7.57 (1 H, m), 7.64 — 7.72 (1 H, m),
8.10 (1 H, d, j=8.3 Hz), 8.42 (1 H, d, J=2.1 Hz)
1H NMR (600 MHZ, fi) 5 ppm ; 1.09 (9 H, s),
1.67 -172 (2 H, m), 1.82 — 1.87 (2 H, m), 2.45 - 2.48
(2 H, m), 2.75 (2 H, t, J=7.2 Hz), 3.09 (2 H, d, J=0.8
HZ), 3.40 (2 H, dd, J=9.9, 1.7 Hz), 3.50 (2 H, d, J=9.9
D—33 543
HZ), 3. 54 (2 H, s), 7.54 (1 H, ddd, J=8.9, 4.3, 2.5 Hz),
7. 62 ( ,t, J.=8 9 HZ), 7.66 (1 H, s), 7.77 (l H, dd,
J=6. 6, 2H5 H) 7.80 “ 7.84 (1 H, m), 7.84 — 7.88 (1 H,
m), 8.40 (1 H, d, J=2.1 Hz)
‘H NMR (600 MHz, CHLOROFORM-D) 0 ppm ; 0.92
(3 H, d, J=6.2 Hz), 1.12 (6 H, d, J=6.2 Hz), 1.76 — 1.85
(1 H, m), 1.89 — 1.98 (3 H, m), 2.56 — 2.64 (2 H, m),
/ \N /‘ 2.84 — 2.91 (1 H, m), 3.27 - 3.32 (1 H, m), 3.41 (1 H,
D—34 525
br. 5.), 3.51 — 3.59 (4 H, m), 3.70 — 3.80 (2 H, m), 3.96
— 5.74 (1 H, m), 7.33 — 7.38 (1 H,
— 4.06 (1 H, m), 5.65
m), 7.45 - 7.51 (3 H, m), 7.69 (1 H, dd, J=8.5, 2.3 Hz),
8.13 (1 H, d, J=8.3 Hz), 8.42 (1 H, d, J=2.1 Hz).
Y1“.\ 0
1H NMR (600 MHz, CHLOROFORM-d) 5 ppm ; 1.08 -
-‘V 1.16 (6 H, m), 2.53 (4 H, d, J=O.8 Hz), 2.58 - 2.66 (2 H,
\ \—/ 111), 2.79 — 2.87 (2 H, m), 3.48 (2 H, s), 3.75 (4 H, t,
D-35 518
r .
F \\< J=.,45Hz) 3.—94 4.09(1H m) 585(1 H, d,_l=10.3
0 Hz), 7.29(2H 7Hz) 757—7.71(3H,m),7.72
‘ -7.77(1H,m),.783 ,m)
11, HNMR (600 MHz, CHLOROFORM—d) 0 ppm;0.92
\r 0 (4H,dJ=.,62Hz)112—118(6H,,.m)175—1.97(3
4%O H,m),244(1H 11111126 89Hz)255(1Hd
\N J=5..,,=.,.,.,,4Hz),299(1Hdd]13427Hz)334(1Hd
D—36 542
J=54.Hz),344.,1~348(3Hm),3.56(2H,,=dde76,
C =\\\<.
0 54,27Hz),37-2 3.80(2H,,.—m)400 4.,07(1Hm)
.84(1H,d,J=7.,.8Hz)722 7.3,,.6(4Hm)751(1H,
' dd,j=6.6.5,2 2,)7.83—7.88(2H,m)
H [—
YRVO 1H NMR (600 MHz, CHLOROFORM——D) 6 ppm ; 1.16
O (6H,6166Hz)185~19/(4H m)249 259(2
”3.?, .
H,m),2.78 286(2Hrr;)310(2HI2rs)346(2
N H,s),3.51 356(2Hm 370 378 2Hm)392
D37_ 5‘24
/ KS, (3H,s),4.026.90~6.94(1~%H )706(1Hdd17425Hz)721409,,(1Hm)5..,,91—597(1Hm)
,J=10.,585HH,.,,=.,72)731(2de87Hz)
(2 H, d, =8.7H).
-206—
[Table 3—7]
Table 3-7
“15:53.37?
1&1 1H NMR (600 MHz, CHLOROFORM—D) 6 ppm ; 1.13
(6 H, d, #66 Hz), 1.91 (4 H, br. 8.), 2.49 - 2.59 (2 H,
m), 2.76 - 2.84 (2 H, m), 3.07 (2 H, br. 3.), 3.49 - 3.56
D-38 (4 H, m), 3.67 * 3.74 (2 H, m), 3.92 (3 H, s), 3.98 —
4.06 (1 H, m), 5.70 - 5.78 (1 H, m), 6.94 — 6.99 (1 H.
m), 7.11 (1 H, dd, J=7.4, 2.5 Hz), 7.21 (1 H, dd, J=10.5,
8.5 Hz), 7.73 (1 H, d, J=7.0 Hz), 8.13 (1 H, d, J=8.7
Hz), 8.46 (1 H, d, _I=2.5 Hz).
1H NMR (600 MHZ, CHLOROFORM"D) 5 ppm ; 1.15
(6 H, d, J=6.6 Hz), 1.85 - 1.97 (4 H, m), 2.51 - 2.58 (2
H, m), 2.78 - 2.85 (2 H, m), 3.10 (2 H, br. 8.), 3.48 (2
D-39 H, s), 3.50 - 3.56 (2 H, m), 3.70 - 3.78 (2 H, m), 3.84
(3 H, s), 4.02 ‘ 4.09 (1 H, m), 6.01 - 6.08 (1 H, m),
6.89 - 6.92 (1 H, m), 6.92 - 6.95 (1 H, m), 7.02 (1 H,
dd, J=8.3, 2.5 Hz), 7.31 (2 H, (1, 1:8.3 Hz), 7.42 (1 H, t
J=8.3 Hz), 7.90 (2 H, d, .I=8.3 H2).
1H NMR (600 MHZ, CHLOROFORM‘D) 5 ppm ; 1.12
(6 H, d, J=6.2 HZ), 1.90 (4 H, br. 5.), 2.51 — 2.58 (2 H,
m), 2.77 " 2.84 (2 H, m), 3.07 (2 H, b1“. 8.), 3.50 — 3.57
D-40 (4 H, m), 3.71 (2 H, d, J=9.9 Hz), 3.84 (3 H, S), 3.98 —
4.05 (1 H, m), 5.74 — 5.80 (1 H, m), 6.93 ‘ 6.99 (2 H,
m), 7.01- 7.05 (1 H, m), 7.43 (1 H, t,.1=8.3 HZ), 7.69 —
7.75 (1 H, m), 8.15 (1 H, d, J=8.3 Hz), 8.46 (1 H, d,
J=2.1 Hz).
1H NMR (600 MHz, CHLOROFORM-D) 6 ppm ; 1.16
(6 H, d, 1:6.6 Hz), 1.84 — 1.97 (4 H, m), 2.49 (2 H, br.
.), 2.82 (2 H, br. 5.), 3.15 (2 H, br. s), 3.47 (2 H, s),
3.54 (2 H,
D-41 d, 1:9.5 Hz), 3.72 — 3.81 (2 H, m), 3.87 (3 H,
s), 3.92 (3 H, s), 4.02 — 4.09 (1 H, m), 5.90 — 5.97 (1 H,
m), 6.90 — 6.94 (1 H, m), 7.05 (1 H, dd, 1:7.4, 2.5 Hz),
7.18 — 7.25 (2 H, m), 7.45 (1 H, dd, #81, 1.9 Hz), 7.62
(1 H, d, 1:1.7 Hz).
‘H NMR (600 MHz, FORM—D) 6 ppm ; 1.15
(6 H, d, J=6.6 Hz), 1.84 — 1.97 (4 H, m), 2.50 (2 H, br.
s), 2.82 (2 H, br. s.), 3.16 (2 H, br. 3.), 3.49 (2 H, s),
3.54 (2 H, d, 1:95 Hz), 3.73 — 3.81 (2 H, m), 3.84 (3 H,
D-42 s), 3.87 (3 H, s), 4.02 — 4.09 (1 H, m), 6.02 — 6.08 (1 H, 536
m), 6.90 — 6.92 (1 H, m), 6.92 ~ 6.95 (1 H, m), 7.03 (1
H, dd, J=8.7, 2.5 Hz), 7.23 (1 H, d, _)=8.3 Hz), 7.43 (1
H, t, J=8.1 Hz), 7.46 (1 H, dd, ,]=8.3, 1.7 Hz), 7.63 —
7.67 (1 H, m).
Starting from the compounds obtained in Reference Example P-D21 and Reference
Example P—D22 as well as from ponding amines, the same procedure as in Example A—
01 was applied to synthesize the following compounds:
- Example D-43: 2-[4-(3—chloro-4—fluorophenyl)-5~oxo— 1
— {4—[2—(pyrrolidin— 1 —
yl)ethyl]pheny1 } -4,5-dihydro-H— 1 ,2,4-triazol-3—yl] —N-(propan-2—yl)acetamide;
' Example D-44: 2-[4—(3-chloro-4—fluorophenyl)oxo{4—[2-(piperidin
y1]phenyl}—4,5-dihydro-1H-1,2,4—triazol-3 -y1]—N—(propanyl)acetamide;
' Example D—45: 2—[4-(3—chlorophenyl)—5-oxo-l
- {4-[2—(pyrrolidin- l -yl)ethyl]phenyl} —4,5-
dihydro-1H—l,2,4-triazol-3 -y1]-N-(propan—2—yl)acetamide;
- Example D-46: 2—[4-(3-chlorophenyl)oxo{4-[2-(piperidin-l-yl)ethyl]phenyl}-4,5-
dihydro— 1 H-l ,2,4-triazolyl]—N—(propan—Z-yl)acetamide;
- Example D-47: 2-[4-(3-chlorophenyl)-1— {4-[2~(3 ,6-dihydropyridin-1(2H)—yl)ethyl]phenyl}-
-oxo-4,5—dihydro-lH—1,2,4—triazolyl]-N—(propan~2~yl)acetamide;
- Example D-48: 2-[4-(3—chlorophenyl)-5—ox0-1—{4-[2—(thiomorpholinyl)ethyl]phenyl}-
4,5—dihydro-lH—1,2,4—triazol-3—y1]-N-(propan-Z—yl)acetamide;
- Example D—49: 2-[4-(3—chlorophenyl) {4- [2-(4—methylpiperidin- l -yl)ethyl]phenyl } —5-
oxo—4—,5—dihydro—1H-l,2,4—triazol—3-yl]-N—(propan—Z-yl)acetamide;
- Example D—50: 2—[4-(3-chlorophenyl) {4—[2—(3~methoxypiperidin- l —yl)ethyl]phenyl} ~5
oxo-4,5-dihydro—1H—l ,2,4-triazolyl]-N—(propan—Z-yl)acetamide;
- Example D-Sl : 2—[4-(3—chlorophenyl){4—[2-(octahydroisoquinolin—2(1H)-
yl)ethyl]phenyl } —4,5-dihydro- l H- l ,2,4-triazol-3 ~y1]-N-(propan-Z-yl)acetamide;
- Example D-52: 2—[4—(3-chlorophenyl)(4-{2-[(2R,6S)-2,6-dimethylmorpholin
yl]ethyl}phenyl)-5—oxo—4,5-dihydro-1H—1,2,4-triazol—3—yl]—N-(propan—Z-yl)acetamide;
- Example D—53: 2-[4-(3-chlor0phenyl)-1—{4—[2—(3~methylmorpholinyl)ethyl]phenyl}
oxo—4,5—dihydro—1H~l,2,4-triazol—3-y1]-N-(propan-Z—yl)acetamide;
- Example D—54: 2—[4-(3—chlorophenyl)- l
— (3 -ethylmorpholin-4—yl)ethyl]phenyl} —5 -oxo—
4,5-dihydro-lH—1,2,4-triazolyl]~N—(propanyl)acetamide;
' Example D-55: 2-[4-(3—chlorophenyl) {4-[2—(4~hydroxy—4-methylpiperidin~ l —
yl)ethyl]phenyl} -5 -ox0—4,5—dihydr0- 1 H-l ,2,4-triazol—3-yl]—N—(propan-Z—yl)acetamide;
- Example D—56: 2-[4—(3-chlor0phenyl)-1—{4-[2-(7—oxa-2—azaspiro[3.5]non—2—
yl)ethyl]phenyl}oxo-4,5-dihydro- 1H— 1 riazoly1]—N—(propan—Z-yl)acetamide;
' Example D-57: 2—[4-(3—chlorophenyl)-l-{4-[2-(4-fluoropiperidinyl)ethyl]phenyl}~5—oxo—
4,5-dihydro— 1 H- 1 riazolyl]-N-(propanyl)acetamide;
' Example D-S 8: 2—[4-(3 ophenyl){4-[2-(4,4-difluoropiperidinyl)ethyl]phenyl}-5 -
-dihydr0-1H-1,2,4-triazol—3-yl]—N—(propan—Z-yl)acetamide;
- Example D-59: 2—[4-(3-chlor0phenyl)ox0(4-{2—[4~(trifluoromethyl)piperidin—l-
~208—
yl] ethyl } phenyl)-4,5 —‘dihydro—1H—1,2,4-triazol—3 -yl] -N-(propanyl)acetamide;
' Example D-60: 2-[4-(3-chloropheny1) {4-[2-(3 ethylmorpholinyl)ethyl]phenyl }
—oxo-4,5-dihydro— 1 H— l ,2,4—triazol—3 -yl]~N-(propan-2~y1)acetamide;
- Example D-6l: 2-[4-(3-chlorophenyl)-1— {4—[2—(2—oxa—6—azaspiro[3.3]hept—6-
yl)ethyl]phenyl}oxo—4,5—dihydro-1H-1,2,4—triazolyl]—N-(propan-Z—yl)acetamide.
Table 4 shows the results of 1H-NMR and MS measurements in Example D-43 to D-46.
[Table 4]
Table 4
MS (ESI pos.)
Structure
m/z([M+H]*)
1H NMR (600 MHZ, FORM—d) 6
ppm ; 1.16 (6 H, d, J=6.6 HZ), 1.85 (4 H, br.
.), 2.50 - 2.97 (7 H, m), 3.46 (2 H, s), 4.01 -
4.09 (l H, m), 5.83 — 5.92 (1 H, m), 7.28 -
7.36 (5 H, m), 7.51 - 7.54 (1 H, m), 7.87 (2
H, d, J=8.3 Hz)
1H NMR (600 MHZ, CHLOROFORM—d) 5
ppm ; 1.16 (6 H, d, J=6.6 Hz), 1.43 - 1.50 (2
H, m), 1.63 (4 H, br. 5.), 2.39 — 2.53 (4 H, m),
2.54 " 2.62 (2 H, m), 2.78 — 2.90 (2 H, m),
3.46 (2 H, s), 3.99 ~ 4.12 (1 H, m), 5.82 -
.93 (l H, m), 7.28 — 7.36 (4 H, m), 7.50 -
7.56 (1 H, In), 7.86 (2 H, d, J=8.7 HZ)
1H NMR (600 MHz, CHLOROFORM-d) 6
ppm ; 1.15 (6 H, dd, J=6.6, 0.8 Hz), 1.81 (4
H, br. 3.), 2.58 (4 H, br. 5.), 2.67 - 2.76 (2 H,
m), 2.82 - 2.90 (2 H, In), 3.47 (2 H, s), 3.96 - 468
4.12 (1 H, m), 5.89 - 6.02 (1 H, m), 7.30 (3
H, m), 7.37 - 7.52 (3 H, In), 7.87 (2 H, d,
J=7.8 Hz)
1H NMR (600 MHZ, CHLOROFORM—d) 5
ppm ; 1.14 (6 H, d, J=6.6 Hz), 1.41 ~ 1.50 (2
H, m), 1.58 ~ 1.67 (4 H, m), 2.40 - 2.52 (4 H,
D-46 m), 2.53 “ 2.61 (2 H, m), 2.78 - 2.89 (2 H, 482
m), 3.47 (2 H, s), 3.98 - 4.10 (1 H, In), 5.90 -
6 0 L00 (1 H, m), 7.27 - 7.34 (3 H, m), 7.38 -
7.4 (3 H, m), 7.86 (2 H, d, J=8.7 Hz)
Tables 5-1 to 5—3 show the results of measurements ofMS and retention time in
HPLC as performed in Examples D-47 to D-61.
[075 8]
[Table 5—1]
Table 5-1
Conditions for LC-MS MS (ESI pos.)
Example ure measurement m/z([M+H]*)
-210—
[Table 5-2]
Table 5-2
ure Conditions for LC-MS MS (ESI pos.)
measurement RT (min)
m/z([M+H]+)
[Table 5-3]
Table 5-3
Conditions for LC—MS MS (ESI pos.)
Example Structure RT (mm)
measurement +H]+)
Test Example 1
- Binding test for Vlb receptor
Human Vlb or was transiently expressed in 293FT cells (Invitrogen). The cells were
collected and then homogenated in a 15 mmol/L tris—hydrochloric acid buffer (pH 7.4 and
containing 2 mmol/L magnesium chloride, 0.3 mmol/L ethylenediaminetetracetic acid, and
1 mmol/L glycol ether diaminetetraacetic acid). The ing homogenate was centrifuged
at 50,000 X g at 4 °C for 20 minutes. The precipitate was resuspended in a 75 mmol/L tris-
hydrochloric acid buffer (pH 7.4 and containing 12.5 mmol/L magnesium chloride,
0.3 mmol/L ethylenediaminetetracetic acid, 1 mmol/L glycol ether diaminetetraacetic acid,
and 250 mmol/L sucrose) to give a crude membrane preparation, which was stored at -80°C
until the binding test was initiated. In the binding test, the crude membrane preparation was
diluted with a 50 mmol/L tris-hydrochloric acid buffer (pH 7.4 and containing 10 mmol/L
magnesium chloride and 0.1% bovine serum n) and mixed with each test compound
and [3H]AVP (final concentration: 0.4 to l nmol/L), ed by incubation at room
—212-
temperature for 60 minutes. The test compound was serially diluted with DMSO so that it
would have final concentrations of 0.01 nmol/L to 1 umol/L at the time of mixing. After the
incubation, the mixture was n filtered through a GF/C filter that was preliminarily
nated with 0.3% polyethyleneimine. The GF/C filter was dried and after adding a
scintillator, the residual radioactivity on the filter was measured using TopCount
(PerkinElmer Inc). The radioactivity in the presence of unlabeled AVP at 10 umol/L was
defined as 0%, and the radioactivity in the absence of unlabeled AVP was defined as 100%.
A dose-response curve was plotted from ctivities in the presence of a test compound at
various concentrations, and the 50% inhibitory concentration (ICso value) of the test
compound was ated. The ICso values of the compounds of the present invention were
in the range of 0.1 to 1000 nM. The results are shown in Tables 6-1 and 6.2
—213-
[Table 6—1]
Table 6-1
Example No. |Csovalue(nmo|/L) Example No. -Example No. leovalue(nmo|/L)
Am 1-5 Ml —B-12 CD (.0
CO v—4
A—OS 10~100 A—35 100~1000 B -16
B ‘17
A—-07 18 A—37 10~100 8-18
A~08 0.82 10 B-19 @VHU! )
16 .0 O “B 00
A—lO 3.7 A-40 10~100 B—Zl 10~100
A—ll 10 A—41 100~1000 BHZZ 10~100
6 3 10~100
100~1000
B NNvDOJ NOOCOW 1
—214—
[Table6—2]
Table6-2
Example No. ICso value (nmol/L) Example No. leo value (nmol/L) Example No. leo value (nmol/L)
D—38 10~100
~100 D—39 10~100
D—40 100~1000
~100 D—41
D-42 \lN ‘0‘]
D—43 )—‘ O1
D-44 16
D~45 10~100
~100 D—l6 10~100 D—46 10~100
D-47 100~1000
U I 4:. 00 10~100
O “11 #500 0.7L") 13-19 10~ 100 U l a o 100~1000
-O —12 D—2O U l 01 o 100~1000
O —13 16 D -21 x] 01 l 01 100~1000
O —14 14 D —22 [\J 01 100~1000
O | ,_‘ 'l
o 22 13-23 (A) (A) UUUU O1 10~100
| >h-OJNH 10~100 l 0101 100~1000
I O1 10~100
. 01 10~100
C—ZO 10~100 3—28 10~100 C11 10~1OO
~21 14 3—29 10~100 UUUUU 01 «oooxxoucn 100~1000
C—22 8.8 3-‘80 [\D . 8 *60 00
D -01 N . L“) ii-61 10~100
D-OZ H \1
D—03 (D . H
D—04 100 ~ 1000 3—34 CO . D.)
O O O1 3—35 l—4 00
i4 3—36 0 . O3 ,_.
U | O .q 01 5 3—37 D—‘ [\‘J
Test Example 2
- ement of Vlb receptor antagonistic activity
CHO cells (ATCC) so d as to express human Vlb receptor in a stable
5anner were cultured in Ham's F-12 medium (containing 10% FBS and 0.5 mg/mL
Geneticin). On the day before the test, seeding was conducted at a density of
-215—
,000 cells/well in a 96-well poly—D~lysine coated black plate. On the day of the test, the
culture medium was removed, and a loading on (1 X HBSS, 10 mmol/L HEPES, 0.1%
bovine serum albumin, 1.25 mmol/L Probenecid, 0.02% Pluronic F-127, 1.5 umol/L Fluo
AM, pH 7.4) was added to each well, followed by incubation in a C02 incubator for an hour.
After the incubation, the loading on was removed. A test solution (1 X HBSS,
mmol/L HEPES, 0.1% bovine serum albumin, 1.25 mmol/L Probenecid, pH 7.4)
ning any one of test compounds was added to wells, followed by incubation in a C02
incubator for 30 minutes. The test compound was serially diluted with DMSO so that it
would have final concentrations of 0.1 nmol/L to 1 umol/L at the time of assaying. After the
incubation, fluorescence intensity levels were measured and AVP added by means of FDSS
(Hamamatsu Photonics K.K.); AVP was added to give a final concentration of 2.5 nmol/L at
the time of assaying. At this tration, AVP shows 70 to 80% of its maximum response.
The fluorescence level in a well to which r test compound nor AVP was added was
defined as 0%, and the fluorescence level in a well to which only AVP was added and no test
compound was added was defined as 100%. A dose-response curve was plotted from
fluorescence levels after the addition of AVP in the presence of a test compound at various
concentrations, and the 50% inhibitory concentration (ICSO value) of the compound was
calculated. The results are shown in Table 7.
[Table 7]
Table 7
lC50 value
Example No. (nmol/L)
A—OZ 3 2
3-02 1 0
C-lZ 3 2
D-Ol 2 1
INDUSTRIAL APPLICABILITY
-216~
The present invention is able to provide agents for treating or preventing mood
disorder, anxiety disorder, phrenia, Alzheimer's disease, Parkinson's disease,
gton's chorea, eating disorder, hypertension, gastrointestinal e, drug addiction,
epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation,
immune-related disease, alopecia, and so forth.
—217-
Claims (1)
1. An azole derivative represented by Formula (I): or a pharrnaceutically acceptable salt of the azole derivative, whereinin the above Formula (I), R1 represents a hydrogen atom, C1-5 alkyl, C3_7 cycloalkyl, or 4— to 8~membered saturated heterocycle, wherein the C1_5 alkyl is optionally substituted by one to three groups selected from the group consisting of y, halogen atoms, cyano, C3_7 cycloalkyl, and C1_5 alkoxy; R2 represents a hydrogen atom or C1-5 alkyl; R3 represents aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or two groups selected from the group consisting of CH alkoxy, C1-5 alkyl, n atoms, romethyl, trifluoromethoxy, cyano, hydroxy, difluoromethoxy, and C1_5 alkylsulfonyl; R4 and R5 which may be the same or different each represent a hydrogen atom, C1-5 alkyl, C3- 7 cycloalkyl, or a 4- to 8—membered saturated or unsaturated heterocycle containing one or more nitrogen, oxygen or sulfur atoms in the ring, wherein the C1_5 alkyl is optionally substituted by one to three groups selected from the group consisting ofhydroxy, halogen atoms, cyano, C3_7 cycloalkyl, and C15 alkoxy, and the 4- to ered saturated or unsaturated heterocycle is optionally substituted by one or two groups ed from the group consisting ofhydroxy, C1-5 alkyl, C1_5 alkoxy, halogen atoms, cyano, C2-5 alkanoyl, and trifluoromethyl, or R4 and R5, together with the adjoining nitrogen atom, form a 4— to 8—membered saturated or -218— unsaturated cycle optionally containing one or more nitrogen, oxygen or sulfur atoms in the ring in addition to the ing nitrogen atom, 2-oxaazaspiro[3.3]heptyl or 7- oxa—2—azaspiro[3.5]non—2-yl, wherein the 4- to 8—membered saturated or unsaturated heterocycle is optionally substituted by one or two groups selected from the group consisting of hydroxy, C1_5 , n atoms, cyano, C2-5 alkanoyl, oxo, aminocarbonyl, mono—C1_5 alkylaminocarbonyl, di—C1_5 alkylaminocarbonyl, trifluoromethyl, amino, mono-CH alkylamino, di—C1_5 alkylamino, C2-5 alkanoylamino, and C1_5 alkyl ally substituted by one or two hydroxyl groups, and the 4— to 8-membered saturated or unsaturated heterocycle optionally has a C1-5 alkylene group crosslinking two different carbon atoms in the ring; the optionally substituted azole ring which is represented by the following formula (0t): [Chem 2] 35::- 1.!“Y2 3 :Y3 _§- ‘31:! “Y4 (0t) has any one of the structrures in the following formula group (II): [Chem 3] yiN 3i /N 5": N f \ N
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011-236487 | 2011-10-27 | ||
JP2011236487 | 2011-10-27 | ||
PCT/JP2012/077541 WO2013062027A1 (en) | 2011-10-27 | 2012-10-25 | Azole derivative |
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Publication Number | Publication Date |
---|---|
NZ623918A NZ623918A (en) | 2015-07-31 |
NZ623918B2 true NZ623918B2 (en) | 2015-11-03 |
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