TW202340191A - 作為CBP/p300抑制劑之四氫-咪唑並喹啉化合物 - Google Patents
作為CBP/p300抑制劑之四氫-咪唑並喹啉化合物 Download PDFInfo
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- TW202340191A TW202340191A TW112106967A TW112106967A TW202340191A TW 202340191 A TW202340191 A TW 202340191A TW 112106967 A TW112106967 A TW 112106967A TW 112106967 A TW112106967 A TW 112106967A TW 202340191 A TW202340191 A TW 202340191A
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- alkyl
- methyl
- methoxycarbonyl
- carboxylic acid
- cycloalkyl
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- 239000003112 inhibitor Substances 0.000 title abstract description 14
- GCGNWZMOENODOJ-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1h-imidazo[4,5-h]quinoline Chemical class C1C=C2C=CC=NC2=C2C1NCN2 GCGNWZMOENODOJ-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 165
- 125000003118 aryl group Chemical group 0.000 claims description 91
- 125000001072 heteroaryl group Chemical group 0.000 claims description 91
- 125000000623 heterocyclic group Chemical group 0.000 claims description 80
- 229910052736 halogen Inorganic materials 0.000 claims description 49
- 150000002367 halogens Chemical class 0.000 claims description 49
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 46
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 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 29
- 150000003839 salts Chemical class 0.000 claims description 24
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 239000001301 oxygen Substances 0.000 claims description 22
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 29
- 238000000034 method Methods 0.000 abstract description 28
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- 208000035475 disorder Diseases 0.000 abstract description 3
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 19
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- -1 imine ethers Chemical class 0.000 description 16
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 125000004429 atom Chemical group 0.000 description 12
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- PQRVSWVLDAPYBG-UHFFFAOYSA-N 6-fluoro-2-methyl-5-nitroquinoline Chemical compound [O-][N+](=O)C1=C(F)C=CC2=NC(C)=CC=C21 PQRVSWVLDAPYBG-UHFFFAOYSA-N 0.000 description 10
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
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- 229920006395 saturated elastomer Polymers 0.000 description 9
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- 239000007864 aqueous solution Substances 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
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- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
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- 239000003999 initiator Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- FBBDOOHMGLLEGJ-UHFFFAOYSA-N methane;hydrochloride Chemical compound C.Cl FBBDOOHMGLLEGJ-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- LQABJUHJAJUXRX-UXDWYNKZSA-N methyl (7S)-2-[[2-(difluoromethoxy)-5-fluorophenyl]-hydroxymethyl]-3-[(1R,3R)-3-methoxycarbonylcyclohexyl]-7-methyl-8,9-dihydro-7H-imidazo[4,5-f]quinoline-6-carboxylate Chemical compound FC(OC1=C(C=C(C=C1)F)C(C=1N(C=2C(=C3CC[C@@H](N(C3=CC=2)C(=O)OC)C)N=1)[C@H]1C[C@@H](CCC1)C(=O)OC)O)F LQABJUHJAJUXRX-UXDWYNKZSA-N 0.000 description 1
- XSRWQTDEIOHXSL-UHFFFAOYSA-N methyl quinoline-6-carboxylate Chemical group N1=CC=CC2=CC(C(=O)OC)=CC=C21 XSRWQTDEIOHXSL-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 108091005763 multidomain proteins Proteins 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- RHFUXPCCELGMFC-UHFFFAOYSA-N n-(6-cyano-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl)-n-phenylmethoxyacetamide Chemical compound OC1C(C)(C)OC2=CC=C(C#N)C=C2C1N(C(=O)C)OCC1=CC=CC=C1 RHFUXPCCELGMFC-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000012748 slip agent Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
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- 239000004094 surface-active agent Substances 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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- 230000002103 transcriptional effect Effects 0.000 description 1
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
本揭示係關於溴結構域之CBP/p300家族的抑制劑。該等化合物可適用於治療與溴結構域之CBP/p300家族的抑制有關之疾病或病症。例如,本揭示係關於用於抑制溴結構域之CBP/p300家族的化合物及組合物、治療與溴結構域之CBP/p300家族的抑制有關之疾病或病症(例如,某些形式之癌症)的方法、以及合成此等化合物之方法。
Description
本揭示係關於用於抑制腺病毒E1A蛋白之p300(亦稱為EP300及KAT3B)結合蛋白及/或環AMP-反應元件-結合蛋白(CREB)結合蛋白(CBP,亦稱為KAT3A,亦即p300之細胞同種同源物)的化合物及方法。該等化合物適用於治療某些形式之癌症。
CBP/p300為離胺酸乙醯基轉移酶,其催化乙醯基連接至組蛋白及其他蛋白受質之離胺酸側鏈。p300(亦稱為EP300及KAT3B)為具有結合至不同蛋白質(包括許多DNA結合轉錄因子)的多個結構域的蛋白質。環AMP-反應元件-結合蛋白(CREB)結合蛋白(CBP,亦稱為KAT3A)為p300之細胞同種同源物。p300及CBP具有廣泛的序列同一性及功能相似性且經常稱為CBP/p300。組蛋白及其他蛋白質之CBP/p300催化的乙醯化為基因活化之關鍵。已在諸如前列腺癌之人類晚期癌症及人類原發性乳腺癌樣本中觀察到提高的p300表達及活性。具有內在乙醯基轉移酶酶活性之CBP/p300之化學抑制比用小分子阻斷轉錄因子更可行,因為轉錄因子之化學抑制劑之發現已經證實極具挑戰性。
因此,需要用於抑制CBP/p300之新穎及有效的化合物,其適用作治療某些相關形式之癌症的療法。
本申請者已發現適用於抑制CBP/p300之新穎化合物及方法。該等化合物及方法適用於治療某些相關形式之癌症,諸如某些形式之乳腺癌及前列腺癌。
較佳地,該化合物為式(I)之CBP/p300抑制劑化合物或其醫藥學上可接受之鹽:
(I),
或其醫藥學上可接受之鹽,
其中,
R
1為-C
1-C
6烷基、-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OR
5、
-N(R
5)
2或-NHR
5;
R
5為-C
1-C
6烷基、-C
3-C
8環烷基、雜環基、芳基或雜芳基;
R
6為-H、-OH、鹵素、側氧、-C
1-C
6烷基、-NO
2、
-CN、-NH
2、-OC
1-C
6烷基、-OC
3-C
6環烷基、-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、-C(O)C
1-C
6烷基、
-C(O)NH
2、-C(O)NH(C
1-C
6烷基)、-C(O)N(C
1-C
6烷基)
2、
-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、
-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2或-N(C
1-C
6烷基)S(O)(C
1-C
6烷基),其中各烷基、烯基、環烷基視情況經一或多個-R
10取代;
R
6’為視情況經一或多個-R
10取代之-C
3-C
8環烷基、
-C
4-C
8環烯基、雜環基、雜芳基或芳基;
R
7在每次出現時獨立地為-H、鹵素、-OH、-CN、
-OC
1-C
6烷基、-NH
2、-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、
-S(O)
2NH(C
1-C
6烷基)、-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、-S(O)
2OH、-C(O)C
1-C
6烷基、-C(O)NH
2、
-C(O)NH(C
1-C
6烷基)、-C(O)N(C
1-C
6烷基)
2、-C(O)OH、
-C(O)OC
1-C
6烷基、 -N(C
1-C
6烷基)SO
2C
1-C
6烷基、
-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2、-S(O)
2NH
2、
-N(C
1-C
6烷基)S(O)(C
1-C
6烷基)或四唑;
R
10在每次出現時獨立地為-C
1-C
6烷基、-C
2-C
6烯基、 -C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OH、鹵素、側氧、-NO
2、-CN、-NH
2、-OC
1-C
6烷基、-OC
3-C
6環烷基、-O芳基、-O雜芳基、-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、
-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、-C(O)C
1-C
6烷基、-C(O)NH
2、-C(O)NH(C
1-C
6烷基)、-NHC(O)C
1-C
6烷基、-C(O)N(C
1-C
6烷基)
2、-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2或-N(C
1-C
6烷基)S(O)(C
1-C
6烷基),其中各烷基、烯基、炔基、環烷基、環烯基、雜環基、雜芳基或芳基視情況經一或多個-R
12取代;
其中任何兩個R
10當在非相鄰原子上時可組合形成橋聯環烷基或雜環基;
其中任何兩個R
10當在相鄰原子上時可組合形成環烷基、雜環基、芳基或雜芳基;
R
12在每次出現時獨立地為鹵素;並且
m為0至5之整數;且
q為0至4之整數。
本揭示之另一態樣係關於一種醫藥組合物,其包含式(I)之化合物或醫藥學上可接受之鹽。該醫藥學上可接受之載劑可進一步包括賦形劑、稀釋劑或界面活性劑。該醫藥組合物對於治療有此需要之受試者中與CBP/p300調節有關之疾病或病症可為有效的。該醫藥組合物可包含用於治療本文所述之疾病的本揭示之化合物。該等組合物可含有至少一種本揭示之化合物及醫藥學上可接受之載劑。
本揭示之另一態樣係關於一種抑制一或多個CBP/p300-家族溴結構域之方法。該方法可包含向有此需要之患者投與治療有效量之式(I)化合物或其醫藥學上可接受之鹽。
相關申請案之交叉引用
本申請案主張2017年9月15日提交之美國臨時申請案第62/559,436號及2018年6月29日提交之美國臨時申請案第62/692,593號之優先權權益,所有該等申請案以引用之方式全部併入本文。
本揭示係關於能夠調節CBP/p300家族溴結構域之活性的化合物及組合物。本揭示係關於藉由向有此需要之患者投與治療有效量之式(I)化合物或其醫藥學上可接受之鹽治療、預防或改善其中CBP/p300溴結構域發揮作用之疾病或病症的方法。本揭示之方法可用於藉由抑制CBP/p300溴結構域之活性治療多種CBP/p300溴結構域依賴性疾病及病症。CBP/p300溴結構域之抑制提供一種治療包括但不限於癌症之疾病的新穎方法。
在某些實施例中,提供新穎的CBP抑制劑化合物。除非另外指出,否則如本文所用之「CBP抑制劑化合物」係指當根據如下實例1031之HTRF生化檢定方案測試時具有一或多種以下特徵之化合物:(1)小於1 µM之CBP IC
50值;及(2)介於0.001與1 µM之間的CBP IC
50值。
在較佳實施例中,提供新穎的選擇性CBP抑制劑化合物。除非另外指出,否則如本文所用之「選擇性CBP抑制劑化合物」係指具有大於其CBP IC
50值之BRD4 IC
50值的CBP抑制劑,其中其BRD4 IC
50值較佳大於1 µM (例如,1微莫耳至10微莫耳或更大),其中IC
50值係如實例1031之程序中所測定。
在本揭示之第一態樣中描述式(I)之化合物:
(I),
及其醫藥學上可接受之鹽,其中R
1、R
2、R
3、R
4及R
4’如上關於式(I)所述。
應理解,除非另外指出,否則所有異構形式均包括在本揭示內,包括其混合物。若化合物含有雙鍵,則取代基可呈E或Z組態。若化合物含有二取代之環烷基,則該環烷基取代基可具有順式或反式組態。亦旨在包括所有互變異構形式。
除非另外指出,否則式(I)之化合物可以其互變異構形式(例如,作為醯胺或亞胺醚)存在。所有此類互變異構形式涵蓋於本文中作為本揭示之一部分。
除非另外指出,否則式(I)之化合物可含有不對稱或掌性中心,且因此以不同立體異構形式存在。旨在除非另外指出,否則式(I)化合物之所有立體異構形式以及其混合物(包括外消旋混合物)形成本揭示之一部分。另外,本揭示包括所有幾何及位置異構物。例如,若式(I)化合物合併有雙鍵或稠環,則順式及反式以及混合物均包括在本揭示之範疇內。本文所揭示之各化合物包括符合化合物之通用結構的所有對映異構物。化合物可呈外消旋或對映異構純形式或在立體化學術語中之任何其他形式。檢定結果可反映針對外消旋形式、對映異構純形式或立體化學術語中之任何其他形式所收集之資料。
非對映異構混合物可基於其物理化學差異,藉由熟習此項技術者所熟知之方法(諸如藉由層析法及/或分級結晶)分離成其單個非對映異構物。對映異構物可藉由以下步驟來分離:藉由與適當的光活性化合物(例如,掌性助劑,諸如掌性醇或莫雪氏醯氯(Mosher's acid chloride))反應使鏡像異構混合物轉化為非對映異構混合物,分離非對映異構物以及將單個非對映異構物轉化(例如水解)為相應的純對映異構物。一些式(I)化合物亦可為阻轉異構物(例如,經取代之聯芳)並且被視為本揭示之一部分。亦可藉由使用掌性HPLC管柱分離對映異構物。
式(I)之化合物可形成亦在本揭示之範疇內的鹽。除非另外指出,否則在本文中對式(I)化合物之提及應理解為對其鹽之提及。
本揭示係關於如本文所述之化合物及其醫藥學上可接受之鹽。本揭示亦包括醫藥組合物,其包含一或多種如本文所述之化合物或其醫藥學上可接受之鹽及醫藥學上可接受之賦形劑。在一些實施例中,本文所報告之醫藥組合物可以單位劑型(例如,膠囊、錠劑或其類似物)提供。在一些實施例中,本文所報告之醫藥組合物可以口服劑型提供。在一些實施例中,式(I)化合物之口服劑型可為膠囊。在一些實施例中,式(I)化合物之口服劑型為錠劑。在一些實施例中,口服劑型包含一或多種填充劑、崩散劑、潤滑劑、助滑劑、防黏劑及/或抗靜電劑。在一些實施例中,經由幹摻合製備口服劑型。在一些實施例中,口服劑型為錠劑並經由幹式造粒製備。
在一些實施例中,本揭示之化合物可在治療有效頻率(例如,每日一次至每週一次)下以1 mg至1 g給予。
本揭示之化合物
本揭示係關於能夠調節CBP/p300家族溴結構域之化合物或其醫藥學上可接受之鹽或異構物,其適用於治療與CBP/p300家族溴結構域之調節有關之疾病及病症。本揭示進一步係關於適用於抑制CBP/p300家族溴結構域之化合物或其醫藥學上可接受之鹽或異構物。
在一些實施例中,本揭示之化合物具有式(I):
(I),
或其醫藥學上可接受之鹽,
其中,
R
1為-C
1-C
6烷基、-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OR
5、
-N(R
5)
2或-NHR
5;
R
5為-C
1-C
6烷基、-C
3-C
8環烷基、雜環基、芳基或雜芳基;
各R
6為-H、-OH、鹵素、側氧、-C
1-C
6烷基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、-NO
2、-CN、-NH
2、-OC
1-C
6烷基、-OC
3-C
6環烷基、-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、-S(O)
2N(C
1-C
6烷基)
2、
-S(O)
2C
1-C
6烷基、-C(O)C
1-C
6烷基、-C(O)NH
2、
-C(O)NH(C
1-C
6烷基)、-C(O)N(C
1-C
6烷基)
2、-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、-S(O)(C
1-C
6烷基)、
-S(O)N(C
1-C
6烷基)
2或-N(C
1-C
6烷基)S(O)(C
1-C
6烷基),其中各烷基、烯基、環烷基或環烯基視情況經一或多個-R
10取代;
R
6’為視情況經一或多個-R
10取代之-C
3-C
8環烷基、
-C
4-C
8環烯基、雜環基、雜芳基或芳基;
R
7在每次出現時獨立地為-H、鹵素、-OH、-CN、
-OC
1-C
6烷基、-NH
2、-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、
-S(O)
2NH(C
1-C
6烷基)、-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、-S(O)
2OH、-C(O)C
1-C
6烷基、-C(O)NH
2、
-C(O)NH(C
1-C
6烷基)、-C(O)N(C
1-C
6烷基)
2、-C(O)OH、
-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、
-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2、-S(O)
2NH
2、
-N(C
1-C
6烷基)S(O)(C
1-C
6烷基)或四唑;
R
10在每次出現時各自獨立地為-C
1-C
6烷基、-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OH、鹵素、側氧、-NO
2、-CN、-NH
2、
-OC
1-C
6烷基、-OC
3-C
6環烷基、-O芳基、-O雜芳基、
-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、
-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、-C(O)C
1-C
6烷基、-C(O)NH
2、-C(O)NH(C
1-C
6烷基)、-NHC(O)C
1-C
6烷基、-C(O)N(C
1-C
6烷基)
2、-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2或-N(C
1-C
6烷基)S(O)(C
1-C
6烷基),其中各烷基、烯基、炔基、環烷基、環烯基、雜環基、雜芳基或芳基視情況經一或多個-R
12取代;
其中任何兩個R
10當在非相鄰原子上時可組合形成橋聯環烷基或雜環基;
其中任何兩個R
10當在相鄰原子上時可組合形成環烷基、雜環基、芳基或雜芳基;
R
12獨立地為鹵素;且
m為0至5之整數;且
q為0至4之整數。
在一些實施例中,本揭示之化合物具有式(I-a):
(I-a),
或其醫藥學上可接受之鹽,
其中:
R
1為-C
1-C
6烷基、-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OR
5、
-N(R
5)
2或-NHR
5;
R
5在每次出現時獨立地為-C
1-C
6烷基、-C
3-C
8環烷基、雜環基、芳基或雜芳基;
R
6為-C
1-C
6烷基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、芳基、螺環烷基、螺雜環基、雜芳基、鹵素、側氧、-(CH
2)
n-OR
8、-C(O)R
8’、-C(O)OR
8或-C(O)NR
8R
9,其中各烷基、環烷基、雜環基、螺環烷基、螺雜環基、雜芳基或芳基視情況經一或多個R
10取代;
R
8及R
9在每次出現時各自獨立地為-H、-C
1-C
6烷基、
-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、芳基、雜芳基,其中各烷基、烯基、炔基、環烷基、環烯基、雜環基、芳基或雜芳基視情況經一或多個R
10或R
11取代;或
R
8及R
9可與其皆連接至的原子組合形成螺雜環基、雜環基或雜芳基,其中所形成的螺雜環基、雜環基或雜芳基視情況經一或多個R
10或R
11取代;
R
8’在每次出現時各自獨立地為-C
1-C
6烷基、-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、芳基、雜芳基,其中各烷基、烯基、炔基、環烷基、環烯基、雜環基、芳基或雜芳基視情況經一或多個R
10或R
11取代;或
R
10在每次出現時各自獨立地為-C
1-C
6烷基、-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OH、鹵素、側氧、-NO
2、-CN、-NH
2、
-OC
1-C
6烷基、-OC
3-C
6環烷基、-O芳基、-O雜芳基、
-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、
-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、-C(O)C
1-C
6烷基、-C(O)NH
2、-C(O)NH(C
1-C
6烷基)、-C(O)N(C
1-C
6烷基)
2、-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、
-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2或-N(C
1-C
6烷基)S(O)(C
1-C
6烷基),其中各烷基、烯基、炔基、環烷基、環烯基、雜環基、雜芳基或芳基視情況經一或多個
-R
12取代;
其中任何兩個R
10當在非相鄰原子上時可組合形成橋聯環烷基或雜環基;
其中任何兩個R
10當在相鄰原子上時可組合形成環烷基、雜環基、芳基或雜芳基;
R
12在每次出現時獨立地為-C
1-C
6烷基、-C
2-C
6烯基、
-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OH、鹵素、側氧、-NO
2、-CN、-NH
2、-OC
1-C
6烷基、-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、
-C(O)C
1-C
6烷基、-C(O)NH
2、-C(O)NH(C
1-C
6烷基)、
-C(O)N(C
1-C
6烷基)
2、-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2或-N(C
1-C
6烷基)S(O)(C
1-C
6烷基);並且
n為1至4之整數。
在一些實施例中,對於式(I-a)之化合物或其醫藥學上可接受之鹽:
R
1為-C
1-C
6烷基、-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OR
5、
-N(R
5)
2或-NHR
5;
R
5為-C
1-C
6烷基、-C
3-C
8環烷基、雜環基、芳基或雜芳基;
R
6為-C
1-C
6烷基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、芳基、螺環烷基、螺雜環基、雜芳基、鹵素、側氧、-(CH
2)
n-OR
8、-C(O)R
8’、-C(O)OR
8或-C(O)NR
8R
9,其中各烷基、環烷基、雜環基、螺環烷基、螺雜環基、雜芳基或芳基視情況經一或多個R
10取代;
R
8及R
9在每次出現時各自獨立地為-H、-C
1-C
6烷基、
-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、芳基、雜芳基,其中各烷基、烯基、炔基、環烷基、環烯基、雜環基、芳基或雜芳基視情況經一或多個R
10或R
11取代;或
R
8及R
9可與其皆連接至的原子組合形成螺雜環基、雜環基或雜芳基,其中所形成的螺雜環基、雜環基或雜芳基視情況經一或多個R
10或R
11取代;
R
8’在每次出現時各自獨立地為-C
1-C
6烷基、-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、芳基、雜芳基,其中各烷基、烯基、炔基、環烷基、環烯基、雜環基、芳基或雜芳基視情況經一或多個R
10或R
11取代;或
R
10在每次出現時各自獨立地為-C
1-C
6烷基、-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OH、鹵素、側氧、-NO
2、-CN、-NH
2、
-OC
1-C
6烷基、-OC
3-C
6環烷基、-O芳基、-O雜芳基、
-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、
-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、-C(O)C
1-C
6烷基、-C(O)NH
2、-C(O)NH(C
1-C
6烷基)、-C(O)N(C
1-C
6烷基)
2、-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、
-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2或-N(C
1-C
6烷基)S(O)(C
1-C
6烷基),其中各烷基、烯基、炔基、環烷基、環烯基、雜環基、雜芳基或芳基視情況經一或多個
-R
12取代;
其中任何兩個R
10當在非相鄰原子上時可組合形成橋聯環烷基或雜環基;
其中任何兩個R
10當在相鄰原子上時可組合形成環烷基、雜環基、芳基或雜芳基;
R
12在每次出現時獨立地為-C
1-C
6烷基、-C
2-C
6烯基、
-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OH、鹵素、側氧、-NO
2、-CN、-NH
2、-OC
1-C
6烷基、-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、
-C(O)C
1-C
6烷基、-C(O)NH
2、-C(O)NH(C
1-C
6烷基)、
-C(O)N(C
1-C
6烷基)
2、-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2或-N(C
1-C
6烷基)S(O)(C
1-C
6烷基);並且
n為1至4之整數。
在一些實施例中,本揭示之化合物具有式(I-b):
(I-b),
或其醫藥學上可接受之鹽,
其中,
R
1為-OR
5;
R
5為-C
1-C
6烷基;
R
6為-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基,其中各環烷基、環烯基、雜環基、雜芳基或芳基視情況經一或多個-R
10取代;
R
7為-H、鹵素、-OH、-CN、-OC
1-C
6烷基、-NH
2、
-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、
-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、-S(O)
2OH、
-C(O)C
1-C
6烷基、-C(O)NH
2、-C(O)NH(C
1-C
6烷基)、
-C(O)N(C
1-C
6烷基)
2、-C(O)OH、-C(O)OC
1-C
6烷基、
-N(C
1-C
6烷基)SO
2C
1-C
6烷基、-S(O)(C
1-C
6烷基)、
-S(O)N(C
1-C
6烷基)
2、-S(O)
2NH
2、-N(C
1-C
6烷基)S(O)(C
1-C
6烷基)或四唑;
R
10在每次出現時各自獨立地為-C
1-C
6烷基、-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OH、鹵素、側氧、-NO
2、-CN、-NH
2、
-OC
1-C
6烷基、-OC
3-C
6環烷基、-O芳基、-O雜芳基、
-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、
-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、-C(O)C
1-C
6烷基、-C(O)NH
2、-C(O)NH(C
1-C
6烷基)、-NHC(O)C
1-C
6烷基、-C(O)N(C
1-C
6烷基)
2、-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2或-N(C
1-C
6烷基)S(O)(C
1-C
6烷基),其中各烷基、烯基、炔基、環烷基、環烯基、雜環基、雜芳基或芳基視情況經一或多個-R
12取代;
R
12為鹵素;
m為0至5之整數。
在一些實施例中,本揭示之化合物具有式(I-c):
(I-c),
或其醫藥學上可接受之鹽,
其中,
R
1為-OR
5;
R
5為-C
1-C
6烷基;
R
6為-OH、鹵素、側氧、-NO
2、-CN、-NH
2、-OC
1-C
6烷基、-OC
3-C
6環烷基、-O芳基、-O雜芳基、-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、-C(O)C
1-C
6烷基、
-C(O)NH
2、-C(O)NH(C
1-C
6烷基)、-C(O)N(C
1-C
6烷基)
2、
-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、
-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2或-N(C
1-C
6烷基)S(O)(C
1-C
6烷基),其中各烷基、烯基、炔基、環烷基、環烯基、雜環基、雜芳基或芳基視情況經一或多個
-R
10取代;
R
7在每次出現時獨立地為-H、鹵素、-OH、-CN、
-OC
1-C
6烷基、-NH
2、-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、
-S(O)
2NH(C
1-C
6烷基)、-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、-S(O)
2OH、-C(O)C
1-C
6烷基、-C(O)NH
2、
-C(O)NH(C
1-C
6烷基)、-C(O)N(C
1-C
6烷基)
2、-C(O)OH、
-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、
-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2、-S(O)
2NH
2、
-N(C
1-C
6烷基)S(O)(C
1-C
6烷基)或四唑;
R
10在每次出現時各自獨立地為-C
1-C
6烷基、-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OH、鹵素、側氧、-NO
2、-CN、-NH
2、
-OC
1-C
6烷基、-OC
3-C
6環烷基、-O芳基、-O雜芳基、
-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、
-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、-C(O)C
1-C
6烷基、-C(O)NH
2、-C(O)NH(C
1-C
6烷基)、-NHC(O)C
1-C
6烷基、-C(O)N(C
1-C
6烷基)
2、-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2或-N(C
1-C
6烷基)S(O)(C
1-C
6烷基),其中各烷基、烯基、炔基、環烷基、環烯基、雜環基、雜芳基或芳基視情況經一或多個-R
12取代;
R
12為鹵素;
m為0至5之整數;且
r為0至5之整數。
在一些實施例中,本揭示之化合物具有式(I-d):
(I-d),
或其醫藥學上可接受之鹽,
其中:
R
1為-OR
5;
R
5為-C
1-C
6烷基;
R
6為視情況經一或多個R
10取代的苯基;
R
10在每次出現時各自獨立地為-C
1-C
6烷基、-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OH、鹵素、側氧、-NO
2、-CN、-NH
2、
-OC
1-C
6烷基、-OC
3-C
6環烷基、-O芳基、-O雜芳基、
-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、
-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、-C(O)C
1-C
6烷基、-C(O)NH
2、-C(O)NH(C
1-C
6烷基)、-C(O)N(C
1-C
6烷基)
2、-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、
-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2或-N(C
1-C
6烷基)S(O)(C
1-C
6烷基),其中各烷基、烯基、炔基、環烷基、環烯基、雜環基、雜芳基或芳基視情況經一或多個
-R
12取代;
其中任何兩個R
10當在非相鄰原子上時可組合形成橋聯環烷基或雜環基;
其中任何兩個R
10當在相鄰原子上時可組合形成環烷基、雜環基、芳基或雜芳基;
R
12在每次出現時獨立地為-C
1-C
6烷基、-C
2-C
6烯基、
-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OH、鹵素、側氧、-NO
2、-CN、-NH
2、-OC
1-C
6烷基、-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、
-C(O)C
1-C
6烷基、-C(O)NH
2、-C(O)NH(C
1-C
6烷基)、
-C(O)N(C
1-C
6烷基)
2、-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2或-N(C
1-C
6烷基)S(O)(C
1-C
6烷基);並且
n為1至4之整數。
在一些實施例中,本揭示之化合物具有式(I-e):
(I-e),
或其醫藥學上可接受之鹽,
其中:
R
1為-OR
5;
R
5為-C
1-C
3烷基;
R
6為視情況經一或多個R
10取代的苯基;
R
10在每次出現時獨立地為鹵素或-OC
1-C
6烷基、-OC
3-C
6環烷基、-O芳基、-O雜芳基,其中各烷基、環烷基、芳基或雜芳基視情況經一或多個-R
12取代;
R
12獨立地為鹵素。
在一些實施例中,對於式(I-e)之化合物或其醫藥學上可接受之鹽:
R
1為-OR
5;
R
5為-C
1-C
3烷基;
R
6為視情況經一或多個R
10取代的苯基;
R
10在每次出現時獨立地為鹵素或-OC
1-C
6烷基、-OC
3-C
6環烷基、-O芳基、-O雜芳基,其中各烷基、環烷基、芳基或雜芳基視情況經一或多個-R
12取代;
R
12為鹵素。
應理解在本揭示通篇中,除非另外指出,否則對式(I)化合物之提及旨在亦包括式(I)、(I-a)、(I-b)、(I-c)、(I-d)及(I-e)以及本文所揭示之此類式之化合物種類。
本揭示之化合物可為以下化合物,其中R
1為-C
1-C
6烷基、-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、
-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OR
5、-N(R
5)
2或-NHR
5。本揭示之化合物可為以下化合物,其中R
1為
-OR
5。本揭示之化合物可為以下化合物,其中R
1為-OR
5且R
5為甲基。
本揭示之化合物可為以下化合物,其中R
5為-C
1-C
6烷基、-C
3-C
8環烷基、雜環基、芳基或雜芳基。本揭示之化合物可為以下化合物,其中R
5為-C
1-C
6烷基。本揭示之化合物可為以下化合物,其中R
5為-C
1-C
3烷基。本揭示之化合物可為以下化合物,其中R
5為甲基。
本揭示之化合物可為以下化合物,其中R
6為-C
1-C
6烷基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、芳基、螺環烷基、螺雜環基、雜芳基、鹵素、側氧、
-(CH
2)
n-OR
8、-C(O)R
8’、-C(O)OR
8或-C(O)NR
8R
9,其中各烷基、環烷基、雜環基、螺環烷基、螺雜環基、雜芳基或芳基視情況經一或多個R
10取代。本揭示之化合物可為以下化合物,其中R
6為-C
3-C
8環烷基、雜環基、芳基、螺環烷基、螺雜環基或雜芳基,其中各環烷基、雜環基、螺環烷基、螺雜環基、雜芳基或芳基視情況經一或多個R
10取代。本揭示之化合物可為以下化合物,其中R
6為視情況經一或多個R
10取代之芳基。本揭示之化合物可為以下化合物,其中R
6為視情況經一或多個R
10取代之苯基。本揭示之化合物可為以下化合物,其中R
6為經一個R
10取代之苯基。本揭示之化合物可為以下化合物,其中R
6為經兩個R
10取代之苯基。
本揭示之化合物可為以下化合物,其中R
10在每次出現時獨立地為-C
1-C
6烷基、-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OH、鹵素、側氧、-NO
2、-CN、-NH
2、-OC
1-C
6烷基、-OC
3-C
6環烷基、-O芳基、-O雜芳基、-NHC
1-C
6烷基、
-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、-C(O)C
1-C
6烷基、-C(O)NH
2、
-C(O)NH(C
1-C
6烷基)、-C(O)N(C
1-C
6烷基)
2、-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、-S(O)(C
1-C
6烷基)、
-S(O)N(C
1-C
6烷基)
2或-N(C
1-C
6烷基)S(O)(C
1-C
6烷基),其中各烷基、烯基、炔基、環烷基、環烯基、雜環基、雜芳基或芳基視情況經一或多個-R
12取代。本揭示之化合物可為以下化合物,其中R
10在每次出現時獨立地為-C
1-C
6烷基、-C
3-C
8環烷基、雜環基、雜芳基、芳基、-OH、鹵素、側氧、CN、-OC
1-C
6烷基、-OC
3-C
6環烷基或-NHC
1-C
6烷基,-N(C
1-C
6烷基)
2其中各烷基、環烷基、雜環基、雜芳基或芳基視情況經一或多個-R
12取代。本揭示之化合物可為以下化合物,其中R
10在每次出現時獨立地為-C
1-C
6烷基、-OC
1-C
6烷基、-OC
3-C
6環烷基或鹵素,其中各烷基或環烷基視情況經一或多個-R
12取代。本揭示之化合物可為以下化合物,其中R
10在每次出現時獨立地為-OC
1-C
6烷基或鹵素,其中各烷基視情況經一或多個-R
12取代。
本揭示之化合物可為以下化合物,其中R
12在每次出現時獨立地為-C
1-C
6烷基、-C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8環烷基、-C
4-C
8環烯基、雜環基、雜芳基、芳基、-OH、鹵素、側氧、-NO
2、-CN、-NH
2、-OC
1-C
6烷基、-NHC
1-C
6烷基、-N(C
1-C
6烷基)
2、-S(O)
2NH(C
1-C
6烷基)、-S(O)
2N(C
1-C
6烷基)
2、-S(O)
2C
1-C
6烷基、-C(O)C
1-C
6烷基、-C(O)NH
2、-C(O)NH(C
1-C
6烷基)、-C(O)N(C
1-C
6烷基)
2、-C(O)OC
1-C
6烷基、-N(C
1-C
6烷基)SO
2C
1-C
6烷基、
-S(O)(C
1-C
6烷基)、-S(O)N(C
1-C
6烷基)
2或-N(C
1-C
6烷基)S(O)(C
1-C
6烷基)。本揭示之化合物可為以下化合物,其中R
12在每次出現時獨立地為鹵素。本揭示之化合物可為以下化合物,其中R
12為氟。本揭示之化合物可為以下化合物,其中R
12為氯。
本揭示之化合物可為以下化合物,其中R
1為-OR
5;R
5為-C
1-C
6烷基;R
6為-C
3-C
8環烷基、雜環基、芳基、螺環烷基、螺雜環基或雜芳基,其中各環烷基、雜環基、螺環烷基、螺雜環基、雜芳基或芳基視情況經一或多個R
10取代;R
10在每次出現時獨立地為-C
1-C
6烷基、-OC
1-C
6烷基、-OC
3-C
6環烷基或鹵素,其中各烷基或環烷基視情況經一或多個-R
12取代且-R
12為鹵素。
本揭示之化合物可為以下化合物,其中R
1為-OR
5;R
5為-C
1-C
3烷基;R
6為視情況經一或多個R
10取代之芳基;R
10在每次出現時獨立地為-C
1-C
6烷基、-OC
1-C
6烷基、-OC
3-C
6環烷基或鹵素,其中各烷基或環烷基視情況經一或多個-R
12取代且-R
12為鹵素。
本揭示之化合物可為以下化合物,其中R
1為-OR
5;R
5為-C
1-C
3烷基;R
6為經一個R
10取代之芳基;R
10為-C
1-C
6烷基、-OC
1-C
6烷基、-OC
3-C
6環烷基或鹵素,其中各烷基或環烷基視情況經一或多個-R
12取代且-R
12為鹵素。
本揭示之化合物可為以下化合物,其中R
1為-OR
5;R
5為-C
1-C
3烷基;R
6為經兩個R
10取代之芳基;R
10在每次出現時獨立地為-OC
1-C
6烷基或鹵素,其中各烷基視情況經一或多個-R
12取代且-R
12為鹵素。
本揭示之化合物可為以下化合物,其中R
1為-OR
5;R
5為甲基;R
6為經兩個R
10取代之苯基;R
10在每次出現時獨立地為-OC
1-C
6烷基或鹵素,其中各烷基視情況經一或多個-R
12取代且-R
12為鹵素。
本揭示之化合物可為以下化合物,其中R
1為-OR
5;R
5為甲基;且R
6為苯基。
本揭示之化合物可為以下化合物,其中R
6為視情況經一或兩個R
10取代之芳基,其中R
10在每次出現時獨立地為鹵素或-OC
1-C
6烷基,其中-OC
1-C
6烷基視情況經鹵素取代。
本揭示之化合物可包含芳基,其中芳基可為具有總共5至14個環成員之環系統,其中系統中之至少一個環為芳族的且其中系統中之各環含有3至7個環成員。例如,芳基可包括但不限於苯基。
本揭示之化合物可包含雜芳基,其中雜芳基為具有5至10個環原子,較佳5、6或9個環原子;具有6、10或14個在環陣列中共用的π電子;及/或除碳原子之外,亦具有1至5個雜原子之基團,其中術語「雜原子」係指氮、氧或硫,且包括任何氧化形式之氮或硫、及任何第四銨化形式之鹼性氮。例如,雜芳基可包括但不限於吡啶、吲哚、苯并吡唑、苯并噁烷(benzoxale)、呋喃并吡啶或異喹啉。
本揭示之化合物可包含雜環,其中雜環基為穩定的5至7員單環或7至10員雙環雜環部分,其為飽和或部分不飽和的,並且除碳原子之外亦具有一或多個、較佳一至四個如上所定義之雜原子。例如,雜環基可包括但不限於二氫呋喃、二氫呋喃吡啶或二氫異呋喃。
合成該等化合物之方法
本揭示之化合物可藉由多種方法(包括標準化學過程)來製備。合適的合成途徑描述於以下給出之實例中。
本揭示之化合物(亦即,式(I)之化合物)或其醫藥學上可接受之鹽可藉由如以下合成流程中部分闡述之有機合成技術中已知之方法來製備。在如下所述之流程中,眾所周知根據一般原理或化學特性,必要時,採用用於敏感性或反應性基團之保護基。根據有機合成之標準方法(T. W. Greene及P. G. M. Wuts, "Protective Groups in Organic Synthesis", 第3版, Wiley, New York 1999)操作保護基。使用熟習此項技術者顯而易知之方法,在化合物合成之適宜階段移除此等基團。選擇過程以及反應條件及其執行順序應與式(I)化合物之製備一致。
熟習此項技術者將認識到立體中心是否存在於式(I)之化合物中。因此,本揭示包括可能的立體異構物(除非在合成中另外指出及/或指定)且不僅包括外消旋化合物,而且亦包括單個對映異構物及/或非對映異構物。除非另外指出,否則當需要作為單個對映異構物或非對映異構物之化合物時,其可藉由立體特異性合成或藉由拆分最終產物或任何適宜的中間物而獲得。最終產物、中間物或起始材料之拆分可藉由此項技術中已知之任何合適的方法完成。參見,例如"Stereochemistry of Organic Compounds" E. L. Eliel, S. H. Wilen及L. N. Mander (Wiley-lnterscience, 1994)。
使用所揭示之化合物之方法
本揭示之一態樣係關於用於醫學中之式(I)化合物。
本揭示之另一態樣係關於一種調節一或多個CBP/p300家族溴結構域之方法,該方法包含向有此需要之患者投與治療有效量之式(I)化合物。本揭示之另一態樣係關於一種抑制一或多個CBP/p300家族溴結構域之方法,該方法包含向有此需要之患者投與治療有效量之式(I)化合物。在另一態樣中,本揭示係關於一種抑制一或多個CBP/p300家族溴結構域之方法,該方法包含向有此需要之患者投與治療有效量之包含式(I)化合物之醫藥組合物。
CBP抑制劑化合物在開發適用於治療某些相關形式之癌症的醫藥組合物中係有用的。CBP抑制劑化合物適用於治療對CBP之抑制有反應的疾病狀態。CREB結合蛋白(CBP)及EP300(p300)為用作轉錄共活化劑之密切相關的多結構域蛋白。其攜帶乙醯基離胺酸結合溴結構域,所述溴結構域向此等蛋白質賦予搭建支架或定位功能,並且經證明適用於設計其生物功能之小分子抑制劑。此等同種同源物在氨基酸層面係高度同源的且共有許多重疊功能。其為催化組蛋白及非組蛋白蛋白質之翻譯後修飾的組蛋白乙醯基轉移酶(HAT)。由於溴結構域攜帶HAT,所以此等蛋白質用作表觀遺傳之讀取物及寫入物。CBP/p300之非組蛋白蛋白質受質係由許多轉錄因子組成,包括核激素受體,諸如雄激素受體(AR)。CBP/p300藉由對AR之乙醯化用作AR信號傳導之共活化劑,AR激活其轉錄活性並提高其蛋白質穩定性。另外,其在離胺酸27處乙醯化組蛋白H3(Ac-H3K27)以提供用於溴結構域之停靠位點,由此提供將核受體橋聯至基本轉錄機構之支架。組蛋白之乙醯化造成在染色質上產生轉錄許可環境。CBP/p300向AR依賴性超增強子之定位由此導致局部化Ac-H3K27之增加,該增加進一步增強在此等基因座處之轉錄。
因此,較佳實施例包括醫藥組合物,其包含具有本文所揭示及/或另外所述之化學結構的選擇性CBP抑制劑。醫藥組合物可為包含選擇性CBP抑制劑化合物之膠囊、錠劑或其他合適的劑型,該化合物可為式(I)、式(I-a)、式(I-b)、式(I-c)、式(I-d)及/或式(I-e)之化合物或其醫藥學上可接受之鹽。包含選擇性CBP抑制劑化合物之醫藥組合物可在整個治療過程中以治療有效量向有此需要之患者(例如,診斷患有咸信對CBP抑制劑化合物有反應之癌症形式的患者)投與以向患者提供所需治療效果。
實例
在以下流程及本文別處使用之定義為:ACN 乙腈
Ac
2O 乙酐
(+)BINAP (±)-2,2′-雙(二苯基膦基)-1,1′-聯萘
Boc 第三丁氧羰基
Brettphos 二環己基[3,6-二甲氧基-2',4',6'-參(1-甲基乙基)[1,1'-聯苯]-2-基]膦
Brettphos Pd G3或第三代BrettPhos催化劑前體: 甲磺酸(2-二環己基膦基-3,6-二甲氧基-2',4',6'-參-異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)
n-BuOH 丁醇
cm 釐米
DCE 1,2-二氯乙烷
DCM 二氯甲烷或氯化甲烷
D-CSA D-樟腦磺酸
DEA 二乙胺
DMC 氯化2-氯-4,5-二氫-1,3-二甲基-1
H-咪唑鎓
DMP 戴斯馬丁高碘烷(Dess-Martin periodinane)
DMTMM 氯化4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基嗎啉鎓
DIEA N,N-二異丙基乙胺
DMAP 4-(二甲胺基)吡啶
DMF N,N-二甲基甲醯胺
DMSO 二甲亞碸
DPPA 二苯基磷醯基疊氮化物
dppf 雙(二苯基膦基)二茂鐵
EDC 1-乙基-(3-二甲胺丙基)碳二亞胺鹽酸鹽
ES 電灑游離
Et
3N 三乙胺
EtOAc 乙酸乙酯
EtOH 乙醇
FA 甲酸
FCC 急驟管柱層析
h 小時
HATU 六氟磷酸2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)-1,1,3,3-四甲基異脲鎓
HCl 氯化氫
HOAc 乙酸
HPLC 高效液相層析
[Ir(COD)Cl]
2氯(1,5-環辛二烯)銥(I)二聚物
(
i-Pr)
2NEt N,N-二異丙基乙胺
L 公升
LCMS 液相層析/質譜法
LDA 二異丙胺化鋰
LRMS 低解析度質譜法
K
2CO
3碳酸鉀
KHMDS 六甲基二矽氮烷鋰
mCPBA 3-氯過氧苯甲酸
MeOH 甲醇
mL 毫升
mmol 毫莫耳
mg 毫克
MHz 百萬赫
MS 質譜法
m/z 質荷比
NBS N-溴琥珀醯亞胺
NH
4Cl 氯化銨
nm 奈米
NMM 4-甲基嗎啉
NMR 核磁共振
Pd
2(dba)
3參(二亞苄基丙酮)二鈀
Ph
3P 三苯膦
PhCHO 苯甲醛
PhMe 甲苯
ppm 百萬分率
rt 室溫
RT 滯留時間
(S)-(-)-MeO-BIPHEP (S)-(-)-2,2'-雙(二苯基膦基)-6,6'-二甲氧基-1,1'-聯苯
SFC 超臨界流體層析
STAB 三乙醯氧基硼氫化鈉
TBS 第三丁基二甲矽基
TBDMS 氯化第三丁基二甲矽基
p-TSA 對甲苯磺酸酐
p-TsOH 對甲苯磺酸
TFA 三氟乙酸
TFAA 三氟乙酸酐
THF 四氫呋喃
TMSCN 三甲基矽基氰化物
UV 紫外線
XPhos 2-二環己基膦基-2′,4′,6′-三異丙基聯苯
ZnI
2碘化鋅
材料
除非另作說明,否則所有材料均係由商業供應商獲得並且在未進一步純化之情況下使用。無水溶劑係由Sigma-Aldrich(Milwaukee, WI)獲得並且直接使用。涉及空氣或水分敏感性試劑之所有反應均在氮氣氛圍下進行並且利用微波輻射之所有反應均在Biotage Initiator EXP EU儀器上進行。
除非另有說明,否則使用以下測量質量觸發之HPLC純化及/或純度及低解析度質譜資料:(1) Waters Acquity超高效液相層析(UPLC)系統(配備有Sample Organizer及Waters Micromass ZQ質譜儀之Waters Acquity UPLC),伴有在220 nm下之UV偵測及低共振電灑正離子模式(ESI) (管柱:Acquity UPLC BEH C18 1.7 µm 2.1 X 50 mm;梯度:5-100%在溶劑A (95/5/0.1%:10 mM甲酸銨/乙腈/甲酸)中之溶劑B (95/5/0.09%:乙腈/水/甲酸)持續2.2 min,接著100-5%在溶劑A中之溶劑B持續0.01 min,隨後保持在5%在溶劑A中之溶劑B下持續0.29 min)或(2) Waters HT2790 Alliance高效液相層析(HPLC)系統(Waters 996 PDA及Waters ZQ Single Quad質譜儀),伴有在220 nm及254 nm下之UV偵測及低共振電灑游離(正/負)模式(ESI) (管柱:XBridge Phenyl或C18,5 µm 4.6x50 mm;梯度:5-95%在溶劑A (含有0.1%甲酸之95%水/5%甲醇)中之溶劑B (含有0.1%甲酸之95%甲醇/5%水)持續2.5 min,接著保持在95%在溶劑A中之溶劑B持續1 min (僅純度及低解析度MS)。
製備化合物之一般方法
本文描述合成本揭示之化合物的方法。本揭示之化合物可根據下文提供之合成流程來合成。流程1之起始材料之製備可見於美國專利第4,404,207號之部分A的實例1中。
除非另有規定,否則以下反應流程中之R
1、R
6、R
6’、R
7、R
10、m及q係如描述及申請專利範圍中所定義。
本文所述之化合物可由市售起始材料製得或使用已知的有機、無機及/或酶促製程來合成。舉例而言,6-氟-2-甲基喹啉可在酸性條件下硝化以得到6-氟-2-甲基-5-硝基喹啉。喹啉之不對稱的銥催化氫化得到(S)-6-氟-2-甲基-5-硝基-1,2,3,4-四氫喹啉。胺甲酸酯形成及後續的親核性芳香族取代產生甲基6-氟-2-甲基-5-硝基喹啉。硝基還原、醯化及酸介導之環化產生式(I)之(S)-7-甲基-3,7,8,9-四氫-6H-咪唑并[4,5-f]喹啉-6-甲酸甲酯核心。
流程1提供適用於合成某些式(I)化合物之方法。
流程 1 實例 413 與 501 : (1R,3R)-3-[(7S)-2-[(R)-(4- 氯苯基 )( 羥基 ) 甲基 ]-6-( 甲氧羰基 )-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -3- 基 ] 環己烷 -1- 甲酸; (1R,3R)-3-[(7S)-2-[(S)-(4- 氯苯基 )( 羥基 ) 甲基 ]-6-( 甲氧羰基 )-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -3- 基 ] 環己烷 -1- 甲酸 步驟 1. 6- 氟 -2- 甲基 -5- 硝基喹啉
將三氟甲磺酸(82.0 mL,0.923 mol)在HNO
3(19.6 mL,0.437 mol)中之溶液在0℃下攪拌20 min。繼之以在0℃下添加於二氯甲烷(300 mL)中之6-氟-2-甲喹啉(50.0 g,0.310 mol)。在室溫(25℃)下攪拌所得混合物15小時。用水(300 mL)稀釋反應混合物。將溶液之pH值用碳酸氫鈉(飽和水溶液)調節至8。用二氯甲烷(3 x 300 mL)萃取所得溶液。將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮。藉由矽膠層析法(用1:4乙酸乙酯/石油醚溶離)純化殘餘物以得到呈淡黃色固體狀之6-氟-2-甲基-5-硝基喹啉(60.0 g,94%)。LCMS (ES,
m/z): 207 [M+H]
+ 步驟 2. (2S)-6- 氟 -2- 甲基 -5- 硝基 -1,2,3,4- 四氫喹啉
將(S)-(-)-MeO-BIPHEP(1.03 g,1.77 mmol)、氯(1,5-環辛二烯)銥(I)二聚物(538 mg,0.80 mmol)於甲苯(100 mL)中之溶液在氮氣氛圍下在室溫(25℃)下攪拌30 min。繼之以添加於甲苯(100 mL)中之I
2(410 mg,1.62 mmol)及6-氟-2-甲基-5-硝基喹啉(33.0 g,0.160 mol)。在氫氣(50 atm)下,在室溫(25℃)下攪拌所得混合物20 h。將所得混合物在真空下濃縮並藉由矽膠層析法(用1:1乙酸乙酯/石油醚溶離)純化以得到粗產物(35.0 g)。將粗產物溶於乙酸乙酯(230 mL)中,接著添加D-樟腦磺酸(36.9 g,0.158 mol)。將所得溶液在60℃下攪拌1 h,接著冷卻至室溫。將固體藉由過濾收集,並用乙酸乙酯(120 mL)沖洗。將固體溶於水(50 mL)中。將溶液之pH值用碳酸氫鈉(飽和水溶液)調節至8。用乙酸乙酯(3 x 120 mL)萃取所得溶液。將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮以得到呈紅色固體狀之(2S)-6-氟-2-甲基-5-硝基-1,2,3,4-四氫喹啉(25.5 g,76%)。LCMS (ES,
m/z): 211 [M+H]
+ 步驟 3. (2S)-6- 氟 -2- 甲基 -5- 硝基 -1,2,3,4- 四氫喹啉 -1- 甲酸甲酯
將(2S)-6-氟-2-甲基-5-硝基-1,2,3,4-四氫喹啉(25.3 g,0.120 mol)、吡啶(39.0 mL,0.484 mol)及氯甲酸甲酯(18.7 mL,0.242 mol)於二氯甲烷(150 mL)中之溶液在室溫(25℃)下攪拌3 h。用1N 氯化氫(水溶液,2 x 70 mL)洗滌反應。將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮以得到呈黃色固體狀之(2S)-6-氟-2-甲基-5-硝基-1,2,3,4-四氫喹啉-1-甲酸甲酯(29.8 g,92%)。LCMS (ES,
m/z): 269 [M+H]
+ 步驟 4. (2S)-6-[[(1R,3R)-3-( 甲氧羰基 ) 環己基 ] 胺基 ]-2- 甲基 -5- 硝基 -1,2,3,4- 四氫喹啉 -1- 甲酸甲酯
將(2S)-6-氟-2-甲基-5-硝基-1,2,3,4-四氫喹啉-1-甲酸甲酯(29.6 g,0.110 mol)、吡啶(29.6 mL,0.368 mol)、碳酸鉀(30.5 g,0.220 mol)及(1R,3R)-3-胺基環己烷-1-甲酸甲酯(25.6 g,162.84 mmol)於DMSO(270 mL)中之溶液在90℃下攪拌15 h,接著冷卻至室溫。將反應藉由添加水(200 mL)驟冷並用乙酸乙酯(3 x 300 mL)萃取。
>將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮。藉由矽膠層析法(用1:1乙酸乙酯/石油醚溶離)純化所得粗產物以得到呈紅色油狀之(2S)-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-5-硝基-1,2,3,4-四氫喹啉-1-甲酸甲酯(32 g,72%)。LCMS (ES,
m/z): 406 [M+H]
+ 步驟 5. (2S)-5- 胺基 -6-[[(1R,3R)-3-( 甲氧羰基 ) 環己基 ] 胺基 ]-2- 甲基 -1,2,3,4- 四氫喹啉 -1- 甲酸甲酯
將(2S)-2-甲基-5-硝基-6-[[(1R,3R)-4-(甲氧羰基)環己基]胺基]-1,2,3,4-四氫喹啉-1-甲酸甲酯(31.0 g,76.46 mmol)、NH
4Cl (24.3 g,454.28 mmol)及Fe (粉末,64.3 g,1.15 mol)於四氫呋喃(300 mL)、乙醇(300 mL)、水(100 mL)中之溶液在80℃下攪拌1 h,接著冷卻至室溫。藉由過濾濾出固體。將所得溶液用水(300 mL)稀釋並用乙酸乙酯(3 x 400 mL)萃取。將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮以得到呈深綠色固體狀之(2S)-5-((R)-2-羥基-2-苯乙醯胺基)-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(27.5 g,92%)。LCMS (ES,
m/z): 376 [M+H]
+ 步驟 6. (2S)-5-[2-(4- 氯苯基 )-2- 羥基乙醯胺基 ]-6-[[(1R,3R)-3-( 甲氧羰基 ) 環己基 ] 胺基 ]-2- 甲基 -1,2,3,4- 四氫喹啉 -1- 甲酸甲酯
將2-(4-氯苯基)-2-羥基乙酸(112 mg,0.60 mmol)、HATU (304 mg,0.80 mmol)、(2S)-5-胺基-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(150 mg,0.40 mmol)及DIEA (155 mg,1.20 mmol)於N,N-二甲基甲醯胺(2 mL)中之溶液在室溫(25℃)下攪拌15 h。將所得溶液用水(30 mL)稀釋並用乙酸乙酯(3 x 50 mL)萃取。將有機層合併,並用鹽水(2 x 25 mL)洗滌。將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮。藉由矽膠層析法(用1:1乙酸乙酯/石油醚溶離)純化所得粗產物以得到呈黃色油狀之(2S)-5-[2-(4-氯苯基)-2-羥基乙醯胺基]-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(70.0 mg,32%)。LCMS (ES,
m/z): 544 [M+H]
+。
步驟 7. (7S)-2-[(4- 氯苯基 )( 羥基 ) 甲基 ]-3-[(1R,3R)-3-( 甲氧羰基 ) 環己基 ]-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -6- 甲酸甲酯
將(2S)-5-[2-(4-氯苯基)-2-羥基乙醯胺基]-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(60.0 mg,0.11 mmol)於AcOH(2 mL)中之溶液在40℃下攪拌15 h,接著冷卻至室溫。用水(10 mL)稀釋反應混合物。將溶液之pH值用碳酸氫鈉(飽和水溶液)調節至8。用乙酸乙酯(3 x 15 mL)萃取所得溶液。將有機層合併,並且經無水硫酸鈉乾燥,過濾並在真空下濃縮。藉由矽膠層析法(用1:1乙酸乙酯/石油醚溶離)純化所得粗產物以得到呈黃色油狀之(7S)-2-[(4-氯苯基)(羥基)甲基]-3-[(1R,3R)-3-(甲氧羰基)環己基]-7-甲基-3H,6H,7H,8H,9H-咪唑并[4,5-f]喹啉-6-甲酸甲酯(46.0 mg,79%)。LCMS (ES,
m/z): 526 [M+H]
+。
步驟 8. (1R,3R)-3-[(7S)-2-[(R)-(4- 氯苯基 )( 羥基 ) 甲基 ]-6-( 甲氧羰基 )-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -3- 基 ] 環己烷 -1- 甲酸; (1R,3R)-3-[(7S)-2-[(S)-(4- 氯苯基 )( 羥基 ) 甲基 ]-6-( 甲氧羰基 )-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -3- 基 ] 環己烷 -1- 甲酸
將(7S)-2-[(4-氯苯基)(羥基)甲基]-3-[(1R,3R)-3-(甲氧羰基)環己基]-7-甲基-3H,6H,7H,8H,9H-咪唑并[4,5-f]喹啉-6-甲酸甲酯(50.0 mg,0.10 mmol)及LiOH (11.4 mg,0.48 mmol)於四氫呋喃(1 mL)與水(1 mL)中之溶液在25℃下攪拌15 h。在真空下濃縮所得混合物。藉由Prep-HPLC (管柱:XBridge Shield RP18 OBD管柱,5um,19 x 150 mm;流動相A:水(含有10 mmol/L NH
4HCO
3)及B:CAN (10%至37%,經12 min);偵測器:UV 254 nm)純化粗產物。將產物級分凍乾以得到呈白色固體狀之(1R,3R)-3-[(7S)-2-[(R)-(4-氯苯基)(羥基)甲基]-6-(甲氧羰基)-7-甲基-3H,6H,7H,8H,9H-咪唑并[4,5-f]喹啉-3-基]環己烷-1-甲酸(10.5 mg,43%);及呈白色固體狀之(1R,3R)-3-[(7S)-2-[(S)-(4-氯苯基)(羥基)甲基]-6-(甲氧羰基)-7-甲基-3H,6H, 7H,8H,9H-咪唑并[4,5-f]喹啉-3-基]環己烷-1-甲酸(7.0 mg,29%)。絕對立體化學未在本文中提供且因此在表1中係未確定的。
第一溶離異構物 (413):
1H-NMR (CD
3OD, 400 MHz) δ (ppm): 7.49 (d,
J= 9.0 Hz, 1H), 7.42-7.33 (m, 5H), 6.19 (s, 1H), 4.92-4.90 (m, 1H), 4.82-4.72 (m, 1H), 3.79 (s, 3H), 3.34-3.20 (m, 1H), 3.02-2.94 (m, 1H), 2.90-2.87 (m, 1H), 2.36-2.09 (m, 4H), 1.99-1.96 (m, 1H), 1.80-1.42 (m, 5H), 1.16 (d,
J= 6.6 Hz, 3H)。LCMS (ES,
m/z): 512 [M+H]
+。
第二溶離異構物 (501):
1H-NMR (CD
3OD, 400 MHz) δ (ppm): 7.52-7.33 (m, 6H), 6.22 (s, 1H), 4.84-4.73 (m, 2H), 3.78 (s, 3H), 3.27-3.16 (m, 1H), 3.04-2.92 (m, 1H), 2.90-2.88 (m, 1H), 2.46-2.35 (m, 2H), 2.30-2.22 (m, 1H), 2.15-2.02 (m, 2H), 1.82-1.71 (m, 1H), 1.63-1.55 (m, 2H), 1.40-1.28 (m, 1H), 1.15 (d,
J= 6.6 Hz, 4H)。LCMS (ES,
m/z): 512 [M+H]
+。
實例 424 與 660 : (1R,3R)-3-[(7S)-2-[(R)-(5- 氟 -2- 甲氧苯基 )( 羥基 ) 甲基 ]-6-( 甲氧羰基 )-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -3- 基 ] 環己烷 -1- 甲酸 (424) ; (1R,3R)-3-[(7S)-2-[(S)-(5- 氟 -2- 甲氧苯基 )( 羥基 ) 甲基 ]-6-( 甲氧羰基 )-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -3- 基 ] 環己烷 -1- 甲酸 (660) 合成中間物 2-(5- 氟 -2- 甲氧苯基 )-2- 羥基乙酸 步驟 1.
2-(5- 氟 -2- 甲氧苯基 )-2-[( 三甲基矽基 ) 氧基 ] 乙腈
將ZnI
2(1.6 mg,0.01 mmol)、5-氟-2-甲氧苯甲醛(1.54 g,9.99 mmol)於三甲基矽烷甲腈(1.5 mL,11.25 mmol)中之溶液在室溫下攪拌1 h。在真空下濃縮所得混合物。藉由矽膠層析法(用1:1乙酸乙酯/石油醚溶離)純化所得粗產物以得到呈白色固體狀之2-(5-氟-2-甲氧苯基)-2-[(三甲基矽基)氧基]乙腈(2.0 g,79%)。
步驟 2. 2-(5- 氟 -2- 甲氧苯基 )-2- 羥基乙酸
2-(5-氟-2-甲氧苯基)-2-[(三甲基矽基)氧基]乙腈(1.50 g,5.92 mmol)於氯化氫(10 mL,12M)中之溶液。將所得溶液在25℃下攪拌1 h,接著在70℃下攪拌2 h。將反應混合物冷卻並在真空下濃縮。藉由逆相層析法(管柱:C18;流動相A:水(含有0.05% TFA)及B:ACN(5%至20%,經30 min);偵測器:UV 254 nm)純化粗產物以得到呈白色固體狀之2-(5-氟-2-甲氧苯基)-2-羥基乙酸(1.10 g,93%)。
步驟 3. 6- 氟 -2- 甲基 -5- 硝基喹啉
將三氟甲磺酸(82.0 mL,0.923 mol)在HNO
3(19.6 mL,0.437 mol)中之溶液在0℃下攪拌20 min。繼之以在0℃下添加於二氯甲烷(300 mL)中之6-氟-2-甲喹啉 (50.0 g,0.310 mol)。在室溫(25℃)下攪拌所得混合物15 h。用水(300 mL)稀釋反應混合物。將溶液之pH值用碳酸氫鈉(飽和水溶液)調節至8。用二氯甲烷(3 x 300 mL)萃取所得溶液。
>將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮。藉由矽膠層析法(用1:4乙酸乙酯/石油醚溶離)純化殘餘物以得到呈淡黃色固體狀之6-氟-2-甲基-5-硝基喹啉(60.0 g,94%)。LCMS (ES,
m/z): 207 [M+H]
+ 步驟 4. (2S)-6- 氟 -2- 甲基 -5- 硝基 -1,2,3,4- 四氫喹啉
將(S)-(-)-MeO-BIPHEP (1.03 g,1.77 mmol)、氯(1,5-環辛二烯)銥(I)二聚物(538 mg,0.80 mmol)於甲苯(100 mL)中之溶液在氮氣氛圍下在室溫(25℃)下攪拌30 min。繼之以添加於甲苯(100 mL)中之I
2(410 mg,1.62 mmol)、6-氟-2-甲基-5-硝基喹啉(33.0 g,0.160 mol)。在氫氣(50 atm)下,在室溫(25℃)下攪拌所得混合物20 h。將所得混合物在真空下濃縮並藉由矽膠層析法(用1:1乙酸乙酯/石油醚溶離)純化以得到粗產物(35.0 g)。將粗產物溶於乙酸乙酯(230 mL)中,接著添加D-樟腦磺酸(36.9 g,0.158 mol)。將所得溶液在60℃下攪拌1 h,接著冷卻至室溫。將固體藉由過濾收集,並用乙酸乙酯(120 mL)沖洗。將固體溶於水(50 mL)中。將溶液之pH值用碳酸氫鈉(飽和水溶液)調節至8。用乙酸乙酯(3 x 120 mL)萃取所得溶液。將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮以得到呈紅色固體狀之(2S)-6-氟-2-甲基-5-硝基-1,2,3,4-四氫喹啉(25.5 g,76%)。LCMS (ES,
m/z): 211 [M+H]
+ 步驟 5. (2S)-6- 氟 -2- 甲基 -5- 硝基 -1,2,3,4- 四氫喹啉 -1- 甲酸甲酯
將(2S)-6-氟-2-甲基-5-硝基-1,2,3,4-四氫喹啉(25.3 g,0.120 mol)、吡啶(39.0 mL,0.484 mol)、氯甲酸甲酯(18.7 mL,0.242 mol)於二氯甲烷(150 mL)中之溶液在室溫(25℃)下攪拌3 h。用1M氯化氫(2 x 70 mL)洗滌反應。將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮以得到呈黃色固體狀之(2S)-6-氟-2-甲基-5-硝基-1,2,3,4-四氫喹啉-1-甲酸甲酯(29.8 g,92%)。LCMS (ES,
m/z): 269 [M+H]
+ 步驟 6. (2S)-6-[[(1R,3R)-3-( 甲氧羰基 ) 環己基 ] 胺基 ]-2- 甲基 -5- 硝基 -1,2,3,4- 四氫喹啉 -1- 甲酸甲酯
將(2S)-6-氟-2-甲基-5-硝基-1,2,3,4-四氫喹啉-1-甲酸甲酯(29.6 g,0.110 mol)、吡啶(29.6 mL,0.368 mol)、碳酸鉀(30.5 g,0.220 mol)、(1R,3R)-3-胺基環己烷-1-甲酸甲酯(25.6 g,162.84 mmol)於DMSO(270 mL)中之溶液在90℃下攪拌15 h,接著冷卻至室溫。將反應藉由添加水(200 mL)驟冷並用乙酸乙酯(3 x 300 mL)萃取。將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮。藉由矽膠層析法(用1:1乙酸乙酯/石油醚溶離)純化所得粗產物以得到呈紅色油狀之(2S)-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-5-硝基-1,2,3,4-四氫喹啉-1-甲酸甲酯(32 g,72%)。LCMS (ES,
m/z): 406 [M+H]
+ 步驟 7. (2S)-5- 胺基 -6-[[(1R,3R)-3-( 甲氧羰基 ) 環己基 ] 胺基 ]-2- 甲基 -1,2,3,4- 四氫喹啉 -1- 甲酸甲酯
將(2S)-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-5-硝基-1,2,3,4-四氫喹啉-1-甲酸甲酯(31.0 g,76.46 mmol)、NH
4Cl (24.3 g,454.28 mmol)、Fe (64.3 g,1.15 mol)於四氫呋喃(300 mL)、乙醇(300 mL)、水(00 mL)中之溶液在80℃下攪拌1 h,接著冷卻至室溫。藉由過濾濾出固體。將所得溶液用水(300 mL)稀釋並用乙酸乙酯(3 x 400 mL)萃取。將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮以得到呈深綠色固體狀之(2S)-5-胺基-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(27.5 g,92%)。LCMS (ES,
m/z): 376 [M+H]
+ 步驟 8. (2S)-5-[2-(5- 氟 -2- 甲氧苯基 )-2- 羥基乙醯胺基 ]-6-[[(1R,3R)-3-( 甲氧羰基 ) 環己基 ] 胺基 ]-2- 甲基 -1,2,3,4- 四氫喹啉 -1- 甲酸甲酯
將2-(5-氟-2-甲氧苯基)-2-羥基乙酸(240 mg,1.20 mmol)、HATU (228 mg,0.60 mmol)、(2S)-5-胺基-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(150 mg,0.40 mmol)、DIEA (0.19 mL,1.20 mmol)於N,N-二甲基甲醯胺(10 mL)中之溶液在25℃下攪拌1 h。用H
2O (10 mL)稀釋所得溶液。用乙酸乙酯(3x15 mL)萃取所得溶液並且合併有機層。用鹽水(2x20 mL)洗滌所得混合物。將混合物經無水硫酸鈉乾燥並在真空下濃縮。藉由矽膠層析法(用3:2乙酸乙酯/石油醚溶離)純化所得粗產物以得到呈黃色固體狀之(2S)-5-[2-(5-氟-2-甲氧苯基)-2-羥基乙醯胺基]-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(180 mg,81%)。LCMS (ES,
m/z): 558 [M+H]
+ 步驟 9. (7S)-2-[(5- 氟 -2- 甲氧苯基 )( 羥基 ) 甲基 ]-3-[(1R,3R)-3-( 甲氧羰基 ) 環己基 ]-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -6- 甲酸甲酯
將(2S)-5-[2-(5-氟-2-甲氧苯基)-2-羥基乙醯胺基]-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(180 mg,0.32 mmol)於AcOH (8 mL)中之溶液在60℃下攪拌隔夜。將反應混合物冷卻並在真空下濃縮。藉由矽膠層析法(用1:1乙酸乙酯/石油醚溶離)純化所得粗產物以得到呈黃色固體狀之(7S)-2-[(5-氟-2-甲氧苯基)(羥基)甲基]-3-[(1R,3R)-3-(甲氧羰基)環己基]-7-甲基-3H,6H,7H,8H,9H-咪唑并[4,5-f]喹啉-6-甲酸甲酯(120 mg,69%)。LCMS (ES,
m/z): 540 [M+H]
+ 步驟 10. (1R,3R)-3-[(7S)-2-[(R)-(5- 氟 -2- 甲氧苯基 )( 羥基 ) 甲基 ]-6-( 甲氧羰基 )-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -3- 基 ] 環己烷 -1- 甲酸; (1R,3R)-3-[(7S)-2-[(S)-(5- 氟 -2- 甲氧苯基 )( 羥基 ) 甲基 ]-6-( 甲氧羰基 )-7- 甲基 -3H,6H,7H, 8H,9H- 咪唑并 [4,5-f] 喹啉 -3- 基 ] 環己烷 -1- 甲酸
將(7S)-2-[(5-氟-2-甲氧苯基)(羥基)甲基]-3-[(1R,3R)-3-(甲氧羰基)環己基]-7-甲基-3H,6H,7H,8H,9H-咪唑并[4,5-f]喹啉-6-甲酸甲酯(120 mg,0.22 mmol)及LiOH (16 mg,0.67 mmol)於四氫呋喃(2.0 mL)、甲醇(2.0 mL)及水(2.0 mL)中之溶液在25℃下攪拌隔夜。在真空下濃縮所得混合物。藉由Prep-HPLC (管柱:XBridge Prep C18 OBD管柱,19x150 mm,5 um;流動相A:水(含有10 mmol/L NH
4HCO
3)及B:ACN(15.0%至29.0%,經14 min);偵測器:UV 220/254nm)純化粗產物。藉由Chiral-Prep-HPLC (管柱:CHIRALPAK IE,2x25 cm,5 um;流動相A:己烷(含有0.1%FA)及B:乙醇(保持50.0%乙醇,經12 min);偵測器:UV 220/254 nm)分離產物。將產物級分濃縮以得到呈白色固體狀之(1R,3R)-3-[(7S)-2-[(R)-(5-氟-2-甲氧苯基)(羥基)甲基]-6-(甲氧羰基)-7-甲基-3H,6H,7H,8H,9H-咪唑并[4,5-f]喹啉-3-基]環己烷-1-甲酸(23.6 mg,20%);及呈白色固體狀之(1R,3R)-3-[(7S)-2-[(S)-(5-氟-2-甲氧苯基)(羥基)甲基]-6-(甲氧羰基)-7-甲基-3H,6H,7H,8H,9H-咪唑并[4,5-f]喹啉-3-基]環己烷-1-甲酸(23.8 mg,20%)。經由HPLC測定對映異構過量:管柱:CHIRALPAK IE-3,管柱尺寸:0.46 x 5 cm;3 µm;流動相:己烷(0.1%FA):EtOH=50:50;流率:1.0 ml/min。為清楚起見,化合物424及660各自之絕對化學未包括在表1中,然而示於上述流程中。
第一溶離異構物 (424):
1H-NMR (CD
3OD, 400 MHz) δ (ppm): 7.56-7.47 (m, 1H), 7.47-7.31 (m, 1H), 7.21-7.09 (m, 1H), 7.09-6.89 (m, 2H), 6.53(s, 1H), 4.81-4.61(m, 2H), 3.85 (s, 3H), 3.78(s, 3H), 3.31-3.18(m, 1H), 3.06-2.82 (m, 2H), 2.57-2.41 (m, 1H), 2.41-2.31 (m, 1H), 2.31-2.09 (m, 3H), 1.83-1.58 (m, 3H), 1.49-1.21 (m, 2H), 1.16 (d,
J= 6.8 Hz, 3H)。LCMS (ES,
m/z): 526 [M+H]
+。
第二溶離異構物 (660):
1H-NMR (CD
3OD, 400 MHz) δ (ppm): 7.69-7.44 (m, 2H), 7.44-7.29 (m, 1H), 7.12-6.99 (m, 1H), 6.98-6.82 (m, 1H), 6.37(s, 1H), 5.03-4.91(m, 1H), 4.81-4.69 (m, 1H), 3.78(s, 3H), 3.61(s, 3H), 3.22-3.04(m, 1H), 3.02-2.87 (m, 2H), 2.54-2.41 (m, 1H), 2.41-2.27 (m, 1H), 2.27-2.08 (m, 3H), 1.82-1.58 (m, 3H), 1.58-1.41 (m, 2H), 1.14 (d,
J= 6.4 Hz, 3H)。LCMS (ES,
m/z): 526 [M+H]
+。
實例 452 與 515 : (1R,3R)-3-[(7S)-2-[(S)-[2-( 二氟甲氧基 )-5- 氟苯基 ]( 羥基 ) 甲基 ]-6-( 甲氧羰基 )-7- 甲基 -3H,6H,7H,8H, 9H- 咪唑并 [4,5-f] 喹啉 -3- 基 ] 環己烷 -1- 甲酸 (515) , (1R,3R)-3-[(7S)-2-[(R)-[2-( 二氟甲氧基 )-5- 氟苯基 ]( 羥基 ) 甲基 ]-6-( 甲氧羰基 )-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -3- 基 ] 環己烷 -1- 甲酸 (452) 合成中間物 2-(2-( 二氟甲氧基 )-5- 氟苯基 )-2- 羥基乙酸 步驟 1. 2-( 二氟甲氧基 )-5- 氟苯甲醛
將5-氟-2-羥苯甲醛(2.0 g,14.3 mmol)、(溴二氟甲基)膦酸二乙酯(5.69 g,21.3 mmol)、氫氧化鉀(16.0 g,285 mmol)於MeCN(100 mL)及水(50 mL)中之溶液在 -30℃下攪拌1 h。用水(20 mL)稀釋反應混合物。用乙酸乙酯(3x100 mL)萃取所得溶液,並且將有機層合併並經無水硫酸鈉乾燥。濾出固體。在真空下濃縮所得混合物。藉由矽膠層析法(用1:1乙酸乙酯/石油醚溶離)純化所得粗產物以得到呈黃色固體狀之2-(二氟甲氧基)-5-氟苯甲醛(1.46 g,54%)。LCMS (ES, m/z): 191 [M+H]
+ 步驟 2. 2-[2-( 二氟甲氧基 )-5- 氟苯基 ]-2-[( 三甲基矽基 ) 氧基 ] 乙腈
將2-(二氟甲氧基)-5-氟苯甲醛(1.46 g,7.68 mmol)、TMSCN (760 mg,7.66 mmol)、ZnI
2(50 mg,0.16 mmol)於二氯甲烷(3 mL)中之溶液在室溫(25℃)下攪拌2 h。在真空下濃縮所得混合物。藉由矽膠層析法(用1:1乙酸乙酯/石油醚溶離)純化所得粗產物以得到呈黃色固體狀之2-[2-(二氟甲氧基)-5-氟苯基]-2-[(三甲基矽基)氧基]乙腈(800 mg,36%)。LCMS (ES, m/z):290 [M+H]
+ 步驟 3. 2-[2-( 二氟甲氧基 )-5- 氟苯基 ]-2- 羥基乙酸
將2-[2-(二氟甲氧基)-5-氟苯基]-2-[(三甲基矽基)氧基]乙腈(800 mg,2.77 mmol)、1,4-二噁烷(2.0 mL)、氯化氫(1.0 mL,12M)於水(2 mL)中之溶液在70℃下攪拌12 h,接著冷卻至室溫。在真空下濃縮所得溶液。藉由逆相管柱層析法(水(含有0.05%TFA)/MeCN)純化粗產物以得到2-[2-(二氟甲氧基)-5-氟苯基]-2-羥基乙酸(400 mg,61%)。LCMS (ES, m/z): 237 [M+H]
+ 步驟 4. (2S)-5-[2-[2-( 二氟甲氧基 )-5- 氟苯基 ]-2- 羥基乙醯胺基 ]-6-[[(1R,3R)-3-( 甲氧羰基 ) 環己基 ] 胺基 ]-2- 甲基 -1,2,3,4- 四氫喹啉 -1- 甲酸甲酯
將(2S)-5-胺基-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(如在上文針對實例424及660之流程中所製備) (200 mg,0.53 mmol)、2-[2-(二氟甲氧基)-5-氟苯基]-2-羥基乙酸(220 mg,0.93 mmol)、DMTMM (350 mg,1.26 mmol)在二氯甲烷(5 mL)中之溶液在室溫(25℃)下攪拌1 h。在真空下濃縮所得溶液。藉由矽膠層析法(用1:1乙酸乙酯/石油醚溶離)純化所得粗產物以得到呈黃色固體狀之(2S)-5-[2-[2-(二氟甲氧基)-5-氟苯基]-2-羥基乙醯胺基]-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(70.0 mg,22%)。LCMS (ES, m/z): 594 [M+H]
+ 步驟 5. (7S)-2-[[2-( 二氟甲氧基 )-5- 氟苯基 ]( 羥基 ) 甲基 ]-3-[(1R,3R)-3-( 甲氧羰基 ) 環己基 ]-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -6- 甲酸甲酯
將(2S)-5-[2-[2-(二氟甲氧基)-5-氟苯基]-2-羥基乙醯胺基]-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(70.0 mg,0.12 mmol)於冰醋酸(2.0 mL)中之溶液在40℃下攪拌隔夜,接著冷卻至室溫。在真空下濃縮所得溶液。藉由矽膠層析法(用1:2乙酸乙酯/石油醚溶離)純化所得粗產物以得到呈黃色固體狀之(7S)-2-[[2-(二氟甲氧基)-5-氟苯基](羥基)甲基]-3-[(1R,3R)-3-(甲氧羰基)環己基]-7-甲基-3H,6H,7H,8H,9H-咪唑并[4,5-f]喹啉-6-甲酸甲酯(50.0 mg,74%)。LCMS (ES, m/z): 576 [M+H]
+ 步驟 6. (1R,3R)-3-[(7S)-2-[(S)-[2-( 二氟甲氧基 )-5- 氟苯基 ]( 羥基 ) 甲基 ]-6-( 甲氧羰基 )-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -3- 基 ] 環己烷 -1- 甲酸; (1R,3R)-3-[(7S)-2-[(R)-[2-( 二氟甲氧基 )-5- 氟苯基 ]( 羥基 ) 甲基 ]-6-( 甲氧羰基 )-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -3- 基 ] 環己烷 -1- 甲酸
將(7S)-2-[[2-(二氟甲氧基)-5-氟苯基](羥基)甲基]-3-[(1R,3R)-3-(甲氧羰基)環己基]-7-甲基-3H,6H,7H, 8H,9H-咪唑并[4,5-f]喹啉-6-甲酸甲酯(50.0 mg,0.09 mmol)、LiOH (10.0 mg,0.42 mmol)於四氫呋喃(2.0 mL)與水(2.0 mL)中之溶液在室溫(25℃)下攪拌隔夜。在真空下濃縮所得混合物。藉由Prep-HPLC (管柱:XBridge Shield RP18 OBD管柱,30x150 mm,5 um;流動相A:水(含有10 mmol/L NH
4HCO
3)及B:ACN (25.0%至35.0%,經8 min);偵測器:UV 254/220 nm)純化粗產物。將產物級分濃縮以得到呈白色固體狀之(1R,3R)-3-[(7S)-2-[(S)-[2-(二氟甲氧基)-5-氟苯基](羥基)甲基]-6-(甲氧羰基)-7-甲基-3H,6H,7H, 8H,9H-咪唑并[4,5-f]喹啉-3-基]環己烷-1-甲酸(4.50 mg,9%)及呈白色固體狀之(1R,3R)-3-[(7S)-2-[(R)-[2-(二氟甲氧基)-5-氟苯基](羥基)甲基]-6-(甲氧羰基)-7-甲基-3H,6H,7H,8H,9H-咪唑并[4,5-f]喹啉-3-基]環己烷-1-甲酸(4.30 mg,9%)。經由HPLC測定對映異構過量:管柱:CHIRALPAK IE-3,管柱尺寸:0.46 x 5 cm;3 µm;共溶劑:IPA (20 mM NH
3);梯度(B%):在4.0 min內10%至50%,在50%下保持2.0 min。為清楚起見,化合物452及515各自之絕對化學未包括在表1中,然而示於上述流程中。
第一溶離異構物 (515) : 1H-NMR (CD
3OD, 400 MHz) δ (ppm): 7.63-7.61 (m, 1H), 7.53 (d,
J= 8.8 Hz, 1H), 7.41(d,
J= 9.2Hz, 1H) 7.20-7.13 (m, 2H), 6.67-6.30 (m, 2H), 4.98-4.95 (m, 1H), 4.76-4.71 (m, 1H), 3.78 (s, 3H), 3.15-2.86 (m, 3H), 2.46-2.20 (m, 5H), 1.81-1.53 (m, 5H), 1.13 (d,
J= 6.8 Hz, 3H)。LCMS (ES,
m/z): 562 [M+H]
+。
第二溶離異構物 (452) : 1H-NMR (CD
3OD, 400 MHz) δ (ppm): 7.55-7.53 (m, 1H), 7.47-7.42 (m, 2H), 7.40-7.12 (m, 2H), 6.85-6.44 (m, 2H), 4.94-4.91 (m, 1H), 4.76-4.71 (m, 1H), 3.78 (s, 3H), 3.22-2.84 (m, 3H), 2.46-2.23 (m, 5H), 1.84-1.61 (m, 5H), 1.14 (d,
J= 6.4 Hz, 3H)。LCMS (ES,
m/z): 562 [M+H]
+;>99.99% ee。
實例 462 : (1R,3R)-3-[(7S)-2-[(R)- 羥基 ( 苯基 ) 甲基 ]-6-( 甲氧羰基 )-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -3- 基 ] 環己烷 -1- 甲酸 步驟 1. 6- 氟 -2- 甲基 -5- 硝基喹啉
將三氟甲磺酸(82.0 mL,0.923 mol)在HNO
3(19.6 mL,0.437 mol)中之溶液在0℃下攪拌20 min。繼之以在0℃下添加於二氯甲烷(300 mL)中之6-氟-2-甲喹啉 (50.0 g,0.310 mol)。在室溫(25℃)下攪拌所得混合物15 h。用水(300 mL)稀釋反應混合物。將溶液之pH值用碳酸氫鈉(飽和水溶液)調節至8。用二氯甲烷(3 x 300 mL)萃取所得溶液。將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮。藉由矽膠層析法(用1:4乙酸乙酯/石油醚溶離)純化殘餘物以得到呈淡黃色固體狀之6-氟-2-甲基-5-硝基喹啉(60.0 g,94%)。LCMS (ES,
m/z): 207 [M+H]
+ 步驟 2. (2S)-6- 氟 -2- 甲基 -5- 硝基 -1,2,3,4- 四氫喹啉
將(S)-(-)-MeO-BIPHEP (1.03 g,1.77 mmol)、氯(1,5-環辛二烯)銥(I)二聚物(538 mg,0.80 mmol)於甲苯(100 mL)中之溶液在氮氣氛圍下在室溫(25℃)下攪拌30 min。繼之以添加於甲苯(100 mL)中之I
2(410 mg,1.62 mmol)、6-氟-2-甲基-5-硝基喹啉(33.0 g,0.160 mol)。在氫氣(50 atm)下,在室溫(25℃)下攪拌所得混合物20 h。將所得混合物在真空下濃縮並藉由矽膠層析法(用1:1乙酸乙酯/石油醚溶離)純化以得到粗產物(35.0 g)。將粗產物溶於乙酸乙酯(230 mL)中,接著添加D-樟腦磺酸(36.9 g,0.158 mol)。將所得溶液在60℃下攪拌1 h,接著冷卻至室溫。將固體藉由過濾收集,並用乙酸乙酯(120 mL)沖洗。將固體溶於水(50 mL)中。將溶液之pH值用碳酸氫鈉(飽和水溶液)調節至8。用乙酸乙酯(3 x 120 mL)萃取所得溶液。將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮以得到呈紅色固體狀之(2S)-6-氟-2-甲基-5-硝基-1,2,3,4-四氫喹啉(25.5 g,76%)。LCMS (ES,
m/z): 211 [M+H]
+ 步驟 3. (2S)-6- 氟 -2- 甲基 -5- 硝基 -1,2,3,4- 四氫喹啉 -1- 甲酸甲酯
將(2S)-6-氟-2-甲基-5-硝基-1,2,3,4-四氫喹啉(25.3 g,0.120 mol)、吡啶(39.0 mL,0.484 mol)、氯甲酸甲酯(18.7 mL,0.242 mol)於二氯甲烷(150 mL)中之溶液在室溫(25℃)下攪拌3 h。用1M氯化氫(2 x 70 mL)洗滌反應。將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮以得到呈黃色固體狀之(2S)-6-氟-2-甲基-5-硝基-1,2,3,4-四氫喹啉-1-甲酸甲酯(29.8 g,92%)。LCMS (ES,
m/z): 269 [M+H]
+ 步驟 4. (2S)-6-[[(1R,3R)-3-( 甲氧羰基 ) 環己基 ] 胺基 ]-2- 甲基 -5- 硝基 -1,2,3,4- 四氫喹啉 -1- 甲酸甲酯
將(2S)-6-氟-2-甲基-5-硝基-1,2,3,4-四氫喹啉-1-甲酸甲酯(29.6 g,0.110 mol)、吡啶(29.6 mL,0.368 mol)、碳酸鉀(30.5 g,0.220 mol)、(1R,3R)-3-胺基環己烷-1-甲酸甲酯(25.6 g,162.84 mmol)於DMSO(270 mL)中之溶液在90℃下攪拌15 h,接著冷卻至室溫。將反應藉由添加水(200 mL)驟冷並用乙酸乙酯(3 x 300 mL)萃取。將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮。藉由矽膠層析法(用1:1乙酸乙酯/石油醚溶離)純化所得粗產物以得到呈紅色油狀之(2S)-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-5-硝基-1,2,3,4-四氫喹啉-1-甲酸甲酯(32 g,72%)。LCMS (ES,
m/z): 406 [M+H]
+ 步驟 5. (2S)-5- 胺基 -6-[[(1R,3R)-3-( 甲氧羰基 ) 環己基 ] 胺基 ]-2- 甲基 -1,2,3,4- 四氫喹啉 -1- 甲酸甲酯
將(2S)-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-5-硝基-1,2,3,4-四氫喹啉-1-甲酸酯(31.0 g,76.46 mmol)、NH
4Cl (24.3 g,454.28 mmol)、Fe (64.3 g,1.15 mol)於四氫呋喃(300 mL)、乙醇(300 mL)、水(100 mL)中之溶液在80℃下攪拌1 h,接著冷卻至室溫。藉由過濾濾出固體。將所得溶液用水(300 mL)稀釋並用乙酸乙酯(3 x 400 mL)萃取。將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮以得到呈深綠色固體狀之(2S)-5-胺基-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(27.5 g,92%)。LCMS (ES,
m/z): 376 [M+H]
+ 步驟 6. (2S)-5-((R)-2- 羥基 -2- 苯乙醯胺基 )-6-[[(1R,3R)-3-( 甲氧羰基 ) 環己基 ] 胺基 ]-2- 甲基 -1,2,3,4- 四氫喹啉 -1- 甲酸甲酯
將(R)-2-羥基-2-苯乙酸(972 mg,6.39 mmol)、HATU (1.20 g,3.16 mmol)、(2S)-5-胺基-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(800 mg,2.13 mmol)、DIEA (1.08 mL,6.20 mmol)於N,N-二甲基甲醯胺(10 mL)中之溶液在室溫(25℃)下攪拌5 h。將所得溶液用水(30 mL)稀釋並用乙酸乙酯(3 x 50 mL)萃取。將有機層合併,並用鹽水(2 x 25 mL)洗滌。將合併之有機層經無水硫酸鈉乾燥,過濾並在真空下濃縮。藉由矽膠層析法(用1:1乙酸乙酯/石油醚溶離)純化所得粗產物以得到呈無色油狀之(2S)-5-((R)-2-羥基-2-苯乙醯胺基)-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(600 mg,55%)。LCMS (ES,
m/z): 510 [M+H]
+ 步驟 7. (7S)-2-[(R)- 羥基 ( 苯基 ) 甲基 ]-3-[(1R,3R)-3-( 甲氧羰基 ) 環己基 ]-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -6- 甲酸甲酯
將(2S)-5-((R)-2-羥基-2-苯乙醯胺基)-6-[[(1R,3R)-3-(甲氧羰基)環己基]胺基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(600 mg,1.18 mmol)於冰醋酸(5 mL,98%)中之溶液在40℃下攪拌隔夜,接著冷卻至室溫。用水(10 mL)稀釋反應混合物。將溶液之pH值用碳酸氫鈉(飽和水溶液)調節至8。用乙酸乙酯(3 x 15 mL)萃取所得溶液。將有機層合併,並且經無水硫酸鈉乾燥,過濾並在真空下濃縮。藉由矽膠層析法(用1:1乙酸乙酯/石油醚溶離)純化所得粗產物以得到呈無色油狀之(7S)-2-[(R)-羥基(苯基)甲基]-3-[(1R,3R)-3-(甲氧羰基)環己基]-7-甲基-3H,6H,7H,8H, 9H-咪唑并[4,5-f]喹啉-6-甲酸甲酯(400 mg,69%)。LCMS (ES,
m/z): 492 [M+H]
+ 步驟 8. (1R,3R)-3-[(7S)-2-[(R)- 羥基 ( 苯基 ) 甲基 ]-6-( 甲氧羰基 )-7- 甲基 -3H,6H,7H,8H,9H- 咪唑并 [4,5-f] 喹啉 -3- 基 ] 環己烷 -1- 甲酸
將(7S)-2-[(R)-羥基(苯基)甲基]-3-[(1R,3R)-3-(甲氧羰基)環己基]-7-甲基-3H,6H,7H,8H,9H-咪唑并[4,5-f]喹啉-6-甲酸甲酯(400 mg,0.81 mmol)、LiOH (100 mg,4.17 mmol)於四氫呋喃(5 mL)與水(2 mL)中之溶液在室溫(25℃)下攪拌隔夜。在真空下濃縮所得混合物。藉由Prep-HPLC (管柱:XBridge Shield RP18 OBD管柱,5 um,19 x 150 mm;流動相A:水(含有10 mmol/L NH
4HCO
3)及B:ACN (3%至30%,經21 min);偵測器:UV 254 nm)純化粗產物。將產物級分凍乾以得到呈白色固體狀之(1R,3R)-3-[(7S)-2-[(R)-羥基(苯基)甲基]-6-(甲氧羰基)-7-甲基-3H,6H,7H,8H,9H-咪唑并[4,5-f]喹啉-3-基]環己烷-1-甲酸(83.7 mg,22%)。經由HPLC測定對映異構過量:管柱:CHIRALPAK IE-3,管柱尺寸:0.46 x 5 cm;3 µm;流動相:己烷(0.1%FA):EtOH=85:15;流率:1.0 ml/min。為清楚起見,絕對化學未包括在表1中,然而在此處示出。
1H-NMR (CD
3OD, 400 MHz) δ (ppm): 7.47-7.28 (m, 7H), 6.12 (s, 1H), 4.84-4.74 (m, 2H), 3.79 (s, 3H), 3.33-3.25 (m, 1H), 3.03-2.96 (m, 1H), 2.86-2.82 (m, 1H), 2.38-2.25 (m, 2H), 2.25-2.07 (m, 3H), 1.79-1.72 (m, 1H), 1.64-1.57 (m, 2H), 1.40-1.29 (m, 2H), 1.16 (d,
J= 6.8 Hz, 3H)。LCMS (ES,
m/z): 478 [M+H]
+;99.13% ee。
使用與用於先前實例之製備類似的標準化學操作及程序製備
表 1中之以下實例。
表 1
實例 1031 : CBP 及 BRD4 活性之 HTRF 生化檢定
實例 編號 | 結構及化合物名稱 | 1H NMR,LCMS | ||
413 | 3-((7S)-2-((4-氯苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H NMR (CD 3OD, 400 MHz) δ (ppm): 7.49 (d, J= 9.0 Hz, 1H), 7.42-7.33 (m, 5H), 6.19 (s, 1H), 4.92-4.90 (m, 1H), 4.82-4.72 (m, 1H), 3.79 (s, 3H), 3.34-3.20 (m, 1H), 3.02-2.94 (m, 1H), 2.90-2.87 (m, 1H), 2.36-2.09 (m, 4H), 1.99-1.96 (m, 1H), 1.80-1.42 (m, 5H), 1.16 (d, J= 6.6 Hz, 3H). LCMS (ES, m/z): 512 | ||
414 | 3-((7S)-2-((3-氟-4-甲基苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H NMR (CD 3OD, 400 MHz) δ (ppm): 7.53-7.38 (m, 2H), 7.22-7.19 (m, 1H), 7.09-7.04 (m, 2H), 6.16 (s, 1H), 4.86-4.70 (m, 2H), 3.79 (s, 3H), 3.30-3.21 (m, 1H), 3.01-2.92 (m, 1H), 2.88-2.84 (m, 1H), 2.43-2.23 (m, 5H), 2.15-2.04 (m, 2H), 2.01-1.97 (m, 1H), 1.81-1.60 (m, 3H), 1.56-1.38 (m, 2H), 1.16 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 510 [M+H] +. | ||
415 | 3-((7S)-2-((3-氟-4-甲基苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H NMR (CD 3OD, 400 MHz) δ (ppm): 7.61-7.52 (m, 2H), 7.33-7.18 (m, 2H), 7.11-7.09 (m, 1H), 6.26 (s, 1H), 5.02-4.99 (m, 1H), 4.80-4.79 (m, 1H), 3.80 (s, 3H), 3.21-3.16 (m, 1H), 3.08-2.90 (m, 2H), 2.49-2.41 (m, 1H), 2.35-2.22 (m, 5H), 2.14-2.03 (m, 2H), 1.81-1.79 (m, 1H), 1.63-1.58 (m, 2H), 1.45-1.30 (m, 1H), 1.21-1.18 (m, 1H), 1.16 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 510 [M+H] +. | ||
416 | 3-((7S)-2-((3-氯-4-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.71-7.54 (m, 2H), 7.54-7.42 (m, 1H), 7.42-7.29 (m, 1H), 7.19-6.97 (m, 1H), 6.20(s, 1H), 4.99-4.89(m, 1H), 4.82-4.74(m, 1H), 3.98(s, 3H), 3.89(s, 3H), 3.29-3.19(m, 1H), 3.11-2.93 (m, 2H), 2.48-2.22 (m, 2H), 2.22-2.08 (m, 3H), 1.91-1.69 (m, 3H), 1.38-1.24 (m, 2H), 1.18 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 542 [M+H] + | ||
417 | 3-((7S)-2-((3-氟-5-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.51-7.42 (m, 2H), 6.94 (s, 1H), 6.79-6.72 (m, 1H), 6.55-6.62 (m, 1H), 6.19 (s, 1H), 5.03-4.90 (m, 1H), 4.84-4.70 (m, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.28-3.10 (m, 1H), 3.05-2.95 (m, 2H), 2.52-2.43 (m, 2H), 2.38-2.27 (m, 1H), 2.17-1.96 (m, 2H), 1.81-1.66 (m, 1H), 1.64-1.58 (m, 2H), 1.43-1.30 (m, 1H), 1.15 (d, J= 6.8 Hz, 3H), 1.02-0.98 (m, 1H). LCMS (ES, m/z): 526 [M+H] +. | ||
418 | 3-((7S)-2-((3-氟-5-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.55-7.37 (m, 2H), 6.80 (s, 1H), 6.77-6.72 (m, 1H), 6.66-6.59 (m, 1H), 6.15 (s, 1H), 4.85-4.70 (m, 2H), 3.80 (s, 6H), 3.28-3.19 (m, 1H), 3.05-2.95 (m, 1H), 2.91-2.87 (m, 1H), 2.42-2.03 (m, 5H), 1.81-1.60 (m, 3H), 1.56-1.38 (m, 2H), 1.16 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 526 [M+H] +. | ||
419 | 3-((7S)-2-((2,3-二氫苯并呋喃-5-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.48-7.38 (m, 2H), 7.25 (s, 1H), 7.15 (d, J= 8.4 Hz, 1H), 6.70 (d, J= 8.0 Hz, 1H), 6.11 (s, 1H), 4.81-4.74 (m, 2H), 4.53 (t, J= 8.8 Hz, 2H), 3.79 (s, 3H), 3.29-3.25 (m, 1H), 3.19-3.14 (m, 2H), 3.03-2.91 (m, 2H), 2.36-2.25 (m, 2H), 2.15-2.07 (m, 3H), 1.77-1.60 (m, 3H), 1.35-1.25 (m, 2H), 1.16 (d, J= 6.4 Hz, 3H). LCMS (ES, m/z): 520 [M+H] +. | ||
420 | 3-((7S)-2-((3-氟-4-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.53-7.39 (m, 2H), 7.17-7.05 (m, 3H), 6.14 (s, 1H), 4.89-4.67 (m, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.32-3.21 (m, 1H), 3.04-2.93 (m, 1H), 2.91-2.89 (s, 1H), 2.40-2.22 (m, 2H), 2.22-2.10 (m, 2H), 2.10-2.05 (m, 1H), 1.81-1.60 (m, 3H), 1.52-1.40 (m, 2H), 1.16 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 526 [M+H] +. | ||
421 | 3-((7S)-2-((3-氯-5-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.52-7.42 (m, 2H), 7.00-6.89 (m, 3H), 6.13 (s, 1H), 4.85-4.73 (m, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.33-3.22 (m, 1H), 3.04-2.90 (m, 2H), 2.42-2.22 (m, 2H), 2.16-2.07 (m, 3H), 1.78-1.54 (m, 3H), 1.48-1.32 (m, 2H), 1.17 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 542 [M+H] +. | ||
423 | 3-((7S)-2-((3-氯苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.47-7.30 (m, 6H), 6.22 (s, 1H), 4.92-4.90 (m, 1H), 4.78-4.74 (m, 1H), 3.78 (m, 3H), 3.33-3.24 (m, 1H), 3.01-2.82 (m, 2H), 2.34-2.14 (m, 5H), 1.76-1.38 (m, 5H), 1.16 (d, J=6.4 Hz, 3H). LCMS (ES, m/z): 512 [M+H] +. | ||
424 | 3-((7S)-2-((5-氟-2-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.56-7.47 (m, 1H), 7.47-7.31 (m, 1H), 7.21-7.09 (m, 1H), 7.09-6.89 (m, 2H), 6.53(s, 1H), 4.81-4.61(m, 2H), 3.85(s, 3H), 3.78(s, 3H), 3.31-3.18(m, 1H), 3.06-2.82 (m, 2H), 2.57-2.41 (m, 1H), 2.41-2.31 (m, 1H), 2.31-2.09 (m, 3H), 1.83-1.58 (m, 3H), 1.49-1.21 (m, 2H), 1.15 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 526 [M+H] + | ||
426 | 3-((7S)-2-((7-氯-2,3-二氫苯并呋喃-5-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.52-7.51 (m, 2H), 7.23-7.13 (m, 2H), 6.10 (s, 1H), 4.85-4.70 (m, 2H), 4.63 (t, J= 8.4 Hz, 2H), 3.79 (s, 3H), 3.31-3.19 (m, 3H), 3.04-2.88 (m, 2H), 2.43-2.21 (m, 2H), 2.20-2.05 (m, 3H), 1.80-1.59 (m, 3H), 1.45-1.30 (m, 2H), 1.16 (d, J= 6.4 Hz, 3H). LCMS (ES, m/z): 554 [M+H] +. | ||
427 | 3-((7S)-2-((7-氟-2,3-二氫苯并呋喃-5-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.51-7.41 (m, 1H), 7.41-7.29 (m, 1H), 7.24-7.13 (m, 1H), 7.11-6.94 (m, 1H), 6.19(s, 1H), 4.95-4.91(m, 1H), 4.81-4.71(m, 1H), 4.63 (t, J= 8.8 Hz, 2H), 3.78(s, 3H), 3.32-3.18(m, 3H), 3.08-2.91 (m, 1H), 2.82-2.67 (m, 1H), 2.39-2.18 (m, 4H), 2.16-1.98 (m, 1H), 1.82-1.68 (m, 1H), 1.68-1.50 (m, 2H), 1.50-1.38 (m, 1H), 1.16 (d, J=6.8 Hz, 3H), 1.14-1.06 (m, 1H). LCMS (ES, m/z): 538 [M+H] + | ||
428 | 3-((7S)-2-((2,3-二氟-6-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.58-7.44 (m, 1H), 7.44-7.34 (m, 1H), 7.31-7.19 (m, 1H), 6.96-6.78 (m, 1H), 6.57(s, 1H), 4.81-4.66(m, 1H), 4.52-4.29(m, 1H), 3.87(s, 3H), 3.79(s, 3H), 3.33-3.21(m, 1H), 3.08-2.84 (m, 2H), 2.59-2.41 (m, 1H), 2.39-2.22 (m, 2H), 2.22-2.12 (m, 1H), 2.12-1.96 (m, 1H), 1.82-1.68 (m, 1H), 1.69-1.52 (m, 2H),1.24-1.07 (m, 4H), 1.24-0.99 (m, 1H). LCMS (ES, m/z): 544 [M+H] + . | ||
429 | 3-((7S)-2-((5-氟-1H-吲唑-7-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 8.06 (s, 1H), 7.56-7.50 (m, 1H), 7.48 - 7.39 (m, 2H), 7.16 - 7.08 (m, 1H), 6.59 (s, 1H), 5.06 - 4.95 (m, 1H), 4.82 - 4.73 (m, 1H), 3.79 (s, 3H), 3.31 - 3.22 (m, 1H), 3.05 - 2.92 (m, 2H), 2.47 - 2.10 (m, 5H), 1.82 - 1.64 (m, 3H), 1.5-1.28 (m, 2H), 1.17 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 536 [M+H] +. | ||
430 | 3-((7S)-2-((2-氯-4-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.74 (d, J= 9.2 Hz, 1H), 7.52 (d, J= 8.8 Hz, 1H), 7.41 (d, J= 8.8 Hz, 1H), 6.99-6.97 (m, 2H), 6.40 (s, 1H), 4.85-4.81 (m, 1H), 4.74-4.71 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.20-3.13(m, 1H), 2.95-2.90 (m, 1H), 2.89-2.85 (m, 1H), 2.47-2.45 (m, 1H), 2.30-2.17 (m, 4H), 1.75-1.64 (m, 4H), 1.54-1.45 (m, 1H), 1.14 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 542 [M+H] +. | ||
431 | 3-((7S)-2-((2-氯-4-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.59 (d, J= 9.2 Hz, 1H), 7.41 (d, J= 9.2 Hz, 1H), 7.24 (d, J= 8.8 Hz, 1H), 7.02 (s, 1H), 6.84 (d, J= 8.8 Hz, 1H), 6.50 (s, 1H), 4.77-4.72 (m, 1H), 4.54-4.53 (m, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.29-3.23(m, 1H), 2.98-2.91 (m, 2H), 2.47-2.45 (m, 1H), 2.36-2.33 (m, 1H), 2.28-2.17 (m, 2H), 2.08-2.03 (m, 1H), 1.72-1.65 (m, 3H), 1.37-1.21 (m, 1H), 1.21-1.18 (m, 1H), 1.15 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 542 [M+H] +. | ||
432 | 3-((7S)-2-((3,4-二氟苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H NMR (CD 3OD, 400 MHz) δ (ppm): 7.51 (d, J= 9.0 Hz, 1H), 7.44 (d, J= 9.0 Hz, 1H), 7.40-7.31 (m, 1H), 7.23-7.18 (m, 1H), 7.15-7.11 (m, 1H), 6.18 (s, 1H), 4.93-4.91 (m, 1H), 4.80-4.76 (m, 1H), 3.79 (s, 3H), 3.26-3.21 (m, 1H), 3.01-2.94 (m, 1H), 2.86-2.84 (m, 1H), 2.41-2.09 (m, 4H), 1.92-1.89 (m, 1H), 1.78-1.48 (m, 5H), 1.16 (d, J= 6.4 Hz, 3H). LCMS (ES, m/z): 514 [M+H] +. | ||
433 | 3-((7S)-2-((3-氯-5-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.62-7.51 (m, 2H), 7.12-7.07 (m, 1H), 7.03-6.97 (m, 1H), 6.86-6.80 (m, 1H), 6.20 (s, 1H), 5.03-4.92 (m, 1H), 4.78 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.24-3.22 (m, 1H), 3.06-2.96 (m, 2H), 2.53-2.36 (m, 2H), 2.32-2.28 (m, 1H), 2.14-2.12 (m, 1H), 2.04-2.00 (m, 1H), 1.83-1.71 (m, 1H), 1.61-1.52 (m, 2H), 1.40-1.31 (m, 1H), 1.16 (d, J= 6.8 Hz, 3H), 1.05-0.97 (m, 1H). LCMS (ES, m/z): 542 [M+H] +. | ||
434 | 3-((7S)-2-((5-氟-1H-吲哚-7-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.87-7.74 (m, 2H), 7.43-7.30 (m, 2H), 7.02-6.92 (m, 1H), 6.76 (s, 1H), 6.59-6.52 (m, 1H), 4.86-4.71 (m, 2H), 3.82 (s, 3H), 3.29-3.09 (m, 2H), 3.06-2.97 (m, 1H), 2.47-2.36 (m, 2H), 2.35-2.24 (m, 1H), 2.16-2.08 (m, 1H), 2.05-1.85 (m, 2H), 1.74-1.60 (m, 1H), 1.59-1.45 (m, 1H), 1.20 (d, J= 6.8 Hz, 3H), 0.93-0.77 (m, 1H), 0.75-0.61 (m, 1H). LCMS (ES, m/z): 535 [M+H] +. | ||
437 | 3-((7S)-2-((3-氯-4-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.64-7.39 (m, 3H), 7.39-7.21 (m, 1H), 7.16-6.89 (m, 1H), 6.17(s, 1H), 5.03-4.91(m, 1H), 4.82-4.68(m, 1H), 3.87(s, 3H), 3.78(s, 3H), 3.29-3.12(m, 1H), 3.02-2.89 (m, 2H), 2.51-2.21 (m, 3H), 2.19-1.93 (m, 2H), 1.84-1.71 (m, 1H), 1.69-1.54 (m, 2H), 1.51-1.36 (m, 1H), 1.16 (d, J= 6.4 Hz, 3H),1.10-0.97 (m, 1H). LCMS (ES, m/z): 542 [M+H] + | ||
438 | 3-((7S)-2-((3-氟-4-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.52-7.40 (m, 2H), 7.32-7.24 (m, 1H), 7.16-7.10 (m, 1H), 7.08-7.00 (m, 1H), 6.17 (s, 1H), 4.98-4.90 (m, 1H), 4.82-4.71 (m, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.30-3.17 (m, 1H), 3.04-2.94 (m, 2H), 2.50-2.29 (m, 2H), 2.27-2.18 (m, 1H), 2.13-1.95 (m, 2H), 1.80-1.68 (m, 1H), 1.61-1.54 (m, 2H), 1.44-1.27 (m, 1H), 1.15 (d, J= 6.8, 3H), 1.09-1.06 (m, 1H). LCMS (ES, m/z): 526 [M+H] +. | ||
440 | 3-((7S)-2-((2,3-二氫苯并呋喃-7-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.83 (s, 2H), 7.30 (d, J= 6.8 Hz, 1H), 7.23 (d, J= 8.0 Hz, 1H), 6.93 (t, J= 7.6 Hz, 1H), 6.42 (s, 1H), 4.85-4.62 (m, 3H), 4.53-4.41 (m, 1H), 3.833 (s, 3H), 3.27-2.98 (m, 5H), 2.53-2.35 (m, 2H), 2.34-2.09 (m, 3H), 1.92-1.85 (m, 1H), 1.75-1.62 (m, 2H), 1.22-1.01 (m, 5H). LCMS (ES, m/z): 520 [M+H] + | ||
442 | 3-((7S)-2-((5-氯-2-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.59-7.47 (m, 1H), 7.47-7.32 (m, 2H), 7.12-6.99 (m, 1H), 7.09-6.93 (m, 1H), 6.51(s, 1H), 4.82-4.57(m, 2H), 3.87(s, 3H), 3.78(s, 3H), 3.32-3.18(m, 1H), 3.05-2.79 (m, 2H), 2.57-2.41 (m, 1H), 2.41-2.31 (m, 1H), 2.31-2.05 (m, 3H), 1.82-1.67 (m, 3H), 1.52-1.22 (m, 2H), 1.16 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 542 [M+H] + | ||
444 | 3-((7S)-2-((2-(二氟甲基)-5-氟苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.86-7.83 (m, 3H), 7.51-7.34 (m, 2H), 7.29-7.23 (m, 1H), 6.64-6.62 (m, 1H), 4.89-4.76 (m, 3H), 3.83(s, 3H), 3.27-3.02(m, 3H), 2.48-2.14(m, 5H), 1.90-1.85 (m, 1H), 1.76-1.69 (m, 2H), 1.27-1.15 (m, 5H). LCMS (ES, m/z): 546 [M+H] +. | ||
445 | 3-((7S)-2-((5-氟-2-異丙氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.58-7.52 (m, 1H), 7.45-7.40 (m, 1H), 7.31-7.29 (m, 1H), 7.08-6.90 (m, 2H), 6.38 (s, 1H), 4.86-4.75 (m, 2H), 4.62-4.50 (m, 1H), 3.79 (s, 3H), 3.30 - 3.17 (m, 1H), 2.95 - 2.86 (m, 2H),2.48- 2.44 (m, 1H), 2.32-2.24 (m, 4H), 1.80 - 1.50 (m, 5H), 1.18 (d, J= 6.0 Hz, 3H), 1.13 (d, J= 6.4 Hz, 3H), 1.03 (d, J= 6.0 Hz, 3H). LCMS (ES, m/z): 554 [M+H] +. | ||
448 | 3-((7S)-2-((5-氟-1H-吲哚-7-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.87-7.76 (m, 2H), 7.42 (s, 1H), 7.32-7.22 (m, 1H), 6.85-6.74 (m, 2H), 6.54-6.51 (m, 1H), 5.27-5.16 (m, 1H), 4.85-4.76 (m, 1H), 3.82 (s, 3H), 3.20-3.03 (m, 2H), 3.02-2.93 (m, 1H), 2.54-2.33 (m, 2H), 2.32-2.20 (m, 1H), 2.14-1.86 (m, 3H), 1.70-1.56 (m, 1H), 1.55-1.44 (m, 1H), 1.19 (d, J= 6.8 Hz, 3H), 1.05-0.81 (m, 2H). LCMS (ES, m/z): 535 [M+H] +. | ||
449 | 3-((7S)-2-((2,5-二氟苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.55-7.50 (m, 1H), 7.43-7.41 (m, 1H), 7.36-7.32 (m, 1H), 7.14-7.08 (m, 2H), 6.42 (s, 1H), 4.87-4.72(m, 2H), 3.78 (s, 3H),3..33-3.20 (m, 1H), 2.96-2.88 (m, 2H), 2.47-2.2.42 (m, 1H), 2.32-2.12 (m, 4H), 1.80-1.67 (m, 3H), 1.59-1.48 (m, 2H), 1.15 (d, J= 6.4 Hz, 3H). LCMS (ES, m/z): 514 [M+H] + | ||
451 | 3-((7S)-2-(羥基(2-甲基苯并[d]噁唑-5-基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.68 (s, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.49-7.40 (m, 3H), 6.32 (s, 1H), 4.89-4.74 (m, 2H), 3.79 (s, 3H), 3.29-3.25 (m, 1H), 3.04-2.98 (m, 1H), 2.85-2.83 (m, 1H), 2.64 (s, 3H), 2.35-2.31 (m, 2H), 2.29-2.26 (m, 2H), 2.13-1.97 (m, 1H), 1.78-1.74 (m, 1H), 1.67-1.61 (m, 2H), 1.44-1.20 (m, 2H), 1.17 (d, J= 6.4 Hz, 3H). LCMS (ES, m/z): 533 [M+H] +. | ||
452 | 3-((7S)-2-((2-(二氟甲氧基)-5-氟苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.54 (d, J= 8.8 Hz, 1H), 7.47-7.42 (m, 2H), 7.40-7.12 (m, 2H), 6.85-6.45 (m, 1H), 6.44 (s, 1H), 4.94-4.91 (m, 1H), 4.76-4.71 (m, 1H), 3.78 (s, 3H), 3.22-2.84 (m, 3H), 2.46-2.23 (m, 5H), 1.84-1.61 (m, 5H), 1.14 (d, J= 6.4 Hz, 3H). LCMS (ES, m/z): 562 [M+H] +. | ||
458 | 3-((7S)-2-(苯并[d]噁唑-5-基(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 8.49 (s, 1H), 7.85-7.77 (m, 1H), 7.67 (d, J= 8.4 Hz, 1H), 7.59-7.51 (m, 1H), 7.50-7.45 (m, 1H), 7.44-7.37 (m, 1H), 6.35 (s, 1H), 4.88-4.83 (m, 1H), 4.81-4.73 (m, 1H), 3.79 (s, 3H), 3.30-3.24 (m, 1H), 3.07-2.93 (m, 1H), 2.86-2.77 (m, 1H), 2.41-2.23 (m, 2H), 2.21-2.05 (m, 2H), 2.03-1.90 (m, 1H), 1.83-1.71 (m, 1H), 1.70-1.53 (m, 2H), 1.52-1.29 (m, 2H), 1.17 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 519 [M+H] +. | ||
460 | 3-((7S)-2-((2,3-二氫苯并呋喃-5-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.4-7.33(m, 2H), 7.34 (s, 1H), 7.15 (d, J= 8.0 Hz, 1H), 6.68 (d, J= 8.0 Hz, 1H), 6.18 (s, 1H), 4.94-4.88 (m, 1H), 4.79-4.75 (m, 1H), 4.53 (t, J= 8.4 Hz, 2H), 3.78 (s, 3H), 3.25-3.15 (m, 3H), 3.01-2.92 (m, 2H), 2.43-2.30 (m, 3H), 2.28-1.98 (m, 2H), 1.78-1.73 (m, 1H), 1.64-1.58 (m, 2H), 1.40-1.31 (m, 1H), 1.15 (d, J= 6.8 Hz, 3H), 1.07-1.04 (m, 1H). LCMS (ES, m/z): 520 [M+H] +. | ||
461 | 3-((7S)-2-((7-氯-2,3-二氫苯并呋喃-5-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.57-7.42 (m, 2H), 7.29 (s, 1H), 7.22 (s, 1H), 6.18 (s, 1H), 5.08-4.93 (m, 1H), 4.83-4.71 (m, 1H), 4.63 (t, J= 8.4 Hz, 2H), 3.79 (s, 3H), 3.30-3.12 (m, 3H), 3.04-2.90 (m, 2H), 2.51-2.38 (m, 1H), 2.39- 2.20 (m, 2H), 2.16-1.98 (m, 2H), 1.82-1.71 (m, 1H), 1.70-1.62 (m, 2H), 1.54-1.39 (m, 1H), 1.16(d, J= 6.4 Hz, 3H), 1.14-1.09 (m, 1H). LCMS (ES, m/z): 554 [M+H] +. | ||
462 | 3-((7S)-2-(羥基(苯基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.51-7.25 (m, 7H), 6.20 (s, 1H), 4.98-4.72 (m, 2H), 3.79(s, 3H), 3.33-3.25(m, 1H), 3.06-2.81 (m, 2H), 2.41-2.20 (m, 2H), 2.18-2.05 (m, 3H), 1.81-1.72 (m, 1H), 1.70-1.53 (m, 2H), 1.48-1.25 (m, 2H), 1.16 (d, J= 6.4 Hz, 3H). LCMS (ES, m/z): 478 [M+H] +. | ||
464 | 3-((7S)-2-((3-氟-2,6-二甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.49-7.41 (m, 2H), 7.17-7.12 (m, 1H), 6.77-6.74 (m, 1H), 6.55(s, 1H), 4.86-4.76(m, 1H), 4.38-4.34(m, 1H),3.84(s, 3H), 3.79(s, 3H), 3.53(s, 3H), 3.33-325(m, 1H), 3.05-2.98(m, 1H), 2.94-2.92 (m, 1H), 2.50-2.48 (m, 1H), 2.31-2.18(m, 3H), 2.02-1.93(m, 1H), 1.79-1.75 (m, 1H), 1.61-1.58 (m, 2H), 1.18-1.16 (m, 4H), 0.99-0.96 (m, 1H). LCMS (ES, m/z): 556 [M+H] + | ||
467 | 3-((7S)-2-(羥基(1-甲基-1H-吲哚-5-基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.61(s, 1H), 7.45-7.38 (m, 3H), 7.38-7.32 (m, 1H), 7.17-7.15 (m, 1H), 6.42(s, 1H), 6.41(s, 1H), 4.91- 4.75 (m, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.31-3.22 (m, 1H), 3.11-3.00 (m, 1H), 2.91-2.85 (m, 1H), 2.45-2.31 (m, 2H), 2.28-2.21 (m, 1H), 2.12-2.00 (m, 1H), 1.99-1.80 (m, 1H), 1.79-1.70 (m, 1H), 1.62-1.40 (m, 2H), 1.17 (d, J= 6.4 Hz, 3H), 1.12-1.09 (m, 1H), 0.92-0.89 (m, 1H). LCMS (ES, m/z): 531 [M+H] +. | ||
470 | 3-((7S)-2-(羥基(4-甲氧苯基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (DMSO, 400 MHz) δ (ppm): 7.49-7.45 (m, 1H), 7.32-7.27 (m, 3H), 6.89-6.86 (m, 2H), 6.50-6.20 (m, 1H), 6.03 (s, 1H), 4.86-4.79 (m, 1H), 4.67-4.62 (m, 1H), 3.72 (s, 3H), 3.67 (s, 3H), 3.08-3.01 (m, 1H), 2.88-2.82 (m, 2H), 2.34-2.29 (m, 1H), 2.18-2.10 (m, 2H), 1.95-1.88 (m, 2H), 1.66-1.61 (m, 1H), 1.58-1.48 (m, 2H), 1.26-1.22 (m, 1H), 1.06 (d, J= 6.8 Hz, 3H), 1.94-0.90 (m, 1H). LCMS (ES, m/z): 508 [M+H] +. | ||
472 | 3-((7S)-2-(羥基(3-甲氧苯基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.50-7.40(m, 2H), 7.27-7.08 (m, 2H), 6.94-6.84(m, 2H), 6.23(s, 1H), 4.91-4.88(m, 1H), 3.79 (s, 6H), 3.34-2.96 (m, 2H), 2.78-2.68 (m, 1H), 2.36-2.05 (m, 5H), 1.78-1.55 (m, 3H), 1.31-1.15 (m, 6H). LCMS (ES, m/z): 508 [M+H] +. | ||
474 | 3-((7S)-2-((7-氟-2,3-二氫苯并呋喃-5-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.58-7.46 (m, 1H), 7.46-7.37 (m, 1H), 7.17-7.01 (m, 2H), 6.15(s, 1H), 5.03-4.92(m, 1H), 4.83-4.71(m, 1H), 4.63 (t, J= 8.4 Hz, 2H), 3.78(s, 3H), 3.31-3.18(m, 3H), 3.02-2.83 (m, 2H), 2.52-2.31 (m, 2H), 2.31-2.21 (m, 1H), 2.16-2.08 (m, 1H), 2.08-1.98 (m, 1H), 1.84-1.69 (m, 1H), 1.69-1.51 (m, 2H), 1.47-1.33 (m, 1H), 1.15 (d, J=6.8 Hz, 3H), 1.12-1.04 (m, 1H). LCMS (ES, m/z): 538 [M+H] + | ||
478 | 3-((7S)-2-((5-氟-1H-吲唑-7-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 8.09 (s, 1H), 7.52-7.50 (m, 1H), 7.49-7.40 (m, 2H), 7.24-7.20 (m, 1H), 6.63(s, 1H), 5.20-5.08 (m,1H), 5.85-5.75 (m, 1H), 3.80 (s, 3H), 3.28-3.15 (m, 1H), 3.04-2.91 (m, 2H), 2.48-2.41 (m, 2H), 2.34 -2.25 (m, 1H), 2.15-1.95 (m, 2H), 1.80-1.45(m, 3H) , 1.14 (d, J= 6.4 Hz, 3H) , 1.10-1.00 (m, 1H), 0.98-0.88 (m, 1H). LCMS (ES, m/z): 536 [M+H] +. | ||
479 | 3-((7S)-2-((3,4-二氟苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H NMR (CD 3OD, 400 MHz) δ (ppm): 7.54-7.38 (m, 3H), 7.22-7.14 (m, 2H), 6.20 (s, 1H), 4.96-4.93 (m, 1H), 4.79-4.74 (m, 1H), 3.78 (s, 3H), 3.24-3.18 (m, 1H), 3.01-2.94 (m, 2H), 2.50-2.21 (m, 3H), 2.17-1.97 (m, 2H), 1.78-1.72 (m, 1H), 1.63-1.55 (m, 2H), 1.49-1.31 (m, 1H), 1.14 (d, J= 6.8 Hz, 3H), 1.09-1.04 (m, 1H). LCMS (ES, m/z): 514 [M+H] +. | ||
480 | 3-((7S)-2-(羥基(1H-吲唑-5-基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.87 (s, 1H), 7.53 (s, 1H), 7.51-7.37 (m, 4H), 6.33 (s, 1H), 4.94-4.89 (m, 1H), 4.79-4.74 (m, 1H), 3.78 (s, 3H), 3.32-3.27(m, 1H), 3.04-2.98 (m, 1H), 2.97-2.84 (m, 1H), 2.33-2.25 (m, 2H), 2.15-1.95 (m, 3H), 1.78-1.72 (m, 1H), 1.62-1.54 (m, 2H), 1.31-1.24 (m, 1H), 1.16 (d, J= 6.4 Hz, 3H), 1.15-1.13 (m, 1H). LCMS (ES, m/z): 518 [M+H] +. | ||
482 | 3-((7S)-2-((2-環丙氧基-5-氟苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.70-7.65 (m, 2H), 7.39-7.29 (m, 2H), 7.17-7.11 (m, 1H), 6.36 (s, 1H), 4.87-4.79 (m, 2H), 3.82 (s, 3H), 3.73-3.71 (m, 1H), 3.33-2.99 (m, 3H), 2.46-2.18 (m, 5H), 1.83-1.68 (m, 3H), 1.46-1.22 (m, 2H), 1.17 (d, J= 6.8 Hz, 3H), 0.70-0.63(m, 2H), 0.43-0.36 (m, 2H). LCMS (ES, m/z): 552 [M+H] +. | ||
488 | 3-((7S)-2-((3,5-二氟苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.63-7.47 (m, 2H), 7.12 (d, J= 6.8 Hz, 3H), 6.90-6.87 (m, 1H), 6.26 (s, 1H), 5.04 - 4.93 (m, 1H), 4.81-4.78 (m, 1H), 3.79 (s, 3H), 3.24-3.15 (m, 1H), 3.02-2.98 (m, 2H), 2.52-2.06 (m, 5H), 1.81-1.59 (m, 3H), 1.52-1.42 (m, 1H), 1.22-1.17 (m, 1H) , 1.15 (d, J= 6.4 Hz, 3H). LCMS (ES, m/z): 514 [M+H] +. | ||
491 | 3-((7S)-2-(環庚基(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.65-7.49 (m, 1H),7.48-7.23 (m, 1H),5.33-5.12(m, 1H), 4.82-4.58(m, 2H), 3.78(s, 3H), 3.28-3.12 (m, 1H), 3.04-2.86 (m, 2H), 2.59-2.41 (m, 2H), 2.41-2.19 (m, 5H), 2.02-1.82 (m, 2H), 1.82-1.53 (m, 9H), 1.53-1.41 (m, 3H), 1.25-1.11 (m, 5H). LCMS (ES, m/z): 498 [M+H] +. | ||
493 | 3-((7S)-2-((3,5-二氟苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.67-7.45 (m, 2H), 7.02 (d, J= 6.4 Hz, 3H), 6.94-6.91 (m, 1H), 6.23 (s, 1H), 4.93-4.92 (m, 1H), 4.81-4.79 (m, 1H), 3.80 (s, 3H), 3.28-3.18 (m, 1H), 3.01-2.88 (m, 2H), 2.42-2.12 (m, 4H), 2.03-1.99 (m, 1H), 1.83-1.63 (m, 4H), 1.52-1.42 (m, 1H), 1.17 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 514 [M+H] +. | ||
499 | 3-((7S)-2-(苯并[d]噁唑-5-基(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 8.49 (s, 1H), 7.99 (s, 1H), 7.65 (d, J= 8.8 Hz, 1H), 7.54-7.45 (m, 2H), 7.44-7.37 (m, 1H), 6.38 (s, 1H), 5.05-4.93 (m, 1H), 4.83-4.71 (m, 1H), 3.79 (s, 3H), 3.30-3.14 (m, 1H), 3.07-2.95 (m, 1H), 2.94-2.86 (m, 1H), 2.49-2.33 (m, 2H), 2.32-2.22 (m, 1H), 2.15-2.03 (m, 1H), 2.02-1.90 (m, 1H), 1.83-1.68 (m, 1H), 1.65-1.44 (m, 2H), 1.31-1.20 (m, 1H), 1.16 (d, J= 6.8 Hz, 3H), 0.97-0.86 (m, 1H). LCMS (ES, m/z): 519 [M+H] +. | ||
501 | 3-((7S)-2-((4-氯苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.52-7.33 (m, 6H), 6.22 (s, 1H), 4.84-4.73 (m, 2H), 3.78 (s, 3H), 3.27-3.16 (m, 1H), 3.04-2.92 (m, 1H), 2.90-2.88 (m, 1H), 2.46-2.35 (m, 2H), 2.30-2.22 (m, 1H), 2.15-2.02 (m, 2H), 1.82-1.71 (m, 1H), 1.63-1.55 (m, 2H), 1.40-1.28 (m, 1H), 1.15 (d, J= 6.8 Hz, 3H), 1.14-1.01(m, 1H). LCMS (ES, m/z): 512 [M+H] +. | ||
515 | 3-((7S)-2-((2-(二氟甲氧基)-5-氟苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.62 (d, J= 9.2 Hz, 1H), 7.53 (d, J= 8.8 Hz, 1H), 7.41(d, J= 9.2Hz, 1H) 7.20-7.13 (m, 2H), 6.67-6.30 (m, 2H), 4.98-4.95 (m, 1H), 4.76-4.71 (m, 1H), 3.78 (s, 3H), 3.15-2.86 (m, 3H), 2.46-2.20 (m, 5H), 1.81-1.53 (m, 5H), 1.13 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 562 [M+H] +. | ||
523 | 3-((7S)-2-((3-氯苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.51-7.30 (m, 6H), 6.24 (s, 1H), 4.93-4.74 (m, 2H), 3.78 (s, 3H), 3.33-3.17 (m, 1H), 3.01-2.94 (m, 1H), 2.82 (m, 1H), 2.37-2.35 (m, 2H), 2.29-2.24 (m, 2H), 2.08-2.05 (m, 1H), 1.77-1.72 (m, 1H), 1.60-1.54 (m, 2H), 1.34-1.30 (m, 1H), 1.15 (d, J= 6.8 Hz, 3H), 1.14-1.05 (m, 1H). LCMS (ES, m/z): 512 [M+H] +. | ||
528 | (1R,3R)-3-((S)-2-((S)-羥基(苯基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.57-7.40 (m, 4H), 7.30-7.28 (m, 3H), 6.12(s, 1H), 4.95-4.90 (m,1H), 4.84-4.79(m, 1H), 3.79(s, 3H), 3.33-3.25(m, 1H), 3.03-2.82 (m, 2H), 2.49-2.30 (m, 2H), 2.29-2.21 (m, 1H), 2.12-2.07 (m, 1H), 1.99-1.90 (m, 1H), 1.85-1.79 (m, 1H), 1.64-1.49 (m, 2H), 1.40-1.29 (m, 1H), 1.16 (d, J= 6.4 Hz, 3H), 0.95-0.89 (m, 1H). LCMS (ES, m/z): 478 [M+H] +. | ||
534 | (1R,3R)-3-((7S)-2-(1-羥基-1-苯丙基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.84-7.80 (m, 2H), 7.58-7.56 (m, 2H), 7.48-7.43 (m, 3H), 4.86-4.82(m, 1H), 4.69-4.65(m, 1H), 3.82(s, 3H), 3.26-3.08(m, 3H), 3.03-2.98 (m, 1H), 2.65-2.45 (m, 2H), 2.52-1.82 (m, 5H), 1.69-1.62 (m, 1H), 1.52-1.48 (m, 1H), 1.20 (d, J= 6.4 Hz, 3H), 1.01 (t, J= 7.2 Hz, 3H), 0.88-0.79 (m, 2H). LCMS (ES, m/z): 506 [M+H] +. | ||
537 | 3-((7S)-2-((3,5-二氟-2-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H NMR (CD 3OD, 400 MHz) δ (ppm): 7.63 (d, J= 8.8 Hz, 1H), 7.55 (d, J= 9.2 Hz, 1H), 7.21-7.19 (m, 1H), 7.08-7.04 (m, 1H), 6.46 (s, 1H), 4.94-4.92 (m, 1H), 4.80-4.78 (m, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.27-3.21 (m, 1H), 3.05 - 2.89 (m, 2H), 2.51-2.41 (m, 1H), 2.38 - 2.15 (m, 4H), 1.80-1.69 (m, 3H), 1.52-1.43 (m, 2H), 1.15 (d, J= 6.4 Hz, 3H). LCMS (ES, m/z): 544 [M+H] +. | ||
538 | 3-((7S)-2-(羥基(3-甲氧苯基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.47-7.24(m, 3H), 7.04-6.86 (m, 3H), 6.21(s, 1H), 4.87-4.73(m, 1H), 3.77 (s, 6H), 3.33-3.32 (m, 1H), 3.00-2.77 (m, 2H), 2.29-2.05 (m, 5H), 1.75-1.31 (m, 5H), 1.79-1.45 (m, 4H). LCMS (ES, m/z): 508 [M+H] +. | ||
542 | 3-((7S)-2-(1-羥基-1-苯乙基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.48-7.45 (m, 1H), 7.44-7.29 (m, 5H), 7.28-7.21 (m, 1H), 4.81-4.66 (m, 2H), 3.78 (s, 3H), 3.41-3.33 (m, 1H), 3.05-2.92 (m, 1H), 2.78-2.71 (m, 1H), 2.43-2.22 (m, 2H), 2.11 (s, 3H), 2.10-1.95 (m, 2H), 1.79-1.71 (m, 2H), 1.65-1.30 (m, 4H), 1.17 (d, J= 6.4 Hz, 3H). LCMS (ES, m/z): 492 [M+H] +. | ||
564 | 3-((7S)-2-((2-(二氟甲基)-5-氟苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.89-7.83 (m, 2H), 7.77-7.72 (m, 1H), 7.53-7.50 (m, 1H), 7.34-7.31 (m, 1H), 7.21-6.93 (m, 1H), 6.74-6.72 (m, 1H), 4.95-4.93 (m, 1H), 4.85-4.81 (m, 2H), 3.83 (s, 3H), 3.19-3.12(m, 1H), 3.02-2.95 (m, 2H), 2.50-2.48 (m, 1H), 2.30-2.16(m, 4H), 1.89-1.73 (m, 4H), 1.50-1.42 (m, 1H), 1.16 (d, J= 6.4 Hz, 3H). LCMS (ES, m/z): 546 [M+H] +. | ||
565 | 3-((7S)-2-(羥基(2-甲基苯并[d]噁唑-5-基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.82 (s, 1H), 7.52 (d, J= 8.4 Hz, 1H), 7.48-7.40 (m, 3H), 6.35 (s, 1H), 4.96-4.89 (m, 1H), 4.79-4.75 (m, 1H), 3.78 (s, 3H), 3.30-3.24 (m, 1H), 3.22-3.01 (m, 1H), 3.00-2.91 (m, 1H), 2.64 (s, 3H), 2.43-2.42 (m, 2H), 2.40-2.25 (m, 1H), 2.09-2.00 (m, 1H), 1.99-1.96 (m, 1H), 1.78-1.73 (m, 1H), 1.56-1.47 (m, 2H), 1.32-1.26 (m, 1H), 1.15 (d, J= 6.4 Hz, 3H), 0.95-0.92 (m, 1H). LCMS (ES, m/z): 533 [M+H] +. | ||
566 | 3-((7S)-2-(呋喃并[2,3-c]吡啶-5-基(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 8.72 (s, 1H), 8.02 - 7.95 (m, 2H), 7.55 - 7.45 (m, 1H), 7.45 - 7.38 (m, 1H), 6.99 (s, 1H), 6.38 (s, 1H), 5.06 - 4.96 (m, 1H), 4.81 - 4.72 (m, 1H), 3.78 (s, 3H), 3.30 - 3.18 (m, 1H), 2.99 - 2.87 (m, 1H), 2.84 - 2.80 (m, 1H), 2.43 - 2.31 (m, 1H), 2.29 - 2.20 (m, 2H), 2.18 - 2.11 (m, 1H), 2.08 - 2.00 (m, 1H), 1.83 - 1.67 (m, 3H), 1.67 - 1.50 (m, 2H), 1.15 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 519 [M+H] +. | ||
572 | 3-((7S)-2-((2,5-二氟苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.68-7.64 (m, 1H), 7.53-7.50 (m, 1H), 7.43-7.40 (m, 1H), 7.08-7.05 (m, 2H), 6.39 (s, 1H), 5.01-4.95 (m, 1H), 4.87-4.72 (m, 1H), 3.81 (s, 3H), 3.31-3.13(m, 1H), 2.97-2.96 (m, 1H), 2.94-2.86 (m, 1H), 2.50-2.46 (m, 1H), 2.44-2.32 (m, 1H), 2.28-2.17 (m, 3H), 1.74-1.60 (m, 3H), 1.53-1.15 (m, 2H), 1.14 (d, J= 6.4 Hz, 3H) . LCMS (ES, m/z): 514 [M+H] + | ||
578 | 3-((7S)-2-((2,3-二氫苯并呋喃-7-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.52-7.45 (m, 2H), 7.41-7.36 (m, 1H), 7.17 (d, J= 7.2 Hz, 1H), 6.90 (t, J= 7.6 Hz, 1H), 6.28 (s, 1H), 4.85-4.70 (m, 2H), 4.53-4.38 (m, 2H), 3.78 (s, 3H), 3.33-3.12 (m, 3H), 2.98-2.85 (m, 2H), 2.48-2.37 (m, 1H), 2.31-2.21 (m, 2H), 2.15-1.92 (m, 2H), 1.78-1.53 (m, 3H), 1.49-1.28 (m, 2H), 1.15 (d, J= 6.4 Hz, 3H). LCMS (ES, m/z): 520 [M+H] + | ||
587 | 3-((7S)-2-(羥基(異喹啉-3-基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 9.16(s, 1H), 8.08-8.97 (m, 3H), 7.79-7.40 (m, 4H), 6.47(s, 1H), 5.12(s, 1H), 4.77-4.73 (m, 1H), 3.78(s, 3H), 3.34-3.20 (m, 1H), 2.93-2.82 (m, 2H), 2.38-2.15 (m, 5H), 1.76-1.54 (m, 5H), 1.15 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 529 [M+H] +. | ||
589 | 3-((7S)-2-(呋喃并[2,3-c]吡啶-5-基(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 8.73 (s, 1H), 8.11 (s, 1H), 8.07 - 8.02 (m, 1H), 7.51 - 7.45-7.38 (m, 2H), 7.03 (s, 1H), 6.36 (s, 1H), 4.80 - 4.72 (m, 2H), 3.78 (s, 3H), 3.27 - 3.14 (m, 1H), 3.01 - 2.89 (m, 2H), 2.45 - 2.38 (m, 2H), 2.28 - 2.20 (m, 1H), 2.12 - 1.98 (m, 2H), 1.76-1.73 (m, 1H), 1.63 - 1.47 (m, 2H), 1.25-1.09 (m, 4H), 1.08-1.01 (m, 1H). LCMS (ES, m/z): 519 [M+H] +. | ||
606 | 3-((7S)-2-(羥基(1H-吲哚-5-基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.74(s, 1H), 7.66-7.53 (m, 2H), 7.42 (d, J= 8.4 Hz, 1H), 7.29 (d, J= 3.2 Hz, 1H), 7.13 (d, J= 8.8 Hz, 1H), 6.51- 6.45 (m, 2H), 4.83- 4.67 (m, 2H), 3.80 (s, 3H), 3.31-3.22 (m, 1H), 3.11-3.00 (m, 1H), 2.36-1.78 (m, 7H), 1.62-1.54 (m, 1H), 1.39-1.25 (m, 3H), 1.19 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 517 [M+H] +. | ||
607 | 3-((7S)-2-(1-羥基-1-苯乙基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD3OD, 400 MHz) δ (ppm): 7.49-7.20 (m, 7H), 4.85-4.71 (m, 2H), 3.78 (s, 3H), 3.43-3.33 (m, 1H), 3.04-2.92 (m, 1H), 2.91-2.80 (m, 1H), 2.41-2.25 (m, 3H), 2.10-1.99 (m, 4H), 1.97-1.82 (m, 1H), 1.75-1.62 (m, 1H), 1.55-1.35 (m, 2H), 1.16 (d, J= 6.4 Hz, 3H), 1.11-0.95 (m, 1H), 0.78-0.62 (m, 1H). LCMS (ES, m/z): 492 [M+H] +. | ||
608 | 3-((7S)-2-(羥基(1H-吲哚-5-基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.86-7.69 (m, 3H), 7.48 (d, J= 8.4 Hz, 1H), 7.32 (d, J= 3.2 Hz, 1H), 7.17 (d, J= 7.6 Hz, 1H), 6.52-6.49 (m, 2H), 4.88-4.86 (m, 1H), 4.76-4.59 (m, 1H), 3.82 (s, 3H), 3.31-3.24 (m, 1H), 3.15-3.01 (m, 1H), 2.35-2.21 (m, 1H), 2.23-2.06 (m, 2H), 2.06-1.85 (m, 4H), 1.73-1.69 (m, 1H), 1.48-1.40 (m, 2H), 1.27-1.22 (m, 1H), 1.21 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 517 [M+H] +. | ||
610 | 3-((7S)-2-((5-氯吡啶-2-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 8.45 (s, 1H), 8.00-7.97 (m, 1H), 7.89-7.87 (m, 1H), 7.82-7.45 (m, 2H), 6.46 (s, 1H), 5.11-5.05 (m, 1H), 4.87-4.83 (m, 1H), 3.82(s, 3H), 3.18-3.12(m, 1H), 3.03-2.94 (m, 2H), 2.45-2.11 (m, 5H), 1.94-1.73 (m, 4H), 1.52-1.48 (m, 1H), 1.18 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 513 [M+H] +. | ||
612 | 3-((7S)-2-(羥基(1H-吲唑-5-基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 8.05 (s, 1H), 8.01 (s, 1H), 7.51-7.46 (m, 2H), 7.42-7.38 (m, 2H), 6.37 (s, 1H), 5.00-4.98 (m, 1H), 4.80-4.75 (m, 1H), 3.78 (s, 3H), 3.27-3.20(m, 1H), 3.02-2.98 (m, 1H), 2.89-2.84 (m, 1H), 2.38-2.36 (m, 2H), 2.31-2.25 (m, 1H), 2.11-1.97 (m, 2H), 1.79-1.76 (m, 1H), 1.56-1.41 (m, 2H), 1.20-1.16 (m, 1H), 1.15 (d, J= 6.8 Hz, 3H), 0.99-0.96 (m, 1H). LCMS (ES, m/z): 518 [M+H] +. | ||
615 | 3-((7S)-2-(環庚基(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.65-7.48 (m, 1H), 7.48-7.22 (m, 1H), 5.13-4.94(m, 1H), 4.82-4.67(m, 2H), 3.78(s, 3H), 3.29-3.12 (m, 1H), 3.08-2.82 (m, 2H), 2.61-2.19 (m, 6H), 2.19-2.01 (m, 1H), 2.01-1.82 (m, 2H), 1.82-1.46 (m, 12H), 1.42-1.32 (m, 2H), 1.15 (d, J= 6.4 Hz, 3H). LCMS (ES, m/z): 498 [M+H] +. | ||
625 | 3-((7S)-2-(環己基(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.60 - 7.53 (m, 1H), 7.45 - 7.39 (m, 1H), 5.07 - 4.97 (m, 1H), 4.80 - 4.69 (m, 2H), 3.79 (s, 3H), 3.27 - 3.15 (m, 1H), 3.01-2.86 (m, 2H), 2.53 - 2.13 (m, 6H), 2.08 - 2.00 (m, 1H), 1.96 - 1.80 (m, 3H), 1.80-1.73 (m, 5H), 1.35 - 1.22 (m, 4H), 1.21 - 1.12 (m, 5H). LCMS (ES, m/z): 484 [M+H] +. | ||
630 | 3-((7S)-2-((5-氯-2-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.86-7.73(m, 1H),7.58-7.48 (m, 1H), 7.48-7.34 (m, 1H), 7.34-7.23 (m, 1H), 6.99-6.84 (m, 1H), 6.37(s, 1H), 5.08-4.92(m, 1H), 4.81-4.61(m, 1H), 3.78(s, 3H), 3.64(s, 3H), 3.27-3.04 (m, 1H), 3.01-2.93 (m, 1H), 2.93-2.82 (m, 1H), 2.59-2.39 (m, 1H), 2.39-2.28(m, 1H), 2.28-2.07(m, 3H), 1.85-1.60 (m, 3H), 1.59-1.38 (m, 2H), 1.14 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 542 [M+H] + | ||
631 | 3-((7S)-2-(羥基(異喹啉-3-基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 9.17(s, 1H), 8.26-8.02 (m, 3H), 7.82-7.50 (m, 4H), 6.51(s, 1H), 5.08-4.75 (m, 2H), 3.78(s, 3H), 3.33-3.15 (m, 1H), 2.99-2.77 (m, 2H), 2.45-2.02 (m, 5H), 1.75-1.48 (m, 3H), 1.15 (d, J= 6.4 Hz, 3H), 1.12-1.07(m, 2H). LCMS (ES, m/z): 529 [M+H] +. | ||
636 | 3-((7S)-2-((2,3-二氫呋喃并[2,3-c]吡啶-5-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.89 (s, 1H), 7.62-7.62 (m, 1H), 7.62-7.52 (m, 1H), 7.47-7.45 (m, 1H), 6.22 (s, 1H), 4.92-4.90 (m, 1H), 4.82-4.72 (m, 1H), 4.70-4.45 (m, 2H), 3.79 (s, 3H), 3.43-3.34 (m, 1H), 3.34-3.17 (m, 2H), 3.02-2.92 (m, 2H), 2.51-2.32 (m, 1H), 2.30-2.09 (m, 3H), 2.01-1.97 (m, 1H), 1.82-1.78 (m, 3H), 1.72-1.40 (m, 2H), 1.16 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 521 [M+H] +. | ||
637 | 3-((7S)-2-(環己基(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.58 - 7.51 (m, 1H), 7.44 - 7.37 (m, 1H), 5.23 - 5.16 (m, 1H), 4.80 - 4.72 (m, 1H), 4.72 - 4.65 (m, 1H), 3.79 (s, 3H), 3.24 - 3.12 (m, 1H), 3.00- 2.85 (m, 2H), 2.53 (td, J= 13.2, 5.5 Hz, 1H), 2.37 - 2.20 (m, 6H), 2.01 - 1.93 (m, 1H), 1.90 - 1.63 (m, 7H), 1.52 - 1.41 (m, 1H), 1.36 - 1.18 (m, 2H), 1.17 - 0.97 (m, 6H). LCMS (ES, m/z): 484 [M+H] +. | ||
638 | 3-((7S)-2-((2,3-二氟-6-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.62-7.51 (m, 1H), 7.49-7.34 (m, 1H), 7.31-7.11 (m, 1H), 6.91-6.78 (m, 1H), 6.58(s, 1H), 4.89-4.81(m, 1H), 4.78-4.66(m, 1H), 3.83(s, 3H), 3.78(s, 3H), 3.27-3.12(m, 1H), 3.01-2.89 (m, 1H), 2.89-2.76 (m, 1H), 2.54-2.41 (m, 1H), 2.41-2.27 (m, 1H), 2.27-2.12 (m, 3H), 2.12-2.02 (m, 1H),1.95-1.83 (m, 1H), 1.78-1.61 (m, 3H),1.14 (d, J= 6.4 Hz, 3H), LCMS (ES, m/z): 544 [M+H] + . | ||
649 | 3-((7S)-2-((3,5-二氟-2-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H NMR (CD 3OD, 400 MHz) δ (ppm): 7.90 (s, 2H), 7.42-7.38 (m, 1H), 7.15-7.10 (m, 1H), 6.51 (s, 1H), 5.09-5.02 (m, 1H), 4.88-4.86 (m, 1H), 3.83 (s, 3H), 3.72 (s, 3H), 3.24-2.94 (m, 3H), 2.53-2.49 (m, 1H), 2.31-2.12 (m,4H), 1.92-1.89 (m, 1H), 1.81-1.71 (m, 2H), 1.56-1.37 (m, 2H), 1.19 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 544 [M+H] +. | ||
654 | 3-((7S)-2-((2,3-二氫呋喃并[2,3-c]吡啶-5-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 8.05-7.93 (s, 1H), 7.64 (d, J= 4.0 Hz, 1H), 7.52-7.49 (m, 1H), 7.42-7.31 (m, 1H), 6.17 (s, 1H), 4.82-4.71 (m, 2H), 4.70-4.45 (m, 2H), 3.78 (s, 3H), 3.21 (m, 1H), 3.29-3.27 (m, 1H), 3.20-3.15 (m, 1H), 3.05-2.94 (m, 2H), 2.50-2.31 (m, 2H), 2.26-2.20 (m, 1H), 2.16-2.03 (m, 2H), 1.74-1.70 (m, 1H), 1.70-1.61 (m, 2H), 1.33 (m, 1H), 1.21-1.11 (m, 4H). LCMS (ES, m/z): 521 [M+H] +. | ||
660 | 3-((7S)-2-((5-氟-2-甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.69-7.44 (m, 2H), 7.44-7.29 (m, 1H), 7.12-6.99 (m, 1H), 6.98-6.82 (m, 1H), 6.37(s, 1H), 5.03-4.91(m, 1H), 4.81-4.69(m, 1H), 3.78(s, 3H), 3.61(s, 3H), 3.22-3.04(m, 1H), 3.02-2.87 (m, 2H), 2.54-2.41 (m, 1H), 2.41-2.27 (m, 1H), 2.27-2.08 (m, 3H), 1.82-1.58 (m, 3H), 1.58-1.41 (m, 2H), 1.14 (d, J= 6.4 Hz, 3H). LCMS (ES, m/z): 526 [M+H] + | ||
662 | 3-((7S)-2-((5-氟-2-異丙氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H NMR (CD 3OD,400 MHz) δ (ppm): δ 7.61 (m,1H), 7.52-7.42 (m, 2H), 7.05-6.98 (m, 1H), 6.90-6.85 (m, 1H), 6.32 (s, 1H), 4.96-4.85 (m, 1H), 4.81-4.76 (m, 1H), 4.49-4.43 (m, 1H), 3.79 (s, 3H), 3.20-3.16 (m, 1H), 2.98 - 2.85 (m, 2H), 2.51 - 2.35 (m, 2H), 2.29 - 2.07 (m, 3H), 1.78 - 1.60 (m, 3H), 1.50-1.39 (m, 2H), 1.18 (d, J= 6.8 Hz, 3H), 1.12 (d, J= 6.0 Hz, 3H), 0.65 (d, J= 6.0 Hz, 3H). LCMS (ES, m/z): 554 [M+H] +. | ||
678 | 3-((7S)-2-((2-環丙氧基-5-氟苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.73-7.61 (m, 3H), 7.26-7.09 (m, 2H), 6.31 (s, 1H), 5.00-4.81 (m, 2H), 3.82 (s, 3H), 3.70-3.68 (m, 1H), 3.13-2.94 (m, 3H), 2.47-2.14 (m, 5H), 1.91-1.64 (m, 3H), 1.49-1.25 (m, 2H), 1.17 (d, J= 6.4 Hz, 3H), 0.59-0.55(m, 2H), 0.12-0.02 (m, 2H). LCMS (ES, m/z): 552 [M+H] +. | ||
682 | 3-((7S)-2-(羥基(4-甲氧苯基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (DMSO, 400 MHz) δ (ppm): 7.48-7.45 (m, 1H), 7.31-7.24 (m, 3H), 6.89-6.86 (m, 2H), 6.21-6.16 (m, 1H), 5.97-5.96 (m, 1H), 4.83-4.75 (m, 1H), 4.68-4.63 (m, 1H), 3.72 (s, 3H), 3.67 (s, 3H), 3.13-3.06 (m, 1H), 2.89-2.81 (m, 2H), 2.27-2.11 (m, 2H), 2.07-1.87 (m, 3H), 1.68-1.57 (m, 3H), 1.36-1.24 (m, 2H), 1.07 (d, J= 6.4 Hz, 3H). LCMS (ES, m/z): 508 [M+H] +. | ||
699 | 3-((7S)-2-((4,4-二氟環己基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.53 (d, J= 9.2 Hz, 1H), 7.42 (d, J= 9.2 Hz, 1H), 5.28-5.12 (m, 1H), 4.80-4.65 (m, 2H), 3.79(s, 3H), 3.23-3.15(m, 1H), 3.03-2.96 (m, 1H), 2.93-2.82 (m, 1H), 2.58-2.25 (m, 7H), 2.05-1.81 (m, 5H), 1.79-1.52 (m, 4H), 1.48-1.22 (m, 2H), 1.14 (d, J= 6.4 Hz, 3H), 1.13-1.09 (m, 1H). LCMS (ES, m/z): 520 [M+H] +. | ||
701 | 3-((7S)-2-(1,3-二氫異苯并呋喃-4-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.62-7.42 (m, 2H), 7.42-7.33 (m, 1H), 7.32-7.16 (m, 1H), 7.06-6.87 (m, 1H), 6.57(s, 1H), 5.85-5.60(m, 1H), 5.36-5.14(m, 1H), 4.83-4.67(m, 3H), 4.41-4.19(m, 1H), 3.79(s, 3H), 3.31-3.16(m, 1H), 3.04-2.95 (m, 2H), 2.57-2.41 (m, 1H), 2.41-2.20 (m, 2H), 2.13-1.91 (m, 2H), 1.90-1.72 (m, 1H), 1.63-1.39 (m, 2H),1.31-1.11 (m, 4H),1.06-0.79 (m, 1H). LCMS (ES, m/z): 520 [M+H] + | ||
708 | 4-((7S)-2-(羥基(苯基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.47-7.28 (m, 7H), 6.25(s, 1H), 4.84-4.74(m, 1H), 4.68-4.54(m, 1H), 3.79(s, 3H), 3.33-3.18(m, 1H), 3.03-2.96 (m, 1H), 2.46-2.12 (m, 4H), 2.05-1.72 (m, 4H), 1.59-1.45 (m, 1H), 1.16 (d, J= 6.6 Hz, 3H), 1.14-1.02 (m, 1H), 0.99-0.87 (m, 1H). LCMS (ES, m/z): 478 [M+H] +. | ||
731 | 3-((7S)-2-((5-氯吡啶-2-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 8.46 (s, 1H), 8.05-8.01 (m, 1H), 7.95-7.89 (m, 1H), 7.88-7.80 (m, 2H), 6.53 (s, 1H), 5..2-4.88 (m, 1H), 4.85-4.80 (m, 1H), 3.83 (s, 3H), 3.18-2.95 (m, 3H), 2.53-2.10 (m, 5H), 2.02-1.62 (m, 4H), 1.59-1.45 (m, 1H), 1.18 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 513 [M+H] +. | ||
735 | 4-((7S)-2-(羥基(苯基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.47-7.28 (m, 7H), 6.25(s, 1H), 4.84-4.74(m, 1H), 4.68-4.54(m, 1H), 3.79(s, 3H), 3.33-3.18(m, 1H), 3.08-2.96 (m, 1H), 2.46-1.72 (m, 8H), 1.59-1.45 (m, 1H), 1.16 (d, J= 6.6 Hz, 3H), 1.14-1.05 (m, 1H), 1.01-0.87 (m, 1H). LCMS (ES, m/z): 478 [M+H] +. | ||
747 | 3-((7S)-2-((4,4-二氟環己基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.56 (d, J= 8.8 Hz, 1H), 7.41 (d, J= 8.8 Hz, 1H), 5.03-4.90 (m, 1H), 4.80-4.65 (m, 2H), 3.79(s, 3H), 3.23-3.15(m, 1H), 3.03-2.96 (m, 1H), 2.93-2.82 (m, 1H), 2.45-2.32 (m, 2H), 2.30-2.03 (m, 6H), 2.02-1.62 (m, 8H), 1.60-1.45 (m, 3H), 1.14 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 520 [M+H] +. | ||
749 | 3-((7S)-2-(1-羥基-1-(吡啶-2-基)ethyl)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 8.52-8.50 (m, 1H), 8.00-7.92 (m, 1H), 7.90-7.62 (m, 3H), 7.60-7.31 (m, 1H), 4.852-4.76 (m, 2H), 3.83-3.72 (m, 3H), 3.30-3.21 (m, 1H), 3.07 (m, 1H), 2.87-2.84 (m, 1H), 2.47-2.39 (m, 1H), 2.35-2.28 (m, 4H), 2.18-2.02 (m, 2H), 2.00-1.85 (m, 2H), 1.85-1.67 (m, 2H), 1.59-1.52 (m, 1H), 1.20-1.11 (m, 4H). LCMS (ES, m/z): 493 [M+H] +. | ||
762 | 3-((7S)-2-(環戊基(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.56 (d, J= 9.2 Hz, 1H), 7.44 (d, J= 9.2 Hz, 1H), 3.31-5.26 (m, 1H), 4.78-4.76 (m, 2H), 3.79 (s, 3H), 3.17-3.14 (m, 1H), 3.01-2.98 (m, 1H), 2.94-2.84 (m, 2H), 2.53-2.52 (m, 1H), 2.37-2.25 (m, 4H), 2.23-2.08 (m, 1H), 1.77-1.56 (m, 10H), 1.36-1.25 (m, 1H), 1.23-1.20 (m, 1H), 1.15 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 470 [M+H] +. | ||
770 | 3-((7S)-2-((3-氟-2,6-二甲氧苯基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.55-7.50 (m, 1H), 7.43-7.41 (m, 1H), 7.17-7.12 (m, 1H), 6.79-6.77(m, 1H), 6.54 (s, 1H), 4.87-4.70 (m, 2H), 3.83-3.50 (m, 9H), 3.33-3.16 (m, 1H), 2.93-2.82 (m, 2H), 2.51-2.46 (m, 1H), 2.35-2.32 (m, 1H), 2.22-2.20 (m, 3H), 2.05-2.02 (m, 1H), 1.92-1.88 (m, 1H), 1.70-1.68 (m, 3H) 1.44 (d, J= 4.0 Hz, 3H). LCMS (ES, m/z): 556 [M+H] + | ||
774 | 3-((7S)-2-(環戊基(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.56 (d, J= 9.2 Hz, 1H), 7.41 (d, J= 9.2 Hz, 1H), 5.11-5.06 (m, 1H), 4.78-4.73 (m, 2H), 3.79 (s, 3H), 3.21-3.17 (m, 1H), 3.01-2.99 (m, 1H), 2.95-2.90 (m, 1H), 2.70-2.68 (m, 1H), 2.50-2.23 (m, 5H), 1.97-1.76 (m, 3H), 1.75-1.57 (m, 9H), 1.23-1.19 (m, 1H), 1.15 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 470 [M+H] +. | ||
781 | 3-((7S)-2-(1-羥基-1-(吡啶-2-基)ethyl)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 8.45-8.43 (m, 1H), 8.15-7.90 (m, 2H), 7.84 (s, 2H), 7.43-7.41 (m, 1H), 5.15-5.04 (m, 1H), 4.84-4.72 (m, 1H), 3.83 (s, 3H), 3.24-3.20 (m, 1H), 3.17-3.05 (m, 1H), 2.95-2.92 (m, 1H), 2.53-2.50 (m, 1H), 2.43-2.41 (m, 1H), 2.37-2.31 (m, 1H), 2.22 (s, 3H), 2.13-1.99 (m, 2H), 1.88-1.82 (m, 1H), 1.75-1.50 (m, 2H), 1.23-1.10 (m, 4H), 0.99-0.71 (m, 1H). LCMS (ES, m/z): 493 [M+H] +. | ||
826 | 3-((7S)-2-((1,3-二氫異苯并呋喃-4-基)(羥基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.64-7.52 (m, 1H), 7.52-7.41 (m, 1H), 7.41-7.31 (m, 1H), 7.31-7.19 (m, 1H), 7.07-6.91 (m, 1H), 6.60(s, 1H), 5.63-5.42(m, 1H), 5.42-5.26(m, 1H), 4.86-4.58(m, 4H), 3.79(s, 3H), 3.32-3.18(m, 1H), 3.04-2.92 (m, 1H), 2.84-2.61 (m, 1H), 2.44-2.21 (m, 3H), 2.13-1.93 (m, 2H), 1.91-1.72 (m, 3H), 1.72-1.43 (m, 2H), 1.18 (d, J = 6.4 Hz, 3H). LCMS (ES, m/z): 520 [M+H] + | ||
957 | 3-((7S)-2-(1-(5-氟-2-甲氧苯基)-1-羥乙基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第二溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.24 (d, J= 8.8 Hz, 1H), 6.99 (d, J= 8.8 Hz, 1H), 6.93-6.84 (m, 2H), 6.66-6.62 (m, 1H), 4.74-4.61 (m, 1H), 4.52-4.39 (m, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.05-2.99 (m, 1H), 2.85-2.70 (m, 2H), 2.69-2.58 (m, 1H), 2.55-2.45 (m, 1H), 2.41-2.32 (m, 1H), 2.31-2.20 (m, 1H), 2.18-2.07 (m, 1H), 1.86-1.60 (m, 7H), 1.52-1.35 (m, 1H), 1.06 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 540 [M+H] +. | ||
960 | 3-((7S)-2-(1-(5-氟-2-甲氧苯基)-1-羥乙基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 6.95-6.81 (m, 4H), 6.68-6.65 (m, 1H), 4.74-4.61(m, 1H), 4.52-4.39 (m, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 2.95-2.60 (m, 4H), 2.49-2.35 (m, 1H), 2.21-2.05 (m, 3H), 1.96-1.85 (m, 2H), 1.80 (s, 3H), 1.72-1.55 (m, 3H), 0.95 (d, J= 6.8 Hz, 3H). LCMS (ES, m/z): 540 [M+H] +. | ||
962 | 3-((7S)-2-(羥基(1-甲基-1H-吲哚-5-基)甲基)-6-(甲氧羰基)-7-甲基-6,7,8,9-四氫-3H-咪唑并[4,5-f]喹啉-3-基)環己烷-1-甲酸 第一溶離異構物 | 1H-NMR (CD 3OD, 400 MHz) δ (ppm): 7.75(s, 1H), 7.45-7.32 (m, 3H), 7.19-7.15 (m, 2H), 6.43(s, 1H), 6.42(s, 1H), 5.04- 4.91 (m, 1H), 4.80- 4.79 (m, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.31-3.22 (m, 1H), 3.11-3.00 (m, 1H), 2.91-2.85 (m, 1H), 2.45-2.31 (m, 2H), 2.28-2.21 (m, 1H), 2.12-2.00 (m, 1H), 1.91-1.70 (m, 2H), 1.55-1.30 (m, 2H), 1.25-1.18 (m, 1H), 1.16 (d, J= 6.8 Hz, 3H), 0.82-0.78 (m, 1H). LCMS (ES, m/z): 531 [M+H] +. | ||
在含有以下各物之檢定緩衝液中以6 µL之最終體積進行檢定:50 mM Hepes (pH 7.5,(0.5M Hepes, pH 7.5溶液;Teknova H1575))、0.5 mM GSH、0.01% BGG (經0.22 µM過濾,Sigma, G7516-25G)、0.005% BSA (經0.22 µM過濾,EMD Millipore Cosporation, 126575)及0.01% Triton X-100 (Sigma, T9284-10L)。對於33 µM至1.7 nM之最終測試濃度(分別為最高至最低劑量),將在DMSO中奈升量之10點、3倍連續稀釋液預分配至1536檢定板(Corning, #3724BC)中。將3 µL之2x蛋白質及3 µL之2 x肽配位體添加至檢定板(用化合物預壓製)中。在測量信號之前,在室溫下培育板持續不同的時間。在PHERAstar (BMG,配備有HTRF光學模組[337/520/490])上或在Envision (PerkinElmer,配備有TRF雷射單元、TRF雙鏡D400/D505以及發射濾光片M520及M495)上量測TR-FRET (時間解析螢光共振能量轉移)。數據係基於以下方程式報告為與對照孔相比之抑制百分比:%inh=1-((TR-FRET比率 -AveLow)/(AveHigh-AveLow)),其中TR-FRET比率=(在520nm下之螢光/在490nm下之螢光) * 10000),AveLow= 無酶對照之平均TR-FRET比率(n=32),且AveHigh=DMSO對照之平均TR-FRET比率(n=32)。藉由包括在Activity Base套裝軟體:IDBS XE Designer Model205中之標準4參數邏輯擬合算法之曲線擬合確定IC50值。使用Levenburg Marquardt算法擬合數據。對於所有檢定形式,數據係基於以下方程式報告為與對照孔相比之抑制百分比:%inh= 100*((FLU-AveLow)/(AveHigh-AveLow)),其中FLU=所量測之螢光,AveLow=無酶對照之平均螢光(n=32),且AveHigh=DMSO對照之平均螢光(n=32)。藉由包括在Activity Base套裝軟體:IDBS XE Designer Model205中之標準4參數邏輯擬合算法之曲線擬合確定IC50值。使用Levenburg Marquardt算法擬合數據。IC
50值示於以下表2中。如下表2中所示,大於或等於0.001 μM且小於或等於0.01 μM之IC
50值係標記為「++++」;大於0.01 μM且小於或等於0.1 μM之值係標記為「+++」;大於0.1 μM且小於或等於1 μM之值係標記為「++」;並且大於1 μM且小於1000 μM之值係標記為「+」。未在特定檢定中測試之化合物係標記為「NT」。
表2 - IC
50值
Claims (21)
- 一種式(I)之化合物: 或其醫藥學上可接受之鹽, 其中: R 1為-OR 5; R 5為-C 1-C 6烷基; R 6為-C 1-C 6烷基、-C 3-C 8環烷基或5-6員雜芳基,其中各烷基、環烷基、雜芳基視情況經一或多個R 10取代; R 10在每次出現時各自獨立地為-C 1-C 6烷基、-C 2-C 6烯基、-C 2-C 6炔基、-C 3-C 8環烷基、-C 4-C 8環烯基、雜環基、雜芳基、芳基、-OH、鹵素、側氧、-NO 2、-CN、-NH 2、 -OC 1-C 6烷基、-OC 3-C 6環烷基、-O芳基、-O雜芳基、 -NHC 1-C 6烷基、-N(C 1-C 6烷基) 2、-S(O) 2NH(C 1-C 6烷基)、 -S(O) 2N(C 1-C 6烷基) 2、-S(O) 2C 1-C 6烷基、-C(O)C 1-C 6烷基、-C(O)NH 2、-C(O)NH(C 1-C 6烷基)、-C(O)N(C 1-C 6烷基) 2、-C(O)OC 1-C 6烷基、-N(C 1-C 6烷基)SO 2C 1-C 6烷基、 -S(O)(C 1-C 6烷基)、-S(O)N(C 1-C 6烷基) 2或-N(C 1-C 6烷基)S(O)(C 1-C 6烷基),其中各烷基、烯基、炔基、環烷基、環烯基、雜環基、雜芳基或芳基視情況經一或多個-R 12取代; 或其中任何兩個R 10當在非相鄰原子上時可組合形成橋聯環烷基或雜環基; 或其中任何兩個R 10當在相鄰原子上時可組合形成環烷基、雜環基、芳基或雜芳基;並且 R 12在每次出現時獨立地為-C 1-C 6烷基、-C 2-C 6烯基、 -C 2-C 6炔基、-C 3-C 8環烷基、-C 4-C 8環烯基、雜環基、雜芳基、芳基、-OH、鹵素、側氧、-NO 2、-CN、-NH 2、 -OC 1-C 6烷基、-NHC 1-C 6烷基、-N(C 1-C 6烷基) 2、-S(O) 2NH(C 1-C 6烷基)、-S(O) 2N(C 1-C 6烷基) 2、-S(O) 2C 1-C 6烷基、-C(O)C 1-C 6烷基、-C(O)NH 2、-C(O)NH(C 1-C 6烷基)、-C(O)N(C 1-C 6烷基) 2、-C(O)OC 1-C 6烷基、-N(C 1-C 6烷基)SO 2C 1-C 6烷基、-S(O)(C 1-C 6烷基)、-S(O)N(C 1-C 6烷基) 2或-N(C 1-C 6烷基)S(O)(C 1-C 6烷基)。
- 如請求項1之化合物,其中R 5為甲基。
- 如請求項2之化合物,其中R 6為-C 1-C 6烷基,其中該烷基視情況經一或多個R 10取代。
- 如請求項3之化合物,其中R 6為甲基。
- 如請求項3之化合物,其中R 10選自-C 3-C 8環烷基、芳基及雜芳基,其中各環烷基、芳基或雜芳基視情況經一或多個-R 12取代。
- 如請求項5之化合物,其中R 10選自環戊基、環己基、苯基及吡唑基,其中各環戊基、環己基、苯基或吡唑基視情況經一或多個-R 12取代。
- 如請求項5之化合物,其中各R 12獨立地選自鹵素。
- 如請求項7之化合物,其中各R 12獨立地選自F及Cl。
- 如請求項7之化合物,選自由下列所組成的群組:
- 如請求項2之化合物,其中R 6為-C 3-C 8環烷基,其中該環烷基視情況經一或多個R 10取代。
- 如請求項10之化合物,其中R 6選自環戊基、環己基及環庚基,其各自視情況經一或多個R 10取代。
- 如請求項10之化合物,其中各R 10獨立地選自鹵素。
- 如請求項12之化合物,其中各R 10為F。
- 如請求項12之化合物,其中該化合物選自由下列所組成的群組:
- 如請求項2之化合物,其中R 6為5-6員雜芳基,其中該雜芳基視情況經一或多個R 10取代。
- 如請求項15之化合物,其中R 6為視情況經一或多個R 10取代的吡啶基。
- 如請求項15之化合物,其中各R 10獨立地選自鹵素,或其中任何兩個R 10當在相鄰原子上時可組合形成環烷基、雜環基、芳基或雜芳基。
- 如請求項17之化合物,其中各R 10為Cl,或其中任何兩個R 10當在相鄰原子上時可組合形成環烷基、雜環基、芳基或雜芳基。
- 如請求項17之化合物,選自由下列所組成的群組:
- 一種化合物,選自由下列所組成的群組:
- 一種醫藥組合物,其包含如請求項1之化合物或其醫藥學上可接受之鹽。
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