CN1344266A - 新的化合物 - Google Patents
新的化合物 Download PDFInfo
- Publication number
- CN1344266A CN1344266A CN00805451A CN00805451A CN1344266A CN 1344266 A CN1344266 A CN 1344266A CN 00805451 A CN00805451 A CN 00805451A CN 00805451 A CN00805451 A CN 00805451A CN 1344266 A CN1344266 A CN 1344266A
- Authority
- CN
- China
- Prior art keywords
- ethyl
- piperidinyl
- dichloro
- phenoxy
- 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.)
- Pending
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 105
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 50
- 238000000034 method Methods 0.000 claims abstract description 36
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000001301 oxygen Chemical group 0.000 claims abstract description 6
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 354
- -1 nitro, hydroxyl Chemical group 0.000 claims description 186
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 91
- 150000001412 amines Chemical class 0.000 claims description 82
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 49
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 47
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 45
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 27
- 150000002576 ketones Chemical class 0.000 claims description 25
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 claims description 24
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 239000012453 solvate Substances 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 9
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 239000005864 Sulphur Substances 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 208000027866 inflammatory disease Diseases 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 125000005030 pyridylthio group Chemical group N1=C(C=CC=C1)S* 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- BUZYGTVTZYSBCU-UHFFFAOYSA-N 1-(4-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C=C1 BUZYGTVTZYSBCU-UHFFFAOYSA-N 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 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 4
- GWRSATNRNFYMDI-UHFFFAOYSA-N 4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-8h-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound FC=1C=C(NC=2N=C3N(C4CCCC4)CC(F)(F)C(=O)N(C)C3=CN=2)C(OC)=CC=1C(=O)NC1CCN(C)CC1 GWRSATNRNFYMDI-UHFFFAOYSA-N 0.000 claims description 4
- RXYIYUOOCZCTQP-UHFFFAOYSA-N 5-methylpyrimidine-2,4-diamine Chemical compound CC1=CN=C(N)N=C1N RXYIYUOOCZCTQP-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000001118 alkylidene group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 4
- WOCAUAGFAOCBHT-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-3-methoxybenzamide Chemical class COC1=CC=CC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 WOCAUAGFAOCBHT-UHFFFAOYSA-N 0.000 claims description 4
- MHIFSXJQGYPPDB-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-4-fluorobenzamide Chemical compound C1=CC(F)=CC=C1C(=O)NCCN1CCC(OC=2C=C(Cl)C(Cl)=CC=2)CC1 MHIFSXJQGYPPDB-UHFFFAOYSA-N 0.000 claims description 4
- FTAFETTVRQXSRZ-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-4-methoxybenzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NCCN1CCC(OC=2C=C(Cl)C(Cl)=CC=2)CC1 FTAFETTVRQXSRZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- LALDGZAOEXVHEY-UHFFFAOYSA-N (4-chlorophenyl)-[1-[2-[(4-phenylpiperidin-4-yl)methylamino]ethyl]piperidin-4-yl]methanone Chemical compound C1=CC(Cl)=CC=C1C(=O)C1CCN(CCNCC2(CCNCC2)C=2C=CC=CC=2)CC1 LALDGZAOEXVHEY-UHFFFAOYSA-N 0.000 claims description 3
- QQZVTJZQPKPZAV-UHFFFAOYSA-N (4-chlorophenyl)-[1-[2-[(5-ethylthiophen-2-yl)methylamino]ethyl]piperidin-4-yl]methanone Chemical compound S1C(CC)=CC=C1CNCCN1CCC(C(=O)C=2C=CC(Cl)=CC=2)CC1 QQZVTJZQPKPZAV-UHFFFAOYSA-N 0.000 claims description 3
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 208000024891 symptom Diseases 0.000 claims description 3
- CBFALSMXAFBKBY-UHFFFAOYSA-N (4-chlorophenyl)-[1-[2-(pyridin-2-ylmethylamino)ethyl]piperidin-4-yl]methanone Chemical compound C1=CC(Cl)=CC=C1C(=O)C1CCN(CCNCC=2N=CC=CC=2)CC1 CBFALSMXAFBKBY-UHFFFAOYSA-N 0.000 claims description 2
- HIRXHSWOYNEDIE-UHFFFAOYSA-N (4-chlorophenyl)-[1-[2-(pyridin-4-ylmethylamino)ethyl]piperidin-4-yl]methanone Chemical compound C1=CC(Cl)=CC=C1C(=O)C1CCN(CCNCC=2C=CN=CC=2)CC1 HIRXHSWOYNEDIE-UHFFFAOYSA-N 0.000 claims description 2
- DPZYXLJALIJPHJ-UHFFFAOYSA-N (4-chlorophenyl)-[1-[2-(quinolin-3-ylmethylamino)ethyl]piperidin-4-yl]methanone Chemical compound C1=CC(Cl)=CC=C1C(=O)C1CCN(CCNCC=2C=C3C=CC=CC3=NC=2)CC1 DPZYXLJALIJPHJ-UHFFFAOYSA-N 0.000 claims description 2
- CAMLOMWWSRNMDR-UHFFFAOYSA-N (4-chlorophenyl)-[1-[2-[(1-methylbenzimidazol-2-yl)methylamino]ethyl]piperidin-4-yl]methanone Chemical compound N=1C2=CC=CC=C2N(C)C=1CNCCN(CC1)CCC1C(=O)C1=CC=C(Cl)C=C1 CAMLOMWWSRNMDR-UHFFFAOYSA-N 0.000 claims description 2
- BZZQZDAWAXXDRW-UHFFFAOYSA-N (4-chlorophenyl)-[1-[2-[(2,5-difluorophenyl)methylamino]ethyl]piperidin-4-yl]methanone Chemical compound FC1=CC=C(F)C(CNCCN2CCC(CC2)C(=O)C=2C=CC(Cl)=CC=2)=C1 BZZQZDAWAXXDRW-UHFFFAOYSA-N 0.000 claims description 2
- QNHDEZAQQYUODX-UHFFFAOYSA-N (4-chlorophenyl)-[1-[2-[(2,6-dichlorophenyl)methylamino]ethyl]piperidin-4-yl]methanone Chemical compound C1=CC(Cl)=CC=C1C(=O)C1CCN(CCNCC=2C(=CC=CC=2Cl)Cl)CC1 QNHDEZAQQYUODX-UHFFFAOYSA-N 0.000 claims description 2
- FIHOVKRJUWICRZ-UHFFFAOYSA-N (4-chlorophenyl)-[1-[2-[(2-chloroquinolin-3-yl)methylamino]ethyl]piperidin-4-yl]methanone Chemical compound C1=CC(Cl)=CC=C1C(=O)C1CCN(CCNCC=2C(=NC3=CC=CC=C3C=2)Cl)CC1 FIHOVKRJUWICRZ-UHFFFAOYSA-N 0.000 claims description 2
- BQSJOJBQVLBVLW-UHFFFAOYSA-N (4-chlorophenyl)-[1-[2-[(3,5-difluorophenyl)methylamino]ethyl]piperidin-4-yl]methanone Chemical compound FC1=CC(F)=CC(CNCCN2CCC(CC2)C(=O)C=2C=CC(Cl)=CC=2)=C1 BQSJOJBQVLBVLW-UHFFFAOYSA-N 0.000 claims description 2
- LRKHJDIAAFTZID-UHFFFAOYSA-N (4-chlorophenyl)-[1-[2-[(3-methylthiophen-2-yl)methylamino]ethyl]piperidin-4-yl]methanone Chemical compound C1=CSC(CNCCN2CCC(CC2)C(=O)C=2C=CC(Cl)=CC=2)=C1C LRKHJDIAAFTZID-UHFFFAOYSA-N 0.000 claims description 2
- ZGEADYISVFOZKM-UHFFFAOYSA-N (4-chlorophenyl)-[1-[2-[(3-nitrophenyl)methylamino]ethyl]piperidin-4-yl]methanone Chemical compound [O-][N+](=O)C1=CC=CC(CNCCN2CCC(CC2)C(=O)C=2C=CC(Cl)=CC=2)=C1 ZGEADYISVFOZKM-UHFFFAOYSA-N 0.000 claims description 2
- SNSLWGMYHQXIKB-UHFFFAOYSA-N (4-chlorophenyl)-[1-[2-[(4-nitrophenyl)methylamino]ethyl]piperidin-4-yl]methanone Chemical compound C1=CC([N+](=O)[O-])=CC=C1CNCCN1CCC(C(=O)C=2C=CC(Cl)=CC=2)CC1 SNSLWGMYHQXIKB-UHFFFAOYSA-N 0.000 claims description 2
- PSTVENQTOPIJHX-UHFFFAOYSA-N (4-chlorophenyl)-[1-[2-[(6-methylpyridin-2-yl)methylamino]ethyl]piperidin-4-yl]methanone Chemical compound CC1=CC=CC(CNCCN2CCC(CC2)C(=O)C=2C=CC(Cl)=CC=2)=N1 PSTVENQTOPIJHX-UHFFFAOYSA-N 0.000 claims description 2
- PFYFSSBSMWQHOT-UHFFFAOYSA-N (4-chlorophenyl)-[1-[2-[(7-hydroxy-3,7-dimethyloctyl)amino]ethyl]piperidin-4-yl]methanone Chemical compound C1CN(CCNCCC(CCCC(C)(C)O)C)CCC1C(=O)C1=CC=C(Cl)C=C1 PFYFSSBSMWQHOT-UHFFFAOYSA-N 0.000 claims description 2
- JIXDOBAQOWOUPA-UHFFFAOYSA-N 1-fluoro-2-methoxybenzene Chemical compound COC1=CC=CC=C1F JIXDOBAQOWOUPA-UHFFFAOYSA-N 0.000 claims description 2
- BMHUXUQPWBADAL-UHFFFAOYSA-N 2-[2-[[2-[4-(4-chlorobenzoyl)piperidin-1-yl]ethylamino]methyl]-4-nitrophenoxy]acetic acid Chemical compound OC(=O)COC1=CC=C([N+]([O-])=O)C=C1CNCCN1CCC(C(=O)C=2C=CC(Cl)=CC=2)CC1 BMHUXUQPWBADAL-UHFFFAOYSA-N 0.000 claims description 2
- GUXFOLSWRZODOX-UHFFFAOYSA-N 2-[3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2,4-dioxoquinazolin-1-yl]-n,n-dimethylacetamide;hydrochloride Chemical compound Cl.O=C1N(CC(=O)N(C)C)C2=CC=CC=C2C(=O)N1CCN(CC1)CCC1C(=O)C1=CC=C(F)C=C1 GUXFOLSWRZODOX-UHFFFAOYSA-N 0.000 claims description 2
- NSFBBZNOSVHEES-UHFFFAOYSA-N 2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-n-[(3-methoxyphenyl)methyl]ethanamine;dihydrochloride Chemical compound Cl.Cl.COC1=CC=CC(CNCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 NSFBBZNOSVHEES-UHFFFAOYSA-N 0.000 claims description 2
- QPIPEHZSHGDUEL-UHFFFAOYSA-N 2-acetamido-n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-1,3-thiazole-4-carboxamide Chemical compound S1C(NC(=O)C)=NC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 QPIPEHZSHGDUEL-UHFFFAOYSA-N 0.000 claims description 2
- WFTYOJFJHQSUGC-UHFFFAOYSA-N 2-bromo-n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-5-methoxybenzamide Chemical compound COC1=CC=C(Br)C(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 WFTYOJFJHQSUGC-UHFFFAOYSA-N 0.000 claims description 2
- RIEYMRNHAOEQFH-UHFFFAOYSA-N 2-chloro-n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]pyridine-3-carboxamide Chemical compound C1=C(Cl)C(Cl)=CC=C1OC1CCN(CCNC(=O)C=2C(=NC=CC=2)Cl)CC1 RIEYMRNHAOEQFH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- ZJWLHFWEFOMZAL-UHFFFAOYSA-N 3-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-6-methoxy-1h-quinazoline-2,4-dione Chemical compound O=C1C2=CC(OC)=CC=C2NC(=O)N1CCN(CC1)CCC1OC1=CC=C(Cl)C(Cl)=C1 ZJWLHFWEFOMZAL-UHFFFAOYSA-N 0.000 claims description 2
- QWSWUJUPZKKMCB-UHFFFAOYSA-N 3-[[2-[4-(4-chlorobenzoyl)piperidin-1-yl]ethylamino]methyl]-6,7-dimethylchromen-4-one Chemical compound O=C1C=2C=C(C)C(C)=CC=2OC=C1CNCCN(CC1)CCC1C(=O)C1=CC=C(Cl)C=C1 QWSWUJUPZKKMCB-UHFFFAOYSA-N 0.000 claims description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
- UXWWZPILDBNLQO-UHFFFAOYSA-N 3-chloro-n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]benzamide;hydrochloride Chemical compound Cl.ClC1=CC=CC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 UXWWZPILDBNLQO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- APSKKFUPDZBWNV-UHFFFAOYSA-N 4-[[2-[4-(4-chlorobenzoyl)piperidin-1-yl]ethylamino]methyl]-1,5-dimethyl-2-phenylpyrazol-3-one Chemical compound O=C1N(C=2C=CC=CC=2)N(C)C(C)=C1CNCCN(CC1)CCC1C(=O)C1=CC=C(Cl)C=C1 APSKKFUPDZBWNV-UHFFFAOYSA-N 0.000 claims description 2
- BAXBAKNPTIKXDR-UHFFFAOYSA-N 4-amino-n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-3-methoxybenzamide Chemical compound C1=C(N)C(OC)=CC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 BAXBAKNPTIKXDR-UHFFFAOYSA-N 0.000 claims description 2
- MSLRDSZTCIDZOZ-UHFFFAOYSA-N 4-chloro-n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-2-[2-(dimethylamino)-2-oxoethoxy]benzamide Chemical class CN(C)C(=O)COC1=CC(Cl)=CC=C1C(=O)NCCN1CCC(OC=2C=C(Cl)C(Cl)=CC=2)CC1 MSLRDSZTCIDZOZ-UHFFFAOYSA-N 0.000 claims description 2
- LXRQUFJGFDAHOE-UHFFFAOYSA-N 4-chloro-n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-3-methoxybenzamide Chemical compound C1=C(Cl)C(OC)=CC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 LXRQUFJGFDAHOE-UHFFFAOYSA-N 0.000 claims description 2
- UDLQORCFOQLNRB-UHFFFAOYSA-N 5-bromo-n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]furan-2-carboxamide Chemical compound C1=C(Cl)C(Cl)=CC=C1OC1CCN(CCNC(=O)C=2OC(Br)=CC=2)CC1 UDLQORCFOQLNRB-UHFFFAOYSA-N 0.000 claims description 2
- NPMFBHDRRWILOH-UHFFFAOYSA-N 5-chloro-n-[3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propyl]pyridin-2-amine Chemical compound N1=CC(Cl)=CC=C1NCCCN1CCC(OC=2C=C(Cl)C(Cl)=CC=2)CC1 NPMFBHDRRWILOH-UHFFFAOYSA-N 0.000 claims description 2
- MNMGURNXXQQXDV-UHFFFAOYSA-N 6-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethylamino]-1,3-dimethylpyrimidine-2,4-dione Chemical compound O=C1N(C)C(=O)N(C)C(NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 MNMGURNXXQQXDV-UHFFFAOYSA-N 0.000 claims description 2
- MMXKXXGRZUAQGP-UHFFFAOYSA-N 6-[3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propylamino]-1,3-dimethylpyrimidine-2,4-dione Chemical compound O=C1N(C)C(=O)N(C)C(NCCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 MMXKXXGRZUAQGP-UHFFFAOYSA-N 0.000 claims description 2
- OVGRJQQHTOESDL-UHFFFAOYSA-N 6-chloro-n-[3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propyl]pyridin-2-amine Chemical compound ClC1=CC=CC(NCCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=N1 OVGRJQQHTOESDL-UHFFFAOYSA-N 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 2
- 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims description 2
- 102000009410 Chemokine receptor Human genes 0.000 claims description 2
- 108050000299 Chemokine receptor Proteins 0.000 claims description 2
- XRJGJSBHSFQMHU-UHFFFAOYSA-N [1-[2-[(4-bromo-1h-pyrazol-5-yl)methylamino]ethyl]piperidin-4-yl]-(4-chlorophenyl)methanone Chemical compound C1=CC(Cl)=CC=C1C(=O)C1CCN(CCNCC=2C(=CNN=2)Br)CC1 XRJGJSBHSFQMHU-UHFFFAOYSA-N 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- NSKZINWLPRKWDC-UHFFFAOYSA-N methyl 4-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethylamino]-4-oxobutanoate Chemical class C1CN(CCNC(=O)CCC(=O)OC)CCC1OC1=CC=C(Cl)C(Cl)=C1 NSKZINWLPRKWDC-UHFFFAOYSA-N 0.000 claims description 2
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- KWXJUNDUJSJTBH-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-1,3-benzothiazol-2-amine Chemical compound C1=C(Cl)C(Cl)=CC=C1OC1CCN(CCNC=2SC3=CC=CC=C3N=2)CC1 KWXJUNDUJSJTBH-UHFFFAOYSA-N 0.000 claims description 2
- QLDSETCYASKHSM-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-1,3-benzoxazol-2-amine Chemical compound C1=C(Cl)C(Cl)=CC=C1OC1CCN(CCNC=2OC3=CC=CC=C3N=2)CC1 QLDSETCYASKHSM-UHFFFAOYSA-N 0.000 claims description 2
- SJDLHXHEAZDEPB-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-1-methylpyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N1=CN=C2N(C)N=CC2=C1NCCN(CC1)CCC1OC1=CC=C(Cl)C(Cl)=C1 SJDLHXHEAZDEPB-UHFFFAOYSA-N 0.000 claims description 2
- ZISSECHEDKXQAI-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-1h-imidazole-5-carboxamide Chemical compound C1=C(Cl)C(Cl)=CC=C1OC1CCN(CCNC(=O)C=2N=CNC=2)CC1 ZISSECHEDKXQAI-UHFFFAOYSA-N 0.000 claims description 2
- PCKWFEMVMVVWBW-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-2,4-dimethyl-1,3-thiazole-5-carboxamide Chemical compound S1C(C)=NC(C)=C1C(=O)NCCN1CCC(OC=2C=C(Cl)C(Cl)=CC=2)CC1 PCKWFEMVMVVWBW-UHFFFAOYSA-N 0.000 claims description 2
- VNNOZQFEDPIYTO-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-2,5-dimethyl-1,3-oxazole-4-carboxamide Chemical compound O1C(C)=NC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1C VNNOZQFEDPIYTO-UHFFFAOYSA-N 0.000 claims description 2
- LHCHQRNVSKTWFV-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-2-(methylsulfanylmethyl)pyrimidin-4-amine Chemical compound CSCC1=NC=CC(NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=N1 LHCHQRNVSKTWFV-UHFFFAOYSA-N 0.000 claims description 2
- JVSQVHSJEFXFRT-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-2-iodobenzamide Chemical compound C1=C(Cl)C(Cl)=CC=C1OC1CCN(CCNC(=O)C=2C(=CC=CC=2)I)CC1 JVSQVHSJEFXFRT-UHFFFAOYSA-N 0.000 claims description 2
- OABROTVIJSOZCG-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-2-methoxyacetamide Chemical compound C1CN(CCNC(=O)COC)CCC1OC1=CC=C(Cl)C(Cl)=C1 OABROTVIJSOZCG-UHFFFAOYSA-N 0.000 claims description 2
- MQERTRHDLBTFFH-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-2-methoxybenzamide Chemical compound COC1=CC=CC=C1C(=O)NCCN1CCC(OC=2C=C(Cl)C(Cl)=CC=2)CC1 MQERTRHDLBTFFH-UHFFFAOYSA-N 0.000 claims description 2
- DYGZKAWWMOSVJK-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-2-methylbenzamide Chemical compound CC1=CC=CC=C1C(=O)NCCN1CCC(OC=2C=C(Cl)C(Cl)=CC=2)CC1 DYGZKAWWMOSVJK-UHFFFAOYSA-N 0.000 claims description 2
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- FBTMKTZWRAXPLD-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-2-phenylacetamide Chemical compound C1=C(Cl)C(Cl)=CC=C1OC1CCN(CCNC(=O)CC=2C=CC=CC=2)CC1 FBTMKTZWRAXPLD-UHFFFAOYSA-N 0.000 claims description 2
- MRTWXQBKCWYQLW-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-2-phenylacetamide;hydrochloride Chemical class Cl.C1=C(Cl)C(Cl)=CC=C1OC1CCN(CCNC(=O)CC=2C=CC=CC=2)CC1 MRTWXQBKCWYQLW-UHFFFAOYSA-N 0.000 claims description 2
- WUBLBLSCBTYXAY-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-2-pyridin-4-yl-1,3-thiazole-4-carboxamide Chemical compound C1=C(Cl)C(Cl)=CC=C1OC1CCN(CCNC(=O)C=2N=C(SC=2)C=2C=CN=CC=2)CC1 WUBLBLSCBTYXAY-UHFFFAOYSA-N 0.000 claims description 2
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- SBCGODLUNFOCIX-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-3-fluoro-4-methoxybenzamide Chemical compound C1=C(F)C(OC)=CC=C1C(=O)NCCN1CCC(OC=2C=C(Cl)C(Cl)=CC=2)CC1 SBCGODLUNFOCIX-UHFFFAOYSA-N 0.000 claims description 2
- KBKXFOOUOMDXLU-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-3-fluorobenzamide Chemical compound FC1=CC=CC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 KBKXFOOUOMDXLU-UHFFFAOYSA-N 0.000 claims description 2
- CBWVUHWMSNTREN-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-3-fluorobenzamide;hydrochloride Chemical compound Cl.FC1=CC=CC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 CBWVUHWMSNTREN-UHFFFAOYSA-N 0.000 claims description 2
- SETIHLUZSWNKTG-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-3-hydroxybenzamide;hydrochloride Chemical compound Cl.OC1=CC=CC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 SETIHLUZSWNKTG-UHFFFAOYSA-N 0.000 claims description 2
- LBJLDURINCUAHI-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-3-methoxy-4-methylbenzamide Chemical compound C1=C(C)C(OC)=CC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 LBJLDURINCUAHI-UHFFFAOYSA-N 0.000 claims description 2
- YSRLFWOFKGYOFR-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-3-methylbenzamide Chemical compound CC1=CC=CC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 YSRLFWOFKGYOFR-UHFFFAOYSA-N 0.000 claims description 2
- YTUKBSHEPUURCK-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-3-methylfuran-2-carboxamide Chemical compound C1=COC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1C YTUKBSHEPUURCK-UHFFFAOYSA-N 0.000 claims description 2
- DZAFQLBGKORWFO-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-3-phenylpropanamide Chemical compound C1=C(Cl)C(Cl)=CC=C1OC1CCN(CCNC(=O)CCC=2C=CC=CC=2)CC1 DZAFQLBGKORWFO-UHFFFAOYSA-N 0.000 claims description 2
- ZYHXWIHFKNVOSJ-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-4-ethoxybenzamide Chemical compound C1=CC(OCC)=CC=C1C(=O)NCCN1CCC(OC=2C=C(Cl)C(Cl)=CC=2)CC1 ZYHXWIHFKNVOSJ-UHFFFAOYSA-N 0.000 claims description 2
- MMRUIYLXLJUSGC-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-4-iodobenzamide Chemical compound C1=C(Cl)C(Cl)=CC=C1OC1CCN(CCNC(=O)C=2C=CC(I)=CC=2)CC1 MMRUIYLXLJUSGC-UHFFFAOYSA-N 0.000 claims description 2
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- NMOPBBNBMLLCEV-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-4-nitrobenzamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)NCCN1CCC(OC=2C=C(Cl)C(Cl)=CC=2)CC1 NMOPBBNBMLLCEV-UHFFFAOYSA-N 0.000 claims description 2
- REXMJLJELCTNFZ-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-4-phenylbutanamide Chemical compound C1=C(Cl)C(Cl)=CC=C1OC1CCN(CCNC(=O)CCCC=2C=CC=CC=2)CC1 REXMJLJELCTNFZ-UHFFFAOYSA-N 0.000 claims description 2
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- VNGXYAQDIVSFEJ-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-5-methoxy-1-benzofuran-2-carboxamide Chemical compound C=1C2=CC(OC)=CC=C2OC=1C(=O)NCCN(CC1)CCC1OC1=CC=C(Cl)C(Cl)=C1 VNGXYAQDIVSFEJ-UHFFFAOYSA-N 0.000 claims description 2
- DJOYNOJKWBOLTJ-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-5-methoxy-2-methylsulfanylpyrimidin-4-amine Chemical compound COC1=CN=C(SC)N=C1NCCN1CCC(OC=2C=C(Cl)C(Cl)=CC=2)CC1 DJOYNOJKWBOLTJ-UHFFFAOYSA-N 0.000 claims description 2
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- BNSSXUYAHFYQHZ-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-6-methyl-2-methylsulfanylpyrimidin-4-amine Chemical compound CSC1=NC(C)=CC(NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=N1 BNSSXUYAHFYQHZ-UHFFFAOYSA-N 0.000 claims description 2
- LIMGNCBIBIFOEN-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-7-ethoxy-1-benzofuran-2-carboxamide Chemical compound O1C=2C(OCC)=CC=CC=2C=C1C(=O)NCCN(CC1)CCC1OC1=CC=C(Cl)C(Cl)=C1 LIMGNCBIBIFOEN-UHFFFAOYSA-N 0.000 claims description 2
- CNUGRMNAHHHHRM-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-7-methoxy-1-benzofuran-2-carboxamide Chemical compound O1C=2C(OC)=CC=CC=2C=C1C(=O)NCCN(CC1)CCC1OC1=CC=C(Cl)C(Cl)=C1 CNUGRMNAHHHHRM-UHFFFAOYSA-N 0.000 claims description 2
- OJZLSZAYGQCTEK-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-7-methylthieno[3,2-d]pyrimidin-4-amine Chemical compound N1=CN=C2C(C)=CSC2=C1NCCN(CC1)CCC1OC1=CC=C(Cl)C(Cl)=C1 OJZLSZAYGQCTEK-UHFFFAOYSA-N 0.000 claims description 2
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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- C07D513/04—Ortho-condensed systems
Abstract
本发明提供通式(I)的化合物,其中:R1代表任选取代的C1-C12烷基或任选取代的3-到10-元饱和或不饱和的环系,该系统包括最多可达2个形成羰基的环碳原子和包括最多可达4个独立选自氮、氧和硫的环杂原子;m是0-1;Q代表OCH2、C1-C4亚烷基或C2-C4亚链烯基;T代表C(O)NH,或当m是0时,T可以另外代表键或NH,或当m是1和Q代表C1-C4亚烷基时,T可以另外代表NH;n是1-4;每个R2和R3独立代表H或C1-C4烷基;V代表N和W代表N或CH;X代表O、C(O)、CH(OH)、SO2、NH或N(C1-C6烷基),条件是当W代表N时,X代表C(O)或SO2和当W代表CH时,则X不是SO2;R4代表任选取代的苯基;R5和R6各独立代表H、C1-C6烷基或羟基C1-C6烷基,或R5和R6与它们所连接的氮原子一起形成4-到7-元饱和的杂环;R7和R8各独立代表H或C1-C6烷基;和R9代表OH或-NR7R8;提供用于制备它们的方法,含有它们的药用组合物和它们在治疗中的用途。
Description
本发明涉及新的化合物,制备它们的方法,含有它们的药用组合物和它们在治疗中的用途。
趋化因子在许多疾病和症状的免疫和炎症反应中起着重要的作用,包括哮喘和过敏性疾病以及自身免疫性疾病如风湿性关节炎和动脉粥样硬化。这些小的分泌型分子是以保守的四个半胱氨酸基元为特征的8-14 kDa蛋白的生长超家族。所述趋化因子超家族可以主要分成两组显示特性结构基元Cys-X-Cys(C-X-C)和Cys-Cys(C-C)族。它们的区别点基于插入到NH-近端的半胱氨酸残基对之间的单个氨基酸和序列相似性。
C-X-C趋化因子包括一些嗜中性粒细胞的有效的化学引诱物和激活剂如白细胞介素-8(IL-8)和嗜中性粒细胞-活化肽2(NAP-2)。
C-C趋化因子包括单核细胞和淋巴细胞,但不包括嗜中性粒细胞的有效的化学引诱物例如人单核细胞趋化蛋白1-3(MCP-1、MCP-2和MCP-3)、RANTES(激活调节型、正常T表达和分泌型)、eotaxin和巨噬细胞炎性蛋白1α和1β(MIP-1α和MIP-1β)。
研究证实,趋化因子的作用是通过G蛋白-偶联受体的亚家族介导的,其中所述受体指定为CCR1、CCR2、CCR2A、CCR2B、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CXCR1、CXCR2、CXCR3和CXCR4。这些受体代表用于药物开发的好的靶,因为调节这些受体的药物可以用于如以上指出的症状和疾病的治疗。
从U.S专利号3 787 419、4 559 349和5 210 086中已知,一些哌啶基衍生物和哌嗪基衍生物分别用作中枢神经系统抑制药、精神抑制药和α1-肾上腺素能受体拮抗剂。
因此根据本发明提供下列通式的化合物其中:R1代表由独立选自以下的一个或多个取代基任选取代的C1-C12烷基:氰基、羟基、C1-C6烷氧基、C1-C6烷硫基和C1-C6烷氧基羰基,或R1代表3-到10-元的饱和或不饱和的环系,其可以包括最多可达2个形成羰基的环碳原子和可以包括最多可达4个独立选自氮、氧和硫的环杂原子,所述环系由一个或多个独立选自以下的取代基任选取代:卤原子,和氰基、硝基、羟基、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷氧基羰基、C1-C6卤代烷基、C1-C6卤代烷氧基、-NR5R6、C3-C6环烷基氨基、C1-C6烷硫基、C1-C6烷硫基C1-C6烷基、C1-C6烷基羰基氨基、-C(O)NR7R8、氨磺酰基(-SO2NH2)、(二)C1-C6烷基氨磺酰基、苯基、苯基氨基、硝基苯基、吡啶基、吡啶基硫代、苯并二噁烷基、噻吩基、呋喃基和C(O)R9-取代的C1-C6烷基或C1-C6烷氧基;m是0或1;Q代表基团OCH2、C1-C4亚烷基或C2-C4亚链烯基;T代表基团C(O)NH,或当m是0时,T可以另外代表键或基团NH,或当m是1和Q代表C1-C4亚烷基时,T可以另外代表基团NH;n是1、2、3或4;每个R2独立代表氢原子或C1-C4烷基;每个R3独立代表氢原子或C1-C4烷基;V代表氮原子;W代表氮原子或基团CH;X代表氧原子或基团C(O)、CH(OH)、NH或N(C1-C6烷基),条件是当W代表氮原子时,则X代表C(O);R4代表由一个或多个独立选自以下的取代基任选取代的苯基:卤原子和氨基、硝基、氰基、磺酰基(-SO3H)、氨磺酰基(-SO2NH2)、C1-C6烷基、C1-C6卤代烷基、C1-C6卤代烷氧基和C1-C6烷基磺酰基;R5和R6各独立代表氢原子或C1-C6烷基或羟基C1-C6烷基,或R5和R6与它们所连接的氮原子一起形成4-到7-元的饱和杂环;R7和R8各独立代表氢原子或C1-C6烷基;和R9代表羟基或-NR7R8基团;条件是(a)当m是0,T是CONH,n是2、3或4和每个R2和R3代表氢,W是CH,X是C(O)或CH(OH)和R1代表取代的3-到10元的不饱和环系时,则所述环系中的一个或多个取代基不包括羟基、卤素、C1-C6烷氧基或C1-C6卤代烷氧基,和(b)当W是N,X是C(O),R4代表3-三氟代甲基苯基,m是0和T是键时,则R1和(CR2R3)n一起不代表C1-C6烷基,和(c)当W是CH,X是O,n是2或3和每个R2和R3代表氢,m是0和T是NH时,则R1不代表以下基团或其药学上可接受的盐或溶剂化物。
在本说明书的上下文中,取代基中的烷基取代基或烷基部分可以是直链或支链。另外,二烷基氨基、二(羟基烷基)氨基或二烷基氨磺酰基中的烷基部分可以是相同或不同。
R1代表由独立选自以下的一个或多个(例如一个、两个、三个或四个)取代基任选取代的C1-C12、优选C1-C10烷基:氰基、羟基、C1-C6优选C1-C4烷氧基(例如甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或己氧基)、C1-C6优选C1-C4烷硫基(例如甲基-、乙基-、丙基-、丁基-、戊基-或己基硫基)和C1-C6优选C1-C4烷氧基羰基(例如甲氧基-、乙氧基-、丙氧基-、丁氧基-、戊氧基-或己氧基羰基),或
R1代表3-到10-元饱和或不饱和的、包括最多可达2个形成羰基的环碳原子和包括最多可达4个独立选自氮、氧和硫的环杂原子的环系,所述环系可以由一个或多个(例如一个、两个、三个或四个)独立选自以下的取代基任选取代:卤原子(氟、氯、溴或碘)和氰基、硝基、羟基、C1-C6烷基(例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔-丁基、戊基或己基)、C3-C6环烷基(环丙基、环丁基、环戊基或环己基)、C1-C6烷氧基(例如甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或己氧基)、C1-C6烷氧基羰基(例如甲氧基-、乙氧基-、丙氧基-、丁氧基-、戊氧基-或己氧基羰基)、C1-C6卤代烷基(例如三氟代甲基)、C1-C6卤代烷氧基(例如三氟代甲氧基)、-NR5R6、C3-C6环烷基氨基(环丙基-、环丁基-、环戊基-或环己基氨基)、C1-C6烷硫基(例如甲基-、乙基-、丙基-、丁基-、戊基-或己基硫基)、C1-C6烷硫基C1-C6烷基(例如甲硫基甲基)、C1-C6烷基羰基氨基(例如甲基-、乙基-、丙基-、丁基-、戊基-或己基羰基氨基)、-C(O)NR7R8、氨磺酰基(-SO2NH2)、(二)C1-C6烷基氨磺酰基(例如(二)甲基氨磺酰基或(二)乙基氨磺酰基)、苯基、苯基氨基、硝基苯基、吡啶基、吡啶基硫代、苯并二噁烷基、噻吩基、呋喃基和C(O)R9-取代的C1-C6烷基或C1-C6烷氧基,所述烷基和烷氧基部分如上所定义。
在基团R1中,3-到10-元饱和或不饱和的环系可以是单环或包括两个或多个稠合环的多环,其实例包括环丁基、环戊基、环己基、降冰片烯基、金刚烷基、哌啶基、苯基、萘基、二氮萘基、1,3-苯并二氧杂环戊基、吡唑基、呋喃基、吡啶基、噻吩基、苯并噁唑基、苯并噻唑基、苯并-γ-吡喃酮基、咪唑基、喹啉基、异喹啉基、苯并咪唑基、嘧啶基、吡唑并嘧啶基、噻吩并嘧啶基、噻唑并嘧啶基、嘧啶二酮、吡嗪基、哒嗪基、嘌呤基、喹喔啉基、噻唑基、异噻唑基和2,4-二氧代-3,4-二氢-喹唑啉基。
优选,R1代表由一个或两个独立选自以下的取代基任选取代的C1-C10烷基:氰基、羟基、C1-C4烷氧基、C1-C4烷硫基和C1-C4烷氧基羰基,或
R1代表3-到10-元饱和或不饱和、包括最多可达2个形成羰基的环碳原子和包括最多可达4个独立选自氮、氧和硫的杂原子的环系,所述环系可以由一个、两个或三个独立选自以下的取代基任选取代:卤原子和氰基、硝基、羟基、C1-C4烷基、C3-C6环烷基、C1-C4烷氧基、C1-C4烷氧基羰基、C1-C3卤代烷基、C1-C4卤代烷氧基、-NR5R6、C3-C6环烷基氨基、C1-C4烷硫基、C1-C4烷硫基C1-C4烷基、C1-C4烷基羰基氨基、-C(O)NR7R8、苯基、苯基氨基、硝基苯基、吡啶基、吡啶基硫代、苯并二噁烷基、噻吩基、呋喃基和C(O)R9-取代的C1-C4烷基或C1-C4烷氧基。
优选Q代表基团OCH2、C1-C3亚烷基或C2-C3亚链烯基。
每一个R2独立代表氢原子或C1-C4烷基(例如甲基、乙基、丙基、异丙基或丁基),特别是氢原子。
每一个R3独立代表氢原子或C1-C4烷基(例如甲基、乙基、丙基、异丙基或丁基),特别是氢原子。
优选n是2或3。
X优选代表氧原子或基团C(O)或NH。
R4代表由一个或多个(例如一个、两个、三个或四个)独立选自以下的取代基任选取代的苯基:卤原子(氟、氯、溴或碘)和氨基、硝基、氰基、磺酰基(-SO3H)、氨磺酰基(-SO2NH2)、C1-C6优选C1-C4烷基(例如甲基、乙基、丙基、丁基、戊基或己基)、C1-C6优选C1-C4卤代烷基(例如三氟代甲基)、C1-C6优选C1-C4卤代烷氧基(例如三氟代甲氧基)和C1-C6优选C1-C4烷基磺酰基(例如甲基-、乙基-、丙基-、丁基-、戊基-或己基磺酰基)。
优选R4代表由一个或两个卤原子、特别是氯原子任选取代的苯基。
R5和R6每一个独立代表氢原子或C1-C6优选C1-C4烷基或羟基C1-C6优选C1-C4烷基,或R5和R6与它们所连接的氮原子一起形成4-到7-元饱和杂环。在每一种情况下烷基部分可以例如是甲基、乙基、丙基、丁基、戊基或己基。在羟基烷基中,羟基可以连接到烷基部分的任何合适的碳原子上。
R7和R8每一个独立代表氢原子或C1-C6优选C1-C4烷基(例如甲基、乙基、丙基、丁基、戊基或己基)。优选,R7和R8每一个独立代表氢原子或甲基。
R9代表羟基或优选-NR5R6基团。
本发明特别优选的化合物的实例包括:4-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-[2-(二甲基氨基)-2-氧代乙氧基]苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-乙氧基苯甲酰胺盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-异丙氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-乙氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-(三氟代甲氧基)苯甲酰胺盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(三氟代甲氧基)苯甲酰胺盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-糠酰胺盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-苯基乙酰胺盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺盐酸盐,3-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-氟代苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-氟代苯甲酰胺盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-羟基苯甲酰胺盐酸盐,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-[2-(甲基氨基)-2-氧代乙氧基]苯甲酰胺盐酸盐,2-[3-{2-[4-(4-氟代苯甲酰基)-1-哌啶基]乙基}-2,4-二氧代-3,4-二氢-1(2H)-喹唑啉基]-N,N-二甲基乙酰胺盐酸盐N-{2-[4-(3,4-二氯代苯甲酰基)-1-哌嗪基]乙基}-3-甲氧基苯甲酰胺盐酸盐,3,4-二氯代-N-{2-[4-(3,4-二氯代苯甲酰基)-1-哌嗪基]乙基}苯甲酰胺,4-氯代-N-{2-[4-(3,4-二氯代苯甲酰基)-1-哌嗪基]乙基}-2-[2-(二甲基氨基)-2-氧代乙氧基]苯甲酰胺盐酸盐,N~7~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲基[1,3]噻唑并[4,5-d]嘧啶-2,7-二胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-9-甲基-9H-嘌呤-6-胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1,3-苯并噻唑-2-胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1,3-苯并噁唑-2-胺,6-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-吡嗪胺,6-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-哒嗪胺,6-({2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}氨基)-1,3-二甲基-2,4-(1H,3H)-嘧啶二酮,N-{1-[4-(3,4-二氯代苯氧基)-哌啶-1-基甲基]-2-甲基-丙基}-4-甲基-苯甲酰胺,盐酸盐,N-{1-[4-(3,4-二氯代-苯氧基)-哌啶-1-基甲基]-2-甲基-丙基}-3-甲氧基-苯甲酰胺,盐酸盐,N-{2-[4-(3,4-二氯代苯胺基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺二盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N-(3-甲氧基苄基)胺二盐酸盐,3-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-6-甲氧基-2,4-(1H,3H)-喹唑啉二酮,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-氟代苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,4-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-硝基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-甲基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-(三氟代甲基)苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3,5-二硝基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-碘代苯甲酰胺,4-氰基-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,4-溴代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-甲基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}4-硝基苯甲酰胺,3-溴代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,3,4-二氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-氟代苯甲酰胺,2,4-二氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-碘代苯甲酰胺,4-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-硝基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-甲基-3-硝基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-氟代-5-(三氟代甲基)苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-(三氟代甲氧基)苯甲酰胺,3,5-二氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(三氟代甲基)苯甲酰胺,3-氰基-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,2-溴代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-糠酰胺,3-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,2-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3,5-二氟代苯甲酰胺,2,3-二氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-萘甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(甲硫基(sulfanyl))烟酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-氟代-6-(三氟代甲基)苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,4-二氟代苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-噻吩甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-喹喔啉甲酰胺,4-({2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}氨基)-4-氧代丁酸甲酯,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}双环[2.2.1]庚-5-烯-2-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}环丁烷甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-甲氧基乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}环己烷甲酰胺,(E)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-苯基-2-丙烯酰胺,2-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}烟酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-苯基乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}环戊烷甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-苯氧基乙酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-(三氟代甲基)苯甲酰胺,4-(叔-丁基)-N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-4-甲基苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-4-硝基苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-甲基苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-4-甲基-3-硝基苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-氰基苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-糠酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-硝基苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-萘甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-(甲硫基)烟酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-(2,3-二氢-1,4-苯并二氧芑-2-基)-1,3-噻唑-4-甲酰胺,N~2~-环丙基-N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,4-嘧啶二胺,2-{[4-({2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}氨基)-2-嘧啶基]氨基}-1-乙醇,2-[[4-({2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}氨基)-2-嘧啶基](甲基)氨基]-1-乙醇,N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N~2~-苯基-2,4-嘧啶二胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(甲硫基)-4-嘧啶胺,N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-6-甲基-2,4-嘧啶二胺,N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N~2~,6-二甲基-2,4-嘧啶二胺,2-氯代-N~4~-环丙基-N~6~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4,6-嘧啶二胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-苯基-2-嘧啶胺,N~2~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N~4~,N~4~,6-三甲基-2,4-嘧啶二胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(三氟代甲基)-2-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(丙硫基)-2-嘧啶胺,N~2~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N~4~-苯基-2,4-嘧啶二胺,N~4~-环丙基-N~2-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,4-嘧啶二胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}[1,8]二氮萘-2-胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(3-吡啶基)-2-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4,6-二甲氧基-2-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(3-呋喃基)-2-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1H-嘌呤-6-胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲基噻吩并[2,3-d]嘧啶-4-胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-7-甲基噻吩并[3,2-d]嘧啶-4-胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-噻吩甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-喹喔啉甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}双环[2.2.1]庚-5-烯-2-甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}环己烷甲酰胺,(E)-N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-苯基-2-丙烯酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-苯氧基乙酰胺,(E)-N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-(4-硝基苯基)-2-丙烯酰胺,2-(1-金刚烷基)-N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}乙酰胺,(4-氯代苯基)(1-{2-[(2-氟代-4,5-二甲氧基苄基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)(1-{2-[(3,4,5-三甲氧基苄基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)(1-{2-[(3-硝基苄基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基){1-[2-(异丁基氨基)乙基]-4-哌啶基}甲酮,4-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-4-乙基己腈,(4-氯代苯基)(1-{2-[(7-羟基-3,7-二甲基辛基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)[1-(2-{[(6-硝基-1,3-苯并二氧杂环戊-5-基)甲基]氨基}乙基)-4-哌啶基)甲酮,[1-(2-{[(5-氯代-1,3-二甲基-1H-吡唑-4-基)甲基]氨基}乙基)-4-哌啶基](4-氯代苯基)甲酮,(4-氯代苯基)[1-(2-{[3-硝基-4-(2-吡啶基硫基)苄基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)[1-(2-{[(E)-3-(4-硝基苯基)-2-丙烯基]氨基}乙基)-4-哌啶基)甲酮,(4-氯代苯基){1-[2-({[5-(3-硝基苯基)-2-呋喃基]甲基}氨基)乙基]4-哌啶基}甲酮,(4-氯代苯基)[1-(2-{[5-硝基-2-(2-吡啶基硫基)苄基]氨基}乙基)-4-哌啶基)甲酮,6-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-2-(甲硫基)烟腈,{1-[2-({[5-氯代-1-甲基-3-(三氟代甲基)-1H-吡唑-4-基]甲基}氨基)乙基]-4-哌啶基}(4-氯代苯基)甲酮,(4-氯代苯基)[1-(2-{[3-(甲硫基)丁基]氨基}乙基)-4-哌啶基)甲酮,(4-氯代苯基)[1-(2-{[(4-苯基-4-哌啶基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)[1-(2-{[(1-苯基-1H-吡唑-5-基)甲基]氨基}乙基)-4-哌啶基]甲酮,3-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]环己烷羧酸乙酯,N-{4-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]苯基}乙酰胺,(4-氯代苯基)(1-{2-[(2,5-二氟代苄基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)(1-{2-[(4-硝基苄基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)(1-{2-[(2,6-二氯代苄基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)(1-{2-[(2-吡啶基甲基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)[1-(2-{[(3-甲基-2-噻吩基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)(1-{2-[(3-羟基-4-甲氧基苄基)氨基]乙基}-4-哌啶基)甲酮,3-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-4H-苯并吡喃-4-酮,[1-(2-{[(5-氯代-1,3-二甲基-1H-吡唑-4-基)甲基]氨基}乙基)-4-哌啶基](4-氯代苯基)甲酮,(4-氯代苯基)[1-(2-{[(2,6-二氯代-4-吡啶基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)[1-(2-{[(2-苯基-1H-咪唑-4-基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)[1-(2-{[(5-乙基-2-噻吩基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)[1-(2-{[(2-氯代-3-喹啉基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)[1-(2-{[(6-甲基-2-吡啶基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)(1-{2-[(3-喹啉基甲基)氨基]乙基}-4-哌啶基)甲酮,4-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-1,5-二甲基-2-苯基-1,2-二氢-3H-吡唑-3-酮,(4-氯代苯基)(1-{2-[(4-吡啶基甲基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)(1-{2-[(3-羟基-4-硝基苄基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)(1-{2-[(3,5-二氟代苄基)氨基]乙基}-4-哌啶基)甲酮,(1-{2-[(2-氯代-6-氟代苄基)氨基]乙基}-4-哌啶基)(4-氯代苯基)甲酮,[1-(2-{[(4-溴代-1H-吡唑-3-基)甲基]氨基}乙基)-4-哌啶基](4-氯代苯基)甲酮,3-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-6,7-二甲基-4H-苯并吡喃4-酮,2-{2-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-4-硝基苯氧基}乙酸,(4-氯代苯基)[1-(2-{[(1-甲基-1H-苯并咪唑-2-基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)[1-(2-{[(2,4-二甲氧基-5-嘧啶基)甲基]氨基}乙基)-4-哌啶基]甲酮,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(甲基氨基)苯甲酰胺,4-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲氧基-4-甲基苯甲酰胺,3-氨基-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1,3-苯并二氧杂环戊-5-甲酰胺,4-氨基-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-氟代-4-甲氧基苯甲酰胺,5-溴代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-糠酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲基-2-糠酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4,5-二甲基-2-糠酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-7-乙氧基-1-苯并呋喃-2-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲氧基-1-苯并呋喃-2-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-7-甲氧基-1-苯并呋喃-2-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(4-氟代苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(2-甲氧基苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3-甲基苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(2-甲基苯基)乙酰胺,2-(3-溴代苯基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}乙酰胺,2-(2-氯代苯基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}乙酰胺,2-(4-氯代苯基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-[2-(三氟代甲基)苯基]乙酰胺,2-(3-氯代苯基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3,4-二甲氧基苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(4-甲氧基苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3,4-二氯代苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3-氟代-4-甲氧基苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(4-乙氧基苯基)乙酰胺,2-(1,3-苯并二氧杂环戊-5-基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-[4-(二甲基氨基)苯基]乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(4-甲基苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3,4-二氟代苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3-甲氧基苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-苯基丁酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-苯基丙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-(3-甲氧基苯基)丙酰胺,2-氨基-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1,3-噻唑-4-甲酰胺,2-(乙酰基氨基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1,3-噻唑-4-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(4-吡啶基)-1,3-噻唑-4-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,4-二甲基-1,3-噻唑-5-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,5-二甲基-1,3-噁唑-4-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1H-咪唑-4-甲酰胺,N-{2-[4-(3,4-氯代苯氧基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺,盐酸盐,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2,6-二甲氧基-4-嘧啶胺,N~4~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-N~2~,N~2~-二甲基-2,4-嘧啶二胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-[(甲硫基)甲基]-4-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-(甲硫基)-6-(三氟代甲基)-4-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-5-甲氧基-2-(甲硫基)-4-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-6-甲基-2-(甲硫基)-4-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-5-甲氧基-2-甲基-4-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-(乙硫基)-6-甲基-4-嘧啶胺,N~2~-环丙基-N~4~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2,4-嘧啶二胺,2-{[4-({3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}氨基)-2-嘧啶基]氨基}-1-乙醇,2-[[4-({3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}氨基)-2-嘧啶基](甲基)氨基]-1-乙醇,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-(甲硫基)-4-嘧啶胺,N~4~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-6-甲基-2,4-嘧啶二胺,N~4~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-N~2~,6-二甲基-2,4-嘧啶二胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-苯基-2-嘧啶胺,N~2~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-5-氟代-2,4-嘧啶二胺,N~2~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-N~4~,N~4~,6-三甲基-2,4-嘧啶二胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(三氟代甲基)-2-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(丙硫基)-2-嘧啶胺,N~2~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-N~4~-苯基-2,4-嘧啶二胺,N~2~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-N~4~,6-二甲基-2,4-嘧啶二胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}[1,8]二氮萘-2-胺,2-{[2-({3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}氨基)-4-嘧啶基]氨基}-1-乙醇,2-[[2-({3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}氨基)-4-嘧啶基](甲基)氨基]-1-乙醇,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(3-吡啶基)-2-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(3-噻吩基)-2-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4,6-二甲氧基-2-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(3-呋喃基)-2-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(2-噻吩基)-2-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-1H-嘌呤-6-胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-5-甲基噻吩并[2,3-d]嘧啶-4-胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-7-甲基噻吩并[3,2-d]嘧啶-4-胺,N~7~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-5-甲基[1,3]噻唑并[4,5-d]嘧啶-2,7-二胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-9-甲基-9H-嘌呤-6-胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-吡啶胺,5-氯代-N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-吡啶胺,6-氯代-N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-吡啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-6-甲基-2-吡啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-1,3-苯并噻唑-2-胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-1,3-苯并噁唑-2-胺,6-氯代-N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-吡嗪胺,6-氯代-N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-3-哒嗪胺,6-({3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}氨基)-1,3-二甲基-2,4(1H,3H)-嘧啶二酮,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,6-二甲氧基-4-嘧啶胺,N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N~2~,N~2~-二甲基-2,4-嘧啶二胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-[(甲硫基)甲基]-4-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲氧基-2-(甲硫基)-4-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-6-甲基-2-(甲硫基)-4-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲氧基-2-甲基-4-嘧啶胺,和N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-6-甲基-N~2~-苯基-2,4-嘧啶二胺。
本发明还提供制备式(I)的化合物的方法,该方法包括:(i)当T代表基团C(O)NH时,以下通式的化合物
R1-(Q)m-COL1
(II)其中L1代表离去基团(例如羟基或卤原子例如氯原子)和R1、m和Q如式(I)中所定义,与以下通式的化合物或其酸加成盐(例如三氟乙酸盐)反应,其中n、R2、R3、V、W、X和R4如式(I)中所定义;或(ii)当T代表基团C(O)NH和W代表氮原子时,以下通式的化合物其中R1、m、Q、T、n、R2、R3和V如式(I)中所定义,与以下通式的化合物反应
L2-X-R4 (V)其中L2代表离去基团(例如卤原子)和X和R4如式(I)中所定义;或(iii)当T代表基团NH和m是0时,以下通式的化合物
R1-L3 (VI)其中L3代表离去基团(例如卤原子)和R1如式(I)中所定义,与以上(i)中所定义的式(III)化合物反应;或(iv)当T代表基团NH,和m是1和Q代表C1-C4亚烷基时,以下通式的化合物
R1-(CH2)P-CHO
(VII)其中p是0、1、2或3和R1如式(I)中所定义,与以上(i)中所定义的式(III)化合物反应;或(v)当T代表键和m是0时,以下通式的化合物
R1-(CR2R3)n-L4 (VIII)其中L4代表离去基团如卤原子(例如氯)和n、R1、R2和R3如式(I)中所定义,与以下通式的化合物反应其中W、X和R4如式(I)中所定义;并且任选在(i)、(ii)、(iii)、(iv)或(v)以后,将式(I)的化合物转化成另一种式(I)的化合物和/或形成式(I)化合物的药学上可接受的盐或溶剂化物。
本发明的方法可以在溶剂例如有机溶剂如二甲基甲酰胺或二氯甲烷中,在温度如15℃或以上例如在20-100℃温度范围内方便地进行。
式(X)的化合物,可以通过哌嗪与以下通式的化合物反应制备
H2N-(CR2R3)n-L5
(XI)其中L5代表卤原子如溴原子和n、R2和R3如在式(I)中所定义。
式(XII)的化合物,可以通过4-哌啶醇与通式(XIII)的化合物R4-OH,其中R4如在式(I)中所定义,在偶合剂如偶氮二羧酸二乙酯和三苯膦存在下,在溶剂如苯或四氢呋喃中,在一般为20-30℃范围内的温度下反应制备。
其中W代表基团CH和X代表基团CH(OH)的式(III)的化合物,可以通过用本领域已知的技术,将其中X代表C(O)的相应的式(III)的化合物还原/氢化制备。
其中W代表基团CH和X代表基团NH的式(III)的化合物,可以通过以下通式的化合物其中R4如在式(I)中所定义,与与式(XI)的化合物反应制备。
式(XV)的化合物,可以通过4-哌啶酮与通式(XVI)的化合物R4-NH2,其中R4如在式(I)中所定义,在还原剂如氰基硼氢化钠或硼氢化钠存在下,在溶剂如甲醇或苯中,在一般为20-90℃范围内温度下反应制备。
其中W代表基团CH和X代表基团N(C(C1-C6烷基)的式(III)的化合物,可以通过用本领域常规技术,将其中X代表基团NH的相应的式(III)化合物烷基化制备。
式(IV)的化合物可以通过式(II)的化合物与式(X)的化合物反应制备。
式II、V、VI、VII、VIII、IX、XI、XIII、XIV和XVI的化合物可以购买得到,为文献中众所周知或可以用已知技术容易地制备。
用标准方法可将式(I)的化合物转化成式(I)的其它化合物。例如,通过使其中R1代表烷氧基取代的苯基的式(I)化合物与三溴化硼在溶剂如二氯甲烷中反应,可以将其转化成其中R1代表羟基取代的苯基的式(I)化合物。另外,通过使其中X代表C(O)的式(I)的化合物与三乙基硅烷和三氟乙酸在溶剂如二氯甲烷中反应,可以将其转化成其中X代表CH(OH)的式(I)的化合物。
本领域技术人员可以理解在本发明的方法中,某些官能基团例如在起始反应物或中间体化合物中的羟基或氨基可能需要用保护基来保护。因此,在制备式(I)的化合物的过程中,在合适的阶段可能涉及除去一个或多个保护基团。
在由J.W.F.McOmie编辑的“有机化学中的保护基”Plenum Press(1973)和“有机合成中的保护基”第二版,T.W.Greene和P.G.M.Wuts,Wiley-Interscience(1991)中说明了官能基团的保护和脱保护。
以上式(I)的化合物可以转化成其药学上可接受的盐或溶剂化物,特别是酸加成盐如盐酸盐、氢溴酸盐、磷酸盐、乙酸盐、延胡索酸盐、马来酸盐、酒石酸盐。柠檬酸盐、草酸盐、甲磺酸盐或对-甲苯磺酸盐。
某些式(I)的化合物能够以立体异构形式存在。本发明包括所有式(I)化合物的几何和光学异构体和其包括外消旋物的混合物的用途是可以理解的。互变异构体及其混合物的用途也形成本发明的一个方面的内容。
式(I)的化合物具有作为药物的活性,特别是作为趋化因子受体(特别是CCR1和/或CCR3)活性的调制剂,并且可以用于治疗自身免疫、炎症、增生性和过度增生性疾病和免疫-调节疾病包括器官或组织移植的排斥反应和获得性免疫缺陷综合征(AIDS)。
这些疾病的实例是;(1)(呼吸道)阻塞性气道疾病包括慢性阻塞性肺疾病(COPD)例如不可逆的COPD;哮喘如支气管、变应性、内源性、外源性和尘埃性哮喘,特别是慢性或慢性顽固性哮喘(例如晚期哮喘和气道过度应答);支气管炎;急性、变应性、萎缩性鼻炎和慢性鼻炎包括干酪性鼻炎、肥厚性鼻炎、脓性鼻炎、干性鼻炎和药物性鼻炎;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以及腺病性鼻炎、季节性鼻炎包括神经性鼻炎(枯草热)和血管舒缩性鼻炎;结节病、农民肺和有关的疾病、纤维样肺和特发间质性肺炎;(2)(骨和关节)类风湿性关节炎、血清阴性脊椎关节炎(包括关节强硬性脊椎炎、银屑病关节炎和赖特病)、贝赫切特病、斯耶格伦综合征和全身性硬化症;(3)(皮肤)银屑病、特应性皮炎、接触性皮炎和其它湿疹性皮炎、脂溢性皮炎、扁平苔藓、天疱疮、大疱性类天疱疮、大疱性表皮松解、荨麻疹、皮肤血管炎(angiodermas)、脉管炎(vasculitides)、红斑、皮肤嗜酸粒细胞增多、葡萄膜炎、簇状脱发和春季结膜炎;(4)(胃肠道)腹腔疾病、直肠炎、嗜酸粒细胞增多胃肠炎、肥大细胞增生病,局限性回肠炎、溃疡性结肠炎、食物有关的变态反应,其可以具有远离肠的影响例如偏头痛、鼻炎和湿疹;(5)(其它组织和系统疾病)多发性硬化、动脉粥样硬化、获得性免疫缺陷综合症(AIDS)、红斑狼疮、系统性红斑狼疮、erythematosus、桥本甲状腺炎、重症肌无力、I型糖尿病、肾病综合症、嗜酸性粒细胞增多筋膜炎、高IgE综合症、瘤型麻风、赛塞利综合症和特发性血小板减少紫癜;和(6)(同种移植物排斥反应)例如肾、心、肝、肺、骨髓、皮肤和角膜移植后的急性或慢性同种移植物排斥反应;和慢性移植物对抗宿主的疾病。
因此,本发明提供如此前所定义用在治疗中的式(I)的化合物或其药学上可接受的盐或溶剂化物。
在另一方面,本发明提供如此前所定义的式(I)化合物或其药学上可接受的盐或溶剂化物在制备用于治疗的药物中的用途。
除了有相反的特别说明外,在本说明书上下文中,术语“治疗”也包括“预防”。术语“治疗的”和“治疗上”也作相应解释。
本发明也提供在患有或有患炎性疾病危险的病人中,治疗炎性疾病的方法,该方法包括给予病人治疗有效量的如上所定义的式(I)的化合物或其药学上可接受的盐或溶剂化物。
当然,对于以上所述治疗用途而言,剂量将根据所使用的化合物、给药的方式、治疗的要求和所针对疾病而变化。
式(I)的化合物和其药学上可接受的盐和溶剂化物可以以其本身使用,但一般以药用组合物的形式给药,在药用组合物中式(I)的化合物/盐/溶剂化物(活性成分)与药学上可接受的辅助剂、稀释剂或载体组合。根据给药的方式,药用组合物优选包含0.05-99%重量,更优选0.05-80%重量,更加优选0.10-70%重量,甚至更优选0.10-50%重量的活性成分,所有的重量比例都基于总的组合物。
本发明也提供含有如上所定义的式(I)化合物或其药学上可接受的盐或溶剂化物以及药学上可接受的辅助剂、稀释剂或载体的药用组合物。
本发明另外提供本发明的药用组合物的制备方法,该方法包括将如上所定义的式(I)的化合物或其药学上可接受的盐或溶剂化物与药学上可接受的辅助剂、稀释剂或载体混合。
所述药用组合物一般可以以溶液、悬浮液、七氟代烷气溶胶和干粉制剂的形式局部给药(例如给予肺和/或气道或给予皮肤);或系统性例如以片剂、胶囊、糖浆、散剂或颗粒剂形式经口服给药,或以溶液或悬浮液形式经胃肠外给药,或经皮下给药或以栓剂形式直肠给药或经皮给药。
现在通过参考以下说明性的实施例进一步解释本发明。
实施例14-氯代-N-{2-[4-(3,4-二氯代苯基)-1-哌啶基]乙基}-2-[2-(二甲基氨基)-2-氧代乙氧基]苯甲酰胺(i)4-(3,4-二氯代苯氧基)-1-哌啶羧酸叔丁基酯
在0℃下,将偶氮二羧酸二乙酯(12.6ml)加入到三苯膦(20.8g)的四氢呋喃(300ml)中的溶液中。15分钟后,加入3,4-二氯苯酚(12.9g),再过10分钟后,用0.5小时滴加入4-羟基-1-哌啶羧酸叔丁酯(14.5g)的四氢呋喃(100ml)溶液。将该溶液在室温下搅拌5小时并浓缩成小容积。将残余物分配在醚和盐水之间。分离有机层,干燥并蒸发成树胶状物。经层析(乙酸乙酯∶异己烷95∶5)纯化,得到小标题产物为油状物(20g)。MS:APCI(+ve):246(M-BOC+2H)(ii)4-(3,4-二氯代苯氧基)哌啶
将来自步骤(i)的产物溶于二氯甲烷(200ml)中并加入三氟乙酸(100ml)。18小时后,在室温下将该溶液蒸发并将生成的树胶状物在乙醚中研磨,得到小标题产物为固体(16.2g)。(iii)2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基氨基甲酸叔丁基酯
将来自步骤(ii)的产物(6.55g)溶于DMF(50ml)中并加入三乙胺(7.9ml)。加入2-溴代乙基氨基甲酸叔丁酯(4.3g)的DMF(5ml)溶液并将该溶液在室温下搅拌3天。加入乙酸乙酯和水,分离有机相,干燥并蒸发成树胶状物。经层析(二氯甲烷∶甲醇95∶5)纯化,得到小标题产物,为树胶状物(5.7g)。MS:APCI(+ve):389(M+H)(iv)2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙胺三氟乙酸盐
将来自步骤(iii)的产物溶于二氯甲烷(200ml)中并加入三氟乙酸(100ml)。18小时后,在室温下蒸发溶剂并将生成的树胶状物在乙醚中研磨,得到小标题产物为固体(5.7g)。MS:APCI(+ve):290(M+H)(v)2-(二甲基氨基)-2-氧代乙基4-氯代-2-[2-(二甲基氨基)-2-氧代乙氧基]苯甲酸酯
将4-氯代-2-羟基苯甲酸(5g)、Cs2CO3(17.5g)和2-氯代-N,N-二甲基乙酰胺(6.6g)的混合物搅拌并在70℃下加热3小时。加入水和乙酸乙酯,分离有机相,干燥并浓缩成树胶状物,将其经层析(乙酸乙酯∶甲醇,9∶1)纯化,得到小标题产物为固体(8.0g)。MS:APCI(+ve):343(M+H)熔点:140-141℃(vi)4-氯代-2-[2-(二甲基氨基)-2-氧代乙氧基]苯甲酸
将来自步骤(v)的产物(1.0g)溶于2∶1水∶甲醇的混合物(15ml)中并加入LiOH.H2O。2小时后,加入2M HCl水溶液和乙酸乙酯,分离有机相,干燥并浓缩,得到小标题产物为固体(1.2g)。MS:APCI(+ve):258(M+H)熔点:141-142℃(vii)4-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-[2-(二甲基氨基)-2-氧代乙氧基]苯甲酰胺
将来自步骤(vi)的产物(0.3g)和N,N-羰基二咪唑(0.19g)溶于DMF(20ml)中并在室温下将该溶液搅拌1小时。加入来自步骤(iv)的产物(0.42g)和三乙胺(0.32ml)。20小时后加入水和乙醚,分离有机相,干燥并浓缩成树胶状物,将其经层析(二氯甲烷∶甲醇,93∶7)纯化,得到标题产物为固体(0.38g)。MS:ESI 528.12(M+H)1H NMR:δ(DMSO)9.17(t,1H),7.88(d,1H),7.48(d,1H),7.38(d,1H),7.24(d,1H),7.13(dd,1H),6.99(dd,1H),5.11(s,2H),4.32(m,1H),3.42(m,2H),2.99(s,3H),2.88(s,3H),2.73(m,2H),2.50(m,2H),2.30(m,2H),1.90(m,2H),1.59(m,2H)。熔点:139-40℃
将来自实施例1步骤(iv)的产物(0.4g)溶于DMF(10ml)中,加入PyBrop(0.541g)、3-乙氧基苯甲酸(0.167g)和N,N-二-异丙基乙胺(0.5g)。在室温下18小时后,加入氯仿和NaHCO3水溶液。分离有机相,干燥并浓缩剩下树胶状物,将其经层析(乙酸乙酯∶甲醇97∶3)纯化,得到油状物。经加入1.0M乙醚的氯化氢溶液,得到标题产物为固体(0.14g)。MS:ESI 437.14(M+H)1H NMR:δ(DMSO)8.87(bs,1H),7.50(m,3H),7.40(m,2H),7.06(m,2H),4.83/4.62(m,1H),4.08(q,2H),3.67(m,3H),3.47(m,1H),3.17(m,3H),2.20(m,2H),2.03(m,2H),1.34(t,3H)。熔点:191-193℃
实施例3N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-异丙氧基苯甲酰胺
用4-异丙氧基苯甲酸,不加入1.0M乙醚的氯化氢溶液,通过如实施例2相同的方法制备,得到标题产物为固体(0.12g)。MS:ESI 451.14(M+H)1H NMR:δ(DMSO)8.22(t,1H),7.8(m,2H),7.49(d,1H),7.25(d,1H),7.00(m,3H),4.7(m,1H),4.45(m,1H),3.36(m,2H),2.73(m,2H),2.48(m,2H),2.29(m,2H),1.91(m,2H),1.60(m,2H),1.28(s,3H),1.27(s,3H)。熔点:113-15℃
实施例4N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-乙氧基苯甲酰胺
用4-乙氧基苯甲酸,不加入1.0M乙醚的氯化氢溶液,通过如实施例2相同的方法制备,得到标题产物为固体(0.1g)。MS:ESI 437.14(M+H)1H NMR:δ(DMSO)8.22(t,1H),7.79(d,2H),7.49(d,1H),7.25(d,1H),7.00(m,3H),4.5(m,1H),4.07(q,2H),3.37(q,2H),2.73(m,2H),2.47(m,2H),2.30(m,2H),1.91(m,2H),1.60(m,2H),1.34(t,3H)。熔点:118-20℃实施例5N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-(三氟代甲氧基)苯甲酰胺盐酸盐
用3-三氟代甲氧基苯甲酸,通过如实施例2相同的方法制备,得到标题产物为固体(0.12g)。MS:ESI 477.09(M+H)1H NMR:δ(DMSO)10.42(bs,1H),9.11(bm,1H),8.0(d,1H),7.88(s,1H),7.6(m,3H),7.37(m,1H),7.06(m,1H),4.70(m,1H),3.71(m,3H),3.48(d,1H),3.20(m,4H),2.2(m,4H)。熔点:180-82℃
用4-甲氧基苯甲酸,未加入1.0M乙醚的氯化氢溶液,通过如实施例2相同的方法制备,得到标题产物为固体(0.11g)。MS:ESI 423.12(M+H)1H NMR:δ(DMSO)8.42(t,1H),7.81(m,2H),7.49(d,1H),7.25(d,1H),6.98(s,3H),4.4(m,1H),3.8(s,3H),3.35(q,2H),2.73(m,2H),2.47(m,2H),2.30(m,2H),1.91(m,2H),1.60(m,2H)。熔点:110-12℃实施例7N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(三氟代甲氧基)苯甲酰胺盐酸盐
用4-三氟代甲氧基苯甲酸,通过如实施例2相同的方法制备,得到标题产物为固体(0.19g)。MS:ESI 477(M+H)1H NMR:δ(DMSO)10.5(bs,1H),9.06(m,1H),8.07(dd,2H),7.55(t,1H),7.49(d,2H),7.36(dd,1H),7.10-7.02(m,1H),4.72(m,1H),3.70(m,3H),3.47(d,1H),3.14(m,2H),2.25(m,2H),2.02(m,2H)。熔点:184-187℃
实施例8N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-糠酰胺盐酸盐
用呋喃-2-羧酸,通过如实施例2相同的方法制备,得到标题产物为固体(0.14g)。MS:ESI 383.09(M+H)1H NMR:δ(DMSO)10.43(bm,1H),8.76(t,1H),7.87(s,1H),7.55(t,1H),7.36(dd,1H),7.21(d,1H),7.06(m,1H),6.64(dd,1H),4.83-4.61(m,1H),3.65(m,3H),3.45(d,1H),3.08(m,4H),2.1(m,4H)。熔点:225-28℃实施例9N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-苯基乙酰胺盐酸盐
用苯乙酸,通过如实施例2相同的方法制备,得到标题产物为固体(0.12g)。MS:ESI 407(M+H)1H NMR:δ(DMSO)10.28(bm,1H),8.46(bm,1H),7.56(t,1H),7.3(m,6H),7.10(m,1H),4.81/4.58(m,1H),3.58(d,1H),3.46(m,4H),3.10(m,4H),2.15(m,5H)。熔点:135-38℃
将实施例1步骤(iv)的产物(2.0g)溶于二氯甲烷(490ml)中,加入三乙胺(1.85ml)和3-甲氧基苯甲酰氯(0.66g)。在室温下72小时后,加入水,分离有机相,干燥并浓缩成树胶状物。将该产物溶于二氯甲烷中并用1.0M乙醚的氯化氢溶液处理,得到标题产物为固体(0.88g)。MS:ESI 423.12(M+H)1H NMR:δ(DMSO)10.6-10.5(m,1H),9.92(s,1H),7.54(m,3H),7.38(m,2H),7.08(m,2H),4.84/4.62(m,1H),3.82(s,3H),3.45(m,8H),2.27(m,4H)。熔点:72-73℃实施例113-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺盐酸盐
将实施例1步骤(iv)的产物(0.15g)溶于DMF(3ml)中,加入N,N-二-异丙基乙胺(0.3ml)和3-氯代苯甲酰氯(0.054ml)。在室温下2小时后,加入水和乙酸乙酯,分离有机相,干燥并浓缩。将残余物经层析(二氯甲烷∶甲醇,95∶5)纯化,得到油状物,将其溶于乙醚中并加入1.0M乙醚的氯化氢溶液,得到标题产物为固体(0.12g)。MS:ESI 427.07(M+H)1H NMR:δ(DMSO)8.42(t,1H),7.94-7.84(m,2H),7.49(d,1H),7.29(m,3H),6.98(dd,1H),4.44(m,1H),3.36(m,2H),2.74(m,2H),2.48(m,2H),2.29(bt,2H),1.92(m,2H),1.60(m,2H)。熔点:118℃
用4-氟代苯甲酰氯,未加入1.0M的乙醚的氯化氢溶液,通过如实施例11相同的方法制备,得到标题产物为固体(0.1g)。MS:ESI 411.10(M+H)1H NMR:δ(DMSO)10.46(bs,1H),9.04(s,1H),7.98(s,1H),7.90(d,1H),7.58(m,3H),7.36(dd,1H),7.05(m,1H),4.84/4.60(m,1H),3.69(m,3H),3.48(bd,1H),3.20(m,4H),2.15(m,4H)。熔点:192℃实施例13N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-氟代苯甲酰胺盐酸盐
用3-氟代苯甲酰氯,通过如实施例11相同的方法制备,得到标题产物为固体(0.09g)。MS:ESI 411.10(M+H)1H NMR:δ(DMSO)10.67(bs,1H),9.06(s,1H),7.80(m,2H),7.55(m,2H),7.40(m,2H),7.05(m,1H),4.84/4.63(m,1H),3.70(m,3H),3.28(m,3H),2.20(m,4H)。熔点:225℃
将实施例10的产物(0.15g)溶于二氯甲烷(10ml)中并加入1.0MBBr3的二氯甲烷溶液(4ml)。在室温下16小时后,经蒸发除去溶剂,加入甲醇并将该溶液浓缩。将残余物溶于2MHCl水溶液中,浓缩至干燥并将残余物在乙醚中研磨,得到标题产物为固体(0.1g)。MS:ESI 409.10(M+H)1H NMR:δ(DMSO)9.98-9.4(bs,2H),8.71(t,1H),7.6(dd,1H),7.4-7.2(m,4H),7.05(m,1H),6.95(dd,1H),4.65(m,1H),3.40(m,8H),2.0(m,4H)。熔点:83-4℃实施例15N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-[2-(甲基氨基)-2-氧代乙氧基]苯甲酰胺盐酸盐(i)[1-(2-氨基乙基)-4-哌啶基](4-氯代苯基)甲酮三氟乙酸盐
向(4-氯代苯基)(4-哌啶基)甲酮盐酸盐(2.5g)和2-溴代乙基氨基甲酸叔丁酯(2.1g)的DMF溶液中加入三乙胺(2.9g),在室温下72小时后,加入水和乙醚。分离有机相,干燥并浓缩。将残余物溶于二氯甲烷(40ml)中,加入三氟乙酸(10ml)并将该溶液放置20小时。蒸发溶剂得到粘性的固体状物,将其在乙醚中研磨,得到小标题产物为固体(2.5g)。(ii)N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺盐酸盐
将步骤(i)的产物(2.5g)溶于二氯甲烷(20ml)中,加入三乙胺(0.75ml)和3-甲氧基苯甲酰氯(0.276g)。16小时后,加入水,分离有机相,干燥并浓缩成树胶状物。将其经层析(乙酸乙酯)纯化得到树胶状物,将其用1.0M乙醚的氯化氢溶液处理,得到小标题产物为固体(0.3g)。MS:ESI 401.16(M+H)1H NMR:δ(DMSO)10.3(bm,1H),8.95(t,1H),8.0(m,2H),7.6(m,2H),7.5(m,2H),7.4(t,1H),7.05(m,1H),3.8(s,3H),3.68(m,4H),3.28(m,5H),2.0(m,4H)。熔点:196-7℃(iii)N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-羟基苯甲酰胺盐酸盐
用以上步骤(ii)的产物(0.24g),通过实施例14的方法制备,得到小标题产物为固体(0.20g)。MS:ESI 387.14(M+H)1H NMR:δ(DMSO)8.62(t,1H),8.05(dd,2H),7.6(dd,2H),7.25(m,3H),6.95(m,1H),4.26(m,9H),2.0(m,4H)。熔点:90-91℃(iv)N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-[2-(甲基氨基)-2-氧代乙氧基]苯甲酰胺盐酸盐
将以上步骤(iii)的产物(0.10g)溶于DMF(3ml)中,加入Cs2CO3(0.23g)和2-氯代-N-甲基乙酰胺(0.26g)并将该混合物在80℃下加热16小时。将混合物冷却至室温,加入水和乙酸乙酯并分离有机相。蒸发溶剂得到树胶状物,将其用1.0M乙醚的氯化氢溶液处理,得到标题产物为固体(0.05g)。MS:ESI 458.18(M+H)1H NMR:δ(DMSO)10.6-10.2(bm,1H),8.95(bm,1H),8.1(m,2H),7.55(m,8H),7.14(bd,1H),4.54(s,2H),4.0(m,1H),3.4(m,8H),2.65(d,3H),2.0(m,4H)。熔点:69-70℃
将3-{2-[4-(4-氟代苯甲酰基)-1-哌啶基]乙基}-2,4(1H,3H)-喹唑啉二酮溶于DMF(5ml)中并加入NaH(60%在矿物油中的分散液)。0.5小时后,加入2-氯代-N,N-二甲基乙酰胺并将该溶液在室温下搅拌16小时。加入水和乙酸乙酯,分离有机相,干燥并浓缩成油状物。经层析(二氯甲烷∶甲醇95∶5)纯化得到油状物,将其用1.0M乙醚的氯化氢溶液处理,得到标题产物为固体(0.015g)。MS:ESI 481.22(M+H)1H NMR:δ(DMSO)8.08(m,3H),7.76(t,1H),7.40(t,2H),7.32(m,2H),5.05(s,2H),4.36(m,1H),3.76(m,3H),3.39(m,2H),3.15(s,3H),2.87(s,3H),2.02(m,2H),1.81(m,2H),1.28(m,2H)。熔点:245-246℃
将苯甲醛(21g)和1-(2-氨基乙基)哌嗪(25.8g)的混合物在Dean和Stark脱水器中搅拌并加热20小时。将冷却的溶液分批用二碳酸二-叔-丁基酯(48g)处理,搅拌72小时并浓缩。将残余物用1M KHSO4水溶液(220ml)处理,搅拌24小时,加入乙醚并分离有机相。用2MNaOH溶液处理含水相,加入二氯甲烷并分离有机相。用盐水洗涤合并的有机相,干燥并浓缩,得到小标题产物为油状物(30g)。MS:APCI(+ve)230(M+H)1H NMR:δ(CDCl3)3.43(t,4H),2.8(t,2H),2.45(m,6H),1.5(s,9H)。(ii)2-[4-(3,4-二氯代苯甲酰基)-1-哌嗪基]乙基氨基甲酸叔丁酯
将来自以上步骤(i)的产物(3g)溶于吡啶(12m1)中,加入3,4-二氯代苯甲酰氯(2.05g)并将该混合物在室温下搅拌18小时。经过滤收集固体并经层析(二氯甲烷∶甲醇∶0.880 NH4OH,90∶9∶1)纯化,得到小标题产物为油状物(3.59g)。MS:APCI(+ve)364(M+H)1H NMR:δ(CDCl3)7.33(m,3H),7.04(m,1H),6 76(bs,1H),3.86(s,3H),3.55(q,2H),3.45(t,4H),2.61(t,3H),2.46(t,4H),1.46(s,9H)。(iii)[4-(2-氨基乙基)-1-哌嗪基](3,4-二氯代苯基)甲酮三氟代乙酸盐
将来自以上步骤(ii)的产物(3.3g)溶于二氯甲烷(50ml)中并加入三氟乙酸(10ml)。在室温下16小时后,除去溶剂,得到小标题产物为油状物(5.9g)。MS:APCI(+ve)264(M+H)(iv)N-{2-[4-(3,4-二氯代苯甲酰基)-1-哌嗪基]乙基}-3-甲氧基苯甲酰胺盐酸盐
将来自以上步骤(iii)的产物(0.15g)溶于吡啶(2ml)中并加入3-甲氧基苯甲酰氯(0.064g)。在室温下16小时后,加入水和乙酸乙酯,分离有机相,干燥并浓缩成油状物。经层析(二氯甲烷∶甲醇,95∶5)纯化,得到油状物,将其用1.0乙醚的氯化氢溶液处理,得到标题产物为固体(0.043g)。MS:ESI 436.12(M+H)1H NMR:δ(DMSO)8.8(bt,1H),7.34(m,2H),7.43(m,4H),7.14(m,1H),3.82(s,3H),3.48(m,12H)。熔点:230℃实施例183,4-二氯代-N-{2-[4-(3,4-二氯代苯甲酰基)-1-哌嗪基]乙基}苯甲酰胺
将苯甲醛(5.3g)和1-(2-氨基哌嗪)(6.45g)的甲苯(100ml)溶液在Dean和Stark脱水器中加热4小时。将该溶液冷却至室温并加入三乙胺(5.05g)。滴加入3,4-二氯代苯甲酰氯(10.48g)的甲苯(50ml)溶液,将该溶液在室温下搅拌18小时并加入水。分离有机相,干燥并浓缩成残余物,将其用1N KHSO4水溶液(65ml)处理。将该混合物剧烈搅拌4小时,加入乙醚,分离含水相并加入NaOH。加入CHCl3,分离有机相,干燥并浓缩成树胶状物。经层析(二氯甲烷∶三乙胺,95∶5)纯化,得到标题产物为泡沫状物(0.25g)。MS:ESI 474.03(M+H)1H NMR:δ(DMSO)8.8(bt,1H),7.34(m,2H),7.43(m,4H),7.14(m,1H),3.82(s,3H),3.48(m,12H)。
将实施例26步骤(ii)的产物(0.3g)、3,4-二氯代苯甲酰氯(0.1g)和三乙胺(0.15g)溶于二氯甲烷(15ml)中。在室温下20小时后,加入水,分离有机相,干燥并蒸发得到树胶状物。经层析(二氯甲烷∶甲醇,20∶1)纯化,得到固体,将其用1.0M乙醚的氯化氢溶液处理,得到标题产物为固体(0.1g)。MS:ESI 541.11(M+H)1H NMR:δ(DMSO-D6)9.54(t,1H),7.91(d,1H),7.74(m,2H),7.43(m,2H),7.18(d,1H),5.12(s,2H),3.2-3.8(m,12H),2.99(s,3H),2.88(s,3H)。熔点:226-7℃
实施例20N~7~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲基[1,3]噻唑并[4,5-d]嘧啶-2,7-二胺MS:APCI(+ve)453(M+1)
实施例21N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-9-甲基-9H-嘌呤-6-胺MS:APCI(+ve)421(M+1)实施例22N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1,3-苯并噻唑-2-胺MS:APCI(+ve)422(M+1)
实施例23N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1,3-苯并噁唑-2-胺MS:APCI(+ve)406(M+1)实施例246-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-吡嗪胺MS:APCI(+ve)403(M+1)
实施例256-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-哒嗪胺MS:APCI(+ve)403(M+1)实施例266-({2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}氨基)-1,3-二甲基-2,4(1H,3H)-嘧啶二酮MS:APCI(+ve)427(M+1)
实施例27N-{1[4-(3,4-二氯代苯氧基)-哌啶-1-基甲基]-2-甲基-丙基}-4-甲基-苯甲酰胺,盐酸盐(i)N-{1[4-(3,4-二氯代苯氧基)-哌啶-1-羰基]-2-甲基-丙基}-乙酰胺
将N-Boc缬氨酸(1.13g)溶于二氯甲烷(5ml)中并加入EDC(0.99g),5分钟后,一次性加入根据实施例1步骤(ii)的产物(1.44g)的二氯甲烷(5ml)溶液。在室温下3小时后,加入碳酸氢钠水溶液和乙酸乙酯。分离有机相并除去溶剂,得到小标题化合物为油状物(1.57g),其没有进一步纯化而在下一步中使用。(ii)2-氨基-1-[4-(3,4-二氯代苯氧基)-哌啶-1-基]-3-甲基-丁-1-酮
将步骤(i)的产物(1.57g)溶于二氯甲烷(14ml)中并加入三氟乙酸(4ml)。在室温下2小时后,将溶剂除去,加入乙酸乙酯和2NNaOH水溶液使pH为8.0。分离有机相并浓缩得到小标题产物为油状物(1.24g),其没有进一步纯化而在下一步使用。(iii)1-[4-(3,4-二氯代苯氧基)-哌啶-1-基甲基]-2-甲基-丙胺
将步骤(ii)的产物(1.12g)溶于THF(10ml)中并加入硼烷/THF复合物(22.7ml)。将该混合物在回流下加热2小时并冷却。蒸发溶剂,将产物溶于甲醇(5ml)中并加入50%HCl水溶液。将混合物加热至70℃达1小时并冷却至室温。除去溶剂,加入乙酸乙酯和2NNaOH水溶液使pH为9.0。分离有机层并蒸发溶剂,得到小标题化合物为油状物(0.98g),其没有进一步纯化而使用。(iv)N{1-[4-(3,4-二氯代苯氧基)-哌啶-1-基甲基]-2-甲基-丙基}-4-甲基-苯甲酰胺,盐酸盐
将步骤(iii)的产物(0.2g)溶于二氯甲烷(5ml)中,加入三乙胺(0.126ml)和4-甲基苯甲酰氯(0.097ml)。在室温下2小时后,加入乙酸乙酯和NaHCO3水溶液,分离有机层并除去溶剂剩下油状物。经反相HPLC(用梯度洗脱剂系统(25%MeCN/NH4OAc水溶液(0.1%)到95%MeCN/NH4OAc水溶液(0.1%)))纯化,得到树胶状物。加入1.0M乙醚的氯化氢溶液得到标题产物,为固体(0.104g)。熔点:131-132℃MS:ESI 450(M+H)1H NMR:δ(DMSO)8.45(t,1H),7.00-7.90(m,7H),4.79(br s,1H),4.24-4.30(m,1H),3.10-3.42(m,5H),2.36(s,3H),1.88-2.40(m,5H),0.92(t,6H)。实施例28N-{1-[4-(3,4-二氯代苯氧基)-哌啶-1-基甲基]-2-甲基-丙基}-3-甲氧基-苯甲酰胺,盐酸盐
将根据实施例27步骤(iii)的产物溶于二氯甲烷(4ml)中,加入三乙胺(0.090ml)和3-甲氧基苯甲酰氯(0.077ml)。在室温下2小时后,加入NaHCO3,将该产物用乙酸乙酯萃取,用Na2SO4干燥合并的有机萃取液并浓缩。用反相HPLC(用梯度洗脱剂系统(25%MeCN/NH4OAc水溶液(0.1%)到95%MeCN/NH4OAc水溶液(0.1%))纯化,得到树胶状物。将产物溶于甲醇中并用1.0M乙醚的氯化氢溶液处理,得到标题产物为固体(0.045g)。MS:ESI 465(M+H)1H NMR:δ(DMSO)8.58-8.63(m,1H),7.01-7.58(m,6H),4.80(brs,1H),4.23-4.59(m,1H),3.83(s,3H),3.04-3.60(m,4H),1.89-2.14(m,5H),0.85(m,6H)。
将3,4-二氯代苯胺(5g)、N-叔-丁氧基羰基-4-哌啶酮(11.7g)、三乙酰氧基硼氢化钠(19.7g)和乙酸(7ml)的二氯甲烷(150ml)中的溶液搅拌16小时。加入2M MaOH溶液和乙醚,分离有机相,干燥并浓缩。将残余物在异己烷∶乙酸乙酯,4∶1混合物下研磨,收集小标题产物为固体(7.25g)。MS:APCI(+ve)345(M+H)1H NMR:δ(DMSO)7.23(d,1H),6.77(d,1H),6.57(dd,1H),5.99(d,1H),3.85(bd,2H),3.40(m,1H),2.90(bm,2H),1.85(m,2H),1.39(s,9H),1.19(m,2H)。(ii)N-(3,4-二氯代苯基)-4-哌啶胺三氟乙酸盐
将以上步骤(i)的产物(6.5g)溶于二氯甲烷(75ml)中并加入三氟乙酸(25ml)。在室温下72小时后,蒸发该溶液并将残余物在乙醚中研磨,得到小标题产物为固体(6.3g)。MS:APCI(+ve)245/7(M+H)1H NMR:δ(DMSO)8.65(bs,1H),8.50(bs,1H),7.26(d,1H),6.81(d,1H),6.60(dd,1H),6.19(bs,1H),3.53(bs,1H),3.30(m,2H),3.0(m,2H),2.02(m,2H),1.50(m,2H)。(iii)2-[4-(3,4-二氯代苯胺基)-1-哌啶基]乙基氨基甲酸叔丁酯
将来自以上步骤(ii)的产物(2.0g)、N-叔-丁氧基羰基-2-溴代乙胺(1.0g)和N,N-二-异丙基乙胺(3.7ml)溶于DMF(25ml)中并搅拌16小时。加入水和乙酸乙酯,分离有机相,干燥并蒸发得到树胶状物。经层析(二氯甲烷∶甲醇95∶5)纯化,得到小标题产物为固体(1.25g)。MS:APCI(+ve)388/90(M+H)1H NMR:δ(DMSO)7.22(d,1H),6.73(d,1H),6.62(t,1H),6.54(dd,1H),5.94(d,1H),3.17(m,1H),3.02(m,2H),2.77(bd,2H),2.31(t,3H),2.06(t,2H),1.84(bd,2H),1.35(m,11H)。(iv)1-(2-氨基乙基)-N-(3,4-二氯代苯基)-4-哌啶胺三氟乙酸盐
将来自以上步骤(iii)的产物(1.2g)溶于二氯甲烷(30ml)中并加入三氟乙酸(10ml)。在室温下27小时后,蒸发反应混合物并将残余物在乙醚中研磨,得到小标题产物为固体(1.6g)。MS:APCI(+ve)288/90(M+H)(v)N-{2-[4-(3,4-二氯代苯胺基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺二盐酸盐
将以上步骤(iv)的产物(0.5g)和三乙胺(1.1ml)溶于DMF(10ml)中,滴加入3-甲氧基苯甲酰氯(0.11ml)。2小时后,加入水和乙酸乙酯,分离有机相,干燥并蒸发。将残余物经层析(二氯甲烷∶甲醇,95∶5)纯化,得到油状物,将其用1.0M乙醚的氯化氢溶液处理,得到标题产物为固体(0.15g)。MS:ESI 422.14(M+H)1H NMR:δ(DMSO)10.44(bs,1H),8.93(t,1H),7.51(m,2H),7.40(t,1H),7.26(d,1H),7.1 1(dd,1H),6.81(d,1H),6.60(dd,1H),3.82(s,3H),2.68(m,4H),3.25(m,5H),2.09(bd,2H),1.76(m,2H)。熔点:170℃
将实施例1步骤(iv)的产物(0.11g)在DMF(1.5ml)和1,2-二氯乙烷(3ml)的混合物中的悬浮液在氮气氛下搅拌。加入三乙酰氧基硼氢化钠(0.097g)、3-甲氧基苯甲醛(0.041g)和三乙胺(0.046g)并将混合物在室温下搅拌18小时。加入氯仿和NaHCO3水溶液,分离有机相,干燥并浓缩成树胶状物。经层析(氯仿∶三乙胺∶甲醇,89∶10∶1)纯化得到油状物,将其用1.0M乙醚的氯化氢溶液处理,得到标题产物为固体(0.067g)。MS:ESI 409.14(M+H)1H NMR:δ(DMSO)7.50(d,1H),7.30(m,3H),7.12(d,1H),7.03(dd,1H),6.97(dd 1H),4.71(bm,1H),4.18(s,2H),3.80(s,3H),3.45(bm,4H),2.23(m,6H),2.04(m,2H)。熔点:247-51℃
实施例313-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-6-甲氧基-2,4(1H,3H)-喹唑啉二酮(i)2-氨基-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲氧基苯甲酰胺
用来自实施例1步骤(iv)的产物(1.0g)和2-氨基-5-甲氧基苯甲酸(0.418g),没有加入1.0M乙醚的氯化氢溶液,通过实施例2的方法制备得到油状物,将其经层析(二氯甲烷∶甲醇,95∶5)纯化,得到小标题产物为油状物(0.82g)。MS:APCI(+ve)438(M+H)(ii)3-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-6-甲氧基-2,4(1H,3H)-喹唑啉二酮
将以上步骤(i)的产物溶于甲苯(10ml)中。加入光气的2.0M甲苯溶液(10ml),将该溶液在回流下加热1小时并冷却。加入乙酸乙酯和NaHCO3水溶液,分离有机相,干燥并浓缩剩下残余物,将其经层析(二氯甲烷∶甲醇,95∶5)纯化。得到标题产物为固体(0.11g)。MS:ESI 464.11(M+H)1H NMR:δ(DMSO)7.49(dd,1H),7.36(d,1H),7.30(dd,1H),7.24(d,1H),6.98(dd 1H),4.44(m,1H),4.03(t,3H),3.80(s,3H),2.76(m,2H),2.32(m,2H),1.89(m,2H),1.57(m,2H)熔点:190℃
以下实施例32-125的化合物通过与实施例10类似的方法制备。
实施例32N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-氟代苯甲酰胺MS:APCI(+ve)BP 411
实施例37N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺MS:APCI(+ve)BP 423实施例38N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-硝基苯甲酰胺MS:APCI(+ve)BP 438
实施例40N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-(三氟代甲基)苯甲酰胺MS:APCI(+ve)BP 461实施例41N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3,5-二硝基苯甲酰胺MS:APCI(+ve)BP 483
实施例434-氰基-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺MS:APCI(+ve)BP 418实施例444-溴代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺MS:APCI(+ve)BP 473
实施例46N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-硝基苯甲酰胺MS:APCI(+ve)BP 438实施例473-溴代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺MS:APCI(+ve)BP 473
实施例483,4-二氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺MS:APCI(+ve)BP 463
实施例49N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-氟代苯甲酰胺MS:APCI(+ve)BP 411实施例502,4-二氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺MS:APCI(+ve)BP 463
实施例51N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲基苯甲酰胺MS:APCI(+ve)BP 407
实施例52N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-碘代苯甲酰胺MS:APCI(+ve)BP 519实施例534-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-硝基苯甲酰胺MS:APCI(+ve)BP 472
实施例54N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-甲基-3-硝基苯甲酰胺MS:APCI(+ve)BP 452
实施例55N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-氟代-5-(三氟代甲基)苯甲酰胺MS:APCI(+ve)BP 479实施例56N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-(三氟代甲氧基)苯甲酰胺MS:APCI(+ve)BP 477
实施例58N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(三氟代甲基)苯甲酰胺MS:APCI(+ve)BP 461实施例593-氰基-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺MS:APCI(+ve)BP 418
实施例602-溴代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲氧基苯甲酰胺MS:APCI(+ve)BP 503
实施例61N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-糠酰胺MS:APCI(+ve)BP 383实施例623-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺MS:APCI(+ve)BP 427
实施例632-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺MS:APCI(+ve)BP 429
实施例64N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3,5-二氟代苯甲酰胺MS:APCI(+ve)BP 429实施例652,3-二氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺MS:APCI(+ve)BP 463
实施例67N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(甲硫基)烟酰胺MS:APCI(+ve)BP 440实施例68N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-氟代-6-(三氟代甲基)苯甲酰胺MS:APCI(+ve)BP 479
实施例70N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-四氢噻吩甲酰胺MS:APCI(+ve)BP 399实施例71N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-喹喔啉甲酰胺MS:APCI(+ve)BP 445
实施例73N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}双环[2.2.1]庚-5-烯-2-甲酰胺MS:APCI(+ve)BP 409实施例74N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}环丁烷甲酰胺MS:APCI(+ve)BP 371
实施例75N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-甲氧基乙酰胺MS:APCI(+ve)BP 361
实施例76N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}环己烷甲酰胺MS:APCI(+ve)BP 399实施例77(E)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-苯基-2-丙烯胺MS:APCI(+ve)BP 419
实施例79N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-苯基乙酰胺MS:APCI(+ve)BP 407实施例80N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}环戊烷甲酰胺MS:APCI(+ve)BP 385
实施例82N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}苯甲酰胺MS:APCI(+ve)BP 371实施例83N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-(三氟代甲基)苯甲酰胺MS:APCI(+ve)BP 439
实施例85N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-4-甲基苯甲酰胺MS:APCI(+ve)BP 385实施例86N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-4-硝基苯甲酰胺MS:APCI(+ve)BP 416
实施例88N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-4-甲基-3-硝基苯甲酰胺MS:APCI(+ve)BP 430实施例89N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-氰基苯甲酰胺MS:APCI(+ve)BP 396
实施例91N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-硝基苯甲酰胺MS:APCI(+ve)BP 416实施例92N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-萘甲酰胺MS:APCI(+ve)BP 421
实施例94N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-(2,3-二氢-1,4-苯并二氧芑-2-基)-1,3-噻唑-4-甲酰胺MS:APCI(+ve)BP 512实施例95N~2~-环丙基-N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,4-嘧啶二胺MS:APCI(+ve)422(M+1)
实施例962-{[4-({2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}氨基)-2-嘧啶基]氨基}-1-乙醇MS:APCI(+ve)426(M+1)实施例972-[[4-({2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}氨基)-2-嘧啶基](甲基)氨基]-1-乙醇MS:APCI(+ve)440(M+1)
实施例98N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N~2~-苯基-2,4-嘧啶二胺MS:APCI(+ve)458(M+1)实施例99N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(甲硫基)-4-嘧啶胺MS:APCI(+ve)413(M+1)
实施例100N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-6-甲基-2,4-嘧啶二胺MS:APCI(+ve)396(M+1)实施例101N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N~2~,6-二甲基-2,4-嘧啶二胺MS:APCI(+ve)410(M+1)
实施例1022-氯代-N~4~-环丙基-N~6~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4,6-嘧啶二胺MS:APCI(+ve)456(M+1)实施例103N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-苯基-2-嘧啶胺MS:APCI(+ve)443(M+1)
实施例104N~2~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N~4~,N~4~,6-三甲基-2,4-嘧啶二胺MS:APCI(+ve)424(M+1)实施例105N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(三氟代甲基)-2-嘧啶胺MS:APCI(+ve)435(M+1)
实施例106N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(丙硫基)-2-嘧啶胺MS:APCI(+ve)441(M+1)实施例107N~2~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N~4~-苯基-2,4-嘧啶二胺MS:APCI(+ve)458(M+1)
实施例108N~4~-环丙基-N~2~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,4-嘧啶二胺MS:APCI(+ve)422(M+1)实施例109N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}[1,8]二氮萘-2-胺MS:APCI(+ve)417(M+1)
实施例110N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(3-吡啶基)-2-嘧啶胺MS:APCI(+ve)444(M+1)实施例111N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-嘧啶胺MS:APCI(+ve)367(M+1)
实施例112N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4,6-二甲氧基-2-嘧啶胺MS:APCI(+ve)427(M+1)实施例113N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(3-呋喃基)-2-嘧啶胺MS:APCI(+ve)433(M+1)
实施例114N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺MS:APCI(+ve)421(M+1)实施例115N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1H-嘌呤-6-胺MS:APCI(+ve)407(M+1)
实施例116N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲基噻吩并[2,3-d]嘧啶-4-胺MS:APCI(+ve)437(M+1)实施例117N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-7-甲基噻吩并[3,2-d]嘧啶-4-胺MS:APCI(+ve)437(M+1)
实施例120N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}双环[2.2.1]庚-5-烯-2-甲酰胺MS:APCI(+ve)BP 387
实施例122(E)-N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-苯基-2-丙烯酰胺MS:APCI(+ve)BP 397实施例123N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-苯氧基乙酰胺MS:APCI(+ve)BP 401
实施例124(E)-N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-(4-硝基苯基)-2-丙烯酰胺MS:APCI(+ve)BP 442
以下实施例126-168的化合物通过与实施例30类似的方法制备。
实施例127(4-氯代苯基)(1-{2-[(3,4,5-三甲氧基苄基)氨基]乙基}-4-哌啶基)甲酮MS:APCI(+ve)BP 447实施例128(4-氯代苯基)(1-{2-[(3-硝基苄基)氨基]乙基}-4-哌啶基)甲酮MS:APCI(+ve)BP 402
实施例129(4-氯代苯基){1-[2-(异丁基氨基)乙基]-4-哌啶基}甲酮MS:APCI(+ve)BP 323
实施例1304-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-4-乙基己腈MS:APCI(+ve)BP 404实施例131(4-氯代苯基)(1-{2-[(7-羟基-3,7-二甲基辛基)氨基]乙基}-4-哌啶基)甲酮MS:APCI(+ve)BP 423
实施例132(4-氯代苯基)[1-(2-{[(6-硝基-1,3-苯并二氧杂环戊-5-基)甲基]氨基}乙基)-4-哌啶基]甲酮MS:APCI(+ve)BP 446
实施例133[1-(2-{[(5-氯代-1,3-二甲基-1H-吡唑-4-基)甲基]氨基}乙基)-4-哌啶基](4-氯代苯基)甲酮MS:APCI(+ve)BP 409实施例134(4-氯代苯基)[1-(2-{[3-硝基-4-(2-吡啶硫基)苄基]氨基}乙基)-4-哌啶基]甲酮MS:APCI(+ve)BP 511
实施例135(4-氯代苯基)[1-(2-{[(E)-3-(4-硝基苯基)-2-丙烯基]氨基}乙基)-4-哌啶基]甲酮MS:APCI(+ve)BP 428实施例136(4-氯代苯基){1-[2-({[5-(3-硝基苯基)-2-呋喃基]甲基}氨基)乙基]-4-哌啶基}甲酮MS:APCI(+ve)BP 468
实施例137(4-氯代苯基)[1-(2-{[5-硝基-2-(2-吡啶基硫基)苄基]氨基}乙基)-4-哌啶基]甲酮MS:APCI(+ve)BP 511实施例1386-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-2-(甲硫基)烟腈MS:APCI(+ve)BP 429
实施例140(4-氯代苯基)[1-(2-{[3-(甲硫基)丁基]氨基}乙基)-4-哌啶基]甲酮MS:APCI(+ve)BP 369实施例141(4-氯代苯基)[1-(2-{[(4-苯基-4-哌啶基)甲基]氨基}乙基)-4-哌啶基]甲酮MS:APCI(+ve)BP 440
实施例142(4-氯代苯基)[1-(2-{[(1-苯基-1H-吡唑-5-基)甲基]氨基}乙基)-4-哌啶基]甲酮MS:APCI(+ve)BP 423实施例1433-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]环己烷羧酸乙酯MS:APCI(+ve)BP 435
实施例144N-{4-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]苯基}乙酰胺MS:APCI(+ve)BP 414实施例145(4-氯代苯基)(1-{2-[(2,5-二氟代苄基)氨基]乙基}-4-哌啶基)甲酮MS:APCI(+ve)BP 393
实施例147(4-氯代苯基)(1-{2-[(2,6-二氯代苄基)氨基]乙基}-4-哌啶基)甲酮MS:APCI(+ve)BP 425
实施例150(4-氯代苯基)(1-{2-[(3-羟基-4-甲氧基苄基)氨基]乙基}-4-哌啶基)甲酮MS:APCI(+ve)BP 403实施例1513-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-4H-苯并吡喃-4-酮MS:APCI(+ve)BP 425
实施例152[1-(2-{[(5-氯代-1,3-二甲基-1H-吡唑-4-基)甲基]氨基}乙基)-4-哌啶基](4-氯代苯基)甲酮MS:APCI(+ve)BP 409实施例153(4-氯代苯基)[1-(2-{[(2,6-二氯代-4-吡啶基)甲基]氨基}乙基)-4-哌啶基]甲酮MS:APCI(+ve)BP 428
实施例154(4-氯代苯基)[1-(2-{[(2-苯基-1H-咪唑-4-基)甲基]氨基}乙基)-4-哌啶基]甲酮MS:APCI(+ve)BP 423实施例155(4-氯代苯基)[1-(2-{[(5-乙基-2-噻吩基)甲基]氨基}乙基)-4-哌啶基]甲酮MS:APCI(+ve)BP 391
实施例157(4-氯代苯基)[1-(2-{[(6-甲基-2-吡啶基)甲基]氨基}乙基)-4-哌啶基]甲酮MS:APCI(+ve)BP 372实施例158(4-氯代苯基)(1-{2-[(3-喹啉基甲基)氨基]乙基}-4-哌啶基]甲酮MS:APCI(+ve)BP 408
实施例1594-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-1,5-二甲基-2-苯基-1,2-二氢-3H-吡唑-3-酮MS:APCI(+ve)BP 467
实施例160(4-氯代苯基)(1-{2-[(4-吡啶基甲基)氨基]乙基}-4-哌啶基)甲酮MS:APCI(+ve)BP 358
实施例162(4-氯代苯基)(1-{2-[(3,5-二氟代苄基)氨基]乙基}-4-哌啶基)甲酮MS:APCI(+ve)BP 393实施例163(1-{2-[(2-氯代-6-氟代苄基)氨基]乙基}-4-哌啶基)(4-氯代苯基)甲酮MS:APCI(+ve)BP 409
实施例1662-{2-[({2-[4-(4-氯代苯甲酰基)-1-吡啶基]乙基}氨基)甲基]-4-硝基苯氧基}乙酸MS:APCI(+ve)BP 476
实施例167(4-氯代苯基)[1-(2-{[(1-甲基-1H-苯并咪唑-2-基)甲基]氨基}乙基)-4-哌啶基]甲酮MS:APCI(+ve)BP 411实施例168(4-氯代苯基)[1-(2-{[(2,4-二甲氧基-5-嘧啶基)甲基]氨基}乙基)-4-哌啶基]甲酮MS:APCI(+ve)BP 419
以下实施例169-209的化合物通过类似实施例2的方法制备。
实施例1704-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺MS:APCI(+ve)BP 459
实施例175N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-氟代-4-甲氧基苯甲酰胺MS:APCI(+ve)BP 441
实施例1765-溴代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-糠酰胺MS:APCI(+ve)BP 463实施例177N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲基-2-糠酰胺MS:APCI(+ve)BP 397
实施例179N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-7-乙氧基-1-苯并呋喃-2-甲酰胺MS:APCI(+ve)BP 477实施例180N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲氧基-1-苯并呋喃-2-甲酰胺MS:APCI(+ve)BP 463
实施例181N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-7-甲氧基-1-苯并呋喃-2-甲酰胺MS:APCI(+ve)BP 463实施例182N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(4-氟代苯基)乙酰胺MS:APCI(+ve)BP 425
实施例184N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3-甲基苯基)乙酰胺MS:APCI(+ve)BP 421实施例185N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(2-甲基苯基)乙酰胺MS:APCI(+ve)BP 421
实施例1872-(2-氯代苯基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}乙酰胺MS:APCI(+ve)BP 441实施例1882-(4-氯代苯基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}乙酰胺MS:APCI(+ve)BP 443
实施例189N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-[2-(三氟代甲基)苯基]乙酰胺MS:APCI(+ve)BP 475实施例1902-(3-氯代苯基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}乙酰胺MS:APCI(+ve)BP 441
实施例191N-(2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3,4-二甲氧基苯基)乙酰胺MS:APCI(+ve)BP 467实施例192N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(4-甲氧基苯基)乙酰胺MS:APCI(+ve)BP 437
实施例193N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3,4-二氯代苯基)乙酰胺MS:APCI(+ve)BP 477实施例194N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3-氟代-4-甲氧基苯基)乙酰胺MS:APCI(+ve)BP 455
实施例195N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(4-乙氧基苯基)乙酰胺MS:APCI(+ve)BP 451实施例1962-(1,3-苯并二氧杂环戊-5-基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}乙酰胺MS:APCI(+ve)BP 451
实施例198N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(4-甲基苯基)乙酰胺MS:APCI(+ve)BP 421
实施例199N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3,4-二氟代苯基)乙酰胺MS:APCI(+ve)BP 443
实施例200N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3-甲氧基苯基)乙酰胺MS:APCI(+ve)BP 437实施例201N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-苯基丁酰胺MS:APCI(+ve)BP 435
实施例202N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-苯基丙酰胺MS:APCI(+ve)BP 421实施例203N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-(3-甲氧基苯基)丙酰胺MS:APCI(+ve)BP 451
实施例2052-(乙酰氨基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1,3-噻唑-4-甲酰胺MS:APCI(+ve)BP 457实施例206N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(4-吡啶基)-1,3-噻唑-4-甲酰胺MS:APCI(+ve)BP 477
实施例208N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,5-二甲基-1,3-噁唑-4-甲酰胺MS:APCI(+ve)BP 412实施例209N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1H-咪唑-4-甲酰胺MS:APCI(+ve)BP 385
通过实施例1步骤(i)-(iv)的方法、用3-氯代苯酚制备,得到产物为油状物(0.5g),其没有进一步纯化而直接在下一步骤中使用。(ii)N-{2-[4-(3,4-氯代苯氧基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺盐酸盐
将以上步骤(i)的产物(0.3g)溶于二氯甲烷(490ml)中,加入三乙胺(4当量)和3-甲氧基苯甲酰氯(1当量)。在室温下72小时后,加入水,分离有机层,干燥并浓缩成树胶状物。将该产物溶于二氯甲烷中并用1.0M乙醚的氯化氢溶液处理,得到标题产物为固体(0.1g)。熔点:175-176℃MS:APCI(+ve):389(M+H)1H NMR:δ(DMSO)8.87(t,1H),7.5(m,2H),7.42(m,1H),7.32(m,1H),7.13(m 2H),6.98(m,2H),4.82(m,1/2H),4.61(m,1/2H),3.81(s,3H),3.69(m,3H),3.68(m,3H),3.47(m,1H),3.13-3.22(m,4H),2.27(m,1H),2.14(m,1H),2.03(m,1H),1.90(m,1H)
实施例211N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺(i)2-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-1H-异吲哚-1,3(2H)-二酮
将来自实施例1步骤(ii)的产物(2.0g)、2-(3-溴代丙基)-1H-异吲哚-1,3(2H)-二酮(1.61g)和三乙胺(2.5ml)的二氯甲烷(40ml)中的溶液在回流下加热48小时。将反应混合物分配在乙酸乙酯/水之间,干燥有机层并在减压下蒸发。经层析纯化,用4%甲醇/二氯甲烷洗脱。产量0.839g。MS:APCI(+ve)433(M+1)(ii)3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基胺二盐酸盐
将来自步骤(i)的产物(0.83g)和水合肼(0.1ml)的乙醇溶液在回流下加热6小时。将沉淀滤出并分配在2M盐酸和二氯甲烷之间,滤出固体并用氢氧化钾水溶液碱化含水层,用二氯甲烷萃取。干燥有机层,在减压下蒸发并用乙醚的氯化氢溶液形成二盐酸盐。产量0.28g。1H NMR:δ(DMSO-d6)11.11(br s,1H),8.13(br s,3H),7.56(d,1H),7.37(s,1H),7.10-7.06(br m,1H),4.84(br s,0.5H),4.65(br s,0.5H),3.60-2.90(m,8H),2.24-2.01(m,6H)。(iii)N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺
将来自步骤(ii)的产物(0.08g)、4-氯代-1-甲基-1H-吡唑并[3,4-d]嘧啶(0.054g)和二异丙基乙胺(0.082g)的1-甲基-2-吡咯烷酮(2ml)中的溶液在50℃下加热3小时。用乙酸乙酯稀释反应混合物并用水洗涤。干燥有机层并在减压下除去溶剂。经层析纯化,用9%甲醇/二氯甲烷洗脱。产量0.052g。MS:APCI(+ve)435(M+1)1H NMR:δ(DMSO-d6)8.25-8.22(m,2H),8.07(s,1H),7.49(d,1H),7.25(d,1H),6.97(dd,1H),4.46-4.42(m,1H),3.88(s,3H),3.49(q,2H),2.70-2.66(m,2H),2.40-2.36(m,2H),2.27-2.22(m,2H),1.92-1.88(m,2H),1.81-1.74(m,2H),1.62-1.59(m,2H)。熔点:120-124℃
实施例212-255
将来自实施例211步骤(ii)的产物(1.5mg)、合适的活化卤代芳族化合物(1.25当量)、二异丙基乙胺(10当量)的1-甲基-2-吡咯烷酮(0.15ml)中的溶液在100℃下加热24小时。将反应混合物蒸发至干燥并将残余物溶于二甲亚砜(0.4ml)中。实施例212N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2,6-二甲氧基-4-嘧啶胺MS:APCI(+ve)441(M+1)
实施例213N~4~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-N~2~,N~2~-二甲基-2,4-嘧啶二胺MS:APCI(+ve)424(M+1)实施例214N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-[(甲硫基)甲基]-4-嘧啶胺MS:APCI(+ve)441(M+1)
实施例215N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-[(甲硫基)-6-(三氟代甲基)-4-嘧啶胺MS:APCI(+ve)495(M+1)实施例216N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-5-甲氧基-2-(甲硫基)-4-嘧啶胺MS:APCI(+ve)457(M+1)
实施例217N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-6-甲基-2-(甲硫基)-4-嘧啶胺MS:APCI(+ve)441(M+1)实施例218N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-5-甲氧基-2-甲基-4-嘧啶胺MS:APCI(+ve)425(M+1)
实施例220N~2~-环丙基-N~4~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2,4-嘧啶二胺MS:APCI(+ve)436(M+1)实施例2212-{[4-({3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}氨基)-2-嘧啶基]氨基}-1-乙醇MS:APCI(+ve)440(M+1)
实施例2222-[[4-({3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}氨基)-2-嘧啶基](甲基)氨基]-1-乙醇MS:APCI(+ve)454(M+1)实施例223N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-(甲硫基)-4-嘧啶胺MS:APCI(+ve)427(M+1)
实施例224N~4~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-6-甲基-2,4-嘧啶二胺MS:APCI(+ve)410(M+1)实施例225N~4~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-N~2~,6-二甲基-2,4-嘧啶二胺MS:APCI(+ve)424(M+1)
实施例226N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-苯基-2-嘧啶胺MS:APCI(+ve)457(M+1)实施例227N~2~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-5-氟代-2,4-嘧啶二胺MS:APCI(+ve)414(M+1)
实施例228N~2~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-N~4~,N~4~,6-三甲基-2,4-嘧啶二胺MS:APCI(+ve)438(M+1)实施例229N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(三氟代甲基)-2-嘧啶胺MS:APCI(+ve)449(M+1)
实施例230N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(丙硫基)-2-嘧啶胺MS:APCI(+ve)455(M+1)实施例231N~2~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-N~4~-苯基-2,4-嘧啶二胺MS:APCI(+ve)472(M+1)
实施例232N~2~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-N~4~,6-二甲基-2,4-嘧啶二胺MS:APCI(+ve)424(M+1)实施例233N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-[1,8]二氮萘-2-胺MS:APCI(+ve)431(M+1)
实施例2342-{[2-({3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}氨基)-4-嘧啶基]氨基}-1-乙醇MS:APCI(+ve)440(M+1)实施例2352-[[2-({3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}氨基)-4-嘧啶基](甲基)氨基]-1-乙醇MS:APCI(+ve)454(M+1)
实施例236N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(3-吡啶基)-2-嘧啶胺MS:APCI(+ve)458(M+1)实施例237N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(3-噻吩基)-2-嘧啶胺MS:APCI(+ve)463(M+1)
实施例238N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-嘧啶胺MS:APCI(+ve)381(M+1)实施例239N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4,6-二甲氧基-2-嘧啶胺MS:APCI(+ve)441(M+1)
实施例240N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(3-呋喃基)-2-嘧啶胺MS:APCI(+ve)447(M+1)实施例241N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(2-噻吩基)-2-嘧啶胺MS:APCI(+ve)463(M+1)
实施例242N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-1H-嘌呤-6-胺MS:APCI(+ve)421(M+1)实施例243N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-5-甲基噻吩并[2,3-d]嘧啶-4-胺MS:APCI(+ve)451(M+1)
实施例244N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-7-甲基噻吩并[3,2-d]嘧啶-4-胺MS:APCI(+ve)451(M+1)实施例245N~7~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-5-甲基[1,3]噻唑并[4,5-d]嘧啶-2,7-二胺MS:APCI(+ve)467(M+1)
实施例246N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-9-甲基-9H-嘌呤-6-胺MS:APCI(+ve)435(M+1)实施例247N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-吡啶胺MS:APCI(+ve)379(M+1)
实施例2485-氯代-N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-吡啶胺MS:APCI(+ve)414(M+1)实施例2496-氯代-N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-吡啶胺MS:APCI(+ve)414(M+1)
实施例250N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-6-甲基-2-吡啶胺MS:APCI(+ve)494(M+1)
实施例251N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-1,3-苯并噻唑-2-胺MS:APCI(+ve)436(M+1)实施例252N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-1,3-苯并噁唑-2-胺MS:APCI(+ve)420(M+1)
实施例2546-氯代-N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-3-哒嗪胺MS:APCI(+ve)417(M+1)实施例2556-({3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}氨基)-1,3-二甲基-2,4(1H,3H)-嘧啶二酮MS:APCI(+ve)441(M+1)
实施例256-292
将来自实施例1步骤(iv)的产物(2.07mg)、合适的活化卤代芳族化合物(1.25当量)、二异丙基乙胺(10当量)的1-甲基-2-吡咯烷酮(0.15ml)溶液在100℃下加热24小时。将反应混合物蒸发至干燥并将残余物溶于二甲亚砜(0.4ml)中。
实施例256N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,6-二甲氧基-4-嘧啶胺MS:APCI(+ve)427(M+1)实施例257N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N~2~,N~2~-二甲基-2,4-嘧啶二胺MS:APCI(+ve)410(M+1)
实施例258N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-[(甲硫基)甲基]-4-嘧啶胺MS:APCI(+ve)427(M+1)实施例259N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲氧基-2-(甲硫基)-4-嘧啶胺MS:APCI(+ve)443(M+1)
实施例260N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-6-甲基-2-(甲硫基)-4-嘧啶胺MS:APCI(+ve)427(M+1)实施例261N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲氧基-2-甲基-4-嘧啶胺MS:APCI(+ve)411(M+1)
实施例262N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-6-甲基-N~2~-苯基-2,4-嘧啶二胺MS:APCI(+ve)472(M+1)。药理学分析钙通量[Ca2+]i测定a)人嗜酸性粒细胞
如前所述(Hansel等,J.Immunol.Methods,1991,.145,105-110),将人嗜酸性粒细胞从EDTA抗凝的外周血中分离。在室温下将所述细胞再悬浮(5×106ml-1)在低钾溶液(LKS;NaCl 118mM,MgSO4 0.8mM,葡萄糖5.5mM,Na2CO3 8.5mM,KCl 5mM,HEPES 20mM,CaCl2 1.8mM,BSA 0.1%,pH 7.4)中并加入5μM FLUO-3/AM+Pluronic F127 2.2μl/ml(Molecular Probes)1小时。加入后,将细胞以200g离心5分钟并以2.5×106ml-1再悬浮在LKS中。然后将细胞以100ml/孔转移到96孔FLIPr平板(与5μM纤连蛋白预温育2小时的来自于Becton Dickinson的聚-D-赖氨酸平板)上。将该平板以200g离心5分钟并将细胞用LKS(200μl;室温)洗涤两次。
将实施例化合物预溶解于DMSO中并加到终浓度为0.1%(v/v)的DMSO。通过加入A50浓度的eotaxin使测试启动并用FLIPR(萤光成像板读出器,Molecular Devices,Sunnyvale,美国)监测fluo-3-萤光(I激发=490nm和I发射=520nm)的瞬间增加。b)人单核细胞
如前所述(Cunoosamy & Holbrook,J.Leukocyte Biology,1998,S2,13),将人单核细胞从EDTA抗凝的外周血中分离。将所述细胞再悬浮(5×106ml-1)在LKS中并在室温下加入5μM FLUO-3/AM+Pluronic F1272.2μl/ml(Molecular Probes)1小时。负载后,将细胞以200g离心5分钟并以0.5×106ml-1再悬浮在LKS中。然后将细胞转移到96孔FLIPr平板(Costar)上。以0.5×106ml-1浓度向每孔中加入100μl细胞。将该平板离心(200g;5分钟;室温)以使细胞粘附。离心后将细胞用LKS(200μl;室温)洗涤两次。
将实施例化合物预溶解于DMSO中并加到终浓度为0.1%(v/v)的DMSO。通过加入A50浓度的MIP-1α使测试启动并用FLIPR(萤光成像板读出器,Molecular Devices,Sunnyvale,美国)监测fluo-3-萤光(I激发=490nm和I发射=520nm)的瞬间增加。
发现所述实施例的化合物是人嗜酸性粒细胞中eotaxin介导的[Ca2+]i的拮抗剂和/或人单核细胞中KIP-lα介导的[Ca2+]i的拮抗剂。人嗜酸性粒细胞趋化性
如前所述(Hansel等,J.Immunol.Methods,1991,145,105-110),将人嗜酸性粒细胞从EDTA抗凝的外周血中分离。在室温下将所述细胞以10×106ml-1再悬浮在含有200 IU/ml青霉素、200μg/ml硫酸链霉素的RPMI中并用10%HIFCS补充。
将所述嗜酸性粒细胞(700μl)与7μl媒介物或化合物(100x所需终浓度(溶于10%DMSO中))在37℃下预温育15分钟。通过加入含有一定浓度的实施例化合物或溶剂的28μl浓缩的eotaxin(0.1-100nM)到趋化性板(ChemoTx,3μm孔,Neuroprobe)的下层孔中,使该板负载。然后将滤膜放置到孔上并将25μl嗜酸性粒细胞悬浮液加到滤膜的顶部。将该板在含95%空气/5%CO2气氛的湿润培养箱中,在37℃温育1小时以使其趋化性。
将含有未迁移细胞的培养基小心地从以上滤膜上吸出。将滤膜用含有5mM EDTA的磷酸缓冲盐溶液(PBS)洗涤一次以便除去任何粘附的细胞。将通过滤膜的迁移细胞经离心(300xg,5分钟,室温)沉淀,除去滤膜并将上清液转移到96孔板(Costar)的每一个孔中。经加入含有0.5%Triton×100的28μl PBS,随后经两轮冷冻/解冻将所述沉淀的细胞溶解。然后将细胞溶解产物加入到上清液中。根据Strath等,在J.Immunol.Methods,1985,83,209中所述的方法,通过测量嗜酸性粒细胞过氧化物酶在上清液中的活性确定嗜酸性粒细胞迁移的数量。
发现某些实施例的化合物是eotaxin介导的人嗜酸性粒细胞趋化性的拮抗剂。
Claims (16)
1.一种下列通式的化合物其中:R1代表由独立选自以下的一个或多个取代基任选取代的C1-C12烷基:氰基、羟基、C1-C6烷氧基、C1-C6烷硫基和C1-C6烷氧基羰基,或R1代表3-到10-元的饱和或不饱和的环系,其可以包括最多可达2个形成羰基的环碳原子和可以包括最多可达4个独立选自氮、氧和硫的环杂原子,所述环系由一个或多个独立选自以下的取代基任选取代:卤原子,和氰基、硝基、羟基、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷氧基羰基、C1-C6卤代烷基、C1-C6卤代烷氧基、-NR5R6、C3-C6环烷基氨基、C1-C6烷硫基、C1-C6烷硫基C1-C6烷基、C1-C6烷基羰基氨基、-C(O)NR7R8、氨磺酰基、(二)C1-C6烷基氨磺酰基、苯基、苯基氨基、硝基苯基、吡啶基、吡啶基硫代、苯并二噁烷基、噻吩基、呋喃基和C(O)R9-取代的C1-C6烷基或C1-C6烷氧基;m是0或1;Q代表基团OCH2、C1-C4亚烷基或C2-C4亚链烯基;T代表基团C(O)NH,或当m是0时,T可以另外代表键或基团NH,或当m是1和Q代表C1-C4亚烷基时,T可以另外代表基团NH;n是1、2、3或4;每个R2独立代表氢原子或C1-C4烷基;每个R3独立代表氢原子或C1-C4烷基;V代表氮原子;W代表氮原子或基团CH;X代表氧原子或基团C(O)、CH(OH)、NH或N(C1-C6烷基),条件是当W代表氮原子时,则X代表C(O);R4代表由一个或多个独立选自以下的取代基任选取代的苯基:卤原子,和氨基、硝基、氰基、磺酰基、氨磺酰基、C1-C6烷基、C1-C6卤代烷基、C1-C6卤代烷氧基和C1-C6烷基磺酰基;R5和R6各独立代表氢原子或C1-C6烷基或羟基C1-C6烷基,或R5和R6与它们所连接的氮原子一起形成4-到7-元的饱和杂环;R7和R8各独立代表氢原子或C1-C6烷基;和R9代表羟基或-NR7R8基团;条件是(a)当m是0,T是CONH,n是2、3或4和每个R2和R3代表氢,W是CH,X是C(O)或CH(OH)和R1代表取代的3-到10-元的不饱和环系时,则所述环系中的一个或多个取代基不包括羟基、卤素、C1-C6烷氧基或C1-C6卤代烷氧基,和(b)当W是N,X是C(O),R4代表3-三氟代甲基苯基,m是0和T是键时,则R1和(CR2R3)n一起不代表C1-C6烷基,和(c)当W是CH,X是O,n是2或3和每个R2和R3代表氢,m是0和T是NH时,则R1不代表以下基团或其药学上可接受的盐或溶剂化物。
2.根据权利要求1的化合物,其中R1代表由独立选自以下的一个或两个取代基任选取代的C1-C10烷基:氰基、羟基、C1-C4烷氧基、C1-C4烷硫基和C1-C4烷氧基羰基,或R1代表3-到10-元饱和或不饱和的环系,其包括最多可达2个形成羰基的环碳原子和包括最多可达4个独立选自氮、氧和硫的环杂原子,所述环系由一个、两个或三个独立选自以下的取代基任选取代:卤原子,和氰基、硝基、羟基、C1-C4烷基、C3-C6环烷基、C1-C4烷氧基、C1-C4烷氧基羰基、C1-C3卤代烷基、C1-C3卤代烷氧基、-NR5R6、C3-C6环烷基氨基、C1-C4烷硫基、C1-C4烷硫基C1-C4烷基、C1-C4烷基羰基氨基、-C(O)NR7R8、苯基、苯基氨基、硝基苯基、吡啶基、吡啶基硫代、苯并二噁烷基、噻吩基、呋喃基和C(O)R9-取代的C1-C4烷基或C1-C4烷氧基。
3.根据权利要求1或2的化合物,其中m是1和Q代表基团OCH2、C1-C3亚烷基或C2-C3亚链烯基。
4.根据权利要求1-3中任一项的化合物,其中T代表基团C(O)NH。
5.根据以上权利要求中任一项的化合物,其中n是2或3。
6.根据以上权利要求中任一项的化合物,其中V代表氮原子和W代表基团CH。
7.根据以上权利要求中任一项的化合物,其中X代表氧原子或基团C(O)或NH。
8.根据以上权利要求中任一项的化合物,其中R4代表由一个或两个卤原子任选取代的苯基。
9.根据权利要求1的式(I)的化合物或其药学上可接受的盐或溶剂化物选自:4-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-[2-(二甲基氨基)-2-氧代乙氧基]苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-乙氧基苯甲酰胺盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-异丙氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-乙氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-(三氟代甲氧基)苯甲酰胺盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(三氟代甲氧基)苯甲酰胺盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-糠酰胺盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-苯基乙酰胺盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺盐酸盐,3-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-氟代苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-氟代苯甲酰胺盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-羟基苯甲酰胺盐酸盐,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-[2-(甲基氨基)-2-氧代乙氧基]苯甲酰胺盐酸盐,2-[3-{2-[4-(4-氟代苯甲酰基)-1-哌啶基]乙基}-2,4-二氧代-3,4-二氢-1(2H)-喹唑啉基]-N,N-二甲基乙酰胺盐酸盐N-{2-[4-(3,4-二氯代苯甲酰基)-1-哌嗪基]乙基}-3-甲氧基苯甲酰胺盐酸盐,3,4-二氯代-N-{2-[4-(3,4-二氯代苯甲酰基)-1-哌嗪基]乙基}苯甲酰胺,4-氯代-N-{2-[4-(3,4-二氯代苯甲酰基)-1-哌嗪基]乙基}-2-[2-(二甲基氨基)-2-氧代乙氧基]苯甲酰胺盐酸盐,N~7~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲基[1,3]噻唑并[4,5-d]嘧啶-2,7-二胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-9-甲基-9H-嘌呤-6-胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1,3-苯并噻唑-2-胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1,3-苯并噁唑-2-胺,6-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-吡嗪胺,6-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-哒嗪胺,6-({2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}氨基)-1,3-二甲基-2,4(1H,3H)-嘧啶二酮,N-{1-[4-(3,4-二氯代苯氧基)-哌啶-1-基甲基]-2-甲基-丙基}-4-甲基-苯甲酰胺,盐酸盐,N-{1-[4-(3,4-二氯代-苯氧基)-哌啶-1-基甲基]-2-甲基-丙基}-3-甲氧基-苯甲酰胺,盐酸盐,N-{2-[4-(3,4-二氯代苯胺基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺二盐酸盐,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N-(3-甲氧基苄基)胺二盐酸盐,3-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-6-甲氧基-2,4(1H,3H)-喹唑啉二酮,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-氟代苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,4-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-硝基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-甲基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-(三氟代甲基)苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3,5-二硝基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-碘代苯甲酰胺,4-氰基-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,4-溴代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-甲基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-硝基苯甲酰胺,3-溴代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,3,4-二氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-氟代苯甲酰胺,2,4-二氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-碘代苯甲酰胺,4-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-硝基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-甲基-3-硝基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-氟代-5-(三氟代甲基)苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-(三氟代甲氧基)苯甲酰胺,3,5-二氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(三氟代甲基)苯甲酰胺,3-氰基-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,2-溴代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-糠酰胺,3-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,2-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3,5-二氟代苯甲酰胺,2,3-二氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-萘甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(甲硫基)烟酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-氟代-6-(三氟代甲基)苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,4-二氟代苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-噻吩甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-喹喔啉甲酰胺,4-({2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}氨基)-4-氧代丁酸甲酯,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}双环[2.2.1]庚-5-烯-2-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}环丁烷甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-甲氧基乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}环己烷甲酰胺,(E)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-苯基-2-丙烯酰胺,2-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}烟酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-苯基乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}环戊烷甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-苯氧基乙酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-(三氟代甲基)苯甲酰胺,4-(叔-丁基)-N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-4-甲基苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-4-硝基苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-甲基苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-4-甲基-3-硝基苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-氰基苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-糠酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-硝基苯甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-萘甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-(甲硫基)烟酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-(2,3-二氢-1,4-苯并二氧芑-2-基)-1,3-噻唑-4-甲酰胺,N~2~-环丙基-N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,4-嘧啶二胺,2-{[4-({2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}氨基)-2-嘧啶基]氨基}-1-乙醇,2-[[4-({2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}氨基)-2-嘧啶基](甲基)氨基]-1-乙醇,N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N~2~-苯基-2,4-嘧啶二胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(甲硫基)-4-嘧啶胺,N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-6-甲基-2,4-嘧啶二胺,N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N~2~,6-二甲基-2,4-嘧啶二胺,2-氯代-N~4~-环丙基-N~6~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4,6-嘧啶二胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-苯基-2-嘧啶胺,N~2~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N~4~,N~4~,6-三甲基-2,4-嘧啶二胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(三氟代甲基)-2-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(丙硫基)-2-嘧啶胺,N~2~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N~4~-苯基-2,4-嘧啶二胺,N~4~-环丙基-N~2~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,4-嘧啶二胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}[1,8]二氮萘-2-胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(3-吡啶基)-2-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4,6-二甲氧基-2-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(3-呋喃基)-2-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1H-嘌呤-6-胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲基噻吩并[2,3-d]嘧啶-4-胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-7-甲基噻吩并[3,2-d]嘧啶-4-胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-噻吩甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-喹喔啉甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}双环[2.2.1]庚-5-烯-2-甲酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}环己烷甲酰胺,(E)-N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-苯基-2-丙烯酰胺,N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-2-苯氧基乙酰胺,(E)-N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}-3-(4-硝基苯基)-2-丙烯酰胺,2-(1-金刚烷基)-N-{2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}乙酰胺,(4-氯代苯基)(1-{2-[(2-氟代-4,5-二甲氧基苄基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)(1-{2-[(3,4,5-三甲氧基苄基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)(1-{2-[(3-硝基苄基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基){1-[2-(异丁基氨基)乙基]-4-哌啶基}甲酮,4-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-4-乙基己腈,(4-氯代苯基)(1-{2-[(7-羟基-3,7-二甲基辛基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)[1-(2-{[(6-硝基-1,3-苯并二氧杂环戊-5-基)甲基]氨基}乙基)-4-哌啶基]甲酮,[1-(2-{[(5-氯代-1,3-二甲基-1H-吡唑-4-基)甲基]氨基}乙基)-4-哌啶基](4-氯代苯基)甲酮,(4-氯代苯基)[1-(2-{[3-硝基-4-(2-吡啶基硫基)苄基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)[1-(2-{[(E)-3-(4-硝基苯基)-2-丙烯基]氨基}乙基)-4-哌啶基)甲酮,(4-氯代苯基){1-[2-({[5-(3-硝基苯基)-2-呋喃基]甲基}氨基)乙基]-4-哌啶基}甲酮,(4-氯代苯基)[1-(2-{[5-硝基-2-(2-吡啶基硫基)苄基]氨基}乙基)-4-哌啶基)甲酮,6-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-2-(甲硫基)烟腈,{1-[2-({[5-氯代-1-甲基-3-(三氟代甲基)-1H-吡唑-4-基]甲基}氨基)乙基]-4-哌啶基}(4-氯代苯基)甲酮,(4-氯代苯基)[1-(2-{[3-(甲硫基)丁基]氨基}乙基)-4-哌啶基)甲酮,(4-氯代苯基)[1-(2-{[(4-苯基-4-哌啶基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)[1-(2-{[(1-苯基-1H-吡唑-5-基)甲基]氨基}乙基)-4-哌啶基]甲酮,3-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]环己烷羧酸乙酯,N-{4-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]苯基}乙酰胺,(4-氯代苯基)(1-{2-[(2,5-二氟代苄基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)(1-{2-[(4-硝基苄基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)(1-{2-[(2,6-二氯代苄基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)(1-{2-[(2-吡啶基甲基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)[1-(2-{[(3-甲基-2-噻吩基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)(1-{2-[(3-羟基-4-甲氧基苄基)氨基]乙基}-4-哌啶基)甲酮,3-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-4H-苯并吡喃-4-酮,[1-(2-{[(5-氯代-1,3-二甲基-1H-吡唑-4-基)甲基]氨基}乙基)-4-哌啶基](4-氯代苯基)甲酮,(4-氯代苯基)[1-(2-{[(2,6-二氯代-4-吡啶基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)[1-(2-{[(2-苯基-1H-咪唑-4-基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)[1-(2-{[(5-乙基-2-噻吩基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)[1-(2-{[(2-氯代-3-喹啉基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)[1-(2-{[(6-甲基-2-吡啶基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)(1-{2-[(3-喹啉基甲基)氨基]乙基}-4-哌啶基)甲酮,4-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-1,5-二甲基-2-苯基-1,2-二氢-3H-吡唑-3-酮,(4-氯代苯基)(1-{2-[(4-吡啶基甲基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)(1-{2-[(3-羟基-4-硝基苄基)氨基]乙基}-4-哌啶基)甲酮,(4-氯代苯基)(1-{2-[(3,5-二氟代苄基)氨基]乙基}-4-哌啶基)甲酮,(1-{2-[(2-氯代-6-氟代苄基)氨基]乙基}-4-哌啶基)(4-氯代苯基)甲酮,[1-(2-{[(4-溴代-1H-吡唑-3-基)甲基]氨基}乙基)-4-哌啶基](4-氯代苯基)甲酮,3-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-6,7-二甲基-4H-苯并吡喃4-酮,2-{2-[({2-[4-(4-氯代苯甲酰基)-1-哌啶基]乙基}氨基)甲基]-4-硝基苯氧基}乙酸,(4-氯代苯基)[1-(2-{[(1-甲基-1H-苯并咪唑-2-基)甲基]氨基}乙基)-4-哌啶基]甲酮,(4-氯代苯基)[1-(2-{[(2,4-二甲氧基-5-嘧啶基)甲基]氨基}乙基)-4-哌啶基]甲酮,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-(甲基氨基)苯甲酰胺,4-氯代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲氧基-4-甲基苯甲酰胺,3-氨基-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1,3-苯并二氧杂环戊-5-甲酰胺,4-氨基-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-氟代-4-甲氧基苯甲酰胺,5-溴代-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-糠酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-甲基-2-糠酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4,5-二甲基-2-糠酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-7-乙氧基-1-苯并呋喃-2-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲氧基-1-苯并呋喃-2-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-7-甲氧基-1-苯并呋喃-2-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(4-氟代苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(2-甲氧基苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3-甲基苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(2-甲基苯基)乙酰胺,2-(3-溴代苯基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}乙酰胺,2-(2-氯代苯基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}乙酰胺,2-(4-氯代苯基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-[2-(三氟代甲基)苯基]乙酰胺,2-(3-氯代苯基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3,4-二甲氧基苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(4-甲氧基苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3,4-二氯代苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3-氟代-4-甲氧基苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(4-乙氧基苯基)乙酰胺,2-(1,3-苯并二氧杂环戊-5-基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-[4-(二甲基氨基)苯基]乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(4-甲基苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3,4-二氟代苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(3-甲氧基苯基)乙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-4-苯基丁酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-苯基丙酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-3-(3-甲氧基苯基)丙酰胺,2-氨基-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1,3-噻唑-4-甲酰胺,2-(乙酰基氨基)-N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1,3-噻唑-4-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-(4-吡啶基)-1,3-噻唑-4-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,4-二甲基-1,3-噻唑-5-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,5-二甲基-1,3-噁唑-4-甲酰胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-1H-咪唑-4-甲酰胺,N-{2-[4-(3,4-氯代苯氧基)-1-哌啶基]乙基}-3-甲氧基苯甲酰胺,盐酸盐,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2,6-二甲氧基-4-嘧啶胺,N~4~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-N~2~,N~2~-二甲基-2,4-嘧啶二胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-[(甲硫基)甲基]-4-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-(甲硫基)-6-(三氟代甲基)-4-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-5-甲氧基-2-(甲硫基)-4-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-6-甲基-2-(甲硫基)-4-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-5-甲氧基-2-甲基-4-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-(乙硫基)-6-甲基-4-嘧啶胺,N~2~-环丙基-N~4~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2,4-嘧啶二胺,2-{[4-({3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}氨基)-2-嘧啶基]氨基}-1-乙醇,2-[[4-({3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}氨基)-2-嘧啶基](甲基)氨基]-1-乙醇,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-(甲硫基)-4-嘧啶胺,N~4~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-6-甲基-2,4-嘧啶二胺,N~4~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-N~2~,6-二甲基-2,4-嘧啶二胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-苯基-2-嘧啶胺,N~2~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-5-氟代-2,4-嘧啶二胺,N~2~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-N~4~,N~4~,6-三甲基-2,4-嘧啶二胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(三氟代甲基)-2-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(丙硫基)-2-嘧啶胺,N~2~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-N~4~-苯基-2,4-嘧啶二胺,N~2~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-N~4~,6-二甲基-2,4-嘧啶二胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}[1,8]二氮萘-2-胺,2-{[2-({3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}氨基)-4-嘧啶基]氨基}-1-乙醇,2-[[2-({3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}氨基)-4-嘧啶基](甲基)氨基]-1-乙醇,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(3-吡啶基)-2-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(3-噻吩基)-2-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4,6-二甲氧基-2-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(3-呋喃基)-2-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-4-(2-噻吩基)-2-嘧啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-1H-嘌呤-6-胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-5-甲基噻吩并[2,3-d]嘧啶-4-胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-7-甲基噻吩并[3,2-d]嘧啶-4-胺,N~7~-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-5-甲基[1,3]噻唑并[4,5-d]嘧啶-2,7-二胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-9-甲基-9H-嘌呤-6-胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-吡啶胺,5-氯代-N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-吡啶胺,6-氯代-N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-吡啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-6-甲基-2-吡啶胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-1,3-苯并噻唑-2-胺,N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-1,3-苯并噁唑-2-胺,6-氯代-N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-2-吡嗪胺,6-氯代-N-{3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}-3-哒嗪胺,6-({3-[4-(3,4-二氯代苯氧基)-1-哌啶基]丙基}氨基)-1,3-二甲基-2,4(1H,3H)-嘧啶二酮,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2,6-二甲氧基-4-嘧啶胺,N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-N~2~,N~2~-二甲基-2,4-嘧啶二胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-2-[(甲硫基)甲基]-4-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲氧基-2-(甲硫基)-4-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-6-甲基-2-(甲硫基)-4-嘧啶胺,N-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-5-甲氧基-2-甲基-4-嘧啶胺,和N~4~-{2-[4-(3,4-二氯代苯氧基)-1-哌啶基]乙基}-6-甲基-N~2~-苯基-2,4-嘧啶二胺。
10.一种用于制备如权利要求1所定义的式(I)化合物的方法,该方法包括(i)当T代表基团C(O)NH时,以下通式的化合物
R1-(Q)m-COL1
(II)其中L1代表离去基团(例如羟基或卤原子,如氯原子)和R1、m和Q如在式(I)中所定义,与以下通式的化合物或其酸加成盐(例如三氟乙酸盐)反应,其中n、R2、R3、V、W、X和R4如式(I)中所定义;或(ii)当T代表基团C(O)NH和W代表氮原子时,以下通式的化合物其中R1、m、Q、T、n、R2、R3和V如式(I)中所定义,与以下通式的化合物反应
L2-X-R4 (V)其中L2代表离去基团(例如卤原子)和X和R4如式(I)中所定义;或(iii)当T代表基团NH和m是0时,以下通式的化合物
R1-L3 (VI)其中L3代表离去基团(例如卤原子)和R1如式(I)中所定义,与以上(i)中所定义的式(III)化合物反应;或(iv)当T代表基团NH,m是1和Q代表C1-C4亚烷基时,以下通式的化合物
R1-(CH2)P-CHO
(VII)其中p是0、1、2或3和R1如式(I)中所定义,与以上(i)中所定义的式(III)化合物反应;或(v)当T代表键和m是0时,以下通式的化合物
R1-(CR2R3)n-L4 (VIII)其中L4代表离去基团如卤原子(例如氯)和n、R1、R2和R3如式(I)中所定义,与以下通式的化合物反应其中W、X和R4如式(I)中所定义;并且任选在(i)、(ii)、(iii)、(iv)或(v)以后,将式(I)的化合物转化成另一种式(I)的化合物和/或形成式(I)化合物的药学上可接受的盐或溶剂化物。
11.一种药用组合物,它包含如权利要求1-9中任一项所要求的式(I)的化合物或其药学上可接受的盐或溶剂化物以及药学上可接受的辅助剂、稀释剂或载体。
12.一种用于制备如权利要求11中所要求的药用组合物的方法,该方法包括将如权利要求1-9中任一项所要求的式(I)的化合物或其药学上可接受的盐或溶剂化物与药学上可接受的辅助剂、稀释剂或载体混合。
13.用于治疗的如权利要求1-9中任一项所要求的式(I)的化合物或其药学上可接受的盐或溶剂化物。
14.如权利要求1-9中任一项所要求的式(I)的化合物或其药学上可接受的盐或溶剂化物,在制备用于治疗的药物中的用途。
15.如权利要求1-9中任一项所要求的式(I)的化合物或其药学上可接受的盐或溶剂化物,在制备用于治疗其中调节趋化因子受体的活性是有益的人的疾病或症状的药物中的用途。
16.一种治疗患有炎性疾病或具有患炎性疾病危险的病人的炎性疾病的方法,该方法包括给予该病人治疗有效量的如权利要求1-9中任一项所要求的式(I)的化合物或其药学上可接受的盐或溶剂化物。
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KR19980703192A (ko) * | 1995-03-22 | 1998-10-15 | 우에하라아끼라 | 티아졸 유도체 |
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IL125658A0 (en) * | 1997-08-18 | 1999-04-11 | Hoffmann La Roche | Ccr-3 receptor antagonists |
US6433165B1 (en) * | 1998-01-21 | 2002-08-13 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
US6613905B1 (en) * | 1998-01-21 | 2003-09-02 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
PT1131291E (pt) | 1998-11-17 | 2005-01-31 | Hoffmann La Roche | Antagonistas iii do receptor 4-aroil-piperidin-ccr-3 |
KR20010108394A (ko) | 1999-03-26 | 2001-12-07 | 다비드 에 질레스 | 신규 화합물 |
-
2000
- 2000-03-22 KR KR1020017012174A patent/KR20010108394A/ko not_active Application Discontinuation
- 2000-03-22 IL IL14435300A patent/IL144353A0/xx unknown
- 2000-03-22 TR TR2001/02800T patent/TR200102800T2/xx unknown
- 2000-03-22 EP EP00921237A patent/EP1165545A1/en not_active Withdrawn
- 2000-03-22 BR BR0009338-6A patent/BR0009338A/pt not_active IP Right Cessation
- 2000-03-22 CA CA002361366A patent/CA2361366A1/en not_active Abandoned
- 2000-03-22 CN CN00805451A patent/CN1344266A/zh active Pending
- 2000-03-22 PL PL00350904A patent/PL350904A1/xx not_active Application Discontinuation
- 2000-03-22 HU HU0202017A patent/HUP0202017A3/hu unknown
- 2000-03-22 AU AU41575/00A patent/AU4157500A/en not_active Abandoned
- 2000-03-22 WO PCT/SE2000/000563 patent/WO2000058305A1/en not_active Application Discontinuation
- 2000-03-22 CZ CZ20013451A patent/CZ20013451A3/cs unknown
- 2000-03-22 EE EEP200100502A patent/EE200100502A/xx unknown
- 2000-03-22 SK SK1182-2001A patent/SK11822001A3/sk unknown
- 2000-03-22 US US09/555,565 patent/US6518286B1/en not_active Expired - Fee Related
- 2000-03-22 JP JP2000608007A patent/JP2002540204A/ja active Pending
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2001
- 2001-07-26 IS IS6024A patent/IS6024A/is unknown
- 2001-09-17 NO NO20014518A patent/NO20014518L/no unknown
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2003
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101622234B (zh) * | 2007-03-06 | 2013-08-07 | 诺瓦提斯公司 | 适于治疗炎性或变应性病症的二环有机化合物 |
CN111004218A (zh) * | 2018-10-08 | 2020-04-14 | 沈阳中化农药化工研发有限公司 | 含哌啶的嘧啶类化合物及用途 |
CN111004218B (zh) * | 2018-10-08 | 2023-10-13 | 沈阳中化农药化工研发有限公司 | 含哌啶的嘧啶类化合物及用途 |
Also Published As
Publication number | Publication date |
---|---|
NO20014518D0 (no) | 2001-09-17 |
PL350904A1 (en) | 2003-02-10 |
HUP0202017A2 (hu) | 2002-11-28 |
US6518286B1 (en) | 2003-02-11 |
TR200102800T2 (tr) | 2002-01-21 |
EE200100502A (et) | 2002-12-16 |
SK11822001A3 (sk) | 2002-09-10 |
JP2002540204A (ja) | 2002-11-26 |
US20030134840A1 (en) | 2003-07-17 |
IL144353A0 (en) | 2002-05-23 |
KR20010108394A (ko) | 2001-12-07 |
CZ20013451A3 (cs) | 2002-04-17 |
CA2361366A1 (en) | 2000-10-05 |
US6946478B2 (en) | 2005-09-20 |
BR0009338A (pt) | 2001-12-26 |
WO2000058305A1 (en) | 2000-10-05 |
AU4157500A (en) | 2000-10-16 |
NO20014518L (no) | 2001-09-17 |
IS6024A (is) | 2001-07-26 |
HUP0202017A3 (en) | 2003-03-28 |
EP1165545A1 (en) | 2002-01-02 |
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