US20170197970A1 - 3-((Hetero-)Aryl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives - Google Patents
3-((Hetero-)Aryl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives Download PDFInfo
- Publication number
- US20170197970A1 US20170197970A1 US15/405,485 US201715405485A US2017197970A1 US 20170197970 A1 US20170197970 A1 US 20170197970A1 US 201715405485 A US201715405485 A US 201715405485A US 2017197970 A1 US2017197970 A1 US 2017197970A1
- Authority
- US
- United States
- Prior art keywords
- decan
- diazaspiro
- cis
- phenyl
- dimethylamino
- 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
- 208000002193 Pain Diseases 0.000 claims abstract description 18
- 230000036407 pain Effects 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 7
- -1 2-cyclobutyl Chemical group 0.000 claims description 168
- 150000001875 compounds Chemical class 0.000 claims description 153
- 229920006395 saturated elastomer Polymers 0.000 claims description 142
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 72
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 72
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 63
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 59
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 56
- 125000006707 (C3-C12) heterocycloalkyl group Chemical group 0.000 claims description 55
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 49
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 48
- 125000001424 substituent group Chemical group 0.000 claims description 47
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims description 45
- ZAJNGDIORYACQU-UHFFFAOYSA-N decan-2-one Chemical compound CCCCCCCCC(C)=O ZAJNGDIORYACQU-UHFFFAOYSA-N 0.000 claims description 42
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 37
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000002619 bicyclic group Chemical group 0.000 claims description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 7
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- LIQULUMCZMZYBG-UHFFFAOYSA-N 2-[8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]benzamide Chemical compound COC1(CCN2C(=O)N(CC22CCC(CC2)(N(C)C)c2ccccc2)c2ccccc2C(N)=O)CCC1 LIQULUMCZMZYBG-UHFFFAOYSA-N 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- CSKUCUPFMABMFT-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CCC2)c2ccccc2)CC1)c1ccccc1 CSKUCUPFMABMFT-UHFFFAOYSA-N 0.000 claims description 4
- PEYSOHBAQODHAN-UHFFFAOYSA-N 2-[1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-5-carbonitrile Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CCC2)c2ncc(cn2)C#N)CC1)c1ccccc1 PEYSOHBAQODHAN-UHFFFAOYSA-N 0.000 claims description 4
- CADAGTHWAKKOFB-UHFFFAOYSA-N 2-[1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-5-carboxamide Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CCC2)C2=NC=C(C=N2)C(N)=O)CC1)C1=CC=CC=C1 CADAGTHWAKKOFB-UHFFFAOYSA-N 0.000 claims description 4
- IHKVAZGDIQNGQL-UHFFFAOYSA-N 2-[3-(2-cyanopyrimidin-5-yl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propylacetamide Chemical compound CCCNC(=O)CN1C(=O)N(CC11CCC(CC1)(N(C)C)c1ccccc1)c1cnc(nc1)C#N IHKVAZGDIQNGQL-UHFFFAOYSA-N 0.000 claims description 4
- WJQFENSSWPOPPV-UHFFFAOYSA-N 5-[8-(dimethylamino)-1-[(1-hydroxycyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonitrile Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2(O)CCC2)c2cnc(nc2)C#N)CC1)c1ccccc1 WJQFENSSWPOPPV-UHFFFAOYSA-N 0.000 claims description 4
- RNYWLUMJTZVZIL-UHFFFAOYSA-N 8-(dimethylamino)-1-[(1-hydroxycyclobutyl)methyl]-3-(2-morpholin-4-ylpyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2(O)CCC2)c2cnc(nc2)N2CCOCC2)CC1)c1ccccc1 RNYWLUMJTZVZIL-UHFFFAOYSA-N 0.000 claims description 4
- UMQSSHVOOUROTJ-UHFFFAOYSA-N 8-(dimethylamino)-1-[(1-hydroxycyclobutyl)methyl]-3-(2-oxo-1H-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2(O)CCC2)c2cnc(=O)[nH]c2)CC1)c1ccccc1 UMQSSHVOOUROTJ-UHFFFAOYSA-N 0.000 claims description 4
- LQVRSOKDJLDEBD-UHFFFAOYSA-N 8-(dimethylamino)-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C1(CCC2(CN(C(N2)=O)C2=CNC3=CC=CC=C23)CC1)C1=CC=CC=C1)C LQVRSOKDJLDEBD-UHFFFAOYSA-N 0.000 claims description 4
- MNYSSPRUXOCYDU-UHFFFAOYSA-N 8-(dimethylamino)-8-thiophen-2-yl-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2)C2=CN=C(N=C2)C(F)(F)F)CC1)C1=CC=CS1 MNYSSPRUXOCYDU-UHFFFAOYSA-N 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- BADXUWHGJCUUAO-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-3-[4-methyl-6-(trifluoromethyl)pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CCC2)c2cnc(cc2C)C(F)(F)F)CC1)c1ccccc1 BADXUWHGJCUUAO-UHFFFAOYSA-N 0.000 claims description 3
- ZRPCPFCBODJNBN-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CCC2)c2cnc(nc2)C(F)(F)F)CC1)c1ccccc1 ZRPCPFCBODJNBN-UHFFFAOYSA-N 0.000 claims description 3
- VFXWBHUMVUTKPM-UHFFFAOYSA-N 1-(cyclopropylmethyl)-8-(dimethylamino)-3-(6-methylsulfonylpyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CC1)CN(C(=O)N2CC3CC3)C4=CN=C(C=C4)S(=O)(=O)C)C5=CC=CC=C5 VFXWBHUMVUTKPM-UHFFFAOYSA-N 0.000 claims description 3
- KWVOQUAYMVJLGD-UHFFFAOYSA-N 1-[(1-hydroxycyclobutyl)methyl]-8-(methylamino)-3-(2-morpholin-4-ylpyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound OC1(CCC1)CN1C(N(CC11CCC(CC1)(C1=CC=CC=C1)NC)C=1C=NC(=NC=1)N1CCOCC1)=O KWVOQUAYMVJLGD-UHFFFAOYSA-N 0.000 claims description 3
- RQCVHTFZRXLYHR-UHFFFAOYSA-N 2-[1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonylbenzonitrile Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CCC2)c2ccc(cc2C#N)S(C)(=O)=O)CC1)c1ccccc1 RQCVHTFZRXLYHR-UHFFFAOYSA-N 0.000 claims description 3
- TXYHBBZZCGMODR-UHFFFAOYSA-N 3-(1-acetylindol-3-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound C(C)(=O)N1C=C(C2=CC=CC=C12)N1C(NC2(C1)CCC(CC2)(C1=CC=CC=C1)N(C)C)=O TXYHBBZZCGMODR-UHFFFAOYSA-N 0.000 claims description 3
- RIFRNOMQSRILKR-UHFFFAOYSA-N 4-[1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethylbenzamide Chemical compound CN(C)C(=O)c1ccc(cc1)N1CC2(CCC(CC2)(N(C)C)c2ccccc2)N(CC2CCC2)C1=O RIFRNOMQSRILKR-UHFFFAOYSA-N 0.000 claims description 3
- PHCGIUQCFALPFL-UHFFFAOYSA-N 5-[8-cyclohexa-2,4-dien-1-yl-8-(dimethylamino)-1-(2-hydroxyethyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonitrile Chemical compound CN(C)C1(CCC2(CC1)CN(C(=O)N2CCO)C3=CN=C(N=C3)C#N)C4CC=CC=C4 PHCGIUQCFALPFL-UHFFFAOYSA-N 0.000 claims description 3
- HMXAPOQVURPVOO-UHFFFAOYSA-N 8-amino-1-[(1-hydroxycyclobutyl)methyl]-8-phenyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound NC1(CCC2(CN(C(=O)N2CC2(O)CCC2)c2cnc(nc2)C(F)(F)F)CC1)c1ccccc1 HMXAPOQVURPVOO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- CKKXZTIXJMGOAZ-UHFFFAOYSA-N 1-(cyclobutylmethyl)-3-(2,4-dimethoxyphenyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ccc(N2CC3(CCC(CC3)(N(C)C)c3ccccc3)N(CC3CCC3)C2=O)c(OC)c1 CKKXZTIXJMGOAZ-UHFFFAOYSA-N 0.000 claims description 2
- TVWJSXRLXLCTDX-UHFFFAOYSA-N 1-(cyclobutylmethyl)-3-(5-methoxypyrazin-2-yl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(C(=O)N2CC2CCC2)c2cnc(OC)cn2)CC1)c1ccccc1 TVWJSXRLXLCTDX-UHFFFAOYSA-N 0.000 claims description 2
- CXNLSSLUZAQVBQ-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(3-fluorophenyl)-8-(methylamino)-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(C(=O)N2CC2CCC2)c2cnc(nc2)C(F)(F)F)CC1)c1cccc(F)c1 CXNLSSLUZAQVBQ-UHFFFAOYSA-N 0.000 claims description 2
- NOLRBXWDANQFCG-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-3-(2-methoxypyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ncc(cn1)N1CC2(CCC(CC2)(N(C)C)c2ccccc2)N(CC2CCC2)C1=O NOLRBXWDANQFCG-UHFFFAOYSA-N 0.000 claims description 2
- IVXALWJKVGHUIV-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methylsulfonylphenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CCC2)c2ccc(cc2)S(C)(=O)=O)CC1)c1ccccc1 IVXALWJKVGHUIV-UHFFFAOYSA-N 0.000 claims description 2
- LHNAJIMZKNXWAF-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-3-(5-fluoropyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CCC2)c2ncc(F)cn2)CC1)c1ccccc1 LHNAJIMZKNXWAF-UHFFFAOYSA-N 0.000 claims description 2
- AULMCACEQAVMDI-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-3-(5-methoxypyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1cnc(cn1)N1CC2(CCC(CC2)(N(C)C)c2ccccc2)N(CC2CCC2)C1=O AULMCACEQAVMDI-UHFFFAOYSA-N 0.000 claims description 2
- KBNGDDUEEOVFJG-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-3-[2-methylsulfonyl-4-(trifluoromethyl)phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CCC2)c2ccc(cc2S(C)(=O)=O)C(F)(F)F)CC1)c1ccccc1 KBNGDDUEEOVFJG-UHFFFAOYSA-N 0.000 claims description 2
- FGEXKJKBKJPJTB-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-(3-pyrrolidin-1-ylphenyl)-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CC1)CN(C(=O)N2CC3CCC3)C4=CC=CC(=C4)N5CCCC5)C6=CC=CC=C6 FGEXKJKBKJPJTB-UHFFFAOYSA-N 0.000 claims description 2
- OWNVCKDNQHHETC-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-(5-pyridin-2-ylthiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CCC2)c2ccc(s2)-c2ccccn2)CC1)c1ccccc1 OWNVCKDNQHHETC-UHFFFAOYSA-N 0.000 claims description 2
- HOEYHTAWVIRWLK-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CCC2)c2ccc(nc2)C(F)(F)F)CC1)c1ccccc1 HOEYHTAWVIRWLK-UHFFFAOYSA-N 0.000 claims description 2
- PJFUCODNYXSDJD-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(methylamino)-3-(4-methylsulfonylphenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CC1)CN(C(=O)N2CC3CCC3)C4=CC=C(C=C4)S(=O)(=O)C)C5=CC=CC=C5 PJFUCODNYXSDJD-UHFFFAOYSA-N 0.000 claims description 2
- IABLZBRYCFZVHR-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(C(=O)N2CC2CCC2)c2cnc(nc2)C(F)(F)F)CC1)c1ccccc1 IABLZBRYCFZVHR-UHFFFAOYSA-N 0.000 claims description 2
- QTGUCRUONHGDJC-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-[ethyl(methyl)amino]-8-phenyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound CCN(C)C1(CCC2(CN(C(=O)N2CC2CCC2)c2cnc(nc2)C(F)(F)F)CC1)c1ccccc1 QTGUCRUONHGDJC-UHFFFAOYSA-N 0.000 claims description 2
- DPHLACUKBKLTLC-UHFFFAOYSA-N 1-(cyclopropylmethyl)-3-(2-fluoro-4-methylsulfonylphenyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(C(=O)N2CC2CC2)c2ccc(cc2F)S(C)(=O)=O)CC1)c1ccccc1 DPHLACUKBKLTLC-UHFFFAOYSA-N 0.000 claims description 2
- GMBAHBICDXONRI-UHFFFAOYSA-N 1-(cyclopropylmethyl)-8-(3-fluorophenyl)-8-(methylamino)-3-(5-methylsulfonylpyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(C(=O)N2CC2CC2)c2ccc(cn2)S(C)(=O)=O)CC1)c1cccc(F)c1 GMBAHBICDXONRI-UHFFFAOYSA-N 0.000 claims description 2
- IZYPXPNEVSAQPS-UHFFFAOYSA-N 1-(cyclopropylmethyl)-8-(3-fluorophenyl)-8-(methylamino)-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(C(=O)N2CC2CC2)c2cnc(nc2)C(F)(F)F)CC1)c1cccc(F)c1 IZYPXPNEVSAQPS-UHFFFAOYSA-N 0.000 claims description 2
- QEKCFPSPDQUCPQ-UHFFFAOYSA-N 1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-fluoro-4-methylsulfonylphenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CC2)c2ccc(cc2F)S(C)(=O)=O)CC1)c1ccccc1 QEKCFPSPDQUCPQ-UHFFFAOYSA-N 0.000 claims description 2
- VMRBLZBUYRDPKY-UHFFFAOYSA-N 1-(cyclopropylmethyl)-8-(dimethylamino)-3-[2-(methylsulfonylmethyl)phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CC2)c2ccccc2CS(C)(=O)=O)CC1)c1ccccc1 VMRBLZBUYRDPKY-UHFFFAOYSA-N 0.000 claims description 2
- ZMJROBJQRUWCEL-UHFFFAOYSA-N 1-(cyclopropylmethyl)-8-(dimethylamino)-3-[4-methyl-6-(trifluoromethyl)pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CC2)c2cnc(cc2C)C(F)(F)F)CC1)c1ccccc1 ZMJROBJQRUWCEL-UHFFFAOYSA-N 0.000 claims description 2
- SDCLLFDDPDQLEP-UHFFFAOYSA-N 1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-3-(5-methylsulfonylpyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CC2)c2ccc(cn2)S(C)(=O)=O)CC1)c1cccc(F)c1 SDCLLFDDPDQLEP-UHFFFAOYSA-N 0.000 claims description 2
- ZSHIWPNQEOKSKO-UHFFFAOYSA-N 1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CC2)c2cnc(nc2)C(F)(F)F)CC1)c1cccc(F)c1 ZSHIWPNQEOKSKO-UHFFFAOYSA-N 0.000 claims description 2
- NCTOFCIDKRISKV-UHFFFAOYSA-N 1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CC2)c2cc(nn2C)C(F)(F)F)CC1)c1cccc(F)c1 NCTOFCIDKRISKV-UHFFFAOYSA-N 0.000 claims description 2
- XHMRPMHNFYRQME-UHFFFAOYSA-N 1-(cyclopropylmethyl)-8-(methylamino)-3-(4-methylsulfonylphenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(C(=O)N2CC2CC2)c2ccc(cc2)S(C)(=O)=O)CC1)c1ccccc1 XHMRPMHNFYRQME-UHFFFAOYSA-N 0.000 claims description 2
- CNHDRXAMCLQRRD-UHFFFAOYSA-N 1-(cyclopropylmethyl)-8-(methylamino)-3-[2-(methylsulfonylmethyl)phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(C(=O)N2CC2CC2)c2ccccc2CS(C)(=O)=O)CC1)c1ccccc1 CNHDRXAMCLQRRD-UHFFFAOYSA-N 0.000 claims description 2
- VQZGEZWXJQFTAL-UHFFFAOYSA-N 1-(cyclopropylmethyl)-8-(methylamino)-3-[4-methyl-6-(trifluoromethyl)pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(C(=O)N2CC2CC2)c2cnc(cc2C)C(F)(F)F)CC1)c1ccccc1 VQZGEZWXJQFTAL-UHFFFAOYSA-N 0.000 claims description 2
- YOQMWJRUSDZLBD-UHFFFAOYSA-N 1-(cyclopropylmethyl)-8-(methylamino)-8-phenyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(C(=O)N2CC2CC2)c2cnc(nc2)C(F)(F)F)CC1)c1ccccc1 YOQMWJRUSDZLBD-UHFFFAOYSA-N 0.000 claims description 2
- YRXRXCPQQDNWGE-UHFFFAOYSA-N 1-[(1-hydroxycyclobutyl)methyl]-8-(methylamino)-3-(2-methylpyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(C(=O)N2CC2(O)CCC2)c2cnc(C)nc2)CC1)c1ccccc1 YRXRXCPQQDNWGE-UHFFFAOYSA-N 0.000 claims description 2
- VVPXICNGCLLAOI-UHFFFAOYSA-N 1-[(1-hydroxycyclobutyl)methyl]-8-(methylamino)-8-phenyl-3-(2-piperazin-1-ylpyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(C(=O)N2CC2(O)CCC2)c2cnc(nc2)N2CCNCC2)CC1)c1ccccc1 VVPXICNGCLLAOI-UHFFFAOYSA-N 0.000 claims description 2
- SZQYBVIUSHTSAN-UHFFFAOYSA-N 1-[(1-hydroxycyclobutyl)methyl]-8-(methylamino)-8-phenyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(C(=O)N2CC2(O)CCC2)c2cnc(nc2)C(F)(F)F)CC1)c1ccccc1 SZQYBVIUSHTSAN-UHFFFAOYSA-N 0.000 claims description 2
- DRPSIHHGKVXDPG-UHFFFAOYSA-N 1-[(1-hydroxycyclobutyl)methyl]-8-(methylamino)-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(C(=O)N2CC2(O)CCC2)c2cncnc2)CC1)c1ccccc1 DRPSIHHGKVXDPG-UHFFFAOYSA-N 0.000 claims description 2
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- AOLIJMPQNSNIJB-UHFFFAOYSA-N 2-[1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]benzonitrile Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CCC2)c2ccccc2C#N)CC1)c1ccccc1 AOLIJMPQNSNIJB-UHFFFAOYSA-N 0.000 claims description 2
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- DNGKPPIKCUWYAV-UHFFFAOYSA-N 2-[3-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyridin-4-yl]acetamide Chemical compound CN(C)C1(CCC2(CN(C(=O)N2)c2cnccc2CC(N)=O)CC1)c1ccccc1 DNGKPPIKCUWYAV-UHFFFAOYSA-N 0.000 claims description 2
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- OKRJYYYMSSJJGI-UHFFFAOYSA-N 2-[8-(dimethylamino)-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethylacetamide Chemical compound CN(C)C(=O)CN1C(=O)N(CC11CCC(CC1)(N(C)C)c1ccccc1)c1ccccc1 OKRJYYYMSSJJGI-UHFFFAOYSA-N 0.000 claims description 2
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- MKWWEMAIMQADIZ-UHFFFAOYSA-N 8-(dimethylamino)-3-[4-methyl-6-(trifluoromethyl)pyridin-3-yl]-8-[3-(trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(C(=O)N2)c2cnc(cc2C)C(F)(F)F)CC1)c1cccc(c1)C(F)(F)F MKWWEMAIMQADIZ-UHFFFAOYSA-N 0.000 claims description 2
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- KXQCSHYIJVXAJI-UHFFFAOYSA-N N-[5-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidin-2-yl]cyclopropanecarboxamide Chemical compound CN(C)C1(CCC2(CN(C(=O)N2)c2cnc(NC(=O)C3CC3)nc2)CC1)c1ccccc1 KXQCSHYIJVXAJI-UHFFFAOYSA-N 0.000 claims description 2
- KECJLVOZJQCMGJ-UHFFFAOYSA-N N-[5-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidin-2-yl]thiophene-2-carboxamide Chemical compound CN(C)C1(CCC2(CN(C(=O)N2)c2cnc(NC(=O)c3cccs3)nc2)CC1)c1ccccc1 KECJLVOZJQCMGJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- SAMWUWRYNMIGPZ-UHFFFAOYSA-N methyl 2-[2-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]phenoxy]acetate Chemical compound COC(=O)COc1ccccc1N1CC2(CCC(CC2)(N(C)C)c2ccccc2)NC1=O SAMWUWRYNMIGPZ-UHFFFAOYSA-N 0.000 claims description 2
- RPTGWBVQHHFBGM-UHFFFAOYSA-N methyl 2-[4-[5-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidin-2-yl]piperazin-1-yl]acetate Chemical compound COC(=O)CN1CCN(CC1)c1ncc(cn1)N1CC2(CCC(CC2)(N(C)C)c2ccccc2)NC1=O RPTGWBVQHHFBGM-UHFFFAOYSA-N 0.000 claims description 2
- FTXLMENZIRBTKI-UHFFFAOYSA-N methyl 2-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]benzoate Chemical compound COC(=O)c1ccccc1N1CC2(CCC(CC2)(N(C)C)c2ccccc2)NC1=O FTXLMENZIRBTKI-UHFFFAOYSA-N 0.000 claims description 2
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- SFDULQWBDDNZMO-UHFFFAOYSA-N methyl 4-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]benzoate Chemical compound COC(=O)c1ccc(cc1)N1CC2(CCC(CC2)(N(C)C)c2ccccc2)NC1=O SFDULQWBDDNZMO-UHFFFAOYSA-N 0.000 claims description 2
- NZJQVCPBDKKIBX-UHFFFAOYSA-N methyl 5-[1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methylpyridine-2-carboxylate Chemical compound COC(=O)c1cc(C)c(cn1)N1CC2(CCC(CC2)(N(C)C)c2ccccc2)N(CC2CCC2)C1=O NZJQVCPBDKKIBX-UHFFFAOYSA-N 0.000 claims description 2
- XBXOKTSXGRDCPQ-UHFFFAOYSA-N methyl 5-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methylpyridine-2-carboxylate Chemical compound COC(=O)c1cc(C)c(cn1)N1CC2(CCC(CC2)(N(C)C)c2ccccc2)NC1=O XBXOKTSXGRDCPQ-UHFFFAOYSA-N 0.000 claims description 2
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- VSLXAAAAZVCACM-UHFFFAOYSA-N 6-[1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-4-carbonitrile Chemical compound CN(C)C1(CCC2(CN(C(=O)N2CC2CCC2)c2cc(ncn2)C#N)CC1)c1ccccc1 VSLXAAAAZVCACM-UHFFFAOYSA-N 0.000 claims 1
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- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
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- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
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- RLTPJVKHGBFGQA-UHFFFAOYSA-N thiadiazolidine Chemical compound C1CSNN1 RLTPJVKHGBFGQA-UHFFFAOYSA-N 0.000 description 1
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- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
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- 210000001519 tissue Anatomy 0.000 description 1
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- GYUURHMITDQTRU-UHFFFAOYSA-N tributyl(pyridin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=N1 GYUURHMITDQTRU-UHFFFAOYSA-N 0.000 description 1
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
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- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions
- the invention relates to 3-((hetero-)aryl)-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)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives according to general formula (I)
- 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-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 , —CO 2 H, —C( ⁇ O)O—C 1 -C 6 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 -C 6 -alkyl, —C( ⁇ O)N(C 1 -C 6 -alkyl) 2 , —O—C 1 -C 6 - alkyl and —S( ⁇ O) 2 —C 1 -C 6 -alkyl; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membere
- heteroaryl means “heteroaryl or aryl”.
- aryl includes but is not limited to phenyl and naphthyl.
- heteroaryl includes but is not limited to -1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl, -primidinyl, -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]pyr
- 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 18 , R 19 , and R 20 independently of one another mean —H, —F, —OH, or —C 1 -C 6 -alkyl; preferably —H.
- 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 1 ; 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 1 , —OCF 3 or —OCH 2 OCH 3 , preferably —F.
- R 3 means -benzyl unsubstituted, mono- or polysubstituted. More preferably.
- 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 1 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 1 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 —. More preferably.
- R 1 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 moiety is connected
- 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.
- 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 —. More preferably, R 1 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.
- 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
- 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 -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]pyridinyl in each case unsubstituted, mono- or polysubstituted
- R 5 means -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, or -thienyl, 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 ; -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 a bicyclic 9-10-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
- R 5 means imidazo[1,2-a]pyrazine, unsubstituted or monosubstituted with —C 1 -C 4 -alkyl.
- R 1 means -phenyl, -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, -imidazol[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl, in each case unsubstituted or substituted with one, two, three or four
- 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:
- R 1 means —H or —CH 3
- R 2 means —C 1 -C 6 -alkyl, linear or branched, saturated, unsubstituted; cyclopropyl connected through —CH 2 —; or tetrahydropyranyl connected through —CH 2 —
- R 3 means -phenyl, benzyl, -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 1 ) 2 , —NH 2 , —NHCH 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, —OH, —O—C 1 -C 4 -alkyl, —C( ⁇ O)NH—C 1 -C 6 -alkyl, —C( ⁇ O)N(C 1 -C 6 -alkyl) 2 or —C( ⁇ O)NRR′ wherein R and R′ together with the nitrogen atom to which they are attached form a ring and mean —(CH 2 ) 3-5 —; 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,
- 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 1 , —C( ⁇ O)NH 2 , C( ⁇ O)NHCH 1 , —C( ⁇ O)N(CH 3 ) 2 , —NH 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 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 —CH 2 — or —CH 2 CH 2 —; more preferably, R 4 means -cyclobutyl, unsubstituted or monosubstituted with —OH, wherein said -cyclobutyl is connected through —CH 2 —; and/or R 5 means -phenyl, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, or imidazo[1,2-a]pyrazine, in each case unsubstituted or
- the compound according to the invention is selected from the group consisting of
- SC_3001 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- pyrimidine-2-carbonitrile
- SC_3002 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- pyrazine-2-carbonitrile
- SC_3003 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- 4-methoxy-pyrimidine-2-carbonitrile
- SC_3004 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-
- —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
- Examples of 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 1 ) 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 2 )—, —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 1 ) ⁇ CH—, —CH ⁇ C(CH 1 )—, —C(CH 1 ) ⁇ 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 4 -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.
- 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 compound according to the invention has a structure according to general formula (I′)
- R 1 to R 5 , R 11 to R 20 are defined as above.
- 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) or (X)
- R 2 means —H or —CH 3 ;
- R 3 means -phenyl or -3-fluorophenyl:
- R C means —H or —OH;
- R E means —H, —CH 3 , —F, —CF 3 , -cyclopropyl, -aziridinyl, —OH; —O—C 1 -C 4 -alkyl; —OCF 3 ; —O—C 1 -C 6 -alkyl-CO 2 H; —O—C 1 -C 4 -alkyl-C( ⁇ O)O—C 1 -C 4 -alkyl; or —O—C 1 -C 4 -alkyl-CONH 2 ;
- R F means —CF 3 , -cyclopropyl, —S( ⁇ O) 2 CH 3 , —NH 2 ; —NHC 1 -C 4 -alkyl; —N(C 1 -C
- the compound according to the invention has a structure according to general formula (XI)
- R 2 means —H or —CH 3 :
- R 3 means -phenyl or -3-fluorophenyl;
- R H means —CN; —C 1 -C 4 -alkyl; —CF 3 ; —C 1 -C 4 -alkyl-C( ⁇ O)NH 2 ; —C 1 -C 4 -alkyl-S( ⁇ O) 2 —C 1 -C 1 -alkyl; —C( ⁇ O)—C 1 -C 4 -alkyl; —C( ⁇ O)OH; —C( ⁇ O)O—C 1 -C 4 -alkyl; —C( ⁇ O)NH 2 ; —C( ⁇ O)NHC 1 -C 4 -alkyl; —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 ; —C( ⁇ O)NH(C 1 -C 4 -alkyl-OH); —C( ⁇ O
- 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 Phamazie, 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 font 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-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-((CIS8-(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
- reaction mixture was allowed to stir another 2 h at reflux, then cooled to RT, diluted with water (150 mL) and the layers partitioned. The aqueous layer was extracted with EtOAc (3 ⁇ 300 mL). The combined organic layers were dried over Na 2 SO 4 and then concentrated in vacuo. The residue was filtered through a plug of silica gel using a DCM/MeOH (19/1 v/v) mixture.
- 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
- Diethylamine 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 wider 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 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-dione
- 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-(methoxymethoxy)-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-methoyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
- Step 1 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
- Dimethylamine hydrochloride (76.4 g, 936.4 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 wt % aq. dimethylamine (780 mL) and KCN (48.76 g, 749.11 mmol) were sequentially added. The reaction mixture was stirred for 48 h and the completion of the reaction was monitored by NMR.
- reaction mixture was diluted with water (1.0 L) and the organic product was extracted with ethyl acetate (2 ⁇ 2.0 L). The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford 90 g (85%) of 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile as an off white solid (TLC system: TLC system: 10% MeOH in DCM; Rf: 0.35, 0.30).
- Step 2 CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
- 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-1-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-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-met yl)-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 CIS4-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]4-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)
- Methyl CIS-5-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carboxylate (INT-990) (950 mg, 2.32 mmol) was suspended in a mixture of MeOH (140 equiv., 325 mmol, 13 mL) and THF (70 equiv., 162 mmol, 13 mL). Lithium hydroxide 2M aq. sol. (1.3 mL) was added. The reaction mixture was stirred 5 days at RT. Additional 1.3 mL of lithium hydroxide 2M aq.
- 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 CIS4-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1008)
- 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-(3-fluorphenyl)-1,3-diazaspiro[4.5]decan-2-one
- step 2 1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-meth l]-1,3-diazaspiro[4.5]decan-2-one was converted into 1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1031).
- Step 1 9,12-dioxa-2,4-diazadispiro[4.2.4 ⁇ 8 ⁇ .2 ⁇ 5 ⁇ ]tetradecan-3-one
- Lithiumaluminumhydride (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 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 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%.
- B) ACN flow rate: 1 ml/min, R f 5.17 min.
- Step 1 Lithium 4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzoate
- Step 2 cis-4[l-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl]-N,N-dimethyl-benzamide (SC_3028)
- Lithium 4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl)benzoate (80 mg, 0.17 mmol) was suspended in DCM (1 mL) and triethylamine (0.23 mL, 1.7 mmol) and dimethylamine (2M solution in THF, 0.17 mL) and T3P (0.20 mL, 0.34 mmol) were sequentially added. The resulting mixture was stirred for 18 h at RT. Water (10 mL) was added and the mixture was extracted with DCM (3 ⁇ 20 mL).
- N-iodosuccinimide 150 &g, 0.67 mmol was added to a suspension of cis-5-[8-(dimethylamino)-1-(3-methoxypropyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3040 (214 mg, 0.44 mmol) in acetonitrile/THF (211 v/v, 10 mL) at RT and the resulting mixture was stirred for 16 h at RT. The reaction mixture was basified with 2N NaOH solution to pH-10 and the organic product was extracted with DCM (10 mL ⁇ 3).
- Step 1 5-(cis-1-(2-(tert-Butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile
- reaction mixture was diluted with water (15 mL) and extracted with diethyl ether (3 ⁇ 25 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , the solvents were removed under reduced pressure and the residue was purified by flash chromatography on silica gel to afford 5-(cis-1-(2-(tert-butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile (100 mg, 34%) as a white solid.
- Step 2 cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4]decan-3-yl]-pyrimidine-2-carbonitrile (SC_3025)
- Step 2 CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3097)
- N-Iodosuccinimide (162 mg, 0.72 mmol) was added to the solution CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-morpholinopyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC-3097) (250 mg, 0.48 mmol) in acetonitrile (8.0 mL) and THF (8.0 mL) at 0° C. and the resulting mixture was stirred for 16 h at RT. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (2 ⁇ 30 mL), the organic layer was washed with 2N aq.
- Preparative reverse phase HPLC conditions column: Luna-Phenyl-Hexyl-C18 (150*19 mm) 5 ⁇ m; mobile phase: 10 mM ammonium bicarbonate/acetonitrile, gradient (T/% B): 0/50, 7/85, 7.1/98, 9/98, 9.1/50, 12/50, flow Rate: 25 ml/min diluent: mobile phase+THF.
- Step 1 tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate
- tert-butyl piperazine-1-carboxylate was reacted with 5-bromo-2-chloropyrimidine to be converted into tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate.
- Step 2 tert-butyl 4-(5-((cis)-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate
- Step 3 CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(piperazin-1-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride (SC_3100)
- Step 1 CIS-2-(8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile
- Step 2 CIS-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3109
- reaction mixture was then quenched with 10 mL water, extracted with DCM (3 ⁇ 10 mL), the combined organic extracts were dried over Na 2 SO 4 and concentrated under reduced pressure (24 mg crude product).
- the aqueous phase was concentrated to dryness (91 mg), suspended in DCM, the precipitate was filtered off and the organic solution was concentrated under reduced pressure to give additional 56 mg of the crude product.
- Step 1 CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile
- Step 2 CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile
- Step 3 CIS-2-(1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile (SC_3112)
- CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (100 mg, 0.259 mmol) was placed into a reaction vial for microwave reactor (5 mL), the vial was flushed with nitrogen, anhydrous n-butanol (50 equiv., 13.0 mmol, 1.2 mL), diisopropylethylamine (5 equiv., 1.30 mmol, 0.224 mL) and piperazine-2-one (1.2 equiv., 0.311 mmol, 31 mg) were added, the vial was sealed and the reaction mixture was stirred for 2.5 h at 140° C.
- CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (1 equiv., 0.47 mmol, 180 mg), Pd(PPh 3 ) 4 (0.1 equiv., 0,047 mmol, 54 mg) and (3-cyanophenyl)boronic acid (1.5 equiv., 0.70 mmol, 103 mg) were dissolved in degassed dry tetrahydrofurane (9.5 mL) and sodium carbonate 1M aq. sol. (1.9 equiv., 0.89 mmol, 0.89 mL) was added.
- Step 1 CIS4-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
- Step 2 CIS-1-(4-methoxybenzyl)-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
- reaction mixture was allowed to warm up to RT and stirred for 16 h. The reaction progress was monitored by LCMS. The reaction mixture was diluted with water (150 mL) and the organic product was extracted with EtOAc (3 ⁇ 60 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
- Step 3 CIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
- reaction progress was monitored by LCMS.
- the reaction mixture was diluted with water (50 mL) and the organic product was extracted with EtOAc (2 ⁇ 50 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
- Step 4 CIS-8-((cyclopropylmethyl)amino)-8-phenyl-3-(2-(trifluormethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3132)
- TFA (4.2 mL) was added drop wise to a solution of CIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (210 mg, 0.363 mmol) in DCM (0.05 mL) at 0° C. under argon atmosphere. The reaction mixture was allowed to warm up to RT and stirred for 16 h. The reaction progress was monitored by LCMS. The excess of TFA was evaporated under reduced pressure and the residual amount of TFA was removed as an azeotropic mixture with DCM (2 ⁇ 5 mL).
- Methyl CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxylate (INT-990) (100 mg, 0.244 mmol) was dissolved in 7N NH 3 in methanol (25 equiv. NH 3 , 0.9 mL) in a microwave reactor vial. The reaction vessel was sealed, the reaction mixture was stirred for 5 days at RT and then concentrated under reduced pressure.
- CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (200 mg, 0.52 mmol), tributyl(2-pyridyl)stannane (1.5 equiv., 0.78 mmol, 286 mg) and Pd(PPh 3 ) 4 (0.1 equiv., 0.052 mmol, 60 mg) were dissolved in degassed anhydrous DMF (150 equiv., 77.7 mmol, 6 mL) under nitrogen atmosphere.
- DMF degassed anhydrous DMF
- Step 1 CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetonitrile
- Step 2 CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetic acid (SC_3169)
- Step 1 CIS-tert-butyl 4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonyl)piperazine-1-carboxylate
- Step 2 CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazine-1-carbonyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3173)
- Et 3 N (0.39 g, 3.89 mmol) was added to the solution of CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (0.5 g, 1.29 mmol) and piperidin-4-ol (0.32 g, 3.24 mmol) in DMF (10 mL) at RT. The reaction mixture was stirred at 130° C. for 16 h, cooled down to RT and concentrated under reduced pressure. The residue was diluted with 10% aq. NaOH and the organic product was extracted with 1/9 v/v MeOH/DCM.
- CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (150 mg, 0.38 mmol), Pd(t-Bu 3 P) 2 (0.1 equiv., 0.02 mmol, 10 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (2 equiv., 0.78 mmol, 201 mg) were dissolved in degassed anhydrous THF (80 equiv., 31 mmol, 2.5 mL) and 1M aq.
- degassed anhydrous THF 80 equiv., 31 mmol, 2.5 mL
- Step 1 CIS-8-(dimethylamino)-3-(2-((2-methoxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 2 CIS-8-(dimethylamino)-3-(2-((2-hydroxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3221)
- BBr 3 (1M in DCM) (2.2 mL, 2.22 mmol) was added to the solution of CIS-8-(dimethylamino)-3-(2-((2-methoxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (0.55 g, 1.06 mmol) in DCM (20 mL) at ⁇ 78° C. over 15 min. The reaction mixture was stirred at RT for 4 h, then quenched with water and concentrated under reduced pressure.
- Microwave reactor vial was loaded with CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (250 mg, 0.65 mmol), flushed with nitrogen, 7N solution of NH 3 in methanol (108 equiv., 70 mmol, 10 mL) and dioxane (37 equiv., 24 mmol, 2 mL) were added, the vial was sealed and the reaction mixture was stirred at 115° C. for 12 h in the microwave reactor. The reaction mixture was then cooled down to 4° C. overnight.
- Step 2 CIS-8-(dimethylamino)-8-phenyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-1,3-diazaspiro [4.3]decan-2-one (SC_3242)
- CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (80 mg, 0.29 mmol), 4-(5-bromopyrimidin-2-yl)piperazine (2 equiv., 0.56 mmol, 142 mg) and potassium phosphate (4 equiv., 1.17 mmol, 248 mg) were suspended in N,N′-dimethylethylenediamine (18 equiv., 5.27 mmol, 0.6 mL) under nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 2 h. diluted with water (10 mL) and extracted with DCM (3 ⁇ 15 mL).
- CIS-8-amino-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one 70 mg, 0.15 mmol
- Acetic acid 0.1 equiv., 0.015 mmol, 0.8 ⁇ L
- acetaldehyde 1.1 equiv., 0.16 mmol, 9 ⁇ L
- Reverse phase preparative HPLC conditions mobile phase: 10 mM ammonium bicarbonate in H 2 O/acetonitrile; column: X-BRIDGE-C18 (150*19), 5 ⁇ m mobile phase gradient (min/%/B): 0/30, 8/82, 8.1/100, 10/100, 10.1/30, 12/30; flow rate: 19 ml/min; diluent: mobile phase+THF.
- Enantiomeric mixture of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (100 mg) was separated by chiral SFC to afford 35 mg of enantiomer 1 (SC-3292) and 40 mg of enantiomer 2 (SC-3293) as off-white solids.
- Preparative SFC conditions column: Chiralpak IA (250 ⁇ 30) mm, 5 nm % CO 2 : 50.0%; % co-solvent: 50.0% (100% Methanol); total flow: 70.0 g/min; back pressure: 100.0 bar; UV: 256 nm; stack time: 13.5 min; load/inj.: 9.5 mg; no. of injections: 11.
- Step 1 5-bromo-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidine
- Step 2 CIS-3-(2-(4-cyclopropyl-H-1,2,3-triazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3313)
- Step 1 CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4]decan-3-yl)pyridin-4-yl)acetonitrile
- CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) was reacted with (3-bromo-pyridin-4-yl)-acetonitrile to be converted into CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetonitrile.
- Step 2 CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetamide (SC_3340)
- Step 1 CIS-7-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one
- Step 2 CIS-8-(dimethylamino)-3-(2-hydroxybenzo[d]oxazol-7-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3352)
- Step 1 CIS-8-(dimethylamino)-8-phenyl-3-(1-tosyl-1H-indol-3-yl)-1,3-diazaspiro[4.5]decan-2-one
- Step 2 CIS-8-(dimethylamino)-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3357)
- Step 1 CIS4-(8-(dimethylamino)-2-oxo-4-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-1-(4-methoxybenzyl)indoline-2,3-dione
- Step 2 CIS-4-(8-(dimethylamino)-2-oxo-4-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-1-(4-methoxybenzyl)indolin-2-one
- Step 3 CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)indolin-2-one (SC_3396)
- SC_3101 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]- SC_3098 SC_3099 1H NMR (DMSO-d6): ⁇ 8.58 (s, 2H), 7.48 (d, 2H), 520.4 8-methylamino-3-[2-(4-methyl- 7.32 (t, 2H), 7.19 (t, 1H), 5.61 (s, 1H), 3.75 (s, 2H), piperazin-1-yl)-pyrimidin-5-yl]-8- 3.66-3.64 (m, 4H), 3.30 (s, 2H), 2.35-2.32 (m, 4H), phenyl-1,3-diazaspiro[4.5]decan-2-one 2.25-2.19 (m, 5H), 2.12-2.07 (m, 2H), 1.90-1.88 (m, 7H), 1.79-1.73 (m, 2H), 1.65-1.63 (m, 1H), 1.50-1.44 (m, 3H) SC_
- SC_3104 cis-1-(Cyclobutyl-methyl)-8- SC_3103 SC_3099 1H NMR (DMSO-d6): ⁇ 8.59 (s, 1H), 7.81 (s, 1H), 487.3 methylamino-3-[4-methyl-6- 7.44 (d, 2H), 7.30 (t, 2H), 7.17 (t, 1H), 3.76 (s, 2H), (trifluoromethyl)-pyridin-3-yl]-8-phenyl- 3.21 (d, 2H), 2.61-2.57 (m, 1H), 2.32 (s, 3H), 1,3-diazaspiro[4.5]decan-2-one 2.29-2.17 (m, 3H), 2.03-1.97 (m, 2H), 1.91-1.88 (m, 5H), 1.84-1.67 (m, 6H), 1.51-1.48 (m, 2H).
- SC_3106 cis-1-(Cyclopropyl-methyl)-8- SC_3105 SC_3099 1H NMR (DMSO-d6): ⁇ 7.90-7.88 (d, 2H), 468.2 methylamino-3-(4-methylsulfonyl- 7.82-7.80 (d, 2H), 7.50-7.48 (d, 2H), 7.35-7.32 (m, 2H), phenyl)-8-phenyl-1,3- 7.22-7.19 (m, 1H), 3.80 (s, 2H), 3.14-3.10 (m, 5H), diazaspiro[4.5]decan-2-one 2.29-2.23 (m, 3H), 1.91-1.79 (m, 7H), 1.42-1.39 (m, 2H), 1.05-1.04 (m, 1H), 0.50-0.47 (m, 2H), 0.34-0.32 (m, 2H).
- SC_3107 cis-1-(Cyclopropyl-methyl)-8- INT-983 1-bromo-2-fluoro-4- SC3103 (step 1), 1H NMR (DMSO-d6): ⁇ 7.85 (t, 1H), 7.79-7.76 (m, 500.2 dimethylamino-3-(2-fluoro-4- (methylsulfonyl)benzene SC_3105 (step 2) 1H), 7.72-7.69 (m, 1H), 7.37-7.33 (m, 4H), methylsulfonyl-phenyl)-8-phenyl-1,3- (step 1), 7.27-7.24 (m, 1H), 3.81 (s, 2H), 3.24 (s, 3H), 3.07 (d, diazaspiro[4.5]decan-2-one (Bromomethyl)cylopropane 2H), 2.71-2.68 (m, 2H), 2.28-2.22 (m, 2H), 1.99 (s, (step 2) 6H), 1.53-1
- SC_3110 cis-8-Dimethylamino-1-[2-(1-methoxy- INT-988 5-bromo2-methyl- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.94-8.90 (s, 2H), 478.3 cyclobutyl)-ethyl]-3-(2-methyl- pyrimidine 7.41-7.34 (d, 4H), 7.32-7.24 (ddd, 1H), pyrimidin-5-yl)-8-phenyl-1,3- 3.76-3.72 (s, 2H), 3.15-3.08 (m, 5H), 2.72-2.65 (m, diazaspiro[4.5]decan-2-one 2H), 2.57-2.52 (s, 3H), 2.25-2.16 (m, 2H), 2.11-2.02 (m, 2H), 2.03-1.99 (s, 6H), 1.99-1.86 (m, 4H), 1.78-1.68 (tq, 1H), 1.65-1.51 (
- SC_3111 cis-5-[1-[(1-Hydroxy-cyclobutyl)- INT-799 5-bromo-2- SC_3103 (step 1), 1H NMR (600 MHz, DMSO) ⁇ 9.24-9.20 (s, 2H), 447.3 methyl]-8-methylamino-2-oxo-8-phenyl- cyanopyrimide SC_3099 (step 2) 7.53-7.48 (m, 2H), 7.37-7.31 (t, 2H), 1,3-diazaspiro[4.5]decan-3-yl]- 7.25-7.19 (t, 1H), 3.93-3.89 (s, 2H), 3.42-3.36 (m, 2H), pyrimidine-2-carbonitrile 2.35-2.26 (td, 2H), 2.18-2.10 (tt, 2H), 2.09-2.04 (s, 1H), 1.97-1.88 (m, 2H), 1.93-1.90 (s, 6H), 1.86-1.77
- SC_3122 cis-8-Dimethylamino-3-[4-methyl-6- INT-976 5-bromo-4-methyl-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.57 (s, 1H), 433.2 (trifluoromethyl)-pyridin-3-yl]-8-phenyl- (trifluoromethyl)pyridine 7.79 (s, 1H), 7.52 (s, 1H), 7.40-7.32 (m, 4H), 1,3-diazaspiro[4.5]decan-2-one 7.30-7.22 (tt, 1H), 3.61 (s, 2H), 2.39-2.30 (m, 5H), 1.96 (s, 6H), 2.00-1.91 (m, 2H), 1.84 (s, 2H), 1.57-1.53 (s, 2H).
- SC_3123 cis-8-Dimethylamino-3-(2- INT-976 1-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 7.98-7.92 (dd, 428.2 methylsulfonyl-phenyl)-8-phenyl-1,3- methylsulfonyl-benzene 1H), 7.81-7.74 (td, 1H), 7.61-7.54 (td, 1H), diazaspiro[4.5]decan-2-one 7.52-7.46 (m, 2H), 7.41-7.31 (m, 2H), 7.35 (s, 2H), 7.29-7.22 (tt, 1H), 3.49 (s, 2H), 3.25 (s, 3H), 2.37 (s, 2H), 1.99-1.96 (m, 1H), 1.98-1.94 (s, 6H), 1.95-1.91 (d, 1H), 1.83-1.79 (m, 2H), 1.58-1.55 (s, 2
- SC_3124 cis-8-Dimethylamino-8-phenyl-3-(2- INT-989 Piperazine-2-one SC_3120 1H NMR (600 MHz, DMSO) ⁇ 8.52 (s, 2H), 436.3 piperazin-1-yl-pyrimidin-5-yl)-1,3- 7.41-7.31 (m, 5H), 3.59-3.54 (m, 4H), 3.52 (s, 2H), diazaspiro[4.5]decan-2-one 2.76-2.70 (m, 4H), 2.55 (s, 3H), 2.49-2.33 (m, 2H), 1.96 (s, 6H), 1.93-1.83 (m, 4H), 1.51-1.43 (s, 2H).
- SC_3127 cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3- INT-1009 2-bromo-benzonitrile
- SC_3128 cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3- INT-1008 2-bromo-benzonitrile
- SC_3136 cis-3-[2-(4-Acetyl-piperazin-1-yl)- SC_3124 acetyl chloride
- SC_3130 478.3 pyrimidin-5-yl]-8-dimethylamino-8- phenyl-1,3-diazaspiro[4.5]decan-2-one
- SC_3137 cis-8-Dimethylamino-8-phenyl-3-(2- INT-989 pyridine-4-boronic acid
- SC_3138 cis-8-Dimethylamino-8-phenyl-3-(2- INT-989 pyridine-3-boronic acid
- SC_3139 cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-991 2-aminoethanol
- SC_3133 1H NMR (600 MHz, DMSO) ⁇ 9.08 (s, 2H), 439.3 1,3-diazaspiro[4.5]decan-3-yl)-N-(2- 8.59 (t, 1H), 7.94 (s, 1H), 7.43-7.30 (m, 5H), hydroxy-ethyl)-pyrimidine-2-carboxylic 7.30-7.21 (m, 1H), 3.72 (s, 2H), 3.51 (q, 2H), acid amide 2.49-2.37 (m, 2H), 2.00-1.90 (m, 10H), 1.89-1.74 (m, 2H), 1.57-1.48 (m, 2H), 1.38-1.32 (m, 1H).
- SC_3141 cis-8-Dimethylamino-3-[2-morpholin-4- INT-976 4-[5-bromo-4- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.59 (d, 1H), 505.3 yl-4-(trifluoromethyl)-pyrimidin-5-yl]-8- (trifluoromethyl)pyrimidin- 7.39-7.35 (m, 5H), 7.27 (d, 1H), 3.73 (t, 4H), 3.67 (q, phenyl-1,3-diazaspiro[4.5]decan-2-one 2-yl]morpholine 4H), 3.28-3.22 (m, 1H), 2.41-2.28 (m, 2H), 1.98 (s, 6H), 1.94-1.80 (m, 3H), 1.53-1.42 (m, 2H).
- SC_3145 cis-8-Dimethylamino-3-[2-(morpholine- INT-991 morpholine SC_3133 1H NMR (600 MHz, DMSO) ⁇ 9.04 (s, 2H), 478.3 4-carbonyl)-pyrimidin-5-yl]-8-phenyl- 7.88 (s, 1H), 7.42-7.30 (m, 5H), 7.30-7.22 (m, 1H), 1,3-diazaspiro[4.5]decan-2-one 3.75-3.58 (m, 6H), 3.51 (t, 2H), 3.20 (t, 2H), 2.50-2.33 (m, 2H), 1.99-1.90 (m, 8H), 1.89-1.74 (m, 2H), 1.54-1.44 (m, 2H).
- SC_3147 cis-8-Dimethylamino-3-[2- INT-976 1-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 7.47 (d, 1H), 442.2 (methylsulfonyl-methyl)-phenyl]-8- (methylsulfonylmethyl)benzene 7.42-7.31 (m, 6H), 7.30-7.22 (m, 3H), 4.50 (s, 2H), phenyl-1,3-diazaspiro[4.5]decan-2-one 3.56 (s, 2H), 2.88 (s, 3H), 2.42-2.28 (m, 2H), 2.07 (s, 2H), 1.98-1.90 (m, 8H), 1.89-1.69 (m, 2H), 1.61-1.48 (d, 2H).
- SC_3148 cis-8-Dimethylamino-3-(4-methyl-2 INT-992 morpholine SC_3120 1H NMR (600 MHz, DMSO) ⁇ 8.14 (s, 1H), 451.3 morpholin-4-yl-pyrimidin-5-yl)-8- 7.40-7.32 (m, 4H), 7.26 (td, 1H), 7.21 (s, 1H), phenyl-1,3-diazaspiro[4.5]decan-2-one 3.69-3.60 (m, 8H), 3.38 (s, 2H), 2.41-2.27 (m, 2H), 2.20 (s, 3H), 1.97 (s, 6H), 1.95-1.76 (m, 4H), 1.54-1.45 (s, 2H).
- SC_3149 cis-8-Dimethylamino-3-[2-(1,1-dioxo- INT-989 thiomorpholine-1,1- SC_3120 1H NMR (600 MHz, DMSO) ⁇ 8.63 (s, 2H), 485.2 [1,4]thiazinan-4-yl)-pyrimidin-5-yl]-8- dioxide hydrochloride 7.50 (br s, 1H), 7.41-7.33 (m, 4H), 7.27 (td, 1H), phenyl-1,3-diazaspiro[4.5]decan-2-one 4.17-4.12 (m, 4H), 3.55 (s, 2H), 3.12-3.06 (m, 4H), 2.47-2.27 (m, 2H), 2.04-1.74 (m, 10H), 1.51-1.42 (m, 2H).
- SC_3150 cis-8-Dimethylamino-3-(4-fluoro- INT-976 3-bromo-4-fluoro- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.70 (d, 1H), 369.2 pyridin-3-yl-8-phenyl-1,3- pyridine 8.36 (dd, 1H), 7.54 (s, 1H), 7.36 (td, 5H), 7.26 (s, 1H), diazaspiro[4.5]decan-2-one 3.61 (s, 2H), 2.44-2.28 (m, 2H), 2.01-1.74 (m, 10H), 1.92 (d, 2H), 1.56-1.45 (m, 2H).
- SC_3151 cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-991 2-(methylamino)ethanol
- SC_3133 1H NMR (600 MHz, DMSO) ⁇ 9.03 (d, 2H), 453.2 1,3-diazaspiro[4.5]decan-3-yl)-N-(2- 7.86 (s, 1H), 7.40-7.23 (m, 5H), 3.69 (s, 2H), 3.61 (q, hydroxy-ethyl)-N-methyl-pyrimidine-2- 1H), 3.50 (t, 1H), 3.45 (d, 1H), 3.17 (t, 1H), 3.01 carboxylic acid amide and 2.83 (both s, together 3H, amide rotamers), 2.49-2.36 (m, 2H), 2.00-1.89 (m, 8H), 1.89-1.73 (m, 2H), 1.55-1.47 (m, 2H).
- SC_3152 cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 5-bromo-2-morpholino- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.24 (s, 1H), 461.3 1,3-diazaspiro[4.5]decan-3-yl)-2- pyridine-4-carbonitrile 7.67-7.30 (m, 5H), 7.29 (s, 1H), 3.70-3.65 (m, 4H), morpholin-4-yl-isonicotinonitrile 3.51-3.44 (m, 4H), 2.37-2.22 (m, 2H), 2.10-1.87 (m, 10H), 1.53-1.31 (m, 2H).
- SC_3154 cis-8-Dimethyamino-3-(2-fluoro-4- INT-976 1-bromo-2-fluoro-4- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 789-7.83 (m, 446.2 methylsulfonyl-phenyl)-8-phenyl-1,3- methylsulfonyl-benzene 1H), 7.76 (dd, 1H), 7.70 (dd, 1H), 7.40-7.32 (m, diazaspiro[4.5]decan-2-one 5H) 7.29-7.23 (m, 1H), 3.69 (s, 2H), 3.23 (s, 3H), 2.43-2.30 (m, 2H), 1.96 (s, 6H), 1.94-1.88 (m, 2H), 1.53-1.47 (m, 2H).
- SC_3155 cis-4-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 4-bromo-3-fluoro- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 7.85-7.79 (m, 393.2 1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro- benzonitrile 2H), 7.73 (s, 1H), 7.62 (dd, 1H), 7.40-7.31 (m, benzonitrile 4H), 7.26 (tt, 1H), 3.69 (s, 2H), 2.40-2.31 (m, 2H), 1.95 (s, 6H), 1.94-1.87 (m, 2H), 1.87-1.75 (m, 2H), 1.52-1.46 (m, 2H).
- SC_3156 cis-4-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 4-bromo-3,5-difluoro- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 7.85 (d, 2H), 411.2 1,3-diazaspiro[4.5]decan-3-yl)-3,5- benonitrile 7.61 (s, 1H), 7.39-7.31 (m, 4H), 7.25 (tt, 1H), 3.53 (s, difluoro-benzonitrile 2H), 2.42-2.33 (m, 2H), 1.98-1.89 (m, 8H), 1.82-1.78 (m, 2H), 1.54-1.47 (m, 2H).
- SC_3157 cis-8-Dimethylamino-3-(2-methoxy- INT-989 methanol instead of n- SC_3120 1H NMR (600 MHz, DMSO) ⁇ 8.76 (s, 2H), 382.2 pyrimidin-5-yl)-8-phenyl-1,3- butanol as a solvent 7.41-7.33 (m, 5H), 7.27 (ddt, 1H), 3.86 (s, 3H), 3.60 (s, diazaspiro[4.5]decan-2-one 2H), 2.47-2.30 (m, 2H), 2.01-1.74 (m, 10H), 1.52-1.45 (m, 2H).
- SC_3158 cis-3-[2-(Benzylamino)-pyrimidin-5-yl]- INT-989 benzylamine
- SC_3120 1H NMR (600 MHz, DMSO) ⁇ 8.43 (s, 2H), 457.3 8-dimethylamino-8-phenyl-1,3- 7.50-7.45 (m, 1H), 7.46-7.33 (m, 5H), 7.31-7.23 (m, diazaspiro[4.5]decan-2-one 4H), 7.19 (tq, 1H), 4.46 (d, 2H), 4.02 (s, 1H), 3.50 (s, 2H), 2.41-2.31 (m, 2H), 1.97 (s, 6H), 1.88 (s, 2H), 1.49-1.41 (m, 2H).
- SC_3159 cis-8-Dimethylamino-3-[2-(4- INT-989 (4-fluorophenyl)boronic SC_3129 1H NMR (600 MHz, DMSO) ⁇ 9.07 (s, 2H), 446.2 fluorophenyl)-pyrimidin-5-yl]-8-phenyl- acid 8.37-8.30 (m, 2H), 7.83 (s, 1H), 7.44-7.35 (m, 4H), 1,3-diazaspiro[4.5]decan-2-one 7.34-7.25 (m, 3H), 3.69 (s, 2H), 2.47-2.30 (m, 2H), 2.08-1.80 (m, 10H), 1.55-1.46 (m, 2H).
- SC_3160 trans-8-Benzyl-8-dimethylamino-3-(2- INT-995 4-(5-bromopyrimidin-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.57 (s, 2H), 451.3 morpholin-4-yl-pyrimidin-5-yl)-1,3- yl)morpholine 7.60 (s, 1H), 7.27 (t, 2H), 7.22-7.15 (m, 3H), diazaspiro[4.5]decan-2-one 3.68-3.62 (m, 4H), 3.64-3.57 (m, 4H), 3.49 (s, 2H), 2.66 (s, 2H), 2.22 (s, 6H), 1.80-1.70 (m, 4H), 1.51-1.43 (m, 4H).
- SC_3161 cis-8-Benzyl-8-dimethylamino-3-(2- INT-994 4-(5-bromopyrimidin-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.45 (s, 2H), 451.3 morpholin-4-yl-pyrimidin-5-yl)-1,3- yl)morpholine 7.27 (t, 2H), 7.22-7.15 (m, 3H), 7.11 (s, 1H), diazaspiro[4.5]decan-2-one 3.68-3.56 (m, 8H), 2.64 (s, 2H), 2.26 (s, 6H), 1.87-1.77 (m, 4H), 1.42 (d, 2H), 1.15 (dt, 2H).
- SC_3163 cis-4-(8-Dimethylamino-2-oxo-8-phenyl- SC_3156 SC_3016 1H NMR (600 MHz, DMSO) ⁇ 8.08 (s, 1H), 429.2 1,3-diazaspiro[4.5]decan-3-yl)-3,5- 7.65-7.58 (m, 2H), 7.48 (br s, 1H), 7.39-7.31 (m, 4H), difluoro-benzamide 7.28-7.22 (m, 1H), 3.49 (s, 2H), 2.40-2.32 (m, 2H), 1.96 (s, 6H), 1.95-1.90 (m, 2H), 1.87-1.77 (m, 2H), 1.54-1.49 (m, 2H).
- SC_3164 cis-4-(8-Dimethylamino-2-oxo-8-phenyl- SC_3155 SC_3016 1H NMR (600 MHz, DMSO) ⁇ 7.95 (s, 1H), 411.2 1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro- 7.72-7.64 (m, 2H), 7.61 (t, 1H), 7.54-7.50 (m, 1H), benzamide 7.40-7.32 (m, 5H), 7.26 (tt, 1H), 3.62 (s, 2H), 2.41-2.31 (m, 2H), 1.96 (s, 6H), 1.93-1.88 (m, 2H), 1.86-1.75 (m, 2H), 1.53-1.45 (m, 2H).
- SC_3165 cis-8-Benzyl-8-dimethylamino-3-[2- INT-994 5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 9.07 (s, 2H), 434.2 (trifluoromethyl)-pyrimidin-5-yl]-1,3- (trifluoromethyl)pyrimidine 7.77 (s, 1H), 7.29 (t, 2H), 7.24-7.17 (m, 3H), 3.55 (s, diazaspiro[4.5]decan-2-one 2H), 2.66 (s, 2H), 2.26 (s, 6H), 1.86 (dt, 4H), 1.44 (d, 2H), 1.25-1.17 (m, 2H).
- SC_3166 trans-8-Benzyl-8-dimethylamino-3-[2- INT-995 5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 9.16 (s, 2H), 434.2 (trifluoromethyl)-pyrimidin-5-yl]-1,3- (trifluoromethyl)pyrimidine 8.28 (s, 1H), 7.27 (t, 2H), 7.22-7.16 (m, 3H), 3.67 (s, diazaspiro[4.5]decan-2-one 2H), 2.66 (s, 2H), 2.24 (s, 6H), 1.84-1.72 (m, 4H), 1.49 (q, 4H).
- SC_3170 cis-8-Dimethylamino-8-phenyl-3-(2- INT-989 piperidine
- SC_3120 1H NMR (DMSO-d6): ⁇ 8.49 (s, 2H), 7.39-7.24 (m, 435.3 piperidin-1-yl-pyrimidin-5-yl)-1,3- 6H), 3.65-3.63 (m, 4H), 3.50 (s, 2H), 2.36-2.32 (m, diazaspiro[4.5]decan-2-one 2H), 1.95-1.86 (m, 10H), 1.61-1.56 (m, 2H), 1.50-1.44 (m, 6H).
- SC_3171 cis-8-Dimethylamino-8-phenyl-3-(2- INT-989 pyrrolidine
- SC_3120 1H NMR (CDCl3): ⁇ 8.43 (s, 2H), 7.41-7.38 (m, 421.3 pyrrolidin-1-yl-pyrimidin-5-yl)-1,3- 2H), 7.32-7.30 (m, 3H), 5.05 (br s, 1H), 3.53 (t, diazaspiro[4.5]decan-2-one 4H), 3.45 (s, 2H), 2.30-2.06 (m, 10H), 1.99-1.96 (m, 6H), 1.62-1.58 (m, 2H).
- SC_3172 cis-8-Dimethylamino-8-phenyl-3-(2- INT-989 pyrimidin-5-ylboronic SC_3129 1H NMR (600 MHz, DMF) ⁇ 9.56 (s, 2H), 9.27 (s, 430,2 pyrimidin-5-yl-pyrimidin-5-yl)-1,3- acid 1H), 9.17 (s, 2H), 8.35 (s, 1H), 7.89 (d, 2H), diazaspiro[4.5]decan-2-one 7.63 (dq, 3H), 3.73 (s, 2H), 3.04 (d, 2H), 2.81 (s, 6H), 2.57 (td, 2H), 2.06 (d, 2H), 1.58 (td, 2H).
- SC_3175 cis-5-(8-Dimethylamino-2-oxo-8-phenyl- SC_3152 SC_3016 480.6 1,3-diazaspiro[4.5]decan-3-yl)-2- morpholin-4-yl-pyridine-4-carboxylic acid amide
- SC_3176 cis-8-Dimethylamino-3-[2-(3,5- INT-989 (3,5-dimethylisoxazol-4- SC_3129 1H NMR (600 MHz, DMSO) ⁇ 9.05 (s, 2H), 447.2 dimethyl-isoxazol-4-yl)-pyrimidin-5-yl]- yl)boronic acid 7.80 (s, 1H), 7.43-7.34 (m, 4H), 7.28 (tt, 1H), 3.68 (s, 8-phenyl-1,3-diazaspiro[4.5]decan-2-one 2H), 2.69 (s, 3H), 2.47 (s, 3
- SC_3178 cis-8-Dimethylamino-3-[2-fluoro-4- INT-976 1-bromo-2-fluoro-4- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 7.80 (t, 1H), 436.2 (trifluoromethyl)-phenyl]-8-phenyl-1,3- (trifluoromethyl)benzene 7.65 (dd, 1H), 7.53 (dd, 1H), 7.40-7.32 (m, 4H), diazaspiro[4.5]decan-2-one 7.29-7.23 (m, 1H), 3.66 (s, 2H), 2.36 (s, 2H), 1.97-1.88 (m, 8H), 1.85-1.75 (m, 2H), 1.53-1.46 (m, 2H).
- SC_3179 cis-8-Dimethylamino-3-(6-morpholin-4- INT-976 4-(5-bromo-2- as SC_3097 step 2
- 1H NMR 600 MHz, DMSO
- ⁇ 8.20 8.20 (d, 1H), 7.89 436.3 yl-pyridin-3-yl)-8-phenyl-1,3- pyridyl)morpholine 7.89 (dd, 1H), 7.37 (p, 5H), 7.27 (d, 1H), 6.79 (d, 1H), diazaspiro[4.5]decan-2-one 3.71-3.66 (m, 4H), 3.53 (s, 2H), 2.43-2.32 (m, 2H), 1.96 (s, 7H), 1.91-1.85 (m, 5H), 1.49-1.42 (m, 2H).
- SC_3180 cis-8-Dimethylamino-8-phenyl-3-(2- INT-976 4-bromo-2- SC_3103 1H NMR (DMSO-d6): ⁇ 7.89-7.87 (m, 2H), 433.2 phenyl-thiazol-4-yl)-1,3- phenylthiazole 7.55 (br s, 1H), 7.43-7.35 (m, 8H), 7.29-7.26 (m, 1H), diazaspiro[4.5]decan-2-one 3.82 (s, 2H), 2.45 (br m, 2H), 1.96-1.79 (m, 10H), 1.53-1.50 (m, 2H).
- SC_3183 cis-8-Dimethylamino-8-phenyl-3-(4- INT-976 2-bromo-4- SC_3103 1H NMR (DMSO-d6): ⁇ 8.09 (br s, 1H), 7.87 (d, 433.2 phenyl-thiazol-2-yl)-1,3- phenylthiazole 2H), 7.51 (s, 1H), 7.37-7.24 (m, 8H), 3.87 (s, 2H), diazaspiro[4.5]decan-2-one 2.43 (m, 2H), 1.96-1.84 (m, 10H), 1.54 (m, 2H).
- SC_3184 cis-8-Dimethylamino-8-phenyl-3-[2- INT-976 1H-pyrrolo[2,3- SC_3103 1H NMR (DMSO-d6): ⁇ 9.07 (s, 2H), 8.35-8.33 (m, 468.2 (1H-pyrrolo[2,3-b)pyridin-1-yl)- b]pyridine 1H), 8.10-8.04 (m, 2H), 7.83 (br s, 1H), pyrimidin-5-yl]-1,3- 7.41-7.37 (m, 4H), 7.29-7.21 (m, 2H), 6.72-6.71 (d, 1H), diazaspiro[4.5]decan-2-one 3.71 (s, 2H), 2.49 (m, 2H), 1.97 (m, 10H), 1.52 (m, 2H).
- SC_3185 cis-8-Dimethylamino-8-phenyl-3-[2- INT-989 (3,4,5- SC_3129 IH NMR (600 MHz, DMSO) ⁇ 9.11 (s, 2H), 481.2 (3,4,5-trifluoro-phenyl)-pyrimidin-5-yl]- trifluorophenyl)boronic 8.12-8.03 (m, 2H), 7.89 (s, 1H), 7.42-7.34 (m, 4H), 1,3-diazaspiro[4.5]decan-2-one acid 7.28 (dq, 1H), 3.71 (s, 2H), 2.48-2.35 (m, 2H), 1.99-1.79 (m, 10H), 1.58-1.47 (m, 2H).
- SC_3187 cis-8-Dimethylamino-3-m-tolyl-8- INT-976 1-bromo-3- SC_3186 363.2 phenyl-1,3-diazaspiro[4.5]decan-2-one methylbenzene
- SC_3188 cis-8-Dimethylamino-8-phenyl-3-p-tolyl- INT-976 1-bromo-4- SC_3186 363.2 1,3-diazaspiro[4.5]decan-2-one methylbenzene
- SC_3189 cis-8-Dimethylamino-8-phenyl-3-[4- INT-976 1-bromo-4- SC_3186 417.2 (trifluoromethyl)-phenyl]-1,3- trifluoromethylbenzene diazaspiro[4.5]decan-2-one
- SC_3190 cis-8-Dimethylamino-8-phenyl-3-[3- INT-976 1-bromo-3- SC_
- SC_3210 cis-8-Dimethylamino-3-[2-(3-hydroxy- INT-989 rac-piperidin-3-ol SC_3182 1H NMR (DMSO-d6): 8.48 (s, 2H), 7.39-7.35 (m, 451.2 piperidin-1-yl)-pyrimidin-5-yl]-8- 5H), 7.27-7.24 (m, 1H), 4.82 (d, 1H), 4.39-4.36 (m, phenyl-1,3-diazaspiro[4.5]decan-2-one 1H), 4.24-4.21 (m, 1H), 3.51 (s, 2H), 3.41-3.36 (m, 1H), 2.92-2.87 (m, 1H), 2.77-2.72 (m, 1H), 2.42-2.32 (m, 2H), 2.00-1.66 (m, 12H), 1.46-1.39 (m, 2H), 1.34 (t, 2H).
- SC_3211 cis-8-Dimethylamino-3-[2-(3-hydroxy- INT-989 rac-piperidin-3-ol SC_3182 1H NMR (DMSO-d6): 8.48 (s, 2H), 7.35 (m, 5H), 451.3 piperidin-1-yl)-pyrimidin-5-yl]-8- 7.25 (m, 1H), 4.82 (d, 1H), 4.39-4.37 (m, 1H), phenyl-1,3-diazaspiro[4.5]decan-2-one 4.24-4.21 (m, 1H), 3.51 (s, 2H), 3.40-3.39 (m, 1H), 2.90-2.87 (m, 1H), 2.77-2.72 (m, 1H), 2.37 (m, 2H), 2.00-1.66 (m, 12H), 1.45 (m, 2H), 1.34 (t, 2H).
- SC_3212 cis-8-Dimethylamino-3-[2-[4-(2- INT-989 2-piperazin-1-ylethanol SC_3120 1H NMR (600 MHz, DMSO) ⁇ 8.53 (s, 2H), 480.3 hydroxy-ethyl)-piperazin-1-yl]- 7.37 (p, 5H), 7.27 (d, 1H), 3.62 (t, 4H), 3.53 (q, 4H), pyrimidin-5-yl]-8-phenyl-1,3- 2.49-2.27 (m, 7H), 1.96 (s, 6H), 1.94-1.73 (m, diazaspiro[4.5]decan-2-one 4H), 1.51-1.40 (m, 2H).
- SC_3213 cis-2-[4-[5-(8-Dimethylamino-2-oxo-8- SC_3146 INT-991 1H NMR (600 MHz, DMSO) ⁇ 8.53 (s, 2H), 494.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- 7.57 (s, 1H), 7.42 (d, 4H), 7.33 (d, 1H), 3.68 (t, 4H), pyrimidin-2-yl]-piperazin-1-yl]-acetic 3.19 (s, 2H), 2.62 (t, 4H), 2.37 (d, 2H), acid 2.20-1.96 (m, 8H), 1.88 (t, 2H), 1.43 (t, 2H).
- SC_3214 cis-8-Dimethylamino-3-[2-(1-methyl- INT-989 1-methyl-4-(4,4,5,5- SC_3208 1H NMR (600 MHz, DMSO + 2vol % TFA) ⁇ 484.3 1H-pyrrolo[2,3-b]pyridin-4-yl)- tetramethyl-1,3,2- 9.85 (s, 1H), 9.13 (s, 2H), 8.41 (d, 2H), 7.99 (s, 1H), pyrimidin-5-yl]-8-phenyl-1,3- dioxaborolan-2-yl)-2,3- 7.72 (s, 2H), 7.66-7.46 (m, 4H), 7.30 (s, 1H), diazaspiro[4.5]decan-2-one dihydropyrrolo[2,3- 3.88 (s, 2H), 3.60 (s, 6H), 2.77-2.71 (m, 2H), b]pyridine 2.30-2.26 (m, 2H),
- SC_3215 cis-8-Benzyl-8-dimethylamino-3-[4- INT-994 5-bromo-4-methyl-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.52 (s, 1H), 447.2 methyl-6-(trifluoromethyl)-pyridin-3-yl]- (trifluoromethyl)pyridine 7.76 (s, 1H), 7.23 (dd, 2H), 7.19-7.11 (m, 4H), 2.62 (s, 1,3-diazaspiro[4.5]decan-2-one 2H), 2.27 (s, 6H), 2.25 (s, 3H), 1.86 (td, 2H), 1.80 (dt, 2H), 1.57-1.49 (m, 2H), 1.09 (td, 2H).
- SC_3217 cis-8-Dimethylamino-3-[4-methyl-6- INT-997 5-bromo-4-methyl-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.58 (s, 1H), 439.2 (trifluoromethyl)-pyridin-3-yl]-8- (trifluoromethyl)pyridine 7.80 (s, 1H), 7.45 (s, 1H), 7.42 (dd, 1H), 7.05 (dd, 1H), thiophen-2-yl-1,3-diazaspiro[4.5]decan- 6.95 (dd, 1H), 3.67 (s, 2H), 2.33 (s, 3H), 2-one 2.32-2.25 (m, 2H), 2.04 (s, 6H), 2.00-1.92 (m, 2H), 1.89-1.76 (m, 2H), 1.62 (dt, 2H).
- SC_3218 cis-8-Dimethylamino-3-[2-(1,1-dioxo- INT-976 4-[5-bromo-4- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.65 (s, 1H), 553.2 [1,4]thiazinan-4-yl)-4-(trifluoromethyl)- (trifluoromethyl)pyrimidin- 7.42 (s, 1H), 7.41-7.31 (m, 5H), 7.25 (tt, 1H), 4.23 (t, pyrimidin-5-yl]-8-phenyl-1,3- 2-yl]-1,4-thiazinane 4H), 3.22 (t, 4H), 2.40-2.26 (m, 2H), diazaspiro[4.5]decan-2-one 1,1-dioxide (prepared as 1.97-1.88 (m, 8H), 1.87-1.75 (m, 2H), 1.54-1.42 (m, 2H).
- SC_3097 step 1) SC_3219 cis-8-Dimethylamino-8-(1-methyl-1H- INT-1000 5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 9.14 (s, 2H), 474.2 benzoimidazol-2-yl)-3-[2- (trifluoromethyl)pyrimidine 8.65 (s, 1H), 7.63 (d, 1H), 7.51 (d, 1H), 7.25 (ddd, 1H), (trifluoromethyl)-pyrimidin-5-yl]-1,3- 7.19 (ddd, 1H), 4.02 (s, 3H), 3.61 (s, 2H), 2.26 (d, diazaspiro[4.5]decan-2-one 2H), 2.18 (s, 6H), 2.16-2.09 (m, 2H), 1.87 (s, 2H), 1.78 (d, 2H).
- SC_3220 cis-8-Dimethylamino-8-(1-methyl-1H- INT-1000 5-bromo-4-methyl-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.56 (s, 1H), 487.3 benzoimidazol-2-yl)-3-[4-methyl-6- (trifluoromethyl)pyridine 8.10 (s, 1H), 7.80 (s, 1H), 7.60 (d, 1H), 7.50 (d, 1H), (trifluoromethyl)-pyridin-3-yl]-1,3- 7.23 (ddd, 1H), 7.17 (td, 1H), 4.02 (s, 3H), 3.50 (s, diazaspiro[4.5]decan-2-one 2H), 2.34-2.25 (m, 5H), 2.19-2.09 (m, 8H), 1.90-1.74 (m, 4H).
- SC_3222 cis-3-[2-(Benzyl-methyl-amino)- INT-976 N-benzyl-5-bromo-N- SC_3103 1H NMR (DMSO-d6): ⁇ 8.52 (s, 2H), 7.39-7.33 (m, 471.2 pyrimidin-5-yl]-8-dimethylamino-8- methylpyrimidin-2- 5H), 7.30-7.17 (m, 6H), 4.81 (s, 2H), 3.52 (s, 2H), phenyl-1,3-diazaspiro[4.5]decan-2-one amine 3.03 (s, 3H), 2.45-2.32 (m, 2H), 1.95-1.86 (m, 10H), 1.47-1.43 (m, 2H).
- SC_3223 cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 ethyl 5- SC_3103 (step 1), 1H NMR (DMSO-d6): ⁇ 9.04 (s, 2H), 8.24-8.23 (m, 585.3 1,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2- bromopyrimidine-2- INT-991 (step 2), 1H), 7.42-7.39 (m, 2H), 7.32-7.31 (m, 3H), 5.70 (s, [2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]- carboxylate (step 1), SC_3133 (step 3) 1H), 3.70-3.60 (m, 16H), 3.54-3.52 (m, 2H), ethyl]-pyrimidine-2-carboxylic acid 2,5,8,11- 3.35 (s, 3H), 2.21-2.00 (m, 12H),
- SC_3226 cis-3-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 5-bromo-4-methyl-2 SC_3103 (step 1), 487.3 1,3-diazaspiro[4.5]decan-3-yl)- (trifluoromethyl)pyridine SC_3016 (step 2) benzamide SC_3227 cis-8-Dimethylamino-3-[3-fluoro-5- INT-976 2-bromo-3-fluoro-5- SC_3186 417.1 (trifluoromethyl)-pyridin-2-yl]-8-phenyl- (trifluoromethyl)pyridine 1,3-diazaspiro[4.5]decan-2-one SC_3228 cis-8-Dimethylamino-3-(5-methyl- INT-976 2-bromo-5- SC_3186 459.1 pyrazin-2-yl)-8-phenyl-1,3- methylpyrazine diazaspiro[4.5
- SC_3234 cis-8-Dimethylamino-8-phenyl-3-(5- INT-976 4-(5-bromothiophen-2- SC_3103 1H NMR (DMSO-d6) ⁇ 8.45-8.43 (d, 2H), 7.87 (br 433.2 pyridin-4-yl-thiophen-2-yl)-1,3- yl)pyridine s, 1H), 7.54-7.53 (d, 1H), 7.49-7.48 (m, 2H), diazaspiro[4.5]decan-2-one 7.38-7.27 (m, 5H), 6.35-6.34 (d, 2H), 3.64 (s, 2H), 2.42 (m, 2H), 1.96-1.90 (m, 10H), 1.51-1.49 (m, 2H).
- SC_3236 cis-8-Dimethylamino-3-(2-morpholin-4- INT-1002 morpholine SC_3120 1H NMR (600 MHz, DMSO) ⁇ 8.07 (d, 1H), 437.3 yl-pyrimidin-4-yl)-8-phenyl-1,3- 7.93 (s, 1H), 7.37 (dt, 5H), 7.27 (t, 1H), 3.65 (s, 2H), diazaspiro[4.5]decan-2-one 3.58 (s, 8H), 2.40-2.27 (m, 2H), 1.94 (s, 6H), 1.92-1.80 (m, 4H), 1.43 (d, 2H).
- SC_3237 cis-3-[2-(3,4-Difluoro-phenyl)- INT-989 (3,4- SC_3129 1H NMR (600 MHz, DMSO) ⁇ 9.08 (s, 2H), 463.2 pyrimidin-5-yl]-8-dimethylamino-8- difluorophenyl)boronic 8.22-8.12 (m, 2H), 7.54 (dt, 1H), 7.41-7.37 (m, 4H), phenyl-1,3-diazaspiro[4.5]decan-2-one acid 7.29 (s, 1H), 3.70 (s, 2H), 2.06-1.75 (m, 12H), 1.50 (d, 2H).
- SC_3241 cis-2-[4-[5-(8-Dimethylamino-2-oxo-8- SC_3213 ammonium chloride SC_3133 1H NMR (600 MHz, DMSO) ⁇ 8.53 (s, 2H), 493.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- 7.38 (d, 5H), 7.27 (s, 1H), 7.23 (s, 1H), 7.11 (s, 1H), pyrimidin-2-yl]-piperazin-1-yl]- 3.67 (t, 4H), 3.54-3.50 (m, 2H), 2.89 (s, 2H), acetamide 2.47 (t, 4H), 2.39-2.35 (m, 2H), 1.96 (s, 7H), 1.93-1.82 (m, 3H), 1.48-1.44 (m, 2H).
- SC_3243 cis-8-Dimethylamino-3-[6-(4-methyl- INT-976 1-(5-bromo-2-pyridyl)-4- SC_3242 (step 2)
- 1H NMR 600 MHz, DMSO
- ⁇ 8.16 8.16
- 449.3 piperazin-1-yl)-pyridin-3-yl]-8-phenyl- methyl-piperazine 7.86 (dd, 1H), 7.41-7.33 (m, 4H), 7.32 (s, 1H), 7.27 (t, 1,3-diazaspiro[4.5]decan-2-one 1H), 6.78 (d, 1H), 3.51 (s, 2H), 2.55-2.45 (m, 4H), 2.42-2.27 (m, 6H), 2.21 (s, 3H), 1.96 (s, 6H), 1.93-1.73 (m, 4H), 1.46 (t, 2H).
- SC_3244 cis-8-Dimethylamino-3-[2-(1,1-dioxo- INT-976 4-(5-bromo-4-methyl- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.20 (s, 1H), 499.3 [1,4]thiazinan-4-yl)-4-methyl-pyrimidin- pyrimidin-2-yl)-1,4- 7.36 (h, 4H), 7.30-7.17 (m, 2H), 4.23-4.17 (m, 4H), 5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan- thiazinane 1,1-dioxide 3.13 (t, 4H), 2.44-2.28 (m, 2H), 2.24 (s, 3H), 2-one 1.97 (s, 6H), 1.91 (d, 4H), 1.55-1.44 (m, 2H).
- SC_3245 cis-8-Dimethylamino-8-phenyl-3-[2- INT-976 5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 9.17 (s, 2H), 419.2 (trifluoromethyl)-pyrimidin-5-yl]-1,3- (trifluoromethyl)- 8.03 (s, 1H), 7.38 (s, 4H), 7.28 (tt, 1H), 3.73 (s, 2H), diazaspiro[4.5]decan-2-one pyrimidine 2.49-2.35 (m, 2H), 1.97 (s, 6H), 1.97-1.92 (m, 2H), 1.90-1.73 (m, 2H), 1.55-1.49 (m, 2H).
- SC_3246 cis-2-[8-Dimethylamino-1-(3-methoxy- INT-979 2-chloropyrimidine-5- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 9.02 (s, 2H), 449.3 propyl)-2-oxo-8-phenyl-1,3- carbonitrile 7.40-7.31 (m, 5H), 3.86 (s, 2H), 3.26 (s, 3H), diazaspiro[4.5]decan-3-yl]-pyrimidine-5- 3.29-3.19 (m, 2H), 2.73-2.67 (m, 2H), 2.16 (td, 2H), 2.00 (s, carbonitrile 7H), 1.83 (dt, 2H), 1.50-1.40 (m, 5H).
- SC_3247 cis-8-Dimethylamino-3-[2-(4-methyl- INT-989 1-Methylpiperazin SC_3120 1H NMR (600 MHz, DMSO) ⁇ 8.54 (s, 2H), 450.3 piperazin-1-yl)-pyrimidin-5-yl]-8- 7.48-7.33 (m, 5H), 7.31-7.21 (m, 1H), 3.63 (dd, 4H), phenyl-1,3-diazaspiro[4.5]decan-2-one 2.45-2.29 (m, 6H), 2.20 (s, 3H), 1.96 (s, 6H), 1.94-1.78 (m, 4H), 1.51-1.42 (m, 2H).
- SC_3248 cis-8-Dimethylamino-1-[(1-hydroxy- SC_3245 [1-[tert- INT-988 (step 1)
- 1H NMR 600 MHz, DMSO
- ⁇ 9.24 (s, 2H) 504.3 cyclobutyl)-methyl]-8-phenyl-3-[2- butyl(dimethyl)silyl]- 7.38 (d, 4H), 7.27 (p, 1H), 3.89 (s, 2H), 2.73-2.67 (m, (trifluoromethyl)-pyrimidin-5-yl]-1,3- oxycyclobutyl]methyl 4- 2H), 2.26 (ddd, 2H), 2.19 (tt, 2H), 2.08 (s, 1H), diazaspiro[4.5]decan-2-one methylbenzenesulfonate 2.00 (s, 6H), 1.92 (qd, 2H), 1.73-1.64 (m, 1H), 1.60-1.50 (m, 3H),
- SC_3249 cis-2-[1-(3-Methoxy-propyl)-8- SC_3246 SC_3099 1H NMR (600 MHz, DMSO) ⁇ 9.05 (s, 2H), 435.3 methylamino-2-oxo-8-phenyl-1,3- 7.49-7.44 (m, 2H), 7.34 (t, 2H), 7.21 (t, 1H), 3.90 (s, diazaspiro[4.5]decan-3-yl]-pyrimidine-5- 2H), 3.26 (s, 3H), 2.23 (td, 2H), 2.07 (s, 1H), carbonitrile 1.91 (d, 5H), 1.86-1.78 (m, 2H), 1.73 (tt, 2H), 1.42 (d, 2H).
- SC_3250 cis-8-Dimethylamino-8-phenyl-3-[6- INT-976 5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.88 (d, 1H), 419.3 (trifluoromethyl)-pyridin-3-yl]-1,3- (trifluoromethyl)pyridine 8.24 (dd, 1H), 7.86 (s, 1H), 7.78 (d, 1H), 7.41-7.34 (m, diazaspiro[4.5]decan-2-one 4H), 7.27 (t, 1H), 3.69 (s, 2H), 2.42 (s, 2H), 1.97 (s, 6H), 1.96-1.74 (m, 4H), 1.53-1.47 (m, 2H).
- SC_3251 cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 5-bromopyridine-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.92 (d, 1H), 376.2 1,3-diazaspiro[4.5]decan-3-yl)-pyridine- carbonitrile 8.15 (dd, 1H), 7.95 (br s, 1H), 7.90 (d, 1H), 2-carbonitrile 7.41-7.34 (m, 4H), 7.27 (t, 1H), 3.69 (s, 2H), 2.44-2.40 (m, 2H), 1.97 (s, 6H), 1.96-1.89 (m, 3H), 1.90-1.70 (m, 1H), 1.53-1.46 (m, 2H).
- SC_3252 cis-8-Dimethylamino-3-(2-morpholin-4- INT-989 morpholine SC_3120 1H NMR (600 MHz, DMSO) ⁇ 8.57 (s, 2H), 437.3 yl-pyrimidin-5-yl)-8-phenyl-1,3- 7.46-7.42 (m, 1H), 7.40-7.34 (m, 4H), 7.27 (td, 1H), diazaspiro[4.5]decan-2-one 3.64 (dd, 4H), 3.59 (dd, 4H), 3.54 (s, 2H), 2.46-2.29 (m, 2H), 1.96 (s, 7H), 1.93-1.73 (m, 3H), 1.50-1.44 (m, 2H).
- SC_3253 cis-8-Dimethylamino-3-(2-methyl- INT-976 5-bromo-2-methyl- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.86 (s, 2H), 366.3 pyrimidin-5-yl)-8-phenyl-1,3- pyrimidine 7.69 (s, 1H), 7.41-7.33 (m, 5H), 7.31-7.19 (m, 1H), diazaspiro[4.5]decan-2-one 3.62 (s, 2H), 2.53 (s, 3H), 2.48-2.31 (m, 2H), 1.97 (s, 6H), 1.95-1.77 (m, 4H), 1.52-1.46 (m, 2H).
- SC_3254 cis-8-Dimethylamino-1-[(2- SC_3253 2-methoxybenzyl SC_3105 1H NMR (DMSO-d6) ⁇ 8.90 (s, 2H), 7.39-7.34 (m, 486.2 methoxyphenyl)-methyl]-3-(2-methyl- bromide 3H), 7.28-7.22 (m, 4H), 6.95-6.87 (m, 2H), 4.58 (s, pyrimidin-5-yl)-8-phenyl-1,3- 2H), 3.89 (s, 3H), 3.63 (s, 2H), 2.68-2.64 (m, 5H), diazaspiro[4.5]decan-2-one 2.35-2.28 (m, 2H), 2.01 (s, 6H), 1.49-1.43 (m, 4H).
- SC_3255 cis-1-[(1-Hydro-cyclobutyl)-methyl]- SC_3248 SC_3099 1H NMR (600 MHz, DMSO) ⁇ 9.26 (s, 2H), 490.3 8-methylamino-8-phenyl-3-[2- 7.51 (d, 2H), 7.34 (t, 2H), 7.22 (t, 1H), 3.92 (s, 2H), (trifluoromethyl)-pyrimidin-5-yl]-1,3- 3.41 (s, 1H), 2.31 (td, 2H), 2.15 (td, 2H), 2.07 (d, 1H), diazaspiro[4.5]decan-2-one 1.93 (d, 7H), 1.83 (dt, 2H), 1.67 (t, 1H), 1.56 (q, 1H), 1.47 (d, 2H).
- SC_3256 cis-8-Dimethylamino-1-[(1-hydroxy- SC_3253 [1-[tert- INT-988 (step 1)
- 1H NMR 600 MHz, DMSO
- ⁇ 8.92 (s, 2H) 450.3 cyclobutyl)-methyl]-3-(2-methyl- butyl(dimethyl)silyl]- 7.37 (d, 4H), 7.27 (td, 1H), 3.79 (s, 2H), 3.27 (s, 1H), pyrimidin-5-yl)-8-phenyl-1,3- oxycyclobutyl]methyl
- SC_3257 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]- SC_3260 SC_3099 1H NMR (600 MHz, DMSO) ⁇ 9.07 (s, 2H), 422.3 8-methylamino-8-phenyl-3-pyrimidin-5- 8.81 (s, 1H), 7.53-7.48 (m, 2H), 7.33 (t, 2H), yl-1,3-diazaspiro[4.5]decan-2-one 7.24-7.18 (m, 1H), 3.86 (s, 2H), 2.29 (td, 2H), 2.14 (tt, 2H), 2.07 (s, 1H), 1.96-1.87 (m, 8H), 1.82 (td, 2H), 1.71-1.62 (m, 1H), 1.54 (dp, 1H), 1.49-1.43 (m, 2H).
- SC_3258 cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 5-bromo-4-methyl- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.57 (s, 1H), 390.2 1,3-diazaspiro[4.5]decan-3-yl)-4-methyl- pyridine-2-carbonitrile 7.92 (s, 1H), 7.61-7.57 (m, 1H), 7.42-7.32 (m, 4H), pyridine-2-carbonitrile 7.25 (tt, 1H), 3.63 (s, 2H), 2.38 (d, 2H), 2.28 (s, 3H), 2.00-1.90 (m, 9H), 1.90-1.72 (m, 1H), 1.59-1.49 (m, 2H).
- SC_3259 cis-8-Dimethylamino-3-(2-methyl- SC_3253 2-(bromomethyl)pyridine
- SC_3260 INT-976 5-bromopyrimidine SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.98 (s, 2H), 352.2 8.76 (s, 1H), 7.78 (s, 1H), 7.41-7.34 (m, 4H), 7.31-7.24 (m, 1H), 3.65 (s, 2H), 2.49-2.34 (m, 2H), 1.97 (s, 6H), 1.95-1.76 (m, 4H), 1.50 (t, 2H).
- SC_3261 cis-8-Dimethylamino-1-[(1-hydroxy- SC_3260 [1-[tert- INT-988 (step 1)
- 1H NMR 600 MHz, DMSO
- SC_3263 cis-8-Dimethylamino-3-(3- INT-976 1-bromo-3-fluoro- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 7.58-7.50 (m, 368.2 fluorophenyl)-8-phenyl-1,3- benzene 2H), 7.41-7.33 (m, 4H), 7.33-7.23 (m, 3H), diazaspiro[4.5]decan-2-one 6.77-6.71 (m, 1H), 3.58 (s, 2H), 2.48-2.31 (m, 2H), 1.97 (s, 6H), 1.92-1.80 (m, 4H), 1.47 (t, 2H).
- SC_3264 cis-8-Dimethylamino-3-(3- INT-976 1-bromo-3- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.13 (t, 1H), 428.2 methylsulfonyl-phenyl)-8-phenyl-1,3- methylsulfonylbenzene 7.88 (d, 1H), 7.65 (s, 1H), 7.53 (t, 1H), 7.47 (dt, 1H), diazaspiro[4.5]decan-2-one 7.41-7.35 (m, 4H), 7.28 (qd, 1H), 3.66 (s, 2H), 3.16 (s, 3H), 2.49-2.36 (m, 2H), 1.97 (s, 6H), 1.96-1.74 (m, 4H), 1.53-1.47 (m, 2H).
- SC_3270 cis-8-Methylamino-1-(oxetan-3-yl- SC_3245 oxetan-3-ylmethyl 4- SC_3099 (for 1H NMR (DMSO-d6): ⁇ 9.24 (s, 2H), 7.49 (d, 2H), 476.2 methyl)-8-phenyl-3-[2-(trifluoromethyl)- methylbenzenesulfonate step1), SC_3105 7.34 (t, 2H), 7.21 (t, 1H), 4.66-4.62 (m, 2H), pyrimidin-5-yl]-1,3- (step 2) (for step 2) 4.44 (t, 2H), 3.87 (s, 2H), 3.55 (d, 2H), 3.28-3.23 (m, diazaspiro[4.5]decan-2-one 1H), 2.36 (m, 1H), 2.20-2.14 (m, 2H), 1.95-1.91 (m, 5H), 1.84-1.77 (m, 2H),
- SC_3271 cis-1-(Cyclopropyl-methyl)-8- SC_3245 (bromomethyl)- SC_3099 (for 1H NMR (DMSO-d6): ⁇ 9.26 (s, 2H), 7.50 (d, 2H), 460.1 methylamino-8-phenyl-3-[2- cyclopropane step1), SC_3105 7.35 (t, 2H), 7.22 (t, 1H), 3.89 (s, 2H), 3.13 (d, 2H), (trifluoromethyl)-pyrimidin-5-yl]-1,3- (for step 2) 2.29-2.23 (m, 3H), 1.92-1.82 (m, 7H), 1.47-1.44 (m, diazaspiro[4.5]decan-2-one 2H), 1.08-1.05 (m, 1H), 0.52-0.48 (m, 2H), 0.36-0.36-0.32 (m, 2H).
- SC_3272 cis-4-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 4-bromobenzonitrile
- SC_3273 cis-8-Dimethylamino-3-(4- INT-976 1-bromo-4-fluoro- SC_3103 368.2 fluorophenyl)-8-phenyl-1,3- benzene diazaspiro[4.5]decan-2-one
- SC_3274 cis-2-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 2-bromobenzonitrile
- SC_3276 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]- SC_3256 SC_3099 1H NMR (600 MHz, DMSO) ⁇ 8.94 (s, 2H), 436.3 8-methylamino-3-(2-methyl-pyrimidin- 7.53-7.47 (m, 2H), 7.39-7.30 (m, 2H), 7.24-7.17 (m, 5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan- 1H), 3.83 (s, 2H), 3.54-3.36 (m, 2H), 2.56 (s, 3H), 2-one 2.28 (td, 2H), 2.18-2.09 (m, 2H), 1.97-1.86 (m, 7H), 1.81 (td, 2H), 1.71-1.61 (m, 1H), 1.59-1.47 (m, 1H), 1.49-1.42 (m, 2H).
- SC_3277 cis-8-Dimethylamino-3-[2-(morpholin-4- INT-976 4-[(5-bromopyrimidin-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.93 (s, 2H), yl-methyl)-pyrimidin-5-yl]-8-phenyl-1,3- yl)methyl]morpholine 7.87-7.65 (m, 1H), 7.42-7.34 (m, 4H), 7.28 (dq, 1H), diazaspiro[4.5]decan-2-one 3.66-3.62 (m, 2H), 3.61 (s, 2H), 3.54 (t, 4H), 2.43 (t, 4H), 1.98 (s, 6H), 1.96-1.74 (m, 4H), 1.52-1.46 (m, 2H).
- SC_3278 cis-8-Dimethylamino-3-[2-(methyl- INT-989 N-methyltetrahydro-2H- SC_3120 1H NMR (DMSO-d6): ⁇ 8.50 (s, 2H), 7.39-7.35 (m, 465.2 tetrahydro-pyran-4-yl-amino)-pyrimidin- pyran-4-amine 5H), 7.27-7.24 (m, 1H), 4.74-4.67 (m, 1H), 5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan- 3.94-3.90 (m, 2H), 3.50 (s, 2H), 3.39 (t, 2H), 2.93 (s, 2-one 3H), 2.35 (m, 2H), 1.99-1.71 (m, 12H), 1.50-1.44 (m, 4H).
- SC_3279 cis-5-[8-Dimethylamino-1-[(1-hydroxy- INT-990 (1-(tert- SC_3105 (step 1), 1H NMR (DMSO-d6): ⁇ 9.12 (s, 2H), 8.63 (t, 1H), 669.4 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- butyldimethylsilyloxy)cyclobutyl)methyl SC_3133 (step 2) 7.36-7.33 (m, 4H), 7.26-7.23 (m, 1H), 5.25 (s, 1H), diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2- 4- 3.85 (s, 2H), 3.52-3.34 (m, 16H), 3.35 (m, 2H), (2-methoxy-ethoxy)-ethoxy]-ethoxy]- methylbenzenesulfonate 3.19 (s, 3H), 2.69-2.66 (m
- SC_3281 cis-2-[[5-(8-Dimethylamino-2-oxo-8- INT-989 2- SC_3120 1H NMR (DMSO-d6): ⁇ 8.48 (s, 2H), 7.39-7.35 (m, 438.2 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- (methylamino)acetamide 5H), 7.27-7.25 (m, 2H), 6.89 (s, 1H), 4.08 (s, 2H), pyrimidin-2-yl]-methyl-amino]- hydrochloride 3.51 (s, 2H), 3.07 (s, 3H), 2.36-2.33 (m, 2H), acetamide 1.94-1.86 (m, 10H), 1.45 (m, 2H).
- SC_3282 cis-2-[[5-(8-Dimethylamino-2-oxo-8- INT-976 tert-butyl (5- SC_3103 (for step 1H NMR (DMSO-d6): ⁇ 8.45 (s, 2H), 7.39-7.33 (m, 424.2 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- bromopyrimidin-2- 1), SC_3100 step 5H), 7.27-7.22 (m, 2H), 6.92 (s, 1H), 6.86 (t, 1H), pyrimidin-2-yl]amino]-acetamide yl)(cyanomethyl)carbamate 3 (for step 2) 3.74 (d, 2H), 3.51 (s, 2H), 2.46-2.28 (m, 2H), (step 1) 1.95-1.86 (m, 10H), 1.45 (m, 2H).
- SC_3284 cis-1-(Cyclopropyl-methyl)-8- INT-984 5-bromo-4-methyl-2- SC_3103 1H NMR (DMSO-d6): ⁇ 8.59 (s, 1H), 7.82 (s, 1H), 487.3 dimethylamino-3-[4-methyl-6- (trifluoromethyl)pyridine 7.35-7.34 (m, 4H), 7.27-7.23 (m, 1H), 3.75 (s, 2H), (trifluoromethyl)-pyridin-3-yl]-8-phenyl- 3.06 (d, 2H), 2.71-2.68 (m, 2H), 2.33-2.24 (m, 5H), 1,3-diazaspiro[4.5]decan-2-one 2.00 (m, 6H), 1.59-1.56 (m, 2H), 1.46 (t, 2H), 1.02-0.99 (m, 1H), 0.53-0.48 (m, 2H), 0.33-0.30 (m, 2H).
- SC_3285 cis-N-[5-(8-Dimethylamino-2-oxo-8- SC_3239 thiophene-2-carbonyl SC_3240 1H NMR (600 MHz, DMSO) ⁇ 8.90 (s, 2H), 477.2 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- chloride 8.08-8.04 (m, 1H), 7.84 (dd, 1H), 7.71 (s, 1H), 7.38 (d, pyrimidin-2-yl]-thiophene-2-carboxylic 5H), 7.27 (td, 1H), 7.19 (dd, 1H), 3.66 (s, 2H), acid amide 2.48-2.34 (m, 2H), 1.99-1.75 (m, 10H), 1.51-1.48 (m, 2H).
- SC_3286 cis-N-[5-(8-Dimethylamino-2-oxo-8- SC_3239 benzoyl chloride
- SC_3240 1H NMR (600 MHz, DMSO) ⁇ 10.84 (s, 1H), 471.3 phenyl-1,3-diazaspiro[4.5]decan-3-y)- 8.91 (s, 2H), 7.98-7.93 (m, 2H), 7.62-7.55 (m, 1H), pyrimidin-2-yl]-benzamide 7.50 (t, 2H), 7.39 (d, 4H), 7.28 (dt, 1H), 3.67 (s, 2H), 2.48-2.32 (m, 2H), 2.05-1.76 (m, 10H), 1.55-1.49 (m, 2H).
- SC_3287 cis-8-Dimethylamino-8-phenyl-3-(5- INT-976 2-bromo-5- SC_3103 1H NMR (DMSO-d6): ⁇ 7.80-7.70 (br s, 1H), 432.2 phenyl-thiophen-2-yl)-1,3- phenylthiophene 7.52 (d, 2H), 7.38-7.28 (m, 7H), 7.20-7.17 (m, 2H), diazaspiro[4.5]decan-2-one 6.27 (d, 1H), 3.61 (s, 2H), 2.49 (m, 2H), 1.95-1.91 (m, 10H), 1.48 (m, 2H).
- SC_3288 cis-1-(Cyclopropyl-methyl)-8- INT-984 1-bromo-2- SC_3103 1H NMR (CDCl3): ⁇ 7.49 (d, 1H), 7.41-7.22 (m, 496.3 dimethylamino-3-[2-(methylsulfonyl- (methylsulfonylmethyl)benzene 8H), 4.45 (s, 2H), 3.64 (s, 2H), 3.15 (d, 2H), methyl)-phenyl]-8-phenyl-1,3- 2.79 (s, 3H), 2.71-2.67 (m, 2H), 2.37 (t, 2H), 2.06 (s, diazaspiro[4.5]decan-2-one 6H), 1.67-1.64 (m, 2H), 1.55-1.44 (m, 2H), 1.10-1.06 (m, 1H), 0.57-0.52 (m, 2H), 0.39-0.35 (m, 2H).
- SC_3290 cis-8-Dimethylamino-8-(3- INT-1024 1-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 7.46 (dd, 1H), 460.3 fluorophenyl)-3-[2-(methylsulfonyl- (methylsulfonylmethyl)benzene 7.39 (td, 2H), 7.33 (dd, 1H), 7.31-7.21 (m, 1H), methyl)-phenyl]-1,3- 7.18 (d, 1H), 7.15 (dd, 1H), 7.08 (td, 1H), 4.50 (s, 2H), diazaspiro[4.5]decan-2-one 3.56 (s, 2H), 2.88 (s, 3H), 2.42-2.24 (m, 2H), 1.99-1.89 (m, 8H), 1.88-1.75 (m, 2H), 1.60-1.48 (m, 2H).
- SC_3291 cis-8-Dimethylamino-8-(4- INT-1025 1-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 7.46 (dd, 1H), 460.3 fluorophenyl)-3-[2-(methylsulfonyl- (methylsulfonylmethyl)benzene 7.43-7.34 (m, 3H), 7.33 (dd, 1H), 7.28 (td, 2H), 7.16 (t, methyl)-phenyl]-1,3- 2H), 4.49 (s, 2H), 3.55 (s, 2H), 2.88 (s, 3H), diazaspiro[4.5]decan-2-one 2.35-2.32 (m, 2H), 1.95 (s, 6H), 1.94-1.88 (m, 2H), 1.88-1.65 (m, 2H), 1.59-1.47 (m, 2H).
- SC_3294 cis-8-Dimethylamino-8-(3- INT-1024 4-(5-bromo-4-methyl- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.13 (s, 1H), 469.3 fluorophenyl)-3-(4-methyl-2-morpholin- pyrimidin-2- 7.40 (td, 1H), 7.22-7.11 (m, 4H), 7.08 (td, 1H), 4-yl-pyrimidin-5-yl)-1,3- yl)morpholine 3.69-3.60 (m, 8H), 2.34-2.31 (m, 2H), 2.20 (s, 3H), diazaspiro[4.5]decan-2-one 1.96 (s, 6H), 1.96-1.70 (m, 4H), 1.56-1.43 (m, 2H).
- SC_3296 cis-3-[2-(4-Acetyl-piperazin-1-yl)-4- INT-976 1-[4-(5-bromo-4-methyl- SC_3103 1H-NMR (DMSO-d6, 400 MHz at 100° C.), ⁇ 492.3 methyl-pyrimidin-5-yl]-8- pyrimidin-2-yl)- (ppm) 8.11 (s, 1H), 7.35-7.24 (m, 5H), 6.88 (s, dimethylamino-8-phenyl-1,3- piperazin-1-yl]-ethanone 1H), 3.73 (bs, 4H), 3.52 (bs, 4H), 3.38 (s, 2H), diazaspiro[4.5]decan-2-one 2.33 (bs, 2H), 2.22 (s, 3H), 2.03-1.87 (m, 13H), 1.56-1.53 (m, 2H).
- SC_3298 cis-3-[2-(4-Acetyl-piperazin-1-yl)-4- INT-976 1-[4-(5-bromo-4- SC_3103 1H-NMR (DMSO-d6, 400 MHz at 100° C.), ⁇ 546.3 (trifluoromethyl)-pyrimidin-5-yl]-8- trifluoromethyl- (ppm) 8.52 (s, 1H), 7.35-7.22 (m, 5H), 7.07 (s, dimethylamino-8-phenyl-1,3- pyrimidin-2-yl)- 1H), 3.79-3.78 (t, 4H, 5.08 Hz), 3.57 (t, 4H, 5.26 Hz), diazaspiro[4.5]decan-2-one piperazin-1-yl]-ethanone 3.39 (s, 2H), 2.36-2.32 (m, 2H), 2.04-1.85 (m, 13H), 1.54-150 (m, 2H).
- SC_3301 cis-8-Dimethylamino-3-isoquinolin-5-yl- INT-976 5-bromo-isoquinoline
- SC_3302 cis-8-Dimethylamino-8-phenyl-3-(1H- INT-976 4-bromo-1H-pyrrolo[2,3- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 11.42 (s, 1H), 390.2 pyrrolo[2,3-b]pyridin-4-yl)-1,3- b]pyridine 7.99 (d, 1H), 7.66 (br s, 1H), 7.43-7.33 (m, 5H), diazaspiro[4.5]decan-2-one 7.27 (t, 1H), 7.22 (t, 1H), 6.65-6.60 (m, 1H), 3.91 (s, 2H), 2.45-2.27 (m, 2H), 1.98-1.82 (m, 10H), 1.56-1.49 (m, 2H).
- SC_3303 cis-8-Dimethylamino-8-phenyl-3-(2- INT-976 4-bromo-2-(pyridin-4- SC_3103 1H NMR (DMSO-d6): ⁇ 8.62 (d, 2H), 7.82 (d, 2H), 434.1 pyridin-4-yl-thiazol-4-yl)-1,3- yl)thiazole 7.61 (broad s, 1H), 7.54 (s, 1H), 7.40-7.37 (m, 4H), diazaspiro[4.5]decan-2-one 7.29-7.27 (m, 1H), 3.84 (s, 2H), 2.49 (m, 2H), 1.96-1.79 (m, 10H), 1.51 (m, 2H).
- SC_3304 cis-8-[Methyl-(tetrahydro-furan-3-yl- INT-1026 4-(5-bromopyrimidin-2- step 2 of SC_3097 1H NMR (DMSO-d6): ⁇ 8.56 (s, 2H), 7.65 (broad 507.3 methyl)-amino]-3-(2-morpholin-4-yl- yl)morpholine (for synthesis), s, 1H), 7.36-7.23 (m, 5H), 3.66-3.55 (m, 10H), pyrimidin-5-yl)-8-phenyl-1,3- SC_3292 and 3.49 (s, 2H), 3.38 (m, 1H), 2.32-2.26 (m, 3H), diazaspiro[4.5]decan-2-one (enantiomer SC_3293 (for 2.11-1.94 (m, 6H), 1.86-1.82 (m, 3H), 1.50-1.41 (m, 3H).
- SC_3310 cis-8-Dimethylamino-8-phenyl-3-[5- INT-976 2-bromo-5- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.32-8.26 (m, 435.2 (trifluoromethyloxy)-pyridin-2-yl]-1,3- (trifluoromethoxy)- 2H), 7.86-7.82 (m, 1H), 7.79 (dd, 1H), diazaspiro[4.5]decan-2-one pyridine 7.41-7.33 (m, 4H), 7.27 (t, 1H), 3.71 (s, 2H), 2.46-2.33 (m, 2H), 1.96 (s, 6H), 1.94-1.72 (m, 4H), 1.47 (t, 2H).
- SC_3311 cis-8-Dimethylamino-3-(5- INT-976 2-bromo-5- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.66 (dd, 1H), 429.2 methylsulfonyl-pyridin-2-yl)-8-phenyl- methylsulfonylpyridine 8.39 (dd, 1H), 8.14 (dd, 1H), 8.06 (s, 1H), 1,3-diazaspiro[4.5]decan-2-one 7.42-7.33 (m, 4H), 7.28 (t, 1H), 3.77 (s, 2H), 3.21 (s, 3H), 2.46-2.32 (m, 2H), 2.03-1.68 (m, 10H), 1.52-1.46 (m, 2H).
- SC_3312 cis-6-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 6-bromopyridine-3- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.66 (d, 1H), 376.2 1,3-diazaspiro[4.5]decan-3-yl)- carbonitrile 8.34 (d, 1H), 8.08 (dd, 1H), 7.41-7.33 (m, 4H), 7.28 (t, nicotinonitrile 1H), 3.74 (s, 2H), 2.46-2.30 (m, 2H), 1.96 (s, 6H), 1.94-1.73 (m, 4H), 1.51-1.44 (m, 2H), SC_3314 cis-8-Dimethylamino-3-[4-methyl-2-(3- INT-976 4-(5-bromo-4-methyl- SC_3103 1HNMR (DMSO-d6, 400 MHz at 100° C.), ⁇ (pp
- SC_3315 cis-5-(8-Dimethylamino-2-oxo-8-phenyl- SC_3312 SC_3016 1H NMR (600 MHz, DMSO) ⁇ 8.80 (d, 1H), 394.2 1,3-diazaspiro[4.5]decan-3-yl)-pyridine- 8.10 (dd, 1H), 7.95-7.89 (m, 2H), 7.79 (s, 1H), 2-carboxylic acid amide 7.42-7.35 (m, 5H), 7.28 (s, 1H), 3.67 (s, 2H), 2.48-2.28 (m, 2H), 1.95 (d, 10H), 1.53-1.46 (m, 2H).
- SC_3317 cis-2-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 2-bromobenzointrile SC_3103 (step 1), 1H NMR (600 MHz, DMSO) ⁇ 7.50 (s, 1H), 393.2 1,3-diazaspiro[4.5]decan-3-yl)- SC_3016 (step 2) 7.42 (dd, 1H), 7.42-7.32 (m, 5H), 7.31 (d, 1H), 7.26 (t, benzamide 1H), 7.23-7.13 (m, 3H), 3.53 (s, 2H), 2.41-2.27 (m, 2H), 1.96 (s, 6H), 1.90 (t, 2H), 1.86-1.68 (m, 2H), 1.52-1.48 (m, 2H).
- SC_3318 cis-8-Dimethylamino-3-[2- INT-997 1-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 7.47 (dd, 1H), 448.2 (methylsulfonyl-methyl)-pheny]-8- (methylsulfonylmethyl)- 7.43-7.36 (m, 2H), 7.34 (dd, 1H), 7.29 (ddd, 1H), thiophen-2-yl-1,3-diazaspiro[4.5]decan- benzene 7.19 (s, 1H), 7.05 (ddd, 1H), 6.94 (d, 1H), 4.50 (s, 2H), 2-one 3.61 (s, 2H), 2.89 (s, 3H), 2.35-2.21 (m, 2H), 2.04 (s, 6H), 1.98-1.90 (m, 2H), 1.86-1.70 (m, 2H), 1.66-1.59 (m, 2H).
- SC_3320 cis-8-Dimethylamino-3-(4-methyl-2- INT-997 4-(5-bromo-4-methyl- SC_3319 1H NMR (600 MHz, DMSO) ⁇ 8.15 (d, 1H), 457.2 morpholin-4-yl-pyrimidin-5-yl)-8- pyrimidin-2- 7.41 (dt, 1H), 7.13 (s, 1H), 7.05 (ddd, 1H), 6.94 (dd, thiophen-2-yl-1,3-diazaspiro[4.5]decan- yl)morpholine 1H), 3.71-3.60 (m, 8H), 3.44 (s, 2H), 2-one 2.32-2.24 (m, 2H), 2.21 (s, 3H), 2.04 (s, 6H), 1.98-1.88 (m, 2H), 1.87-1.75 (m, 2H), 1.62-1.54 (m, 2H).
- SC_3322 cis-8-Dimethylamino-8-phenyl-3-(1H- INT-976 tert-butyl 5- SC_3103 (for step 1H NMR (600 MHz, DMSO) ⁇ 11.45 (s, 1H), 390.2 pyrrolo[2,3-b]pyridin-5-yl)-1,3- bromopyrrolo[2,3- 1), SC_3173 (for 8.38 (s, 1H), 8.00 (d, 1H), 7.85-7.81 (m, 1H), diazaspiro[4.5]decan-2-one b]pyridine-1-carboxylate step 2) 7.70-7.66 (m, 2H), 7.57-7.53 (m, 3H), 7.41 (t, 1H), (step 1) 6.35 (dd, 1H), 3.54 (s, 2H), 2.75-2.41 (m, 8H, overlapps with solvent residual peak), 2.30-2.26 (m, 2H), 1.89 (d, 2H), 1.41-1
- SC_3323 cis-N-[5-(8-Dimethylamino-2-oxo-8- SC_3239 acetyl chloride
- SC_3240 1H NMR (600 MHz, DMSO) ⁇ 10.36 (s, 1H), 409.2 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- 8.82 (s, 2H), 8.40 (s, rotamer), 7.67 (s, 1H), pyrimidin-2-yl]-acetamide (enantiomer 7.44-7.31 (m, 4H), 7.27 (td, 1H), 3.62 (s, 2H), 2.46-2.30 (m, 1) 2H), 2.11 (s, 3H), 2.08 (s, rotamer), 1.96 (s, 6H), 1.97 (s, rotamer), 1.95-1.75 (m, 4H), 1.52-1.47 (m, 2H).
- SC_3324 cis-3-[2-(4-Methyl-piperazin-1-yl)- INT-1026 5-bromo-2-(4- step 2 of SC_3097 1H NMR (DMSO-d6): ⁇ 8.52 (s, 2H), 7.64 (broad 518.3 pyrimidin-5-yl]-8-[methyl-(tetrahydro- methylpiperazin-1- (for synthesis), s, 1H), 7.36-7.23 (m, 5H), 3.66-3.55 (m, 7H), furan-3-yl-methyl)-amino]-8-phenyl-1,3- yl)pyrimidine SC_3292 and 3.48 (s, 2H), 3.37-3.36 (m, 1H), 2.33-2.13 (m, 11H), diazaspiro[4.5]decan-2-one (enantiomer SC_3293 (for 2.01-1.82 (m, 9H), 1.50-1.41 (m, 3H).
- SC_3326 cis-8-Dimethylamino-3-(4,6-dimethyl-2- INT-976 4-(5-bromo-4,6- SC_3103 — 465.3 morpholin-4-yl-pyrimidin-5-yl)-8- dimethyl-pyrimidin-2- phenyl-1,3-diazaspiro[4.5]decan-2-one yl)morpholine
- SC_3327 cis-8-Dimethylamino-3-(2-morpholin-4- INT-1027 morpholine SC_3120 1H NMR (600 MHz, DMSO) ⁇ 8.58 (s, 2H), 443.2 yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3- 7.43 (dd, 1H), 7.40-7.32 (m, 1H), 7.07 (dd, 1H), diazaspiro[4.5]decan-2-one 6.96 (dd, 1H), 3.67-3.61 (m
- SC_3329 cis-8-Dimethylamino-3-[2-methyl-5- INT-997 5-bromo-1-methyl-3- SC_3319 1H NMR (600 MHz, DMSO) ⁇ 7.66-7.63 (m, 428.2 (trifluoromethyl)-2H-pyrazol-3-yl]-8- (trifluoromethyl)pyrazole 1H), 7.42 (dd, 1H), 7.06 (dd, 1H), 6.95 (dd, 1H), thiophen-2-yl-1,3-diazaspiro[4.5]decan- 6.64 (s, 1H), 3.75 (s, 3H), 3.60 (s, 2H), 2-one 2.30-2.26 (m, 2H), 2.04 (s, 6H), 1.98-1.90 (m, 2H), 1.83-1.79 (m, 2H), 1.64-1.57 (m, 2H).
- SC_3330 cis-8-Dimethylamino-3-[2-[(2-hydroxy- INT-1027 2-(methylamino)ethanol SC_3120 1H NMR (600 MHz, DMSO) ⁇ 8.48 (s, 2H), 431.2 ethyl)-methyl-amino]-pyrimidin-5-yl]-8- 7.43 (d, 1H), 7.30 (s, 1H), 7.07 (dd, 1H), 6.96 (d, 1H), thiophen-2-yl-1,3-diazaspiro[4.5]decan- 3.61 (dd, 2H), 3.58-3.51 (m, 4H), 3.09 (s, 3H), 2-one 2.34-2.22 (m, 2H), 2.04 (s, 6H), 1.96-1.76 (m, 4H), 1.56-1.50 (m, 2H).
- SC_3331 cis-8-Dimethylamino-3-[2-(2-oxo-1,3- INT-1027 4-(4,4,5,5-tetramethyl- SC_3208 1H NMR (600 MHz, DMSO) ⁇ 10.46 (s, 1H), 489.2 dihydro-indol-4-yl)-pyrimidin-5-yl]-8- 1,3,2-dioxaborolan-2- 9.12 (s, 2H), 7.87 (d, 1H), 7.47-7.42 (m, 1H), 7.31 (t, thiophen-2-yl-1,3-diazaspiro[4.5]decan- yl)indolin-2-one 1H), 7.08 (dd, 1H), 6.98 (dd, 1H), 6.92 (d, 1H), 2-one 3.83 (s, 2H), 3.77 (s, 2H), 2.35-2.30 (m, 2H), 2.05 (s, 6H), 1.96 (t, 2H), 1.88 (s
- SC_3335 cis-3-(Benzothiazol-7-yl)-8- INT-976 7-bromo-benzothiazole SC_3103 407.1 dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
- SC_3336 cis-8-Dimethylamino-8-(4- INT-1025
- SC_3337 cis-2-[8-Dimethylamino-3-[4-methyl-6- SC_3122 2-chloro-N,N-dimethyl- INT-988 (step 1)
- 1H NMR 600 MHz, DMSO
- ⁇ 8.59 s, 1H
- 518.3 trifluoromethyl)-pyridin-3-yl]-2-oxo-8- acetamide 7.82 (s, 1H), 7.37-7.32 (m, 4H), 7.25 (ddd, 1H), phenyl-1,3-diazaspiro[4.5]decan-1-yl]- 4.00 (s, 2H), 3.80 (s, 2H), 3.07 (s, 3H), 2.87 (s, 3H), N,N-dimethyl-acetamide 2.71-2.64 (m, 2H), 2.55 (s, 3H), 2.34 (s, 3H), 2.03 (td, 2H), 1.98 (s, 6H), 1.67-1.58 (m
- SC_3338 cis-8-Dimethylamino-3-[2-(2-methyl-1- INT-989 2-methyl-4-(4,4,5,5- SC_3208 1H NMR (600 MHz, DMSO) ⁇ 9.57 (s, 1H), 497.3 oxo-2,3-dihydro-isoindol-4-yl)- tetramethyl-1,3,2- 9.08 (s, 2H), 8.52 (d, 1H), 8.43 (s, 1H), 7.77 (d, 1H), pyrimidin-5-yl]-8-phenyl-1,3- dioxaborolan-2- 7.72 (d, 2H), 7.63 (t, 1H), 7.59 (t, 2H), 7.55 (t, 1H), diazaspiro[4.5]decan-2-one yl)isoindolin-1-one 4.86 (s, 2H), 3.59 (s, 2H), 3.13 (s, 3H), 2.72 (d, 2H), 2.61 (s, 6
- SC_3342 cis-8-Dimethylamino-3-[6-(4-methyl-3- INT-976 4-(5-bromo-2-pyridyl)-1- SC_3242 (step 2)
- 1H NMR 600 MHz, CDCl3) ⁇ 8.09 (d, 1H), 463.3 oxo-piperazin-1-yl)-pyridin-3-yl]-8- methyl-piperazin-2-one 8.00 (dd, 1H), 7.45-7.39 (m, 2H), 7.37-7.28 (m, 3H), phenyl-1,3-diazaspiro[4.5]decan-2-one 6.61 (d, 1H), 5.71 (s, 1H), 4.04 (s, 2H), 3.87-3.82 (m, 2H), 3.51 (s, 2H), 3.45 (t, 2H), 3.03 (s, 3H), 2.32-2.02 (m, 10H), 2.02-1.94 (m, 2H), 1.64-1.53 (m,
- SC_3343 cis-8-Dimethylamino-3-(2,4-dimethyl- INT-976 5-bromo-2,4-dimethyl- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.46 (s, 1H), 380.3 pyrimidin-5-yl)-8-phenyl-1,3- pyrimidine 7.33 (m, 5H), 7.28-7.24 (m, 1H), 3.51 (s, 2H), diazaspiro[4.5]decan-2-one 2.54 (s, 3H), 2.41-2.28 (m, 5H), 2.03-1.77 (m, 10H), 1.56-1.49 (m, 2H).
- SC_3344 cis-8-Dimethylamino-3-[2-(1-oxo-2,3- INT-989 4-(4,4,5,5-tetramethyl- SC_3208 1H NMR (600 MHz, DMSO) ⁇ 9.06 (s, 2H) 483.3 dihydro-isoindol-4-yl)-pyrimidin-5-yl]- 1,3,2-dioxaborolan-2- 8.67 (s, 1H), 8.52 (d, 1H), 8.39 (s, 1H), 7.75 (dd, 3H), 8-phenyl-1,3-diazaspiro[4.5]decan-2- yl)isoindolin-1-one 7.66-7.51 (m, 4H), 4.75 (s, 2H), 3.58 (s, 2H), one; 2,2,2-trifluoro-acetic acid 3.18 (s, 2H), 2.75 (d, 2H), 2.60 (s, 6H), 2.27 (t, 2H), 1.91 (d
- SC_3345 cis-8-Dimethylamino-3-[6-[(2-hydroxy- INT-976 2-[[5-bromo-3- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.55-8.51 (m, 492.3 ethyl)-methyl-amino]-5- (trifluoromethyl)-2- 1H), 8.35 (d, 1H), 7.62 (s, 1H), 7.37 (td, 4H), (trifluoromethyl)-pyridin-3-yl]-8-phenyl- pyridyl]-methyl- (td, 1H), 3.63 (s, 2H), 3.50 (td, 2H), 3.20 (t, 2H), 1,3-diazaspiro[4.5]decan-2-one amino]ethanol 2.78 (s, 3H), 2.43-2.36 (m, 2H), 1.96 (s, 6H), 1.95-1.75 (m, 4H), 1.48 (t, 2H).
- SC_3346 cis-8-Dimethylamino-8-phenyl-3-[2-[4- INT-976 3,3,3-trifluoroprop-1- SC_3313 1H NMR (600 MHz, DMSO) ⁇ 9.56 (d, 1H), 487.3 (trifluoromethyl)-1H-[1,2,3]triazol-1-yl]- yne, 2-azido-5-bromo- 9.16 (s, 2H), 7.99 (s, 1H), 7.42-7.35 (m, 4H), pyrimidin-5-yl]-1,3- pyrimidine 7.31-7.25 (m, 1H), 3.75 (s, 2H), 2.49-2.34 (m, 2H), diazaspiro[4.5]decan-2-one 2.05-1.75 (m, 10H), 1.60-1.47 (m, 2H).
- SC_3347 cis-8-Dimethylamino-3-[2-(4-isopropyl- INT-976 3-methylbut-1-yne, 2- SC_3313 1H NMR (600 MHz, DMSO) ⁇ 9.10 (s, 2H), 461.3 1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]- azido-5-bromo- 8.50 (d, 1H), 7.91 (s, 1H), 7.42-7.35 (m, 5H), 7.28 (td, 8-phenyl-1,3-diazaspiro[4.5]decan-2-one pyrimidine 1H), 3.73 (s, 2H), 3.08 (hept, 1H), 2.44 (s, 2H), 2.01-1.76 (m, 10H), 1.59-1.48 (m, 2H), 1.30 (d, 6H).
- SC_3348 cis-8-Dimethylamino-3-[6-(1,1-dioxo- INT-976 1,4-thiazinane 1,1- SC_3242 1H NMR (600 MHz, DMSO) ⁇ 8.23 (d, 1H), 484.2 [1,4]thiazinan-4-yl)-pyridin-3-yl]-8- dioxide, 5-bromo-2- 7.93 (dd, 1H), 7.41-7.33 (m, 5H), 7.27 (t, 1H), 6.98 (d, phenyl-1,3-diazaspiro[4.5]decan-2-one chloro-pyridine (step 1) 1H), 3.97 (t, 4H), 3.53 (s, 2H), 3.04 (t, 4H), 2.43-2.28 (m, 2H), 1.96 (s, 6H), 1.92-1.72 (m, 4H), 1.51-1.40 (m, 2H).
- SC_3350 cis-8-Dimethylamino-3-(1- INT-976 5-bromo-1- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.64 (d, 1H), 468.2 methylsulfonyl-1H-pyrrolo[2,3- methylsulfonyl- 8.28 (d, 1H), 7.65 (dd, 1H), 7.57 (s, 1H), 7.38 (dd, 4H), b]pyridin-5-yl)-8-phenyl-1,3- pyrrolo[2,3-b]pyridine 7.28 (dt, 1H), 6.72 (dd, 1H), 3.68 (s, 2H), 3.65 (s, diazaspiro[4.5]decan-2-one 3H), 2.48-2.29 (m, 2H), 1.98 (s, 10H), 1.53-1.44 (m, 2H).
- SC_3353 cis-8-Dimethylamino-3-[2-fluoro-4- INT-976 1-bromo-2-fluoro-4- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 7.62 (t, 1H), 452.2 (trifluoromethyloxy)-phenyl]-8-phenyl- (trifluoromethoxy)- 7.50-7.46 (m, 1H), 7.40 (dd, 1H), 7.38-7.31 (m, 4H), 1,3-diazaspiro[4.5]decan-2-one benzene 7.25 (t, 1H), 7.21 (d, 1H), 3.57 (s, 2H), 2.38 (d, 2H), 1.97-1.88 (m, 8H), 1.84-1.79 (m, 2H), 1.53-1.46 (m, 2H).
- SC_3355 cis-8-Dimethylamino-3-(1-methyl-1H- INT-976 4-bromo-1-methyl- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.04 (d, 1H), 404.3 pyrrolo[2,3-b]pyridin-1-yl)-8-phenyl- pyrrolo[2,3-b]pyridine 7.70 (s, 1H), 7.47 (d, 1H), 7.41-7.33 (m, 4H), 1,3-diazaspiro[4.5]decan-2-one 7.31-7.24 (m, 2H), 6.65 (d, 1H), 3.91 (s, 2H), 3.74 (s, 3H), 2.44-2.25 (m, 2H), 2.08-1.74 (m, 10H), 1.52 (t, 2H).
- SC_3356 cis-3-(1-Acetyl-1H-indol-4-yl)-8- SC_3351 acetyl chloride
- SC_3358 cis-6-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 6-chloro-5-methyl- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.64 (s, 1H), 390.2 1,3-diazaspiro[4.5]decan-3-yl)-5-methyl- pyridine-3-carbonitrile 8.12 (s, 1H), 7.76 (s, 1H), 7.39-7.34 (m, 4H), 7.27 (s, nicotinonitrile 1H), 3.71 (s, 2H), 2.43-2.15 (m, 5H), 2.11-1.70 (m, 10H), 1.52 (s, 2H).
- SC_3359 cis-6-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 6-chloro-5-fluoro- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.64 (d, 1H), 394.2 1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro- pyridine-3-carbonitrile 8.30 (dd, 1H), 7.95 (s, 1H), 7.40-7.31 (m, 4H), nicotinonitrile 7.29-7.23 (m, 1H), 3.72 (s, 2H), 2.36-2.33 (m, 2H), 1.96 (s, 6H), 1.94-1.79 (m, 4H), 1.52 (t, 2H).
- SC_3361 cis-6-(8-Dimethylamino-2-oxo-8-phenyl- SC_3358 SC_3016 1H NMR (600 MHz, DMSO) ⁇ 8.64 (d, 1H), 408.2 1,3-diazaspiro[4.5]decan-3-yl)-5-methyl- 8.06-8.02 (m, 2H), 7.54 (s, 1H), 7.44 (s, 1H), pyridine-3-carboxylic acid amide 7.38-7.30 (m, 4H), 7.27-7.21 (m, 1H), 3.67 (s, 2H), 2.37-2.26 (m, 5H), 2.05-1.75 (m, 10H), 1.51 (t, 2H).
- SC_3362 cis-6-(8-Dimethylamino-2-oxo-8-phenyl- SC_3359 SC_3016 1H NMR (600 MHz, DMSO) ⁇ 8.65-8.61 (m, 412.2 1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro- 1H), 8.13 (s, 1H), 8.04 (dd, 1H), 7.76 (s, 1H), pyridine-3-carboxylic acid amide 7.59 (s, 1H), 7.39-7.30 (m, 4H), 7.28-7.21 (m, 1H), 3.70 (s, 2H), 2.41-2.23 (m, 2H), 1.96-1.76 (m, 10H), 1.50 (t, 2H).
- SC_3363 cis-8-Dimethylamino-3-[4-methyl-6- INT-1038 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) ⁇ 8.56 (s, 1H), 447.2 (trifluoromethyl)-pyridin-3-yl]-8-m- (trifluoromethyl)pyridine 7.80 (s, 1H), 7.52 (s, 1H), 7.24 (t, 1H), 7.17-7.11 (m, tolyl-1,3-diazaspiro[4.5]decan-2-one 2H), 7.06 (d, 1H), 3.60 (s, 2H), 2.39-2.25 (m, 8H), 2.01-1.78 (m, 10H), 1.58-1.48 (m, 2H).
- SC_3364 cis-3-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 3-bromopyridine-4- SC_3242 1H NMR (600 MHz, DMSO) ⁇ 8.79 (s, 1H), 376.2 1,3-diazaspiro[4.5]decan-3-yl)- carbonitrile 8.50 (d, 1H), 7.84-7.80 (m, 1H), 7.37 (td, 4H), 7.26 (td, isonicotinonitrile 1H), 3.79 (s, 2H), 2.43-2.36 (m, 2H), 1.97 (s, 7H), 1.96-1.91 (m, 2H), 1.88-1.81 (m, 2H), 1.61-1.45 (m, 2H).
- SC_3365 cis-8-Dimethylamino-3-[3-fluoro-5-(2- INT-1045 4-(4,4,5,5-tetramethyl- SC_3354 1H NMR (600 MHz, DMSO) ⁇ 10.51 (s, 1H), 500.2 oxo-1,3-dihydro-indol-4-yl)-pyridin-2- 1,3,2-dioxaborolan-2- 8.39 (d, 1H), 7.96 (dd, 1H), 7.41-7.32 (m, 4H), yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2- yl)indolin-2-one (step 2) 7.28 (dt, 2H), 7.08 (d, 1H), 6.88 (d, 1H), 3.71 (s, 2H), one 3.67 (s, 2H), 2.44-2.22 (m, 2H), 1.98-1.87 (m, 11H), 1.58-1.46 (m, 2H).
- SC_3366 cis-8-Dimethylamino-3-[4-methyl-6- INT-1039 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) ⁇ 8.55 (s, 1H), 517.2 (trifluoromethyl)-pyridin-3-yl]-8-[3- (trifluoromethyl)pyridine 7.79 (s, 1H), 7.51 (t, 2H), 7.38 (dd, 1H), 7.26 (d, 2H), (trifluoromethyloxy)-phenyl]-1,3- 3.62 (s, 2H), 2.40-2.34 (m, 2H), 2.31 (s, 3H), diazaspiro[4.5]decan-2-one 2.01-1.77 (m, 10H), 1.58-1.49 (m, 2H).
- SC_3367 cis-8-Dimethylamino-3-[4-methyl-6- INT-1040 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) ⁇ 8.55 (s, 1H), 501.2 (trifluoromethyl)-pyridin-3-yl]-8-[3- (trifluoromethyl)pyridine 7.79 (s, 1H), 7.69-7.56 (m, 5H), 7.52 (s, 1H), 3.61 (s, (trifluoromethyl)phenyl]-1,3- 2H), 2.44-2.36 (m, 2H), 2.31 (s, 3H), diazaspiro[4.5]decan-2-one 2.02-1.80 (m, 10H), 1.60-1.47 (m, 2H).
- SC_3368 cis-8-Dimethylamino-8-(3- INT-1041 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) ⁇ 8.56 (s, 1H), 463.2 methoxyphenyl)-3-[4-methyl-6- (trifluoromethyl)pyridine 7.80 (s, 1H), 7.51 (s, 1H), 7.31-7.25 (m, 1H), 6.92 (dt, (trifluoromethyl)-pyridin-3-yl]-1,3- 1H), 6.87-6.82 (m, 2H), 3.75 (s, 3H), 3.61 (s, 2H), diazaspiro[4.5]decan-2-one 2.35-2.30 (m, 5H), 1.98 (s, 7H), 1.96-1.90 (m, 2H), 1.88-1.80 (m, 2H), 1.60-1.49 (m, 2H).
- SC_3369 cis-8-(5-Chloro-thiophen-2-yl)-8- INT-1042 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) ⁇ 8.56 (s, 1H), 473.1 dimethylamino-3-[4-methyl-6- (trifluoromethyl)pyridine 7.79 (s, 1H), 7.39 (s, 1H), 7.04-7.00 (m, 1H), 6.80 (d, (trifluoromethyl)-pyridin-3-yl]-1,3- 1H), 3.64 (s, 2H), 2.31 (s, 3H), 2.22-2.15 (m, 2H), diazaspiro[4.5]decan-2-one 2.04 (s, 6H), 1.95-1.87 (m, 2H), 1.83-1.77 (m, 2H), 1.63-1.57 (m, 2H).
- SC_3370 cis-8-Dimethylamino-8-(3- INT-1024 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) ⁇ 8.56 (s, 1H), 451.2 fluorophenyl)-3-[4-methyl-6- (trifluoromethyl)pyridine 7.80 (s, 1H), 7.51 (s, 1H), 7.41 (td, 1H), 7.21-7.12 (m, (trifluoromethyl)-pyridin-3-yl]-1,3- 2H), 7.12-7.06 (m, 1H), 3.61 (s, 2H), diazaspiro[4.5]decan-2-one 2.38-2.30 (m, 5H), 1.97 (s, 6H), 1.96-1.90 (m, 2H), 1.90-1.73 (m, 2H), 1.61-1.45 (m, 2H).
- SC_3371 cis-8-Dimethylamino-3-(2-methylamino- INT-989 methylamine
- SC_3373 cis-N-[5-(8-Dimethylamino-2-oxo-8- SC_3371 Cyclopropancarbonylchlorid SC_3240 1H NMR (600 MHz, DMSO) ⁇ 8.97 (s, 2H), 449.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- 7.83-7.73 (m, 1H), 7.41-7.34 (m, 4H), 7.30-7.24 (m, pyrimidin-2-yl]-N-methyl- 1H), 3.66 (s, 2H), 3.27 (s, 3H), 2.47-2.29 (m, 2H), cyclopropanecarboxylic acid amide 1.99-1.87 (m, 10H), 1.49 (t, 2H), 0.88-0.80 (m, 2H), 0.70 (dt, 2H).
- SC_3374 cis-N-[5-(8-Dimethylamino-2-oxo-8- SC_3371 2,5-dimethylpyrazole-3- SC_3240 1H NMR (600 MHz, DMSO) ⁇ 8.83 (s, 2H), 503.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- carbonyl chloride 7.77 (s, 1H), 7.41-7.32 (m, 4H), 7.27 (td, 1H), 5.48 (s, pyrimidin-2-yl]-N,2,5-trimethyl-2H- 1H), 3.80 (s, 3H), 3.61 (s, 2H), 3.40 (s, 3H), pyrazole-3-carboxylic acid amide 2.46-2.31 (m, 2H), 1.96 (s, 3H), 1.96 (s, 6H), 1.94-1.74 (m, 5H), 1.52-1.42 (m, 2H).
- SC_3375 cis-3-[4,6-Bis(trifluoromethyl)-pyridin- INT-976 5-bromo-2,4- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.98 (s, 1H), 487.2 3-yl]-8-dimethylamino-8-phenyl-1,3- bis(trifluoromethyl)pyridine 8.20 (s, 1H), 7.79 (s, 1H), 7.40-7.32 (m, 4H), 7.26 (td, diazaspiro[4.5]decan-2-one 1H), 3.62 (s, 2H), 2.44-2.24 (m, 2H), 1.98-1.91 (m, 8H), 1.86 (s, 2H), 1.53 (t, 2H).
- SC_3378 cis-8-[Methyl-(oxetan-3-yl-methyl)- INT-1047 2-trifluoromethyl-5- SC_3103 1H NMR (DMSO-d6): ⁇ 9.21-9.15 (s, 2H), 476.2 amino]-8-phenyl-3-[2-(trifluoromethyl)- bromopyrimidine 8.19-8.18 (broad s, 1H), 7.41-7.34 (m, 4H), pyrimidin-5-yl]-1,3- 7.27-7.25 (m, 1H), 4.58-4.56 (m, 2H), 4.18 (s, 1H), 3.69 (s, diazaspiro[4.5]decan-2-one 2H), 3.05-2.99 (m, 1H), 2.41-2.36 (m, 4H), 1.91 (m, 7H), 1.47 (s, 2H).
- SC_3381 cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 5-bromo-2-chloro- SC_3103 (for step 1H NMR (600 MHz, DMSO) ⁇ 8.88 (s, 1H), 507.3 1,3-diazaspiro[4.5]decan-3-yl)-2-(2-oxo pyridine-4-carbonitrile 1), SC_3129 (for 8.24 (s, 1H), 7.85 (s, 1H), 7.52-7.46 (m, 1H), 1,3-dihydro-indol-4-yl)-isonicotinonitrile (step 1), 4-(4,4,5,5- step 2) 7.41-7.29 (m, 6H), 7.27 (td, 1H), 6.92 (d, 1H), 3.84 (s, tetramethyl-1,3,2- 2H), 3.78 (s, 2H), 2.48-2.30 (m, 2H), dioxaborolan-2
- SC_3383 cis-N-[5-(8-Dimethylamino-2-oxo-8- SC_3371 pivaloyl chloride
- SC_3240 1H NMR (600 MHz, DMSO) ⁇ 8.98 (s, 2H), 465.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- 7.42-7.34 (m 4H), 7.30-7.26 (m, 1H), 3.69 (s, 2H), pyrimidin-2-yl]-N,2,2-trimethyl- 3.14 (s, 3H), 2.46-2.41 (m, 2H), 1.99-1.87 (m, propionamide 10H), 1.54-1.45 (m, 2H), 0.97 (s, 9H).
- SC_3384 cis-8-Dimethylamino-3-[2-(1-methyl-2- INT-989 1-methyl-4-(4,4,5,5- SC_3208 1H NMR (600 MHz, CDCl3) ⁇ 9.05 (s, 2H), 497.3 oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5- tetramethyl-1,3,2- 8.08 (d, 1H), 7.47-7.39 (m, 3H), 7.38-7.31 (m, 3H), yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2- dioxoborolan-2- 6.91 (d, 1H), 5.46 (s, 1H), 4.04 (s, 2H), 3.64 (s, one yl)indolin-2-one 2H), 3.27 (s, 3H), 2.35-2.14 (m, 4H), 2.10 (s, 6H), 2.08-2.01 (m, 3H), 1.73-1.
- SC_3387 cis-8-Dimethylamino-3-[6-(2-oxo-1,3- INT-1048 4-(4,4,5,5-tetramethyl- SC_3129 1H NMR (600 MHz, DMSO) ⁇ 8.83 (d, 1H), 482.3 dihydro-indol-4-yl)-pyridin-3-yl]-8- 1,3,2-dioxaborolan-2- 8.11 (dd, 1H), 7.77 (d, 1H), 7.64 (s, 1H), 7.43-7.34 (m, phenyl-1,3-diazaspiro[4.5]decan-2-one yl)indolin-2-one 5H), 7.31-7.24 (m, 2H), 6.84 (d, 1H), 3.73 (s, 2H), 3.68 (s, 2H), 2.45-2.31 (m, 2H), 1.99-1.79 (m, 10H), 1.51 (t, 2H).
- SC_3389 cis-3-[6-(Azetidin-1-yl)-5- INT-976 5-bromo-2-chloro-3- SC_3103 (for step 1H NMR 600 MHz, DMSO) ⁇ 8.40 (d, 1H), (trifluoromethyl)-pyridin-3-yl]-8- (trifluoromethyl)pyridine 1), SC_3120 (for 8.21 (d, 1H), 7.47 (s, 1H), 7.41-7.33 (m, 4H), 453.2 dimethylamino-8-phenyl-1,3- (step 1), azetidine (step step 2, 160° C.
- SC_3390 cis-3-[1-(Cyclopropyl-methyl)-8- SC_3364 bromomethylcyclopropane INT-952 1H NMR (600 MHz, DMSO) ⁇ 8.82 (s, 1H), 430.3 dimethylamino-2-oxo-8-phenyl-1,3- 8.51 (dd, 1H), 7.81 (d, 1H), 7.40-7.33 (m, 4H), diazaspiro[4.5]decan-3-yl]- 7.29-7.23 (m, 1H), 3.93 (s, 2H), 3.10 (d, 2H), isonicotinonitrile 2.76-2.70 (m, 2H), 2.29 (ddd, 2H), 2.02 (s, 6H), 1.58 (d, 2H), 1.52-1.44 (m, 2H), 1.01 (ddt, 1H), 0.55-0.49 (m, 2H), 0.37-0.31 (m, 2H).
- SC_3391 cis-3-[3,5-Bis(trifluoromethyl)-pyridin- INT-976 2-chloro-3,5- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 9.04 (d, 1H), 487.2 2-yl]-8-dimethylamino-8-phenyl-1,3- bis(trifluoromethyl)pyridine 8.58 (d, 1H), 7.96 (s, 1H), 7.41-7.32 (m, 4H), diazaspiro[4.5]decan-2-one 7.29-7.23 (m, 1H), 3.75 (s, 2H), 2.41-2.25 (m, 2H), 1.98-1.89 (m, 10H), 1.52 (t, 2H).
- SC_3392 cis-8-Dimethylamino-3-(5-fluoro-6- INT-976 4-(5-bromo-3-fluoro-2- SC_3103 1H NMR (600 MHz, CDCl3) ⁇ 8.13 (dd, 1H), 454.3 morpholin-4-yl-pyridin-3-yl)-8-phenyl- pyridyl)morpholine 7.76 (d, 1H), 7.42 (t, 2H), 7.33 (dd, 3H), 5.84 (s, 1H), 1,3-diazaspiro[4.5]decan-2-one 3.84 (t, 4H), 3.52 (s, 2H), 3.37 (t, 4H), 2.29-2.12 (m, 4H), 2.08 (s, 6H), 2.01-1.94 (m, 2H), 1.60 (t, 2H).
- SC_3393 cis-8-(3-Chlorophenyl)-8- INT-1044 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) ⁇ 8.57 (s, 1H), 467.2 dimethylamino-3-[4-methyl-6- (trifluoromethyl)pyridine 7.80 (s, 1H), 7.55-7.49 (m, 1H), 7.43-7.37 (m, 1H), (trifluoromethyl)-pyridin-3-yl]-1,3- 7.38-7.29 (m, 3H), 3.61 (s, 2H), 2.40-2.24 (m, diazaspiro[4.5]decan-2-one 5H), 1.99-1.90 (m, 8H), 1.90-1.76 (m, 2H), 1.60-1.47 (m, 2H).
- SC_3394 cis-8-Dimethylamino-3-[5-(2-oxo-1,3- INT-1049 4-(4,4,5,5-tetramethyl SC_3354 1H NMR (600 MHz, DMSO) ⁇ 8.41 (d, 1H), 482.3 dihydro-indol-4-yl)-pyridin-2-yl]-8- 1,3,2-dioxaborolan-2- 8.26 (d, 1H), 7.92 (dd, 1H), 7.75 (s, 1H), 7.41-7.32 (m, phenyl-1,3-diazaspiro[4.5]decan-2-one yl)indolin-2-one 5H), 7.30-7.23 (m, 2H), 7.01 (d, 1H), 6.83 (d, 1H), 3.75 (s, 2H), 3.61 (s, 2H), 2.46-2.30 (m, 2H), 1.96 (s, 6H), 1.94-1.88 (m, 2H), 1.86-1.
- SC_3395 cis-8-Dimethylamino-8-phenyl-3-[5- INT-976 2-bromo-5- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.69 (s, 1H), 426.2 (trifluoromethyl)-[1,3,4]thiadiazol-2-yl]- (trifluoromethyl)-1,3,4- 7.42-7.34 (m, 4H), 7.28 (t, 1H), 3.89 (s, 2H), 1,3-diazaspiro[4.5]decan-2-one thiadiazole 2.45-2.31 (m, 2H), 2.07-1.88 (m, 8H) 1.88-1.84 (m, 2H), 1.60-1.53 (m, 2H).
- SC_3398 cis-8-Dimethylamino-3-(5-methyl-6- INT-976 4-(5-bromo-2-methyl-2- SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.23 (s, 1H), 450.3 morpholin-4-yl-pyridin-2-yl)-8-phenyl- pyridyl)morpholine 7.83 (s, 1H), 7.46-7.33 (m, 5H), 7.30-7.24 (m, 1H), 1,3-diazaspiro[4.5]decan-2-one 3.71 (t, 4H), 3.55 (s, 2H), 2.93 (t, 4H), 2.41-2.37 (m, 2H), 1.96 (s, 6H), 1.91-1.82 (m, 4H), 1.49-1.44 (m, 2H).
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US15/923,948 US20180201616A1 (en) | 2016-01-13 | 2018-03-16 | 3-((Hetero-)Aryl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives |
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US17/010,089 US20210032256A1 (en) | 2016-01-13 | 2020-09-02 | 3-((Hetero-)Aryl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives |
US17/188,860 US20210188860A1 (en) | 2016-01-13 | 2021-03-01 | 3-((Hetero-)Aryl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives |
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US16/207,854 Abandoned US20190106429A1 (en) | 2016-01-13 | 2018-12-03 | 3-((Hetero-)Aryl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives |
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US17/010,089 Abandoned US20210032256A1 (en) | 2016-01-13 | 2020-09-02 | 3-((Hetero-)Aryl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives |
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EP (2) | EP3722284A1 (de) |
JP (2) | JP6893516B2 (de) |
KR (2) | KR20180097732A (de) |
CN (2) | CN108699006B (de) |
AR (2) | AR107434A1 (de) |
AU (1) | AU2017206908B2 (de) |
BR (1) | BR112018014305B1 (de) |
CA (1) | CA3011176C (de) |
CL (1) | CL2018001911A1 (de) |
CO (1) | CO2018008447A2 (de) |
CY (1) | CY1122923T1 (de) |
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EA (2) | EA037598B1 (de) |
EC (1) | ECSP18060834A (de) |
ES (1) | ES2807549T3 (de) |
HR (1) | HRP20200782T1 (de) |
HU (1) | HUE049771T2 (de) |
IL (2) | IL260496B (de) |
LT (1) | LT3402781T (de) |
MX (1) | MX2018008643A (de) |
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PE (1) | PE20221732A1 (de) |
PL (1) | PL3402781T3 (de) |
PT (1) | PT3402781T (de) |
RS (1) | RS60307B1 (de) |
SI (1) | SI3402781T1 (de) |
TW (1) | TWI635082B (de) |
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ZA (1) | ZA201805356B (de) |
Cited By (4)
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US10793556B2 (en) | 2016-01-13 | 2020-10-06 | Gruenenthal Gmbh | 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 |
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CN110862395B (zh) * | 2019-11-13 | 2020-09-29 | 株洲千金药业股份有限公司 | 一种制备他达拉非重要杂质的原料化合物的制备方法 |
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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 |
RS60855B1 (sr) | 2016-01-13 | 2020-10-30 | Gruenenthal Gmbh | Derivati 8-amino-2-okso-1,3-diaza-spiro-[4.5]-dekana |
WO2017121646A1 (en) | 2016-01-13 | 2017-07-20 | Grünenthal GmbH | 3-(carboxyethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
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 |
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Cited By (4)
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 |
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 |
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