CA2494785A1 - Dihydropyrazolopyridine compounds - Google Patents

Info

Publication number

CA2494785A1

CA2494785A1 CA002494785A CA2494785A CA2494785A1 CA 2494785 A1 CA2494785 A1 CA 2494785A1 CA 002494785 A CA002494785 A CA 002494785A CA 2494785 A CA2494785 A CA 2494785A CA 2494785 A1 CA2494785 A1 CA 2494785A1

Authority

CA

Canada

Prior art keywords

dihydro

cyano

pyridine

pyrazolo

substituent

Prior art date

2002-08-07

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
• CIPO
• Discuss

• KKIRMHFZGVTSNH-UHFFFAOYSA-N 2,3-dihydro-1h-pyrazolo[4,3-b]pyridine Chemical class C1=CN=C2CNNC2=C1 KKIRMHFZGVTSNH-UHFFFAOYSA-N 0.000 title abstract description 6
• 150000001875 compounds Chemical class 0.000 claims abstract description 199
• 150000003839 salts Chemical class 0.000 claims abstract description 31
• 239000003814 drug Substances 0.000 claims abstract description 27
• 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 claims abstract description 10
• 230000002265 prevention Effects 0.000 claims abstract description 10
• 208000002249 Diabetes Complications Diseases 0.000 claims abstract description 7
• 230000004770 neurodegeneration Effects 0.000 claims abstract description 6
• 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 6
• 206010012655 Diabetic complications Diseases 0.000 claims abstract description 5
• 230000000091 immunopotentiator Effects 0.000 claims abstract description 5
• 102000019058 Glycogen Synthase Kinase 3 beta Human genes 0.000 claims abstract 3
• -1 dihydropyrazolopyridine compound Chemical class 0.000 claims description 204
• 125000001424 substituent group Chemical group 0.000 claims description 102
• 125000000217 alkyl group Chemical group 0.000 claims description 86
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 51
• 125000004432 carbon atom Chemical group C* 0.000 claims description 49
• 229910052739 hydrogen Inorganic materials 0.000 claims description 36
• 239000001257 hydrogen Substances 0.000 claims description 36
• 125000003118 aryl group Chemical group 0.000 claims description 31
• 229920006395 saturated elastomer Polymers 0.000 claims description 30
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 27
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 26
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 25
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 21
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 17
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 17
• 125000003884 phenylalkyl group Chemical group 0.000 claims description 15
• 125000003545 alkoxy group Chemical group 0.000 claims description 14
• 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 14
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 12
• 125000005359 phenoxyalkyl group Chemical group 0.000 claims description 12
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 11
• 125000004691 alkyl thio carbonyl group Chemical group 0.000 claims description 11
• 125000001188 haloalkyl group Chemical group 0.000 claims description 11
• 125000005842 heteroatom Chemical group 0.000 claims description 11
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 11
• 239000003112 inhibitor Substances 0.000 claims description 11
• NBGKZCPBTGGFPI-UHFFFAOYSA-N 4-(2,1,3-benzoxadiazol-4-yl)-6-piperidin-4-yl-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound N1C2=NNC=C2C(C=2C3=NON=C3C=CC=2)C(C#N)=C1C1CCNCC1 NBGKZCPBTGGFPI-UHFFFAOYSA-N 0.000 claims description 10
• 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 10
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 10
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 10
• 125000005358 mercaptoalkyl group Chemical group 0.000 claims description 10
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
• 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 9
• 208000014644 Brain disease Diseases 0.000 claims description 8
• 208000032274 Encephalopathy Diseases 0.000 claims description 8
• 201000011240 Frontotemporal dementia Diseases 0.000 claims description 8
• 208000027089 Parkinsonian disease Diseases 0.000 claims description 8
• 206010034010 Parkinsonism Diseases 0.000 claims description 8
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
• 208000024827 Alzheimer disease Diseases 0.000 claims description 7
• 201000006474 Brain Ischemia Diseases 0.000 claims description 7
• 125000002252 acyl group Chemical group 0.000 claims description 7
• 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 7
• 125000004414 alkyl thio group Chemical group 0.000 claims description 7
• 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 7
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 7
• 208000028683 bipolar I disease Diseases 0.000 claims description 7
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 7
• 201000010099 disease Diseases 0.000 claims description 7
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
• 229910052757 nitrogen Inorganic materials 0.000 claims description 7
• 125000002071 phenylalkoxy group Chemical group 0.000 claims description 7
• HXFSAZJCIDQZLR-UHFFFAOYSA-N 4-(2-bromo-3-cyanophenyl)-6-piperidin-4-yl-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound BrC1=C(C#N)C=CC=C1C1C(C#N)=C(C2CCNCC2)NC2=NNC=C21 HXFSAZJCIDQZLR-UHFFFAOYSA-N 0.000 claims description 6
• 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 6
• 208000030507 AIDS Diseases 0.000 claims description 6
• 125000005354 acylalkyl group Chemical group 0.000 claims description 6
• 125000002431 aminoalkoxy group Chemical group 0.000 claims description 6
• 125000004858 cycloalkoxyalkyl group Chemical group 0.000 claims description 6
• 229910052736 halogen Inorganic materials 0.000 claims description 6
• 150000002367 halogens Chemical group 0.000 claims description 6
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
• OIWVMOSMPAKHMP-UHFFFAOYSA-N 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-n-phenyl-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-6-carboxamide Chemical compound N#CC=1C(C=2C3=NON=C3C=CC=2)C2=CNN=C2NC=1C(=O)NC1=CC=CC=C1 OIWVMOSMPAKHMP-UHFFFAOYSA-N 0.000 claims description 5
• GOCRKPYVYLNIDP-UHFFFAOYSA-N 6-acetyl-4-(2,1,3-benzoxadiazol-4-yl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C1=CC2=NON=C2C(C2C(C#N)=C(NC3=NNC=C32)C(=O)C)=C1 GOCRKPYVYLNIDP-UHFFFAOYSA-N 0.000 claims description 5
• 125000004442 acylamino group Chemical group 0.000 claims description 5
• 125000002837 carbocyclic group Chemical group 0.000 claims description 5
• 125000001624 naphthyl group Chemical group 0.000 claims description 5
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
• GDSXKHNGRWMYAF-UHFFFAOYSA-N 4-(2,1,3-benzoxadiazol-4-yl)-6-(1-methylpiperidin-4-yl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C1CN(C)CCC1C1=C(C#N)C(C=2C3=NON=C3C=CC=2)C2=CNN=C2N1 GDSXKHNGRWMYAF-UHFFFAOYSA-N 0.000 claims description 4
• LRIXCJBERGXNKA-UHFFFAOYSA-N 4-(2-bromo-3-cyanophenyl)-6-(1-methylpiperidin-3-yl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C1N(C)CCCC1C1=C(C#N)C(C=2C(=C(C#N)C=CC=2)Br)C2=CNN=C2N1 LRIXCJBERGXNKA-UHFFFAOYSA-N 0.000 claims description 4
• DWBDWBNMTKLNBG-UHFFFAOYSA-N 4-(2-bromo-3-cyanophenyl)-6-(2-oxocyclohexyl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound BrC1=C(C#N)C=CC=C1C1C(C#N)=C(C2C(CCCC2)=O)NC2=NNC=C21 DWBDWBNMTKLNBG-UHFFFAOYSA-N 0.000 claims description 4
• BIVGGEVWZOXYMF-UHFFFAOYSA-N 4-(2-bromo-3-cyanophenyl)-6-(2-oxopropyl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C12=CNN=C2NC(CC(=O)C)=C(C#N)C1C1=CC=CC(C#N)=C1Br BIVGGEVWZOXYMF-UHFFFAOYSA-N 0.000 claims description 4
• 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 4
• 201000004384 Alopecia Diseases 0.000 claims description 4
• 208000020925 Bipolar disease Diseases 0.000 claims description 4
• 206010006187 Breast cancer Diseases 0.000 claims description 4
• 208000026310 Breast neoplasm Diseases 0.000 claims description 4
• 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 4
• 206010008120 Cerebral ischaemia Diseases 0.000 claims description 4
• 208000011990 Corticobasal Degeneration Diseases 0.000 claims description 4
• 206010012289 Dementia Diseases 0.000 claims description 4
• 201000010374 Down Syndrome Diseases 0.000 claims description 4
• 208000023105 Huntington disease Diseases 0.000 claims description 4
• 208000009829 Lewy Body Disease Diseases 0.000 claims description 4
• 201000002832 Lewy body dementia Diseases 0.000 claims description 4
• 206010028980 Neoplasm Diseases 0.000 claims description 4
• 206010033799 Paralysis Diseases 0.000 claims description 4
• 208000000609 Pick Disease of the Brain Diseases 0.000 claims description 4
• 208000036757 Postencephalitic parkinsonism Diseases 0.000 claims description 4
• 208000024770 Thyroid neoplasm Diseases 0.000 claims description 4
• 206010044688 Trisomy 21 Diseases 0.000 claims description 4
• 241000700605 Viruses Species 0.000 claims description 4
• 231100000360 alopecia Toxicity 0.000 claims description 4
• 206010008118 cerebral infarction Diseases 0.000 claims description 4
• 208000026106 cerebrovascular disease Diseases 0.000 claims description 4
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
• 230000000302 ischemic effect Effects 0.000 claims description 4
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
• 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 4
• 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• 208000000170 postencephalitic Parkinson disease Diseases 0.000 claims description 4
• 230000000750 progressive effect Effects 0.000 claims description 4
• 201000002510 thyroid cancer Diseases 0.000 claims description 4
• KEQANGSUORISPQ-UHFFFAOYSA-N 4-(1,3-benzodioxol-4-yl)-6-piperidin-4-yl-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound N1C2=NNC=C2C(C=2C=3OCOC=3C=CC=2)C(C#N)=C1C1CCNCC1 KEQANGSUORISPQ-UHFFFAOYSA-N 0.000 claims description 3
• RLPVDFAYJBBJKY-UHFFFAOYSA-N 4-(2-bromo-3-cyanophenyl)-6-(1-methylpiperidin-4-yl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C1CN(C)CCC1C1=C(C#N)C(C=2C(=C(C#N)C=CC=2)Br)C2=CNN=C2N1 RLPVDFAYJBBJKY-UHFFFAOYSA-N 0.000 claims description 3
• URQMLONFZJSQED-UHFFFAOYSA-N 4-(2-chlorophenyl)-6-[(4-phenylpiperazin-1-yl)methyl]-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound ClC1=CC=CC=C1C1C(C#N)=C(CN2CCN(CC2)C=2C=CC=CC=2)NC2=NNC=C21 URQMLONFZJSQED-UHFFFAOYSA-N 0.000 claims description 3
• IRJPSRPQQMWQML-UHFFFAOYSA-N 6-(1-acetyl-3,6-dihydro-2h-pyridin-4-yl)-4-(2,1,3-benzoxadiazol-4-yl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C1N(C(=O)C)CCC(C=2NC3=NNC=C3C(C=2C#N)C=2C3=NON=C3C=CC=2)=C1 IRJPSRPQQMWQML-UHFFFAOYSA-N 0.000 claims description 3
• QMLJQRGHDLRXPS-UHFFFAOYSA-N 6-(1-acetylpiperidin-4-yl)-4-(2-bromo-3-cyanophenyl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C1CN(C(=O)C)CCC1C1=C(C#N)C(C=2C(=C(C#N)C=CC=2)Br)C2=CNN=C2N1 QMLJQRGHDLRXPS-UHFFFAOYSA-N 0.000 claims description 3
• 239000000654 additive Substances 0.000 claims description 3
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
• 239000008194 pharmaceutical composition Substances 0.000 claims description 3
• DQZLWBBXXDZUSQ-UHFFFAOYSA-N 2-bromo-3-(6-propyl-5-pyridin-2-yl-2,4-dihydro-1h-pyrazolo[3,4-b]pyridin-4-yl)benzonitrile Chemical compound C12=CNN=C2NC(CCC)=C(C=2N=CC=CC=2)C1C1=CC=CC(C#N)=C1Br DQZLWBBXXDZUSQ-UHFFFAOYSA-N 0.000 claims description 2
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
• JVOWRAOGIMSUBQ-UHFFFAOYSA-N 4-(2,1,3-benzoxadiazol-4-yl)-6-(1-ethylpiperidin-4-yl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C1CN(CC)CCC1C1=C(C#N)C(C=2C3=NON=C3C=CC=2)C2=CNN=C2N1 JVOWRAOGIMSUBQ-UHFFFAOYSA-N 0.000 claims description 2
• MWLNQUGFUQBKPR-UHFFFAOYSA-N 4-(2,1,3-benzoxadiazol-4-yl)-6-(1-methyl-3,6-dihydro-2h-pyridin-4-yl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C1N(C)CCC(C=2NC3=NNC=C3C(C=2C#N)C=2C3=NON=C3C=CC=2)=C1 MWLNQUGFUQBKPR-UHFFFAOYSA-N 0.000 claims description 2
• NSXZLQYRFCCRCO-UHFFFAOYSA-N 4-(2,1,3-benzoxadiazol-4-yl)-6-(4-methylmorpholin-2-yl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C1N(C)CCOC1C1=C(C#N)C(C=2C3=NON=C3C=CC=2)C2=CNN=C2N1 NSXZLQYRFCCRCO-UHFFFAOYSA-N 0.000 claims description 2
• VZTOZJJBZPADJJ-UHFFFAOYSA-N 4-(2,1,3-benzoxadiazol-4-yl)-6-(4-oxocyclohexyl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C1CC(=O)CCC1C1=C(C#N)C(C=2C3=NON=C3C=CC=2)C2=CNN=C2N1 VZTOZJJBZPADJJ-UHFFFAOYSA-N 0.000 claims description 2
• DTLHIRTZKHRJMP-UHFFFAOYSA-N 4-(2,1,3-benzoxadiazol-4-yl)-6-[4-(dimethylamino)cyclohexyl]-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C1CC(N(C)C)CCC1C1=C(C#N)C(C=2C3=NON=C3C=CC=2)C2=CNN=C2N1 DTLHIRTZKHRJMP-UHFFFAOYSA-N 0.000 claims description 2
• DLBCTRATUZGIOC-UHFFFAOYSA-N 4-(2-bromo-3-cyanophenyl)-6-(4-methylmorpholin-2-yl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C1N(C)CCOC1C1=C(C#N)C(C=2C(=C(C#N)C=CC=2)Br)C2=CNN=C2N1 DLBCTRATUZGIOC-UHFFFAOYSA-N 0.000 claims description 2
• OTXLXZKYZUEGLA-UHFFFAOYSA-N 4-(2-chlorophenyl)-6-pyrrolidin-3-yl-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound ClC1=CC=CC=C1C1C(C#N)=C(C2CNCC2)NC2=NNC=C21 OTXLXZKYZUEGLA-UHFFFAOYSA-N 0.000 claims description 2
• SBNUUJZCQKEMGK-UHFFFAOYSA-N 4-(6-propyl-5-pyridin-2-yl-2,4-dihydro-1h-pyrazolo[3,4-b]pyridin-4-yl)-2,1,3-benzoxadiazole Chemical compound C=1C=CC2=NON=C2C=1C1C2=CNN=C2NC(CCC)=C1C1=CC=CC=N1 SBNUUJZCQKEMGK-UHFFFAOYSA-N 0.000 claims description 2
• PPLIKHQVVOZMJJ-UHFFFAOYSA-N 6-(1-benzoylpiperidin-4-yl)-4-(2-bromo-3-cyanophenyl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound BrC1=C(C#N)C=CC=C1C1C(C#N)=C(C2CCN(CC2)C(=O)C=2C=CC=CC=2)NC2=NNC=C21 PPLIKHQVVOZMJJ-UHFFFAOYSA-N 0.000 claims description 2
• 210000001744 T-lymphocyte Anatomy 0.000 claims description 2
• 230000000996 additive effect Effects 0.000 claims description 2
• 210000003719 b-lymphocyte Anatomy 0.000 claims description 2
• 208000013403 hyperactivity Diseases 0.000 claims description 2
• XAAYSCADZGTCGZ-UHFFFAOYSA-N 4-(2-bromo-3-cyanophenyl)-6-(1-methyl-3,6-dihydro-2h-pyridin-4-yl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C1N(C)CCC(C=2NC3=NNC=C3C(C=2C#N)C=2C(=C(C#N)C=CC=2)Br)=C1 XAAYSCADZGTCGZ-UHFFFAOYSA-N 0.000 claims 1
• OWRKCXPVEMDSRS-UHFFFAOYSA-N 4-(2-bromo-3-cyanophenyl)-6-(1-methylsulfonylpiperidin-4-yl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C1CN(S(=O)(=O)C)CCC1C1=C(C#N)C(C=2C(=C(C#N)C=CC=2)Br)C2=CNN=C2N1 OWRKCXPVEMDSRS-UHFFFAOYSA-N 0.000 claims 1
• 125000001054 5 membered carbocyclic group Chemical group 0.000 claims 1
• 125000004008 6 membered carbocyclic group Chemical group 0.000 claims 1
• ZRWHDAOTUIJZLQ-UHFFFAOYSA-N 6-acetyl-4-(2-bromo-3-cyanophenyl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridine-5-carbonitrile Chemical compound C12=CNN=C2NC(C(=O)C)=C(C#N)C1C1=CC=CC(C#N)=C1Br ZRWHDAOTUIJZLQ-UHFFFAOYSA-N 0.000 claims 1
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical group FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims 1
• 125000003396 thiol group Chemical group [H]S* 0.000 claims 1
• 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 abstract description 39
• 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 abstract description 39
• 230000002401 inhibitory effect Effects 0.000 abstract description 12
• 206010012601 diabetes mellitus Diseases 0.000 abstract description 3
• 150000004677 hydrates Chemical class 0.000 abstract description 2
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 254
• 238000005160 1H NMR spectroscopy Methods 0.000 description 146
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 97
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
• JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical compound NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 81
• 239000000203 mixture Substances 0.000 description 80
• 239000000243 solution Substances 0.000 description 69
• 239000013078 crystal Substances 0.000 description 67
• 239000002904 solvent Substances 0.000 description 61
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 43
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 43
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
• 238000006467 substitution reaction Methods 0.000 description 33
• YBBRQAXNTWMMFZ-UHFFFAOYSA-N 2,1,3-benzoxadiazole-4-carbaldehyde Chemical compound O=CC1=CC=CC2=NON=C12 YBBRQAXNTWMMFZ-UHFFFAOYSA-N 0.000 description 32
• 239000011541 reaction mixture Substances 0.000 description 32
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
• 239000003921 oil Substances 0.000 description 27
• 235000019198 oils Nutrition 0.000 description 27
• 239000003480 eluent Substances 0.000 description 26
• 238000010898 silica gel chromatography Methods 0.000 description 24
• 229910052799 carbon Inorganic materials 0.000 description 22
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
• PHZMJSCJHNIUSL-UHFFFAOYSA-N 2-bromo-3-formylbenzonitrile Chemical compound BrC1=C(C=O)C=CC=C1C#N PHZMJSCJHNIUSL-UHFFFAOYSA-N 0.000 description 20
• 238000006243 chemical reaction Methods 0.000 description 20
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 20
• 238000001816 cooling Methods 0.000 description 19
• XIWBSOUNZWSFKU-UHFFFAOYSA-N ethyl piperidine-3-carboxylate Chemical compound CCOC(=O)C1CCCNC1 XIWBSOUNZWSFKU-UHFFFAOYSA-N 0.000 description 19
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 19
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• 230000000694 effects Effects 0.000 description 18
• RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 description 17
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• PCLWTBWRXMOPOV-UHFFFAOYSA-N tert-butyl 3-(2-cyanoacetyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C(=O)CC#N)C1 PCLWTBWRXMOPOV-UHFFFAOYSA-N 0.000 description 1
• LUQLCBZXGUPTDT-UHFFFAOYSA-N tert-butyl 3-[4-(2-bromo-3-cyanophenyl)-5-cyano-2,4-dihydro-1h-pyrazolo[3,4-b]pyridin-6-yl]piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1C1=C(C#N)C(C=2C(=C(C#N)C=CC=2)Br)C2=CNN=C2N1 LUQLCBZXGUPTDT-UHFFFAOYSA-N 0.000 description 1
• FPLBNXCTFMWLFB-UHFFFAOYSA-N tert-butyl 4-[4-(1,3-benzodioxol-4-yl)-5-cyano-2,4-dihydro-1h-pyrazolo[3,4-b]pyridin-6-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=C(C#N)C(C=2C=3OCOC=3C=CC=2)C2=CNN=C2N1 FPLBNXCTFMWLFB-UHFFFAOYSA-N 0.000 description 1
• COACAIFIQRQXQD-UHFFFAOYSA-N tert-butyl 4-[4-[2-chloro-3-(trifluoromethyl)phenyl]-5-cyano-2,4-dihydro-1h-pyrazolo[3,4-b]pyridin-6-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=C(C#N)C(C=2C(=C(C=CC=2)C(F)(F)F)Cl)C2=CNN=C2N1 COACAIFIQRQXQD-UHFFFAOYSA-N 0.000 description 1
• SGRVJAOBSBISMB-UHFFFAOYSA-N tert-butyl 4-[5-cyano-4-(2,3-dihydro-1h-inden-4-yl)-2,4-dihydro-1h-pyrazolo[3,4-b]pyridin-6-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=C(C#N)C(C=2C=3CCCC=3C=CC=2)C2=CNN=C2N1 SGRVJAOBSBISMB-UHFFFAOYSA-N 0.000 description 1
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• WYKJTFXWQROWFT-UHFFFAOYSA-N tert-butyl n-[2-[4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-2,4-dihydro-1h-pyrazolo[3,4-b]pyridin-6-yl]ethyl]carbamate Chemical compound C1=CC2=NON=C2C(C2C(C#N)=C(NC3=NNC=C32)CCNC(=O)OC(C)(C)C)=C1 WYKJTFXWQROWFT-UHFFFAOYSA-N 0.000 description 1
• SRLXOMBJNAEGJP-UHFFFAOYSA-N tert-butyl n-[[4-(2-bromo-3-cyanophenyl)-5-cyano-2,4-dihydro-1h-pyrazolo[3,4-b]pyridin-6-yl]methyl]-n-methylcarbamate Chemical compound C12=CNN=C2NC(CN(C)C(=O)OC(C)(C)C)=C(C#N)C1C1=CC=CC(C#N)=C1Br SRLXOMBJNAEGJP-UHFFFAOYSA-N 0.000 description 1
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• 125000005934 tert-pentyloxycarbonyl group Chemical group 0.000 description 1
• 125000000335 thiazolyl group Chemical group 0.000 description 1
• 125000001544 thienyl group Chemical group 0.000 description 1
• 210000001519 tissue Anatomy 0.000 description 1
• 231100000419 toxicity Toxicity 0.000 description 1
• 230000001988 toxicity Effects 0.000 description 1
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
• 229940005605 valeric acid Drugs 0.000 description 1
• 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
• 229960000604 valproic acid Drugs 0.000 description 1
• 239000008215 water for injection Substances 0.000 description 1
• 238000001262 western blot Methods 0.000 description 1