TWI614250B - 作為β－分泌酶抑制劑之環丙基稠合噻嗪－２－胺化合物及其使用方法 - Google Patents

Info

Publication number

TWI614250B

TWI614250B TW104125848A TW104125848A TWI614250B TW I614250 B TWI614250 B TW I614250B TW 104125848 A TW104125848 A TW 104125848A TW 104125848 A TW104125848 A TW 104125848A TW I614250 B TWI614250 B TW I614250B

Authority

TW

Taiwan

Prior art keywords

amino

methyl

hept

azabicyclo

thia

Prior art date

2014-08-08

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• 238000000034 method Methods 0.000 title claims abstract description 22
• -1 thiazin-2-amine compound Chemical class 0.000 title claims description 1161
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 title claims description 35
• 239000002439 beta secretase inhibitor Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 398
• 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 43
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
• 208000010877 cognitive disease Diseases 0.000 claims abstract description 9
• 208000028698 Cognitive impairment Diseases 0.000 claims abstract description 6
• 125000000217 alkyl group Chemical group 0.000 claims description 539
• 229910052731 fluorine Inorganic materials 0.000 claims description 285
• 150000003839 salts Chemical class 0.000 claims description 227
• 229910052739 hydrogen Inorganic materials 0.000 claims description 188
• 229910052801 chlorine Inorganic materials 0.000 claims description 143
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 111
• 229910052760 oxygen Inorganic materials 0.000 claims description 105
• 125000003545 alkoxy group Chemical group 0.000 claims description 97
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 92
• 125000001424 substituent group Chemical group 0.000 claims description 92
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 86
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 84
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 80
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 74
• 125000005309 thioalkoxy group Chemical group 0.000 claims description 74
• 125000005842 heteroatom Chemical group 0.000 claims description 72
• OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 70
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 69
• 125000003342 alkenyl group Chemical group 0.000 claims description 68
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 68
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 68
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 65
• 229910052757 nitrogen Inorganic materials 0.000 claims description 62
• 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 57
• 125000000335 thiazolyl group Chemical group 0.000 claims description 57
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 56
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 55
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 55
• 125000000304 alkynyl group Chemical group 0.000 claims description 54
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 51
• 239000001301 oxygen Substances 0.000 claims description 51
• 125000002971 oxazolyl group Chemical group 0.000 claims description 49
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 49
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 49
• 125000002757 morpholinyl group Chemical group 0.000 claims description 46
• 229910052799 carbon Inorganic materials 0.000 claims description 44
• 125000005843 halogen group Chemical group 0.000 claims description 43
• 229920006395 saturated elastomer Polymers 0.000 claims description 41
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 40
• 125000002619 bicyclic group Chemical group 0.000 claims description 40
• 125000002950 monocyclic group Chemical group 0.000 claims description 38
• OADSMBXFJIAAJA-UHFFFAOYSA-N oct-4-enamide Chemical compound CCCC=CCCC(N)=O OADSMBXFJIAAJA-UHFFFAOYSA-N 0.000 claims description 38
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 37
• 125000001188 haloalkyl group Chemical group 0.000 claims description 36
• 229960005206 pyrazinamide Drugs 0.000 claims description 35
• 229910052717 sulfur Inorganic materials 0.000 claims description 34
• 125000001544 thienyl group Chemical group 0.000 claims description 33
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 32
• 229910052794 bromium Inorganic materials 0.000 claims description 31
• 125000000623 heterocyclic group Chemical group 0.000 claims description 30
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 29
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 27
• 125000004432 carbon atom Chemical group C* 0.000 claims description 26
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 26
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
• 125000001072 heteroaryl group Chemical group 0.000 claims description 26
• 125000004193 piperazinyl group Chemical group 0.000 claims description 26
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 25
• 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 24
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 24
• 125000002541 furyl group Chemical group 0.000 claims description 24
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 24
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 23
• 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 claims description 22
• 125000003118 aryl group Chemical group 0.000 claims description 21
• 125000005945 imidazopyridyl group Chemical group 0.000 claims description 20
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 20
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 18
• 210000004556 brain Anatomy 0.000 claims description 17
• YVOLUPPVPQLTHT-UHFFFAOYSA-N pyrido[3,4-b]pyrazin-5-amine Chemical compound C1=CN=C2C(N)=NC=CC2=N1 YVOLUPPVPQLTHT-UHFFFAOYSA-N 0.000 claims description 17
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
• 125000004076 pyridyl group Chemical group 0.000 claims description 15
• GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 14
• 101150065749 Churc1 gene Proteins 0.000 claims description 14
• 206010012289 Dementia Diseases 0.000 claims description 14
• 102100038239 Protein Churchill Human genes 0.000 claims description 14
• DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 claims description 14
• 125000004429 atom Chemical group 0.000 claims description 14
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 14
• PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 claims description 13
• 239000002253 acid Substances 0.000 claims description 13
• 150000001412 amines Chemical class 0.000 claims description 13
• 125000004122 cyclic group Chemical group 0.000 claims description 13
• 125000001153 fluoro group Chemical group F* 0.000 claims description 13
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 11
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 11
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 10
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
• 239000003795 chemical substances by application Substances 0.000 claims description 8
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
• GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 8
• 238000006467 substitution reaction Methods 0.000 claims description 8
• 239000011593 sulfur Substances 0.000 claims description 8
• WZHKDGJSXCTSCK-UHFFFAOYSA-N hept-3-ene Chemical compound CCCC=CCC WZHKDGJSXCTSCK-UHFFFAOYSA-N 0.000 claims description 7
• 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 7
• SQXPNCGBFIIPNW-UHFFFAOYSA-N pyrido[3,2-d]pyrimidine-7-carbonitrile Chemical compound C1=NC=NC2=CC(C#N)=CN=C21 SQXPNCGBFIIPNW-UHFFFAOYSA-N 0.000 claims description 7
• GGIRKCYWVSKBKO-UHFFFAOYSA-N 2-prop-2-ynoxy-1,7-naphthyridine Chemical compound C(C#C)OC1=CC=C2C(=N1)C=NC=C2 GGIRKCYWVSKBKO-UHFFFAOYSA-N 0.000 claims description 6
• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
• 150000003973 alkyl amines Chemical class 0.000 claims description 6
• 210000001175 cerebrospinal fluid Anatomy 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 6
• 230000007505 plaque formation Effects 0.000 claims description 6
• 125000003282 alkyl amino group Chemical group 0.000 claims description 5
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
• IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims description 5
• 239000000126 substance Substances 0.000 claims description 5
• 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 claims description 4
• 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 4
• RSAARLKZPGYNBK-UHFFFAOYSA-N 2-methyloct-4-enoic acid Chemical compound CCCC=CCC(C)C(O)=O RSAARLKZPGYNBK-UHFFFAOYSA-N 0.000 claims description 4
• 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 4
• LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 4
• 201000010374 Down Syndrome Diseases 0.000 claims description 4
• 208000012902 Nervous system disease Diseases 0.000 claims description 4
• 206010044688 Trisomy 21 Diseases 0.000 claims description 4
• 230000002490 cerebral effect Effects 0.000 claims description 4
• 230000007850 degeneration Effects 0.000 claims description 4
• QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 4
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 239000001294 propane Substances 0.000 claims description 4
• LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 claims description 4
• 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 claims description 3
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
• 206010002022 amyloidosis Diseases 0.000 claims description 3
• FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 3
• 239000003814 drug Substances 0.000 claims description 3
• 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 3
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 3
• IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 3
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
• 125000001425 triazolyl group Chemical group 0.000 claims description 3
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
• 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 2
• 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 2
• 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 2
• CYSPWCARDHRYJX-UHFFFAOYSA-N 9h-fluoren-1-amine Chemical compound C12=CC=CC=C2CC2=C1C=CC=C2N CYSPWCARDHRYJX-UHFFFAOYSA-N 0.000 claims description 2
• 208000018282 ACys amyloidosis Diseases 0.000 claims description 2
• 208000007487 Familial Cerebral Amyloid Angiopathy Diseases 0.000 claims description 2
• 208000032849 Hereditary cerebral hemorrhage with amyloidosis Diseases 0.000 claims description 2
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
• KSJCZJIRZMJPDM-BMQQJOASSA-N NC1=N[C@]([C@@H]2C[C@@]2(C1)[C@@H](C)O)(C)C=1C=C(C=C(C=1F)F)NC=1C2=C(N=CN=1)C=C(C=N2)C#N Chemical compound NC1=N[C@]([C@@H]2C[C@@]2(C1)[C@@H](C)O)(C)C=1C=C(C=C(C=1F)F)NC=1C2=C(N=CN=1)C=C(C=N2)C#N KSJCZJIRZMJPDM-BMQQJOASSA-N 0.000 claims description 2
• XDPAZYKPBCXUFJ-RLLQIKCJSA-N NC=1S[C@@]2(C([C@@H]2[C@@](N=1)(C)C=1C=C(C=CC=1F)NC=1C2=C(N=CN=1)C=C(C=N2)C#N)(F)F)CO Chemical compound NC=1S[C@@]2(C([C@@H]2[C@@](N=1)(C)C=1C=C(C=CC=1F)NC=1C2=C(N=CN=1)C=C(C=N2)C#N)(F)F)CO XDPAZYKPBCXUFJ-RLLQIKCJSA-N 0.000 claims description 2
• MLEMABWOTJYIIQ-CKEIUWERSA-N NC=1S[C@H]2C([C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC(=O)C1=NC=C(C=C1)Cl)(F)F Chemical compound NC=1S[C@H]2C([C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC(=O)C1=NC=C(C=C1)Cl)(F)F MLEMABWOTJYIIQ-CKEIUWERSA-N 0.000 claims description 2
• GPAXGFDBMSTBMT-RHXQLXPWSA-N NC=1S[C@H]2C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC(=O)C1=NC=C(C=C1)Cl Chemical compound NC=1S[C@H]2C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC(=O)C1=NC=C(C=C1)Cl GPAXGFDBMSTBMT-RHXQLXPWSA-N 0.000 claims description 2
• XYFSQTNJEYTPOQ-SAUNLDPVSA-N NC=1S[C@H]2C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC1=NC=CC=2C1=NC=C(N=2)OC Chemical compound NC=1S[C@H]2C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC1=NC=CC=2C1=NC=C(N=2)OC XYFSQTNJEYTPOQ-SAUNLDPVSA-N 0.000 claims description 2
• DEKIPLROLJNOMS-SZELWCTASA-N NC=1S[C@H]2C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1C2=C(N=CN=1)C=C(C=N2)C#N Chemical compound NC=1S[C@H]2C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1C2=C(N=CN=1)C=C(C=N2)C#N DEKIPLROLJNOMS-SZELWCTASA-N 0.000 claims description 2
• FRJHFLKQJSUIQF-UOTLPGLASA-N NC=1S[C@H]2C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1C2=C(N=CN=1)C=C(C=N2)F Chemical compound NC=1S[C@H]2C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1C2=C(N=CN=1)C=C(C=N2)F FRJHFLKQJSUIQF-UOTLPGLASA-N 0.000 claims description 2
• WJWLBIZEHREWSF-SZELWCTASA-N NC=1S[C@H]2C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1C2=C(N=CN=1)C=C(C=N2)OC Chemical compound NC=1S[C@H]2C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1C2=C(N=CN=1)C=C(C=N2)OC WJWLBIZEHREWSF-SZELWCTASA-N 0.000 claims description 2
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• FTORBSNCYAFARA-RKFVTTHHSA-N NC=1S[C@H]2C[C@H]2[C@@](N=1)(C)C=1C=C(C=NC=1F)NC1=NC=CC=2C1=NC=C(N=2)OCC#C Chemical compound NC=1S[C@H]2C[C@H]2[C@@](N=1)(C)C=1C=C(C=NC=1F)NC1=NC=CC=2C1=NC=C(N=2)OCC#C FTORBSNCYAFARA-RKFVTTHHSA-N 0.000 claims description 2
• RACYZIPKKNTWRU-PVSQZPHNSA-N NC=1S[C@H]2C[C@H]2[C@@](N=1)(C)C=1C=C(C=NC=1F)NC1=NC=CC=2C1=NC=C(N=2)OCC=1OC=CN=1 Chemical compound NC=1S[C@H]2C[C@H]2[C@@](N=1)(C)C=1C=C(C=NC=1F)NC1=NC=CC=2C1=NC=C(N=2)OCC=1OC=CN=1 RACYZIPKKNTWRU-PVSQZPHNSA-N 0.000 claims description 2
• DGRXKVFCKXWGQP-RAJNIJHNSA-N NC=1S[C@H]2C[C@H]2[C@@](N=1)(CF)C=1C=C(C=C(C=1F)F)NC(=O)C1=NC=C(C=C1C)C#N Chemical compound NC=1S[C@H]2C[C@H]2[C@@](N=1)(CF)C=1C=C(C=C(C=1F)F)NC(=O)C1=NC=C(C=C1C)C#N DGRXKVFCKXWGQP-RAJNIJHNSA-N 0.000 claims description 2
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