CN113474333A - 新的经取代的磺酰脲类衍生物 - Google Patents
新的经取代的磺酰脲类衍生物 Download PDFInfo
- Publication number
- CN113474333A CN113474333A CN202080017147.5A CN202080017147A CN113474333A CN 113474333 A CN113474333 A CN 113474333A CN 202080017147 A CN202080017147 A CN 202080017147A CN 113474333 A CN113474333 A CN 113474333A
- Authority
- CN
- China
- Prior art keywords
- carbamoyl
- hexahydro
- indacen
- sulfonamide
- ethylene
- 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.)
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- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- 238000000034 method Methods 0.000 claims abstract description 39
- 238000002360 preparation method Methods 0.000 claims abstract description 32
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 claims abstract description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 102000003777 Interleukin-1 beta Human genes 0.000 claims abstract description 18
- 108090000193 Interleukin-1 beta Proteins 0.000 claims abstract description 18
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 239000003112 inhibitor Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 claims abstract description 11
- 230000000694 effects Effects 0.000 claims abstract description 8
- 230000008569 process Effects 0.000 claims abstract description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 6
- -1 (1, 2, 3, 5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl Chemical group 0.000 claims description 631
- 229940124530 sulfonamide Drugs 0.000 claims description 164
- JOXWSDNHLSQKCC-UHFFFAOYSA-N ethenesulfonamide Chemical compound NS(=O)(=O)C=C JOXWSDNHLSQKCC-UHFFFAOYSA-N 0.000 claims description 72
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 125000001188 haloalkyl group Chemical group 0.000 claims description 29
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 19
- 102100022691 NACHT, LRR and PYD domains-containing protein 3 Human genes 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 18
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 17
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 150000003573 thiols Chemical class 0.000 claims description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 7
- 102000003810 Interleukin-18 Human genes 0.000 claims description 7
- 108090000171 Interleukin-18 Proteins 0.000 claims description 7
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 7
- 150000003456 sulfonamides Chemical class 0.000 claims description 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 230000001404 mediated effect Effects 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 6
- 125000005309 thioalkoxy group Chemical group 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- JHWUNBMMLDCHCY-CDIAOGBUSA-N tert-butyl (2S)-2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylpyrrolidine-1-carboxylate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/[C@]1(N(CCC1)C(=O)OC(C)(C)C)C JHWUNBMMLDCHCY-CDIAOGBUSA-N 0.000 claims description 5
- 125000004001 thioalkyl group Chemical group 0.000 claims description 5
- MVEXISNMHAYAHC-QIXNEVBVSA-N C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/[C@@H]1N(CCC1)C(=O)OC(C)(C)C Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/[C@@H]1N(CCC1)C(=O)OC(C)(C)C MVEXISNMHAYAHC-QIXNEVBVSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000012948 isocyanate Substances 0.000 claims description 4
- 150000002513 isocyanates Chemical class 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- JHWUNBMMLDCHCY-IVYUTVGYSA-N tert-butyl (2R)-2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylpyrrolidine-1-carboxylate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/[C@@]1(N(CCC1)C(=O)OC(C)(C)C)C JHWUNBMMLDCHCY-IVYUTVGYSA-N 0.000 claims description 4
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 3
- YKRLMZKCVQTOAZ-NSCUHMNNSA-N (e)-prop-1-ene-1-sulfonamide Chemical compound C\C=C\S(N)(=O)=O YKRLMZKCVQTOAZ-NSCUHMNNSA-N 0.000 claims description 3
- HAMGPBKPACGWND-ZOXUKVPXSA-N 1-[(E)-2-[(2R)-1,2-dimethylpyrrolidin-2-yl]ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical compound CN1[C@@](CCC1)(C)/C=C/S(=O)(=O)NC(NC1=C2CCCC2=CC=2CCCC1=2)=O HAMGPBKPACGWND-ZOXUKVPXSA-N 0.000 claims description 3
- LKQFOHSVAQXEGW-JICACKBISA-N 1-[(E)-2-[(2S)-1-acetylpyrrolidin-2-yl]ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical compound C(C)(=O)N1[C@@H](CCC1)/C=C/S(=O)(=O)NC(NC1=C2CCCC2=CC=2CCCC1=2)=O LKQFOHSVAQXEGW-JICACKBISA-N 0.000 claims description 3
- UFBAXSAEQWUUQG-HBIYDYFMSA-N 1-[(E)-2-[(3R)-1-ethylpyrrolidin-3-yl]ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical compound C(C)N1C[C@H](CC1)/C=C/S(=O)(=O)NC(NC1=C2CCCC2=CC=2CCCC1=2)=O UFBAXSAEQWUUQG-HBIYDYFMSA-N 0.000 claims description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 125000004273 azetidin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])C1([H])* 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000000812 cholinergic antagonist Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 3
- GUNGDVGHRJWRKM-WODPRUSTSA-M potassium 1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl-[(E)-2-[(2R)-1-methylpyrrolidin-2-yl]ethenyl]sulfonylazanide Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)[N-]S(=O)(=O)\C=C\[C@@H]1N(CCC1)C.[K+] GUNGDVGHRJWRKM-WODPRUSTSA-M 0.000 claims description 3
- MKVNWSAVCOMAJY-KXBZDOTHSA-M potassium [(E)-2-[(2R)-1,2-dimethylpyrrolidin-2-yl]ethenyl]sulfonyl-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)azanide Chemical compound CN1[C@@](CCC1)(C)/C=C/S(=O)(=O)[N-]C(NC1=C2CCCC2=CC=2CCCC1=2)=O.[K+] MKVNWSAVCOMAJY-KXBZDOTHSA-M 0.000 claims description 3
- 230000011664 signaling Effects 0.000 claims description 3
- HWGCTLVXBZCGHR-SMLPRVBWSA-M sodium 1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl-[(E)-2-[(2R)-1-(thian-4-yl)pyrrolidin-2-yl]ethenyl]sulfonylazanide Chemical compound O=C([N-]S(/C=C/[C@@H](CCC1)N1C1CCSCC1)(=O)=O)NC1=C(CCC2)C2=CC2=C1CCC2.[Na+] HWGCTLVXBZCGHR-SMLPRVBWSA-M 0.000 claims description 3
- UAZOGTYPNXCWSW-WODPRUSTSA-M sodium 1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl-[(E)-2-[(2R)-1-methylpyrrolidin-2-yl]ethenyl]sulfonylazanide Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)[N-]S(=O)(=O)\C=C\[C@@H]1N(CCC1)C.[Na+] UAZOGTYPNXCWSW-WODPRUSTSA-M 0.000 claims description 3
- ZESFSERKOVROJT-KXBZDOTHSA-M sodium [(E)-2-[(2R)-1,2-dimethylpyrrolidin-2-yl]ethenyl]sulfonyl-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)azanide Chemical compound CN1[C@@](CCC1)(C)/C=C/S(=O)(=O)[N-]C(NC1=C2CCCC2=CC=2CCCC1=2)=O.[Na+] ZESFSERKOVROJT-KXBZDOTHSA-M 0.000 claims description 3
- BGUQSGNAZKLTNG-LCDZROKASA-M sodium [(E)-2-[(2R)-1-cyclohexylpyrrolidin-2-yl]ethenyl]sulfonyl-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)azanide Chemical compound C1(CCCCC1)N1[C@H](CCC1)/C=C/S(=O)(=O)[N-]C(NC1=C2CCCC2=CC=2CCCC1=2)=O.[Na+] BGUQSGNAZKLTNG-LCDZROKASA-M 0.000 claims description 3
- ZESFSERKOVROJT-YPXYOWDLSA-M sodium [(E)-2-[(2S)-1,2-dimethylpyrrolidin-2-yl]ethenyl]sulfonyl-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)azanide Chemical compound CN1[C@](CCC1)(C)/C=C/S(=O)(=O)[N-]C(NC1=C2CCCC2=CC=2CCCC1=2)=O.[Na+] ZESFSERKOVROJT-YPXYOWDLSA-M 0.000 claims description 3
- ZURLJICOPSQYSG-XKKCTYCISA-M sodium [(E)-2-[(2S)-1,2-dimethylpyrrolidin-2-yl]ethenyl]sulfonyl-[[2,6-di(propan-2-yl)phenyl]carbamoyl]azanide Chemical compound C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)[N-]S(=O)(=O)\C=C\[C@]1(N(CCC1)C)C.[Na+] ZURLJICOPSQYSG-XKKCTYCISA-M 0.000 claims description 3
- QVYOEJKNXRYRTF-LWEBZGTRSA-M sodium [(E)-2-[(2S)-1-ethylpyrrolidin-2-yl]ethenyl]sulfonyl-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)azanide Chemical compound C(C)N1[C@@H](CCC1)/C=C/S(=O)(=O)[N-]C(NC1=C2CCCC2=CC=2CCCC1=2)=O.[Na+] QVYOEJKNXRYRTF-LWEBZGTRSA-M 0.000 claims description 3
- RYHNWVFHZCXDTA-IVYUTVGYSA-N tert-butyl (2R)-2-[(E)-2-(1,2,3,6,7,8-hexahydro-as-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(N(CCC1)[C@@]1(C)/C=C/S(NC(NC1=C(CCC2)C2=C(CCC2)C2=C1)=O)(=O)=O)=O RYHNWVFHZCXDTA-IVYUTVGYSA-N 0.000 claims description 3
- CTFPPBJDIWQIGK-SXKZTFQGSA-N tert-butyl (2R)-2-[(E)-2-[[2,6-di(propan-2-yl)phenyl]carbamoylsulfamoyl]ethenyl]-2-methylpyrrolidine-1-carboxylate Chemical compound C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)NS(=O)(=O)/C=C/[C@@]1(N(CCC1)C(=O)OC(C)(C)C)C CTFPPBJDIWQIGK-SXKZTFQGSA-N 0.000 claims description 3
- MVEXISNMHAYAHC-SZEUEKNRSA-N tert-butyl (2S)-2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]pyrrolidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1[C@@H](CCC1)\C=C\S(NC(NC1=C2CCCC2=CC=2CCCC1=2)=O)(=O)=O MVEXISNMHAYAHC-SZEUEKNRSA-N 0.000 claims description 3
- RYHNWVFHZCXDTA-CDIAOGBUSA-N tert-butyl (2S)-2-[(E)-2-(1,2,3,6,7,8-hexahydro-as-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylpyrrolidine-1-carboxylate Chemical compound C1CCC2=C(C=C3CCCC3=C12)NC(=O)NS(=O)(=O)/C=C/[C@]1(N(CCC1)C(=O)OC(C)(C)C)C RYHNWVFHZCXDTA-CDIAOGBUSA-N 0.000 claims description 3
- CTFPPBJDIWQIGK-YVIRBKRRSA-N tert-butyl (2S)-2-[(E)-2-[[2,6-di(propan-2-yl)phenyl]carbamoylsulfamoyl]ethenyl]-2-methylpyrrolidine-1-carboxylate Chemical compound C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)NS(=O)(=O)/C=C/[C@]1(N(CCC1)C(=O)OC(C)(C)C)C CTFPPBJDIWQIGK-YVIRBKRRSA-N 0.000 claims description 3
- JOBPHUXYUNDTCM-BVYAJCBJSA-N tert-butyl (2S)-2-[(E)-2-[[4-fluoro-2,6-di(propan-2-yl)phenyl]carbamoylsulfamoyl]ethenyl]-2-methylpyrrolidine-1-carboxylate Chemical compound FC1=CC(=C(C(=C1)C(C)C)NC(=O)NS(=O)(=O)/C=C/[C@]1(N(CCC1)C(=O)OC(C)(C)C)C)C(C)C JOBPHUXYUNDTCM-BVYAJCBJSA-N 0.000 claims description 3
- XPNURYAJJYPXGP-KSEUIEODSA-N tert-butyl (2S)-2-[(E)-2-[[4-fluoro-2,6-di(propan-2-yl)phenyl]carbamoylsulfamoyl]ethenyl]pyrrolidine-1-carboxylate Chemical compound FC1=CC(=C(C(=C1)C(C)C)NC(=O)NS(=O)(=O)/C=C/[C@H]1N(CCC1)C(=O)OC(C)(C)C)C(C)C XPNURYAJJYPXGP-KSEUIEODSA-N 0.000 claims description 3
- MHHOFQLMHPMCKA-QBICGKFKSA-N tert-butyl (2S)-2-[[(2R)-2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylazetidin-1-yl]methyl]-2-methylpyrrolidine-1-carboxylate Chemical compound C[C@]1(CCCN1C(=O)OC(C)(C)C)CN2CC[C@]2(C)/C=C/S(=O)(=O)NC(=O)NC3=C4CCCC4=CC5=C3CCC5 MHHOFQLMHPMCKA-QBICGKFKSA-N 0.000 claims description 3
- MHHOFQLMHPMCKA-HAYNCCBLSA-N tert-butyl (2S)-2-[[(2S)-2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylazetidin-1-yl]methyl]-2-methylpyrrolidine-1-carboxylate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/[C@]1(N(CC1)C[C@]1(N(CCC1)C(=O)OC(C)(C)C)C)C MHHOFQLMHPMCKA-HAYNCCBLSA-N 0.000 claims description 3
- XULFFLKHTKMKRJ-FPBAGDOUSA-N tert-butyl (2S)-2-ethyl-2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]pyrrolidine-1-carboxylate Chemical compound C(C)[C@@]1(N(CCC1)C(=O)OC(C)(C)C)\C=C\S(NC(NC1=C2CCCC2=CC=2CCCC1=2)=O)(=O)=O XULFFLKHTKMKRJ-FPBAGDOUSA-N 0.000 claims description 3
- CSYBHVSNENPHSJ-WYMLVPIESA-N tert-butyl 2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylazetidine-1-carboxylate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/C1(N(CC1)C(=O)OC(C)(C)C)C CSYBHVSNENPHSJ-WYMLVPIESA-N 0.000 claims description 3
- XPTHVLBBFHGHBZ-ACCUITESSA-N tert-butyl 2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]azetidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C(CC1)\C=C\S(NC(NC1=C2CCCC2=CC=2CCCC1=2)=O)(=O)=O XPTHVLBBFHGHBZ-ACCUITESSA-N 0.000 claims description 3
- INIVLSGSRUGPKX-WYMLVPIESA-N tert-butyl 3-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]piperidine-1-carboxylate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/C1CN(CCC1)C(=O)OC(C)(C)C INIVLSGSRUGPKX-WYMLVPIESA-N 0.000 claims description 3
- MRYRWKZDFKTCAZ-NTCAYCPXSA-N tert-butyl 4-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]piperidine-1-carboxylate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/C1CCN(CC1)C(=O)OC(C)(C)C MRYRWKZDFKTCAZ-NTCAYCPXSA-N 0.000 claims description 3
- VDCWMCUZOOQMOA-HVJYDRJSSA-N tert-butyl 5-[(2R)-2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]pyrrolidin-1-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/[C@@H]1N(CCC1)C1CC2C(CN(C2)C(=O)OC(C)(C)C)C1 VDCWMCUZOOQMOA-HVJYDRJSSA-N 0.000 claims description 3
- FAQDVZGAJOXGKB-RRXSNJIPSA-N tert-butyl N-[3-[(2S)-2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]pyrrolidin-1-yl]propyl]-N-methylcarbamate Chemical compound C(C)(C)(C)OC(N(C)CCCN1[C@@H](CCC1)\C=C\S(NC(NC1=C2CCCC2=CC=2CCCC1=2)=O)(=O)=O)=O FAQDVZGAJOXGKB-RRXSNJIPSA-N 0.000 claims description 3
- 229940124291 BTK inhibitor Drugs 0.000 claims description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 2
- 206010016654 Fibrosis Diseases 0.000 claims description 2
- 102000014150 Interferons Human genes 0.000 claims description 2
- 108010050904 Interferons Proteins 0.000 claims description 2
- 102000000588 Interleukin-2 Human genes 0.000 claims description 2
- 108010002350 Interleukin-2 Proteins 0.000 claims description 2
- 102000043136 MAP kinase family Human genes 0.000 claims description 2
- 108091054455 MAP kinase family Proteins 0.000 claims description 2
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 claims description 2
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 239000005557 antagonist Substances 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims description 2
- 239000000739 antihistaminic agent Substances 0.000 claims description 2
- 239000003886 aromatase inhibitor Substances 0.000 claims description 2
- 229940125388 beta agonist Drugs 0.000 claims description 2
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 2
- CISNNLXXANUBPI-UHFFFAOYSA-N cyano(nitro)azanide Chemical compound [O-][N+](=O)[N-]C#N CISNNLXXANUBPI-UHFFFAOYSA-N 0.000 claims description 2
- 230000004761 fibrosis Effects 0.000 claims description 2
- 239000003862 glucocorticoid Substances 0.000 claims description 2
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- NOHWSJQXAFCYBU-LMMOQWNQSA-N tert-butyl (2R)-2-[(E)-2-[(2-methylpropan-2-yl)oxycarbonylsulfamoyl]ethenyl]pyrrolidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)NS(=O)(=O)/C=C/[C@@H]1N(CCC1)C(=O)OC(C)(C)C NOHWSJQXAFCYBU-LMMOQWNQSA-N 0.000 description 1
- NIASXSNPLHNDKA-BNICOGTQSA-N tert-butyl (2R)-2-[(E)-2-sulfamoylethenyl]pyrrolidine-1-carboxylate Chemical compound S(N)(=O)(=O)/C=C/[C@@H]1N(CCC1)C(=O)OC(C)(C)C NIASXSNPLHNDKA-BNICOGTQSA-N 0.000 description 1
- NIASXSNPLHNDKA-JGAIRUGNSA-N tert-butyl (2R)-2-[(Z)-2-sulfamoylethenyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(N(CCC1)[C@H]1/C=C\S(N)(=O)=O)=O NIASXSNPLHNDKA-JGAIRUGNSA-N 0.000 description 1
- AHXRXGFJKWRVIZ-DPCFLFMUSA-N tert-butyl (2R)-2-methyl-2-[(E)-2-[(2-methylpropan-2-yl)oxycarbonylsulfamoyl]ethenyl]pyrrolidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)NS(=O)(=O)/C=C/[C@@]1(N(CCC1)C(=O)OC(C)(C)C)C AHXRXGFJKWRVIZ-DPCFLFMUSA-N 0.000 description 1
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- AHXRXGFJKWRVIZ-JICACKBISA-N tert-butyl (2S)-2-methyl-2-[(E)-2-[(2-methylpropan-2-yl)oxycarbonylsulfamoyl]ethenyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(NS(/C=C/[C@](C)(CCC1)N1C(OC(C)(C)C)=O)(=O)=O)=O AHXRXGFJKWRVIZ-JICACKBISA-N 0.000 description 1
- LWMVEAAMBOPVFI-CCEZHUSRSA-N tert-butyl 2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2,3-dihydroindole-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C(CC2=CC=CC=C12)\C=C\S(NC(NC1=C2CCCC2=CC=2CCCC1=2)=O)(=O)=O LWMVEAAMBOPVFI-CCEZHUSRSA-N 0.000 description 1
- HYKXMVUFFVDQTP-RYEVTAHJSA-N tert-butyl N-[2-[(2R)-2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]pyrrolidin-1-yl]ethyl]-N-methylcarbamate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/[C@@H]1N(CCC1)CCN(C(OC(C)(C)C)=O)C HYKXMVUFFVDQTP-RYEVTAHJSA-N 0.000 description 1
- MHRMTMIVNQWCCU-GZVBAYPNSA-N tert-butyl N-[2-[(2S)-2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylpyrrolidin-1-yl]ethyl]-N-methylcarbamate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/[C@]1(N(CCC1)CCN(C(OC(C)(C)C)=O)C)C MHRMTMIVNQWCCU-GZVBAYPNSA-N 0.000 description 1
- ZGDFDQGZWMHCOD-GHRIWEEISA-N tert-butyl N-[2-[2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylazetidin-1-yl]ethyl]-N-methylcarbamate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/C1(N(CC1)CCN(C(OC(C)(C)C)=O)C)C ZGDFDQGZWMHCOD-GHRIWEEISA-N 0.000 description 1
- YGNHIFAOFSFAFO-FOWTUZBSSA-N tert-butyl N-[2-[2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]azetidin-1-yl]ethyl]-N-methylcarbamate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/C1N(CC1)CCN(C(OC(C)(C)C)=O)C YGNHIFAOFSFAFO-FOWTUZBSSA-N 0.000 description 1
- TVOUVSXGMVEREH-NBVRZTHBSA-N tert-butyl N-[3-[2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylazetidin-1-yl]propyl]-N-methylcarbamate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/C1(N(CC1)CCCN(C(OC(C)(C)C)=O)C)C TVOUVSXGMVEREH-NBVRZTHBSA-N 0.000 description 1
- JHLVEBNWCCKSGY-UHFFFAOYSA-N tert-butyl n-methylcarbamate Chemical compound CNC(=O)OC(C)(C)C JHLVEBNWCCKSGY-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
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- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Abstract
本发明涉及新的通式(I)杂环化合物其可药用盐、可药用溶剂合物、对映体、非对映体和多晶型物。本发明还涉及用于制备本发明化合物的方法、包含所述化合物的药物组合物以及本发明化合物属于NOD样受体家族(NLR)蛋白NLRP3调节剂家族所带来的用途。因此,本发明涉及新的NLRP3调节剂以及涉及新的抑制剂化合物在治疗其中涉及白介素1β活性的疾病或病症中的用途。
Description
技术领域
本发明涉及新的通式(I)杂环化合物其可药用盐、可药用溶剂合物、对映体、非对映体和多晶型物。本发明还涉及用于制备本发明化合物的方法、包含所述化合物的药物组合物以及本发明化合物属于NOD样受体家族(NOD-like receptor,NLR)蛋白NLRP3调节剂家族所带来的用途。因此,本发明涉及新的NLRP3调节剂以及涉及新的抑制剂化合物在治疗其中涉及白介素1β活性的疾病或病症中的用途。
背景技术
NOD样受体家族(NLR)蛋白NLRP3是一种感知多种病原体、环境来源和宿主来源因子的胞内信号传导分子(Wen.,et.al.,Immunity.2013;39:432-441)。NLRP3的激活导致与含有CARD的凋亡相关斑点样蛋白(apoptosis associated speck-like proteincontaining a CARD,ASC)结合。ASC转而与半胱氨酸蛋白酶胱天蛋白酶-1(caspase-1)相互作用,形成一种称为炎性小体(inflammasome)的复合物。这导致胱天蛋白酶-1的激活,其将促炎性细胞因子IL-1β和IL-18裂解成其激活形式,并介导一种称为细胞焦亡(pyroptosis)的炎性细胞死亡类型。其他胞内模式识别受体(pattern recognition receptor,PRR)也能够形成炎性小体。这些包括其他NLR家族成员,例如NLRP1和NLRC4,以及非NLR PRR,例如双链DNA(double-stranded DNA,dsDNA)传感器黑色素瘤缺乏因子2(absent in melanoma 2,AIM2)和干扰素,伽马诱导蛋白16(interferon inducible protein 16,IFI16)(Latz,et.al.,Nat Rev Immunol.2013;13:397-411)。NLRP3依赖性IL-1β加工也可通过胱天蛋白酶-1下游的间接、非规范的途径激活(Lamkanfi,et.al.,Cell.2014;157:1013-1022)。
炎性小体成分例如NLRP3、ASC和胱天蛋白酶-1在肝的免疫细胞,包括库普弗细胞(Kupffer cell)、浸润性巨噬细胞、肝细胞和肝星状细胞中表达。炎性小体的激活依赖于两个连续的信号。信号1由TLR和IL-1R信号传导驱动,包括包含NLRP3、ASC、促胱天蛋白酶-1、促IL-1β和促IL-18在内的成分蛋白的表达。信号2由危险信号(DAMPS)提供,在NASH发生过程中,危险信号主要由应激的或濒死的肝细胞释放或通过“渗漏的”肠道(PAMP)释放。这个过程导致炎性小体成分的寡聚化和促胱天蛋白酶-1的裂解,导致激活的促炎性细胞因子的释放。
NLRP3炎性小体通过激活胱天蛋白酶-1导致促炎性细胞因子白介素-1β(interleukin-1β,IL-1β)和白介素-18(interleukin-18,IL-18)的加工和释放,而充当炎性响应的关键媒介物。NLRP3炎性小体是炎性过程的一个组成部分,并且其异常激活在遗传性病症(例如罕见周期性发热综合征、冷吡啉相关周期性综合征(cryopyrin associatedperiodic syndrome,CAPS)、肿瘤坏死因子受体相关周期性综合征(Tumor necrosisfactorreceptor-associated periodic syndrome,TRAPS))和复杂疾病(例如多发性硬化,炎性肠病(Inflammatory bowel disease,IBD),2型糖尿病,动脉粥样硬化,哮喘,痛风性关节炎和包括帕金森病、阿尔茨海默病和其他脑疾病的炎性中枢神经系统(central nervoussystem,CNS)疾病)中是致病性的。(Masters,et.a1.,Annu Rev Immunol.2009;27:621-668;Strowig,et.al.,Nature 2012,481,278-286;Guo,et.al.,Nat.Med.2015,21,677;Ising,et.al.,Nature2019,575,669-673.)
炎症是对感染和损伤的基本的宿主响应。对促炎性细胞因子白介素-1β(IL-1β)的调节是宿主对感染响应的核心,当其被不当激活时也引起组织损伤。(Dinarello,et.al.,Nat.Rev.Drug Discovery 2012,11,633-652.)NLRP3炎性小体激活在包括促炎性信号传导的诱导、肝细胞损伤和细胞死亡以及负责胶原沉积和肝纤维化的肝星状细胞(hepaticstellate cell,HSC)的活化的每个组成部分中都发挥着关键作用。特别地,从NAFLD到NASH的转换与NLRP3-炎性小体激活和包括含有羧基端CARD的凋亡相关斑点样蛋白(ASC)、胱天蛋白酶-1(CASP-1)和泛连接蛋白在内的炎性小体相关成分的表达增加相关。(Mridha,et.al.,Journal of Hepatology,2017,66(5),1037-1046)
目前对于NLRP3相关疾病的治疗包括靶向IL-1的生物剂。这些是重组IL-1受体拮抗剂阿那白滞素(Anakinra)、中和IL-1β抗体康纳单抗(Canakinumab)和可溶性诱饵IL-1受体利纳西普(Rilonacept)。
Wipo专利申请WO98/32733、WO2001/019390、WO2014/190015、WO2016/123229WO2016/131098公开了作为NLRP3炎性小体抑制剂的磺酰脲类衍生物和相关化合物。WO2017/017469公开了某些作为NLRP3炎性小体抑制剂的环二芳基硼衍生物用于治疗其中涉及白介素1β活性的疾病或病症。最近的一些专利申请,例如WO2017/031161、WO2017/079352、WO2017/129897、WO2017/184623、WO2018/225018、WO2019/043610、WO2019/023147、WO2019/008029、WO2019/068772,也公开了某些类别的作为NLRP3抑制剂的化合物。
我们在本文中公开了新的通式(I)杂环化合物,所述杂环化合物是NLRP3调节剂,用于预防和治疗由NLRP3介导的疾病状态或其中涉及白介素1β活性的病症,包括炎症,冷吡啉相关周期性综合征(CAPS),痛风性关节炎,多发性硬化,炎性肠病(IBD),2型糖尿病,动脉粥样硬化,肝纤维化炎性中枢神经系统(CNS)疾病,例如帕金森病、阿尔茨海默病和其他通过NLRP3途径介导的脑疾病。更特别地,本发明的实施方案可用作治疗多种病理性病症的治疗剂,所述病理性病症包括(但不限于)淋巴瘤、自身免疫疾病、异种免疫疾病、炎性疾病、癌症和神经退行性疾病或病症。
发明概述
本发明公开了由通式(I)限定的杂环化合物,所述杂环化合物是NLRP3凋节剂,用于预防和治疗由NLRP3介导的疾病状态以及治疗其中涉及白介素1β活性的疾病或病症。本发明化合物通过抑制NLRP3用于治疗人或动物体。因此,本发明化合物适合用于预防和治疗由NLRP3介导的疾病状态。
本发明的实施方案
本发明的一个实施方案提供了新的由所述通式(I)代表的杂环化合物、它们的互变异构形式、它们的对映体、它们的非对映体、它们的立体异构体、它们的可药用盐和含有它们或它们的混合物的其药物组合物。
在本发明的另一实施方案中,提供了含有通式(I)化合物、它们的互变异构形式、它们的对映体、它们的非对映体、它们的立体异构体、它们的可药用盐或它们的混合物的药物组合物,该药物组合物与适合的载体、溶剂、稀释剂和通常用于制备这样的组合物的其他媒介组合。
在另一实施方案中,提供了本发明的杂环化合物作为NLRP3调节剂的用途,其通过向哺乳动物施用治疗有效且无毒的量的通式(I)化合物或其可药用组合物。
在又一实施方案中,本发明的式(I)化合物可与一种或更多种适合的药物活性剂组合使用。
在另一实施方案中,提供了用于制备新的本发明化合物的方法。
本发明的另一个目的是提供所述方法中涉及的新的中间体。
本发明的另一个目的是提供用于制备所述方法中涉及的中间体的方法。
发明详述
因此,本发明涉及通式(I)化合物:
其互变异构形式、其立体异构体、其对映体、其可药用盐和含有其的药物组合物,其中,
R1在每次出现时独立地代表氢,卤素,卤代烷基,氰基,任选地经取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C1-C6)烷氧基、(C3-C7)环烷基、NH2、NH(C1-C6)烷基、N(C3-C7)环烷基、N(C1-C6烷基)2、芳基、杂芳基、杂环基、苄基、硫醇、巯基烷基、SO2(C1-C6)烷基、(C1-C6)硫代烷氧基、酰胺;
m和n独立地选自整数0至3;
q和r独立地选自整数1至4;
X是N-R5、O、S、SO2;
R5在每次出现时独立地代表氢,卤素,卤代烷基,氰基,任选地经取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、(C3-C7)环烷基、(C1-C6)烷基SO2(C1-C6)烷基、(C1-C6)烷基N(C1-C6)烷基、(C1-C6)烷基N(C3-C7)环烷基、芳基、杂芳基、杂环基、苄基、叔丁氧基羰基、硫醇、巯基烷基、SO2(C1-C6)烷基、SO2(C3-C7)环烷基、SO2-芳基、SO2-杂环基、(C1-C6)硫代烷基、(C1-C6)硫代烷氧基、(C1-C6)烷基SO2NH2、-CONH2、-CO(C1-C6)烷基、-CO(C1-C6)卤代烷基、-CO-芳基、-CO-杂芳基、-CO-杂环基、4至7元杂环、7至14元双环杂环体系、具有任选地一个或多于一个杂原子的桥环或螺环体系;
R2在每次出现时独立地代表氢,卤素,卤代烷基,氰基,任选地经取代的选自以下的基团:(C1-C6)烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C3-C7)环烷基、苄基、芳基、杂芳基、杂环基、硫醇、硫代烷基、硫代-烷氧基、SO2(C1-C6)烷基、SO(C1-C6)烷基、具有任选地一个或多于一个杂原子的桥环或螺环体系;
R3和R4中的每个在每次出现时代表氢、卤素、卤代烷基、氰基、硝基、酰胺、磺酰胺、酰基、羟基、任选地经取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C6)环烷基、(C1-C6)烷氧基、SO2(C1-C6)烷基、硫醇、巯基烷基苄基、芳基、杂芳基、杂环基;或者R3和R4形成键;
‘B’选自以下环体系:
其中W、Y、Z在每次出现时独立地代表C、N、S、SO2和O,其可任选地被取代;
R6、R7、R8、R9、R10和R11中的每个在每次出现时独立地选自氢、卤素、氰基、酰胺、磺酰胺、酰基、羟基、任选地经取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C6)环烷基、(C1-C6)烷氧基、苄基、芳基、杂芳基、杂环基;或者R7和R8、R8和R9、R9和R10和R10和R11中的每个在任何可能的情况下,可一起形成含有0至2个选自N、O和S(O)p的另外的杂原子的4至7元饱和或部分饱和的环;p=1至2。
当任意以上限定的基团被取代时,它们的所述取代可选自上述的那些或可选自氢、羟基、氰基、卤代、卤代烷基、卤代烷氧基、烷基硫代(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C7)环烷基、C1-C6烷氧基、芳基、杂环基、杂芳基、-COR12、-CSR12、C(O)OR12、C(O)-R12、-C(O)-NR12R13、-C(S)-NR12R13、-SO2R12基团,其中R12和R13中的每个独立地选自氢、任选地经取代的选自以下的基团:(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C7)环烷基、芳基、杂芳基、杂环基基团;
在一个优选实施方案中,R1在每次出现时独立地代表氢、卤素、卤代烷基、任选地经取代的选自(C1-C6)烷基的基团;
在一个优选实施方案中,R2在每次出现时独立地代表氢、卤素、卤代烷基任选地经取代的选自(C1-C6)烷基的基团;
在一个优选实施方案中,R3和R4中的每个在每次出现时独立地代表氢、卤素、卤代烷基、任选地经取代的选自(C1-C6)烷基的基团。
在一个优选实施方案中,R6、R7、R8、R9、R10和R11中的每个在每次出现时独立地选自氢、卤素任选地经取代的选自(C1-C6)烷基、(C1-C6)卤代烷基的基团;
在一个优选实施方案中,上述基团、自由基可选自:
“烷基”以及具有前缀“烷(alk)”的其他基团,例如烷氧基和烷酰基(alkanoyl),如本领域技术人员所熟知,意指可进一步被氧原子取代的碳链,其可进一步为直链或支链,以及其组合,除非碳链另有定义。烷基基团的实例包括但不限于甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基、己基等。在指定的碳原子数量允许的情况下,例如C3-10,术语烷基还包括环烷基基团,以及与环烷基结构组合的直链或支链烷基链的组合。当没有指定碳原子的数量时,C1-6是预期的。经取代的烷基包括被一个或更多个部分取代的烷基,所述部分选自卤代(例如,CI、F、Br和I);卤化烷基(例如,CF3、2-Br-乙基、CH2F、CH2CI、CH2CF3或CF2CF3);羟基;氨基;羧酸酯;甲酰胺;烷基氨基;芳基氨基;烷氧基;芳氧基;硝基;叠氮基;氰基;硫代;磺酸;硫酸酯;膦酸;磷酸酯和膦酸酯以及在“任选地经取代的”的限定下所描述的那些。
“烯基”意指含有至少一个碳-碳双键的碳链,其可以是直链或支链或者其组合,除非碳链另有定义。烯基的实例包括但不限于乙烯基、烯丙基、异丙烯基、己烯基、戊烯基、庚烯基、1-丙烯基、2-丁烯基、2-甲基-2-丁烯基等。在指定的碳原子数量允许的情况下,例如C5-10,术语烯基还包括环烯基基团和直链、支链和环状结构的组合。当没有指定碳原子的数量时,C2-6是预期的。
“炔基”意指含有至少一个碳-碳三键的碳链,其可以是直链或支链或者其组合。炔基的实例包括乙炔基、炔丙基、3-甲基-1-戊炔基等。当没有指定碳原子的数量时,是预期的。
单独使用或与其他基团组合使用的“硫代烷基”基团表示与式-SR’(硫及其氧化形式)的基团连接的如上文所定义的烷基基团,其中R’代表氢、烷基或芳基基团,例如硫代甲基、甲基硫代甲基、苯基硫代甲基等,其可任选地被取代。
如本文所用,“碳环”或“碳环残基”旨在意指任何稳定的单环或双环或三环,其中任意环均可为饱和的、部分不饱和的或芳族的。这样的碳环的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、金刚烷基、环辛基、[3.3.0]双环辛烷、[4.3.0]双环壬烷、[4.4.0]双环癸烷(十氢化萘)、[2.2.2]双环辛烷、芴基、苯基、萘基、茚满基、金刚烷基或四氢萘基(四氢化萘)。从更广泛的角度来看,术语碳环旨在包括(在任何适用的情况下)代表环烷基、苯基和其他饱和的、部分饱和的或芳族的残基的基团;
术语“环烷基”和“环烯基”是指任选地经取代的、饱和的和不饱和的单环、双环或三环碳基团。在适当情况下,环烷基或环烯基基团可具有指定数量的碳原子,例如,C3-C6环烷基或环烯基包括在其范围内具有3、4、5或6个碳原子的碳环基团。这样的取代基的实例可选自环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等。经取代的环烷基或环烯基包括具有一个或更多个部分的取代,所述部分选自卤代(例如,CI、F、Br和I);卤化烷基(例如,CF3、2-Br-乙基、CH2F、CH2CI、CH2CF3或CF2CF3);羟基;氨基;羧酸酯;甲酰胺;烷基氨基;芳基氨基;烷氧基;芳氧基;硝基;叠氮基;氰基;硫代;磺酸;硫酸酯;膦酸;磷酸酯;和膦酸酯以及在“任选地经取代的”的限定下所描述的那些。
“烷氧基”是指指定碳原子数的直链或支链醇盐。
“芳基”意指含有碳环原子的单环或多环芳族环体系。优选的芳基是单环或双环6至10元芳族环体系。苯基和萘基是优选的芳基。
“杂环基”意指饱和的、部分饱和的或不饱和的芳族或非芳族单、双或三环基团,其含有选自氮、硫和氧的一个或更多个杂原子,进一步任选地包括硫的氧化形式,即SO和SO2。杂环基体系可以通过基团的任意数量的碳原子或杂原子与另一部分连接,并且可以是饱和的和不饱和的二者。杂环的实例包括四氢呋喃(tetrahydrofuran,THF)、二氢呋喃、1,4-二氧六环、吗啉、1,4-二噻烷、哌嗪、哌啶、1,3-二氧戊环、咪唑啉、咪唑烷、吡咯烷、吡咯啉、四氢吡喃、四氢-2H-噻喃、二氢吡喃、氧硫杂环戊烷(oxathiolane)、二硫杂环戊烷、1,3-二氧六环、1,3-二噻烷、氧硫杂环己烷(oxathiane)、硫代吗啉等。术语“杂环烷基”是指与如上文所定义的烷基连接的如上文所定义的杂环基团;
“杂芳基”意指含有至少一个选自O、S和N的环杂原子的芳族或部分芳族的杂环。因此,杂芳基包括与其他种类的环,例如芳基、环烷基和非芳族杂环融合的杂芳基。杂芳基基团的实例包括:吡咯基、异唑基、异噻唑基、吡唑基、吡啶基、唑基、二唑基(oxadiazolyl)、噻二唑基(thiadiazolyl)、噻唑基、咪唑基、三唑基、四唑基、呋喃基、三嗪基、噻吩基、嘧啶基、苯并异唑基(benzisoxazolyl)、苯并唑基(benzoxazolyl)、苯并噻唑基(benzthiazolyl)、苯并噻二唑基(benzothiadiazolyl)、二氢苯并呋喃基、吲哚啉基、哒嗪基、吲唑基、异吲哚基、二氢苯并噻吩基、吲哚啉基、哒嗪基、吲唑基、异吲哚基、二氢苯并噻吩基、吲哚嗪基(indolizinyl)、噌啉基、酞嗪基、喹唑啉基、萘啶基(napthyridinyl)、咔唑基、苯并二氧戊环基(benzodioxolyl)、喹喔啉基、嘌呤基、呋吖基(furazanyl)、异苄基呋喃基、苯并咪唑基、苯并呋喃基(benzofuranyt)、苯并噻吩基、喹啉基、吲哚基、异喹啉基、二苯并呋喃基等。对于杂环基和杂芳基基团,包括含有3至15个碳原子的环和环体系,形成1至3个环。
术语“卤代烷基”意指其中至少一个氢被卤素原子替代的烷基结构。在其中两个或更多个氢原子被卤素原子替代的某些实施方案中,卤素原子彼此完全相同。
“卤代烷氧基”基团选自与氧原子直接连接的如上文所限定的适合的卤代烷基,更优选选自氟甲氧基、氯甲氧基、氟乙氧基、氯乙氧基等的基团;
在其中两个或更多个氢原子被卤素原子替代的某些其他实施方案中,卤素原子彼此不完全相同。
“芳氧基烷基”意指如本文所限定的用芳氧基基团取代的烷基基团。
“芳氧基芳基”意指如本文所限定的用芳氧基基团取代的芳基基团。
“芳氧基杂芳基”意指如本文所限定的用芳氧基基团取代的杂芳基基团。
“卤代/卤素”是指氟、氯、溴、碘。氯和氟通常是优选的。
适合的基团和基团上的取代基可选自说明书中任何地方描述的那些。
如本文所用,术语“经取代的”意指指定原子上的任意一个或更多个氢被来自所指示基团的选择替代,前提是不超过所指定原子的正常化合价,并且所述取代导致稳定的化合物。如本文所用,术语“经取代的”意指指定原子上的任意一个或更多个氢被来自所指示基团的选择替代,前提是不超过所指定原子的正常化合价,并且所述取代导致稳定的化合物。
“可药用盐”是指所公开化合物的衍生物,其中母体化合物通过制备其酸或碱盐而修饰。可药用盐的实例包括但不限于碱性残基的无机盐或有机酸盐。这样的常规无毒盐包括但不限于来源于无机和有机酸的那些,所述无机和有机酸选自钠、钾、1,2-乙二磺酸、2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、重碳酸(bicarbonic)、碳酸、柠檬酸、依地酸、乙二磺酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、乙醇酰氨苯胂酸(glycollyarsanilic)、己基间苯二酚酸、海巴酸(hydrabamic)、氢溴酸、氢氯酸、氢碘酸、羟基马来酸、羟基萘甲酸、羟乙磺酸、乳酸、乳糖酸、-月桂基磺酸、马来酸、苹果酸、扁桃酸、甲磺酸、萘磺酸(napsylic)、硝酸、草酸、扑酸、泛酸、苯乙酸、磷酸、聚半乳糖醛酸、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、磺胺酸、硫酸、单宁酸、酒石酸和甲苯磺酸。
术语“任选的”或“任选地”意指随后描述的事件或状况可能发生或可能不发生,并且该描述包括事件或状况发生的情况和不发生的情况。例如,“任选地经取代的烷基”意指“烷基”或“经取代的烷基”。另外,任选地经取代的基团包括未经取代的基团。
除非说明书中另有说明,否则本文中所述的结构还意在包括区别仅在于一个或更多个同位素富集的原子的存在的化合物。
特别可用的化合物可选自但不限于以下:
(R,E)-2-(1-乙基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙磺酰胺((R,E)-2-(1-ethylpyrrolidin-2-y1)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide);
(S,E)-2-(1-乙基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯111磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省14-基)氨甲酰基)-2-(1-丙基吡咯烷-2-基)乙烯111磺酰胺;
(R,E)-2-(1-(环丙基甲基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(甲基磺酰基)-吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-2-(1-乙酰基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙烯-1-磺酰胺;
(E)-2-(1-苄基哌啶-4-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙磺酰胺;
(R,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)-乙烯基)吡咯烷-1-羧酸叔丁酯;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2-甲氧基乙基)吡咯烷-2-基)乙烯磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(异丙基磺酰基)吡咯烷-2-基)乙烯磺酰胺;
(R,E)-2-(1-((3-氟苯基)磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(吡嗪-2-羰基)吡咯烷-2-基)乙烯磺酰胺;
(R,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-甲酰胺;
(R,E)-2-(1-(环丙烷羰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2,2,2-三氟乙酰基)吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2-(甲硫基)乙基)吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2,2,2-三氟乙基)吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-异丁基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-2-(1-(乙基磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-异丙基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(3-(甲基磺酰基)丙基)吡咯烷-2-基)乙烯磺酰胺;
(R,E)-2-(1-苯甲酰基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(R,E)-N-((2-(1-苯甲酰基吡咯烷-2-基)乙烯基)磺酰基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)苯甲酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(噻吩-3-羰基)吡咯烷-2-基)乙烯磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺甲磺酸盐;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺马来酸盐;
(R,Z)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-3-(吡咯烷-2-基)丙-1-烯-1-磺酰胺;
(R,E)-2-(1-(环己基磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,Z)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-2-(1-(环己基甲基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-41基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)12-(1-环己基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(1-甲基哌啶-4-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(R,Z)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-异丙基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(四氢-2H-吡喃-4-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(氧杂环丁烷-3-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(四氢-2H-噻喃-4-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(噻唑-2-基甲基)吡咯烷-2-基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(哌啶-4-基)乙烯磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基哌啶-4-基)乙烯磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(甲基磺酰基)哌啶-4-基)乙烯磺酰胺;
(E)-2-(1-乙酰基哌啶-4-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-磺酰胺;
(E)-4-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-哌啶-1-羧酸叔丁酯;
(E)-2-(1-乙基哌啶-4-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-2-(1-乙基吡咯烷-3-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙烯磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-3-基)乙烯-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(R,E)-2-(1-乙酰基-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基-1-(甲基磺酰基)-吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-2-(1,2-二甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-2-(1-乙基-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-2-(1-(环丙基甲基)-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯磺酰胺;
(S,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-羧酸叔丁酯;
(S,E)-2-(1-(环丙基甲基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(吡啶-3-基磺酰基)-吡咯烷-2-基)乙烯磺酰胺;
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(吡咯烷-2-基)乙烯磺酰胺;
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1-乙基吡咯烷-2-基)乙烯磺酰胺;
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1-(甲基磺酰基)吡咯烷-2-基)乙烯-磺酰胺;
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯磺酰胺;
(S,E)-2-(1-乙酰基吡咯烷-2-基)-N-((2,6-二异丙基苯基)氨甲酰基)乙烯磺酰胺;
(S,E)-2-(1-乙酰基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙烯磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(四氢-2H-吡喃-4-羰基)吡咯烷-2-基)乙烯磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(四氢-2H-吡喃-4-基)乙烯磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-烟酰基吡咯烷-2-基)乙烯磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(四氢呋喃-2-基)乙烯-1-磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(噻吩-2-基甲基)-吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-2-(2-(N-((4-氟-2,6-二异丙基苯基)氨甲酰基)氨磺酰基)乙烯基)-吡咯烷-1-羧酸叔丁酯;
(S,E)-N-((4-氟-2,6-二异丙基苯基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-N-((4-氟-2,6-二异丙基苯基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-异丁基-2-甲基-吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基-1-丙基吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(噻唑-2-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(哌啶-3-基)乙烯-磺酰胺;
(E)-2-(1-乙基哌啶-3-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-磺酰胺;
(E)-3-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-哌啶-1-羧酸叔丁酯;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(甲基磺酰基)哌啶-3-基)乙烯磺酰胺;
(E)-2-(1-乙酰基哌啶-3-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-磺酰胺;
(E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-氮杂环丁烷-1-羧酸叔丁酯;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基氮杂环丁烷-2-基)乙烯-1-磺酰胺;
(E)-2-(氮杂环丁烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(四氢-2H-吡喃-4-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-2-(1-((5-氯噻吩-2-基)磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(S,E)-2-(1-(苄基磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-((4-甲氧基苯基)磺酰基)吡咯烷-2-基)乙烯磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-((4-氟苯基)磺酰基)吡咯烷-2-基)乙烯磺酰胺;
(S,E)-2-(1-((2-氰基苯基)磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(S,E)-2-(1-(环己基磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(S,E)-2-(1-(4-氟苄基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(S,E)-2-(1-((4-氰基苯基)磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-2-(1-(4-氰基苄基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(哌啶-2-基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基哌啶-2-基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)-2-(1-(甲基磺酰基)吡咯烷-2-基)乙烯-1-磺酰胺;
((E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-3-(哌啶-2-基)丙-1-烯-1-磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-2-(1,2-二甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吲哚啉-2-基)乙烯-1-磺酰胺;
(E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吲哚啉-1-羧酸叔丁酯;
((S,E)-2-(1-(环丙基甲基)-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-2-(1-(环丙基磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(R,E)-2-(2-(N-((2,6-二异丙基苯基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(R,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐;
(R,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1,2-二甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-2-(1-乙基-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
双钠(R,E)-((2-(1,2-二甲基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺;
钠(R,E)-((2-(1,2-二甲基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺;
(S,E)-2-(2-(N-((2,6-二异丙基苯基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐;
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1,2-二甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基-1-(氧杂环丁烷-3-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-2-(2-(N-((4-氟-2,6-二异丙基苯基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(S,E)-N-((4-氟-2,6-二异丙基苯基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐;
(S,E)-2-(1,2-二甲基吡咯烷-2-基)-N-((4-氟-2,6-二异丙基苯基)氨甲酰基)乙烯-1-磺酰胺;
(E)-2-(1-乙酰基氮杂环丁烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-(2-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-基)乙基)(甲基)氨基甲酸叔丁酯;
(S,E)-2-(1-烯丙基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-2-(1-(1H-苯并[d]咪唑-6-羰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-2-(1-(环丙基磺酰基)-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(4-甲氧基苄基)吡咯烷-2-基)乙烯-1-磺酰胺;
5-((R)-2-((E)-2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-基)六氢环戊并[c]吡咯-2(1H)-羧酸叔丁酯;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-((2R)-1-(八氢环-戊并[c]吡咯-5-基)吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐;
(E)-2-(1-(环丙基磺酰基)氮杂环丁烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1-(噻唑-2-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-(2-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-基)乙基)(甲基)氨基甲酸叔丁酯;
钾(R,E)-((2-(1,2-二甲基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺;
(E)-(2-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)氮杂环丁烷-1-基)乙基)(甲基)氨基甲酸叔丁酯;
(S,E)-2-(1-(环己基甲基)-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
钠(R,E)-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)((2-(1-(四氢-2H-噻喃-4-基)吡咯烷-2-基)乙烯基)磺酰基)酰胺;
钠(R,E)-((2-(1-环己基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺;
钠(S,E)-((2,6-二异丙基苯基)氨甲酰基)((2-(1,2-二甲基吡咯烷-2-基)乙烯基)磺酰基)酰胺;
钠(R,E)-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)((2-(1-甲基吡咯烷-2-基)乙烯基)磺酰基)酰胺;
钾(R,E)-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)((2-(1-甲基吡咯烷-2-基)乙烯基)磺酰基)酰胺;
钠(S,E)-((2-(1,2-二甲基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺;
钠(S,E)-((2-(1-乙基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2-羟基乙基)吡咯烷-2-基)乙烯-1-磺酰胺;
(E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-羧酸叔丁酯;
(E)-2-(1,2-二甲基氮杂环丁烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-2-乙基-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-羧酸叔丁酯;
(S,E)-2-(2-(N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(S,E)-2-(2-乙基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐;
(S,E)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐;
(S,E)-2-(1,2-二甲基吡咯烷-2-基)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-2-(2-(N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(R,E)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐;
(R,E)-2-(1,2-二甲基吡咯烷-2-基)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-2-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)烯丙基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(R,E)-(2-(2-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)烯丙基)-2-甲基吡咯烷-1-基)乙基)(甲基)氨基甲酸叔丁酯;
(R,E)-3-(1,2-二甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)丙-1-烯-1-磺酰胺;
(S,E)-(3-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-基)丙基)(甲基)氨基甲酸叔丁酯;
(E)-(3-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-基)丙基)(甲基)氨基甲酸叔丁酯;
(E)-(2-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-基)乙基)(甲基)氨基甲酸叔丁酯;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基-1-(2-(甲硫基)乙基)氮杂环丁烷-2-基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基-1-(氧杂环丁烷-3-基)氮杂环丁烷-2-基)乙烯-1-磺酰胺;
(S)-2-(((S)-2-((E)-2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-基)甲基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(S)-2-(((R)-2-((E)-2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-基)甲基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2-氨磺酰基乙基)吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-2-(2-乙基-1-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-2-(1-(丁-2-炔-1-基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
或以上任意化合物的可药用盐。
以下是在描述本发明化合物的制备中使用的缩写列表:
μg:微克
1H NMR:质子核磁共振
bs:宽单峰
CDC13:氘代氯仿
CHC13:氯仿
d:双峰
DAMP:损伤相关分子模式;
DCM:二氯甲烷
dd:双重双峰
DMAC:N,N-(二甲基乙酰胺)
DMAP:4-(二甲基氨基)吡啶
DMF:N,N-二甲基甲酰胺
DMSO:二甲基亚砜
dt:双重三峰
EDTA:乙二胺四乙酸
EtOAc:乙酸乙酯
EtOH:乙醇
HCl(g):氯化氢(气体)
IL1β:白介素1β
K2CO3:碳酸钾
LPS:脂多糖
m:多重峰
MeOH:甲醇
mmol:毫摩
MS:质谱
N2:氮气
Na2CO3:碳酸钠
ng:纳克
NIS:N-碘代琥珀酰亚胺
NLRP3:NOD样受体家族,含热蛋白(pyrin)结构域的蛋白3
PAMP:病原体相关分子模式;
PMA:佛波醇12-肉豆蔻酸酯13-乙酸酯
POCI3:磷酰氯
RM:反应混合物
R.T;r.t:室温
s:单峰
t:三峰
td:三重双峰
THF:四氢呋喃
TLC:薄层色谱法
TLR:Toll样受体。
TNFα:肿瘤坏死因子α
制备的一般性方法
本发明的新的化合物可使用下述反应和技术,连同有机合成领域技术人员已知的常规技术,或如本领域技术人员所理解的基于其的变化来制备。
反应可以在对所用试剂和材料适当,并且适合于受影响的转化的溶剂中进行。优选的方法包括但不限于下述的那些,其中除非下文另有定义,否则所有符号均如前文所限定。
通式(I)化合物可如以下方案中所述连同完全在本领域技术人员范围内的适合的修饰/变化一起制备。
方案1
方案2
方案3
其中A、B、R1、R2、R3和R4中的每个如前文所限定。化合物(2)可以通过本领域技术人员熟悉的多种方法使用如Boc酸酐的试剂从可商购的甲磺酰胺(1)制备。化合物(2)在适合的条件和适当的溶剂下用二苯基次膦酰氯处理,得到化合物3(参考文献Synthesis 2003,15,2321-24)。化合物3在适合的条件下,在碱(如氢化钠)和适当的溶剂存在下用醛或酮衍生物(4)处理,得到化合物(5),该化合物在适合的条件下可以经脱保护得到化合物(6)。化合物(3)在适合的条件下,在碱(如氢化钠)和适当的溶剂存在下用异氰酸酯衍生物(7)处理,得到式(I)化合物(方案1)。或者,式(I)化合物也可以如方案2和方案3中所描绘的来制备。
实施上述方法步骤所必需的特定反应条件、溶剂和其他参数完全在本领域技术人员的能力范围内。
通过以下描述实施本发明的一些优选方式的非限制性实例进一步说明本发明。提供这些并不以任何方式限制本发明的范围。
实施例中给出的1H NMR谱数据(见下文)使用400MHz谱仪(Bruker AVANCE-400)记录,并以δ标度报告。除非另有说明,否则用于NMR的溶剂是使用TMS作为内标的CDCl3。
根据本发明的一个特征,提供了式(5)的中间体的一般性结构,
其中所有符号均均如上文所限定。
在另一实施方案中,提供了式(6)的中间体的一般性结构
其中所有符号均均如上文所限定。
在另一实施方案中,提供了式(15)的中间体的一般性结构
其中所有符号均均如上文所限定。
在另一实施方案中,提供了式(16)的中间体的一般性结构
其中所有符号均均如上文所限定。
在又一实施方案中,提供了按照说明书中公开的方案1和3制备式(5)、(6)、15)和(16)的中间体的方法。
中间体-1a:(R,E)-2-(2-(N-(叔丁氧基羰基)-氨磺酰基)-乙烯基)吡咯烷-1-羧酸叔丁酯的制备
500mL、三颈、圆底的烧瓶配备有磁搅拌器、N2气囊、保温袋、干冰浴。在氮气氛下将((二苯基磷酰基)甲基)磺酰基氨基甲酸叔丁酯(3)(10g,25.3mmol)溶解于DMF(100mL)中。将其冷却至-20℃并添加NaH(2.023g,50.6mmol)。将其逐渐升温至25℃并搅拌30分钟。再次冷却至-20℃,并在-20℃温度下在1小时时期内逐滴添加(R)-2-甲酰基吡咯烷-1-羧酸叔丁酯(Org.Lett.2008,10,4,3045-3048)(6.05g,30.3mmol)在DMF(50mL)中的溶液。在添加之后,将反应混合物升温至室温,并进一步搅拌17小时。将反应混合物冷却至0℃并用饱和柠檬酸溶液(30mL)和水(200mL)酸化,析出固体,过滤、洗涤和干燥以产生(R,E)-2-(2-(N-(叔丁氧基羰基)氨磺酰基)乙烯基)吡咯烷-1-羧酸叔丁酯(4.6g,12.22mmol,48%产率)。
1H NMR(400MHz,DMSO-d6):δ=11.33(s,1H),6.78-6.67(m,1H),6.52(d,J=14.2Hz,1H),4.50-4.42(m,1H),3.33-3.27(m,2H),2.1(br s,1H),1.79-1.71(m,3H),1.44-1.35(m,18H);MS(ESI):m/z(%)=375.30(100%)(M-H)-.
中间体-1b:(S,E)-2-(2-(N-(叔丁氧基羰基)-氨磺酰基)-乙烯基)吡咯烷-1-羧酸叔丁酯的制备
中间体-lb也按照描述合成中间体-1a的程序使用(S)-2-甲酰基吡咯烷-1-羧酸叔丁酯制备。
中间体-2a:(R,E)-2-(2-氨磺酰基乙烯基)吡咯烷-1-羧酸叔丁酯的制备
将化合物[中间体1a](18g)溶解于DMSO(180mL)中并加热至85℃(通过TLC监测起始材料的消失)。冷却反应,倒入水中(900mL)并用EtOAc(3×300mL)萃取。在真空中浓缩溶剂并在硅胶上通过柱色谱纯化(50%EtOAc:正己烷),得到产物(R,E)-2-(2-氨磺酰基乙烯基)吡咯烷-1-羧酸叔丁酯(14.3g,53.7mmol,67%产率)。
1H NMR(400MHz,DMSO-d6):δ=6.99(s,2H),6.40-6.38(m,1H),6.34-6.30(m,1H),4.40-4.32(m,2H),3.28-3.25(m,1H),2.21-1.99(m,1H),1.81-1.67(m,3H),1.38(m,9H);MS(ESI):m/z(%)=299.09(50%)(M+Na)+,275.09(100%)(M-1).
中间体-2b:(S,E)-2-(2-氨磺酰基乙烯基)吡咯烷-1-羧酸叔丁酯的制备
中间体-2b也按照描述合成中间体-2a的程序使用中间体1b制备。
中间体-2c:(R,Z)-2-(2-氨磺酰基乙烯基)吡咯烷-1-羧酸叔丁酯的制备
中间体-2c也按照描述合成中间体-2a的程序获得。
1H NMR(400MHz,DMSO-d6):δ=7.06(s,2H),6.22(d,J=12Hz,1H),(dd,J=12Hz,J=11.2Hz,1H),5.24-4.92(m,1H),3.41-3,23(m,1H),2,31-2.03(m,2H),1.99-1.71(m,1H),1.68-1.62(m,1H),1.39(m,9H);MS(ESI):m/z(%)=299.09(40%)(M+Na)+.
中间体-2d:(S,Z)-2-(2-氨磺酰基乙烯基)吡咯烷-1-羧酸叔丁酯的制备
中间体-2d也按照描述合成中间体-2b的程序获得。
中间体-3a(实施例10):(R,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)-乙烯基)吡咯烷-1-羧酸叔丁酯的制备
将NaH(在矿物油中60%分散体)(3.82gm,96mmol)在0℃下添加至磺酰胺[中间体2a](22.0gm,80mmol)在DMF(220mL)中的溶液。使反应升温至室温并搅拌30分钟。在0℃下分批添加4-异氰酸基-1,2,3,5,6,7-六氢-s-引达省(19.03gm,96mmol),反应升温至室温并搅拌过夜。使用50%柠檬酸水溶液将反应酸化直至pH=2.0,用水(1500mL)稀释,过滤沉淀并干燥以得到产物(38g,80mmol,100%产率)。
1H NMR(400MHz,DMSO-d6):δ=10.42(s,1H),8.09(s,1H),6.96(s,1H),6.71-6.68(m,1H),6.59(d,J=14.8Hz,1H),4.45-4.38(m,1H),3.29-3.27(m,2H),2.79(t,J=7.2Hz,4H),2.65(t,J=7.2Hz,4H),2.30-1.93(m,5H),1.78-1.71(m,3H),1.39-1.33(m,9H);MS(ESI):m/z(%)=498.18(40%)(M+Na)+,474.18(100%)(M-1).
中间体-3b(实施例61):(S,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)-乙烯基)吡咯烷-1-羧酸叔丁酯的制备
中间体-3b也按照描述合成中间体-2b的程序制备。
1H NMR(400MHz,DMSO):δ=10.42(bs,1H),8.09(s,1H),6.96(s,1H),6.71-6.67(m,1H),6.6116.57(m,1H),4.45-4.38(m,1H),3.29-3.25(m,2H),2.81(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.09-1.93(m,5H),1.78-1.71(m,3H),1.33(s,9H);MS(ESI):m/z(%)=498.18(80%)(M+Na)+.
中间体-4a:(R)-2-甲酰基-2-甲基吡咯烷-1-羧酸叔丁酯的制备
向1-(叔丁基)2-甲基(R)-2-甲基吡咯烷-1,2-二羧酸酯(Singh et.al.,RSCAdv.,2013,3,19533-19544)(98g,403mmol)在无水DCM(2000mL)中的溶液以得到溶液。在-78℃下逐滴添加DIBAL-H(806mL,1.5M在甲苯中,537mmol)。将反应混合物在-78℃下搅拌2小时,然后在-78℃温度下用甲醇(100mL)淬灭。反应混合物用50%柠檬酸溶液酸化直至pH=4.0。添加水(1000mL)和DCM(1000mL)。水层用DCM(2×1500mL)萃取。合并的有机层用水(1500mL)、卤水(1000mL)洗涤,并用Na2SO4干燥。除去溶剂以得到产物(83g,389mmol,97%产率)。
1H NMR(400MHz,DMSO-d6):δ=9.28(m,1H),3.64-3.41(m,2H),1.97-1.85(m,2H),1.70-1.50(m,2H),1.38-1.28(m,12H),旋转异构体:MS(ES1):m/z(%)=214.3(100%)(M+H)+.
中间体-4b:(S)-2-甲酰基-2-甲基吡咯烷-1-羧酸叔丁酯的制备
中间体-4b也按照描述合成中间体-4a的程序使用1-(叔丁基)2-甲基(S)-2-甲基吡咯烷-l,2-二羧酸酯制备。
中间体-5a:(R,E)-2-(2-(N-(叔丁氧基羰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯的制备
将NaH(在矿物油中60%分散体)(34gm,851mmol)在0℃下添加至(((二苯基磷酰基)甲基)磺酰基)氨基甲酸叔丁酯(153.0gm,387mmol)在DMF(1530mL)中的溶液。使反应升温至室温并搅拌30分钟。在-20℃下逐滴添加DMF(830mL)中的醛((R)-2-甲酰基-2-甲基吡咯烷-1-羧酸叔丁酯)(83gm,387mmol),反应升温至室温并搅拌过夜。使用50%柠檬酸水溶液(约500mL)将反应酸化直至pH=2.0,用水(3000mL)稀释并用EtOAc(2000mL×2)萃取。合并的有机层用水(2000mL×3)、卤水(1000mL)洗涤,用Na2SO4干燥,浓缩并干燥以得到粗产物。使用25%EtOAC:正己烷在硅胶上通过柱色谱纯化残余物,以获得标题化合物(121g,310mmol,80%产率)。
1H NMR(400MHz,DMSO-d6):δ=11.35(s,1H),6.78(d,J=15.2Hz,1H),6.44(d,J=15.6Hz,1H),3.42-3.36(m,2H),1.99-1.92(m,1H),1.88-1.59(m,3H),
1.49-1.36(m,21H);MS(ESI):m/z(%)=413.15(90%)(M+Na),389.15(100%)(M-1).
中间体-5b:(S,E)-2-(2-(N-(叔丁氧基羰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯的制备
中间体-5b也按照描述合成中间体-5a的程序使用(S)-2-甲酰基-2-甲基吡咯烷-1-羧酸叔丁酯制备。
中间体-6a:(R,E)-2-甲基-2-(2-氨磺酰基乙烯基)吡咯烷-1-羧酸叔丁酯的制备
将中间体5a(121g)溶解于DMSO(1200mL)中并加热至85℃(通过TLC监测起始材料的消失)。冷却反应,倒入水中(3000mL)并用EtOAc(2000mL×4)萃取并用Na2SO4干燥。在真空中浓缩溶剂并在硅胶上通过柱色谱纯化(50%EtOAc:正己烷)以得到产物(61.4g,211mmol,68.2%产率)。
1H NMR(400MHz,DMSO-d6):δ=6.98(s,2H),6.61-6.49(m,1H),6.25(d,J=15.2Hz,1H),3.43-335(m,2H),1.99-1.66(m,4H),1.47-1.43(m,3H),1.40-1.37(m,9H);MS(ESI):m/z(%)=289.13(100%)(M-1).
中间体-6b:(S,E)-2-甲基-2-(2-氨磺酰基乙烯基)吡咯烷-1-羧酸叔丁酯的制备
中间体-6b也按照描述合成中间体-6a的程序使用中间体-5b制备。
中间体-7a(实施例52):(R,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯的制备
将NaH(在矿物油中60%分散体)(10.08gm,252mmol)在0℃下添加至(R,E)-2-甲基-2-(2-氨磺酰基乙烯基)吡咯烷-1-羧酸叔丁酯溶液(中间体6a)(61.0gm,210mmol)在DMF(610mL)中的溶液。使反应升温至室温并搅拌30分钟。在0℃下分批添加4-异氰酸基-1,2,3,5,6,7-六氢-s-引达省(50.2gm,252mmol),反应升温至室温并搅拌过夜。在0℃下使用50%柠檬酸水溶液将反应酸化直至pH=2.0,并用冷水(3000mL)稀释,沉淀通过布氏漏斗过滤并干燥以得到产物(100g,204mmol,97%产率)。
1H NMR(400MHz,DMSO-d6):δ=10.41(s,1H),8.06(s,1H),6.96(s,1H),6.87-6.77(m,1H),6.55(d,J=15.2Hz),3.43-3.37(m,2H),2.81(t,J=6.8Hz,4H),2.67(t,J=6.8Hz,4H),2.00-1.93(m,5H),1.86-1.65(m,3H),1.41-1.43(m,3H),1.40-1.38(s,9H);MS(ESI):m/z(%)=488.16(100%)(M-1).
中间体-7b(实施例111):(S,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯的制备
中间体-7b(实施例111)也按照描述合成中间体-7a的程序使用中间体-6b制备。
中间体-8:(二苯基磷酰基)甲磺酰胺的制备
在N2气氛下将(((二苯基磷酰基)甲基)磺酰基)氨基甲酸叔丁酯(Synthesis2003,15,2321-24)(10.0g,25.3mmol)溶解于DCM(100mL)中。将其冷却至0℃温度并逐滴添加TFA(19.48mL,253mmol),在去除添加冰浴之后进一步搅拌RM 4小时。检查TLC,未观察到起始材料。在减压下浓缩R.M,添加水(50mL),固体析出,过滤并用水(25mL×2)洗涤,用P2O5干燥以产生(二苯基磷酰基)甲磺酰胺(7.3g,24.72mmol,98%产率)。
NMR(400MHz,DMSO-d6):δ=7.86-7.81(m,4H),7.61-7.51(m,6H),6.84(s,2H),4.63(d,J=9.2Hz,2H);MS(ESI):m/z(%)=296.05(100%)(M+H)+.
中间体-9:1-(二苯基磷酰基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)甲磺酰胺的制备
在N2气氛下,将(二苯基磷酰基)甲磺酰胺[中间体8](6.0g,20.32mmol)带入DMF(60mL)中。将其冷却至0℃温度并添加NaH(1.170g,24.38mmol)并在室温下搅拌RM 30分钟。然后添加DMF(15mL)中的4-异氰酸基-1,2,3,5,6,7-六氢-s-引达省(4.86g,24.38mmol)溶液,并在室温下进一步搅拌RM 17小时。检查TLC未观察到起始材料。将反应混合物倒入冰冷水(180mL)中并用饱和柠檬酸酸化,搅拌并过滤以得到粗产物。通过在乙酸乙酯中研磨对粗产物纯化,得到1-(二苯基磷酰基)-N-((1,2,3,5,6,7-六氢-s-引达省-4基)氨甲酰基)甲磺酰胺(9.1g,18.40mmol,91%产率)。
1H NMR(400MHz,DMSO-d6):δ=10.4(bs,1H),8.14(s,1H),7.88-7.83(m,4H),7.63-7.53(m,6H),6.96(s,1H),4.99(d,J=8.8Hz,2H),2.81(t,J=7.2Hz,4H),2.71(t,J=7.2Hz,4H),2.00-1.91(m,4H);MS(ESI):m/z(%)495.14(100%)(M+H)+.
中间体-7b(实施例111):(S,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯的制备
在N2气氛下,将1-(二苯基磷酰基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)甲磺酰胺[中间体9](0.5g,1.011mmol)溶解于DMF(5mL)中。将其冷却至0℃并且在0℃下在N2气氛下添加NaH(0.089g,2.224mmol)。在此之后去除冰浴并在室温下将RM搅拌30分钟。然后在-20℃下将DMF(2.5mL)中的(S)-2-甲酰基-2-甲基吡咯烷-1-羧酸叔丁酯(0.259g,1.213mmol)溶液逐滴添加至以上混悬物中。然后将RM升温至室温并进一步搅拌18小时。检查TLC观察到少量起始材料。用水(15mL)稀释RM,水层用柠檬酸溶液酸化,固体析出,将固体滤出并用水(15mL)洗涤,用P2O5干燥。粗产物使用40%EtOAc:己烷通过柱色谱纯化,以得到(S,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯(0.125g,0.255mmol,25.3%产率)。
中间体-7a(实施例52)也按照描述合成中间体-7b(实施例111)的程序使用(R)-2-甲酰基-2-甲基吡咯烷-1-羧酸叔丁酯制备。
中间体-3a(实施例10)也按照描述合成中间体-7b的程序使用(R)-2-甲酰基吡咯烷-1-羧酸叔丁酯制备。
中间体-3b(实施例61)也按照描述合成中间体-7b的程序使用(S)-2-甲酰基吡咯烷-1-羧酸叔丁酯制备。
中间体-10a:2-甲酰基氮杂环丁烷-1-羧酸叔丁酯的制备
向1-(叔丁基)2-甲基氮杂环丁烷-1,2-二羧酸酯(European Journal ofMedicinal Chemistry,2000,35(11),979-988;Journal of the American ChemicalSociety(2010),132(40),14027-14029)(4.26gm,19.79mmol)在无水DCM(86mL)中的溶液以得到溶液。在-78℃下逐滴添加DIBAL-H(26.4mL,1.5M,在甲苯溶液中,39.6mmol)。将反应混合物在-78℃下搅拌2小时,然后在-78℃温度下用甲醇(5mL)淬灭。反应混合物用50%柠檬酸溶液酸化直至pH=4.0。添加水(100mL)和DCM(50mL)。水层用DCM(2×80mL)萃取。合并的有机层用水(150mL)、卤水(10mL)洗涤,用Na2SO4干燥并蒸发溶剂以得到产物2-甲酰基氮杂环丁烷-1-羧酸叔丁酯(3.4gm,18.36mmol,93%产率)。
中间体-10b:2-甲酰基-2-甲基氮杂环丁烷-1-羧酸叔丁酯的制备
中间体-10b也按照描述合成中间体-10a的程序使用1-(叔丁基)2-甲基2-甲基氮杂环丁烷-1,2-二羧酸酯制备。
中间体-11a:(E)-2-(2-(N-(叔丁氧基羰基)氨磺酰基)乙烯基)氮杂环丁烷-1-羧酸叔丁酯的制备
将NaH(在矿物油中60%分散体)(1.34gm,33.4mmol)在0℃下添加至(((二苯基磷酰基)甲基)磺酰基)氨基甲酸叔丁酯(6.0gm,15.17mmol)在DMF(60mL)中的溶液。使反应升温至室温并搅拌30分钟。在-20℃下逐滴添加DMF(35mL)中的2-甲酰基氮杂环丁烷-1-羧酸叔丁酯(3.37g,18.21mmol),反应升温至室温并搅拌过夜。使用50%柠檬酸水溶液(约10mL)将反应酸化直至pH=2.0,用水(200mL)稀释并用EtOAc(100mL×3)萃取。合并的有机层用水(150mL×3)、卤水(80mL)洗涤,用Na2SO4干燥,浓缩并干燥以得到粗产物。使用30%EtOAC:正己烷在硅胶上通过柱色谱纯化残余物以获得(E)-2-(2-(N-(叔丁氧基羰基)氨磺酰基)乙烯基)氮杂环丁烷-1-羧酸叔丁酯(1.8g,4.97mmol,33%产率)。
1H NMR(400MHz,DMSO-d6):δ=11.36(s,1H),6.86(d,J=15.2Hz,J=5.6Hz,1H),6.65(d,J=14.8Hz,1H),4.88-4.83(m,1H),3.84-3.72(m,2H),2.46-2.40(m,1H),2.02-1.96(m,1H),1.44(s,9H),1.41(s,9H);MS(TOF):m/z(%)=385.2035(100%)(M+Na),361.1853(100%)(M-1).
中间体-11:(E)-2-(2-氨磺酰基乙烯基)氮杂环丁烷-1-羧酸叔丁酯的制备叔丁基
将(E)-2-(2-(N-(叔丁氧基羰基)氨磺酰基)乙烯基)氮杂环丁烷-1-羧酸叔丁酯(中间体11a)(1.8g,4.97mmol)溶解于DMSO(18mL)中并加热至85℃(通过TLC监测起始材料的消失)。冷却反应,倒入水中(90mL)并用EtOAc(40ml×4)萃取并用Na2SO4干燥。在真空中浓缩溶剂并在硅胶上通过柱色谱(60%EtOAc:正己烷)纯化以得到(E)-2-(2-氨磺酰基乙烯基)氮杂环丁烷-1-羧酸叔丁酯(2.02g,3.74mmol,83%产率)。
1H NMR(400MHz,DMSO-d6):δ=7.06(s,2H),6.62-6.57(m,1H),6.49(dd,J=14.8Hz,J=1.2Hz,1H),4.81-4.76(m,1H),3.81-3.71(m,2H),2.41-2.37(m,1H),2.00-1.93(m,1H),1.38(s,9H),;MS(TOF):m/z(%)=285.1431(100%)(M+Na),261.1290(100%)(M-1).
中间体-12a:(E)-2-(2-(N-(叔丁氧基羰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-羧酸叔丁酯的制备
在0℃下将NaH(在矿物油中60%分散体)(1.00gm,25.04mmol)添加至(((二苯基磷酰基)甲基)磺酰基)氨基甲酸叔丁酯(4.5gm,11.38mmol)在DMF(45mL)中的溶液。使反应升温至室温并搅拌30分钟。在-20℃下逐滴添加DMF(30mL)中的2-甲酰基-2-甲基氮杂环丁烷-1-羧酸叔丁酯(Journal of Medicinal Chemistry,2014,57(23),10044-10057)(2.72gm,13.66mmol),反应升温至室温并搅拌过夜。使用50%柠檬酸水溶液将反应酸化直至pH=2.0,用水(100mL)稀释并用EtOAc(80mL×3)萃取。合并的有机层用水(100mL×3)、卤水(50mL)洗涤,用Na2SO4干燥,浓缩并干燥以得到粗产物。使用30%EtOAC:正己烷在硅胶上通过柱色谱纯化残余物以获得(E)-2-(2-(N-(叔丁氧基羰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-羧酸叔丁酯(3.73g,9.91mmol,87%产率)。
1H NMR(400MHz,DMSO-d6):δ=11.39(s,1H),6.94-6.88(m,1H),6.63-6.56(m,1H),3.75-3.71(m,1H),3.66-3.63(m,1H),2.21-2.11(m,2H),1.44-1.41(m,9H),1.38-136(m,9H);MS(ESI):m/z(%)=399.20(100%)(M+Na),375.20(100%)(M-1).
中间体-12:(E)-2-甲基-2-(2-氨磺酰基乙烯基)氮杂环丁烷-1-羧酸叔丁酯的制备
将(E)-2-(2-(N-(叔丁氧基羰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-羧酸叔丁酯(中间体-12a)(3.73g,9.91mmol)溶解于DMSO(20mL)中并加热至85℃(通过TLC监测起始材料的消失)。冷却反应,倒入水中(70mL)并用EtOAc(30mL×4)萃取并用Na2SO4干燥。在真空中浓缩溶剂并在硅胶上通过柱色谱(60%EtOAc:正己烷)纯化以得到(E)-2-甲基-2-(2-氨磺酰基乙烯基)氮杂环丁烷-1-羧酸叔丁酯(2.52g,9.12mmol,92%产率)。
1H NMR(400MHz,DMSO-d6):δ=7.06(s,2H),6.68-6.61(m,1H),6.46-6.40(m,1H),3.82-3.60(m,2H),2.19-1.99(m,2H),1.50(m,3H),1.39-1.37(m,9H);MS(ESI):m/z(%)299.10(100%)(M+Na),275.05(100%)(M-1).
实施例-1
(R,E)-2-(1-乙基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙磺酰胺
在0℃下向中间体3a(1当量)在DCM(2.5mL)中的溶液添加TFA(1当量)。将反应升温至室温,并进一步搅拌3小时。反应混合物在真空中浓缩并通过制备型HPLC纯化以得到产物。在室温下将NaHCO3(1.2当量)添加至该产物(1当量)在MeOH(7.0mL)中的溶液并搅拌5分钟。在室温下添加乙醛(5当量)并搅拌2小时。此后,反应混合物在0℃下用NaBH4(1.5当量)分批处理,然后使反应混合物升温至室温,搅拌过夜。通过制备型HPLC纯化反应混合物以得到纯产物(实施例1)。
或者:在0℃下向中间体3(1当量)在DCM(2.5mL)中的溶液添加TFA(1当量)。将反应升温至室温,并进一步搅拌3小时。反应混合物在真空中浓缩并通过制备型HPLC纯化以得到产物。在0℃下向该产物(1当量)在无水THF(5.0mL)中的溶液添加NaH(1.2当量)并搅拌5分钟。添加溴乙烷(1.6当量)并在室温下搅拌14小时。通过制备型HPLC纯化反应混合物以得到纯产物(实施例1)。
或者:向(R,E)-2-(2-(N-(叔丁氧基羰基)氨磺酰基)-乙烯基)吡咯烷-1-羧酸叔丁酯(3.4g,9.04mmol)在DCM中的溶液添加三氟乙酸(15.3mL)并在室温下搅拌1小时。蒸馏DCM并在0℃下向反应混合物添加过量的三甲胺(5.23g,7.2mL,53.1mmol),随后添加溴乙烷(1.35g,0.926mL,12.74mmol)。粗混合物得到(R,E)-2-(1-乙基吡咯烷-2-基)乙烯-1-磺酰胺。在氮气氛条件下,向(R,E)-2-(1-乙基吡咯烷-2-基)乙烯-1-磺酰胺(2.11g,10.33mmol)在DMF(50mL)中的溶液一次添加氢化钠(在矿物油中60%)(0.5g,12.39mmol)。将所得混悬物在室温下进一步搅拌1小时。进一步添加4-异氰酸基-1,2,3,5,6,7-六氢-s-引达省(2g,10.05mmol),并将反应混合物(RM)室温搅拌16小时。在减压下浓缩反应混合物,并用柠檬酸酸化。通过制备型HPLC纯化粗产物以得到纯产物(实施例1)。
1H NMR(400MHz,DMSO-d6):δ=8.03(s,1H),6.92(s,1H),6.87(d,J=14.8Hz,1H),6.60-6.54(m,1H),3.27-3.16(m,3H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.35-2.33(m,2H),2.09-1.94(m,6H),1.81-1.73(m,2H),1.03(t,J=7.2Hz,3H);MS(ESI):m/z(%)=404.20(100%)(M+H)+.
使用适当起始材料和对实施例1中描述的方法的适合的修改,包括完全在本领域技术人员的范围内的对步骤的可能是必要的适合的添加和/或删除,以类似方式制备以下化合物。
实施例-2
(S,E)-2-(1-乙基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.03(s,1H),6.92(s,1H),6.87(d,J=14.8Hz,1H),6.60-6.54(m,1H),3.27-3.16(m,3H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.35-2.33(m,2H),2.09-1.94(m,6H),1.81-1.73(m,2H),1.03(t,J=7.2Hz,3H);MS(ESI):m/z(%)=404.20(100%)(M+H)+.
实施例-3
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=9.71(brs,1H),7.49(s,1H),6.95(d,J=15.2Hz,1H),6.80(s,1H),6.36(dd,J=7.2Hz,J=15.2Hz,1H),4.08-4.02(m,1H),3.18-3.03(m,2H),2.77(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),2.14-2.07(m,4H),2.03-1.80(m,6H),1.70-1.60(m,1H);MS(ESI):m/z(%)=376.10(100%)(M+H)+,374.05(100%)(M-1).
实施例-4
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-丙基吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.00(s,1H),6.93(s,1H),6.84(d,J=14.8Hz,1H),6.58(dd,J=7.6Hz,J=15.2Hz,1H),3.15(s,1H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.33-2.22(m,2H),2.09-1.91(m,6H),1.78-1.73(m,2H),1.62-1.50(m,1H),1.46-1.33(m,2H),0.82(t,J=7.2Hz,3H);MS(ESI):m/z(%)=418.22(100%)(M+H)+.
实施例-5
(R,E)-2-(1-(环丙基甲基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.42(brs,1H),8.03(s,1H),6.93(s,1H),6.87(d,J=15.2Hz,1H),6.62(dd,J=7.2Hz,J=15.2Hz,1H),3.38-3.22(m,3H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.60-2.57(m,1H),2.30-2.05(m,1H),2.04-1.91(m,5H),1.87-1.71(m,2H),1.70-1.50(m,1H),0.91-0.67(m,1H),0.53-0.35(m,2H),0.18-0.09(m,2H);MS(ESI):m/z(%)=430.20(100%)(M+H)+,428.11(100%)(M-1).
实施例-6
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯-1-磺酰胺
在0℃下向中间体3a(1当量)在DCM(2.5mL)中的溶液添加TFA(1当量)。将反应升温至室温,并进一步搅拌3小时。反应混合物在真空中浓缩并通过制备型HPLC纯化以得到产物。在室温下将固体NaHCO3(1.2当量)添加至该产物(1当量)在MeOH(7.0mL)中的溶液并搅拌5分钟。在室温下添加甲醛(37%溶液)(5当量)并搅拌2小时。此后,反应混合物在0℃下用NaBH4(1.5当量)分批处理,然后使反应混合物升温至室温,搅拌过夜。反应混合物经制备型HPLC纯化以得到纯产物。
或者,实施例6也按照描述合成中间体-7b(实施例111)的程序使用中间体9和(R)-1-甲基吡咯烷-2-甲醛连同有机合成领域技术人员已知的常规技术制备。
1H NMR(400MHz,DMSO-d6):δ=10.53(brs,1H),7.97(s,1H),6.92(s,1H),6.84(d,J=15.2Hz,1H),6.53(dd,J=7.6Hz,J=15.2Hz,1H),3.13-3.04(m,1H),3.05-2.92(m,1H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.33-2.28(m,1H),2.26(s,3H),2.05-1.91(m,5H),1.79-1.72(m,2H),1.59-1.54(m,1H);MS(ESI):m/z(%)=390.17(100%)(M+H)+,388.07(30%)(M-1)
实施例-7
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(甲基磺酰基)-吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.55(bs,1H),8.06(s,1H),6.94(s,1H),6.79-6.69(m,2H),4.50-4.47(m,1H),3.34-3.33(m,1H),2.94(s,3H),2.80(t,J=7.2Hz、4H),2.68(t,J=7.6Hz,4H),2.11H2.07(m,2H),1.95(五重峰,J=7.6Hz,4H),1.88-1.85(m,1H),1.80-1.79(m,2H),MS(ESI):m/z(%)=454.17(100%)(M+H)+.
实施例-8
(R,E)-2-(1-乙酰基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.25(bs,1H),8.07(s,1H),6.95(s,1H),6.73-6.67(m,1H),6.63(d,J=15.2Hz,1H),4.69-4.62(m,1H),3.55-3.42(m,1H),2.83(t,J=7.2Hz,4H),2.69(q,J=7,2Hz,4H),2.21-2.09(m,1H),2.01-1.95(m,6H),1.85(s,3H),1.82-1.72(m,2H);MS(ESI):m/z(%)=418.20(100%)(M+H)+.
实施例-9
(E)-2-(1-苄基哌啶-4-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.23(br s,1H),8.02(s,1H),7.35-7.25(s,5H),6.94(s,1H),6.76-6.63(m,2H),3.55(s,2H),2.89-2.69(m,6H),2.65(t,J=7.2Hz,4H),2.30-2.27(m,1H),2.12-2.07(m,2H),2.00-1.91(m,4H),1.71-1.69(m,2H),1.43-1.38(m,2H);MS(ESI):m/z(%)=480.23(100%)(M+H)+.
实施例-10
(R,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)-乙烯基)吡咯烷-1-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=1042(s,1H),8.09(s,1H),6.96(s,1H),6.71-6.68(m,1H),6.59(d,J=14.8Hz,1H),4.45-4.38(m,1H),3.29-3.27(m,2H),2.79(t,J=7.2Hz,4H),2.65(t,J=7.2Hz,4H),2.30-1.93(m,5H),1.78-1.71(m,3H),1.39-1.33(m,9H);MS(ESI):m/z(%)=498.18(40%)(M+Na)+,474.18(100%)(M-1).
实施例-11
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2-甲氧基乙基)吡咯烷-2-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.38(s,1H),6.77(s,1H),6.67(d,J=15.2Hz,1H),6.04(dd,J1=8.0Hz,J2=15.2Hz,1H),3.37(t,J=6.0Hz,2H),3.37(s,3H),3.13-3.10(m,1H),2.82-2.74(m,6H),2.69(t,J=7.2Hz,4H),2.22-2.13(m,2H),1.95-1.93(m,5H),1.76-1.67(m,2H),1.48-1.41(m,1H);MS(ESI):m/z(%)=434.19(100%)(M+H)+.
实施例-12
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(异丙基磺酰基)吡咯烷-2-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.34(s,1H),6.77(s,1H),6.67(d,J=15.2Hz,1H),6.20-6.19(m,1H),4.39(bs,1H),3.46(q,J=9.6Hz,1H),3.29-3.24(m,2H),2.76(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),2.09-2.04(m,1H),1.93(t,J=7.2Hz,4H),1.87(t,J=8.4Hz,4H),1.73-1.69(m,1H),1.19(d,J=6.4Hz,6H);MS(ESI):m/z(%)=482.13(65%)(M+H)+,504.10(100%)(M+Na)+;
实施例-13
(R,E)-2-(1-((3-氟苯基)磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6);δ=10.46(s,1H),8.07(s,1H),7.71-7.70(m,3H),7.62-7.58(m,1H),6.95(s,1H),6.90(d,J=14.8Hz,1H),6.74(dd,J1=5.6Hz,J2=15.2Hz 1H),4.49(t,J=5.6Hz,1H),3.42-3.38(m,1H),3.18-3.14(m,1H),2.80(t,J=7.6Hz,4H),2.69(t,J=7.2Hz,4H),1.96(五重峰,.J=7.2Hz,4H),1.76-1.60(m,3H),1.55-1.52(m,1H);MS(ES1)m/z(%)=534.18(100%)(M+H)+;
实施例-14
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(吡嗪-2-羰基)吡咯烷-2-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.46(s,1H),8.95-8.88(m,1H),8.78-8.65(m,1H),8.70-8.57(m,1H),8.04(s,1H),6.93(s,1H),6.76(d,J=15.6Hz,1H),6.95(d,J=15.2Hz,1H),4.93-4.90(m,1H),3.84-3.81(m,1H),3.66-3.59(m,1H),2.82(t,J=8.0Hz,4H),2.66(t,J=7.6Hz,4H),2.16-1.97(m,1H),1.95-1.78(m,7H);MS(ESI):m/z(%)=482.16(100%)(M+H)+.
实施例-15
(R,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-甲酰胺
1H NMR(400MHz,DMSO-d6):δ=7.95(s,1H),6.91(s,1H,6.58-6.52(m,2H),5.77(s,2H),4.51-4.48(m,1H),325-3.21(m,1H),2.80(t,J=7,2Hz,4H),2.68(t,J=6.8Hz,4H),2.00-1.91(m,6H),1.81-1.69(m,3H);MS(ESI):m/z(%)=419.16(100%)(M+H)+.
实施例.16
(R,E)-2-(1-(环丙烷羰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.45(s,1H),8.11(d,J=14.4Hz,1H),6.96(s,1H),6.87-6.52(m,2H),4.97-4.65(m,1H),3.76-3.61(m,1H),3.41-3.32(m,1H),2.81(t,J=7.2Hz,4H),2.67(q,J=6.0Hz,4H),2.17-216(m,1H),2.02-1.95(m,5H),1.88-1.74(m,3H),1.76-0.69(m,2H),0.66-0.59(m,2H);MS(ESI):m/z(%)=444.15(100%)(M+H)+.
实施例-17
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2,2,2-三氟乙酰基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.45(s,1H),8.03(s,1H),6.94(s,1H),6.76-6.67(m,2H),4.80(bs,1H),3.75(bs,1H),3.67-3.54(m,1H),2.80(t,J=7.6Hz,4H),2.67(t,J=6.4Hz,4H),2.15-2.5(m,1H),2.00-1.91(m,6H),1.81-1.76(m,1H);MS(ESI):m/z(%)=472.14(100%)(M-H)+.
实施例-18
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2-(甲硫基)乙基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.38(s,1H),8.06(s,1H),6.95(s,1H),6.91(d,J=14.8Hz,1H),6.68(d,J=15.2Hz,1H),3.21-3.12(m,2H),2.81(t,J=7.2Hz,5H),2.68(t,J=7.2Hz,5H),2.46-2.40(m,1H),2.33-2.24(m,1H),2.09-1.91(m,9H),1.74-1.70(m,2H),1.54-1.49(m,1H);MS(ESI):m/z(%)=450.14(100%)(M+H)+.
实施例-19
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2,2,2-三氟乙基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.91(s,1H),6.88(s,1H),6.76(d,J=15.2Hz,1H),6.41(dd,J1=7.2Hz,J2,14.8,1H),3.34-3.21(m,1H),3.16-3.09(m,2H),2.78(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.59-2.54(m,1H),2.02-1.91(m,6H),1.80-1.75(m,2H),1.57-1.48(m,1H);MS(ESI):m/z(%)=458.15(100%)(M+H)+.
实施例-20
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-异丁基吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.4(brs,1H),8.00(s,1H),6.92(s,1H),6.80(d,J=15.2Hz,1H),6.56(dd,J=15.2Hz,J=6.8Hz,1H),3.12-3.00(m,3H),2.80(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.25-2.14(m,2H),2.10-204(m,2H),1.99-1.91(m,4H),1.76-1.65(m,2H),1.55-1.48(m,1H),0.85(t,J=6.8Hz,3H),0.79(d,J=6.4Hz,3H);MS(ES1):m/z(%)=432.21(100%)(M+H)+.
实施例-21
(R,E)-2-(1-(乙基磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.39(brs,1H),8.01(s,1H),7.38(s,1H),6.77(d,J=15.2Hz,1H),6.68(dd,J=15.2Hz,J=5.2Hz,1H),4.63-4.39(m,1H),3.38-3.33(m,2H),3.09-2.97(m,2H),2.80(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.15-2.04(m,1H),2.00-1.91(m,4H),1.88-1.77(m,3H),1.19(t,J=72Hz,3H);MS(ESI):m/z(%)=468.12(100%)(M+H)+.
实施例-22
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-异丙基吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.23(brs,1H),7.96(s,1H),6.92(s,1H),6.89(d,J=15.2Hz,1H),6.61(d,J=15.2Hz,J=7.2Hz,1H),298-2.85(m,2H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.51-2(50(m,1H),2.02-1.91(m,6H),1.75-1.73(m,2H),1.61-1.56(m,1H),1.04(d,J=6.4Hz,3H),0.99(d,J=6.4Hz,3H);MS(ESI):m/z(%)=418.21(100%)(M+H)+,416.18(100%)(M-1).
实施例-23
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(3-(甲基磺酰基)丙基)吡咯烷-2-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.37(brs,1H),8.08(s,1H),6.95(s,1H),6.82(d,J=14.8Hz,1H),6.61(d,J=14.8Hz,J=7.2Hz,1H),3.13-3.06(m,3H),2.98-2.91(m,1H),2.86(s,3H),2.67(t,J=7.2Hz,4H),2.81(t,J=7.2Hz,4H),2.33-2.28(m,1H),2.27-2.20(m,1H),2.03-1.91(m,6H),1.83-1.72(m,4H),1.57-1.50(m,1H);MS(ESI):m/z(%)=496.16(100%)(M+H)+,494.15(100%)(M-1).
实施例-24
(R,E)-2-(1-苯甲酰基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.41(brs,1H),8.03(s,1H),7.54-7.30(m,5H),6.93(s,1H),6.80-6.50(m,2H),4.85-4.49(m,1H),3.62-3.36(m,2H),2.78(t,J=6.8Hz,4H),2.66(t,J=6.8Hz,4H),2.19-2.08(m,1H),1.9411.90(m,4H),1(82-1.76(m,3H);MS(ESI):m/z(%)=480.17(100%)(M+H)+,478.15(100%)(M-1).
实施例-25
(R,E)-N-((2-(1-苯甲酰基吡咯烷-2-基)乙烯基)磺酰基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)苯甲酰胺
1H NMR(400MHz,DMSO-d6):δ=7.61-7.52(m,2H),7.47-7.32(m,8H),7.22-7.09(m,1H),6.97(s,1H),6.56(d,J=14.4Hz,1H),6.31(d,J=14.4Hz,1H),4.76-4.37(m,1H),3.78-3.42(m,1H),2.84-2.67(m,8H),2.10-2.05(m,1H),1.95-1.91(m,4H),1.84-1.76(m,3H),1.68-1.64(m,1H);MS(ESI):m/z(%)=584.19(100%)(M+H)+,606.17(50%)(M+Na),582.17(10%)(M-1).
实施例-26
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.54(s,1H),6.81(s,1H),6.70(d,J=15.2Hz,1H),6.33-6.26(m,1H),3.53-3.46(m,2H),3.15-3.00(m,3H),2.77(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),2.03-1.81(m,7H),1.62-1.43(m,1H);MS(ESI):m/z(%)=390.16(100%)(M+H)+,388.14(100%)(M-1).
实施例-27
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(噻吩-3-羰基)吡咯烷-2-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.36(brs,1H),8.01(s,1H),7.58-7.48(m,1H),7.36-7.22(m,1H),6,93(s,1H),6.81-6.56(m,2H),4.83-4.74(m,1H),378-3.67(m,1H),3.66-352(m,1H),2.79(t,J=72Hz,4H),2.66(t,J=6.8Hz,4H),2.15-1.76(m,8H);MS(ESI):m/z(%)=486.13(100%)(M+H)+,484.11(100%)(M-1).
实施例-28
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺甲磺酸盐
程序:在室温下向(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺(0.105g,0.28mmol)在EtOH(2.0mL)中的溶液添加甲磺酸(27mg,0.280mmol)。使反应回流1小时,然后冷却至室温,形成沉淀,然后通过布氏漏斗过滤,真空干燥以得到产物。
1H NMR(400MHz,DMSO-d6):δ=10.59(brs,1H),9.05(brs,2H),8.27(s,1H),7.13(d,J=15.2Hz,1H),6.97(s,1H),6.90-6.85(m,1H),4.32-4.30(m,1H),3.32-3.12(m,2H),3.99-3.78(m,4H),3.75-3.66(m,4H),2.37(s,1H),2.28-2.12(m,1H),2.10-1.88(m,6H),1.27-1.22(m,1H);MS(ESI):m/z(%)=376.10(100%)(M+H)+.
实施例-29
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺马来酸盐
程序:在室温下向(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺(0.2g,0.533mmol)在EtOH(4.0mL)中的溶液添加马来酸(0.124g,1.07mmol)。使反应回流30分钟。然后冷却至室温,形成沉淀,然后通过布氏漏斗过滤,真空干燥以得到产物。
1H NMR(400MHz,DMSO-d6):δ=9.06(brs,1H),8.15(s,1H),7.12(d,J=15.6Hz,1H),6.96(s,1H),6.87-6.82(m,1H),6.03(s,2H),4.29-4.03(m,4H),3.57-3.23(m,2H),2.98-2.83(m,4H),2.85-2.69(m,4H),2.26-2.10(m,1H),2.09-1.83(m,6H),1.82-163(m,1H);MS(ESI):m/z(%)=376.15(100%)(M+H)+.
实施例-30
(R,Z)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=9.70(brs,1H),7.94(s,1H),6.83(s,1H),6.36(dd,J=11.6Hz,J=1.6Hz,1H),5.82(dd,J=11.2Hz,J=6.0Hz,1H),4.95-4.94(m,1H),3.17-3.03(m,1H),2.99-2.89(m,1H),2.79-2.63(m,9H),2.03-1.76(m,8H);MS(ESI):m/z(%)=376.16(60%)(M+H)+.
实施例-31
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-3-(吡咯烷-2-基)丙-1-烯-1-磺酰胺
程序:在0℃下向相应的N-Boc衍生物(0.20g,0.408mmol)在DCM(2.5mL)中的溶液添加TFA(0.315mL,4.08mmol)。将反应升温至室温并进一步搅拌3小时。反应混合物在真空中浓缩并通过制备型HPLC纯化以得到产物。
1H NMR(400MHz,DMSO-d6):δ=7.54(s,1H),6.80(s,1H),6.69(d,J=15.2Hz,1H),6.29-6.25(m,1H),3.52-344(m,2H),3.17-3.02(m,3H),2.77(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),2.01-1.76(m,8H),1.53-1.50(m,1H);MS(ESI):m/z(%)=390.16(100%)(M+H)+.
实施例-32
(R,E)-2-(1-(环己基磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.4(brs,1H),8.04(s,1H),6.94(s,1H),6.78(d,J=15.2Hz,1H),6.69(dd,J=15.2Hz,J=6.0Hz,1H),4.57-4.53(m,1H),3.45-3.39(m,1H),3.31-3.27(m,1H),3.14-3.08(m,1H),2.80(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.17-2.09(m,1H),2.00-1.91(m,5H),1.88-1.60(m,5H),1.55-1.52(m,1H),1.40-1.00(m,6H);MS(ESI):m/z(%)=522.20(100%)(M+H)+,544.25(100%)(M+Na),520.15(100%)(M-1).
实施例-33
(R,Z)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.85(s,1H),6.84(s,1H),6.52(dd,J=11.2Hz,J=1.2Hz,1H),5.84(dd,J=11.2Hz,J=8.0Hz,1H),4.54-4.53(m,1H),3.24-3.18(m,2H),2,77(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),2.56(s,3H),233-2.18(m,1H),1.99-1.91(m,8H),1.85-1.70(m,1H);MS(ESI):m/z(%)=390.20(100%)(M+H)+,388(100%)(M-1).
实施例-34
(R,E)-2-(1-(环己基甲基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.38(brs,1H),8.06(s,1H),6.94(s,1H),6.82(d,J=14.8Hz,1H),6.62(dd,J=15.2Hz,J=6.8Hz,1H),3.00-3.17(m,2H),2.80(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.40-2.28(m,1H),2.26-2.13(m,1H),2.12-1.90(m,6H),1.89-1.82(m,1H),1.81-1.67(m,2H),1.66-1.47(m,5H),1.45-1.30(m,1H),1.28-0.92(m,3H),0.78-0.69(m,2H);MS(ESI):m/z(%)=472.29(100%)(M+H)+.
实施例-35
(R,E)-2-(1-环己基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.38(brs,1H),8.01(s,1H),6.92(s,1H),6.85(d,J=15.2Hz,1H),6.65(dd,J=14.4Hz,J=6.4Hz,1H),3.90-3.62(m,1H),3.09-2.96(m,1H),2.80(t,J=7.2Hz,4H),2.70-2.67(m,5H),1.99-1.91(m,6H),1.83-1.63(m,7H),1.58-1.50(m,1H),1.27-1.02(m,5H);MS(ESI):m/z(%)=458.29(100%)(M+H)+.
实施例-36
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(1-甲基哌啶-4-基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.46(s,1H),7.29(s,1H),6.77(s,1H),6.64(d,J=15.2Hz,1H),6.11(dd,J=15.2Hz,J=8.0Hz,1H),3.35-3.30(m,1H),2.84-2.80(m,1H),2.76(t,J=7.2Hz,4H),2.72-2.68(m,5H),2.34-2.29(m,1H),2.09(s,3H),1.05-1.88(m,4H),1.85-1.77(m,4H),1.76-1.60(m,4H),1.50-1.35(m,3H);MS(ESI):m/z(%)=473.32(100%)(M+H)+。
实施例-37
(R,Z)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-异丙基吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.14(brs,1H),7.73(s,1H),6.85(s,1H),6.59(d,J=11.2Hz,1H),6.04-5.99(m,1H),4.91-4.89(m,1H),3.48-3.45(m,1H),3.26-3.20(m,1H),3.17-3.01(m,1H),2.78(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),2.25-2.18(m,1H),1.97-1.85(m,6H),1.75-1.66(m,1H),1.22(d,=6.8Hz,3H),1.17(t,J=6.4Hz,3H);MS(ESI):m/z(%)=418.23(100%)(M+H)+,416.21(100%)(M-1).
实施例-38
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(四氢-2H-吡喃-4-基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.30(brs,1H),8.05(s,1H),6.95(s,1H),6.85(d,J=15.2Hz,1H),6.70(dd,J=14.8Hz,J=6.4Hz,1H),3.83-3.73(m,2H),3.69-3.59(m,1H),3.23-3.15(m,2H),3.03-2.91(m,1H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.58-2.53(m,2H),2.00-1.91(m,5H),1.71-1.62(m,3H),1.58-1.52(m,2H),1.42-1.33(m,2H);MS(ESI):m/z(%)=460.30(100%)(M+H)+.
实施例-39
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(氧杂环丁烷-3-基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.41(brs,1H),8.10(s,1H),6.96(s,1H),6.83(d,J=14.8Hz,1H),6.61(dd,J=15.2Hz,J=8.0Hz,1H),4.51-4.44(m,2H),4.43-4.38(m,2H),3.81-3.74(m,1H),3.23-3.17(m,1H),3.00-2.95(m,1H),2.81(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.41-2.33(m,1H),2.01-1.91(m,5H),1.78-1.71(m,2H),1.62-1.55(m,1H);MS(ESI):m/z(%)=432.22(100%)(M+H)+.
实施例-40
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(四氢-2H-噻喃-4-基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.32(brs,1H),8.06(s,1H),6.95(s,1H),6.84(d,J=14.8Hz,1H),6.64(dd,J=14.8Hz,J=6.4Hz,1H),3.71-3.58(m,1H),2.98-2.87(m,1H),2.81(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.63-2.58(m,2H),2.54-2.51(m,2H),2.48-2.38(m,2H),2.13-2.01(m,1H),1.99-1.89(m,6H),1.76-1.62(m,2H),1.58-1.45(m,3H);MS(ESI):m/z(%)=476.24(100%)(M+H)+.
实施例-41
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(噻唑-2-基甲基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.33(brs,1H),8.08(s,1H),7.71(d,J=3.2Hz,1H),6.41(d,J=3.2Hz,1H),6.92-6.86(m,2H),6.70(dd,J=15.2Hz,J=6.8Hz,1H),4.04(d,J=14.8Hz,1H),3.78(d,J=14.8Hz,1H),3.44-3.39(m,1H),3.07-3.02(m,1H),2.77(t,J=6.8Hz,4H),2.61(t,J=6.8Hz,4H),2.43-2.33(m,1H),2.08-1.97(m,1H),1.96-1.87(m,4H),1.80-1.74(m,2H),1.63-1.57(m,1H);MS(ESI):m/z(%)=473.19(100%)(M+H)+
实施例-42
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(哌啶-4-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):ε=10.55(s,1H),8.78(s,1H),8.26(s,2H),6.95(s,1H),6.79-6.70(m,2H),3.29(d,J=11.2Hz,2H),2.80(t,J=6.8Hz,4H),2.66(t,J=6.4Hz,4H),1.95(t,J=6.8Hz,4H),1.90(d,J=13.2Hz,2H);MS(ESI):m/z(%)=390.20(100%)(M+H)+.
实施例-43
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基哌啶-4-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.80(s,1H),6.86(s,1H),6.64(s,1H),6.60(d,J=16.4Hz,1H),6.48(dd,J1=6.0Hz,J2=15.2Hz 1H),3.03-2.99(m,3H),2.78(t,J=7.6Hz,4H),2.68(t,J=7.6Hz,4H),2.38(s,3H),2.36-2.24(m,2H),1.94(t,J=7.2Hz,4H),1.77-1.74(m,2H),1.47-1.37(m,2H);MS(ESI):m/z(%)=404.20(100%)(M+H)+.
实施例-44
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(甲基磺酰基)哌啶-4-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.37(bs,1H),8.11(s,1H),6.96(s,1H),6.78-6.7(m,2H),3.57(d,J=12.0Hz,2H),2.85(s,3H),2.81(t,J=7.2Hz,4H),2.75-2.67(m,6H),1.97(t,J=7.2Hz,4H),1.82(d,J=11.6Hz,2H),1.45-1.37(m,2H);MS(ESI):m/z(%)=468.12(100%)(M+H)+.
实施例-45
E)-2-(1-乙酰基哌啶-4-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.38(bs,1H),8.04(s,1H),6.94(s,1H),6.64(dd,JI=5.6Hz,J2=15.6Hz,1H),6.68(d,J=15.6Hz,1H),4.33(d,J=13.3Hz,1H),3.81(d,J=14.4Hz,1H),3.06(t,J=12.0Hz,1H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.63-2.56(m,2H),2.00-1.91(m,7H),1.72(t,J=15.6Hz,2H),1.35-1.24(m,1H),1.21-1.11(m,1H);MS(ESI):m/z(%)=432.17(J00%)(M+H)+.
实施例-46
(E)-4-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-哌啶-1-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.37(bs,1H),8.05(s,1H),6.96(s,1H),6.8(dd,J1=6.0Hz,J2=15.2Hz,1H),6.69(d,J=15.6Hz,1H),3.93(d,J=11.6Hz,2H),2.81(t,J=7.2Hz,6H),2.66(t,J=6.8Hz,4H),1.97(t,J=7.2Hz,4H),1.71(d,J=11.6Hz,2H),1.39(s,9H),1.23-1.17(m,3H);MS(ESI):m/z(%)=488.18(100%)(M-H)+.
实施例-47
(E)-2-(1-乙基哌啶-4-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.87(s,1H),6.94(s,1H),6.65(d,J=15.6Hz,1H),6.52(dd,J1=6.0Hz,J2=15.2Hz,1H),3.16(d,J=11.6Hz,3H),2.79(t,J=7.2Hz,4H),2.73-2.67(m,6H),1.98-1.91(m,5H),1.82-1.75(m,3H),1.52-1.44(m,2H),1.10(t,J=7.2Hz,3H),MS(ESI):m/z(%)=418.18(100%)(M+H)+,416.17(100%)(M-1)-.
实施例-48
(R,E)-2-(1-乙基吡咯烷-3-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙烯磺酰胺
1H NMR(400MHz,MSO-d6):δ=7.95(s,1H),6.43(s,1H),6.60(d,J=14.4Hz,1H),6.55-6.45(m,1H),3.18(d,J=4.8Hz,2H),3.05-2.95(m,4H),.2.79(t,J=7.2Hz,4H),2.73-2.67(m,5H),1.95(t,J=7.2Hz,4H),1.55(t,J=7.2Hz,3H),1.09(t,J=7.2Hz,2H);MS(ESI):m/z(%)=404.18(100%)(M+H)+.
实施例-49
1H NMR(400MHz,DMSO-d6):δ=7.27(s,1H),6.77(s,1H),6.73(s,1H),6.27(dd,J1=6.8Hz,J2=15.6Hz,1H),5.59(bs,1H),4.12(s,1H),3.78-3.72(m,2H),3.62(t,J=7.6Hz,1H),3.54(t,J=8.0Hz,1H),3.41-3.36(m,2H),3.30-3.24(m,2H),2.76-2.69(m,8H),2.33-2.25(m,1H),1.93-2.90(m,4H),1.20(t,J=6.8Hz,6H);MS(ESI):m/z(%)=432.20(100%)(M)+.
实施例-50
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-3-基)乙烯-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.41(s,1H),6.78(s,1H),6.64(d,J=15.6Hz,1H),6.23(dd,J1=7.6Hz,J2=15.2Hz,1H),3.18-3.14(m,1H),2.99-2.95(m,1H),2.76(t,J=7.6Hz,4H),2.70(t,J=7.2Hz,4H),2.00-1.97(m,2H),1.95(t,J=7.6Hz,4H),1.90-1.88(m,2H),1.76-1.54(m,1H);MS(ESI):m/z(%)=376.15(100%)(M+H)+。
实施例-51
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.56(s,1H),6.91(d,J=156Hz,1H),6.82(s,1H),6.52(d,J=152Hz,1H),3.23-3.19(m,2H),3.14-3.07(m,1H),2.77(t,J=7.6Hz,4H),2.69(t,J=7.2Hz,4H),1.96-1.87(m,8H),1.79-1.74(m,1H),1.34(s,3H);MS(ESI):m/Hz(%)=390.14(100%)(M+H)+.
实施例-52
(R,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.41(s,1H),8.05(s,1H),6.95(s,1H),6.87(d,J=16.0Hz,1H),6.56(d,J=15.6Hz,1H),3.38-3.32(m,2H),2.82(t,J=7.6Hz,4H),2.75(t,J=7.2Hz,4H),1.95(t,J=7.2Hz,5H),1.86-1.69(m,3H),1.48-1.41(m,3H),1.34(s,9H);MS(ESI):m/z(%)=488.16(100%)(M-H)+.
实施例-53
(R,E)-2-(1-乙酰基-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.40(s,1H),8,06(s,1H),6.96(s,1H),6.91(d,J=15.6Hz,1H),6.58(d,J=15.2Hz,1H),3.57-3.50(m,2H),2.81(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.01-1.88(m,8H),1.82-1.74(m,3H),1.52(s,3H);MS(ESI):m/z(%)=432.09(100%)(M+H)+.
实施例-54
1H NMR(400MHz,DMSO-d6):δ=6.88(s,1H),6.65(d,J=15.6Hz,1H),6.21-6.15(m,1H),2.84-2.75(m,6H),2.68-2.58(m,3H),2.35-2.29(m,2H),1.96-1.91(m,7H),1.76-1.59(m,4H),0.97(t,J=7.2Hz,6H),0.88(s,3H);MS(ESI):m/z(%)=446.19(100%)(M+H)+.
实施例-55
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基-1-(甲基磺酰基)-吡咯烷-2-基)乙烯-1-磺酰胺;:
1H NMR(400MHz,DMSO-d6):δ=10.43(bs,1H),8.09(s,1H),6.96(s,1H),6.90(d,J=15.2Hz,1H),6.72(d,J=15.2Hz,1H),3.44(t,J=6.0Hz,2H),2.95(s,3H),2.81(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.07-1.83(m,7H),1.79-1.74(m,1H),1.24(s,3H),MS(ESI):m/z(%)=468.11(100%)(M+H)+.
实施例-56
(R,E)-2-(1,2-二甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.04(s,1H),6.93(s,1H),6.74(d,J=15.6Hz,1H),6.65(d,J=15.2Hz,1H),2.93-2.86(m,1H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.19(s,3H),1.99-1.91(m,5H),1.80-1.69(m,4H),1.13(s,3H),MS(ESI):m/z(%)=404.16(100%)(M+H)+.
或者,实施例56也按照描述合成中间体-7b(实施例111)的程序使用中间体9和(R)-1,2-二甲基吡咯烷-2-甲醛连同有机合成领域技术人员已知的常规技术制备。
实施例-57
(R,E)-2-(1-乙基-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.82(bs,1H),6.96(s,1H),6.92(d,J=9.6Hz,1H),6.41(m,1H),3.60-3.51(m,2H),3.22-3.17(m,2H),2.80-2.73(m,5H),2.61(t,J=7.2Hz,4H),1.97-1.93(m,6H),1.84-1.80(m,1H),1.53(s,3H),0.90(t,J=6.4Hz,3H);MS(ESI):m/z(%)=418.18(100%)(M+H)+;
实施例-58
(R,E)-2-(1-(环丙基甲基)-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.39(s,IH),8.06(s,1H),6.94(s,1H),6.75(d,J=15.6Hz,1H),6.69(d,J=15.6Hz,1H),3.18-3.13(m,1H),2.80(t,J=7.2Hz,5H),2.67(t,J=7.2Hz,4H),2.33-2.11(m,2H),1.94(t,J=7.2Hz,4H),1.80-1.71(m,4H),1.12(s,3H),0.86-0.79(m,1H),0.42(五重峰,J=8.8Hz,2H),0.05-0.04(m,2H);MS(ESI):m/z(%)=444.17(100%)(M+H).
实施例-59
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-磺酰胺
1H NMR(400MHz,DMSO):δ=8.75(bs,1H),7.50(s,1H),6.95(d,J=15.6Hz,1H),6.80(s,1H),6.39-6.33(m,1H),4.08-4.02(m,1H),3.16-4.11(m,2H),2.77(t,J=7.2Hz,4H),2.71(t,J=7.2Hz,4H),2.12-2.08(m,1H),1.96-1.85(m,6H),1.68-1.62(m,1H);MS(ESI):m/z(%)=376.16(100%)(M+H)+.
实施例-60
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯磺酰胺
1H NMR(400MHz,DMSO):δ=8.00(s,1H),6.93(s,1H),6.85(d,J=15.2Hz,1H),6.58-6.52(m,1H),3.12-3.04(m,2H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.36-2.31(m,1H),2.27(s,3H),2.08-1.91(m,5H),1.80-1.72(m,2H),1.70-1.50(m,1H);MS(ESI):m/z(%)=390.17(100%)(M+H)+.
实施例-61
(S,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-羧酸叔丁酯
1H NMR(400MHz,DMSO):δ=10.42(bs,1H),8.09(s,1H),6.96(s,1H),6.71-6.67(m,1H),6.61-6.57(m,1H),4.45-4.38(m,1H),3.29-3.25(m,2H),2.81(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.09-1.93(m,5H),1.78-1.71(m,3H),1.33(s,9H);MS(ESI):m/z(%)=498.18(80%)(M+Na)+.
实施例-62
(S,E)-2-(1-(环丙基甲基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.32(bs,1H),8.02(bs,1H),6.93(s,1H),6.86(d,J=14.8Hz,1H),6.64-6.50(m,1H),3.50-3.20(m,3H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.61-2.56(m,1H),2.15-1.91(m,6H),1.85-1.78(m,2H),1.62-1.53(m,1H),0.86-0.80(m,1H),0.50-0.30(m,2H),0.15-0.14(m,2H);MS(ESI):m/z(%)=430.19(100%)(M+H)+.
实施例-63
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(吡啶-3-基磺酰基)-吡咯烷-2-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.40(bs,1H),9.02(d,=2.0Hz,1H),8.90-8.88(m,1H),8.29-8.26(m,1H),8.04(s,1H),7.68-7.65(m,1H),6.94-6.87(m,2H),6.72-6.67(m,1H),4.52-4.49(m,1H),3.44-3.42(m,1H),3.21-3.15(m,1H),2.80(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),1.99-1.91(m,4H),1.76-1.65(m,4H);MS(ESI):m/z(%)=51711(100%)(M+H)+.
实施例-64
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(吡咯烷-2-基)乙烯磺酰胺
1H NMR(400MHz,DMSO):δ=9.50(bs,1H),7.48(bs,1H),7.17-7.05(m,3H),6.99-6.88(m,1H),6.43(bs,1H),4.15-3.90(m,1H),3.20-3.00(m,4H),2.15-2.00(m,1H),1.99-1.80(m,3H),1.79-1.60(m,1H),1.20-1.00(m,12H);MS(ESI):m/z(%)=380.16(100%)(M+H)+.
实施例-65
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1-乙基吡咯烷-2-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.60(bs,1H),7.86(s,1H),7.27-7.23(m,1H),7.15-7.13(m,2H),6.84(d,J=15.2Hz,1H),6.66-6.61(m,1H),3.32-3.02(m,4H),2.75-2.60(m,1H),2.41-2.25(m,2H),2.05-1.96(m,1H),1.90-1.70(m,2H),1.65-1.45(m,1H),1.12-1.11(m,12H),1.01(t,J=7.2Hz,3H);MS(ESI):m/z(%)=408.19(100%)(M+H)+.
实施例-66
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1-(甲基磺酰基)吡咯烷-2-基)乙烯-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.81(s,1H),7.25-7.21(m,1H),7.13-7.11(m,2H),6.75-6.64(m,2H),4.46(s,1H),3.29-3.24(m,1H),3.10-3.03(m,2H),2.93(s,3H),2.09-2.04(m,1H),1.89-1.83(m,1H),1.77-1.73(m,3H),1.12-1.11(m,12H);MS(ESI):m/z(%)=458.15(100%)(M+H)+.
实施例-67
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.69(s,1H),7.22-7.18(m,1H),7.11-7.09(m,2H),6.75(d,J=15.2Hz,1H),6.55-6.30(m,1H),3.12-2.99(m,3H),2,79-2.76(m,1H),2.23-2.18(m,4H),2.00-1.95(m,1H),1,76-1.68(m,2H),1.54-1.49(m,1H),1.11-1.09(m,12H);MS(ESI):m/z(%)=394.19(100%)(M+H)+.
实施例-68
(S,E)-2-(1-乙酰基吡咯烷-2-基)-N-((2,6-二异丙基苯基)氨甲酰基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.55(bs,1H),7.89-7.86(m,1H),7.28-7.23(m,1H),7.15-7.13(m,2H),6.76-6.69(m,1H),6.63-6.53(m,1H),4.68-4.61(m,1H),3.52-3.39(m,1H),3.08-3.02(m,2H),1.97(s,3H),1.93-1.70(m,5H),1.13-1.11(m,12H);MS(ESI):m/z(%)=422.18(100%)(M+H)+.
实施例-69
(S,E)-2-(1-乙酰基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.30(bs,1H),8.11-8.05(m,1H),6.95(s,1H),6.78-6.56(m,2H),4.72-4.62(m,1H),3.57-3.35(m,2H),2.81(t,J=7.2Hz,4H),2.67(q,J=7.2Hz,4H),1.99-1.95(m,6H),1.85(s,3H),1.84-1.71(m,2H);MS(ESI):m/z(%)=418.16(100%)(M+H)+.
实施例-70
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(四氢-2H-吡喃-4-羰基)吡咯烷-2-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.40(bs,1H),8.03(s,1H),6.94-6.93(m,1H),6.74-6.49(m,2H),6.64-6.50(m,1H),4.84-4.65(m,1H),3.87-3.78(m,2H),3.64-3.52(m,1H),3.50-3.25(m,2H),2.81(t,J=7.6Hz,4H),2.73-2.67(m,5H),2.01-1.89(m,5H),1.82-1.72(m,3H),1.61-1.49(m,4H);MS(ESI):m/z(%)=488.21(100%)(M+H)+.
实施例-71
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(四氢-2H-吡喃-4-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.33(bs,1H),8.07(s,1H),6.96(s,1H),6.80-6.74(m,1H),6.69-6.65(m,1H),3.87-3.83(m,2H),3.37-3.34(m,3H),2.81(t,J=7.6Hz,4H),2.67(t,J=7.6Hz,4H),2.08-1.94(m,4H),1.65-1.62(m,2H),1.55-1.30(m,2H);MS(ESI):m/z(%)=391.15(100%)(M+H)+.
实施例-72
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-烟酰基吡咯烷-2-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.35(bs,1H),8.76-8.59(m,2H),8.05(s,1H),6.72(d,=8Hz,0.72H),7.77(d,J8Hz,0.23H),7.48-7.40(m,1H),6.94(s,1H),6.84(s,1H),6.57-6.55(m,1H),4.86-4.50(m,1H),3.65-3.59(m,1H),3.41-3.37(m,1H),2.78(t,J=7.6Hz,4H),2.65(t,J=7.6Hz,4H),2.20-2.13(m,1H),1.96-1.84(m,7H);MS(ESI):m/z(%)=481.18(100%)(M+H)+.
实施例-73
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(四氢呋喃-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.40(bs,1H),8.11(s,1H),6.96(s,1H),6.81(dd,J=4.0Hz,J=14.8Hz,1H),6.74(dd,J=1.2Hz,J=15.2Hz,1H),4.57-4.53(m,1H),3.86-3.81(m,1H),3.76-3.70(m,1H),2.8l(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.16-2.07(m,1H),2.01-1.94(m,4H),1.90-1.79(m,2H),1.67-1.62(m,1H);MS(ESI):m/z(%)=377.15(100%)(M+H)+.
实施例-74
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(噻吩-2-基甲基)-吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.40(bs,1H),8.10(s,1H),7.43-7.39(m,1H),7.01-6.86(m,4H),6.71-6.63(m,1H),3.93(d,J=14Hz,1H),3.58(d,J=14Hz,1H),3.28-324(m,1H),2.97-2.92(m,1H),2.77(t,J=7.2Hz,4H),2.63(t,J=7.2Hz,4H),2.33-2.04(m,1H),2.04-1.88(m,5H),1.75-1.68(m,2H),1.59-1.54(m,1H);MS(ESI):m/z(%)=472.12(100%)(M+H)+.
实施例-75
(S,E)-2-(2-(N-((4-氟-2,6-二异丙基苯基)氨甲酰基)氨磺酰基)乙烯基)-吡咯烷-1-羧酸叔丁酯
1H NMR(400MHz,DMSO):δ=10.06(bs,1H),7.93(s,1H),6.97-6.95(m,2H),6.72-6.55(m,2H),4.46-4.02(m,1H),3.30-3.26(m,2H),3.02-2.99(m,2H),2.22-1.99(m,1H),1.78-1.68(m,3H),1.45(s,9H),1.11(d,J=6.8Hz,12H);MS(ESI):m/z(%)=398.29(100%)(M-100)+;520.36(15%)(M+Na)+;496.32(100%)(M-H)+.
实施例-76
(S,E)-N-((4-氟-2,6-二异丙基苯基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO):δ=9.40(bs,1H),7.39(bs,1H),7.02-6.76(m,3H),639-6.22(m,1H),4.05-4.04(m,1H),3.17-3.13(m,4H),2.06-1.56(m,5H),1.10-1.09(m,12H);MS(ESI):m/z(%)=398.26(100%)(M-H)+.
实施例-77
(S,E)-N-((4-氟-2,6-二异丙基苯基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯-1-磺酰胺。
1H NMR(400MHz,DMSO-d6):δ=10.90(bs,1H),7.84(bs,1H),6.94(d,J=9.6Hz,2H),6.90(d,J=15.2Hz,1H),6.58-6.53(m,1H),3.08-2.95(m,4H),2.33-2.27(m,1H),2.23(s,3H),2.07-1.97(m,1H),1.78-1.73(m,2H),1.59-1.50(m,1H),6.75(d,J=6.8Hz,12H);MS(ESI):m/z(%)=41226(100%)(M+H)+.
实施例-78
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-异丁基-2-甲基-吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.03(bs,1H),6.89(s,1H),6.88(d,J=15.6Hz,1H),6.54(d,J=15.6Hz,1H),2.81-2.77(m,6H),2.70-2.57(m,5H),2.13-2.00(m,2H),1.98-1.91(m,4H),1.75-1.53(m,5H),1.06(s,3H),0.90-0.79(m,6H);MS(ESI):m/z(%)=446.26(100%)(M+H)+.
实施例-79
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基-1-丙基吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.99(bs,1H),6.90(s,1H),6.67(d,J=15.6Hz,1H),6.57(d,J=16.0Hz,1H),2.93-2.87(m,1H),2.79(t,J=7.2Hz,4H),2.70-2.66(m,5H),2.33-2.29(m,2H),1.99-1.91(m,4H),1.85-1.66(m,4H),1.45-1.33(m,2H),1.09(s,3H),0.80(t,J=7.6Hz,3H);MS(ESI):m/z(%)=432.25(100%)(M+H)+.
实施例-80
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(噻唑-2-基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,)MSO-d6):δ=10.4(bs,1H),8.09(s,1H),7.14(d,=3.6Hz,1H),6.96(s,1H),6.84-6.79(m,1H),6.75(d,J=3.6Hz,1H),6.72-6.66(m,1H),4.59-4.58(m,1H),3.58-3.53(m,1H),3.41-3.34(m,1H),2.81(t,J=7.2Hz,4H),2.64(t,J=7.2Hz,4H),2.30-2.18(m,1H),2.04-1.87(m,7H);MS(ESI):m/z(%)=459.17(100%)(M+H)+.
实施例-81
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(哌啶-3-基)乙烯-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.04(brs,1H),7.57(s,1H),6.81(s,1H),6.67(d,J=15.2Hz,1H),6.24(dd,J=15.2Hz,J=6.0Hz,1H),3.23-3.12(m,2H),2.77(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),2.51-2.49(m,2H),1.97-1.89(m,5H),1.79-1.76(m,2H),1.63-1.59(m,1H),1.37-1.29(m,1H);MS(ESI):m/z(%)=390.15(100%)(M+H)+.
实施例-82
(E)-2-(1-乙基哌啶-3-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.82(s,1H),6.94(s,1H),6.70(d,J=15.2Hz,1H),6.53(dd,J=15.2Hz,J=6.0Hz,1H),2.98-2.89(m,2H),2.79(t,J=7.2Hz,4H),268(t,J=7.2Hz,4H),2.57-2.54(m,2H),2.21-2.09(m,2H),1.99-1.91(m,4H),1.72-1.69(m,2H),1.58-1.50(m,1H),1.24-1.32(m,2H),1.05(t,J=7.2Hz,3H);MS(ESI):m/z(%)=418.18(100%)(M+H)+.
实施例-83
(E)-3-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-哌啶-1-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.4(brs,1H),7.93(s,1H),6.93(s,1H),6.74(d,J=15.2Hz,1H),6.61(dd,J=15.2Hz,J=6.8Hz,1H),3.75-3.64(m,2H),2.93-2.88(m,2H),2.80(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.38-2.33(m,1H),2.00-1.93(m,4H),1.80-1.70(m,1H),1.59-1.55(m,1H),1.39(s,9H),1.36-1.34(m,1H),0.91-0.81(m,1H);MS(ESI):m/z(%)=390.16(100%)[(M-100)+H]+,488.17(100%)(M-1).
实施例-84
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(甲基磺酰基)哌啶-3-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.4(brs,1H),7.98(s,1H),6.93(s,1H),6.79(d4J=15.2Hz,1H),6.66(dd,J=15.2Hz,J=6.4Hz,1H),3.47-3.39(N,2H),2.87(s,3H),2.80(t,J=7.6Hz,4H),2.68(t,J=7.6Hz,4H),2.60-2.46(m,3H),2.00-1.91(m,4H),1.80-1.72(m,2H),1.57-1.49(m,1H),1.35-1.24(m,1H);MS(ESI):m/z(%)=468.14(100%)(M+H)+,490.40(50%)(M+Na),466.11(100%)(M-1).
实施例-85
(E)-2-(1-乙酰基哌啶-3-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.00(s,1H),6.94(s,1H),6.80-6.65(m,2H),4.16-4.10(m,1H),3.77-3.63(m,1H),3.09-2.93(m,1H),2.80(t,J=7.2Hz,4H),2.75-2.64(m,5H),2.39-2.26(m,1H),2.00-1.91(m,7H),1.90-1.77(m,1H),1.74-1.57(m,1H),1.54-1.28(m,2H);MS(ESI):m/z(%)=468.14(100%)(M+H)+,490.40(50%)(M+Na),466.11(100%)(M-1).
实施例-86
(E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-氮杂环丁烷-1-羧酸叔丁酯
实施例86按照描述合成中间体-3a的程序使用中间体-11制备。
1H NMR(400MHz,DMSO-d6):δ=10.57(brs,1H),7.83(s,1H),6.89(s,1H),6.73(d,J=15.2Hz,1H),6.66(dd,J=15.2Hz,J=:4.4Hz,1H),4.73-4.84(m,1H),3.80-3.70(m,2H),2.79(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),2.46-2.33(m,1H),2.04-1.97(m,5H),1.35(s,9H);MS(ESI):m/z(%)=484.84(90%)(M+H)+,460.23(100%)(M-1).
实施例-87
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基氮杂环丁烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.45(brs,1H),7.98(s,1H),6.92(s,1H),6.84(d,J=14.8Hz,1H),6.72(dd,J=15.2Hz,J=5.2Hz 1H),3.95-3.82(m,1H),3.44-3.36(m,2H),3.09-2.95(m,1H),2.80(t,J=7.2Hz,4H),2.68(t,J=6.8Hz,4H),2.30(s,3H),2.26-2.20(m,1H),2.03-1.89(m,4H);MS(ESI):m/z(%)=376.19(100%)(M+H)+,374.16(100%)(M-1).
实施例-88
(E)-2-(氮杂环丁烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.51(s,1H),6.94(d,J=15.2Hz,1H),6.80(s,1H),6.55(dd,J=15.2Hz,J=7.2Hz,1H),5.01-4.95(m,1H),3.89-3.82(m,1H),3.72-3.62(m,1H),2.77(t,J=7.2Hz,4H),2.70(t,J=6.8Hz,4H),2.50-2.33(m,1H),1.96-1.88(m,5H);MS(ESI):mm/z(%)=362.24(100%)(M+H)+.
实施例-89
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(四氢-2H-吡喃-4-基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.36(brs,1H),7.99(s,1H),6.94-6.90(m,2H),6.77(dd,J=14.8Hz,J=5.2Hz,1H),3.99-3.86(m,1H),3.46-3.39(m,2H),3.13-2.96(m,1H),2.80(t,J=7.2Hz,4H),2.66(t,J=7.2Hz,4H),2.51-2.33(m,1H),2.30-2.16(m,1H),1.99-1.92(m,5H),0.82-0.61(m,1H),0.50-0.30(m,2H),0.22-0.08(m,2H);MS(ESI):m/z(%)=416.29(100%)(M+H)+.
实施例-90
(S,E)-2-(1-((5-氯噻吩-2-基)磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.01(s,1H),7.68(t,J=1.2Hz,1H),7.36(d,J=4.0Hz,1H),6.90(s,1H),6.85(s,1H),6.82(s,1H),4.40(d,J=5.2Hz,1H),3.43(t,J=6.8Hz,1H),3.32(s,1H),3.20(d,J=7.6Hz,1H),2.80(t,J=7.2Hz,4H),2.69(t,J=8.8Hz,4H),1.95(m,4H),1.74(m,3H),1.64(s,1H);MS(ESI):m/z(%)=556(100%)(M+1).
实施例-91
(S,E)-2-(1-(苄基磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.86(s,1H),7.42(m,2H),7.34(t,J=4.0Hz,3H),6.87(s,1H),6.71(s,1H),6.45(m,1H),4.46(s,2H),4.37(d,J=8.0Hz,1H),3.22(s,1H),2.78(t,J=7.6Hz,4H),2.66(t,J=7.2Hz,4H),1.99(m,1H),1.95(m,4H),1.74(m,3H);MS(ESI):m/z(%)=530(100%)(M+1).
实施例-92
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-((4-甲氧基苯基)磺酰基)吡咯烷-2-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.93(s,1H),7.79(d,J=2.8Hz,2H),7.12(d,J=2.0Hz,2H),6.90(s,1H),6.85(s,1H),6.66(s,1H),6.60(d,J=5.6Hz,1H),6.57(d,J=4.4Hz,1H),4.4(m,1H),3.84(s,3H),3.22(m,1H),2.78(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),1.99(m,4H),1.68(m,3H),1.60(m,1H);MS(ESI):m/z(%)=546(100%)(M+1).
实施例-93
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-((4-氟苯基)磺酰基)吡咯烷-2-基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.02(s,1H),7.94(d,J=2.0Hz,2H),7.47(d,J=3.6Hz,2H),6.90(s,1H),6.87(s,1H),6.68(d,J=9.6Hz,1H),4.41(m,1H),3.36(m,1H),2.78(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),1.99(m,4H),1.68(m,3H),1.60(m,1H);MS(ESI):m/z(%)=534(100%)(M+1).
实施例-94
(S,E)-2-(1-((2-氰基苯基)磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.11(d,J=1.2Hz,2H),7.90(d,J=1.2Hz,2H),7.83(s,1H),6.82(s,1H),6.70(d,J=14.8Hz,1H),6.30(s,1H),4.51(s,1H),3.32(s,2H),2.77(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),1.92(m,4H),1.80(m,2H),1.74(m,2H);MS(ESI):m/z(%)=541.14(100%)(M+1).
实施例-95
(S,E)-2-(1-(环己基磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.78(s,1H),6.85(s,1H),6.70(d,J=14.8Hz,1H),6.41(s,1H),4.46(s,1H),3.42(m,1H),3.08(s,1H),2.78(t,J=7.6Hz,4H),2.70(t,J=7.2Hz,4H),2.09(d,J=4.8Hz,1H)1.94(m,7H),1.83(m,3H),1.72(m,1H),1.52(s,1H),1.32(m,3H),1.24(s,2H),1.08(s,1H);MS(ESI):m/z(%)=522.19(100%)(M+1).
实施例-96
(S,E)-2-(1-(4-氟苄基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.03(s,1H),7.28(t,J=6.0Hz,2H),7.06(t,J=8.8Hz,2H),6.89(s,1H),6.86(s,1H),6.62(m,1H),3.81(d,J=13.2Hz,2H),3.16(m,2H),2.68(t,J=5.6Hz,4H),2.62(t,J=7.2Hz,4H),2.16(m,1H),1.90(m,1H),1.85(m,4H),1.70(m,2H),1.55(m,.1H);MS(ESI):m/z(%)=484.19(100%)(M+1).
实施例-97
(S,E)-2-(1-((4-氰基苯基)磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.06(d,J=8.4Hz,2H),8.01(t,J=8.6Hz,2H),7.86(s,1H),6.87(s,1H),6.80(d,J=14.8Hz,1H),6.42(d,J=9.6Hz,1H),4.44(t,J=5.6Hz,1H),3.36(m,2H),3.18(m,1H),2.78(t,J=7.2Hz,4H),2.70(t,J=72Hz,4H),1.92(m,4H),1.67(m,3H),1.56(m,1H);MS(ESI):m/z(%)=541.15(100%)(M+1).
实施例-98
(S,E)-2-(1-(4-氰基苄基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.01(s,1H),7.89(d,J=8.4Hz,2H),7.51(d,J=8.4Hz,2H),6.97(d,J=6.0Hz,1H),6.91(s,1H),6.65(m,1H),3.86(d,J=13.6Hz,2H),3.25(m,1H),2.79(m,5H),2.61(m,4H),2.22(m,1H),2.12(m,1H),1.98(m,4H),1.72(m,2H),1.76(m,1H);MS(ESI):m/z(%)=491.15(100%)(M+1).
实施例-99
(S,E)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.90(s,1H),7.59(s,1H),7.26(s,1H),6.98(d,J1=0.8Hz,1H),6.98(t,J2=1.2Hz,1H),6.38(m,1H),4.08(m,1H),3.22(m,2H),2.70(m,8H),2.15(m,1H),1.98(m,6H),1.71(m,1H),1.56(m,1H);MS(ESI):m/z(%)=372.87(100%)(M-1).
实施例-100
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(哌啶-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.41(s,1H),6.86(d,J=15.6Hz,1H),6.79(s,1H),6.28(d,J=6.0Hz,1H),3.61(s,2H),3.14(d,J=12.8Hz,1H),2.81(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),1.98(m,5H),1.81(m,2H),1.69(m,1H),1.48(m,3H);MS(ESI):m/z(%)=390.13(100%)(M+1).
实施例-101
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基哌啶-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.92(s,1H),6.89(s,1H),6.80(d,J=14.8Hz,1H),6.42(d,J=8.4Hz,1H),2.92(t,J=5.2Hz,2H),2.82(t,J=7.2Hz,4H),2.72(t,J=7.2Hz,4H),2.27(m,4H),1.92(m,5H),1.62(m,3H),1.44(s,2H);MS(ESI):m/z(%)=404.15(100%)(M+1).
实施例-102
(E)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.83(s,1H),744(s,1H),6.88(d,J=14.8Hz,1H),6.53(d,J=8.0Hz,1H),3.13(s,3H),2.82(t,J=7.2Hz,4H),2.72(t,J=7.2Hz,4H),2.39(s,2H),2.33(d,J=2.0Hz,3H),2.11(m,5H),1.81(m,2H),1.78(m,1H);MS(ESI):m/z(%)=390.14(100%)(M+1).
实施例-103
(E)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)-2-(1-(甲基磺酰基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.87(s,1H),7.45(s,1H),6.77(d,J=14.8Hz,1H),6.68(d,J=4.8Hz,1H),4.48(t,J=4.0Hz,1H),2.99(s,3H),2.82(t,J=7.2Hz,4H),2.72(t,J=7.2Hz,4H),2.11(m,5H),1.81(m,3H);MS(ESI):m/z(%)=454.09(100%)(M+1).
实施例-104
((E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-3-(哌啶-2-基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.44(s,1H),6.79(s,1H),6.47(d,J=15.2Hz,1H),6.20(m,1H),2.85(t,J=7.2Hz,5H),2.70(t,J=7.2Hz,4H),2.33(t,J=1.6Hz,2H),1.98(m,6H),1.73(m,3H),1.61(s,1H),1.38(m,2H).1.24(s,1H);MS(ESI):m/z(%)=404.20(100%)(M+1).
实施例-105
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.52(s,1H),6.88(d,J=15.6Hz,1H),6.81(s,1H),6.46(d,J=15.6Hz,1H),3.21(m,2H),3.12(m,1H),2.75(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),1.98(m,7H),1.78(s,2H),1.38(s,3H);MS(ESI):m/z(%)=390.24(100%)(M+1).
实施例-106
(S,E)-2-(1,2-二甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.04(s,1H),6.93(s,1H),6.73(d,J=15.2Hz,1H),6.65(d,J=15.2Hz,1H),2.80(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.20(s,3H),1.96(m,4H),1,72(m,4H),1.13(s,3H);MS(ESI):m/z(%)=404.25(100%)(M+1).
或者,实施例106也按照描述合成中间体-7b(实施例111)的程序使用中间体9和(S)-1,2-二甲基吡咯烷-2-甲醛连同有机合成领域技术人员已知的常规技术制备。
实施例-107
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吲哚啉-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.89(s,1H),7.04(d,J=3.2Hz,1H),6.99(d,J=6.8Hz,1H),6.93(d,J=8.0Hz,1H),6.82(d,J=8.0Hz,1H),6.62(d,J=13.8Hz,1H),6.51(d,J=7.6Hz,2H),5.95(s,1H),4.4(t,=7.2Hz,4H),2.67(t,J=7.2Hz,4H),1.95(m,1H);MS(ESI):m/z(%)=424.20(100%)(M+1).
实施例-108
(E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吲哚啉-1-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=8.11(s,1H),7.71(s,1H),7.20(d,J=8.8Hz,1H),7.17(s,1H),6.99(d,J1=0.8Hz,1H),6.97(d,J2=0.8Hz,1H),6.95(s,1H),6.78(d,J=6.0Hz,1H),6.66(d,=15.6Hz,1H-H),5.10(m,1H),5.12(m,1H),3.50(m,1H),2.80(t,J=7.2Hz,5H),2.62(t,J=7.2Hz,4H),1.96(m,5H),1.45(s,10H);MS(ESI):m/z(%)=522.20(100%)(M-1).
实施例-109
((S,E)-2-(1-(环丙基甲基)-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.42(s,1H),6.78(s,1H),6.57(d,J=15.6Hz,1H),6.21(d,J=15.2Hz,1H),2.93(t,J=6.4Hz,1H),2.76(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),2.33(t,J=1.62Hz,1H),2.27(t,J=6.8Hz,1H),2.01(m,1H),1.93(m,4H),1.76(d,J=5.62Hz,1H),1.68(d,J=8.0Hz,1H),1.60(d,J=4.4Hz,1H),1.0(s,2H),0.38(t,J=7.6Hz,2H);MS(ESI):m/z(%)=444.26(100%)(M+1).
实施例-110
(S,E)-2-(1-(环丙基磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.05(s,1H),6.94(s,1H),6.81(d,J=0.8Hz,1H),6.77(d,J=1.2Hz,1H),6.68(d,J=15.2Hz,1H),4.57(m,1H),3.43(m,1H),2.80(t,J=7.2Hz,1H),268(t,J=7.2Hz,4H),1.99(m,5H),1.81(m,2H),0.95(d,J=6.4Hz,4H);MS(ESI):m/z(%)=480.20(100%)(M+1).
实施例-111
(S,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=7.97(s,1H),6.91(s,1H),6.72(d,J=15.2Hz,1H),6.54(d,J=7.68Hz,1H),2.80(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,5H),1.97(m,4H),1.89(s,3H),1.80(m,4H),1.48(s,2H0,1.44(s,2H),1.38(s,10H);MS(ESI):m/z(%)=488.24(100%)(M-1).
实施例-112
(R,E)-2-(2-(N-((2,6-二异丙基苯基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.55(s,1H),7.89(d,J=16.0Hz,1H),7.27(t,J=7.6Hz,1H),7.16(d,J=7.6Hz,2H),6.89-6.79(m,1H),6.56-6.49(m,1H),3.39-3.35(m,2H),3.05-3.00(m,2H),1.93-1.90(m,1H),1.83-1.77(m,2H),169-1.64(m,1H),1.44(s,3H),1.37(s,9H),1.13(d,/=6.8Hz,12H);MS(ESI):m/z(%)=492.24(100%)(M-1)-.
实施例-113
(R,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐
1H NMR(400MHz,DMSO-d6):δ=11.10(bs,1H),9.08(bs,2H),8.24(s,1H),7.27(t,J=7.6Hz,1H),7.16(d,J=7.6Hz,2H),7.11(d,J=15.6Hz,1H),7.05(d,J=15.2Hz,1H),3.33-3.29(m,2H),3.07-3.00(m,2H),2.13-1.83(m,4H),1.46(s,3H),1.12(d,J=6.8Hz,12H);MS(ESI):m/z(%)=392.22(100%)(M-TFA)+;
实施例-114
(R,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1,2-二甲基吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.45(bs,1H),7.83(s,1H),7.25(t,J=7.6Hz,1H),7.15(d,J=8.0Hz,2H),6.73(d,J=15.2Hz,1H),6.68(d,J=15.6Hz,1H),3.33-3.22(m,2H),2.83-2.80(m,1H),2.73-2.67(m,1H),2.15(s,3H),1.80-1.69(m,4H),1.18-1.10(m,15H);MS(ESI):m/z(%)=408.23(100%)(M+H)+.
实施例-115
(S,E)-2-(1-乙基-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.45(bs,1H),8.05(bs,1H),6.93(s,1H),6.74(d,J=15.2Hz,1H),6.68(d,J=15.6Hz,1H),2.96-2.89(m,2H),2.80(t,J=7.2Hz,4H),2.67(1,J=7.6Hz,6H),1.96(五重峰,J=7.2Hz,4H),1.79-1.72(m,4H),1.14(s,3H),1.02(t,J=6.4Hz,3H);MS(ESI):m/z(%)=418.16(100%)(M+H)+.
实施例-116
双钠(R,E)-((2-(1,2-二甲基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺
1H NMR(400MHz,DMSO-d6):δ=6.76(s,1H),6.56(d,J=15.6Hz,1H),6.20(d,J=15.6(Hz,1H),2.75(t,J=7.6Hz,5H),2.69(t,J=7.2Hz,4H),2.64-2.59(m,1H),2.08(s,3H),1.90(五重峰,J=7.2Hz,4H),.74-1.68(m,3H),1.62-1.61(m,1H),1.01(s,3H);MS(ESI)m/z(%)=404.17(100%)(M-2Na)+.
实施例-117
钠(R,E)-((2-(1,2-二甲基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺
1H NMR(400MHz,DMSO-d6):δ=7.36(s,1H),6.77(s,1H),6.57(d,J=15.6Hz,1H),6.19(d,J=15.6Hz,1H),2.76(t,J=72Hz,5H),2.69(t,J=7.21Hz,4H),2.64-2.59(m,1H),2.08(s,3H),1.91(五重峰,J=7.6Hz,4H),1.74-1.68(m,3H),1.62-1.60(m,1H),1.01(s,3H);MS(ESI):m/z(%)=404.17(100%)(M-Na)+.
实施例-118
(S,E)-2-(2-(N-((2,6-二异丙基苯基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.55(s,1H),7.89(s,1H),7.27(t,J=7.6Hz,1H),7.16(d,J=7.6Hz,2H),6.84(d,J=15.6Hz,1H),6.56(d,J=15.6Hz,1H),3.37(t,J=6.4Hz,2H),3.03(t,J=6.4Hz,2H),1.91-1.90(m,1H),1.83-1.77(m,2H),1.69-1.64(m,1H),1.44(s,3H),1.37(s,9H),1.13(d,J=6.8Hz,12H);MS(ESI):m/z(%)=494.31(10%)(M+1)+.
实施例-119
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐
1H NMR(400MHz,DMSO-d6):δ=11.10(bs,1H),9.10(bs,2H),8.28(s,1H),7.27(t,J=7.6Hz,1H),7.16(d,J=7.6Hz,2H),7.12(d,J=15.6Hz,1H),7.00(d,J=15.2Hz,1H),3.35-3.30(m,1H),3.24-3.20(m,1H),3.07-3.00(m,2H),2.10-1.98(m,2H),1.93-1.85(m,2H),1.46(s,3H),1.12(d,J=6.8Hz,12H);MS(ESI):m/z(%)=394.27(100%)(M-TFA)+.
实施例-120
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1,2-二甲基吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.10(bs,1H),7.92(s,1H),7.25(t,J=7.6Hz,1H),7.13(d,J=7.6Hz,2H),6.68(d,J=14.8Hz,1H),6.61(d,J=15.6Hz,1H),3.07-3.02(m,2H),2.85-2.83(m,1H),2.69-2.67(m,1H),2.14(s,3H),1.82-1.66(m,4H),1.12-1.07(m,15H);MS(ESI):m/z(%)=408.23(100%)(M+H)+.
实施例-121
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基-1-(氧杂环丁烷-3-基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.39(bs,1H),8.14(s,1H),6.95(s,1H),6.71-6.59(m,2H),4.65(t,J=6.4Hz,1H),4.55(t,J=6.8Hz,1H),4.45-4.39(m,2H),4.05-3.98(m,1H),3.13-3.07(m,1H),3.02-2.99(m,1H),2.81(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),2.01-1.63(m,8H),1.03(s,3H);MS(ESI):m/z(%)=446.24(100%)(M+H)+.
实施例-122
(S,E)-2-(2-(N-((4-氟-2,6-二异丙基苯基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.61(bs,1H),7.89-7.85(m,1H),6.97(d,J=10Hz,2H),6.90-6.79(m,1H),6.55-6,49(m,1H),3.38-3.35(m,2H),3.03-3.01(m,2H),1.92-1.64(m,3H),1.47-1.43(m,3H),1.36(s,9H),1.11(d,J=7.2Hz,12H);MS(ESI):m/z(%)=512.30(8%)(M+H)+,534.29(8%)(M+Na)+.
实施例-123
(S,E)-N-((4-氟-2,6-二异丙基苯基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐
1H NMR(400MHz,DMSO-d6):δ=11.11(bs,1H),9.08(bs,2H),8.25(s,1H),7.09(d,J=15.6Hz,1H);7.00-6.95(m,3H),3.42-3.40(m,1H),3.21-3.17(m,1H),3.06-2.99(m,2H),2.10-1.83(m,4H),1.45(s,3H),1.11(d,J=5.6Hz,12H);MS(ESI):m/z(%)=412.23(100%)(M+H)+;
实施例-124
(S,E)-2-(1,2-二甲基吡咯烷-2-基)-N-((4-氟-2,6-二异丙基苯基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.87(s,1H),6.93(d,J=10Hz,2H);6.66-6.92(m,2H),3.10-3.04(m,2H),2.83-2.67(m,2H),2.15(s,3H),1.76-1.69(m,4H),1.11-1.09(m,15H);MS(ESI):m/z(%)=426.29(100%)(M+H)+;
实施例-125
(E)-2-(1-乙酰基氮杂环丁烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.40(br s,1H),8.15-8.09(m,1H),6.96-6.71(m,3H),5.14-4.87(m,1H),2.81(t,J=7.2Hz,4H),2.77-2.64(m,4H),2.60-2.56(m,1H),2.01-1.94(m,5H),1.78(s,2H),1.66(s,1H);MS(ESI):m/z(%)=404.11(100%)(M+H)+.
实施例-126
(R,E)-(2-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-基)乙基)(甲基)氨基甲酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.38(brs,1H),8.05(s,1H),6.95(s,1H),6.80(d,J=14.4Hz,1H),6.63(dd,J=14.8Hz J=6.8Hz,1H),3.23-3.07(m,4H),2.81(t,J=7.2Hz,4H),2.72-2.58(m,8H),2.33-2.18(m,2H),2.03-1.91(m,5H),1.83-1.62(m,2H),1.55-1.46(m,1H),1.37(s,9H);MS(ESI):m/z(%)=533.21(100%)(M+H)+.
实施例-127
(S,E)-2-(1-烯丙基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.07(s,1H),6.95(s,1H),6.84(d,J=15.2Hz,1H),6.64(dd,J=15.2Hz,J=7.2Hz,1H),5.85-5.80(m,1H),5.19-5.14(m,1H),5.09-5.07(m,1H),3.28-3.27(m,1H),3.21-3.15(m,1H),3.05-3.01(m,1H),2.86-2.78(m,4H),2.73-2.64(m,4H),2.60-2.56(m,1H),2.30-2.23(m,1H),2.07-1.97(m,5H),1.80-1.70(m,2H),1,59-1.50(m,1H);MS(ESI):m/z(%)=416.14(100%)(M+H)+.
实施例-128
(S,E)-2-(1-(1H-苯并[d]咪唑-6-羰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=12.65(brs,1H),8.40(s,1H),8.04(s,1H),7.85-7.69(m,1H),7.67-7.50(m,1H),7.49-7.23(m,1H),6.92(s,1H),6.91-6.53(m,2H),4.98-4.68(m,1H),3.72-3.53(m,1H),3.50-342(m,1H),2.86-2.72(m,4H),2.66(t,J=6.8Hz,4H),2.29-2.12(m,1H),1.98-1.77(m,7H);MS(ESI):m/z(%)=520.24(90%)(M+H)+.
实施例-129
(S,E)-2-(1-(环丙基磺酰基)-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.01(s,1H),6.94(s,1H),6.86(d,J=15.2Hz,1H),6.71(dd,J=14.8Hz,J=6.4Hz,1H),3.46(t,J=6.8Hz,2H),2.80(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.63-2.56(m,2H),2.07-1.91(m,6H),1.90-1.74(m,1H),1.57(s,3H),0.97-0.89(m,4H);MS(ESI):m/z(%)=494.22(100%)(M+H)+.
实施例-130
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(4-甲氧基苄基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.01(s,1H),7.20(d,J=8.4Hz,2H),7.16(d,J=84Hz,2H),6.97(d,J=6.0Hz,1H),6.91(s,1H),6.65(m,1H),3.86(d,J=13.6Hz,2H),3.25(m,1H),2.80(t,J=7.2Hz,1H),2.68(t,J=7.2Hz,4H),2.12(m,1H),1.98(m,4H),1.72(m,2H),1.76(m,1H);MS(ESI):m/z(%)=496.33(100%)(M+1).
实施例-131
5-((R)-2-((E)-2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-基)六氢环戊并[c]吡咯-2(1H)-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.34(brs,1H),8.03(s,1H),6.94(s,1H),6.84(d,J=14.8Hz,1H),6.66(dd,J=14.8Hz,J=7.6Hz,1H),3.48-3.35(m,1H),3.14-3.07(m,2H),3.99-2.88(m,2H),2.81(t,J=6.8Hz,4H),2.69-2.66(m,5H),2.47-2.39(m,3H),2.01-1.91(m,7H),1.81-1.69(m,2H),1.66-1.50(m,2H),1.38(s,9H),131-1.08(m,2H);MS(ESI):m/z(%)=585.29(100%)(M+H)+.
实施例-132
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-((2R)-1-(八氢环-戊并[c]吡咯-5-基)吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐
1H NMR(400MHz,DMSO-d6):δ=10.54(brs,1H),9.08(s,1H),8.57(s,2H),7.24-7.22(m,1H),6.97(s,1H),6.91-6.81(m,1H),4.50-4.28(m,1H),3.63-3.45(m,2H),3.39-3.16(m,2H),3.17-2.93(m,2H),2.82(t,J=7.2Hz,4H),2.77-2.64(m,5H),2.38-2.09(m,3H),2.01-1.91(m,6H),1.90-1.78(m,1H),1.62-1.39(m,2H),1.05-1.03(m,2H);MS(ESI):m/z(%)=485.25(100%)(M+H)+.
实施例-133
(E)-2-(1-(环丙基磺酰基)氮杂环丁烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.54(brs,1H),8.12(s,1H),6.97-6.93(m,2H),6.86(dd,J=15.2Hz,J=4.8Hz,1H),5.08-5.02(m,1H),4.05-3.99(m,1H),3.66-3.61(m,1H),2.81(t,J=7.2Hz,4H),2.78-2.73(m,1H),2.68(t,J=7.2Hz,4H),2.46-2.43(m,1H),2.15-2.10(m,1H),2.01-1.94(m,4H),1.05-0.98(m,2H),0.94-0.90(m,2H);MS(ESI):m/z(%)=466.08(100%)(M+H)+.
实施例-134
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1-(噻唑-2-基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.59(bs,1H),7.92(s,1H),7.28-7.25(m,1H),7.16-7.13(m,3H),6.85-6.76(m,2H),6.66(d,J=15.2Hz,1H),4.57-4.55(m,1H),3.51-3.50(m,1H),3.39-3.37(m,1H),3.05-2.98(m,2H),2.23-2.19(m,1H),1.99-1.83(m,3H),1.11(d,J=6.8Hz,12H);MS(ESI):m/z(%)=463.16(100%)(M+H)+.
实施例-135
(S,E)-(2-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-基)乙基)(甲基)氨基甲酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.37(bs,1H),8.06(s,1H),6.95(s,1H),6.72(d,J=15.6Hz,1H),6.66(d,J=15.6Hz,1H),3.2-3.17(m,1H),2.81(t,J=6.8(Hz,4H),2.682.65(m,8H),2.43-2.42(m,1H),1.96(五重峰,J=7.2(Hz,4H),1.75-1.65(m,4H),1.41-1.37(m,12H),1.1(s,3H);MS(ESI)m/z(%)=547.32(100%)(M+H)+.
实施例-136
钾(R,E)-((2-(1,2-二甲基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺
1H NMR(400MHz,DMSO-d6):δ=7.33(s,1H),6.77(s,1H),6,58(d,J=15.6Hz,1H),6.18(d,J=15.6Hz,1H),2.77-2.72(m,5(H),2.69(t,J=7.2Hz,4H),2.64-2.58(m,1H),2.08(s,3H),1.90(五重峰,J=7.6Hz,H),1.75-1.70(m,3H),1.62-1.60(m,1H),1.01(s,3H);MS(ESI):m/z(%)=404.21(100%)(M-K)+.
实施例-137
(E)-(2-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)氮杂环丁烷-1-基)乙基)(甲基)氨基甲酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=8.03(s,1H),6.94(m,1H),6.85-6.64(m,2H),3.88-3.72(m,1H),2.96-2.88(m,1H),2.80(t,J=7.2Hz,4H),2.75-2.71(m,4H),2.67(t,J=7.2Hz,4H),2.61-2.54(m,1H),2.46-2.40(m,1H),2.25-2.19(m,1H),1.99-1.92(m,2H),1.41-1.38(m,12H);MS(ESI):m/z(%)=519.26(90%)(M+H)+,517.20(90%)(M-1).
实施例-138
(S,E)-2-(1-(环己基甲基)-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.36(brs,1H),8.04(s,1H),6.95(m,1H),6.78-6.62(m,2H),2.81(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),),2.65-2.55(m,1H),2.26-2.02(m,2H),2.00-1.91(m,5H),1.86-1.71(m,4H),1.70-1.50(m,5H),1.43-1.24(m,1H),1.23-1.13(m,2H),1.12-1.00(m,4H),0.86-0.67(m,2H);MS(TOF):m/z(%))+486.2891(100%)(M+H)+,484.2571(100%)(M-1).
实施例-139
钠(R,E)-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)((2-(1-(四氢-2H-噻喃-4-基)吡咯烷-2-基)乙烯基)磺酰基)酰胺
1H NMR(400MHz,DMSO-d6):δ=7.31(s,1H),6.76(s,1H),6.63(d,J=15.2Hz,1H),6.06(dd,J=15.2Hz,J=7.6Hz,1H),3.43-3.36(m,1H),2.87-2.64(m,10H),2.65-2.42(m,5H),2.03-1.84(m,7H),1.68-1.43(m,5H);MS(ESI):m/z(%)=476.25(100%)(M+H)+,474.20(100%)(M-1).
实施例-140
钠(R,E)-((2-(1-环己基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺
1H NMR(400MHz,DMS0-d6):δ=7.33(s,1H),6.77(s,1H),6.63(d,J=15.2Hz,1H),6.09(dd,J=15.2Hz,J=7.6Hz,1H),3.34-3.42(m,1H),2.84-2.79(m,1H),2.76(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),2.41-2.31(m,1H),1.94-1.80(m,5H),1.75-1.61(m,7H),1.54-1.41(m,2H),1.24-1.07(m,5H);MS(TOF):m/z(%)=458.2811(100%)(M+H)+.
实施例-141
钠(S,E)-((2,6-二异丙基苯基)氨甲酰基)((2-(1,2-二甲基吡咯烷-2-基)乙烯基)磺酰基)酰胺
1H NMR(400MHz,DMSO-d6):δ=7.24(s,1H),7.11(t,J=8.4Hz,1H),7.04(d,J=7.6Hz,2H),6.54(d,J=15.6Hz,1H),6.21(d,J=16.0Hz,1H),3.23-3.16(m,2H),2.74-2.67(m,1H),2.65-2.59(m,1H),2.08(s,3H),1.75-1.71(m,3H),1.61-1.59(m,1H),1.1(d,J=6.4Hz,12H),1.0(s,3H);MS(ESI):m/z(%)=408.25(100%)(M-Na)+.
实施例-142
钠(R,E)-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)((2-(1-甲基吡咯烷-2-基)乙烯基)磺酰基)酰胺
1H NMR(400MHz,DMSO-d6):δ=7.37(s,1H),6.77(s,1H),664(d,J=15.2Hz,1H),6.07(d,J=15.2Hz,1H),3.0-2.95(m,1H),2.76(t,J=7.2Hz,4H),2,69(t,J=7.2Hz,4H),2.59-2.53(m,1H),2.14(s,3H),2.13-2.06(m,2H),1.91(五重峰,J=7.2Hz,4H),1.73-1.60(m,3H),1.54-1.49(m,1H);MS(ESI):m/z(%)=390.20(100%)(M-Na)+.
实施例-143
钾(R,E)-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)((2-(1-甲基吡咯烷-2-基)乙烯基)磺酰基)酰胺
1H NMR(400MHz,DMSO-d6):δ=7.31(s,1H),6.76(s,1H),6.67(d,J=15.2Hz,1H),6.03-6.01(m,1H),2.97(bs,1H),2.76(bs,4H),2.69(bs,4H),2.14-2.08(m,4H),1.91(bs,5H),1.68(bs,3H),1.49(bs,1H),MS(ESI):m/z(%)=390.20(100%)(M-K)+.
实施例-144
钠(S,E)-((2-(1,2-二甲基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺
1H NMR(400MHz,DMSO-d6):δ=7.33(s,1H),6.77(s,1H),6.56(d,J=15.2Hz,H),6.16(d,J=16Hz,1H),2.76(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),2.62(m,1H),2.08(s,3H),1.90(m,4H),1.72(m,4H),1.60(m,3H),1.01(s,3H);MS(ESI):m/z(%)=404.20(100%)(M+1).
实施例-145
钠(S,E)-((2-(1-乙基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺
1H NMR(400MHz,DMSO-d6):δ=7.36(s,1H),6.77(s,1H),6.61(d,J=15.2Hz,1H);6.05(dd,J=8.0Hz,J=15.2Hz,1H);3.10-3.05(m,1H),2.78-2.65(m,10H),2.12-1.85(m,7H),1.71-1.66(m,2H),1.49-1.44(m,1H),0.98(t,J=7.2Hz,3H);MS(ESI):m/z(%)=426.20(50%)(M+H)+.
实施例-146
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2-羟基乙基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.90(s,1H),6.90(s,1H),6.84(d,J=15.8Hz,1H),6.51(d,J=14.8Hz,1H),4.57(s,1H),3.57(d,J=8.8Hz,2H),3.17(s,2H),2.80(t,J=7.2Hz,1H),2.72(t,J=7.2Hz,4H),2.33(d,J=1.6Hz,2H),1.96(m,4H),1.91(s,2H),1.72(m,2H),1.56(m,1H);MS(ESI):m/z(%)=420.23(100%)(M+1).
实施例-147
(E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-羧酸叔丁酯
实施例147按照描述合成中间体-3a的程序使用中间体-12连同有机合成领域技术人员已知的常规技术制备。
1H NMR(400MHz,DMSO-d6):δ=10.47(br s,1H),8.12(s,1H),6.96(s,1H),6.92(d,J=15.2Hz,1H),6.70(d,J=15.2Hz,1H),3.82-3.61(m,2H),2.81(t,J=7.2Hz,4H),2.68(t,J=6.8Hz,4H),2.20-2.08(m,2H),2.00-1.93(m,4H),1.52(s,3H),1.38-1.33(m,9H);MS(TOF):m/z(%)=498.2359(90%)(M+Na)+,474.2308(100%)(M-1).
实施例-148
(E)-2-(1,2-二甲基氮杂环丁烷-2-基)-N-((1,2,3,50,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.91(s,1H),6.91(s,1H),6.79(d,J=14.8Hz,1H),6.72(d,J=15.2Hz,1H),3.33-3.16(m,2H),2.79(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.22(s,3H),2.18-2.11(m,1H),2.00-1.91(m,5H),1.34(s,3H);MS(TOF):m/z(%)=390.2279(70%)(M+H)+,388.2130(100%)(M-1).
实施例-149
(S,E)-2-乙基-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.38(s,1H),8.0(d,J=4.4Hz,1H),6.99(s,1H),6.89(d,J=15.2Hz,1H),6.50(d,J=15.2Hz,1H),3.50(m,1H),3.25(m,1H),2.81(t,J=7.2Hz,4H),2.65(t,J=7.2Hz,5H),1.95(m,4H),1.77(s,3H),1.80(m,4H),1.58(m,1H),1.36(d,J=10Hz,9H),0.81(m,3H);MS(ESI):m/z(%)=502.23(100%)(M-1).
实施例-150
(S,E)-2-(2-(N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=7.95(s,1H),7.42(d,J=15.2Hz,1H),6.79(d,J=7.68Hz,1H),6.55(d,J=15.2Hz,1H),3.39(m,2H),280(q,J=7.6Hz,4H),2.70(t,J=7.2Hz,5H),2.01(m,6H),1.82(m,2H),1.68(m,1H),1.46(d,J=10Hz,3H),1.38(s,3H),1.32(s,7H);MS(ESI):m/z(%)=488.24(100%)(M-1).
实施例-151
(S,E)-2-(2-乙基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐
1H NMR(400MHz,DMSO-d6):δ=9.19(s,1H),90.6(s,1H),8.39(s,1H),7.56(s,1H),7.11(s,1H),6.97(s,1H),6.84(d,J=15.6Hz,1H),3.32(s,1H),3.17(s,1H),2.81(t,J=6.8Hz,4H),2.65(t,J=7.2Hz,4H),2.24(m,1H),1.96(m,6H),1.83(m,4H),0.85(q,J=6.8Hz,3H);MS(ESI):m/z(%)=404.3(100%)(M+1).
实施例-152
(S,E)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐
1H NMR(400MHz,DMSO-d6):δ=7.39(s,1H),7.11(d,J=15.6Hz,1H),7.02(d,J=15.6Hz,1H),2.79(q,J=7.6Hz,5H),2.71(t,J=7.2Hz,4H),2.01(m,9H),1.47(q,J=7.2Hz,3H),1.04(d,J=6.0Hz,2H);MS(ESI):m/z(%)=390.24(100%)(M+1).
实施例-153
(S,E)-2-(1,2-二甲基吡咯烷-2-基)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.88(s,1H),7.43(s,1H),6.72(d,J=15.2Hz,1H),6.62(d,J=15.2Hz,1H),3.09(q,J=7.2Hz,4H),2.75(m,4H),2.60(t,J=6.8Hz,4H),2.21(s,3H),1.95(m,4H),1.78(t,J=10Hz,4H),1.17(m,8H);MS(ESI):m/z(%)=404.30(100%)(M+1).
实施例-154
(R,E)-2-(2-(N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.85(s,1H),7.98(s,1H),7.43(d,J=9.2Hz,1H),6.89(q,J=15.6Hz,1H),6.58(d,J=15.2Hz,1H),3.42-3.36(m,2H),2.81-2.74(m,4H),2.70(t,J=7.2Hz,4H),2.21-1.94(m,5H),1.88-1.75(m,2H),1.72-1.66(m,1H),1.48(d,J=9.6Hz,3H),1.32(s,9H);MS(ESI):m/z(%)=512.21(40%)(M+Na)+;502.28(100%)(M-H)-.
实施例-155
(R,E)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐
1H NMR(400MHz,DMSO-d6):δ=9.09(bs,2H),8.21(s,1H),7.39(s,1H),7.13(d,J=15.6Hz,1H),7.03(d,J=15.2Hz,1H),2.81-2.64(m,10H),2.10-1.89(m,9H),1.48(s,3H);MS(ESI):m/z(%)=390.18(100%)(M-TFA)+.
实施例-156
(R,E)-2-(1,2-二甲基吡咯烷-2-基)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.86(s,1H),7.44(s,1H),6.75(d,J=15.6Hz,1H),6.63(d,J=15.2Hz,1H),2.90-2.88(m,4H),2.80(q,J=7.2Hz,5H),2.20(s,3H),2.04(五重峰,J=7.2(Hz,4H),1.84-1.72(m,4H),1.13(s,3H);MS(ESI):m/z(%)=404.30(100%)(M+H)+;402.50(100%)(M-1)+.
实施例-157
(R,E)-2-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)烯丙基)-2-甲基吡咯烷-1-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.38(s,1H),8.07(d,J=72Hz,1H),6.95(s,1H),6.81(q,J=15.2Hz,1H),6.64(dd,JI=8.0Hz,J2=15.2Hz,1H),3.19-3.17(m,1H),2.91-2.86(m,1H),2.81(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,5H),2.63-2.58(m,1H),1.97(五重峰,J=7.2Hz,4H),1.88-1.83(m,1H),1.70-1.62(m,3H),1.41(d,J=6.8Hz,9H),1.30(s,3H);MS(ES1):m/z(%)=526.28(50%)(M+Na)-;502.28(100%)(M-H)-.
实施例-158
(R,E)-(2-(2-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)烯丙基)-2-甲基吡咯烷-1-基)乙基)(甲基)氨基甲酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.37(bs,1H),8.03(s,1H),6.95(s,1H),6.74(d,J=8.0Hz,2H),3.12(q,J=7.2(Hz,2H),2.90(bs,1H),2.80(t,J=7.2Hz,6H),2.67(t,J=68Hz,5H),2.29-2.26(m,2H),1.96(五重峰,J=7.2Hz,4H),1.68-1.67(m,4H),1.38(s,12H),1.28(s,3H);MS(ESI)m/z(%)=560.31(100%)(M+H)+;559.29(100%)(M-1)-.
实施例-159
(R,E)-3-(1,2-二甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.04(s,1H),6.90(s,1H),6.75-6.72(m,1H),6.62-6.54(m,1H),3.17-3.00(m,1H),2.79(t,J=6.8Hz,5H),2.69(bs,4H),2.36(s,5H),1.95(t,J=7.2Hz,4H),1.81-1.74(m,3H),1.58(bs,1H),1.04(s,3H);MS(ESI):m/z(%)=418.21(100%)(M+H)+.
实施例-160
(S,E)-(3-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-基)丙基)(甲基)氨基甲酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=8.05(s,1H),6.94(s,1H),6.82(d,J=15.2Hz,1H),6.62-6.57(m,1H),3.26-3.22(m,1H),3.30-2.94(m,1H),2.82-2.65(m,13H),2.20-2.18(m,2H),2.03-1.92(m,5H),1.77-1.71(m,3H),1.59-1.48(m,3H),1.40-1.37(m,9H);MS(ESI):m/z(%)=547.5(100%)(M+H)+.
实施例-161
(E)-(3-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-基)丙基)(甲基)氨基甲酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=8.04(s,1H),6.94(s,1H),6.83(d,J=15.2Hz,1H),6.77(d,J=15.2Hz,1H),3.29-3.27(m,2H),2.80(t,J=7.2Hz,4H),2.75-2.72(m,1H),2.68(t,J=7.2Hz,4H),2.50(s,3H),2.37-2.33(m,2H),2.08-2.06(m,1H),2.00-1.92(m,4H),1.58-1.49(m,2H),1.39-1.37(m,9H),1.32(s,3H),1.28-1.22(m,1H);MS(ESI):m/z(%)=547.5(100%)(M+H)+,545.7(100%)(M-1).
实施例-162
(E)-(2-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-基)乙基)(甲基)氨基甲酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=8.05(s,1H),6.95(s,1H),6.83(d,J=14.8Hz,1H),6.75-6.68(m,1H),3.32-3,23(m,1H),3.09-3.02(m,1H),2.80(t,J=7.2Hz,4H),2.75-2.71(m,2H),2.67(t,J=7.2Hz,4H),2.56-2.52(m,1H),2.51(s,3H),2.48-2.43(m,1H),2.05-1.89(m,6H),1.39-1.38(m,9H),1.32(s,3H);MS(TOF):m/z(%)=533.3222(40%)(M+H)+,531.3039(100%)(M-1).
实施例-163
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基-1-(2-(甲硫基)乙基)氮杂环丁烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.36(brs,1H),8.07(s,1H),6.95(s,1H),6.87(d,J=14.8Hz,1H),6.83(d,J=14.8Hz,1H),3.40-3.22(m,2H),3.18-3.04(m,1H),2.81(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.59-2.53(m,2H),241-2.38(m,2H),2.08-1.88(m,8H),1.32(s,3H);MS(TOF):m/z(%)=450.1660(100%)(M+H)+.
实施例-164
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基-1-(氧杂环丁烷-3-基)氮杂环丁烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.4(brs,1H),8.13(s,1H),6.96(s,1H),6.84(d,J=15.2Hz,1H),6.80(d,J=15.2Hz,1H),4.56(t,J=6.0Hz,1H),4.48-4.44(m,2H),4.31(t,J=6.4Hz,1H),3.93-3.87(m,1H),3.38-3.28(m,3H),2.81(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.12-2.06(m,1H),2.01-1.97(m,5H),1.24(s,3H);MS(TOF):m/z(%)=432.1744(80%)(M+H)+.
实施例-165
(S)-2-(((S)-2-((E)-2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-基)甲基)-2-甲基吡咯烷-1-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.4(brs,1H),8.10(s,1H),6.98-6,93(m,2H),6.74(dd,J=15.6Hz,J=5.2Hz,1H),3.30-3.27(m,2H),3.20-3.16(m,2H),2.80(t,J7.2Hz,4H),2.69(t,J=6.8Hz,4H),2.04-1.91(m,7H),1.75-1.46(m,3H),1.39-137(m,9H),1.27(s,3H),1.17(s,3H);MS(TOF):m/z(%)=573.2813(100%)(M+H)+;
实施例-166
(S)-2-(((R)-2-((E)-2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-基)甲基)-2-甲基吡咯烷-1-羧酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.41(brs,1H),8.10(s,1H),6.96(s,1H),6.77-6.73(m,2H),3.41-3.34(m,1H),3.26-3.15(m,3H),2.81(t,J=7.2Hz,4H),2.57(t,J7.2Hz,4H),2.16-1.89(m,7H),1.79-1.47(m,3H),1.40-1.37(m,9H),1.30-1.28(m,3H),1.21-1.20(m,3H);MS(TOF):m/z(%)=573.2814(80%)(M+H)+;
实施例-167
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2-氨磺酰基乙基)吡咯烷-2-基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.42(br s,1H),8.09(s,1H),6.95(s,1H),6.87(d,J=14.8Hz,1H),6.75(s,2H),6.66(dd,J=14.8Hz,J=7.2Hz,1H),3.23-3.07(m,4H),3.01-2.94(m,1H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.63-2.56(m,1H),2.33-2.27(m,1H),2.02-1.93(m,5H),1.73-1.70(m,2H),1.55-1.50(m,1H);MS(TOF):m/z(%)=483.1490(80%)(M+H)+.
实施例-168
(S,E)-2-(2-乙基-1-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.01(s,1H),6.93(s,1H),6.71(d,J=15.2Hz,1H),6.58(d,J=15.6Hz,1H),2.99(m,1H),2.80(t,J=7.2Hz,4H),2.66(t,J=7.2Hz,4H),2.57(m,1H),2.24(s,3H),1.95(m,4H),1.85(m,1H),1.72(m,4H),1.45(m,1H),0.8(t,J=7.2Hz,3H);MS(ESI):m/z(%)=418.19(100%)(M+1);
实施例-169
(R,E)-2-(1-(丁-2-炔-1-基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.84(s,1H),7.03(d,J=15.6Hz,1H),6.91(s,1H),6.35-6.23(m,1H),4.31-4.03(m,3H),3.26-3.07(m,2H),2.82-2.67(m,8H),2.20-2.05(m,1H),1.97-1.83(m,6H),1.74-1.61(m,4H);MS(TOF):m/z(%)=428.1884(100%)(M+H)+.
生物活性:
体外测定:
用PMA(100ng/mL)使THP1单核细胞分化,并在5%CO2存在下在37℃下孵育20小时。在96孔组织培养板中,每孔接种2×105个分化的细胞。使用500ng/mL脂多糖致敏细胞,并在相同条件下孵育4小时。然后用不同浓度的化合物处理细胞30分钟,随后用5mM ATP处理1小时。收集上清液并通过IL-1b(Mabtech Cat#3415-1H-20)或TNF-a(Mabtech;Cat#3510-1H-20)检测试剂盒分析。使用GraphPad Prism V7.0对数据进行分析。使用非线性回归分析通过将百分比细胞存活数据拟合到GraphPad Prism上构建剂量响应曲线(Dose ResponseCurve,DRC)来确定IC50值。表1中列出了代表性化合物的体外IL-1β抑制活性(IC50)。
表1
体内效力研究:
测试化合物在大鼠小鼠中体内效力的证明,经口施用途径。
动物
所有动物实验都是在内部繁育的雌性大鼠和小鼠中进行的。动物以每笼6只动物一组饲养一周,以使它们适应生态箱环境(25±4℃,60%至65%相对湿度,12:12小时光照:黑暗循环,上午7:30开启光照)。所有动物实验均根据下文的经“Zydus研究中心动物伦理委员会”批准的国际有效的指南进行。
体内LPS和ATP诱导的IL-1β测定:
雌性C57小鼠(6至8周)接受了PBS中50μg/小鼠的脂多糖(LPS)的腹膜内注射。立即用测试化合物或载剂处理动物。LPS注射2小时之后,通过腹膜内途径对动物以12.5mg/小鼠施用溶于PBS的ATP。ATP注射30分钟之后,收集血清用于通过ELISA估计IL-1β。
本发明的新化合物可通过公知的技术和方法以及浓度通过与适合的赋形剂组合而配制成适合的可药用组合物。
表2中列出了一些测试化合物的代表性数据:
表2
式(I)化合物或含有它们的药物组合物可用作抑制NLRP3活性的药物并且适合于人和其他温血动物,并且可通过经口、经表面或胃肠外施用来施用。
因此,包含本发明化合物的药物组合物可包含适合的黏合剂、适合的填充剂和/或稀释剂以及任何其他可能是必要的适合的药剂。任选地,药物组合物可用适合的包衣剂适合地进行包衣。
本发明化合物(I)是NLRP3抑制剂并且可用于治疗由NLRP3介导的疾病状态,优选其中涉及白介素1β活性的疾病或病症以及相关障碍。
药物组合物中的活性成分(即根据本发明的式(I)化合物)的量及其单位剂型可根据具体施用方法、具体化合物的效力和期望的浓度广泛地变化或调整。通常来说,活性成分的量的范围将在组合物的以重量计0.5%至90%之间。
本发明式(I)化合物可单独使用或与可由熟练医师容易地鉴定的一种或更多种其他治疗剂任意组合使用。可根据在治疗的疾病类型、严重性、患者在服用的其他药物等来选择这样的其他治疗剂。因此,例如,对于类风湿性关节炎的治疗,可将一种或更多种DMARD与本发明化合物结合使用。
在实施方案之一中,本发明的式(I)化合物可与一种或更多种选自以下治疗剂的适合的药物活性剂以任意组合组合使用。白介素-1β抑制剂(例如利纳西普、卡那单抗和阿那白滞素);免疫抑制剂(例如甲氨蝶呤、巯基嘌呤、环磷酰胺)、代谢障碍药物、糖皮质激素、非甾体抗炎药物、Cox-2特异性抑制剂、TNF-α结合蛋白(例如英夫利昔单抗、依那西普(etanercept))、干扰素-13、干扰素、白介素-2、抗组胺剂、β-激动剂、BTK抑制剂、抗胆碱能剂(anticolinergics)、抗癌剂,或其适合的可药用盐。其他实例用于与以下组合使用:非酒精性脂肪性肝炎(Non-Alcoholic Steato-Hepatitis,NASH)和纤维化药物、抗癌抗生素、激素、芳香化酶抑制剂、抗体、细胞因子、疫苗、药物缀合物、丝裂原激活的蛋白激酶信号传导抑制剂(例如:BAY 43-9006)、Syk抑制剂、mTOR抑制剂、抗体(利妥昔单抗)和BCR/ABL拮抗剂。
虽然已经根据本发明的具体实施方案描述了本发明,但是对于本领域技术人员来说,某些修改和等效物将是明显的,并且旨在包括在本发明的范围内。
Claims (17)
1.具有通式(I)的结构的化合物:
其互变异构形式、其立体异构体、其对映体、其可药用盐和包含其的药物组合物,其中,
R1在每次出现时独立地选自氢,卤素,卤代烷基,氰基,任选地经取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C1-C6)烷氧基、(C3-C7)环烷基、NH2、NH(C1-C6)烷基、N(C3-C7)环烷基、N(C1-C6烷基)2、芳基、杂芳基、杂环基、苄基、硫醇、巯基烷基、SO2(C1-C6)烷基、(C1-C6)硫代烷氧基、酰胺;
X是N-R5、O、S、SO2;
R5在每次出现时独立地选自氢,卤素,卤代烷基,氰基,任选地经取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、(C3-C7)环烷基、(C1-C6)烷基SO2(C1-C6)烷基、(C1-C6)烷基N(C1-C6)烷基、(C1-C6)烷基N(C3-C7)环烷基、芳基、杂芳基、杂环基、苄基、叔丁氧基羰基、硫醇、巯基烷基、SO2(C1-C6)烷基、SO2(C3-C7)环烷基、SO2-芳基、SO2-杂环基、(C1-C6)硫代烷基、(C1-C6)硫代烷氧基、(C1-C6)烷基SO2NH2、-CONH2、-CO(C1-C6)烷基、-CO(C1-C6)卤代烷基、-CO-芳基、-CO-杂芳基、-CO-杂环基、4至7元杂环、7至14元双环杂环体系、具有任选地一个或多于一个杂原子的桥环或螺环体系;
m和n独立地选自整数0至3;
q和r独立地选自整数1至4;
R2在每次出现时独立地选自氢,卤素,氰基,任选地经取代的选自以下的基团:(C1-C6)烷基、(C2-C6)烯基、(C1-C6)烷氧基、(C3-C7)环烷基、苄基、芳基、杂芳基、杂环基、硫醇、硫代烷基、硫代-烷氧基、SO2(C1-C6)烷基、SO(C1-C6)烷基、具有任选地一个或多于一个杂原子的桥环或螺环体系;
R3和R4中的每个在每次出现时独立地选自氢、卤素、卤代烷基、氰基、硝基、酰胺、磺酰胺、酰基、羟基、任选地经取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C6)环烷基、(C1-C6)烷氧基、SO2(C1-C6)烷基、硫醇、巯基烷基、苄基、芳基、杂芳基、杂环基;或者R3和R4形成键;
‘B’选自以下环体系:
其中X、Y、Z在每次出现时独立地选自C、N、S、SO2和O,其可以在任何可能的情况下任选地被取代;
R6、R7、R8、R9、R10和R11中的每个在每次出现时独立地选自氢、卤素、氰基、酰胺、磺酰胺、酰基、羟基、任选地经取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C6)环烷基、(C1-C6)烷氧基、苄基、芳基、杂芳基、杂环基;或者R7和R8、R8和R9、R9和R10或R10和R11中的每个在任何可能的情况下,可以一起形成包含0至2个选自N、O和S(O)p的另外的杂原子的4至7元饱和或部分饱和的环;p=1至2。
2.根据权利要求1所述的化合物,其中R1在每次出现时选自氢、卤素、卤代烷基、任选地经取代的选自(C1-C6)烷基的基团。
3.根据权利要求1所述的化合物,其中R2在每次出现时选自氢、卤素、卤代烷基任选地经取代的选自(C1-C6)烷基的基团。
4.根据权利要求1所述的化合物,其中R3和R4在每次出现时独立地选自氢、卤素、卤代烷基、任选地经取代的选自(C1-C6)烷基的基团。
5.根据权利要求1所述的化合物,其中R6、R7、R8、R9、R10和R11中的每个在每次出现时独立地选自氢、卤素任选地经取代的选自(C1-C6)烷基、(C1-C6)卤代烷基的基团。
6.根据前述权利要求中任一项所述的化合物,其中当任意上述基团被取代时,所述取代选自氢、羟基、氰基、卤代、卤代烷基、卤代烷氧基、烷基硫代(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C7)环烷基、C1-C6烷氧基、芳基、杂环基、杂芳基、-COR12、-CSR12、C(O)OR12、C(O)-R12、-C(O)-NR12R13、-C(S)-NR12R13、-SO2R12基团,其中R12和R13中的每个独立地选自氢,任选地经取代的选自以下的基团:(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C7)环烷基、芳基、杂芳基、杂环基基团。
7.根据权利要求1所述的化合物,所述化合物选自:
(R,E)-2-(1-乙基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙磺酰胺;
(S,E)-2-(1-乙基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-丙基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-2-(1-(环丙基甲基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(甲基磺酰基)-吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-2-(1-乙酰基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙烯-1-磺酰胺;
(E)-2-(1-苄基哌啶-4-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙磺酰胺;
(R,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)-乙烯基)吡咯烷-1-羧酸叔丁酯;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2-甲氧基乙基)吡咯烷-2-基)乙烯磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(异丙基磺酰基)吡咯烷-2-基)乙烯磺酰胺;
(R,E)-2-(1-((3-氟苯基)磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(吡嗪-2-羰基)吡咯烷-2-基)乙烯磺酰胺;
(R,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-甲酰胺;
(R,E)-2-(1-(环丙烷羰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2,2,2-三氟乙酰基)吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2-(甲硫基)乙基)吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2,2,2-三氟乙基)吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-异丁基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-2-(1-(乙基磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-异丙基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(3-(甲基磺酰基)丙基)吡咯烷-2-基)乙烯磺酰胺;
(R,E)-2-(1-苯甲酰基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(R,E)-N-((2-(1-苯甲酰基吡咯烷-2-基)乙烯基)磺酰基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)苯甲酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(噻吩-3-羰基)吡咯烷-2-基)乙烯磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺甲磺酸盐;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺马来酸盐;
(R,Z)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-3-(吡咯烷-2-基)丙-1-烯-1-磺酰胺;
(R,E)-2-(1-(环己基磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,Z)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-2-(1-(环己基甲基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-2-(1-环己基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(1-甲基哌啶-4-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(R,Z)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-异丙基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(四氢-2H-吡喃-4-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(氧杂环丁烷-3-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(四氢-2H-噻喃-4-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(噻唑-2-基甲基)吡咯烷-2-基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(哌啶-4-基)乙烯磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基哌啶-4-基)乙烯磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(甲基磺酰基)哌啶-4-基)乙烯磺酰胺;
(E)-2-(1-乙酰基哌啶-4-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-磺酰胺;
(E)-4-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-哌啶-1-羧酸叔丁酯;
(E)-2-(1-乙基哌啶-4-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-2-(1-乙基吡咯烷-3-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙烯磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-3-基)乙烯-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(R,E)-2-(1-乙酰基-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基-1-(甲基磺酰基)-吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-2-(1,2-二甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-2-(1-乙基-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-2-(1-(环丙基甲基)-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯磺酰胺;
(S,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-羧酸叔丁酯;
(S,E)-2-(1-(环丙基甲基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(吡啶-3-基磺酰基)-吡咯烷-2-基)乙烯磺酰胺;
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(吡咯烷-2-基)乙烯磺酰胺;
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1-乙基吡咯烷-2-基)乙烯磺酰胺;
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1-(甲基磺酰基)吡咯烷-2-基)乙烯-磺酰胺;
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯磺酰胺;
(S,E)-2-(1-乙酰基吡咯烷-2-基)-N-((2,6-二异丙基苯基)氨甲酰基)乙烯磺酰胺;
(S,E)-2-(1-乙酰基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-乙烯磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(四氢-2H-吡喃-4-羰基)吡咯烷-2-基)乙烯磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(四氢-2H-吡喃-4-基)乙烯磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-烟酰基吡咯烷-2-基)乙烯磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(四氢呋喃-2-基)乙烯-1-磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(噻吩-2-基甲基)-吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-2-(2-(N-((4-氟-2,6-二异丙基苯基)氨甲酰基)氨磺酰基)乙烯基)-吡咯烷-1-羧酸叔丁酯;
(S,E)-N-((4-氟-2,6-二异丙基苯基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-N-((4-氟-2,6-二异丙基苯基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-异丁基-2-甲基-吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基-1-丙基吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(噻唑-2-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(哌啶-3-基)乙烯-磺酰胺;
(E)-2-(1-乙基哌啶-3-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-磺酰胺;
(E)-3-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-哌啶-1-羧酸叔丁酯;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(甲基磺酰基)哌啶-3-基)乙烯磺酰胺;
(E)-2-(1-乙酰基哌啶-3-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-磺酰胺;
(E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-氮杂环丁烷-1-羧酸叔丁酯;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基氮杂环丁烷-2-基)乙烯-1-磺酰胺;
(E)-2-(氮杂环丁烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(四氢-2H-吡喃-4-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-2-(1-((5-氯噻吩-2-基)磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(S,E)-2-(1-(苄基磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-((4-甲氧基苯基)磺酰基)吡咯烷-2-基)乙烯磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-((4-氟苯基)磺酰基)吡咯烷-2-基)乙烯磺酰胺;
(S,E)-2-(1-((2-氰基苯基)磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(S,E)-2-(1-(环己基磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(S,E)-2-(1-(4-氟苄基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯磺酰胺;
(S,E)-2-(1-((4-氰基苯基)磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-2-(1-(4-氰基苄基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)-2-(吡咯烷-2-基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(哌啶-2-基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-甲基哌啶-2-基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)-2-(1-甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)-2-(1-(甲基磺酰基)吡咯烷-2-基)乙烯-1-磺酰胺;
((E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-3-(哌啶-2-基)丙-1-烯-1-磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-2-(1,2-二甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(吲哚啉-2-基)乙烯-1-磺酰胺;
(E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吲哚啉-1-羧酸叔丁酯;
((S,E)-2-(1-(环丙基甲基)-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-2-(1-(环丙基磺酰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(R,E)-2-(2-(N-((2,6-二异丙基苯基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(R,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐;
(R,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1,2-二甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-2-(1-乙基-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
双钠(R,E)-((2-(1,2-二甲基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺;
钠(R,E)-((2-(1,2-二甲基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺;
(S,E)-2-(2-(N-((2,6-二异丙基苯基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐;
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1,2-二甲基吡咯烷-2-基)乙烯-1-磺酰胺;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基-1-(氧杂环丁烷-3-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-2-(2-(N-((4-氟-2,6-二异丙基苯基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(S,E)-N-((4-氟-2,6-二异丙基苯基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐;
(S,E)-2-(1,2-二甲基吡咯烷-2-基)-N-((4-氟-2,6-二异丙基苯基)氨甲酰基)乙烯-1-磺酰胺;
(E)-2-(1-乙酰基氮杂环丁烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-(2-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-基)乙基)(甲基)氨基甲酸叔丁酯;
(S,E)-2-(1-烯丙基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-2-(1-(1H-苯并[d]咪唑-6-羰基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-2-(1-(环丙基磺酰基)-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(4-甲氧基苄基)吡咯烷-2-基)乙烯-1-磺酰胺;
5-((R)-2-((E)-2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-基)六氢环戊并[c]吡咯-2(1H)-羧酸叔丁酯;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-((2R)-1-(八氢环-戊并[c]吡咯-5-基)吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐;
(E)-2-(1-(环丙基磺酰基)氮杂环丁烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-N-((2,6-二异丙基苯基)氨甲酰基)-2-(1-(噻唑-2-基)吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-(2-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-基)乙基)(甲基)氨基甲酸叔丁酯;
钾(R,E)-((2-(1,2-二甲基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺;
(E)-(2-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)氮杂环丁烷-1-基)乙基)(甲基)氨基甲酸叔丁酯;
(S,E)-2-(1-(环己基甲基)-2-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
钠(R,E)-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)((2-(1-(四氢-2H-噻喃-4-基)吡咯烷-2-基)乙烯基)磺酰基)酰胺;
钠(R,E)-((2-(1-环己基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺;
钠(S,E)-((2,6-二异丙基苯基)氨甲酰基)((2-(1,2-二甲基吡咯烷-2-基)乙烯基)磺酰基)酰胺;
钠(R,E)-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)((2-(1-甲基吡咯烷-2-基)乙烯基)磺酰基)酰胺;
钾(R,E)-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)((2-(1-甲基吡咯烷-2-基)乙烯基)磺酰基)酰胺;
钠(S,E)-((2-(1,2-二甲基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺;
钠(S,E)-((2-(1-乙基吡咯烷-2-基)乙烯基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)酰胺;
(S,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2-羟基乙基)吡咯烷-2-基)乙烯-1-磺酰胺;
(E)-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-羧酸叔丁酯;
(E)-2-(1,2-二甲基氮杂环丁烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(S,E)-2-乙基-2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-羧酸叔丁酯;
(S,E)-2-(2-(N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(S,E)-2-(2-乙基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐;
(S,E)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐;
(S,E)-2-(1,2-二甲基吡咯烷-2-基)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-2-(2-(N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(R,E)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)-2-(2-甲基吡咯烷-2-基)乙烯-1-磺酰胺2,2,2-三氟乙酸盐;
(R,E)-2-(1,2-二甲基吡咯烷-2-基)-N-((1,2,3,6,7,8-六氢-as-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-2-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)烯丙基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(R,E)-(2-(2-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)烯丙基)-2-甲基吡咯烷-1-基)乙基)(甲基)氨基甲酸叔丁酯;
(R,E)-3-(1,2-二甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)丙-1-烯-1-磺酰胺;
(S,E)-(3-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)吡咯烷-1-基)丙基)(甲基)氨基甲酸叔丁酯;
(E)-(3-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-基)丙基)(甲基)氨基甲酸叔丁酯;
(E)-(2-(2-(2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-基)乙基)(甲基)氨基甲酸叔丁酯;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基-1-(2-(甲硫基)乙基)氮杂环丁烷-2-基)乙烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(2-甲基-1-(氧杂环丁烷-3-基)氮杂环丁烷-2-基)乙烯-1-磺酰胺;
(S)-2-(((S)-2-((E)-2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-基)甲基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(S)-2-(((R)-2-((E)-2-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)氨磺酰基)乙烯基)-2-甲基氮杂环丁烷-1-基)甲基)-2-甲基吡咯烷-1-羧酸叔丁酯;
(R,E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)-2-(1-(2-氨磺酰基乙基)吡咯烷-2-基)乙烯-1-磺酰胺;
(S,E)-2-(2-乙基-1-甲基吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺;
(R,E)-2-(1-(丁-2-炔-1-基)吡咯烷-2-基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨甲酰基)乙烯-1-磺酰胺。
8.药物组合物,其包含治疗有效量的根据前述权利要求中任一项所述的式(I)化合物和任选的一种或更多种可药用载体、稀释剂或赋形剂。
9.治疗以NLRP3调节剂作为药物的疾病以及治疗其中涉及白介素1β活性和白介素-18(IL-18)的疾病或病症的方法,其包括向有此需要的患者施用有效量的根据前述权利要求中任一项所述的式(I)化合物或其适合的药物组合物。
10.根据前述权利要求中任一项所述的式(I)化合物或其药物组合物适合用于治疗其中NLRP3调节剂具有病理生理学功能的疾病的用途。
11.根据权利要求8所述的药物组合物,其与选自以下的一种或更多种适合的药物活性剂组合:白介素-1β抑制剂;免疫抑制剂;代谢障碍药物、糖皮质激素、非甾体抗炎药物、COX-2特异性抑制剂、抗炎药物、TNF-α结合蛋白、干扰素-13、干扰素、白介素-2、抗组胺剂、β-激动剂、BTK抑制剂、抗胆碱能剂、抗癌剂、或其适合的可药用盐、非酒精性脂肪性肝炎(NASH)和纤维化药物、抗癌药物、抗生素、激素、芳香化酶抑制剂、丝裂原激活的蛋白激酶信号传导抑制剂、Syk抑制剂、mTOR抑制剂和BCR/ABL拮抗剂。
13.用于制备根据权利要求1所述的式(I)化合物的方法,所述方法包括以下步骤:
(a)(i)使式(12)化合物与式(3)化合物反应以获得式(13)化合物,其中所有符号均根据权利要求1中所限定:
(ii)使式(13)化合物与DMSO反应以获得式(14)化合物,其中所有符号均根据权利要求1中所限定:
(iii)使式(14)化合物与式(7)化合物异氰酸酯衍生物反应以获得式(I)化合物,其中所有符号均根据权利要求1中所限定:
(b)(i)使式(15)化合物与式(7)化合物异氰酸酯衍生物反应以获得式(16)化合物,其中所有符号均根据权利要求1中所限定:
(ii)使式(16)化合物与式(4)化合物反应以获得式(I)化合物,其中所有符号均根据权利要求1中所限定:
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JP7488267B2 (ja) | 2024-05-21 |
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CA3126467A1 (en) | 2020-07-23 |
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EA202191968A1 (ru) | 2021-11-16 |
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