US20200148650A1 - Isoxazole carboxamide compounds - Google Patents
Isoxazole carboxamide compounds Download PDFInfo
- Publication number
- US20200148650A1 US20200148650A1 US16/588,209 US201916588209A US2020148650A1 US 20200148650 A1 US20200148650 A1 US 20200148650A1 US 201916588209 A US201916588209 A US 201916588209A US 2020148650 A1 US2020148650 A1 US 2020148650A1
- Authority
- US
- United States
- Prior art keywords
- alkyl
- optionally substituted
- cancer
- amino
- group
- 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.)
- Abandoned
Links
- 0 [1*]C1=C([2*])C(C(=O)N*CC)=NO1 Chemical compound [1*]C1=C([2*])C(C(=O)N*CC)=NO1 0.000 description 20
- WGUBFYHEYXFJSA-UHFFFAOYSA-N COC(=O)C1=CC(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)=CC=C1 Chemical compound COC(=O)C1=CC(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)=CC=C1 WGUBFYHEYXFJSA-UHFFFAOYSA-N 0.000 description 4
- UMBYOEAQWFHUJQ-UHFFFAOYSA-N NC(CCC1=CC=CN=C1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NC(CCC1=CC=CN=C1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 UMBYOEAQWFHUJQ-UHFFFAOYSA-N 0.000 description 4
- AWETWPXQJXCCOL-PKDNWHCCSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CC=C(O)C=C2)CC1.Cl Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CC=C(O)C=C2)CC1.Cl AWETWPXQJXCCOL-PKDNWHCCSA-N 0.000 description 3
- YFWHBGUJNPFCJB-JTQLQIEISA-N C[C@H](N)C(=O)CCCCCNC(=O)C1=NOC(C2CC2)=C1 Chemical compound C[C@H](N)C(=O)CCCCCNC(=O)C1=NOC(C2CC2)=C1 YFWHBGUJNPFCJB-JTQLQIEISA-N 0.000 description 3
- INXRWZHHZGRSAZ-LFUZPPSTSA-N C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC(C(=O)NC3=CC=CN=C3)=C2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC(C(=O)NC3=CC=CN=C3)=C2)CC1 INXRWZHHZGRSAZ-LFUZPPSTSA-N 0.000 description 3
- HSUWICFCXAITHA-KYZUINATSA-N NC(=O)C1=C(C2CC2)ON=C1C(=O)N[C@H]1CC[C@H](N)CC1 Chemical compound NC(=O)C1=C(C2CC2)ON=C1C(=O)N[C@H]1CC[C@H](N)CC1 HSUWICFCXAITHA-KYZUINATSA-N 0.000 description 3
- UEDDJKYAALHFEM-KYZUINATSA-N N[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2I)CC1 Chemical compound N[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2I)CC1 UEDDJKYAALHFEM-KYZUINATSA-N 0.000 description 3
- XFZIMSNNCRXFLV-KYZUINATSA-N N[C@H]1CC[C@H](NC(=O)C2=NOC(CCO)=C2)CC1 Chemical compound N[C@H]1CC[C@H](NC(=O)C2=NOC(CCO)=C2)CC1 XFZIMSNNCRXFLV-KYZUINATSA-N 0.000 description 3
- IOXDXKATXNMNKF-UHFFFAOYSA-N O=C(NC1CN(CC2=CN(CC3=CC=C(Cl)C=C3)N=C2)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CN(CC2=CN(CC3=CC=C(Cl)C=C3)N=C2)C1)C1=NOC(C2CC2)=C1 IOXDXKATXNMNKF-UHFFFAOYSA-N 0.000 description 3
- SPDAFJHSJXLNSO-UHFFFAOYSA-N O=C(NCC1CCNCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NCC1CCNCC1)C1=NOC(C2CC2)=C1 SPDAFJHSJXLNSO-UHFFFAOYSA-N 0.000 description 3
- TYWKQPCFZWIICI-UHFFFAOYSA-N O=C(c1n[o]c(C2CC2)c1)NC(C1CCNCC1)c1ccccc1 Chemical compound O=C(c1n[o]c(C2CC2)c1)NC(C1CCNCC1)c1ccccc1 TYWKQPCFZWIICI-UHFFFAOYSA-N 0.000 description 3
- JJAUAPNVIWQHQE-UHFFFAOYSA-N CC(=O)NC1=CC=C(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)C=C1 Chemical compound CC(=O)NC1=CC=C(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)C=C1 JJAUAPNVIWQHQE-UHFFFAOYSA-N 0.000 description 2
- WHCSHHLTBFOYEV-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC=N1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC=N1 WHCSHHLTBFOYEV-UHFFFAOYSA-N 0.000 description 2
- AYYQLGLOGVGFRN-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CSC=N1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CSC=N1 AYYQLGLOGVGFRN-UHFFFAOYSA-N 0.000 description 2
- XUDUHXRTIRQICB-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1 XUDUHXRTIRQICB-UHFFFAOYSA-N 0.000 description 2
- UJCNUGJRVMZAFQ-UHFFFAOYSA-N CC(C)(C)OC(=O)NC1CCC2CC1CCC2N Chemical compound CC(C)(C)OC(=O)NC1CCC2CC1CCC2N UJCNUGJRVMZAFQ-UHFFFAOYSA-N 0.000 description 2
- XKJKFCGYNLPZIJ-UHFFFAOYSA-N CC(C)(C)OC(=O)NCCCCNC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC(C)(C)OC(=O)NCCCCNC(=O)C1=NOC(C2CC2)=C1 XKJKFCGYNLPZIJ-UHFFFAOYSA-N 0.000 description 2
- MNPAWOMHIBEMSL-UHFFFAOYSA-N CC(C)(CNC(=O)C1=NOC(C2CC2)=C1)CNS(=O)(=O)C1CCNCC1 Chemical compound CC(C)(CNC(=O)C1=NOC(C2CC2)=C1)CNS(=O)(=O)C1CCNCC1 MNPAWOMHIBEMSL-UHFFFAOYSA-N 0.000 description 2
- LRNAJBKAJUSNGU-UHFFFAOYSA-N CC(C)C(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound CC(C)C(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 LRNAJBKAJUSNGU-UHFFFAOYSA-N 0.000 description 2
- SMWCQCNEOWJKGA-INIZCTEOSA-N CC(C)[C@H](N)C(=O)N1CCC(CNC(=O)C2=NOC(C3CC3)=C2)CC1.Cl Chemical compound CC(C)[C@H](N)C(=O)N1CCC(CNC(=O)C2=NOC(C3CC3)=C2)CC1.Cl SMWCQCNEOWJKGA-INIZCTEOSA-N 0.000 description 2
- QURRYDBYXRVQEJ-UHFFFAOYSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.Cl Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.Cl QURRYDBYXRVQEJ-UHFFFAOYSA-N 0.000 description 2
- XHAMHQJEXHRRGW-VXLWULRPSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](CC2=CC=C(O)C=C2)NC(=O)OC(C)(C)C)CC1 Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](CC2=CC=C(O)C=C2)NC(=O)OC(C)(C)C)CC1 XHAMHQJEXHRRGW-VXLWULRPSA-N 0.000 description 2
- ODFXAZMOLWBVPI-UHFFFAOYSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(CC2=CC=CC=C2)C1 Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(CC2=CC=CC=C2)C1 ODFXAZMOLWBVPI-UHFFFAOYSA-N 0.000 description 2
- DMQRCZLOGKRZSK-UHFFFAOYSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCNCC1 Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCNCC1 DMQRCZLOGKRZSK-UHFFFAOYSA-N 0.000 description 2
- YOAYLELHEIKQOL-UHFFFAOYSA-N CC1=CC(C(=O)NC2CCCC(N)C2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC1=CC(C(=O)NC2CCCC(N)C2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 YOAYLELHEIKQOL-UHFFFAOYSA-N 0.000 description 2
- TYTJEUXAVDWWFG-UHFFFAOYSA-N CC1=CC(C(=O)NC2CCNC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC1=CC(C(=O)NC2CCNC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 TYTJEUXAVDWWFG-UHFFFAOYSA-N 0.000 description 2
- RSVHJQJDDOFWLU-UHFFFAOYSA-N CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCC(N)CC1 Chemical compound CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCC(N)CC1 RSVHJQJDDOFWLU-UHFFFAOYSA-N 0.000 description 2
- QQXVXSOFCKZIHP-UHFFFAOYSA-N CC1CCC(NC(=O)C2=NOC(C3CC3)=C2)CN1CC1=CC=CC=C1 Chemical compound CC1CCC(NC(=O)C2=NOC(C3CC3)=C2)CN1CC1=CC=CC=C1 QQXVXSOFCKZIHP-UHFFFAOYSA-N 0.000 description 2
- SHFJFJMWSWIQLL-UHFFFAOYSA-N CCC(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound CCC(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 SHFJFJMWSWIQLL-UHFFFAOYSA-N 0.000 description 2
- NAAXOTIDLCPDPU-YNODCEANSA-N CCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](C)N)CC1 Chemical compound CCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](C)N)CC1 NAAXOTIDLCPDPU-YNODCEANSA-N 0.000 description 2
- WIURALIHFXUYAQ-UHFFFAOYSA-N CCCN1CC(CNC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CCCN1CC(CNC(=O)C2=NOC(C3CC3)=C2)C1 WIURALIHFXUYAQ-UHFFFAOYSA-N 0.000 description 2
- BDWQCWLBXBFECT-UHFFFAOYSA-N CCOC(=O)C1(CNC(=O)C2=NOC(C3CC3)=C2)CCNCC1 Chemical compound CCOC(=O)C1(CNC(=O)C2=NOC(C3CC3)=C2)CCNCC1 BDWQCWLBXBFECT-UHFFFAOYSA-N 0.000 description 2
- YVQFFHUNMZEDNW-UHFFFAOYSA-N CN1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CN1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 YVQFFHUNMZEDNW-UHFFFAOYSA-N 0.000 description 2
- ZPQDLNBTKRSEKK-UHFFFAOYSA-N CN1CCOC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=C(Cl)C=C2)C1 Chemical compound CN1CCOC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=C(Cl)C=C2)C1 ZPQDLNBTKRSEKK-UHFFFAOYSA-N 0.000 description 2
- HRHOFJHWSIXUIM-HWYAHNCWSA-N COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)CC2=CNC3=C2C=CC=C3)CC1 Chemical compound COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)CC2=CNC3=C2C=CC=C3)CC1 HRHOFJHWSIXUIM-HWYAHNCWSA-N 0.000 description 2
- SDNTZIURMDKRLY-UHFFFAOYSA-N COC(=O)C1=CC(CN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 Chemical compound COC(=O)C1=CC(CN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 SDNTZIURMDKRLY-UHFFFAOYSA-N 0.000 description 2
- ZUGWYPYZWILBDP-ORGDTZJYSA-N C[C@@H](N)CC(=O)NC1CCC2CC1CCC2NC(=O)C1=NOC(C2CC2)=C1 Chemical compound C[C@@H](N)CC(=O)NC1CCC2CC1CCC2NC(=O)C1=NOC(C2CC2)=C1 ZUGWYPYZWILBDP-ORGDTZJYSA-N 0.000 description 2
- XBAJYZWTVRTOPK-ZPGOUYQLSA-N C[C@@H](N)CC(=O)N[C@H]1CC2(C[C@@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1 Chemical compound C[C@@H](N)CC(=O)N[C@H]1CC2(C[C@@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1 XBAJYZWTVRTOPK-ZPGOUYQLSA-N 0.000 description 2
- HZHHVTLQFBWDOO-ZBKGVPMPSA-N C[C@H](CC(=O)NC1CCC2CC1CCC2NC(=O)C1=NOC(C2CC2)=C1)NC(=O)OC(C)(C)C Chemical compound C[C@H](CC(=O)NC1CCC2CC1CCC2NC(=O)C1=NOC(C2CC2)=C1)NC(=O)OC(C)(C)C HZHHVTLQFBWDOO-ZBKGVPMPSA-N 0.000 description 2
- ARYRABQLELOSSV-OOJLDXBWSA-N C[C@H](N)C(=O)N1CCC(C(COC2=CC=CC=C2)NC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC(C(COC2=CC=CC=C2)NC(=O)C2=NOC(C3CC3)=C2)CC1 ARYRABQLELOSSV-OOJLDXBWSA-N 0.000 description 2
- JKOZWPURDARCIT-PVCZSOGJSA-N C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 JKOZWPURDARCIT-PVCZSOGJSA-N 0.000 description 2
- JKOZWPURDARCIT-XOBRGWDASA-N C[C@H](N)C(=O)N1CCC([C@@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC([C@@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 JKOZWPURDARCIT-XOBRGWDASA-N 0.000 description 2
- JKOZWPURDARCIT-VBKZILBWSA-N C[C@H](N)C(=O)N1CCC([C@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC([C@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 JKOZWPURDARCIT-VBKZILBWSA-N 0.000 description 2
- XBAJYZWTVRTOPK-VXDOAGJBSA-N C[C@H](N)CC(=O)N[C@H]1CC2(C[C@@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1 Chemical compound C[C@H](N)CC(=O)N[C@H]1CC2(C[C@@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1 XBAJYZWTVRTOPK-VXDOAGJBSA-N 0.000 description 2
- XDDGKXJSVYWWHG-CQHAJPFMSA-N C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC(C(=O)NC3=CC=CN=C3)=C2)CC1 Chemical compound C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC(C(=O)NC3=CC=CN=C3)=C2)CC1 XDDGKXJSVYWWHG-CQHAJPFMSA-N 0.000 description 2
- WWFNUNZDLFSISM-UHFFFAOYSA-N Cl.NCCC(=O)NC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound Cl.NCCC(=O)NC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 WWFNUNZDLFSISM-UHFFFAOYSA-N 0.000 description 2
- QFZGMGHNDORILF-UHFFFAOYSA-N NC(CCC1=CC=NC=C1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NC(CCC1=CC=NC=C1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 QFZGMGHNDORILF-UHFFFAOYSA-N 0.000 description 2
- XNRPHFPVYAZSBF-FPYGCLRLSA-N NC1=CC=C(C(=O)/C=C/C2=CN=CC=C2)C=C1 Chemical compound NC1=CC=C(C(=O)/C=C/C2=CN=CC=C2)C=C1 XNRPHFPVYAZSBF-FPYGCLRLSA-N 0.000 description 2
- FNRUGSCIQKVKIF-UHFFFAOYSA-N NC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)C1 Chemical compound NC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)C1 FNRUGSCIQKVKIF-UHFFFAOYSA-N 0.000 description 2
- FLHYTCKHSCVJRI-UHFFFAOYSA-N NC1CCCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)C1 Chemical compound NC1CCCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)C1 FLHYTCKHSCVJRI-UHFFFAOYSA-N 0.000 description 2
- HFGALSSTXWUFML-UHFFFAOYSA-N NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1I Chemical compound NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1I HFGALSSTXWUFML-UHFFFAOYSA-N 0.000 description 2
- YEOAKLWIERNYNY-UHFFFAOYSA-N NCCCCNC(=O)C1=NOC(C2CC2)=C1 Chemical compound NCCCCNC(=O)C1=NOC(C2CC2)=C1 YEOAKLWIERNYNY-UHFFFAOYSA-N 0.000 description 2
- NRCJKSJDNPLTGQ-UHFFFAOYSA-N NCCCS(=O)(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NCCCS(=O)(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 NRCJKSJDNPLTGQ-UHFFFAOYSA-N 0.000 description 2
- NSPRAHPCBJAUQW-UHFFFAOYSA-N NCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br Chemical compound NCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br NSPRAHPCBJAUQW-UHFFFAOYSA-N 0.000 description 2
- XWSSPEMCKWARNL-UHFFFAOYSA-N NCCNS(=O)(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1 Chemical compound NCCNS(=O)(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1 XWSSPEMCKWARNL-UHFFFAOYSA-N 0.000 description 2
- AMRPKXQSIWGNJH-KOMQPUFPSA-N N[C@H]1CC[C@H](NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1 Chemical compound N[C@H]1CC[C@H](NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1 AMRPKXQSIWGNJH-KOMQPUFPSA-N 0.000 description 2
- PBEZGNYNGXOUPM-MGCOHNPYSA-N N[C@H]1CC[C@H](NC(=O)C2=NOC(CCCO)=C2)CC1 Chemical compound N[C@H]1CC[C@H](NC(=O)C2=NOC(CCCO)=C2)CC1 PBEZGNYNGXOUPM-MGCOHNPYSA-N 0.000 description 2
- NZDWRGDFJQBGQO-UHFFFAOYSA-N O=C(NC(C1=CC(CO)=CC=C1)C1CCNCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C1=CC(CO)=CC=C1)C1CCNCC1)C1=NOC(C2CC2)=C1 NZDWRGDFJQBGQO-UHFFFAOYSA-N 0.000 description 2
- WEGNOQIXJVOBEJ-UHFFFAOYSA-N O=C(NC1=CC=CN=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NC1=CC=CN=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 WEGNOQIXJVOBEJ-UHFFFAOYSA-N 0.000 description 2
- SQXAFRSLQDACTP-UHFFFAOYSA-N O=C(NC1CN(CCO)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CN(CCO)C1)C1=NOC(C2CC2)=C1 SQXAFRSLQDACTP-UHFFFAOYSA-N 0.000 description 2
- YQAVFPJRLUUNJI-UHFFFAOYSA-N O=C(NC1CNC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CNC1)C1=NOC(C2CC2)=C1 YQAVFPJRLUUNJI-UHFFFAOYSA-N 0.000 description 2
- CXVCLFMETRTCKG-UHFFFAOYSA-N O=C(NCC1CNC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NCC1CNC1)C1=NOC(C2CC2)=C1 CXVCLFMETRTCKG-UHFFFAOYSA-N 0.000 description 2
- OWMVXHFZCCPOTD-UHFFFAOYSA-N O=C(O)C1=NOC(C2CC2)=C1 Chemical compound O=C(O)C1=NOC(C2CC2)=C1 OWMVXHFZCCPOTD-UHFFFAOYSA-N 0.000 description 2
- MSWJGFLVPJZXRQ-UHFFFAOYSA-N BC1=CC(C(=O)NCCCN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 Chemical compound BC1=CC(C(=O)NCCCN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 MSWJGFLVPJZXRQ-UHFFFAOYSA-N 0.000 description 1
- POXCBXGFLRIVOD-PEQXNDDMSA-N C#CC1=CC=C(NC(=O)C2=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=CC=C2)C=N1.CC1(C)CC(N)CC(C)(CCC(=O)C2=NOC(C3CC3)=C2)C1.CC1=CC=C(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)C=C1.CC1=CC=C(C[C@@H](N)C(=O)N2CCC(C(C)CC(=O)C3=NOC(C4CC4)=C3)CC2)C=C1 Chemical compound C#CC1=CC=C(NC(=O)C2=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=CC=C2)C=N1.CC1(C)CC(N)CC(C)(CCC(=O)C2=NOC(C3CC3)=C2)C1.CC1=CC=C(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)C=C1.CC1=CC=C(C[C@@H](N)C(=O)N2CCC(C(C)CC(=O)C3=NOC(C4CC4)=C3)CC2)C=C1 POXCBXGFLRIVOD-PEQXNDDMSA-N 0.000 description 1
- MGXLJKFQSHQTJE-UHFFFAOYSA-N C#CCCCOCC1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound C#CCCCOCC1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 MGXLJKFQSHQTJE-UHFFFAOYSA-N 0.000 description 1
- XGIXXVDFEKIPGX-BTBCBASRSA-N C#CCCCOCC1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.CC(C)C1=CC(CN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.C[C@H](N)CC(=O)N[C@H]1CC2(C[C@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1.C[C@H](N)CC(=O)N[C@H]1CC2(C[C@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1.N[C@H]1CC[C@H](NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)CC1 Chemical compound C#CCCCOCC1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.CC(C)C1=CC(CN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.C[C@H](N)CC(=O)N[C@H]1CC2(C[C@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1.C[C@H](N)CC(=O)N[C@H]1CC2(C[C@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1.N[C@H]1CC[C@H](NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)CC1 XGIXXVDFEKIPGX-BTBCBASRSA-N 0.000 description 1
- ZZYVJCAPXLBKAE-UHFFFAOYSA-N C#CCOCC1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound C#CCOCC1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 ZZYVJCAPXLBKAE-UHFFFAOYSA-N 0.000 description 1
- YPPAFNAUBZWULD-UHFFFAOYSA-N C#CCOCC1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCN(C(=O)CCN)C1.CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCN(C(=O)CN)C1.O=C(NC1CC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound C#CCOCC1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCN(C(=O)CCN)C1.CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCN(C(=O)CN)C1.O=C(NC1CC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 YPPAFNAUBZWULD-UHFFFAOYSA-N 0.000 description 1
- VIKNLPKNTRZQJY-UHFFFAOYSA-N C1=CC2=C(C=C1)CCC2.C1=CC2=C(C=C1)CCCC2.C1=CC2=C(C=C1)OCCO2.C1=CC2=C(C=C1)OCO2.CC(C)C.CC(C)C.CC(C)C.CC(C)C Chemical compound C1=CC2=C(C=C1)CCC2.C1=CC2=C(C=C1)CCCC2.C1=CC2=C(C=C1)OCCO2.C1=CC2=C(C=C1)OCO2.CC(C)C.CC(C)C.CC(C)C.CC(C)C VIKNLPKNTRZQJY-UHFFFAOYSA-N 0.000 description 1
- JCUSRVOPZRORIJ-UHFFFAOYSA-N C1=CC=C(CNC2CCC3CC2CCC3NCC2=CC=CC=C2)C=C1 Chemical compound C1=CC=C(CNC2CCC3CC2CCC3NCC2=CC=CC=C2)C=C1 JCUSRVOPZRORIJ-UHFFFAOYSA-N 0.000 description 1
- JKTBFKTYHISWRP-UHFFFAOYSA-N C1=NC2=C(C1)CCCC2.CC(C)C.CC(C)C.CC(C)N1C=C2CCCCC2=N1 Chemical compound C1=NC2=C(C1)CCCC2.CC(C)C.CC(C)C.CC(C)N1C=C2CCCCC2=N1 JKTBFKTYHISWRP-UHFFFAOYSA-N 0.000 description 1
- CRPVRFVAEXUCRI-WUIJSPNFSA-N C=CC1=CC(C(=O)N[C@H]2CC[C@H](C)CC2)=NO1.CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)C(C)C)CC1 Chemical compound C=CC1=CC(C(=O)N[C@H]2CC[C@H](C)CC2)=NO1.CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)C(C)C)CC1 CRPVRFVAEXUCRI-WUIJSPNFSA-N 0.000 description 1
- QYVMHFCWHNNRFM-KYZUINATSA-N C=CC1=CC(C(=O)N[C@H]2CC[C@H](N)CC2)=NO1 Chemical compound C=CC1=CC(C(=O)N[C@H]2CC[C@H](N)CC2)=NO1 QYVMHFCWHNNRFM-KYZUINATSA-N 0.000 description 1
- QYVMHFCWHNNRFM-UHFFFAOYSA-O C=Cc1cc(C(NC(CC2)CCC2[NH3+])=O)n[o]1 Chemical compound C=Cc1cc(C(NC(CC2)CCC2[NH3+])=O)n[o]1 QYVMHFCWHNNRFM-UHFFFAOYSA-O 0.000 description 1
- JNPJCWIDMQAWBG-UHFFFAOYSA-N CC#CCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 Chemical compound CC#CCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 JNPJCWIDMQAWBG-UHFFFAOYSA-N 0.000 description 1
- YGQIKJSGHNOBDG-GYNXAAFJSA-N CC#CCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.CC(C)(CCNC(=O)CCN)NC(=O)C1=NOC(C2CC2)=C1.CCCCN(C)CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.NCCC(=O)O[C@H]1CC[C@H](CC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound CC#CCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.CC(C)(CCNC(=O)CCN)NC(=O)C1=NOC(C2CC2)=C1.CCCCN(C)CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.NCCC(=O)O[C@H]1CC[C@H](CC(=O)C2=NOC(C3CC3)=C2)CC1 YGQIKJSGHNOBDG-GYNXAAFJSA-N 0.000 description 1
- UQFHWFBQPJXNEL-UHFFFAOYSA-N CC(=O)C1=CN=CC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)=C1.CC1CC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)C1.CC1CCC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1.O=C(NC(CCN1C=CC=N1)C1=CC=CC=C1)C1=NOC(C2CC2)=C1.O=C(NC1=CC=C(S(=O)(=O)CC2CCCCC2)C=C1)C1=NOC(C2CC2)=C1.O=C(NC1=CC=C(S(=O)(=O)CC2CCNC2)C=C1)C1=NOC(C2CC2)=C1.O=C(NC1CCCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound CC(=O)C1=CN=CC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)=C1.CC1CC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)C1.CC1CCC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1.O=C(NC(CCN1C=CC=N1)C1=CC=CC=C1)C1=NOC(C2CC2)=C1.O=C(NC1=CC=C(S(=O)(=O)CC2CCCCC2)C=C1)C1=NOC(C2CC2)=C1.O=C(NC1=CC=C(S(=O)(=O)CC2CCNC2)C=C1)C1=NOC(C2CC2)=C1.O=C(NC1CCCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 UQFHWFBQPJXNEL-UHFFFAOYSA-N 0.000 description 1
- HNVBBNZWMSTMAZ-UHFFFAOYSA-N CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1 Chemical compound CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1 HNVBBNZWMSTMAZ-UHFFFAOYSA-N 0.000 description 1
- DAISBAYRGAJXIS-UHFFFAOYSA-N CC(=O)CC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=N1.CC(=O)NC1=CC=C(S(=O)(=O)C2CCC(CC(=O)C3=NOC(C4CC4)=C3)CC2)C=C1.O=C(NC1=CN=CC=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound CC(=O)CC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=N1.CC(=O)NC1=CC=C(S(=O)(=O)C2CCC(CC(=O)C3=NOC(C4CC4)=C3)CC2)C=C1.O=C(NC1=CN=CC=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 DAISBAYRGAJXIS-UHFFFAOYSA-N 0.000 description 1
- AUAZPADPHXKJRJ-UHFFFAOYSA-N CC(=O)CC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)C=N1 Chemical compound CC(=O)CC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)C=N1 AUAZPADPHXKJRJ-UHFFFAOYSA-N 0.000 description 1
- ASPXHNGCKOQOPI-UHFFFAOYSA-N CC(=O)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CC(=O)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 ASPXHNGCKOQOPI-UHFFFAOYSA-N 0.000 description 1
- PQEUEORAPSRXFA-UHFFFAOYSA-N CC(=O)NC1=CC=C(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)C=C1.CCC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)C.CCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)C(C)C)CC1.CN1C=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=N1 Chemical compound CC(=O)NC1=CC=C(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)C=C1.CCC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)C.CCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)C(C)C)CC1.CN1C=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=N1 PQEUEORAPSRXFA-UHFFFAOYSA-N 0.000 description 1
- XPICILOQHAUDJU-UHFFFAOYSA-N CC(=O)NC1=CC=C(S(=O)(=O)C2CCC(CC(=O)C3=NOC(C4CC4)=C3)CC2)C=C1 Chemical compound CC(=O)NC1=CC=C(S(=O)(=O)C2CCC(CC(=O)C3=NOC(C4CC4)=C3)CC2)C=C1 XPICILOQHAUDJU-UHFFFAOYSA-N 0.000 description 1
- NPXAEVHVSPFLCI-AKAXFMLLSA-N CC(=O)NC1=CC=C(S(=O)(=O)C[C@H]2C[C@@H](NC(=O)C3=NOC(C4CC4)=C3)C2)C=C1 Chemical compound CC(=O)NC1=CC=C(S(=O)(=O)C[C@H]2C[C@@H](NC(=O)C3=NOC(C4CC4)=C3)C2)C=C1 NPXAEVHVSPFLCI-AKAXFMLLSA-N 0.000 description 1
- MBAOJYAWKIVVQE-SHVUVFPCSA-N CC(=O)NC1=CC=C(S(=O)(=O)C[C@H]2C[C@@H](NC(=O)C3=NOC(C4CC4)=C3)C2)C=C1.CC(=O)NC1=CC=C(S(=O)(=O)C[C@H]2C[C@H](NC(=O)C3=NOC(C4CC4)=C3)C2)C=C1.CN1CCC(CNC(=O)C2=NOC(C3CC3)=C2)CC1.COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](C)N)CC1.COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC(C(=O)NC3=CC=CC=C3)=C2)CC1.O=C(NC1=CC=C(O)N=C1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.O=C(NCC1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound CC(=O)NC1=CC=C(S(=O)(=O)C[C@H]2C[C@@H](NC(=O)C3=NOC(C4CC4)=C3)C2)C=C1.CC(=O)NC1=CC=C(S(=O)(=O)C[C@H]2C[C@H](NC(=O)C3=NOC(C4CC4)=C3)C2)C=C1.CN1CCC(CNC(=O)C2=NOC(C3CC3)=C2)CC1.COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](C)N)CC1.COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC(C(=O)NC3=CC=CC=C3)=C2)CC1.O=C(NC1=CC=C(O)N=C1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.O=C(NCC1CCCCC1)C1=NOC(C2CC2)=C1 MBAOJYAWKIVVQE-SHVUVFPCSA-N 0.000 description 1
- NPXAEVHVSPFLCI-SAZUREKKSA-N CC(=O)NC1=CC=C(S(=O)(=O)C[C@H]2C[C@H](NC(=O)C3=NOC(C4CC4)=C3)C2)C=C1 Chemical compound CC(=O)NC1=CC=C(S(=O)(=O)C[C@H]2C[C@H](NC(=O)C3=NOC(C4CC4)=C3)C2)C=C1 NPXAEVHVSPFLCI-SAZUREKKSA-N 0.000 description 1
- WJRHQPYEXSZCCF-UHFFFAOYSA-N CC(=O)NC1=CC=C(S(=O)(=O)N2CCC(CC(=O)C3=NOC(C4CCC4)=C3)CC2)C=C1 Chemical compound CC(=O)NC1=CC=C(S(=O)(=O)N2CCC(CC(=O)C3=NOC(C4CCC4)=C3)CC2)C=C1 WJRHQPYEXSZCCF-UHFFFAOYSA-N 0.000 description 1
- RJBAUIWRXFBPRX-HQVZTVAUSA-N CC(C(CC1)CCN1C([C@H](CO)N)=O)NC(c1n[o]c(C2CC2)c1)=O Chemical compound CC(C(CC1)CCN1C([C@H](CO)N)=O)NC(c1n[o]c(C2CC2)c1)=O RJBAUIWRXFBPRX-HQVZTVAUSA-N 0.000 description 1
- JAIVQFIYBPKLRA-MBABXSBOSA-N CC(C(CC1)CCN1C([C@H](Cc1c[nH]c2ccccc12)N)=O)NC(c1n[o]c(C2CC2)c1)=O Chemical compound CC(C(CC1)CCN1C([C@H](Cc1c[nH]c2ccccc12)N)=O)NC(c1n[o]c(C2CC2)c1)=O JAIVQFIYBPKLRA-MBABXSBOSA-N 0.000 description 1
- SMMPHNBOMMYVDB-UHFFFAOYSA-N CC(C(CCC1)CN1C1CCC1)NC(c1n[o]c(C2CC2)c1)=O Chemical compound CC(C(CCC1)CN1C1CCC1)NC(c1n[o]c(C2CC2)c1)=O SMMPHNBOMMYVDB-UHFFFAOYSA-N 0.000 description 1
- HZFACLIGPVZAFS-UHFFFAOYSA-N CC(C)(C(CC1)CCC1(C)NC(c1n[o]c(C2CC2)c1)=O)N Chemical compound CC(C)(C(CC1)CCC1(C)NC(c1n[o]c(C2CC2)c1)=O)N HZFACLIGPVZAFS-UHFFFAOYSA-N 0.000 description 1
- LVGJUNJZLYABDC-UHFFFAOYSA-N CC(C)(C)C(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound CC(C)(C)C(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 LVGJUNJZLYABDC-UHFFFAOYSA-N 0.000 description 1
- LQTJEVDOPDKSHB-CMLXJYPYSA-N CC(C)(C)C(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)O)CC1.CCC(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.C[C@@H](N)CC(=O)NCC(C)(C)CNC(=O)C1=NOC(C2CC2)=C1.N[C@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound CC(C)(C)C(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)O)CC1.CCC(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.C[C@@H](N)CC(=O)NCC(C)(C)CNC(=O)C1=NOC(C2CC2)=C1.N[C@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 LQTJEVDOPDKSHB-CMLXJYPYSA-N 0.000 description 1
- JEMVNPONSCAJBY-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(Cl)C=C1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(Cl)C=C1 JEMVNPONSCAJBY-UHFFFAOYSA-N 0.000 description 1
- SQQGDEYAUILTOR-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(Cl)C=C1.CC1=CC(CN)=CC=C1CC(=O)C1=NOC(C2CC2)=C1.CCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)C(C)C)CC1.NC1=CC=NC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)=C1.NCC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C(Cl)=C1.O=C(NC(C(=O)CC1=CC=CC=N1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(Cl)C=C1.CC1=CC(CN)=CC=C1CC(=O)C1=NOC(C2CC2)=C1.CCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)C(C)C)CC1.NC1=CC=NC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)=C1.NCC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C(Cl)=C1.O=C(NC(C(=O)CC1=CC=CC=N1)C1CCCCC1)C1=NOC(C2CC2)=C1 SQQGDEYAUILTOR-UHFFFAOYSA-N 0.000 description 1
- YCHINFGRQBGMTC-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(N)C=C1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(N)C=C1 YCHINFGRQBGMTC-UHFFFAOYSA-N 0.000 description 1
- QDIMYISBIGCFQX-NUKSXHNWSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(N)C=C1.CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC=N1.CC(C)[C@@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1.CC(C)[C@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1.CC1=CC=C(C(C)NC(=O)C2=NOC(C3CC3)=C2)C=C1.N[C@H](CO)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(N)C=C1.CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC=N1.CC(C)[C@@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1.CC(C)[C@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1.CC1=CC=C(C(C)NC(=O)C2=NOC(C3CC3)=C2)C=C1.N[C@H](CO)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 QDIMYISBIGCFQX-NUKSXHNWSA-N 0.000 description 1
- GEWJKFDCRCNCIZ-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC(Cl)=C1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC(Cl)=C1 GEWJKFDCRCNCIZ-UHFFFAOYSA-N 0.000 description 1
- BNAMMUCYIBEDKF-NBASBPDNSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC(Cl)=C1.CC1(C)CCC(C(C)(C)NC(=O)C2=NOC(C3CC3)=C2)CC1.CCC1=CC(C(=O)NC(C2=CC=CC(C)=C2)C(C)(C)C)=NO1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CC2=CC=CN=C2)CC1.O=C(CC1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1)C1=CC=CC=C1.O=C(NC[C@H]1CCNC1)C1=NOC(C2CC2)=C1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC(Cl)=C1.CC1(C)CCC(C(C)(C)NC(=O)C2=NOC(C3CC3)=C2)CC1.CCC1=CC(C(=O)NC(C2=CC=CC(C)=C2)C(C)(C)C)=NO1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CC2=CC=CN=C2)CC1.O=C(CC1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1)C1=CC=CC=C1.O=C(NC[C@H]1CCNC1)C1=NOC(C2CC2)=C1 BNAMMUCYIBEDKF-NBASBPDNSA-N 0.000 description 1
- UENPUAZWOJHRLQ-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC(F)=C1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC(F)=C1 UENPUAZWOJHRLQ-UHFFFAOYSA-N 0.000 description 1
- MRJCOMGTJZRKNS-JSEXXIDJSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC(F)=C1.CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CN=C1.CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)C[C@@H](C)N)CC1.CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)C[C@H](C)N)CC1.C[C@H](N)C(=O)CCCCCNC(=O)C1=NOC(C2CC2)=C1.O=C(NC(C1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC(F)=C1.CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CN=C1.CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)C[C@@H](C)N)CC1.CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)C[C@H](C)N)CC1.C[C@H](N)C(=O)CCCCCNC(=O)C1=NOC(C2CC2)=C1.O=C(NC(C1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 MRJCOMGTJZRKNS-JSEXXIDJSA-N 0.000 description 1
- HZPNJZRCGGFQQB-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC2=C1C=CN2.CC(C)N1CCC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)CC1.CC1=CC=CC(CNC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)=C1.NCCC(=O)NC1CCC2CC1CCC2CC(=O)C1=NOC(C2CC2)=C1.O=C(NC(C1=CC=CC2=C1CCN(C1=CC=CC=C1)C2=O)C1CCNCC1)C1=NOC(C2CC2)=C1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC2=C1C=CN2.CC(C)N1CCC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)CC1.CC1=CC=CC(CNC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)=C1.NCCC(=O)NC1CCC2CC1CCC2CC(=O)C1=NOC(C2CC2)=C1.O=C(NC(C1=CC=CC2=C1CCN(C1=CC=CC=C1)C2=O)C1CCNCC1)C1=NOC(C2CC2)=C1 HZPNJZRCGGFQQB-UHFFFAOYSA-N 0.000 description 1
- OZKSBFWHKJVRAA-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC2=C1C=NN2 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC2=C1C=NN2 OZKSBFWHKJVRAA-UHFFFAOYSA-N 0.000 description 1
- UZBCBRZSJGEMIO-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC=C1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC=C1 UZBCBRZSJGEMIO-UHFFFAOYSA-N 0.000 description 1
- APVCTEJYJGRUCH-ZBTSLMGRSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC=C1.CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)OC(C)(C)C)CC1.CC1=CC=C(C[C@H](N)C(=O)N2CCC(C(C)CC(=O)C3=NOC(C4CC4)=C3)CC2)C=C1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CC[C@H](N)C(=O)N1CCC(C(C)CC(=O)C2=NOC(C3CC3)=C2)CC1.C[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2C(N)=O)CC1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CC=C1.CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)OC(C)(C)C)CC1.CC1=CC=C(C[C@H](N)C(=O)N2CCC(C(C)CC(=O)C3=NOC(C4CC4)=C3)CC2)C=C1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CC[C@H](N)C(=O)N1CCC(C(C)CC(=O)C2=NOC(C3CC3)=C2)CC1.C[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2C(N)=O)CC1 APVCTEJYJGRUCH-ZBTSLMGRSA-N 0.000 description 1
- BIFOUXOYLAVVSP-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CN=C1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=CN=C1 BIFOUXOYLAVVSP-UHFFFAOYSA-N 0.000 description 1
- YQZUPSFXYIXDGW-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=NC=C1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=NC=C1 YQZUPSFXYIXDGW-UHFFFAOYSA-N 0.000 description 1
- IHWSURWRTJOCKQ-RTWCUOFMSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=NC=C1.CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCC1.CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCC1.C[C@@H](N)C(=O)CCCCCNC(=O)C1=NOC(C2CC2)=C1.C[C@@H](N)C(=O)N1CC[C@@H](CNC(=O)C2=NOC(C3CC3)=C2)C1.C[C@H](N)C(=O)N1CC[C@@H](CNC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=NC=C1.CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCC1.CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCC1.C[C@@H](N)C(=O)CCCCCNC(=O)C1=NOC(C2CC2)=C1.C[C@@H](N)C(=O)N1CC[C@@H](CNC(=O)C2=NOC(C3CC3)=C2)C1.C[C@H](N)C(=O)N1CC[C@@H](CNC(=O)C2=NOC(C3CC3)=C2)C1 IHWSURWRTJOCKQ-RTWCUOFMSA-N 0.000 description 1
- STIPOUOPOHSIQH-OQTCZFQDSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CSC=N1.CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.CC1(CC(=O)C2=NOC(C3CC3)=C2)CCC(C(C)(C)N)CC1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CC2=CC=CC=N2)CC1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CC2=CN=CC=C2)CC1.C[C@H](N)C(=O)N1CC[C@H](CNC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CSC=N1.CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.CC1(CC(=O)C2=NOC(C3CC3)=C2)CCC(C(C)(C)N)CC1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CC2=CC=CC=N2)CC1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CC2=CN=CC=C2)CC1.C[C@H](N)C(=O)N1CC[C@H](CNC(=O)C2=NOC(C3CC3)=C2)C1 STIPOUOPOHSIQH-OQTCZFQDSA-N 0.000 description 1
- UQJIZWDJEMIHNC-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCC1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCC1 UQJIZWDJEMIHNC-UHFFFAOYSA-N 0.000 description 1
- UQMCJCTYEJOHOJ-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCC1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCC1 UQMCJCTYEJOHOJ-UHFFFAOYSA-N 0.000 description 1
- WIYXPBGYVLZBDS-CDVIARAJSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Cl.CCCCCNC(=O)C1=NOC(C2CC2)=C1.C[C@@H](N)C(=O)N1CC[C@H](CNC(=O)C2=NOC(C3CC3)=C2)C1.O=C(NC(C1=CC=CC=C1)C1CCC1)C1=NOC(C2CC2)=C1.O=C(NC[C@@H]1CCNC1)C1=NOC(C2CC2)=C1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Cl.CCCCCNC(=O)C1=NOC(C2CC2)=C1.C[C@@H](N)C(=O)N1CC[C@H](CNC(=O)C2=NOC(C3CC3)=C2)C1.O=C(NC(C1=CC=CC=C1)C1CCC1)C1=NOC(C2CC2)=C1.O=C(NC[C@@H]1CCNC1)C1=NOC(C2CC2)=C1 WIYXPBGYVLZBDS-CDVIARAJSA-N 0.000 description 1
- VBWCAPDGFXOUEF-UHFFFAOYSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCNC1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCNC1 VBWCAPDGFXOUEF-UHFFFAOYSA-N 0.000 description 1
- ONRYEOASHUIFMO-CSNYGWFFSA-N CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCNC1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1C.CCOC(=O)C1(CNC(=O)C2=NOC(C3CC3)=C2)CCN(C(=O)[C@H](C)N)CC1.C[C@H](N)C(=O)N1CCC(C)(CCC(=O)C2=NOC(C3CC3)=C2)CC1.C[C@H](N)C(=O)N1CCC(O)(CCC(=O)C2=NOC(C3CC3)=C2)CC1.O=C(NC(C1=CC=CC=C1)C1CCCNC1)C1=NOC(C2CC2)=C1 Chemical compound CC(C)(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCNC1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1C.CCOC(=O)C1(CNC(=O)C2=NOC(C3CC3)=C2)CCN(C(=O)[C@H](C)N)CC1.C[C@H](N)C(=O)N1CCC(C)(CCC(=O)C2=NOC(C3CC3)=C2)CC1.C[C@H](N)C(=O)N1CCC(O)(CCC(=O)C2=NOC(C3CC3)=C2)CC1.O=C(NC(C1=CC=CC=C1)C1CCCNC1)C1=NOC(C2CC2)=C1 ONRYEOASHUIFMO-CSNYGWFFSA-N 0.000 description 1
- XEZBXDCXSGIEOO-UHFFFAOYSA-N CC(C)(C)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CC1=CC(C(=O)NCC2CCCCC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=N1.CC1CCCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)C1.CN1CCC(CC(=O)C(N)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1.NC1CC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)C1.O=C(NC1CCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound CC(C)(C)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CC1=CC(C(=O)NCC2CCCCC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=N1.CC1CCCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)C1.CN1CCC(CC(=O)C(N)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1.NC1CC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)C1.O=C(NC1CCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 XEZBXDCXSGIEOO-UHFFFAOYSA-N 0.000 description 1
- ZYBUJOSROFBYBZ-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CC(C)(C)OC(=O)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 ZYBUJOSROFBYBZ-UHFFFAOYSA-N 0.000 description 1
- ITLCXSHKUNNAHG-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCC(C(=O)C2=CC=CC=C2)CC1 Chemical compound CC(C)(C)OC(=O)N1CCC(C(=O)C2=CC=CC=C2)CC1 ITLCXSHKUNNAHG-UHFFFAOYSA-N 0.000 description 1
- WTARUKRBKMNNAD-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCC(C(N)C2=CC=CC=C2)CC1 Chemical compound CC(C)(C)OC(=O)N1CCC(C(N)C2=CC=CC=C2)CC1 WTARUKRBKMNNAD-UHFFFAOYSA-N 0.000 description 1
- FQFQDORFMYCUTA-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC(C(=O)NC3=CC=CN=C3)=C2)CC1 Chemical compound CC(C)(C)OC(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC(C(=O)NC3=CC=CN=C3)=C2)CC1 FQFQDORFMYCUTA-UHFFFAOYSA-N 0.000 description 1
- POOJWYQUZLELNX-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound CC(C)(C)OC(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 POOJWYQUZLELNX-UHFFFAOYSA-N 0.000 description 1
- KYBZOQRYEKUDBY-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCC(CNC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound CC(C)(C)OC(=O)N1CCC(CNC(=O)C2=NOC(C3CC3)=C2)CC1 KYBZOQRYEKUDBY-UHFFFAOYSA-N 0.000 description 1
- HRTMGHFAFBNPJL-NRFANRHFSA-N CC(C)(C)OC(=O)N1CCC([C@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC(C(=O)O)=C2)CC1 Chemical compound CC(C)(C)OC(=O)N1CCC([C@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC(C(=O)O)=C2)CC1 HRTMGHFAFBNPJL-NRFANRHFSA-N 0.000 description 1
- VXWAFKKVTFBTIW-UHFFFAOYSA-N CC(C)(C)OC(=O)NC1CCC2CC1CCC2NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC(C)(C)OC(=O)NC1CCC2CC1CCC2NC(=O)C1=NOC(C2CC2)=C1 VXWAFKKVTFBTIW-UHFFFAOYSA-N 0.000 description 1
- YSEYOQWNKGURRY-UHFFFAOYSA-N CC(C)(C)OC(=O)NCCC(=O)NC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound CC(C)(C)OC(=O)NCCC(=O)NC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 YSEYOQWNKGURRY-UHFFFAOYSA-N 0.000 description 1
- PEEKEKNZQTYRMG-HAQNSBGRSA-N CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2C(=O)OC2=C(F)C(F)=C(F)C(F)=C2F)CC1 Chemical compound CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2C(=O)OC2=C(F)C(F)=C(F)C(F)=C2F)CC1 PEEKEKNZQTYRMG-HAQNSBGRSA-N 0.000 description 1
- KWIYRINOONPAEE-HAQNSBGRSA-N CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2C(N)=O)CC1 Chemical compound CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2C(N)=O)CC1 KWIYRINOONPAEE-HAQNSBGRSA-N 0.000 description 1
- UKOUVNIKHFFRAW-HAQNSBGRSA-N CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2I)CC1 Chemical compound CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2I)CC1 UKOUVNIKHFFRAW-HAQNSBGRSA-N 0.000 description 1
- OFDNHOWXRHLKPE-JOCQHMNTSA-N CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2OC=O)CC1 Chemical compound CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2OC=O)CC1 OFDNHOWXRHLKPE-JOCQHMNTSA-N 0.000 description 1
- HHVWDKWFWRMKPL-HAQNSBGRSA-N CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)C2=NOC(CCO)=C2)CC1 Chemical compound CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)C2=NOC(CCO)=C2)CC1 HHVWDKWFWRMKPL-HAQNSBGRSA-N 0.000 description 1
- CYHKFPJAUMOHDP-UHFFFAOYSA-N CC(C)(C1)CC(C)(CN)CC1NC(c1n[o]c(C2CC2)c1)=O Chemical compound CC(C)(C1)CC(C)(CN)CC1NC(c1n[o]c(C2CC2)c1)=O CYHKFPJAUMOHDP-UHFFFAOYSA-N 0.000 description 1
- NYBRNJXAGGCHCC-UHFFFAOYSA-N CC(C)(CCNC(=O)CCN)NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC(C)(CCNC(=O)CCN)NC(=O)C1=NOC(C2CC2)=C1 NYBRNJXAGGCHCC-UHFFFAOYSA-N 0.000 description 1
- CDZXXOTXXXHRDC-YHIWFBNFSA-N CC(C)(CNC(=O)C1=NOC(C2CC2)=C1)CNS(=O)(=O)C1CCCCC1.CC(C)N1CC(CNC(=O)C2=NOC(C3CC3)=C2)C1.CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CC(C)C1.CC1=CC=C([C@@H](O)C[C@H](C)NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCOC(=O)C1CC(NC(=O)C2=NOC(C3CC3)=C2)CN(C(=O)[C@@H](N)CC2=CC=C(O)C=C2)C1.O=C(CC1=CC=NC=C1)C1=NOC(C2CC2)=C1.O=C(CC1=CN=CC=C1)C1=NOC(C2CC2)=C1 Chemical compound CC(C)(CNC(=O)C1=NOC(C2CC2)=C1)CNS(=O)(=O)C1CCCCC1.CC(C)N1CC(CNC(=O)C2=NOC(C3CC3)=C2)C1.CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CC(C)C1.CC1=CC=C([C@@H](O)C[C@H](C)NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCOC(=O)C1CC(NC(=O)C2=NOC(C3CC3)=C2)CN(C(=O)[C@@H](N)CC2=CC=C(O)C=C2)C1.O=C(CC1=CC=NC=C1)C1=NOC(C2CC2)=C1.O=C(CC1=CN=CC=C1)C1=NOC(C2CC2)=C1 CDZXXOTXXXHRDC-YHIWFBNFSA-N 0.000 description 1
- VVBHGAZPSBVIHX-UHFFFAOYSA-N CC(C)(CNC(=O)C1=NOC(C2CC2)=C1)CNS(=O)(=O)CCCN Chemical compound CC(C)(CNC(=O)C1=NOC(C2CC2)=C1)CNS(=O)(=O)CCCN VVBHGAZPSBVIHX-UHFFFAOYSA-N 0.000 description 1
- LCMPIZXICSRJJM-UHFFFAOYSA-N CC(C)(CNC(=O)CCN)CNC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC(C)(CNC(=O)CCN)CNC(=O)C1=NOC(C2CC2)=C1 LCMPIZXICSRJJM-UHFFFAOYSA-N 0.000 description 1
- IHIZPCHNVVHJBJ-RRIRSNMHSA-N CC(C)(CNC(=O)CCN)CNC(=O)C1=NOC(C2CC2)=C1.CCC1=CC(C(=O)NC(C2=CC=CC(OC)=C2)C(C)(C)C)=NO1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)N=C1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CCC2=CC=CC=C2)CC1.C[C@H](N)CC(=O)NCC(C)(C)CNC(=O)C1=NOC(C2CC2)=C1.NCC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C(I)=C1 Chemical compound CC(C)(CNC(=O)CCN)CNC(=O)C1=NOC(C2CC2)=C1.CCC1=CC(C(=O)NC(C2=CC=CC(OC)=C2)C(C)(C)C)=NO1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)N=C1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CCC2=CC=CC=C2)CC1.C[C@H](N)CC(=O)NCC(C)(C)CNC(=O)C1=NOC(C2CC2)=C1.NCC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C(I)=C1 IHIZPCHNVVHJBJ-RRIRSNMHSA-N 0.000 description 1
- MOCBJXZMSLGZFU-GFCCVEGCSA-N CC(C)(CNC(=O)C[C@H](N)O)CNC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC(C)(CNC(=O)C[C@H](N)O)CNC(=O)C1=NOC(C2CC2)=C1 MOCBJXZMSLGZFU-GFCCVEGCSA-N 0.000 description 1
- KHAMMUHMCFZYKF-UHFFFAOYSA-N CC(C)(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound CC(C)(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 KHAMMUHMCFZYKF-UHFFFAOYSA-N 0.000 description 1
- UNUOBAPABBWPJZ-ZPUJASNBSA-N CC(C)C(=O)N1CCC(C(CO)NC(=O)C2=NOC(C3CC3)=C2)CC1.CCC1=CC(C(=O)NC(C2=CC=CC(C)=C2)C2CCCCC2)=NO1.CCC1=CC(C(=O)NC(C2=CC=CC=C2)C2CCN(C)CC2)=NO1.C[C@H](N)C(=O)N1CCC(F)(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound CC(C)C(=O)N1CCC(C(CO)NC(=O)C2=NOC(C3CC3)=C2)CC1.CCC1=CC(C(=O)NC(C2=CC=CC(C)=C2)C2CCCCC2)=NO1.CCC1=CC(C(=O)NC(C2=CC=CC=C2)C2CCN(C)CC2)=NO1.C[C@H](N)C(=O)N1CCC(F)(CCC(=O)C2=NOC(C3CC3)=C2)CC1 UNUOBAPABBWPJZ-ZPUJASNBSA-N 0.000 description 1
- UPLAMWNCOXJHIX-ABHZCREHSA-N CC(C)C(C)(C)C1CCC(C)(N)CC1.CC(C)CC1(CC(C)C)CC1.CC(C)CC1(CC(C)C)CCC1.CC(C)CC1(CN)CCCCC1.CC(C)CC1CCC(C)CC1.CC(C)CC1CCCC(N)C1.CC(C)C[C@@H]1CCC[C@@H](C)C1.CC(C)C[C@@H]1CCC[C@H](C)C1.CC(C)C[C@H]1CCC[C@@H](C)C1.CC(C)C[C@H]1CCC[C@H](C)C1.CC(C)C[C@H]1CC[C@@H](C)CC1.CC(C)C[C@H]1CC[C@H](C)CC1 Chemical compound CC(C)C(C)(C)C1CCC(C)(N)CC1.CC(C)CC1(CC(C)C)CC1.CC(C)CC1(CC(C)C)CCC1.CC(C)CC1(CN)CCCCC1.CC(C)CC1CCC(C)CC1.CC(C)CC1CCCC(N)C1.CC(C)C[C@@H]1CCC[C@@H](C)C1.CC(C)C[C@@H]1CCC[C@H](C)C1.CC(C)C[C@H]1CCC[C@@H](C)C1.CC(C)C[C@H]1CCC[C@H](C)C1.CC(C)C[C@H]1CC[C@@H](C)CC1.CC(C)C[C@H]1CC[C@H](C)CC1 UPLAMWNCOXJHIX-ABHZCREHSA-N 0.000 description 1
- KLPVBHXUSKKKBP-UHFFFAOYSA-N CC(C)C(C)(C)C1CCCCC1.CC(C)CC1CCN(C)CC1.CC(C)CC1CCNCC1.CC(C)CCN1CCCC1.CC(C)CCN1CCCCC1.CC(C)CCN1CCN(C)CC1.CC(C)CCN1CCNCC1.CC(C)CCN1CCOCC1 Chemical compound CC(C)C(C)(C)C1CCCCC1.CC(C)CC1CCN(C)CC1.CC(C)CC1CCNCC1.CC(C)CCN1CCCC1.CC(C)CCN1CCCCC1.CC(C)CCN1CCN(C)CC1.CC(C)CCN1CCNCC1.CC(C)CCN1CCOCC1 KLPVBHXUSKKKBP-UHFFFAOYSA-N 0.000 description 1
- LJEFNDGLYFDOLB-UHFFFAOYSA-N CC(C)C(C)(C1)CN1C(C)C Chemical compound CC(C)C(C)(C1)CN1C(C)C LJEFNDGLYFDOLB-UHFFFAOYSA-N 0.000 description 1
- YBDXCUPKMWCTEE-IAUQVTHZSA-N CC(C)C(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)N=C1C.CCOC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.COC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)=C1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CCC2=CC=CC=C2)CC1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CCC2=CC=CC=C2O)CC1 Chemical compound CC(C)C(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)N=C1C.CCOC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.COC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)=C1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CCC2=CC=CC=C2)CC1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CCC2=CC=CC=C2O)CC1 YBDXCUPKMWCTEE-IAUQVTHZSA-N 0.000 description 1
- KSNAXTKCYKUXAM-WBCRJOMXSA-N CC(C)C(N)CCC1=CC=CC=N1.CC(C)C(N)CCC1=CC=CN=C1.CC(C)C(N)CCC1=CC=NC=C1.CC(C)CC(N)CC1=CC=CN=C1.CC(C)C[C@@H](N)CC1=CC=CN=C1.CC(C)C[C@H](CN)C1=CC=CC=N1.CC(C)C[C@H](N)CC1=CC=CN=C1.CCC(CC(C)C)C1=CC=CC=N1.CC[C@H](CC(C)C)C1=CC=CC=N1 Chemical compound CC(C)C(N)CCC1=CC=CC=N1.CC(C)C(N)CCC1=CC=CN=C1.CC(C)C(N)CCC1=CC=NC=C1.CC(C)CC(N)CC1=CC=CN=C1.CC(C)C[C@@H](N)CC1=CC=CN=C1.CC(C)C[C@H](CN)C1=CC=CC=N1.CC(C)C[C@H](N)CC1=CC=CN=C1.CCC(CC(C)C)C1=CC=CC=N1.CC[C@H](CC(C)C)C1=CC=CC=N1 KSNAXTKCYKUXAM-WBCRJOMXSA-N 0.000 description 1
- FHVPNKVFRBYJJG-UHFFFAOYSA-N CC(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(F)C=C1 Chemical compound CC(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(F)C=C1 FHVPNKVFRBYJJG-UHFFFAOYSA-N 0.000 description 1
- UFXAKFBARUHHII-GWTZDRIUSA-N CC(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(F)C=C1.CCC(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(F)C=C1.C[C@H](N)C(=O)N1CCC([C@@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.O=C(NC(C(=O)CC1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound CC(C)C(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(F)C=C1.CCC(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(F)C=C1.C[C@H](N)C(=O)N1CCC([C@@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.O=C(NC(C(=O)CC1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 UFXAKFBARUHHII-GWTZDRIUSA-N 0.000 description 1
- RDBSYQUPONWIEX-KLRMOFGRSA-N CC(C)C1(C)CC(N)CC(C)(C)C1.CC(C)C1(C)CCC(C(C)(C)N)CC1.CC(C)C1CCC[C@@H](C2=NC=CN2C)C1.CC(C)[C@@H]1CCC[C@H](C2=NC=CN2C)C1.CC(C)[C@@H]1CCC[C@H](C2CC2)C1.CC(C)[C@H]1CCC[C@@H](C2CC2)C1.CCC1(C)CC(C(C)C)CC(C)(C)C1.CCOC1CC(C(C)C)C12CCCCC2 Chemical compound CC(C)C1(C)CC(N)CC(C)(C)C1.CC(C)C1(C)CCC(C(C)(C)N)CC1.CC(C)C1CCC[C@@H](C2=NC=CN2C)C1.CC(C)[C@@H]1CCC[C@H](C2=NC=CN2C)C1.CC(C)[C@@H]1CCC[C@H](C2CC2)C1.CC(C)[C@H]1CCC[C@@H](C2CC2)C1.CCC1(C)CC(C(C)C)CC(C)(C)C1.CCOC1CC(C(C)C)C12CCCCC2 RDBSYQUPONWIEX-KLRMOFGRSA-N 0.000 description 1
- UIIAHOHLBQXEIF-RZFOTVLRSA-N CC(C)C1(C)CCCCC1.CC(C)C1(CC2=CC=CC=C2)CCCCC1.CC(C)C1(F)CCCCC1.CC(C)C1(O)CCCCC1.CC(C)C1CCC(N)CO1.CC(C)C1CCC2(CCOCC2)CC1.CC(C)C1CCCN(CC2=CC=CC=C2)C1.CC(C)C1CCCNC1C.CC(C)C1CCOC(C2=CC=C(F)C=C2)C1.CC(C)C1CCOC2(CCCC2)C1.CC(C)CC1CC(C(C)C)CCO1.CC(C)N1CCC(N)CC1.CC(C)N1CCN(C)CC1.CC(C)N1CCN(CC2=CC=CC=C2)CC1.CC(C)[C@@H]1CC[C@@H](C)CO1.CC(C)[C@@H]1CC[C@H](C)CO1.CC(C)[C@@H]1CNC[C@@H](C)C1.CC(C)[C@@H]1CNC[C@H](C)C1.CC(C)[C@H]1CC[C@@H](C)CO1.CC(C)[C@H]1CC[C@H](C)CO1.CC(C)[C@H]1CNC[C@@H](C)C1.CC(C)[C@H]1CNC[C@H](C)C1.CC1CNCC(C(C)C)C1.CCC1(C(C)C)CCCCC1.CCOC(=O)C1(C(C)C)CCNCC1 Chemical compound CC(C)C1(C)CCCCC1.CC(C)C1(CC2=CC=CC=C2)CCCCC1.CC(C)C1(F)CCCCC1.CC(C)C1(O)CCCCC1.CC(C)C1CCC(N)CO1.CC(C)C1CCC2(CCOCC2)CC1.CC(C)C1CCCN(CC2=CC=CC=C2)C1.CC(C)C1CCCNC1C.CC(C)C1CCOC(C2=CC=C(F)C=C2)C1.CC(C)C1CCOC2(CCCC2)C1.CC(C)CC1CC(C(C)C)CCO1.CC(C)N1CCC(N)CC1.CC(C)N1CCN(C)CC1.CC(C)N1CCN(CC2=CC=CC=C2)CC1.CC(C)[C@@H]1CC[C@@H](C)CO1.CC(C)[C@@H]1CC[C@H](C)CO1.CC(C)[C@@H]1CNC[C@@H](C)C1.CC(C)[C@@H]1CNC[C@H](C)C1.CC(C)[C@H]1CC[C@@H](C)CO1.CC(C)[C@H]1CC[C@H](C)CO1.CC(C)[C@H]1CNC[C@@H](C)C1.CC(C)[C@H]1CNC[C@H](C)C1.CC1CNCC(C(C)C)C1.CCC1(C(C)C)CCCCC1.CCOC(=O)C1(C(C)C)CCNCC1 UIIAHOHLBQXEIF-RZFOTVLRSA-N 0.000 description 1
- XQPMJEYZSRBMQQ-XDBWCYGNSA-N CC(C)C1(N)CCC1.CC(C)[C@@H]1CC[C@@H](C)C1.CC(C)[C@@H]1CC[C@H](C)C1.CC(C)[C@H]1CC[C@@H](C)C1.CC(C)[C@H]1CC[C@H](C)C1.CC1CC(C(C)C)C1.CC1CC(C(C)C)C1.CC1CC(C(C)C)C1.CC1CC2(C1)CC(C(C)C)C2.CC1CCC(C(C)C)C1.CC1CCC(C(C)C)CC1.CC1CCC(C(C)C)CC1.CC1CCC(C(C)C)CC1.CCC1CCCC(C(C)C)C1.CC[C@@H]1CCC[C@@H](C(C)C)C1.CC[C@@H]1CCC[C@H](C(C)C)C1.CC[C@H]1CCC[C@@H](C(C)C)C1.CC[C@H]1CCC[C@H](C(C)C)C1.CNC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1 Chemical compound CC(C)C1(N)CCC1.CC(C)[C@@H]1CC[C@@H](C)C1.CC(C)[C@@H]1CC[C@H](C)C1.CC(C)[C@H]1CC[C@@H](C)C1.CC(C)[C@H]1CC[C@H](C)C1.CC1CC(C(C)C)C1.CC1CC(C(C)C)C1.CC1CC(C(C)C)C1.CC1CC2(C1)CC(C(C)C)C2.CC1CCC(C(C)C)C1.CC1CCC(C(C)C)CC1.CC1CCC(C(C)C)CC1.CC1CCC(C(C)C)CC1.CCC1CCCC(C(C)C)C1.CC[C@@H]1CCC[C@@H](C(C)C)C1.CC[C@@H]1CCC[C@H](C(C)C)C1.CC[C@H]1CCC[C@@H](C(C)C)C1.CC[C@H]1CCC[C@H](C(C)C)C1.CNC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1 XQPMJEYZSRBMQQ-XDBWCYGNSA-N 0.000 description 1
- LNJNWXAGDQTBQF-XYPYZODXSA-N CC(C)C1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1 Chemical compound CC(C)C1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1 LNJNWXAGDQTBQF-XYPYZODXSA-N 0.000 description 1
- GRWGEKKQDRXRGE-ZDMFRUBBSA-N CC(C)C1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1.CC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)C.CN(C(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1)C1=CC=CN=C1.COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CNC3=C2C=CC=C3)CC1.COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)CC2=CNC3=CC=CC=C23)CC1.O=C(NC(C1=CC=C(F)C=C1)C1CC1)C1=NOC(C2CC2)=C1.O=C(NC1CC(CC2CCC2)C1)C1=NOC(C2CC2)=C1 Chemical compound CC(C)C1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1.CC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)C.CN(C(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1)C1=CC=CN=C1.COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CNC3=C2C=CC=C3)CC1.COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)CC2=CNC3=CC=CC=C23)CC1.O=C(NC(C1=CC=C(F)C=C1)C1CC1)C1=NOC(C2CC2)=C1.O=C(NC1CC(CC2CCC2)C1)C1=NOC(C2CC2)=C1 GRWGEKKQDRXRGE-ZDMFRUBBSA-N 0.000 description 1
- KZHZNLLEAHQFKY-UHFFFAOYSA-N CC(C)C1=CC(CN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC(C)C1=CC(CN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 KZHZNLLEAHQFKY-UHFFFAOYSA-N 0.000 description 1
- NBOCOMVQCRYVJM-UHFFFAOYSA-N CC(C)C1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1CN Chemical compound CC(C)C1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1CN NBOCOMVQCRYVJM-UHFFFAOYSA-N 0.000 description 1
- NYYCAERAPLKKSK-UHFFFAOYSA-N CC(C)C1=CC=C(C(C)C)C=C1.CC(C)C1=CC=CC(C(C)C)=C1 Chemical compound CC(C)C1=CC=C(C(C)C)C=C1.CC(C)C1=CC=CC(C(C)C)=C1 NYYCAERAPLKKSK-UHFFFAOYSA-N 0.000 description 1
- NIRLRWUUXYSLFQ-UHFFFAOYSA-N CC(C)C1=CN(CC2=CC=C(Cl)C=C2)N=C1.CC(C)C1=CN(CC2=CC=CC=C2)N=C1.CC(C)C1=CN(CC2=COC=N2)N=C1 Chemical compound CC(C)C1=CN(CC2=CC=C(Cl)C=C2)N=C1.CC(C)C1=CN(CC2=CC=CC=C2)N=C1.CC(C)C1=CN(CC2=COC=N2)N=C1 NIRLRWUUXYSLFQ-UHFFFAOYSA-N 0.000 description 1
- IBPFPZXILFYCQW-UHFFFAOYSA-N CC(C)C1=CN=C(C(C)C)C=C1.CC(C)C1=CN=CC(C(C)C)=C1.CC(C)C1=CN=CC(C(C)C)=C1 Chemical compound CC(C)C1=CN=C(C(C)C)C=C1.CC(C)C1=CN=CC(C(C)C)=C1.CC(C)C1=CN=CC(C(C)C)=C1 IBPFPZXILFYCQW-UHFFFAOYSA-N 0.000 description 1
- PLAKTXVNWJHJNZ-UHFFFAOYSA-N CC(C)C1CC(C)N(C(C)C)C1.CC(C)C1CCN(C(C)C)C1.CC(C)C1CCN(C(C)C)C1C1=CC=CC=C1.CC(C)C1CN(C(C)C)CC1C Chemical compound CC(C)C1CC(C)N(C(C)C)C1.CC(C)C1CCN(C(C)C)C1.CC(C)C1CCN(C(C)C)C1C1=CC=CC=C1.CC(C)C1CN(C(C)C)CC1C PLAKTXVNWJHJNZ-UHFFFAOYSA-N 0.000 description 1
- OHFHDVRIXWUVRY-UHFFFAOYSA-N CC(C)C1CCC(C(C)(C)C(C)C)CC1.CC(C)CC1CCC(C(C)C)CC1 Chemical compound CC(C)C1CCC(C(C)(C)C(C)C)CC1.CC(C)CC1CCC(C(C)C)CC1 OHFHDVRIXWUVRY-UHFFFAOYSA-N 0.000 description 1
- HUMTWCPHIKYCBK-WDMQLMRRSA-N CC(C)C1CCC(C(C)C)C(C)C1.CC(C)C1CCC(C(C)C)C(CC2=CC=CC=C2)C1.CC(C)C1CCC(C(C)C)CC1.CC(C)C1CCC(C(C)C)CC1.CC(C)C1CCC(C(C)C)CC1.CC(C)C1CC[C@@H](C(C)C)C[C@@H]1C.CC(C)C1CC[C@@H](C(C)C)C[C@H]1C.CC(C)C1CC[C@@H](C(C)C)[C@@H](CC2=CC=CC=C2)C1.CC(C)C1CC[C@@H](C(C)C)[C@H](CC2=CC=CC=C2)C1 Chemical compound CC(C)C1CCC(C(C)C)C(C)C1.CC(C)C1CCC(C(C)C)C(CC2=CC=CC=C2)C1.CC(C)C1CCC(C(C)C)CC1.CC(C)C1CCC(C(C)C)CC1.CC(C)C1CCC(C(C)C)CC1.CC(C)C1CC[C@@H](C(C)C)C[C@@H]1C.CC(C)C1CC[C@@H](C(C)C)C[C@H]1C.CC(C)C1CC[C@@H](C(C)C)[C@@H](CC2=CC=CC=C2)C1.CC(C)C1CC[C@@H](C(C)C)[C@H](CC2=CC=CC=C2)C1 HUMTWCPHIKYCBK-WDMQLMRRSA-N 0.000 description 1
- XQYQQLDOGXZCTN-UHFFFAOYSA-N CC(C)C1CCC(C(C)C)CC1.CC(C)C1CCCC(C(C)C)C1 Chemical compound CC(C)C1CCC(C(C)C)CC1.CC(C)C1CCCC(C(C)C)C1 XQYQQLDOGXZCTN-UHFFFAOYSA-N 0.000 description 1
- QKBWPHWNCXNMDG-ASOXNDTNSA-N CC(C)C1CCC(C)C(CC2=CC=CC=C2)C1.CC(C)C1CC[C@@H](C)C[C@@H]1C.CC(C)C1CC[C@@H](C)C[C@H]1C.CC(C)C1CC[C@@H](C)[C@H](CC2=CC=CC=C2)C1.CC(C)C1CC[C@@H](N)[C@@H](CC2=CC=CC=C2)C1.CC1CCC(C(C)C)C(C)C1.CC1CCC(C(C)C)CC1.CC1CCC(C(C)C)CC1.CC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1 Chemical compound CC(C)C1CCC(C)C(CC2=CC=CC=C2)C1.CC(C)C1CC[C@@H](C)C[C@@H]1C.CC(C)C1CC[C@@H](C)C[C@H]1C.CC(C)C1CC[C@@H](C)[C@H](CC2=CC=CC=C2)C1.CC(C)C1CC[C@@H](N)[C@@H](CC2=CC=CC=C2)C1.CC1CCC(C(C)C)C(C)C1.CC1CCC(C(C)C)CC1.CC1CCC(C(C)C)CC1.CC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1 QKBWPHWNCXNMDG-ASOXNDTNSA-N 0.000 description 1
- SFCNVKGFPZKDDE-AASZPRJCSA-N CC(C)C1CCC(N)C1.CC(C)[C@@H]1CC[C@@H](C)C1.CC(C)[C@@H]1CC[C@H](C)C1.CC(C)[C@H]1CC[C@@H](C)C1.CC(C)[C@H]1CC[C@H](C)C1.CC1CC(C(C)C)C1.CC1CC(C(C)C)C1.CC1CC(C(C)C)C1.CC1CC(C2CC(C(C)C)C2)C1.CC1CCC(C(C)C)CC1.CC1CCC(C(C)C)CC1.CC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1 Chemical compound CC(C)C1CCC(N)C1.CC(C)[C@@H]1CC[C@@H](C)C1.CC(C)[C@@H]1CC[C@H](C)C1.CC(C)[C@H]1CC[C@@H](C)C1.CC(C)[C@H]1CC[C@H](C)C1.CC1CC(C(C)C)C1.CC1CC(C(C)C)C1.CC1CC(C(C)C)C1.CC1CC(C2CC(C(C)C)C2)C1.CC1CCC(C(C)C)CC1.CC1CCC(C(C)C)CC1.CC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1.CNC1CCC(C(C)C)CC1 SFCNVKGFPZKDDE-AASZPRJCSA-N 0.000 description 1
- YOGWYMFVAMJBFY-UHFFFAOYSA-N CC(C)C1CCCN(C(C)C)C1.CC(C)C1CCN(C(C)C)C1.CC(C)C1CCN(C(C)C)CC1.CC(C)C1CCN(C(C)C)CC1C.CC(C)C1CN(C(C)C)C1 Chemical compound CC(C)C1CCCN(C(C)C)C1.CC(C)C1CCN(C(C)C)C1.CC(C)C1CCN(C(C)C)CC1.CC(C)C1CCN(C(C)C)CC1C.CC(C)C1CN(C(C)C)C1 YOGWYMFVAMJBFY-UHFFFAOYSA-N 0.000 description 1
- NEPALJNLDZOGSW-AHLIPOOESA-N CC(C)CC(N)CC1=CC=CC=C1.CC(C)C[C@@H](N)CC1=CC=CC=C1.CC(C)C[C@H](CN)C1=CC=CC=C1.CC(C)C[C@H](N)CC1=CC=CC=C1.CCC(CC(C)C)C1=CC=CC=C1.CC[C@H](CC(C)C)C1=CC=CC=C1 Chemical compound CC(C)CC(N)CC1=CC=CC=C1.CC(C)C[C@@H](N)CC1=CC=CC=C1.CC(C)C[C@H](CN)C1=CC=CC=C1.CC(C)C[C@H](N)CC1=CC=CC=C1.CCC(CC(C)C)C1=CC=CC=C1.CC[C@H](CC(C)C)C1=CC=CC=C1 NEPALJNLDZOGSW-AHLIPOOESA-N 0.000 description 1
- RLUGYLSREVTIHJ-UHFFFAOYSA-N CC(C)CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1 Chemical compound CC(C)CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1 RLUGYLSREVTIHJ-UHFFFAOYSA-N 0.000 description 1
- CARHOJRLSLGJRQ-UHFFFAOYSA-N CC(C)CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.CC(CNC(=O)CCN)CNC(=O)C1=NOC(C2CC2)=C1.CC1=CC=CC(COCC2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)=C1.CCC(CCNC(=O)CCN)NC(=O)C1=NOC(C2CC2)=C1.O=C(NC1=CC=CC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NCC1=CC=CC=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound CC(C)CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.CC(CNC(=O)CCN)CNC(=O)C1=NOC(C2CC2)=C1.CC1=CC=CC(COCC2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)=C1.CCC(CCNC(=O)CCN)NC(=O)C1=NOC(C2CC2)=C1.O=C(NC1=CC=CC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NCC1=CC=CC=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 CARHOJRLSLGJRQ-UHFFFAOYSA-N 0.000 description 1
- BDBPNHNQKHNFIU-WETMITLUSA-N CC(C)CC(O)C1=CC=CC=C1.CC(C)CC(O)CC1=CC=CC=C1.CC(C)C[C@@H](O)C1=CC=CC=C1.CC(C)C[C@@H](O)CC1=CC=CC=C1.CC(C)C[C@H](O)C1=CC=CC=C1.CC(C)C[C@H](O)CC1=CC=CC=C1 Chemical compound CC(C)CC(O)C1=CC=CC=C1.CC(C)CC(O)CC1=CC=CC=C1.CC(C)C[C@@H](O)C1=CC=CC=C1.CC(C)C[C@@H](O)CC1=CC=CC=C1.CC(C)C[C@H](O)C1=CC=CC=C1.CC(C)C[C@H](O)CC1=CC=CC=C1 BDBPNHNQKHNFIU-WETMITLUSA-N 0.000 description 1
- MTOYBMBVXKOBCW-VMCYOLEESA-N CC(C)CC(O)CN1CCCC1.CC(C)C[C@@H](O)CN.CC(C)C[C@@H](O)CN1CCCC1.CC(C)C[C@H](O)CCN.CC(C)C[C@H](O)CN1CCCC1.CC(C)[C@H](N)CCCO.CCC(O)CC(C)C.CCCC(O)CC(C)C.CCCCC(N)C(C)C.CCCC[C@H](N)C(C)C.CCC[C@H](O)CC(C)C.CC[C@@H](O)CC(C)C Chemical compound CC(C)CC(O)CN1CCCC1.CC(C)C[C@@H](O)CN.CC(C)C[C@@H](O)CN1CCCC1.CC(C)C[C@H](O)CCN.CC(C)C[C@H](O)CN1CCCC1.CC(C)[C@H](N)CCCO.CCC(O)CC(C)C.CCCC(O)CC(C)C.CCCCC(N)C(C)C.CCCC[C@H](N)C(C)C.CCC[C@H](O)CC(C)C.CC[C@@H](O)CC(C)C MTOYBMBVXKOBCW-VMCYOLEESA-N 0.000 description 1
- HPRGMLYYCZMFPP-HAQNSBGRSA-N CC(C)CC1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1 Chemical compound CC(C)CC1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1 HPRGMLYYCZMFPP-HAQNSBGRSA-N 0.000 description 1
- PQIDTSBJAWFCEO-PJVMWODDSA-N CC(C)CC1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1I.CCCC1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1.CCCCCCNC(=O)C1CCC(NC(=O)C2=NOC(C3CC3)=C2)CC1.C[C@@H](N)CC(=O)NC1CCC2CC1CCC2CC(=O)C1=NOC(C2CC2)=C1.C[C@H](N)CC(=O)NC1CCC2CC1CCC2CC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC(C)CC1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1I.CCCC1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1.CCCCCCNC(=O)C1CCC(NC(=O)C2=NOC(C3CC3)=C2)CC1.C[C@@H](N)CC(=O)NC1CCC2CC1CCC2CC(=O)C1=NOC(C2CC2)=C1.C[C@H](N)CC(=O)NC1CCC2CC1CCC2CC(=O)C1=NOC(C2CC2)=C1 PQIDTSBJAWFCEO-PJVMWODDSA-N 0.000 description 1
- VBDICFADMRRWJT-UHFFFAOYSA-N CC(C)CC1=CC=CC=N1.CC(C)CC1=CC=CN=C1.CC(C)CC1=CC=NC=C1.CC(C)CC1=CN(C)C2=C1C=CC=C2.CC(C)CC1=CN(CC2=CC=C(Cl)C=C2)N=C1.CC(C)CC1=CN(CC2=CC=CC=C2)N=C1.CC(C)CC1=CNC2=C1C=CC=C2 Chemical compound CC(C)CC1=CC=CC=N1.CC(C)CC1=CC=CN=C1.CC(C)CC1=CC=NC=C1.CC(C)CC1=CN(C)C2=C1C=CC=C2.CC(C)CC1=CN(CC2=CC=C(Cl)C=C2)N=C1.CC(C)CC1=CN(CC2=CC=CC=C2)N=C1.CC(C)CC1=CNC2=C1C=CC=C2 VBDICFADMRRWJT-UHFFFAOYSA-N 0.000 description 1
- YRMYOTXCEBHJDW-UHFFFAOYSA-N CC(C)CC1=CN(CC2=CC=C(Cl)C=C2)N=C1.CC(C)CC1=CN(CC2=CC=CC=C2)N=C1 Chemical compound CC(C)CC1=CN(CC2=CC=C(Cl)C=C2)N=C1.CC(C)CC1=CN(CC2=CC=CC=C2)N=C1 YRMYOTXCEBHJDW-UHFFFAOYSA-N 0.000 description 1
- MGNHPXXCIRCBNS-UHFFFAOYSA-N CC(C)CC1=CN(CC2=NC=CO2)N=C1 Chemical compound CC(C)CC1=CN(CC2=NC=CO2)N=C1 MGNHPXXCIRCBNS-UHFFFAOYSA-N 0.000 description 1
- VXBIOXFSNPQTSB-UHFFFAOYSA-N CC(C)CC1CC(CC(=O)C2=NOC(C3CC3)=C2)CCO1 Chemical compound CC(C)CC1CC(CC(=O)C2=NOC(C3CC3)=C2)CCO1 VXBIOXFSNPQTSB-UHFFFAOYSA-N 0.000 description 1
- QGUQZTLBFHMOGM-UHFFFAOYSA-N CC(C)CC1CCCCC1.CC(C)CC1CCNCC1.CC(C)CC1CNC1.CC(C)N(C(C)C)C1CCCCC1 Chemical compound CC(C)CC1CCCCC1.CC(C)CC1CCNCC1.CC(C)CC1CNC1.CC(C)N(C(C)C)C1CCCCC1 QGUQZTLBFHMOGM-UHFFFAOYSA-N 0.000 description 1
- ZDSKGEYTNBLLBH-UHFFFAOYSA-N CC(C)CN1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CC(C)CN1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 ZDSKGEYTNBLLBH-UHFFFAOYSA-N 0.000 description 1
- ZGUCFAWFXXPRLQ-DKEOPUEVSA-N CC(C)CNC(=O)C1=C(C2CC2)ON=C1C(=O)C[C@H]1CC[C@H](C)CC1.CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)C(C)C)CC1.C[C@@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC(C(=O)NC3=CC=CC=C3)=C2)CC1.C[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2I)CC1.C[C@H]1CC[C@H](NC(=O)C2=NOC(CCO)=C2)CC1.N[C@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound CC(C)CNC(=O)C1=C(C2CC2)ON=C1C(=O)C[C@H]1CC[C@H](C)CC1.CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)C(C)C)CC1.C[C@@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC(C(=O)NC3=CC=CC=C3)=C2)CC1.C[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2I)CC1.C[C@H]1CC[C@H](NC(=O)C2=NOC(CCO)=C2)CC1.N[C@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 ZGUCFAWFXXPRLQ-DKEOPUEVSA-N 0.000 description 1
- VONUZCGOBJOAQP-MQMHXKEQSA-N CC(C)CNC(=O)C1=C(C2CC2)ON=C1C(=O)C[C@H]1CC[C@H](N)CC1 Chemical compound CC(C)CNC(=O)C1=C(C2CC2)ON=C1C(=O)C[C@H]1CC[C@H](N)CC1 VONUZCGOBJOAQP-MQMHXKEQSA-N 0.000 description 1
- VQUCUHYVDJWBEM-UHFFFAOYSA-N CC(C)COC1CC(NC(=O)C2=NOC(C3CC3)=C2)C1(C)C Chemical compound CC(C)COC1CC(NC(=O)C2=NOC(C3CC3)=C2)C1(C)C VQUCUHYVDJWBEM-UHFFFAOYSA-N 0.000 description 1
- INIRPDUWUMQXOM-XZWUWLMBSA-N CC(C)COC1CC(NC(=O)C2=NOC(C3CC3)=C2)C1(C)C.CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(CC2=CC=CC=C2)C1.CCCCC(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1.CCCCCS(=O)(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCCOC1CC(NC(=O)C2=NOC(C3CC3)=C2)C1(C)C.CCCNS(=O)(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1.C[C@H]1CC[C@H](NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1.O=C(CC1CCC2=CC(O)=CC=C2C1)C1=NOC(C2CC2)=C1 Chemical compound CC(C)COC1CC(NC(=O)C2=NOC(C3CC3)=C2)C1(C)C.CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(CC2=CC=CC=C2)C1.CCCCC(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1.CCCCCS(=O)(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCCOC1CC(NC(=O)C2=NOC(C3CC3)=C2)C1(C)C.CCCNS(=O)(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1.C[C@H]1CC[C@H](NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1.O=C(CC1CCC2=CC(O)=CC=C2C1)C1=NOC(C2CC2)=C1 INIRPDUWUMQXOM-XZWUWLMBSA-N 0.000 description 1
- JIAQBKMRSULUQL-XYPYZODXSA-N CC(C)Cc1cc(C(N[C@H](CC2)CC[C@@H]2N)=O)n[o]1 Chemical compound CC(C)Cc1cc(C(N[C@H](CC2)CC[C@@H]2N)=O)n[o]1 JIAQBKMRSULUQL-XYPYZODXSA-N 0.000 description 1
- ZFMJCQBOVCJSEU-UHFFFAOYSA-N CC(C)N(CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1)C1CCOCC1 Chemical compound CC(C)N(CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1)C1CCOCC1 ZFMJCQBOVCJSEU-UHFFFAOYSA-N 0.000 description 1
- JEGPYYXYVOGDLO-SWKLJNRMSA-N CC(C)N(CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1)C1CCOCC1.COC(=O)C1=CC(CN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.C[C@H]1CC[C@@H](NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1.NCCC(=O)NCCC(CO)NC(=O)C1=NOC(C2CC2)=C1.O=C(NC1=CC=CC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NC1CCCCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound CC(C)N(CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1)C1CCOCC1.COC(=O)C1=CC(CN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.C[C@H]1CC[C@@H](NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1.NCCC(=O)NCCC(CO)NC(=O)C1=NOC(C2CC2)=C1.O=C(NC1=CC=CC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NC1CCCCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 JEGPYYXYVOGDLO-SWKLJNRMSA-N 0.000 description 1
- ZXSPQLQMTAWNTR-UHFFFAOYSA-N CC(C)N1C=C2CCC(CC(=O)C3=NOC(C4CC4)=C3)CC2=N1 Chemical compound CC(C)N1C=C2CCC(CC(=O)C3=NOC(C4CC4)=C3)CC2=N1 ZXSPQLQMTAWNTR-UHFFFAOYSA-N 0.000 description 1
- GBCRRCZZCLLMAZ-WDIIBULCSA-N CC(C)N1C=C2CCC(CC(=O)C3=NOC(C4CC4)=C3)CC2=N1.C[C@@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)CC2CCCCC2)CC1.C[C@@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H]2CC[C@H](C)CC2)CC1.C[C@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)CC2CCCCC2)CC1.NC(CCC1=CC=CC=N1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.NC(CCC1=CC=CN=C1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(CO)=C1 Chemical compound CC(C)N1C=C2CCC(CC(=O)C3=NOC(C4CC4)=C3)CC2=N1.C[C@@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)CC2CCCCC2)CC1.C[C@@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H]2CC[C@H](C)CC2)CC1.C[C@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)CC2CCCCC2)CC1.NC(CCC1=CC=CC=N1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.NC(CCC1=CC=CN=C1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(CO)=C1 GBCRRCZZCLLMAZ-WDIIBULCSA-N 0.000 description 1
- BRPKXOWMZKENQX-UHFFFAOYSA-N CC(C)N1CC(CNC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CC(C)N1CC(CNC(=O)C2=NOC(C3CC3)=C2)C1 BRPKXOWMZKENQX-UHFFFAOYSA-N 0.000 description 1
- FUTMEZGZMHOCNN-UHFFFAOYSA-N CC(C)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CC(C)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 FUTMEZGZMHOCNN-UHFFFAOYSA-N 0.000 description 1
- XZNVMVDRMKWLCA-UHFFFAOYSA-N CC(C)N1CCC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)CC1 Chemical compound CC(C)N1CCC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)CC1 XZNVMVDRMKWLCA-UHFFFAOYSA-N 0.000 description 1
- GGZXWFQYYIFUSU-GXTWGEPZSA-N CC(C)N1CC[C@H](C)[C@H](NC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound CC(C)N1CC[C@H](C)[C@H](NC(=O)C2=NOC(C3CC3)=C2)CC1 GGZXWFQYYIFUSU-GXTWGEPZSA-N 0.000 description 1
- GQWQXDNSYTZRIT-UHFFFAOYSA-N CC(C)OCC(C1CCNCC1)NC(c1n[o]c(C2CC2)c1)=O Chemical compound CC(C)OCC(C1CCNCC1)NC(c1n[o]c(C2CC2)c1)=O GQWQXDNSYTZRIT-UHFFFAOYSA-N 0.000 description 1
- VGGUTGMDHYRIDW-UHFFFAOYSA-N CC(C)OCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1 Chemical compound CC(C)OCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1 VGGUTGMDHYRIDW-UHFFFAOYSA-N 0.000 description 1
- OPAYYHHAEWCBIH-IDUYVCETSA-N CC(C)OCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1OC.CCCCC[C@H](CC(=O)[C@H](CO)NC(=O)C1=NOC(C2CC2)=C1)C(N)=O.O=C(NC(C1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound CC(C)OCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1OC.CCCCC[C@H](CC(=O)[C@H](CO)NC(=O)C1=NOC(C2CC2)=C1)C(N)=O.O=C(NC(C1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 OPAYYHHAEWCBIH-IDUYVCETSA-N 0.000 description 1
- ALUFTSPZQVKRNH-BBQAJUCSSA-N CC(C)OCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CC=C(O)C=C2)CC1 Chemical compound CC(C)OCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CC=C(O)C=C2)CC1 ALUFTSPZQVKRNH-BBQAJUCSSA-N 0.000 description 1
- TYJGAYCVEMJPDT-CWQZNGJJSA-N CC(C)OCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1 Chemical compound CC(C)OCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1 TYJGAYCVEMJPDT-CWQZNGJJSA-N 0.000 description 1
- KSIQFQSWLFNFOB-FBIRKCLLSA-N CC(C)OCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1.COCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CC=C(C)C=C2)CC1.CS(=O)(=O)CCNC(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.O=C(NCCN1CCCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound CC(C)OCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1.COCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CC=C(C)C=C2)CC1.CS(=O)(=O)CCNC(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.O=C(NCCN1CCCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 KSIQFQSWLFNFOB-FBIRKCLLSA-N 0.000 description 1
- KNMDAUPGDPCUAZ-TYJDENFWSA-N CC(C)[C@@H](C(N(CC1)CCC1C(C)NC(c1n[o]c(C2CC2)c1)=O)=O)N Chemical compound CC(C)[C@@H](C(N(CC1)CCC1C(C)NC(c1n[o]c(C2CC2)c1)=O)=O)N KNMDAUPGDPCUAZ-TYJDENFWSA-N 0.000 description 1
- BTRZIUAFHWSHNC-AZDQUVPQSA-N CC(C)[C@@H](CCCCN)C(N)=O.CC(C)[C@H](CCCCN)C(N)=O.CCCCCC(C(N)=O)C(C)C Chemical compound CC(C)[C@@H](CCCCN)C(N)=O.CC(C)[C@H](CCCCN)C(N)=O.CCCCCC(C(N)=O)C(C)C BTRZIUAFHWSHNC-AZDQUVPQSA-N 0.000 description 1
- GDRGPGIFQKKIDL-GOSISDBHSA-N CC(C)[C@@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound CC(C)[C@@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 GDRGPGIFQKKIDL-GOSISDBHSA-N 0.000 description 1
- KNMDAUPGDPCUAZ-RGUGMKFQSA-N CC(C)[C@H](C(N(CC1)CCC1C(C)NC(c1n[o]c(C2CC2)c1)=O)=O)N Chemical compound CC(C)[C@H](C(N(CC1)CCC1C(C)NC(c1n[o]c(C2CC2)c1)=O)=O)N KNMDAUPGDPCUAZ-RGUGMKFQSA-N 0.000 description 1
- GDRGPGIFQKKIDL-SFHVURJKSA-N CC(C)[C@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound CC(C)[C@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 GDRGPGIFQKKIDL-SFHVURJKSA-N 0.000 description 1
- IIYYNKIATLRREG-IBGZPJMESA-N CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(CNC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(CNC(=O)C2=NOC(C3CC3)=C2)CC1 IIYYNKIATLRREG-IBGZPJMESA-N 0.000 description 1
- ORSGHFYILYOHRQ-UHFFFAOYSA-N CC(C1=CC=CC=C1)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CC(C1=CC=CC=C1)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 ORSGHFYILYOHRQ-UHFFFAOYSA-N 0.000 description 1
- HDRZFFOOHXDVCR-ZGTCLIOFSA-N CC(CC(=O)C1=COC(C2CC2)=C1)C1CCN(C(=O)[C@@H](C)N)CC1 Chemical compound CC(CC(=O)C1=COC(C2CC2)=C1)C1CCN(C(=O)[C@@H](C)N)CC1 HDRZFFOOHXDVCR-ZGTCLIOFSA-N 0.000 description 1
- QNDFAZHFQLFURG-UHFFFAOYSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCCN(C2CCC2)C1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCCN(C2CCC2)C1 QNDFAZHFQLFURG-UHFFFAOYSA-N 0.000 description 1
- XMRUIIHZIUMYCQ-WCRLMQHKSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCCN(C2CCC2)C1.CC1=CN(CCC(=O)NCC2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)N=C1.CCC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@@H](C)N.CCCCC(=O)N1CCC([C@H](C)CC(=O)C2=NOC(C3CC3)=C2)CC1.CCCCS(=O)(=O)N1CCC([C@@H](C)NC(=O)C2=NOC(C3CC3)=C2)CC1.CCCCS(=O)(=O)N1CCC([C@H](C)NC(=O)C2=NOC(C3CC3)=C2)CC1.C[C@H]1CC[C@H](NC(=O)C2=NOC(C(F)F)=C2)CC1.NC(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCCN(C2CCC2)C1.CC1=CN(CCC(=O)NCC2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)N=C1.CCC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@@H](C)N.CCCCC(=O)N1CCC([C@H](C)CC(=O)C2=NOC(C3CC3)=C2)CC1.CCCCS(=O)(=O)N1CCC([C@@H](C)NC(=O)C2=NOC(C3CC3)=C2)CC1.CCCCS(=O)(=O)N1CCC([C@H](C)NC(=O)C2=NOC(C3CC3)=C2)CC1.C[C@H]1CC[C@H](NC(=O)C2=NOC(C(F)F)=C2)CC1.NC(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 XMRUIIHZIUMYCQ-WCRLMQHKSA-N 0.000 description 1
- IABJLVMEYWWNHX-ZGTCLIOFSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)C[C@@H](C)N)CC1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)C[C@@H](C)N)CC1 IABJLVMEYWWNHX-ZGTCLIOFSA-N 0.000 description 1
- IABJLVMEYWWNHX-ABLWVSNPSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)C[C@H](C)N)CC1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)C[C@H](C)N)CC1 IABJLVMEYWWNHX-ABLWVSNPSA-N 0.000 description 1
- QZUYUSHSBWOVTA-UHFFFAOYSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)OC(C)(C)C)CC1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)OC(C)(C)C)CC1 QZUYUSHSBWOVTA-UHFFFAOYSA-N 0.000 description 1
- HBAOQRGXRHLOHI-QYCJHNPUSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](C)N)CC1.CC1=CC(C(=O)NC2CCCC(N)C2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CC1=CN=CC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)=C1.CC1CCC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)C1.NC1CCCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)C1.O=C(NC1=CC=CN=C1O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](C)N)CC1.CC1=CC(C(=O)NC2CCCC(N)C2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CC1=CN=CC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)=C1.CC1CCC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)C1.NC1CCCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)C1.O=C(NC1=CC=CN=C1O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 HBAOQRGXRHLOHI-QYCJHNPUSA-N 0.000 description 1
- GEIVEIHETMXUEH-YFKXAPIDSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)C(C)C)CC1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)C(C)C)CC1 GEIVEIHETMXUEH-YFKXAPIDSA-N 0.000 description 1
- OSJOCSMEJDOWGK-MBABXSBOSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CC=C(O)C=C2)CC1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CC=C(O)C=C2)CC1 OSJOCSMEJDOWGK-MBABXSBOSA-N 0.000 description 1
- ABYFSSCYYMDFBU-VXLWULRPSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CCC3=CC=CC=C32)CC1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CCC3=CC=CC=C32)CC1 ABYFSSCYYMDFBU-VXLWULRPSA-N 0.000 description 1
- SYQUIFNHTUKPAB-PZVJSTJYSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CCC3=CC=CC=C32)CC1.CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)CC2=CCC3=C2C=CC=C3)CC1.CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCCC1.CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NCC1CCCCC1.CC1CCCC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)C1.N[C@@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CCC3=CC=CC=C32)CC1.CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)CC2=CCC3=C2C=CC=C3)CC1.CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCCC1.CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NCC1CCCCC1.CC1CCCC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)C1.N[C@@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 SYQUIFNHTUKPAB-PZVJSTJYSA-N 0.000 description 1
- JTLYOTWJMVDFDC-IAXJKZSUSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CO)CC1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CO)CC1 JTLYOTWJMVDFDC-IAXJKZSUSA-N 0.000 description 1
- GYSVDSNOPONGPF-KIYNQFGBSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1 GYSVDSNOPONGPF-KIYNQFGBSA-N 0.000 description 1
- SAQUVZAXWVRQRB-LVDZFKTESA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1.CC1=CC(C(=O)NC2CCC(N)CC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)CC1.CCC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@H](C)N.CCC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=N1.COC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=N1.C[C@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1.CC1=CC(C(=O)NC2CCC(N)CC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)CC1.CCC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@H](C)N.CCC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=N1.COC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=N1.C[C@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 SAQUVZAXWVRQRB-LVDZFKTESA-N 0.000 description 1
- UCCBRFBLWZCVIA-KIYNQFGBSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)O)CC1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)O)CC1 UCCBRFBLWZCVIA-KIYNQFGBSA-N 0.000 description 1
- GEIVEIHETMXUEH-GAGCMDECSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)C(C)C)CC1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)C(C)C)CC1 GEIVEIHETMXUEH-GAGCMDECSA-N 0.000 description 1
- OSJOCSMEJDOWGK-YQYDADCPSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)CC2=CC=C(O)C=C2)CC1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)CC2=CC=C(O)C=C2)CC1 OSJOCSMEJDOWGK-YQYDADCPSA-N 0.000 description 1
- ABYFSSCYYMDFBU-IRCUZVAFSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)CC2=CCC3=C2C=CC=C3)CC1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)CC2=CCC3=C2C=CC=C3)CC1 ABYFSSCYYMDFBU-IRCUZVAFSA-N 0.000 description 1
- JTLYOTWJMVDFDC-SBXXRYSUSA-N CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)CO)CC1 Chemical compound CC(CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](N)CO)CC1 JTLYOTWJMVDFDC-SBXXRYSUSA-N 0.000 description 1
- VOPHJDGXHPLVBH-UHFFFAOYSA-N CC(CCC(=O)CCCN)NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC(CCC(=O)CCCN)NC(=O)C1=NOC(C2CC2)=C1 VOPHJDGXHPLVBH-UHFFFAOYSA-N 0.000 description 1
- VXTSBTMGEALGEH-JPXWEQSISA-N CC(CCC(=O)CCCN)NC(=O)C1=NOC(C2CC2)=C1.CC(CNC(=O)[C@H]1CC[C@H](N)CC1)CC(=O)C1=NOC(C2CC2)=C1.CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.CCCCC(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1.CCCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 Chemical compound CC(CCC(=O)CCCN)NC(=O)C1=NOC(C2CC2)=C1.CC(CNC(=O)[C@H]1CC[C@H](N)CC1)CC(=O)C1=NOC(C2CC2)=C1.CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.CCCCC(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1.CCCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 VXTSBTMGEALGEH-JPXWEQSISA-N 0.000 description 1
- YGCMCKIHPLGIHE-UHFFFAOYSA-N CC(CCNC(=O)CCN)NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC(CCNC(=O)CCN)NC(=O)C1=NOC(C2CC2)=C1 YGCMCKIHPLGIHE-UHFFFAOYSA-N 0.000 description 1
- IRFDDIDQHRSRNF-LPIRWXDWSA-N CC(CCNC(=O)CCN)NC(=O)C1=NOC(C2CC2)=C1.CC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@@H](C)N.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1CC.O=C(NC(C1=CC(CO)=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound CC(CCNC(=O)CCN)NC(=O)C1=NOC(C2CC2)=C1.CC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@@H](C)N.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1CC.O=C(NC(C1=CC(CO)=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 IRFDDIDQHRSRNF-LPIRWXDWSA-N 0.000 description 1
- JMSRKACHIQKYKZ-UHFFFAOYSA-N CC(CNC(=O)CCN)CNC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC(CNC(=O)CCN)CNC(=O)C1=NOC(C2CC2)=C1 JMSRKACHIQKYKZ-UHFFFAOYSA-N 0.000 description 1
- KFADBIGQLKFWDW-RCWADLFESA-N CC(CNC(=O)[C@H]1CC[C@H](N)CC1)CC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC(CNC(=O)[C@H]1CC[C@H](N)CC1)CC(=O)C1=NOC(C2CC2)=C1 KFADBIGQLKFWDW-RCWADLFESA-N 0.000 description 1
- CZZIZJXCGQGDBU-UHFFFAOYSA-N CC(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound CC(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 CZZIZJXCGQGDBU-UHFFFAOYSA-N 0.000 description 1
- JIEJDNPPVSRECT-OLIOOLDLSA-N CC(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.CC1=CC=C(C(C)NC(=O)C2=NOC(C3CC3)=C2)C=C1.C[C@H](N)C(=O)N1CCC([C@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.C[C@H]1C[C@H](NC(=O)C2=NOC(C3CC3)=C2)C1.O=C(NC(C1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound CC(N)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.CC1=CC=C(C(C)NC(=O)C2=NOC(C3CC3)=C2)C=C1.C[C@H](N)C(=O)N1CCC([C@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.C[C@H]1C[C@H](NC(=O)C2=NOC(C3CC3)=C2)C1.O=C(NC(C1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 JIEJDNPPVSRECT-OLIOOLDLSA-N 0.000 description 1
- FQUVAASUKJSNRV-UHFFFAOYSA-N CC(N)C1CCN(C(=O)OC(C)(C)C)CC1 Chemical compound CC(N)C1CCN(C(=O)OC(C)(C)C)CC1 FQUVAASUKJSNRV-UHFFFAOYSA-N 0.000 description 1
- LAYHHKGMSUMIEA-OYTODRSRSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C(=O)C[C@H]1CC[C@H](NC(=O)CN)CC1 Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C(=O)C[C@H]1CC[C@H](NC(=O)CN)CC1 LAYHHKGMSUMIEA-OYTODRSRSA-N 0.000 description 1
- GMXJMVOTRJMHED-UHFFFAOYSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)C Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)C GMXJMVOTRJMHED-UHFFFAOYSA-N 0.000 description 1
- YGBVTVFQYYWDAY-NFJWQWPMSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@@H](C)N Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@@H](C)N YGBVTVFQYYWDAY-NFJWQWPMSA-N 0.000 description 1
- YGBVTVFQYYWDAY-VUWPPUDQSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@H](C)N Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@H](C)N YGBVTVFQYYWDAY-VUWPPUDQSA-N 0.000 description 1
- TXWIRQOOYGXKKK-UKXBKYKQSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@H](C)N.CC1=CC(C(=O)C[C@H]2CC[C@H](NC(=O)CCN)CC2)=NO1.CCCCNC(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.CCCNC(=O)[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2)CC1.CCNCCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1.NCCC(=O)NC1CCCC(NC(=O)C2=NOC(C3CC3)=C2)C1.O=C(NC1=CC=CC=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NCC1=CC=CC=C1O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@H](C)N.CC1=CC(C(=O)C[C@H]2CC[C@H](NC(=O)CCN)CC2)=NO1.CCCCNC(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.CCCNC(=O)[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2)CC1.CCNCCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1.NCCC(=O)NC1CCCC(NC(=O)C2=NOC(C3CC3)=C2)C1.O=C(NC1=CC=CC=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NCC1=CC=CC=C1O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 TXWIRQOOYGXKKK-UKXBKYKQSA-N 0.000 description 1
- YYSYOBKDHWBSQZ-UHFFFAOYSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(F)C=C1 Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(F)C=C1 YYSYOBKDHWBSQZ-UHFFFAOYSA-N 0.000 description 1
- URYASTHWZOHKPU-UHFFFAOYSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(N)C=C1 Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(N)C=C1 URYASTHWZOHKPU-UHFFFAOYSA-N 0.000 description 1
- NVKSYHWSVFKGCX-UHFFFAOYSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCN(C(=O)CCCN)C1 Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCN(C(=O)CCCN)C1 NVKSYHWSVFKGCX-UHFFFAOYSA-N 0.000 description 1
- IMFIEBJOUQEVJE-UHFFFAOYSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCN(C(=O)CCN)C1 Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCN(C(=O)CCN)C1 IMFIEBJOUQEVJE-UHFFFAOYSA-N 0.000 description 1
- FJVJZOBGBSQUEJ-UHFFFAOYSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCN(C(=O)CN)C1 Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCN(C(=O)CN)C1 FJVJZOBGBSQUEJ-UHFFFAOYSA-N 0.000 description 1
- BABKSRFBZIFLPD-UHFFFAOYSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCNC1 Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCNC1 BABKSRFBZIFLPD-UHFFFAOYSA-N 0.000 description 1
- YDCMLHOETCRREQ-UHFFFAOYSA-N CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)OC(C)(C)C)CC1 Chemical compound CC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)OC(C)(C)C)CC1 YDCMLHOETCRREQ-UHFFFAOYSA-N 0.000 description 1
- BVXOPKUJHSAVOF-UHFFFAOYSA-N CC1(C)CC(CC(=O)C2=NOC(C3CC3)=C2)CC(C)(CN)C1 Chemical compound CC1(C)CC(CC(=O)C2=NOC(C3CC3)=C2)CC(C)(CN)C1 BVXOPKUJHSAVOF-UHFFFAOYSA-N 0.000 description 1
- IGPWFQMMZBQBOP-UHFFFAOYSA-N CC1(C)CC(CC(=O)C2=NOC(C3CC3)=C2)CCO1 Chemical compound CC1(C)CC(CC(=O)C2=NOC(C3CC3)=C2)CCO1 IGPWFQMMZBQBOP-UHFFFAOYSA-N 0.000 description 1
- VGEISRJGXRILTJ-UHFFFAOYSA-N CC1(C)CC(N)CC(C)(CCC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CC1(C)CC(N)CC(C)(CCC(=O)C2=NOC(C3CC3)=C2)C1 VGEISRJGXRILTJ-UHFFFAOYSA-N 0.000 description 1
- BIEDZKQORZLFOC-UHFFFAOYSA-N CC1(CC(=O)C2=NOC(C3CC3)=C2)CCC(C(C)(C)N)CC1 Chemical compound CC1(CC(=O)C2=NOC(C3CC3)=C2)CCC(C(C)(C)N)CC1 BIEDZKQORZLFOC-UHFFFAOYSA-N 0.000 description 1
- UFNWDCXWHKZWGH-BGLBCXSPSA-N CC1(CNC(=O)C2=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=CC=C2)=CC=CC=C1.CC1=CC=C(C[C@H](N)C(=O)N2CCC(C(COC(C)C)NC(=O)C3=NOC(C4CC4)=C3)CC2)C=C1.CC1=CC=C(C[C@H](N)C(=O)N2CCC(C(COC3=CC=CC=C3)NC(=O)C3=NOC(C4CC4)=C3)CC2)C=C1.CN(C)CCCNC(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 Chemical compound CC1(CNC(=O)C2=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=CC=C2)=CC=CC=C1.CC1=CC=C(C[C@H](N)C(=O)N2CCC(C(COC(C)C)NC(=O)C3=NOC(C4CC4)=C3)CC2)C=C1.CC1=CC=C(C[C@H](N)C(=O)N2CCC(C(COC3=CC=CC=C3)NC(=O)C3=NOC(C4CC4)=C3)CC2)C=C1.CN(C)CCCNC(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 UFNWDCXWHKZWGH-BGLBCXSPSA-N 0.000 description 1
- TUWBGHSERNVXHW-PZGPUGOMSA-N CC1(CNC(=O)C2=NOC(C3CC3)=C2)CCCCC1.CCC1(C)CC(CC(=O)C2=NOC(C3CC3)=C2)CC(C)(C)C1.CCOC(=O)C1(CNC(=O)C2=NOC(C3CC3)=C2)CCNCC1.N[C@H]1CC[C@@H](C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.O=C(NC(C1=CC=CC=C1)[C@@H]1CCCN1)C1=NOC(C2CC2)=C1.O=C(NCC1(F)CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound CC1(CNC(=O)C2=NOC(C3CC3)=C2)CCCCC1.CCC1(C)CC(CC(=O)C2=NOC(C3CC3)=C2)CC(C)(C)C1.CCOC(=O)C1(CNC(=O)C2=NOC(C3CC3)=C2)CCNCC1.N[C@H]1CC[C@@H](C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.O=C(NC(C1=CC=CC=C1)[C@@H]1CCCN1)C1=NOC(C2CC2)=C1.O=C(NCC1(F)CCCCC1)C1=NOC(C2CC2)=C1 TUWBGHSERNVXHW-PZGPUGOMSA-N 0.000 description 1
- CIXDRJPDHWCKMQ-UHFFFAOYSA-N CC1(CNC(=O)C2=NOC(C3CC3)=C2)CCNCC1 Chemical compound CC1(CNC(=O)C2=NOC(C3CC3)=C2)CCNCC1 CIXDRJPDHWCKMQ-UHFFFAOYSA-N 0.000 description 1
- ATLNIAWTOHFEOT-UHFFFAOYSA-N CC1(N)CCC(C(C)(C)NC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound CC1(N)CCC(C(C)(C)NC(=O)C2=NOC(C3CC3)=C2)CC1 ATLNIAWTOHFEOT-UHFFFAOYSA-N 0.000 description 1
- KZKKDHIIVOQMCY-MGCOHNPYSA-N CC1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1 Chemical compound CC1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1 KZKKDHIIVOQMCY-MGCOHNPYSA-N 0.000 description 1
- UXUSZXBNVJLGEX-MRIWZQHUSA-N CC1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1.CCC1=CC(C(=O)NC(C2=CC=CC=C2Cl)C2CCCCC2)=NO1.CN1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.C[C@@H](N)CC(=O)N[C@H]1CC2(C[C@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1.C[C@@H](N)CC(=O)N[C@H]1CC2(C[C@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1.O=C(NC(C1=CC=CC=C1Cl)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound CC1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1.CCC1=CC(C(=O)NC(C2=CC=CC=C2Cl)C2CCCCC2)=NO1.CN1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.C[C@@H](N)CC(=O)N[C@H]1CC2(C[C@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1.C[C@@H](N)CC(=O)N[C@H]1CC2(C[C@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1.O=C(NC(C1=CC=CC=C1Cl)C1CCCCC1)C1=NOC(C2CC2)=C1 UXUSZXBNVJLGEX-MRIWZQHUSA-N 0.000 description 1
- WKFMDQGNDCVQGB-HAQNSBGRSA-N CC1=CC(C(=O)C[C@H]2CC[C@H](NC(=O)CCN)CC2)=NO1 Chemical compound CC1=CC(C(=O)C[C@H]2CC[C@H](NC(=O)CCN)CC2)=NO1 WKFMDQGNDCVQGB-HAQNSBGRSA-N 0.000 description 1
- FICNBHYNZHGKBL-UHFFFAOYSA-N CC1=CC(C(=O)NC2CC(N)C2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC1=CC(C(=O)NC2CC(N)C2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 FICNBHYNZHGKBL-UHFFFAOYSA-N 0.000 description 1
- PUEMEEKXJOEFRN-PEWKTYRNSA-N CC1=CC(C(=O)NC2CC(N)C2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCC(C)C1.CCCCS(=O)(=O)NCC(C)(C)CNC(=O)C1=NOC(C2CC2)=C1.N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1.N[C@@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.N[C@@H](CO)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound CC1=CC(C(=O)NC2CC(N)C2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCC(C)C1.CCCCS(=O)(=O)NCC(C)(C)CNC(=O)C1=NOC(C2CC2)=C1.N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1.N[C@@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.N[C@@H](CO)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 PUEMEEKXJOEFRN-PEWKTYRNSA-N 0.000 description 1
- UGGBCCJYAPRGEM-UHFFFAOYSA-N CC1=CC(C(=O)NC2CCC(N)C2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC1=CC(C(=O)NC2CCC(N)C2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 UGGBCCJYAPRGEM-UHFFFAOYSA-N 0.000 description 1
- HMTLAJCGDWFJEP-UHFFFAOYSA-N CC1=CC(C(=O)NC2CCC(N)C2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)C1.NC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)C1.O=C(NC1=CC=C(C(F)(F)F)N=C1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.O=C(NC1=CC=CC=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NC1=CN=CC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound CC1=CC(C(=O)NC2CCC(N)C2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)C1.NC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)C1.O=C(NC1=CC=C(C(F)(F)F)N=C1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.O=C(NC1=CC=CC=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NC1=CN=CC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 HMTLAJCGDWFJEP-UHFFFAOYSA-N 0.000 description 1
- FZQXQKFBKGMJPA-UHFFFAOYSA-N CC1=CC(C(=O)NC2CCC(N)CC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC1=CC(C(=O)NC2CCC(N)CC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 FZQXQKFBKGMJPA-UHFFFAOYSA-N 0.000 description 1
- VAPLWEZLCKYWFT-KACRINOLSA-N CC1=CC(C(=O)NC2CCNC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CCCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1.CCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(C)=C1.C[C@@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1.O=C(NC(C(=O)CCC1=CC=CC=C1O)C1CCCCC1)C1=NOC(C2CC2)=C1.O=C(NC1=CC=NC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NC1CCNC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1 Chemical compound CC1=CC(C(=O)NC2CCNC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CCCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1.CCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(C)=C1.C[C@@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1.O=C(NC(C(=O)CCC1=CC=CC=C1O)C1CCCCC1)C1=NOC(C2CC2)=C1.O=C(NC1=CC=NC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NC1CCNC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1 VAPLWEZLCKYWFT-KACRINOLSA-N 0.000 description 1
- VNFLMMWVBISGDE-UHFFFAOYSA-N CC1=CC(C(=O)NC2CCNCC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC1=CC(C(=O)NC2CCNCC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 VNFLMMWVBISGDE-UHFFFAOYSA-N 0.000 description 1
- MIIPKEQMUUWWAJ-BMEVAIEMSA-N CC1=CC(C(=O)NC2CCNCC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CCCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br.C[C@@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.O=C(NC1=CC=CC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NC1CCCCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br Chemical compound CC1=CC(C(=O)NC2CCNCC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CCCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br.C[C@@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.O=C(NC1=CC=CC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NC1CCCCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br MIIPKEQMUUWWAJ-BMEVAIEMSA-N 0.000 description 1
- AUQUTZRJLZNPQK-UHFFFAOYSA-N CC1=CC(C(=O)NCC2CCNCC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC1=CC(C(=O)NCC2CCNCC2)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 AUQUTZRJLZNPQK-UHFFFAOYSA-N 0.000 description 1
- RZZAWQIDDKGGAS-UHFFFAOYSA-N CC1=CC(C(=O)NCCCN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC1=CC(C(=O)NCCCN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 RZZAWQIDDKGGAS-UHFFFAOYSA-N 0.000 description 1
- XRRHJAWARGIZBP-UHFFFAOYSA-N CC1=CC(C(=O)NCCN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC1=CC(C(=O)NCCN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 XRRHJAWARGIZBP-UHFFFAOYSA-N 0.000 description 1
- HDKQMIMAFAXNAU-KJHIPHCISA-N CC1=CC(C2OCCC2NC(=O)C2=NOC(C3CC3)=C2)=CC=C1F.CCC(=O)NC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCCC(=O)NC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCCCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.NCCC(=O)NCC1(CNC(=O)C2=NOC(C3CC3)=C2)CC1.N[C@H]1CC[C@H](OCC2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)CC1 Chemical compound CC1=CC(C2OCCC2NC(=O)C2=NOC(C3CC3)=C2)=CC=C1F.CCC(=O)NC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCCC(=O)NC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCCCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.NCCC(=O)NCC1(CNC(=O)C2=NOC(C3CC3)=C2)CC1.N[C@H]1CC[C@H](OCC2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)CC1 HDKQMIMAFAXNAU-KJHIPHCISA-N 0.000 description 1
- FRTGGNKXUKBMHW-UHFFFAOYSA-N CC1=CC(CN)=CC=C1CC(=O)C1=NOC(C2CC2)=C1 Chemical compound CC1=CC(CN)=CC=C1CC(=O)C1=NOC(C2CC2)=C1 FRTGGNKXUKBMHW-UHFFFAOYSA-N 0.000 description 1
- XUMJCBZCNKBWJL-UHFFFAOYSA-N CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CC(N)C1 Chemical compound CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CC(N)C1 XUMJCBZCNKBWJL-UHFFFAOYSA-N 0.000 description 1
- KVGSBZVVLGNYST-ZVGYFBCQSA-N CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCC(C)CC1.CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCCCC1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1C(C)C.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1CO.NC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)CC1.O=C(NC1=CC=CC=C1)C1=CC([C@@H](NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NC1=CC=CC=C1)C1=CC([C@H](NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NC1CCNCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1 Chemical compound CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCC(C)CC1.CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCCCC1.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1C(C)C.CCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1CO.NC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)CC1.O=C(NC1=CC=CC=C1)C1=CC([C@@H](NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NC1=CC=CC=C1)C1=CC([C@H](NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NC1CCNCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1 KVGSBZVVLGNYST-ZVGYFBCQSA-N 0.000 description 1
- SMZXOWASRFWJMK-UHFFFAOYSA-N CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCC(N)C1 Chemical compound CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCC(N)C1 SMZXOWASRFWJMK-UHFFFAOYSA-N 0.000 description 1
- KLIBPYAKCGMLIO-XSAVEBRISA-N CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCCC(C)C1.CCCCS(=O)(=O)[C@H]1CC[C@@H](NC(=O)C2=NOC(C3CC3)=C2)CC1.N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.N[C@@H](CO)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.N[C@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1.O=C(NCC1CCCCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1 Chemical compound CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCCC(C)C1.CCCCS(=O)(=O)[C@H]1CC[C@@H](NC(=O)C2=NOC(C3CC3)=C2)CC1.N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.N[C@@H](CO)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.N[C@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1.O=C(NCC1CCCCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1 KLIBPYAKCGMLIO-XSAVEBRISA-N 0.000 description 1
- NNIBWDIXLJKESS-UHFFFAOYSA-N CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCCC(N)C1 Chemical compound CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCCC(N)C1 NNIBWDIXLJKESS-UHFFFAOYSA-N 0.000 description 1
- CGXOTXRKAADTMF-UHFFFAOYSA-N CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCNC1 Chemical compound CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCNC1 CGXOTXRKAADTMF-UHFFFAOYSA-N 0.000 description 1
- PDWGPEWGUNDGPX-UHFFFAOYSA-N CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCNCC1 Chemical compound CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NC1CCNCC1 PDWGPEWGUNDGPX-UHFFFAOYSA-N 0.000 description 1
- VYKJXFBBYZAZCP-UHFFFAOYSA-N CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NCC1CCNCC1 Chemical compound CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NCC1CCNCC1 VYKJXFBBYZAZCP-UHFFFAOYSA-N 0.000 description 1
- ONYXTTQVGZEKGF-UHFFFAOYSA-N CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NCCCN Chemical compound CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NCCCN ONYXTTQVGZEKGF-UHFFFAOYSA-N 0.000 description 1
- WQVFZQXQSWWOTB-UHFFFAOYSA-N CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NCCN Chemical compound CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1C(=O)NCCN WQVFZQXQSWWOTB-UHFFFAOYSA-N 0.000 description 1
- GUIGPDQXJOXKLL-UHFFFAOYSA-N CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1CN Chemical compound CC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1CN GUIGPDQXJOXKLL-UHFFFAOYSA-N 0.000 description 1
- KLOYHURFORDCJW-UHFFFAOYSA-N CC1=CC=C(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)C=C1 Chemical compound CC1=CC=C(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)C=C1 KLOYHURFORDCJW-UHFFFAOYSA-N 0.000 description 1
- JIIARNREUSNVRV-UHFFFAOYSA-N CC1=CC=C(C(NC(=O)C2=NOC(C3CC3)=C2)C2CN(C)CCO2)C=C1.CC1CC(CNC(=O)C2=NOC(C3CC3)=C2)CN1CC1=CC=CC=C1.CCC(=O)NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1C.CCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1.CCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br.CCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1C.O=C(NC1CCCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br Chemical compound CC1=CC=C(C(NC(=O)C2=NOC(C3CC3)=C2)C2CN(C)CCO2)C=C1.CC1CC(CNC(=O)C2=NOC(C3CC3)=C2)CN1CC1=CC=CC=C1.CCC(=O)NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1C.CCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1.CCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br.CCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1C.O=C(NC1CCCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br JIIARNREUSNVRV-UHFFFAOYSA-N 0.000 description 1
- WBEPOBRJLHUMGD-DWHKIMGGSA-N CC1=CC=C(CNC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=C1.CCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.COCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.NCCC(=O)N[C@H]1CC2(C[C@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1.O=C(NC1CCCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NCC1CCCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound CC1=CC=C(CNC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=C1.CCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.COCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.NCCC(=O)N[C@H]1CC2(C[C@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1.O=C(NC1CCCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NCC1CCCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 WBEPOBRJLHUMGD-DWHKIMGGSA-N 0.000 description 1
- COOBPLWIQWRJJI-BUWPTAIVSA-N CC1=CC=C(C[C@H](N)C(=O)N2CCC(C(CO)NC(=O)C3=NOC(C4CC4)=C3)CC2)C=C1.CCC1=CC(C(=O)NC(C2=CC=CC=C2)C2CCCCC2)=NO1.CCOC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CC=C(C)C=C2)CC1.O=C(NC(C1=CC(Cl)=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound CC1=CC=C(C[C@H](N)C(=O)N2CCC(C(CO)NC(=O)C3=NOC(C4CC4)=C3)CC2)C=C1.CCC1=CC(C(=O)NC(C2=CC=CC=C2)C2CCCCC2)=NO1.CCOC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CC=C(C)C=C2)CC1.O=C(NC(C1=CC(Cl)=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 COOBPLWIQWRJJI-BUWPTAIVSA-N 0.000 description 1
- YYIWUASXWKRABI-UHFFFAOYSA-N CC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)C=N1 Chemical compound CC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)C=N1 YYIWUASXWKRABI-UHFFFAOYSA-N 0.000 description 1
- KONFZPFZBGRUGK-UHFFFAOYSA-N CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)=C1 Chemical compound CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)=C1 KONFZPFZBGRUGK-UHFFFAOYSA-N 0.000 description 1
- RAKAANCKSXRXJB-UHFFFAOYSA-N CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)=C1.CCC1=CC(C(=O)NC(C2=CC=CC(C)=C2)C(C)(C)C)=NO1.CN(C)C1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=N1.NC1=CC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)=CC=N1 Chemical compound CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)=C1.CCC1=CC(C(=O)NC(C2=CC=CC(C)=C2)C(C)(C)C)=NO1.CN(C)C1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=N1.NC1=CC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)=CC=N1 RAKAANCKSXRXJB-UHFFFAOYSA-N 0.000 description 1
- UXMIJXGHKZPVHH-UHFFFAOYSA-N CC1=CC=CC=C1CCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 Chemical compound CC1=CC=CC=C1CCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 UXMIJXGHKZPVHH-UHFFFAOYSA-N 0.000 description 1
- UNAHVFBJBHOURI-WBDJBZBYSA-N CC1=CC=CC=C1CCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1.CCCCC(=O)NC1CCCC(NC(=O)C2=NOC(C3CC3)=C2)C1.CCCCNC(=O)[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2)CC1.COC1=CC=CC=C1CCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1.C[C@@H](N)CC(=O)CCC1(CNC(=O)C2=NOC(C3CC3)=C2)CCC1.O=C(NC(C1=CC(COCC2=CC=CC=C2I)=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound CC1=CC=CC=C1CCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1.CCCCC(=O)NC1CCCC(NC(=O)C2=NOC(C3CC3)=C2)C1.CCCCNC(=O)[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2)CC1.COC1=CC=CC=C1CCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1.C[C@@H](N)CC(=O)CCC1(CNC(=O)C2=NOC(C3CC3)=C2)CCC1.O=C(NC(C1=CC(COCC2=CC=CC=C2I)=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 UNAHVFBJBHOURI-WBDJBZBYSA-N 0.000 description 1
- DZUYNPUUABJUCM-UHFFFAOYSA-N CC1=CN(CCC(=O)NCC2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)N=C1 Chemical compound CC1=CN(CCC(=O)NCC2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)N=C1 DZUYNPUUABJUCM-UHFFFAOYSA-N 0.000 description 1
- GPYXAXGSIBIUKD-UHFFFAOYSA-N CC1=CN=CC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)=C1 Chemical compound CC1=CN=CC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)=C1 GPYXAXGSIBIUKD-UHFFFAOYSA-N 0.000 description 1
- JMMISGMVJXXAHP-UHFFFAOYSA-N CC1=CNC(C(=O)NCC2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)=C1 Chemical compound CC1=CNC(C(=O)NCC2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)=C1 JMMISGMVJXXAHP-UHFFFAOYSA-N 0.000 description 1
- ZBAOXXFMZDZCNH-GLAWKEQLSA-N CC1=CNC(C(=O)NCC2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)=C1.CCCCC(=O)N1CCC([C@@H](C)CC(=O)C2=NOC(C3CC3)=C2)CC1.CCCCNS(=O)(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1.CCCCS(=O)(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCN(C)CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 Chemical compound CC1=CNC(C(=O)NCC2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)=C1.CCCCC(=O)N1CCC([C@@H](C)CC(=O)C2=NOC(C3CC3)=C2)CC1.CCCCNS(=O)(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1.CCCCS(=O)(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.CCCN(C)CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 ZBAOXXFMZDZCNH-GLAWKEQLSA-N 0.000 description 1
- NJJMJNINRZIGBJ-UHFFFAOYSA-N CC1=NC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1CN Chemical compound CC1=NC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1CN NJJMJNINRZIGBJ-UHFFFAOYSA-N 0.000 description 1
- MTJFYUMKGORGNK-UHFFFAOYSA-N CC1C(NC(=O)C2=NOC(C3CC3)=C2)CCCN1C Chemical compound CC1C(NC(=O)C2=NOC(C3CC3)=C2)CCCN1C MTJFYUMKGORGNK-UHFFFAOYSA-N 0.000 description 1
- BJMMTQYJKARKCF-UHFFFAOYSA-N CC1CC(CNC(=O)C2=NOC(C3CC3)=C2)CN1CC1=CC=CC=C1 Chemical compound CC1CC(CNC(=O)C2=NOC(C3CC3)=C2)CN1CC1=CC=CC=C1 BJMMTQYJKARKCF-UHFFFAOYSA-N 0.000 description 1
- CSNHYPXNSWHVMU-NIJCVPJUSA-N CC1CC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)C1.CCCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(C)=C1.CN1C=CN=C1[C@@H]1CCC[C@H](CC(=O)C2=NOC(C3CC3)=C2)C1.CN1C=CN=C1[C@H]1CCC[C@H](CC(=O)C2=NOC(C3CC3)=C2)C1.O=C(C[C@H]1CCC[C@@H](C2CC2)C1)C1=NOC(C2CC2)=C1.O=C(C[C@H]1CCC[C@H](C2CC2)C1)C1=NOC(C2CC2)=C1.O=C(NC1=CC=C(S(=O)(=O)CCC2CCCCC2)C=C1)C1=NOC(C2CC2)=C1.O=C(NCC1CCCCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br Chemical compound CC1CC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)C1.CCCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(C)=C1.CN1C=CN=C1[C@@H]1CCC[C@H](CC(=O)C2=NOC(C3CC3)=C2)C1.CN1C=CN=C1[C@H]1CCC[C@H](CC(=O)C2=NOC(C3CC3)=C2)C1.O=C(C[C@H]1CCC[C@@H](C2CC2)C1)C1=NOC(C2CC2)=C1.O=C(C[C@H]1CCC[C@H](C2CC2)C1)C1=NOC(C2CC2)=C1.O=C(NC1=CC=C(S(=O)(=O)CCC2CCCCC2)C=C1)C1=NOC(C2CC2)=C1.O=C(NCC1CCCCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br CSNHYPXNSWHVMU-NIJCVPJUSA-N 0.000 description 1
- GSBHKZXOSXYLDU-BKKLMWIWSA-N CCC(=O)N[C@H]1CC[C@H](CC(=O)C(C)NC(=O)C2=NOC(C3CC3)=C2)CC1.CCC1=CC(CN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CCCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.CCCCC1=CC(C(=O)N[C@H]2CC[C@H](C)CC2)=NO1.CCN(CC)CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.O=C(NC(CC1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound CCC(=O)N[C@H]1CC[C@H](CC(=O)C(C)NC(=O)C2=NOC(C3CC3)=C2)CC1.CCC1=CC(CN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1.CCCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1.CCCCC1=CC(C(=O)N[C@H]2CC[C@H](C)CC2)=NO1.CCN(CC)CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.O=C(NC(CC1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 GSBHKZXOSXYLDU-BKKLMWIWSA-N 0.000 description 1
- MBPUSOQYJMZVDU-BGEHQDIKSA-N CCC(C)C(C)C.CC[C@@H](C)C(C)C.CC[C@H](C)C(C)C Chemical compound CCC(C)C(C)C.CC[C@@H](C)C(C)C.CC[C@H](C)C(C)C MBPUSOQYJMZVDU-BGEHQDIKSA-N 0.000 description 1
- RFWNAHVTWWAZNI-UHFFFAOYSA-N CCC(C1=CC=CC=C1)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CCC(C1=CC=CC=C1)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 RFWNAHVTWWAZNI-UHFFFAOYSA-N 0.000 description 1
- SIIYSXFDZRAKHH-UHFFFAOYSA-N CCC(CCC(=O)CCCN)NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CCC(CCC(=O)CCCN)NC(=O)C1=NOC(C2CC2)=C1 SIIYSXFDZRAKHH-UHFFFAOYSA-N 0.000 description 1
- DNLBICLMEBCISH-NYFVRUFYSA-N CCC(CCC(=O)CCCN)NC(=O)C1=NOC(C2CC2)=C1.CCC(CNC(=O)[C@H]1CC[C@H](N)CC1)CC(=O)C1=NOC(C2CC2)=C1.CCCC(=O)CCC(CC)NC(=O)C1=NOC(C2CC2)=C1.CCOC1CC(NC(=O)C2=NOC(C3CC3)=C2)C12CCCCC2.NCCC(=O)NC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C=C1.O=C(NC1CCC(C2=CC=CC=C2)C1)C1=NOC(C2CC2)=C1.O=C(NC1CCC2(CCOCC2)CC1)C1=NOC(C2CC2)=C1.O=C(NC1CCOC2(CCCCC2)C1)C1=NOC(C2CC2)=C1 Chemical compound CCC(CCC(=O)CCCN)NC(=O)C1=NOC(C2CC2)=C1.CCC(CNC(=O)[C@H]1CC[C@H](N)CC1)CC(=O)C1=NOC(C2CC2)=C1.CCCC(=O)CCC(CC)NC(=O)C1=NOC(C2CC2)=C1.CCOC1CC(NC(=O)C2=NOC(C3CC3)=C2)C12CCCCC2.NCCC(=O)NC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C=C1.O=C(NC1CCC(C2=CC=CC=C2)C1)C1=NOC(C2CC2)=C1.O=C(NC1CCC2(CCOCC2)CC1)C1=NOC(C2CC2)=C1.O=C(NC1CCOC2(CCCCC2)C1)C1=NOC(C2CC2)=C1 DNLBICLMEBCISH-NYFVRUFYSA-N 0.000 description 1
- FAJSTZLZUULMAZ-UHFFFAOYSA-N CCC(CCC(=O)CCN)NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CCC(CCC(=O)CCN)NC(=O)C1=NOC(C2CC2)=C1 FAJSTZLZUULMAZ-UHFFFAOYSA-N 0.000 description 1
- ZKOOGKYJAUMOIE-UHFFFAOYSA-N CCC(CCNC(=O)CCN)NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CCC(CCNC(=O)CCN)NC(=O)C1=NOC(C2CC2)=C1 ZKOOGKYJAUMOIE-UHFFFAOYSA-N 0.000 description 1
- APFDTLTXYHWQPW-YDRRXPLNSA-N CCC(CNC(=O)[C@H]1CC[C@H](N)CC1)CC(=O)C1=NOC(C2CC2)=C1 Chemical compound CCC(CNC(=O)[C@H]1CC[C@H](N)CC1)CC(=O)C1=NOC(C2CC2)=C1 APFDTLTXYHWQPW-YDRRXPLNSA-N 0.000 description 1
- WGCQBRKKRGCTIN-UHFFFAOYSA-N CCC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)C Chemical compound CCC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)C WGCQBRKKRGCTIN-UHFFFAOYSA-N 0.000 description 1
- WOPNQOQTJSBHFK-ZRKZCGFPSA-N CCC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@@H](C)N Chemical compound CCC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@@H](C)N WOPNQOQTJSBHFK-ZRKZCGFPSA-N 0.000 description 1
- WOPNQOQTJSBHFK-VPHXOMNUSA-N CCC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@H](C)N Chemical compound CCC(NC(=O)C1=NOC(C2CC2)=C1)C(C)(C)CNC(=O)C[C@H](C)N WOPNQOQTJSBHFK-VPHXOMNUSA-N 0.000 description 1
- VYAJLOAAPYDGIG-UHFFFAOYSA-N CCC(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(F)C=C1 Chemical compound CCC(NC(=O)C1=NOC(C2CC2)=C1)C1=CC=C(F)C=C1 VYAJLOAAPYDGIG-UHFFFAOYSA-N 0.000 description 1
- NAAXOTIDLCPDPU-ZSOXZCCMSA-N CCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1 Chemical compound CCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1 NAAXOTIDLCPDPU-ZSOXZCCMSA-N 0.000 description 1
- HYNZHRPWZASXHW-UHFFFAOYSA-N CCC1=CC(C(=O)NC(C2=CC=CC(Cl)=C2)C(C)(C)C)=NO1 Chemical compound CCC1=CC(C(=O)NC(C2=CC=CC(Cl)=C2)C(C)(C)C)=NO1 HYNZHRPWZASXHW-UHFFFAOYSA-N 0.000 description 1
- JIDLYYOIBYHOMZ-UHFFFAOYSA-N CCC1=CC(C(=O)NC(C2=CC=CC(Cl)=C2)C2CCCCC2)=NO1 Chemical compound CCC1=CC(C(=O)NC(C2=CC=CC(Cl)=C2)C2CCCCC2)=NO1 JIDLYYOIBYHOMZ-UHFFFAOYSA-N 0.000 description 1
- BKBLNGFPINMXHV-UHFFFAOYSA-N CCC1=CC(C(=O)NC(C2=CC=CC(F)=C2)C(C)(C)C)=NO1 Chemical compound CCC1=CC(C(=O)NC(C2=CC=CC(F)=C2)C(C)(C)C)=NO1 BKBLNGFPINMXHV-UHFFFAOYSA-N 0.000 description 1
- KLMMQSBNBPGLPY-UHFFFAOYSA-N CCC1=CC(C(=O)NC(C2=CC=CC(OC)=C2)C(C)(C)C)=NO1 Chemical compound CCC1=CC(C(=O)NC(C2=CC=CC(OC)=C2)C(C)(C)C)=NO1 KLMMQSBNBPGLPY-UHFFFAOYSA-N 0.000 description 1
- ONYFCTIPIXRVNV-UHFFFAOYSA-N CCC1=CC(C(=O)NC(C2=CC=CC=C2)C2CCCCC2)=NO1 Chemical compound CCC1=CC(C(=O)NC(C2=CC=CC=C2)C2CCCCC2)=NO1 ONYFCTIPIXRVNV-UHFFFAOYSA-N 0.000 description 1
- IVNOEWRMRHVATF-UHFFFAOYSA-N CCC1=CC(C(=O)NC(C2=CC=CC=C2)C2CCN(C)CC2)=NO1 Chemical compound CCC1=CC(C(=O)NC(C2=CC=CC=C2)C2CCN(C)CC2)=NO1 IVNOEWRMRHVATF-UHFFFAOYSA-N 0.000 description 1
- CMKPBHHDCOQRKQ-UHFFFAOYSA-N CCC1=CC(C(=O)NC(C2=CC=CC=C2)C2CCOCC2)=NO1 Chemical compound CCC1=CC(C(=O)NC(C2=CC=CC=C2)C2CCOCC2)=NO1 CMKPBHHDCOQRKQ-UHFFFAOYSA-N 0.000 description 1
- OQCVPUVYORUTOA-DXQWOZOISA-N CCC1=CC(C(=O)NC(C2=CC=CC=C2)C2CCOCC2)=NO1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CC2=CC=CC=C2)CC1.N[C@H]1CC[C@H](C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.O=C(NCC1(O)CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound CCC1=CC(C(=O)NC(C2=CC=CC=C2)C2CCOCC2)=NO1.C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CC2=CC=CC=C2)CC1.N[C@H]1CC[C@H](C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.O=C(NCC1(O)CCCCC1)C1=NOC(C2CC2)=C1 OQCVPUVYORUTOA-DXQWOZOISA-N 0.000 description 1
- AQWLDIHVBBJAOT-UHFFFAOYSA-N CCC1=CC(C(=O)NC(C2=CC=CC=C2Cl)C2CCCCC2)=NO1 Chemical compound CCC1=CC(C(=O)NC(C2=CC=CC=C2Cl)C2CCCCC2)=NO1 AQWLDIHVBBJAOT-UHFFFAOYSA-N 0.000 description 1
- RUOZQYANGPTGGT-UHFFFAOYSA-N CCC1=CC(C(C)C)=CC=C1.CCC1=CC=C(C(C)C)C=C1.CCC1=CC=CC=C1C(C)C Chemical compound CCC1=CC(C(C)C)=CC=C1.CCC1=CC=C(C(C)C)C=C1.CCC1=CC=CC=C1C(C)C RUOZQYANGPTGGT-UHFFFAOYSA-N 0.000 description 1
- DEDDMRVIPPPQJT-UHFFFAOYSA-N CCC1=CC(CN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 Chemical compound CCC1=CC(CN)=CC=C1NC(=O)C1=NOC(C2CC2)=C1 DEDDMRVIPPPQJT-UHFFFAOYSA-N 0.000 description 1
- SLMBXSOHABZUPV-UHFFFAOYSA-N CCC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1CN Chemical compound CCC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1CN SLMBXSOHABZUPV-UHFFFAOYSA-N 0.000 description 1
- QGKCKFXBWZVHHK-UHFFFAOYSA-N CCC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)C=N1 Chemical compound CCC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)C=N1 QGKCKFXBWZVHHK-UHFFFAOYSA-N 0.000 description 1
- SWNBVQOJHBBKFV-HAPMWLRASA-N CCC1CCC(C(C)C)CC1.CC[C@H]1CC[C@@H](C(C)C)CC1.CC[C@H]1CC[C@H](C(C)C)CC1 Chemical compound CCC1CCC(C(C)C)CC1.CC[C@H]1CC[C@@H](C(C)C)CC1.CC[C@H]1CC[C@H](C(C)C)CC1 SWNBVQOJHBBKFV-HAPMWLRASA-N 0.000 description 1
- XWFZHAAAWXNRBZ-UHFFFAOYSA-N CCCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1 Chemical compound CCCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1 XWFZHAAAWXNRBZ-UHFFFAOYSA-N 0.000 description 1
- RPWYMIMBJZTEGN-XYPYZODXSA-N CCCC1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1 Chemical compound CCCC1=CC(C(=O)C[C@H]2CC[C@H](N)CC2)=NO1 RPWYMIMBJZTEGN-XYPYZODXSA-N 0.000 description 1
- HGDKEGZVFCEOHZ-BLWQCSFQSA-N CCCCC(=O)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1.CCCCCC(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1.C[C@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H]2CC[C@H](C)CC2)CC1.NC(CCC1=CC=CC=C1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.NC(CCC1=CC=CC=C1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.NCC(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCC(=O)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1.CCCCCC(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1.C[C@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H]2CC[C@H](C)CC2)CC1.NC(CCC1=CC=CC=C1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.NC(CCC1=CC=CC=C1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1.NCC(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 HGDKEGZVFCEOHZ-BLWQCSFQSA-N 0.000 description 1
- ZBBLAZHCKJOMDQ-UHFFFAOYSA-N CCCCC(=O)N1CCCC(C(C)NC(=O)C2=NOC(C3CC3)=C2)C1.CCCCN(C)C(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.O=C(NCC(O)CN1CCCC1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 Chemical compound CCCCC(=O)N1CCCC(C(C)NC(=O)C2=NOC(C3CC3)=C2)C1.CCCCN(C)C(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1.O=C(NCC(O)CN1CCCC1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 ZBBLAZHCKJOMDQ-UHFFFAOYSA-N 0.000 description 1
- YIQJTUNGYIRYBZ-XYPYZODXSA-N CCCCC1=CC(C(=O)N[C@H]2CC[C@H](N)CC2)=NO1 Chemical compound CCCCC1=CC(C(=O)N[C@H]2CC[C@H](N)CC2)=NO1 YIQJTUNGYIRYBZ-XYPYZODXSA-N 0.000 description 1
- DZNQHQKMAKVIIN-UHFFFAOYSA-N CCCCOC1CC(NC(=O)C2=NOC(C3CC3)=C2)C1(C)C Chemical compound CCCCOC1CC(NC(=O)C2=NOC(C3CC3)=C2)C1(C)C DZNQHQKMAKVIIN-UHFFFAOYSA-N 0.000 description 1
- VKDDFCATIJRLPV-UHFFFAOYSA-N CCCN1CC(CNC(=O)C2=NOC(C3CC3)=C2)C1.O=C(NCC1CCC1)C1=NOC(C2CC2)=C1.O=C(NCC1CN(CC2CC2)C1)C1=NOC(C2CC2)=C1 Chemical compound CCCN1CC(CNC(=O)C2=NOC(C3CC3)=C2)C1.O=C(NCC1CCC1)C1=NOC(C2CC2)=C1.O=C(NCC1CN(CC2CC2)C1)C1=NOC(C2CC2)=C1 VKDDFCATIJRLPV-UHFFFAOYSA-N 0.000 description 1
- FJYFGDTVQBRMHV-UHFFFAOYSA-N CCCN1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CCCN1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 FJYFGDTVQBRMHV-UHFFFAOYSA-N 0.000 description 1
- RFLINZCLNGXRCG-UHFFFAOYSA-N CCCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 Chemical compound CCCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 RFLINZCLNGXRCG-UHFFFAOYSA-N 0.000 description 1
- FFTFYQJNZRCHCN-UHFFFAOYSA-N CCN(CC)CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 Chemical compound CCN(CC)CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 FFTFYQJNZRCHCN-UHFFFAOYSA-N 0.000 description 1
- OGSXEYYJKJNKNB-UHFFFAOYSA-N CCN1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CCN1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 OGSXEYYJKJNKNB-UHFFFAOYSA-N 0.000 description 1
- CFIVMPNEUICEEL-UHFFFAOYSA-N CCN1CCC(C(C)C)CC1 Chemical compound CCN1CCC(C(C)C)CC1 CFIVMPNEUICEEL-UHFFFAOYSA-N 0.000 description 1
- IELJUCUWRLXHAJ-UHFFFAOYSA-N CCNCCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 Chemical compound CCNCCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 IELJUCUWRLXHAJ-UHFFFAOYSA-N 0.000 description 1
- MHKXVJFDESXWFH-UHFFFAOYSA-N CCOC(=O)C(=O)CC(=O)C1CC1 Chemical compound CCOC(=O)C(=O)CC(=O)C1CC1 MHKXVJFDESXWFH-UHFFFAOYSA-N 0.000 description 1
- WGLNPQYOEGLGAV-UHFFFAOYSA-N CCOC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1 Chemical compound CCOC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1 WGLNPQYOEGLGAV-UHFFFAOYSA-N 0.000 description 1
- SVAXRPJPGXSHQN-LBPRGKRZSA-N CCOC(=O)C1(CNC(=O)C2=NOC(C3CC3)=C2)CCN(C(=O)[C@H](C)N)CC1 Chemical compound CCOC(=O)C1(CNC(=O)C2=NOC(C3CC3)=C2)CCN(C(=O)[C@H](C)N)CC1 SVAXRPJPGXSHQN-LBPRGKRZSA-N 0.000 description 1
- XMKHEATVFWAIMD-UHFFFAOYSA-N CCOC(=O)C1=NOC(C2CC2)=C1 Chemical compound CCOC(=O)C1=NOC(C2CC2)=C1 XMKHEATVFWAIMD-UHFFFAOYSA-N 0.000 description 1
- FTDZOOCQYLYZRA-UHFFFAOYSA-N CCOC(=O)C1=NOC(C2CC2)=C1I Chemical compound CCOC(=O)C1=NOC(C2CC2)=C1I FTDZOOCQYLYZRA-UHFFFAOYSA-N 0.000 description 1
- QAXARQGLSZUOBN-UHFFFAOYSA-N CCOC(=O)C1=NOC(CCO)=C1 Chemical compound CCOC(=O)C1=NOC(CCO)=C1 QAXARQGLSZUOBN-UHFFFAOYSA-N 0.000 description 1
- RSFOGQGIDJCGHD-TVPLGVNVSA-N CCOC(=O)C1CC(NC(=O)C2=NOC(C3CC3)=C2)CN(C(=O)[C@@H](N)CC2=CC=C(O)C=C2)C1 Chemical compound CCOC(=O)C1CC(NC(=O)C2=NOC(C3CC3)=C2)CN(C(=O)[C@@H](N)CC2=CC=C(O)C=C2)C1 RSFOGQGIDJCGHD-TVPLGVNVSA-N 0.000 description 1
- KKKQJHYNPNJVLX-UHFFFAOYSA-N CCOC1CC(NC(=O)C2=NOC(C3CC3)=C2)C12CCCCC2 Chemical compound CCOC1CC(NC(=O)C2=NOC(C3CC3)=C2)C12CCCCC2 KKKQJHYNPNJVLX-UHFFFAOYSA-N 0.000 description 1
- OKRJTQUCTHQWGF-AIBWNMTMSA-N CCOCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CC=C(O)C=C2)CC1 Chemical compound CCOCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CC=C(O)C=C2)CC1 OKRJTQUCTHQWGF-AIBWNMTMSA-N 0.000 description 1
- CHMJCAMNEOZYHI-WPZCJLIBSA-N CC[C@@H](N)C(=O)N1CCC(C(C)CC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound CC[C@@H](N)C(=O)N1CCC(C(C)CC(=O)C2=NOC(C3CC3)=C2)CC1 CHMJCAMNEOZYHI-WPZCJLIBSA-N 0.000 description 1
- WKZKUJOKBVYNKV-UHFFFAOYSA-N CCc1cc(C(NC(C2CCNCC2)c(cccc2)c2Cl)=O)n[o]1 Chemical compound CCc1cc(C(NC(C2CCNCC2)c(cccc2)c2Cl)=O)n[o]1 WKZKUJOKBVYNKV-UHFFFAOYSA-N 0.000 description 1
- OWVUBUVKOPDCHH-UHFFFAOYSA-N CCc1cc(C(NC(C2CCNCC2)c2cc(Cl)ccc2)=O)n[o]1 Chemical compound CCc1cc(C(NC(C2CCNCC2)c2cc(Cl)ccc2)=O)n[o]1 OWVUBUVKOPDCHH-UHFFFAOYSA-N 0.000 description 1
- OKDKVIISFKLDGC-UHFFFAOYSA-N CN(C(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1)C1=CC=CN=C1 Chemical compound CN(C(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1)C1=CC=CN=C1 OKDKVIISFKLDGC-UHFFFAOYSA-N 0.000 description 1
- QLNOEDFSNPVDPO-UHFFFAOYSA-N CN(C)C1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)C=N1 Chemical compound CN(C)C1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)C=N1 QLNOEDFSNPVDPO-UHFFFAOYSA-N 0.000 description 1
- RSHUQQZOXYHSRN-UHFFFAOYSA-N CN(C)CCCNC(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 Chemical compound CN(C)CCCNC(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 RSHUQQZOXYHSRN-UHFFFAOYSA-N 0.000 description 1
- PIWPVPFHOLCMDI-UHFFFAOYSA-N CN(CCCO)C(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 Chemical compound CN(CCCO)C(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 PIWPVPFHOLCMDI-UHFFFAOYSA-N 0.000 description 1
- OUFREAILJPJXPD-UHFFFAOYSA-N CN(CCCO)CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 Chemical compound CN(CCCO)CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 OUFREAILJPJXPD-UHFFFAOYSA-N 0.000 description 1
- FKTVDEVQJVEDDL-UHFFFAOYSA-N CN(CCO)CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 Chemical compound CN(CCO)CC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 FKTVDEVQJVEDDL-UHFFFAOYSA-N 0.000 description 1
- MXQQAEZVWQCSKF-UHFFFAOYSA-N CN1C=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)C=N1 Chemical compound CN1C=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)C=N1 MXQQAEZVWQCSKF-UHFFFAOYSA-N 0.000 description 1
- VLJLVHLXTQZYFG-GXTWGEPZSA-N CN1C=CN=C1[C@@H]1CCC[C@H](CC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CN1C=CN=C1[C@@H]1CCC[C@H](CC(=O)C2=NOC(C3CC3)=C2)C1 VLJLVHLXTQZYFG-GXTWGEPZSA-N 0.000 description 1
- VLJLVHLXTQZYFG-JSGCOSHPSA-N CN1C=CN=C1[C@H]1CCC[C@H](CC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CN1C=CN=C1[C@H]1CCC[C@H](CC(=O)C2=NOC(C3CC3)=C2)C1 VLJLVHLXTQZYFG-JSGCOSHPSA-N 0.000 description 1
- WVWGGFLXMLMRDN-UHFFFAOYSA-N CN1CC(C)(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CN1CC(C)(NC(=O)C2=NOC(C3CC3)=C2)C1 WVWGGFLXMLMRDN-UHFFFAOYSA-N 0.000 description 1
- MZPHPBOQYIJTKU-UHFFFAOYSA-N CN1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound CN1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 MZPHPBOQYIJTKU-UHFFFAOYSA-N 0.000 description 1
- ZPGBIIMIMTWXGA-UHFFFAOYSA-N CN1CCC(CC(=O)C(N)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1 Chemical compound CN1CCC(CC(=O)C(N)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1 ZPGBIIMIMTWXGA-UHFFFAOYSA-N 0.000 description 1
- SAPQJPLCYKGIEK-UHFFFAOYSA-N CN1CCC(CNC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound CN1CCC(CNC(=O)C2=NOC(C3CC3)=C2)CC1 SAPQJPLCYKGIEK-UHFFFAOYSA-N 0.000 description 1
- AYIZXESLOJMAGF-INHVJJQHSA-N COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](C)N)CC1 Chemical compound COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](C)N)CC1 AYIZXESLOJMAGF-INHVJJQHSA-N 0.000 description 1
- HRHOFJHWSIXUIM-HSTJUUNISA-N COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CNC3=C2C=CC=C3)CC1 Chemical compound COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CNC3=C2C=CC=C3)CC1 HRHOFJHWSIXUIM-HSTJUUNISA-N 0.000 description 1
- AYIZXESLOJMAGF-MYHCZTBNSA-N COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1 Chemical compound COC(=O)C(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1 AYIZXESLOJMAGF-MYHCZTBNSA-N 0.000 description 1
- ZORBUOUNNKOJAD-UHFFFAOYSA-N COC(=O)C1=CC(C(N)C2CCN(C(=O)OC(C)(C)C)CC2)=CC=C1 Chemical compound COC(=O)C1=CC(C(N)C2CCN(C(=O)OC(C)(C)C)CC2)=CC=C1 ZORBUOUNNKOJAD-UHFFFAOYSA-N 0.000 description 1
- XFIFTUCIIZBHOH-UHFFFAOYSA-N COC(=O)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCN(C(=O)OC(C)(C)C)CC2)=CC=C1 Chemical compound COC(=O)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCN(C(=O)OC(C)(C)C)CC2)=CC=C1 XFIFTUCIIZBHOH-UHFFFAOYSA-N 0.000 description 1
- YSCIRASASHVMMU-UHFFFAOYSA-N COC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1CN Chemical compound COC1=CC(NC(=O)C2=NOC(C3CC3)=C2)=CC=C1CN YSCIRASASHVMMU-UHFFFAOYSA-N 0.000 description 1
- GOZSXCZQQLTUAR-UHFFFAOYSA-N COC1=CC=C(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)C=C1 Chemical compound COC1=CC=C(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)C=C1 GOZSXCZQQLTUAR-UHFFFAOYSA-N 0.000 description 1
- RGOYRAQYTLFPSS-BKRCNDDKSA-N COC1=CC=C(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)C=C1.C[C@H]1CC[C@H](NC(=O)C2=NOC(CCCO)=C2)CC1.NC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=N1.O=C(NC(C(=O)CCC1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1.O=C(NC(C1=CC=CC(CNC2=CC=CC=C2)=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound COC1=CC=C(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)C=C1.C[C@H]1CC[C@H](NC(=O)C2=NOC(CCCO)=C2)CC1.NC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=C2)C=N1.O=C(NC(C(=O)CCC1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1.O=C(NC(C1=CC=CC(CNC2=CC=CC=C2)=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 RGOYRAQYTLFPSS-BKRCNDDKSA-N 0.000 description 1
- WWJLEZPYTCVJGW-UHFFFAOYSA-N COC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)C=N1 Chemical compound COC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)C=N1 WWJLEZPYTCVJGW-UHFFFAOYSA-N 0.000 description 1
- UNIMZQLQZCAMAO-UHFFFAOYSA-N COC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)=C1 Chemical compound COC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C(C)(C)C)=C1 UNIMZQLQZCAMAO-UHFFFAOYSA-N 0.000 description 1
- BBJKRIDRLNJDPJ-UHFFFAOYSA-N COC1=CC=CC=C1CCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 Chemical compound COC1=CC=CC=C1CCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 BBJKRIDRLNJDPJ-UHFFFAOYSA-N 0.000 description 1
- MGEHASGNFGUONO-UHFFFAOYSA-N COCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1 Chemical compound COCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCCCC1 MGEHASGNFGUONO-UHFFFAOYSA-N 0.000 description 1
- LTFAPUXYNBJKIT-ZQRQZVKFSA-N COCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CC=C(O)C=C2)CC1 Chemical compound COCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@@H](N)CC2=CC=C(O)C=C2)CC1 LTFAPUXYNBJKIT-ZQRQZVKFSA-N 0.000 description 1
- RMEAHWCMPMKGHR-VPHXOMNUSA-N COCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1 Chemical compound COCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1 RMEAHWCMPMKGHR-VPHXOMNUSA-N 0.000 description 1
- IKTWNUVGAKCQHT-BSPRKIHWSA-N COCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1.C[C@H](N)C(=O)N1CCC(C(COC2=CC=CC=C2)NC(=O)C2=NOC(C3CC3)=C2)CC1.O=C(NCC1=CC=CN=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NCCCN1CCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound COCC(NC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H](C)N)CC1.C[C@H](N)C(=O)N1CCC(C(COC2=CC=CC=C2)NC(=O)C2=NOC(C3CC3)=C2)CC1.O=C(NCC1=CC=CN=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1.O=C(NCCCN1CCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 IKTWNUVGAKCQHT-BSPRKIHWSA-N 0.000 description 1
- UISMDYBPKVARRS-UHFFFAOYSA-N COCCN1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound COCCN1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 UISMDYBPKVARRS-UHFFFAOYSA-N 0.000 description 1
- ITCQNWXLNZGEHP-UHFFFAOYSA-N CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1 Chemical compound CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1 ITCQNWXLNZGEHP-UHFFFAOYSA-N 0.000 description 1
- PIZZXGNMLWTPOV-UHFFFAOYSA-N CS(=O)(=O)CCNC(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 Chemical compound CS(=O)(=O)CCNC(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 PIZZXGNMLWTPOV-UHFFFAOYSA-N 0.000 description 1
- JWTGVEYGSXQDHB-UHFFFAOYSA-N CS(=O)(=O)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound CS(=O)(=O)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 JWTGVEYGSXQDHB-UHFFFAOYSA-N 0.000 description 1
- NPRLQDFKMPSPCT-YTJLLHSVSA-N C[C@@H](C(N(CC1)CCC1C(C(Nc1ccncc1)=O)NC(c1n[o]c(C2CC2)c1)=O)=O)N Chemical compound C[C@@H](C(N(CC1)CCC1C(C(Nc1ccncc1)=O)NC(c1n[o]c(C2CC2)c1)=O)=O)N NPRLQDFKMPSPCT-YTJLLHSVSA-N 0.000 description 1
- GYCAGHIHASRKBT-VIFPVBQESA-N C[C@@H](C(NCCCCNC(c1n[o]c(C2CC2)c1)=O)=O)N Chemical compound C[C@@H](C(NCCCCNC(c1n[o]c(C2CC2)c1)=O)=O)N GYCAGHIHASRKBT-VIFPVBQESA-N 0.000 description 1
- DEBLILUZNYXYIQ-HNNXBMFYSA-N C[C@@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)CC2CCNCC2)CC1 Chemical compound C[C@@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)CC2CCNCC2)CC1 DEBLILUZNYXYIQ-HNNXBMFYSA-N 0.000 description 1
- RHZQHWPNFZGTPO-ZDUSSCGKSA-N C[C@@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)CCCN)CC1 Chemical compound C[C@@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)CCCN)CC1 RHZQHWPNFZGTPO-ZDUSSCGKSA-N 0.000 description 1
- ZNLZHJKGQZDBTK-WBAXXEDZSA-N C[C@@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H]2CC[C@H](N)CC2)CC1 Chemical compound C[C@@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H]2CC[C@H](N)CC2)CC1 ZNLZHJKGQZDBTK-WBAXXEDZSA-N 0.000 description 1
- VIPVGQAHJAMLQW-BONVTDFDSA-N C[C@@H](C[C@H](O)C1=CC=C(F)C=C1)NC(=O)C1=NOC(C2CC2)=C1 Chemical compound C[C@@H](C[C@H](O)C1=CC=C(F)C=C1)NC(=O)C1=NOC(C2CC2)=C1 VIPVGQAHJAMLQW-BONVTDFDSA-N 0.000 description 1
- YFWHBGUJNPFCJB-SNVBAGLBSA-N C[C@@H](N)C(=O)CCCCCNC(=O)C1=NOC(C2CC2)=C1 Chemical compound C[C@@H](N)C(=O)CCCCCNC(=O)C1=NOC(C2CC2)=C1 YFWHBGUJNPFCJB-SNVBAGLBSA-N 0.000 description 1
- INXRWZHHZGRSAZ-SMFUYQKNSA-N C[C@@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC(C(=O)NC3=CC=CN=C3)=C2)CC1 Chemical compound C[C@@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC(C(=O)NC3=CC=CN=C3)=C2)CC1 INXRWZHHZGRSAZ-SMFUYQKNSA-N 0.000 description 1
- JKOZWPURDARCIT-QMRFKDRMSA-N C[C@@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound C[C@@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 JKOZWPURDARCIT-QMRFKDRMSA-N 0.000 description 1
- FNFADEMDVDYJKT-LLVKDONJSA-N C[C@@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound C[C@@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 FNFADEMDVDYJKT-LLVKDONJSA-N 0.000 description 1
- ATTXVGQZCOMGBO-ZJUUUORDSA-N C[C@@H](N)C(=O)N1CC[C@@H](CNC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound C[C@@H](N)C(=O)N1CC[C@@H](CNC(=O)C2=NOC(C3CC3)=C2)C1 ATTXVGQZCOMGBO-ZJUUUORDSA-N 0.000 description 1
- ATTXVGQZCOMGBO-NXEZZACHSA-N C[C@@H](N)C(=O)N1CC[C@H](CNC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound C[C@@H](N)C(=O)N1CC[C@H](CNC(=O)C2=NOC(C3CC3)=C2)C1 ATTXVGQZCOMGBO-NXEZZACHSA-N 0.000 description 1
- VVDZIJVQUBECDD-GFCCVEGCSA-N C[C@@H](N)CC(=O)CCC1(CNC(=O)C2=NOC(C3CC3)=C2)CCC1 Chemical compound C[C@@H](N)CC(=O)CCC1(CNC(=O)C2=NOC(C3CC3)=C2)CCC1 VVDZIJVQUBECDD-GFCCVEGCSA-N 0.000 description 1
- OYXQBAVCTJVIQE-LMWIKNPDSA-N C[C@@H](N)CC(=O)NC1CCC2CC1CCC2CC(=O)C1=NOC(C2CC2)=C1 Chemical compound C[C@@H](N)CC(=O)NC1CCC2CC1CCC2CC(=O)C1=NOC(C2CC2)=C1 OYXQBAVCTJVIQE-LMWIKNPDSA-N 0.000 description 1
- ATCJDSKAWSNOSL-GFCCVEGCSA-N C[C@@H](NC(=O)C1=NOC(C2CC2)=C1)C1CCN(S(=O)(=O)CCCN)CC1 Chemical compound C[C@@H](NC(=O)C1=NOC(C2CC2)=C1)C1CCN(S(=O)(=O)CCCN)CC1 ATCJDSKAWSNOSL-GFCCVEGCSA-N 0.000 description 1
- DEBLILUZNYXYIQ-OAHLLOKOSA-N C[C@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)CC2CCNCC2)CC1 Chemical compound C[C@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)CC2CCNCC2)CC1 DEBLILUZNYXYIQ-OAHLLOKOSA-N 0.000 description 1
- RHZQHWPNFZGTPO-CYBMUJFWSA-N C[C@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)CCCN)CC1 Chemical compound C[C@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)CCCN)CC1 RHZQHWPNFZGTPO-CYBMUJFWSA-N 0.000 description 1
- ZNLZHJKGQZDBTK-ZTFGCOKTSA-N C[C@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H]2CC[C@H](N)CC2)CC1 Chemical compound C[C@H](CC(=O)C1=NOC(C2CC2)=C1)C1CCN(C(=O)[C@H]2CC[C@H](N)CC2)CC1 ZNLZHJKGQZDBTK-ZTFGCOKTSA-N 0.000 description 1
- UVSYXLAVQDKRRI-XLLULAGJSA-N C[C@H](N)C(=O)N1CCC(C(CO)NC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC(C(CO)NC(=O)C2=NOC(C3CC3)=C2)CC1 UVSYXLAVQDKRRI-XLLULAGJSA-N 0.000 description 1
- WORSLKKLGQHAEC-YXWRBFHGSA-N C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CC2=CC=CC=N2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CC2=CC=CC=N2)CC1 WORSLKKLGQHAEC-YXWRBFHGSA-N 0.000 description 1
- LPLRPNHGNCIQQY-YXWRBFHGSA-N C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CC2=CC=CN=C2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CC2=CC=CN=C2)CC1 LPLRPNHGNCIQQY-YXWRBFHGSA-N 0.000 description 1
- SIKPKERGKGBSCZ-YXWRBFHGSA-N C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CC2=CC=NC=C2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CC2=CC=NC=C2)CC1 SIKPKERGKGBSCZ-YXWRBFHGSA-N 0.000 description 1
- RQZGQXPOWFWOGV-NGMICRHFSA-N C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CCC2=CC=CC=C2O)CC1 Chemical compound C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CCC2=CC=CC=C2O)CC1 RQZGQXPOWFWOGV-NGMICRHFSA-N 0.000 description 1
- RSAGJULYTCJUBN-UEDXYCIISA-N C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CCC2=CC=CC=N2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CCC2=CC=CC=N2)CC1 RSAGJULYTCJUBN-UEDXYCIISA-N 0.000 description 1
- JPXFHEXXIMQPFK-UEDXYCIISA-N C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CCC2=CC=CN=C2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CCC2=CC=CN=C2)CC1 JPXFHEXXIMQPFK-UEDXYCIISA-N 0.000 description 1
- BQADLVBKZMFZRG-UEDXYCIISA-N C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CCC2=CC=NC=C2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C(=O)CCC2=CC=NC=C2)CC1 BQADLVBKZMFZRG-UEDXYCIISA-N 0.000 description 1
- NQLHQLSVBOFBBV-LBPRGKRZSA-N C[C@H](N)C(=O)N1CCC(C)(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC(C)(CCC(=O)C2=NOC(C3CC3)=C2)CC1 NQLHQLSVBOFBBV-LBPRGKRZSA-N 0.000 description 1
- FNFADEMDVDYJKT-NSHDSACASA-N C[C@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 FNFADEMDVDYJKT-NSHDSACASA-N 0.000 description 1
- LFNRMVIIPFVSHF-NSHDSACASA-N C[C@H](N)C(=O)N1CCC(F)(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC(F)(CCC(=O)C2=NOC(C3CC3)=C2)CC1 LFNRMVIIPFVSHF-NSHDSACASA-N 0.000 description 1
- YPODMOGJKUPQBP-NSHDSACASA-N C[C@H](N)C(=O)N1CCC(O)(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound C[C@H](N)C(=O)N1CCC(O)(CCC(=O)C2=NOC(C3CC3)=C2)CC1 YPODMOGJKUPQBP-NSHDSACASA-N 0.000 description 1
- YYVRDYMBAHPKHQ-HFXJSBIESA-N C[C@H](N)C(=O)N1CCC([C@@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.C[C@H](N)C(=O)N1CCC([C@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.Cl.Cl Chemical compound C[C@H](N)C(=O)N1CCC([C@@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.C[C@H](N)C(=O)N1CCC([C@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.Cl.Cl YYVRDYMBAHPKHQ-HFXJSBIESA-N 0.000 description 1
- ATTXVGQZCOMGBO-UWVGGRQHSA-N C[C@H](N)C(=O)N1CC[C@@H](CNC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound C[C@H](N)C(=O)N1CC[C@@H](CNC(=O)C2=NOC(C3CC3)=C2)C1 ATTXVGQZCOMGBO-UWVGGRQHSA-N 0.000 description 1
- ATTXVGQZCOMGBO-VHSXEESVSA-N C[C@H](N)C(=O)N1CC[C@H](CNC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound C[C@H](N)C(=O)N1CC[C@H](CNC(=O)C2=NOC(C3CC3)=C2)C1 ATTXVGQZCOMGBO-VHSXEESVSA-N 0.000 description 1
- OYXQBAVCTJVIQE-NICGVCSZSA-N C[C@H](N)CC(=O)NC1CCC2CC1CCC2CC(=O)C1=NOC(C2CC2)=C1 Chemical compound C[C@H](N)CC(=O)NC1CCC2CC1CCC2CC(=O)C1=NOC(C2CC2)=C1 OYXQBAVCTJVIQE-NICGVCSZSA-N 0.000 description 1
- PAAHUBCPWWJXDC-JTQLQIEISA-N C[C@H](N)CC(=O)NCC(C)(C)CNC(=O)C1=NOC(C2CC2)=C1 Chemical compound C[C@H](N)CC(=O)NCC(C)(C)CNC(=O)C1=NOC(C2CC2)=C1 PAAHUBCPWWJXDC-JTQLQIEISA-N 0.000 description 1
- ATCJDSKAWSNOSL-LBPRGKRZSA-N C[C@H](NC(=O)C1=NOC(C2CC2)=C1)C1CCN(S(=O)(=O)CCCN)CC1 Chemical compound C[C@H](NC(=O)C1=NOC(C2CC2)=C1)C1CCN(S(=O)(=O)CCCN)CC1 ATCJDSKAWSNOSL-LBPRGKRZSA-N 0.000 description 1
- YVXXCIUOJACKFB-ZDUSSCGKSA-N C[C@H](NC(=O)OC(C)(C)C)C(=O)CCCCCNC(=O)C1=NOC(C2CC2)=C1 Chemical compound C[C@H](NC(=O)OC(C)(C)C)C(=O)CCCCCNC(=O)C1=NOC(C2CC2)=C1 YVXXCIUOJACKFB-ZDUSSCGKSA-N 0.000 description 1
- CSJMOPOHDWHGOB-BBTNROMNSA-N C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC([C@@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC([C@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC([C@@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1.C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC([C@H](NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 CSJMOPOHDWHGOB-BBTNROMNSA-N 0.000 description 1
- HEFLINOKSRELGB-UHFFFAOYSA-N Cc1cc(CN)ccc1NC(c1n[o]c(C2CC2)c1)=O Chemical compound Cc1cc(CN)ccc1NC(c1n[o]c(C2CC2)c1)=O HEFLINOKSRELGB-UHFFFAOYSA-N 0.000 description 1
- UJYRDBODNJXCLS-UHFFFAOYSA-N N#CC1=CC=C(NC(=O)C2=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=CC=C2)C=N1 Chemical compound N#CC1=CC=C(NC(=O)C2=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCCCC3)=CC=C2)C=N1 UJYRDBODNJXCLS-UHFFFAOYSA-N 0.000 description 1
- YTJBLJKRUFTXIQ-UHFFFAOYSA-N N#Cc(nc1)ccc1NC(c1cccc(C(C2CCNCC2)NC(c2n[o]c(C3CC3)c2)=O)c1)=O Chemical compound N#Cc(nc1)ccc1NC(c1cccc(C(C2CCNCC2)NC(c2n[o]c(C3CC3)c2)=O)c1)=O YTJBLJKRUFTXIQ-UHFFFAOYSA-N 0.000 description 1
- SPAXZTSKFUTDLB-UHFFFAOYSA-N NC(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 Chemical compound NC(=O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 SPAXZTSKFUTDLB-UHFFFAOYSA-N 0.000 description 1
- PTKXPMRBKFCAQS-UHFFFAOYSA-N NC(=O)C1=CN=CC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)=C1 Chemical compound NC(=O)C1=CN=CC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)=C1 PTKXPMRBKFCAQS-UHFFFAOYSA-N 0.000 description 1
- BOAIUUSKRARYPU-UHFFFAOYSA-N NC(CC1)CCC1NS(c(cc1)ccc1NC(c1n[o]c(C2CC2)c1)=O)(=O)=O Chemical compound NC(CC1)CCC1NS(c(cc1)ccc1NC(c1n[o]c(C2CC2)c1)=O)(=O)=O BOAIUUSKRARYPU-UHFFFAOYSA-N 0.000 description 1
- PAJMNMCLJISWMW-UHFFFAOYSA-N NC(CCC1=CC=CC=C1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NC(CCC1=CC=CC=C1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 PAJMNMCLJISWMW-UHFFFAOYSA-N 0.000 description 1
- KKAFBSRZBHULKP-UHFFFAOYSA-N NC(CCC1=CC=CC=N1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NC(CCC1=CC=CC=N1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 KKAFBSRZBHULKP-UHFFFAOYSA-N 0.000 description 1
- FBCUMRISQMLRJD-UHFFFAOYSA-N NC(CCCO)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NC(CCCO)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 FBCUMRISQMLRJD-UHFFFAOYSA-N 0.000 description 1
- SUZKKMZDFBPNCV-UHFFFAOYSA-N NC1=CC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)=CC=N1 Chemical compound NC1=CC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)=CC=N1 SUZKKMZDFBPNCV-UHFFFAOYSA-N 0.000 description 1
- SIYNLBZDIPKGFV-UHFFFAOYSA-N NC1=CC=C(C(=O)CCC2=CN=CC=C2)C=C1 Chemical compound NC1=CC=C(C(=O)CCC2=CN=CC=C2)C=C1 SIYNLBZDIPKGFV-UHFFFAOYSA-N 0.000 description 1
- PSCYPGQTINJSLS-UHFFFAOYSA-N NC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)C=N1 Chemical compound NC1=CC=C(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)C=N1 PSCYPGQTINJSLS-UHFFFAOYSA-N 0.000 description 1
- CJWXFELEZOIJKM-UHFFFAOYSA-N NC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 CJWXFELEZOIJKM-UHFFFAOYSA-N 0.000 description 1
- ROUMQTQTWLBHFJ-UHFFFAOYSA-N NC1=CC=NC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)=C1 Chemical compound NC1=CC=NC(NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)=C1 ROUMQTQTWLBHFJ-UHFFFAOYSA-N 0.000 description 1
- HKEANCAJPJFRIL-UHFFFAOYSA-N NC1CC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)C1 Chemical compound NC1CC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)C1 HKEANCAJPJFRIL-UHFFFAOYSA-N 0.000 description 1
- FQAGAJKMDHMTNF-UHFFFAOYSA-N NC1CC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)C1 Chemical compound NC1CC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)C1 FQAGAJKMDHMTNF-UHFFFAOYSA-N 0.000 description 1
- QGMJRJGFKJOISX-UHFFFAOYSA-N NC1CC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)C1 Chemical compound NC1CC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)C1 QGMJRJGFKJOISX-UHFFFAOYSA-N 0.000 description 1
- RNFOYMCRWYOKTH-UHFFFAOYSA-N NC1CCC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)C1 Chemical compound NC1CCC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)C1 RNFOYMCRWYOKTH-UHFFFAOYSA-N 0.000 description 1
- QVZJODRRYGSSTI-UHFFFAOYSA-N NC1CCC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1 Chemical compound NC1CCC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1 QVZJODRRYGSSTI-UHFFFAOYSA-N 0.000 description 1
- XACRWSNBACEBTC-UHFFFAOYSA-N NC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)CC1 Chemical compound NC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C(Br)=C2)CC1 XACRWSNBACEBTC-UHFFFAOYSA-N 0.000 description 1
- WIYUDJQMERSWHW-UHFFFAOYSA-N NC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)C1 Chemical compound NC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)C1 WIYUDJQMERSWHW-UHFFFAOYSA-N 0.000 description 1
- ANQYTTMOFBDHGQ-UHFFFAOYSA-N NC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)CC1 Chemical compound NC1CCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)CC1 ANQYTTMOFBDHGQ-UHFFFAOYSA-N 0.000 description 1
- ZLASPSJALPMJKK-UHFFFAOYSA-N NC1CCC2CC1CCC2N Chemical compound NC1CCC2CC1CCC2N ZLASPSJALPMJKK-UHFFFAOYSA-N 0.000 description 1
- BTOZELMMYZAUGN-UHFFFAOYSA-N NC1CCC2CC1CCC2NC(=O)C1=NOC(C2CC2)=C1 Chemical compound NC1CCC2CC1CCC2NC(=O)C1=NOC(C2CC2)=C1 BTOZELMMYZAUGN-UHFFFAOYSA-N 0.000 description 1
- MOMWAHBGXRPBAU-UHFFFAOYSA-N NC1CCCC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)C1 Chemical compound NC1CCCC(CS(=O)(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)C1 MOMWAHBGXRPBAU-UHFFFAOYSA-N 0.000 description 1
- UUWWIEQQYHTRTF-UHFFFAOYSA-N NC1CCCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)C1 Chemical compound NC1CCCC(NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2Br)C1 UUWWIEQQYHTRTF-UHFFFAOYSA-N 0.000 description 1
- AIKZVBNAKBHGHW-UHFFFAOYSA-N NCC(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound NCC(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 AIKZVBNAKBHGHW-UHFFFAOYSA-N 0.000 description 1
- CSBJMYQTQMSAFC-UHFFFAOYSA-N NCC(=O)N1CCCC(CC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound NCC(=O)N1CCCC(CC(=O)C2=NOC(C3CC3)=C2)C1 CSBJMYQTQMSAFC-UHFFFAOYSA-N 0.000 description 1
- ZCCBAPXFGRMJTM-UHFFFAOYSA-N NCC(=O)NC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NCC(=O)NC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C=C1 ZCCBAPXFGRMJTM-UHFFFAOYSA-N 0.000 description 1
- SZJHWVAVIWBULF-UHFFFAOYSA-N NCC(=O)NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NCC(=O)NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 SZJHWVAVIWBULF-UHFFFAOYSA-N 0.000 description 1
- NSLOABPUAPAIPG-UHFFFAOYSA-N NCC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C(Cl)=C1 Chemical compound NCC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C(Cl)=C1 NSLOABPUAPAIPG-UHFFFAOYSA-N 0.000 description 1
- AYYDVXFRLVVFLT-UHFFFAOYSA-N NCC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C(I)=C1 Chemical compound NCC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C(I)=C1 AYYDVXFRLVVFLT-UHFFFAOYSA-N 0.000 description 1
- PGNZUVNMKGMBKN-UHFFFAOYSA-N NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(CO)=C1 Chemical compound NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(CO)=C1 PGNZUVNMKGMBKN-UHFFFAOYSA-N 0.000 description 1
- QVYALQAMNUEDKX-UHFFFAOYSA-N NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 QVYALQAMNUEDKX-UHFFFAOYSA-N 0.000 description 1
- FPKXGEGCCMQGSK-UHFFFAOYSA-N NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1CO Chemical compound NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1CO FPKXGEGCCMQGSK-UHFFFAOYSA-N 0.000 description 1
- QVPWWVYLCWOPFJ-UHFFFAOYSA-N NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Cl Chemical compound NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Cl QVPWWVYLCWOPFJ-UHFFFAOYSA-N 0.000 description 1
- PAGWZOYUGAHEKH-UHFFFAOYSA-N NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)N=C1 Chemical compound NCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)N=C1 PAGWZOYUGAHEKH-UHFFFAOYSA-N 0.000 description 1
- RRWZIKFIPYMHOF-UHFFFAOYSA-N NCCC(=O)N1CCCC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound NCCC(=O)N1CCCC(NC(=O)C2=NOC(C3CC3)=C2)C1 RRWZIKFIPYMHOF-UHFFFAOYSA-N 0.000 description 1
- QMTDTAFOAIDCKH-UHFFFAOYSA-N NCCC(=O)NC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NCCC(=O)NC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C=C1 QMTDTAFOAIDCKH-UHFFFAOYSA-N 0.000 description 1
- JJZZGEAFUPELDS-UHFFFAOYSA-N NCCC(=O)NC1CCC2CC1CCC2CC(=O)C1=NOC(C2CC2)=C1 Chemical compound NCCC(=O)NC1CCC2CC1CCC2CC(=O)C1=NOC(C2CC2)=C1 JJZZGEAFUPELDS-UHFFFAOYSA-N 0.000 description 1
- LMWGVUKCNKWEED-UHFFFAOYSA-N NCCC(=O)NC1CCCC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound NCCC(=O)NC1CCCC(NC(=O)C2=NOC(C3CC3)=C2)C1 LMWGVUKCNKWEED-UHFFFAOYSA-N 0.000 description 1
- LHYAZLBDVNIECA-UHFFFAOYSA-N NCCC(=O)NCC1(CNC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound NCCC(=O)NCC1(CNC(=O)C2=NOC(C3CC3)=C2)CC1 LHYAZLBDVNIECA-UHFFFAOYSA-N 0.000 description 1
- AATUOMMDBIIRRL-UHFFFAOYSA-N NCCC(=O)NCCC(CO)NC(=O)C1=NOC(C2CC2)=C1 Chemical compound NCCC(=O)NCCC(CO)NC(=O)C1=NOC(C2CC2)=C1 AATUOMMDBIIRRL-UHFFFAOYSA-N 0.000 description 1
- BOFPTWBGJJSEHM-YVTDUHFPSA-N NCCC(=O)N[C@H]1CC2(C[C@@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1 Chemical compound NCCC(=O)N[C@H]1CC2(C[C@@H](CC(=O)C3=NOC(C4CC4)=C3)C2)C1 BOFPTWBGJJSEHM-YVTDUHFPSA-N 0.000 description 1
- KKKHEELWKHBGOT-AULYBMBSSA-N NCCC(=O)O[C@H]1CC[C@H](CC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound NCCC(=O)O[C@H]1CC[C@H](CC(=O)C2=NOC(C3CC3)=C2)CC1 KKKHEELWKHBGOT-AULYBMBSSA-N 0.000 description 1
- MFMWSGMODXYPFU-UHFFFAOYSA-N NCCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NCCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 MFMWSGMODXYPFU-UHFFFAOYSA-N 0.000 description 1
- VMOGALXSWVRSRP-UHFFFAOYSA-N NCCCC(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1 Chemical compound NCCCC(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1 VMOGALXSWVRSRP-UHFFFAOYSA-N 0.000 description 1
- MZMGWXRUHXCTOQ-UHFFFAOYSA-N NCCCC(=O)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound NCCCC(=O)N1CC(NC(=O)C2=NOC(C3CC3)=C2)C1 MZMGWXRUHXCTOQ-UHFFFAOYSA-N 0.000 description 1
- YSRMCYWNQLOJIP-UHFFFAOYSA-N NCCCC(=O)N1CCCC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound NCCCC(=O)N1CCCC(NC(=O)C2=NOC(C3CC3)=C2)C1 YSRMCYWNQLOJIP-UHFFFAOYSA-N 0.000 description 1
- IXCDRGZUMYUSNQ-UHFFFAOYSA-N NCCCC(=O)NC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NCCCC(=O)NC1=CC=C(CC(=O)C2=NOC(C3CC3)=C2)C=C1 IXCDRGZUMYUSNQ-UHFFFAOYSA-N 0.000 description 1
- QNAUIKFDKFVPQP-UHFFFAOYSA-N NCCCC(=O)NC1CCCC(NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound NCCCC(=O)NC1CCCC(NC(=O)C2=NOC(C3CC3)=C2)C1 QNAUIKFDKFVPQP-UHFFFAOYSA-N 0.000 description 1
- QMLFHTSMWAWBFD-UHFFFAOYSA-N NCCCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NCCCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 QMLFHTSMWAWBFD-UHFFFAOYSA-N 0.000 description 1
- BVRDKKNCGNUNJW-UHFFFAOYSA-N NCCCCC(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1 Chemical compound NCCCCC(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1 BVRDKKNCGNUNJW-UHFFFAOYSA-N 0.000 description 1
- KLRXTOCNTLIDIT-UHFFFAOYSA-N NCCCCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NCCCCC1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 KLRXTOCNTLIDIT-UHFFFAOYSA-N 0.000 description 1
- JDQAWJVDXYCIPB-UHFFFAOYSA-N NCCCCS(=O)(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound NCCCCS(=O)(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 JDQAWJVDXYCIPB-UHFFFAOYSA-N 0.000 description 1
- DAIPOMJSRFYTCI-YPMHNXCESA-N NCCCC[C@H](CC(=O)[C@H](CO)NC(=O)C1=NOC(C2CC2)=C1)C(N)=O Chemical compound NCCCC[C@H](CC(=O)[C@H](CO)NC(=O)C1=NOC(C2CC2)=C1)C(N)=O DAIPOMJSRFYTCI-YPMHNXCESA-N 0.000 description 1
- HSJVKAYIEBECQK-UHFFFAOYSA-N NCCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br Chemical compound NCCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br HSJVKAYIEBECQK-UHFFFAOYSA-N 0.000 description 1
- OYQYJZDSVKIHPX-JOCQHMNTSA-N NCCCNC(=O)[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound NCCCNC(=O)[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2)CC1 OYQYJZDSVKIHPX-JOCQHMNTSA-N 0.000 description 1
- GTKGSPCCUPDBKW-UHFFFAOYSA-N NCCCNS(=O)(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1 Chemical compound NCCCNS(=O)(=O)C1=CC=CC(NC(=O)C2=NOC(C3CC3)=C2)=C1 GTKGSPCCUPDBKW-UHFFFAOYSA-N 0.000 description 1
- OCQAFSUMAAEREM-UHFFFAOYSA-N NCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1 Chemical compound NCCNC(=O)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1 OCQAFSUMAAEREM-UHFFFAOYSA-N 0.000 description 1
- VTQDTCPYGPRRMH-HAQNSBGRSA-N NCCNC(=O)[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound NCCNC(=O)[C@H]1CC[C@H](NC(=O)C2=NOC(C3CC3)=C2)CC1 VTQDTCPYGPRRMH-HAQNSBGRSA-N 0.000 description 1
- UIEFCOHSDDJLIH-UHFFFAOYSA-N NCCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 Chemical compound NCCOCC1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 UIEFCOHSDDJLIH-UHFFFAOYSA-N 0.000 description 1
- DMWQMAUQLFIOCT-LROBGIAVSA-N N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(C(CO)NC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(C(CO)NC(=O)C2=NOC(C3CC3)=C2)CC1 DMWQMAUQLFIOCT-LROBGIAVSA-N 0.000 description 1
- IGPGCMYGNHCSOQ-QSAPEBAKSA-N N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(C(COC2=CC=CC=C2)NC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(C(COC2=CC=CC=C2)NC(=O)C2=NOC(C3CC3)=C2)CC1 IGPGCMYGNHCSOQ-QSAPEBAKSA-N 0.000 description 1
- STSGTEUSWRZNDN-ZZHFZYNASA-N N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 STSGTEUSWRZNDN-ZZHFZYNASA-N 0.000 description 1
- WZYVKCUTEDTQDM-IBGZPJMESA-N N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 WZYVKCUTEDTQDM-IBGZPJMESA-N 0.000 description 1
- GCBOFBCOXXMTTF-QUWDGAPNSA-N N[C@@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound N[C@@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 GCBOFBCOXXMTTF-QUWDGAPNSA-N 0.000 description 1
- WJZLGQMKGSQTHA-QFIPXVFZSA-N N[C@@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound N[C@@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 WJZLGQMKGSQTHA-QFIPXVFZSA-N 0.000 description 1
- NMSBHLWAYZOSNY-DIMJTDRSSA-N N[C@@H](CO)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound N[C@@H](CO)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 NMSBHLWAYZOSNY-DIMJTDRSSA-N 0.000 description 1
- SMWUXBRSKUHRAC-ZDUSSCGKSA-N N[C@@H](CO)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound N[C@@H](CO)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 SMWUXBRSKUHRAC-ZDUSSCGKSA-N 0.000 description 1
- WZYVKCUTEDTQDM-LJQANCHMSA-N N[C@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound N[C@H](CC1=CC=C(O)C=C1)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 WZYVKCUTEDTQDM-LJQANCHMSA-N 0.000 description 1
- GCBOFBCOXXMTTF-QZWVJJBASA-N N[C@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound N[C@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 GCBOFBCOXXMTTF-QZWVJJBASA-N 0.000 description 1
- WJZLGQMKGSQTHA-JOCHJYFZSA-N N[C@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound N[C@H](CC1=CCC2=C1C=CC=C2)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 WJZLGQMKGSQTHA-JOCHJYFZSA-N 0.000 description 1
- SMWUXBRSKUHRAC-CYBMUJFWSA-N N[C@H](CO)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 Chemical compound N[C@H](CO)C(=O)N1CCC(CCC(=O)C2=NOC(C3CC3)=C2)CC1 SMWUXBRSKUHRAC-CYBMUJFWSA-N 0.000 description 1
- LHLHHGMJMDBSAV-MCPYQZEQSA-N N[C@H]1CC[C@@H](C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound N[C@H]1CC[C@@H](C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 LHLHHGMJMDBSAV-MCPYQZEQSA-N 0.000 description 1
- AMRPKXQSIWGNJH-FZNQNYSPSA-N N[C@H]1CC[C@@H](NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1 Chemical compound N[C@H]1CC[C@@H](NC(=O)C2=CC=C(NC(=O)C3=NOC(C4CC4)=C3)C=C2)CC1 AMRPKXQSIWGNJH-FZNQNYSPSA-N 0.000 description 1
- GGFSDDBGAISXJV-HAQNSBGRSA-N N[C@H]1CC[C@H](C(=O)N2CC(NC(=O)C3=NOC(C4CC4)=C3)C2)CC1 Chemical compound N[C@H]1CC[C@H](C(=O)N2CC(NC(=O)C3=NOC(C4CC4)=C3)C2)CC1 GGFSDDBGAISXJV-HAQNSBGRSA-N 0.000 description 1
- LHLHHGMJMDBSAV-DBTMUERSSA-N N[C@H]1CC[C@H](C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 Chemical compound N[C@H]1CC[C@H](C(NC(=O)C2=NOC(C3CC3)=C2)C2=CC=CC=C2)CC1 LHLHHGMJMDBSAV-DBTMUERSSA-N 0.000 description 1
- BVTAHYUBQZPDAU-JDVJWJCPSA-N N[C@H]1CC[C@H](NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)CC1 Chemical compound N[C@H]1CC[C@H](NC(=O)C2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)CC1 BVTAHYUBQZPDAU-JDVJWJCPSA-N 0.000 description 1
- LTACNKSBJBHOSE-LJGSYFOKSA-N N[C@H]1CC[C@H](NC(=O)C2=NOC(C(F)F)=C2)CC1 Chemical compound N[C@H]1CC[C@H](NC(=O)C2=NOC(C(F)F)=C2)CC1 LTACNKSBJBHOSE-LJGSYFOKSA-N 0.000 description 1
- RGWLRHCDZFHBSK-RFJGZHNSSA-N N[C@H]1CC[C@H](OCC2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)CC1 Chemical compound N[C@H]1CC[C@H](OCC2=CC=CC(C(NC(=O)C3=NOC(C4CC4)=C3)C3CCNCC3)=C2)CC1 RGWLRHCDZFHBSK-RFJGZHNSSA-N 0.000 description 1
- LNGIHXMXVZVDQN-ZKCHVHJHSA-N N[C@H]1C[C@H](NC(=O)C2=NOC(C3CC3)=C2)C1 Chemical compound N[C@H]1C[C@H](NC(=O)C2=NOC(C3CC3)=C2)C1 LNGIHXMXVZVDQN-ZKCHVHJHSA-N 0.000 description 1
- TYBFSIGYUKKGAJ-UHFFFAOYSA-N O=C(C(C1CCNCC1)NC(c1n[o]c(C2CC2)c1)=O)NCc1cccnc1 Chemical compound O=C(C(C1CCNCC1)NC(c1n[o]c(C2CC2)c1)=O)NCc1cccnc1 TYBFSIGYUKKGAJ-UHFFFAOYSA-N 0.000 description 1
- STFCNICFHIFEIB-UHFFFAOYSA-N O=C(C(C1CCNCC1)NC(c1n[o]c(C2CC2)c1)=O)Nc1cccnc1 Chemical compound O=C(C(C1CCNCC1)NC(c1n[o]c(C2CC2)c1)=O)Nc1cccnc1 STFCNICFHIFEIB-UHFFFAOYSA-N 0.000 description 1
- OUQIQEATIZDNKF-UHFFFAOYSA-N O=C(CC1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1)C1=CC=CN=C1 Chemical compound O=C(CC1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1)C1=CC=CN=C1 OUQIQEATIZDNKF-UHFFFAOYSA-N 0.000 description 1
- MNGUXYJTLSKEAD-UHFFFAOYSA-N O=C(CC1=CC=NC=C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(CC1=CC=NC=C1)C1=NOC(C2CC2)=C1 MNGUXYJTLSKEAD-UHFFFAOYSA-N 0.000 description 1
- MFINWDDFVCVRPE-UHFFFAOYSA-N O=C(CC1=CN=CC=C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(CC1=CN=CC=C1)C1=NOC(C2CC2)=C1 MFINWDDFVCVRPE-UHFFFAOYSA-N 0.000 description 1
- YGQOVVKWSYQKGJ-UHFFFAOYSA-N O=C(CC1CCC2=CC(O)=CC=C2C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(CC1CCC2=CC(O)=CC=C2C1)C1=NOC(C2CC2)=C1 YGQOVVKWSYQKGJ-UHFFFAOYSA-N 0.000 description 1
- QKHCWUXHZJUZOP-UHFFFAOYSA-N O=C(CC1CCCN(CC2=CC=CC=C2)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(CC1CCCN(CC2=CC=CC=C2)C1)C1=NOC(C2CC2)=C1 QKHCWUXHZJUZOP-UHFFFAOYSA-N 0.000 description 1
- JASUHGDWTVJZLN-UHFFFAOYSA-N O=C(CC1CCOC(C2=CC=C(F)C=C2)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(CC1CCOC(C2=CC=C(F)C=C2)C1)C1=NOC(C2CC2)=C1 JASUHGDWTVJZLN-UHFFFAOYSA-N 0.000 description 1
- XAQIDPCCAFYPBH-UHFFFAOYSA-N O=C(CC1CN(CCC2=CC=CC=C2)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(CC1CN(CCC2=CC=CC=C2)C1)C1=NOC(C2CC2)=C1 XAQIDPCCAFYPBH-UHFFFAOYSA-N 0.000 description 1
- RQCKFLJINHSOFB-UHFFFAOYSA-N O=C(CCC1=CN=CC=C1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound O=C(CCC1=CN=CC=C1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 RQCKFLJINHSOFB-UHFFFAOYSA-N 0.000 description 1
- NQCWOLLRHQWAGJ-SMDDNHRTSA-N O=C(C[C@H]1CCC[C@@H](C2CC2)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(C[C@H]1CCC[C@@H](C2CC2)C1)C1=NOC(C2CC2)=C1 NQCWOLLRHQWAGJ-SMDDNHRTSA-N 0.000 description 1
- NQCWOLLRHQWAGJ-FZMZJTMJSA-N O=C(C[C@H]1CCC[C@H](C2CC2)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(C[C@H]1CCC[C@H](C2CC2)C1)C1=NOC(C2CC2)=C1 NQCWOLLRHQWAGJ-FZMZJTMJSA-N 0.000 description 1
- WBXZKRXYZLOYAU-UHFFFAOYSA-N O=C(Cl)C1=NOC(C2CC2)=C1 Chemical compound O=C(Cl)C1=NOC(C2CC2)=C1 WBXZKRXYZLOYAU-UHFFFAOYSA-N 0.000 description 1
- RXRMFLGGUBUDLQ-UHFFFAOYSA-N O=C(NC(C(=O)CC1=CC=CC=N1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C(=O)CC1=CC=CC=N1)C1CCCCC1)C1=NOC(C2CC2)=C1 RXRMFLGGUBUDLQ-UHFFFAOYSA-N 0.000 description 1
- HCBCOUYDOAUBMK-UHFFFAOYSA-N O=C(NC(C(=O)CC1=CC=CN=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C(=O)CC1=CC=CN=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 HCBCOUYDOAUBMK-UHFFFAOYSA-N 0.000 description 1
- ZRSNSNUUZFGEPB-UHFFFAOYSA-N O=C(NC(C(=O)CCC1=CC=CC=C1O)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C(=O)CCC1=CC=CC=C1O)C1CCCCC1)C1=NOC(C2CC2)=C1 ZRSNSNUUZFGEPB-UHFFFAOYSA-N 0.000 description 1
- JKUKZARIXPHPSP-UHFFFAOYSA-N O=C(NC(C(=O)CCC1=CC=CN=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C(=O)CCC1=CC=CN=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 JKUKZARIXPHPSP-UHFFFAOYSA-N 0.000 description 1
- PMIUWRWTYQUQHQ-UHFFFAOYSA-N O=C(NC(C1=CC(COCC2=CC(F)=CC=C2)=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C1=CC(COCC2=CC(F)=CC=C2)=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 PMIUWRWTYQUQHQ-UHFFFAOYSA-N 0.000 description 1
- HMQNVSFCVRAQAG-UHFFFAOYSA-N O=C(NC(C1=CC(COCC2=CC=CC=C2I)=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C1=CC(COCC2=CC=CC=C2I)=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 HMQNVSFCVRAQAG-UHFFFAOYSA-N 0.000 description 1
- RIXSMWNIZDZROY-UHFFFAOYSA-N O=C(NC(C1=CC(Cl)=CC=C1)C1CCNCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C1=CC(Cl)=CC=C1)C1CCNCC1)C1=NOC(C2CC2)=C1 RIXSMWNIZDZROY-UHFFFAOYSA-N 0.000 description 1
- YJEFHCHSWAQFEH-UHFFFAOYSA-N O=C(NC(C1=CC=C(F)C=C1)C1CC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C1=CC=C(F)C=C1)C1CC1)C1=NOC(C2CC2)=C1 YJEFHCHSWAQFEH-UHFFFAOYSA-N 0.000 description 1
- ZMYRBPRXXJMXMI-UHFFFAOYSA-N O=C(NC(C1=CC=CC(CNC2=CC=CN=C2)=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C1=CC=CC(CNC2=CC=CN=C2)=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 ZMYRBPRXXJMXMI-UHFFFAOYSA-N 0.000 description 1
- FQGCHEMBQVQZKO-UHFFFAOYSA-N O=C(NC(C1=CC=CC2=C1CCN(C1=CC=CN=C1)C2=O)C1CCNCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C1=CC=CC2=C1CCN(C1=CC=CN=C1)C2=O)C1CCNCC1)C1=NOC(C2CC2)=C1 FQGCHEMBQVQZKO-UHFFFAOYSA-N 0.000 description 1
- OZWKDEBRVGAALR-UHFFFAOYSA-N O=C(NC(C1=CC=CC=C1)C1CCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C1=CC=CC=C1)C1CCC1)C1=NOC(C2CC2)=C1 OZWKDEBRVGAALR-UHFFFAOYSA-N 0.000 description 1
- OHFAMNGCPWPOAX-UHFFFAOYSA-N O=C(NC(C1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 OHFAMNGCPWPOAX-UHFFFAOYSA-N 0.000 description 1
- GHGLKBGVMURFST-UHFFFAOYSA-N O=C(NC(C1=CC=CC=C1)C1CCCNC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C1=CC=CC=C1)C1CCCNC1)C1=NOC(C2CC2)=C1 GHGLKBGVMURFST-UHFFFAOYSA-N 0.000 description 1
- NISJTVKRHAGRBV-UHFFFAOYSA-N O=C(NC(C1=CC=CC=C1Cl)C1CCNCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C1=CC=CC=C1Cl)C1CCNCC1)C1=NOC(C2CC2)=C1 NISJTVKRHAGRBV-UHFFFAOYSA-N 0.000 description 1
- FWRZFHPAZRBVCL-UHFFFAOYSA-N O=C(NC(C1=CC=NC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(C1=CC=NC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 FWRZFHPAZRBVCL-UHFFFAOYSA-N 0.000 description 1
- LXIGHBWSZMGLGJ-UHFFFAOYSA-N O=C(NC(CC1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(CC1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 LXIGHBWSZMGLGJ-UHFFFAOYSA-N 0.000 description 1
- JVXHQVUYOZONRL-UHFFFAOYSA-N O=C(NC(CCN1C=NC=N1)C1=CC=CC=C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(CCN1C=NC=N1)C1=CC=CC=C1)C1=NOC(C2CC2)=C1 JVXHQVUYOZONRL-UHFFFAOYSA-N 0.000 description 1
- PQHXSYLWVBBXNK-UHFFFAOYSA-N O=C(NC(CO)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(CO)C1CCCCC1)C1=NOC(C2CC2)=C1 PQHXSYLWVBBXNK-UHFFFAOYSA-N 0.000 description 1
- WWMPEVLPSYRDSA-UHFFFAOYSA-N O=C(NC(COC1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC(COC1=CC=CC=C1)C1CCCCC1)C1=NOC(C2CC2)=C1 WWMPEVLPSYRDSA-UHFFFAOYSA-N 0.000 description 1
- BYLMHPQUSXAJOZ-UHFFFAOYSA-N O=C(NC1=CC=C(C(F)(F)F)N=C1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 Chemical compound O=C(NC1=CC=C(C(F)(F)F)N=C1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 BYLMHPQUSXAJOZ-UHFFFAOYSA-N 0.000 description 1
- LVKCDNPKTYXDSP-UHFFFAOYSA-N O=C(NC1=CC=C(O)N=C1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 Chemical compound O=C(NC1=CC=C(O)N=C1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 LVKCDNPKTYXDSP-UHFFFAOYSA-N 0.000 description 1
- NGQVSYCVNYNLJR-UHFFFAOYSA-N O=C(NC1=CC=C(S(=O)(=O)CC2CCNC2)C=C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1=CC=C(S(=O)(=O)CC2CCNC2)C=C1)C1=NOC(C2CC2)=C1 NGQVSYCVNYNLJR-UHFFFAOYSA-N 0.000 description 1
- BALWJZWSAWBEJJ-UHFFFAOYSA-N O=C(NC1=CC=C(S(=O)(=O)CC2CCNCC2)C=C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1=CC=C(S(=O)(=O)CC2CCNCC2)C=C1)C1=NOC(C2CC2)=C1 BALWJZWSAWBEJJ-UHFFFAOYSA-N 0.000 description 1
- MOGCNYNCOKUNKA-UHFFFAOYSA-N O=C(NC1=CC=C(S(=O)(=O)CCC2CCNCC2)C=C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1=CC=C(S(=O)(=O)CCC2CCNCC2)C=C1)C1=NOC(C2CC2)=C1 MOGCNYNCOKUNKA-UHFFFAOYSA-N 0.000 description 1
- LXCYDHIUOGXGAM-UHFFFAOYSA-N O=C(NC1=CC=CC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NC1=CC=CC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 LXCYDHIUOGXGAM-UHFFFAOYSA-N 0.000 description 1
- YLWFEQGIGSGMNT-UHFFFAOYSA-N O=C(NC1=CC=CC=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NC1=CC=CC=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 YLWFEQGIGSGMNT-UHFFFAOYSA-N 0.000 description 1
- WEGNOQIXJVOBEJ-DEOSSOPVSA-N O=C(NC1=CC=CN=C1)C1=CC([C@@H](NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NC1=CC=CN=C1)C1=CC([C@@H](NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 WEGNOQIXJVOBEJ-DEOSSOPVSA-N 0.000 description 1
- WEGNOQIXJVOBEJ-XMMPIXPASA-N O=C(NC1=CC=CN=C1)C1=CC([C@H](NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NC1=CC=CN=C1)C1=CC([C@H](NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 WEGNOQIXJVOBEJ-XMMPIXPASA-N 0.000 description 1
- KOPPCVHDSKGWGK-UHFFFAOYSA-N O=C(NC1=CC=CN=C1O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 Chemical compound O=C(NC1=CC=CN=C1O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCNCC2)=C1 KOPPCVHDSKGWGK-UHFFFAOYSA-N 0.000 description 1
- AYOHIAPPUWCQEY-UHFFFAOYSA-N O=C(NC1=CC=CN=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NC1=CC=CN=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 AYOHIAPPUWCQEY-UHFFFAOYSA-N 0.000 description 1
- GPHVPZUXRMLKNU-UHFFFAOYSA-N O=C(NC1=CC=NC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NC1=CC=NC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 GPHVPZUXRMLKNU-UHFFFAOYSA-N 0.000 description 1
- DUZDDZCZFNFSJK-UHFFFAOYSA-N O=C(NC1=CC=NN=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NC1=CC=NN=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 DUZDDZCZFNFSJK-UHFFFAOYSA-N 0.000 description 1
- IXENIXBWJTXCFA-UHFFFAOYSA-N O=C(NC1=CN=CC=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NC1=CN=CC=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 IXENIXBWJTXCFA-UHFFFAOYSA-N 0.000 description 1
- LGAWYFIJBZYANF-UHFFFAOYSA-N O=C(NC1=CN=CN=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NC1=CN=CN=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 LGAWYFIJBZYANF-UHFFFAOYSA-N 0.000 description 1
- OKQGBHVDPAWKCC-UHFFFAOYSA-N O=C(NC1CC(CC2CNC2)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CC(CC2CNC2)C1)C1=NOC(C2CC2)=C1 OKQGBHVDPAWKCC-UHFFFAOYSA-N 0.000 description 1
- NLDGYULLCGUCNL-UHFFFAOYSA-N O=C(NC1CC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NC1CC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 NLDGYULLCGUCNL-UHFFFAOYSA-N 0.000 description 1
- KTFVVMAUVTXMBI-UHFFFAOYSA-N O=C(NC1CCC(C2=CC=CC=C2)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CCC(C2=CC=CC=C2)C1)C1=NOC(C2CC2)=C1 KTFVVMAUVTXMBI-UHFFFAOYSA-N 0.000 description 1
- IXBMVLRUTWISOO-UHFFFAOYSA-N O=C(NC1CCC2(CCOCC2)CC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CCC2(CCOCC2)CC1)C1=NOC(C2CC2)=C1 IXBMVLRUTWISOO-UHFFFAOYSA-N 0.000 description 1
- AXVNDTBXOSKXEY-UHFFFAOYSA-N O=C(NC1CCCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NC1CCCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 AXVNDTBXOSKXEY-UHFFFAOYSA-N 0.000 description 1
- PTKPUDKAWXZAIW-UHFFFAOYSA-N O=C(NC1CCCNC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NC1CCCNC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 PTKPUDKAWXZAIW-UHFFFAOYSA-N 0.000 description 1
- YSTRYLLPKRIBIF-UHFFFAOYSA-N O=C(NC1CCCNCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CCCNCC1)C1=NOC(C2CC2)=C1 YSTRYLLPKRIBIF-UHFFFAOYSA-N 0.000 description 1
- ACKYNMVJLUWPSD-UHFFFAOYSA-N O=C(NC1CCNC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1 Chemical compound O=C(NC1CCNC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1 ACKYNMVJLUWPSD-UHFFFAOYSA-N 0.000 description 1
- RRRWLFICXSUTPQ-UHFFFAOYSA-N O=C(NC1CCNC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br Chemical compound O=C(NC1CCNC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br RRRWLFICXSUTPQ-UHFFFAOYSA-N 0.000 description 1
- XCPQCBZQPOUMEK-UHFFFAOYSA-N O=C(NC1CCNCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1 Chemical compound O=C(NC1CCNCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1 XCPQCBZQPOUMEK-UHFFFAOYSA-N 0.000 description 1
- YFTHDWQTNTXBAW-UHFFFAOYSA-N O=C(NC1CCNCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 Chemical compound O=C(NC1CCNCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1 YFTHDWQTNTXBAW-UHFFFAOYSA-N 0.000 description 1
- XBVMZXTXGKCQCE-UHFFFAOYSA-N O=C(NC1CCNCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br Chemical compound O=C(NC1CCNCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br XBVMZXTXGKCQCE-UHFFFAOYSA-N 0.000 description 1
- MBXWSQQVUCXISG-UHFFFAOYSA-N O=C(NC1CCOC1C1=CC=C(F)C(F)=C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CCOC1C1=CC=C(F)C(F)=C1)C1=NOC(C2CC2)=C1 MBXWSQQVUCXISG-UHFFFAOYSA-N 0.000 description 1
- HIFOUUUPIDLUNJ-UHFFFAOYSA-N O=C(NC1CCOC2(CCCC2)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CCOC2(CCCC2)C1)C1=NOC(C2CC2)=C1 HIFOUUUPIDLUNJ-UHFFFAOYSA-N 0.000 description 1
- SNXYWBCBIVPVDA-UHFFFAOYSA-N O=C(NC1CCOC2(CCCCC2)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CCOC2(CCCCC2)C1)C1=NOC(C2CC2)=C1 SNXYWBCBIVPVDA-UHFFFAOYSA-N 0.000 description 1
- IBIQDCYERHGSSO-UHFFFAOYSA-N O=C(NC1CN(C(CO)C2=CC=CC=C2)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CN(C(CO)C2=CC=CC=C2)C1)C1=NOC(C2CC2)=C1 IBIQDCYERHGSSO-UHFFFAOYSA-N 0.000 description 1
- FWOOTQGMUDJZDB-UHFFFAOYSA-N O=C(NC1CN(C2CC2)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CN(C2CC2)C1)C1=NOC(C2CC2)=C1 FWOOTQGMUDJZDB-UHFFFAOYSA-N 0.000 description 1
- RUYANJPQMNZUFD-UHFFFAOYSA-N O=C(NC1CN(C2COC2)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CN(C2COC2)C1)C1=NOC(C2CC2)=C1 RUYANJPQMNZUFD-UHFFFAOYSA-N 0.000 description 1
- SDAFGJPQVPLGIJ-UHFFFAOYSA-N O=C(NC1CN(CC(F)(F)F)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CN(CC(F)(F)F)C1)C1=NOC(C2CC2)=C1 SDAFGJPQVPLGIJ-UHFFFAOYSA-N 0.000 description 1
- XLUJARILFPDGJQ-UHFFFAOYSA-N O=C(NC1CN(CC(F)F)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CN(CC(F)F)C1)C1=NOC(C2CC2)=C1 XLUJARILFPDGJQ-UHFFFAOYSA-N 0.000 description 1
- LLEKGLYOTZRGLG-UHFFFAOYSA-N O=C(NC1CN(CC2=CC=CC=C2)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CN(CC2=CC=CC=C2)C1)C1=NOC(C2CC2)=C1 LLEKGLYOTZRGLG-UHFFFAOYSA-N 0.000 description 1
- LHMCUNAFDJPRQB-UHFFFAOYSA-N O=C(NC1CN(CCF)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CN(CCF)C1)C1=NOC(C2CC2)=C1 LHMCUNAFDJPRQB-UHFFFAOYSA-N 0.000 description 1
- FVHIGPZPVYRGGE-UHFFFAOYSA-N O=C(NC1CN(S(=O)(=O)CCCO)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC1CN(S(=O)(=O)CCCO)C1)C1=NOC(C2CC2)=C1 FVHIGPZPVYRGGE-UHFFFAOYSA-N 0.000 description 1
- JMPCZKBNPUJCDK-UHFFFAOYSA-N O=C(NC1COC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NC1COC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 JMPCZKBNPUJCDK-UHFFFAOYSA-N 0.000 description 1
- RHSFRSNVYZMPDW-UHFFFAOYSA-N O=C(NCC(O)CN1CCCC1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 Chemical compound O=C(NCC(O)CN1CCCC1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 RHSFRSNVYZMPDW-UHFFFAOYSA-N 0.000 description 1
- DJQNXDVNSNJTOW-UHFFFAOYSA-N O=C(NCC1(F)CCNCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NCC1(F)CCNCC1)C1=NOC(C2CC2)=C1 DJQNXDVNSNJTOW-UHFFFAOYSA-N 0.000 description 1
- IZKLHZJGMIWHBZ-UHFFFAOYSA-N O=C(NCC1(O)CCNCC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NCC1(O)CCNCC1)C1=NOC(C2CC2)=C1 IZKLHZJGMIWHBZ-UHFFFAOYSA-N 0.000 description 1
- VNMUIEPJLIIHRJ-UHFFFAOYSA-N O=C(NCC1=CC(O)=CC=C1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 Chemical compound O=C(NCC1=CC(O)=CC=C1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 VNMUIEPJLIIHRJ-UHFFFAOYSA-N 0.000 description 1
- GPCRHGJSBXHWBI-UHFFFAOYSA-N O=C(NCC1=CC=C(Cl)C=C1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 Chemical compound O=C(NCC1=CC=C(Cl)C=C1)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 GPCRHGJSBXHWBI-UHFFFAOYSA-N 0.000 description 1
- HXTFANDNZCQHEJ-UHFFFAOYSA-N O=C(NCC1=CC=CC=C1O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 Chemical compound O=C(NCC1=CC=CC=C1O)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 HXTFANDNZCQHEJ-UHFFFAOYSA-N 0.000 description 1
- LENGXFHTDYEYAY-UHFFFAOYSA-N O=C(NCC1=CC=CC=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NCC1=CC=CC=N1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 LENGXFHTDYEYAY-UHFFFAOYSA-N 0.000 description 1
- AWIKQVWIPXSRDE-UHFFFAOYSA-N O=C(NCC1=CC=CN=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NCC1=CC=CN=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 AWIKQVWIPXSRDE-UHFFFAOYSA-N 0.000 description 1
- SNIXRPMFZOUNFR-UHFFFAOYSA-N O=C(NCC1=CC=NC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NCC1=CC=NC=C1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 SNIXRPMFZOUNFR-UHFFFAOYSA-N 0.000 description 1
- OUSKQELVRVEPFH-UHFFFAOYSA-N O=C(NCC1CCCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NCC1CCCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 OUSKQELVRVEPFH-UHFFFAOYSA-N 0.000 description 1
- VQANLKMRKKEEDJ-UHFFFAOYSA-N O=C(NCC1CCNCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1 Chemical compound O=C(NCC1CCNCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C(Br)=C1 VQANLKMRKKEEDJ-UHFFFAOYSA-N 0.000 description 1
- ILSPUTYXFWOIDD-UHFFFAOYSA-N O=C(NCC1CCNCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br Chemical compound O=C(NCC1CCNCC1)C1=CC=C(NC(=O)C2=NOC(C3CC3)=C2)C=C1Br ILSPUTYXFWOIDD-UHFFFAOYSA-N 0.000 description 1
- SFEBDWDJGAQDRH-UHFFFAOYSA-N O=C(NCC1CN(CC2CC2)C1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NCC1CN(CC2CC2)C1)C1=NOC(C2CC2)=C1 SFEBDWDJGAQDRH-UHFFFAOYSA-N 0.000 description 1
- BTMUAOSGCDQWNC-UHFFFAOYSA-N O=C(NCCCN1CCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NCCCN1CCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 BTMUAOSGCDQWNC-UHFFFAOYSA-N 0.000 description 1
- DQKYMMUAQGXIAH-UHFFFAOYSA-N O=C(NCCCO)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 Chemical compound O=C(NCCCO)C1=CC=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=C1 DQKYMMUAQGXIAH-UHFFFAOYSA-N 0.000 description 1
- XDFMJWPWOKNOER-UHFFFAOYSA-N O=C(NCCN1CCCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 Chemical compound O=C(NCCN1CCCCC1)C1=CC(C(NC(=O)C2=NOC(C3CC3)=C2)C2CCCCC2)=CC=C1 XDFMJWPWOKNOER-UHFFFAOYSA-N 0.000 description 1
- WOIANAPXOVPUMQ-MRVPVSSYSA-N O=C(NC[C@@H]1CCNC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC[C@@H]1CCNC1)C1=NOC(C2CC2)=C1 WOIANAPXOVPUMQ-MRVPVSSYSA-N 0.000 description 1
- WOIANAPXOVPUMQ-QMMMGPOBSA-N O=C(NC[C@H]1CCNC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(NC[C@H]1CCNC1)C1=NOC(C2CC2)=C1 WOIANAPXOVPUMQ-QMMMGPOBSA-N 0.000 description 1
- YRXVWSTZGVYVDM-YOEHRIQHSA-N O=C(N[C@@H](C1=CC=CC=C1)[C@@H]1CCCN1)C1=NOC(C2CC2)=C1 Chemical compound O=C(N[C@@H](C1=CC=CC=C1)[C@@H]1CCCN1)C1=NOC(C2CC2)=C1 YRXVWSTZGVYVDM-YOEHRIQHSA-N 0.000 description 1
- HTOIGKRWCCLVPS-SHTZXODSSA-N O=C(N[C@H]1CC[C@H](C(=O)NCCCCCO)CC1)C1=NOC(C2CC2)=C1 Chemical compound O=C(N[C@H]1CC[C@H](C(=O)NCCCCCO)CC1)C1=NOC(C2CC2)=C1 HTOIGKRWCCLVPS-SHTZXODSSA-N 0.000 description 1
- RPGBZOCKPBJWID-UHFFFAOYSA-N O=C(O)C1=NOC(C2CC2)=C1I Chemical compound O=C(O)C1=NOC(C2CC2)=C1I RPGBZOCKPBJWID-UHFFFAOYSA-N 0.000 description 1
- AGUHXUDCDCOTFM-UHFFFAOYSA-N O=C(O)C1=NOC(CCO)=C1 Chemical compound O=C(O)C1=NOC(CCO)=C1 AGUHXUDCDCOTFM-UHFFFAOYSA-N 0.000 description 1
- WBZKMLWEEZLZAQ-UHFFFAOYSA-N O=C(OC1=C(F)C(F)=C(F)C(F)=C1F)C1=NOC(CCO)=C1 Chemical compound O=C(OC1=C(F)C(F)=C(F)C(F)=C1F)C1=NOC(CCO)=C1 WBZKMLWEEZLZAQ-UHFFFAOYSA-N 0.000 description 1
- AEDUIONFVHQBMP-UHFFFAOYSA-N O=C(c1n[o]c(C2CC2)c1)NC(C1CCNCC1)c1cc(C(NCC2CCCCC2)=O)ccc1 Chemical compound O=C(c1n[o]c(C2CC2)c1)NC(C1CCNCC1)c1cc(C(NCC2CCCCC2)=O)ccc1 AEDUIONFVHQBMP-UHFFFAOYSA-N 0.000 description 1
- AELPLEWKEPAHEE-UHFFFAOYSA-N O=C(c1n[o]c(C2CC2)c1)NC(C1CCNCC1)c1cc(C(Nc2cccnc2)=O)ccc1 Chemical compound O=C(c1n[o]c(C2CC2)c1)NC(C1CCNCC1)c1cc(C(Nc2cccnc2)=O)ccc1 AELPLEWKEPAHEE-UHFFFAOYSA-N 0.000 description 1
- GGYKYHSAAJURIU-UHFFFAOYSA-N O=C(c1n[o]c(C2CC2)c1)NC(C1CCNCC1)c1cccc(C(NCCCN2CCCC2)=O)c1 Chemical compound O=C(c1n[o]c(C2CC2)c1)NC(C1CCNCC1)c1cccc(C(NCCCN2CCCC2)=O)c1 GGYKYHSAAJURIU-UHFFFAOYSA-N 0.000 description 1
- HGTRJALXUKYCMF-UHFFFAOYSA-N OCCCNC(c1cc(C(C2CCNCC2)NC(c2n[o]c(C3CC3)c2)=O)ccc1)=O Chemical compound OCCCNC(c1cc(C(C2CCNCC2)NC(c2n[o]c(C3CC3)c2)=O)ccc1)=O HGTRJALXUKYCMF-UHFFFAOYSA-N 0.000 description 1
- CEOISIINGGXIQI-UHFFFAOYSA-N Oc1cc(CCC(C2)NC(c3n[o]c(C4CC4)c3)=O)c2cc1 Chemical compound Oc1cc(CCC(C2)NC(c3n[o]c(C4CC4)c3)=O)c2cc1 CEOISIINGGXIQI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the present disclosure provides substituted isoxazole carboxamides as SMYD protein inhibitors, such as SMYD3 and SMYD2 inhibitors, and therapeutic methods of treating conditions and diseases wherein inhibition of SMYD proteins such as SMYD3 and SMYD2 provides a benefit.
- Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases.
- Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence.
- epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin.
- methyltransferases e.g., SMYD proteins such as SMYD3 and SMYD2
- the present disclosure provides substituted isoxazole carboxamide compounds represented by Formulae I-XVII below, and the pharmaceutically acceptable salts and solvates thereof, collectively referred to herein as “Compounds of the Disclosure.”
- the present disclosure provides a Compound of the Disclosure and one or more pharmaceutically acceptable carriers.
- the present disclosure provides a method of inhibiting SMYD proteins, such as SMYD3 or SMYD2, or both, in a mammal, comprising administering to the mammal an effective amount of at least one Compound of the Disclosure.
- SMYD proteins such as SMYD3 or SMYD2
- the present disclosure provides methods for treating a disease, disorder, or condition, e.g., cancer, responsive to inhibition of SMYD proteins, such as SMYD3 or SMYD2, or both, comprising administering a therapeutically effective amount of a Compound of the Disclosure.
- a disease, disorder, or condition e.g., cancer
- SMYD proteins such as SMYD3 or SMYD2
- the present disclosure provides the use of Compounds of the Disclosure as inhibitors of SMYD3.
- the present disclosure provides the use of Compounds of the Disclosure as inhibitors of SMYD2.
- the present disclosure provides the use of Compounds of the Disclosure as inhibitors of SMYD proteins.
- the present disclosure provides a pharmaceutical composition for treating a disease, disorder, or condition responsive to inhibition of SMYD proteins, such as SMYD3 or SMYD2, or both, wherein the pharmaceutical composition comprises a therapeutically effective amount of a Compound of the Disclosure in a mixture with one or more pharmaceutically acceptable carriers.
- the present disclosure provides Compounds of the Disclosure for use in treating cancer in a mammal, e.g., breast, cervical, colon, kidney, liver, head and neck, skin, pancreatic, ovary, esophageal, lung, and prostate cancer.
- a mammal e.g., breast, cervical, colon, kidney, liver, head and neck, skin, pancreatic, ovary, esophageal, lung, and prostate cancer.
- the present disclosure provides a Compound of the Disclosure for use in the manufacture of a medicament for treating cancer in a mammal.
- the present disclosure provides kit comprising a Compound of the Disclosure.
- One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD proteins.
- the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions, e.g., cancer, responsive to inhibition of SMYD proteins.
- One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD3.
- the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions. e.g., cancer, responsive to inhibition of SMYD3.
- One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD2.
- the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions, e.g., cancer, responsive to inhibition of SMYD2.
- Compounds of the Disclosure are compounds having Formula I:
- R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-4 alkenyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, and hydroxyalkyl;
- R 2 is selected from the group consisting of hydrogen, halo, and carboxamido
- A is selected from the group consisting of C 1-10 alkylenyl, (cycloalkylenyl)alkyl, optionally substituted C 3-12 cycloalkylenyl, optionally substituted C 6-14 arylenyl, optionally substituted 5- to 14-membered heteroarylenyl, optionally substituted 4- to 14-membered heterocyclenyl, and —C(H)R 3 R 4 ;
- R 1 is ethyl, n-propyl, isopropyl, isobutyl, or cyclopropyl; and R 2 is hydrogen, then A is not optionally substituted, optionally bridged piperidinenyl;
- R 1 is ethyl or cyclopropyl
- R 2 is hydrogen
- X is —N(R 7 )S(—O) 2 —, —N(R 7 )C( ⁇ O)—, or —N(R 7 )C( ⁇ O)C(R 8 )(H)—
- A is not optionally substituted 1,4-cyclohexylenyl
- R 1 is ethyl or cyclopropyl
- R 2 is hydrogen
- X is absent
- Z is amino, alkylamino, dialkylamino, or heterocycloamino, then A is not optionally substituted 1,4-cyclohexylenyl
- R 1 is hydrogen. C 1-6 alkyl, or Cm cycloalkyl; and R 2 is hydrogen, then A is not optionally substituted pyrrolidinenyl;
- R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl. (hydroxy)(aryl)alkyl, (amino)alkyl. (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, optionally substituted C 3-12 cycloalkyl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted C 6-14 aryl, aralkyl, alkoxycarbonyl, and —C( ⁇ O)N(R 5 )(R 6 );
- R 4 is selected from the group consisting of C 1-6 alkyl, hydroxyalkyl, optionally substituted C 3-12 cycloalkyl, optionally substituted C 6-14 aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted 4- to 14-membered heterocyclo, and (heteroaryl)alkyl;
- R 5 is selected from the from the group consisting of hydrogen and C 1-4 alkyl
- R 6 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, fluoroalkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(carboxamido)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (amino)(heteroaryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, (hydroxyalkylamino)alkyl, alkoxyalkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl optionally substituted C 3-12 cycloalkyl
- X is selected from the group consisting of —S( ⁇ O) 2 —, —S( ⁇ O) 2 N(R 7 )—, —N(R 7 )S( ⁇ O) 2 —, —S( ⁇ O) 2 C(R 8 )(H)—, —C( ⁇ O)—, —C( ⁇ O)N(R 7 )—, —N(R 7 )C( ⁇ O)—, —C( ⁇ O)O—, —OC( ⁇ O)—, —C( ⁇ O)C(R 8 )(H)N(R 7 )—, —N(R 7 )C( ⁇ O)C(R 8 )(H)—, —C(R 8 )(H)C( ⁇ O)N(R 7 )—, —C(R 8 )(H)N(R 7 )—, —C(R 8 )(H)N(R 7 )—, and —C( ⁇ O)C(R 8
- Z is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, fluoroalkyl, hydroxyalkyl, amino, alkylamino, dialkylamino, heterocycloamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (amino)(heteroaryl)alkyl (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, (hydroxyalkylamino)alkyl, alkoxyalkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl optionally substituted C 3-12 cyclo
- —X—Z is attached to any available carbon or nitrogen atom of A, R 3 , R 4 , or R 6 ; e.g., when R 4 is C 1-6 alkyl. e.g., ethyl, a hydrogen atom of that ethyl group is replaced with —X—Z to give —CH 2 CH 2 —X—Z or
- R 4 is optionally substituted C 3-12 cycloalkyl, e.g., cyclohexyl, a hydrogen atom of the cyclohexyl group is replaced with —X—Z to give:
- R 4 is optionally substituted 4- to 14-membered heterocyclo, e.g., piperidinyl
- the hydrogen atom attached to the piperidinyl nitrogen atom is replaced with —X—Z to give:
- R 4 is optionally substituted C 6-14 aryl, e.g., phenyl, a hydrogen atom on that phenyl group is replaced with —X—Z to give:
- R 7 is selected from the group consisting of hydrogen and C 1-4 alkyl
- R 8 is selected from the group consisting of hydrogen, C 1-4 alkyl, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, and hydroxyalkyl.
- Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein A is C 1-10 alkylenyl.
- Compounds of the Disclosure are compounds having Formula II:
- R 9a and R 9b are independently selected from the group consisting of hydrogen and C 1-4 alkyl
- R 9c and R 9d are independently selected from the group consisting of hydrogen and C 1-4 alkyl; or
- R 9c and R 9d taken together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl
- R 9e is selected from the group consisting of hydrogen and C 1-4 alkyl
- n 0 or 1:
- X is selected from the group consisting of —N(R 7 )C( ⁇ O)—, —N(R 7 )C( ⁇ O)C(R 8 )(H)—, and —N(R 7 )S( ⁇ O) 2 —;
- R 8 is selected from the group consisting of C 1-4 alkyl, amino, alkylamino, and dialkylamino;
- Z is selected from the group consisting of C 1-6 alkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C 1-4 , cycloalkyl, and R 1 , R 2 , and R 7 are as defined above in connection with Formula I.
- Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein A is optionally substituted C 6-14 arylenyl.
- Compounds of the Disclosure are compounds having Formula III:
- R 10a is selected from the group consisting of hydrogen, halo, C 1-6 alkyl, alkoxy, hydroxyalkyl, and alkoxycarbonyl;
- X is selected from the group consisting of —C( ⁇ O)N(R 7 )—, —N(R 7 )C( ⁇ O)—, —C( ⁇ O)C(R 8 )(H)N(R 7 )—, —C(R 8 )(H)C( ⁇ O)N(R 7 )— and —S( ⁇ O) 2 N(R 7 )—; or X is absent;
- R 8 is selected from the group consisting of C 1-4 alkyl, amino, alkylamino, and dialkylamino;
- Z is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (amino)(heteroaryl)alkyl, heteroalkyl, (amino)(hydroxy)alkyl, (heterocyclo)alkyl, optionally substituted C 3-12 cycloalkyl, and optionally substituted 4- to 14-membered heterocyclo, and R 1 , R 2 , and R 7 are as defined above in connection with Formula I.
- Compounds of the Disclosure are compounds having Formula IV:
- R 10a is selected from the group consisting of hydrogen, halo. C 1-6 alkyl, alkoxy, hydroxyalkyl, and alkoxycarbonyl;
- X is selected from the group consisting of —C( ⁇ O)N(R 7 )—, —N(R 7 )C( ⁇ O)—, —C( ⁇ O)C(R 8 )(H)N(R 7 )—, —C(R 8 )(H)C( ⁇ O)N(R 7 )— and —S( ⁇ O) 2 N(R 7 )—; or X is absent;
- R 8 is selected from the group consisting of C 1-4 alkyl, amino, alkylamino, and dialkylamino;
- Z is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (amino)(heteroaryl)alkyl, heteroalkyl, (amino)hydroxy)alkyl, (heterocyclo)alkyl, optionally substituted C 3-12 cycloalkyl, and optionally substituted 4- to 14-membered heterocyclo, and R 1 , R 2 , and R 7 are as defined above in connection with Formula I.
- Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein A is optionally substituted C 3-12 cycloalkylenyl.
- Compounds of the Disclosure are compounds having Formula V:
- R 10a and R 10b are independently selected from the group consisting of hydrogen and C 1-4 alkyl;
- X is selected from the group consisting of —S( ⁇ O) 2 —, —S( ⁇ O) 2 N(R 7 )—, —N(R 7 )C( ⁇ O)—, —C( ⁇ O)N(R 7 )—, —N(R 7 )S( ⁇ O)—, and —OC( ⁇ O)—; or X is absent;
- Z is selected from the group consisting of amino, alkylamino, dialkylamino, heterocycloamino. (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, and (hydroxyalkylamino)alkyl; n is 0 or 1; and p is 0 or 1, and R 1 , R 2 , and R 7 are as defined above in connection with Formula I.
- Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein A is optionally substituted 4- to 14-membered heterocyclenyl.
- Compounds of the Disclosure are compounds having Formula VI:
- R 11a and R 11b are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, and alkoxycarbonyl;
- X is selected from the group consisting of —C( ⁇ O)—, —S( ⁇ O) 2 —, and —C( ⁇ O)C(R 8 )(H)—;
- Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, optionally substituted C 3-12 cycloalkyl, and aralkyl; and
- r is 0 or 1
- R 1 , R 2 , and R 8 are as defined above in connection with Formula I.
- Compounds of the Disclosure are compounds having Formula XVI:
- R 11c and R 11d are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;
- X is selected from the group consisting of —C( ⁇ O)— and —S( ⁇ O) 2 ; or X is absent; and
- R 1 , and R 2 are as defined above in connection with Formula I.
- Compounds of the Disclosure are compounds having Formula XVI, and the pharmaceutically acceptable salts or solvates. e.g., hydrates, thereof, wherein R 11c and R 11d are hydrogen; X is absent; Z is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, fluoroalkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl. (dialkylamino)alkyl.
- R 2 is hydrogen; and R 1 is as defined above in connection with Formula I.
- Z is selected from the group consisting of aralkyl, and (heteroaryl)alkyl.
- Z is (heteroaryl)alkyl that is substituted with an aralkyl, e.g.,
- R 1 is selected from the group consisting of C 1-4 alkyl and C 3-6 cycloalkyl.
- Compounds of the Disclosure are compounds having Formula XVII:
- R′′ is selected from the group consisting of aralkyl and (heteroaryl)alkyl
- R 1 is as defined above in connection with Formula I.
- Compounds of the Disclosure are compounds having Formula XVII, wherein R 1 is selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl.
- R′′ is aralkyl.
- R′′ is (heteroaryl)alkyl.
- R′′ is benzyl wherein the phenyl group is optionally substituted with one or two substituents, e.g., —CH 2 (4-Cl-Ph), —CH 2 (3-Cl-Ph), —CH 2 (3,4-di-Cl-Ph), and —CH 2 (4-CF 3 -Ph).
- Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein A is —C(H)R 3 R 4 .
- R 3 is selected from the group consisting of C 1-6 alkyl and optionally substituted C 3-12 cycloalkyl; and R 4 is selected from the group consisting of optionally substituted C 3-12 cycloalkyl and optionally substituted C 6-14 aryl.
- R 4 is optionally substituted 4- to 14-membered heterocyclo.
- R 3 is C 1-4 alkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, optionally substituted C 6-14 aryl, and aralkyl.
- —X—Z replaces a hydrogen atom on the R 4 substituent.
- —X—Z can be hydrogen, when X is absent and Z is hydrogen.
- Compounds of the Disclosure are compounds having Formula VII, Formula VIII, or Formula IX:
- R 3 is selected from the group consisting of hydrogen, C 1-4 alkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted C 6-14 aryl, aryloxyalkyl, and aralkyl;
- X is selected from the group consisting of —S( ⁇ O) 2 —, —S( ⁇ O) 2 N(R 7 )—, —S( ⁇ O) 2 C(R 8 )(H)—, —C( ⁇ O)—, —C( ⁇ O)N(R 7 )—, —C( ⁇ O)O—, —OC( ⁇ O)—, and —C( ⁇ O)C(R 8 )(H)—; or X is absent;
- R 8 is selected from the group consisting of C 1-4 alkyl, amino, alkylamino, and dialkylamino;
- Z is selected from the group consisting of C 1-6 alkyl, (amino)alkyl. (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, hydroxyalkyl, optionally substituted C 3-12 cycloalkyl, aralkyl, and (heteroaryl)alkyl, and R 1 , R 2 , and R 7 are as defined above in connection with Formula I.
- R 3 is selected from the group consisting of hydrogen and methyl.
- Compounds of the Disclosure are compounds having Formula X, Formula XI, or Formula XII:
- R 12 is selected from the group consisting of hydrogen, halo, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, (aralkyloxy)alkyl, alkoxyalkyl, heteroalkyl, (hydroxyalkylamino)alkyl, (heterocycloamino)alkyl, and carboxamido, and R 1 , R 2 , X, and Z are as defined above in connection with Formula I.
- X is selected from the group consisting of —C( ⁇ O)N(R 7 )— and —S( ⁇ O) 2 N(R 7 )—;
- Z is optionally substituted C 1-6 alkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl.
- heterocyclo alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C 3-12 cycloalkyl, aralkyl, and (heteroaryl)alkyl; and R 12 is hydrogen.
- X is absent;
- Z is hydrogen; and R 12 is selected from the group consisting of halo, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, (aralkyloxy)alkyl, alkoxyalkyl, heteroalkyl, (hydroxyalkylamino)alkyl, (hetcrocycloamino)alkyl, and carboxamido.
- Compounds of the Disclosure are compounds having Formula XIII, Formula XIV, or Formula XV:
- R 6 is selected from the group consisting of optionally substituted C 1-6 alkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C 3-12 cycloalkyl, aralkyl, and (heteroaryl)alkyl;
- X is selected from the group consisting of —C( ⁇ O)N(R 7 )—, —C( ⁇ O)C(R 8 )(H)—, and —S( ⁇ O) 2 N(R 7 )—; or X is absent;
- R 8 is selected from the group consisting of C 1-4 alkyl, amino, alkylamino, and dialkylamino:
- Z is selected from the group consisting of C 1-4 alkyl, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (amino)heteroaryl)alkyl, and (amino)(hydroxy)alkyl, and R 1 , R 2 , and R 7 are as defined above in connection with Formula I.
- Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:
- X is selected from the group consisting of:
- R 8 is selected from the group consisting of C 1-4 alkyl, amino, alkylamino, and dialkylamino, and R 1 , R 2 , A, and Z are as defined above in connection with Formula I.
- Compounds of the Disclosure are compounds having any one of Formulae I-XVII, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is selected from the group consisting of C 1 0.4 alkyl and C 3-6 cycloalkyl. In another embodiment, R 1 is cyclopropyl. In another embodiment, R 2 is hydrogen.
- a Compound of the Disclosure is not 5-cyclopropyl-N-(pyridin-3-yl)-1,2-oxazole-3-carboxamide.
- Compounds of the Disclosure are compounds of Table 1, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof.
- the chemical names of the compounds of Table 1 are provided in Table 1A.
- Compounds of the Disclosure are compounds of Table 1A, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof.
- Compounds of the Disclosure are compounds of Table 2, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof.
- Compounds of the Disclosure is the compound of Table 3, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof.
- Compounds of the Disclosure are compounds of Tables 1 and 2, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof.
- Compounds of the Disclosure are compounds of Tables 1-3, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof.
- Compounds of the Disclosure are compounds of Table 1, Table 1A, Table 2, and Table 3, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof
- alkyl refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms (i.e., C 1-12 alkyl) or the number of carbon atoms designated (i.e., a C 1 alkyl such as methyl, a C 2 alkyl such as ethyl, a C 3 alkyl such as propyl or isopropyl, etc.).
- the alkyl group is chosen from a straight chain C 1-10 alkyl group.
- the alkyl group is chosen from a branched chain C 3-10 alkyl group.
- the alkyl group is chosen from a straight chain C 1-6 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C 3-6 alkyl group. In another embodiment, the alkyl group is chosen from a straight chain C 1-4 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C 3-4 alkyl group. In another embodiment, the alkyl group is chosen from a straight or branched chain C 3-4 alkyl group. In another embodiment, the alkyl group is partially or completely deuterated, i.e., one or more hydrogen atoms of the alkyl group are replaced with deuterium atoms.
- Non-limiting exemplary C 1-10 alkyl groups include methyl (including —CD 3 ), ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
- Non-limiting exemplary C 1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.
- Non-limiting exemplary C 1-4 groups include methyl, ethyl, propyl, isopropyl, and tert-butyl.
- the term “optionally substituted alkyl” as used by itself or as part of another group means that the alkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, alkoxycarbonyl, and carboxyalkyl.
- the alkyl is a C 1-6 alkyl.
- the alkyl is a C 1-4 alkyl.
- the optionally substituted alkyl is substituted with two substituents.
- the optionally substituted alkyl is substituted with one substituent.
- Non-limiting exemplary optionally substituted alkyl groups include —CH 2 CH 2 NO 2 , —CH 2 CH 2 CO 2 H, —CH 2 CH 2 SO 2 CH 3 , —CH 2 CH 2 COPh, and —CH 2 C 6 H 11 .
- alkylenyl refers to a divalent form of an alkyl group as defined above.
- the alkylenyl is a divalent form of a C 1-6 alkyl.
- the alkylenyl is a divalent form of a C 1-4 alkyl.
- Non-limiting exemplary alkylenyl groups include —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH(CH 3 )CH 2 —, and —CH 2 C(CH 3 ) 2 CH 2 —.
- cycloalkyl refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms (i.e., C 3-12 cycloalkyl) or the number of carbons designated.
- the cycloalkyl group has two rings.
- the cycloalkyl group has one ring.
- the cycloalkyl group is chosen from a C 3-8 cycloalkyl group.
- the cycloalkyl group is chosen from a C 3-6 cycloalkyl group.
- Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, spiro[3.3]heptane, and bicyclo[3.3.1]nonane.
- the term “optionally substituted cycloalkyl” as used by itself or as part of another group means that the cycloalkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted ary
- the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent. In one embodiment, the optionally substituted cycloalkyl is an (amino)cycloalkyl.
- the term “(amino)cycloalkyl” as used by itself or as part of another group means that the optionally substituted cycloalkyl as defined above is substituted with one amino or alkylamino group, and optionally one or two additional substituents.
- the optionally substituted cycloalkyl is an (amino)cyclohexyl.
- the term “(amino)cyclohexyl” as used by itself or as part of another group means that the optionally substituted cycloalkyl as defined above is a cyclohexyl group substituted with one amino or alkylamino group, and optionally one or two additional substituents.
- Non-limiting exemplary optionally substituted cycloalkyl groups include:
- Non-limiting exemplary (amino)cycloalkyl groups include:
- Non-limiting exemplary (amino)cyclohexyl groups include:
- optionally substituted cyclohexyl as used by itself or as part of another group means that the optionally substituted cycloalkyl as defined above is an optionally substituted cyclohexyl group.
- cycloalkylenyl as used herein by itself or part of another group refers to a divalent form of an optionally substituted cycloalkyl group as defined above.
- the cycloalkylenyl is a “cyclohexylenyl.”
- Non-limiting exemplary cycloalkylenyl groups include:
- 1,4-cyclohexylenyl as used herein by itself or part of another group refers to a cyclohexylenyl as defined above wherein the radicals are in the 1 and 4 positions of the cyclohexyl ring.
- Non-limiting exemplary 1,4-cyclohexylenyl groups include:
- (cycloalkylenyl)alkyl refers to an alkyl group substituted with a divalent form of an optionally substituted cycloalkyl group.
- the cycloalkylenyl is a divalent form of optionally substituted cyclohexyl.
- the alkyl is C 1-4 alkyl.
- Non-limiting exemplary (cycloalkylenyl)alkyl groups include:
- cycloalkenyl as used by itself or part of another group refers to a partially unsaturated cycloalkyl group as defined above.
- the cycloalkenyl has one carbon-to-carbon double bond.
- the cycloalkenyl group is chosen from a C 4-8 cycloalkenyl group.
- Exemplary cycloalkenyl groups include cyclopentenyl and cyclohexenyl.
- the term “optionally substituted cycloalkenyl” as used by itself or as part of another group means that the cycloalkenyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted hetero
- the optionally substituted cycloalkenyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkenyl is substituted with one substituent. In another embodiment, the cycloalkenyl is unsubstituted.
- alkenyl refers to an alkyl group as defined above containing one, two or three carbon-to-carbon double bonds.
- the alkenyl group is chosen from a C 2-6 alkenyl group.
- the alkenyl group is chosen from a C 2-4 alkenyl group.
- Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.
- the term “optionally substituted alkenyl” as used herein by itself or as part of another group means the alkenyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclo.
- alkynyl refers to an alkyl group as defined above containing one to three carbon-to-carbon triple bonds.
- the alkynyl has one carbon-to-carbon triple bond.
- the alkynyl group is chosen from a C 2-6 alkynyl group.
- the alkynyl group is chosen from a C 2-4 alkynyl group.
- Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
- alkynyl as used herein by itself or as part of another group means the alkynyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclo.
- haloalkyl as used by itself or as part of another group refers to an alkyl group substituted by one or more fluorine, chlorine, bromine and/or iodine atoms.
- the alkyl group is substituted by one, two, or three fluorine and/or chlorine atoms.
- the haloalkyl group is chosen from a C 1-4 haloalkyl group.
- Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.
- fluoroalkyl as used by itself or as part of another group refers to an alkyl group substituted by one or more fluorine atoms.
- the alkyl group is substituted by one, two, or three fluorine atoms.
- the fluoroalkyl group is chosen from a C 1-4 fluoroalkyl group.
- Non-limiting exemplary fluoroalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and 4,4,4-trifluorobutyl.
- hydroxyalkyl refers to an alkyl group substituted with one or more, e.g., one, two, or three, hydroxy groups.
- the hydroxyalkyl group is a monohydroxyalkyl group, i.e., substituted with one hydroxy group.
- the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups.
- the hydroxyalkyl group is chosen from a C 1-4 hydroxyalkyl group.
- Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as I-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.
- alkoxy refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal oxygen atom.
- the alkoxy group is chosen from a C 1-4 alkoxy group.
- the alkoxy group is chosen from a C 1-4 alkyl attached to a terminal oxygen atom, e.g., methoxy, ethoxy, tert-butoxy, —OCH 2 C ⁇ CH, —OCH 2 C ⁇ CCH 3 , and —OCH 2 CH 2 CH 2 C ⁇ CH.
- alkylthio refers to a sulfur atom substituted by an optionally substituted alkyl group.
- the alkylthio group is chosen from a C 1-4 alkylthio group.
- Non-limiting exemplary alkylthio groups include —SCH 3 , and —SCH 2 CH 3 .
- alkoxyalkyl refers to an alkyl group substituted with an alkoxy group.
- Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sc-butoxymethyl, pentyloxymethyl, —CH 2 OCH 2 C ⁇ CH and —CH 2 OCH 2 CH 2 CH 2 C ⁇ CH.
- haloalkoxy as used by itself or as part of another group refers to a haloalkyl attached to a terminal oxygen atom.
- Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.
- heteroalkyl refers to a stable straight or branched chain hydrocarbon radical containing 1 to 10 carbon atoms and at least two heteroatoms, which can be the same or different, selected from O, N, or S, wherein: 1) the nitrogen atom(s) and sulfur atom(s) can optionally be oxidized; and/or 2) the nitrogen atom(s) can optionally be quaternized.
- the heteroatoms can be placed at any interior position of the heteroalkyl group or at a position at which the heteroalkyl group is attached to the remainder of the molecule.
- the heteroalkyl group contains two oxygen atoms.
- the heteroalkyl contains one oxygen and one nitrogen atom, e.g., a (hydroxyalkylamino)alkyl group, e.g., —CH 2 N(CH 3 )CH 2 CH 2 CH 2 OH. In one embodiment, the heteroalkyl contains two nitrogen atoms.
- Non-limiting exemplary heteroalkyl groups include —CH 2 OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OCH 2 CH 2 OCH 3 , —CH— 2 NHCH 2 CH 2 OCH 2 , —OCH 2 CH 2 NH 2 , —NHCH 2 CH 2 N(H)CH 7 , —NHCH 2 CH 2 OCH 3 , —CH 2 OCH 2 CH 2 NH 2 , —CH 2 OCH 2 CH 2 N(H)CH 2 CH 3 , and —OCH 2 CH 2 OCH 3 .
- aryl refers to a monocyclic or bicyclic aromatic ring system having from six to fourteen carbon atoms (i.e., C 6-14 aryl).
- Non-limiting exemplary aryl groups include phenyl (abbreviated as “Ph”), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups.
- the aryl group is chosen from phenyl or naphthyl.
- the aryl group is phenyl.
- the term “optionally substituted aryl” as used herein by itself or as part of another group means that the aryl as defined above is either unsubstituted or substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl aralkyloxy, (aralkyloxy)alkyl, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, heteroalkyl optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl,
- the optionally substituted aryl is an optionally substituted phenyl. In one embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent.
- the optionally substituted phenyl has at least one amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl. (amino)(heteroaryl)alkyl, or (amino)(hydroxy)alkyl substituent.
- Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, and 2-phenylpropan-2-amine.
- arylenyl as used herein by itself or part of another group refers to a divalent form of an optionally substituted aryl group as defined above.
- the arylenyl is a divalent form of an optionally substituted phenyl.
- the arylenyl is a divalent form of phenyl.
- Non-limiting exemplary alkylenyl groups include:
- aryloxy as used by itself or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom.
- a non-limiting exemplary aryloxy group is PhO—.
- heteroaryloxy as used by itself or as part of another group refers to an optionally substituted heteroaryl attached to a terminal oxygen atom.
- aralkyloxy or “arylalkyloxy” as used by itself or as part of another group refers to an aralkyl group attached to a terminal oxygen atom.
- a non-limiting exemplary aralkyloxy group is PhCH 2 O—.
- (aralkyloxy)alkyl refers to an alkyl group substituted with an aralkyloxy group.
- the alkyl is a C 1-4 alkyl.
- Non-limiting exemplary “(aralkyloxy)alkyl” groups include —CH 4 OCH 1 (3-F-Ph) and —CH 2 OCH 2 CH 2 CH 2 (2-OMe-Ph).
- heteroaryl refers to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring members (i.e., a 5- to 14-membered heteroaryl) and 1, 2, 3, or 4 heteroatoms independently chosen from oxygen, nitrogen or sulfur.
- the heteroaryl has three heteroatoms.
- the heteroaryl has two heteroatoms.
- the heteroaryl has one heteroatom.
- the heteroaryl has 5 ring atoms, e.g., thienyl.
- the heteroaryl has 6 ring atoms, e.g., pyridyl.
- Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, ⁇ -carboliny
- the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.
- the term “optionally substituted heteroaryl” as used by itself or as part of another group means that the heteroaryl as defined above is either unsubstituted or substituted with one to four substituents, e.g., one or two substituents, independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aralkyl, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally
- R 43 is hydrogen or C 1-4 alkyl
- R 44 is alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl
- R 45 is alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
- the optionally substituted heteroaryl has one substituent.
- the substituent is amino, alkylamino, dialkylamino, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, —N(R 43 )(R 44 ), or —N(H)C( ⁇ O)—R 45 .
- the substituent is aralkyl or (heteroaryl)alkyl. Examples include:
- the optionally substituted heteroaryl is an optionally substituted pyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or nitrogen atom can be substituted.
- the term optionally substituted heteroaryl is meant to include heteroaryl groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings. Examples include:
- heteroarylenyl as used herein by itself or part of another group refers to a divalent form of an optionally substituted heteroaryl group as defined above.
- the heteroarylenyl is a divalent form of an optionally substituted pyridyl.
- Non-limiting exemplary heteroarylenyl groups include:
- heterocycle or “heterocyclo” as used by itself or as part of another group refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic groups containing one, two, or three rings having from three to fourteen ring members (i.e., a 3- to 14-membered heterocyclo) and at least one heteroatom.
- Each heteroatom is independently selected from the group consisting of oxygen, sulfur, including sulfoxide and sulfone, and/or nitrogen atoms, which can be quaternized.
- heterocyclo is meant to include cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as ⁇ -lactam, ⁇ -lactam, ⁇ -lactam and ⁇ -lactam, and cyclic carbamate groups such as oxazolidinyl-2-one.
- heterocyclo is also meant to include groups having fused optionally substituted aryl groups, e.g., indolinyl, indolinyl-2-one, benzo[d]oxazolyl-2(3H)one.
- the heterocyclo group is chosen from a 4-, 5-, 6-, 7- or 8-membered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms. In one embodiment, the heterocyclo group is chosen from a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms. In one embodiment, the heterocyclo group is chosen from a 8-, 9-, 10-, 11-, or 12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be optionally linked to the rest of the molecule through a carbon or nitrogen atom.
- Non-limiting exemplary heterocyclo groups include 2-oxopyrrolidin-3-yl, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, 8-azabicyclo[3.2.1]octane (nortropane), 6-azaspiro[2.5]octane, 6-azaspiro[3.4]octane, indolinyl, indolinyl-2-one, 1,3-dihydro-2H-benzo[d]imidazol-2-one
- the term “optionally substituted heterocyclo” as used herein by itself or part of another group means the heterocyclo as defined above is either unsubstituted or substituted with one to four substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl,
- substitution may occur on any available carbon or nitrogen atom, and may form a spirocycle.
- the optionally substituted heterocyclo is substituted with at least one amino, alkylamino, or dialkylamino group.
- Non-limiting exemplary optionally substituted heterocyclo groups include:
- heterocyclenyl refers to a divalent form of an optionally substituted heterocyclo group as defined above.
- the heterocyclenyl is a divalent form of an optionally substituted azetidine.
- the heterocyclenyl is a divalent form of an optionally substituted piperidinyl.
- Non-limiting exemplary heterocyclenyl groups include:
- optionally substituted pyrrolidinyl as used by itself or as part of another group means that the optionally substituted heterocyclo as defined above is an optionally substituted pyrrolidinyl group.
- optionally substituted pyrrolidinonyl refers to a divalent form of an optionally substituted pyrrolidinyl group as defined above.
- optionally substituted pyrrolidinenyl groups include:
- the term “optionally substituted, optionally bridged piperidinenyl” as used by itself or as part of another group refers to a divalent form having the following structure:
- R 2′a , R 2′b , R 3′a , R 3′b , R 4′a , R 4′b , R 5′a , and R 5′b are each independently selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl; or
- R 2′a and R 2′b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 3′a , R 3′b , R 4′a , R 4′b R 5′a , and R 5′b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
- R 3′a and R 3′b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2′a , R 2′b , R 4′a , R 4′b , R 5′a , and R 5′b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
- R 4a and R 4b taken together with the carbon atom to which they are attached form a Cu cycloalkyl; and R 2′a , R 2′b , R 3′a , R 3′b , R 4′a , and R 4′b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
- R 5′a and R 5′b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2′a , R 2′b , R 3′a , R 3′b , R 4′a , and R 4′b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
- R 2′a and R 5′a taken together form a C 1-4 bridge; and R 2′b , R 3′a , R 3′b , R 4′a , R 4′b , and R 5′b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl, or
- R 3′a and R 4′a taken together form a C 1-4 bridge; and R 2′a , R 2′b , R 3′b , R 4′a , R 5′a , and R 5′b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
- R 2′a and R 4′a taken together form a C 1-4 bridge; and R 2′b , R 3′a , R 3′b , R 4′b , R 5′a , and R 5′b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
- R 3′a and R 5′a taken form a C 1-4 bridge; and R 2′a , R 2′b , R 3′b , R 4′a , R 4′b , and R 5′b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl;
- R 6′ is selected from the group consisting of hydrogen and C 1-4 alkyl
- amino as used by itself or as part of another group refers to —NH 2 .
- alkylamino as used by itself or as part of another group refers to —NHR 22 , wherein R 22 is C 1-6 alkyl. In one embodiment, R 22 is C 1-4 alkyl.
- Non-limiting exemplary alkylamino groups include —N(H)CH 3 and —N(H)CH 2 CH 3 .
- dialkylamino as used by itself or as part of another group refers to —NR 23a R 23b , wherein R 23a and R 23b are each independently C 1-6 alkyl. In one embodiment, R 23a and R 23b are each independently C 1-4 alkyl.
- Non-limiting exemplary dialkylamino groups include —N(CH 3 ) 2 and —N(CH 3 )CH 2 CH(CH 3 ) 2 .
- hydroxyalkylamino as used by itself or as part of another group refers to —NR 24a R 24b , wherein R 24a is hydrogen or C 1-4 alkyl, and R 24b is hydroxyalkyl.
- Non-limiting exemplary hydroxyalkylamino groups include —N(H)CH 2 CH 2 OH, —N(H)CH 2 CH 2 CH 2 OH, —N(CH 3 )CH 2 CH 2 OH, and —N(CH 3 )CH 2 CH 2 CH 2 OH
- (hydroxyalkylamino)alkyl refers to an alkyl group substituted with an hydroxyalkylamino group.
- the alkyl is a C 1-4 alkyl.
- a non-limiting exemplary (hydroxyalkylamino)alkyl group is —CH 2 N(CH 3 )CH 2 CH 2 CH 2 OH.
- cycloalkylamino as used by itself or as part of another group refers to —NR 25a R 25b , wherein R 25a is optionally substituted cycloalkyl and R 25b is hydrogen or C 1-4 alkyl.
- heterocycloamino as used by itself or as part of another group refers to —NR 25c R 25d , wherein R 25c is optionally substituted heterocyclo and R 25d is hydrogen or C 1-4 alkyl.
- Non-limiting exemplary heterocycloamino groups include:
- heterocycloaminoalkyl refers to an alkyl group substituted with an heterocycloamino group.
- the alkyl is a C 1-4 alkyl.
- aralkylamino as used by itself or as part of another group refers to —NR 26a R 26b , wherein R 26a is aralkyl and R 26b is hydrogen or C 1-4 alkyl.
- Non-limiting exemplary aralkylamino groups include —N(H)CH 2 Ph and —N(CH 3 )CH 2 Ph.
- (amino)alkyl refers to an alkyl group substituted with an amino group.
- the alkyl is a C 1-4 alkyl.
- Non-limiting exemplary (amino)alkyl groups include —CH 2 NH 2 , —C(NH 2 )(H)CH 3 , —CH 2 CH 2 NH 2 , —CH 2 C(NH 2 )(H)CH 3 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 CH 2 NH 2 , and —CH 2 C(CH 3 ) 2 CH 2 NH 2 .
- (alkylamino)alkyl refers to an alkyl group substituted with an alkylamino group.
- the alkyl is a C 1-4 alkyl.
- a non-limiting exemplary (alkylamino)alkyl group is —CH 2 CH 2 N(H)CH 3 .
- dialkylamino)alkyl refers to an alkyl group substituted by a dialkylamino group.
- the alkyl is a C 1-4 alkyl.
- Non-limiting exemplary (dialkylamino)alkyl groups are —CH 2 CH 2 N(CH 3 ) 2 .
- (cycloalkylamino)alkyl refers to an alkyl group substituted by a cycloalkylamino group.
- the alkyl is a C 1-4 alkyl.
- Non-limiting exemplary (cycloalkylamino)alkyl groups include —CH 2 N(H)cyclopropyl, —CH 2 N(H)cyclobutyl, and —CH 2 N(H)cyclohexyl.
- (aralkylamino)alkyl refers to an alkyl group substituted with an aralkylamino group.
- the alkyl is a C 1-4 alkyl.
- a non-limiting exemplary (aralkylamino)alkyl group is —CH 2 CH 2 CH 2 N(H)CH 2 Ph.
- (hydroxyalkylamino)alkyl refers to an alkyl group substituted with an hydroxyalkylamino group.
- a non-limiting exemplary (hydroxyalkylamino)alkyl group is —CH 2 CH 2 NHCH 2 CH 2 OH
- (cyano)alkyl refers to an alkyl group substituted with one or more cyano, e.g., —CN, groups.
- the alkyl is a C 1-4 alkyl.
- Non-limiting exemplary (cyano)alkyl groups include —CH 2 CH 2 CN, —CH 2 CH 2 CH 2 CN, and —CH 2 C 2 CH 2 CH 2 CH 2 CN.
- (amino)(hydroxy)alkyl refers to an alkyl group substituted with one amino, alkylamino, dialkylamino, or heterocyclo group and one hydroxy group.
- the alkyl is a C 1-6 alkyl.
- the alkyl is a C 1-4 alkyl.
- Non-limiting exemplary (amino)(hydroxy)alkyl groups include:
- (amino)(carboxamido)alkyl refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino, and one carboxamido group.
- the alkyl is a C 1-6 alkyl.
- Non-limiting exemplary (amino)(carboxamido)alkyl groups include:
- (amino)(aryl)alkyl refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino group and one optionally substituted aryl group.
- the alkyl is a C 1-6 alkyl.
- the optionally substituted aryl group is an optionally substituted phenyl.
- Non-limiting exemplary (amino)(aryl)alkyl groups include:
- (amino)(heteroaryl)alkyl refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino group and one optionally substituted heteroaryl group.
- the alkyl is a C 1-6 alkyl.
- the alkyl is a C 1-4 alkyl.
- the optionally substituted heteroaryl group is an optionally substituted pyridyl.
- Non-limiting exemplary (amino)(heteroaryl)alkyl groups include:
- (cycloalkyl)alkyl refers to an alkyl group substituted with one optionally substituted cycloalkyl group.
- the alkyl is a C 1-4 alkyl.
- the cycloalkyl is a C 3-6 cycloalkyl.
- the optionally substituted cycloalkyl group is substituted with an amino or (amino)alkyl group.
- Non-limiting exemplary (cycloalkyl)alkyl groups include:
- (hydroxy)(aryl)alkyl refers to an alkyl group substituted with one hydroxy group and one optionally substituted aryl group.
- the alkyl is a C 1-6 alkyl.
- the optionally substituted aryl group is an optionally substituted phenyl.
- Non-limiting exemplary (hydroxy)(aryl)alkyl groups include:
- the term “carboxamido” as used by itself or as part of another group refers to a radical of formula —C( ⁇ O)NR 26a R 26b , wherein R 26a and R 26b are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, aralkyl, (heteroaryl)alkyl, or optionally substituted heteroaryl, or R 26a and R 26b taken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group. In one embodiment, R 26a and R 26b are each independently hydrogen or optionally substituted alkyl.
- Non-limiting exemplary carboxamido groups include —CONH 2 , —CON(H)CH 3 , CON(CH 3 ) 2 , and —CON(H)Ph.
- (carboxamido)alkyl refers to an alkyl group substituted with a carboxamido group.
- Non-limiting exemplary (carboxamido)alkyl groups include —CH 2 CONH 2 , —C(H)CH 3 —CONH 2 , and —CH 2 CON(H)CH 3 .
- sulfonamido refers to a radical of the formula —SO 2 NR 27a R 27b , wherein R 27a and R 27b are each independently hydrogen, optionally substituted alkyl, or optionally substituted aryl, or R 27a and R 27b taken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group.
- Non-limiting exemplary sulfonamido groups include —SO 2 NH 2 , —SO 2 N(H)CH 3 , and —SO 2 N(H)Ph.
- alkylcarbonyl as used by itself or as part of another group refers to a carbonyl group, i.e., —C( ⁇ O)—, substituted by an alkyl group.
- a non-limiting exemplary alkylcarbonyl group is —COCH 3 .
- arylcarbonyl as used by itself or as part of another group refers to a carbonyl group, i.e., —C( ⁇ O)—, substituted by an optionally substituted aryl group.
- a non-limiting exemplary arylcarbonyl group is —COPh.
- alkylsulfonyl as used by itself or as part of another group refers to a sulfonyl group, i.e., —SO 2 —, substituted by any of the above-mentioned optionally substituted alkyl groups.
- a non-limiting exemplary alkylsulfobnyl group is —SO 2 CH 3 .
- arylsulfonyl as used by itself or as part of another group refers to a sulfonyl group, i.e., —SO 2 —, substituted by any of the above-mentioned optionally substituted aryl groups.
- a non-limiting exemplary arylsulfonyl group is —SO 2 Ph.
- mercaptoalkyl as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted by a —SH group.
- carboxy as used by itself or as part of another group refers to a radical of the formula —COOH.
- carboxyalkyl as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted with a —COOH.
- a non-limiting exemplary carboxyalkyl group is —CH 2 CO 2 H.
- alkoxycarbonyl as used by itself or as part of another group refers to a carbonyl group, i.e., —C( ⁇ O)—, substituted by an alkoxy group.
- Non-limiting exemplary alkoxycarbonyl groups are —CO 2 Me and —CO 2 Et.
- aralkyl or “arylalkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted aryl groups.
- the aralkyl group is a C 1-4 alkyl substituted with one optionally substituted aryl group.
- Non-limiting exemplary aralkyl groups include benzyl, phenethyl, —CHPh 2 , —CH 2 (4-OH-Ph), and —CH(4-F-Ph) 2 .
- ureido refers to a radical of the formula —NR 30a —C( ⁇ O)—NR 30b R 30c , wherein R 22a is hydrogen, alkyl, or optionally substituted aryl, and R 30b and R 30c are each independently hydrogen, alkyl, or optionally substituted aryl, or R 30b and R 30c taken together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclo group.
- Non-limiting exemplary ureido groups include —NH—C(C ⁇ O)—NH 2 and —NH—C(C ⁇ O)—NHCH 3 .
- the term “guanidino” as used by itself or as part of another group refers to a radical of the formula —NR 28a —C( ⁇ NR 29 )—NR 28b R 28c , wherein R 28a , R 28b , and R 28c are each independently hydrogen, alkyl, or optionally substituted aryl, and R 29 is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl, carboxamido, or sulfonamido.
- Non-limiting exemplary guanidino groups include —NH—C(C ⁇ NH)—NH 2 , —NH—C(C ⁇ NCN)—NH 2 , and —NH—C(C ⁇ NH)—NHCH 3 .
- the term “(heterocyclo)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heterocyclo groups.
- the (heterocyclo)alkyl is a C 1-4 alkyl substituted with one optionally substituted heterocyclo group.
- the heterocyclo can be linked to the alkyl group through a carbon or nitrogen atom.
- Non-limiting exemplary (heterocyclo)alkyl groups include:
- (heteroaryl)alkyl refers to an alkyl group substituted with one, two, or three optionally substituted heteroaryl groups.
- the (heteroaryl)alkyl group is a C 1-4 alkyl substituted with one optionally substituted heteroaryl group.
- Non-limiting exemplary (heteroaryl)alkyl groups include:
- alkylcarbonylamino as used by itself or as part of another group refers to an alkylcarbonyl group attached to an amino.
- a non-limiting exemplary alkylcarbonylamino group is —NHCOCH 3 .
- C 1-4 bridge refers to a —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, or —(CH 2 ) 4 — group that joins two carbon atoms of a piperidine to form an azabicyclo group.
- R 3a and R 4a of B can be taken together to form a 6-azabicyclo[3.1.1]heptane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, or 10-azabicyclo[4.3.1]decane group.
- Each methylene unit of the C 1-4 bridge can be optionally substituted with one or two substituents independently selected from the group consisting of C 1-4 alkyl and halo.
- the present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number.
- isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H (or deuterium (D)), 3 H, 11 C, 13 C, 14 C, 5 N, 13 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively, e.g., 3 H, 11 C, and 14 C.
- compositions wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number.
- Isotopically-labelled Compounds of the Disclosure can be prepared by methods known in the art.
- Compounds of the Disclosure may contain one or more asymmetric centers and may thus give rise to enantiomers, diasteromers, and other stereoisomeric forms.
- the present disclosure is meant to encompass the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof.
- the individual enantiomers can be separated according to methods known in the art in view of the present disclosure.
- the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present disclosure as well.
- stereoisomers is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
- chiral center or “asymmetric carbon atom” refers to a carbon atom to which four different groups are attached.
- enantiomer and “enantiomeric” refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.
- racemic refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.
- absolute configuration refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.
- enantiomeric excess refers to a measure for how much of one enantiomer is present compared to the other.
- percent enantiomeric excess is defined as
- *100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R+S 1.
- the percent enantiomeric excess is defined as ([ ⁇ ] obs /[ ⁇ ] max )*100, where [ ⁇ ] obs is the optical rotation of the mixture of enantiomers and [ ⁇ ] max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.
- enantiomerically pure or “enantiopure” refer to a sample of a chiral substance all of whose molecules (within the limits of detection) have the same chirality sense.
- enantiomerically enriched or “enantioenriched” refer to a sample of a chiral substance whose enantiomeric ratio is greater than 50:50. Enantiomerically enriched compounds may be enantiomerically pure.
- the present disclosure encompasses the preparation and use of salts of the Compounds of the Disclosure, including non-toxic pharmaceutically acceptable salts.
- pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and basic salts.
- the pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like
- pharmaceutically acceptable salt refers to any salt, e.g., obtained by reaction with an acid or a base, of a Compound of the Disclosure that is physiologically tolerated in the target patient (e.g., a mammal, e.g., a human).
- Acid addition salts can be formed by mixing a solution of the particular Compound of the Disclosure with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or the like.
- Basic salts can be formed by mixing a solution of the compound of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.
- solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents.
- solvate as used herein is a combination, physical association and/or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a desolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively.
- This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding.
- solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
- “solvate” encompasses both solution-phase and isolatable solvates.
- Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure.
- a pharmaceutically acceptable solvent such as water, methanol, ethanol, and the like
- solvate is a hydrate.
- a “hydrate” relates to a particular subgroup of solvates where the solvent molecule is water.
- Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M.
- Compounds of the Disclosure are inhibitors of SMYD proteins, such as SMYD3 and SMYD2, a number of diseases, conditions, or disorders mediated by SMYD proteins, such as SMYD3 and SMYD2, can be treated by employing these compounds.
- the present disclosure is thus directed generally to a method for treating a disease, condition, or disorder responsive to the inhibition of SMYD proteins, such as SMYD3 and SMYD2, in an animal suffering from, or at risk of suffering from, the disorder, the method comprising administering to the animal an effective amount of one or more Compounds of the Disclosure.
- the present disclosure is further directed to a method of inhibiting SMYD proteins in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
- the present disclosure is further directed to a method of inhibiting SMYD3 in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
- the present disclosure is further directed to a method of inhibiting SMYD2 in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
- the terms “treat,” “treating,” “treatment,” and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.
- the terms “treat.” “treating.” “treatment,” and the like may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.
- the term “treat” and synonyms contemplate administering a therapeutically effective amount of a Compound of the Disclosure to an individual in need of such treatment.
- treatment also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions.
- the treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.
- terapéuticaally effective amount refers to an amount of the active ingredient(s) that is(are) sufficient, when administered by a method of the disclosure, to efficaciously deliver the active ingredient(s) for the treatment of condition or disease of interest to an individual in need thereof.
- the therapeutically effective amount of the agent may reduce (i.e., retard to some extent and preferably stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; modulate protein methylation in the target cells; and/or relieve, to some extent, one or more of the symptoms associated with the cancer.
- the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.
- tainer means any receptacle and closure therefore suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.
- insert means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product.
- the package insert generally is regarded as the “label” for a pharmaceutical product.
- disease or “condition” or “disorder” denotes disturbances and/or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and/or malfunctions.
- Compounds of the Disclosure inhibit SMYD proteins, such as SMYD3 and SMYD2 and can be used in treating diseases and conditions such as proliferative diseases, wherein inhibition of SMYD proteins, such as SMYD3 and SMYD2 provides a benefit.
- the Compounds of the Disclosure can be used to treat a “SMYD protein mediated disorder” (e.g., a SMYD3-mediated disorder or a SMYD2-mediated disorder).
- a SMYD protein mediated disorder is any pathological condition in which a SMYD protein is know to play a role.
- a SMYD-mediated disorder is a proliferative disease.
- inhibiting SMYD proteins is the inhibition of the activity of one or more activities of SMYD proteins such as SMYD3 and SMYD2.
- the activity of the SMYD proteins such as SMYD3 and SMYD2 is the ability of the SMYD protein such as SMYD3 or SMYD2 to transfer a methyl group to a target protein (e.g., histone). It should be appreciated that the activity of the one or more SMYD proteins such as SMYD3 and SMYD2 may be inhibited in vitro or in vivo.
- Examplary levels of inhibition of the activity one or more SMYD proteins such as SMYD3 and SMYD2 include at least 10% inhibition, at least 20% inhibition, at least 30% inhibition, at least 40% inhibition, at least 50% inhibition, at least 60% inhibition, at least 70% inhibition, at least 80% inhibition, at least 90%/0 inhibition, and up to 100% inhibition.
- the family of human SMYD proteins consists of SMYD1, SMYD2, SMYD3. SMYD4 and SMYD5.
- SMYD1, SMYD2, and SMYD3 share a high degree of sequence homology and, with the exception of SMYD5, human SMYD proteins harbor at least one C-terminal tetratrico peptide repeat (TPR) domain.
- TPR C-terminal tetratrico peptide repeat
- the SMYD proteins have been found to be linked to various cancers (See e.g., Hamamoto et al. Nat Cell. Biol. 2004, 6: 731-740), Hu et al. Cancer Research 2009, 4067-4072, and Komatsu et al. Carcinogenesis 2009, 301139-1146.)
- SMYD3 is a protein methyltransferase found to be expressed at high levels in a number of different cancers (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004)). SMYD3 likely plays a role in the regulation of gene transcription and signal transduction pathways critical for survival of breast, liver, prostate and lung cancer cell lines (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004); Hamamoto, R., et al., Cancer Sci., 97(2):113-8 (2006); Van Aller, G. S., et al., Epigenetics, 7(4):340-3 (2012); Liu, C., et al., J. Natl. Cancer Inst., 105(22):1719-28 (2013): Mazur, P. K., et al., Nature, 510(7504):283-7 (2014)).
- RNAi-based technologies have shown that ablation of SMYD3 in hepatocellular carcinoma cell lines greatly reduces cell viability and that its pro-survival role is dependent on its catalytic activity (Hamamoto. R., et al., Nat. Cell Biol., 6(8):731-40 (2004); Van Aller, G. S., et al., Epigenetics, 7(4):340-3 (2012)).
- SMYD3 has also been shown to be a critical mediator of transformation resulting from gain of function mutations in the oncogene, KRAS for both pancreatic and lung adenocarcinoma in mouse models.
- SMYD3 function has also been shown to play a role in immunology and development. For instance, de Almeida reported that SMYD3 plays a role in generation of inducible regulatory T cells (iTreg) cells.
- iTreg inducible regulatory T cells
- SMYD3 ⁇ / ⁇ mice demonstrated exacerbation of RSV-induced disease related to enhanced proinflammatory responses and worsened pathogenesis within the lung (de Almeida et al. Mucosal Immunol. 2015 Feb. 11. doi: 10.1038/mi.2015.4. [Epub ahead of print]).
- SMYD2 (SET and MYND domain-containing protein 2) was first characterized as protein that is a member of a sub-family of SET domain containing proteins which catalyze the site-specific transfer of methyl groups onto substrate proteins.
- SMYD2 was initially shown to have methyltransferase activity towards lysine 36 on histone H3 (H3K36) but has subsequently been shown to have both histone and non-histone methyltrasferase activity.
- SMYD2 has been implicated in the pathogenesis of multiple cancers. It has been shown to be over-expressed, compared to matched normal samples, in tumors of the breast, cervix, colon, kidney, liver, head and neck, skin, pancreas, ovary, esophagus and prostate, as well as hematologic malignancies such as AML, B- and T-ALL, CLL and MCL, suggesting a role for SMYD2 in the biology of these cancers. More specifically, studies using genetic knock-down of SMYD2 have demonstrated anti-proliferative effects in esophageal squamous cell carcinoma (ESCC), bladder carcinoma and cervical carcinoma cell lines.
- ESCC esophageal squamous cell carcinoma
- SMYD2 has also been implicated in immunology. For instance, Xu et al. have shown that SMYD2 is a negative regulator of macrophage activation by suppressing Interleukin-6 and TNF-alpha production. (Xu et al., J Biol Chem. 2015 Feb. 27; 290(9):5414-23).
- the present disclosure provides a method of treating cancer in a patient comprising administering a therapeutically effective amount of a Compound of the Disclosure.
- Compounds of the Disclosure can treat cancer by inhibiting SMYD proteins, such as SMYD3 and SMYD2.
- treatable cancers include, but are not limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell
- Schwannomatosis seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma.
- Sezary's disease small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.
- the cancer is breast, cervix, colon, kidney, liver, head and neck, skin, pancreas, ovary, esophagus, or prostate cancer.
- the cancer is a hematologic malignancy such as acute myeloid leukemia (AML), B- and T-acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or mantle cell lymphoma (MCL).
- AML acute myeloid leukemia
- ALL B- and T-acute lymphoblastic leukemia
- CLL chronic lymphocytic leukemia
- MCL mantle cell lymphoma
- the cancer is esophageal squamous cell carcinoma (ESCC), bladder carcinoma, or cervical carcinoma.
- ESCC esophageal squamous cell carcinoma
- bladder carcinoma esophageal squamous cell carcinoma
- cervical carcinoma esophageal squamous cell carcinoma
- the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukemia (MLL).
- the cancer is NUT-midline carcinoma.
- the cancer is multiple myeloma.
- the cancer is a lung cancer such as small cell lung cancer (SCLC).
- SCLC small cell lung cancer
- the cancer is a neuroblastoma.
- the cancer is Burkitt's lymphoma.
- the cancer is cervical cancer.
- the cancer is esophageal cancer.
- the cancer is ovarian cancer.
- the cancer is colorectal cancer.
- the cancer is prostate cancer.
- the cancer is breast cancer.
- the present disclosure provides a therapeutic method of modulating protein methylation, gene expression, cell proliferation, cell differentiation and/or apoptosis in vivo in the cancers mentioned above by administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need of such therapy.
- Compounds of the Disclosure can be administered to a mammal in the form of a raw chemical without any other components present.
- Compounds of the Disclosure can also be administered to a mammal as part of a pharmaceutical composition containing the compound combined with a suitable pharmaceutically acceptable carrier.
- a suitable pharmaceutically acceptable carrier can be selected from pharmaceutically acceptable excipients and auxiliaries.
- pharmaceutically acceptable carrier or “pharmaceutically acceptable vehicle” encompasses any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Suitable pharmaceutically acceptable vehicles include aqueous vehicles and nonaqueous vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 19th ed. 1995.
- compositions within the scope of the present disclosure include all compositions where a Compound of the Disclosure is combined with one or more pharmaceutically acceptable carriers.
- the Compound of the Disclosure is present in the composition in an amount that is effective to achieve its intended therapeutic purpose. While individual needs may vary, a determination of optimal ranges of effective amounts of each compound is within the skill of the art.
- a Compound of the Disclosure can be administered to a mammal, e.g., a human, orally at a dose of from about 0.0025 to about 1500 mg per kg body weight of the mammal, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, per day to treat the particular disorder.
- a useful oral dose of a Compound of the Disclosure administered to a mammal is from about 0.0025 to about 50 mg per kg body weight of the mammal, or an equivalent amount of the pharmaceutically acceptable salt or solvate thereof.
- the dose is typically about one-half of the oral dose.
- a unit oral dose may comprise from about 0.01 mg to about 1 g of the Compound of the Disclosure, e.g., about 0.01 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, 0.01 mg to about 50 mg, e.g., about 0.1 mg to about 10 mg, of the compound.
- the unit dose can be administered one or more times daily, e.g., as one or more tablets or capsules, each containing from about 0.01 mg to about 1 g of the compound, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.
- a pharmaceutical composition of the present disclosure can be administered to any patient that may experience the beneficial effects of a Compound of the Disclosure.
- mammals e.g., humans and companion animals, although the disclosure is not intended to be so limited.
- the patient is a human.
- a pharmaceutical composition of the present disclosure can be administered by any means that achieves its intended purpose.
- administration can be by the oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, intranasal, transmucosal, rectal, intravaginal or buccal route, or by inhalation.
- the dosage administered and route of administration will vary, depending upon the circumstances of the particular subject, and taking into account such factors as age, gender, health, and weight of the recipient, condition or disorder to be treated, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
- a pharmaceutical composition of the present disclosure can be administered orally.
- a pharmaceutical composition of the present disclosure can be administered orally and is formulated into tablets, dragees, capsules, or an oral liquid preparation.
- the oral formulation comprises extruded multiparticulates comprising the Compound of the Disclosure.
- a pharmaceutical composition of the present disclosure can be administered rectally, and is formulated in suppositories.
- composition of the present disclosure can be administered by injection.
- composition of the present disclosure can be administered transdermally.
- composition of the present disclosure can be administered by inhalation or by intranasal or transmucosal administration.
- composition of the present disclosure can be administered by the intravaginal route.
- a pharmaceutical composition of the present disclosure can contain from about 0.01 to 99 percent by weight, e.g., from about 0.25 to 75 percent by weight, of a Compound of the Disclosure, e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% by weight of a Compound of the Disclosure.
- a Compound of the Disclosure e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% by weight of a Compound of the Disclosure.
- a pharmaceutical composition of the present disclosure is manufactured in a manner which itself will be known in view of the instant disclosure, for example, by means of conventional mixing, granulating, dragee-making, dissolving, extrusion, or lyophilizing processes.
- pharmaceutical compositions for oral use can be obtained by combining the active compound with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
- Suitable excipients include fillers such as saccharides (for example, lactose, sucrose, mannitol or sorbitol), cellulose preparations, calcium phosphates (for example, tricalcium phosphate or calcium hydrogen phosphate), as well as binders such as starch paste (using, for example, maize starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
- saccharides for example, lactose, sucrose, mannitol or sorbitol
- cellulose preparations for example, calcium phosphates (for example, tricalcium phosphate or calcium hydrogen phosphate)
- binders such as starch paste (using, for example, maize starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl
- one or more disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
- Dragee cores are provided with suitable coatings that are resistant to gastric juices.
- suitable coatings that are resistant to gastric juices.
- concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
- suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate can be used.
- Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
- Examples of other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, or soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
- the push-fit capsules can contain a compound in the form of granules, which can be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers, or in the form of extruded multiparticulates.
- the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin.
- stabilizers can be added.
- Possible pharmaceutical preparations for rectal administration include, for example, suppositories, which consist of a combination of one or more active compounds with a suppository base.
- Suitable suppository bases include natural and synthetic triglycerides, and paraffin hydrocarbons, among others. It is also possible to use gelatin rectal capsules consisting of a combination of active compound with a base material such as, for example, a liquid triglyceride, polyethylene glycol, or paraffin hydrocarbon.
- Suitable formulations for parenteral administration include aqueous solutions of the active compound in a water-soluble form such as, for example, a water-soluble salt, alkaline solution, or acidic solution.
- a suspension of the active compound can be prepared as an oily suspension.
- Suitable lipophilic solvents or vehicles for such as suspension may include fatty oils (for example, sesame oil), synthetic fatty acid esters (for example, ethyl oleate), triglycerides, or a polyethylene glycol such as polyethylene glycol-400 (PEG-400).
- An aqueous suspension may contain one or more substances to increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
- the suspension may optionally contain stabilizers.
- kits which comprise a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a manner that facilitates their use to practice methods of the present disclosure.
- the kit includes a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the disclosure.
- the compound or composition is packaged in a unit dosage form.
- the kit further can include a device suitable for administering the composition according to the intended route of administration.
- Compound A is converted to compound B (i.e, a compound having Formula VII, wherein X is —S( ⁇ O) 2 —) by coupling with a suitable sulfonyl chloride (Z—SO 2 Cl) in the presence of a suitable base such as TEA or DIPEA in a suitable solvent such as dichloromethane, acetonitrile, or DMF.
- a suitable base such as TEA or DIPEA
- a suitable solvent such as dichloromethane, acetonitrile, or DMF.
- Compound A was converted to compound C by coupling with a suitable carboxylic acid (ZCO 2 H) in the presence of a suitable coupling reagent such as HATU or HOBT in the presence of a suitable base such as TEA or DIPEA in a suitable solvent such as DMF.
- a suitable coupling reagent such as HATU or HOBT
- a suitable base such as TEA or DIPEA
- a suitable solvent such as DMF.
- Compound A can also be converted to compound C by coupling with a suitable acid chloride (ZCOCl) in the presence of a suitable base such as TEA or DIPEA in the presence of a suitable solvent such as dichloromethane, acetonitrile or DMF.
- Compound purification was carried out as needed using a variety of traditional methods including, but not limited to, preparative chromatography under acidic, neutral, or basic conditions using either normal phase or reverse phase HPLC or flash columns or Prep-TLC plates.
- Compound purity and mass confirmations were conducted using standard HPLC and/or UPLC and/or MS spectrometers and/or LCMS and/or GC equipment (i.e., including, but not limited to the following instrumentation: Waters Alliance 2695 with 2996 PDA detector connected with ZQ detector and ESI source: Shimadzu LDMS-2020; Waters Acquity H Class with PDA detector connected with SQ detector and ESI source; Agilent 1100 Series with PDA detector; Waters Alliance 2695 with 2998 PDA detector; AB SCIEX API 2000 with ESI source; Agilent 7890 GC).
- Step 4 Synthesis of Tert-Butyl 4-(1-(5-cyclopropylisoxazole-3-carboxamido)ethyl)piperidine-1-carboxylate
- tert-Butyl 4-(amino(phenyl)methyl)piperidine-1-carboxylate was added (0.070 g, 0.41 mmol) in DCM (5 mL) followed by triethylamine (0.23 mL, 0.17 mmol). The reaction was stirred at RT for 1 hr. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with sodium bicarbonate and, extracted with DCM.
- Step 1 Synthesis of Tert-Butyl ((2S)-1-(4-(1-(5-cyclopropylisoxazole-3-carboxamido)ethyl)piperidin-1-yl)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)carbamate
- Step 2 Synthesis of N-1-(1-((S)-2-amino-3-(4-hydroxyphenyl)propanoyl)piperidin-4-yl)ethyl)-5-cyclopropylisoxazole-3-carboxamide Hydrochloride
- Step 1 Synthesis of tert-butyl ((S)-1-(4-((S)-(5-cyclopropylisoxazole-3-carboxamido)(phenyl)methyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate and tert-butyl ((S)-1-(4-((R)-(5-cyclopropylisoxazole-3-carboxamido)(phenyl)methyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate
- Step 2 Synthesis of N—((S)-(1-((S)-2-aminopropanoyl)piperidin-4-yl)(phenyl)methyl)-5-cyclopropylisoxazole-3-carboxamide Hydrochloride
- Step 2 Synthesis of N—((R)-(1-((S)-2-aminopropanoyl)piperidin-4-yl)(phenyl)methyl)-5-cyclopropylisoxazole-3-carboxamide Hydrochloride
- Step 2 Synthesis of tert-butyl 4-(3-(methoxycarbonyl)benzoyl)piperidine-1-carboxylate
- Step 4 Synthesis of tert-butyl 4-((5-cyclopropylisoxazole-3-carboxamido)(3-(methoxycarbonyl)phenyl)methyl)piperidine-1-carboxylate
- Step 5 Synthesis of 3-((1-(tert-butoxycarbonyl)piperidin-4-yl)(5-cyclopropylisoxazole-3-carboxamido)methyl)benzoic Acid
- Step 6 Synthesis of Tert-Butyl 4-((5-cyclopropylisoxazole-3-carboxamido)(3-(pyridin-3-ylcarbamoyl)phenyl)methyl)piperidine-1-carboxylate
- Step 7 Synthesis of 5-cyclopropyl-N-(piperidin-4-yl(3-(pyridin-3-ylcarbamoyl)phenyl)methyl)isoxazole-3-carboxamide Hydrochloride
- Step 8 Synthesis of Tert-butyl ((2S)-1-(4-((5-cyclopropylisoxazole-3-carboxamido)(3-(pyridin-3-ylcarbamoyl)phenyl)methyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate
- Step 9 Synthesis of N-((1-((S)-2-aminopropanoyl)piperidin-4-yl)(3-(pyridin-3-ylcarbamoyl)phenyl)methyl)-5-cyclopropylisoxazole-3-carboxamide Hydrochloride
- Step 1 Synthesis of (S)-tert-butyl (1-(4-((5-cyclopropylisoxazole-3-carboxamido)methyl)piperidin-1l-yl)-3-methyl-1-oxobutan-2-yl)carbamate
- Step 2 Synthesis of (S)—N-((1-(2-amino-3-methylbutanoyl)piperidin-4-yl)methyl)-5-cyclopropylisoxazole-3-carboxamide Hydrochloride
- Step 1 Synthesis of (E)-1-(4-aminophenyl)-3-(pyridin-3-yl)prop-2-en-1-one
- Step 3 Synthesis of 5-cyclopropyl-N-(4-(3-(pyridin-3-yl)propanoyl)phenyl)isoxazole-3-carboxamide
- Triethylamine (0.35 mL, 2.61 mmol) and a solution of 1-(4-aminophenyl)-3-(pyridin-3-yl)propan-1-one (0.354 g, 1.56 mmol) in DCM (1 mL) was added at 0° C. to the reaction mixture. The mixture was stirred at rt for 1 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was quenched with saturated NaHCO 3 solution and extracted with DCM.
- Step 4 Synthesis of N-(4-(1-amino-3-(pyridin-3-yl)propyl)phenyl)-5-cyclopropylisoxazole-3-carboxamide
- Step 1 Synthesis of (S)-Tert-butyl (1-((4-(5-cyclopropylisoxazole-3-carboxamido)butyl) amino)-1-oxopropan-2-yl)carbamate
- Step 2 Synthesis of (S)—N-(4-(2-aminopropanamido)butyl)-5-cyclopropylisoxazole-3-carboxamide Hydrochloride
- Step 4 Synthesis of Tert-Butyl ((1r,4r)-4-(5-(2-hydroxyethyl)isoxazole-3-carboxamido)cyclohexyl)carbamate
- Step 5 Synthesis of N-((1r,4r)-4-aminocyclohexyl)-5-(2-hydroxyethyl)isoxazole-3-carboxamide Hydrochloride
- Step 3 Synthesis of Tert-Butyl ((1r,4r)-4-(5-cyclopropyl-4-iodoisoxazole-3-carboxamido)cyclohexyl)carbamate
- Step 4 Synthesis of N-((1r,4r)-4-aminocyclohexyl-5-cyclopropyl-4-iodoisoxazole-3-carboxamide Hydrochloride
- Step 1 Synthesis of 3-(((r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-5-cyclopropylisoxazole-4-carboxylic Acid
- Step 2 Synthesis of Pentafluorophenyl 3-(((1r,4r)-4-((tert-butoxycarbonyl)amino) cyclohexyl)carbamoyl)-5-cyclopropylisoxazole-4-carboxylate
- Step 3 Synthesis of Tert-Butyl ((1r,4r)-4-(4-carbamoyl-5-cyclopropylisoxazole-3-carboxamido)cyclohexyl)carbamate
- the material was purified by trituration with hexane and diethyl ether to obtain tert-butyl ((1 r,4r)-4-4-carbamoyl-5-cyclopropylisoxazole-3-carboxamido)cyclohexyl) carbamate (0.040 g, 71%.).
- Step 4 Synthesis of N3-((1r,4r)-4-aminocyclohexyl)-5-cyclopropylisoxazole-3,4-dicarboxamide Hydrochloride
- Step 1 Synthesis of N 2 ,N 6 -dibenzylbicyclo[3.3.1]nonane-2,6-diamine
- Step 6 Synthesis of Tert-Butyl ((2R)-4-((6-(5-cyclopropylisoxazole-3-carboxamido) bicyclo[3.3.1]nonan-2-yl)amino)-4-oxobutan-2-yl)carbamate
- Step 7 Synthesis of N-(6-((R)-3-aminobutanamido)bicyclo[3.3.]nonan-2-yl)-5-cyclopropylisoxazole-3-carboxamide
- Step 2 Synthesis of Tert-Butyl 3-(4-(5-cyclopropylisoxazole-3-carboxamido) phenylamino)-3-oxopropylcarbamate
- N-(4-aminophenyl)-5-cyclopropylisoxazole-3-carboxamide (170 mg, 0.70 mmol, 1.00 equiv), tetrahydrofuran (5 mL), dichloromethane (5 mL), EDCI (401 mg, 2.09 mmol, 2.99 equiv), DIEA (271 mg, 2.10 mmol, 3.00 equiv), HOBT (283 mg, 2.09 mmol, 3.00 equiv), and 3-[[(tert-butoxy)carbonyl]amino]propanoic acid (264 mg, 1.40 mmol, 2.00 equiv).
- Step 3 Synthesis of N-(4-(3-aminopropanamido)phenyl)-5-cyclopropylisoxazole-3-carboxamide Hydrochloride
- Step 1 Synthesis of Tert-Butyl 3-(5-cyclopropylisoxazole-3-carboxamido)azetidine-1-carboxylate
- Step 3 Synthesis of N-(1-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-5-cyclopropylisoxazole-3-carboxamide
- SAM S-adenosylmethionine
- SAH S-adenosylhomocysteine
- Tris Tris
- Tween20 dimethylsulfoxide (DMSO)
- BSG bovine skin gelatin
- TCEP Tris(2-carboxyethyl)phosphine hydrochloride solution
- 3 H-SAM was purchase from American Radiolabeled Chemicals with a specific activity of 80 Ci/mmol.
- 384-well opaque white OptiPlates and SPA beads (Perkin Elmer, catalog # RPNQ0013) were purchased from PerkinElmer.
- MEKK2 N-terminally GST-tagged MEKK2 (MAP3K2) protein corresponding to reference sequence AAF63496.3 was purchased from Life Technologies (catalog # PV4010). This protein was expressed in High Five insect cells and purified to >85% purity. Protein identity was confirmed by MS/MS analysis after proteolytic digestion. The protein sequence used was:
- Full-length human SMYD3 isoform 1 (BAB86333) was inserted into a modified pET21 b plasmid containing a His6 tag and TEV and SUMO cleavage sites. Because two common variants of SMYD3 exist in the population, site directed mutagenesis was subsequently performed to change amino acid 13 from an asparagine to a lysine, resulting in plasmid pEPZ533. A lysine at position 13 conforms to the more commonly occurring sequence (NP_001161212).
- E. coli (BL21 codonplus RIL strain, Stratagene) were transformed with plasmid pEPZ553 by mixing competent cells and plasmid DNA and incubating on ice for 30 minutes followed by heat shock at 42° C. for 1 minute and cooling on ice for 2 minutes. Transformed cells were grown and selected on LB agar with 100 ⁇ g/mL ampicillin and 17 ⁇ g/mL chloramphenicol at 37° C. overnight. A single clone was used to inoculate 200 mL of LB medium with 100 g/mL ampicillin and 17 ⁇ g/mL chloramphenicol and incubated at 37° C. on an orbital shaker at 180 rpm.
- the culture was diluted 1:100 into 2 L of LB medium and grown until OD 600 was about 0.3 after which the culture was incubated at 15° C. and 160 rpm. Once OD 600 reached about 0.4, IPTG was added to a final concentration of 0.1 mM and the cells were grown overnight at 15° C. and 160 rpm. Cells were harvested by centrifugation at 8000 rpm, for 4 minutes at 4° C. and stored at ⁇ 80° C. for purification.
- Expressed full-length human His-tagged SMYD3 protein was purified from cell paste by Nickel affinity chromatography after equilibration of the resin with Buffer A (25 mM Tris, 200 mM NaCl, 5% glycerol, 5 mM ⁇ -mercaptoethanol, pH7.8).
- Buffer A 25 mM Tris, 200 mM NaCl, 5% glycerol, 5 mM ⁇ -mercaptoethanol, pH7.8.
- the column was washed with Buffer B (Buffer A plus 20 mM imidazole) and His-tagged SMYD3 was eluted with Buffer C (Buffer A plus 300 mM imidazole).
- Buffer A Buffer A plus 20 mM imidazole
- Buffer C Buffer A plus 300 mM imidazole.
- the His tag, TEV and SUMO cleavage sites were removed generating native SMYD3 by addition of ULP1 protein at
- Imidazole was removed by dialysis overnight in Buffer A.
- the dialyzed solution was applied to a second Nickel column and the native SMYD3 protein was collected from the column flow-through.
- the flow-through was dialyzed in Buffer D (25 mM Tris, 5% glycerol, 5 mM ⁇ -mercaptoethanol, 50 mM NaCl, pH7.8) and ULP1 was removed using a Q sepharose fast flow column.
- SMYD3 was eluted in Buffer A and further purified using an S200 size-exclusion column equilibrated with Buffer A. SMYD3 was concentrated to 2 mg/mL with a final purity of 89%.
- SMYD3 (Q9H7B4) (SEQ ID No. 2).
- MEPLKVEKFATAKRGNGLRAVTPLRPGELLFRSDPLAYTVCKGSRGVVCD RCLLGKEKLMRCSQCRVAKYCSAKCQKKAWPDHKRECKCLKSCKPRYPPD
- SVRLLGRVVFKLMDGAPSESEKLYSFYDLESNINKLTEDKKEGLRQLVMT FQHFMREEIQDASQLPPAFDLFEAFAKVICNSFTICNAEMQEVGVGLYPS ISLLNHSCDPNCSIVFNGPHLLLRAVRDIEVGEELTICYLDMLMTSEERR KQLRDQYCFECDCFRCQTQDKDADMLTGDEQVWKEVQESLKKIEELKAHW KWEQVLAMCQAIISSNSERLPDINIYQLKVLDCAMDACINLGLLEEALFY GTRTMEPYRIFFPGSHPVRGVQVMKVGKLQLHQGMFPQAMKNLRLAFD
- the assays were all performed in a buffer consisting of 25 mM Tris-Cl pH 8.0, 1 mM TCEP, 0.005% BSG, and 0.005% Tween 20, prepared on the day of use.
- Compounds in 100% DMSO (1 ul) were spotted into a 384-well white opaque OptiPlate using a Bravo automated liquid handling platform outfitted with a 384-channel head (Agilent Technologies).
- DMSO (1 ul) was added to Columns 11, 12, 23, 24, rows A-H for the maximum signal control and 1 ul of SAH, a known product and inhibitor of SMYD3, was added to columns 11, 12, 23, 24, rows I-P for the minimum signal control.
- the assays were stopped by the addition of non-radiolabeled SAM (10 ul) to a final concentration of 100 uM, which dilutes the 3 H-SAM to a level where its incorporation into MEKK2 is no longer detectable.
- Radiolabeled MEKK2 was detected using a scintillation proximity assay (SPA). 10 uL of a 10 mg/mL solution of SPA beads in 0.5 M citric acid was added and the plates centrifuged at 600 rpm for 1 min to precipitate the radiolabeled MEKK2 onto the SPA beads. The plates were then read in a PerkinElmer TopCount plate reader to measure the quantity of 3 H-labeled MEKK2 as disintegrations per minute (dpm) or alternatively, referred to as counts per minute (cpm).
- dpm disintegrations per minute
- cpm counts per minute
- % ⁇ ⁇ inh 100 - ( dpm cmpd - dpm m ⁇ ⁇ i ⁇ ⁇ n dpm ma ⁇ ⁇ x - dpm m ⁇ ⁇ i ⁇ ⁇ n ) ⁇ 100
- top and bottom are the normally allowed to float, but may be fixed at 100 or 0 respectively in a 3-parameter fit.
- the Hill Coefficient normally allowed to float but may also be fixed at 1 in a 3-parameter fit.
- Y is the % inhibition and X is the compound concentration.
- 293T/17 adherent cells were purchased from ATCC (American Type Culture Collection), Manassas, Va., USA.
- MEM/Glutamax medium, Optimem Reduced Serum medium, penicillin-streptomycin, 0.05% trypsin and 1 ⁇ D-PBS were purchased from Life Technologies, Grand Island, N.Y., USA.
- PBS-10X was purchased from Ambion, Life Technologies, Grand Island. N.Y., USA.
- PBS with Tween 20 (PBST (10 ⁇ ) was purchased from KPL, Gaithersburg, Md., USA.
- Tet System FBS— approved FBS US Source was purchased from Clontech. Mountain View, Calif., USA.
- Tri-methyl-Lysine [A260]-MEKK2 antibody, MEKK2 and SMYD3 plasmids were made at Epizyne.
- Anti-flag monoclonal mouse antibody was purchased from Sigma, St. Louis, Mo., USA.
- Methanol was purchased from VWR. Franklin, Mass., USA.
- 10% Tween 20 was purchased from KPL, Inc., Gaithersburg, Md. USA. Fugene was purchased from Promega, Madison, Wis., USA.
- the Biotek ELx405 was purchased from BioTek, Winooski, Vt., USA.
- the multidrop combi was purchased from Thermo Scientific, Waltham, Mass., USA.
- 293T/17 adherent cells were maintained in growth medium (MEM/Glutamax medium supplemented with 10% v/v Tet System FBS and cultured at 37° C. under 5% CO 2 .
- 293T/17 cells were seeded in assay medium at a concentration of 33,333 cells per cm 2 in 30 mL medium per T150 flask and incubated at 37° C. under 5% CO 2 . Plasmids were prepared for delivery to cells by first mixing 1350 ⁇ L Opti-MEM with Fugene (81 ⁇ L) in a sterile Eppendorf and incubated for five minutes at room temperature (RT).
- MEKK2-flag (13.6 ug/T150)
- SMYD3 p3XFlag-CMV-14 without C-3XFlag plasmids were aliquotted to a 1.7 mL sterile microfuge tube.
- the gene ID for MEKK2 and SMYD3 is NM_006609.3 and Q9H7B4, respectively.
- Entire volume of Opti-MEM/Fugene mixture was then added to a microfuge tube containing DNA plasmid, mixed and then incubated ⁇ 15 minutes at RT.
- the medium on the 293T/17 cells was refreshed, and the DNA/Fugene complex is added aseptically to each flask, rocked gently, and incubated at 37 C for 5 hours. Medium was then removed, and cells were washed once with PBS in the flask. Trypsin 0.05% (3 mL) was added and cells incubated for three minutes. Room temperature MEM+10% Tet system FBS was added and cells were mixed gently, and counted using the Vi-cell. Cells were seeded at 100,000 cells/mL in 50 ⁇ L MEM/10% Tet FBS/Pen/Strep to a 384 well black/clear poly-D-lysine coated plate containing test agent diluted in DMSO.
- test compound was 40 ⁇ M.
- the total concentration of DMSO did not exceed 0.2% (v/v).
- Plates were incubated ⁇ 30 minutes at RT in low-airflow area, followed by incubation at 37° C. under 5% CO 2 for 24 hours.
- Medium was aspirated from all wells of assay plates prior to fixation and permeabilization with ice cold ( ⁇ 20° C.) methanol (90 ⁇ L/well) for ten minutes. Plates were rinsed with PBS three times on BioTek ELx405. PBS was removed with a final aspiration, and Odyssey blocking buffer (50 ⁇ L/well) was added to each well and incubated for one hour at RT.
- Detection antibody solution (IRDye 800 CW goat anti-rabbit IgG diluted 1:400 in diluent (Odyssey Blocking buffer+0.1% Tween 20), plus IRDye 680CW goat anti-mouse IgG at 1:500 in diluent (Odyssey Blocking buffer+0.1% Tween 20) was added (20 ⁇ L/well) and incubated in dark for one hour at RT. Plates were then washed four times with PBS-T (1X) on ELx405. A final rinse with water was performed (115 ⁇ L/well ⁇ three washes on the ELx405).
- Each plate included fourteen control wells of DMSO only treatment (Minimum Inhibition) as well as fourteen control wells for maximum inhibition (Background). The average of the ratio values for each control type was calculated and used to determine the percent inhibition for each test well in the plate. Reference compound was serially diluted two-fold in DMSO for a total of nine test concentrations, beginning at 40 ⁇ M. Percent inhibition was calculated (below).
- Percent ⁇ ⁇ Inhibition 100 - ( ( ( individual ⁇ ⁇ Test ⁇ ⁇ Sample ⁇ ⁇ Ratio ) - ( Background ⁇ ⁇ Avg ⁇ ⁇ Ratio ) ( Minimum ⁇ ⁇ inhibition ⁇ ⁇ Ratio ) ⁇ ( Background ⁇ ⁇ Average ⁇ ⁇ Ratio ) ) * 100 )
- Non-linear regression curves were generated to calculate the IC 50 and dose-response relationship using triplicate wells per concentration of compound.
- SAM S-adenosylmethionine
- SAH S-adenosylhomocysteine
- bicine Tween20
- dimethylsulfoxide DMSO
- bovine skin gelatin BSG
- Tris(2-carboxyethyl)phosphine hydrochloride TCEP
- 3H-SAM was purchase from American Radiolabeled Chemicals with a specific activity of 80 Ci/mmol.
- 384-well streptavidin Flashplates were purchased from PerkinElmer.
- Peptide was synthesized with a N-terminal linker-affinity tag motif and a C-terminal amide cap by 21 st Century Biochemicals.
- the peptide was high high-performance liquid chromatography (HPLC) purified to greater than 95% purity and confirmed by liquid chromatography mass spectrometry (LC-MS).
- HPLC high-performance liquid chromatography
- LC-MS liquid chromatography mass spectrometry
- SMYD2 Full length SMYD2 (NP_064582.2) was cloned into a pFastbac-Htb-lic vector with an N-terminal His6 tag and FLAG tag, preceded by a TEV protease cleavage site.
- the protein was expressed in Sf9 insect cells. Cells were resuspended in lysis buffer (25 mM HEPES-NaOH, pH 7.5, 200 mM NaCl, 5% glycerol, and 5 mM ⁇ -ME) and lysed by sonication.
- lysis buffer 25 mM HEPES-NaOH, pH 7.5, 200 mM NaCl, 5% glycerol, and 5 mM ⁇ -ME
- the protein was purified by Ni-NTA (Qiagen), followed by TEV cleavage to remove the His6 tag, subtractive Ni-NTA (Qiagen), and gel filtration chromatography using an S200 column (GE Healthcare). Purified protein was stored in 20 mM Tris-HCl, pH 8.0, 100 mM NaCl. and 1 mM TCEP.
- Compounds in 100% DMSO (1 ul) were spotted into a polypropylene 384-well V-bottom plates (Greiner) using a Platemate Plus outfitted with a 384-channel head (Thermo Scientific).
- DMSO (1 ul) was added to Columns 11, 12, 23, 24, rows A-H for the maximum signal control and 1 ul of SAH, a known product and inhibitor of SMYD2, was added to columns 11, 12, 23, 24, rows I-P for the minimum signal control.
- the assays were stopped by the addition of non-radioactive SAM (10 ul) to a final concentration of 600 uM, which dilutes the 3 H-SAM to a level where its incorporation into the peptide substrate is no longer detectable.
- 50 ul of the reaction in the 384-well polypropylene plate was then transferred to a 384-well Flashplate and the biotinylated peptides were allowed to bind to the streptavidin surface for at least 1 hour before being washed three times with 0.1% Tween20 in a Biotek ELx405 plate washer.
- the plates were then read in a PerkinElmer TopCount plate reader to measure the quantity of 3 H-labeled peptide bound to the Flashplate surface, measured as disintegrations per minute (dpm) or alternatively, referred to as counts per minute (cpm).
- top and bottom are the normally allowed to float, but may be fixed at 100 or 0 respectively in a 3-parameter fit.
- the Hill Coefficient normally allowed to float but may also be fixed at 1 in a 3-parameter fit.
- I is the compound concentration.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present disclosure provides substituted isoxazole carboxamide compounds having Formula (1) and the pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, A, X, and Z are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to treat a disorder responsive to the blockade of SMYD proteins such as SMYD3 or SMYD2 Compounds of the present disclosure are especially useful for treating cancer.
Description
- The present disclosure provides substituted isoxazole carboxamides as SMYD protein inhibitors, such as SMYD3 and SMYD2 inhibitors, and therapeutic methods of treating conditions and diseases wherein inhibition of SMYD proteins such as SMYD3 and SMYD2 provides a benefit.
- Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases. Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., SMYD proteins such as SMYD3 and SMYD2), many of which are associated with genetic alterations that can cause human disease, such as proliferative disorders. Thus, there is a need for the development of small molecules that are capable of inhibiting the activity of SMYD proteins such as SMYD3 and SMYD2.
- In one aspect, the present disclosure provides substituted isoxazole carboxamide compounds represented by Formulae I-XVII below, and the pharmaceutically acceptable salts and solvates thereof, collectively referred to herein as “Compounds of the Disclosure.”
- In another aspect, the present disclosure provides a Compound of the Disclosure and one or more pharmaceutically acceptable carriers.
- In another aspect, the present disclosure provides a method of inhibiting SMYD proteins, such as SMYD3 or SMYD2, or both, in a mammal, comprising administering to the mammal an effective amount of at least one Compound of the Disclosure.
- In another aspect, the present disclosure provides methods for treating a disease, disorder, or condition, e.g., cancer, responsive to inhibition of SMYD proteins, such as SMYD3 or SMYD2, or both, comprising administering a therapeutically effective amount of a Compound of the Disclosure.
- In another aspect, the present disclosure provides the use of Compounds of the Disclosure as inhibitors of SMYD3.
- In another aspect, the present disclosure provides the use of Compounds of the Disclosure as inhibitors of SMYD2.
- In another aspect, the present disclosure provides the use of Compounds of the Disclosure as inhibitors of SMYD proteins.
- In another aspect, the present disclosure provides a pharmaceutical composition for treating a disease, disorder, or condition responsive to inhibition of SMYD proteins, such as SMYD3 or SMYD2, or both, wherein the pharmaceutical composition comprises a therapeutically effective amount of a Compound of the Disclosure in a mixture with one or more pharmaceutically acceptable carriers.
- In another aspect, the present disclosure provides Compounds of the Disclosure for use in treating cancer in a mammal, e.g., breast, cervical, colon, kidney, liver, head and neck, skin, pancreatic, ovary, esophageal, lung, and prostate cancer.
- In another aspect, the present disclosure provides a Compound of the Disclosure for use in the manufacture of a medicament for treating cancer in a mammal.
- In another aspect, the present disclosure provides kit comprising a Compound of the Disclosure.
- Additional embodiments and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
- It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention as claimed.
- One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD proteins. In view of this property, the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions, e.g., cancer, responsive to inhibition of SMYD proteins.
- One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD3. In view of this property, the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions. e.g., cancer, responsive to inhibition of SMYD3.
- One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD2. In view of this property, the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions, e.g., cancer, responsive to inhibition of SMYD2.
- In one embodiment, Compounds of the Disclosure are compounds having Formula I:
- and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof wherein:
- R1 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-4 alkenyl, C1-4 haloalkyl, C3-6 cycloalkyl, and hydroxyalkyl;
- R2 is selected from the group consisting of hydrogen, halo, and carboxamido;
- A is selected from the group consisting of C1-10 alkylenyl, (cycloalkylenyl)alkyl, optionally substituted C3-12 cycloalkylenyl, optionally substituted C6-14 arylenyl, optionally substituted 5- to 14-membered heteroarylenyl, optionally substituted 4- to 14-membered heterocyclenyl, and —C(H)R3R4;
- with the provisos:
- a) when R1 is ethyl, n-propyl, isopropyl, isobutyl, or cyclopropyl; and R2 is hydrogen, then A is not optionally substituted, optionally bridged piperidinenyl;
- b) when R1 is ethyl or cyclopropyl; R2 is hydrogen; and X is —N(R7)S(—O)2—, —N(R7)C(═O)—, or —N(R7)C(═O)C(R8)(H)—, then A is not optionally substituted 1,4-cyclohexylenyl;
- c) when R1 is ethyl or cyclopropyl; R2 is hydrogen; X is absent; and Z is amino, alkylamino, dialkylamino, or heterocycloamino, then A is not optionally substituted 1,4-cyclohexylenyl; and
- d) when R1 is hydrogen. C1-6 alkyl, or Cm cycloalkyl; and R2 is hydrogen, then A is not optionally substituted pyrrolidinenyl;
- R3 is selected from the group consisting of hydrogen, C1-6 alkyl. (hydroxy)(aryl)alkyl, (amino)alkyl. (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, optionally substituted C3-12 cycloalkyl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted C6-14 aryl, aralkyl, alkoxycarbonyl, and —C(═O)N(R5)(R6);
- R4 is selected from the group consisting of C1-6 alkyl, hydroxyalkyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted 4- to 14-membered heterocyclo, and (heteroaryl)alkyl;
- R5 is selected from the from the group consisting of hydrogen and C1-4 alkyl;
- R6 is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, fluoroalkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(carboxamido)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (amino)(heteroaryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, (hydroxyalkylamino)alkyl, alkoxyalkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl optionally substituted C3-12 cycloalkyl, aralkyl, and (heteroaryl)alkyl;
- X is selected from the group consisting of —S(═O)2—, —S(═O)2N(R7)—, —N(R7)S(═O)2—, —S(═O)2C(R8)(H)—, —C(═O)—, —C(═O)N(R7)—, —N(R7)C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)C(R8)(H)N(R7)—, —N(R7)C(═O)C(R8)(H)—, —C(R8)(H)C(═O)N(R7)—, —C(R8)(H)N(R7)C(═O)—, and —C(═O)C(R8)(H)—; or X is absent, i.e., Z forms a bond with A;
- Z is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, fluoroalkyl, hydroxyalkyl, amino, alkylamino, dialkylamino, heterocycloamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (amino)(heteroaryl)alkyl (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, (hydroxyalkylamino)alkyl, alkoxyalkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl optionally substituted C3-12 cycloalkyl, aralkyl, and (heteroaryl)alkyl;
- wherein —X—Z is attached to any available carbon or nitrogen atom of A, R3, R4, or R6; e.g., when R4 is C1-6 alkyl. e.g., ethyl, a hydrogen atom of that ethyl group is replaced with —X—Z to give —CH2CH2—X—Z or
- or
- when R4 is optionally substituted C3-12 cycloalkyl, e.g., cyclohexyl, a hydrogen atom of the cyclohexyl group is replaced with —X—Z to give:
- or
- when R4 is optionally substituted 4- to 14-membered heterocyclo, e.g., piperidinyl, the hydrogen atom attached to the piperidinyl nitrogen atom is replaced with —X—Z to give:
- when R4 is optionally substituted C6-14 aryl, e.g., phenyl, a hydrogen atom on that phenyl group is replaced with —X—Z to give:
- R7 is selected from the group consisting of hydrogen and C1-4 alkyl; and
- R8 is selected from the group consisting of hydrogen, C1-4 alkyl, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, and hydroxyalkyl.
- In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein A is C1-10 alkylenyl.
- In another embodiment, Compounds of the Disclosure are compounds having Formula II:
- and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:
- R9a and R9b are independently selected from the group consisting of hydrogen and C1-4 alkyl;
- R9c and R9d are independently selected from the group consisting of hydrogen and C1-4alkyl; or
- R9c and R9d taken together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl;
- R9e is selected from the group consisting of hydrogen and C1-4 alkyl;
- m is 0 or 1:
- X is selected from the group consisting of —N(R7)C(═O)—, —N(R7)C(═O)C(R8)(H)—, and —N(R7)S(═O)2—;
- R8 is selected from the group consisting of C1-4 alkyl, amino, alkylamino, and dialkylamino; and
- Z is selected from the group consisting of C1-6 alkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C1-4, cycloalkyl, and R1, R2, and R7 are as defined above in connection with Formula I.
- In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein A is optionally substituted C6-14 arylenyl.
- In another embodiment, Compounds of the Disclosure are compounds having Formula III:
- and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:
- R10a is selected from the group consisting of hydrogen, halo, C1-6 alkyl, alkoxy, hydroxyalkyl, and alkoxycarbonyl;
- X is selected from the group consisting of —C(═O)N(R7)—, —N(R7)C(═O)—, —C(═O)C(R8)(H)N(R7)—, —C(R8)(H)C(═O)N(R7)— and —S(═O)2N(R7)—; or X is absent;
- R8 is selected from the group consisting of C1-4 alkyl, amino, alkylamino, and dialkylamino; and
- Z is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (amino)(heteroaryl)alkyl, heteroalkyl, (amino)(hydroxy)alkyl, (heterocyclo)alkyl, optionally substituted C3-12 cycloalkyl, and optionally substituted 4- to 14-membered heterocyclo, and R1, R2, and R7 are as defined above in connection with Formula I.
- In another embodiment, Compounds of the Disclosure are compounds having Formula IV:
- and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:
- R10a is selected from the group consisting of hydrogen, halo. C1-6 alkyl, alkoxy, hydroxyalkyl, and alkoxycarbonyl;
- X is selected from the group consisting of —C(═O)N(R7)—, —N(R7)C(═O)—, —C(═O)C(R8)(H)N(R7)—, —C(R8)(H)C(═O)N(R7)— and —S(═O)2N(R7)—; or X is absent;
- R8 is selected from the group consisting of C1-4 alkyl, amino, alkylamino, and dialkylamino; and
- Z is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (amino)(heteroaryl)alkyl, heteroalkyl, (amino)hydroxy)alkyl, (heterocyclo)alkyl, optionally substituted C3-12 cycloalkyl, and optionally substituted 4- to 14-membered heterocyclo, and R1, R2, and R7 are as defined above in connection with Formula I.
- In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein A is optionally substituted C3-12 cycloalkylenyl.
- In another embodiment, Compounds of the Disclosure are compounds having Formula V:
- and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:
- R10a and R10b are independently selected from the group consisting of hydrogen and C1-4 alkyl;
- X is selected from the group consisting of —S(═O)2—, —S(═O)2N(R7)—, —N(R7)C(═O)—, —C(═O)N(R7)—, —N(R7)S(═O)—, and —OC(═O)—; or X is absent;
- Z is selected from the group consisting of amino, alkylamino, dialkylamino, heterocycloamino. (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, and (hydroxyalkylamino)alkyl; n is 0 or 1; and p is 0 or 1, and R1, R2, and R7 are as defined above in connection with Formula I.
- In another embodiment. Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein A is optionally substituted 4- to 14-membered heterocyclenyl.
- In another embodiment, Compounds of the Disclosure are compounds having Formula VI:
- and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:
- R11a and R11b are each independently selected from the group consisting of hydrogen, C1-4 alkyl, and alkoxycarbonyl;
- X is selected from the group consisting of —C(═O)—, —S(═O)2—, and —C(═O)C(R8)(H)—;
- Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, optionally substituted C3-12 cycloalkyl, and aralkyl; and
- r is 0 or 1, and R1, R2, and R8 are as defined above in connection with Formula I.
- In another embodiment, Compounds of the Disclosure are compounds having Formula XVI:
- and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:
- R11c and R11d are each independently selected from the group consisting of hydrogen and C1-4 alkyl;
- X is selected from the group consisting of —C(═O)— and —S(═O)2; or X is absent; and
- Z, R1, and R2 are as defined above in connection with Formula I.
- In another embodiment, Compounds of the Disclosure are compounds having Formula XVI, and the pharmaceutically acceptable salts or solvates. e.g., hydrates, thereof, wherein R11c and R11d are hydrogen; X is absent; Z is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, fluoroalkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl. (dialkylamino)alkyl. (heterocyclo)alkyl, (cycloalkyl)alkyl, (hydroxy)(aryl)alkyl, alkoxyalkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C3-12 cycloalkyl, aralkyl, and (heteroaryl)alkyl; R2 is hydrogen; and R1 is as defined above in connection with Formula I. In another embodiment, Z is selected from the group consisting of aralkyl, and (heteroaryl)alkyl. In another embodiment. Z is (heteroaryl)alkyl that is substituted with an aralkyl, e.g.,
- or (heteroaryl)alkyl, e.g.,
- In another embodiment, R1 is selected from the group consisting of C1-4 alkyl and C3-6 cycloalkyl.
- In another embodiment, Compounds of the Disclosure are compounds having Formula XVII:
- and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:
- R″ is selected from the group consisting of aralkyl and (heteroaryl)alkyl; and
- R1 is as defined above in connection with Formula I.
- In another embodiment, Compounds of the Disclosure are compounds having Formula XVII, wherein R1 is selected from the group consisting of C1-6 alkyl and C3-6 cycloalkyl. In another embodiment, R″ is aralkyl. In another embodiment, R″ is (heteroaryl)alkyl. In another embodiment, R″ is benzyl wherein the phenyl group is optionally substituted with one or two substituents, e.g., —CH2(4-Cl-Ph), —CH2(3-Cl-Ph), —CH2(3,4-di-Cl-Ph), and —CH2(4-CF3-Ph).
- In another embodiment. Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein A is —C(H)R3R4. In another embodiment, R3 is selected from the group consisting of C1-6 alkyl and optionally substituted C3-12 cycloalkyl; and R4 is selected from the group consisting of optionally substituted C3-12 cycloalkyl and optionally substituted C6-14 aryl. In another embodiment, R4 is optionally substituted 4- to 14-membered heterocyclo. In another embodiment, R3 is C1-4 alkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, optionally substituted C6-14 aryl, and aralkyl. In each of these embodiments. —X—Z replaces a hydrogen atom on the R4 substituent. In certain instances, —X—Z can be hydrogen, when X is absent and Z is hydrogen.
- In another embodiment, Compounds of the Disclosure are compounds having Formula VII, Formula VIII, or Formula IX:
- and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:
- R3 is selected from the group consisting of hydrogen, C1-4 alkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted C6-14 aryl, aryloxyalkyl, and aralkyl;
- X is selected from the group consisting of —S(═O)2—, —S(═O)2N(R7)—, —S(═O)2C(R8)(H)—, —C(═O)—, —C(═O)N(R7)—, —C(═O)O—, —OC(═O)—, and —C(═O)C(R8)(H)—; or X is absent;
- R8 is selected from the group consisting of C1-4 alkyl, amino, alkylamino, and dialkylamino; and
- Z is selected from the group consisting of C1-6 alkyl, (amino)alkyl. (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, hydroxyalkyl, optionally substituted C3-12 cycloalkyl, aralkyl, and (heteroaryl)alkyl, and R1, R2, and R7 are as defined above in connection with Formula I. In another embodiment, R3 is selected from the group consisting of hydrogen and methyl.
- In another embodiment, Compounds of the Disclosure are compounds having Formula X, Formula XI, or Formula XII:
- and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R12 is selected from the group consisting of hydrogen, halo, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, (aralkyloxy)alkyl, alkoxyalkyl, heteroalkyl, (hydroxyalkylamino)alkyl, (heterocycloamino)alkyl, and carboxamido, and R1, R2, X, and Z are as defined above in connection with Formula I. In another embodiment, X is selected from the group consisting of —C(═O)N(R7)— and —S(═O)2N(R7)—; Z is optionally substituted C1-6 alkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl. (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C3-12 cycloalkyl, aralkyl, and (heteroaryl)alkyl; and R12 is hydrogen. In another embodiment, X is absent; Z is hydrogen; and R12 is selected from the group consisting of halo, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, (aralkyloxy)alkyl, alkoxyalkyl, heteroalkyl, (hydroxyalkylamino)alkyl, (hetcrocycloamino)alkyl, and carboxamido.
- In another embodiment, Compounds of the Disclosure are compounds having Formula XIII, Formula XIV, or Formula XV:
- and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein.
- R6 is selected from the group consisting of optionally substituted C1-6 alkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C3-12 cycloalkyl, aralkyl, and (heteroaryl)alkyl;
- X is selected from the group consisting of —C(═O)N(R7)—, —C(═O)C(R8)(H)—, and —S(═O)2N(R7)—; or X is absent;
- R8 is selected from the group consisting of C1-4 alkyl, amino, alkylamino, and dialkylamino:
- Z is selected from the group consisting of C1-4 alkyl, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (amino)heteroaryl)alkyl, and (amino)(hydroxy)alkyl, and R1, R2, and R7 are as defined above in connection with Formula I.
- In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:
- X is selected from the group consisting of:
- R8 is selected from the group consisting of C1-4 alkyl, amino, alkylamino, and dialkylamino, and R1, R2, A, and Z are as defined above in connection with Formula I.
- In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-XVII, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R1 is selected from the group consisting of C10.4 alkyl and C3-6 cycloalkyl. In another embodiment, R1 is cyclopropyl. In another embodiment, R2 is hydrogen.
- In another embodiment, a Compound of the Disclosure is not 5-cyclopropyl-N-(pyridin-3-yl)-1,2-oxazole-3-carboxamide.
- In another embodiment, Compounds of the Disclosure are compounds of Table 1, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof. The chemical names of the compounds of Table 1 are provided in Table 1A.
- In another embodiment, Compounds of the Disclosure are compounds of Table 1A, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof.
- In another embodiment, Compounds of the Disclosure are compounds of Table 2, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof.
- In another embodiment, Compounds of the Disclosure is the compound of Table 3, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof.
- In another embodiment, Compounds of the Disclosure are compounds of Tables 1 and 2, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof.
- In another embodiment, Compounds of the Disclosure are compounds of Tables 1-3, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof.
- In another embodiment, Compounds of the Disclosure are compounds of Table 1, Table 1A, Table 2, and Table 3, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or different pharmaceutically acceptable salt thereof
- It should be appreciated that the Compounds of the Disclosure in certain embodiments are the free base, various salts, and hydrate forms, and are not limited to the particular salt listed in Table 1, Table 2, and Table 3.
-
TABLE 1 Cpd. Salt No. Structure Form 2 None 3 None 4 HCl 5 None 6 TFA 7 TFA 8 HCl 9 HCl 10 HCl 11 HCl 12 None 13 HCl 14 HCl 15 HCl 16 HCl 17 HCl 18 None 19 None 20 None 21 HCl 22 HCl 23 TFA 24 HCl 25 None 26 None 27 None 28 None 29 None 30 None 31 None 32 None 33 HCl 34 HCl 35 HCOOH 36 None 37 HCl 38 HCl 39 HCl 40 HCl 41 HCl 42 None 43 None 44 HCl 45 HCl 46 None 47 None 48 None 49 HCl 50 None 51 None 52 None 53 None 54 None 55 None 56 HCl 57 None 58 None 59 TFA 60 TFA 61 None 62 HCl 63 HCl 64 None 65 TFA 66 HCl 67 HCl 68 HCl 69 HCl 70 HCl 71 None 72 HCl 73 HCl 74 HCl 75 HCl 76 HCl 77 HCl 78 HCl 79 HCl 80 HCl 81 None 82 HCl 83 HCl 84 HCl 85 HCl 86 HCl 87 HCl 88 HCl 89 HCl 90 HCl 91 HCl 92 HCl 93 HCl 94 HCl 95 None 96 HCl 97 HCl 98 HCl 99 HCl 100 HCl 101 HCl 102 HCl 103 TFA 104 TFA 105 HCl 106 HCl 107 TFA 108 TFA 109 HCl 110 HCl 111 HCl 112 HCl 113 HCl 114 HCl 115 HCl 116 HCl 117 HCl 118 HCl 119 TFA 120 HCl 121 HCl 122 None 123 None 124 None 125 None 126 None 127 None 128 None 129 None 130 TFA 131 HCl 132 HCl 133 HCl 134 None 135 None 136 None 137 None 138 None 139 HCl 140 TFA 141 HCl 142 TFA 143 None 144 None 145 None 146 None 147 TFA 148 None 149 None 150 None 151 None 152 HCl 153 TFA 154 None 155 HCOOH 156 None 157 None 158 TFA 159 TFA 160 HCl 161 HCl 162 HCl 163 HCl 164 HCl 165 None 166 None 167 None 168 None 169 TFA 170 HCl 171 HCl 172 HCl 173 HCl 174 HCl 175 None 176 HCl 177 HCl 178 HCl 179 HCl 180 HCl 181 HCl 182 HCl 183 HCl 184 HCl 185 HCl 186 HCl 187 HCl 188 HCl 189 HCl 190 HCl 191 HCl 192 HCl 193 HCl 194 HCl 195 HCl 196 HCl 197 HCl 198 TFA 199 TFA 200 HCl 201 HCl 202 HCl 203 HCl 204 HCl 205 HCl 206 HCl 207 HCl 208 HCl 209 HCl 210 HCl 211 HCl 212 None 213 HCl 214 HCl 215 HCl 216 HCl 218 HCl 219 HCl 220 HCl 221 HCl 222 HCl 223 HCl 224 HCl 225 HCl 226 HCl 227 HCl 228 HCl 229 HCl 230 HCl 231 HCl 232 HCl 233 TFA 234 HCl 235 TFA 236 TFA 237 HCl 238 TFA 239 TFA 240 TFA 241 HCl 242 HCl 243 HCl 244 TFA 245 TFA 246 TFA 247 HCl 248 HCOOH 249 HCl 250 HCl 251 HCl 252 HCl 253 TFA 254 HCl 255 HCl 256 HCl 257 TFA 258 TFA 259 TFA 260 TFA 261 HCl 262 TFA 263 TFA 264 HCl 265 TFA 266 HCl 267 TFA 268 HCl 269 TFA 270 HCl 271 TFA 272 TFA 273 TFA 274 TFA 275 TFA 276 TFA 277 TFA 278 TFA 279 TFA 280 HCl 281 HCl 282 TFA 283 TFA 284 TFA 285 TFA 286 TFA 287 TFA 288 TFA 290 TFA 291 HCl 292 None 293 TFA 294 TFA 295 TFA 296 TFA 297 None 298 None 299 None 300 HCl 301 HCl 302 HCl 303 None 304 None 305 HCl 306 HCl 307 HCl 308 HCl 309 HCl 310 HCl 311 None 312 HCl 313 HCl 314 HCl 315 HCl 316 None 317 HCl 318 HCl 319 HCl 320 HCl 321 HCl 322 HCl 323 None 324 HCl 325 None 326 HCl 327 HCl 328 HCl 329 HCl 330 HCl 331 HCl 332 None 333 None 334 HCl 335 HCl 336 HCl 337 HCl 338 HCl 339 HCl 340 HCl 341 HCl 342 HCl 343 None 344 HCl 345 HCl 346 HCl 347 HCl 348 HCl 349 HCl 350 None 351 HCl 352 HCl 353 TFA 354 HCl 355 TFA 356 HCl 357 None 358 TFA 359 TFA 360 HCl 361 HCl 362 None 363 HCl 364 HCl 365 TFA 366 HCl 367 HCl 368 None 369 HCl 370 HCl 371 None 372 TFA 373 TFA 374 None 375 None 376 HCl 377 None 378 None 379 HCl 380 HCl 381 HCl 382 None 383 None 384 HCl 385 HCl 386 HCl 387 HCl 388 None 389 None 390 None 391 None 392 HCl 393 None 394 None 395 None 396 HCl 397 None 398 HCl 399 None -
TABLE 2 SMYD2 Biochem Cpd. Salt LCMS IC50 No. Structure Form Chemical Name M + H (μM)* 400 None N-(1-acetylazetidin-3-yl)-5- cyclopropyl-1,2-oxazole-3- carboxamide 250.1 >50.0 401 None 5-cyclopropyl-N-[1-(2- methylpropyl)azetidin-3-yl]-1,2- oxazole-3-carboxamide 264.2 1.55823 402 None 5-cyclopropyl-N-[1-(2- fluoroethyl)azetidin-3-yl]-1,2- oxazole-3-carboxamide 254.1 7.78955 403 None 5-cyclopropyl-N-(1- methanesulfonylazetidin-3-yl)-1,2- oxazole-3-carboxamide 286.1 >50.0 404 None 5-cyclopropyl-N-[1-(2- hydroxyethyl)azetidin-3-yl]-1,2- oxazole-3-carboxamide 252.2 4.67695 405 None 5-cyclopropyl-N-[1-(oxetan-3- yl)azetidin-3-yl]-1,2-oxazole-3- carboxamide 264.2 >50.0 406 None 5-cyclopropyl-N-[1-(2,2- difluoroethyl)azetidin-3-yl]-1,2- oxazole-3-carboxamide 272.2 >50.0 407 None 5-cyclopropyl-N-[1-(2- methoxyethyl)azetidin-3-yl]-1,2- oxazole-3-carboxamide 266.2 2.68352 408 None 5-cyclopropyl-N-[1-(2,2,2- trifluoroethyl)azetidin-3-yl]-1,2- oxazole-3-carboxamide 290.2 >50.0 409 None 5-cyclopropyl-N-(1,3- dimethylazetidin-3-yl)-1,2- oxazole-3-carboxamide 236.2 >50.0 410 None 5-cyclopropyl-N-[1-(propan-2- yl)azetidin-3-yl]-1,2-oxazole-3- carboxamide 250.1 1.04736 411 None 5-cyclopropyl-N-(1- methylazetidin-3-yl)-1,2- oxazole-3-carboxamide 222.1 5.33712 412 None 5-cyclopropyl-N-(1- ethylazetidin-3-yl)-1,2- oxazole-3-carboxamide 236.2 1.50829 413 None 5-cyclopropyl-N-(1- cyclopropylazetidin-3-yl)-1,2- oxazole-3-carboxamide 248.1 1.46882 414 None 5-cyclopropyl-N-(1- propylazetidin-3-yl)-1,2- oxazole-3-carboxamide 250.2 1.70142 415 None N-(1-benzylazetidin-3-yl)-5- cyclopropyl-1,2- oxazole-3-carboxamide 298.1 2.47021 416 None 5-cyclopropyl-N-[1-(1- phenylpropyl)azetidin-3-yl]-1,2- oxazole-3-carboxamide 326.1 0.61999 417 None 5-cyclopropyl-N-[1-(2-hydroxy-1- phenylethyl)azetidin-3-yl]-1,2- oxazole-3-carboxamide 328.2 2.22554 418 None 5-cyclopropyl-N-[1-(1- phenylethyl)azetidin-3-yl]-1,2- oxazole-3-carboxamide 312.1 0.58861 419 None 5-cyclopropyl-N-[1-(2- phenylethyl)azetidin-3-yl]-1,2- oxazole-3-carboxamide 312.1 2.18872 420 HCl N-(azetidin-3-yl)-5-cyclopropyl- 1,2-oxazole-3-carboxamide 208.1 421 None 5-cyclopropyl-N-(pyridin-3-yl)- 1,2-oxazole-3-carboxamide 230.2 >50.0 422 None 5-cyclopropyl-N-(pyridin-4-yl)- 1,2-oxazole-3-carboxamide 230.2 >50.0 423 None 5-cyclopropyl-N-{[1-(propan-2- yl)azetidin-3-yl]methyl}-1,2- oxazole-3-carboxamide 264.1 >50.0 424 None 5-cyclopropyl-N-{[1- (cyclopropylmethyl)azetidin-3- yl]methyl}-1,2- oxazole-3-carboxamide 276.1 >50.0 425 None 5-cyclopropyl-N-[(1- propylazetidin-3-yl)methyl]- 1,2-oxazole-3-carboxamide 264.1 >50.0 426 None N-(azetidin-3-ylmethyl)-5- cyclopropyl-1,2-oxazole-3- carboxamide 222.1 33.04122 427 None (±)-cis-5-cyclopropyl-N-[5- methyl-1-(propan-2-yl)azepan- 4-yl]-1,2-oxazole-3-carboxamide 306.2 >50.0 *IC50 values are an average of n = 1 to n = 50 -
TABLE 1A SMYD3 Biochem SMYD3 LCMA IC50 cell IC50 Cpd. No. Chemical Name M + H (μM)* (μM)* 2 N-(1-((4- 447.15 48.11 acetamidophenyl)sulfonyl)piperidin-4- yl)-5-cyclobutylisoxazole-3-carboxamide 3 N-(4-((4- 431.91 23.37 acetamidophenyl)sulfonyl)cyclohexyl)-5- cyclopropylisoxazole-3-carboxamide 4 5-cyclopropyl-N-(piperidin-4- 250.05 31.8 ylmethyl)isoxazole-3-carboxamide 5 5-cyclopropyl-N-((1-methylpiperidin-4- 264.10 39.33 yl)methyl)isoxazole-3-carboxamide 6 N-((1s,3s)-3-((4- 419.25 32.91 acetamidophenyl)sulfonamido)cyclobutyl) 5-cyclopropylisoxazole-3-carboxamide 7 N-((1r,3r)-3-((4- 419.3 46.75 acetamidophenyl)sulfonamido)cyclobutyl) 5-cyclopropylisoxazole-3-carboxamide 8 N-((1r,4r)-4-aminocyclohexyl)-5- 375.83 20.73 cyclopropyl-4-iodoisoxazole-3- carboxamide 9 N-((1r,4r)-4-aminocyclohexyl)-5-(2- 254 33.25 hydroxyethyl)isoxazole-3-carboxamide 10 N3-((1r,4r)-4-ammocyclohexyl)-5- 349.10 38.97 cyclopropyl-N4-isobutylisoxazole-3,4- dicarboxamide 11 N-((1r,4r)-4-aminocyclohexyl)-5- 236.1 27.42 vinylisoxazole-3-carboxamide 12 5-cyclopropyl-N-(2,2-dimethyl-1- 299.05 12.75 phenylpropyl)isoxazole-3-carboxamide 13 N3-((1r,4r)-4-aminocyclohexyl)-5- 293.15 22.42 cyclopropylisoxazole-3,4-dicarboxamide 14 N-(4-(aminomethyl)phenyl)-5- 259.1 10.54 cyclopropylisoxazole-3-carboxamide 15 N-(1-(4-aminophenyl)ethyl)-5- 271.8 40.11 cyclopropylisoxazole-3-carboxamide 16 N-(4-(1-aminoethyl)phenyl)-5- 272.85 6.52 cyclopropylisoxazole-3-carboxamide 17 N-((1r,3r)-3-aminocyclobutyl)-5- 222.05 24.5 cyclopropylisoxazole-3-carboxamide 18 5-cyclopropyl-N-(1-(4-fluorophenyl)- 289.1 41.22 propyl)isoxazole-3-carboxamide 19 5-cyclopropyl-N-(1-(4-fluorophenyl)-2- 303.05 16.38 methylpropyl)isoxazole-3-carboxamide 20 5-cyclopropyl-N-(1-(4-methoxyphenyl)- 329.1 5.85 2,2-dimethylpropyl)isoxazole-3- carboxamide 21 N-((1r,4r)-4-aminocyclohexyl)-5-(3- 268.1 40.64 hydroxypropyl)isoxazole-3-carboxamide 22 N-(azepan-4-yl)-5-cyclopropylisoxazole- 250.15 14.88 3-carboxamide 23 N-(3-(azetidin-3-ylamino)cyclobutyl)-5- 277.1 32.28 cyclopropylisoxazole-3-carboxamide 24 N-((1r,4r)-4-aminocyclohexyl)-5- 234.79 24.63 isopropylisoxazole-3-carboxamide (-NH2) 25 5-cyclopropyl-N-(cyclopropyl(4- 301.05 16.21 fluorophenyl)methyl)isoxazole-3- carboxamide 26 5-cyclopropyl-N-(3,3-dimethylbutan-2- 237.05 45.92 yl)isoxazole-3-carboxamide 27 N-(1-(4-aminophenyl)-2,2- 336.25 8.54 dimethylpropyl)-5-cyclopropylisoxazole- (+Na) 3-carboxamide 28 5-cyclopropyl-N-(2,2-dimethyl-1- 300.15 38.32 (pyridin-2-yl)propyl)isoxazole-3- carboxamide 29 5-cyclopropyl-N-(1-(4- 275 43.79 fluorophenyl)ethyl)isoxazole- 3-carboxamide 30 5-cyclopropyl-N-(2,2-dimethylpentan-3- 251.15 27.12 yl)isoxazole-3-carboxamide 31 N-(1-(4-acetamidophenyl)-2,2- 356.25 12.82 dimethylpropyl)-5-cyclopropylisoxazole- 3-carboxamide 32 N-(1-(4-chlorophenyl)-2,2- 333.15 9.03 dimethylpropyl)-5-cyclopropylisoxazole- 3-carboxamide 33 N-(4-(aminomethyl)-2-methylphenyl)-5- 272.90 7.79 cyclopropylisoxazole-3-carboxamide 34 N-(4-(aminomethyl)-2-chlorophenyl)-5- 293.05 6.45 cyclopropylisoxazole-3-carboxamide (295.00) 35 N-((5-amino-1,3,3-trimethylcyclohexyl)- 306.30 12.99 methyl)-5-cyclopropylisoxazole-3- carboxamide 36 5-cyclopropyl-N-(2,2-dimethyl-1-(p- 312.90 27.61 tolyl)propyl)isoxazole-3-carboxamide 37 N-(4-(2-aminoethyl)phenyl)-5- 272.15 7.25 cyclopropylisoxazole-3-carboxamide 38 N-(4-(1-aminopropyl)phenyl)-5- 286.96 4.43 cyclopropylisoxazole-3-carboxamide 39 N-(4-(1-amino-2,2- 297 2.52 dimethylpropyl)phenyl)-5- (-NH3) cyclopropylisoxazole-3-carboxamide 40 N-(4-(ammomethyl)-2-iodophenyl)-5- 366.9 7.21 cyclopropylisoxazole-3-carboxamide (-NH3) 41 N-(5-(aminomethyl)pyridin-2-yl)-5- 259.15 22.53 cyclopropylisoxazole-3-carboxamide 42 5-ethyl-N-(1-(3-methoxyphenyl)-2,2- 317.20 24.62 dimethylpropyl)isoxazole-3-carboxamide 43 5-cyclopropyl-N-(1-(3-methoxyphenyl)- 329.25 18.91 2.2-dimethylpropyl)isoxazole-3- carboxamide 44 N-(4-(1-amino-2-methylpropyl)phenyl)- 300.04 2.5 5-cyclopropylisoxazole-3-carboxamide 45 N-(5-(aminomethyl)-6-methylpyridin-2- 273.15 29.74 yl)-5-cyclopropylisoxazole-3- carboxamide 46 5-cyclopropyl-N-(2,2-dimethyl-1-(m- 313.25 22.2 tolyl)propyl)isoxazole-3-carboxamide 47 5-ethyl-N-(1-(3-fluorophenyl)-2,2- 305.15 7.26 dimethylpropyl)isoxazole-3-carboxamide 48 5-cyclopropyl-N-(1-(3-fluorophenyl)- 317.25 7.92 2.2-dimethylpropyl)isoxazole-3- carboxamide 49 5-cyclopropyl-N-(phenyl(piperidin-4- 326.25 8.09 yl)methyl)isoxazole-3-carboxamide 50 5-cyclopropyl-N-(2,2-dimethyl-1- 300.15 9.99 (pyridin-3-yl)propyl)isoxazole-3- carboxamide 51 5-cyclopropyl-N-(2,2-dimethyl-1- 300.20 4.08 (pyridin-4-yl)propyl)isoxazole-3- carboxamide 52 N-(1-cyclobutyl-2,2-dimethylpropyl)-5- 277.2 7.4 cyclopropylisoxazole-3-carboxamide 53 N-(1-cyclopentyl-2,2-dimethylpropyl)-5- 291.25 10.58 cyclopropylisoxazole-3-carboxamide 54 N-(1-cyclohexyl-2,2-dimethylpropyl)-5- 305.01 15.14 cyclopropylisoxazole-3-carboxamide 55 N-(cyclobutyl(phenyl)methyl)-5- 297.2 38.47 cyclopropylisoxazole-3-carboxamide 56 N-(4-(aminomethyl)-3-chlorophenyl)-5- 291.95 16.4 cyclopropylisoxazole-3-carboxamide 57 N-(1-(3-chlorophenyl)-2,2- 321.2 6.06 dimethylpropyl)-5-ethylisoxazole-3- carboxamide 58 N-(1-(3-chlorophenyl)-2,2- 333.2 9.97 dimethylpropyl)-5-cyclopropylisoxazole- 3-carboxamide 59 N-(2-(4-amino-4- 306 10.23 methylcyclohexyl)propan- 2-yl)-5-cyclopropylisoxazole-3- carboxamide 60 N-(4-(2-aminopropan-2-yl)-1- 306 2.98 methylcyclohexyl)- 5-cyclopropylisoxazole-3-carboxamide 61 5-cyclopropyl-N-(2,2-dimethyl-1- 306.15 6.29 (thiazol-4-yl)propyl)isoxazole-3- carboxamide 62 5-cyclopropyl-N-(2,2-dimethyl-1- 306.25 4.35 (piperidin-4-yl)propyl)isoxazole-3- carboxamide 63 N-(((1r,4r)-4-aminocyclohexyl)(phenyl)- 340.25 6.99 methyl)-5-cyclopropylisoxazole-3- carboxamide 64 5-ethyl-N-(phenyl(tetrahydro-2H-pyran- 337.25 37.06 4-yl)methyl)isoxazole-3-carboxamide (+Na) 65 N-(3-(aminomethyl)-3,5,5- 306.15 14.07 trimethylcyclohexyl)- 5-cyclopropylisoxazole-3-carboxamide 66 5-cyclopropyl-N-((S)-phenyl((S)- 312.2 34.2 pyrrolidin-2-yl)methyl)isoxazole-3- carboxamide 67 N-(((1s,4s)-4- 340.25 13 aminocyclohexyl)(phenyl)methyl)- 5-cyclopropylisoxazole-3-carboxamide 68 5-cyclopropyl-N-(2,2-dimethyl-1- 306.25 4.38 (piperidin-3-yl)propyl)isoxazole-3- carboxamide 69 5-cyclopropyl-N-(phenyl(piperidin-3- 326.25 12.68 yl)methyl)isoxazole-3-carboxamide 70 N-(4-(aminomethyl)-3-methylphenyl)-5- 272.97 8.22 cyclopropylisoxazole-3-carboxamide 71 5-ethyl-N-((1-methylpiperidin-4- 328.25 20.51 yl)(phenyl)methyl)isoxazole-3- carboxamide 72 N-((3-chlorophenyl)(piperidin-4- 348.2 1.4 yl)methyl)-5-ethylisoxazole-3- carboxamide 73 N-((3-chlorophenyl)(piperidin-4- 360.25 2.59 yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 74 5-ethyl-N-(phenyl(piperidin-4-yl)- 314.2 7.44 methyl)-isoxazole-3-carboxamide 75 N-((3-((4-chlorobenzyl)carbamoyl) 493.3 13.58 phenyl)(piperidin-4-yl)methyl)-5- cyclopropylisoxazole-3-carboxamide 76 N-((3- 465.35 34.82 ((cyclohexylmethyl)carbamoyl)phenyl)- (piperidin-4-yl)methyl)-5- cyclopropylisoxazole-3-carboxamide 77 N-((3-(cyclohexylcarbamoyl)phenyl)- 451.4 49.05 (piperidin-4-yl)methyl)-5- cyclopropylisoxazole-3-carboxamide 78 N-(4-(ammomethyl)-3-methoxyphenyl)- 270.92 32.1 5-cyclopropylisoxazole-3-carboxamide (-NH2) 79 5-cyclopropyl-N-((S)-1-(((S)-1,6- 368.25 15.03 diamino-1-oxohexan-2-yl)amino)- 3-hydroxy-1-oxopropan-2-yl)isoxazole- 3-carboxamide 80 N-((2-chlorophenyl)(piperidin-4- 348.15 15.86 yl)methyl)-5-ethylisoxazole-3- carboxamide 81 5-cyclopropyl-N-((1-methylpiperidin-4- 340.2 22.81 yl)(phenyl)methyl)isoxazole-3- carboxamide 82 N-((2-chlorophenyl)(piperidin-4- 360.20 9.05 yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 83 5-cyclopropyl-N-(piperidin-4-yl(3- 460.3 30.8 ((pyridin-3-ylmethyl)carbamoyl)- phenyl)methyl)isoxazole- 3-carboxamide 84 5-cyclopropyl-N-(piperidin-4-yl(3-((3- 480.4 10.57 (pyrrolidin-1-yl)propyl)carbamoyl) phenyl)methyl)isoxazole- 3-carboxamide 85 5-cyclopropyl-N-((3-((2-(piperidin-1- 480.4 12.59 yl)ethyl)carbamoyl)phenyl)(piperidin-4- yl)methyl)isoxazole-3-carboxamide 86 5-cyclopropyl-N-((3-((2- 475.35 20.84 (methylsulfonyl)ethyl)carbamoyl)phenyl)- (piperidin-4-yl)methyl)isoxazole-3- carboxamide 87 5-cyclopropyl-N-((3-((3- 454.35 24.56 (dimethylamino)propyl)carbamoyl)- phenyl)(piperidin-4-yl)methyl)- isoxazole-3-carboxamide 88 5-cyclopropyl-N-(piperidin-4-yl(3- 460.35 37.32 ((pyridin-4-ylmethyl)carbamoyl)- phenyl)methyl)isoxazole- 3-carboxamide 89 N-((3-(((1r,4r)-4-aminocyclohexyl)- 466.35 39.36 carbamoyl)phenyl)(piperidin- 4-yl)methyl)-5- cyclopropylisoxazole-3-carboxamide 90 5-cyclopropyl-N-((3-((pent-4-yn-1- 11.77 yloxy)methyl)phenyl)(piperidine-4- yl)methyl)isoxazole- 3-carboxamide 91 N-(4-(aminomethyl)-2-isopropylphenyl)- 283.02 6.08 5-cyclopropylisoxazole-3-carboxamide (−NH2) 92 N-((1r,4r)-4-aminocyclohexyl)-5- 266.1 38.15 isobutylisoxazole-3-carboxamide 93 N-((1r,4r)-4-ammocycloliexyl)-5- 252.1 9.93 propylisoxazole-3-carboxamide 94 N-(4-(aminomethyl)-3-iodophenyl)-5- 383.98 19.48 cyclopropylisoxazole-3-carboxamide 95 N-(1-(2H-indazol-4-yl)-2,2- 339.01 6.82 dimethylpropyl)-5-cyclopropylisoxazole- 3-carboxamide 96 5-cyclopropyl-N-((3-((1- 494.45 48.53 isopropylpiperidin-4- yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)isoxazole- 3-carboxamide 97 5-cyclopropyl-N-((3-((3- 475.40 25.88 hydroxybenzyl)carbamoyl)phenyl)- (piperidin-4-yl)methyl)isoxazole-3- carboxamide 98 5-cyclopropyl-N-((3- 409.3 46.85 (cyclopropylcarbamoyl)phenyl)(piperidin- 4-yl)methyl)isoxazole-3-carboxamide 99 5-cyclopropyl-N-(piperidin-4-yl(3- 394.24 11.9 ((prop-2-yn-1- yloxy)methyl)phenyl)methyl)isoxazole- 3-carboxamide 100 5-cyclopropyl-N-((3- 411.3 17.98 ((diethylamino)methyl)phenyl)(piperidin- 4-yl)methyl)isoxazole-3-carboxamide 101 N-(4-(aminomethyl)-2-ethylphenyl)-5- 268.99 3 cyclopropylisoxazole-3-carboxamide (−NH2) 102 N-((1r,4r)-4-aminocyclohexyl)-5- 266.10 32.62 butylisoxazole-3-carboxamide 103 5-cyclopropyl-N-((3-((2-hydroxy-3- 496.4 14.1 (pyrrolidin-1-yl)propyl)carbamoyl)- phenyl)(piperidin-4-yl)methyl)- isoxazole-3-carboxamide 104 5-cyclopropyl-N-((3-((3- 441.3 11.17 hydroxypropyl)(methyl)carbamoyl)- phenyl)(piperidin-4-yl)methyl)- isoxazole-3-carboxamide 105 5-cyclopropyl-N-(piperidin-4-yl(3- 460.35 45.5 ((pyridin-2-ylmethyl)carbamoyl)- phenyl)methyl)isoxazole- 3-carboxamide 106 5-cyclopropyl-N-(piperidin-4-yl(3- 446.3 4.76 (pyridin-3-ylcarbamoyl)phenyl)methyl)- isoxazole-3-carboxamide 107 5-cyclopropyl-N-((3-(((3- 464.35 16.78 fluorobenzyl)oxy)methyl)phenyl)- (piperidin-4-yl)methyl)isoxazole-3- carboxamide 108 N-((3-((but-2-yn-1-yloxy)methyl)phenyl)- 408.3 6.36 (piperidin-4-yl)methyl)-5- cyclopropylisoxazole-3-carboxamide 109 5-cyclopropyl-N-((3-(((3-hydroxypropyl)- 427.35 34.01 (methyl)amino)methyl)phenyl)(piperidin- 4-yl)methyl)isoxazole- 3-carboxamide 110 5-cyclopropyl-N-((3-(((2-iodobenzyl)- 572.3 4.98 oxy)methyl)phenyl)(piperidin-4-yl)- methyl)isoxazole-3-carboxamide 111 5-cyclopropyl-N-((3-((2- 490.4 11.35 methoxyphenethoxy)methyl)phenyl)- (piperidin-4-yl)methyl)isoxazole-3- carboxamide 112 5-cyclopropyl-N-((3-((2- 474.4 11.25 methylplienethoxy)methyl)phenyl)- (piperidin-4-yl)methyl)isoxazole-3- carboxamide 113 5-cyclopropyl-N-((3- 356.25 3.67 (hydroxymethyl)phenyl)(piperidin-4- yl)methyl)isoxazole-3-carboxamide 114 N-(4-(aminomethyl)-3-ethylphenyl)-5- 268.99 13.86 cyclopropylisoxazole-3-carboxamide (−NH2) 115 5-cyclopropyl-N-((3-((3- 427.3 17.42 hydroxypropyl)carbamoyl)phenyl)- (piperidin-4-yl)methyl)isoxazole-3- carboxamide 116 5-cyclopropyl-N-((3-((2- 475.35 18.31 hydroxybenzyl)carbamoyl)phenyl)- (piperidin-4-yl)methyl)isoxazole-3- carboxamide 117 5-cyclopropyl-N-(piperidin-4-yl(3- 446.40 9.3 (pyridin-2-ylcarbamoyl)phenyl)methyl)- isoxazole-3-carboxamide 118 5-cyclopropyl-N-((3-((2- 427.35 19.37 (ethylamino)ethoxy)methyl)phenyl)- (piperidin-4-yl)methyl)isoxazole-3- carboxamide 119 N-((3-((2-aminoethoxy)methyl)phenyl)- 399.30 13.19 (piperidin-4-yl)methyl)-5- cyclopropylisoxazole-3-carboxamide 120 5-cyclopropyl-N-(piperidin-4-yl(3- 398.35 20.62 (propoxymethyl)phenyl)methyl)isoxazole- 3-carboxamide 121 N-(4-(1-amino-4-hydroxybutyl)phenyl)- 316.10 4.36 5-cyclopropylisoxazole-3-carboxamide 122 5-cyclopropyl-N-(1- 305.10 11.83 oxaspiro[5.5]undecan-4-yl)isoxazole-3- carboxamide 123 5-cyclopropyl-N-(3- 319.3 4.79 ethoxyspiro[3.5[nonan-1-yl)isoxazole-3- carboxamide 124 5-cyclopropyl-N-(3- 305.10 26.51 oxaspiro[5.5]undecan-9-yl)isoxazole-3- carboxamide 125 N-(1-benzyl-6-methylpiperidin-3-yl)-5- 340.10 21.2 cyclopropylisoxazole-3-carboxamide 126 5-cyclopropyl-N-(3-phenylcyclopentyl)- 297.1 29.97 isoxazole-3-carboxamide 127 5-cyclopropyl-N-(2-(3,4- 335.1 49.59 difluorophenyl)tetrahydrofuran-3-yl)- isoxazole-3-carboxamide 128 5-cyclopropyl-N-(2,2- 265.4 44.55 dimethyltetrahydro-2H-pyran- 4-yl)isoxazole-3-carboxamide 129 5-cyclopropyl-N-(6-oxaspiro[4.5]decan- 291.1 18.41 9-yl)isoxazole-3-carboxamide 130 N-((3-((((1r,4r)-4- 1.38 aminocyclohexyl)oxy)methyl)phenyl)- (piperidin-4-yl)methyl)-5- cyclopropylisoxazole-3-carboxamide 131 5-cyclopropyl-N-((3- 16.6 ((isopropyl(tetrahydro-2H-pyran- 4-yl)amino)methyl)phenyl)(piperidin- 4-yl)methyl)isoxazole-3- carboxamide 132 methyl 5-(aminomethyl)-2- 299.83 48.66 (5-cyclopropylisoxazole-3- (M − NH2) carboxamido)benzoate 133 5-cyclopropyl-N-(piperidin-4-yl(3- 466.12 6.48 (pyridin-4- ylcarbamoyl)phenyl)methyl)isoxazole-3- carboxamide 134 N-(3-butoxy-2,2-dimethylcyclobutyl)-5- 307.3 18.73 cyclopropylisoxazole-3-carboxamide 135 5-cyclopropyl-N-(6-hydroxy-1,2,3,4- 299.10 23.68 tetiahydronaphthalen-2-yl)isoxazole-3- carboxamide 136 5-cyclopropyl-N-(3-isobutoxy-2,2- 307.2 9.54 dimethylcyclobutyl)isoxazole-3- carboxamide 137 5-cyclopropyl-N-(2-(4- 331.3 2.56 fluorophenyl)tetrahydro-2H-pyran-4- yl)isoxazole-3-carboxamide 138 N-(1-(1-benzylpyrrolidin-3-yl)ethyl)-5- 340.3 24.96 cyclopropylisoxazole-3-carboxamide 139 5-cyclopropyl-N-((3-(((2- 413.25 41.77 hydroxyethyl)(methyl)amino)methyl)- phenyl)(piperidin-4-yl)methyl) isoxazole-3-carboxamide 140 5-cyclopropyl-N-((3-((4-methyl-1H- 462.17 28.35 pyrrole-2- carboxamido)methyl)phenyl)(piperidin- 4-yl)methyl)isoxazole-3-carboxamide 141 5-cyclopropyl-N-((3-((3-(4-methyl-1H- 491.35 25.42 pyrazol-1- yl)propanamido)methyl)phenyl)(piperidin- 4-yl)methyl)isoxazole-3-carboxamide 142 N-((3-carbamoylphenyl)(piperidin-4- 369.15 3.6 yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 143 N-((1r,4r)-4-aminocyclohexyl)-5- 260.1 18.56 (difluoromethyl)isoxazole-3- carboxamide 144 5-cyclopropyl-N-(2-isobutyltetrahydro- 293.2 7.16 2H-pyran-4-yl)isoxazole-3-carboxamide 145 N-(1-(1-cyclobutylpiperidin-3-yl)ethyl)- 318.4 18.08 5-cyclopropylisoxazole-3-carboxamide 146 5-cyclopropyl-N-(2-isopropyl-4,5,6,7- 315.1 27.28 tetrahydro-2H-indazo1-6-yl)isoxazole-3- carboxamide 147 N-(4-(aminomethyl)-2- 310.15 4.07 (hydroxymethyl)phenyl)-5- (+Na) cyclopropylisoxazole-3-carboxamide 148 N-(4-(1-amino-3-(pyridin-2- 363.3 0.97 yl)propyl)phenyl)-5- cyclopropylisoxazole-3-carboxamide 149 N-(4-(1-amino-3-(pyridin-3- 363.3 0.62 yl)propyl)phenyl)-5- cyclopropylisoxazole-3-carboxamide 150 N-(4-(1-amino-3-(pyridin-4- 363.3 1.39 yl)propyl)phenyl)-5- cyclopropylisoxazole-3-carboxamide 151 N-(4-(1-amino-3-phenylpropyl)phenyl)- 345.12 2.34 5-cyclopropylisoxazole-3-carboxamide (M − NH2) 152 5-cyclopropyl-N-((1-glycylpiperidin-4- 383.4 4.47 yl)(phenyl)methyl)isoxazole-3- carboxamide 153 N-((1-(D-alanyl)piperidin-4- 397.35 1.27 yl)(phenyl)methyl)-5- cyclopropylisoxazole-3-carboxamide 154 N-((1-(L-alanyl)piperidin-4- 397.35 1.53 yl)(phenyl)methyl)-5- cyclopropylisoxazole-3-carboxamide 155 5-cyclopropyl-N-((3- 445.4 4.15 (phenylcarbamoyl)phenyl)(piperidin-4- yl)methyl)isoxazole-3-carboxamide 156 (±)-cis-5-cyclopropyl-N-(3- 275.4 31.11 cyclopropylcyclohexyl)isoxazole-3- carboxamide 157 (±)-trans-5-cyclopropyl-N-(3- 275.3 39.9 cyclopropylcyclohexyl)isoxazole-3- carboxamide 158 (±)-cis-5-cyclopropyl-N-(3-(1-methyl- 315.1 10.07 1H-imidazol-2-yl)cyclohexyl)isoxazole- 3-carboxamide 159 (±)-trans-5-cyclopropyl-N-((1S,3S)-3-(1 315.1 14.94 methyl-1H-imidazol-2- yl)cyclohexyl)isoxazole-3-carboxamide 160 N-(4-(aminomethyl)-3-isopropylphenyl) 322.2 17.14 5-cyclopropylisoxazole-3-carboxamide (+Na) 161 N-(4-(aminomethyl)-3- 310.2 12.36 (hydroxymethyl)phenyl)-5- (+Na) cyclopropylisoxazole-3-carboxamide 162 (R)-5-cyclopropyl-N-(piperidin-4-yl(3- 446.3 49 (pyridin-3- ylcarbamoyl)phenyl)methyl)isoxazole-3- carboxamide 163 (S)-5-cyclopropyl-N-(piperidin-4-yl(3- 446.3 0.85 (pyridin-3- ylcarbamoyl)phenyl)methyl)isoxazole-3- carboxamide 164 N-(4-((2- 337.1 17.78 aminoacetamido)methyl)phenyl)-5- (+Na) cyclopropylisoxazole-3-carboxamide 165 N-((1-benzyl-5-methylpyrrolidin-3- 340.2 43.84 yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 166 N-((4-chlorophenyl)(4-methylmorpholin- 376.2 31.49 2-yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 167 5-cyclopropyl-N-(1,2-dimethylpiperidin- 263.1 28.85 3-yl)isoxazole-3-carboxamide 168 N-(1-benzylpiperidin-3-yl)-5- 326.1 26.38 cyclopropylisoxazole-3-carboxamide 169 5-cyclopropyl-N-((3-(oxetan-3- 425.3 35.06 ylcarbamoyl)phenyl)(piperidin-4- yl)methyl)isoxazole-3-carboxamide 170 N-(4-(2-aminopropan-2-yl)phenyl)-5- 286.88 3.54 cyclopropylisoxazole-3-carboxamide 171 N-(4-(1-amino-2-((1-methylpiperidin-4- 398.25 24.39 yl)amino)-2-oxoethyl)phenyl)-5- cyclopropylisoxazole-3-caxboxamide 172 5-cyclopropyl-N-((3-((6-methylpyridin- 460.3 5.9 3-yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)isoxazole-3-carboxamide 173 5-cyclopropyl-N-((3-(piperidin-3- 452.3 38.93 ylcarbamoyl)phenyl)(piperidin-4- yl)methyl)isoxazole-3-carboxamide 174 N-((3-((5-carbamoylpyridin-3- 489.3 10.82 yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 175 5-cyclopropyl-N-(1-phenyl-3-(1H-1,2,4- 338.15 41.58 triazol-1-yl)propyl)isoxazole-3- carboxamide 176 5-cyclopropyl-N-((3-((6- 475.35 3.45 (methylamino)pyridin-3- yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)isoxazole-3-carboxamide 177 5-cyclopropyl-N-((3-((6- 476.35 4.59 methoxypyridin-3- yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)isoxazole-3-carboxamide 178 N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)- 335.25 0.47 5-cyclopropylisoxazole-3-carboxamide 179 N-((1-(L-alanyl)piperidin-4-yl)methyl)- 321.25 0.75 5-cyclopropylisoxazole-3-carboxamide 180 N-((1-(D-alanyl)piperidin-4-yl)methyl)- 321.2 9.05 5-cyclopropylisoxazole-3-carboxamide 181 5-cyclopropyl-N-(piperidin-4-yl(3- 447.35 7.34 (pyridazin-4- ylcarbamoyl)phenyl)methyl)isoxazole-3- carboxamide 182 5-cyclopropyl-N-(2-((2- 399.30 14.19 hydroxybenzyl)amino)-2-oxo-1- (pipendin-4-yl)ethyl)isoxazole-3- carboxamide 183 5-cyclopropyl-N-(piperidin-4-yl(3-((6- 514.35 8.28 (trifluoromethyl)pyridin-3- yl)carbamoyl)phenyl)methyl)isoxazole- 3-carboxamide 184 5-cyclopropyl-N-(piperidin-4-yl(3- 447.85 2.16 (pyrimidin-5- ylcarbamoyl)phenyl)methyl)isoxazole-3- carboxamide 185 5-cyclopropyl-N-(piperidin-4-yl(3- 447.4 1.7 (pyridazin-3- ylcarbamoyl)phenyl)methyl)isoxazole-3- carboxamide 186 5-cyclopropyl-N-((3-((2-hydroxypyridin- 462.35 29.68 3-yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)isoxazole-3-carboxamide 187 5-cyclopropyl-N-((3-((5-methylpyridin- 460.35 2.88 3-yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)isoxazole-3-carboxarnide 188 N-(1-(1-(D-alanyl)piperidin-4-yl)ethyl)- 335.25 3.69 5-cyclopropylisoxazole-3-carboxamide 189 N-(1-(1-(L-tryptophyl)piperidin-4- 450.4 0.52 yl)ethyl)-5-cyclopropylisoxazole-3- carboxamide 190 N-(1-(1-(D-tryptophyl)piperidin-4- 450.4 10.09 yl)ethyl)-5-cyclopropylisoxazole-3- carboxamide 191 N-((1-(L-tryptophyl)piperidin-4- 436.35 0.56 yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 192 N-((1-(D-tryptophyl)piperidin-4- 435.35 6.5 yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 193 N-((1-(L-seryl)piperidin-4- 413.35 3.51 yl)(phenyl)methyl)-5- cyclopropylisoxazole-3-carboxamide 194 N-((1-(L-tyrosyl)piperidin-4- 489.5 2.69 yl)(phenyl)methyl)-5- cyclopropylisoxazole-3-caxboxamide 195 N-((1-(L-tryptophyl)piperidin-4- 512.29 1.42 yl)(phenyl)methyl)-5- cyclopropylisoxazole-3-carboxamide 196 N-((1-(L-seryl)piperidin-4-yl)methyl)-5- 337.25 3.28 cyclopropylisoxazole-3-carboxamide 197 N-((1-(L-tyrosyl)piperidin-4-yl)methyl)- 413.35 0.43 5-cyclopropylisoxazole-3-carboxamide 198 (±)-trans-5-cyclopropyl-N-(4-(4- 319.2 17.68 fluorophenyl)-4-hydroxybutan-2- yl)isoxazole-3-carboxamide 199 ethyl 1-(L-tyrosyl)-5-(5- 471.4 43.3 cyclopropylisoxazole-3- carboxamido)piperidine-3-carboxylate 200 N-((3-((6-acetamidopyridin-3- 503.45 4.57 yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 201 5-cyclopropyl-N-(piperidin-4-yl(3- 447.3 18.97 (pyrazin-2- ylcarbamoyl)phenyl)methyl)isoxazole-3- carboxamide 202 5-cyclopropyl-N-((3-((6-hydroxypyridin- 462.35 49.68 3-yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)isoxazole-3-carboxamide 203 methyl 2-(1-(L-alanyl)piperidin-4-yl)-2- 379.3 0.74 (5-cyclopropylisoxazole-3- carboxamido)acetate 204 methyl 2-(1-(D-alanyl)piperidin-4-yl)-2- 379.3 7.54 (5-cyclopropylisoxazole-3- carboxamido)acetate 205 N-((1-(L-alanyl)piperidin-4-yl)(3- 517.35 0.29 (pyridin-3-ylcarbamoyl)phenyl)methyl)- 5-cyclopropylisoxazole-3-carboxamide 206 N-((1-(D-alanyl)piperidin-4-yl)(3- 517.45 0.59 (pyridin-3-ylcarbamoyl)phenyl)methyl)- 5-cyclopropylisoxazole-3-carboxamide 207 N-((1-(D-tryptophyl)piperidin-4- 534.5 23.23 yl)(phenyl)methyl)-5- (+Na) cyclopropylisoxazole-3-carboxamide 208 N-(1-(1-(L-valyl)piperidin-4-yl)ethyl)-5- 363.35 0.36 cyclopropylisoxazole-3-carboxamide 209 N-(1-(1-(D-valyl)piperidin-4-yl)ethyl)-5- 363.35 2.42 cyclopropylisoxazole-3-caxboxamide 210 N-(1-(1-(L-seryl)piperidin-4-yl)ethyl)-5- 373.3 1.2 cyclopropylisoxazole-3-carboxamide (+Na) 211 N-(1-(1-(L-tyrosyl)piperidin-4-yl)ethyl)- 427.35 0.2 5-cyclopropylisoxazole-3-carboxamide 212 tert-butyl4-(1-(5-cyclopropylisoxazole- 386.25 28.43 3-carboxamido)ethyl)piperidine-1- (+Na) carboxylate 213 5-cyclopropyl-N-(1-(piperidin-4- 264.2 7.12 yl)ethyl)isoxazole-3-carboxamide 214 5-cyclopropyl-N-(piperidin-4-yl(pyridin- 327.25 3.15 4-yl)methyl)isoxazole-3-carboxamide 215 N-((S)-(1-(L-alanyl)piperidin-4- 397.35 0.21 yl)(phenyl)methyl)-5- cyclopropylisoxazole-3-carboxamide 216 N-((R)-(1-(L-alanyl)piperidin-4- 397.35 4.48 yl)(phenyl)methyl)-5- cyclopropylisoxazole-3-carboxamide 218 5-cyclopropyl-N-(2-oxo-1-(piperidin-4- 370.3 26.87 yl)-2-(pyridin-3- ylamino)ethyl)isoxazole-3-carboxamide 219 5-cyclopropyl-N-(2-oxo-1-(piperidin-4- 384.3 34.17 yl)-2-((pyridin-3- ylmethyl)amino)ethyl)isoxazole-3- carboxamide 220 5-cyclopropyl-N-(piperidin-4-yl(3- 432.35 2.22 ((pyridin-3- ylamino)methyl)phenyl)methyl)isoxazole- 3-carboxamide 221 N-((3-((6-aminopyridin-3- 461.4 7.49 yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 222 5-cyclopropyl-N-((3-(methyl(pyridin-3- 460.4 31.99 yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)isoxazole-3-carboxamide 223 methyl 2-(1-(L-tryptophyl)piperidin-4- 494.18 3.15 yl)-2-(5-cyclopropylisoxazole-3- carboxamido)acetate 224 methyl 2-(1-(D-tiyptophyl)piperidin-4- 494.23 29.42 yl)-2-(5-cyclopropylisoxazole-3- carboxamido)acetate 225 N-(1-(1-(D-seryl)piperidin-4-yl)ethyl)-5- 351.3 5.82 cyclopropylisoxazole-3-carboxamide 226 N-((1-(L-valyl)piperidin-4-yl)methyl)-5- 349.3 0.57 cyclopropylisoxazole-3-carboxamide 227 N-((1-(D-valyl)piperidin-4-yl)methyl)-5- 349.25 4.01 cyclopropylisoxazole-3-carboxamide 228 N-((1-(D-seryl)piperidin-4-yl)methyl)-5- 337.25 13.18 cyclopropylisoxazole-3-carboxamide 229 5-cyclopropyl-N-((3-((1-methyl-1H- 449.4 5.5 pyrazol-4- yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)isoxazole-3-carboxamide 230 N-(1-(1-(D-alanyl)piperidin-4- 349.3 1.93 yl)propyl)-5-cyclopropylisoxazole-3- carboxamide 231 N-(1-(1-(L-alanyl)piperidin-4-yl)propyl)- 349.25 0.9 5-cyclopropylisoxazole-3-carboxamide 232 5-cyclopropyl-N-(2-oxo-1-(piperidin-4- 370.2 6.36 yl)-2-(pyridin-2- ylamino)ethyl)isoxazole-3-carboxamide 233 N-((3-((4-aminopyridin-2- 461.3 5.1 yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 234 N-((3-((6-cyanopyridin-3- 471.4 5.42 yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 235 N-(1-(1-(D-tyrosyl)piperidin-4-yl)ethyl)- 427.3 6.5 5-cyclopropylisoxazole-3-carboxamide 236 N-((1-(D-tyrosyl)piperidin-4-yl)methyl)- 413.25 14.3 5-cyclopropylisoxazole-3-carboxamide 237 5-cyclopropyl-N-(1-(1-((S)-2- 336.2 25.65 hydroxypropanoyl)piperidin-4- yl)ethyl)isoxazole-3-carboxamide 238 (R)-N-(3-(3-aminobutanamido)-2,2- 323.1 4.43 dimethylpropyl)-5-cyclopropylisoxazole- 3-carboxamide 239 (S)-N-(3-(3-aminobutanamido)-2,2- 323.1 6.35 dimethylpropyl)-5-cyclopropylisoxazole- 3-carboxamide 240 N-(3-(3-aminopropanamido)-2,2- 309.1 12.72 dimethylpropyl)-5-cyclopropylisoxazole- 3-carboxamide 241 N-(1-(1-(L-alanyl)piperidin-4-yl)-2-oxo- 455.3 15.58 2-((pyridin-3-ylmethyl)amino)ethyl)-5- cyciopropylisoxazole-3-carboxamide 242 N-(1-(1-(L-alanyl)piperidin-4-yl)-2-oxo- 455.25 22.31 2-((pyridin-4-ylmethyl)amino)ethyl)-5- cyclopropylisoxazole-3-caxboxamide 243 N-(1-(1-(L-alanyl)piperidin-4-yl)-2-((2- 470.35 2.72 hydroxybenzyl)amino)-2-oxoethyl)-5- cyclopropylisoxazole-3-caxboxamide 244 ethyl 2-(5-cyclopropylisoxazole-3- 322.2 20.57 carboxamido)-2-(piperidin-4-yl)acetate 245 N-((3-((2-aminopyridin-4- 461.3 4.13 yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)-5-cyclopropylisoxazoIe-3- carboxamide 246 5-cyclopropyl-N-((3-((6- 489.4 5.95 (dimethylamino)pyridin-3- yl)carbamoyl)phenyl)(piperidin-4- yl)methyl)isoxazole-3-carboxamide 247 N-(1-(1-((R)-3-aminobutanoyl)piperidin- 349.25 0.62 4-yl)ethyl)-5-cyclopropylisoxazole-3- carboxamide 248 N-(1-(1-((S)-3-aminobutanoyl)piperidin- 349.25 1.47 4-yl)ethyl)-5-cyclopropylisoxazole-3- carboxamide 249 (S)-N-(4-(2-aminopropanamido)butyl)-5- 295.15 14.62 cyclopropylisoxazole-3-caxboxamide 250 (R)-N-(4-(2-aminopropanamido)butyl)- 295.15 36.02 5-cyclopropylisoxazole-3-carboxamide 251 N-(((S)-1-(D-alanyl)pyrrolidin-3- 307.15 30.73 yl)methyl)-5-cyclopropylisoxazole-3- caxboxamide 252 N-(((S)-1-(L-alanyl)pyrrolidin-3- 307.05 21.36 yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 253 N-(((R)-1-(D-alanyl)pyrrolidin-3- 307.15 32.34 yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 254 N-(4-aminobutyl)-5- 224.1 41.44 cyclopropylisoxazole-3-carboxamide 255 (R)-5-cyclopropyl-N-(pyrrolidin-3- 236.1 39.25 ylmethyl)isoxazole-3-carboxamide 256 (S)-5-cyclopropyl-N-(pyrrolidin-3- 236.1 37.48 ylmethyl)isoxazole-3-carboxamide 257 5-cyclopropyl-N-((3- 446.35 7.37 (nicotmamido)phenyl)(piperidin-4- yl)methyl)isoxazole-3-carboxamide 258 N-(1-(1-(L-alanyl)piperidin-4-yl)-2-oxo- 441.3 11.47 2-(pyridin-3-ylamino)ethyl)-5- cyclopropylisoxazole-3-carboxamide 259 N-(1-(1-(L-alanyl)piperidin-4-yl)-2-oxo- 455.3 11.04 2-((pyridin-2-ylmethyl)amino)ethyl)-5- cyclopropylisoxazole-3-carboxamide 260 N-(((R)-1-(L-alanyl)pyrrolidin-3- 307.15 15.5 yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 261 N-(1-(1-(L-alanyl)piperidin-4-yl)-2-oxo- 441.3 0.39 2-(pyridin-2-ylamino)ethyl)-5- cyclopropylisoxazole-3-carboxamide 262 N-(1-(1-(L-alanyl)piperidin-4-yl)-2-oxo- 441.35 8.5 2-(pyridin-4-ylamino)ethyl)-5- cyclopropylisoxazole-3-carboxamide 263 5-cyclopropyl-N-((4-hydroxypiperidin-4- 266.15 14.89 yl)methyl)isoxazole-3-carboxamide 264 ethyl 4-((5-cyclopropylisoxazole-3- 322.1 43.56 carboxamido)methyl)piperidine-4- carboxylate 265 5-cyclopropyl-N-((4-methylpiperidin-4- 264.15 41.74 yl)methyl)isoxazole-3-carboxamide 266 5-cyclopropyl-N-((-fluoropiperidin-4- 268.05 18.82 yl)methyl)isoxazole-3-carboxamide 267 N-((1-(L-alanyl)-4-hydroxypiperidin-4- 337.35 5.47 yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 268 ethyl 1-(L-alanyl)-4-((5- 393.15 3.22 cyclopropylisoxazole-3- carboxamido)methyl)piperidine-4- carboxylate 269 N-((1-(L-alanyl)-4-methylpiperidin-4- 335.15 1.67 yl)methyl)-5-cyclopropylisoxazole-3- carboxamide 270 N-((1-(L-alanyl)-4-fluoropiperidin-4- 339.15 4.15 yl)methyl)-5-cyclopropylisoxazoIe-3- carboxamide 271 N-(1-(1-(L-alanyl)piperidin-4-yl)-2- 351.3 2.23 hydroxyethyl)-5-cyclopropylisoxazole-3- carboxamide 272 ethyl 2-(1-(L-tyrosyl)piperidin-4-yl)-2- 485.3 7.39 (5-cyclopropylisoxazole-3- carboxamido)acetate 273 N-(1-(1-(L-tyrosyl)piperidin-4-yl)-2- 465.25 2.37 hydroxyethyl)-5-cyclopropylisoxazole-3- (+Na) carboxamide 274 5-cyclopropyl-N-(2-hydroxy-1- 280.1 5.93 (piperidin-4-yl)ethyl)isoxazole-3- carboxamide 275 N-(6-(3- 333.2 1.8 aminopropanamido)spiro[3.3]heptan-2- yl)-5-cyclopropylisoxazole-3- carboxamide[transisomer 276 5-cyclopropyl-N-(2-methoxy-1- 294.1 11.92 (piperidin-4-yl)ethyl)isoxazole-3- carboxamide 277 5-cyclopropyl-N-(2-phenoxy-1- 356.1 10.51 (piperidin-4-yl)ethyl)isoxazole-3- carboxamide 278 5-cyclopropyl-N-(2-isopropoxy-1- 322.2 15.25 (piperidin-4-yl)ethyl)isoxazole-3- carboxamide 279 N-(6-((R)-3- 347.5 1.25 aminobutanamido)spiro[3.3]heptan-2- yl)-5-cyclopropylisoxazole-3- carboxamide[transisomer 280 N-((1r,4r)-4-aminocyclohexyl)-5- 224.2 18.75 methylisoxazole-3-caxboxamide 281 N-(6-((R)-3- 347.1 5.6 aminobutanamido)spiro[3.3]heptan-2- yl)-5-cyclopropylisoxazole-3- carboxamide[cisisomer 282 N-(1-(1-(L-alanyl)piperidin-4-yl)-2- 387 2.08 methoxyethyl)-5-cyclopropylisoxazole- (+Na) 3-carboxamide 283 N-(1-(1-(L-alanyl)piperidin-4-yl)-2- 427.35 2.67 phenoxyethyl)-5-cyclopropylisoxazole-3 carboxamide 284 N-(1-(1-(L-alajiyl)piperidin-4-yl)-2- 393.35 1.19 isopropoxyethyl)-5- cyclopropylisoxazole-3-carboxamide 285 N-(1-(1-(L-tyrosyl)piperidin-4-yl)-2- 457.25 1.07 methoxyethyl)-5-cyclopropylisoxazole- 3-carboxamide 286 N-(1-(1-(L-tyrosyl)piperidin-4-yl)-2- 519.3 4.35 phenoxyethyl)-5-cyclopropylisoxazole-3 carboxamide 287 N-(1-(1-(L-tyrosyl)piperidin-4-yl)-2- 485.3 5.2 isopropoxyethyl)-5- cyclopropylisoxazole-3-carboxamide 288 N-(6-((S)-3- 347.58 3.94 aminobutanamido)spiro[3,3]heptan-2- yl)-5-cyclopropylisoxazole-3- carboxamide[transisomer 290 N-(6-((S)-3- 347.6 1.82 aminobutanamido)spiro[3.3]heptan-2- yl)-5-cyclopropylisoxazole-3- carboxamide[cisisomer 291 N-(1-(3-aminopropanoyl)piperidin-3-yl)- 307 25.86 5-cyclopropylisoxazole-3-carboxamide 292 5-cyclopropyl-N-((1r,4r)-4-((2-((2- 365.1 4.88 hydroxyethyl)amino)ethyl)carbamoyl)- cyclohexyl)isoxazole-3-carboxamide 293 N-(6-((R)-3- 375.4 0.56 aminobutanamido)bicyclo[3.3.1]nonan- 2-yl)-5-cyclopropylisoxazole-3- carboxamide 294 N-(6-((S)-3- 375.3 0.66 aminobutanamido)bicyclo[3.3.1]nonan- 2-yl)-5-cyclopropylisoxazole-3- carboxamide 295 N-(6-(3- 361.4 1.2 aminopropanamido)bicyclo[3.3.1Jnonan- 2-yl)-5-cyclopropylisoxazole-3- carboxamide 296 5-cyclopropyl-N-((1-oxo-2-(pyridin-3- 472.63 36.37 yl)-1,2,3,4-tetrahydroisoquinolin-5- yl)(piperidin-4-yl)methyl)isoxazole-3- carboxamide 297 N-(1-(4-aminobutanoyl)piperidin-3-yl)- 321.05 18.59 5-cyclopropylisoxazole-3-carboxamide 298 N-(1-(1-(3-aminopropanoyl)piperidin-3- 335.1 37.71 yl)ethyl)-5-cyclopropylisoxazole-3- carboxamide 299 5-cyclopropyl-N-(1-(1-glycylpiperidin-3- 321.1 21.81 yl)ethyl)isoxazole-3-carboxamide 300 5-cyclopropyl-N-(1-(piperidin-4- 292.1 8.7 yl)butyl)isoxazole-3-carboxamide 301 5-cyclopropyl-N-(2-phenyl-1-(piperidin- 340.1 36.88 4-yl)ethyl)isoxazole-3-carboxamide 302 N-(1-(((1r,4r)-4-(2- 378.1 27.66 aminoacetamido)cyclohexyl)amino)-1- oxopropan-2-yl)-5-cyclopropylisoxazole- 3-carboxamide 303 5-cyclopropyl-N-(1-glycylpiperidin-3- 293.1 32.81 yl)isoxazole-3-carboxamide 304 N-(1-(1-(4-aminobutanoyl)piperidin-3- 349.1 21.81 yl)ethyl)-5-cyclopropylisoxazole-3- carboxamide 305 5-cyclopropyl-N-(3-methyl-1-(piperidin- 306.15 9.24 4-yl)butyl)isoxazole-3-carboxamide 306 N-(3-(3-aminopropanamido)-2- 295.1 41.9 methylpropyl)-5-cyclopropylisoxazole-3- carboxamide 307 N-(1-(3-aminopropanamido)pentan-3- 309.1 21.73 yl)-5-cyclopropylisoxazole-3- carboxamide 308 N-(4-(3-aminopropanamido)-2- 309.1 22.05 methylbutan-2-yl)-5- cyclopropylisoxazole-3-carboxamide 309 (1r,4r)-4-(5-cyclopropylisoxazole-3- 322.1 0.71 carboxamido)cyclohexyl3- aminopropanoate 310 N-(3-(4-aminobutanamido)cyclohexyl)- 335.1 27.03 5-cyclopropylisoxazole-3-carboxamide 311 (R)-N-((1-((3- 335.05 10.15 aminobutanamido)methyl)cyclobutyl) methyl)-5-cyclopropylisoxazole-3- carboxamide 312 N-((1r,4r)-4-((3- 335.1 2.75 aminopropyl)carbamoyl)cyclohexyl)-5- cyclopropylisoxazole-3-carboxamide 313 N-(4-((R)-3-aminobutanamido)-3,3- 337.1 0.8 dimethylbutan-2-yl)-5- cyclopropylisoxazole-3-carboxamide 314 N-(4-(3-aminopropanamido)butan-2-yl)- 295.05 27.98 5-cyclopropylisoxazole-3-carboxamide 315 N-(3-(3-aminopropanamido)cyclohexyl)- 321.1 20.78 5-cyclopropylisoxazole-3-carboxamide 316 N-((1r,4r)-4-(3- 295.1 8.58 aminopropanamido)cyclohexyl)-5- methylisoxazole-3-caxboxamide 317 N-((1r,4r)-4-((2- 321.1 3.67 aminoethyl)carbamoyl)cyclohexyl)-5- cyclopropylisoxazole-3-carboxamide 318 N-(4-((S)-3-aminobutanamido)-3,3- 337.1 2.03 dimethylbutan-2-yl)-5- cyclopropylisoxazole-3-carboxamide 319 N-(1-((1r,4r)-4-aminocyclohexane-1- 335.1 1.83 carboxamido)propan-2-yl)-5- cyclopropylisoxazole-3-carboxamide 320 N-(1-(4-aminobutanamido)propan-2-yl)- 295.1 12.94 5-cyclopropylisoxazole-3-carboxamide 321 5 -cyclopropyl-N-(1-(piperidin-3 - 264 26.78 yl)ethyl)isoxazole-3-carboxamide 322 N-(1-(4-aminobutanamido)butan-2-yl)-5- 309.1 17.38 cyclopropylisoxazole-3-carboxamide 323 N-(1-((1r,4r)-4-aminocyclohexane-1- 349.1 1.3 carboxamido)butan-2-yl)-5- cyclopropylisoxazole-3-carboxamide 324 N-(1-(3-aminopropanamido)butan-2-yl)- 295.1 19.68 5-cyclopropylisoxazole-3-carboxamide 325 N-(4-(3-aminopropanamido)phenyl)-5- 315 1.06 cyclopropylisoxazole-3-carboxamide 326 N-(4-(2-aminoacetamido)phenyl)-5- 301.3 4.24 cyclopropylisoxazole-3-carboxamide 327 N-(4-(4-aminobutanamido)phenyl)-5- 329.05 1.19 cyclopropylisoxazole-3-carboxamide 328 N-(4-((3-aminopropyl)amino)phenyl)-5- 301.05 3.74 cyclopropylisoxazole-3-carboxamide 329 N-(4-((2-aminoethyl)amino)phenyl)-5- 287.05 4.63 cyclopropylisoxazole-3-carboxamide 330 N-((1-((3- 307.1 37.55 aminopropanamido)methyl)cyclopropyl) methyl)-5-cyclopropylisoxazole-3- carboxamide 331 N-(4-(3-aminopropanamido)-1- 311.1 13.31 hydroxybutan-2-yl)-5- cyclopropylisoxazole-3-carboxamide 332 5-cyclopropyl-N-(4-(piperidin-4- 355.1 1.37 ylcarbamoyl)phenyl)isoxazole-3- carboxamide 333 N-(4-(((1s,4s)-4- 369.1 8.34 aminocyclohexyl)carbamoyl)phenyl)-5- cyclopropylisoxazole-3-carboxamide 334 N-(4-(((1r,4r)-4- 369.10 3.83 aminocyclohexyl)carbamoyl)phenyl)-5- cyclopropylisoxazole-3-carboxamide 335 N-(3-(N-(2- 351 10 aminoethyl)sulfamoyl)phenyl)-5- cyclopropylisoxazole-3-carboxamide 336 N-(4-(N-(3- 365.10 5.89 aminopropyl)sulfamoyl)phenyl)-5- cyclopropylisoxazole-3-carboxamide 337 N-(3-((2-aminoethyl)carbamoyl)phenyl)- 315 >10 5-cyclopropylisoxazole-3-carboxamide 338 N-(3-(N-(3- 365.1 >10 aminopropyl)sulfamoyl)phenyl)-5- cyclopropylisoxazole-3-carboxamide 339 N-(4-(N-(2- 351.1 7.68 aminoethyl)sulfamoyl)phenyl)-5- cyclopropylisoxazole-3-carboxamide 340 (R)-N-(1-(1-(4-aminobutanoyl)piperidin- 349.15 1.29 4-yl)ethyl)-5-cyclopropylisoxazole-3- carboxamide 341 (S)-N-(1-(1-(4-aminobutanoyl)piperidin- 349.15 3.54 4-yl)ethyl)-5-cyclopropylisoxazole-3- carboxamide 342 N-(1-((R)-3-aminobutanamido)-2,2- 351.2 1.31 dimethylpentan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 343 N-(1-((3-aminopropyl)sulfonyl)azetidin- 329 >10 >40 3-yl)-5-cyclopropylisoxazole-3- carboxamide 344 (R)-N-(1-(1-((3- 385 5.03 23.42 aminopropyl)sulfonyl)piperidin-4- yl)ethyl)-5-cyclopropylisoxazole-3- carboxamide 345 (S)-N-(1-(1-((3- 385 >10 >40 aminopropyl)sulfonyl)piperidin-4- yl)ethyl)-5-cyclopropylisoxazole-3- carboxamide 346 (S)-5-cyclopropyl-N-(1-(1-(2-(piperidin- 389.1 >10 4-yl)acetyl)piperidin-4- yl)ethyl)isoxazole-3-carboxamide 347 (R)-5-cyclopropyl-N-(1-(1-(2-(piperidin- 389.2 2.6 4-yl)acetyl)piperidin-4- yl)ethyl)isoxazole-3-carboxamide 348 N-((R)-1-(1-((1r,4R)-4- 389.2 0.46 5.16 aminocyclohexane-1-carbonyl)piperidin- 4-yl)ethyl)-5-cyclopropylisoxazole-3- carboxamide 349 N-((S)-1-(1-((1r,4S)-4- 389.2 2.79 >40 aminocyclohexane-1-carbonyl)piperidin- 4-yl)ethyl)-5-cyclopropylisoxazole-3- carboxamide 350 N-(1-((1r,4r)-4-aminocyclohexane-1- 333 >10 >40 carbonyl)azetidin-3-yl)-5- cyclopropylisoxazole-3-carboxamide 351 N-(3-((3- 329.10 >10 >40 aminopropyl)carbamoyl)phenyl)-5- cyclopropylisoxazole-3-carboxamide 352 N-(1-(4-aminobutanoyl)azetidin-3-yl)-5- 293.05 >10 >40 cyclopropylisoxazole-3-carboxamide 353 N-(3-bromo-4-(piperidin-4- 433.1/ 1.44 ylcarbamoyl)phenyl)-5- (433) cyclopropylisoxazole-3-carboxamide 354 5-cyclopropyl-N-(2-methyl-4-(piperidin- 369.2 2.17 4-ylcarbamoyl)phenyl)isoxazole-3- carboxamide 355 N-(4-((3-aminopropyl)carbamoyl)-3- 407.05/ 1.77 bromophenyl)-5-cyclopropylisoxazole-3- (409) carboxamide 356 N-(4-((3-aminopropyl)carbamoyl)-2- 343.10 3.52 methylphenyl)-5-cyclopropylisoxazole- 3-carboxamide 447.1/ 7.25 357 N-(3-bromo-4-((piperidin-4- (449) ylmethyl)carbamoyl)phenyl)-5- cyclopropylisoxazole-3-carboxamide 358 N-(4-((3-aminocyclobutyl)carbamoyl)-3- 419/ 1.4 bromophenyl)-5-cyclopropylisoxazole-3- (421.05) carboxamide 359 5-cyclopropyl-N-(4-(N-(piperidin-4- 405 5.81 >40 ylmethyl)sulfamoyl)phenyl)isoxazole-3- carboxamide 360 5-cyclopropyl-N-(3-methyl-4-(piperidin- 369.15 1.41 4-ylcarbamoyl)phenyl)isoxazole-3- carboxamide 361 N-(2-bromo-4-(piperidin-4- 433 1.77 >40 ylcarbamoyl)phenyl)-5- (435) cyclopropylisoxazole-3-carboxamide 362 N-(4-((4-aminocyclohcxyl)carbamoyl)-3- 383.4 3.74 methylphenyl)-5-cyclopropylisoxazole- 3-carboxamide 363 N-(4-((4-aminocyclohcxyl)carbamoyl)-2- 447/ 5.59 >40 bromophenyl)-5-cyclopropylisoxazole-3- (449.0) carboxamide 364 N-(4-((2-aminoethyl)carbamoyl)-3- 329.1 6 methylphenyl)-5-cyclopropylisoxazole- 3-carboxamide 365 N-(4-((2-aminoethyl)carbamoyl)-3- 393.05/ 4.5 >40 bromophenyl)-5-cyclopropylisoxazole-3- (395) carboxamide 366 N-(4-((2-aminoethyl)carbamoyl)-2- 393/ 3.7 38.81 bromophenyl)-5-cyclopropylisoxazole-3- (395.1) carboxamide 367 N-(4-((3-aminopropyl)carbamoyl)-3- 343.1 5.23 methylphenyl)-5-cyclopropylisoxazole- 3-carboxamide 368 N-(3-bromo-4-(pyrrolidin-3- 419.1/ 3.06 >40 ylcarbamoyl)phenyl)-5- (421) cyclopropylisoxazole-3-carboxamide 369 5-cyclopropyl-N-(2-methyl-4- 383.1 8.43 ((piperidin-4- ylmethyl)carbamoyl)phenyl)isoxazole-3- carboxamide 370 N-(4-((3-aminocyclobutyl)carbamoyl)-2- 419.1/ 2.74 >40 bromophenyl)-5-cyclopropylisoxazole-3- (421) carboxamide 371 N-(4-((3-aminocyclohexyl)carbamoyl)-3- 447/ bromophenyl)-5-cyclopropylisoxazole-3- (449.15) 9.11 carboxamide 372 N-(4-(N-(4- 405 2.57 21.71 aminocyclohexyl)sulfamoyl)phenyl)-5- cyclopropylisoxazole-3-carboxamide 373 5-cyclopropyl-N-(4-(N-(piperidin-4- 391 6.04 39.07 yl)sulfamoyl)phenyl)isoxazole-3- carboxamide 374 5-cyclopropyl-N-(4-(N-(pyrrolidin-3- 377.2 4.03 >40 yl)sulfamoyl)phenyl)isoxazole-3- carboxamide 375 N-(4-(N-(3- 377 4.72 >40 aminocyclobutyl)sulfamoyl)phenyl)-5- cyclopropylisoxazole-3-carboxamide 376 N-(1-((S)-3-aminobutanamido)-2,2- 351.1 1.17 dimethylpentan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 377 N-(4-((4-aminocyclohexyl)carbamoyl)-3- 447.3/ 2.81 bromophenyl)-5-cyclopropylisoxazole-3- (449) carboxamide 378 N-(4-((4-aminocyclohexyl)carbamoyl)-2- 383.3 6.36 methylphenyl)-5-cyclopropylisoxazole- 3-carboxamide 379 N-(4-((2-aminoethyl)carbamoyl)-2- 329 2.76 methylphenyl)-5-cyclopropylisoxazole- 3-carboxamide 380 N-(4-((3-aminopropyl)carbamoyl)-2- 406.9 1.74 bromophenyl)-5-cyclopropylisoxazole-3- (409) carboxamide 381 5-cyclopropyl-N-(2-methyl-4- 355 2 (pyrrolidin-3- ylcarbamoyl)phenyl)isoxazole-3- carboxamide 382 N-(2-bromo-4-(pyrrolidin-3- 419/ 2.95 ylcarbamoyl)phenyl)-5- (420.9) cyclopropylisoxazole-3-carboxamide 383 N-(4-((3-aminocyclopentyl)carbamoyl)- 433.1/ 3.23 3-bromophenyl)-5-cyclopropylisoxazole- (435) 3-carboxamide 384 N-(4-((3-aminocyclopentyl)carbamoyl)- 369.15 5.54 2-methylphenyl)-5- cyclopropylisoxazole-3-carboxamide 385 N-(4-((3-aminocyclopentyl)carbamoyl)- 433.15/ 3.29 2-bromophenyl)-5-cyclopropylisoxazole- (435) 3-carboxamide 386 N-(4-((3-aminocyclohexyl)carbamoyl)-2- 383.1 8.02 methylphenyl)-5-cyclopropylisoxazole- 3-carboxamide 387 N-(4-((3-aminocyclohexyl)carbamoyl)-2- 447/ 5.37 bromophenyl)-5-cyclopropylisoxazole-3- (449.0) carboxamide 388 N-(4-(N-(3- 391 5.11 >40 aminocyclopentyl)sulfamoyl)phenyl)-5- cyclopropylisoxazole-3-carboxamide 389 N-(4-(N-(3- 405.15 3.79 38.09 aminocyclohexyl)sulfamoyl)phenyl)-5- cyclopropylisoxazole-3-carboxamide 390 5-cyclopropyl-N-(3-methyl-4- 355.1 4.45 (pyrrolidin-3- ylcarbamoyl)phenyl)isoxazole-3- carboxamide 391 5-cyclopropyl-N-(3-methyl-4- 383.1 >10 ((piperidin-4- ylmethyl)carbamoyl)phenyl)isoxazole-3- carboxamide 392 N-(2-bromo-4-((piperidin-4- 447/ 4.78 ylmethyl)carbamoyl)phenyl)-5- (449.0) cyclopropylisoxazole-3-carboxamide 393 N-(4-((3-aminocyclohexyl)carbamoyl)-3- 383.1 >10 methylphenyl)-5-cyclopropylisoxazole- 3-carboxamide 394 N-((1s,4s)-4-(N-(2- 357 2.12 aminocthyl)sulfamoyl)cyclohexyl)-5- cyclopropylisoxazole-3-carboxamide 395 N-(4-((3-aminocyclopentyl)carbamoyl)- 369 4.61 3-methylphenyl)-5- cyclopropylisoxazole-3-carboxamide 396 N-(4-((3-aminocyclobutyl)carbamoyl)-2- 355.2 3.29 methylphenyl)-5-cyclopropylisoxazole- 3-carboxamide 397 N-(3-((3-aminopropyl)sulfonamido)-2,2- 359.1 2.16 dimethylpropyl)-5-cyclopropylisoxazole- 3-carboxamide 398 5-cyclopropyl-N-(2,2-dimethyl-3- 385.15 1.74 (piperidine-4- sulfonamido)propyl)isoxazole-3- carboxamide 399 N-(4-((3-aminocyclobutyl)carbamoyl)-3- 355 4.56 methylphenyl)-5-cyclopropylisoxazole- 3-carboxamide *IC50 values are an averagoe of n = 1 to n = 50 - For the purpose of the present disclosure, the term “alkyl” as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms (i.e., C1-12 alkyl) or the number of carbon atoms designated (i.e., a C1 alkyl such as methyl, a C2 alkyl such as ethyl, a C3 alkyl such as propyl or isopropyl, etc.). In one embodiment, the alkyl group is chosen from a straight chain C1-10 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C3-10 alkyl group. In another embodiment, the alkyl group is chosen from a straight chain C1-6 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C3-6 alkyl group. In another embodiment, the alkyl group is chosen from a straight chain C1-4 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C3-4 alkyl group. In another embodiment, the alkyl group is chosen from a straight or branched chain C3-4 alkyl group. In another embodiment, the alkyl group is partially or completely deuterated, i.e., one or more hydrogen atoms of the alkyl group are replaced with deuterium atoms. Non-limiting exemplary C1-10 alkyl groups include methyl (including —CD3), ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Non-limiting exemplary C1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl. Non-limiting exemplary C1-4 groups include methyl, ethyl, propyl, isopropyl, and tert-butyl.
- For the purpose of the present disclosure, the term “optionally substituted alkyl” as used by itself or as part of another group means that the alkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, alkoxycarbonyl, and carboxyalkyl. In one embodiment, the alkyl is a C1-6 alkyl. In another embodiment, the alkyl is a C1-4 alkyl. In one embodiment, the optionally substituted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent. Non-limiting exemplary optionally substituted alkyl groups include —CH2CH2NO2, —CH2CH2CO2H, —CH2CH2SO2CH3, —CH2CH2COPh, and —CH2C6H11.
- For the purpose of the present disclosure, the term “alkylenyl” as used herein by itself or part of another group refers to a divalent form of an alkyl group as defined above. In one embodiment, the alkylenyl is a divalent form of a C1-6 alkyl. In one embodiment, the alkylenyl is a divalent form of a C1-4 alkyl. Non-limiting exemplary alkylenyl groups include —CH2CH2—, —CH2CH2CH2—, —CH2CH(CH3)CH2—, and —CH2C(CH3)2CH2—.
- For the purpose of the present disclosure, the term “cycloalkyl” as used by itself or as part of another group refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms (i.e., C3-12 cycloalkyl) or the number of carbons designated. In one embodiment, the cycloalkyl group has two rings. In one embodiment, the cycloalkyl group has one ring. In another embodiment, the cycloalkyl group is chosen from a C3-8 cycloalkyl group. In another embodiment, the cycloalkyl group is chosen from a C3-6 cycloalkyl group. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, spiro[3.3]heptane, and bicyclo[3.3.1]nonane.
- For the purpose of the present disclosure, the term “optionally substituted cycloalkyl” as used by itself or as part of another group means that the cycloalkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl. (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl. In one embodiment, the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent. In one embodiment, the optionally substituted cycloalkyl is an (amino)cycloalkyl. For the purpose of the present disclosure, the term “(amino)cycloalkyl” as used by itself or as part of another group means that the optionally substituted cycloalkyl as defined above is substituted with one amino or alkylamino group, and optionally one or two additional substituents. In one embodiment, the optionally substituted cycloalkyl is an (amino)cyclohexyl. For the purpose of the present disclosure, the term “(amino)cyclohexyl” as used by itself or as part of another group means that the optionally substituted cycloalkyl as defined above is a cyclohexyl group substituted with one amino or alkylamino group, and optionally one or two additional substituents. Non-limiting exemplary optionally substituted cycloalkyl groups include:
- Non-limiting exemplary (amino)cycloalkyl groups include:
- Non-limiting exemplary (amino)cyclohexyl groups include:
- For the purpose of the present disclosure, the term “optionally substituted cyclohexyl” as used by itself or as part of another group means that the optionally substituted cycloalkyl as defined above is an optionally substituted cyclohexyl group.
- For the purpose of the present disclosure, the term “cycloalkylenyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted cycloalkyl group as defined above. In one embodiment, the cycloalkylenyl is a “cyclohexylenyl.” The term “cyclohexylenyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted cyclohexyl group. Non-limiting exemplary cycloalkylenyl groups include:
- For the purpose of the present disclosure, the term “1,4-cyclohexylenyl” as used herein by itself or part of another group refers to a cyclohexylenyl as defined above wherein the radicals are in the 1 and 4 positions of the cyclohexyl ring. Non-limiting exemplary 1,4-cyclohexylenyl groups include:
- For the purpose of the present disclosure, the term “(cycloalkylenyl)alkyl” as used herein by itself or part of another group refers to an alkyl group substituted with a divalent form of an optionally substituted cycloalkyl group. In one embodiment, the cycloalkylenyl is a divalent form of optionally substituted cyclohexyl. In one embodiment, the alkyl is C1-4 alkyl. Non-limiting exemplary (cycloalkylenyl)alkyl groups include:
- For the purpose of the present disclosure, the term “cycloalkenyl” as used by itself or part of another group refers to a partially unsaturated cycloalkyl group as defined above. In one embodiment, the cycloalkenyl has one carbon-to-carbon double bond. In another embodiment, the cycloalkenyl group is chosen from a C4-8 cycloalkenyl group. Exemplary cycloalkenyl groups include cyclopentenyl and cyclohexenyl.
- For the purpose of the present disclosure, the term “optionally substituted cycloalkenyl” as used by itself or as part of another group means that the cycloalkenyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, the optionally substituted cycloalkenyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkenyl is substituted with one substituent. In another embodiment, the cycloalkenyl is unsubstituted.
- For the purpose of the present disclosure, the term “alkenyl” as used by itself or as part of another group refers to an alkyl group as defined above containing one, two or three carbon-to-carbon double bonds. In one embodiment, the alkenyl group is chosen from a C2-6 alkenyl group. In another embodiment, the alkenyl group is chosen from a C2-4 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.
- For the purpose of the present disclosure, the term “optionally substituted alkenyl” as used herein by itself or as part of another group means the alkenyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclo.
- For the purpose of the present disclosure, the term “alkynyl” as used by itself or as part of another group refers to an alkyl group as defined above containing one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-to-carbon triple bond. In one embodiment, the alkynyl group is chosen from a C2-6 alkynyl group. In another embodiment, the alkynyl group is chosen from a C2-4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
- For the purpose of the present disclosure, the term “optionally substituted alkynyl” as used herein by itself or as part of another group means the alkynyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclo.
- For the purpose of the present disclosure, the term “haloalkyl” as used by itself or as part of another group refers to an alkyl group substituted by one or more fluorine, chlorine, bromine and/or iodine atoms. In one embodiment, the alkyl group is substituted by one, two, or three fluorine and/or chlorine atoms. In another embodiment, the haloalkyl group is chosen from a C1-4 haloalkyl group. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.
- For the purpose of the present disclosure, the term “fluoroalkyl” as used by itself or as part of another group refers to an alkyl group substituted by one or more fluorine atoms. In one embodiment, the alkyl group is substituted by one, two, or three fluorine atoms. In another embodiment, the fluoroalkyl group is chosen from a C1-4 fluoroalkyl group. Non-limiting exemplary fluoroalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and 4,4,4-trifluorobutyl.
- For the purpose of the present disclosure, the term “hydroxyalkyl” as used by itself or as part of another group refers to an alkyl group substituted with one or more, e.g., one, two, or three, hydroxy groups. In one embodiment, the hydroxyalkyl group is a monohydroxyalkyl group, i.e., substituted with one hydroxy group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups. In another embodiment, the hydroxyalkyl group is chosen from a C1-4 hydroxyalkyl group. Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as I-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.
- For the purpose of the present disclosure, the term “alkoxy” as used by itself or as part of another group refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal oxygen atom. In one embodiment, the alkoxy group is chosen from a C1-4 alkoxy group. In another embodiment, the alkoxy group is chosen from a C1-4 alkyl attached to a terminal oxygen atom, e.g., methoxy, ethoxy, tert-butoxy, —OCH2C≡CH, —OCH2C≡CCH3, and —OCH2CH2CH2C≡CH.
- For the purpose of the present disclosure, the term “alkylthio” as used by itself or as part of another group refers to a sulfur atom substituted by an optionally substituted alkyl group. In one embodiment, the alkylthio group is chosen from a C1-4 alkylthio group. Non-limiting exemplary alkylthio groups include —SCH3, and —SCH2CH3.
- For the purpose of the present disclosure, the term “alkoxyalkyl” as used by itself or as part of another group refers to an alkyl group substituted with an alkoxy group. Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sc-butoxymethyl, pentyloxymethyl, —CH2OCH2C≡CH and —CH2OCH2CH2CH2C≡CH.
- For the purpose of the present disclosure, the term “haloalkoxy” as used by itself or as part of another group refers to a haloalkyl attached to a terminal oxygen atom. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.
- For the purpose of the present disclosure, the term “heteroalkyl” as used by itself or part of another group refers to a stable straight or branched chain hydrocarbon radical containing 1 to 10 carbon atoms and at least two heteroatoms, which can be the same or different, selected from O, N, or S, wherein: 1) the nitrogen atom(s) and sulfur atom(s) can optionally be oxidized; and/or 2) the nitrogen atom(s) can optionally be quaternized. The heteroatoms can be placed at any interior position of the heteroalkyl group or at a position at which the heteroalkyl group is attached to the remainder of the molecule. In one embodiment, the heteroalkyl group contains two oxygen atoms. In one embodiment, the heteroalkyl contains one oxygen and one nitrogen atom, e.g., a (hydroxyalkylamino)alkyl group, e.g., —CH2N(CH3)CH2CH2CH2OH. In one embodiment, the heteroalkyl contains two nitrogen atoms. Non-limiting exemplary heteroalkyl groups include —CH2OCH2CH2OCH3, —OCH2CH2OCH2CH2OCH3, —CH—2NHCH2CH2OCH2, —OCH2CH2NH2, —NHCH2CH2N(H)CH7, —NHCH2CH2OCH3, —CH2OCH2CH2NH2, —CH2OCH2CH2N(H)CH2CH3, and —OCH2CH2OCH3.
- For the purpose of the present disclosure, the term “aryl” as used by itself or as part of another group refers to a monocyclic or bicyclic aromatic ring system having from six to fourteen carbon atoms (i.e., C6-14 aryl). Non-limiting exemplary aryl groups include phenyl (abbreviated as “Ph”), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is chosen from phenyl or naphthyl. In one embodiment, the aryl group is phenyl.
- For the purpose of the present disclosure, the term “optionally substituted aryl” as used herein by itself or as part of another group means that the aryl as defined above is either unsubstituted or substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl aralkyloxy, (aralkyloxy)alkyl, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, heteroalkyl optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, (C1-4 haloalkoxy)alkyl, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (hydroxyalkylamino)alkyl, (amino)(heteroaryl)alkyl, (heterocycloamino)alkyl (amino)(hydroxy)alkyl, (heteroaryl)alkyl, —N(R43)(R44), —CH2N(H)C(═O)—R45, and —N(H)C(═O)—R45, wherein R43 is hydrogen, C1-4 alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R44 is alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl; and R45 is alkyl, alkoxyalkyl, (heterocyclo)alkyl. (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, or (heteroaryl)alkyl In one embodiment, the optionally substituted aryl is an optionally substituted phenyl. In one embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent. In another embodiment, the optionally substituted phenyl has at least one amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl. (amino)(heteroaryl)alkyl, or (amino)(hydroxy)alkyl substituent. Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, and 2-phenylpropan-2-amine. The term optionally substituted aryl is meant to include aryl groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings. Examples include:
- For the purpose of the present disclosure, the term “arylenyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted aryl group as defined above. In one embodiment, the arylenyl is a divalent form of an optionally substituted phenyl. In one embodiment, the arylenyl is a divalent form of phenyl. Non-limiting exemplary alkylenyl groups include:
- For the purpose of the present disclosure, the term “aryloxy” as used by itself or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO—.
- For the purpose of the present disclosure, the term “heteroaryloxy” as used by itself or as part of another group refers to an optionally substituted heteroaryl attached to a terminal oxygen atom.
- For the purpose of the present disclosure, the term “aralkyloxy” or “arylalkyloxy” as used by itself or as part of another group refers to an aralkyl group attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCH2O—.
- For the purpose of the present disclosure, the term “(aralkyloxy)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an aralkyloxy group. In one embodiment, the alkyl is a C1-4 alkyl. Non-limiting exemplary “(aralkyloxy)alkyl” groups include —CH4OCH1(3-F-Ph) and —CH2OCH2CH2CH2(2-OMe-Ph).
- For the purpose of the present disclosure, the term “heteroaryl” or “heteroaromatic” refers to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring members (i.e., a 5- to 14-membered heteroaryl) and 1, 2, 3, or 4 heteroatoms independently chosen from oxygen, nitrogen or sulfur. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, the heteroaryl has two heteroatoms. In another embodiment, the heteroaryl has one heteroatom. In one embodiment, the heteroaryl has 5 ring atoms, e.g., thienyl. In another embodiment, the heteroaryl has 6 ring atoms, e.g., pyridyl. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term “heteroaryl” is also meant to include possible N-oxides. Exemplary N-oxides include pyridyl N-oxide.
- For the purpose of the present disclosure, the term “optionally substituted heteroaryl” as used by itself or as part of another group means that the heteroaryl as defined above is either unsubstituted or substituted with one to four substituents, e.g., one or two substituents, independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aralkyl, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl. (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, —N(R43)(R44), or —N(H)C(═O)—R45, wherein R43 is hydrogen or C1-4 alkyl; R44 is alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl; and R45 is alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In one embodiment, the optionally substituted heteroaryl has one substituent. In one embodiment, the substituent is amino, alkylamino, dialkylamino, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, —N(R43)(R44), or —N(H)C(═O)—R45. In one embodiment, the substituent is aralkyl or (heteroaryl)alkyl. Examples include:
- In one embodiment, the optionally substituted heteroaryl is an optionally substituted pyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or nitrogen atom can be substituted. The term optionally substituted heteroaryl is meant to include heteroaryl groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings. Examples include:
- For the purpose of the present disclosure, the term “heteroarylenyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted heteroaryl group as defined above. In one embodiment, the heteroarylenyl is a divalent form of an optionally substituted pyridyl. Non-limiting exemplary heteroarylenyl groups include:
- For the purpose of the present disclosure, the term “heterocycle” or “heterocyclo” as used by itself or as part of another group refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic groups containing one, two, or three rings having from three to fourteen ring members (i.e., a 3- to 14-membered heterocyclo) and at least one heteroatom. Each heteroatom is independently selected from the group consisting of oxygen, sulfur, including sulfoxide and sulfone, and/or nitrogen atoms, which can be quaternized. The term “heterocyclo” is meant to include cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as β-lactam, γ-lactam, δ-lactam and ε-lactam, and cyclic carbamate groups such as oxazolidinyl-2-one. The term “heterocyclo” is also meant to include groups having fused optionally substituted aryl groups, e.g., indolinyl, indolinyl-2-one, benzo[d]oxazolyl-2(3H)one. In one embodiment, the heterocyclo group is chosen from a 4-, 5-, 6-, 7- or 8-membered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms. In one embodiment, the heterocyclo group is chosen from a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms. In one embodiment, the heterocyclo group is chosen from a 8-, 9-, 10-, 11-, or 12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be optionally linked to the rest of the molecule through a carbon or nitrogen atom. Non-limiting exemplary heterocyclo groups include 2-oxopyrrolidin-3-yl, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, 8-azabicyclo[3.2.1]octane (nortropane), 6-azaspiro[2.5]octane, 6-azaspiro[3.4]octane, indolinyl, indolinyl-2-one, 1,3-dihydro-2H-benzo[d]imidazol-2-one
- For the purpose of the present disclosure, the term “optionally substituted heterocyclo” as used herein by itself or part of another group means the heterocyclo as defined above is either unsubstituted or substituted with one to four substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino. (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. Substitution may occur on any available carbon or nitrogen atom, and may form a spirocycle. In one embodiment, the optionally substituted heterocyclo is substituted with at least one amino, alkylamino, or dialkylamino group. Non-limiting exemplary optionally substituted heterocyclo groups include:
- For the purpose of the present disclosure, the term “heterocyclenyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted heterocyclo group as defined above. In one embodiment, the heterocyclenyl is a divalent form of an optionally substituted azetidine. In one embodiment, the heterocyclenyl is a divalent form of an optionally substituted piperidinyl. Non-limiting exemplary heterocyclenyl groups include:
- For the purpose of the present disclosure, the term “optionally substituted pyrrolidinyl” as used by itself or as part of another group means that the optionally substituted heterocyclo as defined above is an optionally substituted pyrrolidinyl group.
- For the purpose of the present disclosure, the term “optionally substituted pyrrolidinonyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted pyrrolidinyl group as defined above. Non-limiting exemplary optionally substituted pyrrolidinenyl groups include:
- For the purpose of the present disclosure, the term “optionally substituted, optionally bridged piperidinenyl” as used by itself or as part of another group refers to a divalent form having the following structure:
- wherein:
- R2′a, R2′b, R3′a, R3′b, R4′a, R4′b, R5′a, and R5′b are each independently selected from the group consisting of hydrogen, halo, C1-6 alkyl, C3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C6-14 aryl, aralkyl, and alkoxycarbonyl; or
- R2′a and R2′b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R3′a, R3′b, R4′a, R4′bR5′a, and R5′b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
- R3′a and R3′b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2′a, R2′b, R4′a, R4′b, R5′a, and R5′b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
- R4a and R4b taken together with the carbon atom to which they are attached form a Cu cycloalkyl; and R2′a, R2′b, R3′a, R3′b, R4′a, and R4′b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
- R5′a and R5′b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2′a, R2′b, R3′a, R3′b, R4′a, and R4′b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
- R2′a and R5′a taken together form a C1-4 bridge; and R2′b, R3′a, R3′b, R4′a, R4′b, and R5′b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl, or
- R3′a and R4′a taken together form a C1-4 bridge; and R2′a, R2′b, R3′b, R4′a, R5′a, and R5′b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
- R2′a and R4′a taken together form a C1-4 bridge; and R2′b, R3′a, R3′b, R4′b, R5′a, and R5′b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
- R3′a and R5′a taken form a C1-4 bridge; and R2′a, R2′b, R3′b, R4′a, R4′b, and R5′b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl;
- R6′ is selected from the group consisting of hydrogen and C1-4 alkyl;
- For the purpose of the present disclosure, the term “amino” as used by itself or as part of another group refers to —NH2.
- For the purpose of the present disclosure, the term “alkylamino” as used by itself or as part of another group refers to —NHR22, wherein R22 is C1-6 alkyl. In one embodiment, R22 is C1-4 alkyl. Non-limiting exemplary alkylamino groups include —N(H)CH3 and —N(H)CH2CH3.
- For the purpose of the present disclosure, the term “dialkylamino” as used by itself or as part of another group refers to —NR23aR23b, wherein R23a and R23b are each independently C1-6 alkyl. In one embodiment, R23a and R23b are each independently C1-4 alkyl. Non-limiting exemplary dialkylamino groups include —N(CH3)2 and —N(CH3)CH2CH(CH3)2.
- For the purpose of the present disclosure, the term “hydroxyalkylamino” as used by itself or as part of another group refers to —NR24a R24b, wherein R24a is hydrogen or C1-4 alkyl, and R24b is hydroxyalkyl. Non-limiting exemplary hydroxyalkylamino groups include —N(H)CH2CH2OH, —N(H)CH2CH2CH2OH, —N(CH3)CH2CH2OH, and —N(CH3)CH2CH2CH2OH
- For the purpose of the present disclosure, the term “(hydroxyalkylamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an hydroxyalkylamino group. In one embodiment, the alkyl is a C1-4 alkyl. A non-limiting exemplary (hydroxyalkylamino)alkyl group is —CH2N(CH3)CH2CH2CH2OH.
- For the purpose of the present disclosure, the term “cycloalkylamino” as used by itself or as part of another group refers to —NR25aR25b, wherein R25a is optionally substituted cycloalkyl and R25b is hydrogen or C1-4 alkyl.
- For the purpose of the present disclosure, the term “heterocycloamino” as used by itself or as part of another group refers to —NR25cR25d, wherein R25c is optionally substituted heterocyclo and R25d is hydrogen or C1-4 alkyl. Non-limiting exemplary heterocycloamino groups include:
- For the purpose of the present disclosure, the term “(heterocycloamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an heterocycloamino group. In one embodiment, the alkyl is a C1-4 alkyl.
- For the purpose of the present disclosure, the term “aralkylamino” as used by itself or as part of another group refers to —NR26aR26b, wherein R26a is aralkyl and R26b is hydrogen or C1-4 alkyl. Non-limiting exemplary aralkylamino groups include —N(H)CH2Ph and —N(CH3)CH2Ph.
- For the purpose of the present disclosure, the term “(amino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an amino group. In one embodiment, the alkyl is a C1-4 alkyl. Non-limiting exemplary (amino)alkyl groups include —CH2NH2, —C(NH2)(H)CH3, —CH2CH2NH2, —CH2C(NH2)(H)CH3, —CH2CH2CH2NH2, —CH2CH2CH2CH2NH2, and —CH2C(CH3)2CH2NH2.
- For the purpose of the present disclosure, the term “(alkylamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an alkylamino group. In one embodiment, the alkyl is a C1-4 alkyl. A non-limiting exemplary (alkylamino)alkyl group is —CH2CH2N(H)CH3.
- For the purpose of the present disclosure, the term “(dialkylamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted by a dialkylamino group. In one embodiment, the alkyl is a C1-4 alkyl. Non-limiting exemplary (dialkylamino)alkyl groups are —CH2CH2N(CH3)2.
- For the purpose of the present disclosure, the term “(cycloalkylamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted by a cycloalkylamino group. In one embodiment, the alkyl is a C1-4 alkyl. Non-limiting exemplary (cycloalkylamino)alkyl groups include —CH2N(H)cyclopropyl, —CH2N(H)cyclobutyl, and —CH2N(H)cyclohexyl.
- For the purpose of the present disclosure, the term “(aralkylamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an aralkylamino group. In one embodiment, the alkyl is a C1-4 alkyl. A non-limiting exemplary (aralkylamino)alkyl group is —CH2CH2CH2N(H)CH2Ph.
- For the purpose of the present disclosure, the term “(hydroxyalkylamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an hydroxyalkylamino group. A non-limiting exemplary (hydroxyalkylamino)alkyl group is —CH2CH2NHCH2CH2OH
- For the purpose of the present disclosure, the term “(cyano)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one or more cyano, e.g., —CN, groups. In one embodiment, the alkyl is a C1-4 alkyl. Non-limiting exemplary (cyano)alkyl groups include —CH2CH2CN, —CH2CH2CH2CN, and —CH2C2CH2CH2CH2CN.
- For the purpose of the present disclosure, the term “(amino)(hydroxy)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one amino, alkylamino, dialkylamino, or heterocyclo group and one hydroxy group. In one embodiment, the alkyl is a C1-6 alkyl. In another embodiment, the alkyl is a C1-4 alkyl. Non-limiting exemplary (amino)(hydroxy)alkyl groups include:
- For the purpose of the present disclosure, the term “(amino)(carboxamido)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino, and one carboxamido group. In one embodiment, the alkyl is a C1-6 alkyl. Non-limiting exemplary (amino)(carboxamido)alkyl groups include:
- For the purpose of the present disclosure, the term “(amino)(aryl)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino group and one optionally substituted aryl group. In one embodiment, the alkyl is a C1-6 alkyl. In one embodiment, the optionally substituted aryl group is an optionally substituted phenyl. Non-limiting exemplary (amino)(aryl)alkyl groups include:
- For the purpose of the present disclosure, the term “(amino)(heteroaryl)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino group and one optionally substituted heteroaryl group. In one embodiment, the alkyl is a C1-6 alkyl. In one embodiment, the alkyl is a C1-4 alkyl. In one embodiment, the optionally substituted heteroaryl group is an optionally substituted pyridyl. Non-limiting exemplary (amino)(heteroaryl)alkyl groups include:
- For the purpose of the present disclosure, the term “(cycloalkyl)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one optionally substituted cycloalkyl group. In one embodiment, the alkyl is a C1-4 alkyl. In one embodiment, the cycloalkyl is a C3-6 cycloalkyl. In one embodiment, the optionally substituted cycloalkyl group is substituted with an amino or (amino)alkyl group. Non-limiting exemplary (cycloalkyl)alkyl groups include:
- For the purpose of the present disclosure, the term “(hydroxy)(aryl)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one hydroxy group and one optionally substituted aryl group. In one embodiment, the alkyl is a C1-6 alkyl. In one embodiment, the optionally substituted aryl group is an optionally substituted phenyl. Non-limiting exemplary (hydroxy)(aryl)alkyl groups include:
- For the purpose of the present disclosure, the term “carboxamido” as used by itself or as part of another group refers to a radical of formula —C(═O)NR26aR26b, wherein R26a and R26b are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, aralkyl, (heteroaryl)alkyl, or optionally substituted heteroaryl, or R26a and R26b taken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group. In one embodiment, R26a and R26b are each independently hydrogen or optionally substituted alkyl. Non-limiting exemplary carboxamido groups include —CONH2, —CON(H)CH3, CON(CH3)2, and —CON(H)Ph.
- For the purpose of the present disclosure, the term “(carboxamido)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with a carboxamido group. Non-limiting exemplary (carboxamido)alkyl groups include —CH2CONH2, —C(H)CH3—CONH2, and —CH2CON(H)CH3.
- For the purpose of the present disclosure, the term “sulfonamido” as used by itself or as part of another group refers to a radical of the formula —SO2NR27aR27b, wherein R27a and R27b are each independently hydrogen, optionally substituted alkyl, or optionally substituted aryl, or R27a and R27b taken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group. Non-limiting exemplary sulfonamido groups include —SO2NH2, —SO2N(H)CH3, and —SO2N(H)Ph.
- For the purpose of the present disclosure, the term “alkylcarbonyl” as used by itself or as part of another group refers to a carbonyl group, i.e., —C(═O)—, substituted by an alkyl group. A non-limiting exemplary alkylcarbonyl group is —COCH3.
- For the purpose of the present disclosure, the term “arylcarbonyl” as used by itself or as part of another group refers to a carbonyl group, i.e., —C(═O)—, substituted by an optionally substituted aryl group. A non-limiting exemplary arylcarbonyl group is —COPh.
- For the purpose of the present disclosure, the term “alkylsulfonyl” as used by itself or as part of another group refers to a sulfonyl group, i.e., —SO2—, substituted by any of the above-mentioned optionally substituted alkyl groups. A non-limiting exemplary alkylsulfobnyl group is —SO2CH3.
- For the purpose of the present disclosure, the term “arylsulfonyl” as used by itself or as part of another group refers to a sulfonyl group, i.e., —SO2—, substituted by any of the above-mentioned optionally substituted aryl groups. A non-limiting exemplary arylsulfonyl group is —SO2Ph.
- For the purpose of the present disclosure, the term “mercaptoalkyl” as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted by a —SH group.
- For the purpose of the present disclosure, the term “carboxy” as used by itself or as part of another group refers to a radical of the formula —COOH.
- For the purpose of the present disclosure, the term “carboxyalkyl” as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted with a —COOH. A non-limiting exemplary carboxyalkyl group is —CH2CO2H.
- For the purpose of the present disclosure, the term “alkoxycarbonyl” as used by itself or as part of another group refers to a carbonyl group, i.e., —C(═O)—, substituted by an alkoxy group. Non-limiting exemplary alkoxycarbonyl groups are —CO2Me and —CO2Et.
- For the purpose of the present disclosure, the term “aralkyl” or “arylalkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the aralkyl group is a C1-4 alkyl substituted with one optionally substituted aryl group. Non-limiting exemplary aralkyl groups include benzyl, phenethyl, —CHPh2, —CH2(4-OH-Ph), and —CH(4-F-Ph)2.
- For the purpose of the present disclosure, the term “ureido” as used by itself or as part of another group refers to a radical of the formula —NR30a—C(═O)—NR30bR30c, wherein R22a is hydrogen, alkyl, or optionally substituted aryl, and R30b and R30c are each independently hydrogen, alkyl, or optionally substituted aryl, or R30b and R30c taken together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclo group. Non-limiting exemplary ureido groups include —NH—C(C═O)—NH2 and —NH—C(C═O)—NHCH3.
- For the purpose of the present disclosure, the term “guanidino” as used by itself or as part of another group refers to a radical of the formula —NR28a—C(═NR29)—NR28bR28c, wherein R28a, R28b, and R28c are each independently hydrogen, alkyl, or optionally substituted aryl, and R29 is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl, carboxamido, or sulfonamido. Non-limiting exemplary guanidino groups include —NH—C(C═NH)—NH2, —NH—C(C═NCN)—NH2, and —NH—C(C═NH)—NHCH3.
- For the purpose of the present disclosure, the term “(heterocyclo)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heterocyclo groups. In one embodiment, the (heterocyclo)alkyl is a C1-4 alkyl substituted with one optionally substituted heterocyclo group. The heterocyclo can be linked to the alkyl group through a carbon or nitrogen atom. Non-limiting exemplary (heterocyclo)alkyl groups include:
- For the purpose of the present disclosure, the term “(heteroaryl)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heteroaryl groups. In one embodiment, the (heteroaryl)alkyl group is a C1-4 alkyl substituted with one optionally substituted heteroaryl group. Non-limiting exemplary (heteroaryl)alkyl groups include:
- For the purpose of the present disclosure, the term “alkylcarbonylamino” as used by itself or as part of another group refers to an alkylcarbonyl group attached to an amino. A non-limiting exemplary alkylcarbonylamino group is —NHCOCH3.
- For the purpose of the present disclosure, the term “C1-4 bridge” refers to a —CH2—, —(CH2)2—, —(CH2)3—, or —(CH2)4— group that joins two carbon atoms of a piperidine to form an azabicyclo group. For example, in Formula I, R3a and R4a of B can be taken together to form a 6-azabicyclo[3.1.1]heptane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, or 10-azabicyclo[4.3.1]decane group. Each methylene unit of the C1-4 bridge can be optionally substituted with one or two substituents independently selected from the group consisting of C1-4 alkyl and halo.
- The present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H (or deuterium (D)), 3H, 11C, 13C, 14C, 5N, 13O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively, e.g., 3H, 11C, and 14C. In one embodiment, provided is a composition wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number. In another embodiment, provided is a composition wherein a portion of the atoms at a position within the Compound of the disclosure are replaced, i.e., the Compound of the Disclosure is enriched at a position with an atom having a different atomic mass or mass number.” Isotopically-labelled Compounds of the Disclosure can be prepared by methods known in the art.
- Compounds of the Disclosure may contain one or more asymmetric centers and may thus give rise to enantiomers, diasteromers, and other stereoisomeric forms. The present disclosure is meant to encompass the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present disclosure as well.
- As used herein, the term “stereoisomers” is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
- The term “chiral center” or “asymmetric carbon atom” refers to a carbon atom to which four different groups are attached.
- The terms “enantiomer” and “enantiomeric” refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.
- The term “racemic” refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.
- The term “absolute configuration” refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.
- The stereochemical terms and conventions used in the specification are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated.
- The term “enantiomeric excess” or “ee” refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as |R−S|*100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R+S=1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ([α]obs/[α]max)*100, where [α]obs is the optical rotation of the mixture of enantiomers and [α]max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.
- The terms “enantiomerically pure” or “enantiopure” refer to a sample of a chiral substance all of whose molecules (within the limits of detection) have the same chirality sense.
- The terms “enantiomerically enriched” or “enantioenriched” refer to a sample of a chiral substance whose enantiomeric ratio is greater than 50:50. Enantiomerically enriched compounds may be enantiomerically pure.
- The terms “a” and “an” refer to one or more.
- The term “about,” as used herein, includes the recited number±10%. Thus, “about 10” means 9 to 11.
- The present disclosure encompasses the preparation and use of salts of the Compounds of the Disclosure, including non-toxic pharmaceutically acceptable salts. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and basic salts. The pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; and amino acid salts such as arginate, asparaginate, glutamate and the like. The term “pharmaceutically acceptable salt” as used herein, refers to any salt, e.g., obtained by reaction with an acid or a base, of a Compound of the Disclosure that is physiologically tolerated in the target patient (e.g., a mammal, e.g., a human).
- Acid addition salts can be formed by mixing a solution of the particular Compound of the Disclosure with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or the like. Basic salts can be formed by mixing a solution of the compound of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.
- The present disclosure encompasses the preparation and use of solvates of Compounds of the Disclosure. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term “solvate” as used herein is a combination, physical association and/or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a desolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, “solvate” encompasses both solution-phase and isolatable solvates. Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure. One type of solvate is a hydrate. A “hydrate” relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E. C, van Tonder et al., AAPS Pharm. Sci. Tech., 5(l):Article 12 (2004), and A. L. Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20° C. to about 25° C., then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.
- Since Compounds of the Disclosure are inhibitors of SMYD proteins, such as SMYD3 and SMYD2, a number of diseases, conditions, or disorders mediated by SMYD proteins, such as SMYD3 and SMYD2, can be treated by employing these compounds. The present disclosure is thus directed generally to a method for treating a disease, condition, or disorder responsive to the inhibition of SMYD proteins, such as SMYD3 and SMYD2, in an animal suffering from, or at risk of suffering from, the disorder, the method comprising administering to the animal an effective amount of one or more Compounds of the Disclosure.
- The present disclosure is further directed to a method of inhibiting SMYD proteins in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
- The present disclosure is further directed to a method of inhibiting SMYD3 in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
- The present disclosure is further directed to a method of inhibiting SMYD2 in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
- As used herein, the terms “treat,” “treating,” “treatment,” and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. As used herein, the terms “treat.” “treating.” “treatment,” and the like may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition. The term “treat” and synonyms contemplate administering a therapeutically effective amount of a Compound of the Disclosure to an individual in need of such treatment.
- Within the meaning of the disclosure, “treatment” also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.
- The term “therapeutically effective amount” or “effective dose” as used herein refers to an amount of the active ingredient(s) that is(are) sufficient, when administered by a method of the disclosure, to efficaciously deliver the active ingredient(s) for the treatment of condition or disease of interest to an individual in need thereof. In the case of a cancer or other proliferation disorder, the therapeutically effective amount of the agent may reduce (i.e., retard to some extent and preferably stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; modulate protein methylation in the target cells; and/or relieve, to some extent, one or more of the symptoms associated with the cancer. To the extent the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.
- The term “container” means any receptacle and closure therefore suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.
- The term “insert” means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product. The package insert generally is regarded as the “label” for a pharmaceutical product.
- The term “disease” or “condition” or “disorder” denotes disturbances and/or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and/or malfunctions. As demonstrated below, Compounds of the Disclosure inhibit SMYD proteins, such as SMYD3 and SMYD2 and can be used in treating diseases and conditions such as proliferative diseases, wherein inhibition of SMYD proteins, such as SMYD3 and SMYD2 provides a benefit.
- In some embodiments, the Compounds of the Disclosure can be used to treat a “SMYD protein mediated disorder” (e.g., a SMYD3-mediated disorder or a SMYD2-mediated disorder). A SMYD protein mediated disorder is any pathological condition in which a SMYD protein is know to play a role. In some embodiments, a SMYD-mediated disorder is a proliferative disease.
- In some embodiments inhibiting SMYD proteins, such as SMYD3 and SMYD2, is the inhibition of the activity of one or more activities of SMYD proteins such as SMYD3 and SMYD2. In some embodiments, the activity of the SMYD proteins such as SMYD3 and SMYD2 is the ability of the SMYD protein such as SMYD3 or SMYD2 to transfer a methyl group to a target protein (e.g., histone). It should be appreciated that the activity of the one or more SMYD proteins such as SMYD3 and SMYD2 may be inhibited in vitro or in vivo. Examplary levels of inhibition of the activity one or more SMYD proteins such as SMYD3 and SMYD2 include at least 10% inhibition, at least 20% inhibition, at least 30% inhibition, at least 40% inhibition, at least 50% inhibition, at least 60% inhibition, at least 70% inhibition, at least 80% inhibition, at least 90%/0 inhibition, and up to 100% inhibition.
- The SMYD (SET and MYND domain) family of lysine methyltransferases (KMTs) plays pivotal roles in various cellular processes, including gene expression regulation and DNA damage response. The family of human SMYD proteins consists of SMYD1, SMYD2, SMYD3. SMYD4 and SMYD5. SMYD1, SMYD2, and SMYD3 share a high degree of sequence homology and, with the exception of SMYD5, human SMYD proteins harbor at least one C-terminal tetratrico peptide repeat (TPR) domain. (See e.g., Abu-Farha et al. J Mol Cell Biol (2011) 3 (5) 301-308). The SMYD proteins have been found to be linked to various cancers (See e.g., Hamamoto et al. Nat Cell. Biol. 2004, 6: 731-740), Hu et al. Cancer Research 2009, 4067-4072, and Komatsu et al. Carcinogenesis 2009, 301139-1146.)
- SMYD3 is a protein methyltransferase found to be expressed at high levels in a number of different cancers (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004)). SMYD3 likely plays a role in the regulation of gene transcription and signal transduction pathways critical for survival of breast, liver, prostate and lung cancer cell lines (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004); Hamamoto, R., et al., Cancer Sci., 97(2):113-8 (2006); Van Aller, G. S., et al., Epigenetics, 7(4):340-3 (2012); Liu, C., et al., J. Natl. Cancer Inst., 105(22):1719-28 (2013): Mazur, P. K., et al., Nature, 510(7504):283-7 (2014)).
- Genetic knockdown of SMYD3 leads to a decrease in proliferation of a variety of cancer cell lines (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004); Hamamoto. R., et al., Cancer Sci., 97(2):113-8 (2006); Van Aller, U.S., et al., Epigenetics, 7(4):340-3 (2012); Liu. C., et al., J. Natl. Cancer Inst., 105(22):1719-28 (2013); Mazur. P. K., et al., Nature, 510(7504):283-7 (2014)). Several studies employing RNAi-based technologies have shown that ablation of SMYD3 in hepatocellular carcinoma cell lines greatly reduces cell viability and that its pro-survival role is dependent on its catalytic activity (Hamamoto. R., et al., Nat. Cell Biol., 6(8):731-40 (2004); Van Aller, G. S., et al., Epigenetics, 7(4):340-3 (2012)). Moreover, SMYD3 has also been shown to be a critical mediator of transformation resulting from gain of function mutations in the oncogene, KRAS for both pancreatic and lung adenocarcinoma in mouse models. The dependence of KRAS on SMYD3 was also shown to be dependent on its catalytic activity (Mazur, P. K., et al., Nature, 510(7504):283-7 (2014)). SMYD3 function has also been implicated in colerectal cancers and RNAi mediated knockdown of SMYD3 has been shown to impair colerectal cell proliferation. (Peserico et al., Cell Physiol. 2015 Feb. 28. doi: 10.1002/jcp.24975. [Epub ahead of print]).
- Furthermore. SMYD3 function has also been shown to play a role in immunology and development. For instance, de Almeida reported that SMYD3 plays a role in generation of inducible regulatory T cells (iTreg) cells. In a mouse model of respiratory syncytial virus (RSV) infection, a model in which iTreg cells have a critical role in regulating lung pathogenesis, SMYD3−/− mice demonstrated exacerbation of RSV-induced disease related to enhanced proinflammatory responses and worsened pathogenesis within the lung (de Almeida et al. Mucosal Immunol. 2015 Feb. 11. doi: 10.1038/mi.2015.4. [Epub ahead of print]). In addition, as to development, Proserpio et al. have shown the importance of SMYD3 in the regulation of skeletal muscle atrophy (Proserpio et al. Genes Dev. 2013 Jun. 1; 27(11):1299-312), while Fujii et al. have elucidated the role of SMYD3 in cardiac and skeletal muscle development (Fujii et al. PLoS One. 2011; 6(8):e23491).
- SMYD2 (SET and MYND domain-containing protein 2) was first characterized as protein that is a member of a sub-family of SET domain containing proteins which catalyze the site-specific transfer of methyl groups onto substrate proteins. SMYD2 was initially shown to have methyltransferase activity towards lysine 36 on histone H3 (H3K36) but has subsequently been shown to have both histone and non-histone methyltrasferase activity.
- SMYD2 has been implicated in the pathogenesis of multiple cancers. It has been shown to be over-expressed, compared to matched normal samples, in tumors of the breast, cervix, colon, kidney, liver, head and neck, skin, pancreas, ovary, esophagus and prostate, as well as hematologic malignancies such as AML, B- and T-ALL, CLL and MCL, suggesting a role for SMYD2 in the biology of these cancers. More specifically, studies using genetic knock-down of SMYD2 have demonstrated anti-proliferative effects in esophageal squamous cell carcinoma (ESCC), bladder carcinoma and cervical carcinoma cell lines. (See e.g., Komatsu et al., Carcinogenesis 2009, 30, 1139, and Cho et al., Neoplasia, 2012 June; 14(6):476-86). Moreover, high expression of SMYD2 has been shown to be a poor prognostic factor in both ESCC and pediatric ALL. (See e.g., Komatsu et al. Br J Cancer. 2015 Jan. 20; 112(2):357-64, and Sakamoto et al., Leuk Res. 2014 April; 38(4):496-502). Recently, Nguyen et al., have shown that a small molecule inhibitor of SMYD2 (LLY-507) inhibited the proliferation of several esophageal, liver and breast cancer cell lines in a dose-dependent manner. (Nguyen et al. J Bio Chem. 2015 Mar. 30, pii: jbc.M114.626861. [Epub ahead of print]).
- SMYD2 has also been implicated in immunology. For instance, Xu et al. have shown that SMYD2 is a negative regulator of macrophage activation by suppressing Interleukin-6 and TNF-alpha production. (Xu et al., J Biol Chem. 2015 Feb. 27; 290(9):5414-23).
- In one aspect, the present disclosure provides a method of treating cancer in a patient comprising administering a therapeutically effective amount of a Compound of the Disclosure. While not being limited to a specific mechanism, in some embodiments, Compounds of the Disclosure can treat cancer by inhibiting SMYD proteins, such as SMYD3 and SMYD2. Examples of treatable cancers include, but are not limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma. Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma. Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.
- In another embodiment, the cancer is breast, cervix, colon, kidney, liver, head and neck, skin, pancreas, ovary, esophagus, or prostate cancer.
- In another embodiment, the cancer is a hematologic malignancy such as acute myeloid leukemia (AML), B- and T-acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or mantle cell lymphoma (MCL).
- In another embodiment, the cancer is esophageal squamous cell carcinoma (ESCC), bladder carcinoma, or cervical carcinoma.
- In another embodiment, the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukemia (MLL). In another embodiment the cancer is NUT-midline carcinoma. In another embodiment the cancer is multiple myeloma. In another embodiment the cancer is a lung cancer such as small cell lung cancer (SCLC). In another embodiment the cancer is a neuroblastoma. In another embodiment the cancer is Burkitt's lymphoma. In another embodiment the cancer is cervical cancer. In another embodiment the cancer is esophageal cancer. In another embodiment the cancer is ovarian cancer. In another embodiment the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer.
- In another embodiment, the present disclosure provides a therapeutic method of modulating protein methylation, gene expression, cell proliferation, cell differentiation and/or apoptosis in vivo in the cancers mentioned above by administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need of such therapy.
- Compounds of the Disclosure can be administered to a mammal in the form of a raw chemical without any other components present. Compounds of the Disclosure can also be administered to a mammal as part of a pharmaceutical composition containing the compound combined with a suitable pharmaceutically acceptable carrier. Such a carrier can be selected from pharmaceutically acceptable excipients and auxiliaries. The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable vehicle” encompasses any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Suitable pharmaceutically acceptable vehicles include aqueous vehicles and nonaqueous vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 19th ed. 1995.
- Pharmaceutical compositions within the scope of the present disclosure include all compositions where a Compound of the Disclosure is combined with one or more pharmaceutically acceptable carriers. In one embodiment, the Compound of the Disclosure is present in the composition in an amount that is effective to achieve its intended therapeutic purpose. While individual needs may vary, a determination of optimal ranges of effective amounts of each compound is within the skill of the art. Typically, a Compound of the Disclosure can be administered to a mammal, e.g., a human, orally at a dose of from about 0.0025 to about 1500 mg per kg body weight of the mammal, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, per day to treat the particular disorder. A useful oral dose of a Compound of the Disclosure administered to a mammal is from about 0.0025 to about 50 mg per kg body weight of the mammal, or an equivalent amount of the pharmaceutically acceptable salt or solvate thereof. For intramuscular injection, the dose is typically about one-half of the oral dose.
- A unit oral dose may comprise from about 0.01 mg to about 1 g of the Compound of the Disclosure, e.g., about 0.01 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, 0.01 mg to about 50 mg, e.g., about 0.1 mg to about 10 mg, of the compound. The unit dose can be administered one or more times daily, e.g., as one or more tablets or capsules, each containing from about 0.01 mg to about 1 g of the compound, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.
- A pharmaceutical composition of the present disclosure can be administered to any patient that may experience the beneficial effects of a Compound of the Disclosure. Foremost among such patients are mammals, e.g., humans and companion animals, although the disclosure is not intended to be so limited. In one embodiment, the patient is a human.
- A pharmaceutical composition of the present disclosure can be administered by any means that achieves its intended purpose. For example, administration can be by the oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, intranasal, transmucosal, rectal, intravaginal or buccal route, or by inhalation. The dosage administered and route of administration will vary, depending upon the circumstances of the particular subject, and taking into account such factors as age, gender, health, and weight of the recipient, condition or disorder to be treated, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
- In one embodiment, a pharmaceutical composition of the present disclosure can be administered orally. In another embodiment, a pharmaceutical composition of the present disclosure can be administered orally and is formulated into tablets, dragees, capsules, or an oral liquid preparation. In one embodiment, the oral formulation comprises extruded multiparticulates comprising the Compound of the Disclosure.
- Alternatively, a pharmaceutical composition of the present disclosure can be administered rectally, and is formulated in suppositories.
- Alternatively, a pharmaceutical composition of the present disclosure can be administered by injection.
- Alternatively, a pharmaceutical composition of the present disclosure can be administered transdermally.
- Alternatively, a pharmaceutical composition of the present disclosure can be administered by inhalation or by intranasal or transmucosal administration.
- Alternatively, a pharmaceutical composition of the present disclosure can be administered by the intravaginal route.
- A pharmaceutical composition of the present disclosure can contain from about 0.01 to 99 percent by weight, e.g., from about 0.25 to 75 percent by weight, of a Compound of the Disclosure, e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% by weight of a Compound of the Disclosure.
- A pharmaceutical composition of the present disclosure is manufactured in a manner which itself will be known in view of the instant disclosure, for example, by means of conventional mixing, granulating, dragee-making, dissolving, extrusion, or lyophilizing processes. Thus, pharmaceutical compositions for oral use can be obtained by combining the active compound with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
- Suitable excipients include fillers such as saccharides (for example, lactose, sucrose, mannitol or sorbitol), cellulose preparations, calcium phosphates (for example, tricalcium phosphate or calcium hydrogen phosphate), as well as binders such as starch paste (using, for example, maize starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one or more disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
- Auxiliaries are typically flow-regulating agents and lubricants such as, for example, silica, talc, stearic acid or salts thereof (e.g., magnesium stearate or calcium stearate), and polyethylene glycol. Dragee cores are provided with suitable coatings that are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate can be used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
- Examples of other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, or soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain a compound in the form of granules, which can be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers, or in the form of extruded multiparticulates. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers can be added.
- Possible pharmaceutical preparations for rectal administration include, for example, suppositories, which consist of a combination of one or more active compounds with a suppository base. Suitable suppository bases include natural and synthetic triglycerides, and paraffin hydrocarbons, among others. It is also possible to use gelatin rectal capsules consisting of a combination of active compound with a base material such as, for example, a liquid triglyceride, polyethylene glycol, or paraffin hydrocarbon.
- Suitable formulations for parenteral administration include aqueous solutions of the active compound in a water-soluble form such as, for example, a water-soluble salt, alkaline solution, or acidic solution. Alternatively, a suspension of the active compound can be prepared as an oily suspension. Suitable lipophilic solvents or vehicles for such as suspension may include fatty oils (for example, sesame oil), synthetic fatty acid esters (for example, ethyl oleate), triglycerides, or a polyethylene glycol such as polyethylene glycol-400 (PEG-400). An aqueous suspension may contain one or more substances to increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. The suspension may optionally contain stabilizers.
- In another embodiment, the present disclosure provides kits which comprise a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a manner that facilitates their use to practice methods of the present disclosure. In one embodiment, the kit includes a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the disclosure. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit further can include a device suitable for administering the composition according to the intended route of administration.
- Compounds of the Disclosure are prepared using methods known to those skilled in the art in view of this disclosure, or by the illustrative methods shown in the General Schemes below. In the General Schemes, R1, R2, R3, and Z of Formulae A-C are as defined in connection with Formula VII, unless otherwise indicated. In the General Schemes, suitable protecting can be employed in the synthesis, for example, when Z is (amino)alkyl or any other group that may require protection. (See, Wuts, P. G. M.; Greene, T. W., “Greene's Protective Groups in Organic Synthesis”, 4th Ed., J. Wiley & Sons, N Y, 2007).
- Compound A is converted to compound B (i.e, a compound having Formula VII, wherein X is —S(═O)2—) by coupling with a suitable sulfonyl chloride (Z—SO2Cl) in the presence of a suitable base such as TEA or DIPEA in a suitable solvent such as dichloromethane, acetonitrile, or DMF.
- Compound A was converted to compound C by coupling with a suitable carboxylic acid (ZCO2H) in the presence of a suitable coupling reagent such as HATU or HOBT in the presence of a suitable base such as TEA or DIPEA in a suitable solvent such as DMF. Compound A can also be converted to compound C by coupling with a suitable acid chloride (ZCOCl) in the presence of a suitable base such as TEA or DIPEA in the presence of a suitable solvent such as dichloromethane, acetonitrile or DMF.
- General methods and experimental procedures for preparing and characterizing compounds of Tables 1 and 2 are set forth in the general schemes above and the examples below. Wherever needed, reactions were heated using conventional hotplate apparatus or heating mantle or microwave irradiation equipment. Reactions were conducted with or without stirring, under atmospheric or elevated pressure in either open or closed vessels. Reaction progress was monitored using conventional techniques such as TLC, HPLC, UPLC, or LCMS using instrumentation and methods described below. Reactions were quenched and crude compounds isolated using conventional methods as described in the specific examples provided. Solvent removal was carried out with or without heating, under atmospheric or reduced pressure, using either a rotary or centrifugal evaporator.
- Compound purification was carried out as needed using a variety of traditional methods including, but not limited to, preparative chromatography under acidic, neutral, or basic conditions using either normal phase or reverse phase HPLC or flash columns or Prep-TLC plates. Compound purity and mass confirmations were conducted using standard HPLC and/or UPLC and/or MS spectrometers and/or LCMS and/or GC equipment (i.e., including, but not limited to the following instrumentation: Waters Alliance 2695 with 2996 PDA detector connected with ZQ detector and ESI source: Shimadzu LDMS-2020; Waters Acquity H Class with PDA detector connected with SQ detector and ESI source; Agilent 1100 Series with PDA detector; Waters Alliance 2695 with 2998 PDA detector; AB SCIEX API 2000 with ESI source; Agilent 7890 GC).
- Compound structure confirmations were carried out using standard 300 or 400 MHz NMR spectrometers with nOe's conducted whenever necessary.
- The following abbreviations are used herein:
-
Abbreviation Meaning ACN acetonitrile atm. atmosphere DCM dichloromethane DHP dihydropyran DIBAL diisobutyl aluminum hydride DIEA diisopropyl ethylamine DMF dimethyl formamide DMF-DMA dimethyl formamide dimethyl acetal DMSO dimethyl sulfoxide Dppf 1,1′- bis(diphenylphosphino)ferrocene EA ethyl acetate ESI electrospray ionization EtOH Ethanol FA formic acid GC gas chromatography H hour Hex hexanes HMDS hexamethyl disilazide HPLC high performance liquid chromatography IPA Isopropanol LCMS liquid chromatography/mass spectrometry MeOH Methanol Min Minutes NBS N-bromo succinimide NCS N-chloro succinimide NIS N-iodo succinimide NMR nuclear magnetic resonance nOe nuclear Overhauser effect Prep. Preparative PTSA para-toluene sulfonic acid Rf retardation factor rt room temperature RT retention time sat. Saturated SGC silica gel chromatography TBAF tetrabutyl ammonium fluoride TEA Triethylamine TFA trifluoroacetic acid THF Tetrahydrofuran TLC thin layer chromatography UPLC ultra performance liquid chromatography -
-
- Into a 10-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen Na (164 g, 1.20 equiv) was added in portions to ethanol (5 L). A solution of (CO2Et)2 (869 g, 1.00 equiv) and 1-cyclopropylethan-1-one (500 g, 5.94 mol, 1.00 equiv) was added dropwise with stirring at 0-20° C. The resulting solution was stirred for 1 h at 20-30° C. and then for an additional 1 h at 80° C. The resulting solution was diluted with 15 L of H2O. The pH was adjusted to 2 with hydrochloric acid (12N). The resulting mixture was extracted with ethyl acetate and the organic layers combined and washed with NaHCO3 (sat. aq.). The extract was concentrated under vacuum yielding 820 g (crude) of ethyl 4-cyclopropyl-2,4-dioxobutanoate as yellow oil. TLC (ethyl acetate/petroleum ether=1/5): Rf=0.5.
-
- Into a 10 L round-bottom flask, was placed a solution of ethyl 4-cyclopropyl-2,4-dioxobutanoate (177 g) in ethanol (1.1 L) and NH2OH—HCl (200 g). The resulting solution was stirred for 1 h at 20-30° C. The resulting solution was allowed to react, with stirring, for an additional 1 h at 80° C. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 143 g (the two step yield was 66.3%) of ethyl 5-cyclopropylisoxazole-3-carboxylate as a yellow oil. TLC (ethyl acetate/petroleum ether=1/5): Rf=0.2.
-
- Into a 10-L round-bottom flask was placed ethyl 5-cyclopropylisoxazole-3-carboxylate (280 g, 1.55 mol, 1.00 equiv) and a solution of sodium hydroxide (74.3 g, 1.20 equiv) in water (4 L). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was washed with ether. The pH value of the aqueous solution was adjusted to 2-3 with hydrochloric acid (12N). The resulting solution was extracted with ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 220 g (93%) of 5-cyclopropylisoxazole-3-carboxylic acid as an off-white solid. 1H-NMR (300 MHz CDCl3): δ 8.42 (brs, 1H), 6.37 (s, 1H), 2.16-2.05 (m, 1H), 1.29-1.12 (m, 2H), 1.12-0.99 (m, 2H): LCMS m/z=153.9 [M+H]−.
-
- To a stirred solution of 5-cyclopropylisoxazole-3-carboxylic acid (0.750 g, 4.90 mmol) in DCM (5 ml) was added oxalyl chloride (1.68 ml, 19.60 mmol) and 2 drops of DMF. The reaction was stirred at RT 2 hr. After complete consumption of starting material, the solvent was removed under reduced pressure to obtain 5-cyclopropylisoxazole-3-carbonyl chloride as a residue (0.6 g, crude). The material was used without further purification.
-
-
- To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.0 g, 21.7 mmol) in DMF (20 mL) was added HATU (12.39 g, 32.60 mmol) and diisopropylethylamine (18.94 ml, 108.6 mmol). The solution was stirred for 10 min at 0° C. After that N,O-dimethylhydroxylamine hydrochloride (2.12 g, 21.7 mmol) was added and stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (4.3 g, 71%). LCMS: m/z=173.05 (M-Boc)+.
-
- To a stirred solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (4.3 g, 15.8 mmol) in dry THF (20 mL) was added a solution of methyl magnesium bromide (20 mL, 23.71 mmol, 1.6 M in THF:toluene) at −78° C. and the reaction was stirred at −78° C. for 2 h and RT for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to a crude residue which was purified by column chromatography to afford tert-butyl 4-acetylpiperidine-1-carboxylate (2.8 g, 62%).
-
- To a stirred solution of compound tert-butyl 4-acetylpiperidine-1- (2.8 g, 9.68 mmol) in dry MeOH (6 mL) was added ammonium acetate (8.9 g, 16.2 mmol) and the reaction was stirred at RT for 15 min, sodium cyanoborohydride (2.43 g, 38.7 mmol) was then added. The reaction mixture was heated to reflux for 16 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with 0.5 M NaOH solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain a residue of tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (2.1 g, crude). This was used in the next step without further purification. LCMS: m/z=191.25 (M-Boc)+.
-
- To a stirred solution of 5-cyclopropylisoxazole-3-carboxylic acid (1.0 g, 6.5 mmol) in DMF (3 mL) was added HATU (3.72 g, 9.8 mmol) and diisopropylethylamine (3.5 ml, 19.6 mmol). The solution was stirred for 10 min at 0° C. tert-Butyl 4-(1-aminoethyl)piperidine-1-carboxylate (1.45 g, 6.5 mmol) was added and the reaction stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford compound tert-butyl 4-(1-(5-cyclopropylisoxazole-3-carboxamido)ethyl)piperidine-1-carboxylate (2.1 g, 84%). 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J=8.9 Hz, 1H), 6.46 (s, 1H), 3.98-3.90 (m, 2H), 3.79 (p, J=7.3 Hz, 1H), 2.53-2.47 (m, 2H), 2.19-2.16 (m, 1H), 1.6-1.58 (m, 3H), 1.38 (s, 9H), 1.18-0.86 (m, 9H); LCMS: m/z=386.25 (M+H)+.
-
- To a stirred solution of tert-butyl 4-(l-(5-cyclopropylisoxazole-3-carboxamido)ethyl)piperidine-1-carboxylate (2.1 g, 5.8 mmol) in dioxane (5 mL) was added 4 M dioxane:HCl (20 mL) at 0° C. and the reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the solvent was removed under reduced pressure to obtain a crude residue which was purified by repeated washing with ether and pentane to obtain 5-cyclopropyl-N-(1-(piperidin-4-yl)ethyl)isoxazole-3-carboxamide hydrochloride (1.3 g, 86%). 1H NMR (400 MHz, DMSO-d6) δ 8.95-8.86 (m, 1H), 8.54 (t, J=11.8 Hz, 2H), 6.49 (s, 1H), 3.91-3.77 (m, 1H), 3.24 (d, 0.1=12.4 Hz, 2H), 2.88-2.66 (m, 2H), 2.18 (tt, J=8.4, 5.0 Hz, 1H), 1.86-1.60 (m, 3H), 1.44-1.27 (m, 2H), 1.15-1.03 (m, 5H), 0.95-0.84 (m, 2H); LCMS: m/z=264.20 (M+H)+.
-
-
- To a stirred solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (0.5 g, 1.83 mmol) in THF (1.5 mL) was added a 1M solution of phenyl magnesium bromide in THF (3.67 mL, 3.67 mmol) at 0° C. The reaction was stirred overnight at RT. The reaction completion was monitored by TLC and the reaction was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried using Na2SO4 and concentrated under reduced pressure to a residue. The residue was purified by column chromatography to obtain ten-butyl 4-benzoylpiperidine-1-carboxylate (0.188 g, 35.5%) LCMS: m/z=190.1 (M+H)+.
-
- To a solution of tert-butyl 4-benzoylpiperidine-1-carboxylate (0.188 g, 0.65 mmol) in MeOH (5 mL) was added ammonium acetate (0.6 g, 7.8 mmol). The reaction was stirred for 10 minutes at 25° C., then sodium cyanoborohydride (0.163 g, 2.59 mmol) was added. The reaction heated to 60° C. for 16 hours. The reaction completion was monitored by TLC and the reaction was quenched with 0.5N NaOH solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried using Na2SO4 and concentrated under reduced pressure to a residue which was purified by column chromatography to obtain tert-butyl 4-(amino(phenyl)methyl)piperidine-1-carboxylate (0.2 g, 40%). LCMS: m/z=190.3 (M+H)+.
-
- To a stirred solution of 5-cyclopropylisoxazole-3-carboxylic acid (0.1 g, 0.34 mmol) in DCM (5 ml) was added oxalyl chloride (0.2 ml, 0.68 mmol) and 2 drops of DMF. The reaction was stirred at RT 2 hr. After complete consumption of starting material, the solvent was removed under reduced pressure to obtain a residue. The residue was dissolved in DCM and cooled to 0° C. tert-Butyl 4-(amino(phenyl)methyl)piperidine-1-carboxylate was added (0.070 g, 0.41 mmol) in DCM (5 mL) followed by triethylamine (0.23 mL, 0.17 mmol). The reaction was stirred at RT for 1 hr. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with sodium bicarbonate and, extracted with DCM. The organic layer was separated, washed with brine, dried using Na2SO4 and concentrated under reduced pressure to obtain a residue which was purified by column chromatography to obtain tert-butyl 4-((5-cyclopropylisoxazole-3-carboxamido)(phenyl)methyl)piperidine-1-carboxylate (0.057 g, 50%) LCMS: m/z=326.23 (M+H)+.
-
- To a stirred solution of tert-butyl 4-((5-cyclopropylisoxazole-3-carboxamido)(phenyl)methyl)piperidine-1-carboxylate (0.057 g, 0.13 mmol) in dioxane (1 mL) at 0° C. was added 4 M dioxane:HCl (2 mL). The reaction was stirred at rt for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the solvent was removed under reduced pressure and the residue was purified by washing with ether and pentane to obtain 5-cyclopropyl-N-(phenyl(piperidin-4-yl)methyl)isoxazole-3-carboxamide hydrochloride (0.028 g, 65%). 1H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J=9.0 Hz, 1H), 8.70 (d, J=11.2 Hz, 1H), 8.36 (d, J=11.7 Hz, 1H), 7.46-7.37 (m, 2H), 7.39-7.22 (m, 3H), 6.47 (s, 1H), 4.71 (t, J=9.5 Hz, 1H), 3.22-3.13 (m, 2H), 2.77 (q, J=11.0, 10.1 Hz, 2H), 2.23-2.03 (m, 3H), 1.47-1.19 (m, 3H), 1.14-1.02 (m, 2H), 0.94-0.83 (m, 2H); LCMS: m/z=326.25 (M+H).
-
-
- To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl) propanoic acid (0.188 g, 0.68 mmol) in DMF (2 mL) was added EDCI (0.191 g, 1.10 mmol), HOBt (0.135 g, 1.10 mmol), and triethylamine (0.3 mL, 2.27 mmol). The solution was stirred for 30 min at 0° C. 5-Cyclopropyl-N-(1-(piperidin-4-yl)ethyl)isoxazole-3-carboxamide hydrochloride (0.2 g, 0.66 mmol) was then added and the reaction stirred at rt overnight. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl ((2S)-1-(4-(1-(5-cyclopropylisoxazole-3-carboxamido)ethyl)piperidin-1-yl)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)carbamate (0.09 g, 25%). LCMS: m/z=428.05 (M-Boc)+.
-
- To a stirred solution of tert-butyl ((2S)-1-(4-(1-(5-cyclopropylisoxazole-3-carboxamido)ethyl)piperidin-1-yl)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)carbamate (0.09 g, 0.17 mmol) in dioxane (1 mL) was added 4 M dioxane:HCl (5 mL) at 0° C. and the reaction mixture stirred at rt for 3 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the solvent was removed under reduced pressure to obtain a crude residue which was purified by repeated washing with ether and pentane to obtain N-(1-((S)-2-amino-3-(4-hydroxyphenyl)propanoyl)piperidin-4-yl)ethyl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride (0.020 g, 28%). 1H NMR (400 MHz, DMSO-d6) δ 9.44-9.35 (m, 1H), 8.46 (q, J=7.3 Hz, 1H), 8.12 (s, 3H), 6.99 (dd, J=173, 7.9 Hz, 2H), 6.75-6.66 (m, 2H), 6.46 (d, J=3.5 Hz, 1H), 4.52 (p, J=6.8, 6.2 Hz, 1H), 4.37 (d, J=12.8 Hz, 1H), 3.83-3.59 (m, 2H), 2.96-2.73 (m, 2H), 2.47-2.33 (m, 2H), 2.27-2.12 (m, 1H), 1.76-1.62 (m, 1H), 1.62-1.35 (m, 2H), 1.14-0.81 (m, 9H); LCMS: m/z=427.35 (M+H)+.
-
-
- To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (0.044 g, 0.230 mmol) in DMF (1 mL) was added HATU (0.131 g, 0.34 mmol) and diisopropyl ethylamine (0.12 mL, 0.69 mmol). The solution was stirred for 10 min at 0° C. Next, 5-cyclopropyl-N-(phenyl(piperidin-4-yl)methyl)isoxazole-3-carboxamide ((0.1 g, 0.277 mmol) was added and the reaction stirred at rt for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by preparative chiral HPLC to afford tert-butyl ((S)-1-(4-((S)-(5-cyclopropylisoxazole-3-carboxamido)(phenyl)methyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate (0.13 g, 18%) and tert-butyl ((S)-1-(4-((R)-(5-cyclopropylisoxazole-3-carboxamido)(phenyl)methyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate (0.12 g, 17.4%).
-
- To a stirred solution of tert-butyl ((S)-1-(4-(5)-5-cyclopropylisoxazole-3-carboxamido)(phenyl)methyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate (0.05 g, 0.126 mmol) in dioxane (1 mL) at 0° C. was added 4 M dioxane:HCl (3 mL). The reaction mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material the solvent was removed under reduced pressure to obtain a crude residue. The material was purified by repeated washing with ether and pentane to obtain N—((S)-(1-((S)-2-aminopropanoyl)piperidin-4-yl)(phenyl)methyl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride (0.035 g, 50%). 1H NMR (400 MHz, DMSO-d6): δ 9.19 (dd. J=9.0, 6.3 Hz, 1H), 8.09 (s, 3H), 7.44-7.21 (m, 5H), 6.46 (s, 1H), 4.69 (q, J=10.0 Hz, 1H), 4.29 (s, 2H), 3.76 (d, J=13.7 Hz, 1H), 2.98-2.96 (m, 1H), 2.66-2.50 (m, 1H), 2.23-2.06 (m, 2H), 2.02-1.91 (m, 1H), 1.30 (d, J=6.8 Hz, 1H), 1.21 (dd, J=24.0, 9.9 Hz, 4H), 1.14-0.83 (m, 5H); LCMS: m/z=397.35 (M+H)+.
-
- To a stirred solution of tert-butyl ((S)-1-(4-((R)-(5-cyclopropylisoxazole-3-carboxamido)(phenyl)methyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate (0.06 g, 0.12 mmol) in dioxane (1 mL) at 0° C. was added 4 M dioxane:HCl (3 mL). The reaction mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material the solvent was removed under reduced pressure to obtain a crude residue. The material was purified by repeated washing with ether and pentane to obtain N—(R)-(1-((S)-2-aminopropanoyl)piperidin-4-yl)(phenyl)methyl)-5-cyclopropylisoxazole-3-carboxamide (0.02 g, 30%). 1H NMR (400 MHz, DMSO-d6): δ 9.20 (t, J=8.8 Hz, 1H), 8.08 (s, 3H), 7.46-7.21 (m, 5H), 6.46 (d, J 1.5 Hz, 1H), 4.7-4.68 (m, 1H), 4.35-4.32 (m, 2H), 3.90 (d, J=13.7 Hz, 1H), 3.07-2.87 (m, 1H), 2.66-2.51 (m, 1H), 2.23-2.06 (m, 2H), 1.95 (d, J=11.4 Hz, 1H), 1.36-1.00 (m, 8H), 1.01-0.82 (m, 2H); LCMS: m/z=397.22 (M+H)+.
-
-
- To a stirred solution of methyl 3-iodobenzoate (3.0 g, 11.45 mmol) in anhydrous THF (100 mL) was added isopropyl magnesium chloride (6.27 mL, 12.59 mmol, 2M solution in THF) at −40° C., tert-Butyl 4-formylpiperidine-1-carboxylate (2.68 g, 12.59 mmol) was added. The reaction was stirred at rt overnight. The reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl 4-(hydroxy(3-(methoxycarbonyl)phenyl)methyl)piperidine-1-carboxylate (2.91 g, 73%). LCMS: m/z=350.15 (M+H)+.
-
- To a stirred solution of 4-(hydroxy(3-(methoxycarbonyl)phenyl) methyl)piperidine-1-carboxylate (1.9 g, 5.44 mmol) in DCM (30 mL) was added Dess Martin periodane (3.0 g, 7.07 mmol) at 0° C. The reaction mixture was stirred at rt for 1 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched by the addition of a mixture of saturated solution of Na2S2O3 (10 mL) and NaHCO3 (10 mL). The organic layer was extracted, dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl 4-(3-(methoxycarbonyl)benzoyl)piperidine-1-carboxylate (1.78 g, 94%). LCMS: m/z=348.15 (M+H)+.
-
- To a stirred solution of tert-butyl 4-(3-(methoxycarbonyl)benzoyl)piperidine-1-carboxylate (1.5 g, 4.32 mmol) in methanol (30 mL) at 0° C. was added ammonium acetate (4.0 g, 51.8 mmol) followed by portionwise addition of sodium cyanoborohydride (1.0 g, 17.2 mmol). The reaction mixture was heated to reflux at 80° C. for 12 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with dilute HCl solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl 4-(amino(3-(methoxycarbonyl)phenyl)methyl)piperidine-1-carboxylate (1.05 g, 70%).
-
- To a stirred solution of 5-cyclopropylisoxazole-3-carboxylic acid (0.65 g, 1.86 mmol) in DMF (10 mL) was added HATU (1.0 g, 2.8 mmol) and diisopropylethylamine (1.2 ml, 7.44 mmol). The reaction mixture was stirred for 10 min at 0° C. and then tert-butyl 4-(amino(3-(methoxycarbonyl)phenyl)methyl)piperidine-1-carboxylate (0.284 g, 1.86 mmol) was added. The reaction mixture was stirred at rt for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl 4-((5-cyclopropylisoxazole-3-carboxamido)(3-(methoxycarbonyl) phenyl)methyl)piperidine-1-carboxylate (0.789 g, 95%).
-
- To a stirred solution of tert-butyl 4-((5-cyclopropylisoxazole-3-carboxamido)(3-(methoxycarbonyl)phenyl)methyl)piperidine-1-carboxylate (0.77 g, 1.59 mmol) in THF:MeOH:H2O (1:1:1, 15 mL) was added lithium hydroxide (0.133 g, 3.18 mmol). The reaction mixture was then stirred at rt for 12 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material the solvent was removed under reduced pressure to obtain a crude residue. The residue was taken up in MeOH and acidified with dilute HCl to pH=2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 3-((l-(ten-butoxycarbonyl)piperidin-4-yl)(5-cyclopropylisoxazole-3-carboxamido)methyl)benzoic acid (0.580 g, crude).
-
- To a stirred solution of 3-((1-(tert-butoxycarbonyl)piperidin-4-yl)(5-cyclopropylisoxazole-3-carboxamido)methyl)benzoic acid (0.5 g, 1.06 mmol) in DMF (3 mL) was added HATU (0.607 g, 1.59 mmol) and diisopropylethylamine (0.63 mL, 3.73 mmol). The solution was stirred for 10 min at 0° C. Then pyridin-3-amine (0.14 g, 1.49 mmol) was added and stirred at rt for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl-4-((5-cyclopropylisoxazole-3-carboxamido)(3-(pyridin-3-ylcarbamoyl)phenyl)methyl)piperidine-1-carboxylate (0.445 g, 76%). LCMS: m/z=446.4 (M-Boc)−.
-
- To a stirred solution of tert-butyl-4-((5-cyclopropylisoxazole-3-carboxamido)(3-(pyridin-3-ylcarbamoyl)phenyl)methyl)piperidine-1-carboxylate (0.445 g, 0.81 mmol) in dioxane (4 mL) at 0° C. was added 4 M dioxane:HCl (8 mL) and the reaction mixture stirred at rt for 3 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material the solvent was removed under reduced pressure to obtain a crude residue which was purified by repeated washing with ether and pentane to obtain 5-cyclopropyl-N-(piperidin-4-yl(3-(pyridin-3-ylcarbamoyl)phenyl)methyl) isoxazole-3-carboxamide hydrochloride (0.380 g, 96%). LCMS: m/z=446.25 (M+H)+.
-
- To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (0.089 g, 0.474 mmol) in DMF (3 mL) was added HATU (0.225 g, 0.592 mmol) and diisopropylethylamine (0.23 mL, 1.38 mmol). The solution was stirred for 10 min at 0° C. Next 5-cyclopropyl-N-(piperidin-4-yl(3-(pyridin-3-ylcarbamoyl)phenyl)methyl) isoxazole-3-carboxamide hydrochloride (0.19 g, 0.395 mmol) was added and the reaction stirred at rt for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl ((2S)-1-(4-((5-cyclopropylisoxazole-3-carboxamido)(3-(pyridin-3-ylcarbamoyl)phenyl)methyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate (0.170 g, 83%). LCMS: m/z=517.4 (M-Boc)+.
-
- To a stirred solution of tert-butyl ((2S)-1-(4-((5-cyclopropylisoxazole-3-carboxamido)(3-(pyridin-3-ylcarbamoyl)phenyl methyl)piperidin-1-yl)-1-oxopropan-2-yl)carbamate (0.170 g, 0.275 mmol) in dioxane (3 mL) at 0° C. was added 4 M dioxane:HCl (2 mL) and the reaction mixture stirred at rt for 3 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material the solvent was removed under reduced pressure to obtain a crude residue which was purified by repeated washing with ether and pentane to obtain N-((1-((S)-2-aminopropanoyl)piperidin-4-yl)(3-(pyridin-3-ylcarbamoyl)phenyl)methyl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride (0.135 g, 83%). 1H NMR (400 MHz. DMSO-d6)(mixture of diastereomers): δ 11.09 (d, J=14.5 Hz, 1H), 9.38-9.24 (m, 2H), 8.64 (d, 0.1=8.0 Hz, 1H), 8.55 (dd, J=5.4, 1.4 Hz, 1H), 8.17-8.09 (m, 4H), 8.03-7.94 (m, 1H), 7.84 (dd, J=8.4, 5.2 Hz, 1H), 7.71 (dd, J=7.7, 5.0 Hz, 1H), 7.56 (td, J=7.7, 4.2 Hz, 1H), 6.51 (d, J=3.7 Hz, 1H), 4.90-4.74 (m, 1H), 4.48-4.32 (m, 1H), 4.35-4.23 (m, 2H), 3.92 (d, J=13.6 Hz, 1H), 3.79 (dd, J=13.8, 9.2 Hz, 1H), 3.69-3.53 (m, 1H), 3.18-2.91 (m, 211), 2.67-2.51 (m, 211), 2.19-2.17 (m, 311), 1.97 (d, J=12.6 Hz, 111), 1.35-0.97 (m, 2H), 0.95-0.82 (m, 2H); LCMS: m/z=517.35 (M+H)+.
-
-
- To a stirred solution of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.514 g, 2.43 mmol) in DCM (10 mL) was added triethylamine (0.68 mL, 4.87 mmol) and the solution was stirred at 0° C. for 10 min. 5-Cyclopropylisoxazole-3-carbonyl chloride (0.6 g, 3.166 mmol) in DCM (5 mL) was added dropwise and the reaction mixture stirred at rt overnight. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was diluted with excess of DCM and washed with water and, the organic layer was separated, washed with brine, dried using Na2SO4 and concentrated under reduced pressure to obtain a residue which was purified by column chromatography to afford tert-butyl 4-((5-cyclopropylisoxazole-3-carboxamido)methyl)piperidine-1-carboxylate (0.750 g, 89%). 1H NMR (DMSO-d6, 400 MHz) δ 8.69-8.66 (t, J=5.8 Hz, 1H) 6.46 (s, 1H), 3.90 (d, J=12.4 Hz, 2-), 3.11-3.08 (m, J=6.4 Hz, 2H), 2.67 (brs, 2H), 2.19-2.15 (m, 1H), 1.70-1.68 (m, 1H), 1.6 (brs, 1H), 1.58 (brs, 1H), 1.38 (s, 9H), 1.11-1.06 (m, 2H), 0.90-0.89 (m, 4H).
-
- To a stirred solution of tert-butyl 4-((5-cyclopropylisoxazole-3-carboxamido)methyl)piperidine-1-carboxylate (0.750 g, 2.148 mmol) in MeOH (4 mL) at 0° C. was added 4 M methanolic HCl (6 mL). The reaction was stirred at rt for 16 hours. The progress of the reaction was monitored by TLC. After complete consumption of starting material the solvent was removed under reduced pressure and the residue was washed with DCM and hexanes to obtain 5-cyclopropyl-N-(piperidin-4-ylmethyl)isoxazole-3-carboxamide hydrochloride (0.590 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.78 (t, J=6.1 Hz, 1H), 8.59 (m, 1H), 6.49 (s, 1H), 3.27-3.09 (m, 4H), 2.80 (q, J=11.8 Hz, 2H), 2.18 (m, 1H), 1.79 (m, 3H), 1.41-1.26 (m, 2H), 1.09 (m, 2H), 1.00-0.87 (m, 2H); LCMS: m/z=250.05 (M+H).
-
-
- To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.156 g, 0.72 mmol) in DMF (2 mL) was added EDCI (0.172 g, 0.9 mmol), HOBt (0.121 g, 0.9 mmol), and triethylamine (0.3 mL, 1.8 mmol). The solution was stirred for 30 min at 0° C. 5-Cyclopropyl-N-(piperidin-4-ylmethyl)isoxazole-3-carboxamide (0.15 g, 0.6 mmol) was added and the reaction stirred at rt overnight. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford (S)-tert-butyl (1-(4-((5-cyclopropylisoxazole-3-carboxamido)methyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (0.185 g, 68%). LCMS m/z=349.1 (M-Boc)+.
-
- To a stirred solution of (S)-tert-butyl (1-(4-((5-cyclopropylisoxazole-3-carboxamido)methyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (0.185 g, 0.33 mmol) in dioxane (1 mL) at 0° C. was added 4M dioxane:HCl (3 mL). The reaction mixture was stirred at rt for 3 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material the solvent was removed under reduced pressure to obtain a crude residue. The material was purified by repeated washing with ether and pentane to obtain (S)—N—((-(2-amino-3-methylbutanoyl)piperidin-4-yl)methyl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride (0.1 g, 69%). 1H NMR (400 MHz. DMSO-d6): δ 8.75 (dt, J=7.1, 3.4 Hz, 1H), 8.03 (s, 3H), 6.48 (s, 1H), 4.43-4.31 (m, 1H), 4.27 (s, 1H), 3.93 (d, J=13.6 Hz, 1H), 3.21-2.97 (m, 3H), 2.66-2.53 (m, 1H), 2.18 (tt, J=8.4, 5.0 Hz, 1H), 2.01 (h, J=6.9 Hz, 1H), 1.89-1.78 (m, 1H), 1.70 (t, J=12.7 Hz, 1H), 1.26 (dd, J=10.3, 4.4 Hz, 1H), 1.16-0.82 (m, 12H); LCMS: m/z=349.3 (M+H)+.
-
-
- To a stirred solution of 1-(4-aminophenyl)ethanone (2.0 g, 14.81 mmol) in MeOH:Water (1:1, 30 mL) was added nicotinaldehyde (1.58 g, 14.81 mmol) and potassium hydroxide (1.24 g, 22.22 mmol). The reaction mixture was stirred at rt for 12 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with dilute HCl and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford (E)-1-(4-aminophenyl)-3-(pyridin-3-yl)prop-2-en-1-one (2.0 g, 60%). LCMS: m/z=225.3 (M+H)+.
-
- To a stirred solution of (E)-1-(4-aminophenyl)-3-(pyridin-3-yl)prop-2-en-1-one (2.0 g, 8.9 mmol) in methanol (20 mL), 10% palladium-carbon (0.2 g) was added and the reaction mixture stirred under hydrogen atmosphere at 1 atm pressure at rt for 3 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to obtain a crude residue of 1-(4-aminophenyl)-3-(pyridin-3-yl)propan-1-one (1.5 g) which was used in the next step without purification. LCMS: m/z=227.05 (M+H)+.
-
- To a stirred solution of 5-cyclopropylisoxazole-3-carboxylic acid (0.2 g, 1.3 mmol) and 2 drops of DMF in DCM (10 mL) was added oxalyl chloride (1 mL). The reaction mixture was stirred at rt for 2 h. After complete consumption of starting material, the solvent was removed under reduced pressure to obtain a crude residue. The residue was redissolved in DCM (5 mL). Triethylamine (0.35 mL, 2.61 mmol) and a solution of 1-(4-aminophenyl)-3-(pyridin-3-yl)propan-1-one (0.354 g, 1.56 mmol) in DCM (1 mL) was added at 0° C. to the reaction mixture. The mixture was stirred at rt for 1 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford 5-cyclopropyl-N-(4-(3-(pyridin-3-yl)propanoyl)phenyl)isoxazole-3-carboxamide (0.4 g, 42%). LCMS: m/z=362.05 (M+H) +.
-
- To a stirred solution of 5-cyclopropyl-N-(4-(3-(pyridin-3-yl)propanoyl)phenyl)isoxazole-3-carboxamide (0.05 g, 0.13 mmol) in dry MeOH (10 mL) was added ammonium acetate (0.127 g, 1.66 mmol) and the reaction stirred at rt for 15 min. Sodium cyanoborohydride (0.034 g, 0.55 mmol) was then added. The reaction mixture was heated to reflux for 16 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with 0.5 M NaOH solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by prep HPLC to afford compound N-(4-(1-amino-3-(pyridin-3-yl)propyl)phenyl)-5-cyclopropylisoxazole-3-carboxamide (0.030 g, 12%). 1H NMR (400 MHz, Methanol-d4): δ 8.41-8.29 (m, 2H), 7.88-7.79 (m, 2H), 7.69-7.65 (m, 1H), 7.49-7.41 (m, 2H), 7.39-7.35 (m, 1H), 6.48 (s, 1H), 4.21 (dd, J=8.8, 6.3 Hz, 1H), 2.70-2.51 (m, 2H), 2.34-2.23 (m, 2H), 2.2-2.15 (m, 1H), 1.31 (d, J=18.9 Hz, 1H), 1.21-1.11 (m, 2H), 1.04-0.95 (m, 2H); LCMS: m/z=362.17 (M+1)−.
-
-
- To a stirred solution of 5-cyclopropylisoxazole-3-carboxylic acid (0.5 g, 3.2 mmol) in DMF (3 mL) was added EDCI.HCl (0.93 g, 4.9 mmol), HOBt (0.66 g, 4.9 mmol) and triethylamine (1.41 mL, 9.8 mmol). The solution was stirred for 10 min at 0° C. After that tert-butyl (4-aminobutyl) carbamate (0.67 g, 3.5 mmol) was added and the reaction stirred at rt for 16 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl (4-(5-cyclopropylisoxazole-3-carboxamido)butyl)carbamate (0.25 g, 20%). LCMS: m/z=234.05 (M-Boc)+.
-
- To a stirred solution of tert-butyl (4-(5-cyclopropylisoxazole-3-carboxamido)butyl)carbamate (0.24 g, 0.74 mmol) in dioxane (2 mL), was added 4M dioxane:HCl (2 mL) at 0° C. and the reaction mixture was stirred at rt for 5 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the solvent was removed under reduced pressure to obtain a crude residue which was purified by Prep HPLC to obtain N-(4-aminobutyl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride (0.16 g, 96%). 1H NMR (400 MHz, DMSO-d6):δ 8.71 (t, J=5.9 Hz, 1H), 7.76 (s, 2H), 6.48 (s, 1H), 3.23 (q, J=6.0 Hz, 2H), 2.78 (q, J=6.1 Hz, 2H), 2.18 (td, J=8.6, 4.5 Hz, 1H), 1.54 (p, J=3.4 Hz, 4H), 1.1-1.08 (m, 2H), 0.96-0.87 (m, 2H); LCMS (method A, ESI): m/z=224.10 (M+H)+.
-
-
- To a stirred solution of (S)-2-((tert-butoxycarbonyl) amino)propanoic acid (0.08 g, 0.37 mmol) in DMF (2 mL) was added EDCI.HCl (0.098 g, 0.51 mmol), HOBt (0.069 g, 0.51 mmol), and triethylamine (0.14 mL, 1.0 mmol). The solution was stirred for 10 min at 0° C. N-(4-Aminobutyl)-5-cyclopropylisoxazole-3-carboxamide (0.065 g, 0.34 mmol) was added and the reaction stirred at it for 16 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford (S)-tert-butyl (1-((4-(5-cyclopropylisoxazole-3-carboxamido)butyl)amino)-1-oxopropan-2-yl)carbamate (0.08 g, 59%). LCMS: m/z=296.15 (M-Boc)+.
-
- To a stirred solution of (S)-tert-butyl (1-((4-(5-cyclopropylisoxazole-3-carboxamido)butyl)amino)-1-oxopropan-2-yl)carbamate (0.08 g, 0.20 mmol) in dioxane (2 mL) at 0° C. was added 4M dioxane:HCl solution (4 mL). The reaction mixture was stirred at rt for 5 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the solvent was removed under reduced pressure to obtain a crude residue which was purified by repeated washing with ether and pentane to obtain (S)—N-(4-(2-aminopropanamido)butyl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride (0.049 g, 83%). 1H NMR (400 MHz, DMSO-d6): δ 8.67 (t, J=5.9 Hz, 1H), 8.39 (t, J=5.6 Hz, 1H), 8.10 (s, 3H), 6.47 (s, 1H), 3.80-3.70 (m, 1H), 3.26-3.03 (m, 4H), 2.24-2.12 (m, 1H), 1.56-1.36 (m, 4H), 1.33 (d, J=6.9 Hz, 3H), 1.16-1.02 (m, 2H), 0.96-0.87 (m, 2H); LCMS (method A, ESI): m/z=295.15 (M+H)+.
-
-
- To a stirred solution of but-3-yn-1-ol (2 g, 28.5 mmol) in ethanol (15 mL), was added ethyl nitro acetate (7.59 g, 57.06 mmol) and DABCO (0.32 g, 2.85 mmol). The reaction was heated in a sealed tube at 80° C. The progress of the reaction was monitored by TLC. After complete consumption of staring material the reaction was quenched with water and extracted with ethyl acetate, the organic layer was separated, washed with brine, dried using Na2SO4 and concentrated under reduced pressure to obtain a residue which was purified by column chromatography to obtain ethyl 5-(2-hydroxyethyl)isoxazole-3-carboxylate (3.1 g, 59%). LCMS: m/z=186 (M+H)+.
-
- To a stirred solution of ethyl 5-(2-hydroxyethyl)isoxazole-3-carboxylate (0.7 g, 3.78 mmol) in THF: MeOH: H2O (1:1:1, 15 ml) was added LiOH (0.317 g, 7.56 mmol). The reaction was stirred at rt for 16 hr. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the solvent was removed under reduced pressure and the residue was acidified with dilute HCl to pH 2. The solid precipitated was collected by filtration and dried under reduced pressure to obtain 5-(2-hydroxyethyl)isoxazole-3-carboxylic acid (0.529 g, crude). 1H NMR (400 MHz, DMSO-d6): δ 11.0 (brs, 1H), 6.40 (s, 1H), 3.69-3.65 (m, 2H), 3.0-2.95 (m, 2H).
-
- To a solution of 5-(2-hydroxyethyl)isoxazole-3-carboxylic acid (0.529 g, 1.27 mmol) in DMF (5 mL) at 0° C. under an N2 atmosphere was added DCC (0.26 g, 1.27 mmol) followed by pentafluorophenol (0.233 g, 1.27 mmol). The reaction was stirred at rt for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried using Na2SO4 and concentrated under reduced pressure to obtain a residue which was purified by column chromatography to give pentafluorophenyl 5-(2-hydroxyethyl)isoxazole-3-carboxylate (0.26 g, 63%). 1H NMR (400 MHz, DMSO-d6): δ 6.40 (s, 1H), 3.7-3.65 (m, 2H), 3.0-2.96 (m, 2H).
-
- To a stirred solution of pentafluorophenyl 5-(2-hydroxyethyl)isoxazole-3-carboxylate (0.25 g, 0.77 mmol) in DMF (5 mL) was added tert-butyl ((1r, 4r)-4-aminocyclohexyl) carbamate (0.16 g, 0.77 mmol). The reaction was stirred at rt for 2 hr. and the progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried using Na2SO4 and concentrated under reduced pressure to obtain a residue which was purified by column chromatography to obtain tert-butyl ((1 r,4r)-4-(5-(2-hydroxyethyl)isoxazole-3-carboxamido)cyclohexyl)carbamate (0.130 g, 47%). LCMS: m/z=254 (M+H)+.
-
- To a stirred solution of tert-butyl ((1 r,4r)-4-(5-(2-hydroxyethyl)isoxazole-3-carboxamido)cyclohexyl)carbamate (0.1 g, 0.28 mmol) in methanol (1 mL) at 0° C. was added 4 M methanol:HCl (10 mL). The reaction was at rt stirred for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the solvent was removed under reduced pressure and the residue was purified by washings with diethyl ether and hexane to obtain compound N-((1r,4r)-4-aminocyclohexyl)-5-(2-hydroxyethyl)isoxazole-3-carboxamide hydrochloride (0.060 g, 83%). 1H NMR (400 MHz, DMSO-d5) δ 8.62-8.54 (m, 1H), 8.04 (d, J=5.6 Hz, 3H), 6.58 (s, 1H), 4.89 (s, 1H), 3.70 (t, J=6.3 Hz, 3H), 2.93 (t, J=6.3 Hz, 3H), 2.02-1.95 (m, 2H), 1.85 (d, J=7.1 Hz, 2H), 1.51-1.34 (m, 4H), LCMS: m/z=254 (M+H)+.
-
-
- To the stirred solution of ethyl 5-cyclopropylisoxazole-3-carboxylate (1 g, 5.52 mmol) in TFA (16 ml), was added N-iodosuccinimide (1.48 g, 6.62 mmol) and reaction mixture stirred at rt for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure. The material was purified by column chromatography to afford ethyl 5-cyclopropyl-4-iodoisoxazole-3-carboxylate (1.27 g, 75%).
-
- To a stirred solution of ethyl 5-cyclopropyl-4-iodoisoxazole-3-carboxylate (1.27 g, 4.14 mmol) in THF:MeOH:H2O (1:1:1, 9 ml) was added LiOH (1.04 g, 24.8 mmol). The solution was stirred at rt for 16 hr. After complete consumption of starting material, the residue was acidified to pH 2 with Amberlyst. The reaction mixture was filtration and concentrated under reduced pressure to obtain a compound 5-cyclopropyl-4-iodoisoxazole-3-carboxylic acid (1.01 g, 87%). LCMS: m/z=278.9 (M+H)+.
-
- To a stirred solution of 5-cyclopropyl-4-iodoisoxazole-3-carboxylic acid (1.0 g, 3.59 mmol) in DMF (10 ml) was added EDCI (0.892 g, 4.66 mmol) and HOBT (0.533 g, 3.94 mmol). The solution was stirred for 10 min at 0° C. Next tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (0.769 g, 3.59 mmol) was added and the reaction was stirred at it for 2 hr. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and the solid precipitated was collected by filtration and dried under reduced pressure to obtain a residue. The material was purified by column chromatography to afford tert-butyl ((1 r,4r)-4-(5-cyclopropyl-4-iodoisoxazole-3-carboxamido)cyclohexyl)carbamate (0.48 g, 28%).
-
- To a stirred solution of tert-butyl ((1r,4r)-4-(5-cyclopropyl-4-iodoisoxazole-3-carboxamido)cyclohexyl)carbamate (0.1 g, 0.210 mmol) in methanol (3 ml) at 0° C. was added 4 M methanolic:HCl (3 ml). The reaction was stirred for at rt for 1 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the solvent was removed under reduced pressure and the residue was purified by washing with diethyl ether to obtain N-((1r,4r)-4-aminocyclohexyl)-5-cyclopropyl-4-iodoisoxazole-3-carboxamide hydrochloride (0.008 g, 10%). 1H NMR (400 MHz. DMSO-d6) δ 8.70 (d, J=7.9 Hz, 1H), 7.92 (s, 3H), 3.67 (d, J=10.0 Hz, 1H), 2.96 (t, J=9.5 Hz, 1H), 2.20-2.17 (m, 1H), 1.97 (d, J=9.4 Hz, 2H), 1.87 (d, J 10.4 Hz, 2H), 1.39 (q, J=12.2, 11.2 Hz, 4H), 1.21-1.11 (m, 2H), 1.07-0.98 (m, 2H); LCMS (method C, ESI): m/z=375 (M+H)+.
-
-
- To the stirred solution of tert-butyl ((1r,4r)-4-(5-cyclopropyl-4-iodoisoxazole-3-carboxamido)cyclohexyl)carbamate (1.6 g, 3.37 mmol) in DMF:H2O (4:1, 10 ml) was added Pd(OAc)2 (0.037 g, 0.168 mmol) and dppf (0.186 g, 0.337 mmol) and the reaction heated at 55° C. under CO balloon pressure overnight. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was filtered, diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried using Na2SO4 and concentrated under reduced pressure to obtain a residue which was purified by column chromatography to obtain 3-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-5-cyclopropylisoxazole-4-carboxylic acid (0.350 g, 26%).
-
- To the stirred solution of 3-(((1r,4r)-4-((tert-butoxycarbonyl)amino) cyclohexyl)carbamoyl)-5-cyclopropylisoxazole-4-carboxylic acid (0.2 g, 0.508 mmol) in DMF (2 mL) at 0° C. was added pentafluorophenol (0.093 g, 0.508 mmol) and DCC (0.054 g, 0.508 mmol). The reaction was stirred at rt for 30 min. After complete consumption of starting material, the reaction was quenched with water and extracted with DCM; the organic layer was separated, washed with sodium bicarbonate solution, dried using Na2SO4 and concentrated under reduced pressure to obtain pentafluorophenyl 3-(((r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-5-cyclopropylisoxazole-4-carboxylate (0.250 g). The material was used without further purification LCMS: m/z=583.12 (M+Na) +.
-
- Ammonia was bubbled through a stirred solution of pentafluorophenyl 3-(((1 r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-5-cyclopropylisoxazole-4-carboxylate (0.08 g, 0.143 mmol) in DCM (2 mL) at 0° C. for 30 min. The reaction was then stirred at rt for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was evaporated to complete dryness. The material was purified by trituration with hexane and diethyl ether to obtain tert-butyl ((1 r,4r)-4-4-carbamoyl-5-cyclopropylisoxazole-3-carboxamido)cyclohexyl) carbamate (0.040 g, 71%.).
-
- To a stirred solution of tert-butyl ((1r,4r)-4-(4-carbamoyl-5-cyclopropylisoxazole-3-carboxamido)cyclohexyl)carbamate (0.040 g, 0.101 mmol) in dioxane (2 mL) at 0° C. was added 4 M dioxane:HCl (3 mL). The reaction was stirred at rt for 1 h and progress monitored by TLC. After complete consumption of starting material, the solvent was removed under reduced pressure and the residue was purified by washing with diethyl ether to obtain N3-((1 r,4r)-4-aminocyclohexyl)-5-cyclopropylisoxazole-3,4-dicarboxamide hydrochloride (0.022 g, 75%). 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=7.8 Hz, 1H), 8.50-8.45 (m, 1H), 7.91 (s, 3H), 7.64 (s, 1H), 3.83 (brs, 1H), 3.0-2.97 (m, 2H), 1.96 (d, J=7.6 Hz, 2H), 1.91-1.84 (m, 2H), 1.49-136 (m, 4H), 1.24-1.21 (m, 2H), 1.15-1.10 (m, 2H); LCMS: m/z=293.15 (M+H)+.
-
-
- To a solution of bicyclo[3.3.1]nonane-2,6-dione (1.0 g, 6.5707 mmol) in THF (10 mL) was added benzyl amine (2.87 mL, 26.283 mmol) under N2 atmosphere at rt and stirred for 5 minutes. AcOH (0.8 mL, 1.3798 mmol) was added and mixture was cooled to 0° C. Sodium triacetoxy borohydride (5.57 g, 26.283 mmol) was added portionwise over 30 min. The reaction was allowed to stir at rt overnight. The reaction was diluted with water (20 mL) and neutralized with saturated aq. solution of NaHCO3 (80 mL). The mixture was extracted with DCM (40 mL×4). The combined organic layer was washed with saturated aq solution of NaHCOJ(50 mL), brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to give crude product, which was purified by column chromatography using mobile phase 0.3% methanol in DCM to obtain N2,N6-dibenzylbicyclo[3.3.1]nonane-2,6-diamine (1.3 g, yield 59.14%) LCMS: m/z=335.16 [M+H]+.
-
- To a suspension of 10% Pd/C (dry) in MeOH (3 mL) was added solution of N2,N6-dibenzylbicyclo[3.3.1]nonane-2,6-diamine (1.3 g, 3.886 mmol) in MeOH (10 mL). The reaction was stirred overnight under a H2 atmosphere. The reaction was filtered through a celite pad and washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to obtain title compound (0.5 g, yield 83.4%). LCMS: m/z=155.20 [M+H]+.
-
- To a solution of bicyclo[3.3.1]nonane-2,6-diamine (500 mg, 3.241 mmol) in a mixture of MeOH (10 mL) and THF (20 mL) at 0° C. under N2 atmosphere was added a solution of Boc-anhydride (0.37 mL, 1.620 mmol) in mixture of MeOH (20 mL) and THF (50 mL) over a period of 6 hours. The reaction was allowed to stir at rt overnight. The reaction was concentrated under reduced pressure to give crude product which was purified by column chromatography using basic alumina as stationary phase and 0-4% MeOH in DCM as mobile phase to obtain title compound (290 mg, yield 35.17%). LCMS: m/z=255.25 [M+H]+.
-
- To a solution of 5-cyclopropylisoxazole-3-carboxylic acid (175 mg, 1.14 mmol) in DMF at 0° C. under N2 atmosphere was added HATU (650 mg, 1.71 mmol). The reaction stirred for 20 min. and then then tert-butyl (6-aminobicyclo[3.3.1]nonan-2-yl)carbamate (290 mg, 1.14 mmol) was added followed by addition of DIPEA (0.6 mL, 3.42 mmol). The reaction was brought to rt and stirred overnight. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated to give crude product which was purified by column chromatography using mobile phase to 0-12% ethyl acetate in hexane to obtain the title compound (300 mg, yield 75.5%). LCMS: m/z=334.36 [M−56]+.
-
- To a solution of tert-butyl (6-(5-cyclopropylisoxazole-3-carboxamido)bicyclo[3.3.1]nonan-2-yl)carbamate (300 mg, 0.7702 mmol) in DCM (3 mL) at 0° C. under N2 atmosphere was added TFA (1.5 mL). The reaction was allowed to stir at rt for 2 hours. The reaction was concentrated under reduced pressure and triturated with diethyl ether to obtain the title compound as the TFA salt (300 mg, yield 96.5%). LCMS: m/z=290.36 [M+H]+.
-
- To a solution of the TFA salt of (R)-3-((tert-butoxycarbonyl) amino)butanoic acid (50 mg, 0.246 mmol) in DMF (1.0 mL) at 0° C. was added HATU (140 mg, 0.369 mmol). After stirring for 15 minutes, the TFA salt of N-(6-aminobicyclo[3.3.1]nonan-2-yl)-5-cyclopropylisoxazole-3-carboxamide (100 mg, 0.246 mmol) was added followed by addition of DIPEA (0.126 mL, 0.738 mmol). The reaction was brought to rt and stirred overnight. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to give crude product which was purified by column chromatography using mobile phase 0-70% ethyl acetate in hexane to obtain the title compound (80 mg, 67.9%). LCMS: m/z=475.16 [M+H]+.
-
- To a solution of tert-butyl ((2R)-4-((6-(5-cyclopropylisoxazole-3-carboxamido)bicyclo[3.3.1]nonan-2-yl)amino)-4-oxobutan-2-yl)carbamate (80 mg, 0.1686 mmol) in DCM (0.8 mL) at 0° C. under N2 atmosphere was added TFA (0.4 mL) dropwise. The reaction was allowed to stir at room temperature for 2 hours. The reaction was concentrated under reduced pressure to give crude product which was triturated with diethyl ether (10 mL) and hexanes (10 mL) to obtain the title compound as TFA salt (50 mg, 60.7%). 1H NMR (400 MHz, DMSO-d6) δ 8.667 (d, 1H), 8.180 (d, 111, 7.792 (s, 3H), 6.478 (s, 1H), 4.067 (s, 1H), 3.907 (s, 1H), 3.39 (s, 1H), 2.42 (s, 2H), 2.18 (s, 2H), 2.42 (s, 2H), 1.91-1.88 (m, 4H), 1.78-1.65 (m, 4H), 1.54-1.50 (m, 4H), 1.16-1.09 (m, 5H), 0.917 (s, 1H); LCMS: m/z=375.4 [M+1]−.
-
-
- Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed dichloromethane (40 mL) and benzene-1,4-diamine (1.059 g, 9.79 mmol, 1.05 equiv); then 5-cyclopropyl-1,2-oxazole-3-carbonyl chloride (1.6 g, 9.33 mmol, 1.00 equiv) in 10 mL DCM was added dropwise. The resulting solution was stirred for 12 h at room temperature. The resulting mixture was concentrated under vacuum. The solids were filtered off. The filtrate was extracted with 2×100 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (10:1). This resulted in 750 mg (33%) of N-(4-aminophenyl)-5-cyclopropylisoxazole-3-carboxamide as a yellow solid. LCMS: rt=1.04 min, m/z=285.0 [M+CN]+.
-
- Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed N-(4-aminophenyl)-5-cyclopropylisoxazole-3-carboxamide (170 mg, 0.70 mmol, 1.00 equiv), tetrahydrofuran (5 mL), dichloromethane (5 mL), EDCI (401 mg, 2.09 mmol, 2.99 equiv), DIEA (271 mg, 2.10 mmol, 3.00 equiv), HOBT (283 mg, 2.09 mmol, 3.00 equiv), and 3-[[(tert-butoxy)carbonyl]amino]propanoic acid (264 mg, 1.40 mmol, 2.00 equiv). The resulting solution was stirred for 6 h at room temperature. The mixture was concentrated under vacuum. The residue was diluted with 50 mL of H2O and extracted with DCM. The organic phase was collected and dried over anhydrous sodium sulfate. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (5:1). This resulted in 120 mg (41%) of tert-butyl 3-(4-(5-cyclopropylisoxazole-3-carboxamido)phenylamino)-3-oxopropylcarbamate as a light yellow solid. LCMS: m/z=437.1 [M+Na]+.
-
- Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl 3-(4-(5-cyclopropylisoxazole-3-carboxamido)phenylamino)-3-oxopropylcarbamate (120 mg, 0.29 mmol, 1.00 equiv) and 1,4-dioxane (5 mL). Then hydrogen chloride was introduced into the mixture. The resulting solution was stirred for 2 h at room temperature. The mixture was then concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, detector, UV 254 nm. The result solution was acidified by dilute hydrochloric acid (1N), then concentrated and dried. This resulted in 21.4 mg (24%) of N-(4-(3-aminopropanamido)phenyl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride as a white solid. 1H-NMR (300 MHz, D2O): δ 7.54-7.37 (m, 4H), 6.36 (s, 1H), 3.25 (t, J=6.6 Hz, 2H), 2.77 (t, J=6.6 Hz, 2H), 2.12-2.04 (m, 1H), 1.08-1.02 (m, 2H), 0.97-0.92 (m, 2H). LCMS: m/z=315.0 [M+H]+.
-
-
- To a solution of 5-cyclopropylisoxazole-3-carboxylic acid (1.53 g) in DMF (20 mL) was added HATU (6.84 g, DIPEA (3.87 g) and tert-butyl 3-aminoazetidine-1-carboxylate (2.58 g). The resulting mixture was stirred at r.t. overnight. The reaction mixture was diluted with ethyl acetate (120 mL), washed with brine (30 mL×4), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluant petroleum ether: ethyl acetate gradient elution 100:0 to 50:50) to afford tert-butyl 3-(5-cyclopropylisoxazole-3-carboxamido)azetidine-1-carboxylate (2.55 g, 83%) as a pale yellow solid. ESI-LCMS (m/z): 330[M+Na]+.
-
- To a solution of tert-butyl 3-(5-cyclopropylisoxazole-3-carboxamido)azetidine-1-carboxylate (2.55 g) in DCM (10 mL) was added TFA (4 mL) drop-wise. The resulting mixture was stirred at r.t. overnight. The reaction mixture was concentrated under reduced pressure and the residue was treated with ammonia in MeOH (7N, 30 mL) and the solution concentrated under reduced pressure. The residue was purified by flash column chromatography (eluant: DCM:MeOH (MeOH:7N NH3 100:1) 10:1) to afford N-(azetidin-3-yl)-5-cyclopropylisoxazole-3-carboxamide (1.35 g, 78%) as a white solid. ESI-LCMS (m/z): 208[M+H]+.
-
- Into the stirred solution of N-(azetidin-3-yl)-5-cyclopropylisoxazole-3-carboxamide (400 mg, 1.9 mmol) and 1-(4-chlorobenzyl)-1H-pyrazole-4-carbaldehyde (425 mg, 1.9 mmol) in MeOH (10 mL) was added NaBH3CN (363 mg, 5.8 mmol). The mixture was stirred at 60° C. for 20 h. The product was purified by reversed phased pre-HPLC (NH4HCO3. CH3CN:H2O=5%-95%) to afford N-(l-((1-(4-chlorobenzyl)-1H-pyrazol-4-yl)methyl)azetidin-3-yl)-5-cyclopropylisoxazole-3-carboxamide as a white solid (70 mg, 8.8%). ESI-LCMS (m/z): 412 [M+H]−; 1HNMR (400 MHz, CD3OD) d ppm: 7.64 (s, 1H), 7.50 (s, 1H), 7.37-7.33 (m, 2H), 7.20 (d, J=8.81 Hz, 2H), 6.37 (s, 1H), 5.32 (s, 2H), 4.61-4.58 (m, 1H), 3.70-3.66 (m, 2H), 3.61 (s, 2H), 3.22-3.18 (m, 2H), 2.19-2.15 (m, 1H), 1.18-1.13 (m, 2H), 1.00-0.96 (m, 2H).
- S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), Tris, Tween20, dimethylsulfoxide (DMSO), bovine skin gelatin (BSG), and Tris(2-carboxyethyl)phosphine hydrochloride solution (TCEP) were purchased from Sigma-Aldrich at the highest level of purity possible. 3H-SAM was purchase from American Radiolabeled Chemicals with a specific activity of 80 Ci/mmol. 384-well opaque white OptiPlates and SPA beads (Perkin Elmer, catalog # RPNQ0013) were purchased from PerkinElmer.
- N-terminally GST-tagged MEKK2 (MAP3K2) protein corresponding to reference sequence AAF63496.3 was purchased from Life Technologies (catalog # PV4010). This protein was expressed in High Five insect cells and purified to >85% purity. Protein identity was confirmed by MS/MS analysis after proteolytic digestion. The protein sequence used was:
-
(SEQ ID No. 1). MAPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGL EFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVL DIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTH PDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIA WPLQGWQATFGGGDHPPKSDLVPRHNQTSLYKKAGTMDDQQALNSIMQDL AVLHKASRPALSLQETRKAKSSSPKKQNDVRVKFEHRGEKRILQFPRPVK LEDLRSKAKIAFGQSMDLHYTNNELVIPLTTQDDLDKALELLDRSIHMKS LKILLVINGSTQATNLEPLPSLEDLDNTVFGAERKKRLSIIGPTSRDRSS PPPGYIPDELHQVARNGSFTSINSEGEFIPESMEQMLDPLSLSSPENSGS GSCPSLDSPLDGESYPKSRMPRAQSYPDNHQEFSDYDNPIFEKFGKGGTY PRRYHVSYHHQEYNDGRKTFPRARRTQGNQLTSPVSFSPTDHSLSTSSGS SIFTPEYDDSRIRRRGSDIDNPTLTVMDISPPSRSPRAPTNWRLGKLLGQ GAFGRVYLCYDVDTGRELAVKQVQFDPDSPETSKEVNALECEIQLLKNLL HERIVQYYGCLRDPQEKTLSIFMEYMPGGSIKDQLKAYGALTENVTRKYT RQILEGVHYLHSNMIVHRDIKGANILRDSTGNVKLGDFGASKRLQTICLS GTGMKSVTGTPYWMSPEVISGQGYGRKADIWSVACTVVEMLTEKPPWAEF EAMAAIFKIATQPTNPKLPPHVSDYTRDFLKRIFVEAKLRPSADELLRHM FVHYH. - Full-length human SMYD3 isoform 1 (BAB86333) was inserted into a modified pET21 b plasmid containing a His6 tag and TEV and SUMO cleavage sites. Because two common variants of SMYD3 exist in the population, site directed mutagenesis was subsequently performed to change amino acid 13 from an asparagine to a lysine, resulting in plasmid pEPZ533. A lysine at position 13 conforms to the more commonly occurring sequence (NP_001161212).
- E. coli (BL21 codonplus RIL strain, Stratagene) were transformed with plasmid pEPZ553 by mixing competent cells and plasmid DNA and incubating on ice for 30 minutes followed by heat shock at 42° C. for 1 minute and cooling on ice for 2 minutes. Transformed cells were grown and selected on LB agar with 100 μg/mL ampicillin and 17 μg/mL chloramphenicol at 37° C. overnight. A single clone was used to inoculate 200 mL of LB medium with 100 g/mL ampicillin and 17 μg/mL chloramphenicol and incubated at 37° C. on an orbital shaker at 180 rpm. Once in log growth, the culture was diluted 1:100 into 2 L of LB medium and grown until OD600 was about 0.3 after which the culture was incubated at 15° C. and 160 rpm. Once OD600 reached about 0.4, IPTG was added to a final concentration of 0.1 mM and the cells were grown overnight at 15° C. and 160 rpm. Cells were harvested by centrifugation at 8000 rpm, for 4 minutes at 4° C. and stored at −80° C. for purification.
- Expressed full-length human His-tagged SMYD3 protein was purified from cell paste by Nickel affinity chromatography after equilibration of the resin with Buffer A (25 mM Tris, 200 mM NaCl, 5% glycerol, 5 mM β-mercaptoethanol, pH7.8). The column was washed with Buffer B (Buffer A plus 20 mM imidazole) and His-tagged SMYD3 was eluted with Buffer C (Buffer A plus 300 mM imidazole). The His tag, TEV and SUMO cleavage sites were removed generating native SMYD3 by addition of ULP1 protein at a ratio of 1:200 (ULP1:SMYD3). Imidazole was removed by dialysis overnight in Buffer A. The dialyzed solution was applied to a second Nickel column and the native SMYD3 protein was collected from the column flow-through. The flow-through was dialyzed in Buffer D (25 mM Tris, 5% glycerol, 5 mM β-mercaptoethanol, 50 mM NaCl, pH7.8) and ULP1 was removed using a Q sepharose fast flow column. SMYD3 was eluted in Buffer A and further purified using an S200 size-exclusion column equilibrated with Buffer A. SMYD3 was concentrated to 2 mg/mL with a final purity of 89%.
-
-
SMYD3 (Q9H7B4) (SEQ ID No. 2). MEPLKVEKFATAKRGNGLRAVTPLRPGELLFRSDPLAYTVCKGSRGVVCD RCLLGKEKLMRCSQCRVAKYCSAKCQKKAWPDHKRECKCLKSCKPRYPPD SVRLLGRVVFKLMDGAPSESEKLYSFYDLESNINKLTEDKKEGLRQLVMT FQHFMREEIQDASQLPPAFDLFEAFAKVICNSFTICNAEMQEVGVGLYPS ISLLNHSCDPNCSIVFNGPHLLLRAVRDIEVGEELTICYLDMLMTSEERR KQLRDQYCFECDCFRCQTQDKDADMLTGDEQVWKEVQESLKKIEELKAHW KWEQVLAMCQAIISSNSERLPDINIYQLKVLDCAMDACINLGLLEEALFY GTRTMEPYRIFFPGSHPVRGVQVMKVGKLQLHQGMFPQAMKNLRLAFDIM RVTHGREHSLIEDLILLLEECDANIRAS. - The assays were all performed in a buffer consisting of 25 mM Tris-Cl pH 8.0, 1 mM TCEP, 0.005% BSG, and 0.005% Tween 20, prepared on the day of use. Compounds in 100% DMSO (1 ul) were spotted into a 384-well white opaque OptiPlate using a Bravo automated liquid handling platform outfitted with a 384-channel head (Agilent Technologies). DMSO (1 ul) was added to Columns 11, 12, 23, 24, rows A-H for the maximum signal control and 1 ul of SAH, a known product and inhibitor of SMYD3, was added to columns 11, 12, 23, 24, rows I-P for the minimum signal control. A cocktail (40 ul) containing the SMYD3 enzyme was added by Multidrop Combi (Thermo-Fisher). The compounds were allowed to incubate with SMYD3 for 30 min at room temperature, then a cocktail (10 ul) containing SAM and MEKK2 was added to initiate the reaction (final volume=51 ul). The final concentrations of the components were as follows: SMYD3 was 0.4 nM, 3H-SAM was 8 nM, MEKK2 was 12 nM. SAH in the minimum signal control wells was 1 mM, and the DMSO concentration was 2%. The assays were stopped by the addition of non-radiolabeled SAM (10 ul) to a final concentration of 100 uM, which dilutes the 3H-SAM to a level where its incorporation into MEKK2 is no longer detectable. Radiolabeled MEKK2 was detected using a scintillation proximity assay (SPA). 10 uL of a 10 mg/mL solution of SPA beads in 0.5 M citric acid was added and the plates centrifuged at 600 rpm for 1 min to precipitate the radiolabeled MEKK2 onto the SPA beads. The plates were then read in a PerkinElmer TopCount plate reader to measure the quantity of 3H-labeled MEKK2 as disintegrations per minute (dpm) or alternatively, referred to as counts per minute (cpm).
-
- Where dpm=disintegrations per minute, cmpd=signal in assay well, and min and max are the respective minimum and maximum signal controls.
-
- Where top and bottom are the normally allowed to float, but may be fixed at 100 or 0 respectively in a 3-parameter fit. The Hill Coefficient normally allowed to float but may also be fixed at 1 in a 3-parameter fit. Y is the % inhibition and X is the compound concentration.
- SMYD3 biochemical assay data for representative Compounds of the Disclosure are presented in Table 1 in the column titled “SMYD3 Biochem IC50 (μM).”
- 293T/17 adherent cells were purchased from ATCC (American Type Culture Collection), Manassas, Va., USA. MEM/Glutamax medium, Optimem Reduced Serum medium, penicillin-streptomycin, 0.05% trypsin and 1×D-PBS were purchased from Life Technologies, Grand Island, N.Y., USA. PBS-10X was purchased from Ambion, Life Technologies, Grand Island. N.Y., USA. PBS with Tween 20 (PBST (10×)) was purchased from KPL, Gaithersburg, Md., USA. Tet System FBS— approved FBS US Source was purchased from Clontech. Mountain View, Calif., USA. Odyssey blocking buffer, 800CW goat anti-rabbit IgG (H+L) antibody, 680CW Goat anti-mouse IgG (H+L) and Licor Odyssey infrared scanner were purchased from Licor Biosciences. Lincoln, Nebr., USA. Tri-methyl-Lysine [A260]-MEKK2 antibody, MEKK2 and SMYD3 plasmids were made at Epizyne. Anti-flag monoclonal mouse antibody was purchased from Sigma, St. Louis, Mo., USA. Methanol was purchased from VWR. Franklin, Mass., USA. 10% Tween 20 was purchased from KPL, Inc., Gaithersburg, Md. USA. Fugene was purchased from Promega, Madison, Wis., USA. The Biotek ELx405 was purchased from BioTek, Winooski, Vt., USA. The multidrop combi was purchased from Thermo Scientific, Waltham, Mass., USA.
- 293T/17 adherent cells were maintained in growth medium (MEM/Glutamax medium supplemented with 10% v/v Tet System FBS and cultured at 37° C. under 5% CO2.
- Cell treatment, In Cell Western (ICW) for detection of trimethyl-lysine-MEKK2 and MEKK2.
- 293T/17 cells were seeded in assay medium at a concentration of 33,333 cells per cm2 in 30 mL medium per T150 flask and incubated at 37° C. under 5% CO2. Plasmids were prepared for delivery to cells by first mixing 1350 μL Opti-MEM with Fugene (81 μL) in a sterile Eppendorf and incubated for five minutes at room temperature (RT). MEKK2-flag (13.6 ug/T150) MEKK2 p3XFlag-CMV-14 with C-3XFlag and SMYD3 (0.151 ug/T150) SMYD3 p3XFlag-CMV-14 without C-3XFlag plasmids were aliquotted to a 1.7 mL sterile microfuge tube. The gene ID for MEKK2 and SMYD3 is NM_006609.3 and Q9H7B4, respectively. Entire volume of Opti-MEM/Fugene mixture was then added to a microfuge tube containing DNA plasmid, mixed and then incubated×15 minutes at RT. The medium on the 293T/17 cells was refreshed, and the DNA/Fugene complex is added aseptically to each flask, rocked gently, and incubated at 37 C for 5 hours. Medium was then removed, and cells were washed once with PBS in the flask. Trypsin 0.05% (3 mL) was added and cells incubated for three minutes. Room temperature MEM+10% Tet system FBS was added and cells were mixed gently, and counted using the Vi-cell. Cells were seeded at 100,000 cells/mL in 50 μL MEM/10% Tet FBS/Pen/Strep to a 384 well black/clear poly-D-lysine coated plate containing test agent diluted in DMSO. The final top concentration of test compound was 40 μM. The total concentration of DMSO did not exceed 0.2% (v/v). Plates were incubated×30 minutes at RT in low-airflow area, followed by incubation at 37° C. under 5% CO2 for 24 hours. Medium was aspirated from all wells of assay plates prior to fixation and permeabilization with ice cold (−20° C.) methanol (90 μL/well) for ten minutes. Plates were rinsed with PBS three times on BioTek ELx405. PBS was removed with a final aspiration, and Odyssey blocking buffer (50 μL/well) was added to each well and incubated for one hour at RT. Primary antibody solution was prepared (anti-trimethyl-MEKK2 at 1:600 dilution plus mouse anti-flag antibody at 1:10,000 dilution in diluent (Odyssey Blocking buffer+0.1% Tween 20)) and 20 μL per well was dispensed using the Multidrop Combi. Assay plates were then sealed with foil, and incubated overnight at 4° C. Plates were washed five times with PBS-Tween (1X) on Biotek ELx405 and blotted on paper towel to remove excess reagent. Detection antibody solution (IRDye 800 CW goat anti-rabbit IgG diluted 1:400 in diluent (Odyssey Blocking buffer+0.1% Tween 20), plus IRDye 680CW goat anti-mouse IgG at 1:500 in diluent (Odyssey Blocking buffer+0.1% Tween 20) was added (20 μL/well) and incubated in dark for one hour at RT. Plates were then washed four times with PBS-T (1X) on ELx405. A final rinse with water was performed (115 μL/well×three washes on the ELx405). Plates were then centrifuged upside down, on paper towel, at 200×g to remove excess reagent. Plates were left to dry in dark for one hour. The Odyssey Imager was used to measure the integrated intensity of 700 and 800 wavelengths at resolution of 84 μm, medium quality, focus offset 4.0, 700 channel intensity=3.5 to measure the MEKK2-flag signal, 800 channel intensity=5 to measure the Trimethyl-MEKK2 signal of each well.
- First, the ratio for each well was determined by:
-
- Each plate included fourteen control wells of DMSO only treatment (Minimum Inhibition) as well as fourteen control wells for maximum inhibition (Background). The average of the ratio values for each control type was calculated and used to determine the percent inhibition for each test well in the plate. Reference compound was serially diluted two-fold in DMSO for a total of nine test concentrations, beginning at 40 μM. Percent inhibition was calculated (below).
-
- Non-linear regression curves were generated to calculate the IC50 and dose-response relationship using triplicate wells per concentration of compound.
- SMYD3 cell assay data for representative Compounds of the Disclosure are presented in Table 1 in the column titled “SMYD3 Cell IC50 (μM).”
- S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), bicine, Tween20, dimethylsulfoxide (DMSO), bovine skin gelatin (BSG), and Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) were purchased from Sigma-Aldrich at the highest level of purity possible. 3H-SAM was purchase from American Radiolabeled Chemicals with a specific activity of 80 Ci/mmol. 384-well streptavidin Flashplates were purchased from PerkinElmer.
- Peptide was synthesized with a N-terminal linker-affinity tag motif and a C-terminal amide cap by 21st Century Biochemicals. The peptide was high high-performance liquid chromatography (HPLC) purified to greater than 95% purity and confirmed by liquid chromatography mass spectrometry (LC-MS). The sequence was ARTKQTARKSTGGKAPRKQLATKAARKSA(K-Biot)-amide. (SEQ ID No: 3)
- Full length SMYD2 (NP_064582.2) was cloned into a pFastbac-Htb-lic vector with an N-terminal His6 tag and FLAG tag, preceded by a TEV protease cleavage site. The protein was expressed in Sf9 insect cells. Cells were resuspended in lysis buffer (25 mM HEPES-NaOH, pH 7.5, 200 mM NaCl, 5% glycerol, and 5 mM β-ME) and lysed by sonication. The protein was purified by Ni-NTA (Qiagen), followed by TEV cleavage to remove the His6 tag, subtractive Ni-NTA (Qiagen), and gel filtration chromatography using an S200 column (GE Healthcare). Purified protein was stored in 20 mM Tris-HCl, pH 8.0, 100 mM NaCl. and 1 mM TCEP.
- The assays were all performed in a buffer consisting of 20 mM Bicine (pH=7.6), 1 mM TCEP, 0.005% Bovine Skin Gelatin, and 0.002% Tween20, prepared on the day of use. Compounds in 100% DMSO (1 ul) were spotted into a polypropylene 384-well V-bottom plates (Greiner) using a Platemate Plus outfitted with a 384-channel head (Thermo Scientific). DMSO (1 ul) was added to Columns 11, 12, 23, 24, rows A-H for the maximum signal control and 1 ul of SAH, a known product and inhibitor of SMYD2, was added to columns 11, 12, 23, 24, rows I-P for the minimum signal control. A cocktail (40 ul) containing the SMYD2 enzyme was added by Multidrop Combi (Thermo-Fisher). The compounds were allowed to incubate with SMYD2 for 30 min at room temperature, then a cocktail (10 ul) containing 3H-SAM and peptide was added to initiate the reaction (final volume=51 ul). The final concentrations of the components were as follows: SMYD2 was 1.5 nM, 3H-SAM was 10 nM, and peptide was 60 nM, SAH in the minimum signal control wells was 1000 uM, and the DMSO concentration was 2%. The assays were stopped by the addition of non-radioactive SAM (10 ul) to a final concentration of 600 uM, which dilutes the 3H-SAM to a level where its incorporation into the peptide substrate is no longer detectable. 50 ul of the reaction in the 384-well polypropylene plate was then transferred to a 384-well Flashplate and the biotinylated peptides were allowed to bind to the streptavidin surface for at least 1 hour before being washed three times with 0.1% Tween20 in a Biotek ELx405 plate washer. The plates were then read in a PerkinElmer TopCount plate reader to measure the quantity of 3H-labeled peptide bound to the Flashplate surface, measured as disintegrations per minute (dpm) or alternatively, referred to as counts per minute (cpm).
-
- Where dpm=disintegrations per minute, cmpd=signal in assay well, and min and max are the respective minimum and maximum signal controls.
-
- Where top and bottom are the normally allowed to float, but may be fixed at 100 or 0 respectively in a 3-parameter fit. The Hill Coefficient normally allowed to float but may also be fixed at 1 in a 3-parameter fit. I is the compound concentration.
- SMYD2 biochemical assay data for representative Compounds of the Disclosure are presented in Tables 2 and 3 in the column titled “SMYD2 Biochem IC50 (μM).”
- Having now fully described this invention, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof.
- Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
- All patents and publications cited herein are fully incorporated by reference herein in their entirety.
Claims (27)
1. A compound having Formula I:
or a pharmaceutically acceptable salt or hydrate thereof,
wherein:
R1 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-4 alkenyl, C1-4 haloalkyl, C3-6 cycloalkyl, and hydroxyalkyl;
R2 is selected from the group consisting of hydrogen, halo, and carboxamido;
A is selected from the group consisting of C1-10 alkylenyl, (cycloalkylenyl)alkyl, optionally substituted C3-12 cycloalkylenyl, optionally substituted C6-14 arylenyl, optionally substituted 5- to 14-membered heteroarylenyl, and —C(H)R3R4;
with the provisos:
a) when R1 is ethyl or cyclopropyl; R2 is hydrogen; and X is —N(R7)S(═O)2—N(R7)C(═O)—, or —N(R7)C(═O)C(R8)(H)—, then A is not optionally substituted 1,4-cyclohexylenyl; and
b) when R1 is ethyl or cyclopropyl; R2 is hydrogen; X is absent; and Z is amino, alkylamino, dialkylamino, or heterocycloamino, then A is not optionally substituted 1,4-cyclohexylenyl;
R3 is selected from the group consisting of hydrogen, C1-6 alkyl, (hydroxy)(aryl)alkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, optionally substituted C3-12 cycloalkyl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted C6-14 aryl, aralkyl, alkoxycarbonyl, and —C(═O)N(R5)(R6);
R4 is selected from the group consisting of C1-6 alkyl, hydroxyalkyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted 4- to 14-membered heterocyclo, and (heteroaryl)alkyl;
R5 is selected from the from the group consisting of hydrogen and C1-4 alkyl;
R6 is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, fluoroalkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(carboxamido)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (amino)(heteroaryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, (hydroxyalkylamino)alkyl, alkoxyalkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl optionally substituted C3-12 cycloalkyl, aralkyl, and (heteroaryl)alkyl;
X is selected from the group consisting of —S(═O)2—, —S(═O)2N(R7)—, —N(R7)S(═O)2—,—S(═O)2C(R8)(H)—, —C(═O)—, —C(═O)N(R7)—, —N(R7)C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)C(R8)(H)N(R7)—, —N(R7)C(═O)C(R8)(H)—, —C(R8)(H)C(═O)N(R7)—, —C(R8)(H)N(R7)C(═O)—, and —C(═O)C(R8)(H)—; or X is absent;
Z is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, fluoroalkyl, hydroxyalkyl, amino, alkylamino, dialkylamino, heterocycloamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (amino)(heteroaryl)alkyl (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, (hydroxyalkylamino)alkyl, alkoxyalkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl optionally substituted C3-12 cycloalkyl, aralkyl, and (heteroaryl)alkyl;
wherein —X—Z is attached to any available carbon or nitrogen atom of A, R3, R4, or R6;
R7 is selected from the group consisting of hydrogen and C1-4 alkyl; and
R8 is selected from the group consisting of hydrogen, C1-4 alkyl, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, and hydroxyalkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein A is C1-10 alkylenyl.
3. The compound of claim 2 , or a pharmaceutically acceptable salt or hydrate thereof, having Formula II:
wherein:
R9a and R9b are independently selected from the group consisting of hydrogen and C1-4 alkyl;
R9c and R9d are independently selected from the group consisting of hydrogen and C1-4 alkyl; or
R9c and R9d taken together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl;
R9 is selected from the group consisting of hydrogen and C1-4 alkyl;
m is 0 or 1;
X is selected from the group consisting of —N(R7)C(═O)—, —N(R7)C(═O)C(R8)(H)—, and —N(R7)S(═O)2—;
R8 is selected from the group consisting of C1-4 alkyl, amino, alkylamino, and dialkylamino; and
Z is selected from the group consisting of C1-6 alkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C3-12 cycloalkyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein A is optionally substituted C6-14 arylenyl.
5. The compound of claim 4 , or a pharmaceutically acceptable salt or hydrate thereof, having Formula III:
wherein:
R10a is selected from the group consisting of hydrogen, halo, C1-6 alkyl, alkoxy, hydroxyalkyl, and alkoxycarbonyl;
X is selected from the group consisting of —C(═O)N(R7)—, —N(R7)C(═O)—, —C(═O)C(R8)(H)N(R7)—, —C(R8)(H)C(═O)N(R7)— and —S(═O)2N(R7)—; or X is absent;
R8 is selected from the group consisting of C1-4 alkyl, amino, alkylamino, and dialkylamino; and
Z is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (amino)(heteroaryl)alkyl, heteroalkyl, (amino)(hydroxy)alkyl, (heterocyclo)alkyl, optionally substituted C3-12 cycloalkyl, and optionally substituted 4- to 14-membered heterocyclo.
7. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein A is optionally substituted C3-12 cycloalkylenyl.
8. The compound of claim 7 , or a pharmaceutically acceptable salt or hydrate thereof, having Formula V:
wherein:
R10a and R10b are independently selected from the group consisting of hydrogen and C1-4 alkyl;
X is selected from the group consisting of —S(═O)2—, —S(═O)2N(R7)—, —N(R7)C(═O)—, —C(═O)N(R7)—, —N(R7)S(═O)—, and —OC(═O)—; or X is absent;
Z is selected from the group consisting of amino, alkylamino, dialkylamino, heterocycloamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, and (hydroxyalkylamino)alkyl;
n is 0 or 1; and
p is 0 or 1.
9. (canceled)
10. (canceled)
11. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein A is —C(H)R3R4.
12-14. (canceled)
15. The compound of claim 11 , or a pharmaceutically acceptable salt or hydrate thereof, having Formula VII, Formula VIII, or Formula IX:
wherein:
R3 is selected from the group consisting of hydrogen, C1-4 alkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted C6-14 aryl, aryloxyalkyl, and aralkyl
X is selected from the group consisting of —S(═O)2—, —S(═O)2N(R7)—, —S(═O)2C(R8)(H)—, —C(═O)—, —C(═O)N(R7)—, —C(═O)O—, —OC(═O)—, and —C(═O)C(R8)(H)—; or X is absent;
R8 is selected from the group consisting of C1-4 alkyl, amino, alkylamino, and dialkylamino; and
Z is selected from the group consisting of C1-6 alkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, hydroxyalkyl, optionally substituted C3-12 cycloalkyl, aralkyl, and (heteroaryl)alkyl.
16. (canceled)
17. The compound of claim 11 , or a pharmaceutically acceptable salt or hydrate thereof, having Formula X, Formula XI, or Formula XII:
18. The compound of claim 17 , or a pharmaceutically acceptable salt or hydrate thereof, wherein:
X is selected from the group consisting of —C(═O)N(R7)— and —S(═O)2N(R7)—;
Z is optionally substituted C1-6 alkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C3-12 cycloalkyl, aralkyl, and (heteroaryl)alkyl; and
R12 is hydrogen.
19. (canceled)
20. The compound of claim 11 , or a pharmaceutically acceptable salt or hydrate thereof, having Formula XIII, Formula XIV, or Formula XV:
wherein:
R6 is selected from the group consisting of optionally substituted C1-6 alkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, (amino)(hydroxy)alkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C3-12 cycloalkyl, aralkyl, and (heteroaryl)alkyl;
X is selected from the group consisting of —C(═O)N(R7)—, —C(═O)C(R8)(H)—, and —S(═O)2N(R7)—; or
X is absent;
R8 is selected from the group consisting of C1-4 alkyl, amino, alkylamino, and dialkylamino;
Z is selected from the group consisting of C1-4 alkyl, amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (amino)(heteroaryl)alkyl, and (amino)(hydroxy)alkyl.
21-24. (canceled)
25. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from the group consisting of C1-4 alkyl and C3-6 cycloalkyl.
26. The compound of claim 25 , or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is cyclopropyl.
28. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
29. A method of treating a patient comprising administering to the patient a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein the patient has cancer.
30. The method of claim 29 , wherein the cancer is selected from the group consisting of adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.
31-38. (canceled)
39. A method of treating a SMYD protein mediated disorder comprising administering to a subject in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof in an effective amount to treat the SMYD protein mediated disorder.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/588,209 US20200148650A1 (en) | 2014-09-10 | 2019-09-30 | Isoxazole carboxamide compounds |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462048759P | 2014-09-10 | 2014-09-10 | |
US201562146794P | 2015-04-13 | 2015-04-13 | |
PCT/US2015/049213 WO2016040498A1 (en) | 2014-09-10 | 2015-09-09 | Isoxazole carboxamide compounds |
US201715510593A | 2017-03-10 | 2017-03-10 | |
US16/588,209 US20200148650A1 (en) | 2014-09-10 | 2019-09-30 | Isoxazole carboxamide compounds |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2015/049213 Division WO2016040498A1 (en) | 2014-09-10 | 2015-09-09 | Isoxazole carboxamide compounds |
US15/510,593 Division US10428029B2 (en) | 2014-09-10 | 2015-09-09 | Isoxazole carboxamide compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
US20200148650A1 true US20200148650A1 (en) | 2020-05-14 |
Family
ID=55459522
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/510,593 Active US10428029B2 (en) | 2014-09-10 | 2015-09-09 | Isoxazole carboxamide compounds |
US16/588,209 Abandoned US20200148650A1 (en) | 2014-09-10 | 2019-09-30 | Isoxazole carboxamide compounds |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/510,593 Active US10428029B2 (en) | 2014-09-10 | 2015-09-09 | Isoxazole carboxamide compounds |
Country Status (6)
Country | Link |
---|---|
US (2) | US10428029B2 (en) |
EP (1) | EP3193603A4 (en) |
JP (1) | JP2017526706A (en) |
AU (1) | AU2015315167A1 (en) |
CA (1) | CA2960274A1 (en) |
WO (1) | WO2016040498A1 (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3193605A4 (en) | 2014-09-10 | 2018-04-18 | Epizyme, Inc. | Substituted piperidine compounds |
JP2017538659A (en) | 2014-09-10 | 2017-12-28 | エピザイム インコーポレイテッド | SMYD inhibitor |
WO2016040511A1 (en) | 2014-09-10 | 2016-03-17 | Epizyme, Inc. | Isoxazole carboxamides as irreversible smyd inhibitors |
WO2016040502A1 (en) | 2014-09-10 | 2016-03-17 | Epizyme, Inc. | Substituted cyclohexylamine compounds |
US10426168B2 (en) | 2015-06-17 | 2019-10-01 | Sumitomo Chemical Company, Limited | Agent for controlling noxious arthropods |
AU2019341709A1 (en) * | 2018-09-21 | 2021-04-15 | Novartis Ag | Isoxazole carboxamide compounds and uses thereof |
CN109879868B (en) * | 2019-03-07 | 2022-04-22 | 南通大学 | Preparation and application of pyrazole amide compound containing 2-aryl oxazole structure |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3065225A (en) * | 1960-02-05 | 1962-11-20 | Hoffmann La Roche | N', n4-di-isoxazolylcarbonyl-sulfanilamide derivatives |
DE19930075A1 (en) * | 1999-06-30 | 2001-01-04 | Bayer Ag | New amino and amidosulfonamides as antiviral agents |
GB0017518D0 (en) * | 2000-07-17 | 2000-08-30 | Merck Sharp & Dohme | Therapeutic agents |
WO2002080928A1 (en) * | 2001-04-03 | 2002-10-17 | Merck & Co., Inc. | N-substituted nonaryl-heterocyclo amidyl nmda/nr2b antagonists |
JP2004537526A (en) * | 2001-06-12 | 2004-12-16 | メルク エンド カムパニー インコーポレーテッド | NR2B receptor antagonist for treatment or prevention of migraine |
DE10306250A1 (en) * | 2003-02-14 | 2004-09-09 | Aventis Pharma Deutschland Gmbh | Substituted N-aryl heterocycles, processes for their preparation and their use as pharmaceuticals |
US7393873B2 (en) * | 2003-07-02 | 2008-07-01 | Merck & Co., Inc. | Arylsulfonamide derivatives |
US7709645B2 (en) * | 2004-07-27 | 2010-05-04 | Sgx Pharmaceuticals, Inc. | Pyrrolo-pyridine kinase modulators |
DE602005013819D1 (en) * | 2004-12-22 | 2009-05-20 | Astrazeneca Ab | PYRIDINCARBOXYL ACID AMID DERIVATIVES FOR USE AS ANTICROBIAL AGENTS |
US7291743B2 (en) * | 2005-03-29 | 2007-11-06 | Geneblue Corporation | Isoxazole derivatives and methods of treating nitric oxide mediated diseases |
NL2000284C2 (en) | 2005-11-04 | 2007-09-28 | Pfizer Ltd | Pyrazine derivatives. |
WO2008040149A1 (en) * | 2006-09-05 | 2008-04-10 | Dexian Dou | Composition and method for treating immune-mediated skin disorders |
CN101675040A (en) * | 2007-05-03 | 2010-03-17 | 辉瑞有限公司 | Pyridine derivatives |
US20090062286A1 (en) * | 2007-05-04 | 2009-03-05 | Kenneth William Foreman | Crystal Structure of SMYD3 Protein |
CA2786438C (en) * | 2010-01-29 | 2015-10-13 | Hanmi Science Co., Ltd. | Thieno[3,2-d]pyrimidine derivatives having inhibitory activity on protein kinases |
WO2013043826A1 (en) * | 2011-09-21 | 2013-03-28 | Abbvie Inc. | Tricyclic compounds useful as protein kinase inhibitors |
EP3868541A1 (en) * | 2012-12-18 | 2021-08-25 | Alcyone Lifesciences, Inc. | Micro-molding device and system for making a catheter for reducing or preventing backflow in a delivery system |
AU2014237312B2 (en) * | 2013-03-15 | 2019-03-28 | Shifa Biomedical Corporation | Anti-proprotein convertase subtilisin kexin type 9 (anti-PCSK9) compounds and methods of using the same in the treatment and/or prevention of cardiovascular diseases |
EP3193604B1 (en) * | 2014-09-10 | 2021-06-16 | Epizyme, Inc. | Substituted n-(pyrrolidin-3-yl)isoxazole-3-carboxamide compounds |
WO2016040511A1 (en) | 2014-09-10 | 2016-03-17 | Epizyme, Inc. | Isoxazole carboxamides as irreversible smyd inhibitors |
JP2017538659A (en) | 2014-09-10 | 2017-12-28 | エピザイム インコーポレイテッド | SMYD inhibitor |
US20170247326A1 (en) | 2014-09-10 | 2017-08-31 | Epizyme, Inc. | Substituted Pyrrolidine Carboxamide Compounds |
WO2016040502A1 (en) | 2014-09-10 | 2016-03-17 | Epizyme, Inc. | Substituted cyclohexylamine compounds |
EP3193605A4 (en) | 2014-09-10 | 2018-04-18 | Epizyme, Inc. | Substituted piperidine compounds |
-
2015
- 2015-09-09 US US15/510,593 patent/US10428029B2/en active Active
- 2015-09-09 AU AU2015315167A patent/AU2015315167A1/en not_active Abandoned
- 2015-09-09 WO PCT/US2015/049213 patent/WO2016040498A1/en active Application Filing
- 2015-09-09 CA CA2960274A patent/CA2960274A1/en not_active Abandoned
- 2015-09-09 EP EP15839331.4A patent/EP3193603A4/en not_active Withdrawn
- 2015-09-09 JP JP2017513199A patent/JP2017526706A/en active Pending
-
2019
- 2019-09-30 US US16/588,209 patent/US20200148650A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
US20170190676A1 (en) | 2017-07-06 |
WO2016040498A1 (en) | 2016-03-17 |
EP3193603A4 (en) | 2018-02-28 |
AU2015315167A1 (en) | 2017-03-16 |
CA2960274A1 (en) | 2016-03-17 |
US10428029B2 (en) | 2019-10-01 |
EP3193603A1 (en) | 2017-07-26 |
JP2017526706A (en) | 2017-09-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10266526B2 (en) | Substituted 1,2,3-triazoles as SMYD inhibitors for treating cancer | |
US10428029B2 (en) | Isoxazole carboxamide compounds | |
EP3193604B1 (en) | Substituted n-(pyrrolidin-3-yl)isoxazole-3-carboxamide compounds | |
US10669243B2 (en) | Isoxazole carboxamides as irreversible SMYD inhibitors | |
US10577363B2 (en) | Substituted piperidine compounds | |
US20200048195A1 (en) | Substituted pyrrolidine carboxamide compounds | |
US10106510B2 (en) | Substituted isoxazoles for treating cancer | |
US20200123142A1 (en) | Substituted Cyclohexylamine Compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |
|
AS | Assignment |
Owner name: EPIZYME, INC., MASSACHUSETTS Free format text: TERMINATION AND RELEASE OF SECURITY INTEREST IN PATENTS AT REEL/FRAME: 051057/0848;ASSIGNOR:BIOPHARMA CREDIT PLC;REEL/FRAME:061165/0501 Effective date: 20220812 |