CA2984183C - Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl, pyrrolo[2,3-b]pyridinyl acrylamides and epoxides thereof - Google Patents
Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl, pyrrolo[2,3-b]pyridinyl acrylamides and epoxides thereof Download PDFInfo
- Publication number
- CA2984183C CA2984183C CA2984183A CA2984183A CA2984183C CA 2984183 C CA2984183 C CA 2984183C CA 2984183 A CA2984183 A CA 2984183A CA 2984183 A CA2984183 A CA 2984183A CA 2984183 C CA2984183 C CA 2984183C
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- CA
- Canada
- Prior art keywords
- pyrrolo
- carboxamide
- pyrazine
- acryloy1
- acryloylpiperidin
- 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.)
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- -1 Pyrrolo[2,3-d]pyrimidinyl Chemical group 0.000 title claims abstract description 250
- NMHJLFCSJVRQPZ-UHFFFAOYSA-N N-(1H-pyrrolo[2,3-b]pyridin-2-yl)prop-2-enamide Chemical class C(C=C)(=O)NC1=CC=2C(=NC=CC=2)N1 NMHJLFCSJVRQPZ-UHFFFAOYSA-N 0.000 title abstract description 5
- 150000002118 epoxides Chemical class 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 191
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 144
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 108
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 60
- 150000003839 salts Chemical class 0.000 claims description 37
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 8
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 claims description 6
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 6
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 claims description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- GNZFGTAFCUIGFC-UHFFFAOYSA-N 5h-pyrrolo[2,3-b]pyrazine-7-carboxamide Chemical compound C1=CN=C2C(C(=O)N)=CNC2=N1 GNZFGTAFCUIGFC-UHFFFAOYSA-N 0.000 claims description 2
- PSVKVGPZESILJX-UHFFFAOYSA-N N-[(3-fluorophenyl)methyl]-2-[(1-prop-2-enoylpiperidin-4-yl)amino]-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)NC=1N=C2C(=NC=1)NC=C2C(=O)NCC1=CC(=CC=C1)F PSVKVGPZESILJX-UHFFFAOYSA-N 0.000 claims description 2
- MKAUQAKDAAKSRU-UHFFFAOYSA-N N-benzyl-2-[(1-prop-2-enoylpiperidin-4-yl)amino]-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)NC=1N=C2C(=NC=1)NC=C2C(=O)NCC1=CC=CC=C1 MKAUQAKDAAKSRU-UHFFFAOYSA-N 0.000 claims description 2
- IZZOHSQGSBUSSA-UHFFFAOYSA-N 2-(3,3-dimethyl-4-prop-2-enoylpiperazin-1-yl)-N-prop-2-ynyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide Chemical compound C(C=C)(=O)N1C(CN(CC1)C=1N=C2C(=NC=1)NC=C2C(=O)NCC#C)(C)C IZZOHSQGSBUSSA-UHFFFAOYSA-N 0.000 claims 1
- PZUIMDYIXNUSML-UHFFFAOYSA-N N-(3,3-difluorocyclohexyl)-5-(1-prop-2-enoylpiperidin-4-yl)oxy-1H-pyrrolo[2,3-b]pyridine-3-carboxamide Chemical compound FC1(F)CCCC(C1)NC(=O)c1c[nH]c2ncc(OC3CCN(CC3)C(=O)C=C)cc12 PZUIMDYIXNUSML-UHFFFAOYSA-N 0.000 claims 1
- RCSTVYJCDQIIIZ-UHFFFAOYSA-N N-(3,4-dihydro-1H-isochromen-4-yl)-2-(3,3-dimethyl-4-prop-2-enoylpiperazin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide Chemical compound C(C=C)(=O)N1C(CN(CC1)C=1N=C2C(=NC=1)NC=C2C(=O)NC1COCC2=CC=CC=C12)(C)C RCSTVYJCDQIIIZ-UHFFFAOYSA-N 0.000 claims 1
- QKPQJLUXUWAMKR-UHFFFAOYSA-N N-[(1-hydroxy-3-methylcyclopentyl)methyl]-2-(1-prop-2-enoylpiperidin-4-yl)oxy-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)OC=1N=C2C(=NC=1)NC=C2C(=O)NCC1(CC(CC1)C)O QKPQJLUXUWAMKR-UHFFFAOYSA-N 0.000 claims 1
- UEYBAGIDTNOHPH-UHFFFAOYSA-N N-[(1-hydroxycyclopentyl)methyl]-2-(1-prop-2-enoylpiperidin-4-yl)oxy-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)OC=1N=C2C(=NC=1)NC=C2C(=O)NCC1(CCCC1)O UEYBAGIDTNOHPH-UHFFFAOYSA-N 0.000 claims 1
- STFDTGAGIRHBTI-HUUCEWRRSA-N N-[(1R,2R)-2-fluorocyclopentyl]-2-(1-prop-2-enoylpiperidin-4-yl)oxy-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)OC=1N=C2C(=NC=1)NC=C2C(=O)N[C@H]1[C@@H](CCC1)F STFDTGAGIRHBTI-HUUCEWRRSA-N 0.000 claims 1
- COUBAMSIYIHZMU-KGLIPLIRSA-N N-[(1S,3R)-3-fluorocyclopentyl]-5-(1-prop-2-enoylpiperidin-4-yl)oxy-1H-pyrrolo[2,3-b]pyridine-3-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)OC=1C=C2C(=NC=1)NC=C2C(=O)N[C@@H]1C[C@@H](CC1)F COUBAMSIYIHZMU-KGLIPLIRSA-N 0.000 claims 1
- PSJBAJBUPMFCEK-UHFFFAOYSA-N N-[2-(6,7-difluoro-1,3-benzoxazol-2-yl)ethyl]-2-[(1-prop-2-enoylpiperidin-4-yl)amino]-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)NC=1N=C2C(=NC=1)NC=C2C(=O)NCCC=1OC2=C(N=1)C=CC(=C2F)F PSJBAJBUPMFCEK-UHFFFAOYSA-N 0.000 claims 1
- HQKDPAPKTVITQC-UHFFFAOYSA-N N-benzyl-5-(1-prop-2-enoylpiperidin-4-yl)oxy-1H-pyrrolo[2,3-b]pyridine-3-carboxamide N-(3,3-difluorocyclohexyl)-5-(1-prop-2-enoylpiperidin-4-yl)oxy-1H-pyrrolo[2,3-b]pyridine-3-carboxamide Chemical compound C=CC(=O)N1CCC(CC1)Oc1cnc2[nH]cc(C(=O)NCc3ccccc3)c2c1.FC1(F)CCCC(C1)NC(=O)c1c[nH]c2ncc(OC3CCN(CC3)C(=O)C=C)cc12 HQKDPAPKTVITQC-UHFFFAOYSA-N 0.000 claims 1
- BVOCPVIXARZNQN-UHFFFAOYSA-N nipecotamide Chemical compound NC(=O)C1CCCNC1 BVOCPVIXARZNQN-UHFFFAOYSA-N 0.000 claims 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 187
- 239000000203 mixture Substances 0.000 abstract description 39
- 108010024121 Janus Kinases Proteins 0.000 abstract description 17
- 102000015617 Janus Kinases Human genes 0.000 abstract description 17
- 230000003405 preventing effect Effects 0.000 abstract description 8
- 230000001404 mediated effect Effects 0.000 abstract description 5
- 125000003373 pyrazinyl group Chemical group 0.000 abstract description 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 230000009021 linear effect Effects 0.000 description 432
- 125000000217 alkyl group Chemical group 0.000 description 353
- 238000006243 chemical reaction Methods 0.000 description 221
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 192
- 238000002953 preparative HPLC Methods 0.000 description 191
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 177
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 155
- 239000012071 phase Substances 0.000 description 133
- 125000003118 aryl group Chemical group 0.000 description 121
- 239000000243 solution Substances 0.000 description 120
- 238000005160 1H NMR spectroscopy Methods 0.000 description 111
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 109
- 150000003857 carboxamides Chemical class 0.000 description 105
- 125000001072 heteroaryl group Chemical group 0.000 description 100
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 94
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 92
- 238000010898 silica gel chromatography Methods 0.000 description 87
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 82
- 125000000623 heterocyclic group Chemical group 0.000 description 77
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 74
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 72
- 229910052739 hydrogen Inorganic materials 0.000 description 71
- 239000011734 sodium Substances 0.000 description 71
- 239000001257 hydrogen Substances 0.000 description 69
- 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 63
- 229910021529 ammonia Inorganic materials 0.000 description 56
- 229960000510 ammonia Drugs 0.000 description 56
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 56
- 239000007787 solid Substances 0.000 description 56
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 55
- 239000012044 organic layer Substances 0.000 description 53
- 150000002431 hydrogen Chemical group 0.000 description 51
- 229910052938 sodium sulfate Inorganic materials 0.000 description 51
- 235000011152 sodium sulphate Nutrition 0.000 description 51
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 50
- 125000001424 substituent group Chemical group 0.000 description 45
- 239000012267 brine Substances 0.000 description 44
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 44
- 125000001475 halogen functional group Chemical group 0.000 description 43
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 42
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 42
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 41
- 229910052805 deuterium Inorganic materials 0.000 description 41
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 41
- 229910052736 halogen Inorganic materials 0.000 description 40
- 150000002367 halogens Chemical class 0.000 description 40
- 239000003208 petroleum Substances 0.000 description 40
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- 125000002950 monocyclic group Chemical group 0.000 description 36
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 33
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 32
- 125000003545 alkoxy group Chemical group 0.000 description 32
- 125000003282 alkyl amino group Chemical group 0.000 description 31
- 125000004663 dialkyl amino group Chemical group 0.000 description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 150000007942 carboxylates Chemical class 0.000 description 30
- 238000010568 chiral column chromatography Methods 0.000 description 30
- 239000000543 intermediate Substances 0.000 description 30
- 229910052757 nitrogen Inorganic materials 0.000 description 30
- 239000000463 material Substances 0.000 description 29
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- 208000035475 disorder Diseases 0.000 description 28
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 27
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 25
- 125000004093 cyano group Chemical group *C#N 0.000 description 25
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 23
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 23
- 238000007792 addition Methods 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 22
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 21
- 241001465754 Metazoa Species 0.000 description 20
- 125000000753 cycloalkyl group Chemical group 0.000 description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 description 20
- 239000003921 oil Substances 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 125000002877 alkyl aryl group Chemical group 0.000 description 18
- 229910052799 carbon Inorganic materials 0.000 description 18
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 18
- 150000001412 amines Chemical class 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 235000017557 sodium bicarbonate Nutrition 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 16
- 230000001363 autoimmune Effects 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 14
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 14
- 125000004429 atom Chemical group 0.000 description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- 229960005419 nitrogen Drugs 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 13
- 238000001816 cooling Methods 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 230000037396 body weight Effects 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
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- 150000002924 oxiranes Chemical class 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 11
- 229910000104 sodium hydride Inorganic materials 0.000 description 11
- 238000004808 supercritical fluid chromatography Methods 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 10
- IXLVUUFUDRJUSL-RPBOFIJWSA-N 5-[[4-(3-acetamidophenyl)phenyl]methyl]-n-[(1s,2r)-2-phenylcyclopropyl]-1,3-oxazole-4-carboxamide Chemical compound CC(=O)NC1=CC=CC(C=2C=CC(CC3=C(N=CO3)C(=O)N[C@@H]3[C@H](C3)C=3C=CC=CC=3)=CC=2)=C1 IXLVUUFUDRJUSL-RPBOFIJWSA-N 0.000 description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 229920001774 Perfluoroether Polymers 0.000 description 10
- 125000006598 aminocarbonylamino group Chemical group 0.000 description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 10
- 239000012453 solvate Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 9
- 206010013774 Dry eye Diseases 0.000 description 9
- 239000007832 Na2SO4 Substances 0.000 description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 206010023332 keratitis Diseases 0.000 description 9
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 8
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- 229910000024 caesium carbonate Inorganic materials 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 230000001684 chronic effect Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 210000000056 organ Anatomy 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 7
- 208000024827 Alzheimer disease Diseases 0.000 description 7
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 7
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 7
- 239000005977 Ethylene Substances 0.000 description 7
- 206010052779 Transplant rejections Diseases 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 208000010668 atopic eczema Diseases 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 235000019253 formic acid Nutrition 0.000 description 7
- 244000144972 livestock Species 0.000 description 7
- 239000005022 packaging material Substances 0.000 description 7
- 229910052702 rhenium Inorganic materials 0.000 description 7
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Landscapes
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| US11957931B2 (en) * | 2017-04-26 | 2024-04-16 | Yale University | Compositions and methods for treating vitiligo |
| CN110831933A (zh) | 2017-05-25 | 2020-02-21 | 亚瑞克西斯制药公司 | 喹唑啉衍生物作为突变kras、hras或nras的调节剂 |
| BR112020002265A2 (pt) | 2017-08-01 | 2020-07-28 | Theravance Biopharma R&D Ip, Llc | compostos pirazólicos e triazólicos bicíclicos como inibidores de jak quiinase |
| PE20251292A1 (es) | 2018-03-08 | 2025-05-14 | Incyte Corp | Compuestos diolicos de aminopirazina como inhibidores de pi3k-gamma |
| US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
| CN112584833A (zh) | 2018-08-01 | 2021-03-30 | 亚瑞克西斯制药公司 | 杂环螺化合物及其用于治疗癌症的使用方法 |
| US11021482B2 (en) * | 2018-08-10 | 2021-06-01 | Adaris Therapeutics, Inc. | Pyrrolopyrimidine ITK inhibitors |
| US10851102B2 (en) | 2019-01-23 | 2020-12-01 | Theravance Biopharma R&D Ip, Llc | Imidazole and triazole containing bicyclic compounds as JAK inhibitors |
| CN112430235B (zh) * | 2019-08-26 | 2024-04-05 | 东莞市东阳光仿制药研发有限公司 | 一种pf-06651600中间体的制备方法 |
| KR102228668B1 (ko) * | 2019-10-08 | 2021-03-17 | (주)부흥산업사 | 메틸피퍼리딘 아미노피롤로 피리미딘의 제조방법 |
| CN111407767B (zh) * | 2020-03-28 | 2021-05-25 | 中山大学 | 一种磺胺间甲氧嘧啶衍生物在制备抗肿瘤药物中的应用 |
| WO2023151069A1 (zh) * | 2022-02-14 | 2023-08-17 | 湖南南新制药股份有限公司 | 吡咯并[2,3-d]六元杂芳环衍生物、其制备方法和药物用途 |
| CN119060058A (zh) * | 2024-08-21 | 2024-12-03 | 武汉九州钰民医药科技有限公司 | 一种甲苯磺酸利特昔替尼的合成方法 |
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| DE69916833T2 (de) | 1998-06-19 | 2005-04-14 | Pfizer Products Inc., Groton | Pyrrolo(2,3-d)pyrimidin-verbindungen |
| PA8474101A1 (es) | 1998-06-19 | 2000-09-29 | Pfizer Prod Inc | Compuestos de pirrolo [2,3-d] pirimidina |
| SK287188B6 (sk) | 1999-12-10 | 2010-02-08 | Pfizer Products Inc. | Pyrolo [2,3-d]pyrimidínová zlúčenina, jej použitie a farmaceutická kompozícia alebo kombinácia s jej obsahom |
| JP4068958B2 (ja) | 2000-06-26 | 2008-03-26 | ファイザー・プロダクツ・インク | 免疫抑制剤としてのピロロ（２，３−ｄ）ピリミジン化合物 |
| US7301023B2 (en) | 2001-05-31 | 2007-11-27 | Pfizer Inc. | Chiral salt resolution |
| RU2309147C9 (ru) | 2002-11-21 | 2008-03-20 | Пфайзер Продактс Инк. | Производные 3-аминопиперидина и способы их получения |
| US7491827B2 (en) | 2002-12-23 | 2009-02-17 | Millennium Pharmaceuticals, Inc. | Aryl sulfonamides useful as inhibitors of chemokine receptor activity |
| BRPI0414019A (pt) | 2003-08-27 | 2006-10-24 | Biota Inc | nucleosìdios ou nucleotìdio tricìclicos como agentes terapêuticos |
| PT1913000E (pt) | 2005-07-29 | 2012-02-28 | Pfizer Prod Inc | Derivados de pirrolo[2,3-d]pirimidina, suas substâncias intermédias e processo de síntese |
| JP5098843B2 (ja) | 2007-06-29 | 2012-12-12 | Ｊｆｅスチール株式会社 | 金属試料中の着目元素の固溶含有率を求める方法 |
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| EP2328890B1 (en) | 2008-08-06 | 2012-01-25 | Pfizer Inc. | 6 substituted 2-heterocyclylamino pyrazine compounds as chk-1 inhibitors |
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