AU2009260060B2 - Thiazolyl- and oxazolyl-isoquinolinones and methods for using them - Google Patents
Thiazolyl- and oxazolyl-isoquinolinones and methods for using them Download PDFInfo
- Publication number
- AU2009260060B2 AU2009260060B2 AU2009260060A AU2009260060A AU2009260060B2 AU 2009260060 B2 AU2009260060 B2 AU 2009260060B2 AU 2009260060 A AU2009260060 A AU 2009260060A AU 2009260060 A AU2009260060 A AU 2009260060A AU 2009260060 B2 AU2009260060 B2 AU 2009260060B2
- Authority
- AU
- Australia
- Prior art keywords
- compound
- thiazolo
- hydroxy
- isoquinolin
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 238000000034 method Methods 0.000 title claims abstract description 52
- UYCKMHZYQJAMEH-UHFFFAOYSA-N 3-(1,3-oxazol-2-yl)-2h-isoquinolin-1-one Chemical class C=1C2=CC=CC=C2C(=O)NC=1C1=NC=CO1 UYCKMHZYQJAMEH-UHFFFAOYSA-N 0.000 title abstract description 9
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 claims abstract description 29
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 claims abstract description 29
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims description 138
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 239000001257 hydrogen Substances 0.000 claims description 38
- 150000003839 salts Chemical group 0.000 claims description 38
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 28
- -1 C 1 C 6 alkyl Chemical class 0.000 claims description 26
- 125000002947 alkylene group Chemical group 0.000 claims description 26
- 125000004419 alkynylene group Chemical group 0.000 claims description 26
- 206010028980 Neoplasm Diseases 0.000 claims description 25
- 125000004450 alkenylene group Chemical group 0.000 claims description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 201000010099 disease Diseases 0.000 claims description 21
- 150000002431 hydrogen Chemical class 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 17
- 229920006395 saturated elastomer Polymers 0.000 claims description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 15
- 125000006413 ring segment Chemical group 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 11
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 10
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 10
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 230000010410 reperfusion Effects 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 208000027866 inflammatory disease Diseases 0.000 claims description 8
- 208000028867 ischemia Diseases 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 7
- UFGKEUKYVUYZPF-UHFFFAOYSA-N 2-[2-(dimethylamino)ethyl]-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound C1=CC=C2C(N=C(S3)CCN(C)C)=C3NC(=O)C2=C1 UFGKEUKYVUYZPF-UHFFFAOYSA-N 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 5
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 5
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- 230000000451 tissue damage Effects 0.000 claims description 5
- 231100000827 tissue damage Toxicity 0.000 claims description 5
- 101100516568 Caenorhabditis elegans nhr-7 gene Proteins 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- HGVOVHQTFMXKDZ-AOOOYVTPSA-N 2-[[(2s,6r)-2,6-dimethylmorpholin-4-yl]methyl]-9-hydroxy-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound C1[C@@H](C)O[C@@H](C)CN1CC(S1)=NC2=C1NC(=O)C1=CC=CC(O)=C21 HGVOVHQTFMXKDZ-AOOOYVTPSA-N 0.000 claims description 3
- KXXIEYFYYLEDAM-UHFFFAOYSA-N 9-hydroxy-2-(piperidin-1-ylmethyl)-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound OC1=CC=CC(C(NC=2S3)=O)=C1C=2N=C3CN1CCCCC1 KXXIEYFYYLEDAM-UHFFFAOYSA-N 0.000 claims description 3
- VCOZPOCXDYPYDE-UHFFFAOYSA-N 9-hydroxy-2-(pyrrolidin-1-ylmethyl)-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound OC1=CC=CC(C(NC=2S3)=O)=C1C=2N=C3CN1CCCC1 VCOZPOCXDYPYDE-UHFFFAOYSA-N 0.000 claims description 3
- 230000016273 neuron death Effects 0.000 claims description 3
- VTYYKKIMVNWVEB-PHIMTYICSA-N 2-[[(2r,6s)-2,6-dimethylpiperidin-1-yl]methyl]-9-hydroxy-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound C[C@H]1CCC[C@@H](C)N1CC(S1)=NC2=C1NC(=O)C1=CC=CC(O)=C21 VTYYKKIMVNWVEB-PHIMTYICSA-N 0.000 claims description 2
- 101100521345 Mus musculus Prop1 gene Proteins 0.000 claims description 2
- 108700017836 Prophet of Pit-1 Proteins 0.000 claims description 2
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 4
- 208000037765 diseases and disorders Diseases 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 45
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 20
- 238000011282 treatment Methods 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 239000011734 sodium Substances 0.000 description 14
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- 239000007788 liquid Substances 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
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- 239000007858 starting material Substances 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 238000003818 flash chromatography Methods 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 7
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- 239000000460 chlorine Substances 0.000 description 7
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- 239000000651 prodrug Substances 0.000 description 7
- 229940002612 prodrug Drugs 0.000 description 7
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 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 description 6
- 229910004298 SiO 2 Inorganic materials 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
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- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
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- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 4
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 4
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- YCHPNSOKVRTPES-UHFFFAOYSA-N 2-bromo-1,3-oxazole Chemical compound BrC1=NC=CO1 YCHPNSOKVRTPES-UHFFFAOYSA-N 0.000 description 4
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- GMYYWYJJRGDHJA-UHFFFAOYSA-N 9-methoxy-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound C1=2N=CSC=2NC(=O)C2=C1C(OC)=CC=C2 GMYYWYJJRGDHJA-UHFFFAOYSA-N 0.000 description 3
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7385708P | 2008-06-19 | 2008-06-19 | |
| US61/073,857 | 2008-06-19 | ||
| PCT/US2009/047767 WO2009155402A1 (en) | 2008-06-19 | 2009-06-18 | Thiazolyl- and oxazolyl-isoquinolinones and methods for using them |
Publications (2)
| Publication Number | Publication Date |
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| AU2009260060A1 AU2009260060A1 (en) | 2009-12-23 |
| AU2009260060B2 true AU2009260060B2 (en) | 2015-01-22 |
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| AU2009260060A Ceased AU2009260060B2 (en) | 2008-06-19 | 2009-06-18 | Thiazolyl- and oxazolyl-isoquinolinones and methods for using them |
Country Status (12)
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| US (3) | US8299090B2 (enExample) |
| EP (2) | EP2303895B1 (enExample) |
| JP (2) | JP5564495B2 (enExample) |
| AR (1) | AR072265A1 (enExample) |
| AU (1) | AU2009260060B2 (enExample) |
| CA (1) | CA2728454C (enExample) |
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| ES (1) | ES2530815T3 (enExample) |
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| TW (1) | TWI471329B (enExample) |
| WO (1) | WO2009155402A1 (enExample) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SA109300394B1 (ar) | 2008-06-19 | 2013-01-22 | ويث | ثيازوليل- وأوكسازوليل- أيزوكوينولينونات وطرق لاستخدامها |
| CA2728466A1 (en) | 2008-06-19 | 2009-12-23 | Wyeth Llc | Thienyl- and furanyl-isoquinolinones and methods for using them |
| US9173395B2 (en) | 2011-07-04 | 2015-11-03 | Bayer Intellectual Property Gmbh | Use of substituted isoquinolinones, isoquinolindiones, isoquinolintriones and dihydroisoquinolinones or in each case salts thereof as active agents against abiotic stress in plants |
| KR20140036312A (ko) * | 2011-07-13 | 2014-03-25 | 산텐 세이야꾸 가부시키가이샤 | Ｐａｒｐ 저해 활성을 갖는 신규 화합물 |
| LT3325623T (lt) | 2015-07-23 | 2019-10-25 | Inst Curie | Dbait molekulės ir parp inhibitorių derinio panaudojimas vėžiui gydyti |
| WO2017156350A1 (en) | 2016-03-09 | 2017-09-14 | K-Gen, Inc. | Methods of cancer treatment |
| WO2018162439A1 (en) | 2017-03-08 | 2018-09-13 | Onxeo | New predictive biomarker for the sensitivity to a treatment of cancer with a dbait molecule |
| US20200407720A1 (en) | 2018-03-13 | 2020-12-31 | Onxeo | A dbait molecule against acquired resistance in the treatment of cancer |
| WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
| WO2024261243A1 (en) | 2023-06-21 | 2024-12-26 | Hemispherian As | Combination comprising a deoxycytidine derivative and a parp inhibitor for use in a method of treating hr proficient cancer |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002036599A1 (en) * | 2000-10-31 | 2002-05-10 | Smithkline Beecham P.L.C. | Thieno[2,3-c]isoquinolines for use as inhibitors of parp |
| WO2007149907A2 (en) * | 2006-06-20 | 2007-12-27 | Abbott Laboratories | Pyrazoloquinazolinones as parp inhibitors |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0005745B1 (en) * | 1978-05-26 | 1982-07-14 | Gruppo Lepetit S.P.A. | Pyrazolo (3,4-c) and thiazolo (5,4-c) isoquinolines, methods for preparing them, these compounds for use as antiinflammatory, cns-depressant and anti-anxiety agents and pharmaceutical compositions thereof |
| AUPS137402A0 (en) * | 2002-03-26 | 2002-05-09 | Fujisawa Pharmaceutical Co., Ltd. | Novel tricyclic compounds |
| ATE540928T1 (de) * | 2002-11-22 | 2012-01-15 | Mitsubishi Tanabe Pharma Corp | Isochinolinverbindungen und ihre medizinische verwendung |
| WO2007014907A1 (en) | 2005-08-01 | 2007-02-08 | Wietek Holding Gmbh | Process for the recycling of plastics |
| SA109300394B1 (ar) * | 2008-06-19 | 2013-01-22 | ويث | ثيازوليل- وأوكسازوليل- أيزوكوينولينونات وطرق لاستخدامها |
| CA2728466A1 (en) * | 2008-06-19 | 2009-12-23 | Wyeth Llc | Thienyl- and furanyl-isoquinolinones and methods for using them |
-
2009
- 2009-06-17 SA SA109300394A patent/SA109300394B1/ar unknown
- 2009-06-18 AU AU2009260060A patent/AU2009260060B2/en not_active Ceased
- 2009-06-18 US US12/487,247 patent/US8299090B2/en not_active Expired - Fee Related
- 2009-06-18 DK DK09767711.6T patent/DK2303895T3/en active
- 2009-06-18 EP EP09767711.6A patent/EP2303895B1/en active Active
- 2009-06-18 ES ES09767711T patent/ES2530815T3/es active Active
- 2009-06-18 JP JP2011514801A patent/JP5564495B2/ja not_active Expired - Fee Related
- 2009-06-18 WO PCT/US2009/047767 patent/WO2009155402A1/en not_active Ceased
- 2009-06-18 CA CA2728454A patent/CA2728454C/en active Active
- 2009-06-18 EP EP14185672.4A patent/EP2896626A1/en not_active Withdrawn
- 2009-06-19 TW TW98120713A patent/TWI471329B/zh not_active IP Right Cessation
- 2009-06-19 AR ARP090102266A patent/AR072265A1/es active IP Right Grant
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2012
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2014
- 2014-03-28 JP JP2014067493A patent/JP2014122242A/ja not_active Withdrawn
- 2014-11-07 US US14/535,877 patent/US9265769B2/en active Active
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2016
- 2016-01-21 HK HK16100665.6A patent/HK1212698A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002036599A1 (en) * | 2000-10-31 | 2002-05-10 | Smithkline Beecham P.L.C. | Thieno[2,3-c]isoquinolines for use as inhibitors of parp |
| WO2007149907A2 (en) * | 2006-06-20 | 2007-12-27 | Abbott Laboratories | Pyrazoloquinazolinones as parp inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2009155402A1 (en) | 2009-12-23 |
| SA109300394B1 (ar) | 2013-01-22 |
| HK1156310A1 (en) | 2012-06-08 |
| US8906935B2 (en) | 2014-12-09 |
| US20150133443A1 (en) | 2015-05-14 |
| JP2011525185A (ja) | 2011-09-15 |
| EP2896626A1 (en) | 2015-07-22 |
| DK2303895T3 (en) | 2015-01-12 |
| US20090318442A1 (en) | 2009-12-24 |
| TWI471329B (zh) | 2015-02-01 |
| JP2014122242A (ja) | 2014-07-03 |
| US8299090B2 (en) | 2012-10-30 |
| ES2530815T3 (es) | 2015-03-05 |
| CA2728454C (en) | 2017-01-17 |
| US9265769B2 (en) | 2016-02-23 |
| EP2303895B1 (en) | 2014-09-24 |
| AU2009260060A1 (en) | 2009-12-23 |
| JP5564495B2 (ja) | 2014-07-30 |
| EP2303895A1 (en) | 2011-04-06 |
| TW201002725A (en) | 2010-01-16 |
| AR072265A1 (es) | 2010-08-18 |
| US20130059843A1 (en) | 2013-03-07 |
| HK1212698A1 (en) | 2016-06-17 |
| CA2728454A1 (en) | 2009-12-23 |
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