WO2019097282A1 - Isoindoline derivatives for the treatment of cns diseases - Google Patents
Isoindoline derivatives for the treatment of cns diseases Download PDFInfo
- Publication number
- WO2019097282A1 WO2019097282A1 PCT/IB2017/057247 IB2017057247W WO2019097282A1 WO 2019097282 A1 WO2019097282 A1 WO 2019097282A1 IB 2017057247 W IB2017057247 W IB 2017057247W WO 2019097282 A1 WO2019097282 A1 WO 2019097282A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- isoindoline
- piperazin
- ylisoindoline
- fluorobenzenesulphonyl
- compound according
- Prior art date
Links
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical class C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 title claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 4
- 201000010099 disease Diseases 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 110
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- 125000005843 halogen group Chemical group 0.000 claims abstract description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 8
- 125000006431 methyl cyclopropyl group Chemical group 0.000 claims abstract description 5
- 125000001424 substituent group Chemical group 0.000 claims abstract description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract 3
- 125000001544 thienyl group Chemical group 0.000 claims abstract 3
- 238000000034 method Methods 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 208000010877 cognitive disease Diseases 0.000 claims description 6
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- QNMJMGLHDVVDCM-UHFFFAOYSA-N 2-(2,3-difluorophenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound FC1=C(C=CC=C1F)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 QNMJMGLHDVVDCM-UHFFFAOYSA-N 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- PMKDLPXTADKLHI-UHFFFAOYSA-N 2-(2,4-difluorophenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound FC1=C(C=CC(=C1)F)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 PMKDLPXTADKLHI-UHFFFAOYSA-N 0.000 claims description 3
- PQJWXGYNGOQYGW-UHFFFAOYSA-N 2-(2,5-difluorophenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound FC1=C(C=C(C=C1)F)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 PQJWXGYNGOQYGW-UHFFFAOYSA-N 0.000 claims description 3
- AUXDWOSDIXJYTD-UHFFFAOYSA-N 2-(3,4-difluorophenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound FC=1C=C(C=CC=1F)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 AUXDWOSDIXJYTD-UHFFFAOYSA-N 0.000 claims description 3
- DQRRCEAXOWZPPG-UHFFFAOYSA-N 2-(3-fluorophenyl)sulfonyl-4-(4-methylpiperazin-1-yl)-1,3-dihydroisoindole Chemical compound FC=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCN(CC1)C DQRRCEAXOWZPPG-UHFFFAOYSA-N 0.000 claims description 3
- GPDZNAWSSFSFCD-UHFFFAOYSA-N 2-(3-methylphenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound CC=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 GPDZNAWSSFSFCD-UHFFFAOYSA-N 0.000 claims description 3
- VAGQKIQCMSEQNF-UHFFFAOYSA-N 2-(4-tert-butylphenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound C(C)(C)(C)C1=CC=C(C=C1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 VAGQKIQCMSEQNF-UHFFFAOYSA-N 0.000 claims description 3
- JVYQDPVQNFLBSK-UHFFFAOYSA-N 4-(1,4-diazepan-1-yl)-2-(3-fluorophenyl)sulfonyl-1,3-dihydroisoindole Chemical compound N1(CCNCCC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)F JVYQDPVQNFLBSK-UHFFFAOYSA-N 0.000 claims description 3
- JKPQTUQEPCBYEF-UHFFFAOYSA-N 4-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-(3-fluorophenyl)sulfonyl-1,3-dihydroisoindole Chemical compound C12N(CC(NC1)C2)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)F JKPQTUQEPCBYEF-UHFFFAOYSA-N 0.000 claims description 3
- IZQBWJYOGPYETJ-UHFFFAOYSA-N 4-[2-(3-fluorophenyl)sulfonyl-1,3-dihydroisoindol-4-yl]-1,4-oxazepane Chemical compound FC=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCOCCC1 IZQBWJYOGPYETJ-UHFFFAOYSA-N 0.000 claims description 3
- HJGLGUQVUYINFX-UHFFFAOYSA-N 4-piperazin-1-yl-2-[3-(trifluoromethyl)phenyl]sulfonyl-1,3-dihydroisoindole Chemical compound FC(C=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1)(F)F HJGLGUQVUYINFX-UHFFFAOYSA-N 0.000 claims description 3
- LGMHXLWJFUULTD-UHFFFAOYSA-N 4-piperazin-1-yl-2-thiophen-2-ylsulfonyl-1,3-dihydroisoindole Chemical compound N1(CCNCC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C=1SC=CC=1 LGMHXLWJFUULTD-UHFFFAOYSA-N 0.000 claims description 3
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 3
- ACJVILXLJDXICL-UHFFFAOYSA-N 1-[2-(3-fluorophenyl)sulfonyl-1,3-dihydroisoindol-4-yl]-N,N-dimethylpyrrolidin-3-amine Chemical compound FC=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CC(CC1)N(C)C ACJVILXLJDXICL-UHFFFAOYSA-N 0.000 claims description 2
- FVGCOXQJUBYCIG-UHFFFAOYSA-N 1-[2-(3-methoxyphenyl)sulfonyl-1,3-dihydroisoindol-4-yl]-N,N-dimethylpyrrolidin-3-amine Chemical compound COC=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CC(CC1)N(C)C FVGCOXQJUBYCIG-UHFFFAOYSA-N 0.000 claims description 2
- KGFODASKXHFJDE-UHFFFAOYSA-N 2-(2,4-difluorophenyl)sulfonyl-N-piperidin-4-yl-1,3-dihydroisoindol-4-amine Chemical compound FC1=C(C=CC(=C1)F)S(=O)(=O)N1CC2=CC=CC(=C2C1)NC1CCNCC1 KGFODASKXHFJDE-UHFFFAOYSA-N 0.000 claims description 2
- PZLVXPMSROJQQT-UHFFFAOYSA-N 2-(2,6-difluorophenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound FC1=C(C(=CC=C1)F)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 PZLVXPMSROJQQT-UHFFFAOYSA-N 0.000 claims description 2
- UZFYJPAXAUCAPB-UHFFFAOYSA-N 2-(2-fluorophenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound FC1=C(C=CC=C1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 UZFYJPAXAUCAPB-UHFFFAOYSA-N 0.000 claims description 2
- PKPHCCQLVPEGDI-UHFFFAOYSA-N 2-(3,4-difluorophenyl)sulfonyl-4-(4-methylpiperazin-1-yl)-1,3-dihydroisoindole Chemical compound FC=1C=C(C=CC=1F)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCN(CC1)C PKPHCCQLVPEGDI-UHFFFAOYSA-N 0.000 claims description 2
- YVFPAGSTZXRONH-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound COC=1C=C(C=CC=1OC)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 YVFPAGSTZXRONH-UHFFFAOYSA-N 0.000 claims description 2
- VMXWTTRAAXEFBE-UHFFFAOYSA-N 2-(3,5-difluorophenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound FC=1C=C(C=C(C=1)F)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 VMXWTTRAAXEFBE-UHFFFAOYSA-N 0.000 claims description 2
- CQLDFXCYOOIHBR-UHFFFAOYSA-N 2-(3-chloro-2-fluorophenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound ClC=1C(=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1)F CQLDFXCYOOIHBR-UHFFFAOYSA-N 0.000 claims description 2
- ZWCIQNUJXKUNSZ-UHFFFAOYSA-N 2-(3-chlorophenyl)sulfonyl-4-(4-methylpiperazin-1-yl)-1,3-dihydroisoindole Chemical compound ClC=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCN(CC1)C ZWCIQNUJXKUNSZ-UHFFFAOYSA-N 0.000 claims description 2
- CNFVPYMDMWABBM-UHFFFAOYSA-N 2-(3-chlorophenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound ClC=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 CNFVPYMDMWABBM-UHFFFAOYSA-N 0.000 claims description 2
- IQWSNNJTFCGCMD-UHFFFAOYSA-N 2-(3-fluoro-4-methoxyphenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound FC=1C=C(C=CC=1OC)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 IQWSNNJTFCGCMD-UHFFFAOYSA-N 0.000 claims description 2
- FKDUNQSGEWNDJP-UHFFFAOYSA-N 2-(3-fluorophenyl)sulfonyl-N-pyrrolidin-3-yl-1,3-dihydroisoindol-4-amine Chemical compound FC=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)NC1CNCC1 FKDUNQSGEWNDJP-UHFFFAOYSA-N 0.000 claims description 2
- FLYLMPOUAFPFRE-UHFFFAOYSA-N 2-(3-methoxyphenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound COC=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 FLYLMPOUAFPFRE-UHFFFAOYSA-N 0.000 claims description 2
- SMTMHHXICGFWMI-UHFFFAOYSA-N 2-(3-methoxyphenyl)sulfonyl-N-pyrrolidin-3-yl-1,3-dihydroisoindol-4-amine Chemical compound COC=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)NC1CNCC1 SMTMHHXICGFWMI-UHFFFAOYSA-N 0.000 claims description 2
- UHLLZVBXVVAFNL-UHFFFAOYSA-N 2-(3-methylphenyl)sulfonyl-4-(4-methylpiperazin-1-yl)-1,3-dihydroisoindole Chemical compound CC=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCN(CC1)C UHLLZVBXVVAFNL-UHFFFAOYSA-N 0.000 claims description 2
- KOEQAYJMVFHGHJ-UHFFFAOYSA-N 2-(4-fluoro-3-methoxyphenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound FC1=C(C=C(C=C1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1)OC KOEQAYJMVFHGHJ-UHFFFAOYSA-N 0.000 claims description 2
- KHGMIFUGMWBECP-UHFFFAOYSA-N 2-(4-fluorophenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound FC1=CC=C(C=C1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 KHGMIFUGMWBECP-UHFFFAOYSA-N 0.000 claims description 2
- FYSJBPFJDAEZPY-UHFFFAOYSA-N 2-(5-chlorothiophen-2-yl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound ClC1=CC=C(S1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 FYSJBPFJDAEZPY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- NOJNWCLPMNOBBV-UHFFFAOYSA-N 4-(1,4-diazepan-1-yl)-2-(3-methoxyphenyl)sulfonyl-1,3-dihydroisoindole Chemical compound N1(CCNCCC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)OC NOJNWCLPMNOBBV-UHFFFAOYSA-N 0.000 claims description 2
- VWCBBERIMXHTKX-UHFFFAOYSA-N 4-(1,4-diazepan-1-yl)-2-[3-(trifluoromethyl)phenyl]sulfonyl-1,3-dihydroisoindole Chemical compound N1(CCNCCC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)C(F)(F)F VWCBBERIMXHTKX-UHFFFAOYSA-N 0.000 claims description 2
- FJAMPNDYGLGPAY-UHFFFAOYSA-N 4-(3-methylpiperazin-1-yl)-2-[3-(trifluoromethyl)phenyl]sulfonyl-1,3-dihydroisoindole Chemical compound CC1CN(CCN1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)C(F)(F)F FJAMPNDYGLGPAY-UHFFFAOYSA-N 0.000 claims description 2
- OZSYSQROXMPNPL-UHFFFAOYSA-N 4-(4-cyclopropylpiperazin-1-yl)-2-[3-(trifluoromethyl)phenyl]sulfonyl-1,3-dihydroisoindole Chemical compound C1(CC1)N1CCN(CC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)C(F)(F)F OZSYSQROXMPNPL-UHFFFAOYSA-N 0.000 claims description 2
- SYZBIFHJAXXTKT-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)-2-[3-(trifluoromethyl)phenyl]sulfonyl-1,3-dihydroisoindole Chemical compound CN1CCN(CC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)C(F)(F)F SYZBIFHJAXXTKT-UHFFFAOYSA-N 0.000 claims description 2
- ZZZGVKJXORKYHN-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)-2-thiophen-2-ylsulfonyl-1,3-dihydroisoindole Chemical compound CN1CCN(CC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C=1SC=CC=1 ZZZGVKJXORKYHN-UHFFFAOYSA-N 0.000 claims description 2
- GHVHRAPIAXNBQW-UHFFFAOYSA-N 4-(4-tert-butylpiperazin-1-yl)-2-[3-(trifluoromethyl)phenyl]sulfonyl-1,3-dihydroisoindole Chemical compound C(C)(C)(C)N1CCN(CC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)C(F)(F)F GHVHRAPIAXNBQW-UHFFFAOYSA-N 0.000 claims description 2
- FJAMPNDYGLGPAY-CQSZACIVSA-N 4-[(3R)-3-methylpiperazin-1-yl]-2-[3-(trifluoromethyl)phenyl]sulfonyl-1,3-dihydroisoindole Chemical compound C[C@@H]1CN(CCN1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)C(F)(F)F FJAMPNDYGLGPAY-CQSZACIVSA-N 0.000 claims description 2
- HKTKPTGGWIMUPS-UHFFFAOYSA-N 4-[2-(3-fluorophenyl)sulfonyl-1,3-dihydroisoindol-4-yl]morpholine Chemical compound FC=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCOCC1 HKTKPTGGWIMUPS-UHFFFAOYSA-N 0.000 claims description 2
- NGWWSRDMMYUCIV-UHFFFAOYSA-N 4-[2-(3-methylphenyl)sulfonyl-1,3-dihydroisoindol-4-yl]morpholine Chemical compound CC=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCOCC1 NGWWSRDMMYUCIV-UHFFFAOYSA-N 0.000 claims description 2
- MZWURYVHXGWDGS-UHFFFAOYSA-N 4-[4-(cyclopropylmethyl)piperazin-1-yl]-2-[3-(trifluoromethyl)phenyl]sulfonyl-1,3-dihydroisoindole Chemical compound C1(CC1)CN1CCN(CC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)C(F)(F)F MZWURYVHXGWDGS-UHFFFAOYSA-N 0.000 claims description 2
- GMVUVGHFGFVWII-UHFFFAOYSA-N 4-piperazin-1-yl-2-[3-(trifluoromethoxy)phenyl]sulfonyl-1,3-dihydroisoindole Chemical compound N1(CCNCC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)OC(F)(F)F GMVUVGHFGFVWII-UHFFFAOYSA-N 0.000 claims description 2
- ZCZWGTMGRHMGMS-UHFFFAOYSA-N 4-piperazin-1-yl-2-[4-(trifluoromethyl)phenyl]sulfonyl-1,3-dihydroisoindole Chemical compound FC(C1=CC=C(C=C1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1)(F)F ZCZWGTMGRHMGMS-UHFFFAOYSA-N 0.000 claims description 2
- CVVCXDWVGORKOX-UHFFFAOYSA-N N,N-diethyl-1-[2-(3-fluorophenyl)sulfonyl-1,3-dihydroisoindol-4-yl]piperidin-4-amine Chemical compound C(C)N(C1CCN(CC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)F)CC CVVCXDWVGORKOX-UHFFFAOYSA-N 0.000 claims description 2
- XRDPNLMIAULDMS-UHFFFAOYSA-N N,N-diethyl-1-[2-(3-methylphenyl)sulfonyl-1,3-dihydroisoindol-4-yl]piperidin-4-amine Chemical compound C(C)N(C1CCN(CC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)C)CC XRDPNLMIAULDMS-UHFFFAOYSA-N 0.000 claims description 2
- HFXUMIPNLAPOOZ-UHFFFAOYSA-N N-(azetidin-3-yl)-2-(3-fluorophenyl)sulfonyl-1,3-dihydroisoindol-4-amine Chemical compound N1CC(C1)NC1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)F HFXUMIPNLAPOOZ-UHFFFAOYSA-N 0.000 claims description 2
- QFILKRSGWKRWHQ-UHFFFAOYSA-N N-pyrrolidin-3-yl-2-[3-(trifluoromethyl)phenyl]sulfonyl-1,3-dihydroisoindol-4-amine Chemical compound FC(C=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)NC1CNCC1)(F)F QFILKRSGWKRWHQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 2
- HFGFKOOAFGOOCI-UHFFFAOYSA-N 2-(3-fluorophenyl)sulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound FC=1C=C(C=CC=1)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 HFGFKOOAFGOOCI-UHFFFAOYSA-N 0.000 claims 1
- IPUVWXXSODSQFS-UHFFFAOYSA-N 2-naphthalen-1-ylsulfonyl-4-piperazin-1-yl-1,3-dihydroisoindole Chemical compound C1(=CC=CC2=CC=CC=C12)S(=O)(=O)N1CC2=CC=CC(=C2C1)N1CCNCC1 IPUVWXXSODSQFS-UHFFFAOYSA-N 0.000 claims 1
- XMYBOPDYXMMRQG-UHFFFAOYSA-N 3-[(4-piperazin-1-yl-1,3-dihydroisoindol-2-yl)sulfonyl]benzonitrile Chemical compound N1(CCNCC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C=1C=C(C#N)C=CC=1 XMYBOPDYXMMRQG-UHFFFAOYSA-N 0.000 claims 1
- KEJAJALVKJZSKV-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)-2-naphthalen-1-ylsulfonyl-1,3-dihydroisoindole Chemical compound CN1CCN(CC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC=CC2=CC=CC=C12 KEJAJALVKJZSKV-UHFFFAOYSA-N 0.000 claims 1
- SJICNMBBZYWHOQ-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)-2-naphthalen-2-ylsulfonyl-1,3-dihydroisoindole Chemical compound CN1CCN(CC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC2=CC=CC=C2C=C1 SJICNMBBZYWHOQ-UHFFFAOYSA-N 0.000 claims 1
- AIENJNZJTHJGJO-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)-2-pyridin-3-ylsulfonyl-1,3-dihydroisoindole Chemical compound CN1CCN(CC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C=1C=NC=CC=1 AIENJNZJTHJGJO-UHFFFAOYSA-N 0.000 claims 1
- WSNPYXMRZFFWJL-UHFFFAOYSA-N 4-(4-propan-2-ylpiperazin-1-yl)-2-[3-(trifluoromethyl)phenyl]sulfonyl-1,3-dihydroisoindole Chemical compound C(C)(C)N1CCN(CC1)C1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)C(F)(F)F WSNPYXMRZFFWJL-UHFFFAOYSA-N 0.000 claims 1
- GUBXALONMWWGDV-UHFFFAOYSA-N N-(azetidin-3-yl)-2-(3-methylphenyl)sulfonyl-1,3-dihydroisoindol-4-amine Chemical compound N1CC(C1)NC1=C2CN(CC2=CC=C1)S(=O)(=O)C1=CC(=CC=C1)C GUBXALONMWWGDV-UHFFFAOYSA-N 0.000 claims 1
- 229940124639 Selective inhibitor Drugs 0.000 abstract description 2
- 208000015114 central nervous system disease Diseases 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
- 125000001624 naphthyl group Chemical group 0.000 abstract 1
- 125000004076 pyridyl group Chemical group 0.000 abstract 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 189
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- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000016978 synaptic transmission, cholinergic Effects 0.000 description 1
- 230000007593 synaptic transmission, glutaminergic Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- ABDUQCAVIKCNGN-CYBMUJFWSA-N tert-butyl (2R)-4-(2,3-dihydro-1H-isoindol-4-yl)-2-methylpiperazine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1[C@@H](CN(CC1)C1=C2CNCC2=CC=C1)C ABDUQCAVIKCNGN-CYBMUJFWSA-N 0.000 description 1
- CMIBWIAICVBURI-SSDOTTSWSA-N tert-butyl (3r)-3-aminopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](N)C1 CMIBWIAICVBURI-SSDOTTSWSA-N 0.000 description 1
- CMIBWIAICVBURI-ZETCQYMHSA-N tert-butyl (3s)-3-aminopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@H](N)C1 CMIBWIAICVBURI-ZETCQYMHSA-N 0.000 description 1
- WDPWEXWMQDRXAL-UHFFFAOYSA-N tert-butyl 1,4-diazepane-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCNCC1 WDPWEXWMQDRXAL-UHFFFAOYSA-N 0.000 description 1
- UXAWXZDXVOYLII-UHFFFAOYSA-N tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)CC1NC2 UXAWXZDXVOYLII-UHFFFAOYSA-N 0.000 description 1
- WQBMVRTXKYXMKT-UHFFFAOYSA-N tert-butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)(O)C(F)(F)C1 WQBMVRTXKYXMKT-UHFFFAOYSA-N 0.000 description 1
- OGYMPCFAVCVEJK-UHFFFAOYSA-N tert-butyl 3-(2,3-dihydro-1H-isoindol-4-ylamino)azetidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC(C1)NC1=C2CNCC2=CC=C1 OGYMPCFAVCVEJK-UHFFFAOYSA-N 0.000 description 1
- KLKSMCRLLDPCOQ-UHFFFAOYSA-N tert-butyl 3-(2,3-dihydro-1H-isoindol-4-ylamino)pyrrolidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC(CC1)NC1=C2CNCC2=CC=C1 KLKSMCRLLDPCOQ-UHFFFAOYSA-N 0.000 description 1
- WPGLRFGDZJSQGI-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(N)C1 WPGLRFGDZJSQGI-UHFFFAOYSA-N 0.000 description 1
- CMIBWIAICVBURI-UHFFFAOYSA-N tert-butyl 3-aminopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)C1 CMIBWIAICVBURI-UHFFFAOYSA-N 0.000 description 1
- FMLPQHJYUZTHQS-UHFFFAOYSA-N tert-butyl 3-methylpiperazine-1-carboxylate Chemical compound CC1CN(C(=O)OC(C)(C)C)CCN1 FMLPQHJYUZTHQS-UHFFFAOYSA-N 0.000 description 1
- MCWNBNWRKKBLFH-UHFFFAOYSA-N tert-butyl 4-(1,4-oxazepan-4-yl)-1,3-dihydroisoindole-2-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC2=CC=CC(=C2C1)N1CCOCCC1 MCWNBNWRKKBLFH-UHFFFAOYSA-N 0.000 description 1
- UCGJUIPGISDABN-UHFFFAOYSA-N tert-butyl 4-(2,3-dihydro-1H-isoindol-4-yl)-1,4-diazepane-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CCN(CCC1)C1=C2CNCC2=CC=C1 UCGJUIPGISDABN-UHFFFAOYSA-N 0.000 description 1
- YXHQWBYFBUXNDZ-UHFFFAOYSA-N tert-butyl 4-(2,3-dihydro-1H-isoindol-4-yl)piperazine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CCN(CC1)C1=C2CNCC2=CC=C1 YXHQWBYFBUXNDZ-UHFFFAOYSA-N 0.000 description 1
- FKBLENSHBHJUCP-UHFFFAOYSA-N tert-butyl 4-(2,3-dihydro-1H-isoindol-4-ylamino)piperidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)NC1=C2CNCC2=CC=C1 FKBLENSHBHJUCP-UHFFFAOYSA-N 0.000 description 1
- VHXMMJUVLBCYQU-UHFFFAOYSA-N tert-butyl 4-(4-cyclopropylpiperazin-1-yl)-1,3-dihydroisoindole-2-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC2=CC=CC(=C2C1)N1CCN(CC1)C1CC1 VHXMMJUVLBCYQU-UHFFFAOYSA-N 0.000 description 1
- NFVKEDRXHPYXCP-UHFFFAOYSA-N tert-butyl 4-(4-methylpiperazin-1-yl)-1,3-dihydroisoindole-2-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC2=CC=CC(=C2C1)N1CCN(CC1)C NFVKEDRXHPYXCP-UHFFFAOYSA-N 0.000 description 1
- RLUTWCNFJMWOCW-UHFFFAOYSA-N tert-butyl 4-(4-propan-2-ylpiperazin-1-yl)-1,3-dihydroisoindole-2-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC2=CC=CC(=C2C1)N1CCN(CC1)C(C)C RLUTWCNFJMWOCW-UHFFFAOYSA-N 0.000 description 1
- IXLJMPMBXNJVRU-UHFFFAOYSA-N tert-butyl 4-(4-tert-butylpiperazin-1-yl)-1,3-dihydroisoindole-2-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC2=CC=CC(=C2C1)N1CCN(CC1)C(C)(C)C IXLJMPMBXNJVRU-UHFFFAOYSA-N 0.000 description 1
- IHHKTYFZAGXFSC-UHFFFAOYSA-N tert-butyl 4-[3-(dimethylamino)pyrrolidin-1-yl]-1,3-dihydroisoindole-2-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC2=CC=CC(=C2C1)N1CC(CC1)N(C)C IHHKTYFZAGXFSC-UHFFFAOYSA-N 0.000 description 1
- YKNXVJUGGNXHLL-UHFFFAOYSA-N tert-butyl 4-[4-(diethylamino)piperidin-1-yl]-1,3-dihydroisoindole-2-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC2=CC=CC(=C2C1)N1CCC(CC1)N(CC)CC YKNXVJUGGNXHLL-UHFFFAOYSA-N 0.000 description 1
- LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 description 1
- BFCZVUVSPUKWET-UHFFFAOYSA-N tert-butyl 4-bromo-1,3-dihydroisoindole-2-carboxylate Chemical compound C1=CC(Br)=C2CN(C(=O)OC(C)(C)C)CC2=C1 BFCZVUVSPUKWET-UHFFFAOYSA-N 0.000 description 1
- XINYKSLFQDHSMU-UHFFFAOYSA-N tert-butyl 4-morpholin-4-yl-1,3-dihydroisoindole-2-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC2=CC=CC(=C2C1)N1CCOCC1 XINYKSLFQDHSMU-UHFFFAOYSA-N 0.000 description 1
- BWEJWKFFUGLGTK-UHFFFAOYSA-N tert-butyl 5-(2,3-dihydro-1H-isoindol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C2CN(C(C1)C2)C1=C2CNCC2=CC=C1 BWEJWKFFUGLGTK-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/4995—Pyrazines or piperazines forming part of bridged ring 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D487/08—Bridged systems
Definitions
- the invention relates to the field of chemical compounds, isoindoline derivatives, their use as a medicament and pharmaceutical compositions comprising said compounds.
- the compounds are selective inhibitors of serotonin 5- HT6 receptor and can be useful in the treatment of central nervous system (CNS) diseases, in particular in the treatment of neuropsychiatric disorders such as cognitive disorders and dementia of various origin.
- CNS central nervous system
- Receptor 5-HT6 is a subtype of 5-HT receptor, a receptor for endogenous neurotransmitter called 5-hydroxytryptamine or serotonin, a mediator of serotoninergic transmission. Receptor 5-HT6 is localized almost exclusively in the brain. It is engaged in such functions as cognitive functions, memory and emotions. Blockade of 5-HT6 receptor increases glutaminergic and cholinergic transmission in the brain and facilitates release of dopamine and norepinephrine in the prefrontal cortex.
- Alzheimer’s disease is the most common cause of dementia in older adults that is characterized by progressive behavioral disorders/changes and by decline of memory function.
- some medicaments i.e. reversible acetylcholinesterase inhibitors like donepezil, rivastigmine, tacrine and galantamine, were introduced in the clinic for the treatment of Alzheimer’s disease, in most patients benefits of their use are limited. Therefore there is still a need for new medicaments based on different mechanism of action, including inhibition of serotoninergic transmission via 5-HT6 receptor.
- selective 5-HT6 inhibitors such as idalopirdine (2-(6-fluoro-1 H- indol-3-yl)-N-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)ethanamine) and interpidine (phenylsulphonyl-8-(piperazin-1 -yl)quinoline have been evaluated under clinical trials.
- idalopirdine (2-(6-fluoro-1 H- indol-3-yl)-N-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)ethanamine
- interpidine phenylsulphonyl-8-(piperazin-1 -yl)quinoline
- New isoindoline derivatives useful as 5-HT6 receptor antagonists are disclosed in Chinese patent application CN2015-10489790.
- the object of the invention are isoindoline derivatives, presented by the
- R 1 represents hydrogen atom and R 2 represents a moiety of the Formula G1
- R 1 and R 2 are connected with each other to form together with nitrogen atom to which they are attached a moiety of the Formula G2
- A is selected from the group consisting of:
- - phenyl substituted with one or two substituents selected from the group consisting of halogen atoms, straight or branched C1 -C4 alkyl, C1 -C2-alkoxyl, CF 3 , CN, and -OCF3,
- X is selected from the group consisting of -NR 4 -, -0-, and -CHN(R 5 )2;
- R 3 is selected from the group consisting of hydrogen atom, methyl, ethyl, and cyclopropyl;
- R 4 is selected from the group consisting of hydrogen atom, straight or branched C1 - C4 alkyl, straight or branched C1 -C4 alkyl substituted with one or two halogen atoms, cyclopropyl, and methylcyclopropyl;
- R 5 represents C1 -C2 alkyl
- k is an integer equal 1 or 2;
- l is an integer equal 1 or 2;
- n is an integer equal 0, 1 or 2;
- n is an integer 0 or 1 when X represents -NR 4 - or -CHN(R 5 )2, wherein n is 1 only when m is 1 , and
- n 0 when X represents -0-;
- the compounds of the invention exhibit the ability of selective inhibition of 5-HT6 receptors as well as metabolic stability and can find use as medicaments.
- the invention provides also a pharmaceutical composition comprising the compound of the Formula (I) as defined above as an active ingredient.
- the invention provides also a use of the compound of the Formula (I) as defined above in a method of treatment of cognitive diseases.
- Preferred halogen atoms are fluorine and chlorine.
- straight or branched C1 -C4 alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, tert- butyl and sec-butyl groups.
- C1 -C2- alkoxy includes methoxy (-OCH 3 ) and ethoxy (-OC2H5) groups.
- the compounds of the invention can form acid addition salts.
- Salts of the compounds of the Formula (I) of the invention comprise acid addition salts with inorganic and organic acids.
- Inorganic and organic acids capable of forming pharmaceutically acceptable salts with the compounds possessing basic nitrogen atom are well known in the art.
- Salts with inorganic acids include in particular hydrochlorides, hydrobromides, sulphates and phosphates.
- Salts with inorganic acids include in particular methanesulphonates, ethanesulphonates, toluenesulphonates, benzenesulphonates, naphthalenedisulphonates, acetates, propionates, lactates, tartrates, malates, citrates, fumarates, maleates and benzoates.
- compound of the Formula (I) according to the invention comprises chiral center
- such a compound may exist in the form of optical isomers and their mixtures.
- Such optical isomers and their mixtures at different ratios, including racemic mixtures, are encompassed by the invention.
- this relates to the compounds of the Formula (I) wherein R 3 represents methyl.
- the first variant of the compounds of the Formula (I) are those compounds, wherein R 1 and R 2 are linked with each other to form, together with nitrogen atom to which they are attached, a moiety of the Formula G2
- R 4 represents hydrogen atom.
- this subgroup includes the compounds of the Formula (I) wherein n is equal 0.
- Preferred compounds in the above subgroups are those wherein m is equal 1.
- R 3 represents methyl and R 4 represents hydrogen atom.
- R 3 represents hydrogen atom and R 4 represents hydrogen atom.
- R 3 represents hydrogen atom and R 4 represents straight or branched C1 -C4 alkyl, cyclopropyl or methylcyclopropyl.
- Another specific subgroup of the compounds of the Formula (I) wherein X represents -NR 4 - and n is 0 are the compounds wherein m is 0 or 2, R 3 represents hydrogen atom and R 4 represents hydrogen atom.
- Another specific subgroup of the compounds of the Formula (I) wherein X represents -NR 4 - are the compounds wherein n is 1 .
- n 1
- m equals 1
- R 3 represents hydrogen atom
- R 4 represents hydrogen atom.
- a second subgroup in this first variant are the compounds of the Formula (I) wherein X represents -O- and n is 0.
- R 3 represents hydrogen atom.
- a third subgroup in this first variant are the compounds of the Formula (I) wherein X represents -CHN(R 5 )2.
- R 5 represents methyl.
- Second variant of the compounds of the Formula (I) are those compounds wherein R 1 represents hydrogen atom and R 2 represents a moiety of the Formula G1
- One subgroup in this second variant are the compounds wherein k is equal 1 and l is equal 1 .
- the G1 moiety is azetidin-3-yl group.
- Second subgroup in this second variant are the compounds wherein k is equal 1 and l is equal 2.
- the G1 moiety is pyrrolidin-3-yl group.
- Third subgroup in this second variant are the compounds wherein k is equal 2 and l is equal 2.
- the G1 moiety is piperidin-4-yl group.
- any one of the above variants and subgroups A represents phenyl substituted with one or two substituents selected from the group consisting of halogen atoms, straight or branched C1 -C4 alkyl, C-1 -C2-alkoxyl, CF 3 , CN, and
- A represents phenyl substituted with one fluorine or one chlorine atom, fluorine and chlorine atoms, two fluorine atoms or two chlorine atoms.
- Specific compounds of the Formula (I) of the invention include the compounds selected from the group consisting of the following:
- the compounds of the invention of the Formula (I) can be prepared starting from the compound of the Formula (II)
- R 1 and R 2 are as defined for the Formula (I), and wherein amine group in the moiety G1 or in the moiety G2 when X represents -NR 4 - and R 4 represents hydrogen atom, is protected with amine protecting group,
- Amine protecting group in the moiety G1 can be benzyloxycarbonyl group (Cbz) or tert-butoxycarbonyl group (Boc).
- Arylsulphonyl chlorides A-SO 2 -CI, wherein A is as defined for the Formula (I) are commercially available compounds.
- the compound of the Formula (II) can be prepared from 4-bromoisoindoline that is commercially available known compound, by
- Nitrogen protecting group in 4-bromoisoindoline is different than optional protecting group in the amine R 1 R 2 NH, so as it could be selectively removed without removal of the latter.
- protecting group in the amine R 1 R 2 NH is Boc group
- nitrogen atom in 4-bromoisoindoline will be protected with Cbz protecting group
- protecting group in the amine R 1 R 2 NH is Cbz group or is absent
- nitrogen atom in 4-bromoisoindoline will be protected with Boc protecting group.
- Reaction of the compound of the Formula (II) with arylsulphonyl chloride A-SO2-CI can be performed in an organic solvent, for example dichloromethane, in the presence of a tertiary amine for example trimethylamine, as a proton acceptor, at about 0°C.
- Reaction product can be purified by preparative column chromatography, and then amine protecting group, if present, can be removed. Removal of amine protecting Boc group is performed in a known manner in acidic medium, for example using HCl solution in alcohol, for example 4M HCl in methanol, or solution of trifluoroacetic acid in dichloromethane.
- Removal of amine protecting Cbz group can be performed in a known manner using hydrogen in the presence of Pd(C) in methanol.
- acid addition salt of the final compound of the invention is obtained, hydrochloride in the case of HCl in methanol.
- acid addition salt can be analogously obtained, for example hydrochloride can be obtained using HCl solution in methanol.
- Protection of 4-bromoisoindoline can be performed by reaction with benzylochloroformate or tert-butoxycarbonyl anhydride, to form benzyl or tert- butyl ester of 4-bromoisoindoline-2-carboxylic acid, respectively, at about 0°C, in an organic solvent, for example dichloromethane, in the presence of tertiary amine, for example trimethylamine, as a proton acceptor.
- an organic solvent for example dichloromethane
- tertiary amine for example trimethylamine
- Reaction of protected 4-bromoisoindoline (1 eq) with amine R 1 R 2 NH (2 eq) is performed using microwave-assisted Buchwald-Hartwig N-arylation method ((Pd 2 dba3 0.04 eq, BINAP 0.06 eq, NaOtBut 2 eq) in dioxane.
- Amine derivative thus obtained is purified using preparative column chromatography.
- deprotection of Cbz group is performed by treatment with hydrogen in the presence of 10% Pd(C), in MeOH, or deprotection of Boc group is performed in the dichloromethane/trifluoroacetic acid mixture.
- Amines R 1 R 2 NH are commercially available known compounds. When needed, protection of nitrogen atom in G1 and G2 moieties can be performed in a known manner.
- Compounds of the Formula (I) of the invention can find use in the treatment of cognitive disorders, including memory and cognition disorders, in the treatment of dementia of various etiology, including dementia associated with Alzheimer’s disease, as well as in the treatment of cognitive dysfunction in schizophrenia.
- the compounds of the formula (I) of the invention can be administered as a chemical compound, however usually will be used in the form of a pharmaceutical composition comprising the compound of the invention or its pharmaceutically acceptable salt in combination with pharmaceutically acceptable carrier(s) and auxiliary substance(s).
- composition of the invention can be administered by any suitable route, preferably oral, parenteral or inhalation route and will be in the form of a preparation destined for use in medicine, depending on the intended administration route.
- compositions for oral administration can have the form of solid or liquid preparations.
- Solid preparations can have, for example, the form of a tablet or capsule produced in a conventional manner from pharmaceutically acceptable inactive excipients such as binders (for example, pregelatinised corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (for example lactose, saccharose, carboxymethylcellulose, microcrystalline cellulose or calcium hydrogenphosphate); disintegrants (for example crosspovidone, corn starch or sodium starch glycolate); lubricants (for example magnesium stearate, talc or silica), wetting agents (for example sodium laurylsulphate).
- binders for example, pregelatinised corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose
- fillers for example lactose, saccharose, carboxymethylcellulose, microcrystalline cellulose or calcium hydrogenphosphate
- disintegrants for example crosspovidone, corn starch or sodium starch
- Tablets can be coated with coatings well known in the art, such as simple coatings, delayed/controlled- release coatings or enteric coatings.
- Liquid preparations for oral administration can be in a form of, for example, solutions, syrups or suspensions, or can have the form of dry solid product for reconstitution in water or other suitable vehicle before use.
- Such liquid preparations can be prepared using conventional means from pharmaceutically acceptable inactive excipients, such as suspending agents (for example sorbitol syrup, cellulose derivatives or hydrogenated edible oils), emulsifiers (for example lecithine or acacia gum), nonaqueous vehicles (for example mandelic oil, oil esters, ethyl alcohol or fractionated vegetable oils), and preservatives (for example methyl or propyl p- hydroxy benzoate or sorbic acid).
- suspending agents for example sorbitol syrup, cellulose derivatives or hydrogenated edible oils
- emulsifiers for example lecithine or acacia gum
- nonaqueous vehicles for example mandelic oil, oil esters, ethyl alcohol or fractionated vegetable oils
- preservatives for example methyl or propyl p- hydroxy benzoate or sorbic acid.
- Preparations can also include suitable buffering agents, flavoring agents, coloring agents and sweeteners.
- Preparations for oral administration can be formulated so as to obtain controlled release of the active compound using methods known for a person skilled in the art.
- compositions for parenteral administration can, for example, have the form of a unit dosage form, such as ampoules, or multi-dosage containers, with the addition of a preservative.
- Compositions can have the form such as suspension, solution or emulsion in an oily or aqueous vehicle, and can include excipients such as suspending agents, stabilizers, and/or dispersing agents.
- the active ingredient can be formulated as a powder for reconstitution before use in a suitable carrier, for example sterile, pyrogen-free water.
- the method of treatment with the use of the compounds of the present invention will comprise administration of a therapeutically effective amount of the compound of the invention, preferably in the form of a pharmaceutical composition, to the subject in need of such treatment.
- Proposed dosage of the compounds of the invention is from 0.1 to about 1000 mg per day, in a single dose or in divided doses. It will be apparent for a person skilled in the art that selection of a dosage required for obtaining desirable biological effect will depend on many factors, for example specific compound, the indication, the manner of administration, the age and condition of a patient and that exact dosage will be ultimately determined by a responsible physician.
- Example 1 2-(3-Chloro-2-fluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline hydrochloride
- Example _ 19 2-(3-Methoxybenzenesulhonyl)-4-piperazin-1 -ylisoindoline hydrochloride
- Example 21 4-Piperazin-1 -yl-2-(3-trifluoromethoxybenzenesulfonyl)isoindoline hydrochloride
- Example 26 4-(3-Methyl-piperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline hydrochloride
- Example 27 4-(3R-methyl-piperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline hydrochloride
- Example 28 4-(3S-methyl-piperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline hydrochloride
- Example 29 4-(3S-methyl-piperazin-1 -yl)-2-(3-fluoromethylbenzenesulphonyl)- isoindoline hydrochloride
- Example 34 4-(4-methylpiperazin-1 -yl)-2-(3-trifluoromethoxybenzenesulphonyl) isoindoline hydrochloride
- Example 36 4-(4-Methylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl- isoindoline hydrochloride
- Example 37 4-(4-methylpiperazin-1 -yl)-2-(naphthtalene-1 -suphfonyl)isoindoline hydrochloride
- Example 42 4-(4-lsopropylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline hydrochloride
- Example 43 4-(4-Cyclopropylpiperazin-1 -yl)-2-(3-trifluoromethylbenzene- sulphonyl)isoindoline hydrochloride
- Example 44 4-(4-Cyclopropylmethylpiperazin-1 -yl)-2-(3-trifluoromethylbenzene- sulphonyl)isoindoline hydrochloride
- Example 45 4-(4-Tert-butylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline hydrochloride
- Example 46 4-(4-propylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline hydrochloride
- Example 47 4-[(4-(2,2-Difluoroethyl)piperazin-1 -yl]-2-(3-trifluoromethylbenzene- sulphonyl)isoindoline hydrochloride
- Example 49 4-[1 ,4]Diazepan-1 -yl-2(3-trifluoromethylbenzenesulphonyl)isoindoline hydrochloride
- Example 50 4-[1 ,4]Diazepan-1 -yl-2-(3-methoxybenzenesulphonyl)isoindoline hydrochloride
- Example 51 4-(2,5-Diazabicyclo[2.2.1 ]hept-2-yl)-2-(3-fluorobenzenesulphonyl)- isoindoline hydrochloride
- Example 52 4-(2,5-Diazabicyclo[2.2.1 ]hept-2-yl)-2-(3-trifluorobenzene- sulphonyl)isoindoline hydrochloride
- Example 65 ⁇ 1 -[2-(3-Methoxybenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3-yl ⁇ - dimethylamine hydrochloride
- Plasmids with genes encoding for human serotonin and dopamine receptors were purchased from UMR cDNA Resource Center (www.cdna.org), cell line HEK293 (Human Embryonic Kidney) was obtained from cell lines bank ATCC (American Type Culture Collection), and in all cases Lipofectamine 2000 (Invitrogen) was used as a transfecting agent.
- CHO-K1 cell line with stable expression of 5- HT 2 A receptor was provided by commercial source (PerkinElmer BioSignal).
- HEK293 line was grown under standard culture conditions (37°C, 5% C0 2 saturation 95% humidity) in Dulbecco’s Modified Eagle’s Medium (DMEM), with high glucose contents, enriched with 5% fetal bovine serum (FBS), and geneticin antibiotic at 500 pg/mL (G418; Sigma-Aldrich).
- DMEM Dulbecco
- FBS fetal bovine serum
- G418 fetal bovine serum
- G418 fetal bovine serum
- Frozen pellets of HEK293 cells with stable expression of tested receptors were homogenized for 15 s (Polytron) in Tris-HCl buffer (50 mM, pH 7.7) with 0.1 mM EDTA, and subsequently centrifuged for 15 min/4°C/50 OOOg. Centrifuged material was suspended in supplemented Tris-HCl buffer at 0.5-0.7 mg protein/mL. Samples containing 1 mL of the suspension were frozen and stored at -80°C until used in the experiment.
- Tests were performed in a 96-well plate; total volume of a sample was 0.2 mL. Solutions and cell suspension were prepared in Tris-HCl buffer (50 mM, pH 7.7), containing: for 5-HTu receptors 50 mM Tris-HCl, 0.1 mM EDTA, 4 mM MgC , 10 mM pargiline and 0.1% ascorbic acid; for 5-HT 6 receptor 50 mM Tris-HCl, 0.5 mM EDTA and 4 mM MgCl 2 ; for 5-HTzb receptors 50 mM Tris-HCl, 4 mM MgC , 10 pM pargiline and 0.1% ascorbic acid; and for dopamine receptors D 2 L 50 mM Tris-HCl, 1 mM EDTA, 4 mM MgC , 120 mM NaCl, 5 mM KCl, 1.5 mM CaCl 2 and 0.1% ascorbic acid.
- JANUS Automated Workstation-Expanded Platform (PerkinElmer) was used for plate pipetting. Tested compound was dissolved in DMSO to obtain stock solution at 1 mM. For experiments a range of 7-8 concentrations (10 11 -10 4 M) in an appropriate buffer were used.
- radioligands were used: for 5-HTu receptor [ 3 H]-8-OH-DPAT (2.5 nM; specific activity 135.2 Ci/mmol); for 5-HT 2 A receptor [ 3 H]-ketanserin (1 nM; specific activity 53.4 Ci/mmol); for 5-HT 6 receptor [ 3 H]-LSD (2 nM; specific activity 83.6 Ci/mmol); for 5-HTz receptor [ 3 H]-5-CT (0.8 nM; specific activity 39.2 Ci/mmol) and for dopamine D 2 L receptor [ 3 H]-raclopride (2.5 nM; specific activity 76.0 Ci/mmol).
- Non-specific binding was defined with 10 mM of serotonin in 5-HTu and 5-HTz binding experiments, whereas chlorpromazine and methiothepine were used in 5- HT 2A R and 5-HT 6 R assays, respectively.
- chlorpromazine and methiothepine were used in 5- HT 2A R and 5-HT 6 R assays, respectively.
- dopamine D 2L receptors haloperidol at 10 mM concentration was used.
- the established equilibrium state (1 h at room temperature for 5-HTu i 5- HT 2A receptors; 1 h at 37°C for 5-HT 6 , 5-HTz and D 2L receptors) was fixed by filtration of protein fraction through Um ' Filter GF/B plates and washed several times with cold Tris-HCl buffer (50 mM, pH 7.7) using harvester (Unifilter Harvester - PerkinElmer).
- L is a radioligand concentration used in the experiment
- KD is its equilibrium (affinity) constant
- IC50 is the concentration of a compound required for displacement of 50% of the radioligand from its binding sites. Results were means of at least three separate experiments.
- Isolated membranes from CHO cells wherein desired receptor was stably overexpressed were incubated for 60 min at room temperature with tested compound at 1 mM concentration in the presence of labelled radioisotope ([3H]methylpiperine in the case of D3 receptor or [3H]Na-Me-Histamine in the case of H3 receptor).
- Non specific binding was estimated using non-specific ligand (+)butaclamol at 10 pM (D3 receptor) or (R)a-Me-histamine at 1 pM (H3 receptor).
- Affinity results were read using scintillation counter and calculated as a percent inhibition with respect to the affinity of control compound (Mackenzie, R.G. et al. (1994), Eur. J.. Pharmacol. ; Lovenberg, T.W. et al. (1999), Mol. Pharmacol. )
- the ability of the compounds to inhibit 5-HT 6 receptor activation by agonist (5-CT) stimulation was assessed in the measurement of accumulation of cyclic AMP using LANCE® Ultra cAMP Assay (PerkinElmer). Plasmid with gene encoding the human serotonin 5-HT 6 receptor was purchased from UMR cDNA Resource Center (www.cdna.org), HEK293 (Human Embryonic Kidney) cell line was obtained from cell lines bank ATCC (American Type Culture Collection), and Lipofectamine 2000 (Invitrogen) was used as a transfecting agent.
- Cell suspension was transferred onto 384-well plates, in the amount of 1000 cells per well.
- Cell suspension (5 pi) was supplemented with a solution of tested compound at appropriate concentration (concentration in the range 10 11 -10 4 M) and 5-CT agonist (100 nM) and incubated for 30 min at room temperature.
- cyclic AMP was determined by LANCE® Ultra cAMP Assay (Perkin Elmer) in accordance with the manufacturer’s protocol.
- Tested compound (1 mM) was incubated at 37°C with rat microsomes activated with NADPH (1.3 mM NADP, 3.3 mM G6P, 0.8 U/mL G6PDH andi 3.3 mM MgC ) at 0.5 mg/ml_. Samples of reaction mixture were collected at time intervals (0, 20, 40 and 60 min), and the reaction was stopped by precipitation of proteins with cooled in ice-bath ACNihhO 4:1 v/v solution containing internal standard. Samples were analyzed using LC MS/MS technique.
- the amount of a compound is given as a compound peak area/internal standard peak area (AUCNCE/AUCIS) ratio. Percentage of the compound after time t was calculated according to the formula:
- Elimination rate constant k for a compound is equal to the module of the slope of the straight line a of the relationship of natural logarithm of percentage of the compound as a function of time:
- Half-life ti/2 for a compound is calculated according to the formula:
- volume of distribution V d is:
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Abstract
A compound of the formula (I) wherein R1 represents hydrogen atom and R2 represents moiety of the formula G1, or R1 and R2 are connected with each other to form with nitrogen atom to which they are attached a moiety of the formula G2; A is selected from the group consisting of phenyl substituted with one or two substituents selected from the group consisting of halogen atom, straight or branched C1- C4 alkyl, C1-C2 alkoxyl, CF3, CN, and -OCF3, naphthyl, quinolinyl, thienyl, thienyl substituted with halogen atom, and pyridyl; X is selected from the group consisting of -NR4, -0-, and -CHN(R5)2; R3is selected from the group consisting of hydrogen atom, methyl, ethyl, and cyclopropyl; R4is selected from the group consisting of hydrogen atom, straight or branched C1-C4 alkyl, straight or branched C1-C4 alkyl substituted with one or two halogen atoms, cyclopropyl and methylcyclopropyl; R5represents C1-C2 alkyl; k is an integer equal 1 or 2; I is an integer equal 1 or 2; m is an integer equal 0, 1 or 2; n is an integer 0 or 1 when X represents -NR4"or -CHN(R5) 2, wherein n is 1 only when m is 1; and n is 0 when X represents -0-; and acid addition salts thereof, can be useful as selective inhibitors of 5HT6 in the treatment of CNS diseases.
Description
Isoindoline derivatives for the treatment of CNS diseases
Field of the invention
The invention relates to the field of chemical compounds, isoindoline derivatives, their use as a medicament and pharmaceutical compositions comprising said compounds. The compounds are selective inhibitors of serotonin 5- HT6 receptor and can be useful in the treatment of central nervous system (CNS) diseases, in particular in the treatment of neuropsychiatric disorders such as cognitive disorders and dementia of various origin.
Prior art
Receptor 5-HT6 is a subtype of 5-HT receptor, a receptor for endogenous neurotransmitter called 5-hydroxytryptamine or serotonin, a mediator of serotoninergic transmission. Receptor 5-HT6 is localized almost exclusively in the brain. It is engaged in such functions as cognitive functions, memory and emotions. Blockade of 5-HT6 receptor increases glutaminergic and cholinergic transmission in the brain and facilitates release of dopamine and norepinephrine in the prefrontal cortex.
Alzheimer’s disease is the most common cause of dementia in older adults that is characterized by progressive behavioral disorders/changes and by decline of memory function. Although some medicaments, i.e. reversible acetylcholinesterase inhibitors like donepezil, rivastigmine, tacrine and galantamine, were introduced in the clinic for the treatment of Alzheimer’s disease, in most patients benefits of their use are limited. Therefore there is still a need for new medicaments based on different mechanism of action, including inhibition of serotoninergic transmission via 5-HT6 receptor.
Recently, selective 5-HT6 inhibitors such as idalopirdine (2-(6-fluoro-1 H- indol-3-yl)-N-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)ethanamine) and interpidine (phenylsulphonyl-8-(piperazin-1 -yl)quinoline have been evaluated under clinical trials. Their use as agents that improve cognitive functions in dementia of various etiology, including dementia associated with Alzheimer’s disease, as well as in the treatment of schizophrenia has been tested.
New isoindoline derivatives useful as 5-HT6 receptor antagonists are disclosed in Chinese patent application CN2015-10489790.
In the search of multitarget medicaments affecting various receptors, including 5-HT6 receptor and simultaneously also dopamine D2/D3 and histamine receptors Elias et al. (Elias, 0. et al. , Bioorg. Med. Chem. Lett. 2016 Sep 1 ;26( 17):4211 -5) there are reported benzenesulphonyl-2-isoindoline derivatives. In these compounds benzene ring was unsubstituted.
There is a need to search for novel compounds, which display high selectivity in inhibition of 5-HT6 receptor in relation to other serotonin receptors, and low affinity for dopamine receptors, to avoid undesirable side effects.
Summary of the invention
The object of the invention are isoindoline derivatives, presented by the
Formula (I)
wherein
R1 represents hydrogen atom and R2 represents a moiety of the Formula G1
or R1 and R2 are connected with each other to form together with nitrogen atom to which they are attached a moiety of the Formula G2
G2
A is selected from the group consisting of:
- phenyl substituted with one or two substituents selected from the group consisting of halogen atoms, straight or branched C1 -C4 alkyl, C1 -C2-alkoxyl, CF3, CN, and -OCF3,
- naphthyl,
- quinolinyl,
- thienyl,
- thienyl substituted with halogen atom, and
- pyn'dyl;
X is selected from the group consisting of -NR4-, -0-, and -CHN(R5)2;
R3 is selected from the group consisting of hydrogen atom, methyl, ethyl, and cyclopropyl;
R4 is selected from the group consisting of hydrogen atom, straight or branched C1 - C4 alkyl, straight or branched C1 -C4 alkyl substituted with one or two halogen atoms, cyclopropyl, and methylcyclopropyl;
R5 represents C1 -C2 alkyl;
k is an integer equal 1 or 2;
l is an integer equal 1 or 2;
m is an integer equal 0, 1 or 2;
n is an integer 0 or 1 when X represents -NR4- or -CHN(R5)2, wherein n is 1 only when m is 1 , and
n is 0 when X represents -0-;
and acid addition salts thereof, in particular pharmaceutically acceptable salts.
The compounds of the invention exhibit the ability of selective inhibition of 5-HT6 receptors as well as metabolic stability and can find use as medicaments.
The invention provides also a pharmaceutical composition comprising the compound of the Formula (I) as defined above as an active ingredient.
The invention provides also a use of the compound of the Formula (I) as defined above in a method of treatment of cognitive diseases.
Detailed description of the invention
The term„halogen” as used herein to define the compound of the invention means fluorine, chlorine, bromine and iodine atoms.
Preferred halogen atoms are fluorine and chlorine.
The term“straight or branched C1 -C4 alkyl” includes methyl, ethyl, propyl, isopropyl, n-butyl, tert- butyl and sec-butyl groups.
The term “C1 -C2- alkoxy” includes methoxy (-OCH3) and ethoxy (-OC2H5) groups.
Due to the presence of amine groups the compounds of the invention can form acid addition salts.
Salts of the compounds of the Formula (I) of the invention comprise acid addition salts with inorganic and organic acids. Preferred are pharmaceutically acceptable salts. Inorganic and organic acids capable of forming pharmaceutically acceptable salts with the compounds possessing basic nitrogen atom are well
known in the art. Salts with inorganic acids include in particular hydrochlorides, hydrobromides, sulphates and phosphates. Salts with inorganic acids include in particular methanesulphonates, ethanesulphonates, toluenesulphonates, benzenesulphonates, naphthalenedisulphonates, acetates, propionates, lactates, tartrates, malates, citrates, fumarates, maleates and benzoates.
It should be understood that in the case when compound of the Formula (I) according to the invention comprises chiral center, such a compound may exist in the form of optical isomers and their mixtures. Such optical isomers and their mixtures at different ratios, including racemic mixtures, are encompassed by the invention. In particular, this relates to the compounds of the Formula (I) wherein R3 represents methyl.
The first variant of the compounds of the Formula (I) are those compounds, wherein R1 and R2 are linked with each other to form, together with nitrogen atom to which they are attached, a moiety of the Formula G2
G2
One subgroup of this variant are the compounds of the Formula (I) wherein X represents -NR4.
Advantageously, especially in terms of metabolic stability of the compounds, R4 represents hydrogen atom.
In particular, this subgroup includes the compounds of the Formula (I) wherein n is equal 0.
When n is equal 0, this means that methylene bridge connecting the opposite carbon atoms in the ring of moiety G2 is absent.
Preferred compounds in the above subgroups are those wherein m is equal 1.
Preferably, in the above subgroups R3 represents methyl and R4 represents hydrogen atom.
Also preferably, in the above subgroups R3 represents hydrogen atom and R4 represents hydrogen atom.
Also preferably, in the above subgroups R3 represents hydrogen atom and R4 represents straight or branched C1 -C4 alkyl, cyclopropyl or methylcyclopropyl.
Another specific subgroup of the compounds of the Formula (I) wherein X represents -NR4- and n is 0 are the compounds wherein m is 0 or 2, R3 represents hydrogen atom and R4 represents hydrogen atom.
Another specific subgroup of the compounds of the Formula (I) wherein X represents -NR4- are the compounds wherein n is 1 . When n equals 1 , this means that the molecule possesses methylene bridge connecting the opposite carbon atoms in the ring of moiety G2, and in such a case moiety G2 is a bicyclic one. Preferably, m equals 1 , R3 represents hydrogen atom and R4 represents hydrogen atom.
A second subgroup in this first variant are the compounds of the Formula (I) wherein X represents -O- and n is 0. Preferably, in this subgroup R3 represents hydrogen atom.
A third subgroup in this first variant are the compounds of the Formula (I) wherein X represents -CHN(R5)2. Preferably, in this subgroup R5 represents methyl.
Second variant of the compounds of the Formula (I) are those compounds wherein R1 represents hydrogen atom and R2 represents a moiety of the Formula G1
G1
One subgroup in this second variant are the compounds wherein k is equal 1 and l is equal 1 . In such a case the G1 moiety is azetidin-3-yl group.
Second subgroup in this second variant are the compounds wherein k is equal 1 and l is equal 2. In such a case the G1 moiety is pyrrolidin-3-yl group.
Third subgroup in this second variant are the compounds wherein k is equal 2 and l is equal 2. In such a case the G1 moiety is piperidin-4-yl group.
Preferably, in the compounds of the invention of the Formula (I) as defined above and in any one of the above variants and subgroups A represents phenyl substituted with one or two substituents selected from the group consisting of halogen atoms, straight or branched C1 -C4 alkyl, C-1 -C2-alkoxyl, CF3, CN, and
-OCF3.
Preferably, A represents phenyl substituted with one fluorine or one chlorine atom, fluorine and chlorine atoms, two fluorine atoms or two chlorine atoms.
Specific compounds of the Formula (I) of the invention include the compounds selected from the group consisting of the following:
2-(3-chlorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(2-fluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(3-fluorobenzenesulphonyl)-4-piperazin-1 -ylizoindoline,
2-(4-fluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(2, 3-difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(2,4-difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(2, 5-difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(2,6-difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(3,4-difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(3, 5-difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(3-chloro-2-fluorobenzenesulphonyl)-4-piperazin- 1 -ylisoindoline,
2-(3-fluoro-4-methoxybenzenesulphonyl)-4-piperazin- 1 -ylisoindoline,
2-(4-fluoro-3-methoxybenzenesulphonyl)-4-piperazin- 1 -ylisoindoline,
2-(3-methylbenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(3-trifluoromethylbenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(4-trifluoromethylbenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(4-tert-butylbenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
3-(4-piperazyn- 1 -yl-isoindolin-2-ylsulphonyl)benzonitrile,
2-(3-methoxybenzenesulphonyl)-4-piperazin- 1 -ylisoindoline,
2-(3,4-dimethoxybenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
4-piperazin-1 -yl-2-(3-trifluoromethoxybenzenesulphonyl)isoindoline,
2-(naphthtalene-1 -sulphonyl)-4-piperazin- 1 -ylisoindoline,
8-(quinoline-2-sulphonyl)-4-piperazin-1 -ylisoindoline,
4-piperazin-1 -yl-2-(thiophene-2-sulphonyl)isoindoline,
2-(5-chlorothiophene-2-sulphonyl)-4-piperazin-1 -ylisoindoline,
4-(3-methylpiperazin- 1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)isoindoline,
4-(3R-methyl-piperazin-1 -yl)-2-(3-trifluorometylbenzenesulphonyl)isoindoline,
4-(3S-methyl-piperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)isoindoline,
2-(3-fluorobenzenesulphonyl)-4-(3S-methylpiperazin- 1 -yl)isoindoline,
2-(3-chlorobenzenesulphonyl)-4-(4-methylpiperazin-1 -yl)isoindoline,
2-(3-fluorobenzenesulphonyl)-4-(4-methylpiperazin-1 -yl)isoindoline,
2-(3,4-difluorobenzenesulphonyl)-4-(4-methylpiperazin- 1 -yl)isoindoline, 2-(3-methoxybenzenesulphonyl)-4-(4-methylpiperazin-1 -yl)isoindoline,
4-(4-methylpiperazin- 1 -y)-2-(3-trifluoromethoxybenzenesulphonyl)isoindoline, 2-(3-methylbenzenesulphonyl)-4-(4-methylpiperazin- 1 -yl)isoindoline,
4-(4-methylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)isoindoline,
4-(4-methylpiperazin-1 -yl)-2-(naphthalene-1 -suphonyl)isoindoline,
4-(4-methylpiperazin-1 -yl)-2-(naphthalene-2-sphonyl)isoindoline,
4-(4-methylpiperazin-1 -yl)-2-(pyridin-3-suphonyl)isoindoline,
8-(quinoline-2-suphonyl)-4-(4-methylpiperazin-1 -yl)isoindoline,
4-(4-methylpiperazin-1 -yl)-2-(thiophene-2-sulphonyl)isoindoline,
4-(4-isopropylpiperazin-1 -yl)-2-(3-trifluoromethyobenzenesulphonyl)isoindoline,
4-(4-cyclopropylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline,
4-(4-cyclopropylmethylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline,
4-(4-tert-butylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)isoindoline,
4-(4-propylpiperazin-1 -yl)-2-(3 trifluoromethylbenzenesulphonyl)isoindoline,
4-[(4-(2,2-difluoroethyl)piperazin-1 -yl]-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline,
4-[1 ,4]diazepan-1 -yl-2-(3-fluorobenzenesulphonyl)isoindoline,
4-[1 ,4]diazepan-1 -yl-2-(3-trifluoromethylbenzenesulphonyl)isoindoline,
4-[1 ,4]diazepan-1 -yl-2-(3-methoxybenzenesulphonyl)isoindoline,
4-(2,5-diazabicyclo[2.2.1 ]hept-2-yl)-2-(3-fluorobenzenesulphonyl)isoindoline, 4-(2,5-diazabicyclo[2.2.1 ]hept-2-yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline,
[2-(3-fluorobenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3-ylamine,
[2-(3-trifluoromethylbenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3-ylamine,
[2-(3-methoxybenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3-ylamine,
[2-(3-fluorobenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3R-ylamine,
[2-(3-trifluoromethylbenzenesulphonyl)-isoindolino-4-yl]pyrrolidin-3R-ylamine,
[2-(3-fluorobenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3S-ylamine,
[2-(3-trifluoromethylbenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3S-ylamine, azetidin-3-yl-[2-(3-fluorobenzenesulphonyl)isoindolin-4-yl]amine,
azetidin-3-yl-[2-(3-methoxybenzenesulphonyl)isoindolin-4-yl]amine,
diethyl-{1 -[2-(3-fluorobenzenesulphonyl)isoindolin-4-yl]piperidin-4-yl}amine,
diethyl-{1 -[2-(3-methylbenzenesulphonyl)isoindolin-4-yl]piperidin-4-yl}amine,
{1 -[2-(3-fluorobenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3-yl}dimethylamine,
{1 -[2-(3-methoxybenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3-yl}dimethylamine,
2-(3-fluorobenzenesulphonyl)-4-morpholin-4-yloizoindoline,
2-(3-metylobenzenesulphonyl)-4-morfolin-4-yl-isoindoline,
2-(3-fluorobenzenesulphonyl)-4-[1 ,4]oxazepan-4-yl-isoindoline,
2-(3-methylbenzenesulphonyl)-4-[1 ,4]oxazepan-4-ylisoindoline,
[2-(2,4-difluorobenzenesulphonyl)-isoindolin-4-yl]piperidin-4-ylamine,
and pharmaceutically acceptable salts thereof, especially acid addition salts.
The compounds of the invention of the Formula (I) can be prepared starting from the compound of the Formula (II)
wherein R1 and R2 are as defined for the Formula (I), and wherein amine group in the moiety G1 or in the moiety G2 when X represents -NR4- and R4 represents hydrogen atom, is protected with amine protecting group,
by reaction of the compound of the Formula (II) with arylsulphonyl chloride A-SO2- Cl wherein A is as defined for the Formula (I),
and subsequently removal of amine protecting group.
Amine protecting group in the moiety G1 , or in the moiety G2, if present, can be benzyloxycarbonyl group (Cbz) or tert-butoxycarbonyl group (Boc).
Arylsulphonyl chlorides A-SO2-CI, wherein A is as defined for the Formula (I) are commercially available compounds.
The compound of the Formula (II) can be prepared from 4-bromoisoindoline that is commercially available known compound, by
- protecting nitrogen atom in 4-bromoisoindoline with protecting group to form protected 4-bromoisoindoline,
- reacting protected 4-bromoisoindoline with amine R1R2NH, wherein R1 and R2 have the meanings as defined for the Formula (I), and amine group in the moiety G1 or G2 (when X represents NR4- and R4 represents hydrogen atom) is protected with amine protecting group; and
- removing nitrogen protecting group in 4-bromoisoindoline without removal of protecting group from G1 or G2 moieties.
Nitrogen protecting group in 4-bromoisoindoline is different than optional protecting group in the amine R1R2NH, so as it could be selectively removed without removal of the latter. Thus, when protecting group in the amine R1R2NH is Boc group, nitrogen atom in 4-bromoisoindoline will be protected with Cbz protecting group, and when protecting group in the amine R1R2NH is Cbz group or is absent, nitrogen atom in 4-bromoisoindoline will be protected with Boc protecting group.
Reaction of the compound of the Formula (II) with arylsulphonyl chloride A-SO2-CI can be performed in an organic solvent, for example dichloromethane, in the presence of a tertiary amine for example trimethylamine, as a proton acceptor, at about 0°C. Reaction product can be purified by preparative column chromatography, and then amine protecting group, if present, can be removed. Removal of amine protecting Boc group is performed in a known manner in acidic medium, for example using HCl solution in alcohol, for example 4M HCl in methanol, or solution of trifluoroacetic acid in dichloromethane. Removal of amine protecting Cbz group can be performed in a known manner using hydrogen in the presence of Pd(C) in methanol. As a result of removal of Cbz protecting group in an acidic medium acid addition salt of the final compound of the invention is obtained, hydrochloride in the case of HCl in methanol. When there is no need to remove amine protecting group in the final compound of the invention, acid addition salt can be analogously obtained, for example hydrochloride can be obtained using HCl solution in methanol.
Protection of 4-bromoisoindoline can be performed by reaction with benzylochloroformate or tert-butoxycarbonyl anhydride, to form benzyl or tert- butyl ester of 4-bromoisoindoline-2-carboxylic acid, respectively, at about 0°C, in an organic solvent, for example dichloromethane, in the presence of tertiary amine, for example trimethylamine, as a proton acceptor.
Reaction of protected 4-bromoisoindoline (1 eq) with amine R1R2NH (2 eq) is performed using microwave-assisted Buchwald-Hartwig N-arylation method ((Pd2dba3 0.04 eq, BINAP 0.06 eq, NaOtBut 2 eq) in dioxane. Amine derivative thus obtained is purified using preparative column chromatography. In the subsequent step deprotection of Cbz group is performed by treatment with hydrogen in the presence of 10% Pd(C), in MeOH, or deprotection of Boc group is performed in the dichloromethane/trifluoroacetic acid mixture.
Amines R1R2NH are commercially available known compounds. When needed, protection of nitrogen atom in G1 and G2 moieties can be performed in a known manner.
Compounds of the Formula (I) of the invention can find use in the treatment of cognitive disorders, including memory and cognition disorders, in the treatment of dementia of various etiology, including dementia associated with Alzheimer’s disease, as well as in the treatment of cognitive dysfunction in schizophrenia.
In the treatment of diseases and disorders mentioned above the compounds of the formula (I) of the invention can be administered as a chemical compound, however usually will be used in the form of a pharmaceutical composition comprising the compound of the invention or its pharmaceutically acceptable salt in combination with pharmaceutically acceptable carrier(s) and auxiliary substance(s).
In the treatment of diseases and disorders mentioned above the pharmaceutical composition of the invention can be administered by any suitable route, preferably oral, parenteral or inhalation route and will be in the form of a preparation destined for use in medicine, depending on the intended administration route.
Compositions for oral administration can have the form of solid or liquid preparations. Solid preparations can have, for example, the form of a tablet or capsule produced in a conventional manner from pharmaceutically acceptable inactive excipients such as binders (for example, pregelatinised corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (for example lactose, saccharose, carboxymethylcellulose, microcrystalline cellulose or calcium hydrogenphosphate); disintegrants (for example crosspovidone, corn starch or sodium starch glycolate); lubricants (for example magnesium stearate, talc or silica), wetting agents (for example sodium laurylsulphate). Tablets can be coated with coatings well known in the art, such as simple coatings, delayed/controlled- release coatings or enteric coatings. Liquid preparations for oral administration can be in a form of, for example, solutions, syrups or suspensions, or can have the form of dry solid product for reconstitution in water or other suitable vehicle before use. Such liquid preparations can be prepared using conventional means from pharmaceutically acceptable inactive excipients, such as suspending agents (for example sorbitol syrup, cellulose derivatives or hydrogenated edible oils), emulsifiers (for example lecithine or acacia gum), nonaqueous vehicles (for example mandelic oil, oil esters, ethyl alcohol or fractionated vegetable oils), and preservatives (for example methyl or propyl p- hydroxy benzoate or sorbic acid). Preparations can also include suitable buffering agents, flavoring agents, coloring agents and sweeteners.
Preparations for oral administration can be formulated so as to obtain controlled release of the active compound using methods known for a person skilled in the art.
Parenteral route of administration includes administration by intramuscular and intravenous injections, as well as intravenous infusions. Compositions for parenteral administration can, for example, have the form of a unit dosage form, such as ampoules, or multi-dosage containers, with the addition of a preservative. Compositions can have the form such as suspension, solution or emulsion in an oily or aqueous vehicle, and can include excipients such as suspending agents, stabilizers, and/or dispersing agents. Alternatively, the active ingredient can be formulated as a powder for reconstitution before use in a suitable carrier, for example sterile, pyrogen-free water.
The method of treatment with the use of the compounds of the present invention will comprise administration of a therapeutically effective amount of the compound of the invention, preferably in the form of a pharmaceutical composition, to the subject in need of such treatment.
Proposed dosage of the compounds of the invention is from 0.1 to about 1000 mg per day, in a single dose or in divided doses. It will be apparent for a person skilled in the art that selection of a dosage required for obtaining desirable biological effect will depend on many factors, for example specific compound, the indication, the manner of administration, the age and condition of a patient and that exact dosage will be ultimately determined by a responsible physician.
Preparation of the compounds of the invention is illustrated in the Examples presented below. Syntheses presented in the Examples are not optimized in terms of yields, the amount of the reagents and final form of the compounds obtained.
The following abbreviations are used:
BINAP - 2,2'-bis(diphenylphosphino)-1 , T-binaphthyl
Boc- tert-butoxycarbonyl
DCM - dichloromethane
TEA - triethylamine
Preparation of intermediates
Intermediate 4-bromoisoindoline-2-carboxylic acid benzyl ester
4-Bromoisoindoline hydrochloride (3.0 g, 13 mmol, 1 eq) was suspended in dry DCM (50 ml), and then TEA (5.4 ml, 39 mmol, 3 eq) was added. Reaction mixture was cooled to 0°C in an ice-bath, and then benzyl chloroformate (2.7 ml, 19 mmol, 1 .5 eq) dissolved in 10 ml DCM was added dropwise. Reaction was carried out under inert gas (nitrogen) atmosphere while stirring at room temperature for 3h. Reaction mixture was extracted thrice with saturated NaHCC solution, then once with water and with saturated NaCl solution. Organic phase was dried over anhydrous Na2S04, and then concentrated under reduced pressure to obtain white solid which was dried under vacuum.
White solid, yield: 90% (3.8 g), Ci6Hi4BrN02, MW 332.19, monoisotopic mass 331 .02, [M+H]+ 332.2, UPLC Rt = 8.12. 1H NMR (300 MHz, CDCU) d (ppm) 4.73 (dd, J= 1 1 .6, 1 .4 Hz, 2H), 4.79-4.89 (m, 2H), 5.22 (d, J = 2.2 Hz, 2H), 7.09-7.50 (m, 7H).
Intermediate 2: 4-bromoisoindoline-2-carboxylic acid tert-butyl ester
The compound was obtained in analogous manner as Intermediate 1 , using Boc anhydride as acylating agent (4.1 g, 4.19 mmol, 1 .5 eq).
Creamy solid, yield: 94% (3.6 g), Ci3Hi6BrN02, MW 298.18, monoisotopic mass 297.04, [M+H]+ 298.1 , UPLC Rt = 8.07. 1H NMR (300 MHz, CDCb) d (ppm) 1 .44-1 .62 (m, 9H), 4.52-4.80 (m, 4H), 7.01 -7.62 (m, 3H).
Intermediate 3: 4-(4-tert-butoxycarbonylpiperazin-1 -yl)isoindoline-2-carboxylic acid benzyl ester
Intermediate 1 (500 mg, 1 .5 mmol, 1 eq), Pd2dba3 (55 mg, 0.06 mmol, 0.04 eq), BINAP (56 mg, 0.09 mmol, 0.06 eq), sodium tert-butanolate (202 mg, 2.1 mmol, 1 .4 eq) and Boc-piperazine (601 mg, 3.0 mmol, 2 eq) was suspended in 15 ml of dioxane under inert gas (nitrogen). The whole was stirred for 10 minutes at room temperature and the reaction was continued for further 1 .5 h at 130°C at microwave-assisted conditions. Subsequently, reaction mixture was filtered through Celite 545. Organic solvent was evaporated under reduced pressure to obtain brown oily residue. The compound was purified by preparative column chromatography (silicagel 60, particle size 0.063-0.200 mm, 70-230 mesh ASTM) in the DCM/MeOH (9/0.3; v/v) system.
Brown oil, yield: 62% (407 mg), C25H31N3O4, MW 437.53, monoisotopic mass 437.53, [M+H]+ 438.2, UPLC Rt = 8.80. 1H NMR (300 MHz, CDCb) d (ppm) 1 .48 (d, J = 1 .4 Hz, 9H), 2.92 (q, J= 4.6 Hz, 4H), 3.50-3.60 (m, 4H), 4.65-4.80 (m, 4H), 5.23 (d, J = 5.5 Hz, 2H), 6.81 -7.00 (m, 2H), 7.20-7.47 (m, 6H).
Intermediate 4: 4-(isoindolin-4-yl)-piperazine-1 -carboxylic acid tert-butyl ester
Previously obtained 4-(4-tert-butoxycarbonylpiperazin-1 -yl)isoindoline-2- carboxylic acid benzyl ester (Intermediate 3: 407 mg, 0,93 mmol) was dissolved in 20 ml MeOH. Under inert gas (nitrogen) atmosphere 80 mg 10% Pd(C) (ca. 20% on the mass of Intermediate 3) were added, and then nitrogen was replaced with hydrogen. Reaction was continued at room temperature while stirring for about 5 h. Reaction mixture was filtered through Celite 545. Organic solvent was evaporated under reduced pressure to obtain light-brown oil which was used for further reactions without purification.
Light-brown oil, yield: 98% (276 mg), C17H25N3O2, MW 303.40, monoisotopic mass 303.19, [M+H]+ 304.4, UPLC Rt = 4,73. 1H NMR (300 MHz, CDCb) d (ppm) 1 .47 (d,
Intermediate 5: 4-(4-tert-butoxycarbonyl-3-methylpiperazin-1 -yl)-isoindoline-2- carboxylic acid benzyl ester
Obtained in an analogous manner as Intermediate 3, using 1 -Boc-3- methylpiperazine (600 mg, 3.0 mmol, 2 eq) instead of Boc-piperazine.
Brown oil, yield: 70% (474 mg), C26H33N3O4, MW 451 .56, monoisotopic mass 451 .25, [M+H]+ 452.2, UPLC Rt = 9.19. 1H NMR (300 MHz, CDCb) d (ppm) 1 .45 (d, J = 6.6 Hz, 3H), 1 .49 (d, J = 1 .4 Hz, 9H), 2.85-3.01 (m, 1 H), 3.05-3.20 (m, 4H), 3.30-3.48 (m, 2H), 4.60-4.75 (m, 4H), 5.23-5.28 (m, 2H), 6.80-7.01 (m, 2H), 7.18-7.45 (m, 6H).
Intermediate 6: 4-(isoindolin-4-yl)-2-methyl-piperazine-1 -carboxylic acid tert-butyl ester
Obtained from Intermediate 5 in an analogous manner as Intermediate 4. Light-brown oil, yield: 99% (330 mg), C18H27N3O2, MW 317.43, monoisotopic mass 317.21 , [M+H]+ 318.2, UPLC Rt = 4.54. 1H NMR (300 MHz, CDCb) d (ppm) 1 .46 (d, J = 6.4 Hz, 3H), 2.80-2.95 (m, 1 H), 3.01 -3.17 (m, 4H), 3.28-3.46 (m, 2H), 4.62-4.75 (m, 4H), 7.10-7.39 (m, 3H).
Intermediate 7: 4-(4-tert-butoxycarbonyl-3S-methyl-piperazin-1 -yl)isoindoline-2- carboxylic acid benzyl ester
Obtained in an analogous manner as Intermediate 3, using 1 -Boc-3/?-methyl- piperazine (600 mg, 3.0 mmol, 2 eq) instead of Boc-piperazine.
Brown oil, yield: 65% (440 mg), C26H33N3O4, MW 451 .56, monoisotopic mass 451 .25, [M+H]+ 452.2, UPLC Rt = 9.17. 1H NMR (300 MHz, CDCb) d (ppm) 1 .44 (d, J = 6.4 Hz, 3H), 1 .48 (d, J=1 .3 Hz, 9H), 2.86-3.00 (m, 1 H), 3.04-3.18 (m, 4H), 3.31 -3.48 (m, 2H), 4.62-4.78 (m, 4H), 5.20-5.28 (m, 2H), 6.81 -7.03 (m, 2H), 7.15-7.44 (m, 6H). Intermediate 8: 4-(isoindolin-4-yl)-2S-methyl-piperazine-1 -carboxylic tert-acid butyl ester
Obtained from Intermediate 7 in an analogous manner as Intermediate 4. Light-brown oil, yield: 98% (303 mg), C18H27N3O2, MW 317.43, monoisotopic mass 317.21 , [M+H]+ 318.2, UPLC Rt = 4.53. 1H NMR (300 MHz, CDCb) d (ppm) 1 .45 (d,
J = 6.5 Hz, 3H), 2.81 -2.93 (m, 1 H), 3.03-3.18 (m, 4H), 3.30-3.46 (m, 2H), 4.65-4.76 (m, 4H), 7.1 1 -7.44 (m, 3H).
Intermediate 9: 4-(4-tert-butoxycarbonyl-3R-methyl-piperazin-1 -yl)isoindoline-2- carboxylic acid benzyl ester
Obtained in an analogous manner as Intermediate 3, replacing Boc- piperazine with 1 -Boc-3S-piperazine (600 mg, 3.0 mmol, 2 eq).
Orange oil, yield: 72% (488 mg), C26H33N3O4, MW 451 .56, monoisotopic mass 451 .25, [M+H]+ 452.2, UPLC Rt = 9.16.
Intermediate 10: 4-(isoindolin-4-yl)-2R-methyl-piperazine-1 -carboxylic acid tert- butyl ester
Obtained from Intermediate 9 in an analogous manner as Intermediate 4. Light-brown oil, yield: 95% (326 mg), C18H27N3O2, MW 317.43, monoisotopic mass 317.21 , [M+H]+ 318.2, UPLC Rt = 4.53. 1H NMR (300 MHz, CDCb) d (ppm) 1.45 (d,
J = 6.5 Hz, 3H), 2.81-2.93 (m, 1 H), 3.03-3.18 (m, 4H), 3.30-3.46 (m, 2H), 4.65-4.76
(m, 4H), 7.11-7.44 (m, 3H).
Intermediate 11 : 4-(4-tert-butoxycarbonyl-[1 ,4]diazepan-1 -yl)isoindoline-2- carboxylic acid benzyl ester
Obtained in an analogous manner as Intermediate 3, replacing Boc- piperazine with 1 -Boc-homopiperazine (600 mg, 3.0 mmol, 2 eq).
Orange oil, yield: 59% (400 mg), C26H33N3O4, MW 451.56, monoisotopic mass 451.25, [M+H]+ 452.2, UPLC Rt = 9.28.
Intermediate 12: 4-(isoindolin-4-yl)-[1 ,4]diazepan-1 -carboxylic acid tert-butyl ester
Obtained from Intermediate 11 in an analogous manner as Intermediate 4. Light-brown oil, yield: 98% (276 mg), C18H27N3O2, MW 317.43, monoisotopic mass 317.21 , [M+H]+ 318.2, UPLC Rt = 4.62.
Intermediate 13: 4-(5-tert-butoxycarbonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)- izoindoline-2-carboxylic acid benzyl ester
Obtained in an analogous manner as Intermediate 3, replacing Boc- piperazine with 2-Boc-2,5-diazabicyclo[2.2.1]heptane (595 mg, 3.0 mmol, 2 eq). Brown oil, yield: 64% (432 mg), C26H31N3O4, MW 449.54, monoisotopic mass 449.23, [M+H]+ 450.1 , UPLC Rt = 9.28.
Intermediate 14: 5-(isoindolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester
Obtained from Intermediate 13 in an analogous manner as Intermediate 4. Light-brown oil, yield: 97% (294 mg), C18H25N3O2, MW 315.41 , monoisotopic mass 315.19, [M+H]+ 316.2, UPLC Rt = 5.55.
Intermediate 15: 4-(1 -tert-butoxyazetidin-3-ylamino)isoindoline-2-carboxylic acid benzyl ester
Obtained in an analogous manner as Intermediate 3, replacing Boc- piperazine with 1 -Boc-3-(amino)azetidine (516 mg, 3.0 mmol, 2 eq).
Brown oil, yield: 49% (311 mg), C24H29N3O4, MW 423.50, monoisotopic mass 423.22, [M+H]+ 424.2, UPLC Rt = 8.53.
Intermediate 16: 3-(isoindolin-4-ylamino)azetidine-1 -carboxylic acid tert-butyl ester
Obtained from Intermediate 15 in an analogous manner as Intermediate 4. Light-brown oil, yield: 97% (206 mg), C16H23N3O2, MW 289.37, monoisotopic mass 289.18, [M+H]+ 289.2, UPLC Rt = 4.88.
Intermediate 17: 4-(1 -tert-butoxypyrrolidin-3-ylamino)isoindoline-2-carboxylic acid benzyl ester
Obtained in an analogous manner as Intermediate 3, replacing Boc- piperazine with 1 -Boc-3-(amino)pyrrolidine (559 mg, 3.0 mmol, 2 eq).
Brown oil, yield: 53% (348 mg), C25H31 N3O4, MW 437.53, monoisotopic mass 437.23, [M+H]+ 438.2, UPLC Rt = 8.89.
Intermediate 18: 3-(isoindolin-4-ylamino)-pyrrolidine-1 -carboxylic acid tert-butyl ester
Obtained from Intermediate 17 in an analogous manner as Intermediate 4. Light-brown oil, yield: 96% (232 mg), C17H25N3O2, MW 303.40, monoisotopic mass 303.19, [M+H]+ 304.2, UPLC Rt = 5.12.
Intermediate 19: 4-(1 -tert-butoxypyrrolidin-3R-ylamino)isoindoline-2-carboxylic acid benzyl ester
Obtained in an analogous manner as Intermediate 3, replacing Boc- piperazine with (R)-1 -Boc-3-aminopyrrolidine (559 mg, 3.0 mmol, 2 eq).
Brown oil, yield: 55% (361 mg), C25H31 N3O4, MW 437.53, monoisotopic mass 437.23, [M+H]+ 438.2, UPLC Rt = 8.91.
Obtained from Intermediate 19 in an analogous manner as Intermediate 4. Light-brown oil, yield: 98% (245 mg), C17H25N3O2, MW 303.40, monoisotopic mass 303.19, [M+H]+ 304.2, UPLC Rt = 5.15.
Intermediate 21 : 4-(1 -tert-butoxypyrrolidin-3S-ylamino)isoindoline-2-carboxylic acid benzyl ester
Obtained in an analogous manner as Intermediate 3, replacing Boc- piperazine with (S)-1 -Boc-3-aminopyrrolidine (559 mg, 3.0 mmol, 2 eq).
Brown oil, yield: 47% (308 mg), C25H31N3O4, MW 437.53, monoisotopic mass 437.23, [M+H]+ 438.2, UPLC Rt = 8.93.
Obtained in an analogous manner as Intermediate 4.
Light-brown oil, yield: 97% (207 mg), C17H25N3O2, MW 303.40, monoisotopic mass 303.19, [M+H]+ 304.2, UPLC Rt = 5.17.
Intermediate 23: 4-(1 -tert-butoxypiperidin-4-ylamino)isoindoline-2-carboxylic acid benzyl ester
Obtained in an analogous manner as Intermediate 3, replacing Boc-
piperazine with 4-amino- 1 -Boc-piperidine (600 mg, 3.0 mmol, 2 eq).
Brown oil, yield: 54% (366 mg), C26H33N3O4, MW 451.56, monoisotopic mass 451.25, [M+H]+ 452.2, UPLC Rt = 9.07.
Intermediate 24: 4-(isoindolin-4-ylamino)piperidine-1 -carboxylic acid tert-butyl ester
Obtained in an analogous manner as Intermediate 4.
Light-brown oil, yield: 99% (255 mg), C18H27N3O2, MW 317.43, monoisotopic mass 317.21 , [M+H]+ 318.2, UPLC Rt = 5.49.
Intermediate 25: 4-(4-methylpiperazin-1 -yl)isoindoline-2-carboxylic acid tert-butyl ester
Obtained in an analogous manner as Intermediate 3, using Intermediate 2 (450 mg, 1.5 mmol, 1eq) and 1 -methylpiperazine (300 mg, 3.0 mmol, 2 eq) as starting materials.
Clear oil, yield: 74% (352 mg), C18H27N3O2, MW 317,43 monoisotopic mass 317.21 , [M+H]+ 318.2, UPLC Rt = 5.50.
Intermediate 25 (352 mg, 1.12 mmol) was dissolved in DCM (5 ml) and TFA (1 ml) was added. The whole was stirred at room temperature for 1 h, then organic solvents were evaporated under reduced pressure to yield oily residue, which was used for further reactions without purification.
Light-brown oil, yield: 99% (239 mg), C13H 19N3, MW 217.31 , monoisotopic mass 217.16, [M+H]+ 218.2, UPLC Rt = 4.43.
Obtained in an analogous manner as Intermediate 3, using Intermediate 2 (450 mg, 1.5 mmol, 1eq) and 1 -isopropylpiperazine (385 mg, 3.0 mmol, 2 eq) as starting materials.
Clear oil, yield: 77% (400 mg), C20H31N3O2, MW 345.48 monoisotopic mass 345.24, [M+H]+ 345.2, UPLC Rt = 4.59.
Intermediate 28: 4-(4-lsopropylpiperazin-1 -yl)isoindoline
Obtained from Intermediate 27 in an analogous manner as Intermediate 26. Light-brown oil, yield: 97% (275 mg), C15H23N3, MW 245.36, monoisotopic mass 245.19, [M+H]+ 246.2, UPLC Rt = 3.60.
Intermediate 29: 4-(4-cyclopropylpiperazin-1 -yl)isoindoline-2-carboxylic acid tert- butyl ester
Obtained in an analogous manner as Intermediate 3, using Intermediate 2 (450 mg, 1.5 mmol, 1eq) and 1 -cyclopropylpiperazine (378 mg, 3.0 mmol, 2 eq) as starting materials.
Clear oil, yield: 69% (355 mg), C20H29N3O2, MW 343.46 monoisotopic mass 343.23, [M+H]+ 343.2, UPLC Rt = 4.91.
Intermediate 30: 4-(4-cyclopropylpiperazin-1 -yl)isoindoline
Obtained from Intermediate 29 in an analogous manner as Intermediate 26.
Light-brown oil, yield: 96% (241 mg), C15H21N3, MW 243.35, monoisotopic mass 243.17, [M+H]+ 244.2, UPLC Rt = 3.75.
Intermediate 31 : 4-(4-cyclopropylmethylpiperazin-1 -yl)isoindoline-2-carboxylic acid tert-butyl ester
Obtained in an analogous manner as Intermediate 3, using Intermediate 2 (450 mg, 1.5 mmol, 1eq) and 1 -cyclopropylmethylpiperazine (421 mg, 3.0 mmol, 2 eq) as starting materials.
Clear oil, yield: 65% (349 mg), C21H31N3O2, MW 357.49 monoisotopic mass 357.24, [M+H]+ 357.2, UPLC Rt = 4.84.
Intermediate 32: 4-(4-cyclopropylmethylpiperazin-1 -yl)isoindoline
Obtained from Intermediate 31 in an analogous manner as Intermediate 26. Light-brown oil, yield: 98% (246 mg), C16H23N3, MW 257.37, monoisotopic mass 257.19, [M+H]+ 258.3, UPLC Rt = 3.49.
Intermediate 33: 4-(4-tert-butylpiperazin-1 -yl)isoindoline-2-carboxylic acid tert- butyl ester
Obtained in an analogous manner as Intermediate 3, using Intermediate 2 (450 mg, 1.5 mmol, 1eq) and 1 -tert-butylpiperazine (423 mg, 3.0 mmol, 2 eq) as starting materials.
Clear oil, yield: 59% (318 mg), C21H33N3O2, MW 359.51 monoisotopic mass 359.26,
[M+H]+ 360.3, UPLC Rt = 4.70.
Obtained from Intermediate 33 in an analogous manner as Intermediate 26. Light-brown oil, yield: 97% (222 mg), C16H25N3, MW 259.39, monoisotopic mass 259.20, [M+H]+ 260.3, UPLC Rt = 3.25.
Intermediate 35: 4-[4-(2,2-difluoroethyl)piperazin-1 -yl]isoindoline-2-carboxylic acid tert-butyl ester
Obtained in an analogous manner as Intermediate 3, using Intermediate 2 (450 mg, 1.5 mmol, 1eq) and 1 -propylpiperazine (380 mg, 3.0 mmol, 2 eq) as starting materials.
Clear oil, yield: 61% (320 mg), C20H31N3O2, MW 345.48 monoisotopic mass 345.24.21 , [M+H]+ 346.3, UPLC Rt = 5.28.
Obtained from Intermediate 35 in an analogous manner as Intermediate 26. Light-brown oil, yield: 98% (240 mg), C14H19F2N3, MW 245.36, monoisotopic mass 245.19, [M+H]+ 246.2, UPLC Rt = 4.01.
Intermediate 37: 4-[4-(2,2-difluoroethyl)piperazin-1 -yl]isoindoline-2-carboxylic acid tert-butyl ester
Obtained in an analogous manner as Intermediate 3, using Intermediate 2 (450 mg, 1.5 mmol, 1eq) and 1 -(2,2-difluoroethyl)piperazine (450 mg, 3.0 mmol, 2 eq) as starting materials.
Clear oil, yield: 61% (336 mg), C19H27F2N3O2, MW 367.43 monoisotopic mass 367.21 , [M+H]+ 367.3, UPLC Rt = 5.25.
Obtained from Intermediate 37 in an analogous manner as Intermediate 26.
Light-brown oil, yield: 98% (240 mg), C14H19F2N3, MW 267.32, monoisotopic mass 267.15, [M+H]+ 267.2, UPLC Rt = 3.45.
Intermediate 39: 4-(4-diethylaminopiperidin-1 -yl)isoindoline-2-carboxylic acid tert- butyl ester
Obtained in an analogous manner as Intermediate 3, using Intermediate 2 (450 mg, 1.5 mmol, 1eq) and N,N-diethyl-4-piperidinamine (511 mg, 3.0 mmol, 2 eq) as starting materials.
Clear oil, yield: 64% (359 mg), C22H35N3O2, MW 373.53 monoisotopic mass 373.27, [M+H]+ 374.3, UPLC Rt = 4.71.
Intermediate 40: [1 -(isoindolin-4-yl)piperidin-4-yl]diethylamine
Obtained from Intermediate 39 in an analogous manner as Intermediate 26. Light-brown oil, yield: 98% (258 mg), C17H27N3, MW 273.42, monoisotopic mass 273.22, [M+H]+ 274.2, UPLC Rt = 3.68.
Intermediate 41 : 4-(3-dimethylaminopyrrolidin-1 -yl)isoindoline-2-carboxylic acid tert-butyl ester
Obtained in an analogous manner as Intermediate 3, using Intermediate 2 (450 mg, 1 .5 mmol, 1 eq) and N,N-dimethyl-3-pyrrolidinamine (342 mg, 3.0 mmol, 2 eq) as starting materials.
Clear oil, yield: 59% (293 mg), C19H29N3O2, MW 331 .45 monoisotopic mass 331 .23, [M+H]+ 332.3, UPLC Rt = 4.43.
Intermediate 42: [1 -(isoindolin-4-yl)pyrrolidin-3-yl]dimethylamine
Obtained from Intermediate 41 in an analogous manner as Intermediate 26. Light-brown oil, yield: 96% (196 mg), C14H21 N3, MW 231 .34, monoisotopic mass 231 .17, [M+H]+ 232.2, UPLC Rt = 3.24.
Intermediate 43: 4-morpholin-4-ylisoindoline-2-carboxylic acid tert-butyl ester
Obtained in an analogous manner as Intermediate 3, using Intermediate 2 (450 mg, 1 .5 mmol, 1 eq) and morpholine (300 mg, 3.0 mmol, 2 eq) as starting materials.
Clear oil, yield: 68% (350 mg), C17H24N2O3, MW 304.38 monoisotopic mass 304.18, [M+H]+ 3105.2, UPLC Rt = 5.03.
Obtained in an analogous manner as Intermediate 25.
Light-brown oil, yield: 98% (190 mg), C12H1 6N2O, MW 204.27, monoisotopic mass 204.13, [M+H]+ 205.2, UPLC Rt = 3.98.
Obtained in an analogous manner as Intermediate 3, using Intermediate 2 (450 mg, 1 .5 mmol, 1 eq) and homomorpholine (303 mg, 3.0 mmol, 2 eq) as starting materials.
Clear oil, yield: 67% (320 mg), C18H26N2O3, MW 318.41 monoisotopic mass 318.19, [M+H]+ 319.2, UPLC Rt = 5.25.
Obtained in an analogous manner as Intermediate 26.
Light-brown oil, yield: 98% (215 mg), C13H18N2O, MW 218.29, monoisotopic mass 218.14, [M+H]+ 218.2, UPLC Rt = 3.76.
General method for the preparation of the compounds of the invention
An amine (0.5 mmol, 1 eq) (selected from respective Intermediates) was dissolved in DCM (5 ml), and TEA (210 mΐ, 1 .5 mmol, 3 eq) was added. Then the mixture was cooled to 0°C, and suitable arylsulphonyl chloride (0.6 mmol, 1 .2 eq) was added in two portions while stirring for 4-5 h. After this time DCM was evaporated under reduced pressure and raw product was purified using preparative column chromatography (silicagel 60, particle size 0.063-0.200 mm, 70-230 mesh ASTM) in ethyl acetate/hexane system (3/7; v/v) for Boc derivatives or DCM/MeOH (9/0.5; v/v) for other amines. Deprotection of the tert-butoxycarbonyl (Boc) group (in case of Boc-derivatives) carried out using 1 .25M HCl in MeOH (complete conversion after ca. 5 h), yielded final compounds as water-soluble hydrochlorides. Other compounds that do not require removal of the tert-butoxycarbonyl (Boc) group from amine function were also converted into water-soluble hydrochlorides using 1 .25M HCl in MeOH.
Obtained from Intermediate 4 and 3-chlorobenzenesulfonyl chloride.
Boc derivative: clear oil, yield: 85% (203 mg), C23H28CIN3O4S, MW 478.00, monoisotopic mass 477.15, [M+H]+ 478.2, UPLC Rt = 8.84.
Hydrochloride: white solid, yield: 98% (172 mg), C18H21 CI2N3O2S, MW 413.35, monoisotopic mass 377.09 (C18H20CIN3O2S) [M+H]+ 378.1 , UPLC Rt = 4.72. 1H NMR (300 MHz, CDC ) d (ppm) 2.83- 2.91 (m, 4H), 3.51 -3.59 (m, 4H), 4.57-4.66 (m, 4H), 6.85 (dd, J = 12.3, 7.7 Hz, 2H), 7.21 (d, J = 8.0 Hz, 1 H), 7.42-7.58 (m, 2H), 7.75- 7.80 (m, 1 H), 7.88 (t, J = 1 .8 Hz, 1 H).
Example 2: 2-(2-Fluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline hydrochloride
Obtained from Intermediate 4 and 2-fluorobenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 87% (201 mg), C23H28FN3O4S, MW 461 .55, monoisotopic mass 461 .18, [M+H]+ 462.2, UPLC Rt = 8.31 .
Hydrochloride: white solid, yield: 99% (171 mg), C18H21 FCIN3O2S, MW 397.89, monoisotopic mass 361 .13 (C18H20FN3O2S ) [M+H]+ 362.1 , UPLC Rt = 4.20. 1H NMR (300 MHz, CDCb) d (ppm) 2.83-2.92 (m, 4H), 3.49-3.57 (m, 4H), 4.72 (s, 4H), 6.86 (dd, J = 13.2, 7.6 Hz, 2H), 7.12-7.33 (m, 3H), 7.51 -7.62 (m, 1 H), 7.92-8.02 (m, 1 H). Example 3: 2-(3-Fluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline hydrochloride
Obtained from Intermediate 4 and 3-fluorobenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 88% (203 mg), C23H28FN3O4S, MW 461 .55, monoisotopic mass 461.18, [M+H]+ 462.5, UPLC Rt = 8.42.
Hydrochloride: white solid, yield: 98% (172 mg), C18H21FCIN3O2S, MW 397.89, monoisotopic mass 361 .13 (C18H20FN3O2S) [M+H]+ 362.1 , UPLC Rt = 4.21 .
Example 4: 2-(4-Fluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline hydrochloride
Obtained from Intermediate 4 and 4-fluorobenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 80% (184 mg), C23H28FN3O4S, MW 461 .55, monoisotopic mass 461 .18, [M+H]+ 462.2, UPLC Rt = 8.39.
Hydrochloride: white solid, yield: 100% (159 mg), C18H21 FCIN3O2S, MW 397.89, monoisotopic mass 361 .13 (C18H20FN3O2S) [M+H]+ 362.1 , UPLC Rt = 4.21 . 1H NMR (300 MHz, CDCb) d (ppm) 2.82-2.90 (m, 4H), 3.49-3.58 (m, 4H), 4.54-4.66 (m, 4H), 6.84 (dd, J = 1 1 .3, 7.6 Hz, 2H), 7.1 1 -7.25 (m, 3H), 7.86-7.96 (m, 2H).
Example 5: 2-(2,3-Difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline
hydrochloride
Obtained from Intermediate 4 and 2,3-difluorobenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 90% (216 mg), C23H27F2N3O4S, MW 479.54, monoisotopic mass 479.17, [M+H]+ 480.4, UPLC Rt = 8.05.
Hydrochloride: white solid, yield: 100% (187 mg), C18H20CIF2N3O2S, MW 415.89, monoisotopic mass 379.12 (C18H19F2N3O2S) [M+H]+ 380.3, UPLC Rt = 4.39. 1H NMR (300 MHz, CDCb) d (ppm) 2.87 (t, J = 5.2 Hz, 4H), 3.53 (t, J = 5.5 Hz, 4H), 4.72 (s, 4H), 6.86 (dd, J = 1 1 .5, 7.6 Hz, 2H), 7.18-7.23 (m, 1 H), 7.24-7.27 (m, 1 H), 7.32- 7.43 (m, 1 H), 7.72 (ddt, J = 7.7, 5.7, 1 .6, 1 .6 Hz, 1 H). 13C NMR (75 MHz, CDCb) d (ppm) 52.5, 53.6, 79.9, 1 17.0, 1 17.1 , 1 17.2, 121 .9, 122.1 , 124.2, 124.3, 124.4, 125.7, 125.7, 129.3, 137.39, 148.15.
Example 6: 2-(2,4-Difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline
hydrochloride
Obtained from Intermediate 4 and 2,4-difluorobenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 93% (223 mg), C23H27F2N3O4S, MW 479.54, monoisotopic mass 479.17, [M+H]+ 480.2, UPLC Rt = 8.07.
Hydrochloride: white solid, yield: 100% (193 mg), C18H20CIF2N3O2S, MW 415.89, monoisotopic mass 379.12 (C18H19F2N3O2S) [M+H]+ 380.1 , UPLC Rt = 4.38. 1H NMR (300 MHz, CDCb) d (ppm) 2.86 (t, J = 5.1 Hz, 4H), 3.48-3.55 (m, 4H), 4.75 (s, 4H), 6.86-6.95 (m, 1 H), 6.96-7.03 (m, 1 H), 7.18-7.25 (m, 1 H), 7.30-7.38 (m, 1 H), 7.55- 7.65 (m, 1 H), 7.92-8.01 (m, 1 H).
Example 7: 2-(2,5-Difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline
hydrochloride
Obtained from Intermediate 4 and 2,5-difluorobenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 89% (213 mg), C23H27F2N3O4S, MW 479.54, monoisotopic mass 479.17, [M+H]+ 480.4, UPLC Rt = 8.46.
Hydrochloride: white solid, yield: 100% (185 mg), C18H20CIF2N3O2S, MW 415.89, monoisotopic mass 379.12 (C18H19F2N3O2S) [M+H]+ 380.1 , UPLC Rt = 4.44. 1H NMR (300 MHz, CDCb) d (ppm) 3.22-3.44 (m, 8H), 4.72 (d, J = 7.8 Hz, 4H), 6.97 (d,
J = 7.4 Hz, 2H), 7.12-7.34 (m, 3H), 7.67-7.71 (m, 1 H).
Example 8 2-(2,6-Difluorobenzenesulphonyl)-4-piperazin ylisoindoline
Obtained from Intermediate 4 and 2,6-difluorobenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 90% (216 mg), C23H27F2N3O4S, MW 479.54, monoisotopic mass 479.17, [M+H]+ 480.4, UPLC Rt = 7.81 .
Hydrochloride: white solid, yield: 100% (187 mg), C18H20CIF2N3O2S, MW 415.89, monoisotopic mass 379.12 (C18H 19F2N3O2S ) [M+H]+ 380.2, UPLC Rt = 4.15.
Example 9: 2-(3,4-Difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline
hydrochloride
Obtained from Intermediate 4 and 3,4-difluorobenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 90% (216 mg), C23H27F2N3O4S, MW 479.54, monoisotopic mass 479.17, [M+H]+ 480.4, UPLC Rt = 8.56.
Hydrochloride: white solid, yield: 100% (187 mg), C18H20CIF2N3O2S, MW 415.89, monoisotopic mass 379.12 (C18H19F2N3O2S) [M+H]+ 380.3, UPLC Rt = 4.56. 1H NMR (300 MHz, CDCb) d (ppm) 3.25-328 (m, 8H), 4.52 (s, 4H), 6.90-7.01 (m, 2H), 7.20 (t, J = 7.6 Hz, 1 H), 7.26-7.33 (m, 1 H), 7.59-7.73 (m, 2H). 13C NMR (75 MHz, CDCb) d (ppm) 43.4, 52.5, 53.7, 1 17.1 , 1 17.4, 1 18.3, 1 18.6, 1 19.23, 124.7, 129.5, 129.7, 133.3, 137.7.
Example 10: 2-(3,5-Difluorobenzenesulhonyl)-4-piperazin-1 -ylisoindoline
hydrochloride
Boc derivative: clear oil, yield: 80% (192 mg), C23H27F2N3O4S, MW 479.54, monoisotopic mass 479.17, [M+H]+ 480.3, UPLC Rt = 8.17.
Hydrochloride: white solid, yield: 100% (166 mg), C18H20CIF2N3O2S, MW 415.89, monoisotopic mass 379.12 (C18H19F2N3O2S) [M+H]+ 380.3, UPLC Rt = 4.52.
Example 1 1 : 2-(3-Chloro-2-fluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline hydrochloride
Obtained from Intermediate 4 and 3-chloro-2-fluorobenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 81% (201 mg), C23H27CIFN3O4S, MW 495.99, monoisotopic mass 495.14, [M+H]+ 496.3, UPLC Rt = 8.82.
Hydrochloride: white solid, yield: 100% (175 mg), C18H20CI2FN3O2S, MW 432.34, monoisotopic mass 395.08 (C18H19CIFN3O2S) [M+H]+ 396.3, UPLC Rt = 4.72. 1H NMR (300 MHz, CDC ) d (ppm) 3.18-3.41 (m, 8H), 4.64-4.75 (m, 4H), 6.95 (d, J = 7.3 Hz, 2H), 7.16-7.31 (m, 2H), 7.55-7.64 (m, 1 H), 7.79-7.89 (m, 1 H).
Example 12: 2-(3-Fluoro-4-methoxybenzenesulphonyl)-4-piperazin-1 -ylisoindoline hydrochloride
Obtained from Intermediate 4 and 3-fluoro-4-methoxybenzenesulphonyl chloride. Boc derivative: clear oil, yield: 75% (184 mg), C24H30FN3O4S, MW 491 .58, monoisotopic mass 491 .19, [M+H]+ 492.3, UPLC Rt = 7.84.
Hydrochloride: white solid, yield: 96% (154 mg), C19H23CIFN3O2S, MW 427.92, monoisotopic mass 391 .14 (C19H22FN3O2S) [M+H]+ 392.3, UPLC Rt = 4.33.
Example 13: 2-(4-Fluoro-3-methoxybenzenesulfonyl)-4-piperazin-1 -ylisoindoline hydrochloride
Obtained from Intermediate 4 and 4-fluoro-3-methoxybenzenesulphonyl chloride. Boc derivative: clear oil, yield: 78% (192 mg), C24H30FN3O4S, MW 491.58, monoisotopic mass 491.19, [M+H]+ 492.2, UPLC Rt = 7.97.
Hydrochloride: white solid, yield: 100% (167 mg), C19H23CIFN3O2S, MW 427.92, monoisotopic mass 391.14 (C19H22FN3O2S) [M+H]+ 392.3, UPLC Rt = 4.37.
Example 14: 2-(3-Methylbenzenesulphonyl)-4-piperazin-1 -ylisoindoline
hydrochloride
Obtained from Intermediate 4 and 3-methylbenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 72% (165 mg), C24H31 N3O4S, MW 457.59, monoisotopic mass 457.20, [M+H]+ 458.3, UPLC Rt = 7.96.
Hydrochloride: white solid, yield: 100% (142 mg), C19H24CIFN3O2S, MW 393.93, monoisotopic mass 357.15 (C19H23N3O2S) [M+H]+ 358.4, UPLC Rt = 4.48.
Example 15: 2-(3-Trifluoromethylbenzenesulphonyl)-4-piperazin-1 -ylisoindoline hydrochloride
Boc derivative: clear oil, yield: 82% (210 mg), C24H28F3N3O4S, MW 51 1 .56, monoisotopic mass 51 1 .18, [M+H]+ 512.4, UPLC Rt = 8.87.
Hydrochloride: white solid, yield: 100% (184 mg), C19H21 CIF3N3O2S, MW 447.90, monoisotopic mass 41 1.12 (C19H20F3N3O2S) [M+H]+ 412.3, UPLC Rt = 4.99. 1H NMR (300 MHz, CDC ) d (ppm) 2.85-2.94 (m. , 4H), 3.36-3.79 (m, 4H), 4.61 (s, 4H), 6.95- 7.21 (m, 3H), 7.82-7.88 (m, 1 H), 8.12-8.15 (m, 3H).
Example 16: 2-(4-Trifluoromethylbenzenesulphonyl)-4-piperazin-1 -ylisoindoline hydrochloride
Obtained from Intermediate 4 and 4-trifluoromethylbenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 77% (197 mg), C24H28F3N3O4S, MW 51 1 .56, monoisotopic mass 51 1 .18, [M+H]+ 512.4, UPLC Rt = 8.93.
Hydrochloride: white solid, yield: 97% (167 mg), C19H21 CIF3N3O2S, MW 447.90, monoisotopic mass 41 1 .12 (C19H20F3N3O2S ) [M+H]+ 412.3, UPLC Rt = 5.06.
Example 17: 2-(4-Tert-butylbenzenesulphonyl)-4-piperazin-1 -ylisoindoline hydrochloride
Obtained from Intermediate 4 and 4-tert-butylbenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 70% (175 mg), C27H37F3N3O4S, MW 499.67, monoisotopic mass 499.25, [M+H]+ 500.5, UPLC Rt = 9.53.
Hydrochloride: white solid, yield: 100% (152 mg), C22H30CIN3O2S, MW 436.01 , monoisotopic mass 399.19 (C22H29N3O2S) [M+H]+ 400.4, UPLC Rt = 5.51 . 1H NMR (300 MHz, CDCb) d (ppm) 1 .33 (s, 9H), 2.83-2.90 (m, 4H), 3.51 -3.58 (m, 4H), 4.59 (s,
4H), 6.83 (dd, J = 14.3, 7.3 Hz, 2H), 7.20 (t, J = 7.6 Hz, 1 H), 7.50-7.57 (m, 2H), 7.78-7.84 (m, 2H).
Example 18: 3-(4-Piperazin-1 -yl-isoindolin-2-ylsulphonyl)benzonitrile hydrochloride
Obtained from Intermediate 4 and 3-cyanobenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 72% (169 mg), C24H28N404S, MW 468.57, monoisotopic mass 468.18, [M+H]+ 468.2, UPLC Rt = 9.53.
Hydrochloride: white solid, yield: 100% (146 mg), C19H21 CIN402S, MW 404.91 , monoisotopic mass 368.13 (C19H20N4O2S) [M+H]+ 369.3, UPLC Rt = 5.17.
Example _ 19: 2-(3-Methoxybenzenesulhonyl)-4-piperazin-1 -ylisoindoline hydrochloride
Obtained from Intermediate 4 and 3-methoxybenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 75% (178 mg), C24H31 N3O5S, MW 473.59, monoisotopic mass 473.20, [M+H]+ 474.2, UPLC Rt = 8.35.
Hydrochloride: white solid, yield: 100% (154 mg), C19H24CIN3O3S, MW 409.93, monoisotopic mass 373.15 (C19H23N3O3S) [M+H]+ 374.4, UPLC Rt = 4.35.
Obtained from Intermediate 4 and 3,4-dimethoxybenzenesulphonyl chloride. Boc derivative: clear oil, yield: 69% (174 mg), C25H33N3O6S, MW 503.61 , monoisotopic mass 503.21 , [M+H]+ 504.4, UPLC Rt = 7.88.
Hydrochloride: white solid, yield: 100% (152 mg), C20H26CIN3O4S, MW 439.96, monoisotopic mass 403.16 (C20H25N3O4S) [M+H]+ 404.4, UPLC Rt = 3.94. 1H NMR (300 MHz, CDCb) d (ppm) 2.82-2.89 (m, 4H), 3.48-3.57 (m, 4H), 3.92 (d, J = 1 .1 Hz, 6H), 4.51 -4.65 (m, 4H), 6.83 (dd, J = 14.3, 7.9 Hz, 2H), 6.95 (d, J = 8.2 Hz, 1 H), 7.20 (t, J = 7.9 Hz, 1 H), 7.34 (d, J=2.3 Hz, 1 H), 7.48-7.54 (m, 1 H).
Example 21 : 4-Piperazin-1 -yl-2-(3-trifluoromethoxybenzenesulfonyl)isoindoline hydrochloride
Boc derivative: clear oil, yield: 71% (187 mg), C24H28F3N3O5S, MW 527.56, monoisotopic mass 527.17, [M+H]+ 528.4, UPLC Rt = 3.99.
Hydrochloride: white solid, yield: 97% (160 mg), C19H21 CIF3N3O3S, MW 463.90, monoisotopic mass 427.12 (C19H20F3N3O3S ) [M+H]+ 427.2, UPLC Rt = 4.90.
Example 22: 2-(Naphthalene-1 -sulphonyl)-4-piperazin-1 -ylisoindoline hydrochloride
Boc derivative: clear oil, yield: 65% (160 mg), C27H31 N3O4S, MW 493.62, monoisotopic mass 493.20, [M+H]+ 494.2, UPLC Rt = 9.07.
Hydrochloride: white solid, yield: 94% (131 mg), C22H24CIN3O2S, MW 429.96, monoisotopic mass 393.15 (C22H23N3O2S) [M+H]+ 394.3, UPLC Rt = 5.50. 1H NMR (300 MHz, CDCb) d (ppm) 2.77-2.93 (m, 4H), 3.44-3.58 (m, 4H), 4.71 (s, 4H), 6.83 (dd, J = 1 1 .4, 7.6 Hz, 2H), 7.16-7.24 (m, 1 H), 7.49-7.73 (m, 3H), 7.92 (dd, J = 8.3, 1 .0
Hz, 1 H), 8.07 (d, J = 8.2 Hz, 1 H), 8.25 (dd, J = 7.3, 1 .2 Hz, 1 H), 8.84-8.94 (m, 1 H).
Example 23 8-(Quinoline-2-sulphonyl)-4-piperazin ylisoindoline hydrochloride
Obtained from Intermediate 4 and quinolone-8-sulphonyl chloride.
Boc derivative: clear oil, yield: 60% (148 mg), C26H30N4O4S, MW 494.61 , monoisotopic mass 494.20, [M+H]+ 495.4, UPLC Rt = 8.03.
Hydrochloride: white solid, yield: 90% (1 16 mg), C21H23CIN4O2S, MW 430.95, monoisotopic mass 394.15 (C21H22N4O2S) [M+H]+ 395.4, UPLC Rt = 4.03.
Example 24: 4-Piperazin-1 -yl-2-(thiophene-2-sulphonyl)isoindoline hydrochloride
Obtained from Intermediate 4 and 2-thiophenesulphonyl chloride.
Boc derivative: clear oil, yield: 55% (124 mg), C21H27N3O4S2, MW 449.59, monoisotopic mass 449.14, [M+H]+ 450.1 , UPLC Rt = 9.06.
Hydrochloride: creamy solid, yield: 92% (98 mg), C16H20CIN3O2S2, MW 385.93, monoisotopic mass 349.09 (C26H19N3O2S2) [M+H]+ 350.1 , UPLC Rt = 4.02.
Obtained from Intermediate 4 and 5-chlorothiophenesulphonyl chloride.
Boc derivative: clear oil, yield: 58% (140 mg), C21H26CIN3O4S2, MW 484.03, monoisotopic mass 483.11 , [M+H]+ 484.0, UPLC Rt = 8.16.
Hydrochloride: creamy solid, yield: 90% (110 mg), C16H19CI2N3O2S2, MW 420.38, monoisotopic mass 383.05 (C16H18CIN3O2S2) [M+H]+ 384.0, UPLC Rt = 4.82.
Example 26: 4-(3-Methyl-piperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline hydrochloride
Obtained from Intermediate 6 and 3-trifluoromethylbenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 78% (205 mg), C25H30F3N3O4S, MW 525.58, monoisotopic mass 525.19, [M+H]+ 526.2, UPLC Rt = 9.18.
Hydrochloride: white solid, yield: 96% (173 mg), C20H23CIF3N3O2S, MW 461.93, monoisotopic mass 425.14 (C20H22F3N3O2S) [M+H]+ 426.1 , UPLC Rt = 5.16.
Example 27: 4-(3R-methyl-piperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline hydrochloride
Obtained from Intermediate 8 and 3-trifluoromethylbenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 80% (210 mg), C25H30F3N3O4S, MW 525.58, monoisotopic mass 525.19, [M+H]+ 526.1 , UPLC Rt = 9.19.
Hydrochloride: white solid, yield: 98% (181 mg), C20H23CIF3N3O2S, MW 461 .93, monoisotopic mass 425.14 (C20H22F3N3O2S) [M+H]+ 426.1 , UPLC Rt = 5.18. 1H NMR (300 MHz, CDCb) d (ppm) 2.17 (s, 1 H), 3.02 (d, J = 12.9 Hz, 1 H), 3.17 (d, J = 10.5 Hz, 3H), 3.22-3.37 (m, 2H), 3.48 (q, J = 7.0 Hz, 3H), 4.58 (s, 2H), 4.66 (s, 2H), 6.93 (t, J = 8.2 Hz, 2H), 7.28 (s, 1 H), 7.66-7.75 (m, 1 H), 7.85 (d, J = 7.6 Hz, 1 H), 8.09 (d, J = 8.2 Hz, 1 H), 8.14 (s, 1 H).
Example 28: 4-(3S-methyl-piperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline hydrochloride
Obtained from Intermediate 10 and 3-trifluoromethylbenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 82% (215 mg), C25H30F3N3O4S, MW 525.58, monoisotopic mass 525.19, [M+H]+ 526.1 , UPLC Rt = 9.17.
Hydrochloride: white solid, yield: 97% (184 mg), C20H23CIF3N3O2S, MW 461 .93, monoisotopic mass 425.14 (C20H22F3N3O2S) [M+H]+ 426.1 , UPLC Rt = 5.19.
Example 29: 4-(3S-methyl-piperazin-1 -yl)-2-(3-fluoromethylbenzenesulphonyl)- isoindoline hydrochloride
Obtained from Intermediate 10 and 3-fluorobenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 79% (188 mg), C24H30FN3O4S, MW 475.58, monoisotopic mass 475.19, [M+H]+ 476.2, UPLC Rt = 8.98.
Hydrochloride: white solid, yield: 99% (161 mg), C19H23CIFN3O2S, MW 41 1 .92, monoisotopic mass 375.15 (C19H22FN3O2S) [M+H]+ 376.1 , UPLC Rt = 4.74.
Example 30: 2-(3-Chlorobenzenesulphonyl)-4-(4-methylpiperazin-1 -yl)isoindoline hydrochloride
Obtained from Intermediate 26 and 3-chlorobenzenesulphonyl chloride.
Hydrochloride: white solid, yield: 80% (171 mg), C19H23CI2N3O2S, MW 428.38, monoisotopic mass 391.1 1 (C19H22CIN3O2S) [M+H]+ 392.4, UPLC Rt = 4.64. 1H NMR (300 MHz, CDCb) d (ppm) 2.37 (s, 3H), 2.54-2.61 (m, 4H), 2.94-3.00 (m, 4H), 4.60 (d, J = 2.0 Hz, 4H), 6.81 -6.87 (m, 2H), 7.17-7.24 (m, 1 H), 7.43-7.50 (m, 1 H), 7.51 - 7.55 (m, 1 H), 7.75-7.79 (m, 1 H), 7.88 (t, J = 1 .6 Hz, 1 H).
Example 31 : 2-(3-Fluorobenzenesulphonyl)-4-(4-methylpiperazin-1 -yl)isoindoline hydrochloride
Obtained from Intermediate 26 and 3-fluorobenzenesulphonyl chloride.
Hydrochloride: white solid, yield: 72% (148 mg), C19H23CIFN3O2S, MW 41 1 .92, monoisotopic mass 375.14 (C19H22FN3O2S) [M+H]+ 376.4, UPLC Rt = 4.43.
Example 32: 2-(3,4-Difluorobenzenesulphonyl)-4-(4-methylpiperazin-1 -yl)- isoindoline hydrochloride
Obtained from Intermediate 26 and 3,4-difluorobenzenesulphonyl chloride. Hydrochloride: white solid, yield: 70% (150 mg), C19H22CIF2N3O2S, MW 429.91 , monoisotopic mass 393.13 (C19H21F2N3O2S) [M+H]+ 394.4, UPLC Rt = 4.51. 1H NMR (300 MHz, CDCb) d (ppm) 2.37 (s, 3H), 2.52-2.62 (m, 4H), 2.92-3.02 (m, 4H), 4.59 (d, J = 3.3 Hz, 4H), 6.84 (dd, J = 7.5, 4.3 Hz, 2H), 7.21 (t, J = 7.8 Hz, 1 H), 7.29-
7.37 (m, 1 H) 7.63-7.77 (m, 2H).
Example 33: 4-(2-(3-methoxybenzenesulphonyl)-4-(4-methylpiperazin-1 -yl)- isoindoline hydrochloride
Obtained from Intermediate 26 and 3-methoxybenzenesulphonyl chloride. Hydrochloride: white solid, yield: 70% (135 mg), C20H26CIN3O3S, MW 423.96, monoisotopic mass 387.16 (C20H25N3O3S) [M+H]+ 388.3, UPLC Rt = 4.64.
Example 34: 4-(4-methylpiperazin-1 -yl)-2-(3-trifluoromethoxybenzenesulphonyl) isoindoline hydrochloride
Obtained from Intermediate 26 and 3-trifluoromethoxybenzenesulphonyl chloride. Hydrochloride: white solid, yield: 75% (160 mg), C20H23CIF3N3O3S, MW 477.93, monoisotopic mass 444.13 (C20H22F3N3O3S) [M+H]+ 442.4, UPLC Rt = 5.04.
Example 35: 2-(3-Methylbenzenesulphonyl)-4-(4-methylpiperazin-1 -yl)isoindoline hydrochloride
Obtained from Intermediate 26 and 3-methylbenzenesulphonyl chloride. Hydrochloride: white solid, yield: 74% (153 mg), C20H26CIN3O2S, MW 407.96, monoisotopic mass 371 .17. (C20H25N3O2S) [M+H]+ 372.4, UPLC Rt = 4.51 . 1H NMR (300 MHz, CDCb) d (ppm) 2.37 (s, 3H), 2.42 (s, 3H), 2.54-2.61 (m, 4H), 2.94-3.00 (m, 4H), 4.59 (s, 4H), 6.82 (d, J = 7.6 Hz, 2H), 7.19 (t, J = 7.6 Hz, 1 H), 7.35-7.43 (m,
2H), 7.66-7.72 (m, 2H).
Example 36: 4-(4-Methylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl- isoindoline hydrochloride
Obtained from Intermediate 26 and 3-trifluoromethylbenzenesulphonyl chloride. Hydrochloride: white solid, yield: 69% (159 mg), C20H23CIF3N3O2S, MW 461 .93, monoisotopic mass 425.14 (C20H22F3N3O2S) [M+H]+ 425.4, UPLC Rt = 4.91 . 1H NMR (300 MHz, CDCb) d (ppm) 2.38 (s, 3H), 2.54-2.63 (m, 4H), 2.91 -3.00 (m, 4H), 4.61 (d, J = 1 .5 Hz, 4H), 6.83 (d, J = 8.2 Hz, 2H), 7.20 (t, J = 7.6 Hz, 1 H), 7.64-7.71 (m,
1 H), 7.83 (d, J = 7.9 Hz, 1 H), 8.07 (d, J = 7.95 Hz, 1 H), 8.14 (s, 1 H).
Example 37: 4-(4-methylpiperazin-1 -yl)-2-(naphthtalene-1 -suphfonyl)isoindoline hydrochloride
Obtained from Intermediate 26 and naphthalene-1 -sulphonyl chloride.
Hydrochloride: white solid, yield: 68% (151 mg), C23H26CIN3O2S, MW 443.99, monoisotopic mass 407.17 (C23H24N3O2S) [M+H]+ 408.5, UPLC Rt = 4.96. 1H NMR (300 MHz, CDCb) d (ppm) 2.39 (s, 3H), 2.60 (br. s., 4H), 2.89 -3.07 (m, 4H), 4.70 (d, J = 7.18 Hz, 4H), 6.73-6.88 (m, 2H), 7.19 (t, J = 7.82 Hz, 1 H), 7.47-7.73 (m, 3H), 7.91 (d, J = 7.95 Hz, 1 H), 8.06 (d, J = 8.21 Hz, 1 H), 8.23 (d, J = 7.44 Hz, 1 H), 8.89 (d, J = 8.46 Hz, 1 H).
Example 38: 4-(4-Methylpiperazin-1 -yl)-2-(naphthalene-2-sulphonyl)isoindoline hydrochloride
Obtained from Intermediate 26 and naphthalene-2-sulphonyl chloride.
Hydrochloride: white solid, yield: 77% (171 mg), C23H26CIN3O2S, MW 443.99, monoisotopic mass 407.17 (C23H24N3O2S) [M+H]+ 408.4, UPLC Rt = 4.94. 1H NMR (300 MHz, CDCb) d (ppm) 2.37 (s, 3H), 2.53-2.62 (m, 4H), 2.90-2.99 (m, 4H), 4.65 (s, 4H), 6.76-6.83 (m, 2H), 7.1 1 -7.20 (m, 1 H), 7.59-7.67 (m, 2H), 7.85-7.91 (m, 2H), 7.94-8.02 (m, 2H), 8.46 (s, 1 H).
Example 39: 4-(4-Methylpiperazin-1 -yl)-2-(pyridine-3-sulphonyl)isoindoline hydrochloride
Obtained from Intermediate 26 and pyridine-3-sulphonyl chloride.
Hydrochloride: creamy solid, yield: 78% (154 mg), C18H23CIN4O2S, MW 394.92, monoisotopic mass 358.46 (C18H22N4O2S) [M+H]+ 359.4, UPLC Rt = 3.23. 1H NMR (300 MHz, CDCb) d (ppm) 2.12-2.48 (m, 3H), 2.72 (m, 4H), 3.01 (m, 4H), 4.61 (m, 4H), 6.84 (d, J = 6.9 Hz, 2H), 7.20 (m, 1 H), 7.47 (m, 1 H), 8.15 (d, J = 6.4 Hz, 1 H), 8.77 (m, 1 H), 9.09 (m, 1 H).
Obtained from Intermediate 26 and quinoline-8-sulphonyl chloride.
Hydrochloride: creamy solid, yield: 79% (176 mg), C22H25CIN4O2S, MW 444.98, monoisotopic mass 408.16 (C22H24N4O2S) [M+H]+ 409.4, UPLC Rt = 3.99. 1H NMR (300 MHz, CDCU) d (ppm) 2.36 (s, 3H), 2.52-2.62 (m, 4H), 2.94-3.03 (m, 4H), 4.96 (s, 2H), 5.05 (s, 2H), 6.79 (d, J = 7.9 Hz, 2H), 7.15 (t, J = 7.6 Hz, 1 H), 7.45 (dd, J = 8.3, 4.2 Hz, 1 H), 7.60-7.68 (m, 1 H), 8.01 (dd, J = 8.2, 1 .5 Hz, 1 H), 8.19 (dd, J = 8.4, 1 .8 Hz, 1 H), 8.56 (dd, J = 7.3, 1 .4 Hz, 1 H), 8.97 (dd, J = 4.3, 1 .8 Hz, 1 H). Example _ 41_: 4-(4-Methylpiperazin-1 -yl)-2-thiophenesulphonylisoindoline hydrochloride
Obtained from Intermediate 26 and thiophene-2-sulphonyl chloride.
Hydrochloride: creamy solid, yield: 70% (140 mg), C17H22CIN3O2S2, MW 399.96, monoisotopic mass 363.1 1 (C17H21N3O2S2) [M+H]+ 364.3, UPLC Rt = 4.01 . 1H NMR (300 MHz, CDCU) d (ppm) 2.37 (s, 3H), 2.53-2.63 (m, 4H), 2.93-3.03 (m, 4H), 4.62 (d, J = 2.0 Hz, 4H), 6.84 (d, J = 7.6 Hz, 2H), 7.13 (dd, J = 5.0, 3.7 Hz, 1 H), 7.21 (t, J = 7.8 Hz, 1 H), 7.58 (dd, J = 5.1 , 1 .2 Hz, 1 H), 7.65 (dd, J = 3.8, 1 .2 Hz, 1 H).
Example 42: 4-(4-lsopropylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline hydrochloride
Obtained from Intermediate 28 and 3-trifluoromethylbenzenesulphonyl chloride. Hydrochloride: white solid, yield: 79% (194 mg), C22H27CIF3N3O2S, MW 489.98, monoisotopic mass 453.17 (C22H26F3N3O2S) [M+H]+ 454.2, UPLC Rt = 5.90.
Example 43: 4-(4-Cyclopropylpiperazin-1 -yl)-2-(3-trifluoromethylbenzene- sulphonyl)isoindoline hydrochloride
Obtained from Intermediate 30 and 3-trifluoromethylbenzenesulphonyl chloride. Hydrochloride: white solid, yield: 84% (159 mg), C22H25CIF3N3O2S, MW 487.97, monoisotopic mass 451.15 (C22H24F3N3O2S) [M+H]+ 452.2, UPLC Rt = 5.99. 1H NMR (300 MHz, CDCb) d (ppm) 1 .13 (d, J = 6.5 Hz, 4H), 2.70 (d, J = 4.14 Hz, 4H), 2.71 - 2.74 (m, 1 H), 2.93-3.04 (m, 4H), 4.62 (s, 4H), 6.83 (dd, J = 7.7, 2.9 Hz, 2H), 7.20 (t, J = 7.7 Hz, 1 H), 7.62-7.72 (m, 1 H), 7.83 (d, J = 7.8 Hz, 1 H), 8.08 (d, J = 8.0 Hz, 1 H), 8.15 (s, 1 H).
Example 44: 4-(4-Cyclopropylmethylpiperazin-1 -yl)-2-(3-trifluoromethylbenzene- sulphonyl)isoindoline hydrochloride
Obtained from Intermediate 32 and 3-trifluoromethylbenzenesulphonyl chloride. Hydrochloride: white solid, yield: 86% (216 mg), C23H27CIF3N3O2S, MW 501 .99, monoisotopic mass 465.17 (C23H26F3N3O2S ) [M+H]+ 465.2, UPLC Rt = 6.1 1 .
Example 45: 4-(4-Tert-butylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline hydrochloride
Obtained from Intermediate 34 and 3-trifluoromethylbenzenesulphonyl chloride. Hydrochloride: white solid, yield: 81% (159 mg), C23H29CIF3N3O2S, MW 504.01 , monoisotopic mass 467.19 (C23H28F3N3O2S) [M+H]+ 468.3, UPLC Rt = 6.25.
Example 46: 4-(4-propylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline hydrochloride
Obtained from Intermediate 36 and 3-trifluoromethylbenzenesulphonyl chloride. Hydrochloride: white solid, yield: 75% (185 mg), C22H27CIF3N3O2S, MW 489.98, monoisotopic mass 453.17 (C22H26F3N3O2S) [M+H]+ 454.3, UPLC Rt = 5.40.
Example 47: 4-[(4-(2,2-Difluoroethyl)piperazin-1 -yl]-2-(3-trifluoromethylbenzene- sulphonyl)isoindoline hydrochloride
Obtained from Intermediate 36 and 3-trifluoromethylbenzenesulphonyl chloride. Hydrochloride: white solid, yield: 78% (159 mg), C21H23CIF5N3O2S, MW 511.94, monoisotopic mass 475.14 (C21H22F5N3O2S) [M+H]+ 476.3, UPLC Rt = 6.25.
Example 48: 4-[1 ,4]Diazepan-1 -yl-2(3-fluorobenzenesulphonyl)isoindoline
hydrochloride
Boc derivative: clear oil, yield: 77% (183 mg), C24H30FN3O4S, MW 475.58, monoisotopic mass 475.19, [M+H]+ 476.2, UPLC Rt = 8.98.
Hydrochloride: creamy solid, yield: 98% (155 mg), C19H23CIFN3O2S, MW 41 1 .92, monoisotopic mass 375.15 (C19H22FN3O2S) [M+H]+ 376.1 , UPLC Rt = 4.74.
Example 49: 4-[1 ,4]Diazepan-1 -yl-2(3-trifluoromethylbenzenesulphonyl)isoindoline hydrochloride
Obtained from Intermediate 12 and 3-trifluoromethylbenzenesulphonyl chloride. Boc derivative: clear oil, yield: 80% (210 mg), C25H30F3N3O4S, MW 525.58, monoisotopic mass 525.19, [M+H]+ 526.1 , UPLC Rt = 9.17.
Hydrochloride: white solid, yield: 95% (175 mg), C20H23CIF3N3O2S, MW 461 .93, monoisotopic mass 425.14 (C20H22F3N3O2S) [M+H]+ 426.1 , UPLC Rt = 5.19.
Example 50: 4-[1 ,4]Diazepan-1 -yl-2-(3-methoxybenzenesulphonyl)isoindoline hydrochloride
Obtained from Intermediate 12 and 3-methoxybenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 77% (188 mg), C25H33N3O5S, MW 487.61 , monoisotopic mass 487.21 , [M+H]+ 488.2, UPLC Rt = 9.17.
Hydrochloride: white solid, yield: 98% (160 mg), C20H26CIN3O3S, MW 423.14, monoisotopic mass 387.16 (C20H25N3O3S) [M+H]+ 388.2, UPLC Rt = 4.62. 1H NMR (300 MHz, CDCb) d (ppm) 3.23-3.31 (m, 8H), 3.52 (br. s. , 2H), 3.80 (s, 3H), 4.54 (s, 2H),
4.61 (s, 2H), 6.86 (d, J = 7.62 Hz, 1 H), 6.96 (d, J = 8.21 Hz, 1 H), 7.06 (dd, J = 5.86, 2.93 Hz, 1 H), 7.13-7.22 (m, 1 H), 7.32 (d, J = 1 .17 Hz, 1 H), 7.38-7.43 (m, 2H).
Example 51 : 4-(2,5-Diazabicyclo[2.2.1 ]hept-2-yl)-2-(3-fluorobenzenesulphonyl)- isoindoline hydrochloride
Obtained from Intermediate 14 and 3-fluoromethylbenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 75% (178 mg), C24H28FN3O4S, MW 473.56, monoisotopic mass 473.18, [M+H]+ 474.4, UPLC Rt = 9.17.
Hydrochloride: creamy solid, yield: 98% (161 mg), C19H21CIFN3O2S, MW 409.91 , monoisotopic mass 373.13 (C19H20FN3O2S) [M+H]+ 374.2, UPLC Rt = 4.25.
Example 52: 4-(2,5-Diazabicyclo[2.2.1 ]hept-2-yl)-2-(3-trifluorobenzene- sulphonyl)isoindoline hydrochloride
Obtained from Intermediate 14 and 3-trifluoromethylbenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 79% (207 mg), C25H28F3N3O4S, MW 523.57, monoisotopic mass 523.18, [M+H]+ 474.4, UPLC Rt = 9.17.
Hydrochloride: creamy solid, yield: 97% (161 mg), C20H21 CIF3N3O2S, MW 459.91 , monoisotopic mass 423.12.13 (C20H20F3N3O2S) [M+H]+ 424.2, UPLC Rt = 4.78.
Obtained from Intermediate 18 and 3-fluoromethylbenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 75% (170 mg), C23H28FN3O4S, MW 461 .55, monoisotopic mass 461 .18, [M+H]+ 462.2, UPLC Rt = 9.17.
Hydrochloride: white solid, yield: 98% (142 mg), C18H21CIFN3O2S, MW 397.89, monoisotopic mass 361 .13 (C18H20FN3O2S) [M+H]+ 362.2, UPLC Rt = 5.1 1 .
Example 54: [2-(3-Trifluoromethylbenzenesulphonyl)isoindolin-4-yl]oyrrolidin-3-yl- amine hydrochloride
Obtained from Intermediate 18 and 3-trifluoromethylbenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 77% (200 mg), C24H28F3N3O4S, MW 51 1 .56, monoisotopic mass 51 1 .18, [M+H]+ 512.2, UPLC Rt = 9.17.
Hydrochloride: white solid, yield: 100% (173 mg), C19H21CIF3N3O2S, MW 449.90, monoisotopic mass 41 1.12 (C19H20F3N3O2S) [M+H]+ 412.1 , UPLC Rt = 5.09. 1H NMR (300 MHz, CDCb) d (ppm) 3.28-3.45 (m, 2H), 3.60 (m, 4H), 4.37 (m, 1 H), 4.57 (s, 2H), 4.75 (m, 2H), 6.77-6.92 (m, 2H), 7.19 (t, J = 7.9 Hz, 1 H), 7.66 (t, J = 7.6 Hz, 1 H), 7.79 (d, J = 7.0 Hz, 1 H), 8.00-8.16 (m, 3H).
Example 55: [2-(3-Methoxybenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3-ylamine hydrochloride
Obtained from Intermediate 18 and 3-methoxybenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 78% (185 mg), C24H31 N3O5S, MW 473.59, monoisotopic mass 473.20, [M+H]+ 474.3, UPLC Rt = 9.17.
Hydrochloride: white solid, yield: 100% (160 mg), C19H24CIN3O3S, MW 409.93, monoisotopic mass 373.15 (C19H23N3O3S) [M+H]+ 374.2, UPLC Rt = 5.05.
Example 56: [2-(3-Fluorobenzenesulphonyl)isoindoline-4-yl]pyrrolidin-3R-ylamine hydrochloride
Obtained from Intermediate 18 and 3-fluoromethylbenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 73% (168 mg), C23H28FN3O4S, MW 461 .55, monoisotopic mass 461 .18, [M+H]+ 462.2, UPLC Rt = 9.17.
Hydrochloride: white solid, yield: 100% (145 mg), C18H21CIFN3O2S, MW 397.89, monoisotopic mass 361 .13 (C18H20FN3O2S) [M+H]+ 362.2, UPLC Rt = 5.1 1 .
Example 57: [2-(3-Trifluoromethylbenzenesulphonyl)isoindolin-4-yl]-pyrrolidin-3R- ylamine hydrochloride
Obtained from Intermediate 20 and 3-trifluoromethylbenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 81% (207 mg), C24H28F3N3O4S, MW 51 1 .56, monoisotopic mass 51 1 .18, [M+H]+ 512.2, UPLC Rt = 9.17.
Hydrochloride: white solid, yield: 100% (182 mg), C19H21CIF3N3O2S, MW 449.90, monoisotopic mass 41 1 .12 (C19H20F3N3O2S) [M+H]+ 412.1 , UPLC Rt = 5.09.
Example 58: [2-(3-Fluorobenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3S-ylamine hydrochloride
Obtained from Intermediate 22 and 3-fluorobenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 79% (182 mg), C23H28FN3O4S, MW 461 .55, monoisotopic mass 461 .18, [M+H]+ 462.2, UPLC Rt = 9.17.
Hydrochloride: white solid, yield: 100% (157 mg), C18H21CIFN3O2S, MW 397.89, monoisotopic mass 361 .13 (C18H20FN3O2S) [M+H]+ 362.2, UPLC Rt = 5.05.
Example 59: [2-(3-Trifluoromethylbenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3S- ylamine hydrochloride
Obtained from Intermediate 22 and 3-trifluoromethylbenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 83% (212 mg), C24H28F3N3O4S, MW 51 1 .56, monoisotopic mass 51 1 .18, [M+H]+ 512.2, UPLC Rt = 9.17.
Hydrochloride: white solid, yield: 100% (187 mg), C19H21CIF3N3O2S, MW 449.90, monoisotopic mass 41 1 .12 (C19H20F3N3O2S) [M+H]+ 412.1 , UPLC Rt = 5.09.
Example 60: Azetidin-3-yl-[2-(3-fluorobenzenesulphonyl)isoindolin-4-yl]amine hydrochloride
Obtained from Intermediate 16 and 3-fluorobenzenesulphonyl chloride.
Boc derivative: clear oil, yield: 85% (190 mg), C22H26FN3O4S, MW 447.52, monoisotopic mass 447.16, [M+H]+ 448.2, UPLC Rt = 8.77.
Hydrochloride: white solid, yield: 100% (163 mg), C17H19CIFN3O2S, MW 383.87, monoisotopic mass 347.1 1 (C17H18FN3O2S) [M+H]+ 348.2, UPLC Rt = 4.31 .
Example 61 : Azetidin-3-yl-[2-(3-methoxybenzenesulfonyl)isoindolin-4-yl]amine hydrochloride
Boc derivative: clear oil, yield: 80% (177 mg), C23H29N3O4S, MW 443.56, monoisotopic mass 443.19, [M+H]+460.2, UPLC Rt = 8.77.
Hydrochloride: creamy solid, yield: 98% (187 mg), C18H22CIN3O2S, MW 379.90, monoisotopic mass 343.14 (C18H21 N3O2S ) [M+H]+ 396.2, UPLC Rt = 4.76.
Example 62: Diethyl-{1 -[2-(3-fluorobenzenesulphonyl)isoindolin-4-yl]-piperidin-4- yl amine hydrochloride
Obtained from Intermediate 38 and 3-fluorobenzenesulphonyl chloride.
Hydrochloride: creamy solid, yield: 79% (185 mg), C23H31CIFN3O2S, MW 468.03, monoisotopic mass 431 .20 (C23H30FN3O2S) [M+H]+ 432.3, UPLC Rt = 4.77.
Example 63: Diethyl-{1 -[2-(3-methylbenzenesulphonyl)isoindolin-4-yl]piperidin-4- yl amine hydrochloride
Obtained from Intermediate 38 and 3-methylbenzenesulphonyl chloride. Hydrochloride: creamy solid, yield: 84% (195 mg), C24H34CIFN3O2S, MW 463.21 , monoisotopic mass 427.23 (C24H33N3O2S) [M+H]+ 427.6, UPLC Rt = 5.07. 1H NMR (300
MHz, CDCU) d (ppm) 1 .45 (t, J = 7.29 Hz, 6H), 1 .84-2.00 (m, 2H), 2.19 (d, J = 12.0 Hz, 2H), 2.43 (s, 3H), 2.67-2.79 (m, 2H), 3.16 (q, J = 7.0 Hz, 4H), 3.24-3.42 (m, 3H), 4.52-4.62 (m, 4H), 6.84 (dd, J = 18.1 , 7.6 Hz, 2H), 7.16-7.23 (m, 1 H), 7.35-
7.46 (m, 2H), 7.66-7.72 (m, 2H).
Example 64 {1 -[2-(3-Fluorobenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3-yl}- dimethylamine hydrochloride
Obtained from Intermediate 40 and 3-fluorobenzenesulphonyl chloride.
Hydrochloride: creamy solid, yield: 75% (160 mg), C20H25CIFN3O2S, MW 425.95, monoisotopic mass 389.16 (C20H24FN3O2S) [M+H]+ 390.2, UPLC Rt = 4.98.
Example 65: {1 -[2-(3-Methoxybenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3-yl}- dimethylamine hydrochloride
Obtained from Intermediate 40 and 3-methoxybenzenesulphonyl chloride. Hydrochloride: creamy solid, yield: 78% (171 mg), C21H28CIN3O3S, MW 437.98, monoisotopic mass 401.18 (C21H27N3O3S) [M+H]+ 402.2, UPLC Rt = 4.52. 1H NMR (300 MHz, CDCb) d (ppm) 1 .79-1 .93 (m, 2H), 2.31 (s, 6H), 2.74-2.84 (m, 1 H), 3.22-3.26 (m, 1 H), 3.38-3.46 (m, 3H), 3.84 (s, 3H), 4.57 (d, J = 5.86 Hz, 2H), 4.75 (s, 1 H), 4.85 (s, 1 H), 6.43 (d, J = 8.21 Hz, 1 H), 6.55 (d, J = 7.62 Hz, 1 H), 7.06-7.12 (m, 2H), 7.37 (br. s., 1 H), 7.41 -7.47 (m, 2H).
Example 66: 2-(3-Fluorobenzenesulphonyl)-4-morpholin-4-ylisoindoline
hydrochloride
Obtained from Intermediate 42 and 3-fluorobenzenesulphonyl chloride.
Hydrochloride: creamy solid, yield: 79% (157 mg), C18H20CIFN2O3S, MW 398.88, monoisotopic mass 362.1 1 (C18H19FN2O3S) [M+H]+ 363.1 , UPLC Rt = 6.90.
Example 67: 2-(3-Methylbenzenesulphonyl)-4-morpholine-4-ylisoindoline
hydrochloride
Hydrochloride: white solid, yield: 81% (158 mg), C19H23CIFN2O3S, MW 394.92, monoisotopic mass 358.14 (C19H22N2O3S) [M+H]+ 359.3, UPLC Rt = 7.1 1 . 1H NMR (300 MHz, CDCb) d (ppm) 2.42 (s, 3H), 2.90-2.94 (m, 4H), 3.80-3.84 (m, 4H), 4.59 (s, 4H), 6.83 (t, J = 8.3 Hz, 2H), 7.21 (t, J = 7.7 Hz, 1 H), 7.35-7.46 (m, 2H), 7.70 (d, J = 1 .2 Hz, 2H).
Example 68: 2-(3-Fluorobenzenesulphonyl)-4-[1 ,4]oxazepan-4-ylisoindoline hydrochloride
Hydrochloride: creamy solid, yield: 79% (175 mg), C19H22CIFN2O3S, MW 443.56, monoisotopic mass 376.13 (C19H21FN2O3S) [M+H]+ 376.2, UPLC Rt = 7.15. 1H NMR (300 MHz, CDCb) d (ppm) 1 .91 -2.05 (m, 2H), 3.28-3.38 (m, 4H), 3.76-3.87 (m, 4H), 4.56- 4.66 (m, 4H), 6.74 (dd, J = 13.0, 7.8 Hz, 2H), 7.1 1 -7.19 (m, 1 H), 7.23-7.32 (m, 1 H), 7.51 (td, J = 8.0, 5.2 Hz, 1 H), 7.56-7.63 (m, 1 H), 7.65-7.71 (m, 1 H). 19F NMR (282
MHz, CDCb) d ppm -109.47 (d, J = 5.1 Hz. ). 13C NMR (75 MHz, CDCb) d ppm 30.7, 51 .6, 53.6, 53.7, 55.3, 69.6, 70.6, 76.5, 1 14.5, 1 14.9, 1 16.2, 1 19.8, 120.1 , 123.17, 125.8, 129.1 , 131 .0, 137.6.
Obtained from Intermediate 44 and 3-methylbenzenesulphonyl chloride. Hydrochloride: creamy solid, yield: 85% (197 mg), C20H25CIN2O3S, MW 408.94, monoisotopic mass 372.15 (C20H24N2O3S) [M+H]+ 373.2, UPLC Rt = 7.33.
Example 70: [2-(2,4-Difluorobenzenesulphonyl)isoindolin-4-yl]piperidin-4-yl-amine hydrochloride
Obtained from Intermediate 24 and 2,4-difluorobenzenesulphonyl chloride. Boc derivative: clear oil, yield: 81% (200 mg), C24H29F2N3O4S, MW 493.57, monoisotopic mass 493.18, [M+H]+ 494.1 , UPLC Rt = 8.53.
Hydrochloride: creamy solid, yield: 100% (175 mg), C19H22CIF2N3O2S, MW 429.91 , monoisotopic mass 393.13 (C19H21 F2N3O2S ) [M+H]+ 394.1 , UPLC Rt = 4.65.
Procedure for determination of in vitro activity (affinity) of the compounds using specific radioligand displacement method.
Cell lines HEK293 with stable expression of human serotonin receptors 5-HT , 5-HTd, 5-HT7b and dopamine D2L receptors and CHO-K1 with receptor 5-HT2A expression:
Plasmids with genes encoding for human serotonin and dopamine receptors were purchased from UMR cDNA Resource Center (www.cdna.org), cell line HEK293 (Human Embryonic Kidney) was obtained from cell lines bank ATCC (American Type Culture Collection), and in all cases Lipofectamine 2000 (Invitrogen) was used as a transfecting agent. CHO-K1 cell line with stable expression of 5- HT2A receptor was provided by commercial source (PerkinElmer BioSignal).
HEK293 line was grown under standard culture conditions (37°C, 5% C02 saturation 95% humidity) in Dulbecco’s Modified Eagle’s Medium (DMEM), with high
glucose contents, enriched with 5% fetal bovine serum (FBS), and geneticin antibiotic at 500 pg/mL (G418; Sigma-Aldrich). CHO-K1 line was cultured with 5- HΪ2A receptor was performed in accordance with instructions of the provider.
For affinity measurements, cells were subcultured in 10 cm diameter Petri dishes and grown to 90% confluence. Cells were washed twice with phosphate buffer (PBS) and centrifuged (1000g) in PBS buffer containing 0.1 mM EDTA and 1 mM dithiothreitol. Subsequently, cell pellets were frozen and stored at -80°C. Procedure of the preparation of biological material for affinity measurements
Frozen pellets of HEK293 cells with stable expression of tested receptors were homogenized for 15 s (Polytron) in Tris-HCl buffer (50 mM, pH 7.7) with 0.1 mM EDTA, and subsequently centrifuged for 15 min/4°C/50 OOOg. Centrifuged material was suspended in supplemented Tris-HCl buffer at 0.5-0.7 mg protein/mL. Samples containing 1 mL of the suspension were frozen and stored at -80°C until used in the experiment.
In vitro activity studies, determination of affinity values
Tests were performed in a 96-well plate; total volume of a sample was 0.2 mL. Solutions and cell suspension were prepared in Tris-HCl buffer (50 mM, pH 7.7), containing: for 5-HTu receptors 50 mM Tris-HCl, 0.1 mM EDTA, 4 mM MgC , 10 mM pargiline and 0.1% ascorbic acid; for 5-HT6 receptor 50 mM Tris-HCl, 0.5 mM EDTA and 4 mM MgCl2; for 5-HTzb receptors 50 mM Tris-HCl, 4 mM MgC , 10 pM pargiline and 0.1% ascorbic acid; and for dopamine receptors D2L 50 mM Tris-HCl, 1 mM EDTA, 4 mM MgC , 120 mM NaCl, 5 mM KCl, 1.5 mM CaCl2 and 0.1% ascorbic acid. JANUS Automated Workstation-Expanded Platform (PerkinElmer) was used for plate pipetting. Tested compound was dissolved in DMSO to obtain stock solution at 1 mM. For experiments a range of 7-8 concentrations (10 11-104 M) in an appropriate buffer were used.
The following radioligands were used: for 5-HTu receptor [3H]-8-OH-DPAT (2.5 nM; specific activity 135.2 Ci/mmol); for 5-HT2A receptor [3H]-ketanserin (1 nM; specific activity 53.4 Ci/mmol); for 5-HT6 receptor [3H]-LSD (2 nM; specific activity 83.6 Ci/mmol); for 5-HTz receptor [3H]-5-CT (0.8 nM; specific activity 39.2 Ci/mmol) and for dopamine D2L receptor [3H]-raclopride (2.5 nM; specific activity 76.0 Ci/mmol).
Non-specific binding was defined with 10 mM of serotonin in 5-HTu and 5-HTz binding experiments, whereas chlorpromazine and methiothepine were used in 5- HT2AR and 5-HT6R assays, respectively. In the case of dopamine D2L receptors haloperidol at 10 mM concentration was used.
The established equilibrium state (1 h at room temperature for 5-HTu i 5- HT2A receptors; 1 h at 37°C for 5-HT6, 5-HTz and D2L receptors) was fixed by
filtration of protein fraction through Um'Filter GF/B plates and washed several times with cold Tris-HCl buffer (50 mM, pH 7.7) using harvester (Unifilter Harvester - PerkinElmer).
The level of radioactivity retained on the filters was measured with a MicroBeta TriLux counter (PerkinElmer) and was used for plotting displacement curve and determination of binding constant K\ calculated from Cheng-Prusoff equation (Cheng, Y.; Prusoff, W.H. Relationship between the inhibition constant (K1 ) and the concentration of inhibitor which causes 50 percent inhibition (IC50) of an enzymatic reaction. Biochem Pharmacol. 1973, 22, 3099):
wherein L is a radioligand concentration used in the experiment, and KD is its equilibrium (affinity) constant. IC50 is the concentration of a compound required for displacement of 50% of the radioligand from its binding sites. Results were means of at least three separate experiments.
All the procedures of K\ values determination were developed at the Department of Medicinal Chemistry, Institute of Pharmacology of the Polish Academy of Sciences and are described in the following publications:
Bojarski, A.J.; Cegta, M.T.; Charakchieva-Minol, S.; Mokrosz, M.J.; Mackowiak, M.; Misztal, S.; Mokrosz, J.L. Structure-activity relationship studies of CNS agents. Part 9: 5-HT1A and 5-HT2 receptor affinity of some 2- and 3-substituted1 ,2,3,4- tetrahydro-beta-carbolines. Pharmazie 1993, 48, 289-294.
Paluchowska, M.H.; Bugno, R.; Tatarczyhska, E.; Nikiforuk, A.; Lenda, T.; Chojnacka-Wojcik, E. The influence of modifications in imide fragment structure on 5-HT(1A) and 5-HT(7) receptor affinity and in vivo pharmacological properties of some new 1 -(m-trifluoromethylphenyl)piperazines. Bioorg. Med. Chem. 2007, 15, 7116.
Zajdel, P.; Marciniec, K.; Maslankiewicz, A.; Satata, G.; Duszyhska, B.; Bojarski, A. J.; Partyka, A.; Jastrz§bska-Wi§sek, M.; Wrobel, D.; Wesotowska, A.; Pawtowski, M. Quinoline- and isoquinoline-sulfonamide derivatives of LCAP as potent CNS multi-receptor-5-HT(1A)/5-HT(2A)/5-HT(7) and D(2)/D(3)/D(4)-agents: The synthesis and pharmacological evaluation Bioorg. Med. Chem. 2012, 20, 1545-1556. Zajdel P, Kurczab R, Grychowska K, Satata G, Pawtowski M, Bojarski AJ. The multiobjective based design, synthesis and evaluation of the arylsulfonamide/ amide derivatives of aryloxyethyl- and arylthioethyl- piperidines and pyrrolidines as a novel class of potent 5-HT7 receptor antagonists. Eur J Med Chem. 2012, 56, 348-60.
Procedure of studies of affinity towards human D3 and H3 receptors Radioisotopic method was used to determine the affinity of compounds for human dopamine receptor D3 (test in the presence of D3 receptor antagonist) and human histamine receptor H (test in the presence of H3 receptor agonist). Isolated membranes from CHO cells wherein desired receptor was stably overexpressed were incubated for 60 min at room temperature with tested compound at 1 mM concentration in the presence of labelled radioisotope ([3H]methylpiperine in the case of D3 receptor or [3H]Na-Me-Histamine in the case of H3 receptor). Non specific binding was estimated using non-specific ligand (+)butaclamol at 10 pM (D3 receptor) or (R)a-Me-histamine at 1 pM (H3 receptor). Affinity results were read using scintillation counter and calculated as a percent inhibition with respect to the affinity of control compound (Mackenzie, R.G. et al. (1994), Eur. J.. Pharmacol. ; Lovenberg, T.W. et al. (1999), Mol. Pharmacol. )
Results are presented in the following Table 1 which includes also data for comparative compounds.
Comparative Compound 1 : 2-Benzenesulphonyl-4-piperazin-1 -ylisoindoline hydrochloride
Comparative Compound 2: 2-Benzenesulfonyl-4-(4-methylpiperazin-1 -yl)isoindoline hydrochloride
Table 1 . Affinity of the compounds of the invention towards serotonine 5-HT6, 5- HT , 5-HT2A, 5-HT7, dopamine D2 and D3 as well as histamine H3 receptors.
In vitro studies of functional activity.
Assessment of modulation of the 5-HT6 activity: The ability of the compounds to inhibit 5-HT6 receptor activation by agonist (5-CT) stimulation was assessed in the measurement of accumulation of cyclic AMP using LANCE® Ultra cAMP Assay (PerkinElmer). Plasmid with gene encoding the human serotonin 5-HT6 receptor was purchased from UMR cDNA Resource Center (www.cdna.org), HEK293 (Human Embryonic Kidney) cell line was obtained from cell lines bank ATCC (American Type
Culture Collection), and Lipofectamine 2000 (Invitrogen) was used as a transfecting agent.
Cell suspension was transferred onto 384-well plates, in the amount of 1000 cells per well. Cell suspension (5 pi) was supplemented with a solution of tested compound at appropriate concentration (concentration in the range 10 11-104 M) and 5-CT agonist (100 nM) and incubated for 30 min at room temperature. Then, cyclic AMP was determined by LANCE® Ultra cAMP Assay (Perkin Elmer) in accordance with the manufacturer’s protocol.
Analysis of the results of 5-HT6 activity modulation:
All measurements were performed in duplicates and repeated in at least two or three independent experiments. Antagonistic properties of new compounds were analyzed using Prism 5.0 (GraphPad Software, San Diego, CA) software from the dose response curve and Kb calculated from the equation (Craig D.A. The Cheng- Prusoff relationship: something lost in the translation. Trends Pharmacol Sc/. 1993, 14, 89-91 ):
wherein: A - agonist concentration, IC50 - concentration of a ligand required for 50% inhibition of receptor response to reference compound, EC50 - concentration of an agonist that causes a half of maximum receptor response.
Results are presented in Table 2.
Table 2. Profile of functional activity of selected representative compounds towards 5-HT6 receptors.
Procedure for assessment of metabolic stability
Tested compound (1 mM) was incubated at 37°C with rat microsomes activated with NADPH (1.3 mM NADP, 3.3 mM G6P, 0.8 U/mL G6PDH andi 3.3 mM MgC ) at 0.5 mg/ml_. Samples of reaction mixture were collected at time intervals (0, 20, 40 and 60 min), and the reaction was stopped by precipitation of proteins with cooled in ice-bath ACNihhO 4:1 v/v solution containing internal standard. Samples were analyzed using LC MS/MS technique.
Reactions without NADPH activation were performed as negative controls. Verapamil and donepezil were used as positive controls of microsomal reactions.
The amount of a compound is given as a compound peak area/internal standard peak area (AUCNCE/AUCIS) ratio. Percentage of the compound after time t was calculated according to the formula:
Elimination rate constant k for a compound is equal to the module of the slope of the straight line a of the relationship of natural logarithm of percentage of the compound as a function of time:
k = \a\ [min c]
Half-life ti/2 for a compound is calculated according to the formula:
0.693
wherein volume of distribution Vd is:
Vinc G mΐ
ViT Lmg.
[ protein bound x
1000]
wherein Vinc is volume of intrinsic clearance Results of the test are presented in Table 3 below.
Table 3. Metabolic stability date for selected representative compounds
Claims
1 . A compound of the formula (I)
wherein
G1
or R1 and R2 are connected with each other to form with nitrogen atom to which they are attached a moiety of the formula G2
G2
A is selected from the group consisting of:
- phenyl substituted with one or two substituents selected from the group consisting of halogen atom, straight or branched C1 -C4 alkyl, C1 -C2 alkoxyl, CF3, CN, and -OCF3,
- naphthyl,
- quinolinyl,
- thienyl,
thienyl substituted with halogen atom,
and
- pyn'dyl;
X is selected from the group consisting of -NR4-, -0-, and -CHN(R5)2;
R3 is selected from the group consisting of hydrogen atom, methyl, ethyl, and cyclopropyl;
R4 is selected from the group consisting of hydrogen atom, straight or branched C1 - C4 alkyl, straight or branched C1 -C4 alkyl substituted with one or two halogen atoms, cyclopropyl and methylcyclopropyl;
R5 represents C1 -C2 alkyl;
k is an integer equal 1 or 2;
l is an integer equal 1 or 2;
m is an integer equal 0, 1 or 2;
n is an integer 0 or 1 when X represents -NR4- or -CHN(R5)2, wherein n is 1 only when m is 1 ;
and n is 0 when X represents -0-;
and acid addition salts thereof.
2. The compound according to claim 1 , wherein R1 and R2 are connected to form together with nitrogen atom to which they are attached a moiety of the formula G2.
3. The compound according to claim 2, wherein X represents -NHR4-.
4. The compound according to claim 3, wherein R4 represents hydrogen atom.
5. The compound according to claim 3, wherein R4 represents straight or branched C1 -C4 alkyl, cyclopropyl or methylcyclopropyl, especially methyl.
6. The compound according to claim 2, wherein n is 0.
7. The compound according to any one of claims 2 to 5, wherein n is 1 .
8. The compound according to any one of claims 2 to 5 or 7, wherein m is 1.
9. The compound according to any one of claims 2 to 7, wherein m is 2.
10. The compound according to any one of claims 2 to 7, wherein m is 0.
11. The compound according to any one of claims 2 to 10, wherein R3 represents methyl.
12. The compound according to any one of claims 2 to 10, wherein R3 represents hydrogen atom.
13. The compound according to claim 4, wherein m is 0 or 2, and R3 represents hydrogen atom.
14. The compound according to claim 4, wherein m is 1 , and R3 represents hydrogen atom.
15. The compound according to claim 2, wherein X represents -O- and n is 0.
16. The compound according to claim 15, wherein R3 represents hydrogen atom.
17. The compound according to claim 2, wherein X represents -CHN(R5)2.
18. The compound according to claim 17, wherein R5 represents methyl.
19. The compound according to claim 1 , wherein R1 represents hydrogen atom and R2 represents moiety of the formula G 1 .
20. The compound according to claim 19, wherein k is 1 and l is 1 , and moiety G1 is azetidin-3-yl.
21 . The compound according to claim 19, wherein k is 1 and l is 2, and moiety G1 is pyrrolidin-3-yl.
22. The compound according to claim 19, wherein k is 2 and l is 2, and moiety
G1 is piperidin-4-yl.
23. The compound according to any one of the preceding claims, wherein A represents phenyl substituted with one or two substituents selected from the group consisting of halogen atom, straight or branched C1 -C4 alkyl, C1 -C2 alkoxyl, CF3, CN, and -OCF3.
24. The compound according to claim 1 , selected form the group consisting of the following:
2-(3-chlorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(2-fluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(3-fluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(4-fluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(2, 3-difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(2,4-difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(2, 5-difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(2,6-difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(3,4-difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(3, 5-difluorobenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(3-chloro-2-fluorobenzenesulphonyl)-4-piperazin- 1 -ylisoindoline,
2-(3-fluoro-4-methoxybenzenesulphonyl)-4-piperazin- 1 -ylisoindoline,
2-(4-fluoro-3-methoxybenzenesulphonyl)-4-piperazin- 1 -ylisoindoline,
2-(3-methylbenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(3-trifluoromethylbenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(4-trifluoromethylbenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(4-tert-butylbenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
3-(4-piperazin-1 -ylisoindolin-2-ylsulphonyl)benzonitrile,
2-(3-methoxybenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(3,4-dimethoxybenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(3-trifluoromethoxybenzenesulphonyl)-4-piperazin-1 -ylisoindoline,
2-(naphthalene-1 -sulphonyl)-4-piperazin-1 -ylisoindoline,
8-(quinoline-2-sulphonyl)-4-piperazin-1 -ylisoindoline,
4-piperazin-1 -yl-2-(thiophene-2-sulphonyl)isoindoline,
2-(5-chlorothiophene-2-sulphonyl)-4-piperazin-1 -ylisoindoline,
4-(3-methylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)isoindoline,
4-(3R-methyl-piperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)isoindoline,
4-(3S-methyl-piperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)isoindoline,
2-(3-fluorobenzenesulphonyl)-4-(3S-methylpiperazin-1 -yl)isoindoline,
2-(3-chlorobenzenesulphonyl)-4-(4-methylpiperazin-1 -yl)isoindoline,
2-(3-fluorobenzenesulphonyl)-4-(4-methylpiperazin-1 -yl)isoindoline,
2-(3,4-difluorobenzenesulphonyl)-4-(4-methylpiperazin-1 -yl)isoindoline,
2-(3-methylbenzenesulphonyl)-4-(4-methylpiperazin-1 -yl)isoindoline,
4-(4-methylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)isoindoline,
4-(4-methylpiperazin-1 -yl)-2-(naphthalene-1 -sulphonyl )isoindoline,
4-(4-methylpiperazin-1 -yl)-2-(naphthalene-2-sulphonyl)isoindoline,
4-(4-methylpiperazin-1 -yl)-2-(pyridine-3-sulphonyl)isoindoline,
8-(quinoline-2-sulphonyl)-4-(4-methylpiperazin-1 -yl)isoindoline,
4-(4-methylpiperazin-1 -yl)-2-(thiophene-2-sulphonyl)isoindoline,
4-(4-isopropylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)isoindoline, 4-(4-cyclopropylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)isoindoline,
4-(4-cyclopropylmethylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline,
4-(4-tert-butylpiperazin-1 -yl)-2-(3-trifluoromethylbenzenesulphonyl)isoindoline,
4-[(4-(2,2-difluoroethyl)piperazin-1 -yl]-2-(3-trifluoromethylbenzenesulphonyl)- isoindoline,
4-[1 ,4]diazepan-1 -yl-2-(3-fluorobenzenesulphonyl)isoindoline,
4-[1 ,4]diazepan-1 -yl-2-(3-trifluoromethylbenzenesulphonyl)isoindoline, 4-[1 ,4]diazepan-1 -yl-2-(3-methoxybenzenesulphonyl)isoindoline,
4-(2,5-diazabicyclo[2.2.1 ]hept-2-yl)-2-(3-fluorobenzenesulphonyl)isoindoline,
4-(2,5-diazabicyclo[2.2.1 ]hept-2-yl)-2-(3-fluorobenzenesulphonyl)isoindoline,
4-(2,5-diazabicydo[2.2.1 ]hept-2-yl)-2-(3-trifluoromethylbenzenesulphonyl)isoindoline, [2-(3-fluorobenzenesulphonyl)-isoindolin-4-yl]pyrrolidin-3-ylamine,
[2-(3-trifluoromethylbenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3-ylamine,
[2-(3-methoxybenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3-ylamine,
[2-(3-fluorobenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3R-ylamine,
[2-(3-trifluoromethylbenzenesulphonyl)-isoindolin-4-yl]pyrrolidin-3R-ylamine,
[2-(3-fluorobenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3S-ylamine,
[2-(3-trifluoromethylbenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3S-ylamine, azetidin-3-yl-[2-(3-fluorobenzenesulphonyl)isoindolin-4-yl]amine,
azetidin-3-yl-[2-(3-methylbenzenesulphonyl)isoindolin-4-yl]amine,
diethyl-{1 -[2-(3-fluorobenzenesulphonyl)isoindolin-4-yl]piperidin-4-yl}amine, diethyl-{1 -[2-(3-methylbenzenesulphonyl)isoindolin-4-yl]piperidin-4-yl}amine,
{1 -[2-(3-fluorobenzenesulphonyl)isoindolin-4-yl]pyrrolidin-3-yl}dimethylamine,
{1 -[2-(3-methoxybenzenesulphonyl)isoindolin-4-yl]-pyrrolidin-3-yl}dimethylamine, 2-(3-fluorobenzenesulphonyl)-4-morpholin-4-ylisoindoline,
2-(3-methylbenzenesulphonyl)-4-morpholin-4-ylisoindoline,
2-(3-fluorobenzenesulphonyl)-4-[1 ,4]oxazepan-4-ylisoindoline,
2-(3-trifluorobenzenesulphonyl)-4-[1 ,4]oxazepan-4-ylisoindoline,
[2-(2,4-difluorobenzenesulphonyl)isoindolin-4-yl]piperidin-4-ylamine,
and acid addition salts thereof.
25. The compound as defined in any one of claims 1 to 24 for use as a medicament.
26. A pharmaceutical composition comprising the compound as defined in any one of claims 1 to 24 and pharmaceutically acceptable excipients.
27. Method for treating cognitive disorders which comprises administering to a subject in a need of such treatment an effective amount of the compound as defined in any one of claims 1 to 24 or a pharmaceutical composition comprising said compound.
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