CA2900855C - Aminopyrimidinyl compounds - Google Patents
Aminopyrimidinyl compounds Download PDFInfo
- Publication number
- CA2900855C CA2900855C CA2900855A CA2900855A CA2900855C CA 2900855 C CA2900855 C CA 2900855C CA 2900855 A CA2900855 A CA 2900855A CA 2900855 A CA2900855 A CA 2900855A CA 2900855 C CA2900855 C CA 2900855C
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- diazabicyclo
- pyrimidin
- amino
- oct
- 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 Aminopyrimidinyl compounds Chemical class 0.000 title claims abstract description 174
- 150000001875 compounds Chemical class 0.000 claims abstract description 397
- 150000003839 salts Chemical class 0.000 claims abstract description 63
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 173
- 125000000217 alkyl group Chemical group 0.000 claims description 148
- 125000001072 heteroaryl group Chemical group 0.000 claims description 102
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 70
- 125000003118 aryl group Chemical group 0.000 claims description 59
- 229910052739 hydrogen Inorganic materials 0.000 claims description 57
- 239000001257 hydrogen Substances 0.000 claims description 57
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 50
- 125000000623 heterocyclic group Chemical group 0.000 claims description 49
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 47
- 150000002431 hydrogen Chemical group 0.000 claims description 46
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 43
- 229910052805 deuterium Inorganic materials 0.000 claims description 43
- 125000005843 halogen group Chemical group 0.000 claims description 43
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 39
- 229910052757 nitrogen Inorganic materials 0.000 claims description 39
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 claims description 39
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 37
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 37
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 28
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 125000001153 fluoro group Chemical group F* 0.000 claims description 22
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 22
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 21
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 125000002950 monocyclic group Chemical group 0.000 claims description 18
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 125000003282 alkyl amino group Chemical group 0.000 claims description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 8
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 7
- 229910052701 rubidium Inorganic materials 0.000 claims description 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 5
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 claims description 4
- 229940116839 Janus kinase 1 inhibitor Drugs 0.000 claims description 3
- GFBLFDSCAKHHGX-UHFFFAOYSA-N cyclobutanecarbonitrile Chemical compound N#CC1CCC1 GFBLFDSCAKHHGX-UHFFFAOYSA-N 0.000 claims description 3
- AUQDITHEDVOTCU-UHFFFAOYSA-N cyclopropyl cyanide Chemical compound N#CC1CC1 AUQDITHEDVOTCU-UHFFFAOYSA-N 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000006420 1-fluorocyclopropyl group Chemical group [H]C1([H])C([H])([H])C1(F)* 0.000 claims description 2
- 229940123371 Tyrosine kinase 2 inhibitor Drugs 0.000 claims description 2
- BEHYAANJUKYBTH-UHFFFAOYSA-N imidazo[1,2-a]pyridine-2-carboxamide Chemical compound C1=CC=CC2=NC(C(=O)N)=CN21 BEHYAANJUKYBTH-UHFFFAOYSA-N 0.000 claims description 2
- SDIDYFBTIZOPLA-UHFFFAOYSA-N n-ethylbenzamide Chemical compound CCNC(=O)C1=CC=CC=C1 SDIDYFBTIZOPLA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 19
- 125000005842 heteroatom Chemical group 0.000 claims 15
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 claims 13
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 10
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 6
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims 6
- 125000002619 bicyclic group Chemical group 0.000 claims 5
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- AJIADPABISZKBM-OKIDVHRISA-N C(#N)[C@H]1[C@@H](C1)C(=O)N[C@@]12CN(C[C@H]2[C@H]1C)C1=NC(=NC=C1F)NC=1C=NN(C=1)C Chemical compound C(#N)[C@H]1[C@@H](C1)C(=O)N[C@@]12CN(C[C@H]2[C@H]1C)C1=NC(=NC=C1F)NC=1C=NN(C=1)C AJIADPABISZKBM-OKIDVHRISA-N 0.000 claims 1
- XCUMNONQZGLEJF-DRJHQHNCSA-N C(#N)[C@H]1[C@@H](C1)C(=O)N[C@@]12CN(C[C@]2(C1)CO)C1=NC(=NC=C1F)NC=1C=NN(C=1)C Chemical compound C(#N)[C@H]1[C@@H](C1)C(=O)N[C@@]12CN(C[C@]2(C1)CO)C1=NC(=NC=C1F)NC=1C=NN(C=1)C XCUMNONQZGLEJF-DRJHQHNCSA-N 0.000 claims 1
- FSKSWECVEGBILU-GASCZTMLSA-N CC=1C=C(C=NC=1C(NC)=O)NC1=NC=CC(=N1)N1C[C@H]2CC[C@@H](C1)N2C(=O)NCC(F)(F)F Chemical compound CC=1C=C(C=NC=1C(NC)=O)NC1=NC=CC(=N1)N1C[C@H]2CC[C@@H](C1)N2C(=O)NCC(F)(F)F FSKSWECVEGBILU-GASCZTMLSA-N 0.000 claims 1
- BUWBRTXGQRBBHG-MJBXVCDLSA-N FC1([C@@H](C1)C(=O)N1[C@H]2CN(C[C@@H]1CC2)C1=NC(=NC=C1)NC=1C=NN(C=1)C)F Chemical compound FC1([C@@H](C1)C(=O)N1[C@H]2CN(C[C@@H]1CC2)C1=NC(=NC=C1)NC=1C=NN(C=1)C)F BUWBRTXGQRBBHG-MJBXVCDLSA-N 0.000 claims 1
- VFTQZQGHFFDMQS-RSNHQYPWSA-N FC1([C@@H](C1)C(=O)N[C@@]12CN(C[C@H]2[C@H]1C)C1=NC(=NC=C1F)NC=1C=NN(C=1)C)F Chemical compound FC1([C@@H](C1)C(=O)N[C@@]12CN(C[C@H]2[C@H]1C)C1=NC(=NC=C1F)NC=1C=NN(C=1)C)F VFTQZQGHFFDMQS-RSNHQYPWSA-N 0.000 claims 1
- BUWBRTXGQRBBHG-HZSPNIEDSA-N FC1([C@H](C1)C(=O)N1[C@H]2CN(C[C@@H]1CC2)C1=NC(=NC=C1)NC=1C=NN(C=1)C)F Chemical compound FC1([C@H](C1)C(=O)N1[C@H]2CN(C[C@@H]1CC2)C1=NC(=NC=C1)NC=1C=NN(C=1)C)F BUWBRTXGQRBBHG-HZSPNIEDSA-N 0.000 claims 1
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims 1
- HRJDPMNBBKGHKT-UHFFFAOYSA-N n-ethyl-2-methylbenzamide Chemical compound CCNC(=O)C1=CC=CC=C1C HRJDPMNBBKGHKT-UHFFFAOYSA-N 0.000 claims 1
- DWJMBQYORXLGAE-UHFFFAOYSA-N pyridine-2-sulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=N1 DWJMBQYORXLGAE-UHFFFAOYSA-N 0.000 claims 1
- GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 6
- 229940122245 Janus kinase inhibitor Drugs 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 description 409
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 219
- 238000006243 chemical reaction Methods 0.000 description 213
- 238000000034 method Methods 0.000 description 184
- 239000000243 solution Substances 0.000 description 131
- 238000005160 1H NMR spectroscopy Methods 0.000 description 128
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 127
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 94
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 90
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 89
- 238000010898 silica gel chromatography Methods 0.000 description 82
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 79
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 79
- 239000012071 phase Substances 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 52
- 238000002953 preparative HPLC Methods 0.000 description 52
- 238000000746 purification Methods 0.000 description 45
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- 229910021529 ammonia Inorganic materials 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 28
- 239000003208 petroleum Substances 0.000 description 28
- 239000007787 solid Substances 0.000 description 28
- 239000002253 acid Substances 0.000 description 27
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 26
- BSEXNZMHLUMQKR-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1.NC(=O)C1CC1 BSEXNZMHLUMQKR-UHFFFAOYSA-N 0.000 description 25
- 239000012044 organic layer Substances 0.000 description 24
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 23
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 23
- 238000003821 enantio-separation Methods 0.000 description 23
- 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 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 22
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 101000844245 Homo sapiens Non-receptor tyrosine-protein kinase TYK2 Proteins 0.000 description 21
- 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- 230000008569 process Effects 0.000 description 20
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 235000011114 ammonium hydroxide Nutrition 0.000 description 18
- 238000010511 deprotection reaction Methods 0.000 description 18
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 18
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 16
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 16
- 238000000926 separation method Methods 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000007821 HATU Substances 0.000 description 15
- 108010024121 Janus Kinases Proteins 0.000 description 15
- 102000015617 Janus Kinases Human genes 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- 239000007858 starting material Substances 0.000 description 14
- 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 13
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 235000019253 formic acid Nutrition 0.000 description 13
- 238000003556 assay Methods 0.000 description 12
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 10
- 101150041968 CDC13 gene Proteins 0.000 description 9
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 9
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 9
- 230000001404 mediated effect Effects 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 9
- KMLMOVWSQPHQME-REOHCLBHSA-N (1s)-2,2-difluorocyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1CC1(F)F KMLMOVWSQPHQME-REOHCLBHSA-N 0.000 description 8
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 150000003857 carboxamides Chemical class 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 7
- 102000004127 Cytokines Human genes 0.000 description 7
- 108090000695 Cytokines Proteins 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- 239000000908 ammonium hydroxide Substances 0.000 description 7
- 150000008064 anhydrides Chemical class 0.000 description 7
- 150000001721 carbon Chemical group 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 125000004663 dialkyl amino group Chemical group 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 239000003643 water by type Substances 0.000 description 7
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 6
- 101100294115 Caenorhabditis elegans nhr-4 gene Proteins 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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EP2336117A1 (en) | 2005-05-26 | 2011-06-22 | Neuron Systems, Inc | Heterocyclic compounds for treating retinal diseases |
WO2011072141A1 (en) | 2009-12-11 | 2011-06-16 | Neuron Systems, Inc. | Compositions and methods for the treatment of macular degeneration |
HK1217439A1 (zh) | 2013-01-23 | 2017-01-13 | Aldeyra Therapeutics, Inc. | 與毒性醛相關的疾病和治療 |
JP6577958B2 (ja) | 2014-04-11 | 2019-09-18 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | スピロ[3H−インドール−3,2’−ピロリジン]−2(1H)−オン誘導体およびMDM2−p53阻害剤としてのそれらの使用 |
US10576064B2 (en) | 2014-07-03 | 2020-03-03 | Boehringer Ingelheim International Gmbh | Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one compounds and derivatives as MDM2-P53 inhibitors |
NO2721710T3 (en]) | 2014-08-21 | 2018-03-31 | ||
HUE046057T2 (hu) | 2014-08-21 | 2020-02-28 | Boehringer Ingelheim Int | Új spiro[3H-indol-3,2'-pirrolidin]-2(1H)-on vegyületek és származékok, mint MDM2-P53-inhibitorok |
EP4400106A1 (en) | 2015-08-21 | 2024-07-17 | Aldeyra Therapeutics, Inc. | Deuterated compounds and uses thereof |
EP3347097B1 (en) | 2015-09-11 | 2021-02-24 | Sunshine Lake Pharma Co., Ltd. | Substituted aminopyrimidine derivatives as modulators of the kinases jak, flt3 and aurora |
PE20181205A1 (es) | 2015-10-09 | 2018-07-23 | Boehringer Ingelheim Int | Nuevos compuestos de espiro[3h-indol-3,2'-pirrolidin]-2(1h)-ona y derivados como inhibidores de mdm2-p53 |
CA3020506A1 (en) * | 2016-04-28 | 2017-11-02 | Theravance Biopharma R&D Ip, Llc | Pyrimidine compounds as jak kinase inhibitors |
AU2017264697A1 (en) | 2016-05-09 | 2018-11-22 | Aldeyra Therapeutics, Inc. | Combination treatment of ocular inflammatory disorders and diseases |
US10111882B2 (en) | 2016-09-14 | 2018-10-30 | Gilead Sciences, Inc. | SYK inhibitors |
TW201822764A (zh) | 2016-09-14 | 2018-07-01 | 美商基利科學股份有限公司 | Syk抑制劑 |
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