CA2941196C - 2,7-diazaspiro[3.5]nonane compounds - Google Patents

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Publication number

CA2941196C

CA2941196C CA2941196A CA2941196A CA2941196C CA 2941196 C CA2941196 C CA 2941196C CA 2941196 A CA2941196 A CA 2941196A CA 2941196 A CA2941196 A CA 2941196A CA 2941196 C CA2941196 C CA 2941196C

Authority

CA

Canada

Prior art keywords

6alkyl

diazaspiro

nonane

sulfonyl

group

Prior art date

2014-03-17

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• DROZYMFJWSYDRY-UHFFFAOYSA-N 2,7-diazaspiro[3.5]nonane Chemical class C1NCC11CCNCC1 DROZYMFJWSYDRY-UHFFFAOYSA-N 0.000 title description 7
• 150000001875 compounds Chemical class 0.000 claims abstract description 383
• 238000011282 treatment Methods 0.000 claims abstract description 42
• 239000003814 drug Substances 0.000 claims abstract description 36
• 230000002265 prevention Effects 0.000 claims abstract description 29
• 208000007153 proteostasis deficiencies Diseases 0.000 claims abstract description 15
• 208000030159 metabolic disease Diseases 0.000 claims abstract description 13
• 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 13
• 230000004770 neurodegeneration Effects 0.000 claims abstract description 11
• -1 haloC1-6alkyl Chemical group 0.000 claims description 904
• 125000000623 heterocyclic group Chemical group 0.000 claims description 427
• 125000001072 heteroaryl group Chemical group 0.000 claims description 403
• 229910052739 hydrogen Inorganic materials 0.000 claims description 387
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 385
• 239000001257 hydrogen Substances 0.000 claims description 379
• 229910052799 carbon Inorganic materials 0.000 claims description 257
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 243
• 125000005843 halogen group Chemical group 0.000 claims description 233
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 150
• 125000005842 heteroatom Chemical group 0.000 claims description 137
• 150000003839 salts Chemical class 0.000 claims description 88
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 67
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 67
• 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 64
• 229910052757 nitrogen Inorganic materials 0.000 claims description 64
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 59
• 229910052717 sulfur Inorganic materials 0.000 claims description 57
• 229920006395 saturated elastomer Polymers 0.000 claims description 56
• 239000012453 solvate Substances 0.000 claims description 49
• 239000008194 pharmaceutical composition Substances 0.000 claims description 41
• 125000004432 carbon atom Chemical group C* 0.000 claims description 39
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 38
• 125000004429 atom Chemical group 0.000 claims description 37
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 34
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
• UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 claims description 28
• 125000002393 azetidinyl group Chemical group 0.000 claims description 27
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 24
• 208000018737 Parkinson disease Diseases 0.000 claims description 20
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 20
• 208000024827 Alzheimer disease Diseases 0.000 claims description 19
• 206010012601 diabetes mellitus Diseases 0.000 claims description 19
• 238000002360 preparation method Methods 0.000 claims description 19
• 230000001771 impaired effect Effects 0.000 claims description 16
• 208000002339 Frontotemporal Lobar Degeneration Diseases 0.000 claims description 15
• 201000011240 Frontotemporal dementia Diseases 0.000 claims description 15
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 15
• 208000000501 Lipidoses Diseases 0.000 claims description 14
• 206010024585 Lipidosis Diseases 0.000 claims description 14
• 208000001089 Multiple system atrophy Diseases 0.000 claims description 14
• 125000005549 heteroarylene group Chemical group 0.000 claims description 14
• 239000000651 prodrug Substances 0.000 claims description 13
• 229940002612 prodrug Drugs 0.000 claims description 13
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 12
• 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims description 11
• 125000006591 (C2-C6) alkynylene group Chemical group 0.000 claims description 11
• 102000004877 Insulin Human genes 0.000 claims description 10
• 108090001061 Insulin Proteins 0.000 claims description 10
• 206010022489 Insulin Resistance Diseases 0.000 claims description 10
• 229940125396 insulin Drugs 0.000 claims description 10
• 238000004519 manufacturing process Methods 0.000 claims description 10
• GVNJESYLNCMALL-UHFFFAOYSA-N n-(3-cyanophenyl)-7-methylsulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1CN(S(=O)(=O)C)CCC11CN(C(=O)NC=2C=C(C=CC=2)C#N)C1 GVNJESYLNCMALL-UHFFFAOYSA-N 0.000 claims description 10
• 208000013016 Hypoglycemia Diseases 0.000 claims description 9
• 230000002218 hypoglycaemic effect Effects 0.000 claims description 9
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 8
• 201000003883 Cystic fibrosis Diseases 0.000 claims description 8
• 201000010374 Down Syndrome Diseases 0.000 claims description 8
• 208000004930 Fatty Liver Diseases 0.000 claims description 8
• 208000002705 Glucose Intolerance Diseases 0.000 claims description 8
• 108700006761 Glyceraldehyde-3-phosphate dehydrogenase deficiency Proteins 0.000 claims description 8
• 206010019708 Hepatic steatosis Diseases 0.000 claims description 8
• 208000023105 Huntington disease Diseases 0.000 claims description 8
• 206010020772 Hypertension Diseases 0.000 claims description 8
• 208000031773 Insulin resistance syndrome Diseases 0.000 claims description 8
• 208000001145 Metabolic Syndrome Diseases 0.000 claims description 8
• 208000014060 Niemann-Pick disease Diseases 0.000 claims description 8
• 208000008589 Obesity Diseases 0.000 claims description 8
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 8
• 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 8
• 230000000747 cardiac effect Effects 0.000 claims description 8
• 208000010706 fatty liver disease Diseases 0.000 claims description 8
• 208000006058 glyceraldehyde-3-phosphate dehydrogenase deficiency Diseases 0.000 claims description 8
• 201000001421 hyperglycemia Diseases 0.000 claims description 8
• 201000008980 hyperinsulinism Diseases 0.000 claims description 8
• 235000020824 obesity Nutrition 0.000 claims description 8
• 201000009104 prediabetes syndrome Diseases 0.000 claims description 8
• 231100000240 steatosis hepatitis Toxicity 0.000 claims description 8
• 206010067889 Dementia with Lewy bodies Diseases 0.000 claims description 7
• 208000032928 Dyslipidaemia Diseases 0.000 claims description 7
• 208000009829 Lewy Body Disease Diseases 0.000 claims description 7
• 208000017170 Lipid metabolism disease Diseases 0.000 claims description 7
• 208000033510 neuroaxonal dystrophy Diseases 0.000 claims description 7
• 208000002593 pantothenate kinase-associated neurodegeneration Diseases 0.000 claims description 7
• 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 claims description 6
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 30
• 229910052760 oxygen Inorganic materials 0.000 claims 12
• SGODQWIOWBOYKT-UHFFFAOYSA-N 7-(benzenesulfonyl)-n-phenyl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1C2(CCN(CC2)S(=O)(=O)C=2C=CC=CC=2)CN1C(=O)NC1=CC=CC=C1 SGODQWIOWBOYKT-UHFFFAOYSA-N 0.000 claims 9
• RPFCWYZXPVGZMD-UHFFFAOYSA-N n-(3-fluorophenyl)-7-methylsulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1CN(S(=O)(=O)C)CCC11CN(C(=O)NC=2C=C(F)C=CC=2)C1 RPFCWYZXPVGZMD-UHFFFAOYSA-N 0.000 claims 9
• BCYYATIMCMWEAV-UHFFFAOYSA-N n-(4-methoxyphenyl)-7-methylsulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1=CC(OC)=CC=C1NC(=O)N1CC2(CCN(CC2)S(C)(=O)=O)C1 BCYYATIMCMWEAV-UHFFFAOYSA-N 0.000 claims 9
• VIFSDEIEVJLEFA-UHFFFAOYSA-N 7-(benzenesulfonyl)-n-(4-methoxyphenyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1=CC(OC)=CC=C1NC(=O)N1CC2(CCN(CC2)S(=O)(=O)C=2C=CC=CC=2)C1 VIFSDEIEVJLEFA-UHFFFAOYSA-N 0.000 claims 8
• LVWKQKBWFTVHLB-UHFFFAOYSA-N 7-(benzenesulfonyl)-n-(3-fluorophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound FC1=CC=CC(NC(=O)N2CC3(C2)CCN(CC3)S(=O)(=O)C=2C=CC=CC=2)=C1 LVWKQKBWFTVHLB-UHFFFAOYSA-N 0.000 claims 7
• BLOKECMLIIWMCH-UHFFFAOYSA-N 7-(benzenesulfonyl)-n-propan-2-yl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1N(C(=O)NC(C)C)CC21CCN(S(=O)(=O)C=1C=CC=CC=1)CC2 BLOKECMLIIWMCH-UHFFFAOYSA-N 0.000 claims 7
• MIPCJURDXWBZGS-UHFFFAOYSA-N 7-methylsulfonyl-n-phenyl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1CN(S(=O)(=O)C)CCC11CN(C(=O)NC=2C=CC=CC=2)C1 MIPCJURDXWBZGS-UHFFFAOYSA-N 0.000 claims 7
• IJMSCUUGZYBRML-UHFFFAOYSA-N 2h-benzotriazol-5-yl-[7-[2-(3-chlorophenyl)ethylsulfonyl]-2,7-diazaspiro[3.5]nonan-2-yl]methanone Chemical compound ClC1=CC=CC(CCS(=O)(=O)N2CCC3(CN(C3)C(=O)C3=CC4=NNN=C4C=C3)CC2)=C1 IJMSCUUGZYBRML-UHFFFAOYSA-N 0.000 claims 3
• BSZDGZNXEHKOFN-UHFFFAOYSA-N 7-[4-(difluoromethoxy)phenyl]sulfonyl-2-(4-methoxyphenyl)sulfonyl-2,7-diazaspiro[3.5]nonane Chemical compound FC(OC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)S(=O)(=O)C2=CC=C(C=C2)OC)CC1)F BSZDGZNXEHKOFN-UHFFFAOYSA-N 0.000 claims 1
• YCBIHKFWSRJXRS-UHFFFAOYSA-N C(C)OC1=C(C#N)C=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(=NS2)CC2=CC=C(C=C2)F)CC1 Chemical compound C(C)OC1=C(C#N)C=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(=NS2)CC2=CC=C(C=C2)F)CC1 YCBIHKFWSRJXRS-UHFFFAOYSA-N 0.000 claims 1
• FKCLZIVMKRFCRZ-UHFFFAOYSA-N C(C)OC1=C(C=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(=NS2)CC2=CC=C(C=C2)F)CC1)C Chemical compound C(C)OC1=C(C=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(=NS2)CC2=CC=C(C=C2)F)CC1)C FKCLZIVMKRFCRZ-UHFFFAOYSA-N 0.000 claims 1
• WJXUIGMNGALNNT-UHFFFAOYSA-N C(C)OC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)S(=O)(=O)C2=CC=C(C=C2)OC)CC1 Chemical compound C(C)OC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)S(=O)(=O)C2=CC=C(C=C2)OC)CC1 WJXUIGMNGALNNT-UHFFFAOYSA-N 0.000 claims 1
• HBLZORMEGDDHIS-UHFFFAOYSA-N C(CCC)C1=NSC(=N1)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC Chemical compound C(CCC)C1=NSC(=N1)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC HBLZORMEGDDHIS-UHFFFAOYSA-N 0.000 claims 1
• JYEGKASWJXCIKA-UHFFFAOYSA-N C1(CC1)C1=NSC(=N1)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC Chemical compound C1(CC1)C1=NSC(=N1)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC JYEGKASWJXCIKA-UHFFFAOYSA-N 0.000 claims 1
• CMMABCBPOOMCOE-UHFFFAOYSA-N C1(CCCCC1)CS(=O)(=O)N1CCC2(CN(C2)C2=NC(=NS2)CC2=CC=C(C=C2)F)CC1 Chemical compound C1(CCCCC1)CS(=O)(=O)N1CCC2(CN(C2)C2=NC(=NS2)CC2=CC=C(C=C2)F)CC1 CMMABCBPOOMCOE-UHFFFAOYSA-N 0.000 claims 1
• VNIAWHHUQWYCOJ-UHFFFAOYSA-N CC(C)(C)C1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(CC3=CC=C(F)C=C3)=NS2)CC1 Chemical compound CC(C)(C)C1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(CC3=CC=C(F)C=C3)=NS2)CC1 VNIAWHHUQWYCOJ-UHFFFAOYSA-N 0.000 claims 1
• YKLHLZIAFZPUSO-UHFFFAOYSA-N CC1=C(C=CC=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(CC3=CC=C(F)C=C3)=NS2)CC1 Chemical compound CC1=C(C=CC=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(CC3=CC=C(F)C=C3)=NS2)CC1 YKLHLZIAFZPUSO-UHFFFAOYSA-N 0.000 claims 1
• ARHGNEIOPCFZNY-UHFFFAOYSA-N CC1=CC=CC(=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(CC3=CC=C(F)C=C3)=NS2)CC1 Chemical compound CC1=CC=CC(=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(CC3=CC=C(F)C=C3)=NS2)CC1 ARHGNEIOPCFZNY-UHFFFAOYSA-N 0.000 claims 1
• KGUKWEDPHVNDKQ-UHFFFAOYSA-N CCC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(CC3=CC=C(F)C=C3)=NS2)CC1 Chemical compound CCC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(CC3=CC=C(F)C=C3)=NS2)CC1 KGUKWEDPHVNDKQ-UHFFFAOYSA-N 0.000 claims 1
• BJHKGLLTPVFOEP-UHFFFAOYSA-N COC(=O)C1=CC(=CC=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(CC3=CC=C(F)C=C3)=NS2)CC1 Chemical compound COC(=O)C1=CC(=CC=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(CC3=CC=C(F)C=C3)=NS2)CC1 BJHKGLLTPVFOEP-UHFFFAOYSA-N 0.000 claims 1
• IWOCHYNSRVWKSO-UHFFFAOYSA-N COC1=C(C=CC=C1)C(C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)(C)C Chemical compound COC1=C(C=CC=C1)C(C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)(C)C IWOCHYNSRVWKSO-UHFFFAOYSA-N 0.000 claims 1
• MHRQDCKRJIRAFO-UHFFFAOYSA-N COC1=C(C=CC=C1)C(C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)C Chemical compound COC1=C(C=CC=C1)C(C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)C MHRQDCKRJIRAFO-UHFFFAOYSA-N 0.000 claims 1
• RGIRIWHIJQNILO-UHFFFAOYSA-N COC1=CC(=C(OC)C=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(CC3=CC=C(F)C=C3)=NS2)CC1 Chemical compound COC1=CC(=C(OC)C=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(CC3=CC=C(F)C=C3)=NS2)CC1 RGIRIWHIJQNILO-UHFFFAOYSA-N 0.000 claims 1
• WPJNCPYUPFONJY-UHFFFAOYSA-N COC1=CC=C(C=C1)S(=O)(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC Chemical compound COC1=CC=C(C=C1)S(=O)(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC WPJNCPYUPFONJY-UHFFFAOYSA-N 0.000 claims 1
• UPGFIQGDOOBHOO-UHFFFAOYSA-N COC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C(=O)C2(CC2)C2=CC=CC=C2)CC1 Chemical compound COC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C(=O)C2(CC2)C2=CC=CC=C2)CC1 UPGFIQGDOOBHOO-UHFFFAOYSA-N 0.000 claims 1
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• YTTDVPXXNPDYCY-UHFFFAOYSA-N COC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C(C(C)(C2=C(C=CC=C2)C)C)=O)CC1 Chemical compound COC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C(C(C)(C2=C(C=CC=C2)C)C)=O)CC1 YTTDVPXXNPDYCY-UHFFFAOYSA-N 0.000 claims 1
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• ZBAGHHKSZNNJHX-UHFFFAOYSA-N COC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C(C(CC)C2=CC=CC=C2)=O)CC1 Chemical compound COC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C(C(CC)C2=CC=CC=C2)=O)CC1 ZBAGHHKSZNNJHX-UHFFFAOYSA-N 0.000 claims 1
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• GELNOZSZHVTGCZ-UHFFFAOYSA-N COC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(=NS2)CC2=CC(=CC=C2)C(F)(F)F)CC1 Chemical compound COC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C2=NC(=NS2)CC2=CC(=CC=C2)C(F)(F)F)CC1 GELNOZSZHVTGCZ-UHFFFAOYSA-N 0.000 claims 1
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• LUGMFRPNCUQLKE-UHFFFAOYSA-N FC1=CC=C(CC2=NSC(=N2)N2CC3(C2)CCN(CC3)S(=O)(=O)C3=CC(=CC=C3)F)C=C1 Chemical compound FC1=CC=C(CC2=NSC(=N2)N2CC3(C2)CCN(CC3)S(=O)(=O)C3=CC(=CC=C3)F)C=C1 LUGMFRPNCUQLKE-UHFFFAOYSA-N 0.000 claims 1
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