CA2627089A1 - 1 h-indazoles, benzothiazoles, 1,2-benzoisoxazoles, 1,2-benzoisothiazoles, and chromones and preparation and uses thereof - Google Patents

Info

Publication number

CA2627089A1

CA2627089A1 CA002627089A CA2627089A CA2627089A1 CA 2627089 A1 CA2627089 A1 CA 2627089A1 CA 002627089 A CA002627089 A CA 002627089A CA 2627089 A CA2627089 A CA 2627089A CA 2627089 A1 CA2627089 A1 CA 2627089A1

Authority

CA

Canada

Prior art keywords

carbon atoms

diazabicyclo

ylcarbonyl

alkyl

cycloalkyl

Prior art date

2005-11-09

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

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 title abstract 2
• 238000002360 preparation method Methods 0.000 title description 24
• 150000004777 chromones Chemical class 0.000 title description 2
• CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical class C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 title 1
• KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical class C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 211
• 238000000034 method Methods 0.000 claims abstract description 193
• 239000000203 mixture Substances 0.000 claims abstract description 56
• 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 claims abstract description 41
• 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 claims abstract description 41
• 238000011282 treatment Methods 0.000 claims abstract description 28
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
• 201000010099 disease Diseases 0.000 claims abstract description 21
• 230000004913 activation Effects 0.000 claims abstract description 9
• 230000002950 deficient Effects 0.000 claims abstract description 5
• 125000004432 carbon atom Chemical group C* 0.000 claims description 265
• 125000000217 alkyl group Chemical group 0.000 claims description 149
• -1 cyano, hydroxyl Chemical group 0.000 claims description 145
• 229910052731 fluorine Inorganic materials 0.000 claims description 102
• 229910052801 chlorine Inorganic materials 0.000 claims description 101
• 229910052794 bromium Inorganic materials 0.000 claims description 96
• 229910052740 iodine Inorganic materials 0.000 claims description 79
• 101100477978 Hypocrea jecorina (strain QM6a) sor6 gene Proteins 0.000 claims description 70
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 57
• 125000003545 alkoxy group Chemical group 0.000 claims description 48
• 229910052736 halogen Inorganic materials 0.000 claims description 48
• 150000002367 halogens Chemical class 0.000 claims description 48
• 150000003839 salts Chemical class 0.000 claims description 46
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 45
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 34
• 102000005962 receptors Human genes 0.000 claims description 34
• 108020003175 receptors Proteins 0.000 claims description 34
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 33
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 32
• 125000004043 oxo group Chemical group O=* 0.000 claims description 26
• 239000012458 free base Substances 0.000 claims description 25
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 24
• 101100134929 Gallus gallus COR9 gene Proteins 0.000 claims description 23
• 125000000623 heterocyclic group Chemical group 0.000 claims description 23
• 229920006395 saturated elastomer Polymers 0.000 claims description 22
• 239000012453 solvate Substances 0.000 claims description 21
• 101150020251 NR13 gene Proteins 0.000 claims description 19
• 125000003118 aryl group Chemical group 0.000 claims description 19
• 206010012289 Dementia Diseases 0.000 claims description 18
• 208000010877 cognitive disease Diseases 0.000 claims description 17
• 238000011321 prophylaxis Methods 0.000 claims description 15
• 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 14
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 14
• 206010027175 memory impairment Diseases 0.000 claims description 14
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 14
• 208000000044 Amnesia Diseases 0.000 claims description 13
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 13
• 229910052760 oxygen Inorganic materials 0.000 claims description 12
• 125000002632 imidazolidinyl group Chemical group 0.000 claims description 11
• 102000004196 processed proteins & peptides Human genes 0.000 claims description 11
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 11
• 229910052717 sulfur Inorganic materials 0.000 claims description 11
• 208000026139 Memory disease Diseases 0.000 claims description 10
• 241001465754 Metazoa Species 0.000 claims description 10
• 150000001204 N-oxides Chemical class 0.000 claims description 10
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 10
• 229910052757 nitrogen Inorganic materials 0.000 claims description 10
• 125000004193 piperazinyl group Chemical group 0.000 claims description 10
• 125000006413 ring segment Chemical group 0.000 claims description 10
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 9
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• 125000005959 diazepanyl group Chemical group 0.000 claims description 9
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• 125000002757 morpholinyl group Chemical group 0.000 claims description 8
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• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 7
• CDQFTKBQYMHUKI-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-(6-morpholin-4-yl-1h-indazol-3-yl)methanone Chemical compound C1CN(CC2)CCC2N1C(=O)C(C1=CC=2)=NNC1=CC=2N1CCOCC1 CDQFTKBQYMHUKI-UHFFFAOYSA-N 0.000 claims description 6
• PGHTXZVHWVYKII-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-(6-pyrrolidin-1-yl-1h-indazol-3-yl)methanone Chemical compound C1CN(CC2)CCC2N1C(=O)C(C1=CC=2)=NNC1=CC=2N1CCCC1 PGHTXZVHWVYKII-UHFFFAOYSA-N 0.000 claims description 6
• YANZINWIXKAPBJ-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-(1,4-oxazepan-4-yl)-1h-indazol-3-yl]methanone Chemical compound C1CN(CC2)CCC2N1C(=O)C(C1=CC=2)=NNC1=CC=2N1CCCOCC1 YANZINWIXKAPBJ-UHFFFAOYSA-N 0.000 claims description 6
• CZUBGJIEWJEYLG-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-(4-methylpiperazin-1-yl)-1h-indazol-3-yl]methanone Chemical compound C1CN(C)CCN1C1=CC=C(C(=NN2)C(=O)N3C4CCN(CC4)CC3)C2=C1 CZUBGJIEWJEYLG-UHFFFAOYSA-N 0.000 claims description 6
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
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• 125000002947 alkylene group Chemical group 0.000 claims description 6
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• 208000027061 mild cognitive impairment Diseases 0.000 claims description 6
• 125000005961 oxazepanyl group Chemical group 0.000 claims description 6
• 201000000980 schizophrenia Diseases 0.000 claims description 6
• LTTRHAHKHBGLFJ-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-(5-methoxy-1,2-benzothiazol-3-yl)methanone Chemical compound C12=CC(OC)=CC=C2SN=C1C(=O)N1CCN2CCC1CC2 LTTRHAHKHBGLFJ-UHFFFAOYSA-N 0.000 claims description 5
• NASKHXNSXLBWOS-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-(6-fluoro-2h-pyrazolo[3,4-b]pyridin-3-yl)methanone Chemical compound N=1NC2=NC(F)=CC=C2C=1C(=O)N1CCN2CCC1CC2 NASKHXNSXLBWOS-UHFFFAOYSA-N 0.000 claims description 5
• XDLAJOHFJBFDBR-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-(6-thiomorpholin-4-yl-1h-indazol-3-yl)methanone Chemical compound C1CN(CC2)CCC2N1C(=O)C(C1=CC=2)=NNC1=CC=2N1CCSCC1 XDLAJOHFJBFDBR-UHFFFAOYSA-N 0.000 claims description 5
• SDGFKGORCOJBTQ-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-(3-methoxypyrrolidin-1-yl)-1h-indazol-3-yl]methanone Chemical compound C1C(OC)CCN1C1=CC=C(C(=NN2)C(=O)N3C4CCN(CC4)CC3)C2=C1 SDGFKGORCOJBTQ-UHFFFAOYSA-N 0.000 claims description 5
• BDJQBBPBWIKLPI-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-(4-methyl-1,4-diazepan-1-yl)-1h-indazol-3-yl]methanone Chemical compound C1CN(C)CCCN1C1=CC=C(C(=NN2)C(=O)N3C4CCN(CC4)CC3)C2=C1 BDJQBBPBWIKLPI-UHFFFAOYSA-N 0.000 claims description 5
• KGLWXAZNCVRDSK-UHFFFAOYSA-N 1-[3-(1,4-diazabicyclo[3.2.2]nonane-4-carbonyl)-1h-indazol-6-yl]-3-propylimidazolidin-2-one Chemical compound O=C1N(CCC)CCN1C1=CC=C(C(=NN2)C(=O)N3C4CCN(CC4)CC3)C2=C1 KGLWXAZNCVRDSK-UHFFFAOYSA-N 0.000 claims description 5
• 208000006011 Stroke Diseases 0.000 claims description 5
• 125000004423 acyloxy group Chemical group 0.000 claims description 5
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
• 125000004414 alkyl thio group Chemical group 0.000 claims description 5
• 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 5
• 230000005540 biological transmission Effects 0.000 claims description 5
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
• 230000004064 dysfunction Effects 0.000 claims description 5
• 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 5
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• 125000004434 sulfur atom Chemical group 0.000 claims description 5
• 208000011580 syndromic disease Diseases 0.000 claims description 5
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
• FOPHMSZZCWXLSE-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-(6-pyrrolidin-1-yl-1,2-benzothiazol-3-yl)methanone Chemical compound C1CN(CC2)CCC2N1C(=O)C(C1=CC=2)=NSC1=CC=2N1CCCC1 FOPHMSZZCWXLSE-UHFFFAOYSA-N 0.000 claims description 4
• IVDYMQJQBOZDLZ-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[5-(oxan-3-yloxy)-1h-indazol-3-yl]methanone Chemical compound C1CN(CC2)CCC2N1C(=O)C(C1=C2)=NNC1=CC=C2OC1CCCOC1 IVDYMQJQBOZDLZ-UHFFFAOYSA-N 0.000 claims description 4
• UNMAWYMYPJVFBB-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-1,2-benzothiazol-3-yl]methanone Chemical compound C1CN(CC2)CCC2N1C(=O)C(C1=CC=2)=NSC1=CC=2N1CCN2CCC1CC2 UNMAWYMYPJVFBB-UHFFFAOYSA-N 0.000 claims description 4
• XEKACKLBOIHKMY-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-(4-methyl-1,4-diazepan-1-yl)-1,2-benzothiazol-3-yl]methanone Chemical compound C1CN(C)CCCN1C1=CC=C(C(=NS2)C(=O)N3C4CCN(CC4)CC3)C2=C1 XEKACKLBOIHKMY-UHFFFAOYSA-N 0.000 claims description 4
• OTCDNWYAYRJYFI-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-(4-methylpiperazin-1-yl)-1,2-benzothiazol-3-yl]methanone Chemical compound C1CN(C)CCN1C1=CC=C(C(=NS2)C(=O)N3C4CCN(CC4)CC3)C2=C1 OTCDNWYAYRJYFI-UHFFFAOYSA-N 0.000 claims description 4
• SDGFKGORCOJBTQ-INIZCTEOSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-[(3s)-3-methoxypyrrolidin-1-yl]-1h-indazol-3-yl]methanone Chemical compound C1[C@@H](OC)CCN1C1=CC=C(C(=NN2)C(=O)N3C4CCN(CC4)CC3)C2=C1 SDGFKGORCOJBTQ-INIZCTEOSA-N 0.000 claims description 4
• NFDXQGNDWIPXQL-UHFFFAOYSA-N 1-cyclooctyldiazocane Chemical group C1CCCCCCC1N1NCCCCCC1 NFDXQGNDWIPXQL-UHFFFAOYSA-N 0.000 claims description 4
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
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• AZIYSLGXZWNCRO-OALUTQOASA-N [6-[(1s,4s)-5-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-1,2-benzothiazol-3-yl]-(1,4-diazabicyclo[3.2.2]nonan-4-yl)methanone Chemical compound C([C@]1(N(C=2C=C3SN=C(C3=CC=2)C(=O)N2C3CCN(CC3)CC2)C[C@@]2(C1)[H])[H])N2C1CC1 AZIYSLGXZWNCRO-OALUTQOASA-N 0.000 claims description 4
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• FZSKECBLOWFYPD-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-(1-ethyl-6-methoxyindazol-3-yl)methanone Chemical compound C12=CC=C(OC)C=C2N(CC)N=C1C(=O)N1CCN2CCC1CC2 FZSKECBLOWFYPD-UHFFFAOYSA-N 0.000 claims description 3
• JOQVMBXCUQJRSB-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-(6-phenyl-2h-pyrazolo[3,4-b]pyridin-3-yl)methanone Chemical compound C1CN(CC2)CCC2N1C(=O)C(C1=CC=2)=NNC1=NC=2C1=CC=CC=C1 JOQVMBXCUQJRSB-UHFFFAOYSA-N 0.000 claims description 3
• CHVCZOHUBWQHTK-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-(6-phenylmethoxy-1h-indazol-3-yl)methanone Chemical compound C1CN(CC2)CCC2N1C(=O)C(C1=CC=2)=NNC1=CC=2OCC1=CC=CC=C1 CHVCZOHUBWQHTK-UHFFFAOYSA-N 0.000 claims description 3
• VXAYFZPZFVZCPZ-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-(7-fluoro-6-methoxy-1,2-benzothiazol-3-yl)methanone Chemical compound N=1SC2=C(F)C(OC)=CC=C2C=1C(=O)N1CCN2CCC1CC2 VXAYFZPZFVZCPZ-UHFFFAOYSA-N 0.000 claims description 3
• AMKLHPFMAYQUSV-MRXNPFEDSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[5-[(3r)-3-methoxypyrrolidin-1-yl]-1h-indazol-3-yl]methanone Chemical compound C1[C@H](OC)CCN1C1=CC=C(NN=C2C(=O)N3C4CCN(CC4)CC3)C2=C1 AMKLHPFMAYQUSV-MRXNPFEDSA-N 0.000 claims description 3
• MODJKVLWMQXWNQ-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-(1-methylpyrrolidin-3-yl)oxy-1,2-benzothiazol-3-yl]methanone Chemical compound C1N(C)CCC1OC1=CC=C(C(=NS2)C(=O)N3C4CCN(CC4)CC3)C2=C1 MODJKVLWMQXWNQ-UHFFFAOYSA-N 0.000 claims description 3
• OPBMDLXCLRKRON-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-(5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl)-1,2-benzothiazol-3-yl]methanone Chemical compound CN1CC2CCC1CN2C(C=C1SN=2)=CC=C1C=2C(=O)N1CCN2CCC1CC2 OPBMDLXCLRKRON-UHFFFAOYSA-N 0.000 claims description 3
• BHNLNIXBMVMWBJ-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-(oxan-3-yloxy)-1h-indazol-3-yl]methanone Chemical compound C1CN(CC2)CCC2N1C(=O)C(C1=CC=2)=NNC1=CC=2OC1CCCOC1 BHNLNIXBMVMWBJ-UHFFFAOYSA-N 0.000 claims description 3
• UKVXPHCQATZHCH-UHFFFAOYSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-(oxan-4-yloxy)-1h-indazol-3-yl]methanone Chemical compound C1CN(CC2)CCC2N1C(=O)C(C1=CC=2)=NNC1=CC=2OC1CCOCC1 UKVXPHCQATZHCH-UHFFFAOYSA-N 0.000 claims description 3
• YYMONJYIJHVWEZ-IAGOWNOFSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-[(1r,4r)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-1,2-benzothiazol-3-yl]methanone Chemical compound C([C@@]1(N(C[C@@]2([H])C1)C)[H])N2C(C=C1SN=2)=CC=C1C=2C(=O)N1CCN2CCC1CC2 YYMONJYIJHVWEZ-IAGOWNOFSA-N 0.000 claims description 3
• YYMONJYIJHVWEZ-IRXDYDNUSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-[(1s,4s)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-1,2-benzothiazol-3-yl]methanone Chemical compound C([C@]1(N(C[C@]2([H])C1)C)[H])N2C(C=C1SN=2)=CC=C1C=2C(=O)N1CCN2CCC1CC2 YYMONJYIJHVWEZ-IRXDYDNUSA-N 0.000 claims description 3
• DXGBMYLWFPPWLO-MRXNPFEDSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-[(3r)-3-methoxypyrrolidin-1-yl]-1,2-benzothiazol-3-yl]methanone Chemical compound C1[C@H](OC)CCN1C1=CC=C(C(=NS2)C(=O)N3C4CCN(CC4)CC3)C2=C1 DXGBMYLWFPPWLO-MRXNPFEDSA-N 0.000 claims description 3
• SDGFKGORCOJBTQ-MRXNPFEDSA-N 1,4-diazabicyclo[3.2.2]nonan-4-yl-[6-[(3r)-3-methoxypyrrolidin-1-yl]-1h-indazol-3-yl]methanone Chemical compound C1[C@H](OC)CCN1C1=CC=C(C(=NN2)C(=O)N3C4CCN(CC4)CC3)C2=C1 SDGFKGORCOJBTQ-MRXNPFEDSA-N 0.000 claims description 3
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• LLSRLLPHUVVLQJ-UHFFFAOYSA-N 1-cycloheptyldiazepane Chemical group C1CCCCCC1N1NCCCCC1 LLSRLLPHUVVLQJ-UHFFFAOYSA-N 0.000 claims description 3
• PPNCOQHHSGMKGI-UHFFFAOYSA-N 1-cyclononyldiazonane Chemical group C1CCCCCCCC1N1NCCCCCCC1 PPNCOQHHSGMKGI-UHFFFAOYSA-N 0.000 claims description 3
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