US20170197947A1 - 3-((Hetero-)Aryl)-Alkyl-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives - Google Patents
3-((Hetero-)Aryl)-Alkyl-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives Download PDFInfo
- Publication number
- US20170197947A1 US20170197947A1 US15/405,896 US201715405896A US2017197947A1 US 20170197947 A1 US20170197947 A1 US 20170197947A1 US 201715405896 A US201715405896 A US 201715405896A US 2017197947 A1 US2017197947 A1 US 2017197947A1
- Authority
- US
- United States
- Prior art keywords
- methyl
- phenyl
- diazaspiro
- cis
- decan
- 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*]N([2*])C1([3*])C([15*])([16*])C([13*])([14*])C2(N([4*])C(=O)N(C([5*])([7*])[8*])C2([11*])[12*])C([17*])([18*])C1([19*])[20*] Chemical compound [1*]N([2*])C1([3*])C([15*])([16*])C([13*])([14*])C2(N([4*])C(=O)N(C([5*])([7*])[8*])C2([11*])[12*])C([17*])([18*])C1([19*])[20*] 0.000 description 19
- VTYCOLALETXHKD-HDICACEKSA-N CCN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 Chemical compound CCN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 VTYCOLALETXHKD-HDICACEKSA-N 0.000 description 2
- JNVNMRNNXAYZDI-IYBDPMFKSA-N CN(C)[C@](CC1)(CC[C@@]1(CN1)NC1=O)c1ccccc1 Chemical compound CN(C)[C@](CC1)(CC[C@@]1(CN1)NC1=O)c1ccccc1 JNVNMRNNXAYZDI-IYBDPMFKSA-N 0.000 description 2
- SXPDQRKVJXDRPL-FJZXDREZSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 SXPDQRKVJXDRPL-FJZXDREZSA-N 0.000 description 2
- LCLNQGFHMKVZDG-HDJSIYSDSA-N CN(C)[C@]1(C2=CC=CS2)CC[C@@]2(CC1)CNC(=O)N2 Chemical compound CN(C)[C@]1(C2=CC=CS2)CC[C@@]2(CC1)CNC(=O)N2 LCLNQGFHMKVZDG-HDJSIYSDSA-N 0.000 description 2
- BSQYCUAKIRLPGJ-PSWAGMNNSA-N C#CCN1C[C@]2(CC[C@](C3=CC=CC=C3)(N(C)C)CC2)N(CC2CCC2)C1=O Chemical compound C#CCN1C[C@]2(CC[C@](C3=CC=CC=C3)(N(C)C)CC2)N(CC2CCC2)C1=O BSQYCUAKIRLPGJ-PSWAGMNNSA-N 0.000 description 1
- AOALKPFERXJXEU-GKWYABRHSA-N C#CCN1C[C@]2(CC[C@](C3=CC=CC=C3)(N(C)C)CC2)NC1=O.CCOC(=O)CN1C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)N=N1 Chemical compound C#CCN1C[C@]2(CC[C@](C3=CC=CC=C3)(N(C)C)CC2)NC1=O.CCOC(=O)CN1C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)N=N1 AOALKPFERXJXEU-GKWYABRHSA-N 0.000 description 1
- XPYKCYOAQJQSEY-IXJDERBESA-N C#CCN1C[C@]2(CC[C@](C3=CC=CC=C3)(N(C)C)CC2)NC1=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CNN=N1)C(=O)N2 Chemical compound C#CCN1C[C@]2(CC[C@](C3=CC=CC=C3)(N(C)C)CC2)NC1=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CNN=N1)C(=O)N2 XPYKCYOAQJQSEY-IXJDERBESA-N 0.000 description 1
- VHAUQAURFYKHJI-UYXDNPQJSA-N C#CCN1C[C@]2(CC[C@](C3=CC=CC=C3)(N(C)C)CC2)NC1=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2 Chemical compound C#CCN1C[C@]2(CC[C@](C3=CC=CC=C3)(N(C)C)CC2)NC1=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2 VHAUQAURFYKHJI-UYXDNPQJSA-N 0.000 description 1
- CQPVRGMVYKZOIX-HJIFVQOFSA-N C1=CC=C(C2(CCC3CCOC3)CCC3(CC2)OCCO3)C=C1.CC(C)(C)S(=O)CC1(C2=CC=CC=C2)CCC2(CC1)OCCO2.CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2.CN(CC1CCOC1)C1(C2=CC=CC=C2)CCC(=O)CC1.CN(CC1CCOC1)C1(C2=CC=CC=C2)CCC2(CC1)NC(=O)NC2=O.CN(CC1CCOC1)C1(C2=CC=CC=C2)CCC2(CC1)OCCO2.CN(CC1CCOC1)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)NC2=O.CN(CC1CCOC1)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2.Cl.NC1(C2=CC=CC=C2)CCC2(CC1)OCCO2.O=C1CCC2(CC1)OCCO2 Chemical compound C1=CC=C(C2(CCC3CCOC3)CCC3(CC2)OCCO3)C=C1.CC(C)(C)S(=O)CC1(C2=CC=CC=C2)CCC2(CC1)OCCO2.CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2.CN(CC1CCOC1)C1(C2=CC=CC=C2)CCC(=O)CC1.CN(CC1CCOC1)C1(C2=CC=CC=C2)CCC2(CC1)NC(=O)NC2=O.CN(CC1CCOC1)C1(C2=CC=CC=C2)CCC2(CC1)OCCO2.CN(CC1CCOC1)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)NC2=O.CN(CC1CCOC1)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2.Cl.NC1(C2=CC=CC=C2)CCC2(CC1)OCCO2.O=C1CCC2(CC1)OCCO2 CQPVRGMVYKZOIX-HJIFVQOFSA-N 0.000 description 1
- ONFGKVHYIBVRCL-ZXGQQQLHSA-N C=CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C(C(N)=O)C=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN=CC=N1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(C#N)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(O)CCCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC(N)=O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)CC(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)CCO)CC3)N(CC3CCC3)C2=O)C=C1 Chemical compound C=CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C(C(N)=O)C=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN=CC=N1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(C#N)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(O)CCCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC(N)=O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)CC(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)CCO)CC3)N(CC3CCC3)C2=O)C=C1 ONFGKVHYIBVRCL-ZXGQQQLHSA-N 0.000 description 1
- BUFBUOAMVOIRII-ZILJFZKASA-N C=CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1 Chemical compound C=CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1 BUFBUOAMVOIRII-ZILJFZKASA-N 0.000 description 1
- KXEKBWONZHCGOC-UHFFFAOYSA-N CC(=O)N1C(=O)N(CC2=CC=NC(Cl)=C2)CC12CCC(C1=CC=CC=C1)(N(C)C)CC2.CC(=O)N1C(=O)NCC12CCC(C1=CC=CC=C1)(N(C)C)CC2.CN(C)C1(C2=CC=CC=C2)CCC2(CC1)CN(CC1=CC=NC(Cl)=C1)C(=O)N2 Chemical compound CC(=O)N1C(=O)N(CC2=CC=NC(Cl)=C2)CC12CCC(C1=CC=CC=C1)(N(C)C)CC2.CC(=O)N1C(=O)NCC12CCC(C1=CC=CC=C1)(N(C)C)CC2.CN(C)C1(C2=CC=CC=C2)CCC2(CC1)CN(CC1=CC=NC(Cl)=C1)C(=O)N2 KXEKBWONZHCGOC-UHFFFAOYSA-N 0.000 description 1
- KSFOCGWRNWGDNZ-ROYMVJMXSA-N CC(=O)N1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(C(C)=O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound CC(=O)N1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(C(C)=O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 KSFOCGWRNWGDNZ-ROYMVJMXSA-N 0.000 description 1
- NFXOCAOYHFJZRF-DMRIWGJVSA-N CC(=O)NC1(C#N)CCC(C2=CC=CC=C2)(N(C)C)CC1.CCN1C(=O)NC[C@]12CC[C@@](C1=CC=CC=C1)(N(C)C)CC2.CCN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CCNC1(CN)CCC(C2=CC=CC=C2)(N(C)C)CC1.CN(C)C1(C2=CC=CC=C2)CCC(=O)CC1.CN(C)C1(C2=CC=CC=C2)CCC(N)(C#N)CC1 Chemical compound CC(=O)NC1(C#N)CCC(C2=CC=CC=C2)(N(C)C)CC1.CCN1C(=O)NC[C@]12CC[C@@](C1=CC=CC=C1)(N(C)C)CC2.CCN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CCNC1(CN)CCC(C2=CC=CC=C2)(N(C)C)CC1.CN(C)C1(C2=CC=CC=C2)CCC(=O)CC1.CN(C)C1(C2=CC=CC=C2)CCC(N)(C#N)CC1 NFXOCAOYHFJZRF-DMRIWGJVSA-N 0.000 description 1
- ZIRLFWOGCGMSSF-UHFFFAOYSA-N CC(C)C(C)CC1=CSC=C1.CC(C)C1=C(N2CCCCC2)N=CC=C1.CC(C)C1=C(N2CCN(C)CC2)N=CC=C1.CC(C)C1=C(N2CCNCC2)N=CC=C1.CC(C)C1=C(N2CCOCC2)N=CC=C1.CC(C)C1=CC(Br)=CC=C1.CC(C)C1=CN(CC(N)=O)N=N1.CC(C)C1=CN(CCO)N=N1.CC(C)CC1=CC=NC=C1.CC(C)CC1=CN=CC=C1.CC(C)CC1=CN=CN=C1.CC(C)CC1=NC=CC=N1.CC(C)CN1C=CN=C1.CSC1=CC=CC(C(C)C)=C1 Chemical compound CC(C)C(C)CC1=CSC=C1.CC(C)C1=C(N2CCCCC2)N=CC=C1.CC(C)C1=C(N2CCN(C)CC2)N=CC=C1.CC(C)C1=C(N2CCNCC2)N=CC=C1.CC(C)C1=C(N2CCOCC2)N=CC=C1.CC(C)C1=CC(Br)=CC=C1.CC(C)C1=CN(CC(N)=O)N=N1.CC(C)C1=CN(CCO)N=N1.CC(C)CC1=CC=NC=C1.CC(C)CC1=CN=CC=C1.CC(C)CC1=CN=CN=C1.CC(C)CC1=NC=CC=N1.CC(C)CN1C=CN=C1.CSC1=CC=CC(C(C)C)=C1 ZIRLFWOGCGMSSF-UHFFFAOYSA-N 0.000 description 1
- ZNUWDVRQQOHYRX-UHFFFAOYSA-N CC(C)C(C)CC1=CSC=C1.CC(C)C1=C(N2CCOCC2)N=CC=C1 Chemical compound CC(C)C(C)CC1=CSC=C1.CC(C)C1=C(N2CCOCC2)N=CC=C1 ZNUWDVRQQOHYRX-UHFFFAOYSA-N 0.000 description 1
- FTSIOGYPKOJRNC-UHFFFAOYSA-N CC(C)C1=C(N2CCCCC2)N=CC=C1.CC(C)C1=C(N2CCN(C)CC2)N=CC=C1.CC(C)C1=C(N2CCNCC2)N=CC=C1.CC(C)C1=C2\OCO\C2=C\C=C\1.CC(C)C1=CC(N2CCCCC2)=NC=C1.CC(C)C1=CC(N2CCCCC2)=NC=C1.CC(C)C1=CC(N2CCN(C)CC2)=NC=C1.CC(C)C1=CC(N2CCNCC2)=NC=C1.CC(C)C1=CC(N2CCOCC2)=NC=C1.CC(C)C1=CC=NC=C1.CC(C)C1=CN(CC(N)=O)N=N1.CC(C)C1=CN(CCO)N=N1.CC(C)C1=CN=CC=C1.CC(C)C1=CNN=N1.CC(C)C1=NC=CC=C1.CC(C)C1=NC=CC=N1.CC(C)CC1=CC(Br)=CC=C1.CC(C)CC1=CC=NC=C1.CC(C)CC1=CN=CC=C1.CC(C)CC1=CN=CN=C1.CC(C)CC1=NC=CC=N1.CC(C)CN1C=CN=C1.CC1=NC=C(C(C)C)C=C1.CSC1=CC=CC(CC(C)C)=C1 Chemical compound CC(C)C1=C(N2CCCCC2)N=CC=C1.CC(C)C1=C(N2CCN(C)CC2)N=CC=C1.CC(C)C1=C(N2CCNCC2)N=CC=C1.CC(C)C1=C2\OCO\C2=C\C=C\1.CC(C)C1=CC(N2CCCCC2)=NC=C1.CC(C)C1=CC(N2CCCCC2)=NC=C1.CC(C)C1=CC(N2CCN(C)CC2)=NC=C1.CC(C)C1=CC(N2CCNCC2)=NC=C1.CC(C)C1=CC(N2CCOCC2)=NC=C1.CC(C)C1=CC=NC=C1.CC(C)C1=CN(CC(N)=O)N=N1.CC(C)C1=CN(CCO)N=N1.CC(C)C1=CN=CC=C1.CC(C)C1=CNN=N1.CC(C)C1=NC=CC=C1.CC(C)C1=NC=CC=N1.CC(C)CC1=CC(Br)=CC=C1.CC(C)CC1=CC=NC=C1.CC(C)CC1=CN=CC=C1.CC(C)CC1=CN=CN=C1.CC(C)CC1=NC=CC=N1.CC(C)CN1C=CN=C1.CC1=NC=C(C(C)C)C=C1.CSC1=CC=CC(CC(C)C)=C1 FTSIOGYPKOJRNC-UHFFFAOYSA-N 0.000 description 1
- HTHSEUMQBNGQNH-UHFFFAOYSA-N CC(C)C1=C2\OCO\C2=C\C=C\1.CC(C)C1=CC(N2CCCCC2)=NC=C1.CC(C)C1=CC(N2CCCCC2)=NC=C1.CC(C)C1=CC(N2CCN(C)CC2)=NC=C1.CC(C)C1=CC(N2CCNCC2)=NC=C1.CC(C)C1=CC(N2CCOCC2)=NC=C1.CC(C)C1=CC(S(C)(=O)=O)=CC=C1.CC(C)C1=CC=NC=C1.CC(C)C1=CN=CC=C1.CC(C)C1=CNN=N1.CC(C)C1=NC=CC=C1.CC(C)C1=NC=CC=N1.CC(C)C1=NC=CN=C1.CC1=NC=C(C(C)C)C=C1.CCC1=CC=C(C(C)C)C=C1.COCCOC1=CC=CC(C(C)C)=C1 Chemical compound CC(C)C1=C2\OCO\C2=C\C=C\1.CC(C)C1=CC(N2CCCCC2)=NC=C1.CC(C)C1=CC(N2CCCCC2)=NC=C1.CC(C)C1=CC(N2CCN(C)CC2)=NC=C1.CC(C)C1=CC(N2CCNCC2)=NC=C1.CC(C)C1=CC(N2CCOCC2)=NC=C1.CC(C)C1=CC(S(C)(=O)=O)=CC=C1.CC(C)C1=CC=NC=C1.CC(C)C1=CN=CC=C1.CC(C)C1=CNN=N1.CC(C)C1=NC=CC=C1.CC(C)C1=NC=CC=N1.CC(C)C1=NC=CN=C1.CC1=NC=C(C(C)C)C=C1.CCC1=CC=C(C(C)C)C=C1.COCCOC1=CC=CC(C(C)C)=C1 HTHSEUMQBNGQNH-UHFFFAOYSA-N 0.000 description 1
- FWKAENLBGIBANM-UHFFFAOYSA-N CC(C)C1=CC(C2CC2)=CC=C1.CC(C)C1=CC(S(C)(=O)=O)=CC=C1.CC(C)C1=CC=C(C(N)=O)C=C1.CC(C)C1=CC=C(O)C=C1.CC(C)C1=CC=C2OCOC2=C1.CC(C)C1=CC=CC(C(N)=O)=C1.CC(C)C1=CC=CC=C1.CC(C)C1=CC=CC=C1Br.CC(C)C1=CC=CC=C1C#N.CC(C)C1=CC=CC=C1C(N)=O.CC(C)C1=NC=CN=C1.CCC1=CC=C(C(C)C)C=C1.COC(=O)C1=CC=C(C(C)C)C=C1.COC1=CC=C(C(C)C)C=C1.COC1=CC=CC(C(C)C)=C1.COC1=CC=CC=C1C(C)C.COCCOC1=CC=C(C(C)C)C=C1.COCCOC1=CC=CC(C(C)C)=C1.[C-]#[N+]C1=CC=C(C(C)C)C=C1.[C-]#[N+]C1=CC=C(OC)C(C(C)C)=C1.[C-]#[N+]C1=CC=CC(C(C)C)=C1 Chemical compound CC(C)C1=CC(C2CC2)=CC=C1.CC(C)C1=CC(S(C)(=O)=O)=CC=C1.CC(C)C1=CC=C(C(N)=O)C=C1.CC(C)C1=CC=C(O)C=C1.CC(C)C1=CC=C2OCOC2=C1.CC(C)C1=CC=CC(C(N)=O)=C1.CC(C)C1=CC=CC=C1.CC(C)C1=CC=CC=C1Br.CC(C)C1=CC=CC=C1C#N.CC(C)C1=CC=CC=C1C(N)=O.CC(C)C1=NC=CN=C1.CCC1=CC=C(C(C)C)C=C1.COC(=O)C1=CC=C(C(C)C)C=C1.COC1=CC=C(C(C)C)C=C1.COC1=CC=CC(C(C)C)=C1.COC1=CC=CC=C1C(C)C.COCCOC1=CC=C(C(C)C)C=C1.COCCOC1=CC=CC(C(C)C)=C1.[C-]#[N+]C1=CC=C(C(C)C)C=C1.[C-]#[N+]C1=CC=C(OC)C(C(C)C)=C1.[C-]#[N+]C1=CC=CC(C(C)C)=C1 FWKAENLBGIBANM-UHFFFAOYSA-N 0.000 description 1
- NZFYGBRMWCGUGP-UHFFFAOYSA-N CC(C)C1=CC(C2CC2)=CC=C1.CC(C)C1=CC=C(C(N)=O)C=C1.CC(C)C1=CC=C(O)C=C1.CC(C)C1=CC=C2OCOC2=C1.CC(C)C1=CC=CC(C(N)=O)=C1.CC(C)C1=CC=CC=C1.CC(C)C1=CC=CC=C1Br.CC(C)C1=CC=CC=C1C#N.CC(C)C1=CC=CC=C1C(N)=O.COC(=O)C1=CC=C(C(C)C)C=C1.COC1=CC=C(C(C)C)C=C1.COC1=CC=CC(C(C)C)=C1.COC1=CC=CC=C1C(C)C.COCCOC1=CC=C(C(C)C)C=C1.[C-]#[N+]C1=CC=C(C(C)C)C=C1.[C-]#[N+]C1=CC=C(OC)C(C(C)C)=C1.[C-]#[N+]C1=CC=CC(C(C)C)=C1 Chemical compound CC(C)C1=CC(C2CC2)=CC=C1.CC(C)C1=CC=C(C(N)=O)C=C1.CC(C)C1=CC=C(O)C=C1.CC(C)C1=CC=C2OCOC2=C1.CC(C)C1=CC=CC(C(N)=O)=C1.CC(C)C1=CC=CC=C1.CC(C)C1=CC=CC=C1Br.CC(C)C1=CC=CC=C1C#N.CC(C)C1=CC=CC=C1C(N)=O.COC(=O)C1=CC=C(C(C)C)C=C1.COC1=CC=C(C(C)C)C=C1.COC1=CC=CC(C(C)C)=C1.COC1=CC=CC=C1C(C)C.COCCOC1=CC=C(C(C)C)C=C1.[C-]#[N+]C1=CC=C(C(C)C)C=C1.[C-]#[N+]C1=CC=C(OC)C(C(C)C)=C1.[C-]#[N+]C1=CC=CC(C(C)C)=C1 NZFYGBRMWCGUGP-UHFFFAOYSA-N 0.000 description 1
- DJBAFQQHRFSGLU-BXFJNQSESA-N CC(C)CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1CCC1.COC1=CC=C(CN2CC3(CCC(=O)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2CC3(CCC(C#N)(N(C)CC(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2CC3(CCC4(CC3)OCCO4)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2CC3(CCC4(CC3)OCCO4)NC2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)CC(C)C)CC3)N(CC3CCC3)C2=O)C=C1 Chemical compound CC(C)CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1CCC1.COC1=CC=C(CN2CC3(CCC(=O)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2CC3(CCC(C#N)(N(C)CC(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2CC3(CCC4(CC3)OCCO4)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2CC3(CCC4(CC3)OCCO4)NC2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)CC(C)C)CC3)N(CC3CCC3)C2=O)C=C1 DJBAFQQHRFSGLU-BXFJNQSESA-N 0.000 description 1
- IFWPOYXGSFWZQQ-NNTVRFIESA-N CC(C)CN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound CC(C)CN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 IFWPOYXGSFWZQQ-NNTVRFIESA-N 0.000 description 1
- OJBHSHNATAIJJT-UHFFFAOYSA-N CC(N(C(CN1)(CC2)CCC2(c2ccccc2)N(C)C)C1=O)=O Chemical compound CC(N(C(CN1)(CC2)CCC2(c2ccccc2)N(C)C)C1=O)=O OJBHSHNATAIJJT-UHFFFAOYSA-N 0.000 description 1
- OVCZKUBGGGMGRB-UHFFFAOYSA-N CC(N(C(CN1Cc2cc(Cl)ncc2)(CC2)CCC2(c2ccccc2)N(C)C)C1=O)=O Chemical compound CC(N(C(CN1Cc2cc(Cl)ncc2)(CC2)CCC2(c2ccccc2)N(C)C)C1=O)=O OVCZKUBGGGMGRB-UHFFFAOYSA-N 0.000 description 1
- UKPBJXHAQIRHIP-CALCHBBNSA-N CC1=CC(F)=CC([C@]2(N(C)C)CC[C@@]3(CC2)CNC(=O)N3)=C1 Chemical compound CC1=CC(F)=CC([C@]2(N(C)C)CC[C@@]3(CC2)CNC(=O)N3)=C1 UKPBJXHAQIRHIP-CALCHBBNSA-N 0.000 description 1
- STCDCANXGQREKB-OKZTUQRJSA-N CC1=CC([C@]2(N(C)C)CC[C@@]3(CC2)CNC(=O)N3)=CC=C1.CN(C)C1(C#N)CCC2(CC1)CNC(=O)N2 Chemical compound CC1=CC([C@]2(N(C)C)CC[C@@]3(CC2)CNC(=O)N3)=CC=C1.CN(C)C1(C#N)CCC2(CC1)CNC(=O)N2 STCDCANXGQREKB-OKZTUQRJSA-N 0.000 description 1
- YPKYWFDEWBDBAU-UHFFFAOYSA-N CC1=CC=C(C2(N(C)C)CCC(=O)CC2)S1 Chemical compound CC1=CC=C(C2(N(C)C)CCC(=O)CC2)S1 YPKYWFDEWBDBAU-UHFFFAOYSA-N 0.000 description 1
- LJOYDKOPDZOISV-NIQXJIHUSA-N CC1=CC=C(S(=O)(=O)N2C(=O)NC[C@]23CC[C@](C2=CC=CC=C2)(N(C)C)CC3)C=C1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=NC=C1)C(=O)N2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(S(=O)(=O)C3=CC=C(C)C=C3)C2=O)C=C1 Chemical compound CC1=CC=C(S(=O)(=O)N2C(=O)NC[C@]23CC[C@](C2=CC=CC=C2)(N(C)C)CC3)C=C1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=NC=C1)C(=O)N2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(S(=O)(=O)C3=CC=C(C)C=C3)C2=O)C=C1 LJOYDKOPDZOISV-NIQXJIHUSA-N 0.000 description 1
- IEGCBYNTJSCOHW-IJNUANGGSA-N CC1=CC=C(S(=O)(=O)N2C(=O)NC[C@]23CC[C@](C2=CC=CC=C2)(N(C)C)CC3)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(S(=O)(=O)C3=CC=C(C)C=C3)C2=O)C=C1 Chemical compound CC1=CC=C(S(=O)(=O)N2C(=O)NC[C@]23CC[C@](C2=CC=CC=C2)(N(C)C)CC3)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(S(=O)(=O)C3=CC=C(C)C=C3)C2=O)C=C1 IEGCBYNTJSCOHW-IJNUANGGSA-N 0.000 description 1
- QHXPRPHTYUYGFZ-VCGPDEQWSA-N CCC(=O)CN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CCCNC(=O)CN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CCN1C(=O)N(CC2=CC=CC=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3=CC=CC=C3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCS(C)=O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(C[C@@H](C)O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(C[C@H](C)O)C2=O)C=C1.COCCCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 Chemical compound CCC(=O)CN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CCCNC(=O)CN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CCN1C(=O)N(CC2=CC=CC=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3=CC=CC=C3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCS(C)=O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(C[C@@H](C)O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(C[C@H](C)O)C2=O)C=C1.COCCCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 QHXPRPHTYUYGFZ-VCGPDEQWSA-N 0.000 description 1
- LDPDINZBWJEWOF-SKLBTBCUSA-N CCCCC(=O)CN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)O)C2=O)C=C1.O=C(O)C(F)(F)F Chemical compound CCCCC(=O)CN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)O)C2=O)C=C1.O=C(O)C(F)(F)F LDPDINZBWJEWOF-SKLBTBCUSA-N 0.000 description 1
- BPACIMCKJYLOBH-YLNRVVQCSA-N CCCCCCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=CC=CC=C1)C(=O)N2CC1(O)CCC1.COC1=CC=C(CN2C[C@]3(CC[C@@](N)(C4=CC=CC=C4)CC3)N(CC3(O)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC#N)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(O)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCOC3)C2=O)C=C1.COCCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 Chemical compound CCCCCCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=CC=CC=C1)C(=O)N2CC1(O)CCC1.COC1=CC=C(CN2C[C@]3(CC[C@@](N)(C4=CC=CC=C4)CC3)N(CC3(O)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC#N)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(O)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCOC3)C2=O)C=C1.COCCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 BPACIMCKJYLOBH-YLNRVVQCSA-N 0.000 description 1
- JHZUWDSSIMWLCI-YQWOERLASA-N CCCCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(C#N)=CC=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=C(F)C=C4)(N(C)C)CC3)NC2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=C(OC)C=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC3CCCCC3)C2=O)C=C1 Chemical compound CCCCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(C#N)=CC=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=C(F)C=C4)(N(C)C)CC3)NC2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=C(OC)C=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC3CCCCC3)C2=O)C=C1 JHZUWDSSIMWLCI-YQWOERLASA-N 0.000 description 1
- FKWRBUUCQWQVMY-LHUAYVSOSA-N CCCN(C)C(=O)CN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(Br)=CC=C1)C(=O)N2CC1CCC1.COC(=O)CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)CC3(C#N)CC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)N(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC=C(C)C)C2=O)C=C1.COCCC[C@]1(N(C)C)CC[C@@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.CSC1=CC=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)=C1 Chemical compound CCCN(C)C(=O)CN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(Br)=CC=C1)C(=O)N2CC1CCC1.COC(=O)CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)CC3(C#N)CC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)N(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC=C(C)C)C2=O)C=C1.COCCC[C@]1(N(C)C)CC[C@@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.CSC1=CC=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)=C1 FKWRBUUCQWQVMY-LHUAYVSOSA-N 0.000 description 1
- XDOGMOPWFZHGNF-PGJGVDHKSA-N CCCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(OC)=CC=C1)C(=O)N2CC1CCC1.CCCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(C#N)=CC=C1)C(=O)N2CC1CCC1.CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(OC)=CC=C1)C(=O)N2CC1CCC1.CCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC#N)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound CCCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(OC)=CC=C1)C(=O)N2CC1CCC1.CCCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(C#N)=CC=C1)C(=O)N2CC1CCC1.CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(OC)=CC=C1)C(=O)N2CC1CCC1.CCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC#N)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 XDOGMOPWFZHGNF-PGJGVDHKSA-N 0.000 description 1
- RQHFJAUUKXHHEN-ZILJFZKASA-N CCCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(OC)=CC=C1)C(=O)N2CC1CCC1.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(OC)=CC=C1)C(=O)N2CC1CCC1 Chemical compound CCCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(OC)=CC=C1)C(=O)N2CC1CCC1.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(OC)=CC=C1)C(=O)N2CC1CCC1 RQHFJAUUKXHHEN-ZILJFZKASA-N 0.000 description 1
- GHFWSINEVIVLSZ-ZRZAMGCNSA-N CCCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1CCC1 Chemical compound CCCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1CCC1 GHFWSINEVIVLSZ-ZRZAMGCNSA-N 0.000 description 1
- QDTIPJNVPRDSPB-KDURUIRLSA-N CCCN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 Chemical compound CCCN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 QDTIPJNVPRDSPB-KDURUIRLSA-N 0.000 description 1
- GASBMGHKRCNCJD-UTACTUGESA-N CCCNC(=O)CCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C(Br)C=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(C(N)=O)C=C1)C(=O)N2CC1CCC1.CNC(=O)CCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC(F)=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=C(F)C=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC(OC)=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(F)CCC3)C2=O)C=C1 Chemical compound CCCNC(=O)CCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C(Br)C=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(C(N)=O)C=C1)C(=O)N2CC1CCC1.CNC(=O)CCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC(F)=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=C(F)C=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC(OC)=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(F)CCC3)C2=O)C=C1 GASBMGHKRCNCJD-UTACTUGESA-N 0.000 description 1
- HDTPZWYGAVLHRK-CALCHBBNSA-N CCC[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)CNC(=O)N2 Chemical compound CCC[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)CNC(=O)N2 HDTPZWYGAVLHRK-CALCHBBNSA-N 0.000 description 1
- FCLNXUSXKVWEGG-XUGKJROYSA-N CCC[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)NC2=O.CCC[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)NC2=O.CCC[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2.CCC[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)NC(=O)NC2=O.CCN=C1CCC2(CC1)OCCO2.CCNC1(C2=CC=CC=C2)CCC(=O)CC1.CCNC1(C2=CC=CC=C2)CCC2(CC1)OCCO2.Cl.O=C1CCC2(CC1)OCCO2 Chemical compound CCC[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)NC2=O.CCC[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)NC2=O.CCC[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2.CCC[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)NC(=O)NC2=O.CCN=C1CCC2(CC1)OCCO2.CCNC1(C2=CC=CC=C2)CCC(=O)CC1.CCNC1(C2=CC=CC=C2)CCC2(CC1)OCCO2.Cl.O=C1CCC2(CC1)OCCO2 FCLNXUSXKVWEGG-XUGKJROYSA-N 0.000 description 1
- RJEQPUXGNQSAOC-UHFFFAOYSA-N CCN(C)C1(C2=CC=CC=C2)CCC(=O)CC1 Chemical compound CCN(C)C1(C2=CC=CC=C2)CCC(=O)CC1 RJEQPUXGNQSAOC-UHFFFAOYSA-N 0.000 description 1
- BJMFQOOQKBCZDK-DIVCQZSQSA-N CCN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)CC(=O)N(CC1=CC(C#N)=CC=C1)C2 Chemical compound CCN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)CC(=O)N(CC1=CC(C#N)=CC=C1)C2 BJMFQOOQKBCZDK-DIVCQZSQSA-N 0.000 description 1
- NUWRJELLXFNSMZ-NHMSXRHVSA-N CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C(C#N)C=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(S(C)(=O)=O)=CC=C1)C(=O)N2CC1CCC1.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(OC)=CC=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)(C)O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)(C)OC)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(OC)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCCC3)C2=O)C=C1 Chemical compound CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C(C#N)C=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(S(C)(=O)=O)=CC=C1)C(=O)N2CC1CCC1.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(OC)=CC=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)(C)O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)(C)OC)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(OC)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCCC3)C2=O)C=C1 NUWRJELLXFNSMZ-NHMSXRHVSA-N 0.000 description 1
- DVNBSRBHPMPLGU-OYYNBGRBSA-N CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1CCC1.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2CC1CCC1 Chemical compound CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1CCC1.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2CC1CCC1 DVNBSRBHPMPLGU-OYYNBGRBSA-N 0.000 description 1
- VPHWOYGDOIEGDY-KWCMQKQKSA-N CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=N1)C(=O)N2CC1CCC1.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN=CC=C1)C(=O)N2CC1CCC1.COC(=O)C1=CC=CC=C1CN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)(C)C#N)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3=CC=NC=N3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3COC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCO)C2=O)C=C1 Chemical compound CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=N1)C(=O)N2CC1CCC1.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN=CC=C1)C(=O)N2CC1CCC1.COC(=O)C1=CC=CC=C1CN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)(C)C#N)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3=CC=NC=N3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3COC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCO)C2=O)C=C1 VPHWOYGDOIEGDY-KWCMQKQKSA-N 0.000 description 1
- WPOZHHVGJUCWFL-IYARVYRRSA-N CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)C2 Chemical compound CCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)C2 WPOZHHVGJUCWFL-IYARVYRRSA-N 0.000 description 1
- HUPOWBPHQXBURL-HZYKXWROSA-N CCN1C(=O)N(CC2=CC=C(S(C)(=O)=O)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(C(C)(C)C1=CC=CC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(C(C)(C)C1=CC=CC=C1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(C1(C3=CC=CC=C3)CC1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C3OCOC3=CC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(C3CC3)=CC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(S(C)(=O)=O)=CC=C1)C(=O)N2.COC1=CC=CC=C1CN1C(=O)N(CC2=C(OC)C=CC=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 Chemical compound CCN1C(=O)N(CC2=CC=C(S(C)(=O)=O)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(C(C)(C)C1=CC=CC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(C(C)(C)C1=CC=CC=C1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(C1(C3=CC=CC=C3)CC1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C3OCOC3=CC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(C3CC3)=CC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(S(C)(=O)=O)=CC=C1)C(=O)N2.COC1=CC=CC=C1CN1C(=O)N(CC2=C(OC)C=CC=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 HUPOWBPHQXBURL-HZYKXWROSA-N 0.000 description 1
- UTCNYLFMSOUPOT-FGRRURHHSA-N CCN1C(=O)N(CC2=CC=CN=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(O)CCC3)C2=O)C=C(C#N)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)NCC#N)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3=CC=CN=C3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCCCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCOCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC3(OC)CCC3)C2=O)C=C1 Chemical compound CCN1C(=O)N(CC2=CC=CN=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(O)CCC3)C2=O)C=C(C#N)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)NCC#N)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3=CC=CN=C3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCCCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCOCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC3(OC)CCC3)C2=O)C=C1 UTCNYLFMSOUPOT-FGRRURHHSA-N 0.000 description 1
- KTUJDHIVGYUTGQ-UHFFFAOYSA-N CCOC(=O)C1CC(C#N)(C2=NC=CC=C2)CCC1=O.N#CC1(C2=NC=CC=C2)CCC(=O)CC1.N#CCC1=NC=CC=C1 Chemical compound CCOC(=O)C1CC(C#N)(C2=NC=CC=C2)CCC1=O.N#CC1(C2=NC=CC=C2)CCC(=O)CC1.N#CCC1=NC=CC=C1 KTUJDHIVGYUTGQ-UHFFFAOYSA-N 0.000 description 1
- HFMQPHYKNIISTI-HNRBIFIRSA-N CCOC(=O)CN1C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)N=N1 Chemical compound CCOC(=O)CN1C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)N=N1 HFMQPHYKNIISTI-HNRBIFIRSA-N 0.000 description 1
- BBNCHAWUKDMINI-IMFSSFSCSA-N CCOC(=O)CN1C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)N=N1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CC(N)=O)N=N1)C(=O)N2 Chemical compound CCOC(=O)CN1C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)N=N1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CC(N)=O)N=N1)C(=O)N2 BBNCHAWUKDMINI-IMFSSFSCSA-N 0.000 description 1
- FOXOURPZPKZSPS-IMFSSFSCSA-N CCOC(=O)CN1C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)N=N1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CCO)N=N1)C(=O)N2 Chemical compound CCOC(=O)CN1C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)N=N1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CCO)N=N1)C(=O)N2 FOXOURPZPKZSPS-IMFSSFSCSA-N 0.000 description 1
- WLSDKXAVRWLHEM-STDKVVRYSA-N CCOC(=O)CN1C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)N=N1.COC(=O)CN1C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(O)CCC3)C2=O)N=N1 Chemical compound CCOC(=O)CN1C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)N=N1.COC(=O)CN1C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(O)CCC3)C2=O)N=N1 WLSDKXAVRWLHEM-STDKVVRYSA-N 0.000 description 1
- SXWUIDOQKQNILZ-ZRZAMGCNSA-N CCOC(C[n]1nnc(CN(C[C@](CC2)(CC[C@]2(c2ccccc2)N(C)C)N2)C2=O)c1)=O Chemical compound CCOC(C[n]1nnc(CN(C[C@](CC2)(CC[C@]2(c2ccccc2)N(C)C)N2)C2=O)c1)=O SXWUIDOQKQNILZ-ZRZAMGCNSA-N 0.000 description 1
- ILYIPDKAQYOSRJ-VRIXPXKTSA-N CC[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CC(N)=O)N=N1)C(=O)N2CC1CCC1.CC[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CCO)N=N1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=CC=NC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=CN=CC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=CN=CN=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=NC=CC=N1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCN1C=CN=C1)C(=O)N2.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CC(N)=O)N=N1)C(=O)N2CC1(O)CCC1 Chemical compound CC[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CC(N)=O)N=N1)C(=O)N2CC1CCC1.CC[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CCO)N=N1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=CC=NC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=CN=CC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=CN=CN=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=NC=CC=N1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCN1C=CN=C1)C(=O)N2.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CC(N)=O)N=N1)C(=O)N2CC1(O)CCC1 ILYIPDKAQYOSRJ-VRIXPXKTSA-N 0.000 description 1
- DATFYVRZBBZSOV-WEPYUEKNSA-N CN(C)C(=O)CN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC(=O)O.O=C(O)C(F)(F)F Chemical compound CN(C)C(=O)CN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC(=O)O.O=C(O)C(F)(F)F DATFYVRZBBZSOV-WEPYUEKNSA-N 0.000 description 1
- IEVQOYQXKCFWOT-UHFFFAOYSA-N CN(C)C(CC1)(CCC1(CN1Cc2cc(Cl)ncc2)NC1=O)c1ccccc1 Chemical compound CN(C)C(CC1)(CCC1(CN1Cc2cc(Cl)ncc2)NC1=O)c1ccccc1 IEVQOYQXKCFWOT-UHFFFAOYSA-N 0.000 description 1
- OGSDLIAKYFZEGW-UHFFFAOYSA-N CN(C)C1(C#N)CCC2(CC1)CNC(=O)N2.O=C1CCC2(CC1)CNC(=O)N2.O=C1NC(=O)C2(CCC3(CC2)OCCO3)N1.O=C1NCC2(CCC3(CC2)OCCO3)N1 Chemical compound CN(C)C1(C#N)CCC2(CC1)CNC(=O)N2.O=C1CCC2(CC1)CNC(=O)N2.O=C1NC(=O)C2(CCC3(CC2)OCCO3)N1.O=C1NCC2(CCC3(CC2)OCCO3)N1 OGSDLIAKYFZEGW-UHFFFAOYSA-N 0.000 description 1
- BVQCYMYEGQJUCE-UHFFFAOYSA-N CN(C)C1(C#N)CCC2(CC1)OCCO2.CN(C)C1(C2=CC=CC=C2)CCC(=O)CC1.CN(C)C1(C2=CC=CC=C2)CCC2(CC1)OCCO2.O=C1CCC2(CC1)OCCO2 Chemical compound CN(C)C1(C#N)CCC2(CC1)OCCO2.CN(C)C1(C2=CC=CC=C2)CCC(=O)CC1.CN(C)C1(C2=CC=CC=C2)CCC2(CC1)OCCO2.O=C1CCC2(CC1)OCCO2 BVQCYMYEGQJUCE-UHFFFAOYSA-N 0.000 description 1
- FCNMFIASRXITOQ-YCOHQTMZSA-N CN(C)C1(C2=CC=CC=C2)CCC(=O)CC1.CN(C)C1(C2=CC=CC=C2)CCC2(CC1)CNC(=O)N2.CN(C)C1(C2=CC=CC=C2)CCC2(CC1)NC(=O)NC2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2 Chemical compound CN(C)C1(C2=CC=CC=C2)CCC(=O)CC1.CN(C)C1(C2=CC=CC=C2)CCC2(CC1)CNC(=O)N2.CN(C)C1(C2=CC=CC=C2)CCC2(CC1)NC(=O)NC2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2 FCNMFIASRXITOQ-YCOHQTMZSA-N 0.000 description 1
- JEROXGFNMKTBEG-KACWVIIFSA-N CN(C)C1(C2=CC=CC=C2)CCC(=O)CC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)CNC(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)NC(=O)NC2=O Chemical compound CN(C)C1(C2=CC=CC=C2)CCC(=O)CC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)CNC(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)NC(=O)NC2=O JEROXGFNMKTBEG-KACWVIIFSA-N 0.000 description 1
- UAECQTQNBBOYPI-RZZCVUFKSA-N CN(C)C1(C2=CC=CC=C2)CCC2(CC1)CN(CC1=CN(CC(N)=O)N=N1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)N(CCC1=NC=CC=C1)C2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=NC=CC=C1)C(=O)N2.CNC1(C2=CC=CC=C2)CCC2(CC1)CN(CC1=CNN=N1)C(=O)N2.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CC(N)=O)N=N1)C(=O)N2.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CCO)N=N1)C(=O)N2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(C(=O)OCC3=CC=CC=C3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(S(=O)(=O)C3=CC=C(C)C=C3)C2=O)C=C1 Chemical compound CN(C)C1(C2=CC=CC=C2)CCC2(CC1)CN(CC1=CN(CC(N)=O)N=N1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)N(CCC1=NC=CC=C1)C2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=NC=CC=C1)C(=O)N2.CNC1(C2=CC=CC=C2)CCC2(CC1)CN(CC1=CNN=N1)C(=O)N2.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CC(N)=O)N=N1)C(=O)N2.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CCO)N=N1)C(=O)N2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(C(=O)OCC3=CC=CC=C3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(S(=O)(=O)C3=CC=C(C)C=C3)C2=O)C=C1 UAECQTQNBBOYPI-RZZCVUFKSA-N 0.000 description 1
- UJZVUTQSDWBVKO-GMEQQEMVSA-N CN(C)C1(C2=CC=CC=C2)CCC2(CC1)CN(CC1=CN(CCO)N=N1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C(C#N)C=CC=C1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(C#N)=CC=C1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CNN=N1)C(=O)N2.COC1=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C(C#N)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=C(OC)C=C4)(N(C)C)CC3)NC2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC(OC)=C4)(N(C)C)CC3)NC2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCCO)C2=O)C=C1 Chemical compound CN(C)C1(C2=CC=CC=C2)CCC2(CC1)CN(CC1=CN(CCO)N=N1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C(C#N)C=CC=C1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(C#N)=CC=C1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CNN=N1)C(=O)N2.COC1=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C(C#N)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=C(OC)C=C4)(N(C)C)CC3)NC2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC(OC)=C4)(N(C)C)CC3)NC2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCCO)C2=O)C=C1 UJZVUTQSDWBVKO-GMEQQEMVSA-N 0.000 description 1
- MAUJZHMACUBWNC-ZXRPYLEOSA-N CN(C)C1(C2=CC=CC=C2)CCC2(CC1)NC(=O)NC2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)N(CCC1=CC=CC=C1)C2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)NC2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=CC=CC=C1)C(=O)N2 Chemical compound CN(C)C1(C2=CC=CC=C2)CCC2(CC1)NC(=O)NC2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)N(CCC1=CC=CC=C1)C2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)NC2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=CC=CC=C1)C(=O)N2 MAUJZHMACUBWNC-ZXRPYLEOSA-N 0.000 description 1
- MWFVWRDGDVLNIJ-UHFFFAOYSA-N CN(C)C1(C2=CC=CS2)CCC(=O)CC1 Chemical compound CN(C)C1(C2=CC=CS2)CCC(=O)CC1 MWFVWRDGDVLNIJ-UHFFFAOYSA-N 0.000 description 1
- NRXBCVRFSOXKBZ-UHFFFAOYSA-N CN(C)C1(C2=NC=CC=C2)CCC(=O)CC1.COC(=O)NC1(C2=NC=CC=C2)CCC2(CC1)OCCO2.N#CC1(C2=NC=CC=C2)CCC(=O)CC1.N#CC1(C2=NC=CC=C2)CCC2(CC1)OCCO2.NC(=O)C1(C2=NC=CC=C2)CCC2(CC1)OCCO2.NC1(C2=NC=CC=C2)CCC2(CC1)OCCO2 Chemical compound CN(C)C1(C2=NC=CC=C2)CCC(=O)CC1.COC(=O)NC1(C2=NC=CC=C2)CCC2(CC1)OCCO2.N#CC1(C2=NC=CC=C2)CCC(=O)CC1.N#CC1(C2=NC=CC=C2)CCC2(CC1)OCCO2.NC(=O)C1(C2=NC=CC=C2)CCC2(CC1)OCCO2.NC1(C2=NC=CC=C2)CCC2(CC1)OCCO2 NRXBCVRFSOXKBZ-UHFFFAOYSA-N 0.000 description 1
- GOBRHSNCPYYXSB-UHFFFAOYSA-N CN(C)C1(C2=NC=CN=C2)CCC(=O)CC1 Chemical compound CN(C)C1(C2=NC=CN=C2)CCC(=O)CC1 GOBRHSNCPYYXSB-UHFFFAOYSA-N 0.000 description 1
- SOQQQHJQTOJEOW-UHFFFAOYSA-N CN(C)C1(CC2=CC=CC=C2)CCC(=O)CC1 Chemical compound CN(C)C1(CC2=CC=CC=C2)CCC(=O)CC1 SOQQQHJQTOJEOW-UHFFFAOYSA-N 0.000 description 1
- XJDRPLDPZDAROR-KDURUIRLSA-N CN(C)[C@](CC1)(CC[C@@]1(CN1CC#C)NC1=O)c1ccccc1 Chemical compound CN(C)[C@](CC1)(CC[C@@]1(CN1CC#C)NC1=O)c1ccccc1 XJDRPLDPZDAROR-KDURUIRLSA-N 0.000 description 1
- BHNBGYKHHFLUSJ-PSWAGMNNSA-N CN(C)[C@](CC1)(CC[C@@]1(CN1Cc(cc2)ccc2OC)NC1=O)c1ccccc1 Chemical compound CN(C)[C@](CC1)(CC[C@@]1(CN1Cc(cc2)ccc2OC)NC1=O)c1ccccc1 BHNBGYKHHFLUSJ-PSWAGMNNSA-N 0.000 description 1
- IHUFDVVXUQAUSC-OYRHEFFESA-N CN(C)[C@](CC1)(CC[C@@]1(CN1Cc2c[n](CCO)nn2)NC1=O)c1ccccc1 Chemical compound CN(C)[C@](CC1)(CC[C@@]1(CN1Cc2c[n](CCO)nn2)NC1=O)c1ccccc1 IHUFDVVXUQAUSC-OYRHEFFESA-N 0.000 description 1
- GMXJRLCDFKLCGY-ISILISOKSA-N CN(C)[C@](CC1)(CC[C@@]1(CN1Cc2cc(OC)ccc2)N(CC2CCC2)C1=O)c1ccccc1 Chemical compound CN(C)[C@](CC1)(CC[C@@]1(CN1Cc2cc(OC)ccc2)N(CC2CCC2)C1=O)c1ccccc1 GMXJRLCDFKLCGY-ISILISOKSA-N 0.000 description 1
- JJODJBUGAYAMHN-OKILXGFUSA-N CN(C)[C@]1(C2=CC=C(Cl)S2)CC[C@]2(CC1)CNC(=O)N2 Chemical compound CN(C)[C@]1(C2=CC=C(Cl)S2)CC[C@]2(CC1)CNC(=O)N2 JJODJBUGAYAMHN-OKILXGFUSA-N 0.000 description 1
- NODDPJDKVOQNJT-IYBDPMFKSA-N CN(C)[C@]1(C2=CC=C(F)C=C2)CC[C@]2(CC1)CNC(=O)N2 Chemical compound CN(C)[C@]1(C2=CC=C(F)C=C2)CC[C@]2(CC1)CNC(=O)N2 NODDPJDKVOQNJT-IYBDPMFKSA-N 0.000 description 1
- QKBKXSRRKYXSHF-IYBDPMFKSA-N CN(C)[C@]1(C2=CC=CC(C(F)(F)F)=C2)CC[C@]2(CC1)CNC(=O)N2 Chemical compound CN(C)[C@]1(C2=CC=CC(C(F)(F)F)=C2)CC[C@]2(CC1)CNC(=O)N2 QKBKXSRRKYXSHF-IYBDPMFKSA-N 0.000 description 1
- ZRBAFZXGNDDDBU-IYBDPMFKSA-N CN(C)[C@]1(C2=CC=CC(Cl)=C2)CC[C@]2(CC1)CNC(=O)N2 Chemical compound CN(C)[C@]1(C2=CC=CC(Cl)=C2)CC[C@]2(CC1)CNC(=O)N2 ZRBAFZXGNDDDBU-IYBDPMFKSA-N 0.000 description 1
- JRCJVXKVCDKQGZ-IYBDPMFKSA-N CN(C)[C@]1(C2=CC=CC(F)=C2)CC[C@]2(CC1)CNC(=O)N2 Chemical compound CN(C)[C@]1(C2=CC=CC(F)=C2)CC[C@]2(CC1)CNC(=O)N2 JRCJVXKVCDKQGZ-IYBDPMFKSA-N 0.000 description 1
- UIJPVGKIXCWNMB-TYKWCNGQSA-N CN(C)[C@]1(C2=CC=CC(F)=C2)CC[C@]2(CC1)CNC(=O)N2CC1(O)CCC1 Chemical compound CN(C)[C@]1(C2=CC=CC(F)=C2)CC[C@]2(CC1)CNC(=O)N2CC1(O)CCC1 UIJPVGKIXCWNMB-TYKWCNGQSA-N 0.000 description 1
- IDCFFWNUAWPGTH-BGYRXZFFSA-N CN(C)[C@]1(C2=CC=CC(F)=C2)CC[C@]2(CC1)CNC(=O)N2CC1CC1 Chemical compound CN(C)[C@]1(C2=CC=CC(F)=C2)CC[C@]2(CC1)CNC(=O)N2CC1CC1 IDCFFWNUAWPGTH-BGYRXZFFSA-N 0.000 description 1
- IEIWRCFYAQBAPT-ZSIWRTTDSA-N CN(C)[C@]1(C2=CC=CC(F)=C2)CC[C@]2(CC1)CNC(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC(F)=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC(F)=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound CN(C)[C@]1(C2=CC=CC(F)=C2)CC[C@]2(CC1)CNC(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC(F)=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC(F)=C4)(N(C)C)CC3)NC2=O)C=C1 IEIWRCFYAQBAPT-ZSIWRTTDSA-N 0.000 description 1
- RXWLBWHJUMFRIW-IYBDPMFKSA-N CN(C)[C@]1(C2=CC=CC(OC(F)(F)F)=C2)CC[C@]2(CC1)CNC(=O)N2 Chemical compound CN(C)[C@]1(C2=CC=CC(OC(F)(F)F)=C2)CC[C@]2(CC1)CNC(=O)N2 RXWLBWHJUMFRIW-IYBDPMFKSA-N 0.000 description 1
- LYUMOYWHNOPVRL-LFCZWZAFSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@@](N)(C(=O)NC(C)(C)C2=CC=CC=C2)CC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@](N)(CNC(C)(C)C2=CC=CC=C2)CC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@](NC(=O)OC(C)(C)C)(C(=O)NC(C)(C)C2=CC=CC=C2)CC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@](NC(=O)OC(C)(C)C)(C(=O)O)CC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(C(C)(C)C1=CC=CC=C1)C(=O)N2.Cl Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@@](N)(C(=O)NC(C)(C)C2=CC=CC=C2)CC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@](N)(CNC(C)(C)C2=CC=CC=C2)CC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@](NC(=O)OC(C)(C)C)(C(=O)NC(C)(C)C2=CC=CC=C2)CC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@](NC(=O)OC(C)(C)C)(C(=O)O)CC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(C(C)(C)C1=CC=CC=C1)C(=O)N2.Cl LYUMOYWHNOPVRL-LFCZWZAFSA-N 0.000 description 1
- PEMMEPOUXAICFL-UBRVONBISA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@@](N)(C(=O)O)CC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@](NC(=O)OC(C)(C)C)(C(=O)O)CC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)NC2=O Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@@](N)(C(=O)O)CC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@](NC(=O)OC(C)(C)C)(C(=O)O)CC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)NC2=O PEMMEPOUXAICFL-UBRVONBISA-N 0.000 description 1
- ZWPXGMYPZDYTFI-ABXOJXOFSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)CNC(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)CNC(=O)N2 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)CNC(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)CNC(=O)N2 ZWPXGMYPZDYTFI-ABXOJXOFSA-N 0.000 description 1
- FXCXWTFQQJOMPJ-MXVIHJGJSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)CNC(=O)N2CC1CC1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)CNC(=O)N2CC1CC1 FXCXWTFQQJOMPJ-MXVIHJGJSA-N 0.000 description 1
- HGSIGDMRMZBEEU-MEMLXQNLSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)CNC(=O)N2CC1CCC1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)CNC(=O)N2CC1CCC1 HGSIGDMRMZBEEU-MEMLXQNLSA-N 0.000 description 1
- WAGINGIPPXOFQK-NFJJTDDTSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)N(CCC1=CC=NC=C1)C2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)N(CCC1=CN=CC=C1)C2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)N(CCN1C=CN=C1)C2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CC(N)=O)N=N1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CC(N)=O)N=N1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CCO)N=N1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CCO)N=N1)C(=O)N2CC1CCC1.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CCO)N=N1)C(=O)N2CC1(O)CCC1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)N(CCC1=CC=NC=C1)C2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)N(CCC1=CN=CC=C1)C2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@@]2(CC1)NC(=O)N(CCN1C=CN=C1)C2=O.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CC(N)=O)N=N1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CC(N)=O)N=N1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CCO)N=N1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CCO)N=N1)C(=O)N2CC1CCC1.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN(CCO)N=N1)C(=O)N2CC1(O)CCC1 WAGINGIPPXOFQK-NFJJTDDTSA-N 0.000 description 1
- WOGYFAYRXFNCPA-SMANZJKWSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(C1(C3=CC=CC=C3)CC1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(N3CCCCC3)=NC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=N1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CN=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=NC=C1)C(=O)N2.CN1CCN(C2=NC=CC(CN3C[C@]4(CC[C@](C5=CC=CC=C5)(N(C)C)CC4)NC3=O)=C2)CC1.COC1=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3=CC=C(C#N)C=C3)C2=O)C=CC=C1.COC1=CC=CC=C1CN1C[C@]2(CC[C@](C3=CC=CC=C3)(N(C)C)CC2)NC1=O Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(C1(C3=CC=CC=C3)CC1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(N3CCCCC3)=NC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=N1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CN=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=NC=C1)C(=O)N2.CN1CCN(C2=NC=CC(CN3C[C@]4(CC[C@](C5=CC=CC=C5)(N(C)C)CC4)NC3=O)=C2)CC1.COC1=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3=CC=C(C#N)C=C3)C2=O)C=CC=C1.COC1=CC=CC=C1CN1C[C@]2(CC[C@](C3=CC=CC=C3)(N(C)C)CC2)NC1=O WOGYFAYRXFNCPA-SMANZJKWSA-N 0.000 description 1
- SBQIQTZZHZLKQH-QWDMNTCDSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C(C#N)C=CC=C1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C(C(N)=O)C=CC=C1)C(=O)N2CC1(O)CCC1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C(C#N)C=CC=C1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C(C(N)=O)C=CC=C1)C(=O)N2CC1(O)CCC1 SBQIQTZZHZLKQH-QWDMNTCDSA-N 0.000 description 1
- PSTHQZQQDLJHJL-XSKZJKETSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C(C(N)=O)C=CC=C1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(C(N)=O)=CC=C1)C(=O)N2CC1(O)CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)OC(C)(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CC(F)(F)C3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC(C)(C)O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC(C)(C)OC)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)CC#N)CC3)N(CC3CCC3)C2=O)C=C1.COCCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=C(C(N)=O)C=CC=C1)C(=O)N2CC1(O)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(C(N)=O)=CC=C1)C(=O)N2CC1(O)CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)OC(C)(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CC(F)(F)C3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC(C)(C)O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC(C)(C)OC)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)CC#N)CC3)N(CC3CCC3)C2=O)C=C1.COCCN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1 PSTHQZQQDLJHJL-XSKZJKETSA-N 0.000 description 1
- OGEHTTUFEOWVLC-LJVMLWLPSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(Br)=CC=C1)C(=O)N2CC1CCC1.CSC1=CC=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)=C1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(Br)=CC=C1)C(=O)N2CC1CCC1.CSC1=CC=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)=C1 OGEHTTUFEOWVLC-LJVMLWLPSA-N 0.000 description 1
- MNAATIFRMAAPLO-ZQKFSSBKSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(C(N)=O)=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(O)C=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=C(O)C=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(O)CCC3)C2=O)=C1.COCCOCCOCCOCCOCCOCCOC1=CC=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)=C1.COCCOCCOCCOCCOCCOCCOCCOCCOC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(C(N)=O)=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(O)C=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=C(O)C=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(O)CCC3)C2=O)=C1.COCCOCCOCCOCCOCCOCCOC1=CC=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)=C1.COCCOCCOCCOCCOCCOCCOCCOCCOC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1 MNAATIFRMAAPLO-ZQKFSSBKSA-N 0.000 description 1
- OKAFPDJUUIECNH-NRKJYUQYSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(N3CCNCC3)=NC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(N3CCOCC3)=NC=C1)C(=O)N2 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(N3CCNCC3)=NC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(N3CCOCC3)=NC=C1)C(=O)N2 OKAFPDJUUIECNH-NRKJYUQYSA-N 0.000 description 1
- YZWQQCKQJPBROQ-MKYRXWKGSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(S(C)(=O)=O)=CC=C1)C(=O)N2CC1CCC1.CSC1=CC=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)=C1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(S(C)(=O)=O)=CC=C1)C(=O)N2CC1CCC1.CSC1=CC=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)=C1 YZWQQCKQJPBROQ-MKYRXWKGSA-N 0.000 description 1
- TXAADOHHNBHHNQ-ZDYFMSIJSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(C#N)C=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(C(F)(F)F)N=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CN=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC(F)=CC=C4)(N(C)C)CC3)NC2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC(O)=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC3CCOCC3)C2=O)C=C1.COCCOCCOCCOCCOCCOCCOCCOCCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(C#N)C=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(C(F)(F)F)N=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CN=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC(F)=CC=C4)(N(C)C)CC3)NC2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC(O)=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC3CCOCC3)C2=O)C=C1.COCCOCCOCCOCCOCCOCCOCCOCCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 TXAADOHHNBHHNQ-ZDYFMSIJSA-N 0.000 description 1
- SXIWCPDXXLBKHL-LJVMLWLPSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(O)C=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(O)C=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1 SXIWCPDXXLBKHL-LJVMLWLPSA-N 0.000 description 1
- NXGJURVXIRZRSZ-VNBTXWSHSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(O)C=C1)C(=O)N2CC1CCC1.COCCOCCOCCOCCOCCOCCOCCOCCOC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(O)C=C1)C(=O)N2CC1CCC1.COCCOCCOCCOCCOCCOCCOCCOCCOC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1 NXGJURVXIRZRSZ-VNBTXWSHSA-N 0.000 description 1
- ZLHQWZUANZZKMM-QBGARVCYSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(S(C)(=O)=O)C=C1)C(=O)N2CC1CCC1.COC1=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)=CC=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(C(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(C)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(O)CCCCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCCCC#N)C2=O)C=C1.COCCCCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(S(C)(=O)=O)C=C1)C(=O)N2CC1CCC1.COC1=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)=CC=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(C(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(C)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(O)CCCCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCCCC#N)C2=O)C=C1.COCCCCN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 ZLHQWZUANZZKMM-QBGARVCYSA-N 0.000 description 1
- UGMHTGXNTSNAJX-ZRZAMGCNSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2 UGMHTGXNTSNAJX-ZRZAMGCNSA-N 0.000 description 1
- RMTBZVIRNJGNBJ-VNBPEFGNSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1(O)CCC1.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.COC(=O)CN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(N)=O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCCO3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCS(C)(=O)=O)C2=O)C=C1.O=C(O)C(F)(F)F Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1(O)CCC1.CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.COC(=O)CN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(N)=O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCCO3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCS(C)(=O)=O)C2=O)C=C1.O=C(O)C(F)(F)F RMTBZVIRNJGNBJ-VNBPEFGNSA-N 0.000 description 1
- KPJRFIXOSIKMKO-IFOKINNXSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2.COC1=CC=CC=C1CN1C(=O)N(CC2=CC=CC=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=CC=C1CN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2.COC1=CC=CC=C1CN1C(=O)N(CC2=CC=CC=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=CC=C1CN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 KPJRFIXOSIKMKO-IFOKINNXSA-N 0.000 description 1
- ROOGJRTXASWVHE-HNRBIFIRSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2CC1CCC1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CC=C1)C(=O)N2CC1CCC1 ROOGJRTXASWVHE-HNRBIFIRSA-N 0.000 description 1
- KSVNURZPWXDBJU-QUMHCIGMSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CN=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)N3CCCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC(=O)O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC(=O)OC(C)(C)C)C2=O)C=C1.COCCCC(=O)CN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COCCC[C@]1(N(C)C)CC[C@@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2.COCOC1=CC([C@]2(N(C)C)CC[C@@]3(CC2)CN(CC2=CC=C(OC)C=C2)C(=O)N3)=CC=C1.COCOC1=CC=C([C@]2(N(C)C)CC[C@@]3(CC2)CN(CC2=CC=C(OC)C=C2)C(=O)N3)C=C1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=CN=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)N3CCCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC(=O)O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC(=O)OC(C)(C)C)C2=O)C=C1.COCCCC(=O)CN1C(=O)N(CC2=CC=C(OC)C=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COCCC[C@]1(N(C)C)CC[C@@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2.COCOC1=CC([C@]2(N(C)C)CC[C@@]3(CC2)CN(CC2=CC=C(OC)C=C2)C(=O)N3)=CC=C1.COCOC1=CC=C([C@]2(N(C)C)CC[C@@]3(CC2)CN(CC2=CC=C(OC)C=C2)C(=O)N3)C=C1 KSVNURZPWXDBJU-QUMHCIGMSA-N 0.000 description 1
- HXGNKSJAQAAYFK-HLTAQJJGSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=NC(Cl)=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=NC(N3CCCCC3)=C1)C(=O)N2 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=NC(Cl)=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=NC(N3CCCCC3)=C1)C(=O)N2 HXGNKSJAQAAYFK-HLTAQJJGSA-N 0.000 description 1
- GXYOKOWUFJNMLN-HLTAQJJGSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=NC(Cl)=C1)C(=O)N2.CN1CCN(C2=CC(CN3C[C@]4(CC[C@](C5=CC=CC=C5)(N(C)C)CC4)NC3=O)=CC=N2)CC1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=NC(Cl)=C1)C(=O)N2.CN1CCN(C2=CC(CN3C[C@]4(CC[C@](C5=CC=CC=C5)(N(C)C)CC4)NC3=O)=CC=N2)CC1 GXYOKOWUFJNMLN-HLTAQJJGSA-N 0.000 description 1
- BKDQAZPPXHFWDF-CERZQCSDSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=NC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=NC=CC=N1)C(=O)N2CC1CCC1.COC1=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3=C(OC)C=CC(C#N)=C3)C2=O)C=C(C#N)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCOC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCCOC(F)(F)F)C2=O)C=C1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=NC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=NC=CC=N1)C(=O)N2CC1CCC1.COC1=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3=C(OC)C=CC(C#N)=C3)C2=O)C=C(C#N)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCOC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCCOC(F)(F)F)C2=O)C=C1 BKDQAZPPXHFWDF-CERZQCSDSA-N 0.000 description 1
- HNYZRWMYNZMNKG-ULGTYOBMSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1CCC1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CN=CC=C1)C(=O)N2CC1CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1CCC1 HNYZRWMYNZMNKG-ULGTYOBMSA-N 0.000 description 1
- VHGFZHKUJGLTFA-ACZWOSLHSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=CC=CC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=CC=CC=C1)C(=O)N2CC1(O)CCC1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=CC=CC=C1)C(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CCC1=CC=CC=C1)C(=O)N2CC1(O)CCC1 VHGFZHKUJGLTFA-ACZWOSLHSA-N 0.000 description 1
- ZWPXGMYPZDYTFI-IWDCYMRNSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2 ZWPXGMYPZDYTFI-IWDCYMRNSA-N 0.000 description 1
- DOCIVHZRSAVBEH-OHDIVAPBSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC(=O)O.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)OC(C)(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1.O=C(O)C(F)(F)F Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC(=O)O.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)OC(C)(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1.O=C(O)C(F)(F)F DOCIVHZRSAVBEH-OHDIVAPBSA-N 0.000 description 1
- PGQAECBTSNCFQC-PZZVVJTASA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1(C#N)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1(C(N)=O)CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(C#N)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1(C#N)CCC1.CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1(C(N)=O)CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(C#N)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 PGQAECBTSNCFQC-PZZVVJTASA-N 0.000 description 1
- YUXZRZGVSWLFPZ-OEANFSLJSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1(C)CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(C)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1(C)CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(C)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 YUXZRZGVSWLFPZ-OEANFSLJSA-N 0.000 description 1
- XTOFPDULVYSIOU-QLATVXGRSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1(O)CCC1.COC1=C(OC)C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(OCC4=CC=CC=C4)CCC3)C2=O)C=C1.COC1=C(OC)C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1(O)CCC1.COC1=C(OC)C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3(OCC4=CC=CC=C4)CCC3)C2=O)C=C1.COC1=C(OC)C=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 XTOFPDULVYSIOU-QLATVXGRSA-N 0.000 description 1
- FXCXWTFQQJOMPJ-BGYRXZFFSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1CC1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1CC1 FXCXWTFQQJOMPJ-BGYRXZFFSA-N 0.000 description 1
- ZTMIIBCRCDMRSM-HFCHJGAVSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1 ZTMIIBCRCDMRSM-HFCHJGAVSA-N 0.000 description 1
- YJPUPASLILZCRP-HFCHJGAVSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1CCC1.COC1=CC=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)=C1 Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CC1CCC1.COC1=CC=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)=C1 YJPUPASLILZCRP-HFCHJGAVSA-N 0.000 description 1
- YQLJETOWZKVMJZ-HDICACEKSA-N CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CCC(F)(F)F Chemical compound CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2CCC(F)(F)F YQLJETOWZKVMJZ-HDICACEKSA-N 0.000 description 1
- LCLNQGFHMKVZDG-OKILXGFUSA-N CN(C)[C@]1(C2=CC=CS2)CC[C@]2(CC1)CNC(=O)N2 Chemical compound CN(C)[C@]1(C2=CC=CS2)CC[C@]2(CC1)CNC(=O)N2 LCLNQGFHMKVZDG-OKILXGFUSA-N 0.000 description 1
- TVRKUNRXMWDNQB-QAQDUYKDSA-N CN(C)[C@]1(CC2=CC=CC=C2)CC[C@@]2(CC1)CNC(=O)N2 Chemical compound CN(C)[C@]1(CC2=CC=CC=C2)CC[C@@]2(CC1)CNC(=O)N2 TVRKUNRXMWDNQB-QAQDUYKDSA-N 0.000 description 1
- TVRKUNRXMWDNQB-CALCHBBNSA-N CN(C)[C@]1(CC2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2 Chemical compound CN(C)[C@]1(CC2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2 TVRKUNRXMWDNQB-CALCHBBNSA-N 0.000 description 1
- WSVHWFZWBTYMNN-KDURUIRLSA-N CN(CC1COC1)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2 Chemical compound CN(CC1COC1)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CNC(=O)N2 WSVHWFZWBTYMNN-KDURUIRLSA-N 0.000 description 1
- UDKBWGQFDQVUGM-UHFFFAOYSA-N CN1C(C2(N(C)C)CCC(=O)CC2)=NC2=C1C=CC=C2 Chemical compound CN1C(C2(N(C)C)CCC(=O)CC2)=NC2=C1C=CC=C2 UDKBWGQFDQVUGM-UHFFFAOYSA-N 0.000 description 1
- TZNQWEYVUZTFJM-HDICACEKSA-N CN1C2=C(C=CC=C2)N=C1[C@]1(N(C)C)CC[C@@]2(CC1)CNC(=O)N2 Chemical compound CN1C2=C(C=CC=C2)N=C1[C@]1(N(C)C)CC[C@@]2(CC1)CNC(=O)N2 TZNQWEYVUZTFJM-HDICACEKSA-N 0.000 description 1
- TZNQWEYVUZTFJM-IYARVYRRSA-N CN1C2=C(C=CC=C2)N=C1[C@]1(N(C)C)CC[C@]2(CC1)CNC(=O)N2 Chemical compound CN1C2=C(C=CC=C2)N=C1[C@]1(N(C)C)CC[C@]2(CC1)CNC(=O)N2 TZNQWEYVUZTFJM-IYARVYRRSA-N 0.000 description 1
- CMRTVWARCMJAKN-UHFFFAOYSA-N CN1C=CC(C2(C#N)CCC(=O)CC2)=N1 Chemical compound CN1C=CC(C2(C#N)CCC(=O)CC2)=N1 CMRTVWARCMJAKN-UHFFFAOYSA-N 0.000 description 1
- XQMYRHKNNWRZEC-UHFFFAOYSA-N CN1C=CC(C2(N(C)C)CCC(=O)CC2)=N1 Chemical compound CN1C=CC(C2(N(C)C)CCC(=O)CC2)=N1 XQMYRHKNNWRZEC-UHFFFAOYSA-N 0.000 description 1
- QNBCHHJSUDHSIL-HNRBIFIRSA-N CN[C@](CC1)(CC[C@@]1(CN1Cc2cc(OC)ccc2)N(CC2CCC2)C1=O)c1ccccc1 Chemical compound CN[C@](CC1)(CC[C@@]1(CN1Cc2cc(OC)ccc2)N(CC2CCC2)C1=O)c1ccccc1 QNBCHHJSUDHSIL-HNRBIFIRSA-N 0.000 description 1
- MGEUYHWWCXAPPB-LJVMLWLPSA-N CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(OC)=CC=C1)C(=O)N2CC1CCC1.COC1=CC=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)=C1 Chemical compound CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC(OC)=CC=C1)C(=O)N2CC1CCC1.COC1=CC=CC(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)=C1 MGEUYHWWCXAPPB-LJVMLWLPSA-N 0.000 description 1
- KWEVHJMBGMADAC-HBKTWFDVSA-N CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1(O)CCC1.COC1=CC=C(CN2C[C@]3(CC[C@@](N)(C4=CC=CC=C4)CC3)N(CC3(O)CCC3)C2=O)C=C1 Chemical compound CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1(O)CCC1.COC1=CC=C(CN2C[C@]3(CC[C@@](N)(C4=CC=CC=C4)CC3)N(CC3(O)CCC3)C2=O)C=C1 KWEVHJMBGMADAC-HBKTWFDVSA-N 0.000 description 1
- OBYJQGHBTMPBJK-GZJMYJGLSA-N CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)CC#N)CC3)N(CC3CCC3)C2=O)C=C1 Chemical compound CN[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)CC#N)CC3)N(CC3CCC3)C2=O)C=C1 OBYJQGHBTMPBJK-GZJMYJGLSA-N 0.000 description 1
- OASZOYBGRJVSSI-OUUMWZLZSA-N COC(=O)CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)CCO)CC3)N(CC3CCC3)C2=O)C=C1 Chemical compound COC(=O)CN(C)[C@]1(C2=CC=CC=C2)CC[C@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2CC1CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)CCO)CC3)N(CC3CCC3)C2=O)C=C1 OASZOYBGRJVSSI-OUUMWZLZSA-N 0.000 description 1
- FDGGUNFHJNUGRQ-DOUCUMEJSA-N COC1(CCN2C(=O)NC[C@]23CC[C@](C2=CC=CC=C2)(N(C)C)CC3)CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC3(OC)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound COC1(CCN2C(=O)NC[C@]23CC[C@](C2=CC=CC=C2)(N(C)C)CC3)CCC1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC3(OC)CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 FDGGUNFHJNUGRQ-DOUCUMEJSA-N 0.000 description 1
- DIFSATBFVKGPKV-UHFFFAOYSA-N COC1=CC(C2(N(C)C)CCC(=O)CC2)=CC=C1 Chemical compound COC1=CC(C2(N(C)C)CCC(=O)CC2)=CC=C1 DIFSATBFVKGPKV-UHFFFAOYSA-N 0.000 description 1
- YTIBEDIVGQBBTF-CALCHBBNSA-N COC1=CC([C@]2(N(C)C)CC[C@@]3(CC2)CNC(=O)N3)=CC=C1 Chemical compound COC1=CC([C@]2(N(C)C)CC[C@@]3(CC2)CNC(=O)N3)=CC=C1 YTIBEDIVGQBBTF-CALCHBBNSA-N 0.000 description 1
- YNQNTDHIBFUDOR-UHFFFAOYSA-N COC1=CC=C(CN2C(=O)NC3(CCC4(CC3)OCCO4)C2=O)C=C1.COC1=CC=C(CN2CC3(CCC(=O)CC3)NC2=O)C=C1.COC1=CC=C(CN2CC3(CCC4(CC3)OCCO4)NC2=O)C=C1.O=C1CCC2(CC1)OCCO2.O=C1NC(=O)C2(CCC3(CC2)OCCO3)N1 Chemical compound COC1=CC=C(CN2C(=O)NC3(CCC4(CC3)OCCO4)C2=O)C=C1.COC1=CC=C(CN2CC3(CCC(=O)CC3)NC2=O)C=C1.COC1=CC=C(CN2CC3(CCC4(CC3)OCCO4)NC2=O)C=C1.O=C1CCC2(CC1)OCCO2.O=C1NC(=O)C2(CCC3(CC2)OCCO3)N1 YNQNTDHIBFUDOR-UHFFFAOYSA-N 0.000 description 1
- PUYZUJPEPOWCBI-UHFFFAOYSA-N COC1=CC=C(CN2CC3(CCC(=O)CC3)NC2=O)C=C1.COC1=CC=C(CN2CC3(CCC(C#N)(N(C)C)CC3)NC2=O)C=C1.COC1=CC=C(CN2CC3(CCC(C4=CC=CC(F)=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound COC1=CC=C(CN2CC3(CCC(=O)CC3)NC2=O)C=C1.COC1=CC=C(CN2CC3(CCC(C#N)(N(C)C)CC3)NC2=O)C=C1.COC1=CC=C(CN2CC3(CCC(C4=CC=CC(F)=C4)(N(C)C)CC3)NC2=O)C=C1 PUYZUJPEPOWCBI-UHFFFAOYSA-N 0.000 description 1
- SQOAEJCURKWZGP-XRAMAGQNSA-N COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC(F)=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC(F)=CC=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC(F)=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC(F)=CC=C4)(N(C)C)CC3)NC2=O)C=C1 SQOAEJCURKWZGP-XRAMAGQNSA-N 0.000 description 1
- YSJKGOYGPSKNGB-ISILISOKSA-N COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=C(O)C=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1 Chemical compound COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=C(O)C=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1 YSJKGOYGPSKNGB-ISILISOKSA-N 0.000 description 1
- SXAGLSCQRQEMTA-PLQXJYEYSA-N COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=C(OC)C=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=C(OC)C=C4)(N(C)C)CC3)NC2=O)C=C1 SXAGLSCQRQEMTA-PLQXJYEYSA-N 0.000 description 1
- PSAKXDMCNQHWLB-ARMFMHIHSA-N COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC(O)=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COCOC1=CC([C@]2(N(C)C)CC[C@@]3(CC2)CN(CC2=CC=C(OC)C=C2)C(=O)N3)=CC=C1.COCOC1=CC([C@]2(N(C)C)CC[C@@]3(CC2)CN(CC2=CC=C(OC)C=C2)C(=O)N3CC2CCC2)=CC=C1 Chemical compound COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC(O)=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COCOC1=CC([C@]2(N(C)C)CC[C@@]3(CC2)CN(CC2=CC=C(OC)C=C2)C(=O)N3)=CC=C1.COCOC1=CC([C@]2(N(C)C)CC[C@@]3(CC2)CN(CC2=CC=C(OC)C=C2)C(=O)N3CC2CCC2)=CC=C1 PSAKXDMCNQHWLB-ARMFMHIHSA-N 0.000 description 1
- JESRFVWPARRVJH-PLQXJYEYSA-N COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC(OC)=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC(OC)=C4)(N(C)C)CC3)NC2=O)C=C1 JESRFVWPARRVJH-PLQXJYEYSA-N 0.000 description 1
- OLCNWYAAMVWJTM-DIVCQZSQSA-N COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)CC2=O)C=C1OC Chemical compound COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)CC2=O)C=C1OC OLCNWYAAMVWJTM-DIVCQZSQSA-N 0.000 description 1
- AFWBSHLDZMMAJC-NRKJYUQYSA-N COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC#N)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(N)=O)C2=O)C=C1 Chemical compound COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC#N)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(N)=O)C2=O)C=C1 AFWBSHLDZMMAJC-NRKJYUQYSA-N 0.000 description 1
- FRSGTLKXGAWKHR-SKLBTBCUSA-N COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)OC(C)(C)C)C2=O)C=C1.O=C(O)C(F)(F)F Chemical compound COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)OC(C)(C)C)C2=O)C=C1.O=C(O)C(F)(F)F FRSGTLKXGAWKHR-SKLBTBCUSA-N 0.000 description 1
- NGIBMHXDCRSRCZ-KLLIIFEOSA-N COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)OC(C)(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(=O)OC(C)(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 NGIBMHXDCRSRCZ-KLLIIFEOSA-N 0.000 description 1
- HOFWQOJTFUCBTE-LJVMLWLPSA-N COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)(C)O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)(C)OC)C2=O)C=C1 Chemical compound COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)(C)O)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)(C)OC)C2=O)C=C1 HOFWQOJTFUCBTE-LJVMLWLPSA-N 0.000 description 1
- MNWGTHXVUMBWJP-PLCQLYEZSA-N COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 MNWGTHXVUMBWJP-PLCQLYEZSA-N 0.000 description 1
- VIHCJXKWCTXBQW-XRAMAGQNSA-N COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC3CCC3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 VIHCJXKWCTXBQW-XRAMAGQNSA-N 0.000 description 1
- AUVGXHMIFKLXMZ-MKYRXWKGSA-N COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC=C(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC(C)(C)O)C2=O)C=C1 Chemical compound COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CC=C(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCC(C)(C)O)C2=O)C=C1 AUVGXHMIFKLXMZ-MKYRXWKGSA-N 0.000 description 1
- CDDVGCJEDLXZCL-LUNKEPTNSA-N COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCO)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCO[Si](C)(C)C(C)(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCO)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(CCO[Si](C)(C)C(C)(C)C)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 CDDVGCJEDLXZCL-LUNKEPTNSA-N 0.000 description 1
- FITDMKGJYVSQIJ-JPLNIPNSSA-N COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(S(=O)(=O)C3=CC=C(C)C=C3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 Chemical compound COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)N(S(=O)(=O)C3=CC=C(C)C=C3)C2=O)C=C1.COC1=CC=C(CN2C[C@]3(CC[C@](C4=CC=CC=C4)(N(C)C)CC3)NC2=O)C=C1 FITDMKGJYVSQIJ-JPLNIPNSSA-N 0.000 description 1
- DRRFOVBFWCBAIQ-JPLNIPNSSA-N COC1=CC=CC=C1CN1C(=O)N(CC2=CC=CC=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=CC=C1CN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 Chemical compound COC1=CC=CC=C1CN1C(=O)N(CC2=CC=CC=C2)C[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2.COC1=CC=CC=C1CN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 DRRFOVBFWCBAIQ-JPLNIPNSSA-N 0.000 description 1
- UMNBKYXXMOXLCV-BGYRXZFFSA-N COCCCN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 Chemical compound COCCCN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 UMNBKYXXMOXLCV-BGYRXZFFSA-N 0.000 description 1
- YORZABKEBRCBTH-SZPZYZBQSA-N COCCC[C@]1(N(C)C)CC[C@@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2 Chemical compound COCCC[C@]1(N(C)C)CC[C@@]2(CC1)CN(CC1=CC=C(OC)C=C1)C(=O)N2 YORZABKEBRCBTH-SZPZYZBQSA-N 0.000 description 1
- LNFLMKXVPAZCEG-KDURUIRLSA-N COCCN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 Chemical compound COCCN1C(=O)NC[C@]12CC[C@](C1=CC=CC=C1)(N(C)C)CC2 LNFLMKXVPAZCEG-KDURUIRLSA-N 0.000 description 1
- LCNXBSPBMIKNDQ-WMPKNSHKSA-N COCOC1=CC([C@]2(N(C)C)CC[C@@]3(CC2)CN(CC2=CC=C(OC)C=C2)C(=O)N3)=CC=C1 Chemical compound COCOC1=CC([C@]2(N(C)C)CC[C@@]3(CC2)CN(CC2=CC=C(OC)C=C2)C(=O)N3)=CC=C1 LCNXBSPBMIKNDQ-WMPKNSHKSA-N 0.000 description 1
- POBZXYYGFIWEJE-MCZWQBSQSA-N COCOC1=CC=C([C@]2(N(C)C)CC[C@]3(CC2)CC(=O)N(CC2=CC=C(OC)C=C2)C3)C=C1 Chemical compound COCOC1=CC=C([C@]2(N(C)C)CC[C@]3(CC2)CC(=O)N(CC2=CC=C(OC)C=C2)C3)C=C1 POBZXYYGFIWEJE-MCZWQBSQSA-N 0.000 description 1
- AHHOCSMWLFKYIY-UHFFFAOYSA-N N#CC1(C2=NC=CN=C2)CCC(=O)CC1 Chemical compound N#CC1(C2=NC=CN=C2)CCC(=O)CC1 AHHOCSMWLFKYIY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- the invention relates to 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and use in medicine, particularly in various neurological disorders, including but not limited to pain, neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, substance abuse/dependence.
- Opioid receptors are a group of Gi/o protein-coupled receptors which are widely distributed in the human body.
- the opioid receptors are currently subdivided into four major classes, i.e. the three classical opioid receptors mu-opioid (MOP) receptor, kappa-opioid (KOP) receptor, and delta-opioid (DOP) receptor as well as the opioid receptor-like (ORL-1) receptor, which was more recently discovered based on its high homology with said classical opioid receptors.
- MOP mu-opioid
- KOP kappa-opioid
- DOP delta-opioid
- ORL-1 opioid receptor-like receptor
- ORL-1 receptor After identification of the endogenous ligand of the ORL-1 receptor, known as nociceptin/orphanin FQ, a highly basic 17 amino acid peptide isolated from tissue extracts in 1995, the ORL-1 receptor was renamed “nociceptin opioid peptide receptor” and abbreviated as “NOP-receptor”.
- the classical opioid receptors (MOP, KOP and DOP) as well as the NOP receptor are widely distributed/expressed in the human body, including in the brain, the spinal cord, on peripheral sensory neurons and the intestinal tract, wherein the distribution pattern differs between the different receptor classes.
- Nociceptin acts at the molecular and cellular level in very much the same way as opioids. However, its pharmacological effects sometimes differ from, and even oppose those of opioids. NOP-receptor activation translates into a complex pharmacology of pain modulation, which, depending on route of administration, pain model and species involved, leads to either pronociceptive or antinociceptive activity. Furthermore, the NOP receptor system is upregulated under conditions of chronic pain. Systemic administration of selective NOP receptor agonists was found to exert a potent and efficacious analgesia in non-human primate models of acute and inflammatory pain in the absence of side effects.
- NOP receptors The activation of NOP receptors has been demonstrated to be devoid of reinforcing effects but to inhibit opioid-mediated reward in rodents and non-human primates (Review: Schroeder et al, Br J Pharmacol 2014; 171 (16): 3777-3800, and references therein).
- NOP receptor agonists might be useful inter alia in the treatment of neuropsychiatric disorders (Witkin et al, Pharmacology & Therapeutics, 141 (2014) 283-299; Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858).
- the DOP receptor is also implicated to modulate not only pain but also neuropsychiatric disorders (Mabrouk et al, 2014; Pradhan et al., 2011).
- MOP receptor agonists show only reduced effectiveness under conditions of chronic and neuropathic pain.
- peripherally restricted opioid receptor ligands that do not easily cross the blood-brain barrier and therefore distribute poorly to the central nervous system (see for instance WO 2015/192039).
- peripherally acting compounds might combine effective analgesia with limited side-effects.
- a further approach has been to provide multi-opioid receptor analgesics that modulate more than one of the opioid receptor subtypes to provide additive or synergistic analgesia and/or reduced side effects like abuse liability or tolerance.
- medicaments which are effective in the treatment of pain and which have advantages compared to the compounds of the prior art.
- medicaments should contain such a small dose of active ingredient that satisfactory pain therapy can be ensured without the occurrence of intolerable treatment-emergent adverse events.
- a first aspect of the invention relates to 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives according to general formula (I)
- n 1, 2 or 3; R 1 and R 2 independently of one another mean
- —C 1 -C 6 -alkyl linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH 3 , —CN and —CO 2 CH 3 ; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH 3 , —CN and —CO 2 CH 3 ; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or a 3-12-
- —C 1 -C 6 -alkyl linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said —C 1 -C 6 -alkyl is optionally connected through —C( ⁇ O)—, —C( ⁇ O)O—, or —S( ⁇ O) 2 —; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C( ⁇ O)—, —C( ⁇ O)O—, —C( ⁇ O)O—CH 2
- —C 1 -C 6 -alkyl linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH 2 , and —O—C 1 -C 6 -alkyl; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH 2 , —C 1 -C
- aryl includes but is not limited to phenyl and naphthyl.
- heteroaryl includes but is not limited to -1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyri
- cycloalkyl includes but is not limited to -cyclopropyl, -cyclobutyl, -cyclopentyl and -cyclohexyl.
- heterocycloalkyl includes but is not limited to -aziridinyl, -azetidinyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -sulfamorpholinyl, -oxiridinyl, -oxetanyl, tetrahydropyranyl, and -pyranyl.
- asymmetric group such as —C( ⁇ O)O— or —C( ⁇ O)O—CH 2 —
- said asymmetric group may be arranged in either direction.
- R 4 when R 4 is connected to the core structure through —C( ⁇ O)O—, the arrangement may be either R 4 —C( ⁇ O)O-core or core-C( ⁇ O)O—R 4 .
- R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 independently of one another mean —H, —F, —OH, or —C 1 -C 6 -alkyl; preferably —H.
- R 7 and R 8 together with the carbon atom to which they are attached form a ring and mean —(CH 2 ) 2 — (i.e. form a cyclopropyl ring) or —(CH 2 ) 3 —(i.e. form a cyclobutyl ring).
- R 1 means —H; and R 2 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 1 means —H and R 2 means —CH 3 .
- R 1 means —CH 3 ; and R 2 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 1 means —CH 3 and R 2 means —CH 3 .
- R 1 and R 2 together with the nitrogen atom to which they are attached form a ring and mean —(CH 2 ) 3-6 —.
- R 1 and R 2 together with the nitrogen atom to which they are attached form a ring and mean —(CH 2 ) 3 —.
- R 3 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 3 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —OCH 3 .
- R 3 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted, optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted.
- R 3 means -phenyl unsubstituted, mono- or polysubstituted.
- R 3 means -phenyl unsubstituted, mono- or disubstituted with —F, —Cl, —CH 3 , —CF 3 , —OH, —OCH 3 , —OCF 3 or —OCH 2 OCH 3 , preferably —F.
- R 3 means -benzyl unsubstituted, mono- or polysubstituted.
- R 3 means -benzyl unsubstituted, mono- or disubstituted with —F, —Cl, —CH 3 , —CF 3 , —OH, —OCH 3 , —OCF 3 or —OCH 2 OCH 3 , preferably —F.
- R 3 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
- R 3 means -thienyl or -pyridinyl, in each case unsubstituted, mono- or polysubstituted. More preferably, R 3 means -thienyl, -pyridinyl, -imidazolyl or benzimidazolyl, in each case unsubstituted or monosubstituted with —F, —Cl or —CH 3 .
- R 4 means —H.
- R 4 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 4 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with a substituent selected from the group consisting of —F, —Cl, —Br, —I, —CN, —CF 3 , —OH, —O—C 1 -C 4 -alkyl, —OCF 3 , —O—(CH 2 CH 2 —O) 1-30 —H, —O—(CH 2 CH 2 —O) 1-30 —CH 3 , —OC( ⁇ O)C 1 -C 4 -alkyl, —C( ⁇ O)C 1 -C 4 -alkyl, —C( ⁇ O)C 1 -C 4 -alkyl,
- R 4 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —O—C 1 -C 4 -alkyl or —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 .
- R 4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein the 3-12-membered cycloalkyl moiety is connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is connected through —CH 2 — or —CH 2 CH 2 —.
- R 4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 -C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 -C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , —S( ⁇ O)C 1 -C 4 -alkyl and —S( ⁇ O) 2 C 1 -C 4 -alkyl; wherein said 3-12-membered cycloalkyl mo
- R 4 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 4 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —CH 2 — or —CH 2 CH 2 —.
- R 4 means -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 -C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 -C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , —S( ⁇ O)C 1 -C 4 -alkyl and —S( ⁇ O) 2 C 1 -C 4 -alkyl; wherein said -
- R 4 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 4 means -phenyl, unsubstituted, mono- or polysubstituted; wherein said -phenyl is connected through —CH 2 — or —CH 2 CH 2 —.
- R 4 means -phenyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 -C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 -C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , —S( ⁇ O)C 1 -C 4 -alkyl and —S( ⁇ O) 2 C 1 -C 4 -alkyl; wherein said -phenyl is connected through —CH 2 — or —CH 2 CH 2 —.
- R 4 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 4 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said -phenyl is connected through —CH 2 — or —CH 2 CH 2 —.
- R 4 means -pyridinyl, -pyrimidinyl, -pyrazinyl, or -pyrazolinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 -C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 -C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , —S( ⁇ O)C 1 -C 4 -alkyl and —S( ⁇ O) 2 C 1 -C 4 -alkyl; wherein
- n means 1 or 2.
- n means 1.
- R 5 means -phenyl, unsubstituted, mono- or polysubstituted.
- R 5 means -phenyl unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F; —Cl; —Br; —I; —CN; —OH; —C 1 -C 4 -alkyl; —CF 3 ; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl,
- R 5 means -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, triazolyl, or -1,3-benzodioxolyl, in each case unsubstituted, mono- or polysubstituted.
- R 5 means -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, triazolyl, or -1,3-benzodioxolyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F; —Cl; —Br; —I; —CN; —OH; —C 1 -C 4 -alkyl; —CF 3 ; —C 1 -C 4 -alkyl-OH; —C 1 -C 4 -alkyl-C( ⁇ O)NH 2 ; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstituted; -3-12
- the compound according to the invention has a structure according to any of general formulas (II-A) to (VIII-C):
- R C means —H, —OH, —F, —CN or —C 1 -C 4 -alkyl; preferably —H or —OH;
- R D means —H or —F; or a physiologically acceptable salt thereof.
- R 5 is selected from the group consisting of:
- n means 1 or 2;
- R 1 means —H or —CH 3 ;
- R 2 means —H or —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —OH, —OCH 3 , —C( ⁇ O)OCH 3 , or —CN;
- R 3 means —C 1 -C 4 -alkyl, optionally monosubstituted with —OCH 3 ;
- -phenyl, -thienyl or -pyridinyl in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —CN, —CH 3 , —CH 2 CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCF 3 , —OH, —OCH 3 ,
- —C 1 -C 6 -alkyl linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, ⁇ O, —OH, —O—C 1 -C 4 -alkyl, —CO 2 H, —C( ⁇ O)O—C 1 -C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NH—C 1 -C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , —C( ⁇ O)NH—C 1 -C 4 -alkyl-CN, —C( ⁇ O)NCH 3 —C 1 -C 4 -alkyl-CN, —C( ⁇ O)NH-cyclopropyl-CN, —C( ⁇ O)
- n means 1 or 2; and/or R 1 means —H or —CH 3 ; and/or R 2 means —C 1 -C 6 -alkyl, linear or branched, saturated, unsubstituted; preferably, R 2 means —CH 3 or —CH 2 CH 3 ; more preferably, R 1 and R 2 both mean —CH 3 ; and/or R 3 means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —CN, —CH 3 , —CH 2 CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCF 3 , —OH, —OCH 3 , —C( ⁇ O)NH 2 , C( ⁇ O)NHCH 3 , —C( ⁇ O)N(CH 3 ) 2
- —C 1 -C 6 -alkyl linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C 1 -C 4 -alkyl; or 3-6-membered cycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C 1 -C 4 -alkyl, wherein said 3-6-membered cycloalkyl is connected through —C 1 -C 6 -alkylene; preferably R 4 means 3-6-membered cycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently
- the compound according to the invention is selected from the group consisting of
- SC_2001 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-methylsulfonyl-phenyl)-methyl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one
- SC_2002 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
- SC_2003 CIS-8-Dimethylamino-1-isopropyl-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
- SC_2004 CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]
- —C 1 -C 4 -alkyl can be linear or branched, saturated or unsaturated.
- Linear saturated alkyl includes methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl.
- branched saturated alkyl include but are not limited to iso-propyl, sec-butyl, and tert-butyl.
- linear unsaturated alkyl include but are not limited to vinyl, propenyl, allyl, and propargyl.
- —C 1 -C 4 -alkyl can be unsubstituted, mono- or polysubstituted.
- substituted alkyl examples include but are not limited to —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , —CH 2 CH 2 CH 2 OCH 3 , —CH 2 CH 2 S( ⁇ O) 2 CH 3 , —CH 2 C( ⁇ O)NH 2 , —C(CH 3 ) 2 C( ⁇ O)NH 2 , —CH 2 C(CH 3 ) 2 C( ⁇ O)NH 2 , and —CH 2 CH 2 C( ⁇ O)N(CH 3 ) 2 .
- —C 1 -C 6 -alkylene- can be unsubstituted, mono- or polysubstituted.
- saturated alkylene examples include but are not limited to —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH 2 CH 2 —, —CH(CH 3 )CH 2 —, —CH 2 CH(CH 3 )—, —CH(CH 3 )—CH(CH 3 )—, —C(CH 3 ) 2 CH 2 —, —CH 2 C(CH 3 ) 2 —, —CH(CH 3 )C(CH 3 ) 2 —, —C(CH 3 ) 2 CH(CH 3 )—, C(CH 3 ) 2 C(CH 3 ) 2 —, —CH 2 CH 2 CH 2 —, and —C(CH 3 ) 2 CH 2 CH 2 —.
- unsaturated alkylene examples include but are not limited to —CH ⁇ CH—, —C ⁇ C—, —C(CH 3 ) ⁇ CH—, —CH ⁇ C(CH 3 )—, —C(CH 3 ) ⁇ C(CH 3 )—, —CH 2 CH ⁇ CH—, —CH ⁇ CHCH 2 —, —CH ⁇ CH—CH ⁇ CH—, and —CH ⁇ CH—C ⁇ C—.
- —C 1 -C 6 -alkylene- can be unsubstituted, mono- or polysubstituted.
- substituted —C 1 -C 6 -alkylene- include but are not limited to —CHF—, —CF 2 —, —CHOH— and —C( ⁇ O)—.
- moieties may be connected through —C 1 -C 6 -alkylene-, i.e. the moieties may not be directly bound to the core structure of compound according to general formula (I), but may be connected to the core structure of compound according to general formula (I) or its periphery through a —C 1 -C 6 -alkylene-linker.
- 3-12-membered cycloalkyl moiety means a non-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to 12 ring carbon atoms but no heteroatoms in the ring.
- preferred saturated 3-12-membered cycloalkyl moieties according to the invention include but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, hydrindane, and decaline.
- Examples of preferred unsaturated 3-12-membered cycloalkyl moiety moieties according to the invention include but are not limited to cyclopropene, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, 1,3-cyclohexadiene, and 1,4-cyclohexadiene.
- the 3-12-membered cycloalkyl moiety which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
- the ring atoms of the condensed moieties are not included in the 3 to 12 ring atoms of the 3-12-membered cycloalkyl moiety.
- 3-12-membered cycloalkyl moieties condensed with 3-12-membered heterocycloalkyl moieties include but are not limited to octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, and decahydroquinoxalin, which in each case are connected through the 3-12-membered cycloalkyl moiety.
- 3-12-membered cycloalkyl moieties condensed with 6-14-membered aryl moieties include but are not limited to 2,3-dihydro-1H-indene and tetraline, which in each case are connected through the 3-12-membered cycloalkyl moiety.
- 3-12-membered cycloalkyl moieties condensed with 5-14-membered heteroaryl moieties include but are not limited to 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which in each case are connected through the 3-12-membered cycloalkyl moiety.
- the 3-12-membered cycloalkyl moiety may optionally be connected through —C 1 -C 6 -alkylene-, i.e. the 3-12-membered cycloalkyl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C 1 -C 6 -alkylene-linker.
- Examples include but are not limited to —CH 2 -cyclopropyl, —CH 2 -cyclobutyl, —CH 2 -cyclopentyl, —CH 2 -cyclohexyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclobutyl, —CH 2 CH 2 -cyclopentyl, and —CH 2 CH 2 -cyclohexyl.
- the 3-12-membered cycloalkyl moiety can be unsubstituted, mono- or polysubstituted.
- substituted 3-12-membered cycloalkyl moieties include but are not limited to —CH 2 -1-hydroxy-cyclobutyl.
- “3-12-membered heterocycloalkyl moiety” means a non-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to 12 ring atoms, wherein each cycle comprises independently of one another 1, 2, 3, 4 or more heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, whereas sulfur may be oxidized (S( ⁇ O) or (S( ⁇ O) 2 ), whereas the remaining ring atoms are carbon atoms, and whereas bicyclic or tricyclic systems may share common heteroatom(s).
- Examples of preferred saturated 3-12-membered heterocycloalkyl moieties according to the invention include but are not limited to aziridin, azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, triazolidine, tetrazolidine, oxiran, oxetane, tetrahydrofurane, tetrahydropyrane, thiirane, thietane, tetrahydrothiophene, diazepane, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, morpholine, thiomorpholine.
- Examples of preferred unsaturated 3-12-membered heterocycloalkyl moiety moieties according to the invention include but are not limited to oxazoline, pyrazoline, imidazoline, isoxazoline, thiazoline, isothiazoline, and dihydropyran.
- the 3-12-membered heterocycloalkyl moiety which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
- the ring atoms of the condensed moieties are not included in the 3 to 12 ring atoms of the 3-12-membered heterocycloalkyl moieties.
- 3-12-membered heterocycloalkyl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline, octahydro-2H-benzo[b][1,4]-oxazin, and decahydroquinoxalin, which in each case are connected through the 3-12-membered heterocycloalkyl moiety.
- An examples of a 3-12-membered heterocycloalkyl moiety condensed with a 6-14-membered aryl moiety includes but is not limited to 1,2,3,4-tetrahydroquinoline, which is connected through the 3-12-membered heterocycloalkyl moiety.
- An example of a 3-12-membered heterocycloalkyl moiety condensed with a 5-14-membered heteroaryl moieties includes but is not limited to 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connected through the 3-12-membered heterocycloalkyl moiety.
- the 3-12-membered heterocycloalkyl moiety may optionally be connected through —C 1 -C 6 -alkylene-, i.e. the 3-12-membered heterocycloalkyl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C 1 -C 6 -alkylene-linker.
- Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 3-12-membered heterocycloalkyl moiety.
- Examples include but are not limited to —CH 2 -oxetane, —CH 2 -pyrrolidine, —CH 2 -piperidine, —CH 2 -morpholine, —CH 2 CH 2 -oxetane, —CH 2 CH 2 -pyrrolidine, —CH 2 CH 2 -piperidine, and —CH 2 CH 2 -morpholine.
- the 3-12-membered heterocycloalkyl moiety can be unsubstituted, mono- or polysubstituted.
- substituted 3-12-membered heterocycloalkyl moieties include but are not limited to 2-carboxamido-N-pyrrolidinyl-, 3,4-dihydroxy-N-pyrrolidinyl, 3-hydroxy-N-pyrimidinyl, 3,4-dihydroxy-N-pyrimidinyl, 3-oxo-N-piperazinyl, -tetrahydro-2H-thiopyranyl dioxide and thiomorpholinyl dioxide.
- 6-14-membered aryl moiety means an aromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14 ring carbon atoms but no heteroatoms in the ring.
- 6-14-membered aryl moieties according to the invention include but are not limited to benzene, naphthalene, anthracen, and phenanthren.
- the 6-14-membered aryl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
- the ring atoms of the condensed moieties are not included in the 6 to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.
- 6-14-membered aryl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to 2,3-dihydro-1H-indene and tetraline, which in each case are connected through the 6-14-membered aryl moiety.
- 6-14-membered aryl moiety condensed with a 3-12-membered heterocycloalkyl moiety includes but is not limited to 1,2,3,4-tetrahydroquinoline, which is connected through the 6-14-membered aryl moiety.
- 6-14-membered aryl moieties condensed with 5-14-membered heteroaryl moieties include but are not limited to quinoline, isoquinoline, phenazine and phenoxacine, which in each case are connected through the 6-14-membered aryl moiety.
- the 6-14-membered aryl moiety may optionally be connected through —C 1 -C 6 -alkylene-, i.e. the 6-14-membered aryl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C 1 -C 6 -alkylene-linker.
- Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 6-14-membered aryl moiety. Examples include but are not limited to —CH 2 —C 6 H 5 , —CH 2 CH 2 —C 6 H 5 and —CH ⁇ CH—C 6 H 5 .
- the 6-14-membered aryl moiety can be unsubstituted, mono- or polysubstituted.
- substituted 6-14-membered aryl moieties include but are not limited to 2-fluorophenyl, 3-fluorophenyl, 2-methoxyphenyl and 3-methoxyphenyl.
- “5-14-membered heteroaryl moiety” means an aromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14 ring atoms, wherein each cycle comprises independently of one another 1, 2, 3, 4 or more heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, whereas the remaining ring atoms are carbon atoms, and whereas bicyclic or tricyclic systems may share common heteroatom(s).
- Examples of preferred 5-14-membered heteroaryl moieties according to the invention include but are not limited to pyrrole, pyrazole, imidazole, triazole, tetrazole, furane, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine, pyrazine, indolicine, 9H-chinolicine, 1,8-naphthyridine, purine, imidazo[1,2-a]pyrazine, and pteridine.
- the 5-14-membered heteroaryl moiety which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted.
- the ring atoms of the condensed moieties are not included in the 6 to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.
- 5-14-membered heteroaryl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which in each case are connected through the 5-14-membered heteroaryl moiety.
- 5-14-membered heteroaryl moiety condensed with a 3-12-membered heterocycloalkyl moiety includes but is not limited to 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connected through the 5-14-membered heteroaryl moiety.
- 5-14-membered heteroaryl moieties condensed with 6-14-membered aryl moieties include but are not limited to quinoline, isoquinoline, phenazine and phenoxacine, which in each case are connected through the 5-14-membered heteroaryl moiety.
- the 5-14-membered heteroaryl moiety may optionally be connected through —C 1 -C 6 -alkylene-, i.e. the 5-14-membered heteroaryl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C 1 -C 6 -alkylene-linker.
- Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 5-14-membered heteroaryl moiety.
- Examples include but are not limited to —CH 2 -oxazole, —CH 2 -isoxazole, —CH 2 -imidazole, —CH 2 -pyridine, —CH 2 -pyrimidine, —CH 2 -pyridazine, —CH 2 CH 2 -oxazole, —CH 2 CH 2 -isoxazole, —CH 2 CH 2 -imidazole, —CH 2 CH 2 -pyridine, —CH 2 CH 2 -pyrimidine, and —CH 2 CH 2 -pyridazine.
- the 5-14-membered heteroaryl moiety can be unsubstituted, mono- or polysubstituted.
- 5-14-membered heteroaryl moieties include but are not limited to 2-methoxy-4-pyridinyl, 2-methoxy-5-pyridinyl, 3-methoxy-4-pyridinyl, 3-methoxy-6-pyridinyl, 4-methoxy-2-pyridinyl, 2-methylsulfonyl-5-pyridinyl, 3-methylsulfonyl-6-pyridinyl, 3-methoxy-6-pyridazinyl, 2-nitrilo-5-pyrimidinyl, 4-hydroxy-2-pyrimidinyl, 4-methoxy-pyrimidinyl, and 2-methoxy-6-pyrazinyl.
- the compounds according to the invention have a structure according to general formula (I′)
- R 1 to R 5 , R 7 , R 8 , R 10 to R 20 and n are defined as above, or a physiologically acceptable salt thereof.
- the excess of the cis-isomer so designated is at least 50% de, more preferably at least 75% de, yet more preferably at least 90% de, most preferably at least 95% de and in particular at least 99% de.
- the compound according to the invention has a structure according to general formula (IX)
- R C means —H or —OH
- R 3 means -phenyl or -3-fluorophenyl
- R 5 means 6-14-membered aryl, unsubstituted, mono- or polysubstituted; or 5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted; or a physiologically acceptable salt thereof.
- R 5 is selected from -phenyl, -pyridyl, pyrimidinyl, or -triazolyl, in each case unsubstituted, mono- or polysubstituted.
- the compounds according to the invention are in the form of the free bases.
- the compounds according to the invention are in the form of the physiologically acceptable salts.
- salt is to be understood as being any form of the compound in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution.
- the term is also to be understood as meaning complexes of the compound with other molecules and ions, in particular complexes which are associated via ionic interactions.
- Preferred salts are physiologically acceptable, in particular physiologically acceptable salts with anions or acids or also a salt formed with a physiologically acceptable acid.
- Physiologically acceptable salts with anions or acids are salts of the particular compound in question with inorganic or organic acids which are physiologically acceptable, in particular when used in humans and/or mammals.
- physiologically acceptable salts of particular acids include but are not limited to salts of hydrochloric acid, sulfuric acid, and acetic acid.
- the invention also includes isotopic isomers of a compound according to the invention, wherein at least one atom of the compound is replaced by an isotope of the respective atom which is different from the naturally predominantly occurring isotope, as well as any mixtures of isotopic isomers of such a compound.
- Preferred isotopes are 2 H (deuterium), 3 H (tritium), 13 C and 14 C.
- Certain compounds according to the invention are useful for modulating a pharmacodynamic response from one or more opioid receptors (mu, delta, kappa, NOP/ORL-1) either centrally or peripherally, or both.
- the pharmacodynamic response may be attributed to the compound either stimulating (agonizing) or inhibiting (antagonizing) the one or more receptors.
- Certain compounds according to the invention may antagonize one opioid receptor, while also agonizing one or more other receptors.
- Compounds according to the invention having agonist activity may be either full agonists or partial agonists.
- agonists compounds that bind to receptors and mimic the regulatory effects of endogenous ligands are defined as “agonists”.
- antagonists Compounds that bind to a receptor but produce no regulatory effect, but rather block the binding of ligands to the receptor, are defined as “antagonists”.
- the compounds according to the invention are agonists at the mu opioid (MOP) and/or kappa opioid (KOP) and/or delta opioid (DOP) and/or nociceptin opioid (NOP/ORL-1) receptors.
- MOP mu opioid
- KOP kappa opioid
- DOP delta opioid
- NOP/ORL-1 nociceptin opioid
- the compounds according to the invention potently bind to the MOP and/or KOP and/or DOP and/or NOP receptors.
- the compounds according to the invention can be modulators at the MOP and/or KOP and/or DOP and/or NOP receptors, and therefore the compounds according to the invention can be used/administered to treat, ameliorate, or prevent pain.
- the compounds according to the invention are agonists of one or more opioid receptors. In some embodiments, the compounds according to the invention are agonists of the MOP and/or KOP and/or DOP and/or NOP receptors.
- the compounds according to the invention are antagonists of one or more opioid receptors. In some embodiments, the compounds according to the invention are antagonists of the MOP and/or KOP and/or DOP and/or NOP receptors.
- the compounds according to the invention have both, (i) agonist activity at the NOP receptor; and (ii) agonist activity at one or more of the MOP, KOP, and DOP receptors.
- the compounds according to the invention have both, (i) agonist activity at the NOP receptor; and (ii) antagonist activity at one or more of the MOP, KOP, and DOP receptors.
- the compounds according to the invention have both, (i) antagonist activity at the NOP receptor; and (ii) agonist activity at one or more of the MOP, KOP, and DOP receptors.
- the compounds according to the invention have both, (i) antagonist activity at the NOP receptor; and (ii) antagonist activity at one or more of the MOP, KOP, and DOP receptors.
- the compounds according to the invention have selective agonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
- the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the MOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
- the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the KOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
- the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the DOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
- the compounds according to the invention have selective agonist activity at the KOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
- the compounds according to the invention have agonist activity at the MOP receptor, agonist activity at the KOP receptor, and antagonist activity at the DOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
- the compounds according to the invention have selective agonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention
- the compounds according to the invention have selective antagonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention
- the compounds according to the invention have antagonist activity at the NOP receptor as well as agonist activity at the DOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention
- no significant activity means that the activity (agonist/antagonist) of the given compound at this receptor is lower by a factor of 1000 or more compared to its activity (agonist/antagonist) at one or more of the other opioid receptors.
- a further aspect of the invention relates to the compounds according to the invention as medicaments.
- a further aspect of the invention relates to the compounds according to the invention for use in the treatment of pain.
- a further aspect of the invention relates to a method of treating pain comprising the administration of a pain alleviating amount of a compound according to the invention to a subject in need thereof, preferably to a human.
- the pain is preferably acute or chronic.
- the pain is preferably nociceptive or neuropathic.
- a further aspect of the invention relates to the compounds according to the invention for use in the treatment of neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, and substance abuse/dependence.
- a further aspect of the invention relates to a method of treating any one of the aforementioned disorders, diseases or conditions comprising the administration of a therapeutically effective amount of a compound according to the invention to a subject in need thereof, preferably to a human.
- Another aspect of the invention relates to a pharmaceutical composition which contains a physiologically acceptable carrier and at least one compound according to the invention.
- the composition according to the invention is solid, liquid or pasty; and/or contains the compound according to the invention in an amount of from 0.001 to 99 wt. %, preferably from 1.0 to 70 wt. %, based on the total weight of the composition.
- composition according to the invention can optionally contain suitable additives and/or auxiliary substances and/or optionally further active ingredients.
- physiologically acceptable carriers examples include fillers, solvents, diluents, colorings and/or binders. These substances are known to the person skilled in the art (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende füre, Editio Cantor Aulendoff).
- the pharmaceutical composition according to the invention contains the compound according to the invention in an amount of preferably from 0.001 to 99 wt. %, more preferably from 0.1 to 90 wt. %, yet more preferably from 0.5 to 80 wt. %, most preferably from 1.0 to 70 wt. % and in particular from 2.5 to 60 wt. %, based on the total weight of the pharmaceutical composition.
- the pharmaceutical composition according to the invention is preferably for systemic, topical or local administration, preferably for oral administration.
- Another aspect of the invention relates to a pharmaceutical dosage form which contains the pharmaceutical composition according to the invention.
- the pharmaceutical dosage form according to the invention is produced for administration twice daily, for administration once daily or for administration less frequently than once daily.
- Administration is preferably systemic, in particular oral.
- the pharmaceutical dosage form according to the invention can be administered, for example, as a liquid dosage form in the form of injection solutions, drops or juices, or as a semi-solid dosage form in the form of granules, tablets, pellets, patches, capsules, plasters/spray-on plasters or aerosols.
- auxiliary substances etc. and the amounts thereof to be used depend on whether the form of administration is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example to the skin, the mucosa or into the eyes.
- compositions in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, readily reconstitutable dry preparations and also sprays are suitable for parenteral, topical and inhalatory administration.
- the amount of the compounds according to the invention to be administered to the patient varies in dependence on the weight of the patient, on the type of administration, on the indication and on the severity of the disease. Usually, from 0.00005 mg/kg to 50 mg/kg, preferably from 0.001 mg/kg to 10 mg/kg, of at least one compound according to the invention is administered.
- Another aspect of the invention relates to a process for the preparation of the compounds according to the invention. Suitable processes for the synthesis of the compounds according to the invention are known in principle to the person skilled in the art.
- the compounds according to the invention can be obtained via different synthesis routes. Depending on the synthesis route, different intermediates are prepared and subsequently further reacted.
- the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIa):
- R 1 , R 2 and R 3 are defined as above.
- the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIb):
- R 1 , R 2 and R 3 are defined as above and PG is a protecting group.
- the protecting group is -p-methoxybenzyl. Therefore, in another preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIc):
- R 1 , R 2 and R 3 are defined as above.
- the -p-methoxybenzyl moiety represents a protecting group which can be cleaved in the course of the synthesis route.
- the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of
- RT room temperature (23 ⁇ 7° C.)
- M are indications of concentration in mol/l
- aq.” means aqueous
- sat.” means saturated
- sol.” means solution
- conc.” means concentrated.
- the mixing ratios of solvents or eluents for chromatography are specified in v/v.
- CIS refers to the relative configuration of compounds described herein, in which both nitrogen atoms are drawn on the same face of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:
- TRANS refers to compounds, in which both nitrogen atoms are on opposite faces of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:
- Step 1 CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione
- Step 2 CIS-8-Dimethylamino-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
- Step 3 CIS-8-Dimethylamino-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one
- Step 1 CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 2 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 1 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile
- Step 2 1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl) cyclobutanecarboxamide
- Step 3 1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane carbonitrile
- Step 1 1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one
- Step 2 1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione
- Step 3 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
- Step 4 CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 5 CIS-1-(cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- KOtBu (57.0 g, 508.4 mmol) was added to the solution of 2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate (89.0 g, 889.8 mmol) in THF (500 mL) at 0° C. and stirred for 16 h at RT. The reaction mixture was quenched with sat. aq. NH 4 Cl and extracted with EtOAc (2 ⁇ 500 mL).
- Step 1 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile
- Step 3 methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate
- Step 1 8-(Dimethylamino)-1,4-dioxaspiro 4.5]decane-8-carbonitrile
- Dimethylamine hydrochloride 52 g, 0.645 mol was added to the solution of 1,4-dioxaspiro-[4.5]-decan-8-one (35 g, 0.224 mmol) in MeOH (35 mL) at RT under argon atmosphere. The solution was stirred for 10 min and 40 wt % aq. dimethylamine (280 mL, 2.5 mol) and KCN (32 g, 0.492 mol) were sequentially added. The reaction mixture was stirred for 48 h at RT, then diluted with water (100 mL) and extracted with EtOAc (2 ⁇ 200 mL).
- Step 2 N,N-dimethyl-8-phenyl-1,4-dioxaspiro-[4.5]decan-8-amine
- Step 1 9,12-Dioxa-2,4-diazadispiro[4.2.4 ⁇ 8 ⁇ .2 ⁇ 5 ⁇ ]tetradecane-1,3-dione
- Step 2 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4 ⁇ 8 ⁇ .2 ⁇ 5 ⁇ ]tetradecane-1,3-dione
- Step 3 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4 ⁇ 8 ⁇ .2 ⁇ 5 ⁇ ]tetradecan-3-one
- Step 4 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione
- Step 1 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione
- Step 2 8-(dimethylamino)-8-phenyl-1, 3-diazaspiro[4,5]decan-2-one
- Step 3 CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 1 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester
- Step 2 cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid trifluoroacetic acid salt
- CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester 200 mg, 0.4 mmol was dissolved in TFA (5 mL) and heated to reflux overnight. After cooling to RT all volatiles are removed in vacuo. The residue was taken up in THF (1 mL) and added dropwise to diethyl ether (20 mL).
- CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid (INT-977) trifluoroacetic acid salt (119 mg, 0.35 mmol) was dissolved in DCM (5 mL). Triethylamine (0.21 mL, 1.6 mmol), dimethylamine (0.54 mL, 1.1 mmol) and T3P (0.63 mL, 1.1 mmol) were sequentially added. The reaction mixture was stirred at RT overnight, then diluted with 1 M aq. Na 2 CO 3 (5 mL).
- Step 1 CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 2 CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 1 CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) was converted into CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.
- Step 2 CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- step 2 CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was converted into CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-984).
- Step 1 CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- N-Iodosuccinimide (3.11 g, 13.92 mmol) was added to the solution of CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[phenyl-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-950) (4 g, 9.28 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 80 mL) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with 2N aq. NaOH to pH-10 and the organic product was extracted with DCM (3 ⁇ 10 mL).
- Step 2 CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro [4.5]decan-2-one
- Step 3 CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-986)
- step 2 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-952) was converted into CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987).
- Step 1 CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 2 CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-988)
- Step 1 and step 2 ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (INT-1004)
- Step 3 4-ethylamino-4-phenyl-cyclohexanone (INT-1005)
- Step 4 cis and trans mixture of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (INT-1006 and INT-1007)
- Step 5 CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (INT-1006)
- Step 6 CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1008)
- CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (5.0 g, 18.31 mmol, 1.0 eq.) in dry THF (500 ml) was added t-BuOK (3.07 g, 27.46 mmol, 1.5 eq.) and the reaction mixture was stirred at RT for 15 min.
- 3-Bromo-propyne (3.24 g, 13.18 mmol, 1.2 eq., 80% in toluene) was added and stirring was continued at RT for 18 h.
- the reaction mixture was poured into ice-water and extracted with DCM (800 ml).
- CIS-2-(4-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetate (INT-1011) (2.0 g, 4.54 mmol, 1.0 eq.) in DMSO (30 ml) was added NaOH (727 mg, 18.18 mmol, 4.0 eq.) at RT and the reaction mixture was heated to 70° C. for 30 min.
- Step 1 CIS-3-benzyl-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 2 CIS-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1021)
- step 1 CIS-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was reacted with N-iodosuccinimide to be converted into CIS-1-(2-methoxybenzyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1022).
- Step 1 synthesis of CIS-1-amino-4-(dimethylamino)-4-phenylcyclohexanecarboxylic acid
- Step 2 synthesis of CIS-1-(tert-butoxycarbonylamino)-4-(dimethylamino)-4-phenylcyclohexanecarboxylic acid (INT-1023)
- CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one (SC-2147) was treated with TFA to be converted into CIS-8-(dimethylamino)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one (INT-1028).
- Titanium ethoxide (58.45 g, 256.4 mmol) was added to a solution of 1,4-dioxaspiro[4.5]decan-8-one (20 g, 128.20 mmol) and 2-methylpropane-2-sulfinamide (15.51 g, 128.20 mmol) in THF (200 mL) at RT and the reaction mixture was stirred at RT for 18 h. The reaction mixture was cooled to 0° C. and quenched by dropwise addition of sat. aq. NaHCO 3 (500 mL) over a period of 30 min. The organic product was extracted with EtOAc (3 ⁇ 100 mL).
- Step 2 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide
- Phenylmagnesium bromide (1M in THF, 116 mL, 116 mmol) was added dropwise to a solution of 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide (10 g, 38.61 mmol) in THF (500 mL) at ⁇ 10° C. under argon atmosphere. The reaction mixture was stirred for 2 h at ⁇ 10° C. to 0° C. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH 4 Cl (50 mL) at 0° C. and the organic product was extracted with EtOAc (3 ⁇ 100 mL).
- Step 4 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine
- Step 5 N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine)
- Step 6 4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone
- Step 7 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
- Step 8 CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
- Diastereomeric mixture of 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (1.0 g) was separated by reverse phase preparative HPLC to afford 400 mg of isomer 1 (CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 60 mg of isomer 2 (TRANS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 300 mg of mixture of both isomers.
- Reverse phase preparative HPLC conditions mobile phase: 10 mM ammonium bicarbonate in H 2 O/acetonitrile, column: X-BRIDGE-C18 (150*30), 5 ⁇ m, gradient (T/B %): 0/35, 8/55, 8.1/98, 10/98, 10.1/35, 13/35, flow rate: 25 ml/min, diluent: mobile phase+THF.
- Step 9 CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1026)
- Step 1 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
- Step 2 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
- Step 1 9,12-dioxa-2,4-diazadispiro[4.2.4 ⁇ 8 ⁇ .2 ⁇ 5 ⁇ ]tetradecan-3-one
- Lithiumaluminiumhydride (2.2 equiv., 292 mmol) was suspended in THF (400 mL) and the suspension was cooled to 0° C.
- 8-(Dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (B, 75 mg, 0,261 mmol) (step 1 of INT-965) was added portionwise at 0° C.
- the reaction mixture was stirred 1.5 h at 0° C., then overnight at RT and then 2 h at 40° C.
- the reaction mixture was cooled down to 0° C., quenched carefully with sat. aq.
- Step 3 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (INT-1037)
- Step 1 CIS-1-acetyl-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 2 CIS-1-acetyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1064)
- Step 1 TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
- Step 2 TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1059)
- TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione was treated with LiAlH 4 to be converted into TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1059). Mass: m/z 274.2 (M+H) + .
- Step 1 CIS-1-acetyl-3-((2-chloropyridin-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- CIS-1-acetyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1064) (1 g, 3.17 mmol) in DMF (37 mL) was added sodium hydride (60 wt % in mineral oil, 1.25 equiv., 3.96 mmol, 159 mg) portionwise at 0° C.
- the reaction mixture was stirred for 15 min at 0° C. and 2-chloro-4-(chloromethyl)pyridine (1.25 equiv., 3.96 mmol, 0.485 mL) was added.
- reaction mixture was stirred at RT for 2 h, then cooled down to 0° C., quenched with sat. aq. NaHCO 3 (10 mL), water (10 mL) and extracted with EtOAc (2 ⁇ 50 mL). Combined organic phase was washed with brine, dried over anhydr. Na 2 SO 4 and concentrated under reduced pressure.
- Step 2 CIS-3-((2-chloropyridin-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1065)
- Step 3 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine
- Step 4 CIS- and TRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1068 and INT-1069)
- HPLC: 98.53%, Column: Xbridge C-18 (100 ⁇ 4.6), 5 ⁇ , Diluent: MeOH, Mobile phase: A) 0.05% TFA in water; B) ACN flow rate: 1 ml/min, R t 5.17 min.
- reaction completion was monitored by TLC.
- the reaction mixture was quenched with sat. aq. NH 4 Cl and the organic product was extracted with EtOAc (2 ⁇ 10 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
- Step 1 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
- Dimethylamine hydrochloride (76.36 g, 936.39 mmol) was added to a solution of 3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione INT-966 (90 g, 312.13 mmol) in MeOH (180 mL) at RT under argon atmosphere. The solution was stirred for 15 min and 40% aq. dimethylamine (780 mL) and KCN (48.76 g, 749.11 mmol) were sequentially added. The reaction mixture was stirred for 48 h while being monitored by NMR. The reaction mixture was diluted with water (1.0 L) and the organic product was extracted with EtOAc (2 ⁇ 2.0 L).
- Step 2 CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
- Step 1 CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- CIS-8-dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-968) was converted into CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-(methoxymethoxy)phenyl)-1,3-diazaspiro[4.5]decan-2-one.
- Step 2 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
- KOtBu (411 mg, 3.66 mmol) was added to a solution of CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (250 mg, 0.73 mmol) in THF (6 mL) under nitrogen atmosphere and the reaction mixture was stirred at RT for 30 min. After cooling to 0° C. 3-(chloromethyl)pyridine hydrochloride (180 mg, 1.10 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min and then at RT for 3 days.
- N-Iodosuccinimide (437 mg, 1.95 mmol) was added to a suspension of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2002) (600 mg, 1.30 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 20 mL) at RT and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with 2N aq. NaOH to pH-10 and the organic product was extracted with DCM (3 ⁇ 10 mL).
- the reaction mixture was allowed to stir at RT for 16 h and then diluted with water (15 mL).
- the organic product was extracted with ethyl acetate (3 ⁇ 25 mL).
- the combined organic extracts were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
- the residue was dissolved in THF (8 mL) and cooled to 0° C.
- a 1M TBAF solution in THF (1.8 mL, 1.81 mmol) was added at 0° C.
- the reaction mixture was allowed to stir at RT for 2 h.
- the reaction mixture was diluted with water (10 mL), the organic product was extracted with DCM (3 ⁇ 25 mL).
- the combined organic extracts were washed with sat. aq.
- Powdered sodium hydroxide (21 mg, 0.5 mmol) was dissolved in 0.2 mL of dry DMSO. After stirring at RT for 30 min CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(4-hydroxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2089) (60 mg, 0.13 mmol) was added and the resulting mixture was stirred for another 30 min.
- N-Iodosuccinimide (233 mg, 1.035 mmol) was added to a solution of CIS-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2026) (320 mg, 0.690 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 30 mL) at 0° C. and the resulting mixture was stirred for 5 h at RT. The reaction mixture was cooled to 0° C.
- N-Iodosuccinimide 233 mg, 1.035 mmol
- the reaction mixture was allowed to warm up to RT and was stirred for further 11 h.
- the reaction mixture was basified with 2N aq. NaOH to pH-10 and the organic product was extracted with ethyl acetate (3 ⁇ 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
- the reaction mixture was diluted with sat. aq. NaHCO 3 (20 mL) and the organic product was extracted with EtOAc (4 ⁇ 50 mL). The combined organic layer was dried over anhydr. Na 2 SO 4 and concentrated in vacuo.
- the crude product was purified by column chromatography (using 230-400 mesh silica gel and 2-5% MeOH in DCM as eluent) to afford 250 mg of product which was further purified by prep.
- CIS-8-dimethylamino-8-phenyl-3-prop-2-ynyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1010) (1.0 g, 3.21 mmol, 1.0 eq.) in dioxane/MeOH (50 ml, 9:1) were added sodium azide (418 mg, 6.42 mmol, 2.0 eq.) and cuprous chloride (32 mg, 0.32 mmol, 0.1 eq.) at RT.
- the reaction mixture was stirred at 80° C. for 18 h, then quenched with water and concentrated under reduced pressure.
- the resulting residue was purified by column chromatography (silica gel neutralized with aq.
- Step 1 synthesis of tert-butyl CIS-4-(dimethylamino)-4-phenyl-1-(2-phenylpropan-2-ylcarbamoyl)cyclohexylcarbamate
- Step 2 synthesis of CIS-1-amino-4-(dimethylamino)-4-phenyl-N-(2-phenylpropan-2-yl)cyclohexanecarboxamide hydrochloride
- Step 3 synthesis of CIS-N,N-dimethyl-1-phenyl-4-((2-phenylpropan-2-ylamino)methyl)cyclohexane-1,4-diamine
- Step 3 synthesis of CIS-8-(dimethylamino)-8-phenyl-3-(2-phenylpropan-2-yl)-1,3-diazaspiro[4.5]decan-2-one SC_2170
- 1,1′-Carbonyldiimidazole (0.90 g, 5.58 mmol) was added to a solution of CIS-N,N-dimethyl-1-phenyl-4-((2-phenylpropan-2-ylamino)methyl)cyclohexane-1,4-diamine (1.7 g, 4.65 mmol) in DMF (20 mL) at RT. The reaction mixture was stirred at RT for 16 h.
- Step 1 synthesis of CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one
- CIS-8-(dimethylamino)-8-phenyl-1-(p-tolylsulfonyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1028) (200 mg, 0.47 mmol, 1 equiv.) was dissolved in DMF (3.6 mL) under argon atmosphere and the solution was cooled down to 0° C.
- Sodium hydride 60 wt % in mineral oil, 2.1 equiv., 0.98 mmol, 39 mg
- 4-(Bromomethyl)pyridine hydrobromide (1.05 equiv., 0.49 mmol, 124 mg) was added at 0° C.
- Step 2 synthesis of CIS-8-(dimethylamino)-8-phenyl-3-(pyridin-4-ylmethyl)-1,3-diazaspiro[4.5]decan-2-one (SC_2180)
- CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one (110 mg, 0.212 mmol, 1 equiv.) was dissolved in THF (2 mL) and MeOH (4.4 mL) under argon atmosphere. Magnesium turnings (103 mg, 4.24 mmol, 20 equiv.) were added and the resulting mixture was stirred at RT for 18 h. The reaction mixture was diluted with DCM (30 mL) and water (10 mL), stirred at RT for 1.5 h, filtered through celite and the solid residue was washed with DCM (3 ⁇ ).
- SC_2159 CIS-2-[4-[[1-(Cyclobutyl- INT-1030 ammonia SC_2145 1HNMR (DMSO-d6, 400 MHz), ⁇ (ppm) 480.1 methyl)-8-dimethylamino-2- 7.86 (s, 1H), 7.66 (s, 1H), 7.23-7.33 (m, oxo-8 -phenyl-1,3- 6H), 5.00 (s, 2H), 4.30 (s, 2H), 3.09(s, diazaspiro[4.5]decan-3-yl]- 2H), 3.04 (s, 2H), 2.61-2.64 (m, 2H), methyl]-1H-[1,2,3]triazol- 1.95.-2.02 (m, 11H), 1.69-1.78 (m, 4H), 1-yl]-acetamide 1.28-1.33 (m, 4H).
- SC_2172 CIS-8-Dimethylamino-1,3- INT-976 1-(bromomethyl)- SC_2097 1H NMR (DMSO-d6): ⁇ 7.32-7.14 (m, 514.2 bis[(2-methoxyphenyl)- 2-methoxybenzene 9H), 6.99-6.90 (m, 4H), 4.32-4.27 (m, methyl]-8-phenyl- 4H), 3.84-3.77 (m, 6H), 3.14 (s, 2H), 1,3-diazaspiro[4.5]decan-2- 2.58-2.54 (m, 2H), 2.03-1.97 (m, 2H), one 1.89 (s, 6H), 1.29-1.22 (m, 4H).
- SC_2174 CIS-8-Dimethylamino-1-[(1- SC_2170 (1-(tert- INT-799 1H NMR (DMSO-d6): ⁇ 7.36-7.14 (m, 476.3 hydroxy-cyclobutyl)- butyldimethyl- (step 1) 10H), 5.88 (m, 1H), 3.33 (s, 2H), 3.03 methyl]-3-(1-methyl-1- silyloxy)cyclo- (s, 2H), 2.68-2.64 (m, 2H), 2.09-1.95 (m, phenyl-ethyl)-8-phenyl-1,3- butyl)methyl- 10H), 1.89-1.81 (m, 2H), 1.61-1.56 (m, diazaspiro[4.5]decan-2-one 4-methylbenzene- 7H), 1.48-1.28 (m, 5H).
- SC_2176 CIS-3-(1,3-Benzodioxol-4- INT-976 4-(bromomethyl)- SC_2097 1H NMR (600 MHz, DMSO) ⁇ 7.37-7.27 408.2 yl-methyl)-8-dimethylamino- 1,3-benzodioxole (m, 4H), 7.27-7.20 (m, 1H), 6.88 (s, 1H), 8-phenyl-1,3- 6.83-6.76 (m, 2H), 6.67 (dd, 1H), 5.96 diazaspiro[4.5]decan-2-one (s, 2H), 4.18 (s, 2H), 2.95 (s, 2H), 2.30-2.26 (m, 2H), 1.93 (s, 6H), 1.84- 1.63 (m, 4H), 1.33 (t, 2H).
- SC_2177 CIS-8-Dimethylamino-1-[(1- SC_2171 (1-(tert- INT-799 1H NMR (DMSO-d6): ⁇ 7.34-7.17 (m, 474.2 hydroxy-cyclobutyl)- butyldimethyl- (step 1) 8H), 7.15-7.13 (m, 2H), 5.89 (s, 1H), methyl]-8-phenyl-3-(1- silyloxy)cyclo- 3.29 (s, 2H), 3.09 (s, 2H), 2.64-2.61 (m, phenyl-cyclopropyl)-1,3- butyl)methyl- 2H), 2.08-2.03 (m, 4H), 1.96 (s, 6H), diazaspiro[4.5]decan-2-one 4-methylbenzene- 1.91-1.84 (m, 2H), 1.64-1.61 (m, 1H), sulfonate 1.42-1.29 (m, 5H), 1.29-1.26 (m, 2
- SC_2179 CIS-8-Dimethylamino-3-[(2- INT-976 1-(bromomethyl)- SC_2097 1H NMR (600 MHz, DMSO) ⁇ 7.37-7.27 394.3 methoxyphenyl)-methyl]-8- 2-methoxybenzene (m, 4H), 7.27-7.19 (m, 2H), 7.08 (dd, phenyl-1,3- 1H), 6.96 (dd, 1H), 6.91 (td, 1H), 6.85 diazaspiro[4.5]decan-2-one (s, 1H), 4.19 (s, 2H), 3.75 (s, 3H), 2.96 (s, 2H), 2.30 (d, 2H), 1.93 (s, 6H), 1.86-1.69 (m, 4H), 1.38-1.32 (m, 2H).
- SC_2184 CIS-8-Dimethylamino-8- INT-1065 piperidine SC_2183 1H NMR (600 MHz, CDCl3) ⁇ 8.09 (d, 448.3 phenyl-3-[(2-piperidin-1- 1H), 7.38 (dd, 2H), 7.30 (d, 3H), 6.48 yl-pyridin-4-yl)-methyl]- (s, 1H), 6.42 (dd, 1H), 5.47 (s, 1H), 1,3-diazaspiro[4.5]decan-2- 4.23 (s, 2H), 3.54-3.46 (m, 4H), 2.96 (s, one 2H), 2.20-2.15 (m, 4H), 2.07 (s, 6H), 1.92-1.84 (m, 2H), 1.66-1.60 (m, 6H), 1.47-1.39 (m, 2H).
- hMOP human mu-opioid receptor
- hKOP human kappa-opioid receptor
- hDOP human delta-opioid receptor
- hNOP human nociceptin/orphanin FQ peptide receptor
- the hMOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl (pH 7.4) supplemented with 0.052 mg/ml bovine serum albumin (Sigma-Aldrich Co. St. Louis. Mo.).
- the final assay volume 250 ⁇ l/well included 1 nM of [N-allyl-2.3- 3 H]naloxone as ligand (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). and either test compound in dilution series or 25 ⁇ M unlabelled naloxone for determination of unspecific binding.
- the test compound was diluted with 25% DMSO in H 2 O to yield a final 0.5% DMSO concentration. which also served as a respective vehicle control.
- the assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd. Buckinghamshire. UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). After incubation for 90 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux ⁇ -counter (PerkinElmer Life Sciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [ 3 H]naloxone-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation. (Cheng and Prusoff. 1973).
- the hKOP receptor binding assay is run as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl (pH 7.4) supplemented with 0.076 mg BSA/ml.
- the final assay volume of 250 ⁇ l per well includes 2 nM of [ 3 H]U69,593 as ligand, and either test compound in dilution series or 100 ⁇ M unlabelled naloxone for determination of unspecific binding.
- the test compound is diluted with 25% DMSO in H 2 O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well.
- the assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 ⁇ l final assay volume per well) which has been preloaded for 15 minutes at room temperature with hKOP receptor membranes (14.8 ⁇ g/250 ⁇ l final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 90 minutes at room temperature. After this incubation, the microtiter plates are sealed with a topseal and centrifuged for 20 minutes at 500 rpm.
- the signal rate is measured after a short delay of 5 minutes by means of a 1450 Microbeta Trilux ⁇ -counter (PerkinElmer Life Sciences/Wallac, Turku, Finland).
- Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [ 3 H]U69.593-specific receptor binding are calculated by nonlinear regression analysis and Ki values are calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
- the hDOP receptor binding assay is performed as homogeneous SPA-assay using the assay buffer 50 mM TRIS-HCl, 5 mM MgCl 2 (pH 7.4).
- the final assay volume (250 ⁇ l/well) includes 1 nM of [Tyrosyl-3,5- 3 H]2-D-Ala-deltorphin II as ligand, and either test compound in dilution series or 10 ⁇ M unlabelled naloxone for determination of unspecific binding.
- the test compound is diluted with 25% DMSO in H 2 O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well.
- the assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 ⁇ l final assay volume per well) which has been preloaded for 15 minutes at room temperature with hDOP receptor membranes (15.2 ⁇ g/250 ⁇ l final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 120 minutes at room temperature and centrifuged for 20 minutes at 500 rpm. The signal rate is measured by means of a 1450 Microbeta Trilux ⁇ -counter (PerkinElmer Life Sciences/Wallac, Turku, Finland).
- IC50 Half-maximal inhibitory concentration
- the hNOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl. 10 mM MgCl 2 . 1 mM EDTA (pH 7.4).
- the final assay volume (250 ⁇ l/well) included 0.5 nM of [leucyl- 3 H]nociceptin as ligand (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). and either test compound in dilution series or 1 ⁇ M unlabelled nociceptin for determination of unspecific binding.
- the test compound was diluted with 25% DMSO in H 2 O to yield a final 0.5% DMSO concentration. which also served as a respective vehicle control.
- the assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd. Buckinghamshire. UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). After incubation for 60 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux 1-counter (PerkinElmer Life Sciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [ 3 H]nociceptin-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation. (Cheng and Prusoff. 1973).
- the [ 35 S]GTP ⁇ S assays are carried out essentially as described by Gillen et al (2000). They are run as homogeneous scintillation proximity (SPA) assays in microtiter luminescence plates, where each well contains 1.5 mg of WGA-coated SPA-beads.
- SPA scintillation proximity
- hNOP hMOP
- hDOP hKOP receptor expressing cell membranes from CHO-K1 or HEK293 cells
- 10 or 5 ⁇ g membrane protein per assay are incubated with 0.4 nM [ 35 S]GTP ⁇ S and serial concentrations of receptor-specific agonists in buffer containing 20 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl2, 1 mM EDTA, 1 mM dithiothreitol, 1.28 mM NaN 3 , and 10 ⁇ M GDP for 45 min at room temperature.
- microtiter plates are then centrifuged for 10 min at 830 to sediment the SPA beads.
- the microtiter plates are sealed and the bound radioactivity [cpm] is determined after a delay of 15 min by means of a 1450 Microbeta Trilux (PerkinElmer, Waltham, Mass.).
- the unstimulated basal binding activity (UBS obs [cpm]) is determined from 12 unstimulated incubates and is set as 100% basal binding.
- the arithmetic mean of the observed total [ 35 S]GTP ⁇ S binding (TB obs [cpm]) of all incubates (duplicates) stimulated by the receptor-specific agonists i.e. N/OFQ, SNC80, DAMGO, or U69,593
- TB obs [%] percent total binding relative to the basal binding activity (i.e. 100% binding).
- the potency (EC 50 ) of the respective agonist and its maximal achievable total [ 35 S]GTP ⁇ S binding (TB calc [%]) above its calculated basal binding (UBS calc [%]) are determined from its transformed data (TB obs [%]) by means of nonlinear regression analysis with XLfit for each individual concentration series. Then the difference between the calculated unstimulated [ 35 S]GTP ⁇ S binding (UBS calc [%]) and the maximal achievable total [ 35 S]GTP ⁇ S binding (TB calc [%]) by each tested agonist is determined (i.e. B1 calc [%]).
- the percentage efficacies of test compounds at the hDOP, hMOP, or hKOP receptor are determined versus the calculated maximal enhancement of [ 35 S]GTP ⁇ S binding by the full agonists SNC80 (B1 calc-SNC80 [%]), DAMGO (B1 calc-DAMGO [%]) and U69,593 (B1 calc-U69,593 [%]) which are set as 100% relative efficacy at each receptor, respectively.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Addiction (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/984,919 US20180327392A1 (en) | 2016-01-13 | 2018-05-21 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US16/265,080 US10829480B2 (en) | 2016-01-13 | 2019-02-01 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-l,3-diaza-spiro-[4.5]-decane derivatives |
US17/007,258 US20200399252A1 (en) | 2016-01-13 | 2020-08-31 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US17/188,743 US20210179592A1 (en) | 2016-01-13 | 2021-03-01 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US18/103,180 US20230174520A1 (en) | 2016-01-13 | 2023-01-30 | 3-((Hetero-)Aryl)-Alkyl-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP16151013 | 2016-01-13 | ||
EP16151013.6 | 2016-01-13 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/984,919 Continuation US20180327392A1 (en) | 2016-01-13 | 2018-05-21 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
US20170197947A1 true US20170197947A1 (en) | 2017-07-13 |
Family
ID=55129634
Family Applications (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/405,896 Abandoned US20170197947A1 (en) | 2016-01-13 | 2017-01-13 | 3-((Hetero-)Aryl)-Alkyl-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives |
US15/984,919 Abandoned US20180327392A1 (en) | 2016-01-13 | 2018-05-21 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US16/265,080 Active US10829480B2 (en) | 2016-01-13 | 2019-02-01 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-l,3-diaza-spiro-[4.5]-decane derivatives |
US17/007,258 Abandoned US20200399252A1 (en) | 2016-01-13 | 2020-08-31 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US17/188,743 Abandoned US20210179592A1 (en) | 2016-01-13 | 2021-03-01 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US18/103,180 Pending US20230174520A1 (en) | 2016-01-13 | 2023-01-30 | 3-((Hetero-)Aryl)-Alkyl-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives |
Family Applications After (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/984,919 Abandoned US20180327392A1 (en) | 2016-01-13 | 2018-05-21 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US16/265,080 Active US10829480B2 (en) | 2016-01-13 | 2019-02-01 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-l,3-diaza-spiro-[4.5]-decane derivatives |
US17/007,258 Abandoned US20200399252A1 (en) | 2016-01-13 | 2020-08-31 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US17/188,743 Abandoned US20210179592A1 (en) | 2016-01-13 | 2021-03-01 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US18/103,180 Pending US20230174520A1 (en) | 2016-01-13 | 2023-01-30 | 3-((Hetero-)Aryl)-Alkyl-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives |
Country Status (28)
Country | Link |
---|---|
US (6) | US20170197947A1 (hu) |
EP (1) | EP3402784B1 (hu) |
JP (1) | JP6893517B2 (hu) |
KR (1) | KR20180098369A (hu) |
CN (1) | CN108602777B (hu) |
AR (1) | AR107360A1 (hu) |
AU (1) | AU2017206909B2 (hu) |
BR (1) | BR112018014303B1 (hu) |
CA (1) | CA3011177A1 (hu) |
CL (1) | CL2018001912A1 (hu) |
CO (1) | CO2018008444A2 (hu) |
CY (1) | CY1122818T1 (hu) |
DK (1) | DK3402784T3 (hu) |
EA (1) | EA037481B1 (hu) |
EC (1) | ECSP18060848A (hu) |
ES (1) | ES2797904T3 (hu) |
HR (1) | HRP20200837T1 (hu) |
HU (1) | HUE049813T2 (hu) |
IL (1) | IL260491B (hu) |
LT (1) | LT3402784T (hu) |
MX (1) | MX2018008644A (hu) |
PE (1) | PE20181375A1 (hu) |
PL (1) | PL3402784T3 (hu) |
PT (1) | PT3402784T (hu) |
RS (1) | RS60315B1 (hu) |
SI (1) | SI3402784T1 (hu) |
TW (1) | TWI636048B (hu) |
WO (1) | WO2017121648A1 (hu) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10793556B2 (en) | 2016-01-13 | 2020-10-06 | Gruenenthal Gmbh | 8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US10793528B2 (en) | 2016-01-13 | 2020-10-06 | Grünenthal GmbH | 3-((hetero-)aryl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US10807989B2 (en) | 2016-01-13 | 2020-10-20 | Grünenthal GmbH | 3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US10807988B2 (en) | 2016-01-13 | 2020-10-20 | Grünenthal GmbH | 3-((hetero-)aryl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US10829480B2 (en) | 2016-01-13 | 2020-11-10 | Gruenenthal Gmbh | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-l,3-diaza-spiro-[4.5]-decane derivatives |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA202092490A1 (ru) | 2018-04-18 | 2020-12-23 | Констеллейшен Фармасьютикалс, Инк. | Модуляторы метилмодифицирующих ферментов, композиции и их применения |
US11919912B2 (en) | 2018-05-21 | 2024-03-05 | Constellation Pharmaceuticals, Inc. | Modulators of methyl modifying enzymes, compositions and uses thereof |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2734265B1 (fr) | 1995-05-17 | 1997-06-13 | Adir | Nouveaux composes spiro heterocycliques, leur procede de preparation et les compositions pharmaceutiques les contenant |
JP4380992B2 (ja) | 2001-04-18 | 2009-12-09 | ユーロ−セルティーク エス.エイ. | ノシセプチン類似体 |
DE10130020A1 (de) | 2001-06-25 | 2003-12-04 | Gruenenthal Gmbh | Substituierte 1-Oxa-2,8-diaza-spiro[4.5]dec-2-en-derivate |
DE10210195B4 (de) | 2002-03-07 | 2005-12-15 | Schwarz Pharma Ag | Verwendung von 1,3-Diazaspiro-[4,5]decan-2,4-dithion zur Behandlung von Schmerz |
AU2003245753B2 (en) | 2002-07-05 | 2009-12-24 | Targacept, Inc. | N-aryl diazaspiracyclic compounds and methods of preparation and use thereof |
DE10252667A1 (de) * | 2002-11-11 | 2004-05-27 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
NZ544282A (en) | 2003-05-23 | 2009-07-31 | Zealand Pharma As | Triaza-spiro compounds as nociceptin analogues and uses thereof |
JO2676B1 (en) | 2004-04-06 | 2012-06-17 | جانسين فارماسوتيكا ان. في | Derivatives of second-aza-spiro- (5,4) -dikan and their use as antihistamines |
KR20110079776A (ko) | 2006-10-19 | 2011-07-07 | 에프. 호프만-라 로슈 아게 | 당뇨병을 위한 11베타-에이치에스디1 억제제로서의 이미다졸론 및 이미다졸리딘온 유도체 |
MX2009011006A (es) | 2007-04-09 | 2009-11-02 | Janssen Pharmaceutica Nv | Derivados de 1,3,8-trisustituido-1,3,8-triaza-espiro[4.5]decano-4- ona como ligandos del receptor de orl-1 para el tratamiento de ansiedad y depresion. |
NZ588779A (en) | 2008-03-27 | 2012-06-29 | Gruenenthal Chemie | Substituted 4-aminocyclohexane derivatives |
WO2010151815A2 (en) | 2009-06-25 | 2010-12-29 | Abbott Laboratories | 3,9-diazaspiro[5,5]undecane amides and ureas and methods of use thereof |
TWI582092B (zh) | 2010-07-28 | 2017-05-11 | 歌林達股份有限公司 | 順式-四氫-螺旋(環己烷-1,1’-吡啶[3,4-b]吲哚)-4-胺-衍生物 |
CA2896871A1 (en) * | 2012-12-31 | 2014-07-03 | Kerry L. Spear | Heterocyclic compounds and methods of use thereof |
WO2015192039A1 (en) | 2014-06-13 | 2015-12-17 | Purdue Pharma L.P. | Heterocyclic morphinan derivatives and use thereof |
RS60855B1 (sr) | 2016-01-13 | 2020-10-30 | Gruenenthal Gmbh | Derivati 8-amino-2-okso-1,3-diaza-spiro-[4.5]-dekana |
TWI640514B (zh) | 2016-01-13 | 2018-11-11 | 歌林達有限公司 | 3-(羧甲基)-8-胺基-2-側氧基-1,3-二氮-螺-[4.5]-癸烷衍生物 |
LT3402811T (lt) | 2016-01-13 | 2022-06-10 | Novo Nordisk A/S | Egf(a) analogai su riebalų rūgščių pakaitais |
EA037598B1 (ru) * | 2016-01-13 | 2021-04-20 | Грюненталь Гмбх | Производные 3-((гетеро-)арил)-8-амино-2-оксо-1,3-диазаспиро[4,5]декана |
WO2017121646A1 (en) | 2016-01-13 | 2017-07-20 | Grünenthal GmbH | 3-(carboxyethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
AR107354A1 (es) | 2016-01-13 | 2018-04-18 | Bristol Myers Squibb Co | Salicilamidas espiroheptanos y compuestos relacionados como inhibidores de rock |
KR20180098369A (ko) | 2016-01-13 | 2018-09-03 | 그뤼넨탈 게엠베하 | 3-((헤테로-)아릴)-알킬-8-아미노-2-옥소-1,3-디아자-스피로-[4.5]-데칸 유도체 |
-
2017
- 2017-01-13 KR KR1020187021562A patent/KR20180098369A/ko active IP Right Grant
- 2017-01-13 PL PL17701638T patent/PL3402784T3/pl unknown
- 2017-01-13 WO PCT/EP2017/025006 patent/WO2017121648A1/en active Application Filing
- 2017-01-13 JP JP2018536484A patent/JP6893517B2/ja active Active
- 2017-01-13 EP EP17701638.3A patent/EP3402784B1/en active Active
- 2017-01-13 RS RS20200585A patent/RS60315B1/sr unknown
- 2017-01-13 TW TW106101125A patent/TWI636048B/zh active
- 2017-01-13 EA EA201891609A patent/EA037481B1/ru unknown
- 2017-01-13 AU AU2017206909A patent/AU2017206909B2/en active Active
- 2017-01-13 ES ES17701638T patent/ES2797904T3/es active Active
- 2017-01-13 CA CA3011177A patent/CA3011177A1/en active Pending
- 2017-01-13 PT PT177016383T patent/PT3402784T/pt unknown
- 2017-01-13 SI SI201730268T patent/SI3402784T1/sl unknown
- 2017-01-13 DK DK17701638.3T patent/DK3402784T3/da active
- 2017-01-13 LT LTEP17701638.3T patent/LT3402784T/lt unknown
- 2017-01-13 PE PE2018001302A patent/PE20181375A1/es unknown
- 2017-01-13 BR BR112018014303-0A patent/BR112018014303B1/pt active IP Right Grant
- 2017-01-13 HU HUE17701638A patent/HUE049813T2/hu unknown
- 2017-01-13 MX MX2018008644A patent/MX2018008644A/es unknown
- 2017-01-13 CN CN201780006494.6A patent/CN108602777B/zh active Active
- 2017-01-13 US US15/405,896 patent/US20170197947A1/en not_active Abandoned
- 2017-01-13 AR ARP170100095A patent/AR107360A1/es unknown
-
2018
- 2018-05-21 US US15/984,919 patent/US20180327392A1/en not_active Abandoned
- 2018-07-09 IL IL260491A patent/IL260491B/en unknown
- 2018-07-13 CL CL2018001912A patent/CL2018001912A1/es unknown
- 2018-08-13 EC ECSENADI201860848A patent/ECSP18060848A/es unknown
- 2018-08-13 CO CONC2018/0008444A patent/CO2018008444A2/es unknown
-
2019
- 2019-02-01 US US16/265,080 patent/US10829480B2/en active Active
-
2020
- 2020-05-04 CY CY20201100402T patent/CY1122818T1/el unknown
- 2020-05-22 HR HRP20200837TT patent/HRP20200837T1/hr unknown
- 2020-08-31 US US17/007,258 patent/US20200399252A1/en not_active Abandoned
-
2021
- 2021-03-01 US US17/188,743 patent/US20210179592A1/en not_active Abandoned
-
2023
- 2023-01-30 US US18/103,180 patent/US20230174520A1/en active Pending
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10793556B2 (en) | 2016-01-13 | 2020-10-06 | Gruenenthal Gmbh | 8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US10793528B2 (en) | 2016-01-13 | 2020-10-06 | Grünenthal GmbH | 3-((hetero-)aryl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US10807989B2 (en) | 2016-01-13 | 2020-10-20 | Grünenthal GmbH | 3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US10807988B2 (en) | 2016-01-13 | 2020-10-20 | Grünenthal GmbH | 3-((hetero-)aryl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US10829480B2 (en) | 2016-01-13 | 2020-11-10 | Gruenenthal Gmbh | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-l,3-diaza-spiro-[4.5]-decane derivatives |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10829480B2 (en) | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-l,3-diaza-spiro-[4.5]-decane derivatives | |
US10793556B2 (en) | 8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives | |
US10793528B2 (en) | 3-((hetero-)aryl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives | |
US10807989B2 (en) | 3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives | |
US20230303573A1 (en) | 3-((Hetero-)Aryl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives | |
US20190016685A1 (en) | 1,3-diaza-spiro-[3.4]-octane derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: GRUENENTHAL GMBH, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KUEHNERT, SVEN;KOENIGS, RENE MICHAEL;KLESS, ACHIM;AND OTHERS;SIGNING DATES FROM 20170327 TO 20170502;REEL/FRAME:042497/0249 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |