CN100575330C - 新化合物 - Google Patents
新化合物 Download PDFInfo
- Publication number
- CN100575330C CN100575330C CN200480013447A CN200480013447A CN100575330C CN 100575330 C CN100575330 C CN 100575330C CN 200480013447 A CN200480013447 A CN 200480013447A CN 200480013447 A CN200480013447 A CN 200480013447A CN 100575330 C CN100575330 C CN 100575330C
- Authority
- CN
- China
- Prior art keywords
- acetate
- biphenyl
- trifluoromethyl
- oxygen base
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 270
- 238000002360 preparation method Methods 0.000 claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 208000023504 respiratory system disease Diseases 0.000 claims abstract description 7
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 540
- 229910052760 oxygen Inorganic materials 0.000 claims description 324
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 320
- 239000001301 oxygen Substances 0.000 claims description 320
- 235000010290 biphenyl Nutrition 0.000 claims description 270
- 238000000034 method Methods 0.000 claims description 163
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 90
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 84
- -1 5-cyanobiphenyl-2-yl Chemical group 0.000 claims description 80
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 77
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 58
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 49
- 150000003839 salts Chemical class 0.000 claims description 49
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 47
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 46
- 201000010099 disease Diseases 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 239000003814 drug Substances 0.000 claims description 33
- 239000012453 solvate Substances 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical group 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 206010039083 rhinitis Diseases 0.000 claims description 21
- 125000006269 biphenyl-2-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(*)C([H])=C([H])C([H])=C1[H] 0.000 claims description 20
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 16
- 208000006673 asthma Diseases 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 239000000460 chlorine Substances 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 150000002431 hydrogen Chemical group 0.000 claims description 13
- 150000003863 ammonium salts Chemical class 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- LRYZJEXQHWCLJY-UHFFFAOYSA-N 1-phenyl-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1C1=CC=CC=C1 LRYZJEXQHWCLJY-UHFFFAOYSA-N 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 150000003254 radicals Chemical class 0.000 claims description 9
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 102100029100 Hematopoietic prostaglandin D synthase Human genes 0.000 claims description 5
- 101000988802 Homo sapiens Hematopoietic prostaglandin D synthase Proteins 0.000 claims description 5
- 125000006317 cyclopropyl amino group Chemical group 0.000 claims description 5
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 5
- BHMBVRSPMRCCGG-OUTUXVNYSA-N prostaglandin D2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)[C@@H](O)CC1=O BHMBVRSPMRCCGG-OUTUXVNYSA-N 0.000 claims description 5
- BHMBVRSPMRCCGG-UHFFFAOYSA-N prostaglandine D2 Natural products CCCCCC(O)C=CC1C(CC=CCCCC(O)=O)C(O)CC1=O BHMBVRSPMRCCGG-UHFFFAOYSA-N 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- XJKSTNDFUHDPQJ-UHFFFAOYSA-N 1,4-diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=C(C=2C=CC=CC=2)C=C1 XJKSTNDFUHDPQJ-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000005493 quinolyl group Chemical group 0.000 claims description 4
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 150000003457 sulfones Chemical class 0.000 claims description 3
- 150000003462 sulfoxides Chemical class 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 claims description 2
- MQRAOAVBULIDBM-UHFFFAOYSA-N CC(=O)OOC1=C(C=C(C=C1)Cl)C2=CN=C(N=C2)N Chemical compound CC(=O)OOC1=C(C=C(C=C1)Cl)C2=CN=C(N=C2)N MQRAOAVBULIDBM-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- UEDBHEFYEKZZBA-UHFFFAOYSA-N ac1np5zy Chemical compound C1=CC=[C+]=C[CH]1 UEDBHEFYEKZZBA-UHFFFAOYSA-N 0.000 abstract description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 276
- 238000001819 mass spectrum Methods 0.000 description 209
- 239000002585 base Substances 0.000 description 201
- 238000005481 NMR spectroscopy Methods 0.000 description 194
- 239000000047 product Substances 0.000 description 170
- 239000000203 mixture Substances 0.000 description 101
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 70
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 52
- 229940095574 propionic acid Drugs 0.000 description 46
- 235000019439 ethyl acetate Nutrition 0.000 description 42
- 230000009467 reduction Effects 0.000 description 35
- 238000003756 stirring Methods 0.000 description 35
- 238000009834 vaporization Methods 0.000 description 35
- 230000008016 vaporization Effects 0.000 description 35
- 238000010898 silica gel chromatography Methods 0.000 description 33
- 238000001704 evaporation Methods 0.000 description 32
- 230000008020 evaporation Effects 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 29
- 239000002904 solvent Substances 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 239000003112 inhibitor Substances 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 238000010438 heat treatment Methods 0.000 description 18
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 17
- 238000005406 washing Methods 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- 208000011580 syndromic disease Diseases 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 13
- 239000004327 boric acid Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 230000001154 acute effect Effects 0.000 description 12
- 239000005557 antagonist Substances 0.000 description 12
- 229910052796 boron Inorganic materials 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 9
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- 208000030507 AIDS Diseases 0.000 description 7
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- 238000005984 hydrogenation reaction Methods 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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Classifications
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Abstract
本发明涉及作为用于治疗呼吸系统疾病的有用的药物化合物的取代的苯氧基乙酸、包含所述化合物的药物组合物以及其制备方法。
Description
本发明涉及作为用于治疗呼吸系统疾病的有用的药物化合物的取代的苯氧基乙酸、包含所述化合物的药物组合物以及其制备方法。
EPA 1 170 594公开了一种用于识别可用于治疗前列腺素D2介导的疾病状态的化合物、孤儿受体CRTH2的配体的方法。GB 1356834公开了一系列据说具有消炎、镇痛以及退热活性的化合物。已经发现一些苯氧基乙酸化合物为CRTH2受体的活性物质,并因此预期可潜在地用于治疗多种呼吸性疾病包括哮喘和COPD。
因此第一方面,本发明提供了式(I)的化合物或可药用盐或溶剂合物:
其中:
X为卤素、氰基、硝基、S(O)nR6或被一个或多个卤素原子取代的C1-4烷基;
Y选自氢、卤素、CN、硝基、SO2R3、OR4、SR4、SOR3、SO2NR4R5、CONR4R5、NR4R5、NR6SO2R3、NR6CO2R6、NR6COR3、C2-C6链烯基、C2-C6炔基、C3-C7环烷基或C1-6烷基,后四种基团任选被一个或多个独立地选自卤素、OR6和NR6R7、S(O)nR6其中n为0、1或2的取代基取代;
Z为芳基或环A,其中A为包含一个或多个氮原子的六员杂芳环或可为包含一个或多个O、N、S原子的6,6或6,5稠合的二环,所述的芳基或A环都任选被一个或多个独立地选自下述基团的取代基取代:氢、卤素、CN、OH、SH、硝基、COR9、CO2R6、SO2R9、OR9、SR9、SOR9、SO2NR10R11、CONR10R11、NR10R11、NHSO2R9、NR9SO2R9、NR6CO2R6、NHCOR9、NR9COR9、NR6CONR4R5、NR6SO2NR4R5、芳基、杂芳基、C2-C6链烯基、C2-C6炔基、C3-C7环烷基或C1-6烷基,后四种基团任选被一个或多个独立地选自卤素、C3-C7环烷基、OR6、NR6R7、S(O)nR6(其中n为0、1或2)、CONR6R7、NR6COR7、SO2NR6R7和NR6SO2R7的取代基取代;
R1和R2独立地表示氢原子、卤素、C2-C6链烯基、C2-C6炔基、C3-C7环烷基或C1-6烷基,后四种基团任选被一个或多个独立地选自卤素、C3-C7环烷基、NR6R7、OR6、S(O)nR6(其中n为0、1或2)的取代基取代;
或者
R1和R2一起能形成3-8员环,所述的环任选包含一个或多个选自O、S、NR6的原子并且自身任选被一个或多个C1-C3烷基或卤素取代;
R3表示C3-C7环烷基或C1-6烷基,其可任选被一个或多个独立地选自下述基团的取代基取代:卤素、C3-C7环烷基、OR6和NR6R7、S(O)nR6(其中n=0、1或2)、CONR6R7、NR6COR7、SO2NR6R7和NR6SO2R7;
R4和R5独立地表示氢、C3-C7环烷基或C1-6烷基,后两种基团任选被一个或多个独立地选自下述基团的取代基取代:卤素、C3-C7环烷基、OR6和NR6R7、S(O)nR6(其中n=0、1或2)、CONR6R7、NR6COR7、SO2NR6R7和NR6SO2R7;
或者
R4和R5与其相连的氮原子一起能形成3-8员饱和的杂环,所述的环任选包含一个或多个选自O、S(O)n(其中n=0、1或2)、NR8的原子,并且自身任选被卤素或C1-3烷基取代;
R6和R7独立地表示氢原子或C1-C6烷基;
R8为氢、C1-4烷基、-COC1-C4烷基、CO2C1-C4烷基或CONR6C1-C4烷基;
R9表示芳基、杂芳基、C3-C7环烷基或C1-6烷基,后两种基团可任选被一个或多个独立地选自下述基团的取代基取代:卤素、C3-C7环烷基、芳基、杂芳基、OR6和NR6R7、S(O)nR6(其中n=0、1或2)、CONR6R7、NR6COR7、SO2NR6R7和NR6SO2R7;
R10和R11独立地表示芳基或杂芳基、氢、C3-C7环烷基或C1-6烷基,后两种基团任选被一个或多个独立地选自下述基团的取代基取代:卤素、C3-C7环烷基、芳基、杂芳基、OR6和NR6R7、S(O)nR6(其中n=0、1或2)、CONR6R7、NR6COR7、SO2NR6R7和NR6SO2R7;
或者
R10和R11与其相连的氮原子一起能形成3-8员饱和的杂环,所述的环任选包含一个或多个选自O、S(O)n(其中n=0、1或2)、NR8的原子,并且自身任选被卤素或C1-C3烷基取代。
芳基的实例包括苯基和萘基。
杂芳基定义为5-7员芳香环或可为任选包含一个或多个选自N、S和O的杂原子的6,6-或6,5-稠合的二环。二环可通过碳或氮连接并且可通过5或6员环连接且可为完全或部分饱和的。
实例包括吡啶、嘧啶、噻唑、噁唑、吡唑、咪唑、呋喃、异噁唑、吡咯、异噻唑和薁、萘基、茚、喹啉、异喹啉、吲哚、中氮茚、苯并[b]呋喃、苯并[b]噻吩、1H-吲唑、苯并咪唑、苯并噻唑、苯并噁唑、嘌呤、4H-喹嗪、肉啉、酞嗪、喹唑啉、喹噁啉、1,8-萘啶、蝶啶、喹诺酮和1,2-亚甲基二氧基苯。
芳基或杂芳基可任选被一个或多个独立地选自下述基团的取代基取代:氢、卤素、CN、OH、SH、硝基、CO2R6、SO2R9、OR9、SR9、SOR9、SO2NR10R11、CONR10R11、NR10R11、NHSO2R9、NR9SO2R9、NR6CO2R6、NHCOR9、NR9COR9,芳基、杂芳基、C2-C6链烯基、C2-C6炔基、C3-C7环烷基或C1-6烷基,后四种基团任选被一个或多个独立地选自卤素、C3-C7环烷基、OR6、NR6R7、S(O)nR6(其中n为0、1或2)、CONR6R7、NR6COR7、SO2NR6R7和NR6SO2R7的取代基取代。取代基可存在任何合适的位置,包括在氮原子上的适当的取代基。
基团A为包含一个或多个氮原子的6员杂环或可为包含一个或多个O、N、S原子的6,6或6,5稠合的二环。合适环的实例包括吡啶、嘧啶、吡嗪、哒嗪、吲哚、喹啉、异喹啉、苯并咪唑、苯并噻唑、苯并呋喃、苯并噁唑、苯并噻吩、酞嗪和喹唑啉。
在本说明书的上下文中,除非另有说明,烷基或链烯基或取代基中的烷基或链烯基部分可为直链或支链的。
针对R4、R5和R10和R11定义的杂环为饱和的杂环,实例包括吗啉、氮杂环丁烷、吡咯烷、哌啶和哌嗪。取代基可存在所述环的碳以及适当的氮原子上。
优选地X为三氟甲基、硝基、氰基或卤素。更优选地X为三氟甲基、硝基、氰基、氯或氟,甚至更优选地X为三氟甲基、氯或氟。最优选地X为三氟甲基或氯。
优选地Y为氢、卤素或C1-3烷基。更优选地Y为氢、氟或甲基。最优选地Y为氢。
优选地Z为苯基、吡啶基、嘧啶基、萘基、喹啉基、苯并[b]噻吩基或苯并呋喃基,各基团任选如上被取代,更优选地为如上任选取代的苯基。对所有的Z基团优选的取代基包括这里例举的那些取代基,尤其是卤素、C1-3烷基、氰基、SO2R9、OR9、SR9、CO2R6、NHSO2R9、NR9SO2R9和SO2NR10R11。
更优选地当Z为苯基的时候,其任选被1~3个,优选地1或2个取代基取代,所述的取代基选自SEt、SO2Me、SO2Et、氯、氟、氰基、甲氧基、丙氧基、CO2H、甲基、乙基、丙基、丁基、氨基、羟基、NHCONHEt、NHCONHMe、NHCONHPr、NHCONH-环丙基、CONH2、SO2NH2、OCF3、COMe、CO2Me、硝基、苯基、SCF3、1-吡咯烷基磺酰基、二甲基氨基磺酰基、((苯基甲基)氨基)磺酰基、[(2,2,2-三氟乙基)]氨基]磺酰基、[(5-甲基-2-噻唑基)氨基]磺酰基、(苯基氨基)磺酰基、(二乙基氨基)磺酰基、(环丙基氨基)磺酰基、氨基磺酰基、(甲基氨基)磺酰基、(4-甲基-1-哌嗪基)磺酰基、NHCO2Me、(二甲基氨基)磺酰基、4-吗啉基磺酰基、1-氮杂环丁基磺酰基以及1-吡咯烷基羰基。
更优选地当Z为吡啶基的时候,其任选被1或2个选自SO2NH2、甲基、氨基、氯和NMeSO2Me的基团取代。
更优选地当Z为嘧啶的时候,其任选被1或2个选自氨基、甲基、吗啉基、二甲基氨基、甲基氨基、苄基氨基、哌啶、NMeSO2Me、(甲基磺酰基)(苄基)氨基、(乙基磺酰基)(苄基)氨基、乙酰基(苯基甲基)氨基、5-甲基-1,1-二氧代(dioxido)-1,2,5-噻二唑烷-2-基、1,1-二氧代-2-异噻唑烷基、3-羟基-1-氮杂环丁基、4-甲基-1-哌嗪基、1-吡咯烷基和NHSO2NMe2的基团取代。
当Z为萘基的时候,优选地其被甲氧基取代。
当Z为喹啉基、苯并[b]噻吩基或苯并呋喃基的时候,这些基团优选地不被取代。
优选地R1和R2独立地为氢或C1-3烷基。更优选地R1和R2二者都为氢或一个为氢并且另一个为甲基或乙基或都为甲基。最优选地R1和R2都为氢。
优选的本发明的化合物包括这里例举的那些化合物,游离碱形式以及其可药用盐和溶剂合物。
某些式(I)化合物可以以立体异构体的形式存在。可以理解,本发明包含式(I)化合物的所有几何和光学异构体和其包括外消旋体的混合物。互变异构体和其混合物也同样为本发明的一个方面。
上面的式(I)化合物可以转化为药学上可接受的盐或溶剂合物,优选碱加成盐例如钠盐、钾盐、钙盐、铝盐、锂盐、镁盐、锌盐、苄星青霉素、氯普鲁卡因、胆碱、二乙醇胺、乙醇胺、乙基二胺、葡甲胺、氨丁三醇或普鲁卡因,或酸加成盐例如盐酸盐、氢溴酸盐、磷酸盐、醋酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、草酸盐、甲基磺酸盐或p-甲苯磺酸盐。
本领域熟练技术人员都知道,在本发明的方法中需要用保护基对起始反应物和中间体中的功能基团进行保护。因此,在适当的时候式(I)化合物的制备可以包括一个或多个保护基的脱除。功能基团的保护和脱保护在《有机化学中的保护基团(Protective Groups in Organic Chemistry)》,J.W.F.McOmie编辑,Plenum出版社(1973),以及《有机合成中的保护基(ProtectiveGroups in Organic Synthesis)》,第3版,T.W.Greene & P.G.M.Wuts,Wiley-Interscience(1999)中有完全的描述。
式(I)的化合物可通过将式(II)的化合物:
其中X、Y和Z如式(I)中定义或为其保护的衍生物,与式(III)的化合物进行反应而制备得到:
L-CR1R2CO2R12 (III)
其中R1和R2如式(I)中定义或为其保护的衍生物,R12为H或C1-C10烷基并且L为离去基并任选之后以任何顺序:
·去除任何保护基
·水解酯基R12得到相应的酸
·氧化硫醚至亚砜或砜
·形成可药用盐。
该反应可在合适的溶剂如DMF中利用碱如碳酸钾等进行反应得到。合适的基团R12包括包括C1-6烷基例如甲基、乙基和叔丁基。合适的L为离去基团例如卤素,尤其为氯或溴。L也可为羟基因此Mitsunobu反应可用化合物(II)利用例如三苯基膦和偶氮二羧酸二乙基酯进行。
酯基团R12的水解可利用常规的步骤进行,例如甲基和乙基酯利用氢氧化钠水溶液处理,叔丁基酯用酸如三氟乙酸进行处理。
式(II)的化合物可通过将式(IV)的化合物与式(V)的化合物通过Suzuki偶联反应然后当R13不为氢H的时候对基团R13脱保护进行制备:
其中X、Y和Z如式(I)中定义或为其保护的衍生物,R13为H或合适的保护基,例如苄基,L1为碘、溴、氯或三氟甲磺酸基且R14和R15为H或C1-C6烷基或R14和R15一起能形成任选被一个或多个C1-C3烷基取代的5或6员环。
该反应可在合适的溶剂如二噁烷中利用钯催化剂如[1,1-双(二苯基膦基)二茂铁]二氯钯和碱如氟化铯,优选地在升高的温度下进行。
式(IV)的化合物可从式(VI)的化合物进行制备,通过形成有机金属(VII),然后与硼酸酯反应,如路线I所示。
路线I
其中X、Y如式(I)中定义或为其保护的衍生物,R13如式(IV)中定义,E为氢或卤素并且M为金属如Na或Li。例如当R13为苄基且E为溴的时候,丁基锂可用来形成中间体(VII)其中M=Li。反应在-78℃在乙醚中进行,然后用硼酸酯如三甲基硼酸酯中止。
式(IV)的化合物也可利用式(VIII)的化合物与合适的硼酸酯例如(IX)或(X)的钯催化的偶联反应进行制备。
其中X、Y和R13如上定义且G为卤素或三氟甲磺酸基。
式(II)的化合物也可将式(XI)的化合物与式(XII)的化合物利用Suzuki偶联方法进行制备。
其中X、Y、Z、R13、L1、R14和R15如上定义并且式(XI)和(XII的化合物)能利用上述同样的方法进行制备。
式(II)的化合物,其中Z=杂芳基,也可利用环合成进行制备,例如式(XIII)的化合物可通过将式(XIV)的化合物与式(XV)的化合物反应而形成得到。
X、Y和R13如上定义且R16为如式(I)中定义的Z上定义的取代基或其保护的衍生物。反应可在溶剂中如乙醇中在回流状态下进行,并且如果式(XV)化合物为盐,可以使用碱如乙醇钠。
当R16为基团S-烷基,可进一步通过氧化得到亚砜或砜,利用氧化剂如mcpba在DCM中在RT进行。然后用在式1中针对Z定义的适当的亲核试剂进行取代。路线2;
路线2
上述步骤的顺序可以变化,例如式(XVI)的化合物可通过将式(XVII)的化合物与式(XII)的化合物利用Suzuki偶联反应进行制备。
式(I)的化合物也可通过将式(XVIII)的化合物与式(V)的化合物利用如上定义的Suzuki偶联方法进行制备,其中X、Y、R1、R2、R12、R14和R15如上定义。
式(XVIII)的化合物可通过方法A或B进行制备。
方法A
将酸首先转换成酰氯,利用例如草酰氯在DCM中在RT进行,然后与3-甲基-3-氧杂环丁烷甲醇在碱如三乙基胺存在下得到酯。将氧杂环丁烷酯利用三氟化硼乙醚化物在DCM中在-78℃至RT重排成OBO酯。用碱如仲丁基锂在低温去质子然后用三甲基硼酸酯中止得到保护的二元酸,然后利用HCl然后氢氧化钠脱保护。
方法B
式(IV)的化合物(其中R13=Bn且R14和R15=H)以及频哪醇可在合适的溶剂如乙醚中在RT搅拌反应得到硼酸酯(boronate ester)。苄基利用在RT下利用钯炭作为催化剂的氢化去除,然后用式(III)的化合物利用碱或mitsunobu条件进行烷基化。用酸如HCl或三氟乙酸处理然后去除保护基。
另一方面,本发明提供了式(I)的化合物、其前药、可药用盐或溶剂合物在用于治疗中的用途。
式(I)化合物具有作为药品尤其作为CRTh2受体活性的调节剂的活性,并且其可用于治疗(治疗或预防)人类的或非类人动物的由PGD2和其代谢物的过多或未受调节的产生而加剧或引起的病症/疾病。这些病症/疾病的例子包括:
(1)(呼吸道)阻碍性气道疾病包括:哮喘(例如支气管哮喘、过敏性哮喘、内因性哮喘、外因性哮喘和灰尘性哮喘尤其是慢性或顽固性哮喘(例如晚期哮喘和气道高敏性));慢性阻碍性肺病(COPD)(例如不可逆性COPD);支气管炎(包括嗜曙红细胞性支气管炎);急性鼻炎、过敏性鼻炎、萎缩性鼻炎或慢性鼻炎(例如干酪鼻炎、肥厚性鼻炎、化脓性鼻炎、干燥性鼻炎),药物性鼻炎、膜性鼻炎(包括格鲁布性鼻炎、纤维蛋白性鼻炎和假膜性鼻炎),腺病性鼻炎,长期过敏性鼻炎,季节性鼻炎(包括神经性鼻炎(花粉症)和血管收缩性鼻炎);鼻息肉;肉状瘤病;农民肺和相关疾病;肺纤维症;先天间质性肺炎;囊肿性纤维化;镇咳活性;与发炎或导致医原性相关的慢性咳嗽的治疗;
(2)(骨和关节)关节炎包括类风湿性关节炎、传染性关节炎、自体免疫性关节炎、血清反应阴性关节炎、脊椎关节炎(例如僵硬性脊椎炎、牛皮癣性关节炎和Reiter氏疾病),Behcet氏疾病,Sjogren氏综合征和全身性硬化症;
(3)(皮肤和眼睛)牛皮癣,特应性皮炎,接触性皮炎,其它湿疹性皮炎,皮脂溢性皮炎,扁平苔癣,天疱疮,大泡天疱疮,大疱性表皮松懈,荨麻疹,血管性皮肤病,结节性脉管炎,红斑,皮肤嗜曙红细胞增多症,慢性皮肤溃疡,葡萄膜炎,斑秃症和春季结膜炎;
(4)(胃肠道)腹部疾病、直肠炎、嗜酸粒细胞性胃肠炎,肥大细胞增生病,Crohn氏疾病,溃疡性结肠炎,过敏性结肠病;肠道作用以外的食物相关性过敏(例如偏头痛、鼻粘膜炎和湿疹);
(5)(中枢和外周神经系统)神经退化疾病和痴呆症(例如阿兹海默氏疾病、肌萎缩性侧索硬化和其它运动神经细胞疾病、Creutzfeldt-Jacob氏疾病和其它感染性蛋白质疾病、HIV脑病(AIDS痴呆综合征)、亨廷顿氏(Huntington)疾病、额颞缝性痴呆、Lewybody性痴呆和脉管性痴呆),多神经症(例如Guillain-Barré综合症、慢性炎性脱髓鞘多神经根神经病、多病灶运动神经病),神经丛病变,CNS脱髓鞘(例如多发性硬化、急性散布/出血性脑脊髓炎,和亚急性硬化性全脑炎),神经肌肉紊乱(例如重症肌无力和Lambert-Eaton综合症),脊椎疾病(例如热带的痉挛性下肢轻瘫,和僵硬综合症),副肿瘤性综合症(例如小脑恶化和脑脊髓炎),CNS损伤,偏头痛和中风。
(6)(其它组织和系统疾病)动脉粥样硬化症,获得性免疫缺陷综合症(AIDS),狼疮性红斑症;全身性狼疮,红斑症;桥本氏(Hashimoto)甲状腺炎,I型糖尿病,肾病综合征,嗜曙红细胞过多性筋膜炎,高IgE综合征,麻风病,先天性血小板减少症;术后粘连,脓血症和心、脑、外周性支、肝炎(酒精性肝炎、脂肪肝炎和病毒性肝炎)、血管球性肾炎、肾损害、慢性肾衰竭和其它器官的局部缺血性/再灌注损伤;
(7)(同种异体移植物的排斥)例如急性或慢性肾、心脏、肝、肺、骨髓、皮肤和角膜移植的排斥反应;以及慢性移植物抗宿主疾病;
(8)与PGD2或其代谢物水平升高有关的疾病。
(1)(呼吸道)-气道阻塞性急性包括:哮喘、包括支气管性、过敏性、内源性、外源性、运动诱导性、药物诱导性(包括阿斯匹林和NSAID-造成的)和粉尘造成的哮喘,间歇以及持久性以及所有严重程度的,以及气道高反应性的其他原因诱导的;慢性阻塞性肺疾患(COPD);支气管炎、包括感染性以及嗜酸支气管炎;肺气肿;支气管扩张;囊性纤维化病;结节病;农民肺以及相关的疾病;超敏感性肺炎;肺纤维化、包括隐原性纤维化肺泡炎、自发性间质性肺炎、合并抗肿瘤治疗以及慢性感染的纤维化、包括肺结核以及曲霉病以及其他的真菌感染;肺移植的合并症;肺脉管系统的血管炎和血栓形成疾病,以及肺动脉高压;镇咳药活性包括治疗与炎症有关的慢性咳嗽以及气道的分泌性疾病以及医源性咳嗽;急性以及慢性鼻炎包括药物性鼻炎,以及血管运动性鼻炎;长期过敏性鼻炎、季节性鼻炎包括神经性鼻炎(花粉症);鼻息肉病;急性病毒感染包括普通感冒,以及由于呼吸性合胞体病毒、流行性感冒病毒、冠形病毒(包括SARS)和腺病毒的感染。
(2)(骨和关节)关节炎,与下列疾病有关的或包括骨关节炎/骨关节病,原发和继发于先天性髋关节发育不良;颈背以及腰部脊椎炎,以及腰(背)部以及颈痛;类风湿性关节炎和斯提耳(氏)病;血清反应阴性脊椎关节病包括强直性脊柱炎、牛皮癣性关节炎、反应性关节炎以及未分化的脊关节病(spondarthropathy);脓毒性关节炎以及其他的感染相关的关节病以及骨病如结核病、包括波特病以及蓬塞(氏)综合征;急性以及慢性晶体诱导的(crystal-induced)滑膜炎包括尿酸痛风、焦磷酸钙沉积病,以及磷灰石钙相关的腱、粘液囊以及滑液炎症;贝切特(氏)病;原发和继发性斯耶格伦(氏)综合征;全身性硬化症以及限制性硬皮病;系统性红斑狼疮、混合性结缔组织病,以及未分化结缔组织病;炎性肌病包括皮和多肌炎肌炎;polymalgiarheumatica;幼年型关节炎包括自发性炎性关节炎,无论是关节脱臼(jointdistribution)以及相关的综合征,以及风湿热及其全身性并发症;血管炎包括巨细胞动脉炎、高安(氏)动脉炎、丘-施二氏综合征、结节性多动脉炎、微小多动脉炎以及与病毒感染、超敏反应、冷球蛋白类,以及副蛋白有关的血管炎;腰(背)痛;家族性地中海热、穆-韦二氏综合征以及家族性肾上腺脑白质营养不良、Kikuchi疾病;药物造成的关节痛、肌腱炎,以及肌病。
(3)(皮肤)牛皮癣、特应性皮炎、接触性皮炎或其他的湿疹性皮肤病,以及延迟类型的超敏反应;植物性皮炎以及光照性皮炎;皮溢脂性皮炎、疱疹样皮炎、扁平苔藓、硬化萎缩苔癣、坏疽性脓皮症、皮肤结节病、盘状红斑狼疮、天疱疮、类天疱疮、大疱性表皮松解症、荨麻疹、血管性水肿、血管炎、中毒性红斑、皮肤嗜酸粒细胞增多、斑秃、男性型秃、斯威特(氏)综合征、韦伯-克里斯迁综合征、多形性红斑;蜂窝组织炎,感染以及非感染性;脂膜炎;皮肤淋巴瘤、非黑素瘤皮肤癌以及其他的发育异常损害;药物诱导的疾病包括确定的药物出疹。
(4)(眼睛)睑缘炎;结膜炎,包括长期和春季过敏性结膜炎;虹膜炎;前以及后色素层(葡萄膜)炎;脉络膜炎;影响视网膜的自体免疫性疾病;变性或炎性疾病;眼炎包括交感性眼炎;肉样瘤病;感染性包括病毒、真菌以及细菌。
(5)(胃肠道)舌炎、龈炎、牙周炎;食管炎、包括反流性;嗜酸粒细胞性胃肠炎、肥大细胞增生病,Crohn氏疾病、结肠炎包括溃疡性结肠炎、直肠炎、肛门瘙痒;腹部疾病、过敏性肠综合征,以及肠道作用以外的食物相关性过敏(例如偏头痛、鼻粘膜炎和湿疹);
(6)(腹部的)肝炎,包括自体免疫性、酒精性以及病毒性;肝脏的纤维化和硬化;胆囊炎;胰腺炎,急性和慢性的。
(7)(泌尿生殖器的)肾炎包括慢性间质性肾炎和肾小球肾炎;肾病综合征;膀胱炎包括急性和慢性的(慢性间质性)膀胱炎和杭纳(氏)溃疡;急性和慢性尿道炎、前列腺炎、附睾炎、卵巢炎和输卵管炎;女阴阴道炎;佩伦涅(氏)征;勃起机能障碍(男性和女性)。
(8)(同种异体移植物的排斥)例如急性或慢性肾、心脏、肝、肺、骨髓、皮肤和角膜移植或输血后的排斥反应;以及慢性移植物抗宿主疾病;
(9)(CNS)阿兹海默氏疾病以及其他的痴呆性疾病包括CJD和nvCJD;淀粉样变性病;多发性硬化以及其他的脱髓鞘综合征;脑动脉粥样硬化和血管炎;颞动脉炎;重症肌无力;急性以及慢性疼痛(急性、间歇性或持久性,无论是中枢或外周起源的)包括内脏痛、头疼、偏头痛、三叉神经痛、不典型面痛、关节和骨头痛、源自癌症以及肿瘤转移的疼痛、神经性疼痛综合征包括糖尿病性、疱疹后以及HIV-相关的神经病变;神经类肉瘤病;恶性肿瘤、感染性或自体免疫过程的中枢以及外周神经系统并发症。
(10)其他的自体免疫性以及过敏性疾病包括桥本甲状腺炎、格雷夫斯(氏)病、阿狄森(氏)综合征、糖尿病、自发性血小板性紫癜、嗜酸细胞性筋膜炎、高IgE综合征、抗磷脂综合征。
(11)其他具有炎性或免疫性成分的疾病;包括获得性免疫缺陷综合征(AIDS)、麻风病、塞扎里综合征以及类肿瘤综合征。
(12)(心血管);动脉粥样硬化、影响冠状以及外周循环的疾病;心包炎;心肌炎、炎性以及自体免疫性心肌疾病包括心肌结节病;缺血再灌注损伤;心内膜炎、心瓣炎以及主动脉炎包括感染性(如梅毒的);血管炎;主静脉以及外周静脉疾病包括静脉炎和血栓症、包括深部静脉血栓形成以及静脉曲张并发症。
(13)(肿瘤)治疗常见的癌症包括前列腺、乳腺、肺、卵巢、胰腺、肠和结肠、胃、皮肤和脑肿瘤以及影响骨髓的恶性肿瘤(包括白血病)以及淋巴增生性体系,如何杰金(氏)淋巴瘤以及非-何杰金(氏)淋巴瘤;包括预防和治疗转移性疾病以及肿瘤复发以及类肿瘤性综合征。
(14)与PGD2或其代谢物水平升高有关的疾病。
因此,本发明提供上文中定义的式(I)化合物或其药学上可接受的盐或溶剂合物的治疗用途。
本发明的化合物优选用于治疗属于CRTh2受体亚家族的趋化因子受体的疾病。
本发明化合物可以治疗的病症尤其为哮喘、鼻炎和其它与PGD2或其代谢物水平升高有关的疾病。本发明化合物优选用于治疗哮喘。
更进一步的方面,本发明提供了如上定义的式(I)化合物或其药学上可接受的盐或溶剂合物在制备用于治疗的药物中的用途。
更进一步的方面,本发明提供上文提到的式(I)化合物或其药学上可接受的盐或溶剂合物在制备与用于治疗哮喘和鼻炎(例如吸入或口服类固醇,吸入β2-受体激动剂和口服白细胞三烯受体拮抗剂)的药物相联合的药物中的用途。
本发明还涉及联合治疗,其中式(I)化合物或其可药用盐、溶剂化物或其体内可水解的酯,或包含式(I)化合物的药物组合物或制剂与其它治疗剂同时或相继或以复合制剂的形式给药,用于治疗一种或多种列出的病症。
特别是,为了治疗炎性疾病类风湿性关节炎、牛皮癣、炎性肠病、COPD、哮喘和过敏性鼻炎,本发明化合物可与诸如下述的药剂联合:TNF-α抑制剂如抗-TNF单克隆抗体(如Remicade、CDP-870和阿达木单抗)以及TNF受体免疫球蛋白分子(如);全身或局部使用的非选择性COX)-1/COX-2抑制剂(例如吡罗昔康、双氯芬酸、丙酸如萘普生、氟比洛芬、非诺洛芬、酮洛芬和布洛芬、灭酸酯类如甲灭酸、吲哚美辛、舒林酸、阿扎丙宗、吡唑酮如保泰松、水杨酸酯如阿司匹林);COX-2抑制剂(例如美洛昔康、塞来考昔、罗非考昔、伐地考昔、lumarocoxib、帕瑞考昔和艾托考昔);糖皮质激素(无论经局部、口服、肌肉内、静脉内或关节内途径给药);甲氨喋呤、来氟米特(lefunomide);羟氯喹、d-青霉胺、金诺芬或其它肠胃外或口服金制剂。
本发明还涉及本发明化合物与以下药剂的组合:白细胞三烯生物合成抑制剂、5-脂肪氧化酶(5-LO)抑制剂或5-脂肪氧化酶活化蛋白(FLAP)拮抗剂,例如弃白通;ABT-761;芬留顿;替泊沙林;雅培-79175(Abbott-79175);雅培-85761(Abbott-85761);N-(5-取代的)-噻吩-2-烷基磺胺;2,6-二叔丁基苯酚腙;甲氧基四氢吡喃如Zeneca ZD-2138;化合物SB-210661;吡啶基取代的2-氰基萘化合物如L-739,010;2-氰基喹啉化合物如L-746,530;吲哚和喹啉化合物如MK-591、MK-886和BAYx 1005。
本发明还涉及本发明化合物与白细胞三烯(LT)B4、LTC4、LTD4和LTE4的受体拮抗剂的组合,该受体拮抗剂选自吩噻嗪-3-1s如L-651,392;脒基化合物如CGS-25019c;benzoxalamines如昂唑司特;苯甲酰亚胺酰胺类如BIIL284/260;和例如扎鲁司特、阿鲁司特、孟鲁司特、普仑司特、维鲁司特(MK-679)、RG-12525、Ro-245913、伊拉司特(CGP 45715A)和BAY x 7195的化合物。
本发明还涉及本发明化合物与磷酸二酯酶(PDE)抑制剂的组合,所述抑制剂例如甲基黄嘌呤类包括胆茶碱和氨茶碱;和选择性PDE同工酶抑制剂包括PDE4抑制剂和同工型PDE4D的抑制剂,和PDE5抑制剂。
本发明还涉及本发明化合物与1型组胺受体拮抗剂的组合,所述拮抗剂例如口服、局部或肠道外用药的西替立嗪、氯雷他定、地氯雷他定、非索非那定、阿伐斯汀、特非那定、阿司咪唑、氮卓斯汀、左卡巴司汀、氯苯那敏、异丙嗪、赛克利嗪、和咪唑斯汀。
本发明还涉及本发明化合物与胃保护性2型组胺受体拮抗剂的组合。
本发明还涉及本发明化合物与4型组胺受体拮抗剂的组合。
本发明还涉及本发明化合物与α-1/α-2肾上腺素受体激动剂血管收缩拟交感神经药的组合,所述药剂例如环己丙甲胺、去氧肾上腺素、苯丙醇胺、麻黄碱、伪麻黄碱、盐酸萘甲唑啉、盐酸氧甲唑啉、盐酸四氢唑啉、盐酸木甲唑啉、盐酸曲马唑啉和盐酸乙基去甲肾上腺素。
本发明还涉及本发明化合物与抗胆碱能药物的组合,所述抗胆碱能药物包括毒蕈碱受体受体(M1、M2和M3)拮抗剂如阿托品、东莨菪碱、溴环扁吡酯(glycopyrrrolate)、异丙托溴铵、噻托溴铵、氧托溴铵、哌仑西平和替伦折平。
本发明还涉及本发明化合物与β-肾上腺素受体激动剂(包括β-受体1-4亚型)的组合,所述β-肾上腺素受体激动剂例如异丙肾上腺素、沙丁胺醇、福莫特罗、沙美特罗、叔丁喘宁、间羟异丙肾上腺素、甲磺酸比托特罗、和吡布特罗。
本发明还涉及本发明化合物与色原酮(chromone),包括色甘酸钠和奈多罗米钠的组合。
本发明还进一步涉及本发明的化合物与I型胰岛素样生长因子(IGF-1)模拟物的组合。
本发明还涉及本发明化合物与吸入的糖皮质激素的组合,所述糖皮质激素例如氟尼缩松、曲安奈德、二丙酸氯地米松、布地奈德、丙酸氟替卡松、环索奈德、和糠酸莫米松。
本发明还涉及本发明化合物与基质金属蛋白酶(MMPs)抑制剂的组合,该基质金属蛋白酶是间质溶解素、胶原蛋白酶和明胶酶,以及聚集蛋白聚糖酶;尤其是胶原蛋白酶-1(MMP-1)、胶原蛋白酶-2(MMP-8)、胶原蛋白酶-3(MMP-13)、间质溶解素-1(MMP-3)、间质溶解素-2(MMP-10)、和间质溶解素-3(MMP-11)和MMP-9及MMP-12。
本发明还涉及本发明化合物与诸如下述的趋化因子受体功能调节剂的组合:CCR1、CCR2、CCR2A、CCR2B、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10和CCR11的拮抗剂(针对C-C家族);CXCR1、CXCR2、CXCR3、CXCR4和CXCR5的拮抗剂(针对C-X-C家族)和CX3CR1的拮抗剂(针对C-X3-C家族)。
本发明进一步涉及本发明化合物与以下药剂的组合:细胞因子或细胞因子功能激动剂或拮抗剂,包括α-、β-和γ-干扰素;白介素(IL)包括IL-1至15以及白介素拮抗剂或抑制剂,包括作用于细胞因子信号通路的药剂。
本发明还涉及本发明化合物与免疫球蛋白(Ig)或Ig制剂或拮抗剂或调节Ig功能的抗体如抗-IgE(如奥马佐单抗)的组合。
本发明还涉及本发明化合物与其它全身或局部用药的抗炎药物包括沙利度胺及其衍生物、类视黄醇、地蒽酚、和卡泊三醇的组合。
本发明还涉及本发明化合物与抗菌剂包括青霉素衍生物、四环素类、大环内酯类、β-内酰胺、氟喹诺酮类、和吸入性氨基糖甙类;和抗病毒剂包括阿昔洛维、泛西洛维、缬昔洛韦、更昔洛韦、西多福韦;金刚烷胺、金刚乙胺;三氮唑核苷;扎那米韦和扎那米韦;蛋白酶抑制剂如印地那韦、那非那韦、利托那韦、和沙奎那韦;核苷反转录酶抑制剂如地达诺新、拉米夫定、司他夫定、扎西他宾、齐多夫定;非核苷反转录酶抑制剂如奈韦拉平、依法韦仑的组合。
本发明还涉及本发明化合物与心血管药物如钙通道阻滞剂、β-肾上腺素受体阻滞剂、血管紧张素-转化酶(ACE)抑制剂、血管紧张素-2受体拮抗剂;降脂药物如他汀类、贝特类;血细胞形态调节剂如己酮可可碱;溶栓剂、和抗凝剂包括血小板聚集抑制剂的组合。
本发明还涉及本发明化合物与CNS药物如抗抑郁药(例如舍曲林)、抗帕金森症药(如塞利吉林、L-多巴、罗平尼咯、普拉克索、MAOB抑制剂如selegine和雷沙吉兰、comP抑制剂如托卡朋(Tasmar)、A-2抑制剂、多巴胺再摄取抑制剂、NMDA拮抗剂、烟碱激动剂、多巴胺激动剂和神经元一氧化氮合酶的抑制剂)、和抗阿耳茨海默症药如多奈哌齐、他克林、COX-2抑制剂、丙戊茶碱或美曲磷酯的组合。
本发明还涉及本发明化合物与治疗急慢性疼痛的药物,包括作用于中枢和外周的镇痛药如阿片样类似物及衍生物、卡马西平、苯妥英、丙戊酸钠、阿米替林和其它抗抑郁病药、和非甾体抗炎药的组合。
本发明还涉及本发明化合物与肠胃外或局部用药的局部麻醉药如利多卡因的组合。
本发明还涉及本发明化合物与以下药物的组合:(i)类胰蛋白酶抑制剂;(ii)血小板活化因子(PAF)拮抗剂;(iii)白细胞介素转化酶(ICE)抑制剂;(iv)IMPDH抑制剂;(v)黏附分子抑制剂包括VLA-4拮抗剂;(vi)组织蛋白酶(cathepsins);(vii)MAP激酶抑制剂;(viii)葡萄-6磷酸脱氢酶抑制剂;(ix)激肽-B1-和B2-受体拮抗剂;(x)抗痛风药物如秋水仙碱;(xi)黄嘌呤氧化酶抑制剂如别嘌醇;(xii)排尿酸剂如丙磺舒、磺吡酮、和苯溴马隆;(xiii)生长激素促分泌剂;(xiv)转化生长因子(TGFβ);(xv)血小板衍生生长因子(PDGF);(xvi)成纤维细胞生长因子如碱性成纤维细胞生长因子(bFGF);(xvii)粒细胞巨噬细胞集落刺激因子(GM-CSF);(xviii)辣椒素软膏;(xix)速激肽NK1和NK3受体拮抗剂如NKP-608C、SB-233412(他奈坦)、和D-4418;(xx)弹性酶抑制剂如UT-77和ZD-0892;(xxi)TNF-α转化酶抑制剂(TACE);(xxii)诱发性一氧化氮合酶(iNOS)抑制剂或(xxiii)TH2细胞表达的化学引诱物受体-类似分子(如CRTH2拮抗剂);(xxiv)P38抑制剂。
本发明化合物还可以与抗骨质疏松药物包括激素药物如雷洛昔芬、和双膦酸盐如阿伦膦酸盐组合使用。
本发明的化合物也可与用于治疗骨关节炎的现有的治疗剂联合用药。可以联合用药的合适的药物包括标准的非甾体消炎药(下文中为NSAID′s)如吡罗昔康、双氯芬酸,丙酸如萘普生、氟比洛芬、非诺洛芬、酮洛芬和布洛芬、灭酸类如甲灭酸、吲哚美辛、舒林酸、阿扎丙宗、吡唑酮如保泰松、水杨酸酯如阿司匹林;COX-2抑制剂例如塞来考昔、伐地考昔、罗非考昔和艾托考昔、镇痛药以及关节内治疗药如皮质激素和透明质酸类衍生物;和营养补充剂如葡萄糖胺。
本发明化合物还可以与现有的治疗癌症的药物组合使用。用于组合的合适药物包括:
(i)如用于医学肿瘤学的抗增殖/抗肿瘤药及其组合,例如烷化剂(如顺铂、碳铂、环磷酰胺、氮芥、美法仓、苯丁酸氮芥、白消安和亚硝基脲);抗代谢物(例如抗叶酸剂,如氟嘧啶如5-氟尿嘧啶和替加氟、雷替曲塞、甲氨喋呤、阿糖胞苷、羟基脲、吉西他滨和紫杉醇;抗肿瘤抗生素(例如蒽环类抗生素,如阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素-C、更生霉素和光辉霉素);抗有丝分裂剂(例如长春花生物碱类,如长春新碱、长春碱、长春地辛和长春瑞滨,以及紫杉烷类,如紫杉醇和多西紫杉醇);和拓扑异构酶抑制剂(例如表鬼臼毒素类,如依托泊苷和替尼泊苷、安沙可林、托泊替康和喜树碱类);
(ii)细胞生长抑制剂如抗雌激素药(例如他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬和iodoxyfene)、雌激素受体下调药(如氟维司群)、抗雄激素药(例如比卡鲁胺、氟他胺、尼鲁米特和醋酸环丙氯地孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林和布舍瑞林)、孕激素类(如醋酸甲地孕酮)、芳香酶抑制剂(例如阿纳托唑、来曲唑、vorazole和依西美坦)和5α-还原酶抑制剂如非那司提;
(iii)抑制癌细胞入侵的药物(例如金属蛋白酶抑制剂如马立马司他和尿激酶纤维蛋白溶酶原激活剂受体功能的抑制剂);
(iv)生长因子功能抑制剂,例如诸如下述的抑制剂,包括生长因子抗体、生长因子受体抗体(例如抗-erbb2抗体曲妥单抗和抗-erbb1抗体西妥昔单抗[C225])、法尼基转移酶抑制剂、酪氨酸激酶抑制剂和丝氨酸/苏氨酸激酶抑制剂、例如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂,如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉基丙氧基)喹唑啉-4-胺(吉非替尼,AZD 1839)、N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)喹唑啉-4-胺(erlotinib,OSI-774)和6-丙烯酰基氨基-N-(3-氯-4-氟苯基)-7-(3-吗啉基丙氧基)喹唑啉-4-胺(CI 1033))、例如血小板衍生的生长因子家族的抑制剂和例如肝细胞生长因子家族的抑制剂;
(v)抗血管生成剂,例如那些抑制血管内皮生长因子作用的药物,(例如抗-血管内皮生长因子抗体贝伐单抗、例如在国际专利申请WO 97/22596、WO 97/30035、WO 97/32856和WO 98/13354中公开的那些化合物)和以其它机制起作用的化合物(例如利诺胺、整联蛋白αvβ3功能的抑制剂和血管他丁);
(vi)脉管损坏剂如考布他汀A4和国际专利申请WO 99/02166、WO00/40529、WO 00/41669、WO 01/92224、WO 02/04434和WO 02/08213中公开的化合物;
(vii)反义治疗剂,例如定向于上面列出靶点的那些物质如ISIS 2503、抗-ras反义物;
(viii)基因治疗方法,包括例如替换异常基因如异常p53或异常BRCA1或BRCA2的方法、GDEPT(基因定向的酶前药治疗)方法例如那些使用胞嘧啶脱氨酶、胸苷激酶或细菌硝基还原酶的方法和增加病人对化学治疗或放射治疗耐受性的方法例如多元抗药性基因治疗;和
(ix)免疫治疗方法,包括例如在体外和体内增加病人肿瘤细胞免疫原性的方法,如用细胞因子如白介素2、白介素4或粒细胞巨噬细胞集落刺激因子转染、减少T-细胞无反应性的方法、使用转染的免疫细胞如转染了细胞因子的树突细胞的方法、使用转染了细胞因子的肿瘤细胞系的方法和使用抗独特型抗体的方法。
另一方面,本发明提供了如前定义的式(I)的化合物,或其可药用盐或溶剂合物在制备用于治疗其中调节CRTh2受体活性是有益的的疾病或病症的药物中的用途。
具体地,本发明提供了如前定义的式(I)的化合物,或其可药用盐或溶剂合物在制备用于治疗前列腺素D2介导的疾病的药物中的用途,以及在制备用于患有呼吸性疾病或处于患所述疾病的风险的患者中呼吸性疾病的药物中的用途。
在本说明书的上下文中,术语″治疗″也包括″预防性″,除非有相反的指出。术语″治疗性″和″治疗地″也应作相应的理解。
本发明还提供了一种治疗由PGD2或其代谢物介导的疾病的方法,其中前列腺素类结合其受体(尤其是CRTh2)受体,所述的方法包括对病人施用治疗有效量的如前定义的式(I)的化合物,或其可药用盐或溶剂合物或前药。
本发明还提供了一种治疗病人的炎性疾病,尤其是牛皮癣的方法,所述的病人患所述疾病或处于患所述疾病的危险中,所述的方法包括向病人施用治疗有效量的如前定义的式(I)的化合物,或其可药用盐或溶剂合物。
为了上述治疗用途,施用的剂量将当然地,随施用的化合物、给药方式以及期望的治疗以及显示的疾病而变。
式(I)的化合物、其前药以及可药用盐和溶剂合物可以其自身使用并且通常以药物组合物的形式进行给药,所述的药物组合物中式(I)化合物/盐/溶剂合物(活性成分)与可药用佐剂、稀释剂或载体结合。取决于给药方式,药物组合物优选地包括0.05~99%w(重量百分比),更优选地0.05~80%w,更优选地0.10~70%w,并更优选地0.10~50%w的活性成分,所有的重量百分比基于总的组合物。
本发明还提供了一种药物组合物,包括如前定义的式(I)的化合物,或其可药用盐或溶剂合物以及可药用佐剂、稀释剂或载体。
药物组合物可以溶液、悬浮剂、七氟烷烃气雾剂以及干粉制剂的形式进行局部给药(如对肺和/或气道或对皮肤);或以片剂、胶囊剂、糖浆剂、散剂或颗粒剂的形式进行全身给药如经口给药,或以溶液或悬浮液的形式进行肠胃外给药或经皮下给药或以栓剂的形式经直肠给药或透皮给药。优选地本发明的化合物经口服给药。
本发明现在利用下述的非限制性实施例进行说明,其中,除非另有说明:
(i)当给出数据的时候,以δ值的形式给出主要诊断性质子的1HNMR数据,以相对于作为内标的四甲基硅烷(TMS)以百万分之一(ppm)给出;
(ii)质谱(MS):通常只报告显示分子质量的离子;除非另有说明,提供的质量离子为带正电质量离子-(M+H)+;
(iii)实施例和方法中的标题化合物和小标题化合物利用AdvancedChemical Development Inc,Canada的ACD labs/命名程序(6.0版本)进行命名;
(iv)除非另有说明,反相制备性HPLC利用Symmetry、NovaPak或Ex-Terra反相硅胶柱进行;
(v)溶剂利用MgSO4或Na2SO4干燥;
(vi)使用下述缩写:
EtOAc 乙酸乙酯
DCM 二氯甲烷
NMP N-甲基吡咯烷
DMF N,N-二甲基甲酰胺
THF 四氢呋喃
mcpba 3-氯过氧苯甲酸(Aldrich 77%max)
Pd(dppf)Cl2 [1,1’-双(二苯基膦基)二茂铁]二氯钯(II)与二氯甲烷的复合物
RT 室温
实施例1
{[5-氯-4′-(乙硫基)联苯-2-基]氧基}乙酸
(i)(2-溴-4-氯苯氧基)乙酸叔丁基酯
在RT,将溴乙酸叔丁基酯(2.6ml)加入到4-溴-2-氯苯酚(3g)和碳酸钾(6.2g)在DMF(40ml)中的搅拌混合物中。16小时后,将反应在乙醚和水之间分配,分离出有机物,干燥并减压蒸发。将残留物经硅胶层析纯化,用4%EtOAc/异己烷洗脱。产量4.05g。
1H NMR CDCl3:δ7.55(1H,d);7.21(1H,dd);6.72(1H,d);4.57(2H,s);1.48(9H,s)
(ii){[5-氯-4′-(乙硫基)联苯-2-基]氧基}乙酸叔丁基酯
将步骤(i)(2g)的产物、4-(乙硫基)苯基硼酸(1.5g)、氟化铯(2g)和Pd(dppf)Cl2(0.2g)在二噁烷(40ml)中的混合物加热回流3小时。冷却后将混合物在乙醚和水之间分配。分离出有机物,干燥并减压蒸发。将残留物经硅胶层析纯化,用5%EtOAc/异己烷洗脱。产量0.92g。
MS:APCI(+ve):379/381(M+1)
(iii){[5-氯-4′-(乙硫基)联苯-2-基]氧基}乙酸
标题化合物通过将步骤(ii)的产物(0.3g)和三氟乙酸(4ml)在DCM(10ml)中的混合物在RT搅拌5小时进行制备。将溶剂减压蒸发,将残留物用乙醚研磨然后经反相HPLC纯化。产量0.106g。
1H NMR DMSO-d6:δ13.07(1H,s);7.54(2H,d);7.35-7.33(4H,m);7.02(1H,d);4.74(2H,s);3.02(2H,q);1.27(3H,t)
MS:APCI(-ve):321/3(M-1)
实施例2
{[5-氯-4′-(乙基磺酰基)联苯-2-基]氧基}乙酸
(i){[5-氯-4′-(乙基磺酰基)联苯-2-基]氧基}乙酸叔丁基酯
在RT,将Mcpba(1.2g)加入到实施例1步骤(ii)的产物(0.6g)在DCM(6.2g)在DMF(40ml)中的搅拌混合物中。16小时后,将反应在乙醚和水之间分配,分离出有机物,干燥并减压蒸发。将残留物经硅胶层析纯化,用4%EtOAc/异己烷洗脱。产量4.05g。
1H NMR CDCl3:δ7.55(1H,d);7.21(1H,dd);6.72(1H,d);4.57(2H,s);1.48(9H,s)
(ii){[5-氯-4′-(乙硫基)联苯-2-基]氧基}乙酸叔丁基酯
将步骤(i)(2g)的产物、4-(乙硫基)苯基硼酸(1.5g)、氟化铯(2g)和Pd(dpPf)Cl2(0.2g)在二噁烷(40ml)中的混合物加热回流3小时。冷却后将混合物在乙醚和水之间分配。分离出有机物,干燥并减压蒸发。将残留物经硅胶层析纯化,用5%EtOAc/异己烷洗脱。产量0.92g。
MS:APCI(+ve):379/381(M+1)
(iii){[5-氯-4′-(乙硫基)联苯-2-基]氧基}乙酸
标题化合物通过将步骤(ii)的产物(0.3g)和三氟乙酸(4ml)在DCM(10ml)中的混合物在RT搅拌5小时进行制备。将溶剂减压蒸发,将残留物用乙醚研磨然后经反相HPLC纯化。产量0.106g。
1H NMR DMSO-d6:δ13.07(1H,s);7.54(2H,d);7.35-7.33(4H,m);7.02(1H,d);4.74(2H,s);3.02(2H,q);1.27(3H,t)
MS:APCI(-ve):321/3(M-1)
实施例2
{[5-氯-4′-(乙基磺酰基)联苯-2-基]氧基}乙酸
(i){[5-氯-4′-(乙基磺酰基)联苯-2-基]氧基}乙酸叔丁基酯
在RT,将Mcpba(1.2g)加入到实施例1步骤(ii)的产物(0.6g)在DCM
实施例4
[(5-氯-4′-氰基联苯-2-基)氧基]乙酸
(i)[(5-氯-4′-氰基联苯-2-基)氧基]乙酸叔丁基酯
小标题化合物利用实施例1步骤(ii)的方法、利用实施例1步骤(i)的产物和4-氰基苯基硼酸进行制备。产量0.524g。
1H NMR CDCl3:δ7.70(4H,s);7.32-7.26(2H,m);6.79(1H,d);4.51(2H,s);1.48(9H,s)
(ii)[(5-氯-4′-氰基联苯-2-基)氧基]乙酸
标题化合物利用实施例1步骤(iii)的方法、利用步骤(i)的产物进行制备。产量0.109g。
1H NMR DMSO-d6:δ13.14(1H,s);7.90(2H,d);7.80(2H,d);7.45-7.41(2H,m);7.10(1H,d);4.78(2H,s)
MS:APCI(-ve):286/8(M-1)
实施例5
[(5-氯-4′-甲氧基联苯-2-基)氧基]乙酸
(i)[(5-氯-4′-甲氧基联苯-2-基)氧基]乙酸叔丁基酯
小标题化合物利用实施例1步骤(ii)的方法、利用实施例1步骤(i)的产物和4-甲氧基苯基硼酸进行制备。产量0.610g。
1H NMR CDCl3:δ7.54(2H,d);7.31-7.18(2H,m);6.96(2H,d);6.76(1H,d);4.46(2H,s);3.84(3H,s);1.46(9H,s)
(ii)[(5-氯-4′-甲氧基联苯-2-基)氧基]乙酸
标题化合物利用实施例1步骤(iii)的方法、利用步骤(i)的产物进行制备。产量0.119g。
1H NMR DMSO-d6:δ13.08(1H,s);7.53(2H,d);7.32-7.29(2H,m);7.01-6.96(3H,m);4.72(2H,s);3.79(3H,s)
MS:APCI(-ve):291/3(M-1)
实施例6
(4-氯-2-喹啉-8-基苯氧基)乙酸,三氟乙酸盐
(i)(4-氯-2-喹啉-8-基苯氧基)乙酸叔丁基酯
小标题化合物利用实施例1步骤(ii)的方法、利用实施例1步骤(i)的产物和8-喹啉硼酸进行制备。产量0.356g。
1H NMR CDCl3:δ8.90-8.88(1H,m);8.18(1H,d);7.85(1H,d);7.76(1H,d);7.60(1H,t);7.40-7.30(3H,m);6.87(1H,d);4.37(2H,s);1.37(9H,s)。
(ii)(4-氯-2-喹啉-8-基苯氧基)乙酸,三氟乙酸盐
标题化合物进行制备利用实施例1步骤(iii)的方法、利用步骤(i)的产物。产量0.25g。
1HNMR DMSO-d6:δ8.91-8.89(1H,m);8.62(1H,d);8.12(1H,d);7.85-7.67(3H,m);7.46(1H,dd);7.38(1H,d);7.09(1H,d);4.61(2H,s)。
MS:APCI(-ve):312/4(M-1)
实施例7
[(5-氯-3′,4′-二甲氧基联苯-2-基)氧基]乙酸
(i)[(5-氯-3′,4′-二甲氧基联苯-2-基)氧基]乙酸叔丁基酯
小标题化合物利用实施例1步骤(ii)的方法、利用实施例1步骤(i)的产物和3,4-二甲氧基苯基硼酸进行制备。产量0.86g。
1H NMR CDCl3:δ7.33-7.12(4H,m);6.93(1H,d);6.79(1H,d);4.46(2H,s);3.93(3H,s);3.92(3H,s);1.46(9H,s)
(ii)[(5-氯-3′,4′-二甲氧基联苯-2-基)氧基]乙酸
标题化合物利用实施例1步骤(iii)的方法、利用步骤(i)的产物进行制备。产量0.32g。
1H NMR DMSO-d6:δ13.08(1H,s);7.36-7.27(3H,m);7.12-6.98(3H,m);4.74(2H,s);3.78(6H,2xs)。
MS:APCI(-ve):321/3(M-1)
实施例8
2′-(羧基甲氧基)-5′-氯联苯-4-羧酸
标题化合物利用实施例1步骤(ii)和步骤(iii)的方法、利用实施例1步骤(i)的产物和4-羧基苯基硼酸进行制备。产量0.035g。
1H NMR DMSO-d6:δ7.98-7.38(6H,m);7.08-7.05(1H,m);4.75(2H,s)。
MS:APCI(-ve):305(M-1)
实施例9
{[5-氯-4′-(甲基磺酰基)联苯-2-基]氧基}乙酸
标题化合物利用实施例1步骤(ii)和实施例2的方法、利用实施例1步骤(i)的产物和4-(甲硫基)苯硼酸进行制备。产量0.1g。
1H NMR DMSO-d6:δ7.97-7.08(7H,m);4.78(2H,s);3.31(3H,bs)。
MS:APCI(-ve):339(M-1)
实施例10
{[5-氯-4′-(乙基磺酰基)-2′-甲基联苯-2-基]氧基}乙酸
(i)4-溴-3-甲基苯基乙基硫醚
在0℃下,将溴(2.2ml)加入到1-(乙硫基)-3-甲基苯(6.6g)的乙酸溶液(20ml)中。将混合物在RT搅拌2小时然后减压去除溶剂。将残留物经硅胶层析纯化,用DCM洗脱。产量6.6g。
MS:APCI(+ve):247/9(M+1)
(ii)2-[4-(乙硫基)-2-甲基苯基]-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷
将步骤(i)的产物(6.6g)、4,45,5-四甲基-[1,3,2]-二氧杂硼杂环戊烷(1.94ml)、三乙基胺(2.4ml)、乙酸钯(0.06g)和2-(二环己基膦基)联苯(0.3g)在二噁烷(20ml)中的混合物在85℃加热2小时。将混合物用氯化铵水溶液中止,用乙醚萃取,将有机物干燥并减压蒸发。将残留物经硅胶层析纯化,用50%异己烷/DCM洗脱。产量0.7g。
1H NMR CDCl3:δ7.66(1H,d);7.08-7.05(2H,m);2.94-2.92(2H,q);2.5(3H,s);1.43-1.27(15H,m)。
(iii){[5-氯-4′-(乙基磺酰基)-2′-甲基联苯-2-基]氧基}乙酸
标题化合物利用实施例1步骤(ii)和实施例2的方法、利用步骤(ii)的产物和实施例1步骤(i)的产物进行制备。产量0.035g。
1H NMR DMSO-d6:δ7.79-6.99(6H,m);4.67(2H,s);3.35(2H,q);2.23(3H,s);1.15(3H,t)
MS:APCI(-ve):367(M-1)
实施例11
[(5-氰基联苯-2-基)氧基]乙酸
标题化合物利用实施例1的方法、利用3-溴-4-羟基苄腈和苯基硼酸进行制备。产量0.175g。
1H NMR DMSO-d6:δ13.18(1H,s);7.81-7.17(8H,m);4.87(2H,s)。
MS:APCI(-ve):252(M-1)
实施例12
[(5-硝基联苯-2-基)氧基]乙酸
标题化合物利用实施例1的方法、利用2-溴-4-硝基苯酚和苯基硼酸进行制备。产量0.065g。
1H NMR DMSO-d6:δ13.26(1H,s);8.23(1H,dd);8.12(1H,d);7.63(2H,d);7.50-7.38(3H,m);7.25(1H,d);4.94(2H,s)。
MS:APCI(-ve):272(M-1)
实施例13
{[4′-(甲硫基)-5-(三氟甲基)联苯-2-基]氧基}乙酸
(i)2-碘-4-(三氟甲基)苯酚
在0℃,将碘化钠(3.32g)然后氯胺-T(5.91g)加入至4-三氟甲基苯酚(3.0g)在DMF(30ml)中的搅拌混合物中。将混合物温热至RT,搅拌1小时,用稀盐酸稀释然后用乙醚萃取。将有机层用硫代硫酸钠水溶液洗涤,干燥并减压去除溶剂。产量5.25g。
MS:APCI(-ve):287(M-1)
(ii){[4′-(甲硫基)-5-(三氟甲基)联苯-2-基]氧基}乙酸
标题化合物利用实施例1的方法、利用步骤(i)的产物和4-(甲硫基)苯硼酸进行制备。产量0.13g。
1H NMR DMSO-d6:δ13.16(1H,s);7.68-7.18(7H,m);4.85(2H,s);2.51(3H,s)。
MS:APCI(-ve):341(M-1)
实施例14
{[4′-(甲基磺酰基)-5-(三氟甲基)联苯-2-基]氧基}乙酸,铵盐
标题化合物利用实施例1和2的方法、利用实施例13步骤(i)的产物和4-(甲硫基)苯硼酸进行制备。产量0.14g。
1H NMR DMSO-d6:δ13.21(1H,s);8.00-7.69(6H,m);7.27(1H,d);4.89(2H,s);3.27(3H,s)。
MS:APCI(-ve):373(M-1)
实施例15
{[4′-(乙基磺酰基)-2′-甲基-5-(三氟甲基)联苯-2-基]氧基}乙酸
标题化合物利用实施例1和2的方法、利用实施例13步骤(i)的产物和实施例10步骤(ii)的产物进行制备。产量0.055g。
1H NMR DMSO-d6:δ7.80-7.12(6H,m);4.63(2H,s);3.39-3.29(2H,q);2.23(3H,s);1.18-1.11(3H,t)。
MS:APCI(-ve):401(M-1)
实施例16
(4-氯-2-嘧啶-5-基苯氧基)乙酸,铵盐
(i)苄基2-溴-4-氯苯基醚
将苄基溴(13.1ml)加入到2-溴-4-氯苯酚(20.7g)和碳酸钾(27.6g)在DMF(200ml)中的搅拌混合物。72小时后,将混合物在乙醚和水之间分配,将有机层用水洗涤,干燥,并将溶剂减压蒸发。将残留物经硅胶层析纯化,用2%EtOAc/异己烷洗脱。产量18.1g。
1H NMR CDCl3:δ7.55(1H,s);7.46-7.18(6H,m);6.84(1H,d);5.14(2H,s)。
(ii)[2-(苄氧基)-5-氯苯基]硼酸
在-70℃,将丁基锂的溶液(1.6M己烷溶液)(50ml)滴加至步骤(i)的产物(23g)在乙醚(300ml)中的搅拌混合物中。1小时后,再加入18ml丁基锂,放置0.75小时,然后加入三甲基硼酸酯(10ml),并将混合物温热至RT并放置16小时。加入2M盐酸(100ml),搅拌1小时然后分离出有机层并用氢氧化钠水溶液萃取。将碱性层用2M盐酸溶液酸化,用乙醚萃取,干燥并减压蒸发。将残留物用异己烷研磨并过滤。产量10.8g。
1H NMR CDCl3:δ7.82(1H,d);7.44-7.34(6H,m);6.90(1H,d);5.99(2H,s);5.12(2H,s)。
(iii)5-[2-(苄氧基)-5-氯苯基]嘧啶
将步骤(ii)的产物(0.2g)、5-溴嘧啶(0.16g)、碳酸钠(0.21g)和四(三苯基膦)钯(0)(0.05g)在二噁烷(6ml)中的混合物加热回流48小时。将混合物在EtOAc和水之间分配,分离出有机物,干燥,并减压蒸发。将残留物经硅胶层析纯化,用20%EtOAc/异己烷洗脱。产量0.283g。
MS:APCI(+ve):297/9(M+1)
(iv)4-氯-2-嘧啶-5-基苯酚
将步骤(iii)的产物(0.28g)、10%钯炭(0.04g)在乙醇(20ml)中的混合物在2Bar氢化24小时。过滤后将溶剂减压蒸发。产量0.19g。
MS:APCI(+ve):207/9(M+1)
(v)(4-氯-2-嘧啶-5-基苯氧基)乙酸叔丁基酯
小标题化合物利用实施例1步骤(i)的方法进行制备。产量0.216g。
MS:APCI(+ve):321/3(M+1)
(vi)(4-氯-2-嘧啶-5-基苯氧基)乙酸,铵盐
标题化合物利用实施例1步骤(iii)的方法进行制备。产量0.033g。
1H NMR DMSO-d6:δ9.15(1H,s);9.08(2H,s);7.57(1H,d);7.44(1H,dd);7.10(1H,d);4.67(2H,s)
MS:APCI(+ve):265/7(M+1)
实施例17
{2-[5-(氨基磺酰基)吡啶-2-基]-4-氯苯氧基}乙酸
标题化合物利用实施例16的方法进行制备。产量0.022g。
1H NMR DMSO-d6:δ13.19(1H,s);9.05(1H,s);8.29(1H,d);8.21(1H,d);7.84(1H,d);7.65(2H,s);7.49(1H,dd);7.16(1H,d);4.86(2H,s)
MS:APCI(+ve):343/5(M+1)
实施例18
[2-(2-氨基嘧啶-5-基)-4-氯苯氧基]乙酸,三氟乙酸盐
标题化合物利用实施例16的方法进行制备。产量0.036g。
1H NMR DMSO-d6:δ8.56(2H,s);7.45(1H,d);7.33(1H,dd);7.05(1H,d);4.76(2H,s)
MS:APCI(+ve):280/2(M+1)
实施例19
[4-氯-2-(4-甲基-2-吗啉-4-基嘧啶-5-基)苯氧基]乙酸
(i)2-[2-(苄氧基)-5-氯苯基]-N-甲氧基-N-甲基乙酰胺
将1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(8.6g)加入到(2-苄氧基-5-氯苯基)-乙酸(10.6g)、N,O-二甲基羟基胺盐酸盐(4.4g)、1-羟基苯并三唑(6.9g)和N,N-二异丙基乙基胺(20ml)在DMF(150ml)中的溶液中,并将混合物在RT搅拌16小时,然后在乙酸乙酯和水之间分配。将有机物用2M盐酸、水洗涤,干燥,并减压蒸发。产量12.2g。
MS:APCI(+ve):320/2(M+1)
(ii)1-[2-(苄氧基)-5-氯苯基]丙酮
在-70℃,将氯化甲基镁溶液(3M的THF溶液)(6ml)滴加至步骤(i)的产物(5.2g)在THF(150ml)中的搅拌混合物中。1小时后将混合物温热至RT,搅拌1小时,然后用氯化铵水溶液中止。将混合物在乙醚和水之间分配,分离出有机物,干燥,并减压蒸发。将残留物经硅胶层析纯化,用10%EtOAc/异己烷洗脱。产量2.22g。
1H NMR CDCl3:δ7.40-7.30(5H,m);7.26-7.12(2H,m);6.85(1H,d);5.03(2H,s);3.67(2H,s);2.12(3H,s)
(iii)(3Z)-3-[2-(苄氧基)-5-氯苯基]-4-(二甲基氨基)丁-3-烯-2-酮
将步骤(ii)的产物(5.72g)和二甲基甲酰胺二甲基缩醛(3.5ml)在甲苯(50ml)中的混合物在100℃加热12小时。将溶剂减压蒸发得到油状物,6.37g。
MS:APCI(+ve):330/2(M+1)
(iv)5-[2-(苄氧基)-5-氯苯基]-4-甲基-2-(甲硫基)嘧啶
将步骤(iii)的产物(4.3g)的乙醇溶液(20ml)加入到乙醇钠(0.98g)和S-甲基异硫脲硫酸盐(S-methyl isothiouronium sulphate)(2g)在乙醇(30ml)中的搅拌的混合物中,并将混合物加热回流8小时。再加入2g的S-甲基异硫脲硫酸盐和1.18g乙醇钠并继续加热16小时。将混合物冷却,在乙醚和水之间分配,将有机物用水洗涤,干燥,并减压蒸发。将残留物经硅胶层析纯化,用3-5%EtOAc/异己烷洗脱。产量1.84g。
MS:APCI(+ve):357/9(M+1)
(v)5-[2-(苄氧基)-5-氯苯基]-4-甲基-2-(甲基磺酰基)嘧啶
小标题化合物利用实施例2步骤(i)的方法进行制备。产量0.85g。
MS:APCI(+ve):389/91(M+1)
(vi)4-氯-2-[4-甲基-2-(甲基磺酰基)嘧啶-5-基]苯酚
小标题化合物利用实施例16步骤(iv)的方法进行制备。产量0.5g。
MS:APCI(+ve):299/301(M+1)
(vii){4-氯-2-[4-甲基-2-(甲基磺酰基)嘧啶-5-基]苯氧基}乙酸叔丁基酯
小标题化合物利用实施例1步骤(i)的方法进行制备。产量0.65g。
MS:APCI(+ve):413(M+1)
(viii)[4-氯-2-(4-甲基-2-吗啉-4-基嘧啶-5-基)苯氧基]乙酸叔丁基酯
将步骤(vii)的产物(0.15g)和吗啉(0.15ml)在二噁烷(3ml)中的溶液在90℃加热24小时,冷却并减压蒸发溶剂。产品以粗品使用。
MS:APCI(+ve):420/422(M+1)
(ix)[4-氯-2-(4-甲基-2-吗啉-4-基嘧啶-5-基)苯氧基]乙酸
标题化合物利用实施例1步骤(iii)的方法进行制备。产量0.046g。
1H NMR DMSO-d6:δ8.12(1H,s);7.39(1H,dd);7.25(1H,d);7.00(1H,d);4.71(2H,s);3.73-3.67(8H,m);2.18(3H,s)。
MS:APCI(+ve):364/6(M+1)
实施例20
{4-氯-2-[2-(二甲基氨基)嘧啶-5-基]苯氧基}乙酸
(i)5-[2-(苄氧基)-5-氯苯基]-2-氯嘧啶
小标题化合物利用实施例1步骤(ii)的方法、利用实施例16步骤(ii)的产物(3.2g)和2-氯-5-溴嘧啶(2.59g)进行制备。产量2.43g。
MS:APCI(+ve):331/3(M+1)
(ii)5-[2-(苄氧基)-5-氯苯基]-2-(丙硫基)嘧啶
将丙硫醇(3.1ml)加入到氢化钠(1.4g,60%油中的分散体)在DMF(30ml)中的搅拌的悬浮液中。1小时后,加入步骤(i)的产物(2.4g)的DMF溶液(10ml)。将反应混合物在RT搅拌1小时然后在EtOAc和水之间分配。将有机物用水、盐水洗涤,干燥并减压蒸发。将残留物经硅胶层析纯化,用5%EtOAc/异己烷洗脱。产量1.87g。
MS:APCI(+ve)371(M+1)
(iii)5-[2-(苄氧基)-5-氯苯基]-2-(丙基磺酰基)嘧啶
小标题化合物利用实施例2步骤(i)的方法、利用步骤(ii)的产物进行制备。
MS:APCI(+ve)403(M+1)
(iv){4-氯-2-[2-(丙基磺酰基)嘧啶-5-基]苯氧基}乙酸叔丁基酯
小标题化合物利用实施例16步骤(iv)和实施例1步骤(i)的方法、利用步骤(iii)的产物进行制备。产量1.04g。
MS:APCI(+ve)427(M+1)
(v){4-氯-2-[2-(二甲基氨基)嘧啶-5-基]苯氧基}乙酸
将二甲基胺盐酸盐(0.82g)加入到步骤(iv)的产物(0.2g)和N,N-二异丙基乙基胺(0.9ml)在NMP(5ml)中的搅拌混合物中。将反应混合物在90℃加热6小时然后用EtOAc稀释,用水、盐水洗涤,干燥并减压蒸发。将残留物溶解在DCM(10ml)中然后加入三氟乙酸(10ml)并在RT搅拌18小时。将反应混合物蒸发至干,并将残留物经反相HPLC纯化,然后用甲醇研磨得到白色的固体。产量0.035g。
1H NMR DMSO-d6:δ8.60(2H,s);7.42(1H,d);7.32(1H,dd);7.05(1H,d);4.77(2H,s);3.16(6H,s)。
MS:APCI(-ve)306(M-1)
实施例21
[4-氯-2-(2-吗啉-4-基嘧啶-5-基)苯氧基]乙酸
标题化合物从实施例20步骤(iv)的产物和吗啉,利用实施例20步骤(v)的方法进行制备。
1H NMR DMSO-d6:δ13.10(1H,brs);8.65(2H,s);7.45(1H,d);7.34(1H,dd);7.06(1H,d);4.77(2H,s);3.75(4H,m);3.67(4H,m)
MS:APCI(-ve)348(M-1)
实施例22
{4-氯-2-[2-(甲基氨基)嘧啶-5-基]苯氧基}乙酸
标题化合物从实施例20步骤(iv)的产物和甲基胺盐酸盐,利用实施例20步骤(v)的方法进行制备。
1H NMR DMSO-d6:δ8.54(2H,s);7.42(1H,d);7.32(1H,dd);7.25(1H,brs);7.04(1H,d);4.76(2H,s);2.84(3H,s)
MS:APCI(-ve)292(M-1)
实施例23
{2-[2-(苄基氨基)嘧啶-5-基]-4-氯苯氧基}乙酸
标题化合物从实施例20步骤(iv)的产物和苄基胺利用实施例20步骤(v)的方法进行制备。
1H NMR DMSO-d6:δ13.09(1H,brs);8.54(2H,s);7.90(1H,t);7.42(1H,d);7.35-7.29(5H,m);7.22(1H,m);7.03(1H,d);4.76(2H,s);4.55(2H,d)。
MS:APCI(-ve)368(M-1)
实施例24
[4-氯-2-(2-哌啶-1-基嘧啶-5-基)苯氧基]乙酸
标题化合物从实施例20步骤(iv)的产物和哌啶,利用实施例20步骤(v)的方法进行制备。
1H NMR DMSO-d6:δ13.10(1H,brs);8.59(1H,d);7.32(1H,dd);7.04(1H,d);4.77(2H,s);3.79(4H,t);1.65(2H,m);1.53(4H,m)
MS:APCI(-ve)346(M-1)
实施例25
(4-氯-2-{2-[甲基(甲基磺酰基)氨基]嘧啶-5-基}苯氧基)乙酸
(i)N-(5-溴嘧啶-2-基)-N-甲基甲磺酰胺
在0℃,将氢化钠(0.22g,60%油中的分散体)加入到(5-溴嘧啶-2-基)甲基胺(0.85g)在DMF(10ml)中的溶液中并搅拌30分钟。滴加甲磺酰氯(0.62g),将混合物温热至RT并再搅拌2小时。将反应用水中止,并且然后用EtOAc萃取。将有机物用水洗涤,干燥,并减压蒸发。将残留物经硅胶层析纯化,用1%甲醇/DCM洗脱。产量0.42g。
MS:APCI(+ve):266(M+1)
(ii)N-[5-(5-氯-2-羟基苯基)嘧啶-2-基]-N-甲基甲磺酰胺
小标题化合物利用实施例1步骤(ii)的方法,利用步骤(i)的产物和2-羟基-5-氯硼酸(0.27g)进行制备。产量0.2g。
MS:APCI(+ve):314(M+1)
(iii)(4-氯-2-{2-[甲基(甲基磺酰基)氨基]嘧啶-5-基}苯氧基)乙酸
标题化合物利用实施例1步骤(i)和(iii)的方法、利用步骤(ii)的产物进行制备。产量0.017g。
1H NMR DMSO-d6:δ13.16(1H,s);8.94(2H,s);7.57(1H,d);7.45-7.42(1H,m);7.14(1H,d);4.82(2H,s);3.55(3H,s);3.47(3H,s)。
MS:APCI(-ve):370(M-1)
实施例26
[[2′,5-二氯-4′-(乙基磺酰基)[1,1’-联苯]-2-基]氧基]-乙酸
(i)2-氯-4-(乙硫基)-1-碘-苯
将3-氯-4-碘-苯胺(5.6g)、亚硝酸异戊酯(8.8ml)和乙基二硫化物(ethyldisulphide)(13.4ml)在乙腈(100ml)中的溶液在60℃加热24小时。将溶剂减压去除,并将残留物经硅胶层析纯化,用1%乙酸乙酯/异己烷洗脱。产量4.02g。
1H NMR CDCl3:δ7.70(1H,d);7.36(1H,d);6.87(1H,dd);2.94(2H,q);1.32(3H,t)
(ii)[[[2′,5-二氯-4′-(乙硫基)[1,1’-联苯]-2-基]氧基]甲基]-苯
小标题化合物利用实施例1步骤(ii)的方法、利用步骤(i)的产物和实施例16步骤(ii)的产物进行制备。产量3.64g。
1H NMR CDCl3:δ7.4(1H,s);7.32-7.18(9H,m);6.92(1H,d);5.03(2H,s);2.99(2H,q);1.36(3H,t)
(iii)[[[2′,5-二氯-4′-(乙基磺酰基)[1,1’-联苯]-2-基]氧基]甲基]-苯
小标题化合物利用实施例2步骤(i)的方法、利用步骤(ii)的产物进行制备。产量3.8g。
1H NMR CDCl3:δ8.00(1H,s);7.81(1H,d);7.48(1H,d);7.36-7.20(7H,m);6.95(1H,d);5.04(2H,s);3.16(2H,q);1.32(3H,t)
(iv)2′,5-二氯-4′-(乙基磺酰基)-[1,1′-联苯]-2-醇
小标题化合物利用实施例16步骤(iv)的方法、利用步骤(iii)的产物进行制备。产量2.44g。
1H NMR CDCl3:δ8.03(1H,s);7.85(1H,d);7.55(1H,d);7.30(1H,d);7.16(1H,s);6.92(1H,d);5.20(2H,s);3.17(2H,q);1.36(3H,t)
(v)[2′,5-二氯-4′-(乙基磺酰基)[1,1’-联苯]-2-基]氧基]-乙酸,乙基酯
小标题化合物利用实施例1步骤(i)的方法、利用步骤(iv)的产物和溴乙酸乙基酯进行制备。产量2.23g
(vi)[[2′,5-二氯-4′-(乙基磺酰基)[1,1’-联苯]-2-基]氧基]-乙酸
将步骤(v)的产物(2.23g)、1M氢氧化钠水溶液(10ml)和THF(20ml)的混合物在RT搅拌3小时。将混合物用2M盐酸酸化,用乙醚萃取,并将有机物用水洗涤,干燥,并减压蒸发。将残留物从乙酸乙酯/异己烷中重结晶,产量0.45g。
1H NMR CDCl3:δ13.02(1H,s);8.02(1H,s);7.89(1H,d);7.69(1H,d);7.48(1H,dd);7.34(1H,d);7.08(1H,d);4.70(2H,s);3.44(2H,q);1.16(3H,t)。
MS:APCI(-ve):387/9(M-1)
Mpt.163-4℃
实施例27
[[2′-氯-4′-(乙基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
(i)2-溴-1-(苯基甲氧基)-4-(三氟甲基)-苯
小标题化合物利用实施例16步骤(i)的方法、利用2-溴-4-三氟甲基苯酚进行制备。产量58.7g。
1HNMR CDCl3:δ7.83(1H,s);7.51-7.32(6H,m);6.98(1H,d);5.21(2H,s)。
(ii)[2-(苯基甲氧基)-5-(三氟甲基)苯基]-硼酸
小标题化合物利用实施例16步骤(ii)的方法、利用步骤(i)的产物进行制备。产量30.7g。
1H NMR CDCl3:δ8.14(1H,d);7.68(1H,dd);7.44-7.39(5H,m);7.05(1H,d);5.79(2H,s);5.20(2H,s)。
(iii)[2-羟基-5-(三氟甲基)苯基]-硼酸
小标题化合物利用实施例16步骤(iv)的方法、利用步骤(ii)的产物进行制备。产量3.54g。
(iv)2′-氯-4′-(乙硫基)-5-(三氟甲基)-[1,1′-联苯]-2-醇
将乙酸钯(0.045g)和三-p-甲苯基膦(0.213g)在甲醇(10ml)中的混合物在RT搅拌30分钟。加入步骤(iii)的产物(1g)、碳酸钠(1.27g)、实施例(26)步骤(i)的产物(1.19g)和甲醇(20ml),并将混合物加热回流6小时。将溶剂减压去除,并将残留物在乙醚和2M盐酸之间分配。分离出有机物,干燥并减压蒸发。将残留物经硅胶层析纯化,用10%乙酸乙酯/异己烷洗脱。产量0.503g。
MS:ESI(-ve):331/3(M-1)
(v)2′-氯-4′-(乙基磺酰基)-5-(三氟甲基)-[1,1′-联苯]-2-醇
小标题化合物利用实施例2步骤(i)的方法,利用步骤(iv)的产物进行制备。产量0.277g
MS:ESI(-ve):363/5(M-1)
(vi)[[2′-氯-4′-(乙基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,1,1-二甲基乙基酯
小标题化合物利用实施例1步骤(i)的方法,利用步骤(v)的产物进行制备。产量0.253g。
(vii)[[2′-氯-4′-(乙基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
标题化合物利用实施例1步骤(iii)的方法,利用步骤(vi)的产物进行制备。产量0.154g。
1H NMR CDCl3:δ13.12(1H,s);8.04(1H,s);7.91(1H,d);7.81(1H,d);7.72(1H,d);7.63(1H,s);7.25(1H,d);4.82(2H,s);3.45(2H,q);1.17(3H,t)。
MS:APCI(-ve):421/3(M-1)
Mpt.167℃
实施例28
[[5-氯-4′-(乙基磺酰基)-2′-氟[1,1’-联苯]-2-基]氧基]-乙酸
(i)1-溴-4-(乙硫基)-2-氟-苯
在0℃,将溴(0.3ml)加入到1-乙硫基-3-氟-苯(1g)在氯仿(20ml)中的溶液中,然后温热至RT。2小时后将混合物用DCM稀释,用硫代硫酸钠水溶液洗涤,干燥,并减压蒸发。将残留物经硅胶层析纯化,用10%乙醚/异己烷洗脱。产量1.2g。
(ii)1-溴-4-(乙基磺酰基)-2-氟-苯
小标题化合物利用实施例2步骤(i)的方法,利用步骤(i)的产物进行制备。产量0.94g。
1H NMR CDCl3:δ.7.81-7.0(3H,m);3.17-3.10(2H,q);1.32-1.19(3H,t)。
(iii)[[[5-氯-4′-(乙基磺酰基)-2′-氟[1,1’-联苯]-2-基]氧基]甲基]-苯
小标题化合物利用实施例1步骤(ii)的方法,利用步骤(ii)的产物和实施例16步骤(ii)的产物进行制备。产量0.55g
(iv)5-氯-4′-(乙基磺酰基)-2′-氟-[1,1′-联苯]-2-醇
小标题化合物利用实施例16步骤(iv)的方法,利用步骤(ii)的产物进行制备,产量0.35g。
MS:ESI(-ve)313(M-1)
(v)[[5-氯-4′-(乙基磺酰基)-2′-氟[1,1’-联苯]-2-基]氧基]-乙酸
标题化合物利用实施例1步骤(i)和步骤(iii)的方法,利用步骤(iv)的产物进行制备,产量0.205g。
MS:ESI(-ve)371(M-1)
实施例29
[[4′-(乙基磺酰基)-2′-氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,钠盐
标题化合物利用实施例28的方法进行制备,产量0.26g。
MS:ESI(-ve)405(M-1)
实施例30
[[5-氯-4′-(乙基磺酰基)-2′-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
(i)1-溴-4-(乙硫基)-2-(三氟甲基)-苯
将碘乙烷(0.84ml)加入到3-三氟甲基-苯硫酚(2g)和碳酸钾(1.42g)在DMF(20ml)中的搅拌混合物中。72小时后将混合物在乙醚和水之间分配,分离出有机物,干燥并减压蒸发。将残留物溶解在乙酸(20ml)中,冷却至0℃,然后加入溴(0.51ml)。将混合物在RT搅拌16小时,减压去除溶剂,并将残留物经硅胶层析纯化,用25%DCM/异己烷洗脱。产量2.05g。
(ii)5-氯-4′-(乙硫基)-2′-(三氟甲基)-[1,1′-联苯]-2-醇
小标题化合物利用实施例1步骤(ii)的方法,利用步骤(i)的产物和5-氯-2-羟基苯基-硼酸进行制备,产量0.26g。
MS:ESI(-ve)347(M-1)
(iii)[[5-氯-4′-(乙硫基)-2′-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,1,1-二甲基乙基酯
小标题化合物利用实施例1步骤(i)的方法,利用步骤(ii)的产物进行制备,产量0.26g。
MS:APCI(-ve)389/391(M-1)-叔丁基
(iv)[[5-氯-4′-(乙基磺酰基)-2′-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
标题化合物利用实施例2步骤(i)和实施例1步骤(iii)的方法,利用步骤(iii)的产物进行制备,产量0.045g。
MS:ESI(-ve)421(M-1)
实施例31
2-[[5-氯-4′-(乙基磺酰基)[1,1’-联苯]-2-基]氧基]-丙酸
(i)2-(2-溴-4-氯苯氧基)-丙酸,1,1-二甲基乙基酯
小标题化合物利用实施例1步骤(i)的方法,利用2-溴-4-氯苯酚和2-溴丙酸,叔丁基酯进行制备,产量1.1g。
1H NMR DMSO-d6:δ7.54-7.1(2H,m);6.74-6.71(1H,d);3.70(3H,s);1.78-1.76(1H,d);1.48(9H,s)。
(ii)2-[[5-氯-4′-(乙硫基)[1,1’-联苯]-2-基]氧基]-丙酸,1,1-二甲基乙基酯
小标题化合物利用实施例1步骤(ii)的方法,利用步骤(i)的产物和4-(乙硫基)苯硼酸进行制备,产量1.2g。
MS:APCI(-ve)336(M-11)-叔丁基
(iii)2-[[5-氯-4′-(乙基磺酰基)[1,1’-联苯]-2-基]氧基]-丙酸
标题化合物利用实施例2步骤(i)和实施例1步骤(iii)的方法,利用步骤(ii)的产物进行制备,产量0.08g。
1H NMR DMSO-d6:δ7.97-6.96(7H,m);4.79-4.76(1H,m);3.39-3.31(2H,t);1.39-1.37(3H,d);1.16-1.07(3H,t)。
MS:ESI(-ve)367(M-1)
实施例32
2-[[4′-(乙基磺酰基)-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
(i)1-溴-4-(乙基磺酰基)-2-甲基-苯
小标题化合物利用实施例2步骤(i)的方法,利用实施例10步骤(i)的产物进行制备,产量4.3g。
MS:ESI(+ve)264(M+1)
(ii)[2-(苯基甲氧基)-5-(三氟甲基)苯基]-硼酸
小标题化合物利用实施例16步骤(ii)的方法,利用实施例27步骤(i)的产物进行制备,产量5.5g。
1H NMR CDCl3:δ8.14-7.62(2H,m);7.43-7.38(5H,m);7.01(1H,m);5.67(2H,s);5.19-5.16(2H,s)。
(iii)[[[4′-(乙基磺酰基)-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]甲基]-苯
小标题化合物利用实施例1步骤(ii)的方法,利用步骤(i)和(ii)的产物进行制备,产量2.72g。
MS:ESI(+ve)452(M+1+NH3)
(iv)4′-(乙基磺酰基)-2′-甲基-5-(三氟甲基)-[1,1′-联苯]-2-醇
小标题化合物利用实施例16步骤(iv)的方法,利用步骤(iii)的产物进行制备,产量2.1g。
MS:ESI(+ve)362(M+1+NH3)
(v)2-[[4′-(乙基磺酰基)-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,甲基酯
在0℃,将偶氮二羧酸二乙基酯(0.14ml)加入到步骤(iv)的产物(0.3g)、甲基-R-乳酸酯(0.083ml)和三苯基膦(0.228g)在THF(10ml)中的搅拌混合物中。4小时后,将混合物用水稀释并用乙酸乙酯萃取,分离出有机物,干燥并减压蒸发。将残留物经硅胶层析纯化,用50%乙醚/异己烷洗脱。产量0.4g。
MS:ESI(+ve)448(M+1+NH3)
(vi)2-[[4′-(乙基磺酰基)-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
将步骤(v)的产物(0.4g)和氢氧化锂(2当量)在THF(10ml)和水(10ml)中的混合物在RT搅拌过夜。将混合物在乙酸乙酯/水之间分配,将水层用2M盐酸酸化并用乙酸乙酯萃取。将有机层干燥,减压蒸发,并将残留物经反相HPLC纯化。产量0.035g。
1H NMR DMSO-d6:δ7.78-7.44(5H,m);7.16-7.14(1H,d);4.91-4.86(1H,q);3.30-3.25(2H,q);2.22(3H,s);1.33-1.24(3H,d);1.10-1.07(3H,t)。
MS:ESI(+ve)434(M+1+NH3)
实施例33
2-[[4′-(乙基磺酰基)-2′-甲基-5-(三氟甲基)[1,1’联苯]-2-基]氧基]-(2R)-丙酸,钠盐
标题化合物利用实施例32的方法,利用甲基-S-乳酸酯进行制备,产量0.2g。
1H NMR DMSO-d6:δ7.77-7.38(5H,m);7.02-7.00(1H,d);4.32(1H,m);3.39-3.25(2H,q);2.32(3H,s);1.21-1.07(6H,d+t)。
MS:ESI(+ve)434(M+1+NH3)
实施例34
2-[[2′,5-二氯-4′-(乙基磺酰基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,钠盐
标题化合物利用实施例32步骤(v)和(vi)的方法,利用实施例26步骤(iv)的产物进行制备,产量0.18g。
1H NMR DMSO-d6:δ7.99-7.23(5H,m);6.93-6.91(1H,d);4.26-4.24(1H,q);3.46-3.37(2H,q);1.20-1.06(6H,d+t)。
MS:ESI(-ve)402/403(M-1)
实施例35
2-[[2′-氯-4′-(乙基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
标题化合物利用实施例32步骤(v)和(vi)的方法,利用实施例2步骤(v)的产物进行制备,产量0.05g。
1H NMR DMSO-d6:δ7.98-7.23(5H,m);6.93-6.91(1H,d);4.68(1H,m);3.20-3.15(2H,q);1.48-1.39(3H,m);1.34-1.30(3H,t)。
MS:ESI(-ve)436(M-1)
实施例36
2-[[4′-(乙基磺酰基)-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-2-甲基-丙酸,钠盐
标题化合物利用实施例1步骤(i)和实施例26步骤(vi)的方法,利用实施例34步骤(iv)的产物进行制备,产量0.18g。
1H NMR DMSO-d6:δ7.72(1H,s);7.71(1H,d);7.56(1H,d);7.44(1H,d);7.35(1H,s);7.10(1H,d);2.29(3H,s);1.38(6H,s);1.13(3H,t)。
MS:ESI(-ve)429(M-1)
实施例37
2-[[4′-(乙基磺酰基)-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-丁酸,钠盐
标题化合物利用实施例1步骤(i)和实施例26步骤(vi)的方法,利用实施例34步骤(iv)的产物进行制备,产量0.29g。
1H NMR DMSO-d6:δ7.78(1H,s);7.71(1H,d);7.64(1H,d);7.41(1H,s);7.01(1H,d);4.27(1H,brs);3.36(2H,q);2.33(3H,brs);1.64-1.55(2H,m);1.11(3H,t);0.66(3H,brs)。
MS:ESI(-ve)429(M-1)
实施例38
[4-氯-2-[2-[(甲基磺酰基)(苯基甲基)氨基]-5-嘧啶基]苯氧基]-乙酸
(i)N-(5-溴-2-嘧啶基)-N-(苯基甲基)-甲磺酰胺
在0℃,将氢化钠(0.1g,60%在油中的分散体)加入到苄基-(5-溴-嘧啶-2-基)-胺(0.55g)在DMF(8ml)中的搅拌混合物中。30分钟后,加入甲磺酰基氯(0.286g),并将混合物在RT搅拌2小时然后在乙酸乙酯和水之间分配。分离出有机物用水洗涤,干燥并减压蒸发。将残留物经硅胶层析纯化,用二氯甲烷洗脱。产量0.41g。
MS:APCI(+ve)344(M+1)
(ii)N-[5-(5-氯-2-羟基苯基)-2-嘧啶基]-N-(苯基甲基)-甲磺酰胺
小标题化合物利用实施例1步骤(ii)的方法,利用步骤(i)和5-氯-2-羟基苯基-硼酸的产物进行制备,产量0.25g。
MS:APCI(+ve)390(M+1)
(iii)[4-氯-2-[2-[(甲基磺酰基)(苯基甲基)氨基]-5-嘧啶基]苯氧基]-乙酸
标题化合物利用实施例1步骤(i)和步骤(iii)的方法,利用步骤(ii)的产物进行制备,产量0.07g。
1HNMR DMSO-d6:δ13.16(1H,s);8.93(2H,s);7.56(1H,d);7.44-7.41(1H,m);7.37-7.31(4H,m);7.27-7.23(1H,m);7.12(1H,d);5.28(2H,s);4.81(2H,s);3.59(3H,s)。
MS:APCI(-ve):446(M-1)
实施例39
[4-氯-2-[2-[(乙基磺酰基)(苯基甲基)氨基]-5-嘧啶基]苯氧基]-乙酸
(i)N-(5-溴-2-嘧啶基)-N-(苯基甲基)-乙磺酰胺
小标题化合物利用实施例38步骤(i)的方法,利用苄基-(5-溴-嘧啶-2-基)-胺和乙烷磺酰氯进行制备,产量0.31g。
MS:APCI(+ve)358(M+1)
(ii)N-[5-(5-氯-2-羟基苯基)-2-嘧啶基]-N-(苯基甲基)-乙烷磺酰胺
小标题化合物利用实施例1步骤(ii)的方法,利用步骤(i)的产物和5-氯-2-羟基苯基-硼酸进行制备,产量0.25g。
MS:APCI(+ve)404(M+1)
(iii)[4-氯-2-[2-[(乙基磺酰基)(苯基甲基)氨基]-5-嘧啶基]苯氧基]-乙酸
标题化合物利用实施例1步骤(i)和步骤(iii)的方法,利用步骤(ii)的产物进行制备,产量0.13g。
1H NMR DMSO-d6:δ13.14(1H,s);8.92(2H,s);7.56(1H,d);7.44-7.31(5H,m);7.27-7.23(1H,m);7.12(1H,d);5.27(2H,s);4.81(2H,s);3.87(2H,q);1.25(3H,t)。
MS:APCI(-ve):460(M-1)
实施例40
[2-[2-[乙酰基(苯基甲基)氨基]-5-嘧啶基]-4-氯苯氧基]-乙酸
(i)N-(5-溴-2-嘧啶基)-N-(苯基甲基)-乙酰胺
小标题化合物利用实施例38步骤(i)的方法,利用苄基-(5-溴-嘧啶-2-基)-胺和乙酰氯进行制备,产量0.21g。
MS:APCI(+ve)306(M+1)
(ii)N-[5-(5-氯-2-羟基苯基)-2-嘧啶基]-N-(苯基甲基)-乙酰胺
小标题化合物利用实施例1步骤(ii)的方法,利用步骤(i)的产物和5-氯-2-羟基苯基-硼酸进行制备,产量0.16g。
MS:APCI(+ve)354(M+1)
(iii)[2-[2-[乙酰基(苯基甲基)氨基]-5-嘧啶基]-4-氯苯氧基]-乙酸
标题化合物利用实施例1步骤(i)和步骤(iii)的方法,利用步骤(ii)的产物进行制备,产量0.08g。
1H NMR DMSO-d6:δ9.01(2H,s);7.59(1H,d);7.44(1H,q);7.30-7.18(5H,m);7.13(1H,d);5.26(2H,s);4.81(2H,s);2.45(3H,s)。
MS:APCI(+ve):412(M+1)
实施例41
[[4′-(乙基磺酰基)-5-氟-2′-甲基[1,1’-联苯]-2-基]氧基]-乙酸
(i)[4-(乙硫基)-2-甲基苯基]-硼酸
将实施例10步骤(i)的产物(120.7g)在THF(500ml)中的溶液中的100ml部分溶液加入到搅拌的镁屑(13.4g)在THF(100ml)中的混合物中。加入二溴乙烷(0.2ml),并将混合物开始后温和地回流。滴加剩余的溴化物溶液保持溶液回流。加入完毕后,将混合物冷却至RT,然后在0℃下,通过套管转移至三甲基硼酸酯(112ml)在THF(200ml)中的搅拌混合物中。将混合物温热至RT,搅拌2小时然后用2M盐酸(300ml)中止。在RT下搅拌18小时后,减压去除THF,将混合物用乙醚萃取。分离出有机物,用水洗涤,干燥并减压蒸发。将残留物用乙醚/异己烷研磨并过滤。产量53.02g。
1H NMR CDCl3:δ8.08(1H,d);7.18(1H,d);7.15(1H,s);3.04(2H,q);2.76(3H,s);1.38(3H,t)
(ii)(2-溴-4-氟苯氧基)-乙酸,1,1-二甲基乙基酯
小标题化合物利用实施例1步骤(i)的方法进行制备。
(iii)[[4′-(乙基磺酰基)-5-氟-2′-甲基[1,1’-联苯]-2-基]氧基]-乙酸
标题化合物利用实施例27步骤(iv)、实施例2步骤(i)和实施例1步骤(iii)的方法,利用步骤(i)和(ii)的产物进行制备,产量0.045g。
1H NMR DMSO-d6:δ7.8-7.64(2H,m);7.42(2H,d);7.8-6.0(3H,m);4.10(2H,s);3.20(2H,q);1.18(3H,t)
MS:APCI(-ve):351(M-1)
实施例42
[[4′-(乙基磺酰基)-4,5-二氟-2′-甲基[1,1’-联苯]-2-基]氧基]-乙酸
标题化合物利用实施例41的方法进行制备,产量0.081g。
1H NMR DMSO-d6:δ7.76(1H,s);7.71(1H,dd);7.44(1H,d);7.23(1H,t);7.01-6.94(1H,m);4.32(2H,s);3.39(2H,m);2.25(3H,s);1.18(3H,t)。MS:APCI(-ve):369(M-1)
实施例43
[[4′-(乙基磺酰基)-3,5-二氟-2′-甲基[1,1’-联苯]-2-基]氧基]-乙酸
标题化合物利用实施例41的方法进行制备,产量0.15g。
1H NMR DMSO-d6:δ7.82-7.70(2H,m);7.49-7.38(2H,m);7.02-6.90(1H,m);4.40(2H,d);3.34(2H,q);1.11(3H,t)。
实施例44
[2-(2-氨基-5-甲基-3-吡啶基)-4-(三氟甲基)苯氧基]-乙酸
(i)[4-(三氟甲基)苯氧基]-乙酸
在-78℃下,将氢化钠(2.96g,60%油中的分散体)加入到4-羟基苯基-三氟甲烷(10g)在四氢呋喃(150ml)中的搅拌混合物中。撤除冷浴,将混合物搅拌1小时然后加入溴乙酸甲基酯(7ml)。1小时后,加入水,减压蒸除四氢呋喃,并将残留物在乙酸乙基酯/2M盐酸之间分配。将有机层减压蒸发,并将残留物溶解在四氢呋喃(120ml)中。加入甲醇(30ml)、水(30ml)和浓氢氧化钠溶液(6ml),并将混合物在室温搅拌过夜。将有机物减压去除,并将残留物在乙酸乙酯和2M盐酸之间分配。分离出有机物,干燥并减压蒸发,产量12.42g。
1H NMR DMSO-d6:δ13.13(1H,s);7.65(2H,d);7.10(2H,d);4.80(2H,s)。
MS:APCI(-ve)219(M-1)
(ii)[4-(三氟甲基)苯氧基]-乙酸,(3-甲基-3-氧杂环丁基)甲基酯
将草酰氯(14ml)加入到步骤(i)的产物(12.42g)和N,N-二甲基甲酰胺(2滴)在二氯甲烷(100ml)中的溶液中,并在RT搅拌72小时。将混合物减压蒸发,将残留物溶解在二氯甲烷(100ml)中然后加入三乙基胺(20ml)和3-甲基-3-氧杂环丁烷甲醇(17ml)。2小时后将混合物用水洗涤,减压蒸发,并将残留物经硅胶层析纯化用二氯甲烷洗脱,产量14.2g。
1H NMR DMSO-d6:δ7.66(2H,d);7.14(2H,d);4.98(2H,s),4.34(2H,d);4.24(2H,s);4.19(2H,d),1.21(3H,s)。
(iii)4-甲基-1-[[4-(三氟甲基)苯氧基]甲基]-2,6,7-三氧杂二环[2.2.2]辛烷
在-78℃下,将三氟化硼乙醚合物(1.48ml)加入到步骤(ii)的产物(14.2g)的二氯甲烷溶液中。撤除冷浴,将混合物搅拌3小时,然后加入三乙基胺(6.2ml)。将混合物减压减少至一半体积然后过滤。将滤液减压蒸发然后将残留物经硅胶层析纯化(用1柱体积的纯三乙基胺预洗脱),用二氯甲烷洗脱,产量11.1g。
1H NMR DMSO-d6:δ7.62(2H,d);7.14(2H,d);4.04(2H,s);3.91(6H,s);0.77(3H,s)。
MS:APCI(+ve)305(M+1)
(iv)[2-二羟硼基(borono)-4-(三氟甲基)苯氧基]-乙酸
在-78℃,用10分钟将仲丁基锂溶液(66ml,1.4M的环己烷溶液)滴加至步骤(iii)的产物(9.44g)在THF(100ml)中的搅拌混合物中。3小时后将混合物温热至-40℃保持5分钟,然后冷却至-78℃。加入三甲基硼酸酯(14.1ml),10分钟后将反应用2M盐酸中止。将混合物温热至RT,并将有机相分离出。将水层用乙酸乙酯萃取,将有机物合并并减压蒸发。将残留物溶解在甲醇(500ml)中然后加入bondelut-NH2树脂(180g),并将混合物漩涡0.5小时然后过滤。将树脂用10%乙酸/甲醇洗涤,然后减压蒸发洗涤液并在高真空下干燥。将残留物溶解在甲醇(50ml)、四氢呋喃(50ml)和饱和的氢氧化钠水溶液(2ml)中,放置30分钟,然后加入2M盐酸(50ml),并将有机物减压蒸发。将残留的水层用乙酸乙酯萃取,分离出有机物,干燥并减压蒸发,产量5.05g。
1H NMR DMSO-d6:δ8.07(1H,s);7.89(1H,d);7.75(1H,dd);7.14(1H,d);4.85(2H,s)。
MS:APCI(-ve)263(M-1)
(v)[2-(2-氨基-5-甲基-3-吡啶基)-4-(三氟甲基)苯氧基]-乙酸
将步骤(iv)的产物(0.1g)、2-氨基-3-溴-5-甲基吡啶(0.071g)、四(三苯基膦)钯(0)(0.046g)、碳酸钠(0.12g)在甲醇(2ml)中的混合物在CEM微波炉(可变的功率至150W)中在100℃加热10分钟。将混合物负载至SCX树脂(磺酸树脂)上,用甲醇快速洗脱然后将产物用甲醇/氨水洗脱。将甲醇/氨水滤液减压蒸发然后负载至bondelut-NH2树脂上。将树脂用甲醇快速洗脱然后将产物用甲醇/乙酸洗脱。将甲醇/乙酸滤液蒸发,并将残留物经RPHPLC纯化。产量0.089g。
1H NMR DMSO-d6:δ7.87(1H,s);7.79(1H,d);7.69(1H,s);7.63(1H,s);7.26(1H,d);4.9(2H,s);2.2(3H,s)。
MS:APCI(-ve)325(M-1)
实施例45-123
下述化合物以类似于实施例44的方法进行合成。
实施例45
[[4′-氨基-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.62(1H,d);7.32(1H,s);7.05(1H,d);6.81(1H,d);6.47(1H,s);6.44(1H,d);4.74(2H,s);1.98(3H,s)。
MS:APCI(-ve)324(M-1)
实施例46
[[4′-氨基-2′-氯-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.65(1H,d);7.4(1H,s),7.15(1H,d);7.04(1H,d);6.7(1h,s);6.56(1H,d);4.76(2H,s)。
MS:APCI(-ve)344/6(M-1)
实施例47
[[2′-氯-4′-羟基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ9.98(1H,s);7.69(1H,d);7.44(1H,s);7.21(1H,d);7.14(1H,d);6.91(1h,s);6.80(1H,d);4.76(2H,s)。
MS:APCI(-ve)345/7(M-1)
实施例48
[2-(2,4-二甲氧基-5-嘧啶基)-4-(三氟甲基)苯氧基]-乙酸
1H NMR DMSO-d6:δ8.32(1H,s);7.71(1H,d);7.63(1H,s);7.20(1H,d);4.8(2H,s);3.95(3H,s);3.87(3H,s)。
MS:APCI(-ve)357(M-1)
实施例49
[[2′-氯-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.75(1H,d);7.55(1H,m),7.50(1H,s);7.42(1H,m);7.41(1H,d);7.40(1H,d);7.19(1H,d);4.78(2H,s)。
MS:APCI(-ve)329/31(M-1)
实施例50
[[2′,5-双(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.83(1H,d);7.75(1H,d);7.71(1H,d);7.63(1H,t);7.44(1H,s);7.43(1H,d);4.74(2H,m)。
MS:APCI(-ve)363(M-1)
实施例51
[[5′-氟-2′-甲氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.68(1H,d);7.51(1H,s);7.20(1H,d);7.17(1H,m);7.15(1H,m);7.10(1H,d);4.78(2H,s);3.7(3H,s)。
MS:APCI(-ve)343(M-1)
实施例52
[[5′-氰基-2′-甲氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.87(1H,d);7.74(1H,s);7.71(1H,d);7.56(1H,s);7.29(1H,d);7.19(1H,d);4.77(2H,s);3.81(3H,s)。
MS:APCI(-ve)350(M-1)
实施例53
[[4′-氯-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.71(1H,d),7.47(1H,s),7.34(1H,d),7.30(1H,d),7.24(1H,s),7.13(1H,d),4.73(2H,s),2.11(3H,s)
MS:APCI(-ve)343/345(M-1)
实施例54
[[2′,5′-二甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.64(1H,d),7.35(1H,s),7.13(1H,d),7.07(1H,d),7.02(1H,d),6.94(1H,s),4.50(2H,s),2.30(3H,s),2.08(3H,s)
MS:APCI(-ve)323(M-1)
实施例55
[[5′-氯-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.70(1H,d),7.43(1H,s),7.38(1H,s),7.29(1H,d),7.19(1H,d),7.14(1H,s),4.70(2H,s),2.14(3H,s)
MS:APCI(-ve)343/345(M-1)
实施例56
[[2′-氟-6′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.71(1H,d),7.44(1H,s),7.27(1H,q),7.18(1H,t),7.11(1H,d),7.04(1H,d),4.67(2H,s),2.06(3H,s)
MS:APCI(-ve)327(M-1)
实施例57
[[4′-氟-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.70(1H,d),7.42(1H,s),7.30(1H,t),7.12(1H,d),7.10(1H,d),7.04(1H,d),4.69(2H,s),2.11(3H,s)
MS:APCI(-ve)327(M-1)
实施例58
[[4′-[[(乙基氨基)羰基]氨基]-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMRDMSO-d6:δ8.49(1H,s),7.62(1H,d),7.31(1H,s),7.29(1H,s),7.24(1H,d),7.04(1H,d),7.00(1H,d),6.25(1H,t),4.60(2H,s),3.10(2H,m),1.06(3H,t)
MS:APCI(-ve)395(M-1)
实施例59
[[2′-甲基-4′-[[(甲基氨基)羰基]氨基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ8.52(1H,s),7.65(1H,d),7.39(1H,s),7.26(1H,s),7.26(1H,d),7.07(1H,d),7.00(1H,d),6.05(1H,d),4.72(2H,s),2.09(3H,s)
MS:APCI(+ve)383(M+1)
实施例60
[[4′-[[(环丙基氨基)羰基]氨基]-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ8.33(1H,s),7.66(1H,d),7.37(1H,s),7.31(1H,s),7.26(1H,d),7.08(1H,d),7.00(1H,d),6.46(1H,s),4.75(2H,s),2.54(1H,m),0.63(2H,m),0.42(2H,m)。
MS:APCI(+ve)409(M+1)
实施例61
[[2′-甲基-4′-[[(丙基氨基)羰基]氨基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
1H NMR DMSO-d6:δ8.48(1H,s),7.64(1H,d),7.36(1H,s),7.30(1H,s),7.24(1H,d),7.07(1H,d),7.00(1H,d),6.23(1H,t),4.68(2H,s),3.05(2H,q),2.10(3H,s),1.44(2H,m),0.88(3H,d)
MS:APCI(+ve)411(M+1)
实施例62
[[2′,4′-二甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.63(1H,d),7.34(1H,s),7.03(4H,m),4.50(2H,s),2.32(3H,s),2.11(3H,s)
MS:APCI(-ve)323(M-1)
实施例63
[[5′-氟-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.65(1H,d),7.38(1H,s),7.29(1H,d),7.27(1H,d),7.11(1H,d),7.06(1H,m),4.40(2H,s),2.13(3H,s)
MS:APCI(-ve)327(M-1)
实施例64
[[4′-(氨基羰基)-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ(1H,s),7.77(1H,s),7.70(1H,d),7.63(1H,d),7.34(1H,s),7.30(1H,s),7.25(1H,d),6.98(1H,d),4.22(2H,s),2.21(3H,s)。
MS:APCI(+ve)354(M+1)
实施例65
[[3′-氟-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.66(1H,d),7.40(1H,s),7.27(1H,d),7.24(1H,d),7.16(1H,t),7.05(1H,d),4.45(2H,s),2.07(3H,s)。
MS:APCI(1ve)327(M-1)
实施例66
[[2′,5′-二氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.68(1H,d),7.58(1H,s),7.53(1H,m),7.30(1H,m),7.28(1H,m),7.09(1H,d),4.44(2H,s)。
实施例67
[[5′-(氨基磺酰基)-2′-氯-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.93(1H,d),7.82(1H,d),7.76(1H,s),7.73(1H,d),7.53(1H,s),7.10(1H,d),4.38(2H,s)。
MS:APCI(+ve)408/410(M+1)
实施例68
[[4′-氰基-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.78(1H,s),7.71(1H,t),7.71(1H,m),7.46(1H,s),7.40(1H,d),7.11(1H,d),4.61(2H,s),2.18(3H,s)
MS:APCI(-ve)334(M-1)
实施例69
[[4′-氯-2′-氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.73(1H,d),7.60(1H,s),7.56(1H,s),7.52(1H,d),7.36(1H,d),7.17(1H,d),4.70(2H,s)。
实施例70
[[2′,5′-二氟-4′-甲氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.63(1H,d),7.60(1H,m),7.52(1H,s),7.19(1H,m),7.06(1H,d),4.39(2H,s),3.91(3H,s)。
实施例71
[[2′-氟-5′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.74(1H,d),7.57(1H,s),7.25(1H,d),7.26(1H,s),7.19(1H,d),7.14(1H,d),4.85(2H,s),2.35(3H,s)。
实施例72
[[2′-氟-4′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.67(1H,d),7.46(1H,s),7.40(1H,t),7.10(1H,d),7.07(1H,d),7.07(1H,s),4.49(2H,s),2.34(3H,s)。
实施例73
[[4′-甲氧基-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.62(1H,d),7.33(1H,s),7.08(1H,d),7.00(1H,d),6.82(1H,s),6.78(1H,d),4.45(2H,s),3.80(3H,s),2.13(3H,s)。
实施例74
[[4′-(氨基磺酰基)-2′,5′-二氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.83(1H,m),7.75(1H,d),7.69(1H,s),7.63(1H,m),7.18(1H,d),4.53(2H,s)。
MS:APCI(-ve)410(M-1)
实施例75
[2-苯并[b]噻吩-3-基-4-(三氟甲基)苯氧基]-乙酸
1H NMR DMSO-d6:δ8.04(1H,d),7.87(1H,s),7.78(1H,d),7.69(1H,d),7.67(1H,s),7.38(2H,m),7.24(1H,d),4.81(2H,s)。
MS:APCI(-ve)351(M-1)
实施例76
[[5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.69(1H,d),7.60(3H,m),7.41(3H,m),7.20(1H,d),4.88(2H,s)。
MS:APCI(-ve)295(M-1)
实施例77
[2-(2-苯并呋喃基)-4-(三氟甲基)苯氧基]-乙酸
1H NMR DMSO-d6:δ8.24(1H,s),7.85(1H,s),7.75(1H,d),7.70(2H,d),7.33(3H,m),5.07(2H,s)。
MS:APCI(-ve)335(M-1)
实施例78
[[4′-氯-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.70(1H,d),7.64(1H,d),7.62(1H,s),7.62(1H,d),7.50(1H,d),7.50(1H,d),7.21(1H,d),4.81(2H,s)
MS:APCI(-ve)329/331(M-1)
实施例79
[[3′-(1-甲基乙基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.67(1H,d),7.57(1H,s),7.48(1H,s),7.38(1H,t),7.36(1H,d),7.25(1H,d),7.20(1H,d),4.85(2H,s)。
MS:APCI(-ve)337(M-1)
实施例80
[[3′,4′-二氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.76(1H,d),7.71(1H,d),7.65(1H,s),7.51(1H,d),7.48(1H,s),7.25(1H,d),4.89(2H,s)。
MS:APCI(-ve)331(M-1)
实施例81
[2-(1,3-苯并二氧杂环戊烯-5-基)-4-(三氟甲基)苯氧基]-乙酸
1H NMR DMSO-d6:δ7.63(1H,d),7.57(1H,s),7.22(1H,s),7.16(1H,d),7.05(1H,d),6.98(1H,d),6.04(2H,s),4.83(2H,s)。
MS:APCI(-ve)339(M-1)
实施例82
[[4′-乙基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.66(1H,d),7.58(1H,s),7.51(2H,d),7.27(2H,d),7.18(1H,d),4.86(2H,s),2.65(2H,q),1.22(3H,t)。
MS:APCI(-ve)323(M-1)
实施例83
[[3′-氟-5-(三氟甲基)[1,1’:4’,1”-三联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.74(1H,d),7.65(2H,m),7.60(1H,m),7.59(2H,m),7.58(1H,m),7.52(2H,m),7.43(1H,m),7.12(1H,m),4.51(2H,s)
MS:APCI(-ve)389(M-1)
实施例84
[[4′-(三氟甲氧基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.82(2H,d),7.62(1H,d),7.58(1H,s),7.41(2H,d),7.05(1H,d),4.39(2H,s)
MS:APCI(-ve)379(M-1)
实施例85
[[2′,3′-二氯-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.68(1H,d),7.66(1H,d),7.47(1H,d),7.48(1H,s),7.41(1H,t),7.05(1H,d),4.26(2H,d)
MS:APCI(-ve)363(M-1)
实施例86
[[4′-(1,1-二甲基乙基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.59(1H,d),7.57(2H,d),7.51(1H,s),7.44(2H,d),7.04(1H,d),4.47(2H,s)
MS:APCI(-ve)351(M-1)
实施例87
[2-(6-甲氧基-2-萘基)-4-(三氟甲基)苯氧基]-乙酸
1H NMR DMSO-d6:δ8.07(1H,s),7.87(1H,d),7.85(2H,s),7.62(2H,d),7.34(1H,s),7.17(1H,d),7.08(1H,d),4.41(2H,s)
MS:APCI(-ve)375(M-1)
实施例88
[[4′-(乙硫基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.61(2H,d),7.59(1H,d),7.52(1H,s),7.35(2H,d),7.07(1H,d),4.50(2H,s),3.02(2H,q),1.27(3H,t)
MS:APCI(-ve)355(M-1)
实施例89
[[4′-乙酰基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ8.02(2H,d),7.77(2H,d),7.64(1H,s),7.72(1H,d),7.23(1H,d),4.83(2H,s),2.63(3H,s)
MS:APCI(-ve)337(M-1)
实施例90
[2-(2-氯-5-甲基-4-吡啶基)-4-(三氟甲基)苯氧基]-乙酸,铵盐
1H NMR DMSO-d6:δ8.30(1H,d),7.75-7.66(1H,m),7.49(1H,d),7.04(2H,d),4.28(2H,s),2.15(3H,s)
MS:APCI(-ve)449(M-1)
实施例91
[[5′-(氨基磺酰基)-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,铵盐
1H NMR DMSO-d6:δ7.73-7.65(3H,m),7.63(1H,d),7.44(1H,d),7.37(1H,d),7.01(1H,d),4.23(2H,s),2.24(3H,s)
MS:APCI(-ve)388(M-1)
实施例92
[2-(8-喹啉基)-4-(三氟甲基)苯氧基]-乙酸,铵盐
1H NMR CDCl3:δ8.85-8.82(1H,m),8.33-8.29(1H,m),7.95-7.91(1H,m),7.82-7.78(1H,m),7.68-7.58(3H,m),7.50-7.46(1H,m),7.14-7.10(1H,m),4.54(2H,s)
MS:APCI(-ve)346(M-1)
实施例93
[[3′-氰基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,铵盐
1H NMR CDCl3:δ8.00(1H,d),7.87-7.83(1H,m),7.66-7.52(4H,m),6.99(1H,d),4.68(2H,s)
MS:APCI(-ve)320(M-1)
实施例94
[2-[4-甲基-6-[甲基(甲基磺酰基)氨基]-3-吡啶基]-4-(三氟甲基)苯氧基]-乙酸,铵盐
1H NMR DMSO-d6:δ8.20(1H,s),7.71(1H,m),7.51-7.47(1H,m),7.33(1H,s),7.09(1H,d),4.52(2H,s),3.32(3H,s),3.18(3H,d),2.21(3H,s)
MS:APCI(-ve)419(M-1)
实施例95
[[2′-甲基-5′-(甲基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,铵盐
1H NMR DMSO-d6:δ7.83-7.80(1H,m),7.74-7.69(2H,m),7.55(1H,d),7.49(1H,d),7.09(1H,d),4.46(2H,s),3.23(3H,s),2.26(3H,s)
MS:APCI(+ve)406(M+1)
实施例96
2′-(羧基甲氧基)-5′-(三氟甲基)-[1,1′-联苯]-3-羧酸,3-甲基酯
1H NMR DMSO-d6:δ8.15-8.13(1H,m),7.99-7.93(2H,m),7.68-7.55(3H,m),7.10(1H,d),4.46(2H,s),3.87(3H,s)
MS:APCI(-ve)353(M-1)
实施例97
2′-(羧基甲氧基)-5′-(三氟甲基)-[1,1′-联苯]-2-羧酸,2-甲基酯
1H NMR DMSO-d6:δ7.77(1H,M),7.66-7.59(2H,m),7.51-7.42(3H,m),4.23(2H,s),3.59(4H,s)
MS:APCI(-ve)353(M-1)
实施例98
[[5-(三氟甲基)[1,1’:4’,1”-三联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.75-7.62(7H,m),7.53-7.46(3H,m),7.42-7.35(1H,m),7.21-7.15(1H,m),4.76(2H,s)
MS:APCI(-ve)371(M-1)
实施例99
[[3′-氟-2′,4′-二甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.66-7.62(1H,m),7.55(1H,d),7.34(2H,d),7.16(1H,d),4.78(2H,s),2.25(6H,d)
MS:APCI(-ve)341(M-1)
实施例100
[[2′-硝基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,铵盐
1H NMR DMSO-d6:δ8.00(1H,m),7.83-7.76(1H,m),7.70-7.55(4H,m),6.94(1H,d),4.08(2H,s)
MS:APCI(-ve)340(M-1)
实施例101
[[2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.65-7.61(1H,m),7.34-7.32(1H,m),7.28-7.14(4H,m),7.02-6.98(1H,m),4.36(2H,s),2.13(3H,s)
MS:APCI(-ve)340(M-1)
实施例102
[[3′-氯-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.72-7.66(1H,m),7.47-7.40(2H,m),7.30-7.22(1H,m),7.18-7.14(1H,m),7.10-7.06(1H,m),4.56(2H,s),2.14(3H,s)
MS:APCI(-ve)343(M-1)
实施例103
[[5-(三氟甲基)[1,1′:3′,1″-三联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.92(1H,t),7.76-7.72(2H,m),7.68-7.59(4H,m),7.56-7.34(4H,m),7.19-7.15(1H,m),4.69(2H,s)
MS:APCI(-ve)371(M-1)
实施例104
2′-(羧基甲氧基)-5′-(三氟甲基)-[1,1′-联苯]-4-羧酸,4-甲基酯
1H NMR DMSO-d6:δ8.03-7.99(2H,m),7.82-7.79(2H,m),7.70-7.66(1H,m),7.63-7.61(1H,m),7.17-7.14(1H,m),4.62(2H,s),3.88(3H,s)MS:APCI(-ve)353(M-1)
实施例105
[[4′-硝基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ8.30-8.26(2H,m),7.99-7.94(2H,m),7.75-7.67(2H,m),7.20(1H,d),4.65(2H,s)
MS:APCI(-ve)340(M-1)
实施例106
[[5-(三氟甲基)-3′-[(三氟甲基)硫基][1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ8.05(1H,s),7.91-7.87(1H,m),7.74-7.58(4H,m),7.17(1H,d),4.64(2H,s)
MS:APCI(-ve)395(M-1)
实施例107
[[5-(三氟甲基)-4′-[(三氟甲基)硫基][1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.79(4H,s),7.76-7.72(1H,m),7.69-7.67(1H,m),7.25(1H,d),4.89(2H,s)
MS:APCI(-ve)395(M-1)
实施例108
[[4′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.67-7.63(1H,m),7.57-7.54(1H,m),7.51-7.47(2H,m),7.25(2H,d),7.17(1H,d),4.82(2H,s),2.35(3H,s)
MS:APCI(-ve)309(M-1)
实施例109
[[4′-氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.71-7.58(4H,m),7.31-7.18(3H,m),4.86(2H,s)MS:APCI(-ve)314(M-1)
实施例110
[[3′-氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.74-7.69(1H,m),7.66-7.64(1H,m),7.53-7.42(3H,m),7.26-7.18(2H,m),4.88(2H,s)
MS:APCI(-ve)314(M-1)
实施例111
[[3′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.70-7.63(1H,m),7.56(1H,d),7.42-7.28(3H,m),7.21-7.15(2H,m),4.82(2H,s),2.34(3H,s)
MS:APCI(-ve)309(M-1)
实施例112
[2-(3-吡啶基)-4-(三氟甲基)苯氧基]-乙酸
1H NMR DMSO-d6:δ8.88(1H,s),8.56-8.53(1H,m),8.15-8.09(1H,m),7.68-7.60(2H,m),7.48-7.42(1H,m),7.10(1H,d),4.43(2H,s)
MS:APCI(+ve)298(M+1)
实施例113
[[2′-氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ8.02(1H,d),7.92-7.90(1H,m),7.79-7.54(4H,m),7.28(1H,d),4.90(2H,s)
MS:APCI(-ve)313(M-1)
实施例114
[[2′-甲氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.59(1H,d),7.42(1H,s),7.37-7.30(2H,m),7.11-6.95(3H,m),4.42(2H,s),3.72(3H,s)
MS:APCI(-ve)325(M-1)
实施例115
[[3′-甲氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.62(1H,d),7.56-7.54(1H,m),7.34(1H,t),7.27-7.25(1H,m),7.16(1H,d),7.11(1H,d),6.95-6.90(1H,m),4.56(2H,s),3.79(3H,s)
MS:APCI(-ve)325(M-1)
实施例116
[[4′-甲氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.62-7.54(4H,m),7.04(1H,d),6.98(2H,d),4.45(2H,s),3.79(3H,s)
MS:APCI(-ve)325(M-1)
实施例117
[[3′-(乙基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ8.19-8.17(1H,m),8.11-8.07(1H,m),7.87-7.83(1H,m),7.73-7.64(3H,m),7.11(1H,d),4.39(2H,s),3.38(2H,q),1.14(3H,t)
MS:APCI(-ve)387(M-1)
实施例118
[[3′-丙氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.70-7.65(1H,m),7.59(1H,d),7.33(1H,t),7.22-7.10(3H,m),6.95-6.91(1H,m),4.86(2H,s),3.97(2H,t),1.79-1.68(2H,m),0.98(3H,t)
MS:APCI(-ve)353(M-1)
实施例119
[[4′-丙氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.65-7.61(1H,m),7.56-7.50(3H,m),7.16(1H,d),7.01-6.96(2H,m),4.85(2H,s),3.97(2H,t),1.80-1.70(2H,m),0.99(3H,t)
MS:APCI(-ve)353(M-1)
实施例120
[2-(2-氨基-4-甲基-5-嘧啶基)-4-(三氟甲基)苯氧基]-乙酸
1H NMR DMSO-d6:δ7.99(s,1H),7.62(dd,1H),7.43(d,1H),7.01(d,1H),6.56(s,2H),4.41(s,2H),2.15(s,3H)。
MS:APCI(+ve)328
实施例121
[[4′-氰基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR CD3OD:δ7.86-7.73(m,4H),7.65(dd,1H),7.60(d,1H),7.14(d,1H),4.66(s,2H)
MS:APCI(+ve)320
实施例122
[[4′,5-双(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR DMSO-d6:δ7.90(2H,d),7.78(2H,d),7.67(1H,d),7.62(1H,s),7.10(1H,d),4.47(2H,s)
MS:APCI(-ve)363(M-1)
实施例123
[2-(2-萘基)-4-(三氟甲基)苯氧基]-乙酸
1H NMR DMSO-d6:δ8.15(1H,s),7.93(4H,m),7.67(1H,s),7.64(1H,d),7.53(2H,m),7.09(1H,d),4.44(2H,s)
MS:APCI(-ve)345(M-1)
实施例124
[[4′-(1-吡咯烷基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
(i)1-[(4-溴苯基)磺酰基]-吡咯烷
将4-溴苯磺酰氯(0.5g)和吡咯烷(0.284g)的乙腈溶液(5ml)在RT搅拌48小时然后在乙酸乙酯和水之间分配。分离出有机物,用水洗涤,干燥并减压蒸发。将残留物用异己烷研磨并过滤,产量0.5g。
1H NMR CDCl3:δ7.72-7.65(4H,m);3.28-3.21(4H,m);1.84-1.76(4H,m)
(ii)[[4′-(1-吡咯烷基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
标题化合物利用实施例44的方法进行制备,产量0.13g。
1H NMR CD3OD:δ7.83-7.75(m,4H),7.56-7.52(m,1H),7.50(d,1H),7.01(d,1H),4.46(s,2H),3.20-3.14(m,4H),1.72-1.65(m,4H)。
MS:APCI(-ve)428.
实施例125-134
下述化合物以类似于实施例124的方法进行合成。
实施例125
[[4′-[(二甲基氨基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR CD3OD:δ7.92-7.81(m,4H),7.67-7.61(m,2H),7.14(d,1H),4.64(s,2H),2.73(s,6H)。
MS:APCI(+ve)402
实施例126
[[4′-[[(苯基甲基)氨基]磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR CD3OD:δ7.92-7.77(m,4H),7.68(d,1H),7.62(s,1H),7.29-7.14(m,6H),4.73(s,2H),4.13(s,2H)。
MS:APCI(-ve)464.
实施例127
[[4′-[[(2,2,2-三氟乙基)氨基]磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR CD3OD:δ7.93-7.79(m,4H),7.64(d,1H),7.59(d,1H),7.12(d,1H),4.64(s,2H),3.63(t,2H)。
MS:APCI(-ve)456
实施例128
[[4′-[[(5-甲基-2-噻唑基)氨基]磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR CD3OD:δ7.97-7.92(m,2H),7.82-7.78(m,2H),7.67-7.61(m,1H),7.61-7.58(m,1H),7.12(d,2H),6.82(d,1H),4.61(s,2H),2.27(d,3H)。
MS:APCI(-ve)471
实施例129
[[4′-[(苯基氨基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR CD3OD:δ7.81-7.73(m,4H),7.60(dd,1H),7.54(d,1H),7.25-7.02(m,6H),4.55(s,2H)。
MS:APCI(-ve)450.
实施例130
[[4′-[(二乙基氨基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR CD3OD:δ7.85(s,4H),7.63(dd,1H),7.59(d,1H),7.11(d,1H),4.58(s,2H),3.27(q,4H),1.16(t,6H)。
MS:APCI(-ve)450.
实施例131
[[4′-[(环丙基氨基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR CD3OD:δ7.95-7.84(m,4H),7.64(dd,1H),7.61(d,1H),7.12(d,1H),4.61(s,2H),2.23-2.16(m,1H),0.58-0.53(m,4H)。
MS:APCI(-ve)414.
实施例132
[[4′-(氨基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR CD3OD:δ7.94(d,2H),7.81(d,2H),7.63(dd,1H),7.58(d,1H),7.12(d,1H),4.60(s,2H)。
MS:APCI(-ve)374.
实施例133
[[4′-[(甲基氨基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR CD3OD:δ7.80-7.74(m,4H),7.53(dd,1H),7.50(d,1H),4.48(s,2H),2.47(s,3H)。
MS:APCI(-ve)388
实施例134
[[4′-[(4-甲基-1-哌嗪基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸
1H NMR CD3OD:δ7.85-7.70(m,4H),7.55-7.51(m,1H),7.49(d,1H),7.00(d,1H),4.41(s,2H),3.03-2.95(m,4H),2.48(t,4H),2.21(s,3H)。
MS:APCI(-ve)457
实施例135
[2-[4-甲基-2-(5-甲基-1,1-二氧代-1,2,5-噻二唑烷-2-基)-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸
(i)2,5-二溴-4-甲基-嘧啶
将亚硝酸异戊酯(21ml)加入到5-溴-4-甲基-2-嘧啶胺(1.75g)在溴仿(30ml)中的搅拌的悬浮液中,并将混合物在85℃加热4小时。冷却后,加入异己烷(300ml),并将溶液通过硅胶垫。将硅胶用石油醚(1000ml)、二氯甲烷(200ml)洗涤,然后将产物用乙酸乙酯洗脱。将乙酸乙酯层减压蒸发,并将残留物经硅胶层析纯化,用5%乙醚/异己烷洗脱,产量0.9g。
1H NMR CDCl3:δ8.52(s,1H),2.64(s,3H)
MS:APCI(-ve)249/51/53
(ii)5-溴-4-甲基-2-(5-甲基-1,1-二氧代-1,2,5-噻二唑烷-2-基)-嘧啶
将氢化钠(0.128g,60%油中的分散体)加入到2-甲基-1,2,5-噻二唑烷1,1-二氧化物(0.433g)在THF(10ml)中的搅拌混合物中。加入DMF(10ml),并将混合物在80℃加热5分钟,然后加入步骤(i)的产物(0.8g)的DMF溶液(5ml)。将混合物在60℃加热10分钟,倾入到水(100ml)中,用柠檬酸酸化,并用乙酸乙酯萃取。将有机物减压蒸发,并将残留物经硅胶层析纯化用乙醚洗脱,产量0.58g。
1H NMR CDCl3:δ8.50(s,1H),4.05(t,2H),3.45(t,2H),2.87(s,3H),2.58(s,3H)。
MS:APCI(+ve)307/9
(iii)[2-[4-甲基-2-(5-甲基-1,1-二氧代-1,2,5-噻二唑烷-2-基)-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸
标题化合物利用实施例44的方法进行制备,产量0.05g。
1H NMR CDCl3:δ8.34(s,1H),7.47(dd,1H),7.32(d,1H),6.90(d,1H),4.36(s,2H),4.05(t,2H),3.40(t,4H),2.77(s,3H),2.27(s,3H)。
MS:APCI(+ve)447
实施例136-137
下述化合物以类似于实施例135的方法进行合成。
实施例136
[2-[4-甲基-2-[甲基(甲基磺酰基)氨基]-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸
1H NMR CDCl3:δ8.37(s,1H),7.63(dd,1H),7.40(d,1H),6.96(d,1H),4.60(s,2H),3.57(s,3H),3.53(s,3H),2.40(s,3H)。
MS:APCI(-ve)418
实施例137
[2-[2-(1,1-二氧-2-异噻唑烷基)-4-甲基-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸,铵盐
1H NMR CDCl3:δ8.37(s,1H),7.60(dd 1H),7.36(d,1H),7.02(d,1H),4.53(s,2H),4.09(t,2H),3.49(t,2H),2.51(五重峰,2H),2.39(s,3H)。
MS:APCI(+ve)432.
实施例138
[2-[2-(3-羟基-1-氮杂环丁基)-4-甲基-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸
(i)1-(5-溴-4-甲基-2-嘧啶基)-3-氮杂环丁醇
将实施例135步骤(i)的产物(0.75g)、氮杂环丁-3-醇盐酸盐(0.66g)和三乙基胺(0.9ml)在乙醇(10ml)中的混合物在RT搅拌2小时。将溶剂减压去除,并将残留物经硅胶层析纯化,用60%乙醚/异己烷作为洗脱剂洗脱,产量0.7g。
1H NMR CDCl3:δ8.22(s,1H),4.78-4.72(m,1H),4.40-4.33(m,2H),3.99-3.93(m,2H),2.45(s,3H)
(ii)[2-[2-(3-羟基-1-氮杂环丁基)-4-甲基-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸
标题化合物以类似于实施例44的方法进行制备,产量0.04g。
1H NMR CD3OD:δ8.09(s,1H),7.64(m,1H),7.43(d,1H),7.08(d,1H),4.71-4.64(m,1H),4.61(s,2H),4.41-4.34(m,2H),3.96-3.91(m,2H),2.25(s,3H)。
MS:APCI(+ve)384
实施例139-141
下述化合物以类似于实施例138的方法进行合成。
实施例139
[2-[4-甲基-2-(4-甲基-1-哌嗪基)-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸
1H NMR CDCl3:δ8.19(s,1H),7.57(d,1H),7.38(d,1H),6.99(d,1H),4.51(s,2H),4.3-3.8(br s,4H),3-2.8(br s,4H),2.63(s,3H),2.29(s,3H)。
MS:APCI(+ve)411
实施例140
[2-[4-甲基-2-(1-吡咯烷基)-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸
1H NMR CD3OD:δ7.95(s,1H),7.36(d,1H),7.59-7.54(m,1H),7.01(d,1H),4.65(s,2H),3.50(t,4H),2.15(s,3H),1.96-1.91(m,4H)。
MS:APCI(+ve)382
实施例141
[2-[2-(二甲基氨基)-4-甲基-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸
1H NMR CD3OD:δ8.05(s,1H),7.67-7.63(m,1H),7.44(d,1H),7.10(d,1H),4.75(s,2H),3.20(s,6H)。
MS:APCI(+ve)356
实施例142
[2-[5-甲基-2-[甲基(甲基磺酰基)氨基]-4-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸
(i)N-(4-氯-5-甲基-2-嘧啶基)-N-甲基-甲磺酰胺
将N-甲基磺酰胺(3.35g)、2,4-二氯-5-甲基嘧啶(5g)和碳酸钾(4.3g)在DMF(50ml)中的混合物在80℃加热4小时。将反应用水(200ml)中止,并用乙酸乙酯萃取。将有机物干燥,减压蒸发,并将残留物用醚研磨。过滤出固体(4-异构体),并将滤液减压蒸发并进行RPHPLC以得到2-异构体,产量0.37g。
1H NMR CDCl3:δ8.35(s,1H),3.51(s,3H),3.48(s,3H),2.29(d,3H)。
(ii)[2-[5-甲基-2-[甲基(甲基磺酰基)氨基]-4-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸
标题化合物以类似于实施例44的方法进行制备,产量0.04g。
1H NMR CD3OD:δ8.50(s,1H),7.16(d,1H),7.74(dd,1H),7.62(d,1H),4.68(s,2H),3.50(s,3H),3.45(s,3H),2.19(s,3H)。
MS:APCI(+ve)420
实施例143
[2-[2-[[(二甲基氨基)磺酰基]氨基]-4-甲基-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸
(i)N′-(5-溴-4-甲基-2-嘧啶基)-N,N-二甲基-磺酰胺
将5-溴-4-甲基-2-嘧啶胺(0.75g)和二甲基磺酰氯(0.43ml)在吡啶(20ml)中的混合物在80℃加热17小时。减压去除溶剂,并将残留物经硅胶层析纯化,用乙醚然后用乙酸乙酯洗脱。然后将残留物经RPHPLC纯化。产量0.12g。
MS:APCI(-ve)295/6
(ii)[2-[2-[[(二甲基氨基)磺酰基]氨基]-4-甲基-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸
标题化合物以类似于实施例44的方法进行制备,产量0.01g。
1H NMR CD3OD:δ8.27(s,1H),7.68(d,1H),7.49(s,1H),7.11(d,1H),4.70(s,2H),2.98(s,6H),2.32(s,3H)。
MS:APCI(+ve)435。
实施例144
[[2′-氯-4′-[(甲氧基羰基)氨基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]乙酸
i)2-氯-2’-(苯基甲氧基)-5’-(三氟甲基)-[1,1’-联苯]-4-胺
将实施例32步骤(ii)的产物(0.5g)和4-溴-3-氯苯胺(0.38g)溶解在甲苯(4ml)中。依次加入乙醇(1ml)、2M碳酸钠水溶液(1ml)和Pd(PPh3)4(0.115g),并将混合物加热回流4小时。将反应冷却,蒸发,溶解在EtOAc中,用水和盐水洗涤,干燥(MgSO4)并蒸发。将残留物经硅胶层析纯化,用10%EtOAc/异己烷洗脱。产量0.23g。
1H NMR DMSO-d6:7.67(ddd,1H),7.4(d,1H),7.27-7.34(m,6H),7.01(d,1H),6.7(d,1H),6.55(dd,1H),5.47(s,2H),5.18(s,2H)
ii)4’-氨基-2’-氯-5-(三氟甲基)-[1,1’-联苯]-2-醇
将5%Pt/C(0.088g)加入到步骤(i)的产物的乙醇溶液(20ml)中并在RT和1bar氢化18小时。加入另外的Pt/C(0.1g)并继续在2bar下氢化3小时。过滤去除催化剂,并将滤液蒸发得到固体残留物。将残留物经硅胶层析纯化,用50%EtOAc/异己烷洗脱。产量0.083g。
1H NMR DMSO-d6:δ.10.2(s,1H),7.49(d,1H),7.3(d,1H),7.03(d,1H),6.96(d,1H),6.68(d,1H),6.54(dd,1H),5.44(s,2H)
iii)[[4’-氨基-2’-氯-5-(三氟甲基)-[1,1’-联苯]-2-基]氧基]乙酸,1,1-二甲基乙基酯
小标题化合物利用实施例1步骤(i)的方法,利用步骤(ii)的产物进行制备。产量0.07g。不经表征用于步骤(iv)。
iv)[[2’-氯-4’-[(甲氧基羰基)氨基]-5-(三氟甲基)-[1,1’-联苯]-2-基]氧基]乙酸,1,1-二甲基乙基酯
将步骤(iii)的产物(0.07g)溶解在DCM(5ml)中,加入三乙基胺(0.024ml),然后加入氯甲酸甲酯(0.013ml)并搅拌20小时。继续分三次以上加入另外的三乙基胺(0.024ml)和氯甲酸甲酯(0.013ml)直至反应完成。蒸发去除溶剂得到粗产物,不经进一步的表征用于步骤(v)。
v)[[2’-氯-4’-[(甲氧基羰基)氨基]-5-(三氟甲基)-[1,1’-联苯]-2-基]氧基]乙酸
标题化合物利用实施例1步骤(iii)的方法,利用步骤(iv)的产物进行制备。
1H NMR DMSO-d6:δ.9.94(s,1H),7.69(dd,2H),7.41-7.47(m,2H),7.35(d,1H),7.13(d,1H),4.65(s,2H),3.7(s,3H)
MS:APCI(-ve)402
实施例145
2-[[2′-氯-4′-(甲基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
i)2-氯-1-碘-4-(甲硫基)苯
将甲硫醇钠(5g)加入到4-氟-2-氯-碘苯的溶液(18.3g)中并搅拌20小时。将混合物倾入到水中,用醚萃取,用盐水洗涤,干燥(MgSO4)并蒸发。产量18.5g。
1H NMR DMSO-d6:δ.7.81(d,1H),7.43(dd,1H),6.98(dd,1H),3.32(s,3H)
ii)2-氯-1-碘-4-(甲基磺酰基)苯
分批将Mcpba(8.6g)加入至步骤(i)的产物(5g)在DCM(100ml)中的搅拌混合物中。1小时后,将反应用DCM(200ml)稀释,用饱和的碳酸氢钠水溶液洗涤,干燥(MgSO4)并减压蒸发。产量3.2g。
1H NMR DMSO-d6:δ.8.26(d,1H),8.06(d,1H),7.59(dd,1H),3.32(s,3H)
iii)2’-氯-4’-(甲基磺酰基)-5-(三氟甲基)-[1,1’-联苯]-2-基]氧基]甲基]苯
小标题化合物利用实施例144步骤(i)的方法,利用步骤(ii)的产物和实施例32步骤(ii)的产物进行制备。产量2.2g
1H NMR DMSO-d6:δ.8.11(s,1H),7.95(dd,1H),7.82(d,1H),7.72(d,1H),7.61(d,1H),7.41(d,1H),7.27-7.36(m,5H),5.25(s,2H),3.35(s,3H)
iv)2’-氯-4’-(甲基磺酰基)-5-(三氟甲基)-[1,1’-联苯]-2-醇
小标题化合物利用实施例144步骤(ii)的方法,利用步骤(iii)的产物进行制备。产量0.95g。
1H NMR DMSO-d6:δ.10.72(s,1H),8.08(d,1H),7.93(dd,1H),7.63-7.68(m,2H),7.49(d,1H),7.14(d,1H),3.35(s,3H)
MS:APCI(-ve)349
v)2-[[2′-氯-4′-(甲基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,1,1-二甲基乙基酯
小标题化合物利用实施例32步骤(v)的方法,利用步骤(iv)的产物和R-乳酸叔丁基酯进行制备。产量0.25g。
1H NMR DMSO-d6:δ.8.11(d,1H),7.97(d,1H),7.82(dd,1H),7.73(d,1H),7.62(d,1H),7.15(d,1H),5.0(brs,1H),3.36(s,3H),1.36-1.39(m,12H)
vi)2-[[2′-氯-4′-(甲基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
标题化合物利用实施例1步骤(iii)的方法,利用步骤(v)的产物进行制备。产量0.12g。
1H NMR DMSO-d6:δ.8.09(d,1H),7.95(dd,1H),7.82(s,1H),7.76(dd,1H),7.58(d,1H),7.14(d,1H),4.87(q,1H),3.36(s,3H),1.35(d,3H)
MS:APCI(-ve)421
实施例146
2-[[3′-氰基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
i)4,4,5,5-四甲基-2-[2-(苯基甲氧基)-5-(三氟甲基)苯基]-1,3,2-二氧杂硼杂环戊烷
将频哪醇(1.82g)加入到实施例32步骤(ii)的产物(4.54g)的醚溶液(40ml)中并在RT搅拌20小时。将反应用醚(100ml)稀释,用盐水洗涤,干燥(MgSO4)并蒸发。产量5.7g。
1H NMR DMSO-d6:δ.7.82(d,1H),7.79(d,1H),7.6(d,2H),7.4(t,2H),7.32(d,1H),7.27(d,1H),5.24(s,2H),1.32(s,12H)
ii)2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-4-(三氟甲基)苯酚
将10%Pd/C(0.5g)加入到步骤(i)的产物的EtOAc溶液(80ml)中并在RT和1bar下氢化1小时,并在3bar下氢化3小时。过滤去除催化剂,并将滤液蒸发得到固体产物。产量4.2g。
1H NMR DMSO-d6:δ.9.99(d,1H),7.72(s,1H),7.63(d,1H),6.99(d,1H),1.3(d,12H)
iii)2-[2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-4-(三氟甲基)苯氧基]-(2S)-丙酸,1,1-二甲基乙基酯
小标题化合物利用实施例32步骤(v)的方法,利用步骤(ii)的产物和R-乳酸叔丁基酯进行制备。产量4.0g。将粗品进行步骤(iv)。
iv)2-[2-二羟硼基-4-(三氟甲基)苯氧基]-(2S)-丙酸
将TFA(10ml)加入到步骤(iii)的产物(4.0g)的DCM溶液(100ml)中并搅拌30分钟。将TFA蒸发,并将残留物溶解在1M盐酸(30ml)和乙腈(30ml)的混合物中,1小时后将混合物蒸发至干,溶解在1M氢氧化钠中,用醚洗涤并用浓盐酸和水调节至pH2。然后用醚萃取,用盐水洗涤,干燥(MgSO4)并蒸发。产量2.0g。将粗品进行步骤(v)。
v)2-[[3′-氰基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
标题化合物利用实施例144步骤(i)的方法,利用步骤(iv)的产物和3-溴苄腈进行制备。
1H NMR DMSO-d6:δ.8.13(t,1H),8.01(tdt,1H),7.85(dt,1H),7.71-7.76(m,2H),7.65(dt,1H),7.17-7.2(m,1H),5.11(q,1H),1.47(d,3H)
MS:APCI(-ve)334
实施例147
2-[[4′-[(二甲基氨基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
标题化合物利用实施例144步骤(i)的方法,利用实施例146步骤(iv)的产物和4-溴-N,N-二甲基-苯磺酰胺进行制备。
1H NMR DMSO-d6:δ.7.95(d,2H),7.83(d,2H),7.77(d,1H),7.73(s,1H),7.21(d,1H),5.14(q,1H),2.69(s,6H),1.51(d,3H)
MS:APCI(-ve)416
实施例148
2-[[2′-氯-4′-[(二甲基氨基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
i)3-氯-4-碘苯磺酰胺
在-5至-1℃,用1小时将亚硝酸钠(3.27g)的水溶液滴加至3-氯-4-碘苯胺(10.0g)在THF(120ml)和浓盐酸(50ml)中的搅拌混合物中,然后加入氯化镁(6.39g),并将得到的混合物倾入到用二氧化硫饱和的乙酸(50ml)以及包含氯化亚铜(2.14g)的搅拌混合物中。在34℃加热30分钟后,将混合物倾入到盐水中,用EtOAc萃取,用碳酸氢钠水溶液和盐水洗涤,干燥(MgSO4)并蒸发。将残留物溶解在THF(100ml)中,加入0.880氨水(100ml)并搅拌2小时。将混合物用盐水稀释,用EtOAc萃取,用盐水洗涤,干燥(MgSO4)并蒸发。将残留物用异己烷/醚(4∶1)处理并过滤得到小标题化合物。产量5.67g。
1H NMR DMSO-d6:δ.8.18(d,1H),7.92(d,1H),7.56(s,1H),7.47(dd,1H)
ii)3-氯-4-碘-N,N-二甲基苯磺酰胺
将氢化钠(0.33g)加入到步骤(i)的产物(1.2g)的DMF溶液(25ml)中并搅拌20分钟。滴加碘甲烷(0.5ml)并且然后再搅拌1小时。将反应混合物用水中止,用EtOAc萃取,干燥(MgSO4)并蒸发。将残留物用醚处理得到为白色固体的小标题化合物。产量0.45g。
1H NMR DMSO-d6:δ.8.05(d,1H),7.82(d,1H),7.31(dd,1H),2.75(s,6H)
iii)2-[[2′-氯-4′-[(二甲基氨基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
标题化合物利用实施例144步骤(i)的方法,利用步骤(ii)的产物和实施例146步骤(iv)的产物进行制备。
1H NMR DMSO-d6:δ.7.86(t,1H),7.75-7.79(m,3H),7.61(d,1H),7.14(d,1H),4.88(q,1H),2.7(s,6H),1.35(d,3H)
MS:APCI(-ve)450
实施例149
2-[[2′-氟-4′-(甲基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
i)三氟甲烷磺酸,2-氟-4-(甲基磺酰基)苯基酯
将2-氟-4-(甲基磺酰基)苯酚(1.44g)溶解在DCM(20ml)中,加入三乙基胺(1.17ml),然后加入三氟甲烷磺酸酐(1.57ml)并搅拌1小时。将溶液用盐水洗涤,干燥(MgSO4)并蒸发得到小标题化合物。
1H NMR CDCl3:δ7.83-7.92(m,2H),7.55-7.61(m,1H),3.11(s,3H)
ii)2-[[2′-氟-4′-(甲基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
标题化合物利用实施例144步骤(i)的方法,利用步骤(i)的产物和实施例146步骤(iv)的产物进行制备。
1H NMR DMSO-d6:δ.7.79-7.9(m,3H),7.74(dd,1H),7.64(s,1H),7.12(d,1H),4.87(q,1H),3.31(s,3H),1.35(d,3H)
MS:APCI(-ve)405
实施例150
[[2′,5-二氯-4′-(甲基磺酰基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
i)[[[2′,5-二氯-4′-(甲基磺酰基)[1,1’-联苯]-2-基]氧基]甲基]苯
小标题化合物利用实施例144步骤(i)的方法,利用实施例16步骤(ii)的产物和实施例145步骤(ii)的产物进行制备。产量1.08g。
1H NMR DMSO-d6:δ.8.09(d,1H),7.94(dd,1H),7.67(d,1H),7.49(dd,1H),7.22-7.34(m,7H),5.14(s,2H),3.35(s,3H)
ii)[[[2′,5-二氯-4′-(甲基磺酰基)[1,1′-联苯]-2-醇
小标题化合物利用实施例144步骤(ii)的方法,利用步骤(i)的产物进行制备。产量0.45g。
1H NMR DMSO-d6:δ.10.04(s,1H),8.06(d,1H),7.91(dd,1H),7.63(d,1H),7.32(dd,1H),7.2(d,1H),6.97(d,1H),3.34(s,3H)
iii)[[2′,5-二氯-4′-(甲基磺酰基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,1,1-二甲基乙基酯
小标题化合物利用实施例32步骤(v)的方法,利用步骤(ii)的产物和R-乳酸叔丁基酯进行制备。产量0.24g。
1H NMR DMSO-d6:δ.8.09(d,1H),7.95(d,1H),7.7(d,1H),7.48(dd,1H),7.33(d,1H),6.98(d,1H),4.85(brs,1H),3.35(s,3H),1.37(s,9H),1.32(d,3H)
iv)[[2′,5-二氯-4′-(甲基磺酰基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
标题化合物利用实施例1步骤(iii)的方法,利用步骤(iii)的产物进行制备。产量0.11g。
1H NMR DMSO-d6:δ.8.07(d,1H),7.92(dd,1H),7.81(s,1H),7.42(dd,1H),7.28(d,1H),6.97(d,1H),4.65(q,1H),3.35(s,3H),1.29(d,3H)
MS:APCI(-ve)387
实施例151
[[5-氯-4′-[(二甲基氨基)磺酰基][1,1’-联苯]-2-基]氧基]-(2S)-丙酸
i)2-[5-氯-2-(苯基甲氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷
小标题化合物利用实施例146步骤(i)的方法,利用实施例16步骤(ii)的产物进行制备。产量3.3g。
1H NMR DMSO-d6:δ.7.27-7.64(m,7H),6.85(d,1H),5.09(s,2H),1.36(s,12H)
ii)4-氯-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯酚
小标题化合物进行制备利用实施例146步骤(ii)的方法,利用步骤(i)的产物。经硅胶层析纯化,利用50%EtOAc/异己烷洗脱。产量1.89g。
1H NMR DMSO-d6:δ.7.76-7.79(s,1H),6.79-7.62(m,3H),1.36(s,12H)
iii)2-[4-氯-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯氧基]-(2S)-丙酸,1,1-二甲基乙基酯
小标题化合物利用实施例32步骤(v)的方法,利用步骤(ii)的产物和R-乳酸叔丁基酯进行制备。产量3.5g。将粗物质进行步骤(iv)。
iv)2-(2-二羟硼基-4-氯苯氧基)-(2S)-丙酸
小标题化合物利用实施例146步骤(iv)的方法,利用步骤(iii)的产物进行制备。产量2.5g。将粗物质进行步骤(v)。
v)[[5-氯-4′-[(二甲基氨基)磺酰基][1,1’-联苯]-2-基]氧基]-(2S)-丙酸
标题化合物利用实施例144步骤(i)的方法,利用步骤(iv)的产物和4-溴-N,N-二甲基苯磺酰胺并利用THF作为溶剂进行制备。产量(0.068g)。
1H NMR DMSO-d6:δ.8.01(d,2H),7.75(d,2H),7.3-7.41(m,2H),6.93(d,1H),4.56(bm,1H),2.65(s,6H),1.33(d,3H)。
MS:APCI(-ve)382
实施例152
[[2′,5-二氯-4′-[(二甲基氨基)磺酰基][1,1’-联苯]-2-基]氧基]-(2S)-丙酸
标题化合物利用实施例144步骤(i)的方法,利用实施例151步骤(iv)的产物、实施例148步骤(ii)的产物以及甲醇作为溶剂进行制备。产量(0.08g)。
1H NMR DMSO-d6:δ.7.9(bm,1H),7.82(s,1H),7.74(dd,1H),7.4(dd,1H),7.26(d,1H),6.92(d,1H),4.34(bm,1H),2.7(s,6H),1.2(d,3H)
MS:APCI(-ve)416
实施例153
[(5-氯-3′-氰基[1,1’-联苯]-2-基)氧基]-(2S)-丙酸
标题化合物利用实施例144步骤(i)的方法,利用实施例151步骤(iv)的产物、3-溴苯腈并用THF作为溶剂进行制备。
1H NMR DMSO-d6:δ.8.25(s,1H),8.06(d,1H),7.79(d,1H),7.63(t,1H),7.4(d,1H),7.33(dd,1H),6.95(d,1H),4.64(q,1H),1.32(d,3H)
MS:APCI(-ve)300
实施例154
[[5-氯-4′-[(二甲基氨基)磺酰基]-2′-氟[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
i)4-溴-N,N-二甲基-3-氟苯磺酰胺
小标题化合物利用实施例148步骤(ii)的方法,利用4-溴-3-氟苯磺酰胺1.14g进行制备。
ii)[[5-氯-4′-[(二甲基氨基)磺酰基]-2′-氟[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
标题化合物利用实施例144步骤(i)的方法,利用步骤(i)的产物、实施例151步骤(iv)的产物并利用THF作为溶剂进行制备。
1H NMR DMSO-d6:δ.7.94(t,1H),7.58-7.62(m,2H),7.35-7.4(m,2H),6.93(d,1H),4.48(q,1H),2.7(s,6H),1.26(d,3H)
MS:ESI(+ve)402
实施例155
[[5-氯-4′-(4-吗啉基磺酰基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
将实施例151步骤(iv)的产物(0.126g)、碳酸钠(0.22g)、4-[(4-溴苯基)磺酰基]吗啉(0.16g)和Pd(dppf)Cl2(0.03g)在二噁烷(10ml)中的混合物加热回流4小时。将混合物蒸发并经RVHPLC(MeCN/aqNH4Cl)纯化。产量0.09g。
1H NMR DMSO-d6:δ.8.03(d,2H),7.74(d,2H),7.31-7.39(m,2H),6.93(d,1H),4.55(m,1H),3.65(m,2H),2.92(m,2H),1.34(d,3H)
MS:APCI(-ve)426
实施例156
[[5-氯-2′-氟-4′-(甲基磺酰基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
标题化合物利用实施例155的方法,利用实施例151步骤(iv)的产物和实施例149步骤(i)的产物进行制备。
MS:ESI(-ve)371
实施例157
2-[[4′-(1-氮杂环丁基磺酰基)-5-氯[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
标题化合物利用实施例144步骤(i)的方法,利用实施例151步骤(iv)的产物、1-[(4-溴苯基)磺酰基]氮杂环丁烷并利用THF作为溶剂进行制备。产量0.028g。
1H NMR DMSO-d6:δ.7.97(d,2H),7.82(d,2H),7.39-7.43(m,2H),7.01(d,1H),4.85(m,1H),3.72(t,4H),2.04(q,2H),1.42(d,3H)
MS:ESI(-ve)394
实施例158
2-[[5-氯-2′-甲基-4′-(1-吡咯烷基羰基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,钠盐
标题化合物利用实施例155的方法,利用实施例151步骤(iv)的产物和1-(4-溴-3-甲基苯甲酰基)吡咯烷进行制备。产量0.152g。
1H NMR DMSO-d6:δ.7.2-7.41(m,4H),7.25(s,1H),6.85(d,1H),4.22(m,1H),3.56(m,4H),2.2(s,3H),1.85(m,4H),1.17(d,3H)
MS:APCI(-ve)388
实施例159
2-[(2′,4′-二氯-5-氰基[1,1’-联苯]-2-基)氧基]-(2S)-丙酸
i)2-(2-溴-4-氰基苯氧基)-(2S)-丙酸
将偶氮二羧酸二乙基酯(2.12g)加入到2-溴-4-氰基苯酚(2.0g)、甲基-R-乳酸酯(1.47g)和三苯基膦(2.65g)在THF(80ml)中的搅拌混合物中。20小时后,将混合物滤过硅胶,利用异己烷/EtOAc作为溶剂,并将滤液蒸发至干。将残留物溶解在DCM(50ml)中,用TFA(10ml)处理并搅拌2小时。将溶液蒸发,并将残留物在EtOAc和碳酸氢钠水溶液之间分配。将水相用2M盐酸酸化,用EtOAc萃取,干燥(MgSO4)并蒸发得到小标题化合物。
1H NMR DMSO-d6:δ.7.87(s,1H),7.56(d,1H),6.83(d,1H),4.91(q,1H),1.7(d,3H)
MS:APCI(-ve)270
ii)2-[(2′,4′-二氯-5-氰基[1,1’-联苯]-2-基)氧基]-(2S)-丙酸
标题化合物利用实施例16步骤的方法(iii)利用步骤(i)的产物和2,6-二氯苯基硼酸进行制备。
1H NMR DMSO-d6:δ.7.58-7.78(m,4H),7.46(d,1H),7.02(d,1H),4.51(q,1H),1.26(d,3H)
MS:APCI(-ve)334
实施例160
2-[[5-氰基-2′-氟-4′-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
标题化合物利用实施例16步骤(iii)的方法,利用实施例159步骤(i)的产物和3-氰基苯基硼酸进行制备。
1H NMR DMSO-d6:δ.7.81-8.04(m,4H),7.56(t,1H),7.18(d,1H),5.1(q,1H),1.4(d,3H)
MS:APCI(-ve)352
实施例161
2-[(3′-氰基-5-氟[1,1’-联苯]-2-基)氧基]-(2S)-丙酸,钠盐
i)2-(2-溴-4-氟苯氧基)-(2S)-丙酸,1,1-二甲基乙基酯
小标题化合物利用实施例159步骤(i)的方法,利用2-溴-4-氟苯酚(2.5g)进行制备。产量3.0g。
1H NMR DMSO-d6:δ.7.28-7.32(m,1H),6.89-6.98(m,1H),6.78-6.83(m,1H),4.56(q,1H),1.62(d,3H),1.4(s,9H)
ii)2-(2-溴-4-氟苯氧基)-(2S)-丙酸
小标题化合物利用实施例146步骤(iv)的方法,利用步骤(i)的产物进行制备。产量1.2g。不经表征进行步骤(iii)。
iii)2-[(3′-氰基-5-氟[1,1’-联苯]-2-基)氧基]-(2S)-丙酸,钠盐
标题化合物利用实施例155的方法,利用步骤(ii)的产物和3-氰基苯基硼酸进行制备。将产物溶解在乙腈中,用1M氢氧化钠处理并蒸发得到标题化合物。
1H NMR DMSO-d6:δ.8.4(s,1H),8.13(d,1H),7.75(d,1H),7.6(t,1H),6.9-7.2(m,3H),4.4(q,1H),1.28(d,3H)
MS:APCI(-ve)284
实施例162
2-[(2′,4′-二氯-5-氟[1,1’-联苯]-2-基)氧基]-(2S)-丙酸,钠盐
标题化合物利用实施例155的方法,利用实施例161步骤(ii)的产物和2,4-二氯苯基硼酸进行制备。将产物溶解在乙腈中,用1M氢氧化钠处理并蒸发得到标题化合物。
1H NMR DMSO-d6:δ7.66-7.72(m,2H),7.43(d,1H),6.86-7.11(m,3H),4.18(q,1H),1.2(d,3H)
MS:APCI(-ve)327
实施例163
2-[[2′-氯-5-氟-4′-(甲基磺酰基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
i)苄基2-溴-4-氟苯基醚
小标题化合物利用实施例16步骤(i)的方法,利用2-溴-4-氟苯酚并用丙酮作为溶剂进行制备。产量27.5g。
1H NMR DMSO-d 6:.7.27-7.49(m,6H),6.82-6.99(m,2H),5.12
ii)[2-(苄氧基)-5-氟苯基]硼酸
小标题化合物利用实施例16步骤(ii)的方法,利用步骤(i)的产物进行制备。产量18.77g。
iii)2-[5-氟-2-(苯基甲氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷
小标题化合物利用实施例146步骤(i)的方法,利用步骤(ii)的产物进行制备。产量4.1g。
1H NMR DMSO-d6:7.58(d,1H),7.29-7.4(m,3H),7.26(s,1H),7.04(dt,1H),6.84(d,2H),5.07(s,2H),1.36(s,12H)
iv)4-氟-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯酚
小标题化合物利用实施例146步骤(ii)的方法,利用步骤(iii)的产物并利用乙醇作为溶剂进行制备。
v)4-氟-2-[2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯氧基]-(2S)-丙酸,1,1-二甲基乙基酯
小标题化合物利用实施例32步骤(v)的方法,利用步骤(iv)的产物和叔丁基R-乳酸酯进行制备。产量2.6g。将粗物质进行步骤(vi)。
vi)2-[2-二羟硼基-4-(三氟甲基)苯氧基]-(2S)-丙酸
小标题化合物利用实施例146步骤(iv)的方法,利用步骤(v)的产物进行制备。产量1.65g。
MS:APCI(-ve)227
vii)2-[[2′-氯-5-氟-4′-(甲基磺酰基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸
标题化合物利用实施例155的方法,利用步骤(vi)的产物和实施例145步骤(ii)的产物进行制备。
1H NMR DMSO-d6:δ.8.06(s,1H),7.86-7.93(m,2H),7.03-7.23(m,2H),6.9-6.97(m,1H),4.43(q,1H),1.24(d,3H)
MS:APCI(-ve)371
实施例164
2-[[2′-氯-5-氟-5′-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,钠盐
标题化合物利用实施例155的方法,利用实施例161步骤(ii)的产物和2-溴-1-氯-4-(三氟甲基)苯进行制备。将产物溶解在乙腈中,用1M氢氧化钠处理并蒸发得到标题化合物。产量0.07g。
1H NMR DMSO-d6:δ.8.31(bs,1H),7.68-7.77(m,2H),7.09-7.15(m,2H),6.9-6.93(m,1H),4.25(q,1H),1.21(d,3H)
MS:APCI(-ve)361
实施例165
[[4’-(乙基磺酰基)-6-甲基-5-硝基[1,1’-联苯]-2-基]氧基]乙酸
i)(2-溴-3-甲基-4-硝基苯氧基)乙酸,甲基酯
用45分钟将溴(5.27g)的乙酸溶液(3ml)滴加至3-甲基-4-硝基苯酚(5.04g)的乙酸溶液(43ml)中,并且然后再搅拌1小时。将溶剂蒸发,加入水,用醚萃取,干燥(Na2SO4)并蒸发。将粗物质溶解在DMF(10ml)中,加入碳酸钾(3.79g),然后加入溴乙酸甲基酯(3.37ml),并将混合物在RT搅拌30分钟并在60℃搅拌2小时。将混合物冷却并倾入到EtOAc和水的混合物中。分离出有机相,用水、碳酸钾水溶液和盐水洗涤,干燥(Na2SO4)并蒸发。将残留物从甲苯/异己烷中重结晶,产量1.8g。
1H NMR CDCl3:δ7.86(d,1H),6.69(d,1H),4.81(s,2H),3.83(s,3H),2.19(s,3H)。
(ii)[[4’-(乙基磺酰基)-6-甲基-5-硝基[1,1’-联苯]-2-基]氧基]乙酸,甲基酯
小标题化合物利用实施例1步骤(ii)的方法,利用步骤(i)的产物(1.78g)和4-(乙硫基)苯基硼酸(1.6g)进行制备。产量2.59g。
1H NMR CDCl3:δ8.02(d,1H),8.0(d,2H),7.45(d,2H),6.75(d,1H),4.65(s,2H),3.76(s,3H),3.2(q,2H),2.25(s,3H),1.36(t,3H)
(iii)[[4’-(乙基磺酰基)-6-甲基-5-硝基[1,1’-联苯]-2-基]氧基]乙酸
标题化合物利用实施例26步骤(vi)的方法,利用步骤(ii)的产物进行制备。产量0.22g.
1H NMR DMSO-d6:δ.13.16(bs,1H),8.06(d,1H),7.97(d,2H),7.57(d,2H),7.12(d,1H),4.8(s,2H),3.38(q,2H),2.14(s,3H)1.16(t,3H)
MS:APCI(+ve):412(M+MeOH+H+)
实施例166
[[5-氯-4’-(乙基磺酰基)-6-甲基[1,1’-联苯]-2-基]氧基]乙酸
i)[[5-氨基-4’-(乙基磺酰基)-6-甲基[1,1’-联苯]-2-基]氧基]乙酸,甲基酯
将10%Pd/C(0.15g)加入到实施例165步骤(ii)的产物的EtOAc溶液(20ml)中并在RT在3bar下氢化2小时。将混合物滤过celite,并将滤液蒸发得到小标题化合物。产量1.4g。
1H NMR CDCl3:δ7.95(d,2H),7.48(d,2H),6.7(d,1H),6.65(d,1H),4.4(s,2H),3.71(s,3H),3.51(bs,2H),3.18(q,2H),1.88(s,3H)1.34(t,3H)
ii)[[5-氯-4’-(乙基磺酰基)-6-甲基[1,1’-联苯]-2-基]氧基]乙酸,甲基酯
将氯化亚铜(0.18g)溶解在乙腈(6ml)中,加入异戊基胺(0.24ml),然后滴加步骤(i)的产物的乙腈溶液(6ml)。将混合物搅拌12小时,蒸发,并将硅胶层析纯化用30-50%醚/异己烷洗脱。产量2.59g。
1H NMR CDCl3:δ7.97(d,2H),7.46(d,2H),7.34(d,1H),6.65(d,1H),4.32(s,2H),3.73(s,3H),3.19(q,2H),2.09(s,3H)1.35(t,3H)
iii)[[5-氯-4’-(乙基磺酰基)-6-甲基[1,1’-联苯]-2-基]氧基]乙酸
标题化合物利用实施例26步骤(vi)的方法,利用步骤(ii)的产物进行制备。经RPHPLC(MeCN/aqNH4Cl)纯化。产量0.07g。
1H NMR DMSO-d6:δ.7.94(d,2H),7.53(d,2H),7.44(d,1H),6.91(d,1H),4.64(s,2H),3.36(q,2H),2.03(s,3H),1.15(t,3H)
MS:APCI(+ve)367(M+MeOH+H+)
实施例167
[[4′-(甲基磺酰基)-2′,5-双(三氟甲基)[1,1’-联苯]-2-基]氧基]乙酸
i)4-溴-1-(甲硫基)-2-(三氟甲基)苯
将异戊基亚硝酸酯(0.67ml)滴加至4-溴-2-(三氟甲基)苯胺(1.2g)和二甲基硫醚(0.45ml)在乙腈(12ml)中的溶液中。将反应缓慢加热至回流并且然后回流直至气体停止放出。蒸发挥发性组分,将残留物吸附到硅胶上,并将产物用异己烷洗脱。产量0.8g。
1H NMR DMSO-d6:δ.7.59(dd,2H),7.23(d,1H),2.51(s,3H)
ii)4,4,5,5-四甲基-2-[4-(甲硫基)-3-(三氟甲基)苯基]-1,3,2-二氧杂硼杂环戊烷
将Pd2dba3(0.135g)和三环己基膦(0.199g)溶解在二噁烷(20ml)中并搅拌30分钟。依次加入乙酸钾(0.867g)、双(频哪醇合)二硼烷(1.65g)和步骤(i)的产物,并将混合物在90℃加热3小时。将反应冷却,蒸发,在醚和盐水之间分配,分离,干燥(Na2SO4)并蒸发。将残留物经硅胶层析纯化,用10%醚/异己烷洗脱。产量0.695g。
1H NMR DMSO-d6:δ.7.31(d,2H),2.53(s,3H),1.3(s,12H)
iii)2-溴-4-(三氟甲基)苯氧基乙酸,1,1-二甲基乙基酯
标题化合物利用实施例1步骤(i)的方法,利用2-溴-4-(三氟甲基)苯酚进行制备。
1H NMR DMSO-d6:δ.6.8-7.83(m,3H),4.65(s,2H),1.48(s,9H)
iv)[[4′-(甲硫基)-2′,5-双(三氟甲基)[1,1’-联苯]-2-基]氧基]乙酸,1,1-二甲基乙基酯
标题化合物利用实施例1步骤(ii)的方法,利用步骤(ii)和(iii)的产物进行制备。产量0.564g。不经表征进行步骤(v)。
v)[[4′-(甲基磺酰基)-2′,5-双(三氟甲基)[1,1’-联苯]-2-基]氧基]乙酸,1,1-二甲基乙基酯
将步骤(iv)的产物(0.564g)溶解在50%丙酮水溶液(10ml)中,加入碳酸氢钠(0.94g),然后加入oxone(1.5g)的水溶液(ml)并搅拌3小时,将反应用偏亚硫酸氢钠水溶液中止,用EtOAc萃取,用碳酸钾水溶液洗涤,干燥(Na2SO4)并蒸发得到小标题化合物。产量0.32g。
1H NMR DMSO-d6:δ.8.31(d,1H),8.29(s,1H),8.18(dd,1H),7.83(s,1H),7.81(d,1H),7.32(d,1H),4.9(s,2H),3.36(s,2H),1.41(s,9H)
vi)[[4′-(甲基磺酰基)-2′,5-双(三氟甲基)[1,1’-联苯]-2-基]氧基]乙酸
标题化合物利用实施例26步骤(vi)的方法,利用步骤(v)的产物进行制备。产量0.2g。
1H NMR DMSO-d6:δ.8.33(s,1H),8.3(d,1H),8.19(d,1H),7.83(s,1H),7.81(d,1H),7.34(d,1H),4.92(s,2H),3.36(s,2H)
MS:APCI(-ve)441
实施例168
2-[4-氯-2-[4-甲基-6-[甲基(甲基磺酰基)氨基]-3-吡啶基]苯氧基]-(2S)-丙酸
i)N-(5-溴-4-甲基-2-吡啶基)甲磺酰胺
将5-溴-4-甲基吡啶-2-胺(1.56g)溶解在DCM(40ml)中,加入三甲基胺(1.4ml),然后加入甲烷磺酰氯(1.9g),并将混合物搅拌20分钟。将溶液用水洗涤,干燥(MgSO4)并蒸发。将残留物溶解在THF中,用TBAF处理,搅拌16小时并蒸发。将残留物经硅胶层析纯化,用27%EtOAc/异己烷洗脱。产量1.3g。不经表征进行步骤(ii)。
ii)N-(5-溴-4-甲基-2-吡啶基)-N-甲基甲磺酰胺
将步骤(i)的产物(2.23g)、碳酸钾(2.33g)和碘甲烷(0.7ml)在DMF(20ml)中搅拌20小时。将反应用水中止,用EtOAc萃取,干燥(MgSO4)并蒸发。将残留物经硅胶层析纯化,用30%EtOAc/异己烷洗脱。产量1.5g。不经表征进行步骤(ii)。
iii)2-[4-氯-2-[4-甲基-6-[甲基(甲基磺酰基)氨基]-3-吡啶基]苯氧基]-(2S)-丙酸
标题化合物利用实施例155的方法,利用步骤(ii)的产物和实施例151步骤(iv)的产物进行制备。产量0.125g。
1H NMR DMSO-d6:δ.8.18(s,1H),7.26-7.44(m,3H),6.94(d,1H),4.8(m,1H),3.32(s,3H),3.2(s,3H),2.2(s,3H),1.32(d,3H)
MS:APCI(-ve)397
实施例169
2-[2-[4-甲基-2-[(甲基磺酰基)氨基]-5-嘧啶基]-4-(三氟甲基)苯氧基]-(2S)-丙酸
i)N-(5-溴-4-甲基-2-嘧啶基)甲磺酰胺钾
将甲烷磺酰氯(0.75ml)加入到5-溴-4-甲基-2-嘧啶胺(1.8g)的THF溶液(60ml)中,然后快速滴加1M叔丁醇钾/THF(20ml)。30分钟后过滤出形成的沉淀并干燥。产量3.2g。
1H NMR DMSO-d6:δ.8.13(s,1H),2.81(s,3H),2.26(s,3H)
ii)N-(5-溴-4-甲基-2-嘧啶基)-N-[[2-(三甲基甲硅烷基)乙氧基]甲基]甲磺酰胺
将[2-(氯甲氧基)乙基]三甲基甲硅烷(0.4ml)加入到步骤(i)的产物在DMF(10ml)中的溶液中并搅拌20分钟。将混合物倾入到水中,用醚萃取,用盐水洗涤,干燥(MgSO4)并蒸发。将残留物经硅胶层析纯化,用20%EtOAc/异己烷洗脱。产量0.53g。
1H NMR DMSO-d6:8.88(s,1H),5.49(s,2H),3.59-3.64(m,5H),2.63(s,3H),0.9(t,2H),0.0(t,9H)
iii)2-[2-[4-甲基-2-[(甲基磺酰基)[[2-(三甲基甲硅烷基)乙氧基]甲基]氨基]-5-嘧啶基]-4-(三氟甲基)苯氧基]-(2S)-丙酸
标题化合物利用实施例144步骤(i)的方法,利用步骤(ii)的产物和实施例146步骤(iv)的产物进行制备。不经表征进行步骤(iv)。
iv)2-[2-[4-甲基-2-[(甲基磺酰基)氨基]-5-嘧啶基]-4-(三氟甲基)苯氧基]-(2S)-丙酸
将步骤(iii)的产物用TFA(20ml)处理并搅拌20分钟。蒸发TFA,并将残留物经RVHPLC(CH3CN/aqTFA)纯化。
1H NMR DMSO-d6:δ8.84(s,1H),7.77(dd,2H),7.65(d,1H),7.14(d,5H),5.04(q,1H),3.4(s,3H),2.3(s,3H),1.41(d,3H)
MS:APCI(-ve)418
实施例170
[(5-氯-3′-氰基[1,1’-联苯]-2-基)氧基]-乙酸
(i)5′-氯-2′-甲氧基-[1,1′-联苯]-3-腈
小标题化合物利用实施例1步骤(ii)的方法,利用3-碘苄腈和5-氯-2-甲氧基苯基硼酸进行制备。产量0.465g。
1H NMR CDCl3:δ7.82(1H,t),7.71(1H,dt),7.62(1H,dt),7.51(1H,t),7.32(2H,dd),7.26(1H,m),6.93(1H,d),3.81(3H,s)
(ii)5′-氯-2′-羟基-[1,1′-联苯]-3-腈
在0℃,将三溴化硼的溶液(1M二氯甲烷溶液,6ml)加入到步骤(i)的产物在二氯甲烷(10ml)中的搅拌混合物中。15分钟后,将混合物温热至室温,搅拌16小时,然后倾入到冰上。将混合物用二氯甲烷然后乙酸乙酯萃取,合并有机物,干燥并减压蒸发。将残留物经硅胶层析纯化,用30-70%乙醚/异己烷洗脱。产量0.415g。
1H NMR CDCl3:δ7.83(1H,s),7.75(1H,d),7.68(1H,d),7.58(1H,t),7.25(2H,m),6.89(1H,d),5.00(1H,s)
(iii)[(5-氯-3′-氰基[1,1’-联苯]-2-基)氧基]-乙酸,1,1-二甲基乙基酯
小标题化合物利用实施例1步骤(i)的方法,利用步骤(ii)的产物进行制备。产量0.60g。
1H NMR CDCl3:δ7.90(1H,s),7.82(1H,d),7.63(1H,d),7.53(1H,td),7.28(2H,m),6.78(1H,d),4.52(2H,s),1.47(10H,s)
(iv)[(5-氯-3′-氰基[1,1’-联苯]-2-基)氧基]-乙酸
标题化合物利用实施例1步骤(iii)的方法,利用步骤(iii)的产物进行制备。产量0.265g。
1HNMR DMSO-d6:δ.13.12(1H,s),8.08(1H,s),7.94(1H,d),7.82(1H,d),7.64(1H,t),7.43(2H,m),7.10(1H,d),4.78(2H,s)。
MS:APCI(-ve):286
药理数据
配体结合试验
[3H]PGD2从Perkin Elmer Life Sciences购买得到,其比活性为100-210Ci/mmol。所有其它化学药品为分析级别。
表达rhCRTh2/Gα16的HEK细胞通常在含有10%胎牛血清(HyClone)、1mg/ml遗传霉素、2mM L-谷氨酰胺和1%非必须的氨基酸的DMEM中保持。对于膜的制备,粘附着的转染HEK细胞在两层的组织培养单元(Fisher,目录号TKT-170-070E)生长至汇合。培养的最后18小时加入500mM丁酸钠诱导受体表达至最大水平。粘附着的细胞用磷酸盐缓冲溶液(PBS,每细胞单元50ml)洗涤一次,并每细胞单元加入50ml的冰冷却的膜均匀化缓冲溶液[20mM HEPES(pH 7.4)、0.1mM二硫苏糖醇、1mM EDTA、0.1mM苯基甲基磺酰氟和100μg/ml杆菌肽]进行分离。通过在4℃下在220xg下离心10分钟沉淀细胞,再悬浮在体积为原始一半的新的膜均化缓冲溶液中并用Polytron均浆器进行破坏2×20秒并一直将试管保持在冰中。完整的细胞通过在4℃下在220xg下离心10分钟除去,而膜片碎片通过在4℃下在90000xg下离心分离30分钟沉淀。将最后的沉淀再悬浮在每细胞单元4ml膜片均匀化缓冲溶液中,并测量蛋白质含量。膜以合适的等分试样的形式在-80℃温度下存储。
所有试验在Corning透明白底96-孔NBS板(Fisher)中进行。在试验前,含有CRTh2的HEK细胞膜包被到SPA PVT WGA珠粒(Amersham)上。包被的时候,将膜与珠粒在4℃下代表性地以每毫克珠粒25μg膜蛋白比例持续搅拌过夜进行孵育。(最佳包被浓度根据每批膜来测定)珠粒通过离心(800xg7分钟,在4℃下)来沉淀小球,用分析缓冲液(50mM HEPES pH 7.4含有5mM氯化镁)来洗涤一次并最后以10mg/ml的珠粒浓度重新悬浮在分析缓冲液中。
每个试验含有20μl的6.25nM[3H]PGD2、20μl膜饱和的SPA珠粒,二者均在试验缓冲溶液,以及10μl化合物溶液或13,14-二氢-15-酮前列腺素D2(DK-PGD2,用于非特异性结合的测定,Cayman化学公司)。化合物和DK-PGD2溶于DMSO中并用相同的溶剂稀释至100x所需要的最终浓度。加入分析缓冲溶液得到10%DMSO的最终浓度(此时化合物达到10x所需要的最终浓度),并将此溶液加到试验板中。该试验板在室温下孵育2小时并在Wallac Microbeta液体闪烁计数器(每孔1分钟)上进行计数。
式(I)的化合物的IC50值小于(<)10μM。
具体地,实施例9的pIC50=7.4,实施例25的pIC50=8.0,以及实施例133的pIC50=8.2。
Claims (19)
1.式(I)的化合物或其可药用盐或溶剂合物:
其中:
X为卤素、氰基、硝基或被一个或多个卤素原子取代的C1-4烷基;
Y选自氢、卤素或C1-3烷基;
Z为苯基、萘基或环A,其中A为包含一个或多个氮原子的六员杂芳环或为包含一个或多个O、N、S原子的6,6或6,5稠合的二环,所述的苯基、萘基或A环都任选被一个或多个独立地选自下述基团的取代基取代:氢、卤素、CN、OH、硝基、COR9、CO2R6、SO2R9、OR9、SR9、SO2NR10R11、CONR10R11、NR10R11、NHSO2R9、NR9SO2R9、NR6CO2R6、NR9COR9、NR6CONR4R5、NR6SO2NR4R5、苯基或C1-6烷基,所述C1-6烷基任选被一个或多个卤素取代,
R1和R2独立地表示氢原子或C1-3烷基;
R4和R5独立地表示氢、C3-C7环烷基或C1-6烷基;
R6独立地表示氢原子或C1-C6烷基;
R8为C1-4烷基;
R9表示C1-6烷基,所述C1-6烷基任选被一个或多个选自卤素和苯基的取代基取代;
R10和R11独立地表示苯基、氢、C3-C7环烷基或C1-6烷基,所述C1-6烷基任选被一个或多个独立地选自卤素和苯基的取代基取代;
或者
R10和R11与其相连的氮原子一起能形成3-8员饱和的杂环,所述的环任选包含一个或多个选自O、S(O)n、NR8的原子,其中n=0、1或2,
条件是:所述化合物不是[(5-氰基联苯-2-基)氧基]乙酸、[(5-硝基联苯-2-基)氧基]乙酸、[[(2’,4’,5’-三氯)-4,5-二氯-[1,1’-联苯]-2-基]氧基]乙酸、[(3,5-二氯[1,1’-联苯]-2-基)氧基]乙酸、[(5-氯联苯-2-基)氧基]乙酸、2-[(3,5-二溴-[1,1’-联苯]-2-基)氧基]乙酸、或2-[(5-溴-[1,1’-联苯]-2-基)氧基]乙酸。
2.根据权利要求1的化合物或其可药用盐或溶剂合物,其中X为三氟甲基、硝基、氰基或卤素。
3.根据权利要求1的化合物或其可药用盐或溶剂合物,其中Z为苯基、吡啶基、嘧啶基、萘基、喹啉基、苯并[b]噻吩基或苯并呋喃基,各基团任选被如权利要求1中定义的取代基取代。
4.根据权利要求2的化合物或其可药用盐或溶剂合物,其中Z为苯基、吡啶基、嘧啶基、萘基、喹啉基、苯并[b]噻吩基或苯并呋喃基,各基团任选被如权利要求1中定义的取代基取代。
5.根据权利要求1的化合物或其可药用盐或溶剂合物,其中Z为任选被如权利要求1中定义的取代基取代的苯基。
6.根据权利要求2的化合物或其可药用盐或溶剂合物,其中Z为任选被如权利要求1中定义的取代基取代的苯基。
7.根据权利要求3的化合物或其可药用盐或溶剂合物,其中Z为任选被如权利要求1中定义的取代基取代的苯基。
8.根据权利要求1的化合物或其可药用盐或溶剂合物,其中R1和R2二者都为氢或一个为氢并且另一个为甲基或乙基或都为甲基。
9.根据权利要求2的化合物或其可药用盐或溶剂合物,其中R1和R2二者都为氢或一个为氢并且另一个为甲基或乙基或都为甲基。
10.根据权利要求3的化合物或其可药用盐或溶剂合物,其中R1和R2二者都为氢或一个为氢并且另一个为甲基或乙基或都为甲基。
11.根据权利要求5的化合物或其可药用盐或溶剂合物,其中R1和R2二者都为氢或一个为氢并且另一个为甲基或乙基或都为甲基。
12.根据权利要求1~11中任一项的化合物,选自:
{[5-氯-4′-(乙硫基)联苯-2-基]氧基}乙酸,
{[5-氯-4′-(乙基磺酰基)联苯-2-基]氧基}乙酸,
[(4′,5-二氯联苯-2-基)氧基]乙酸,
[(5-氯-4′-氰基联苯-2-基)氧基]乙酸,
[(5-氯-4′-甲氧基联苯-2-基)氧基]乙酸,
(4-氯-2-喹啉-8-基苯氧基)乙酸,
[(5-氯-3′,4′-二甲氧基联苯-2-基)氧基]乙酸,
2′-(羧基甲氧基)-5′-氯联苯-4-羧酸,
{[5-氯-4′-(甲基磺酰基)联苯-2-基]氧基}乙酸,
{[5-氯-4′-(乙基磺酰基)-2′-甲基联苯-2-基]氧基}乙酸,
{[4′-(甲硫基)-5-(三氟甲基)联苯-2-基]氧基}乙酸,
{[4′-(甲基磺酰基)-5-(三氟甲基)联苯-2-基]氧基}乙酸,
{[4′-(乙基磺酰基)-2′-甲基-5-(三氟甲基)联苯-2-基]氧基}乙酸,
(4-氯-2-嘧啶-5-基苯氧基)乙酸,
{2-[5-(氨基磺酰基)吡啶-2-基]-4-氯苯氧基}乙酸,
[2-(2-氨基嘧啶-5-基)-4-氯苯氧基]乙酸,三氟乙酸盐,
[4-氯-2-(4-甲基-2-吗啉-4-基嘧啶-5-基)苯氧基]乙酸,
{4-氯-2-[2-(二甲基氨基)嘧啶-5-基]苯氧基}乙酸,
[4-氯-2-(2-吗啉-4-基嘧啶-5-基)苯氧基]乙酸,
{4-氯-2-[2-(甲基氨基)嘧啶-5-基]苯氧基}乙酸,
{2-[2-(苄基氨基)嘧啶-5-基]-4-氯苯氧基}乙酸,
[4-氯-2-(2-哌啶-1-基嘧啶-5-基)苯氧基]乙酸,
(4-氯-2-{2-[甲基(甲基磺酰基)氨基]嘧啶-5-基}苯氧基)乙酸,
[[2′,5-二氯-4′-(乙基磺酰基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′-氯-4′-(乙基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[5-氯-4′-(乙基磺酰基)-2′-氟[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-(乙基磺酰基)-2′-氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[5-氯-4′-(乙基磺酰基)-2′-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
2-[[5-氯-4′-(乙基磺酰基)[1,1’-联苯]-2-基]氧基]-丙酸,
2-[[4′-(乙基磺酰基)-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
2-[[4′-(乙基磺酰基)-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2R)-丙酸,
2-[[2′,5-二氯-4′-(乙基磺酰基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
2-[[2′-氯-4′-(乙基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
2-[[4′-(乙基磺酰基)-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-2-甲基-丙酸,
2-[[4′-(乙基磺酰基)-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-丁酸,
[4-氯-2-[2-[(甲基磺酰基)(苯基甲基)氨基]-5-嘧啶基]苯氧基]-乙酸,
[4-氯-2-[2-[(乙基磺酰基)(苯基甲基)氨基]-5-嘧啶基]苯氧基]-乙酸,
[2-[2-[乙酰基(苯基甲基)氨基]-5-嘧啶基]-4-氯苯氧基]-乙酸,
[[4′-(乙基磺酰基)-5-氟-2′-甲基[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-(乙基磺酰基)-4,5-二氟-2′-甲基[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-(乙基磺酰基)-3,5-二氟-2′-甲基[1,1’-联苯]-2-基]氧基]-乙酸,
[2-(2-氨基-5-甲基-3-吡啶基)-4-(三氟甲基)苯氧基]-乙酸,
[[4′-氨基-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-氨基-2′-氯-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′-氯-4′-羟基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[2-(2,4-二甲氧基-5-嘧啶基)-4-(三氟甲基)苯氧基]-乙酸,
[[2′-氯-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′,5-双(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[5′-氟-2′-甲氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[5′-氰基-2′-甲氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-氯-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′,5′-二甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[5′-氯-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′-氟-6′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-氟-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-[[(乙基氨基)羰基]氨基]-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′-甲基-4′-[[(甲基氨基)羰基]氨基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-[[(环丙基氨基)羰基]氨基]-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′-甲基-4′-[[(丙基氨基)羰基]氨基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′,4′-二甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[5′-氟-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-(氨基羰基)-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[3′-氟-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′,5′-二氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[5′-(氨基磺酰基)-2′-氯-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-氰基-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-氯-2′-氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′,5′-二氟-4′-甲氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′-氟-5′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′-氟-4′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-甲氧基-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-(氨基磺酰基)-2′,5′-二氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[2-苯并[b]噻吩-3-基-4-(三氟甲基)苯氧基]-乙酸,
[2-(2-苯并呋喃基)-4-(三氟甲基)苯氧基]-乙酸,
[[4′-氯-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[3′-(1-甲基乙基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[3′,4′-二氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[2-(1,3-苯并二氧杂环戊烯-5-基)-4-(三氟甲基)苯氧基]-乙酸,
[[4′-乙基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[3′-氟-5-(三氟甲基)[1,1’:4’,1”-三联苯]-2-基]氧基]-乙酸,
[[4′-(三氟甲氧基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′,3′-二氯-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-(1,1-二甲基乙基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[2-(6-甲氧基-2-萘基)-4-(三氟甲基)苯氧基]-乙酸,
[[4′-(乙硫基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-乙酰基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[2-(2-氯-5-甲基-4-吡啶基)-4-(三氟甲基)苯氧基]-乙酸,
[[5′-(氨基磺酰基)-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[2-(8-喹啉基)-4-(三氟甲基)苯氧基]-乙酸,
[[3′-氰基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[2-[4-甲基-6-[甲基(甲基磺酰基)氨基]-3-吡啶基]-4-(三氟甲基)苯氧基]-乙酸,
[[2′-甲基-5′-(甲基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
2′-(羧基甲氧基)-5′-(三氟甲基)-[1,1′-联苯]-3-羧酸,3-甲基酯,
2′-(羧基甲氧基)-5′-(三氟甲基)-[1,1′-联苯]-2-羧酸,2-甲基酯,
[[5-(三氟甲基)[1,1’:4’,1”-三联苯]-2-基]氧基]-乙酸,
[[3′-氟-2′,4′-二甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′-硝基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[3′-氯-2′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[5-(三氟甲基)[1,1’:3’,1”-三联苯]-2-基]氧基]-乙酸,
2′-(羧基甲氧基)-5′-(三氟甲基)-[1,1′-联苯]-4-羧酸,4-甲基酯,
[[4′-硝基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[5-(三氟甲基)-3′-[(三氟甲基)硫基][1,1’-联苯]-2-基]氧基]-乙酸,
[[5-(三氟甲基)-4′-[(三氟甲基)硫基][1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[3′-氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[3′-甲基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[2-(3-吡啶基)-4-(三氟甲基)苯氧基]-乙酸,
[[2′-氟-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[2′-甲氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[3′-甲氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-甲氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[3′-(乙基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[3′-丙氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-丙氧基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[2-(2-氨基-4-甲基-5-嘧啶基)-4-(三氟甲基)苯氧基]-乙酸,
[[4′-氰基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′,5-双(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[2-(2-萘基)-4-(三氟甲基)苯氧基]-乙酸,
[[4′-(1-吡咯烷基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-[(二甲基氨基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-[[(苯基甲基)氨基]磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-[[(2,2,2-三氟乙基)氨基]磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-[(苯基氨基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-[(二乙基氨基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-[(环丙基氨基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-(氨基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-[(甲基氨基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[[4′-[(4-甲基-1-哌嗪基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,
[2-[4-甲基-2-(5-甲基-1,1-二氧代-1,2,5-噻二唑烷-2-基)-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸,
[2-[4-甲基-2-[甲基(甲基磺酰基)氨基]-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸,
[2-[2-(1,1-二氧-2-异噻唑烷基)-4-甲基-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸,铵盐,
[2-[4-甲基-2-(4-甲基-1-哌嗪基)-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸,
[2-[4-甲基-2-(1-吡咯烷基)-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸,
[2-[2-(二甲基氨基)-4-甲基-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸,
[2-[5-甲基-2-[甲基(甲基磺酰基)氨基]-4-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸,
[2-[2-[[(二甲基氨基)磺酰基]氨基]-4-甲基-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸,
[[2′-氯-4′-[(甲氧基羰基)氨基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]乙酸,
2-[[2′-氯-4′-(甲基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
2-[[3′-氰基-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
2-[[4′-[(二甲基氨基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
2-[[2′-氯-4′-[(二甲基氨基)磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
2-[[2′-氟-4′-(甲基磺酰基)-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
[[2′,5-二氯-4′-(甲基磺酰基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
[[5-氯-4′-[(二甲基氨基)磺酰基][1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
[[2′,5-二氯-4′-[(二甲基氨基)磺酰基][1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
[(5-氯-3′-氰基[1,1’-联苯]-2-基)氧基]-(2S)-丙酸,
[[5-氯-4′-[(二甲基氨基)磺酰基]-2′-氟[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
[[5-氯-4′-(4-吗啉基磺酰基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
[[5-氯-2′-氟-4′-(甲基磺酰基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
2-[[4′-(1-氮杂环丁基磺酰基)-5-氯[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
2-[[5-氯-2′-甲基-4′-(1-吡咯烷基羰基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
2-[(2′,4′-二氯-5-氰基[1,1’-联苯]-2-基)氧基]-(2S)-丙酸,
2-[[5-氰基-2′-氟-4′-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
2-[(3′-氰基-5-氟[1,1’-联苯]-2-基)氧基]-(2S)-丙酸,钠盐,
2-[(2′,4′-二氯-5-氟[1,1’-联苯]-2-基)氧基]-(2S)-丙酸,钠盐,
2-[[2′-氯-5-氟-4′-(甲基磺酰基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
2-[[2′-氯-5-氟-5′-(三氟甲基)[1,1’-联苯]-2-基]氧基]-(2S)-丙酸,
[[4’-(乙基磺酰基)-6-甲基-5-硝基[1,1’-联苯]-2-基]氧基]乙酸,
[[5-氯-4’-(乙基磺酰基)-6-甲基[1,1’-联苯]-2-基]氧基]乙酸,
[[4′-(甲基磺酰基)-2′,5-双(三氟甲基)[1,1’-联苯]-2-基]氧基]乙酸,
2-[4-氯-2-[4-甲基-6-[甲基(甲基磺酰基)氨基]-3-吡啶基]苯氧基]-(2S)-丙酸,
2-[2-[4-甲基-2-[(甲基磺酰基)氨基]-5-嘧啶基]-4-(三氟甲基)苯氧基]-(2S)-丙酸,和
[(5-氯-3′-氰基[1,1’-联苯]-2-基)氧基]-乙酸,
或其可药用盐或溶剂合物。
13.化合物,选自:
[[4′-[[(5-甲基-2-噻唑基)氨基]磺酰基]-5-(三氟甲基)[1,1’-联苯]-2-基]氧基]-乙酸,和
[2-[2-(3-羟基-1-氮杂环丁基)-4-甲基-5-嘧啶基]-4-(三氟甲基)苯氧基]-乙酸,
或其可药用盐或溶剂合物
14.根据权利要求1~13中任一项的式(I)的化合物或其可药用盐或溶剂合物在制备用于治疗的药物中的用途。
15.药物组合物,包括权利要求1~13中任一项定义的式(I)的化合物,或其可药用盐或溶剂合物以及可药用佐剂、稀释剂或载体。
16.权利要求1~13中任一项定义的式(I)的化合物,或其可药用盐或溶剂合物在制备用于治疗前列腺素D2介导的疾病的药物中的用途。
17.权利要求1~13中任一项定义的式(I)的化合物,或其可药用盐或溶剂合物在制备用于治疗患者的呼吸性疾病的药物中的用途,所述的患者患有所述的疾病或者处于患所述疾病的风险中。
18.权利要求17的用途,其中呼吸性疾病为哮喘和鼻炎。
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