AU2016333855A1 - Substituted pyrazolo[3,4-b]pyridin-6-carboxylic acids and their use - Google Patents

Info

Publication number

AU2016333855A1

AU2016333855A1 AU2016333855A AU2016333855A AU2016333855A1 AU 2016333855 A1 AU2016333855 A1 AU 2016333855A1 AU 2016333855 A AU2016333855 A AU 2016333855A AU 2016333855 A AU2016333855 A AU 2016333855A AU 2016333855 A1 AU2016333855 A1 AU 2016333855A1

Authority

AU

Australia

Prior art keywords

pyridine

carboxylic acid

phenyl

pyrazolo

cyclobutyl

Prior art date

2015-10-09

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• Discuss

• UHBHAVOFBLUPBB-UHFFFAOYSA-N 1h-pyrazolo[3,4-b]pyridine-6-carboxylic acid Chemical class N1C(C(=O)O)=CC=C2C=NN=C21 UHBHAVOFBLUPBB-UHFFFAOYSA-N 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 268
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 528
• -1 oxan-4-yl Chemical group 0.000 claims description 304
• 239000002253 acid Substances 0.000 claims description 273
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 236
• 125000005466 alkylenyl group Chemical group 0.000 claims description 232
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 174
• 238000000034 method Methods 0.000 claims description 150
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 141
• 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 141
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 110
• 150000003839 salts Chemical class 0.000 claims description 80
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 74
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 72
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 68
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 64
• 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 62
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 60
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 58
• 239000003814 drug Substances 0.000 claims description 48
• 229910052739 hydrogen Inorganic materials 0.000 claims description 47
• 239000001257 hydrogen Substances 0.000 claims description 47
• 201000003883 Cystic fibrosis Diseases 0.000 claims description 46
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 43
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 42
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 37
• 125000001424 substituent group Chemical group 0.000 claims description 37
• 229910052757 nitrogen Inorganic materials 0.000 claims description 35
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 34
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 32
• 125000001188 haloalkyl group Chemical group 0.000 claims description 32
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 30
• 239000008194 pharmaceutical composition Substances 0.000 claims description 29
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 28
• 229910052736 halogen Inorganic materials 0.000 claims description 28
• 150000002367 halogens Chemical group 0.000 claims description 28
• 125000000623 heterocyclic group Chemical group 0.000 claims description 27
• 238000011282 treatment Methods 0.000 claims description 26
• 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 25
• 125000002950 monocyclic group Chemical group 0.000 claims description 25
• 229940124597 therapeutic agent Drugs 0.000 claims description 25
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 22
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 22
• SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims description 22
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 22
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 21
• 229910052760 oxygen Inorganic materials 0.000 claims description 20
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 18
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 16
• 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 16
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 14
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 14
• 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 14
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 13
• 239000003937 drug carrier Substances 0.000 claims description 12
• 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 12
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 12
• 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 11
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 9
• BERPCVULMUPOER-UHFFFAOYSA-N Quinolinediol Chemical compound C1=CC=C2NC(=O)C(O)=CC2=C1 BERPCVULMUPOER-UHFFFAOYSA-N 0.000 claims description 9
• 125000004043 oxo group Chemical group O=* 0.000 claims description 9
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
• JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical group O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 8
• 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 8
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 7
• 229910052702 rhenium Inorganic materials 0.000 claims description 7
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 6
• 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 claims description 6
• 125000003118 aryl group Chemical group 0.000 claims description 4
• DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 4
• 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 4
• 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 3
• 101100063435 Caenorhabditis elegans din-1 gene Proteins 0.000 claims description 3
• 229910052703 rhodium Inorganic materials 0.000 claims description 3
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
• 101001110286 Homo sapiens Ras-related C3 botulinum toxin substrate 1 Proteins 0.000 claims description 2
• 102100022122 Ras-related C3 botulinum toxin substrate 1 Human genes 0.000 claims description 2
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
• 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
• 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
• 150000001735 carboxylic acids Chemical class 0.000 claims 12
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 186
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 156
• 239000011541 reaction mixture Substances 0.000 description 105
• 239000000203 mixture Substances 0.000 description 77
• 239000000243 solution Substances 0.000 description 67
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 60
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 55
• 239000007858 starting material Substances 0.000 description 55
• 229910001868 water Inorganic materials 0.000 description 55
• 108010079245 Cystic Fibrosis Transmembrane Conductance Regulator Proteins 0.000 description 52
• 235000019439 ethyl acetate Nutrition 0.000 description 52
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
• 230000015572 biosynthetic process Effects 0.000 description 51
• 238000003786 synthesis reaction Methods 0.000 description 50
• 239000012074 organic phase Substances 0.000 description 47
• 230000035772 mutation Effects 0.000 description 46
• 102100023419 Cystic fibrosis transmembrane conductance regulator Human genes 0.000 description 44
• 235000002639 sodium chloride Nutrition 0.000 description 43
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 40
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 40
• 230000002829 reductive effect Effects 0.000 description 34
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 33
• 238000003818 flash chromatography Methods 0.000 description 31
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
• 239000012071 phase Substances 0.000 description 29
• 125000003386 piperidinyl group Chemical group 0.000 description 29
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
• 150000002431 hydrogen Chemical class 0.000 description 26
• 239000000741 silica gel Substances 0.000 description 26
• 229910002027 silica gel Inorganic materials 0.000 description 26
• 125000002393 azetidinyl group Chemical group 0.000 description 25
• 239000012267 brine Substances 0.000 description 25
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 24
• 238000006243 chemical reaction Methods 0.000 description 24
• 239000007787 solid Substances 0.000 description 24
• 125000004076 pyridyl group Chemical group 0.000 description 23
• 125000000719 pyrrolidinyl group Chemical group 0.000 description 23
• 239000002904 solvent Substances 0.000 description 23
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
• 239000008346 aqueous phase Substances 0.000 description 22
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 22
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
• 239000007864 aqueous solution Substances 0.000 description 21
• 201000010099 disease Diseases 0.000 description 20
• 125000004193 piperazinyl group Chemical group 0.000 description 20
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 19
• 239000012047 saturated solution Substances 0.000 description 19
• DELJOESCKJGFML-RQOWECAXSA-N (z)-3-aminobut-2-enenitrile Chemical compound C\C(N)=C\C#N DELJOESCKJGFML-RQOWECAXSA-N 0.000 description 18
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
• 239000000460 chlorine Substances 0.000 description 18
• 235000017557 sodium bicarbonate Nutrition 0.000 description 18
• 125000001412 tetrahydropyranyl group Chemical group 0.000 description 18
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 17
• 235000019441 ethanol Nutrition 0.000 description 17
• 125000002757 morpholinyl group Chemical group 0.000 description 17
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 17
• NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 16
• 239000000543 intermediate Substances 0.000 description 16
• 238000000746 purification Methods 0.000 description 16
• 239000003643 water by type Substances 0.000 description 16
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 15
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 125000003566 oxetanyl group Chemical group 0.000 description 15
• 239000000725 suspension Substances 0.000 description 15
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
• 229920006395 saturated elastomer Polymers 0.000 description 14
• 229910052938 sodium sulfate Inorganic materials 0.000 description 14
• JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical class NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 13
• 208000021386 Sjogren Syndrome Diseases 0.000 description 13
• 239000003795 chemical substances by application Substances 0.000 description 13
• 208000035475 disorder Diseases 0.000 description 13
• 238000001914 filtration Methods 0.000 description 13
• 235000011152 sodium sulphate Nutrition 0.000 description 13
• 238000003756 stirring Methods 0.000 description 13
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
• 125000004429 atom Chemical group 0.000 description 12
• 125000004432 carbon atom Chemical group C* 0.000 description 12
• 229940079593 drug Drugs 0.000 description 12
• 230000000694 effects Effects 0.000 description 12
• 125000003373 pyrazinyl group Chemical group 0.000 description 12
• 125000000714 pyrimidinyl group Chemical group 0.000 description 12
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
• 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 11
• 239000003480 eluent Substances 0.000 description 11
• 239000002244 precipitate Substances 0.000 description 11
• DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 11
• 125000004568 thiomorpholinyl group Chemical group 0.000 description 11
• 125000005960 1,4-diazepanyl group Chemical group 0.000 description 10
• ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 10
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
• 208000035467 Pancreatic insufficiency Diseases 0.000 description 10
• 125000005842 heteroatom Chemical group 0.000 description 10
• 239000012299 nitrogen atmosphere Substances 0.000 description 10
• IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 10
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
• 238000002360 preparation method Methods 0.000 description 9
• 125000002098 pyridazinyl group Chemical group 0.000 description 9
• 229910052717 sulfur Inorganic materials 0.000 description 9
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-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
• NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 8
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 8
• 239000012458 free base Substances 0.000 description 8
• JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 description 8
• 108090000623 proteins and genes Proteins 0.000 description 8
• 125000003226 pyrazolyl group Chemical group 0.000 description 8
• 238000010992 reflux Methods 0.000 description 8
• 239000002002 slurry Substances 0.000 description 8
• ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 8
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
• 102000012605 Cystic Fibrosis Transmembrane Conductance Regulator Human genes 0.000 description 7
• YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 7
• 235000011054 acetic acid Nutrition 0.000 description 7
• 239000003153 chemical reaction reagent Substances 0.000 description 7
• 229910052801 chlorine Inorganic materials 0.000 description 7
• 125000001072 heteroaryl group Chemical group 0.000 description 7
• 125000002632 imidazolidinyl group Chemical group 0.000 description 7
• 239000002502 liposome Substances 0.000 description 7
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 7
• 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
• 229910000027 potassium carbonate Inorganic materials 0.000 description 7
• 239000000047 product Substances 0.000 description 7
• JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 6
• 125000005940 1,4-dioxanyl group Chemical group 0.000 description 6
• BAJYSJUMDLMTGH-UHFFFAOYSA-N 3-cyclobutyl-3-oxopropanenitrile Chemical compound N#CCC(=O)C1CCC1 BAJYSJUMDLMTGH-UHFFFAOYSA-N 0.000 description 6
• VKZGTORDNRVMIN-UHFFFAOYSA-N 4-methyl-3-oxopentanenitrile Chemical compound CC(C)C(=O)CC#N VKZGTORDNRVMIN-UHFFFAOYSA-N 0.000 description 6
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
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