HRP20210791T2 - 1-cijano-pirolidin spojevi kao usp30 inhibitori - Google Patents
1-cijano-pirolidin spojevi kao usp30 inhibitori Download PDFInfo
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- HRP20210791T2 HRP20210791T2 HRP20210791TT HRP20210791T HRP20210791T2 HR P20210791 T2 HRP20210791 T2 HR P20210791T2 HR P20210791T T HRP20210791T T HR P20210791TT HR P20210791 T HRP20210791 T HR P20210791T HR P20210791 T2 HRP20210791 T2 HR P20210791T2
- Authority
- HR
- Croatia
- Prior art keywords
- cyanopyrrolidin
- carboxamide
- methyl
- alkylene
- pyrazol
- Prior art date
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- 101150099494 Usp30 gene Proteins 0.000 title 1
- 239000003112 inhibitor Substances 0.000 title 1
- QJRYYOWARFCJQZ-UHFFFAOYSA-N pyrrolidine-1-carbonitrile Chemical class N#CN1CCCC1 QJRYYOWARFCJQZ-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 39
- -1 cyano, hydroxyl Chemical group 0.000 claims 37
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 30
- 125000000623 heterocyclic group Chemical group 0.000 claims 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims 18
- 125000003118 aryl group Chemical group 0.000 claims 15
- 125000001072 heteroaryl group Chemical group 0.000 claims 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 14
- 229910052731 fluorine Inorganic materials 0.000 claims 12
- 150000003839 salts Chemical class 0.000 claims 11
- 125000002950 monocyclic group Chemical group 0.000 claims 10
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 9
- 125000001153 fluoro group Chemical group F* 0.000 claims 9
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims 8
- 125000004043 oxo group Chemical group O=* 0.000 claims 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims 8
- 206010028980 Neoplasm Diseases 0.000 claims 7
- 125000002947 alkylene group Chemical group 0.000 claims 7
- 201000011510 cancer Diseases 0.000 claims 7
- 230000006735 deficit Effects 0.000 claims 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 7
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 6
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims 6
- 125000004450 alkenylene group Chemical group 0.000 claims 6
- 229910052736 halogen Inorganic materials 0.000 claims 6
- 125000001424 substituent group Chemical group 0.000 claims 6
- 150000002367 halogens Chemical class 0.000 claims 5
- 239000001257 hydrogen Substances 0.000 claims 5
- 229910052739 hydrogen Inorganic materials 0.000 claims 5
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 5
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims 4
- HCMJWOGOISXSDL-UHFFFAOYSA-N (2-isothiocyanato-1-phenylethyl)benzene Chemical compound C=1C=CC=CC=1C(CN=C=S)C1=CC=CC=C1 HCMJWOGOISXSDL-UHFFFAOYSA-N 0.000 claims 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 3
- 208000006136 Leigh Disease Diseases 0.000 claims 3
- 208000017507 Leigh syndrome Diseases 0.000 claims 3
- 208000008955 Mucolipidoses Diseases 0.000 claims 3
- 208000018737 Parkinson disease Diseases 0.000 claims 3
- 125000003368 amide group Chemical group 0.000 claims 3
- 125000002393 azetidinyl group Chemical group 0.000 claims 3
- 125000002619 bicyclic group Chemical group 0.000 claims 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 3
- 125000005843 halogen group Chemical group 0.000 claims 3
- 125000002883 imidazolyl group Chemical group 0.000 claims 3
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims 3
- 125000002757 morpholinyl group Chemical group 0.000 claims 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 3
- 125000004193 piperazinyl group Chemical group 0.000 claims 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims 3
- 125000004076 pyridyl group Chemical group 0.000 claims 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 3
- 208000011580 syndromic disease Diseases 0.000 claims 3
- 150000003573 thiols Chemical class 0.000 claims 3
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 claims 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 2
- 108010001058 Acyl-CoA Dehydrogenase Proteins 0.000 claims 2
- 102000002735 Acyl-CoA Dehydrogenase Human genes 0.000 claims 2
- 101000619542 Homo sapiens E3 ubiquitin-protein ligase parkin Proteins 0.000 claims 2
- 206010025323 Lymphomas Diseases 0.000 claims 2
- 206010058799 Mitochondrial encephalomyopathy Diseases 0.000 claims 2
- 201000002169 Mitochondrial myopathy Diseases 0.000 claims 2
- 208000001769 Multiple Acyl Coenzyme A Dehydrogenase Deficiency Diseases 0.000 claims 2
- 125000003545 alkoxy group Chemical group 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 2
- 229960004203 carnitine Drugs 0.000 claims 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 2
- 230000007812 deficiency Effects 0.000 claims 2
- 125000005045 dihydroisoquinolinyl group Chemical group C1(NC=CC2=CC=CC=C12)* 0.000 claims 2
- 208000035475 disorder Diseases 0.000 claims 2
- 239000011737 fluorine Substances 0.000 claims 2
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims 2
- 230000004065 mitochondrial dysfunction Effects 0.000 claims 2
- 230000035772 mutation Effects 0.000 claims 2
- 230000004770 neurodegeneration Effects 0.000 claims 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 2
- 102000045222 parkin Human genes 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims 2
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims 2
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims 2
- KYSZVTIOUUTKKL-OAHLLOKOSA-N (3R)-3-[2-oxo-3-(4-phenyl-1,3-thiazol-2-yl)-1,3-diazinan-1-yl]pyrrolidine-1-carbonitrile Chemical compound O=C1N(CCCN1C1=NC(=CS1)C1=CC=CC=C1)[C@@H]1CCN(C1)C#N KYSZVTIOUUTKKL-OAHLLOKOSA-N 0.000 claims 1
- ZXEHRZKEYJQAKZ-CQSZACIVSA-N (3R)-3-[2-oxo-3-(4-phenyl-1,3-thiazol-2-yl)imidazolidin-1-yl]pyrrolidine-1-carbonitrile Chemical compound O=C1N(CCN1C=1SC=C(N=1)C1=CC=CC=C1)[C@H]1CN(CC1)C#N ZXEHRZKEYJQAKZ-CQSZACIVSA-N 0.000 claims 1
- RAJVURXVMCCVHL-QGZVFWFLSA-N (3R)-3-[3-(3-morpholin-4-ylphenyl)-2-oxoimidazolidin-1-yl]pyrrolidine-1-carbonitrile Chemical compound O1CCN(CC1)C=1C=C(C=CC=1)N1C(N(CC1)[C@H]1CN(CC1)C#N)=O RAJVURXVMCCVHL-QGZVFWFLSA-N 0.000 claims 1
- NUXIWBUQKROULG-CJNGLKHVSA-N (3aR,6aR)-1-(1-phenylimidazole-4-carbonyl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carbonitrile Chemical compound C1(=CC=CC=C1)N1C=NC(=C1)C(=O)N1[C@@H]2[C@H](CC1)CN(C2)C#N NUXIWBUQKROULG-CJNGLKHVSA-N 0.000 claims 1
- DYMWDTUJPDRKIQ-HIFRSBDPSA-N (3aR,6aR)-1-(2,3-dihydroindole-1-carbonyl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carbonitrile Chemical compound N1(CCC2=CC=CC=C12)C(=O)N1[C@@H]2[C@H](CC1)CN(C2)C#N DYMWDTUJPDRKIQ-HIFRSBDPSA-N 0.000 claims 1
- KZDRRAFABXZMLL-PBHICJAKSA-N (3aR,6aR)-1-(3-chloro-4-morpholin-4-ylbenzoyl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carbonitrile Chemical compound ClC=1C=C(C(=O)N2[C@@H]3[C@H](CC2)CN(C3)C#N)C=CC=1N1CCOCC1 KZDRRAFABXZMLL-PBHICJAKSA-N 0.000 claims 1
- VDYFFYRCVQDLHN-CJNGLKHVSA-N (3aR,6aR)-1-(3-phenoxyazetidine-1-carbonyl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carbonitrile Chemical compound O(C1=CC=CC=C1)C1CN(C1)C(=O)N1[C@@H]2[C@H](CC1)CN(C2)C#N VDYFFYRCVQDLHN-CJNGLKHVSA-N 0.000 claims 1
- CMMRNABFYAATQI-HIFRSBDPSA-N (3aR,6aR)-1-(3-phenyl-1,2-oxazole-5-carbonyl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carbonitrile Chemical compound C1(=CC=CC=C1)C1=NOC(=C1)C(=O)N1[C@@H]2[C@H](CC1)CN(C2)C#N CMMRNABFYAATQI-HIFRSBDPSA-N 0.000 claims 1
- JHHSTONZRLHGMH-CJNGLKHVSA-N (3aR,6aR)-1-(3-phenyl-1H-pyrazole-5-carbonyl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carbonitrile Chemical compound C1(=CC=CC=C1)C1=NNC(=C1)C(=O)N1[C@@H]2[C@H](CC1)CN(C2)C#N JHHSTONZRLHGMH-CJNGLKHVSA-N 0.000 claims 1
- ZBZYXZNQWJSPLU-ZBFHGGJFSA-N (3aR,6aR)-1-(3-phenylazetidine-1-carbonyl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carbonitrile Chemical compound C1(=CC=CC=C1)C1CN(C1)C(=O)N1[C@@H]2[C@H](CC1)CN(C2)C#N ZBZYXZNQWJSPLU-ZBFHGGJFSA-N 0.000 claims 1
- PPHZJOGUKRXUKE-MOPGFXCFSA-N (3aR,6aR)-1-(3-phenylbenzoyl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carbonitrile Chemical compound C1(=CC(=CC=C1)C(=O)N1[C@@H]2[C@H](CC1)CN(C2)C#N)C1=CC=CC=C1 PPHZJOGUKRXUKE-MOPGFXCFSA-N 0.000 claims 1
- OUGVBBDEQQIAEA-QAPCUYQASA-N (3aR,6aR)-1-(4-fluoro-3-pyridin-4-ylbenzoyl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carbonitrile Chemical compound FC1=C(C=C(C(=O)N2[C@@H]3[C@H](CC2)CN(C3)C#N)C=C1)C1=CC=NC=C1 OUGVBBDEQQIAEA-QAPCUYQASA-N 0.000 claims 1
- LVLDVEIEEYCFQX-CJNGLKHVSA-N (3aR,6aR)-1-[3-(4-methoxyphenyl)-1,2-oxazole-5-carbonyl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carbonitrile Chemical compound COC1=CC=C(C=C1)C1=NOC(=C1)C(=O)N1[C@@H]2[C@H](CC1)CN(C2)C#N LVLDVEIEEYCFQX-CJNGLKHVSA-N 0.000 claims 1
- IHVYISFJPUVGPN-DYVFJYSZSA-N (3aR,6aR)-1-[3-(4-methoxyphenyl)-1H-pyrazole-5-carbonyl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carbonitrile Chemical compound COC1=CC=C(C=C1)C1=NNC(=C1)C(=O)N1[C@@H]2[C@H](CC1)CN(C2)C#N IHVYISFJPUVGPN-DYVFJYSZSA-N 0.000 claims 1
- QKSAQXTVNSAFHP-PBHICJAKSA-N (3aR,6aR)-1-[3-methoxy-4-(1-methylpyrazol-4-yl)benzoyl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carbonitrile Chemical compound COC=1C=C(C(=O)N2[C@@H]3[C@H](CC2)CN(C3)C#N)C=CC=1C=1C=NN(C=1)C QKSAQXTVNSAFHP-PBHICJAKSA-N 0.000 claims 1
- XISMVCGRSIDEMH-KDOFPFPSSA-N (3aR,6aR)-1-[4-(3-chloropyridin-4-yl)-3-methoxybenzoyl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carbonitrile Chemical compound ClC=1C=NC=CC=1C1=C(C=C(C(=O)N2[C@@H]3[C@H](CC2)CN(C3)C#N)C=C1)OC XISMVCGRSIDEMH-KDOFPFPSSA-N 0.000 claims 1
- KWDLHMCDAUEXPE-DYVFJYSZSA-N (3aR,6aR)-1-[4-fluoro-3-(1-methylpyrazol-4-yl)benzoyl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carbonitrile Chemical compound FC1=C(C=C(C(=O)N2[C@@H]3[C@H](CC2)CN(C3)C#N)C=C1)C=1C=NN(C=1)C KWDLHMCDAUEXPE-DYVFJYSZSA-N 0.000 claims 1
- XFIIBVSNYNKNHD-OTYXRUKQSA-N (3aR,6aR)-5-cyano-N-(4-cyano-2,5-difluorophenyl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-1-carboxamide Chemical compound FC1=CC(NC(=O)N2CC[C@@H]3CN(C[C@H]23)C#N)=C(F)C=C1C#N XFIIBVSNYNKNHD-OTYXRUKQSA-N 0.000 claims 1
- QLSFKZAGQZHUKY-RISCZKNCSA-N (3aR,6aR)-5-cyano-N-(4-cyano-2-fluorophenyl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-1-carboxamide Chemical compound FC1=C(NC(=O)N2CC[C@@H]3CN(C[C@H]23)C#N)C=CC(=C1)C#N QLSFKZAGQZHUKY-RISCZKNCSA-N 0.000 claims 1
- YPTROWCJXWUAJD-NEPJUHHUSA-N (3aR,6aR)-5-cyano-N-(5-methylpyridin-2-yl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-1-carboxamide Chemical compound CC1=CN=C(C=C1)NC(=O)N2CC[C@H]3[C@@H]2CN(C3)C#N YPTROWCJXWUAJD-NEPJUHHUSA-N 0.000 claims 1
- ORRROJOQVQBSPY-APWZRJJASA-N (3aR,6aR)-5-cyano-N-[2-fluoro-4-(2-methylpyridin-4-yl)phenyl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-1-carboxamide Chemical compound C(#N)N1C[C@@H]2N(CC[C@@H]2C1)C(=O)NC1=C(C=C(C=C1)C1=CC(=NC=C1)C)F ORRROJOQVQBSPY-APWZRJJASA-N 0.000 claims 1
- DDFGJQDAKCUHFI-RNCFNFMXSA-N (3aR,6aR)-5-cyano-N-[2-fluoro-4-(trifluoromethoxy)phenyl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-1-carboxamide Chemical compound FC1=C(NC(=O)N2CC[C@@H]3CN(C[C@H]23)C#N)C=CC(OC(F)(F)F)=C1 DDFGJQDAKCUHFI-RNCFNFMXSA-N 0.000 claims 1
- NKSQYNVJOYRSIC-RNCFNFMXSA-N (3aR,6aR)-5-cyano-N-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-1-carboxamide Chemical compound FC1=C(NC(=O)N2CC[C@@H]3CN(C[C@H]23)C#N)C=CC(=C1)C(F)(F)F NKSQYNVJOYRSIC-RNCFNFMXSA-N 0.000 claims 1
- RNGVIKCHXWALJA-RNCFNFMXSA-N (3aR,6aR)-5-cyano-N-[2-fluoro-5-(trifluoromethyl)phenyl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-1-carboxamide Chemical compound FC1=C(NC(=O)N2CC[C@@H]3CN(C[C@H]23)C#N)C=C(C=C1)C(F)(F)F RNGVIKCHXWALJA-RNCFNFMXSA-N 0.000 claims 1
- HYNKWSOOZFQERY-MJGOQNOKSA-N (3aR,6aR)-5-cyano-N-[3-(2-methylpyridin-4-yl)phenyl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-1-carboxamide Chemical compound CC1=NC=CC(=C1)C1=CC=CC(NC(=O)N2CC[C@@H]3CN(C[C@H]23)C#N)=C1 HYNKWSOOZFQERY-MJGOQNOKSA-N 0.000 claims 1
- SVUMILBXHLHUDA-MJGOQNOKSA-N (3aR,6aR)-5-cyano-N-[4-(2-methylpyridin-4-yl)phenyl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-1-carboxamide Chemical compound CC1=NC=CC(=C1)C1=CC=C(NC(=O)N2CC[C@@H]3CN(C[C@H]23)C#N)C=C1 SVUMILBXHLHUDA-MJGOQNOKSA-N 0.000 claims 1
- DOIDLBGKYGDVFZ-MFKMUULPSA-N (3aR,6aR)-5-cyano-N-[4-(trifluoromethyl)phenyl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-1-carboxamide Chemical compound FC(F)(F)C1=CC=C(NC(=O)N2CC[C@@H]3CN(C[C@H]23)C#N)C=C1 DOIDLBGKYGDVFZ-MFKMUULPSA-N 0.000 claims 1
- CYVRCSJGFVTEQR-SJORKVTESA-N (3aR,6aR)-5-cyano-N-[5-(2-methylpyridin-4-yl)pyridin-2-yl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-1-carboxamide Chemical compound CC1=NC=CC(=C1)C1=CC=C(NC(=O)N2CC[C@@H]3CN(C[C@H]23)C#N)N=C1 CYVRCSJGFVTEQR-SJORKVTESA-N 0.000 claims 1
- GHNFOWXDBIRISI-RNCFNFMXSA-N (3aR,6aR)-N-(5-chloro-2-fluorophenyl)-5-cyano-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-1-carboxamide Chemical compound FC1=C(NC(=O)N2CC[C@@H]3CN(C[C@H]23)C#N)C=C(Cl)C=C1 GHNFOWXDBIRISI-RNCFNFMXSA-N 0.000 claims 1
- MQCRFGXSNFOGHX-UHFFFAOYSA-N 1-(1-cyanopiperidin-3-yl)-3-(3-phenoxyphenyl)urea Chemical compound O=C(NC1CCCN(C1)C#N)NC1=CC(OC2=CC=CC=C2)=CC=C1 MQCRFGXSNFOGHX-UHFFFAOYSA-N 0.000 claims 1
- IEVPIDPBYIXIQS-UHFFFAOYSA-N 1-(1-cyanopyrrolidin-3-yl)-1-(2-methoxyethyl)-3-[4-(trifluoromethyl)phenyl]urea Chemical compound C(#N)N1CC(CC1)N(C(=O)NC1=CC=C(C=C1)C(F)(F)F)CCOC IEVPIDPBYIXIQS-UHFFFAOYSA-N 0.000 claims 1
- BVCHAZYUWHUTRV-UHFFFAOYSA-N 1-(1-cyanopyrrolidin-3-yl)-1-methyl-3-(3-phenoxyphenyl)urea Chemical compound C(#N)N1CC(CC1)N(C(=O)NC1=CC(=CC=C1)OC1=CC=CC=C1)C BVCHAZYUWHUTRV-UHFFFAOYSA-N 0.000 claims 1
- GWDQHNQUCHQQRO-UHFFFAOYSA-N 1-(1-cyanopyrrolidin-3-yl)-1-methyl-3-(4-phenylphenyl)urea Chemical compound C1(=CC=C(C=C1)NC(N(C)C1CN(CC1)C#N)=O)C1=CC=CC=C1 GWDQHNQUCHQQRO-UHFFFAOYSA-N 0.000 claims 1
- KWNPSLOQFQUTQM-UHFFFAOYSA-N 1-(1-cyanopyrrolidin-3-yl)-1-methyl-3-[4-(trifluoromethyl)phenyl]urea Chemical compound C(#N)N1CC(CC1)N(C(=O)NC1=CC=C(C=C1)C(F)(F)F)C KWNPSLOQFQUTQM-UHFFFAOYSA-N 0.000 claims 1
- XQEFAFBXFYSLKT-UHFFFAOYSA-N 1-(1-cyanopyrrolidin-3-yl)-3-(2,4-dichlorophenyl)-1-methylurea Chemical compound C(#N)N1CC(CC1)N(C(=O)NC1=C(C=C(C=C1)Cl)Cl)C XQEFAFBXFYSLKT-UHFFFAOYSA-N 0.000 claims 1
- PKXOQIGWZSOFLZ-UHFFFAOYSA-N 1-(1-cyanopyrrolidin-3-yl)-3-(2,4-dichlorophenyl)urea Chemical compound C(#N)N1CC(CC1)NC(=O)NC1=C(C=C(C=C1)Cl)Cl PKXOQIGWZSOFLZ-UHFFFAOYSA-N 0.000 claims 1
- IKMSDOIVAJZXOW-UHFFFAOYSA-N 1-(1-cyanopyrrolidin-3-yl)-3-(3-phenoxyphenyl)urea Chemical compound C(#N)N1CC(CC1)NC(=O)NC1=CC(=CC=C1)OC1=CC=CC=C1 IKMSDOIVAJZXOW-UHFFFAOYSA-N 0.000 claims 1
- KVJUCLCWNJFXJK-UHFFFAOYSA-N 1-(1-cyanopyrrolidin-3-yl)-3-(4-phenylphenyl)urea Chemical compound C1(=CC=C(C=C1)NC(=O)NC1CN(CC1)C#N)C1=CC=CC=C1 KVJUCLCWNJFXJK-UHFFFAOYSA-N 0.000 claims 1
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- NCQUDMJRPXRBPA-CYBMUJFWSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-3-(1-pyrazin-2-ylpyrazol-3-yl)azetidine-1-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)N1CC(C1)C1=NN(C=C1)C1=NC=CN=C1 NCQUDMJRPXRBPA-CYBMUJFWSA-N 0.000 claims 1
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- ISGLFFANKQXKOM-GFCCVEGCSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-3-(2-methylpyridin-4-yl)-1,2-oxazole-5-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)C1=CC(=NO1)C1=CC(=NC=C1)C ISGLFFANKQXKOM-GFCCVEGCSA-N 0.000 claims 1
- BFHJEVCILOORMW-MRXNPFEDSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-3-(2-phenylpyrimidin-4-yl)azetidine-1-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)N1CC(C1)C1=NC(=NC=C1)C1=CC=CC=C1 BFHJEVCILOORMW-MRXNPFEDSA-N 0.000 claims 1
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- DGEZWOPHEMOPTB-CQSZACIVSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-3-(3,4-dimethylphenyl)-1,2-oxazole-5-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)C1=CC(=NO1)C1=CC(=C(C=C1)C)C DGEZWOPHEMOPTB-CQSZACIVSA-N 0.000 claims 1
- ZIVSOTIVNKAORH-GFCCVEGCSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-3-(3-methoxyphenyl)-1,2-oxazole-5-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)C1=CC(=NO1)C1=CC(=CC=C1)OC ZIVSOTIVNKAORH-GFCCVEGCSA-N 0.000 claims 1
- DNVLSGQWQVJZKR-GFCCVEGCSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-3-(4-methoxyphenyl)-1,2-oxazole-5-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)C1=CC(=NO1)C1=CC=C(C=C1)OC DNVLSGQWQVJZKR-GFCCVEGCSA-N 0.000 claims 1
- HRRKEFUZNGSJAZ-CQSZACIVSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-3-(4-methoxyphenyl)azetidine-1-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)N1CC(C1)C1=CC=C(C=C1)OC HRRKEFUZNGSJAZ-CQSZACIVSA-N 0.000 claims 1
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- MGBGNRGIGOLJIE-GFCCVEGCSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-3-fluoro-4-(pyrimidin-2-ylamino)benzamide Chemical compound C(#N)N1C[C@@H](CC1)NC(C1=CC(=C(C=C1)NC1=NC=CC=N1)F)=O MGBGNRGIGOLJIE-GFCCVEGCSA-N 0.000 claims 1
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- SCWRPIOZZNFBHK-OAHLLOKOSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-3-fluoro-5-(1-methylpyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(C1=NC=C(C=C1F)C=1C=C2C(=NC=1)N(C=C2)C)=O SCWRPIOZZNFBHK-OAHLLOKOSA-N 0.000 claims 1
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- MUTOEPQXYPYQIO-CYBMUJFWSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-3-fluoro-6-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)C=1N=C2N(C=C(C=C2)C=2C=NN(C=2)C)C=1F MUTOEPQXYPYQIO-CYBMUJFWSA-N 0.000 claims 1
- FFBLJPPQYUNUEM-CQSZACIVSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-3-fluoro-N-methyl-4-(4-methylimidazol-1-yl)benzamide Chemical compound C(#N)N1C[C@@H](CC1)N(C(C1=CC(=C(C=C1)N1C=NC(=C1)C)F)=O)C FFBLJPPQYUNUEM-CQSZACIVSA-N 0.000 claims 1
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- ZAPPZFCYJDQNFP-GFCCVEGCSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-3-phenyl-1,2-oxazole-5-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)C1=CC(=NO1)C1=CC=CC=C1 ZAPPZFCYJDQNFP-GFCCVEGCSA-N 0.000 claims 1
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- KIKXBSPVKMTGPW-VNHYZAJKSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-3-fluorobenzamide Chemical compound C(#N)N1C[C@@H](CC1)NC(C1=CC(=C(C=C1)N1C[C@@H](O[C@@H](C1)C)C)F)=O KIKXBSPVKMTGPW-VNHYZAJKSA-N 0.000 claims 1
- MMXHCXOZTITRAO-UONOGXRCSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-4-[(3S)-3-ethylpyrrolidin-1-yl]-2-fluorobenzamide Chemical compound CC[C@H]1CCN(C1)C2=CC(=C(C=C2)C(=O)N[C@@H]3CCN(C3)C#N)F MMXHCXOZTITRAO-UONOGXRCSA-N 0.000 claims 1
- XSXTXDWCAMVUOX-GFCCVEGCSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-4-[(4-cyclopropylpyrimidin-2-yl)amino]-2,3-difluorobenzamide Chemical compound C(#N)N1C[C@@H](CC1)NC(C1=C(C(=C(C=C1)NC1=NC=CC(=N1)C1CC1)F)F)=O XSXTXDWCAMVUOX-GFCCVEGCSA-N 0.000 claims 1
- KIPIUXKKAQHKET-CQSZACIVSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-4-[(4-cyclopropylpyrimidin-2-yl)amino]-3-fluorobenzamide Chemical compound C(#N)N1C[C@@H](CC1)NC(C1=CC(=C(C=C1)NC1=NC=CC(=N1)C1CC1)F)=O KIPIUXKKAQHKET-CQSZACIVSA-N 0.000 claims 1
- VRHSERRLMSCTNY-GFCCVEGCSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-4-[methyl(2-methylpropanoyl)amino]pyridine-2-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(C1=NC=CC(=C1)N(C(C(C)C)=O)C)=O VRHSERRLMSCTNY-GFCCVEGCSA-N 0.000 claims 1
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- LDNIOCQCXSKBHU-OAHLLOKOSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-4-phenylpyridine-2-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(C1=NC=CC(=C1)C1=CC=CC=C1)=O LDNIOCQCXSKBHU-OAHLLOKOSA-N 0.000 claims 1
- NZDKORJPNQAFGO-CQSZACIVSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-4-pyrimidin-2-yl-2,3-dihydro-1,4-benzoxazine-7-carboxamide Chemical compound O=C(N[C@@H]1CCN(C1)C#N)C1=CC2=C(C=C1)N(CCO2)C1=NC=CC=N1 NZDKORJPNQAFGO-CQSZACIVSA-N 0.000 claims 1
- NBNOQFSROZEDEU-GFCCVEGCSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-5-(1,3-dimethylpyrazol-4-yl)-3-fluoropyridine-2-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(C1=NC=C(C=C1F)C=1C(=NN(C=1)C)C)=O NBNOQFSROZEDEU-GFCCVEGCSA-N 0.000 claims 1
- LFGKFGRTXYUMGM-CYBMUJFWSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-5-(1,3-dimethylpyrazol-4-yl)pyridine-2-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(C1=NC=C(C=C1)C=1C(=NN(C=1)C)C)=O LFGKFGRTXYUMGM-CYBMUJFWSA-N 0.000 claims 1
- ZBRSEYITNRTCDH-CQSZACIVSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-5-(1-ethylpyrazol-4-yl)-4-methylpyridine-2-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(C1=NC=C(C(=C1)C)C=1C=NN(C=1)CC)=O ZBRSEYITNRTCDH-CQSZACIVSA-N 0.000 claims 1
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- UMJNRKKTDHUXSS-OAHLLOKOSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-5-(1-methylpyrazol-4-yl)-1H-indole-2-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)C=1NC2=CC=C(C=C2C=1)C=1C=NN(C=1)C UMJNRKKTDHUXSS-OAHLLOKOSA-N 0.000 claims 1
- UKXYUWAVQXPACQ-CYBMUJFWSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-5-(1-methylpyrazol-4-yl)pyridine-2-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(C1=NC=C(C=C1)C=1C=NN(C=1)C)=O UKXYUWAVQXPACQ-CYBMUJFWSA-N 0.000 claims 1
- LCQRHTRMMYJKTN-GFCCVEGCSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-5-(1-methylpyrazol-4-yl)pyrimidine-2-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)C1=NC=C(C=N1)C=1C=NN(C=1)C LCQRHTRMMYJKTN-GFCCVEGCSA-N 0.000 claims 1
- GUPSFTJGPXXICE-OAHLLOKOSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-5-(4-fluorophenyl)pyridine-2-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(C1=NC=C(C=C1)C1=CC=C(C=C1)F)=O GUPSFTJGPXXICE-OAHLLOKOSA-N 0.000 claims 1
- FSPFJSXSVJVCOY-GFCCVEGCSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-5-[2-methyl-6-(trifluoromethyl)pyrimidin-4-yl]pyridine-2-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(C1=NC=C(C=C1)C1=NC(=NC(=C1)C(F)(F)F)C)=O FSPFJSXSVJVCOY-GFCCVEGCSA-N 0.000 claims 1
- YJNBVLPRGJAYOP-BZSJEYESSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-5-methyl-1-(1-phenylethyl)pyrazole-3-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)C1=NN(C(=C1)C)C(C)C1=CC=CC=C1 YJNBVLPRGJAYOP-BZSJEYESSA-N 0.000 claims 1
- AZFOKQFMOPFJSH-CQSZACIVSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-5-methyl-1-(pyridin-2-ylmethyl)pyrazole-3-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)C1=NN(C(=C1)C)CC1=NC=CC=C1 AZFOKQFMOPFJSH-CQSZACIVSA-N 0.000 claims 1
- PHNYTORUZVDISA-OAHLLOKOSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-5-phenylpyridine-2-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(C1=NC=C(C=C1)C1=CC=CC=C1)=O PHNYTORUZVDISA-OAHLLOKOSA-N 0.000 claims 1
- QEHDEJVTUAFCHT-CQSZACIVSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-5-phenylpyrimidine-2-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)C1=NC=C(C=N1)C1=CC=CC=C1 QEHDEJVTUAFCHT-CQSZACIVSA-N 0.000 claims 1
- FJAKNGKONIPPPQ-CYBMUJFWSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-5-pyridin-2-ylpyridine-2-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)C1=CC=C(C=N1)C1=NC=CC=C1 FJAKNGKONIPPPQ-CYBMUJFWSA-N 0.000 claims 1
- ZXSWQIGDJADBQU-LLVKDONJSA-N N-[(3R)-1-cyanopyrrolidin-3-yl]-5-pyridin-4-yl-1,2-oxazole-3-carboxamide Chemical compound C(#N)N1C[C@@H](CC1)NC(=O)C1=NOC(=C1)C1=CC=NC=C1 ZXSWQIGDJADBQU-LLVKDONJSA-N 0.000 claims 1
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- 208000033808 peripheral neuropathy Diseases 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 claims 1
- 208000020016 psychiatric disease Diseases 0.000 claims 1
- 230000001105 regulatory effect Effects 0.000 claims 1
- 201000000980 schizophrenia Diseases 0.000 claims 1
- 210000002784 stomach Anatomy 0.000 claims 1
- FCHKJPINELGUMC-ABAIWWIYSA-N tert-butyl (3aR,6aR)-1-[(4-chloro-2-fluorophenyl)carbamoyl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carboxylate Chemical compound ClC1=CC(=C(C=C1)NC(=O)N1[C@@H]2[C@H](CC1)CN(C2)C(=O)OC(C)(C)C)F FCHKJPINELGUMC-ABAIWWIYSA-N 0.000 claims 1
- 210000001550 testis Anatomy 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- 210000001519 tissue Anatomy 0.000 claims 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims 1
- 201000010866 very long chain acyl-CoA dehydrogenase deficiency Diseases 0.000 claims 1
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- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- 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
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Claims (26)
1. Spoj formule (II)
[image]
tautomer iste, ili farmaceutski prihvatljiva sol navedenog spoja ili tautomera, pri čemu:
m je 0 ili 1;
kad je m 1, Z je -C(R6)(R7)-;
R2 predstavlja atom vodika, opcionalno supstituiran C1-C6 alkil, ili C1-C6 alkoksi skupinu;
R3, R4 i R5 svaki zasebno predstavljaju atom vodika, opcionalno supstituiran C1-C3 alkil, ili C1-C3 alkoksi skupinu;
R1, R6, R7 i R8 svaki zasebno predstavljaju atom vodika, atom fluora, cijano, hidroksil, opcionalno supstituiran C1-C3 alkil, ili C1-C3 alkoksi skupinu;
R9 predstavlja atom vodika, atom fluora, cijano, hidroksil, C1-C6 alkil, C1-C3 alkoksi skupinu, ili 3 do 8-dijelni cikloalkil prsten, ili oblikuje heterociklički prsten s R10;
R10predstavlja atom vodika, opcionalno supstituiran C1-C6 alkil, ili oblikuje heterociklički prsten s R9, ili oblikuje monociklični prsten s R11;
Y predstavlja kovalentnu vezu, -(C0-C3)-alkilen-N(R11)-(C0-C3)-alkilen ili C1-C3 alkilen;
R11 predstavlja atom vodika, C1-C6 alkil, ili oblike monocikličnog prstena s R10;
R12predstavlja supstituirani monociklični, opcionalno supstituirani biciklični ili opcionalno supstituirani triciklični 3 do 14-dijelni heteroaril, heterociklil, ili cikloalkil prsten;
naznačen time što R12, kad supstituiran, je supstituiran s jednim ili više od -Q1-(R13)p, naznačen time što:
p je 0 ili 1;
Q1 predstavlja halogeni atom, cijano, okso, hidroksil, kovalentnu vezu, -C0-C3 alkilen-NR14-, -C0-C3 alkilen-NR14R15, -C0-C3 alkilen-CONR14-, -C0-C3 alkilen-NR14CO-, -C0-C3 alkilen-NR14SO2-, atom kisika, -C0-C3 alkilen-CO-, -C0-C3 alkilen-S(O)q-, -C0-C3 alkilen-SO2NR14, -C0-C3 alkilen-SO2NR14R15, -C1-C6 alkoksi, C1-C6 haloalkoksi, C1-C6 hidroksialkil, -C0-C3 alkilen-SO2R14, -C0-C3alkilen-NR14COR15, -C0-C3 alkilen-NR14CONR15R16, -C0-C3 alkilen-NR14SO2NR15R16, -C0-C3 alkilen-CONR14R15, -C0-C3 alkilen-CO2R14, -C0-C3 alkilen-NR14CO2R15, -C0-C3 alkilen-SO2NR14R15, -C0-C3 alkilen -C(O)R14 i -C0-C3 alkilen -NR14SO2R15, NO2, C1-C6 alkilen, -C2-C6 alkenilen, ili opcionalno supstituiranu -C1-C6 alkil skupinu;
q je 0, 1 ili 2;
R14, R15 i R16 svaki zasebno predstavljaju atom vodika, C1-C6 alkil, ili C1-C6 alkilen skupinu;
gdje je p 1, R13 predstavlja 4 do 10-dijelni heteroaril, heterociklil, aril, ili 3 do 8-dijelni cikloalkil prsten; pri čemu se R13 može opcionalno supstituirati s jednim ili više supstituenata odabranih od halogena, C1-C6 haloalkila, C1-C6 alkoksi, C1-C6 haloalkoksi, C1-C6 alkil, C2-C6 alkenil, C2-C6 alkinil, C1-C6 hidroksialkil, okso, cijano, -Q2-R17, -Q2-NR17CONR18R19, -Q2-NR17R18, -Q2-COR17, -Q2-NR17COR18, -Q2-NR17CO2R18, -Q2-SO2R17, Q2-CONR17R18, -Q2-CO2R17, -Q2-SO2NR17R18, -Q2-NR17SO2R18, heterociklila, cikloalkila, heteroarila, i arila; pri čemu navedeni heterociklil, cikloalkil, heteroaril i aril prsteni mogu opcionalno biti supstituirani s jednim ili više supstituenata, koji mogu biti isti ili različiti, odabrani od Cl, F, OMe, Me, COCH3, CONH2, NHC(O)CH(CH3)2, i CO2CH2CH3;
Q2 predstavlja kovalentnu vezu, atom kisika, -CO-, ili C1-C6 alkilen ili C2-C6 alkenilen skupinu;
R16, R17, R18 svaki zasebno predstavljaju vodik, C1-C6 alkil, heterociklil, heteroaril, aril, ili cikloalkil; i
pri čemu su opcionalni supstituenti alkila od R1, R2, R3 , R4, R5, R6 R7, R8, R10 i Q1, koji mogu biti isti ili različiti, odabrani od C1-C3 alkoksi, halogena, hidroksila, tiola, cijano, amino, amido, nitro i SF5.
2. Spoj u skladu sa zahtjevom 1, naznačen time što su heteroaril, heterociklil, ili cikloalkil prsten iz R12 odabrani iz skupine koja sadrži pirolidinil, tiazolil, piridinil, dihidropiridinil, izoksazolil, oksazolil, imidazolil, pirazolil, piridazinil, pirimidinil, indolil, benzimidazolil, kvinolinil, azetidinil, indazolil, pirazolopiridinil, imidazopiridinil, indolinil, piperazinil, morfolinil, diazepanil, tetrahidro-2H-pirido[3,4-b]indolil, benzomorfolinil i pirolopiridinil.
3. Spoj u skladu sa zahtjevom 1 ili zahtjevom 2, naznačen time što je heterociklil prsten iz R12dušik koji sadrži prsten odabran od azetidinila i pirolidinila, i Y je kovalentna veza koja je spojena na dušik prstena azetidinila ili pirolidinila.
4. Spoj u skladu s bilo kojim od zahtjeva 1 do 3, naznačen time što su heteroaril, heterociklil, aril ili cikloalkil prsten iz R13 odabrani iz skupine koja sadrži fenil, piridinil, pirazolil, imidazolil, izoksazolil, morfolinil, piperdinil, piperazinil, kvinolinil, pirolidinil, benzopirazolil, izoindolinil, tetrahidrokvinolinil, homopiperazinil, pirimidinil, imidazopirimidinil, imidazopiridinil, indazolil, pirolopiridinil, izoksazolil, benzoimidazolil, piridazinil, ciklopropil, pirazolopirimidinil, pirolopirimidinil, dihidroizokvinolinil, i imidazopirazinil.
5. Spoj formule (II)
[image]
tautomer iste, ili farmaceutski prihvatljiva sol navedenog spoja ili tautomera, pri čemu:
m je 0 ili 1;
kad je m 1, Z je -C(R6)(R7)-;
R2 predstavlja atom vodika, opcionalno supstituiran C1-C6 alkil, ili C1-C6 alkoksi skupinu;
R3, R4 i R5 svaki zasebno predstavljaju atom vodika, opcionalno supstituiran C1-C3 alkil, ili C1-C3 alkoksi skupinu;
R1, R6, R7 i R8 svaki zasebno predstavljaju atom vodika, atom fluora, cijano, hidroksil, opcionalno supstituiran C1-C3 alkil, ili C1-C3 alkoksi skupinu;
R9 predstavlja atom vodika, atom fluora, cijano, hidroksil, C1-C6 alkil, C1-C3 alkoksi skupinu, ili 3 do 8-dijelni cikloalkil prsten, ili oblikuje heterociklički prsten s R10;
R10 predstavlja atom vodika, opcionalno supstituiran C1-C6 alkil, ili oblikuje heterociklički prsten s R9, ili oblikuje monociklični prsten s R11;
Y predstavlja kovalentnu vezu, -(C0-C3)-alkilen-N(R11)-(C0-C3)-alkilen ili C1-C3 alkilen;
R11 predstavlja atom vodika, C1-C6 alkil, ili oblike monocikličnog prstena s R10;
R12predstavlja supstituirani monociklični, opcionalno supstituirani biciklični ili opcionalno supstituirani triciklični 3 do 14-dijelni aril prsten;
naznačen time što R12, kad supstituiran, je supstituiran s jednim ili više od -Q1-(R13)p, naznačen time što:
p je 0 ili 1;
Q1 predstavlja halogeni atom, cijano, okso, hidroksil, kovalentnu vezu, -C0-C3 alkilen-NR14-, -C0-C3 alkilen-NR14R15, -C0-C3 alkilen-CONR14-, -C0-C3 alkilen-NR14CO-, -C0-C3 alkilen-NR14SO2-, atom kisika, -C0-C3 alkilen-CO-, -C0-C3 alkilen-S(O)q-, -C0-C3 alkilen-SO2NR14R15, -C1-C6 alkoksi, C1-C6 haloalkoksi, C1-C6 hidroksialkil, -C0-C3 alkilen-SO2R14, --C0-C3 alkilen-NR14COR15, -C0-C3 alkilen-NR14CONR15R16, -C0-C3 alkilen-NR14SO2NR15R16, -C0-C3 alkilen-CONR14R15, -C0-C3 alkilen-CO2R14, -C0-C3 alkilen-NR14CO2R15, -C0-C3 alkilen-SO2NR14R15, -C0-C3 alkilen-C(O)R14 i -C0-C3 alkilen -NR14SO2R15, NO2, C1-C6 alkilen, -C2-C6 alkenilen, ili opcionalno supstituiranu -C1-C6 alkil skupinu;
q je 0, 1 ili 2;
R14, R15 i R16 svaki zasebno predstavljaju atom vodika, C1-C6 alkil, ili C1-C6 alkilen skupinu;
gdje je p 1, R13 predstavlja 4 do 10-dijelni heteroaril, heterociklil, ili 3 do 8-dijelni cikloalkil prsten; pri čemu se R13 može opcionalno supstituirati s jednim ili više supstituenata odabranih od halogena, C1-C6 haloalkila, C1-C6 alkoksi, C1-C6 haloalkoksi, C1-C6 alkil, C2-C6 alkenil, C2-C6 alkinil, C1-C6 hidroksialkil, okso, cijano, -Q2-R17, -Q2-NR17CONR18R19, -Q2-NR17R18, -Q2-COR17, -Q2-NR17COR18, -Q2-NR17CO2R18, -Q2-SO2R17, Q2-CONR17R18, -Q2-CO2R17, -Q2-SO2NR17R18, -Q2-NR17SO2R18, heterociklila, cikloalkila, heteroarila, i arila; pri čemu navedeni heterociklil, cikloalkil, heteroaril i aril prsteni mogu opcionalno biti supstituirani s jednim ili više supstituenata, koji mogu biti isti ili različiti, odabrani od Cl, F, OMe, Me, COCH3, CONH2, NHC(O)CH(CH3)2, i CO2CH2CH3;
Q2 predstavlja kovalentnu vezu, atom kisika, -CO-, ili C1-C6 alkilen ili C2-C6 alkenilen skupinu;
R16, R17, R18 svaki zasebno predstavljaju vodik, C1-C6 alkil, heterociklil, heteroaril, aril, ili cikloalkil;
pri čemu su opcionalni supstituenti alkila od R1, R2, R3 , R4, R5, R6 R7, R8, R10 i Q1, koji mogu biti isti ili različiti, odabrani od C1-C3 alkoksi, halogena, hidroksila, tiola, cijano, amino, amido, nitro i SF5; i
gdje spoj nije formule
[image]
6. Spoj u skladu sa zahtjevom 5, naznačen time što je aril prsten iz R12 fenil.
7. Spoj u skladu sa zahtjevom 5 ili zahtjevom 6, naznačen time što su heteroaril, heterociklil, ili cikloalkil prsten iz R13odabrani iz skupine koja sadrži piridinil, pirazolil, imidazolil, izoksazolil, morfolinil, piperdinil, piperazinil, kvinolinil, pirolidinil, benzopirazolil, izoindolinil, tetrahidrokvinolinil, homopiperazinil, pirimidinil, imidazopirimidinil, imidazopiridinil, indazolil, pirolopiridinil, izoksazolil, benzoimidazolil, piridazinil, ciklopropil, pirazolopirimidinil, pirolopirimidinil, dihidroizokvinolinil, i imidazopirazinil.
8. Spoj u skladu s bilo kojim od zahtjeva 1 do 7, naznačen time što je Q1 odabran od halogena, cijano, okso, kovalentne veze, -NR14R15, -NR14CO-, atoma kisika, C1-C6 alkoksi, -NR14-, -NR14COR15, C1-C6 alkil, C1-C3 alkilen, pri čemu su alkil i alkoksi opcionalno supstituirani s fluorom; i R14 i R15 svaki zasebno predstavljaju atom vodika ili C1-C3 alkil.
9. Spoj formule (II)
[image]
tautomer iste, ili farmaceutski prihvatljiva sol navedenog spoja ili tautomera, pri čemu:
m je 0 ili 1;
kad je m 1, Z je -C(R6)(R7)-;
R2 predstavlja atom vodika, opcionalno supstituiran C1-C6 alkil, ili C1-C6 alkoksi skupinu;
R3, R4 i R5 svaki zasebno predstavljaju atom vodika, opcionalno supstituiran C1-C3 alkil, ili C1-C3 alkoksi skupinu;
R1, R6, R7 i R8 svaki zasebno predstavljaju atom vodika, atom fluora, cijano, hidroksil, opcionalno supstituiran C1-C3 alkil, ili C1-C3 alkoksi skupinu;
R9 predstavlja atom vodika, atom fluora, cijano, hidroksil, C1-C6 alkil, C1-C3 alkoksi skupinu, ili 3 do 8-dijelni cikloalkil prsten, ili oblikuje heterociklički prsten s R10;
R10 predstavlja atom vodika, opcionalno supstituiran C1-C6 alkil, ili oblikuje heterociklički prsten s R9, ili oblikuje monociklični prsten s R11;
Y predstavlja kovalentnu vezu, -(C0-C3)-alkilen-N(R11)-(C0-C3)-alkilen ili C1-C3 alkilen;
R11 predstavlja atom vodika, C1-C6 alkil, ili oblikuje monociklični prsten s R10;
R12 predstavlja monociklični, biciklični ili triciklični 3 do 14-dijelni aril prsten;
naznačen time što je R12 supstituiran s jednim ili više od -Q1-(R13)p, naznačen time što:
p je 1;
Q1 predstavlja cijano, okso, hidroksil, kovalentnu vezu, -C0-C3 alkilen-NR14-, -C0-C3 alkilen-NR14R15, -C0-C3 alkilen-CONR14-, -C0-C3 alkilen-NR14CO-, -C0-C3 alkilen-NR14SO2-, atom kisika, -C0-C3 alkilen-CO-, -C0-C3 alkilen-S(O)q-, -C0-C3 alkilen-SO2NR14, -C0-C3 alkilen-SO2NR14R15, -C1-C6 alkoksi, C1-C6 haloalkoksi, C1-C6 hidroksialkil, -C0-C3 alkilen-SO2R14, -C0-C3 alkilen-NR14COR15, -C0-C3 alkilen-NR14CONR15R16, -C0-C3 alkilen-NR14SO2NR15R16, -C0-C3 alkilen-CONR14R15, -C0-C3 alkilen-CO2R14, -C0-C3 alkilen-NR14CO2R15, -C0-C3 alkilen-SO2NR14R15, -C0-C3 alkilen-C(O)R14 i -C0-C3 alkilen-NR14SO2R15, NO2, C1-C6 alkilen, -C2-C6 alkenilen, ili opcionalno supstituiranu -C1-C6 alkil skupinu;
q je 0, 1 ili 2;
R14, R15 i R16 svaki zasebno predstavljaju atom vodika, C1-C6 alkil, ili C1-C6 alkilen skupinu;
gdje je p 1, R13 predstavlja 4 do 10-dijelni aril prsten; pri čemu se R13 supstituira s jednim ili više supstituenata odabranih od C1-C6 haloalkila, C1-C6 alkoksi, C1-C6 haloalkoksi, C1-C6 alkil, C2-C6 alkenil, C2-C6 alkinil, C1-C6 hidroksialkil, okso, cijano, -Q2-R17, -Q2-NR17CONR18R19, -Q2-NR17R18, -Q2-COR17, -Q2-NR17COR18, -Q2-NR17CO2R18, -Q2-SO2R17, Q2-CONR17R18, -Q2-CO2R17, -Q2-SO2NR17R18, -Q2-NR17SO2R18, heterociklila, cikloalkila, heteroarila, i arila; pri čemu navedeni heterociklil, cikloalkil, heteroaril i aril prsteni mogu opcionalno biti supstituirani s jednim ili više supstituenata, koji mogu biti isti ili različiti, odabrani od Cl, F, OMe, Me, COCH3, CONH2, NHC(O)CH(CH3)2, i CO2CH2CH3;
Q2 predstavlja kovalentnu vezu, atom kisika, -CO-, ili C1-C6 alkilen ili C2-C6 alkenilen skupinu;
R16, R17, R18 svaki zasebno predstavljaju vodik, C1-C6 alkil, heterociklil, heteroaril, aril, ili cikloalkil; i
pri čemu su opcionalni supstituenti alkila od R1, R2, R3 , R4, R5, R6 R7, R8, R10 i Q1, koji mogu biti isti ili različiti, odabrani od C1-C3 alkoksi, halogena, hidroksila, tiola, cijano, amino, amido, nitro i SF5.
10. Spoj u skladu sa zahtjevom 9, naznačen time što je Q1 odabran od cijano, okso, kovalentne veze, -NR14R15, -NR14CO-, atoma kisika, C1-C6 alkoksi, -NR14-, -NR14COR15, C1-C6 alkil, C1-C3 alkilen, pri čemu su alkil i alkoksi opcionalno supstituirani s fluorom; i R14 i R15 svaki zasebno predstavljaju atom vodika ili C1-C3 alkil.
11. Spoj u skladu s bilo kojim od zahtjeva 1 do 10, naznačen time što je m 0.
12. Spoj u skladu s bilo kojim od zahtjeva 1 do 11, naznačen time što R10 predstavlja atom vodika, opcionalno supstituiran C1-C6 alkil, ili oblike opcionalno supstituiranog heterocikličnog prstena s R9 , ili oblike opcionalno supstituiranog 5 ili 6-dijelnog monocikličnog prstena s R11.
13. Spoj u skladu s bilo kojim od zahtjeva 1 do 12, naznačen time što R1, R3 , R4, R5 i R6 ,R7 i R8, ako prisutni, svaki zasebno predstavljaju atom vodika, i naznačeno time što R2 predstavlja vodik ili metil.
14. Spoj u skladu s bilo kojim od zahtjeva 1 do 13, naznačen time što R9 predstavlja vodik, atom fluora, hidroksil, metil, metoksi, ciklopropil, ili oblikuje 5-dijelni heterociklički prsten s R10.
15. Spoj u skladu s bilo kojim od zahtjeva 1 do 14, naznačen time što R10 oblikuje 5-dijelni heterociklički prsten s R9.
16. Spoj u skladu s bilo kojim od zahtjeva 1 do 15, imajući strukturu formule (III)
[image]
tautomer iste, ili farmaceutski prihvatljiva sol navedenog spoja ili tautomera, naznačen time što su m, Z, R1, R2, R3 , R4, R5, R8 , R9, R10, R12 i Y definirani u bilo kojem od zahtjeva 1 do 15 za spojeve formule (II).
17. Spoj formule (II) u skladu sa zahtjevom 1, koji je odabran od skupine koja sadrži:
(R)-N-(1-cijanopirolidin-3-il)-5-fenilpikolinamid;
6-(benzil(metil)amino)-N-(1-cijanopirolidin-3-il)nikotinamid;
(R)-N-(1-cijanopirolidin-3-il)-3-fenilazetidin-1-karboksamid;
N-(1-cijanopirolidin-3-il)-4-feniltiazol-2-karboksamid;
3-(3-klorofenil)-N-(1-cijanopirolidin-3-il)izoksazol-5-karboksamid;
N-(1-cijanopirolidin-3-il)-1-fenil-1H-imidazol-4-karboksamid;
N-(1-cijanopirolidin-3-il)-1-(2,4-difluorobenzil)-5-oksopirolidin-3-karboksamid;
N-(1-cijanopirolidin-3-il)-5-okso-1-fenilpirolidin-3-karboksamid;
N-(1-cijanopirolidin-3-il)-2-fenilkvinolin-4-karboksamid;
6-(4-karbamoilpiperidin-1-il)-N-(1-cijanopirolidin-3-il)nikotinamid;
N-(1-cijanopirolidin-3-il)-6-(4-(2,4-difluorofenil)piperazin-1-il)nikotinamid;
etil 4-(5-((1-cijanopirolidin-3-il)karbamoil)piridin-2-il)piperazin-1-karboksilat;
N-(1-cijanopirolidin-3-il)-6-(2-(piridin-3-il)pirolidin-1-il)nikotinamid;
N-(1-cijanopirolidin-3-il)-6-(4-fenoksipiperidin-1-il)nikotinamid;
N-(1-cijanopirolidin-3-il)-6-(4-(piridin-4-il)piperidin-1-il)nikotinamid;
6-(benzil(metil)amino)-N-(1-cijanopirolidin-3-il)pikolinamid;
N-(1-cijanopirolidin-3-il)-6-(3,4-dihidroizokvinolin-2(1H)-il)pikolinamid;
N-(1-cijanopirolidin-3-il)-6-(4-fenoksipiperidin-1-il)pikolinamid;
N-(1-cijanopirolidin-3-il)-2-(3,4-dihidroizokvinolin-2(1H)-il)isonikotinamid;
2-(4-acetil-1,4-diazepan-1-il)-N-(1-cijanopirolidin-3-il)isonikotinamid;
(R)-N-(1-cijanopirolidin-3-il)-6-fenilpikolinamid;
(R)-N-(1-cijanopirolidin-3-il)-4-fenilpikolinamid;
(R)-N-(1-cijanopirolidin-3-il)-3-fenilizoksazol-5-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-5-(piridin-4-il)izoksazol-3-karboksamid;
(R)-6-(4-klorofenil)-N-(1-cijanopirolidin-3-il)nikotinamid;
(R)-2-(2-klorofenil)-N-(1-cijanopirolidin-3-il)tiazol-5-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-5-(1-metil-1H-pirazol-4-il)pirimidin-2-karboksamid;
N-((R)-1-cijanopirolidin-3-il)-3-fenilpirolidin-1-karboksamid;
(S)-N-(1-cijanopirolidin-3-il)-6-fenilpikolinamid;
(R)-1-(1-cijanopirolidin-3-il)-3-(imidazo[1,2-a]piridin-2-il)-1-metilurea;
(3aR,6aR)-1-(3-fenil-1H-pirazol-5-karbonil)heksahidropirolo[3,4-b]pirol-5(1H)-karbonitril;
(3aR,6aR)-1-(3-fenilizoksazol-5-karbonil)heksahidropirolo[3,4-b]pirol-5(1H)-karbonitril;
(3aR,6aR)-1-(1-fenil-1H-imidazol-4-karbonil)heksahidropirolo[3,4-b]pirol-5(1H)-karbonitril;
(3aR,6aR)-1-(3-(4-metoksifenil)-1H-pirazol-5-karbonil)heksahidropirolo[3,4-b]pirol-5(1H)-karbonitril;
(3aR,6aR)-1-(3-(4-metoksifenil)izoksazol-5-karbonil)heksahidropirolo[3,4-b]pirol-5(1H)-karbonitril;
(3aR,6aR)-1-(2-okso-6-fenil-1,2-dihidropiridin-3-karbonil)heksahidropirolo[3,4-b]pirol-5(1H)-karbonitril;
(R)-N-(1-cijanopirolidin-3-il)-5-fenilpirimidin-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-3-(piridin-4-il)izoksazol-5-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-3-(piridin-3-il)izoksazol-5-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-3-(piridin-2-il)izoksazol-5-karboksamid;
N-(1-cijanopirolidin-3-il)-5-fenilpiridazin-3-karboksamid;
N-((3S,4R)-1-cijano-4-metilpirolidin-3-il)-2-feniltiazol-5-karboksamid;
N-((3R,4S)-1-cijano-4-metilpirolidin-3-il)-2-feniltiazol-5-karboksamid;
N-((3S,4R)-1-cijano-4-metilpirolidin-3-il)-5-feniltiazol-2-karboksamid;
N-((3R,4S)-1-cijano-4-metilpirolidin-3-il)-5-feniltiazol-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-2-(izoindolin-2-il)isonikotinamid;
(R)-N-(1-cijanopirolidin-3-il)-2-(3,4-dihidroizokvinolin-2(1H)-il)isonikotinamid;
(R)-N-(1-cijanopirolidin-3-il)-6-(1-metil-1H-pirazol-4-il)-1H-benzo[d]imidazol-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-6-(1-metil-1H-pirazol-4-il)-1H-indol-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-N-metil-6-(1-metil-1H-pirazol-4-il)-1H-benzo[d]imidazol-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-N-metil-3-fenoksiazetidin-1-karboksamid;
2-(2-klorofenil)-N-((3R,4R)-1-cijano-4-hidroksipirolidin-3-il)tiazol-5-karboksamid;
(R)-N-(1-cijanopirolidin-3 -il)-5-(4-metoksifenil)-1H-pirazol-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-5-(piridin-2-il)-1H-pirazol-3-karboksamid;
(R)-N-(1-cijanopirolidin-3 -il)-5 -(2-metoksifenil)-1H-pirazol-3 -karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-5-(2-fluorofenil)-1H-pirazol-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-6-morfolinonikotinamid;
(R)-N-(1-cijanopirolidin-3-il)-3-(4-metoksifenil)izoksazol-5-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-1H-indazol-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-5-fenil-1H-pirazol-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-5-(piridin-3-il)-1H-pirazol-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-5-(1-metil-1H-pirazol-4-il)pikolinamid;
(R)-N-(1-cijanopirolidin-3-il)-6-(1-metil-1H-pirazol-4-il)nikotinamid;
(R)-N-(1-cijanopirolidin-3-il)-6-(1-metil-1H-pirazol-4-il)pirazolo[1,5-a]piridin-3-karboksamid;
(R)-6-(3-cijanofenil)-N-(1-cijanopirolidin-3-il)imidazo[1,2-a]piridin-2-karboksamid;
(R)-6-(4-cijanofenil)-N-(1-cijanopirolidin-3-il)imidazo[1,2-a]piridin-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-3-fluoro-5-(1-metil-1H-indazol-5-il)pikolinamid;
(R)-N-(1-cijanopirolidin-3-il)-3-fluoro-5-(1-metil-1H-pirolo[2,3-b]piridin-5-il)pikolinamid;
(R)-N-(1-cijanopirolidin-3-il)-5-(1,3-dimetil-1H-pirazol-4-il)-3-fluoropikolinamid;
(R)-3-kloro-N-(1-cijanopirolidin-3-il)-5-(4-fluorofenil)pikolinamid;
(R)-N-(1-cijanopirolidin-3-il)-6-(1-metil-1H-pirazol-4-il)imidazo[1,2-a]piridin-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-6-(1,3-dimetil-1H-pirazol-4-il)imidazo[1,2-a]piridin-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-5-(1-metil-1H-pirazol-4-il)-1H-indazol-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-6-(1-metil-1H-pirazol-4-il)-1H-indazol-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-6-(3,5-dimetilizoksazol-4-il)-1H-indol-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-6-(1,3-dimetil-1H-pirazol-4-il)-1H-indol-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-5-(1-metil-1H-pirazol-4-il)-1H-indol-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-5-(1-etil-1H-pirazol-4-il)-4-metilpikolinamid;
(R)-N-(1-cijanopirolidin-3-il)-3-fenoksiazetidin-1-karboksamid;
(R)-3-(1H-benzo[d]imidazol-2-il)-N-(1-cijanopirolidin-3-il)azetidin-1-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-4-fenilpiperazin-1-karboksamid;
N-((R)-1-cijanopirolidin-3-il)-2-fenilmorfolin-4-karboksamid;
(R)-4-(2-kloro-6-fluorobenzil)-N-(1-cijanopirolidin-3-il)-1,4-diazepan-1-karboksamid;
(R)-4-benzil-N-(1-cijanopirolidin-3-il)-1,4-diazepan-1-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-1,3,4,9-tetrahidro-2H-pirido[3,4-b]indol-2-karboksamid;
N-((R)-1-cijanopirolidin-3-il)-2-((2S,6R)-2,6-dimetilmorfolino)-5-fluoroizonikotinamid;
(R)-N-(1-cijanopirolidin-3-il)-5-fluoro-2-(izoindolin-2-il)izonikotinamid;
N-((R)-1-cijanopirolidin-3-il)-5-metil-1-(1-feniletil)-1H-pirazol-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-5-metil-1-(piridin-2-ilmetil)-1H-pirazol-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-1-izobutil-6-(1-metil-1H-pirazol-4-il)-1H-indazol-3 - karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-6-(3,5-dimetilisoksazol-4-il)-1-izobutil-1H-indazol-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-1-(ciklopropilmetil)-6-(3,5-dimetilizoksazol-4-il)-1H-indazol-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-N-metil-6-(1-metil-1H-pirazol-4-il)imidazo[1,2-a]piridin-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-N-metil-5-(1-metil-1H-pirazol-4-il)-1H-indol-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-6-(3,5-dimetilizoksazol-4-il)-N-metil-1H-benzo[d]imidazol-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-7-(1-metil-1H-pirazol-4-il)imidazo[1,2-a]piridin-3-karboksamid;
(R)-7-(3-cijanofenil)-N-(1-cijanopirolidin-3-il)imidazo[1,2-a]piridin-3 -karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-N-metil-7-(2-metilpiridin-4-il)imidazo[1,2-a]piridin-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-N-metil-7-(6-metilpiridin-3-il)imidazo[1,2-a]piridin-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-7-(1,3-dimetil-1H-pirazol-4-il)-N-metilimidazo[1,2-a]piridin-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-7-(2,6-dimetilpiridin-4-il)-N-metilimidazo[1,2-a]piridin-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-N-etil-7-(2-metilpiridin-4-il)imidazo[1,2-a]piridin-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-7-morfolinoimidazo[1,2-a]piridin-3-karboksamid;
(R)-6-(3-cijanofenil)-N-(1-cijanopirolidin-3-il)-3-fluoroimidazo[1,2-a]piridin-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-3-fluoro-6-(1-metil-1H-pirazol-4-il)imidazo[1,2-a]piridin-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-6-(1-etil-1H-pirazol-4-il)-3-fluoroimidazo[1,2-a]piridin-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-6-(1,3-dimetil-1H-pirazol-4-il)-3-fluoroimidazo[1,2-a]piridin-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-6-(3,5-dimetilizoksazol-4-il)-3-fluoroimidazo1,2-a]piridin-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-5-(4-fluorofenil)pikolinamid;
N-((2R,3R)-1-cijano-2-metilpirolidin-3-il)-5-(4-fluorofenil)pikolinamid;
(R)-N-(1-cijanopirolidin-3-il)-5-(1,3-dimetil-1H-pirazol-4-il)pikolinamid;
(R)-N-(1-cijanopirolidin-3-il)-5-(2-metil-6-(trifluorometil)pirimidin-4-il)pikolinamid;
(R)-N-(1-cijanopirolidin-3-il)-3-fluoro-5-(pirazolo1,5-a]pirimidin-5-il)pikolinamid;
(R)-N-(1-cijanopirolidin-3-il)-3-fluoro-5-(imidazo[1,2-a]piridin-6-il)pikolinamid;
(R)-N-(1-cijanopirolidin-3-il)-3-metoksi-3-fenilazetidin-1-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-N-metil-3-fenilazetidin-1-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-3-(4-metoksifenil)azetidin-1-karboksamid;
(R)-3-(4-klorofenil)-N-(1-cijanopirolidin-3-il)azetidin-1-karboksamid;
(R)-3-(3-klorofenil)-N-(1-cijanopirolidin-3-il)azetidin-1-karboksamid;
(3aR,6aR)-1-(3-fenilazetidin-1-karbonil)heksahidropirolo[3,4-b]pirol-5(1H)-karbonitril;
(3aR,6aR)-5-cijano-N-(5-fenilpiridin-2-il)heksahidropirolo[3,4-b]pirol-1(2H)-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-N-etil-3-fenilazetidin-1-karboksamid;
(R)-3-(2-okso-3-(4-feniltiazol-2-il)imidazolidin-1-il)pirolidin-1-karbonitril;
(R)-3-(2-okso-3-(4-feniltiazol-2-il)tetrahidropirimidin-1(2H)-il)pirolidin-1-karbonitril;
(R)-N-(1-cijanopirolidin-3-il)-4-(pirimidin-2-il)-3,4-dihidro-2H-benzo[b][1,4]oksazin-7-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-4-(4-ciklopropilpirimidin-2-il)-3,4-dihidro-2H-benzo[b][1,4]oksazin-7-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-4-(N-metilizobutiramido)pikolinamid;
(R)-N-(1-cijanopirolidin-3-il)-[2,3’-bipiridin]-6’-karboksamid;
(R)-N-(1-cijanopiroldin-3-il)-[2,4’-bipiridin]-2’-karboksamid;
(R)-3-(4-klorofenil)-N-(1-cijanopirolidin-3-il)izoksazol-5-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-3-(4-(trifluorometil)fenil)izoksazol-5-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-3-(3,4-dimetoksifenil)izoksazol-5-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-3-(3-metoksifenil)izoksazol-5-karboksamid;
N-((R)-1-cijanopirolidin-3-il)-1-fenilpirolidin-3-karboksamid;
N-((R)-1-cijanopirolidin-3-il)-3-(piridin-2-il)pirolidin-1-karboksamid;
N-((R)-1-cijanopirolidin-3-il)-3-(1-metil-1H-pirazol-4-il)pirolidin-1-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-3-(2-metoksipiridin-4-il)-N-metilizoksazol-5-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-1-metil-6-(1-metil-1H-pirazol-4-il)-1H-indol-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-1-metil-5-(1-metil-1H-pirazol-4-il)-1H-indol-2-karboksamid;
(R)-1-(1-cijanopirolidin-3 -il)-3-(2-(izoindolin-2-il)piridin-4-il)-1-metilurea;
(R)-N-(1-cijanopirolidin-3-il)-3-fluoro-1-metil-5-(1-metil-1H-pirazol-4-il)-1H-indol-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-7-(1-metil-1H-pirazol-4-il)imidazo[1,5-a]piridin-3-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-3-(1-fenil-1H-pirazol-3-il)azetidin-1-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-3-(1-(pirazin-2-il)-1H-pirazol-3-il)azetidin-1-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-3-(2-fenilpirimidin-4-il)azetidin-1-karboksamid;
(R)-3-(2-(4-klorofenil)pirimidin-4-il)-N-(1-cijanopirolidin-3-il)azetidin-1-karboksamid;
(R)-3-(benziloksi)-N-(1-cijanopirolidin-3-il)-3-fenilazetidin-1-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-1-(4-ciklopropilpirimidin-2-il)indolin-5-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-1-(4-ciklopropilpirimidin-2-il)-N-metilindolin-5-karboksamid;
(3aR,6aR)-5-cijano-N-(2’-metil-[3,4’-bipiridin]-6-il)heksahidropirolo[3,4-b]pirol-1(2H)-karboksamid;
1-(3-fenil-1H-pirazol-5-karbonil)heksahidropirolo[3,4-b]pirol-5(1H)-karbonitril;
(3aR,6aR)-1-(3-fenoksiazetidin-1-karbonil)heksahidropirolo[3,4-b]pirol-5(1H)-karbonitril;
(R)-N-(1-cijanopirolidin-3-il)-6-(3,5-dimetilizoksazol-4-il)-N-metil-1H-indol-2-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-N-metil-5-(1-metil-1H-pirazol-4-il)-1H-pirolo[2,3-c]piridin-2-karboksamid;
N-((R)-1-cijanopirolidin-3-il)-N-metil-2-fenilmorfolin-4-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-N-metilindolin-1-karboksamid;
(R)-1-(1-cijanopirolidin-3 -il)-1-metil-3-(6-(trifluorometil)piridin-3 -il)urea;
(R)-3-(5-kloropiridin-2-il)-1-(1-cijanopirolidin-3 -il)-1-metilurea;
(3aR,6aR)-1-(indolin-1-karbonil)heksahidropirolo[3,4-b]pirol-5(1H)-karbonitril;
(R)-N-(1-cijanopirolidin-3-il)-3-(2-metilpiridin-4-il)izoksazol-5-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-3-(3,4-dimetilfenil)izoksazol-5-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-3-(2,4-difluorofenil)izoksazol-5-karboksamid; i
(R)-N-(1-cijanopirolidin-3-il)-N-metil-3-(2-metilpiridin-4-il)izoksazol-5-karboksamid;
tautomer istih, ili farmaceutski prihvatljiva sol navedenog spoja ili tautomera.
18. Spoj u skladu sa zahtjevom 5, koji je odabran od:
(R)-N-(1-cijanopirolidin-3-il)-3-metoksi-4-(1-metil-1H-pirazol-4-il)benzamid;
N-((R)-1-cijanopirolidin-3-il)-4-((2S,6R)-2,6-dimetilmorfolino)-3-fluorobenzamid;
N-(1-cijanopirolidin-3-il)-4-(3,5-dimetilizoksazol-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-4-morfolinobenzamid;
(R)-N-(1-cijanopirolidin-3-il)-3-fluoro-4-morfolinobenzamid;
(R)-4-(3-kloropiridin-4-il)-N-(1-cijanopirolidin-3-il)benzamid;
(R)-4-(3-kloropiridin-4-il)-N-(1-cijanopirolidin-3-il)-3-metoksibenzamid;
(R)-N-(1-cijanopirolidin-3-il)-3-metoksi-4-(2-metilpiridin-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-3-metoksi-4-(2-morfolinopiridin-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-4-fluoro-3-(piridin-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-4-fluoro-3-(1-metil-1H-pirazol-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-4-(1-metil-1H-pirazol-4-il)benzamid;
(S)-N-(1-cijanopirolidin-3-il)-4-(piridin-4-il)benzamid;
(R)-4-(3-kloropiridin-4-il)-N-(1-cijanopirolidin-3-il)-N-metilbenzamid;
(3aR,6aR)-1-(4-fluoro-3-(piridin-4-il)benzoil)heksahidropirolo[3,4-b]pirol-5(1H)-karbonitril;
(3aR,6aR)-1-(4-fluoro-3-(1-metil-1H-pirazol-4-il)benzoil)heksahidropirolo[3,4-b]pirol-5(1H)-karbonitril;
(3aR,6aR)-1-(4-(3-kloropiridin-4-il)-3-metoksibenzoil)heksahidropirolo[3,4-b]pirol-5(1H)-karbonitril;
(3aR,6aR)-1-(3-metoksi-4-(1-metil-1H-pirazol-4-il)benzoil)heksahidropirolo[3,4-b]pirol-5 (1H)-karbonitril;
(R)-N-(1-cijanopirolidin-3-il)-3-(N-metilizobutiramido)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(4-metil-1H-imidazol-1-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-3-fluoro-4-(1-metil-1H-pirazol-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(1-metil-1H-pirazol-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2,5-difluoro-4-(1-metil-1H-pirazol-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-4-(1,3-dimetil-1H-pirazol-4-il)-3-fluorobenzamid;
(R)-N-(1-cijanopirolidin-3-il)-4-(1,3-dimetil-1H-pirazol-4-il)-2-fluorobenzamid;
(R)-N-(1-cijanopirolidin-3-il)-4-(1-etil-1H-pirazol-4-il)-2-fluorobenzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(1-(2-metoksietil)-1H-pirazol-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(5-(trifluorometil)-1H-pirazol-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(1-metil-1H-indazol-5-il)benzamid;
(R)-N-(1-cijanopiroldin-3-il)-3-fluoro-N-metil-4-(1-metil-1H-pirazol-4-il)benzamid;
(3aR,6aR)-5-cijano-N-(2-fluoro-4-(trifluorometil)fenil)heksahidropirolo[3,4-b]pirol-1(2H)-karboksamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(pirimidin-2-ilamino)benzamid;
N-((3R,4S)-1-cijano-4-metilpirolidin-3-il)-2-fluoro-4-((R)-3-metoksipirolidin-1-il)benzamid;
N-(1-cijano-3-metilpirolidin-3-il)-2-fluoro-4-(1-metil-1H-pirazol-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-3-(1-metil-1H-pirazol-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(2-metilpirimidin-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3 -il)-2-fluoro-5 -(1-metil-1H-pirazol-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(pirimidin-4-il)benzamid;
(R)-N-(1-cijanopiroldin-3-il)-2-fluoro-4-(imidazo[1,2-a]pirimidin-6-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-metoksi-4-(1-metil-1H-pirazol-4-il)benzamid
(R)-N-(1-cijanopirolidin-3-il)-3,5-difluoro-4-(1-metil-1H-pirazol-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2,6-difluoro-4-(1-metil-1H-pirazol-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-3-metoksi-4-(1-metil-1H-pirazol-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(imidazo[1,2-a]piridin-6-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(2-morfolinopiridin-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2,3-difluoro-4-(1-metil-1H-pirazol-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-3-fluoro-4-(pirimidin-2-ilamino)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(pirolidin-1-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2,5-difluoro-4-morfolinobenzamid;
(R)-N-(1-cijanopirolidin-3-il)-2,5-difluoro-4-(pirolidin-1-il)benzamid;
N-((R)-1-cijanopirolidin-3-il)-2-fluoro-4-((R)-3-metoksipirolidin-1-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-3-metoksi-4-(pirimidin-2-ilamino)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-3-metoksi-4-((4-metilpirimidin-2-il)amino)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-((4-metoksipirimidin-2-il)amino)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(piridazin-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(pirazolo1,5-a]pirimidin-5-il)benzamid;
3-kloro-N-((3R,4S)-1-cijano-4-metilpirolidin-3-il)-4-morfolinobenzamid;
N-((3R,4R)-1-cijano-4-ciklopropilpirolidin-3-il)-3-fluoro-4-(1-metil-1H-pirazol-4-il)benzamid;
N-((3S,4S)-1-cijano-4-metoksipirolidin-3-il)-N-metil-4-(1-metil-1H-pirazol-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-4-(2,6-dimetilpirimidin-4-il)-2-fluorobenzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(5-fluoro-2-metilpirimidin-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(2-(trifluorometil)pirimidin-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(2-metil-3H-pirolo[2,3-d]pirimidin-4-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(imidazo[1,2-a]pirazin-3-il)benzamid;
(R)-1-(1-cijanopirolidin-3-il)-1-metil-3-(4-(1-metil(-1H-pirazol-4-il)fenil)urea;
(R)-1-(1-cijanopirolidin-3 -il)-1-metil-3-(4-(trifluorometil)fenil)urea;
(3aR,6aR)-N-(4-kloro-2-fluorofenil)-5-cijanoheksahidropirolo[3,4-b]pirol-1(2H)-karboksamid;
(3aR,6aR)-5-cijano-N-(2-fluoro-4-(trifluorometoksi)fenil)heksahidropirolo[3,4-b]pirol-1(2H)-karboksamid;
(3aR,6aR)-5-cijano-N-(4-cijano-2-fluorofenil)heksahidropirolo[3,4-b]pirol-1(2H)-karboksamid;
(3aR,6aR)-5-cijano-N-(4-cijano-2,5-difluorofenil)heksahidropirolo[3,4-b]pirol-1(2H)-karboksamid;
(3aR,6aR)-N-(5-kloro-2-fluorofenil)-5-cijanoheksahidropirolo[3,4-b]pirol-1(2H)-karboksamid;
(3aR,6aR)-5-cijano-N-(2-fluoro-5-(trifluorometil)fenil)heksahidropirolo[3,4-b]pirol-1(2H)-karboksamid;
(3aR,6aR)-5-cijano-N-(4-(trifluorometil)fenil)heksahidropirolo[3,4-b]pirol-1(2H)-karboksamid;
(R)-1-(1-cijanopirolidin-3 -il)-1-etil-3 -(4-(trifluorometil)fenil)urea;
1-(1-cijanopirolidin-3 -il)-1-(2-metoksietil)-3 -(4-(trifluorometil)fenil)urea;
(R)-N-(1-cijanopirolidin-3-il)-N-etil-3-fluoro-4-(1-metil-1H-pirazol-4-il)benzamid;
(R)-3 -(3 -(3 -morfolinofenil)-2-oksoimidazolidin-1-il)pirolidine-1-karbonitril;
(R)-N-(1-cijanopirolidin-3-il)-4-((4-ciklopropilpirimidin-2-il)amino)-3-fluorobenzamid;
(R)-N-(1-cijanopirolidin-3-il)-4-((4-ciklopropilpirimidin-2-il)amino)-2,3-difluorobenzamid;
(R)-N-(1-cijanopirolidin-3 -il)-3 -fluoro-4-(4-metil-1H-imidazol-1-il)benzamid;
(R)-N-(1-cijanopirolidin-3-il)-3-fluoro-N-metil-4-(4-metil-1H-imidazol-1-il)benzamid;
(3aR,6aR)-5-cijano-N-(3-(2-metilpiridin-4-il)fenil)heksahidropirolo[3,4-b]pirol-1(2H)-karboksamid;
(3aR,6aR)-5-cijano-N-(4-(2-metilpiridin-4-il)fenil)heksahidropirolo[3,4-b]pirol-1(2H)-karboksamid;
(3aR,6aR)-5-cijano-N-(2-fluoro-4-(2-metilpiridin-4-il)fenil)heksahidropirolo[3,4-b]pirol-1(2H)-karboksamid;
(3aR,6aR)-5-cijano-N-(2-fluoro-4-(1-metil-1H-pirazol-4-il)fenil)heksahidropirolo[3,4-b]pirol-1(2H)-karboksamid;
1-(1-cijanopirolidin-3 -il)-3 -(2,4-diklorofenil)urea;
1-(1-cijanopirolidin-3 -il)-3 -(4-(trifluorometil)fenil)urea;
3 -(3 -klorofenil)-1-(1-cijanopirolidin-3-il)-1-metilurea;
1-(1-cijanopirolidin-3 -il)-3 -(2,4-diklorofenil)-1-metilurea;
1-(1-cijanopirolidin-3 -il)-1-metil-3 -(4-(trifluorometil)fenil)urea; i
(3aR,6aR)-1-(3-kloro-4-morfolinobenzoil)heksahidropirolo[3,4-b]pirol-5(1H)-karbonitril;
tautomer istih, ili farmaceutski prihvatljiva sol navedenog spoja ili tautomera.
19. Spoj u skladu sa zahtjevom 9, koji je odabran od:
N-(1-cijanopirolidin-3-il)-2’-metoksi-[1,1’-bifenil]-4-karboksamid;
N-(1-cijanopirolidin-3-il)-4-fenoksibenzamid;
2-([1,1’-bifenil]-4-il)-N-(1-cijanopirolidin-3-il)acetamid;
(R)-N-(1-cijanopirolidin-3-il)-[1,1’-bifenil]-4-karboksamid;
(3aR,6aR)-1-([1,1’-bifenil]-3-karbonil)heksahidropirolo[3,4-b]pirol-5(1H)-karbonitril;
N-(1-cijanopirolidin-3-il)-N-metil-[1,1’-bifenil]-4-karboksamid;
N-((3R,4R)-1-cijano-4-fluoropirolidin-3 -il)-[1,1’-bifenil]-4-karboksamid;
N-(1-cijanopiperidin-3-il)-[1,1’-bifenil]-3-karboksamid;
1-(3 -benzilfenil)-3 -(1-cijanopiperidin-3 -il)urea;
1-(1-cijanopiperidin-3 -il)-3 -(3 -fenoksifenil)urea;
1-(3 -benzilfenil)-3 -(1-cijanopirolidin-3 -il)urea;
1-([1,1’-bifenil]-4-il)-3-(1-cijanopirolidin-3-il)urea;
1-(1-cijanopirolidin-3 -il)-3 -(3 - fenoksifenil)urea;
3 -(3 -benzilfenil)-)-1-(1-cijanopirolidin-3-il)-1-metilurea;
1-(1-cijanopirolidin-3-il)-1-metil-3-(3- fenoksifenil)urea; i
3-([1,1’-bifenil]-4-il)-1-(1-cijanopirolidin-3-il)-1-metilurea;
tautomer istih, ili farmaceutski prihvatljiva sol navedenog spoja ili tautomera.
20. Spoj odabran od:
2’-kloro-N-(1-cijanopirolidin-3-il)-[1,1’-bifenil]-4-karboksamid;
3’- kloro-N-(1- cijanopirolidin-3-il)-[1,1’- bifenil]-4- karboksamid; i
(R)-N-(1-cijanopirolidin-3-il)-2-fluoro-4-(N-methilfenilsulfonamido)benzamid;
tautomer istih, ili farmaceutski prihvatljiva sol navedenog spoja ili tautomera.
21. Spoj u skladu s bilo kojim od zahtjeva 1 do 20, tautomer istoga, ili farmaceutski prihvatljiva sol navedenog spoja ili tautomera, za uporabu kao lijek.
22. Spoj u skladu s bilo kojim od zahtjeva 1 do 20, tautomer istoga, ili farmaceutski prihvatljiva sol navedenog spoja ili tautomera, za uporabu u liječenju stanja koje uključuje mitohondrijsku disfunkciju, ili rak.
23. Spoj za uporabu u skladu sa zahtjevom 22, naznačen time što je stanje koje uključuje mitohondrijsku disfunkciju odabrano od neurodegenerativne bolesti; mitohondrijske encefalopatije, laktične acidoze, i sindroma epizoda sličnih moždanom udaru; Leberove nasljedne optičke neuropatije; raka; neuropatije; ataksije; retinitis pigmentosa - Leighovog sindroma naslijeđenog od majke; Danonove bolesti: dijabetesa: metaboličkih poremećaja; ishemijske bolesti srca koja dovodi do infarkta miokarda; psihijatrijskih bolesti, primjerice shizofrenije; višestrukog nedostatka sulfataza; mukolipidoze II; mukolipidoze III; mukolipidoze IV; GM1-gangliosidoze; neuronske ceroidne lipofuscinoze; Alpersove bolesti; Barthovog sindroma; poremećaja beta – oksidacije; manjka karnitin – acil – karnitina; manjka karnitina; sindroma deficita kreatina; deficita koenzima Q10; deficita kompleksa I; deficita kompleksa II; deficita kompleksa III; deficita kompleksa IV; deficita kompleksa V; COX deficita; sindroma kronične progresivne vanjske oftalmoplegije; CPT I deficita; CPT II deficita; glutarne acidurije tipa II; Kearns-Sayreovog sindroma; laktčne acidoze; nedostatka acil-CoA dehidrogenaze dugih lanaca; Leighove bolesti ili sindroma; smrtonosne infantilne kardiomiopatije; Luftove bolesti; glutarne acidurije tipa II; nedostatka acil-CoA dehidrogenaze srednjih lanaca; miokloničke epilepsije i sindroma rastrganih crvenih vlakana; mitohondrijske citopatije; sindroma mitohondrijske recesivne ataksije; sindroma iscrpljivanja mitohondrijske DNK; mioneurogastrointestinalnog poremećaja i encefalopatije; Pearsonovog sindroma; manjka piruvat dehidrogenaze; manjka piruvat karboksilaze; POLG mutacija; nedostatka 3-hidroksiacil-CoA dehidrogenaze kratkih / srednjih lanaca; i nedostatka acil-CoA dehidrogenaze vrlo dugih lanaca.
24. Spoj za korištenje u skladu sa zahtjevom 23, naznačen time što je neurodegenerativna bolest odabrana od Parkinsonove bolesti, Alzheimerove bolesti, amiotrofične lateralne skleroze, Huntingtonove bolesti, ishemije, moždanog udara, demencije Lewyevih tjelešaca, i frontotemporalne demencije; i Parkinsonove bolesti povezane s mutacijama α – sinukleina, parkina i PINK1, autosomalne recesivne Parkinsonove bolesti kod mladih, gdje je parkin mutirao.
25. Spoj za korištenje u skladu sa zahtjevom 22, naznačen time što je rak odabran od raka dojki, jajnika, prostate, pluća, bubrega, želuca, debelog crijeva, testisa, glave i vrata, gušterače, mozga, melanoma, raka kosti ili drugih karcinoma tkiva organa i raka krvnih stanica poput limfoma ili leukemija, limfoma, multiplog mijeloma, kolorektalnog raka, i ne-sitnostaničnog oblika raka pluća; raka kod kojeg su apoptozni putevi neregulirani; i raka kod kojeg su proteini BCL-2 familije mutirani, ili prekomjerno ili nedovoljno izraženi.
26. Farmaceutski sastav koji obuhvaća spoj formule (II) kao što je definiran u bilo kojem od zahtjeva 1 do 20, tautomer istog, ili farmaceutski prihvatljiva sol navedenog spoja ili tautomera, zajedno s jednim ili više farmaceutski prihvatljivih pomoćnih tvari.
Applications Claiming Priority (4)
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GBGB1505429.9A GB201505429D0 (en) | 2015-03-30 | 2015-03-30 | Novel compounds |
GBGB1512829.1A GB201512829D0 (en) | 2015-07-21 | 2015-07-21 | Novel compounds |
EP16713043.4A EP3277677B9 (en) | 2015-03-30 | 2016-03-24 | 1-cyano-pyrrolidine compounds as usp30 inhibitors |
PCT/GB2016/050851 WO2016156816A1 (en) | 2015-03-30 | 2016-03-24 | 1-cyano-pyrrolidine compounds as usp30 inhibitors |
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GB201616511D0 (en) | 2016-09-29 | 2016-11-16 | Mission Therapeutics Limited | Novel compounds |
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