JP6927042B2 - グアニジン誘導体及びその医薬用途 - Google Patents
グアニジン誘導体及びその医薬用途 Download PDFInfo
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- JP6927042B2 JP6927042B2 JP2017541135A JP2017541135A JP6927042B2 JP 6927042 B2 JP6927042 B2 JP 6927042B2 JP 2017541135 A JP2017541135 A JP 2017541135A JP 2017541135 A JP2017541135 A JP 2017541135A JP 6927042 B2 JP6927042 B2 JP 6927042B2
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- 150000002357 guanidines Chemical class 0.000 title claims description 124
- 229940083094 guanine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 6
- -1 5-chloro-2-thienyl group Chemical group 0.000 claims description 327
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 175
- 125000004432 carbon atom Chemical group C* 0.000 claims description 108
- 125000005843 halogen group Chemical group 0.000 claims description 69
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 59
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 55
- 125000001153 fluoro group Chemical group F* 0.000 claims description 54
- 229910052731 fluorine Inorganic materials 0.000 claims description 52
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 50
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 49
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 49
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 45
- 239000003795 chemical substances by application Substances 0.000 claims description 42
- 125000003545 alkoxy group Chemical group 0.000 claims description 40
- 229910052801 chlorine Inorganic materials 0.000 claims description 38
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 34
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 28
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 27
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 125000003277 amino group Chemical group 0.000 claims description 25
- 201000004681 Psoriasis Diseases 0.000 claims description 22
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 20
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 19
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 19
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 19
- 229910052727 yttrium Inorganic materials 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 208000023275 Autoimmune disease Diseases 0.000 claims description 15
- 208000026935 allergic disease Diseases 0.000 claims description 15
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 15
- 230000001225 therapeutic effect Effects 0.000 claims description 15
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 13
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 9
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- 108090000623 proteins and genes Proteins 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 102000004169 proteins and genes Human genes 0.000 claims description 7
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 229940124384 agent for atopic dermatitis Drugs 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 210000004877 mucosa Anatomy 0.000 claims description 2
- 102100029007 Translocation protein SEC62 Human genes 0.000 claims 1
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- 239000003112 inhibitor Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 369
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 267
- 238000003786 synthesis reaction Methods 0.000 description 237
- 230000015572 biosynthetic process Effects 0.000 description 236
- 238000005160 1H NMR spectroscopy Methods 0.000 description 230
- 238000006243 chemical reaction Methods 0.000 description 166
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 132
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 127
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 126
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 110
- 239000002904 solvent Substances 0.000 description 102
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 101
- 239000000203 mixture Substances 0.000 description 97
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 93
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 87
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 75
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 74
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 71
- 230000002829 reductive effect Effects 0.000 description 70
- 239000011541 reaction mixture Substances 0.000 description 69
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 68
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 64
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 63
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine group Chemical group NC(=N)N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 62
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 58
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 55
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 54
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 54
- 239000003153 chemical reaction reagent Substances 0.000 description 53
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 52
- 239000007810 chemical reaction solvent Substances 0.000 description 48
- 238000000034 method Methods 0.000 description 48
- 239000012043 crude product Substances 0.000 description 47
- 239000000243 solution Substances 0.000 description 47
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 45
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- 230000035484 reaction time Effects 0.000 description 40
- SQBNAFJLXJOGQC-UHFFFAOYSA-N 2-[[5,6-bis(4-chlorophenyl)pyridin-3-yl]methyl]guanidine Chemical compound NC(N)=NCc1cnc(-c2ccc(Cl)cc2)c(c1)-c1ccc(Cl)cc1 SQBNAFJLXJOGQC-UHFFFAOYSA-N 0.000 description 39
- 101150113681 MALT1 gene Proteins 0.000 description 39
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 38
- 235000010290 biphenyl Nutrition 0.000 description 38
- 239000004305 biphenyl Substances 0.000 description 38
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 38
- 102100038732 Mucosa-associated lymphoid tissue lymphoma translocation protein 1 Human genes 0.000 description 37
- 108700026676 Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Proteins 0.000 description 36
- 238000005859 coupling reaction Methods 0.000 description 36
- 238000010898 silica gel chromatography Methods 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 34
- 239000012044 organic layer Substances 0.000 description 34
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
- 238000006722 reduction reaction Methods 0.000 description 32
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000012046 mixed solvent Substances 0.000 description 30
- 239000002798 polar solvent Substances 0.000 description 29
- 229910000027 potassium carbonate Inorganic materials 0.000 description 29
- 235000011181 potassium carbonates Nutrition 0.000 description 29
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 28
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 27
- 230000000694 effects Effects 0.000 description 27
- 229910052751 metal Inorganic materials 0.000 description 27
- 239000002184 metal Substances 0.000 description 27
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 27
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 26
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 26
- 229960004198 guanidine Drugs 0.000 description 26
- 150000007530 organic bases Chemical class 0.000 description 25
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- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 24
- SYVRJQOZOKBHDH-UHFFFAOYSA-N C1(=CC=CC=C1)S(=O)(=O)NC(SC)=NC(=O)OC(C)(C)C Chemical compound C1(=CC=CC=C1)S(=O)(=O)NC(SC)=NC(=O)OC(C)(C)C SYVRJQOZOKBHDH-UHFFFAOYSA-N 0.000 description 23
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 23
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- 102000035195 Peptidases Human genes 0.000 description 22
- 108091005804 Peptidases Proteins 0.000 description 22
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 22
- 235000017557 sodium bicarbonate Nutrition 0.000 description 22
- MNNBCLKLPFXCPB-UHFFFAOYSA-N 1-(benzenesulfonyl)-2-[[6-(4-chlorophenyl)-5-[4-(trifluoromethyl)phenyl]pyridin-3-yl]methyl]guanidine Chemical compound N\C(NS(=O)(=O)c1ccccc1)=N/Cc1cnc(-c2ccc(Cl)cc2)c(c1)-c1ccc(cc1)C(F)(F)F MNNBCLKLPFXCPB-UHFFFAOYSA-N 0.000 description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 16
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- 230000008719 thickening Effects 0.000 description 2
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- 125000004306 triazinyl group Chemical group 0.000 description 2
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Images
Classifications
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Description
R1及びR4は、それぞれ独立して、水素原子、フッ素原子、塩素原子、メチル基、トリフルオロメチル基、メトキシ基、イソプロポキシ基、トリフルオロメトキシ基又はシアノ基であり、R2、R3、R5及びR6は、それぞれ独立して、水素原子、フッ素原子又は塩素原子であり、X〜Zの組み合わせは、X=CH、Y=N、かつ、Z=CR7であるか、X=CH、Y=CH、かつ、Z=Nであるか、X=N、Y=CH、かつ、Z=CHであるか、又は、X=N、Y=CH、かつ、Z=Nであり、R7は、水素原子、フッ素原子、メチル基、メトキシ基又はヒドロキシ基であり、R8は、水素原子又はメチル基であり、Aは、S(=O)2であり、R9は、ジメチルアミノ基、ベンジル基、炭素数3〜6のシクロアルキル基、1個の水素原子がハロゲン原子、炭素数1〜3のアルコキシ基、ヒドロキシ基若しくはシアノ基、で置換されていてもよいフェニル基、又は、1個の水素原子がハロゲン原子、メチル基若しくはシアノ基、で置換されていてもよいヘテロアリール基であり、R10は、水素原子、メチル基、ヒドロキシ基又はアミノ基であること、
R1及びR4は、それぞれ独立して、水素原子、フッ素原子、塩素原子、メチル基、トリフルオロメチル基、メトキシ基、トリフルオロメトキシ基又はシアノ基であり、R2、R3、R5及びR6は、水素原子であり、X〜Zの組み合わせは、X=CH、Y=N、かつ、Z=CR7であるか、X=CH、Y=CH、かつ、Z=Nであるか、X=N、Y=CH、かつ、Z=CHであるか、又は、X=N、Y=CH、かつ、Z=Nであり、R7は、水素原子、フッ素原子、メチル基、メトキシ基又はヒドロキシ基であり、R8は、水素原子であり、Aは、S(=O)2であり、R9は、ジメチルアミノ基、炭素数3〜6のシクロアルキル基、2−チエニル基、5−クロロ−2−チエニル基、3−チエニル基、2−フリル基、3−フリル基、2−ベンゾチエニル基、又は、1個の水素原子がハロゲン原子、炭素数1〜3のアルコキシ基、ヒドロキシ基若しくはシアノ基、で置換されていてもよいフェニル基であり、R10は、水素原子、メチル基、ヒドロキシ基又はアミノ基であること、
R1及びR4は、それぞれ独立して、水素原子、フッ素原子、塩素原子、メチル基、トリフルオロメチル基、メトキシ基、トリフルオロメトキシ基又はシアノ基であり、R2、R3、R5及びR6は、水素原子であり、X〜Zの組み合わせは、X=CH、Y=N、かつ、Z=CR7であるか、又は、X=CH、Y=CH、かつ、Z=Nであり、R7は、水素原子であり、R8は、水素原子であり、Aは、C(=O)であり、R9は、エトキシ基、アミノ基、ジメチルアミノ基、2−チアゾリル基、4−チアゾリル基、2−チエニル基、3−チエニル基、2−ピリジル基、2−フリル基、1〜3個の水素原子がそれぞれ独立してフッ素原子、メトキシ基若しくはフェニル基、で置換されてもよい炭素数2〜5のアルキル基、1又は2個の水素原子がフッ素原子で置換されてもよい炭素数3〜6のシクロアルキル基、又は、1個の水素原子がフッ素原子、塩素原子、トリフルオロメチル基、メトキシ基若しくはシアノ基、で置換されていてもよいフェニル基であり、R10は、水素原子であること、
R1及びR4は、塩素原子であり、R2、R3、R5及びR6は、水素原子であり、X〜Zの組み合わせは、X=CH、Y=N、かつ、Z=CR7であるか、又は、X=CH、Y=CH、かつ、Z=Nであり、R7は、水素原子であり、R8は、水素原子であり、Aは、C(=O)であり、R9は、エトキシ基、アミノ基、ジメチルアミノ基、2−チアゾリル基、4−チアゾリル基、2−チエニル基、3−チエニル基、2−ピリジル基、2−フリル基、1〜3個の水素原子がそれぞれ独立してフッ素原子、メトキシ基若しくはフェニル基、で置換されてもよい炭素数2〜5のアルキル基、1又は2個の水素原子がフッ素原子で置換されてもよい炭素数3〜6のシクロアルキル基、又は、1個の水素原子がフッ素原子、塩素原子、トリフルオロメチル基、メトキシ基若しくはシアノ基、で置換されていてもよいフェニル基であり、R10は、水素原子であること、又は、
R1及びR4は、塩素原子であり、R2、R3、R5及びR6は、水素原子であり、Xは、CHであり、Yは、Nであり、Zは、CR7であり、R7は、水素原子であり、R8は、水素原子であり、Aは、C(=O)であり、R9は、エトキシ基、アミノ基、ジメチルアミノ基、2−チアゾリル基、4−チアゾリル基、2−チエニル基、3−チエニル基、2−ピリジル基、2−フリル基、1〜3個の水素原子がそれぞれ独立してフッ素原子、メトキシ基若しくはフェニル基、で置換されてもよい炭素数2〜5のアルキル基、1又は2個の水素原子がフッ素原子で置換されてもよい炭素数3〜6のシクロアルキル基、又は、1個の水素原子がフッ素原子、塩素原子、トリフルオロメチル基、メトキシ基若しくはシアノ基、で置換されていてもよいフェニル基であり、R10は、水素原子であること、が好ましい。
R1及びR4は、塩素原子であり、R2、R3、R5及びR6は、水素原子であり、X〜Zの組み合わせは、X=CH、Y=N、かつ、Z=CR7であるか、X=CH、Y=CH、かつ、Z=Nであるか、X=N、Y=CH、かつ、Z=CHであるか、X=N、Y=CH、かつ、Z=Nであり、R7は水素原子、フッ素原子、メチル基、メトキシ基又はヒドロキシ基であり、R8は、水素原子であり、Aは、S(=O)2であり、R9は、ジメチルアミノ基、炭素数3〜6のシクロアルキル基、2−チエニル基、5−クロロ−2−チエニル基、3−チエニル基、2−フリル基、3−フリル基、2−ベンゾチエニル基、又は、1個の水素原子がハロゲン原子、炭素数1〜3のアルコキシ基、ヒドロキシ基若しくはシアノ基、で置換されていてもよいフェニル基であり、R10は、水素原子、メチル基、ヒドロキシ基又はアミノ基であること、又は、
R1及びR4は、それぞれ独立して、水素原子、フッ素原子、塩素原子、メチル基、トリフルオロメチル基、メトキシ基、トリフルオロメトキシ基又はシアノ基であり、R2、R3、R5及びR6は、水素原子であり、Xは、CHであり、Yは、Nであり、Zは、CR7であり、R7は、水素原子又はフッ素原子であり、R8は、水素原子であり、Aは、S(=O)2であり、R9は、ジメチルアミノ基、炭素数3〜6のシクロアルキル基、2−チエニル基、5−クロロ−2−チエニル基、3−チエニル基、2−フリル基、3−フリル基、2−ベンゾチエニル基、又は、1個の水素原子がハロゲン原子、メトキシ基、エトキシ基、ヒドロキシ基若しくはシアノ基、で置換されていてもよいフェニル基であり、R10は、水素原子であること、がより好ましい。
上記炭素数1〜3のアルキル基及び上記炭素数1〜3のアルコキシ基は、それぞれ独立して、1〜5個の水素原子がそれぞれ独立してハロゲン原子で置換されていてもよく、
X及びYは、それぞれ独立して、N又はCHを表し、Zは、N又はCR7を表すが、X、Y及びZが、同時にNを表すことはなく、同時にN以外の基を表すこともなく、
R7は、水素原子、ハロゲン原子、炭素数1〜3のアルキル基、炭素数1〜3のアルコキシ基又はヒドロキシ基を表し、
R8は、水素原子又は炭素数1〜3のアルキル基を表し、
Aは、S(=O)2、C(=O)又はCH2を表し、
R9は、炭素数1〜3のアルコキシ基、アミノ基、ジメチルアミノ基、1〜3個の水素原子がそれぞれ独立してハロゲン原子、メトキシ基若しくはフェニル基、で置換されていてもよい炭素数1〜6のアルキル基、1〜3個の水素原子がそれぞれ独立してハロゲン原子で置換されていてもよい炭素数3〜6のシクロアルキル基、1又は2個の水素原子がそれぞれ独立してハロゲン原子、トリフルオロメチル基、炭素数1〜3のアルコキシ基、ヒドロキシ基若しくはシアノ基、で置換されていてもよいアリール基、又は、1個の水素原子がハロゲン原子、メチル基若しくはシアノ基、で置換されていてもよいヘテロアリール基を表し、
R10は、水素原子、炭素数1〜3のアルキル基、ヒドロキシ基又はアミノ基を表す。]
上記の一般式(I)で示されるグアニジン誘導体(以下、グアニジン誘導体(I))において、R8及びR10が水素原子であるグアニジン誘導体(I−a)は、例えば、スキーム2に記載の方法により得ることができる。
ヘテロアリールメチルアルコール誘導体(III)は、ヘテロアリールエステル誘導体(II−a)の還元反応により得ることができる。
ヘテロアリール誘導体(IV)は、ヘテロアリールメチルアルコール誘導体(III)のハロゲン化反応により得ることができる。また、別法として、ヘテロアリールメチルアルコール誘導体(III)のスルホニル化反応によっても得ることができる。
N−(ヘテロアリールメチル)フタルイミド誘導体(V)は、ヘテロアリール誘導体(IV)とフタルイミドカリウムとの置換反応により得ることができる。
フェニルヘテロアリール誘導体(VII)は、金属触媒及び塩基存在下、N−(ヘテロアリールメチル)フタルイミド誘導体(V)とフェニルボロン酸誘導体(VI−a)とのカップリング反応により得ることができる。
ジフェニルヘテロアリール誘導体(VIII−a)は、金属触媒及び塩基存在下、フェニルヘテロアリール誘導体(VII)とフェニルボロン酸誘導体(VI−b)とのカップリング反応により得ることができる。本工程における、試薬、触媒、配位子、塩基、反応溶媒及び反応温度の条件は、工程1−4と同様である。
ジフェニルヘテロアリールメチルアミン誘導体(IX−a)は、ヒドラジン一水和物存在下、ジフェニルヘテロアリール誘導体(VIII−a)の脱保護反応により得ることができる。
グアニジン誘導体(XI−a)は、ジフェニルヘテロアリールメチルアミン誘導体(IX−a)とグアニジノ化剤(X)とのグアニジノ化反応により得ることができる。
グアニジン誘導体(I−a)は、酸存在下、グアニジン誘導体(XI−a)の脱保護反応により得ることができる。
ヘテロアリールメチルアミン誘導体(XII)は、ヒドラジン一水和物存在下、N−(ヘテロアリールメチル)フタルイミド誘導体(V)の脱保護反応により得ることができる。本工程における、試薬、反応溶媒及び反応温度の条件は、工程1−6と同様である。
グアニジン誘導体(XIII)は、ヘテロアリールメチルアミン誘導体(XII)とグアニジノ化剤(X)とのグアニジノ化反応により得ることができる。本工程における試薬、塩基、反応溶媒及び反応温度の条件は、工程1−7と同様である。
フェニルヘテロアリール誘導体(XIV)は、金属触媒及び塩基存在下、グアニジン誘導体(XIII)とフェニルボロン酸誘導体(VI−a)とのカップリング反応により得ることができる。本工程における、試薬、触媒、配位子、塩基、反応溶媒及び反応温度の条件は、工程1−4と同様である。なお、本工程において、tert−ブトキシカルボニル基の脱保護反応が進行することがある。
グアニジン誘導体(I−a)は、金属触媒及び塩基存在下、フェニルヘテロアリール誘導体(XIV)とフェニルボロン酸誘導体(VI−b)とのカップリング反応により得ることができる。本工程における試薬、触媒、配位子、塩基、反応溶媒及び反応温度の条件は、工程1−5と同様である。なお、本工程において、tert−ブトキシカルボニル基の脱保護反応が進行することがある。
グアニジン誘導体(I)において、R1=R4、R2=R5及びR3=R6であるグアニジン誘導体(I−b)、(I−c)、(I−d)又は(I−e)は、例えば、スキーム3に記載の方法により得ることができる。
ジフェニルヘテロアリール誘導体(XV)は、金属触媒及び塩基存在下、ヘテロアリールエステル誘導体(II−b)とフェニルボロン酸誘導体(VI−a)とのカップリング反応により得ることができる。
ジフェニルヘテロアリールアルコール誘導体(XVI−a)は、ジフェニルヘテロアリール誘導体(XV)の還元反応により得ることができる。本工程における、試薬、反応溶媒、反応温度及び反応時間の条件は、工程1−1と同様である。
ジフェニルヘテロアリール誘導体(XVII)は、ジフェニルヘテロアリールアルコール誘導体(XVI−a)のハロゲン化反応により得ることができる。また、別法として、ジフェニルヘテロアリールアルコール誘導体(XVI−a)のスルホニル化反応によっても得ることができる。本工程における、試薬、反応溶媒、反応温度及び反応時間の条件は、工程1−2と同様である。
ジフェニルヘテロアリール誘導体(VIII−b)は、ジフェニルヘテロアリール誘導体(XVII)とフタルイミドカリウムとの置換反応により得ることができる。本工程における、試薬、反応溶媒、反応温度及び反応時間の条件は、工程1−3と同様である。
ジフェニルヘテロアリールメチルアミン誘導体(IX−b)は、ヒドラジン一水和物存在下、ジフェニルヘテロアリール誘導体(VIII−b)の脱保護反応により得ることができる。本工程における、試薬、反応溶媒、反応温度及び反応時間の条件は、工程1−6と同様である。
ジフェニルヘテロアリールケトン誘導体(XIX)は、N,O−ジメチルヒドロキシルアミン塩酸塩存在下、ジフェニルヘテロアリール誘導体(XV)へのアルキル金属試薬(XVIII)の求核付加反応により得ることができる。
ジフェニルヘテロアリールアルコール誘導体(XVI−b)は、ジフェニルヘテロアリールケトン誘導体(XIX)の還元反応により得ることができる。
アルキルアジド誘導体(XX)は、ジアザビシクロウンデセン存在下、ジフェニルヘテロアリールアルコール誘導体(XVI−b)とジフェニルリン酸アジドとのアジド化反応により得ることができる。
ジフェニルヘテロアリールメチルアミン誘導体(IX−b)は、アルキルアジド誘導体(XX)の還元反応により得ることができる。
カルバムイミド酸誘導体(XXII)は、ジフェニルヘテロアリールメチルアミン誘導体(IX−b)とカルボンイミド酸誘導体(XXI)とのカルバムイミド化反応により得ることができる。
グアニジン誘導体(I−b)は、カルバムイミド酸誘導体(XXII)とアミン誘導体(XXIII)とのグアニジノ化反応により得ることができる。
グアニジン誘導体(XI−b)は、ジフェニルヘテロアリールメチルアミン誘導体(IX−b)とグアニジノ化剤(X)とのグアニジノ化反応により得ることができる。本工程における、試薬、反応溶媒、反応温度及び反応時間の条件は、工程1−7と同様である。
グアニジン誘導体(I−c)は、酸存在下、グアニジン誘導体(XI−b)の脱保護反応により得ることができる。本工程における、試薬、反応溶媒、反応温度及び反応時間の条件は、工程1−8と同様である。
グアニジン誘導体(XXV)は、ジフェニルヘテロアリールメチルアミン誘導体(IX−b)とグアニジノ化剤(XXIV)とのグアニジノ化反応により得ることができる。
グアニジン誘導体(XXVI)は、酸存在下、グアニジン誘導体(XXV)の脱保護反応により得ることができる。本工程における、試薬、反応溶媒、反応温度及び反応時間の条件は、工程1−8と同様である。
グアニジン誘導体(I−d)は、グアニジン誘導体(XXVI)とスルホニル化剤(XXVII)とのスルホニル化反応により得ることができる。
グアニジン誘導体(I−e)は、グアニジン誘導体(XXVI)とアシル化剤(XXVIII)とのアシル化反応により得ることができる。また、別法としてグアニジン誘導体(XXVI)とカルボン酸(XXIX)との縮合反応により得ることができる。
グアニジン誘導体(I)において、R8=Hであるグアニジン誘導体(I−f)又は(I−g)は、例えば、スキーム4に記載の方法により得ることができる。
ジフェニルエタノン誘導体(XXXII)は、ルイス酸存在下、フェニル酢酸クロリド誘導体(XXX)とベンゼン誘導体(XXXI)とのフリーデルクラフツ反応により得ることができる。
エナミン誘導体(XXXIII)は、ジフェニルエタノン誘導体(XXXII)とN,N−ジメチルホルムアミドジメチルアセタールとの縮合反応により得ることができる。
シアノピリドン誘導体(XXXIV)は、塩基存在下、エナミン誘導体(XXXIII)と2−シアノアセトアミドとの付加環化反応により得ることができる。
ジフェニルピリジン誘導体(XXXVI)は、シアノピリドン誘導体(XXXIV)とアルキル化剤(XXXV)とのアルキル化反応により得ることができる。
シアノピリジン誘導体(XXXVII)は、シアノピリドン誘導体(XXXIV)のハロゲン化反応により得ることができる。また、別法として、シアノピリドン誘導体(XXXIV)のスルホニル化反応によっても得ることができる。
ジフェニルピリジン誘導体(XXXVI)は、シアノピリジン誘導体(XXXVII)のフッ化カリウムとのフッ素化反応により得ることができる。
ジフェニルピリジン誘導体(XXXVI)は、金属触媒及び塩基存在下、シアノピリジン誘導体(XXXVII)とアルキル金属誘導体(XXXVIII)とのカップリング反応により得ることができる。
ジフェニルヘテロアリールメチルアミン誘導体(IX−c)は、ジフェニルピリジン誘導体(XXXVI)の還元反応により得ることができる。
ジフェニルヘテロアリールメチルアミン誘導体(IX−c)は、塩基存在下、エナミン誘導体(XXXIII)とアミノアセトアミジン臭化水素酸塩との付加環化反応により得ることができる。
グアニジン誘導体(XI−c)は、ジフェニルヘテロアリールメチルアミン誘導体(IX−c)とグアニジノ化剤(X)とのグアニジノ化反応により得ることができる。本工程における、試薬、反応溶媒、反応温度及び反応時間の条件は、工程1−7と同様である。
グアニジン誘導体(I−f)は、酸存在下、グアニジン誘導体(XI−c)の脱保護反応により得ることができる。本工程における、試薬、反応溶媒、反応温度及び反応時間の条件は、工程1−8と同様である。
グアニジン誘導体(I−g)は、酸存在下、グアニジン誘導体(I−f)の水和反応により得ることができる。
グアニジン誘導体(I)において、R1〜R3が、水素原子であるグアニジン誘導体(I−i)、又は、R4〜R6が、水素原子であるグアニジン誘導体(I−j)は、例えば、スキーム5に記載の方法により得ることができる。
グアニジン誘導体(I−i)又はグアニジン誘導体(I−j)は、グアニジン誘導体(I−h)(R1〜R3が、それぞれ、水素原子若しくはハロゲン原子である場合、又は、R4〜R6が、それぞれ、水素原子若しくはハロゲン原子である場合)の還元反応により得ることができる。
1H−NMR(DMSO−d6)δ:4.54(2H,d,J=5.0Hz),5.52(1H,t,J=5.0Hz),8.15−8.16(1H,m),8.37−8.38(1H,m).
MS(ESI)[M+H]+:222.
1H−NMR(CDCl3)δ:4.55(2H,s),8.01(1H,d,J=2.3Hz),8.35(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:240.
1H−NMR(CDCl3)δ:4.82(2H,s),7.74−7.78(2H,m),7.87−7.89(2H,m),8.03(1H,d,J=2.3Hz),8.45(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:351.
1H−NMR(CDCl3)δ:4.88(2H,s),7.36(2H,d,J=8.6Hz),7.42(2H,d,J=8.6Hz),7.73−7.76(3H,m),7.84−7.89(2H,m),8.50(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:383.
1H−NMR(CDCl3)δ:4.88(2H,s),7.41−7.45(5H,m),7.74(2H,m),7.75(1H,d,J=2.4Hz),7.86(2H,m),8.49(1H,d,J=2.4Hz).
MS(ESI)[M+H]+:349.
1H−NMR(CDCl3)δ:4.88(2H,s),7.29−7.32(1H,m),7.38−7.41(3H,m),7.73−7.75(3H,m),7.87(2H,m),8.52(1H,d,J=2.4Hz).
MS(ESI)[M+H]+:383.
1H−NMR(CDCl3)δ:4.89(2H,s),7.24−7.26(1H,m),7.31−7.39(2H,m),7.49(1H,m),7.72(1H,d,J=2.2Hz),7.74(2H,m),7.87(2H,m),8.55(1H,d,J=2.4Hz).
MS(ESI)[M+H]+:383.
1H−NMR(CDCl3)δ:2.41(3H,s),4.88(2H,s),7.25(2H,d,J=8.2Hz),7.33(2H,d,J=8.2Hz),7.73(3H,m),7.86(2H,dd,J=5.4,3.2Hz),8.47(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:363.
1H−NMR(CDCl3)δ:3.86(3H,s),4.87(2H,s),6.97(2H,d,J=8.8Hz),7.37(2H,d,J=8.8Hz),7.73(3H,dd,J=5.4,3.2Hz),7.86(2H,dd,J=5.4,3.2Hz),8.46(1H,d,J=2.4Hz).
MS(ESI)[M+H]+:379.
1H−NMR(CDCl3)δ:4.89(2H,s),7.55(2H,d,J=8.6Hz),7.74−7.76(5H,m),7.87(2H,dd,J=5.4,3.2Hz),8.56(1H,d,J=2.7Hz).
MS(ESI)[M+H]+:374.
1H−NMR(CDCl3)δ:4.88(2H,s),7.11−7.16(2H,m),7.38−7.42(2H,m),7.73−7.76(3H,m),7.84−7.88(2H,m),8.49(1H,d,J=2.7Hz).
MS(ESI)[M+H]+:367.
1H−NMR(CDCl3)δ:4.89(2H,s),7.55(2H,d,J=8.2Hz),7.71(2H,d,J=8.2Hz),7.73−7.76(3H,m),7.87(2H,dd,J=5.7,2.9Hz),8.54(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:417.
1H−NMR(CDCl3)δ:4.88(2H,s),7.29(2H,d,J=8.6Hz),7.46(2H,d,J=8.6Hz),7.73−7.76(3H,m),7.85−7.88(2H,m),8.51(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:433.
1H−NMR(CDCl3)δ:1.37(6H,d,J=7.8),4.57−4.63(1H,m),4.87(2H,s),6.94(2H,dt,J=9.4,2.5Hz),7.35(2H,dt,J=9.4,2.5Hz),7.71−7.76(3H,m),7.84−7.88(2H,m),8.45(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:407.
1H−NMR(CDCl3)δ:4.94(2H,s),7.07(2H,d,J=8.2Hz),7.20−7.28(6H,m),7.73−7.75(3H,m),7.85−7.89(2H,m),8.78(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:459.
1H−NMR(CDCl3)δ:4.95(2H,s),7.08(2H,dd,J=6.6,2.0Hz),7.22−7.31(6H,m),7.72−7.76(3H,m),7.85−7.88(2H,m),8.79(1H,d,J=2.2Hz).
MS(ESI)[M+H]+:425.
1H−NMR(CDCl3)δ:4.95(2H,s),7.03−7.14(4H,m),7.22−7.28(3H,m),7.43(1H,t,J=1.8Hz),7.73−7.77(3H,m),7.86−7.89(2H,m),8.78(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:459.
1H−NMR(CDCl3)δ:2.31(3H,s),4.93(2H,s),7.04(2H,d,J=7.8Hz),7.09(2H,dt,J=8.9,2.3Hz),7.16−7.20(2H,m),7.22−7.25(2H,m),7.71−7.75(3H,m),7.87(2H,ddd,J=11.5,6.1,2.2Hz),8.77(1H,d,J=2.2Hz).
MS(ESI)[M+H]+:439.
1H−NMR(CDCl3)δ:3.78(3H,s),4.93(2H,s),6.77(2H,d,J=8.2Hz),7.09(2H,d,J=7.7Hz),7.23−7.26(4H,m),7.71−7.75(3H,m),7.85−7.88(2H,m),8.75(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:455.
1H−NMR(CDCl3)δ:4.94(2H,s),7.03(2H,d,J=8.6Hz),7.25(2H,d,J=8.2Hz),7.40(2H,d,J=8.6Hz),7.52(2H,d,J=8.2Hz),7.72(2H,m),7.77(1H,d,J=2.3Hz),7.85(2H,m),8.78(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:450.
1H−NMR(CDCl3)δ:4.94(2H,s),6.91−6.95(2H,m),7.07(2H,dt,J=8.8,2.3Hz),7.24−7.30(4H,m),7.72−7.75(3H,m),7.85−7.88(2H,m),8.77(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:443.
1H−NMR(CDCl3)δ:4.95(2H,s),6.96(1H,m),7.01(1H,m),7.06−7.10(3H,m),7.16−7.21(1H,m),7.24−7.27(2H,m),7.72−7.77(3H,m),7.88(2H,dd,J=5.4,2.7Hz),8.78(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:443.
1H−NMR(CDCl3)δ:4.96(2H,s),7.05−7.09(2H,m),7.25−7.28(2H,m),7.43(2H,d,J=7.6Hz),7.51(2H,d,J=8.3Hz),7.72−7.78(3H,m),7.85−7.89(2H,m),8.80(1H,d,J=2.0Hz).
MS(ESI)[M+H]+:493.
1H−NMR(CDCl3)δ:4.95(2H,s),7.08−7.15(4H,m),7.24−7.27(2H,m),7.32−7.35(2H,m),7.74(2H,m),7.76(1H,d,J=1.8Hz),7.87(2H,m),8.78(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:509.
1H−NMR(CDCl3)δ:2.23(3H,d,J=1.4Hz),4.94(2H,s),6.90(1H,dd,J=7.8,1.4Hz),7.02(2H,m),7.09(2H,m),7.24−7.27(2H,m),7.74(3H,m),7.85−7.88(2H,m),8.77(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:457.
1H−NMR(CDCl3)δ:2.32(3H,s),4.95(2H,s),6.68(1H,d,J=11.0Hz),6.95(1H,dd,J=7.8,0.9Hz),7.07(2H,m),7.21(2H,m),7.29(1H,d,J=7.8Hz),7.72−7.76(2H,m),7.78(1H,d,J=2.3Hz),7.85−7.89(2H,m),8.79(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:457.
1H−NMR(CDCl3)δ:3.28(3H,s),4.95(2H,s),6.66(1H,d,J=1.8Hz),6.99(1H,dd,J=8.2,1.8Hz),7.03(2H,m),7.20(2H,m),7.32(1H,d,J=8.2Hz),7.72−7.77(3H,m),7.87(2H,m),8.77(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:489.
1H−NMR(CDCl3)δ:4.95(2H,s),7.14(2H,dd,J=6.6,2.9Hz),7.18(2H,d,J=8.8Hz),7.24−7.29(5H,m),7.73(2H,dd,J=5.5,3.0Hz),7.77(1H,d,J=2.2Hz),7.87(2H,dd,J=5.5,3.0Hz),8.77(1H,d,J=2.0Hz).
MS(ESI)[M+H]+:425.
1H−NMR(CDCl3)δ:4.95(2H,s),6.95(1H,dt,J=7.6,1.3Hz),7.16−7.28(7H,m),7.73−7.76(3H,m),7.86−7.89(2H,m),8.79(1H,d,J=2.0Hz).
MS(ESI)[M+H]+:459.
1H−NMR(CDCl3)δ:4.95(2H,s),7.09(1H,dd,J=7.7,1.8Hz),7.17(3H,t,J=8.6Hz),7.22−7.26(3H,m),7.36(1H,d,J=8.2Hz),7.73−7.75(3H,m),7.88(2H,dd,J=5.2,3.4Hz),8.82(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:459.
1H−NMR(CDCl3)δ:2.34(3H,s),4.94(2H,d,J=5.9Hz),7.02(2H,d,J=8.2Hz),7.08(2H,d,J=8.2Hz),7.19(2H,d,J=8.8Hz),7.27(2H,d,J=8.5Hz),7.73(2H,dd,J=5.4,3.2Hz),7.75(1H,d,J=2.3Hz),7.86(2H,dd,J=5.7,2.9Hz),8.74(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:439.
1H−NMR(CDCl3)δ:3.80(3H,s),4.93(2H,s),6.81(2H,d,J=9.5Hz),7.05(2H,d,J=9.4Hz),7.20(2H,d,J=8.9Hz),7.27(2H,d,J=8.9Hz),7.73(2H,dd,J=5.5,3.0Hz),7.75(1H,d,J=2.2Hz),7.87(2H,dd,J=5.5,3.0Hz),8.73(1H,d,J=2.2Hz).
MS(ESI)[M+H]+:455.
1H−NMR(CDCl3)δ:4.96(2H,s),7.22(4H,d,J=1.4Hz),7.24−7.27(2H,m),7.58(2H,d,J=8.6Hz),7.74(2H,dd,J=5.4,3.2Hz),7.78(1H,d,J=2.3Hz),7.88(2H,dd,J=5.7,2.9Hz),8.82(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:450.
1H−NMR(CDCl3)δ:4.94(2H,s),6.95−7.00(2H,m),7.08−7.12(2H,m),7.19−7.26(4H,m),7.72−7.77(3H,m),7.87(2H,dd,J=5.4,3.2Hz),8.77(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:443.
1H−NMR(CDCl3)δ:4.96(2H,s),7.20−7.32(6H,m),7.55(2H,d,J=8.2Hz),7.73−7.76(2H,m),7.78(1H,d,J=2.3Hz),7.85−7.88(2H,m),8.81(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:493.
1H−NMR(CDCl3)δ:4.95(2H,s),7.11−7.18(4H,m),7.19−7.25(4H,m),7.71−7.78(3H,m),7.87(2H,dd,J=5.4,3.2Hz),8.79(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:509.
1H−NMR(CDCl3)δ:1.32(3H,s),1.34(3H,s),4.50−4.56(1H,m),4.93(2H,s),6.78(2H,td,J=5.8,3.5Hz),7.00−7.03(2H,m),7.20(2H,dt,J=8.8,2.2Hz),7.26−7.29(2H,m),7.71−7.75(3H,m),7.84−7.88(2H,m),8.73(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:483.
1H−NMR(CDCl3)δ:2.30(3H,s),3.79(3H,s),4.93(2H,s),6.79(2H,d,J=8.6Hz),7.03(2H,d,J=8.2Hz),7.07(2H,d,J=8.6Hz),7.21(2H,d,J=8.2Hz),7.70−7.74(3H,m),7.86(2H,dd,J=5.7,2.9Hz),8.72(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:435.
1H−NMR(CDCl3)δ:2.31(3H,s),4.95(2H,s),7.04(2H,d,J=8.2Hz),7.17(2H,d,J=8.2Hz),7.28(2H,d,J=8.2Hz),7.52(2H,d,J=8.2Hz),7.71−7.76(3H,m),7.85−7.89(2H,m),8.80(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:473.
1H−NMR(DMSO−d6)δ:2.57(3H,s),8.89(4H,s).
1H−NMR(CDCl3)δ:1.51(9H,s),2.46(3H,s).
1H−NMR(CDCl3)δ:1.52(9H,s),2.29(3H,s),7.50−7.62(3H,m),7.93−7.96(2H,m),10.33(1H,s).
1H−NMR(CDCl3)δ:1.53(9H,s),2.30(3H,s),7.21(1H,t,J=9.1Hz),7.29(1H,t,J=7.7Hz),7.56−7.62(1H,m),7.98(1H,td,J=7.6,1.6Hz),10.39(1H,brs).
1H−NMR(CDCl3)δ:1.53(9H,s),2.30(3H,s),7.27−7.32(1H,m),7.51(1H,td,J=8.1,5.3Hz),7.65(1H,dt,J=8.1,2.0Hz),7.74(1H,dq,J=7.8,0.8Hz),10.26(1H,brs).
1H−NMR(CDCl3)δ:1.53(9H,s),2.28(3H,s),7.17−7.23(2H,m),7.93−7.98(2H,m),10.27(1H,brs).
1H−NMR(CDCl3)δ:1.52(9H,s),2.34(3H,s),7.08(1H,dd,J=5.0,3.8Hz),7.61(1H,dd,J=5.0,1.3Hz),7.68(1H,dd,J=3.8,1.3Hz),10.20(1H,brs).
1H−NMR(CDCl3)δ:1.52(9H,s),2.32(3H,s),7.42(2H,d,J=2.3Hz),8.03(1H,t,J=2.3Hz),10.28(1H,brs).
1H−NMR(CDCl3)δ:1.53(9H,s),2.34(3H,s),6.52(1H,dd,J=3.6,1.8Hz),7.08(1H,dd,J=3.6,0.9Hz),7.57(1H,dd,J=1.8,0.9Hz),10.25(1H,s).
1H−NMR(CDCl3)δ:1.52(9H,s),2.33(3H,s),6.71−6.72(1H,m),7.48(1H,dd,J=4.5,2.7Hz),7.98(1H,dd,J=1.8,0.9Hz),10.20(1H,brs).
1H−NMR(CDCl3)δ:1.53(9H,s),2.59(3H,s),7.43−7.48(2H,m),7.50−7.57(1H,m),8.27−8.29(2H,m).
1H−NMR(CDCl3)δ:1.52(9H,s),2.55(3H,s),7.11−7.13(1H,m),7.58(1H,dd,J=4.9,1.2Hz),7.89(1H,dd,J=3.9,1.2Hz),12.39(1H,brs).
参考例15で合成した2−((5,6−ビス(4−クロロフェニル)ピリジン−3−イル)メチル)イソインドリン−1,3−ジオン(9.5g)をメタノール(40mL)に懸濁させた後、ヒドラジン一水和物(6mL)を加えた。2時間加熱還流した後、反応混合物を室温に冷却して酢酸エチルで希釈し、ろ過した。ろ液を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮することで(5,6−ビス(4−クロロフェニル)ピリジン−3−イル)メタンアミン(5.3g)を得た。
2.グアニジノ化反応
先に合成した(5,6−ビス(4−クロロフェニル)ピリジン−3−イル)メタンアミン(3.5g)をテトラヒドロフラン(30mL)に溶解させた後、参考例42で合成したN−(フェニルスルホニル)−N’−(tert−ブトキシカルボニル)−S−メチルイソチオ尿素(3.9g)を加えた。反応混合物を60℃で6時間撹拌した後、減圧濃縮した。粗生成物をシリカゲルクロマトグラフィー(n−ヘキサン/酢酸エチル)で精製することで表題化合物(6.4g)を得た。
1H−NMR(CDCl3)δ:1.51(9H,s),4.60(2H,d,J=5.4Hz),6.99−7.00(2H,m),7.23−7.27(6H,m),7.35−7.39(2H,m),7.44−7.49(1H,m),7.55(1H,d,J=1.8Hz),7.80−7.83(2H,m),8.55(1H,d,J=1.4Hz),8.99(1H,t,J=5.4Hz),10.00(1H,s).
MS(ESI)[M+H]+:611.
1H−NMR(CDCl3)δ:1.51(9H,s),4.60(2H,d,J=5.9Hz),6.99(2H,dt,J=8.9,2.3Hz),7.23(2H,dt,J=8.8,2.3Hz),7.26−7.30(5H,m),7.35−7.39(2H,m),7.44−7.48(1H,m),7.55(1H,d,J=2.3Hz),7.80−7.84(2H,m),8.56(1H,d,J=2.3Hz),8.99(1H,t,J=5.4Hz),10.00(1H,s).
MS(ESI)[M+H]+:577.
1H−NMR(CDCl3)δ:1.51(9H,s),4.60(2H,d,J=5.9Hz),6.97−7.04(3H,m),7.14(1H,t,J=7.7Hz),7.24−7.27(3H,m),7.35−7.40(2H,m),7.42(1H,t,J=1.8Hz),7.45−7.49(1H,m),7.56(1H,d,J=1.8Hz),7.80−7.83(2H,m),8.56(1H,d,J=2.3Hz),9.00(1H,t,J=5.7Hz),10.00(1H,s).
MS(ESI)[M+H]+:611.
1H−NMR(CDCl3)δ:1.50(9H,s),2.32(3H,s),4.59(2H,d,J=5.9Hz),7.00(2H,dt,J=8.9,2.3Hz),7.06(2H,d,J=7.7Hz),7.16−7.19(2H,m),7.21−7.26(2H,m),7.34−7.39(2H,m),7.43−7.47(1H,m),7.52(1H,d,J=2.3Hz),7.80−7.83(2H,m),8.54(1H,d,J=2.3Hz),8.98(1H,t,J=5.4Hz),9.99(1H,s).
MS(ESI)[M+H]+:591.
1H−NMR(CDCl3)δ:1.50(9H,s),3.80(3H,s),4.59(2H,d,J=5.9Hz),6.79(2H,d,J=8.2Hz),7.01(2H,d,J=7.7Hz),7.22−7.27(4H,m),7.35−7.39(2H,m),7.44−7.48(1H,m),7.51(1H,d,J=1.4Hz),7.82(2H,d,J=8.2Hz),8.53(1H,d,J=1.4Hz),8.97(1H,t,J=5.4Hz),9.99(1H,s).
MS(ESI)[M+H]+:607.
1H−NMR(CDCl3)δ:1.51(9H,s),4.61(2H,d,J=5.9Hz),6.98(2H,d,J=8.2Hz),7.25−7.29(2H,m),7.38(2H,t,J=8.2Hz),7.41(2H,d,J=8.6Hz),7.47(1H,tt,J=7.5,1.6Hz),7.56(2H,d,J=8.6Hz),7.60(1H,d,J=2.3Hz),7.81−7.83(2H,m),8.59(1H,d,J=1.8Hz),9.01(1H,t,J=5.4Hz),10.00(1H,s).
MS(ESI)[M+H]+:602.
1H−NMR(CDCl3)δ:1.51(9H,s),4.60(2H,d,J=5.9Hz),6.93−7.00(4H,m),7.24−7.29(4H,m),7.37(2H,t,J=7.7Hz),7.46(1H,t,J=7.5Hz),7.55(1H,d,J=2.3Hz),7.81−7.83(2H,m),8.55(1H,d,J=2.3Hz),8.99(1H,t,J=5.4Hz),10.00(1H,s).
MS(ESI)[M+H]+:595.
1H−NMR(CDCl3)δ:1.51(9H,s),4.60(2H,d,J=5.9Hz),6.96−7.01(4H,m),7.07(1H,dq,J=10.0,1.4Hz),7.17−7.23(1H,m),7.23−7.26(2H,m),7.38(2H,t,J=7.7Hz),7.47(1H,t,J=7.2Hz),7.56(1H,d,J=2.3Hz),7.80−7.83(2H,m),8.56(1H,d,2.3Hz),9.00(1H,t,J=5.7Hz),10.00(1H,s).
MS(ESI)[M+H]+:595.
1H−NMR(CDCl3)δ:1.51(9H,s),4.61(2H,d,J=5.4Hz),6.99(2H,dt,J=8.9,2.3Hz),7.24−7.28(2H,m),7.36−7.48(5H,m),7.53(2H,d,J=8.2Hz),7.59(1H,d,J=2.3Hz),7.81−7.84(2H,m),8.58(1H,d,J=1.8Hz),9.01(1H,t,J=5.7Hz),10.00(1H,s).
MS(ESI)[M+H]+:645.
1H−NMR(CDCl3)δ:1.51(9H,s),4.60(2H,d,J=5.4Hz),6.99(2H,d,J=8.6Hz),7.11(2H,d,J=8.6Hz),7.24−7.27(2H,m),7.32−7.39(4H,m),7.47(1H,t,J=7.5Hz),7.57(1H,d,J=1.8Hz),7.82(2H,d,J=7.7Hz),8.56(1H,d,J=1.8Hz),8.99(1H,brs),10.00(1H,s).
1H−NMR(CDCl3)δ:1.51(9H,s),2.25(3H,d,J=1.4Hz),4.59(2H,d,J=5.9Hz),6.89(1H,dd,J=7.8,1.8Hz),7.02(4H,tt,J=9.1,3.1Hz),7.25(2H,dd,J=6.2,3.9Hz),7.37(2H,td,J=6.9,1.7Hz),7.44−7.49(1H,m),7.53(1H,d,J=2.3Hz),7.79−7.83(2H,m),8.54(1H,d,J=2.3Hz),8.99(1H,t,J=5.5Hz),10.00(1H,s).
MS(ESI)[M+H]+:609.
1H−NMR(CDCl3)δ:1.51(9H,s),2.34(3H,s),4.61(2H,d,J=5.9Hz),6.71(1H,d,J=11.4Hz),6.96−6.99(3H,m),7.20(2H,dd,J=6.6,2.1Hz),7.26(1H,t,J=7.8Hz),7.37(2H,td,J=6.7,1.5Hz),7.43−7.49(1H,m),7.56(1H,d,J=2.3Hz),7.80−7.83(2H,m),8.56(1H,d,J=1.8Hz),9.00(1H,t,J=6.2Hz),10.00(1H,s).
MS(ESI)[M+H]+:609.
1H−NMR(CDCl3)δ:1.51(9H,s),3.30(3H,s),4.61(2H,d,J=5.9Hz),6.68(1H,d,J=1.8Hz),6.97(2H,dt,J=9.0,2.3Hz),7.01(1H,dd,J=8.2,1.8Hz),7.20(2H,dt,J=8.8,2.3Hz),7.31(1H,d,J=8.2Hz),7.37−7.40(2H,m),7.45−7.49(1H,m),7.56(1H,d,J=1.8Hz),7.84(2H,td,J=4.8,2.7Hz),8.54(1H,d,J=1.8Hz),8.98(1H,t,J=5.7Hz),10.00(1H,s).
MS(ESI)[M+H]+:641.
1H−NMR(CDCl3)δ:1.51(9H,s),4.60(2H,d,J=5.9Hz),7.05−7.07(2H,m),7.19−7.30(6H,m),7.36(3H,t,J=7.6Hz),7.45(1H,t,J=7.4Hz),7.57(1H,d,J=2.2Hz),7.80−7.83(2H,m),8.54(1H,d,J=2.2Hz),8.98(1H,t,J=5.5Hz),9.99(1H,s).
MS(ESI)[M+H]+:577.
1H−NMR(CDCl3)δ:1.51(9H,s),4.60(2H,d,J=5.9Hz),6.89(1H,dt,J=7.7,1.3Hz),7.11(1H,t,J=1.8Hz),7.17−7.22(2H,m),7.27−7.30(2H,m),7.34−7.53(5H,m),7.80−7.82(2H,m),8.57(1H,d,J=2.2Hz),8.99(1H,t,J=6.0Hz),9.98(1H,d,J=7.8Hz).
MS(ESI)[M+H]+:611.
1H−NMR(CDCl3)δ:1.51(9H,s),4.62(2H,d,J=5.9Hz),7.01(1H,dd,J=7.7,1.8Hz),7.17−7.24(5H,m),7.29(1H,dd,J=7.5,1.6Hz),7.33−7.43(4H,m),7.52(1H,d,J=1.8Hz),7.80−7.82(2H,m),8.59(1H,d,J=2.3Hz),9.00(1H,t,J=6.1Hz),9.98(1H,s).
MS(ESI)[M+H]+:611.
1H−NMR(CDCl3)δ:1.50(9H,s),2.36(3H,s),4.59(2H,d,J=5.4Hz),6.95(2H,d,J=7.7Hz),7.09(2H,d,J=8.2Hz),7.21(2H,d,J=8.6Hz),7.24−7.27(2H,m),7.37(2H,t,J=7.5Hz),7.44(1H,d,J=7.2Hz),7.55(1H,d,J=2.3Hz),7.81(2H,d,J=7.2Hz),8.52(1H,d,J=2.3Hz),8.97(1H,t,J=5.4Hz),9.98(1H,s).
MS(ESI)[M+H]+:591.
1H−NMR(CDCl3)δ:1.51(9H,s),3.82(3H,s),4.59(2H,d,J=5.9Hz),6.81(2H,d,J=9.2Hz),6.98(2H,d,J=9.1Hz),7.22(2H,d,J=8.6Hz),7.26(2H,d,J=8.8Hz),7.36−7.39(2H,m),7.44−7.48(1H,m),7.56(1H,d,J=2.2Hz),7.81−7.83(2H,m),8.51(1H,d,J=2.2Hz),8.97(1H,t,J=5.6Hz),9.99(1H,s).
MS(ESI)[M+H]+:607.
1H−NMR(CDCl3)δ:1.51(9H,s),4.60(2H,d,J=5.9Hz),7.18−7.27(6H,m),7.39(2H,t,J=7.9Hz),7.48(1H,t,J=7.0Hz),7.58(2H,d,J=8.2Hz),7.61(1H,d,J=2.3Hz),7.82(2H,d,J=7.7Hz),8.60(1H,d,J=2.3Hz),9.01(1H,t,J=5.7Hz),10.00(1H,s).
MS(ESI)[M+H]+:602.
1H−NMR(CDCl3)δ:1.51(9H,s),4.60(2H,d,J=5.9Hz),6.96−7.05(4H,m),7.23(4H,s),7.35−7.40(2H,m),7.45−7.48(1H,m),7.56−7.57(1H,m),7.81−7.84(2H,m),8.55(1H,d,J=2.3Hz),8.99(1H,t,J=5.7Hz),9.99(1H,s).
MS(ESI)[M+H]+:595.
1H−NMR(CDCl3)δ:1.51(9H,s),4.61(2H,d,J=5.9Hz),7.19(2H,d,J=7.7Hz),7.23−7.27(4H,m),7.36(2H,t,J=7.7Hz),7.44(1H,t,J=7.5Hz),7.55(2H,d,J=8.2Hz),7.58(1H,d,J=1.8Hz),7.82(2H,d,J=7.7Hz),8.59(1H,d,J=2.3Hz),9.01(1H,t,J=5.4Hz),10.00(1H,s).
MS(ESI)[M+H]+:645.
1H−NMR(CDCl3)δ:1.51(9H,s),4.60(2H,d,J=5.9Hz),7.08(2H,d,J=8.6Hz),7.14(2H,d,J=8.6Hz),7.22−7.25(4H,m),7.34−7.39(2H,m),7.42−7.48(1H,m),7.57(1H,d,J=1.8Hz),7.82(2H,d,J=8.2Hz),8.56(1H,d,J=1.8Hz),8.99(1H,t,J=5.4Hz),9.99(1H,brs).
MS(ESI)[M+H]+:661.
1H−NMR(CDCl3)δ:1.34(3H,s),1.36(3H,s),1.50(9H,s),4.51−4.57(1H,m),4.59(2H,d,J=5.4Hz),6.79(2H,dt,J=9.4,2.5Hz),6.93−6.98(2H,m),7.20−7.23(2H,m),7.25−7.28(2H,m),7.35−7.40(2H,m),7.46(1H,tt,J=7.5,1.6Hz),7.55(1H,d,J=2.3Hz),7.81−7.84(2H,m),8.50(1H,d,J=2.3Hz),8.97(1H,t,J=5.7Hz),9.98(1H,s).
MS(ESI)[M+H]+:635.
1H−NMR(CDCl3)δ:1.48(9H,s),2.30(3H,s),3.79(3H,s),4.56(2H,d,J=5.9Hz),6.77(2H,d,J=8.6Hz),6.98(2H,d,J=8.6Hz),7.03(2H,d,J=7.7Hz),7.19(2H,d,J=8.2Hz),7.35(2H,tt,J=7.5,1.6Hz),7.43(1H,tt,J=7.2,1.6Hz),7.51(1H,d,J=2.3Hz),7.78−7.81(2H,m),8.48(1H,d,J=2.3Hz),8.93(1H,t,J=5.7Hz),9.96(1H,s).
MS(ESI)[M+H]+:587.
1H−NMR(CDCl3)δ:1.51(9H,s),2.33(3H,s),4.60(2H,d,J=5.9Hz),7.06(2H,d,J=8.2Hz),7.18(4H,dd,J=11.8,8.2Hz),7.36(2H,t,J=7.7Hz),7.44(1H,t,J=7.5Hz),7.52(2H,d,J=8.2Hz),7.55(1H,d,J=1.8Hz),7.81(2H,d,J=8.2Hz),8.58(1H,d,J=2.3Hz),8.99(1H,t,J=5.7Hz),10.00(1H,brs).
MS(ESI)[M+H]+:625.
1H−NMR(CDCl3)δ:1.52(9H,s),4.59(2H,d,J=5.9Hz),6.92−6.97(1H,m),7.00(2H,dt,J=8.9,2.3Hz),7.17−7.29(7H,m),7.39−7.45(1H,m),7.57(1H,d,J=2.2Hz),7.93(1H,td,J=7.6,1.7Hz),8.54(1H,d,J=2.2Hz),9.09(1H,t,J=5.9Hz),10.04(1H,s).
MS(ESI)[M+H]+:629.
1H−NMR(CDCl3)δ:1.51(9H,s),4.60(2H,d,J=5.9Hz),7.00−7.04(2H,m),7.15(1H,tdd,J=8.3,2.6,0.8Hz),7.24−7.28(6H,m),7.34(1H,td,J=8.0,5.4Hz),7.49(1H,dt,J=8.0,2.1Hz),7.55(1H,d,J=2.2Hz),7.61(1H,dq,J=7.8,0.8Hz),8.55(1H,d,J=2.2Hz),9.05(1H,t,J=5.6Hz),9.92(1H,s).
MS(ESI)[M+H]+:629.
1H−NMR(CDCl3)δ:1.51(9H,s),4.58(2H,d,J=5.9Hz),6.98−7.06(4H,m),7.24−7.29(6H,m),7.54(1H,d,J=1.8Hz),7.79−7.84(2H,m),8.55(1H,d,J=1.8Hz),9.01(1H,t,J=5.9Hz),9.94(1H,s).
MS(ESI)[M+H]+:629.
1H−NMR(CDCl3)δ:1.50(9H,s),4.63(2H,d,J=5.4Hz),6.94(1H,dd,J=5.0,3.6Hz),7.05(2H,dt,J=8.9,2.3Hz),7.24−7.28(6H,m),7.39(1H,dd,J=5.0,1.4Hz),7.53(1H,dd,J=3.6,1.4Hz),7.63(1H,d,J=1.8Hz),8.58(1H,d,J=2.3Hz),9.04(1H,t,J=5.9Hz),9.86(1H,s).
MS(ESI)[M+H]+:617.
1H−NMR(CDCl3)δ:1.50(9H,s),4.61(2H,d,J=5.9Hz),7.04(2H,dt,J=8.9,2.3Hz),7.22−7.30(8H,m),7.59(1H,d,J=1.8Hz),7.83(1H,dd,J=3.2,1.4Hz),8.58(1H,d,J=1.8Hz),9.01(1H,t,J=5.7Hz),9.94(1H,s).
MS(ESI)[M+H]+:617.
1H−NMR(CDCl3)δ:1.51(9H,s),4.63(2H,d,J=5.6Hz),6.37(1H,dd,J=3.5,1.8Hz),6.92(1H,dd,J=3.4,1.0Hz),7.07(2H,dt,J=8.9,2.3Hz),7.22−7.30(7H,m),7.64(1H,d,J=2.2Hz),8.57(1H,d,J=2.2Hz),9.11(1H,t,J=5.4Hz),9.88(1H,s).
MS(ESI)[M+H]+:601.
1H−NMR(CDCl3)δ:1.50(9H,s),4.61(2H,d,J=5.6Hz),6.54(1H,dd,J=2.0,1.0Hz),7.05(2H,d,J=8.3Hz),7.22−7.31(7H,m),7.62(1H,d,J=2.0Hz),7.80(1H,t,J=0.7Hz),8.59(1H,d,J=2.0Hz),9.02(1H,t,J=5.5Hz),9.87(1H,s).
MS(ESI)[M+H]+:601.
1H−NMR(CDCl3)δ:1.50(9H,s),2.33(3H,s),4.64(2H,d,J=5.9Hz),6.92(1H,dd,J=5.0,3.6Hz),7.06(2H,d,J=8.2Hz),7.18(2H,d,J=8.2Hz),7.23−7.26(2H,m),7.36(1H,dd,J=4.8,1.1Hz),7.51−7.55(3H,m),7.63(1H,d,J=2.3Hz),8.61(1H,d,J=2.3Hz),9.04(1H,t,J=5.4Hz),9.86(1H,brs).
MS(ESI)[M+H]+:631.
1H−NMR(CDCl3)δ:1.51(9H,s),4.88(2H,d,J=5.9Hz),7.04(2H,dt,J=8.9,2.2Hz),7.21−7.29(6H,m),7.38−7.41(2H,m),7.48−7.49(1H,m),7.76(1H,d,J=2.0Hz),8.19−8.21(2H,m),8.74(1H,d,J=2.2Hz),9.02(1H,t,J=5.5Hz),12.51(1H,s).(上記スペクトルデータは、アミド結合に起因する異性体の内、主異性体の値を表記した。)
MS(ESI)[M+H]+:575.
1H−NMR(CDCl3)δ:1.50(9H,s),4.81(2H,d,J=6.1Hz),7.05−7.10(3H,m),7.21−7.28(6H,m),7.46(1H,dd,J=4.9,1.2Hz),7.79(2H,dd,J=4.9,1.7Hz),8.75(1H,d,J=2.2Hz),8.99(1H,t,J=5.9Hz),12.23(1H,s).
MS(ESI)[M+H]+:581.
1H−NMR(CDCl3)δ:4.44(2H,d,J=5.4Hz),6.46(2H,brs),6.66(1H,brs),6.95(2H,d,J=7.7Hz),7.18−7.23(6H,m),7.30(2H,t,J=7.7Hz),7.42(1H,t,J=7.0Hz),7.49(1H,s),7.72(2H,d,J=8.6Hz),8.49(1H,s).
MS(ESI)[M+H]+:511.
1H−NMR(CD3OD)δ:4.63(2H,s),7.18(2H,d,J=8.8Hz),7.37−7.42(6H,m),7.47−7.53(3H,m),7.77(2H,m),8.47(1H,brs),8.77(1H,brs).
MS(ESI)[M+H]+:511.
1H−NMR(CDCl3)δ:4.42(2H,d,J=5.4Hz),6.43(2H,brs),6.95(2H,dd,J=8.4,1.6Hz),7.18(2H,dd,J=8.2,1.4Hz),7.22−7.25(5H,m),7.27−7.32(3H,m),7.38−7.43(1H,m),7.49(1H,d,J=2.0Hz),7.72−7.75(2H,m),8.47(1H,d,J=2.0Hz).
MS(ESI)[M+H]+:477.
1H−NMR(CDCl3)δ:4.46(2H,d,J=5.9Hz),6.37−6.63(3H,m),6.94−7.00(3H,m),7.10(1H,t,J=7.7Hz),7.20−7.25(3H,m),7.31(2H,t,J=7.7Hz),7.38−7.45(2H,m),7.51(1H,d,J=2.3Hz),7.73−7.76(2H,m),8.50(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:511.
1H−NMR(CDCl3)δ:2.30(3H,s),4.40(2H,d,J=5.4Hz),6.38(2H,brs),6.94−6.98(2H,m),7.03(2H,d,J=8.2Hz),7.11−7.15(2H,m),7.20(2H,dd,J=8.6,2.7Hz),7.24−7.33(3H,m),7.38−7.43(1H,m),7.48(1H,d,J=2.1Hz),7.73−7.76(2H,m),8.45(1H,d,J=2.1Hz).
MS(ESI)[M+H]+:491.
1H−NMR(CDCl3)δ:3.76(3H,s),4.40(2H,d,J=4.1Hz),6.43(2H,brs),6.74(2H,d,J=8.6Hz),6.96(2H,d,J=8.2Hz),7.16−7.21(4H,m),7.26−7.31(3H,m),7.40(1H,t,J=7.5Hz),7.46(1H,d,J=1.6Hz),7.73(2H,d,J=8.2Hz),8.43(1H,d,J=1.6Hz).
MS(ESI)[M+H]+:507.
1H−NMR(DMSO−d6)δ:4.44(2H,d,J=5.4Hz),6.91(1H,brs),7.11(2H,d,J=8.6Hz),7.35−7.48(7H,m),7.64(1H,d,J=2.0Hz),7.66(2H,brs),7.78(2H,d,J=8.6Hz),8.57(1H,d,J=2.0Hz).
MS(ESI)[M+H]+:502.
1H−NMR(CDCl3)δ:4.45(2H,d,J=5.4Hz),6.33−6.64(3H,m),6.89−6.97(4H,m),7.20−7.25(4H,m),7.31(2H,t,J=7.5Hz),7.42(1H,t,J=7.5Hz),7.50(1H,d,J=2.3Hz),7.73−7.76(2H,m),8.49(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:495.
1H−NMR(CDCl3)δ:4.49(2H,d,J=5.9Hz),6.25(3H,brs),6.95−7.00(4H,m),7.05(1H,dt,J=9.7,2.2Hz),7.16−7.26(3H,m),7.34(2H,t,J=7.7Hz),7.44(1H,t,J=7.5Hz),7.54(1H,d,J=2.3Hz),7.78−7.80(2H,m),8.52(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:545.
1H−NMR(CDCl3)δ:4.51(2H,d,J=5.9Hz),6.11(3H,brs),6.98−7.01(2H,m),7.10(2H,d,J=8.6Hz),7.25−7.38(6H,m),7.45(1H,t,J=7.5Hz),7.56(1H,d,J=2.0Hz),7.80−7.83(2H,m),8.55(1H,d,J=2.0Hz).
MS(ESI)[M+H]+:561.
1H−NMR(CDCl3)δ:4.49(2H,d,J=5.4Hz),6.38(3H,brs),6.96(2H,d,J=8.6Hz),7.23(2H,d,J=8.6Hz),7.29−7.55(8H,m),7.75(2H,d,J=8.2Hz),8.54(1H,s).
MS(ESI)[M+H]+:545.
1H−NMR(CDCl3,55℃)δ:2.23(3H,d,J=1.8Hz),4.47(2H,d,J=5.5Hz),6.02−6.10(3H,brm),6.88(1H,dd,J=7.8,1.8Hz),6.99−7.02(4H,m),7.23(2H,m),7.33(2H,m),7.40−7.45(1H,m),7.51(1H,d,J=2.3Hz),7.70(2H,m),8.51(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:509.
1H−NMR(CDCl3,55℃)δ:2.31(3H,s),4.47(2H,d,J=5.9Hz),6.13(3H,brs),6.69(1H,d,J=11.0Hz),6.92(1H,d,J=8.2Hz),6.98(2H,m),7.16−7.21(3H,m),7.33(2H,m),7.42(1H,m),7.54(1H,d,J=2.3Hz),7.80(2H,m),8.50(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:509.
1H−NMR(CDCl3)δ:3.27(3H,s),4.47(2H,d,J=5.5Hz),6.21(3H,brm),6.67(1H,d,J=1.8Hz),6.95−7.00(3H,m),7.19(2H,d,J=8.2Hz),7.27(1H,d,J=6.4Hz),7.34(2H,t,J=7.5Hz),7.44(1H,t,J=7.5Hz),7.54(1H,d,J=1.6Hz),7.80(2H,d,J=7.3Hz),8.49(1H,d,J=1.6Hz).
MS(ESI)[M+H]+:541.
1H−NMR(CDCl3)δ:4.46(2H,d,J=5.6Hz),6.27(2H,brs),7.04(2H,dd,J=7.8,1.7Hz),7.17(2H,d,J=8.8Hz),7.22(2H,d,J=8.8Hz),7.25−7.33(6H,m),7.41(1H,t,J=7.3Hz),7.54(1H,d,J=2.2Hz),7.77(2H,d,J=7.3Hz),8.50(1H,d,J=2.2Hz).
MS(ESI)[M+H]+:477.
1H−NMR(CDCl3)δ:4.50(2H,d,J=5.9Hz),6.15(2H,brs),6.89(1H,dt,J=7.9,1.6Hz),7.12(1H,t,J=1.6Hz),7.19(1H,t,J=7.9Hz),7.23(4H,s),7.25−7.30(2H,m),7.34(2H,m),7.43(1H,tt,J=7.5,1.6Hz),7.53(1H,d,J=2.3Hz),7.81(2H,m),8.55(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:511.
1H−NMR(CDCl3)δ:4.51(2H,d,J=5.4Hz),6.16(2H,brs),7.03(1H,dd,J=7.5,1.6Hz),7.15−7.19(2H,m),7.20−7.23(3H,m),7.25−7.32(2H,m),7.33−7.43(4H,m),7.50(1H,d,J=2.3Hz),7.79−7.82(2H,m),8.57(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:511.
1H−NMR(CDCl3)δ:2.36(3H,s),4.48(2H,d,J=5.4Hz),6.13(3H,brs),6.95(2H,d,J=8.2Hz),7.08(2H,d,J=7.7Hz),7.21(2H,m),7.23−7.26(2H,m),7.34(2H,t,J=7.5Hz),7.43(1H,t,J=7.5Hz),7.55(1H,d,J=2.3Hz),7.81(2H,m),8.49(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:491.
1H−NMR(CDCl3)δ:3.82(3H,s),4.48(2H,d,J=5.9Hz),6.10(3H,brs),6.81(2H,d,J=8.6Hz),6.98(2H,d,J=8.6Hz),7.21(2H,d,J=8.6Hz),7.25(2H,d,J=8.2Hz),7.34−7.37(2H,m),7.44(1H,m),7.55(1H,d,J=2.3Hz),7.81−7.83(2H,m),8.48(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:507.
1H−NMR(DMSO−d6)δ:4.44(2H,d,J=5.4Hz),6.86(1H,brs),7.25(2H,d,J=6.8Hz),7.30(2H,d,J=6.8Hz),7.35−7.39(4H,m),7.46(1H,t,J=7.0Hz),7.64−7.67(3H,m),7.83(2H,d,J=7.2Hz),8.57(1H,s).
MS(ESI)[M+H]+:502.
1H−NMR(CDCl3)δ:4.46(2H,d,J=5.9Hz),6.30−6.56(3H,m),6.93−7.02(4H,m),7.19(4H,s),7.32(2H,t,J=7.7Hz),7.42(1H,m),7.52(1H,d,J=2.3Hz),7.76(2H,m),8.50(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:495.
1H−NMR(CDCl3)δ:4.48(2H,d,J=5.4Hz),6.38−6.57(3H,m),7.15(2H,d,J=8.2Hz),7.19−7.22(4H,m),7.30(2H,m),7.40(1H,t,J=7.5Hz),7.50(2H,d,J=8.2Hz),7.53(1H,d,J=2.3Hz),7.74(2H,d,J=7.2Hz),8.54(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:545.
1H−NMR(CDCl3)δ:4.51(2H,d,J=5.4Hz),6.13(3H,brs),7.09(2H,d,J=8.2Hz),7.13(2H,d,J=8.2Hz),7.21−7.24(4H,m),7.34(2H,m),7.43(1H,t,J=6.6Hz),7.56(1H,d,J=1.8Hz),7.81(2H,d,J=8.2Hz),8.54(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:561.
1H−NMR(CDCl3)δ:1.35(6H,d,J=5.9Hz),4.48(2H,d,J=5.9Hz),4.51−4.58(1H,m),6.07(3H,brs),6.78(2H,d,J=8.6Hz),6.95(2H,d,J=8.6Hz),7.19−7.22(2H,m),7.24−7.28(2H,m),7.35(2H,t,J=7.7Hz),7.44(1H,t,J=7.5Hz),7.54(1H,d,J=2.1Hz),7.80−7.83(2H,m),8.48(1H,d,J=2.1Hz).
MS(ESI)[M+H]+:535.
1H−NMR(CDCl3)δ:2.31(3H,s),3.81(3H,s),4.45(2H,d,J=5.9Hz),6.05(3H,brs),6.79(2H,d,J=8.6Hz),7.00(2H,d,J=8.6Hz),7.04(2H,d,J=8.2Hz),7.19(2H,d,J=8.2Hz),7.35(2H,m),7.43(1H,m),7.53(1H,d,J=2.1Hz),7.82(2H,d,J=7.7Hz),8.44(1H,d,J=2.1Hz).
MS(ESI)[M+H]+:487.
1H−NMR(CDCl3)δ:2.31(3H,s),4.54(2H,s),6.79(2H,brs),7.03−7.07(4H,m),7.22(2H,d,J=8.2Hz),7.32(2H,t,J=7.5Hz),7.40(1H,t,J=7.2Hz),7.53(2H,d,J=7.7Hz),7.64(1H,brs),7.77(2H,d,J=7.7Hz),7.97(1H,brs),8.71(1H,brs).
MS(ESI)[M+H]+:525.
1H−NMR(CDCl3)δ:4.47(2H,d,J=5.9Hz),6.34(3H,brs),6.92−7.00(3H,m),7.13(1H,t,J=7.7Hz),7.19−7.27(6H,m),7.40(1H,dd,J=12.4,6.6Hz),7.55(1H,d,J=2.0Hz),7.83(1H,t,J=6.8Hz),8.52(1H,d,J=2.0Hz).
MS(ESI)[M+H]+:529.
1H−NMR(CDCl3)δ:4.48(2H,d,J=5.6Hz),6.27(3H,brs),6.99(2H,d,J=8.5Hz),7.11−7.15(1H,m),7.20−7.25(6H,m),7.29−7.34(1H,m),7.45−7.58(3H,m),8.52(1H,s).
MS(ESI)[M+H]+:529.
1H−NMR(CDCl3)δ:4.46(2H,d,J=5.6Hz),6.26(3H,brs),6.98−7.02(4H,m),7.21−7.33(6H,m),7.52(1H,s),7.76−7.79(2H,m),8.52(1H,d,J=2.0Hz).
MS(ESI)[M+H]+:529.
1H−NMR(CDCl3)δ:4.45(2H,d,J=5.0Hz),6.41(3H,brs),6.87(1H,s),7.00(2H,d,J=8.6Hz),7.15−7.24(6H,m),7.31(1H,d,J=5.0Hz),7.40(1H,s),7.53(1H,s),8.51(1H,s).
MS(ESI)[M+H]+:517.
1H−NMR(CDCl3)δ:4.43(2H,d,J=5.4Hz),6.46(3H,brs),6.99(2H,dt,J=8.9,2.3Hz),7.14−7.25(8H,m),7.51(1H,d,J=2.3Hz),7.70(1H,dd,J=2.7,1.4Hz),8.50(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:517.
1H−NMR(CDCl3)δ:4.48(2H,d,J=5.9Hz),6.24−6.40(3H,brs),6.34(1H,dd,J=3.6,1.8Hz),6.81(1H,dd,J=3.6,0.9Hz),7.04(2H,dt,J=8.9,2.3Hz),7.21(4H,s),7.24−7.28(3H,m),7.60(1H,d,J=2.1Hz),8.54(1H,d,J=2.1Hz).
MS(ESI)[M+H]+:501.
1H−NMR(CDCl3)δ:4.46(2H,d,J=5.9Hz),6.31(3H,brs),6.49(1H,s),7.02(2H,dt,J=8.8,2.3Hz),7.21(4H,s),7.24−7.28(3H,m),7.56(1H,d,J=2.3Hz),7.73(1H,s),8.53(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:501.
1H−NMR(CDCl3)δ:2.35(3H,s),4.61(2H,d,J=5.4Hz),6.85(2H,brs),6.90(1H,q,J=4.2Hz),7.12(4H,t,J=9.1Hz),7.29−7.33(3H,m),7.47(1H,td,J=3.4,1.2Hz),7.58(2H,d,J=6.8Hz),7.99(1H,brs),8.24(1H,brs),8.83(1H,brs).
MS(ESI)[M+H]+:531.
1H−NMR(CDCl3)δ:4.60(2H,brs),7.03(2H,d,J=8.2Hz),7.21−7.26(7H,m),7.35−7.39(2H,m),7.43−7.47(1H,m),7.68(1H,s),8.15(2H,d,J=7.7Hz),8.63(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:475.
1H−NMR(CD3OD)δ:4.94(2H,s),7.25−7.29(3H,m),7.39−7.48(7H,m),7.99(1H,dd,J=5.0,0.9Hz),8.13(1H,m),8.51(1H,s),8.91(1H,s).
MS(ESI)[M+H]+:481.
1H−NMR(CDCl3)δ:3.91(2H,s),7.99(1H,d,J=1.4Hz),8.29(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:221.
1H−NMR(CDCl3)δ:1.52(9H,s),4.45(2H,d,J=5.9Hz),7.43−7.47(2H,m),7.52−7.56(1H,m),7.74−7.77(3H,m),8.18(1H,d,J=1.8Hz),8.98(1H,t,J=5.2Hz),9.97(1H,s).
1H−NMR(CDCl3)δ:1.51(9H,s),4.53(2H,d,J=5.9Hz),7.25−7.27(2H,m),7.36−7.50(6H,m),7.75−7.77(2H,m),8.26(1H,d,J=2.3Hz),8.99(1H,t,J=5.4Hz),9.98(1H,s).
MS(ESI)[M+H]+:535.
1H−NMR(CDCl3)δ:1.51(9H,s),3.96(3H,s),4.52(2H,d,J=5.9Hz),7.00−7.10(3H,m),7.36−7.41(2H,m),7.46−7.50(2H,m),7.74−7.78(2H,m),8.24(1H,d,J=2.3Hz),8.98(1H,t,J=5.7Hz),9.97(1H,brs).
MS(ESI)[M+H]+:549.
1H−NMR(CDCl3)δ:4.48(2H,d,J=5.9Hz),6.44(2H,brs),6.61(1H,brs),6.95−6.89(3H,m),7.13(1H,dd,J=8.4,1.6Hz),7.19(2H,d,J=8.2Hz),7.31(3H,m),7.42(1H,t,J=7.5Hz),7.54(1H,d,J=1.8Hz),7.73(2H,d,J=7.2Hz),8.51(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:529.
1H−NMR(CDCl3)δ:3.89(3H,s),4.45(2H,d,J=5.4Hz),6.34(3H,brs),6.72−6.86(3H,m),7.19−7.24(4H,m),7.33(2H,t,J=7.7Hz),7.43(1H,t,J=7.2Hz),7.50(1H,d,J=1.8Hz),7.76(2H,d,J=7.7Hz),8.48(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:525.
1H−NMR(CDCl3)δ:4.03(3H,s),8.23(1H,s),8.73(1H,s).
MS(ESI)[M+H]+:206.
1H−NMR(CDCl3)δ:4.01(3H,s),7.93(1H,d,J=7.7Hz),8.03(1H,d,J=8.2Hz).
MS(ESI)[M+H]+:206.
1H−NMR(CDCl3)δ:3.99(3H,s),7.13(2H,dt,J=8.8,2.3Hz),7.25−7.28(2H,m),7.29−7.35(4H,m),8.29(1H,d,J=2.3Hz),9.25(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:358.
1H−NMR(CDCl3)δ:4.05(3H,s),7.09−7.14(4H,m),7.29−7.33(4H,m),8.17(1H,d,J=0.5Hz),8.72(1H,d,J=0.5Hz).
MS(ESI)[M+H]+:358.
1H−NMR(CDCl3)δ:4.03(3H,s),7.10−7.13(2H,m),7.23−7.34(6H,m),7.84(1H,d,J=7.7Hz),8.16(1H,d,J=7.7Hz).
MS(ESI)[M+H]+:358.
1H−NMR(CDCl3)δ:2.03(1H,t,J=5.7Hz),4.83(2H,d,J=5.5Hz),7.11(2H,dt,J=8.8,2.2Hz),7.23(2H,dt,J=8.4,2.1Hz),7.26−7.30(4H,m),7.73(1H,d,J=2.3Hz),8.66(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:330.
1H−NMR(CDCl3)δ:3.54(1H,s),4.86(2H,s),7.05−7.09(4H,m),7.26−7.29(5H,m),8.56(1H,s).
MS(ESI)[M+H]+:330.
1H−NMR(CDCl3)δ:3.82−3.85(1H,m),4.85(2H,d,J=5.0Hz),7.08−7.11(2H,m),7.23−7.32(7H,m),7.70(1H,d,J=8.2Hz).
MS(ESI)[M+H]+:330.
1H−NMR(CDCl3)δ:4.80(2H,s),7.14(2H,d,J=8.2Hz),7.39(4H,dd,J=8.7,2.7Hz),7.45(2H,d,J=8.7Hz),8.30(1H,s),9.02(1H,s).
MS(ESI)[M+H]+:348.
1H−NMR(CDCl3)δ:4.75(2H,s),7.05−7.11(4H,m),7.26−7.30(4H,m),7.49(1H,s),8.57(1H,s).
1H−NMR(CDCl3)δ:5.10(2H,s),7.00−7.06(4H,m),7.24−7.30(5H,m),7.75(2H,ddd,J=11.6,6.1,2.0Hz),7.91(2H,ddd,J=11.6,6.1,2.0Hz),8.50(1H,s).
MS(ESI)[M+H]+:459.
1H−NMR(CDCl3)δ:5.12(2H,s),7.04−7.07(2H,m),7.12−7.15(2H,m),7.18−7.21(2H,m),7.25−7.27(3H,m),7.62(1H,d,J=7.7Hz),7.76(2H,ddd,J=11.4,6.0,2.2Hz),7.91(2H,ddd,J=11.3,5.9,2.3Hz).
MS(ESI)[M+H]+:459.
1H−NMR(CDCl3)δ:4.01(2H,s),7.11(2H,d,J=8.2Hz),7.24−7.27(6H,m),7.69(1H,d,J=1.4Hz),8.63(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:329.
1H−NMR(CDCl3)δ:4.07(2H,s),7.04−7.10(4H,m),7.23−7.32(5H,m),8.55(1H,s).
MS(ESI)[M+H]+:329.
1H−NMR(CDCl3)δ:4.07(2H,s),7.09(2H,dt,J=8.9,2.3Hz),7.24(2H,dd,J=6.6,2.0Hz),7.27−7.35(5H,m),7.66(1H,d,J=7.7Hz).
1H−NMR(CDCl3)δ:1.60(3H,s),7.11−7.15(2H,m),7.25−7.34(6H,m),8.06(1H,d,J=1.8Hz),9.03(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:344.
1H−NMR(CDCl3)δ:1.64(3H,d,J=6.8Hz),4.78(1H,q,J=6.8Hz),7.11−7.13(2H,m),7.23−7.32(6H,m),7.65(1H,d,J=2.3Hz),8.64(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:369.
1H−NMR(CDCl3)δ:1.48(3H,d,J=6.8Hz),4.29(1H,m),7.11(2H,q,J=8.2Hz),7.24−7.27(6H,m),7.71(1H,d,J=2.3Hz),8.65(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:345.
1HNMR(CDCl3)7.07−7.09(m,4H),7.27−7.29(m,2H)7.35−7.39(m,4H),7.46−7.50(m,2H),7.55−7.59(1H,m),7.94−7.96(m,2H).
MS(ESI):354(M+H).
1H−NMR(CDCl3)δ:4.72(2H,d,J=5.9Hz),6.92−6.96(2H,m),7.08(2H,dt,J=8.9,2.3Hz),7.24−7.41(11H,m),7.49(1H,ddd,J=10.0,5.0,2.3Hz),7.64(1H,d,J=2.3Hz),7.73−7.75(2H,m),8.09(1H,t,J=5.7Hz),8.67(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:588.
1H−NMR(DMSO−d6)δ:4.43(2H,s),4.61(2H,s),7.11(2H,d,J=8.3Hz),7.27(2H,d,J=8.5Hz),7.32−7.46(7H,m),7.62(3H,d,J=7.3Hz),8.14(2H,brs),8.56(1H,d,J=1.5Hz).
MS(ESI)[M+H]+:526.
1H−NMR(CD3OD)δ:4.55(2H,s),7.07(2H,dt,J=8.9,2.3Hz),7.24−7.27(2H,m),7.29−7.32(6H,m),7.42(1H,tt,J=7.4,1.4Hz),7.67−7.69(2H,m),7.72(1H,d,J=2.2Hz),8.52(1H,d,J=2.2Hz).
MS(ESI)[M+H]+:527.
1H−NMR(DMSO−d6)δ:2.74(3H,s),3.17(1H,d,J=5.2Hz),4.04(1H,s),4.45(2H,s),7.10−7.12(2H,m),7.24−7.45(8H,m),7.59−7.70(4H,m),8.53(1H,s).
MS(ESI)[M+H]+:525.
1H−NMR(CDCl3)δ:4.65(2H,d,J=5.9Hz),7.05(2H,d,J=7.2Hz),7.10(2H,dt,J=8.8,2.3Hz),7.24−7.33(7H,m),7.41(2H,t,J=7.0Hz),7.73(1H,s),7.83(1H,brs),8.71(1H,s).
MS(ESI)[M+H]+:473.
1H−NMR(CDCl3)δ:4.41(2H,d,J=5.9Hz),5.89(2H,s),6.49(1H,brs),7.05(2H,d,J=8.6Hz),7.17−7.26(6H,m),7.57(1H,d,J=1.8Hz),8.54(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:396.
1H−NMR(DMSO−d6)δ:4.69(2H,brs),7.22(2H,d,J=8.2Hz),7.29−7.33(3H,m),7.39(2H,dd,J=8.6,1.4Hz),7.44(2H,dt,J=8.9,2.3Hz),7.92(1H,brs),8.72(3H,s),9.53(1H,brs),10.23(1H,brs).
MS(ESI)[M+H]+:414.
1H−NMR(CDCl3)δ:1.53(9H,s),4.71(2H,d,J=4.9Hz),6.97−7.07(4H,m),7.20(1H,s),7.24−7.29(4H,m),7.38−7.42(2H,m),7.45−7.52(1H,m),7.86−7.88(2H,m),8.55(1H,s),9.48(1H,t,J=4.6Hz),10.00(1H,s).
MS(ESI)[M+H]+:611.
1H−NMR(CDCl3)δ:1.53(9H,s),4.74(2H,d,J=5.0Hz),6.96−6.98(1H,m),7.02−7.05(4H,m),7.24−7.29(7H,m),7.42(1H,dd,J=5.0,1.4Hz),7.56(1H,dd,J=3.2,1.4Hz),8.57(1H,s),9.56(1H,t,J=4.5Hz),9.85(1H,s).
MS(ESI)[M+H]+:617.
1H−NMR(CDCl3)δ:1.53(9H,s),4.99(2H,d,J=5.1Hz),7.04−7.07(4H,m),7.22−7.28(4H,m),7.38−7.41(3H,m),7.47−7.51(1H,m),8.21−8.23(2H,m),8.61(1H,s),9.42(1H,t,J=4.8Hz),12.50(1H,s).(上記スペクトルデータは、アミド結合に起因する異性体の内、主異性体の値を表記した。)
MS(ESI)[M+H]+:575.
1H−NMR(CDCl3)δ:1.56(9H,s),4.72(2H,d,J=4.5Hz),7.09−7.12(2H,m),7.20−7.24(3H,m),7.27−7.32(2H,m),7.40−7.53(5H,m),7.63(1H,d,J=8.2Hz),7.91−7.93(2H,m),9.93(1H,t,J=4.5Hz),10.00(1H,s).
MS(ESI)[M+H]+:611.
1H−NMR(CDCl3)δ:1.56(3H,d,J=6.9Hz),1.61(9H,s),5.02−5.05(1H,m),7.08−7.11(2H,m),7.22−7.29(6H,m),7.46−7.60(4H,m),7.90−7.93(2H,m),8.63(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:625.
1H−NMR(CDCl3)δ:4.54(2H,d,J=5.6Hz),6.96−7.04(4H,m),7.21−7.23(2H,m),7.28−7.44(6H,m),7.82(2H,d,J=7.3Hz),8.43(1H,s).
MS(ESI)[M+H]+:511.
1H−NMR(CDCl3)δ:4.56(2H,d,J=5.6Hz),6.90(1H,dd,J=4.9,3.3Hz),7.00−7.05(4H,m),7.23−7.29(4H,m),7.33(1H,dd,J=4.9,1.3Hz),7.44(1H,s),7.47(1H,d,J=3.3Hz),8.44(1H,s).
MS(ESI)[M+H]+:517.
1H−NMR(CDCl3)δ:4.57(2H,brs),7.03−7.07(4H,m),7.26−7.30(5H,m),7.34−7.39(3H,m),8.17(2H,d,J=6.1Hz),8.52(1H,s).
MS(ESI)[M+H]+:475.
1H−NMR(CD3OD)δ:4.74(2H,s),7.17−7.20(2H,m),7.38−7.45(6H,m),7.50−7.52(3H,m),7.70(2H,d,J=7.2Hz),7.87(1H,d,J=8.0Hz),8.43(1H,d,J=8.0Hz).
MS(ESI)[M+H]+:511.
1H−NMR(CDCl3)δ:1.53(3H,d,J=6.9Hz),4.95(1H,s),6.12(2H,s),6.99−6.97(2H,m),7.21−7.42(11H,m),7.52(1H,d,J=2.3Hz),7.72(2H,d,J=7.3Hz),8.57(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:525.
1H−NMR(CDCl3)δ:1.49(9H,s),1.51(9H,s),4.71(2H,d,J=5.9Hz),7.11(2H,d,J=8.7Hz),7.22−7.30(6H,m),7.71(1H,d,J=2.3Hz),8.65(1H,d,J=2.3Hz),8.73(2H,t,J=5.5Hz),11.52(1H,brs).
1H−NMR(CDCl3)δ:4.33(2H,brs),6.99(2H,d,J=8.7Hz),7.12(4H,s),7.19(2H,d,J=8.7Hz),7.23(2H,brs),7.52(1H,d,J=2.3Hz),8.42(1H,brs),8.48(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:371.
1H−NMR(CDCl3)δ:4.46(2H,d,J=5.4Hz),6.43(3H,brs),7.00(2H,dd,J=8.4,2.9Hz),7.20−7.26(6H,m),7.44−7.52(2H,m),7.69(1H,d,J=7.7Hz),8.00(1H,d,J=7.7Hz),8.08(1H,d,J=1.4Hz),8.50(1H,s).
MS(ESI)[M+H]+:536.
1H−NMR(CDCl3)δ:4.45(2H,d,J=5.9Hz),6.39(3H,brs),6.98(2H,d,J=8.2Hz),7.20(4H,s),7.22−7.26(3H,m),7.37−7.40(1H,m),7.50(1H,s),7.62−7.65(1H,m),7.76(1H,d,J=1.8Hz),8.50(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:545.
1H−NMR(CDCl3)δ:3.62(3H,s),4.41(2H,d,J=5.5Hz),6.65−6.74(3H,m),6.86−6.90(3H,m),6.94(1H,brs),7.14−7.19(6H,m),7.35(1H,t,J=7.8Hz),7.46(1H,s),7.77(1H,d,J=7.8Hz),8.47(1H,s).
MS(ESI)[M+H]+:541.
1H−NMR(CDCl3)δ:3.70(3H,s),4.42(2H,d,J=5.4Hz),6.53(2H,brs),6.79(1H,brs),6.91−6.94(3H,m),7.15−7.21(7H,m),7.24−7.27(2H,m),7.46(1H,s),8.47(1H,s).
MS(ESI)[M+H]+:541.
1H−NMR(DMSO−d6)δ:1.27(3H,t,J=6.9Hz),3.99(2H,m),4.44(2H,d,J=10.0Hz),6.90(2H,brs),7.01(1H,d,J=6.9Hz),7.11(2H,d,J=8.7Hz),7.19−7.29(6H,m),7.37−7.42(4H,m),7.67(1H,s),8.55(1H,s).
MS(ESI)[M+H]+:555.
1H−NMR(CDCl3)δ:4.51(2H,d,J=5.0Hz),6.19(3H,brs),7.06(2H,d,J=8.6Hz),7.25(4H,s),7.30(2H,d,J=8.2Hz),7.58(1H,d,J=2.3Hz),7.70(1H,d,J=8.2Hz),8.25(1H,dd,J=7.9,2.0Hz),8.52(1H,s),9.04(1H,s).
MS(ESI)[M+H]+:537.
1H−NMR(CDCl3)δ:3.78(3H,s),4.43(2H,d,J=5.4Hz),6.41(2H,brs),6.63(1H,brs),7.02(2H,dt,J=8.8,2.3Hz),7.18−7.22(4H,m),7.23−7.25(2H,m),7.55(1H,d,J=2.3Hz),7.59(1H,s),7.63(1H,s),8.50(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:515.
1H−NMR(CDCl3)δ:4.45(2H,s),6.45(1H,brs),6.71(1H,d,J=4.1Hz),7.02(2H,d,J=8.6Hz),7.18−7.26(7H,m),7.56(1H,s),8.52(1H,s).
MS(ESI)[M+H]+:551.
1H−NMR(DMSO−d6)δ:4.47(2H,d,J=4.1Hz),6.99(2H,brs),7.05(2H,d,J=7.8Hz),7.22(2H,d,J=8.7Hz),7.32−7.36(4H,m),7.42−7.49(2H,m),7.60(1H,brs),7.65(1H,s),7.80(1H,s),7.88(2H,d,J=8.2Hz),8.57(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:567.
1H−NMR(CDCl3)δ:1.01(1H,t,J=12.6Hz),1.14(2H,m),1.31(3H,m),1.73(2H,d,J=13.7Hz),2.05(2H,t,J=6.2Hz),2.70−2.77(1H,m),4.45(2H,d,J=5.5Hz),6.29(2H,brs),6.42(1H,brs),7.08(2H,dt,J=8.8,2.3Hz),7.20−7.23(4H,m),7.25−7.28(2H,m),7.64(1H,d,J=1.8Hz),8.58(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:517.
1H−NMR(CDCl3)δ:1.27(1H,m),1.50(1H,m),1.64(2H,m),1.82−1.92(4H,m),3.36(1H,m),4.44(2H,d,J=5.9Hz),6.29(2H,brs),6.38(1H,brs),7.07(2H,dt,J=8.8,2.2Hz),7.20−7.24(4H,m),7.27(2H,dt,J=8.2,2.5Hz),7.63(1H,d,J=1.8Hz),8.57(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:503.
1H−NMR(CDCl3)δ:0.82(2H,m),1.04(2H,m),2.42(1H,m),4.47(2H,d,J=5.5Hz),6.19(2H,brs),6.27(1H,brs),7.08(2H,dt,J=8.8,2.2Hz),7.21−7.24(4H,m),7.24−7.28(2H,m),7.65(1H,d,J=1.8Hz),8.58(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:475.
1H−NMR(CDCl3)δ:4.13(2H,s),4.27(2H,s),5.99(2H,brs),6.40(1H,brs),7.06(2H,d,J=8.2Hz),7.17−7.23(9H,m),7.24−7.28(2H,m),7.51(1H,s),8.48(1H,s).
MS(ESI)[M+H]+:525.
1H−NMR(CDCl3)δ:2.58(6H,s),4.45(2H,d,J=5.4Hz),6.25(2H,brs),6.39(1H,brs),7.07(2H,d,J=8.2Hz),7.19−7.27(6H,m),7.64(1H,s),8.58(1H,s).
MS(ESI)[M+H]+:478.
1H−NMR(DMSO−d6)δ:4.59(2H,m),7.18(2H,s),7.30−7.40(6H,m),7.59(1H,s),7.81(1H,s),7.90(1H,s),8.72(1H,s).
MS(ESI)[M+H]+:482.
1H−NMR(CDCl3)δ:4.68(2H,s),7.08(2H,d,J=8.6Hz),7.23−7.29(6H,m),7.68(2H,d,J=8.2Hz),7.70(1H,d,J=2.3Hz),8.26(2H,d,J=8.6Hz),8.70(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:500.
1H−NMR(CDCl3)δ:3.38(3H,s),3.97(2H,s),4.52(2H,s),7.08(2H,dt,J=8.9,2.3Hz),7.22−7.28(6H,m),7.66(1H,d,J=1.8Hz),8.62(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:443.
1H−NMR(CDCl3)δ:0.92(3H,t,J=7.2Hz),1.60−1.69(2H,m),2.33(2H,t,J=7.5Hz),4.54(2H,s),7.08(2H,d,J=8.2Hz),7.22−7.29(6H,m),7.67(1H,s),8.63(1H,s).
MS(ESI)[M+H]+:441.
1H−NMR(DMSO−d6)δ:0.86(3H,t,J=6.9Hz),1.25−1.29(4H,m),1.56−1.60(2H,m),2.42(2H,t,J=7.3Hz),4.70(2H,d,J=6.4Hz),7.20−7.23(2H,m),7.28−7.32(2H,m),7.36−7.39(2H,m),7.44(2H,dd,J=6.4,1.8Hz),7.86(1H,d,J=1.8Hz),8.70(1H,d,J=1.8Hz),9.52(1H,brs),11.75(2H,s).
MS(ESI)[M+H]+:469.
1H−NMR(CDCl3)δ:4.64(2H,s),7.01−7.08(4H,m),7.23−7.28(6H,m),7.71(1H,d,J=2.3Hz),8.16−8.20(2H,m),8.67(1H,d,2.3Hz).
MS(ESI)[M+H]+:493.
1H−NMR(CDCl3)δ:4.58(2H,s),7.03−7.14(4H,m),7.23−7.28(6H,m),7.38(1H,m),7.70(1H,d,J=2.3Hz),7.92(1H,td,J=7.7,1.8Hz),8.64(1H,d,2.3Hz).
MS(ESI)[M+H]+:493.
1H−NMR(CDCl3)δ:4.61(2H,s),7.06(2H,d,J=8.2Hz),7.22−7.28(7H,m),7.59(1H,dd,J=5.0,1.3Hz),7.70(1H,d,J=2.3Hz),8.08(1H,dd,J=3.0,1,3Hz),8.65(1H,d,J=2.3Hz),.
MS(ESI)[M+H]+:481.
1H−NMR(CDCl3)δ:3.84(3H,s),4.64(2H,s),6.88(2H,d,J=9.1Hz),7.06(2H,d,J=8.6Hz),7.23−7.28(6H,m),7.73(1H,d,J=2.3Hz),8.14(2H,d,J=9.1Hz),8.67(1H,d,2.3Hz).
MS(ESI)[M+H]+:505.
1H−NMR(CDCl3)δ:1.53−1.88(8H,m),2.68(1H,m),4.48(2H,s),7.09(2H,d,J=8.6Hz),7.23−7.30(6H,m),7.68(1H,d,J=2.3Hz),8.64(1H,d,2.3Hz).
MS(ESI)[M+H]+:467.
1H−NMR(CDCl3)δ:0.75(2H,m),0.94(2H,m),1.63(1H,m),4.50(2H,s),7.09(2H,dt,J=8.9,2.3Hz),7.23−7.30(6H,m),7.67(1H,d,J=2.3Hz),8.63(1H,d,2.3Hz).
MS(ESI)[M+H]+:439.
1H−NMR(CDCl3)δ:1.18−2.36(11H,m),4.50(2H,s),7.08−7.30(8H,m),7.69(1H,d,J=2.3Hz),8.64(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:481.
1H−NMR(CD3OD)δ:1.16−1.99(10H,m),2.40−2.44(1H,m),4.85(2H,s),7.23−7.25(2H,m),7.36−7.46(6H,m),8.36(1H,d,J=2.3Hz),8.83(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:481.
1H−NMR(CDCl3)δ:2.65(2H,t,J=7.9Hz),2.95(2H,t,J=7.9Hz),4.50(2H,s),7.08(2H,d,J=8.6Hz),7.15−7.30(11H,m),7.66(1H,d,J=2.3Hz),8.63(1H,d,2.3Hz).
MS(ESI)[M+H]+:503.
1H−NMR(CDCl3)δ:3.64(2H,s),4.47(2H,s),7.07(2H,d,J=8.6Hz),7.20−7.30(11H,m),7.62(1H,d,J=2.3Hz),8.61(1H,d,2.3Hz).
MS(ESI)[M+H]+:489.
1H−NMR(CDCl3)δ:4.61(2H,s),7.04(2H,d,J=8.2Hz),7.23−7.25(6H,m),7.34(2H,m),7.68(1H,d,J=2.1Hz),8.09(2H,m),8.64(1H,d,J=2.1Hz).
MS(ESI)[M+H]+:509.
1H−NMR(CDCl3)δ:4.59(2H,s),7.02(2H,d,J=8.7Hz),7.22−7.24(6H,m),7.61(2H,d,J=8.2Hz),7.67(1H,s),8.24(2H,d,J=7.8Hz),8.61(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:543.
1H−NMR(CDCl3)δ:4.57(2H,s),6.41(1H,dd,J=3.2,1.8Hz),7.03(2H,d,J=8.7Hz),7.08(1H,m),7.21−7.24(6H,m),7.39(1H,s),7.68(1H,s),8.61(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:465.
1H−NMR(CDCl3)δ:2.92(3H,s),3.04(3H,s),4.54(2H,s),7.07−7.10(2H,m),7.22−7.29(6H,m),7.67(1H,d,J=1.8Hz),8.63(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:442.
1H−NMR(CDCl3)δ:1.20(3H,t,J=7.2Hz),4.06(2H,q,J=7.2Hz),4.55(2H,s),7.07−7.09(2H,m),7.23−7.30(6H,m),7.67(1H,d,J=2.3Hz),8.64(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:443.
1H−NMR(CD3OD)δ:1.34(3H,t,J=7.2Hz),4.33(2H,q,J=7.2Hz),4.84(2H,s),7.23−7.24(2H,m),7.35−7.44(6H,m),8.30(1H,s),8.79(1H,s).
MS(ESI)[M+H]+:443.
1H−NMR(CDCl3)δ:4.57(2H,s),7.08(2H,d,J=8.2Hz),7.22−7.28(6H,m),7.41(1H,m),7.74(1H,d,J=2.1Hz),7.82(1H,m),8.21(1H,d,J=7.8Hz),8.63(1H,d,J=4.1Hz),8.69(1H,d,J=2.1Hz).
MS(ESI)[M+H]+:476.
1H−NMR(DMSO−d6)δ:4.64(2H,brs),7.17(2H,brs),7.28(2H,d,J=8.2Hz),7.34−7.41(5H,m),7.92(1H,brs),8.72(1H,s),9.01(1H,d,1.8Hz).
MS(ESI)[M+H]+:482.
1H−NMR(CDCl3)δ:3.15(2H,q,J=10.8Hz),4.55(2H,s),7.08−7.11(2H,m),7.24−7.31(6H,m),7.66(1H,d,J=2.3Hz),8.64(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:481.
1H−NMR(CDCl3)δ:1.61−2.29(9H,m),4.54(2H,s),7.08−7.10(2H,m),7.23−7.30(6H,m),7.67(1H,d,J=2.3Hz),8.64(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:517.
1H−NMR(CDCl3)δ:1.55(6H,s),4.41(2H,s),7.06(2H,d,J=8.7Hz),7.15(1H,t,J=7.3Hz),7.23−7.30(8H,m),7.36(2H,m),7.58(1H,d,J=1.8Hz),8.57(1H,d,J=1.8Hz).
MS(ESI)[M+H]+:517.
1H−NMR(DMSO−d6)δ:4.43(2H,m),7.27−7.29(2H,m),7.37−7.39(2H,m),7.61−7.63(2H,m),8.01−8.07(2H,m).
1H−NMR(CDCl3)δ:4.21(2H,s),7.12−7.14(2H,m),7.28−7.41(6H,m),8.67(1H,s).
MS(ESI)[M+H]+:330.
1H−NMR(CDCl3)δ:1.56(9H,s),4.85(2H,d,J=4.5Hz),7.13−7.15(2H,m),7.26−7.28(2H,m),7.36−7.38(2H,m),7.43−7.48(5H,m),7.91−7.93(2H,m),8.66(1H,s),9.84(1H,s),10.01(1H,2).
1H−NMR(CDCl3)δ:4.69(2H,s),6.54(1H,s),7.10−7.13(2H,m),7.33−7.42(9H,m),7.90−7.93(2H,m),8.64(1H,s).
MS(ESI)[M+H]+:512.
1H−NMR(DMSO−d6)δ:7.08(2H,d,J=8.2Hz),7.28(2H,dd,J=8.6,0.9Hz),7.33(2H,dd,J=8.6,0.9Hz),7.43(2H,d,J=8.6Hz),8.27(1H,s).
MS(ESI)[M+H]+:341.
1H−NMR(CDCl3)δ:4.14(3H,s),7.05−7.08(2H,m),7.25−7.34(6H,m),7.87(1H,s).
1H−NMR(CDCl3)δ:7.09−7.11(2H,m),7.26−7.36(6H,m),7.97(1H,s).
1H−NMR(CDCl3)δ:7.12−7.14(2H,m),7.29−7.33(4H,m),7.38(2H,d,J=8.7Hz),8.09(1H,s).
1H−NMR(CDCl3)δ:7.09−7.11(2H,m),7.25−7.36(6H,m),8.03(1H,d,J=8.2Hz).
1H−NMR(CDCl3)δ:2.86(3H,s),7.07−7.09(2H,m),7.25−7.32(6H,m),7.88(1H,s).
1H−NMR(CDCl3)δ:3.87(2H,s),4.05(3H,s),7.05−7.09(2H,m),7.20−7.33(6H,m),7.51(1H,s).
1H−NMR(CDCl3)δ:1.51(9H,d,J=5.9Hz),4.04(3H,s),4.52(2H,d,J=5.9Hz),6.93(2H,dt,J=8.9,2.3Hz),7.19−7.33(8H,m),7.39−7.43(2H,m),7.80−7.82(2H,m),9.08(1H,t,J=5.6Hz),9.92(1H,s).
MS(ESI)[M+H]+:641.
1H−NMR(CDCl3)δ:1.51(9H,s),4.57(2H,d,J=6.4Hz),6.93−6.95(2H,m),7.22−7.35(8H,m),7.42(1H,m),7.65(1H,d,J=9.1Hz),7.78−7.80(2H,m),9.03(1H,m),9.95(1H,s).
MS(ESI)[M+H]+:629.
1H−NMR(CDCl3)δ:2.57(3H,s),4.47(2H,d,J=5.9Hz),5.91(2H,s),6.96−6.98(2H,m),7.27−7.37(10H,m),7.82−7.84(2H,m).
MS(ESI)[M+H]+:625.
1H−NMR(CDCl3)δ:4.01(3H,s),4.38(2H,d,J=6.3Hz),6.42(2H,brs),6.92(2H,d,J=8.5Hz),7.17−7.28(9H,m),7.38(1H,t,J=7.4Hz),7.52(1H,s),7.76(2H,dd,J=8.4,1.3Hz).22
MS(ESI)[M+H]+:541.
1H−NMR(CDCl3)δ:4.47(2H,d,J=5.9Hz),6.93−6.95(2H,m),7.24−7.27(8H,m),7.39(1H,m),7.67(1H,d,J=9.1Hz),7.74−7.75(2H,m).
MS(ESI)[M+H]+:529.
1H−NMR(CDCl3)δ:2.56(3H,s),4.48(2H,d,J=5.4Hz),6.94−6.96(2H,m),7.26−7.38(10H,m),7.81(2H,d,J=7.7Hz).
MS(ESI)[M+H]+:541.
1H−NMR(DMSO−d6)δ:4.16(2H,d,J=5.9Hz),6.78(1H,brs),6.94(2H,d,J=6.8Hz),7.21−7.47(12H,m),7.70(2H,brs).
MS(ESI)[M+H]+:527.
1H−NMR(CDCl3)δ:4.47(2H,d,J=5.9Hz),6.33−6.36(3H,brm),7.16(2H,d,J=7.7Hz),7.21−7.32(7H,m),7.40(1H,m),7.47−7.54(3H,m),7.76−7.77(2H,m),8.54(1H,d,J=2.3Hz).
MS(ESI)[M+H]+:511.
1H−NMR(CDCl3)δ:4.53(2H,d,J=6.0Hz),6.14(3H,brs),7.06(2H,d,J=7.6Hz),7.25−7.49(10H,m),7.61(1H,d,J=2.4Hz),7.82(2H,d,J=7.6Hz),8.56(1H,d,J=2.0Hz).
MS(ESI)[M+H]+:511.
1H−NMR(DMSO−d6)δ:4.45(2H,s),6.72(2H,d,J=7.3Hz),6.90(2H,d,J=6.9Hz),7.32(2H,d,J=5.0Hz),7.37−7.41(4H,m),7.48(1H,m),7.67(2H,s),7.75(1H,s),8.53(1H,s).
MS(ESI)[M+H]+:493.
1H−NMR(DMSO−d6)δ:4.47(2H,d,J=5.5Hz),6.74(2H,d,J=8.2Hz),6.98(2H,brs),7.14(4H,d,J=8.2Hz),7.38(2H,t,J=7.5Hz),7.46(3H,dd,J=12.8,7.8Hz),7.56(1H,s),7.67(2H,d,J=5.9Hz),7.94(1H,brs),8.60(1H,s),9.94(1H,brs).21
MS(ESI)[M+H]+:493.
1H−NMR(DMSO−d6)δ:4.44(2H,d,J=5.9Hz),6.83−6.86(3H,m),7.08−7.17(6H,m),7.28(2H,t,J=4.3Hz),7.39(4H,dd,J=10.6,8.4Hz),7.71(1H,s),8.57(1H,s).
MS(ESI)[M+H]+:527.
1H−NMR(DMSO−d6)δ:4.43(2H,d,J=5.5Hz),6.73(1H,s),6.84(2H,d,J=8.2Hz),7.05−7.15(4H,m),7.34−7.48(6H,m),7.59(1H,s),7.68(2H,s),8.48(1H,s),10.01(1H,brs).
MS(ESI)[M+H]+:527.
グアニジン誘導体(I)又はその薬理学的に許容される塩が、MALT1のプロテアーゼ活性を阻害することは、文献(Cancer Cell、2012年、第22巻、p.825―837)記載の方法に準じ、in vitroの実験系で評価した。すなわち、リコンビナントMALT1が蛍光標識した人工ペプチド基質を切断することで生じる蛍光値の上昇に対する、化合物による蛍光値の低下の度合いを測定することで評価した。
PCRにて増幅したヒトMALT1遺伝子(GenBankアクセッション番号:AB026118.1)の全長cDNAを、pGEX6P3ベクター(GE Healthcare)のGST遺伝子の下流に存在するSalIサイトにインフレームとなるよう組み込んだベクター(以下、pGEX6P3―MALT1ベクター)を作製した。次いで、pGEX6P3―MALT1ベクターをタンパク質発現用大腸菌(BL21−RIL−codon plus−DE3、Agilent)にトランスフォームした後、アンピシリン耐性スクリーニング及びコロニーPCRによる解析を行って、リコンビナントGST融合MALT1を発現する大腸菌株を得た。タンパク質の発現誘導はイソプロピル−β−チオガラクトピラノシドで行った。発現誘導後、大腸菌の培養液から遠心により大腸菌沈殿物を回収し、大腸菌沈殿物を破砕後、遠心して上清を得た。上清を、GSTrap FFカラム(GE Health Care)を用いて精製し、リコンビナントGST融合MALT1を得た。
1検体当たり、89μLの酵素溶液(4.8μg/mL GST融合MALT1、50mmol/L MES、150mmol/L NaCl、10% sucrose、0.1% CHAPS、10mmol/L ジチオトレイトール、1mol/L tri−ammonium citrate)に、各濃度の被験化合物(DMSO希釈溶液)を1μLずつ添加し、混合液とした。混合液を、室温で30分間インキュベートした後、混合液の蛍光値を測定した(1回目測定の蛍光値)(Ex:380nm、Em:460nm;Envision(Perkin Elmer))。次に、混合液に200μmol/Lの基質(Ac−LRSR−AMC、SM Biochemicals)を10μL添加し(最終濃度:20μmol/L)、30℃で80分間インキュベートして反応させた後、その反応液の蛍光値を測定した(2回目測定の蛍光値)(Ex:380nm、Em:460nm;Envision(Perkin Elmer))。なお、「被験化合物非添加(DMSOのみ添加)、酵素非添加かつ基質添加のウェル」、及び、「被験化合物非添加(DMSOのみ添加)、酵素添加かつ基質添加のウェル」を設けた。
阻害率(%)=100×(1―(Fsample―Fback)/(Fpositive―Fback))
グアニジン誘導体(I)又はその薬理学的に許容される塩が、自己免疫疾患の一つである乾癬に対して治療効果を発揮することは、文献(The Journal of Dermatological Science、2014年、第76巻、第2号、p.96−103)に準じた方法により、イミキモド誘発乾癬モデルマウスを用いたin vivoの実験系で評価した。すなわち、イミキモド誘発乾癬モデルの症状進行に伴って増加する耳介の厚みを指標として、耳介の肥厚に対する化合物による抑制効果を検証することで評価した。
グアニジン誘導体(I)又はその薬理学的に許容される塩が、アレルギー性疾患の一つであるアトピー性皮膚炎に対して治療効果を発揮することは、文献(Plos One、第8巻、第7号、e6614)に準じた方法により、オキサゾロン誘発アトピー性皮膚炎モデルマウスを用いたin vivoの実験系で評価した。すなわち、オキサゾロン誘発アトピー性皮膚炎モデルの症状進行に伴って増加する耳介の厚みを指標として、耳介の肥厚に対する化合物による抑制効果を検証することで評価した。
Claims (13)
- 以下の一般式(I)で示されるグアニジン誘導体又はその薬理学的に許容される塩。
前記炭素数1〜3のアルキル基及び前記炭素数1〜3のアルコキシ基は、それぞれ独立して、1〜5個の水素原子がそれぞれ独立してハロゲン原子で置換されていてもよく、
X及びYは、それぞれ独立して、N又はCHを表し、Zは、N又はCR7を表すが、X、Y及びZが、同時にNを表すことはなく、同時にN以外の基を表すこともなく、
R7は、水素原子、ハロゲン原子、炭素数1〜3のアルキル基、炭素数1〜3のアルコキシ基又はヒドロキシ基を表し、
R8は、水素原子又は炭素数1〜3のアルキル基を表し、
Aは、S(=O)2、C(=O)又はCH2を表し、
R9は、炭素数1〜3のアルコキシ基、アミノ基、ジメチルアミノ基、1〜3個の水素原子がそれぞれ独立してハロゲン原子、メトキシ基若しくはフェニル基、で置換されていてもよい炭素数1〜6のアルキル基、1〜3個の水素原子がそれぞれ独立してハロゲン原子で置換されていてもよい炭素数3〜6のシクロアルキル基、1又は2個の水素原子がそれぞれ独立してハロゲン原子、トリフルオロメチル基、炭素数1〜3のアルコキシ基、ヒドロキシ基若しくはシアノ基、で置換されていてもよいアリール基、又は、1個の水素原子がハロゲン原子、メチル基若しくはシアノ基、で置換されていてもよいヘテロアリール基を表し、
R10は、水素原子、炭素数1〜3のアルキル基、ヒドロキシ基又はアミノ基を表す。] - R1及びR4は、それぞれ独立して、水素原子、フッ素原子、塩素原子、メチル基、トリフルオロメチル基、メトキシ基、イソプロポキシ基、トリフルオロメトキシ基又はシアノ基であり、
R2、R3、R5及びR6は、それぞれ独立して、水素原子、フッ素原子又は塩素原子であり、
X〜Zの組み合わせは、X=CH、Y=N、かつ、Z=CR7であるか、X=CH、Y=CH、かつ、Z=Nであるか、X=N、Y=CH、かつ、Z=CHであるか、又は、X=N、Y=CH、かつ、Z=Nであり、
R7は、水素原子、フッ素原子、メチル基、メトキシ基又はヒドロキシ基であり、
R8は、水素原子又はメチル基であり、
Aは、S(=O)2であり、
R9は、ジメチルアミノ基、ベンジル基、炭素数3〜6のシクロアルキル基、1個の水素原子がハロゲン原子、炭素数1〜3のアルコキシ基、ヒドロキシ基若しくはシアノ基、で置換されていてもよいフェニル基、又は、1個の水素原子がハロゲン原子、メチル基若しくはシアノ基、で置換されていてもよいヘテロアリール基であり、
R10は、水素原子、メチル基、ヒドロキシ基又はアミノ基である、請求項1記載のグアニジン誘導体又はその薬理学的に許容される塩。 - R1及びR4は、それぞれ独立して、水素原子、フッ素原子、塩素原子、メチル基、トリフルオロメチル基、メトキシ基、トリフルオロメトキシ基又はシアノ基であり、
R2、R3、R5及びR6は、水素原子であり、
X〜Zの組み合わせは、X=CH、Y=N、かつ、Z=CR7であるか、X=CH、Y=CH、かつ、Z=Nであるか、X=N、Y=CH、かつ、Z=CHであるか、又は、X=N、Y=CH、かつ、Z=Nであり、
R7は、水素原子、フッ素原子、メチル基、メトキシ基又はヒドロキシ基であり、
R8は、水素原子であり、
Aは、S(=O)2であり、
R9は、ジメチルアミノ基、炭素数3〜6のシクロアルキル基、2−チエニル基、5−クロロ−2−チエニル基、3−チエニル基、2−フリル基、3−フリル基、2−ベンゾチエニル基、又は、1個の水素原子がハロゲン原子、炭素数1〜3のアルコキシ基、ヒドロキシ基若しくはシアノ基、で置換されていてもよいフェニル基であり、
R10は、水素原子、メチル基、ヒドロキシ基又はアミノ基である、請求項1記載のグアニジン誘導体又はその薬理学的に許容される塩。 - R1及びR4は、塩素原子であり、
R2、R3、R5及びR6は、水素原子であり、
X〜Zの組み合わせは、X=CH、Y=N、かつ、Z=CR7であるか、X=CH、Y=CH、かつ、Z=Nであるか、X=N、Y=CH、かつ、Z=CHであるか、X=N、Y=CH、かつ、Z=Nであり、
R7は水素原子、フッ素原子、メチル基、メトキシ基又はヒドロキシ基であり、
R8は、水素原子であり、
Aは、S(=O)2であり、
R9は、ジメチルアミノ基、炭素数3〜6のシクロアルキル基、2−チエニル基、5−クロロ−2−チエニル基、3−チエニル基、2−フリル基、3−フリル基、2−ベンゾチエニル基、又は、1個の水素原子がハロゲン原子、炭素数1〜3のアルコキシ基、ヒドロキシ基若しくはシアノ基、で置換されていてもよいフェニル基であり、
R10は、水素原子、メチル基、ヒドロキシ基又はアミノ基である、請求項1記載のグアニジン誘導体又はその薬理学的に許容される塩。 - R1及びR4は、それぞれ独立して、水素原子、フッ素原子、塩素原子、メチル基、トリフルオロメチル基、メトキシ基、トリフルオロメトキシ基又はシアノ基であり、
R2、R3、R5及びR6は、水素原子であり、
Xは、CHであり、
Yは、Nであり、
Zは、CR7であり、
R7は、水素原子又はフッ素原子であり、
R8は、水素原子であり、
Aは、S(=O)2であり、
R9は、ジメチルアミノ基、炭素数3〜6のシクロアルキル基、2−チエニル基、5−クロロ−2−チエニル基、3−チエニル基、2−フリル基、3−フリル基、2−ベンゾチエニル基、又は、1個の水素原子がハロゲン原子、メトキシ基、エトキシ基、ヒドロキシ基若しくはシアノ基、で置換されていてもよいフェニル基であり、
R10は、水素原子である、請求項1記載のグアニジン誘導体又はその薬理学的に許容される塩。 - R1及びR4は、それぞれ独立して、水素原子、フッ素原子、塩素原子、メチル基、トリフルオロメチル基、メトキシ基、トリフルオロメトキシ基又はシアノ基であり、
R2、R3、R5及びR6は、水素原子であり、
X〜Zの組み合わせは、X=CH、Y=N、かつ、Z=CR7であるか、又は、X=CH、Y=CH、かつ、Z=Nであり、
R7は、水素原子であり、
R8は、水素原子であり、
Aは、C(=O)であり、
R9は、エトキシ基、アミノ基、ジメチルアミノ基、2−チアゾリル基、4−チアゾリル基、2−チエニル基、3−チエニル基、2−ピリジル基、2−フリル基、1〜3個の水素原子がそれぞれ独立してフッ素原子、メトキシ基若しくはフェニル基、で置換されてもよい炭素数2〜5のアルキル基、1又は2個の水素原子がフッ素原子で置換されてもよい炭素数3〜6のシクロアルキル基、又は、1個の水素原子がフッ素原子、塩素原子、トリフルオロメチル基、メトキシ基若しくはシアノ基、で置換されていてもよいフェニル基であり、
R10は、水素原子である、請求項1記載のグアニジン誘導体又はその薬理学的に許容される塩。 - R1及びR4は、塩素原子であり、
R2、R3、R5及びR6は、水素原子であり、
X〜Zの組み合わせは、X=CH、Y=N、かつ、Z=CR7であるか、又は、X=CH、Y=CH、かつ、Z=Nであり、
R7は、水素原子であり、
R8は、水素原子であり、
Aは、C(=O)であり、
R9は、エトキシ基、アミノ基、ジメチルアミノ基、2−チアゾリル基、4−チアゾリル基、2−チエニル基、3−チエニル基、2−ピリジル基、2−フリル基、1〜3個の水素原子がそれぞれ独立してフッ素原子、メトキシ基若しくはフェニル基、で置換されてもよい炭素数2〜5のアルキル基、1又は2個の水素原子がフッ素原子で置換されてもよい炭素数3〜6のシクロアルキル基、又は、1個の水素原子がフッ素原子、塩素原子、トリフルオロメチル基、メトキシ基若しくはシアノ基、で置換されていてもよいフェニル基であり、
R10は、水素原子である、請求項1記載のグアニジン誘導体又はその薬理学的に許容される塩。 - 請求項1〜7のいずれか一項記載のグアニジン誘導体又はその薬理学的に許容される塩を有効成分として含有する、医薬。
- 請求項1〜7のいずれか一項記載のグアニジン誘導体又はその薬理学的に許容される塩を有効成分として含有する、Mucosa−associated lymphoid tissue lymphoma translocation protein 1阻害剤。
- 請求項1〜7のいずれか一項記載のグアニジン誘導体又はその薬理学的に許容される塩を有効成分として含有する、自己免疫疾患の治療剤又は予防剤。
- 請求項1〜7のいずれか一項記載のグアニジン誘導体又はその薬理学的に許容される塩を有効成分として含有する、乾癬の治療剤又は予防剤。
- 請求項1〜7のいずれか一項記載のグアニジン誘導体又はその薬理学的に許容される塩を有効成分として含有する、アレルギー性疾患の治療剤又は予防剤。
- 請求項1〜7のいずれか一項記載のグアニジン誘導体又はその薬理学的に許容される塩を有効成分として含有する、アトピー性皮膚炎の治療剤又は予防剤。
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