TW200800899A - Novel compounds - Google Patents
Novel compounds Download PDFInfo
- Publication number
- TW200800899A TW200800899A TW095132193A TW95132193A TW200800899A TW 200800899 A TW200800899 A TW 200800899A TW 095132193 A TW095132193 A TW 095132193A TW 95132193 A TW95132193 A TW 95132193A TW 200800899 A TW200800899 A TW 200800899A
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- compound
- lower alkyl
- substituted
- dmso
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 338
- 238000000034 method Methods 0.000 claims abstract description 228
- 150000003839 salts Chemical class 0.000 claims abstract description 57
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 25
- 239000011435 rock Substances 0.000 claims abstract description 25
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- 239000003112 inhibitor Substances 0.000 claims abstract description 11
- 230000002265 prevention Effects 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 175
- 239000000203 mixture Substances 0.000 claims description 111
- 125000000217 alkyl group Chemical group 0.000 claims description 93
- 229910052736 halogen Inorganic materials 0.000 claims description 39
- 150000002367 halogens Chemical class 0.000 claims description 39
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 37
- 125000001424 substituent group Chemical group 0.000 claims description 37
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 36
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 33
- 208000002193 Pain Diseases 0.000 claims description 23
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 19
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
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- 150000001412 amines Chemical class 0.000 claims description 14
- 201000008482 osteoarthritis Diseases 0.000 claims description 14
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 239000005977 Ethylene Substances 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 8
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- 206010020853 Hypertonic bladder Diseases 0.000 claims description 7
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- 238000004519 manufacturing process Methods 0.000 claims description 7
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- 201000011510 cancer Diseases 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
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- 125000003107 substituted aryl group Chemical group 0.000 claims description 6
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- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
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- 230000004770 neurodegeneration Effects 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 208000020431 spinal cord injury Diseases 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
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- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
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- 239000004480 active ingredient Substances 0.000 claims description 4
- 208000005298 acute pain Diseases 0.000 claims description 4
- 208000021328 arterial occlusion Diseases 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 230000009401 metastasis Effects 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 150000002923 oximes Chemical group 0.000 claims description 4
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- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 4
- 230000009385 viral infection Effects 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 3
- 230000002107 myocardial effect Effects 0.000 claims description 3
- 125000005493 quinolyl group Chemical group 0.000 claims description 3
- 108010041788 rho-Associated Kinases Proteins 0.000 claims description 3
- 102000000568 rho-Associated Kinases Human genes 0.000 claims description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 3
- 230000002485 urinary effect Effects 0.000 claims description 3
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- 101100097467 Arabidopsis thaliana SYD gene Proteins 0.000 claims description 2
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- 101100495925 Schizosaccharomyces pombe (strain 972 / ATCC 24843) chr3 gene Proteins 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 210000003802 sputum Anatomy 0.000 claims description 2
- 208000024794 sputum Diseases 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims 3
- 125000004639 dihydroindenyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 201000000585 muscular atrophy Diseases 0.000 claims 2
- 210000000056 organ Anatomy 0.000 claims 2
- 208000031229 Cardiomyopathies Diseases 0.000 claims 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims 1
- 102000016736 Cyclin Human genes 0.000 claims 1
- 108050006400 Cyclin Proteins 0.000 claims 1
- 206010028289 Muscle atrophy Diseases 0.000 claims 1
- 101000585507 Solanum tuberosum Cytochrome b-c1 complex subunit 7 Proteins 0.000 claims 1
- 125000005577 anthracene group Chemical group 0.000 claims 1
- 238000001354 calcination Methods 0.000 claims 1
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical group [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 claims 1
- 230000000295 complement effect Effects 0.000 claims 1
- 239000000470 constituent Substances 0.000 claims 1
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- 230000020763 muscle atrophy Effects 0.000 claims 1
- 125000004971 nitroalkyl group Chemical group 0.000 claims 1
- 230000028327 secretion Effects 0.000 claims 1
- 208000024891 symptom Diseases 0.000 claims 1
- 230000003612 virological effect Effects 0.000 claims 1
- 150000001408 amides Chemical class 0.000 abstract description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 241
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 212
- 238000002360 preparation method Methods 0.000 description 189
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 159
- -1 isodecyl Chemical group 0.000 description 131
- 235000019439 ethyl acetate Nutrition 0.000 description 75
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 66
- 239000000243 solution Substances 0.000 description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 54
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 50
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 239000012044 organic layer Substances 0.000 description 45
- 230000008569 process Effects 0.000 description 43
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 40
- 239000002904 solvent Substances 0.000 description 38
- 239000012267 brine Substances 0.000 description 37
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 37
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 33
- 238000005481 NMR spectroscopy Methods 0.000 description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
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- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 24
- 239000011734 sodium Substances 0.000 description 24
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 23
- 235000019341 magnesium sulphate Nutrition 0.000 description 23
- 101150041968 CDC13 gene Proteins 0.000 description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 239000013078 crystal Substances 0.000 description 21
- 239000000843 powder Substances 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
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- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 11
- 239000003054 catalyst Substances 0.000 description 11
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 10
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- 239000000725 suspension Substances 0.000 description 10
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical class NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 9
- 238000007796 conventional method Methods 0.000 description 9
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- 238000002347 injection Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 125000004076 pyridyl group Chemical group 0.000 description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
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- 238000004587 chromatography analysis Methods 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
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- 238000000746 purification Methods 0.000 description 6
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- 241001465754 Metazoa Species 0.000 description 4
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- 229910052796 boron Inorganic materials 0.000 description 4
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- 125000004432 carbon atom Chemical group C* 0.000 description 4
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- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 4
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- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
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- 229910000160 potassium phosphate Inorganic materials 0.000 description 4
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- 239000001117 sulphuric acid Substances 0.000 description 4
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- 150000007522 mineralic acids Chemical class 0.000 description 1
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- 229960005181 morphine Drugs 0.000 description 1
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- 208000021722 neuropathic pain Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 230000011164 ossification Effects 0.000 description 1
- JMJRYTGVHCAYCT-UHFFFAOYSA-N oxan-4-one Chemical compound O=C1CCOCC1 JMJRYTGVHCAYCT-UHFFFAOYSA-N 0.000 description 1
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- NAYYNDKKHOIIOD-UHFFFAOYSA-N phthalamide Chemical class NC(=O)C1=CC=CC=C1C(N)=O NAYYNDKKHOIIOD-UHFFFAOYSA-N 0.000 description 1
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- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 239000001120 potassium sulphate Substances 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- LVOICKNPHXSSQM-UHFFFAOYSA-N prop-2-en-1-one Chemical compound C=C[C]=O LVOICKNPHXSSQM-UHFFFAOYSA-N 0.000 description 1
- JOOIICMXVKYRGU-UHFFFAOYSA-N prop-2-enamide;dihydrochloride Chemical compound Cl.Cl.NC(=O)C=C JOOIICMXVKYRGU-UHFFFAOYSA-N 0.000 description 1
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- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 1
- 125000004590 pyridopyridyl group Chemical group N1=C(C=CC2=C1C=CC=N2)* 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- MAZOHJVAXBNBPX-UHFFFAOYSA-N ruthenium hydrochloride Chemical compound Cl.[Ru] MAZOHJVAXBNBPX-UHFFFAOYSA-N 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical group O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical group C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
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- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 description 1
- OVHFBTBLBHIKLB-QGZVFWFLSA-N tert-butyl N-[(1R)-3-(4-bromoanilino)-3-oxo-1-phenylpropyl]carbamate Chemical compound C(C)(C)(C)OC(N[C@H](CC(=O)NC1=CC=C(C=C1)Br)C1=CC=CC=C1)=O OVHFBTBLBHIKLB-QGZVFWFLSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical group CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- XCAQIUOFDMREBA-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)OC(C)(C)C XCAQIUOFDMREBA-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- DYVOLUUJJDFBFC-UHFFFAOYSA-N tripotassium butan-1-olate Chemical compound [K+].[K+].[K+].CCCC[O-].CCCC[O-].CCCC[O-] DYVOLUUJJDFBFC-UHFFFAOYSA-N 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 210000003708 urethra Anatomy 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
- 239000000080 wetting agent Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Description
200800899 九、發明說明: L W J^t Λ 發明領域 本發明係關於可有效作為Rho激酶(ROCK)抑制劑的新 5 穎醯胺衍生物及其鹽類。 【先前技術1 發明背景
Rho激酶(ROCK)為在Rho下游之低分子量功能性GTP-結合蛋白的絲胺酸/蘇胺酸激酶,並且已鑑定出ROCK I和 10 ROCKII的兩種ROCK異構物。該酵素涉及各種的生物學事 件如細胞骨架控制、細胞生長、細胞遷移、細胞凋亡、炎 症等。迄今,已曾報告該酵素涉及循環系統疾病、腫瘤浸 潤、骨生成等的病理學(請看例如,Satoh H.等人,J. P/mmaco/· 79,補充文件I,211 (1999),Kuwahara K.等人, 15 452 ’ 314-318 (1999),Sawada N·等人, 101 ’ 2030-2033 (2000) ’ Kataoka C.等人,⑼Wow· 2002 年2月;39 (2) ·· 245-50 ; Imamura F.等人,办η· /· Cancer 及烈· 200 ; 91 : 811-16,Itoh Κ·等人,施ί· Med 1999 ; 5 : 221-5,
Nakajima M.# A 9 Clin. exp. Pharmacol Physiol 2003^7 2〇月;30 (7) : 457-63),以及最近的研究發現該酵素涉及軟骨 細胞分化和神經性疼痛等(請看例如,Guoyan W.等人,/. BioL Chem. 2004 > 279 (13) 5 13205-13214 > Tatsumi S ? 2005 ; 131 (2) : 491-498)。為闡述尺〇(:民在體 内的許多功能,已廣泛地研究許多可抑制該酵素(ROCK抑 5 200800899 制劑)之功能的化合物(請看例如’ WO98/06433、 WO00/09162、WOOO/7835卜 WOOl/17562、WO02/076976、 P1256574、W002/100833、W003/082808、W02004/009555、 W02004/024717、W02004/108724、W02005/003101、 5 W02005/035501、W02005/035503、W02005/035506、 W02005/058891、W02005/074642、W02005/074643、 W02005/080934、W02005/082367、W02005/082890、 W02005/097790、W02005/100342、W02005/103050、 W02005/105780、W02005/108397、W02006/044753、 10 W02006/051311、W02006/057270、W02006/058120、 W02006/072792等),以及這些ROCK抑制劑通常被認為具 有治療南企壓、動脈粥樣硬化症、中風、心絞痛、動脈阻 基、末稍動脈疾病、末稍循環疾病、勃起功能障礙、急性 和慢性疼痛、癡呆症、阿茲海默症、帕金森氏症、神經元 15 變性、氣喘、肌萎縮性侧索硬化症(ALS)、脊索損傷、風濕 性關節炎、骨關節炎、骨質疏鬆症、牛皮癖、多發性硬化 症、糖尿病、泌尿器官疾病如膀胱過動症(〇AB)和良性前列 腺肥大(BPH)、轉移、癌症、青光眼、高眼壓症、視網膜病、 自體免疫疾病、病毒性感染、心肌保護等的效果。 20 【潑^明内容】 發明概要 本發明係關於新穎的醯胺衍生物及其鹽類。 更明確而言,係關於作為R0CK抑制劑的新穎醯胺衍生 物及其鹽類,含其之醫藥組成物及利用其於治療和/或預防 6 200800899 ROCK-相關疾病的方法。 本發明的一目的為提供作為尺〇(::&抑制劑的新而有效 醯胺衍生物及其鹽類。 本發明進一步的目的為提供含該醯胺衍生物及其鹽類 作為活性成分的醫藥組成物。 本發明又進一步的目的為利用該醯胺衍生物及其鹽類 於治療和/或預防R〇CK_相關疾病的方法。
本發明的新穎醯胺衍生物可以下列通式[η為代表··
[I] 10 其巾 Α為選擇性取代芳基、選擇性取代環烷基或選擇性取代 雜環基的低級烷基; L!為-H或-NH2 ; 1^2為 CRi4或N ; 15 L3 為 CH 或N ; L4 為 CR2 或N ; ‘ Rl為_H&R2為或低級烷基,或仏和仏2共同形成低級 伸烷基; m R14為-Η或鹵素; 20 Χ為鍵結、一CHR3…NR4-、-CHRs-Xi或-X2_CHR6·; R3為-Η、選擇性取代低級烷基、_〇Η、·ΝΗ2、選擇性 取代雜環基; 7 200800899 R4為-Η或選擇性取代低級烷基; XA-NH-、-CHR7-、-CHR15-X3-或; R5為-Η、選擇性取代低級烧基、-〇H、-NH2、-c⑼顺2、 -c(o)(m8、-mhc(o)〇r9或選擇性取代芳基; 5 R?為-H '選擇性取代低級烷基、選擇性取代雜環基、 -OH 或-NR10R16 ; R8和R9各為獨立的-Η或選擇性取代低級烷基;
Rio和Ri6各為獨立的或選擇性取代低級烧基;
Ri5為-H、選擇性取代低級烧基或_NIiC(〇)〇R^ 10 Rn為_H或選擇性取代低級烷基; X3 為-NH-或-CHR18 ;
Ri8為_H或-丽2 ; X2^?-(CH2)n-NRi1-^i-〇_ ; R6為-H或選擇性取代低級烷基; 15 η為0或1 ;
Rn為-Η、選擇性取代低級烷基、選擇性取代烷醯基或 _S〇2R12 ; R12為·Η或選擇性取代低級烷基。
t實施方式;J 20較佳實施例之詳細說明 本專利申請的上述及其後說明中,屬於本發明專利範 圍内的各種適當實施例詳細說明如下。 除非另有說明,否則專利說明書中之“低級,,意指具有i 至6個碳原子的直鏈或支鏈(通常簡稱為Ci_C6)。 8 200800899 用於本發明化合物之“低級烷基,,包括具有1至6個碳原 子的直鏈或支鏈燒基,例如甲基、乙基 、丙基、丁基、異 • H — τ基、第三丁基、戍基、異戍基、新戍基、第 • =戍基、^甲丁基、A甲丁基、1,2-二甲戊基、己基、異 5己基、^甲戍基、甲戊基、3-甲戊基、1,1-二曱丁基、1,2- 一甲丁基、2,2_二曱丁基、1,3·二甲丁基、2,3-二曱丁基、 3,3_二甲丁基、^乙丁基、2-乙丁基、1,1,2-三甲丙基、1,2,2- 馨 二甲丙基、L乙基小曱丙基、1-乙基-2-甲丙基等。其中,以 具有1至4個兔原子者較佳,以及最佳為甲基、乙基、丙基、 10 異丙基和第三丁基。 用於本發明化合物之“芳基,,包括具有6至14個碳原子 的單、雙_或三-環芳族輕基例如苯基、萘基、茚基等,一 %被氫化的__或二·環芳基如四氫萘基、三氫茚基等。其 中以具有6至1〇個碳原子者較佳,以及最佳為苯基、蔡基 15 和二氫茚基。 用於本發明化合物之“環絲,,含有⑻.員飽和經基 例如環丙基、環丁某、擾Λ 衣丁基%戍基、環己基、環庚基等 以環己基較佳。 用於本發明化合物之,,雜環 20 # 衣基包括含有1至4個選自 乳、氮和硫之雜原子的5至8_員 璟盥If 、早裱,以及其5至6-員單環狀 %與本%、%烷%或其他單環 施例包括雜芳基如料基、咪的雙環雜環,其實 吨基、痛絲、料基、三唾/、/絲、㈣基、°比 (thiopyranyi)、料基“㈣基、_ 基、硫代°比°南基 —氧戏環基(di〇x〇IailyI)、 9 200800899 礞 5 噻唑基、異噻唑基、噻二唑基、噻讲基、噚唑基(oxaz〇iyi)、 異口等唑基(isoxazolyl)、噚二唑基(oxadiaz〇lyl)、呋喃氮烷基 (furazanyl)、 σ井基等’飽和雜環基如吼嘻烧基(pyrrolidinyl)、派唆基 (piperidinyl)、哌畊基(piperazinyl)、嗎啉基(眶_ 硫嗎啉基等,以及融合雜環如吲哚基、異吲哚基、吲唑基 (indazolyl)、吲哚啉基(indolinyl)、異吲哚啉基、喹啉基 (quinolyl)、啥嗤琳基(qUinaz〇Hnyi)、嗟嗜琳基 (quinoxalinyl)、異喹啉基、3,4_二氫異喹啉基、四氫異喹啉 10 基、八氫異喹啉基、苯并咪唑基、苯并噻吩基、苯并噻唑 基、苯并呋喃基、苯并呋喃氮烷基、咪唑吼啶基 (imidazopyridyl)、咪唾吼讲基(imidazopyrazinyl)、吼〇多π比π定 基(pyridopyridyl)、呔讲基(phthalazinyl)、萘咬基 (naphthyridinyl)、吲哚啉基(indolizinyl)、嘌呤基、喹嗪基 15 (quinolizinyl)、噌啉基(cinnolinyl)、異笨并二氫哌喃基 (isochromanyl)、笨并二氫哌喃基等。較佳者為其5至6_員單 環雜環與苯環或環己烷環融合之具有1或2個選自氮、氧和 硫雜原子的5至6-員單環雜環或雙環雜環基,例如吡咯基、 σ比咬基、吱喃基、吲哚基、吲哚琳基、嗟吩基、嗟0坐基、 20 苯并吱喃基、苯并嗟嗤基、苯并嗟吩基、啥琳基、3,4_二氣 異13奎琳基、四氫異啥淋基和八氫異喧淋基。 “共同形成低級伸烷基”一詞意指心和尺2共同形成低級 伸燒基並形成與鄰近苯環融合的一部分含氮雜環。&和& 較佳為共同形成乙烯或丙浠,以及1和R2更佳為共同形成 10 200800899 癱 5 乙烯,旅且其與融合鄰近苯環形成一部分°比洛^(pyrroline) 環而形成吲哚啉(indoline)。 用於本發明化合物之“低級烷醯基”包括甲醯基、乙醯 基、丙醯基、丁醯基、異丁醯基、戊醯基(valeryl)、異戊醯 基、新戊醯基(pivaloyl)、己醯基、3,3-二甲基丁醯基等。 用於本發明化合物之“鹵素”包括氟、氣、溴和碘等。 用於本發明化合物之“取代”基的取代基為通常用於本 技術中作為取代基的任何取代基,以及該“取代”基可具有 一或多個相同或不同的取代基。 10 用於“取代芳基”、“取代環烷基”和“取代雜環基”的取代 基包括,但不侷限於’經基;鹵素如氟、氯、漠和峨;低 級烷基;鹵(低級)烧基如氯甲基、二氣曱基、三氣甲基、氟 甲基、二氟甲基、三氟曱基、溴曱基、二溴甲基、三溴曱 基、氯乙基、二氣乙基、三氯乙基、氟乙基、二氟乙基、 15 • 三氟乙基等;低級烷氧基如甲氧基、乙氧基、丙氧基、異 丙氧基、丁氧基、異丁氧基、第二丁氧基、第三丁氧基、 戊氧基、第三戊氧基、新戊氧基、已氧基、異己氧基等; 羧基;胺基;硝基等。 用於“取代低級烷基”和“取代低級烷醯基,,的取代基包 20 括,但不侷限於,羥基;鹵素如氟、氯、溴和碘;羧基; 氰基;胺基;硝基等。 下列為本發明較佳的具體實施例。 當X為如上述的鍵結、_CHR3-或-NR4-時,A較佳為可 分別被取代的低級烷基,或單或雙-環芳基、環烷基、雜芳 11 200800899 基或融合雜環,以及A更佳為笨基、萘基、二氫茚基、環已 基、噻吩基、呋喃基、吼咯基、吼啶基、吲哚基、吲哚啉 基、苯并呋喃基、苯并噻唑基、喹啉基、3,4_二氫異喹啉基、 四氫異喹啉基和八氫異喹啉基,其分別可被選擇性取代及 5最佳為未被取代。當X為如上述的-CHR5-Xl-或-x2-CHR6_ %,A較佳為分別可被選擇性取代的芳基、環烷基或單環雜 環基,以及A更佳為選擇性取代苯基、環己基或噻吩基,以 及A最佳為苯基、環己基或噻吩基。用於八的取代基較佳為 羥基、i素、低級烷基、低級烷氧基、羧基、氰基、胺基 10 或硝基。 L1、L2、L3和L4為如上之定義,以及Ll更佳為-H或NH2, L2 為 CH 或N,L3 為 CH,和 L4 為 CR2。 心和化為如上之定義,以及較佳為各自獨立的_H或共 同形成乙稀和隨後形成一部分吼0各琳環。 15 尺3較佳為、低級烧基、-OH或-NH2,以及更佳為 H。 R4較佳為-H或低級烷基,以及r4更佳為_H。 Χι為如上之定義,以及X!更佳為或-CHR7-,其中 I為-H或吼咯烷基、哌啶基、哌啡基、嗎啉基或硫嗎啉基, 20其分別可被選擇性取代,或-oh'-nr^r〗6,以及&最佳為 _H、嗎啉基、-oh或-魏!^6,其中R1〇和Ri6各為獨立的_H 或選擇性取代低級烧基,以及R1(^nR1G更佳為各自獨立的$ 或低級烷基。 R5為如上之定義,以及R5更佳為-H、低級烷基、以經 12 200800899 基或羧基取代的低級烷基、-oh、-nh2、-c(o)nh2、-C(0)0R8 或_nhc(o)or9,其中118和119為各自獨立的-H或低級烷基。 x2較佳為-(CH2)n-NRn·或-0-,其中η為0及Rn為如上定 義,以及X2更佳為-(CH2)n-NRlr4-0-,其中η為0及Rn為 5 _H、低級烷基、以羥基或羧基取代的低級烷基、低級烷醯 基、以羥基或胺基取代的低級烷醯基,或s〇2r12,其中Rl2 為-Η或低級烷基。 R6為如上之定義。 本化合物[I]適合的醫藥上可接受鹽類已習知為無毒性 ίο鹽類並且包括例如’與驗或酸加成鹽的鹽類例如與
胺基酸的鹽類(例如,精胺酸、 可参考本專利說明及熟習 製造本發明化合物或其鹽類。 物的代表性反應製程,但用於八 程並不僅侷限於下列的舉例性製 t、乙醇胺鹽、三乙醇胺鹽、 鹽等);無機酸加成鹽(例 鹽、硫酸氫鹽、磷酸鹽等); 甲酸鹽、乙酸鹽、三氟醋酸 、檸檬酸鹽、反丁烯二酸鹽、 酸鹽等);以及與鹼性或酸性 天門冬胺酸、麩胺酸等)。 本技術之人士所習知的方法 下列為用於合成本發明化合 合成本發明化合物的反應製 製程。 13 200800899 製程1
Ri (ID Ο α、'Λ X ΌΗ ο A. 1 X Ν
(I)
Ri (III) 上式中,各I、L!、L2、L3、L4、X和Α代表與上述相 同的定義。製程1為用於製造化合物(I),其中藉由化合物卩工) 和(III)的醯胺化作用合成化合物⑴。 化合物(II)和(ΙΠ)若有時可購自市面,或根據熟習有機 化學之人士所習知的一般方法合成自市售的化合物。 製程1為從溶劑内的胺化合物(II)和魏酸化合物(hi)製 造化合物(I)的製程。 10 15 可藉由一般的冷凝法進行此製程,例如利用冷凝劑。 當使用冷凝劑時,祇要能加速酸胺鍵之形成者均可被 用作為冷疑劑而並無特殊的限制其可包括二環己基辦-亞 胺(DCC)、二異丙基羰二亞胺(DIPCI)、1(3-二甲基胺丙 基)-3-乙基魏二亞胺鹽酸鹽(WSCD),以及二甲胺 基)(3H-[1,2,3]二峻[4,5_b]吼ϋ定_3_基氧基)亞甲基]·ν_甲臭 曱烷六氟磷酸銨、(〇-(7_氮雜苯并三唑小基)_u,3,3_四甲二 脲六氟磷酸鹽)(HATU)、笨并三唑小基1 丞虱基二吡咯啶基磷 六氟填酸(PyBOP)、溴·三対烧基璘代六氟磷酸鹽 (PyBROP)。 孤 在此實例中,一般為使用鹼。此製程中祇要具有、、 作用並非僅限於使用鹼,以及其可包括有機胺如二、乙2速 14 20 200800899 三丁基胺、二異丙基乙胺(DIEA)。 此製程中使用的溶劑祇要無反應活性並無特殊限制, 以及可包括醯胺如二甲基甲醯胺和二甲基乙酿胺;齒化辦
如二氯甲烷、氯仿。 I 5 其溫度視起始材料、溶劑等而隨著時間而變化,值其 通常為室溫。 加入鹼之後的反應時間視起始材料、溶劑等而變化, 但其通常為從1至30小時。 反應之後,該混合物被分層於水和不溶於水的有機溶 劑如醋酸乙醋、氣仿等之間,然後分離有機層。以水、鹽 酸、飽和碳酸氫鈉溶液、食鹽水等清洗該有機層,在無2 硫酸鎂或硫酸鈉上乾燥,以及在真空内蒸發。藉由習知的 方法如矽膠管柱層析法等純化該標的化合物。
上式中,各Ri、R5、k、L2、L3、L4和A代表與上述相 同的定義,以及n為0或1。製程2係用於製造化合物(化),其 中藉由化合物(II)和(IV)的反應合成化合物(ib)。 化合物(II)和(IV)若有時可購自市面,或根據熟習有機 20 化學之人士所習知的一般方法合成自市售的化合物。 製程2為從溶劑内的胺化合物(II)和異氰酸化合物(IV) 15 200800899 製造化合物(lb)的製程。 在此製程中,將化合物(IV)加入溶劑内的化合物(II), 並於加入後較佳為在室溫下攪拌。 用於溶解化合物(IV)的溶劑祇要無反應活性並無特殊 5 的限制,以及可包括二呤烷、氯仿、二甲基曱醯胺、二氯 甲烷等。 反應時間視起始材料、溶劑等而變化,但其通常為從1 至30小時。 反應之後,該混合物被分層於水和不溶於水的有機溶 10 劑如醋酸乙酯、氣仿等之間,然後分離有機層。以水、鹽 酸、飽和碳酸氫鈉溶液、食鹽水等清洗該有機層,在無水 硫酸鎂或硫酸鈉上乾燥,以及在真空内蒸發。藉由習知的 方法如矽膠管柱層析法等純化該標的化合物。 製程3
上式中’各R!、R5、Li、L2、L3、L4、A和η代表與上 述相同的定義。製程3係用於製造化合物(lb),其中藉由化 合物(II)和(V)的反應合成化合物(lb)。 化合物(II)和(V)若有時可購自市面,或根據熟習有機 20 化學之人士所習知的一般方法合成自市售的化合物。 製程3為從溶劑内的胺化合物(II)和疊氮化合物(V)製 16 200800899 造化合物(lb)的製程。 在此製程中,首先將疊氮化合物(V)溶解於溶劑内,然 後在加熱下攪拌,例如約70至90°C。 • 用於溶解化合物(V)的溶劑祇要無反應活性並無特殊 5的限制,以及可包括二噚烷、氯仿、二甲基曱醯胺、二氯 甲烷等。 然後在低溫下例如約-10至2〇t下將胺化合物(π)加入 奋液,加入後溫度較佳為升至室溫以反應兩種化合物。 反應時間視起始材料、溶劑等而變化,但其通常為從工 10 至30小時。 反應之後,該混合物被分層於水和不溶於水的有機溶 j如醋酸乙_、氯仿等之間,然後分離有機層。以水、鹽 =、飽和碳酸氫鈉溶液、食鹽水等清洗該有機層,在無水 U石4鐫或硫酸鈉上乾燥,以及在真空内蒸發。藉由習知的 务如妙膠官柱層析法等純化該標的化合物。
Ri (VI) ΑγηΝΗ2 (VII)
成化合物 述相1…各Rl R5 Ll、L2、L3、L4、歸11代表與上 化人:Γ定義以及巧任何的離去基。製程4係用於製造 (ibL⑽,其中藉由化合物(VI)和(VII)的反應合 17 20 200800899 化合物(νί)和㈣若有時可講自市面,或根據熟習有 機化學之人士所習知的—般方法合成自市售的化合物。或 . 纟’可㈣本專利綱書⑽述的其他製備方法合成化人 物(VI) 〇 5 製程4為·—般方法從溶_的胺基甲酸化合物(VI) 和胺化合物(VII)製造化合物(Ib)的製程。 在此實例中,-般為使用驗。此製程中祇要具有加速 • 作用並非僅限於使用驗,以及其可包括有機胺如三乙胺、 二丁基胺、二異丙基乙胺(DIEA)。 10 ㈣程中使用的溶劑祇要無反應活性並無特殊限制, 以及可包括醯胺如二甲基甲醯胺和二甲基乙酿胺;自化經 如,一氣甲烧、氯仿。
其溫度視起始材料、溶劑等而隨著時間而變化,但其 通常為室溫。 A 15 加入鹼之後的反應時間視起始材料、溶劑等而變化5 φ 但其通常為從1至30小時。 反應之後,該混合物被分層於水和不溶於水的有機溶 劑如醋酸乙醋、氯仿等之間,然後分離有機層。以水、鹽 • 酸、飽和碳酸氫鈉溶液、食鹽水等清洗該有機層,在無水 20硫酸鎂或硫酸鈉上乾燥,以及在真空内蒸發。藉由習知的 方法如矽膠管柱層析法等純化該標的化合物。 18 200800899 製程5
Ri (II) (VIII) ⑽ 上式中,各Ri、R5、L!、L2、L3、L4、A、η和Y代表與 上述相同的定義。製程5係用於製造化合物(Ic),其中藉由 5化合物(Π)和(vm)的胺基曱酸酯化合成化合物(Ic)。 化合物(II)和(VIII)若有時可購自市面,或根據熟習有 機化學之人士所習知的一般方法合成自市售的化合物。 製程5為從溶劑内的胺基化合物(π)和羰基化合物(νιιι) 製造化合物(Ic)的製程。化合物(vm)較佳為被逐滴加入化 10 合物(II)。 15 在此實例中,一般為使用鹼。此製程中祇要具有加速 作用並非僅限於使用鹼,以及其可包括例如吡啶。口、 此製程中使用的溶劑祇要無反應活性並無特殊限制, 以及可包括二氯甲烧、二甲基甲酸胺、二甲基乙驢胺、1 仿等 氯 其溫度視起始材料、溶劑等而隨著時間而變化, 通常為室溫。 旦其 加入驗之後的反應時間視起始材料、溶劑等而變 但其通常為從1至30小時。 ’ 反應之後’該混合物被分層於水和不溶於水的 劑如醋酸乙S旨、氯仿等之間,㈣分離有機層。以水、岭 鹽 19 200800899 酸、飽和碳酸氫鈉溶液、食鹽水等清洗該有機層,在無水 硫酸鎮或硫酸鈉上乾燥,以及在真空内蒸發。藉由習知的 方法如石夕膠管柱層析法等純化該標的化合物。 製程6
上式中,各R!、L!、L2、L3、L4、X、Y和A代表與上 述相同的定義。製程6係用於製造化合物(Id),其中藉由化 合物(IX)和(X)的反應合成化合物(Id)。 化合物(IX)若有時可購自市面,或根據熟習有機化學 10之人士所習知的一般方法合成自市售的化合物。 製程6為從溶劑内的化合物(IX)和硼酯(X)製造化合物 (M)的製程。 在此製程中’首先將化合物(IX)和硼酯(X)溶解於溶劑 内。 15 用於溶解化合物(ϊχ)的溶劑祇要無反應活性並無特殊 限制,以及可包括1,2-二甲氧乙院等。 然後在氮氣下將無機鹼和鈀催化劑加入溶液,以及在 加入後較佳為加熱至至。 *使用無機㈣,該製程中的無麟祇要能加速c_c 20鍵的$成並無特殊限制,以及包括破酸納 、碳酸鉀、碳酸 絶、破酸鉀、酷酸納、醋酸奸、氫氧化鈉、氫氧化鉀等。 20 200800899 當使用把催化劑時,該製程内的鈀催化劑祇要能加速 c-c鍵的形成並無特殊限制,以及包括(二苯基膦基) 一亞鐵]一氯鈀(II)、與二氯甲烷的複合物、二氯雙(三環己 基膦基)鈀(II)、二氯雙(三鄰甲苯基膦基)鈀(11)、二氯雙(三 5苯基膦基)鈀卬)、醋酸鈀(II)、四個(三苯基膦基)鈀(〇)、三(二 亞苄基丙酮)雙鈀(0)-氣仿加成物等。 反應時間視起始材料、溶劑等而變化,但其通常為 至30小時。 反應之後,該混合物被分層於水和不溶於水的有機溶 10劑如醋酸乙酯、氯仿等之間,然後分離有機層。以水 '鹽 酸、飽和碳酸氫鈉溶液、食鹽水等清洗該有機層,在無水 硫酸鎂或硫酸鈉上乾燥,以及在真空内蒸發。藉由習知的 方法如矽膠管柱層析法等純化該標的化合物。 製程7
上式中’各Ri、L!、l2、L3、L4、X、Y和A代表與上 述相同的定義。製程7係用於製造化合物(ie),其中藉由化 合物(XI)和(XII)的反應合成化合物(le)。 化合物(XI)若有時可購自市面,或根據熟習有機化學 20 之人士所習知的一般方法合成自市售的化合物。 製程7為從溶劑内的硼酯化合物(XI)和化合物(χπ)製 21 200800899 造化合物(le)的製程。 在此製程中,首先將硼酯化合物(χϊ)和化合物(χπ)溶 解於溶劑内。 用於溶解化合物(XI)的溶劑祇要無反應活性並無特殊 5限制,以及可包括1,4_二噚烷、1,2_二甲氧乙烷等。 然後在氮氣下將無機驗和把催化劑加入溶液,以及在 加入後較佳為加熱至80至150°C。 當使用無機驗時,該製程中的無機鹼祇要能加速c_c 鍵的形成並無特殊限制,以及包括碳酸鈉、碳酸鉀、碳酸 1〇铯、磷酸鉀、醋酸鈉、醋酸鉀、氫氧化鈉、氫氧化鉀等。 當使用鈀催化劑時,該製程内的鈀催化劑祇要能加速 C-C鍵的形成並無特殊限制,以及包括山广雙(二苯基膦基) 二亞鐵]二氯鈀(II)、與二氯甲烷的複合物、二氯雙(三環己 基膦基)鈀(II)、二氯雙(三鄰曱苯基膦基)鈀(11)、二氯雙(三 15笨基膦基)鈀(π)、醋酸鈀(ϊΐ)、四個(三苯基膦基)#巴(〇)、三(二 亞苄基丙酮)雙鈀(〇)-氯仿加成物等。 反應時間視起始材料、溶劑等而變化,但其通常為從} 至30小時。 反應之後,該混合物被分層於水和不溶於水的有機溶 20劑如醋酸乙酯、氣仿等之間,然後分離有機層。以水、鹽 酸、飽和碳酸氫鈉溶液、食鹽水等清洗該有機層,在無水 硫酸錢或硫酸鈉上乾燥,以及在真空内蒸發。藉由習知的 方法如矽膠管柱層析法等純化該標的化合物。 藉由習知的方法如碎化、再結晶、管柱層析、再沈澱 22 200800899 等分離和純化上述製程獲得的化合物,並需要時利用習知 的方法將其轉變成所欲的鹽類。 應注意由於不對稱碳該化合物[η可包括一或多種立體 異構物,並且全部該類異構物和其混合物均屬於本發明的 5 範圍内。 進一步應注意由於弱酸、弱鹼等的效應本化合物⑴可 能發生異構化或重排,並且因異構化或重排所獲得的化合 物亦屬於本發明的範圍内。 應注意本發明亦包括溶合型式的化合物[η (例如溶劑 10 合物等)以及化合物[I]之任何型式的結晶。 應注意本發明亦包括化合物⑴的醫藥上可接受前驅 藥。醫藥上可接受前驅藥指其在生理條件下可被轉變成 -COOH、·ΝΗ2、-ΟΗ等之功能基而形成本發明的化合物卩]。 本發明之化合物或其鹽類可抑制任何Rh〇激酶如 15 I和π的活動。因此,本發明之化合物可有效 用於治療和/或預防各種的rock-相關疾病。可利用本發明 化合物/台療和/或預防的R〇CK_相關疾病包括,但不侷限 於,局血昼、動脈粥樣硬化症、中風、心絞痛 '動脈阻塞、 末稍動脈疾病、末稍循環疾病、勃起功能障礙、急性和慢 2〇性疼痛、癡呆症、阿茲海默症、帕金森氏症、神經元變性、 氣喘、肌萎縮性側索硬化症(ALS)、脊索損傷、風濕性關節 k、月關郎k、月貝疏鬆症、牛皮癖、多發性硬化症、糖 尿病、泌尿器官疾病如膀胱過動症(OAB)和良性前列腺肥大 (BPH)、轉移、癌症、青光眼、高眼壓症、視網膜病、自體 23 200800899 5 免疫疾病、病毒性感染、心肌保護等。由於本發明化合物 或其鹽類具有減輕疼痛和軟骨保護的效果,因此可利用本 發明化合物治療和/或預防的ROCK-相關疾病較佳為骨關 節炎、風濕性關節炎和骨質疏鬆症,以及最佳為骨關節炎。 用於治療之目的時,本發明之化合物[I]及其醫藥上可 接受鹽類可為含其一該化合物作為活性成分的醫藥製備物 型式,並混合醫藥上可接受載劑如適合用於口服、非經口、 外部包括局部、内部、靜脈内、肌肉内、吸入、鼻内、關 節内、脊柱内、經氣管或經眼投藥之有機或無機的固體或 10 液體賦形劑。該醫藥製備物可為固體、半固體或溶液如膠 囊、錠劑、藥丸、糖衣錠、粉末、顆粒、栓劑、軟膏、乳 霜、乳液、吸入劑、注射劑、泥劑(cataplasms)、凝膠、貼 片、眼藥水、溶液、糖漿、喷霧劑、懸浮劑、乳劑等。需 要時這些製備物可加入輔助物質、穩定劑、濕潤劑或乳化 15 劑、緩衝劑及其他常用的添加物。 ❿ 化合物[I]的劑量雖然視病人的年齡和病況而定,但可 有效治療ROCK-相關疾病的化合物[I]平均單一劑量通常約 為0.1、1、10、50、100、250、500和 1,000毫克。其每天的 投藥劑量通常為介於0.1毫克/體重和約1,〇〇〇毫克/體重之 20 間。 在製造上述的醫藥投與劑型過程中,該化合物⑴或其 鹽類亦可結合其他的物質。 提供下列的製備物及實施例以作為說明本發明之目 的0 24 200800899 製備物1 在室溫下將4-硝苯基氯甲酸酯(6.40克)分成數部分加 • 入二氯甲烷(135毫升)和吡啶(32.1毫升)内的冬(4-吡啶基)苯 胺(4.50克)懸浮液内,然後在相同溫度下將混合物攪拌4小 彝 5 時。將4-硝苯基氯曱酸酯(1.60克)加入該混合物然後將混合 物在室溫下攪拌2小時。在真空内濃度該獲得的混合物並將 水(80毫升)加入殘留物。藉由過濾收集沈澱固體。以醋酸乙 ^ 酯(40毫升)磨碎該固體而產生黃色固體的4-硝苯基[4-(4-吡 啶基)苯基]甲酸酯(7.58克)。 10 1H-NMR (DMSO-d6) : δ7·59 (2H,d,J = 9·3 Hz),7.71 (2H,d,J = 8·6 Hz),7.91 (2H,d,J = 7·5 Hz), 7.93 (2H,d,J = 8·6 Hz),8.33 (2H,d,J = 9·3 Hz),8·70 (2H,d,J = 7.5 Hz), 10.70 (1H,s) MS (ESI,m/z) : 336 (M+H) 15 製備物2 φ 依照類似下述實施例4的方法獲得下列的化合物。 (2S)-苯基[({[4-(44啶基)苯基]胺基}羰基)胺基]醋酸 第三丁酯 1H-NMR (CDC13) : δ1·41 (9H,s),5.51 (1H,d,J = 7.2 20 Ηζ),6·26 (1H,d,J = 7·2 Ηζ),7·17 (1H,s),7·29·7·45 (9H,m), ’ 7·50 (2H,d,J = 8·5 Hz),8.59 (2H,d,J = 5·7 Hz) MS (ESI,m/z) : 404 (M+H) 製備物3 依照類似下述實施例4的方法獲得下列的化合物。 25 200800899 (2R)-苯基[({[4-(4·-比啶基)苯基]胺基}羰基)胺基]_酸 第三丁酯 1H-NMR (CDC13) : δ1·41 (9H,s),5.51 (1H,d,J = 7.2 Hz),6.26 (1H,d,J = 7.2 Hz),7·17 (1H,s),7·29-7·45 (9H,m), 5 7·50 (2H,d,J = 8·5 Hz),8·59 (2H,d,J = 5.7 Hz) MS (ESI,m/z) : 404 (M+H) 製備物4 在室溫下將三乙胺(0.519毫升)和疊氮磷酸二苯酉旨 (0.802毫升)加入四氫呋喃(1〇毫升)内的引哚_3_曱酸(5〇〇 10毫克)溶液。在6〇°C下將混合物攪拌2小時。在室溫下將醋 酸乙酯(10毫升)加入混合物,然後以飽和碳酸氫鈉水溶液 x2、水和食鹽水清洗有機層,在硫酸鎂上乾燥及在真空内 濃縮。以醋酸乙酯(2毫升)再結晶該殘留固體。以正已烷/ 氣仿(3 · 1,1耄升)清洗結晶物。再一次以醋酸乙酯再結晶 15該結晶物而產生白色結晶的出_叫|哚_3-羰基疊氮化物(192 毫克)。 1H-NMR (CDC13) : 67.25 (2H? m)5 7.52 (iH? m)? 8.05 (1H,m),8.20 (1H,S), 12.2 (1H,S) 製備物5 20 依照類似製備物4的方法獲得下列的化合物。 1-苯并呋喃-2_羰基疊氮化物 1H-NMR (DMS0_d6) : S7 41 (1H,t,卜 7 9 Hz), 7別 (1Η,υ = 7.9Ηζ),7·77(1Η,〇 = 79Ηζ) 7 86 (ΐΗ(ΐ,ι = 7·9Ηζ),7·91 (1H,S) 26 200800899 製備物6 在至'/m下將二乙&c(18.3毫升)和二碳酸二第三丁基醋 (26.0克)加入丙酮/H20(l : 1,72毫升)内的苯胺醋酸(6.0克) >谷液,然後在室溫下將混合物檀拌隔夜。在真空内蒸發丙 5酮及以二乙醚(40毫升)清洗殘留溶液。以1當量鹽酸將該水 溶液酸化至pH=3然後以氯仿(7〇毫升x3)萃取該混合物。以 艮鹽水清洗该結合有機層然後在硫酸儀上乾燥。在真空内 蒸發該溶劑然後藉由矽膠管桎析層法(2 5 〇克,氯仿内的1 〇 〇/〇 曱醇)純化殘留物而獲得棕色油狀的[(第三丁氧羰基)(苯基) 10 胺基]醋酸(8.78克)。 1H-NMR (DMSO-d6) : δΐ·38 (9H, s),4.20 (2H,s),7.21 (1Η,m),7·26 (2Η,m),7·32 (2Η,m) 製備物7 將[4-(4-吨啶基)苯基]胺(5·35克)和[(第三丁氧羰基)(苯 15 基)胺基]醋酸(7.90克)溶解於N,N-二甲基甲醯胺(250毫升) 内,然後在室溫下將Ν,Ν·二異丙基乙胺(12·0毫升)和1^[(二 甲胺基)(3Η-[1,2,3]三唾[4,5-b]咐咬冬基氧基)亞曱基]-Ν·甲 基甲烷六氟磷酸銨(13.1克)加入混合物。在室溫下攪拌隔夜 之後,將水(250毫升)加入獲得之混合物然後以醋酸乙酉旨 2〇 (5〇〇毫升)萃取該混合物。以食鹽水清洗有機層然後在硫酸 鎂上乾燥。在真空内蒸發溶劑然後利用矽膠管柱層析法 (250克,正已烷/醋酸乙酯(1 ··丨)然後氯仿内的2%甲醇)純化 其殘留物。在真空内濃縮該結合的部分。從正己烷(100毫 升)内的5%醋酸乙酯結晶殘留物。藉由過濾法收木結晶物然 27 200800899 後以正己烷(20毫升)内的5%醋酸乙酯清洗而產生(2_氧代 ·2·{[4_(4_吼啶基)苯基]胺基}乙基)苯基胺基甲酸第三丁酯。 1H-NMR (DMSO-d6) : δ1·37 (9Η,s),4·37 (2Η,s),7.19 (1Η,m),7.35 (4Η,d,J = 4·4 Ηζ),7·70 (2Η,dd,J = 1.7, 4.6 5 Ηζ),7·76 (2Η,d,J = 8.8 Ηζ),7·82 (2Η,d,J = 8·8 Ηζ),8·6〇 (2Η,dd,J = 1.7, 4·6 Ηζ),10.30 (1Η,s) MS (ESI,m/z) ·· 404 (Μ+Η) Μ備物8 將(2_氧代-2-{[4-(4-吼啶基)苯基]胺基}乙基)苯基胺基 10甲酸第三丁酯(1·30克)溶解於二氯甲烷(26毫升)内的50%三 氟醋酸内,然後在室溫下將混合物攪拌2小時。在真空内蒸 發溶劑然後從正己烷-醋酸乙酯(1 : 1,15毫升)再結晶殘留 物。藉由過據收集結晶物然後以正己烧-醋酸乙酯(1 : 1,5 毫升)清洗而產生黃色結晶的2-苯胺-N-[4-(4-4b唆基)苯基] 15 乙醯胺雙(三氟醋酸鹽)(1.46克)。 1H-NMR (DMSO_d6) : δ3·93 (2H,s),6·60 (3H,m),7.11 (2H,m),7.87 (2H, d,J = 8·9 Ηζ),8·06 (2H,d,J = 8·9 Hz), 8·33 (2H,d,J = 6.9 Hz),8·89 (2H,d,J = 6.9 Hz),10.40 (1H,s) MS (ESI,m/z) : 304 (M+H) 20 製備物9 在室溫下將1當重鼠氧化納水溶液(51.7毫升)加入甲酵 (160宅升)内的2-苯胺-Ν-[4-(4-πΛσ定基)苯基]乙酸胺雙(三氟 醋酸鹽)(11.0克)混合物。在室溫下攪拌2小時之後,在真空 内蒸發甲醇。將水(2 0毫升)加入獲得的混合物然後藉由過濾 28 200800899 收集殘留的固體。以水(30毫升)清洗結晶物而產生無色結晶 的2-苯胺-1^-[4-(4-11比0定基)苯基]乙酿胺(5.16克)。 1H NMR (DMSO-d6) : δ3·9〇 (2H, d,J = 6·〇 Ηζ),6·02 (1Η,t,J = 6·0 Ηζ),6·60 (3Η, m)5 7·10 (2Η,t,J 二 7.4 Ηζ), 5 7·68 (2Η,dd,J = 1.7, 4.6 Ηζ),7.79 (4Η,m),8·59 (2Η,d,J == 6.0 Hz),10.20 (lH,s) MS (ESI m/z) : 304 (M+H)
製備物M 依照類似下述實施例27的方法獲得下列化合物。 10 2-氧代-2-[(2-氧-2-{[4-(4-n比啶基)苯基]胺基}乙基)(苯 基)胺基]醋酸乙酯 1H NMR (DMSO-d6) : δ2·02 (3H,s),4.45 (4H,s),7.53 (5Η,m),7.69 (2Η,d,J = 6·2 Ηζ),7.72 (2Η,d,J 二 8·8 Ηζ), 7.80 (2Η,d,J = 8·8 Ηζ),8·59 (2Η,d,J = 6·2 Ηζ),1〇·28 (1Η,s) 15 MS (ESI m/z) : 404 (M+H) 製備物11 在室溫下將二異丙基乙胺(0.189毫升)和N-[(二甲胺 基)(3H-[1,2,3]三唑[4,5-b]吼啶-3-基氧基)亞曱基]-N-曱基甲 烷六氟磷酸銨(207毫克)加入N,N-二甲基甲醯胺(ι·〇毫升)内 20的2_苯胺-N-[4_(4-°比咬基)苯基]乙酿胺(5〇 〇毫克)和[(第三 丁氧羰基)胺基]醋酸(86.6毫克)混合物,然後在相溫度下將 混合物攪拌24小時。將水(3.0¾升)加入混合物然後以醋酸 乙酯(6.0毫升)萃取獲得之混合物。以食鹽水清洗有機層, 在硫酸镁上乾燥及在真空内派縮。藉由生產級薄層色譜法 29 200800899 (氯仿内的10%甲醇)純化殘留物而產生黃色結晶的{2-氧代 _2-[(2_氧-2-{[4-(4-t定基)苯基]胺基}乙基)(苯基)胺基]乙 基}胺基甲酸第三丁酯(36.5毫克)。 1H-NMR (DMSO-d6) : δ1·38 (9H,s)5 3·50 (2H,m),4.46 5 (2H,s),6·84 (1H,m),7·41 (1H,m),7·49 (4H,m), 7.68 (2H, d,J = 6.0 Hz),7.73 (2H,d,J = 8·8 Hz),7·81 (2H,d,J = 8.8 Hz),8·59 (2H,d,J = 6.0 Hz),10·26 (1H,s) MS (ESI,m/z) : 461 (M+H) 製備物12 10 在室溫下將溴乙酸苄酯(1 · 8 5毫升)和2 -第三丁亞胺基 -2-二乙胺基-1,3-二甲基全氫-i,3,2-二氮膦(2.14克)加入Ν,Ν· 二甲基甲醯胺(7.0毫升)内的苯胺醋酸乙酯(7〇〇毫克)溶液然 後在60°C下將混合物攪拌3天。在室溫下將水(10毫升)加入 混合物然後以醋酸乙酯(2〇毫升)萃取獲得之混合物。以食鹽 15 水清洗有機層然後在硫酸鎂上乾燥。在真空内蒸發溶劑然 後利用矽膠管柱層析法(250克,正已烷内10%醋酸乙酯然後 正己烷内的20%醋酸乙酯)純化其殘留物而獲得棕色油狀的 苄基乙基2,2,-(笨亞胺基)二醋酸酯(1.5i克)。 1H-NMR (CDC13) : δ1·26 (3H,t,J = 7·1 Hz), 4.14 (2H, 20 s),4·19 (2H,s),4.20 (2H,q,J = 7·1 Hz),6·61 (2H,d,J = 8·3
Hz),6.79 (1H,t,J = 8·3 Hz),7·21 (2H,t,J = 8·3 Hz),7.34 (5H,m) 製備物13 將苄基乙基2,2,_(苯亞胺基)二醋酸酯(1.0克)溶解於甲 30 200800899 醇(15¾升)内然後混合物加入1〇%把上碳(1〇〇毫克)。在室溫 的氫氣(3大氣壓)下將混合物攪拌3小時然後通過矽藻土 (celite)過濾。在真空内濃縮濾過物而產生棕色油狀的[(> 乙氧基_2·側氧乙基)(苯基)胺基]醋酸(〇·698 g)。 5 1H-NMR (DMSO-d6) : δΐ.19 (3H, t? J = 7.1 Hz)? 4.08 (2H,s),4·11 (2H,q,J = 7·1 Ηζ),4·17 (2H,s),6·51 (2H, d,J =8.4 Hz),6.67 (1H,t,J = 8.4 Hz), 7·16 (2H,t,J = 8.4 Hz) 製備物14 依照類似製備物7的方法獲得下列化合物。 ίο [(2·氧代比啶基)苯基]胺基}乙基)(苯基)胺基] 醋酸乙酯 1H-NMR (DMSO-d6) : δ1·26 (3H,t,J = 7.1 Hz),4.21 (2H,s),4·22 (2H,q,J = 7·1 Hz),4.39 (2H,s),6·57 (2H,d,J =8.1 Hz),6·72 (1H,t,J = 8.1 Hz),7.21 (2H,t,J = 8.1 Hz), 15 7.68 (2H,d,J = 6·2 Hz),7·74 (2H,d,J = 8·8 Hz),7.81 (2H,d, J = 8.8 Hz),8.59 (2H, d,J = 6.2 Hz),10.34 (1H,s) 製備物15 將三乙胺(1·66毫升)、曱基_(2S)-2-胺基-3-第三丁氧丙 酸鹽酸鹽(1.26克)和醋酸銅(11)(1.19克)加入二氯甲烷(40毫 20 升)内的苯基硼酸(1.46克)和4A分子篩(4.5克)溶液,然後在 室溫下將混合物攪拌5天。以曱醇(15毫升)内之7當量氨水冷 卻反應,然後通過矽藻土過濾混合物。在真空内濃縮濾過 物以及藉由石夕凝膠管柱層析法(溶析物;正己烧/醋酸乙酉旨 (2 : 1))純化殘留物而產生無色糖漿狀的甲基-(2S)-2-苯胺基 31 200800899 -3-第三丁氧丙酸鹽(500毫克)。 1H-NMR (CDC13) : δ1·17 (9H,s),3.68 (1H,dd,J = 4.2, 8·8 Ηζ),3·73 (3H,s),3.78 (1H,dd,J = 3.9, 8.8 Ηζ),4·19 (1H, dd,J = 3.9, 4.2 Hz),4.43-4.54 (1H,br),6.63 (2H,d,J = 8.0 5 Hz),6.74 (1H,t,J = 8.0 Hz),7.17 (2H,t,J = 8.0 Hz) MS (ESI, m/z) : 252 (M+H) 製備物16 將1當量氫氧化鈉水溶液(2·75毫升)加入甲醇(2.30毫升) 内的曱基(2S)-2-苯胺基-3-第三丁氧丙酸鹽(230毫克)溶 10 液,然後在室溫下將混合物攪拌2小時。以1當量鹽酸(2.7 毫升)將獲得之溶液酸化至pH=4然後以水(2.7毫升)稀釋。在 0 °C下將混合物攪拌2 0分鐘然後藉由過濾收集沈澱物接著 以水(2.7毫升)清洗而獲得灰白色的(2S)-2-苯胺基-3-第三丁 氧丙酸(100毫克)。 15 1H-NMR (DMSO-d6) : 51.13 (9H? s)? 3.25-3.42 (2H? br)5 3·61 (1H,dd,J = 5.1,8·7 Hz),3·64 (1H,dd,J = 4.5, 8.7 Hz), 4.05 (m,dd,J = 4.9, 5.1 Hz),6.56 (1H,t,J = 7·3 Hz),6.63 (2H, d,J = 8.0 Hz),7.06 (2H,dd,J = 7.3, 8.0 Hz) MS (ESI,m/z) : 238 (M+H) 20 製備物17 依照類似製備物7的方法獲得下列化合物。 (2S)-2·苯胺基-3_第三丁氧基-N-[4-(4-吼啶基)苯基]丙 醯胺 1H-NMR (CDC13) : δ1·24 (9H,s),3·74 (1H,dd5 J = 5.0, 32 200800899 9·0 Ηζ),3·88 (1H,dd,J = 4.9, 9.0 Ηζ),3·96 (1H,ddd,J = 3.8, 4.9, 5.0 Hz),4.72 (1H,d,J = 3.8 Hz),6·73 (2H,d,J = 7.8 Hz),6·85 (1H,t,J = 7.3 Hz),7.24 (2H,dd,J 二 7.3, 7.8 Hz), 7.48 (2H,d,J = 6.0 Hz),7·61 (2H,d,J = 9.0 Hz), 7·67 (2H,d, 5 J = 9·0 Hz),8·63 (2H,d,J = 6.0 Hz),8·95 (1H, s) MS (ESI,m/z) : 390 (M+H)
製備物M 在室溫下將(漠曱基)苯(1.1克)加入N,N-二甲基曱醯胺 (20毫升)内的(2S)-2-胺丙酸乙酯鹽酸鹽(ίο克)和碳酸鉀(1.8 10 克)懸浮液。在室溫下將反應混合物攪拌7小時。以醋酸乙 酯稀釋該獲得之混合物然後依序以水和食鹽水清洗。在無 水硫酸鎂上乾燥有機層,過濾及在真空内濃縮。利用以20% 醋酸乙酯/正己烷溶析的矽膠管柱層析法純化殘留物而產 生(2S)-2-(苄胺基)丙酸乙酯。 15 1H-NMR (CDC13) : δ1·33·1·27 (6H,m),3.37 (1H,q5 J =: 7.0 Ηζ),3·67 (1H,d,J = 12.5 Ηζ),3·80 (1H,d,J = 12.5 Hz), 4.19 (2H,q,J = 7·0 Hz),7·33-7·32 (5H,m) MMM19 在室溫下將二碳酸二第三丁基酯(232毫克)加入N,N-二 2〇 甲基甲醯胺(4.0毫升)内的(2S)-2-(苄胺基)丙酸乙酯(200毫 克)和三乙胺(107毫克)溶液。在室溫下將該反應混合物授拌 5小時。以醋酸乙醋稀釋該溶液然後依序以水和食鹽水清 洗。在無水硫酸鎮上乾燥有機層,過渡及在真空内濃縮而 產生(2S)-2-[苄基(第三丁氧羰基)胺基]丙酸乙酯。 33 200800899 1H-NMR (CDC13) : δ1·24 (3H5 t,J = 7.0 Ηζ),1_53·1_34 (12H,m),3.93-3.91 (1H,m),4.15-4.09 (2H,m),4.62-4.49 (2H,m),7.32-7.29 (5H,m) 製備物20 5 依照類似製備物16的方法獲得下列化合物。 (2S>2-[节基(第三丁氧羰基)胺基]丙酸 1H-NMR (DMSO-d6) : 51.39-1.19 (12H? m)9 4.04-4.02 (1H,m),4·44·4·42 (2H,m),7.35-7.30 (5H,m) 製備物21 10 依照類似製備物7的方法獲得下列化合物。 苄基((IS)-l-甲基-2-氧代-2- {[4-(4-吼啶基)苯基]胺基} 乙基)胺基甲酸第三丁酯
1H-NMR (DMSO-d6) : 51.33-1.30 (12H, m)9 4.60-4.42 (3H,m),7.31-7.23 (6H,m),7.82-7.69 (6H,m),7.60 (2H,d,J 15 = 5.0 Hz) MS (ESI,m/z) : 432 (M+H) 製備物22 依照類似製備物15的方法獲得下列化合物。 (2S)-2-苯胺丙酸乙酯 20 1H-NMR (CDC13) : δΐ.25 (3H,t,J = 7·0 Hz),1.47 (3H, d,J = 6.5 Ηζ),4·22-4·13 (3H,m),6.61 (2H, d,J = 7·5 Hz), 6.74 (1H,dd,J = 7.5, 7.5 Hz),7_17 (2H,dd,J = 7.5, 7·5 Hz) 製備物23 依照類似製備物16的方法獲得下列化合物。 34 200800899 (2S)-2-苯胺丙酸 1H-NMR (DMSO-d6) : 51.36 (3H? d9 I = 7.0 Hz), 3.92 (1H,q,J = 7.0 Hz),6.57-6.52 (3H,m),7.06 (2H,dd,J = 7.5, 7.5 Hz) 5 製備物24 依照類似製備物15的方法獲得下列化合物。 (2R)-2-苯胺丙酸甲酯
1H-NMR (CDC13) : δ1·48 (3H,d,J = 7.0 Hz),3.73 (3H, s),4.19-4.12 (1H,m), 6·61 (2H,d,J = 7·5 Ηζ),6·74 (1H,dd, 10 J = 7.5, 7.5 Hz),7.18 (2H,dd,J = 7.5, 7.5 Hz) 製備物25 依照類似製備物16的方法獲得下列化合物。 (2R)_2-苯胺丙酸 1H-NMR (DMSO-d6) : δΐ.36 (3H,d,J = 7 0 Hz),3.92 15 (1H,r,J = 7.0 Ηζ),6·57-6·52 (3Ή,m),7.06 (2H,dd,J 二 8.0, 8.0 Hz) 製備物26 依照類似製備物15的方法獲得下列化合物。 (2R)-2-苯胺-3-第三丁氧基丙酸甲酯 20 1H-NMR (CDC13) ·· δ1·17 (9Ή,s),3·68 (1H,dd,J = 4.2, 8·8 Hz),3.73 (3H,s),3·78 (1H,dd,J = 3.9, 8·8 Ηζ),4·19 (1H, ddd,J = 3.9, 4.2, 9.0 Hz),4·48 (1H,d,J = 9.0Hz),6.63 (2H, d,J = 8.0 Hz),6.74 (1H,t,J = 8·0 Hz),7.17 (2H,t, J = 8.0 Hz) 35 200800899 MS (ESI, m/z) : 252 (M+H) 數備物27 依照類似製備物16的方法獲得下列化合物。 (2R)-2-苯胺-3-第二丁氧基丙酸 5 1H-NMR (DMSO-d6) : 51.13 (9H? s)9 3.25-3.42 (2H? br)9 3.61 (1H,dd,J = 5.1,8·7 Hz),3·64 (1H,dd,J = 4.5, 8.7 Hz), 4.05 (1H,dd,J = 4·9, 5.1 Hz),6.56 (1H,t,J = 7.3 Hz),6.63 (2H,d,J = 8.0 Hz),7.06 (2H,dd,J = 7.3, 8.0 Hz) MS (ESI,m/z) : 238 (M+H) 10 製備物28 依照類似製備物7的方法獲得下列化合物。 (2R)-2-苯胺-3-第三丁氧基-N-[4-(4-吼啶基)苯基]丙醯胺 1H-NMR (CDC13) : δ1·25 (9H,s),3.74 (1H,dd,J = 5.0, 9.0 Hz),3.88 (1H,dd,J = 4.9, 9.0 Hz),3.96 (1H, ddd,J = 15 3·8,4·9, 5.0 Hz),4.72 (m,d,J = 3.8 Hz),6·74 (2H,d,J = 7.8
Hz),6·85 (1H,t,J = 7.3 Hz),7·24 (2H,dd,J = 7.3, 7.8 Hz), 7.48 (2H,d,J = 6.0 Hz),7.61 (2H,d,J = 9·0 Hz),7·67 (2H,d, J = 9·0 Hz),8·63 (2H,d,J = 6·0 Hz),8·95 (1H,s) MS (ESI,m/z) : 390 (M+H) 20 製備物29 依照類似製備物7的方法獲得下列化合物。 2-({[4-(4-0比σ定基)苯基]胺基}幾基)-1-。弓卜朵琳甲酸第二 丁酯 1H-NMR (CDC13) ·· δ1·59 (9H,s),3.40-3.66 (2H,br), 36 200800899 5·〇2_6·〇〇 (in,m),7·03 (1H,t, J = 7·4 Hz),7.18-7.27 (2H, m),?·47 (2H,d,J = 5·9 Hz),7.58-7.68 (5H,m),8.63 PH,d, J = 5.9 Hz) MS (ESI,m/z) : 416 (M+H) 5 製備物& 在5°c下將氯化苯基乙醯(11.9克)逐滴加入二氣甲烷 (1〇〇毫升)内的5-溴吲哚啉(13.86克)和三乙胺(8·50克)溶液 然後在室溫下將混合物攪拌16小時。將該混合物倒入水中 然後以醋酸乙酯萃取。以食鹽水清洗分離的有機層,在硫 10 酸鎂上乾燥然後在真空内蒸發。利用以己烷/醋酸乙酯(i : 1)溶析的石夕膠管柱層析法純化殘留物而產生白色粉末的5_ 漠-1-(苯乙酿基)《引σ朵琳(16.01克)。 1H-NMR (DMSO-d6) : δ3·17 (2Η,t,J = 6·8 Ηζ),3.84 (2Η,s),4.18 (2Η,t,J = 6·8 Ηζ),7.2-7.35 (6Η,m),7.42 (1Η 15 s),7.98 (1H,d,J = 6.9 Hz) ESI-MS (m/z) : 340,338 (M+Na) 製備物31 在室溫下將N,N-二異丙基乙胺(6.53克)逐滴加入'队 二甲基甲酸胺(100¾升)内的5-漠3卜朵琳(5 〇克)、2-π比唆基 20 醋酸鹽酸鹽(4·82克)和苯并三唑-1-基·氧基三吡洛。定基鱗丄 氟磷酸(PyBOP)(15.8克)溶液,然後在相同溫度下將混合物 挽拌20小時。將混合物倒入醋酸乙酯和水的混合物内,並 且以水和食鹽水清洗分離的有機層,在硫酸鎂上乾燥以及 在真空内蒸發。利用以醋酸乙酯溶析的矽膠管柱層析法純 37 200800899 化殘留物而產生淡棕色粉末的5_溴_1-(2-吼啶基乙醯基)ϋ引 口朵淋(5.23克)。 1H-NMR (DMSO-d6) : δ3·16 (2Η,t,J = 6.8 Ηζ),4·01 (2Η,s),4.22 (2Η,t,J = 6.8 Ηζ),7.25-7.45 (4Η,m),7.7-7.8 5 (1H,m),7·98 (1H,d,J = 8·7 Hz),8·45-8·5 (1H,m) ESI-MS (m/z) : 319,317 (M+Na) I備物—32 在室溫下將[1,Γ-雙(二苯基膦基)二亞鐵]二氯鈀(11)、 與二氯甲烷的複合物(1·23克)和磷酸鉀(31.9克)加入1,2-二 10 甲氧乙烷(500毫升)内的1-乙醯基-5-溴吲哚啉(12.01克)和4- 吡啶基硼酸(9.22克)溶液,然後在100°C下將混合物攪拌20 小時。在真空内蒸發該混合物以除去1,2-二甲氧乙烷,然後 將殘留物溶解於醋酸乙酯(600毫升)和水(300毫升)的混合 物内。以食鹽水清洗分離的有機層,在硫酸鎂上乾燥以及 15 在真空内蒸發。利用以醋酸乙醋溶析的石夕膠管柱層析法純 化殘留物而產生白色粉末的1-乙醯基-5-(4-°比咬基弓丨哚淋 (4.42克)。 1H-NMR (DMSO_d6): δ2·19 (3H,s)5 3·22 (6.8H,t),4.16 (6·8Η,t),7.6-7.75 (4H,m),8·14 (1H,d,J = 6.9 Hz), 8.58 20 (2H,d, J = 6.0 Hz) ESI-MS (m/z) : 239 (M+H) 輩備物33 將1當量氫氧化鈉水溶液(1·8毫升)加入乙醇(20毫升)内 的1-乙醯基-5(4_吡唆基)η引哚琳(715毫克)懸浮液,然後使該 38 200800899 混合物回流16小時。以醋酸乙酯萃取該混合物,然後以食 鹽水清洗分離的有機層,在硫酸鎂上乾燥以及在真空内蒸 發。利用以醋酸乙酯溶析的矽膠管柱層析法純化殘留物而 產生黃色粉末的5-(4-吡啶基)吲哚啉(240毫克)。 5 1H-NMR (DMSO-d6) : 52.99 (2H? t? J = 6.8 Hz)5 3.50 (2H,t,J = 6.8 Hz),5·93 (1H,brs),6.57 (1H,d,J = 8.1 Hz), 7.42 (1H,d,J = 8.1 Hz),7.51 (1H,s),7.55-7.6 (2H,m), 8.45-8.5 (2H9 m) 製備物34 10 依照類似製備物1的方法獲得下列化合物。 4-硝苯基- 5_(4-吡啶基)-1 -吲哚啉甲酸鹽 1H-NMR (DMSO-d6) : 3.27-3.37 (2H? m)? 4.28-4.40 (2H5 m),7.61 (2H, d,J = 8.7 Hz),7.89 (1H,d,J = 8·1 Hz),7·99 (1H, d, J = 8·1 Hz),8·05 (1H, s),8.32 (2H,d,J = 6·4 Hz), 15 8·35 (2H,d,J = 8·7 Hz),8·88 (2H,d,J = 6.4 Hz) MS (ESI, m/z) : 362 (M+H) 製備物35 依照類似製備物7的方法獲得下列化合物。 {2-氧代-2-[5-(4-吼啶基)-2,3-二氫-1H-吲哚-1-基]乙基} 20 苯基胺基甲酸第三丁酯 1H-NMR (CDC13) : δ1·44 (9H,s),3.25-3.36 (2H,m), 4.08-4.19 (2H,m),4·47 (2H,s),7·21 (1H,dd,J = 7.1,7·1 Hz),7.30-7.55 (8H,m),8·35 (1H,d,J = 8·3 Hz),8.61 (2H,d, J = 5.4 Hz) 39 200800899 MS (ESI,m/z) : 430 (M+H) 製備物36 將(CK7-氮雜苯并三唑-1-基)-U,3,3-四甲基脲六氟磷 酸鹽)(HATU)(2.68克)加入Ν,Ν-二甲基甲醯胺(30毫升)内的 5 4-溴苯胺(1·1克)、(2S)-2-[(第三丁氧基羰基)胺基]-3-苯基丙 酸(1.87克)和二異丙基乙胺(L82克)溶液,然後將混合物攪 拌24小時。加入水然後以醋酸乙酯萃取混合物。以食鹽水 清洗分離的有機層,在硫酸鎂上乾燥以及在真空内蒸發。 利用矽膠管柱層析法純化殘留物而產生{(IS)-1 -苄基-2-[(4-10 溴苯基)胺基]-2·側氧乙基}胺基甲酸第三丁酯(2.62克)。 MS (ESI, m/z) : 420 (M+H) 製備物37 將[U?-雙(二苯基膦基)二亞鐵]二氯鈀(11)(58毫克)加 入二甲氧乙烷(30毫升)内的{(IS)-l-苄基-2-[(4-溴苯基)胺 15 基]-2-側氧乙基}胺基甲酸第三丁酯(1.0克)、4-(4,4,5,5-四甲 基-1,3,2-二氧硼烷-2-基)吼啶(587毫克)和磷酸鉀(1·52克)懸 浮液,然後在120°C下將混合物攪拌4小時。加入水然後以 氯仿萃取該混合物。以食鹽水清洗分離的有機層,硫酸鎂 上乾燥以及真空内蒸發。利用矽膠管柱層析法純化殘留物 20 而產生[(1S)-1-节基-2-氧代-2-{[4-(4-吼啶基)苯基]胺基}乙 基]胺基甲酸第三丁酯(830毫克)。 1H-NMR (DMSO-d6) : δ1·33 (9H,s),2.8-3.1 (2H,m), 4·3-4·45 (1H,m),7.1-7.3 (5H,m),7.31 (2H,d,J = 8.8 Hz), 7·68 (2H,d,J = 8·8 Hz),7·76 (2H,d,J = 6.8 Hz), 8·90 (2H,d, 40 200800899 J = 6.8 Hz) MS (ESI,m/z) : 418 (M+H) 製備物38 依照類似製備物36的方法獲得下列化合物。 5 [(1RH-节基冬氧代-2-{[4-(4-吼啶基)苯基]胺基}乙基] 胺基甲酸第三丁酯 1H-NMR (DMSO-d6): δ1·33 (9H,s),2.74-3.10 (2H,m), 4.16-4.45 (1H,m),7.11 -7.40 (6H, m),7.64-7.87 (6H,m)5 8.56-8.64 (2H,m)5 10·04_10·31 (1H,br) 10 MS (ESI,m/z) : 418 (M+H) 製備物39 依照類似製備物36的方法獲得下列化合物。 [(1S)-1-节基-2-氧代-2-{[4-(4-吼啶基)苯基]胺基}乙基] 甲基胺基甲酸第三丁酯 15 iH-NMR (DMSO-d6) : δϊ.20-1.36 (9Η, m)9 2.61-2.87 (5H,m),4.70-5.18 (1H,m),7.12-7·40 (5H,m),7.64-7.89 (6H,m),8.57-8.64 (2H,m),9.95-10.31 (1H,br) MS (ESI,m/z) ·· 432 (M+H) M備物40 20 將10%氫氧化鈀(〇·3克)加入乙醇(30毫升)内的(2E)-2- 氰基-3-苯基丙烯酸乙酯(1·2克)溶液,然後在3大氣壓下將該 混合物氫化2小時。藉由矽藻土墊上的過濾移除催化劑之 後,在真空内蒸發該濾過物。將殘留物溶解於1當量鹽酸(2 毫升)内然後以氣仿清洗。藉由添加飽和碳酸氫鈉溶液將分 41 200800899 離的含水層調節至pH=7,然後以醋酸乙酯萃取。以食鹽水 清洗分離的有機層,硫酸鎂上乾燥以及真空内蒸發。利用 矽膠管柱層析法純化殘留物而產生3-胺基-2-苄基丙酸乙酯 (388毫克)。 5 1H-NMR (DMSO-d6) : 51.06 (3H? t5 J = 7.2 Hz)? 2.56- 2.89 (5H,m),2.95-3.65 (2H,br),3.98 (2H,q,j = 7·2Ηζ), 7.07-7.33 (5H? m) MS (ESI,m/z) : 208 (M+H) 製備物41 10 將二碳酸二第三丁基酯(408毫克)和三乙胺加入四氫吱 喃(20毫升)内的3-胺基-2-节基丙酸乙酯(380毫克)溶液,然 後在室溫下將混合物攪拌2小時。加入水然後以醋酸乙g旨萃 取混合物。以食鹽水清洗分離的有機層,在硫酸鎂上乾燥 以及在真空内蒸發。利用矽膠管柱層析法純化殘留物而產 15 生油狀的2-苄基-3-[(第三丁氧羰基)胺基]丙酸乙酯(566毫 克)。 1H-NMR (DMSO-d6) : δ1·06 (3H,t,J = 7.2 Hz),1 37 (9H,s),2.69-2.88 (3H,m),3·01-3·24 (2H,m),3·96 (2H,q j =7.2 Hz),6.94-7.06 (1H,m),7.10-7.33 (5H,m) 20 MS (ESI, m/z) : 330 (M+Na) 製備物42 將1當量氫氧化鈉水溶液(6.0毫升)加入四氫呋喃(15毫 升)内的2-苄基-3-[(第三丁氧羰基)胺基]丙酸乙酯(310亳克) 溶液,然後在60°C下將混合物攪拌5小時。冷卻該混合物然 42 200800899 5 後藉由添加1當量鹽酸將混合物調節至pH=2。以醋腸乙酯 萃取混合物及以食鹽水清洗分離的有機層,硫酸鎂上乾 垛,然後在真空内蒸發。利用矽膠管柱層析法純化殘留物 而產生2-苄基-3-[(第三丁氧基羰基)胺基]丙酸(228毫克)的 原油。 复俄物43 • 依知類似製備物36的方法獲得下列化合物。 (2-节基-3-氧代-3_{[4_(H定基)苯基]胺基}丙基)胺基 甲酸第三丁酯 10 1H-NMR (DMSO-d6): δΐ.35 (9H,s),2.67-3.30 (5H, m), 6-91-7.04 (1H, m), 7.11-7.34 (5H, m), 7.60-7.82 (6H, m)! 8·54_8·64 (2H,m),9.96-10.10 (iH,br) MS(ESI,m/z) : 432(M+H) 製備物44 15 依A?、涵似製備物3 6的方法獲得下列化合物。 • [(IS)-l-节基-2-(5-漠-2,3-二氯·1H令朵小基)側氧乙 基]胺基甲酸第三丁酯 20 1H-NMR (DMSO-d6): δ1·32 (9H,s),2.74-3.24 (4H, m) 3.80-4.10 (1H? m), 4.13-4.32 m)? 4.35.4.55 (1^ m)! 7.12-7.50 (8H,m),8.01 (1H,d5 J = 8.5 Hz) MS (ESI,m/z) : 468 (M+Na) 簠備物45 依類似製備物37的方法獲得下列化合物。 {(IS)-l-节基-2-氧代邻,比唆基)_2,3_二氯.叫卜朵 43 200800899 5 -1-基]乙基}胺基曱酸第三丁酯 1H-NMR (DMSO-d6) : δ1·33 (9Ή,s),2.76-3.30 (4H,m), 3.80-4.10 (1H,m),4·15_4·38 (1H,m),4·39_4·60 (1H, m), 7.12-7.50 (5H,m),7.61-7.74 (4H,m),8.12-8.26 (1H,m), 8.55-8.63 (2H,m) MS (ESI, m/z) : 444 (M+H) 盤備物46 依照類似製備物36的方法獲得下列化合物。 {(lS)-3-[(4-溴苯基)胺基]-3-氧代冬苯基丙基}胺基甲 10 酸第三丁酯 1H-NMR (DMSO-d6) : δ1·33 (9H,s),2.72 (2H,d,J = 7.5 Hz),4.84-5.12 (1H,m),7.14-7.37 (5H,m),7.40-7.59 (4H,m),9.94-10.05 (lH,br) MS (ESI,m/z) : 442 (M+Na) 15 製備物47 依照類似製備物37的方法獲得下列化合物。 [(lS)-3_氧代小苯基-3-{[4-(4-吼啶基)苯基]胺基}丙基] 胺基甲酸第三丁酯 1H-NMR (DMSO-d6) : δ1·34 (9H,s),2·76 (2H,d,J = 20 7·5 Hz),4.86-5.14 (1H,m),7J6-7.40 (5H,m),7.48-7.59 (1Η, m),7.63-7.82 (6H,m),8.55-8.63 (2H,m),10.03-10.il (1H, br) MS (ESI, m/z) : 418 (M+H) 製備物48 44 200800899 依照類似製備物36的方法獲得下列化合物。 {(lR)-3-[(4-溴苯基)胺基]-3-氧代-1-苯基丙基}胺基甲 酸第三丁酯 1H-NMR (DMSO-d6) : δ1·33 (9H,s),2·72 (2H,d,J = 5 7·5 Hz),4.84-5.11 (1H,m),7.14-7.38 (5H,m),7.40-7.60 (4H, m),9.94-10.04 (lH,br) MS (ESI,m/z) : 442 (M+Na) 製備物49 依照類似製備物37的方法獲得下列化合物。 10 [(lR)-3·氧代-1-苯基-3-{[4-(4·吼啶基)苯基]胺基}丙基] 胺基甲酸第三丁酯 1H-NMR (DMSO-d6) : δΐ.34 (9Η,s),2.76 (2Η,d,J = 7·5 Hz),4.86-5.14 (1H,m),7.14-7.40 (5H,m),7.47-7.60 (1H, m),7.62-7.82 (6H,m),8.55-8.63 (2H,m),10.02-10.12 (1H, 15 br) MS (ESI,m/z) : 418 (M+H) 製備物50 依照類似製備物1的方法獲得下列化合物。 4-石肖苯基-2,4*-二°比咬-5-基胺基甲酸酉旨 20 未純化,無資料 製備物51 依照類似製備物36的方法獲得下列化合物。 Ν-α-(第三丁氧基羰基)-2-氟-Ν·[4-(4-吼啶基)苯基]-D-苯基丙胺醯胺 45 200800899 1H-NMR (DMSO-d6): δ1·33 (9H,s),2.85-2.95 (IH,m), 3.0-3.1 (1H,m),4.4-4.5 (1H, m), 7.1-7.35 (5H,m),7.65-7.8 (6H,m),8.55-8.6 (2H,m),10·16 (1H,brs) MS (ESI,m/z) : 436 (M+H) 5 製備物52 依照類似製備物36的方法獲得下列化合物。 拳 N-α -(第三丁氧基羰基)-3·氟-N-[4-(4-吼啶基)苯基]-D-苯基丙胺醯胺 1H-NMR (DMSO-d6): δ1·32 (9H,s),2·85-2·95 (1H,m), 10 3.0-3.1 (lH,m),4·3·4·4 (1H,m),7.0-7.35 (5H,m),7·65-7·85 (6H,m),8.55-8.6 (2H,m),10.25 (1H,brs) MS (ESI, m/z) : 436 (M+H) 製備物53 依照類似製備物36的方法獲得下列化合物。 15 N-β -(弟二丁氧基讓基)-4-氣·Ν-[4-(4-π比咬基)苯基]-D_ 苯基丙胺醯胺 IH-NMR (DMSO-d6) : δΐ.32 (9Ή5 s)9 2.8-2.9 (1H? m)5 2.95-3.05 (1H,m),4.25-4.35 (1H,m),7.15-7.45 (3H,m), 7.3-7.4 (2H,m),7.65-7.85 (6H,m),8.55-8.6 (2H,m),10.25 20 (1H,brs) MS (ESI,m/z) : 436 (M+H) 製備物54 依照類似製備物36的方法獲得下列化合物。 N- 〇: (第二丁氧基域基)-4-亂比咬基)苯基]-L_ 46 200800899 苯基丙胺醯胺 1H-NMR (DMSO-d6) : δ1·32 (9H,s),2.8-2.9 (1H,m), 2.95-3.05 (1H,m),4.25-4.35 (1H,m),7.15-7.45 (3H,m), 7.3-7.4 (2H,m),7.65-7·85 (6H,m),8.55-8.6 (2H,m),10.25 5 (1H,brs) MS (ESI,m/z) : 436 (M+H) 製備物55 依照類似製備物36的方法獲得下列化合物。 Ν· α -(第三丁氧基羰基)-2-氯-N-[4-(4-吼啶基)苯基]-D· 10 苯基丙胺醯胺 1H-NMR (DMSO-d6) : δΐ·33 (9H,s),2.95-3.05 (1H,m), 3·1-3·2 (1H,m),4·4-4·5 (1H,m),7.2-7.45 (5H, m),7.65-7.8 (6H,m),8·55-8·65 (2H,m),10.14 (1H,brs) MS (ESI, m/z) : 462 (M+H) 15 製備物56 依照類似製備物36的方法獲得下列化合物。 N- α ·(第三丁氧基羰基)-4-氯-N-[4-(4-吼啶基)苯基]-D-苯基丙胺醯胺 1H-NMR (DMSO-d6) : δ1·33 (9H,s),2.8-2.9 (1H,m), 20 2.95-3.05 (1H,m),4.3-4.4 (1H,m),7.15-7.4 (5H,m),7.74 (2H,d,J = 8.7 Hz),7·81 (2H d,J = 8.7Hz),7:65-7.7 (2H,m), 8·55·8.65 (2H,m),10.26 (1H,brs) MS (ESI,m/z) : 462 (M+H) M備物57 47 200800899 依照類似製備物36的方法獲得下列化合物。 N- α -(第三丁氧基羰基)-4-三氟甲基-Ν·[4-(4·-比啶基) 苯基]苯基丙胺醯胺 1H-NMR (DMSO-d6) : δΐ.30 (9Ή? s)? 2.9-3.0 (1H? m)? 5 4·35·4·45 (1H,m),7·24 (1H,d,J = 8.5m),7.75 (2H,d,J = 8·7 Hz),7.81 (2H,d,J = 8.7 Hz),8.6-8.65 (2H,m),10.31 (1H? brs) MS (ESI,m/z) : 486 (M+H) 製備物58 10 依照類似製備物36的方法獲得下列化合物。 N- α -(第三丁氧基羰基)-4-甲氧基-N-[4-(4-吼啶基)苯 基]-L-苯基丙胺醯胺 1H-NMR (DMSO-d6): δ1·33 (9H,s),2.65-2.75 (1H,m), 2.85-2.95 (1H,m),3·71 (3H,s),4.35-4.45 (1H,m),7.0-7.3 15 (5H,m),7.65-7.8 (6H,m),8·6-8·65 (2H,m),10.22 (1H,brs) MS (ESI,m/z) : 448 (M+H) 製備物59 依照類似製備物36的方法獲得下列化合物。 [(1R)_2_氧代-2-[[4-(4-吼啶基)苯基]胺基]-1-(2-噻吩基 20 甲基)乙基]胺基甲酸第三丁酯 1H-NMR (DMSO-d6) : δ1·37 (9H,s),2.98-3.06 (1H,m), 3.2-3.27 (1H,m),4.3-4.4 (1H,m),6·95 (2H,d,J = 4·4 Hz), 7.22 (1H,d,J = 8.2 Hz),7.35 (1H,d,J = 4·6 Hz),7·65·7·7 (2H,m),7.75 (2H,d,J = 8.9 Hz),7.80 (2H,d,J = 8.9 Hz), 48 200800899 5 8.59-8.62 (2H? m)? 10.30 (1H? brs) MS (ESI,m/z) ·· 424 (M+H) 製備物60 依照類似製備物36的方法獲得下列化合物。 [(lS)-2·氧代-2-[[4-(4-u比啶基)苯基]胺基]-1-(2-噻吩基 甲基)乙基]胺基甲酸第三丁酯 1H-NMR (DMSO-d6) : δΐ.37 (9Ή,s),2.98-3.06 (1H,m), 3.2-3.27 (1H,m),4.3-4.4 (1H,m),6.95 (2H,d,J = 4·4 Hz), 7·22 (1H,d,J = 8.2 Hz), 7·35 (1H,d,J = 4.6 Hz),7.65-7.7 10 (2H,m),7·75 (2H,d,J = 8.9 Hz),7.80 (2H,d,J = 8.9 Hz), 8.59-8.62 (2H,m),10.30 (1H,brs) MS (ESI,m/z) : 424 (M+H) M備物61 依照類似製備物36的方法獲得下列化合物。 15 [(lS)-2_氧代-2_[[4-(4·吼啶基)苯基]胺基]-1-(噻唑-4-基 甲基)乙基]胺基甲酸第三丁酯 1H_NMR (DMSO-d6): δ1·35 (9H,s),3.05-3.13 (1H,m), 3.17-3.23 (1H,m),4.46-4.53 (1H, m),7·13 (1H,d,J = 8.1 Hz),7.39 (1H,s),7.67-7.7 (2H,m),7.75 (2H,d,J = 8.8 Hz), 20 7·79 (2H,d,J = 8.8 Hz),8.59-8.62 (2H,m),10.26 (1H,brs) MS (ESI,m/z) : 425 (M+H) 製備物62 依照類似製備物36的方法獲得下列化合物。 [(1R)_2-氧代_2-[[4-(4-吼啶基)苯基]胺基H-(噻唑-4-基 49 200800899 甲基)乙基]胺基甲酸第三丁酯 1H-NMR (DMSO-d6) : 51.35 (9H? s)? 3.05-3.13 (1H5 m)? 3.17-3.23 (1H,m),4.46-4.53 (1H,m),7.13 (1H,d,J = 8·1 Hz),7.39 (1H,s),7.67-7:7 (2H,m),7·75 (2H,d,J = 8.8 Hz), 5 7.79 (2H,d,J = 8.8 Hz),8·59-8·62 (2H,m),10.26 (1H,brs) MS (ESI,m/z) : 425 (M+H) 製備物63 依照類似製備物36的方法獲得下列化合物。 _ Ν-α -(第三丁氧羰基)·Ν_ α _甲基-N_[4-(4-吼啶基)苯 10 基]-D-苯基丙胺醯胺 1H-NMR (DMSO-d6) : δ1·31 (9H,s),2.6-2.7 (1H,m), 2·89 (3H, s),3·2·3.3 (1H,m),7.2-7.35 (4H,m),7.65-7.7 (2H, m),7.75-7.85 (4H,m),8.55-8.65 (2H,m),10.22 (1H,brs) MS (ESI,m/z) : 432 (M+H) 15 盤備物64 φ 依照類似製備物36的方法獲得下列化合物。 (3R)-3-[[4-(4-处啶基)苯基]胺甲醯基]-3,4-二氫異喹啉 -2(1Η)-甲酸第三丁酯 1H-NMR (DMSO-d6) ·· δ1·31 (9H,s),3·02 (1H,q,J = * 20 7·4 Ηζ),3·25 (1H,dd,J = 5.8, 15.2 Hz),4.36-4.90 (3H,m), ‘ 7.24 (4H,br),7.62-7.84 (6H,m),8.60 (2H,d,J = 6.0 Hz), 10.24 (1H? s) MS (ESI,m/z) : 430 (M+H) 製備物65 50 200800899 依照類似製備物36的方法獲得下列化合物。 (3S)-3-[[4-(4-吼啶基)苯基]胺曱醯基]-3,4-二氫異喹啉 -2(1Η)-曱酸第三丁酯 1H-NMR (DMSO-d6) : δ1·31 (9H,s),3·02 (1H,q,J = 5 7.4 Hz),3.25 (1H,dd,J = 5.8, 15.2 Ηζ),4·36-4·90 (3H,m), 7.24 (4H,br),7.62-7.84 (6H,m),8.60 (2H,d,J = 6.0 Hz), 10.24 (1H,s) MS (ESI,m/z) : 430 (M+H) 製備物66 10 依照類似製備物36的方法獲得下列化合物。 Ν-α-(第三丁氧羰基)-N-[4-(4-吼啶基)苯基]-D-色胺醯胺 1H-NMR (DMSO-d6) : δΐ.34 (9H5 s)? 2.96-3.05 (1H? m)? 3.1-3.18 (1H,m),4.36-4.46 (m,m),6.94-7.02 (2H,m), 7.03-7.08 (1H,m),7.18 (1H,s),7.32 (1H,d,J = 8·0 Hz), 15 7.64 - 7.71 (3H,m),7.76 (2H,d,J = 9.0 Hz), 7.95 (2H,d,J = 9·0Ηζ),8.59-8.62 (2H,m),10.24 (1H,s) MS (ESI,m/z) : 457 (M+H) 製備物67 依照類似製備物36的方法獲得下列化合物。 20 {(lR)-l-(l-苯并噻吩-3-基甲基)-2-氧代-2-[[4·(4-吼啶基) 苯基]胺基]乙基}胺基甲酸第三丁酯 1H-NMR (DMSO-d6) : δΐ.33 (9Η,s),3.1-3.2 (1Η,m), 3·23-3·3 (1H,m),4.48-4.58 (1H,m),7·23 (1H,d,J = 8·1 Hz), 7.34-7.45 (2H,m),7.51 (1H,s),7.66-7.68 (2H,m),7·76 (2H, 51 200800899 d,J = 8.8 Ηζ),7·80 (2H,d,J := 8.8 Hz),7.95-8.02 (2H, m), 8.59,8·62 (2H,m)5 10·31 (1H,s) MS (ESI,m/z) : 474 (M+H) 製備物68 5 依知類似製備物3 6的方法獲得下列化合物。 {(1R)·2·氧代-1-苯基·2-[[4_(4·σ比咬基)苯基]胺基]乙基} 胺基甲酸第三丁酯 1H-NMR (DMSO-d6): 61.40 (9H? s)? 5.39 (1H? J = 8.1 Hz),7.28-7.34 (1H,m),7·37 (2H,t,J = 7·1 Hz),7·52 (2H,d, 10 J = 7·1Ηζ),7·58(1Η,d,J = 8.2 Hz),7·67 (2H,dd,J = 1.6, 4.5 Hz), 7·74 (2H,d,J = 8·8 Hz),7.79 (2Ή,d,J = 8.9 Hz),8.60 (2H,dd,J = 1.6, 4·5 Hz),10·46 (1H,s) MS (ESLm/z) : 404 (M+H) 製備物69 15 依照類似製備物36的方法獲得下列化合物。 {(1S)-2·氧代-1-苯基_2-[[4-(4·吼啶基)苯基]胺基]乙基} 胺基甲酸第三丁酯 1H-NMR (DMSO_d6): δ1·40 (9H,s),5.39 (1H,d,J = 8.1 Hz), 7.28-7.34 (1H,m),7·37 (2H,t,J = 7·1 Ηζ),7·52 (2H,d, 20 J = 7.1 Hz),7.58 (1H,d,J = 8.2Hz),7.67 (2H,dd,J = 1.6, 4·5 Hz),7·74 (2H,d,J = 8·8 Hz),7·79 (2H,d,J = 8.9 Hz), 8.60 (2H,dd,J = 1.6, 4.5 Hz),10.46 (1H,s) MS (ESI,m/z) ·· 404 (M+H) M備物70 52 200800899 依照類似製備物36的方法獲得下列化合物。 {(IS)-l-(2-氯苯基)_2_氧代-2-[[4-(4-吼啶基)苯基]胺基] 乙基}胺基甲酸第三丁酯 1H-NMR (DMSO-d6) : δΐ.41 (9H,s),5·66 (1H,d,J = 5 8·2 Hz),7.33-7.38 (2H,m),7·40-7·45 (1H,m),7.46-7.52 (1Η, m),7·69 (2H,dd,J = 1.6, 4·6 Hz),7.76-7.83 (5H, m),8.60 (2H,dd,J = 1.6, 4.6 Hz),10.46 (1H,s) MS (ESI,m/z) : 460 (M+H) 製備物71 10 依照類似製備物36的方法獲得下列化合物。 {1-(2-氟苯基)-2-氧代-2-[ [4-(4·吼啶基)苯基]胺基]乙 基}胺基甲酸第三丁酯 1H-NMR (DMSO-d6) : δ1·40 (9H,s),5.61 (1H,d,J = 8.2 Hz),7.21 (2H,q,J = 7.7 Hz), 7.34-7.42 (1H,m),7.42-15 7.50 (m,m),7.66-7.73 (3H, m),7·78 (4H,dd,J = 9.0, 16.1
Hz),8.60 (2H,dd,J = 1.7, 4.6 Hz),10.43 (1H,s) MS (ESI,m/z) : 444 (M+Na) 製備物72 依照類似製備物36的方法獲得下列化合物。 20 {(IS)-2-氧代-2-[[4-(4-吼啶基)苯基]胺基]·1-[2-(三氟甲 基)苯基]乙基}胺基甲酸第三丁酯 1H-NMR (DMSO-d6) : δ1·39 (9Η,s),5.69 (1Η,d,J = 7·7 Hz),7.51-7.56 (1H,m),7.66-7.75 (5H,m),7·76-7·82 (4H, m),8·08 (1H,d,J = 7·8 Hz),8·60 (2H,dd,J = 1.6, 4·5 Hz), 53 200800899 10.44 (1H,s) MS (ESI,m/z) : 472 (M+H) 製備物73 依照類似製備物36的方法獲得下列化合物。 5 {1-(2-甲氧苯基)-2-氧代-2-[[4-(4-吼啶基)苯基]胺基]乙 基}胺基甲酸第三丁酯 1H-NMR (DMSO-d6) : 51.40 (9H? s)? 3.83 (3H? s)? 5.61 (1H,d,J = 8.4 Hz),6·94 (1H,td,J = 0.9, 7·5 Hz),7.02 (1H, d,J = 8.2 Hz),7.30 (1H,t,J = 7.6 Hz),7·34 (1H,dd,J = 1.6, 10 7.6 Hz),7.38 (1H,d,J = 8.3 Hz),7.68 (2H,dd,J = 1.5, 4.5
Hz),7.78 (4H,t,J = 9·9 Hz),8·59 (2H,dd,J = 1.6, 4.6 Hz), 10_15 (1H,s) MS (ESI,m/z) : 456 (M+H) M備物74 15 依照類似製備物36的方法獲得下列化合物。 φ {(IS)-l-(4-氟苯基)-2-氧代-2-[[4-(4-吼啶基)苯基]胺基] 乙基}胺基甲酸第三丁酯 1H-NMR (DMSO-d6) ·· δ1·40 (9H,s),5.39 (1H,d,J = 8.0 Hz),7.20 (2H,t,J = 8.8 Hz),7.52-7.58 (3H,m),7.67 (2H, ^ 20 dd,J = 1.6, 4.6 Hz),7·73 (2H,d,J = 8.8 Hz),7·79 (2H,d,J = ’ 8.8 Hz),8.60 (2H,dd,J = 1.6, 4.6 Hz),10.46 (1H,s) MS (ESI,m/z) : 444 (M+H) 製備物75 依照類似製備物36的方法獲得下列化合物。 54 200800899 {1-(2-咬喃基)-2-氧代-2-[[4-(4-σ比咬基)苯基]胺基]乙基} 胺基甲酸第三丁酯 1H-NMR (DMSO-d6) : δ8·60 (2H,dd,J = 1.5, 4.5 Hz), 7·81 (2H,d,J = 8.9 Hz),7.75 (2H,d,J = 8·9 Ηζ),7·69 (2H, 5 dd,J = 1·6, 4.5 Hz),7.65 (1H,m),6.43 (1H,dd,J = 1.9, 3.1 Hz),6.40 (1H,s),5·45 (1H,d,J = 8.3 Hz),1.40 (9H,s) MS (ESI, m/z) : 394 (M+H) 製備物76 依照類似製備物36的方法獲得下列化合物。 10 {(1S)_2-氧代·2·[[4-(4-吼啶基)苯基]胺基]-1-(2-噻吩基) 乙基}胺基甲酸第三丁酯 1H-NMR (DMSO-d6): δ1·40 (9H,s),5.60 (1H,d,J = 8.0 Ηζ),7·00 (1H,dd,J = 8.0, 3.6 Hz),7.12-7.15 (1H,m),7.48 (1H,d,J = 4.2 Hz),7.61 (1H,d,J = 7.5 Hz),7.67-7.7 (2H, 15 m),7·74 (1H,d,J = 8.7 Hz),7·81 (2H,d,J = 8·7 Hz),8.32 (1H,s),8.59-8.62 (2H,m),10.52 (1H,brs) MS (ESI, m/z) : 410 (M+H) 製備物77 依照類似製備物36的方法獲得下列化合物。 20 N-(4-溴苯基)-N- -(第三丁氧羰基)-D-苯基丙胺醯胺 1H-NMR (DMSO-d6) : 51.32 (9H? s)? 2.84 (1Π5 dd5 J = 10.1,13.6 Hz),2.98 (1H,dd,J = 4.6, 13.7 Hz),4.26-4.36 (1H, m),7.18 (2H,m),7.25-7.35 (4H,m),7·49 (2H,d,J = 8.8 Hz), 7·57 (2H,d,J = 8.8 Hz),10.17 (1H,s) 55 200800899 MS (ESI,m/z) : 441 (M+Na) 製備物78 依照類似實施例53的方法獲得下列化合物。 N-(4-溴苯基)_D-苯基丙胺醯胺 5 1H-NMR (DMSO-d6) : δ2·74 (1H,dd,J = 8.0, 13·4 Hz), 3.02 (1H,dd,J = 5.5, 13·4 Hz),3.58 (1H,dd,J = 5.5, 8.0 Hz), 7.16-7.21 (1H,m),7.23-7.30 (4H,m),7.48 (2H,d,J = 8.9 Hz),7.61 (2H,d,J = 8.9 Hz) MS (ESI,m/z) : 319 (M+H) 10 M備物79 將1, r-氧代雙(2-溴乙烷)(545毫克)和二異丙基乙胺 (607毫克)加入N,N-二甲基甲醯胺(5毫升)内的N-(4-溴苯 基)-D-苯基丙胺醯胺(500亳克)溶液,然後在50°C下將混合 物攪拌6小時。在冷卻至5°C之後,將該混合物倒入水中然 15 後以St酸乙自旨萃取。以水和食鹽水清洗有機層,硫酸ί美上 乾燥及真空内蒸發。利用以己烷/醋酸乙酯(1 : 1)溶析的矽 膠管柱層析法純化殘留物而產生(2R)-N-(4-漠、苯基)-2·嗎淋 -4-基-3-苯基丙醯胺(430毫克)粉末。 1H-NMR (DMSO-d6): δ2·56-2·69 (4H,m),2.88 (1H,dd, 20 J = 5.0, 13·2 Ηζ),3·07 (1H,dd,J = 9.6, 13·2 Ηζ),3·45 (1H, dd,J = 5.1,9.6 Hz),3.52-3.62 (4H,m),7.13-7.18 (1H,m), 7.20-7.25 (4H,m),7.45 (2H,d,J = 9·0 Hz),7.51 (2H,d,J = 9.0 Hz),9·93 (1H,s) MS (ESI,m/z) : 391 (M+H) 56 200800899 製備物80 依照類似實施例53的方法獲得下列化合物。 N-(4->臭苯基)-L-苯基丙胺酿胺 1H-NMR (DMSO-d6) : δ2·74 (1H,dd,J = 8.0, 13.4 Hz), 5 3.02 (1H,dd,J = 5.5, 13·4 Hz),3.58 (1H,dd,J = 5.5, 8·0 Hz), 7.16-7.21 (1H,m),7.23-7.30 (4H,m),7·48 (2H,d,J = 8.9 Hz),7.61 (2H, d,J = 8.9 Hz) MS (ESI,m/z) : 319 (M+H) ⑩ 製備物81 10 依照類似製備物79的方法獲得下列化合物。 (2S)-N-(4-溴苯基)-2-嗎啉-4-基-3-苯基丙醯胺 1H-NMR (DMSO-d6): δ2·56·2·69 (4H,m),2.88 (1H,dd, J = 5.0, 13.2 Hz),3.07 (1H,dd,J = 9.6, 13·2 Hz),3·45 (1H, dd,J = 5.1,9·6 Hz),3·52-3·62 (4H,m),7.13-7.18 (1H,m), 15 7.20-7.25 (4H,m),7·45 (2H,d,J = 9.0 Hz),7.51 (2H,d,J = • 9.0 Hz),9·93 (1H,s) MS (ESI,m/z) : 391 (M+H) M備物82 依照類似製備物36的方法獲得下列化合物。 ’ 20 N-(4-溴苯基)-2-羥基-3-苯基丙醯胺 • 1H-NMR (DMSO-d6) : δ2·8·2·86 (1H,m),3.0-3.06 (1H, m),4.2-4.26 (1H,m),5.87 (1H,brs), 7·15·7·3 (6H,m), 7.45-7.5 (2H,m),7.65-7.7 (2H,m),9.85 (1H,brs) MS (ESI,m/z) : 342 (M+H) 57 200800899 Μ備物8芝 將二異丙基乙胺(908毫克)和4_二甲基胺基吡啶(114 宅克)加入一氯甲烷(60毫升)和四氫呋喃(3〇毫升)内的ν_(4_ 溴苯基)-2-羥基-3-苯基丙醯胺(丨.5克)溶液,接著在5它下逐 5滴加入甲碩醯氯(805毫克),然後在室溫下將混合物攪拌20 小時。將此合物倒入水中然後在真空内濃縮。以醋酸乙酯 萃取殘留物,以食鹽水清洗,硫酸鎂上乾燥及真空内蒸發 而產生卜苄基-2-[(4-漠苯基)胺基]-2-側氧乙基甲績酸鹽粗 產物。將該甲磺酸鹽粗產物溶解於N,N-二甲基甲醯胺(3〇毫 10 升)然後加入4_哌啶醇(1.19克)。在8(TC下將混合物攪拌5小 時然後倒入水中。以醋酸乙酯萃取混合物,水和食鹽水清 洗,硫酸鎂上乾燥及真空内蒸發。利用以醋酸乙酯溶析的 矽膠管柱層析法純化殘留物而產生N_(4-溴苯基)-2-(4-羥基 哌啶-1-基)-3·苯基丙醯胺(894毫克)粉末。 15 1H-NMR (DMSO-d6) ·· δ1·3-1·4 (2H,m),1.64-1.74 (2H, m),2·26-2·4 (2H,m),2·78-2·92 (2H,m),3.01,3.1 (1H,m), 3.36-3.46 (2H,m),4·52 (1H,d,J = 3·9 Hz),7.1-7.26 (5H,m), 7·44 (2H,d,J = 8.8 Hz),7·52 (2H,d,J = 8.8 Hz), 9.86 (1H, brs) 20 MS (ESI,m/z) : 403 (M+H) 數備物84 將4-旅咬醇(5·〇5克)加入乙醇(20毫升)内的溴(苯基)醋 酸乙酯(5.0克)溶液,然後在60°c下將該混合物攪拌4小時。 將混合物倒入稀釋破酸氫鈉水溶液然後以醋酸乙酯萃取。 58 200800899 以水和食鹽水清洗有機層’硫酸鎮上乾燥以及真空内蒸 發。利用以己烷/醋酸乙酯(3:7)溶析的矽膠管柱層析法純 化殘留物而產生黃色油狀的(4-經基旅π定-1-基)(苯基)醋酸 乙酯(5.21克)。 5 1H-NMR (CDC13) : δ1·21 (3Η,t,J = 7·1 Ηζ),1·4-1·45 (1Η,m),1.56-1.7 (2Η,m),1·82-1·96 (2Η,m)5 2.66-2.86 (2Η, m),3.65-3.78 (1H,m)5 4·(Μ·08 (1H,m),4·1-4·24 (2H,m), 7.3-7.37 (3H,m),7.41-7.46 (2H,m) MS (ESI,m/z) : 264 (M+H) 10 製備物85 使6當量鹽酸(80毫升)内的(4-羥基哌啶-i-基)(苯基)醋 酸乙S旨(5.2克)懸浮液回流14小時,然後在真空内蒸發混合 物。以曱醇磨碎殘留物然後藉由過濾收集及真空内乾燥而 產生(4-羥基哌啶-1-基)(苯基)醋酸鹽酸鹽(465克)粉末。 15 1H-NMR (DMSO-d6) : δΙ.6-1.8 (2Η, m)? 1.85-2.05 (2H? m),2.7-3.9 (4H,m),4.8-5.2 (1H,m),5·27 (1H,brs),7.45-7.6 (5H,m) MS (ESI,m/z) : 236 (M+H) 製備物86 20 將醋酸(135毫克)和三乙醯氧氫硼化鈉(503毫克)加入 1,2·—氯乙烷(30毫升)内的N_(4_溴苯基)_D_苯基丙胺醯胺 (600¾克)和四氫_4H_吡喃_4_酮(23〇毫克)混合物,然後在室 溫下將混合物攪拌5小時。將混合物倒入飽和碳酸氫鈉水溶 液内然後以醋酸乙酯萃取。以食鹽水清洗有機層,硫酸鎂 59 200800899 5 上乾燥及真空内蒸發。利用以氯仿/甲醇(100 : 1)溶析的矽 膠管柱層析法純化殘留物而產生Ν·(4-溴苯基)-Ν- α -(四氫 -2Η-吡喃-4-基)-D-苯基丙胺醯胺(323毫克)粉末。 1H-NMR (DMSO-d6) : δΐ.05-1.31 (2H9 m), 1.58-1.74 (2H,m),2.0-2.07 (1H,m),2.76-2.84 (2H,m),3.14-3.25 (1Η, m),3.5-3.59 (1H,m),3.7-3.77 (1H,m),7·15-7·22 (1H,m), 7.22-7.28 (4H,m),7·44-7·48 (2H,m),7.52-7.55 (2H,m), 9.95 (m,brs) MS (ESI,m/z) : 403 (M+H) 10 M備物87 依照類似製備物36的方法獲得下列化合物。 [(1SH-苄基-2-(3,4’-雙吼啶-6·基胺基)-2_側氧乙基]胺 基甲酸第三丁酯 1H-NMR (DMSO-d6) : δΐ.32 (9H,s),2.6-3.2 (2H,m), 15 • 4.4-4.6 (1H,m),7.1-7.4 (7H,m),7.7-7.8 (2H,m),8.15-8.3 (1H,m),7.6-7.7 (2H,m),8.84 (1H,s),10.90 (1H,s) MS (ESI,m/z):無資料 製備物88 依照類似製備物36的方法獲得下列化合物。 20 [(1 R)-l-苄基-2-(3,4’-雙吼啶-6-基胺基)-2-側氧乙基]胺 基甲酸第三丁酯 1H-NMR (DMSO-d6) : 51.32 (9H? s)5 2.77-2.88 (2H? m)? 2.97-3.06 (1H, m),4.03-4.12 (1H,m),7·06 (1H,d,J = 8.3 Hz),7.16-7.3 (5Ή,m),7.39 (1H,d,J = 8.3 Hz),7·78 (1H,d, 60 200800899 J = 4.4 Hz), 8.19-8 (1H, m),8.65 (1H,d,J = 4.4 Hz),10.89 (1H,brs) MS (ESI,m/z) : 419 (Μ+Ή) 製備物89 5 依照類似製備物36的方法獲得下列化合物。 [(1S)-1·苄基-2-(2,4’-雙吼啶-5-基胺基)-2-侧氧乙基]胺 基甲酸第三丁酯 1H-NMR (DMSO-d6) : δΐ.33 (9Ή? s)9 2.78-3.13 (2H5 m), 4.15-4.47 (1H,m),7.13-7.41 (6H,m),8.01 (2H, dd,J = 1.5, 10 4.6 Hz), 8·11 (1H,d,J = 8.6 Hz),8.24 (1H,dd,J = 2.5, 8.6
Hz), 8.67(2H,dd,J = 1.5, 4.6 Hz),8.86 (1H,d,J = 2.5 Hz), 10.35-10.55 (lH,m) MS (ESI,m/z) : 419 (M+H) 製備物90 15 依照類似製備物36的方法獲得下列化合物。 [(1R)-1-节基-2-(2,4’-雙吼啶-5-基胺基)-2-側氧乙基]胺 基曱酸第三丁酯 1H-NMR (DMSO-d6) : 51.33 (9H? s)5 2.82-2.94 (1H? m)5 3.0-3.06 (1H,m),4.34-4.4 (1H, m),7·18·7·36 (5H,m),7.95 20 (1H,s),8.01 (2H,dd,J = 5.0, 1.7 Hz),8.11 (1H,d,J = 8.7
Hz),8·23 (1H,dd,J = 8.7, 2.5 Hz), 8·67 (2H,dd,J = 5.0, 1.7 Hz),8.86 (1H,d,J = 2·4 Hz),10.48 (1H,brs) MS (ESI,m/z) : 419 (M+H) 製備物91 61 200800899 將0·8克分子碳酸鉀水溶液(25毫升)加入1,2-二甲氡乙 烷(25毫升)内的攪拌中(4-頌苯基)硼酸(1.6克)、4-氯《^氟。比 啶(1.11克)和四個(三苯基膦基)鈀(462毫克)懸浮液,然後在 氮氣下將該混合物回流20小時。冷卻之後,在真空内移除 5 1,2-二甲氧乙烷。殘留物加入醋酸乙酯,以水清洗,硫酸錢 上乾燥,然後濃縮產生棕色固體的3-氟-4-(4-硝苯基”比咬 (2.23 克)。 _ 1H-NMR (DMSO-d6):S7.52-7.64 (2H,m),7.73 (1H,dd, J = 5.0, 2.6 Ηζ),7·97 (2H,dd,J = 8·8, 1·3 Ηζ),8·39 (2H,dd, 10 J = 8.8, ι·3 Hz),8·59 (1H,d,J = 5·0 Hz), 8·76 (1H,d,J = 2.6
Hz) MS (ESI,m/z) ·· 189 (M+H) 盥備物92 將水合肼(1.6克)逐滴加入乙醇(74毫升)内的3_氟_4_(4_ 15硝苯基)吼啶(2.23克)、三氣鐵(130毫克)和活性碳(112克, • 起始材料的50重量%)回流混合物,然後將混合物授拌3小 時。藉由加熱中的過濾移除不可溶材料,然後以乙醇清洗。 在真空内移除大部分的乙醇,然後將水加入殘留物。藉由 過濾收集獲得的固體,利用以己烷/醋酸乙酯(1 : 2)溶析的 20秒膠管柱層析法純化而產生4-(3-氟吡啶基)苯胺(1.36克) 的淡橘色固體。 1H-NMR (DMSO-d6) : 55.59 (2H? brs)? 6.67 (2H? dd5 J = 8·6, 1.6 Hz),7.42 (2H,dd,J = 8.6, 1·6 Hz),7·53 (1H,dd,J = 7·4, 5.1 Hz),8.36 (1H,dd,J = 3.4, 1.1 Hz),8·51 (1H,d,J = 62 200800899 3.4 Hz) MS (ESI,m/z) : 189 (M+H) M備物93 依照類似製備物36的方法獲得下列化人物。 N 基丙胺醯胺 α-(第三丁氧麟)*[4_(3如κ基)苯基]办苯 1H-NMR (DMSO-d6) : δΐ 33 rcm 、, 、 ’ (9H,s),2·82-3.04 (2H,m), 4.32-4.4 (1H,m),7·16-7·38 (6H,m),7·6·7·66 (1H,m),7·67 (2H,d,J = 8·7 Hz),7·76 (2H,d,J = 8·7 Hz),8.48 (1H,d,J = 10 5·8 Hz),8·63 (1H,d,J = 2.8 Hz),1G.29 (1H,brs) MS (ESI, m/z) : 458 (M+Na)
製備物M 在室溫下將三氟甲續酸if (3.32克)逐滴加入吼。定(15亳 升)内的3-甲基-4-硝基苯酚(1.5克)溶液,然後將混合物攪拌 15 1小時。將混合物倒入水中然後以醋酸乙酯萃取。以1當量 鹽酸和食鹽水清洗有機層,硫酸鎂上乾燥以及真空内蒸 發。利用以己烷/醋酸乙酯(9 : 1)溶析的矽膠管柱層析法純 化殘留物而產生黃色油狀的3-甲基硝苯基三氟甲磺酸鹽 (1.91 克)。 20 1H-NMR (DMSO-d6) : δ2·57 (3Η, s),7·64 (1Η,d,J = 9.0, 2.7 Hz), 7·78 (1H,d,J = 2·7 Ηζ),8·18 (1H,d,J = 9·〇 Hz) MS(ESI,m/z):無資料 製備物95 63 200800899
4-(3-甲基-4-硝苯基)吡啶
·% (犯,s),7.81 (2H,dd,J = 2·0, 8.4 HZ),7.98 (1H,d,J = [z),8·71 (2H,dd,J = 1.8, 4·5 MS (ESI, m/z) : 215 (M+H) 製備物96 依照類似製備物92的方法獲得下列化合物。 2-甲基-4·吡啶-4-基苯胺 1H-NMR (DMSO-d6) ·· δ2.13 (3H,s),5.28 (2H,s),6.70 (1Η,d,J = 8.4 Ηζ),7.38-7.48 (2Η,m),7·56 (2Η,dd,J = 1.6, 4·6 Hz),8.47 (2H,dd,J = 1.6, 4.6 Hz) MS (ESI, m/z) : 185 (M+H) 製備物97 在室溫下將二碳酸二第三丁基酯(3.19克)和4-二甲基 胺基吡啶(66毫克)加入二氯甲烷(30毫升)内的4-(4-硝笨基) 嘧啶-2-胺(1.17克)溶液,然後將混合物攪拌20小時。加入水 (1〇毫升)及以食鹽水清洗有機層,硫酸鎂上乾燥及真空内蒸 發。利用以氯仿/甲醇(20 : 1)溶析之矽膠管柱層析法純化殘 留物而產生[4-(4-硝苯基)嘧啶-2-基]亞胺基二碳酸二第三 丁基酯(1.72克)粉末。 1H-NMR (DMSO-d6) ·· δΐ.41 (18H,s),8.22 (1H,d,J = 5.3 Hz),8.40-8.47 (4H, m),9.04 (1H,d,J = 5·3 Hz) 64 200800899 MS (ESI,m/z) : 439 (M+Na) 製備物98 依照類似製備物92的方法獲得下列化合物。 [4-(4-胺基苯基),°定-2-基]亞胺基二碳酸二第二丁基醋 5 1H-NMR (DMSO-d6): δ1·39 (18H,s),5·91 (2H,s),6·65 (2Η,d,J = 8·6 Ηζ),7.74 (1Η,d,J = 5·5 Ηζ),7·91 (2Η,d,J = 8·6 Hz),8·63 (1H,d,J = 5.5 Hz) MS (ESI,m/z):無資料 M備物99 10 依照類似製備物36的方法獲得下列化合物。 N-(4-{2-[雙(第三丁氧羰基)胺基]嘧啶-4-基}苯基)-N-α ·(第三丁氧羰基)-D-苯基丙胺醯胺 1H-NMR (DMSO-d6) : δ1·33·1·4 (27Η,m),2·86(1Η,dd, J = 13.5, 9.9 Hz),3.01 (IH,dd,J = 13.5, 4·6 Hz),4.33-4.39
15 (1H,m),7:18-7.21 (2H,m),7.27-7.34 (4H,m),7·78 (2H,d,J =8·9 Hz),7·98 (1H,d, J = 5.4 Hz),8.18 (2H,d,J = 8.8 Hz), 8·84 (1H,d,J = 5.4 Hz),10.31 (1H,brs) MS (ESI, m/z) : 656 (M+Na) 製備物100 20 依照類似製備物36的方法獲得下列化合物。 N-(4-{2-[雙(第三丁氧羰基)胺基]嘧啶-4-基}苯基)-N-α -(第三丁氧羰基)-D-苯基丙胺醯胺 1H-NMR (DMSO-d6) : δΐ.32-1.40 (27H? m)5 2.81-2.87 (1H,m),2.98-3.02 (1H,m),4.30-4.35 (1H,m),7.09-7.14 65 200800899 5 (2H,m),7·21 (1H,d,J = 8·1 Ηζ),7·36 (2H,dd,J = 5.8, 8·2 Hz),7·78 (2H,d,J = 8.8 Hz),7·98 (1H,d,J = 5·4 Hz),8·18 (2H,d,J = 8·9 Hz),8.84 (1H,d,J = 5.4 Hz) MS (ESI, m/z) : 674 (M+Na) 製備物101 依照類似製備物36的方法獲得下列化合物。 N-(4-p-[雙(第三丁氧羰基)胺基]嘧啶-4-基}苯基)-N- • 〇!-(第二丁氧讓基)-4-氣-D-苯基丙胺酿胺 1H-NMR (DMSO-d6) : δ1·33-1·40 (27H,m),2.85 (1H, 10 dd,J = 10.4,13·4 Ηζ),3·02 (1H,d,J = 4.6,13·4 Hz), 4.31-4.37 (1H,m),7·23 (1H,d,J = 8·2 Hz),7·36 (4H,s), 7·79 (2H,d,J = 8.8 Hz),7.98 (1H,d,J = 5·3 Hz),8·19 (2H,d, J = 8.8 Hz),8.85 (1H,d,J = 5·3 Hz),10.38 (1H,br) MS (ESI,m/z) : 691 (M+Na) 15 製備物102 依照類似製備物36的方法獲得下列化合物。 N-(4-{2-[雙(第三丁氧羰基)胺基]嘧啶-4-基}苯基)-Να; -(弟 二丁氧 _炭基 )-0- 曱基-D_赂胺 酸酸胺 1H-NMR (DMSO-d6) : δ1·33-1·40 (27H,m),2.79 (1H, ’ 20 dd,J = 10.2, 13.6 Ηζ),2·95(1Η,dd,J = 4.5, 13·6 Hz),3.71 (3H,s),4.27-4.32 (1H,m),6.85 (2H, d,J = 8.5 Hz), 7.14 (1H, d,J = 7.9 Hz),7.24 (2H,d,J = 8.5 Hz),7.79 (2H,d,J = 8.9 Hz),7.98 (1H,d,J = 5·4 Hz),8.18 (2H,d,J = 8.8 Hz),8.84 (1H,d,J = 5.3 Hz),10.34 (1H,br) 66 200800899 MS (ESI,m/z) : 686 (M+Na) 製備物103 依照類似製備物36的方法獲得下列化合物。 [4-(4-{[(2R)-2-嗎啉-4-基-3-苯基丙醯基]胺基}苯基)嘧 5 啶-2-基]亞胺基二碳酸二第三丁基酯 1H-NMR (DMSO-d6): δ1·39 (18H,s),2.63-2.67 (4H,m), 2·90 (m,dd,J = 5.0, 13.2 Hz),3J0 (1H,dd,J = 9·6, 13·2 Hz),3·52 (1H,dd,J = 5.0,9.6 Hz),3·56-3·59 (4H,m), 7.13-7.19 (1H,m),7.24-7.25 (4H,m),7.74 (2H,d,J = 8.9 10 Hz),7.97 (1H,d,J = 5.3 Hz),8.14 (2H,d,J = 8.8 Hz),8.84 (1H,d,J = 5·4 Hz),10.13 (lH,br) MS (ESI,m/z) : 604 (M+H) 製備物104 依照類似製備物36的方法獲得下列化合物。 15 Ν-α-(第三丁氧羰基)-4-氰基-N-[4-(4-吼啶基)苯基]-D- 苯基丙胺醯胺 1H-NMR (DMSO-d6) : δΐ.20-1.36 (9H,m),2.88-2.99 (1H,m),3.05-3.15 (1H,m),4.34-4.44 (1H,m),7.26 (1H,d,J = 8.5 Hz),7.54 (2H,d,J = 8.0Hz),7.67-7.84 (8H,m),8.59-20 8.62 (2H,m),10.28 (1H,s) MS (ESI,m/z) : 443 (M+H) 製備物105 依照類似製備物36的方法獲得下列化合物。 Ν· α -(第三丁氧羰基)-0·第三丁基-N-[4-(4-吼啶基)苯 67 200800899 5 基]-D-酪胺酸醯胺 1H-NMR (DMSO-d6) : δΐ.23 (9H? s)9 L33(9H? s)? 2.78-2.98 (2H,m),4.29-4.38 (1H,m),6·86 (2H,d,J = 8.2 Hz), 7.16 (1H,d,J = 8.2 Hz),7.21 (2H,d,J = 8.2 Hz),7.67-7.74 (4Ή,m),7.77-7.81 (2H,m),8.59-8.62 (2H,m),10.17 (1H,s) MS (ESI,m/z) : 490 (M+H) M備物106 • 依照類似製備物36的方法獲得下列化合物。 N- α -(第三丁氧羰基)-4-硝基-Ν-[4-(4·-比啶基)苯基]-D· 10 苯基丙胺醯胺 1H-NMR (DMSO-d6) : δΙ.20-1.35 (9H? m)? 2.94-3.23 (2H,m),4.26-4.48 (1H,m),7.29 (1H,d,J = 8.5 Hz),7·64 (2H,d,J = 8.5 Hz),7·68·7·71 (2H,m),7·76 (2H,d,J = 8.8 Hz),7.82 (2H,d,J = 8.8 Hz),8·19 (2H,d,J = 8.6 Hz), 15 • 8.59-8.62 (2H,m), 10.41 (1H,s) MS (ESI,m/z) ·· 463 (M+H) 製備物107 依照類似製備物36的方法獲得下列化合物。 [(1R)-1_ 节基-2-(5->臭-2,3-二氮-ΙΗ-ϋ弓|ϋ朵-1_基)-2-側氧乙 • 20 基]胺基曱酸第三丁酯 1H-NMR (DMSO-d6) : δ1·31 (9H,s),2·8-2·88 (1H,m), 2.96-3.06 (2H,m),3.1-3.2 (1H,m),3.9-3.99 (1H,m), 4.18-4.26 (1H,m),4.4-4.48 (1H,m),7.17-7.45 (7H,m),8.01 (1H,d,J = 8.6 Hz) 68 200800899 MS (ESI,m/z) : 467 (M+Na) 製備物108 依照類似製備物37的方法獲得下列化合物。 [(1R)-1-节基-2-氧代-2·(5』比啶_4_基·2,3-二氫-1H·吲哚 5 -1-基)乙基]胺基曱酸第三丁酉旨 1H-NMR (DMSO-d6): δ1·33 (9Η,s),2.81-3.30 (4Η, m), 3.82-4.04 (1H,m),4.22-4.33 (1H,m),4.44-4.54 (1H, m), 7.16-7.37 (5H,m),7.45 (1H,d,J = 7·8 Hz),7.64-7.73 (4H, m),8.15-8.26 (1H,m),8·56·8·63 (2H,m) 10 MS (ESI,m/z) : 444 (M+H) 叛備物109 將醋酸鉀(1.03克)和二氯雙(三苯基膦基)鈀(244毫克) 加入1,4-二噚烷(6毫升)内的[(IS)-l-苄基-2-(5-溴-2,3-二氫 -1H-吲哚-1-基)-2-側氧乙基]胺基甲酸第三丁酯(1.55克)和 15 4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-雙-1,3,2-二氧硼烷(972 毫克)溶 液,然後使混合物在氮氣下回流3小時。將該混合物倒入水 中然後以醋酸乙酯萃取。以食鹽水清洗有機層,硫酸鎂上 乾燥及真空内蒸發。利用石夕膠管柱層析法純化殘留物而產 生{(IS)-l-节基-2·氧代-2-[5-(4,4,5,5-四甲基-i,3,2-二氧删烧 20 -2-基)-2,3-二氫-1H-吲哚-1-基]乙基}胺基甲酸第三丁酉旨 (1·44克)的粉末。 1H-NMR (DMSO-d6) : δ1·18_1·32 (21Η,m),2.75-2.91 (1H, m), 2.95-3.22 (3H,m),3.79-4.01 (1H,m),4.12-4.23 (1H,m),4·35-4·52 (1H,m), 7.13-7.51 (7H,m), 7·97·8·05 69 200800899 (1H5 m) MS (ESI,m/z) : 493 (M+H) 製備物110 將2克分子破酸鈉水溶液(2.0毫升)和四個(三苯基膦基) 5 鈀G6毫克)加入1,4-二噚烷(10毫升)内的{(IS)-l·苄基-2-氧 代-2-[5-(4,4,5,5·四甲基4,3,2-二氧硼烷-2-基)-2,3-二氫 4H-吲哚· 1 -基]乙基}胺基甲酸第三丁商(672毫克)和4-氯-2-嘧 啶胺(265毫克)溶液,然後使混合物在氮氣下回流3小時。將 混合物倒入水中然後以醋酸乙酯萃取。以食鹽水清洗有機 10 層,硫酸鎂上乾燥及真空内蒸發。利用石夕膠管柱層析法純 化殘留物而產生{(lS)-2-[5-(2-胺基嘧啶-4-基)-2,3-二氫·1Η-吲哚-1-基Η-苄基-2-側氧乙基}胺基曱酸第三丁酯的粉末。 1H-NMR (DMSO_d6) : δ1·33 (9Η,s),2·75·2·91 (1Η,m), 2.95-3.22 (3H,m),3·79-4·01 (1H,m),4·12·4·23 (1H,m), 15 4.35-4.52 (lH,m),6.60(2H,brs)57.00-7.40 (6H,m),7.90-7·96 (2H,m),7.97-8.05 (1H,m),8·23·8·28 (1H,m) MS (ESI,m/z) : 460 (M+H) 製備物111 依照類似製備物110的方法獲得下列化合物。 20 {(1RH-苄基-2-氧代-2-[5-(4,4,5,5-四甲基_1,3,2-二氧蝴 烷-2-基)-2,3-二氫-1H』弓丨哚-1 -基]乙基}胺基甲酸第三丁酯 1H-NMR (DMSO-d6) : δ1·18-1·32 (21H,m),2.75-2.91 (1H,m),2.95-3.22 (3H,m),3.79-4.01 (1H,m),4.12-4.23 (1H,m),4.35-4.52 (1H,m),7·13·7·51 (7H,m),7.97-8.05 70 200800899 (1H,m) MS (ESI,m/z) : 493 (M+H) 製備物112 依照類似製備物109的方法獲得下列化合物。 5 {(lR)-2-[5-(2-胺基嘧啶-4_ 基)-2,3-二氫-1H-吲哚·1_ 基]-1-苄基_2_側氧乙基}胺基甲酸第三丁酯 1H-NMR (DMSO-d6) : δΐ.33 (9Ή, s)5 2.75-2.91 (1H? m)? 2.95-3.22 (3H,m),3.79-4.01 (1H,m),4.12-4.23 (1H,m), 4.35-4.52 (1H,m),6.60 (2H,brs),7.00-7.40 (6Ή,m),7·90-10 7·96 (2H,m),7·97-8·05 (1H,m),8.23-8.28 (1H,m) MS (ESI,m/z) ·· 460 (M+H)) 製備物113 依照類似製備物36的方法獲得下列化合物。 {4-[4·({(2S)-2-[(第三丁氧羰基)胺基]-2-苯乙醯基}胺 15 基)苯基]嘧啶_2-基}亞胺基二碳酸二第三丁基酯 1H-NMR (DMSO-d6):51.39-1.40 (27H? m)? 5.38 (1H9 d? J = 8·1 Hz),7.29-7.38 (4H,m),7.50-7.52 (2H,m),7.61 (1H, d,J = 7.8 Hz),7.77 (2H,d,J = 8.9 Hz), 7.97 (1H,d,J = 5.3 Hz),8.17 (2H,d,J = 8.9 Hz),8.84 (1H, d,J = 5.3 Hz),10.55 20 (1H,br) MS (ESI,m/z):無資料 M備物114 依照類似製備物36的方法獲得下列化合物。 {4-[4-({(2R)-2-[(第三丁氧羰基)胺基]-2·苯乙醯基}胺 71 200800899 5 基)苯基]嘧啶-2-基}亞胺基二碳酸二第三丁基酯 1H-NMR (DMSO-d6): δ1·39·1·40 (27H,m),5.38 (1H,d, J = 8.1 Hz),7.29-7.38 (4H,m),7.50-7.52 (2H,m),7.61 (1Η, d,J = 7.8 Hz),7.77 (2H,d,J = 8.9 Hz),7.97(1H,d,J = 5.3 Hz),8.17 (2H,d,J = 8.9 Hz),8.84 (1H,d,J = 5.3 Hz),10.55 (lH,bir) MS (ESI, m/z) : 642 (M+Na) • 製備物115 依照類似製備物36的方法獲得下列化合物。 10 [4-(4- {[(2S)-2-[(第三丁氧羰基)胺基]-2-(2-噻吩基)乙 醯基]胺基}苯基)嘧啶-2-基]亞胺基二碳酸二第三丁基酯 1H-NMR (DMSO-d6): δΐ.39 (18H,s),2.63-2.67 (4H,m), 2.90 (lH,dd,J = 5.0, 13·2 Ηζ),3·10 (1H, dd,J = 9·6, 13.2 Hz),3.52 (1H,dd,J = 5.0,9.6 Hz),3.56-3.59 (4H,m), 15 7·13·7·19 (1H,m),7.74 (2H, d,J = 8.9 Hz),7.97 (1H,d,J = 5.3 Hz),8.14 (2H,d,J = 8.8 Hz),8.84 (1H,d,J = 5.4 Hz), 10.13 (lH,br) MS (ESI,m/z) : 604 (M+H) 製備物116 • 20 依照類似製備物36的方法獲得下列化合物。 [4-(4- {[(2S)-2-[(第三丁氧羰基)胺基]-2-(2-噻吩基)乙 醯基]胺基}苯基)嘧啶-2-基]亞胺基二碳酸二第三丁基酯 1H-NMR (DMSO-d6) : δΙ.37-1.40 (27H? m)5 3.09-3.15 (1H,m),3.212-3.27 (1H,m),4.33-4.39 (IH,m),6.95 (2H,s), 72 200800899 7.25 (1H,d,J = 8·1 Hz),7.34 (1H,dd,J = 1.3, 4·7 Hz),7.79 (2H,d,J = 8·9 Hz),7·98 (1H,d,J = 5.4 Hz),8.18 (2H,d,J = 8.8 Hz),8.84 (1H,d,J = 5.3 Hz),10.42 (1H,br) MS(ESI, m/z):無資料 5 製備物117 依照類似製備物1的方法獲得下列化合物。 [4-(4-{[(4-硝基苯氧基)羰基]胺基}苯基)嘧啶-2-基]亞 胺基二碳酸二第三丁基酯 ⑩ 1H-NMR (DMSO-d6) : δ1·41 (18H,s),7·59 (2H, dd,J = 10 9.0, 2·1 Hz),7.70 (2H,d,J = 8.8 Hz),8.00 (1H,d,J = 5.4
Hz),8·21 (2H,d,J = 8.8 Hz),8.86 (1H,d,J = 5.4 Hz),10.83 (1H,brs) MS (ESI,m/z):無資料 製備物118 15 依照類似實施例4的方法獲得下列化合物。 ^ {4-[4-({[(lS)-2-羥基-1-苯乙基]胺甲醯基}胺基)苯基] 嘧啶-2-基}亞胺基二碳酸二第三丁基酯 1H-NMR (DMSO-d6): δ1·39 (18H,s),3.57-3.70 (2H,m), 4.74-4.79 (1H,m),5.03 (1H,t,J = 5.3 Ηζ),6·88 (1H,d,J = # 20 7.8 Hz),7.22-7.27 (1H,m),7.33-7.34 (4H, m),7.55 (2H,d,J = • 8·8 Hz),7·92 (1H, d,J = 5.5 Hz),8.08 (2H,d,J = 8.9 Hz), 8.78 (1H,d,J = 5.4 Hz),9.04 (1H,br) MS (ESI,m/z) : 572 (M+Na) 製備物119 73 200800899 使Hi-乙酿基_2,3_二氫_1H,哚I基)乙酮(6〇克)和 N,N-二甲基甲醯基二曱縮醛(14.2克)之混合物在11〇。〇下回 流4小時,然後在真空内蒸發。以二異丙醚磨碎殘留物,過 濾收集,在真空内乾燥而產生粗(2E)-1-(1-乙醯基_2,3-二氫 5 -1HH5-基)-3-(二甲基胺基)丙-2-烯-1_酮(7.4克)。將鹽酸 胍(3.56克)和第三丁氧化鉀(3.86克)加入甲醇(1〇〇毫升)内的 粗產物溶液,然後在100°C下將混合物攪拌3小時。冷卻至 室溫之後,藉由過濾收集反應的沈澱物,以曱醇清洗及真 空内乾燥而產生4-(1-乙醯基_2,3_二氫-1H-吲哚-5-基)嘧咬 1〇 -2·胺(2.71克)的灰色粉末。 1H-NMR (DMSO-d6) : δ2·18 (3H,s),3·20 (2H,d,J = 8·8 Ηζ),4·15 (2H,d,J = 8·8 Ηζ),6·55 (2H,brs),7·〇6 (1H,d, J = 5.3 Hz),7·90 (1H,d,J = 5.3 Hz),7·96 (1H,s),8.09 (1H, d,J = 8.7 Hz) 15 MS(ESI,m/z) : 255(M+H) 製備物12❹ 將氫氧化鈉(顆粒)(2.8克)加入乙醇(60毫升)和丨,釦二 嘮烷(40毫升)内的4-(1-乙醯基-2,3-二氫-1H-吲哚、5_基)。密咬 -2-胺(1.27克)溶液,然後使混合物回流6小時。使合成溶液 2〇 冷卻至室溫然後以1當量鹽酸中和。在真空内蒸發混合物然 後以氯仿萃取殘留物。以食鹽水清洗有機層’硫g曼鎂上乾 燥及真空内蒸發而產生粗4-(2,3_二氫-1H-吲哚基)嘧啶 -2-胺(1·〇3克)的粉末。 1H-NMR (DMSO-d6) ·· δ2·97 (2Η,d,J — 8.6 j^z) 3 51 74 200800899 5 (2H,d,J = 8·6 Hz),6.03 (1H,brs),6·36 (2H,brs),6·51 (1H, d,J = 8·2 Hz),6·92 (1H,d,J = 5·3 Hz), 7·71 (1H,d,J = 8·2Ηζ),7·79 (1H,s),8·13 (1H,d,J = 5.3 Hz) MS (ESI,m/z) : 213 (M+H) 製備物121 依照類似製備物36的方法獲得下列化合物。 {(lS)-2-[5-(2·胺基嘧啶-4-基)·2,3-二氫-1H-吲哚-1-基]-2-氧代-1-苯乙基}胺基甲酸第三丁酯 1H-NMR (DMSO-d6) : δ1·39 (9Ή,s),3.06-3.28 (2Η,m), 10 3.73-3.88 (1H,m),4·34-4·43 (1H, m),5·54 (1H,d,J = 7.4 Hz),6·58 (2H,s),7.06 (1H, d,J = 5.2 Hz),7.30-7.58 (6H,m), 7.91-7.96 (2H,m),8.16 (1H,d,J = 8.3 Hz),8·25 (1H,d,J = 5.2Hz) MS (ESI,m/z) : 446 (M+H) 15 製備物122 依照類似製備物36的方法獲得下列化合物。 {(lR)-2-[5-(2-胺基嘧唆-4-基)-2,3-二氫-1H-吲哚-1-基]-2-氧代-1-苯乙基}胺基甲酸第二丁酉旨 1H-NMR (DMSO-d6): δΐ·39 (9H,s),3.06-3.28 (2H,m), ’ 20 3·73-3·88 (1H,m),4.34-4.43 (1H,m),5·54 (1H,d,J = 7.4 Hz),6.58 (2H,s),7.06 (1H,d,J = 5.2 Hz),7.30-7.58 (6H,m), 7.91-7.96 (2H,m),8.16 (1H,d,J = 8.3 Hz),8.25 (1H,d,J = 5.2 Hz) MS (ESI,m/z) : 446 (M+H) 75 200800899 5 製備物123 依照類似製備物36的方法獲得下列化合物。 [(IS)-2-[5-(2-胺基嘧啶-4-基)-2,3-二氫 4H-吲哚-1· 基]-1 -(4-亂节基)-2-侧氧乙基]胺基曱酸第三丁酯 1H-NMR (DMSO-d6): δΐ·32 (9H,s),2.64-2.74 (1H,m), 2.91- 3.00 (1H,m),3.06-3.25 (2H,m),3.73-3.83 (1H,m), 3.92- 4.03 (1H,m),4.24-4.37 (1H,m),6·58 (2H,brs), 參 7·03·7·13 (3H,m),7.26-7.35 (2H,m),7.88-7.99 (2H, m), 8.13-8.21 (1H,m),8·26 (1H,d,J = 5.2 Hz) 10 MS (ESI,m/z) : 478 (M+H) 製備物124 依照類似製備物36的方法獲得下列化合物。 [(1化)-1_卞基_2-(6->臭-3,4_二鼠啥淋_1(211)-基)-2-側氧乙 基]胺基甲酸第三丁酯 15 參 1H-NMR (DMSO-d6) : δΐ.33 (9H, s), 1.62-1.86 (2H? m)5 2.56-2.66 (2H,m),2.72-2.86 (2H,m),3.82-3.92 (1H,m), 4.76-4.82 (1H,m),6.76-7.1 (2H,m),7.1-7.26 (4H,m),7.32 (1H,d,J = 7.9 Hz),7.36-7.4 (2H,m),7.42-7.52 (1H,m) MS (ESI,m/z) : 481 (M+Na) • 20 實施例1 將(異氰酸基甲基)苯(86毫克)加入N,N-二甲基甲醯胺 (4毫升)内的[4-(4-吼啶基)苯基]胺(100毫克)懸浮液,以及在 室溫下將混合物攪拌2小時。該混合物被分層於醋酸乙酯和 水之間。分離有機層,以水和食鹽水清洗,硫酸鎮上乾燥 76 200800899 及真空内蒸發。以醋酸乙酯磨碎殘留物而產生1-苄基 -3-[4-(4-吼啶基)苯基]脲(135毫克)的黃色粉末。 1H-NMR (DMSO-d6): δ4.30 (2H,d,J = 6 Hz),6.67 (1H, t,J = 6 Hz),7.20-7.40 (5H,m),7·54 (2H,d,J = 8 Hz),7.64 5 (2H,d,J = 6Hz),7.71 (2H,d,J = 8 Hz),8·55 (2H,d,J = 6Hz),8.81 (1H,s) 實施例2 依照類似實施例1的方法獲得下列化合物。 1-(4-曱氧基苄基)-3-[4-(4-u比啶基)苯基]脲 10 1H-NMR (DMSO-d6): 53,73 (3H? s)? 4.24 (2Η? άΊ = 5.8
Hz),6.63 (1H,t,J = 5.8 Hz),6.90 (2H,d,J = 8·6 Hz), 7·24 (2H,d,J = 7.9 Hz),7.55 (2H,d,J = 8·6 Hz),7·66 (2H,dd,J =1.6, 4.6 Hz),7.72 (2H,d,J = 8.6 Hz),8·57 (2H,dd,J = 1·6, 4·6 Hz),8·77 (1H, s) 15 MS (ESI,m/z) : 334 (M+H) 實施例3 依照類似實施例1的方法獲得下列化合物。 1-[(1R)-1-苯乙基]-3-[4-(4_吨口定基)笨基]脲 1H-NMR (DMSO-d6) : 51.40 (3H5 d? J = 7.0 Hz)? 4.84 20 (1H,quint,J = 7.0 Hz),7.13 (1H,d,J = 7.9 Hz),7·25 (1H, m),7.36 (4H,m),7·62 (2H,d,J = 8.9 Hz),7.99 (2H,d,J = 8.9 Hz),8.29 (2H,d,J = 6.8 Hz),8.82 (2H,d,J = 6.8 Hz), 9.32 (1H,s) MS (ESI, m/z) : 318 (M+H) 77 200800899 5 10 實施例4 在室溫下將(2S)-2-胺基-2-苯乙醇(4.60克)加入二氯甲 烷(150毫升)内的4-硝苯基[4-(4-吼啶基)苯基]胺基甲酸 (7.50克)和N,N_二異丙基乙胺(5.84毫升)溶液,然後在相同 溫度下將混合物攪拌20小時。在真空内濃縮獲得之混合物 然後將水(45毫升)和酷酸乙i旨(45毫升)加入殘留物。藉由過 濾收集沈澱固體然後以水(30毫升x5)清洗而獲得黃色結 晶。以醋酸乙S旨(30宅升)磨碎该結晶而產生1 -[(IS)-2-^基-1_ 苯乙基]-3-[4-(4吼啶基)苯基]脲(6.1克)的淡黃色結晶。 1H-NMR (DMSO-d6) : 53.54-3.73 (2H5 m)9 4.73-4.82 (1H,m),5·02 (1H,t,J = 5.0 Hz), 6.80 (1H,d, J = 7.8 Hz), 7.20-7.29 (1H,m),7.30-7.38 (4H,m),7·52 (2H,d,J = 8.5 Hz),7.65(2H,d,J = 5·4 Hz),7·72 (2H,d,J = 8.5 Hz),8.56 (2H,d,J = 5.4 Hz),8.92 (lH,s) 15 MS (ESI,m/z) : 334 (M+H) • 實施例5 依照類似實施例4的方法獲得下列化合物。 1-[(1S)-1-苯乙基]-3-[4-(4-吼啶基)苯基]脲 1H-NMR (DMSO-d6) : δΐ.39 (3H,d,J = 6.8 Hz),4.83 • 20 (1H,quint, J = 6·8 Ηζ),6·73 (1H,d,J = 7·9 Ηζ),7·24 (1H, m),7·35 (4H,d,J = 4·4 Hz),7·51 (2H,d,J = 8.7 Hz),7.65 (2H,d,J = 6.2 Hz),7.71 (2H,d,J = 8.7 Hz),8.55 (2H,d, J = 6.2 Hz),8.65 (1H, s) MS (ESI,m/z) : 318 (M+H) 78 200800899 實施例6 依照類似實施例4的方法獲得下列化合物。 l-[(lR)-2-羥基-1-苯乙基]-3-[4-(4-吼啶基)苯基]脲 1H-NMR (DMSO-d6) : 53.54-3.73 (2H? m)? 4.73-4.83 • 5 (1Ή,m),5.02 (1H,t,J = 5·0 Hz),6.8() (1H,d,J = 7·8 Hz), 7.20-7.40 (5H,m),7.52 (2H,d,J = 8.5 Hz),7.66 (2H,d,J = 5.4 Hz),7.73 (2H, d,J = 8·5 Hz),8·57 (2H,d,J = 5.4 Hz), 8.90 (1H,s) ® MS (ESI,m/z) : 334 (M+H) 10 實施例7 依照類似實施例4的方法獲得下列化合物。 (2R)-苯基[({[4-(4-吼啶基)苯基]胺基}羰基)胺基]醋酸 甲酯 1H-NMR (CDC13): δ3·74 (3H,s),5.28 (1H,s),5·60 (1H, 15 d,J = 8.0 Ηζ),7.23 (m,s),7.34-7.56 (9Η,m),7.71 (2Η,d,J =8.2 Hz),8.60 (2H,d,J = 6.0 Hz) MS (ESI, m/z) : 362 (M+H) 實施例8 依照類似實施例4的方法獲得下列化合物。 • 20 (2S)_苯基[({[4-(4-吼啶基)苯基]胺基}羰基)胺基]醋酸 • 甲酯 1H-NMR (CDC13): δ3·74 (3H,s),5·28 (1H,s),5·60 (1H, d,J = 8.0 Ηζ),7.23 (1Η,s),7.34-7.56 (9Η, m),7.71 (2Η,d5 J = 8.2 Hz),8.60 (2H,d,J = 6·0 Hz) 79 200800899 MS (ESI,m/z) : 362 (M+H) 實施例9 將二氯甲烷(1·0毫升)和三氟醋酸(954微升)内的(2S)_ 笨基[({[4_(4-吼啶基)苯基]胺基}幾基)胺基]醋酸第三丁醋 5 (50·0*克)在室溫下放置2小時。在真空内濃縮獲得的混合 物然後以氯仿(2毫升)稀釋殘留物,再濃縮。殘留物加入醋 酸乙酯(2.0毫升)及藉由過濾收集沈澱固體,然後以醋酸乙 酯(2.0毫升)清洗而產生(2S)-苯基[({[4-(4“比啶基)苯基]胺 基}羰基)胺基]醋酸三氟醋酸鹽(39毫克)的淡白色結晶。 10 1H-NMR (DMSO-d6) : 55.27 (1H? d9 J = 7.2 Hz)? 7.24 (1H,d,J = 7·2 Hz),7.31-7.45 (5H,m),7.59 (2H,d,J = 8.7 Hz),7·94 (2H,d,J = 8.7 Hz),8.17 (2H,d,J = 6.5 Hz),8.78 (2H, d,J = 6.5 Hz),9.18 (1H,s) MS (ESI,m/z) : 348 (M+H-CF3C02H) 15 實施例10 依照類似實施例9的方法獲得下列化合物。 (2R)-苯基[({[4-(4-吨啶基)苯基]胺基}羰基)胺基]醋酸 三氟醋酸鹽 1H-NMR (DMSO-d6) : 65.27 (1H? d? J = 7.2 Hz), 7.24 20 (1H,d,J = 7.2 Hz),7.31-7.45 (5H,m),7.59 (2H,d,J = 8·7
Hz),7·94 (2H,d,J = 8.7 Hz),8·17 (2H,d,J = 6.5 Hz),8.78 (2H,d,J = 6.5 Hz),9·18 (1H,s) MS (ESI,m/z) : 348 (M+H-CF3C02H) 實施例11 80 200800899 依照類似實施例4的方法獲得下列化合物。 (2R)·2·苯基-2·[({[4_(4_η比咬基)苯基]胺基}幾基)胺基] 乙醯胺 1H-NMR (DMSO-d6) : δ5·31 (1Η,d,J = 7·6 Ηζ),7.10 5 (1Η,d,J = 7·6 Ηζ),7.20-7.55 (8Η,m),7.65 (2Η,d, J = 5·1 Hz),7·71 (2H,d,J = 8·4 Hz),7.83 (1H, s),8.56 (2H,d,J = 5·1 Hz),9.08 (1H,s) MS (ESI,m/z) : 347 (M+H) 實施例12 10 依照類似實施例4的方法獲得下列化合物。 (2S)-2-苯基-2-[({[4-(4-叹啶基)苯基]胺基丨羰基)胺基] 乙醯胺 1H-NMR (DMSO-d6) : 65.31 (iH? d5 J = 7.6 Hz)? 7.10 (1H,d,J = 7.6 Hz),7.20-7.55 (8H,m),7 65 (2H,d,J = 5·1 15 Hz)? 7.71 (2H? d5 J = 8.4 Hz)5 7.83 (1H? s)5 8.56 (2H9 d5 J = 5.1 Hz),9.08 (1H,s) MS (ESI,m/z) ·· 347 (M+H) 實施例13 依照類似實施例4的方法獲得下列化合物。 m-NMR (DMSO-dWUi (1H,m), 2 49 (1H,m),2 81 (1H,m),2.91 (1H,m),5.19 (1H,q,j = 7 7 Hz),6·6ι ⑽,d
J = 7·7 Hz),7·26 (4H,m),7·57 (2H,d,J = 8·6 Hz),7.67 (2H d? J = 5.5 Hz)? 7.74 (2H? d5 J - 8.6 Hz), 8.57 (2H5 d? J = 5 5 81 200800899 5 • Hz),8.65 (1H,s) MS (ESI,m/z) : 330 (M+H) 實施例14 依照類似實施例4的方法獲得下列化合物。 l-[(lR)-2,3_ 二氫基]-3-[4_(4_ 吡啶基)苯基]脲 iH-NMR (DMSO-d6): 51.78 (1H? m)? 2.45 (1H? m)? 2.84 (1H,m),2·93 (1H,m),5.19 (1H,q,J = 8·1 Hz),6.61 (1H,d, J = 8·1 Hz),7·26 (4H,m),7.57 (2H, d,J = 8.6 Hz),7.67 (2H, d,J = 5·7 Hz),7.74 (2H,d, J = 8.6 Hz),8·57 (2H,d,J = 5.7 10 Hz),8.65 (1H,s) MS (ESI, m/z) : 330 (M+H) 實施例15 依照類似實施例4的方法獲得下列化合物。 , Ν-[4·(4-吡啶基)苯基]-3,4-二氫-2(1Η)-異喹啉甲醯胺 15 • 1H-NMR (DMSO-d6) : 52.87 (2H? t5 J = 5.8 Hz)? 3.72 (2H,t,J = 5.8 Hz),4.66 (2H,s),7.20 (4H,s),7.67 (4Ή,m), .7·74 (2H,d,J = 8.8 Hz),8.57 (2H,dd,J = 1.6, 4.6 Hz),8.81 (1H,s) MS (ESI,m/z) : 330 (M+H) * 20 實施例16 依照類似實施例4的方法獲得下列化合物。 1-(環己基甲基)-3-[4-(4-吼啶基)苯基]脲 1H-NMR (DMSO-d6) : δθ.92 (2H, m)? 1.18 (3H? m)? 1.39 (1H,m),1·69 (5H,m),2·95 (2H,t,J = 5·7 Hz),6·25 (1H,t,J = 82 200800899 5 5·7 Ηζ),7·52 (2H,d,J = 8.8 Ηζ),7·65 (2H,d,J = 5·8 Hz), 7.71 (2H,d,J = 8·8 Hz),8·56 (2H,d,J = 5.8 Hz),8.62 (1H,s) MS (ESI,m/z) : 310 (M+H) 實施例17 依照類似實施例4的方法獲得下列化合物。 1-[(1S)-1-環己基乙基]-3-[4-(4-吼啶基)苯基]脲 1H-NMR (DMSO_d6) : δ0·90-1.35 (9H,m),1.64 (5H,m), • 3.55 (1H,m),6.09 (1H,d,J = 9·1 Hz),7.51 (2Ή,d,J = 8·4 Hz),7.65 (2H,d,J = 5.0 Hz),7·71 (2H,d,J = 8·4 Hz),8·55 10 (3H,m) MS (ESI, m/z) : 324 (M+H) 實施例18 依照類似實施例4的方法獲得下列化合物。 1-[(1ΪΙ)·1-環己基乙基]-3-[4-(4-吼啶基)苯基]脲 15 • 1H-NMR (DMSO-d6): δ0·90-1·35 (9H,m),1.70 (5H,m), 3.52 (1H,m),6·09 (1H,d,J = 8·4 Ηζ),7·51 (2H,d,J = 8·1 Hz),7·65 (2H,d,J = 3.5 Hz),7.71 (2H,d,’J = 8.1 Hz),8.55 (3H,m) MS (ESI,m/z) : 324 (M+H) • 20 實施例19 依照類似實施例4的方法獲得下列化合物。 N-[4-(4-吼啶基)苯基]八氫_2(1H)_異喹啉甲醯胺 1H-NMR (DMSO-d6) : δ1·18-1·89 (12H,m),4.37 (4H, m),7·61 (2H,d,J = 8.8 Ηζ),7·66 (2H,dd,J = 1.5, 4.5 Hz), 83 200800899 7·71 (2H,d,J = 8.8 Ηζ),8·57 (2H,dd,J = 1.5, 4.5 Hz),8 6〇 (0.82H,s),8·66 (0.18H,s) MS (ESI,m/z) : 336 (M+H) 實施例20 5 將二噚烷(1.5毫升)内的1H-叫丨哚-3-羰基疊氮化物(82 〇 毫克)溶液在90°C下攪拌3小時,然後在下將[4-(4“比唆巧 苯基]胺(50.0毫克)加入混合物。在室溫下將混合物攪拌隔 夜然後在真空内蒸發溶劑。將殘留物溶解於氣仿(3〇毫升) 内然後依序以飽和礙酸氫鈉水溶夜和食鹽水清洗有機層。 !〇在真空内蒸發溶劑而產生H1H,貪3_基)作吼唆曰基) 苯基]脲(46·6毫克)的白色結晶。 & 1H-NMR (DMSO-d6) : δ7·02 fm + τ UH,t,J = 7·4 Ηζ),7·09 (m,W = 7·4 HZ),7.35 (1H,d,j。7 7 Hz),7 53 (2H,m), 7.66 (4H,m),7.77 (2H,m),8.58 (3H,s),8 88 (ih,s), i〇 77 15 (1H,s)
MS (ESI,m/z) : 329 (M+H) 實施例21 依照類似實施例20的方法獲得下列化人物。 20 1-(1-苯并吱喃-2-基)-3-[4-(4心定基)苯基]脲 m-NMR(DMS〇-ci6):56.51(lH,s),7i7(2H,m),747 (2H,m),7.65 (2H,d,J = 8·6 Hz),7 7Ω 4 了 /•川(2H,d,J = 5.8 Hz), 7.81 (2H, d, J — 8.6 Hz)? 8.60 (2tJ pi τ c 、,d,J = 5.8 Hz),9·09 (1H, s),9·83 (1H,s) MS (ESI,m/z) : 330 (M+H) 84 200800899 實施例22 依照類似實施卿的枝獲得下列化合物。 HU-苯并妙2·基Η例〜定基)苯基]脈 1Η-ΝΜΚ (DMSO-d6) : 57 nu τ ^ ό7·26 (1Η,t,J = 7·8 Ηζ),7_40 (1Η,t,J = 7.8 Ηζ),7·70 (6Η,7 μ j τ ,叫,7·83 (2H,d,J = 8.8 Hz), 7·91 (1H,d,J = 7.5 Hz), 8.61 QH 心 τ ,: , UH,dd,J= 1.5, 4.4 HZ),9.44 (1H,s)
MS (ESI, m/z) *. 347 (M+H) 實施例23 10 在室溫下將节氧縣氣(75.5微升)逐滴加入二氣甲烧 (1.50毫升)和t定(356.4微升)内的4_(4_D比咬基)苯胺⑼毫克) 懸洋液,然後在相同溫度下將混合物授掉j小時。在真空内 濃縮獲得的混合物然後將水(1〇毫升)加入殘留物。以醋 醋05毫升)萃取水溶液然後依序以飽和碳酸氫納水減和 15食鹽水清洗有機層’然後乾燥和濃縮。以二異_(2 〇毫升) 磨碎該殘留si義Μ [4_(4_対)苯基]胺基w麵(犯 毫克)的黃色固體。 θ * 丄 JTL· JNMK (UMSO-d6): 20 7·63 (2H,d,J = 8·7 Hz),7.68 (2H,d, J = 8·7 Hz),8·59 (2H,d,J = 6.3 Hz) MS (ESI, m/z) : 305 (M+H) 實施例24 s),/.33-7.48 (5H,m), 6·3 Hz),7.78 (2H,d, 依照類似製備物7的方法獲得下列化合物。 3-苯基-N-[4-(4-n比啶基)苯基]丙醯胺 85 200800899 1H-NMR (DMSO-d6) : δ2·66 (2H,t,J = 7·9 Hz),2.93 (2H,t,J = 7.9 Hz),7.15-7.23 (1H,m),7.24-7.33 (4H,m), 7.68 (2H,d,J = 5.9 Hz),7·74 (2H,d, J = 8·8 Hz),7.78 (2H,d, J = 8.8 Hz),8.59 (2H,d,J = 5.9 Hz),10.13 (1H,s) 5 MS (ESI,m/z) : 303 (M+H) 實施例25 依照類似製備物7的方法獲得下列化合物。 2-苯乳基-1^-[4_(4_0比11定基)苯基]乙酿胺 1H-NMR (DMSO-d6) : δ4·74 (2H,s),6.93-7.07 (3H,m), 10 7.27-7.39 (2H,m),7·70 (2H,d,J = 4·7 Hz),7.77-7.88 (4Ή, m),8·60 (2H,d,J = 4·7 Hz),10.30 (1H,s) MS (ESI,m/z) : 305 (M+H) 實施例26 在室溫下將1當量鹽酸(16.5毫升)加入二氫呋喃(100.6 15 毫升)内的2-苯胺基-N»[4-(4-吼啶基)苯基]乙醯胺(5.03克)混 合物然後在室溫下攪拌1小時。加入四氫呋喃(300毫升)然後 以冰浴攪拌20分鐘冷卻混合物。藉由過濾收集結晶及以醋 酸乙酯(50毫升)清洗而產生2-苯胺基-N-[4-(4•吼啶基)苯基] 乙醯胺鹽酸鹽(5.00克)的黃色結晶。 20 1H-NMR (DMSO-d6): δ3·95 (2H,s),6·60 (1H,t,J = 7.1
Hz),6.64 (2H,d,J = 7J Ηζ),7·11 (2H,t,J = 7·1 Hz),7.90 (2H,d,J = 8.8 Hz),8.06 (2H,d,J = 8.8 Hz),8·34 (2H,d,J = 7.0 Hz),8.88 (2H,d,J = 7.0 Hz),10.60 (1H,s) MS (ESI,m/z) : 304 (M+H) 86 200800899 實施例27 在室溫下將三乙胺(0.092毫升)和氯化乙酸(〇 〇352毫升) 加入N,N-二曱基甲醯胺(ι·〇毫升)内的苯胺基·Ν_[4·(4·η比 啶基)苯基]乙醯胺(50 mg)溶液,然後在室溫下將混合物攪 5拌隔夜。將水(3毫升)加入混合物然後以醋酸乙酯(5毫升)萃 取獲得之混合物。以食鹽水清洗有機層然後在硫酸鎂上乾 燥。在真空内蒸發溶劑然後利用生產級薄層色譜法(氣仿内 的10%甲醇)純化殘留物而產生白色非晶形2-[乙醯基(苯基) 胺基]-N-[4-(4-吼。定基)苯基]乙酿基(46.9毫克)。 10 1H-NMR (DMSO-d6) : 51.84 (3H? s)5 4.43 (2H? s)? 7.38 (1H,m),7·47 (4H,m),7·69 (2H,d,J = 6.2 Hz),7.73 (2H,d, J = 8.8 Hz),7·80 (2H,d,J = 8.8 Hz),8·59 (2H,d,J = 6.2 Hz), 10.25 (IH, s) MS (ESI,m/z) : 346 (M+H) 15 實施例28 在室溫下將1當量氫氧化鈉水溶液(〇l 57毫升)加入甲 醇(0·6〇毫升)内的[(2=氧代·2·{[4·(4-,比啶基)苯基]胺基}乙 基)(苯基)胺基]醋酸乙酯(40.8毫克)混合物,然後在室溫下 將混合物攪拌隔夜。以1當量鹽酸中和混合物然後藉由過滤 20 收集沈澱物。以正己烷/醋酸乙酯(1 : 1,1.0毫升)清洗固體 而產生[〇氧代-2·{[4·(4_吼啶基)苯基]胺基}乙基苯基)胺 基]醋酸(24·8毫克)的白色結晶。 1H-NMR (DMSO-d6) : δ4·23 (2Η,s),4.33 (2Η,s),6.55 (2Η,d,J = 7·9 Ηζ),6·72 (1Η,t,J = 7·9 Ηζ),7·21 (2Η,t,J = 87 200800899 7·9 Ηζ),7·68 (2H,d,J = 6.0 Ηζ),7·73 (2H,d,J = 8.6 Hz), 7·80 (2H,d,J = 8·6 Hz),8.60 (2H,d,J = 6.0 Hz),10.67 (1H, s) MS (ESI,m/z) : 362 (M+H) 實施例29 5 將4當量氯化氫·醋酸乙酯(2.41毫升)加入醋酸乙酯 (0.60毫升)内的N-[4-(4-^b啶基)苯基]小第三丁氧羰基吲哚 啉-2-甲醯胺(100毫克)懸浮液,然後在室溫下將該混合物攪 拌1.5小時。以正己烷(6.0毫升)稀釋獲得的混合物之後藉由 過濾收集固體,然後以醋酸乙酯/正己烧(1 : 2,1.〇毫升)清 10洗而產生Ν-[4·(4-σΛσ定基)苯基㈣。朵琳甲醯胺(8〇毫克)的 淡白色結晶。 1H-NMR (DMSO-d6) : δ3·21 (1Η,dd5 J = 7·2,16·3Ηζ), 3·49 (1Η,dd,J — 10·1,16·3 Ηζ),4.67 (1Η,dd,J = 7 2,1〇·1 Hz),6.83 (1H,dd,J 一 7.3,7.5 Hz),6·85 (1Π,d,J = 7 8 Hz), 15 7.10 (1H,dd,J = 7.5, 7.8 Hz),7.16 (1H,d,J = 7·3 Hz),7·97 (2H,d,J = 9.0 Hz),8·11 (2H,d,j = 9·〇 Hz),8.41 (2H d,J 二 6.9 Hz),8·92 (2H,d,J = 6·9 Hz),10.84 (ih,s) MS (ESI,m/z) : 316 (M+H_2HC1) 實施例30 2〇 依照類似實施例29的方法獲得下列化合物。 2-胺基-N-(2-氧代-2-{[4-(4-吡啶基)苯基]胺基}乙 基)-N·苯乙醯胺 1H-NMR (CDC13): δ3·29 (2H,s),4·46 (2H, s),7.30 (2H, m),7.43 (3Η,m),7·48 (2Η,dd,J = 4.6 Ηζ),7.61 (2Η, d,J = 88 200800899 8·2 Hz),7.68 (2H,d,J = 8·2 Ηζ),8·64 (2H,d,J = 4·6 Hz), 8·69 (1H,s) MS (ESI,m/z) : 361 (M+H) 實施例31 5 在0°C下將吼啶(0.0533毫升)和甲磺醯氯(0.0204毫升) 加入二氯甲烷(0.80毫升)内的2-苯胺基-N- [4-(4-吼啶基)苯 基]乙醯胺(40.0毫克)溶液,然後在室溫下將混合物攪拌2 天。在室溫下將水(4.0毫升)加入混合物然後以醋酸乙酯(6.0 毫升)萃取混合物。依序以飽和礙酸氫納水溶液和食鹽水清 10 洗有機層,硫酸鎮上乾燥及真空内濃縮。利用生產級薄層 色譜法(氣仿内的4%甲醇)純化殘留物而產生2-[(甲磺醯 基)(苯基)胺基]-N-[4_(4-吼啶基)苯基]乙醯胺(31·4毫克)的 白色結晶。 1H-NMR (CDC13) ·· δ3·08 (3Η,s),4.52 (2Η,s),7.37-15 7·53 (7Η,m),7.64 (4H,m),8.16 (m,s),8.64 (2Η,d,J = 6.0
Hz) MS (ESI, m/z) : 382 (M+H) 實施例32 依照類似製備物7的方法獲得下列化合物。 20 2-[甲基(苯基)胺基]-N-[4-(4•吼啶基)苯基]乙醯胺 1H-NMR (CDC13) ·· δ3·11 (3H,s),3·99 (2H,s),6·86 (2H, d,J = 7_9 Ηζ),6.92 (1Η,t,J = 7·5 Hz), 7.32 (2Η,dd,J = 7.5, 7.9 Hz),7.48 (2H,dd,J = 1.7, 4.4 Hz),7.64 (4H,m),8.56 (1H,s),8.63 (2H,dd,J = 1.7, 4.4 Hz) 89 200800899 MS (ESI,m/z) : 318 (M+H) 實施例33 依照類似實施例28的方法獲得下列化合物。 2_[經乙醯基(苯基)胺基]-N_[4_(4-吡啶基)苯基]乙醯胺
5 1H-NMR (CD€i3): 63.96 (2H5 s)? 4.49 (2H? s)? 7.33 (2H m),7·47 (5H,m),7.62 (2H,d,J = 8.9 Ηζ),7·67 (2H,d,J = 8.9 Hz),8.43 (1H,s),8·64 (2H,dd,J = 1.6, 4.6 Hz) MS (ESI,m/z) : 390 (M+H) 實施例34 10 將[(2-氧代-2-{[4-(4-0比°定基)苯基]胺基}乙基)(苯基)胺 基]醋酸乙酯(50.0毫克)溶解於甲醇/四氫呋喃(1 ··丨,1〇毫升) 内然後將氫硼化鈉(14·6毫克)分成數部分加入以冰浴冷卻 的擾掉中混合物。在0°C下將混合物攪拌5小時然後將水(2 〇 毫升)加入獲得的混合物。以1當量鹽酸中和該混合物然後 I5以醋酸乙酯(3.0毫升)萃取。以食鹽水清洗有機層然後在硫 酸鎂上乾燥。在真空内蒸發溶劑然後利用石夕膠管柱層析法 (2克,氯仿内10%甲醇)純化殘留物而產生2_[(2•羥乙基苯 基)胺基]-N-[4-(4-吼啶基)苯基]乙醯胺(214毫克)的白色結 晶。 20 1H-NMR (CDC13) : 63.00 (1H, s), 3.7〇 (2H, t, J = 4.9
Hz), 4.04 (2H, t, J = 4.9 Hz), 4.07 (2H, s), 6.79 (2H, d, J = 8.6 Hz), 6.85 (1H, t, J = 7.1 Hz), 7.28 (2H, dd, J = 7.1, 8.6 Hz), 7.43 (2H, dd, J = 1.5, 5.0 Hz), 7.54 (2H, d, J = 8.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 8.57 (2H, dd, J = L5> 5>〇 Hz)j 9.82 90 200800899 (1H, s) MS (ESI,m/z) : 384 (M+H)
膏施例M 將4 ^里氯化鼠·醋酸乙I旨(1.8毫升)力口入醋酸乙酉旨(〇 c 5毫升)内的(2S)-2_苯胺基第三丁氧基-N-[4_(4-吼啶基)苯 基]丙醯胺(70¾克)懸浮液,然後在室溫下將混合物攪拌$ 小時。以正己烧(2.5¾升)稀釋獲得的混合物然後藉由過濾 收集固體及以正己烷(2.5毫升)清洗而產生(2s)-2_苯胺基_3_ 馨羥基-N-[4-(4-吡啶基)苯基]丙醯胺二鹽酸鹽(72毫克)的淡白 |〇色固體。 1H-NMR (DMSO-d6): δ3·74-3·87 (2H,m),4·17 (1H,t,J 二 5.5 Ηζ),5.60-5.97 (2Η,br),6·64 (1Η,t,J = 7·2 Ηζ),6.74 (2H,d,J = 7·8 Hz),7·12 (2H,dd5 J = 7.2, 7·8 Hz),7·93 (2H, 山 J = 8·7 Hz),8.07 (2H,d,J = 8·7 Hz),8·39 (2H,d,J 二 6.6 15 Hz),8.90 (2H,d,J = 6.6 Hz),10.67 (ih,s) MS (ESI,m/z) : 334 (M+H-2HC1) f施例36 依照類似實施例29的方法獲得下列化合物。 (2S)-2-(苄胺基)-N-[4-(4^比啶基)苯基]丙醯胺二鹽酸鹽 , 20 1H-NMR (DMSO-d6) : 61.62 (3H, d? J = 7.0 Hz)? 4.26- • 4·12 (3H,m),7.45-7.43 (4H,m),7.60-7.58 (2H, m), 7.93 (2H, d, J = 8·5 Hz),8.10 (2H,d,J = 8.5 Hz),8·35 (2H,d,J = ό·5 Hz),8·92 (2H,d,J = 6.5 Hz) f施例37 91 200800899 依照類似製備物7的方法獲得下列化合物。 (2S)-2-苯胺基-Ν-[4_(4·吼啶基)苯基]丙醯胺二鹽酸鹽 1H-NMR (DMSO-d6) : δΐ.43 (3Η? ά, J = 7.0 Ηζ)? 4.08-4·03 (1Ή,m),6.56 (1Η,dd,J = 7.5, 7.5 Ηζ),6.62 (2Η,d,J = 5 8.0 Hz),7.08 (2H,dd,J = 8.0, 8.0 Hz),7·67 (2H, d,J = 6.0
Hz),7.79 (4H, m),8.59 (2H,d,J = 6.0 Hz) 實施例38 依照類似製備物7的方法獲得下列化合物。 (2R)-2-苯胺基-Ν_[4-(4·吼啶基)苯基]丙醯胺 10 ΪΗ-NMR (DMSO-d6) : 51.43 (3H? d? J = 7.0 Hz)? 4.08- 4·01 (1H,m),6.56 (2H,dd,J = 7.5, 7.5 Hz),6.62 (2H,d,J = 8.0 Hz),7.08 (2H,dd, J = 8.0, 8.0 Hz),7·68 (2H,d,J = 6.0 Hz),7·79 (4H,m),8·59 (2H, d,J = 6.0 Hz) MS (ESI,m/z) : 318 (M+H) 15 實施例39 依照類似實施例35的方法獲得下列化合物。 (2R)-2-苯胺基-3-羥基-N-[4-(4eb啶基)苯基]丙醯胺二 鹽酸鹽 1H-NMR (DMSO-d6): δ3·74·3·87 (2H,m),4.17 (1H,t,J = 20 5.5 Hz),5.63-5.99 (2H,r),6·64 (1H,t,J = 7·2 Hz),6.74 (2H, d,J = 7.8 Hz),7.12 (2H,dd,J = 7.2, 7.8 Hz),7·93 (2H,d,J = 8.7 Hz),8.07 (2H,d,J = 8.7 Hz),8.39 (2H,d,J = 6.6 Hz), 8.90 (2H,d,J = 6.6 Hz),10.67 (1H,s) MS (ESI,m/z) : 334 (M+H-2HC1) 92 200800899 實施例40 依照類似製備物7的方法獲得下列化合物。 (2S)-2_本胺基-3 -甲基-Ν-[4-(4-σ比σ定基)苯基]丁酿胺
1H-NMR (CDC13) : δ1·09 (3Η,d,J = 7.2 Ηζ),1.13 (3Η, 5 d,J = 7.2 Ηζ),2·45·2·58 (1Η,m),3·69 (1Η,dd,J = 2·9, 3·6 Hz),3.98 (1H,d,J = 2·9 Hz),6.72 (2H,d,J = 7·5 Hz),6·86 (1H,t,J = 7.3 Hz),7.24 (2H,dd,J = 7.3, 7·5 Hz),7.47 (2H, d,J = 6.0 Hz),7.60 (2H,d,J = 9.0 Hz),7.67 (2H,d,J = 9.0 Hz),8·63 (2H,d,J = 6.0 Hz),8.82 (1H,s) 10 MS (ESI,m/z) : 346 (M+H) 實施例41 依照類似製備物7的方法獲得下列化合物。 (2R)-2-苯胺基-3-甲基-N-[4-(4-n比啶基)苯基]丁醯胺 1H_NMR (CDC13) : δ1·Ό9 (3H,d,J = 7·2 Ηζ),1·13 (3H, 15 d,J = 7.2 Hz),2.45-2.58 (1H,m),3.69 (m,dd,J = 2.9, 3.6 Hz),3.98 (1H,d,J = 2.9 Hz),6.72 (2H,d,J = 7.5 Hz),6.86 (1H,t,J = 7.3 Hz), 7·24 (2H,dd,J = 7.3, 7.5 Hz),7·47 (2H, d,J = 6.0 Hz),7.60 (2H,d,J = 9.0 Hz),7·67 (2H, d,J = 9.0 Hz),8·63 (2H,d,J = 6.0 Hz),8.82 (1H,s) 20 MS (ESI,m/z) : 346 (M+H) 實施例42 依照類似製備物7的方法獲得下列化合物。 ((1 S,2R)-2-經基-3-乳代-1-苯基-3- {[4-(4-吼σ定基)苯基] 胺基}丙基)胺基曱酸第三丁酯 93 200800899 1H-NMR (DMSO-d6): δ1·31 (9H,s),4·25·4·33 (1H,m), 5·00·5·07 (1H,m),5·88 (1H,d,J = 7.1 Hz),7.07 (1H,d,J = 9.1 Hz), 7·20·7·40 (5H,m),7.69 (2H,d,J = 6.3 Hz), 7.74-7.83 (4H,d,J = 6.3 Hz),10.00 (1H,s) 5 MS (ESI,m/z) : 434 (M+H) 實施例43 依照類似製備物7的方法獲得下列化合物。 Ν-[4·(4-吡啶基)苯基]-2-喹諾啉曱醯胺 1H-NMR (DMSO-d6):57.77 (3H? m)? 7.92 (3H? m)? 8.15 10 (3H,m),8.29 (2H,m),8.64 (3H,m),10.96 (1H,s) MS (ESI,m/z) : 326 (M+H) 實施例44 依照類似製備物7的方法獲得下列化合物。 2-(1Η-吲哚-1-基)-N-[4-(4_吼啶基)苯基]乙醯胺 15 1H-NMR (DMSO=d6):85.11 (2H,s),6.47 (1H,d,J = 3.1
Hz),7.04 (1H,t,J = 7.0 Hz),7.13 (1H,t,J = 7·0 Ηζ),7·40 (1H,d,J = 3.1 Hz),7.44 (1H,d,J = 7.Ό Hz),7.57 (m,d,J = 7.0 Hz),7·69 (2H,dd,J = 1.7, 4·6 Hz),7·75 (2H,d,J = 8·8 Hz),7·82 (2H,d,J = 8.8 Hz),8.60 (2H,dd,J = 1.7, 4.6 Hz), 20 10.60 (1H,s) MS (ESI, m/z) : 328 (M+H) 實施例45 在〇°C下將草酸醯氯(0.053毫升)和一滴N,N-二甲基甲 醯胺加入二氯甲烷(1.8毫升)内的1H-吡咯-2-甲酸(45·0毫克) 94 200800899 混合物。15分鐘之後,在(TC下將[4-(各吡啶基)苯基]胺(68 9 毫克)和吡啶(0.131毫升)加入混合物然後在室溫下將獲得 之混合物攪拌隔夜。將水(3毫升)加入混合物。藉由過濾收 集沈澱物然後以水清洗而產生队[4_(4- σ比咬基)苯基[识·叹 5咯甲酸(65.2毫克)的白色結晶。 1H-NMR (DMSO-d6):S6.19 (1H,m),7.00 (1H,m),7·11 (1Η,m),7.73 (2Η,d,J = 4·6 Ηζ),7.83 (2Η,d,J = 8·8 Ηζ), 7.92 (2H,d,J = 8.8 Hz),8.61 (2H,d,J = 4.6 Hz),9·94 (1H, s),11.74 (lH,s) 10 MS (ESI,m/z) : 264 (M+H) 實施例46 依fl?、類似貫施例4 5的方法獲得下列化合物。 1-甲基-N-[4-(4-吡啶基)苯基]-1H-。比咯-2-甲醯胺 1H-NMR (DMSO-d6) : δ3.90 (3H,s),6·11 (1H, dd,J = 15 2.6, 3.8 Hz),7·04 (1H,m),7·07 (1H,m),7·71 (2H,d,J = 6·〇
Hz),7.81 (2H,d,J = 8.6 Hz),7·89 (2H,d,J = 8·6 Hz),8·6〇 (2H,d,J = 6.0Hz),9.93(lH,s) MS (ESI,m/z) : 278 (M+H) 實施例47 20 在室溫下將[1,Γ-雙(二苯基膦基)二亞鐵]二氣鈀(H)、與 二氯甲烷的複合物(1.24克)和磷酸鉀(32.2克)加入込2-二甲 氧乙烷(500毫升)的5-溴-1-(苯乙醯基)巧哚啉(15·98克)和 4-(4,4,5,5-四甲基-l,3,2-二氧硼烷-2-基)吡啶(12.4克)溶液, 然後在10 0 °C下將混合物攪拌6 0小時。在真空内蒸發混合物 95 200800899 以移除1,2_二甲氧乙烷然後將殘留物溶解於醋酸乙酉曰(6〇 毫升)和水(300毫升)的混合物内。以食鹽水清洗分離的有機 層,在硫酸鎂上乾燥及真空内蒸發。利用以醋酸乙醋溶析 ' 的石夕膠管柱層析法純化殘留物而產生1-(苯乙醢基)-5 (4 , 5 啶基)°引哚啉(8.02克)的白色粉末。 1H-NMR (DMSO-d6): δ3·24 (6·8Η,t),3·88 (2H,s),·
(6·8Η,t),7.2-7.4 (5H,m),7·6-7·75 (4H,m), 8·16 (lH,山 J 6.9 Hz),8.55-8.65 (2H,m) φ ESI-MS (m/z) : 315 (M+H) 10 j[施例48 依照類似實施例47的方法獲得下列化合物。 5-(4-°比ϋ定基)-1 -(2-吼定基乙酿基户弓卜朵淋 1H-NMR (DMSO-d6) : δ3·25 (2Η,t,J = 6.8 Ηζ),4 06 (2Η,s),4.76 (2Η,t,J = 6·8 Ηζ),7·25·7·7 (7Η,m),8·15 (1Η, 15 d,J = 8·1 Ηζ),8.51 (1Η,d,J = 4·7 Ηζ),8·57 (2Η,d,J 二 6·〇
Hz) Φ ESI-MS (m/z) : 316 (M+H) f施例49 將異氰笨酸酯(53毫克)加入苯乙腈(i〇毫升)内的5-(4-, 20吡啶基)°引哚啉(8〇毫克)溶液,然後在8〇°c下將混合物攪拌6 小時。將混合物蒸發至乾燥然後利用以醋酸乙酯/甲醇(1〇 : 1)溶析的矽膠管柱層析法純化殘留物而產生N-笨基·5、(七 吡啶基)-1-吲哚啉甲醯胺(6〇毫克)的淡棕色粉末。 1H-NMR (DMSO-d6) : δ3·37 (2H,t,J = 6.8 Ηζ),4·2〇 96 200800899 (2H,t,J = 6·8 Ηζ),7·0-7·1 (1H,m),7·25·7·35 (2H,m), 7.55-7.65 (4H,m),7·68 (2H, d,J = 6.0 Hz),7·98 (1H,d,J = 8.1 Hz),8·56 (2H, d,J = 6.0 Hz),8.61 (1H,s) • ESI-MS (m/z) : 316 (M+H) • 5 實施例50 依照類似實施例4的方法獲得下列化合物。 N-卞基_5-(4-σΛϋ定基)-1-ϋ引0朵琳甲酿胺 1H-NMR (DMSO-d6) ·· δ3·22 (2Η,t,J = 8.6 Ηζ),4.02 • (2Η,t,J = 8·6 Ηζ),4.36 (2Η,d,J = 5.8 Ηζ),7·19-7·28 (1Η, 10 m),7.29-7.42 (5H,m),7.59(lH,dd,J=1.8,8.6Hz),7.63- 7·69 (3H,m),7.93 (1H,d,J = 8.6 Hz),8.55 (2H,d,J = 6·3 Hz) ESI-MS (m/z) : 330 (M+H) 實施例51 15 依照類似實施例4的方法獲得下列化合物。 N-[(lS)-2-|^基-1-苯乙基]-5-(4-σ比咬基)-1-σ弓卜朵琳甲酿胺 1H-NMR (DMSO-d6) : 53.23 (2H? t5 J = 8.6 Hz), 3.57-3·74 (2H,m),4·10 (2H,t,J = 8·6 Hz),4.83-4.95 (1H,m), 4·92 (1H,t,J = 5.9 Hz),6·88 (1H,d,J = 7·8 Hz),7·23 (1H,t, • 20 J = 7.1 Hz),7·32 (2H,t,J = 7·1 Hz),7·39 (2H,d,J = 7·1 Hz), . 7·57 (1H,d,J = 8.5 Hz),7.64 (2H,d,J = 5·6 Hz),7·65 (1H, s),7.87 (1H,d,J = 8·5 Hz),8·54 (2H,d,J = 5.6 Hz) ESI-MS (m/z) : 360 (M+H) 實施例52 97 200800899 依照類似實施例29的方法獲得下列化合物。 N- {2-氧代-2-[5·(4-0比 σ定基)-2,3·二氮-1H-°引 ϋ朵-1-基]乙 基}苯胺二鹽酸鹽 IH-NMR (DMSO-d6) : 53.31 (2H, t? J = 8.4 Hz)? 4.20 5 (2H,s),4·31 (2H,t,J = 8.4 Hz),6·72 (1H,t,J = 7·2 Hz), 6.84 (2H,d,J = 8.0 Hz),7.17 (2H,dd,J = 7.2, 8.0 Hz),7.99 (1H,d,J = 8.5 Hz),8.05 (1H,s),8·22 (1H,d,J = 8.5 Hz), 8·39 (2H,d,J = 6.9 Hz),8.90 (2H,d,J = 6·9 Hz) ESI-MS (m/z) : 330 (M+H-2HC1) 10 實施例53 將醋酸乙酯(5毫升)内的4當量氯化氫加入乙醇(30毫升) 内的[(IS)-l-苄基-2-氧代-2-{[4-(4·-比啶基)苯基]胺基}乙基] 胺基甲酸第三丁酯(800毫克)溶液,然後在60°C下將混合物 攪拌1小時。藉由真空内的蒸發移除溶劑然後從2-丙醇再結 15 晶殘留物而產生(2S)-2-胺基-3-苯基-N-[4-(4-吼啶基)苯基] 丙醯胺二鹽酸鹽(625毫克)的白色粉末。 1H=NMR (DMSO-d6) : 53.1-3.3 (2H? m)9 4.35-4.5 (1H? m),7.2-7.4 (5H,m),7.87 (2H,d,J = 8·8 Hz),8.07 (2H,d,J = 8.8 Hz),8.33 (2H,d,J = 6.8 Hz),8.54 (3H,br),8.90 (2H,d, 20 J = 6.8 Hz) MS (ESI,m/z) : 318 (M+H,游離型) 實施例54 依照類似實施例53的方法獲得下列化合物。 (2R)-2-胺基-3-苯基-Ν-[4-(4-σι!ΐ咬基)苯基]丙酿胺 98 200800899 1H-NMR (DMSO-d6) : δ2·75 (1H,dd,J = 7.7, 13.4 Hz), 3.02 (1H,dd5 J = 5.5, 13.4 Hz),3·60 (1H,dd,J = 5.5, 7.7 Hz), 7.13-7.34 (5H,m),7.63-7.85 (6H,m),8.55-8.65 (2H,m) MS (ESI,m/z) : 318 (M+H) 5 實施例55 依照類似實施例53的方法獲得下列化合物。 (2S)-2-(甲基胺基)-3-苯基-N-[4-(4-吼啶基)苯基]丙醯胺 1H-NMR (DMSO-d6) : δ2·24 (3H,s),2.82 (1H,dd,J = 7.4, 13·4 Hz),2·94 (1H,dd,J 二 6.4, 13·4 Hz),3.30-3.41 (1Η, 10 m),7·10·7·33 (6H,m),7.63-7.84 (7H,m),8.56-8.64 (2H,m), 9.90-10.15 (1H,br) MS (ESI,m/z) : 332 (M+H) 實施例56 依照類似實施例53的方法獲得下列化合物。 15 (2R,3 S)-3 =胺基-2·羥基-3 -苯基·Ν-[4-(4-。比啶基)苯基] 丙醯胺 1H-NMR (DMSO-d6) : 54.11 (1H? s9 J - 3.8 Hz)9 4.23 (1H,s,J = 3.8 Hz),5.64-6.15 (1H,br),7.15-7.46 (5H,m), 7.65-7.89 (6H,m),8.55-8.65 (2H,m),9.40-10.30 (1H,br) 20 MS (ESI, m/z) : 334 (M+H) 實施例57 依照類似實施例53的方法獲得下列化合物。 3-胺基-2·节基定基)苯基]丙酿胺 IH-NMR (DMSO-d6) : 52.63-2.99 (5H? m)? 6.91-7.04 99 200800899 (1H,m),7.10-7.33 (5H,m),7.61-7.82 (6H,m),8·54·8·64 (2H,m) MS (ESI,m/z) : 332 (M+H) 實施例58 5 依照類似實施例53的方法獲得下列化合物。 (2S)-1-氧代-3-苯基小[5-(4-吼啶基)-2,3-二氫4H-吲哚 -1-基]-2-丙胺 1H-NMR (DMSO-d6) : δΐ.78-1.92 (2H? br)9 2.64-2.80 (1H,m),2·89-3·24 (3H,m),3.73-3.98 (2H,m),4.16-4.38 10 (1H,m),7.12-7.32 (5H,m),7.61-7.73 (4H, m),8.16-8.28 (1H,m),8·54- 8·64 (2H,m) MS (ESI,m/z) : 344 (M+H) 實施例59 依照類似實施例53的方法獲得下列化合物。 15 (3 S)-3 -胺基-3 -苯基σ定基)苯基]丙酿胺 1H-NMR (DMSO-d6) : 52.62 (2H? d? J = 7.0 Hz)? 4.32 (1H,t,J = 7.0 Hz),7.16-7.48 (6H,m),7.63-7.84 (7H,m), 8.55-8.65 (2H,m),10.21-10.35 (1H,br) MS (ESI,m/z) : 318 (M+H) 20 實施例60 依照類似實施例53的方法獲得下列化合物。 (3R)-3-胺基-3-苯基-N-[4-(4-σ比ϊί定基)苯基]丙酿胺 1H-NMR (DMSO-d6) : δ2.62 (2H,d,J = 7·0Ηζ),4.33 (m,t,J = 7·0 Ηζ),7·16·7·48 (6H,m),7·63·7·84 (7H,m), 100 200800899 8·54·8·65 (2H,m),10.20-10.36 (1H,br) MS (ESI, m/z) : 318 (M+H) 資施例61 依照類似實施例4的方法獲得下列化合物。 5 1-(2-羥基苄基)-3-[4-(4-吼嚏基)苯基]脲 1H-NMR (DMSO-d6) ·· δ4·22 (2H,m),6.60-6.90 (3H,m), 7·00-7.20 (2H,m),7.50-7.75 (6H,m),8.50-8.60 (3H,m), 9.13 (lH,brs) ® MS (ESI,m/z) : 320 (Μ+Ή) 10 實施例62 將N,N-二異丙基乙胺(1·3毫升)加入N,N-二甲基甲醯胺 (10毫升)内的4-(4-吼啶基)苯胺(4〇0毫克)、〇_ (7_氮雜苯并三 唾小基)-1,1,3,3-四曱基脲六氟磷酸鹽(1.34克)、經基_7_氮 雜苯并三唑(480毫克)和(2-硝基苯氧基)醋酸(695毫克)溶 15液,並將其在室溫下攪拌隔夜。將此反應混合物倒入水(30 ^ 毫升)然後攪拌30分鐘。收集不可溶材料,以水清洗,乾燥 及利用矽膠管柱層析法(梯度5 CHC13,CHC13内的10% MeOH)純化。在氫氣的大氣壓下將凡义二甲基甲醯胺(1() 毫升)内的等份獲得產物(1 〇〇毫克)和丨〇%鈀碳催化劑(5〇% • 20濕度,30毫克)於室溫下攪拌3小時。在減壓下移除及蒸發 • 催化劑。利用矽膠管柱層析法(梯度,CHCl3,CHCl3内的 10% MeOH)純化反應產物然後從Et〇H再結晶而獲得2_(2_ 胺基苯氧基)-Ν-[4-(4·-比啶基)苯基]乙醯胺(3〇毫克)的淡白 色粉末。 101 200800899 1H-NMR (DMSO-d6) : 54.67 (2H5 s)? 5.07 (2H? s)9 6.45-6·57 (1H,m),6.63-6.90 (3H,m),7·11 (2H,dd,J = 1.6, 4.6 Hz),7·83 (4H,s),8.61 (2H,dd,J = 1.6, 4.6 Hz),10.17 (1H,s) MS (ESI,m/z) : 342 (M+Na) 5 實施例63 依照類似實施例62的方法獲得下列化合物。
3-(2·胺基苯基)比σ定基)苯基]丙酸胺 1H-NMR (DMSO-d6) : 52.53-2.67 (2H5 m)5 2.70-2.84 (2H,m),4·92 (2H,s),6·48 (1H, dd,J = 1.3, 7.2 Hz), 6.61 10 (1H,dd,J = 1.0, 7.9 Hz),6.84-6.99 (2H,m),7.68 (2H,dd,J =1·6,4·6 Hz),7.70-7.84 (4H,m),8.59 (2H,dd,J = 1·6,4·6 Hz),10.12 (1H,s) MS (ESI,m/z) : 318 (M+H) 實施例64 15 依照類似製備物7的方法獲得下列化合物。 3-(3-經基苯基)-1^-[4-(4-°比11定基)苯基]丙酿胺 iH-NMR (DMSO-d6) : 52.54-2.70 (2H? m)9 2.75-2.91 (2H,m),6·54·6·71 (3H,m),7.07 (1H,t,J = 7·9 Hz),7.68 (2H,dd,J = 1.6, 4.6 Hz), 7.70-7.84 (4H,m),8.59 (2H,dd,J = 20 1.6, 4·6 Hz),9·29 (1H,s),10.11 (1H,s) MS (ESI,m/z) : 319 (M+H) 實施例65 依照類似實施例1的方法獲得下列化合物。 l-[4-(4-u比啶基)苯基]-3-(2-噻吩基甲基)脲 102 200800899 1H-NMR (DMSO-d6) : δ4·48 (2H,d,J = 5.8 Ηζ),6·77 (1H,t,J = 6·0 Hz),6·97 (1H,dd,J = 3.6, 5.1 Hz),7.00-7.02 (1H,m),7.40 (1H,dd,J = 1.5, 5·1 Hz),7·56 (2H,d,J = 8.8 Hz),7·66 (2H,dd,J = 1.8, 4.6 Hz),7.73 (2H,d,J = 8.8 Hz), 5 8·57 (2H,dd,J = 1.6, 4·5 Hz),8.82 (1H,s) MS (ESI, m/z) : 310 (M+H) 實施例66 依照類似實施例1的方法獲得下列化合物。 l-[4-(4-nb啶基)苯基]-3-(3-噻吩基曱基)脲 10 1H-NMR (DMSO-d6) : δ4·30 (2H,d,J = 5.6 Hz),6.64 (1H,t,J = 5.9 Ηζ),7·Ό9 (1H,dd,J = 1.1,5·0 Hz),7.31-7.34 (1H,m),7.50 (1H,dd,J = 3.0, 5.1Hz),7.56 (2H,d,J = 8·8 Hz),7·66 (2H, dd,J = 1·6, 4·5 Hz),7·73 (2H,d,J = 8·8 Hz), 8·57 (2H,dd,J = 1·7, 4.5 Hz),8.76 (1H,s) 15 MS (ESI,m/z) : 310 (M+H) 實施例67 依照類似實施例1的方法獲得下列化合物。 l-[(lR)-2·羥基-1_(2-噻吩基)乙基]-3-[4-(4-吨啶基)苯 基]脈 20 1H-NMR (DMSO-d6) : 83.64-3.76 (2H? m)? 5.01-5.09
(1H,m),5·19 (1H,t,J = 5·3 Ηζ),6·76 (1H,d,J = 8·3 Hz), 6·99 (1H,dd,J = 3.5, 5.0 Hz),7.02 (1H,d,J = 3.5 Hz),7.38 (1H,dd,J = 1.2, 5.0 Hz),7.54 (2H,d,J = 8.8 Hz),7.66 (2H, dd,J = 1.6, 4.6 Hz),7.73 (2H,d,J = 8·8 Hz),8·57 (2H,dd,J 103 200800899 =1.6, 4·6 Hz),8.89 (1H,s) MS (ESI, m/z) : 340 (M+H) 實施例68 依照類似實施例1的方法獲得下列化合物。 ’ 5 l-[(lS)-2-羥基-1_(2-噻吩基)乙基]-3-[4-(4-吼啶基)苯基]脲 1H-NMR (DMSO-d6) : 53.64-3.76 (2H,m),5.01-5.09 (1H,m),5.19 (1H,t,J = 5·3 Hz), 6·76 (1H,d,J = 8.3 Hz), 6·99 (1H,dd,J = 3.5, 5.0 Hz),7.02 (1H,d,J = 3·5 Hz),7.38 響 (1H,dd, J = 1·2, 5.0 Hz),7·54 (2H,d,J = 8·8 Hz),7·66 (2H, 10 dd,J = 1.6, 4.6 Hz),7.73 (2H,d,J = 8.8 Hz),8.57 (2H,dd,J = 1.6, 4.6 Hz), 8.89 (1H, s) MS (ESI,m/z) : 340 (M+H) 實施例69 依照類似實施例1的方法獲得下列化合物。 15 1-[(18)-2-殖基=1-(3-嘆吩基)乙基]-3-[4-(4-°比〇定基)本基] 脲 ⑩ 1H=NMR (DMSO-d6) : 53.61-3.72 (2H? m), 4.84-4.91 (1H,m),5·00 (1H,t,J = 5.2 Hz),6·67 (1H,d,J = 8.4 Hz), 7·12 (1H,dd,J = 1.4, 5·1 Hz),7·31-7·33 (1H,m),7.48 (1H, , 20 dd,J = 3.0, 5.0 Hz),7·53 (2H,d,J = 8·7 Hz),7·66 (2H,dd,J = • 1.6, 4.5 Hz),7·72 (2H,d,J = 8·7 Hz),8·57 (2H,dd,J = 1.6, 4.5 Hz),8.82 (1H,s) MS (ESI,m/z) : 340 (M+H) 實施例70 104 200800899 將N-氯琥珀醯亞胺(303毫克)加入二氯甲烧(1〇毫升)内 的1·[(1Κ>2-輕基小仏噻吩基)乙基]冬㈣Ο比啶基)苯基] 脲(700¾克)和醋酸(734毫克)溶液,然後使混合物回流3小 時。在真空内蒸發該混合物然後利用以氯仿/甲醇(9 :丨)溶 5析的矽膠管柱層析法純化殘留物然後從乙醇再結晶而獲得 1-[(111)-1_(5_氯_2_噻吩基)_2_羥乙基]_3-[4_(4_。比啶基)苯基] 脲(280毫克)的結晶。 1H-NMR (DMSO-d6) : 83.63-3.74 (2H? m)9 4.93-5.00 (1H,m),5.31 (1H,t,J = 5.1 Ηζ),6·83 (1H,d,J = 8·1 Hz), 10 6·88 (1H,dd,J = 0.9, 3·8 Hz),6·97 (1H,d,J = 3.8 Hz),7.53 (2H,d,J = 8.8 Hz),7.66 (2H,dd,J = 1·7, 4.5 Hz),7·73 (2H, d,J = 8.8 Hz),8·57 (2H,dd,J = 1.6, 4.5 Hz),8.92 (1H,s) MS (ESI,m/z) : 374 (M+H) 會施例71 !5 依照類似實施例1的方法獲得下列化合物。 l-[(lS)-l-(2-氯苯基)_2·羥乙基]-3·[4-(4-吼啶基)苯基]脲 1H-NMR (DMSO-d6) : 53.51-3,59 (1H? m)5 3.68-3.76 (1H,m),5.12-5.19 (2H,m),6.98 (1H,d,J = 7·6 Hz),7.28 (1H,td,J = 2_0, 7.8 Hz),7.35 (1H,td,J = 1.4, 3·8 Hz),7·43 20 (2H,ddd,J = 1.6, 3.6, 7.8 Hz),7·51 (2H,d,J = 8·8 Hz),7·65 (2H,dd,J = 1.6, 4·5 Hz),7·71 (2H,d,J = 8·8 Hz),8·56 (2H, dd,J = 1·6, 4.5 Hz),8.97 (lH,s) MS (ESI,m/z) : 368 (M+H) 會施例72 105 200800899 依照類似實施例1的方法獲得下列化合物。 1-{(1S)_2-經基-1-[2-(三氟曱基)苯基]乙基}-3-[4-(4-〇比 啶基)苯基]脲 1H-NMR (DMSO-d6) : 63.43-3.53 (1H, m)5 3.67-3.74 5 (1H,m),5.10-5.17 (1H,m),5.22 (1H,t,J = 5.3 Ηζ),7·05 (1H,d,J = 6.9 Hz),7.44-7.51 (3H,m),7·62·7·72 (7H,m), 8·56 (2H,d,J = 1·6, 4·5 Hz),8·93 (1H,s) MS (ESI,m/z) : 402 (M+H) 實施例73 10 依照類似實施例1的方法獲得下列化合物。 1-{(1化)-1-节基-2-經乙基-3-[4-(4-°比°定基)苯基]脈 1H-NMR (DMSO-d6) : δ2_72 (1H,dd,J = 7.4, 13·6 Hz), 2.85 (1H,q,J = 6·8 Hz),3.32-3.44 (2H,m),3.80-3.90 (1H, m),4.92 (1H,t,J = 5.1 Hz),6.19 (1H,d,J = 8.3 Hz),7.17-15 7.22 (1H,m),7.23-7.33 (4H,m),7.50 (2Ή,d,J = 8·8 Hz), 8.56 (2H,dd,J = 1.7, 4.7 Hz),8.74 (1H,s) MS (ESI,m/z) : 348 (M+H) 會施例74 依照類似實施例1的方法獲得下列化合物。 20 l_[(lR)-l-(2-氟苄基)-2•羥乙基]-3-[4-(4-吼啶基)苯基]脲 1H-NMR (DMSO_d6) : δ2·75 (1H,dd,J = 8.2, 13.8 Hz), 2·91 (1H,dd,J = 6.0, 13·8 Ηζ),3·37·3·48 (2H,m),3·90-4·00 (1H,m),4·95 (1H,t,J = 5·1 Hz),6·18 (1H,d,J = 8.6 Hz), 7·10-7·17 (2H,m),7.21-7.29 (1H,m),7·33 (1H,td,J = 1.7, 106 200800899 7·6 Ηζ),7·48 (2H,d,J = 8.7 Hz),7.64 (2H,dd,J = 1.6, 4.6 Hz),7·69 (2H,d,J = 8·7 Hz),8.56 (2H,dd,J = 1.6, 4.6 Hz), 8.72 (1H,s) MS (ESI,m/z) : 366 (M+H) 5 實施例75 依照類似實施例1的方法獲得下列化合物。 1-[(1R)-1_(3-氟苄基)-2-羥乙基]-3-[4-(4-吼啶基)苯基]脲 1H-NMR (DMSO-d6) : δ2·74 (1H,dd,J = 7.7, 13·7 Hz), 2.88 (1H,dd,J = 6.4, 13.7 Hz),3.34-3.45 (2H,m), 3.81-3.95 10 (1H,m),4.95 (1H,t,J = 5.0 Hz),6.22 (1H,d,J = 8.4 Hz), 6·98·7·12 (3H,m),7.34 (1H,q,J = 11.1 Hz),7·50 (2H,d5 J = 8.7 Hz),7·65 (2H,dd,J = 1.6, 4·8 Hz),7.71 (2H,d,J = 8.8 Hz),8·56 (2H,dd,J = 1.5, 4·8 Hz),8·74 (1H,s) MS (ESI,m/z) : 366 (M+H) 15 實施例76 依照類似製備物7的方法獲得下列化合物。 l-[(lR)-l-(4-氟节基)-2-經乙基]-3-[4-(4-σ比咬基)苯基]腺 1H-NMR (DMSO-d6) ·· δ2·71 (1Η,dd,J = 7·5, 13·7 Ηζ), 2·85 (1Η,dd,J = 6.5, 13.7 Ηζ),3·34-3·45 (2Η,m),3·78-3·88 20 (1Η,m),4·93 (1Η,t,J = 5.0 Ηζ),6.19 (1Η,d,J = 8.3 Ηζ), 7·12 (2H,t,J = 8·8 Hz),7.25-7.31 (2H,m),7·50 (2H,d,J = 8.7 Hz),7.65 (2H,dd,J = 1.7, 4.6 Hz),7·71 (2H,d,J = 8.8 Hz),8·56 (2H,dd,J = 1.7, 4.6 Hz),8.73 (1H,s) MS (ESI,m/z) : 366 (M+H) 107 200800899 實施例77 依照類似實施例1的方法獲得下列化合物。 H(lR)-l-(4-氯节基)-2-羥乙基]-3·[4-(4·吼啶基)苯基]脲 1H-NMR (DMSO-d6) : δ2·71 (1Η,dd,J = 7.6, 13·6 Ηζ), ’ 5 2·85 (1Η,dd,J = 6.3, 13·6 Ηζ),3·34-3.44 (2Η,m),3·79·3·90 (1H,m),4·94 (1H,t,J = 5.3 Hz),6.19 (1H,d,J = 8.4 Hz), 7.27 (2H,d,J = 8.3 Hz),7.35 (2H,d, J = 8·3 Hz),7·49 (2H,d, J = 8.8 Hz),7.65 (2H,dd,J = 1.8, 4·6 Hz),7.70 (2H,d,J = ’ 8.6 Hz),8·56 (2H,dd,J = 1.8, 4·7 Hz),8·71 (1H,s) 10 MS (ESI,m/z) : 382 (M+H) 實施例78 依照類似實施例1的方法獲得下列化合物。 l-[(lR)-2-羥基小(2-噻吩基甲基)乙基]-3-[4-(4-吼啶基) 苯基]脲 15 1H,NMR (DMSO-d6) : δ2·93 (1H,dd,J = 7.4, 14·8 Hz), • 3.11 (1Η,dd,J = 6.2, 14·8 Ηζ),3.35-3.49 (2Η,m),3.81-3.91 (1H,m),4.96 (1H,t,J = 5.2 Hz), 6.23 (1H,d,J = 8·3 Hz), 6.91 (1H,br),6·96 (1H,dd,J = 3.4, 4·9 Hz),7·34 (1H,dd,J = 1.1,5.0 Hz),7.53 (2H,d,J = 8.8 Hz),7·66 (2H,dd,J = 1.4, • 2〇 4.4 Hz),7.71 (2H,d,J = 8·8 Hz),8·57 (2H,dd,J = 1.6, 4.5 ^ Hz),8·79 (1H,s) MS (ESI? m/z) : 354 (M+H) 實施例79 依照類似實施例1的方法獲得下列化合物。 108 200800899 1-[(1幻-2-經基-1-(3-11塞吩基甲基)乙基]-3-[4-(4-0比°定基) 苯基]脲 1H-NMR (DMSO-d6) : δ2·75 (1H,dd,J = 7.3, 14·3 Hz), 2.88 (1H,dd,J = 6.5, 14.3 Hz),3.34-3.46 (2H,m),3.82-3.93 5 (1H, m),4.90 (1H,t,J = 5.2 Hz), 6·18 (1H,d,J = 8.3 Hz), 7·03 (1H,dd,J = 1.2, 4.9 Hz),7.19-7.23 (1H,m)5 7·46 (1H, dd,J = 2.9, 4.9 Hz),7.52 (2H,d,J = 8.8 Hz),7·65 (2H,dd,J = 1·6, 4·6 Hz),7·71 (2H,d,J = 8·8 Hz),8·57 (2H,dd,J = 1.6, 4·6 Hz),8·76 (1H,s) 10 MS (ESI,m/z) : 354 (M+H) 實施例80 依照類似實施例1的方法獲得下列化合物。 l-[(lS,2S)-2-羥基-1·(羥甲基)-2-苯乙基]-3-[4-(4·吼啶 基)苯基]脲 15 1H-NMR (DMSO-d6) : 63.37-3.45 (1H9 m)? 3.48-2.56 (1H,m),3.73-3.83 (1H,m),4.90 (1H,dd,J = 4.5, 6·1 Hz), 4.98 (1H,br),5.70 (1H,d,J = 3·9 Hz),6·22 (1H,d,J = 8.7 Hz), 7.21 (1H,t,J = 7.2 Hz),7.31 (2H,t,J = 7.4 Hz),7·39 (2H,d,J = 7·4 Hz),7·44 (2H,d,J = 8.8 Hz),7.63 (2H,dd,J = 20 1.5, 4.4 Hz),7·68 (2H,d,J = 8·7 Hz),8·56 (2H,dd,J = 1.5, 4.4 Hz),8.91 (1H,s) MS (ESI,m/z) : 364 (M+H) 實施例81 依照類似實施例1的方法獲得下列化合物。 109 200800899 l-[(2S)-2-羥基-2-苯乙基]-3-[4·(4^比啶基)苯基]脲 1H-NMR (DMSO-d6) : 63.10-3.20 (1H? m)5 3.36-3.46 (1H,m),4.61-4.69 (1H, m),5.60 (1H, d,J = 4·3 Hz),6.31 (1H,dd,J = 4·9, 6·1 Hz),7·24-7·29 (1H,m),7.32-7.42 (4H, 5 m),7.53 (2H,d,J = 8.8 Hz),7.65 (2H,dd,J = 1.6, 4.5 Hz), 7.71 (2H,d,J = 8.8 Hz),8.57 (2H,dd,J = 1.6, 4.5 Hz),8.89 (m,S) MS (ESI,m/z) : 334 (M+H) 實施例82 10 依照類似實施例1的方法獲得下列化合物。 l-[(lR)-3-羥基-1-苯丙基]-3-[4-(4』比啶基)苯基]脲 1H-NMR (DMSO-d6): δ1·79-1·93 (2H,m),3.36-3.48 (2H,m),4·61 (1H,t,J = 4.9 Ηζ),4·86 (1H,q,J = 7·4 Hz), 6.80 (1H,d,J = 8·1 Hz),7·20·7·26 (1H,m),7.30-7.37 (4H, 15 m),7.51 (2H,d,J = 8.8 Hz), 7·64 (2H,dd,J = 1.6, 4.5 Hz), 7.70 (2H,d,J = 8.8 Hz),8·56 (2H,dd,J = 1.6, 4.5 Hz),8.71 (1H? s) MS (ESI,m/z) : 370 (M+Na) 實施例83 20 依照類似實施例1的方法獲得下列化合物。 1-[(1S)_3-羥基-1-苯丙基]-3_[4-(4·吼啶基)苯基]脲 IH-NMR (DMSO-d6) : δΐ.79-1.93 (2H? m)? 3.36-3.48 (2H,m),4·61 (1H,t,J = 4·9 Hz),4·86 (1H,q,J = 7·4 Hz), 6·80 (1H,d,J = 8·1 Hz),7·20-7·26 (1H,m),7·30-7·37 (4H, 110 200800899 m),7.51 (2H,d,J = 8·8 Ηζ),7·64 (2H,dd,J = 1.6, 4.5 Hz), 7.70 (2H,d,J = 8.8 Hz),8.56 (2H,dd,J = 1.5, 4.5 Hz),8.71 (1H,s) MS (ESI,m/z) ·· 370 (M+H) 5 實施例84 依照類似實施例1的方法獲得下列化合物。 1-(2,4’·二吡啶-5-基)-3-[(lS)-2-羥基-1-苯乙基]脲 1H-NMR (DMSO-d6) : δ3·51-3·76 (2H,m),4.71-4.86 (1H,m),5·04 (1H,t,J = 5·1 Hz),6·97 (1H,d,J = 7.8 Hz), 10 7.19-7.31 (1H,m),7.34 (4Ή,d,J = 4.4 Hz),7.94-8.10 (4H, m),8·63 (3H,d,J = 6.0 Hz),9·11 (1H,s) MS (ESI,m/z) : 335 (M+H) 實施例85 依照類似實施例53的方法獲得下列化合物。 15 2-氟-N-[4-(4-吼啶基)笨基]-D-苯基丙胺醯胺 1H-NMR (DMSO-d6) : δ2·75-2·85 (1H,m),2.95-3.05 (IH,m),3·6-3·65 (1H,m),7.1-7.4 (4H,m),7.65-7.8 (6H,m), 8.55-8.6 (2H,m) MS (ESI,m/z) : 336 (M+H) 20 實施例86 依照類似實施例53的方法獲得下列化合物。 3·氣-Ν_[4-(4-πΛσ定基)苯基]-D·苯基丙胺酿胺 1H-NMR (DMSO-d6) : 52.75-2.85 (1H9 m)5 2.95-3.05 (1H,m),3.55-3.65 (1H,m),6·95-7·1 (3H,m),7·25·7·35 (1H, 111 200800899 5 m),7.65-7.8 (6H,m),8.55-8.6 (2H,m) MS (ESI,m/z) : 336 (M+H) 實施例87 依照類似實施例53的方法獲得下列化合物。 4-氟-N-[4-(4-u比啶基)苯基]苯基丙胺醯胺. 1H-NMR (DMSO-d6): δ1·50·2·26 (1H,br)5 2.75 (1H,dd, J = 7.8, 13·4 Ηζ),2·99 (1H,dd,J = 5.5, 13·4 Hz),3.57 (1H, dd,J = 5.5, 7·8 Hz),7.06-7.14 (2H,m),7.24-7.32 (2H,m), 7·69 (2H,dd,J = 1.6, 4.4 Hz),7.73-7.82 (4H,m),8.60 (2H, 10 dd,J = 1.6, 4.4 Hz),9.20-10.80 (1H,br) MS (ESI,m/z) : 336 (M+H) 實施例88 依照類似實施例53的方法獲得下列化合物。 4-氣-Ν-[4-(4-ϋΛσ定基)苯基]-L-苯基丙胺酿胺 15 IH^NMR (DMSO-d6) : δΐ.60-2.28 (1H5 br)9 2.75 (1Η? dd9 J = 7.8, 13·4 Ηζ),2·99 (1Η,dd,J = 5.5, 13.4 Ηζ),3.57 (1Η, dd,J = 5.5, 7·8 Hz),7.06-7.14 (2H,m),7.25-7.32 (2H,m), 7.69 (2H,dd,J = 1.5, 4.4 Hz),7.74-7.82 (4H,m),8.60 (2H, dd,J = 1.5, 4.4 Hz),9.20-10.80 (1H,br) " 20 MS (ESI,m/z) : 336 (M+H) 實施例89 依照類似實施例53的方法獲得下列化合物。 2-氣-1^-[4-(4-11比°定基)苯基]-1^-苯基丙胺酸胺 1H-NMR (DMSO-d6): δ1·62_2·30 (1H,br),2·89 (1H,dd, 112 200800899 5 J = 7.9, 13.6 Ηζ),3·15 (1H,dd,J = 6.1,13.6 Ηζ),3·66 (1H, dd,J = 6.1,7·9 Hz),7.21-7.29 (2H,m),7·35·7·45 (2H,m), 7.69 (2H,dd,J = 1,6, 4.5 Hz),7.74-7.83 (4H,m)5 8.60 (2H, dd,J = 1.6, 4·6 Hz),9.20-10.80 (1H,br) MS (ESI,m/z) : 352 (M+H) 實施例90 依照類似實施例53的方法獲得下列化合物。 4-氣-N_[4-(4·咐*咬基)苯基]_D-苯基丙胺酿胺 1H-NMR (DMSO-d6) : δ2·7·2·8 (1H,m), 2·95-3·05 (1H, 10 m),3.55-3.6 (1H,m),7.28 (2H,d,J = 8.4 Hz),7.33 (2H,d,J = 8.4 Hz),7·65-7·7 (2H,m),7·76 (2H,d,J = 9.0 Hz), 7.80 (2H, d? J = 9.0 Hz) MS (ESI,m/z) : 352 (M+H) 實施例91 15 依照類似製備物36以及其後實施例53的方法獲得下列 化合物。 3,4-二氯-N-[4-(4-吡啶基)苯基]-D-苯基丙胺醯胺 1H-NMR (DMSO-d6) : δ2·7·2·8 (1H,m),2.95-3.05 (1H, m),3·55·3·6 (1H,m),7.2-7.25 (1H,m),7.55-7.6 (1H,m), * 20 7.65-7.7 (2H,m),7·76 (2H,d,J = 8.8 Hz),7.80 (2H, d,J = 8.8 Hz), 8·55-8·65 (2H,m) MS (ESI,m/z) : 386 (M+H) 實施例92 依照類似實施例53的方法獲得下列化合物。 113 200800899 4-三氟甲基·Ν-[4-(4-艰啶基)苯基]-D-苯基丙胺醯胺 1H-NMR (DMSO-d6) : 51.72-2.28 (1H9 br)5 2.84 (2H9 dd5 J = 8.2, 13.3 Hz),3·11 (1H,dd,J = 5.4, 13.3 Hz),3·63 (1H, dd,J = 5·4, 8.2 Hz),7·49 (2H,d,J = 8.0 Hz),7.65 (2H,d,J = 5 8.0 Hz),7·69 (2H,dd,J = 1.5, 4.4 Hz),7.74-7.83 (4H, m), 8.60 (2H,dd,J = 1.5, 4.4 Hz), 9.30-10.80 (1H,br) MS (ESI,m/z) : 386 (M+H) 實施例93 依照類似實施例53的方法獲得下列化合物。 10 4-甲氧基-Ν-[4-(4-η比啶基)苯基]-D-苯基丙胺醯胺 1H-NMR (DMSO-d6) : 52.65-2.75 (1H? m)? 2.9-3.0 (1H5 m),3·5-3·6 (1H,m),3·71 (3H,s),6·84 (2H,d,J = 8·6 Hz), 7·17 (2H,d,J = 8.6 Hz), 7.65-7.7 (2H,m),7.75-7.85 (4H,m), 8.55-8.65 (2H? m) 15 MS (ESI5 m/z) : 348 (M+H) 實施例94 依照類似實施例5 3的方法獲得下列化合物。 1^_[4_(4-0比唆基)苯基]-3-(2-1[7塞吩基)-〇_丙胺酿胺 1H-NMR (DMSO-d6) : δ3·0-3·08 (1H,m),3.17-3.25 (1H, 20 m),3.56-3.63 (1H,m),6.86-6.96 (2H,m),7·33 (1H,d, J = 4.8 Hz),7.69 (2H,d,J = 4.4 Hz), 7.76-7.82 (4H,m),8·60 (2H,d,J = 6.1 Hz) MS (ESI,m/z) ·· 324 (M+H) 實施例95 114 200800899 依照類似實施例53的方法獲得下列化合物。 N-[4-(4-吼σ定基)苯基]-3-(2-σ塞吩基)-L-丙胺蕴胺 1H-NMR (DMSO-d6) : 53.0-3.08 (1H5 m)? 3.17-3.25 (1H? m),3.56-3.63 (1H,m),6·86_6·96 (2H,m),7.33 (1Η,d,J = 5 4.8 Hz),7.69 (2H,d,J = 4.4 Hz),7.76-7.82 (4H,m),8.60 (2H,d,J = 6.1 Hz) MS (ESI,m/z) : 324 (Μ+Ή) 實施例96 依照類似實施例53的方法獲得下列化合物。 10 定基)苯基]-3·(σ·σ坐-4-基)-L-丙胺酿胺 1H-NMR (DMSO-d6) : 52.92-2.99 (1H? m)? 3.17-3.24 (1H,m),3.73-3.78 (1H,m),7·42 (1H,d,J = 2·0 Hz), 7·66-7·7 (2H,m),7.75-7.5 (4H,m),8.58-8.63 (2H,m) MS (ESI,m/z) : 323 (M+H) 15 實施例97 依照類似實施例53的方法獲得下列化合物。 N-[4-(4-ctb咬基)苯基]-3-(0塞°坐-4_基)-1^-内胺自篮胺 1H-NMR (DMSO-d6) : 52.92-2.99 (1H? m)? 3.17-3.24 (1H,m),3.73-3.78 (1H,m),7.42 (1H,d,J = 2·0 Ηζ),7·66-20 7·7 (2H,m),7·75·7·5 (4H,m),8.58-8.63 (2H,m) MS (ESI,m/z) : 323 (M+H) 實施例98 依照類似實施例53的方法獲得下列化合物。 N- α -甲基-N_[4-(4-吼啶基)苯基]_D-苯基丙胺醯胺 115 200800899 m-NMR (DMSO-C16): δ1.94-2.ΐ3 (1H,br),2 24 (3H,s), 2·83 (1H,dd,J = 7.3, 13.4 Hz), 2.94 (1H,灿】=6 5, 13 4 Hz),3.29-3.41 (1H, m),7.15-7.29 (5H,m),7 68 (2H,dd,】= 1.6,4.4 Hz),7.72-7.80 (4H,m),8.6〇 (2j| 仙 j = i 6 44
Hz)9 9.94-10.10 (1H5 br) MS (ESI,m/z) ·· 332 (M+H) 實施例99
依照類似製備物36的方法獲得下列化人物。 Ν· α,Ν- α -二曱基养㈣4』比啶基)苯基]丄_苯基丙胺 10 醯胺 lH-NMR(DMSO-d6): 62.33 (6H,s))2 83.2.89 (1H,m), 3.03-3.11 (1H,m),3.43-3.48 (1H,m),7 13 718 (m, m), 7.22-7.28 (4H,m), 7.65-7.68 (2H, m),7 7i (2H,山】=9」 Hz),7.76 (2H, d,卜 W Hz), 8.55_8 6 (2h,m),9% (m, 15 brs) MS (ESI,m/z) : 346 (M+H) 實施例100 將甲雜液(37重量%)(0.36毫升)和i〇%㈣催化劑 (200¾克)加入曱醇(1〇毫升)内的N_[4_(4_吡啶基)苯基]_D_ 20苯基丙胺醯胺(280毫克)溶液,然後在室溫下將混合物氫化5 小時。藉由矽藻土墊上的過濾移除催化劑,然後在真空内 条發過渡物。以一異丙鱗磨碎殘留物而產生N- ck,N- J —甲 基-N-[4-(4-吼啶基)苯基]七-苯基丙胺醯胺(95毫克)的白色 粉末。 116 200800899 m-NMR(DMSO-d6) : δ2.39(6Η,s),2.86-2.97(1H,m), 3.02- 3·12(1Η,m),3·47-3·57(1Η,m),7·13-7·29(5Η,m), 7.64-7.73 (4H,m),7·73-7·79(2Η,m),8·56-8·64(2Η,m), 9.96-10.08 (1H,br) 5 MS(ESI5 m/z) : 346(M+H) 實施例101 依照類似實施例53的方法獲得下列化合物。 (3R)-N-[4-(4-吼啶基)苯基]·1,2,3,4-四氫異喹啉-3-甲醯胺 1H-NMR (DMSO-d6): δ2·88 (1Η,dd,J = 10.0, 16.2 Ηζ), 10 3.00 (1Η,dd,J = 4.7, 16.2 Ηζ),3.66 (m,dd,J = 4.7, 10.0
Hz),3·97 (2H,dd,J = 16.6, 20·3 Hz),7.05-7.10 (1H,m), 7.11- 7.18 (3H,m),7.70 (2H, dd,J = 1.6, 4·6 Hz),7·81 (2H,d, J = 8.8 Hz),7·85 (2H,d,J = 8.9 Hz),8.60 (2H,dd,J = 1.6, 4.6 Hz) 15 MS (ESI, m/z) : 330 (M+H) 實施例102 依照類似實施例53的方法獲得下列化合物。 (3S)-N-[4_(4-吼啶基)苯基]_1,2,3,4_四氫異喹啉-3-甲醯胺 1H-NMR (DMSO-d6): δ2·88 (1H,dd,J = 10.0, 16.2 Hz), 20 3·00 (1H,dd,J = 4.7, 16·2 Ηζ),3·66 (1H,dd,J = 4.7, 10.0
Hz),3·97 (2H,dd,J = 16.6, 20.3 Hz),7.05-7.10 (1H,m), 7.11- 7.18 (3H,m),7·70 (2H,dd,J = 1.6, 4.6 Hz), 7.81 (2H,d, J = 8.8 Hz),7.85 (2H,d,J = 8.9 Hz),8.60 (2H,dd,J = 1.6, 4.6 Hz),10.12 (1H,s) 117 200800899 MS (ESI,m/z) : 330 (M+H) 實施例103 在5C下將異氣酸二氯乙酸醋(261毫克)逐滴加入二氯 甲烷(24毫升)内的N-[4-(4-吡啶基)苯基]-D-苯基丙胺醯胺 5 (400毫克)溶液’然後在相同溫度下將混合物攪拌1小時。在 真空内蒸發混合物然後以己烷磨碎殘留物而獲得N-[4-(4-吼啶基)苯基]-Ν-α ·[(三氯乙醯基)胺甲醯基]苯基丙胺醯 胺的粗產物。將該粗產物溶解於甲醇(2〇毫升)内然後加入矽 膠(10克)。在室溫下將混合物攪拌20小時然後在真空内蒸 10 發。利用矽膠管柱層析法純化殘留物以及從乙醇再結晶而 獲得Ν_ α -胺甲酸基_1^-[4-(4-°比咬基)苯基]_D-苯基丙胺醯 胺(287毫克)的白色結晶。 1H-NMR (DMSO-d6): δ2.8-2.87 (1H,m),2.92-3.04 (1H, m),4·52-4·60 (1H,m),5.63 (2H,brs),6.35 (1H,d,J 二 8·4 15 Hz),7·17-7·3 (4H,m),7·67-7·82 (6H,m),8.56-8.63 (2H,m), 10.28 (1H? brs) MS (ESI,m/z) : 360 (M+H) 實施例104 依照類似實施例53的方法獲得下列化合物。 20 Ν-[4·(4-σΛ唆基)苯基]-D-色胺醯胺 1H-NMR (DMSO-d6) : δ2·87-2·94 (1Η,in),3.13-3.19 (1Η,m),3·63·3·69 (1Η,m),6·94·6·99 (1Η,m),7·03-7·〇8 (1H,m),7·18 (1H,d,J = 2.3 Hz),7.33 (1H,d,J 二 8·2 Hz), 7.60 (1H,d,J = 7.9 Hz),7.67-7.71 (2H,m),7.76-7.82 (4H, 118 200800899 m),8·57-8·62 (2H,m),10.85 (1H,brs) MS (ESI,m/z) : 357 (M+H) 實施例105 依照類似實施例53的方法獲得下列化合物。 5 3 -(1-苯弁嗟吩-3 -基)-N- [4-(4-π比咬基)苯基]-D-丙胺酿胺 1H-NMR (DMSO-d6) : δ2·98-3·05 (1Η,m),3.28-3.35 (1H,m),3.72-3.77 (1H,m),7.33-7.44 (2H,m),7.52 (1H,s), 7·67·7·71 (2H,m),7·76·7·82 (4H,m),8.58-8·62 (2H,m) MS (ESI,m/z) : 374 (M+H) 10 實施例106 依照類似製備物36以及其後實施例53的方法獲得下列 化合物。 (2R)-2-胺基-4-苯基-N-[4-(4-u比啶基)苯基]丁醯胺 1H-NMR (DMSO-d6): δ1·68·1·8 (1H,m),1.92-2.02 (1H, 15 m),2.6-2.8 (2H,m),7.14-7.31 (3H,m),7.67-7.72 (2H,m), 7.9-8.02 (4H,m),8.58-8.62 (2H,m) MS (ESI,m/z) : 332 (M+H) 實施例107 依照類似製備物36以及其後實施例53的方法獲得下列 20 化合物。 (3R)-3·胺基-4-苯基-Ν·[4-(4-吼啶基)苯基]丁醯胺 1H-NMR (DMSO-d6) : 82.23-2.31 (1H5 m)? 2.38-2.43 (1H,m),2.6-2.75 (2H,m),7.19-7.34 (2H,m),7·64-7·68 (2H, m),7.73 (2H,d,J = 8.9 Hz),7.78 (2H,s,J = 8·9 Hz), 119 200800899 5 8.57-8.62 (2H,m),10·32 (1H,brs) MS (ESI,m/z) : 332 (M+H) 實施例108 依照類似實施例53的方法獲得下列化合物。 (2R)-2-胺基-2-苯基-N-[4-(4-吼啶基)苯基]乙醯胺 1H-NMR (DMSO-d6) : 54.57 (1H? s)? 7.24-7.29 (1H? m)? 7.34 (2H,t,J = 7·3 Hz),7.49 (2H,d,J = 7.3 Hz), 7·68 (2H, dd5 J = 1.6, 4.6 Hz),7·79 (4H,t,J = 9.5 Hz),8.59 (2H, dd,J =1.6? 4.6 Hz) 10 MS (ESI,m/z) : 304 (M+H) 實施例109 依照類似實施例53的方法獲得下列化合物。 (2S)-2-胺基-2-苯基·Ν-[4-(4-吼啶基)苯基]乙醯胺 1H-NMR (DMSO-d6) : 84.57 (1H? s)? 7.24-7.29 (1H? m)5 15 7·34 (2H,t,J = 7.3 Hz),7.49 (2H,d,J = 7.3 Hz),7·68 (2H, dd,J = 1.6, 4.6 Hz),7.79 (4H,t,J = 9.5 Hz),8.59 (2H,dd,J =1.6, 4.6 Hz) MS (ESI,m/z) : 304 (M+H) 實施例110 " 20 依照類似實施例53的方法獲得下列化合物。 (2S)-2-胺基-2-(2-氯苯基)-N-[4-(4-吼啶基)苯基]乙醯胺 1H-NMR (DMSO-d6): δ4·89 (1H,s),7.28-7.38 (2H,m), 7.44 (1H,dd,J = 1.7, 7·6 Ηζ),7·56 (1H,dd,J = 1·9, 7.5 Hz), 7.69 (2H,dd,J = 1.6, 4·6 Hz),7·82 (4H,td,J = 2.5, 9.2 Hz), 120 200800899 8.60 (2H,dd,J= 1·6,4.6Ηζ) MS (ESI,m/z) : 338 (M+H) 實施例111 依照類似實施例5 3的方法獲得下列化合物。 5 2-胺基-2-(2-亂笨基)-1^-[4-(4-|7比11定基)苯基]乙酿胺
1H-NMR (DMSO-d6): δ4·79 (1H,s),7.14-7.23 (2H,m), 7.29-7.37 (1H,m),7.53 (1H,td,J = 1.7, 7·6 Hz), 7·69 (2H, dd,J = 1.6, 4.5 Hz),7·81 (4H,t,J = 9·8 Hz),8.60 (2H,dd,J ⑩ =1.6, 4.5 Hz) 10 MS (ESI,m/z) ·· 322 (M+H) 實施例112 依照類似實施例53的方法獲得下列化合物。 (2S)-2-胺基-N-[4-(4-』比啶基)苯基]-2-[2-(三氟甲基)苯 基]乙醯胺 15 1H-NMR (DMSO-d6): δ4·87 (1H,s),7·50 (1H,t,J = 7.5
Hz),7.66-7.73 (4H,m),7.76-7.86 (5H,m),8·60 (2H,dd,J = 1·6, 4.6 Hz) MS (ESI,m/z) : 372 (M+H) 實施例113 _ 20 依照類似實施例53的方法獲得下列化合物。 , 2-胺基-2_(2-甲氧苯基)-N-[4-(4-吼啶基)苯基]乙醯胺 1H-NMR (DMSO-d6) : 53.79 (3H5 s)? 4.74 (1H9 s)? 6.93 (1H,td,J = 0.9, 7.4 Hz),7.00 (2H,d,J = 7.5 Hz),7.26 (1H, td,J = 1.7, 7.8 Hz),7.34 (1H,dd,J = 1.7, 7.5 Hz),7·69 (2H, 121 200800899 5 dd,J = 1.6, 4.6 Hz),7.81 (4H,dd,J = 9.0, 14.2 Hz),8.59 (2H, dd,J= 1·6,4·6Ηζ) MS (ESI,m/z) : 334 (M+H) 實施例114 依照類似實施例53的方法獲得下列化合物。 (2S)-2-胺基-2-(4-氟苯基)-N-[4-(4-u比啶基)苯基]乙醯胺 1H-NMR (DMSO-d6) : 54.58 (1H9 s)? 7.17 (2H, t? J = 8.8 Hz),7·53 (2H,dd,J = 5.6, 8.8 Hz),7.68 (2H,dd,J = 1.6, 4.6 Hz),7.93 (4H,s),8·59 (2H,dd,J = 1.6, 4.6 Hz) 10 MS (ESI,m/z) : 322 (M+H) 實施例115 依照類似實施例53的方法獲得下列化合物。 2·胺基-2-(2-呋喃基)-N-[4-(4吼啶基)苯基]乙醯胺 1H-NMR (DMSO-d6) : δ8·60 (2H,d,J = 6.1 Hz),7.80 15 • (4H,s),7.69 (2H,d,J = 6.1 Hz),7.59 (1H,s),6.41 (1H,dd,J =1.8, 3.2 Hz),6.34 (1H,d,J = 3.2 Hz),4.61 (1H,s) MS (ESI,m/z) : 316 (M+Na) 實施例116 依照類似實施例53的方法獲得下列化合物。 . 20 (2S)-2-胺基-Ν-[4-(4-σ比ϋ定基)苯基]-2-(2-σ塞吩基)乙酿胺 1H-NMR (DMSO-d6) : δ4·79 (1Η,s),6.97 (1Η,dd,J = 5.0, 3·4 Ηζ),7·07 (1H,d,J = 3·4 Ηζ),7·41 (1H,dd,J = 5.0, 1.0 Hz),7.67-7.7 (2H,m),7.78-7.83 (4H,m),8.58-8.62 (2H,m) MS (ESI,m/z) : 310 (M+H) 122 200800899 9 5 • 實施例117 依照類似製備物37的方法獲得下列化合物。 (2R)-2-嗎啉-4-基-3-苯基-N-[4-(4-吼啶基)苯基]丙醯胺 1H-NMR (DMSO-d6): δ2·58-2·72 (4H,m),2.89 (1H,dd, J = 4.9, 13·0 Hz),3·10 (1H,dd,J = 9.8, 13·0 Hz),3·50 (1H,q, J = 4.9 Hz),3.58 (4H,br),7.13-7.19 (1H,m),7.22-7.27 (4Ή, m),7.67 (2H,dd,J = 1.7, 4.5 Hz),7.70 (2H,d,J = 8.9 Hz), 7.76 (2H,d,J = 8·9 Hz),8.59 (2H,dd,J = 1.7, 4.5 Hz),10.00 (1H,s) 10 MS (ESI,m/z) : 388 (M+H) 實施例118 依照類似製備物37的方法獲得下列化合物。 (2S)-2-嗎啉-4-基-3-苯基-Ν-[4·(4-吼啶基)苯基]丙醯胺 1H-NMR (DMSO-d6):52.58-2.72 (4Η,m),2.89 (1Η,dd, 15 J = 4.9, 13.0 Hz),3.10 (1H,dd,J = 9.8, 13.0 Hz),3.50 (1H,q, • J = 4.9 Hz),3.58 (4H,bT),7·13»7.19 (1H,m),7.22-7.27 (4H, m),7.67 (2H,dd,J = 1.7, 4.5 Hz),7.70 (2H,d,J = 8.9 Hz), 7·76 (2H,d,J = 8.9 Hz),8.59 (2H,dd,J 二 1.7, 4.5 Hz),10.00 (1H,s) - 20 MS (ESI,m/z) : 388 (M+H) 實施例119 依照類似製備物36的方法獲得下列化合物。 2-嗎琳-4-基-2-苯基定基)苯基]乙酿胺 1H-NMR (DMSO-d6) : 82.35-2.47 (4H? m)5 3.58-3.77 123 200800899 5 (4H,m),4.03 (1H,s),7.29-7.34 (1H,m),7.35-7.40 (2H,m), 7.54 (1H,d,J = 7.0 Hz),7.66-7.69 (2H,m),7.76-7.8 (4H,m), 8.58-8.62 (2H,m),10.32 (1H,s) MS (ESI,m/z) : 374 (M+H) 實施例120 依照類似製備物37的方法獲得下列化合物。 2-(4-¾基娘σ定-1-基)-3-苯基-Ν-[4-(4-ϋ比σ定基)苯基]丙酿胺 1H-NMR (DMSO-d6) : δΐ.33-1.42 (2Η, m)9 1.66-1.78 (2H,m),2.3-2.42 (2H,m),2.8-2.96 (3H,m),3.06-3.16 (1H, 10 m),3·37-3·44 (1H,m),3·45·3·55 (1H,m),4.53 (1H,d,J = 4.1 Hz),7.12-7.18 (1H,m),7.21-7.26 (4H,m),7.64-7.66 (2H, m),7.71(2H,d,J = 8.9Hz),7.76(2H,d,J = 8.9Hz),8.58-8·62 (2H,m),9·94 (1H,brs) MS (ESI,m/z) : 402 (M+H) 15 實施例121 依照類似製備物36的方法獲得下列化合物。 2-(4_羥基哌啶-1-基)-2-苯基-N-[4-(4-吡啶基)苯基]乙醯胺 iH-NMR (DMSO-d6) : 51.4-1.52 (2H? m)5 1.66-1.78 (2H? m),1·98·2·08 (1H,m),2.15-2.22 (1H,m),2.55-2.63 (1H,m), • 20 % 2.7-2.78 (1H,m),3.42-3.52 (1H,m),4.02-4.06 (1H,m),4.58 (1H,dd,J = 4.0 Hz),7.26-7.39 (4H,m),7.45-7.52 (2H,m), 7.64-7.68 (2H,m),7.76-7.81 (3H,m),8.58-8.62 (2H,m), 10.24 (1H5 brs) MS (ESI,m/z) : 388 (M+H) 124 200800899 實施例122 依照類似製備物36的方法獲得下列化合物。 2-(1,1-二氧化硫嗎啉-4-基)-2-苯基-N-[4-(4-吼啶基)苯 基]乙醯胺 5 1H-NMR (DMSO-d6) : 82.84-2.94 (2H? m)9 2.96-3.06 (2H,m),3.11-3.27 (4H,m),4.55 (1H,s),7.32」7·57 (5H,m), 7·69 (2H,d,J = 6.2 Hz),7.78-7.84 (4H,m),8.60 (2H,d,J = 6.1 Hz),10.33 (1H,brs) MS (ESI,m/z) : 422 (M+H) 10 實施例123 依照類似製備物37的方法獲得下列化合物。· Ν-[4·(4-吼啶基)苯基]-N-α ·(四氫-2H-吼喃-4·基)-D-苯 基丙胺醯胺 1H-NMR (DMSO-d6) : δΙ.1-1.32 (2Η, m)9 1.6-1.75 (2H9 15 m),2.1-2.22 (1H,m),2.5-2.6 (1H,m),2.79-2.98 (2H,m), 3.15- 3.28 (2H,m),3.56-3.63 (1H,m),3.7-3.78 (2H,m), 7.15- 7.22 (1H,m),7.24-7.28 (4H,m),7.66-7.69 (2H,m), 7·72 (2H,d,J = 8.8 Hz),7·78 (2H,d,J = 8.8 Hz),8.58-8.62 (2H,m),10.03 (1H,brs) 20 MS (ESI,m/z) : 402 (M+H) 實施例124 依照類似製備物36以及其後實施例53的方法獲得下列 化合物。 己基-N-[4-(4-0ttσ定基)苯基]-D-丙胺酿胺 125 200800899 1H-NMR (DMSO-d6) : δ0.79-1.00 (2H,m),1.06-1.38 (4H,m),1.39-1.84 (7H,m),3.35-3.42 (1H,m),7.66-7.71 (2H,m),7.76 -7·81 (4H,m),8.56-8.62 (2H,m) MS (ESI,m/z) : 324 (M+H) 5 實施例125 依照類似製備物36以及其後實施例53的方法獲得下列 化合物。 (2R)-2-胺基-2-J哀己基定基)苯基]乙酿胺 1H-NMR (DMSO-d6) : δ0.96-1.28 (5H,m),1.49-1.64 10 (3H,m),1.65-1.78 (3H,m),3·13 (1H, d,J = 5·6 Ηζ),7·68 (2H,dd,J = 1.6, 4.6 Hz),7.75-7.83 (4H,m),8.59 (2H,dd,J = 1.6, 4.6 Hz) MS (ESI,m/z) : 310 (M+H) 實施例126 15 依照類似製備物36以及其後實施例53的方法獲得下列 化合物。 (2S)-2-胺基-2-環己基-N-[4-(4-啦啶基)苯基]乙醯胺 1H-NMR (DMSO-d6) : 50.95-1.29 (5H9 m)? 1.49-1.64 (3H,m),1.65-1.80 (3H,m),3.13 (1H,d,J = 5.6 Hz),7.68 20 (2H,dd,J = 1.6, 4.6 Hz),7.74-7.84 (4H,m),8.59 (2H,dd,J = 1.6, 4.6 Hz) MS (ESI,m/z) : 310 (M+H) 實施例127 依照類似製備物36的方法獲得下列化合物。 126 200800899 (2化)-2-經基-3 -苯基-N-[4-(4-0tb ϋ定基)苯基]丙酿胺 1H-NMR (DMSO-d6) : δ2·86 (1Η,dd,J = 8.2, 13.6 Ηζ), 3·08 (m,dd,J = 4.2, 13·6 Ηζ),4.28 (1Η,br),5.90 (m,s), 7J4-7.31 (5H,m),7·69 (2H,d,J = 6.1 Hz),7·78 (2H,d,J = 5 8.9 Hz),7.86 (2H,d,J = 8.8 Hz), 8.60 (2H,d,J = 6·2 Hz), 9.91 (1H,s) MS (ESI,m/z) : 319 (M+H) 實施例128 依照類似製備物36的方法獲得下列化合物。 10 (2S)-2-羥基-3-苯基-N-[4-(4-吼啶基)苯基]丙醯胺 1H-NMR (DMSO-d6) : δ2·86 (1H,dd,J = 8.2, 13.6 Hz), 3·08 (1H,dd,J = 4.2, 13.6 Hz),4.28 (1H,br),5·90 (1H,s), 7.14-7.31 (5H,m),7·69 (2H,d,J = 6.1 Hz),7.78 (2H,d,J = 8·9 Hz),7·86 (2H,d,J = 8.8 Hz),8.60 (2H, d,J = 6.2 Hz), 15 9.91 (m,s) MS (ESI,m/z) ·· 319 (M+H) 實施例129 依照類似製備物36的方法獲得下列化合物。 (2R)-2-羥基-2-苯基-N-[4-(4-吼啶基)苯基]乙醯胺 20 lH-NMR(DMSO-d6):85.14(lH,s),6.51(lH,s),7.28- 7·33 (1H,m),7.34-7.40 (2H,m),7·52·7·56 (2H,m),7·69 (2H, dd,J = 1.6, 4·5 Hz),7.79 (2H,d,J = 8·8 Hz),7·89 (2H,d,J = 8.8 Hz),8.60 (2H,dd,J = 1.6, 4.5 Hz),10.15 (1H,s) MS(ESI,m/z) : 327(M+Na) 127 200800899 實施例130 依照類似製備物36的方法獲得下列化合物。 (28)-2-經基-2-苯基-^^-[4-(4-11比咬基)苯基]乙酿胺 1H-NMR (DMSO-d6) : δ5·14 (1H,s),6.51 (1H,s),7.28-5 7.33 (1Η,m),7·34·7·40 (2Η,m),7.52-7.56 (2Η,m),7.69 (2Η, dd,J = 1.6, 4·5 Hz),7.79 (2H,d,J = 8·8 Hz),7.89 (2H,d,J = 8.8 Hz),8.60 (2H,dd,J = 1.6, 4.5 Hz),10.15 (1H,s) MS(ESI,m/z) : 327(M+Na) 實施例131 10 依照類似實施例53的方法獲得下对化合物。 N-3,4’-二ϋ比°定-6-基-L-苯基丙胺酿胺 1H-NMR (DMSO-d6) ·· δ2·6-2·8 (1Η,m),3.0-3.15 (1Η, m),7.1-7.3 (5H,m),7.75-7.85 (2H,m),8.6-8.7 (2H,m),8.81 (1H? s) 15 MS (ESI,m/z):無資料 實施例132 依照類似實施例53的方法獲得下列化合物。 N-3,4’-二17比定-6-基-D-苯基丙胺酿胺 1H-NMR (DMSO-d6) ·· δ2·76 (1H,dd,J = 8.3, 13.4 Hz), 20 3·06 (1H,dd,J = 5.2, 13·4 Hz),3.76 (1H,dd,J = 5.2, 8·3 Hz), 7·15·7·23 (1H,m),7.23讓7·31 (4H,m),7.76 (2H,dd,J = 1.6, 4.5 Hz),8·19-8·31 (2H, m),8.63 (2H,dd,J = 1.6, 4.5 Hz), 8·76·8·72 (1H,m) MS (ESI,m/z) : 319 (M+H) 128 200800899 5 實施例133 依照類似實施例53的方法獲得下列化合物。 Ν-2,4’-二°比ϋ定-5-基-L-本基丙胺酿胺 1H_NMR (DMSO-d6) : δ2·76 (1Η, dd,J = 7.9, 13·4 Ηζ), 3·03 (1Η,dd,J = 5·6, 13.4 Ηζ),3·64 (1Η,dd,J = 5.6, 7.9 Ηζ), 7.12-7.38 (5H,m),8.01 (2H,dd,J = 1.6, 4·6 Hz),8.10 (1H,d, J = 8·6 Hz),8·26 (1H,dd,J = 2.5, 8.6 Hz),8.66 (2H,dd,J = 1.6, 4.6 Hz),8.91 (1H,d,J = 2.5 Hz) MS (ESI,m/z) : 319 (M+H) 10 實施例134 依照類似實施例53的方法獲得下列化合物。 N-2,4’ -二ϋ比°定-5-基^ -D -本基> 丙;^酿胺 1H-NMR (DMSO-d6) ·· δ2·78 (1Η,dd,J = 7.9, 13.4 Ηζ), 3.03 (1Η,dd,J = 5.6, 13.4 Ηζ),3.64 (1Η,dd,J = 5.6, 7·9 Ηζ), 15 7.17-7.23 (1H,m),7.23-7.33 (4H,m),8·01 (2H,dd,J = 1.6, 4.6 Hz),8.08-8.13 (1H,m), 8.25 (1H,dd,J = 2.6, 8.8 Hz), 8.66 (2H,dd,J = 1.6, 4.6 Hz),8.88-8.93 (1H,m) MS (ESI? m/z) : 319 (M+H) 實施例135 - 20 依照類似實施例53的方法獲得下列化合物。 N_[4-(3-氣13比咬_4-基)苯基]-D_苯基丙胺酿胺 1H-NMR (DMSO-d6) : 53.1-3.27 (4H? m)? 4.3-4.4 (1H9 m),7.23-7.36 (4H,m),7.69-7.81 (4H,m),8.45-8.52 (2H,m), 8.55 (1H,d, J = 5.1 Hz),8·75(1Η,d,J = 3.0 Hz) 129 200800899 MS (ESI,m/z) : 335 (M+H) 實施例136 依照類似製備物36以及其後實施例53的方法獲得下列 化合物。 5 Ν·(2·甲基-4-11比。定-4-基苯基)-D-苯基丙胺酿基 1H-NMR (DMSO-d6) : 53.1-3.27 (2H5 m)5 4.3-4.4 (1H? m),7.23-7.36 (4H,m),7.69-7.81 (4H,m),8·45-8·52 (2Ή,m), 8·55 (1H,d,J = 5.1 Hz),8·75 (1H,d,J = 3.0 Hz) MS (ESI, m/z) : 335 (M+H) 10 實施例137 依照類似實施例53的方法獲得下列化合物。 N-[4_(2-胺基吻°定-4-基)苯基]-D-苯基丙胺酿胺 1H-NMR (DMSO-d6) : δ2·74 (1H,dd,J = 13.5, 8·0 Hz), 3·02 (1H,dd,J = 13.5, 5.5 Hz),3.60 (1H,dd,J = 7.8, 5·5 Hz), 15 6.59 (2H,s),7.08 (1H,d,J = 5.1 Hz),7.17-7.30 (5H,m), 7·73 (2H,d,J = 8.8 Hz),8.03 (2H,dd,J = 8.8 Hz),8·23 (1H, d? J = 5.0 Hz) MS (ESI,m/z) : 334 (M+H) 實施例138 20 依照類似實施例53的方法獲得下列化合物。 N-[4_(2-胺基ΰ密咬-4-基)苯基]-4-氣-D-苯基丙胺酿胺 1H-NMR (DMSO-d6) : δ2·73 (1Η,dd,J = 8.0, 13.5 Ηζ), 2·99 (1Η,dd,J = 5·5, 13·5 Ηζ),3·56 (1Η,dd,J = 5.5, 8.0 Ηζ), 6·59 (2H,s),7.07-7.11 (3H,m),7.26-7.30 (2H,m),7.73 (2H,d, 130 200800899 J = 8·8 Ηζ),8·03 (2H,d,J = 8.8 Hz), 8.26 (1H,d,J = 5.4 Hz) MS (ESI,m/z) : 352 (M+H) 實施例139 依照類似製備物36以及其後實施例53的方法獲得下列 5 化合物。 N-[4-(2-胺基,唆-4-基)苯基]-3-氣-D-苯基丙胺酿胺 1H-NMR (DMSO-d6) : 62.76 (IH5 dd5 J = 8.2? 13.5 Πζ)5 3·03 (1H, dd,J = 5.3, 13·5 Hz), 3.60 (m,dd,J = 5.3, 8.2 Hz), 6.59 (2H,s),6.99-7.04 (1H,m),7.07-7.13 (3H,m),7.28-7.34 10 (1H,m),7·73 (2H,d,J = 8.8 Hz),8.04 (2H,d,J = 8.8 Hz), 8.27(lH,d,J = 5.0Hz) MS (ESI,m/z) : 352 (M+H) 實施例140 依照類似製備物36以及其後實施例53的方法獲得下列 15 化合物。 N-[4-(2-胺基0密ϋ定-4-基)苯基]-2 -亂-D-苯基丙胺酸胺 1H-NMR (DMSO-d6) : δ2·80 (1Η,dd,J = 8.0, 13.6 Ηζ), 3·03 (1H,dd,J = 6·0, 13·6 Hz),3·61 (1H,dd,J = 6.0, 8.0 Hz), 6·59 (2H,s),7.07-7.15 (1H,m),7.22-7.28 (1H,m),7.31-7.35 20 (1H,m),7·72 (2H,d,J = 8.8 Hz),8.03 (2H,d,J = 8.8 Hz), 8.26(lH,d,J = 5.3Hz) MS (ESI,m/z) : 352 (M+H) 實施例141 依照類似實施例53的方法獲得下列化合物。 131 200800899 N-[4-(2胺基♦唆-々-基)苯基]-4-鼠-D-苯基丙胺酿胺 1H-NMR (DMSO-d6) : 52.73 (1H5 dd? J = 8.2? 13.5 Hz)? 2.99 (1H,dd,J = 5.5, 13.5 Hz),3.55-3.59 (1H,m),6·59 (2H, s),7·08 (1H,d,J = 5.4 Hz),7.26-7.34 (4H,m),7.72 (2H,d,J 5 = 8.8 Hz),8.03 (2H,d,J = 8.8 Hz)、8·26 (1H,d,J = 5.3 Hz) MS (ESI,m/z) : 368 (M+H) 實施例142 依照類似實施例53的方法獲得下列化合物。 N-[4-(2-胺基嘧啶-4-基)苯基]-0-甲基_D-酪胺酸醯胺 10 1H-NMR (DMSO_d6) : δ2·68 (1H,dd,J = 7.8, 13·5 Hz), 2·95 (1H,dd,J = 5.6, 13·5 Ηζ),3·54 (1H,dd,J = 5.6, 7·8 Hz), 3.71 (3H,s), 6·59 (2H,s),6·84 (2H,d,J = 8.7 Hz),7.08 (1H, d,J = 5·3 Hz),7.16 (2H,d,J = 8·6 Hz),7·74 (2H,d,J = 8.8 Hz),8.03 (2H,d,J = 8·8 Hz),8·26 (1H,d,J = 5.3 Hz) 15 MS (ESI,m/z) : 364 (M+H) 實施例143 依照類似實施例53的方法獲得下列化合物。 (2R)_N_[4-(2-胺基嘧啶-4-基)苯基]-2-嗎啉-4-基-3-苯基 丙醯胺 20 1H-NMR (DMSO_d6) : δ2·68 (1H,dd,J = 7.8, 13.5 Hz), 2.95 (1H,dd,J = 5.6, 13.5 Hz),3.54 (1H,dd,J = 5.6, 7.8 Hz), 3.71 (3H,s),6·59 (2H,s),6.84 (2H,d,J = 8.7 Hz),7.08 (1H, d,J = 5.3 Hz),7.16 (2H,d,J = 8.6 Hz),7.74 (2H,d,J = 8.8 Hz),8.03 (2H,d,J = 8.8 Hz),8.26 (1H,d,J = 5.3 Hz) 132 200800899 MS (ESI,m/z) : 364 (M+H) 實施例144 依照類似製備物36以及其後實施例53的方法獲得下列 化合物。 5 N- [4-(2-胺基嘧啶-4-基)苯基]_2-(4-羥基哌啶-1 -基)-2- 苯基乙醯胺 1H-NMR (DMSO-d6): δ2.63-2.67 (4H,m),2·89 (1H,dd, J = 5.0, 13.2 Hz),3.10 (1H,dd,J = 9.7, 13.2 Hz),3.51 (1H, dd,J = 5.0, 9.7 Hz),3.56-3.59 (4H,m),6·60 (2H, s),7.06 10 (1H,d,J = 5.3 Hz),7.13-7.19 (1H,m),7·24-7·25 (4H,m), 7.67 (2H,d,J = 8.9 Hz),8.01 (2H,d,J = 8·8 Hz),8·26 (1H,d, J = 5.2 Hz),10.02 (1H,br) MS (ESI,m/z) : 404 (M+H) 實施例145 15 依照類似製備物36以及其後實施例53的方法獲得下列 化合物。 N-[4-(4-吼啶基)苯基]-D-纈胺酸醯胺 1H-NMR (DMSO-d6) : δ0·87 (3H, d,J = 6.8 Hz),0.94 (3H,d,J = 6·8 Hz),1.95 (1H,septet,J = 6.8 Ηζ),3·14 (IH,d, 20 J = 5.5 Hz),7·69 (2H,dd,J = 4.5, 1.6 Hz),7·76-7·83 (4H,m), 8.60(2H,dd,J = 4.5, 1.6 Hz) MS(ESI, m/z) : 270(M+H) 實施例146 依照類似製備物36以及其後實施例53的方法獲得下列 133 200800899 化合物。 Ν·[4-(4-吼啶基)苯基]-D-亮胺酸醯胺 1H-NMR (DMSO-d6) : δ0·89 (3Η,d,J = 6.6 Ηζ),0.92 (3Η, d,J = 6.6 Hz),1.3-1.38 (1Η,m),1.45-1.53 (1Η,m), • 5 1.76 (1H,septet, J = 6.6 Hz),3.32-3.38 (1H,m),7.69 (2H,dd, J = 4.6, 1.6 Hz),7.77-7.83 (4H,m),8·60 (2H,dd,J = 4.6, 1.6 Hz) MS (ESI,m/z) : 284 (M+H) • 實施例147 10 依照類似實施例53的方法獲得下列化合物。 4_氣基-N-[4-(4-^比11定基)苯基]-D-苯基丙胺酿胺 1H-NMR (DMSO-d6) : δ2·84 (1H,dd,J = 13.4, 8.2 Hz), 3.09 (1H,dd,J = 13.4, 5·3 Ηζ),3·64 (1H,dd,J = 8.2, 5·3 Hz), 7.47 (2H,d,J = 8.2 Hz),7.66-7.71 (2H,m),7.72-7.82 (6H, 15 m)5 8.57-8.63 (2H? m) MS (ESI,m/z) : 343 (M+H) • 實施例148 依照類似實施例53的方法獲得下列化合物。 N-[4-(4-吡啶基)苯基]-D-酪胺酸醯胺 . 20 1H-NMR (DMSO-d6) : δ2·64 (1H, dd,J = 13.5, 7·8 Hz), . 2.89 (1H,dd,J = 13.5, 5.6 Hz),3.52 (1H,dd,J = 7.6, 5·7 Hz), 6.66 (2H,d,J = 8.4 Hz),7.03 (2H,d,J = 8·4 Hz),7.67-7.70 (2H,m),7.74-7.81 (4H,m),8.57-8.62 (2H,m),9.15 (1H,s) MS (ESI,m/z) : 334 (M+H) 134 200800899 5 實施例149 依照類似實施例53的方法獲得下列化合物。 4-石肖基比σ定基)苯基]-D-苯基丙胺酿胺 1H-NMR (DMSO-d6) : 63.25-3.33 (1H5 m)5 3.42-3.50 (1H,m),4.48-4.56 (1H,m),7·70 (2H,d,J = 8.7 Ηζ),7·89 (2H,d,J = 8.8 Hz),8.07 (2H,d,J = 8·7 Hz),8·21 (2H,d,J = 8.7 Hz),8.31 (2H,d,J = 6.7 Hz),8.55 (3H,brs),8·89 (2H,d, • J = 6.7 Hz),11.72 (lH,brs) MS (ESI, m/z) : 334 (M+H) 10 實施例150 依照類似實施例53的方法獲得下列化合物。 (2R)-1 -氧代-3-笨基-1 -(5-°比σ定-4-基·2,3-二鼠-1H-0引 口朵 -1-基)丙-2-胺二鹽酸鹽 1H-NMR (DMSO-d6) : 82.86-2.97 (1H5 m)5 3.10-3.30 15 (3H,m),3.45-3.55 (1H,m),4.23-4.33 (1H,m),4.44-4.56 (1H,br),7·23-7·35 (5H,m),7.93-7.99 (2H,m),8.20-8.26 (1H,m),8.28-8.34 (2H,rn),8.57-8.80 (3H,br),8.87-8.92 (2H,m) MS (ESI,m/z) : 344 (M+H) Λ 20 實施例151 依照類似實施例53的方法獲得下列化合物。 4-{l-[(2S)-2_胺基-3·苯基丙醯基]_2,3_二氫-1H-吲哚-5-基},σ定-2-胺 1H-NMR (DMSO-d6) : 82.65-2.76 (1H? m)9 2.93-2.99 135 200800899 (1H,m),3.01-3.21 (2H,m),3·76-3·84 (m,m),3.85-3.95 (1H,m),4.22-4.34 (1H,m),6.58 (2H,brs),7.07 (1H,d,J = 5·3 Hz),7.14-7.30 (5H,m),7.89-7.97 (2H,m),8.15-8.21 (1H, m),8.25 (1H,d,J = 5.3 Hz) 5 MS (ESI,m/z) : 360 (M+H) 實施例152 依照類似實施例53的方法獲得下列化合物。 4-{l_[(2R)-2-胺基-3-苯基丙醯基]_2,3-二氫-1H-吲哚-5-基}續。定-2-胺 10 iH-NMR (DMSO-d6) : 52.65-2.76 (1H, m)? 2.93-2.99 (1H,m),3·01·3·21 PH,m),3.76-3.84 (1H,m),3.85-3.95 (1H,m),4.22-4.34 (1H,m),6·58 (2H,brs),7.07 (1H,d,J = 5.3 Hz),7.14-7.30 (5H,m),7.89-7.97 (2H,m),8.15-8.21 (1H, m),8.25(lH,d,J = 5.3 Hz) 15 MS (ESI,m/z) : 360 (M+H) 實施例153 依照類似實施例53的方法獲得下列化合物。 (2S)-2-胺基-N-[4-(2-胺基嘧啶-4-基)苯基]-2-笨基乙醯胺 IH-NMR (DMSO-d6) : δ4·56 (1H,s),6·60 (2H,s),7.07 20 (m,d,J = 5.3 Hz),7.24-7.28 (m,m),7·32-7·36 (2Η,m), 7.47-7.50 (2H,m),7·76 (2H,d,J = 8·7 Hz), 8.03 (2H,d,J = 8.8 Hz),8·26 (1H,d,J = 5.1 Hz) MS (ESI,m/z) : 320 (M+H) 實施例154 136 200800899 依照類似實施例53的方法獲得下列化合物。 (2R)-2-胺基-N-[4-(2-胺基嘧啶-4-基)苯基]-2-苯基乙醯胺 1H-NMR (DMSO-d6) ·· δ4·56 (1H,s),6.58 (2H,s),7.07 (1Η,d,J = 5·3 Ηζ),7·24-7·28 (1Η, m),7.32-7.36 (2Η,m), 5 7.47-7.50 (2H,m),7·76 (2H,d,J = 8.8 Hz),8.03 (2H, d,J = 8.8 Hz), 8·26 (1H,d,J = 5·2Ηζ) MS (ESI,m/z) : 320 (M+H) 實施例155 依照類似實施例53的方法獲得下列化合物。 10 (2S)-2-胺基-N-[4-(2-胺基嘧啶-4-基)苯基]-2-(2-噻吩基) 乙醯胺 1H-NMR (DMSO-d6) : δ4·79 (1H,br),6·60 (2H,s),6.97 ’(1H,dd,J = 3.4, 4.9 Hz),7.06-7.09 (2H,m),7·41 (1H,dd,J = 1.3, 5.0 Hz), 7·76 (2H, d, J = 8.8 Hz),8.05 (2H,d,J = 8.8 15 Hz),8.27 (1H,d,J = 5.1 Hz) MS (ESI,m/z) : 326 (M+H) 實施例156 依照類似實施例53的方法獲得下列化合物。 (2S)-2-胺基-N-[4-(2-胺基嘧啶-4-基)苯基]-2-(2-噻吩基) 20 乙醯胺 1H-NMR (DMSO-d6) : δ2·97 (1H,dd,J = 8.8, 13.6 Hz), 3·10 (1H,dd,J = 5.5, 13·6 Hz),4.74-4.78 (1H,m),7.01-7.06 (1H,m),7·09·7·11 (2H,m),7·32 (1H,dd,J = 7_7, 14.4 Hz), 7.68-7.73 (4H,m),7.80-7.82 (2H,m),8.59-8.61 (2H,m), 137 200800899 5 10.34 (1H? br) MS (ESI,m/z) : 340 (Μ+Η) 實施例157 依照類似實施例53的方法獲得下列化合物。 1-[4-(2-胺基嘧啶-4-基)苯基]-3-[(lS>2-羥基-1-苯乙基]脲 IH-NMR (DMSO-d6) : 53.56-3.69 (2H5 m)5 4.73-4.78 (1H,m),5.01 (1H,t,J = 5.1 Hz), 6·54 (2H,s),6.83 (1H, d,J =7.7 Hz),7·03 (1H,d,J = 5·3 Hz),7.21-7.27 (1H,m), 7.32-7.34 (4H,m),7·48 (2H,d,J = 8.8 Hz),7·96 (2H,d,J = 10 8.9 Hz), 8·22 (1H,d,J = 5.3 Hz), 8·93 (1H,br) MS (ESI,m/z) : 350(M+H) 實施例158 依照類似實施例53的方法獲得下列化合物。 4-{l-[(2S)-2·胺基-2-苯乙醯基]-2,3_二氫-1H_吲哚_5_基} 15 嘴唆-2-胺 • IH-NMR (DMSO-d6) : 52.24 (2H? s)? 3.05-3.24 (2H? m)9 3.73-3.82 (1H,m),4.36-4.44 (1H,m),4.80 (iH,s),6.58 (2H, s),7.06 (1H,d,J = 5.3 Hz),7.25-7.30 (1H,m),7.33-7.43 (4H, m),7.91-7.95 (2H,m),8·22 (1H,d,J = 8.8 Hz),8·25 (1H,d, Λ 20 J = 5.2 Hz) MS (ESI,m/z) : 346 (M+H) 實施例159 依照類似實施例53的方法獲得下列化合物。 4-{l-[(2R)-2·胺基-2-苯乙醯基]·2,3·二氫-1H-吲哚-5-基} 138 200800899 嘴咬-2-胺 1H-NMR (DMSO-d6): δ2·24 (2H,s),3.05-3.24 (2H,m), 3.73-3.82 (1H,m),4·36·4·44 (1H,m),4.80 (1H,s),6·58 (2H, s),7.06 (1H,d,J = 5.3 Hz),7.25-7.30 (1H,m),7·33-7·43 (4H, * 5 m),7.91-7.95 (2H,m),8·22 (1H,d,J = 8·8 Hz),8·25 (1H,d, J = 5.2 Hz) MS (ESI,m/z) : 346 (M+H) 實施例160 ® 依照類似實施例53的方法獲得下列化合物。 10 4-{l-[(2S)-2-胺基-3-(4-氟苯基)丙醯基]-2,3-二氩-1H- 吲哚-5-基}續咬-2-胺 1H-NMR (DMSO-d6) : 82.64-2.74 (1H? m)9 2.91-3.00 (1H,m),3.06-3.25 (2H,m),3.73-3.83 (1H,m),3·92·4·03 (1H,m),4.24-4.37 (1H,m),6.58 (2H,brs),7.03-7.13 (3H, 15 m),7.26J.35 (2H,m),7.88-7.99 (2H,m),8.13-8.21 (1H,m), 8.25 (lH,d,J = 5.2Hz) • MS (ESI,m/z) : 378 (M+H) 實施例161 依照類似製備物36以及其後實施例53的方法獲得下列 • 20 化合物。 • 4_{(28)-2-胺基-3-[5-(2-胺基°密11定-4-基)-2,3-二鼠-111· σ弓卜朵-1-基]-3-氧丙基}苯盼 1H-NMR (DMSO-d6) : 52.70-2.78 (1H? m)9 2.86-2.95 (1H,m),2.96-3.07 (1H,m),3.09-3.20 (1H,m),3.70-3.79 139 200800899 (1H,m),3.91-3.99 (1H,m),4.18-4.29 (1H,m),6·59 (2H, brs),6.64 (2H,d,J = 8·5 Hz),7·04(2Η,d,J = 8.4 Hz),7.07 (1H,d,J = 5.3 Hz),7.89-7.99 (2H,m),8·17(1Η,d,J = 8.4 Hz),8.26 (1H,d,J = 5.2 Hz),9.23 (1H,brs) ’ 5 MS (ESI,m/z) : 376 (M+H) 實施例162 依照類似製備物37以及其後實施例53的方法獲得下列 化合物。 • (2R)-1-氧代-3-苯基-1-(6-吡啶-4-基-3,4-二氫喹啉 10 -1(2H)-基)丙-2-胺二鹽酸鹽. 1H-NMR (DMSCM6) : δ1·35·1·85 (3H,m),3.0-3.3 (2H, m),3.85-4.0 (1H,m),4·7·4·9 (1H,m),6.75-6.95 (1H,m), 7.1-7.4 (4H,m),7·75·7·95 (3H,m),8.36 (2H,d,J = 6.2 Hz), 8.6-8.8 (1H,m),8·93 (2H,d,J = 6.2 Hz),8.9-9.0 (2H,m) 15 MS (ESI, m/z) : 358 (M+H) 140 200800899
表1 :實施例號碼及其化學化合物 Ex :實施例號碼;Str.:化學構造式; Ex Str. Ex Str. 1 广N 〇 6 广M H0、r O 人N人J U* H H 2 广Ν 〇 rr^ MeO^^ 7 广N MeCV〇 〇 U H H 3 jCj Me 0 ^ N1N人〆1 U H H 8 广N Μβ0γ° 〇 f^Y^N 人 N U H H 4 ι^ίΛ·0^ 9 HO丫〇〇 t^rS 人 Η H CF3CO2H 5 J〇 Me 0 人 N 人J U H H 10 广N H V〇 〇 人 H H CF3CO2H 141 200800899 表ι(續)
Ex Str. Ex Str. 11 广N Η2Νγ〇 〇 U H H 16 广N 〇 12 广N ,丫〇 〇 U H H 17 jGn Me 0 Ο^Λ以 13 18 jGn Me 0 qV〆 14 N 19 广N 〇 rr^ |Q0ji 人口 15 广N 〇 00、〜 20 142 200800899
表ι(績) Ex Str. Ex Str. 21 Η Η 26 广N ΗΧ/Υ^ Ι^-νΝ^ΛΝΛ^ HCI U H 22 Η Η 27 广N Me-f°〇 23 广Ν 28 0 广N H〇^S 〇 f^|f^ 24 广Ν 〇 29 αχτ0 25 广Ν 〇 〇r。’〆 30 NH2 r^N 143 200800899 表1 (續)
Ex Str. Ex Str. 31 Me^£〇〇 36 Me 32 jCj Me 0 37 广N h1/y^ 〇rNt^2HCI 33 OH 广N 38 广N HXrr° σΝ^ 34 r^N HO,0 39 广N σΧΗ^ 35 广N HX/Y^ ητΝ^^ u、〇H 40 广N HXjfY^ 〇rN^^ Me a Me 144 200800899 表1 (績)
Ex Str· Ex Str. 41 广N 'η 46 广N M 〇 42 jCj BocNH 0 crt^ 47 广N <xr° 43 广N 〇 rr^ 48 广N <xr^ A o 44 rj 49 Γκ <XT" ό 45 广N H 50 广N 〇〇T^ w\ 145 200800899 表1 (績)
Ex Str. Ex Str. 51 ον。 56 rj NH2 〇 crt^ 52 广Ν 〇^ΝχΛ) 2Ηα 57 广N 〇 rV^ 53 广Ν 〇 NH2 H 2HCI 58 〇ndNi^° 54 广N 〇 nr^ cn^ 59 k 1 NH2〇 rr^ 55 广N 0 60 jGn nh2o 146 200800899 表1 (績)
Ex Str. Ex Str. 61 jCj OH 〇 66 广N 〇 62 jGn nh2 0 67 63 jGn NH2 0 68 广N sHCm〇> 64 N 〇 f^Y^1 69 广N H〇) 0 65 广N 〇 rr〇 (ιγΛ^ 70 147 200800899 表1 (績)
Ex Str. Ex Str. 71 广N H0) 〇 76 Η H 72 广N H〇) 0 Γϊ^ 77 mv〇° Η H 73 Η H 78 Η H 74 CkXNlXX^ j. Η H 79 C〇AX)^ Η H 75 F^xx^o^ Η H 80 οζχ 又 Λη2 h h 148 200800899
表1 (績)
149 200800899 表1 (續)
Ex Str. Ex Str.
150 200800899 表ι(續)
Ex Str. Ex Str· 101 广N 03^ 106 Ol^xnXt° nh2 h 102 广N 107 〇LwNxr° H 103 广N 〇 H2N>〇 108 ΟλΧτ° k H 104 J NH2 H 109 0^0° Ah2 h 105 H 110 ςχΛ〇^ Cl nh2 h 151 200800899 表1 (續)
Ex Str. Ex Str. 111 F NH2 H 116 H 112 CF3 NH2 H 117 广N 0 ^γΟ 113 OMe NH2 H 118 广N 0 rT^ 114 Ah2 h 119 °r° 115 〇Λ^ν NH2 H 120 广N 0 rJ^ OH 152 200800899 表1 (續)
Ex Str. Εχ Str. 121 〇ΛΧ^Ν OH 126 0/NJ〇r° Αη2 η 122 〇Λ^Ν οΗ ,/ \、 0 0 127 广Ν 〇 123 广Ν 〇 128 广Ν 〇 cn^ 124 129 ΟΛ, 0Η Η 125 Ολ^ ^η2 η 130 〇Λ^Ν Ιη η 153 200800899 表ι(績)
Ex Str. Ex Str. 131 广N 〇 U nh2h 136 NH2 Me 132 广N 〇 nf^ U Ah2h 137 nh2 N人N 〇广 U nh2h 133 广N £ U Ih2h 138 nh2 N^N 0 FJ^J nh2 h 134 xr^° cn^N 139 nh2 N^N 〇 kJ nh2 h 135 Ργ^Ν 〇 cny^ 140 nh2 N^Svj 154 200800899 表1 (續)
Ex Str. Ex Str. 141 nh2 N^N 0 Clxr^y° 146 Y>V^ 1 nh2 h 142 nh9 丄2 N^N 〇 Me〇^ NH2 H 147 |^N 0 UCXJ nh2 h 143 nh2 0 148 广N 〇 h〇A^ NH2 H 144 NH, i OH 149 广N 0 jTT"X^、 021^人> 2 HCl HCI 145 r^N JUNXJ^ Sh2 h 150 〇n^NcP^N HCI HCI 155 200800899 表1 (續)
Ex Str. Ex Str. 151 nh2 156 nh2 N^SsJ 〇 kJ nh2 h 152 nh2 157 nh2 N^N ηοί 0 rr^ U H H 153 nh2 N^N Ah2 h 158 nh2 nh2 154 nh2 N^SsI 〇AJ〇^ nh2 h 159 K 11 I CXxn^5n nh2 155 nh9 丄 N^N nh2 h 160 nh2 fj〇^^n 156 200800899 表ι(績)
5 藥理學檢測^ "、㈣和治療上述人誠動物疾病 =::示於上述實施例之本發明化合物_代表性 0物進仃對下列RGCK ·抑制活性的測試。 1· ROCK酵素抑制性檢測 10 Μ明化合物#R0CK酵素抑制活性的檢測如下。將
Rh〇激酶基f MYTP的水溶液加入96-孔平板内。在代下將 其培養隔夜,利用含BSA的阻斷緩衝液阻斷平板的反應。 含各種化合物濃度之反應緩衝液的平板内加入適當濃度的 人類ROCK I (Canma Biosciences公司)、ATp、p 磷酸甘油 15酯、EGTA、正釩酸鈉和DTT,然後將平板培養丨小時。在 以清洗緩衝液清洗平板之後,將抗磷酸蘇胺酸抗體加入平 板,然後將平板培養1小時。再次以清洗緩衝液清洗平板之 後,將HRP-共輛抗填酸化蛋白抗體加入平板然後培養w、 時。再次以清洗緩衝液清洗平板之後,將色度基質TMB微 20 孔過氧化酶基質加入平板,然後將平板培養適當的時間。 157 200800899 在培養之後,將h2so4加入平板以終止反應,然後利用質譜 儀測量吸光度(450奈米)。根據各化合物的吸光度,利用 PHsm軟體適配資料以獲得IC5G值。 表2 :實施例號碼及其人類r〇CKIIC50值 化合物 人類ROCK I 化合物 人類ROCK I 實施例1 342 實施例73 84 實施例3 240 實施例86 5 實施例4 122 實施例98 21 實施例26 77 實施例108 14 實施例53 18 實施例109 12 實施例54 10 實施例119 212 實施例58 53 實施例151 86 實施例67 112 實施例154 42 實施例72 25 實施例155 72
2·藉由ROCK抑制劑測定後肢重量分佈的變化 碘乙酸一鈉(MIA)的關節内注射可誘發人類膝關節内 的骨關節炎狀組織病理性變化,此模式可極有效用於人類 骨關節炎的研究。最近’已報告關節疼痛的臨床分數與組 織病理上的等級有極大的關連性65,丨I%, 20 0 3)並且此模式可有效被用作㈣定骨關節炎疼痛的治 療效果。錢烧(Takeda公司,日本)麻醉雄性史道大氣並從 右膝膜骨下動帶的關節内單-注射1毫克Μ酸—鈉 (MIA ; Sigma公司,美目以_市)。以生理食鹽水溶解 慰,並彻27號、G.5啊投與顺升_積。注射後三 158 200800899 的化合物。在投與化合物60分鐘之後,將緩激素的生理食 鹽水溶液注入大鼠的後肢關節腔内(3微克分子/部位/50微 升),然後觀察大鼠對投與緩激素後的疼痛反應。其疼痛分 數分成下述的五級程度:0—無跋足至10秒後跛足;丨一⑺ 5至3〇秒後跋足;2—1〇秒内舉起後肢或31秒以上後跋足;3 一在10秒内呈三足步態然後跋足;4—10秒或以上後呈三足 步態然後跛足。在各試驗組中使用1〇個大鼠模式。已證明 _ 在投與緩繳素後可導致分數約為3的疼痛反應。投與32毫克 /公斤之本發明化合物可明顯改善該大鼠模式的疼痛反 10應。實施例26劑量的化合物可視情況改善緩激素誘發的疼 痛反應,明確而言,32毫克/公斤的劑暈其疼痛分數可明顯 從載器内的2.7降低至1.4。 4·藉由ROCK抑制劑測定軟骨表面病變的變化 破乙酸一鈉(MIA)的關節内注射可誘發人類膝關節内 15的骨關節炎狀組織病理性變化,此模式可極有效用於人類 φ 骨關節炎的研究。為測定化合物對骨關節炎内之關節軟骨 損傷的有效性,我們測定化合物對該模式内軟骨損傷的效 果。以氟烷(Takeda公司,日本)麻醉雄性83大鼠並從右膝臏 骨下韋刃帶的關節内單一注射1毫克碘乙酸一鈉(MIA ; Sigma . 2〇公司,美國SLLouis市)。以生理食鹽水溶解MIA,並利用27 . 號、〇·5吋針投與5〇微升的體積。注射後三週,分離右脛骨 並且以0-4級測定脛骨表面的病變。每種試驗的各組包括八 隻動物。注射MIA三週之後軟骨的肉眼病變嚴重程度分數 為約3。關節内每週注射兩次化合物可抑制軟骨的損傷。 160 200800899 週,利用雙足平衡法測痛儀(Linton儀器公司,英國Norfork 市)測定後肢重量分佈。使大鼠適應該測試儀,並且在穩定 之後每隔5秒1 2 3 4貝取一次數據。口服化學化合物以重建左和右 肢間的重重差異。每種試驗的各組包括八隻動物。 5 表3 :實施例號碼及其重量分佈£〇50值 <化合物 重量分佈ED5〇值(毫克/公斤) 實施例1 <3 實施例3 <3 實施例4 <3 實施例26 <3 實施例53 <3 實施例54 <3 實施例58 <3 實施例67 <3 實施例72 <3 159 1 · R Ο C K抑制劑對緩激素誘發關節疼痛模式的疼痛減輕效果 緩激素已知為各種疼痛中的一種重要疼痛相關介質以 2 及更明確而言玻尿酸鈉(sodium hyaluronate)已報告可於緩 10 激素誘發關節疼痛模式中有效減輕骨關節炎的疼痛。因 3 此,我們測試本化合物在此模式中的效果。 4 製造關節疼痛模式及測定疼痛的程度基本上係根據 200800899 5.藉由ROCK抑制劑測定後肢血流的效應 為證明本發明化合物對末稍動脈疾病的有效性,我們 進行一項測定該化合物對大鼠後肢血流影響的試驗。 在口服投與化合物之後以腹腔内注射巴比妥(曰本 5 Kant0化學公司)麻醉雄性韋斯(Wistar)大鼠。將大鼠置於加 熱板上以進行隨後的後肢企流分析。我們利用雷射都卜勒 金流測定儀(PeriScan系統公司,瑞典Stockholm市)測定後肢 血流影像。在記錄都卜勒影像之後,計算雙肢的平均灌注 值’然後測定化合物對後肢血流的效應。各試驗的進行為 10利用約4隻動物。 表4 :實施例號碼及血流增加之。/〇 化合物 血流增加% (10毫克/公斤腹腔) 實施例4 >130% 實施例54 >130% 實施例67 >130% 實施例86 >130% 實施例98 >130% 實施例108 >130% 實施例154 >130% 6·藉由ROCK抑制劑測定對苯腎上腺素誘發尿道壓力上升 的抑制效應 為測定本發明化合物對良性前列腺肥大相關之尿道功 能障礙的效果,我們研究靜脈内投與化合物對腎上腺素誘 161 200800899 發大鼠尿道壓力上升的抑制效應。 在切開 ’美國 以尿烧(Sigma公司’美國)麻醉雄性韋斯大氣。 腹部中線之後,從膀胱頂部將導尿管(3·5 Fr公司
Millar市)插入測定尿道壓力的尿道内。在確認笨腎上腺素 (30微克/公斤靜脈)-誘發尿道壓力的上升之後,以遂择节丨曰' 的方式靜脈投與本化合物。在投與化合物之後每隔5分鐘注 射苯腎上腺素(30微克/公斤靜脈),然後測定化合物對笨腎 上腺素誘發尿道壓力上升的抑制效應。各試驗的進行為利 用約4隻動物。
10 表5 :實施例號碼及其對尿道壓力上升的抑制效應 化合物 對尿道壓古占升的抑制效應ed30 (¾克/公/f靜脈) 實施例109 <1 實施例151 <1 實施例154 <1 • 【圖式簡單說明】 (無) 【主要元件符號說明】 (無) 162
Claims (1)
- 200800899 申請專利範圍: 種式[1]化合物或其醫藥上可接受鹽類: 其中[I] 510 A為補性取代絲、選擇性取代環絲或選擇性 取代雜環基的低級烧基; Li 為-H或-ΝΗ2 ; L2為 CR14 或Ν ; 為CH或N ; L4 為 CR2 或N ; Ri為-H及R2為-H或低級烷基,或RjuR2共同形成低 級伸烷基; Rl4為-H或鹵素; X為鍵結 ' -CHR3-、-NR4·、-CHR5%-或-X2-CHR6-; R3為-Η、選擇性取代低級烷基、-〇H、-NH2、選擇 性取代雜環基; R4為-H或選擇性取代低級烧基; Χι 為-NH-、-CHR7-、-CHR15-X3-或-0-; 為-Η、選擇性取代低級烷基、-oh、-NH2、 -C(0)NH2、-C(0)0R8、-NHC(0)0R9 或選擇性取代芳基; R7為-Η、選擇性取代低級烧基、選擇性取代雜環 基、-ΟΗ或-NR10R16 ; 163 200800899 Rs和&各為獨立的或選擇性取代低級烷基; 和R!6各為獨立的或選擇性取代低級烷基; Rl5為_Ή、選擇性取代低級烷基或-NHC(0)0Ri7 ; Rn為·Η或選擇性取代低級烷基; 5 Χ3 為-ΝΗ·或 _CHR18 ; Ris 為-Η或 _NH2 ; X2為-(CHH-或·。-; R6為-Η或選擇性取代低級烷基; η為0或1 ; 0 Rn為_Η、選擇性取代低級烷基、選擇性取代烷醯 基或-S02R12 ; Ru為-Η或選擇性取代低級烷基。 2.如申请專利範圍第1項之化合物,其中該化合物為下列 式[Γ]化合物或其醫藥上可接受鹽類: 其中 Α為可刀別被每自由-0Η、函素、低級烧基、低級 烧氧基、羰基、氰基、媽和雜構成之取代基所取代 的低級烧基或芳基、環烧基或雜環基; Li 為-Η或-ΝΗ2 ; 164 200800899 l2為cr14*n ; L3為CH或N ; L4 為 CR2 或N ; 1為-11及112為1或曱基,或心和112共同形成低級伸 5 烧基; Ri4為-H或鹵素; X為鍵結、-CHR3·、·ΝΚ^4·、·〇ΗΚ5-Χι-或; R3為-η,或被選自由-OH、鹵素、羧基、氰基、-ΝΗ2 和石肖基構成之取代基所取代的低級烧基,或-OH、 10 -NH2,或可被選自由-OH、鹵素、低級烧基、低級烧氧 基、羧基、氰基、-NH2和硝基構成之取代基所取代的雜 環基; R4為-H,或可被選自由-OH、鹵素、羧基、氰基、 -NH2和頌基構成之取代基所取代的低級烧基; 15 X!為-NH-、-CHR7-、-CHR15-X3-或,0-; R5為-Η,或被選自由-OH、鹵素、羧基、氰基、-NH2 和硝基構成之取代基所取代的低級烷基,或-OH、 -nh2、-c(o)nh2、-c(o)or8、-nhc(o)or9,或被選自 由-OH、鹵素、低級烷基、低級烷氧基、羧基、氰基、 20 -NH2和硝基構成之取代基所取代的芳基; R7為·Η,或可被選自由-OH、鹵素、羧基、氰基、 -ΝΗ2和硝基構成之取代基所取代的低級烷基,或可被選 自由-ΟΗ、鹵素、低級烷基、低級烷氧基、羧基、氰基、 -ΝΗ2和硝基構成之取代基所取代的雜環基,或_〇Η、 165 200800899 -NRl〇Rl6 ; R8、R9、Rio和Ri6為各自獨立的-Η,或被選自由 -OH、鹵素、魏基、氰基、·ΝΗ2和頌基構成之取代基所 h 取代低級烷基; 5 Ri5為-H,或可被選自由-OH、鹵素、羧基、氰基、 -NH2和瑞基構成之取代基所取代的低級烧基,或 -NHC(0)0R17; R17為-Η,或可被選自由-OH、鹵素、羧基、氰基、 -NH2和瑣基構成之取代基所取代的低級烧基; 10 X3 為-NH-或-CHR18 ; R18 為-Η 或-NH2 ; x2 為-(CH2)n-NR『或-Ο-; 116為-11,或可被選自由-OH、鹵素、羧基、氰基、 -NH2和硝基構成之取代基所取代的低級烷基; 15 η為0或1 ; ^^為增,或分別可被選自由-ΟΗ、鹵素、羧基、氰 • 基、-ΝΗ2和硝基構成之取代基所取代的低級烷基、低級 院酸基,或-SO2R12 ; R!2為-Η或可被選自由-ΟΗ、鹵素、羧基、氰基、-ΝΗ2 事 2〇 和硝基構成之取代基所取代的低級烷基。 3.如申請專利範圍第2項之化合物,其中 A為低級烷基,或單-或雙-環芳基、環烷基、雜芳 基或融合雜環,其各別可被選自由-OH、鹵素、低級炫 基、低級烷氧基、羧基、氰基、-NH2和硝基構成的取代 166 200800899 基所取代; 1^為-:»或-:^112; L2為CH或N ; L3 為 CH ; 5 L4 為 CR2 ; Ri和R2各為獨立的-Η或共同形成乙烯; X鍵結、-CHR3-或-NR4-; R3為-Η,或可被選自由-OH、鹵素、羧基、氰基、 -NH2和硝基構成之取代基所取代的低級烷基,或-OH、 10 -NH2,或可被選自由-OH、鹵素、低級烷基、低級烷氧 基、羧基、氰基、-NH2和硝基構成之取代基所取代的飽 和雜壞基, R4為,或可被選自由-OH、鹵素、羧基、氰基、 -NH2和構成之取代基所取代的低級烷基; 15 或其鹽類。 4·如申請專利範圍第3項之化合物,其中 A為選自由吼嘻基、T2比IT定基、。塞吩基、吱喃基所構 成之基的苯基、萘基、二氫茚基、環己基、雜芳基,或 選自由吲哚基、吲哚啉基、喹啉基、3,4-二氫異喹啉基、 20 八氫異喹啉基、苯并噻唑基和苯并呋喃基所構成之基的 融合雜環基,其分別可被選自由-ΟΗ、鹵素、低級烷基、 低級烧氧基、魏基、氰基、-ΝΗ2和梢基構成之基的取代 基所取代; Li 為-Η或-ΝΗ2 ; 167 200800899 1^2為(:11或N ; L3 為 CH ;10 1520 L4 為 CR2 ; 1^和112各為獨立的-Η或共同形成乙烯; X為鍵結、-CHR3-或-ΝΗ·; R3為-Η、-OH、-NH2,或°比洛烧基、旅σ定基、旅口井 基、嗎啉基或硫嗎啉基,其分別可被選自由-ΟΗ、鹵素、 低級烷基、低級烷氧基、羧基、氰基、小氐和硝基構成 之基的取代基所取代; 或其鹽類。 5. 如申請專利範圍第4項之化合物,其中 Α為選自由吼洛基、吼咬基、嗟吩基、咬喃基所構 成之基的苯基、萘基、二氫茚基、環己基、雜芳基,或 選自由吲哚基、吲哚琳基、啥琳基、3,4-二氳異啥琳基、 八氫異喹啉基、苯并噻唑基和苯并呋喃基所構成之基的 融合雜環基; !^為-11 或-NH2 ; L2為CH或N ; L^CH ; L4 為 CR2 ; 心和!^各為獨立的-H或共同形成乙烯; X為鍵結、-CH2-或-NH-; 或其鹽類。 6. 如申請專利範圍第2項之化合物,其中 168 200800899 A為芳基、環烧基或單環雜環基,其分別可被選自 由-OH、鹵素、低級烷基、低級烷氧基、羧基、氰基、 -NH2和确基構成之基的取代基所取代; ^為-H 或-NH2 ; 5 L2*CH或N ; L3為CH或N ; L4 為 CR2 或N ; Ri為-H及R2為-H或甲基’或R^R2共同形成低級伸 烷基; 10 X is -CHR5-X1- or -X2-CHR6-; Xia-NH-、-CHR7-、-CHR15-X3-或-ο-; 115為_11,或可被選自由-OH、鹵素、羧基、氰基、 -NH2和硝基構成之取代基所取代的低級烷基,或-OH、 -NH2、-c(o)nh2、-c(o)or8、-nhc(o)or9,或可被選 15 自由-OH、鹵素、低級烷基、低級烷氧基、羧基、氰基、 -NH2和頌基構成之取代基所取代的芳基; R7為-H,或可被選自由-OH、鹵素、羧基、氰基、 -NH2和硝基構成之取代基所取代的低級烷基,或可被選 自由-OH、鹵素、低級烷基、低級烷氧基、羧基、氰基、 20 -NH2和硝基構成之取代基所取代的飽和雜環基,或 OH、-NR10R16 ; Rg、R9、Ri〇和R16各為獨立的-Η ’或選自由-OH、 鹵素、羧基、氰基、-nh2和硝基構成之取代基所取代的 低級烷基; 169 200800899 R15為-Η,及可被選自由-OH、鹵素、羧基、氰基、 -NH2和硝基構成之取代基所取代的低級烷基,或 -nhc(o)or17 ; R17為-Η,或可被選自由-OH、鹵素、羧基、氰基、 -NH2和瑞基構成之取代基所取代的低級烧基; X3 為-NH-或-CHR18 ; 1118為-11 或-NH2 ; X2為-NRn-或-Ο-; 10 15 20 R6為·Η,或可被選自由-OH、鹵素、羧基、氰基、 -NH2和梢基構成之取代基所取代的低級烧基, Rn為,或分別可被選自由-OH、鹵素、羧基、氰 基、-NH2和墙基構成之取代基所取代的低級烧基、低級 烧酿基’或-S02R12 ; Rl 2為或低級烧基, 或其鹽類。 如申請專利範圍第6項之化合物,其中 A為苯基、環己基或噻吩基,其分別可被選自由 -OH、鹵素、低級烷基、低級烷氧基、羧基、氰基、-NH2 和硝基構成的取代基所取代; “為-!!或-NH2 ; L2為CH或N ; L3 為 CH; L4為CR】, IM〇R2各為獨立的-H或共同形成乙烯或丙烯; 170 200800899 x為m; 11為_·!-或-CHil7-; R5為-H,或可被-OH或羧基取代的低級烷基,或 -OH ' -NH2 ' -C(0)NH2 ' -C(0)0R8 ^ -NHC(0)0R9 ; Ry為-Η ’或分別可被選自由-OH、鹵素、低級院基、 低級烧氧基、羧基、氰基、-NH2和硝基構成之取代基所 取代的吡咯烷基、哌啶基、哌啡基、嗎啉基或硫碼啉基, 或-OH、-NRi〇Ri6 ; R8、R9、Rl〇和Rl6為各自獨立的-Η,或被選自由 -OH、鹵素、羧基、氰基、-ΝΗ2和硝基構成之取代基所 取代低級基, 或其鹽類。 8.如申請專利範圍第7項之化合物,其中 Α為苯基、環己基或噻吩基; 15 20 或·ΝΗ2 ; L2為CH或Ν ; L3 為 CH ; L4 為 CR2 ; 1和112各為獨立的_H或共同形成乙烯; X為-CHR5-Xr ; 又1為-1^11_ 或-CHR7-; R5為-Η,或可被-OH或羧基取代的低級烷基,或 -OH、-NH2、-C(0)NH2、-C(0)0R8、-NHC(0)0R9 ; R7為-Η、嗎啉基、-OH或-NRh)!^ ; 171 200800899 9. Rs '反9、R10和Ri6為各自獨立的-Η,或低級烷基。 種製造式[I]化合物的方法: 其中 5 Α為選擇性取代芳基、選擇性取代環烷基或選擇性 取代雜環基的低級燒基; L1 為-Η 或-ΝΗ2 ; 為cr14*n ; 10L3為CH或N ; b為 cr2*n ; R1為-Η及R2為-Η或低級烷基,或R>R2共同形成低 級伸烷基; Rl4為-H或鹵素; X為鍵結、-CHR3…NR4-、-CHRs-Xid-XrCm ; 汉3為_H、選擇性取代低級烷基、_〇H、-NH2、選擇 性取代雜環基; R4為-H或選擇性取代低級烷基; &為-丽-、-CHR7‘、-CHR15-X3·或·0-; R5為、選擇性取代低級烷基、_0H、_NH2、 -c(o)nh2、·ο(ο)οιι8、-NHC(0)0R9 或選擇性取代芳基· R7為-H、選擇性取代低級烷基、選擇性取代雜琿 基、-OH 或-NR10R16 ; 乂 172 200800899 R8和R9各為獨立的-Η或選擇性取代低級烷基; Rio和Ri6各為獨立的-Η或選擇性取代低級烷基; R15為-H、選擇性取代低級烷基或-NHC(0)0R17 ; R17為-Η或選擇性取代低級烷基; Χ3 為-ΝΗ-或-CHR18 ; R18 為-Η 或-NH2 ; X2為-(CH^n-NRii·或-Ο-,R6為-Η或選擇性取代低級烷基; η為0或1 ; Rn為-Η、選擇性取代低級烧基、選擇性取代烧S& 基或-SO2R12, R12為-H或選擇性取代低級烷基, 或其鹽類,其包括: (1)與式[II]化合物反應:其中R!、u、L2、L3*L4分別如上述之定義,或其在胺 基的反應衍生物或其鹽類與式[III]化合物的反應:OH [III] 其中A和X分別如上述之定義,或其在羥基的反應衍生 物或其鹽類而產生式[I]化合物: 173 200800899其中Ri、L〗、L2、L3、L4、X和A分別如上述之定義,或 其鹽類,或 (2)與式[Π]化合物反應:Ri [II] 其中I、L!、L2、L3和L4分別如上述之定義,或其鹽類 與式[IV]化合物的反應: A^nN=c=0 R5 [IV] 10其中A和I分別如上述之定義,以及11為〇或1而產生式 [lb]化合物:〇 U 人 N Η ^ 其中R〗、R5、、L2、L3、L4、Α和η分別如上述之定義, 或其鹽類,或 (3)與式[II]化合物反應:174 [II] 15 200800899 其中R!、b、L2、L3和L4分別如上述之定義,或其鹽類 與式[V]化合物的反應·· 〇[V] 其中A、R5和η分別如上述之定義,而產生式[lb]化合物··[lb] 其中Ri、R5、Li、L2、L3、L4、A和η分別如上述之定義, 或其鹽類,或 (4)與式[VI]化合物反應: Ri [VI] 10其中R!、、L2、L3和L4分別如上述之定義,以及γ為 任何的離去基,與式[νπ]化合物的反應:[VII] 其中A、R5和η分別如上述之定義,而產生式[lb]化合物:其中Ri、R5、L〗、L2、L3、L4、A和η分別如上述之定義, 或其鹽類,或 175 15 200800899 (5)與式[II]化合物反應:fX 占 1 [Π]] 其中R〗、L〗、L2、1^3和1^4分別如上述之定義,或其鹽類, 與式[VIII]化合物的反應:5[VIII] 其中A、R5和η分別如上述之定義,Y為任何的離去基, 而產生式[Ic]化合物:Ri [Ic] 其中R!、R5、L〗、L2、L3、L4、A和η分別如上述之定義, 10或其鹽類,或 (6)與式[1又]化合物反應:Ri [IX] 其中、L〗、L3、L4、X、Y和A分別如上述之定義,或 其鹽類,與式[X]化合物的反應:176 15 200800899 其中1^和1^2分別如上述之定義,或其鹽類,而產生式[Id] 化合物:Ri [Id] 5其中R!、、L2、L3、L4、X和A分另如上述之定義,或 其鹽類,或 (7)與式[XI]化合物反應:其中、L3、L4、X和A分別如上述之定義,或其鹽類, 與式[XII]化合物的反應: γ[XII] 其中L!、LjnY分別如上述之定義,或其鹽類,而產生 式[le]化合物:[Ie] 其中Ri、L!、L2、L3、L4、X和A分另如上述之定義,或 其鹽類。 177 15 200800899 10·-種醫藥組成物,其包含一如申請專利範圍第i項的化 合物或其醫藥上可接受的㈣以作為活性成分,且混合 4 有醫藥上可接受载劑或賦形劑。 , 11.-種如中請專鄕Bfl項之化合物或其醫藥上可接受 5 之顏於製造祕抑制Rho激酶(ROCK)之筚物的用拎 m如巾請專利範圍幻項之化合物或受 之鹽類於製造用於治療和/或預防高血壓、動脈粥樣硬 • 化症、中風、心絞痛、動脈阻塞、末稍動脈疾病、末稍 循環疾病、勃起功能障礙、急性和慢性疼痛、癡呆症、 10 阿茲海默症、帕金森氏症、神經元變性、氣喘、肌萎縮 f生侧索硬化症(ALS)、脊索損傷、風濕性關節炎、骨關 即炎、骨質疏鬆症、牛皮癖、多發性硬化症、糖尿病、 泌尿器官疾病如膀胱過動症(0AB)和良性前列腺肥大 (H)轉私癌症、青光眼、咼眼壓症、視網膜病、 15 自體免疫疾病、病毒性感染或心、肌保護之藥物的用途。 • 13·—種如申請專利範圍第丨項之化合物或其醫藥上可接受 之鹽類於製造用於治療和/或預防骨關節炎、末稍動脈 疾病或良性前列腺肥大(BPH)之藥物的用途。 • 14· 一種R0CK抑制劑,其含有如申請專利範圍第丨項之活性 2〇 成分或其醫藥上可接受的鹽類。 丨5·-種用於治療和/或預防選自由高血壓、動脈粥樣硬化 症、中風、心絞痛、動脈阻塞、末稍動脈疾病、末稍循 環疾病、勃起功能障礙、急性和慢性疼痛、癡呆症、阿 兹海默症、帕金森氏症、神經元變性、氣喘、肌萎縮性 178 200800899 側索硬化症(ALS)、脊索損傷、風濕性關節炎、骨關節 炎:骨質疏鬆症、牛皮癖、多發性硬化症、糖尿病、泌 尿器官疾病如膀胱過動症(0AB)和良性前列腺肥大 $ (BI>H)、轉移、癌症、青光眼、高眼壓症、視網膜病、 5 自體免疫疾病、病毒性錢和心肌倾所構成群組之 ⑽CK-相關疾病的方法,其包括將如申請專利範圍第i 項之化合物或其醫藥上可接受之鹽類投與至—需此類 Φ 治療的病人。 ' ⑺16·-種用於〉、台療和/或預防選自由骨關節炎、末稍動脈疾 10 病和良性前列腺肥大(BPH)所構成群組之ROCK·相關疾 病的方法,其包括將如申請專利範圍第丨項之化合物或 其醫藥上可接受之鹽類投與至一需此類治療的病人。 17· 一種用於治療和/或預防選自由高血壓、動脈粥樣硬化 症、中風、心絞痛、動脈阻塞、末稍動脈疾病、末稍循 環疾病、勃起功能障礙、急性和慢性疼痛、癡呆症、阿 籲 兹海默症、帕金森氏症、神經元變性、氣喘、肌萎縮性 側索硬化症(ALS)、脊索損傷、風濕性關節炎、骨關節 k、骨質疏鬆症、牛皮癣、多發性硬化症、糖尿病、泌 ▲ 尿器官疾病如膀胱過動症(OAB)和良性前列腺肥大 (BPH)、轉移、癌症、青光眼、高眼壓症、視網膜病、 自體免疫疾病、病毒性感染和心肌保護所構成群組之 ROCK-相關疾病的醫藥組成物,其含有如申請專利範圍 第1項之化合物或其醫藥上可接受的鹽類。 18· —種用於治療和/或預防選自由骨關節炎、末稍動脈疾 179 200800899" 病和良性前列腺肥大(BPH)所構成群組之ROCK-相關疾 病的醫藥組成物,其含有如申請專利範圍第1項之化合 物或其醫藥上可接受的鹽類。 180 200800899 七、指定代表囷: (一) 本案指定代表圖為:第()圖。(無) (二) 本代表圖之元件符號簡單說明:八、本案若有化學式時,請揭示最能顯示發明特的化學式:4
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-
2006
- 2006-08-29 KR KR1020087007086A patent/KR20080040027A/ko not_active Application Discontinuation
- 2006-08-29 JP JP2008510929A patent/JP5212101B2/ja not_active Expired - Fee Related
- 2006-08-29 EP EP06783173A patent/EP1922306A2/en not_active Withdrawn
- 2006-08-29 US US12/065,043 patent/US8211919B2/en not_active Expired - Fee Related
- 2006-08-29 CN CNA2006800321580A patent/CN101253152A/zh active Pending
- 2006-08-29 WO PCT/JP2006/317412 patent/WO2007026920A2/en active Application Filing
- 2006-08-29 CA CA002620818A patent/CA2620818A1/en not_active Abandoned
- 2006-08-31 TW TW095132193A patent/TW200800899A/zh unknown
Also Published As
Publication number | Publication date |
---|---|
US20090105231A1 (en) | 2009-04-23 |
CN101253152A (zh) | 2008-08-27 |
JP2009506979A (ja) | 2009-02-19 |
JP5212101B2 (ja) | 2013-06-19 |
KR20080040027A (ko) | 2008-05-07 |
EP1922306A2 (en) | 2008-05-21 |
WO2007026920A2 (en) | 2007-03-08 |
US8211919B2 (en) | 2012-07-03 |
WO2007026920A3 (en) | 2007-06-28 |
CA2620818A1 (en) | 2007-03-08 |
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