RU2009147819A - Комбинация ингибиторов снк и parp для лечения злокачественных новообразований - Google Patents
Комбинация ингибиторов снк и parp для лечения злокачественных новообразований Download PDFInfo
- Publication number
- RU2009147819A RU2009147819A RU2009147819/15A RU2009147819A RU2009147819A RU 2009147819 A RU2009147819 A RU 2009147819A RU 2009147819/15 A RU2009147819/15 A RU 2009147819/15A RU 2009147819 A RU2009147819 A RU 2009147819A RU 2009147819 A RU2009147819 A RU 2009147819A
- Authority
- RU
- Russia
- Prior art keywords
- alkyl
- cancer
- heterocyclyl
- aryl
- substituted
- Prior art date
Links
- 239000012661 PARP inhibitor Substances 0.000 title claims abstract 3
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 title claims abstract 3
- 206010028980 Neoplasm Diseases 0.000 title claims 21
- 201000011510 cancer Diseases 0.000 title claims 21
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract 30
- 125000003118 aryl group Chemical group 0.000 claims abstract 26
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract 16
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract 9
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims abstract 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract 8
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract 7
- 150000003839 salts Chemical class 0.000 claims abstract 7
- -1 isociano Chemical group 0.000 claims abstract 6
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract 5
- 150000001875 compounds Chemical class 0.000 claims abstract 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract 3
- 229940043355 kinase inhibitor Drugs 0.000 claims abstract 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims abstract 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract 2
- 229910052760 oxygen Inorganic materials 0.000 claims abstract 2
- 229910052717 sulfur Inorganic materials 0.000 claims abstract 2
- 125000001544 thienyl group Chemical group 0.000 claims abstract 2
- 125000000217 alkyl group Chemical group 0.000 claims 99
- 229930194542 Keto Natural products 0.000 claims 7
- 229910052799 carbon Inorganic materials 0.000 claims 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 7
- 229910052736 halogen Inorganic materials 0.000 claims 7
- 150000002367 halogens Chemical class 0.000 claims 7
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 7
- 125000000468 ketone group Chemical group 0.000 claims 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 7
- 208000026310 Breast neoplasm Diseases 0.000 claims 6
- 208000008839 Kidney Neoplasms Diseases 0.000 claims 6
- 206010041067 Small cell lung cancer Diseases 0.000 claims 6
- 208000024770 Thyroid neoplasm Diseases 0.000 claims 6
- 150000001721 carbon Chemical group 0.000 claims 6
- 208000020816 lung neoplasm Diseases 0.000 claims 6
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims 6
- 208000000587 small cell lung carcinoma Diseases 0.000 claims 6
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims 6
- 206010006187 Breast cancer Diseases 0.000 claims 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 5
- 206010060862 Prostate cancer Diseases 0.000 claims 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 5
- 206010038389 Renal cancer Diseases 0.000 claims 5
- 201000010982 kidney cancer Diseases 0.000 claims 5
- 201000005202 lung cancer Diseases 0.000 claims 5
- 238000000034 method Methods 0.000 claims 5
- 201000002510 thyroid cancer Diseases 0.000 claims 5
- 125000003545 alkoxy group Chemical group 0.000 claims 4
- PEUGKEHLRUVPAN-YFKPBYRVSA-N (3s)-piperidin-3-amine Chemical compound N[C@H]1CCCNC1 PEUGKEHLRUVPAN-YFKPBYRVSA-N 0.000 claims 3
- 206010005003 Bladder cancer Diseases 0.000 claims 3
- 208000003174 Brain Neoplasms Diseases 0.000 claims 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims 3
- 208000006168 Ewing Sarcoma Diseases 0.000 claims 3
- 208000007766 Kaposi sarcoma Diseases 0.000 claims 3
- 206010029260 Neuroblastoma Diseases 0.000 claims 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims 3
- 206010033128 Ovarian cancer Diseases 0.000 claims 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 3
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 3
- 201000000170 Thyroid lymphoma Diseases 0.000 claims 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims 3
- 210000000481 breast Anatomy 0.000 claims 3
- 201000010881 cervical cancer Diseases 0.000 claims 3
- 201000004101 esophageal cancer Diseases 0.000 claims 3
- 206010017758 gastric cancer Diseases 0.000 claims 3
- 201000010536 head and neck cancer Diseases 0.000 claims 3
- 208000014829 head and neck neoplasm Diseases 0.000 claims 3
- 229910052739 hydrogen Inorganic materials 0.000 claims 3
- 208000032839 leukemia Diseases 0.000 claims 3
- 210000004072 lung Anatomy 0.000 claims 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 3
- 201000001441 melanoma Diseases 0.000 claims 3
- 230000001394 metastastic effect Effects 0.000 claims 3
- 206010061289 metastatic neoplasm Diseases 0.000 claims 3
- 201000000050 myeloid neoplasm Diseases 0.000 claims 3
- 230000000683 nonmetastatic effect Effects 0.000 claims 3
- 201000002528 pancreatic cancer Diseases 0.000 claims 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 3
- 201000011549 stomach cancer Diseases 0.000 claims 3
- 210000001685 thyroid gland Anatomy 0.000 claims 3
- 201000005112 urinary bladder cancer Diseases 0.000 claims 3
- 210000001072 colon Anatomy 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 210000003494 hepatocyte Anatomy 0.000 claims 2
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 claims 2
- 210000003734 kidney Anatomy 0.000 claims 2
- YHONVYJMVUMQAJ-UHFFFAOYSA-N 2-(carbamoylamino)-n-(1-ethylpiperidin-3-yl)-5-methylthiophene-3-carboxamide Chemical compound C1N(CC)CCCC1NC(=O)C1=C(NC(N)=O)SC(C)=C1 YHONVYJMVUMQAJ-UHFFFAOYSA-N 0.000 claims 1
- FPSWBSQHEQBJSL-UHFFFAOYSA-N 4-(carbamoylamino)-2-morpholin-4-yl-1,3-thiazole-5-carboxylic acid Chemical compound S1C(C(O)=O)=C(NC(=O)N)N=C1N1CCOCC1 FPSWBSQHEQBJSL-UHFFFAOYSA-N 0.000 claims 1
- RTJBIQCMDFNUBB-UHFFFAOYSA-N 5-(carbamoylamino)-2-methyl-1,3-oxazole-4-carboxylic acid Chemical compound CC1=NC(C(O)=O)=C(NC(N)=O)O1 RTJBIQCMDFNUBB-UHFFFAOYSA-N 0.000 claims 1
- 229940121977 Checkpoint kinase inhibitor Drugs 0.000 claims 1
- 206010009944 Colon cancer Diseases 0.000 claims 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- 101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 claims 1
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 claims 1
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 claims 1
- 208000015634 Rectal Neoplasms Diseases 0.000 claims 1
- QNKJYHQPXXAMHX-VIFPVBQESA-N [3-[(3s)-3-aminoazepane-1-carbonyl]-5-ethylthiophen-2-yl]urea Chemical compound S1C(CC)=CC(C(=O)N2C[C@@H](N)CCCC2)=C1NC(N)=O QNKJYHQPXXAMHX-VIFPVBQESA-N 0.000 claims 1
- CJCKGXRROSPGDG-NSHDSACASA-N [3-[(3s)-3-aminoazepane-1-carbonyl]-5-pyridin-2-ylthiophen-2-yl]urea Chemical compound C1[C@@H](N)CCCCN1C(=O)C1=C(NC(N)=O)SC(C=2N=CC=CC=2)=C1 CJCKGXRROSPGDG-NSHDSACASA-N 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 125000003368 amide group Chemical group 0.000 claims 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims 1
- 125000004452 carbocyclyl group Chemical group 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 210000005229 liver cell Anatomy 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 claims 1
- 206010038038 rectal cancer Diseases 0.000 claims 1
- 201000001275 rectum cancer Diseases 0.000 claims 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 3
- 101100294115 Caenorhabditis elegans nhr-4 gene Proteins 0.000 abstract 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US94020307P | 2007-05-25 | 2007-05-25 | |
| US60/940,203 | 2007-05-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| RU2009147819A true RU2009147819A (ru) | 2011-06-27 |
Family
ID=39672970
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2009147819/15A RU2009147819A (ru) | 2007-05-25 | 2008-05-23 | Комбинация ингибиторов снк и parp для лечения злокачественных новообразований |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20100249112A1 (https=) |
| EP (1) | EP2167086A1 (https=) |
| JP (1) | JP2010527981A (https=) |
| KR (1) | KR20100020981A (https=) |
| CN (1) | CN101743003A (https=) |
| AU (1) | AU2008256562A1 (https=) |
| BR (1) | BRPI0811059A2 (https=) |
| CA (1) | CA2687786A1 (https=) |
| MX (1) | MX2009012705A (https=) |
| RU (1) | RU2009147819A (https=) |
| WO (1) | WO2008146035A1 (https=) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010081778A1 (en) * | 2009-01-17 | 2010-07-22 | Universität Zürich | Blockers of parp for the prevention and treatment of helicobacter pylori induced gastric cancer |
| US8871765B2 (en) | 2010-07-27 | 2014-10-28 | Cadila Healthcare Limited | Substituted 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one derivatives as poly (ADP-ribose) polymerase-1 inhibitors |
| CA2869309C (en) | 2012-04-05 | 2021-02-09 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase and combination therapies thereof |
| PL2938598T3 (pl) | 2012-12-31 | 2017-05-31 | Cadila Healthcare Limited | Podstawione pochodne ftalazyn-1 (2H)-onu jako selektywne inhibitory polimerazy-1 poli(ADP-rybozy) |
| JP6457696B2 (ja) | 2015-07-23 | 2019-01-23 | アンスティテュ・キュリＩｎｓｔｉｔｕｔ Ｃｕｒｉｅ | 癌を処置するためのＤｂａｉｔ分子とＰＡＲＰインヒビターとの組合せの使用 |
| HK1258570A1 (zh) | 2015-09-30 | 2019-11-15 | Vertex Pharmaceuticals Inc. | 使用dna损伤剂及atr抑制剂的组合治疗癌症的方法 |
| WO2018162439A1 (en) | 2017-03-08 | 2018-09-13 | Onxeo | New predictive biomarker for the sensitivity to a treatment of cancer with a dbait molecule |
| EP3609884A4 (en) | 2017-04-10 | 2021-01-06 | Sierra Oncology, Inc. | CHK1 (SRA737) / PAPI COMBINATION METHOD FOR INHIBITION OF TUMOR GROWTH |
| EP3461480A1 (en) | 2017-09-27 | 2019-04-03 | Onxeo | Combination of a dna damage response cell cycle checkpoint inhibitors and belinostat for treating cancer |
| KR20200130856A (ko) | 2018-03-13 | 2020-11-20 | 옹쎄오 | 암 치료에서 획득한 내성에 대한 디베이트 분자 |
| CA3095709A1 (en) | 2018-04-05 | 2019-10-10 | Noviga Research Ab | Novel combinations of a tubulin polymerization inhibitor and a poly (adp-ribose) polymerase (parp) inhibitor for use in the treatment of cancer |
| WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
| TW202204348A (zh) | 2020-04-07 | 2022-02-01 | 美商西爾拉癌症醫學公司 | Ｃｈｋ１抑制劑之合成方法 |
| WO2022000946A1 (zh) * | 2020-06-29 | 2022-01-06 | 中国药科大学 | 含有酞嗪-1(2h)-酮结构的parp抑制剂、其制法及医药用途 |
| CN112375070B (zh) * | 2020-06-29 | 2023-03-28 | 中国药科大学 | 含有酞嗪-1(2h)-酮结构的parp抑制剂、其制法及医药用途 |
| KR20260030809A (ko) | 2023-06-21 | 2026-03-06 | 테트라곤 바이오사이언시스 엘티디 | Hr 능숙형 암을 치료하는 방법에 사용하기 위한 데옥시시티딘 유도체 및 parp 억제제를 포함하는 조합 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0408284B8 (pt) * | 2003-03-12 | 2021-05-25 | Kudos Pharm Ltd | compostos derivados de ftalazinona, seu uso e composição farmacêutica compreendendo os mesmos |
| KR20060123403A (ko) * | 2003-12-01 | 2006-12-01 | 쿠도스 파마슈티칼스 리미티드 | 암 치료를 위한 ｄｎａ 손상 수복 억제제 |
| BRPI0418351A (pt) * | 2004-01-05 | 2007-05-08 | Astrazeneca Ab | composto ou um sal farmaceuticamente aceitável do mesmo, métodos de limitar a proliferação celular em um humano ou animal, de tratamento de um humano ou animal sofrendo de cáncer, de tratamento de profilaxia de cáncer, de tratamento de um humano ou animal sofrendo de uma doença neoplásica, de tratamento de um humano ou animal sofrendo de uma doença prolifetativa de tratamento de cáncer, para o tratamento de infecções associadas com cáncer, para o tratamento profilático de infecções associadas com cáncer, composição farmacêutica, uso de um composto ou um sal farmaceuticamente aceitável do mesmo, método de inibir a chk1 quinase, e, processo para a preparação de um composto ou um sal farmaceuticamente aceitável do mesmo |
| EP1836320A2 (en) * | 2005-01-07 | 2007-09-26 | Arqule, Inc. | Compositions for modulation of parp and methods for screening for same |
| WO2008020180A2 (en) * | 2006-08-17 | 2008-02-21 | Kudos Pharmaceuticals Limited | Methods of increasing the sensitivity of cancer cells to dna damage |
-
2008
- 2008-05-23 CN CN200880024432A patent/CN101743003A/zh active Pending
- 2008-05-23 US US12/601,328 patent/US20100249112A1/en not_active Abandoned
- 2008-05-23 CA CA2687786A patent/CA2687786A1/en not_active Abandoned
- 2008-05-23 BR BRPI0811059A patent/BRPI0811059A2/pt not_active IP Right Cessation
- 2008-05-23 WO PCT/GB2008/050372 patent/WO2008146035A1/en not_active Ceased
- 2008-05-23 JP JP2010508909A patent/JP2010527981A/ja active Pending
- 2008-05-23 KR KR1020097026995A patent/KR20100020981A/ko not_active Withdrawn
- 2008-05-23 MX MX2009012705A patent/MX2009012705A/es unknown
- 2008-05-23 RU RU2009147819/15A patent/RU2009147819A/ru not_active Application Discontinuation
- 2008-05-23 EP EP08750767A patent/EP2167086A1/en not_active Withdrawn
- 2008-05-23 AU AU2008256562A patent/AU2008256562A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| JP2010527981A (ja) | 2010-08-19 |
| WO2008146035A1 (en) | 2008-12-04 |
| CN101743003A (zh) | 2010-06-16 |
| CA2687786A1 (en) | 2008-12-04 |
| MX2009012705A (es) | 2009-12-08 |
| US20100249112A1 (en) | 2010-09-30 |
| BRPI0811059A2 (pt) | 2017-05-09 |
| KR20100020981A (ko) | 2010-02-23 |
| AU2008256562A1 (en) | 2008-12-04 |
| EP2167086A1 (en) | 2010-03-31 |
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